KR930004511B1 - The seperation method of alpha-halo alkanoic acid optical isomers composition - Google Patents

The seperation method of alpha-halo alkanoic acid optical isomers composition Download PDF

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KR930004511B1
KR930004511B1 KR1019910002756A KR910002756A KR930004511B1 KR 930004511 B1 KR930004511 B1 KR 930004511B1 KR 1019910002756 A KR1019910002756 A KR 1019910002756A KR 910002756 A KR910002756 A KR 910002756A KR 930004511 B1 KR930004511 B1 KR 930004511B1
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oxazolidinone
phenyl
methyl
alpha
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KR920016397A (en
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김인오
송충의
이상기
이재균
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한국과학기술연구원
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    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/125—Saturated compounds having only one carboxyl group and containing ether groups, groups, groups, or groups
    • C07C59/135—Saturated compounds having only one carboxyl group and containing ether groups, groups, groups, or groups containing halogen
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    • C07—ORGANIC CHEMISTRY
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Abstract

A method for the separation of a recemic mixture of alpha- haloalkanoic acid comprises reacting a metal salt of a cpd. of formula (II) with a cpd. of formula (III) to obtain a pair of diastereoisomers of formula (IV), separating the diastereoisomers by column chromatography, esterifying the obtd. cpd., and reducing the optically pure cpd. of formula (V). In the formulas, R=C1-10 alkyl or C6-12 aryl; X=Cl, Br or I; R1=C1-10 alkyl or C6-12 aryl; R2=H, C1-10 alkyl or C6-12 aryl. The optically pure alpha- haloalkanoic acids are useful as intermediates in the mfr. of medicines or agricultural chemicals.

Description

α-할로알카노익산 라세미 혼합물의 광학 분할방법Optical division method of α-haloalkanoic acid racemic mixture

본 발명은 다음 일반식(I)의 α-할로알카노익산 라세미 혼합물의 새로운 광학 분할방법에 관한 것이다.The present invention relates to a new optical splitting method of the α-haloalkanoic acid racemic mixture of the following general formula (I).

Figure kpo00001
Figure kpo00001

상기 일반식(I)에서 R은 C1-10알킬기 또는 C5-12아릴기 이고 X는 염소원자 또는 브롬원자 또는 요오드원자를 나타낸다. 광학적으로 순수한 α-할로알카노익산들은 의약 농약 및 천연물등을 합성하는데 있어서 매우 중요한 중간체들이다. 특히 (S)-α-할로프로피오닉산은 (R)-Diclofop-methyl(Hoechst), (R)-fluszifop-butyl(ICI) 등 많은 페녹시프로피오닉산계 제초제의 중간체로서 공업적으로 대단히 중요하다.In the general formula (I), R is a C 1-10 alkyl group or C 5-12 aryl group and X represents a chlorine atom or bromine atom or iodine atom. Optically pure α-haloalkanoic acids are important intermediates for the synthesis of pharmaceutical pesticides and natural products. In particular, (S) -α-halopropionic acid is of great industrial importance as an intermediate of many phenoxypropionic acid herbicides such as (R) -Diclofop-methyl (Hoechst) and (R) -fluszifop-butyl (ICI).

Figure kpo00002
Figure kpo00002

광학적으로 순수한 α-할로알카노익산은 이들 화합물을 광학활성 유기염기인 (+)-신코닌, (-)-신코니딘, 브루신등을 이용하여 분할하거나 [H.J.nestler, Z. Naturforsch. B ; Anorg, Chem. Org. Chem. 35B(3)(1980)366 ; J. Crosby, Eur.Pat. Appl. 163435(1985) ; C.A.105(1985) 114607v], α-아미노산, α-히드록시산등을 화학적으로 변환시켜 얻는다. 또한 최근에는 리파제등의 효소를 이용해 라세미 혼합물로부터 각각의 광학이성질체를 분할하는 방법등이 발표되었다.[A.M.Klibanov, US-Pat, 4,601,987; A.M. Klibanov, J. Am. Chem, Soc., 1984 106, 2687].Optically pure [alpha] -haloalkanoic acid can be used to divide these compounds using optically active organic bases such as (+)-cinconine, (-)-cinconidine, brucin and the like [H. J. nestler, Z. Naturforsch. B; Anorg, Chem. Org. Chem. 35B (3) (1980) 366; J. Crosby, Eur. Pat. Appl. 163435 (1985); C.A. 105 (1985) 114607 v], α-amino acids, α-hydroxy acids and the like obtained by chemical conversion. Recently, a method of dividing each optical isomer from a racemic mixture using an enzyme such as lipase has been published. [A.M. Klibanov, US-Pat, 4,601,987; A.M. Klibanov, J. Am. Chem, Soc., 1984 106, 2687.

그러나 이들 공지의 방법들은 분리 공정이 까다로울 뿐 아니라 수율이 낮으므로 대규모 생산에는 이용할 수 없었다. 본 발명은 천연물로부터 얻어지는 광학활성 β-아미노알코올로부터 간단히 합성될 수 있는 다음 일반식(II)의 광학활성 옥사졸리디논 유도체를 키랄유도체(chiral derivating agent)로 이용하여 매우 간단한 크로마토그래피 조작에 의해 분리될 수 있는 한쌍의 디아스테레오 이성질체를 생성시킴으로서 보다 용이하고 경제적으로 많은 양의 광학적으로 순수한 α-할로알카노익산들을 얻는 방법이다.However, these known methods are not only difficult to separate, but also have low yields and cannot be used for large scale production. The present invention is isolated by a very simple chromatographic operation using an optically active oxazolidinone derivative of the following general formula (II) as a chiral derivating agent, which can be simply synthesized from optically active β-aminoalcohols obtained from natural products. It is a method to obtain a large amount of optically pure α-haloalkanoic acids easier and economically by generating a pair of diastereo isomers that can be made.

