KR101705535B1 - Method for Preparing an Optically Active 1-(3-hydroxyphenyl)ethylamine - Google Patents
Method for Preparing an Optically Active 1-(3-hydroxyphenyl)ethylamine Download PDFInfo
- Publication number
- KR101705535B1 KR101705535B1 KR1020090028153A KR20090028153A KR101705535B1 KR 101705535 B1 KR101705535 B1 KR 101705535B1 KR 1020090028153 A KR1020090028153 A KR 1020090028153A KR 20090028153 A KR20090028153 A KR 20090028153A KR 101705535 B1 KR101705535 B1 KR 101705535B1
- Authority
- KR
- South Korea
- Prior art keywords
- hydroxyphenyl
- ethylamine
- tartaric acid
- chiral
- salt
- Prior art date
Links
- WFRNDUQAIZJRPZ-UHFFFAOYSA-N 3-(1-aminoethyl)phenol Chemical compound CC(N)C1=CC=CC(O)=C1 WFRNDUQAIZJRPZ-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title abstract description 19
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 38
- 230000003287 optical effect Effects 0.000 claims abstract description 33
- WFRNDUQAIZJRPZ-LURJTMIESA-N 3-[(1s)-1-aminoethyl]phenol Chemical compound C[C@H](N)C1=CC=CC(O)=C1 WFRNDUQAIZJRPZ-LURJTMIESA-N 0.000 claims abstract description 21
- WFRNDUQAIZJRPZ-ZCFIWIBFSA-N 3-[(1r)-1-aminoethyl]phenol Chemical compound C[C@@H](N)C1=CC=CC(O)=C1 WFRNDUQAIZJRPZ-ZCFIWIBFSA-N 0.000 claims abstract description 17
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 15
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 15
- 239000011975 tartaric acid Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims description 21
- 229960001270 d- tartaric acid Drugs 0.000 claims description 14
- 229960001367 tartaric acid Drugs 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims 2
- 238000006460 hydrolysis reaction Methods 0.000 claims 2
- 229940071182 stannate Drugs 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 7
- 206010012289 Dementia Diseases 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 7
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- LUJMEECXHPYQOF-UHFFFAOYSA-N 3-hydroxyacetophenone Chemical compound CC(=O)C1=CC=CC(O)=C1 LUJMEECXHPYQOF-UHFFFAOYSA-N 0.000 description 3
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 2
- TVKZDKSHNITMRZ-UHFFFAOYSA-N 3-(ethylamino)phenol Chemical compound CCNC1=CC=CC(O)=C1 TVKZDKSHNITMRZ-UHFFFAOYSA-N 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- -1 chiral tartaric acid Chemical class 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 1
- CJWGCBRQAHCVHW-ZETCQYMHSA-N (1s)-1-(3-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC([C@H](C)N)=C1 CJWGCBRQAHCVHW-ZETCQYMHSA-N 0.000 description 1
- XUJHKPSBHDQIOD-UHFFFAOYSA-N (2-bromo-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl)methanesulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)C(Br)C1C2(C)C XUJHKPSBHDQIOD-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- CJWGCBRQAHCVHW-UHFFFAOYSA-N 1-(3-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC(C(C)N)=C1 CJWGCBRQAHCVHW-UHFFFAOYSA-N 0.000 description 1
- ASNHGEVAWNWCRQ-UHFFFAOYSA-N 4-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OCC1(O)COC(O)C1O ASNHGEVAWNWCRQ-UHFFFAOYSA-N 0.000 description 1
- COJRWHSKVYUZHQ-ZCFIWIBFSA-N C[C@H](c1cc(O)ccc1)O Chemical compound C[C@H](c1cc(O)ccc1)O COJRWHSKVYUZHQ-ZCFIWIBFSA-N 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical class [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/86—Separation
- C07C209/88—Separation of optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/22—Tin compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
본 발명은 키랄 주석산(tartaric acid)을 광학분할제로 사용하여 라세미 1-(3-히드록시페닐)에틸아민을 광학분할하여 (S)-1-(3-히드록시페닐)에틸아민 또는 (R)-1-(3-히드록시페닐)에틸아민을 제조하는 방법에 관한 것이다.The present invention relates to a method of optically resolving racemic 1- (3-hydroxyphenyl) ethylamine using chiral tartaric acid as an optical resolution agent to give (S) -1- (3-hydroxyphenyl) ethylamine or (R ) -1- (3-hydroxyphenyl) ethylamine. ≪ / RTI >
리바스티그민, 1-(3-히드록시페닐)에틸아민, 주석산, 광학분할제, 광학순도, 치매 1- (3-hydroxyphenyl) ethylamine, tartaric acid, optical resolution agent, optical purity, dementia
Description
본 발명은 하기 화학식 1로 표시되는 광학활성을 갖는 (S)-1-(3-히드록시페닐)에틸아민과 하기 화학식 2로 표시되는 (R)-1-(3-히드록시페닐)에틸아민을 제조하는 방법에 관한 것이다. 보다 구체적으로, 본 발명은 키랄 주석산(tartaric acid)을 광학분할제로 사용하여 라세미 1-(3-히드록시페닐)에틸아민을 광학분할하여 (S)-1-(3-히드록시페닐)에틸아민 혹은 (R)-1-(3-히드록시페닐)에틸아민을 제조하는 방법에 관한 것이다.(S) -1- (3-hydroxyphenyl) ethylamine represented by the following formula (1) and (R) -1- (3-hydroxyphenyl) ethylamine represented by the following formula To a process for producing the same. More particularly, the present invention relates to optically resolving racemic 1- (3-hydroxyphenyl) ethylamine using chiral tartaric acid as an optical resolution agent to give (S) -1- (3-hydroxyphenyl) ethyl Amine or (R) -1- (3-hydroxyphenyl) ethylamine.
