Refining method of solifenacin intermediate

文档序号：802016 发布日期：2021-03-26 浏览：20次中文

阅读说明：本技术 索菲那新中间体的精制方法 (Refining method of solifenacin intermediate ) 是由李彦雄蒙发明徐亮郭俊罗凤玲于 2020-12-23 设计创作，主要内容包括：本发明涉及一种索菲那新中间体及其精制方法。所述索菲那新中间体的精制方法包括以下步骤：将有机溶剂和索菲那新中间体粗品混合,使所述索菲那新粗品溶解,然后降温析出晶体,收集所述晶体；所述有机溶剂选自甲苯、二甲苯和氯苯中的一种或几种；所述的索非那新中间体的结构如式(1)所式。区别于常规的纯化方法,本发明通过特定的有机溶剂对索菲那新中间体粗品进行重结晶,有效提高了索菲那新中间体的纯度,能够显著降低反应物的残留,并显著降低工艺副产物。HPLC检测索菲那新中间体的纯度可达到98.6％以上,杂质限量均小于0.1％。(The invention relates to a solifenacin intermediate and a refining method thereof. The refining method of the solifenacin intermediate comprises the following steps: mixing an organic solvent and the crude product of the sofhenanew intermediate to dissolve the crude product of the sofhenanew, cooling to separate out crystals, and collecting the crystals; the organic solvent is selected from one or more of toluene, xylene and chlorobenzene; the structure of the solifenacin intermediate is shown as a formula (1). Different from the conventional purification method, the method provided by the invention has the advantages that the crude product of the new intermediate of the solifenacin is recrystallized by the specific organic solvent, so that the purity of the new intermediate of the solifenacin is effectively improved, the residue of reactants can be obviously reduced, and the process by-products can be obviously reduced. The purity of the sofhenanew intermediate can reach more than 98.6 percent through HPLC detection, and the limit of impurities is less than 0.1 percent.)

1. A refining method of a solifenacin intermediate is characterized by comprising the following steps:

mixing an organic solvent and the crude product of the sofhenanew intermediate to dissolve the crude product of the sofhenanew, cooling to separate out crystals, and collecting the crystals;

the organic solvent is selected from one or more of toluene, xylene and chlorobenzene;

the structure of the solifenacin intermediate is as shown in formula (1):

2. the method of purifying a solifenacin intermediate as claimed in claim 1, wherein the organic solvent is a mixed solvent of toluene and chlorobenzene.

3. The method for purifying a solifenacin intermediate as claimed in claim 2, wherein the volume ratio of toluene to chlorobenzene is (1 to 10): 1.

4. The refining method of a solifenacin intermediate according to claim 1, wherein the mass-to-volume ratio of the crude solifenacin intermediate to the organic solvent is 1g: (3-20) mL.

5. The refining method of a solifenacin intermediate as claimed in claim 4, wherein the mass-to-volume ratio of the crude solifenacin intermediate to the organic solvent is 1g: (5-10) mL.

6. The method for purifying a solifenacin intermediate as claimed in claim 1, wherein the temperature of the system is 10 ℃ to 100 ℃ when the crude solifenacin is dissolved.

7. The method of purifying a solifenacin intermediate as claimed in claim 6, wherein the temperature of the system after the temperature reduction is 0 ℃ to 10 ℃.

8. The method of purifying a solifenacin intermediate as claimed in claim 7, wherein the cooling rate is 2 ℃/min to 15 ℃/min.

9. The refining method of a solifenacin intermediate according to any one of claims 1 to 8, wherein the preparation method of the crude solifenacin intermediate comprises the steps of:

mixing a compound with a structure shown in a formula (3), a chiral catalyst and alkali for reaction;

the chiral catalyst is selected from a BIAMH system catalyst, a D-BIMAH system catalyst or a P-BIMAH system catalyst;

the alkali is selected from potassium tert-butoxide, potassium ethoxide or sodium ethoxide;

the solvent is selected from ethanol, methanol, isopropanol, toluene or dichloromethane;

the reaction temperature of the reaction is 10-60 ℃.

10. The method for purifying a solifenacin intermediate as claimed in any one of claims 1 to 8, wherein the time for precipitating crystals is 0.5 to 5 hours; and/or the presence of a gas in the gas,

after the step of cooling and precipitating crystals, the operation of filtering is also included; and/or the presence of a gas in the gas,

after the step of collecting the crystals, the operation of drying the crystals is also included.

