JPH0435464B2 - - Google Patents
Info
- Publication number
- JPH0435464B2 JPH0435464B2 JP57140299A JP14029982A JPH0435464B2 JP H0435464 B2 JPH0435464 B2 JP H0435464B2 JP 57140299 A JP57140299 A JP 57140299A JP 14029982 A JP14029982 A JP 14029982A JP H0435464 B2 JPH0435464 B2 JP H0435464B2
- Authority
- JP
- Japan
- Prior art keywords
- optically active
- dibenzyl
- carboxy
- general formula
- represented
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000002148 esters Chemical class 0.000 claims description 27
- 239000013078 crystal Substances 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- BSWUHWZVMBPALP-SJORKVTESA-N (4r,5s)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid Chemical compound N1([C@H]([C@H](N(C1=O)CC=1C=CC=CC=1)C(=O)OC)C(O)=O)CC1=CC=CC=C1 BSWUHWZVMBPALP-SJORKVTESA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 238000000354 decomposition reaction Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- RVNXWRRDPPIXHE-RBUKOAKNSA-N (4s,5r)-1,3-dibenzyl-2-oxo-5-propan-2-yloxycarbonylimidazolidine-4-carboxylic acid Chemical compound N1([C@@H]([C@@H](N(C1=O)CC=1C=CC=CC=1)C(=O)OC(C)C)C(O)=O)CC1=CC=CC=C1 RVNXWRRDPPIXHE-RBUKOAKNSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- RVNXWRRDPPIXHE-MOPGFXCFSA-N (4r,5s)-1,3-dibenzyl-2-oxo-5-propan-2-yloxycarbonylimidazolidine-4-carboxylic acid Chemical compound N1([C@H]([C@H](N(C1=O)CC=1C=CC=CC=1)C(=O)OC(C)C)C(O)=O)CC1=CC=CC=C1 RVNXWRRDPPIXHE-MOPGFXCFSA-N 0.000 description 2
- OUWRJFDZBGBXKT-ZWKOTPCHSA-N (4s,5r)-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid Chemical compound N1([C@@H]([C@@H](N(C1=O)CC=1C=CC=CC=1)C(=O)OCC)C(O)=O)CC1=CC=CC=C1 OUWRJFDZBGBXKT-ZWKOTPCHSA-N 0.000 description 2
- BSWUHWZVMBPALP-DLBZAZTESA-N (4s,5r)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid Chemical compound N1([C@@H]([C@@H](N(C1=O)CC=1C=CC=CC=1)C(=O)OC)C(O)=O)CC1=CC=CC=C1 BSWUHWZVMBPALP-DLBZAZTESA-N 0.000 description 2
- -1 (keto-imidazolide)-2-keto-tetrahydrofuran Chemical compound 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- OUWRJFDZBGBXKT-MSOLQXFVSA-N (4r,5s)-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid Chemical compound N1([C@H]([C@H](N(C1=O)CC=1C=CC=CC=1)C(=O)OCC)C(O)=O)CC1=CC=CC=C1 OUWRJFDZBGBXKT-MSOLQXFVSA-N 0.000 description 1
- DTGGNTMERRTPLR-UHFFFAOYSA-N 1,2-diphenylethanamine Chemical compound C=1C=CC=CC=1C(N)CC1=CC=CC=C1 DTGGNTMERRTPLR-UHFFFAOYSA-N 0.000 description 1
- AZJLZOVPJNPLGE-UHFFFAOYSA-N 1-(4-methylphenyl)-2-phenylethanamine Chemical compound C1=CC(C)=CC=C1C(N)CC1=CC=CC=C1 AZJLZOVPJNPLGE-UHFFFAOYSA-N 0.000 description 1
- DYPUFZGNHHLMAL-UHFFFAOYSA-N 2-(4-chlorophenyl)-1-phenylethanamine Chemical compound C=1C=CC=CC=1C(N)CC1=CC=C(Cl)C=C1 DYPUFZGNHHLMAL-UHFFFAOYSA-N 0.000 description 1
- ZICDZTXDTPZBKH-UHFFFAOYSA-N 2-(4-methylphenyl)-1-phenylethanamine Chemical compound C1=CC(C)=CC=C1CC(N)C1=CC=CC=C1 ZICDZTXDTPZBKH-UHFFFAOYSA-N 0.000 description 1
- OWOUKRYOZIZVFK-UHFFFAOYSA-N 2-methylphenethylamine Chemical compound CC1=CC=CC=C1CCN OWOUKRYOZIZVFK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 150000007925 phenylethylamine derivatives Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NLYMVJUAPLEDSY-UHFFFAOYSA-N propyl 2-oxoimidazolidine-1-carboxylate Chemical compound CCCOC(=O)N1CCNC1=O NLYMVJUAPLEDSY-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は、一般式()および()
(上式中、R1は炭素数1〜5のアルキル基ま
たはアルケニル基を示す。)
で示される光学活性なハーフエステルの混合物
に、一般式()
(式中、R2,R3は水素原子、ハロゲン原子ま
たはメチル基を示す。)
で示される光学活性なd−またはl−アミンを反
応させて一般式()または()で示される光
学活性なハーフエステルと一般式()で示され
る光学活性なd−またはl−アミンとの塩である
析出結晶を得、次いでこれを分解する(但し、一
般式()および()におけるR1がメチル基
であり、一般式()におけるR2がメチル基で
R3が水素原子である場合の組合せを除く)こと
を特徴とする光学活性なハーフエステルの分離法
に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to general formulas () and () (In the above formula, R 1 represents an alkyl group or an alkenyl group having 1 to 5 carbon atoms.) A mixture of optically active half esters represented by the general formula () (In the formula, R 2 and R 3 represent a hydrogen atom, a halogen atom, or a methyl group.) By reacting an optically active d- or l-amine represented by the formula () or (), the optically active A precipitated crystal, which is a salt of a half ester and an optically active d- or l-amine represented by the general formula (), is then decomposed (provided that R 1 in the general formulas () and () is methyl). group, and R 2 in the general formula () is a methyl group.
