CN105753692B - One kind 2 methylpropanoic acids of synthesis [(2S) 4（2,4 difluorophenyls）The base of 2 methylol, 4 amylene 1] ester method - Google Patents
One kind 2 methylpropanoic acids of synthesis [(2S) 4（2,4 difluorophenyls）The base of 2 methylol, 4 amylene 1] ester method Download PDFInfo
- Publication number
- CN105753692B CN105753692B CN201610190054.8A CN201610190054A CN105753692B CN 105753692 B CN105753692 B CN 105753692B CN 201610190054 A CN201610190054 A CN 201610190054A CN 105753692 B CN105753692 B CN 105753692B
- Authority
- CN
- China
- Prior art keywords
- difluorophenyl
- bases
- water
- added
- hours
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 23
- 150000002148 esters Chemical class 0.000 title claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 16
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 title claims abstract description 12
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical class CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 title abstract description 4
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical group CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 title abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 79
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 66
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 52
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 44
- 239000000243 solution Substances 0.000 claims abstract description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 40
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims abstract description 37
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 20
- CFXQEHVMCRXUSD-UHFFFAOYSA-N 1,2,3-Trichloropropane Chemical compound ClCC(Cl)CCl CFXQEHVMCRXUSD-UHFFFAOYSA-N 0.000 claims abstract description 18
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 18
- -1 full Substances 0.000 claims abstract description 16
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims abstract description 12
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical class FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims abstract description 10
- 102000004190 Enzymes Human genes 0.000 claims abstract description 9
- 108090000790 Enzymes Proteins 0.000 claims abstract description 9
- 238000005406 washing Methods 0.000 claims abstract description 9
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 claims abstract description 7
- GXSGGPZZNIICCS-UHFFFAOYSA-N 1-(1,3-dichloropropan-2-yl)-2,4-difluorobenzene Chemical compound ClCC(CCl)C1=C(C=C(C=C1)F)F GXSGGPZZNIICCS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 5
- 239000000284 extract Substances 0.000 claims abstract description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims abstract 4
- 239000001294 propane Substances 0.000 claims abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 41
- 238000003756 stirring Methods 0.000 claims description 26
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 20
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 20
- 239000010410 layer Substances 0.000 claims description 18
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 16
- 239000012044 organic layer Substances 0.000 claims description 15
- 229920002554 vinyl polymer Polymers 0.000 claims description 14
- 239000000376 reactant Substances 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 150000001336 alkenes Chemical class 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- GDVWHSXICZMXTR-UHFFFAOYSA-N 1-(1,1-dichloropropan-2-yl)-2,4-difluorobenzene Chemical compound ClC(C(C)C1=C(C=C(C=C1)F)F)Cl GDVWHSXICZMXTR-UHFFFAOYSA-N 0.000 claims description 8
- 229910000030 sodium bicarbonate Inorganic materials 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
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 229910010277 boron hydride Inorganic materials 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 239000004519 grease Substances 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
- 239000007788 liquid Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical group CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 2
- 239000011734 sodium Substances 0.000 claims 2
- BBFFPPPLCCJCRI-UHFFFAOYSA-N 2,4-difluoro-1-propylbenzene Chemical compound CCCC1=CC=C(F)C=C1F BBFFPPPLCCJCRI-UHFFFAOYSA-N 0.000 claims 1
- VIZORQUEIQEFRT-UHFFFAOYSA-N Diethyl adipate Chemical compound CCOC(=O)CCCCC(=O)OCC VIZORQUEIQEFRT-UHFFFAOYSA-N 0.000 claims 1
- 150000001298 alcohols Chemical class 0.000 claims 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- 239000007832 Na2SO4 Substances 0.000 abstract description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 abstract description 10
- 125000004212 difluorophenyl group Chemical group 0.000 abstract description 3
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical class CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 abstract description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 abstract description 2
- 239000012267 brine Substances 0.000 abstract 1
- 238000004821 distillation Methods 0.000 abstract 1
- 239000011435 rock Substances 0.000 abstract 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 abstract 1
- 238000000935 solvent evaporation Methods 0.000 abstract 1
- 238000002390 rotary evaporation Methods 0.000 description 12
- 239000003921 oil Substances 0.000 description 11
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 description 5
- 229960001589 posaconazole Drugs 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010007134 Candida infections Diseases 0.000 description 3
- 238000003747 Grignard reaction Methods 0.000 description 3
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 description 2
- 206010054949 Metaplasia Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000015689 metaplastic ossification Effects 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 150000004756 silanes Chemical class 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 150000000178 1,2,4-triazoles Chemical class 0.000 description 1
- 241001614291 Anoplistes Species 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 208000032826 Ring chromosome 3 syndrome Diseases 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 229940099075 noxafil Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/25—Preparation of halogenated hydrocarbons by splitting-off hydrogen halides from halogenated hydrocarbons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
- C07C17/269—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions of only halogenated hydrocarbons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Abstract
The method of one kind synthesis 2 methylpropanoic acids [base of 4 amylene of (2S) 4 (2,4 difluorophenyl) 2 methylol 1] ester, including：1,2,3 trichloropropane is added drop-wise in 1,3 difluorobenzenes, adds alchlor to react；It is added in hydrochloric acid solution and extracts, uses saturation NaHCO successively3Solution, water, full, brine It；Anhydrous Na2SO4Dry filter, solvent evaporation obtain 1,3 dichloro 2 (2,4 difluorophenyl) propane；(2, the 4 difluorophenyl) propane of 1,3 dichloro 2 and potassium hydroxide are added in the tert-butyl alcohol, flow back 3.5 6h；Remove the tert-butyl alcohol, water on the rocks, neutrality is neutralized with hydrochloric acid at 5~5 DEG C, is extracted in three times with dichloromethane, uses anhydrous Na2SO4Dry filter, product of distillation are dissolved in the product that DMSO addition diethyl malonates and hydroxide react to obtain and are dissolved in toluene with lithium chloride, sodium borohydride reaction acquisition product, add sodium acid carbonate, the Esterified Enzymes of Novo SP 435, isobutyric anhydride and react；By washing, crystallizing, dry acquisition target product；Synthesis path is：
Description
Technical field
The present invention relates to the preparation method of posaconazole intermediate, is specially a kind of synthesis 2 Methylpropionic acid-[(2S) -4-
(2,4- difluorophenyl) -2- methylol -4- amylene -1- bases] ester method.
