CN107759632A - A kind of preparation method of chiral phosphorus acid esters - Google Patents
A kind of preparation method of chiral phosphorus acid esters Download PDFInfo
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- CN107759632A CN107759632A CN201610697419.6A CN201610697419A CN107759632A CN 107759632 A CN107759632 A CN 107759632A CN 201610697419 A CN201610697419 A CN 201610697419A CN 107759632 A CN107759632 A CN 107759632A
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- 238000002360 preparation method Methods 0.000 title abstract description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 title abstract description 4
- 239000002253 acid Substances 0.000 title abstract description 4
- 150000002148 esters Chemical class 0.000 title abstract description 4
- 229910052698 phosphorus Inorganic materials 0.000 title abstract description 4
- 239000011574 phosphorus Substances 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 196
- 238000000034 method Methods 0.000 claims abstract description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 96
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 41
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 38
- 238000010438 heat treatment Methods 0.000 claims description 31
- 239000012046 mixed solvent Substances 0.000 claims description 31
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- BWILYWWHXDGKQA-UHFFFAOYSA-M potassium propanoate Chemical compound [K+].CCC([O-])=O BWILYWWHXDGKQA-UHFFFAOYSA-M 0.000 claims description 10
- 239000004331 potassium propionate Substances 0.000 claims description 10
- 235000010332 potassium propionate Nutrition 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 7
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 claims description 7
- 239000004324 sodium propionate Substances 0.000 claims description 7
- 235000010334 sodium propionate Nutrition 0.000 claims description 7
- 229960003212 sodium propionate Drugs 0.000 claims description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- 235000011056 potassium acetate Nutrition 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- WHWZQTMFSVKQPF-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol;sodium Chemical compound [Na].OC1=C(F)C(F)=C(F)C(F)=C1F WHWZQTMFSVKQPF-UHFFFAOYSA-N 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- 229960004109 potassium acetate Drugs 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 229960004249 sodium acetate Drugs 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims 1
- HFHFGHLXUCOHLN-UHFFFAOYSA-N 2-fluorophenol Chemical compound OC1=CC=CC=C1F HFHFGHLXUCOHLN-UHFFFAOYSA-N 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- -1 Sodium alkoxide Chemical class 0.000 claims 1
- JZJNHPJBZWEHPD-UHFFFAOYSA-N [F].[Na] Chemical compound [F].[Na] JZJNHPJBZWEHPD-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 239000012065 filter cake Substances 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- 238000007605 air drying Methods 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000002798 polar solvent Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 4
- 229960000329 ribavirin Drugs 0.000 description 4
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 4
- 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 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 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 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- NDQKGYXNMLOECO-UHFFFAOYSA-N acetic acid;potassium Chemical compound [K].CC(O)=O NDQKGYXNMLOECO-UHFFFAOYSA-N 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- QDQVXVRZVCTVHE-YFKPBYRVSA-N propan-2-yl (2s)-2-aminopropanoate Chemical compound CC(C)OC(=O)[C@H](C)N QDQVXVRZVCTVHE-YFKPBYRVSA-N 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229960002063 sofosbuvir Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- FSDYDBAXNANUQE-UHFFFAOYSA-N tris(2,4-dichlorophenyl) phosphate Chemical compound ClC1=CC(Cl)=CC=C1OP(=O)(OC=1C(=CC(Cl)=CC=1)Cl)OC1=CC=C(Cl)C=C1Cl FSDYDBAXNANUQE-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- C07F9/2454—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
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The application belongs to pharmaceutical synthesis field, is related to a kind of preparation method of chiral phosphorus acid esters.Specifically, the application is related to the method that compound shown in Formulas I R is converted into compound shown in Formulas I S.The preparation method of the application has the advantages of high income, product chiral purity is high, be adapted to industrialized production the advantages of.
Description
Technical field
The application belongs to pharmaceutical synthesis field, in particular to a kind of preparation method of chiral phosphorus acid esters.
Background technology
Lucky moral is developed after purchase method not Saite and has listed Suo Feibuwei (sofosbuvir, PSI-7977, GS-
7977,).2013, FDA approval Suo Feibuwei were combined with Ribavirin (RBV), for the type of HCV genes 2 and 3 types
The oral medication of patient；And ratify, with injecting spent glycol interferon (pegIFN) and Ribavirin (RBV) drug combination, to be used for
Treat the first patient of HCV genes 1 and 4 types.Suo Feibuwei treatment cycle is longer, it usually needs the course for the treatment of in 12 weeks -24 weeks, controls
Treatment expense is extremely expensive, and the whole world only has only a few patient and can bear the treatment and benefit at present.