Figure kpo00003
Figure kpo00003

상기 일반식(II)에서 R1은 C1-10알릴기 또는 C6-12아릴기이다.In General Formula (II), R 1 is a C 1-10 allyl group or C 6-12 aryl group.

본 발명에 의한 일반식(I)의 세라믹 혼합물들의 분리방법은 아래 반응식으로 나타낼 수 있다.The separation method of the ceramic mixtures of general formula (I) according to the present invention can be represented by the following reaction scheme.

Figure kpo00004
Figure kpo00004

Figure kpo00005
Figure kpo00005

본 발명을 상세히 설명하면 다음과 같다.The present invention is described in detail as follows.

본 발명에 의한 α-할로알카노익산 라세미혼합물의 분할 방법의 특징은 일반식(III)의 α-할로알카노익산 유도체의 라세미 혼합물과 일반식(II)의 광학활성화합물을 반응시켜 한쌍의 디아스테레오 이성질체를 생성시킨후 이들의 상이한 물리적 성질을 이용하여 이들을 분리하고 이들로부터 광학적으로 순수한 α-할로알카노익산의 각각의 이성질체를 얻는 것이다.Characterization of the method for cleaving the α-haloalkanoic acid racemic mixture according to the present invention is characterized by the reaction of the racemic mixture of the α-haloalkanoic acid derivative of formula (III) with the optically active compound of formula (II) The diastereo isomers of are produced and then their different physical properties are used to separate them and to obtain the respective isomers of optically pure α-haloalkanoic acid from them.

일반식(III)의 화합물은 일반식(I)의 화합물들을 티오닐크롤라이드, 삼브롬화인, 옥살릴클로라이 등과 반응시켜 얻는다.Compounds of formula (III) are obtained by reacting compounds of formula (I) with thionylcrolide, phosphorus tribromide, oxalylchlori and the like.

본 발명에서 사용된 일반식(II)의 광학활성 옥사졸리디논 화합물들은 (S)-발린올, (1R,2S)-노레페드린, (1S,2R)-노레페드린, (S)-페닐 글리신올, (S)-알라닌올, (S)-페닐알라닌올, (S)-로이신올, (S)-tert-로이신올등과 같이 천연물로부터 쉽게 얻어지는 광학활성을 갖는 β-아미노알코올을 포스겐이나 디에틸카르보네이트 등과 반응시켜 얻으며 이때의 수득율은 거의 정량적으로서 90% 이상이다. 이들 합성법에 관한 보다 상세한 내용은 문헌[J.Am. Chem. Soc. 73(1951) 4199]등에 기재되어 있다.Optically active oxazolidinone compounds of the general formula (II) used in the present invention include (S) -valinol, (1R, 2S) -norephedrine, (1S, 2R) -norephedrine, (S) -phenyl Β-amino alcohols having optical activity easily obtained from natural products such as glycineol, (S) -alanineol, (S) -phenylalanineol, (S) -leucineol, and (S) -tert-leucineol, etc. It is obtained by reacting with diethyl carbonate and the like, the yield is almost 90% or more in quantitative terms. More details on these synthesis methods can be found in J. Am. Chem. Soc. 73 (1951) 4199, and the like.

일반식(II)의 화합물들을 같은 당량의 n-부틸리튬이나 나트륨하이드라이드 등과 반응시켜 일반식(II)의 화합물의 알칼리금속염을 얻은 후 이것을 계속해서 같은 당량의 일반식(III)의 화합물을 얻게 되며 이때의 수율은 거의 정량적이다. 이때 적합한 반응온도는 -20℃에서 20℃ 사이이다. 일반식(IV)의 화합물을 2개의 디아스테레오머 이성질체의 혼합물로서 이들은 일반적인 칼럼 크로마토그래피 방법에 의해서 쉽게 분리되어진다. 이때 R이 알킬인 경우에는 각 디아스테레오 이성질체의 전개비율(Rf)이 2에서 3사이로 매우 커다란 차이를 나타내므로 이들 디아스테레오 이성질체들은 단순한 크로마토그래피 조작에 의해 완벽하게 분리되는 반면 R이 아릴기인 경우에는 각 디아스테레오 이성질체의 전개비율이 일반적으로 1.5이하이았다. 또한 전개 용매로는 에틸아세테이트와 헥산을 4 : 1에서 10 : 1로 혼합하여 사용한 것이 가장 바람직하였다.Compounds of formula (II) are reacted with the same equivalents of n-butyllithium or sodium hydride to obtain alkali metal salts of compounds of formula (II), which are then obtained to obtain compounds of formula (III) of the same equivalents. Yield is almost quantitative. Suitable reaction temperatures at this time are between -20 ° C and 20 ° C. Compounds of formula (IV) are mixtures of two diastereomeric isomers which are readily separated by conventional column chromatography methods. In this case, when R is alkyl, the diastereo isomer ratio (R f ) is very large, ranging from 2 to 3, and these diastereoisomers are completely separated by simple chromatography, whereas R is an aryl group. In general, the development ratio of each diastereoisomer was less than 1.5. As the developing solvent, ethyl acetate and hexane were most preferably used in a mixture of 4: 1 to 10: 1.

