CN112175003A

CN112175003A - Preparation method of phenyl hydrogen phosphonate and intermediate thereof

Info

Publication number: CN112175003A
Application number: CN201910586195.5A
Authority: CN
Inventors: 张庆文; 任杰; 刘秀萍
Original assignee: Shanghai Institute of Pharmaceutical Industry; China State Institute of Pharmaceutical Industry
Current assignee: Shanghai Institute of Pharmaceutical Industry; China State Institute of Pharmaceutical Industry
Priority date: 2019-07-01
Filing date: 2019-07-01
Publication date: 2021-01-05
Anticipated expiration: 2039-07-01
Also published as: CN112175003B; CN114409706B; CN114409706A

Abstract

The invention discloses a preparation method of phenyl hydrogen phosphonate and an intermediate thereof. The invention provides a preparation method of phenyl hydrogen phosphonate, which comprises the following steps of (1) in an aprotic solvent, carrying out nucleophilic substitution reaction shown in the specification on a mixture of a Grignard reagent, tert-butyl alcohol and (R) -9- (2-hydroxypropyl) adenine and a benzene sulfonyl oxygen group methyl phosphonate compound shown in a formula I to obtain tenofovir disoproxil diphenyl ester (14); in a solvent, in the presence of alkali, carrying out hydrolysis reaction on the tenofovir disoproxil diphenyl ester as shown in the specification to obtain phenyl hydrogen phosphonate as shown in the formula (1); wherein X is halogen or C₁‑C₆Alkyl or nitro. The preparation method has the advantages of cheap and easily obtained raw materials, simple reaction operation, high repeatability and good amplifiability.

Description

Preparation method of phenyl hydrogen phosphonate and intermediate thereof

Technical Field

The invention relates to a preparation method of phenyl hydrogen phosphonate and an intermediate thereof. In particular, the present invention relates to processes for the preparation of phenylhydrogen (((((R) -1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) phosphonate and intermediates thereof.

Background

Tenofovir fumarate (TAF), chemically ((S) - ((((R) -1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (phenoxy) phosphoryl) -L-alanine isopropyl ester, (2E) -2-butenedioate (2:1), is a targeted prodrug of the reverse transcriptase inhibitor Tenofovir (PMPA), clinically used as a single agent for the treatment of chronic hepatitis B, and as a compound for the treatment of AIDS.

Phenylhydrogen ((((R) -1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) phosphonate (1, hereinafter referred to as tenofovir phenyl ester) is a key intermediate for the synthesis of propanefenovir fumarate (TAF). For example, the preparation method applied by Gilead corporation, patent WO2013052094(CN103842366B), discloses that tenofovir phenyl ester 1 is chlorinated with thionyl chloride to obtain 2; 2 reacting with L-alanine isopropyl ester hydrochloride (3) to obtain a mixture 4 of the propofol tenofovir and the diastereoisomer with the (R, R, S) configuration; 4 in acetonitrile and in the presence of phenol and DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene), and obtaining the prophenoltenofovir (5) with high diastereoisomer purity through crystallization-induced kinetic resolution. Propofol tenofovir (5) is reacted with fumaric acid to form the salt according to, for example, US8754065B, yielding Propofol tenofovir fumarate (2:1) (TAF).

Two preparation methods of tenofovir disoproxil 1 exist. A preparation method (Gilead company patents WO 2002008241 and WO2013052094, Brown Ripin and other Organic Process Research & Development,2010,14(5):1194-1201) is that adenine (6) and (R) -propylene carbonate (7) are used as starting materials, sodium hydroxide or potassium hydroxide is used as a catalyst in N, N-Dimethylformamide (DMF), and (R) -9- (2-hydroxypropyl) adenine (8) is obtained by reaction; performing alkylation reaction on 8 and diethyl p-toluenesulfonyloxymethylphosphonate (DESMP,9) under the catalysis of magnesium tert-butoxide (MTB) to obtain (R) -9- [2- (diethoxyphosphonomethoxy) propyl ] adenine (10); 10 removing diethyl under the action of trimethyl bromosilane (TMSBr) or the substituted combination of trimethyl chlorosilane and sodium bromide to obtain an intermediate tenofovir (PMPA, 11); 11 in acetonitrile and in the presence of 4-Dimethylaminopyridine (DMAP) and triethylamine, and obtaining tenofovir phenyl ester 1 through esterification of triphenyl phosphite.

The defect is that 8 is firstly reacted with diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) (9) to prepare a diethyl ester intermediate 10, then diethyl is removed to prepare tenofovir (11), and the reaction steps are long; in the nucleophilic substitution reaction for preparing intermediate 10 from intermediates 8 and 9, magnesium tert-butoxide (MTB) which is expensive, poorly durable, and troublesome in post-treatment, and NMP (N-methylpyrrolidone) which is a high boiling point solvent are used, and intermediate 10 cannot be isolated and purified; the preparation of tenofovir (11) from intermediate 10 via a hydrolysis reaction requires the use of expensive, corrosive and moisture sensitive trimethylbromosilane (TMSBr), or an alternative combination thereof. Riley et al (Organic Process Research & Development,2016,20(4):742-750) reported isolation and purification of intermediate 10, but because of the high water solubility of the diethyl ester intermediate 10, continuous extraction using chloroform was required for 24 hours; chloroform is a potential mutagenic agent, is not friendly to the environment and is a first class of solvent with limited use; the use of dichloromethane instead of chloroform resulted in a significant decrease in extraction yield (see pages 747 to 748, read work AND PRODUCT ISOLATION); the method is not suitable for industrial production. In addition, when tenofovir phenyl ester 1 is synthesized from tenofovir (11), triphenyl phosphite which is irritant, allergenic and environmentally toxic is used; and only one of the three phenyl esters can be used, and the atom economy is poor. In particular, the preparation of tenofovir phenyl ester 1 from tenofovir (11) requires anhydrous reaction conditions. However, tenofovir (11) is a stable monohydrate and removal of the crystalline water prior to use is difficult: it is necessary to remove the crystal water azeotropically by adding cyclohexane or toluene to NMP or by vacuum drying (70-90 ℃ C.) in a rotary type dryer. In practical applications, the two methods are often combined. The tenofovir after the crystal water is removed is very easy to absorb moisture and is combined with water again to form stable tenofovir monohydrate. Therefore, the tenofovir dehydration operation is complicated, the efficiency is low and the energy consumption is large.

Chinese patent CN104817593B discloses another preparation method of tenofovir disoproxil 1. Taking diphenyl phosphite (12) as an initial raw material, and carrying out hydroxymethylation reaction with paraformaldehyde to obtain diphenyl hydroxymethylphosphonate (13); 13, reacting with p-toluenesulfonyl chloride (TsCl) to obtain p-toluenesulfonyloxymethylphosphonic acid diphenyl ester (Ia); ia and (R) -9- (2-hydroxypropyl) adenine (8) are subjected to nucleophilic substitution reaction (condensation reaction in the original patent) under the catalysis of alkali to obtain diphenyl (R) - ((1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) phosphonate (14, which is referred to as tenofovir disoproxil hydrochloride for short in the following); 14, obtaining the tenofovir disoproxil 1 through alkaline hydrolysis. Wherein, the base used in the nucleophilic substitution reaction is potassium tert-butoxide, sodium hydride, magnesium tert-butoxide or lithium tert-butoxide, and the solvent used in the nucleophilic substitution reaction is NMP, DMF or tetrahydrofuran. Among them, the base used in the alkaline hydrolysis reaction is an inorganic base, preferably an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably an aqueous solution of an alkali metal hydroxide; the solvent used in the alkaline hydrolysis reaction is tetrahydrofuran or methanol. One synthetic route for tenofovir disoproxil 1 disclosed in CN104817593B is shown below:

chinese patent application CN105153231A discloses a preparation method of tenofovir disoproxil 1 very similar to CN 104817593B. The synthetic route of tenofovir disoproxil 1 disclosed in CN105153231A is shown as follows:

the preparation method of the tenofovir phenyl ester 1 bypasses an intermediate tenofovir (PMPA), the needed phenyl ester is directly introduced from the raw material, expensive, corrosive and moisture sensitive trimethyl bromosilane (TMSBr) or substituted combination thereof is abolished from the source, and the water removal step of tenofovir monohydrate, which is complicated to operate and low in efficiency, is avoided. However, when we repeat the operation steps of the embodiment of the above patent CN104817593B, we find that there are three technical bottlenecks: first, the reaction of diphenyl phosphite (12) with paraformaldehyde does not allow the stable production of diphenyl hydroxymethylphosphonate (13) in high yield.

