HTMZGLE DEMVATNES: SUBSTETUTED TETWOLOPYREMIDENES Thai: For fha Dayna of 9h. 0. MEWS.“ STATE UNEVERSSTY Harald Powafl 1961 J'fHEgs' Y“ F V ,9— (I L I B R A R Y ‘ Michigan Sutc University ’ l Mii..,3'f L/«E! .iv i“. 1'4 " ' I . i ,‘ 4.2" ’Ii '..-\/f-.'\; \ I . LQN‘Q‘NLL. {MEC’W'LAN TETRAZOLE DERIVATIVES: SUBSTITUTED TETRAZOLOPYRIMLDINES By Harold Powell A THESIS Submitted to the School for Advanced Graduate Studies of Michigan State University of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1961 1/" 5 .5 f. ‘ x : I I LL " r. 1r- ;. J ‘ l ACKNOWLEDGMENT The writer wishes to express appreciation to Doctor Robert M. Herbst for his advice, guidance and encouragement. Acknowledgment is also made to Michigan State University for their financial aid in the form of Graduate Teaching Assistantships and to Parke, Davis and Company for their fellowship during the academic years of l959-l960 and l960-l96l. ii To my Parents iii TETRAZOLE DERIVATIVES: SUBSTITUTED TETRAZOLOPYRIMIDINES By Harold Powell MJMENMU‘ Submitted to the School for Advanced Graduate Studies of Michigan State University of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry Year l961 Approved /<)CL/VJ’///}/, / $41 [/zf ABSTRACT TETRAZOLE DERIVATIVES: SUBSTITUTED TETRAZOLOPYRIMIDINES by Harold Powell The structural resemblance between tetrazolopyrimidines (Structure I) and purines (Structure II) prompted the preparation of three series R/Nfi-MIY R SEE ”Nil/N N R R | N/ R (I) (II) of tetrazolopyrimidines: 7-substituted-S-methyltetrazolopyrimidine (Structure III), 9—substituted—S,6,7,8-tetrahydrotetrazolo[5,l—biquin- azoline (Structure IV) and 8-substituted-6,7—dihydro—SH-cyclopenta[d]— tetrazolo[l,S-a]pyzimidine (Structure V). ,N. \ N\N¢ E (III) (IV) (V) The investigation was concerned with: (1) increasing the yield of hydroxytetrazolopyrimidines using the procedure of Bulow (l) modi- fied by Brady and Herbst (2); (ii) the synthesis of chlorotetrazolo— pyrimidines from hydroxytetrazolOpyrimidines5 (iii) the alkylation of ammonia, amines, mercaptides and sodium methoxide with the chloro- tetrazolopyrimidines. (It was found that when a substituted ammonium salt of S-aminotetrazole, 2 Harold Powell such as the piperidinium salt, was condensed with fimketo esters there was a marked increase in the yield of hydroxytetrazolopyrimidines (Structures III, IV, and V; R = -OH). Chlorotetrazolopyrimidines (Structures III, IV and V; R = —Cl) were obtained in high yield by treating the hydroxytetrazolopyrimidines with an excess of phosphoryl chloride. Substituted tetrazolopyrimidines were prepared by displacement reactions with the chlorotetrazolopyrimidines (Structures III, IV and V; R is methoxy, mercapto, benzylthio, allylthio, amino and a variety of secondary and tertiary amino groups). Most of the compounds prepared were submitted to Parke, Davis and Company for screening as cancer antimetabolites and central nervous system stimulants. LITERATURE CITED 1. Bfiiow, c., Ber., kg, ut29(i909). 2. Brady, L. and R. M. Herbst, J- Org. Chem., gt, 922 (1959). TABLE OF CONTENTS Page INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . 1 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . A Emmmmnum... ... ... ... ... ... ... ... ... 15 7-Hydroxy-S-methyltet:azolopyrimidine . . . . . . . . . . . lS 7-Chloro-S-methyltetrazolopyrimidine . . . . . . . . . . . l6 7-Methoxy-S-methyltet1azolopyrimidine . . . . . . . . . . . l6 7-Amino-S—methyltetrazolopyrimidine . . . . . . . . . . . . 17 7-Hydrazino-S-methyltetrazolopytimidine . . . . . . . . . . l7 7- Benm alhydrazino- -S— —methyltetrazolOpyrimidine . . . . . . . l8 7-Diethylamino-S-methyltetrazolopyrimidine . . . . . . . . l8 7-(Bis-2-hydroxyethyiamino)—5-methyltetrazolOpyrimidine . . l9 7-Di-i§g-propylamino—S—methyltetrazolopyrimidine . . . . . l9 7-Di-n—propylamino-S-methyltetrazolopyrimidine . . . . . . 2O 7—Diallylamino-S-methyltetrazolopyrimidine . . . . . . . . 2O 7—(2-Methoxyethylamino)-S-methyltetrazolopyrimidine . . . . 2l 7-(j-Methoxypropylamino)-S-methyltetrazolopyrimidine . . . 2l 7-(j-iso-Propoxyjn—propylamino)-S-methyltetrazolopyrimidine 22 7-PyrrOlidyl-S-methyltetrazolopyrimidine . . . . . . . . . 22 7-Piperidyl-S-methyltetrazolopyrimidine . . . . . . . . . . 2} 7-Morpholinyl—S-methyltetrazolopyrimidine . . . . . . . . . 23 Reaction of Zinc Dust with 7 Chloro- 5— methyl- tetrazolopyrimidine . . . . . . . . . . . . . . 2h Reaction of Thionyl Chlo ide witL 7- (Bis 2- -hydroxy- ethyl amino)- S-methyltetz azo;>;y: imidine . . . . . . . 2h 9—Hydro-S,6,7,8-tetrahydzotetrazolo[5,l-biquinazoline 9-Chloro-S,6,7,8—tetzahydrotetrazolo[5,l—quuinazoline . . 27 iv TABLE OF CONTENTS - continued Page 9-(2'-Diethylaminoethyiamino)-S,6,7,8-tetrahydrotetrazolo- [5,1-b1quinazoline . . . . . . . . . . . . . . . . . . . 27 9-(2'-Methoxyethylamino)-S,6,7,8-tetrahydrotetrazolo- [5,l—blquinazoline . . . . . . . . . . . . . . . . . . . 28 9— '-iso- -Propoxypropylamino)— S, 6 7, 8- -tet1ahydiotetra7olo— [3:I-biquinazoline . . . . . . . . . . . . 28 9- (3'~Methoxyp10pylamino)- 5,6, 7, 8-tet1ahydrotetrazolo- [5, l- biquinazoline . . . . . . . . . . . . . . . 29 9-Piperidyl-S,6,7,8-tetrahydrotetrazolo[5,l-blquinazoline . . 29 9-Morphinyl-S,6,7,8-tetrahydrotetrazolo[5,l-blquinazoline . . 30 9-Pyrrolidyl-S,6,7,8-tetrahydrotetrazolo[5,l-blquinazoline . 30 9-Amino-S,6,7,8-tetrahydrotetrazolo[5,l—biquinazoline . . . . 3l 9-Dimethylamino-S, 6,7, 8- tetrahydrotetrazolo[5, 1-bi- quinazoline . . . . . . . . . . . . . . . . . jl 9- Diethylamino- S, 6 ,7 8- tetrahydrotetrazolo[5, l- b]- quinazoline . . . . . . . . . . . . . 52 9- Ih+:p10pylamino-S, 6,7, 8-tetrahydrotet1azolo[5 l-bl- _quinazoline . . . . . . . . . . . . . . . . . . )2 9— Diallylamino— -S, 6, 7, 8- tetrahydrotetrazolo[5, l- bl- quinazoline . . . . . . . . . . . . . . . 35 9-Methoxy-S,6,7,8-tetrahydrotetrazolo[5,l-blquinazoline . . . 33 8-Mercapto-S,6,7,8-tetrahydrotetrazolo[5,l—blquinazoline . . 3b 9-Allylthio-5,6,7,8-tetrahydrotetrazolo[5,l-blquinazoline . . 3b 9-Benzylthio-S,6,7,8-tet1ahydrotetrazolo[S,l-b]quinazoline. . 35 9- (Bis-hydroxyethylamino)-S, 6,7, 8-—tetrahydrotetrazolo— [5,1- blquinazoline . . . . . . . . . . . . . . . 36 9-(fl—Dimethylaminopropylamino)—5,6,7,8-tetrahydrotetrazolo- [5 l-b] inazoline . . . . . . . . . . . . . . . . . . . 36 2 qu 9-(3'-Diethylaminopropylamino)-S,6,7,8-tetrahydro- tetrazolo[5,l-blquinazoline . . . . . . . . . . . . . . 37 TABLE OF CONTENTS - Continued Page 9- (<'-Bi s-2- -hydroxyethy ami nopzopylamino)-S, 6,7, 8- tet1ahydrotet1azolo[5, l -bT quinazoline . . . . . . . . 37 9—(3'-Bis—2-chloroethylaminoprOpylamino)-5,6,7 8 tetzahydrotetrazolo[5,l-quuinazoline with sodium allylmercaptide . . . . . . . . . . . . . . . . . . . 38 Attempted reaction of 9—chloro-S,6,7,8—tetrahydro— tetrazolo[5,l-quuinazoline with sodium allylmercaptide 39 Attempted reaction of 9-chloro-S,6,7,8-tetrahydro- tetrazoloTS,l-quuinazoline with di-iso-propylamine. . 39 8- -Hydroxy- -6 ,7 -dihydro— —SH- cyclopenta[thetrazolo[l, S— aT- pyrimidine . . . . . . DO 8-Chloro-6 ,7-dihyd1o-SH-cyclopenta[thetrazolo[l,S-aT- pyrimidine . . . . . . . . . . . . . . . . Al 8- -Methoxy- -6 ,7 dihydro-SH— cyclopenta[thetrazolo[l,S-aT- pyrimidine . . . . . . . . . . . . . . . . b2 8 -Amino— 6 ,7- -dihyd10- SH- cyclopenta[thetrazolo[l,S—aT- pyrimidine . . . . . . . . . . . . . . . . . b2 8— Dimethylamino-—6 ,7-—dihyd1o-—SH—cyclopenta[dTtetrazolo- [l, S— anyrimidine . . . . . . . . . . . . . . . . . h) 8- Diethylamino- -6 ,7 -dihydro- SH- cyclopenta[thetrazolo- [l, 5- anyrimidine . . . . . . . . . . . . . h} 8- Diallylamino-—6,7-—dihyd1o—SH—cyclOpenta[thetrazolo- [l, S— anyrimidine . . . . . . . . . . . . . . . . . hh 8— Di-n-propylamino- -6 ,7 -dihydro- ~5H— cyclopenta[dT- tetrazolo[l, S— anyrimidine . . . . . . . . . . . . . uh 8- (Bis- 2'- hydroxyethylamino) -6 ,7 —dihydro- -SH- cyclopenta[dT- tetrazolo[l, S— aT pyrimidine . . . . . . . . . . . AS 8- (3- Diethylaminopropylamino) -6 ,7- -dihydro- SH- cyclopenta- [thetrazolo[l, S— aT pyrimidine . . . . . . . NS 8-(j'-Bis—2-hydrox ethylaminopropylamino)-6 7-dihydro- 'y : SH-cyclopenta[thetrazolo[l,S-aprrimidine . . . . . . A6 8- (i’ —Bis— 2— chloroethylaminopropylamino) -6 ,7- dihydro- SH— cyclopenta[dTtetrazolo[l, S— anyrimidine- dihydrochlozide . . . . . . . . . . . . . . . . . N6 vi TABLE OF CONTENTS - continued. Page 8- (3- iso— Propoxy- -n—propylamino) -6 ,7 -dihydro- ~SW cyclopenta- Td TtetrazoloTl, W —a prrimidine. . . . . . b7 8- (2 —Hethoxyethylamino) -6 ,7 dihydro—SH- cyclOpentaTdT- tetrazolo[l, W anyrimidine . . . . . . . . . A8 8- (3 -Methoxypropylamino) -6 ,7 —dihydro- -SH- cyclOpenta[dT- tettazolo[l, W anyrimidine . . . . . . . . . . . D8 8- -Piperidyl— 6 W ~dihydro— 6H- cyclopenta[d]tetrazolo- [l, W aT pyrimidine . . . . . . . . . . . . . 89 8- -Pyrrolidyl- -6 ,7 dihydro-SH- cyclopenta[thetrazolo[l,S-aT- pyrimidine . . . . . . . . . . . . . . . N9 8— —Morpholinyl— —6 7- dihydro- -SH— cyclOpenta[thetrazolo- [l, W anyrimidine . . . . . . . . . . . . . . . SO 8- -Mercapto —6 ,7- -dihydro- -SH- cyclopenta[d]tetrazolo[l,S-a]- pyrimidine . . . . . . . . . . . . . . . . SO 8- -Benzylthio- -6 ,7— —dihydro- SH- cyclopenta[d]tetrazolo- [l, W a] pyrimidine . . . . . . . . . . . . . . Sl 8—Allylthio- 6 7- dihydro— SH-cyclopenta[thetrazolo[l,5-a]- pyrimidine . . . . . .. . . . . . . . . . . . . . S2 h-Hydroxy-2-methylthio—S,6—trimethylenepyrimidine . . . . . 52 h—Hydroxy-2—hydrazino-5,6-trimethylenepyrimidine .... . . . 53 Diazotization of 2- -Hydrazinopyrimidine. 8— —Hydroxy- -6 ,7- -dihydro— 6H— cyclopenta[thetrazolo~ [l, W aT pyrimidine . . . . . . . . . . . . . . . . 53 SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 LITERATURE CITED . . . . . . . . . . . . . . . . . . . . . . . . 56 vii TABLE II III TABLE OF TABLES 7-Substituted-S-methyltetrazolopyiimidines . 9-3ubstituted-5,6,7,B—tetrahydrotetrazo1o[s,1—b1— quinazolines . . . . . . . . . . . . . 8- Substituted- 6 7- -dihydr 0- SH— cyclopenta[d]- tetrazolo[1,5-alpyrimidines . . viii 1L INTRODUCTION The "lock and key" concept of antimetabolite action has led to the discovery of numerous compounds which inhibit the growth of many kinds of bacteria. Purines (Structure I) are important growth factors in biogenetic processes and are associated with biological activity. The pharmaco- R- /N H _ UN N\' N/ R' H logical properties of the purines vary. Adenine (Structure II), which dilates the coronary arteries, has a powerful effect on blood pressure (l). Guanine (Structure III) like adenine causes constriction of the N /N\\ H N_/ ~_ N 1 u i“, 2 U N1, 31112 1’1 0 1'1 (II) (III) pulmonary bronchioles (l). 