Process for preparation of ipragliflozin and salts thereof

Abstract

The invention discloses an improved method for preparing ipragliflozin and salts thereof. More specifically, the present invention discloses the chiral resolution of racemic ipragliflozin and its salts, which is industrially advantageous and economically important.

Description

Technical Field

[0001] The present invention relates to an improved process for preparing ipraglimine and its salts. More specifically, the present invention relates to the chiral resolution of racemic ipraglimine and its salts, which is industrially advantageous and economically important. Background Art

[0002] Imeglimin has a chemical name of (6R)-(+)-4-dimethylamino-2-imino-6-methyl-1,2,5,6-tetrahydro-1,3,5-triazine hydrochloride, and has a structural compound of formula (I).

[0003]

[0004] Igligram was originally discovered by Poxel and developed in collaboration with Dainippon Sumitomo Pharma Co., Ltd. in Japan. The brand is marketed for the treatment of type 2 diabetes. Igliflozin was first approved for the treatment of type 2 diabetes in Japan on June 23, 2021. Igliflozin is undergoing Phase 3 clinical trials in the United States and Europe.

[0005] US7034021B2 first disclosed ipraglimine. In addition, US7034021B2 did not disclose the preparation method of ipraglimine by any specific example. US7501511B2 (hereinafter referred to as US'511) discloses a separation method for preparing ipraglimine hydrochloride, which includes reacting racemic ipraglimine free base with (-)-di-O, O'-p-tolyl-L-tartaric acid in an alcohol solvent, then filtering and recrystallizing from a DMF / ethanol mixture to obtain the corresponding tartrate of the compound of formula (VII), with a yield of 33% and a chiral purity of 70% ee. The tartrate is dissolved in a water / ethyl acetate mixture and then treated with hydrochloric acid. The product is recovered from the aqueous phase by recrystallization in ethanol to obtain the compound ipraglimine hydrochloride of formula (I), which is a white powder with a total yield of 10%. The organic phase is recovered to recover (-)-di-O, O'-p-tolyl-L-tartaric acid.

[0006] The schematic diagram of the ipraglimin hydrochloride process disclosed in US'511 is shown in Scheme-I below.

[0007]

[0008] Solution-I

[0009] The process disclosed in US'511 has several disadvantages, such as low yield and low chiral purity. In addition, many impurities are generated during the process, which are carried into the final material (API), i.e., ipraglimin hydrochloride.

[0010] US8742103B2 (hereinafter referred to as US'103) discloses a method for preparing ipraglimin hydrochloride, which comprises reacting a compound of formula (II) with a compound of formula (III) in a solvent in the presence of p-toluenesulfonic acid (PTSA) to obtain a racemic compound of formula (IV). Further, the racemic compound of formula (IV) reacts with L(+)-tartaric acid to obtain (+)ipraglimin-L-tartrate in a yield of 40-45%. The separated tartrate diastereomers are further converted into hydrochloride in a yield of 50-55%, and then the tartrate of (+)ipraglimin is recovered from the mother liquor.

[0011] The schematic diagram of the process flow of iplagetamine hydrochloride disclosed in US'103 is shown in Scheme-II below.

[0012]

[0013] The main disadvantage of the ipraglimin hydrochloride process disclosed in US'103 is that it results in a very low yield, i.e., 40-45%, and there is no mention of the chiral purity of ipraglimin tartrate. Another disadvantage of the ipraglimin hydrochloride process disclosed in US'103 is the final ipraglimin hydrochloride yield, which is in the range of 50-55%, followed by an additional step of recovering ipraglimin tartrate from the mother liquor, which is not suitable for large-scale industrial production.

[0014] As is evident from the above, all the prior art techniques discussed above suffer from numerous disadvantages such as incomplete reactions, lengthy and cumbersome process handling procedures, additional steps for recovery from mother liquors, higher temperature conditions, longer reaction times, use of excess reagents and solvents, which affect the overall yield as well as the quality of the final product.