Background technology
Posaconazole (chemical name：4- [4- [4- [4- [[(3R, 5R) -5- (2,4 difluorobenzene base) -5- (1,2,4- triazoles -
1- ylmethyls) penta ring -3- bases of oxa-] methoxyl group] phenyl] piperazine -1- bases] phenyl] -2- [the amyl- 3- yls of (2S, 3S) -2- hydroxyls] -
1,2,4- triazole -3- ketone, English name：Posaconazole), structural formula is as follows：
Developed by Schering Plough company of the U.S., the U.S. FDA of in September, 2006 approval listing, is a kind of highly lipophilic wide spectrum three
Triazole antifungal agent.Trade name Noxafil (promise section flies), oral suspensions, it is mainly used in preventing 13 years old and above patient
Intrusive mood Aspergillus and monilial infection, and treatment pars oralis pharyngis monilial infection and to Fluconazole and the mouth of voriconazole resistance
Pharyngeal monilial infection.
2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- bases] ester is that husky health is moored in synthesis
The intermediate of azoles, its structural formula are as follows：
European patent EP 2789610 (A1), world patent WO 2011144653 (A1), WO 2011144656 (A1) with
It is as follows and WO 2011144657 (A1) discloses the method that the intermediate is synthesized by 1,3- difluorobenzenes：
This method will use expensive trimethyl chloromethyl base silane class material, cause 1- (1- chloromethyl vinyls base)-
2,4- difluorobenzene production costs are high.In addition, grignard reaction is also used in this method.The reaction needs anhydrous and oxygen-free condition, difficult
In operation, it is not easy to realize industrialized production；In addition, also to use the compound chloracetyl chloride of strong and stimulating in this method, pollute
It is larger..
The content of the invention
The present invention is directed to above-mentioned the deficiencies in the prior art, there is provided one kind is without using expensive trimethyl chloromethyl base silicon
Alkane, the compound chloracetyl chloride without using strong and stimulating；Prepare cost it is low, do not use grignard reaction, without anhydrous and oxygen-free condition,
It is easily operated, easily realize industrialized production, and post-process simple, synthesize 2 Methylpropionic acid-[(2S) -4- (2,4- easily to operate
Difluorophenyl) -2- methylol -4- amylene -1- bases] ester method.