6-Mercaptopurine (2) (Structure IV) and S-bis-(2-chloroethyl)-aminouracil (3) (Structure V) causes the re- f 1 | I H ,. SH H (IV) (V) gression of certain tumors. 2 The replacement of one atom in the ring by another usually leads to the formation of an antagonist which inhibits the growth of micro- organisms. An example of such an analogue is 2-aza-adenine (Structure VI) where one of the carbon atoms of adenine is replaced by a nitrogen (b). 11/“ N 1 N\/ ‘ hill 2 H (VI) This antimetabolite is known to inhibit the growth of Streptococcus faecalis, L. casei and L. arabinosus. When carbon atom number 8 is replaced by a nitrogen atom a triazolopyrimidine (Structure VII) is obtained (5) and when nitrOgen atoms l and 3 are exchanged for carbon atoms a benzimidazole (Structure VIII) is formed (6). Both analogs (VII) (VIII) inhibit the growth of microorganisms. It seemed reasonable from this evidence that it might be profit- ainle to prepare some substituted tetrazolopyrimidines (Structure IX) aJid.submit them for screening as cancer antimetabolites and as possible Cxantral nervous system stimulants. R /N\\——‘“ ‘\\ \\N%& I (IX) 3 The work herein reported describes the preparation of three series of tetrazolopyrimidines: 7-substituted-S—methyltetrazolopyrimidine (Structure X), 9—substituted—5,6,7,8-tetrahydrotetrazolo[5,l-b]quin— azoline (Structure XI) and 8-substituted-o,7—dihydro-SH-cyclopenta[d]- tetrazolo[l,5-alpyrimidine (Structure XII). DISCUSSION Tetrazolopyrimidines were first described by Balow (7) as products formed by the condensation of S-aminotetrazole with B—diketones or B- keto esters. The condensation with fi—diketones was accomplished in ethyl alcohol solution in the presence of a catalytic amount of piper- idine. The condensation with B-keto esters was done in glacial acetic acid. R-C=C) IQNF=5V R,/MW==J rah-93% + “kl/{LI > \ R" R = alkyl, phenyl R = alkyl, phenyl R'= alkyl, -OC2H5 R"= alkyl, -OH More recently Bower and Doyle (8) observed the formation of '7-hydroxy-S-methyltetrazolopyrimidine by cyclization of 2-azido-h- lrydroxy—o-methylpyrimidine. N CH3-/ \n-NHNHZ HONO > ‘§\U N T O H Of the two procedures, the method of Bulow appears to be the more SLJitable for the preparation of tetrazolopyrimidines because of the aInailability of the starting materials and the smaller number of steps irn/olved. However, the yield of product by both methods was low. Brady and Herbst (9) repeated the procedure of Bfilow (7). They CCHWdensed S—aminotetrazole with acetylacetone in ethyl alcohol solu- ticnu with a catalytic amount of piperidine and obtained 5,7-dimethyl- t'63trazolopyrimidine in a yield of h9% of theory. From S-aminotetrazole b S and acetoacetic ester in refluxing glacial acetic acid they obtained 7-hydroxy—S—methyltetrazolOpyrimidine in a yield of 17% of theory. Furthermore they observed that the yield of 7-hydroxy-S-methyltetra- zolopyrimidine increased to bO% of theory when S—aminotetrazole was condensed with acetoacetic ester in ethyl alcohol solution with a catalytic amount of piperidine. Stolle and Orth (10) reported that the condensation of S-amino- tetrazole alone with carbonyl compounds proceeds very slowly and only under drastic conditions to form azomethines. Recently Finnegan and Henry ’11) suggested that the difficulty in bringing about such con- densations was due to the acidic character of S-aminotetrazole. They showed that excellent yields of azomethines could be obtained under mild conditions when salts of S-aminotetrazole with nitrogen bases were condensed with aldehydes. HZN-r— base \ R-CH=N—|= R‘CHO + H-N\/ ‘ acid H-N\N%N In view of these facts it seemed probable that the yield of tetrazolopyrimidines could be increased by the use of equimolar quantities of base and S-aminotetrazole in the condensation with B-keto esters and B-diketones. The piperidinium salt of S-amino- tetrazole was prepared according to the procedure of Henry (12) using equimolar quantities of S-aminotetrazole and piperidine in ethyl alcohol. The condensation of this salt with acetoacetic ester gave ‘the piperidinium salt of 7-hydroxy-S-methyltetrazolopyrimidine from Ivhich the free hydroxytetrazolopyrimidine was obtained by treatment Vvith acid. The yield of 7-hydroxy-S-methyltetrazo10pyrimidine 6 increased to 78% of theory. When the sodium salt of S-aminotetrazole was used in place of the piperidinium salt in aqueous alcohol the yield of tetrazolopyrimidine was only 2l% of theory. The condensation of ethyl cyclohexanone-2—carboxylate with the piperidinium salt of S- aminotetrazole in ethyl alcohol solution gave 9-hydroxy-S,6,7,8-tetra- hydrotetrazolo[5,l—biquinazoline in a yield of 77% of theory. Brady and Herbst (9) had obtained the same compound in a yield of 25% when using only a catalytic amount of piperidine. The identity of 7-hydroxy- S-methyltetrazolopyrimidine and 9-hydroxy-S,6,7,8-tetrahydrotetrazolo [S,l-b]quinazoline (Structure A) was established in each case by the comparison of melting points and mixture melting points with authentic samples (9). N. / ‘\=;_ ~ \ ‘\\//%\N/3 \\j//£i;:§ Q H 3 (A) (B) 8—Hydroxy—6,7-dihydro—SH-cyclopenta[d]tetrazolo[l,S-a]pyrimidine (Structure B) was prepared by the condensation of the piperidinium salt of S—aminotetrazole with 2-carbethoxycyclopentanone in ethyl alcohol solution. The yield of the hydroxytetrazolopyrimidine was b9% of theory. The identity of 8-hydro-6,7-dihydro-SH-cyclopenta- [d]tetrazolo[l,S-a]pyrimidine was established by an independent Sywmhesis outlined in Chart I. CHART I NH g z + HZN-C—SCHs- HI > -COZC2H5 NHZNH2 CL r1 fir-N3 ‘ W “59/" N\I\(N \ - /J‘\//' \/ \\ N I I g < 8 < HONO if (III) (II) The reactions illustrated in Chart I parallel the procedures used by Brady and Herbst (9) to establish the structure of some tetrazolo- pyrimidines. Compound I, h-hydroxy-2-methylthio-5,6-trimethylene- pyrimidine, was prepared by repeating the procedure of Ross, Goodmand and Baker (l3) and the product pruified by recrystallization. Compound II, 2-hydrazino-b-hydroxy-S,6—trimethylenepyrimidine melted with de— composition at 2530 C. Libermann and Rouaix (lb) reported this com- pound to melt at 255-2560 C. Elemental analysis was in good agree- ment with calculated values for the hydrazinopryimidine. Compound III, 8-hydroxy-6,7-dihydro-SH-cyclopenta[d]tetrazolo[l,5-a]pyrimidine, gave an identical infrared spectrum and melting point, and showed no de- pression of mixture melting point with the product from the condensa- tion of the piperidinium salt of S-aminotetrazole and 2-carbethoxy- cyclopentanone. In an attempt to draw an analogy between pyrimidines and tetra- Zolopyrimidines the reaction of hydroxypyrimidines and phosphoryl 8 chloride was studied. When hydroxypyrimidines are treated with an excess of phosphoryl chloride chloropyrimidines are produced in high yield. These chloropyrimidines serve as useful intermediates in the preparation of substituted pyrimidines. Chlorotetrazolopyrimidines were desired as intermediates in the synthesis of other substituted tetrazolopyrimidines. 7-Chloro-S-methyltetrazolopyrimidine (Structure C) was prepared by treating 7-hydroxy-S-methyltetrazolopyrimidine with an excess of phosphoryl chloride. 9-Chloro-S,6,7,8-tetrahydro- tetrazolo[5,l—b]quinazoline (Structure D) and 8-chloro-6,7-dihydro- (C) (D) (E) SH—cyclopenta[d]tetrazolo[l,S-a]pyrimidine (Structure E) were prepared in an identical manner from the appropriate hydroxytetrazolopyrimidines. Hydrolysis of 7-chloro-S~methyltetrazolopyrimidine gave the corres- ponding hydroxytetrazolopyrimidine. An attempt was made to reduce 7-chloro-S—methyltetrazolopyrimidine to S—methyltetrazolOpyrimidine with zinc dust. The product isolated differed from the starting material but contained chlorine. A mixture melting point of the product isolated from the reaction and an authentic sample of 2—amino-b-chloro-S-methylpyrimidine (15) showed no depression. The removal of a halogen from the pyrimidine ring by zinc dust reduc- tion generally occurs readily. The destruction of the tetrazole ring Iwas not eXpected under such mild conditions. However, Brady and Herbst (9) had observed the destruction of the tetrazole ring when they 9 attempted the catalytic hydrogenation of 7-hydroxy-S-methyltetrazolo- pyrimidine; 2-amino—b-hydwoxy-S-methylpyrimidine was the only product isolated after the hydrogenation. The methods used for the displacement of the halogen from various substituted tetrazolopyrimidines are analogous to those reported in the literature as standard methods for the synthesis of substituted pyrimidines. The reaction of 7-chloro-methyltetrazolopyrimidine with sodium methoxide in methyl alcohol gave 7-methoxy-5-methyltetrazolopyrimidine. 9—Chloro-5,6,7,B—tetrahydrotetrazolo[5,l-b]quinazoline and 8-chloro- 6,7-dihydro-SH-cyclopenta[ditetrazolo[l,5-a]pyrimidine gave the cor- responding methoxy derivatives when treated under similar conditions. With thiourea in ethyl alcohol solution 9-chloro-S,6,7,8-tetra- hydrotetrazolo[5,l-b]quinazoline gave 9-mercapto-S,6,7,8-tetrahydro- tetraazolo[5,l-biquinazoline. In the same manner the 8-mercapto deriv- ative was prepared from 8-chloro-6,7-dihydro-SH-cyc10penta[thetrazolo- [l,S-a]pyrimidine. Other thio derivatives were prepared by interaction of the chlorotetrazolopyrimidine with the appropriate sodium mercaptide in ethyl alcohol. The thio derivatives prepared in this way were 9- benzylthio-S,6,7,8-tetrahydrotetrazolo[S,l-b]quinazoline, 8-allylthio and 8-benzylthio-6,7-dihydro-SH-cyclopenta[ditetrazoloil,S-aipyrimidine. However, when 9—chloro-S,6,7,8-tetrahydrotetrazolo[5,l-b]quinazoline was treated with sodium allylmercaptide in ethyl alcohol, the expected product was not obtained. The material isolated gave negative tests for chlorine and sulfur and melted at 1290 C. A mixture melting point of this material with 9-ethoxy-S,6,7,8—tetrahydrotetrazolo[5,l-biquin- eazoline showed no depression. A molecular model of 9-allylthio-S,6,7,8- lO tetrahydrotetrazolo[5,l-biquinazoline indicated steric interference between the allyl group and the tetrazole and cyclohexane rings which could render the displacement of the halogen by the allyl mercapto group difficult. However, 9-allylthio—S,6,7,8-tetrahydrotetrazolo[5,l— b]quinazoline could be prepared by treating the sodium salt of 9-mercapto-5,6,7,8-tetrahydrotetrazolo[5,l-biquinazoline with allyl- bromide in aqueous acetone. 