JP2018090521A - (1S) -4- [4- (Dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) ) Method for producing tartrate salt, and (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbohydrate using the tartrate salt Method for producing nitrile and its salt - Google Patents
(1S) -4- [4- (Dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) ) Method for producing tartrate salt, and (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbohydrate using the tartrate salt Method for producing nitrile and its salt Download PDFInfo
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Abstract
【課題】化学純度及び光学純度の極めて高い（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩を高収率で得る製造方法を提供する。【解決手段】 ラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルと、（＋）−ジ−（ｐ−トルオイル）酒石酸とを反応させて、（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩を得た後、該酒石酸塩を１−ブタノールを含む溶媒にて晶析を行い、晶析体として当該酒石酸塩を得ることを特徴とする製造方法を提供する。【選択図】なし(1S) -4- [4- (Dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile having extremely high chemical purity and optical purity Provided is a production method for obtaining hemi (+)-di- (p-toluoyl) tartrate in a high yield. Racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile and (+)-di- (P-Toluoyl) reacted with tartaric acid to give (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzo After obtaining nitrile hemi (+)-di- (p-toluoyl) tartrate, the tartrate is crystallized with a solvent containing 1-butanol, and the tartrate is obtained as a crystallized body. A manufacturing method is provided. [Selection figure] None
Description
本発明は、（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩の製造方法、及び該酒石酸塩を用いた（１Ｓ）−１−［３−（ジメチルアミノ）プロピル］−１−（４−フルオロフェニル）−１，３−ジヒドロイソベンゾフラン−５−カルボニトリル及びその塩の製造方法に関する。 The present invention relates to (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (P-Toluoyl) Tartrate Production Method and (1S) -1- [3- (Dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran Using the Tartrate It relates to a process for producing -5-carbonitrile and its salts.
（１Ｓ）−１−［３−（ジメチルアミノ）プロピル］−１−（４−フルオロフェニル）−１，３−ジヒドロイソベンゾフラン−５−カルボニトリル及びその塩の製造方法（以下、「エスシタロプラム」ともいう。）は以下の構造（６）を持ち、その蓚酸塩（７）は周知の抗うつ薬である。 (1S) -1- [3- (Dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile and a salt thereof (hereinafter referred to as “escitalopram”) ) Has the following structure (6), and its oxalate (7) is a well-known antidepressant.
前記エスシタロプラム（６）は、以下の合成経路で製造する方法が知られており、エスシタプラム蓚酸塩（７）として単離されている。 A method for producing escitalopram (6) by the following synthesis route is known, and is isolated as escitalopram succinate (7).
（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩（４）は、エスシタロプラムの重要中間体であり、ラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリル（３）と（＋）−ジ−（ｐ−トルオイル）酒石酸とを反応させて製造する方法が知られている（下記特許文献１参照）。 (1S) -4- [4- (Dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) ) Tartrate (4) is an important intermediate of escitalopram and is racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) ) -Benzonitrile (3) and (+)-di- (p-toluoyl) tartaric acid are produced by a reaction (see Patent Document 1 below).
前記方法では、ラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩（（３）の誘導体）の製造後に光学分割が行われ、エナンチオ選択率が９１〜９８％である酒石酸塩（４）が得られることが知られている。 In this method, racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- ( It is known that optical resolution is performed after the production of p-toluoyl) tartrate (derivative of (3)) to obtain tartrate (4) having an enantioselectivity of 91-98%.
上記特許文献１の製造方法では、５０％以上の１−プロパノールを含む溶媒中でラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリル（３）と（＋）−ジ−（ｐ−トルオイル）酒石酸とを反応させて、光学分割を行い、（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩（４）を得ている。しかしながら、本発明者らがこの方法によって得た酒石酸塩は（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリル（３）と（＋）−ジ−（ｐ−トルオイル）酒石酸のエステル体である不純物１及び不純物２の不純物量が増加することが判明した。当該不純物を除去するためには、酒石酸塩の精製を繰り返す必要があり、大きく収率を損失することとなった。そのため、前記光学分割で酒石酸塩を得る工程において、精製工程を不要とするため、高い化学純度及び光学純度で酒石酸塩を得ることが望まれていた。 In the production method of Patent Document 1, racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl]-in a solvent containing 50% or more of 1-propanol. 3- (hydroxymethyl) -benzonitrile (3) and (+)-di- (p-toluoyl) tartaric acid are reacted to carry out optical resolution to give (1S) -4- [4- (dimethylamino)- 1- (4′-Fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate (4) is obtained. However, the tartrate salt obtained by the present inventors is (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl). ) -Benzonitrile (3) and (+)-di- (p-toluoyl) tartaric acid ester bodies were found to increase the amount of impurities 1 and 2. In order to remove the impurities, it was necessary to repeat purification of the tartrate salt, resulting in a large yield loss. Therefore, in the process of obtaining a tartrate salt by the optical resolution, it has been desired to obtain a tartrate salt with high chemical purity and optical purity in order to eliminate a purification step.
したがって、本発明の目的は、前記工程において高い化学純度及び光学純度で（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩（４）を得ることにより、高い化学純度、及び光学純度のエスシタロプラム（６）及びその塩を提供することにある。 Accordingly, the object of the present invention is to provide (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (1S) -4- [4- (dimethylamino) -1-hydroxybutyl] -3- (Hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate (4) is obtained to provide escitalopram (6) and a salt thereof having high chemical purity and optical purity. .
本発明者らが、化学純度及び光学純度の高い酒石酸塩を得る方法について鋭意検討を行ったところ、ラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルと、（＋）−ジ−（ｐ−トルオイル）酒石酸とを反応させて、（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩を得た後、該酒石酸塩を１−ブタノールを含む溶媒にて晶析を行い、晶析体として当該酒石酸塩を得ることで、不純物である上記エステル体の含有量が低く、高い化学純度及び光学純度を満足する該酒石酸塩が、高収率で得られることを見出し、本発明を完成させるに至った。 When the present inventors diligently studied about the method of obtaining tartrate salt with high chemical purity and optical purity, racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1 -Hydroxybutyl] -3- (hydroxymethyl) -benzonitrile and (+)-di- (p-toluoyl) tartaric acid are reacted to give (1S) -4- [4- (dimethylamino) -1- After obtaining (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate, the tartrate was replaced with 1-butanol. Crystallization is performed using a solvent containing the tartrate as a crystallized body, so that the content of the ester body as an impurity is low and the tartrate satisfying high chemical purity and optical purity is high yield. Obtained in Heading the door, which resulted in the completion of the present invention.
すなわち、第一の本発明は、
（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩の製造方法であって、
ラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルと、（＋）−ジ−（ｐ−トルオイル）酒石酸とを反応させて、（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩を得た後、該酒石酸塩を１−ブタノールを含む溶媒にて晶析を行い、晶析体として当該酒石酸塩を得ることを特徴とする製造方法である。
That is, the first aspect of the present invention is
(1S) -4- [4- (Dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) A method for producing tartrate,
Racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile and (+)-di- (p-toluoyl) ) Reaction with tartaric acid to give (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+ ) -Di- (p-toluoyl) tartrate is obtained, followed by crystallization of the tartrate with a solvent containing 1-butanol, and obtaining the tartrate as a crystallized product. is there.
