Preparation method of citric acid ixazomib intermediate

Abstract

The invention provides a preparation method of an ixazomib citrate intermediate compound, which comprises the following step: in the presence of a triazine condensing agent, reacting a compound shown as a formula I with a compound shown as a formula II or a salt thereof in an organic solvent to prepare a compound shown as a formula III. The method is simple in reaction operation, high in raw material conversion rate, simple in post-treatment, less in three wastes, low in EHS risk and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis, specifically relating to a method for preparing an ixazomib citrate intermediate. Background Technology

[0002] Ixazomib citrate is a third-generation protease inhibitor developed by Takeda Pharma of Japan, following bortezomib and carfilzomib. In 2015, it was approved by the U.S. Food and Drug Administration (FDA) for use in combination with lenalidomide and dexamethasone to treat multiple myeloma that has received at least one prior therapy. Its brand name is Ninlaro.

[0003] Ixazomib citrate, chemically named 2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo-1,3,2-dioxoboronyl-4,4-diacetic acid, has the following chemical structure:

[0004] Patent US8859504B2 discloses a method for synthesizing ixazomib citrate, the reaction formula of which is as follows:

[0005] Patent CN106608883A reports another method for synthesizing ixazomib citrate, with the following reaction formula:

[0006] Both of the aforementioned different process routes use a common intermediate, 2,5-dichlorobenzoylglycine (Int1), which is then used to prepare ixazomib citrate via direct condensation or condensation followed by hydrolysis. Since 2,5-dichlorobenzoyl chloride is unstable and must be prepared in-house, condensation followed by hydrolysis is currently the common method for preparing the ixazomib citrate intermediate Int1. The condensing agents used include DCC / HOBT, TBTU, EDC / HOBT, HBTU, HCTU, TCTU, HATU, or PyBOP. However, some problems still exist when using this method for large-scale production. The post-processing of the above condensation system is cumbersome, usually requiring multiple acid-base extraction, concentration, and crystallization operations, generating a large amount of waste and resulting in low yield. The above condensation system can introduce potentially genotoxic impurities such as 1,1,3,3-tetramethylurea, HMPA, and other hydrazine-derived impurities, increasing quality risks. The impurities DCU, HOBt, polysubstituted phosphoramide impurities, and other urea-derived impurities generated by the above condensation system are difficult to remove, usually requiring multiple recrystallizations, which increases the complexity of the process and production costs.

[0007] Therefore, it is of great significance to develop a method for preparing ixazomib citrate intermediates that is low in cost, simple in post-processing, produces less waste, has a high yield, and is suitable for industrial production. Summary of the Invention

[0008] This invention provides a method for preparing an intermediate compound of formula III, namely ixazomib citrate.

[0009] The present invention provides a method for preparing the intermediate compound of formula III of ixazomib citrate, characterized in that the compound of formula I is reacted with the compound of formula II or its salt in an organic solvent in the presence of a triazine condensing agent and optionally an organic base to prepare the compound of formula III; the reaction formula of the method is as follows: , Where R 1 For H, Li, Na, or K; R 2 It can be H, aliphatic hydrocarbon group or aromatic hydrocarbon group.

[0010] Furthermore, in the preparation method of the present invention described above, the molar ratio of the condensing agent to the compound of formula I is (1.00~3.00):1, preferably (1.00~2.00):1.

[0011] Further, in the preparation method of the present invention described above, the triazine condensing agent is selected from 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM) and its hydrate, 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine tetrafluoroborate and its hydrate, 2,4,6-triazine... One or more of 1,3,5-triazine, 2-methoxy-4,6-dichloro-1,3,5-triazine, 4,6-dibenzyloxy-2-chloro-1,3,5-triazine and 4,6-diphenoxy-2-chloro-1,3,5-triazine, preferably 2-chloro-4,6-dimethoxy-1,3,5-triazine or 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine hydrochloride and their hydrates.

[0012] In some embodiments, in the preparation method of the present invention described above, the triazine condensing agent is selected from one or more of 2-chloro-4,6-dimethoxy-1,3,5-triazine, 2,4,6-trichloro-1,3,5-triazine, 2-methoxy-4,6-dichloro-1,3,5-triazine, 4,6-dibenzyloxy-2-chloro-1,3,5-triazine, and 4,6-diphenoxy-2-chloro-1,3,5-triazine, preferably 2-chloro-4,6-dimethoxy-1,3,5-triazine; the molar ratio of the organic base to the compound of formula I is (1.00~5.00):1, preferably (1.00~3.00):1. Further, the organic base is selected from one or more of triethylamine, diethylamine, diisopropylethylamine, N-methylmorpholine, N-methylcyclohexylamine, and pyridine, preferably N-methylmorpholine.

