TW201620920A - A process of making fosaprepitant dimeglumine - Google Patents

Abstract

A process of effectively reducing palladium content in fosaprepitant dimeglumine to below 0.3 ppm which is the detection limit using the current analytical method.

Description

Method for preparing fosapride dimethylglucamine

The present invention relates to a process for effectively reducing the palladium content of fosapride dimethylglucamine to less than 0.3 ppm.

Fosapride dimethylglucamine, [3-{[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy]- 3-(4-Fluorophenyl)morpholinyl-4-yl]methyl}-5-oxo-2H-1,2,4-triazol-1-yl]-phosphonic acid dimethylglucamine having the following The structure shown:

Ezet® for injection is a new intravenous injection for the prevention of chemotherapy-induced nausea and vomiting (CINV). Emend® for injection is an intravenous injection of an oral dosage form of Emend® (Aprepitant), ie, when administered with Emend® for injection, valsartan is rapidly converted to aprepitant in the body.

As shown in Scheme 1, U.S. Patent No. 5,691,336 discloses that fosapride dimethylglucamine is produced from fasapride dibenzyl ester.

A mixture containing fosapride dibenzyl ester, N -methyl-D-glucosamine, 10% by weight of 10% Pd/C, water and methanol was hydrogenated (40 psi) at 20-30 °C for 2 hours. After the reaction was completed, the mixture was filtered to remove the catalyst, followed by concentration. The concentrate was dissolved in methanol and the solution was added to isopropanol which aided in product precipitation. The resulting fosapride dimethylglucamine was isolated in a yield of 90.4% and a purity greater than 99%. Since it is directly formed from the hydrogenation reaction of the palladium medium, the obtained fosapride dimethylglucamine will contain a specific amount of palladium.

If fosapride dimethylglucamine is used parenterally, the residual palladium content should be strictly controlled. The palladium content limit is set to less than 1 ppm according to the provisions of the United States Pharmacopoeia (USP) 36 and the European Pharmacopoeia (EP) 7.7. Unfortunately, most patents and literature do not mention the residual palladium content of the obtained fosapride dimethylglucamine. There is currently only one patent application WO2012164576A2, which reports that the isolated fushapitate dimethylglucamine contains 30 ppm of palladium. Considering that this patent application is also With a very similar process (Scheme 1) as described in U.S. Patent No. 5,691,336, such levels of palladium can be used as a basis for the palladium content of the produced fosapride dimethylglucamine.

A tri-n-butylphosphine system has been proposed (U.S. Patent No. 7,915,407 B2) to reduce the residual palladium content prior to precipitation of the product. However, the residual palladium content in the produced fosapride dimethylglucamine was still unknown.

As disclosed in the patent application WO2012164576A2, the residual palladium content of the produced fosapride dimethylglucamine can be reduced by the treatment of the remover. The crude product of fosapride dimethylglucamine is prepared according to a similar process (Scheme 1) as described in U.S. Patent No. 5,691,336. The resulting fosapride dimethylglucamine, which yielded 45.8%, contained 30 ppm of palladium. The fosaprepitant dimethoxy dimeglumine crude product was dissolved in methanol, was added remover ^{(10wt%, Silia-DMT ®} ; available from Silicycle Inc.), and stirred at 20-30 ℃ 15 hours. The remover was filtered off, and the filtrate was added to isopropyl alcohol to precipitate a product. The resulting fosapride dimethylglucamine, which has a yield of 80%, contains 2-3 ppm of palladium.

In view of the foregoing prior art, there is still a need for a process capable of reducing the residual palladium content by at least 1 ppm.

First, the present invention provides a method for preparing fosapride dimethylglucamine, comprising: (a) providing a solution of fusapamil dibenzyl ester dissolved in a solvent; (b) in the presence of an amine Hydrogenating from the solution of step (a); (c) adding N-methyl-D-glucosamine to the solution from step (b) to provide fosapride dimethylglucamine.

Secondly, the present invention provides a method for preparing fosapride dimethylglucamine comprising: (a) providing a solution of a fasapride dibenzyl ester dissolved in a solvent; (b) hydrogenating the solution from the step (a) in the presence of a monoamine; (c) adding a remover to the obtained a solution of the step (b); (d) filtering the mixture obtained from the step (c); and (e) adding N-methyl-D-glucosamine to the solution obtained from the step (d) to provide a fusha Pyridinium dimethylamine.