Technical Field

The invention relates to the field of drug synthesis, in particular to a refining method of a solifenacin intermediate.

Background

Solifenacin (Osimertinib), chemically known as (3R) -1-azabicyclo [2, 2, 2] octan-3-yl (1S) -1-phenyl-1, 4-dihydroisoquinoline-2- (1H) -carboxylate, is a selective muscarinic M3 receptor antagonist developed by astella, japan and is mainly used for treating overactive bladder with symptoms of urgency and frequency. The structural formula of the solifenacin is shown as a formula (1-1):

as can be seen from formula (1-1), solifenacin contains two chiral centers, one of which is in formula (1)(named as (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline) and the other chiral center is in the formula (2)The above are all chiral structural units commonly used in the art. Wherein, (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline is used as a key chiral intermediate of solifenacin, and the purity of the solifenacin directly influences the purity and the drug effect of the solifenacin.

In recent years, (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline having optical activity has been attracting attention, and many routes or methods for synthesizing (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline have been developed, and one of the synthesis methods which is commonly used is as follows:

adopting a one-pot asymmetric hydrogenation preparation method, mixing a compound with a structure shown in a formula (3), a chiral catalyst and alkali, and reacting to prepare (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline. Although the preparation process of the method is simple and the reaction conditions are easy to control, the purity of the crude (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline product is only about 95 percent, the process impurities such as the compound residue, isomer and the like shown in the formula (3) can reach about 4 percent through a conventional impurity removing mode and a large amount of purification processes, the purification effect is not obvious for a plurality of times, the quality requirement of a high-grade intermediate cannot be met, namely, the single impurity residue is less than 0.1 percent, and after the purification for a plurality of times, the yield of the (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline is very low, thereby further causing the low production efficiency and the rise of the cost.

Disclosure of Invention

Based on the above, the present invention provides a method for purifying a solifenacin intermediate having a structure represented by formula (1), wherein the purity of the solifenacin intermediate having a structure represented by formula (1) obtained by the method is 98.6% or more, and the impurity limit amounts are all less than 0.1%.

The technical scheme is as follows:

a refining method of a solifenacin intermediate comprises the following steps:

mixing an organic solvent and the crude product of the sofhenanew intermediate to dissolve the crude product of the sofhenanew, cooling to separate out crystals, and collecting the crystals;

the organic solvent is selected from one or more of toluene, xylene and chlorobenzene;

the structure of the solifenacin intermediate is as shown in formula (1):

in one embodiment, the organic solvent is a mixed solvent of toluene and chlorobenzene.

In one embodiment, the volume ratio of the toluene to the chlorobenzene is (1-10): 1.

In one embodiment, the volume ratio of the toluene to the chlorobenzene is (2-5): 1.

In one embodiment, the mass-to-volume ratio of the crude product of the solifenacin intermediate to the organic solvent is 1g: (3-20) mL.

In one embodiment, the mass-to-volume ratio of the crude product of the solifenacin intermediate to the organic solvent is 1g: (5-10) mL.

In one embodiment, when the crude product of the solifenacin is dissolved, the temperature of the system is 10-100 ℃.

In one embodiment, when the crude product of the solifenacin is dissolved, the temperature of the system is 20-80 ℃.

In one embodiment, when the crude product of the solifenacin is dissolved, the temperature of the system is 50-80 ℃.

In one embodiment, after the temperature reduction operation is performed, the temperature of the system is 0 ℃ to 10 ℃.

In one embodiment, the cooling rate is 2 ℃/min to 15 ℃/min.

In one embodiment, the cooling rate is 2 ℃/min to 10 ℃/min.

In one embodiment, the preparation method of the crude product of the solifenacin intermediate comprises the following steps:

mixing a compound with a structure shown in a formula (3), a chiral catalyst and alkali for reaction;

the chiral catalyst is selected from a BIAMH system catalyst, a D-BIMAH system catalyst or a P-BIMAH system catalyst;

the alkali is selected from potassium tert-butoxide, potassium ethoxide or sodium ethoxide;

the solvent is selected from ethanol, methanol, isopropanol, toluene or dichloromethane;

the reaction temperature of the reaction is 10-60 ℃.

In one embodiment, the time for precipitating the crystals is 0.5h to 5 h.

In one embodiment, after the step of cooling to precipitate the crystals, the operation of filtering is further included.

In one embodiment, after the step of collecting the crystals, the step of drying the crystals is further included.