The present invention relates to a method for separating optically active half esters (excluding combinations in which R 3 is a hydrogen atom).
一般式()および()で示されるそれぞれ
の光学活性なハーフエステルは、それぞれ異つた
方法で還元することにより、具体的には前者を水
素化ホウ素ナトリウムで還元し、、後者をジボラ
ン還元することにより、ビオチンの重要な中間体
である(3S,4R)−(1,3−ジベンジル−2−
ケト−イミダゾリド)−2−ケト−テトラヒドロ
フランに誘導することができるなど、医薬の中間
体などとして重要な化合物である。 The optically active half esters represented by general formulas () and () are reduced by different methods, specifically, the former is reduced with sodium borohydride, and the latter is reduced with diborane. (3S,4R)-(1,3-dibenzyl-2-
It is an important compound as a pharmaceutical intermediate because it can be derived into (keto-imidazolide)-2-keto-tetrahydrofuran.
かかる一般式()および()で示される光
学活性なハーフエステルは、たとえば1,3−ジ
ベンジル−4,5−ジカルボキシイミダゾリジン
−2−オンと相当するアルコールとを加熱するこ
とにより両者の混合物として得られ(特願昭57−
71777号)、それぞれの光学活性なハーフエステル
を得るためにはかかる混合物から両者を分離する
必要がある。 The optically active half esters represented by the general formulas () and () can be obtained by heating a mixture of 1,3-dibenzyl-4,5-dicarboximidazolidin-2-one and the corresponding alcohol, for example. (Patent application 1983-
No. 71777), it is necessary to separate both from such a mixture in order to obtain each optically active half ester.
この分離法について、本発明者らはすでに一般
式()および()においてR1がメチル基で
ある(4S,5R)−1,3−ジベンジル−4−カル
ボキシ−5−メトキシカルボニルイミダゾリジン
−2−オンおよび(4S,5R)−1,3−ジベンジ
ル−5−カルボキシ−4−メトキシカルボニルイ
ミダゾリジン−2−オンの混合物に、一般式
()においてR2がメチル基であり、R3が水素原
子であるd−またはl−α−フエニル−β−(p
−トリル)エチルアミンを作用させることによ
り、それぞれのハーフエステルを分離する方法を
開発し、特許出願を行つた(特願昭57−61498号)
が、その後更に研究の結果、かかる原料混合物と
分割剤の組合わせ以外の場合でも殆んど同様に分
離し得ることを見出し、本発明に至つた。 Regarding this separation method, the present inventors have already discovered (4S,5R)-1,3-dibenzyl-4-carboxy-5-methoxycarbonylimidazolidine-2 in which R 1 is a methyl group in the general formulas () and (). -one and (4S,5R)-1,3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one, in the general formula (), R 2 is a methyl group and R 3 is hydrogen The atom d- or l-α-phenyl-β-(p
-Developed a method to separate each half ester by the action of (tolyl)ethylamine, and filed a patent application (Japanese Patent Application No. 1983-61498)
However, as a result of further research, it was discovered that separation could be achieved in almost the same way even in cases other than the combination of the raw material mixture and the dividing agent, leading to the present invention.
すなわち本発明は、一般式()および()
で示される光学活性なdrまたはl−アミンを作用
させることにより、一般式()および()で
示される光学活性なハーフエステルを分離する方
法を提供するものである。 That is, the present invention provides general formulas () and ()
The present invention provides a method for separating optically active half esters represented by the general formulas () and () by acting with an optically active dr or l-amine represented by the formulas () and ().