上記本発明の製造方法においては、以下の態様が好適に採り得る。
［１］前記晶析における溶媒として、さらにハロゲン化炭化水素を含むこと。
［２］前記ハロゲン化炭化水素がクロロホルム、ジクロロメタンから選ばれる少なくとも１種であること。
［３］前記晶析における溶媒量が、（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩１質量部に対して５〜２０容量部であること。
［４］前記ハロゲン化炭化水素の溶媒量が、晶析における溶媒量１００容量部に対し０〜３０容量部であること。
［５］前記晶析における晶析温度が０℃〜８０℃の範囲であること。
［６］前記晶析において晶析温度が４０℃〜８０℃の範囲で前記酒石酸塩を析出せしめた後、さらに前記酒石酸塩を含む溶液を０℃〜４０℃まで冷却すること。
さらに第二の本発明は、上記の製造方法によって（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩を製造した後、得られた（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩を用いて、（１Ｓ）−１−［３−（ジメチルアミノ）プロピル］−１−（４−フルオロフェニル）−１，３−ジヒドロイソベンゾフラン−５−カルボニトリルを製造する方法である。
In the production method of the present invention, the following modes can be suitably employed.
[1] Further containing a halogenated hydrocarbon as a solvent in the crystallization.
[2] The halogenated hydrocarbon is at least one selected from chloroform and dichloromethane.
[3] The amount of solvent in the crystallization is (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile. It should be 5 to 20 parts by volume with respect to 1 part by mass of hemi (+)-di- (p-toluoyl) tartrate.
[4] The solvent amount of the halogenated hydrocarbon is 0 to 30 parts by volume with respect to 100 parts by volume of the solvent in crystallization.
[5] The crystallization temperature in the crystallization is in the range of 0 ° C to 80 ° C.
[6] After precipitating the tartrate salt in the crystallization temperature range of 40 ° C to 80 ° C, the solution containing the tartrate salt is further cooled to 0 ° C to 40 ° C.
Furthermore, the second present invention provides (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl)-by the above production method. After producing benzonitrile hemi (+)-di- (p-toluoyl) tartrate, the obtained (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1- Hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate was used to give (1S) -1- [3- (dimethylamino) propyl] -1- ( 4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile.
本発明によれば、光学分割工程において、高収率で化学純度及び光学純度の極めて高い（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩を得ることが可能である。この製造方法によって得られた前記酒石酸塩よりエスシタロプラム及びその塩を製造することで、高収率で化学純度及び光学純度の極めて高いエスシタロプラム及びその塩を提供することができる。 According to the present invention, in the optical resolution step, (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxy having a very high chemical purity and optical purity is obtained in a high yield. Butyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate can be obtained. By producing escitalopram and its salt from the tartrate obtained by this production method, it is possible to provide escitalopram and its salt with high yield and extremely high chemical purity and optical purity.
＜本発明における酒石酸塩（４）の製造方法＞
本願発明の製造方法は、ラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルと、（＋）−ジ−（ｐ−トルオイル）酒石酸とを反応させて、（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩を得た後、該酒石酸塩を１−ブタノールを含む溶媒にて晶析を行い、晶析体として当該酒石酸塩を得ることが特徴である。本発明における酒石酸塩（４）は、下記の合成経路により製造することができる。
<Method for Producing Tartrate (4) in the Present Invention>
The production method of the present invention comprises racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile and (+) Reaction with di- (p-toluoyl) tartaric acid to give (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) ) -Benzonitrile hemi (+)-di- (p-toluoyl) tartrate is obtained, and then the tartrate is crystallized with a solvent containing 1-butanol to obtain the tartrate as a crystallized body. Is a feature. The tartrate salt (4) in the present invention can be produced by the following synthesis route.
ラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルの遊離体（３ｂ）の製造には、公知の方法を用いることができる。例えば、ラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルの酸塩（３ａ）を、有機溶媒と水の２層系の溶媒中で塩基を反応させて遊離体（３ｂ）を得ることができる。 For the preparation of racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile free (3b) This method can be used. For example, racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile acid salt (3a) A free form (3b) can be obtained by reacting a base in a two-layer solvent of water and water.
ちなみに、前記ラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルの酸塩は、例えば、以下のように製造することができる。すなわち、化合物（１）と４−ブロモフルオロベンゼンのグリニヤール反応を行い、得られた化合物（２）と塩化３，３−ジメチルアミノプロピルのグリニャール反応を行うことにより、当該酸塩を得ることができる。 By the way, the racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile acid salt is, for example, Can be manufactured as follows. That is, the acid salt can be obtained by conducting a Grignard reaction between the compound (1) and 4-bromofluorobenzene, and carrying out a Grignard reaction between the obtained compound (2) and 3,3-dimethylaminopropyl chloride. .
前記酸塩における酸として、様々な酸を使用することができるが、例えば、臭化水素酸、酢酸などを挙げることができる。前記酸塩を遊離化させる前記塩基としては、様々な塩基を使用することができるが、例えば、水酸化ナトリウム、炭酸カリウムなどを挙げることができる。 Various acids can be used as the acid in the acid salt, and examples thereof include hydrobromic acid and acetic acid. Various bases can be used as the base for liberating the acid salt, and examples thereof include sodium hydroxide and potassium carbonate.
前記遊離化の溶媒としては、例えば、酢酸エチル、ジエチルエーテル、トルエン、クロロホルム、ジクロロメタンを使用することができ、好ましくは、クロロホルムを使用することができる。前記遊離化の溶媒の溶媒量としては、４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリル１質量部に対して３〜２０容量部、好ましくは４〜８容量部の溶媒を使用することができる。前記遊離化の反応温度としては、０〜６０℃の範囲で適宜決定することができる。 As the liberation solvent, for example, ethyl acetate, diethyl ether, toluene, chloroform, or dichloromethane can be used, and preferably, chloroform can be used. As the solvent amount of the liberation solvent, 1 part by mass of 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile is used. On the other hand, 3 to 20 parts by volume, preferably 4 to 8 parts by volume of solvent can be used. The liberation reaction temperature can be appropriately determined in the range of 0 to 60 ° C.
前記ラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルの遊離体（３ｂ）を酒石酸化して、前記酒石酸塩（４）を得ることができる。セミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルの遊離体（３ｂ）を有機溶媒に溶解し、ジ−（ｐ−トルオイル）酒石酸を溶解した溶液を加え、遊離体（３ａ）を酒石酸塩化させることで、酒石酸塩が析出する。この時、ジ−（ｐ−トルオイル）酒石酸として、（＋）−ジ−（ｐ−トルオイル）酒石酸を用いた場合には、（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩（４ａ）が選択的に析出する。一方ジ−（ｐ−トルオイル）酒石酸として、（−）−ジ−（ｐ−トルオイル）酒石酸を用いた場合には、（１Ｒ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（−）−ジ−（ｐ−トルオイル）酒石酸塩が選択的に析出する。従って、用いるジ-(p-トルオイル)酒石酸によって、光学純度がおよそ９３％以上の光学分割された酒石酸塩を得ることができる。 The racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile educt (3b) is tartar oxidized, The tartrate salt (4) can be obtained. Semi-form 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile free form (3b) was dissolved in an organic solvent. Then, a solution in which di- (p-toluoyl) tartaric acid is dissolved is added, and the educt (3a) is tartrated to precipitate the tartrate. At this time, when (+)-di- (p-toluoyl) tartaric acid is used as di- (p-toluoyl) tartaric acid, (1S) -4- [4- (dimethylamino) -1- (4 '-Fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate (4a) is selectively precipitated. On the other hand, when (-)-di- (p-toluoyl) tartaric acid is used as di- (p-toluoyl) tartaric acid, (1R) -4- [4- (dimethylamino) -1- (4'- Fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (-)-di- (p-toluoyl) tartrate is selectively precipitated. Therefore, the optically resolved tartrate having an optical purity of about 93% or more can be obtained depending on the di- (p-toluoyl) tartaric acid used.
