CN105384673B - The synthetic method of 3 fluoro azetidine derivatives - Google Patents
The synthetic method of 3 fluoro azetidine derivatives Download PDFInfo
- Publication number
- CN105384673B CN105384673B CN201510756697.XA CN201510756697A CN105384673B CN 105384673 B CN105384673 B CN 105384673B CN 201510756697 A CN201510756697 A CN 201510756697A CN 105384673 B CN105384673 B CN 105384673B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- fluoro
- synthetic method
- water
- 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.)
- Active
Links
- WQYAZBFZFIUIPL-UHFFFAOYSA-N 3-fluoroazetidine Chemical class FC1CNC1 WQYAZBFZFIUIPL-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000010189 synthetic method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 90
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 claims description 13
- PSCXEUSWZWRCMQ-UHFFFAOYSA-N F[S](F)F Chemical compound F[S](F)F PSCXEUSWZWRCMQ-UHFFFAOYSA-N 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 7
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000003444 phase transfer catalyst Substances 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 claims description 3
- PAFUZNZXLJBLPH-UHFFFAOYSA-M tetraethylazanium;fluoride;trihydrate Chemical group O.O.O.[F-].CC[N+](CC)(CC)CC PAFUZNZXLJBLPH-UHFFFAOYSA-M 0.000 claims description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 4
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 2
- 125000004494 ethyl ester group Chemical group 0.000 claims 2
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 claims 2
- 238000000034 method Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000011084 recovery Methods 0.000 abstract description 4
- 230000032050 esterification Effects 0.000 abstract description 3
- 238000005886 esterification reaction Methods 0.000 abstract description 3
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 230000004224 protection Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- 239000007788 liquid Substances 0.000 description 42
- 230000015572 biosynthetic process Effects 0.000 description 38
- 238000003786 synthesis reaction Methods 0.000 description 38
- 238000005160 1H NMR spectroscopy Methods 0.000 description 33
- 239000000543 intermediate Substances 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- 238000000926 separation method Methods 0.000 description 25
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- 238000001035 drying Methods 0.000 description 24
- 239000010410 layer Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 15
- 239000004576 sand Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 238000001514 detection method Methods 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 238000007792 addition Methods 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 0 CCC(CC)(C(C)=*)N Chemical compound CCC(CC)(C(C)=*)N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- DZAHXNNEQCZPGJ-UHFFFAOYSA-N CCCCOC(OC)=O.COC(O)=O Chemical compound CCCCOC(OC)=O.COC(O)=O DZAHXNNEQCZPGJ-UHFFFAOYSA-N 0.000 description 2
- HTEGELRXSMYLMT-UHFFFAOYSA-N N#CC#N.[Si] Chemical compound N#CC#N.[Si] HTEGELRXSMYLMT-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- KFBKQXJQGDLQHE-UHFFFAOYSA-N CCC(C)(C(OC)=O)[IH]N Chemical compound CCC(C)(C(OC)=O)[IH]N KFBKQXJQGDLQHE-UHFFFAOYSA-N 0.000 description 1
- XRPKRSLLVXAECN-UHFFFAOYSA-N CCCC.[F] Chemical compound CCCC.[F] XRPKRSLLVXAECN-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- XEUCQOBUZPQUMQ-UHFFFAOYSA-N Glycolone Chemical compound COC1=C(CC=C(C)C)C(=O)NC2=C1C=CC=C2OC XEUCQOBUZPQUMQ-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- BGTDPWDQIVMDGC-UHFFFAOYSA-N azanium;fluoride;trihydrate Chemical compound [NH4+].O.O.O.[F-] BGTDPWDQIVMDGC-UHFFFAOYSA-N 0.000 description 1
- VMTHENQVKJTLFE-UHFFFAOYSA-N butan-1-amine;trihydrate;hydrofluoride Chemical compound O.O.O.[F-].CCCC[NH3+] VMTHENQVKJTLFE-UHFFFAOYSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- -1 sulfur trifluoride fluoro, thionyl chloride Chemical compound 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a kind of synthetic method of 3 fluoro azetidine derivatives; this method is using chemical compounds I as raw material; reacted with trimethylsilyl cyanide after obtaining compound ii, obtain compound VI through esterification, N protections and fluoro-reaction or protect to obtain compound VI through hydrolysis, fluoro, esterification and N.Synthesising method reacting condition of the invention is gentleer, simple to operate, often step reaction yield is all higher, and total recovery is up to 85%.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of synthesis of 3- fluoro-azetidine derivatives
Method.
Background technology
The azetidine of fluorine substitution has due to its unique physicochemical property and internal metabolic characteristic in Field of Drug Discovery
It is widely applied, such as the azacyclo- all substituted in the structures such as inhibitors of dipeptidyl IV, Cannibinoid receptor modulators containing fluorine
Butane segment.The synthesis of these reactive compounds is mainly connected by different substituents with the azetidine that 3- fluorine substitutes,
Therefore, 3- fluoro-azetidine derivatives will be a kind of pharmaceutical intermediate with very big market potentiality.
Synthesis for 3- fluoro-azetidine derivatives, the route of the document reports of patent ZL 201210236105.8
It is as follows：
Reagent and yield：(a)(Boc)2O, NaHCO3, EA, water, yield：75.5%；(b) NFSI, THF, LiHMDS, -78
DEG C, yield：68.4%.
The method of this report has the following disadvantages：Total recovery is than relatively low, and 51.6%, second step is needed using fluorine on NFSI
Reacted at -78 DEG C, it is higher to equipment requirement；The preparation of raw material needs the reaction of 3 steps, and the 3rd step needs to use high-pressure hydrogenation,
The risk prepared on a large scale is larger.
The content of the invention
The purpose of the present invention is overcome the deficiencies in the prior art and provides a kind of conjunction of 3- fluoro-azetidine derivatives
Into method, this method reaction condition is gentleer, simple to operate, often step reaction yield is all higher, and total recovery is up to 85%.
The preparation method of the present invention first reacts to obtain compound ii using chemical compounds I as raw material with trimethylsilyl cyanide, then according to
It is secondary be esterified through thionyl chloride, di-tert-butyl dicarbonate or benzyl chloroformate N-protected, diethylin sulfur trifluoride fluoro, changed
Compound VI.
Specific preparation method is as follows：
Wherein R is tertbutyloxycarbonyl or benzyloxycarbonyl group.
