CN107793381B - Preparation method of 3-fluoro-oxetane-3-methanol and intermediate thereof - Google Patents
Preparation method of 3-fluoro-oxetane-3-methanol and intermediate thereof Download PDFInfo
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- CN107793381B CN107793381B CN201610803041.3A CN201610803041A CN107793381B CN 107793381 B CN107793381 B CN 107793381B CN 201610803041 A CN201610803041 A CN 201610803041A CN 107793381 B CN107793381 B CN 107793381B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- BBAFPURKVADOED-UHFFFAOYSA-N (3-fluorooxetan-3-yl)methanol Chemical compound OCC1(F)COC1 BBAFPURKVADOED-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- -1 p-methylphenylsulfonyl Chemical group 0.000 claims abstract description 38
- 239000003960 organic solvent Substances 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 33
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 15
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims abstract description 3
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 48
- 238000006264 debenzylation reaction Methods 0.000 claims description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 23
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims description 17
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical group BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 16
- ZYHRCFBHAKRMMN-UHFFFAOYSA-N 3-fluorooxetane Chemical compound FC1COC1 ZYHRCFBHAKRMMN-UHFFFAOYSA-N 0.000 claims description 8
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 8
- 239000011777 magnesium Substances 0.000 claims description 8
- 229910052749 magnesium Inorganic materials 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 238000005688 desulfonylation reaction Methods 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- 238000006243 chemical reaction Methods 0.000 description 54
- 238000001035 drying Methods 0.000 description 52
- 238000005406 washing Methods 0.000 description 33
- 239000000243 solution Substances 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000000543 intermediate Substances 0.000 description 17
- 238000000605 extraction Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 239000008346 aqueous phase Substances 0.000 description 14
- 239000002585 base Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- 238000005070 sampling Methods 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 7
- 238000004821 distillation Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- VKVRJIRYDHEVTB-UHFFFAOYSA-N (3-fluorooxetan-3-yl)methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1(F)COC1 VKVRJIRYDHEVTB-UHFFFAOYSA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 4
- 229910015845 BBr3 Inorganic materials 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- GLYOPNLBKCBTMI-UHFFFAOYSA-N [2-chloro-2-(1-chloro-2-phenylethoxy)ethyl]benzene Chemical compound C=1C=CC=CC=1CC(Cl)OC(Cl)CC1=CC=CC=C1 GLYOPNLBKCBTMI-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 2
- LADPCMZCENPFGV-UHFFFAOYSA-N chloromethoxymethylbenzene Chemical compound ClCOCC1=CC=CC=C1 LADPCMZCENPFGV-UHFFFAOYSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000005869 desulfonation reaction Methods 0.000 description 2
- JZDGQBBBLAUGTR-UHFFFAOYSA-N diethyl 2-fluoro-2-(phenylmethoxymethyl)propanedioate Chemical compound CCOC(=O)C(F)(C(=O)OCC)COCC1=CC=CC=C1 JZDGQBBBLAUGTR-UHFFFAOYSA-N 0.000 description 2
- GOWQBFVDZPZZFA-UHFFFAOYSA-N diethyl 2-fluoropropanedioate Chemical compound CCOC(=O)C(F)C(=O)OCC GOWQBFVDZPZZFA-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 229960003750 ethyl chloride Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002221 fluorine Chemical class 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000002921 oxetanes Chemical class 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a preparation method of 3-fluoro-oxetane-3-methanol and an intermediate thereof, which comprises the following steps: in an organic solvent, carrying out a ring closing reaction on a compound shown as a formula 5 and strong base to obtain a compound shown as a formula 6; r 1 Is methylsulfonyl, p-methylphenylsulfonyl, p-trifluoromethylphenylsulfonyl or trifluoromethylsulfonyl; the method has the characteristics of high yield, simple and convenient operation, simple post-treatment and the like, and is suitable for large-scale production.
Description
Technical Field
The invention relates to a preparation method of 3-fluoro-oxetane-3-methanol and an intermediate thereof.
Background
The oxetane compound is an important medical intermediate, and plays an important role in drug development by virtue of a unique structure of the oxetane compound. The unique cyclic rigid structure of the compound can increase the metabolic stability of drug molecules and simultaneously maintain or reduce the lipophilicity of the drug molecules. Furthermore, it possesses sufficient volume to occupy the drug target cavity, while the oxygen atom and acceptor on the four-membered ring can form hydrogen bonds, which all contribute to the enhancement of drug activity (angle. Chem. Int. Ed.,2006,45,7736-7739 j.med. Chem.2010,53, 3227-3246.
3-Fluorooxetane-3-methanol is one of the oxetane compounds having a fluorine substituent at the 3-position in addition to the oxetane structure. Fluorine is the most electronegative atom of the periodic table of elements and has wide applications in both organic and pharmaceutical chemistry. In fact, the substitution of fluorine for hydrogen tends to improve the biological activity of the drug and, due to the strong fluorocarbon bond, is more resistant to the metabolic chemical environment in the body. How to synthesize fluorine-containing organic intermediates and drugs has been one of the most important research fields in medicinal chemistry. The 3-fluoro-oxetane-3-methanol has been successfully applied to the synthesis of drugs, and drug molecules constructed by the methanol show good biological activity.