8-Allylthio-6,7-dihydro-SH-cyclopenta[d]- tetrazolo[l,S—a]pyrimidine was prepared by treating the appropriate chlorotetrazolopyrimidine with sodium allylmercaptide, however, the yield was low. Better results were obtained by the same procedure used for the preparation of 9-allylthio-S,6,7,8-tetrahydrotetrazolo[5,l-b]- quinazoline. Primary and substituted amino derivatives were synthesized from the three chlorotetrazolopyrimidines. These amino derivatives are listed in Tables I, II and III. Most of the aminotetrazolopyrimidines were jprepared by the addition of an ethyl alcohol solution of the amine to a solution or suSpension of the chlorotetraZOIOpyrimidine in the same solvent. The reactions were on occasions carried out in a beaker when the product precipitated completely in less than five minutes. 7-Amino- S—methyltetrazolopyrimidine was prepared by treating an alcohol solu— tion of 7-chloro-S-methyltetrazolopyrimidine with concentrated aqueous anmmwdad 9-Amino-S,6,7,8-tetrahydrotetrazolo[5,l—biquinazoline and 8~amino-6,7-dihydro-SH-cyclopenta[d]tetrazolo[l,S—a]pyrimidine were Iarepared in a similar manner. When 9-chloro-S,6,7,8—tetrahydrotetra- ‘ZQlo[S,l-b]quinazoline was treated with di-isg-propylamine in ethyl Eilcohol solution none of the expected di-isg-propylamino derivative Idas isolated. Instead the product was found to be 9-ethoxy-S,6,7,8- tetrahydro[5,l—b]quinazoline. ll However, 7-chloro-Er-methyltetrazolopyrimidine on treatment with diiiso-propylamine gave 7-dijiso-propylamino-S-methyltetrazolopyrimidine but in low yield. Steric interference attributable to the lSOpIOpyl group was perhaps responsible for the failure in the former reaction and the low yield in the latter. Nitrogen mustards, 8-(j'-bis—2-chloroethylaminopropylamino)—6,7- dihydro-SH-cyclopenta[ditetrazolo[l,S-aipyrimidine dihydrochloride and 9-(5'-bis-2-chloroethylaminopropylamino)-S,6,7,8—tetrahydrotetrazolo— [5,l-biquinazoline hydrochloride were prepared by treating the appro- priate bis-Z—hydzoxyethylamino derivatives with phosphoryl chloride. The fact that one nitrogen mustard was isolated as the monohydro— Chloride and the other as a dihydrochloride could be due to steric hindrance of the nitrogen attached to the pyrimidine portion of the rnolecule. In an attempt to prepare a nitrogen mustard from 7-(bis-2- hydroxyethylamino)-S-methyltetrazolopyrmidine with phosphoryl chloride in chloroform a material containing chlorine was isolated. The ele- rnental analysis indicated that one hydroxyl group had been replaced by a chlorine. The product was not further characterized. Tables I, II and III list all of the substituted tetrazolopyrim- idines prepa'ed during this study. Samples of most of the tetrazolo- qurimidines were submitted to Parke, Davis and Company for screening Eis cancer antimetabolites and central nervous system stimulants. TABLE I . / N‘ CH3777/ l 7-Substituted—S-methyltetrazolopyrimidines. \Qfl R Formula M.P., OC. Yield, % -c1 C5H4N5Cl 108-105 87 -OCH3 C6H7N50 160-161 63 -NH2 C5H6N5 270(dec) 22 -N(CH2CH3)2 CQHMN6 173-175 81 -N(CH;CH2CH3)2 clleN6 115-117 85 -N[CH.CH3)2]2 CllHlaNs 215-216 18 -N(CH2CH=CH )2 C11H14N6 120-122 77 -N(CH2CHZOH 2 (19111411602 155-157 69 -NHCH2CHZOCH3 C8H12N6O 178-175.5 68 -NHCH2CH2CHZOCH3 C9H14N6O 158-156 77 -NHCH2CH2CHZOCH(CH3)2 C11H18N6O 135-136 65 -NHNH2 C5H7N7 232(dec) 7o -NC4H8 chlz'N6 213-218 88 —NC5H10 C10H14N6 197.5-199 99 -NC4H80 CQHIZNSO 227-228 96 1} TABLE II. 9-Substituted-S,6,7,8-tetrahydrotetrazolo[5,l-b]quinazolines R Formula M.P., cC. Yield, % -c1 CBHBNSCI 95-95.5 81 -OCH3 chllmso 158 80 41112 CBHlONs 288(dec) 78 —N(CH3)2 C10H14N6 227(dec) 81 -N(CH2CH3)2 clewN6 122 68 -N(CH2CH2CH3)2 cmHZZN6 108 76 -N(CH2CH=CH2)2 C14H18N6 102 78 —NHCH2CHZOCH3 C11H16N50 208—205 63 -r~1Hc112c11zcrrrzocrr3 C12H18N6O 179.5 71 -NHCH2CH2CHZOCH(CH3)2 C14H22N60 187-187.5 71 -NH(CH2)2N(CH2CH3)2 cmstm7 218-215(dec) 61 -NH(CHZ)3N(CH3)2 C13H21N7 198 83 -NH(cH2)3‘.N(CH2c113)2 C15H25N7 208.5-205 98 —NH(CH2)3N(CHZCH20H)2 C15H15N702 157 56 -NH(CH2)3N(CH2CH2CI)Z-HCl c15H24N7c13 188 93 -NC4H8 C12H16N6 253(dec) 76 ~NC5H10 C13H16N6 175 85 -Nc4Heo clelsmao 217(dec) 98 -SH C8H9N58 201 79 -SCH2C6H5 C15H15NSS 110 56 4301201:er C11H13N5S 75 51 lb TABLE III. 8-Substituted-é,7-dihydro-5H-cyclopenta[d]tetrazolo[l,S-a]- pyrimidines. (ZR/Q R R Formula M.P., OC. Yield, % -c1 C7H6N5Cl 37 87 -OCH3 CBHQNSO 187—188 63 'NHZ C7H8N6 227(dec) 57 -N(CH3)2 C9H12N6 191 91 -N(CHZCH3)2 C11H16N6 135—136 76 -N(CH2CH2CH3)2 C13H20N6 118 33 -N(CH2CH=CH2)2 C13H16N5 93-98 85 -N(CH2CHZOH)2 C11H16N602 151 61 -NH(CH2)3N(CHZCH3)2 C14H23N7 169 59 —NH(CH2)ZOCH3 cloquNeo 199(dec) 78 -NH(CH2)3OCH3 C11H16N6O 181.5-182 83 -NH(CH2)30CH(CH3)2 c13H20N50 175 69 -NH(CH2)3NQCHZCH20H)2 C14H23N702 128 58 -NH(CH2)3N(CH2CH2C1)2-2HCl C14H22N7Cl4 161 80 -NC4H3 C11H14N6 230(dec) 8o -Nc,H10 C12H16N6 182 68 -NC4H80 cllaquso 207(dec) 78 -SH C7H7NSS 183(dec) 78 -SCH2C6H5 C14H13N58 9o 69 -€GQGPGQ CufinN§ a) 80 - l . Iv..|i1|‘|.~1l.\lll. ‘41.! EXPERI MEN 1711* ’ __ 7-Hydroxy-5-methyltetrazolopyrimidine. Ten grams (O.ll7 mole) of anhydrous S—aminotetrazole and 10 g. (0.117 mole) of piperidine in 20 ml. of ethyl alcohol were heated together on a steam-bath for five minutes. After this period the reaction mixture was allowed to cool to room temperature. To the mixture was added 37 g. (0.238 mole) of ethyl acetoacetate in 20 ml. of ethyl alcohol. The resulting yellow solution was heated at reflux temperature for twenty-four hours. The solution was evaporated to dryness on a steam-bath. A small sample of the residue was dissolved in ethyl alcohol, treated with Norit-A, filtered and dry ether was added to the solution until it became cloudy. The piperidine salt of 7-hydroxy-S-methyltetrazolopyrimidine separated while the solution was chilled in the refrigerator. This material melted at 186.5-l870 C. Analysis. Calculated for C10H16N60: C, 50.8; H, 6.8; N, 35.6. Found: C, 50.7; H, 6.9; N, 35.8. The remainder of the residue was dissolved in hot water, treated with Norit—A and filtered. The filtrate was chilled and adjusted to pH 2 by addition of acetic acid. The mixture was chilled for twenty- four hours and the crystalline material which separated was isolated by filtration. Twelve and one-tenth grams (89% of theory) of *All analyses were done by Micro-Tech Laboratories, Skokie, Ill. "“All melting points were taken in open capillaries and are uncorrected. 15 16 7-hydroxy-S-methyltetrazolopyrimidine was isolated. This material melted with decomposition at 286.50 C. Brady and Herbst (9) reported this compound to melt and decompose at 287-2880 C. 7-Chloro—5-methyltetrazolopyrimidine. Fourteen and eight-tenths grams (0.098 mole) of 7-hydroxy-S-methyl- tetrazolopyrimidine and 38 ml. of phosphorus oxychloride were heated on a steam—bath for forty minutes. Then the reaction mixture was poured over crushed ice. The solid material which separated was isolated by filtration and recrystallized from methyl alcohol to give 18.5 g. (87% of theory) of 7—chloro-5-methyltetrazolopyrimidine, melting point 108- 1050 c. Kano and Makisumi (16) reported this compound to melt at 115- 1160 C. Analysis. Calculated for C5H4N5Cl: C, 35.8; H, 2.8; N, 81.3; C1, 20.9. Found: C, 35.6; H, 2.6; N, 81.5; CI, 20.7. 7-Methoxy—S-methyltetrazolopyrimidine. To a solution of 11.3 g. (0.06 mole) of 7—chloro-S-methyltetrazolo- pyrimidine in 90 ml. of methyl alcohol was added with stirring 3.6 g. (0.06 mole) of sodium methoxide. The reaction mixture was heated at re- flux temperature and stirred for three hours. At the end of this period 30 ml. of water was added to the reaction mixture. The mixture was chilled and the precipitate which separated was isolated on a filter. Recrystallization of the crude material from methyl alcohol gave 6.2 g. (63% of theory) of 7-methoxy—S-methyltetrazolopyrimidine, which melted at 160-1610 C. Analysis. Calculated for C6H7N50: C, 83.6; H, 8.3; N, 82.8. Found: C, 83.7; H, 8.3; N, 82.6. 1? 7-Amino-5-methyltetrazolopyrimidine. One gram (0.006 mole) of 7-chloro-5-methy1tetrazolopyrimidine was dissolved in 50 m1. of ethyl alcohol. To this solution was added 20 m1. of concentrated aqueous ammonia. The resulting yellow solution was allowed to stand at room temperature for eighteen hours. At the end of this period the solution was evaporated to dryness and the residue washed with water. The residue was recrystallized from 80% ethyl alcohol to give 0.2 g. (22% of theory) of 7-amino—5-methyltetra- zolopyrimidine. This material melted with decomposition at 2700 C. Kano and Makisumi (16) reported this compound to melt with decompo- sition at 2700 C. Analysis. Calculated for C5H6N6: C, 80.0; H, 8.0; N, 56.0. Found: C, 80.2; H, 8.1; N, 55.9. 7-Hydrazino-5-methy1tetrazolopyrimidine. Seventeen and one-tenth grams (0.1 mole) of 7—chloro-5-methyltetra- zolopyrimidine was added with stirring to a solution of 3.8 g. (0.1 mole) of 95% aqueous hydrazine. The reaction mixture was stirred at reflux temperature for five hours. Then the mixture was evaporated to dryness. The residue was recrystallized from hot water to give 11.8 g. (70% of theory) of 7-hydrazino-5-methyltetrazolopyrimidine, which melted with decomposition at 2320 C. Analysis. Calculated for C5H7N7: C, 36.3; H, 8.3; N, 59.8. Found: C, 36.2; H, 8.2; N, 59.1. 18 7-Benzalhydrazine-f3-methyltetrazolopyrmidine. A mixture of 1.5 g. (0.009 mole) of 7—hydrazino-5-methy1tetra- zolopyrimidine, 1 g. (0.009 mole) of benzaldehyde, 10 m1. of concen- trated hydrochloric acid, 10 m1. of water and 30 ml. of ethyl alcohol was heated at reflux temperature for ten hours. When the solution was cooled to room temperature, orange crystals separated. These crystals were removed by filtration, then dissolved in ethyl alcohol and treated with Norit-A. The pale yellow powder which separated was dried at 1000 C., melting point 2580 C. with decomposition. Analysis. Calculated for C12H11N7: C, 56.9; H, 8.8; N, 38.7. Found: C, 57.2; H, 8.5; N, 38.8. 7-Diethylamino-S-methyltetrazolgpyrimidine. Two grams (0.012 mole) of 7-chloro-S-methyltetrazolopyrimidine was dissolved in 20 m1. of ethyl alcohol. To the solution was added, dropwise with stirring, a solution of 1.7 g. (0.028 mole) of diethyl- amine in 10 ml. of ethyl alcohol. The resulting yellow mixture was warmed on a steam-bath for ten minutes, evaporated to dryness and the residue washed with cold water. The crude material was recrystallized from ethyl alcohol to give 2 g. (81 % of theory) of 7-diethylamino—5- methyltetrazolopyrimidine, melting point 173—1750 C. Kano and Makisumi (16) reported this compound to melt at 179° C. Ana sis. Calculated for C9H14N6: C, 52.8; H, 6.8; N, 80.8. Found: C, 52.5; H, 6.9; N, 81.0. l9 7-(Bis-2-hydroxyethy1amino)-5-methyltetrazolqurimidine. A mixture of 2 g. (0.012 mole) of 7-chloro—5-methyltetrazolopyrim- idine, 2.5 g. (0.028 mole) of diethanolamine and 20 ml. of ethyl alcohol was heated at reflux temperature on a steam-bath for two hours. At the end of this time the reaction mixture was evaporated to dryness and the residue recrystallized from hot water. One and nine-tenths grams (69% of theory) of 7-(bis-2-hydroxyethylamino)—5—methyltetrazolo- pyrimidine was isolated. The product was dried at 100° C.; its melt- ing point is 155-157° C. Analysis. Calculated for C9H14N602: C, 58.8; H, 5.9; N, 35.3. Found: C, 58.8; H, 5.9; N, 35.5. 