The invention also discloses another preparation method, using chemical compounds I as raw material, is first reacted with trimethylsilyl cyanide
To compound ii, then successively through phase transfer catalyst or sour water solution, diethylin sulfur trifluoride fluoro, thionyl chloride esterification, two
Dimethyl dicarbonate butyl ester or benzyl chloroformate N-protected, obtain compound VI.
Specific preparation method is as follows：
Wherein R is tertbutyloxycarbonyl or benzyloxycarbonyl group.
In the above method, each preferable condition of step is as follows：
In the step of chemical compounds I prepare compound II, the mol ratio of chemical compounds I and trimethylsilyl cyanide for 1.0: 1.0~
1.0∶1.5；Reaction dissolvent is tetrahydrofuran, toluene, ethyl acetate, acetonitrile, 2- methyltetrahydrofurans, glycol dimethyl ether or first
One kind in acetal；Reaction temperature is 20~110 DEG C.
In the step of compound ii prepare compound III, the mol ratio of compound ii and thionyl chloride is 1.0: 1.0~1.0
∶3.0；Reaction dissolvent is methanol；Reaction temperature is 30~65 DEG C.
In the step of compound III prepare compound IV, alkali is in sodium acid carbonate, sodium carbonate, potassium carbonate or triethylamine
It is a kind of；Compound III, di-tert-butyl dicarbonate or benzyl chloroformate, the mol ratio of alkali are 1.0: 0.95~1.05: 1.0~4.0；
Reaction dissolvent is one kind in ethyl acetate/water, methylene chloride/water, tetrahydrofuran/water, methanol or ethanol；Reaction temperature is 0
~40 DEG C.
In the step of compounds Ⅳ prepare compound VI, the mol ratio of compounds Ⅳ and diethylin sulfur trifluoride is 1.0:
1.0~1.0: 2.0；Reaction dissolvent is one kind in dichloromethane, dichloroethanes or chloroform；Reaction temperature is -70~20 DEG C.
In the step of compound ii prepare compound VII, phase transfer catalyst is tetraethyl ammonium fluoride trihydrate or four fourths
Base ammonium fluoride trihydrate；Acid is watery hydrochloric acid or dilute sulfuric acid；Compound ii is 1.0 with the mol ratio of phase transfer catalyst or acid:
1.0~3.0；Reaction dissolvent be tetrahydrofuran, toluene, ethyl acetate, acetonitrile, 2- methyltetrahydrofurans, glycol dimethyl ether or
One kind in dimethoxym ethane；Reaction temperature is 0~40 DEG C.
In the step of VII prepare compound of compound VIII, compound VII and the mol ratio of diethylin sulfur trifluoride are 1.0:
1.0~2.0；Reaction dissolvent is one kind in dichloromethane, dichloroethanes or chloroform；Reaction temperature is -70~20 DEG C.
In the step of VIII prepare compound of compound Ⅸ, the mol ratio of compound VIII and thionyl chloride for 1.0: 1.0~
3.0；Reaction dissolvent is methanol；Reaction temperature is 30~65 DEG C.
In the step of Ⅸ prepare compound of compound VI, alkali is in sodium acid carbonate, sodium carbonate, potassium carbonate or triethylamine
It is a kind of；Compound Ⅸ, di-tert-butyl dicarbonate or benzyl chloroformate, the mol ratio of alkali are 1.0: 0.95~1.05: 1.0~4.0；
Reaction dissolvent is one kind in ethyl acetate/water, methylene chloride/water, tetrahydrofuran/water, methanol or ethanol；Reaction temperature is 0
~40 DEG C.
Synthesising method reacting condition of the invention is gentleer, simple to operate, often step reaction yield is all higher, total recovery
Up to 85%.
Embodiment
Embodiment 1
The synthesis of compound ii：
Raw material I (17.1g, 0.1mol, 1.0eq.), THF (100mL) and trimethylsilyl cyanide are added in 250mL four-hole bottles
(10.4g, 0.105mol, 1.05eq.), it is complete to be warming up to 65 DEG C of reaction 5h, TLC display reactions.It is concentrated to give off-white powder
27.0g, theoretical 27.0g, yield：100%.1H-NMR (400MHz, CDCl3) δ (ppm) 4.41-4.33 (d, J=9.8Hz,
2H), 4.10-3.99 (d, J=9.8Hz, 2H), 1.52-1.39 (s, 9H), 0.32-0.22 (s, 9H).
The synthesis of compound III：
Intermediate II (27.0g, 0.1mol, 1.0eq.), methanol (100mL) are added in 250mL four-hole bottles, protochloride is added dropwise
Sulfone (11.9g, 0.1mol, 1.0eq.), 65 DEG C of backflow 3h, LC-MS display reactions are complete.Off-white powder 16.8g is concentrated to give, is managed
By 16.76g, yield：100%.Direct plunge into and react in next step.1H-NMR(400MHz,D2O) δ (ppm) 4.55-4.41 (d, J=
12.5Hz, 2H), 4.21-4.05 (d, J=12.5Hz, 2H), 3.90-3.78 (s, 3H).
