CN87104388A - The method for preparing mercapto-acylproline - Google Patents
The method for preparing mercapto-acylproline Download PDFInfo
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- CN87104388A CN87104388A CN198787104388A CN87104388A CN87104388A CN 87104388 A CN87104388 A CN 87104388A CN 198787104388 A CN198787104388 A CN 198787104388A CN 87104388 A CN87104388 A CN 87104388A CN 87104388 A CN87104388 A CN 87104388A
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- salt
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- thiocarbamide
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- 238000000034 method Methods 0.000 title claims abstract description 18
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 14
- -1 salt compound Chemical class 0.000 claims abstract description 11
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 125000005843 halogen group Chemical group 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 125000001475 halogen functional group Chemical group 0.000 claims abstract description 4
- 230000005540 biological transmission Effects 0.000 claims abstract 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 2
- 230000003276 anti-hypertensive effect Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 10
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 9
- 229960000830 captopril Drugs 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 4
- 238000009834 vaporization Methods 0.000 description 4
- 230000008016 vaporization Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 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 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JQZIKLPHXXBMCA-UHFFFAOYSA-N triphenylmethanethiol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(S)C1=CC=CC=C1 JQZIKLPHXXBMCA-UHFFFAOYSA-N 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- BUPXDXGYFXDDAA-UHFFFAOYSA-N 3-bromo-2-methylpropanoic acid Chemical compound BrCC(C)C(O)=O BUPXDXGYFXDDAA-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 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 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 208000034809 Product contamination Diseases 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- UIJGNTRUPZPVNG-UHFFFAOYSA-N benzenecarbothioic s-acid Chemical compound SC(=O)C1=CC=CC=C1 UIJGNTRUPZPVNG-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-M hydrosulfide Chemical compound [SH-] RWSOTUBLDIXVET-UHFFFAOYSA-M 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000035924 thermogenesis Effects 0.000 description 1
- 229920001187 thermosetting polymer Polymers 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to the 1-[3-sulfydryl of a kind of preparation following formula (I)-(2S)-first propionyl]-tetramethyleneimine-(2S)-carboxylic acid, or it has the novel method of the pharmaceutically acceptable salt of valuable antihypertensive active.According to the present invention; make ω-halo acyl group proline(Pro) of III; wherein X represents halogen; or its salt and the isothiourea salt compound of thiocarbamide reaction generation II in organic dipolar aprotic transmission solvent or its hydrohalogen; this compound also can be hydrolyzed at after separating, and can make the product of formula I change salt in case of necessity or disengage from salt.
Description
The present invention relates to a kind of 1-[3-sulfydryl of preparation following structural-(2S)-first propionyl]-tetramethyleneimine-(2S)-carboxylic acid
Or the novel method of its pharmaceutically acceptable salt.
The international captopril (captopril) that is commonly referred to as of known formula I compound, it has valuable antihypertensive active.
According to 1,576, No. 161 English Patent is described, and the fontanelle atom of halogen acyl group proline(Pro) can change sulfydryl into all ingredients.Reaction is to use negatively charged ion R-S
-(wherein R represents hydrogen, C
1-4Alkyl, phenyl-(C
1-4Alkyl), triphenyl-(C
1-2Alkyl) or structural formula be
Group, R wherein
1Represent C
1-4Alkyl or phenyl) finishes.
At different R-S
-In the negatively charged ion, have only the sulphur atom substituting group of those compounds that wherein in the halogen atom substitution reaction, form the person of being removed just to be suitable for preparing sulfenyl methyl oxy-propyl levoproline, that is it is as same blocking group.The following meaning of R belongs to this class: hydrogen, the tertiary butyl, benzyl, trityl and
, R wherein
1As above definition.
Do not speak of in the literary composition about R and represent hydrogen the simplest such situation.
