CN107868105A - A kind of preparation method of Suo Feibuwei key intermediates - Google Patents
A kind of preparation method of Suo Feibuwei key intermediates Download PDFInfo
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- CN107868105A CN107868105A CN201610855558.7A CN201610855558A CN107868105A CN 107868105 A CN107868105 A CN 107868105A CN 201610855558 A CN201610855558 A CN 201610855558A CN 107868105 A CN107868105 A CN 107868105A
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- 239000000543 intermediate Substances 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000012046 mixed solvent Substances 0.000 claims abstract description 13
- IJMWOMHMDSDKGK-UHFFFAOYSA-N Isopropyl propionate Chemical compound CCC(=O)OC(C)C IJMWOMHMDSDKGK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000047 product Substances 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- 239000007787 solid Substances 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- -1 fluoro- phenoxy groups Chemical group 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- 239000012296 anti-solvent Substances 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 7
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 claims description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 235000011089 carbon dioxide Nutrition 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 claims description 5
- QDQVXVRZVCTVHE-YFKPBYRVSA-N propan-2-yl (2s)-2-aminopropanoate Chemical compound CC(C)OC(=O)[C@H](C)N QDQVXVRZVCTVHE-YFKPBYRVSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical group CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000004140 cleaning Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000012452 mother liquor Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 claims description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 2
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000012141 concentrate Substances 0.000 claims 1
- 238000006317 isomerization reaction Methods 0.000 claims 1
- 235000019260 propionic acid Nutrition 0.000 claims 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims 1
- 150000002118 epoxides Chemical class 0.000 abstract 3
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 4
- 208000006454 hepatitis Diseases 0.000 description 4
- 231100000283 hepatitis Toxicity 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 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 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 229940126701 oral medication Drugs 0.000 description 2
- 229960002063 sofosbuvir Drugs 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 229940126656 GS-4224 Drugs 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 101800001014 Non-structural protein 5A Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical class [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical class O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010568 chiral column chromatography Methods 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 108700008776 hepatitis C virus NS-5 Proteins 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 150000003904 phospholipids Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076563 sovaldi Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/242—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic of hydroxyaryl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2479—Compounds containing the structure P(=X)n-N-acyl, P(=X)n-N-heteroatom, P(=X)n-N-CN (X = O, S, Se; n = 0, 1)
- C07F9/2487—Compounds containing the structure P(=X)n-N-acyl, P(=X)n-N-heteroatom, P(=X)n-N-CN (X = O, S, Se; n = 0, 1) containing the structure P(=X)n-N-C(=X) (X = O, S, Se; n = 0, 1)
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to one kind to prepare Suo Feibuwei key intermediates (s) [(2, 3, 4, 5, 6 phenyl-pentafluoride epoxides) phenoxy group phosphoryl amino] isopropyl propionate preparation method, methods described is that will be mixed with (s) [(2, 3, 4, 5, 6 phenyl-pentafluoride epoxides) phenoxy group phosphoryl amino] isopropyl propionate and (R) [(2, 3, 4, 5, 6 phenyl-pentafluoride epoxides) phenoxy group phosphoryl amino] isopropyl propionate isomers crude reaction, recrystallized repeatedly through acetone methyl tertiary butyl ether(MTBE) mixed solvent system, obtain product S isomers, the inventive method reaction product yield is high.
Description
Technical field
The present invention relates to a kind of preparation method of Suo Feibuwei intermediates, belong to pharmaceutical synthesis field.
Background technology
Suo Feibuwei (sofosbuvir, trade name Sovaldi) is the oral medication hepatitis of Gilead companies of U.S. research and development
Medicine, in December, 2013 through FDA ratify list.Suo Feibuwei is first to be approved for the full oral medication of parallel comment
The medicine of scheme, it is the HCV polymerase nucleotide class inhibitor of first listing in the whole world, by acting on HCV NS5B polymerase targets
Point viral interference inhereditary material RNA synthesis, replicated so as to terminate the RNA chains of HCV virus, and Multi-genotype HCV is controlled
Therapeutic effect individually shares with Suo Feibuwei or with NS5A protease inhibitors, and hepatitis patient takes continued viral response in 12 weeks
Rate reaches more than 95%, and clinical effectiveness is notable, is considered as the breakthrough medicine for the treatment of hepatitis C by medical field.According to world health group
Statistics is knitted, the infection rate of global hepatitis is about 3%, about 1.8 hundred million people's HCV infections, and globalization fashion trend is presented in hepatitis.Suo Feibu
Wei lists only 1 year, and its sales volume was 10,000,000,000 dollars, most reaches soon referred to as in history and sells 10,000,000,000 dollars of medicine year.