The synthesis of compounds Ⅳ：
Intermediate III (16.8g, 0.1mol, 1.0eq.), H are added in 250mL four-hole bottles2O (80mL), sodium acid carbonate
(21.0g, 0.25mol, 2.5eq.), deflate, add EA (40mL) and di-tert-butyl dicarbonate (21.8g, 0.1mol,
1.0eq.), 10 DEG C of stirring 14h.Liquid separation, aqueous phase are extracted (40mL × 2) with EA, anhydrous sodium sulfate drying, are filtered, concentration, sand processed,
Column chromatography (EA:PE=1:3) colorless oil 20.1g, theoretical 23.1g, yield：87.0%.1H-NMR(400MHz,CDCl3)
δ (ppm) 4.31-4.24 (d, J=10.0Hz, 2H), 4.06-4.00 (d, J=10.0Hz, 2H), 3.94-3.89 (s, 3H),
3.72-3.68(s,1H),1.49-1.46(s,9H)。
The synthesis of compound VI：
Intermediate IV (387g, 1.674mol, 1.0eq.), DCM (3L), -40 DEG C of dropwise addition diethylamine are added in 5L four-hole bottles
Base sulfur trifluoride (378g, 2.343mol, 1.4eq.), add nature and rise to 10 DEG C of stirring 18h.TLC monitoring reactions finish.Reaction
Liquid is poured into saturated aqueous solution of sodium bicarbonate (2L), is deflated, and liquid separation, anhydrous sodium sulfate drying, is filtered, concentration, sand processed, column chromatography
(EA:PE=1:10~1:3) yellow liquid 288.9g, theoretical 390.33g, yield：74.0%.1H-NMR(400MHz,
CDCl3)δ(ppm)4.50-4.30(m,2H),4.27-4.09(m,2H),3.93-3.85(s,3H),1.52-1.43(s,9H)。
The synthesis of compounds Ⅳ：
Intermediate III (16.8g, 0.1mol, 1.0eq.), H are added in 250mL four-hole bottles2O (80mL), sodium acid carbonate
(21.0g, 0.25mol, 2.5eq.), deflate, then the EA of benzyl chloroformate (17.1g, 0.1mol, 1.0eq.) is added dropwise thereto
(40mL) solution, 10 DEG C of stirring 14h.Liquid separation, aqueous phase EA extractions (40mL × 2), anhydrous sodium sulfate drying, filter, concentrate, system
Sand, column chromatography (EA:PE=1:3) colorless oil 22.8g, theoretical 26.5g, yield：86.0%.1H-NMR(400MHz,
CDCl3) δ (ppm) 7.46-7.31 (m, 5H), 5.20-5.09 (s, 2H), 4.45-4.28 (d, J=9.6Hz, 2H), 4.16-
4.07 (d, J=9.6Hz, 2H), 3.95-3.86 (s, 3H), 3.78-3.67 (s, 1H).
The synthesis of compound VI：
Intermediate IV (13.8g, 0.052mol, 1.0eq.), DCM (100mL), -40 DEG C of dropwise additions are added in 250mL four-hole bottles
Diethylin sulfur trifluoride (11.7g, 0.073mol, 1.4eq.), add nature and rise to 10 DEG C of stirring 18h.TLC monitoring has been reacted
Finish.Reaction solution is poured into saturated aqueous solution of sodium bicarbonate (100mL), is deflated, and liquid separation, anhydrous sodium sulfate drying, is filtered, concentration,
Sand processed, column chromatography (EA:PE=1:10~1:3) yellow liquid 10.0g, theoretical 13.9g, yield：72.0%.1H-NMR
(400MHz,CDCl3)δ(ppm)7.46-7.31(m,5H),5.18-5.08(s,2H),4.41-4.25(m,2H),4.25-4.09
(m,2H),3.72-3.64(s,3H)。
Embodiment 2
The synthesis of compound ii：
Raw material I (17.1g, 0.10mol, 1.0eq.), toluene (100mL) and trimethyl cyanogen silicon are added in 250mL four-hole bottles
Alkane (11.9g, 0.12mol, 1.2eq.), 110 DEG C of backflow 3h, TLC display reactions are complete.27.0g off-white powders are concentrated to give, are managed
By 27.0g, yield：100%.1H-NMR(400MHz,CDCl3) δ (ppm) 4.41-4.33 (d, J=9.8Hz, 2H), 4.10-
3.99 (d, J=9.8Hz, 2H), 1.52-1.39 (s, 9H), 0.32-0.22 (s, 9H).
The synthesis of compound VII：
In 500mL four-hole bottles, intermediate II (14.7g, 0.054mol, 1.0eq.) is added, adds tetrahydrofuran
(100mL) dissolves, addition tetraethyl ammonium fluoride trihydrate (12.2g, 0.060mol, 1.1eq.), 40 DEG C of insulation reaction 2h,
TLC detection reactions are complete.Adding water (200mL), liquid separation, water layer is extracted once respectively with EA (100mL, 50mL), merges organic phase,
Saturated sodium-chloride water solution (100mL × 2) washs, and anhydrous sodium sulfate drying, colorless oil 12.5g is concentrated to give, after cooling
It is changed into white solid, theoretical yield：10.7g crude yield：100%.1H-NMR(400MHz,CDCl3)δ(ppm)5.36(brs,
1H), 4.38 (d, J=9.64Hz, 2H), 3.79 (d, J=9.64Hz, 2H), 1.47 (s, 9H).
The synthesis of compound VIII：
In 1L single port bottles, intermediate VII (66.6g, 0.336mol, 1.0eq.) is added, after being dissolved with DCM (600mL), is protected
Hold less than 10 DEG C and diethylin sulfur trifluoride (81.2g, 0.504mol, 1.5eq.) is added dropwise, about 15min keeps 10 DEG C instead after dripping off
15h is answered, TLC detections reaction is completely.Reaction solution is stirred down and poured into 1L mixture of ice and water, stands liquid separation, water layer DCM
(100mL × 1) is extracted, and merges DCM layers, then is washed respectively with 1L water, 1L saturated sodium bicarbonates, 1L saturated sodium-chlorides, and DCM layers are used
Anhydrous sodium sulfate drying, filter, be concentrated to give light brown oily substance 66.3g, sand column chromatography (PE~PE processed:EA=10:1) obtain
Light yellow liquid 59.3g, solidified on standing, theoretical yield：67.27g yield：88.1%.1H-NMR(400MHz,CDCl3)δ
(ppm)4.43-4.50(m,2H),4.29-4.37(m,2H),1.48(s,9H)。
The synthesis of compound Ⅸ：
In 500mL four-hole bottles, methanol (150mL) solution of intermediate VIII (15.2g, 0.076mol, 1.0eq.), drop are added