7-Di-iso-propylamino-S-methyltetrazolopyrimidine. A mixture of l g. (0.006 mole) of 7-chloro-5—methyltetrazolopyrim- idine, 1.1 g. (0.012 mole) of dijisgpropylamine and 20 ml. of ethyl alcohol was heated at reflux temperature for two hours. The mixture was evaporated to dryness and the residue washed with cold water. The residue recrystallized from 95% ethyl alcohol to give 0.2 g. (18% of theory) of 7-di-i§g:propylamino-5-methyltetrazolopyrimidine, melting point 215-2160 c. Analysis. Calculated for CliHieNe‘ C, 56.8; H, 7.7; N, 35.9. Found: C, 56.6; H, 7.8; N, 35.9. 2O 7—Di-ngpropylamino-5-methyltetrazolopyrimidine. A mixture of l g. (0.006 mole) of 7-chloro-5-methyltetrazolopyrim- idine, 1.2 g. {0.012 mole) of di-gfpropylamine and 20 ml. of ethyl alcohol was heated at reflux temperature for two hours. The residue which remained after evaporating the mixture to dryness was washed with cold water and recrystallized from 70% ethyl alcohol. One and two-tenths grams (85% of theory) of 7-dijn-propy1amino-5-methyltetrazolo- pyrimidine was isolated; it melted at 115—1170 c. Analysis. Calculated for C11H18N6: C, 56.8; H, 7.7; N, 35.9. Found: C, 56.8; H, 7.7; N, 35.9. 7—Dia11ylamino-5-methyltetrazolopyrimidine. One and one-tenth grams (0.012 mole) of diallylamine was added to a solution of 1 g. (0.006 mole) of 7-chloro-5-methyltetrazolopyrimidine in 20 ml. of ethyl alcohol. The reaction mixture was heated at reflux temperature for three hours and then evaporated to dryness. The resi- due was recrystallized from 80% ethyl alcohol to give 1.0 g. (77% of theory) of 7-diallylamino-S-methyltetrazolopyrimidine, melting point 120-1220 C. Anayysis. Calculated for C11H14N5: C, 57.8; H, 6.1; N, 36.5. Found: C, 57.5; H, 6.2; N, 36.6. 7-(2—Methoxyethy1amino)-5-meto1tetrazolopyrimidine. To a solution of 2 g. (0.012 mole) of 7—chloro-5-methyltetrazolo— pyrimidine in 50 m1. of ethyl alcohol was added 3 g. (0.028 mole) of 60% 2-methoxyethy1amine. The mixture was warmed in a beaker on a steam-bath for twenty minutes and then evaporated to dryness. The residue was washed with water and then recrystallized from 80% ethyl alcohol to give 1.6 g. (68% of theory) of 7-(2-methoxyethylamino)-5- methyltetrazolOpyrimidine, melting point 178-175.5° C. Analysis. Calculated for CaHizNoo‘ C, 86.1; H, 5.8; N, 80.8. Found: C, 86.0; H, 5.8; N, 80.6. 7-(3-Methoxypropylamino)~5-methy1tetrazolopyrimidine. Five and one-tenth grams (0.058 mole) of 3-methoxypropy1amine was added dr0pwise to a solution of 5 g. (0.029 mole) of 7-chloro—5-methy1— tetrazolopyrimidine in 75 m1. of ethyl alcohol. The reaction mixture was evaporated to dryness after heating at reflux temperature for three hours. The residue was recrystallized from ethyl alcohol. Four and eight-tenths grams (77% of theory) of 7-(3-methoxypropy1amino)-5-methy1- tetrazolOpyrimidine was isolated, melting point 158-156° C. Analysis. Calculated for C9H14N60: C, 88.6; H, 6.3; N, 37.8. Found: c, 88.7; H, 6.3; N, 37.7. 7—(3-iso-Propoxy-n-propylamino)-5—methy1tetrazolgpyrimidine. A solution of 13.8 g. (0.12 mole) of jjisg-propoxy-nfpropylamine in 50 m1. of ethyl alcohol was added with stirring to 10 g. (0.059 mole) of 7—chloro-5-methyltetrazolopyrimidine dissolved in 50 m1. of ethyl alcohol. The reaction mixture was stirred and heated at reflux temperature for three hours. The mixture was then evaporated to dry- ness and the residue recrystallized from 80% ethyl alcohol. Nine and six-tenths grams (65% of theory) of 7-(3fiisg—propoxyjn-propylamino)-5- methyltetrazolopyrimidine was isolated; the product melted at 135- 1360 C. Ana sis. Calculated for C11H18N503 C, 52.8; H, 7.3; N, 33.6. Found: C, 53.1; H, 7.3; N, 33.6. 7:Eyrroligyl-5-methyltetrazolopyrimidine. A mixture of 2 g. (0.012 mole) of 7-chloro-5-methyltetrazolopyrim- idine, 1.6 g. (0.028 mole) of pyrrolidine and 20 m1. of ethyl alcohol was heated at reflux temperature for two hours. At the end of this period the mixture was poured over crushed ice and the solid which separated was isolated by filtration. The solid was recrystallized from 95% ethyl alcohol to give 2.1 g. (88% of theory) of 7—pyrrolidyl- 5-methyltetrazolopyrimidine, which melted with decomposition at 213- 218° c. Analysis. Calculated for C9H12N6: C, 52.9; H, 5.9; N, 81.2. Found: C, 52.7; H, 5.9; N, 81.3. 2) 7-Piperidyl-5—methyltetrazolopyiimidine. A mixture of 1 g. (0.006 mole) of 7—chloro—5-methy1tetrazolOpyrim- idine, 20 ml. of ethyl alcohol and l g. (0.012 mole) of piperidine was heated at reflux temperature for one hour. The reaction mixture was allowed to cool to room temperature and a white solid separated. The solid was collected on a filter. Recrystallization of the crude material from ethyl alcohol gave 1.3 g.(99%cfi7theory) of 7—piperidyl- 5-methy1tetrazolopyrimidine, melting point 197.5—199° C. Kano and Makisumi (16) reported this compound to melt and decompose at 203° C. Analysis. Calculated for C10H14N6: C, 55.0; H, 6.5; N, 38.5. Found: C, 55.1; H, 6.5; N, 38.3. 7—Morpholinyl-5-methyltetrazolopyrimidine. Two grams (0.028 mole) of morpholine was added to a solution of 2 g.'(0.0l2 mole) of 7-chloro-5—methyltetrazolopyrimidine in 20 ml. of ethyl alcohol. The mixture was poured over crushed ice after heating at reflux temperature for two hours. The solid which separated was recrystallized from 95% ethyl alcohol. TWo and five—tenths grams (96% of theohy) of 7-morpholinyl—5-methy1tetrazolopyrimidine was iso- lated; it melted with decomposition at 227-228° C. Analysis. Calculated for C9H12N60: C, 89.1; H, 5.5; N, 38.2. Found: C, 89.3; H, 5.5; N, 38.8. _.. .‘p 1min: “Arr-i ~ 9‘; __._._.. —. 1.5-l ‘. . .' .- 5'. 1"“ u.— l? 28 Reaction of Zinc Dust with 7-Chloro-5—methyltetrazolqurimidine. A mixture of 20 g. (0.3 gram atom) of zinc dust, 16.8 g. (0.099 mole) of 7-chloro-5-methy1tetrazolopyrimidine and 100 m1. of water was heated at reflux temperature for one hour. During this time foam collected in the condenser, this was washed down into the reaction mixture with 80 m1. of ethyl alcohol. Then the reaction mixture was heated at reflux temperature and stirred for an additional twenty-two hours. The unreacted zinc dust was removed by filtration and washed with acetone. The filtrates were combined and evaporated to dryness. The residue was recrystallized from 50% ethyl alcohol to give 10.1 g. (78% of theory) of 2-amino-8—chloro-5-methylpyrimidine as long white needles, melting point 181.5° C. This compound is reported by Gabriel and Colman (15) to have a melting point of 182-183° C. A mix- ture melting point of this material and the product obtained using the procedure of Gabriel and Colman (15) gave no depression of the melting point. Analysis. Calculated for C5H6N3C1: N, 29.2 Found: N, 29.1, 29.3. Reaction of Thionyl Chloride with 7—(Bis-2-hydroxyethylamino)-5-methyl- tetrazolopyrimidine. A solution of 9 g. (0.063 mole) of thiohyl chloride (Eastman White Label) in 30 ml. of dry chloroform was added dropwise with stir- ring to 5 g. (0.021 mole) of 7-(bis-2-hydroxyethy1amino)-5-methy1- tetrazolopyrimidine su3pended in 50 m1. of dry chloroform in an ice bath. The ice bath was removed at the end of one hour and the reaction 25 mixture was stirred at room temperature for twenty hours. The excess thionyl chloride and chloroform were removed EEHXEEEQ' The residue was dissolved in ethyl alcohol and dry ether was added until the solu— tion became turbid. The crystalline material which separated while the solution was chilled in the refrigerator was isolated on a filter. The product melted with decomposition at 115° C. Analysis. Calculated for C9H14N6OC12: N, 29.0 Found: N, 29.0, 29.1. 26 9-Hydro:5,6,7,8-tetrahydrotetrazolo[5,1-b]quinazoline. A mixture of 25 g. (0.3 mole) of anhydrous 5-aminotetrazole, 25 g. (0.3 mole) of piperidine and 50 m1. of ethylzflcohol was heated under reflux on a steam—bath for ten minutes. Then a solution of 58.8 g. (0.32 mole) of 2-carbethoxycyclohexanone in 100 m1. of ethyl alcohol was added and the mixture was heated under reflux for twenty—four hours. At the end of this time the resulting orange solution was allowed to cool to room temperature while a colorless crystalline product separated. A small sample of these crystals was removed and dissolved in ethyl alcohol. This solution was diluted with dry ethyl ether until perman- ent turbidity developed. The crystalline material from the ethyl alcohol-ether solution was the piperidinium salt of 9-hydroxy-5,6,7,8- tetrahydrotetrazolo[5,1-b1quinazoline. After drying the material at 100° c. it melted at 165—167° c. Analysis. Calculated for C13HZON6: C, 56.5; H, 7.3; N, 30.8. Found: C, 56.7; H, 7.6; N, 30.8. The remainder of the crystalline material was separated by filtra- tion, placed in 100 m1. of water and adjusted to pH 2 with cold concen- trated hydrochloric acid. The solution was chilled over night and the crystalline material that separated was recrystallized from water. After drying at looO c. the yield was 83.2 g. (77% of theory) of pro— duct that melted with decomposition at 228-225° C. The same melting point was reported by Brady and Herbst (9). 27 9-Chloro-5,6,7,8—tetrahydrotetrazolo[5,l—b]quinazoline. Fifteen milliliters of phosphorus oxychloride and 10 g. (0.05 mole) of 9-hydroxy—5,6,7,8-tetrahydrotetrazolo[5,l-b]quinazoline were heated together on a steam—bath in a 100 ml. flask fitted with a drying tube for forty-five minutes. At the end of the heating period the solution was poured over crushed ice with stirring. The solid material which separated was isolated on a filter and recrystallized from 90% ethyl alcohol. The yield of 9-chloro—5,6,7,8-tetrahydrotetrazolo[5,l-b]- quinazoline was 8.8 g. (81% of theory), melting point 95-95.5° C. Analysis. Calculated for C5H8N5C1: C, 85.8; H, 3.9; N, 33.8; C1, 16.9. Found: C, 85.9; H, 3.9; N, 33.8; C1, 17.1. 9—(2'-Diethy1aminoethy1amino)-5,6,7,8-tetrahydrotetrazolo[5,1-b1guin- azoline. To 11 g. (0.052 mole) of 9-chloro-5,6,7,8-tetrahydrotetrazolo- [5,1-b]quinazoline suSpended in 150 m1. of ethyl alcohol was added dropwise with stirring a solution of 12 g. (0.108 mole) of N, N—diethyl— ethylenediamine in 70 m1. of ethyl alcohol. The resulting mixture was heated at reflux temperature and stirred for four hours, evaporated to dryness and the resulting residue recrystallized from 90% ethyl alcohol. Nine and one-tenth grams (61% of theory) of pure material was isolated; it melted with decomposition at 218-215° C. Analysis. Calculated for C14H23N7: C, 58.1; H, 8.0; N, 33.9. Found: C, 57.9; H, 8.0; N, 33.7. 