CN117624049A - Method for synthesizing and refining key intermediate of tolvaptan - Google Patents

Abstract

The invention discloses a method for synthesizing and refining a key intermediate of tolvaptan, which comprises the following steps: the intermediate is 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2, 3,4, 5-tetrahydro-1H-1-benzazepine; adding concentrated hydrochloric acid and stannous chloride into a solution of 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzoazepin-5-one, and performing nitroreduction in an inert atmosphere, wherein the concentration of hydrochloric acid in a reaction system is 5-36.5wt%, and the stannous chloride is stannous chloride solid or hydrate thereof and stannous chloride solution; and after the reaction is finished, cooling, washing by adopting alcohols, and recrystallizing in a mixed solution of alcohol and alkali to obtain the catalyst. The method has the advantages of less environmental pollution, higher yield, higher purity and content of the product, simple operation, reduced waste liquid discharge, contribution to reducing production cost and improving economic benefit, and is suitable for industrial production.

Description

Method for synthesizing and refining key intermediate of tolvaptan

Technical Field

The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and particularly relates to a method for synthesizing and refining a key intermediate of tolvaptan.

Background

The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.

Tolvaptan is named Tolvaptan, samsca, N- [4- [ (7-chloro-2, 3,4, 5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl ] -3-methylphenyl ] -2-methylbenzamide, and has the following structure:

tolvaptan is a selective vasopressin V2 receptor antagonist, which can prevent AVP from combining with a V2 receptor at the far end of a kidney unit, so that the water excrement in urine is increased, but the sodium potassium secretion and the blood potassium value of urine are not changed, the osmotic pressure of urine is reduced, and the blood sodium value is increased, so that the tollvan is clinically used for treating hypervolemic hyponatremia and isovolumetric hyponatremia caused by liver cirrhosis, heart failure and abnormal antidiuretic hormone secretion Syndrome (SIADH). The medicine has good tolerance, does not damage electrolyte balance, and has lighter adverse reaction. Therefore, the method has better development and application prospects.

The preparation methods of the product are stannous chloride reduction methods, the existing defects are low yield, the post-treatment is complicated, the pKa=2 of stannic chloride can be decomposed into metal oxide byproducts such as stannic oxide, stannic oxide and the like at the pH of more than or equal to 4, the liquid separation is difficult, the using amount of the used extraction solvent is large, and the product is not suitable for industrial production.

The preparation method adopts a metal chloride and palladium-carbon catalyst reduction method, and has the following defects: the hydrogenation operation is needed, the pressure of hydrogen is high, and the hydrogenation process belongs to a dangerous process and is not suitable for industrial production.

For the above-mentioned hydrogenation reduction reaction of nitro, some of the prior art adopts stannous chloride reduction method, and the stannous chloride reduction method can raise the yield to above 90%, but the stannous chloride reduction method has great environmental pollution, and is not suitable for industrial production.

In addition, noble metal catalyzed hydrogenation processes are also common for the hydrogenation of nitro groups to amino groups. However, since the compound II contains chlorine atoms at the 7-position, a great amount of chlorine atoms fall off due to the noble metal catalytic hydrogenation method, so that a difficult-to-separate byproduct 1- (4-amino-2-methylbenzoyl) -5-oxo-2, 3,4, 5-tetrahydro-1H-1-benzazepine (hereinafter referred to as a byproduct III) is generated, and the product purity is low and is still not suitable for industrial production.

The structures of the compound I, the compound II and the byproduct III are respectively as follows:

disclosure of Invention

Aiming at the defects existing in the prior art, the invention aims to provide a method for synthesizing and refining a key intermediate of tolvaptan, which has the advantages of less environmental pollution, higher yield, higher purity and content of products, simple operation, reduced waste liquid discharge, contribution to reducing production cost and improving economic benefit, and is suitable for industrial production.

In order to achieve the above object, the present invention is realized by the following technical scheme:

a method for synthesizing and refining a key intermediate of tolvaptan comprises the following steps:

the intermediate is 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2, 3,4, 5-tetrahydro-1H-1-benzazepine;

hydrochloric acid and stannous chloride are added into a solution of 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzoazepin-5-ketone, nitro reduction is carried out in an inert atmosphere, the concentration of the hydrochloric acid in a reaction system is 5 to 36.5 weight percent, and the stannous chloride is anhydrous stannous chloride or hydrate thereof and stannous chloride solution.