Add thionyl chloride (9.0g, 0.076mol, 1.0eq.), 65 DEG C of reaction 2h, LC-MS detection reactions be heated to reflux after dripping off completely,
Revolving removes methanol and obtains brown oil 19.0g.After being dissolved with 200mL mixture of ice and water, add 2g activated carbon decolorizing 0.5h, mistake
Filter, with bubble filter wash cake, filtrate is directly thrown in next step.1H-NMR(400MHz,D2O)δ(ppm)4.68-4.49(m,2H),4.48-
4.32(m,2H),3.87-3.75(s,3H)。
The synthesis of compound VI：
Will intermediate Ⅸ the aqueous solution add 500mL four-hole bottles in, be added portionwise sodium acid carbonate (16.0g, 0.190mol,
2.5eq.), keeping temperature is no more than 10 DEG C.After adding, disposably add di-tert-butyl dicarbonate (16.6g, 0.076mol,
EA (100mL) solution 1.0eq.), 10 DEG C of stirring 15h, TLC display reactions are complete.Liquid separation is stood, water layer extracts (50mL with EA
× 1), merge EA layers, saturated sodium-chloride water solution washing (100mL × 1), anhydrous sodium sulfate drying, be concentrated to give light yellow liquid
Body 17.1g, theoretical yield：17.7g, two step yields：96.6%.1H-NMR(400MHz,CDCl3)δ(ppm)4.50-4.30(m,
2H),4.27-4.09(m,2H),3.93-3.85(s,3H),1.52-1.43(s,9H)。
The synthesis of compound VI：
Will intermediate Ⅸ the aqueous solution add 500mL four-hole bottles in, be added portionwise sodium acid carbonate (16.0g, 0.190mol,
2.5eq.), keeping temperature is no more than 10 DEG C.After adding, the EA of benzyl chloroformate (12.96g, 0.076mol, 1.0eq.) is added dropwise
(100mL) solution, 10 DEG C of stirring 15h, TLC display reactions are complete.Liquid separation is stood, water layer is extracted (50mL × 1) with EA, merges EA
Layer, saturated sodium-chloride water solution washing (100mL × 1), anhydrous sodium sulfate drying, is concentrated to give light yellow liquid 19.7g, theoretical
Yield：20.3g, two step yields：97.0%.1H-NMR(400MHz,CDCl3)δ(ppm)7.46-7.31(m,5H),5.18-5.08
(s,2H),4.41-4.25(m,2H),4.25-4.09(m,2H),3.72-3.64(s,3H)。
Embodiment 3
The synthesis of compound ii：
In 2L four-hole bottles, intermediate I (200.0g, 1.168mol, 1.0eq.) is added, after being dissolved with EA (1.2L), is added
Trimethylsilyl cyanide (173.8g, 1.752mol, 1.5eq.), 20 DEG C of reaction 4h, TLC detection reactions are complete, revolving, remove molten
Agent, obtain yellow oil 359.0g, theoretical yield：315.8g crude yield 100%.1H-NMR(400MHz,CDCl3)δ
(ppm) 4.41-4.33 (d, J=9.8Hz, 2H), 4.10-3.99 (d, J=9.8Hz, 2H), 1.52-1.39 (s, 9H), 0.32-
0.22(s,9H)。
The synthesis of compound III：
Intermediate II (27.0g, 0.1mol, 1.0eq.), MeOH (100mL) are added in 250mL four-hole bottles, chlorination is added dropwise
Sulfoxide (23.8g, 0.2mol, 2.0eq.), 40 DEG C of reaction 4h, LC-MS display reactions are complete.Off-white powder 16.8g is concentrated to give,
Theoretical 16.8g, yield：100%.Direct plunge into and react in next step.1H-NMR(400MHz,D2O)δ(ppm)4.55-4.41(d,J
=12.5Hz, 2H), 4.21-4.05 (d, J=12.5Hz, 2H), 3.90-3.78 (s, 3H).
The synthesis of compounds Ⅳ：
Intermediate III (16.8g, 0.1mol, 1.0eq.), H are added in 250mL four-hole bottles2O (80mL), sodium carbonate
(10.6g, 0.1mol, 1.0eq.), deflate, add THF (40mL) and di-tert-butyl dicarbonate (20.73g, 0.095mol,
0.95eq.), 25 DEG C of stirring 14h.Liquid separation, aqueous phase are extracted (40mL × 2) with EA, anhydrous sodium sulfate drying, are filtered, and are concentrated, system
Sand, column chromatography (EA:PE=1:3) colorless oil 20.8g, theoretical 23.1g, yield：90.0%.1H-NMR(400MHz,
CDCl3) δ (ppm) 4.31-4.24 (d, J=10.0Hz, 2H), 4.06-4.00 (d, J=10.0Hz, 2H), 3.94-3.89 (s,
3H),3.72-3.68(s,1H),1.49-1.46(s,9H)。
The synthesis of compound VI：
Addition intermediate IV (20.8g, 0.09mol, 1.0eq.), dichloroethanes (200mL) in 500mL four-hole bottles, -70 DEG C
Diethylin sulfur trifluoride (14.5g, 0.09mol, 1.0eq.) is added dropwise, adds nature and rises to 0 DEG C of stirring 18h.TLC monitoring reactions
Finish.Reaction solution is poured into saturated aqueous solution of sodium bicarbonate (100mL), is deflated, liquid separation, anhydrous sodium sulfate drying, and filtering is dense
Contracting, sand processed, column chromatography (EA:PE=1:10~1:3) yellow liquid 18.05g, theoretical 20.99g, yield：86.0%.1H-
NMR(400MHz,CDCl3)δ(ppm)4.50-4.30(m,2H),4.27-4.09(m,2H),3.93-3.85(s,3H),1.52-
1.43(s,9H)。
The synthesis of compounds Ⅳ：
Intermediate III (16.8g, 0.1mol, 1.0eq.), H are added in 250mL four-hole bottles2O (80mL), potassium carbonate
(13.8g, 0.1mol, 1.0eq.), deflate, then benzyl chloroformate (16.2g, 0.095mol, 0.95eq.) is added dropwise thereto
DCM (40mL) solution, 20 DEG C of stirring 14h.Liquid separation, aqueous phase DCM extractions (40mL × 2), anhydrous sodium sulfate drying, filter, concentration,
Sand processed, column chromatography (EA:PE=1:3) colorless oil 23.3g, theoretical 26.5g, yield：88.0%.1H-NMR(400MHz,
CDCl3) δ (ppm) 7.46-7.31 (m, 5H), 5.20-5.09 (s, 2H), 4.45-4.28 (d, J=9.6Hz, 2H), 4.16-
4.07 (d, J=9.6Hz, 2H), 3.95-3.86 (s, 3H), 3.78-3.67 (s, 1H).