Other documents also report various methods for preparing diphenyl hydroxymethylphosphonate (13). Mackman et al (Bioorganic & Medicinal Chemistry,2010,18(10):3606-3617) reported that polyformaldehyde was reacted with iodotrimethylsilane (TMSI), diphenyl phosphite (12) was added and reacted in the dark, and finally, diphenyl hydroxymethylphosphonate (13) was obtained by column chromatography with a yield of 55%. The drawback is the use of expensive, photo-labile Trimethyoldosilane (TMSI).

EXAMPLE 3 of US4740608 discloses that paraformaldehyde is first reacted with TMSI, followed by the addition of diphenyl methylphosphite (15) and finally by column chromatography to yield diphenyl hydroxymethylphosphonate in 76% yield. The disadvantages are that 15 is not available commercially, additional preparation is required, a round tube distiller (bulb to bulb) is required for purification, and the yield is only 50%.

PREPARATION EXAMPLE 4 of US6613848B1 discloses reacting diphenyl phosphite (12) with paraformaldehyde in xylene at 138 ℃, cooling to room temperature to precipitate a solid, purifying with tetrahydrofuran to obtain diphenyl hydroxymethylphosphonate (13) in 96% yield and melting point 72-96 ℃. However, repeating the operation of the examples did not reveal the formation of the desired product.

Secondly, according to CN104817593B paragraph [0055]Operation, the main product obtained by the reaction of the diphenyl hydroxymethylphosphonate (13) and the p-toluenesulfonyl chloride (TsCl) is confirmed to be p-toluenesulfonate phenyl ester (Ia') through the structure, and the yield is 70 percent; the target compound Ia was not obtained. Paragraph [0056 ] CN104817593B]、[0057]The nmr hydrogen spectra data of the prepared product are disclosed as:¹H NMR(CDCl₃)7.40-7.60(m,4H),6.90-7.35(m,6H),5.3(m,2H),3.8(d,1H),3.75(d,1H),3.2(s, 3H). It should be noted that the target compound diphenyl p-toluenesulfonyloxymethylphosphonate (Ia) has three benzene ring structures in the molecular structure, two are monosubstituted phenyl groups, and 10 phenyl arylhydrogens should exist; one is a para-disubstituted phenyl group, there should be 4 phenylarylhydrogens; there are a total of 14 phenylarylhydrogens. However, CN104817593B discloses a total of 10 aromatic hydrogens at two positions of 7.40-7.60(m,4H) and 6.90-7.35(m, 6H). In addition, the molecular structure of the target compound Ia has a methylene group bonded to the P and O atoms. However, 5.3(m,2H), 3.8(d,1H) and 3.75(d,1H) in the nmr spectrum disclosed in CN104817593B do not correspond to the methylene group. Thus, the nuclear magnetic resonance hydrogen spectrum of the product disclosed in CN104817593B does not conform to the molecular structure of the target compound diphenyl p-toluenesulfonyloxymethylphosphonate (Ia).

Thirdly, when the diphenyl tenofovir 14 is prepared by nucleophilic substitution reaction of Ia and 8, the objective compound 14 cannot be isolated according to the procedure of CN104817593B example, using potassium tert-butoxide, sodium hydride, magnesium tert-butoxide or lithium tert-butoxide as a base, and NMP, DMF or tetrahydrofuran as a solvent.

We have found a technical bottleneck similar to that of CN104817593B described above when we repeated the operation steps of the embodiment of the above patent application CN 105153231A. For example, the procedure of example 1 in accordance with CN105153231A did not yield the desired compound diphenyl p-toluenesulfonyloxymethylphosphonate (Ia).

Disclosure of Invention

The invention aims to solve the technical problem of the process defect of the existing preparation method of tenofovir phenyl ester and an intermediate thereof, which restricts industrial production, and provides a new preparation method of phenyl hydrogen phosphonate and the intermediate thereof. According to the preparation method, the target compound can be finally prepared by taking the diphenyl hydroxymethylphosphonate (13) as an initial material and passing through the benzenesulfonyloxymethylphosphonate compound and the diphenyl tenofovir oxide 14. The preparation method has the advantages of cheap and easily obtained raw materials, simple reaction operation, high repeatability and good amplifiability.

The present invention solves the above-mentioned problems by the following technical means.

The invention provides a preparation method of a benzene sulfonyl oxygen methyl phosphonate compound shown in a formula I, which comprises the following steps of adding an acid-binding agent into a mixture of diphenyl hydroxymethyl phosphonate (13) and a compound shown in a formula II in an organic solvent at the temperature of-20-0 ℃ to carry out a sulfonylation reaction shown in the following step to obtain the benzene sulfonyl oxygen methyl phosphonate compound shown in the formula I; the temperature of the sulfonylation reaction is-20 ℃ to 20 ℃;

wherein X is halogen or C₁-C₆Alkyl or nitro.

Wherein, the organic solvent can be an organic solvent conventional in the reaction in the field, such as an aprotic solvent, and in the invention, preferably one or more of a halogenated alkane solvent (such as dichloromethane), an aromatic hydrocarbon solvent (such as toluene), an ester solvent (such as ethyl acetate) and a ketone solvent (such as acetone); preferably dichloromethane.

The acid-binding agent can be an acid-binding agent conventional in the reaction in the field, and in the invention, a tertiary amine acid-binding agent (such as triethylamine and/or pyridine) is preferred, and triethylamine is more preferred.

The amount of the organic solvent to be used is not particularly limited so as not to affect the reaction. In the present invention, the molar volume ratio of diphenyl hydroxymethylphosphonate (13) to the organic solvent is preferably 0.1 to 1mol/L (e.g., 0.4 mol/L).

The molar ratio of the diphenyl hydroxymethylphosphonate (13) to the compound shown in the formula II can be a molar ratio conventionally used in the reactions in the field, and in the present invention, is preferably 1:1 to 1:1.2 (e.g., 1: 1.02).

The molar ratio of the acid-binding agent to the compound represented by the formula II may be a molar ratio conventionally used in the reaction in the field, and in the present invention, is preferably 1:1 to 2:1 (e.g., 1.1:1 to 1.7: 1).

The acid-binding agent is added into the mixture of the diphenyl hydroxymethylphosphonate (13) and the compound shown in the formula II, and the temperature is preferably-15 ℃ to-5 ℃ (for example, -10 ℃).

The temperature of the sulfonylation reaction is preferably-10 ℃ to 15 ℃; when the acid-binding agent is triethylamine, the temperature is more preferably-10-0 ℃; when the acid-binding agent is pyridine, the temperature is more preferably-10 ℃ to 15 ℃.

The sulfonylation reaction may be carried out in the presence of a shielding gas conventional in such reactions in the art, preferably one or more of argon, nitrogen, helium and neon.

The progress of the sulfonylation reaction can be monitored by a monitoring method (such as TLC, LCMS, HPLC or NMR) which is conventional in the art, and is generally regarded as the end point of the reaction when the diphenyl hydroxymethylphosphonate disappears or the content thereof is not reduced any more, and the sulfonylation reaction time is preferably 0.5 to 48 hours (e.g. 40 minutes to 21 hours).

In one embodiment of the invention, the halogen may be fluorine, chlorine, bromine or iodine (e.g., chlorine).

In one embodiment of the present invention, C is₁-C₆Alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) of (C)₁-C₄The alkyl group of (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) is preferably methyl.

