JPH0474165A - Production of optically active 1-(p-chlorophenyl)-1-(2-pyridyl)-3-dimethylaminopropane - Google Patents
Production of optically active 1-(p-chlorophenyl)-1-(2-pyridyl)-3-dimethylaminopropaneInfo
- Publication number
- JPH0474165A JPH0474165A JP18645890A JP18645890A JPH0474165A JP H0474165 A JPH0474165 A JP H0474165A JP 18645890 A JP18645890 A JP 18645890A JP 18645890 A JP18645890 A JP 18645890A JP H0474165 A JPH0474165 A JP H0474165A
- Authority
- JP
- Japan
- Prior art keywords
- resolving agent
- optically active
- mol
- chlorpheniramine
- chlorophenyl
- 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.)
- Granted
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 title description 15
- 239000000126 substance Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract description 19
- 150000003839 salts Chemical class 0.000 abstract description 18
- 238000000034 method Methods 0.000 abstract description 17
- 239000002904 solvent Substances 0.000 abstract description 10
- 150000001875 compounds Chemical class 0.000 abstract description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 abstract description 6
- 239000011707 mineral Substances 0.000 abstract description 6
- 150000001413 amino acids Chemical class 0.000 abstract description 5
- 239000000243 solution Substances 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000007864 aqueous solution Substances 0.000 abstract description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 150000007524 organic acids Chemical class 0.000 abstract description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- SOYKEARSMXGVTM-HNNXBMFYSA-N dexchlorpheniramine Chemical compound C1([C@H](CCN(C)C)C=2N=CC=CC=2)=CC=C(Cl)C=C1 SOYKEARSMXGVTM-HNNXBMFYSA-N 0.000 description 19
- 229960001882 dexchlorpheniramine Drugs 0.000 description 19
- 229960003291 chlorphenamine Drugs 0.000 description 18
- 230000003287 optical effect Effects 0.000 description 14
- 239000013078 crystal Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- PICQEJDBZKDWOD-CQSZACIVSA-N (2r)-2-(benzenesulfonamido)-3-phenylpropanoic acid Chemical compound C([C@H](C(=O)O)NS(=O)(=O)C=1C=CC=CC=1)C1=CC=CC=C1 PICQEJDBZKDWOD-CQSZACIVSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- QJBGCXNTFZBQJR-CYBMUJFWSA-N (2r)-2-(benzenesulfonamido)-2-phenylacetic acid Chemical compound N([C@@H](C(=O)O)C=1C=CC=CC=1)S(=O)(=O)C1=CC=CC=C1 QJBGCXNTFZBQJR-CYBMUJFWSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- SVCQSZKHLAERDL-SECBINFHSA-N (2r)-2-[(4-methylphenyl)sulfonylamino]butanedioic acid Chemical compound CC1=CC=C(S(=O)(=O)N[C@H](CC(O)=O)C(O)=O)C=C1 SVCQSZKHLAERDL-SECBINFHSA-N 0.000 description 1
- LVFFZQQWIZURIO-UHFFFAOYSA-N 2-phenylbutanedioic acid Chemical compound OC(=O)CC(C(O)=O)C1=CC=CC=C1 LVFFZQQWIZURIO-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
〈産業上の利用分野〉
本発明はａ−１−（ｐ−クロルフェニル）−１−（２−
ピリジル）−３−ジメチルアミノプロパン（以下、１−
（ｐ−クロルフェニル）−１−（２−ピリジル）−３
−ジメチルアミノプロパンをクロルフェニラミンと称す
る）を光学分割法により光学活性クロルフェニラミンを
製造する方法に関する。ｄ−クロルフェニラミンは優れ
た抗ヒスタミン作用を有し、現在、医薬品として多量に
使用されている。Detailed Description of the Invention <Industrial Application Field> The present invention provides a-1-(p-chlorophenyl)-1-(2-
pyridyl)-3-dimethylaminopropane (hereinafter referred to as 1-
(p-chlorophenyl)-1-(2-pyridyl)-3
- dimethylaminopropane is referred to as chlorpheniramine) by an optical resolution method to produce optically active chlorpheniramine. d-Chlorpheniramine has an excellent antihistamine effect and is currently used in large quantities as a pharmaceutical.