前記酒石酸塩化の際の溶媒としては、例えば、メタノール、エタノール、ＩＰＡ、１−ブタノール、アセトニトリル、酢酸エチル、ジクロロメタン、クロロホルムなどを使用することができる。酒石酸塩化の際の溶媒量としてはラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリル（３ａ）１質量部に対して４〜１５容量部の溶媒を使用することができ、好ましくは８〜１２容量部、最も好適には６〜９容量部の範囲であることが好ましい。 As the solvent for the tartarization, for example, methanol, ethanol, IPA, 1-butanol, acetonitrile, ethyl acetate, dichloromethane, chloroform and the like can be used. The amount of solvent in the tartrate formation is racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile (3a). 4 to 15 parts by volume of solvent can be used for 1 part by mass, preferably 8 to 12 parts by volume, and most preferably 6 to 9 parts by volume.
また、酒石酸塩化に用いる溶媒にはアキラルな酸を含んでもよい。アキラルな酸は遊離体（３）のエナンチオマーと塩を形成し、光学異性体の溶解度を向上させる効果があり、光学異性体の分離効果を更に高くする。具体的にアキラルな酸は、ギ酸、酢酸、トリフルオロ酢酸を使用することができ、特に酢酸を使用することが好ましい。 The solvent used for tartaric acidification may contain an achiral acid. The achiral acid forms a salt with the enantiomer of the free form (3), has the effect of improving the solubility of the optical isomer, and further increases the separation effect of the optical isomer. Specifically, formic acid, acetic acid and trifluoroacetic acid can be used as the achiral acid, and it is particularly preferable to use acetic acid.
前記酒石酸塩化に用いる（＋）−ジ−（ｐ−トルオイル）酒石酸の使用量としては、ラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリル（３ａ）に対して０．２５〜１．０当量の該酒石酸を使用し、好ましくは０．３〜０．５当量の該酒石酸を使用することができる。 The amount of (+)-di- (p-toluoyl) tartaric acid used for the tartaric acidification is racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl. ] 0.25-1.0 equivalents of the tartaric acid, preferably 0.3-0.5 equivalents of the tartaric acid, relative to -3- (hydroxymethyl) -benzonitrile (3a) it can.
（＋）−ジ−（ｐ−トルオイル）酒石酸の添加方法としては、（＋）−ジ−（ｐ−トルオイル）酒石酸を固体のまま添加してもよく、或いは（＋）−ジ−（ｐ−トルオイル）酒石酸を溶媒に溶解させて、溶液の状態で添加してもよい。 As a method for adding (+)-di- (p-toluoyl) tartaric acid, (+)-di- (p-toluoyl) tartaric acid may be added as a solid, or (+)-di- (p- Toluoyl) Tartaric acid may be dissolved in a solvent and added in the form of a solution.
また、酒石酸塩化の温度としては、０〜８０℃の範囲で行うことができ、特に５０〜７０℃の範囲で行うことが好ましい。 Moreover, as temperature of tartarization, it can carry out in the range of 0-80 degreeC, and it is preferable to carry out especially in the range of 50-70 degreeC.
なお、上記生成した酒石酸塩（４）を単離した後、後述する晶析を行っても良いし、あるいは、酒石酸塩（４）が析出した反応溶媒からそのまま晶析を行っても良い。また、反応溶媒からそのまま晶析を行う際には、反応溶媒を除去後、１−ブタノールを含む溶媒を添加して晶析を行っても良いし、反応溶媒として１−ブタノールを含む溶媒を用いて、反応終了後、そのまま晶析を行っても良い。 In addition, after isolating the produced | generated tartrate (4), you may crystallize mentioned later, or you may crystallize as it is from the reaction solvent which tartrate (4) precipitated. Further, when crystallization is performed as it is from the reaction solvent, the reaction solvent may be removed, and then the crystallization may be performed by adding a solvent containing 1-butanol, or a solvent containing 1-butanol is used as the reaction solvent. After the reaction, crystallization may be performed as it is.
酒石酸塩化を行う際に、反応温度が高い程酒石酸塩化は速やかに進行するが、一方で反応温度が高い程、エステル体の副生も増加する傾向にある。後述するとおり、１−ブタノールは、酒石酸塩（４）の溶解度が低く、酒石酸塩化によって生成した酒石酸塩が反応系で析出するため、反応温度が高くてもエステル体の副生を抑制することができること、及び、工程が簡便化されるという点で、反応溶媒として１−ブタノールを含む溶媒を用い、反応終了後、そのまま１−ブタノールを含む溶媒にて晶析を行うことが特に好ましい。 When tartrate formation is performed, the tartrate formation proceeds more rapidly as the reaction temperature is higher. On the other hand, as the reaction temperature is higher, the amount of ester by-products tends to increase. As will be described later, 1-butanol has low solubility of tartrate (4), and tartrate produced by tartrate formation precipitates in the reaction system, so that by-product formation of the ester is suppressed even when the reaction temperature is high. It is particularly preferable to use a solvent containing 1-butanol as a reaction solvent, and to perform crystallization in a solvent containing 1-butanol as it is after completion of the reaction, in that it can be performed and the process is simplified.
＜本発明にかかる酒石酸塩（４）の晶析＞
本発明の製造方法では、上記方法にて（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩（４）を得た後、該酒石酸塩を１−ブタノールを含む溶媒にて晶析を行い、晶析体として当該酒石酸塩を得ることが特徴である。本発明の製造方法により、高収率で化学純度及び光学純度の極めて高い酒石酸塩（４）を得ることが可能である。
<Crystal crystallization of tartrate salt (4) according to the present invention>
In the production method of the present invention, (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile is prepared by the above method. After obtaining hemi (+)-di- (p-toluoyl) tartrate (4), the tartrate is crystallized with a solvent containing 1-butanol, and the tartrate is obtained as a crystallized body. It is a feature. By the production method of the present invention, it is possible to obtain a tartrate salt (4) with high yield and extremely high chemical purity and optical purity.
晶析時において、晶析体として化学純度の高い酒石酸塩を得るためには、酒石酸塩を一旦溶媒に溶解させることが必要であるが、上記のとおり溶媒に溶解した状態で加熱すると、エステル体の副生が増加する傾向にある。表１は主な溶媒に対する２５℃での酒石酸塩（４）の溶解度を示すものである。 At the time of crystallization, in order to obtain a tartrate salt having a high chemical purity as a crystallized body, it is necessary to dissolve the tartrate salt once in a solvent. There is a tendency for by-products to increase. Table 1 shows the solubility of tartrate (4) at 25 ° C. in the main solvents.