Suo Feibuwei is the prodrug of uridine analog, molecular formula C22H23FN3O9P, molecular weight 529.45, it is tied
Structure formula is as follows.453.3
Route currently used for synthesizing Suo Feibuwei mainly includes following two methods：
Wherein method I, the nucleophilic substitution of phosphorus chiral centre can cause the complete conversion of configuration, if can be with routinizing
Two kinds of diastereoisomers, i.e. S configurations and R configurations are separated, and this will be relatively cheap reagent, for synthesizing single institute
Need isomer products sofosbuvir, however, intermediate 1 is not sufficiently stable, it is anhydrous it is non-alcoholic under the conditions of, with silica gel chiral column chromatography
It is possible, but unrealistic that analysis separation, which obtains single acyl chlorides isomers, typically by the use of crude mixture as Phosphation reagent,
The product of generation is also 1:1 non-enantiomer mixture.
Method II has higher reaction yield and very high stereoselectivity using Pentafluorophenol as reaction reagent,
And the key for obtaining high yield and high selectivity is the optical purity of reaction raw materials phospholipid fragments, therefore obtain the tool of high-purity
There are the intermediate of the S configurations (or Sp configurations) of single optical purity, (s)-[(2,3,4,5,6- five fluoro- phenoxy group)-benzene oxygen
Base-phosphoryl amino] isopropyl propionate, turn into crucial.
CN104017020A, which discloses a kind of high-purity that obtains, has the method for Sp optical isomers, and this method is through anti-
After Sp the and Rp mixtures that should be obtained, it is methyl tertiary butyl ether(MTBE) (MTBE)/hexane mixed solvent with 5% during crystallization treatment to carry out
Crystallized, obtain the Sp isomers that HPLC purity is 99.5%, yield 53%, yield is still relatively low.
The content of the invention
It is an object of the invention to provide a kind of new method for preparing Suo Feibuwei key intermediate Sp isomers.The side
Method comprises the following steps
By reaction raw materials phenyl dichloro phosphate, ALANINE isopropyl ester hydrochloride, Pentafluorophenol in DCM reaction dissolvents
Reacted, comprising (s)-[(2,3,4,5,6- five fluoro- phenoxy group)-phenoxy group-phosphoryl amino] isopropyl propionate and
(R)-[(2,3,4,5,6- five fluoro- phenoxy group)-phenoxy group-phosphoryl amino] isopropyl propionate, i.e. two kinds of Sp and Rp isomers
Reacting coarse product.
Then, gained reacting coarse product is dissolved in the mixed solvent, concentration recrystallization is i.e. available.
The mixed solvent includes positive solvent and anti-solvent, the positive solvent be selected from methyl iso-butyl ketone (MIBK), ethyl acetate or
Acetone, the anti-solvent are selected from as n-hexane, normal heptane, methyl tertiary butyl ether(MTBE).
Preferably, the positive solvent is acetone, and the anti-solvent is methyl tertiary butyl ether(MTBE).
The ratio of the positive solvent and anti-solvent is between 1:1-1:Between 10, preferably between 1:4 to 1:Between 10.
Specifically, it is prepared by the present invention：
Dichloromethane (DCM) is filled into the reaction bulb of dried and clean, under nitrogen protection by phenyl dichloro phosphate
Add in the reactor, the dry ice bath is cooled to less than 0 DEG C, then disposably adds ALANINE isopropyl ester hydrochloride and continues to stir
Mix 30min.Reactant is cooled to by -60 DEG C of internal temperatures by dry ice/acetone batch, the DCM solution of triethylamine (TEA) is added dropwise
Into reaction system, heat up naturally, reaction is overnight.