Compound shown in Formulas I-S can be as the intermediate for preparing Suo Feibuwei, and it reacts to obtain rope with the compound of formula II
Fei Buwei：
In the preparation method of compound shown in existing Formulas I-S, products therefrom includes diastereoisomer impurity Formulas I-R institutes
Show compoundWO2011123645 discloses one kind and converts compound shown in Formulas I-R
For the method for compound shown in Formulas I-S, but this method is cumbersome, and products therefrom yield needs further to improve.Also, product
In compound, compound property shown in Formulas I-R shown in more residual Formulas I-R approached with compound shown in Formulas I-S, it is difficult to remove,
Influence the chiral purity of target product Suo Feibuwei obtained by subsequent reactions.
The content of the invention
On the one hand, the application offer is a kind of is converted into compound shown in Formulas I-S by compound shown in Formulas I-R in the solution
Method, including compound shown in Formulas I-R is converted into compound shown in Formulas I-S under the conditions of existing for nucleophilicity alkali, solvent：
The nucleophilicity alkali is selected from sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium acetate, potassium acetate, sodium propionate, potassium propionate
Or Pentafluorophenol sodium.
In some embodiments of the application, compound shown in Formulas I-R is converted into chemical combination shown in Formulas I-S in the solution
In the method for thing, the nucleophilicity alkali preferably is selected from sodium methoxide.
In some embodiments of the application, compound shown in Formulas I-R is converted into chemical combination shown in Formulas I-S in the solution
In the method for thing, the inventory of the nucleophilicity alkali is selected from 0.02~0.50 equivalent, preferably be selected from 0.02,0.05,0.08,0.10,
0.12nd, 0.15,0.18,0.20,0.22,0.25,0.28,0.30,0.32,0.35,0.38,0.40,0.42,0.45,0.48 or
0.50 equivalent.
In some embodiments of the application, compound shown in Formulas I-R is converted into chemical combination shown in Formulas I-S in the solution
In the method for thing, the solvent is selected from ethyl acetate, dichloromethane, acetone, acetonitrile, DMF, Isosorbide-5-Nitrae-dioxy
Six rings, tetrahydrofuran, 2- methyltetrahydrofurans, methyl tertiary butyl ether(MTBE), isopropyl ether, ether, glycol dimethyl ether, normal heptane, just
Hexane or any two or more mixed solvent, preferably are selected from ethyl acetate, methyl tertiary butyl ether(MTBE), isopropyl ether, ether, ethylene glycol two
Methyl ether, normal heptane, n-hexane, hexamethylene or any two or more mixed solvent, more preferably from methyl tertiary butyl ether(MTBE), isopropyl
Ether, the mixed solvent of ethyl acetate and n-hexane, mixed solvent, ethyl acetate and the isopropyl of ethyl acetate and methyl tertiary butyl ether(MTBE)
The mixed solvent of ether.
In some embodiments of the application, compound shown in Formulas I-R is converted into chemical combination shown in Formulas I-S in the solution
In the method for thing, the solvent load is selected from 1~10 times of volume, preferably be selected from 1 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times,
9 times or 10 times of volumes.
In some embodiments of the application, compound shown in Formulas I-R is converted into chemical combination shown in Formulas I-S in the solution
In the method for thing, when solvent is selected from the mixed solvent of two kinds of solvents, the volume ratio of highly polar solvent and low polar solvent is selected from
1:1~1:10, it preferably is selected from 1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9 or 1:10.
On the other hand, the application provides one kind and is placed in heating environment and compound shown in Formulas I-R is converted into shown in Formulas I-S and changes
The method of compound, is included in the presence of base reagent, and compound shown in Formulas I-R is changed into I-S institutes by the way of heating, drying
Show compound, the wherein composition before heating, drying shown in Formulas I-R is in solid form, and compound shown in gained I-S is in solid shape
Formula：
In some embodiments of the application, compound shown in Formulas I-R is converted into Formulas I-S by the heating environment that is placed in
In the method for shown compound, the base reagent is selected from sodium carbonate, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium acid carbonate, second
Sour sodium, potassium acetate, sodium propionate, potassium propionate or Pentafluorophenol sodium, preferably are selected from sodium carbonate, sodium methoxide or potassium propionate.
In some embodiments of the application, compound shown in Formulas I-R is converted into Formulas I-S by the heating environment that is placed in
In the method for shown compound, the heating, drying is selected from normal heating drying or heating under reduced pressure drying.