Compared with the prior art, the invention has the following beneficial effects:

according to the invention, the intermediate of the solifenacin with the structure shown in the formula (1) is dissolved in a specific organic solvent, and then the temperature is reduced to precipitate crystals, so that the purity of the intermediate of the solifenacin is effectively improved, the residues of the compound with the structure shown in the formula (3) and the isomer can be remarkably reduced, the residual quantity is less than 0.1%, the purity of the intermediate of the solifenacin can reach more than 98.6% through HPLC detection, and the impurity limit is less than 0.1%. In addition, the yield of the solifenacin intermediate can reach 82%.

Detailed Description

The present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

(S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline shown as a formula (1) is used as a key chiral intermediate of solifenacin, and the purity of the (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline directly influences the purity and the drug effect of the solifenacin. One of the more common synthetic methods is as follows:

adopting a one-pot asymmetric hydrogenation preparation method, mixing a compound with a structure shown in a formula (3), a chiral catalyst and alkali, and reacting to prepare (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline. Although the preparation process of the method is simple and the reaction conditions are easy to control, the purity of the (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline crude product is only about 95 percent, the process impurities such as the compound residue shown in the formula (3) and isomers reach about 4 percent through a conventional impurity removal mode and a large amount of purification processes, the purification effect is not obvious for a plurality of times, and the quality requirement of a high-grade intermediate cannot be met, namely, the single impurity residue is below 0.1 percent.

Aiming at the problems, the invention provides a refining method which can ensure that the purity of the new intermediate of the solifenacin reaches more than 98.6 percent and the impurity limit is less than 0.1 percent.

The specific technical scheme is as follows:

a refining method of a solifenacin intermediate comprises the following steps:

mixing an organic solvent and the crude product of the sofhenanew intermediate to dissolve the crude product of the sofhenanew, cooling to separate out crystals, and collecting the crystals;

the organic solvent is selected from one or more of toluene, xylene and chlorobenzene;

the structure of the solifenacin intermediate is as shown in formula (1):

the method has the advantages that the solifenacin intermediate with the structure shown in the formula (1) is dissolved in a specific organic solvent, then the temperature is reduced to precipitate crystals, the purity of the solifenacin intermediate is effectively improved, the residues of the compound with the structure shown in the formula (3) and the isomers can be remarkably reduced, the residual quantity is less than 0.1%, the purity of the solifenacin intermediate can reach more than 98.6% through HPLC detection, and the impurity limit quantity is less than 0.1%.

Compared with the method which adopts a single organic solvent and a compound organic solvent, the method utilizes the solubility difference of (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline and impurities among different organic solvents, and after cooling, the impurities are still dissolved in the organic solvent as far as possible, while (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline is crystallized and precipitated, and after solid-liquid separation, the solid is mainly (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline and has extremely low impurity content.

In one embodiment, the organic solvent is a mixed solvent of toluene and chlorobenzene. Utilizing the solubility difference of (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline and impurities in toluene and chlorobenzene, after cooling, most of impurities are still dissolved in an organic solvent, and (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline is crystallized and precipitated. After solid-liquid separation, the solid is mainly (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, and the content of impurities is extremely low. HPLC detection shows that the purity of the solifenacin intermediate can reach over 99.8 percent, and the impurity limit is less than 0.1 percent.

In one preferable embodiment, the organic solvent is formed by mixing toluene and chlorobenzene according to a volume ratio of (1-10): 1. It is understood that, in the present invention, the volume ratio of toluene to chlorobenzene may be set to, but not limited to, 1:1, 1.1:1, 1.5:1, 1.9:1, 2:1, 2.2:1, 2.5:1, 3:1, 3.1:1, 3.2:1, 3.3:1, 3.5:1, 3.8:1, 4:1, 4.1:1, 4.2:1, 4.5:1, 4.6:1, 4.7:1, 4.8:1, 4.9:1, 4.95:1, 4.98:1, 4.988:1, 4.9:1, 5:1, 5.1:1, 5.2:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1 and 10: 1. Particularly preferably, the organic solvent is formed by mixing toluene and chlorobenzene according to the volume ratio of (2-5): 1, and the purity of the sofhenanew intermediate can reach more than 99.8% through HPLC detection, and the limit of impurities is less than 0.05%.

