Improved process for the synthesis of ipilimumab

Abstract

An improved process for the preparation of Ipatasertib is described, which is achieved by efficient preparation of its intermediate 1-(4-chlorophenyl)imidazolidine-2,4-dione followed by condensation reaction with morpholine in the presence of ammonium chloride. In particular, the present invention relates to a process for the preparation of Ipatasertib by using a continuous process for distillation, drying and recycling of the dried morpholine back to the reactor to remove water produced in the reaction, thus providing Ipatasertib in high yield. More particularly, the present invention relates to a process for providing Ipatasertib in very high purity by simple washing with toluene and water. More particularly, the present invention relates to a process for industrial application scale, economically efficient.

Description

Technical Field

[0001] This invention describes an improved method for preparing ipitorin, which involves the efficient preparation of its intermediate 1-(4-chlorophenyl)imidazolidine-2,4-dione, followed by a condensation reaction with morpholine in the presence of ammonium chloride. Therefore, this invention belongs to the technical field of methods for the synthesis of pharmaceutical compounds. Background Technology

[0002] The chemical name of ipitoin is 1-(4-chlorophenyl)-1,5-dihydro-4-(4-morpholinyl)-2 H -Imidazol-2-one. It is marketed by Boehringer Ingelheim under the brand name Pexion®.

[0003] Ipitorin is a centrally acting substance used to treat epilepsy and noise phobia in dogs. It acts as a GABA-containing compound. A It is a low-affinity partial agonist of the benzodiazepine receptor binding site. It is the first compound with this mechanism to be approved for the treatment of canine epilepsy and for relieving anxiety and fear associated with canine noise phobia. Furthermore, ipilitoxine has a weak calcium channel blocking effect, which may contribute to its anticonvulsant properties.

[0004] The known synthetic strategy for preparing ipitorin (B) describes the condensation reaction of intermediate 1-(4-chlorophenyl)imidazolidine-2,4-dione (A) with morpholine.

[0005] Ipitorin was first disclosed in patent DE19532668. This patent describes a small-scale synthesis method for ipitorin, in which 1-(4-chlorophenyl)imidazolidine-2,4-dione (A) and morpholine (23 equivalents) are refluxed in the presence of p-toluenesulfonic acid as a catalyst. A conversion of less than 60% was obtained by removing the water formed during the reaction in a Soxhlet extractor filled with water-bound solids (e.g., calcined sodium sulfate, magnesium sulfate, NaOH, KOH, zeolite).

[0006]

[0007] The product was separated by distillation to half its volume, cooling in an ice bath, and filtration. The solid contained approximately 40% of the starting material, which was removed by extraction with hot acetone. Furthermore, the product needed to be crystallized from n-propanol. This method yielded lower than expected for industrial processes and presented several challenges for industrial application: Soxhlet extraction equipment was unsuitable for industrial-scale production, extraction with hot acetone to remove unreacted starting material was not a common industrial practice, and crystallization in n-propanol required large amounts of solvent due to the poor solubility of ipilexoin.

[0008] Patent DE19532668 does not describe the preparation of intermediate 1-(4-chlorophenyl)imidazolidine-2,4-dione (A).

[0009] J. Med. Chem. 2006, Vol. 49, pp. 1855-1866 describes the preparation of ipitorin (B) by reflux of 1-(4-chlorophenyl)imidazolidine-2,4-dione (A) and morpholine (20 equivalents) in the presence of morpholine hydrochloride (2 equivalents). Upon cooling the mixture to room temperature, a solid precipitates. The solid is separated by filtration, washed with water, and crystallized from the alcohol. This method is described on a laboratory scale with a yield of 67%, which is fairly general for a potential industrial process. Furthermore, morpholine hydrochloride is not an inexpensive chemical, and crystallization in alcohol requires a large amount of solvent due to the poor solubility of ipitorin in alcohol.

[0010] The preparation of intermediate 1-(4-chlorophenyl)imidazolidine-2,4-dione (A) is not described in J. Med. Chem. 2006, Vol. 49, pp. 1855-1866.

