阅读说明：本技术 一种磷丙替诺福韦杂质的制备方法 (Preparation method of fosaprevir impurity ) 是由 冉艳 蒲通 陈恬 王乃星 李建学 朱燕萍 钟惺 泮育平 于 2020-03-13 设计创作，主要内容包括：本发明公开了一种式II所示的磷丙替诺福韦杂质的制备方法,所述制备方法的反应路线如下:<Image he="120" wi="700" file="DDA0002409878550000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>所述反应在复合催化剂的催化下进行；所述复合催化剂是由有机碱A和有机碱B组成,所述的有机碱A选自三乙胺、N,N-二异丙基乙胺、二乙胺、二异丙胺中的至少一种,所述的有机碱B选自4-二甲氨基吡啶、咪唑、吡啶、4-二甲基吡啶中的至少一种。本发明具有反应转化率高、所得产物纯度高的优势。(The invention discloses a preparation method of a fosinoprofovir impurity shown in a formula II, which comprises the following reaction route: the reaction is carried out under the catalysis of a composite catalyst; the composite catalyst consists of an organic base A and an organic base B, wherein the organic base A is selected from at least one of triethylamine, N-diisopropylethylamine, diethylamine and diisopropylamine, and the organic base B is selected from at least one of 4-dimethylaminopyridine, imidazole, pyridine and 4-dimethylpyridine. The method has the advantages of high reaction conversion rate and high purity of the obtained product.)

1. A preparation method of PMPA anhydride shown in formula II comprises the following reaction route:

the reaction is carried out under the catalysis of a composite catalyst; the composite catalyst consists of an organic base A and an organic base B, wherein the organic base A is selected from at least one of triethylamine, N-diisopropylethylamine, diethylamine and diisopropylamine, and the organic base B is selected from at least one of 4-dimethylaminopyridine, imidazole, pyridine and 4-dimethylpyridine.

2. The process for the preparation of PMPA anhydride of claim 1, characterized in that: in the composite catalyst, the molar ratio of the organic base A to the organic base B is 1: 0.5 to 1.

3. The process for the preparation of PMPA anhydride according to claim 2, characterized in that: the composite catalyst is prepared from triethylamine and 4-dimethylaminopyridine according to a molar ratio of 1: 0.5-1, preferably the molar ratio of the triethylamine to the 4-dimethylaminopyridine is 1: 0.5.

4. process for the preparation of PMPA anhydride according to any one of claims 1 to 4, characterized in that: the preparation method is carried out as follows: dissolving the compound I in an organic solvent, adding a composite catalyst and a dehydrating agent, and preparing PMPA anhydride shown in a formula II through a dehydration reaction.

5. The process for the preparation of PMPA anhydride according to claim 4, characterized in that: PMPA anhydride was obtained using the following work-up procedure: after the reaction is finished, cooling the reaction liquid to room temperature, adjusting the pH value to 2-3, fully stirring and filtering, adding water into the obtained filter cake, uniformly stirring, adjusting the pH value to 9-10, fully stirring and filtering, cooling the obtained filtrate to 0-5 ℃, adjusting the pH value to 2-3 again, carrying out heat preservation and crystallization for 2-10 h, filtering, and drying the obtained filter cake at 75-90 ℃ for 8-10 h to obtain the white solid PMPA anhydride.

6. The process for the preparation of PMPA anhydride according to claim 5, characterized in that: the pH value is adjusted to 2-3, and heat preservation and crystallization are carried out for 2-10 h according to the following steps: adjusting the pH value to 3, adding a small amount of seed crystals, stirring for 2-4 h under heat preservation, precipitating a solid, continuously adjusting the pH value to 2.0-2.5, and crystallizing for 4-6 h under heat preservation.

7. The process for the preparation of PMPA anhydride according to claim 4 or claim, characterized in that: the organic solvent is selected from one of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, toluene and sulfolane, preferably acetonitrile; the dehydrating agent is one of N, N '-dicyclohexylcarbodiimide, diisopropylcarbodiimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, and N, N' -dicyclohexylcarbodiimide is more preferable.

8. The process for the preparation of PMPA anhydride according to claim 4 or claim, characterized in that: the molar ratio of the composite catalyst to the compound I is 2-4, and more preferably 2.5-3; the feeding weight ratio of the organic solvent to the compound I is 6-12, and the preferable weight ratio is 8-10; the molar ratio of the dehydrating agent to the compound I is 0.5-2, and more preferably 1.5-2.

9. The process for the preparation of PMPA anhydride according to claim 5 or claim, characterized in that: the reaction temperature of the dehydration reaction is 40-80 ℃, and more preferably 50-60 ℃; the reaction time of the dehydration reaction is 15-30 h, and more preferably 20-24 h.

