CN111285867B

CN111285867B - Preparation method of benzoquinolizine derivative

Info

Publication number: CN111285867B
Application number: CN201811501536.6A
Authority: CN
Inventors: 丁静波; 龚彦春; 周西朋; 秦小飞; 刘永强
Original assignee: Jiangsu Vcare Pharmatech Co Ltd
Current assignee: Jiangsu Vcare Pharmatech Co Ltd
Priority date: 2018-12-10
Filing date: 2018-12-10
Publication date: 2022-06-03
Anticipated expiration: 2038-12-10
Also published as: CN111285867A

Abstract

The invention relates to a preparation method of a benzo-quinolizine derivative, belongs to the technical field of medicinal chemistry, and particularly relates to a chiral resolution method of tetrabenazine. The (3R,11bR) -tetrabenazine or (3S,11bS) -tetrabenazine with high optical purity is simply, conveniently and effectively prepared by taking tetrabenazine racemate as a raw material and performing the steps of salification with chiral acid, pulping, dissociation and the like. Compared with the prior art, the method has the advantages of mild reaction conditions in each step, high yield, simple and convenient operation and stable process, and is suitable for large-scale industrial production.

Description

Preparation method of benzoquinolizine derivative

Technical Field

The invention relates to a preparation method of a benzo-quinolizine derivative, belonging to the technical field of medicinal chemistry.

Background

Tetrabenazine (TBZ) is available under the trade name XENAZINE and is a hexahydro-dimethoxy-phenylquinazoline derivative, the chemical name of which is 3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-benzo [ a ] quinolin-2-one. The drug was approved for marketing by the FDA in the united states at 8/15/2008 and was the first drug approved for the treatment of huntington's disease in the united states. After years of marketing, the sale of tetrabenazine in the United states exceeds 3.3 billion dollars, about 20 billion yuan higher than RMB, and the average growth rate in recent two years exceeds 20%.

Tetrabenazine (TBZ) is an urgent need for the treatment of rare diseases, and pharmacological activity is produced primarily by reversibly inhibiting monoamine transporter 2(VMAT2) of the central nervous system to decrease the supply of monoamines such as 5-hydroxytryptamine, dopamine and norepinephrine. Since tetrabenazine is a racemic mixture of RR and SS configurations, and VMAT-2 affinity (Ki 4.61nM) of (+) -tetrabenazine is 2.4 times that of (-) -tetrabenazine (Ki 11.20nM) (med. chem. let.2010, ASAP.) in an in vitro activity test, a method for efficiently preparing optically pure (3R,11bR) -tetrabenazine is very important.

The existing method for preparing optically active tetrabenazine mainly comprises a chiral chromatographic column resolution method (WO2008058261) and an asymmetric synthesis method (WO 2008154243; US 20080306269). Taking the method of WO20O08058261 as an example, 5-methyl-2-hexanone is first reacted with dimethylamine hydrochloride and paraformaldehyde to produce 3-dimethylaminomethyl-5-methyl-hexane-2-one, and the resulting 3-dimethylaminomethyl-5-methyl-hexane-2-one is then reacted with methyl iodide to produce the corresponding quaternary ammonium salt. The quaternary ammonium salt (firstly carries out elimination reaction in a heating reaction system to generate 3-isobutyl-3-butene-2-ketone) and then reacts with 6, 7-dimethoxy-3, 4-dihydroisoquinoline to generate TBZ. The method has the defects that the isomer 1- (dimethylamino) -6-methyl-3-heptanone (the content is up to 30 percent) is generated when the 5-methyl-2-hexanone is subjected to Mannich reaction to prepare the 3- [ (dimethylamino) methyl ] -5-methyl-2-hexanone, the boiling points of the isomer and the product are relatively close, the purification cannot be carried out by adopting a rectification method, the purification is difficult, and column chromatography separation and purification are needed. In addition, the reaction yield is extremely low (16%), and the excess of 5-methyl-2-hexanone starting material needs to be recovered. Furthermore, methyl iodide is also used, which is toxic and expensive.

