Preparation method of key intermediate of rucotinib phosphate

Abstract

The invention belongs to the technical field of medicines, and relates to a preparation method of a rucotinib phosphate key intermediate, in particular to a preparation method of 3-cyclopentyl acrylonitrile. Comprising the following steps: reacting 3-cyclopentyl propionyl chloride with ammonia water to generate 3-cyclopentyl propionamide; 3-cyclopentyl propionamide is dehydrated in the presence of a dehydrating agent such as phosphorus oxychloride to generate 3-cyclopentyl propionitrile; in a certain solvent, 3-cyclopentyl propionitrile reacts with a halogenating reagent (NCS, NBS and the like) to generate 2-halogenated-3-cyclopentyl propionitrile; and finally, in a certain solvent, eliminating the 2-halogenated-3-cyclopentyl propionitrile under an alkaline condition to generate the target product 3-cyclopentyl acrylonitrile. The method is simple to operate, mild in condition, excellent in yield and quality and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to a method for preparing a key intermediate of ruxolitinib phosphate. Background Art

[0002] Ruxolitinib is the first clinically effective, selective JAK1 / 2 inhibitor developed jointly by Incyte and Novartis Pharmaceuticals AG. Ruxolitinib is used for adult patients with intermediate-risk or high-risk primary myelofibrosis, myelofibrosis secondary to polycythemia vera, or myelofibrosis secondary to essential thrombocythemia, and is also a drug currently approved for the treatment of myelofibrosis.

[0003] The preparation method of 3-cyclopentyl acrylonitrile currently adopts the following route, such as CN105418616:

[0004]

[0005] This route uses the classic Horner-Wittig reaction, which has a mild reaction and high yield, but the raw material cyclopentyl formaldehyde is expensive (2000 / kg), which has exceeded the market price of the product 3-cyclopentyl acrylonitrile (1800 / kg);

[0006] Currently, there are not many preparation routes of 3-cyclopentylacrylonitrile suitable for industrial production reported in the literature. Therefore, finding a method with mild conditions, simple operation and low cost that can be successfully used for the industrial production of 3-cyclopentylacrylonitrile, a key intermediate of ruxolitinib phosphate, is a technical problem that is urgently needed to be solved in this field. Summary of the invention

[0007] In order to make up for the deficiencies of the prior art, the present invention provides a method for preparing a key intermediate of ruxolitinib phosphate.

[0008] The present invention is achieved through the following technical solutions:

[0009] A method for preparing a key intermediate of ruxolitinib phosphate, wherein the synthetic route is shown in the following reaction formula:

[0010]

[0011] Further, the synthesis steps are as follows:

[0012] (1) 3-cyclopentylpropionyl chloride and 2-20 parts of aqueous ammonia react to generate 3-cyclopentylpropionamide;

[0013] (2) 3-cyclopentylpropionamide is dehydrated in the presence of a dehydrating agent to generate 3-cyclopentylpropionitrile;

[0014] (3) In a certain solvent, 3-cyclopentylpropionitrile reacts with a halogenating agent to generate 2-halogenated-3-cyclopentylpropionitrile;

[0015] (4) In a certain solvent, 2-halogenated-3-cyclopentylpropionitrile is eliminated under alkaline conditions to generate the target product 3-cyclopentylacrylonitrile.

[0016] Furthermore, step (1) comprises: adding 2-20 parts of aqueous ammonia, cooling to 0°C, adding 1 part of 3-cyclopentylpropionyl chloride at a temperature of 0-10°C, and stirring at 0-10°C for half an hour after the addition is complete; then adding 0.5 to 20 parts of ethyl acetate to extract the liquid, extracting the aqueous phase once more with 0.5 to 20 parts of ethyl acetate, combining the organic phases, drying with 0.2 to 1 part of anhydrous magnesium sulfate, filtering, and directly subjecting the filtrate to the next step.

[0017] Furthermore, step (2) comprises: controlling the temperature at 20-30°C, adding 1 to 10 parts of a dehydrating agent to the filtrate obtained in step (1), and then heating to 70-80°C and keeping the temperature for 5 hours; then cooling to 15°C, controlling the temperature at 15-30°C, and dripping water; after dripping, standing and separating the liquids, extracting the aqueous phase once with 0.5 to 20 parts of ethyl acetate, combining the organic phases and washing them once with water; drying the organic phase with 0.2 to 1 part of anhydrous magnesium sulfate, filtering, and directly subjecting the filtrate to the next step.