[화학식 1][Chemical Formula 1]
[화학식 2](2)
하기 화학식 3으로 표시되는 리바스티그민은 광학활성을 가진 화합물로서 항콜린에스터라제인 생리활성을 가지고 있어 치매치료제(상품명: 엑셀론)로 사용되고 있다.[미국특허 5,602,176, 한국특허 등록 0133686]Ribastigmine represented by the following formula (3) is an optically active compound and has physiological activity as anticholinesterase, and is used as a therapeutic agent for dementia (trade name: excelon). [US Patent 5,602,176, Korean Patent Registration 0133686]
[화학식 3](3)
리바스티그민을 제조하기 위해서는 하기 반응식 1에서 보여 주듯이 핵심중간체로서 상기 화학식 1로 표시되는 (S)-1-(3-히드록시페닐)에틸아민을 제조하는 기술이 필수적이다. [국제특허 WO 2006/048720; J. Am.Chem. Soc. 125, 14260(2003); 국제특허 WO 2006/068386; 국제특허 WO 2008/020452] In order to prepare the ribastigmine, a technique for preparing (S) -1- (3-hydroxyphenyl) ethylamine represented by the above formula (1) is essential as a core intermediate as shown in Reaction Scheme 1 below. [International Patent WO 2006/048720; J. Am. Chem. Soc. 125, 14260 (2003); International Patent WO 2006/068386; WO 2008/020452]
[반응식 1][Reaction Scheme 1]
(S)-1-(3-히드록시페닐)에틸아민을 제조하는 종래의 기술로서, 하기 반응식 2에서 기술하듯이 광학분할제로서 키랄 만델산을 사용하여 라세미 1-(3-메톡시페닐)에틸아민을 광학분할하여 (S)-1-(3-메톡시페닐)에틸아민을 제조하고, 메톡시기의 메틸기를 제거하는 탈메틸화 반응시켜 (S)-1-(3-히드록시페닐)에틸아민을 제조하는 방법[일본특허 공개 평 11-106368], 및 하기 반응식 3에서 기술하듯이 3-히드록시아세토페논을 비대칭환원 반응시켜 (R)-1-(3-히드록시페닐)에틸알코홀을 제조하고 아지드화 반응과 환원반응을 통해 (S)-1-(3-히드록시페닐)에틸아민을 제조하는 방법 등이 알려져 있다[Tetrahedron Letters, 32, 7175 (1991)]. (S) -1- (3-hydroxyphenyl) ethylamine using racemic 1- (3-methoxyphenyl) ethylamine using chiral mandelic acid as the optical resolution agent, (S) -1- (3-methoxyphenyl) ethylamine was prepared by optically resolving ethylamine to give the methyl group of the methoxy group, (R) -1- (3-hydroxyphenyl) ethyl alcohol as described in Reaction Scheme 3 and 3-hydroxyacetophenone by an asymmetric reduction reaction as disclosed in Japanese Patent Application Laid-Open No. 11-106368, (S) -1- (3-hydroxyphenyl) ethylamine is prepared by azidation and reduction reaction [Tetrahedron Letters, 32, 7175 (1991)].
[반응식 2][Reaction Scheme 2]
[반응식 3] [Reaction Scheme 3]
상기 제법들은 광학활성을 갖는 중간체를 제조한 후 여러 단계의 추가 반응이 필요하다는 단점이 있다.These processes have the disadvantage that several steps of additional reaction are required after producing an optically active intermediate.