If R represents the tertiary butyl, benzyl or trityl, then agents useful for same should be tert-butyl mercaptan, benzyl mercaptan or trityl mercaptan, and all these reagent all are inflammable, carcinogenic and virose compound.In order to carry out the replacement of halogen atom, the carboxyl temporary protection of proline(Pro) must be got up.In addition, the yield of this reaction is extremely low.For example, people such as K.Hofmann have described quite similar situation in benzyl mercaptan [J.Am.Chem.Soc.71,1253(1949)]: make the reaction of 4-chlorinated butyl derivative and dibenzylsulfide sodium alkoxide obtain S-benzyl-4-sulfydryl butyl derivative (productive rate is 66%); Generate nescent hydrogen by the reaction of the sodium in ethanol and remove protecting group.Therefore, ultimate production can reach 34%.Appoint with tert-butyl mercaptan and trityl mercaptan to obtain unfavorable result, because steric hindrance is much better than in both cases.In general; can in the opposite direction this class protecting group be incorporated in the molecule promptly existing sulfhydryl compound and iso-butylene or thionyl chloride reaction [T.W.Greene, Protective Groups in Organic Synthesis; p.193,1981].
If R represents formula
Group, then prepared captopril productive rate is extremely low.According to 1,576, the embodiment of No. 161 English Patents can make similar 1-(2-sulfydryl acetyl with thiobenzoic acid)-proline(Pro), the productive rate that calculates the gained proline(Pro) can be low to moderate 15%.
2,065, No. 643 English Patent has been described this situation, and wherein R represents hydrogen: make N-[3-halo-(2S)-first propionyl]-(S)-proline(Pro) and sodium sulfhydrate reaction.Add the thermosetting reaction product through the long period; Yet the amount of the corresponding disulphide that is produced is 5 mol %.This by product must reduce with zinc with an independent step under sour existence condition.Output is 71%.If sodium sulfhydrate is dissolved in N, in the dinethylformamide, then above-mentioned productive rate reduces to 65%.In fact, can obtain optimum, yet the by product of reaction product and appearance can only be separated with column chromatography with the hydrosulfide of ammonia aqueous solution.Also can obtain 92% captopril in this way, the mixture of 6% disulphide and 0.5% symmetrical sulfide.The latter is irreversible by by-product contamination, and promptly it can not be converted into captopril.In addition, the solubleness of this sulfide approaches the solubleness of captopril; Therefore, can not they be separated with simple preparation method.The above fact [Chem.Pharm.Bull., 30,3129(1982)] further affirmed in people's such as M.Shimazaki article.Therefore, a kind of method in back is unsuitable for plant-scale production.
According to 4,332, No. 725 United States Patent (USP) is described, and available Sulfothiorine is converted into mercapto groups with fontanelle atom.In this case, at first form so-called Bunte salt, add the thermogenesis captopril with concentrated hydrochloric acid then, its productive rate is 70%.
According to disclosed No. 3526023 German patent applications, under 60-100 ℃, make N-[3-halo-(2S)-first propionyl]-(S)-proline(Pro) is at water, produces following formula: compound with the thiocarbamide reaction in alkanol or the moisture alkanol
Wherein X represents halogen atom.This compound is in reaction mixture, during without separation, promptly with alkali metal hydroxide or carbonate hydrolysis.
Yet, reproduce back-currently known methods and be practically impossible.
ω-halo acyl group proline(Pro) production formula economically I compound by following structural
Wherein X represents halogen, reacts when the ω that makes the formula III-halo acyl group proline(Pro) or its salt and thiocarbamide transmit in the solvent at organic dipolar aprotic, produces the isothiuronium salts compound of following formula
Or its hydrohalogen, this compound also can be hydrolyzed at after separating, and in case of necessity, can make the product of formula I be converted into salt or disengages from salt.
The free carboxy of formula I compound can be converted into salt with inorganic or organic bases.If obtain the salt of formula I compound with method of the present invention, then available known method obtains the free carboxy acid again.
In the formula III, X represents halogen atom, preferably bromine atoms.
The reaction of formula III compound or its salt and thiocarbamide is only transmitted solvent at organic dipolar aprotic, N for example, and dinethylformamide carries out in N,N-dimethylacetamide or the dimethyl sulfoxide (DMSO).This reaction can be under atmospheric pressure, in 20-28 ℃, preferably finish for 50-70 ℃.Reaction times is generally 15-50 hour, if also use the such acid binding agent of organic bases, then forms corresponding hydrogen fontanelle compound additive salt.Necessary, can react at next step, i.e. isolate the compound of formula II before the hydrolysis.Usually the hydrogen fontanelle compound additive salt of formula II compound is still stayed in the solution, therefore, generally can make it hydrolysis without separating.