Pentafluorophenol, same nitrogen protection are added into above-mentioned reaction system, TEA is added dropwise at 0-5 DEG C or so in control temperature
DCM solution, about 4h is reacted after adding.
After reaction terminates, reaction suspension is filtered to remove to the triethylamine hydrochloride of most of suspensions, filter by filter
Cake is washed with the DCM of excess, and cleaning solution is incorporated into main filtrate.Filtrate is concentrated and dried to acquisition crude product under reduced pressure, will be with
Upper crude product is dissolved in the in the mixed solvent of acetone-methyl tertiary butyl ether(MTBE), and solution is filtered with silica gel, and with acetone-methyl tertiary butyl ether(MTBE)
Solvent wash clean material untill, the eluent amount of being concentrated into solid separate out, cool down, filter, obtain solid, dry.Mother liquor continues
It has been concentrated into a large amount of solids to separate out, has filtered, dry to obtain solid；Secondary mother liquid continues to be concentrated into solid precipitation, filters, must consolidate
Body.Merge above-mentioned three batches of solids.
Three batches of solids of gained are beaten with the mixed solvent 25mL of acetone-methyl tertiary butyl ether(MTBE), continued in 5 DEG C of stirrings
5h, crystallization is separated out, obtain the Sp isomers that purity is 99.8%.
The product being prepared by the present invention, reaction yield is high, and can obtain the Sp isomers of high-purity.
Specific embodiment
(s)-[(five fluoro- phenoxy groups of the 2,3,4,5,6-)-phenoxy group-phosphoryl amino] preparation of isopropyl propionate
Dichloromethane (90mL) is filled into the reaction bulb of dried and clean, under nitrogen protection by phenyl dichloro phosphate
10.5g (50.2mmol) is filled with the reactor, and the dry ice bath is cooled to 0 DEG C, then disposably adds ALANINE isopropyl ester salt
Hydrochlorate 8.4g (50.2mmol), and continue to stir 30min.Reactant is cooled to by -60 DEG C of internal temperature by dry ice/acetone batch
Degree, the DCM solution (TEA 9.1g are dissolved in 8mL DCM) of triethylamine is added drop-wise in reaction system, is heated up, was reacted naturally
Night.
Pentafluorophenol 9.76g (53mmol) is added into above-mentioned reaction system, same nitrogen protection, control temperature is in 0-5
DEG C or so, TEA DCM solution (TEA 9.1g are dissolved in 8mL DCM) is added dropwise, about 4h is reacted after adding.
After reaction terminates, reaction suspension is filtered to remove to the triethylamine hydrochloride of most of suspensions, filter by filter
Cake is washed with the DCM of excess, and cleaning solution is incorporated into main filtrate.Filtrate is concentrated and dried to acquisition crude product under reduced pressure, will be with
Upper crude product is dissolved in the mixed solvent (1 of acetone-methyl tertiary butyl ether(MTBE):8,100mL) in, solution is filtered with silica gel, and with acetone-first
Untill the solvent wash clean material of base tertbutyl ether, the eluent amount of being concentrated into solid separates out, and cools down, and filters, obtains solid, dries
It is dry.Mother liquor continues to be concentrated into a large amount of solids precipitations, filters, dries to obtain solid；Secondary mother liquid continues to be concentrated into solid precipitation,
Filter, obtain solid.Merge above-mentioned three batches of solids.
Three batches of solids of gained are beaten with the mixed solvent 40mL of acetone-methyl tertiary butyl ether(MTBE), obtained by HPLC pure
Spend the Sp isomers 14.79g for 99.8%, reaction yield 65%.
Claims (6)
1. one kind prepares following formula Suo Feibuwei intermediates (s)-[(five fluoro- phenoxy groups of 2,3,4,5,6-)-phenoxy group-phosphoryl ammonia
Base] isopropyl propionate preparation method,
Methods described includes：
(1) by reaction raw materials phenyl dichloro phosphate, ALANINE isopropyl ester hydrochloride, Pentafluorophenol in DCM reaction dissolvents
Reacted, obtain obtain comprising S and R isomerization reaction crude products (s)-[(2,3,4,5,6- five fluoro- phenoxy group)-phenoxy group-
Phosphoryl amino] isopropyl propionate and (R)-[(five fluoro- phenoxy groups of 2,3,4,5,6-)-phenoxy group-phosphoryl amino] propionic acid it is different
Propyl ester；
(2) (s)-[(five fluoro- phenoxy groups of 2,3,4,5,6-)-phenoxy group-phosphoryl amino] isopropyl propionate is made from comprising S and R
Isomers crude product in, recrystallized with mixed solvent；
(3) further gained crystallization is beaten with mixed solvent, obtains purified isomer product (s)-[(2,3,4,5,6-
Five fluoro- phenoxy groups)-phenoxy group-phosphoryl amino] isopropyl propionate.