The synthesis method described in CN101553487A also requires separation by column chromatography, and the optical purity of the product is low, less than 80%, and it is difficult to purify again, so it is not suitable for industrial production.

CN101985447A discloses that camphor sulfonic acid reacts with tetrabenazine, and then the (3R,11bR) -tetrabenazine is obtained by crystallization filtration and dissociation under alkaline conditions, but the dosage of the method in the patent is less than 2g, and the yield is only 6% when the method is industrialized, and the loss is large.

The methods for preparing the optically active tetrabenazine have the defects of complex operation, low yield or high toxicity and are not suitable for industrial production, so that the method for preparing the optically active tetrabenazine with simple and convenient operation and high yield is urgently needed to be established.

Drawings

The invention will be further explained with reference to the drawings.

FIG. 1 is a chiral HPLC chromatogram showing unresolved tetrabenazine;

FIG. 2 is a chiral HPLC chromatogram showing (3R,11bR) -tetrabenazine after chiral resolution in example 6;

FIG. 3 is a chiral HPLC chromatogram showing (3S,11bS) -tetrabenazine after chiral resolution in example 9;

disclosure of Invention

The invention aims to solve the technical problem of providing a method for preparing the optically active tetrabenazine, which has simple and convenient operation and high yield and is suitable for industrial production.

The applicant has found that the optical purity and yield of tetrabenazine chiral acid salt is highest by resolving tetrabenazine with different chiral acids, such as D-camphoric acid, D-mandelic acid, D-malic acid, D-dibenzoyltartaric acid, D-di-p-methylbenzyltartaric acid, but the (3S,11bS) configuration is obtained, so that the (3R,11bR) configuration tetrabenazine chiral acid salt obtained with L-di-p-methylbenzyltartaric acid dissociates under alkaline conditions to obtain tetrabenazine with (3R,11bR) configuration. The applicant further screens the solvent in the salt forming step, and finally determines that the optical purity of the chiral acid salt can be improved by using ethyl acetate for recrystallization, the method has stable yield and ee value when kilogram-level production is amplified, good process reproducibility and simple and convenient operation, and the reaction process is as follows:

the invention provides a chiral resolution method of tetrabenazine, which is characterized by comprising the following steps:

a. salifying and crystallizing: using tetrabenazine as a raw material, salifying with di-p-methylbenzoyl tartaric acid in a solvent, crystallizing, filtering, suspending the obtained solid in the solvent, stirring, and filtering to obtain (3R,11bR) -tetrabenazine di-p-methylbenzoyl tartrate or (3S,11bS) -tetrabenazine di-p-methylbenzoyl tartrate;

b. dissociation: and (b) dissolving the (3R,11bR) -tetrabenazine di-p-methylbenzoyl tartrate or (3S,11bS) -tetrabenazine di-p-methylbenzoyl tartrate obtained in the step a in a solvent, adjusting the pH value to be alkaline by using an alkaline aqueous solution, extracting and spin-drying to obtain the (3R,11bR) -tetrabenazine or (3S,11bS) -tetrabenazine.

The di-p-methylbenzoyl tartaric acid is selected from L-di-p-methylbenzoyl tartaric acid, D-di-p-methylbenzoyl tartaric acid or hydrate thereof, and the structure of the di-p-methylbenzoyl tartaric acid is shown as a formula (I) and a formula (II):

the invention also provides a preparation method of tetrabenazine with a (3R,11bR) configuration, which is characterized by comprising the following steps:

a. salifying and crystallizing: using tetrabenazine as a raw material, salifying with L-di-p-methylbenzoyl tartaric acid in a solvent, crystallizing, filtering, suspending the obtained solid in the solvent, stirring, and filtering to obtain (3R,11bR) -tetrabenazine L-di-p-methylbenzoyl tartrate;

b. dissociation: and (b) dissolving the (3R,11bR) -tetrabenazine L-di-p-methylbenzoyl tartrate obtained in the step a in a solvent, adjusting the pH value to be alkaline by using an alkaline aqueous solution, extracting and spin-drying to obtain the (3R,11bR) -tetrabenazine.

