KR100248550B1 - 4-아미노-5-헥센산의 제조방법 - Google Patents
4-아미노-5-헥센산의 제조방법 Download PDFInfo
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- KR100248550B1 KR100248550B1 KR1019920023550A KR920023550A KR100248550B1 KR 100248550 B1 KR100248550 B1 KR 100248550B1 KR 1019920023550 A KR1019920023550 A KR 1019920023550A KR 920023550 A KR920023550 A KR 920023550A KR 100248550 B1 KR100248550 B1 KR 100248550B1
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- Prior art keywords
- ethyl
- hexenoate
- amino
- hydroxy
- hexenoic acid
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- PJDFLNIOAUIZSL-UHFFFAOYSA-N vigabatrin Chemical compound C=CC(N)CCC(O)=O PJDFLNIOAUIZSL-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 13
- DLPNYKZTMBRGLC-UHFFFAOYSA-N 2-hydroxybut-3-enyl formate Chemical compound C=CC(O)COC=O DLPNYKZTMBRGLC-UHFFFAOYSA-N 0.000 claims description 6
- 239000004386 Erythritol Substances 0.000 claims description 4
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 4
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 4
- 229940009714 erythritol Drugs 0.000 claims description 4
- 235000019414 erythritol Nutrition 0.000 claims description 4
- AGGDACKPJYQQTJ-UHFFFAOYSA-N ethyl 6-hydroxyhex-4-enoate Chemical compound CCOC(=O)CCC=CCO AGGDACKPJYQQTJ-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 3
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 claims description 3
- NKTXPLUMJAFZLC-UHFFFAOYSA-N ethyl 4-[(2,2,2-trichloroacetyl)amino]hex-5-enoate Chemical compound CCOC(=O)CCC(C=C)NC(=O)C(Cl)(Cl)Cl NKTXPLUMJAFZLC-UHFFFAOYSA-N 0.000 claims description 3
- UPXKHUBIJAUPSR-UHFFFAOYSA-N 2-hydroxyhex-4-enoic acid Chemical compound CC=CCC(O)C(O)=O UPXKHUBIJAUPSR-UHFFFAOYSA-N 0.000 claims description 2
- -1 formyloxy-4-hexenoate Chemical compound 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- ISYPOFVXIZTQMA-UHFFFAOYSA-N ethyl 6-(2,2,2-trichloroethanimidoyl)oxyhex-4-enoate Chemical compound CCOC(=O)CCC=CCOC(=N)C(Cl)(Cl)Cl ISYPOFVXIZTQMA-UHFFFAOYSA-N 0.000 claims 2
- 238000000034 method Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 229910004298 SiO 2 Inorganic materials 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 2
- JLIXDVYXSMNNOY-UHFFFAOYSA-N ethyl 6-formyloxyhex-4-enoate Chemical compound CCOC(=O)CCC=CCOC=O JLIXDVYXSMNNOY-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- 102100035923 4-aminobutyrate aminotransferase, mitochondrial Human genes 0.000 description 1
- 101710115046 4-aminobutyrate aminotransferase, mitochondrial Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229940106773 sabril Drugs 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960005318 vigabatrin Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/20—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
- C07C211/24—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/04—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines without replacement of the other oxygen atom of the carboxyl group, e.g. imino-ethers
- C07C257/06—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines without replacement of the other oxygen atom of the carboxyl group, e.g. imino-ethers having carbon atoms of imino-carboxyl groups bound to hydrogen atoms, to acyclic carbon atoms, or to carbon atoms of rings other than six-membered aromatic rings
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- Chemical & Material Sciences (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
본 발명은 열전위에 의한 4-아미노-5-헥센산의 신규한 합성법 및 이로 인해 생성된 신규한 중간체에 관한 것이다.
Description
본 발명은 열전위 반응을 사용한 4-아미노-5-헥센산의 신규한 합성방법 및 이 과정에서 생성되는 신규한 중간체에 관한 것이다.