In some embodiments of the application, compound shown in Formulas I-R is converted into Formulas I-S by the heating environment that is placed in
In the method for shown compound, the temperature of the heating environment is selected from 30~120 DEG C, preferably be selected from 30 DEG C, 40 DEG C, 50 DEG C, 60 DEG C,
70 DEG C, 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C or 120 DEG C.
In some embodiments of the application, compound shown in Formulas I-R is converted into Formulas I-S by the heating environment that is placed in
In the method for shown compound, the content of compound shown in initial Formulas I-R be 0.05%~5.00%, preferably 0.05%,
0.10%th, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.60%, 0.70%,
0.80%th, 0.90%, 1.00%, 1.20%, 1.40%, 1.60%, 1.80%, 2.00%, 2.20%, 2.40%, 2.60%,
2.80%th, 3.00%, 3.20%, 3.40%, 3.60%, 3.80%, 4.00%, 4.20%, 4.40%, 4.60%, 4.80%,
5.00%.
In some embodiments of the application, compound shown in Formulas I-R is converted into Formulas I-S by the heating environment that is placed in
In the method for shown compound, the time for being placed in heating environment can containing according to compound shown in end-product Chinese style I-R
Amount determines that, for example, when the content of compound shown in Formulas I-R is less than 0.4%, described the step of being placed in heating environment terminates.It is excellent
Selection of land, when compound shown in Formulas I-R content be less than 0.35%, 0.30%, 0.25%, 0.20%, 0.15%, 0.10%,
0.08%th, 0.06%, 0.04%, 0.02% or 0.01% when, described the step of being placed in heating environment, terminates.
In some embodiments of the application, compound shown in Formulas I-R is converted into Formulas I-S by the heating environment that is placed in
In the method for shown compound, the time for being placed in heating environment is selected from 1h~48h, preferably be selected from 1h, 3h, 6h, 9h, 12h, 15h,
18h, 21h, 24h, 27h, 30h, 33h, 36h, 39h, 42h, 45h or 48h.
On the other hand, the application provides a kind of method that compound shown in Formulas I-R is converted into compound shown in Formulas I-S,
Including：1) by compound shown in Formulas I-R under the conditions of existing for nucleophilicity alkali, solvent, it is converted into compound shown in Formulas I-S；With
2) in the presence of nucleophilicity alkali, compound shown in remaining Formulas I-R in step 1) is further turned by the way of heating, drying
Compound shown in Formulas I-S is turned to, wherein the nucleophilicity alkali is selected from sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium acetate, acetic acid
Potassium, sodium propionate, potassium propionate or Pentafluorophenol sodium.
In some embodiments of the application, method that compound shown in Formulas I-R is converted into compound shown in Formulas I-S
In, the nucleophilicity alkali preferably is selected from sodium methoxide.
In some embodiments of the application, method that compound shown in Formulas I-R is converted into compound shown in Formulas I-S
In, the inventory of nucleophilicity alkali is selected from 0.02~0.50 equivalent wherein in step 1), preferably be selected from 0.02,0.05,0.08,0.10,
0.12nd, 0.15,0.18,0.20,0.22,0.25,0.28,0.30,0.32,0.35,0.38,0.40,0.42,0.45,0.48 or
0.50 equivalent.
In some embodiments of the application, method that compound shown in Formulas I-R is converted into compound shown in Formulas I-S
In, solvent is selected from ethyl acetate, dichloromethane, acetone, acetonitrile, DMF, Isosorbide-5-Nitrae-dioxy in the step 1)
Six rings, tetrahydrofuran, 2- methyltetrahydrofurans, methyl tertiary butyl ether(MTBE), isopropyl ether, ether, glycol dimethyl ether, normal heptane, just
Hexane or any two or more mixed solvent, preferably are selected from ethyl acetate, methyl tertiary butyl ether(MTBE), isopropyl ether, ether, ethylene glycol two
Methyl ether, normal heptane, n-hexane, hexamethylene or any two or more mixed solvent, more preferably from methyl tertiary butyl ether(MTBE), isopropyl
Ether, the mixed solvent of ethyl acetate and n-hexane, mixed solvent, ethyl acetate and the isopropyl of ethyl acetate and methyl tertiary butyl ether(MTBE)
The mixed solvent of ether.
In some embodiments of the application, method that compound shown in Formulas I-R is converted into compound shown in Formulas I-S
In, solvent load is selected from 1~10 times of volume in the step 1), preferably be selected from 1 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times,
9 times or 10 times of volumes.
In some embodiments of the application, method that compound shown in Formulas I-R is converted into compound shown in Formulas I-S
In, in the step 1), when solvent is selected from the mixed solvent of two kinds of solvents, the volume ratio of highly polar solvent and low polar solvent
Selected from 1:1~1:10, it preferably is selected from 1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9 or 1:10.
