CN103626712B - A kind of intermediate for the preparation of Linezolid and its preparation method - Google Patents
A kind of intermediate for the preparation of Linezolid and its preparation method Download PDFInfo
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- CN103626712B CN103626712B CN201210300907.0A CN201210300907A CN103626712B CN 103626712 B CN103626712 B CN 103626712B CN 201210300907 A CN201210300907 A CN 201210300907A CN 103626712 B CN103626712 B CN 103626712B
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- benzylidene
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 title abstract description 21
- 229960003907 linezolid Drugs 0.000 title abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 28
- 150000007530 organic bases Chemical class 0.000 claims description 9
- -1 4-isopropoxy-benzylidene Chemical group 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- UOHBMRODJBFDPN-UHFFFAOYSA-N C(C)(C)(C)O.[Li] Chemical compound C(C)(C)(C)O.[Li] UOHBMRODJBFDPN-UHFFFAOYSA-N 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 125000003545 alkoxy group Chemical group 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 description 38
- 238000002425 crystallisation Methods 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 230000008025 crystallization Effects 0.000 description 20
- 239000007787 solid Substances 0.000 description 18
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000010907 mechanical stirring Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 238000010936 aqueous wash Methods 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 230000001186 cumulative effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 0 CC**C(CC1C)=CC(C)*1(C)C=* Chemical compound CC**C(CC1C)=CC(C)*1(C)C=* 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000002360 explosive Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- SUYSQRHNTDVWKJ-UHFFFAOYSA-N 1,3-dichlorobenzene;formaldehyde Chemical compound O=C.ClC1=CC=CC(Cl)=C1 SUYSQRHNTDVWKJ-UHFFFAOYSA-N 0.000 description 2
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 description 2
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- JRHHJNMASOIRDS-UHFFFAOYSA-N 4-ethoxybenzaldehyde Chemical compound CCOC1=CC=C(C=O)C=C1 JRHHJNMASOIRDS-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 235000014493 Crataegus Nutrition 0.000 description 1
- 241001092040 Crataegus Species 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000000721 bacterilogical effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- BHYSAYLKHNDGLB-UHFFFAOYSA-N benzaldehyde;propan-2-ol Chemical compound CC(C)O.O=CC1=CC=CC=C1 BHYSAYLKHNDGLB-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000275 quality assurance Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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 carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The present invention relates to a kind of new midbody compound as shown in structural formula I for the preparation of Linezolid and its preparation method. The cheaper starting materials of preparation method of the present invention is easy to get, operational path is short, simple to operate, cost is low, reaction process mild condition safety, and the reaction times is short, it is not necessary to the device of particular requirement, is suitable for suitability for industrialized production.Wherein R1For alkoxyl group.
Description
Technical field
The present invention relates to the field of the midbody compound of a kind of chemical synthetic drug and its preparation method, specifically, the present invention relates to the midbody compound and its preparation method of preparing Linezolid (Linezolid).
Background technology
Antibiotic resistance is one of most serious problems of facing of the clinical and public health in the whole world, and it occurs with surprising speed and also will increase in the near future in recent years. When spread of germs increases substantially, resistance becomes the problem in society and healthcare environment. Multi-drug resistant is a problem constantly increased, and current doctor to be faced the infection illness not having effective therapy, and therefore, the antiseptic-germicide of the novel structure with new binding mode becomes more and more important in the treatment of bacteriological infection.
In the antiseptic-germicide of novelty, vancomycin-resistant bacterium, due to the chemical structure of its uniqueness and mechanism of action, to drug tolerant bacteria, is particularly had good killing action by Linezolid. US Patent No. 5688792 discloses Linezolid (Linezolid, structural formula IV), its chemistry (S)-N-[[3-[the fluoro-4-of 3-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide by name, it is first oxazolidinone antibacterial medicine that Pfizer releases for 2000, is mainly used in treatment drug resistant bacterial infections and surgical infection.
About the synthesis of Linezolid, the technique of document report can be divided into two classes substantially: a class is sodium azide technique, and a class is non-sodium azide technique. Earlier process is mostly sodium azide technique, as shown in Equation 1, the difference is that the technique preparing structural formula V or structural formula VI compound different. Such as US5688792, US6107519, US7291614, WO2009063505, CN101638392, J.Med.Chem.1996,39 (3): 673-679; Chinese Journal of New Drugs 2002,11 (5): 378-380; China's pharmaceutical chemistry magazine 2005,15 (2): 89-93 etc.