이에 본 발명자들은 간단한 공정으로 라세미 1-(3-히드록시페닐)에틸아민에서 (S)-1-(3-히드록시페닐)에틸아민을 얻기 위하여 다양한 키랄 유기산의 광학분할 효과를 탐색한 결과, 특이하게도 키랄 주석산(tartaric acid)이 매우 뛰어난 광학분할 효과를 가진다는 사실을 발견하였다. Accordingly, the inventors of the present invention have conducted a simple process to investigate the optical resolution effect of various chiral organic acids to obtain (S) -1- (3-hydroxyphenyl) ethylamine from racemic 1- (3-hydroxyphenyl) ethylamine , In particular chiral tartaric acid, has a very good optical resolution effect.
한편, 라세미 1-페닐에틸아민의 광학분할과 관련하여, 광학분할제로서 키랄 주석산, 키랄 만델산, 키랄 캠퍼술폰산, 키랄 브로모캠퍼술폰산 등 다양한 키랄 유기산을 사용하여 광학활성을 갖는 키랄 1-페닐에틸아민을 제조할 수 있는 기술이 보고되어 있다[Organic Synthesis Collective Vol. 5, 932].On the other hand, with respect to the optical resolution of racemic 1-phenylethylamine, various chiral organic acids such as chiral tartaric acid, chiral mandelic acid, chiral camphor sulfonic acid, chiral bromocamphorsulfonic acid, A technique for preparing phenylethylamine has been reported [Organic Synthesis Collective Vol. 5, 932].
보다 구체적으로, 상기 문헌에 따르면 라세미 1-페닐에틸아민의 광학분할제로서 L-주석산을 사용하여 광학분할할 때 라세미 1-페닐에틸아민과 L-주석산의 몰비를 1 : 1을 사용하면 (S)-페닐에틸아민과 L-주석산의 1 : 1의 염 ((S)-1-phenylethylamine hydrogen L-tartrate salt)이 생성되고, 이를 가수분해하여 (S)-1-페닐에틸아민을 얻는다고 개시되어 있다. 그러나, 라세미 1-페닐에틸아민 대신 라세미 1-(3-히드록시페닐)에틸아민을 상기한 문헌의 개시 내용을 기초로 L-주석산으로 광학분할하면 광학분할 효과가 거의 없었다. 이러한 효과의 차이는 1-페닐에틸아민과 달리 1-(3-히드록시페닐)에틸아민의 페닐 치환체인 3-히드록시기가 큰 영향을 미치기 때문으로 추정된다. More specifically, according to the above literature, when the ratio of racemic 1-phenylethylamine to L-tartaric acid is 1: 1 when optical resolution is performed using L-tartaric acid as the optical resolving agent of racemic 1-phenylethylamine (S) -1-phenylethylamine hydrogen L-tartrate salt of (S) -phenylethylamine and L-tartaric acid is produced and hydrolyzed to obtain (S) -1-phenylethylamine Lt; / RTI > However, when optically resolving racemic 1- (3-hydroxyphenyl) ethylamine instead of racemic 1-phenylethylamine with L-tartaric acid based on the above-mentioned disclosure, there was little optical resolution effect. It is presumed that this difference in the effect is due to the fact that the 3-hydroxy group, which is a phenyl substituent of 1- (3-hydroxyphenyl) ethylamine, has a large effect, unlike 1-phenylethylamine.
이러한 3-히드록시기의 영향을 고려하여, 본 발명자들은 키랄 주석산을 광학 분할제로 이용하여 광학활성을 갖는 1-(3-히드록시페닐)에틸아민을 제조하기 위한 연구를 계속하였다. 그 결과, 라세미 1-(3-히드록시페닐)에틸아민과 L-주석산의 몰비를 1 : 0.5로 하여 염 형성을 통한 광학분할시키면 효과적으로 광학분할이 이루어지며 생성되는 염도 (R)-1-(3-히드록시페닐)에틸아민과 L-주석산의 2 : 1의 염((R)-1-(3-hydroxyphenyl)ethylamine hemi L-tartrate salt, 키랄 주석산 염)이 생성되며, 얻어지는 1-(3-히드록시페닐)에틸아민의 키랄 센터도 1-페닐에틸아민의 경우와는 반대로 (R)-형태가 얻어지는 놀라운 결과를 얻을 수 있었다. In consideration of the influence of the 3-hydroxy group, the present inventors have continued the research for preparing optically active 1- (3-hydroxyphenyl) ethylamine by using chiral tartaric acid as an optical resolution agent. As a result, optical resolution was achieved by optical resolution through salt formation at a molar ratio of racemic 1- (3-hydroxyphenyl) ethylamine to L-tartaric acid of 1: 0.5, (3-hydroxyphenyl) ethylamine hemi L-tartrate salt, chiral tartrate salt) of 2: 1 (3-hydroxyphenyl) ethylamine and L- The chiral center of 3-hydroxyphenyl) ethylamine was also found to have surprising results in that the (R) -form was obtained as opposed to the case of 1-phenylethylamine.