Thirdly, the method further comprises: (f) concentrating the solution obtained from the step (e); (g) adding the solution obtained from the step (f) to a solvent to obtain a mixture, wherein the solvent Is selected from the group consisting of: isopropanol, acetone, acetonitrile, methanol, ethanol, and combinations thereof; and (h) filtering the mixture from step (g) to provide a fosapride dimethyl glucamine, wherein from step (h) The resulting fushapitate dimethylglucamine has a palladium content of less than 0.3 ppm.

The invention will be described in more detail, with the contents of examples and comparative examples provided below.

In a prior study of this case, a similar process as described in U.S. Patent No. 5,691,336 (Scheme 1) will be used. The hydrogenation reaction (about 15 psi) was completed in 16 hours at 20-30 ° C in the presence of 3 wt% 10% Pd/C. After precipitation of the product, the produced fosapride dimethylglucamine, which yielded 88%, had a purity greater than 99% and contained 30.6 ppm of palladium. Attempts to reduce residual palladium content are achieved in accordance with the remover treatment process described in the WO2012164576A2 patent application. Test eight removers (Si-DMT®, Si-Thiol®, Si-Thiourea®, Si-Cysteine®, before product precipitation) Si-TAAcOH®, Si-TAAcONa®, Si-Triamine®, and Si-Imidazole®; remover kits from Silicycle Inc.). After the catalyst was filtered off, a remover (10 wt%) selected from the above components was added to a solution containing fosapride dimethylglucamine at 20-30 °C. This mixture was stirred at 20-30 ° C for about 15 hours. This mixture was filtered to remove the remover, and then the filtrate was added to isopropyl alcohol to precipitate the product. The resulting fosapride dimethylglucamine is isolated in a yield of 78-89%, a purity greater than 99%, and contains 4.8-29.4 ppm palladium. The residual palladium content can be reduced to less than 0.3 ppm by using a large amount of remover (e.g., 30 wt% Si-Thiourea®) at 20-30 ° C and stirring for a long time (e.g., 45 hr). Due to the instability of the product, the yield of fosapride dimethylglucamine was 46.8%. From an industrial point of view, long contact times and poor yields hinder this process.

Here, Applicants disclose a novel process for the preparation of fosapride dimethylglucamine having a residual palladium content of less than 0.3 ppm. A mixture containing fosapride dibenzyl ester, amines, 10% Pd/C, and methanol was hydrogenated at 20-30 ° C for 2 hours (Scheme 2).

A faster reaction rate can be observed by substituting N -methyl-D-glucosamine with an amine. A 3 wt% 10% Pd/C was used in a 15 psi hydrogen atmosphere and the corresponding fosapride diamine salt was produced after 1 hour at 20-30 °C. The amines may be selected from the group consisting of diethylamine, triethylamine, dimethylamine (dissolved in tetrahydrofuran), ammonia (dissolved in ethanol), and methylamine. After the reaction was completed, the mixture was filtered to remove the catalyst (which produced a fosapride diamine salt dissolved in a methanol solution). N -methyl-D-glucosamine was added at 20-30 ° C, and the mixture was stirred at this temperature for 1 hour to achieve an exchange between the amine and N -methyl-D-glucosamine. This solution was added to isopropanol which contributed to the precipitation of the product, followed by obtaining the obtained fosapride dimethylglucamine in a yield of 80-90%, a purity of more than 99%, and containing 10 ppm of palladium.

Another attempt to reduce the palladium content was achieved by adding a remover prior to exchange between the amine and N -methyl-D-glucosamine (Scheme 3).

Schematic 3

In a new round of steps, remove removers (eg 10% by weight of Si-Thiol®) prior to amine exchange. The mixture was stirred at 20-30 ° C for about 15 hours, and then the mixture was filtered to precipitate a product. Fortunately, the produced fosapride dimethylglucamine, which has a yield of 80-90%, contains less than 0.3 ppm of palladium.

Example

The following examples are provided to further describe but not to limit the invention.