The preparation method can also comprise the following steps that after the sulfonylation reaction is finished, the reaction solution is subjected to extraction or filtration, washing, column chromatography or recrystallization; wherein, when the acid-binding agent is triethylamine, the reaction liquid is preferably subjected to extraction, washing and recrystallization; when the acid-binding agent is pyridine, the reaction liquid is preferably filtered, washed and subjected to column chromatography; the extraction may be performed as is conventional in the art, and the organic solvent to be extracted in the present invention is an ester solvent (e.g., ethyl acetate); the washing operation may be a conventional operation in the art, and in the present invention, when the acid-binding agent is triethylamine, the washing is preferably a saturated brine washing; when the acid-binding agent is pyridine, the washing is preferably 0.5mol/L sulfuric acid aqueous solution, water, 15% potassium bicarbonate aqueous solution and saturated brine; the operation of the column chromatography may be a conventional operation in the art, and the mobile phase of the column chromatography in the present invention is preferably a mixed solvent of an alkane solvent and an ester solvent (for example, a mixed solvent of n-heptane and ethyl acetate, preferably in a volume ratio of 5: 1). The recrystallization may be a conventional one in the art, and in the present invention, it is preferable to perform recrystallization in a mixed solvent of an alkane solvent and an ester solvent (for example, a mixed solvent of n-heptane and ethyl acetate, preferably 5:1 in volume).

The preparation method can also comprise the following steps: step (a), diphenyl phosphite (12) and a silanization reagent are subjected to silanization reaction, and then the obtained silanization reaction system and benzyl chloromethyl ether are subjected to alkylation reaction as shown in the specification to obtain benzyl oxygen methyl diphenyl phosphonate (13);

in the step (b), in a solvent, carrying out debenzylation reaction on the benzyloxymethyl diphenyl phosphonate as shown in the specification to obtain the hydroxymethyl diphenyl phosphonate (13);

in step (a), the silylating agent may be a silylating agent conventional in this type of reaction in the art, for example, one or more of N, O-bis (trimethylsilyl) trifluoroacetamide (BSTFA), N, O-bis (trimethylsilyl) acetamide, trimethylchlorosilane, hexamethyldisilazane, hexamethyldisiloxane, trimethylsilyl trifluoromethanesulfonate, and trimethylsilylimidazole; preferably N, O-bis (trimethylsilyl) trifluoroacetamide (BSTFA).

The molar ratio of the silylation agent to the diphenyl phosphite can be a molar ratio conventional in the reaction of this kind in the art, and in the present invention, is preferably 1.2:1 to 1:1 (e.g., 1.03: 1).

The temperature of the silylation reaction can be any temperature conventional in the art for such reactions, for example, from 0 ℃ to 45 ℃ (e.g., from 35 ℃ to 45 ℃).

The alkylation reaction may be carried out in the presence of a shielding gas conventional in such reactions in the art, preferably one or more of argon, nitrogen, helium and neon.

The molar ratio of the benzyl chloromethyl ether to the diphenyl phosphite can be a molar ratio conventional in the reaction of this kind in the art, and in the present invention, is preferably 1.2:1 to 1:1 (e.g., 1.02: 1).

The temperature of the alkylation reaction may be as conventional in the art, for example, from 30 ℃ to 100 ℃ (e.g., from 70 ℃ to 80 ℃).

The progress of the alkylation reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, LCMS, HPLC, or NMR), and is typically terminated when the diphenyl phosphite is lost or no longer reduced, preferably for a period of time from 1 hour to 10 hours (e.g., 2 hours).

The alkylation reaction can also comprise the following post-treatment steps, and after the alkylation reaction is finished, the benzyl oxy methyl diphenyl phosphonate is obtained by extraction, washing and concentration.

In step (b), the solvent is preferably a halogenated hydrocarbon solvent (e.g., dichloromethane) and/or an alcohol solvent (e.g., ethanol and/or methanol).

The debenzylation reaction may be conventional in the art such as a chemical reduction method or a catalytic hydrogenation method in the presence of hydrogen and a catalyst; the operation and reaction conditions of the catalytic hydrogenation process may be those conventional in such reactions in the art, wherein the catalyst is preferably palladium on carbon (e.g., 10% palladium on carbon), raney nickel or palladium hydroxide; the hydrogen pressure of the catalytic hydrogenation process is preferably 1.5 MPa; the temperature of the catalytic hydrogenation process can be from 0 ℃ to 100 ℃ (e.g., from 10 ℃ to 30 ℃).

The progress of the hydrodebenzylation reaction can be monitored by conventional monitoring methods in the art (e.g. TLC, LCMS, HPLC or NMR), and is generally the end point of the reaction when the diphenyl benzyloxymethylphosphonate disappears or the content thereof is not reduced any more, and the time of the hydrodebenzylation reaction is preferably 1 to 48 hours (e.g. 20 hours).

The invention provides a preparation method of tenofovir disoproxil diphenyl ester, which comprises the following steps of carrying out nucleophilic substitution reaction shown in the specification on a mixture of a Grignard reagent, tertiary butanol and (R) -9- (2-hydroxypropyl) adenine and a benzene sulfonyl oxygen group methyl phosphonate compound shown in a formula I in an aprotic solvent to obtain tenofovir disoproxil diphenyl ester (14);

wherein X is as defined above.

Wherein the aprotic solvent can be an aprotic solvent which is conventional in the reactions in the field, such as a polar aprotic solvent and an apolar solvent, and in the invention, is preferably one or more of a halogenated alkane solvent (such as dichloromethane), a cycloalkane solvent (such as cyclohexane), a cyclic ether solvent (such as tetrahydrofuran), an ester solvent (such as ethyl acetate) and acetonitrile; cyclohexane is preferred.

The amount of the aprotic solvent to be used is not particularly limited so as not to affect the reaction. In the present invention, the molar volume ratio of the (R) -9- (2-hydroxypropyl) adenine to the aprotic solvent is preferably 0.1 to 1mol/L (e.g., 0.3 mol/L).

The grignard reagent may be a grignard reagent conventional in such reactions in the art, for example, one or more of methyl magnesium chloride, phenyl magnesium chloride, methyl magnesium bromide and phenyl magnesium bromide, preferably methyl magnesium chloride;

the grignard reagent may be in the form of a solution as is conventional in such reactions in the art, for example in the form of a solution of tetrahydrofuran; the molar volume of the Grignard reagent in the solution form is preferably 0.5mol/L to 10mol/L (e.g., 3 mol/L).

The molar ratio of the grignard reagent to the (R) -9- (2-hydroxypropyl) adenine may be a molar ratio conventionally used in such reactions in the art, and is preferably 0.9:1 to 1.2:1 (e.g., 1.04:1) in the present invention.

The molar ratio of the grignard reagent to the tert-butanol may be a molar ratio conventionally used in the reaction of this kind in the art, and in the present invention, is preferably 0.8:1 to 1.2:1 (e.g., 1.04:1 to 1: 1).

The molar ratio of the benzenesulfonyloxymethylphosphonate compound shown in the formula I to the (R) -9- (2-hydroxypropyl) adenine can be a conventional molar ratio in the reaction in the field, and is preferably 2: 1-3: 1 (such as 2.5: 1).

The temperature of the nucleophilic substitution reaction may be a temperature conventional in such reactions in the art, for example, 30 ℃ to 100 ℃ (e.g., 75 ℃ ± 5 ℃).

The nucleophilic substitution reaction may be carried out in the presence of a shielding gas as is conventional in such reactions in the art, preferably one or more of argon, nitrogen, helium and neon.

The progress of the nucleophilic substitution reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, LCMS, HPLC or NMR), and is generally determined as the end point of the reaction when the (R) -9- (2-hydroxypropyl) adenine disappears or is no longer reduced, and the time for the alkylation reaction is preferably 1 hour to 10 hours (e.g., 4 hours).

The mixture of the grignard reagent, the tert-butanol and the (R) -9- (2-hydroxypropyl) adenine can be prepared by adding the grignard reagent to the mixed system of the (R) -9- (2-hydroxypropyl) adenine and the tert-butanol in the aprotic solvent at a temperature of-10 ℃ to 10 ℃ (for example, -5 ℃ to 5 ℃) and mixing to obtain the mixture of the grignard reagent, the tert-butanol and the (R) -9- (2-hydroxypropyl) adenine.