한편, (R)-1-(3-히드록시페닐)에틸아민과는 반대의 키랄성을 가진 (S)-1-(3-히드록시페닐)아민을 얻기 위해서는, 아래에 도시된 바와 같이 L-주석산 대신 D-주석산을 사용하여 키랄 주석산 염 형성을 통한 광학분할을 하면 광학 순도가 높은 (S)-1-(3-히드록시페닐)아민을 얻을 수 있다.On the other hand, in order to obtain (S) -1- (3-hydroxyphenyl) amine having chirality opposite to (R) -1- (3-hydroxyphenyl) ethylamine, (S) -1- (3-hydroxyphenyl) amine with high optical purity can be obtained by optical resolution through formation of chiral tartrate using D-tartaric acid instead of tartaric acid.
본 발명은 상기한 바와 같은 결과에 기초하여 완성된 것으로, 공지된 기술에 비하여 단순한 공정을 통하여 제조되므로 경제적이면서도 대량생산에 적합한 광학활성을 갖는 1-(3-히드록시페닐)에틸아민의 제조방법을 제공하는 것이다. 즉, 본 발명은 키랄 주석산을 광학분할제로 사용하여 라세미 1-(3-히드록시페닐)에틸아민을 광학분할함으로써 광학활성을 갖는 1-(3-히드록시페닐)에틸아민을 대량으로 제조할 수 있는 경제적인 제조방법이다.The present invention has been completed on the basis of the above-described results, and it is an object of the present invention to provide a process for producing 1- (3-hydroxyphenyl) ethylamine which is economical and has optical activity suitable for mass production since it is produced through a simple process, . That is, the present invention provides a method for producing optically active 1- (3-hydroxyphenyl) ethylamine in a large amount by optically resolving racemic 1- (3-hydroxyphenyl) ethylamine using chiral tartaric acid as an optical resolution agent It is an economical manufacturing method.
본 발명은 치매치료제인 리바스티그민의 핵심 중간체인 광학활성을 갖는 1-(3-히드록시페닐)에틸아민을 제공하기 위한 것으로, 여러 단계의 반응을 필요로 하는 공지 기술의 문제점을 해결하기 위하여 라세미 1-(3-히드록시페닐)에틸아민의 광학 분할을 위하여 키랄 주석산을 사용하고, 키랄 주석산과 라세미 1-(3-히드록시페닐)에틸아민의 몰비를 특정 범위로 조정함으로써 경제적이면서도 대량생산에 적합한 광학활성을 갖는 1-(3-히드록시페닐)에틸아민을 제조하는 방법을 제공하기 위한 것이다. The present invention provides 1- (3-hydroxyphenyl) ethylamine having optical activity, which is a key intermediate of ribastigmine, a treatment for dementia, and has been developed to solve the problems of the prior art The chiral tartaric acid is used for optical resolution of racemic 1- (3-hydroxyphenyl) ethylamine, and the molar ratio of chiral tartaric acid and racemic 1- (3-hydroxyphenyl) ethylamine is adjusted to a specific range, (3-hydroxyphenyl) ethylamine having optical activity suitable for mass production.
본 발명은 하기 화학식 4로 표시되는 라세미 1-(3-히드록시페닐)에틸아민과 D-주석산 또는 L-주석산을 반응시켜 디아스테레오머 형의 염을 제조하고, 이를 가수분해하여 광학활성을 갖는 (S)-1-(3-히드록시페닐)에틸아민 또는 (R)-1-(3-히드록시페닐)에틸아민을 제조하는 방법을 제공한다.The present invention relates to a process for preparing a diastereomer salt by reacting racemic 1- (3-hydroxyphenyl) ethylamine represented by the following formula (4) with D-tartaric acid or L-tartaric acid, (S) -1- (3-hydroxyphenyl) ethylamine or (R) -1- (3-hydroxyphenyl) ethylamine.
[화학식 4][Chemical Formula 4]
본 발명에 따른 광학활성을 갖는 1-(3-히드록시페닐)에틸아민의 제조방법은 라세미 1-(3-히드록시페닐)에틸아민과 키랄 주석산을 특정 몰비로 혼합하여 광학분할하는 방법으로서 공지된 기술에 비하여 단순한 공정을 통하여 제조되므로 경제적이면서도 대량생산에 적합한 방법이다.The method for producing optically active 1- (3-hydroxyphenyl) ethylamine according to the present invention is a method of optically resolving racemic 1- (3-hydroxyphenyl) ethylamine and chiral tartaric acid in a specific molar ratio It is economical and suitable for mass production since it is manufactured through a simple process as compared with the known technology.
