JP2019119710A - Process for producing hydrobromide of diol compound - Google Patents
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Abstract
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本発明は、ジオール化合物の臭化水素酸塩の新規な製造方法に関する。詳しくは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)−ベンゾニトリル臭化水素塩を、高純度、且つ高い単離収率で製造する方法に関する。 The present invention relates to a novel process for the preparation of hydrobromides of diol compounds. Specifically, 4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hydrobromide is highly pure and highly isolated. Relates to the method of manufacturing at a rate.
(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−カルボニトリルオキサレート(以下、「エスシタロプラムシュウ酸塩」とも言う)は下記の構造式(1)で示される化合物であり、抗うつ剤として利用されている。 (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile oxalate (hereinafter, also referred to as “escitalopram oxalate” Is a compound represented by the following structural formula (1) and is used as an antidepressant.
このエスシタロプラムシュウ酸塩(1)は、以下の合成経路により製造する方法が知られている。具体的には、まず、5−シアノフタリド(2)を4−ブロモフルオロベンゼン及び3−クロロ−N,N−ジメチル−1−プロパンアミンの各グリニャール試薬と順次グリニャール反応させ、ジオール化合物(4)(化学名称: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)を製造する。次いで、光学分割した後、塩化トシル等による環化反応、シュウ酸塩化を行うことで、エスシタロプラムシュウ酸塩(1)を製造する。 The method of producing this escitalopram oxalate (1) by the following synthetic route is known. Specifically, first, 5-cyanophthalide (2) is sequentially subjected to Grignard reaction with 4-bromofluorobenzene and 3-chloro-N, N-dimethyl-1-propanamine with respective Grignard reagents to obtain diol compound (4) ( The chemical name: 4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile) is prepared. Then, after optical resolution, cyclization reaction with tosyl chloride or the like and oxalation are performed to produce escitalopram oxalate (1).
上記グリニャール反応では、複数の不純物が副生するため、純度を向上させるために、生成物である上記ジオール化合物(4)の精製を行う必要がある。その精製方法として、ジオール化合物(4)は油状物であるため、安定な固体形態であるジオール化合物(4)の臭化水素酸塩の形態で結晶化して単離することが一般的である。当該ジオール化合物(4)の臭化水素酸塩(以下、単に臭化水素酸塩とも言う。)の製造方法として、いくつかの方法が知られている。特許文献1において、グリニャール反応後、後処理を行い、ジエチルエーテルと水との混合溶媒からなるジオール化合物(4)の溶液を調製する。次いで、臭化水素酸を加え臭化水素酸塩を結晶化させた後、ジエチルエーテルを留去し、臭化水素酸塩と水との懸濁液を得る。当該懸濁液を分離し、臭化水素酸塩を製造する方法が開示されている。また、非特許文献1において、反応及び後処理後、トルエン、テトラヒドロフラン、ジクロロメタン、及び、水の混合溶媒からなるジオール化合物(4)の溶液を得る。当該溶液に臭化水素酸を加え、臭化水素酸塩を結晶化させた後、分離することにより臭化水素酸塩を製造する方法が開示されている。 In the Grignard reaction, since a plurality of impurities are by-produced, it is necessary to purify the diol compound (4), which is a product, in order to improve the purity. As a purification method thereof, it is general to crystallize and isolate in the form of hydrobromide of diol compound (4) which is a stable solid form because diol compound (4) is an oily substance. Several methods are known as a method for producing a hydrobromide of the diol compound (4) (hereinafter, also simply referred to as hydrobromide). In Patent Document 1, after the Grignard reaction, post-treatment is performed to prepare a solution of a diol compound (4) composed of a mixed solvent of diethyl ether and water. Then, hydrobromic acid is added and the hydrobromide is crystallized, and then diethyl ether is distilled off to obtain a suspension of hydrobromide and water. A method of separating the suspension and producing hydrobromide is disclosed. In addition, in Non-Patent Document 1, after reaction and post-treatment, a solution of diol compound (4) comprising a mixed solvent of toluene, tetrahydrofuran, dichloromethane and water is obtained. There is disclosed a method for producing a hydrobromide by adding hydrobromic acid to the solution, crystallizing the hydrobromide, and separating it.
本発明者らが上記特許文献1記載の方法の追試を行ったところ、臭化水素酸塩と水との懸濁液の分離性が著しく悪く、結果として多量の母液が分離後の結晶中に残存することが判明した。また、ジオール化合物(4)に含まれる不純物は、グリニャール反応の過反応物等が主要であるが、これらの不純物は非水溶性であるため、水を主成分とする母液中への溶解度が低く、単離した臭化水素酸塩中に含有される。そのため、精製効率が十分とはいえず、得られる臭化水素酸塩の純度の点で課題があった。一方、上記非特許文献1記載の方法は、臭化水素酸塩を含む懸濁液の分離性は良好であり、特許文献1と比較して、高い純度の臭化水素酸塩を製造することができる。しかしながら、臭化水素酸塩の懸濁液を得る際に結晶化した臭化水素酸塩の一部が反応容器内壁に固着する現象(スケーリング)が生じること、固着した結晶は反応容器内壁に強固に固着しており、簡便な操作での単離が困難であり、結果的に臭化水素酸塩の単離収率の点でなお課題があった。すなわち本発明の目的は、上記ジオール化合物(4)の臭化水素酸塩を高純度、且つ、高収率で製造する方法を提供することにある。 When the present inventors conducted a follow-up test of the method described in Patent Document 1, the separation of the hydrobromide and water suspension was extremely poor, and as a result, a large amount of mother liquor was in the separated crystals. It turned out to remain. Moreover, although the impurities contained in the diol compound (4) are mainly the overreact of Grignard reaction etc., since these impurities are non-water soluble, the solubility in the mother liquor mainly composed of water is low. , Contained in the isolated hydrobromide. Therefore, the purification efficiency is not sufficient, and there is a problem in terms of the purity of the obtained hydrobromide. On the other hand, the method described in the above Non-patent Document 1 has good separation property of the suspension containing hydrobromide and produces hydrobromide having high purity as compared with Patent Document 1. Can. However, there is a phenomenon (scaling) that a part of the crystallized hydrobromide adheres to the inner wall of the reaction vessel when obtaining a hydrobromide suspension, and the adhered crystals are firmly attached to the inner wall of the reaction vessel It is difficult to isolate by simple operation, and as a result, there is still a problem in terms of isolation yield of hydrobromide. That is, an object of the present invention is to provide a method for producing the hydrobromide of the diol compound (4) with high purity and high yield.