[0011] Patent WO2022153263 describes a method for preparing ipilitin (B) using a similar process, involving the reflux of 1-(4-chlorophenyl)imidazolidine-2,4-dione (a) and morpholine (6 equivalents) in the presence of morpholine hydrochloride (2 equivalents). After cooling the mixture to 35°C, methanol was added to precipitate the solid, which was then filtered and washed successively with methanol, water, and methanol. The product was crystallized in DMSO and methanol to obtain ipilitin (B) in a yield of 53%, which is fairly typical for a potential industrial process. Furthermore, morpholine hydrochloride is not an inexpensive chemical, and crystallization in DMSO / methanol requires a large amount of solvent, which is not an optimal mixture for industrial production.

[0012]

[0013] Patent WO2022153263 describes a one-step process for preparing the intermediate 1-(4-chlorophenyl)imidazolidine-2,4-dione (A): 4-chloroaniline is suspended in xylene, urea and chloroacetic acid are added, the system is heated to 80°C for 2 h, and then heated to 125°C for 2 h. After a cumbersome post-processing procedure, 1-(4-chlorophenyl)imidazolidine-2,4-dione (a) is obtained with a yield of 21%. This method has very low efficiency for industrial application.

[0014] Khimiya Geterotsiklicheskikh Soedinenii, 1978, Vol. 1, pp. 87-89 and Russian Journal of Organic Chemistry 2011, Vol. 47, pp. 960-963 both employ this one-step process to prepare 1-(4-chlorophenyl)imidazolidine-2,4-dione (A) from 4-chloroaniline, urea, and chloroacetic acid in the absence of solvents, with yields of 53% and 62%, respectively. In this method, the heating of the solid to 120-130°C in the absence of solvents is unsuitable for industrial applications.

[0015] J. Prakt. Chem., 1926, Vol. 113, pp. 233-267 describes a three-step method for the preparation of 1-phenylhydantoin, involving the heating reaction of aniline, chloroacetic acid, and sodium acetate in water. Due to the formation of phenylaminodiacetic acid, the yield of the intermediate aminophenylacetic acid is only 32%. After purification, the aminophenylacetic acid is reacted with potassium cyanate, cyclized with hydrochloric acid, and crystallized from an alcohol to convert to 1-phenylhydantoin. The overall yield is 19%.

[0016]

[0017] Patent EP0116825 uses a similar process to prepare 1-phenylhydantoin. Commercially available products are treated with potassium cyanate and catalytic acetic acid at 60°C. N An aqueous solution of 1-phenylglycine was then added to hydrochloric acid, heated to 90°C, filtered, and crystallized to give 1-phenylhydantoin, with a yield of 25%.

[0018] European Journal of Medicinal Chemistry 2009, Vol. 44, pp. 3471-3479, using a similar two-step experimental procedure, from N 1-Phenylonylurea was prepared from ethyl phenylglycine ester with a yield of 40%.

[0019] Drug Research 1968, Volume 1, pp. 189-196, describes the synthesis of 1-(4-chlorophenyl)-imidazolidine-2,4-dione (A) by reflux reaction of 4-chlorophenylurea, ethyl chloroacetate, and sodium ethoxide in ethanol, with a yield of 70%. This reaction has two main drawbacks: the formation of byproducts; and the need for in-house preparation due to the high price and difficulty in obtaining 4-chlorophenylurea on an industrial scale.

[0020]

[0021] The Journal of Pharmaceutical Sciences, 1973, Vol. 62, pp. 340-341, describes the process of acid-catalyzing reflux of 4-chlorophenylurea and glyoxal in ethanol, followed by fractional recrystallization, to obtain 1-(4-chlorophenyl)-imidazolidine-2,4-dione (A) in 30% yield. However, this process has very low efficiency for industrial application.