본 발명의 한 면에서는, 라세미 1-(3-히드록시페닐)에틸아민과 D-주석산을 반응시켜 광학활성을 갖는 (S)-1-(3-히드록시페닐)에틸아민을 제조하는 방법을 제공한다.In one aspect of the present invention, there is provided a process for producing (S) -1- (3-hydroxyphenyl) ethylamine having optical activity by reacting racemic 1- (3-hydroxyphenyl) ethylamine with D- .
본 발명에 따른 (S)-1-(3-히드록시페닐)에틸아민의 제조방법을 반응식으로 간략하게 도시하면 다음과 같다.The process for producing (S) -1- (3-hydroxyphenyl) ethylamine according to the present invention will be briefly described as follows.
[반응식 4][Reaction Scheme 4]
본 발명의 다른 한 면에서는, 라세미 1-(3-히드록시페닐)에틸아민과 L-주석 산을 반응시켜 광학활성을 갖는 (R)-1-(3-히드록시페닐)에틸아민을 제조하는 방법을 제공한다.In another aspect of the present invention, there is provided a process for producing (R) -1- (3-hydroxyphenyl) ethylamine having optical activity by reacting racemic 1- (3-hydroxyphenyl) ethylamine with L- . ≪ / RTI >
본 발명에서 키랄 주석산인 D-주석산 또는 L-주석산은 라세미 1-(3-히드록시페닐)에틸아민에 대하여 0.5 당량 이하로 사용하는 것이 바람직하며, 더욱 바람직하게는 0.2당량 내지 0.5당량으로 사용하는 것이다. 얻어지는 디아스테레오머 형태의 염은 아민과 산의 몰 비가 2:1인 (S)- 또는 (R)-1-(3-히드록시페닐)에틸아민과 키랄 주석산의 염으로서, (S)-1-(3-히드록시페닐)에틸아민의 키랄 D-주석산 염 또는 (R)-1-(3-히드록시페닐)에틸아민의 키랄 L-주석산 염이다.In the present invention, D-tartaric acid or L-tartaric acid is preferably used in an amount of 0.5 equivalent or less, more preferably 0.2 equivalent to 0.5 equivalent of racemic 1- (3-hydroxyphenyl) ethylamine . The obtained diastereomer salt is a salt of (S) - or (R) -1- (3-hydroxyphenyl) ethylamine and chiral tartrate having a molar ratio of amine to acid of 2: - (3-hydroxyphenyl) ethylamine or a chiral L-tartrate salt of (R) -1- (3-hydroxyphenyl) ethylamine.
본 발명에 따라 얻어진 (S)- 또는 (R)-1-(3-히드록시페닐)에틸아민과 주석산의 염을 가수분해하는 공정은, 디아스테레오머 형태의 염에서 광학활성을 갖는 1-페닐에틸아민을 얻을 수 있는 다양한 공지의 방법을 사용하여 실시될 수 있다. 구체적인 예로는 얻어진 염을 물에 용해시키고 염기를 투입하여 중화시키면 (S)- 또는 (R)-1-(3-히드록시페닐)에틸아민이 석출되며 이를 여과하여 얻게 된다. 얻어진 (S)- 또는 (R)-1-(3-히드록시페닐)에틸아민의 광학순도는 키랄 컬럼(Daicel Crownpack CR(+) column)을 사용하여 용이하게 분석할 수 있다.The step of hydrolyzing a salt of (S) - or (R) -1- (3-hydroxyphenyl) ethylamine and tartaric acid obtained according to the present invention is a step of hydrolyzing a salt of an optically active 1-phenyl Can be carried out using various known methods for obtaining ethylamine. As a specific example, (S) - or (R) -1- (3-hydroxyphenyl) ethylamine is precipitated by dissolving the obtained salt in water and neutralizing by adding a base, which is obtained by filtration. The optical purity of the obtained (S) - or (R) -1- (3-hydroxyphenyl) ethylamine can be easily analyzed using a chiral column (Daicel Crownpack CR (+) column).
본 발명은 이하의 실시예에 의하여 더욱 구체화되지만, 이로 인하여 본 발명의 권리 범위가 한정되지는 않는다.The present invention is further illustrated by the following examples, but the scope of the present invention is not limited thereby.