In one embodiment, the mass-to-volume ratio of the crude product of the solifenacin intermediate to the organic solvent is 1g: (3-20) mL. Controlling the addition amount of the crude product and the organic solvent within such a range is more advantageous in improving the purity of (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline and in reducing the content of impurities. It is understood that the ratio by mass/volume of the crude Sorafenesine intermediate to the organic solvent in the present invention may be, but not limited to, 1g:3mL, 1g:3.1mL, 1g:3.2mL, 1g:3.5mL, 1g:4mL, 1g:4.2mL, 1g:4.5mL, 1g:4.8mL, 1g:5mL, 1g:5.1mL, 1g:5.2mL, 1g:5.3mL, 1g:5.5mL, 1g:5.8mL, 1g:5.9mL, 1g:6mL, 1g:6.06mL, 1g:6.2mL, 1g:6.5mL, 1g:6.6mL, 1g:6.8mL, 1g:7mL, 1g:7.1mL, 1g:7.2mL, 1g:7.3mL, 1g:7.5mL, 1g: 6.7 mL, 1g:8mL, 1g:7.8mL, 1g:7.1 g:8mL, 1g:7.1 g:7mL, 1g:8mL, 1g:7.8mL, 1g:8mL, 1g:7.8mL, 1g:7.3mL, 1g:8, 12mL of 1g, 13mL of 1g, 14mL of 1g, 15mL of 1g, 16mL of 1g, 17 mL of 1g, 18mL of 1g, 19mL of 1g and 20mL of 1 g. Particularly preferably, the mass-to-volume ratio of the crude product of the solifenacin intermediate to the organic solvent is 1g: (5-10) mL.

In one embodiment, when the crude product of the solifenacin is dissolved, the temperature of the system is 10-100 ℃. The temperature for dissolution is controlled, which is more beneficial to improving the purity of (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline and reducing the content of impurities. As will be understood, in the present invention, the dissolution temperature can be, but is not limited to, 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃, 16 ℃, 17 ℃, 18 ℃, 19 ℃, 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃, 30 ℃, 31 ℃, 32 ℃, 33 ℃, 34 ℃, 35 ℃, 36 ℃, 37 ℃, 38 ℃, 39 ℃, 40 ℃, 41 ℃, 42 ℃, 46 ℃, 47 ℃, 50 ℃, 51 ℃, 53 ℃, 54 ℃, 55 ℃, 56 ℃, 57 ℃, 58 ℃, 59 ℃, 60 ℃, 62 ℃, 64 ℃, 66 ℃, 68 ℃, 70 ℃, 71 ℃, 72 ℃, 75 ℃, 80 ℃, 86 ℃, 88 ℃, 90 ℃, 91 ℃, 92 ℃, 95 ℃, 98 ℃ and 100 ℃. Preferably, when the crude product of the solifenacin is dissolved, the temperature of the system is 20-80 ℃. Particularly preferably, when the crude product of the solifenacin is dissolved, the temperature of the system is 50-80 ℃.

In one embodiment, after the temperature reduction operation is performed, the temperature of the system is 0 ℃ to 10 ℃. Controlling the crystallization temperature is more beneficial to the growth of crystals, improving the purity of (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline and reducing the content of impurities. It is understood that, in the present invention, the crystallization temperature can be, but not limited to, 0 ℃, 0.1 ℃, 0.2 ℃, 0.3 ℃, 0.4 ℃, 0.5 ℃, 0.6 ℃, 0.7 ℃, 0.8 ℃, 0.9 ℃, 1 ℃, 1.1 ℃, 1.2 ℃, 1.3 ℃, 1.4 ℃, 1.5 ℃, 1.6 ℃, 1.7 ℃, 1.8 ℃, 1.9 ℃,2 ℃, 2.5 ℃,3 ℃, 3.1 ℃, 3.2 ℃, 3.3 ℃, 3.4 ℃, 3.5 ℃, 3.6 ℃, 3.7 ℃, 3.8 ℃, 3.9 ℃, 4.0 ℃, 4.1 ℃, 4.2 ℃, 4.6 ℃, 4.7 ℃, 5.0 ℃, 5.3 ℃, 5.4 ℃, 5.5 ℃, 5.6 ℃, 5.7 ℃, 5.8 ℃, 5.9 ℃, 6.0 ℃, 6.2 ℃, 6.4 ℃, 6.6.8 ℃, 6.8 ℃, 7.0.7 ℃, 7.0 ℃, 7.7 ℃, 5.5.4 ℃, 5.5.5.5 ℃, 5.5.5.9 ℃, 8 ℃, 9.9.9, 9.9 ℃, 10.6.6 ℃.