The isothiuronium salts compound of formula II or its hydrogen fontanelle compound additive salt are preferably under alkali (as the hydrazine) existence condition.In 0-30 ℃, be preferably in 10-15 ℃ and under atmospheric pressure be hydrolyzed.Available known method (as extracting and evaporation) is separated the product of formula I from reaction mixture.
The isothiuronium salts compound of formula II not only can obtain but also can be to be hydrolyzed to captopril near quantitative productive rate.Even a kind of product in back is by recrystallization, overall yield is still more than 80%.The captopril that obtains is not polluted by corresponding disulphide or symmetrical sulfide, and therefore, its purity is at least 99.5%(and records with iodimetry,iodometry).
Can further illustrate method of the present invention by following non-limiting examples.
The preparation of initial compounds:
The 1-[3-bromo-(2S)-methyl-propionyl]-tetramethyleneimine-(2S)-carboxylic acid-hydrate
With the 3.34g(0.02 mole) 3-bromo-2 Methylpropionic acid and 4.60g(0.02 mole) tetramethyleneimine=(2S)-benzyl carboxylate hydrochloride is dissolved in the 50ml anhydrous methylene chloride.Under 0 ℃ of cooling conditions, be dissolved in the triethylamine of 5ml anhydrous methylene chloride toward the middle 1.9g of adding of stirring the mixture of gained, under same temperature, add the 3.29g(0.019 mole then) N, N '-dicyclohexyl-carbodiimide (being dissolved in the 20ml methylene dichloride).Reaction mixture was stirred 2 hours down at 0 ℃, then restir 12 hours at room temperature.Mixture after the filtration hydrochloric acid of 20ml 9%, 20ml water, the sodium bicarbonate aqueous solution of 20ml5% is used the extracting of 20ml water again.Dry organic solution and evaporate it on the sal epsom that burnt obtains 6.40g(95%) faint yellow oily 1-(3-bromo-2-first propionyl)-tetramethyleneimine-(2S)-benzyl carboxylate.
Thin-layer chromatography (Tlc.) (silica gel, benzene: Glacial acetic acid=3: 1): two spots, Rf=0.44 and 0.48, being equivalent to the diastereomer ratio is 1: 1.
This oily matter is dissolved in the 60ml ethyl acetate, and in gained solution, adds the palladium/carbon catalyst of 0.6g10%.Under atmospheric pressure make reaction mixture hydrogenation till tlc. does not show the ester existence.Remove by filter catalyzer, use eluent ethyl acetate, organic solvent is removed in distillation, and water is with the residue recrystallization.In this way, can obtain 2.00g(42.5%) title compound.Fusing point: 69-72 ℃.
[α]
25 D=-88.1 ° of (C=1; Ethanol)
Embodiment 1
The 1-[3-sulfydryl-(2S)-the first propionyl]-tetramethyleneimine-(2S)-carboxylic acid
With the 10.56g(0.0374 mole) 1-[3-bromo-(2S)-first propionyl]-tetramethyleneimine-(2S)-carboxylic acid and 3.04g(0.040 mole) thiocarbamide is dissolved in 30ml N, in N '-N,N-DIMETHYLACETAMIDE.Reaction mixture was stirred 15-20 hour under 60 ℃, nitrogen environment.Organic solvent is removed in decompression, and residue is dissolved in the 50ml distilled water.In gained solution, add the 6.00g(0.12 mole at nitrogen environment) hydrazine hydrate, make the flask cooling with frozen water simultaneously.Under cooling conditions, this reaction mixture was stirred 30 minutes, then restir 30 minutes at room temperature.Add the sulfuric acid of 100ml 5%, filter out white precipitate, wash with water, use washed with dichloromethane then.Each uses 30ml methylene dichloride extracting filtrate four times, merges organic solution, and each uses the water washing twice of 20ml, and each uses the methylene dichloride extracting water twice of 15ml, merges organic phase, and is dry on the sal epsom that burnt, filtration and reduction vaporization.With 7.54g(99%) remaining oily matter from the 25ml trieline, crystallize out.In this way, can obtain 6.10g(80%) title compound.Fusing point: 104-106 ℃.