[0015] Therefore, there is still a need in the art for an improved method for preparing ipraglimin hydrochloride with high chiral purity and high yield to overcome the shortcomings of the prior art methods. In order to achieve the above-mentioned object, the inventors surprisingly found an effective method for preparing ipraglimin hydrochloride, which provides great advantages over the prior art methods in terms of high yield, high chiral purity and less effluent, and the method is simple, scalable, and suitable for large-scale industrial production of ipraglimin hydrochloride. Summary of the invention

[0016] The main object of the present invention is to provide a method for preparing ipaglinamine hydrochloride compound of formula (I), which achieves high yield and high chiral purity by isolating ipaglinamine hydrochloride in one batch and avoiding recovery from mother liquor.

[0017] Another object of the present invention is to provide a method for preparing an ipraglimine hydrochloride compound of formula (I), by treating it with a suitable chiral amino acid or its derivative to split the racemic ipraglimine base compound of formula (III) to obtain an R-ipraglimine-L-amino acid salt of formula (IV), which has a high yield, a chiral purity greater than 99.85%, and an HPLC purity greater than 99.5%, and then treating it with hydrochloric acid to obtain R-ipraglimine hydrochloride.

[0018] To achieve the above object, the present invention provides a method for preparing an ipraglamine hydrochloride compound of formula (I), the method comprising:

[0019] a) reacting a compound of formula (II) with a compound of formula (III) in a solvent under appropriate conditions in the presence of p-toluenesulfonic acid monohydrate,

[0020]

[0021] The racemic compound of formula (IV) is obtained.

[0022]

[0023] b) reacting the racemic compound of formula (IV) with a suitable chiral amino acid or its derivative in the presence of a base and a solvent to obtain an R-ipilimin-L-amino acid salt compound of formula (V),

[0024]

[0025] c) reacting the compound of formula (V) with hydrochloric acid in the presence of a solvent to obtain ipraglimine hydrochloride of formula (I), and d) optionally purifying the ipraglimine hydrochloride of formula (I) obtained in step (c) using an alcohol solvent.

[0026] On the other hand, the present invention provides a method for preparing an ipaglinamine hydrochloride compound of formula (I) by resolving racemic ipaglinamine base (IV) or an ipaglinamine hydrochloride compound of formula (IV), the method comprising the following steps:

[0027] a) reacting a racemic compound of formula (IV) or a compound of formula (VI) with a suitable chiral amino acid or a derivative thereof in the presence or absence of a base and in the presence of a solvent to obtain an R-ipraglimin-L-amino acid salt compound of formula (V);

[0028]

[0029] b) reacting the compound of formula (V) with hydrochloric acid in the presence of a solvent to obtain ipraglimine hydrochloride of formula (I), and c) optionally purifying the ipraglimine hydrochloride of formula (I) obtained in step (b) using an alcohol solvent. DETAILED DESCRIPTION

[0030] In an attempt to develop an improved process for preparing ipraglimin hydrochloride and overcome the disadvantages of the prior art, the present inventors have developed a process for obtaining ipraglimin hydrochloride with high chirality, HPLC purity and good yield.

[0031] The present invention provides a method for preparing an ipraglamine hydrochloride compound of formula (I), the method comprising:

[0032] a) reacting a compound of formula (II) with a compound of formula (III) in a solvent under appropriate conditions in the presence of p-toluenesulfonic acid monohydrate,

[0033]

[0034]

[0035] The racemic compound of formula (IV) is obtained.

[0036]

[0037] b) reacting the racemic compound of formula (IV) with a suitable chiral amino acid or its derivative in the presence of a base and a solvent to obtain an R-ipilimin-L-amino acid salt compound of formula (V),

[0038]

[0039] c) reacting the compound of formula (V) with hydrochloric acid in the presence of a solvent to obtain ipraglimine hydrochloride of formula (I), and d) optionally purifying the ipraglimine hydrochloride of formula (I) obtained in step (c) using an alcohol solvent.