비가바트린 또는 비닐 GABA로 공지된 4-아미노-5-헥센산은 간질 치료용으로 사브릴(SABRIL)이라는 상표명으로 시판되는 GABA-T 억 제제이다[참조: S. M. Grant, et al, “review article on vi'gabatrin”, in Drugs, 41(6): 889-926, 1991].
근본적으로, 이 방법은 에리트리톨로부터 출발하여 (1) 이중결합을 형성하기 위한 제거단계, (2) 클라이젠(Claisen) 전위 및 (3) 오버만(Overman) 전위로 이루어진 공지된 열 반응을 기본으로 한다. 포함된 반응 순서는 하기의 반응 도식으로 도시된다:
[반응도식 A]
상기식에서,
Et는 에틸이다.
상기 방법의 단계(a)는 에리트리톨(1)로부터 4-포르밀옥시-3-하이드록시-1-부텐(2)을 제조하기 위한 공지된 열전위 반응을 포함한다[참조: Provost, C., Ann. Chem. [10], 10, 398, 1928]. 후처리가 불필요할 경우에도, 생성물을 재증류시키면 보다 순수한 화합물이 보다 높은 수율로 수득될 수 있다. 단계(b)는 제2의 열전위 반응을 수행한 후, 가수분해시킴을 포함하며, 여기서 동일계에서 생성되는 알콜의 제거 조건하에 과량(4 대 1)의 오르토아세테이트의 존재하에 4-포르밀옥시-3-하이드록시- 1-부텐을 140 내지 150℃로 가열한다[참조: Johnson W. and Coll, J. Am. Chem. Soc. 92, 741, 1970]. 가수분해 및 과량의 오르토아세테이트의 제거에 이어서, 이렇게 하여 얻은 생성물인 에틸-6-포르밀옥시-4-헥세노에이트를 그 자체로 사용하거나, 임의로 증류하여 정제하거나, SiO2상에서 섬광 크로마토그래피를 수행할 수 있다. 또한, 이러한 열전위는 약 140 내지 150℃에서 비등하는 불활성 용매(예를 들어, 크실렌) 하에서 오르토아세테이트 1당량을 사용하여 수행할 수 있다. 이러한 반응의 반응 시간은 증류되는 알콜(메탄을 또는 에탄올)을 측정함으로써 모니터링할 수 있다.
단계(c)는 당해 포르메이트를 약 15 내지 25℃에서 , 촉매량의 알콜성 HCl 기체를 첨가한 무수 에탄올 중에서 교반함으로써 포르메이트를 이의 상응하는 알콜인 에틸-6-하이드록시-4-헥세노에이트로 전환시킴을 포함한다. 단계(d)는 불활성 기체, 바람직하게는 질소하에 약 0℃에서 촉매량(약 0.1당량)의 NaH의 존재하에서 비양성자성 무수 용매(바람직하게는 무수 에테르) 중에서 트리클로로아세토니트릴을 에틸-6-하이드록시-4-헥세노에이트와 반응시켜 동일 반응계 내에서 이미 데이트 중간체(5)를 형성시키고, 이를 열전위에 의해 에틸-4-트리클로로아세트아미도-5-헥세노에이트(6)로 전환시킴을 포함하며, 이 때의 전위는 문헌[참조: Overman, L.J., Am. Chem, Soc. 98, 2901, 1976]의 기술을 사용하여 수행시킨다. 최종 단계는 상기 이미데이트를, 바람직하게는 산성 가수분해, 다른 방법으로는 염기성 가수분해 조건을 사용하여 가수분해시켜 목적한 4-아미노-헥센산을 이의 HCl 염으로서 수득함을 포함한다. 유리산 또는 기타 약제학적으로 허용되는 이의 염은 당해 분야에 익히 공지된 표준 방법에 의해 수득될 수 있다.