[0022]

[0023] Tetrahedron Letters 2011, Vol. 52, pp. 6148-6151, describes the synthesis of 1-(4-chlorophenyl)-imidazolidine-2,4-dione (A), by combining dibutyl phosphate and N 2-Cyano-2-(4-chloroaniline)methyl acetate was reacted by heating at 100°C under solvent-free conditions. Although this type of cyclization reaction provided a yield of 85%, this method faces many difficulties in industrial application: solvent-free reaction conditions; the cost of dibutyl phosphate; and... N The use of a cyano intermediate, which is prepared by reacting methyl 2-(4-chloroaniline)acetate with cyanogen bromide, a highly toxic chemical that can cause cyanide poisoning.

[0024] Summary of the Invention

[0025] This invention overcomes many shortcomings of existing ipitorin preparation processes, providing an economical, efficient, and scalable method that can prepare the target compound and corresponding intermediates in high yield and high purity without any chromatographic purification or recrystallization steps. The method described below has the following advantages: it employs large-scale and cost-effective reaction conditions; impurities are minimized and removed through simple separation techniques; recrystallization is not required; and ipitorin can be obtained with very high purity and overall yield. Therefore, this invention describes an improved method for preparing ipitorin.

[0026] In a first aspect, the present invention provides a method for preparing high-purity ipitorine, the method comprising the following steps: a) The compound of formula (I) is obtained by alkylation.

[0027] Wherein R is selected from H, (C1-C4)-alkyl (preferably ethyl), allyl, or benzyl, and the alkylation reaction includes the following steps: a1) React 4-chloroaniline with a base and additives in a solvent at room temperature for 15-60 min. The alkali is selected from potassium carbonate, sodium carbonate, potassium acetate, or sodium acetate. The additive is selected from potassium iodide or sodium iodide. The solvent is selected from acetonitrile, tetrahydrofuran, dimethylformamide, acetone, or alcohol. a2) Add the compound of formula (II) and heat at a reaction temperature of 50-80℃ for 3-24 h.

[0028] Where X is a halogen or leaving group, and R is as defined above. a3) Add water and cool at room temperature to precipitate compound (I). a4) Distill the ethanol / water mixture and add water. a5) Compound (I) was separated by filtration and washed with solvent. b) To obtain the compound of formula (III) by Urech-type hydantoin synthesis, the method comprising the following steps:

[0029] b1) React the compound of formula (I) with potassium cyanate or sodium cyanate in a solvent selected from acetic acid or hydrochloric acid at a reaction temperature of 100-120°C for 4-24 h. b2) Upon cooling at room temperature, compound (III) precipitates. b3) Compound (III) was separated by filtration, washed with solvent, and dried. c) Obtaining ipitorin via an acid-catalyzed reversible reaction, including the following steps: c1) Morpholine, used as both reactant and solvent, reacts with ammonium chloride at a reaction temperature of 110-140℃ for 0.5-1.5 h. c2) Compound (III) is added to a mixture of morpholine and ammonium chloride at a temperature of 110-140°C. c3) Heat the mixture to a temperature of 110-140°C. c4) The morpholine was distilled, dried with a desiccant, and the dried morpholine was returned to the reaction mixture, which was maintained at 110-140°C, for 6-12 h. c5) Cool the reaction mixture to a temperature of 100-120°C. c6) Toluene and morpholine are slowly added to the reaction mixture at a temperature of 100-120°C. c7) Cool the reaction mixture at room temperature to precipitate ipilyn. c8) Filter out the solid, and stir at 20-55°C (preferably room temperature) to resuspend the solid in the solvent for 1-2 h (preferably 1 h). The solvent may be toluene, ethyl acetate, acetone, acetonitrile, THF, ethanol, or isopropanol, with toluene being the most preferred. c9) The solid is filtered out, washed with a solvent (preferably water), and dried under vacuum at a temperature of 40-60°C (preferably 50°C).

[0030] In a preferred embodiment, in step a1), the base is potassium carbonate, the additive is potassium iodide, the solvent is ethanol, and the reaction is carried out at room temperature for 30 min.