Sodium azide technique is due to sodiumazide explosive, and safety in production has a big risk and is not suitable for amplifying and producing. Therefore non-sodium azide technique is the emphasis of research always. Non-sodium azide technique the earliest is the sub-acid amides technique (such as formula 2) of phthalic acid. This technique is hydrolyzed by structural formula �� compound hydrazine, obtains structural formula VIII compound, then acetylize obtains Linezolid (US5688792; WO9924393, WO2005099353, US7429661; US2006008754, China's pharmaceutical chemistry magazine 2003,13 (1): 28-30).
When the shortcoming of this technique prepares structural formula VIII compound by structural formula �� compound, hydrazinolysis needs more violent condition, easily causes azoles ring and decomposes, causes product Linezolid not easily to be purified, and receipts rate is low.
WO9737980(G is hydrogen), WO2010031769(G be allyl group, substituted allyl or quaternary carbon alkyl) and WO2010084514(G be benzyl or substituted benzyl) technique that discloses is the non-sodium azide technique of another kind of synthesis Linezolid, concluded as amine foundry skill, as shown in Equation 3.
This technique be structural formula VI compound is carried out ammonia solution or with primary amine generation substitution reaction, more de-alkyl obtains structural formula VIII compound. The shortcoming of this technique be ammonia solution or amine for time, it is easy to there are two amine generations, it is difficult to remove, affect quality.
WO9924393, WO2002085849, Org.Proce.Res.Dev.2003,7 (4): 533-546, West China pharmaceutical journal 2007,22 (2): 179-181 etc. there was reported a kind of non-sodium azide technique, and this technique is that structural formula III compound and S-diacetyl halogen propyl alcohol amine (structural formula �� compound) direct reaction obtain Linezolid, it is called for short diacetyl halogen propyl alcohol amine technique, as shown in Equation 4.
Owing to S-diacetyl halogen propyl alcohol amine need to prepare (such as formula 5) by following technique, and the difficult crystallization of S-halogen propyl alcohol amine (structural formula �� V compound), impurity is more, and receipts rate is lower, affects end product quality and whole technique cost.
Within 2007, above-mentioned technique has been improved by Pfizer, reports again the operational path (WO2007116284) of a synthesis Linezolid, is called for short imines alcohol technique, as shown in Equation 6.
There is following shortcoming in this technique:
1. when preparing structural formula �� VI compound, the reaction times need more than 20 hour and reaction not exclusively, the reaction times too long being unfavorable for produce. Needing in addition to add the recrystallisation solvent such as normal heptane, octane-iso to reaction solution, structural formula �� VI compound could crystallization. Owing to mixed solvent reclaims than single solvent difficulty, production cost is relatively high. And normal heptane, octane-iso are all inflammable and explosive, production safety risk is bigger.
2. when isolating construction formula �� VII compound, adopt and add methyl alcohol or Virahol condensing mode crystallization repeatedly to reaction solution (methylene dichloride is solvent), not only operate loaded down with trivial details, and methyl alcohol and methylene dichloride or Virahol and methylene dichloride ratio, quantity are all subject to the impact of working condition (such as temperature, pressure and concentration time), it is difficult to stable and consistent, cause quality and the crystallization yield of structural formula �� VII compound to be difficult to stablize, do not meet drug quality and ensure requirement. Adopting mixed solvent crystallization in addition, separated from solvent reclaims also difficulty, produces uneconomical.
3. meeting by-product chlorobenzaldehyde, bromobenzaldehyde or 2,4 dichloro benzene formaldehyde etc. during structural formula �� VII compound hydrolysis, these aldehyde are solid aldehyde, remove completely cumbersome, and reclaiming purifies also needs recrystallization, cost height, and receipts rate is low.
4. adopting methylene dichloride to be reaction solvent when preparing finished product Linezolid, ethyl acetate is recrystallisation solvent. Owing to methylene dichloride belongs to II kind solvent, toxicity is relatively big, and product safety has a big risk. In addition owing to solvent residual amount is strictly controlled, production cost is relatively high.
