A kind of ruxolitinib phosphate intermediate and preparation method thereof

Abstract

The present invention belongs to the field of medicine, and specifically relates to a ruxolitinib phosphate intermediate and a preparation method thereof, wherein N,N-diethylformamide is added to acetonitrile, oxalyl chloride is added dropwise to prepare a Vilsmayer reagent, and then 4-methylpyrrolopyrimidine is added to react to obtain the ruxolitinib phosphate intermediate, and the structural formula thereof is shown in Formula 2e: The ruxolitinib phosphate intermediate prepared by the present invention is non-sticky and has low hygroscopicity, and can be directly used in the next step reaction in a solid form, which is more conducive to industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a ruxolitinib phosphate intermediate and a preparation method thereof. Background Art

[0002] Ruxolitinib Phosphate can be used as an inhibitor of the Janus Kinase (JAK) family of protein tyrosine kinases, which is used to treat inflammatory diseases, myeloproliferative disorders and other diseases. It was approved for marketing by the US FDA in 2011 by Incyte, becoming the first approved drug specifically for the treatment of myelofibrosis. It was approved for marketing by the EU and Japan PMDA in 2012 and 2014 respectively, and approved for marketing by China CFDA in 2017. This product is an oral JAK1 and JAK2 tyrosine kinase inhibitor used to treat adult patients with intermediate-risk or high-risk primary myelofibrosis, myelofibrosis secondary to polycythemia vera, or myelofibrosis secondary to essential thrombocythemia.

[0003] The chemical name of the compound is: (3R)-3-cyclopentyl-3-4-[(7H pyrrolo[2,3-D]pyrimidin-4-yl)-1H-pyrazolyl]propionitrile phosphate, and the structural formula is as follows:

[0004]

[0005] Publication No. CN116761792A discloses a synthetic route of ruxolitinib phosphate:

[0006]

[0007] This route reports a method for synthesizing ruxolitinib phosphate, which uses compound 2c (structural formula shown in 2c) and compound 3a (structural formula shown in 3a) to condense to directly obtain ruxolitinib in high yield. Compared with the process in the original research company's patent CN102348693B, it has more cost advantages.

[0008] However, the patented process has the following deficiencies:

[0009] ①. Compound 2d (structural formula shown in 2d) obtained by repeated experiments is viscous and hygroscopic, which may affect the solid-liquid separation efficiency and product storage during the production process.

[0010] ②. Probably because of the above-mentioned defects of compound 2d, after obtaining compound 2d by this process, water is added to dissolve it, and sodium hydroxide is added to neutralize it to prepare an aqueous solution of compound 2c for the next step of feeding. Storing it in the form of a solution is usually not conducive to the stability of the substance.

[0011] Based on this, the present invention is proposed. Summary of the invention

[0012] The purpose of the present invention is to provide a ruxolitinib phosphate intermediate and a preparation method thereof, which mainly solves the disadvantages of compound 2d being viscous and hygroscopic. By screening the Vilsmeier reagent, it is found that compound 2e is a light yellow sandy solid, which is easy to separate solid from liquid, and has significantly improved hygroscopicity. It can be directly used as an intermediate in solid form for the next step of feeding, reducing the neutralization step and the product stability problem that may be caused by storage in solution form.

[0013] The present invention also provides a method for synthesizing the intermediate, using the following compounds 2e, 2f, and 2g to replace 2d, respectively. The specific technical scheme is as follows:

[0014] (1) Oxalyl chloride and N,N-diethylformamide are used to prepare the Vilsmeier reagent, which is reacted with compound 1a (4-methylpyrrolopyrimidine, whose structural formula is shown in formula 1a, and the same applies below) to generate compound 2e:

[0015]

[0016] (2) The Vilsmeier reagent prepared by using oxalyl chloride and N,N-diethylformamide reacts with compound 1a to generate compound 2f:

[0017]

[0018] (3) The Vilsmeier reagent prepared by using oxalyl chloride and N,N-diethylformamide reacts with compound 1a to generate compound 2g:

[0019]

[0020] Among the above-mentioned compounds 2e, 2f and 2g, compound 2e has good viscosity and hygroscopicity, so compound 2e is selected as the target compound. The specific preparation method of compound 2e and the method for further preparing the phosphate of compound 1 are as follows:

[0021] (1) Synthesis of intermediate 2e: Under nitrogen protection, add N,N-diethylformamide to acetonitrile, cool to 0±5°C, and add oxalyl chloride dropwise under temperature control. After the addition is completed, heat to 25±5°C and stir for half an hour, add compound 1a, and then heat to 80±5°C and stir for 2 hours. After the reaction is completed, cool to 60±5°C and add tetrahydrofuran dropwise. After the addition is completed, cool to 0±5°C and stir for 2 hours, and filter to obtain a wet product of compound 2e.

[0022] (2) Synthesis of Compound 1 Phosphate: Add the wet compound 2e to water, add sodium hydroxide solution at a temperature of 0-10°C, add 3a and ethanol after the addition, raise the temperature to 80±5°C and stir for 6 hours. After the reaction is completed, add dichloromethane and water for extraction, add isopropanol phosphoric acid solution to the organic phase, slowly cool down after the addition to crystallize, filter and dry to obtain Compound 1 Phosphate.

[0023] Beneficial effects of the present invention:

[0024] 1. Compound 2e is the intermediate of ruxolitinib phosphate, and its chemical name is: (E)-N-(3-(diethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethylammonium chloride hydrochloride, which is a light yellow sandy solid, easy to filter and separate, and has low hygroscopicity.