In some embodiments of the application, method that compound shown in Formulas I-R is converted into compound shown in Formulas I-S
In, the nucleophilicity alkali in the step 2) comes from the complete nucleophilicity alkali of unreacted in step 1).
In some embodiments of the application, method that compound shown in Formulas I-R is converted into compound shown in Formulas I-S
In, the heating, drying in the step 2) is selected from normal heating drying or heating under reduced pressure drying.
In some embodiments of the application, method that compound shown in Formulas I-R is converted into compound shown in Formulas I-S
In, heating-up temperature in the step 2) is selected from 30~120 DEG C, preferably be selected from 30 DEG C, 40 DEG C, 50 DEG C, 60 DEG C, 70 DEG C, 80 DEG C, 90
DEG C, 100 DEG C, 110 DEG C or 120 DEG C.
In some embodiments of the application, method that compound shown in Formulas I-R is converted into compound shown in Formulas I-S
In, the content of compound shown in the initial Formulas I-R in the step 2) (compound shown in remaining Formulas I-R i.e. in step 1) is
0.05%~5.00%, preferably 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%,
0.45%th, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00%, 1.20%, 1.40%, 1.60%,
1.80%th, 2.00%, 2.20%, 2.40%, 2.60%, 2.80%, 3.00%, 3.20%, 3.40%, 3.60%, 3.80%,
4.00%th, 4.20%, 4.40%, 4.60%, 4.80%, 5.00%.
In some embodiments of the application, method that compound shown in Formulas I-R is converted into compound shown in Formulas I-S
In, the heat time in the step 2) can determine according to the content of compound shown in end-product Chinese style I-R, for example, working as formula
When the content of compound shown in I-R is less than 0.4%, described the step of being placed in heating environment, terminates.Preferably, when shown in Formulas I-R
The content of compound be less than 0.35%, 0.30%, 0.25%, 0.20%, 0.15%, 0.10%, 0.08%, 0.06%,
0.04%th, 0.02% or 0.01% when, described the step of being placed in heating environment, terminates.
In some embodiments of the application, method that compound shown in Formulas I-R is converted into compound shown in Formulas I-S
In, the heat time in the step 2) is selected from 1h~48h, preferably be selected from 1h, 3h, 6h, 9h, 12h, 15h, 18h, 21h, 24h,
27h, 30h, 33h, 36h, 39h, 42h, 45h or 48h.
In this application, the content of compound shown in compound shown in described Formulas I-S or Formulas I-R can use efficient
Liquid phase process is determined, and condition determination is selected from：1) instrument, peace instrument UPLC143001 is worn；Chromatographic column,
IA4.6*250mm, 5um；Mobile phase, n-hexane/isopropanol；2) instrument, peace instrument UPLC143001 is worn；Chromatographic column, Agilent
ZORBAX SB-C18,3.5 μm, 4.6*150mm；Mobile phase, mobile phase A：Phosphate buffer/acetonitrile.
In this application, the equivalent refers to the amount of the material of molar amount.For example, base reagent described herein
Inventory is selected from 0.02~0.20 equivalent, refers to the mole of formula base reagent relative to compound and its chiral photo-isomerisation shown in Formulas I-S
The mole of body is 0.02~0.20 times.
In this application, the solvent load is selected from 1~10 times of volume and refers to the volume (in terms of milliliter) of solvent divided by anti-
Answer quality (in gram) institute's value of thing.For example, in following embodiments 1, having described below " will contain Formulas I-R shownization
Compound about 1 shown in compound and Formulas I-S:1 mixture (10.0g) ethyl acetate/n-hexane (30mL, 1:4, v/v) mixed
It is dispersed with stirring in bonding solvent ", solvent load is 3 times of amounts (30/10=3) herein.
In this application, the inventory of the base reagent refers to：The amount of the material of base reagent and the chemical combination shown in up-to-date style I-R that feeds intake
The ratio of the amount sum of the material of compound shown in thing and Formulas I-S.For example, when the inventory of base reagent is selected from 0.02 equivalent,
Refer to the amount of the material of compound shown in compound shown in initial Formulas I-R and Formulas I-S in the amount and reaction system of the material of base reagent
The ratio of sum is 0.02.
In this application, described highly polar solvent refers to the solvent containing highly polar group, and example includes ethyl acetate, two
Chloromethanes, acetone, acetonitrile, N,N-dimethylformamide, 1,4- dioxane, tetrahydrofuran, 2- methyltetrahydrofurans or methyl
Tertbutyl ether etc..