In one embodiment, the cooling rate is 0.1 ℃/min to 5 ℃/min. Controlling the cooling rate, being more beneficial to the growth of crystals, improving the purity of (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline and reducing the content of impurities. It is understood that, in the present invention, the cooling rate can be set to, but not limited to, 2 ℃/min, 2.5 ℃/min, 3 ℃/min, 3.1 ℃/min, 3.2 ℃/min, 3.3 ℃/min, 3.4 ℃/min, 3.5 ℃/min, 3.6 ℃/min, 3.7 ℃/min, 3.8 ℃/min, 3.9 ℃/min, 4.0 ℃/min, 4.1 ℃/min, 4.2 ℃/min, 4.6 ℃/min, 4.7 ℃/min, 5 ℃/min, 5.5 ℃/min, 6 ℃/min, 7 ℃/min, 7.5 ℃/min, 8 ℃/min, 8.5 ℃/min, 8.6 ℃/min, 9 ℃/min, 9.8 ℃/min, 10 ℃/min, 10.5 ℃/min, 10.8 ℃/min, 11.0 ℃/min, 11.3 ℃/min, 11.8 ℃/min, 12 ℃/min, 12.5 ℃/min, 13 ℃/min, 13.6 ℃/min, 14 ℃/min, 14.7 ℃/min, 14.8 ℃/min and 15 ℃/min. Preferably, the cooling rate is 2 ℃/min to 10 ℃/min when the cooling operation is carried out.

In one embodiment, the time for precipitating the crystals is 0.5h to 5 h. The time for precipitating the crystals is controlled within the range, which is beneficial to the cooperative control of the purity and the yield of the solifenacin intermediate.

In one embodiment, the preparation method of the crude product of the solifenacin intermediate comprises the following steps:

mixing a compound with a structure shown in a formula (3), a chiral catalyst and alkali for reaction;

the chiral catalyst is selected from a BIAMH system catalyst, a D-BIMAH system catalyst or a P-BIMAH system catalyst;

the alkali is selected from potassium tert-butoxide, potassium ethoxide or sodium ethoxide;

the solvent is selected from ethanol, methanol, isopropanol, toluene or dichloromethane;

the reaction temperature of the reaction is 10-60 ℃.

In one embodiment, after the step of cooling to precipitate the crystals, the operation of filtering is further included. Preferably, solid-liquid separation is carried out by adopting a suction filtration mode, and a filter cake and filtrate are separately collected. In order to further improve the purity of the new intermediate of solifenacin, the same batch of crude products can be refined for 1 time, and then the refining method provided by the invention can be repeated for 2-3 times on the obtained product. In order to improve the yield, the solvent of the filtrate obtained after single refining can be removed by adopting a rotary evaporation mode to obtain a solid, and the refining method of the invention is repeated for 2-3 times.

In one embodiment, after the step of collecting the crystals, the step of drying the crystals is further included. Preferably, the crystal is dried by adopting a vacuum drying mode, and the drying temperature is 20-80 ℃. More preferably, the drying temperature is 40 ℃ to 60 ℃.

The following examples and comparative examples are further described below, and the starting materials used in the following examples can be commercially available, unless otherwise specified, and the equipment used therein can be commercially available, unless otherwise specified.

Example 1

The embodiment provides a solifenacin intermediate and a refining method thereof, and the steps are as follows:

step 1) synthesizing a crude product of the new intermediate of the solifenacin:

under the argon atmosphere, adding 1000g of a compound with a structure shown in a formula (3) into the high-pressure kettle, adding 10L of ethanol for full dissolution, continuously introducing argon for bubbling degassing, continuously bubbling for 1h, and degassing completely; then adding 5g of catalyst (S) -diop RuCl2(R) -P-Me-BIMAH (purchased from Zhongshan Yintai medicine science and technology Co., Ltd.) into the high-pressure kettle under the argon atmosphere, adding 120g of potassium tert-butoxide, replacing argon with hydrogen after the feeding is finished, slowly introducing hydrogen, and stirring for reaction at 25-35 ℃; after the reaction is finished, removing the catalyst by suction filtration, carrying out reduced pressure concentration on the filtrate to obtain a crude product of the sofhenanew intermediate, and detecting the purity of the crude product of the sofhenanew intermediate by HPLC to be 96%.