〈従来の技術〉
従来知られている准−クロルフェニラミンの光学分割法
としては、濯−フェニルコハク酸をブルシンやキニーネ
などの光学活性の天然塩基を用いて光学分割し、得られ
たｄ−フェニルコハク酸を用いて濯−クロルフェニラミ
ンの光学分割を行う方法（米国特許第３０３０３７１号
明細書）およびＮ−トシル−Ｄ−アスパラギン酸を用い
て巌−クロルフェニラミンの光学分割を行う方法（特開
昭４８−３６１７７号公報）などがある。<Prior art> As a conventionally known optical resolution method for quasi-chlorpheniramine, d-phenylsuccinic acid is optically resolved using an optically active natural base such as brucine or quinine, and the obtained d- A method for optically resolving chlorpheniramine using phenylsuccinic acid (US Pat. No. 3,030,371) and a method for optically resolving chlorpheniramine using N-tosyl-D-aspartic acid ( JP-A No. 48-36177).
〈発明が解決しようとする課題〉
しかしながら、従来知られている前者の方法は、光学分
割剤自体を光学分割しなくてはならないという点で工業
的に有利な方法とは言い難い。また後者の方法は２０℃
にて３日間放置して塩を結晶化させなくてはならない点
でやはり実用性に乏しい。<Problems to be Solved by the Invention> However, the former method known so far cannot be said to be an industrially advantageous method in that the optical resolving agent itself must be optically resolved. Also, the latter method is 20℃
It is still impractical in that the salt must be left for three days to crystallize.
〈課題を解決するための手段〉
そこで本発明者らは、８−クロルフェニラミンを工業的
に実用化可能な方法で分割することを目的として鋭意検
討した。その結果、この目的は一般式（１）
（式中、ｎはＯまたは１を意味する）
で示される光学活性アミノ酸ベンゼンスルホニル誘導体
を分割剤として用いて光学分割することにより達成され
ることが判った。<Means for Solving the Problems> Therefore, the present inventors conducted extensive studies with the aim of dividing 8-chlorpheniramine by an industrially practical method. As a result, it was found that this objective could be achieved by optical resolution using an optically active amino acid benzenesulfonyl derivative represented by the general formula (1) (where n means O or 1) as a resolving agent. Ta.
すなわち、本発明はｄ−クロルフェニラミンを、一般式
（１）
（式中、ｎは０または１を意味する）
で示される光学活性アミノ酸ベンゼンスルホニル誘導体
を分割剤として用いて光学分割することを特徴とする光
学活性クロルフェニラミンの製造方法である。That is, the present invention provides optical resolution of d-chlorpheniramine using an optically active amino acid benzenesulfonyl derivative represented by the general formula (1) (wherein n means 0 or 1) as a resolving agent. This is a characteristic method for producing optically active chlorpheniramine.
以下、本発明の構成を詳しく説明する。Hereinafter, the configuration of the present invention will be explained in detail.
本発明で用いる分割剤は、前記式（Ｉ）で示される光学
活性アミノ酸ベンゼンスルホニル誘導体であり、その０
体およびＬ体のいずれも用いることができる。The resolving agent used in the present invention is an optically active amino acid benzenesulfonyl derivative represented by the above formula (I), and its
Both the form and the L form can be used.
本発明で分割剤として用いる前記式（Ｉ）で示される光
学活性アミノ酸ベンゼンスルホニル誘導体は光学活性フ
ェニルアラニンまたは光学活性フェニルグリシンのベン
ゼンスルホニル化物である。The optically active amino acid benzenesulfonyl derivative represented by the formula (I) used as a resolving agent in the present invention is a benzenesulfonylated product of optically active phenylalanine or optically active phenylglycine.