Within 2011, above-mentioned technique has been improved again by the good Pharmaceutical Technology Co., Ltd of Ningbo Bai Te, sees Chinese patent application CN102153521A(technique as shown in Equation 6, G1For hydrogen, G2For hydrogen, alkyl or substituted alkyl, R2For benzyl).
Although this patent solves the part shortcoming of imines alcohol technique, but still there is following shortcoming:
1. when preparing structural formula �� VI compound, the reaction times reaches 20 hours and reacts not exclusively, and the reaction times is grown very much and is unfavorable for producing. Structural formula �� VI compound is unstable, easily decomposes, not easily preserves.
2. when preparing structural formula �� VII compound, needing back flow reaction more than 10 hours, the reaction times is grown very much and is unfavorable for producing, and the reaction of this step reaction structure formula III compound is not exclusively, aftertreatment crystallization also is difficult to remove completely, causes quality product reduction and receipts rate low, and cost becomes high.
Therefore, a kind of safe, practical, economic technique preparing Linezolid of urgent needs.
Summary of the invention
The present invention provides a kind of intermediate for the preparation of Linezolid, and its structural formula is as follows:
Wherein R1For alkoxyl group, it is preferable that R1For C1��C4Alkoxyl group, it is most preferred that R1For methoxyl group, oxyethyl group, isopropoxy or tert.-butoxy.
Present invention also offers the preparation method of a kind of structural formula I compound. The method comprises: in the presence of an organic base, and structural formula II compound and formula II I are obtained by reacting structural formula I in organic solvent, and temperature of reaction is 0 ~ 100 DEG C, and synthetic route is as follows:
Wherein R1For alkoxyl group, it is preferable that R1For C1��C4Alkoxyl group, it is most preferred that R1For methoxyl group, oxyethyl group, isopropoxy or tert.-butoxy, R2For benzyl or C1-8Alkyl, it is preferable that benzyl or the tertiary butyl.
The molar ratio of structural formula II compound and structural formula III compound is 0.1:1-10:1, it is preferable that 0.5:1-2:1, it is most preferred that 1:1-2:1.
Described organic bases is the organic bases that pKa is greater than 12, it is preferable that tertiary alkanol compound alkali, it is most preferred that trimethyl carbinol lithium. The molar ratio of described alkali and structural formula III compound is 0.1:1-10:1, it is preferable that 1:1-5:1, it is most preferred that 2:1-3:1.
Organic solvent is aprotic solvent, it is preferable that DMF, DMAc, THF, acetonitrile, C1-6The mixture of straight chain, side chain and ring-type ether and/or chlorinated solvent and/or these solvents, it is most preferred that methyl tertiary butyl ether or methylene dichloride.
Temperature of reaction preferably 40 ~ 55 DEG C.
Structural formula III compound can refer to J.Med.Chem.1996,39 (3): 673-679, the document preparations such as West China pharmaceutical journal 2007,22 (2): 179-181 and China's pharmaceutical chemistry magazine 2003,13 (1): 28-30.
Such as, after reaction terminates, it is preferable that after processing through aqueous solution extraction, it may also be useful to weakly polar organic solvent, alcohol (comprises C1-6Side chain and straight chain alcohol, and polyvalent alcohol) or ether (comprise MTBE, THF, and other C1-6Straight chain, side chain or ring-type ether), it is most preferred that Virahol makes structural formula I compound crystal.
By structural formula I compound acid hydrolysis, then with diacetyl oxide or Acetyl Chloride 98Min. acetylize, Linezolid can be obtained.
Advantage of the present invention:
When 1, preparing structural formula II compound, the reaction times only needs 3-5 hour, just R1For the 1/4 of the reaction times such as chlorine, bromine, hydrogen. And structural formula II compound is direct crystallization from reaction solution, it is not necessary to as R1Inflammable and explosive recrystallisation solvent is added like that for when chlorine, bromine, simple to operate, produce safer. Owing to recrystallisation solvent is single solvent, more easily reclaiming than mixed solvent, production cost is low, and environmental influence is less.