[0040] In an embodiment of step a), the solvent is selected from C1-C4 alcohols, preferably methanol, ethanol, isopropanol, isobutanol, water and mixtures thereof; more preferably, the solvent is isobutanol.

[0041] In an embodiment of step b), the chiral amino acid is selected from L-glutamic acid, N-tosyl-L-glutamic acid, L-alanine, L-aspartic acid, L-leucine, L-phenylalanine, L-tyrosine, and L-valine.

[0042] In an embodiment of step b), the solvent is selected from C1-C4 alcohols, preferably methanol, ethanol, isopropanol, isobutanol and mixtures thereof; the base is an organic base such as triethylamine, or an inorganic base such as sodium hydroxide.

[0043] In step c) of the embodiment, the solvent is selected from C1-C4 alcohols, preferably methanol, ethanol, isopropanol, isobutanol and mixtures thereof, or C1-C5 ketones, preferably acetone, methyl ethyl ketone.

[0044] In step d) of this embodiment, the solvent is selected from C1-C4 alcohols, preferably methanol, ethanol, isopropanol, isobutanol, water and mixtures thereof; more preferably, the solvent is a mixture of methanol and isopropanol.

[0045] In a preferred example, the chiral amino acid is selected from L-glutamic acid or its derivatives, such as N-toluenesulfonyl-L-glutamic acid or N-sulfonyl-L-glutamic acid.

[0046] Accordingly, the method for preparing the ipraglimin hydrochloride compound of formula (I) using L-amino acid or its derivatives as chiral resolving agent is illustrated in Scheme III below.

[0047] Scheme III

[0048]

[0049] The starting materials of the present invention, the compound of formula (II), metformin hydrochloride, and the compound of formula (III), are commercially available.

[0050] Therefore, in one embodiment, the present invention provides a method for preparing the ipraglimin hydrochloride compound of formula (I).

[0051]

[0052] The following steps are involved:

[0053] a) reacting a compound of formula (II) with a compound of formula (III) in a solvent under appropriate conditions in the presence of p-toluenesulfonic acid monohydrate

[0054]

[0055] The racemic compound of formula (IV) is obtained.

[0056]

[0057] b) reacting the racemic compound of formula (IV) with L-glutamic acid or a derivative thereof in the presence of a base and a solvent to obtain a compound of formula (V),

[0058]

[0059] c) reacting the compound of formula (V) with hydrochloric acid in the presence of a solvent to obtain ipraglimine hydrochloride of formula (I), and d) optionally purifying the ipraglimine hydrochloride of formula (I) obtained in step (c) using an alcohol solvent.

[0060] In a preferred embodiment, the chiral amino acid is selected from L-glutamic acid or its derivatives, such as N-toluenesulfonyl-L-glutamic acid or N-sulfonyl-L-glutamic acid.

[0061] Accordingly, the method for preparing the ipraglimin hydrochloride compound of formula (I) using L-glutamic acid or its derivatives as a chiral resolving agent is illustrated in Scheme IV below.

[0062] Scheme IV

[0063]

[0064] In another embodiment, the present invention provides a method for preparing the ipraglimine hydrochloride compound of formula (I) by splitting the racemic ipraglimine base compound of formula (IV) or racemic ipraglimine hydrochloride (VI), the method comprising the following steps:

[0065] a) reacting a racemic compound of formula (IV) or a compound of formula (VI) with a suitable chiral amino acid or a derivative thereof in the presence or absence of a base and in the presence of a solvent to obtain an R-ipraglimin-L-amino acid salt compound of formula (V);

[0066]

[0067] b) reacting the compound of formula (V) with hydrochloric acid in the presence of a solvent to obtain ipraglimine hydrochloride of formula (I), and c) optionally purifying the ipraglimine hydrochloride of formula (I) obtained in step (b) using an alcohol solvent.