After the reaction is finished, cooling, filtering, washing with an organic solvent, and recrystallizing the obtained wet product in a mixed solution of the organic solvent and alkali, wherein the alkali is amine or pyridine;

the solubility of the salt generated by the reaction of tin chloride and the alkali in the organic solvent is large, and the solubility of the intermediate of tolvaptan in the alcohol is small.

The reducing property of stannous chloride means that stannous chloride can reduce oxygen ions in oxide into water molecules. During this process, stannous chloride loses electrons and oxygen ions get electrons, thus forming water molecules. In this process, stannous chloride acts as a reducing agent. Hydrochloric acid mainly suppresses the occurrence of hydrolysis reaction of tin chloride and supplies hydrogen during the reaction.

The tin chloride reacts with alkali (such as triethylamine) to form salt, and the alcohol is used as a solvent of a recrystallization system, so that the salt formed by the tin chloride and the alkali is dissolved, and the intermediate of the tolvaptan is less in solubility, and is recrystallized and separated out to obtain a purer intermediate of the tolvaptan.

In some embodiments, the organic solvent in the solution of 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzazepin-5-one is selected from one or two of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, toluene, dioxane, dichloromethane, chloroform, carbon tetrachloride.

Preferably, the organic solvent in the solution of 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzazepin-5-one is selected from methanol, dichloromethane, ethanol, isopropanol, acetonitrile, tetrahydrofuran or ethyl acetate. Methanol, ethanol or isopropanol is further preferred.

In some embodiments, stannous chloride is used in an amount of 1 to 20 times the mass of 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzazepin-5-one in the reaction system.

In some embodiments, the concentrated hydrochloric acid is used in an amount of 1 to 40 times the mass of 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzazepin-5-one in the reaction system.

In some embodiments, in the nitroreduction reaction, the reaction temperature is 20 to 85 ℃ and the reaction time is 1 to 24 hours;

preferably, the reaction temperature is 40-65 ℃ and the reaction time is 2-8 h.

In some embodiments, when washed with an alcohol, the alcohol is methanol, ethanol, or isopropanol.

In some embodiments, the alcohol is selected from one or a combination of methanol, ethanol, or isopropanol in a mixture of the alcohol and the base;

preferably, the alcohol is methanol or ethanol.

In some embodiments, the base is selected from one or a combination of pyridine, monoethylamine, diethylamine, triethylamine, isopropylamine, propylamine, or diisopropylamine in a mixture of alcohol and base.

Preferably, the base is selected from one or a combination of pyridine, monoethylamine, diethyl amine or triethylamine;

further preferably, the base is triethylamine.

In some embodiments, the amount of alcohol used in the recrystallization is 1 to 20 times, preferably 2 to 10 times, more preferably 2 to 5 times the mass of 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzazepin-5-one;

the amount of the base to be used is 0.1 to 5 times, preferably 0.1 to 2 times, and more preferably 0.1 to 1 times the mass of 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzazepin-5-one.

In some embodiments, the temperature of recrystallization is from-20 to 65 ℃ and the recrystallization time is from 1 to 24 hours.

Preferably, the temperature of recrystallization is-10-35 ℃, and the recrystallization time is 1-8 h.

The beneficial effects achieved by one or more embodiments of the present invention described above are as follows:

(1) The method adopts the metal chloride and the hydrochloric acid as the reaction system for hydrogenation reduction of the nitro, and the reaction system for reduction of the nitro not only can obtain higher reaction yield, but also can effectively avoid the occurrence of dechlorination of side reaction, thereby obtaining higher product purity.

(2) The post-treatment (refining) method adopts the organic solvent and alkali, so that the post-treatment (refining) step is greatly simplified, the post-treatment period is reduced, the yield and the product content are higher, and the byproduct of the metal tin is thoroughly removed.

(3) The method has less environmental pollution and lower production cost, and is suitable for industrial production.

Drawings

The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.