10. The process for the preparation of PMPA anhydride of claim 1, characterized in that: the preparation method of the PMPA anhydride is implemented as follows: dissolving a compound I in acetonitrile, adding a composite catalyst of triethylamine/4-dimethylaminopyridine and a dehydrating agent N, N' -dicyclohexylcarbodiimide, performing dehydration reaction at 50-60 ℃ for 20-24 h, cooling a reaction solution to room temperature after the reaction is finished, adjusting the pH to 2-3, fully stirring and filtering, adding water into an obtained filter cake, uniformly stirring, adjusting the pH to 9-10, fully stirring and filtering, cooling the obtained filtrate to 0-5 ℃, adjusting the pH to 3 again, adding a small amount of seed crystal, stirring at a constant temperature for 2-4 h, precipitating a solid, continuously adjusting the pH to 2.0-2.5, performing heat preservation and crystallization for 4-6 h, filtering, and drying the obtained filter cake at 75-90 ℃ for 8-10 h to obtain white solid PMPA anhydride;

the molar ratio of triethylamine to 4-dimethylaminopyridine in the composite catalyst is 1: 0.5-1, wherein the feeding molar ratio of the composite catalyst to the compound I is 2.5-3, the feeding molar ratio of the dehydrating agent to the compound I is 1.5-2, and the feeding weight ratio of acetonitrile to the compound I is 8-10.

Technical Field

The invention relates to a preparation method of a drug impurity, in particular to a preparation method of PMPA anhydride impurity (chemical name is (R) - [ [2- (6-amino-9H-purine-9-yl) propoxy ] methyl ] phosphoric anhydride, CAS:1607007-18-0) in a phosphopropanetenofovir bulk drug, belonging to the technical field of medicines and intermediates thereof.

Background

Fosforvir phosphate (TAF) is a new generation of nucleoside reverse transcriptase inhibitors developed by the united states giride corporation on the basis of Tenofovir Disoproxil Fumarate (TDF). Unlike the chain phosphate structure in TDF, TAF contains phenol phosphate and isopropyl phosphoryl alaninate fragment, so that the plasma stability is outstanding, the structural integrity can be maintained to a great extent after entering infected cells, and metabolic instability and renal and bone toxicity caused by metabolic instability can be effectively avoided. Since 2016, various anti-HBV or anti-HIV TAF single or compound preparations (such as Vemlidy, Genvoya, Odefsey, Descovy) were successively approved by European drug administration and U.S. FDA, and TAF is becoming a serious apparatus of Gilide in infectious inflammation. The currently reported process route for synthesizing the fospronofovir is mainly from a starting material PMPA, and the starting material PMPA is connected with a phenoxy part to obtain a key intermediate 1 (GS-6948). Then activating, grafting L-isopropyl alanine part to obtain free alkali GS-7340, and finally salifying with fumaric acid to obtain TAF.

Currently, two process routes are mainly used for synthesizing the key intermediate 1 (GS-6948). The original Gmelide 2001 route to WO0208241A2 reported on DCC/Et via PMPA with phenol₃GS-6948 was produced under N conditions (scheme 1). In 2012, the DMAP/Et reaction of PMPA and triphenyl phosphite was reported by Gilidde in the route of WO2013052094A2₃N condensation to give the key intermediate GS-6948 (scheme 2). It has been found that PMPA anhydride participates as a key reactive intermediate in either the conditions of scheme 1 or scheme 2Among them, and become a key process impurity present in the synthesis stage of PMPA to GS-6948. It is even mentioned in the route of the patent WO2013052094A2 that the PMPA anhydride content should be less than 5% when determining the end of the reaction.

Currently, the synthetic route for preparing PMPA anhydride impurities is very few, and CN 109081853A discloses that PMPA anhydride is prepared from PMPA as a raw material by DIPEA/DCC under the DMF condition, but the yield is very low, only about 40%, and a preparation column is required for purification and refining in the later stage, so that the operation is complex.

Disclosure of Invention

The invention aims to provide a preparation method of a phosphopronofovir impurity-PMPA anhydride with high reaction conversion rate and high purity of the obtained product.

In order to achieve the purpose, the invention adopts the following technical scheme:

a preparation method of PMPA anhydride shown in formula II comprises the following reaction route:

the reaction is carried out under the catalysis of a composite catalyst; the composite catalyst consists of an organic base A and an organic base B, wherein the organic base A is selected from at least one of triethylamine, N-diisopropylethylamine, diethylamine and diisopropylamine, and the organic base B is selected from at least one of 4-dimethylaminopyridine, imidazole, pyridine and 4-dimethylpyridine.

The invention specifically recommends that the preparation method is carried out as follows: dissolving the compound I in an organic solvent, adding a composite catalyst and a dehydrating agent, and preparing PMPA anhydride shown in a formula II through a dehydration reaction.

According to the preparation method of PMPA anhydride, the use of the composite catalyst can effectively improve the reaction conversion rate.