In order to solve the above-mentioned technical problem, the technical solution adopted by the present invention is：One kind synthesis 2 Methylpropionic acid-[(2S)-
4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- bases] ester method, include the step of the synthetic method：
(1) 1,2,3- trichloropropane is added into (for example being added dropwise dropwise) into 5~-5 DEG C of 1,3- difluorobenzenes, reactant mixture
Alchlor (having gas releasing after addition) is added portionwise after stirring 20-40min；After adding 0.5- is reacted at 5~-5 DEG C
1.5 hours, then it is warming up to 20-45 DEG C and continues to react 1.5-8 hours；Fed the mixture into after completion of the reaction at 5~-5 DEG C
Into hydrochloric acid solution, extracted 3-5 times with dichloromethane after stirring, merge the dichloromethane layer extracted every time, then successively
With saturation NaHCO3Solution, water, saturated aqueous common salt wash respectively；The organic layer (dichloromethane layer) of acquisition uses anhydrous Na2SO4It is dry
Filtered after dry, oil product 1,3- bis- chloro- 2- (2,4- difluorophenyl) propane are obtained after removing dichloromethane；
(2) by 1,3-, bis- chloro- 2- (2,4- difluorophenyl) propane prepared by step (1) method and potassium hydroxide or hydroxide
Sodium is added in alcohol compound, is heated to reflux 3.5-6 hours；Alcohol compound is removed after completion of the reaction, and alcohol is removed to gained
Frozen water is added in the mixture of class compound, neutrality is neutralized with hydrochloric acid at 5~-5 DEG C, is extracted in three times with dichloromethane, is closed
And organic layer (dichloromethane extract layer), then use anhydrous Na2SO4Filtered after drying, oil product 1- is obtained after removing dichloromethane
(1- chloromethyl vinyls base) -2,4- difluorobenzenes；
(3) 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes prepared by step (2) are taken and is dissolved in DMSO (dimethyl Asias
Sulfone) in, then add diethyl malonate and hydroxide, the stirring reaction 4-10 hours at 15-35 DEG C；Then water is added,
And gained mixture is stirred into 0.5-1.5 hours, thus obtained solution is extracted first with extractant, at 25-30 DEG C；
The water layer separated after extraction carries out second with extractant, at 25-30 DEG C and extracted；Merge the organic layer extracted twice (to extract
Layer where agent), then washed with sodium hydrate aqueous solution, be then washed with water, distill the solvent under reduced pressure of organic layer after washing
Obtain oil product 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates；
(4) 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1, the 3- diethyl malonates prepared step (3) are molten
In the in the mixed solvent that isopropyl alcohol and water is formed, lithium chloride, boron hydride, reactant mixture are added after being cooled to -10~0 DEG C
Reaction 15-30 hours are stirred at room temperature；The pH=1-3 of reaction solution is first adjusted after completion of the reaction；Reaction solution is adjusted again
PH=9-11；Then proceed to separate organic layer after stirring 0.5-2 hours, remove isopropanol；Gained grease adds toluene and water,
Stirring standing separates toluene layer, and the toluene removal of toluene layer is produced into 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,
Ammediol；
(5) 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3-PD prepared by step (4) is dissolved in first
Benzene, sodium acid carbonate, the Esterified Enzymes of Novo SP 435 (Novo435 enzymes), isobutyric anhydride are added at -15~-5 DEG C；Then insulated and stirred
React 20-40 hours；Solid is filtered after completion of the reaction, and filtrate with sodium bicarbonate solution, water washing, is then removed toluene and obtained successively
Oily crude product；The crude product is dissolved in normal heptane at 50-60 DEG C, and gained clear liquid progressively cools to less than 10 DEG C and (includes 10
DEG C), 10-15 hours are stood at this temperature, filter out crystal, crystal produces product 2 Methylpropionic acid-[(2S) -4- (2,4- after drying
Difluorophenyl) -2- methylol -4- amylene -1- bases] ester.
2 Methylpropionic acid of the present invention-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- bases] ester
Synthetic method is as follows：
The mol ratio of 1,2,3- trichloropropanes in step (1) of the present invention, 1,3- difluorobenzene and alchlor is 1~1.2:
1:1~1.2, preferably 1:1:1.
Alchlor is divided into 4-6 batches and added in step (1) of the present invention, and the operation can effectively prevent reactant mixture excessively
It is sticky, it is difficult to the appearance for the problems such as stirring.
Hydrochloric acid solution is the hydrochloric acid solution of 2mol/l concentration in step (1) of the present invention, and the dosage of hydrochloric acid solution is with 1,2,3-
Trichloropropane meter, concentration of 1,2, the 3- trichloropropane in hydrochloric acid solution are 0.05-0.2mol/100ml (i.e. using 0.05-
The 1 of 0.2mol, 2,3- trichloropropanes, the corresponding hydrochloric acid solution 100ml using 2mol/l concentration)；Preferably 0.1mol/100ml.
The dichloromethane and the volume ratio of hydrochloric acid solution extracted every time in step (1) of the present invention is 1:1, such as, if adopted
With the hydrochloric acid solution 200ml of 2mol/l concentration, then it is 200ml to extract the dichloromethane used every time.
1,3-, bis- chloro- 2- (2,4- difluorophenyl) propane and potassium hydroxide or sodium hydroxide rubs in step (2) of the present invention
You are than being 1:1-2, preferably 1:1.1.
The use ratio of 1,3-, bis- chloro- 2- (2,4- difluorophenyl) propane and alcohol compound is in step (2) of the present invention
0.15-0.25mol：150ml；Preferably 0.20mol：150ml.
The use ratio of 1,3-, bis- chloro- 2- (2,4- difluorophenyl) propane and frozen water is 0.15- in step (2) of the present invention
0.25mol：150ml；Preferably 0.20mol：150ml.
Concentration of hydrochloric acid is 5mol/l in step (2) of the present invention.
The use ratio of 1,3-, bis- chloro- 2- (2,4- difluorophenyl) propane and dichloromethane in step (2) of the present invention is
0.15-0.25mol：450ml；Preferably 0.20mol：450ml.
The alcohol compound of step (2) of the present invention is the tert-butyl alcohol, ethanol, propyl alcohol or isopropanol.
1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes and DMSO amount ratios are 30-75g in step (3) of the present invention：
100ml；1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes：Hydroxide：The mol ratio of diethyl malonate is 1.0：1.5-
3.0：1.0-4.0 preferable 1.0：2-2.5：3-4.0.