但し、本発明は一般式()および()にお
いてR1がメチル基である光学活性なハーフエス
テルの混合物を原料とし、かつ一般式()にお
いてR1がメチル基であり、R3が水素原子である
光学活性なd−またはl−アミンを使用する場合
の組合せを除く。 However, in the present invention, a mixture of optically active half esters in which R 1 is a methyl group in the general formulas () and () is used as a raw material, and in the general formula (), R 1 is a methyl group and R 3 is a hydrogen atom. Excluding combinations in which an optically active d- or l-amine is used.
以下、本発明の方法は、一般式()および一
般式()で示される光学活性なハーフエステル
の混合物に、一般式()で示される光学活性d
−アミンまたはl−アミンを作用させて、一般式
()または一般式()で示される光学活性な
ハーフエステルと一般式()で示される光学活
性なd−アミンまたはl−アミンとの塩による析
出結晶を得、次いでこれを分解することにより一
般式()または一般式()で示される光学活
性なハーフエステルに単独に得る方法である。 Hereinafter, in the method of the present invention, a mixture of optically active half esters represented by general formula () and general formula () is added to an optically active d represented by general formula ().
- By reacting an amine or l-amine with a salt of an optically active half ester represented by the general formula () or the general formula () and an optically active d-amine or l-amine represented by the general formula () This is a method of obtaining precipitated crystals and then decomposing them to independently obtain an optically active half ester represented by the general formula () or ().
この方法において析出結晶を別したのちの
液を濃縮することにより得られる固体を酸分解
し、遊離した光学活性なd−またはl−アミンを
分離、除去したのち再結晶処理を行うことによ
り、優先的に一般式()または()で示され
る光学活性なハーフエステルを単独で得ることも
できる。 In this method, the solid obtained by concentrating the liquid after separating the precipitated crystals is acid-decomposed, and the free optically active d- or l-amine is separated and removed, followed by recrystallization treatment. Generally, the optically active half ester represented by the general formula () or () can also be obtained alone.
以下、更に具体的に説明する。 This will be explained in more detail below.
一般式()および()で示される光学活性
なハーフエステルの混合物に、所定量の溶媒およ
び一般式()で示される光学活性なd−または
l−アミンを加え、一般式()および()で
示される光学活性なハーフエステルと一般式
()で示される光学活性なd−またはl−アミ
ンとの塩を生成せしめ、これを溶媒に溶解させ
る。 A predetermined amount of a solvent and an optically active d- or l-amine represented by the general formula () are added to a mixture of optically active half esters represented by the general formula () and (). A salt of an optically active half ester represented by the formula (2) and an optically active d- or l-amine represented by the general formula (2) is produced, and this salt is dissolved in a solvent.
ここで分割剤として使用される前記一般式
()で示される光学活性アミンとしては、たと
えばα−フエニル−β−フエニルエチルアミン、
α−フエニル−β−(p−トリル)エチルアミン、
α−フエニル−β−(p−クロロフエニル)エチ
ルアミン、α−(p−トリル)−β−フエニルエチ
ルアミンなどのそれぞれ光学活性体が例示され
る。 Examples of the optically active amine represented by the general formula () used as a resolving agent include α-phenyl-β-phenylethylamine,
α-phenyl-β-(p-tolyl)ethylamine,
Optically active substances such as α-phenyl-β-(p-chlorophenyl)ethylamine and α-(p-tolyl)-β-phenylethylamine are exemplified.
光学活性なd−またはl−アミンの使用量は、
一般式()および()で示される光学活性な
ハーフエステルの混合物に対して通常的0.7〜1.2
モル倍、好ましくは0.8〜1.1モル倍である。 The amount of optically active d- or l-amine used is
Typically 0.7 to 1.2 for mixtures of optically active half esters represented by general formulas () and ().
It is twice the molar amount, preferably 0.8 to 1.1 times the molar amount.
使用される溶媒としては、メタノール、エタノ
ール、イソプロパノール、アセトン等の水可溶性
有機溶媒と水との混合溶媒またはベンゼン、トル
エン、クロロホルム、酢酸エチル等が例示され
る。 Examples of the solvent used include a mixed solvent of water and a water-soluble organic solvent such as methanol, ethanol, isopropanol, and acetone, and benzene, toluene, chloroform, and ethyl acetate.
溶媒の使用量は、生成した一般式()および
()で示される光学活性なハーフエステルと一
般式()で示される光学活性なd−またはl−
アミンとの塩をその溶解液から分別晶析させるに
適当な量である。 The amount of solvent used is determined between the optically active half esters represented by the general formulas () and () produced and the optically active d- or l-
This amount is suitable for fractional crystallization of a salt with an amine from its solution.
反応温度については−20℃〜使用溶媒の沸点の
範囲内(但し、使用溶媒の融点以下であることは
ない)で任意であるが、生成した塩が析出する温
度以上が好ましい。 The reaction temperature is arbitrary within the range of -20° C. to the boiling point of the solvent used (however, it is not below the melting point of the solvent used), but it is preferably at least the temperature at which the produced salt precipitates.