실시예 Example
실시예 1: (S)-1-(3-히드록시페닐)에틸아민의 제조 Example 1: Preparation of (S) -1- (3-hydroxyphenyl) ethylamine
에탄올(50mL)과 에틸 아세테이트(50mL)에 라세미 1-(3-히드록시페닐)에틸아민(5.0g, 36.4mmol)과 D-주석산(1.91g, 12.7mmol, 0.35당량)을 넣고 가열하여 용해시킨 후 상온으로 천천히 냉각시켰다. 용액을 상온에서 4시간 교반시키고 석출된 결정을 여과하여 얻고 감압 건조시켜 (S)-1-(3-히드록시페닐)에틸아민의 키랄 D-주석산의 염 (3.09g)을 얻었다.To a solution of racemic 1- (3-hydroxyphenyl) ethylamine (5.0 g, 36.4 mmol) and D-tartaric acid (1.91 g, 12.7 mmol, 0.35 eq.) In ethanol (50 mL) and ethyl acetate (50 mL) And then slowly cooled to room temperature. The solution was stirred at room temperature for 4 hours, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 3.09 g of a chiral D-tartaric acid salt of (S) -1- (3-hydroxyphenyl) ethylamine.
1H NMR (CD3OD, 400 MHz) 1.55 (d, 3H), 4.28 (m, 1H), 4.31 (s, 1H), 6.77(m, 1H), 6.86 (m, 2H), 7.21 (m, 1H) 1 H NMR (CD 3 OD, 400 MHz) 1.55 (d, 3H), 4.28 (m, 1H), 4.31 (s, 1H), 6.77 (m, 1H), 6.86 (m, 2H), 7.21 (m, 1H)
상기 실험에서 얻어진 염(3.09g)을 물(18mL)에 용해시킨 후 수산화나트륨 (0.58g)을 넣고 교반하고, 석출된 고체를 여과하고, 감압건조하여 (S)-1-(3-히드록시페닐)에틸아민(1.41g)을 얻었다.Sodium hydroxide (0.58 g) was added to the solution, and the precipitated solid was filtered and dried under reduced pressure to give (S) -1- (3-hydroxyphenyl) Phenyl) ethylamine (1.41 g).
1H NMR (CD3OD, 400 MHz) 1.35 (d, 3H), 3.94 (m, 1H), 6.64 (m, 1H), 6.76 (m, 2H), 7.12 (m, 1H) 1 H NMR (CD 3 OD, 400 MHz) 1.35 (d, 3H), 3.94 (m, 1H), 6.64 (m, 1H), 6.76 (m, 2H), 7.12 (m, 1H)
광학순도 분석 조건은 키랄 컬럼(Daicel Crownpack CR(+) column)을 사용하였다: 이동상은 pH 1.5의 과염소산 수용액이며, 검출파장은 254nm이고, 전개속도는 0.8mL/min였다. (광학순도: S : R = 94 : 6)The optical purity was analyzed using a Daicel Crownpack CR (+) column. The mobile phase was a perchloric acid aqueous solution having a pH of 1.5, the detection wavelength was 254 nm, and the developing rate was 0.8 mL / min. (Optical purity: S: R = 94: 6)
실시예 2: (S)-1-(3-히드록시페닐)에틸아민의 제조 Example 2: Preparation of (S) -1- (3-hydroxyphenyl) ethylamine
에탄올(50mL)과 에틸 아세테이트(75mL)에 라세미 1-(3-히드록시페닐)에틸아민(5.0g, 36.4mmol)과 D-주석산(2.73g, 18.2mmol, 0.5당량)을 넣고 가열하여 용해시킨 후 상온으로 천천히 냉각시켰다. 용액을 상온에서 3.5시간 교반시키고 석출된 결정을 여과하여 얻고 감압 건조시켜 (S)-1-(3-히드록시페닐)에틸아민의 키랄 D-주석산의 염 (2.78g)을 얻었다. 얻어진 염을 실시예 1에 기재된 방법에 따라 가수분해하였다.(광학순도: S : R = 95 : 5)To a solution of racemic 1- (3-hydroxyphenyl) ethylamine (5.0 g, 36.4 mmol) and D-tartaric acid (2.73 g, 18.2 mmol, 0.5 eq.) In ethanol (50 mL) and ethyl acetate (75 mL) And then slowly cooled to room temperature. The solution was stirred at room temperature for 3.5 hours, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain a salt of chiral D-tartaric acid (2.78 g) of (S) -1- (3-hydroxyphenyl) ethylamine. The obtained salt was hydrolyzed according to the method described in Example 1. (optical purity: S: R = 95: 5)
실시예 3: (S)-1-(3-히드록시페닐)에틸아민의 제조 Example 3: Preparation of (S) -1- (3-hydroxyphenyl) ethylamine
에탄올(65mL)에 라세미 1-(3-히드록시페닐)에틸아민(4.5g, 32.8mmol)과 D-주석산(0.99g, 6.60mmol, 0.2당량)을 넣고 가열하여 용해시킨 후 상온으로 천천히 냉각시켰다. 용액을 상온에서 4시간 교반시키고 석출된 결정을 여과하여 얻고 감압 건조시켜 (S)-1-(3-히드록시페닐)에틸아민의 키랄 D-주석산의 염 (2.11g)을 얻었다. 얻어진 염을 실시예 1에 기재된 방법에 따라 가수분해하였다.(광학순도: S : R = 95 : 5)(4.5 g, 32.8 mmol) and D-tartaric acid (0.99 g, 6.60 mmol, 0.2 equivalent) were added to ethanol (65 mL) and heated to dissolve. . The solution was stirred at room temperature for 4 hours, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 2.11 g of a chiral D-tartaric acid salt of (S) -1- (3-hydroxyphenyl) ethylamine. The obtained salt was hydrolyzed according to the method described in Example 1. (optical purity: S: R = 95: 5)