28 9-(2'-Methoxyethy1amino)-5,6,7,8—tetrahydrotetrazolo[5,1—blguinazoline. Eleven grams (0.052 mole) of 9-chloro-5,6,7,8—tetrahydrotetrazolo- [5,l-b]quinazoline was suspended in 100 ml. of ethyl alcohol. A mix- ture of 12 g. (0.108 mole) of 65—70% 2—methoxyethylamine in 100 ml. of ethyl alcohol was added dropwise to the stirred suspension. The re- action mixture was stirred and heated at reflux temperature for two hours. The mixture was evaporated to dryness and the residue recrystal- lized from 90% ethyl alcohol. The yield of pure material was 7.8 g. (63% of theory), melting point 208-205° C. Analysis. Calculated for C11H16N6O: C, 53.2; H, 6.5; N, 33.9. Found: C, 53.5; H, 6.7; N, 33.9. 9—(3'-iso-Prgpoxypropylamino)e5,6,7,8-tetrahydrotetrazolo[5,1-bl- quinazoline. A solution of 10.5 g. (0.09 mole) of 31isg-propoxy-g-propylamine in 100 m1. of ethyl alcohol was added to 10 g. (0.085 mole) of 9-chloro- 5,6,7,8-tetrahydrotetrazolo[5,1-b]quinazoline suspended in 100 m1. of ethyl alcohol. The mixture was heated at reflux temperature with con— tinuous stirring for two hours, then chilled at 0° C. for twenty-four hours. The solid material which separated was collected on a filter, washed with cold water and recrystallized from 90% ethyl alcohol. The 9.3 g. of pure product corresponded to a yield of 71% of theory, melt- ing point 187-187.5° C. Analysis. Calculated for C14H22N60: C, 57.9; H, 7.6; N, 28.9. Found: C, 58.2; H, 7.6; N, 28.8. 29 9-(3'-Methoxypropyiamino)-5,6,7,8-tetrahydrotetrazolo[SLl-blquinazoline. To 10 g. (0.085 mole) of 9-chloro-5,6,7,8-tetrahydrotetrazolo[5,1—b]— quinazoline suspended in 100 m1. of ethyl alcohol was added with stir- ring a solution of (0.09 mole) of 3-methoxypropy1amine in 100 m1. of ethyl alcohol. The mixture was stirred under reflux for two and one- half hours. The solution was then evaporated to one half its volume, chilled for twenty—four hours and the resulting solid collected by filtration. The residue was recrystallized from 80% ethyl alcohol to give 8.8 g. (71% of theory) of 9-(3'-methoxypropy1amino)-5,6,7,8-tetra- hydrotetrazolo[5,1-blquinazoline, melting point 179-179.5° C. Analysis. Calculated for C12H18N60: C, 58.9; H, 6.9; N, 32.0. Found: C, 58.9; H, 7.0; N, 32.2. 9-Piperidy1-5i6,7,8-tetrahydrotetrazolo[5il-b]quinazoline. Fourteen and three-tenths grams (0.068 mole) of 9-chloro—5,6,7,8— tetrahydrotetrazolo[5,l-blquinazoline was dissolved in 200 m1. of ethyl alcohol. To the solution was added with stirring 11.5 g. (0.136 mole) of piperidine. The mixture was heated at reflux temperature for two and one—half hours and then chilled. The resulting solid was separated by filtration. Recrystallization of the crude material from 95% ethyl alcohol resulted in 18.9 g. (85% of theory) of 9-piperidy1-5,6,7,8-tetra- hydrotetrazolo[5,1-blquinazoline, melting point 175° C. Analysis. Calculated for C13H18N6: C, 60.8; H, 7.0; N, 32.5. Found: C, 60.7; H, 7.0; N, 32.2. 3O 9—Morpholinyl-5,6,7,8-tetrahydrotetrazolo[5,1—blguinazoline. Ten grams (0.085 mole) of 9-chloro-5,6,7,8-tetrahydrotetrazolo- [5,1-b]quinazoline was dissolved in 200 m1. of ethyl alcohol and a solution of 7.8 g. (0.09 mole) of morpholine in 100 m1. of ethyl alcohol was added dropwise with constant stirring. After stirring and heating at reflux temperature for two and one-half hours the mixture was chilled and the solid that separated was collected by filtration. This solid was recrystallized from 95% ethyl alcohol to give (98% of theohy) of 9—morpholiny1-5,6,7,8—tetrahydrotetrazolo[5,l-b]quinazoline, which melted with decomposition at 217° C. Analysis. Calculated for C12H16N60: C, 55.8; H, 6.2; N, 32.3. Found: C, 55.5; H, 6.8; N, 32.2. 9-Ryrrolidy175,6,7,8-tetrahydrotetrazolo[5i1—b]guinazoline. To a solution of 15 g. (0.071 mole) of 9-chloro-5,6,7,8—tetra- hydrotetrazolo[5,l—blquinazoline dissolved in 225 m1. of ethyl alcohol was added with stirring 10 g. (0.182 mole) of pyrrolidine. The mixture was stirred and heated at reflux temperature for two and one—half hours, chilled and the solid which separated collected on a filter. The residue was recrystallized first from ethyl alcohol and then from chloroform to give 13.2 g. (76% of theory) of 9-pyrrolidy1-5,6,7,8-tetrahydro- tetrazolo[5,l-blquinazoline, which melted with decomposition at 253° C. Analysis. Calculated for C12H16N6: C, 59.0; H, 6.6; N, 38.8. Found: C, 59.3; H, 6.8; N, 38.1. 31 9—Amino-5,6,7,8—tetrahydrotetrazolo[5,l-blquinazoline. To a mixture of 8.7 g. (0.081 mole) of 9—chloro-5,6,7,8-tetra— hydrotetrazolo[5,1-blquinazoline and 100 m1. of ethyl alcohol was added with constant shaking 100 m1. of concentrated aqueous ammonia. The resulting pink solution was allowed to stand at room temperature for three days. The solid material which separated was collected by fil- tration and recrystallized from 95% ethyl alcohol. The yield of 9-amino-5,6,7,8-tetrahydrotetrazolo[5,1-b]quinazoline was 5.7 g. (78% of theory), which melted with decomposition at 288C C. Analysis. Calculated for CBchNé: C, 50.5; H, 5.3; N, 88.2. Found: C, 50.6; H, 5.5; N, 88.0. 9-Dimethy1amino-5,6,7i8-tetrahydrotetrazolo[5,l-b]quinazoline. To 15 g. (0.071 mole) of 9-chloro-5,6,7,8-tetrahydrotetrazolo- [5,1-b]quinazoline suSpended in 100 m1. of ethyl alcohol was added with stirring 25.5 g. (0.1 mole) of 25% aqueous dimethylamine. The mixture was stirred at room temperature for three hours and at reflux temper- ature for two and one-half hours. The mixture was diluted with 150 ml. of water, chilled for twenty-four hours and the resulting precipitate collected by filtration. The crude material was recrystallized from 95% ethyl alcohol and then from an 87% ethyl alcohol-13% chloroform mixture. Twelve and four-tenths grams (81% of theory) of 9-dimethyl- amino-5,6,7,8-tetrahydrotetrazolo[5,1-b1quinazoline was obtained which melted with decomposition at 227° C. Analysis. Calculated for C10H14N6: C, 55.0; H, 6.5; N, 38.5. Found: C, 58.9; H, 6.8; N, 38.8. 32 9-Diethylaminof5 6 7 8-tetrahydrotetrazolo[5,1—blquinazoline. )J‘J’ A solution of 8.3 g. (0.11 mole) of diethylamine in 100 m1. of ethyl alcohol was added dropwise, with stirring, to 12 g. (0.057 mole) of 9-chloro-5,6,7,8—tetrahydrotetrazolo[5,1-b]quinazoline suspended in 100 ml. of ethyl alcohol. The mixture was stirred and heated at reflux temperature for two and one-half hours, evaporated to dryness and the residue then washed with cold water. The residue was recrys- tallized from 90% ethyl alcohol to give 9.5 g. (68% of theory) of 9-diethylamino-5,6,7,8-tetrahydrotetrazolo[5,l—b]quinazoline, melting point 122° C. Analysis. Calculated for ClZHlBNB: C, 58.5; H, 7.8; N, 38.1. Found: C, 58.8; H, 7.8; N, 33.9. 9-Di-nepropylamino-5,6,7,87tetrahydrotetrazolo[5,l-blguinazoline. To a solution of 10 g. (0.085 mole) of 9—chloro-5,6,7,8-tetra- hydrotetrazolo[5,1-blquinazoline in 200 m1. of ethyl alcohol was added with stirring 9 g. (0.09 mole) of di-n-propylamine. The reaction mixture was heated at reflux temperature and stirred for two hours. The resulting solution was evaporated to dryness and the residue re- crystallized from 95% ethyl alcohol. Nine and four-tenths grams (76% of theory) of 9-di-2-propy1amino-5,6,7,8-tetrahydrotetrazolo[5,1-b]~ quinazoline was isolated, melting point 108° C. Analysis. Calculated for C14H22N6: C, 61.3; H, 8.1; N, 30.6. Found: C, 61.1; H, 7.8; N, 30.7. J) 9—Dia11y1amino-5,6,7,8—tetrahydrotetrazolo[5,l-blquinazoline. A solution of 8.7 g. (0.09 mole) of diallylamine in 100 ml. of ethyl alcohol was added with stirring to 10 g. (0.085 mole) of 9-chloro- 5,6,7,8-tetrahydrotetvazolo[5,l-blquinazoline suspended in 100 m1. of ethyl alcohol. The solution was heated at reflux temperature for two hours evaporated to dryness and the residue washed with water. The 9 residue was recrystallized from 90% ethyl alcohol to give 8.9 g. (78% of theory) of 9-dia11ylamino—5,6,7,8-tetrahydrotetrazolo[5,1-b1quinazo- line, melting point 102C C. Analysis. Calculated foi Cqulgst C, 62.2; H, 6.7; N, 31.1. Found: C, 62.3; H, 6.9; N, 31.3. 9-Methoxy-5,6,7,8-tetrahydrotetrazolo[5,1-b1quinazoline. Fifteen grams (0.071 mole) of 9-chloro-5,6,7,8-tetrahydrotetrazolo- [5,l-blquinazoline was added to a sodium methoxide solution, prepared by dissolving 1.7 g. (0.078 glam atom) of sodium in 200 m1. of methyl alcohol. The reaction mixture was stirred at reflux temperature for three hours cooled to room temperature, diluted with 200 m1. of cold 2 water and the resulting precipitate collected on a filter. The solid material was recrystallized from 71% ethyl alcohol. The yield of 9-methoxy—5,6,7,8-tetrahydrotetrazolo[5,l—b]quinazoline was 11.6 g. (80% of theory). This material melted at 158° C. When the resolidified melt was heated a second time it melted at 162C C. Analysis. Calculated for CngleO: c, 52.7; H, 5.8; N, 38.1. Found: C, 52.7; H, 5.5; N, 38.1. )8 9-Mercapto-5,6L7,8-tetrahyd'otetrazolo[5,l-b]quinazoline. A mixture of 7.2 g. (0.095 mole) of thiourea, 20 g. (0.095 mole) of 9-chloro—5,6,7,8-tetrahydrotetrazolo[5,l-blquinazoline and 100 m1. of ethyl alcohol was stirred and heated at reflux temperature for three hours. The mixture was then cooled to room temperature and the yellow solid which separated was collected on a filter. The yellow solid was placed in 100 m1. of water and concentrated aqueous ammonia added until a homogenous solution was obtained. Then cold concentrated hydrochloric acid was added to adjust solution to pH 2. The resulting yellow solid was collected on a filter washed with water and dried at ) 100° c. The yield of 9-melcapto-5,6,7,8-tetrahydrotetrazolo[5,1-b]— quinazoline was 15.8 g. (79% of theory), melting point 201° C. Analysis. Calculated for CaHgNjS: C, 86.8; H, 8.8; N, 33.8; S, 15.5. Found: C, 86.5; H, 8.5; N, 33.6; S, 15.5. 9-Allylthio-5,6,z,8—tetrahydrotetrazolo[5,l-thuinazoline. Twenty grams (0.096 mole) of 9-mercapto-5,6,7,8-tetrahydrotetra- zolo[5,1-b1quinazoline and 5.3 g. (0.096 mole) of potassium hydroxide were dissolved in a mixture of 200 m1. of acetone and 30 m1. of water. To this solution was added 16.7 g. of allyl bromide. The mixture was heated at reflux temperature for nineteen hours. After this period an additional 0.8 g. of potassium hydroxide and 5 g. of allyl bromide were added. The mixture was heated under the same conditions for an additional six hours. The mixture was then allowed to stir at room temperature for twenty-four hours, after which the layers were separ- ated. The upper layer was evaporated to dryness, the residue treated ‘I I! ~ ‘3'. i..