上記反応によつて一般式()および()で
示される光学活性なハーフエステルの一般式
()で示される光学活性アミン塩を生成せしめ
たのち、反応混合物を徐冷し、光学活性体の一体
の塩を析出させる。 After producing the optically active amine salt represented by the general formula () of the optically active half ester represented by the general formula () and () through the above reaction, the reaction mixture is slowly cooled, and the optically active substance is integrated. precipitates salt.
このとき該塩が析出するようにこれと同種の種
晶を混合系に接種することがより好ましい。 At this time, it is more preferable to inoculate the mixed system with seed crystals of the same type as the salt so as to precipitate it.
このようにして得た結晶は、これを別し、乾
燥させ酸によつてこれを分解する。 The crystals thus obtained are separated, dried and decomposed with acid.
ここで使用される酸は塩酸、硫酸、リン酸等で
あり、その量はろ別した結晶に対して1モル倍以
上任意であるが、通常約1モル〜1.1モルである。
分解液はこれを有機溶媒(たとえばトルエン、ク
ロロホルム、エーテル、酢酸エチル等の単独もし
くはこれらの混合溶媒)で抽出を行い、抽出油層
は必要に応じて水洗したのち、溶媒を留去するこ
とにより光学活性な一方のハーフエステルを得る
ことができる。 The acid used here is hydrochloric acid, sulfuric acid, phosphoric acid, etc., and the amount thereof is arbitrary, at least 1 mole based on the filtered crystals, but is usually about 1 mol to 1.1 mol.
The decomposed solution is extracted with an organic solvent (for example, toluene, chloroform, ether, ethyl acetate, etc. alone or a mixture of these solvents), and the extracted oil layer is washed with water if necessary, and then optically analyzed by distilling off the solvent. An active half-ester can be obtained.
尚、抽出処理によつて得られる水層および抽出
油層を水洗した水は、これをアルカリ(たとえば
水酸化ナトリウム、水酸カリウム、炭酸ナトリウ
ム、炭酸カリウムなど)で中和し、有機溶媒(た
とえばトルエン、クロロホルム、エーテル、酢酸
エチル等で)抽出し、抽出油層を水洗後、溶媒を
留去することにより、分割剤として用いた一般式
()で示される光学活性なd−またはl−アミ
ンを高収率で回収することができる。この分割剤
が高収率で回収し得ることは工業的に実施するう
えでの大きな利点である。 Note that the water obtained by washing the aqueous layer and extracted oil layer obtained by the extraction process is neutralized with an alkali (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.), and then treated with an organic solvent (e.g., toluene). The optically active d- or l-amine represented by the general formula ( It can be recovered in high yield. The fact that this resolving agent can be recovered in high yield is a major advantage in industrial implementation.
一方、析出した結晶を別したのちの液はこ
れを濃縮し、得られた固体を酸によつて分解し、
分解液を抽出したのち抽出油層から抽出溶液を除
去して、光学活性な他方のハーフエステルを過剰
に含む一般式()および()で示される光学
活性なハーフエステルの混合物を得、次いでこれ
をベンゼン、トルエン、キシレン等の適当な溶媒
に溶解させたのち徐冷し、光学活性な他方のハー
フエステルを析出させ(優先晶析)、これを別、
乾燥することにより光学活性な他方のハーフエス
テルを得ることができる。このとき光学活性な他
方のハーフエステルが析出する前にこれと同種の
種晶を混合系に接種することがより好ましい。 On the other hand, after separating the precipitated crystals, the liquid is concentrated, and the resulting solid is decomposed with acid.
After extracting the decomposition liquid, the extraction solution is removed from the extracted oil layer to obtain a mixture of optically active half esters represented by the general formulas () and () containing an excess of the other optically active half ester, and then this is After dissolving it in a suitable solvent such as benzene, toluene, xylene, etc., it is slowly cooled to precipitate the other optically active half ester (preferential crystallization), which is separated separately.
By drying, the other optically active half ester can be obtained. At this time, it is more preferable to inoculate the mixed system with seed crystals of the same type as the other optically active half ester before it precipitates.
ここで分解に用いる酸および抽出溶媒とは前記
したと同様のものが使用される。また優先晶析に
用いるベンゼン、トルエンまたはキシレン等の量
は光学活性な他方のハーフエステルをその溶解度
から分別晶析させるに適当な量である。 The acid and extraction solvent used for decomposition are the same as those described above. Further, the amount of benzene, toluene, xylene, etc. used for preferential crystallization is an amount suitable for fractional crystallization of the other optically active half ester based on its solubility.
以下、実施例によつて本発明を具体的に説明す
る。 Hereinafter, the present invention will be specifically explained with reference to Examples.
