CN117603179A - Efficient synthesis method of sofosbuvir intermediate - Google Patents
Efficient synthesis method of sofosbuvir intermediate Download PDFInfo
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- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 title claims abstract description 23
- 229960002063 sofosbuvir Drugs 0.000 title claims abstract description 22
- 238000001308 synthesis method Methods 0.000 title claims abstract description 17
- 239000000463 material Substances 0.000 claims abstract description 65
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 27
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 15
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 12
- 230000035484 reaction time Effects 0.000 claims abstract description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000011630 iodine Substances 0.000 claims abstract description 11
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 11
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 10
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000011777 magnesium Substances 0.000 claims abstract description 7
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 7
- 239000011701 zinc Substances 0.000 claims abstract description 7
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 42
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 239000011541 reaction mixture Substances 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 15
- 239000012044 organic layer Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000003818 flash chromatography Methods 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N ortho-diethylbenzene Natural products CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000005086 pumping Methods 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 239000000543 intermediate Substances 0.000 abstract description 10
- 238000002360 preparation method Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 52
- 239000002994 raw material Substances 0.000 description 30
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
- 229910052786 argon Inorganic materials 0.000 description 13
- 238000005406 washing Methods 0.000 description 8
- 208000006154 Chronic hepatitis C Diseases 0.000 description 4
- 208000005176 Hepatitis C Diseases 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 208000010710 hepatitis C virus infection Diseases 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 241000711549 Hepacivirus C Species 0.000 description 2
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010960 commercial process Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229940076563 sovaldi Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The invention relates to the technical field of synthesis of medical intermediates, in particular to a high-efficiency synthesis method of a sofosbuvir intermediate, which comprises the following synthesis routes
Description
Technical Field
The invention relates to the field of synthesis of medical intermediates, in particular to a high-efficiency synthesis method of a sofosbuvir intermediate.
Background
Sofosbuvir (also known as Sofosbuvir, trade name Sovaldi) is a new drug developed by company Ji Lide for the treatment of chronic hepatitis c, approved by the united states Food and Drug Administration (FDA) for 12 th month of 2013 and approved by the european medicines administration (EMEA) for 16 th month of 2014 for various countries in the european union.
Sofosbuvir is an inhibitor of the Hepatitis C Virus (HCV) nucleotide analogue NS5B polymerase, and is the only drug currently marketed that targets NS5B polymerase. It is useful for treating chronic hepatitis C, and is particularly useful as a combination in a combination antiviral treatment regimen for treating Chronic Hepatitis C (CHC) infection.
Is an important intermediate for preparing a Sofosbuvir drug, and a preparation method of the compound is disclosed in patent WO2014100505, and the synthetic route is as follows:
in the synthetic route, the compound I is prepared by reacting the compound II with a phosphorus ylide reagent, which is also a synthetic method commonly adopted in the prior art at present, and the compound I is prepared by a classical Wittig reaction. However, the yield of the compound I synthesized by the method is only 79%, and the reaction yield is low; at the same time, low temperature conditions are required in the reaction, which further increases the synthesis costs of the commercial process.
The microchannel reactor has the characteristics of high specific surface area and regular laminar flow, and reactants can continuously participate in subsequent reactions when reacting in the microchannel reactor, so that high-efficiency space-time yield is obtained. Meanwhile, compared with the traditional preparation process, the microchannel reactor has the advantages of high mass transfer rate, short residence time, good repeatability, convenience in automatic control and the like.
However, there is no report on the preparation of sofosbuvir intermediate compound I using a microchannel reactor.
Disclosure of Invention
Aiming at the problems of long reaction time, low yield, high cost and the like in the prior art, which influence the mass production of the sofosbuvir intermediate, the invention provides a high-efficiency synthesis method of the sofosbuvir intermediate.