Figure kpo00006
Figure kpo00006

상기 일반식(IV)의 디아스테레오 이성질체에 있어서, 각각 한쌍의 기호

Figure kpo00007
(R2가 수소원자인 경우),
Figure kpo00008
(R2가 수소원자가 아닌 경우)의 첫머리 글자는 α-할로알카노익산 부위의 것이고 두번째 글자는 또는 글자들은 광학활성옥사졸리디논기에 관한 것이다. 또한, 이때 광학활성 옥사졸리디논 부위의 RS 또는 SR 등의 표시는 각각 치환체 R1과 R2가 있는 비대칭 탄소의 절대구조를 뜻한다.In the diastereo isomer of the general formula (IV), each pair of symbols
Figure kpo00007
(When R 2 is a hydrogen atom),
Figure kpo00008
The first letter of the letter (when R 2 is not a hydrogen atom) is the α-haloalkanoic acid moiety and the second letter or the letter relates to the optically active oxazolidinone group. In this case, RS or SR of the optically active oxazolidinone moiety means an absolute structure of an asymmetric carbon having substituents R 1 and R 2 , respectively.

일반식(IV) 화합물을 각각의 디아스테레오 이성질체로 분리한 후 이들 각각의 이성질체를 알칼리금속알콕사이드와 테트라하이드로푸란 용매존재하에서 -20℃-0℃에서 반응시키면 99.5% 이상의 광학적순도를 갖는 일반식(IV)의 에스테르 혼합물을 얻는다. 특히 이때 키랄유도체로 사용된 일반식(II)의 옥사졸리디논화합물은 분해되거나 라세미화 되지 않고 거의 완벽하게 재회수되며 이것이 본 발명의 커다란 장점중의 하나이다. 이미 앞서 설명한 바와같이 알킬-(S)-2-할로프로피오네이트는 (R)-페녹시프로피오닉산 유도체 계통 제초제의 합성에 특히 주용한 중간제 이다.Compound (IV) is separated into diastereo isomers and each of the isomers is reacted at -20 ° C-0 ° C in the presence of an alkali metal alkoxide and tetrahydrofuran solvent to obtain a general formula having an optical purity of 99.5% or more. Obtain the ester mixture of IV). In particular, the oxazolidinone compound of the general formula (II) used as the chiral derivative is not completely degraded or racemized and is almost completely recovered. This is one of the great advantages of the present invention. As already described above, alkyl- (S) -2-halopropionate is an intermediate that is particularly dominant in the synthesis of (R) -phenoxypropionic acid derivative herbicides.

Figure kpo00009
Figure kpo00009

이렇게 얻어진 광학적으로 순수한 일반식(V)의 에스테르화합물을 가수분해하거나 벤질에스테르의 경우 팔라듐 촉매 존재하에서 수소화 반응시키면 광학적으로 순수한(광학적순도 99.5% 이상)일반식(I)의 α-할로알카노익산을 얻을 수 있다.The optically pure ester compound of formula (V) thus obtained is hydrolyzed or hydrogenated in the case of benzyl ester in the presence of a palladium catalyst to give optically pure (more than 99.5% of optical purity) α-haloalkanoic acid of formula (I). Can be obtained.

Figure kpo00010
Figure kpo00010

이상에서 기술한 바와같이 본 발명에 의한 α-할로알카노익산 라세미 혼합물의 분할방법은 기존의 방법들과는 달리 간편한 방법으로 각각의 이성질체를 거의 정략적인 수율로 분리할 수 있는 매우 경제적이며 우수한 방법이다.As described above, the method of dividing the α-haloalkanoic acid racemic mixture according to the present invention is a very economical and excellent method that can separate each isomer in almost quantitative yield by a simple method unlike the existing methods. .

본 발명을 다음의 몇가지 대표적인 실시예를 들어 상세히 설명한다. 특별한 언급이 없는 한 다음의 반응들은 질소대기하에서 진행한다.The invention is illustrated in detail by the following several representative examples. Unless otherwise noted, the following reactions proceed under nitrogen atmosphere.

[실시예 1]Example 1

N-[2-브로모프로피오닐]-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논N- [2-bromopropionyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

108.5ml의 n-부틸리튬(2.5M THF 용액)을 450ml의 테트라하이드로푸란에 48.13g의 (4R,5S)-4-메틸-5-페닐-2-옥사졸리디논을 녹인 용액에 -10℃의 온도에서 첨가하고 이 온도에서 30분간 교반한다. 이 반응용액을 28.4ml의 (+)-2-브로모 프로피오닐 브로마이드를 150ml의 무수테트라하이드로푸란에 녹인 용액에 -10℃에서 첨가한다.108.5 ml of n-butyllithium (2.5 M THF solution) was dissolved in 450 ml of tetrahydrofuran in 48.13 g of (4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone at -10 ° C. Add at temperature and stir for 30 minutes at this temperature. The reaction solution is added to a solution in which 28.4 ml of (+)-2-bromo propionyl bromide is dissolved in 150 ml of anhydrous tetrahydrofuran at -10 ° C.