[0013] In some embodiments, in the preparation method of the present invention described above, when the triazine condensing agent is 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride and its hydrate or 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine tetrafluoroborate and its hydrate, an organic base may or may not be present.

[0014] Furthermore, in the preparation method of the present invention described above, the volume-to-mass ratio (mL / g) of the organic solvent to the compound of formula I is (3~30):1, preferably (4~20):1.

[0015] Furthermore, in the preparation method of the present invention described above, the organic solvent is selected from one or more of dichloromethane, ethyl acetate, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide, preferably N,N-dimethylformamide.

[0016] Furthermore, in the preparation method of the present invention described above, the molar ratio of compound II or its salt to compound I is (1.00~3.00):1, preferably (1.00~2.00):1.

[0017] Furthermore, in the preparation method of the present invention described above, the reaction temperature is -30~40℃, preferably -10~30℃.

[0018] Furthermore, in the preparation method of the present invention described above, the R... 2 It is selected from hydrogen, methyl, ethyl, tert-butyl, n-butyl, benzoyl and benzyl, preferably methyl or ethyl.

[0019] Furthermore, in the preparation method of the present invention described above, the salt of the compound of formula II is selected from hydrochloride, trifluoroacetate, sulfate and sulfonate, preferably hydrochloride.

[0020] This invention provides a method for preparing an ixazomib citrate intermediate, using triazine condensing agents such as 2-chloro-4,6-dimethoxy-1,3,5-triazine, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine hydrochloride and its hydrate. The condensing agents in this method are inexpensive and readily available, reducing production costs. Furthermore, the method features simple reaction operation, mild process, and environmentally friendly reaction conditions. Simultaneously, the reaction yield is high, the purity of the obtained product is high (purity > 98%), and the post-processing is simple, significantly reducing waste and making it suitable for industrial production. Detailed Implementation

[0021] The present invention will be further illustrated below with reference to specific embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and protection of the technical solutions of the present invention. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products.

[0022] Example 1 10.00 g of 2,5-dichlorobenzoic acid, 14.61 g of glycine ethyl ester hydrochloride, 10.11 g of CDMT, and 100 mL of DMF were added to a reaction flask. The mixture was stirred and the temperature was maintained at -10 to 0 °C. 15.89 g of NMM was added dropwise, and the reaction was kept at this temperature for 1 h. After the reaction was complete, the reaction solution was added dropwise to 4500 mL of purified water to crystallize. The crystals were filtered and dried under reduced pressure to obtain 13.17 g of compound III, an off-white solid, with a yield of 91.11% and a chromatographic purity of 99.57%.

[0023] The product of this embodiment was detected using an HPLC-PDA detector under the following chromatographic conditions: Instrument: HPLC-PDA detector (Labsolution CS workstation); Column: CORTECS C18 (4.6 mm × 150 mm, 2.7 μm); Detection wavelength: 225nm; Injection volume: 5 μl; Flow rate: 1.0 ml / min; Column temperature: 25℃; Sample inlet temperature: 5℃; Test sample concentration: 1 mg / ml; Mobile phase A: formic acid-water (0.05:100); Mobile phase B: formic acid-acetonitrile (0.02:100); Elution gradient:

[0024] Example 2 10.00 g of 2,5-dichlorobenzoic acid, 7.31 g of glycine ethyl ester hydrochloride, 18.38 g of CDMT, and 40 mL of DMF were added to a reaction flask. The mixture was stirred and the temperature was maintained at 0–10 °C. 15.89 g of NMM was added dropwise, and the reaction was maintained at this temperature for 1 h. After the reaction was complete, the reaction solution was added dropwise to 4500 mL of purified water to induce crystallization. The crystals were filtered and dried under reduced pressure to obtain 13.08 g of compound III, an off-white solid, with a yield of 90.49% and a chromatographic purity of 98.68%.

[0025] Example 3 10.00 g of 2,5-dichlorobenzoic acid, 7.67 g of glycine ethyl ester hydrochloride, 9.19 g of CDMT, and 40 mL of DMF were added to a reaction flask. The mixture was stirred and the temperature was maintained at 10–20 °C. 13.24 g of NMM was added dropwise, and the reaction was kept at this temperature for 1 h. After the reaction was complete, the reaction solution was added dropwise to 4500 mL of purified water to crystallize. The crystals were filtered and dried under reduced pressure to obtain 13.11 g of compound III, an off-white solid, with a yield of 90.69% and a chromatographic purity of 98.35%.

[0026] Example 4 10.00 g of 2,5-dichlorobenzoic acid, 9.50 g of glycine ethyl ester hydrochloride, 10.11 g of CDMT, and 200 mL of DMF were added to a reaction flask. The mixture was stirred and the temperature was maintained at 20–30 °C. 13.24 g of NMM was added dropwise, and the reaction was kept at this temperature for 1 h. After the reaction was complete, the reaction solution was added dropwise to 4500 mL of purified water to crystallize. The crystals were filtered and dried under reduced pressure to obtain 13.25 g of compound III, an off-white solid, with a yield of 91.66% and a chromatographic purity of 99.70%.

