WO2019041317A1 - Method for preparing sofosbuvir fluorolactone intermediate - Google Patents

Abstract

Provided is a method for preparing an important intermediate, ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl) methylbenzoate, of sofosbuvir.

Description

Method for preparing sofbreve lactone intermediate

Cross-reference to related applications

This application claims the priority of the Chinese Patent Application No. 201710747827.2, entitled "Preparation of a Sofabrufloxacin Intermediate" by the Chinese Patent Office on August 28, 2017, the entire contents of which are hereby incorporated by reference. The citations are incorporated herein by reference.

Technical field

The present invention relates to an intermediate of sofosbuvir ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl) The preparation method of methyl benzoate belongs to the technical field of medicine.

Background technique

Hepatitis C virus, abbreviated as hepatitis C and hepatitis C, is a viral hepatitis caused by hepatitis C virus (HCV) infection, mainly transmitted by blood transfusion, acupuncture, mother and baby, according to the statistics of the World Health Organization. The global HCV infection rate is about 3%. It is estimated that about 180 million people are infected with HCV, and about 3.5 million new cases of hepatitis C are reported each year. Hepatitis C is a global epidemic that can lead to chronic inflammation, necrosis and fibrosis in the liver, and some patients can develop cirrhosis or even hepatocellular carcinoma (HCC). The mortality associated with HCV infection (hepatic failure and death from hepatocellular carcinoma) will continue to increase in the next 20 years, which is extremely harmful to the health and life of patients and has become a serious social and public health problem.

The global hepatitis C virus (HCV) infection rate is high and there is a lack of effective therapeutic drugs. Antiviral therapy is currently recognized as the most effective solution: long-acting interferon PEG-IFNα combined with ribavirin, is now the standard solution (SOC) for EASL approved chronic hepatitis C treatment, followed by ordinary Combination therapy with IFNα or complex IFN and ribavirin is superior to IFNα alone. Direct-acting antiviral (DAA) protease inhibitor boceipide (BOC) or telaprevir (TVR), triple therapy with interferon plus ribavirin, approved for clinical use in the United States in May 2011 It is recommended for HCV-infected patients with genotype 1 and can improve the cure rate;

In 2013, FDA approved Gilead Sofosbuvir (trade name: Sova1di) as part of a joint antiviral treatment program for the treatment of chronic hepatitis C infection. Sofosbuvir (S)-isopropyl-2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro) Pyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphono)amino)propionate is a type C An inhibitor of HCV NS5B RNA-dependent RNA polymerase necessary for hepatitis virus replication. The drug is a nucleotide prodrug that is metabolized in the cell to form a pharmacologically active uracil analog triphosphate (GS-461203), which prevents the replication of the HCV gene by inhibiting the activity of HCV NS5B polymerase. Gilead said that Sova1di can be used alone or in combination with ribavirin.

Sofabruvir is the first drug approved for total oral therapy for hepatitis C. It can eliminate the need for traditional injectable drug interferon when used in the treatment of specific genotypes of chronic hepatitis C, according to several studies. Compared with the current treatment plan, Gilead's anti-infective drug has a superior clearance rate and fewer adverse reactions. In 2014, global sales exceeded US$10 billion and it has broad market prospects.

The existing preparation method of sofosbuvir is generally obtained by docking uridine with a side chain of phosphoric acid. Sofibuvir and its analogues were first disclosed in patent WO 2008/121634 A2, using non-pairing by docking nucleoside (2) and chlorinated phosphoric acid side chain (1) in the presence of N-methylimidazole The mixture of the isomers was then subjected to chiral preparation to obtain Sp-sofibru, and the synthetic route was as follows:

Side chain 2 is an important intermediate for the synthesis of sofosbuvir. The synthetic route is as follows:

The side chain has a plurality of chiral centers, and the chiral centers are concentrated on the fluorofuran ring. Therefore, how to synthesize the fluorofuran ring lactone (formula A) is the key to the synthesis of the fragment 2.

The general synthetic route for synthesizing structural formula A is as follows:

The synthetic route has a total of 8 steps of reaction, using a large amount of phosphorus-containing compounds (triphenylphosphine), strong oxidizing agents (potassium permanganate) and heavy metal salts (cerium chloride), the process is complicated, and the pollution is large, which is not conducive to industrial production.

The present invention provides a synthesis of ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methylbenzoic acid The preparation method of the ester (structural formula A) is as follows. The reaction step is short and the process is simple. Low cost, suitable for industrial production. The synthetic route is as follows:

Summary of the invention

The present invention provides a synthesis of ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methylbenzoic acid The preparation method of the ester (structural formula A), the synthetic route is as follows:

The invention comprises the following steps:

1. Preparation of intermediate 18

a. Under anhydrous conditions, D-glucose is dispersed in absolute ethanol, stirred with glacial acetic acid for 30 min, then diethylamine in ethanol is added dropwise, the temperature is controlled to not exceed 20 ° C, and the reaction solution is heated to 75 ° C. After an hour, the temperature was lowered to 55 ° C, the reaction was kept for 2 h, and concentrated under reduced pressure to give a brown oil.