In this application, described low polar solvent refers to the solvent for not containing highly polar group, and example includes isopropyl ether, second
Ether, glycol dimethyl ether, normal heptane, n-hexane or hexamethylene etc..
The application it was unexpectedly found that, when use nucleophilicity alkali, especially sodium methoxide when, Formulas I-R can be effectively improved
Shown compound is converted into Formulas I-S efficiency, effectively reduces the content of compound shown in products therefrom Chinese style I-R, method operation
Simplicity, be adapted to industrialized production the advantages of.
In addition, the application simultaneously it was unexpectedly found that, when using base reagent, especially sodium methoxide, products therefrom exists
Heating environment can occur compound shown in I-R and be converted into Formulas I-S phenomenons, effectively reduce compound shown in products therefrom Chinese style I-R
Content, method is easy to operate, be adapted to industrialized production the advantages of.
Embodiment
The present invention is further illustrated with embodiment below, but the embodiment is not meant to limit the scope of the invention.
Embodiment A
Pentafluorophenol solution：In in 500mL reaction bulbs, Pentafluorophenol (109.8g, 1.0eq) and dichloromethane are added
(250mL, 2.5 times of amounts (v/m)), are cooled to less than 10 DEG C, triethylamine (66.4g, 1.1eq) are slowly added dropwise, it is stand-by to be down to room temperature.
In 2L reaction bulbs, dichloro-phenyl phosphate (125.9g, 1.0eq) and dichloromethane (900mL, 9 times of amounts (v/m)), nitrogen are added
The lower cooling of protection but to -60~-50 DEG C, add ALANINE isopropyl ester hydrochloride (100.0g) dichloromethane (400mL, 4 times
Measure (v/m)) solution, -60~-50 DEG C are cooled to, dichloromethane (200mL, the 2 times of amounts of triethylamine (126.8g, 2.1eq) are added dropwise
(v/m)) solution, after completion of dropwise addition, -60~-50 DEG C of reaction 1.5h is incubated, -40~-30 DEG C is then risen to, Pentafluorophenol is added dropwise
Solution, after completion of dropwise addition, natural temperature reaction 2h.Acetic acid (10.8g, 0.3eq) is added into reaction solution, stirs 20min, use is cold
Water (600mL*3,6 times of amounts (v/m)) washing 3 times, (organic phase does not detect triethylamine, chromatographic column to organic phase through vapor detection：DB-
624 (30m*0.53mm*3.00 μm, injector temperature：180 DEG C, detector temperature：250 DEG C, flow velocity 3.5ml/min, split ratio
5/1, temperature programming：50 DEG C of holding 4min, 180 DEG C of holding 3min are risen to 15 DEG C/min) use anhydrous sodium sulfate drying 8h, mistake
Filter, 25~35 DEG C of filtrate are concentrated under reduced pressure into no liquid outflow, add n-hexane (300mL, 3 times of amounts (v/m)) and continue to be concentrated under reduced pressure
Flowed out to no liquid, concentrated to obtain compound target product (I-R:I-S=about 1:1).
Embodiment 1
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (10.0g) ethyl acetate/
N-hexane (30mL, 1:4, v/v) in the mixed solvent is dispersed with stirring, and adds 20~30 DEG C of sodium methoxide (0.119g, 0.1 equivalent)
12h is stirred, adds acetic acid (0.132g, 0.1 equivalent) stirring 20min, filtering, filter cake (compound purity shown in Formulas I-S
99.19%, compound purity 0.18% shown in Formulas I-R) 40 DEG C of forced air dryings, obtain white solid 7.33g (chemical combination shown in Formulas I-S
Thing purity 99.34%, compound purity 0.06% shown in Formulas I-R), yield 73.3%.
Embodiment 2
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (10.0g) ethyl acetate/
N-hexane (40mL, 1:4, v/v) in the mixed solvent is dispersed with stirring, and adds 20~30 DEG C of sodium methoxide (0.119g, 0.1 equivalent)
12h is stirred, adds acetic acid (0.132g, 0.1 equivalent) stirring 20min, filtering, filter cake (compound purity shown in Formulas I-S
99.11%, compound purity 0.28% shown in Formulas I-R) 40 DEG C of forced air dryings, obtain white solid 7.21g (chemical combination shown in Formulas I-S
Thing purity 99.30%, compound purity 0.10% shown in Formulas I-R), yield 72.1%.