[0031] In a preferred embodiment, in step a2), X is chlorine, R is ethyl, the temperature is 60°C, and the time is 5 h.

[0032] In a preferred embodiment, the cooling in step a3) and / or step b2) and / or step c8) is cooling to room temperature.

[0033] In a preferred embodiment, the washing is performed with water in step a5).

[0034] In a preferred embodiment, in step b1), the compound of formula (I) is reacted with potassium cyanate at a temperature of 110°C for 6 h, wherein the solvent is acetic acid.

[0035] In a preferred embodiment, in step b3), the washing is performed with water, and the drying is performed under vacuum at a temperature of 50°C.

[0036] In a preferred embodiment, step c1) is performed at 120°C for 1 hour.

[0037] In a preferred embodiment, step c2) is performed at a temperature of 120°C.

[0038] In a preferred embodiment, the heating in step c3) is performed at a temperature of 130°C.

[0039] In a preferred embodiment, in step c4), the drying is performed through a column filled with activated 3Å molecular sieves, and the reaction mixture is maintained at 130°C for 8 h.

[0040] As used herein, the term "alkyl" means a saturated, monovalent straight-chain or branched hydrocarbon chain. Examples of alkyl groups include, but are not limited to, (C1-C4)-alkyl groups, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Ethyl is preferred.

[0041] As used herein, the term "allyl" refers to 2-propenyl.

[0042] As used herein, the term “benzyl” means -CH2-aryl, where the aryl group is a substituted or unsubstituted benzene ring.

[0043] As used in this article, the term "room temperature" can be considered as a temperature of 20 to 30°C.

[0044] The synthetic route of a specific embodiment of the method of the present invention is shown in the following scheme:

[0045] Advantages of this invention: - High process yield (68% overall yield); - The process produces the target product with very high purity (HPLC purity >99.5%, actually reaching 99.8%), without the need for recrystallization; -The process is economical and efficient; - The process is simple and suitable for industrial-scale production.

[0046] Known processes excluding the morpholine drying step are far less advantageous than the method of the present invention because they require longer reaction times, much lower yields, and must be repeated three times to obtain ipilitin of the same purity. Comparative results are shown in one embodiment. These results highlight the importance of continuously drying morpholine during synthesis, which yields ipilitin in a solid form with very high yields and purity after a simple purification process. Detailed Implementation

[0047] Example Example 1 Synthesis of ethyl 2-(4-chloroaniline)acetate

[0048] 4-Chloroaniline (100 g, 0.78 mol) was dissolved in ethanol (200 mL) and added to a mechanically stirred reactor. Potassium carbonate (109.42 g, 0.79 mol) and potassium iodide (130.13 g, 0.78 mol) were added, and the mixture was stirred at room temperature for 30 min. Ethyl chloroacetate (84.74 mL, 0.78 mmol) was added in one step, and the reaction was heated to 60 °C for 5 h. Water (600 mL) was added, and the mixture was cooled to room temperature. As the temperature decreased, a creamy solid began to precipitate. When room temperature was reached, 400 mL of the ethanol / water mixture was distilled off. Then, 300 mL of water was added, and 300 mL of the solvent mixture was distilled off again. Finally, the solid was separated by filtration and washed with water (500 mL) to give the target compound in the form of a creamy solid (175.75 g, containing 10% water as determined by KF, yield 94% on anhydrous basis). The wet solids are used directly in the next step without drying. MS (ES+) m / z : 214 (M+H) + .