The following is a literature report of 3-fluoro oxetane-3-methanol synthesis method.
The literature Tetrahedron Letters,2014, 55, 4117 reports the preparation of 3-fluorooxetane-3-methanol, see formula 1. The route takes 1 as a starting material and obtains 3-fluoro-oxetane-3-methanol through five-step synthesis, and the total yield is 17%. Reacting the initial raw material 1 with formaldehyde under the action of sodium bicarbonate to obtain 2; then 2, in a Dimethylformamide (DMF) solvent, using imidazole for catalysis and reacting with tert-butyldiphenylchlorosilane to obtain a compound 3;3, reducing the mixture in a tetrahydrofuran solvent by using sodium borohydride to obtain 4;4 reacting with p-toluenesulfonyl chloride by using butyl lithium as alkali in tetrahydrofuran solvent, and closing the ring to obtain 5. Deprotection of compound 5 under tetrabutylammonium fluoride (TBAF) affords 6. This route, while allowing the synthesis of 3-fluorooxetane-3-methanol, has some significant limitations. The route uses tert-butyldiphenylchlorosilane with large molecular weight as a protecting group of an intermediate, and the atom economy is poor; in the fourth step, one hydroxyl group needs to be selectively protected, and because the two hydroxyl groups have no great difference in chemical properties and steric hindrance, the synthesis difficulty is extremely high, and the yield is low; in the fifth step, expensive TBAF is used as a deprotection reagent, and fluorine ions in the TBAF are easy to corrode glass lining and stainless steel during post-treatment, so that high requirements on equipment are met. In summary, the disadvantages of this route lead to various limitations in industrial production.
Patent document WO2005092881A1 reports another synthesis method of 3-fluoro-oxetane-3-methanol. The route takes 2-methylene-1, propylene glycol as the starting material to obtain 3-fluoro-oxetane-3-methanol through four-step synthesis, see formula 2, and the total yield is 4.3%. In the second, third and fourth steps of the method, the intermediate is purified by silica gel column chromatography, so that the intermediate is difficult to apply in scale-up production; in addition, the method uses a highly toxic dibutyltin oxide synthetic intermediate, so that the safety risk is higher when a large amount of the intermediate is used, and the problem of environmental pollution is easily caused.
Disclosure of Invention
The invention aims to solve the technical problems that the preparation process of 3-fluorooxetane-3-methanol and the intermediate thereof in the prior art is high in total cost, low in yield, not friendly to environment and not suitable for large-scale production, so that the preparation method of the 3-fluorooxetane-3-methanol and the intermediate thereof is provided, has the characteristics of high yield, simplicity and convenience in operation, simplicity in post-treatment and the like, and is suitable for large-scale production.
The invention mainly solves the technical problems through the following technical scheme.
The invention provides a preparation method of a 3-fluoro-oxetane intermediate compound shown as a formula 6, which comprises the following steps: in an organic solvent, carrying out a ring closing reaction on a compound shown as a formula 5 and strong base; r 1 Is methylsulfonyl, p-toluenesulfonyl,P-trifluoromethylbenzenesulfonyl or trifluoromethylsulfonyl;
the conditions and methods of the ring closure reaction can be referred to those conventional in the art, and the following conditions and methods are particularly preferred in the present invention:
in the ring closure reaction in the present invention, the organic solvent is preferably one or more of tetrahydrofuran, dioxane and 2-methyltetrahydrofuran, and more preferably tetrahydrofuran.
In the ring closing reaction of the invention, the strong base is preferably one or more of n-butyllithium, sec-butyllithium, butyllithium and sodium hydride, and more preferably n-butyllithium.
In the ring closure reaction of the present invention, the molar ratio of the compound represented by formula 5 to the strong base is preferably 1.
In the ring closure reaction of the present invention, the amount ratio of the compound represented by formula 5 to the organic solvent is preferably 0.08 to 0.5mol/L, and more preferably 0.11 to 0.25mol/L.
The time for the ring-closing reaction in the present invention is preferably 1 to 8 hours, more preferably 2 to 3 hours, and it is further preferable to detect whether the reaction is completed by TLC.
The temperature of the ring closure reaction in the invention is preferably 40-70 ℃, and more preferably 55-65 ℃.
In the ring closure reaction of the present invention, preferably, the compound represented by the formula 5 is added to the strong base; more preferably, the organic solution of the compound shown in the formula 5 is added into the organic solution of strong base to carry out ring closing reaction, the temperature of the organic solution of strong base is 55 ℃, and the temperature of the organic solution shown in the formula 5 is 65 ℃ after the organic solution of strong base is added into the organic solution of strong base, and the solution is kept for 2 hours; preferably, the adding mode is dripping; the organic solution of the compound shown in the formula 5 is a mixed solution of the compound shown in the formula 5 and the organic solvent; the organic solution of the strong base is a mixed solution of the strong base and the organic solvent.