FIG. 1 is a liquid spectrum of tolvaptan intermediate obtained in example 1;

FIG. 2 is a liquid spectrum of tolvaptan intermediate obtained in example 2;

fig. 3 is a liquid-phase spectrum of tolvaptan intermediate obtained in example 3.

Detailed Description

It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the invention. 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 invention is further illustrated below with reference to examples.

Example 1

The preparation method of tolvaptan intermediate 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2, 3,4, 5-tetrahydro-1H-1-benzazepine of the embodiment is as follows:

to a 50L reactor was added 3.0kg of Compound II, 6.0kg of stannous chloride, 6.7kg of 36.5wt% concentrated hydrochloric acid and 30L of methanol.

And 3, replacing nitrogen for 3 times, starting stirring, controlling the reaction temperature of the reaction kettle to 55+/-2 ℃ and reacting for 4 hours.

After TLC shows that the reaction is complete, the temperature is reduced to 10 ℃, the filtration is carried out, and filter cakes are washed by methanol; 12L of methanol, 1.5kg of triethylamine and 2.65kg of compound I as an off-white solid powder were added to the wet product, and the product was recrystallized and filtered to give the compound I in a yield of 96.4% and a HPLC purity of 99.646%.

Example 2

The preparation method of tolvaptan intermediate 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2, 3,4, 5-tetrahydro-1H-1-benzazepine of the example is as follows:

into a 5L reaction flask were charged 300.0g of Compound II, 630.0g of stannous chloride dihydrate, 1570.0g of 36.5wt% concentrated hydrochloric acid and 5L of methanol.

And 3, replacing nitrogen for 3 times, starting stirring, controlling the reaction temperature of the reaction kettle to 55+/-2 ℃, and reacting for 8 hours.

After TLC shows that the reaction is complete, the temperature is reduced to 5 ℃, the filtration is carried out, and filter cakes are washed by methanol; 1.2L of methanol, 120g of triethylamine, crystallization at room temperature for 1h and filtration are added to the obtained wet product to obtain 256.2g of compound I as off-white solid powder, wherein the yield is 93.2% and the HPLC purity is 99.626%.

Example 3

The preparation method of tolvaptan intermediate 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2, 3,4, 5-tetrahydro-1H-1-benzazepine of the example is as follows:

into a 2L reactor was charged 100.0g of Compound II, 210.0g of stannous chloride dihydrate, 374.0g of 36.5% by weight concentrated hydrochloric acid and 1L of ethanol.

And 3, replacing nitrogen for 3 times, starting stirring, controlling the reaction temperature of the reaction kettle to 55+/-2 ℃, and reacting for 8 hours.

After TLC shows that the reaction is complete, the temperature is reduced to 0 ℃, the filtration is carried out, and the filter cake is washed by ethanol; 300mL of ethanol, 42.3g of triethylamine, and filtration were added to the wet product to obtain 86.2g of compound I as an off-white solid powder in 94.1% yield and 99.545% purity by HPLC.

Example 4

The difference from example 3 is that: ethanol was replaced with isopropanol, and the other steps were the same as in example 3. The yield of final compound i was 91.6% >, HPLC purity 99.589%.

Example 5

The difference from example 3 is that: triethylamine was replaced with monoethylamine, and the same as in example 3 was carried out. The yield of final compound i was 87.6% and HPLC purity 99.699%.

Example 6

The difference from example 3 is that: triethylamine was replaced with diethylamine, and the procedure was the same as in example 3. The yield of final compound i was 88.2% and HPLC purity was 99.754%.

Example 7

The difference from example 3 is that: the triethylamine was replaced with pyridine, and the other was the same as in example 3. The yield of final compound i was 85.4% and HPLC purity 99.736%.

Example 8

10.0g of 7-chloro-1- (4-nitro-2-methylbenzoyl) -5-oxo-2, 3,4, 5-tetrahydro-1H-1-benzazepine are reacted withAdding 100ml of methanol and 50ml of concentrated hydrochloric acid into a reaction bottle, adding 30.0g of stannous chloride, replacing 3 times with nitrogen, starting stirring, controlling the reaction temperature of a reaction kettle at 55+/-2 ℃ and reacting for 4 hours.