Example 1

Adding fosapride dibenzyl ester (2g, 2.52mmole, 1 equiv), triethylamine (0.51g, 5.04mmole, 2 equiv) and methanol (40mL) to a three-necked circle containing a stir bar at 20-30 °C Bottom flask. The mixture was stirred at 20-30 ° C for about 10 minutes to form a homogeneous phase solution. 10% Pd/C (60 mg, 3 wt%) was added, followed by hydrogenation (about 15 psi) at 20-30 ° C for 1 hour. The mixture was filtered through a pad of celite and washed with MeOH (8 mL). Si-Thiol® (0.2 g, 10 wt%) was added to the mixed filtrate and washing solution at 20-30 ° C, and the mixture was stirred at this temperature for about 15 hours. The mixture was filtered and the cake was washed with MeOH (4 mL). N-methyl-D-glucosamine (1.08 g, 5.54 mmole, 2.2 equiv) was added to the mixed filtrate and washings at 20-30 ° C, and the mixture was stirred at this temperature for about 1 hour. The solution was concentrated to a volume of about 10 mL at a temperature of no more than 35 ° C and 20-30 torr. This concentrated solution was added dropwise to isopropyl alcohol (40 mL) at 20-30 ° C, and the resulting mixture was stirred at this temperature for about 1 hour. The mixture was filtered and the filter cake was washed with isopropyl alcohol (10 mL). Fushapirate dimethylglucamine (2.25 g) was obtained in a yield of 90% and a purity greater than 99%, which was a white powder containing less than 0.3 ppm of palladium.

Example 2

A new round of the experiment was carried out by repeating the conditions described in Example 1 except that Si-Thiol ^® (0.4 g, 20 wt%) was used. Fushapirate dimethylglucamine (2.26 g) was obtained in a yield of 90.4% and a purity greater than 99% was a white powder containing less than 0.3 ppm palladium.

Example 3

A new round of the experiment was carried out by repeating the conditions described in Example 1 except that Si-Thiol® (0.6 g, 30 wt%) was used. Fushapirate dimethylglucamine (2.29 g) was obtained in a yield of 91.6% and a purity greater than 99% was a white powder containing less than 0.3 ppm palladium.

Example 4

A new round of the experiment was carried out by repeating the conditions described in Example 1 except that Si-Thiourea® (0.2 g, 10 wt%) was used. Fushapirate dimethylglucamine (2.2 g) was obtained in a yield of 88% and a purity greater than 99% as a white powder containing less than 0.8 ppm palladium.

Example 5

A new round of the experiment was carried out by repeating the conditions described in Example 1 except that Si-Thiourea® (0.4 g, 20% by weight) was used. Fushapirate dimethylglucamine (2.14 g) was obtained in a yield of 85.6% and a purity greater than 99% was a white powder containing less than 0.7 ppm palladium.

Example 6

A new round of the experiment was carried out by repeating the conditions described in Example 1 except that Si-Thiourea® (0.6 g, 30 wt%) was used. Fushapirate dimethylglucamine (2.12 g) was obtained in a yield of 84.8% and a purity greater than 99% was a white powder containing less than 0.7 ppm palladium.

Example 7

Adding fosapride dibenzyl ester (3g, 3.78mmole, 1 equiv), diethylamine (0.55g, 7.56mmole, 2 equiv) and methanol (60mL) to a three-necked circle containing a stir bar at 20-30 °C Bottom flask. The mixture was stirred at 20-30 ° C for about 10 minutes to form a homogeneous phase solution. 10% Pd/C (90 mg, 3 wt%) was added, followed by hydrogenation (about 15 psi) at 20-30 ° C for 1 hour. The mixture was filtered through a pad of celite and washed with MeOH (12 mL). Si-Thiourea ® (0.9 g, 30 wt%) was added to the mixed filtrate and washing solution at 20-30 ° C, and the mixture was stirred at this temperature for about 15 hours. The mixture was filtered and the cake was washed with methanol (12 mL). N-methyl-D-glucosamine (1.62 g, 8.32 mmole, 2.2 equiv) was added to the mixed filtrate and washings at 20-30 ° C, and the mixture was stirred at this temperature for about 1 hour. The solution was concentrated to a volume of about 15 mL at a temperature of no more than 35 ° C and 20-30 torr. Concentrate and dissolve at 20-30 ° C The droplets were added to isopropanol (60 mL), and the resulting mixture was stirred at this temperature for about 1 hour. The mixture was filtered and the cake was washed with isopropyl alcohol (15 mL). Fushapirate dimethylglucamine (3.23 g) was obtained in a yield of 85% and a purity greater than 99% as a white powder containing less than 0.3 ppm palladium.