Wherein, the volume ratio of the alkali to the organic solvent in the strong alkali organic solution is preferably 0.01 to 0.2, more preferably 0.12 to 0.15; the molar volume ratio of the compound shown in the formula 5 to the organic solvent in the organic solvent of the compound shown in the formula 5 is preferably 0.01-2, and more preferably 0.2-0.3.
The ring closure reaction in the invention can also comprise the following post-treatment steps after the reaction is finished: extracting, washing, drying, filtering, crystallizing and drying; the extraction can be a conventional extraction mode in the field, and preferably a saturated saline solution layer is used, and the water phase is extracted by ethyl acetate; the washing mode can be a conventional washing mode in the field, and preferably saturated salt water is used for washing; the drying, filtration and crystallization can be carried out in a conventional manner in the art.
In the method for preparing the 3-fluorooxetane intermediate of the compound represented by the formula 6, the method preferably further comprises the following steps: in an organic solvent, carrying out debenzylation reaction on a compound shown as a formula 4 and a debenzylation reagent to obtain the compound shown as the formula 5;
the debenzylation reagent is boron tribromide and/or boron trichloride, and preferably boron tribromide.
The debenzylation reaction in the present invention, the organic solvent may refer to the conventional solvent of the reaction in the field, and the present invention particularly preferably uses dichloromethane and/or 1,2 chloroethane, and more preferably uses dichloromethane.
In the debenzylation reaction of the present invention, the molar ratio of the compound represented by formula 4 to the debenzylation reagent can be determined according to the conventional proportion of such reactions in the field, and the present invention particularly preferably ranges from 1.5 to 1.
In the debenzylation reaction, the dosage ratio of the compound shown in the formula 4 and the organic solvent can refer to the conventional dosage ratio of the reactions in the field, and the dosage ratio is particularly preferably 0.1-1 mol/L, and more preferably 0.26mol/L.
The temperature of the debenzylation reaction in the debenzylation reaction of the present invention can be referred to the reaction temperature in the field, and is preferably-5 ℃ to 10 ℃, and more preferably 0 ℃ to 5 ℃.
The time for the debenzylation reaction in the present invention may be any time that is conventional in the art, and is particularly preferably 1 to 8 hours, more preferably 2 hours, and even more preferably until the reaction product is completely consumed by TLC detection in the present invention.
In the debenzylation reaction of the present invention, preferably, the debenzylation reagent is added to an organic solution of the compound represented by formula 4 to perform the debenzylation reaction, and the organic solution of the compound represented by formula 4 is a mixed solution of the compound represented by formula 4 and the organic solvent.
The debenzylation reaction also comprises the steps of layered extraction, washing, drying and distillation after the reaction is finished; the layered extraction can be a conventional layered extraction method in the field, the method is particularly preferably used for adjusting the pH = 7-8 by using saturated sodium bicarbonate, layering is carried out, and an aqueous phase is extracted by using ethyl acetate; the washing can be the conventional washing method in the field, and the invention is particularly preferably washed by using saturated common salt water; the drying may be a conventional drying method in the art, and the present invention particularly preferably uses anhydrous sodium sulfate for drying; the distillation may be a conventional drying method in the art, and distillation under reduced pressure is particularly preferred in the present invention.
In the method for preparing the intermediate of 3-fluorooxetane of the compound represented by the formula 6, preferably, the method further comprises the following steps: in an organic solvent, under an alkaline condition, carrying out an upper protection reaction on a compound shown as a formula 3 and sulfonyl chloride to obtain a compound shown as a formula 4; the alkali is preferably one or more of triethylene diamine, triethylamine, diisopropylethylamine, potassium carbonate and sodium hydride, and is further preferably diisopropylethylamine; in the upper protection reaction, the organic solvent is preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate or dichloromethane, and more preferably dichloromethane;
in the protection reaction, the sulfonyl chloride is preferably one or more of methylsulfonyl chloride, p-methylbenzenesulfonyl chloride, p-trifluoromethylsulfonyl chloride and trifluoromethylsulfonyl chloride, and more preferably p-methylbenzenesulfonyl chloride.
The molar ratio of the compound shown in formula 3 and sulfonyl chloride in the protection reaction in the invention can be referred to the conventional ratio of the reactions in the field, and the invention particularly preferably adopts 2.
The molar ratio of the compound represented by formula 3 to the base in the protection reaction of the present invention can be referred to the conventional ratio of the reaction in this field, and 2. In the up-protection reaction of the present invention, preferably, the sulfonyl chloride is added to an organic solution of the compound represented by formula 3 to perform the up-protection reaction, and the organic solution of the compound represented by formula 3 is a mixed solution of the compound represented by formula 3 and the organic solvent.
The reaction temperature of the protection reaction in the invention can refer to the conventional temperature of the reaction in the field, and the reaction temperature is particularly 0-10 ℃, and further preferably 0-5 ℃; the reaction time can be referred to the conventional time of this type of reaction in the art, and the present invention is particularly preferably half an hour, and more preferably, the reaction time is measured by TLC until the reactants are consumed.