- I. .3 . .h ..- .6 ..wh’fi u MI. 1 air. 35 with acetone and filtered to remove potassium bromide. The filtrate was evaporated to dryness and the residue recrystallized from ethyl alcohol. The lower, aqueous layer contained only potassium bromide. Twelve and one-tenth grams (51% of theory) of 9-allylthio-5,6,7,8- tetrahydrotetrazolo[5,l-b]quinazoline was isolated, melting point 75" C. Analysis. Calculated fo7 CllHlijS: C, 53.8; H, 5.3; N, 28.3; S, 13.0. Found: C, 53.5; H, 5.8; N, 28.2; S, 13.1. 9-Benqylthio-5,6,7,8—tetrahydrotetrazolo[5,l—b]quinazoline. To a freshly prepared solution of 1.7 g. (0.075 gram atom) of sodium in 50 ml. of ethyl alcohol was added 9.3 g. (0.075 mole) of a-toluenethiol. After careful mixing, the solution of sodium benzyl- mercaptide was added dropwise with stirring at room temperature to 15.8 g. (0.075 mole) of 9-chloro—5,6,7,8-tetrahydrotetrazolo[5,l—bl- quinazoline suspended in 100 ml. of ethyl alcohol. The mixture was stirred at room temperature for twenty-four hours. At the end of this time the mixture was filtered to remove the sodium chloride. The sodium chloride was washed with ethyl acetate. The filtrates were combined and evaporated until a yellow oil separated. The oil was dissolved in 1:1 ethyl alcohol-ethyl acetate mixture and treated with Norit-A. Upon standing colorless crystals separated from the clear solution. After a second recrystallization from the same solvent mixture 12.8 g. (56% of theory) of 9-ben:ylthio-5,6,7,8-tetrahydrotetrazolo[5,l-b]quinazoline was isolated, melting point 110C C. Analysis. Calculated for Clel, 5S: C, 60.6; H, 5.1; N, 23.6; S, 10.8. Found: C, 60.6; H, 5.1; N, 23.8; S, 10.9. 9-(Bisjhydroxyethylamino)-5,6,7,8-tetrahydrotetrazolo[5,1-b]guinazoline. A solution of 18.9 g. (0.18 mole) of diethanolamine in 70 ml. of ethyl alcohol was added dropwise with stirring to a suspension of 15 g. (0.071 mole) of 9-chloro-5,6,7,8-tetrahydrotetrazolo[5,l-blquinazoline in 100 ml. of ethyl alcohol. The reaction mixture was heated at reflux temperature and stirred for three hours. The solution was evaporated to two-thirds its volume and chilled. The solid which formed was col- lected on a filter and recrystallized from 90% ethyl alcohol to give 9-(bis-hydroxyethylamino)-5,6,7,8-tetrahydrotetrazolo[5,l-blquinazoline, melting point 132C c. Analysis. Calculated for C12H1RN602: C, 51.8; H, 6.5; N, 30.2. Found: C, 51.5; H, 6.5; N, 30.8. 9-(3'-Dimethylaminopropylamino)-5,6,7,8-tetrahydrotetrazolo[5,l-b1- guinazoline. Ten and six-tenths grams (0.1 mole) of 3-dimethylaminOpropylamine was added dropwise with stirring to a solution of 11 g. (0.052 mole) of 9-chloro-5,6,7,8-tetrahydrotetrazolo[5,1-b]quinazoline in 100 ml. of ethyl alcohol. The mixture was warmed gently on a steam-bath for thirty minutes, chilled and crystallization induced by scratching the wall of the flask. After cooling in the refrigerator for two days the precipitate which separated was isolated by filtration. The yield of 9-(3'-dimethy1aminopropylamino)—5,6,7,8-tetfahydf0tetfaZOlO[5,l-b]- )7 quinazoline was 11.8 g. (83% of theory), melting point 198C C. Analysis. Calculated for C13H21N7: C, 56.7; H, 7.7; N, 35.6. Found: C, 56.5; H, 7.7; N, 35.7. 9-(3'-Diethylaminopropylamino)-5,6,7,8-tetrahydrotetrazolo[Ell-b1- ,guinazoline. Eleven grams (0.052 mole) of 9-chloro-5,6,7,8-tetrahydrotetrazolo- [5,l-b1quinazoline was dissolved in 100 m1. of ethyl alcohol by warm- ing on a steam-bath. To the solution was added dropwise with constant agitation 13.8 g. (0.1 mole) of 3-diethylaminopropylamine.. The solu- tion was warmed on a steam-bath for thirty minutes, chilled in the refrigerator for twenty-four hours and the resulting solid removed by filtration. This solid was recrystallized from ethyl alcohol to give 18.7 g. (98% of theory) of 9—(3'-diethylaminopropylamino)-5,6,7,8— tetrahydrotetrazolo[5,l-blquinazoline, melting point 208.5-205O C. Analysis. Calculated for C15H25N7: C, 59.8; H, 8.3; N, 32.3. Found: C, 59.8; H, 8.8; N, 32.5. 9-(3'-Bis-2ghydroxyethylaminopropylamino)-5,6,7,8—tetrahydrotetrazolo- [5,l-blqpinazoline. To a solution of 11 g. (0.052 mole) of 9-chloro-5,6,7,8-tetra- hydrotetrazolo[5,1-b]quinazoline in 90 ml. of ethyl alcohol was added dropwise with stirring 16.8 g. (0.1 mole) of 3-bis—2-hydroxyethy1amino- propylamine. The mixture was warmed on a steam-bath for one hour.‘ This solution was evaporated to a viscous, oily consistency and chilled for twenty-four hours. The colorless precipitate which separated was 38 collected on a filter and recrystallized from ethyl alcohol to give 9.6 g. (56% of theory) of 9-(3'-bis-hydroxyethylaminopropy1amino)- 5,6,7,8-tetrahydrotetrazolo[5,l-b]quinazoline, melting point 1570 C. Analysis. Calculated for C15H25N702: C, 53.7; H, 7.5; N, 29.2. Found: C, 58.0; H, 7.8; N, 29.5. 9-(3'-Bis-2—chloroethylaminoprgpylamino)—5,6,7,8-tetrahydrotetrazolo- [5,1—b1quinazoline hydrochloride. Ten and eight-tenths grams (0.032 mole) of 9-(3'-bis-2-hydroxy— ethylaminOpropylamino)-5,6,7,8-tetrahydrotetrazolo[5,l—biquinazoline was added to 30 ml. of thionylchloride (Eastman White label). Hydrogen chloride and sulfur dioxide evolved while the mixture stood at room temperature for fifteen minutes. After warming the mixture for five minutes on a steam-bath, the excess thionyl chloride was removed in yagug and the viscous residue was washed first with dry chloroform and then with dry ethyl ether. The residue was dissolved in ethyl alcohol and dry ethyl ether added until the solution was turbid. The solution was allowed to cool in the refrigerator for four days and the pale yellow solid which separated was collected by fitration in a dry box. The yield of 9-(3'-bis-2-chloroethylaminopropylamino)-5,6,7,8-tetra- hydrotetrazolo[5,l-b]quinazoline hydrochloride was 12.1 g. (93% of theory). It melted with decomposition at 1880 C. Analysis. Calculated for C15H24N7C13: C, 88.1; H, 5.9; N, 28.0; C1, 26.0. Found: C, 88.8; H, 6.2; N, 23.8; C1, 25.8. 39 Attempted reaction of 9—chloro—5,6,7,8-tetrahydrotetrazolo[5,l-b]- gginazoline with sodium albylmercaptide. The method employed is essentially identical with that employed for the preparation of the benzylthio derivative. To 15 g. (0.071 mole) of 9-chloro—5,6,7,8-tetrahydrotetrazolo[5,l-b]quinazoline sus- pended in 100 m1. of ethyl alcohol was added dropwise with stirring a solution of sodium allylmercaptide. The sodium allylmercaptide was prepared by dissolving 1.6 g. (0.07 gram atom) of sodium in 30 ml. of ethyl alcohol followed by 5.3 g. (0.07 mole) of allylmercaptan. After complete addition of the sodium allylmercaptide the resulting red solu- tion was stirred at room temperature for twenty-four hours. The reac- tion mixture was evaporated to dryness and the solid residue was ex- tracted with warm ethyl acetate to remove the organic product from sodium chloride. The solid which separated from the ethyl acetate was recrystallized twice from ethyl alcohol. This material gave a negative test for sulfur. This compound was found to be 9-ethoxy-5,6,7,8-tetra— hydrotetrazolo[5,l-biquinazoline. It melted at 1290 C. Analysis. Calculated for ClCH13N50: C, 58.8; H, 6.0; N, 32.0. Found: C, 58.8; H, 6.0; N, 31.9. Attempted reaction of 9-chloro-5,6,7,8-tetrahydrotetrazolo[5,1-b]- quinazoline with di-iso-propylamine. To 13 g. (0.06 mole) of 9-chloro-5,6,7,8,—tetrahydrotetrazolo- [5,l-b]quinazoline suspended in 100 ml. of ethyl alcohol, a solution of 12.3 g. (0.12 mole) of diisopropylamine in 100 m1. of ethyl alcohol was added dropwise with stirring. The mixture was stirred at room 8o temperature for two hours and heated under reflux for three hours. The resulting reddish-brown solution was evaporated to dryness and the residual solid recrystallized twice from ethyl alcohol. Two grams of pure material were isolated, melting point 1300 C. The mixture melting point with 9—ethoxy—5,6,7,8-tetrahydrotetrazolo[5,l-quuin- azoline showed no depression. Analysis. Calculated for C10H13N50: N, 31.9. Found: N, 31.9. 8-Hydroxy-6,7-dihydro-5H-cyclopenta[d]tetrazolo[l,51alpyrimidine. A mixture of 111.3 g. (1.3 moles) of anhydrous 5-aminotetrazole, 111.3 g. (1.3 moles) of piperidine and 100 m1. of ethyl alcohol was heated on a steam-bath for twenty minutes and then cooled to room temperature. A solution of 208.8 0. (1.8 moles) of 2-carbethoxycyclo- pentanone in 110 ml. of ethyl alcohol was added to the mixture. The resulting mixture was heated at reflux temperature for twenty hours. At the end of this time the ethyl alcohol was removed.inlyagug until recrystallization started. The solid was separated by filtration and was washed with ether until colorless. A small sample of the solid was recrystallized several times by dissolving in hot ethyl alcohol, chilling and adding ether until the solution was slightly turbid. The colorless crystalline material was isolated by filtration, melting point 170C C. Elemental analysis indicated that the material is the piperidinium salt of 8-hydroxy-6,7-dihydro-5H-cyclopenta[d]tetrazolo- [1,5-a]pyrimidine. ' ‘7‘.'."'«-"5:'f""£'l .Fl‘."u‘v‘5 ‘ ' 5'." “ -.-.. ”.4 fl £61.: 81 Analysis. Calculated for C12H18N60: C, 55.8; H, 6.2; N, 32.3. Found: C, 58.3; H, 7.2; N, 32.3. The remainder of the material was dissolved in 150 m1. of water and the solution adjusted to pH 2 with cold concentrated hydrochloric acid. The suspension was heated on the steam-bath until a homogenous solution was obtained and then filtered. The filtrate was allowed to cool to room temperature and the crystalline material which separated was removed by filtration. This material was recrystallized from hot water. The yield was 113.3 g. (89% of theory) of pure material, melt- ing point with decomposition 178-1790 C. Analysis. Calculated for C7H7N50: C, 87.5; H, 8.0; N, 39.5. Found: C, 87.6; H, 8.2; N, 39.8. 8-Chloro-6,7-dihydro-5H-gyclopenta[d]tetrazolo[1,5-alpyrimidine. Ten grams (0.056 mole) of 8-hydroxy-6,7-dihydro-5H-cyclopenta[d]- tetrazolo[1,5-a]pyrimidine and 13 ml. of phosphorus oxychloride were heated on a steam-bath for thirty-five minutes in a flask fitted with a drying tube. The resulting pale yellow solution was poured over crushed ice with constant stirring. The colorless precipitate which formed was collected on a filter and recrystallized from 90% ethyl alcohol. Nine and five-tenths grams (87% of theory) of 8-chloro-6,7- dihydro-5H-cyclopenta[d]tetrazolo[l,5-a]pyrimidine was isolated as colorless needles, melting point 37C C. Analysis. Calculated for C7H6N5Cl: C, 83.0; H, 3.1; N, 35.8; C1, 18.1. Found: C, 83.2; H, 3.8; N, 35.6; C1, 18.2. 