実施例 1
(4S,5R)−1,3−ジベンジル−4−カルボ
キシ−5−エトキシカルボニルイミダゾリジン−
2−オンおよび(4S,5R)−1,3−ジベンジル
−5−カルボキシ−4−エトキシカルボニルイミ
ダゾリジン−2−オン(1:1)の混合物382.4
g(合計1モル)、イソプロパノール2.5および
水2.5をフラスコに仕込み、50℃に加温する。
これにd−α−フエニル−β−(p−トリル)エ
チルアミン211.3g(1モル)を滴下する。徐冷
し、30〜31℃で別途調整した(4S,5R)−1,3
−ジベンジル−4−カルボキシ−5−エトキシカ
ルボニルイミダゾリジン−2−オンとd−α−フ
エニル−β−(P−トリル)エチルアミンの塩の
結晶を種晶として少量加え、10℃までさらに徐冷
し、10℃で2時間保温したのち、析出した結晶を
別する。別乾燥した結晶に水500c.c.および濃
塩酸47.0gを加え、酸分解したのち酢酸エチル
300c.c.を加えて(4S,5R)−1,3−ジベンジル
−4−カルボキシ−5−エトキシカルボニルイミ
ダゾリジン−2−オンを抽出分離する。抽出液を
水100c.c.で2回洗浄したのち、酢酸エチルを留去
し、(4S,5R)−1,3−ジベンジル−4−カル
ボキシ−5−エトキシカルボニルイミダゾリジン
−2−オン165.6g(収率43.3%)を得た。Example 1 (4S,5R)-1,3-dibenzyl-4-carboxy-5-ethoxycarbonylimidazolidine-
Mixture of 2-one and (4S,5R)-1,3-dibenzyl-5-carboxy-4-ethoxycarbonylimidazolidin-2-one (1:1) 382.4
(1 mole in total), 2.5 g of isopropanol, and 2.5 g of water are placed in a flask and heated to 50°C.
211.3 g (1 mol) of d-α-phenyl-β-(p-tolyl)ethylamine was added dropwise to this. (4S, 5R)-1,3 which was slowly cooled and adjusted separately at 30-31℃
A small amount of crystals of the salt of -dibenzyl-4-carboxy-5-ethoxycarbonylimidazolidin-2-one and d-α-phenyl-β-(P-tolyl)ethylamine was added as a seed crystal, and the mixture was further slowly cooled to 10°C. After incubating at 10°C for 2 hours, separate the precipitated crystals. 500 c.c. of water and 47.0 g of concentrated hydrochloric acid were added to the separately dried crystals, and after acid decomposition, ethyl acetate was added.
300 c.c. is added to extract and separate (4S, 5R)-1,3-dibenzyl-4-carboxy-5-ethoxycarbonylimidazolidin-2-one. After washing the extract twice with 100 c.c. of water, ethyl acetate was distilled off to obtain 165.6 g of (4S,5R)-1,3-dibenzyl-4-carboxy-5-ethoxycarbonylimidazolidin-2-one. (yield 43.3%).
〔α〕20 365=−18.9゜(C=1,DMF)
m.p. 113.5〜115℃
実施例 2
(4S,5R)−1,3−ジベンジル−4−カルボ
キシ−5−メトキシカルボニルイミダゾリジン−
2−オンおよび(4S,5R)−1,3−ジベンジル
−5−カルボキシ−4−メトキシカルボニルイミ
ダゾリジン−2−オン(1:1)の混合物368.4
g(合計1モル)、アセトン3および水3を
フラスコに仕込み60℃に加温する。これにl−α
−フエニル−β−(p−トリル)エチルアミン
211.3g(1モル)を滴下する。徐冷し、34〜35
℃で別途調整した(4S,5R)−1,3−ジベンジ
ル−4−カルボキシ−5−メトキシカルボニルイ
ミダゾリジン−2−オンとl−α−フエニル−β
−(p−トリル)エチルアミンの塩の結晶を種晶
として少量加え、15℃までさらに徐冷し、15℃で
2時間保温したのち、析出した結晶を別する。
別乾燥した結晶に水500c.c.および濃塩酸46gを
加え、酸分解したのち酢酸エチル300c.c.を加えて
(4S,5R)−1,3−ジベンジル−4−カルボキ
シ−5−メトキシカルボニルイミダゾリジン−2
−オンを抽出分離する。抽出液を水100c.c.で2回
洗浄したのち、酢酸エチルを留去し、(4S,5R)
−1,3−ジベンジル−4−カルボキシ−5−メ
トキシカルボニルイミダゾリジン−2−オン
154.4g(収率41.9%)を得た。 [α] 20 365 = -18.9° (C = 1, DMF) mp 113.5 ~ 115°C Example 2 (4S, 5R) -1,3-dibenzyl-4-carboxy-5-methoxycarbonylimidazolidine-
Mixture of 2-one and (4S,5R)-1,3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one (1:1) 368.4
(1 mol in total), 3 mols of acetone, and 3 ml of water were placed in a flask and heated to 60°C. To this l-α
-phenyl-β-(p-tolyl)ethylamine
211.3g (1 mol) is added dropwise. Slowly cool, 34-35
(4S,5R)-1,3-dibenzyl-4-carboxy-5-methoxycarbonylimidazolidin-2-one and l-α-phenyl-β prepared separately at °C.