上記課題に対し本発明者らは鋭意検討を行った。上記非特許文献1記載に方法におけるスケーリングの発生は、臭化水素酸塩を結晶化させる際の溶媒中に、グリニャール反応の反応溶媒或いはその後の後処理溶媒として用いた低極性溶媒であるトルエンやジクロロメタンが含まれることに起因しているものと推測し、臭化水素酸塩の懸濁液として用いる溶媒系について検討を行った。その結果、エステル系溶媒と水との混合溶媒中で上記ジオール化合物(4)と臭化水素とを接触させて、臭化水素酸塩を生成させることにより該混合溶媒中で臭化水素酸塩を結晶化すること、さらに、結晶化した臭化水素酸塩を単離することで、臭化水素酸塩中に母液が取り込まれることなく、高純度の臭化水素酸塩を高い単離収率で製造できることを見出し、本発明を完成させるに至った。 The present inventors diligently studied the above problems. The occurrence of scaling in the method described in the above-mentioned Non-Patent Document 1 can be determined by using toluene as a low polar solvent used as a reaction solvent for Grignard reaction or a post-treatment solvent thereafter in the solvent for crystallizing hydrobromide. The solvent system used as a hydrobromide suspension was examined on the assumption that it was caused by the inclusion of dichloromethane. As a result, in the mixed solvent, the diol compound (4) is brought into contact with hydrogen bromide in a mixed solvent of an ester solvent and water to form a hydrobromide, and the hydrobromide in the mixed solvent is formed. By isolating the crystallized hydrobromide, crystallizing the hydrobromide, high isolation and collection of high purity hydrobromide without the mother liquor being taken into hydrobromide. It has been found that it can be manufactured at a rate, and the present invention has been completed.
すなわち第1の本発明は、エステル系溶媒及び水の混合溶媒中で、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)−ベンゾニトリルと臭化水素とを接触させることを特徴とする、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)−ベンゾニトリル臭化水素塩の製造方法である。さらに、本発明においては、以下の態様を好適に採り得る。
1)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)−ベンゾニトリルと臭化水素との接触を0〜30℃の範囲で行うこと
2)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モルに対して、臭化水素を0.8〜2.4モルの範囲で用いること
3)エステル系溶媒100容量部に対し、水を20〜500容量部用いること
4)エステル系溶媒が、ギ酸メチル、ギ酸エチル、酢酸メチル、酢酸エチル、酢酸イソプロピルより選択される少なくとも1種であること
さらに、第2の本発明は、5−シアノフタリドに、4−フルオロフェニルマグネシウムブロミド及びN,N−ジメチルアミノプロピルマグネシウムクロリドを反応させて、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)−ベンゾニトリルを得、次いで、エステル系溶媒及び水の混合溶媒中で、得られた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)−ベンゾニトリルと臭化水素とを接触させることを特徴とする、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)−ベンゾニトリル臭化水素塩の製造方法である。
That is, according to the first aspect of the present invention, 4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) is used in a mixed solvent of an ester solvent and water. 4- [4- (Dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzo, characterized in that a benzonitrile and hydrogen bromide are brought into contact with each other. It is a manufacturing method of nitrile hydrobromide. Furthermore, in the present invention, the following aspects can be suitably taken.
1) Contact of 4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile with hydrogen bromide in the range of 0 to 30 ° C. 2) 4- [4- (Dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile 0 mole hydrogen bromide per mole Use in the range of 8 to 2.4 mol 3) Use 20 to 500 parts by volume of water with respect to 100 parts by volume of ester based solvent 4) Methyl ester, methyl formate, methyl acetate, ethyl acetate And at least one selected from isopropyl acetate. Furthermore, the second aspect of the present invention relates to 5-cyanophthalide, 4-fluorophenyl magnesium bromide and N, N-dimethylamine. Minopropyl magnesium chloride is reacted to give 4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile, which is then ester based The obtained 4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile and hydrogen bromide in a mixed solvent of solvent and water (4) (4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl) -3- (hydroxymethyl) -benzonitrile hydrobromide, which is characterized in that It is a method.
さらに、第3の本発明は、第1或いは第2の本発明の製造方法によって、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)−ベンゾニトリル臭化水素塩を製造した後、得られた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)−ベンゾニトリル臭化水素塩を用いて、(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−カルボニトリルオキサレートを製造する方法である。 Furthermore, according to the third aspect of the present invention, there is provided 4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl] -3- (4) according to the first or second production method of the present invention. 4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl)-obtained after producing hydroxymethyl) -benzonitrile hydrobromide (1S) -1- [3- (Dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile oxalate using benzonitrile hydrobromide It is a method of manufacturing.
本発明の製造方法によれば、高純度の臭化水素酸塩を高い単離収率で製造することができる。また、臭化水素酸塩を含む懸濁液の分離性が良好であり、また、スケーリングが発生しないため、操作性の観点においても優位である。さらに、当該方法により製造された臭化水素酸塩は高純度であるため、更なる精製操作を必要とせずに、好適にエスシタロプラムシュウ酸塩の製造に利用することができる。 According to the production method of the present invention, high purity hydrobromide can be produced with high isolation yield. In addition, the separability of the hydrobromide-containing suspension is good, and scaling does not occur, which is also advantageous in terms of operability. Furthermore, since the hydrobromide prepared by the method is high in purity, it can be suitably used for the preparation of escitalopram oxalate without the need for further purification operation.
本発明の製造方法は、エステル系溶媒と水との混合溶媒中で上記ジオール化合物(4)と臭化水素とを接触させて、該ジオール化合物(4)の臭化水素酸塩を製造することが特徴である。上記混合溶媒を用いることで、グリニャール反応の過反応物等の不純物を効率的に除去できると共に、臭化水素酸塩中に溶媒が取り込まれることなく効率的に高純度の臭化水素酸塩を得ることができる。以下、本発明の製造方法について詳細に説明する。 According to the production method of the present invention, the above-mentioned diol compound (4) and hydrogen bromide are brought into contact in a mixed solvent of an ester solvent and water to produce a hydrobromide of the diol compound (4). Is a feature. By using the above mixed solvent, impurities such as a Grignard reaction overreact can be efficiently removed, and the hydrobromide can be efficiently incorporated with a high purity hydrobromide without the solvent being incorporated into the hydrobromide. You can get it. Hereinafter, the manufacturing method of the present invention will be described in detail.
(エステル系溶媒と水との混合溶媒)
本発明の製造方法において、使用するエステル系溶媒とは、エステル骨格を有する有機溶媒であり、具体的には、ギ酸メチル、ギ酸エチル、ギ酸プロピル、ギ酸ブチル、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸n−ブチル、酢酸イソブチル、プロピオン酸メチル、プロピオン酸エチル、アセト酢酸メチル、アセト酢酸エチル、安息香酸エチル、安息香酸プロピル、イソ吉草酸エチル、サリチル酸メチル等のカルボン酸エステルが挙げられる。何れのエステル系溶媒も、試薬や工業用等、特に制限されること無く使用できる。上記の中でも、臭化水素酸塩の乾燥時に除去し易い点から、ギ酸メチル、ギ酸エチル、酢酸メチル、酢酸エチル、酢酸イソプロピルが好ましく、ギ酸メチル、酢酸メチル、酢酸エチルがより好ましい。これらのエステル系溶媒は単独で用いても或いは複数のエステル系溶媒を混合して用いても良い。
(Mixed solvent of ester solvent and water)
In the production method of the present invention, the ester solvent used is an organic solvent having an ester skeleton, and specifically, methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, Carboxylic acid esters such as isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl propionate, ethyl propionate, methyl acetoacetate, ethyl acetoacetate, ethyl benzoate, propyl benzoate, ethyl isovalerate and methyl salicylate . Any ester solvents can be used without particular limitation, such as reagents and industrial use. Among the above, methyl formate, ethyl formate, methyl acetate, ethyl acetate and isopropyl acetate are preferable, and methyl formate, methyl acetate and ethyl acetate are more preferable, from the viewpoint of easy removal of the hydrobromide during drying. These ester solvents may be used alone or in combination of a plurality of ester solvents.