In order to achieve the above purpose, the present invention provides the following technical solutions:
a high-efficiency synthesis method of a sofosbuvir intermediate comprises the following steps:
in the first step, a compound II, a compound III, catalyst iodine and magnesium or zinc react in a micro-channel reactor to prepare a compound IV, wherein the synthetic route is as follows:
in the second step, the thionyl chloride is adopted to carry out dehydration reaction on the compound IV, so as to obtain a compound I, and the synthetic route can be expressed as follows:
the first reaction step comprises the following steps:
(1) Mixing the compound II with a solvent, and uniformly stirring to prepare a material A solution;
(2) Mixing the compound III with a solvent, and uniformly stirring to prepare a material B solution;
(3) Mixing magnesium or zinc with a solvent, and uniformly stirring to prepare a material C solution;
(4) Mixing catalyst iodine with a solvent, and uniformly stirring to prepare a material D solution;
(5) Pumping the material A solution, the material B solution, the material C solution and the material D solution obtained in the steps into a micro-channel reactor at a controlled speed respectively, and mixing and reacting for 40-250 s at a reaction temperature of 10-40 ℃ to obtain a reaction product containing a compound IV; the product was then quenched, extracted, the combined organic layers were washed, dried, and concentrated in vacuo to give compound IV.
Further preferably, the flow rate of the solution of the material A is 3-7 mL/min.
Further preferably, the flow rate of the solution of the material B is 5-10 mL/min.
Further preferably, the flow rate of the solution of the material C is 1-3 mL/min.
Further preferably, the flow rate of the solution of the material D is 0.3-0.7 mL/min.
Further preferably, the molar ratio of compound II to compound III in the first reaction step is 1:1 to 1.5.
Further preferably, in the first reaction step the molar ratio of compound II, magnesium or zinc, iodine is 1: (1-2): (0.001-0.01).
Further preferably, the reaction solvent in the first step is one or more of tetrahydrofuran, diethyl ether, benzene or toluene.
Further preferably, the reaction temperature in the microchannel reactor is 20 to 30 ℃.
Further preferably, the reaction time in the microchannel reactor is 60 to 220s.
The specific method of the second reaction step is that under the protection of nitrogen, the compound IV and the solvent are stirred and mixed; dripping thionyl chloride into the mixture, and then stirring for reaction; after the reaction was completed, the reaction mixture was poured into a mixture of ice water/HCl, the reaction mixture was extracted, the organic layer was washed, dried and the solvent was removed, and the residue was purified by flash chromatography on silica gel to give compound I.
Further preferably, the molar ratio of compound IV to thionyl chloride in the second reaction step is 1:3 to 10.
Further preferably, the reaction solvent in the second reaction step is one or more of benzene, toluene, xylene, pyridine, methylene chloride, chloroform, acetonitrile or tetrahydrofuran.
Further preferably, the reaction temperature in the second reaction step is 10 to 60 ℃.
Compared with the prior art, the invention has the beneficial effects that:
the invention takes the compound II and the compound III as raw materials, prepares the compound IV through a micro-channel reactor, and then further dehydrates the compound IV to obtain the compound I. The invention adopts the microchannel reactor to carry out continuous flow type reaction, has less material remained in the microchannel reactor, fully mixes all the reaction materials, has short reaction time, can accurately control the reaction time and the reaction temperature, and avoids the generation of a large amount of byproducts caused by local overheating or prolonged reaction time, thereby effectively solving the problems of long reaction time, more byproducts, overhigh reaction temperature, high equipment requirement, low yield and purity and the like in each reaction step in the prior art. In addition, the synthetic method has mild reaction conditions, does not need low-temperature reaction, and has low requirements on equipment; and the preparation process is simple, the yield and purity of the target compound are high, the production cost is low, and the method is suitable for industrial mass production.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless otherwise specified, the reagents used in the examples of the present invention are all commercially available products.
EXAMPLE 1 Synthesis of Compound IV
(1) Preparing a material A solution: compound II (10 g,76.8 mmol) was added to tetrahydrofuran, diluted to 50mL, stirred well and placed in feed tank a under argon protection for use.