비교예 1: (S)-1-(3-히드록시페닐)에틸아민의 제조 Comparative Example 1: Preparation of (S) -1- (3-hydroxyphenyl) ethylamine
에탄올(20mL)과 에틸 아세테이트(20mL)에 라세미 1-(3-히드록시페닐)에틸아민(2.0g, 14.5mmol)과 D-주석산(2.19g, 14.5mmol, 1.0당량)을 넣고 가열하여 용해시킨 후 상온으로 천천히 냉각시켰다. 용액을 상온에서 3시간 교반시키고 석출된 결정을 여과하여 얻고 감압 건조시켜 (S)-1-(3-히드록시페닐)에틸아민의 D-주석산의 염 (3.51g)을 얻었다. 얻어진 염을 실시예 1에 기재된 방법에 따라 가수분해하였다.(광학순도: S : R 50 : 50)To a solution of rac 1- (3-hydroxyphenyl) ethylamine (2.0 g, 14.5 mmol) and D-tartaric acid (2.19 g, 14.5 mmol, 1.0 eq.) In ethanol (20 mL) and ethyl acetate (20 mL) And then slowly cooled to room temperature. The solution was stirred at room temperature for 3 hours, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 3.51 g of D-tartaric acid salt of (S) -1- (3-hydroxyphenyl) ethylamine. The obtained salt was hydrolyzed according to the method described in Example 1. (Optical purity: S: R 50: 50)
실시예 4: (R)-1-(3-히드록시페닐)에틸아민의 제조 Example 4: Preparation of (R) -1- (3-hydroxyphenyl) ethylamine
에탄올(40mL)과 에틸 아세테이트(40mL)에 라세미 1-(3-히드록시페닐)에틸아민(3.0g, 21.9mmol)과 L-주석산(1.64g, 18.2mmol, 0.5당량)을 넣고 가열하여 용해시킨 후 상온으로 천천히 냉각시켰다. 용액을 상온에서 4시간 교반시키고 석출된 결정을 여과하여 얻고 감압 건조시켜 (R)-1-(3-히드록시페닐)에틸아민의 키랄 L-주석산의 염 (1.43g)을 얻었다. 얻어진 염을 실시예 1에 기재된 방법에 따라 가수분해하여 (R)-1-(3-히드록시페닐)에틸아민을 얻었다.(광학순도: S : R = 7 : 93)To a solution of racemic 1- (3-hydroxyphenyl) ethylamine (3.0 g, 21.9 mmol) and L-tartaric acid (1.64 g, 18.2 mmol, 0.5 eq.) In ethanol (40 mL) and ethyl acetate (40 mL) And then slowly cooled to room temperature. The solution was stirred at room temperature for 4 hours, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain a salt of chiral L-tartaric acid (1.43 g) of (R) -1- (3-hydroxyphenyl) ethylamine. The resulting salt was hydrolyzed according to the method described in Example 1 to give (R) -1- (3-hydroxyphenyl) ethylamine. (Optical purity: S: R = 7: 93)
[표 1][Table 1]
(S:R)Optical purity
(S: R)
(D-주석산)0.35
(D-tartaric acid)
(S)-1-(3-히드록시페닐)에틸아민의 키랄 주석산 염
(1:0.5 염)
(S) -1- (3-hydroxyphenyl) ethylamine Chiral tin salt of
(1: 0.5 salt)
(D-주석산)0.5
(D-tartaric acid)
(D-주석산)0.2
(D-tartaric acid)
(D-주석산)One
(D-tartaric acid)
(L-주석산)0.5
(L-tartaric acid)
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020090028153A KR101705535B1 (en) | 2009-04-01 | 2009-04-01 | Method for Preparing an Optically Active 1-(3-hydroxyphenyl)ethylamine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020090028153A KR101705535B1 (en) | 2009-04-01 | 2009-04-01 | Method for Preparing an Optically Active 1-(3-hydroxyphenyl)ethylamine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20100109739A KR20100109739A (en) | 2010-10-11 |
| KR101705535B1 true KR101705535B1 (en) | 2017-02-28 |
Family
ID=43130645
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020090028153A KR101705535B1 (en) | 2009-04-01 | 2009-04-01 | Method for Preparing an Optically Active 1-(3-hydroxyphenyl)ethylamine |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR101705535B1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100188980B1 (en) | 1994-03-24 | 1999-06-01 | 디. 제이. 우드, 무어 제임스 더블유 | Separation of the enantiomers of amlodipine via their diastereomeric tartrates |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0725874A (en) * | 1993-07-13 | 1995-01-27 | Yoshitomi Pharmaceut Ind Ltd | Production of optically active 3-amino-2-benzhydrylquinuclidine compound |