Preferably, in the composite catalyst, the molar ratio of the organic base A to the organic base B is 1: 0.5 to 1. Further preferably, the composite catalyst is prepared by mixing triethylamine and 4-dimethylaminopyridine according to a molar ratio of 1: 0.5-1, and more preferably the molar ratio of triethylamine to 4-dimethylaminopyridine is 1: 0.5.

preferably, the molar ratio of the composite catalyst to the compound I is 2-4, and more preferably 2.5-3.

Preferably, the reaction temperature of the dehydration reaction is 40-80 ℃, and more preferably 50-60 ℃.

Preferably, the reaction time of the dehydration reaction is 15-30 h, and more preferably 20-24 h.

Preferably, the organic solvent is selected from one of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, toluene and sulfolane, and more preferably acetonitrile. Preferably, the charging weight ratio of the organic solvent to the compound I is 6-12, and more preferably 8-10.

Preferably, the dehydrating agent is one selected from Ν, Ν '-dicyclohexylcarbodiimide, diisopropylcarbodiimide, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, and Ν, Ν' -dicyclohexylcarbodiimide is more preferable. Preferably, the molar ratio of the dehydrating agent to the compound I is 0.5-2, and more preferably 1.5-2.

Preferably, the PMPA anhydride is obtained by the following work-up: after the reaction is finished, cooling the reaction liquid to room temperature, adjusting the pH value to 2-3, fully stirring and filtering, adding water into the obtained filter cake, uniformly stirring, adjusting the pH value to 9-10, fully stirring and filtering, cooling the obtained filtrate to 0-5 ℃, adjusting the pH value to 2-3 again, carrying out heat preservation and crystallization for 2-10 h, filtering, and drying the obtained filter cake at 75-90 ℃ for 8-10 h to obtain the white solid PMPA anhydride. The post-treatment method of the invention has simple operation, high product yield and high HPLC purity of more than 98 percent. Further preferably, the pH value is adjusted to 2-3, and heat preservation and crystallization are carried out for 2-10 h according to the following steps: adjusting the pH value to 3, adding a small amount of seed crystals, stirring for 2-4 h under heat preservation, precipitating a solid, continuously adjusting the pH value to 2.0-2.5, and crystallizing for 4-6 h under heat preservation.

In the present invention, hydrochloric acid is generally used to adjust the pH to acidic, and sodium hydroxide is generally used to adjust the pH to basic.

The process for the preparation of the PMPA anhydride according to the invention is particularly preferably carried out as follows: dissolving a compound I in acetonitrile, adding a composite catalyst of triethylamine/4-dimethylaminopyridine and a dehydrating agent N, N' -dicyclohexylcarbodiimide, performing dehydration reaction at 50-60 ℃ for 20-24 h, cooling a reaction solution to room temperature after the reaction is finished, adjusting the pH to 2-3, fully stirring and filtering, adding water into an obtained filter cake, uniformly stirring, adjusting the pH to 9-10, fully stirring and filtering, cooling the obtained filtrate to 0-5 ℃, adjusting the pH to 3 again, adding a small amount of seed crystal, stirring at a constant temperature for 2-4 h, precipitating a solid, continuously adjusting the pH to 2.0-2.5, performing heat preservation and crystallization for 4-6 h, filtering, and drying the obtained filter cake at 75-90 ℃ for 8-10 h to obtain white solid PMPA anhydride;

the molar ratio of triethylamine to 4-dimethylaminopyridine in the composite catalyst is 1: 0.5-1, wherein the feeding molar ratio of the composite catalyst to the compound I is 2.5-3, the feeding molar ratio of the dehydrating agent to the compound I is 1.5-2, and the feeding weight ratio of acetonitrile to the compound I is 8-10.

Compared with the prior art, the invention has the advantages that:

(1) the invention uses the composite catalyst to prepare the impurity PMPA anhydride of the fosinoprofovir, and can effectively improve the reaction conversion rate.

(2) The post-treatment method adopted by the invention is simple to operate, and the product has high yield and high purity (the HPLC purity is more than 98%).

(3) The dehydration reaction condition of the invention is mild (the preferable reaction temperature is 50-60 ℃), and the catalyst dosage is less.

In conclusion, the preparation method of the impurity PMPA anhydride of the fosinoprofovir has the advantages of mild reaction conditions, simple post-treatment operation and high purity of the obtained product, and is more beneficial to the research of the impurity reference substance of the fosinoprofovir.

Drawings

FIG. 1 HPLC plot of PMPA anhydride in example I;

FIG. 2 implementationPreparation of PMPA anhydride from example I¹An H-NMR spectrum;

FIG. 3 preparation of PMPA anhydride in example I¹³A C-NMR spectrum;

Detailed Description

The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift () at 10^-6The units in (ppm) are given. NMR was measured using a (Bruker Avance III 600) nuclear magnetic spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Measurement of Tetramethylsilane (TMS) MS as an internal standard (Agilent 6120B (ESI)) HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100 × 4.6.6 mm).

Known starting materials for the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical, Shaoshou chemical technology, and Bailingwei technology.