Embodiment 3
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (10.0g) ethyl acetate/
N-hexane (60mL, 1:4, v/v) in the mixed solvent is dispersed with stirring, and adds 20~30 DEG C of sodium methoxide (0.119g, 0.1 equivalent)
12h is stirred, adds acetic acid (0.132g, 0.1 equivalent) stirring 20min, filtering, filter cake (compound purity shown in Formulas I-S
99.18%, compound purity 0.19% shown in Formulas I-R) 40 DEG C of forced air dryings, obtain white solid 7.06g (chemical combination shown in Formulas I-S
Thing purity 99.33%, compound purity 0.05% shown in Formulas I-R), yield 70.6%.
Embodiment 4
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (10.0g) ethyl acetate/
N-hexane (40mL, 1:3, v/v) in the mixed solvent is dispersed with stirring, and adds 20~30 DEG C of sodium methoxide (0.119g, 0.1 equivalent)
17h is stirred, adds acetic acid (0.132g, 0.1 equivalent) stirring 20min, filtering, filter cake (compound purity shown in Formulas I-S
98.77%, compound purity 0.46% shown in Formulas I-R) 40 DEG C of forced air dryings, obtain white solid 6.85g (chemical combination shown in Formulas I-S
Thing purity 99.03%, compound purity 0.19% shown in Formulas I-R), yield 68.5%.
Embodiment 5
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (10.0g) ethyl acetate/
N-hexane (40mL, 1:5, v/v) in the mixed solvent is dispersed with stirring, and adds 20~30 DEG C of sodium methoxide (0.119g, 0.1 equivalent)
17h is stirred, adds acetic acid (0.132g, 0.1 equivalent) stirring 20min, filtering, filter cake (compound purity shown in Formulas I-S
98.69%, compound purity 0.51% shown in Formulas I-R) 40 DEG C of forced air dryings, obtain white solid 6.77g (chemical combination shown in Formulas I-S
Thing purity 99.02%, compound purity 0.17% shown in Formulas I-R), yield 67.7%.
Embodiment 6
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (10.0g) ethyl acetate/
N-hexane (50mL, 1:3, v/v) in the mixed solvent is dispersed with stirring, and adds sodium methoxide (0.143g, 0.12 equivalent) 20~30
DEG C stirring 24h, add acetic acid (0.160g, 0.12 equivalent) stirring 20min, filtering, filter cake (compound purity shown in Formulas I-S
99.12%, compound purity 0.19% shown in Formulas I-R) 40 DEG C of forced air dryings, obtain white solid 7.10g (chemical combination shown in Formulas I-S
Thing purity 99.24%, compound purity 0.08% shown in Formulas I-R), yield 71.0%.
Embodiment 7
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (10.0g) ethyl acetate/
N-hexane (50mL, 1:3, v/v) in the mixed solvent is dispersed with stirring, and adds 20~30 DEG C of sodium methoxide (0.238g, 0.2 equivalent)
24h is stirred, adds acetic acid (0.267g, 0.2 equivalent) stirring 20min, filtering, filter cake (compound purity shown in Formulas I-S
99.15%, compound purity 0.14% shown in Formulas I-R) 40 DEG C of forced air dryings, obtain white solid 6.48g (chemical combination shown in Formulas I-S
Thing purity 99.25%, compound purity 0.05% shown in Formulas I-R), yield 64.8%.
Embodiment 8
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (20.0g) ethyl acetate/
N-hexane (100mL, 1:4, v/v) in the mixed solvent is dispersed with stirring, and adds sodium carbonate (0.936g, 0.2 equivalent) 20~30
DEG C stirring 20h, filtering, 40 DEG C of filter cake (compound purity 98.73% shown in Formulas I-S, compound purity 1.01% shown in Formulas I-R)
Forced air drying, obtain white solid 13.26g (compound purity 99.05% shown in Formulas I-S, compound purity shown in Formulas I-R
0.66%), yield 66.3%.
Embodiment 9
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (20.0g) is in methyl- tert fourth
It is dispersed with stirring in the solvent of base ether (80mL), and adds 20~30 DEG C of stirring 25h of potassium propionate (0.627g, 0.1 equivalent), filtering,
40 DEG C of forced air dryings of filter cake (compound purity 97.69% shown in Formulas I-S, compound purity 1.67% shown in Formulas I-R), are obtained white
Solid 12.70g (compound purity 98.77% shown in Formulas I-S, compound purity 0.57% shown in Formulas I-R), yield 63.5%.
Embodiment 10
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (8.0g) is in isopropyl ether
It is dispersed with stirring in the solvent of (45mL), and adds 20~30 DEG C of stirring 17h of sodium carbonate (0.187g, 0.1 equivalent), filtering, filter cake
(compound purity 96.85% shown in Formulas I-S, compound purity 2.34% shown in Formulas I-R) 40 DEG C of forced air dryings, obtain white solid
5.40g (compound purity 98.55% shown in Formulas I-S, compound purity 0.66% shown in Formulas I-R), yield 67.5%.
