CS241476B2

CS241476B2 - Method of substituted n-5-tetrazolyl-1-oxo-1h-thiazolo- (3,2-a )pyrimidine-2-carboxamides production

Method of substituted n-5-tetrazolyl-1-oxo-1h-thiazolo- (3,2-a )pyrimidine-2-carboxamides production Download PDF

Info

Publication number: CS241476B2
Authority: CS; Czechoslovakia
Prior art keywords: pyrimidine; oxo; mmol; heated; ethyl
Prior art date: 1979-11-23

Application number

CS807820A

Other languages

Czech (cs)

English (en)

Other versions

CS782080A2 (en

Inventor

Saul B Kadin

Original Assignee

Pfizer

Priority date

1979-11-23

Filing date

1980-11-18

Publication date

1986-03-13

1980-11-18 Application filed by Pfizer filed Critical Pfizer

1985-06-13 Publication of CS782080A2 publication Critical patent/CS782080A2/cs

1986-03-13 Publication of CS241476B2 publication Critical patent/CS241476B2/cs

Links

238000000034 method Methods 0.000 title claims description 28
238000004519 manufacturing process Methods 0.000 title description 6
-1 carbophenoxy Chemical group 0.000 claims abstract description 93
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 84
150000003839 salts Chemical class 0.000 claims abstract description 24
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 19
239000001257 hydrogen Substances 0.000 claims abstract description 13
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
125000000217 alkyl group Chemical group 0.000 claims abstract description 7
230000008569 process Effects 0.000 claims description 15
238000002360 preparation method Methods 0.000 claims description 2
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
150000001875 compounds Chemical class 0.000 abstract description 56
239000002253 acid Substances 0.000 abstract description 41
150000007513 acids Chemical class 0.000 abstract description 17
239000000543 intermediate Substances 0.000 abstract description 15
230000003266 anti-allergic effect Effects 0.000 abstract description 10
239000000043 antiallergic agent Substances 0.000 abstract description 6
125000002947 alkylene group Chemical group 0.000 abstract description 5
239000003699 antiulcer agent Substances 0.000 abstract description 3
230000004071 biological effect Effects 0.000 abstract description 2
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 abstract 1
150000002431 hydrogen Chemical group 0.000 abstract 1
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 175
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 102
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 102
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
239000011541 reaction mixture Substances 0.000 description 72
239000000243 solution Substances 0.000 description 69
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 68
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239000000047 product Substances 0.000 description 61
229910052757 nitrogen Inorganic materials 0.000 description 60
229910052799 carbon Inorganic materials 0.000 description 59
239000012043 crude product Substances 0.000 description 58
238000001914 filtration Methods 0.000 description 48
238000001953 recrystallisation Methods 0.000 description 46
238000004458 analytical method Methods 0.000 description 45
FUXJMHXHGDAHPD-UHFFFAOYSA-N pyrimidine-2-carboxamide Chemical class NC(=O)C1=NC=CC=N1 FUXJMHXHGDAHPD-UHFFFAOYSA-N 0.000 description 45
ZFCHNZDUMIOWFV-UHFFFAOYSA-N pyrimidine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=N1 ZFCHNZDUMIOWFV-UHFFFAOYSA-N 0.000 description 44
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 43
ZFCHNZDUMIOWFV-UHFFFAOYSA-M pyrimidine-2-carboxylate Chemical compound [O-]C(=O)C1=NC=CC=N1 ZFCHNZDUMIOWFV-UHFFFAOYSA-M 0.000 description 39
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
238000006243 chemical reaction Methods 0.000 description 35
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230000000694 effects Effects 0.000 description 30
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239000002904 solvent Substances 0.000 description 26
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 25
UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 24
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239000004480 active ingredient Substances 0.000 description 22
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239000000126 substance Substances 0.000 description 21
ULRPISSMEBPJLN-UHFFFAOYSA-N 2h-tetrazol-5-amine Chemical compound NC1=NN=NN1 ULRPISSMEBPJLN-UHFFFAOYSA-N 0.000 description 20
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208000025865 Ulcer Diseases 0.000 description 18
LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 18
238000012360 testing method Methods 0.000 description 18
238000010438 heat treatment Methods 0.000 description 17
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
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238000007792 addition Methods 0.000 description 16
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239000007788 liquid Substances 0.000 description 14
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 14
231100000397 ulcer Toxicity 0.000 description 14
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 13
239000002775 capsule Substances 0.000 description 13
238000007363 ring formation reaction Methods 0.000 description 13
NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 12
150000001408 amides Chemical class 0.000 description 12
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
150000002148 esters Chemical class 0.000 description 11
238000001704 evaporation Methods 0.000 description 11
238000004809 thin layer chromatography Methods 0.000 description 11
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
239000003153 chemical reaction reagent Substances 0.000 description 10
238000011282 treatment Methods 0.000 description 10
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 9
239000000427 antigen Substances 0.000 description 9
102000036639 antigens Human genes 0.000 description 9
108091007433 antigens Proteins 0.000 description 9
230000006378 damage Effects 0.000 description 9
238000000354 decomposition reaction Methods 0.000 description 9
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 8
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 8
239000000908 ammonium hydroxide Substances 0.000 description 8
238000001816 cooling Methods 0.000 description 8
230000008020 evaporation Effects 0.000 description 8
230000005764 inhibitory process Effects 0.000 description 8
150000002500 ions Chemical class 0.000 description 8
239000003921 oil Substances 0.000 description 8
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159000000000 sodium salts Chemical class 0.000 description 8
210000002784 stomach Anatomy 0.000 description 8
239000003826 tablet Substances 0.000 description 8
JVSMPWHQUPKRNV-UHFFFAOYSA-N 2h-tetrazol-5-amine;hydrate Chemical compound O.NC=1N=NNN=1 JVSMPWHQUPKRNV-UHFFFAOYSA-N 0.000 description 7
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208000026935 allergic disease Diseases 0.000 description 7
150000001412 amines Chemical class 0.000 description 7
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230000000767 anti-ulcer Effects 0.000 description 7
238000009835 boiling Methods 0.000 description 7
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DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
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230000036783 anaphylactic response Effects 0.000 description 6
150000008064 anhydrides Chemical class 0.000 description 6
238000003556 assay Methods 0.000 description 6
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
239000003085 diluting agent Substances 0.000 description 6
229960001340 histamine Drugs 0.000 description 6
125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
239000011734 sodium Substances 0.000 description 6
229910052708 sodium Inorganic materials 0.000 description 6
RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 5
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
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238000001990 intravenous administration Methods 0.000 description 5
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125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
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RZZPDXZPRHQOCG-OJAKKHQRSA-O CDP-choline(1+) Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 RZZPDXZPRHQOCG-OJAKKHQRSA-O 0.000 description 4
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241000282412 Homo Species 0.000 description 4
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USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
238000004090 dissolution Methods 0.000 description 4
231100000673 dose–response relationship Toxicity 0.000 description 4
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239000007924 injection Substances 0.000 description 4
238000002347 injection Methods 0.000 description 4
238000002955 isolation Methods 0.000 description 4
239000008101 lactose Substances 0.000 description 4
229960001375 lactose Drugs 0.000 description 4
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
238000000746 purification Methods 0.000 description 4
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QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
210000002966 serum Anatomy 0.000 description 4
150000003512 tertiary amines Chemical class 0.000 description 4
230000036269 ulceration Effects 0.000 description 4
210000002700 urine Anatomy 0.000 description 4
HNOGSSUZDLBROJ-UHFFFAOYSA-N 5-ethyl-1,3-thiazol-2-amine Chemical compound CCC1=CN=C(N)S1 HNOGSSUZDLBROJ-UHFFFAOYSA-N 0.000 description 3
GUABFMPMKJGSBQ-UHFFFAOYSA-N 5-methyl-1,3-thiazol-2-amine Chemical compound CC1=CN=C(N)S1 GUABFMPMKJGSBQ-UHFFFAOYSA-N 0.000 description 3
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 3
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MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 3
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FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 3
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125000004429 atom Chemical group 0.000 description 3
IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 3
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UZKJVTMKNCSEDS-UHFFFAOYSA-N diethyl 2-[[(4-butan-2-yl-1,3-thiazol-2-yl)amino]methylidene]propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)=CNC1=NC(C(C)CC)=CS1 UZKJVTMKNCSEDS-UHFFFAOYSA-N 0.000 description 3
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 3
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