In the upper protection reaction, after the reaction is finished, the preferable steps of layering extraction, washing, drying, concentration, crystallization, filtration and drying are carried out; the layered extraction can be a conventional layered treatment method in the field, and the invention particularly preferably uses a saturated saline solution layer, and the water phase is extracted by ethyl acetate; the drying can be a conventional drying mode in the field, and the invention particularly preferably uses anhydrous sodium sulfate; the crystallization mode can be a conventional drying mode in the field, and the invention particularly preferably uses petroleum ether as a solvent; the filtration and drying can be carried out in the conventional operation mode in the field.
In the method for preparing the intermediate of 3-fluorooxetane of the compound represented by formula 6, the method preferably further comprises the following steps: in an organic solvent, carrying out a reduction reaction on a compound shown as a formula 2 and a reduction reagent to obtain a compound shown as a formula 3; the reducing agent is preferably one or more of sodium borohydride, sodium triacetoxyborohydride, lithium borohydride, lithium aluminum hydride or diisobutyl aluminum hydride, and further preferably sodium borohydride; the solvent is preferably one or more of methanol, ethanol, tetrahydrofuran or 2-methyltetrahydrofuran, and is further preferably tetrahydrofuran;
the time for the reduction reaction in the present invention can be referred to the conventional time for such reactions in the art, and the present invention is particularly preferably 1 to 8 hours, more preferably 6 hours, and even more preferably the reaction is completed by TLC detection.
In the reduction reaction of the present invention, the molar ratio of the compound represented by formula 2 to the reducing agent can be determined according to the conventional proportion of the reaction in the field, and the present invention particularly preferably comprises 3.
The reduction reaction of the invention, the ratio of the amount of the compound shown in formula 2 and the organic solvent can be referred to the conventional ratio of the reactions in the field, and the invention is particularly preferable
0.2 to 0.5mol/L, more preferably 0.3mol/L.
The reduction reaction of the invention also comprises the following post-treatment after the reaction is finished: extracting by layers, washing, drying and concentrating again; the layering may be in a manner conventional in the art, with the use of water being particularly preferred in the present invention; the extraction can be the conventional extraction method in the field, and the invention particularly preferably adopts ethyl acetate; the washing can be a conventional washing mode in the field, and the washing with saturated salt water is particularly preferred in the invention; the drying may be a drying method conventional in the art, and the drying using anhydrous sodium sulfate is particularly preferred in the present invention.
In the method for preparing the intermediate of 3-fluorooxetane of the compound represented by the formula 6, preferably, the method further comprises the following steps: carrying out a benzyloxymethyl reaction on a compound shown as a formula 1 and benzyl chloromethyl ether in an organic solvent under an alkaline condition to obtain the compound shown as a formula 2; wherein R is methyl or ethyl;
the above benzyloxymethyl reaction described in the present invention may be a conventional procedure in the art, and the following procedures are particularly preferred in the present invention:
in the above benzyloxymethyl reaction of the present invention, the base is preferably one or more of sodium ethoxide, sodium hydride, potassium tert-butoxide and sodium tert-butoxide, and further preferably sodium hydride; the organic solvent is preferably one or more of tetrahydrofuran, dimethyltetrahydrofuran, DMF and methyl tert-butyl ether, and further preferably tetrahydrofuran.
In the above benzyloxymethyl reaction according to the present invention, the molar ratio of the compound represented by the formula 1 to benzyl chloromethyl ether is preferably 2 to 1, more preferably 4. In the present invention, the above benzyloxymethyl group is reacted, and the molar ratio of the base to the compound represented by formula 1 is preferably 1.
In the above-mentioned benzyloxymethyl group reaction of the present invention, the amount ratio of the base to the organic solvent is preferably 1 to 2mol/L, more preferably 1.25mol/L.
The benzyl oxygen methyl reaction is carried out, wherein the reaction temperature is preferably-20-0 ℃, and preferably-10-5 ℃; the reaction time is preferably 1 to 10 hours, more preferably 5 hours, and still more preferably until the completion of the consumption of the reaction product by TLC detection.
The benzyl-oxygen-methyl reaction is carried out in the invention, and the post-reaction treatment preferably comprises layered extraction, liquid separation, washing, drying, suction filtration and concentration; the layered extraction mode can be a conventional extraction mode in the field, the invention particularly preferably uses a saturated saline solution layer, and the water phase is extracted by ethyl acetate; the washing mode can be a washing mode conventional in the field, and the invention particularly preferably uses saturated sodium bicarbonate for washing; the drying mode can be a conventional drying mode in the field, and the invention particularly preferably uses anhydrous sodium sulfate for drying; the suction filtration and the concentration can be carried out in a conventional operation mode in the field.
The invention provides a preparation method of a compound 3-fluoro-oxetane intermediate shown in a formula 5, which comprises the following steps: in an organic solvent, carrying out debenzylation reaction on a compound shown as a formula 4 and a debenzylation reagent to obtain a compound shown as a formula 5;
the debenzylation reagent is one of boron tribromide or boron trichloride, and preferably boron tribromide.
In the debenzylation reaction of the present invention, the organic solvent may be a solvent that is conventional in the art for such reactions, preferably dichloromethane or 1,2 chloroethane, more preferably dichloromethane.