[0027] Example 5 10.00 g of 2,5-dichlorobenzoic acid, 7.67 g of glycine ethyl ester hydrochloride, 9.19 g of CDMT, and 80 mL of DMF were added to a reaction flask. The mixture was stirred and the temperature was maintained at 0–10 °C. 5.30 g of NMM was added dropwise, and the reaction was kept at this temperature for 1 h. After the reaction was complete, the reaction solution was added dropwise to 4500 mL of purified water to crystallize. The crystals were filtered and dried under reduced pressure to obtain 13.02 g of compound III, an off-white solid, with a yield of 90.07% and a chromatographic purity of 99.15%.

[0028] Example 6 10.00 g of 2,5-dichlorobenzoic acid, 6.57 g of glycine methyl ester hydrochloride, 10.11 g of CDMT, and 80 mL of DMF were added to a reaction flask. The mixture was stirred and the temperature was maintained at 0–10 °C. 13.24 g of NMM was added dropwise, and the reaction was kept at this temperature for 1 h. After the reaction was complete, the reaction solution was added dropwise to 4500 mL of purified water to crystallize. The crystals were filtered and dried under reduced pressure to obtain 12.51 g of compound III, an off-white solid, with a yield of 91.17% and a chromatographic purity of 99.37%.

[0029] Example 7 10.00 g of 2,5-dichlorobenzoic acid, 13.15 g of glycine methyl ester hydrochloride, 18.38 g of CDMT, and 200 mL of DMF were added to a reaction flask. The mixture was stirred and the temperature was maintained at 10–20 °C. 15.89 g of NMM was added dropwise, and the reaction was maintained at this temperature for 1 h. After the reaction was complete, the reaction solution was added dropwise to 4500 mL of purified water to crystallize. The crystals were filtered and dried under reduced pressure to obtain 12.49 g of compound III, an off-white solid, with a yield of 91.03% and a chromatographic purity of 99.21%.

[0030] Example 8 10.31 g of lithium 2,5-dichlorobenzoate, 7.67 g of glycine ethyl ester hydrochloride, 10.11 g of CDMT, and 80 mL of DMF were added to a reaction flask. The mixture was stirred and the temperature was maintained at 0–10 °C. 13.24 g of NMM was added dropwise, and the reaction was maintained at this temperature for 1 h. After the reaction was complete, the reaction solution was added dropwise to 4500 mL of purified water to crystallize. The crystals were filtered and dried under reduced pressure to obtain 12.93 g of compound III, an off-white solid, with a yield of 89.45% and a chromatographic purity of 99.23%.

[0031] Example 9 11.15 g of sodium 2,5-dichlorobenzoate, 7.67 g of glycine ethyl ester hydrochloride, 10.11 g of CDMT, and 80 mL of DMF were added to a reaction flask. The mixture was stirred and the temperature was maintained at 0–10 °C. 13.24 g of NMM was added dropwise, and the reaction was kept at this temperature for 1 h. After the reaction was complete, the reaction solution was added dropwise to 4500 mL of purified water to crystallize. The crystals were filtered and dried under reduced pressure to obtain 13.09 g of compound III, an off-white solid, with a yield of 90.56% and a chromatographic purity of 99.51%.

[0032] Example 10 11.99 g of potassium 2,5-dichlorobenzoate, 7.67 g of glycine ethyl ester hydrochloride, 10.11 g of CDMT, and 80 mL of DMF were added to a reaction flask. The mixture was stirred and the temperature was maintained at 0–10 °C. 13.24 g of NMM was added dropwise, and the reaction was maintained at this temperature for 1 h. After the reaction was complete, the reaction solution was added dropwise to 4500 mL of purified water to crystallize. The crystals were filtered and dried under reduced pressure to obtain 13.05 g of compound III, an off-white solid, with a yield of 90.31% and a chromatographic purity of 99.34%.

[0033] Example 11 10.00 g of 2,5-dichlorobenzoic acid, 7.67 g of glycine ethyl ester hydrochloride, 16.97 g of DMTMM and 100 mL of DMF were added to a reaction flask. The mixture was stirred and the temperature was maintained at 0–10 °C for 1 h. After the reaction was complete, the reaction solution was added dropwise to 4500 mL of purified water to crystallize. The crystals were filtered and dried under reduced pressure to obtain 13.06 g of compound III, an off-white solid, with a yield of 90.35% and a chromatographic purity of 99.42%.