2. according to the method for claim 1, wherein the mixed solvent includes positive solvent and anti-solvent.
3. according to the method for claim 2, wherein the positive solvent is selected from methyl iso-butyl ketone (MIBK), ethyl acetate or acetone,
The anti-solvent is selected from as n-hexane, normal heptane, methyl tertiary butyl ether(MTBE).
4. method according to claim 3, wherein the positive solvent is acetone, the anti-solvent is methyl tertiary butyl ether(MTBE).
5. method according to claim 4, wherein the ratio of the positive solvent and anti-solvent is 1:4~1:10.
6. any one claim methods described is in claim 1-5：
(1) dichloromethane (DCM) is filled into the reaction bulb of dried and clean, under nitrogen protection added phenyl dichloro phosphate
Enter in the reactor, the dry ice bath is cooled to less than 0 DEG C, then disposably adds ALANINE isopropyl ester hydrochloride and continues to stir
30min.Reactant is cooled to by -60 DEG C of internal temperatures by dry ice/acetone batch, the DCM solution of triethylamine (TEA) is added drop-wise to
In reaction system, heat up naturally, reaction is overnight；
(2) Pentafluorophenol, same nitrogen protection are added into above-mentioned reaction system, TEA is added dropwise at 0-5 DEG C or so in control temperature
DCM solution, about 4h is reacted after adding；
(3) after reaction terminates, reaction suspension is filtered to remove to the triethylamine hydrochloride of most of suspensions, filter cake by filter
Washed with the DCM of excess, cleaning solution is incorporated into main filtrate, and filtrate is concentrated and dried acquisition crude product under reduced pressure, will be thick above
Product are dissolved in the in the mixed solvent of acetone-methyl tertiary butyl ether(MTBE), and solution is filtered with silica gel, and molten with acetone-methyl tertiary butyl ether(MTBE)
Untill agent wash clean material, the eluent amount of being concentrated into solid separates out, and cools down, and filters, obtains solid 1, dries；Mother liquor continues to concentrate
To there are a large amount of solids to separate out, filter, dry to obtain solid 2；Secondary mother liquid continues to be concentrated into solid precipitation, filters, obtains solid 3,
Merge above-mentioned three batches of solids；
(4) three batches of solids of gained are beaten with the mixed solvent 25mL of acetone-methyl tertiary butyl ether(MTBE), obtain purified isomer product
(s)-[(five fluoro- phenoxy groups of 2,3,4,5,6-)-phenoxy group-phosphoryl amino] isopropyl propionate.
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| CN201610855558.7A CN107868105A (en) | 2016-09-27 | 2016-09-27 | A kind of preparation method of Suo Feibuwei key intermediates |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110964057A (en) * | 2019-12-25 | 2020-04-07 | 东南大学 | Method for preparing sofosbuvir intermediate by using microfluid reaction device |
| CN111040010A (en) * | 2019-12-23 | 2020-04-21 | 上海红蓝医药科技有限公司 | Synthetic method of sofosbuvir intermediate |
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2016
- 2016-09-27 CN CN201610855558.7A patent/CN107868105A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111040010A (en) * | 2019-12-23 | 2020-04-21 | 上海红蓝医药科技有限公司 | Synthetic method of sofosbuvir intermediate |
| CN110964057A (en) * | 2019-12-25 | 2020-04-07 | 东南大学 | Method for preparing sofosbuvir intermediate by using microfluid reaction device |
| CN110964057B (en) * | 2019-12-25 | 2022-05-06 | 东南大学 | Method for preparing sofosbuvir intermediate by using microfluid reaction device |
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