エステル系溶媒の使用量は、良好な分離性及び精製効率の観点からジオール化合物(4)100質量部に対して、200〜2000容量部の範囲で用いることが好ましい。上記範囲の中でも、バッチ当たりの製造量を考慮すると、ジオール化合物(4)100質量部に対して、200〜1750容量部がより好ましく、200〜1500容量部が最も好ましい。 The amount of the ester solvent used is preferably in the range of 200 to 2000 parts by volume with respect to 100 parts by mass of the diol compound (4) from the viewpoint of good separability and purification efficiency. Among the above ranges, 200 to 1750 parts by volume is more preferable, and 200 to 1500 parts by volume is the most preferable based on 100 parts by mass of the diol compound (4), in consideration of the production amount per batch.
本発明の製造方法において、使用する水は、特に制限されることなく、水道水、イオン交換水、蒸留水等を使用することができる。水の使用量は、良好な分離性及び精製効率の観点からジオール化合物(4)100質量部に対して、200〜2000容量部の範囲で用いることが好ましい。上記範囲の中でも、バッチ当たりの製造量を考慮すると、ジオール化合物(4)100質量部に対して、200〜1750容量部がより好ましく、200〜1500容量部が最も好ましい。なお、エステル溶媒及び水の組成比は、特に制限されず、ジオール化合物(4)100質量部に対し、各々上記範囲となるように用いれば良いが、良好な分離性及び精製効率、並びにバッチ当たりの製造量の観点から、エステル系溶媒を100容量部に対して、水を20〜500容量部の範囲で用いることが特に好ましい。 In the production method of the present invention, water to be used is not particularly limited, and tap water, ion exchanged water, distilled water and the like can be used. The amount of water used is preferably in the range of 200 to 2000 parts by volume with respect to 100 parts by mass of the diol compound (4) from the viewpoint of good separability and purification efficiency. Among the above ranges, 200 to 1750 parts by volume is more preferable, and 200 to 1500 parts by volume is the most preferable based on 100 parts by mass of the diol compound (4), in consideration of the production amount per batch. The composition ratio of the ester solvent and water is not particularly limited and may be in the above range with respect to 100 parts by mass of the diol compound (4), but good separability and purification efficiency, and per batch It is particularly preferable to use water in an amount of 20 to 500 parts by volume with respect to 100 parts by volume of an ester solvent from the viewpoint of the production amount of
(ジオール化合物(4))
本発明の製造方法において、ジオール化合物(4)は特に制限無く使用することができる。例えば、市販品のジオール化合物(4)を使用しても良く、或いは、特許文献1及び非特許文献1の製造方法等により製造したジオール化合物(4)を使用しても良い。ただし、ジオール化合物(4)は粘度の高い油状物であるため、上記特許文献1或いは非特許文献1の方法により製造したジオール化合物(4)を、反応容器から取り出さず、そのまま本発明に使用することが、効率的であり操作性が簡便である点から好ましい。当該製造方法は、具体的には、5−シアノフタリドを4−ブロモフルオロベンゼン及び3−クロロ−N,N−ジメチル−1−プロパンアミンの各グリニャール試薬(4−フルオロフェニルマグネシウムブロミド及びN,N−ジメチルアミノプロピルマグネシウムクロリド)と順次反応させ、生成物であるジオール化合物(4)を含む反応溶液を得る。後処理として、当該反応溶液と、塩酸や塩化アンモニウム水溶液等とを混合し、未反応のグリニャール試薬を失活させる。次いで、分液や濾過等の操作により、後処理で生じるマグネシウム由来の副生物を除去することにより、ジオール化合物(4)を含む溶液を製造する。当該溶液を濃縮し、溶媒を留去することで、ジオール化合物(4)を製造できる。上記グリニャール反応及び反応後の後処理時に用いる有機溶媒としては、トルエン等の炭化水素類、ジエチルエーテル等のエーテル類、ジクロロメタン等のハロゲン化炭化水素類等の低極性有機溶媒が挙げられる。
(Diol compound (4))
In the production method of the present invention, the diol compound (4) can be used without particular limitation. For example, a commercially available diol compound (4) may be used, or a diol compound (4) produced by the production method of Patent Document 1 and Non-patent Document 1 may be used. However, since the diol compound (4) is an oil having a high viscosity, the diol compound (4) produced by the method of Patent Document 1 or Non-patent Document 1 is used as it is in the present invention without taking it out from the reaction vessel. It is preferable from the viewpoint of efficiency and ease of operation. Specifically, the production method is carried out as follows: 5-cyanophthalide, 4-bromofluorobenzene and 3-chloro-N, N-dimethyl-1-propanamine Grignard reagents (4-fluorophenyl magnesium bromide and N, N- The reaction is sequentially carried out with dimethylaminopropylmagnesium chloride) to obtain a reaction solution containing the product diol compound (4). As post-treatment, the reaction solution is mixed with hydrochloric acid, an aqueous solution of ammonium chloride or the like to deactivate the unreacted Grignard reagent. Next, a solution containing the diol compound (4) is produced by removing magnesium by-product generated in the post-treatment by an operation such as liquid separation or filtration. The diol compound (4) can be produced by concentrating the solution and distilling off the solvent. Examples of the organic solvent used in post-treatment after the Grignard reaction and reaction include hydrocarbons such as toluene, ethers such as diethyl ether, and low polar organic solvents such as halogenated hydrocarbons such as dichloromethane.
以上のようにして製造されるジオール化合物(4)は、グリニャール過反応物等の不純物が複数含まれ、以下の実施例に記載の条件により高速液体クロマトグラフィー(HPLC)で分析した時の純度が、通常、80.0〜95.0%である。当該ジオール化合物(4)は、本発明により、その純度を大幅に向上できるため、好適に本発明に使用することができる。また、上記濃縮操作後のジオール化合物(4)中の上記低極性有機溶媒の残留量は、製造装置のスケールや能力を勘案して適宜決定すれば良いが、あまり多すぎると上述のとおり、臭化水素酸塩の製造時にスケーリングが生じやすい傾向にあるため、ジオール化合物(4)100質量部に対して、150質量部以下であることが好ましい。当該有機溶媒の残留量は、ガスクロマトグラフィー(GC)等により測定すれば良い。ただし、ジオール化合物(4)が油状物であり、均一性が低いことを考慮すると、後述のように、ジオール化合物(4)とエステル系溶媒とを混合し調製された溶液を測定することにより、低極性有機溶媒の残留量を算出することが、分析の精度の点から好ましい。 The diol compound (4) produced as described above contains a plurality of impurities such as a Grignard perreactant, and has a purity as determined by high performance liquid chromatography (HPLC) under the conditions described in the following examples. , Usually from 80.0 to 95.0%. The diol compound (4) can be suitably used in the present invention because its purity can be greatly improved according to the present invention. Further, the residual amount of the low polar organic solvent in the diol compound (4) after the concentration operation may be appropriately determined in consideration of the scale and ability of the production apparatus, but if it is too large, as described above Since scaling tends to easily occur during the production of the hydrohydro acid salt, it is preferably 150 parts by mass or less with respect to 100 parts by mass of the diol compound (4). The residual amount of the organic solvent may be measured by gas chromatography (GC) or the like. However, in consideration of the fact that the diol compound (4) is an oily substance and the uniformity is low, as described later, by measuring the solution prepared by mixing the diol compound (4) and the ester solvent, It is preferable from the viewpoint of analysis accuracy to calculate the residual amount of the low polar organic solvent.