A small amount of -(p-tolyl)ethylamine salt crystals were added as seed crystals, and the mixture was further slowly cooled to 15°C, kept at 15°C for 2 hours, and the precipitated crystals were separated.
Separately, 500 c.c. of water and 46 g of concentrated hydrochloric acid were added to the dried crystals, and after acid decomposition, 300 c.c. of ethyl acetate was added to form (4S, 5R)-1,3-dibenzyl-4-carboxy-5-methoxycarbonyl. imidazolidine-2
- Extract and separate ion. After washing the extract twice with 100 c.c. of water, ethyl acetate was distilled off and (4S, 5R)
-1,3-dibenzyl-4-carboxy-5-methoxycarbonylimidazolidin-2-one
154.4g (yield 41.9%) was obtained.
〔α〕20 365=−28.3゜(C=1,DMF)
m.p. 148〜149℃
液は濃縮し、得られた固体に水600c.c.および
濃塩酸64gを加え、酸分解したのち酢酸エチル
300c.c.を加えて(4S,5R)−1,3−ジベンジル
−5−カルボキシ−4−メトキシカルボニルイミ
ダゾリジン−2−オンが過剰に含まれる(4S,
5R)−1,3−ジベンジル−4−カルボキシ−5
−メトキシカルボニルイミダゾリジン−2−オン
および(4S,5R)−1,3−ジベンジル−5−カ
ルボキシ−4−メトキシカルボニルイミダゾリジ
ン−2−オンの混合物を抽出分離する。抽出液を
水100c.c.で2回洗浄したのち、酢酸エチルを留去
する。得られた固体をベンゼン6に溶解させ
る。その後徐冷して、(4S,5R)−1,3−ジベ
ンジル−5−カルボキシ−4−メトキシカルボニ
ルイミダゾリジン−2−オンの種晶を接種したの
ち(4S,5R)−1,3−ジベンジル−5−カルボ
キシ−4−メトキシカルボニルイミダゾリジン−
2−オンを優先的に析出させる。15℃まで徐冷し
て15℃で2時間保温したのち、析出結晶を別乾
燥し(4S,5R)−1,3−ジベンジル−5−カル
ボキシ−4−メトキシカルボニルイミダゾリジン
−2−オン175.0g(収率47.5%)を得た。 [α] 20 365 = -28.3゜ (C = 1, DMF) mp 148-149℃ The liquid was concentrated, 600 c.c. of water and 64 g of concentrated hydrochloric acid were added to the obtained solid, and after acid decomposition, ethyl acetate was added.
(4S, 5R)-1,3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one is contained in excess (4S, 5R) by adding 300 c.c.
5R)-1,3-dibenzyl-4-carboxy-5
A mixture of -methoxycarbonylimidazolidin-2-one and (4S,5R)-1,3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one is extracted and separated. After washing the extract twice with 100 c.c. of water, ethyl acetate is distilled off. The solid obtained is dissolved in benzene 6. After that, it was slowly cooled, seed crystals of (4S,5R)-1,3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one were inoculated, and then (4S,5R)-1,3-dibenzyl -5-Carboxy-4-methoxycarbonylimidazolidine-
2-one is preferentially precipitated. After slowly cooling to 15°C and keeping at 15°C for 2 hours, the precipitated crystals were separately dried to yield 175.0 g of (4S, 5R)-1,3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one. (yield 47.5%).