In step (3) of the present invention at 25-30 DEG C stirring reaction 4-6 hours；Then water is added, the addition of water now
It is 2-6 with DMSO volume ratios：1, be preferably:3:1.
Hydroxide can be one kind in potassium hydroxide, cesium hydroxide, lithium hydroxide etc. in step (3) of the present invention.
Extractant can be dichloromethane in step (3) of the present invention, (60-90 DEG C, wherein 60-90 DEG C refers to petroleum ether
The specification of petroleum ether), chloroform, one kind in n-hexane or hexamethylene etc..
Extractant, the extractant of second of extraction and the DMSO volume ratios that step (3) of the present invention extracts first are 2:1:1.
The sodium hydrate aqueous solution concentration of step (3) of the present invention (contains 5g for 5% in weight/volume, i.e. 100ml solution
Sodium hydroxide)；Sodium hydrate aqueous solution and DMSO volume ratios are 1-3:1.
2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3- diethyl malonates in step (4) of the present invention：Chlorination
Lithium：The mol ratio of boron hydride is 1:2-4:2-4；Preferably 1:2:2.
Boron hydride is sodium borohydride or potassium borohydride in step (4) of the present invention；The volume ratio of isopropyl alcohol and water is 8-12：
1。
2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3-PD in step (5) of the present invention：Sodium acid carbonate：
The mol ratio of isobutyric anhydride is 1:2:1；The Esterified Enzymes of Novo SP 435 and 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -
The weight ratio of 1,3-PD is 1:20-25；Preferably, the Esterified Enzymes of Novo SP 435 and 2- [2- (2,4- difluorophenyl) -2-
Propylene -1- bases] -1,3-PD weight ratio be 1:20.
The advantages of the present invention：
1. the present invention is used 1,2,3- trichloropropane and 1,3- difluorobenzene as raw material first, conjunction is first prepared in two steps
Into the intermediate of posaconazole --- 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes；Preparation process is neither using expensive
Trimethyl chloromethyl base silane class material, so as to constituent reduction production cost；And preparation technology is more gentle, is easy to grasp
Make, the anhydrous and oxygen-free condition for also not using traditional handicraft grignard reaction to need, more easily operate, easily realize industrial metaplasia
Production.
2. the present invention cleverly employs 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes and takes and be dissolved in DMSO (dimethyl
Sulfoxide) in, then add diethyl malonate and hydroxide, at 15-35 DEG C stirring reaction 4-10 hours reacted, instead
Answer mild condition, small toxicity, energy consumption is low；Then stable, relatively stable to the aqueous vapor in air and oxygen under normal temperature and pressure, operation is used
Easy sodium borohydride is handled as reducing agent, obtains final goal product.And the target product prepared, post processing is simple,
Need only to extract, wash, be evaporated under reduced pressure, you can obtain final product, high income；And the extractant used and hydroxide etc.
Material is easy to get, is cheap, applied widely.
Embodiment
The present invention is described in further detail below by embodiment, but the present invention is not limited solely to following examples.
Embodiment 1
1st, by 1,2,3- trichloropropane (29.40g, 0.20mol) be added drop-wise to dropwise 0 DEG C 1,3- difluorobenzenes (22.82g,
In 0.20mol), reactant mixture continues to divide 5 batches to add alchlor (26.66g, 0.20mol) altogether after stirring 30min, adds
There is gas releasing afterwards.Reacted after adding at 0 DEG C 1 hour, then (20-35 degrees Celsius) continues reaction 6 hours at room temperature.Reaction
After at 0 DEG C by mixture be carefully added into 200ml concentration be 2mol/l hydrochloric acid solution in, use dichloro after stirring
Methane extracts three times, each 200ml, combined dichloromethane layer, with saturation NaHCO3Solution, water, saturated aqueous common salt wash respectively
Once.Organic layer anhydrous Na2SO4Filtered after drying, rotary evaporation obtains oil product 1, bis- chloro- 2- of 3- after removing dichloromethane
(2,4- difluorophenyl) propane 38.26g (0.17mol), yield 85%.
2nd, by 1,3-, bis- chloro- 2- (2,4- difluorophenyl) propane 45.01g (0.20mol) potassium hydroxide 12.34g
(0.22mol) is added in the 150ml tert-butyl alcohols, is heated to reflux 5 hours.It is evaporated under reduced pressure after completion of the reaction and removes the tert-butyl alcohol, gained
150ml frozen water is added in mixture, is neutralized to neutrality with 5mol/l hydrochloric acid at 0 DEG C, is extracted in three times with 450ml dichloromethane
Take, merge organic layer, anhydrous Na2SO4Filtered after drying, rotary evaporation obtains oil product 1- (1- chloromethyls after removing dichloromethane
Vinyl) -2,4- difluorobenzenes 33.95g (0.18mol), yield 90%.