The synthesis of compound VI：
Addition intermediate IV (13.8g, 0.052mol, 1.0eq.), dichloroethanes (100mL) in 250mL four-hole bottles, -70
DEG C be added dropwise diethylin sulfur trifluoride (8.4g, 0.052mol, 1.0eq.), add nature rise to 0 DEG C stirring 18h.TLC monitoring is anti-
It should finish.Reaction solution is poured into saturated aqueous solution of sodium bicarbonate (100mL), is deflated, liquid separation, liquid separation, anhydrous sodium sulfate drying, mistake
Filter, concentration, sand processed, column chromatography (EA:PE=1:10~1:3) yellow liquid 11.1g, theoretical 13.9g, yield：79.8%.1H-NMR(400MHz,CDCl3)δ(ppm)7.46-7.31(m,5H),5.18-5.08(s,2H),4.41-4.25(m,2H),
4.25-4.09(m,2H),3.72-3.64(s,3H)。
Embodiment 4
The synthesis of compound ii：
Raw material I (17.1g, 0.10mol, 1.0eq.), acetonitrile (100mL) and trimethyl cyanogen silicon are added in 250mL four-hole bottles
Alkane (11.9g, 0.12mol, 1.2eq.), 60 DEG C of reaction 3h, TLC display reactions are complete.27.0g off-white powders are concentrated to give, are managed
By 27.0g, yield：100%.1H-NMR(400MHz,CDCl3) δ (ppm) 4.41-4.33 (d, J=9.8Hz, 2H), 4.10-
3.99 (d, J=9.8Hz, 2H), 1.52-1.39 (s, 9H), 0.32-0.22 (s, 9H).
The synthesis of compound VII：
In 500mL four-hole bottles, intermediate II (14.7g, 0.054mol, 1.0eq) is added, adds toluene (100mL) dissolving,
4-butyl ammonium fluoride trihydrate (34.1g, 0.108mol, 2.0eq) is added, 30 DEG C of reaction 4h, sampling, TLC, which is detected, to have reacted
Entirely.Add water 200mL, liquid separation, water layer is extracted once respectively with EA (100mL, 50mL), merges organic phase, and saturated sodium-chloride is water-soluble
Liquid (100mL × 2) washs, and anhydrous sodium sulfate drying, is concentrated to give colorless oil 11.7g, is changed into white solid after cooling, manages
By yield：10.8g.Crude yield 100%.1H-NMR(400MHz,CDCl3) δ (ppm) 5.36 (brs, 1H), 4.38 (d, J=
9.64Hz, 2H), 3.79 (d, J=9.64Hz, 2H), 1.47 (s, 9H).
The synthesis of compound VIII：
In 1L single port bottles, intermediate VII (66.6g, 0.336mol, 1.0eq.) is added, is dissolved with dichloroethanes (600mL)
Afterwards, less than -70 DEG C are added dropwise diethylin sulfur trifluoride (54.2g, 0.336mol, 1.0eq.), and about 15min removes cold after dripping off
But, 0 DEG C of reaction 15h, TLC detection reaction is complete.Reaction solution is stirred down and poured into 1L mixture of ice and water, stands liquid separation, water layer
Extracted with DCM (100mL × 1), merge DCM layers, then washed respectively with 1L water, 1L saturated sodium bicarbonates, 1L saturated sodium-chlorides,
DCM layer anhydrous sodium sulfate dryings, filter, be concentrated to give light brown oily substance 67.5g, sand column chromatography (PE~PE processed:EA=
10:1) light yellow liquid 53.82g, solidified on standing, theoretical yield are obtained：67.27g yield：80.0%.1H-NMR
(400MHz,CDCl3)δ(ppm)4.43-4.50(m,2H),4.29-4.37(m,2H),1.48(s,9H)。
The synthesis of compound Ⅸ：
In 500mL four-hole bottles, methanol (150mL) solution of intermediate VIII (15.2g, 0.076mol, 1.0eq.), drop are added
Add thionyl chloride (18.1g, 0.152mol, 2.0eq.), 40 DEG C of reaction 3h, LC-MS detection reactions are heated to after dripping off completely, rotation
Methanol is evaporated off and obtains brown oil 19.8g.After being dissolved with 200mL mixture of ice and water, add 2g activated carbon decolorizing 0.5h, mistake
Filter, with bubble filter wash cake, filtrate is directly thrown in next step.1H-NMR(400MHz,D2O)δ(ppm)4.68-4.49(m,2H),4.48-
4.32(m,2H),3.87-3.75(s,3H)。
The synthesis of compound VI：
Will intermediate Ⅸ the aqueous solution add 500mL four-hole bottles in, be added portionwise potassium carbonate (10.5g, 0.076mol,
1.0eq.), keeping temperature is no more than 10 DEG C.After adding, disposably add di-tert-butyl dicarbonate (15.8g, 0.0722mol,
DCM (100mL) solution 0.95eq.), 25 DEG C of stirring 15h, TLC display reactions are complete.Liquid separation is stood, water layer is extracted with DCM
(50mL × 1), merge DCM layers, saturated sodium-chloride water solution washing (100mL × 1), anhydrous sodium sulfate drying, be concentrated to give shallow
Yellow liquid 16.8g, theoretical yield：17.7g.Two step yields：95.0%.1H-NMR(400MHz,CDCl3)δ(ppm)4.50-
4.30(m,2H),4.27-4.09(m,2H),3.93-3.85(s,3H),1.52-1.43(s,9H)。
The synthesis of compound VI：
Will intermediate Ⅸ the aqueous solution add 500mL four-hole bottles in, be added portionwise sodium carbonate (8.06g, 0.076mol,
1.0eq.), keeping temperature is no more than 10 DEG C.After adding, benzyl chloroformate (12.32g, 0.0722mol, 0.95eq.) is added dropwise
THF (100mL) solution, 20 DEG C of stirring 15h, TLC display reactions are complete.Liquid separation is stood, water layer is extracted (50mL × 1) with EA, is closed
And organic layer, saturated sodium-chloride water solution washing (100mL × 1), anhydrous sodium sulfate drying, it is concentrated to give light yellow liquid
19.3g theoretical yield：20.3g, two step yields：95.0%.1H-NMR(400MHz,CDCl3)δ(ppm)7.46-7.31(m,
5H),5.18-5.08(s,2H),4.41-4.25(m,2H),4.25-4.09(m,2H),3.72-3.64(s,3H)。
Embodiment 5
The synthesis of compound III：
Intermediate II (27.0g, 0.1mol, 1.0eq.), methanol (100mL) are added in 250mL four-hole bottles, protochloride is added dropwise
Sulfone (35.7g, 0.3mol, 3.0eq.), 30 DEG C of reaction 7h, LC-MS display reactions are complete.Off-white powder 16.9g is concentrated to give, is managed
By 16.76g, yield：100%.Direct plunge into and react in next step.1H-NMR(400MHz,D2O) δ (ppm) 4.55-4.41 (d, J=
12.5Hz, 2H), 4.21-4.05 (d, J=12.5Hz, 2H), 3.90-3.78 (s, 3H).