반응혼합물을 약 30분간 교반 반응시킨후 150ml의 암모늄클롤이드 수용액에 붓는다. 유기층을 에틸아세테이트로 추출한후 모아진 유기층을 무수망초로 건조한 후 감압하에서 용매를 제거하면 흰색 결정의 N-[2-브로모프로피오닐]-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논의 디아스테레오 이성질체의 혼합물이 얻어진다. 이렇게 합성한 디아스테레오이성질체 혼합물을 컬럼크로마토그래피(전개용매 : n-헥산 : 에틸아세테이트=7 : 1)를 통해 각각의 이성질체로 분리한다.The reaction mixture is stirred for about 30 minutes and then poured into 150 ml of an aqueous solution of ammonium chloride. The organic layer was extracted with ethyl acetate and the combined organic layers were dried over anhydrous forget-me-not, and the solvent was removed under reduced pressure. A mixture of diastereo isomers of oxazolidinones is obtained. The diastereoisomeric mixture thus synthesized is separated into individual isomers through column chromatography (developing solvent: n-hexane: ethyl acetate = 7: 1).

i) 첫번째 전개용질 : N-[(2S)-2-브로모프로피오닐]-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논i) first developing solute: N-[(2S) -2-bromopropionyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR(CDCl3)δ : 0.94(d,J=6.6HzH,3H,-N-CH(CH3)-), 1.86(d,J=6.7Hz,3H,CH3-CH(Br)-), 4.77('p',1H,-N-CH(CH3-CH-), 5.75(q,J=7Hz,1H,CH3-CH(Br)-), 5.76(d,J=7Hz,1H,-CH(C6H5)-O-), 7.2-7.6(m,5H,C6H5)NMR (CDCl 3 ) δ: 0.94 (d, J = 6.6 HzH, 3H, -N-CH (CH 3 )-), 1.86 (d, J = 6.7 Hz, 3H, CH 3 -CH (Br)-), 4.77 ('p', 1H, -N-CH (CH 3 -CH-), 5.75 (q, J = 7Hz, 1H, CH 3 -CH (Br)-), 5.76 (d, J = 7Hz, 1H, -CH (C 6 H 5 ) -O-), 7.2-7.6 (m, 5H, C 6 H 5 )

mp : 90℃mp: 90 ℃

ii) 두번째 전개용질 : N-[(2R)-2-브로모프로피오닐]-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논ii) second developing solute: N-[(2R) -2-bromopropionyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR(CDCl3)δ : 0.91(d,J=6.6Hz,3H,-N-CH(CH3)-), 1.86(d,J=6.7Hz,CH3-CH(Br)-), 4.84('p',1H,-N-CH(CH3)-CH-), 5.68(q,J=7Hz,1H,CH3-CH(Br)-), 5.74(d,J=7Hz,1H,-CH(C6H5)-O-), 7.2-7.6(m,5H,-C6H5)NMR (CDCl 3 ) δ: 0.91 (d, J = 6.6 Hz, 3H, -N-CH (CH 3 )-), 1.86 (d, J = 6.7 Hz, CH 3 -CH (Br)-), 4.84 ( 'p', 1H, -N-CH (CH 3 ) -CH-), 5.68 (q, J = 7Hz, 1H, CH 3 -CH (Br)-), 5.74 (d, J = 7Hz, 1H,- CH (C 6 H 5 ) -O-), 7.2-7.6 (m, 5H, -C 6 H 5 )

mp : 98℃mp: 98 ℃

[실시예 2]Example 2

N-[2-클로로프로피오닐)-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논N- [2-chloropropionyl)-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

실험방법은 실시예 1에서와 동일하며 수율은 거의 정략적임.The experimental method was the same as in Example 1, and the yield was almost political.

i) 첫번째 전개용질 : N-[(2R)-2-클로로프로피오닐]-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논i) First developing solute: N-[(2R) -2-chloropropionyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR(CDCl3)δ : 0.9(d,J=8Hz,3H,-N-CH(CH3)-), 1.6(d,J=6Hz,3H,CH3-CH(Cl)-), 4.80('p',1H,-N-CH(CH3)-CH-), 5.62(q,J=7Hz,1H,CH3-CH(Cl)-), 5.77(d,J=7Hz,1H,-CH(C6H5)-O-), 7.4(m,5H,C6H5-)NMR (CDCl 3 ) δ: 0.9 (d, J = 8Hz, 3H, -N-CH (CH 3 )-), 1.6 (d, J = 6Hz, 3H, CH 3 -CH (Cl)-), 4.80 ( 'p', 1H, -N-CH (CH 3 ) -CH-), 5.62 (q, J = 7Hz, 1H, CH 3 -CH (Cl)-), 5.77 (d, J = 7Hz, 1H,- CH (C 6 H 5 ) -O-), 7.4 (m, 5H, C 6 H 5- )

mp : 95℃mp: 95 ℃

ii) 두번째 전개용질 : N-[(2R)-2-클로로프로피오닐]-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논ii) second developing solute: N-[(2R) -2-chloropropionyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR(CDCl3)δ : 0.91(d,J=8Hz,3H-N-CH(CH3)-), 1.6(d,J=6Hz,3H,CH3-CH(Cl)-), 4.83('p',1H,-N-CH(CH3)-CH-), 5.52(q,J=7Hz,1H,CH3-CH(Cl)-), 5.70(d,J=7Hz,1H,-CH(C6H5)-O-), 7.4(m,5H,C6H5-)NMR (CDCl 3 ) δ: 0.91 (d, J = 8 Hz, 3H-N-CH (CH 3 )-), 1.6 (d, J = 6Hz, 3H, CH 3 -CH (Cl)-), 4.83 (' p ', 1H, -N-CH (CH 3 ) -CH-), 5.52 (q, J = 7 Hz, 1H, CH 3 -CH (Cl)-), 5.70 (d, J = 7 Hz, 1H, -CH (C 6 H 5 ) -O-), 7.4 (m, 5H, C 6 H 5- )