The molar ratio of the tetrabenazine to the di-p-methylbenzoyl tartaric acid is 1: 0.5 to 1.5, preferably 1: 0.8 to 1.2.

The solvent in step a is selected from one or more of ethyl acetate, acetone, ethanol, water and isopropanol, and the solvent in step b is water.

The solvent in step a of the present invention is selected from ethyl acetate or acetone.

The mass volume ratio of the tetrabenazine to the solvent in the step a is 1 g: 10 mL-100 mL, preferably the mass-to-volume ratio is 1 g: 10mL to 40mL, more preferably 1 g: 10mL to 20 mL.

The base in the aqueous alkaline solution used in step b of the present invention is selected from sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.

The invention also relates to application of the di-p-methylbenzoyl tartaric acid or the hydrate thereof in resolving tetrabenazine isomer. The di-p-methylbenzoyl tartaric acid is selected from L-di-p-methylbenzoyl tartaric acid, D-di-p-methylbenzoyl tartaric acid or hydrate thereof, and the structure of the di-p-methylbenzoyl tartaric acid is shown as a formula (I) and a formula (II):

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

(1) the optical purity of the chiral acid salt obtained by the first crystallization is more than 80 percent, the yield is high, and the optical purity (ee value) of the (3R,11bR) -tetrabenazine or the (3S,11bS) -tetrabenazine obtained by the second crystallization, filtration and dissociation can reach 99 percent;

(2) the production process of the amplification kilogram level is stable, the reproducibility is good, and the operation is simple and convenient.

Detailed Description

The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.

Tetrabenazine optical purity was determined using a Waters Xbridge C18150 mm X4.6 mm 3.5 μm, mobile phase A: 100% pure acetonitrile, mobile phase B: 0.1% aqueous ammonia at a flow rate of 1 mL/min.

Example 1A pilot and scale-up experiment was carried out on D-camphorsulfonic acid according to the method of patent CN101985447A

And (3) small trial: 5g (0.0157mol) of tetrabenazine and 1.83g (0.00788mol) of D-camphorsulfonic acid are dissolved in acetone (50mL), refluxed and stirred for 30 minutes, cooled and crystallized, and filtered to obtain 2.13g of (3R,11bR) -tetrabenazine D-camphorsulfonate as a white solid with an ee value of 80%, and recrystallized again by acetone to obtain 1.64g of (3R,11bR) -tetrabenazine-D-camphorsulfonate with an ee value of 98.7%;

the resulting (3R,11bR) -tetrabenazine-D-camphorsulfonate was suspended in water, 30% aqueous sodium hydroxide was added to adjust the pH to 11-12, methylene chloride (400mL) was added for extraction, the organic phase was separated, washed with brine (400mL), dried, and spin-dried to give (3R,11bR) -tetrabenazine as a white solid 0.95g, with an ee of 98.7%, and a total yield of 19%.

Amplification: 972.9g (3.067mol) of tetrabenazine and 356.2g (1.53mol) of D-camphorsulfonic acid are dissolved in acetone (10.2L), refluxed and stirred for 30 minutes, cooled and crystallized, and filtered to obtain 900g of (3R,11bR) -tetrabenazine D-camphorsulfonate as a white solid with an ee value of 42%, and the salt is recrystallized for a plurality of times from acetone to obtain 132.7g of (3R,11bR) -tetrabenazine-D-camphorsulfonate with an ee value of 98.4%;

the resulting (3R,11bR) -tetrabenazine-D-camphorsulfonate was suspended in water, 30% aqueous sodium hydroxide was added to adjust the pH to 11-12, methylene chloride (120mL) was added for extraction, the organic phase was separated, washed with brine (120mL), the organic phase was dried and spun to give (+) - (3R,11bR) -tetrabenazine 61.5g, ee 98.4%, 6.3% overall yield.