After TLC shows that the reaction is complete, the temperature is reduced to 10 ℃, the filtration is carried out, and filter cakes are washed by methanol; 50mL of isopropyl alcohol, 4.5g of triethylamine, recrystallization and filtration were added to the wet product thus obtained to obtain 5.65g of Compound I as an off-white solid powder in a yield of 61.6% and a HPLC purity of 99.269%

Example 9

10.0g of 7-chloro-1- (4-nitro-2-methylbenzoyl) -5-oxo-2, 3,4, 5-tetrahydro-1H-1-benzazepine are reacted withAdding 100ml of methanol and 50ml of concentrated hydrochloric acid into a reaction bottle, adding 30.0g of stannous chloride, replacing 3 times with nitrogen, starting stirring, controlling the reaction temperature of a reaction kettle at 55+/-2 ℃ and reacting for 4 hours.

After TLC shows that the reaction is complete, the temperature is reduced to 10 ℃, the filtration is carried out, and filter cakes are washed by methanol; 50mL of ethanol, 5.1g of pyridine, recrystallization and filtration were added to the wet product obtained to obtain 6.98g of compound I as an off-white solid powder with a yield of 76.2% and an HPLC purity of 99.255%

Example 10

10.0g of 7-chloro-1- (4-nitro-2-methylbenzoyl) -5-oxo-2, 3,4, 5-tetrahydro-1H-1-benzazepine are reacted withAdding 100ml of ethanol and 50ml of concentrated hydrochloric acid into a reaction bottle, adding 20.8g of stannous chloride, replacing 3 times with nitrogen, starting stirring, controlling the reaction temperature of a reaction kettle at 55+/-2 ℃ and reacting for 4 hours.

After TLC shows that the reaction is complete, the temperature is reduced to 0 ℃, the filtration is carried out, and filter cakes are washed by methanol; 50mL of ethanol, 5.1g of monoethylamine, recrystallization and filtration were added to the wet product to obtain 5.46g of compound I as an off-white solid powder with a yield of 59.6% and an HPLC purity of 99.736%.

Example 11

10.0g of 7-chloro-1- (4-nitro-2-methylbenzoyl) -5-oxo-2, 3,4, 5-tetrahydro-1H-1-benzazepine are reacted withAdding 100ml of ethanol and 50ml of concentrated hydrochloric acid into a reaction bottle, adding 20.8g of stannous chloride, replacing 3 times with nitrogen, starting stirring, controlling the reaction temperature of a reaction kettle at 55+/-2 ℃ and reacting for 4 hours.

After TLC shows that the reaction is complete, the temperature is reduced to 0 ℃, the filtration is carried out, and filter cakes are washed by methanol; 50mL of ethanol, 6.2g of isopropylamine, recrystallization and filtration were added to the wet product to obtain 6.11g of compound I as an off-white solid powder in a yield of 66.7% and an HPLC purity of 99.215%.

Comparative example 1

210.0g of 7-chloro-1- (4-nitro-2-methylbenzoyl) -5-oxo-2, 3,4, 5-tetrahydro-1H-1-benzazepine are reacted withAdding 2000ml of ethanol and 1050ml of concentrated hydrochloric acid into a reaction bottle, slowly adding 530.0g of stannous chloride at 30 ℃, stirring for reaction overnight, pouring the reaction solution into 2L of ice water, regulating the pH value to about 8 with saturated sodium hydroxide solution, extracting four times with 1500ml of dichloromethane, mixing organic phases, adding a proper amount of anhydrous sodium sulfate for drying,suction filtration, concentration of the filtrate to dryness, recrystallization twice from 200ml dimethylformamide, drying gave 102.6g of white powder with a yield of 53.3% and an HPLC purity of 99.180%.

Comparative example 2

To the compound 7-chloro-1- (4-nitro-2-methylbenzoyl) -5-oxo-2, 3,4, 5-tetrahydro-1H-1-benzazepineTo a suspension of (22.0 g,61.32 mmol) in concentrated hydrochloric acid (70 mL) and ethanol (140 mL) was added stannous chloride dihydrate (41.51 g,183.96 mmol) in portions, and the mixture was reacted at room temperature for 4 hours after the addition. After the TLC detection reaction is finished, the ethanol is removed by decompression, the rest reaction liquid is placed in a refrigerator for freezing overnight, a large amount of solid is precipitated, the filtration is carried out, after a filter cake is washed by a small amount of water, the filter cake is dissolved by 150ml of water, 20% sodium hydroxide solution is added dropwise while stirring to adjust the pH to be 9, the filtration is carried out, and the filter cake is recrystallized by absolute ethanol to obtain pale yellow solid which is the compound I (16.13 g, the yield is 80.0 percent) and the HPLC purity is 99.184 percent.

