CN113264936B

CN113264936B - JAK inhibitor key intermediate and preparation method thereof

Info

Publication number: CN113264936B
Application number: CN202110569423.5A
Authority: CN
Inventors: 孙光祥; 朱怡君; 金生华; 陈益林; 钱凯; 袁义淞; 张锡予; 王兵
Original assignee: Changzhou Pharmaceutical Factory Co ltd
Current assignee: Changzhou Pharmaceutical Factory Co ltd
Priority date: 2021-05-25
Filing date: 2021-05-25
Publication date: 2022-08-09
Anticipated expiration: 2041-05-25
Also published as: CN113264936A

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a phosphoric acid reed cotinib intermediate and a preparation method thereof, which comprises the following steps: carrying out hydrolysis deprotection reaction on the compound 2 under the action of phosphoric acid to generate a phosphate compound 3; in a certain solvent, directly adding the compound 3 with cyclopentyl acrylonitrile under the action of DBU to obtain a compound 4. Wherein, the compound 3 is not reported in documents, and the method has simple operation, mild condition, excellent yield and quality and is suitable for industrial production.

Description

JAK inhibitor key intermediate and preparation method thereof

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a JAK inhibitor trinomidine phosphate key intermediate and a preparation method thereof.

Background

Lucotinib Phosphate (Ruxolitinib Phosphate), developed by Incyte, was approved by the FDA in 2011 and marketed as the first approved drug for the treatment of myelofibrosis. European union and japanese PMDA were released into the market in 2012 and 2014 successively, and chinese CFDA was released into the market in 2017. The product is an oral JAK1 and JAK2 tyrosine kinase inhibitor, and is used for treating adult patients with intermediate-risk or high-risk primary myelofibrosis, myelofibrosis secondary to polycythemia vera or myelofibrosis secondary to primary thrombocythemia. The structural formula is as follows:

the synthesis method of the currently reported phosphoric acid reed cotinib is as follows:

method 1 Qiyan Lin et al in OL, 2009,11 (9): 1999, 2002, compounds 6 and 7 are used as starting materials, asymmetric addition is carried out under the catalysis of a small molecular compound 8 to obtain a compound 9, then aldehyde group is converted into cyano group to obtain a compound 10, and finally SEM protecting group is removed and salification is carried out to obtain a target product 1.

The method 2 comprises the following steps: zhou Jia et al in patent ZL CN105669676 uses

compounds

11 and 12 as starting materials, and obtains compound 14 by coupling and removing protective groups, and then adds with alkyne compound to obtain compound 15, and then obtains target chiral compound 16 by rhodium asymmetric catalytic hydrogenation, and finally hydrolyzes and salifies to obtain compound 1.

The method 3 comprises the following steps: zhou Jia et al in patent ZL CN102348693 use

compounds

11 and 12 as starting materials, and through coupling, removing protecting group to obtain compound 14, then adding cyclopentyl acrylonitrile to obtain compound 4, and then through resolution, hydrolysis and salification to obtain target chiral compound of rukulitinib 1.

In the existing synthesis method, the key chiral intermediate 9 or 16 is obtained by asymmetric induction, reduction or resolution of chiral micromolecules and chiral ligands. However, in the synthesis of key intermediate 4 of scheme 3, there are more reaction by-products: when the compound 2 is subjected to the removal of the pyrazole nitrogen protecting group by hydrochloric acid, the pivalic acid hydroxymethyl group is also easily removed, and more impurities 5 are generated

Affecting the product quality and reducing the yield. When compound 14 is added to cyclopentylacrylonitrile under the action of DBU, more bis (cyclopentylacrylonitrile) by-product 6 is generated

Affecting the product quality, reducing the yield and being not suitable for industrial amplification.

Therefore, finding a method with mild conditions and simple operation, which can be successfully used for the industrial production of the key intermediate 4 of the tricitabine phosphate, is a technical problem which needs to be solved in the field at present.

Disclosure of Invention

The technical problem to be solved by the invention is as follows: provides a key intermediate preparation method of the tricitabine phosphate with mild condition and simple operation.

The technical scheme for solving the technical problems is as follows:

a preparation method of a tricitabine phosphate intermediate is characterized by comprising the following steps:

(1) removing a protecting group of the compound 2 under the action of phosphoric acid to generate a compound 3;

(2) in a certain solvent, adding the compound 3 and cyclopentyl acrylonitrile to obtain a compound 4;

the reaction formula is shown as follows:

preferably, the solvent used in step (1) is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, methyl tert-butyl ether.