光学活性フェニルアラニンおよび光学活性フェニルグリ
シンは、現在、医薬品、甘味料などの原料として広く使
われており、安価に入手することができる。また、光学
活性アミノ酸のベンゼンスルホニル化物は、たとえば、
ｐＨを１０にコントロールした光学活性アミノ酸の水溶
液に、溶媒に溶かしたベンゼンスルホニルクロライドを
ゆっくり添加していく方法により非常に高収率で得られ
る。もちろん、これ以外の方法で製造したものであって
も何ら問題ない。また、この光学活性アミノ酸ベンゼン
スルホニル誘導体は非常に安定な化合物であり、分割、
回収の際に分解したリラセミ化することもない。Optically active phenylalanine and optically active phenylglycine are currently widely used as raw materials for pharmaceuticals, sweeteners, and the like, and can be obtained at low cost. Furthermore, benzenesulfonylated optically active amino acids are, for example,
It can be obtained in a very high yield by slowly adding benzenesulfonyl chloride dissolved in a solvent to an aqueous solution of an optically active amino acid whose pH is controlled at 10. Of course, there is no problem even if it is manufactured by a method other than this. In addition, this optically active amino acid benzenesulfonyl derivative is a very stable compound and can be split,
There is no possibility of lyracemization, which is caused by decomposition during recovery.
すなわち本発明で用いる分割剤は、安価に工業的に入手
可能な化合物である。That is, the resolving agent used in the present invention is a compound that can be obtained industrially at low cost.
本発明において、原料として用いられるｄ−クロルフェ
ニラミンは、ｄ−クロルフェニラミンと！−クロルフェ
ニラミンとを等壷金むラセミ型混合物だけでなく、いず
れか一方の光学異性体を等量以上に含む混合物をも包含
する。In the present invention, d-chlorpheniramine used as a raw material is d-chlorpheniramine! - It includes not only racemic mixtures containing chlorpheniramine, but also mixtures containing equal or more of either optical isomer.
ｄ−クロルフェニラミンの光学分割は、次の手順と条件
で行う。Optical resolution of d-chlorpheniramine is performed under the following procedure and conditions.
まず溶媒中で、ｄ−クロルフェニラミン１モルに対して
０．５〜３．０モル、好ましくは１．０〜２．５モルの
光学活性アミノ酸ペンセンスルホニル誘導体を接触させ
てジアステレオマー塩をつくる。この時、塩酸、硫酸、
りん酸などの鉱酸あるいは酢酸などの有機酸を０．１〜
１．５モル、好ましくは０．７〜１．３モル共存させて
もよい。First, in a solvent, 0.5 to 3.0 mol, preferably 1.0 to 2.5 mol of an optically active amino acid pencenesulfonyl derivative is brought into contact with 1 mol of d-chlorpheniramine to form a diastereomer salt. Create. At this time, hydrochloric acid, sulfuric acid,
Mineral acids such as phosphoric acid or organic acids such as acetic acid from 0.1 to
1.5 mol, preferably 0.7 to 1.3 mol, may be present.
ここで使用する溶媒としては、准−クロルフェニラミン
と光学活性アミノ酸ベンゼンスルホニル誘導体を溶解す
るとともに、溶液中でこれらの化合物を化学的に変質せ
しめることなく、かつジアステレオマー塩を析出せしめ
るものであればよい。たとえば、エタノール、メタノー
ルなどのアルコール類や、酢酸メチル、酢酸エチルなど
のエステル類、メチルエチルケトン、アセトンなどのケ
トン類などが使用できる。また、これらの溶媒は単独で
も、また混合溶媒として使用することもできる。さらに
、これらの溶媒は水との混合溶媒として使用することも
できる。The solvent used here is one that dissolves the quasi-chlorpheniramine and the optically active amino acid benzenesulfonyl derivative, does not chemically alter these compounds in solution, and precipitates diastereomeric salts. Good to have. For example, alcohols such as ethanol and methanol, esters such as methyl acetate and ethyl acetate, and ketones such as methyl ethyl ketone and acetone can be used. Further, these solvents can be used alone or as a mixed solvent. Furthermore, these solvents can also be used as a mixed solvent with water.