Comparative Example 1:

Fusapidine dinonyl ester (5 g, 6.29 mmole, 1 equiv) and methanol (37.5 mL) were added to a three-necked round bottom flask containing a stir bar at 20-30 °C. The mixture was stirred at 20-30 ° C for about 10 minutes to form a homogeneous phase solution. After addition of N-methyl-D-glucosamine (2.70 g, 2.2 equiv) and 10% Pd/C (0.15 g, 3 wt%), the mixture was subjected to hydrogenation (about 15 psi) at 20-30 ° C for 16 hours. The mixture was filtered through a pad of celite and washed with MeOH (10 mL). The mixed filtrate and washings are concentrated to a volume of about 20 mL at a temperature of no more than 35 ° C and 20-30 torr. This concentrated solution was added dropwise to isopropyl alcohol (100 mL) at 20-30 ° C, and the resulting mixture was stirred at this temperature for about 1 hour. The mixture was filtered and the filter cake was washed with isopropyl alcohol (10 mL). Fushapirate dimethylglucamine (5.56 g) was obtained in a yield of 88% and a purity greater than 99% as a white powder containing less than 30.6 ppm palladium.

Comparative Example 2:

Fusapamil dibenzyl ester (5 g, 6.29 mmole, 1 equiv) and methanol (37.5 mL) were added to a three-necked round bottom flask containing a stir bar at 20-30 °C. The mixture was stirred at 20-30 ° C for about 10 minutes to form a homogeneous phase solution. After addition of N-methyl-D-glucosamine (2.70 g, 2.2 equiv) and 10% Pd/C (0.15 g, 3 wt%), the mixture was subjected to hydrogenation (about 15 psi) at 20-30 ° C for 16 hours. The mixture was filtered through a pad of celite and washed with MeOH (10 mL). Add Si-Thiol ® (0.5g, 10wt%) to the mixed filtrate and washing solution at 20-30 ° C, then The mixture was stirred at this temperature for about 15 hours. The mixture was filtered and the cake was washed with MeOH (10 mL). The mixed filtrate and washings are concentrated to a volume of about 20 mL at a temperature of no more than 35 ° C and 20-30 torr. This concentrated solution was added dropwise to isopropyl alcohol (100 mL) at 20-30 ° C, and the resulting mixture was stirred at this temperature for about 1 hour. The mixture was filtered and the filter cake was washed with isopropyl alcohol (10 mL). Fushapirate dimethylglucamine (5.61 g) was obtained in a yield of 88.8% and a purity greater than 99% was a white powder containing less than 5.7 ppm palladium.

Comparative Example 3:

A new round of the experiment was carried out by repeating the conditions described in Comparative Example 2, except that Si-Thiourea® (0.5 g, 10 wt%) was used. Fushapirate dimethylglucamine (5.75 g) was obtained in a yield of 91% and a purity greater than 99% as a white powder containing less than 4.8 ppm palladium.

Comparative Example 4:

A new round of examples was carried out by repeating the conditions described in Comparative Example 2, except that Si-DMT® (0.5 g, 10 wt%) was used. Fushapirate dimethylglucamine (5.5 g) was obtained in a yield of 87% and a purity greater than 99% as a white powder containing less than 8.1 ppm palladium.

Comparative Example 5:

A new round of the experiment was carried out by repeating the conditions described in Comparative Example 2, except that Si-Thiourea® (1.5 g, 30 wt%) and a stirring time of 45 hours were used. Fushapirate dimethylglucamine (2.96 g) was obtained in a yield of 46.8% with a purity greater than 99% and was a white powder containing less than 0.3 ppm palladium.