なお、上記の製造方法において、反応或いは後処理時に溶媒としてエステル系溶媒を使用し、エステル系溶媒を主成分とするジオール化合物(4)の溶液を製造する場合は、上記濃縮操作を行わずに当該溶液をそのまま本発明に使用しても良い。その場合であっても、上記低極性有機溶媒を含む場合は、残留量が上記範囲となるようにすれば良い。 In the above production method, when a solvent of ester compound is used as a solvent at the time of reaction or post-treatment and a solution of diol compound (4) mainly composed of ester solvent is produced, the above concentration operation is not performed. The solution may be used as it is in the present invention. Even in this case, when the low polar organic solvent is contained, the residual amount may be in the above range.
(臭化水素)
本発明の製造方法において使用する臭化水素は、臭化水素ガスや水溶液である臭化水素酸等、その形態は制限されないが、取り扱いが容易である点から、臭化水素酸が好ましい。臭化水素酸に含まれる臭化水素の濃度は、通常、45〜50%であり、そのまま使用しても良く、水で希釈し濃度を下げて使用しても良い。ただし、上述のジオール化合物(4)体溶液の調製に使用する水の使用量は、臭化水素酸に含まれる水の量を加味して決定する必要がある。
(Hydrogen bromide)
Hydrogen bromide used in the production method of the present invention is not particularly limited in its form, such as hydrogen bromide gas and hydrobromic acid which is an aqueous solution, but hydrobromic acid is preferable from the viewpoint of easy handling. The concentration of hydrogen bromide contained in hydrobromic acid is usually 45 to 50%, and may be used as it is, or may be diluted with water and used at a reduced concentration. However, the amount of water used to prepare the diol compound (4) body solution described above needs to be determined in consideration of the amount of water contained in hydrobromic acid.
臭化水素の使用量は、ジオール化合物(4)を十分に臭化水素酸塩に変換できる点、及び単離収率の観点からジオール化合物(4)1モルに対して、0.8〜2.4モルの範囲で用いることが好ましい。エステル系溶媒は臭化水素により加水分解を起こし、アルコールとカルボン酸を生じることが知られており、また、臭化水素酸塩はアルコール及びカルボン酸に対する溶解度が比較的高いため、エステル系溶媒の加水分解の程度によっては臭化水素酸塩の単離収率が低下する傾向にある。上記範囲の中でも、より高い単離収率で臭化水素酸塩が得られる点で、臭化水素の使用量としてはジオール化合物(4)1モルに対して、0.85〜2.4モルがより好ましく、0.85〜2.2モルがさらに好ましく、0.9〜2.2モルが最も好ましい。なお、当然のことながら、臭化水素酸等の溶液形態を使用する場合、溶液中の正味の臭化水素の量を算出して、使用量を決定する必要がある。 The amount of hydrogen bromide used is 0.8 to 2 with respect to 1 mole of diol compound (4) from the viewpoint of sufficient conversion of diol compound (4) to hydrobromide and isolation yield. It is preferable to use in the range of 4 moles. It is known that ester solvents cause hydrolysis by hydrogen bromide to form alcohols and carboxylic acids, and hydrobromide has a relatively high solubility in alcohols and carboxylic acids, so Depending on the degree of hydrolysis, the isolation yield of hydrobromide tends to decrease. Within the above range, the amount of hydrogen bromide used is 0.85 to 2.4 moles per mole of the diol compound (4), since hydrobromide can be obtained with a higher isolation yield. Is more preferable, 0.85 to 2.2 mol is more preferable, and 0.9 to 2.2 mol is most preferable. As a matter of course, when using a solution form such as hydrobromic acid, it is necessary to calculate the amount of net hydrogen bromide in the solution to determine the amount used.
(製造条件)
本発明の製造方法では、エステル系溶媒と水との混合溶媒中で上記ジオール化合物(4)と臭化水素とを接触させる。当該製造に用いる設備としては、公知の製造設備を用いることができる。具体的には、ガラス製、ステンレス製、テフロン(登録商標)製、グラスライニング等の反応容器を使用し、メカニカルスターラー、マグネティックスターラー等を用いて撹拌下で接触せしめれば良い。エステル系溶媒と水との混合溶媒中で上記ジオール化合物(4)と臭化水素とを接触させる方法は特に制限されず、例えば、ジオール化合物(4)をエステル系溶媒と水との混合溶媒に溶解させた溶液を調製し、これに臭化水素(例えば臭化水素酸)を加える方法、或いは、臭化水素酸に上記ジオール化合物(4)の溶液を加える方法等が挙げられる。ただし、エステル系溶媒の加水分解抑制、及び、接触時の発熱による温度の制御の観点から、前者の方法であるジオール化合物(4)の溶液に臭化水素を加える方法がより好ましい。なお、上記ジオール化合物(4)の溶液の調製は、ジオール化合物(4)と水とは混和しないため、エステル系溶媒とジオール化合物(4)を混合した後に水を加えることが、均一な溶液を調製できる点から好ましい。
(Manufacturing conditions)
In the production method of the present invention, the diol compound (4) and hydrogen bromide are brought into contact in a mixed solvent of an ester solvent and water. Well-known manufacturing equipment can be used as equipment used for the said manufacture. Specifically, reaction vessels such as glass, stainless steel, Teflon (registered trademark), glass lining, etc. may be used, and contact may be made with stirring using a mechanical stirrer, a magnetic stirrer or the like. The method for bringing the diol compound (4) and hydrogen bromide into contact with each other in a mixed solvent of an ester solvent and water is not particularly limited. For example, the diol compound (4) may be used as a mixed solvent of an ester solvent and water There is a method of preparing a dissolved solution and adding hydrogen bromide (for example, hydrobromic acid) thereto, or a method of adding a solution of the above diol compound (4) to hydrobromic acid. However, the method of adding hydrogen bromide to the solution of the diol compound (4), which is the former method, is more preferable from the viewpoint of the hydrolysis suppression of the ester solvent and the control of the temperature by heat generation at the time of contact. In addition, since preparation of the solution of the said diol compound (4) does not mix with a diol compound (4) and water, adding an water after adding an ester solvent and a diol compound (4) is the uniform solution It is preferable from the point which can be prepared.