[α]
25 D=-129.5 ° of (C=2; Ethanol)
Embodiment 2
The 1-[3-sulfydryl-(2S)-the first propionyl]-tetramethyleneimine-(2S)-carboxylic acid
With the 2.64g(0.010 mole) 1-[3-bromo-(2S)-first propionyl]-tetramethyleneimine-(2S)-carboxylic acid and 0.76g(0.010 mole) thiocarbamide is dissolved in the 10ml dimethyl sulfoxide (DMSO).This solution was stirred 24 hours down at 60-70 ℃, add 30ml 10% aqueous sodium hydroxide solution then, with this mixture restir 1 hour.Hydrochloric acid with 20% under cooling conditions makes this mixture acidifying, reaches till 1 up to the pH value, uses the extracting of 4 * 20ml methylene dichloride then.Merge organic solution, dry on the sal epsom that burnt, and reduction vaporization.Crystallization goes out remaining oily matter from trieline.Obtain 1.64g(81%) title compound.Fusing point: 104-106 ℃.
[α]
25 D=-129.5 ° of (C=2; Ethanol)
Embodiment 3
The 1-[3-sulfydryl-(2S)-the first propionyl]-tetramethyleneimine-(2S)-carboxylic acid
With the 5.28g(0.02 mole) 1-[3-bromo-(2S)-first propionyl]-tetramethyleneimine-(2S)-carboxylic acid and 1.67g(0.022 mole) thiocarbamide is dissolved in 15ml N, in N '-dimethyl formamide, and under 60 ℃, compound stirred 24 hours.Organic solvent is removed in underpressure distillation, and residue is dissolved in the 30ml distilled water.Add the hydrazine of 6.0g 50% in the solution that cooled off with frozen water, stirred reaction mixture is 1 hour under the frozen water cooling conditions.Add the sulfuric acid of 50ml 5% then, leach throw out, water and washed with dichloromethane.10g sodium-chlor is added to water, and with the methylene dichloride extracting water of 4 * 30ml.Merge organic solution, dry on anhydrous magnesium sulfate, filter and removal of solvent under reduced pressure.The oily matter of remnants is crystallized out from the 20ml trieline, obtains 3.33g(82%) title compound.Fusing point: 104-106 ℃.
[α]
25 D=-129.5 ° (C=2, ethanol)
Embodiment 4
A.1-[(2S)-methyl-3-isothiuronium salts propionyl]-tetramethyleneimine-(2S)-carboxylate salt
With the 5.64g(0.02 mole) 1-[3-bromo-(2S)-first propionyl]-tetramethyleneimine-(2S)-carboxylic acid-hydrate is dissolved in the 50ml methylene dichloride, and the sal epsom that gained solution was burnt with 5g stirred 1 hour.The filtering siccative is also used the 10ml washed with dichloromethane, merges organic solution and reduction vaporization.Residue is dissolved in the anhydrous N,N-dimethylacetamide of 15ml, uses the 1.52g(0.02 mole) thiocarbamide handle and under nitrogen environment, stirred 24 hours, the flask that reaction mixture will be housed simultaneously is placed in 70 ℃ the oil bath.Cool off the dilution in acetonitrile that this mixture is also used 150ml with frozen water.In the gained mixture, under fully stirring, within 30-40 minute, dropwise adding the 2.8ml(0.02 mole) triethylamine (being dissolved in the 20ml acetonitrile).Again reaction mixture was stirred 2 hours, leaches formed throw out and be suspended in the 20ml acetonitrile, filter, be resuspended in the 20ml acetonitrile, filter and be drying to obtain 4.2g(81% afterwards) title compound.Fusing point: 187-189 ℃
[α]
25 D=-107～-111 ° of (C=1; Ethanol)
Thin-layer chromatography (6 parts of pyridines of 20: 11: 6, water and Glacial acetic acid mixture, 4 parts of acetate): Rf=0.41
(butanols, the ratio of Glacial acetic acid and water are 7: 1: 3 mixture): Rf=0.2.