濯−クロルフェニラミンに光学活性アミノ酸ベンゼンス
ルホニル誘導体を接触させる方法としては、前記溶媒中
にｄ−クロルフェニラミンを一挙に加えてもよいし、順
次加えてもよい。As a method for bringing the optically active amino acid benzenesulfonyl derivative into contact with d-chlorpheniramine, d-chlorpheniramine may be added to the solvent all at once or sequentially.
さらに、あらかじめｄ−クロルフェニラミンと分割剤と
からつくった塩を形成したのち、該溶媒中に溶解させて
もよい。Furthermore, a salt made from d-chlorpheniramine and a resolving agent may be formed in advance and then dissolved in the solvent.
次に、か（して得られたジアステレオマー塩を含む溶液
を冷却および／あるいは濃縮する。Next, the solution containing the resulting diastereomeric salt is cooled and/or concentrated.
すると、難溶性のジアステレオマー塩が溶液から晶析し
てくる。Then, a poorly soluble diastereomeric salt crystallizes out of the solution.
難溶性のジアステレオマー塩を溶液から析出させる際の
温度は使用する溶媒の凝固点から沸点の範囲であればよ
く、目的に応じて適宜法められるが、通常は０℃から１
００℃の範囲で十分である。The temperature at which a sparingly soluble diastereomeric salt is precipitated from a solution may range from the freezing point to the boiling point of the solvent used, and is determined as appropriate depending on the purpose, but is usually between 0°C and 1°C.
A range of 00°C is sufficient.
難溶性のジアステレオマー塩の結晶は、濾過、遠心分離
などの通常の固液分離法によって容易に分離することが
できる。Crystals of poorly soluble diastereomeric salts can be easily separated by conventional solid-liquid separation methods such as filtration and centrifugation.
一方、難溶性のジアステレオマー塩を分離した残りの母
液を冷却および／あるいは濃縮し、易溶性のジアステレ
オマー塩を析出せしめたのちこれを分離することもでき
る。On the other hand, it is also possible to cool and/or concentrate the remaining mother liquor from which the poorly soluble diastereomeric salts have been separated, to precipitate the easily soluble diastereomeric salts, and then to separate them.
かくして得られる各ジアステレオマー塩を適当な方法で
分解することによって、ｄ−クロルフェニラミンまたは
Ｐ〜クロルフェニラミンと分割剤を分離・採取すること
ができる。By decomposing each diastereomer salt thus obtained by an appropriate method, d-chlorpheniramine or P-chlorpheniramine and the resolving agent can be separated and collected.
ジアステレオマー塩の分解方法は任意であり、たとえば
水性溶媒中、酸またはアルカリで処理する方法などが適
用できる。たとえばジアステレオマー塩を水中に溶解ま
たは分散させた中に硫酸や塩酸などの鉱酸を添加すると
水に難溶性の光学活性アミノ酸ベンゼンスルホニル誘導
体が析出し、ｄ−クロルフェニラミンまたは！−クロル
フェニラミンの鉱酸塩が水中に溶解する。Any method can be used to decompose the diastereomeric salt, and for example, a method of treating with acid or alkali in an aqueous solvent can be applied. For example, when a mineral acid such as sulfuric acid or hydrochloric acid is added to a diastereomer salt dissolved or dispersed in water, an optically active amino acid benzenesulfonyl derivative that is sparingly soluble in water precipitates, and d-chlorpheniramine or! - The mineral salt of chlorpheniramine dissolves in water.
通常の手段で分割剤を固液分離したのち、母液を濃縮・
晶析すればｄ−クロルフェニラミンまたは！−クロルフ
ェニラミン鉱酸塩が得られる。After solid-liquid separation of the resolving agent by normal means, the mother liquor is concentrated and
If crystallized, d-chlorpheniramine or! - Chlorpheniramine mineral salt is obtained.