The preparation method can also comprise the following post-treatment steps, after the nucleophilic substitution reaction is finished, concentrating, extracting by using an organic solvent (such as a halogenated alkane solvent, such as dichloromethane), extracting by using an acid aqueous solution (such as a 1mol/L sulfuric acid aqueous solution), alkalifying (such as 25% ammonia water for adjusting the pH to 11), extracting by using an organic solvent (such as a halogenated alkane solvent, such as dichloromethane), and concentrating to obtain the tenofovir disoproxil diphenyl ester; the extraction operations and conditions may be those conventional in the art.

The preparation method can also comprise the following steps of adding an acid-binding agent into a mixture of diphenyl hydroxymethylphosphonate (13) and a compound shown in a formula II at the temperature of-20-0 ℃ in an organic solvent to carry out sulfonylation reaction shown in the specification to obtain a benzenesulfonyloxy methylphosphonate compound shown in the formula I; the temperature of the sulfonylation reaction is-20 ℃ to 20 ℃;

wherein X is as defined above.

In the sulfonylation reaction, the organic solvent may be an organic solvent conventional in the reaction in the art, such as an aprotic solvent, and in the present invention, preferably one or more of a haloalkane solvent (e.g., dichloromethane), an aromatic hydrocarbon solvent (e.g., toluene), an ester solvent (e.g., ethyl acetate), and a ketone solvent (e.g., acetone); preferably dichloromethane.

In the sulfonylation reaction, the acid-binding agent may be an acid-binding agent conventional in the reaction in the field, and in the present invention, a tertiary amine acid-binding agent (such as triethylamine and/or pyridine) is preferred, and triethylamine is more preferred.

In the sulfonylation reaction, the amount of the organic solvent used is not particularly limited so as not to affect the reaction. In the present invention, the molar volume ratio of diphenyl hydroxymethylphosphonate (13) to the organic solvent is preferably 0.1 to 1mol/L (e.g., 0.4 mol/L).

In the sulfonylation reaction, the molar ratio of the diphenyl hydroxymethylphosphonate (13) to the compound shown in the formula II can be a molar ratio which is conventional in the reaction in the field, and in the present invention, is preferably 1:1 to 1:1.2 (for example, 1: 1.02).

In the sulfonylation reaction, the molar ratio of the acid-binding agent to the compound represented by the formula II may be a molar ratio conventionally used in the reaction in the field, and in the present invention, is preferably 1:1 to 2:1 (e.g., 1.1:1 to 1.7: 1).

In the sulfonylation reaction, the acid-binding agent is added into the mixture of the diphenyl hydroxymethylphosphonate (13) and the compound shown in the formula II, and the temperature is preferably-15 ℃ to-5 ℃ (for example, -10 ℃).

In the sulfonylation reaction, the temperature of the sulfonylation reaction is preferably-10 ℃ to 15 ℃; when the acid-binding agent is triethylamine, the temperature is more preferably-10-0 ℃; when the acid-binding agent is pyridine, the temperature is more preferably-10 ℃ to 15 ℃.

In the sulfonylation, the sulfonylation may be carried out in the presence of a shielding gas which is conventional in such reactions in the art, and the shielding gas is preferably one or more of argon, nitrogen, helium and neon.

The preparation method can also comprise the following steps that after the sulfonylation reaction is finished, the reaction solution is subjected to extraction or filtration, washing, column chromatography or recrystallization; wherein, when the acid-binding agent is triethylamine, the reaction liquid is preferably subjected to extraction, washing and recrystallization; when the acid-binding agent is pyridine, the reaction liquid is preferably filtered, washed and subjected to column chromatography; the extraction may be performed as is conventional in the art, and the organic solvent to be extracted in the present invention is an ester solvent (e.g., ethyl acetate); the washing operation may be a conventional operation in the art, and in the present invention, when the acid-binding agent is triethylamine, the washing is preferably a saturated brine washing; when the acid-binding agent is pyridine, the washing is preferably 0.5mol/L sulfuric acid aqueous solution, water, 15% potassium bicarbonate aqueous solution and saturated brine; the operation of the column chromatography may be a conventional operation in the art, and the mobile phase of the column chromatography in the present invention is preferably a mixed solvent of an alkane solvent and an ester solvent (for example, a mixed solvent of n-heptane and ethyl acetate, preferably 5:1 in volume ratio). The recrystallization may be a conventional one in the art, and in the present invention, it is preferable to perform recrystallization in a mixed solvent of an alkane solvent and an ester solvent (for example, a mixed solvent of n-heptane and ethyl acetate, preferably 5:1 in volume).

The invention provides a preparation method of phenyl hydrogen phosphonate, which comprises the following steps,

in an aprotic solvent, carrying out nucleophilic substitution reaction on a mixture of a Grignard reagent, tert-butyl alcohol and (R) -9- (2-hydroxypropyl) adenine and a benzenesulfonyloxymethylphosphonate compound shown as a formula I as shown in the specification to obtain tenofovir disoproxil diphenyl ester (14);

wherein X is halogen or C₁-C₆Alkyl or nitro;

in a solvent, in the presence of alkali, carrying out hydrolysis reaction on the tenofovir disoproxil diphenyl ester as shown in the specification to obtain phenyl hydrogen phosphonate as shown in the formula (1);

in step (1), the aprotic solvent may be an aprotic solvent which is conventional in the reactions of the type in the art, such as a polar aprotic solvent and an apolar solvent, and in the present invention, preferably one or more of a haloalkane solvent (e.g., dichloromethane), a cycloalkane solvent (e.g., cyclohexane), a cyclic ether solvent (e.g., tetrahydrofuran), an ester solvent (e.g., ethyl acetate), and acetonitrile; cyclohexane is preferred.

The molar ratio of the grignard reagent to the tert-butanol may be a molar ratio conventionally used in the reaction of this kind in the art, and in the present invention, is preferably 0.8:1 to 1.2:1 (e.g., 1:1 to 1.04: 1).

The step (1) may further include a post-treatment step, wherein after the nucleophilic substitution reaction is completed, the reaction product is concentrated, extracted with an organic solvent (such as a haloalkane solvent, such as dichloromethane), extracted with an aqueous acid solution (such as a 1mol/L aqueous sulfuric acid solution), basified (such as a 25% aqueous ammonia solution adjusted to pH 11), re-extracted with an organic solvent (such as a haloalkane solvent, such as dichloromethane), and concentrated to obtain tenofovir disoproxil; the extraction operations and conditions may be those conventional in the art.

In step (2), the solvent may be a solvent conventional in such reactions in the art, such as water and cyclic ether solvents (e.g., tetrahydrofuran).

In step (2), the base may be a base conventional in such reactions in the art, such as an alkali metal hydroxide (e.g., one or more of lithium hydroxide, sodium hydroxide, and potassium hydroxide) and/or an alkali metal carbonate (e.g., one or more of lithium carbonate, sodium carbonate, and potassium carbonate). The base may be in the form of an aqueous solution (e.g. a 1. + -. 0.5mol/L aqueous solution) as is conventional in such reactions in the art.

In step (2), the molar ratio of the base to the tenofovir disoproxil ester can be a molar ratio which is conventional in reactions of this type in the art, for example (2 ± 0.5): 1.

wherein X is as defined above.

In the sulfonylation reaction, the temperature of the sulfonylation reaction is preferably-10 ℃ to 15 ℃; when the acid-binding agent is triethylamine, the temperature is more preferably-10-0 ℃; or, when the acid-binding agent is pyridine, the temperature is more preferably-10 ℃ to 15 ℃.

Further, the preparation method can also comprise the following steps:

step (a), diphenyl phosphite (12) and a silanization reagent are subjected to silanization reaction, and then the obtained silanization reaction system and benzyl chloromethyl ether are subjected to alkylation reaction as shown in the specification to obtain benzyl oxygen methyl diphenyl phosphonate (13);

The step (a) can also comprise a post-treatment step, wherein after the alkylation reaction is finished, the diphenyl benzyloxymethylphosphonate is obtained by extraction, washing and concentration.