[0068] In an embodiment of step a), the chiral amino acid is selected from L-glutamic acid, N-tosyl-L-glutamic acid, L-alanine, L-aspartic acid, L-leucine, L-phenylalanine, L-tyrosine, and L-valine.

[0069] In an embodiment of step a), the solvent is selected from acetonitrile, C1-C4 alcohols, preferably methanol, ethanol, isopropanol, isobutanol and mixtures thereof.

[0070] In step b) of the embodiment, the solvent is selected from C1-C4 alcohols, preferably methanol, ethanol, isopropanol, isobutanol and mixtures thereof, or C1-C5 ketones, preferably acetone, methyl ethyl ketone.

[0071] In step c) of this embodiment, the solvent is selected from C1-C4 alcohols, preferably methanol, ethanol, isopropanol, isobutanol, water and mixtures thereof; more preferably, the solvent is a mixture of methanol and isopropanol.

[0072] Accordingly, the method for preparing the ipraglimine hydrochloride compound of formula (I) by resolving the racemic ipraglimine base compound of formula (IV) or the ipraglimine hydrochloride compound of formula (VI) using L-glutamic acid or its derivatives as a chiral resolving agent is illustrated in Scheme V below.

[0073] Plan V:

[0074]

[0075] Example:

[0076] The following examples illustrate some embodiments of the invention described herein. These examples should not be construed as limiting the spirit or scope of the invention in any way.

[0077] Example 1: Synthesis of racemic ipraglimine hydrochloride

[0078] Metformin hydrochloride (100 g) was suspended in isobutyl alcohol (400 ml), and acetaldehyde diethyl acetal (85.94 g) and p-toluenesulfonic acid (11.52 g) were added to the suspension. The suspension was heated to reflux until a clear solution was obtained. After the reaction was completed, part of the solvent was distilled. The suspension was cooled to 10-20 ° C and stirred for 2 hours. The solid was separated by filtration and washed with isobutyl alcohol (50 ml). The solid was dried to obtain racemic ipraglimine hydrochloride (100 g).

[0079] Example 2: Chiral resolution of racemic ipraglimine hydrochloride to obtain (R)-ipraglimine-L-glutamate

[0080] Racemic ipraglimine hydrochloride (20 g) and L-glutamic acid (15.4 g) were added to methanol (250 ml) at 20-35°C. Triethylamine (10.6 g) was added and the suspension was heated to 55-60°C and stirred for 2 hours. The suspension was cooled to room temperature, seeded with a small amount of R-ipraglimine-L-glutamate, and stirred overnight to obtain a solid. The reaction mass was cooled to 5-10°C and stirred for 2 hours. The white crystals obtained were separated by filtration and washed with methanol (10 ml). The solid was dried to obtain R-(+)-ipraglimine-L-glutamate (15.3 gm).

[0081] Purity: HPLC 99.70%

[0082] Example 3: Resolution of racemic ipraglimine hydrochloride

[0083] At 20-35 ° C, racemic ipraglimine hydrochloride (20 g) and N-tosyl-L-glutamic acid (31.54 g) were dissolved in methanol (50 ml), and triethylamine (10.59 g) was added under the condition of less than 30 ° C. The suspension was heated to 55-60 ° C and stirred for 2.0 hours. The suspension was cooled to room temperature. The suspension was inoculated with R-ipraglimine-N-tosyl-L-glutamate. The solution was stirred for 6 hours, and the reaction mass was cooled to 5-10 ° C for 2.0 hours to obtain a solid. The white crystals thus obtained were separated by filtration and washed with methanol (5 ml). The solid was dried to obtain R-ipraglimine-N-tosyl-L-glutamate (20 g).