The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A method for synthesizing and refining a key intermediate of tolvaptan is characterized by comprising the following steps: the method comprises the following steps:

the intermediate is 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2, 3,4, 5-tetrahydro-1H-1-benzazepine;

adding concentrated hydrochloric acid and stannous chloride into a solution of 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzazepin-5-ketone, and performing nitroreduction in an inert atmosphere, wherein the concentration of hydrochloric acid is 5-36.5wt% and the concentration of stannous chloride is 5-15wt% in a reaction system;

and after the reaction is finished, cooling, washing by adopting an organic solvent, and recrystallizing in a mixed solution of alcohol and alkali, wherein the alkali is amine or pyridine.

2. The method for synthesizing and refining the key intermediate of tolvaptan according to claim 1, wherein the method is characterized in that: the organic solvent in the solution of 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzoazepin-5-one is selected from one or two of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, toluene, dioxane, dichloromethane, chloroform and carbon tetrachloride;

preferably, the organic solvent in the solution of 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzazepin-5-one is selected from the group consisting of methanol, dichloromethane, ethanol, isopropanol, acetonitrile, tetrahydrofuran, ethyl acetate; methanol or ethanol is further preferred.

3. The method for synthesizing and refining the key intermediate of tolvaptan according to claim 1, wherein the method is characterized in that: in the reaction system, the dosage of stannous chloride is 1 to 20 times of the mass of 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzazepin-5-ketone.

4. The method for synthesizing and refining the key intermediate of tolvaptan according to claim 1, wherein the method is characterized in that: in the reaction system, the dosage of the concentrated hydrochloric acid is 1 to 40 times of the mass of 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzoazepine-5-ketone.

5. The method for synthesizing and refining the key intermediate of tolvaptan according to claim 1, wherein the method is characterized in that: in the nitroreduction reaction, the reaction temperature is 20-85 ℃ and the reaction time is 1-24 h;

preferably, the reaction temperature is 40-65 ℃ and the reaction time is 2-8 h.

6. The method for synthesizing and refining the key intermediate of tolvaptan according to claim 1, wherein the method is characterized in that: when the organic solvent is adopted for washing, the organic solvent is methanol or ethanol.

7. The method for synthesizing and refining the key intermediate of tolvaptan according to claim 1, wherein the method is characterized in that: the alcohol is selected from one or a combination of methanol, ethanol or isopropanol;

preferably, the alcohol is methanol or ethanol.

8. The method for synthesizing and refining the key intermediate of tolvaptan according to claim 1, wherein the method is characterized in that: in the mixed solution of alcohol and alkali, the alkali is selected from one or a combination of pyridine, monoethylamine, diethylamine, triethylamine, isopropylamine, propylamine or diisopropylamine;

preferably, the base is selected from one or a combination of pyridine, monoethylamine, diethyl amine or triethylamine;

further preferably, the base is triethylamine.

9. The method for synthesizing and refining the key intermediate of tolvaptan according to claim 1, wherein the method is characterized in that: in the recrystallization, the amount of the alcohol is 1 to 20 times, preferably 2 to 10 times, more preferably 2 to 5 times the mass of the 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzazepin-5-one;

the amount of the base to be used is 0.1 to 5 times, preferably 0.1 to 2 times, and more preferably 0.1 to 1 times the mass of 7-chloro-1, 2,3, 4-tetrahydro-1- (2-methyl-4-nitrobenzoyl) -5H-1-benzazepin-5-one.

10. The method for synthesizing and refining the key intermediate of tolvaptan according to claim 1, wherein the method is characterized in that: the temperature of recrystallization is-20-65 ℃, and the recrystallization time is 1-24 h;

preferably, the temperature of recrystallization is-10-35 ℃, and the recrystallization time is 1-8 h.