[실시예 3]Example 3

N-[2-브로모부티릴]-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논N- [2-bromobutyryl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

실험방법은 실시예 1에서와 동일하며 수율은 거의 정략적임.The experimental method was the same as in Example 1, and the yield was almost political.

i) 첫번째 전개용질 : N-[(2-브로모부티릴]-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논i) first developing solute: N-[(2-bromobutyryl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR(CDCl3)δ : 0.90(d,J=7Hz,3H,-N-CH(CH3)-), 1.06(m,J=7Hz,3H,CH3-CH2-), 1.8-2.35(m,2H,CH3-CH2-CH(Br)-(d,J=7Hz,3H,CH3-CH(Br)-), 4.81('p',1H,-N-CH(CH3)-CH-), 5.61(q,J=7Hz,1H,CH2-CH(Br)-), 5.77(d,J=7Hz,1H,-CH(C6H5)-O-), 7.1-7.6(m,5H,-C6H5)NMR (CDCl 3 ) δ: 0.90 (d, J = 7Hz, 3H, -N-CH (CH 3 )-), 1.06 (m, J = 7Hz, 3H, CH 3 -CH 2- ), 1.8-2.35 ( m, 2H, CH 3 -CH 2 -CH (Br)-(d, J = 7Hz, 3H, CH 3 -CH (Br)-), 4.81 ('p', 1H, -N-CH (CH 3 ) -CH-), 5.61 (q, J = 7 Hz, 1H, CH 2 -CH (Br)-), 5.77 (d, J = 7 Hz, 1H, -CH (C 6 H 5 ) -O-), 7.1- 7.6 (m, 5H, -C 6 H 5 )

mp : 73℃mp: 73 ℃

ii) 두번째 전개용질 : N-[(2R)-2-브로모부티릴]-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논ii) second developing solute: N-[(2R) -2-bromobutyryl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR(CDCl3)δ : 0.95(d,J=7Hz,3H,-N-CH(CH3)-), 1.1(t,J=7Hz,3H,CH3-CH2-), 2.11(m,2H,CH3-CH2-CH(Br)-), 4.83(m,1H,-N-CH(CH3)-CH-), 5.54(t,J=7Hz,1H,-CH2-CH(Br)-), 5.70(d,J=7Hz,1H,-CH(C6H5)-O-), 7.2-7.5(br,s,5H,-C6H5)NMR (CDCl 3 ) δ: 0.95 (d, J = 7 Hz, 3H, -N-CH (CH 3 )-), 1.1 (t, J = 7 Hz, 3H, CH 3 -CH 2- ), 2.11 (m, 2H, CH 3 -CH 2 -CH (Br)-), 4.83 (m, 1H, -N-CH (CH 3 ) -CH-), 5.54 (t, J = 7 Hz, 1H, -CH 2 -CH ( Br)-), 5.70 (d, J = 7 Hz, 1H, -CH (C 6 H 5 ) -O-), 7.2-7.5 (br, s, 5H, -C 6 H 5 )

mp : 94℃mp: 94 ℃

[실시예 4]Example 4

N-[2-브로모-3-메틸부티릴]-(4R,5S)-4-메틸-5-페닐-옥사졸리디논N- [2-bromo-3-methylbutyryl]-(4R, 5S) -4-methyl-5-phenyl-oxazolidinone

실험방법은 실시예 1에서와 동일하며 수율은 거의 정략적임.The experimental method was the same as in Example 1, and the yield was almost political.

i) 첫번째 전개용질 : N-[(2S)-2-브로모-3-메틸부티릴]3-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논i) First developing solute: N-[(2S) -2-bromo-3-methylbutyryl] 3- (4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR(CDCl3)δ : 0.92(d,J=7HzH,3H,-N-CH(CH3)-), 1.05(d,J=7Hz,3H,CH3)2CH), 1.15(d,J=7Hz,3H,(CH3)2CH-), 2.35(sym.m.1H,(CH3)2CH-), 4.82('p',1H,-N-CH(CH3)-CH-), 5.56(d,J=7Hz,1H,(CH3)2CH-CH(Br)-), 5.75(d,J=7Hz,1H,-CH(C6H5)-O-), 7.2-7.6(m,5H,-C6H5)NMR (CDCl 3 ) δ: 0.92 (d, J = 7HzH, 3H, -N-CH (CH 3 )-), 1.05 (d, J = 7Hz, 3H, CH 3 ) 2 CH), 1.15 (d, J = 7 Hz, 3H, (CH 3 ) 2 CH-), 2.35 (sym.m.1H, (CH 3 ) 2 CH-), 4.82 ('p', 1H, -N-CH (CH 3 ) -CH- ), 5.56 (d, J = 7Hz, 1H, (CH 3 ) 2 CH-CH (Br)-), 5.75 (d, J = 7Hz, 1H, -CH (C 6 H 5 ) -O-), 7.2 -7.6 (m, 5H, -C 6 H 5 )

ii) 두번째 전개용질 : N-[(2R)-2-브로모-3-메틸부티릴]-(4R,5S)-4-메틸-5-페닐-5-옥사졸리디논ii) second developing solute: N-[(2R) -2-bromo-3-methylbutyryl]-(4R, 5S) -4-methyl-5-phenyl-5-oxazolidinone