When 2, preparing structural formula I compound, the reaction times only needs 3-4 hour, compares R1For shortening half when hydrogen, alkyl, and the reaction of structural formula III compound is thoroughly, for obstacle has been cleared away in follow-up crystallization, it is to increase quality product and receipts rate.
3, present configuration type I compound crystallization in single Virahol, its advantage is that the amount that Virahol adds can control, the crystallization yield of structural formula I compound and steady quality, and simple to operate, receipts rate height, meets quality assurance requirements.
4, during structural formula I compound hydrolysis the aldehyde of by product be aubepine, p-ethoxybenzaldehyde, to isopropoxide benzaldehyde or to tert.-butoxy phenyl aldehyde. These aldehyde are all liquid aldehydes, and alkali cleaning can directly be applied mechanically after dewatering. On the contrary, R is worked as1During for chlorine, bromine etc., by product is chlorobenzaldehyde, bromobenzaldehyde or 2,4 dichloro benzene formaldehyde etc., and these aldehyde are solid aldehyde. Solid aldehyde alkali does not wash clean, it is necessary to recrystallization, it is necessary to drying, cost recovery height, receipts rate is low, operates loaded down with trivial details.
5, when preparing finished product Linezolid, reaction solvent of the present invention and recrystallisation solvent are all ethyl acetate. Its advantage is not only the present invention and is used single solvent, and solvent recovering rate height, cost is low. The more important thing is that ethyl acetate is III kind solvent, compare R1For needing methylene dichloride (II kind solvent) toxicity used less during halogen, security is higher, and environmental influence is also little.
Unless otherwise indicated, otherwise the following term used in specification sheets and claim has following meanings:
The carbon content of various alkane structure part is represented by the prefix of the minimum and maximum carbonatoms indicating this structure part, i.e. prefix Ci-jInstruction integer " i ", to the structure part of integer " j " individual carbon atom, comprises end value. Therefore, such as C1-8Alkyl refers to the alkyl of 1-8 carbon atom, comprises end value.
Term alkyl groups mean linear and branched group, but the separate base of mentioned such as " propyl group " only comprises straight chain group, and such as the branched chain isomer of " sec.-propyl " then to be pointed out individually. Especially, alkyl is C1-4Alkyl.
Term " room temperature " refers to the temperature range of about 20 DEG C-30 DEG C.
Embodiment
Further explain and describe content of the present invention by the following examples. Described embodiment only understands content of the present invention to help, it should not be understood to the restriction to present subject matter and protection domain.
Embodiment
In above-mentioned discussion and following embodiment, following abbreviations has following meanings. If abbreviation do not defined, then it has the implication of general acceptance.
The preparation of the chloro-3-of embodiment 1 (S)-1-[(4-methoxyl group-E-benzylidene)-amino]-propyl-2-alcohol
Method A
4-methoxybenzaldehyde (140.2g is added successively to being equipped with in the 1L tri-neck round-bottomed flask of mechanical stirring, reflux exchanger and heating in water bath pot, 1.03mol, 1.03 equivalents), dehydrated alcohol or THF(270ml), ammoniacal liquor (28.0wt%, 91.2g, 1.5mol, 1.5 equivalents), stir after 10 minutes, add S-epoxy chloropropane (92.5g, 1.0mol, 1.0 equivalents), it is heated to 40 DEG C. Stirring reaction 3 hours at the temperature of 35 ~ 40 DEG C, the S-epoxy chloropropane of now GC display residue 0.23 area %. To cumulative volume, mixture vacuum concentration being about 150ml, crystallisation by cooling, collecting precipitation thing, drying under reduced pressure solid 5 hours at the temperature of 40 DEG C, obtain the title compound 170.7g of white crystalline solid, receipts rate 75%, mp89-90 DEG C.