In the debenzylation reaction of the present invention, the molar ratio of the compound represented by formula 4 to the debenzylation reagent is preferably 1.
In the debenzylation reaction of the present invention, the dosage ratio of the compound represented by formula 4 to the solvent is preferably 0.1 to 1mol/L, and more preferably 0.26mol/L.
The time for the debenzylation reaction in the present invention may be any time that is conventional in the art, and is particularly preferably 1 to 8 hours, more preferably 2 hours, and even more preferably until the reaction product is completely consumed by TLC detection in the present invention.
The temperature of the debenzylation reaction in the debenzylation reaction of the present invention can be referred to the reaction temperature in the field, and is preferably-5 ℃ to 10 ℃, and more preferably 0 ℃ to 5 ℃.
In the debenzylation reaction of the present invention, preferably, the debenzylation reagent is added to an organic solution of the compound represented by formula 4 to perform the debenzylation reaction, and the organic solution of the compound represented by formula 4 is a mixed solution of the compound represented by formula 4 and the organic solvent.
The debenzylation reaction also comprises the steps of layered extraction, washing, drying and distillation after the reaction is finished; the layered extraction can be a conventional layered extraction method in the field, the method is particularly preferably used for adjusting the pH = 7-8 by using saturated sodium bicarbonate, layering is carried out, and an aqueous phase is extracted by using ethyl acetate; the washing can be the conventional washing method in the field, and the invention is particularly preferably washed by using saturated common salt water; the drying may be a conventional drying method in the art, and the present invention particularly preferably uses anhydrous sodium sulfate for drying; the distillation may be a conventional drying method in the art, and distillation under reduced pressure is particularly preferred in the present invention.
The invention also provides a preparation method of the 3-fluoro-oxetane-3-methanol, which comprises the following steps: the method comprises the following steps: (1) preparing a compound shown in a formula 6 according to the method; (2) In an organic solvent, carrying out desulfonylation reaction on magnesium and a compound shown as a formula 6;
the desulfonation reaction described herein can be performed by reference to procedures and methods conventional in the art, and the following procedures and methods are particularly preferred in the present invention:
in the production method of the present invention, in the step (2), the organic solvent is preferably a protic solvent, more preferably an alcoholic solvent, and still more preferably methanol.
In the preparation method of the present invention, in the step (2), the time for the desulfonation reaction is preferably 1 to 12 hours, and more preferably 10 hours.
In the production method according to the present invention, in the step (2), the molar ratio of the compound 6 to magnesium is preferably 1.
In the preparation method of the invention, the dosage ratio of the compound 6 and the organic solvent is preferably 0.1-2 mol/L, and more preferably 0.2mol/L.
In the preparation method of the invention, after reaction, the method further comprises the following steps: neutralizing unreacted magnesium, extracting, washing, drying and concentrating; the neutralization is preferably performed by using hydrochloric acid, the concentration of the hydrochloric acid is preferably 3-8%), and more preferably 5%, wherein the concentration of the hydrochloric acid refers to the mass fraction of HCl in the hydrochloric acid; the washing can be a conventional washing mode in the field, and the washing with saturated salt water is particularly preferred in the invention; the drying can be a conventional drying mode in the field, and the drying is particularly preferably carried out by adopting anhydrous sodium sulfate; the concentration, particularly preferred in the present invention, is concentration under reduced pressure, which may be a conventional procedure in the art.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The invention has the beneficial effects that:
1. when the compound shown as the formula 6 is prepared by the prior art, more impurities exist among molecules during ring closing, and the yield is low;
2. in the prior art, the existence of both sulfonyl and benzyl and the selective removal of benzyl generally adopt palladium carbon as a debenzylation protection reagent, and in the preparation process of the compound shown as the formula 5, the effect is not ideal when the palladium carbon is adopted, and the catalyst poisoning causes low yield and poor reproducibility;
3. when the compound shown as the formula 4 is prepared by using the prior art, a large amount of pyridine is needed as a solvent and alkali to complete the reaction, the pyridine is expensive, volatile, smelly and toxic, and the problems of environmental pollution, health and safety risks of operators and the like exist when the pyridine is used in large amount;
4. in the preparation process of the compound shown as the formula 3, a lithium aluminum hydride-diethyl ether reduction system is generally adopted in the prior art, both the lithium aluminum hydride and the diethyl ether are highly flammable, and the large-scale production has great safety risk and is difficult to apply to large-scale production.
5. When the compound shown as the formula 2 is prepared, a large amount of solvent is needed for the subsequent treatment, and the cost is high.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
Adding sodium hydride (3.6g, 0.15mol) into tetrahydrofuran (120 mL) in batches, cooling to-10 to-5 ℃, controlling the temperature to be-10 to-5 ℃, dropwise adding diethyl fluoromalonate (15g, 0.084 mol) for 3 to 4 hours, and finishing dropwise adding. The system is gray clear, and is stirred for half an hour at the temperature of minus 10 ℃ to minus 5 ℃. Chloromethyl benzyl ether (16.4 g, 0.1mol) is dripped, the temperature is controlled between minus 10 ℃ and minus 5 ℃, and the dripping is finished within 4 to 6 hours. After the dripping is finished, keeping the temperature at minus 10 ℃ to minus 5 ℃ and stirring for 1 hour, then sampling and sending to TLC, and finishing the reaction. Saturated saline solution was added to the system, stirred for half an hour, separated, and the aqueous phase was extracted once with ethyl acetate. The organic phase was combined, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 2-fluoro-2-benzyloxymethyl-malonic acid diethyl ester (23.8g, 0.080mol) in a yield of 95%.