[0034] Comparative Example 1 The preparation of compound 3 was performed according to Example 1 of patent CN117164473A. 5.00 g of 2,5-dichlorobenzoic acid, 3.93 g of glycine methyl ester hydrochloride, 5.27 g of EDCI, and 50 mL of dichloromethane were added to a reaction flask. The mixture was stirred and heated to 25°C, and 3.18 g of triethylamine was added dropwise under controlled temperature. After the reaction was complete, the reaction solution was washed once with 50 mL of saturated sodium carbonate and once with 50 mL of 1N HCl. The organic phase was collected, dried, and concentrated. The concentrated solid was dissolved in 10 mL of isopropyl acetate, and 10 mL of n-heptane was added dropwise to induce crystallization. The temperature was then lowered to 0-5°C, and crystallization was maintained for 1 hour. The crystals were filtered and dried to obtain 5.66 g of compound III, a white solid, with a yield of 82.50% and a chromatographic purity of 93.89%.

[0035] Comparative Example 2 Referring to patent CN106608883A, 1.91 g of 2,5-dichlorobenzoic acid, 1.49 g of HOBT, and 2.47 g of DCC were added sequentially to 30 mL of dichloromethane. After stirring the reaction solution for 30 min, 1.26 g of glycine methyl ester hydrochloride and 2.09 mL of LDIPEA were added. The reaction was carried out at room temperature for 12 h, and the solvent was removed by concentration under reduced pressure. 50 mL of ethyl acetate was added, and the mixture was filtered to remove insoluble matter. The filtrate was successively extracted with 5% NaHCO3 solution and saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2.24 g of compound III, a white solid, with a yield of 85.47% and a chromatographic purity of 87.75%.

Claims

1. A method for preparing an intermediate compound of formula III, namely, ixazomib citrate, characterized in that, In the presence of a triazine condensing agent and optionally an organic base, a compound of formula I is reacted with a compound of formula II or a salt thereof in an organic solvent to give a compound of formula III; the reaction formula of the method is as follows: ， Where R 1 For H, Li, Na, or K; R 2 It can be H, aliphatic hydrocarbon group or aromatic hydrocarbon group.

2. According to the preparation method of claim 1, the molar ratio of the triazine condensing agent to the compound of formula I is (1.00~3.00):1, preferably (1.00~2.00):

1.

3. The preparation method according to claim 1 or 2, wherein the triazine condensing agent is selected from 2-chloro-4,6-dimethoxy-1,3,5-triazine, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine hydrochloride and its hydrate, 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine tetrafluoroborate and its hydrate, 2,4,6-trichloro-1,3,5-triazine, and 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine tetrafluoroborate and its hydrate, and 2,4,6-trichloro-1,3,5-triazine. One or more of 2-chloro-4,6-dichloro-1,3,5-triazine, 4,6-dibenzyloxy-2-chloro-1,3,5-triazine, and 4,6-diphenoxy-2-chloro-1,3,5-triazine, preferably 2-chloro-4,6-dimethoxy-1,3,5-triazine or 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine hydrochloride and their hydrates.

4. The preparation method according to claim 1 or 2, wherein the triazine condensing agent is selected from one or more of 2-chloro-4,6-dimethoxy-1,3,5-triazine, 2,4,6-trichloro-1,3,5-triazine, 2-methoxy-4,6-dichloro-1,3,5-triazine, 4,6-dibenzyloxy-2-chloro-1,3,5-triazine and 4,6-diphenoxy-2-chloro-1,3,5-triazine, preferably 2-chloro-4,6-dimethoxy-1,3,5-triazine; the molar ratio of the organic base to the compound of formula I is (1.00~5.00):1, preferably (1.00~3.00):

1.

5. The preparation method according to claim 1 or 4, wherein the organic base is selected from one or more of triethylamine, diethylamine, diisopropylethylamine, N-methylmorpholine, N-methylcyclohexylamine and pyridine, preferably N-methylmorpholine.

6. The preparation method according to claim 1, wherein the volume-to-mass ratio (mL / g) of the organic solvent to the compound of formula I is (3~30):1, preferably (4~20):

1.

7. The preparation method according to claim 1 or 6, wherein the organic solvent is selected from one or more of dichloromethane, ethyl acetate, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide, preferably N,N-dimethylformamide.

8. According to the preparation method of claim 1, the molar ratio of compound II or its salt to compound I is (1.00~3.00):1, preferably (1.00~2.00):

1.

9. The preparation method according to any one of claims 1 to 8, wherein the reaction temperature is -30 to 40°C, preferably -10 to 30°C.

10. The preparation method according to claim 1, wherein R 2 It is selected from hydrogen, methyl, ethyl, tert-butyl, n-butyl, benzoyl and benzyl, preferably methyl or ethyl.

11. The preparation method according to claim 1 or 8, wherein the salt of the compound of formula II is selected from hydrochloride, trifluoroacetate, sulfate and sulfonate, preferably hydrochloride.

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