表からもわかるとおり、メタノールをはじめとする炭素数１〜３のアルコール溶媒は酒石酸塩（４）の溶解度が比較的高いため、晶析時の熱履歴によってエステル体が副生しやすい。一方本発明の製造方法で用いる１−ブタノールは、これらの溶媒と比して酒石酸塩の溶解度が極めて低く、比較的高温でも酒石酸塩（４）が析出する。一旦析出した酒石酸塩（４）は再溶解することがなく、結果として、晶析時の熱履歴によるエステル体の副生を抑制することができ、且つ１−ブタノール自体が酒石酸塩（４）に対する貧溶媒となるため、高収率で化学純度及び光学純度の極めて高い酒石酸塩（４）を得ることが可能である。 As can be seen from the table, since the alcohol solvent having 1 to 3 carbon atoms including methanol has a relatively high solubility of the tartrate (4), an ester is easily formed as a by-product due to the thermal history during crystallization. On the other hand, 1-butanol used in the production method of the present invention has a very low solubility of tartrate compared to these solvents, and the tartrate (4) precipitates even at a relatively high temperature. The precipitated tartrate (4) does not re-dissolve, and as a result, the by-product of the ester body due to the thermal history during crystallization can be suppressed, and 1-butanol itself is based on the tartrate (4). Since it becomes a poor solvent, it is possible to obtain a tartrate salt (4) with high yield and extremely high chemical purity and optical purity.
本発明の製造方法において晶析時に用いる１−ブタノールを含む溶媒の使用量としては、（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩１質量部に対して５〜２０容量部が好ましい。８〜１２容量部の範囲であることが好ましい。 The amount of the solvent containing 1-butanol used for crystallization in the production method of the present invention is (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl. ] -5 to 20 parts by volume are preferred with respect to 1 part by mass of -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate. A range of 8 to 12 parts by volume is preferable.
前記のとおり、酒石酸塩化の溶媒として１−ブタノールを含む溶媒を用い、反応終了後、そのまま１−ブタノールを含む溶媒にて晶析を行う場合には、エステル体の副生の抑制効果、収率、化学純度及び光学純度の観点から遊離体（３ｂ）１質量部あたり４〜１５容量部が好ましい。光学純度の向上効果、及び収率の観点から、特に５〜１０容量部、最も好適には６〜９容量部の範囲であることが好ましい。酒石酸塩化の溶媒量を上記の範囲とすることで、晶析時の溶媒量を前記範囲内とすることができる。 As described above, when a solvent containing 1-butanol is used as a solvent for tartrate formation and crystallization is performed in a solvent containing 1-butanol as it is after the reaction is completed, the effect of suppressing the by-product of the ester body, yield From the viewpoints of chemical purity and optical purity, 4 to 15 parts by volume per 1 part by mass of the free form (3b) is preferable. From the viewpoint of the optical purity improvement effect and the yield, it is particularly preferably in the range of 5 to 10 parts by volume, most preferably 6 to 9 parts by volume. By setting the amount of tartrate to the above range, the amount of solvent during crystallization can be within the above range.
上記１−ブタノールを含む溶媒としては、他の溶媒との混合溶媒としても良い。混合溶媒として用いる溶媒としては、クロロホルム、ジクロロメタン等のハロゲン化炭化水素、酢酸エチル、アセトニトリル等が挙げられる。これらの溶媒の中でも光学純度の向上効果が期待できるため、クロロホルム、ジクロロメタン等のハロゲン化炭化水素を用いることが特に好ましい。 The solvent containing 1-butanol may be a mixed solvent with other solvents. Examples of the solvent used as the mixed solvent include halogenated hydrocarbons such as chloroform and dichloromethane, ethyl acetate, and acetonitrile. Among these solvents, it is particularly preferable to use halogenated hydrocarbons such as chloroform and dichloromethane since the effect of improving optical purity can be expected.
上記他の溶媒の使用量は、得られる酒石酸塩（４）の単離収率や、反応釜の収量、化学純度、光学純度等を勘案して適宜決定すれば良いが、１−ブタノールを含む溶媒全体を１００容量部とした場合に０〜３０容量部の範囲、特に５〜２５容量部で用いることが好ましい。 The amount of the other solvent used may be appropriately determined in consideration of the isolated yield of the obtained tartrate (4), the yield of the reaction kettle, the chemical purity, the optical purity, etc., but includes 1-butanol When the whole solvent is 100 parts by volume, it is preferably used in the range of 0 to 30 parts by volume, particularly 5 to 25 parts by volume.
本発明の製造方法における酒石酸塩（４）の晶析温度は特に制限されないが、高収率、且つ高純度で酒石酸塩（４）を得るという観点から０℃〜８０℃の範囲であることが好ましい。高純度で酒石酸塩（４）を得るためには、晶析溶媒に酒石酸塩を溶解させた後に、酒石酸塩（４）を析出させるのが好ましく、４０〜８０℃の範囲、特に５０〜７０℃の範囲で酒石酸塩（４）の溶解、及び析出を行うことが好ましい。 The crystallization temperature of the tartrate (4) in the production method of the present invention is not particularly limited, but may be in the range of 0 ° C. to 80 ° C. from the viewpoint of obtaining the tartrate (4) with high yield and high purity. preferable. In order to obtain the tartrate salt (4) with high purity, it is preferable to precipitate the tartrate salt (4) after dissolving the tartrate salt in the crystallization solvent, and it is preferably in the range of 40 to 80 ° C, particularly 50 to 70 ° C. It is preferable to dissolve and precipitate the tartrate (4) in the range of.
また酒石酸塩（４）の析出には、種晶を添加することもできる。種晶を添加することで、結晶の析出を制御することができ、純度の高い酒石酸塩（４）を取得することができる。種晶の添加量は（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩（４）１００質量部に対して、０．０１質量部〜１質量部が好ましく、特に０．１〜０．５質量部が好ましい。 A seed crystal can also be added to the precipitation of the tartrate (4). By adding a seed crystal, precipitation of the crystal can be controlled, and a highly pure tartrate salt (4) can be obtained. The amount of seed crystals added was (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+) −. 0.01-100 mass parts is preferable with respect to 100 mass parts of di- (p-toluoyl) tartrate (4), and 0.1-0.5 mass part is especially preferable.
また、上記温度で酒石酸塩（４）を析出、熟成した後、析出した酒石酸塩（４）を単離することも可能であるが、さらに高収率で酒石酸塩（４）を得ることが可能であることから、上記酒石酸塩（４）を含む溶液を０℃〜４０℃まで冷却し、さらに酒石酸塩（４）を析出させることが好ましい。この時、冷却速度が速すぎると粒子サイズの細かい結晶が析出しやすく、ろ過性が低下する傾向にあるため、冷却速度の好ましい範囲は、１０〜５０℃／ｈｒであり、好ましくは２０〜３０℃／ｈｒである。さらに上記酒石酸塩（４）を含む溶液の冷却後は上記温度を保持して酒石酸塩（４）析出の熟成を行うことが好ましい。熟成時間は、１〜１２時間より好ましくは２〜６時間あれば十分である。 It is also possible to isolate the precipitated tartrate (4) after precipitation and aging at the above temperature, but it is possible to obtain the tartrate (4) in a higher yield. Therefore, it is preferable to cool the solution containing the tartrate (4) to 0 ° C. to 40 ° C., and further precipitate the tartrate (4). At this time, if the cooling rate is too high, crystals with fine particle size are likely to precipitate, and the filterability tends to decrease. Therefore, the preferable range of the cooling rate is 10 to 50 ° C./hr, preferably 20 to 30. ° C / hr. Further, after cooling the solution containing the tartrate (4), it is preferable to perform the aging of the tartrate (4) precipitation while maintaining the temperature. It is sufficient that the aging time is 1 to 12 hours, more preferably 2 to 6 hours.
前記方法で得られた酒石酸塩（４）の単離には、例えば、加圧ろ過、減圧ろ過、遠心分離など公知の分離方法を用いることができる。 For the isolation of the tartrate salt (4) obtained by the above method, for example, a known separation method such as pressure filtration, vacuum filtration, and centrifugation can be used.