[0025] 2. Compound 2e can be directly fed to the next step in solid form without the need for alkali neutralization and the resulting compound stability issues. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is the LC-MS spectrum of compound 2e;

[0027] Figure 2 is the H-NMR spectrum of compound 2e. DETAILED DESCRIPTION

[0028] The present invention is further described in detail below through specific embodiments in conjunction with the accompanying drawings.

[0029] Embodiment 1:

[0030]

[0031] 273.5g (2.70mol) N,N-diethylformamide and 150ml acetonitrile (ACN) were added to a 1L three-necked flask, and the nitrogen was replaced three times, and the temperature was lowered to 0±5°C. 85.8g (0.68mol) of oxalyl chloride was added dropwise under temperature control. After the addition, the temperature was raised to 20-30°C and stirred for 30 minutes. 30g of compound 1a (0.23mol) was added, and the temperature was raised to 80-85°C and reacted for 2 hours after the addition. After the reaction was completed, the temperature was lowered to 60±5°C, 300ml of tetrahydrofuran was added dropwise, and the temperature was slowly lowered to 0±5°C after the addition, stirred for 2 hours, filtered, and dried to obtain 85.4g of light yellow solid, which is compound 2e (structural formula is shown in formula 2e), and the yield: 101.8% (detected to contain 7.6% N,N-diethylformamide and 1.3% acetonitrile), purity: 99.4%. For compound 2e: 1H NMR (DMSO-d6) δ 12.73 (s, 1H), 8.92 (s, 1H), 7.78 (s, 1H), 6.58 (s, 1H), 3.52-3.53 (d, 4H), 2.74 (s, 4H), 1.26-1.29 (t, 6H), 0.58 (s, 6H) ppm; LC-MS (ESI): m / e = 300.3 (M+, base peak, the molecular weight of compound 2e is 372.34, and the molecular weight of the compound without anion is 300.43).

[0032] Its identification structure data are as follows:

[0033] The LCMS spectrum of compound 2e is shown in Figure 1 ;

[0034] The HNMR spectrum of compound 2e is shown in Figure 2 .

[0035] Example 2

[0036]

[0037] Add 85.4g of compound 2e and 120ml of water to a 1L three-necked flask, cool to 0±5°C, add sodium hydroxide solution (15g of sodium hydroxide, 60ml of water), add 76.5g (0.23mol) of compound 3a and 75ml of ethanol after the dropwise addition, and react at 30±5°C for 6 hours. After the reaction is completed, add 360ml of dichloromethane and extract with 240ml of water, and extract the aqueous phase once with 180ml of dichloromethane. Combine the organic phases and wash once with 240ml of water. Obtain the organic phase, add isopropanol phosphoric acid solution (27.3g of phosphoric acid, 0.24mol, 60ml of isopropanol) at 30±5°C, stir for 1 hour after the dropwise addition, cool to 15±5°C, stir for 2 hours, filter, obtain the wet product, and dry at 50°C to obtain the phosphate of compound 1. Yield: 89.5%, purity: 99.6%.

[0038] Compound 2d and compound 2e were prepared by the above process description. According to the hygroscopicity test method of the pharmacopoeia, compound 2d was detected to be hygroscopic, and compound 2e was slightly hygroscopic. The specific data are as follows:

[0039] Compound Name Weight before test Weight after test Weight gain percentage Hygroscopicity Compound 2d 5.0g 5.21g 4.2％ Hygroscopic Compound 2e 5.0g 5.03g 0.6％ Slightly hygroscopic

[0040] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a ruxolitinib phosphate intermediate, characterized in that: The following steps are involved: N,N-diethylformamide is added to acetonitrile, oxalyl chloride is added dropwise to prepare Vilsmeier reagent, and then 4-methylpyrrolopyrimidine is added, and the structural formula of 4-methylpyrrolopyrimidine is shown in Formula 1a; after the reaction is completed, tetrahydrofuran is added, and the temperature is reduced and crystallization is carried out, and the ruxolitinib phosphate intermediate is obtained by filtration, and its structural formula is shown in Formula 2e.

2. The method for preparing a ruxolitinib phosphate intermediate according to claim 1, characterized in that: The temperature of the oxalyl chloride is controlled at -5 to 5°C during the addition process.

3. The method for preparing a ruxolitinib phosphate intermediate according to claim 1, characterized in that: The temperature of the 4-methylpyrrolopyrimidine is controlled at 20-30° C. during the addition process.

4. The method for preparing a ruxolitinib phosphate intermediate according to claim 1, characterized in that: The molar ratio of the amount of 4-methylpyrrolopyrimidine to oxalyl chloride and N,N-diethylformamide is 1:(2.5-3.5):(11-13).

5. The method for preparing a ruxolitinib phosphate intermediate according to claim 1, characterized in that: The volume ratio of the amount of 4-methylpyrrolopyrimidine to acetonitrile and tetrahydrofuran is 1:(4-6):(9-11).

6. The method for preparing a ruxolitinib phosphate intermediate according to claim 1, characterized in that: The reaction temperature is 80-85°C.

7. The method for preparing a ruxolitinib phosphate intermediate according to claim 1, characterized in that: The crystallization temperature is -5 to 5°C.

8. A ruxolitinib phosphate intermediate, characterized in that: Its structural formula is shown in Formula 2e, and it is prepared by the preparation method of a ruxolitinib phosphate intermediate as described in any one of claims 1 to 7.

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