b, adding water to the above oil, after replacing the nitrogen three times, adding calcium oxide, the control temperature does not exceed 20 ° C, after the addition, after stirring at 20 ° C for 20 min, heating to 40 ° C for 4 h;

c, the reaction solution is cooled to below 3 ° C, concentrated sulfuric acid is added to adjust the pH between 2.4-2.7, the control temperature does not exceed 3 ° C, after the pH adjustment is completed, the reaction liquid is heated to 45 ° C, the reaction is stirred for 12 h, and then cooled to 25 °C, filtration, filter cake washed with appropriate amount of water, the filtrate was concentrated to dry;

d. After the residue was refluxed with acetone/water (V/V=10:1) for 30 min, the heating was stopped, filtered, and the filter cake was refluxed twice with acetone/water (V/V=10:1). The filtrate was combined. Concentrated, the residue is recrystallized from acetone to give intermediate 18;

2. Preparation of intermediate 19

The intermediate 18 is dissolved in dichloromethane, triethylamine is added, the temperature is lowered to -20 ° C, benzoyl chloride is added dropwise, and the temperature is controlled to not exceed 5 ° C. After the completion of the dropwise addition, the stirring reaction is continued for 3-5 hours. The reaction liquid was washed successively with aqueous sodium hydrogencarbonate solution and saturated brine, and the organic phase was dried and concentrated under reduced pressure. The residue was added ethyl acetate / n-hexane (V/V = 10:1), and the mixture was filtered and dried. Intermediate 19;

Preparation of ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methylbenzoate

The intermediate 19 was dissolved in dichloromethane, and the temperature was lowered to -15 ° C, and then diethylaminosulfur trifluoride was slowly added. After the addition, the mixture was naturally warmed to room temperature and stirred for 18 hours. After the reaction was completed, 1 N hydrochloric acid was used and saturated. The reaction solution was washed with brine, dried and evaporated to dryness affording ((2,,,,,,,,,,,,,,,,,,,,,,,,,, ) Methyl benzoate (Structure A).

The advantages of the invention are:

1) Short synthetic route, simple process and no dangerous process;

2) Avoid the use of phosphorus-containing compounds (triphenylphosphine), strong oxidants (potassium permanganate) and heavy metal salts (barium chloride), which are complicated in process and polluted, which is not conducive to industrial production;

3) The total yield of the route is high, the raw materials are cheap and easy to obtain, the intermediate is simple to purify, the cost is low, and it is suitable for industrial production.

Example

Example 1 (3R,4R,5R)-3,4-Dihydroxy-5-(hydroxymethyl)-3-methyldihydrofuran-2(3H)-one (Intermediate 18)

Under anhydrous conditions, D-glucose 180.0 g (1.0 mol, 1.0 eq) was dispersed in 250 ml of absolute ethanol, and 60.0 g (1.0 mol, 1.0 eq) of glacial acetic acid was added and stirred for 30 min, then 33% dimethylamine was added dropwise. Ethanol solution 139.4g (1.02mol, 1.02 eq), the control temperature does not exceed 20 °C. After the reaction solution was heated to 75 ° C for 2 hours, the temperature was lowered to 55 ° C, and the reaction was kept for 2 hours. Concentration under reduced pressure at 50 ° C gave a brown oil. After adding 400 ml of water to the oil and replacing it with nitrogen for 3 times, 73.1 g (1.3 mol, 1.3 eq) of calcium oxide was added to control the temperature not exceeding 20 ° C. After the addition, the mixture was stirred at 20 ° C for 20 min and then heated to 40 ° C. 4h. The reaction solution was cooled to below 3 ° C, concentrated sulfuric acid was added dropwise to adjust the pH between 3.0 and 3.2, and the controlled temperature did not exceed 3 ° C. After the pH adjustment was completed, the reaction solution was heated to 45 ° C and stirred for 12 h, then cooled to 25 ° C. Filtration, the filter cake was washed with an appropriate amount of water and the filtrate was concentrated to dry. After the residue was refluxed with acetone/water (V/V = 10:1) 1 L for 30 min, the heating was stopped, and the mixture was filtered, and then the filter cake was refluxed twice with 500 ml each of acetone/water (V/V = 10:1). The filtrate was combined and concentrated. The residue was added to acetone (200 ml), dissolved by heating, and then filtered with hot water and stirred at room temperature to obtain 3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyl Dihydrofuran-2(3H)-one (Intermediate 18) 105 g, off-white solid, yield 65%.

Example 2 ((2R,3R,4R)-3-(benzoyloxy)-4-hydroxy-4-methyl-5-oxotetrahydrofuran-2-yl)methylbenzoate (intermediate Preparation of 19)

Intermediate 18 100 g (0.62 mol) was dissolved in 800 ml of dichloromethane, 186.9 g (1.85 mol, 3.0 eq) of triethylamine was added, and the mixture was dropped to -20 ° C, and benzoyl chloride 177.7 g (1.26 mol, 2.05 eq) was added dropwise. ), the control temperature does not exceed 0 ° C, after the completion of the dropwise addition, continue to stir the reaction for 3-5 h. After completion of the reaction, the reaction mixture was washed successively with 5% aqueous sodium hydrogencarbonate (500 ml) and brine (500 ml), and the organic phase was dried and concentrated under reduced pressure. 10:1) stirring and crystallization, filtration, and drying to give ((2R,3R,4R)-3-(benzoyloxy)-4-hydroxy-4-methyl-5-oxotetrahydrofuran-2-yl Methyl benzoate (Intermediate 19), 182.7 g, off-white solid, yield 80%.

Example 3 ((2R,3R,4R)-3-(Benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methylbenzoate (Structure A Preparation

180 g (0.486 mol, 1.0 eq) of intermediate 19 and 1.5 L of dichloromethane were added to a 3 L reaction flask, stirred and dissolved, and the temperature was lowered to -15 ° C, and 86.2 g of diethylaminosulfur trifluoride (0.534 mol) was slowly added dropwise. , 1.1 eq), the control temperature does not exceed -5 ° C, after the addition, naturally rise to room temperature, stirring for 18 h, after the reaction is completed, the reaction solution is washed successively with 1N hydrochloric acid 700 ml, saturated brine (800 x 2), and the organic phase is dried and concentrated. To dry, ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methylbenzoate (structural formula) A), 164.7 g, off-white solid, yield 91%.

Claims (6)

1. A process for the preparation of a sofosbuvir fluorolactone intermediate of formula A, which is ((2R,3R,4R)-3-(benzoyloxy)- 4-Fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methylbenzoate characterized by the steps comprising:

   

   (1) Preparation of Intermediate 18

   a. Under anhydrous conditions, D-glucose is dispersed in absolute ethanol, stirred for 30 min with glacial acetic acid, and then ethanol solution of diethylamine is added dropwise, the temperature is controlled to not exceed 20 ° C, and the reaction solution is heated to 75 ° C for reaction. The temperature was lowered to 55 ° C, the reaction was kept for 2 h, and concentrated under reduced pressure to give a brown oil.

   b, adding water to the above oil, replacing the nitrogen three times, adding calcium oxide, controlling the temperature does not exceed 20 ° C, after the addition, stirring at 20 ° C for 20 min, heating to 40 ° C reaction;

   c, the reaction solution is cooled to below 3 ° C, concentrated sulfuric acid is added to adjust the pH to acidity, the control temperature does not exceed 3 ° C, after the pH adjustment is completed, the reaction liquid is heated to 45 ° C, stirred for 12 h, then cooled to 25 ° C, filtered, The filter cake is washed with an appropriate amount of water, and the filtrate is concentrated to dryness;

   d, the residue was heated with acetone / water for 30min, the heating was stopped, filtered, and the filter cake was extracted twice with acetone / water, the filtrate was combined and concentrated, the residue was recrystallized from acetone to give intermediate 18;

   (2) Preparation of intermediate 19

   The intermediate 18 is dissolved in dichloromethane, triethylamine is added, the temperature is lowered to -20 ° C, benzoyl chloride is added dropwise, and the temperature is controlled to not exceed 5 ° C. After the completion of the dropwise addition, the stirring reaction is continued for 3-5 hours. The reaction liquid was washed successively with aqueous sodium hydrogencarbonate solution and saturated brine, and the organic phase was dried and concentrated under reduced pressure. The residue was added to ethyl acetate / n-hexane of V/V = 10:1, stirred and crystallized, filtered, and dried. Intermediate 19;

   (3) Preparation of sofosbuvir lactone intermediate

   The intermediate 19 was dissolved in dichloromethane, and the temperature was lowered to -15 ° C, and then diethylaminosulfur trifluoride was slowly added. After the addition, the mixture was naturally warmed to room temperature and stirred for 18 hours. After the reaction was completed, 1 N hydrochloric acid was used and saturated. The reaction solution was washed with brine, dried and evaporated to dryness affording ((2,,,,,,,,,,,,,,,,,,,,,,,,,, ) methyl benzoate.
2. A process for the preparation of a sofosbuvir fluorolactone intermediate according to claim 1 wherein the step of synthesizing compound 18 In the step (a), the reaction solution was heated to 75 ° C for 2 h.
3. A process for the preparation of a sofosbuvir fluorolactone intermediate according to claim 1, characterized in that in the step (b) of synthesizing the compound 18, the reaction solution is heated to 40 ° C for 4 h.
4. A process for the preparation of a sofosbuvir fluorolactone intermediate according to claim 1, characterized in that in the step (c) of synthesizing the compound 18, the concentrated sulfuric acid is adjusted to a pH between 3.0 and 3.2.
5. A process for the preparation of a sofosbuvir fluorolactone intermediate according to claim 1, characterized in that in the step (d) of synthesizing the compound 18, the acetone/water ratio is V/V = 10:1.
6. A process for the preparation of a sofosbuvir fluorolactone intermediate according to claim 1, characterized in that in the process of synthesizing the compound 19, the benzoyl chloride is added dropwise to a temperature not exceeding 0 °C.