The invention provides p-nitrobenzenesulfonyloxy diphenyl methylphosphonate shown as a formula Ib;

the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the preparation method of the invention can adopt the diphenyl hydroxymethylphosphonate (13) as an initial material to finally prepare the target compound through the benzenesulfonyloxymethylphosphonate compound and the diphenyl tenofovir disoproxil 14. The preparation method has the advantages of cheap and easily obtained raw materials, simple reaction operation, high repeatability and good amplifiability.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

The NMR spectrometer model was an INOVA-400 from Varian. The mass spectrometer model was Micromass Q-Tof micro, electrospray ionization (ESI), positive ionization mode from Waters corporation. The element Analyzer was a Thermo SCIENTIFIC FLASH 2000 Organic Elemental Analyzer.

Example 1

Preparation of Diphenyl hydroxymethylphosphonate (13)

To diphenyl phosphite (12) (30g, 128.1mmol) was added dropwise N, O-bis (trimethylsilyl) trifluoroacetamide (BSTFA) (33.96g, 131.9mmol) under argon, stirring and cooling in an ice-water bath. After the dripping is finished, the temperature is raised to 38 ℃, and the heat preservation and the stirring are carried out for 1.5 hours; benzyl chloromethyl ether (20.46g, 130.6mmol) was then added, the temperature was raised to 75 ℃ and stirring was continued for 2 h. The temperature was reduced to room temperature, and methylene chloride (180ml) and water (30ml) were added to separate layers. The organic phase was washed with a 5% aqueous solution of sodium hydroxide and saturated brine, dried over anhydrous sodium sulfate, and rotary-evaporated to give a pale yellow oil, diphenyl benzyloxymethylphosphonate (16) (34g, yield 75%).¹H NMR(400 MHz,CDCl₃)7.32-7.39(m,9H),7.18-7.24(m,6H),4.73(s,2H),4.07(d,J＝8.0 Hz,2H)；ESI-MS(m/z):355.14[M+H]⁺。

The obtained 16 was dissolved in absolute ethanol (170ml) and added to a Parr hydrogenation vessel, 10% palladium on carbon (4.5g) was added, 1.5 MPa hydrogen was charged, and hydrogenation was carried out with stirring at room temperature for 20 hours. The palladium on carbon was filtered off, and the solvent was rotary evaporated to give colorless oily liquid 13(24.7g, yield 73%).¹H NMR(400 MHz,CDCl₃)7.31-7.35(m,4H),7.19-7.21(m,6H),4.16(d,J＝4.0 Hz,2H)；³¹P NMR(162 MHz,CDCl₃)17.50；ESI-MS(m/z):265.08[M+H]⁺。

Example 2

Preparation of p-methyl benzenesulfonyloxymethylphosphonic acid diphenyl ester (Ia) (acid-binding agent triethylamine)

Under the protection of argon and with stirring, 7.2g (27.3 mmol) of diphenyl hydroxymethylphosphonate (13) and 5.3g (27.8 mmol) of TsCl are dissolved in anhydrous dichloromethane (70ml), the temperature is reduced to-10 ℃, triethylamine (3.2g, 31.6mmol) is slowly added dropwise, the mixture is stirred at the temperature of 10 ℃ for reaction for 1.5h, water (35ml) is added for demixing, the organic phase is separated and washed with saturated sodium chloride, and the mixture is dried by anhydrous sodium sulfate and then is evaporated in a rotary manner. The crude product was recrystallized from a mixed solvent (n-heptane: ethyl acetate: 7:5) and dried in vacuo (40 ℃, 4.5h) to give diphenyl p-toluenesulfonyloxymethylphosphonate (Ia) as a white solid (9.23g, yield 81%).¹H NMR(400 MHz,CDCl₃)7.81(d,J＝8.0 Hz,2H),7.30-7.36(m,6H),7.21-7.24(m,2H),7.14-7.19(m,4H),4.47(d,J＝12.0 Hz,2H),2.46(s,3H)。³¹P NMR(162 MHz,CDCl₃)8.41。

Example 3

Preparation of diphenyl p-toluenesulfonyloxymethylphosphonate (Ia) (acid-binding agent pyridine)

Diphenyl hydroxymethylphosphonate (13) (1.0g, 3.8mmol) and TsCl (0.72g, 3.8mmol) were dissolved in dry dichloromethane (8ml) with stirring and under argon. The temperature was reduced to-10 ℃ and pyridine (0.50g, 6.3mmol) was added dropwise. After the reaction is stirred for 4 hours at the temperature of minus 10 ℃, the temperature is increased to 14 ℃, and the stirring is continued for 17 hours. The resulting reaction product was filtered to remove insoluble matter, and the filtrate was washed with a 0.5mol/L aqueous sulfuric acid solution, water, a 15% aqueous potassium hydrogencarbonate solution and saturated brine in this order, dried over anhydrous sodium sulfate and rotary-evaporated. The resulting residue was purified by silica gel column chromatography (n-heptane: ethyl acetate ═ 5:1) to give diphenyl p-toluenesulfonyloxymethylphosphonate (Ia) as a white solid (1.19g, yield 75%).³¹P NMR(162 MHz,CDCl₃)8.41. Elemental analysis (C)₂₀H₁₉O₆PS) actual measurementValues C57.78 (57.41), H4.60 (4.58).

Example 4

Preparation of p-nitrobenzenesulfonyloxymethyl diphenyl phosphonate (Ib) (acid-binding agent triethylamine)

Diphenyl hydroxymethylphosphonate (13) (15.5g, 58.6mmol) and p-nitrobenzenesulfonyl chloride (NsCl) (13.26g, 59.8mmol) were dissolved in dry dichloromethane (150ml) with stirring and under argon. Cooling to-10 deg.C, slowly adding triethylamine (7.12g, 70.3mmol), stirring at-10 deg.C, and reacting for 40 min. Water was added, transferred to a separatory funnel and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and rotary evaporated. The resulting yellow solid residue was recrystallized from a mixed solvent (n-heptane: ethyl acetate ═ 7:5) and dried in vacuo (40 ℃, 3.5h) to give a pale yellow solid (20.8g, yield 79%).¹H NMR(400 MHz,CDCl₃)8.36(d,J＝12Hz,2H),8.11(d,J＝12Hz,2H),7.33(t,J＝8Hz,4H),7.20-7.24(m,2H),7.12-7.15(m,4H),4.64(d,J＝8Hz,2H)。

Example 5

Preparation of p-nitrobenzenesulfonyloxymethyl diphenyl phosphonate (Ib) (acid-binding agent pyridine)

Diphenyl hydroxymethylphosphonate (13) (1.0g, 3.8mmol) and NsCl (0.84g, 3.8mmol) were dissolved in dry dichloromethane (8ml) with stirring and under argon. The temperature was reduced to-10 ℃ and pyridine (0.50g, 6.3mmol) was added dropwise. Stirring and reacting for 4h at the temperature of minus 10 ℃, heating to 12 ℃, and continuing stirring for 12 h. The resulting reaction product was filtered to remove insoluble matter, and the filtrate was washed with a 0.5mol/L aqueous sulfuric acid solution, water, a 15% aqueous potassium hydrogencarbonate solution and saturated brine in this order, dried over anhydrous sodium sulfate and rotary-evaporated. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate 5:1) to give diphenyl p-nitrobenzenesulfonyloxymethylphosphonate (Ib) as a white solid (1.10)g, yield 65%).³¹P NMR(162 MHz，CDCl₃) 7.00; elemental analysis (C)₁₉H₁₆NO₈PS) found C50.62 (50.78), H3.63 (3.59), N3.17 (3.12).