[0018] Furthermore, in step (2), the dehydrating agent is any one of phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid, and trifluoroacetic anhydride.

[0019] Furthermore, step (3) comprises the following steps: controlling the temperature at 20-30°C, adding 1 to 2 parts of a halogenating agent to the filtrate obtained in step (2), then heating to 70-80°C and keeping the temperature for 2 hours; then cooling to 15°C, controlling the temperature at 15-30°C, and dripping 1 to 10 parts of water; after dripping, standing and separating the liquids, extracting the aqueous phase once with 0.5 to 20 parts of ethyl acetate, combining the organic phases and washing them once with water; drying the organic phase with 0.2 to 1 part of anhydrous magnesium sulfate, filtering, and directly subjecting the filtrate to the next step.

[0020] Furthermore, in step (3), the halogenating agent is any one of NCS (N-chlorosuccinimide), NBS (N-bromosuccinimide), NIS (N-iodosuccinimide), chlorine, bromine, iodine, phosphorus pentachloride, and sulfonyl chloride.

[0021] Furthermore, step (4) comprises the following steps: controlling the temperature at 0-5°C, adding alkali to the filtrate obtained in step (3) in batches, keeping the temperature at 0-5°C for reaction for 2 hours after the addition, then controlling the temperature at 0-5°C, and dropping 1 to 10 parts of water; standing the mixture for separation after the dropping, extracting the aqueous phase once with 0.5 to 20 parts of ethyl acetate, combining the organic phases and washing them once with water; drying the organic phase with 0.2 to 1 part of anhydrous magnesium sulfate, and filtering; first concentrating the filtrate under reduced pressure with a water pump (vacuum 20-30 mmHg, temperature 50-60°C) to recover ethyl acetate until no liquid flows out to obtain an oily substance, and then performing reduced pressure distillation with an oil pump and a distillation column (distillation column 20 cm long, glass spring filler 10 cm long), vacuum 0.4-5 mmHg, collecting a fraction at 80-90°C, and obtaining a colorless transparent liquid 3-cyclopentyl acrylonitrile.

[0022] Furthermore, in step (4), the base is any one of potassium hydroxide, potassium tert-butoxide and sodium tert-butoxide.

[0023] The above ingredients are all measured by mass.

[0024] Compared with the prior art, the present invention has the following advantages: the present invention uses economically available 3-cyclopentyl propionyl chloride, and obtains 3-cyclopentyl acrylonitrile through amination, dehydration, halogenation and elimination, thereby overcoming the defect of expensive raw materials in the prior art. The method is simple to operate, has mild conditions and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The present invention will be further described below in conjunction with the accompanying drawings.

[0026] Figure 1 It is the gas chromatogram of 3-cyclopentyl acrylonitrile in Example 2. DETAILED DESCRIPTION

[0027] The present invention is described below with reference to examples, but the present invention is not limited thereto. In the art, simple replacement or improvement made by technicians in the field to the present invention belongs to the technical solution protected by the present invention.

[0028] Example 1

[0029] The target product 3-cyclopentyl acrylonitrile is synthesized as follows:

[0030] (1) 3-cyclopentylpropionyl chloride and 2-20 parts of aqueous ammonia react to generate 3-cyclopentylpropionamide;

[0031] Specifically, add ammonia water, cool to 0°C, control the temperature at 0-10°C and add 3-cyclopentylpropionyl chloride dropwise, keep the temperature at 0-10°C and stir for half an hour after the addition is complete; then add 0.5-20 parts of ethyl acetate to extract the liquid, extract the aqueous phase once with 0.5-20 parts of ethyl acetate, combine the organic phases, dry with anhydrous magnesium sulfate, filter, and directly use the filtrate for the next step.

[0032] (2) 3-cyclopentylpropionamide is dehydrated in the presence of a dehydrating agent to generate 3-cyclopentylpropionitrile;

[0033] Step (2) comprises the following steps: controlling the temperature at 20-30°C, adding 1-10 parts of a dehydrating agent to the filtrate obtained in step (1), then heating to 70-80°C and keeping the temperature for 5 hours; then cooling to 15°C, controlling the temperature at 15-30°C, and dripping water; standing for separation after dripping, extracting the aqueous phase once with 0.5-20 parts of ethyl acetate, combining the organic phases and washing them once with water; drying the organic phase with 0.2-1 parts of anhydrous magnesium sulfate, filtering, and directly subjecting the filtrate to the next step. The dehydrating agent is any one of phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid, and trifluoroacetic anhydride.