Example 2
Dissolving 2-fluoro-2-benzyloxymethyl-diethyl malonate (20g, 0.067mol) in tetrahydrofuran (220 mL), uniformly stirring, adding sodium borohydride (4.2g, 0.11mol), controlling the temperature to be between 30 and 45 ℃, after addition, stirring for 1 hour, sampling, sending to TLC, after the reaction is finished, adding water into the system, stirring for half an hour, concentrating until an off-white solid is separated, adding ethyl acetate, adjusting the pH to be 1-2 by using 1mol/L hydrochloric acid, separating liquid, extracting the water phase for 2 times by using ethyl acetate, combining the organic phases, adjusting the pH to be 7 to 8 by using 50% sodium hydroxide solution, washing the organic phase by using water, washing by using saturated saline water, drying by using anhydrous sodium sulfate, concentrating and drying to obtain 2-fluoro-2-benzyloxymethyl-propylene glycol (13g, 0.061mol), wherein the yield is 90%.
Example 3
Dissolving 2-fluoro-2-benzyloxymethyl-propylene glycol (10g, 0.0467mol) in tetrahydrofuran (120 mL), adding diisopropylethylamine (14.1g, 0.11mol), uniformly stirring, controlling the temperature to be 0-5 ℃, dropwise adding p-methylbenzenesulfonyl chloride (21.2g, 0.11mol), stirring for half an hour, sampling, sending to TLC, and finishing the reaction; the reaction was quenched by adding saturated brine, the layers were separated, the aqueous phase was extracted 2 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, crystallized with petroleum ether, filtered, and dried to give 2- (benzyloxymethyl) -2-fluoro-bis (p-toluenesulfonate) -1, 3-propanediol ester (20.7g, 0.0397mol) in a yield of 85%.
Example 4
Dissolving 2- (benzyloxymethyl) -2-fluoro-bis (p-toluenesulphonic acid) -1, 3-propanediol ester (15g, 0.0287mol) in dichloromethane (112 mL), stirring uniformly, controlling the temperature to be 0-5 ℃, dropwise adding BBr3 (8.7g, 0.0348mol), stirring for 1 hour, sampling and sending to TLC, and finishing the reaction; the PH =7 to 8 was adjusted with saturated sodium bicarbonate, the layers were separated, and the aqueous phase was extracted 2 times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 2- (hydroxymethyl) -2-fluoro-bis (p-toluenesulphonic acid) -1, 3-propanediol ester (9.9 g, 0.0229mol) in 80% yield.
Example 5
Dissolving 2- (benzyloxymethyl) -2-fluoro-bis (p-methylbenzenesulfonic acid) -1, 3-propanediol ester (0.0287 mol) in dichloromethane (28.7 mL), uniformly stirring, controlling the temperature to be 0-5 ℃, dropwise adding BBr3 (0.287 mol), stirring for 1 hour, sampling, sending to TLC, and finishing the reaction; the PH =7 to 8 was adjusted with saturated sodium bicarbonate, the layers were separated, and the aqueous phase was extracted 2 times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 2- (hydroxymethyl) -2-fluoro-bis (p-toluenesulphonic acid) -1, 3-propanediol ester in a yield of 72%.
Example 6
Dissolving 2- (benzyloxymethyl) -2-fluoro-bis (p-toluenesulfonic acid) -1, 3-propanediol ester (0.0287 mol) in 1, 2-dichloroethane (287 mL), stirring uniformly, controlling the temperature to be 0-5 ℃, dropwise adding BBr3 (0.0144 mol), stirring for 1 hour, sampling, and sending to TLC to complete the reaction; the PH =7 to 8 was adjusted with saturated sodium bicarbonate, the layers were separated, and the aqueous phase was extracted 2 times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 2- (hydroxymethyl) -2-fluoro-bis (p-toluenesulfonate) -1, 3-propanediol ester in 73% yield.
Example 7
Adding n-butyllithium (9.2 mL) into tetrahydrofuran (108 mL), stirring uniformly, heating to 55 ℃, dropwise adding a tetrahydrofuran (90 mL) solution of 2- (hydroxymethyl) -2-fluoro-di (p-toluenesulfonic acid) -1, 3-propanediol ester (9.5 g, 0.0220mol), continuously heating to 65 ℃, keeping the temperature for 2 hours, cooling to 20 ℃, adding saturated saline solution, carrying out layering, extracting an aqueous phase by using ethyl acetate, combining organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, concentrating to obtain a non-distillate, adding petroleum ether to precipitate crystals, filtering, drying in an oven, and drying to obtain 3-fluorooxetane-3-methanol-p-toluenesulfonate (5.2g, 0.02mol), wherein the yield is 91% and the purity is 98.5%.