Embodiment 11
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (5.0g) ethyl acetate/
Isopropyl ether (25mL, 1:5, v/v) in the mixed solvent is dispersed with stirring, and add potassium tert-butoxide (0.124g, 0.1 equivalent) 20~
30 DEG C of stirring 17h, filtering, filter cake (compound purity 92.67% shown in Formulas I-S, compound purity 6.45% shown in Formulas I-R) 40
DEG C forced air drying, obtains white solid 3.42g (compound purity 95.88% shown in Formulas I-S, compound purity shown in Formulas I-R
3.25%), yield 68.4%.
Embodiment 12
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (5.0g) ethyl acetate/
Methyl tertiary butyl ether(MTBE) (25mL, 1:4, v/v) in the mixed solvent is dispersed with stirring, and adds sodium acid carbonate (0.093g, 0.1 equivalent)
20~30 DEG C of stirring 17h, filtering, filter cake (compound purity 97.70% shown in Formulas I-S, compound purity shown in Formulas I-R
6.37%) 40 DEG C of forced air dryings, white solid 3.50g (compound purity 94.65% shown in Formulas I-S, chemical combination shown in Formulas I-R are obtained
Thing purity 4.45%), yield 70.0%.
Embodiment 13
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (5.0g) ethyl acetate/
N-hexane (30mL, 1:4, v/v) in the mixed solvent is dispersed with stirring, and add anhydrous sodium acetate (0.091g, 0.1 equivalent) 20~
30 DEG C of stirring 17h, filtering, filter cake (compound purity 95.43% shown in Formulas I-S, compound purity 3.47% shown in Formulas I-R) 40
DEG C forced air drying, obtains white solid 3.31g (compound purity 96.75% shown in Formulas I-S, compound purity shown in Formulas I-R
2.11%), yield 66.2%.
Embodiment 14
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (5.0g) ethyl acetate/
N-hexane (15mL, 1:4, v/v) in the mixed solvent is dispersed with stirring, and adds 20~30 DEG C of potassium acetate (0.108g, 0.1 equivalent)
Stir 17h, filtering, 40 DEG C of drums of filter cake (compound purity 94.22% shown in Formulas I-S, compound purity 4.29% shown in Formulas I-R)
It is air-dried dry, white solid 3.39g (compound purity 95.17% shown in Formulas I-S, compound purity 3.35% shown in Formulas I-R) is obtained,
Yield 67.8%.
Embodiment 15
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (5.0g) ethyl acetate/
N-hexane (30mL, 1:3, v/v) in the mixed solvent is dispersed with stirring, and adds 20~30 DEG C of sodium propionate (0.106g, 0.1 equivalent)
Stir 17h, filtering, 40 DEG C of drums of filter cake (compound purity 93.22% shown in Formulas I-S, compound purity 5.07% shown in Formulas I-R)
It is air-dried dry, white solid 3.21g (compound purity 94.13% shown in Formulas I-S, compound purity 4.19% shown in Formulas I-R) is obtained,
Yield 64.2%.
Embodiment 16
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (5.0g) ethyl acetate/
N-hexane (20mL, 1:4, v/v) in the mixed solvent is dispersed with stirring, and adds 20~30 DEG C of potassium propionate (0.157g, 0.1 equivalent)
Stir 17h, filtering, 40 DEG C of drums of filter cake (compound purity 94.32% shown in Formulas I-S, compound purity 4.11% shown in Formulas I-R)
It is air-dried dry, white solid 3.55g (compound purity 96.45% shown in Formulas I-S, compound purity 2.01% shown in Formulas I-R) is obtained,
Yield 71.0%.
Embodiment 17
Compound about 1 shown in compound shown in Formulas I-R and Formulas I-S will be contained:1 mixture (5.0g) ethyl acetate/
N-hexane (25mL, 1:4, v/v) in the mixed solvent is dispersed with stirring, and add Pentafluorophenol sodium (0.227g, 0.1 equivalent) 20~
30 DEG C of stirring 17h, filtering, filter cake (compound purity 94.66% shown in Formulas I-S, compound purity 4.32% shown in Formulas I-R) 40
DEG C forced air drying, obtains white solid 3.60g (compound purity 96.64% shown in Formulas I-S, compound purity shown in Formulas I-R
2.38%), yield 72.0%.