[0084] Purity: HPLC 99.95%

[0085] Example 4: Resolution of racemic ipraglimine hydrochloride

[0086] At 20-35°C, racemic ipraglimine hydrochloride (70 g) and N-tosyl-L-glutamic acid (110.42 g) were added to acetonitrile (700 ml). Triethylamine (37.08 g) was added at less than 30°C. The suspension was heated to 60-65°C and water (35 ml) was added. The reaction mass was stirred for 2.0 hours and cooled to room temperature. The white crystals were separated by filtration and washed with acetonitrile (35 ml), and the wet cake was further purified in a mixture of acetonitrile and water. The solid thus obtained was dried to obtain (82.6 g) R-ipraglimine-N-tosyl-L-glutamate.

[0087] Purity: HPLC 99.95%

[0088] Example 5: Preparation of R-Iglinamine Hydrochloride from (R)-Iglinamine-Toluenesulfonyl-L-Glutamic Acid

[0089] Igliflozin-N-tosyl-L-glutamate (80 g) was suspended in acetone (400 ml) and IPA.HCl (84 g) was added. The suspension was heated to reflux for 2.0 hours, cooled to room temperature and stirred for 2 hours. The solid was filtered and washed with acetone (80 ml). The solid was dried to obtain a crude product (R)-Igliflozin hydrochloride (32.0 g).

[0090] Purity: HPLC 99.5%

[0091] Example 6: Preparation of R-Iglinamine Hydrochloride from (R)-Iglinamine-N-Toluenesulfonyl-L-Glutamic Acid

[0092] Iraglimin-N-tosyl-L-glutamate (20 g) was suspended in acetone (100 ml) to which concentrated hydrochloric acid (4.8 g) was added. The suspension was heated to reflux for 2.0 hours and cooled to room temperature. Stirred for 2 hours. The solid was filtered and washed with acetone (80 ml). The solid was dried to obtain a crude product (R)-Iraglimin hydrochloride (7.4 g).

[0093] Purity: HPLC 99.5%

[0094] Example 7: Purification of (R)-Igliptin Hydrochloride

[0095] At 55-60°C, the crude (R)-Igliptin hydrochloride (10.0 g) was dissolved in methanol (20 ml). The clear solution was filtered and the solvent was distilled off to obtain a suspension. IPA (50 ml) was added and heated to 55-60°C. Stir for 1.0 hour and cool to room temperature. The solid was filtered and washed with IPA (10 ml). The solid was dried to obtain pure (R)-Igliptin hydrochloride (8.5 g).

[0096] Purity: HPLC 99.99%, specific rotation = +5.3°

[0097] Example 8: Preparation of racemic ipraglimine base from ipraglimine hydrochloride

[0098] Racemic ipraglimine hydrochloride (25 g) was reacted with sodium methoxide (7.04 g) in methanol (100 ml) at room temperature. The salt was removed by filtration. The methanol as the filtrate was collected and distilled off to obtain ipraglimine base (19 g).

[0099] Example 9: Resolution of racemic ipraglimine base

[0100] At 50-55°C, racemic ipraglimin (18 g) and N-tosyl-L-glutamic acid (34.87 g) were added to acetonitrile (90 ml). The mixture was stirred for 2 hours, and the white crystals were separated by filtration and washed with acetonitrile (18 ml). The obtained solid was dried to obtain R-ipraglimin-N-tosyl-L-glutamate (22.0 g).

[0101] Example 10: Preparation of R-Iglinamine Hydrochloride from (R)-Iglinamine-N-Toluenesulfonyl-L-Glutamic Acid

[0102] The ilpatrimon-N-tosyl-L-glutamate (20 g) obtained from Example 9 was suspended in acetone (100 ml) and IPA.HCl (21.0 g) was added. The suspension was heated to reflux for 2.0 hours, cooled to room temperature and stirred for 2 hours. The solid was filtered and washed with acetone (20 ml). The solid was dried to obtain crude (R) ilpatrimon hydrochloride (8.0 g).

[0103] Purity: HPLC 99.5%.