본 방법의 잇점은 다음과 같이 요약할 수 있다:
(1) 본 방법은 발암성 물질을 사용하거나 형성시키지 않으며, 어떠한 위험한 반응물 또는 용매도 사용하지 않고,
(2) 출발 물질은 저렴한 원료 물질(감자 전분)로부터 제조될 수 있으며,
(3) 반응 순서는 최종 가수분해 전에 단지 1회의 정제에 의해 종결되고,
(4) 필요한 유기 용매의 수가 많지 않으며,
(5) 과량의 반응물(예를 들어, 트리클로로오르토아세테이트) 및 용매(예를 들어, 크실렌)가 회수되거나 재사용될 수 있고,
(6) 바람직하지 않은 부산물이 없으며,
(7) 반응은 온도 조절과 관련된 문제없이 용이하게 수행되고, 생성물은 크로마토그래피에 의한 후처리를 필요로 하지 않고 정제할 수 있다.
하기의 실시예는 본 발명의 신규한 방법을 설명한다.
[실시예 1]
4-아미노-5-헥센산
[단계 A : 4-포르밀옥시-3-하이드록시-1-부텐]
수성 포름산(150g, 75%) 중의 에리트리톨(50g, 0.5mol)의 용액을 100℃ 이상으로 12시간 동안 가열한 후, 물 및 포름산을 증류 제거하고, 반응 혼합물을 분젠 버너(Bunsen burner)로 200℃ 이상으로 가열한다. 생성물을 증류시켜 모으고(비점: 230℃, 30g), 정류시켜야 한다(비점: 90℃, 15mm).
1H NMR(90MHz) (CDCl3, TMS) δ ppm. 3.23(s, 1H, OH), 3.6(m, 1H, CH), 4.23(t, 2H, CH2), 5.33(m, 2H, CH2=), 5.83(m, 1H, -CH=), 8.16(s, 1H, HCO2).
[단계 B : 에틸-6-포르밀옥시-4-헥세노에이트]
트리에틸오르토아세테이트(6g, 40mmol) 중의 4-포르밀옥시-3 -하이드록시-1-부텐(1.06g, 10mmol) 및 프로피온산(1방울)의 용액을140℃에서 에탄올을 증류 제거시키는 조건하에서 가열한다. 2시간 후에 과량의 에틸오르토아세테이트를 진공 중에서 증류 제거한다. 잔류물을 물로 가수분해시키고, AcOEt로 추출한다. 생성물을 SiO2상에서 섬광 크로마토그래피(용출액, AcOEt: 헥산, 2:8)를 수행하여 정제(1g, 60%)하지만, 보다 많은 양이 포함될 경우는 증류 정제가 바람직하다.
1H NMR(90MHz) (CDCl3, TMS) δ ppm. 1.26(t, 3H, CH3, J=6Hz), 2.4(s 4H, CH2)2), 4.1(q, 2H, CH2, J=6Hz), 4.6(d, 2H, CH2-C=, J=6Hz), 5.73(m, 2H, CH=CH), 8.06(s, 1H, HCO2).
[단계 C : 에틸-6-하이드록시-4-헥세노에이트]
알콜성 HCl 기체의 포화 용액 몇 방울을 함유하는 무수 EtOH(10ml) 중의 6-포르밀옥시-6-헥세노에이트(0.9g, 5mmol)의 용액을 20℃에서 2시간 동안 방치한다. 용매를 진공 제거시키고, 잔류물을 더 이상 정제하지 않고 다음 단계에서 사용한다(0.7g, 정량적). 이 화합물은 SiO2상에서의 섬광 크로마토그래피에 의해 부분적으로 분해되는 것으로 밝혀졌다.
1H NMR(90MHz) (CDCl3, TMS) δ ppm. 1.26(t, 3H, CH3, J=6Hz), 2.4(s, 4H, (CH2)2), 2.83(s, 1H, OH), 4.1(s, 2H, CH2-C=) 4.16(q, 2H, CH3CH2, J=6Hz), 5.7(s, 2H, CH=CH).