NMR(CDCl3)δ : 0.92(d,J=6Hz,3H,-N-CH(CH3)-), 1.06(d,J=7Hz,3H,(CH3)2CH-), 1.18(d,J=7Hz,3H,(CH3)2CH-), 2.37(sym.m,1H,(CH3)2CH-), 4.84('q',1H,-N-CH(CH3)-CH), 5.49(d,J=7Hz8.8 1H,1(CH3)2CH(Br)-), 5.71(d,J=7.4,1H,-CH(C2H5)-O-), 7.2-7.6(m,5H,-C6H5)NMR (CDCl 3 ) δ: 0.92 (d, J = 6Hz, 3H, -N-CH (CH 3 )-), 1.06 (d, J = 7Hz, 3H, (CH 3 ) 2 CH-), 1.18 (d , J = 7Hz, 3H, (CH 3 ) 2 CH-), 2.37 (sym.m, 1H, (CH 3 ) 2 CH-), 4.84 ('q', 1H, -N-CH (CH 3 )- CH), 5.49 (d, J = 7 Hz8.8 1H, 1 (CH 3 ) 2 CH (Br)-), 5.71 (d, J = 7.4,1H, -CH (C 2 H 5 ) -O-), 7.2-7.6 (m, 5H, -C 6 H 5 )

mp : 79℃mp: 79 ℃

[실시예 5]Example 5

N-[2-브로모헥사노일]-(4R,5S)-4-메틸-5-페닐-옥사졸리디논N- [2-bromohexanoyl]-(4R, 5S) -4-methyl-5-phenyl-oxazolidinone

실험방법은 실시예 1에서와 동일하며 수율은 거의 정력적임.The experimental method was the same as in Example 1, and the yield was almost energetic.

i) 첫번째 전개용질 : N-[(2S)-2-브로모헥사노일]-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논i) First developing solute: N-[(2S) -2-bromohexanoyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR(CDCl3)δ : 0.9(m,6H,CH3-CH2-, N-CH(CH3)-), 1.4(m,4H,CH3-CH2-CH2-), 2.1(m,2H,-CH2-CH(Br)-), 4.80('p',J=7Hz,1H,-N-CH(CH3)-CH-), 5.65(t,8Hz,1H,-CH2-CH(Br)-), 5.75(d,J=8Hz,1H,-CH(C6H5)-O-), 7.2-7.6(m,5H-C6H5)NMR (CDCl 3 ) δ: 0.9 (m, 6H, CH 3 -CH 2- , N-CH (CH 3 )-), 1.4 (m, 4H, CH 3 -CH 2 -CH 2- ), 2.1 (m , 2H, -CH 2 -CH (Br)-), 4.80 ('p', J = 7Hz, 1H, -N-CH (CH 3 ) -CH-), 5.65 (t, 8Hz, 1H, -CH 2 -CH (Br)-), 5.75 (d, J = 8 Hz, 1H, -CH (C 6 H 5 ) -O-), 7.2-7.6 (m, 5H-C 6 H 5 )

mp : 111℃mp: 111 ℃

ii) 두번째 전개용질 : N-[(2R)-2-브로모헥사노일]-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논ii) second developing solute: N-[(2R) -2-bromohexanoyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR(60MHz,CDCl3)δ : 0.9(m,6H,CH3-CH2-CH3-CH-), 1.4(m,4H,CH3-CH2-CH2-), 2.1(m,2H,-CH2-CH(Br)-), 4.84('p',1H,-N-CH(CH3-CH-), 5.62(t,J=7.4Hz,1H,-CH2-CH(Br)-), 5.71(d,J=7.7Hz,1H,-CH(C6H5)-O-), 7.2-7.6(m,5H,-C6H5)NMR (60MHz, CDCl 3 ) δ: 0.9 (m, 6H, CH 3 -CH 2 -CH 3 -CH-), 1.4 (m, 4H, CH 3 -CH 2 -CH 2- ), 2.1 (m, 2H , -CH 2 -CH (Br)-), 4.84 ('p', 1H, -N-CH (CH 3 -CH-), 5.62 (t, J = 7.4Hz, 1H, -CH 2 -CH (Br )-), 5.71 (d, J = 7.7 Hz, 1H, -CH (C 6 H 5 ) -O-), 7.2-7.6 (m, 5H, -C 6 H 5 )

mp : 89℃mp: 89 ℃

[실시예 6]Example 6

N-[브로모페닐아세틸]-(4R,5S)-메틸-5-페닐-2-옥사졸리디논N- [bromophenylacetyl]-(4R, 5S) -methyl-5-phenyl-2-oxazolidinone

실험방법은 실시예 1에서와 동일하며 수율은 거의 정략적임.The experimental method was the same as in Example 1, and the yield was almost political.