ジオール化合物(4)と臭化水素とを接触させる際の温度は、特に制限されないが、あまり高すぎると、臭化水素によるエステル系溶媒の加水分解が進行しやすい傾向にあるため、0〜30℃の範囲で行うことが好ましい。上記範囲の中でも、エステル系溶媒の加水分解抑制の観点から、0〜20℃がより好ましく、0〜15℃が最も好ましい。 The temperature at which the diol compound (4) and hydrogen bromide are brought into contact with each other is not particularly limited, but if it is too high, it tends to promote hydrolysis of the ester solvent by hydrogen bromide. It is preferable to carry out in the range of ° C. Among the above ranges, from the viewpoint of hydrolysis suppression of the ester solvent, 0 to 20 ° C. is more preferable, and 0 to 15 ° C. is the most preferable.
臭化水素を加える際は15分間以上かけて滴下しながら加えることが好ましい。15分間未満の場合、多量の臭化水素酸塩が短時間に結晶化するため、撹拌不良を起こす場合がある。また、臭化水素を加えると発熱を生じるため、温度制御の観点からも好ましい。 When hydrogen bromide is added, it is preferably added dropwise over 15 minutes. If it is less than 15 minutes, a large amount of hydrobromide crystallizes in a short time, which may cause poor stirring. Moreover, since addition of hydrogen bromide generates heat, it is also preferable from the viewpoint of temperature control.
通常、臭化水素を加えた後、5分間〜1時間撹拌することにより、臭化水素酸塩が結晶化するが、再現性良く結晶化させるために、種晶として臭化水素酸塩を添加しても良い。種晶の使用量は、特に制限されないが、ジオール化合物(4)1gに対して0.01〜0.1gの範囲で用いれば十分である。なお、種晶の添加は、全量の臭化水素を加えた後でも良く、一部の臭化水素、具体的にはジオール化合物1モルに対して0.3モル以上を加えた段階でも良い。 In general, hydrobromide is crystallized by adding hydrogen bromide and then stirring for 5 minutes to 1 hour, but in order to reproducibly crystallize, hydrobromide is added as a seed crystal. You may. The use amount of the seed crystals is not particularly limited, but it is sufficient to use in the range of 0.01 to 0.1 g with respect to 1 g of the diol compound (4). The seed crystals may be added after the entire amount of hydrogen bromide is added, or may be added to a portion of hydrogen bromide, specifically, 0.3 mol or more per 1 mol of the diol compound.
以上のようにして、臭化水素酸塩を結晶化させた後、30分間以上熟成することで、臭化水素酸塩の結晶化量を最大化できる。また、熟成時間は30時間以内とすることで、エステル系溶媒の加水分解による単離収率の低下を抑えることができる。なお、当該熟成温度は、上記結晶化温度と同様の理由により0〜30℃が好ましい。上記範囲の中でも、より加水分解を抑制できる点から、0〜20℃がより好ましく、0〜15℃が最も好ましい。 As described above, after the hydrobromide is crystallized, it is possible to maximize the crystallization amount of the hydrobromide by maturing for 30 minutes or more. In addition, by setting the ripening time to be within 30 hours, it is possible to suppress the decrease in the isolation yield due to the hydrolysis of the ester solvent. The ripening temperature is preferably 0 to 30 ° C. for the same reason as the crystallization temperature. Among the above-mentioned range, 0 to 20 ° C. is more preferable, and 0 to 15 ° C. is the most preferable in that hydrolysis can be further suppressed.
(分離、乾燥操作)
以上のようにして、臭化水素酸塩を結晶化した後、得られた懸濁液を減圧濾過や加圧濾過、遠心分離等の公知の方法により固液分離することで、臭化水素酸塩の湿体を単離できる。固液分離操作において、分離後の湿体はエステル系溶媒、水、或いは、それらの混合溶媒により洗浄し母液を十分に取り除くことが好ましい。洗浄に使用するエステル系溶媒や水の量は、ジオール化合物(4)100質量部に対して50〜1000容量部で、十分な洗浄効果が得られる。また、当該洗浄操作は、複数回実施しても良い。
(Separation, drying operation)
After the hydrobromide is crystallized as described above, hydrobromic acid is obtained by solid-liquid separation of the obtained suspension by known methods such as vacuum filtration, pressure filtration, centrifugation and the like. A wet body of salt can be isolated. In the solid-liquid separation operation, it is preferable that the wet body after separation be washed with an ester solvent, water, or a mixed solvent thereof to sufficiently remove the mother liquor. With respect to the amount of ester solvents and water used for washing, a sufficient washing effect can be obtained with 50 to 1000 parts by volume with respect to 100 parts by weight of the diol compound (4). In addition, the cleaning operation may be performed a plurality of times.
固液分離後の湿体は、常圧下、減圧下、或いは、窒素やアルゴンなどの不活性ガスの通気下において乾燥させることにより、エステル系溶媒や水を除去できる。乾燥温度は、エステル系溶媒の種類によるが、−20〜120℃である。乾燥時間はエステル系溶媒等の残留量を確認しながら適宜決定すれば良いが、通常、0.5〜100時間である。 The ester-based solvent and water can be removed by drying the wet body after solid-liquid separation under normal pressure, under reduced pressure, or under aeration of an inert gas such as nitrogen or argon. The drying temperature is -20 to 120 ° C. depending on the type of ester solvent. The drying time may be appropriately determined while confirming the residual amount of the ester solvent and the like, but is usually 0.5 to 100 hours.
(ジオール化合物(4)の臭化水素酸塩)
上記本発明の製造方法によって製造されるジオール化合物(4)の臭化水素酸塩は、グリニャール反応の副生物等の不純物が低減され、高い純度を有する。そのため、更なる精製操作を必要とせず、好適にエスシタロプラムシュウ酸塩(1)の製造に使用することができる。また、従来の方法と比較して、分離性が良好であり、スケーリング等を抑制できるため、操作性の観点で優位である。さらに、ジオール化合物(4)の臭化水素酸塩の単離収率が高いため、製造コストの観点からも優位である。
(Hydrobromide of diol compound (4))
The hydrobromide of the diol compound (4) produced by the production method of the present invention is reduced in impurities such as byproducts of the Grignard reaction, and has high purity. Therefore, it can be suitably used for the production of escitalopram oxalate (1) without the need for further purification operation. Moreover, compared with the conventional method, since separability is favorable and scaling etc. can be suppressed, it is superior in the viewpoint of operativity. Furthermore, since the isolation yield of the hydrobromide of diol compound (4) is high, it is advantageous from the viewpoint of production cost.