B.1-[3-sulfydryl-(2S)-first propionyl]-tetramethyleneimine-(2S)-carboxylic acid
With the 2ml(0.02 mole) 50% hydrazine dropwise is added to the 2.59g(0.01 mole) 1-[(2S)-methyl-3-isothiuronium salts propionyl]-solution that tetramethyleneimine-(2S)-carboxylicesters stirred under nitrogen and frozen water cooling conditions in 25ml water in.Under cooling conditions,, remove cooling bath then and continue and stirred 30 minutes mixture restir 30 minutes.Reaction mixture is cooled to also use below 10 ℃ once more the mixture process of 2ml concentrated hydrochloric acid and 2ml water.Mixture was stirred 30 minutes, add 6-10g sodium-chlor then also with 3 * 20ml methylene dichloride extract product.Merge organic solution, use the 15ml water washing, and with 5ml methylene dichloride extracting water.Merge organic phase, dry on anhydrous magnesium sulfate, filter and reduction vaporization.Crystallization goes out the residual oily matter of 2.03g from the 10ml trieline.With normal hexane washed product and dry, obtain 1.62g(80%) title compound.Fusing point: 103-104 ℃.
[α]
25 D=-129～-130 ° of (C=2; Ethanol)
Claims (8)
1, by the ω-halo-acyl group proline(Pro) of following structural III
Wherein X represents halogen, 1-[3-sulfydryl-(2 the S)-first propionyl of preparation following structural I]-tetramethyleneimine-(2S)-carboxylic acid
Or the method for its pharmaceutically acceptable salt, wherein make the ω-halo acyl group proline(Pro) of formula III or the isothiuronium salts compound of its salt and thiocarbamide reaction generation following structural II in utmost point dipolar aprotic transmission solvent is being arranged
Or its hydrogen fontanelle compound, this compound also can be hydrolyzed at after separating, and can make the product of structural formula I change salt in case of necessity or disengage from salt.
2, method according to claim 1; wherein make the ω-halo-acyl group proline(Pro) of structural formula III or the corresponding hydrohalogen of its salt and thiocarbamide isothiuronium salts compound of reaction generation structural formula II in organic dipolar aprotic transmission solvent; also separablely go out this compound; hydrolysis then, and can make the product of structural formula I change salt in case of necessity or from salt, disengage.
3, method according to claim 1; wherein make the ω-fontanel generation-acyl group proline(Pro) of structural formula III or the isothiuronium salts compound of its salt and thiocarbamide reaction generation structural formula II in organic dipolar aprotic transmission solvent; also separablely go out this compound; hydrolysis then, and can make the product of structural formula I change salt into or obtain it again in case of necessity from salt.
4, according to each described method among the claim 1-3, wherein dipolar aprotic transmission solvent is N, dinethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide (DMSO).
5, according to each described method among the claim 1-3, wherein the reaction with thiocarbamide is under 20-80 ℃, is preferably in to carry out under 50-70 ℃.
6,, wherein under the acid binding agent existence condition, carry out with the reaction of thiocarbamide according to the method described in claim 1 or 3.
7, according to each and the described method of claim 6 among the claim 1-3, wherein the isothiuronium salts compound is hydrolyzed in the presence of hydrazine.
8, according to each and the described method of claim 6 among the claim 1-3, wherein the isothiuronium salts compound is under 0-30 ℃, is preferably in to be hydrolyzed under 10-15 ℃.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU862689A HU196959B (en) | 1986-06-27 | 1986-06-27 | Process for producing merkapto-acyl-proline derivatives |
| HU2689/86 | 1986-06-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN87104388A true CN87104388A (en) | 1988-03-02 |
Family