3rd, 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes 37.72g (0.20mol) is dissolved in 100ml dimethyl sulfoxide (DMSO)s,
12.00g (0.30mol) sodium hydroxides and 90.5ml (0.60mol) diethyl malonate are subsequently added into, reactant mixture is in room temperature
Lower stirring 8 hours.300ml water is added after completion of the reaction, continues stirring 1 hour.Resulting solution uses 200ml and 100ml rings respectively
Hexane is extracted twice, and is merged hexamethylene layer, be washed once with 150ml 5% (w/v) sodium hydroxide solution, then use
150ml water washings once, anhydrous Na2SO4Filtered after drying, rotary evaporation removes hexamethylene and obtains oil product 2- [2- (2,4- bis-
Fluorophenyl) pi-allyl] -1,3- diethyl malonates 56.21g (0.18mol), yield 90%.
4th, by 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3- diethyl malonates 12.48g (0.04mol)
The in the mixed solvent that 100ml isopropanols and 10ml water are formed is dissolved in, lithium chloride 3.36g is added after being cooled to -5 DEG C
Reaction 20 hours is stirred at room temperature in (0.08mol), sodium borohydride 3.04g (0.08mol), reactant mixture.After completion of the reaction
Adjusted with 4.0mol/l hydrochloric acid to pH value of solution=1.Then (there is 20g hydrogen in w/v, i.e. 100 milliliters of solution with 20% again
Sodium oxide molybdena) sodium hydroxide solution adjusted to pH=10.Organic layer is separated after continuing stirring 1 hour, rotary evaporation removes isopropanol.
100ml toluene and 100ml water are added in gained grease, separates toluene layer, rotary evaporation removes toluene and produces oil product 2-
[2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3-PD 7.30g (0.032mol), yield 80%；
5th, 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3-PD 22.80g (0.10mol) is dissolved in
150ml toluene, sodium acid carbonate 16.8g (0.20mol), the Esterified Enzyme 1.0g of Novo SP 435, isobutyric anhydride are added at -15 DEG C
15.8ml (0.10mol), mixture stirring reaction 24 hours at same temperature.Solid is filtered after completion of the reaction, and filtrate is used successively
Each 100ml washings of sodium bicarbonate solution and water of 5% (w/v), rotary evaporation obtain oily crude product after removing toluene.
The crude product is dissolved in 80ml normal heptanes at 50-60 DEG C, and gained clear liquid progressively cools to 10 DEG C, stands 12 hours at this temperature,
Crystal is filtered out, product 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylols -4- penta is produced after being dried at 40 DEG C
Alkene -1- bases] ester 22.37g (0.075mol), yield 75%.
Embodiment 2
1st, by 1,2,3- trichloropropane (26.54g, 0.18mol) be added drop-wise to dropwise 0 DEG C 1,3- difluorobenzenes (17.11g,
In 0.15mol), reactant mixture continues to divide 4 batches to add alchlor (24.00g, 0.18) altogether after stirring 30min, after addition i.e.
There is gas releasing.Reacted 1 hour at 0 DEG C after adding, then continue reaction 6 hours at room temperature.After completion of the reaction will be mixed at 0 DEG C
Compound is carefully added into the hydrochloric acid solution that 150ml concentration is 2mol/l, after stirring with dichloromethane extraction three times, every time
150ml, combined dichloromethane layer, with saturation NaHCO3Solution, water, saturated aqueous common salt washed once respectively.Organic layer is with anhydrous
Na2SO4Filtered after drying, rotary evaporation obtains oil product 1,3- bis- chloro- 2- (2,4- difluorophenyl) propane after removing dichloromethane
29.26g (0.13mol), yield 87%.
2nd, by 1,3- bis- chloro- 2- (2,4- difluorophenyl) propane (33.76g, 0.15mol), sodium hydroxide (6.8g,
0.17mol) it is added in 100ml isopropanols, is heated to reflux 5 hours.It is evaporated under reduced pressure after completion of the reaction and removes the tert-butyl alcohol, gained mixes
100ml frozen water is added in compound, is neutralized to neutrality with 5mol/l hydrochloric acid at 0 DEG C, is extracted in three times with 300ml dichloromethane,
Merge organic layer, anhydrous Na2SO4Filtered after drying, rotary evaporation obtains oil product 1- (1- chloromethyl second after removing dichloromethane
Alkenyl) -2,4- difluorobenzenes 22.63g (0.12mol), yield 80%.
3rd, 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes 50g (0.265mol) is dissolved in 150ml dimethyl sulfoxide (DMSO)s, connect
The lithium hydroxide and 1.06mol diethyl malonates for adding 0.53mol, reactant mixture is stirred at room temperature 10 hours.Instead
450ml water is added after answering, continues stirring 1.5 hours.Resulting solution uses 300ml and 150ml petroleum ethers (60-90 DEG C) respectively
It is extracted twice, merges petroleum ether layer, washed once with 150ml 5% (w/v) sodium hydroxide solution, then with 200ml water
It washed once, anhydrous Na2SO4Filtered after drying, rotary evaporation remove petroleum ether obtain oil product 2- [2- (2,4- difluorophenyl)-
2- propylene -1- bases] -1,3- diethyl malonates 76.20g (0.244mol), yield 92%.