i) 첫번째 전개용질 : N-[(2S)-브로모페닐아세틸]-(4R,5S)-메틸-5-페닐-2-옥사졸리디논i) First developing solute: N-[(2S) -bromophenylacetyl]-(4R, 5S) -methyl-5-phenyl-2-oxazolidinone

NMR(CDCl3)δ : 0.9(d,J=9Hz,3H,-N-CH(CH3)-), 4.85('p',1H,-N-CH(CH3)-CH-), 5.75(d,J=7Hz,1H,-CH(C6H5)-O-), 6.93(s,1H,C6H5CH(Br)-), 7.8(m,10H,2 C6H5-)NMR (CDCl 3 ) δ: 0.9 (d, J = 9Hz, 3H, -N-CH (CH 3 )-), 4.85 ('p', 1H, -N-CH (CH 3 ) -CH-), 5.75 (d, J = 7Hz, 1H, -CH (C 6 H 5 ) -O-), 6.93 (s, 1H, C 6 H 5 CH (Br)-), 7.8 (m, 10H, 2 C 6 H 5 -)

mp : 161℃mp: 161 ℃

ii) 첫번째 전개용질 : N-[(2R)-브로모페닐아세틸]-(4R,5S)-메틸-5-페닐-2-옥사졸리디논ii) first developing solute: N-[(2R) -bromophenylacetyl]-(4R, 5S) -methyl-5-phenyl-2-oxazolidinone

NMR(CDCl3)δ : 0.9(d,J=9Hz,3H,-N-CH(CH3)-), 4.9(m,1H,-N-CH(CH3)-CH-), 5.8(d,J=7Hz,1H,-CH(C6H5)-O-), 6.9(s,1H,C6H5CH(Br)-), 7.8(m,10H,2 C6H5)NMR (CDCl 3 ) δ: 0.9 (d, J = 9Hz, 3H, -N-CH (CH 3 )-), 4.9 (m, 1H, -N-CH (CH 3 ) -CH-), 5.8 (d , J = 7Hz, 1H, -CH (C 6 H 5 ) -O-), 6.9 (s, 1H, C 6 H 5 CH (Br)-), 7.8 (m, 10H, 2 C 6 H 5 )

[실시예 7]Example 7

N-[2-브로모-4-페닐부티릴]-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논N- [2-bromo-4-phenylbutyryl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

실험방법은 실시예 1에서와 동일하며 수율은 거의 정략적임.The experimental method was the same as in Example 1, and the yield was almost political.

i) 첫번째 전개용질 : N-[(2S)-브로모-4-페닐부티릴]-(4R,5S)-메틸-5-페닐-2-옥사졸리디논i) First developing solute: N-[(2S) -bromo-4-phenylbutyryl]-(4R, 5S) -methyl-5-phenyl-2-oxazolidinone

NMR(200MHz,CDCl3)δ 0.94(d,J=7Hz,3H,CH3-CH-N), 2.0-3.0(d,4H,-CH2CH2-), 4.8('p',1H,CH3-CH(N)-CH), 5.7(d,J=7Hz,1H,CH3-CH-Br), 5.8(d,J=7Hz,1H,-CH(O)-C6H5), 7.0-7.4(m,10H,2 C6H5-)NMR (200MHz, CDCl 3 ) δ 0.94 (d, J = 7Hz, 3H, CH 3 -CH-N), 2.0-3.0 (d, 4H, -CH 2 CH 2- ), 4.8 ('p', 1H, CH 3 -CH (N) -CH), 5.7 (d, J = 7Hz, 1H, CH 3 -CH-Br), 5.8 (d, J = 7Hz, 1H, -CH (O) -C 6 H 5 ) , 7.0-7.4 (m, 10H, 2 C 6 H 5- )

ii) 두번째 전개용질 : N-[(2R)-브로모-4-페닐부티릴]-(4R,5S)-메틸-5-페닐-2-옥사졸리디논ii) second developing solute: N-[(2R) -bromo-4-phenylbutyryl]-(4R, 5S) -methyl-5-phenyl-2-oxazolidinone

NMR(200MHz,CDCl3)δ : 0.94(d,J=7Hz,3H,CH3-CH-N), 2.0-3.0(m,4H,-CH2CH2-), 4.8('p',1H,CH3-CH(N)-CH), 5.7(d,J=7Hz,1H,CH3-CH-Br), 5.8(d,J=7Hz,1H,-CH(O)-C6H5), 7.0-7.4(m,10H,2-C6H5)NMR (200MHz, CDCl 3 ) δ: 0.94 (d, J = 7Hz, 3H, CH 3 -CH-N), 2.0-3.0 (m, 4H, -CH 2 CH 2- ), 4.8 ('p', 1H , CH 3 -CH (N) -CH), 5.7 (d, J = 7Hz, 1H, CH 3 -CH-Br), 5.8 (d, J = 7Hz, 1H, -CH (O) -C 6 H 5 ), 7.0-7.4 (m, 10H, 2-C 6 H 5 )