[단계 D : 에틸-트리클로로아세트아미도-5-헥세노에이트]
수소화나트륨(오일 중의 50% 분산액 0.03g, 0.5mmol)을 N2하에 0℃에서 무수에테르(50ml) 중의 에틸-6-하이드록시-4-헥세노에이트(0.7g, 5mmol)와 트리 클로로 아세토니트릴(0.6g, 5mmol)의 용액에 가한다. 1시간 후에, 에탄올(0.5mmol)을 가하고, 용매를 진공 제거한다. 임데이트의 형성을 NMR로 조사한다(NH, 8.5ppm 이하). 크실렌(30ml) 중의 조(crude) 이미데이트의 용액을 환류하에서 48시간 동안 가열한다. 이어서, 용매를 진공 제거하고, 잔류물을 SiO2상의 섬광 크로마토그래피(용출액, AcOEt:헥산, 2:8)로 정제하여 표제 생성물(1.1g, 70% 이하)을 수득한다.
1H NMR(90MHz) (CDCl3, TMS) δ ppm. 1.23(t, 3H, CH3, J=6Hz), 2.0 (t, 2H, CH2-CH2-CO2, J=5Hz), 2.36(s, 2H, CH2CO2), 4.1(q, 2H, CH3CH2, J=6Hz), 4.4(t, 1H, CH-CH2, J=5Hz), 5.1(m, 2H, CH2), 5.76(m, 1H, CH=CH2), 7.2(s, 1H, NH).
샘플을 분석하기 위해 증류시킨다(비점: 150℃, 0.5mmHg).
C10H14NO3Cl3에 대한 원소분석:
계산치 : C: 39.69 H: 4.66 N: 4.64
실측치 : C: 39.87 H: 4.62 N: 4.49
[단계 E : 4-아미노-5-헥센산]
6N HCl(10ml) 중의 에틸기-4-트리클로로아세트아미도 - 5-헥세노에이트(0.3g, 1mmol)의 현탁액을 환류하에서 6시간 동안 가열한다. 이어서, 혼합물을 진공 농축시키고, 물(10ml)로 희석시킨 후, AcOEt로 2회 세척하고 진공 중에서 건조시켜 표제 생성물(0.18g, 100%)을 수득한다. NMR 및 TLC(NH4OH:EtOH, 3:7) 분석 결과는 4-아미노-5-헥센산의 표준 샘플의 결과와 동일하다.
1H NMR(90MHz) (D2O), δ ppm. (TMS) 1.83(m, 2H, CH2CO2), 2.33(m, 2H, CH2CH2) 3.66(m, 1H, CH-C=), 5.35(m, 3H, CH2=CH).
Claims (3)
- 에리트리톨을 열전위시키켜 4-포르밀옥시-3-하이드록시-1-부텐으로 전환시키는 단계(a), 4-포르밀옥시-3-하이드록시-1-부텐을 열전위시켜 에틸-6-포르밀옥시-4-헥세노에이트로 전환시킨 후, 당해 포르메이트를 이의 상응하는 알콜인 에틸-6-하이드록시-4-헥세노에이트로 전환시키는 단계(b) 및 전환된 에틸-6-하이드록시- 4-헥세노에이트를 트리클로로아세토니트릴과 반응시켜 에틸-6-트리클로로아세트이미독시-4-헥세노에이트로 전환시킨 후, 열전위시켜 에틸-4-트리클로로아세트아미도-5-헥세노에이트로 전환시키고, 이를 가수분해시켜 목적하는 4-아미노-5-헥센산으로 전환시키는 단계(c)를 포함하여, 4-아미노-5-헥센산 또는 약제학적으로 허용되는 이의 염을 제조하는 방법.
- 에틸-6-트리클로로아세트이미독시-4-헥세노에이트.