Example 8
Adding n-butyllithium (44 mL) into tetrahydrofuran (108 mL), uniformly stirring, heating to 40 ℃, dropwise adding a tetrahydrofuran (90 mL) solution of 2- (hydroxymethyl) -2-fluoro-bis (p-toluenesulfonate) -1, 3-propanediol ester (9.5 g,0.0220 mol), continuously heating to 70 ℃, keeping the temperature for 2 hours, cooling to 20 ℃, adding saturated saline solution, carrying out layering, extracting an aqueous phase with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating to obtain no fraction, adding petroleum ether to precipitate crystals, filtering, drying in an oven to obtain 3-fluorooxetane-3-methanol-p-toluenesulfonate with the yield of 86%.
Example 9
Adding n-butyllithium (9.2 mL) into tetrahydrofuran (20 mL), stirring uniformly, heating to 40 ℃, dropwise adding a tetrahydrofuran (20 mL) solution of 2- (hydroxymethyl) -2-fluoro-di (p-toluenesulfonic acid) -1, 3-propanediol ester (9.5 g,0.0220 mol), continuously heating to 70 ℃, keeping the temperature for 2 hours, cooling to 20 ℃, adding saturated saline solution, carrying out layering, extracting an aqueous phase with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a non-distillate, adding petroleum ether to precipitate crystals, filtering, drying in an oven, and drying to obtain 3-fluorooxetane-3-methanol-p-toluenesulfonate with the yield of 84%.
Example 10
Dissolving 2- (hydroxymethyl) -2-fluoro-di (p-toluenesulfonic acid) -1, 3-propylene glycol ester (9.5 g, 0.0220mol) in tetrahydrofuran (298 mL), cooling to 0 ℃, dropwise adding n-butyllithium (9.2 mL) into the solution, continuously heating to 55-65 ℃ after dropwise adding is finished, keeping the temperature for 2 hours, cooling to 20 ℃, adding saturated saline solution, carrying out layering, extracting an aqueous phase with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating to obtain no fraction, adding petroleum ether to precipitate crystals, filtering, drying in an oven, and drying to obtain 3-fluoro-oxetane-3-methanol-p-toluenesulfonic acid ester (3.1g, 0.01mol), wherein the yield is 55%.
Example 11
3-Fluorooxetane-3-methanol-p-toluenesulfonate (5 g, 0.0192mol) was added to methanol (100 mL) and stirred uniformly, then magnesium chips (4.7 g, 0.196mol) were added to the reaction mixture and stirred at room temperature for 10 hours, unreacted magnesium chips were neutralized with 5% hydrochloric acid and extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-fluorooxetane-3-methanol (1.7 g) with a yield of 85%.
Example 12
Adding 0.36Kg of sodium hydride into 12L of tetrahydrofuran in batches, cooling to-10 to-5 ℃, controlling the temperature to-10 to-5 ℃, dropwise adding 1.5Kg of diethyl fluoromalonate after 3 to 4 hours. The system is gray clear, and is stirred for half an hour at the temperature of minus 10 to minus 5 ℃. Chloromethyl benzyl ether (1.64 Kg) is dripped, the temperature is controlled between minus 10 ℃ and minus 5 ℃, and the dripping is finished within 4 to 6 hours. After the dripping is finished, stirring the mixture for 1 hour at the temperature of between 10 ℃ below zero and 5 ℃ below zero, sampling and sending the mixture to TLC, and finishing the reaction. Saturated saline was added to the system, stirred for half an hour, separated, and the aqueous phase was extracted once with ethyl acetate. The organic phases were combined and washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 2-fluoro-2-benzyloxymethyl-malonic acid diethyl ester (2.36 Kg) in 94% yield.
Example 13
Dissolving 2-fluoro-2-benzyloxymethyl-diethyl malonate (2.0 Kg) in tetrahydrofuran (22L), uniformly stirring, adding sodium borohydride (0.42 Kg), controlling the temperature to be 30-45 ℃, after the addition, stirring for 1 hour, sampling, sending to TLC, after the reaction is finished, adding water into the system, stirring for half an hour, concentrating until an off-white solid is separated out, adding ethyl acetate, adjusting the pH to be 1-2 by using 1mol/L hydrochloric acid, separating, extracting the water phase for 2 times by using ethyl acetate, combining the organic phases, adjusting the pH to be 7-8 by using a 50% sodium hydroxide solution, washing the organic phases with water, washing with saturated salt water, drying by using anhydrous sodium sulfate, concentrating and drying to obtain 2-fluoro-2-benzyloxymethyl-propylene glycol (1.31 Kg), wherein the yield is 91%.