(2) Preparing a material B solution: compound III (15.9 g,88 mmol) was added to tetrahydrofuran, diluted to 80mL, stirred well and placed in feed tank B under argon protection for use.
(3) Preparing a material C solution: magnesium turnings (2.6 g,107.5 mmol) are added into tetrahydrofuran, diluted to 20mL, stirred evenly and placed into a raw material tank C for use under the protection of argon.
(4) Preparing a material D solution: iodine (58 mg,0.23 mmol) was added to tetrahydrofuran, diluted to 5mL, stirred well, placed in feed tank D, and protected with argon.
(5) Opening a valve at the bottom of a raw material tank, respectively conveying a material A solution in the raw material tank A, a material B solution in the raw material tank B, a material C solution in the raw material tank C and a material D solution in the raw material tank D through a feed pump, setting the flow rate of the raw material tank A to 5mL/min, the flow rate of the raw material tank B to 8mL/min, the flow rate of the raw material tank C to 2mL/min and the flow rate of the raw material tank D to 0.5mL/min through a counting pump, preheating the material A solution, the material B solution, the material C solution and the material D solution, setting the temperature of a heat exchanger to 20 ℃, and keeping the reaction time in a channel to 150s. After the reaction, saturated NH was used 4 Cl quenches the reaction mixture. With Et 2 O extraction of the reaction mixture, washing of the combined organic layers with brine, washing with Na 2 SO 4 Drying and vacuum concentration gave compound IV in 97.5% yield, 99.4% purity.
EXAMPLE 2 Synthesis of Compound IV
(1) Preparing a material A solution: compound II (10 g,76.8 mmol) was added to benzene, diluted to 50mL, stirred well and placed in feed tank a under argon protection for use.
(2) Preparing a material B solution: compound III (14 g,77.3 mmol) was added to benzene, diluted to 80mL, stirred well and placed in feed tank B under argon protection for use.
(3) Preparing a material C solution: magnesium turnings (3.7 g,152.3 mmol) are added into benzene, diluted to 20mL, stirred uniformly and placed in a raw material tank C for use under the protection of argon.
(4) Preparing a material D solution: iodine (193 mg,0.76 mmol) was added to benzene, diluted to 5mL, stirred well, placed in feed tank D, and protected with argon.
(5) Opening a valve at the bottom of a raw material tank, respectively conveying a material A solution in the raw material tank A, a material B solution in the raw material tank B, a material C solution in the raw material tank C and a material D solution in the raw material tank D through a feed pump, setting the flow rate of the raw material tank A to be 5mL/min through a counting pump, and setting the flow rate of the raw material tank B to be 8And (3) carrying out mL/min, namely, the flow rate of the raw material tank C is 2mL/min, the flow rate of the raw material tank D is 0.5mL/min, then preheating the solution of the material A, the solution of the material B, the solution of the material C and the solution of the material D, setting the temperature of a heat exchanger to be 40 ℃, and keeping the reaction time in a channel to be 60s. After the reaction, saturated NH was used 4 Cl quenches the reaction mixture. With Et 2 O extraction of the reaction mixture, washing of the combined organic layers with brine, washing with Na 2 SO 4 Drying and vacuum concentration gave compound IV in 93.1% yield, 99.2% purity.
EXAMPLE 3 Synthesis of Compound IV
(1) Preparing a material A solution: compound II (10 g,76.8 mmol) was added to diethyl ether, diluted to 50mL, stirred well and placed in a feed tank a under argon protection for use.
(2) Preparing a material B solution: compound III (20.8 g,114.9 mmol) was added to diethyl ether, diluted to 80mL, stirred well and placed in a feed tank B under argon protection for use.
(3) Preparing a material C solution: zinc powder (5.1 g,78 mmol) was added to diethyl ether, diluted to 20mL, stirred well, placed in a feed tank C and protected with argon.