The synthesis of compounds Ⅳ：
Intermediate III (16.8g, 0.1mol, 1.0eq.), methanol (80mL), triethylamine are added in 250mL four-hole bottles
(40.5g, 0.4mol, 4.0eq.), di-tert-butyl dicarbonate (22.9g, 0.105mol, 1.05eq.) is added after being cooled to 0 DEG C,
40 DEG C of stirring 14h.TLC detection reactions are complete, and water (100mL) and EA (100mL), liquid separation are added after concentration of reaction solution, and aqueous phase is used
EA extracts (40mL × 2), merges organic phase, anhydrous sodium sulfate drying, filters, concentration, sand processed, column chromatography (EA:PE=1:3)
Colorless oil 21.3g, theoretical 23.1g, yield：92.0%.1H-NMR(400MHz,CDCl3)δ(ppm)4.31-4.24(d,J
=10.0Hz, 2H), 4.06-4.00 (d, J=10.0Hz, 2H), 3.94-3.89 (s, 3H), 3.72-3.68 (s, 1H), 1.49-
1.46(s,9H)。
The synthesis of chemical combination VI：
Intermediate IV (21.3g, 0.092mol, 1.0eq.), chloroform (200mL), -20 DEG C of drops are added in 500mL four-hole bottles
Add diethylin sulfur trifluoride (29.7g, 0.184mol, 2.0eq.), add nature and rise to 20 DEG C of stirring 18h.TLC monitoring reactions
Finish.Reaction solution is poured into saturated aqueous solution of sodium bicarbonate (200mL), is deflated, liquid separation, anhydrous sodium sulfate drying, and filtering is dense
Contracting, sand processed, column chromatography (EA:PE=1:10~1:3) yellow liquid 17.2g, theoretical 21.5g, yield：80.0%.1H-NMR
(400MHz,CDCl3)δ(ppm)4.50-4.30(m,2H),4.27-4.09(m,2H),3.93-3.85(s,3H),1.52-1.43
(s,9H)。
The synthesis of compounds Ⅳ：
Intermediate III (16.8g, 0.1mol, 1.0eq.), ethanol (80mL), triethylamine are added in 250mL four-hole bottles
(40.5g, 0.4mol, 4.0eq.), addition benzyl chloroformate (17.9g, 0.105mol, 1.05eq.) after being cooled to 0 DEG C, 40 DEG C
Stir 14h.TLC detection reactions are complete, water (100mL) and EA (100mL) added after concentration of reaction solution, liquid separation, aqueous phase is extracted with EA
Take (40mL × 2), merge organic phase, anhydrous sodium sulfate drying, filter, concentration, sand processed, column chromatography (EA:PE=1:3) obtain colourless
Grease 23.85g, theoretical 26.5g, yield：90.0%.1H-NMR(400MHz,CDCl3)δ(ppm)7.46-7.31(m,5H),
5.20-5.09 (s, 2H), 4.45-4.28 (d, J=9.6Hz, 2H), 4.16-4.07 (d, J=9.6Hz, 2H), 3.95-3.86
(s,3H),3.78-3.67(s,1H)。
The synthesis of compound VI：
Intermediate IV (13.8g, 0.052mol, 1.0eq.), chloroform (100mL), -20 DEG C of drops are added in 250mL four-hole bottles
Add diethylin sulfur trifluoride (16.8g, 0.104mol, 2.0eq.), add nature and rise to 20 DEG C of stirring 18h.TLC monitoring reactions
Finish.Reaction solution is poured into saturated aqueous solution of sodium bicarbonate (100mL), is deflated, liquid separation, liquid separation, anhydrous sodium sulfate drying, mistake
Filter, concentration, sand processed, column chromatography (EA:PE=1:10~1:3) yellow liquid 11.5g, theoretical 13.9g, yield：83.0%.1H-NMR(400MHz,CDCl3)δ(ppm)7.46-7.31(m,5H),5.18-5.08(s,2H),4.41-4.25(m,2H),
4.25-4.09(m,2H),3.72-3.64(s,3H)。
Embodiment 6
The synthesis of compound VII：
In 2L four-hole bottles, intermediate II (27.0g, 0.1mol, 1.0eq.) is added, it is molten to add ethyl acetate (200mL)
Solution, adds 0.5N diluted hydrochloric acid aqueous solutions (600mL, 0.3mol, 3.0eq.), and 0 DEG C of insulation reaction 1h, TLC detection reaction is complete.Point
Liquid, water layer are extracted once respectively with EA (100mL, 50mL), merge organic phase, and saturated sodium-chloride water solution (100mL × 2) is washed
Wash, anhydrous sodium sulfate drying, be concentrated to give colorless oil 20.0g, be changed into white solid, theoretical yield after cooling：19.8g,
Crude yield：100%.1H-NMR(400MHz,CDCl3) δ (ppm) 5.36 (brs, 1H), 4.38 (d, J=9.64Hz, 2H),
3.79 (d, J=9.64Hz, 2H), 1.47 (s, 9H).