単離後の酒石酸塩（４）の乾燥には、例えば、減圧乾燥などの方法を用いることができる。減圧乾燥においては、２０〜５０℃の温度で行うことができ、好ましくは３０〜４０℃で行うことができる。 For example, a method such as drying under reduced pressure can be used to dry the tartrate salt (4) after isolation. The drying under reduced pressure can be performed at a temperature of 20 to 50 ° C., preferably 30 to 40 ° C.
上記方法で得られた酒石酸塩（４）は、リスラリーや晶析（再結晶を含む）等の公知の方法にて純度を向上させることができる。リスラリーや晶析（再結晶を含む）等に用いられる溶媒としては、例えば、1-プロパノール、イソプロピルアルコール、2-プロパノール、1-ブタノール等が挙げられる。 Purity of the tartrate salt (4) obtained by the above method can be improved by a known method such as reslurry or crystallization (including recrystallization). Examples of the solvent used for reslurry and crystallization (including recrystallization) include 1-propanol, isopropyl alcohol, 2-propanol, 1-butanol and the like.
＜本発明にかかる酒石酸塩（４）＞
上記本発明の製造方法によって得られる酒石酸塩（４）、すなわち、（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩（４）は、その化学純度が９９％以上、不純物のエステル体が０．１％以下、光学純度が９７％以上と極めて高い純度を有し、更に高収率で得ることができる。
<Tartrate salt according to the present invention (4)>
Tartrate (4) obtained by the production method of the present invention, that is, (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- ( Hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate (4) has a chemical purity of 99% or higher, an impurity ester form of 0.1% or lower, and an optical purity of 97% or higher. And can be obtained in a high yield.
＜エスシタロプラム及びその塩の製造方法＞
本発明にかかる酒石酸塩（４）を脱酒石酸して遊離体（５）とする遊離化反応を行い、次に該遊離体の閉環反応によりエスシタロプラム（６）を得ることができる。更に、エスシタロプラム（６）に酸付加する塩化反応により、エスシタロプラムの塩を得ることができる。特に、個体として得るためにエスシタロプラム蓚酸塩（７）とすることが好ましい。これらの製造方法としては、公知の方法を特に制限なく用いることができる。
<The manufacturing method of escitalopram and its salt>
An escitalopram (6) can be obtained by subjecting the tartrate salt (4) according to the present invention to a detartaric acid to liberate the free form (5), followed by a ring-closing reaction of the free form. Furthermore, a salt of escitalopram can be obtained by a chlorination reaction for acid addition to escitalopram (6). In particular, escitalopram succinate (7) is preferred for obtaining as an individual. As these production methods, known methods can be used without particular limitation.
以下、実施例を挙げて本発明を詳細に説明するが、本発明はこれらの実施例によって制限されるものではない。 EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited by these Examples.
＜化学純度の測定＞
本願発明にかかる酒石酸塩（４）の化学純度の測定は、ＨＰＬＣ法を用いて以下の条件で行った。
<Measurement of chemical purity>
The chemical purity of the tartrate salt (4) according to the present invention was measured under the following conditions using the HPLC method.
装置：ウォーターズ社製２６９５
検出器：紫外吸光光度計（ウォーターズ社製２４８９）
検出波長：２３７ｎｍ
カラム：内径４．６ｍｍ、長さ２５ｃｍのステンレス管に５μｍの液体クロマトグラ
フィー用オクタデシルシリル化シリカゲルが充填されたもの
移動相Ａ：アセトニトリル／緩衝液＝１０／９０
移動相Ｂ：アセトニトリル／緩衝液＝６５／３５
緩衝液：リン酸二水素カリウム３．４ｇを水１０００ｍＬに溶かし、リン酸を加えて
ｐＨ３．０に調製する
移動相の送液：移動相Ａ及び移動相Ｂの混合比を次のように変えて濃度勾配制御する
カラム温度：４５℃付近の一定温度
注入量：２０μＬ
サンプル濃度：０．５ｍｇ／ｍＬ
Apparatus: 2695 manufactured by Waters
Detector: Ultraviolet absorptiometer (Waters 2489)
Detection wavelength: 237 nm
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm packed with 5 μm of octadecylsilylated silica gel for liquid chromatography Mobile phase A: acetonitrile / buffer = 10/90
Mobile phase B: acetonitrile / buffer = 65/35
Buffer solution: 3.4 g of potassium dihydrogen phosphate is dissolved in 1000 mL of water, and phosphoric acid is added to adjust the pH to 3.0. Mobile phase feeding: Change the mixing ratio of mobile phase A and mobile phase B as follows. Control the concentration gradient Column temperature: Constant temperature around 45 ° C Injection volume: 20 μL
Sample concentration: 0.5 mg / mL
＜光学純度の測定＞
本願発明にかかる酒石酸塩（４）の光学純度の測定は、ＨＰＬＣ法を用いて以下の条件で行った。
<Measurement of optical purity>
The optical purity of the tartrate salt (4) according to the present invention was measured using the HPLC method under the following conditions.
装置：ウォーターズ社製２６９５
検出器：紫外吸光光度計（ウォーターズ社製２４８９）
検出波長：２４０ｎｍ
カラム：ＣＨＩＲＡＬＣＥＬ ＯＤ−Ｈ（内径４．６ｍｍ、長さ２５ｃｍのステンレス管に５
μｍのセルロース誘導体をコーティングしたシリカゲルが充填されたもの）
移動相：ヘキサン／エタノール／ジエチルアミン＝９８／２／０．１
流速：０．７ｍＬ／ｍｉｎ
カラム温度：３０℃付近の一定温度
注入量：１０μＬ
サンプル濃度：２．０ｍｇ／ｍＬ
なお、酒石酸塩（４）の光学純度とは、得られたクロマトグラムにおける酒石酸塩（４）のピーク面積値の、Ｓ体とＲ体の面積値の合計に対する百分率で示した値である。また、該条件によるＨＰＬＣ分析における酒石酸塩（４）の保持時間は３４．１分付近である。またＲ体の酒石酸塩の保持時間は３７．５分付近である。
Apparatus: 2695 manufactured by Waters
Detector: Ultraviolet absorptiometer (Waters 2489)
Detection wavelength: 240 nm
Column: CHIRALCEL OD-H (5 on a stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm)
Filled with silica gel coated with cellulose derivative of μm)
Mobile phase: hexane / ethanol / diethylamine = 98/2 / 0.1
Flow rate: 0.7 mL / min
Column temperature: constant temperature around 30 ° C. Injection volume: 10 μL
Sample concentration: 2.0 mg / mL
In addition, the optical purity of tartrate (4) is the value shown by the percentage with respect to the sum total of the area value of S body and R body of the peak area value of tartrate (4) in the obtained chromatogram. Further, the retention time of the tartrate (4) in the HPLC analysis under the above conditions is around 34.1 minutes. The retention time of the R form tartrate is around 37.5 minutes.