[0049] Example 2 Synthesis of 1-(4-chlorophenyl)imidazolidine-2,4-dione

[0050] Wet ethyl 2-(4-chloroaniline)ethyl acetate (158.17 g, 0.74 mol, anhydrous) was added to a mechanically stirred reactor. Acetic acid (1.05 L, 9.90 mol, 80% v / v) was added with stirring. Potassium cyanate (120.10 g, 1.48 mol) was added slowly in portions to the solution. The mixture was then heated to reflux and maintained at that temperature for 6 h. The reaction mixture was cooled to room temperature and a white solid precipitated. The solid was then separated by filtration and washed with water (160 mL). The wet solid was transferred to an oven and dried under vacuum at 50 °C. The target compound was given as a white solid (123.83 g, 79% yield). MS (ES+) m / z : 211 (M+H) + The purity of the product is greater than 99%. Purity was determined by HPLC (Luna C18 column, 250×4.6 mm, 5 μm; mobile phase: acetonitrile / water gradient elution; flow rate: 1 mL / min; injection volume: 5 µL; column temperature: 50℃; detection wavelength: 254 nm).

[0051] Example 3 Synthesis of ipitor

[0052] Morpholine (608.4 mL, 7.06 mol) was added to a mechanically stirred reactor. Ammonium chloride (125.8 g, 2.35 mol) was added to the reactor with stirring. The mixture was heated to 120 °C for 1 h. 1-(4-chlorophenyl)imidazolidine-2,4-dione (123.8 g, 0.59 mol) was added to the solution, and the mixture was heated to 130 °C. Morpholine was immediately distilled, dried by passing it through a column packed with activated 3 Å molecular sieves (60 g), and returned to the reactor. The mixture was maintained at 130 °C for 8 h, during which time morpholine was continuously distilled, dried, and returned to the reactor. The reaction mixture was then cooled to 110 °C. At this temperature, toluene (620 mL) and morpholine (202 mL) were slowly added. After the addition was complete, the system was cooled to room temperature, and a white solid began to precipitate as the temperature decreased. When room temperature was reached, the solid was separated by filtration. The solid was resuspended in toluene (620 mL), stirred at room temperature for 1 h, filtered, and washed with water (630 mL) to give a white solid. The wet solid was transferred to an oven and dried under vacuum at 50 °C. The target compound was given as a white solid (148.01 g, 90% yield). MS (ES+) m / z 280 (M+H) + The product purity was 99.8%. Purity was determined by HPLC (Luna C18 column, 250 × 4.6 mm, 5 μm; mobile phase: acetonitrile / water gradient elution; flow rate: 1 mL / min; injection volume: 5 µL; column temperature: 40℃; detection wavelength: 254 nm). Example 4 This paper describes the experimental procedures for synthesizing ipilotoin from dried morpholine without the use of 3Å molecular sieves. Morpholine (442.20 mL, 5.12 mol) was added to a mechanically stirred reactor. Ammonium chloride (91.43 g, 1.70 mol) was added to the reactor with stirring. The mixture was heated to 120 °C for 1 h. 1-(4-chlorophenyl)imidazolidine-2,4-dione (90 g, 0.42 mol) was added to the solution, and the mixture was heated to 130 °C. The mixture was maintained at 130 °C for 24 h. Morpholine (147 mL) was then added, and the mixture was cooled to 110 °C. At this temperature, toluene (450 mL) was slowly added, and the mixture was cooled to room temperature. When room temperature was reached, the solid was separated by filtration. The solid was then suspended in toluene (450 mL), filtered, and washed with water (450 mL). This process was repeated twice, and the final solid was dried under vacuum at 50 °C. The target compound was obtained as a white solid (73.45 g, 61% yield). MS (ES) +m / z: 280 (M+H) + The purity of the product was 99.8%. Purity was determined by HPLC (Luna C18 column, 250×4.6 mm, 5 μm; mobile phase: acetonitrile / water gradient elution; flow rate: 1 mL / min; injection volume: 5 µL; column temperature: 40℃; detection wavelength: 254 nm).

[0053] The results showed that when the distillation / drying step of morpholine was not included in the process, the yield was reduced by 30%, the reaction time increased to three times, and the purification process had to be repeated three times to obtain ipiltoin of the same purity.