エスシタロプラムシュウ酸塩(1)の製造方法として、具体的には、上記本発明の製造方法によって製造されるジオール化合物(4)の臭化水素酸塩を脱塩した後、(+)−ジ−(p−トルオイル)酒石酸と反応させ光学分割を行い、4−[(1S)−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(5)の(+)−ジ−(p−トルオイル)酒石酸塩を得る。次いで、脱塩した後、閉環反応によりエスシタロプラム(6)を得る。更に、エスシタロプラム(6)にシュウ酸を付加する塩化反応により、エスシタロプラムシュウ酸塩(1)を得ることができる。 Specifically as the method for producing escitalopram oxalate (1), after dehydrobromide of the diol compound (4) produced by the above-mentioned production method of the present invention is desalted, (+)-di- (P-toluoyl) is reacted with tartaric acid to perform optical resolution, 4-[(1S) -4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) benzo The (+)-di- (p-toluoyl) tartrate of nitrile (5) is obtained. Then, after desalting, cyclization reaction is performed to obtain escitalopram (6). Furthermore, escitalopram oxalate (1) can be obtained by a chlorination reaction in which oxalic acid is added to escitalopram (6).
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何等制限されることはない。 Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited by these examples.
なお、実施例、比較例のジオール化合物(4)、及び、ジオール化合物(4)の臭化水素酸塩の純度は、高速液体クロマトグラフィー(HPLC)により測定した。当該測定に使用した装置、測定の条件は、下記の通りである。なお、ジオール化合物(4)、及び、ジオール化合物(4)の臭化水素酸塩の純度は、下記条件で測定される全ピーク(溶媒由来のピークを除く)の面積値の合計に対するジオール化合物(4)のピーク面積値の割合である。 The purity of the hydrobromides of the diol compound (4) and the diol compound (4) of Examples and Comparative Examples was measured by high performance liquid chromatography (HPLC). The apparatus used for the said measurement and the conditions of measurement are as follows. The purity of the hydrobromide of the diol compound (4) and the diol compound (4) is the diol compound relative to the sum of the area values of all the peaks (excluding the peak derived from the solvent) measured under the following conditions It is a ratio of the peak area value of 4).
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
Device: Waters 2695
Detector: Ultraviolet absorptiometer (2489 manufactured by Waters)
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 octadecylsilylated silica gel for liquid chromatography Mobile phase A: acetonitrile / buffer solution = 10/90
Mobile phase B: acetonitrile / buffer = 65/35
Buffer solution: Dissolve 3.4 g of potassium dihydrogen phosphate in 1000 mL of water and add phosphoric acid to adjust to pH 3.0 Transfer of mobile phase: The mixing ratio of mobile phase A and mobile phase B is changed as follows Concentration gradient control Column temperature: Constant temperature around 45 ° C
実施例1
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、テトラヒドロフラン480mL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、撹拌した。35℃に昇温した後、4−ブロモフルオロベンゼンのグリニャール試薬(4−フルオロフェニルマグネシウムブロミド)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時間攪拌した。次いで、25℃付近に冷却し、4−ブロモフルオロベンゼンのグリニャール試薬(4−フルオロフェニルマグネシウムブロミド)を調製した。
Example 1
In a 1000 mL four-necked flask fitted with a stirring blade and a thermometer and argon-substituted, 480 mL of tetrahydrofuran is added, and 12.1 g (499.9 mmol) of magnesium and 6.6 g (37.7 mmol) of 4-bromofluorobenzene are added. It stirred. After the temperature was raised to 35 ° C., 1.2 g (1.23 mmol) of 4-bromofluorobenzene Grignard reagent (4-fluorophenyl magnesium bromide) was added, and the temperature was raised to the reflux temperature. After the temperature was raised, 79.2 g (452.4 mmol) of 4-bromofluorobenzene was dropped, and after dropping, the mixture was stirred at reflux temperature for 1 hour. Then, it was cooled to around 25 ° C. to prepare a 4-bromofluorobenzene Grignard reagent (4-fluorophenyl magnesium bromide).
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、テトラヒドロフラン180mLを加え、マグネシウム10.3g(423.0mmol)、3−クロロ−N,N−ジメチル−1−プロパンアミンのグリニャール試薬(N,N−ジメチルアミノプロピルマグネシウムクロリド)2.5g(4.15mmol)を加え、撹拌した。還流温度に昇温後、3−クロロ−N,N−ジメチル−1−プロパンアミン4.6g(37.7mmol)とトルエン6.5mLとの溶液を加え、30分間撹拌した。撹拌後、さらに3−クロロ−N,N−ジメチル−1−プロパンアミン45.9g(377.0mmol)とトルエン65mLとの溶液を滴下し、滴下後、還流温度で1時間攪拌した。次いで、25℃付近に冷却し、3−クロロ−N,N−ジメチル−1−プロパンアミンのグリニャール試薬(N,N−ジメチルアミノプロピルマグネシウムクロリド)を調製した。 A stirring blade and a thermometer are attached, 180 mL of tetrahydrofuran is added to a 500 mL four-necked flask purged with argon, and Grignard of 10.3 g (423.0 mmol) of magnesium, 3-chloro-N, N-dimethyl-1-propanamine The reagent (N, N-dimethylaminopropyl magnesium chloride) 2.5 g (4.15 mmol) was added and stirred. After raising the temperature to the reflux temperature, a solution of 4.6 g (37.7 mmol) of 3-chloro-N, N-dimethyl-1-propanamine and 6.5 mL of toluene was added, and the mixture was stirred for 30 minutes. After stirring, a solution of 45.9 g (377.0 mmol) of 3-chloro-N, N-dimethyl-1-propanamine and 65 mL of toluene was further added dropwise, and after dropwise addition, the mixture was stirred at reflux temperature for 1 hour. Then, it was cooled to around 25 ° C. to prepare a 3-chloro-N, N-dimethyl-1-propanamine Grignard reagent (N, N-dimethylaminopropyl magnesium chloride).