The synthesis of compound VIII：
In 500mL single port bottles, intermediate VII (19.8g, 0.1mol, 1.0eq.) is added, after being dissolved with chloroform (200mL) ,-
Less than 20 DEG C are added dropwise diethylin sulfur trifluoride (32.2g, 0.2mol, 2.0eq.), and about 15min keeps 20 DEG C of reactions after dripping off
15h, TLC detection reaction are complete.Reaction solution is stirred down and poured into 200mL mixture of ice and water, stands liquid separation, water layer DCM
(100mL × 1) extracts, and merges organic layer, then washed respectively with 100mL water, 100mL saturated sodium bicarbonates, 100mL saturated sodium-chlorides
Wash, organic layer anhydrous sodium sulfate drying, filter, be concentrated to give light brown oily substance 23.4g, sand column chromatography (PE~PE processed:EA
=10:1) light yellow liquid 15.2g, solidified on standing, theoretical yield are obtained：20.0g yield：76.0%.1H-NMR
(400MHz,CDCl3)δ(ppm)4.43-4.50(m,2H),4.29-4.37(m,2H),1.48(s,9H)。
The synthesis of compound Ⅸ：
In 500mL four-hole bottles, methanol (150mL) solution of intermediate VIII (15.2g, 0.076mol, 1.0eq.), drop are added
Add thionyl chloride (27.1g, 0.228mol, 3.0eq.), 30 DEG C of reaction 5h, LC-MS detection reactions are complete after dripping off, and revolving removes
Methanol obtains brown oil 15.3g, theoretical 12.9g, crude yield：100%, directly throw in next step.1H-NMR(400MHz,
D2O)δ(ppm)4.68-4.49(m,2H),4.48-4.32(m,2H),3.87-3.75(s,3H)。
The synthesis of compound VI：
The crude product (15.3g, 0.076mol, 1.0eq.) of intermediate Ⅸ is added in reaction bulb, adds methanol
(150mL), and triethylamine (30.8g, 0.304mol, 4.0eq.), keeping temperature are no more than 0 DEG C.After adding, two are disposably added
Dimethyl dicarbonate butyl ester (17.4g, 0.0798mol, 1.05eq.), 40 DEG C of stirring 15h, TLC display reactions are complete.Concentration of reaction solution
Water (100mL) and EA (100mL) are added afterwards, stands liquid separation, and water layer is extracted (50mL × 1) with EA, merges EA layers, saturated sodium-chloride
The aqueous solution washs (100mL × 1), anhydrous sodium sulfate drying, is concentrated to give light yellow liquid 16.3g, theoretical yield：17.7g two
Walk yield：92.0%.1H-NMR(400MHz,CDCl3)δ(ppm)4.50-4.30(m,2H),4.27-4.09(m,2H),3.93-
3.85(s,3H),1.52-1.43(s,9H)。
The synthesis of compound VI：
The crude product (15.3g, 0.076mol, 1.0eq.) of intermediate Ⅸ is added in reaction bulb, adds ethanol
(150mL), and triethylamine (30.8g, 0.304mol, 4.0eq.), keeping temperature are no more than 0 DEG C.After adding, chloro-carbonic acid benzyl is added
Ester (13.6g, 0.0798mol, 1.05eq.), 40 DEG C of stirring 15h, TLC display reactions are complete.Water is added after concentration of reaction solution
(100mL) and EA (100mL), liquid separation is stood, water layer is extracted (50mL × 1) with EA, merges EA layers, and saturated sodium-chloride water solution is washed
Wash (100mL × 1), anhydrous sodium sulfate drying, be concentrated to give light yellow liquid 18.9g, theoretical yield：20.3g, two step yields：
93.0%.1H-NMR(400MHz,CDCl3)δ(ppm)7.46-7.31(m,5H),5.18-5.08(s,2H),4.41-4.25(m,
2H),4.25-4.09(m,2H),3.72-3.64(s,3H)。
Claims (8)
1. a kind of synthetic method of 3- fluoro-azetidine derivatives, including：
Wherein R is tertbutyloxycarbonyl or benzyloxycarbonyl group；
Wherein in the step of compound ii prepare compound III, the mol ratio of compound ii and thionyl chloride is 1.0: 1.0~1.0:
3.0；Reaction dissolvent is methanol；Reaction temperature is 30~65 DEG C.
2. a kind of synthetic method of 3- fluoro-azetidine derivatives, including：
Wherein R is tertbutyloxycarbonyl or benzyloxycarbonyl group；
Wherein in the step of compound ii prepare compound VII, phase transfer catalyst is tetraethyl ammonium fluoride trihydrate or the tetrabutyl
Ammonium fluoride trihydrate；Acid is watery hydrochloric acid or dilute sulfuric acid；
Wherein in the step of VIII prepare compound of compound Ⅸ, the mol ratio of compound VIII and thionyl chloride is 1.0: 1.0~3.0；
Reaction dissolvent is methanol；Reaction temperature is 30~65 DEG C.
3. the synthetic method of 3- fluoro-azetidine derivatives according to claim 1 or claim 2, its feature
It is：In the step of chemical compounds I prepare compound II, the mol ratio of chemical compounds I and trimethylsilyl cyanide is 1.0: 1.0~1.0:
1.5；Reaction dissolvent is tetrahydrofuran, toluene, ethyl acetate, acetonitrile, 2- methyltetrahydrofurans, glycol dimethyl ether or dimethoxym ethane
In one kind；Reaction temperature is 20~110 DEG C.
4. the synthetic method of 3- fluoro-azetidine derivatives according to claim 1, it is characterised in that：In chemical combination
In the step of III prepare compound of thing IV, alkali is one kind in sodium acid carbonate, sodium carbonate, potassium carbonate or triethylamine；Compound III,
Di-tert-butyl dicarbonate or benzyl chloroformate, the mol ratio of alkali are 1.0: 0.95~1.05: 1.0~4.0；Reaction dissolvent is acetic acid
One kind in ethyl ester/water, methylene chloride/water, tetrahydrofuran/water, methanol or ethanol；Reaction temperature is 0~40 DEG C.
5. the synthetic method of 3- fluoro-azetidine derivatives according to claim 1, it is characterised in that：In chemical combination
In the step of IV prepare compound of thing VI, the mol ratio of compounds Ⅳ and diethylin sulfur trifluoride is 1.0: 1.0~1.0: 2.0；
Reaction dissolvent is one kind in dichloromethane, dichloroethanes or chloroform；Reaction temperature is -70~20 DEG C.
6. the synthetic method of 3- fluoro-azetidine derivatives according to claim 2, it is characterised in that：In chemical combination
In the step of II prepare compound of thing VII, compound ii is 1.0: 1.0~3.0 with the mol ratio of phase transfer catalyst or acid；Reaction
Solvent is one in tetrahydrofuran, toluene, ethyl acetate, acetonitrile, 2- methyltetrahydrofurans, glycol dimethyl ether or dimethoxym ethane
Kind；Reaction temperature is 0~40 DEG C.
7. the synthetic method of 3- fluoro-azetidine derivatives according to claim 2, it is characterised in that：In chemical combination
In the step of VII prepare compound of thing VIII, the mol ratio of compound VII and diethylin sulfur trifluoride is 1.0: 1.0~2.0；Reaction
Solvent is one kind in dichloromethane, dichloroethanes or chloroform；Reaction temperature is -70~20 DEG C.