さらに、得られた鉱酸塩を水酸化ナトリウムなどのアル
カリ水溶液に加え、トルエン、クロロホルムなどの有機
溶媒で抽出したのち、濃縮・蒸留すればｄ−クロルフェ
ニラミンまたは！クロルフェニラミンが得られる。Furthermore, if the obtained mineral salt is added to an alkaline aqueous solution such as sodium hydroxide, extracted with an organic solvent such as toluene or chloroform, and then concentrated and distilled, d-chlorpheniramine or! Chlorpheniramine is obtained.
本発明で分割剤として用いる光学活性アミノ酸ベンゼン
スルホニル誘導体は水に難溶性であり、ジアステレオマ
ー塩溶液から高収率で回収することができ、しかも回収
の過程で分解、ラセミ化することはない。The optically active amino acid benzenesulfonyl derivative used as a resolving agent in the present invention is sparingly soluble in water and can be recovered in high yield from a diastereomer salt solution, without decomposition or racemization during the recovery process. .
つまりこの分割剤は光学活性が保持されているので再使
用して光学分割を行うことができる。In other words, since this resolving agent retains its optical activity, it can be reused to perform optical resolution.
〈実施例〉 以下、実施例により本発明を具体的に説明する。<Example> Hereinafter, the present invention will be specifically explained with reference to Examples.
なお、実施例中クロルフェニラミンの光学純度（％ｅｅ
）は、以下の条件で高速液体クロマトグラフィー（ＨＰ
Ｌ Ｃ）により分析を行った。In addition, in the examples, the optical purity (%ee) of chlorpheniramine
) was performed using high performance liquid chromatography (HP) under the following conditions.
Analysis was carried out by LC).
カラム：ＣＨＩＲＡＬＰＡＫ ＡＤ
（ダイセル）
移動層：ｎ−ヘキサン会イソプロパツール・ジエチルア
ミン混液
（９７，５： ２．５ ： ０．０２５）流 量：
１． Ｏｍｌ ／ ｍｉｎ検出器：ＵＶ２５４ｎｍ
保持時間：６体−１１，３ｍ１ｎ
２体−１３，４ｍ１ｌ
実施例１
濯−クロルフエニラミン２７．４ｇ（０，１モル）、ベ
ンゼンスルホニル−Ｄ−フェニルアラニン６１．１ｇ（
０，２モル）およびエタノール３００ｍ１をフラスコに
仕込み、約５０’Ｃで１０分間加熱して溶解した。これ
を室温まで徐冷し、さらに室温で３０分間撹拌したのち
析出した結晶を炉別し、ｄ−クロルフェニラミンのベン
ゼンスルホニル−Ｄ−フェニルアラニン塩の白色結晶２
６．６ｇを得た。Column: CHIRALPAK AD (Daicel) Mobile phase: n-hexane isopropanol/diethylamine mixture (97.5: 2.5: 0.025) Flow rate:
1. Oml/min Detector: UV254nm Retention time: 6 bodies - 11,3 ml 2 bodies - 13,4 ml Example 1 Irrigation - 27.4 g (0.1 mol) of chlorpheniramine, 61.1 g of benzenesulfonyl-D-phenylalanine (
0.2 mol) and 300 ml of ethanol were placed in a flask and heated at about 50'C for 10 minutes to dissolve. This was slowly cooled to room temperature and further stirred at room temperature for 30 minutes, and the precipitated crystals were separated in a furnace and white crystals of benzenesulfonyl-D-phenylalanine salt of d-chlorpheniramine 2.
6.6g was obtained.