Example 6

Preparation of diphenyl p-chlorobenzenesulfonamidomethylphosphonate (Ic)

Diphenyl hydroxymethylphosphonate (13) (1.0g, 3.8mmol) and p-chlorobenzenesulfonyl chloride (CsCl) (0.96g, 4.5mmol) were dissolved in dry dichloromethane (8mL) with stirring under argon. The temperature was reduced to-10 ℃ and pyridine (0.50g, 6.3mmol) was added dropwise. Stirring for 4h at-10 ℃, heating to 13 ℃, and continuing stirring for reaction for 12 h. The resulting reaction product was filtered to remove insoluble matter, and the filtrate was washed with a 0.5mol/L aqueous sulfuric acid solution, water, a 15% aqueous potassium hydrogencarbonate solution and saturated brine in this order, dried over anhydrous sodium sulfate and rotary-evaporated. The resulting residue was purified by silica gel column chromatography (n-heptane: ethyl acetate ═ 5:1) to give diphenyl p-chlorobenzenesulfonyloxymethylphosphonate (Ic) as a white solid (1.11g, yield 67%).¹H NMR(400MHz，CDCl₃)7.83-7.86(d，J＝8.8Hz，2H)，7.50-7.53(d，J＝8.8Hz，2H)，7.31-7.35(t，J＝8Hz，4H)，7.19-7.23(m，2H)，7.12-7.15(m，4H)，4.51-4.53(d，J＝9.6Hz，2H)；³¹P NMR(162 MHz，CDCl₃) 7.79; elemental analysis (C)₁₉H₁₆ClO₆PS) found C52.15 (52.01), H3.69 (3.68).

Comparative example 1

Failure to prepare diphenyl p-toluenesulfonyloxymethylphosphonate (Ia)

Diphenyl hydroxymethylphosphonate (13) (2.64g, 10.0mmol) and triethylamine (1.31g, 13.0mmol) were dissolved in anhydrous dichloromethane (10ml), cooled in an ice water bath to below 10 ℃ and p-toluenesulfonyl chloride was added in portions(TsCl) (2.09g, 11.0 mmol). The ice-water bath was removed and stirred at room temperature for 2 h. Water was added to the obtained reaction product to extract and layer, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and rotary-evaporated to obtain a white solid which was phenyl p-toluenesulfonate (Ia') (1.74g, 70%) and did not give the desired compound Ia.¹H NMR(400 MHz,CDCl₃)7.71(d,J＝12.0 Hz,2H),7.28-7.32(m,4H),7.26-7.27(m,1H),6.98-7.01(m,2H),2.46(s,3H)；ESI-MS(m/z):271.06[M+Na]⁺(ii) a Elemental analysis (C)₁₃H₁₂O₃S) found C62.84 (62.89), H4.90 (4.87).

Comparative example 2

Failure to prepare diphenyl p-toluenesulfonyloxymethylphosphonate (Ia)

Diphenyl hydroxymethylphosphonate (13) (1.0g, 3.78mmol), p-toluenesulfonyl chloride (TsCl) (1.44g, 7.58mmol), anhydrous dichloromethane (2ml) and triethylamine (0.76g, 7.51mmol) were refluxed for 3.5h and cooled to room temperature. And washing the obtained reactant with water for three times, drying the reactant with anhydrous sodium sulfate, and then carrying out rotary evaporation to obtain the target compound Ia.

Example 7

Preparation of diphenyl (R) - (((1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) phosphonate (14, tenofovir disoproxil)

Preparation of diphenyl p-toluenesulfonyloxymethylphosphonate (Ia)

A suspension of (R) -9- (2-hydroxypropyl) adenine (8) (3.19g,16.5mmol), t-butanol (1.22g,16.5mmol) and cyclohexane (55ml) was cooled to 0 ℃ under argon protection and stirring, and a 3mol/L solution of methylmagnesium chloride in tetrahydrofuran (5.5ml,16.5mmol) was added dropwise and stirred at 0 ℃ for 50 min. Ia (17.28g, 41.3mmol) was then added in portions and the reaction was stirred for 4h at 75 ℃. Cyclohexane is distilled off at atmospheric pressure, the residue obtainedThe material was dissolved in water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and rotary evaporated. The resulting yellow oil was dissolved in methylene chloride and extracted with 1mol/L aqueous sulfuric acid. The acid aqueous phases were combined, the pH was adjusted to 11 with 25% ammonia and the alkalised aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, rotary evaporated and dried under vacuum (42 ℃,4h) to give 14 as a near white solid (2.90g, 40% yield).¹H NMR(400MHz,CDCl₃)8.34(s,1H),7.87(s,1H),7.29-7.35(m,4H),7.16-7.21(m,4H),7.08(d,J＝8.0Hz,2H),5.72(br s,2H),4.36(dd,J＝12.0,4.0Hz,1H),4.11-4.19(m,2H),4.00-4.08(m,1H),3.91(dd,J＝12.0,8.0Hz,1H),1.26(d,J＝8.0Hz,3H)；ESI-MS(m/z):440.34[M+H]⁺。

Example 8

Preparation of diphenyl p-nitrobenzenesulfonyloxymethylphosphonate (Ib)

A suspension of (R) -9- (2-hydroxypropyl) adenine (8) (0.59g, 3.0mmol), t-butanol (0.23g, 3.0mmol) and cyclohexane (10mL) was cooled to 0 ℃ under argon with stirring, and a 3mol/L solution of methylmagnesium chloride in tetrahydrofuran (1.0mL, 3.0mmol) was added dropwise and stirred at 0 ℃ for 60 min. P-nitrobenzenesulfonyloxymethyl-diphenyl phosphonate (Ib) (3.42g, 7.6mmol) was added thereto, and the mixture was stirred at room temperature for 30min, then heated to 75 ℃ and stirred for 4 h. The n-hexane was distilled off under normal pressure, and the resulting residue was dissolved in water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and rotary evaporated. The resulting orange oil was dissolved in methylene chloride and extracted with 1mol/L aqueous sulfuric acid. The acid aqueous phases were combined, the pH was adjusted to 11 with 25% ammonia and the alkalised aqueous phase was extracted with dichloromethane. The combined organic phases were rotary evaporated over anhydrous sodium sulfate and dried in vacuo (40 ℃,4h) to give 14 as a off-white solid (0.60g, 45% yield).³¹P NMR(162MHz,CDCl₃)13.74；ESI-MS(m/z)440.23[M+H]⁺. Elemental analysis (C)₁₂H₂₂N₅O₄P) found C57.07 (57.40), H5.02 (5.05), N15.89 (15.94).

Example 9

P-chlorobenzenesulfonyloxymethyl diphenyl phosphonate (Ic) as raw material

A suspension of (R) -9- (2-hydroxypropyl) adenine (8) (0.51g, 2.6mmol), t-butanol (0.19g, 2.6mmol) and cyclohexane (5mL) was cooled to 0 ℃ under argon with stirring, and a 3mol/L solution of methylmagnesium chloride in tetrahydrofuran (0.9mL, 2.7mmol) was added dropwise and stirred at 0 ℃ for 30 min. Diphenyl p-chlorobenzenesulfonacyloxymethyl phosphonate (Ic) (2.88g, 6.6mmol) was added thereto, and the mixture was stirred at room temperature for 30 min. Then the temperature is increased to 75 ℃ and the mixture is stirred for 4 hours. The n-hexane was distilled off under normal pressure, and the resulting residue was dissolved in water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and rotary evaporated. The resulting orange oil was dissolved in methylene chloride and extracted with 1mol/L aqueous sulfuric acid. The acid aqueous phases were combined, the pH was adjusted to 11 with 25% ammonia and the alkalised aqueous phase was extracted with dichloromethane. The combined organic phases were rotary evaporated over anhydrous sodium sulfate and dried in vacuo (40 ℃,4h) to give 14 as a off-white solid (0.50g, 43% yield). ESI-MS (M/z)440.19[ M + H ]]⁺。

Comparative example 3

Preparation of diphenyl p-toluenesulfonyloxymethylphosphonate (Ia)

(R) -9- (2-hydroxypropyl) adenine (8) (1.5g, 7.8mmol) was dissolved in DMF (6ml) under argon protection, magnesium tert-butoxide (MTB) (1.1g, 6.2mmol) was added at room temperature, and after stirring for 1h, diphenyl p-toluenesulfonyloxymethylphosphonate (Ia) (3.26g, 7.8mmol) was added and the reaction was stirred at 75 ℃ for 4h, Ia had reacted to completion. Adjusting pH to 5-6 with acetic acid, stirring for 15min, pouring into water, and extracting with dichloromethane. Washing the organic phase by saturated saline, drying by anhydrous sodium sulfate, and then carrying out rotary evaporation to obtain an oily complex product. The target product tenofovir disoproxil fumarate 14 can not be obtained.