The D-camphorsulfonic acid is used for resolving tetrabenazine, the process is unstable during amplification, the ee value can meet the requirement after repeated recrystallization, the total yield is lower and is only 6.3%, and the loss is large.

Example 2 screening of chiral acids

Dissolving 5g (0.0157mol) of tetrabenazine in acetone (50mL), respectively adding 1 mol equivalent of D-camphoric acid, D-mandelic acid, D-malic acid, D-dibenzoyltartaric acid, D-di-p-methylbenzyltartaric acid or L-di-p-methylbenzyltartaric acid, heating and refluxing, stirring for 30 minutes, cooling and crystallizing, respectively filtering to obtain tetrabenazine chiral acid salts, wherein the structures of the chiral acids are shown in Table 1, and the ee value and the yield of the tetrabenazine chiral acid salts are shown in Table 2.

TABLE 1 chiral acid structural formula

TABLE 2 results of chiral acid screening experiments

In the table, "/" indicates that no solid precipitated.

As can be seen from table 2, when D-camphoric acid, D-mandelic acid, and D-malic acid were used to resolve tetrabenazine, the ee value and yield of optical purity were both low, when D-dibenzoyltartaric acid was used to resolve tetrabenazine, no solid was precipitated, no optically pure tetrabenazine chiral acid salt was obtained, when D-di-p-methylbenzyltartaric acid was used to resolve tetrabenazine, (3S,11bS) -tetrabenazine chiral acid salt was obtained, when L-di-p-methylbenzyltartaric acid was used to resolve tetrabenazine, (3R,11bR) -tetrabenazine chiral acid salt was obtained, and both yield and ee value were high.

Example 3 solvent screening

Taking 5g (0.0157mol) of tetrabenazine, using L-di-p-methylbenzoyl tartaric acid as chiral acid 6.06g (0.0157mol, 1equal), and examining solvents in a salt forming step, comparing acetone, ethanol, acetone/water, isopropanol and ethyl acetate to obtain ee values and yields of (3R,11bR) -tetrabenazine chiral acid salt, and the results are shown in Table 3.

TABLE 3 solvent screening

Serial number	Solvent(s)	Ratio of tetrabenazine to solvent	ee value	Yield of the product
					1.	Acetone (II)	1g：10mL	80％	37％
2.	Ethanol	1g：10mL	/	/
					3.	Acetone: 1:1 of water	1g：10mL	68％	35％
4.	Isopropanol (I-propanol)	1g：10mL	/	/
					5.	Ethyl acetate	1g：10mL	86％	47％
6.	Ethyl acetate	1g：20mL	88％	44％
					7.	Ethyl acetate	1g：30mL	89％	42％
8.	Ethyl acetate	1g：40mL	89％	37％

In the table, "/" indicates that no solid precipitated.

As can be seen from table 3, when ethanol and isopropanol are used as solvents, no solid is precipitated by cooling, the yield and ee value of the chiral acid salt obtained by using a mixed solvent of acetone and water with a volume ratio of 1:1 are relatively low, the ee value of the chiral acid salt obtained by using acetone is relatively high, the ee value of the tetrabenazine chiral acid salt with a (3R,11bR) configuration obtained by selecting ethyl acetate as a solvent is highest, and the yield is gradually reduced although the ee value is slightly increased along with the increase of the amount of ethyl acetate, so that the mass-to-volume ratio of tetrabenazine to ethyl acetate is determined to be 1 g: the range of 10mL to 20mL is most preferable.

Example 4

Step a: weighing 100g (0.315mol) of tetrabenazine and 121.72g (0.315mol, 1equal) of L-di-p-methylbenzoyl tartaric acid, dissolving in ethyl acetate (1L), heating and refluxing for 30 minutes, cooling and crystallizing, and filtering to obtain 120g of crude (3R,11bR) -tetrabenazine-L-di-p-methylbenzoyl tartrate in a white solid state, wherein the ee value of the salt is detected to be 85%. Suspending the filtered white solid crude product in ethyl acetate (1.2L), heating to 60 ℃, refluxing for 30 minutes, cooling to 40-50 ℃, crystallizing, and filtering to obtain 100g of (3R,11bR) -tetrabenazine-L-di-p-methylbenzoyl tartrate, wherein the ee value is 99.6%, and the yield is 45%.