(4) Preparing a material D solution: iodine (20 mg,0.08 mmol) was added to diethyl ether, diluted to 5mL, stirred well, placed in feed tank D, and protected with argon.
(5) Opening a valve at the bottom of a raw material tank, respectively conveying a material A solution in the raw material tank A, a material B solution in the raw material tank B, a material C solution in the raw material tank C and a material D solution in the raw material tank D through a feed pump, setting the flow rate of the raw material tank A to 5mL/min, the flow rate of the raw material tank B to 8mL/min, the flow rate of the raw material tank C to 2mL/min and the flow rate of the raw material tank D to 0.5mL/min through a counting pump, preheating the material A solution, the material B solution, the material C solution and the material D solution, setting the temperature of a heat exchanger to 10 ℃, and keeping the reaction time in a channel to 220s. After the reaction, saturated NH was used 4 Cl quenches the reaction mixture. With Et 2 O extraction of the reaction mixture, washing of the combined organic layers with brine, washing with Na 2 SO 4 Drying and vacuum concentration to obtain compound IV with yield of 90.2% and purity of 99.3%.
EXAMPLE 4 Synthesis of Compound I
To the reaction vessel, compound IV (5 g,21.5 mmol) and 50mL pyridine were added under nitrogen and mixed with stirring. Thionyl chloride (14 g,118 mmol) was added dropwise to the mixture at-10℃and then the reaction was stirred by heating to 30 ℃. After the reaction was completed, the reaction mixture was poured into a mixture of ice water/1N HCl. The reaction mixture was extracted with diethyl ether, the organic layer was washed with 1N HCl and MgSO 4 The organic layer was dried, the solvent removed in vacuo and the residue purified by flash chromatography on silica gel (petroleum ether: diethyl ether, V: v=35:1) to give compound I in 97.2% yield and 99.4% purity.
EXAMPLE 5 Synthesis of Compound I
To the reaction vessel, compound IV (5 g,21.5 mmol) and 50mL of benzene were added under nitrogen and mixed with stirring. Thionyl chloride (25.5 g,214 mmol) was added dropwise to the mixture at-10℃and then the reaction was stirred by heating to 10 ℃. After the reaction was completed, the reaction mixture was poured into a mixture of ice water/1N HCl. The reaction mixture was extracted with diethyl ether, the organic layer was washed with 1N HCl and MgSO 4 The organic layer was dried, the solvent removed in vacuo and the residue purified by flash chromatography on silica gel (petroleum ether: diethyl ether, V: v=35:1) to give compound I in 92.8% yield, 99.2% purity.
EXAMPLE 6 Synthesis of Compound I
To the reaction vessel, compound IV (5 g,21.5 mmol) and 50mL of dichloromethane were added under nitrogen and mixed with stirring. Thionyl chloride (7.7 g,64.7 mmol) was added dropwise to the mixture at-10℃and then the reaction was stirred by heating to 60 ℃. After the reaction was completed, the reaction mixture was poured into a mixture of ice water/1N HCl. The reaction mixture was extracted with diethyl ether, the organic layer was washed with 1N HCl and MgSO 4 The organic layer was dried, the solvent removed in vacuo and the residue purified by flash chromatography on silica gel (petroleum ether: diethyl ether, V: v=35:1) to give compound I in 91.4% yield, 99.3% purity.