この結晶を水１００ｍ１．濃硫酸１０ｍ１の混液に懸濁
し、室温で強く撹拌すると結晶形が変化し、ベンゼンス
ルホニル−Ｄ−フェニルアラニンの白色結晶が析出した
。撹拌を約１時間続けたのちが過し、結晶を水洗して乾
燥し、１７．９ｇのベンゼンスルホニル−Ｄ−フェニル
アラニンを得た（回収率９８％）。次いで母液に水酸化
ナトリウムを加えて強塩基性にし、遊離する油をクロロ
ホルムで抽出し水洗したのち、濃縮、蒸留して淡黄色油
状のｄ−クロルフェニラミン７．９ｇを得た。用いたｄ
−クロルフェニラミン量に対して収率は５７．７％、Ｈ
ＰＬＣによる光学純度は９２％ｅｅであった。Add this crystal to 100ml of water. When suspended in a mixed solution of 10 ml of concentrated sulfuric acid and strongly stirred at room temperature, the crystal form changed and white crystals of benzenesulfonyl-D-phenylalanine were precipitated. After stirring for about 1 hour, the crystals were washed with water and dried to obtain 17.9 g of benzenesulfonyl-D-phenylalanine (recovery rate 98%). Next, sodium hydroxide was added to the mother liquor to make it strongly basic, and the liberated oil was extracted with chloroform and washed with water, concentrated and distilled to obtain 7.9 g of d-chlorpheniramine as a pale yellow oil. d used
- Yield is 57.7% based on the amount of chlorpheniramine, H
Optical purity by PLC was 92%ee.
実施例２
実施例１においてエタノールを酢酸エチルに代え、他は
全く同様にして行ったところ、ｄクロルフェニラミンの
ベンゼンスルホニル−Ｄ−フェニルアラニン塩の白色結
晶８．９ｇ（収率２０．３％）を得た。ＨＰＬＣによる
分析の結果、ｄ−クロルフェニラミンの光学純度は９０
％ｅｅであった。Example 2 The same procedure as in Example 1 was repeated except that ethanol was replaced with ethyl acetate, and 8.9 g of white crystals of benzenesulfonyl-D-phenylalanine salt of d-chlorpheniramine was obtained (yield: 20.3%). I got it. As a result of HPLC analysis, the optical purity of d-chlorpheniramine was 90.
%ee.
実施例３
濯−クロルフエニラミン２７．４ｇ（０，１モル）、ベ
ンゼンスルホニル−Ｄ−フェニルグリシン５８．２ｇ（
０，２モル）および２０％含水メタノール４００ ｍｌ
をフラスコに仕込み、約５０℃で１０分間加熱して溶解
した。これを室温まで徐冷し、さらに室温で３０分間撹
拌したのち析出した結晶を炉別し、ｄ−クロルフェニラ
ミンのベンゼンスルホニル−Ｄ−フェニルグリシン塩の
白色結晶２０．６ｇ（収率４８．１％）を得た。Example 3 - 27.4 g (0.1 mol) of chlorpheniramine, 58.2 g (0.1 mol) of benzenesulfonyl-D-phenylglycine (
0.2 mol) and 400 ml of 20% aqueous methanol
was placed in a flask and heated at about 50°C for 10 minutes to dissolve. This was slowly cooled to room temperature and further stirred at room temperature for 30 minutes, and the precipitated crystals were separated in a furnace. 20.6 g of white crystals of benzenesulfonyl-D-phenylglycine salt of d-chlorpheniramine (yield 48.1 %) was obtained.
ＨＰＬＣによる分析の結果、ｄ−クロルフェニラミンの
光学純度は９３％ｅｅであった。As a result of HPLC analysis, the optical purity of d-chlorpheniramine was 93%ee.
〈発明の効果〉
（１）本発明で使用する分割剤は、安価な原料から１段
階反応で高収率で得られるため、工業的に給供可能な化
合物である。<Effects of the Invention> (1) The resolving agent used in the present invention is a compound that can be supplied industrially because it can be obtained in high yield from inexpensive raw materials in a one-step reaction.
（２）本発明で使用する分割剤は、化学的に非常に安定
なため、ジアステレオマー塩溶液から極めて高収率でラ
セミ化することなく回収することができるため、分割剤
の再使用が可能である。(2) The resolving agent used in the present invention is chemically very stable and can be recovered from diastereomer salt solutions in extremely high yields without racemization, making it easy to reuse the resolving agent. It is possible.