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、テトラヒドロフラン150mL、5−シアノフタリド60g(377.0mmol)を加え、撹拌した。5℃付近に冷却後、0〜15℃で4−ブロモフルオロベンゼンのグリニャール試薬(4−フルオロフェニルマグネシウムブロミド)を3時間かけて滴下した。滴下後、1時間攪拌した。次いで、0〜15℃で3−クロロ−N,N−ジメチル−1−プロパンアミンのグリニャール試薬(N,N−ジメチルアミノプロピルマグネシウムクロリド)を3時間かけて滴下した。滴下後、1時間攪拌した。次いで、0〜15℃で蒸留水18mLを滴下し、さらに、0〜30℃で酢酸100gと蒸留水220mLとの溶液を滴下した。滴下後、外温60℃で減圧濃縮を行い、テトラヒドロフランを留去した。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分間撹拌した。撹拌後、有機層と水層を分液し、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つの有機層を混合した。混合した有機層に蒸留水90mLを加え、60で30分間撹拌した。次いで、有機層と水層を分液し、得られた有機層を外温60℃で減圧濃縮を行い、トルエンを留去した。減圧濃縮後、釜残としてジオール化合物(4)を得た。 A stirring blade and a thermometer were attached, and 150 mL of tetrahydrofuran and 60 g (377.0 mmol) of 5-cyanophthalide were added to a 2000 mL four-necked flask purged with argon, and stirred. After cooling to around 5 ° C., Grignard reagent (4-fluorophenyl magnesium bromide) of 4-bromofluorobenzene was dropped over 3 hours at 0 to 15 ° C. After dropping, the mixture was stirred for 1 hour. Then, Grignard reagent (N, N-dimethylaminopropyl magnesium chloride) of 3-chloro-N, N-dimethyl-1-propanamine was added dropwise over 3 hours at 0 to 15 ° C. After dropping, the mixture was stirred for 1 hour. Next, 18 mL of distilled water was dropped at 0 to 15 ° C., and a solution of 100 g of acetic acid and 220 mL of distilled water was further dropped at 0 to 30 ° C. After the dropwise addition, the solution was concentrated under reduced pressure at an external temperature of 60 ° C. to evaporate tetrahydrofuran. To the concentrated residue, 360 mL of distilled water, 480 mL of toluene, and 50 g of 25% aqueous ammonia were added, and the mixture was stirred at 60 ° C. for 30 minutes. After stirring, the organic layer and the aqueous layer were separated, 90 mL of toluene was added to the aqueous layer, and the mixture was stirred at 60 ° C. for 30 minutes. After stirring, the organic layer and the aqueous layer were separated, and the two obtained organic layers were mixed. 90 mL of distilled water was added to the combined organic layer, and stirred at 60 for 30 minutes. Then, the organic layer and the aqueous layer were separated, and the obtained organic layer was concentrated under reduced pressure at an external temperature of 60 ° C. to distill off toluene. After concentration under reduced pressure, a diol compound (4) was obtained as a residue.
釜残のジオール化合物(4)に、酢酸エチル360mLを加え、25℃で15分間撹拌した。得られた溶液をHPLCで測定した結果、ジオール化合物(4)の純度は92.20%であり、ジオール化合物(4)の含有量は98.8g(288.5mmol)であった。また、同溶液をGCで測定した結果、トルエンの残留量は62.4gであり、ジオール化合物(4)に対して63.2重量%であった。水360mLを加えた後、25℃で15分間撹拌し、ジオール化合物(4)の溶液を調製した。 Ethyl acetate (360 mL) was added to the residual diol compound (4), and the mixture was stirred at 25 ° C. for 15 minutes. As a result of measuring the obtained solution by HPLC, the purity of the diol compound (4) was 92.20%, and the content of the diol compound (4) was 98.8 g (288.5 mmol). In addition, as a result of measuring the solution by GC, the remaining amount of toluene was 62.4 g, which was 63.2 wt% with respect to the diol compound (4). After adding 360 mL of water, the solution was stirred at 25 ° C. for 15 minutes to prepare a solution of diol compound (4).
当該溶液に、48%臭化水素酸19.5g(115.7mmol)を30℃以下で30分間かけて滴下した。25℃付近で種晶としてジオール化合物(4)の臭化水素酸塩60.0mg(0.18mmol)を加え、30分間撹拌し、ジオール化合物(4)の臭化水素酸塩の結晶化を確認した。次いで、5℃付近に冷却し、48%臭化水素酸48.6g(288.5mmol)を5℃付近で30分間かけて滴下した。5℃付近で1時間撹拌した後、遠心分離により析出した結晶を分離し、水100mLで結晶を洗浄した。さらに、酢酸エチル100mLで結晶を洗浄した。得られた湿体を40℃で15時間乾燥し、ジオール化合物(4)の臭化水素酸塩118.4g(279.8mmol)を得た。ジオール化合物(4)のモル数を基準とした、ジオール化合物(4)の臭化水素酸塩の単離収率は97.0%であった。また、得られたジオール化合物(4)の臭化水素酸塩をHPLCで測定した結果、ジオール化合物(4)の臭化水素酸塩の純度は99.54%であった。また、ジオール化合物(4)の臭化水素酸塩の結晶化時に、容器壁面への結晶の付着(スケーリング)は認められなかった。 To the solution was added dropwise 19.5 g (115.7 mmol) of 48% hydrobromic acid at 30 ° C. or less over 30 minutes. Add 60.0 mg (0.18 mmol) of hydrobromide of diol compound (4) as seed crystals at around 25 ° C and stir for 30 minutes to confirm crystallization of hydrobromide of diol compound (4) did. Then, it was cooled to around 5 ° C., and 48.6 g (288.5 mmol) of 48% hydrobromic acid was added dropwise over 30 minutes at around 5 ° C. After stirring for 1 hour at around 5 ° C., the precipitated crystals were separated by centrifugation and the crystals were washed with 100 mL of water. The crystals were further washed with 100 mL of ethyl acetate. The resulting wet product was dried at 40 ° C. for 15 hours to obtain 118.4 g (279.8 mmol) of hydrobromide of diol compound (4). The isolated yield of hydrobromide of diol compound (4) was 97.0% based on the number of moles of diol compound (4). Further, as a result of measuring the hydrobromide of the obtained diol compound (4) by HPLC, the purity of the hydrobromide of diol compound (4) was 99.54%. Moreover, at the time of crystallization of the hydrobromide of diol compound (4), adhesion (scaling) of crystals to the wall of the container was not observed.
実施例2〜15
種晶を加えた後の48%臭化水素酸の量、結晶化及び熟成温度を変更した以外は、実施例1と同様にして実施した。条件と結果を表2に示した。いずれの実施例においてもジオール化合物(4)の臭化水素酸塩の結晶化時の容器壁面への結晶の付着(スケーリング)は認められなかった。
Examples 2 to 15
The procedure of Example 1 was repeated except that the amount of 48% hydrobromic acid after addition of the seed crystals, and the crystallization and ripening temperature were changed. Conditions and results are shown in Table 2. In any of the examples, no adhesion (scaling) of crystals to the wall of the vessel was observed during the crystallization of the hydrobromide of diol compound (4).
実施例16
撹拌翼、温度計を取り付けた1000mLの四つ口フラスコに、実施例1で取得したジオール化合物(4)の臭化水素酸塩100.0g(236.2mmol)、トルエン500mL、水400mL、23%水酸化ナトリウム水溶液123.3g(708.7mmol)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400mLの水で洗浄した。有機層を減圧濃縮した後、1−プロパノール500mLを加え25℃で15分間撹拌した。当該溶液に、(+)−ジ−(p−トルオイル)酒石酸41.1g(106.3mmol)と1−プロパノール250mLとの溶液を40℃付近で加えた。次いで、種晶200mgを加えた後、40℃で1時間撹拌し、さらに、25℃で3時間撹拌した。遠心分離により析出した結晶を分離し、1−プロパノール100mLで結晶を2回洗浄した。得られた湿体を40℃で30時間乾燥し、4−[(1S)−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(5)の(+)−ジ−(p−トルオイル)酒石酸塩38.0g(70.8mmol)を得た。
Example 16
100.0 g (236.2 mmol) of hydrobromide of the diol compound (4) obtained in Example 1 in a 1000 mL four-necked flask equipped with a stirring blade and a thermometer, 500 mL of toluene, 400 mL of water, 23% 123.3 g (708.7 mmol) of sodium hydroxide aqueous solution was added, and it stirred at 25 degreeC for 30 minutes. After stirring, the organic layer and the aqueous layer were separated, and the organic layer was washed with 400 mL of water. The organic layer was concentrated under reduced pressure, 500 mL of 1-propanol was added, and the mixture was stirred at 25 ° C. for 15 minutes. To the solution was added a solution of 41.1 g (106.3 mmol) of (+)-di- (p-toluoyl) tartaric acid and 250 mL of 1-propanol at around 40 ° C. Then, after adding 200 mg of seed crystals, the mixture was stirred at 40 ° C. for 1 hour, and further stirred at 25 ° C. for 3 hours. The precipitated crystals were separated by centrifugation, and the crystals were washed twice with 100 mL of 1-propanol. The resulting wet product is dried at 40 ° C. for 30 hours to give 4-[(1S) -4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) benzo. 38.0 g (70.8 mmol) of (+)-di- (p-toluoyl) tartrate of nitrile (5) were obtained.