8. the synthetic method of 3- fluoro-azetidine derivatives according to claim 2, it is characterised in that：In chemical combination
In the step of Ⅸ prepare compound of thing VI, alkali is one kind in sodium acid carbonate, sodium carbonate, potassium carbonate or triethylamine；Compound Ⅸ,
Di-tert-butyl dicarbonate or benzyl chloroformate, the mol ratio of alkali are 1.0: 0.95~1.05: 1.0~4.0；Reaction dissolvent is acetic acid
One kind in ethyl ester/water, methylene chloride/water, tetrahydrofuran/water, methanol or ethanol；Reaction temperature is 0~40 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510756697.XA CN105384673B (en) | 2015-11-09 | 2015-11-09 | The synthetic method of 3 fluoro azetidine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510756697.XA CN105384673B (en) | 2015-11-09 | 2015-11-09 | The synthetic method of 3 fluoro azetidine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105384673A CN105384673A (en) | 2016-03-09 |
| CN105384673B true CN105384673B (en) | 2017-11-14 |
Family
ID=55417501
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510756697.XA Active CN105384673B (en) | 2015-11-09 | 2015-11-09 | The synthetic method of 3 fluoro azetidine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105384673B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115974688A (en) * | 2023-02-02 | 2023-04-18 | 滕州市悟通香料有限责任公司 | Synthesis method of p-tert-butyl methyl phenylacetate |
| CN117003681A (en) * | 2023-07-04 | 2023-11-07 | 苏州汉德创宏生化科技有限公司 | An inhibitor intermediate and its synthesis method |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101463007A (en) * | 2007-12-21 | 2009-06-24 | 上海药明康德新药开发有限公司 | Fluoro or difluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation |
| CN101715455A (en) * | 2007-04-10 | 2010-05-26 | 尔察祯有限公司 | Antibacterial 1,4,5-substituted aminoglycoside analogs |
| CN102731362A (en) * | 2012-07-09 | 2012-10-17 | 南京药石药物研发有限公司 | Method for preparing 1-carboxylic acid tert-butyl ester-3-fluoro-azetidine derivative |
| CN103842340A (en) * | 2011-07-29 | 2014-06-04 | 卡尔约药物治疗公司 | Nuclear transport modulators and uses thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102212026A (en) * | 2010-04-01 | 2011-10-12 | 上海艾特斯医药科技有限公司 | Preparation method for 1-tertbutyloxycarbonyl-3-iodoazetidine |
| EP2738156B1 (en) * | 2011-07-26 | 2018-01-03 | Kbp Biosciences Usa Inc. | 9-aminomethyl substituted tetracycline compounds |
-
2015
- 2015-11-09 CN CN201510756697.XA patent/CN105384673B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101715455A (en) * | 2007-04-10 | 2010-05-26 | 尔察祯有限公司 | Antibacterial 1,4,5-substituted aminoglycoside analogs |
| CN101463007A (en) * | 2007-12-21 | 2009-06-24 | 上海药明康德新药开发有限公司 | Fluoro or difluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation |
| CN103842340A (en) * | 2011-07-29 | 2014-06-04 | 卡尔约药物治疗公司 | Nuclear transport modulators and uses thereof |
| CN102731362A (en) * | 2012-07-09 | 2012-10-17 | 南京药石药物研发有限公司 | Method for preparing 1-carboxylic acid tert-butyl ester-3-fluoro-azetidine derivative |
Non-Patent Citations (1)
| Title |
|---|
| 氟化剂的研究进展;杨燕等;《中国科技信息》;20101231(第21期);144-145 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105384673A (en) | 2016-03-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108503573B (en) | A kind of new preparation method of Bu Waxitan | |
| CN104262344A (en) | A preparing method of Idelalisib | |
| CN105384673B (en) | The synthetic method of 3 fluoro azetidine derivatives | |
| CN106068271A (en) | 2` replaces 2,2` anhydro uridine or 2` replaces 2,2` dehydration cytidine compounds and its production and use | |
| CN111909088B (en) | Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor using BTC/Ph3PO chlorination system | |
| CN107513050B (en) | A kind of preparation method of enoic acid bromolactonization | |
| CN103880770B (en) | The preparation method of chiral 3 morpholine methanol classes and 3 morpholine formic acid compounds | |
| CN103435592A (en) | 2-((4R,6S)-6-formaldehyde-2,2-dimethyl-1,3 dioxane-4-base)-methyl acetate preparation method | |
| CN107417643B (en) | Synthesis process of dyclonine hydrochloride | |
| CN104829588B (en) | A kind of Preparation Method And Their Intermediate of benzo [b] thiophene | |
| CN106608896B (en) | A kind of synthetic method of pharmaceutical intermediate | |
| CN105294501B (en) | A kind of preparation method of Carfilzomib midbody compound | |
| CN106554333B (en) | A kind of synthetic method of pharmaceutical intermediate | |
| CN107417548A (en) | Than his intermediate of department and preparation method thereof | |
| CN102432616B (en) | Method for preparing L-prolinamide and intermediate thereof | |
| CN109265385B (en) | Synthesis process of chiral catalyst | |
| CN105017251B (en) | A kind of Preparation Method And Their Intermediate of nk 1 receptor antagonist | |
| CN104402813A (en) | Novel method for synthesizing sorafenib | |
| CN104086475A (en) | Preparation method of N-carbobenzoxy-L-prolinamide | |
| CN105175490A (en) | Preparation method of argatroban intermediate | |
| CN107353265B (en) | A kind of preparation method of chlorolactonization of enoic acid | |
| CN105753770A (en) | Protein kinase inhibitor preparation method, protein kinase inhibitor intermediate, intermediate preparation method and application | |
| CN102731362B (en) | Method for preparing 1-carboxylic acid tert-butyl ester-3-fluoro-azetidine derivative | |
| CN109369678A (en) | A new synthetic method of natural product isomer (-)-6-epi-Porantheridine | |
| CN105001108B (en) | The preparation method of the dimethyl glutamate derivatives of optical voidness 3,4 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240308 Address after: Room 208-7, Block A, Baitai Biotech Building, No.10 Xinghuo Road, Jiangbei New District, Nanjing City, Jiangsu Province, 211899 Patentee after: Nanjing Paite Meisheng Technology Co.,Ltd. Country or region after: China Address before: Building C, 11th Floor, Dingye Baitai Biological Building, No.10 Xinghuo Road, Nanjing High tech Industrial Development Zone, Jiangsu Province, 210061 Patentee before: 4RINGCHEM BIOPHARMACEUTICALS CO.,LTD. Country or region before: China |
|
| TR01 | Transfer of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Synthesis method of 3-fluoro nitro heterocyclic butane derivatives Granted publication date: 20171114 Pledgee: Bank of Nanjing Jiangbei District branch of Limited by Share Ltd. Pledgor: Nanjing Paite Meisheng Technology Co.,Ltd. Registration number: Y2024980016037 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |