CN109438397B - Synthetic method of sofosbuvir intermediate - Google Patents
Synthetic method of sofosbuvir intermediate Download PDFInfo
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Abstract
The invention relates to a compound represented by the formula (I):
Description
Technical Field
The invention relates to a synthetic method of a medical intermediate, in particular to a synthetic method of a sofosbuvir intermediate.
Technical Field
Sofosbuvir (also known as Sofosbuvir, the english name Sofosbuvir, trade name Sovaldi) is a new drug developed by gilide corporation for the treatment of chronic hepatitis c and is approved by the U.S. Food and Drug Administration (FDA) to be marketed in the united states at 12/6 d in 2013 and by the european drug administration (EMEA) at 16 d 1/2014. Has not yet been marketed in China. The medicine is the first medicine which can safely and effectively treat certain types of hepatitis C without combining interferon. Clinical trials have demonstrated that the overall sustained virological response rate (SVR) of this drug in combination with peginterferon and ribavirin is as high as 90% for type 1 and 4 hepatitis c; for type 2 hepatitis C, the SVR of the medicine and ribavirin is 89-95%; aiming at type 3 hepatitis C, the SVR of the medicine and ribavirin is 61-63%.
Compound (I) is a key intermediate for synthesizing sofosbuvir, and Peiyuanan Wang et al reported An effective and diseaseoselective Synthesis of PSI-6130: A clinical effects Inhibitor of HCV NS5B Polymerase in the journal of American Chemical Society, 2009,14: 6189-6824, wherein (2S,3R) -ethyl-3- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) -2, 3-dihydroxy-2-methylpropionate is cyclized by thionyl chloride to form An intermediate (2S,3R) -ethyl-3- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) -2, 3-dihydroxy-2-cycl sulfite, oxidizing the intermediate (2S,3R) -ethyl-3- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) -2, 3-dihydroxy-2-cyclic sulfite with sodium hypochlorite or sodium periodate to obtain the intermediate (2S,3R) -ethyl-3- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) -2, 3-dihydroxy-2-cyclic sulfate, the intermediate (2S,3R) -ethyl-3- ((R) -2, 3-dihydroxy-2-cyclic sulfate, the intermediate (2S,3R) -ethyl-2, 3-cyclic sulfate, the intermediate (2S,3R) -2-dihydroxy-2-cyclic sulfate, and the intermediate (2S,3R) are fluorinated, Hydrolyzing and benzoylating to obtain the sofosbuvir intermediate 3, 5-dibenzoyl-2-deoxy-2-fluoro-2 methyl-D-ribose-gamma-lactone, wherein the specific reaction route is as follows:
the oxidizing agent used in the reaction is sodium hypochlorite or sodium periodate, which presents the following disadvantages: sodium periodate is irritating to eyes, upper respiratory tract, mucous membrane and skin, and proper protective clothing and gloves are needed to be worn and protective glasses or masks are needed to be used in the using process; sodium hypochlorite is absorbed by inhalation, ingestion and skin contact, and workers who often contact sodium hypochlorite with hands have a great deal of sweat on palms, thin nails and hair loss, and the sodium hypochlorite has a sensitizing effect, and chlorine gas emitted by the sodium hypochlorite possibly causes poisoning. When sodium hypochlorite or sodium periodate is used for oxidation reaction, byproducts NaCl or NaI are generated to be unfavorable for subsequent treatment.
Disclosure of Invention
In order to solve the above problems, the present invention provides the following technical solutions: a compound of formula (I):
the synthesis method of the sofosbuvir intermediate has the innovation points that: the synthetic route is as follows:
the method comprises the following steps:
(1) dissolving a compound (2S,3R) -ethyl-3- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) -2, 3-dihydroxy-2-methylpropionate (II) in dichloromethane, and carrying out cyclization under an alkaline condition to generate an intermediate product (III);
(2) adding a catalyst into the intermediate product (III) generated in the step (1), and then dropwise adding hydrogen peroxide to perform an oxidation reaction to generate an intermediate product (IV);
(3) dissolving the intermediate product (IV) in ethyl acetate, stirring for dissolving, and then performing a fluoro reaction to generate an intermediate product (2R,3R) -ethyl-3- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) -2-fluoro-2-methyl-3-hydroxypropionate (V);
(4) hydrolyzing an intermediate product (2R,3R) -ethyl-3- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) -2-fluoro-2-methyl-3-hydroxypropionate (V), and then cyclizing to generate an intermediate product 2-deoxy-2-fluoro-2 methyl-D-ribose-gamma-lactone (VI);
(5) dissolving the intermediate product 2-deoxy-2-fluoro-2-methyl-D-ribose-gamma-lactone (VI) in acetonitrile, and sequentially dropwise adding triethylamine and benzoyl chloride for substitution reaction to generate the sofosbuvir intermediate 3, 5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribose-gamma-lactone (I).
Further, the alkaline environment in the step (1) is a triethylamine environment, the dosage of triethylamine in the invention is 1.75-2.0 times of the molar mass of the raw material (II), the reagent of cyclization reaction in the invention is thionyl chloride, the dosage of thionyl chloride in the invention is 1.3-1.6 times of the molar mass of the raw material (II), the reaction time of the reaction in the invention is 20-40 min, and the reaction temperature is-10 ℃.
Further, in the step (2), the catalyst is sodium tungstate dihydrate, the mass fraction of hydrogen peroxide is 25-35%, the molar mass ratio of the hydrogen peroxide to the raw material (II) is 1.8-3: 1, the molar mass ratio of the hydrogen peroxide to the sodium tungstate dihydrate is 4-6: 1, the reaction temperature of the oxidation reaction is 20-25 ℃, and the reaction time is 8-10 hours.
Furthermore, in the step (3) of the present invention, a reagent used for the fluorination reaction is tetraethylammonium fluoride dihydrate, the molar mass ratio of the tetraethylammonium fluoride dihydrate to the raw material (II) is 0.7-1.3: 1, and the reaction time of the fluorination reaction is 5-6 hours.
Furthermore, in the step (4) of the invention, the mass fraction of the hydrolysis reagent is 15-25% of hydrochloric acid, the molar mass ratio of the hydrochloric acid to the raw material (II) is 0.9-1.1: 1, the cyclization reagent is barium hydroxide, the molar mass ratio of the barium hydroxide to the raw material (II) is 0.5-1: 1, and the reaction time is 12-16 h.
Further, in the step (5), reagents for replacing the reaction are triethylamine and benzoyl chloride, the molar mass ratio of the triethylamine, the benzoyl chloride and the raw material (II) is 1.5-2.6: 1.4-2.1: 1, the reaction temperature is 0-5 ℃, and the reaction time is 2-4 hours.
The invention has the advantages that: compared with the prior art, the hydrogen peroxide with stronger oxidation property is used for replacing sodium hypochlorite or sodium periodate in the prior art, water is generated in the reaction process, the next treatment is not needed, the method is economic and environment-friendly, and the industrial production cost is greatly saved; and in the reaction process, a catalyst sodium tungstate is added, and the sodium tungstate is also a strong oxidant, so that the reaction strength is further increased, and the method has a huge industrial production prospect.
Detailed Description
The following examples are presented to enable those skilled in the art to more fully understand the present invention and are not intended to limit the scope of the embodiments of the present invention.
Example 1
A synthetic method of a sofosbuvir intermediate (I) comprises the following specific steps:
step one, synthesizing a compound (III): adding 24.8g (0.1mol) of the compound (II), 200g of dichloromethane and 20.2g (0.2mol) of triethylamine into a dry three-necked bottle at 0-5 ℃, stirring to 0 ℃, slowly dropwise adding 17.9g (0.15mol) of thionyl chloride, reacting for 30min, adding 100g of ice water and 200g of dichloromethane, stirring for 30min, separating an organic layer, and washing the organic layer with 100g of water and 20% of saline respectively to obtain a dichloromethane solution of the compound (III).
Step two, synthesis of a compound (IV): and (2) adding 1.65g (0.05mol) of sodium tungstate dihydrate into the dichloromethane solution of the compound (III) in the step one, dropwise adding 28.3g (0.25mol) of 30% hydrogen peroxide at 23 ℃, continuously reacting for 9h after dropping till the compound (III) disappears, filtering and recovering the sodium tungstate dihydrate, and cleaning the filtrate with 50g of 10% sodium bisulfite and 50g of clear water respectively, and concentrating to dryness to obtain the compound (IV).
Step three: synthesis of Compound (V): 150g of ethyl acetate was added to the compound (IV), and the mixture was stirred and dissolved, 10.1g (0.1mol) of triethylamine and 18.5g (0.1mol) of tetraethylammonium fluoride dihydrate were added thereto, and the mixture was refluxed at elevated temperature for about 5 hours to thereby obtain a compound (V) which disappeared.
Step four: synthesis of Compound (VI): and (3) concentrating the three solutions, adding 150g of ethanol for dissolution, adding 50g of 20% hydrochloric acid, heating for reflux, adding barium hydroxide in batches, reacting for 14h, slightly cooling, filtering to remove the generated barium sulfate, evaporating ethanol and water, and adding 120g of acetonitrile for dissolution to obtain an acetonitrile solution of the compound (VI), wherein the total amount of the barium hydroxide is about 6.8g (0.08 mol).
Step five: synthesis of Compound (I): 20.2g (0.2mol) of triethylamine is added into the acetonitrile solution of the compound (VI), 25.3g (0.18mol) of benzoyl chloride is dripped at the temperature of 2.5 ℃, and the reaction lasts for 3 hours until the compound (VI) disappears. The acetonitrile is evaporated by decompression, 130g of ethyl acetate is added, 50g of water is added for washing twice, the ethyl acetate is evaporated by distillation, 200g of isopropanol is added for recrystallization, and 18.2g of the product white solid 3, 5-dibenzoyl-2-deoxy-2-fluoro-2 methyl-D-ribose-gamma-lactone (I) is obtained.
Example 2
A synthetic method of a sofosbuvir intermediate (I) comprises the following specific steps:
step one, synthesizing a compound (III): adding 22.6g (0.09mol) of the compound (II), 180g of dichloromethane and 18.2g (0.18mol) of triethylamine into a dry three-necked bottle at 0-5 ℃, stirring to 0 ℃, slowly dripping 15.5g (0.13mol) of thionyl chloride, reacting for 20min, adding 100g of ice water and 200g of dichloromethane, stirring for 30min, separating an organic layer, and washing the organic layer with 100g of water and 20% of saline water respectively to obtain a dichloromethane solution of the compound (III).
Step two, synthesis of a compound (IV): adding 15g (0.045mol) of sodium tungstate dihydrate into the dichloromethane solution of the compound (III) in the first step, dropwise adding 26.4g (0.27mol) of 35% hydrogen peroxide at 20 ℃, continuing to react for 8 hours until the compound (III) disappears, filtering and recovering the sodium tungstate dihydrate, and respectively cleaning the filtrate with 50g of 10% sodium bisulfite and 50g of clear water, and concentrating to dryness to obtain the compound (IV).
Step three: synthesis of Compound (V): ethyl acetate 150g was added to compound (IV), and the mixture was stirred to dissolve it, 11.1g (0.11mol) of triethylamine and 16.7g (0.09mol) of tetraethylammonium fluoride dihydrate were added thereto, and the mixture was refluxed at elevated temperature for about 5.5 hours to thereby obtain compound (V) which disappeared from compound (IV).
Step four: synthesis of Compound (VI): and (3) concentrating the three solutions, adding 134g of ethanol for dissolution, adding 60g of 15% hydrochloric acid, heating for reflux, adding barium hydroxide in batches, reacting for 12 hours, slightly cooling, filtering to remove the generated barium sulfate, evaporating ethanol and water, and adding 120g of acetonitrile for dissolution to obtain an acetonitrile solution of a compound (VI), wherein the total amount of the barium hydroxide is about 5.4g (0.064 mol).
Step five: synthesis of Compound (I): adding 18.6g (0.18mol) of triethylamine into the acetonitrile solution of the compound (VI), dropwise adding 23.4g (0.17mol) of benzoyl chloride at 0 ℃, and reacting for 4 hours until the compound (VI) disappears. The acetonitrile is evaporated by decompression, 130g of ethyl acetate is added, 50g of water is added for washing twice, the ethyl acetate is evaporated by distillation, 200g of isopropanol is added for recrystallization, and 17.3g of the product white solid 3, 5-dibenzoyl-2-deoxy-2-fluoro-2 methyl-D-ribose-gamma-lactone (I) is obtained.
Example 3
A synthetic method of a sofosbuvir intermediate (I) comprises the following specific steps:
step one, synthesizing a compound (III): adding 29.76g (0.12mol) of the compound (II), 230g of dichloromethane and 21.2g (0.21mol) of triethylamine into a dry three-necked flask at low temperature, stirring to 0 ℃, slowly adding 18.6g (0.156mol) of thionyl chloride dropwise, reacting for 40min, adding 100g of ice water and 200g of dichloromethane, stirring for 30min, separating an organic layer, and washing the organic layer with 100g of water and 20% of saline water respectively to obtain a dichloromethane solution of the compound (III).
Step two, synthesis of a compound (IV): adding 1.75g (0.053mol) of sodium tungstate dihydrate into the dichloromethane solution of the compound (III) in the first step, dropwise adding 29.9g (0.22mol) of 25% hydrogen peroxide at 25 ℃, continuing to react for 10 hours until the compound (III) disappears, filtering and recovering the sodium tungstate dihydrate, and respectively cleaning the filtrate with 50g of 10% sodium bisulfite and 50g of clear water, and concentrating to dryness to obtain the compound (IV).
Step three: synthesis of Compound (V): 160g of ethyl acetate is added to the compound (IV), stirred and dissolved, 12.1g (0.12mol) of triethylamine and 20.3g (0.11mol) of tetraethylammonium fluoride dihydrate are added, and the mixture is heated and refluxed for about 6 hours until the compound (IV) disappears to obtain a compound (V).
Step four: synthesis of Compound (VI): and (3) concentrating the three solutions, adding 150g of ethanol for dissolution, adding 46g of 25% hydrochloric acid, heating and refluxing, adding 7.3g (0.085mol) of barium hydroxide in batches, reacting for 16h, slightly cooling, filtering to remove the generated barium sulfate, evaporating ethanol and water, adding 120g of acetonitrile for dissolution, and thus obtaining an acetonitrile solution of the compound (VI).
Step five: synthesis of Compound (I): in the compound (VI) acetonitrile solution, adding triethylamine 23.2g (0.23mol), at 5 ℃, dropwise adding benzoyl chloride 26.5g (0.19mol), finishing the dripping, reaction for 3h until the compound (VI) disappears. The acetonitrile is evaporated by decompression, 130g of ethyl acetate is added, 50g of water is added for washing twice, the ethyl acetate is evaporated by distillation, 200g of isopropanol is added for recrystallization, and 19.3g of the product white solid 3, 5-dibenzoyl-2-deoxy-2-fluoro-2 methyl-D-ribose-gamma-lactone (I) is obtained.
The white solid 3, 5-dibenzoyl-2-deoxy-2-fluoro-2 methyl-D-ribo-gamma-lactone (I) synthesized in examples 1 to 3 has a total yield of 43.3 to 51.6% based on the compound (II).
The physical parameters are as follows: specific rotation degree: 131.6 ° (c 0.50, CHCl)3) Nuclear magnetic hydrogen spectrum1H NMR(DMSO-d6)δ1.67(d,3H,J＝24.2Hz,CH3) 4.62-4.73(m,2H, H-5, 5'), 5.11-5.15(m,1H, H-4),5.77(dd,1H, J ═ 7.0,18.4Hz, H-3),7.45(m,2H, m-Ar),7.55(m,2H, m-Ar),7.62(m,1H, p-Ar),7.70(m,1H, p-Ar),7.93(m,2H, o-Ar),8.06(m,2H, p-Ar),8.08(m,2H, Ar), mass spectrum (ESI-MS): 373(M +1), elemental analysis (C)20H17FO6%) (measured/calculated): c64.48/64.51, H4.62/4.60.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (6)
1. A compound of formula (I):
the synthetic method of the sofosbuvir intermediate is characterized by comprising the following steps: the synthetic route is as follows:
the method comprises the following steps:
(1) dissolving a compound (2S,3R) -ethyl-3- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) -2, 3-dihydroxy-2-methylpropionate (II) in dichloromethane, and carrying out cyclization under an alkaline condition to generate an intermediate product (III);
(2) adding a catalyst into the intermediate product (III) generated in the step (1), and then dropwise adding hydrogen peroxide to perform an oxidation reaction to generate an intermediate product (IV);
(3) dissolving the intermediate product (IV) in ethyl acetate, stirring for dissolving, and then carrying out a fluorination reaction to generate an intermediate product (2R,3R) -ethyl-3- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) -2-fluoro-2-methyl-3-hydroxypropionate (V);
(4) hydrolyzing an intermediate product (2R,3R) -ethyl-3- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) -2-fluoro-2-methyl-3-hydroxypropionate (V), and then cyclizing to generate an intermediate product 2-deoxy-2-fluoro-2 methyl-D-ribose-gamma-lactone (VI);
(5) dissolving the intermediate product 2-deoxy-2-fluoro-2-methyl-D-ribose-gamma-lactone (VI) in acetonitrile, and sequentially dropwise adding triethylamine and benzoyl chloride to perform substitution reaction to generate a sofosbuvir intermediate 3, 5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribose-gamma-lactone (I);
the cyclized reagent in the step (4) is barium hydroxide;
and (3) reagents for the substitution reaction in the step (5) are triethylamine and benzoyl chloride.
2. The synthesis method of the sofosbuvir intermediate as claimed in claim 1, characterized in that: the alkaline environment in the step (1) is a triethylamine environment, the dosage of triethylamine is 1.75-2.0 times of the molar mass of the raw material (II), the reagent for the cyclization reaction is thionyl chloride, the dosage of the thionyl chloride is 1.3-1.6 times of the molar mass of the raw material (II), the reaction time is 20-40 min, and the reaction temperature is-10 ℃.
3. The synthesis method of the sofosbuvir intermediate as claimed in claim 1, characterized in that: in the step (2), the catalyst is sodium tungstate dihydrate, the mass fraction of the hydrogen peroxide is 25-35%, the molar mass ratio of the hydrogen peroxide to the raw material (II) is 1.8-3: 1, the molar mass ratio of the hydrogen peroxide to the sodium tungstate dihydrate is 4-6: 1, the reaction temperature of the oxidation reaction is 20-25 ℃, and the reaction time is 8-10 hours.
4. The synthesis method of the sofosbuvir intermediate as claimed in claim 1, characterized in that: the reagent used in the fluorination reaction in the step (3) is tetraethylammonium fluoride dihydrate, the molar mass ratio of the tetraethylammonium fluoride dihydrate to the raw material (II) is 0.7-1.3: 1, and the reaction time of the fluorination reaction is 5-6 h.
5. The synthesis method of the sofosbuvir intermediate as claimed in claim 1, characterized in that: in the step (4), the mass fraction of the hydrolysis reagent is 15-25% of hydrochloric acid, the molar mass ratio of the hydrochloric acid to the raw material (II) is 0.9-1.1: 1, the molar mass ratio of the barium hydroxide to the raw material (II) is 0.5-1: 1, and the reaction time is 12-16 h.
6. The synthesis method of the sofosbuvir intermediate as claimed in claim 1, characterized in that: the molar mass ratio of the triethylamine to the benzoyl chloride to the raw material (II) is 1.5-2.6: 1.4-2.1: 1, the reaction temperature is 0-5 ℃, and the reaction time is 2-4 hours.
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