Comparative example 4

Preparation of diphenyl p-nitrobenzenesulfonyloxymethylphosphonate (Ib)

(R) -9- (2-hydroxypropyl) adenine (8) (1.5g, 7.8mmol) was dissolved in DMF (6ml) under argon protection, magnesium tert-butoxide (MTB) (1.1g, 6.2mmol) was added at room temperature, and after stirring for 1h, diphenyl p-nitrobenzenesulfonamidomethylphosphonate (Ib) (3.5g, 7.8mmol) was added, and the reaction was stirred at 75 ℃ for 4h, after which Ib had reacted completely. Adjusting pH to 5-6 with acetic acid, stirring for 15min, pouring into water, and extracting with dichloromethane. Washing the organic phase by saturated saline, drying by anhydrous sodium sulfate, and then carrying out rotary evaporation to obtain an oily complex product. The target product tenofovir disoproxil fumarate 14 can not be obtained.

Example 10

Preparation of phenylhydro (((((R) -1- (6-amino-9H-purin-9-yl) propan) -2-yl) oxy) methyl) phosphonate (1, tenofovir disoproxil phenyl ester)

6(2.0g, 4.6mmol) and tetrahydrofuran (9ml) were cooled to 0 ℃ under argon with stirring and 1mol/L aqueous lithium hydroxide solution (9ml) was added. The reaction was then allowed to warm to room temperature and stirred for 15 h. The reaction solution was extracted with ethyl acetate, and then the pH was adjusted to 2 with 12mol/L hydrochloric acid. Seed crystal of 1 was added to the obtained acid aqueous solution, and stirred at room temperature for 30min and then stirred in an ice-water bath for 30 min. Filtration and vacuum drying (50 ℃, 15h) gave 1 as a white solid (1.35g, 82% yield).¹H NMR(400MHz,D₂O)8.39(s,1H),8.32(s,1H),7.31(t,J＝8.0Hz,2H),7.18(t,J＝8.0Hz,1H),6.81(d,J＝8.0Hz,2H),4.51(dd,J＝16.0,4.0Hz,1H),4.27(dd,J＝12.0,8.0Hz,1H),4.11-4.19(m,1H),3.89(dd,J＝12.0,8.0Hz,1H),3.64(dd,J＝16.0,8.0Hz,1H),1.36(d,J＝8.0Hz,3H)；ESI-MS(m/z):364.04[M+H]⁺。

If diethyl p-toluenesulfonyloxymethylphosphonate (6) is used to react with (R) -9- (2-hydroxypropyl) adenine to produce the diethyl ester intermediate 10, followed by removal of the diethyl ester to produce tenofovir (11), as described in Organic Process Research & Development 2010,14, 1194-one 1201, the reaction steps are lengthy and require the use of expensive, corrosive and moisture sensitive trimethylbromosilane (TMSBr) or an alternative combination thereof. In addition, the diethyl ester intermediate 10 produced is water soluble and difficult to crystallize from aqueous work-up mixtures. If extraction is carried out, chloroform is used for continuous extraction for 24 hours; chloroform is a potential mutagenic agent, is not friendly to the environment and is a first class of solvent with limited use; the adoption of dichloromethane instead of chloroform leads to a significant reduction in extraction yield; the method is not suitable for industrial production. Therefore, the hydrolysis reaction of the next step is directly carried out without separation and purification; however, the direct hydrolysis of the unextracted and purified diethyl ester 7 results in a decrease in the yield and purity of the subsequent product. In particular, the first preparation of the diethyl ester intermediate 10 followed by the removal of the diethyl ester to prepare tenofovir (11) is a lengthy reaction step and the hydrolysis of diethyl ester 7 requires the use of expensive, corrosive and moisture sensitive trimethylbromosilane (TMSBr) or an alternative combination thereof. The preparation method of tenofovir phenyl ester 1 provided by the invention bypasses the tenofovir monohydrate (PMPA) intermediate which is easy to form a stable monohydrate, and avoids the water removal step of tenofovir monohydrate which is complicated to operate and low in efficiency; the required phenyl ester is directly introduced from cheap and easily available raw material diphenyl phosphite to obtain tenofovir diphenyl ester 14, the tenofovir diphenyl ester 1 can be prepared by hydrolysis reaction catalyzed by alkali metal hydroxide, the reaction steps are direct and simple, and expensive, corrosive and moisture sensitive trimethyl bromosilane (TMSBr) or substituted combination thereof is abolished from the source. In addition, the prepared tenofovir disoproxil 14 has low water solubility, can be easily extracted from an aqueous post-treatment mixture, remarkably simplifies separation and purification, eliminates a first toxic and harmful solvent chloroform, and is beneficial to improving the yield and purity of subsequent reaction.

Claims

1. A preparation method of a benzene sulfonyl oxygen methyl phosphonate compound shown in a formula I is characterized by comprising the following steps of adding an acid-binding agent into a mixture of diphenyl hydroxymethyl phosphonate and a compound shown in a formula II in an organic solvent at the temperature of-20-0 ℃ to perform a sulfonylation reaction shown in the following formula I to obtain the benzene sulfonyl oxygen methyl phosphonate compound shown in the formula I; the temperature of the sulfonylation reaction is-20 ℃ to 20 ℃;

wherein X is halogen or C₁-C₆Alkyl or nitro.

2. The method for preparing benzenesulfonyloxymethylphosphonate compounds as shown in claim 1, wherein in the sulfonylation reaction, the organic solvent is one or more of halogenated alkane solvents, aromatic hydrocarbon solvents, ester solvents and ketone solvents;

and/or in the sulfonylation reaction, the acid-binding agent is a tertiary amine acid-binding agent;

and/or, in the sulfonylation reaction, the molar volume ratio of the diphenyl hydroxymethylphosphonate to the organic solvent is 0.1-1 mol/L;

and/or in the sulfonylation reaction, the molar ratio of the diphenyl hydroxymethylphosphonate to the compound shown in the formula II is 1: 1-1: 1.2;

and/or in the sulfonylation reaction, the molar ratio of the acid-binding agent to the compound shown in the formula II is 1: 1-2: 1;

and/or in the sulfonylation reaction, the acid-binding agent is added into the mixture of the diphenyl hydroxymethylphosphonate and the compound shown in the formula II at the temperature of-15 to-5 ℃;

and/or, in the sulfonylation reaction, the temperature of the sulfonylation reaction is-10 ℃ to 15 ℃;

and/or, in the sulfonylation reaction, the sulfonylation reaction is carried out in the presence of a protective gas;

and/or, the sulfonylation reaction also comprises the following post-treatment steps, after the sulfonylation reaction is finished, the reaction solution is extracted or filtered, washed, subjected to column chromatography or recrystallized;

and/or, the halogen is fluorine, chlorine, bromine or iodine;

and/or, said C₁-C₆The alkyl group of (a) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