82 8—Methoxy-6,7-dihydro-5H—cyclopenta[d]tetrazolo[1,5-a]pyrimidine. One and eight-tenths grams (0.08 gram atom) of freshly cut sodium was dissolved in 80 ml. of methyl alcohol. To this solution was added, in small portions with stirring, 15 g. (0.076 mole) of 8-chloro-6,7— dihydro-5H-cyclopenta[d]tetrazolo[l,5—a]pyrimidine. The reaction mix- ture was stirred and heated at reflux temperature for three hours, and then chilled. The precipitate which formed was collected by filtra- _v'u p-45] tion. The solid was recrystallized from ethyl alcohol to give 9.9 g. (63% of theory) of 8-methoxy-6,7-dihydro-5H-cyclopenta[dltetrazolo- [1,5-aipyrimidine, which melted at 187—1880 C. Analysis. ; Calculated for C8H9N50: C, 50.3; H, 8.7; N, 36.6. Found: C, 50.3; H, 8.8; N, 36.5. 8-Amino-6,Zfdihydro-5H-cyclopenta[d]tetrazolo[1,5-a]pyrimidine. Five and eight-tenths grams (0.03 mole) of 8-chloro-6,7-dihydro- 5H-cyclopenta[d]tetrazolo[1,5—a1pyrimidine was dissolved in 80 ml. of ethyl alcohol. This solution was added to 80 m1. of concentrated aqueous ammonia. The resulting red solution was allowed to stand at room temperature for three days. The solid material which separated was removed by filtration and recrystallized from 95% ethyl alcohol. The yield of 8-amino-6,7-dihydro-5H-cyclopenta[d]tetrazolo[l,5-a]pyrim- idine was 2.9 g (57% of theory). This material melted with decomposi- tion at 2270 C. Analysis. Calculated for C7H8N5: C, 87.7; H, 8.6; N, 87.7. Found: C, 87.8; H, 8.6; N, 87.6. 83 8-Dimethylamino-6,7-dihydro-5H-cyclopenta[d1tetrazoloil,5-aipyrimidine. To a solution of 8 g. (0.082 mole) of 8-chloro-6,7-dihydro-5H- cyclopenta[d]tetrazolo[1,5-a]pyrimidine in 50 ml. of ethyl alcohol was added dropwise with stirring 15 g. (0.083 mole) of 25% aqueous dimethyl- amine; a colorless precipitate formed immediately. The mixture was chilled and the solid removed by filtration. The solid was recrystal- lized from 80% ethyl alcohol to give 7.9 g. (91% of theory) of 8-di- methylamino-6,7—dihydro-5H-cyclopenta[d]tetrazolo[l,5—a]pyrimidine, melting point 191C C. Analysis. Calculated for chIZNS: c, 52.9; H, 5.9; N, 81.2. Found: C, 53.1; H, 6.0; N, 81.1. 8-Diethylamino-6,7—dihydro-5H—cyclopenta[thetrazolo[1,5-alpyrimidine. Eleven grams (0.15 mole) of diethylamine was added with stirring to a solution of 15 g. (0.076 mole) of 8-chloro-6,7-dihydro-5H—cyclo- penta[d]tetrazolo[1,5-a]pyrimidine in 70 m1. of ethyl alcohol. The reaction mixture was stirred and heated at reflux temperature for two hours, evaporated to dryness and the residue recrystallized from ethyl alcohol. Thirteen and three—tenths grams (76% of theory) of 8—diethyl- amino-6,7-dihydro-5H-cyclopenta[d]tetrazolo[1,5-a1pyrimidine was iso- lated. After drying at 1000 C., the product melted at 135-136C C. Analysis. Calculated for C11H16N6: C, 56.9; H, 6.9; N, 36.2. Found: C, 56.9; H, 7.1; N, 36.2. {.13} _‘.l A 88 8-Dia1lylamino-é,7—dihydro-5H-cyclopenta[d]tetrazolo[1,5;a]pyrimidine. Fourteen and seven-tenths grams (0.15 mole) of diallylamine was added with stirring to a solution of 15 g. (0.076 mole) of 8-chloro- 6,7—dihydro—5H-cyclopenta[d]tetrazolo[1,5-a]pyrimidine in 70 m1. of ethyl alcohol. The mixture was allowed to stand at room temperature for twenty-four hours. The residue left after evaporating the solvent from the reaction mixture was recrystallized from ethyl alcohol to give 8.8 g. (85% of theory) of 8-dia11ylamino-6,7-dihydro—5H-cyclo- penta[d1tetrazolo[1,5-a]pyrimidine, melting point 93-98C C. . 4 Analysis. Calculated for C13H16N6: C, 60.9; H, 6.3; N, 32.8. Found: C, 61.0; H, 6.8; N, 32.8. 8-Di—nepgppylamino-6,7-dihydro-5H-cyclgpenta[d]tetrazolo[1,5-alpyrimidine. Six and three-tenths grams (0.032 mole) of 8-chloro-6,7-dihydro- 5H-cyclopenta[d]tetrazolo[1,5-a1pYrimidine was dissolved in 25 ml. of ethyl alcohol. To this solution was added 3.2 g. (0.068 mole) of di— _D-propylamine in 25 ml. of ethyl alcohol. The mixture was heated at reflux temperature for two hours and then evaporated to dryness. The residue was recrystallized from ethyl alcohol to give 2.7 g. (53% of theory) of 8-di-g-propylamino-6,7-dihydro-5H-cyclopenta[d]tetrazolo- [1,5-a1pyrimidine which melted at 1180 C. Analysis. Calculated for C13H20N6: C, 60.0; H, 7.7; N, 32.3. Found : C, 60.1; H, 7.8; N, 32.3. 8S 8-(Bis—2’-hydroxyethylamino)—6,7-dihydro-5H—cyc1openta[d]tetrazolo- [1,5-a]pyrimidine. To a solution of 15.3 g. (0.077 mole) of 8-chloro-6,7-dihydro-5H- cyclopenta[d]tetrazolo[1,5-a1pyrimidine in 50 m1. of ethyl alcohol was added with stirring a solution of 16.2 g. (0.15 mole) of diethanolamine in 20 m1. of ethyl alcohol. The reaction mixture was stirred and heated at reflux temperature for thirty minutes. The product separated as a crystalline solid after chilling the reaction mixture for twelve hours and was collected on a filter. The solid was recrystallized from 50% ethyl alcohol to give 12.8 g. (61% of theory) of 8-(bis—2'-hydroxy- lfli'af-r“ 3.51:? k, A :;4 ethylamino)-6,7-dihydro-5H-cyclopenta[d]tetrazolo[1,5-a]pyrimidine, melting point 1510 c. Analysis. Calculated for C11H16N602: C, 50.0; H, 6.1; N, 31.8. Found: C, 50.1; H, 6.8; N, 31.8. 8-(3-Diethylaminopropylamino)-6,7-dihydro-5H-cyclopenta[dltetrazolo— [l,5-a]pyrimidine. To a solution of 7 g. (0.035 mole) of 8-chloro-6,7-dihydro-5H- cyclopenta[d]tetrazolo[1,5-a]pyrimidine in 50 ml. of ethyl alcohol was added with stirring 8.6 g. (0.07 mole) of 3-diethylaminopropylamine in 20 m1. of ethyl alcohol. The solution was heated on a steam-bath for thirty minutes, chilled for twenty—four hours, and the resulting precipitate collected on a filter. The solid was recrystallized from ethyl alcohol to give 5.7 g. (59% of theory) of pure material, which melted at 1690 C. ho Analysis. Calculated for C14H23N7: C, 58.1; H, 8.0; N, 33.9. Found: C, 58.1; H, 8.1; N, 33.8. 8-(3’-Bis-2-Hydroxyethylaminopropylamino)-6,7-dihydro-5H-cyclopenta- [d]tetrazolo[1,5-alpyrimidine. Fifteen grams(0.076 mole) of 8-chloro-6,7-dihydro-5H-cyclopenta- [d]tetrazolo[1,5—aiPYrimidine was added to a solution of (0.076 mole) of 3-bis-2'-hydroxyethylaminopropylamine in 85 ml. of ethyl alcohol. The reaction mixture was heated at reflux temperature and stirred for one hour. The solution was reduced to one-half its volume by evapora- tion and made basic with an aqueous solution of potassium hydroxide. Fifty milliliters of acetone was then added and the soluble material removed by filtration. The filtrate was chilled and the resulting precipitate was collected on a filter. The solid was recrystallized from ethyl alcohol to give lh.l g. (58% of theory) of 8-(3'—bis—2- hydroxyethylamino)~6,7-dihydro-5H-cyclopenta[d]tetrazolo[1,5-a)pyrim- idine, melting point 121;0 C. Analysis. Calculated for C14H23N702: C, 52.3; H, 7.2; N, 30.5. Found: C, 52.2; H, 7.2; N, 30.b. 8-(3'-Bis-2—chloroethylaminopropylamino)-6,7-dihydro-5H-cyclopenta[d]- tetrazolo[l,5—a]pyrimidinefidihydrochloride. To 30 ml. of thionyl chloride (Eastman white label) was added 10 g. (0.031 mole) of 8—(3'-bis-2-hydroxyethylaminopropylamino)-6,7— dihydro-SH-cyclopenta[dltetrazolo[1,5—alpyrimidine. After the evolu- tion of gases ceased the mixture was allowed to stand at room temperature A7 for thirty minutes and was then heated on a steam-bath for ten minutes. The excess thionyl chloride was removed in vagug. The residue was washed first with dry chloroform, then with ether. The insoluble ma- terial was dissolved in ethyl alcohol, treated with Norit-A, chilled and the clear solution diluted with ether until turbid. The white powder which separated on standing in the refrigerator was removed by filtration and dried to give 10.6 g. (80% of theory) of pure product, melting point 1610 c. Analysis. Calculated for C14H22N7Cl4: C, 39.1; H, 5.2; N, 22.8; Cl, 33.0. Found: C, 39.2; H, 5.h; N, 22.9; C1, 32.9. 8-(3-iso-Propoxy-n-propylamino)—6,7-dihydro-5H-cyclqpenta[d]tetrazolo- [l,5-a]pyrimidine. To 13 g. (0.069 mole) of 8-chloro-6,7—dihydro-5H—cyclopenta[d]- tetrazolo[l,5—a]pyrimidine in 75 m1. of ethyl alcohol was added with stirring 16 g. (0.138 mole) of 3iisg-propoxypr0pylamine. The mixture was heated at reflux temperature for two and one-half hours. Then 200 ml. of water was added to the mixture and, after chilling for sixteen hours, the precipitate that formed was collected by filtration and recrystallized from ethyl alcohol. The yield of pure material was 13.2 g. (69% of theory), melting point 1750 C. Analysis. Calculated for C13H20N60: C, 56.5; H, 7.3; N, 30.h. Found: C, 56.5; H, 7.3; N, 30.5. (’1 4 '04 [”mlm..n ‘9'“. ' 5...: “19"»! h8 8-(2-Methoxyethylamino)-6,7-dihydro-5H-cyclopenta[d]tetrazolo[l,5-a]- pyrimidine. Seven grams (0.035 mole) of 8-chloro-6,7-dihydro-5H-cyclopenta- [d]tetzazolo[l,5-alpyrimidine was dissolved in 50 ml. of ethyl alcohol. To this solution was added with stirring 8 g. (0.07 mole) of 65% aqueous 2-methoxyethylamine. This mixture was heated at reflux temper- ature and stirred for two hours, evaporated to dryness and the result- ing residue recrystallized from 95% ethyl alcohol. The yield of 8- (2-methoxyethylamino)-6,7-dihydro-5H-cyclopenta[d]tetrazolo[l,5-a]pyrim- i idine was 6.b g. (78% of theory); this material melted with decomposi- tion at 1990 C. Analysis. Calculated for C10H14N60: C, 51.3; H, 6.0; N, 35.9. Found: C, 51.2; H, 6.2; N, 35.9. 8-(3-Methoxypropylamino)-6,7-dihydro-5H-cyclopenta[d]-tetrazolo[l,5-a]- pyrimidine. To lb g. (0.071 mole) of 8-chloro—6,7-dihydro-5H—cyclopenta[d]- tetrazolo[1,5-alpyrimidine in 75 ml. of ethyl alcohol was added with stirring a solution of l2.h g. (0.1b mole) of 3-methoxypropylamine in 25 ml. of ethyl alcohol. The reaction mixture was heated at reflux temperature and stirred for two and one—half hours, 200 ml. of water added and chilled for sixteen hours. The colorless precipitate that formed was removed by filtration and recrystallized from 95% ethyl alcohol. Fight and six-tenths grams (h3% of theory) of 8-(3-methoxy- prOpylamino)-6,7-dihydro-5H-cyclopenta[d]tetrazolo[l,5—aJPYrimidine was isolated, melting point 181.5-182O C. L9 Analysis. Calculated for C11H16N60: C, 53.2; H, 6.5; N, 33.9. Found: C, 53.h; H, 6.h; N, 33.9. 8-Piperigyl-6,7-dihydro-5H-cyclopenta[d]tetrazolo[1,5-a1pyrimidine. Eleven grams (0.056 mole) of 8-chloro-6,7-dihydro-5H-cyclopenta- [d]tetrazolo[1,5-alpyrimidine was dissolved in 100 ml. of ethyl alcohol. To this solution was added 9.5 g. (0.11 mole) of piperidine in 50 ml. of ethyl alcohol. The mixture was stirred and heated at reflux temper— ature for two hours. The reaction mixture was then chilled, 200 m1. of water added and the resulting colorless precipitate collected by _____-_. - _--. . ‘TTT-Tr‘t '7‘." ‘7.