[0034] (3) in a solvent, 3-cyclopentylpropionitrile and a halogenating agent react to generate 2-halogenated-3-cyclopentylpropionitrile;

[0035] Step (3) comprises: controlling the temperature at 20-30° C., adding 1 to 2 parts of a halogenating agent to the filtrate obtained in step (2), and then heating to 70-80° C. and keeping the temperature for 2 hours; then cooling to 15° C., controlling the temperature at 15-30° C., and dripping 1 to 10 parts of water; standing the mixture for separation after dripping, extracting the aqueous phase once with 0.5 to 20 parts of ethyl acetate, combining the organic phases and washing them once with water; drying the organic phase with 0.2 to 1 part of anhydrous magnesium sulfate, filtering, and directly subjecting the filtrate to the next step; the halogenating agent is any one of NCS (N-chlorosuccinimide), NBS (N-bromosuccinimide), NIS (N-iodosuccinimide), chlorine, bromine, iodine, phosphorus pentachloride, and sulfuryl chloride.

[0036] (4) In a solvent, 2-halogenated-3-cyclopentylpropionitrile is eliminated under alkaline conditions to generate the target product 3-cyclopentylacrylonitrile.

[0037] Step (4) comprises the following steps: controlling the temperature at 0-5°C, adding alkali to the filtrate obtained in step (3) in batches, keeping the temperature at 0-5°C for reaction for 2 hours after the addition, then controlling the temperature at 0-5°C, and dripping 1-10 parts of water; standing the liquid for separation after dripping, extracting the aqueous phase with 0.5-20 parts of ethyl acetate once, combining the organic phases and washing with water once; drying the organic phase with 0.2-1 parts of anhydrous magnesium sulfate, and filtering; firstly concentrating the filtrate under reduced pressure with a water pump (vacuum 20-30 mmHg, temperature 50-60°C) to recover ethyl acetate until no liquid flows out to obtain an oily substance, and then vacuum distilling with an oil pump and a distillation column (distillation column 20 cm long, glass spring filler 10 cm long), vacuum 0.4-5 mmHg, collecting 80-90°C fractions, and obtaining colorless transparent liquid 3-cyclopentyl acrylonitrile. The alkali is any one of potassium hydroxide, potassium tert-butoxide, and sodium tert-butoxide.

[0038] In this embodiment, the above ingredients are all measured in parts by mass.

[0039] Example 2

[0040] 1. Preparation of 3-cyclopentylpropionamide

[0041] Add ammonia water (680g, 10mol, 10eq), cool to 0℃, control the temperature at 0-10℃ and add 3-cyclopentylpropionyl chloride (160g, 1mol, 1eq) dropwise. After the addition, keep the temperature at 0-10℃ and stir for half an hour. Then add ethyl acetate (1000g) to extract the liquid, extract the aqueous phase with ethyl acetate (500g) once more, combine the organic phases, dry with anhydrous magnesium sulfate, and filter. The filtrate is directly used for the next step.

[0042] 2. Preparation of 3-cyclopentylpropionitrile

[0043] Control the temperature at 20-30℃, add phosphorus oxychloride (306g, 2mol, 2eq) to the filtrate from the previous step, then heat to 70-80℃ and keep warm for 5 hours; then cool to 15℃, control the temperature at 15-30℃, and drop water (1000g); after the drop is complete, let stand to separate the liquids, extract the aqueous phase with ethyl acetate (200g) once, combine the organic phases and wash them with water (200g) once; dry the organic phase with anhydrous magnesium sulfate, filter, and directly use the filtrate for the next step.

[0044] 3. Preparation of 2-chloro-3-cyclopentylpropionitrile

[0045] Control the temperature at 20-30℃, add NCS (200g, 1.5mol, 1.5eq) to the filtrate from the previous step, then heat to 70-80℃ and keep warm for 2 hours; then cool to 15℃, control the temperature at 15-30℃, and drop water (1000g); after the drop is complete, let stand to separate the liquids, extract the aqueous phase with ethyl acetate (200g) once, combine the organic phases and wash them with water (200g) once; dry the organic phase with anhydrous magnesium sulfate, filter, and directly use the filtrate for the next step.