Comparative example 1 Synthesis of Compound IV
Magnesium turnings (2.6 g,107.5 mm) were added to the reaction vessel under argon atmosphereol), iodine (58 mg,0.23 mmol) and 50mL tetrahydrofuran were mixed with stirring. A solution of Compound III (15.9 g,88 mmol) in tetrahydrofuran (50 mL) was added and the mixture was stirred overnight at 20deg.C. A solution of Compound II (10 g,76.8 mmol) in tetrahydrofuran (50 mL) was then added to the mixture and the reaction stirred at 20deg.C for 4h. After the reaction, saturated NH was used 4 Cl quenches the reaction mixture. With Et 2 O extraction of the reaction mixture, washing of the combined organic layers with brine, washing with Na 2 SO 4 Drying and vacuum concentration to obtain compound IV with a yield of 95.3% and a purity of 99.2%.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. A high-efficiency synthesis method of a sofosbuvir intermediate is characterized by comprising the following steps of: the method comprises the following steps:
in the first step, a compound II, a compound III, catalyst iodine and magnesium or zinc react in a micro-channel reactor to prepare a compound IV, wherein the synthetic route is as follows:
step two, adopting thionyl chloride to carry out dehydration reaction on the compound IV to obtain a compound I, wherein the synthetic route is as follows:
the first reaction step comprises the following steps:
(1) Mixing the compound II with a solvent, and uniformly stirring to prepare a material A solution;
(2) Mixing the compound III with a solvent, and uniformly stirring to prepare a material B solution;
(3) Mixing magnesium or zinc with a solvent, and uniformly stirring to prepare a material C solution;
(4) Mixing catalyst iodine with a solvent, and uniformly stirring to prepare a material D solution;
(5) Pumping the material A solution, the material B solution, the material C solution and the material D solution obtained in the steps into a micro-channel reactor at a controlled speed respectively, and mixing and reacting for 40-250 s at a reaction temperature of 10-40 ℃ to obtain a reaction product containing a compound IV; the product was then quenched, extracted, the combined organic layers rinsed, dried and concentrated in vacuo to give compound IV.
2. The efficient synthesis method of the sofosbuvir intermediate according to claim 1, which is characterized in that: in the microchannel reactor, the flow rate of each material solution is as follows: the flow rate of the solution of the material A is 3-7 mL/min; the flow rate of the solution of the material B is 5-10 mL/min; the flow rate of the solution of the material C is 1-3 mL/min; the flow rate of the solution of the material D is 0.3-0.7 mL/min.
3. The efficient synthesis method of the sofosbuvir intermediate according to claim 1, which is characterized in that: in the first reaction step, the molar ratio of the compound II to the compound III is 1:1 to 1.5.
4. The efficient synthesis method of the sofosbuvir intermediate according to claim 1, which is characterized in that: in the first reaction step, the molar ratio of the compound II to magnesium or zinc to iodine is 1: (1-2): (0.001-0.01).
5. The efficient synthesis method of the sofosbuvir intermediate according to claim 1, which is characterized in that: in the first step of reaction, the reaction solvent is one or more of tetrahydrofuran, diethyl ether, benzene or toluene.
6. The efficient synthesis method of the sofosbuvir intermediate according to claim 1, which is characterized in that: in the first step of reaction, the reaction temperature is 20-30 ℃; the reaction time is 60-220 s.
7. The efficient synthesis method of the sofosbuvir intermediate according to claim 1, which is characterized in that: the second step of reaction is specifically that the compound IV and the solvent are stirred and mixed under the protection of nitrogen; dripping thionyl chloride into the mixture, and then stirring for reaction; after the reaction was completed, the reaction mixture was poured into a mixture of ice water/HCl, the reaction mixture was extracted, the organic layer was washed, dried and the solvent was removed, and the residue was purified by flash chromatography on silica gel to give compound I.
8. The efficient synthesis method of the sofosbuvir intermediate according to claim 1 or 7, characterized in that: in the second reaction step, the molar ratio of the compound IV to thionyl chloride is 1:3 to 10.
9. The efficient synthesis method of the sofosbuvir intermediate according to claim 1 or 7, characterized in that: in the second step of reaction, the reaction solvent is one or more of benzene, toluene, xylene, pyridine, dichloromethane, chloroform, acetonitrile or tetrahydrofuran.
10. The efficient synthesis method of the sofosbuvir intermediate according to claim 1 or 7, characterized in that: in the second reaction step, the reaction temperature is 10-60 ℃.
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