Claims (12)
1. a kind of method that compound shown in Formulas I-R is converted into compound shown in Formulas I-S in the solution, including by Formulas I-R institutes
Show that compound under the conditions of existing for nucleophilicity alkali, solvent, is converted into compound shown in Formulas I-S：
The nucleophilicity alkali is selected from sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium acetate, potassium acetate, sodium propionate, potassium propionate or five
Fluorophenol sodium.
2. according to the method for claim 1, it is characterised in that the nucleophilicity alkali is selected from sodium methoxide.
3. according to the method for claim 1, it is characterised in that the inventory of the nucleophilicity alkali is selected from 0.02~0.50 and worked as
Amount.
4. according to the method for claim 1, it is characterised in that the solvent be selected from ethyl acetate, dichloromethane, acetone,
Acetonitrile, N,N-dimethylformamide, 1,4- dioxane, tetrahydrofuran, 2- methyltetrahydrofurans, methyl tertiary butyl ether(MTBE), isopropyl
Ether, ether, glycol dimethyl ether, normal heptane, n-hexane or any two or more mixed solvent, preferably are selected from ethyl acetate, first
Base tertbutyl ether, isopropyl ether, ether, glycol dimethyl ether, normal heptane, n-hexane, hexamethylene or any two or more mixing
Solvent, more preferably from methyl tertiary butyl ether(MTBE), isopropyl ether, mixed solvent, ethyl acetate and the methyl- tert of ethyl acetate and n-hexane
The mixed solvent of the mixed solvent of butyl ether, ethyl acetate and isopropyl ether.
5. according to the method for claim 1, it is characterised in that the solvent load is selected from 1~10 times of volume.
6. a kind of method for being placed in heating environment and compound shown in Formulas I-R being converted into compound shown in Formulas I-S, it is included in alkali examination
In the presence of agent, compound shown in Formulas I-R is changed into compound shown in I-S, wherein heating, drying by the way of heating, drying
Composition shown in preceding Formulas I-R is in solid form, and compound shown in gained I-S is in solid form：
7. according to the method for claim 6, it is characterised in that the base reagent is selected from sodium carbonate, sodium methoxide, the tert-butyl alcohol
Potassium, sodium tert-butoxide, sodium acid carbonate, sodium acetate, potassium acetate, sodium propionate, potassium propionate or Pentafluorophenol sodium, preferably are selected from sodium carbonate, first
Sodium alkoxide or potassium propionate.
8. according to the method for claim 6, it is characterised in that the heating, drying, which is selected from normal heating and dries or depressurize, to be added
Heat drying.
9. according to the method for claim 6, it is characterised in that the temperature of the heating environment is selected from 30~120 DEG C.
10. according to the method for claim 6, it is characterised in that the content of compound shown in initial Formulas I-R for 0.05%~
5.00%.
11. according to the method for claim 6, it is characterised in that at the end of method, the content of compound shown in Formulas I-R
Less than 0.35%.
12. a kind of method that compound shown in Formulas I-R is converted into compound shown in Formulas I-S, including：1) by change shown in Formulas I-R
Compound is converted into compound shown in Formulas I-S under the conditions of existing for nucleophilicity alkali, solvent；With 2) in the presence of nucleophilicity alkali, adopt
Compound shown in remaining Formulas I-R in step 1) is further converted to compound shown in Formulas I-S with the mode of heating, drying, its
Described in nucleophilicity alkali be selected from sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium acetate, potassium acetate, sodium propionate, potassium propionate or five fluorine
Sodium phenate
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| CN110835358A (en) * | 2018-08-16 | 2020-02-25 | 上海复星星泰医药科技有限公司 | Preparation method of sofosbuvir intermediate |
| CN111087421A (en) * | 2019-12-24 | 2020-05-01 | 南京正大天晴制药有限公司 | Preparation method of phosphamide compound for chiral drug synthesis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110835358A (en) * | 2018-08-16 | 2020-02-25 | 上海复星星泰医药科技有限公司 | Preparation method of sofosbuvir intermediate |
| CN110835358B (en) * | 2018-08-16 | 2022-08-05 | 上海复星星泰医药科技有限公司 | Preparation method of sofosbuvir intermediate |
| CN111087421A (en) * | 2019-12-24 | 2020-05-01 | 南京正大天晴制药有限公司 | Preparation method of phosphamide compound for chiral drug synthesis |
| CN111087421B (en) * | 2019-12-24 | 2022-10-18 | 南京正大天晴制药有限公司 | Preparation method of phosphamide compound for chiral drug synthesis |
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| CN109476687A (en) | 2019-03-15 |
| CN109476687B (en) | 2020-12-04 |
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