＜本発明における遊離体（３）＞
撹拌翼、温度計を取り付け、アルゴン置換した１０００ｍＬの四つ口フラスコに、ＴＨＦ４８０ｍＬを加え、マグネシウム１２．１ｇ（４９９．９ｍｍｏｌ）、４−ブロモフルオロベンゼン６．６ｇ（３７．７ｍｍｏｌ）を加え、撹拌し、３５℃に昇温した。昇温後、ブロモフルオロベンゼンのグリニャール試薬１．２ｇ（１．２３ｍｍｏｌ）を加え、還流温度まで昇温した。昇温後、４−ブロモフルオロベンゼン７９．２ｇ（４５２．４ｍｍｏｌ）を滴下し、滴下後還流温度で１時間攪拌する。撹拌後、室温付近の温度まで冷却し、ブロモフルオロベンゼンのグリニャール試薬を調製した。
<Educt in the present invention (3)>
To a 1000 mL four-necked flask equipped with a stirring blade and a thermometer and purged with argon, 480 mL of THF was added, and 12.1 g (499.9 mmol) of magnesium and 6.6 g (37.7 mmol) of 4-bromofluorobenzene were added and stirred. The temperature was raised to 35 ° C. After the temperature increase, 1.2 g (1.23 mmol) of Grignard reagent of bromofluorobenzene was added, and the temperature was raised to the reflux temperature. After raising the temperature, 79.2 g (452.4 mmol) of 4-bromofluorobenzene is added dropwise, and the mixture is stirred for 1 hour at the reflux temperature after the addition. After stirring, the mixture was cooled to a temperature around room temperature to prepare a Grignard reagent for bromofluorobenzene.
撹拌翼、温度計を取り付け、アルゴン置換した５００ｍＬの四つ口フラスコに、ＴＨＦ１８０ｍＬを加え、マグネシウム１０．３ｇ（４２３．０ｍｍｏｌ）、Ｎ，Ｎ−ジメチルプロピルアミンのグリニャール試薬２．５ｇ（４．１５ｍｍｏｌ）を加え、還流温度に昇温した。昇温後、Ｎ，Ｎ−ジメチルプロピルアミン４．６ｇ（３７．７ｍｍｏｌ）、トルエン６．５ｍＬを加え、３０分撹拌する。撹拌後、Ｎ，Ｎ−ジメチルプロピルアミン４５．９ｇ（３７７．０ｍｍｏｌ）、トルエン６５ｍＬを滴下し、滴下後還流温度で１時間攪拌した。撹拌後、室温付近の温度まで冷却し、Ｎ，Ｎ−ジメチルプロピルアミンのグリニャール試薬を調製した。 To a 500 mL four-necked flask equipped with a stirring blade and a thermometer and purged with argon, 180 mL of THF was added, and 10.3 g (423.0 mmol) of magnesium and 2.5 g (4.15 mmol) of Grignard reagent of N, N-dimethylpropylamine were added. ) Was added and the temperature was raised to reflux temperature. After heating, 4.6 g (37.7 mmol) of N, N-dimethylpropylamine and 6.5 mL of toluene are added and stirred for 30 minutes. After stirring, 45.9 g (377.0 mmol) of N, N-dimethylpropylamine and 65 mL of toluene were added dropwise, and the mixture was stirred at reflux temperature for 1 hour. After stirring, the mixture was cooled to a temperature around room temperature to prepare a Grignard reagent of N, N-dimethylpropylamine.
撹拌翼、温度計を取り付け、アルゴン置換した２０００ｍＬの四つ口フラスコに、ＴＨＦ１５０ｍＬ、５−シアノフタリド（１）６０ｇ（３７７．０ｍｍｏｌ）を加え、０〜１５℃で撹拌する。０〜１５℃の温度範囲内でブロモフルオロベンゼンのグリニャール試薬を滴下時間３時間で滴下した。滴下後、１時間攪拌し、０〜１５℃の温度範囲内でＮ，Ｎ−ジメチルプロピルアミンのグリニャール試薬を滴下時間３時間で滴下した。滴下後、１時間攪拌し、蒸留水１８ｍＬを０〜１５℃の温度範囲内で滴下した。その後、酢酸１００ｇ蒸留水２２０ｍＬを混合し、酢酸水溶液を調整し、酢酸水溶液を０〜３０℃の温度範囲内で滴下した。滴下後、外温４０〜６０℃の温度範囲で減圧濃縮を行い、ＴＨＦを濃縮した。濃縮残渣に、蒸留水３６０ｍＬ、トルエン４８０ｍＬ、２５％アンモニア水５０ｇを加え、６０℃で３０分撹拌する。撹拌後、有機層と水層に分液し、水層にトルエン９０ｍＬを加え、６０℃で３０分撹拌した。撹拌後、有機層と水層を分液し、得られた２つの有機層を混合する。混合した有機層に蒸留水９０ｍＬを加え、６０〜８０℃で３０分撹拌した。撹拌後、有機層と水層を分液し、得られた有機層を外温６０℃で減圧濃縮した。濃縮残渣に、ジエチルエーテル３６０ｍＬを加え、２５℃で撹拌し、溶液を均一化し、蒸留水３６０ｍＬ、４８％臭化水素酸１９．１ｇ（１１３．１ｍｍｏｌ）を室温付近の温度で加え、３０分撹拌し結晶の析出を確認した。結晶の析出確認後、４８％臭化水素酸４１．３ｇ（２４５．１ｍｍｏｌ）を室温付近の温度で加え、減圧濃縮を行い、ジエチルエーテルを濃縮した。ジエチルエーテル濃縮後、減圧濾過により析出した結晶を濾別し、蒸留水１２０ｍＬ、ジエチルエーテル１２０ｍＬにより、濾別した結晶を洗浄した。得られた白色結晶を３０〜５０℃で１２時間減圧乾燥し、白色結晶として４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルの臭化水素酸塩１１８．１ｇ（２７９．０ｍｍｏｌ）を得た。 To a 2000 mL four-necked flask equipped with a stirring blade and a thermometer and purged with argon, 150 mL of THF and 60 g (377.0 mmol) of 5-cyanophthalide (1) are added and stirred at 0 to 15 ° C. The Grignard reagent of bromofluorobenzene was added dropwise at a dropping time of 3 hours within a temperature range of 0 to 15 ° C. After dropping, the mixture was stirred for 1 hour, and a Grignard reagent of N, N-dimethylpropylamine was added dropwise within a temperature range of 0 to 15 ° C. over a dropping time of 3 hours. After dripping, it stirred for 1 hour and 18 mL of distilled water was dripped within the temperature range of 0-15 degreeC. Then, acetic acid 100g distilled water 220mL was mixed, the acetic acid aqueous solution was adjusted, and the acetic acid aqueous solution was dripped within the temperature range of 0-30 degreeC. After dripping, it concentrated under reduced pressure in the temperature range of external temperature 40-60 degreeC, and concentrated THF. Distilled water (360 mL), toluene (480 mL) and 25% aqueous ammonia (50 g) are added to the concentrated residue, and the mixture is stirred at 60 ° C. for 30 minutes. After stirring, the organic layer and the aqueous layer were separated, and 90 mL of toluene was added to the aqueous layer, followed by stirring at 60 ° C. for 30 minutes. After stirring, the organic layer and the aqueous layer are separated, and the obtained two organic layers are mixed. Distilled water 90mL was added to the mixed organic layer, and it stirred at 60-80 degreeC for 30 minutes. After stirring, the organic layer and the aqueous layer were separated, and the resulting organic layer was concentrated under reduced pressure at an external temperature of 60 ° C. Add 360 mL of diethyl ether to the concentrated residue, stir at 25 ° C. to homogenize the solution, add 360 mL of distilled water and 19.1 g (113.1 mmol) of 48% hydrobromic acid at a temperature near room temperature, and stir for 30 minutes. Then, precipitation of crystals was confirmed. After confirming the precipitation of crystals, 41.3 g (245.1 mmol) of 48% hydrobromic acid was added at a temperature close to room temperature, followed by concentration under reduced pressure, and diethyl ether was concentrated. After concentration in diethyl ether, the precipitated crystals were filtered off under reduced pressure, and the filtered crystals were washed with 120 mL of distilled water and 120 mL of diethyl ether. The obtained white crystals were dried under reduced pressure at 30 to 50 ° C. for 12 hours to give 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxy There were obtained 118.1 g (279.0 mmol) of hydrobromide of methyl) -benzonitrile.