3. The method for preparing benzenesulfonyloxymethylphosphonate compounds represented by formula I as claimed in claim 2, wherein in the sulfonylation reaction, when the organic solvent is a haloalkane solvent, the haloalkane solvent is dichloromethane;

and/or, in the sulfonylation reaction, when the organic solvent is an aromatic hydrocarbon solvent, the aromatic hydrocarbon solvent is toluene;

and/or, in the sulfonylation reaction, when the organic solvent is an ester solvent, the ester solvent is ethyl acetate;

and/or, in the sulfonylation reaction, when the organic solvent is a ketone solvent, the ketone solvent is acetone;

and/or, in the sulfonylation reaction, when the acid-binding agent is a tertiary amine acid-binding agent, the tertiary amine acid-binding agent is triethylamine and/or pyridine;

and/or, in the sulfonylation reaction, the molar volume ratio of the diphenyl hydroxymethylphosphonate to the organic solvent is 0.4 mol/L;

and/or in the sulfonylation reaction, the molar ratio of the diphenyl hydroxymethylphosphonate to the compound shown in the formula II is 1: 1.02;

and/or in the sulfonylation reaction, the molar ratio of the acid-binding agent to the compound shown in the formula II is 1.1: 1-1.7: 1;

and/or in the sulfonylation reaction, the acid-binding agent is added into the mixture of the diphenyl hydroxymethylphosphonate and the compound shown in the formula II at the temperature of-10 ℃;

and/or, in the sulfonylation reaction, when the acid-binding agent is triethylamine, the temperature of the sulfonylation reaction is-10 ℃ to 0 ℃; or when the acid-binding agent is pyridine, the temperature of the sulfonylation reaction is-10 to 15 ℃;

and/or, in the sulfonylation reaction, when the sulfonylation reaction is carried out in the presence of a protective gas, the protective gas is one or more of argon, nitrogen, helium and neon;

and/or, when the sulfonylation reaction further comprises the post-treatment step and the acid-binding agent is triethylamine, the preparation method comprises the post-treatment step that the reaction solution is extracted, washed and recrystallized; or when the acid-binding agent is pyridine, filtering, washing and carrying out column chromatography on the reaction solution;

and/or, when the sulfonylation reaction further comprises the post-treatment step, and the acid-binding agent is triethylamine, the washing is saturated brine washing; or when the acid-binding agent is pyridine, the washing is sequentially carried out by 0.5mol/L sulfuric acid aqueous solution, water, 15% potassium bicarbonate aqueous solution and saturated brine;

and/or, when the sulfonylation reaction further comprises the post-treatment step, the extracted organic solvent is an ester solvent;

and/or, when the sulfonylation reaction further comprises the post-treatment step, the mobile phase of the column chromatography is a mixed solvent of an alkane solvent and an ester solvent;

and/or, when the sulfonylation reaction further comprises the post-treatment step, the recrystallization is carried out in a mixed solvent of an alkane solvent and an ester solvent.

4. The method for preparing the benzenesulfonyloxymethylphosphonate compound represented by the formula I as claimed in any one of claims 1 to 3, further comprising the following steps:

step (a), carrying out silanization reaction on diphenyl phosphite and a silanization reagent, and then carrying out alkylation reaction on the obtained silanization reaction system and benzyl chloromethyl ether as shown in the specification to obtain benzyl oxy methyl diphenyl phosphonate;

in a solvent, carrying out debenzylation reaction on the benzyl oxymethyl diphenyl phosphonate as shown in the specification to obtain the hydroxymethyl diphenyl phosphonate;

5. a preparation method of tenofovir disoproxil diphenyl ester is characterized by comprising the following steps of carrying out nucleophilic substitution reaction shown in the specification on a mixture of a Grignard reagent, tert-butyl alcohol and (R) -9- (2-hydroxypropyl) adenine and a benzene sulfonyl oxygen group methyl phosphonate compound shown in a formula I in an aprotic solvent to obtain tenofovir disoproxil diphenyl ester;

wherein X is as defined in claim 1 or 2.

6. The method for preparing tenofovir disoproxil diphenyl ester according to claim 5, wherein the aprotic solvent is one or more of a haloalkane solvent, a cycloalkane solvent, a cyclic ether solvent, an ester solvent and acetonitrile;

and/or the molar volume ratio of the (R) -9- (2-hydroxypropyl) adenine to the aprotic solvent is 0.1-1 mol/L;

and/or the Grignard reagent is one or more of methyl magnesium chloride, phenyl magnesium chloride, methyl magnesium bromide and phenyl magnesium bromide;

and/or, the grignard reagent is in the form of a solution;

and/or the molar ratio of the Grignard reagent to the (R) -9- (2-hydroxypropyl) adenine is 0.9: 1-1.2: 1;

and/or the molar ratio of the Grignard reagent to the tert-butyl alcohol is 0.8: 1-1.2: 1;

and/or the molar ratio of the benzenesulfonyloxymethylphosphonate compound shown as the formula I to the (R) -9- (2-hydroxypropyl) adenine is 2: 1-3: 1;

and/or the temperature of the nucleophilic substitution reaction is 30-100 ℃;

and/or, the nucleophilic substitution reaction is carried out in the presence of a protective gas;

and/or the mixture of the Grignard reagent, the tertiary butanol and the (R) -9- (2-hydroxypropyl) adenine is prepared by the following operation method, the Grignard reagent is added into the mixed system of the (R) -9- (2-hydroxypropyl) adenine and the tertiary butanol for mixing in the aprotic solvent at the temperature of-10 ℃ to obtain the mixture of the Grignard reagent, the tertiary butanol and the (R) -9- (2-hydroxypropyl) adenine;

and/or the preparation method further comprises the following post-treatment steps of after the nucleophilic substitution reaction is finished, concentrating, extracting with an organic solvent, extracting with an acid aqueous solution, alkalifying, re-extracting with the organic solvent, and concentrating to obtain the tenofovir disoproxil diphenyl ester.

7. The method of preparing tenofovir disoproxil diphenyl ester as claimed in claim 6, wherein when said aprotic solvent is a haloalkane solvent, said haloalkane solvent is dichloromethane;

and/or when the aprotic solvent is a naphthenic solvent, the naphthenic solvent is cyclohexane;

and/or when the aprotic solvent is a cyclic ether solvent, the cyclic ether solvent is tetrahydrofuran;

and/or when the aprotic solvent is an ester solvent, the ester solvent is ethyl acetate;

and/or the molar volume ratio of the (R) -9- (2-hydroxypropyl) adenine to the aprotic solvent is 0.3 mol/L;

and/or, the Grignard reagent is methyl magnesium chloride;

and/or, the grignard reagent is in the form of a solution of tetrahydrofuran;

and/or the Grignard reagent is in a solution form, and the molar volume ratio of the Grignard reagent in the solution form is 0.5-10 mol/L;

and/or the molar ratio of the Grignard reagent to the (R) -9- (2-hydroxypropyl) adenine is 1.04: 1;

and/or the molar ratio of the Grignard reagent to the tert-butyl alcohol is 1.04: 1-1: 1;

and/or the molar ratio of the benzenesulfonyloxymethylphosphonate compound shown in the formula I to the (R) -9- (2-hydroxypropyl) adenine is 2.5: 1;

and/or the temperature of the nucleophilic substitution reaction is 75 +/-5 ℃;

and/or the protective gas in the nucleophilic substitution reaction in the presence of the protective gas is one or more of argon, nitrogen, helium and neon;

and/or in the post-treatment step, the organic solvent in the organic solvent extraction is a halogenated alkane solvent; preferably dichloromethane;

and/or in the post-treatment step, the aqueous solution of the acid is a 1mol/L sulfuric acid aqueous solution;

and/or in the post-treatment step, the alkalization is 25% ammonia water to adjust the pH value to 11;

and/or in the post-treatment step, the organic solvent in the organic solvent re-extraction is a halogenated alkane solvent; preferably dichloromethane;

and/or the benzenesulfonyloxymethylphosphonate compound shown in the formula I is prepared by the preparation method of any one of claims 1 to 4.

8. A preparation method of phenyl hydrogen phosphonate is characterized by comprising the following steps,

preparing tenofovir diphenyl ester by adopting the preparation method of tenofovir diphenyl ester according to any one of claims 5 to 7;

9. the method for producing phenylhydrogenphosphonate according to claim 8, wherein in the step (2), the solvent is water and a cyclic ether solvent; the cyclic ether solvent is preferably tetrahydrofuran;

and/or, in the step (2), the alkali is alkali metal hydroxide and/or alkali metal carbonate; the alkali metal hydroxide is preferably one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide; the alkali metal carbonate is preferably one or more of lithium carbonate, sodium carbonate and potassium carbonate;

and/or, in the step (2), the alkali is in the form of aqueous solution; preferably 1 +/-0.5 mol/L aqueous solution;

and/or in the step (2), the molar ratio of the base to the tenofovir disoproxil is (2 +/-0.5): 1.

10. A p-nitrobenzenesulfonyloxy methyl diphenyl phosphonate shown as a formula Ib,