撹拌翼、温度計を取り付けた500mLの四つ口フラスコに、4−[(1S)−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(5)の(+)−ジ−(p−トルオイル)酒石酸塩30.0g(56.0mmol)、トルエン200mL、水150mL、23%水酸化ナトリウム水溶液29.2g(168.0mmol)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200mLの水で洗浄した。有機層を減圧濃縮した後、トルエン150mLとトリエチルアミン12.5g(123.2mmol)を加え25℃で15分間撹拌した。当該溶液に、塩化トシル11.7g(61.6mmol)とトルエン50mLとの溶液を−15℃付近で加えた。−15℃で1時間撹拌した後、水50mL、23%水酸化ナトリウム水溶液10.7g(61.6mmol)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50mLで洗浄した。有機層を外温60℃で減圧濃縮を行い、トルエンを留去した。減圧濃縮後、釜残としてエスシタロプラム(6)を得た。 In a 500 mL four-necked flask equipped with a stirring blade and a thermometer, 4-[(1S) -4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) ) 30.0 g (56.0 mmol) of (+)-di- (p-toluoyl) tartrate salt of benzonitrile (5), 200 mL of toluene, 150 mL of water, 29.2 g (168.0 mmol) of 23% aqueous sodium hydroxide solution The mixture was further 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 200 mL of water. The organic layer was concentrated under reduced pressure, 150 mL of toluene and 12.5 g (123.2 mmol) of triethylamine were added, and the mixture was stirred at 25 ° C. for 15 minutes. To the solution was added a solution of 11.7 g (61.6 mmol) of tosyl chloride and 50 mL of toluene at around -15 ° C. After stirring at -15 ° C for 1 hour, 50 mL of water and 10.7 g (61.6 mmol) of a 23% aqueous solution of sodium hydroxide 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 50 mL of water. The organic layer was concentrated under reduced pressure at an external temperature of 60 ° C., and toluene was distilled off. After concentration under reduced pressure, escitalopram (6) was obtained as a residue.
釜残のエスシタロプラム(6)に、アセトニトリル100mLを加え25℃で30分間撹拌した。当該溶液にシュウ酸5.0g(55.0mmol)とアセトニトリル100mLとの溶液を50℃付近で加えた後、50℃で30分撹拌した。次いで、種晶10mgを加えた後、50℃で1時間撹拌し、さらに、25℃で3時間撹拌した。遠心分離により析出した結晶を分離し、アセトニトリル20mLで結晶を2回洗浄した。得られた湿体を40℃で30時間乾燥し、エスシタロプラムシュウ酸塩(1)16.5g(39.8mmol)を得た。得られたエスシタロプラムシュウ酸塩(1)をHPLCで測定した結果、エスシタロプラムシュウ酸塩(1)の純度は99.87%であった。 Acetonitrile 100mL was added to escitalopram (6) of the bottom, and it stirred at 25 degreeC for 30 minutes. A solution of 5.0 g (55.0 mmol) of oxalic acid and 100 mL of acetonitrile was added to the solution near 50 ° C., and the mixture was stirred at 50 ° C. for 30 minutes. Next, after adding 10 mg of seed crystals, the mixture was stirred at 50 ° C. for 1 hour, and further stirred at 25 ° C. for 3 hours. The precipitated crystals were separated by centrifugation, and the crystals were washed twice with 20 mL of acetonitrile. The resulting wet product was dried at 40 ° C. for 30 hours to obtain 16.5 g (39.8 mmol) of escitalopram oxalate (1). As a result of measuring the obtained escitalopram oxalate (1) by HPLC, the purity of escitalopram oxalate (1) was 99.87%.
比較例1
酢酸エチルをジエチルエーテルに変更し、また、臭化水素酸を加えた後、ジエチルエーテルを濃縮したこと以外は、実施例1と同様にして、ジオール化合物(4)の臭化水素酸塩117.9g(278.5mmol)を得た。ジオール化合物(4)のモル数を基準とした、ジオール化合物(4)の臭化水素酸塩の単離収率は96.5%であった。また、得られたジオール化合物(4)の臭化水素酸塩をHPLCで測定した結果、ジオール化合物(4)の臭化水素酸塩の純度は97.12%であった。
Comparative Example 1
The hydrobromide of the diol compound (4) was prepared in the same manner as in Example 1 except that ethyl acetate was changed to diethyl ether and hydrobromic acid was added and then diethyl ether was concentrated. 9 g (278.5 mmol) were obtained. The isolated yield of hydrobromide of diol compound (4) was 96.5% based on the number of moles of diol compound (4). Further, the hydrobromide of the obtained diol compound (4) was measured by HPLC, and as a result, the purity of the hydrobromide of diol compound (4) was 97.12%.
比較例2
酢酸エチルをトルエンに変えたこと以外は、実施例1と同様にして、ジオール化合物(4)の臭化水素酸塩108.9g(257.3mmol)を得た。ジオール化合物(4)のモル数を基準とした、ジオール化合物(4)の臭化水素酸塩の単離収率は89.2%であった。また、得られたジオール化合物(4)の臭化水素酸塩をHPLCで測定した結果、ジオール化合物(4)の臭化水素酸塩の純度は99.13%であった。なお、ジオール化合物(4)の臭化水素酸塩の結晶化時に、容器壁面への結晶の付着(スケーリング)が生じ、約9.1gのジオール化合物(4)の臭化水素酸塩は単離できなかった。
Comparative example 2
In the same manner as in Example 1 except that ethyl acetate was changed to toluene, 108.9 g (257.3 mmol) of hydrobromide of diol compound (4) was obtained. The isolated yield of hydrobromide of diol compound (4) was 89.2% based on the number of moles of diol compound (4). Further, as a result of measuring the hydrobromide of the obtained diol compound (4) by HPLC, the purity of the hydrobromide of diol compound (4) was 99.13%. In addition, at the time of crystallization of hydrobromide of diol compound (4), adhesion (scaling) of crystals to the vessel wall occurs, and hydrobromide of about 9.1 g of diol compound (4) is isolated. could not.
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