Step b: and (3R,11bR) -tetrabenazine-L-di-p-methylbenzoyl tartrate obtained in the step a is suspended in a proper amount of water, the pH value is adjusted to 11-12 by using 30% sodium hydroxide solution under the condition of vigorous stirring, dichloromethane (300mL) is used for extraction, an organic phase is separated, saturated saline solution (200mL) is used for washing, drying and spin-drying to obtain 40g of (3R,11bR) -tetrabenazine, the ee value is 99.6 percent and the total yield is 40 percent.

Example 5

Step a: weighing 1Kg (3.15mol) of tetrabenazine and 1.46Kg (3.78mol, 1.2 equil) of L-di-p-methylbenzoyl tartaric acid, dissolving in ethyl acetate (10L), heating and refluxing for 30 minutes, cooling and crystallizing, filtering to obtain 1.217Kg of crude (3R,11bR) -tetrabenazine-L-di-p-methylbenzoyl tartrate in white solid, and detecting the ee value of the salt to be 86%. Suspending the filtered white solid crude product in ethyl acetate (12L), heating to 60 ℃, refluxing for 30 minutes, cooling to 45-55 ℃, crystallizing, and filtering to obtain 1.03Kg of (3R,11bR) -tetrabenazine-L-di-p-methylbenzoyl tartrate, wherein the ee value is 99.4%, and the yield is 46.5%.

Step b: and (3R,11bR) -tetrabenazine-L-di-p-methylbenzoyl tartrate obtained in the step a is suspended in a proper amount of water, the pH value is adjusted to 9-10 by using a sodium carbonate solution under the condition of vigorous stirring, dichloromethane (4L) is used for extraction, an organic phase is separated, saturated salt solution (2L) is used for washing, drying and spin-drying to obtain 405g of (3R,11bR) -tetrabenazine, the ee value is 99.4 percent and the total yield is 40.5 percent.

Example 6

Step a: weighing 3Kg (9.45mol) of tetrabenazine and 3.65Kg (9.45mol, 1equal) of L-di-p-methylbenzoyl tartaric acid, dissolving in ethyl acetate (48L), heating and refluxing for 30 minutes, cooling and crystallizing, and filtering to obtain 3.65Kg of crude (3R,11bR) -tetrabenazine-L-di-p-methylbenzoyl tartrate in white solid state, wherein the ee value of the salt is detected to be 88%. Suspending the filtered white solid crude product in ethyl acetate (58L), heating to 58 ℃, refluxing for 30 minutes, cooling to 45-55 ℃, crystallizing, and filtering to obtain 3.1Kg of (3R,11bR) -tetrabenazine-L-di-p-methylbenzoyl tartrate, wherein the ee value is 99.9%, and the yield is 45%.

Step b: and (3R,11bR) -tetrabenazine-L-di-p-methylbenzoyl tartrate obtained in the step a is suspended in a proper amount of water, the pH value is adjusted to 10-11 by using potassium carbonate solution under the condition of vigorous stirring, dichloromethane (6L) is used for extraction, an organic phase is separated, saturated saline (3L) is used for washing, drying and spin-drying to obtain 1.26Kg of (3R,11bR) -tetrabenazine, the ee value is 99.9% (a chiral HPLC chromatogram is shown in figure 2, the retention time is 16.599min), and the total yield is 42%.

Example 7

Step a: weighing 5Kg (15.75mol) of tetrabenazine and 6.69Kg (17.33mol, 1.1 equil) of L-di-p-methylbenzoyl tartaric acid, dissolving in ethyl acetate (100L), heating and refluxing for 30 minutes, cooling and crystallizing, and filtering to obtain 5.98Kg of crude (3R,11bR) -tetrabenazine-L-di-p-methylbenzoyl tartrate in white solid, wherein the ee value of the salt is detected to be 86%. Suspending the filtered white solid crude product in ethyl acetate (119L), heating to 58 ℃, refluxing for 30 minutes, cooling to 45-55 ℃, crystallizing, and filtering to obtain 5.093Kg of (3R,11bR) -tetrabenazine-L-di-p-methylbenzoyl tartrate, wherein the ee value is 99.2%, and the yield is 46%.