Preferably, the solvent used in step (2) is selected from acetonitrile, tetrahydrofuran, acetone.

Preferably, the molar ratio of cyclopentyl acrylonitrile to compound 3 in the step (2) is 4-2: 1.

Preferably, the proportion of the solvent in the step (2) is 15-30 times of the volume.

The reagents and starting materials used in the present invention are commercially available unless otherwise specified. The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.

The positive progress effects of the invention provided by the invention are as follows: the compound 3 is obtained by removing the protecting group through phosphoric acid, and the phosphoric acid and cyclopentyl acrylonitrile are added to obtain the key intermediate 4 of the triclitinib phosphate, so that the defects of more byproducts and lower yield caused by stronger acidity or alkalinity in the existing method are overcome. The method is simple to operate, mild in conditions and suitable for industrial production.

In a second aspect, the present invention provides an intermediate compound 3 of tricitabinib phosphate, which has the following structural formula:

drawings

FIG. 1 is a hydrogen spectrum of Compound 3 of example 1.

FIG. 2 is a mass spectrum of Compound 3 of example 1.

FIG. 3 is a TGA profile of compound 3 of example 1.

FIG. 4 shows the DSC profile of compound 3 of example 1.

FIG. 5 is a hydrogen spectrum of Compound 4 of example 1.

Detailed Description

The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.

Example 1:

preparation of (1H-pyrazol-4-yl) -7H-pyrolo [2,3-d ] pyrimidin-7-yl) methyl pivalate phosphate (Compound 3)

Compound 2(50g, 134.6mmol, 1eq) was dissolved in 250ml tetrahydrofuran, and 250ml phosphoric acid solution (1N) was added and heated to 50 ℃ for 4 h. TLC check (DCM: MeOH ═ 15:1) compound 2 had been essentially completely consumed and cooled. The solid was precipitated, filtered, the filter cake washed with tetrahydrofuran and dried at 50 ℃ to give about 48.1g of a white solid 3 (yield 90.0%). ¹ HNMR(DMSO-d ₆ ,400MHz):δ8.79(s,1H),8.52(s, 2H),7.72(d,1H,J＝4Hz),7.14(d，1H,J＝4Hz)，6.25(s,2H),1.10(m,9H)。MS(ESI ⁺ )： m/z 300.1[M+H] ⁺ 。

Preparation of (4- (1- (2-cyano-1-cyclopropenylethyl) -1H-pyrazol-4-yl) -7H-pyrolo [2,3-d ] pyrimidi n-7-yl) methyl pivalate (Compound 4)

A500 ml reaction flask was charged with the above compound 3(30g,75.5mmol,1eq), cyclopentylacrylonitrile (36.6g,0.3mol,4eq), 300ml acetonitrile, DBU (11.5g,75.5mmol,1eq) in that order, replaced with nitrogen 3 times, heated to 60 ℃ and reacted for 5 hours, and the system was clear. TLC detecting the material to complete the reaction, cooling, concentrating, adding ethyl acetate and water to the residueThe organic layer was dried and concentrated, and the residue was purified with ethyl acetate and n-hexane to obtain about 25.4g of an off-white solid (yield about 80.2%). ¹ HNMR(DMSO-d ₆ , 400MHz):δ8.86～8.81(d,2H,J＝20),8.42(s,1H),7.77(d,1H),7.13(d，1H)，6.26(d, 2H),6.84(d,1H),4.59～4.53(m,1H),3.28～3.18(m,2H),2.47～2.41(m,1H), 1.84～1.81(m,1H),1.62～1.33(m,7H),1.31(s,9H)。MS(ESI ⁺ )：m/z 46.16[M+H] ⁺ 。 MS(ESI ⁺ )：m/z 421.3[M+H] ⁺ 。

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.

Claims

1. A preparation method of a tricitabine phosphate intermediate is characterized by comprising the following steps:

(2) in a certain solvent, adding the compound 3 and cyclopentyl acrylonitrile in the presence of DBU to obtain a compound 4; the reaction formula is shown as follows:

wherein the solvent used in step (1) is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, methyl tert-butyl ether;

wherein the solvent used in the step (2) is selected from acetonitrile, tetrahydrofuran and acetone, and the molar ratio of cyclopentyl acrylonitrile to the compound 3 in the step (2) is 4-2: 1;

the said intermediate of the tricitabinib phosphate is compound 4.