4th, by 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3- diethyl malonates 12.48g (0.04mol)
The in the mixed solvent that 200ml isopropanols and 20ml water are formed is dissolved in, lithium chloride 5.04g is added after being cooled to -5 DEG C
Reaction 25 hours is stirred at room temperature in (0.12mol), lithium borohydride 0.12mol, reactant mixture.Use after completion of the reaction
4.0mol/l hydrochloric acid is adjusted to pH value of solution=1.Then adjusted again with 20% (w/v) sodium hydroxide solution to pH=10.
Organic layer is separated after continuing stirring 1 hour, rotary evaporation removes isopropanol.150ml toluene and 150ml are added in gained grease
Water, toluene layer being separated, rotary evaporation removes toluene and produces oil product 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,
Ammediol 7.53g (0.033mol), yield 82%.
5th, 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3-PD 34.2g (0.15mol) is dissolved in
150ml toluene, sodium acid carbonate 25.2g (0.30mol), the Esterified Enzyme 1.0g of Novo SP 435, isobutyric anhydride are added at -15 DEG C
23.4ml (0.15mol), mixture stirring reaction 30 hours at same temperature.Solid is filtered after completion of the reaction, and filtrate is used successively
Each 150ml washings of sodium bicarbonate solution and water of 5% (w/v), rotary evaporation obtain oily crude product after removing toluene.
The crude product is dissolved in 120ml normal heptanes at 50-60 DEG C, and gained clear liquid progressively cools to 10 DEG C, stands 15 hours at this temperature,
Crystal is filtered out, product 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylols -4- penta is produced after being dried at 40 DEG C
Alkene -1- bases] ester 33.11g (0.111mol), yield 74%.
It was found from above-described embodiment, method reaction product of the invention is easily operated, and post processing is simple, is easy to industrial metaplasia
Production.
Claims (9)
1. the side of one kind synthesis 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- bases] ester
Method, it is characterised in that：The step of synthetic method, includes：
(1) 1,2,3- trichloropropane is added in 5~-5 DEG C of 1,3- difluorobenzenes, divided after reactant mixture stirring 20-40min
Criticize and add alchlor；0.5-1.5 hours are reacted after adding at 5~-5 DEG C, 20-45 DEG C is then warming up to and continues to react 1.5-
8 hours；Reactant mixture is added in hydrochloric acid solution at 5~-5 DEG C after completion of the reaction, dichloromethane is used after stirring
Extraction 3-5 times, combined dichloromethane layer, is then washed respectively with saturation NaHCO3 solution, water, saturated aqueous common salt successively；Obtain
Organic layer dried with anhydrous Na 2SO4 after filter, remove after dichloromethane to obtain oil product 1, chloro- 2- (2, the 4- difluoros of 3- bis-
Phenyl) propane；
(2) 1,3- bis- chloro- 2- (2,4- difluorophenyl) propane prepared by step (1) method is added with potassium hydroxide or sodium hydroxide
Enter into alcohol compound, be heated to reflux 3.5-6 hours；Alcohol compound is removed after completion of the reaction, and alcohols is removed to gained
Frozen water is added in the mixture of compound, neutrality is neutralized with hydrochloric acid at 5~-5 DEG C, is extracted, is associated with three times with dichloromethane
Machine layer, filtered after then being dried with anhydrous Na 2SO4, remove after dichloromethane oil product 1- (1- chloromethyl vinyls base)-
2,4- difluorobenzenes；
(3) 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes prepared by step (2) are taken and are dissolved in DMSO, then add third
Diethyl adipate and hydroxide, the stirring reaction 4-10 hours at 15-35 DEG C；Then water is added, and gained mixture is stirred
0.5-1.5 hours are mixed, thus obtained solution is extracted first with extractant, at 25-30 DEG C；The water separated after extraction
Layer carries out second with extractant, at 25-30 DEG C and extracted；Merge the organic layer extracted twice, then use sodium hydrate aqueous solution
Washing, is then washed with water, and distills the solvent under reduced pressure of organic layer after washing to obtain oil product 2- [2- (2,4- difluorophenyl)
Pi-allyl] -1,3- diethyl malonates；
(4) 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3- diethyl malonates prepared by step (3) are dissolved in different
The in the mixed solvent that third alcohol and water is formed, lithium chloride, boron hydride are added after being cooled to -10~0 DEG C, reactant mixture is in room
Warm lower stirring reaction 15-30 hours；The pH=1-3 of reaction solution is first adjusted after completion of the reaction；The pH=of reaction solution is adjusted again
9-11；Then proceed to separate organic layer after stirring 0.5-2 hours, remove isopropanol；Gained grease adds toluene and water, stirring
Standing separates toluene layer, and the toluene removal of toluene layer is produced into 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3- third
Glycol；
(5) 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3-PD prepared by step (4) is dissolved in toluene, -15
Sodium acid carbonate, NovoSP435 Esterified Enzymes, isobutyric anhydride are added at~-5 DEG C；Then insulated and stirred reaction 20-40 hours；Reaction
After filter solid, filtrate with sodium bicarbonate solution, water washing, then removes toluene and obtains oily crude product successively；This is slightly produced
Thing is dissolved in normal heptane at 50-60 DEG C, and gained clear liquid progressively cools to less than 10 DEG C, stands 10-15 hours at such a temperature, filter
Go out crystal, crystal produces product 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylenes -1- after drying
Base] ester.