撹拌翼、温度計を取り付けた２０００ｍＬの四つ口フラスコに、４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルの臭化水素酸塩を加え、クロロホルム４７２ｍＬ、蒸留水３７４ｍＬ、２３％水酸化ナトリウム水溶液９７．０ｇを加え、２５℃で３０分撹拌した。撹拌後、有機層と水層を分液し、有機層に蒸留水１１８ｍＬを加え、３０分撹拌した。撹拌後、有機層と水層を分液し、得られた有機層を外温５０℃で減圧濃縮し、４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリル遊離体（３）９５．４ｇ（２７９．０ｍｍｏｌ、収率７４％）を取得した。 To a 2000 mL four-necked flask equipped with a stirring blade and a thermometer, 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzo was added. Nitrile hydrobromide was added, chloroform 472 mL, distilled water 374 mL, and 23% aqueous sodium hydroxide solution 97.0 g were added, and the mixture was stirred at 25 ° C. for 30 minutes. After stirring, the organic layer and the aqueous layer were separated, 118 mL of distilled water was added to the organic layer, and the mixture was stirred for 30 minutes. After stirring, the organic layer and the aqueous layer were separated, and the obtained organic layer was concentrated under reduced pressure at an external temperature of 50 ° C. to give 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1- Hydroxybutyl] -3- (hydroxymethyl) -benzonitrile educt (3) 95.4 g (279.0 mmol, yield 74%) was obtained.
実施例１
撹拌翼、温度計を取り付けた１００ｍＬの三つ口フラスコに、ラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリル遊離体（３）１０ｇ（２９．３ｍｍｏｌ）、１−ブタノール４５ｍＬ（遊離体（３）１質量部に対して４．５容量部）、クロロホルム４．４ｍＬ（遊離体（３）１質量部に対して０．４４容量部）を加えた。得られた混合液を６０℃に加熱し、１−ブタノール３０ｍＬ（遊離体（３）１質量部に対して３．０容量部）、酢酸０．４ｍＬの混合溶液に溶解した（＋）−ジ−（ｐ−トルオイル）酒石酸４．５ｇ（１１．７ｍｍｏｌ）の溶液を混合し、遊離体（３）を酒石酸塩化した。酒石酸塩化後、１−ブタノール７５ｍＬ（酒石酸塩（４）１質量部に対して９．４容量部）、クロロホルム４．４ｍＬ（酒石酸塩（４）１質量部に対して０．４４容量部）の溶媒組成のまま、種晶２５ｍｇを加え、６０℃で１時間撹拌し、結晶が析出したのを目視により確認した。結晶の析出確認後、冷却速度２０℃／ｈｒで２０℃まで冷却し、さらに同温度で３時間熟成し結晶を析出させた。熟成後、減圧濾過により析出した結晶を濾別し、１−ブタノール１０ｍＬ（遊離体（３）１質量部に対して１容量部）により、濾別した結晶を２回洗浄した。得られた白色結晶を４０℃で１２時間減圧乾燥し、白色結晶として（酒石酸塩（４）５．４ｇ（１０．０ｍｍｏｌ）を得た(収率：３８％、化学純度９９．８３％、不純物１ ０．００２％、不純物２ ０．０１５％、光学純度９８．８３％）。
Example 1
In a 100 mL three-necked flask equipped with a stirring blade and a thermometer, racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) was added. ) -Benzonitrile free form (3) 10 g (29.3 mmol), 1-butanol 45 mL (4.5 parts by volume with respect to 1 part by weight of free form (3)), 4.4 mL chloroform (free form (3) 1 0.44 parts by volume with respect to parts by mass). The obtained mixed solution was heated to 60 ° C. and dissolved in a mixed solution of 30 mL of 1-butanol (3.0 parts by volume with respect to 1 part by mass of the free form (3)) and 0.4 mL of acetic acid (+)-di- A solution of 4.5 g (11.7 mmol) of-(p-toluoyl) tartaric acid was mixed to tartarate the educt (3). After tartrate formation, 75 mL of 1-butanol (9.4 parts by volume with respect to 1 part by mass of tartrate (4)) and 4.4 mL of chloroform (0.44 parts by volume with respect to 1 part by mass of tartrate (4)) While maintaining the solvent composition, 25 mg of seed crystals were added, and the mixture was stirred at 60 ° C. for 1 hour, and it was visually confirmed that crystals were precipitated. After confirming the precipitation of crystals, it was cooled to 20 ° C. at a cooling rate of 20 ° C./hr, and further aged for 3 hours at the same temperature to precipitate crystals. After aging, the precipitated crystals were collected by filtration under reduced pressure, and the crystals separated by filtration were washed twice with 10 mL of 1-butanol (1 part by volume with respect to 1 part by mass of the free form (3)). The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain 5.4 g (10.0 mmol) of tartrate (4) as white crystals (yield: 38%, chemical purity 99.83%, impurities 1 0.002%, Impurity 2 0.015%, optical purity 98.83%).
実施例２〜９、比較例１〜２
溶媒と溶媒量を表２記載の条件とした以外は実施例１と同様にして酒石酸塩（４）を得た。結果を表２に示す。なお、１−ブタノールの使用量は４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリル遊離体（３）の１−ブタノール溶液と（＋）−ジ−（ｐ−トルオイル）酒石酸の１−ブタノール溶液の混合後の量であり、（＋）−ジ−（ｐ−トルオイル）酒石酸は遊離体（３）１質量部に対して３．０容量部の１−ブタノールに溶解して使用した。
Examples 2-9, Comparative Examples 1-2
A tartrate salt (4) was obtained in the same manner as in Example 1 except that the solvent and the amount of the solvent were changed as shown in Table 2. The results are shown in Table 2. The amount of 1-butanol used is that of 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile free form (3). 1-butanol solution and (+)-di- (p-toluoyl) tartaric acid after mixing 1-butanol solution, (+)-di- (p-toluoyl) tartaric acid is free mass (3) 1 mass It was used by dissolving in 3.0 parts by volume of 1-butanol.
＜本発明にかかる酒石酸塩の光学純度＞
実施例１〜９により得られた本発明にかかる酒石酸塩（４）の収率は３５〜４３％、化学純度は９８．５３〜９９．８５％、光学純度は９６．７５〜９９．８４％と高収率、高純度であることを示した。特に化学純度は、不純物１、不純物２の生成が抑制されているため、従来法など（比較例１及び２）により得られる酒石酸塩（４）の化学純度（９８．０２％又は９７．５５％）をはるかに超えるものである。なお、比較例２は前記特許文献１の方法による。
<Optical purity of tartrate salt according to the present invention>
The yield of the tartrate salt (4) according to the present invention obtained in Examples 1 to 9 is 35 to 43%, the chemical purity is 98.53 to 99.85%, and the optical purity is 96.75 to 99.84%. And showed high yield and high purity. In particular, since the chemical purity of the impurities 1 and 2 is suppressed, the chemical purity (98.02% or 97.55%) of the tartrate salt (4) obtained by the conventional method or the like (Comparative Examples 1 and 2) is used. ) Much more. In addition, the comparative example 2 is based on the method of the said patent document 1. FIG.