[실시예 8]Example 8

벤질-(2R)-2-브로모프로피오네이트Benzyl- (2R) -2-bromopropionate

15.5g(0.1431mol)의 벤질 알코올과 57ml(2.5M 테트라하이드로후란용액)의 부틸리튬으로 반응시켜 얻은 리튬벤질레이트를 44.5g(0.1425mol)의 N-[(2R)-2-브로모프로피오닐]-(4R,5S)-4-메틸-5-페닐-2-옥사졸리디논을 350ml의 테트라하이드로후란에 녹인 용액에 -10℃에서 천천히 첨가한다. 1시간 교반후 반응물을 암모늄클로라이드 수용액에 부어 중성이 되게 한 다음 에틸아세테이트로 유기물을 추출한다. 유기층을 무수망초로 건조시킨후 용매를 제거한후 감압증류하여 생성물을 얻는다.44.5 g (0.1425 mol) of N-[(2R) -2-bromopropy was obtained by reacting lithium benzylate obtained by reacting 15.5 g (0.1431 mol) of benzyl alcohol with 57 ml (2.5 M tetrahydrofuran solution) of butyllithium. Onyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone is slowly added to a solution of 350 ml of tetrahydrofuran at -10 ° C. After stirring for 1 hour, the reaction mixture was poured into an aqueous ammonium chloride solution to neutralize and the organics were extracted with ethyl acetate. The organic layer is dried over anhydrous forget-me-not, the solvent is removed, and the product is evaporated under reduced pressure.

수율 : 99% 이상Yield: 99% or more

bP : 85℃/0.4mmHgbP: 85 ℃ / 0.4mmHg

NMR(CDCl3)δ : 1.8(d,J=7Hz,3H,CH3-CH(Br)-), 4.4(q,J=7Hz,1H,CH3-CH(Br)-), 5.2(s,2H,-CH2-C6H5), 7.4(s,5H,-C6H5)NMR (CDCl 3 ) δ: 1.8 (d, J = 7Hz, 3H, CH 3 -CH (Br)-), 4.4 (q, J = 7Hz, 1H, CH 3 -CH (Br)-), 5.2 (s , 2H, -CH 2 -C 6 H 5 ), 7.4 (s, 5H, -C 6 H 5 )

[실시예 9]Example 9

부틸-(2S)-2-브로모프로피오네이트Butyl- (2S) -2-bromopropionate

실험방법은 실시예 9와 동일함.Experimental method is the same as in Example 9.

수율 : 92%Yield: 92%

bp : 86-7℃/15mmHgbp: 86-7 ℃ / 15mmHg

[α]d=18.9°[α] d = 18.9 °

[실시예 10]Example 10

(2S)-2-브로모프로피오닉산(2S) -2-bromopropionic acid

4.9g(0.02mol)의 벤질-(2S)-2-브로모프로피오네이트를 100ml의 에틸알코올에 녹인뒤에 여기에 500mg의 10% 팔라듐 활성탄을 첨가하여 수소환원 반응기에서(수소압력 30psi)2-4시간 교반하면서 반응시킨다. 반응완결후 팔라듐 활성탄을 여과제거하고 에틸알코올을 증류 제거하여 2.9g의 프로피오닉산을 얻었다.4.9 g (0.02 mol) of benzyl- (2S) -2-bromopropionate was dissolved in 100 ml of ethyl alcohol, followed by addition of 500 mg of 10% palladium activated carbon in a hydrogen reduction reactor (hydrogen pressure 30 psi) 2- The reaction is stirred for 4 hours. After completion of the reaction, palladium activated carbon was filtered off, and ethyl alcohol was distilled off to obtain 2.9 g of propionic acid.

수율 : 95% 이상Yield: 95% or more

bp : 72-80℃/0.3-0.4mmHgbp: 72-80 ℃ / 0.3-0.4mmHg

[α]x=-26.6℃(c-q,CHCl3)(ee=99.9%)[α] x = -26.6 ° C. (cq, CHCl 3 ) (ee = 99.9%)

Claims (1)

일반식(II) 화합물의 금속염을 일반식(III)의 화합물과 반응시켜 일반식(IV)의 한쌍의 디아스테레오 이성질체를 생성시킨 후 컬럼크로마토그래피를 통해 이들 이성질체를 분리하고 컬럼크로마토그래피를 통해 분리된 일반식(IV)의 화합물의 각각의 광학이성질체를 에스테르화하여 광학적으로 순수한 일반식(V)의 화합물을 얻고 일반식(V)의 화합물을 환원시키는 α-할로알카노익산라세미 혼합물의 광학분말 방법.The metal salt of the compound of formula (II) is reacted with the compound of formula (III) to generate a pair of diastereoisomers of formula (IV), and these isomers are separated by column chromatography and separated by column chromatography. Of the α-haloalkanoic acid racemic mixture which esterifies each of the optical isomers of the compound of formula (IV) to obtain an optically pure compound of formula (V) and reduces the compound of formula (V). Powder method.
Figure kpo00011
Figure kpo00011
 상기식들 중에서 R은 C1-10알킬기 또는 C0-12아릴기이고, X는 염소원자 또는 브롬원자 또는 요오드원자이고, R1은 C1-10알킬기 또는 C6-12아릴기이고, R2는 수소원자 또는 C1-10알킬기 또는 C6-12아릴기이고, R'는 에스테르잔기임.In the above formula, R is a C 1-10 alkyl group or C 0-12 aryl group, X is a chlorine atom or bromine atom or iodine atom, R 1 is a C 1-10 alkyl group or C 6-12 aryl group, R 2 is a hydrogen atom or a C 1-10 alkyl group or C 6-12 aryl group, and R 'is an ester residue.
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