2. synthesis 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylols -4- penta according to claim 1
Alkene -1- bases] ester method, it is characterised in that：1,2,3- trichloropropanes, 1,3- difluorobenzenes and alchlor in step (1)
Mol ratio is 1~1.2:1:1~1.2；Alchlor is divided into 4-6 batches and added；Hydrochloric acid solution is 2mol/l concentration in step (1)
Hydrochloric acid solution, the concentration of the dosage of hydrochloric acid solution with 1,2,3- trichloropropane meter, 1,2,3- trichloropropanes in hydrochloric acid solution
For 0.05-0.2mol/100ml.
3. synthesis 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylols -4- penta according to claim 1
Alkene -1- bases] ester method, it is characterised in that：The dichloromethane and the volume ratio of hydrochloric acid solution extracted every time in step (1) is 1:
1。
4. synthesis 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylols -4- penta according to claim 1
Alkene -1- bases] ester method, it is characterised in that：1,3-, bis- chloro- 2- (2,4- difluorophenyl) propane and potassium hydroxide in step (2)
Or the mol ratio of sodium hydroxide is 1:1-2；The use ratio of 1,3- bis- chloro- 2- (2,4- difluorophenyl) propane and alcohol compound
For 0.15-0.25mol：150ml；The use ratio of bis- chloro- 2- of 3- (2,4- difluorophenyl) propane and frozen water is 0.15-
0.25mol：150ml.
5. synthesis 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylols -4- penta according to claim 1
Alkene -1- bases] ester method, it is characterised in that：Concentration of hydrochloric acid is 5mol/l in step (2)；Alcohol compound is the tert-butyl alcohol, second
Alcohol, propyl alcohol or isopropanol；The use ratio of 1,3-, bis- chloro- 2- (2,4- difluorophenyl) propane and dichloromethane in step (2)
For 0.15-0.25mol：450ml.
6. synthesis 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylols -4- penta according to claim 1
Alkene -1- bases] ester method, it is characterised in that：1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes and DMSO dosages in step (3)
Than for 30-75g：100ml；1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes：Hydroxide：The mol ratio of diethyl malonate
For 1.0：1.5-3.0：1.0-4.0.
7. synthesis 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylols -4- penta according to claim 1
Alkene -1- bases] ester method, it is characterised in that：In step (3) at 25-30 DEG C stirring reaction 4-6 hours；Then water is added, this
When addition and the DMSO volume ratios of water be 2-6：1；Hydroxide is potassium hydroxide, cesium hydroxide, hydroxide in step (3)
One kind in lithium.
8. synthesis 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylols -4- penta according to claim 1
Alkene -1- bases] ester method, it is characterised in that：Extractant is dichloromethane, petroleum ether, chloroform, n-hexane in step (3)
Or one kind in hexamethylene；Extractant, the extractant of second of extraction and the DMSO volume ratios that step (3) extracts first are 2:
1:1；The sodium hydrate aqueous solution concentration of step (3) is 5% (weight/volume)；Sodium hydrate aqueous solution and DMSO volume ratios are
1-3:1。
9. synthesis 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylols -4- penta according to claim 1
Alkene -1- bases] ester method, it is characterised in that：2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] described in step (4) -
1,3- diethyl malonate：Lithium chloride：The mol ratio of boron hydride is 1:2-4:2-4；Boron hydride described in step (4) is
Sodium borohydride or potassium borohydride；The volume ratio of isopropyl alcohol and water is 8-12：1；2- in step (5) [2- (2,4- difluorophenyl)-
2- propylene -1- bases] -1,3-PD：Sodium acid carbonate：The mol ratio of isobutyric anhydride is 1:2:1；NovoSP435 Esterified Enzymes and 2-
The weight ratio of [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3-PD is 1:20-25.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610190054.8A CN105753692B (en) | 2016-03-30 | 2016-03-30 | One kind 2 methylpropanoic acids of synthesis [(2S) 4（2,4 difluorophenyls）The base of 2 methylol, 4 amylene 1] ester method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610190054.8A CN105753692B (en) | 2016-03-30 | 2016-03-30 | One kind 2 methylpropanoic acids of synthesis [(2S) 4（2,4 difluorophenyls）The base of 2 methylol, 4 amylene 1] ester method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105753692A CN105753692A (en) | 2016-07-13 |
| CN105753692B true CN105753692B (en) | 2017-12-26 |
Family
ID=56346737
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610190054.8A Expired - Fee Related CN105753692B (en) | 2016-03-30 | 2016-03-30 | One kind 2 methylpropanoic acids of synthesis [(2S) 4（2,4 difluorophenyls）The base of 2 methylol, 4 amylene 1] ester method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105753692B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102906087A (en) * | 2010-05-19 | 2013-01-30 | 桑多斯股份公司 | Process for the preparation of chiral triazolones |