Claims

1. A method for preparing an ipaglinamine hydrochloride compound represented by formula (I), characterized in that: The method comprises: a) reacting a compound of formula (II) with a compound of formula (III) in a solvent under appropriate conditions in the presence of p-toluenesulfonic acid monohydrate, The racemic compound of formula (IV) is obtained. b) reacting the racemic compound of formula (IV) with a suitable chiral amino acid or its derivative in the presence of a base and a solvent to obtain an R-ipilimin-L-amino acid salt compound of formula (V), c) reacting the compound of formula (V) with hydrochloric acid in the presence of a solvent to obtain ipraglimine hydrochloride of formula (I), and d) optionally purifying the ipaglimine hydrochloride of formula (I) obtained in step (c) using an alcohol solvent.

2. A method for preparing an ipaglinamine hydrochloride compound of formula (I) by resolving racemic ipaglinamine base or ipaglinamine hydrochloride, characterized in that: The method comprises the following steps: a) reacting a racemic compound of formula (IV) or a compound of formula (VI) with a suitable chiral amino acid or a derivative thereof in the presence or absence of a base and in the presence of a solvent to obtain an R-ipraglimin-L-amino acid salt compound of formula (V); b) reacting the compound of formula (V) with hydrochloric acid in the presence of a solvent to obtain ipraglimine hydrochloride of formula (I), c) optionally purifying the ipraglimin hydrochloride of formula (I) obtained in step (b) using an alcohol solvent.

3. The method according to claim 1, characterized in that in, The solvent used in step a) is selected from C1-C4 alcohols, preferably methanol, ethanol, isopropanol, isobutanol, water and mixtures thereof; more preferably, the solvent is isobutanol.

4. The method according to claim 1 or 2, characterized in that: in, The chiral amino acid is selected from L-glutamic acid, N-tosyl-L-glutamic acid, L-alanine, L-aspartic acid, L-leucine, L-phenylalanine, L-tyrosine and L-valine.

5. The method according to claim 1 or 2, characterized in that: in, The solvent used in the chiral resolution step is selected from acetonitrile, C1-C4 alcohol, preferably methanol, ethanol, isopropanol, isobutanol and mixtures thereof.

6. The method according to claim 1 or 2, characterized in that: in, The solvent used for the reaction of the compound of formula (V) with hydrochloric acid is selected from C1-C4 alcohols, preferably methanol, ethanol, isopropanol, isobutanol and mixtures thereof, or C1-C5 ketones, preferably acetone or methyl ethyl ketone.

7. The method according to claim 1 or 2, characterized in that: in, The solvent used for purifying ipraglimin hydrochloride of formula (I) is selected from C1-C4 alcohols, preferably methanol, ethanol, isopropanol, isobutanol, water and mixtures thereof; more preferably, the solvent is a mixture of methanol and isopropanol.

8. The method according to claim 1 or 2, characterized in that: in, The chiral amino acid is L-glutamic acid or its derivatives.

9. The method according to claim 8, characterized in that in, The L-glutamic acid derivative is selected from N-tosyl-L-glutamic acid or N-sulfonyl L-glutamic acid.

10. The method for preparing the ipraglamine hydrochloride compound of formula (I) according to claim 1, characterized in that: The method comprises the following steps: a) reacting a compound of formula (II) with a compound of formula (III) in a solvent in the presence of p-toluenesulfonic acid monohydrate under appropriate conditions, The racemic compound of formula (IV) is obtained. b) reacting the racemic compound of formula (IV) with L-glutamic acid or a derivative thereof in the presence of a base and a solvent to obtain a compound of formula (V); c) reacting the compound of formula (V) with hydrochloric acid in the presence of a solvent to obtain ipraglimine hydrochloride of formula (I), and d) optionally purifying the ipaglimine hydrochloride of formula (I) obtained in step (c) using an alcohol solvent.

11. The method according to claim 10, characterized in that in, The L-glutamic acid derivative is selected from N-tosyl-L-glutamic acid or N-sulfonyl-L-glutamic acid.

Images