Example 14
Dissolving 2-fluoro-2-benzyloxymethyl-propylene glycol (1.0 Kg) in tetrahydrofuran (12L), adding diisopropylethylamine (1.41 Kg), uniformly stirring, controlling the temperature to be 0-5 ℃, dropwise adding p-methylbenzenesulfonyl chloride (2.12 Kg), stirring for half an hour, sampling, sending to TLC, and finishing the reaction; adding saturated saline solution to quench the reaction, demixing, extracting the water phase for 2 times by using ethyl acetate, combining organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, concentrating and drying, crystallizing by using petroleum ether, filtering and drying to obtain 2- (benzyloxymethyl) -2-fluoro-bis (p-toluenesulfonic acid) -1, 3-propylene glycol ester (2.05 Kg), wherein the yield is 84%.
Example 15
Dissolving 2- (benzyloxymethyl) -2-fluoro-bis (p-methylbenzenesulfonic acid) -1, 3-propanediol ester (1.5 Kg) in dichloromethane (11.2L), stirring uniformly, controlling the temperature to be 0-5 ℃, and dropwise adding BBr 3 (0.87 Kg), after the dropwise addition, stirring for 1 hour, sampling and sending to TLC, and after the reaction is finished; the PH =7 to 8 was adjusted with saturated sodium bicarbonate, the layers were separated, and the aqueous phase was extracted 2 times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 2- (hydroxymethyl) -2-fluoro-bis (p-toluenesulfonate) -1, 3-propanediol ester (1.01 Kg) in 81% yield.
Example 16
Adding n-butyl lithium (0.92L) into tetrahydrofuran (10.8L), stirring uniformly, heating to 55 ℃, dropwise adding a tetrahydrofuran (9L) solution of 2- (hydroxymethyl) -2-fluoro-di (p-toluenesulfonate) -1, 3-propanediol ester (0.95 Kg), continuously heating to 65 ℃, keeping the temperature for 2 hours, cooling to 20 ℃, adding saturated saline solution, layering, extracting an aqueous phase with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating until no fraction exists, adding petroleum ether to precipitate crystals, filtering, drying in an oven, and drying to obtain 3-fluorooxetane-3-methanol-p-toluenesulfonate (0.52 Kg), wherein the yield is 91% and the purity is 98.7%.
Example 17
3-fluorooxetane-3-methanol-p-toluenesulfonate (0.5 Kg) was added to methanol (10L) and stirred uniformly, then magnesium chips (0.47 Kg) were added to the reaction solution and stirred at room temperature for 10 hours, the unreacted magnesium chips were neutralized with 5% hydrochloric acid, followed by extraction with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-fluorooxetane-3-methanol (0.17 Kg) with a yield of 85%.
Claims (12)
1. A method for preparing a 3-fluorooxetane intermediate of a compound shown in formula 6, which is characterized by comprising the following steps: in an organic solvent, carrying out a ring closing reaction on a compound shown as a formula 5 and strong base; r 1 Is methylsulfonyl, p-methylbenzenesulfonyl, p-trifluoromethylbenzenesulfonyl or trifluoromethylsulfonyl;
wherein the strong base is one or more of n-butyllithium, sec-butyllithium and sodium hydride;
wherein the organic solvent is one or more of tetrahydrofuran, dioxane and 2-methyltetrahydrofuran.
2. The method of claim 1, wherein the compound of formula 5 is added to the strong base.
3. The preparation method according to claim 1, wherein the molar ratio of the compound represented by the formula 5 to the strong base is 1 to 1; and/or the dosage ratio of the compound shown in the formula 5 to the organic solvent is 0.1 to 0.5mol/L; and/or the temperature of the ring closing reaction is 40-70 ℃.
4. The production method according to claim 1, wherein the amount ratio of the compound represented by the formula 5 to the organic solvent is 0.11 to 0.25mol/L;
and/or the temperature of the ring closing reaction is 55-65 ℃.
5. The method of claim 1, further comprising the steps of: carrying out debenzylation reaction on a compound shown as a formula 4 and a debenzylation reagent in an organic solvent to obtain the compound shown as a formula 5; the debenzylation reagent is boron tribromide and/or boron trichloride;
。
6. the method according to claim 5, wherein the organic solvent is dichloromethane and/or 1, 2-dichloroethane.
7. The preparation method according to claim 5, wherein the molar ratio of the compound represented by the formula 4 to the debenzylation reagent is 1.
8. The preparation method according to claim 5, wherein the molar ratio of the compound represented by the formula 4 to the debenzylation reagent is 1.
9. The process according to claim 5, wherein the molar ratio of the compound represented by formula 4 to the debenzylation reagent is 1.
10. The preparation method according to claim 5, wherein the dosage ratio of the compound represented by the formula 4 to the organic solvent is 0.1 to 1mol/L; and/or the temperature of the debenzylation reaction is-5 ℃ to 10 ℃.
11. The preparation method according to claim 5, wherein the compound represented by the formula 4 and the organic solvent are used in a ratio of 0.26mol/L; and/or the temperature of the debenzylation reaction is 0-5 ℃.
12. A preparation method of 3-fluoro-oxetane-3-methanol is characterized by comprising the following steps: (1) The preparation method of the compound shown in the formula 6 comprises the steps of preparing a 3-fluoro oxetane intermediate shown in the formula 6 according to the preparation method of the compound shown in the claim 1; (2) In an organic solvent, carrying out desulfonylation reaction on magnesium and a compound shown as a formula 6;
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