＜（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩（４ｂ）からエスシタロプラム蓚酸塩（７）への製造例＞
＜本発明にかかる酒石酸塩（４）の遊離化＞
本発明にかかる酒石酸塩（４）を脱酒石酸して遊離体（５）とする遊離化反応を行い、次に該遊離体の閉環反応によりエスシタロプラム（６）を得ることができる。更に、エスシタロプラム（６）に酸付加する塩化反応により、エスシタロプラムの塩を得ることができる。特に、個体として得るためにエスシタロプラム蓚酸塩（７）とすることが好ましい。これらの製造方法としては、公知の方法を特に制限なく用いることができる。以下に、エスシタロプラム（６）及びエスシタロプラム蓚酸塩（７）の製造の実施例を示した。
<(1S) -4- [4- (Dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p- Toluoyl) Tartrate (4b) to escitalopram succinate (7)>
<Liberation of tartrate (4) according to the present invention>
An escitalopram (6) can be obtained by subjecting the tartrate salt (4) according to the present invention to a detartaric acid to liberate the free form (5), followed by a ring-closing reaction of the free form. Furthermore, a salt of escitalopram can be obtained by a chlorination reaction for acid addition to escitalopram (6). In particular, escitalopram succinate (7) is preferred for obtaining as an individual. As these production methods, known methods can be used without particular limitation. Below, the Example of manufacture of escitalopram (6) and escitalopram succinate (7) was shown.
実施例１０
＜（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）遊離体（５）の製造＞
撹拌翼、温度計を取り付けた１００ｍＬの三つ口フラスコに、実施例１で取得した再結晶体（４ｂ）４．３ｇ（８．０ｍｍｏｌ、純度９９．８３％、光学純度９８．８３％）、トルエン２１ｍＬ、水２１ｍＬ、２３％水酸化ナトリウム水溶液２．８ｇを加え２５℃で３０分間撹拌した。撹拌後、有機層と水層を分離し、有機層を４．３ｍＬの水で洗浄した。有機層を硫酸ナトリウムで乾燥した後減圧濃縮し、（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルの遊離体（５）２．７ｇ（８．０ｍｍｏｌ、収率１００％）を取得した。
Example 10
<(1S) -4- [4- (Dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p- Tolu oil) Production of free form (5)>
In a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 4.3 g (8.0 mmol, purity 99.83%, optical purity 98.83%) of the recrystallized product (4b) obtained in Example 1; Toluene (21 mL), water (21 mL), and 23% aqueous sodium hydroxide solution (2.8 g) were added, and the mixture was stirred at 25 ° C. for 30 minutes. After stirring, the organic layer and the aqueous layer were separated, and the organic layer was washed with 4.3 mL of water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl)- 2.7 g (8.0 mmol, yield 100%) of benzonitrile free form (5) was obtained.
＜エスシタロプラム（６）の製造＞
（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルの遊離体（５）２．７ｇにトルエン２４ｍＬ、トリエチルアミン１．８ｇを加え−５℃で３０分撹拌した。塩化トシルのトルエン溶液（１．７ｇ／８ｍＬ）を加え、５℃で１時間撹拌した。次いで水５ｍＬ、２５％アンモニア水１．４ｇを加え、２５℃で３０分間撹拌した。撹拌後、有機層と水層を分離し、有機層を水５ｍＬで洗浄した。有機層を硫酸ナトリウムで乾燥した後減圧濃縮し、（１Ｓ）−１−［３−（ジメチルアミノ）プロピル］−１−（４−フルオロフェニル）−１，３−ジヒドロイソベンゾフラン−５−カルボニトリル（エスシタロプラム）２．３ｇ（７．２ｍｍｏｌ、収率８９％）の黄色オイルを取得した。
<Manufacture of escitalopram (6)>
(1S) -4- [4- (Dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile free form (5) 2.7 g of toluene 24 mL and triethylamine 1.8g were added and it stirred at -5 degreeC for 30 minutes. A toluene solution of tosyl chloride (1.7 g / 8 mL) was added and stirred at 5 ° C. for 1 hour. Next, 5 mL of water and 1.4 g of 25% aqueous ammonia were added, and the mixture was stirred at 25 ° C. for 30 minutes. After stirring, the organic layer and the aqueous layer were separated, and the organic layer was washed with 5 mL of water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile. 2.3 g (7.2 mmol, 89% yield) of yellow oil (escitalopram) was obtained.
＜エスシタロプラム蓚酸塩（７）の製造＞
得られたエスシタロプラム（６）２．３ｇ（７．２ｍｍｏｌ）を撹拌翼、温度計を取り付けた１００ｍＬの三つ口フラスコに加え、アセトニトリル１２ｍＬを加え溶解し、５０℃で３０分撹拌した。撹拌後、蓚酸０．７ｇ（７．９ｍｍｏｌ）をアセトニトリル１２ｍＬに溶解した溶液を加え、３０分撹拌し、種晶２．３ｍｇを加え、結晶の析出を確認した。撹拌後、溶液を５℃まで冷却し1時間熟成した。減圧ろ過を行い、アセトニトリル２．３ｍＬで２回洗浄することによって得られた白色結晶を４０℃で１５時間減圧乾燥し、（１Ｓ）−１−［３−（ジメチルアミノ）プロピル］−１−（４−フルオロフェニル）−１，３−ジヒドロイソベンゾフラン−５−カルボニトリル蓚酸塩（エスシタロプラム蓚酸塩）の白色結晶２．６ｇ（６．４ｍｍｏｌ）を得た（収率８９％、純度９９．９０％、光学純度９８．８１％）。
<Manufacture of escitalopram succinate (7)>
2.3 g (7.2 mmol) of the obtained escitalopram (6) was added to a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 12 mL of acetonitrile was added and dissolved, and the mixture was stirred at 50 ° C. for 30 minutes. After stirring, a solution prepared by dissolving 0.7 g (7.9 mmol) of succinic acid in 12 mL of acetonitrile was added, stirred for 30 minutes, 2.3 mg of seed crystals were added, and precipitation of crystals was confirmed. After stirring, the solution was cooled to 5 ° C. and aged for 1 hour. The white crystals obtained by filtration under reduced pressure and washed twice with 2.3 mL of acetonitrile were dried under reduced pressure at 40 ° C. for 15 hours, and (1S) -1- [3- (dimethylamino) propyl] -1- ( 2.6 g (6.4 mmol) of white crystals of 4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile succinate (escitalopram succinate) were obtained (yield 89%, purity 99.90%). , Optical purity 98.81%).
Claims (10)
ラセミ体の４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルと、（＋）−ジ−（ｐ−トルオイル）酒石酸とを反応させて、（１Ｓ）−４−［４−（ジメチルアミノ）−１−（４’−フルオロフェニル）−１−ヒドロキシブチル］−３−（ヒドロキシメチル）−ベンゾニトリルヘミ（＋）−ジ−（ｐ−トルオイル）酒石酸塩を得た後、該酒石酸塩を１−ブタノールを含む溶媒にて晶析を行い、晶析体として当該酒石酸塩を得ることを特徴とする製造方法。 (1S) -4- [4- (Dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) A method for producing tartrate,
Racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile and (+)-di- (p-toluoyl) ) Reaction with tartaric acid to give (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+ ) -Di- (p-toluoyl) tartrate, and then crystallizing the tartrate with a solvent containing 1-butanol to obtain the tartrate as a crystallized product.
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