- 에틸-4-트리클로로아세트아미도-5-헥세노에이트.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019990036254A KR100249593B1 (ko) | 1991-12-10 | 1999-08-30 | 에틸-6-포르밀옥시-4-헥세노에이트 |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP91403351.9 | 1991-12-10 | ||
| EP91403351A EP0546230A1 (en) | 1991-12-10 | 1991-12-10 | Novel process for preparing 4-amino-5-hexenoic acid |
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| Application Number | Title | Priority Date | Filing Date |
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| KR1019990036254A Division KR100249593B1 (ko) | 1991-12-10 | 1999-08-30 | 에틸-6-포르밀옥시-4-헥세노에이트 |
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| Application Number | Title | Priority Date | Filing Date |
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| KR1019920023550A KR100248550B1 (ko) | 1991-12-10 | 1992-12-08 | 4-아미노-5-헥센산의 제조방법 |
| KR1019990036254A KR100249593B1 (ko) | 1991-12-10 | 1999-08-30 | 에틸-6-포르밀옥시-4-헥세노에이트 |
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| Country | Link |
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| US (4) | US5380936A (ko) |
| EP (3) | EP0546230A1 (ko) |
| JP (1) | JP3229408B2 (ko) |
| KR (2) | KR100248550B1 (ko) |
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| JP2009046452A (ja) | 2007-08-22 | 2009-03-05 | Erick M Carreira | ホスホルアミダイト配位子およびそれを用いたアリルアミンの製造方法 |
| US20100218570A1 (en) * | 2009-03-02 | 2010-09-02 | Todd Basche | Combination lock assemblies and methods for marking combination lock assemblies including random selection of characters |
| US20100218571A1 (en) * | 2009-03-02 | 2010-09-02 | Todd Basche | Combination lock assemblies and methods for marking combination lock assemblies including distributions of consonants and vowels |
| EP2537827B1 (en) | 2011-06-24 | 2014-06-11 | Targeon SAS | Process for preparing 4-amino-5-hexenoic acid from succinimide |
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| US31980A (en) * | 1861-04-09 | Duane hull | ||
| US3879448A (en) * | 1970-02-07 | 1975-04-22 | Takeda Chemical Industries Ltd | 4-hexenoic compounds |
| FR2085653B1 (ko) * | 1970-04-30 | 1973-06-08 | Roussel Uclaf | |
| US3960927A (en) * | 1975-03-18 | 1976-06-01 | Richardson-Merrell Inc. | Olefinic derivatives of amino acids |
| US4039549A (en) * | 1975-03-18 | 1977-08-02 | Merrell Toraude Et Compagnie | Olefinic derivatives of amino acids |
| USRE31980E (en) * | 1975-03-18 | 1985-09-03 | Merrell Toraude Et Compagnie | Olefinic derivatives of amino acids |
| US4178463A (en) * | 1978-01-30 | 1979-12-11 | Merrell Toraude Et Compagnie | Process for making 4-aminohex-5-enoic acid |
| US4672140A (en) * | 1981-01-02 | 1987-06-09 | Monsanto Company | Acyloxyalkenoic acids and process therefor |
| US4692538A (en) * | 1982-04-14 | 1987-09-08 | Bristol-Myers Company | Trichloroethanimidic acid esters |
| GB2133002B (en) * | 1982-12-30 | 1986-01-29 | Merrell Toraude & Co | Process for preparing 4-amino-5-hexenoic acid |
| US4912232A (en) * | 1983-10-14 | 1990-03-27 | Dow Chemical Company | Preparation of N-hydrocarbylcarbonyl-5-(1-hydrocarbylcarbonyloxy)hydrocarbyl-pyrrolidin-2-one |
| DE3568771D1 (en) * | 1984-10-10 | 1989-04-20 | Givaudan & Cie Sa | Hexanoates, process for their preparation and perfumes and/or flavouring agents having a content of such compounds |
| DE3784812D1 (de) * | 1986-08-13 | 1993-04-22 | Ciba Geigy Ag | Verfahren zur herstellung von 5-amino-4-hydroxyvaleriansaeure-derivaten. |
| YU48319B (sh) * | 1988-08-01 | 1998-05-15 | Monsanto Company | Bezbednosni herbicidni derivati benzoeve kiseline |
| CA2028782C (en) * | 1989-11-07 | 2003-10-14 | Christian T. Goralski | Process for the production of vinyl-gaba |
| DE4010709A1 (de) * | 1990-04-03 | 1991-10-10 | Huels Chemische Werke Ag | Verfahren zur herstellung von 3-carboxamido-5-vinyl-2-pyrrolidon |
| JPH0692903A (ja) * | 1992-09-09 | 1994-04-05 | Yuki Gosei Kogyo Co Ltd | ５−ホルミルオキシ−３−ペンテン酸またはそのエステルおよびその製造法 |
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