| KR100828883B1 (en) * | 2006-10-27 | 2008-05-09 | 씨제이제일제당 (주) | Method for the separation of S---amlodipine from racemic amlodipine |
-
2009
- 2009-04-01 KR KR1020090028153A patent/KR101705535B1/en active IP Right Grant
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100188980B1 (en) | 1994-03-24 | 1999-06-01 | 디. 제이. 우드, 무어 제임스 더블유 | Separation of the enantiomers of amlodipine via their diastereomeric tartrates |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20100109739A (en) | 2010-10-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20110105758A1 (en) | Process for the preparation of enantiomerically enriched cyclic beta-aryl or heteroarylcarbocyclic acids | |
| TW499409B (en) | Method for preparing of L-phenylephrine hydrochloride | |
| KR20070057703A (en) | Enantiomerically pure atomoxetine and tomoxetine mandelate | |
| CN103304447B (en) | (S) synthesis technique of-rivastigmine | |
| KR20160125115A (en) | Preparation Method for 3-Hydroxytetrahydrofuran | |
| KR101705535B1 (en) | Method for Preparing an Optically Active 1-(3-hydroxyphenyl)ethylamine | |
| JPH02289A (en) | Optically active amine-boron-based compound, asymmetric reducing agent containing the same compound as active ingredient and production of optically active compound using the same agent | |
| JP4483165B2 (en) | Process for producing optically active 3- (methylamino) -1- (2-thienyl) propan-1-ol and production intermediate | |
| JPWO2014034957A1 (en) | (R) -1,1,3-Trimethyl-4-aminoindane production method | |
| KR101344077B1 (en) | Method for Preparation of Beta-indolyl Esters Using Chiral Palladium Complexes | |
| JP2011012032A (en) | Method for producing optically active 3-aminopiperidine and production intermediate | |
| JP4874122B2 (en) | How to get tolterodine | |
| KR102323561B1 (en) | Aminoalcohol-boron-binol complexes and a method for preparing optically active aminoalcohol derivatives using the same | |
| US20030204114A1 (en) | Phenyl propenone compounds | |
| CN108409731B (en) | Chiral resolution of aryl-substituted 1H-pyridine [3,4-b ] indole-3-carboxylic acid methyl ester | |
| KR101459088B1 (en) | R-Rabeprazol, metal salt and thereof and method for preparing the same | |
| JP2010037206A (en) | Method for producing optically active o-methylserine or its salt | |
| DE102008033165A1 (en) | Process for producing an optically active β-hydroxycarboxylic acid derivative | |
| WO2013058241A1 (en) | Method for producing (r)-2-amino-2-ethylhexanol | |
| JP2009522229A (en) | Racemic separation of 2,6-trans-dimethylmorpholine | |
| JPH0570412A (en) | Production of optically active beta-amino alcohol | |
| WO2014024203A1 (en) | An improved process for - the preparation of dexmethylphenidate hydrochloride. | |
| JPH11180930A (en) | Production of optically active trans-cyclobutanedicarboxylic acids | |
| JP4305388B2 (en) | Method for producing 1,2,4-butanetriol | |
| KR101513561B1 (en) | A Novel Method for Preparing Fexofenadine HCl |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E902 | Notification of reason for refusal | ||
| E90F | Notification of reason for final refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| FPAY | Annual fee payment |
Payment date: 20200205 Year of fee payment: 4 |