〔α〕20 365=+27.4゜(C=1,DMF)
m.p. 148゜〜149゜
実施例 3
(4S,5R)−1,3−ジベンジル−4−カルボ
キシ−5−イソプロポキシカルボニルイミダゾリ
ジン−2−オンおよび(4S,5R)−1,3−ジベ
ンジル−5−カルボキシ−4−イソプロポキシカ
ルボニルイミダゾリジン−2−オン(1:1)の
混合物396.4g(合計1モル)、イソプロパノール
2.5および水2.5をフラスコに仕込み、50℃に
加温する。これにd−α−フエニル−β−(p−
トリル)エチルアミン211.3g(1モル)を滴下
する。徐冷し、31〜32℃で別途調整した、(4S,
5R)−1,3−ジベンジル−4−カルボキシ−5
−イソプロポキシカルボニルイミダゾリジン−2
−オンとd−α−フエニル−β−(p−トリル)
エチルアミンの塩のをして少量加え、10℃までさ
らに徐冷し、10℃で2時間保温したのち析出した
結晶を別する。別乾燥した結晶に水500c.c.お
よび濃塩酸50gを加え、酸分解したのち、酢酸エ
チル300c.c.を加えて、(4S,5R)−1,3−ジベン
ジル−4−カルボキシ−5−イソプロポキシカル
ボニルイミダゾリジン−2−オンを抽出分離す
る。抽出液を水100c.c.で2回洗浄したのち酢酸エ
チルを留去し、(4S,5R)−1,3−ジベンジル
−4−カルボキシ−5−イソプロポキシカルボニ
ルイミダゾリジン−2−オン179.2g(収率45.2
%)を得た。 [α] 20 365 = +27.4° (C = 1, DMF) mp 148° ~ 149° Example 3 (4S, 5R) -1,3-dibenzyl-4-carboxy-5-isopropoxycarbonylimidazolidine- 396.4 g (total 1 mol) of a mixture of 2-one and (4S,5R)-1,3-dibenzyl-5-carboxy-4-isopropoxycarbonylimidazolidin-2-one (1:1), isopropanol
Charge 2.5 and 2.5 of water into a flask and warm to 50℃. This was added to d-α-phenyl-β-(p-
211.3 g (1 mol) of tolyl)ethylamine are added dropwise. (4S,
5R)-1,3-dibenzyl-4-carboxy-5
-isopropoxycarbonylimidazolidine-2
-on and d-α-phenyl-β-(p-tolyl)
Add a small amount of ethylamine salt, further slowly cool to 10°C, keep at 10°C for 2 hours, and separate the precipitated crystals. After adding 500 c.c. of water and 50 g of concentrated hydrochloric acid to the separately dried crystals for acid decomposition, 300 c.c. of ethyl acetate was added to (4S,5R)-1,3-dibenzyl-4-carboxy-5- Isopropoxycarbonylimidazolidin-2-one is extracted and separated. After washing the extract twice with 100 c.c. of water, ethyl acetate was distilled off, and 179.2 g of (4S,5R)-1,3-dibenzyl-4-carboxy-5-isopropoxycarbonylimidazolidin-2-one was obtained. (Yield 45.2
%) was obtained.
〔α〕20 365=−26.9゜(C=1,DMF)
m.p. 140〜142℃
別時に得た液を濃縮した。以下、実施例2
に準じて酸分解、抽出、水洗および酢酸エチルを
留去して得られた固体をベンゼンに溶解後、徐冷
して(4S,5R)−1,3−ジベンジル−5−カル
ボキシ−4−イソプロポキシカルボニルイミダゾ
リジン−2−オンの種晶を接種した。以下、実施
例2と同様に処理して(4S,5R)−1,3−ジベ
ンジル−5−カルボキシ−4−イソプロポキシカ
ルボニルイミダゾリジン−2−オンを得た。 [α] 20 365 = -26.9° (C = 1, DMF) mp 140-142°C The liquid obtained separately was concentrated. Below, Example 2
The solid obtained by acid decomposition, extraction, water washing and distillation of ethyl acetate was dissolved in benzene and slowly cooled to give (4S,5R)-1,3-dibenzyl-5-carboxy-4-iso. Seeds of propoxycarbonylimidazolidin-2-one were inoculated. Thereafter, the same treatment as in Example 2 was carried out to obtain (4S,5R)-1,3-dibenzyl-5-carboxy-4-isopropoxycarbonylimidazolidin-2-one.
〔α〕20 365=+27.0゜(C=1,DMF)
m.p. 140〜142℃
実施例 4
(4S,5R)−1,3−ジベンジル−4−カルボ
キシ−5−メトキシカルボニルイミダゾリジン−
2−オンおよび(4S,5R)−1,3−ジベンジル
−5−カルボキシ−4−メトキシカルボニルイミ
ダゾリジン−2−オン(1:1)の混合物368.4
g(合計1モル)、イソプロパノール1.5および
水1.5をフラスコに仕込み50℃に加温する。こ
れにd−α−フエニル−β−フエニルエチルアミ
ン197.3g(1モル)を滴下する。徐冷して35℃
で別途調整した(4S,5R)−1,3−ジベンジル
−5−カルボキシ−4−メトキシカルボニルイミ
ダゾリジン−2−オンとd−α−フエニル−β−
フエニルエチルアミンの塩の結晶を種晶として少
量加え、20℃までさらに徐冷し、20℃で2時間保
温したのち、析出した結晶を別する。別乾燥
した結晶に水500c.c.および濃塩酸46.5gを加え酸
分解したのち、酢酸エチル300c.c.を加えて(4S,
5R)−1,3−ジベンジル−5−カルボキシ−4
−メトキシカルボニルイミダゾリジン−2−オン
を抽出分離する。抽出液を水100c.c.で2回洗浄し
たのち酢酸エチルを留去し、(4S,5R)−1,3
−ジベンジル−5−カルボキシ−4−メトキシカ
ルボニルイミダゾリジン−2−オン155.1g(収
率42.1%)を得た。 [α] 20 365 = +27.0° (C = 1, DMF) mp 140-142°C Example 4 (4S, 5R)-1,3-dibenzyl-4-carboxy-5-methoxycarbonylimidazolidine-
Mixture of 2-one and (4S,5R)-1,3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one (1:1) 368.4
(1 mole in total), 1.5 g of isopropanol, and 1.5 g of water were placed in a flask and heated to 50°C. 197.3 g (1 mol) of d-α-phenyl-β-phenylethylamine was added dropwise to this. Slowly cool to 35℃
(4S,5R)-1,3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one and d-α-phenyl-β-
A small amount of phenylethylamine salt crystals are added as seed crystals, and the mixture is further slowly cooled to 20°C, kept at 20°C for 2 hours, and the precipitated crystals are separated. After acid decomposition by adding 500 c.c. of water and 46.5 g of concentrated hydrochloric acid to the separately dried crystals, 300 c.c. of ethyl acetate was added (4S,
5R)-1,3-dibenzyl-5-carboxy-4
-Methoxycarbonylimidazolidin-2-one is extracted and separated. After washing the extract twice with 100 c.c. of water, ethyl acetate was distilled off and (4S,5R)-1,3
-Dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one 155.1 g (yield 42.1%) was obtained.