Claims

1. A method for preparing high-purity ipitor, comprising the following steps: a) The compound of formula (I) is obtained by alkylation. Wherein R is selected from H, (C1-C4)-alkyl, allyl, or benzyl, and the alkylation reaction Includes the following steps: a1) React 4-chloroaniline with a base and additives in a solvent at room temperature for 15-60 min. The alkali is selected from potassium carbonate, sodium carbonate, potassium acetate, or sodium acetate. The additive is selected from potassium iodide or sodium iodide. The solvent is selected from acetonitrile, tetrahydrofuran, dimethylformamide, acetone, or alcohol. a2) Add the compound of formula (II) and heat at a reaction temperature of 50-80℃ for 3-24 h. Where X is a halogen or leaving group, and R is as defined above. a3) Add water and cool at room temperature to precipitate compound (I). a4) Distill the ethanol / water mixture and add water. a5) Compound (I) was separated by filtration and washed with a solvent. b) To obtain the compound of formula (III) by the synthesis of Urech-type hydantoin, comprising the following steps: b1) React the compound of formula (I) with potassium cyanate or sodium cyanate in a solvent selected from acetic acid or hydrochloric acid at a reaction temperature of 100-120°C for 4-24 h. b2) Cool at room temperature to precipitate compound (III). b3) Compound (III) was separated by filtration, washed with solvent, and dried. c) Obtaining ipitorin via an acid-catalyzed reversible reaction, including the following steps: c1) Morpholine, used as both reactant and solvent, reacts with ammonium chloride at a reaction temperature of 110-140℃ for 0.5-1.5 h. c2) Compound (III) was added to a mixture of morpholine and ammonium chloride at a temperature of 110-140°C. c3) Heat the mixture to a temperature of 110-140°C. c4) The morpholine was distilled, dried with a desiccant, and the dried morpholine was returned to the reaction mixture, which was maintained at 110-140°C, for 6-12 h. c5) Cool the reaction mixture to a temperature of 100-120°C. c6) Toluene and morpholine are slowly added to the reaction mixture at a temperature of 100-120°C. c7) Cool the reaction mixture at room temperature to precipitate ipilyn. c8) Filter out the solid, and stir at 20-55°C to resuspend the solid in the solvent for 1-2 hours. c9) Filter out the solid, wash with solvent, and dry under vacuum at a temperature of 40-60℃.

2. The method according to the preceding claims, wherein in step a1), the base is potassium carbonate, the additive is potassium iodide, the solvent is ethanol, and the reaction is carried out at room temperature for 30 min.

3. The method according to any one of the preceding claims, wherein in step a2), X is chlorine, R is ethyl, the temperature is 60°C, and the time is 5 h.

4. The method according to any one of the preceding claims, wherein the cooling in step a3) and / or step b2) and / or step c8) is cooling to room temperature.

5. The method according to any one of the preceding claims, wherein in step a5), the washing is performed with water.

6. The method according to any one of the preceding claims, wherein in step b1), the compound of formula (I) is reacted with potassium cyanate at a temperature of 110°C for 6 h, and the solvent is acetic acid.

7. The method according to any one of the preceding claims, wherein in step b3), the washing is performed with water and the drying is performed under vacuum at a temperature of 50°C.

8. The method according to any one of the preceding claims, wherein step c1) is performed at 120°C for 1 hour.

9. The method according to any one of the preceding claims, wherein step c2) is performed at a temperature of 120°C.

10. The method according to any one of the preceding claims, wherein the heating in step c3) is performed at a temperature of 130°C.

11. The method according to any one of the preceding claims, wherein in step c4), the drying is performed through a column filled with activated 3Å molecular sieves, and the reaction mixture is maintained at 130°C for 8 h.

12. The method according to any one of the preceding claims, wherein in step c8), the solvent is selected from the group consisting of toluene, ethyl acetate, acetone, acetonitrile, THF, ethanol and isopropanol.

13. The method according to any one of the preceding claims, wherein in step c8), the mixture is stirred at room temperature for 1 h.

14. The method according to any one of the preceding claims, wherein in step c9), the solvent is water.

15. The method according to any one of the preceding claims, wherein in step c9), drying is performed under vacuum at a temperature of 50°C.

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