（３）本発明方法は、収率および光学純度においても従
来方法と何ら遜色がなく優れている。(3) The method of the present invention is superior to conventional methods in terms of yield and optical purity.
（４）従って、本発明によれば工業的に実用化可能な光
学活性クロルフェニラミンの製造方法が提供できる。(4) Therefore, according to the present invention, an industrially practical method for producing optically active chlorpheniramine can be provided.
Claims (1)
ル）−３−ジメチルアミノプロパンを、一般式 ▲数式、化学式、表等があります▼……（ I ） （式中、ｎは０または１を意味する） で示される光学活性アミノ酸ベンゼンスルホニル誘導体
を分割剤として用いて光学分割することを特徴とする光
学活性１−（ｐ−クロルフェニル）−１−（２−ピリジ
ル）−３−ジメチルアミノプロパンの製造方法。[Claims] dl-1-(p-chlorophenyl)-1-(2-pyridyl)-3-dimethylaminopropane is expressed by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I) ( An optically active 1-(p-chlorophenyl)-1-(2) characterized in that it is optically resolved using an optically active amino acid benzenesulfonyl derivative represented by -pyridyl)-3-dimethylaminopropane manufacturing method.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18645890A JP2671572B2 (en) | 1990-07-13 | 1990-07-13 | Process for producing optically active 1- (p-chlorophenyl) -1- (2-pyridyl) -3-dimethylaminopropane |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18645890A JP2671572B2 (en) | 1990-07-13 | 1990-07-13 | Process for producing optically active 1- (p-chlorophenyl) -1- (2-pyridyl) -3-dimethylaminopropane |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0474165A true JPH0474165A (en) | 1992-03-09 |
| JP2671572B2 JP2671572B2 (en) | 1997-10-29 |
Family
ID=16188816
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18645890A Expired - Fee Related JP2671572B2 (en) | 1990-07-13 | 1990-07-13 | Process for producing optically active 1- (p-chlorophenyl) -1- (2-pyridyl) -3-dimethylaminopropane |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2671572B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7666936B2 (en) | 2005-04-22 | 2010-02-23 | Juki Corporation | Coating film forming method, coating material, releasing agent and rubber material |
| CN106432056A (en) * | 2016-09-17 | 2017-02-22 | 青岛辰达生物科技有限公司 | Preparation method of niraparib intermediate of (3S)-3-(4-aminophenyl) piperidine-1-tert-butyl formate |
| CN109265390A (en) * | 2017-10-13 | 2019-01-25 | 再鼎医药(上海)有限公司 | A kind of preparation method and intermediate of the intermediate for synthesizing antineoplastic medicament niraparib |
-
1990
- 1990-07-13 JP JP18645890A patent/JP2671572B2/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7666936B2 (en) | 2005-04-22 | 2010-02-23 | Juki Corporation | Coating film forming method, coating material, releasing agent and rubber material |
| CN106432056A (en) * | 2016-09-17 | 2017-02-22 | 青岛辰达生物科技有限公司 | Preparation method of niraparib intermediate of (3S)-3-(4-aminophenyl) piperidine-1-tert-butyl formate |
| CN109265390A (en) * | 2017-10-13 | 2019-01-25 | 再鼎医药(上海)有限公司 | A kind of preparation method and intermediate of the intermediate for synthesizing antineoplastic medicament niraparib |
| CN109265390B (en) * | 2017-10-13 | 2020-02-21 | 再鼎医药(上海)有限公司 | Preparation method of intermediate for synthesizing antitumor drug niraparib and intermediate |
| US10927077B2 (en) | 2017-10-13 | 2021-02-23 | Zai Lab (Shanghai) Co., Ltd. | Process for preparing intermediate of anti-tumor drug niraparib and intermediate thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2671572B2 (en) | 1997-10-29 |
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