〔α〕20 365=+27.8゜(C=1,DMF) m.p. 148〜149.5℃ [α] 20 365 = +27.8゜ (C = 1, DMF) mp 148 ~ 149.5℃
Claims (1)
たはアルケニル基を示す。) で示される光学活性なハーフエステルの混合物
に、一般式() (式中、R2,R3は水素原子、ハロゲン原子ま
たはメチル基を示す。) で示される光学活性なd−またはl−アミンを反
応させて一般式()または()で示される光
学活性なハーフエステルと一般式()で示され
る光学活性なd−またはl−アミンとの塩である
析出結晶を得、次いでこれを分解する(但し、一
般式()および()におけるR1がメチル基
であり、一般式()におけるR2がメチル基で
R3が水素原子である場合の組合せを除く)こと
を特徴とする光学活性なハーフエステルの分離
法。[Claims] 1 General formulas () and () (In the above formula, R 1 represents an alkyl group or an alkenyl group having 1 to 5 carbon atoms.) A mixture of optically active half esters represented by the general formula () (In the formula, R 2 and R 3 represent a hydrogen atom, a halogen atom, or a methyl group.) By reacting an optically active d- or l-amine represented by the formula () or (), the optically active A precipitated crystal, which is a salt of a half ester and an optically active d- or l-amine represented by the general formula (), is then decomposed (provided that R 1 in the general formulas () and () is methyl). group, and R 2 in the general formula () is a methyl group.
1. A method for separating optically active half esters (excluding combinations where R 3 is a hydrogen atom).
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP14029982A JPS5929670A (en) | 1982-08-11 | 1982-08-11 | Separation of optically active half ester |
EP83103665A EP0092194B1 (en) | 1982-04-16 | 1983-04-15 | Method of obtaining optically active half esters |
DE8686112335T DE3382001D1 (en) | 1982-04-16 | 1983-04-15 | METHOD FOR PRODUCING OPTICALLY ACTIVE SEMI-BEST. |
EP86112335A EP0220435B1 (en) | 1982-04-16 | 1983-04-15 | A method for preparing optically active half esters |
DE8383103665T DE3372365D1 (en) | 1982-04-16 | 1983-04-15 | Method of obtaining optically active half esters |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP14029982A JPS5929670A (en) | 1982-08-11 | 1982-08-11 | Separation of optically active half ester |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5929670A JPS5929670A (en) | 1984-02-16 |
JPH0435464B2 true JPH0435464B2 (en) | 1992-06-11 |
Family
ID=15265552
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP14029982A Granted JPS5929670A (en) | 1982-04-16 | 1982-08-11 | Separation of optically active half ester |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5929670A (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5592343A (en) * | 1979-01-06 | 1980-07-12 | Yoshio Katsuta | Preparation of optically active substituted isovaleric acid |
JPS55118455A (en) * | 1979-03-02 | 1980-09-11 | Sumitomo Chem Co Ltd | Method of collecting optically active d-alpha-methyl-beta- mercapto propionic acid derivative |
JPS55136245A (en) * | 1979-04-09 | 1980-10-23 | Sumitomo Chem Co Ltd | Optical resolution of alpha-isopropyl-p-chlorophenyl-acetic acid |
-
1982
- 1982-08-11 JP JP14029982A patent/JPS5929670A/en active Granted
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5592343A (en) * | 1979-01-06 | 1980-07-12 | Yoshio Katsuta | Preparation of optically active substituted isovaleric acid |
JPS55118455A (en) * | 1979-03-02 | 1980-09-11 | Sumitomo Chem Co Ltd | Method of collecting optically active d-alpha-methyl-beta- mercapto propionic acid derivative |
JPS55136245A (en) * | 1979-04-09 | 1980-10-23 | Sumitomo Chem Co Ltd | Optical resolution of alpha-isopropyl-p-chlorophenyl-acetic acid |
Also Published As
Publication number | Publication date |
---|---|
JPS5929670A (en) | 1984-02-16 |
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