Comparative Example 6:

Adding fosapride dibenzyl ester (2g, 2.52mmole, 1 equiv), triethylamine (0.51g, 5.04mmole, 2 equiv) and methanol (40mL) to a three-necked stirrer at 20-30 °C Round-bottomed flask. The mixture was stirred at 20-30 ° C for about 10 minutes to form a homogeneous phase solution. Add 10% Pd/C (60 mg, 3 wt%), then the mixture was subjected to a hydrogenation reaction (about 15 psi) at 20-30 ° C for 1 hour. The mixture was filtered through a pad of celite and washed with MeOH (8 mL). N-methyl-D-glucosamine (1.08 g, 5.54 mmole, 2.2 equiv) was added to the mixed filtrate and washings at 20-30 ° C, and the mixture was stirred at this temperature for about 1 hour. The solution was concentrated to a volume of about 10 mL at a temperature of no more than 35 ° C and 20-30 torr. This concentrated solution was added dropwise to isopropyl alcohol (40 mL) at 20-30 ° C, and the resulting mixture was stirred at this temperature for about 1 hour. The mixture was filtered and the filter cake was washed with isopropyl alcohol (10 mL). Fushapirate dimethylglucamine (2.11 g) was obtained in a yield of 84.3% and a purity greater than 99% was a white powder containing less than 11 ppm palladium.

Comparative Example 7:

A new round of the procedure was repeated following the conditions described in Comparative Example 7, except that diethylamine (0.37 g, 5.04 mmole, 2 equiv) was used. Fushapirate dimethylglucamine (2.01 g) was obtained in a yield of 80.5% and a purity greater than 99% was a white powder containing less than 12.5 ppm palladium.

Although the foregoing invention has been shown and described with reference In addition, each of the references provided herein is hereby incorporated by reference in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety. This application is in conflict with the reference materials provided herein.

Claims (13)

A method for preparing fosapride dimethylglucamine, comprising: (a) providing a solution of fusapamil dibenzyl ester dissolved in a solvent; (b) hydrogenating from the step of a monoamine (a) And (c) adding N-methyl-D-glucosamine to the solution obtained from step (b) to provide fosapride dimethylglucamine. A method for preparing fosapride dimethylglucamine, comprising: (a) providing a solution of fusapamil dibenzyl ester dissolved in a solvent; (b) hydrogenating from the step of a monoamine (a) a solution of (c) adding a remover to the solution obtained from step (b); (d) filtering the mixture obtained from step (c); and (e) adding N-methyl-D-grape The amine is passed to the solution from step (d) to provide fosapride dimethylglucamine. The method of any one of the preceding claims, wherein the solvent is methanol. The method of any of claims 1 to 2, wherein the amine is selected from the group consisting of methylamine, dimethylamine, diethylamine, triethylamine, ammonia, and combinations thereof. The method of claim 3, wherein the amine is selected from the group consisting of dimethylamine and triethylamine. The method of any one of the preceding claims, wherein the hydrogenating step is operated in the presence of 10% Pd/C. The method of any one of claims 1 or 2, wherein the hydrogenating step is Operate at 20-30 °C. The method of claim 1, wherein the fosapride dimethylglucamine obtained from the method has a palladium content of less than 15 ppm. The method of claim 2, wherein the remover is selected from the group consisting of: Si-DMT ^® , Si-Thiol ^® , Si-Thiourea ^® , Si-Cysteine ^® , Si-TAAcOH ^® , Si-TAAcONa ^® , Si-Triamine ^® , Si-Imidazole ^® and combinations thereof. The method of claim 2, wherein the fosapride dimethylglucamine obtained from the method has a palladium content of less than 2 ppm. The method of claim 10, wherein the fosapride dimethylglucamine obtained from the method has a palladium content of less than 1 ppm. The method of claim 11, wherein the fosapride dimethylglucamine obtained from the method has a palladium content of less than 0.5 ppm. The method of claim 2, further comprising: (f) concentrating the solution obtained from the step (e); (g) adding the solution from the step (f) to a solvent to obtain a mixture Wherein the solvent is selected from the group consisting of: isopropanol, acetone, acetonitrile, methanol, ethanol, and combinations thereof; and (h) filtering the mixture from step (g) to provide a fosapride dimethylglucamine, wherein The fosapride dimethylglucamine obtained after the step (h) has a palladium content of less than 0.3 ppm.