— . wrung . . filtration. The product was recrystallized from ethyl alcohol. Nine and two-tenths grams (68% of theory) of 8-piperidyl-6,7—dihydro-5H- cyclopenta[d]tetrazolo[1,5-a)pyrimidine was isolated, melting point leO C. Analysis. Calculated for C12H16N6: C, 59.0; H, 6.6; N, 3h.b. Found: C, 59.1; H, 6.8; N, 3b.7. 8—Eyrrolidyl-6,7-dihydro-5H-cyclopenta[d]tetrazolo[1,5-a1pyrimidine. Eleven grams (0.056 mole) of 8-chloro-6,7-dihydro-5H-cyclopenta- [d]tetrazolo[1,5—alpyrimidine was dissolved in 150 ml. of ethyl alcohol and to this solution was added with stirring 7.1 g. (0.11 mole) of pyrrolidine in 50 ml. of ethyl alcohol. The mixture was stirred at reflux temperature for two hours, cooled to room temperature and the solid that formed was collected by filtration. The solid material was recrystallized from a mixture of equal volumes of ethyl alcohol and chloroform. Ten and two-tenths grams (80% of theory) of product was 50 isolated; it melted with decomposition at 2300 C. Analysis. Calculated for CllHine‘ C, 57.h; H, 6.1; N, 36.5. Found: C, 57.b; H, 6.1; N, 36.3. 8-Morpholiny1-6,7—dihydro-5H-cyclopenta[d]tetrazolo[1,5-a]pyrimidine. To 9.3 g. (0.0b7 mole) of 8-chloro-6,7-dihydro—5H—cyclopenta[d]- tetrazolo[l,5-a]pyrimidine in 100 m1. of 95% ethyl alcohol was added with stirring 8.1 g. (0.09b mole) of morpholine in 50 m1. of 95% ethyl alcohol. After several minutes a colorless precipitate separated. The mixture was stirred at reflux temperature for three hours, diluted with 150 ml. of water, chilled for forty—eight hours and the precipi- tate which separated was collected on a filter. The crude material was recrystallized from a 3:2 ethyl alcohol-chloroform mixture to give 9.1 g. (78% of theory) of 8—morpholinyl—6,7—dihydro-5H-cyc10penta[d]- tetrazolo[l,5-a]pyrimidine, which melted with decomposition at 2070 C. Analysis. Calculated for C11H14N60: C, 53.6; H, 5.7; N, 3h.1. Found: C, 53.9; H, 5.8; N, 3h.l. 8-Mercapto-6,7-dihydro—5H-cyclopenta[d]tetrazolo[1,5-a1pyrimidine. Seven and one-tenths grams (0.036 mole) of 8-chloro-6,7-dihydro- 5H-cyclopenta[d]tetrazolo[l,5-a]pyrimidine was dissolved in 100 ml. of ethyl alcohol. To this solution was added 2.7 g. (0.036 mole) of thiourea. The mixture was heated at reflux temperature for four hours. At the end of this time 1.h g. (0.036 mole) of sodium hydroxide dis- solved in 20 m1. of water was slowly added and the mixture was heated at reflux temperature an additional thirty minutes. The solution was . st.» l'i. a .. I‘m—...! - “C, DAV nah: K0. —. u 51 chilled and adjusted to pH 2 with cold concentrated hydrochloric acid. The yellow precipitate which formed was collected on a filter and the filtrate evaporated to dryness. The residue obtained by evaporation of the filtrate was dissolved in dilute sodium hydroxide and precipi- tated by the addition of cold concentrated hydrochloric acid. The solid was collected on a filter, combined with the first isolated yellow solid, redissolved in dilute sodium hydroxide and reprecipitated by the addition of cold concentrated hydrochloric acid. The yield of 8-mercapto-6,7-dihydro-5H-cyclopenta[dltetrazolo[1,5—alpyrimidine was 5.1 g. (7h% of theory); it melted with decomposition at 1830 C. Analysis. Calculated for C7H7NSS: C, b3.5; H, 3.7; N, 36.2; S, 16.6. Found: C, h3.5; H, 3.7; N, 36.b; S, 16.6. 8—Benzylthio—6,7—dihydro—5H-cyclopenta[d]tetrazolo[1,5-a]pyrimidine. One gram (0.0b gram atom) of freshly cut sodium was dissolved in 50 ml. of ethyl alcohol. When the last trace of sodium had dissolved, 5 g. (0.0h mole) of a—toluenethiol was added. This solution was added from a drOpping funnel, over a period of fifteen minutes, to 8 9. (0.0L mole) of 8-chloro-6,7-dihydro-5H-cyclopenta[d]tetrazolo[1,5-a]pyrimidine dissolved in 100 ml. of ethyl alcohol. 0n addition of the sodium benzyl mercaptide the solution became red. As the mercaptide was consumed the solution became pink while a colorless precipitate formed. The mixture was stirred at room temperature for one hour. The solution was evapor- ated to dryness and the residue was extracted with ethyl acetate. The clear filtrate was chilled. The solid that separated was collected by filtration and recrystallized from a mixture of ethyl alcohol and ethyl ‘n‘b Q—a‘“ emotf . a ililluzdilnll i ..ili‘lll er 2C. acetate. The yield of pure material was 7.8 g. (69% of theory), melt- ing point 90C C. Analysis. Calculated for C14H13NSS: C, 59.3; H, h.6; N, 2h.7; S. 11.3. Found: C, 59.3; H, h.7; N, 2b.7; S, 11.h. 8—Allylthio—6,7—dihydro-5ngyclopenta[dltetrazolo[1,5-alpyrimidine. r | Five and one-tenth grams (0.026 mole) of 84mrcqfixr6,7-dihydro-5H— cyclopenta[dltetrazolo[1,5—alpyrimidine was dissolved in a mixture of 50 ml. of acetone. 10 ml. of water and 1.5 g. (0.026 mole) of potassium hydroxide. After the addition of 6.2 g. (0.052 mole) allyl bromide "nflwm Dunn—mzwr‘v’ v-A, _ a v a - '- ‘ . ~ . . II. to the mixture, it was heated at reflux temperature for six hours. At the end of this period 5 g. of allyl bromide, 20 m1. of acetone and 5 ml. of water were added and the mixture heated an additional eighteen hours. The solution was evaporated to dryness, the residue washed with water and the solid material collected on a filter. The solid was recrystallized from 80% ethyl alcohol to give 2.b g. (h0% of theory) of 8-a11y1thio—6,7—dihydro-5H—cyclopenta[d]tetrazolo[1,5-alpyrimidine, melting point 603 C. 8153. F :5 Calculated for chH11N53: c, 51.5; H, u.8; N, 30.0; s, 13.7. Found: C, 51.6; H, 5.0; N, 29.8; S, 13.9. L—Hydroxy-2-methylthio-5,6-trimethylenepy:imidine. To a solution of 12 g. (0.215 mole) of potassium hydroxide in 150 ml. of water was added 23 g. (0.107 mole) of 2-methyl-2—thiopseudourea iodide, 17 g. (0.107 mole) of 2-carbethoxycyclopentanone and 50 ml. of ethyl alcohol. The mixture was shaken and allowed to stand at room 53 temperature for seventy-two hours. At the end of this time a precipi- tate was removed by filtration. The filtrate was made acidic to litmus paper with cold concentrated hydrochloric acid. A white precipitate formed and was collected on a filter. The solid was recrystallized from ethyl alcohol to give 2 g. (10% of theory) of b-hydroxy-2—methyl— thio-5,6-trimethylenepyrimidine, which melted with decomposition at 270° C. Curd, Richardson and Fose (17) reported this compound to melt at 270-2720 C. and Ross Goodman and Baker (13) reported it to melt and ) decompose at 2711-276O C. Q h-Hydioxy-2—hydrazino—5,6-trimethylenepyrimidine. aux-sans! : in v A a!» A mixture of l g. (0.005 mole) of b-hydroxy-Z—methylthio-5,6—tri— methylenepyrimidine, 1.8 g. (0.005 mole) of 95% anhydrous hydrazine and 20 ml. of ethyl alcohol was heated at reflux temperature for twenty hours. At the end of this period the mixture was chilled and the crystalline material which separated was collected on a filter. The c'ude material was recrystallized from 95% ethyl alcohol to give 0.5 g. (63% of theory) of h-hydroxy-2-hydrazino-5,6-trimethylenepyrimidine, which melted with decomposition at 253° C. Libermann and Rouaix (lb) reported this compound to melt at 255—2560 C. Analysis. Calculated for C7H10N40: C, 50.6; H, 6.1; N, 33.7. Found : C, 50.8; H, 6.1; N, 33.8. Diazotization of 2—hydrazinopyrimidine. ‘8:Hydroxy-6,7~dihydro~5H~cyclopenta[dltetrazolo[1,5-alpyrimidine. One and four-tenths grams (0.008 mole) of h—hydroxy-2-hydrazino— 5,6-trimethylenepyrimidine was dissolved in 2 ml. of concentrated Sh hydrochloric acid in 10 ml. of water. The solution was stirred in an ice bath and saturated sodium nitrite solution was added until the first excess of nitrous acid was indicated by the starch-potassium iodide endpoint. After fifteen minutes of stirring the mixture was made basic by the addition of solid sodium carbonate to pH 8. The ice bath was removed and the mixture was allowed to stand at room temper- ('- ature for one hour. At the end of this time the mixture was made ; acidic to litmus paper by the addition of hydrochloric acid, chilled .“"E"J "n .. )"C- _' and the crystalline material which separated removed by filtration. The product was recrystallized from water, melting point 1780 C. (dec). {tkfii‘vm ‘14."... Mixture melting point and infrared spectrum indicated this product to be identical with the product obtained from the condensation of the piperi- dinium salt of 5—aminotetrazole and 2-carbethoxycyclOpentanone. SUMMARY An increase in the yield of two hydroxytetrazolopyrimidines has been accomplished by using an equimolar quantity of piperidine in place of a catalytic amount in the procedure of Brady and Herbst. A new hydroxytetrazolopyrimidine has been prepared, 8-hydroxy-6,7- dihydro-SH-cyclopenta[d]tetrazolo[l,S—a]pyrimidine. f ' The hydroxytetrazolopyrimidines have been converted into chloro- tetrazolopyrimidines. Three series of substituted tetrazolopyrimidines have been prepared by displacement reactions with the chlorotetrazolopyrimidines, where L“. the chlorine has been replaced by a methoxy, mercapto, benzylthio, allylthio, amine and variety of secondary and tertiary amino groups. Most of the substituted tetrazolopyrimidines prepared have been submitted for screening as cancer antimetabolites and central ner- vous stimulants. SS 10. ll. 12. 13. lb. 15. 16. 1?. LITERATURE CITED Mathews, A. P. "Physiological Chemistry," The Williams and Wilkins Co., New York, 1939, ed. 6, p. l52-lSh. Elion, G. B5, 3. Singer, G. Hitchings, M. E. Balis and.G. B. Brown, J. Biol. Chem., ggg, 6h7(l953). Lyttle, D. A. and H. G. Petering, J. Am. Chem. Soc., ég, 6b59(l958). Wooley, D. W. and E. Shaw, J. Biol. Chem., lég, hOl(l9Sl). Roblin, R. 0., J. O. Lampen Jr., J. P. English, Q. P. Cole and J. R. vaughan, J. Am. Chem. Soc., él, 290(l9b5). Wooley, D. W. J. Biol. Chem., gig, 225(l9hb). : Bfilow, C., Ber., g3, bb29(l909). Bower, J. D. and F. P. Doyle, J. Chem. Soc., 727(1957). Brady, L. E. and R. M. Herbst, J. Org. Chem., 2g, 922-6(1959). Stolle, R. and O. Orth, Ber., fig. 2100(1925). Henry, R. A. and W. G. Finnegan, J. Am. Chem. 300., Zé, 926(19Sb) Henry, R. A., J. Am. Chem. Soc., 15, 6303(1952). Ross, L. 0., L. Goodman and B. R. Baker, J. Am. Chem. Soc., El 3108(1959)- Libermann, D. and A. Rouaix, Compt. rend., Egg, 98h-6(l95b). 3 Gabriel, 3. and J. Colman, Ber.,‘ig, 2921(1899). Kano, H. and Y. Makisumi, Chem. and Pharm. Bull. (Tokyo), é, 583-6(l958)- Curd, F. H. s. D. N. Richardson and F. L. Rose, J. Chem. Soc., 378(19u63. :fi—‘uM-‘g saw-.... I... u». .A - ui. g . .. Human ._ 3.". ”éjifl‘. 4 _‘ m ‘ CHEMISTRY Lmnmy 75 5550 1293 03 IIvlnlluwmmWWWWill