Step b: and (3R,11bR) -tetrabenazine-L-di-p-methylbenzoyl tartrate obtained in the step a is suspended in a proper amount of water, the pH value is adjusted to 11-12 by potassium carbonate solution under the condition of vigorous stirring, dichloromethane (10L) is used for extraction, an organic phase is separated, saturated saline solution (5L) is used for washing, drying and spin-drying to obtain 2.075Kg of (3R,11bR) -tetrabenazine, the ee value is 99.2 percent, and the total yield is 41.5 percent.

Example 8

Step a: 200g (0.63mol) of tetrabenazine and 243.4g (0.63mol, 1equal) of D-di-p-methylbenzoyl tartaric acid are weighed and dissolved in ethyl acetate (3.2L), heated and refluxed for 30 minutes, cooled to 45-55 ℃ for crystallization, filtered to obtain 239g of crude (3S,11bS) -tetrabenazine-D-di-p-methylbenzoyl tartrate in white solid, and the ee value of the salt is detected to be 85%. Suspending the filtered white solid crude product in ethyl acetate (3.8L), heating to 58 ℃, refluxing for 30 minutes, cooling to 45-55 ℃, crystallizing, and filtering to obtain 186g of (3S,11bS) -tetrabenazine-D-di-p-methylbenzoyl tartrate, wherein the ee value is 98.5%, and the yield is 45%.

Step b: and (3S,11bS) -tetrabenazine-D-di-p-methylbenzoyl tartrate obtained in the step a is suspended in a proper amount of water, the pH is adjusted to 11-12 by potassium hydroxide solution under the condition of vigorous stirring, dichloromethane (500mL) is used for extraction, an organic phase is separated, saturated saline solution (250mL) is used for washing, drying and spin-drying to obtain 84g of (3S,11bS) -tetrabenazine, the ee value is 99.9% (a chiral HPLC diagram is shown in figure 3, the retention time is 10.927min), and the total yield is 42%.

Claims

1. The chiral resolution method of tetrabenazine is characterized by comprising the following steps:

b. dissociation: b, dissolving the (3R,11bR) -tetrabenazine di-p-methyl benzoyl tartrate or the (3S,11bS) -tetrabenazine di-p-methyl benzoyl tartrate obtained in the step a in a solvent, adjusting the pH value to be alkaline by using an alkaline aqueous solution, extracting and spin-drying to obtain (3R,11bR) -tetrabenazine or (3S,11bS) -tetrabenazine;

wherein the solvent in the step a is ethyl acetate; the solvent in step b is water.

2. The method of claim 1, wherein the di-p-methylbenzoyl tartaric acid is selected from the group consisting of L-di-p-methylbenzoyl tartaric acid, D-di-p-methylbenzoyl tartaric acid, and hydrates thereof, and has the structure shown in formula (I) and formula (II):

。

3. the method according to claim 2, characterized in that it comprises the following steps:

4. A process according to any one of claims 1 to 3, wherein the molar ratio of tetrabenazine to di-p-methylbenzoyltartaric acid is from 1: 0.5 to 1.5.

5. The method of claim 4, wherein the molar ratio of tetrabenazine to di-p-methylbenzoyl tartaric acid is 1: 0.8-1.2.

6. The method according to any one of claims 1 to 3, wherein the mass-to-volume ratio of tetrabenazine to the solvent of step a is 1 g: 10 mL-40 mL.

7. The method of claim 6, wherein the mass to volume ratio of tetrabenazine to solvent of step a is from 1g to 10mL to 20 mL.

8. A process according to any one of claims 1 to 3, wherein the base in the aqueous alkaline solution used in step b is selected from sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.