ID=10960651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN198787104388A Pending CN87104388A (en) | 1986-06-27 | 1987-06-24 | The method for preparing mercapto-acylproline |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS6327475A (en) |
| KR (1) | KR900007217B1 (en) |
| CN (1) | CN87104388A (en) |
| AR (1) | AR243159A1 (en) |
| AT (2) | AT395012B (en) |
| CH (1) | CH673279A5 (en) |
| CS (1) | CS276394B6 (en) |
| DD (1) | DD263757A5 (en) |
| DE (1) | DE3721430A1 (en) |
| DK (1) | DK329787A (en) |
| ES (1) | ES2004451A6 (en) |
| FI (1) | FI87770C (en) |
| GR (1) | GR871012B (en) |
| HU (1) | HU196959B (en) |
| IT (1) | IT1206792B (en) |
| NO (1) | NO168941C (en) |
| PL (1) | PL153449B1 (en) |
| PT (1) | PT85190B (en) |
| SE (1) | SE462751B (en) |
| SU (1) | SU1650007A3 (en) |
| YU (1) | YU46319B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1116871C (en) * | 1996-09-26 | 2003-08-06 | 美迪特药物有限公司 | Pharmaceutical compositions containing S-alkylisothiouronium derivatives |
| CN103086939A (en) * | 2011-10-28 | 2013-05-08 | 华中药业股份有限公司 | Recrystallization method of 1-(3-bromo-2-D-methyl propionyl)pyrrolidine-2-carboxylic acid |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE421551B (en) * | 1980-03-26 | 1982-01-04 | Sandvik Ab | DRILLING TOOL FOR ROTATION AND / OR DRILLING |
| HU208954B (en) * | 1990-09-21 | 1994-02-28 | Egyt Gyogyszervegyeszeti Gyar | Process for producing 1-(3-mercapto-(2s)-methyl-1-oxo-propyl)-l-prolyn |
| JPS62125081A (en) * | 1985-11-21 | 1987-06-06 | キングプリンテイング株式会社 | Printing method |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU509899B2 (en) * | 1976-02-13 | 1980-05-29 | E.R. Squibb & Sons, Inc. | Proline derivatives and related compounds |
| IL58849A (en) * | 1978-12-11 | 1983-03-31 | Merck & Co Inc | Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them |
| GB2065643B (en) * | 1979-12-13 | 1983-08-24 | Kanegafuchi Chemical Ind | Optically active n-mercaptoalkanoylamino acids |
| IE54551B1 (en) * | 1982-01-22 | 1989-11-22 | Ici Plc | Amide derivatives |
| KR860001391B1 (en) * | 1984-07-23 | 1986-09-22 | 보령제약 주식회사 | Method for preparing pyrrolidine derivative |
-
1986
- 1986-04-07 AT AT0091186A patent/AT395012B/en not_active IP Right Cessation
- 1986-06-27 HU HU862689A patent/HU196959B/en unknown
-
1987
- 1987-06-24 CN CN198787104388A patent/CN87104388A/en active Pending
- 1987-06-24 CH CH2372/87A patent/CH673279A5/de not_active IP Right Cessation
- 1987-06-24 YU YU118187A patent/YU46319B/en unknown
- 1987-06-26 AT AT0162087A patent/AT387381B/en not_active IP Right Cessation
- 1987-06-26 FI FI872859A patent/FI87770C/en not_active IP Right Cessation
- 1987-06-26 AR AR87307987A patent/AR243159A1/en active
- 1987-06-26 SE SE8702654A patent/SE462751B/en not_active IP Right Cessation
- 1987-06-26 ES ES8702024A patent/ES2004451A6/en not_active Expired
- 1987-06-26 CS CS874794A patent/CS276394B6/en unknown
- 1987-06-26 DK DK329787A patent/DK329787A/en not_active Application Discontinuation
- 1987-06-26 KR KR1019870006546A patent/KR900007217B1/en active Pre-grant Review Request
- 1987-06-26 GR GR871012A patent/GR871012B/en unknown
- 1987-06-26 IT IT8721085A patent/IT1206792B/en active
- 1987-06-26 SU SU874202836A patent/SU1650007A3/en active
- 1987-06-26 NO NO872690A patent/NO168941C/en unknown
- 1987-06-26 JP JP62159491A patent/JPS6327475A/en active Pending
- 1987-06-26 PT PT85190A patent/PT85190B/en not_active IP Right Cessation
- 1987-06-26 PL PL1987266478A patent/PL153449B1/en unknown
- 1987-06-26 DD DD87304203A patent/DD263757A5/en not_active IP Right Cessation
- 1987-06-29 DE DE19873721430 patent/DE3721430A1/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1116871C (en) * | 1996-09-26 | 2003-08-06 | 美迪特药物有限公司 | Pharmaceutical compositions containing S-alkylisothiouronium derivatives |
| CN103086939A (en) * | 2011-10-28 | 2013-05-08 | 华中药业股份有限公司 | Recrystallization method of 1-(3-bromo-2-D-methyl propionyl)pyrrolidine-2-carboxylic acid |
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