[0046] 4.3-Preparation of Cyclopentyl Acrylonitrile

[0047] Control the temperature at 0-5℃, add sodium tert-butoxide (144.1g, 1.5mol, 1.5eq) to the filtrate from the previous step in batches, and keep the temperature at 0-5℃ for 2 hours. Then control the temperature at 0-5℃, add water (500g) dropwise; after the addition, let it stand for separation, extract the aqueous phase with ethyl acetate (200g) once, combine the organic phases and wash them with water (200g) once; dry the organic phase with anhydrous magnesium sulfate and filter. The filtrate was first concentrated under reduced pressure by a water pump (vacuum 20-30 mmHg, temperature 50-60°C) to recover ethyl acetate until no liquid flowed out to obtain an oily substance, and then subjected to reduced pressure distillation by an oil pump plus a distillation column (distillation column 20 cm long, glass spring filler 10 cm long), vacuum 0.4-5 mmHg, and 80-90°C fractions were collected to obtain 65.1 g (total yield of 4 steps: 53%) of colorless transparent liquid 3-cyclopentylacrylonitrile with a purity of 99.5% (the sum of cis-isomers and trans-isomers). The peak time of the obtained product was consistent with that of the standard sample.

[0048] Example 2

[0049] 1. Preparation of 3-cyclopentylpropionamide

[0050] Add ammonia water (340g, 5mol, 5eq), cool to 0℃, control the temperature at 0-10℃ and add 3-cyclopentylpropionyl chloride (160g, 1mol, 1eq) dropwise. After the addition is complete, keep the temperature at 0-10℃ and stir for half an hour. Then add ethyl acetate (500g) to extract the liquid, extract the aqueous phase with ethyl acetate (100g) once more, combine the organic phases, dry with anhydrous magnesium sulfate, and filter. The filtrate is directly used for the next step.

[0051] 2. Preparation of 3-cyclopentylpropionitrile

[0052] Control the temperature at 20-30℃, add phosphorus oxychloride (153g, 1mol, 1eq) to the filtrate from the previous step, then heat to 70-80℃ and keep warm for 5 hours; then cool to 15℃, control the temperature at 15-30℃, and drop water (500g); after the drop is complete, let stand to separate the liquids, extract the aqueous phase with ethyl acetate (100g) once, combine the organic phases and wash them with water (100g) once; dry the organic phase with anhydrous magnesium sulfate, filter, and directly use the filtrate for the next step.

[0053] 3. Preparation of 2-chloro-3-cyclopentylpropionitrile

[0054] Control the temperature at 20-30℃, add NCS (133g, 1mol, 1eq) to the filtrate in the previous step, then heat to 70-80℃ and keep warm for 2 hours; then cool to 15℃, control the temperature at 15-30℃, and drop water (500g); after the drop is complete, let it stand for separation, extract the aqueous phase with ethyl acetate (100g) once, combine the organic phases and wash them with water (100g) once; dry the organic phase with anhydrous magnesium sulfate, filter, and directly use the filtrate for the next step.

[0055] 4.3-Preparation of Cyclopentyl Acrylonitrile

[0056] Control the temperature at 0-5℃, add sodium tert-butoxide (96.1g, 1mol, 1eq) to the filtrate in the previous step in batches, and keep the temperature at 0-5℃ for 2 hours. Then control the temperature at 0-5℃, add water (500g) dropwise; after the addition, let it stand for separation, extract the aqueous phase with ethyl acetate (100g) once, combine the organic phases and wash them with water (100g) once; dry the organic phase with anhydrous magnesium sulfate and filter. The filtrate was first concentrated under reduced pressure by a water pump (vacuum 20-30 mmHg, temperature 50-60°C) to recover ethyl acetate until no liquid flowed out to obtain an oily substance, and then an oil pump was added to a distillation column (distillation column 20 cm long, glass spring filler 10 cm long) for reduced pressure distillation, vacuum 0.4-5 mmHg, and the 80-90°C fraction was collected to obtain 60.0 g of colorless transparent liquid 3-cyclopentyl acrylonitrile (total yield of 4 steps: 49%), with a purity of 99.5% (the sum of cis isomers and trans isomers). The peak time of the obtained product was consistent with that of the standard sample. See attached Figure 1 , from which we can also see that the product is a mixture of cis and trans isomers.

[0057] Unless otherwise specified, the reagents and raw materials used in the present invention are commercially available. If there is a conflict between the Chinese name of the compound in the present invention and the structural formula, the structural formula shall prevail, unless there is an obvious error in the structural formula.