| EP2789610A1 (en) * | 2013-04-10 | 2014-10-15 | Sandoz Ag | Purification of Posaconazole Intermediates |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09188637A (en) * | 1996-01-09 | 1997-07-22 | Mitsubishi Chem Corp | Production of 3-bromo-2-(substituted)-1-propene |
-
2016
- 2016-03-30 CN CN201610190054.8A patent/CN105753692B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102906087A (en) * | 2010-05-19 | 2013-01-30 | 桑多斯股份公司 | Process for the preparation of chiral triazolones |
| EP2789610A1 (en) * | 2013-04-10 | 2014-10-15 | Sandoz Ag | Purification of Posaconazole Intermediates |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105753692A (en) | 2016-07-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104672220B (en) | The activator of peroxisome proliferator-activated receptor | |
| CN102190628B (en) | Preparation method of 5-fluoro-6-ethyl-4-hydroxypyrimidine intermediate and Voriconazole | |
| CN102746231A (en) | Celecoxib preparation process | |
| CN103613583A (en) | 1, 3-substituent-4-substituted pyrazol acylhydrazone derivative and preparation method and application thereof | |
| CN105753692B (en) | One kind 2 methylpropanoic acids of synthesis [(2S) 4（2,4 difluorophenyls）The base of 2 methylol, 4 amylene 1] ester method | |
| CN105732311B (en) | The method of one kind 2 [base of 2 (2,4 difluorophenyl) 2 propylene 1] 1,3 propane diols of synthesis | |
| CN105622413B (en) | The synthetic method of 2 [2 (2,4 difluorophenyl) pi-allyl] 1,3 diethyl malonates | |
| CN105755060B (en) | A kind of synthetic method of 2 Methylpropionic acid-[(2S) -4- (2,4- difluorophenyl) -2- methylol -4- amylene -1- base] ester | |
| CN105753693B (en) | The synthetic method of 2 methylpropanoic acids [base of 4 amylene of (2S) 4 (2,4 difluorophenyl) 2 methylol 1] ester | |
| CN105777486B (en) | A kind of synthetic method of 2- [2- (2,4- difluorophenyl) -2- propylene -1- bases] -1,3-PD | |
| CN105732310B (en) | The synthetic method of 2 [base of 2 (2,4 difluorophenyl) 2 propylene 1] 1,3 propane diols | |
| CN113666915B (en) | Preparation method of posaconazole intermediate | |
| CN105601469B (en) | The synthetic method of 1 (1 chloromethyl vinyl base) 2,4 difluorobenzenes | |
| CN105622412B (en) | The method of one kind 2 [2 (2,4 difluorophenyl) pi-allyl] 1,3 diethyl malonates of synthesis | |
| CN105777539B (en) | One kind 2 [2（2,4 difluorophenyls）Pi-allyl] 1,3 diethyl malonates synthetic method | |
| CN107827883A (en) | A kind of novel diazo first ester type compound and preparation method thereof | |
| CN103788073A (en) | Novel method for preparing voriconazole key intermediate | |
| CN106986787A (en) | A kind of synthetic method of posaconazole intermediate | |
| CN104418848B (en) | Preparation method of rivaroxaban | |
| CN106748816A (en) | A kind of synthetic method of the amino butanol of Du Lutewei key intermediates (R) 3 | |
| CN105237513B (en) | A kind of trinitrogenazole alcohol heteroaromatic ether derivative and its preparation method and application | |
| CN104829592B (en) | The synthetic method of 4 piperidyl 1H pyrroles, 3 Carbox amide hydrochloride | |
| CN105646137B (en) | The method of one kind 1 (1 chloromethyl vinyl base) 2,4 difluorobenzenes of synthesis | |
| CN110698462A (en) | 1,3, 5-substituent-4-pyrazole amide derivative and preparation method thereof | |
| CN103497089B (en) | A kind of method preparing Isosorbide-5-Nitrae-pentadiine-3-alcohol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20160809 Address after: 315100 Zhejiang city of Ningbo province of Yinzhou District No. 1699 Jiangwan Road, building 2 Mansion Applicant after: Wei Feng Address before: 315000 Zhejiang city of Ningbo province high tech Zone Jinghua Road No. 188 Building 2 room 1048 Applicant before: NINGBO XINKAI BIOTECHNOLOGY Co.,Ltd. |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20161213 Address after: Camphor Street Jiangdong District 315040 in Zhejiang province Ningbo City No. 515 building 053 (10-1) (central office) Applicant after: NINGBO XINKAI BIOTECHNOLOGY Co.,Ltd. Address before: 315100 Zhejiang city of Ningbo province of Yinzhou District No. 1699 Jiangwan Road, building 2 Mansion Applicant before: Wei Feng |
|
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220810 Address after: Taiwan Industrial Park, Gaocheng Town, Gaoqing County, Zibo City, Shandong Province 255000 Patentee after: SHANDONG HANSHEN CHEMICAL TECHNOLOGY Co.,Ltd. Address before: Building 053 (10-1), 515 Zhangshu street, Jiangdong District, Ningbo City, Zhejiang Province (centralized office area) Patentee before: NINGBO XINKAI BIOTECHNOLOGY Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20171226 |