Claims

1. A method for preparing a key intermediate of ruxolitinib phosphate, characterized in that: The synthetic route is shown in the following reaction formula:

2. The preparation method according to claim 1, characterized in that: The synthesis steps are as follows: (1) 3-cyclopentylpropionyl chloride reacts with aqueous ammonia to generate 3-cyclopentylpropionamide; (2) 3-cyclopentylpropionamide is dehydrated in the presence of a dehydrating agent to generate 3-cyclopentylpropionitrile; (3) in a solvent, 3-cyclopentylpropionitrile and a halogenating agent react to generate 2-halogenated-3-cyclopentylpropionitrile; (4) In a certain solvent, 2-halogenated-3-cyclopentylpropionitrile is eliminated under alkaline conditions to generate the target product 3-cyclopentylacrylonitrile.

3. The preparation method according to claim 2, characterized in that: Step (1) comprises: adding 2-20 parts by mass of aqueous ammonia, cooling to 0°C, adding dropwise 1 part of 3-cyclopentylpropionyl chloride at a temperature of 0-10°C, and stirring at 0-10°C for half an hour after the addition is complete; then adding 0.5-20 parts of ethyl acetate to extract and separate the liquids, extracting the aqueous phase once more with 0.5-20 parts of ethyl acetate, combining the organic phases, drying with anhydrous magnesium sulfate, filtering, and directly subjecting the filtrate to the next step.

4. The preparation method according to claim 2, characterized in that: The steps of step (2) are as follows: controlling the temperature at 20-30°C, adding 1-10 parts of a dehydrating agent to the filtrate obtained in step (1), then heating to 70-80°C and keeping the temperature for 5 hours; then cooling to 15°C, controlling the temperature at 15-30°C, and dripping water; after dripping, standing and separating the liquids, extracting the aqueous phase once with 0.5-20 parts of ethyl acetate, combining the organic phases and washing them once with water; drying the organic phase with 0.2-1 parts of anhydrous magnesium sulfate, filtering, and directly subjecting the filtrate to the next step.

5. The preparation method according to claim 2, characterized in that: In step (2), the dehydrating agent is any one of phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid and trifluoroacetic anhydride.

6. The preparation method according to claim 2, characterized in that: Step (3) comprises the following steps: controlling the temperature at 20-30°C, adding 1 to 2 parts of a halogenating agent to the filtrate obtained in step (2), then heating to 70-80°C and keeping the temperature for 2 hours; then cooling to 15°C, controlling the temperature at 15-30°C, and dripping 1 to 10 parts of water; after dripping, standing and separating the liquids, extracting the aqueous phase once with 0.5 to 20 parts of ethyl acetate, combining the organic phases and washing them once with water; drying the organic phase with 0.2 to 1 part of anhydrous magnesium sulfate, filtering, and directly subjecting the filtrate to the next step.

7. The preparation method according to claim 2, characterized in that: In step (3), the halogenating agent is any one of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, chlorine, bromine, iodine, phosphorus pentachloride and sulfonyl chloride.

8. The preparation method according to claim 2, characterized in that: The step (4) comprises the following steps: controlling the temperature at 0-5°C, adding alkali to the filtrate obtained in step (3) in batches, keeping the temperature at 0-5°C for reaction for 2 hours after the addition, then controlling the temperature at 0-5°C, and dripping 1-10 parts of water; standing the solution for separation after the dripping, extracting the aqueous phase once with 0.5-20 parts of ethyl acetate, combining the organic phases and washing them once with water; drying the organic phase with 0.2-1 parts of anhydrous magnesium sulfate, and filtering; firstly using a water pump to reduce pressure and concentrate the filtrate to recover ethyl acetate until no liquid flows out to obtain an oily substance, and then using an oil pump to add a distillation column for reduced pressure distillation, and vacuum distilling at 0.4-5 mmHg, collecting a fraction at 80-90°C to obtain a colorless transparent liquid 3-cyclopentyl acrylonitrile.

9. The preparation method according to claim 8, characterized in that: In step (4), the water pump decompression concentration conditions are vacuum 20-30 mmHg, temperature 50-60° C.; the distillation column is 20 cm long, and the glass spring filler is 10 cm long.

10. The preparation method according to claim 2, characterized in that: In step (4), the base is any one of potassium hydroxide, potassium tert-butoxide and sodium tert-butoxide.

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