Method B
4-methoxybenzaldehyde (140.2g is added successively to being equipped with in the 1L tri-neck round-bottomed flask of mechanical stirring, reflux exchanger and heating in water bath pot, 1.03mol, 1.03 equivalents), MTBE(270ml), ammoniacal liquor (28.0wt%, 91.2g, 1.5mol, 1.5 equivalents), stir after 10 minutes, add S-epoxy chloropropane (92.5g, 1.0mol, 1.0 equivalents), it is heated to 40 DEG C. Stirring reaction 5 hours at the temperature of 35 ~ 40 DEG C, the S-epoxy chloropropane of now GC display residue 3.2 area %. Being separated each layer while hot, abandon lower water layer, by organic layer crystallisation by cooling, collecting precipitation thing also washs with cold MTBE. Drying under reduced pressure solid 5 hours at the temperature of 40 DEG C, obtain the title compound 161.6g of white crystalline solid, receipts rate 71%, mp90-91 DEG C.
Embodiment 2 (S)-5-{ [(4-methoxyl group-benzylidene)-amino]-methyl } preparation of-3-(the fluoro-4-morpholine-4-base-phenyl of 3-)-azoles alkane-2-ketone
In (fluoro-4-morpholine-4 bases-phenyl of 3-)-benzyl carbamate (20g, 60.5mmol, 1.0 equivalents), add trimethyl carbinol lithium (12.11g, 151.4mmol, 2.5 equivalents), add methylene dichloride (80ml) afterwards, be at room temperature uniformly mixed thing. Disposable in the suspension of gained add the chloro-3-of (S)-1-[(4-methoxyl group-E-benzylidene)-the amino]-propyl-2-alcohol (20.68g, 90.8mmol, 1.5 equivalents) being dissolved in methylene dichloride (40ml). The dilute suspension of gained is heated to backflow (about 41 DEG C) keep 4 hours. After reaction solution is cooled to room temperature, washs organic layer with water (1 �� 100ml, 1 �� 50ml), then abandon these Aqueous wash things. Organic phase is dry by anhydrous sodium sulphate (3g), to filter, filtrate concentrates to dry. Add Virahol (50mL), it is cooled to 0 ~ 5 DEG C of crystallization, filters out crystallization, then vacuum-drying at the temperature of 50 DEG C, obtain the title compound 22.5g of off-white color solid crystal powder, receipts rate 90%, mp132-132.5 DEG C.1HNMR(500MHz, CDCl3) �� 3.05 (t, J=4Hz, 4H), 3.84 (s, 3H), 3.87 (t, J=4.5Hz, 4H), 3.89 (s, 1H), 3.95 (dd, J=13,5Hz, 1H), 4.04 (m, 1H), 4.10 (t, J=8.5Hz, 1H), 4.93 (dt, J=13.5,5.5Hz, 1H), 6.91 (m, 2H), 6.94 (s, 1H) 7.13 (m, 1H), 7.45 (dd, J=15,3Hz, 1H), 7.64 (d, J=8Hz, 2H), 8.30 (s, 1H);13CNMR(CDCl3) �� 48.47,51.20,55.53,63.39, (67.12,72.09,107.60 d, J=104.5Hz), 114.04,114.185,118.93,128.67,130.12,133.133.62,133.71, (136.35 d, J=17.5Hz), 154.74,156.64,162.21,164.20.
The preparation of embodiment 3 (S)-N-[3-(the fluoro-4-morpholine-4-base-phenyl of 3-)-2-oxo-azoles alkane-5-base-methyl]-ethanamide (Linezolid)
Method A
To (S)-5-{ [(4-methoxyl group-benzylidene)-amino]-methyl }-3-(the fluoro-4-morpholine-4-base-phenyl of 3-)-azoles alkane-2-ketone (186.1g, 450mmol, 1.0 equivalents) in add ethyl acetate (900ml) and water (900ml). Adding the HCl/water solution (75ml, 900mmol, 2.0 equivalents) of 12M in non-homogeneous mixture, after several minutes, solid pass into solution, at room temperature continues to stir 2 hours, and it is complete that HPLC analyzes display hydrolysis reaction. Separation of phases, abandons organic layer, and aqueous phase ethyl acetate (500ml) is washed. Ethyl acetate (900ml) is added to aqueous phase, sodium hydroxide (about 36g) aqueous solution with 50%, by pH regulator to 6.7, separates organic phase, and aqueous phase extracts once by ethyl acetate (500mL) again, merge organic phase, once, anhydrous sodium sulphate (50g) is dry in washing, filters filtering sodium sulfate, filtrate adds diacetyl oxide (85ml, 900mmol, 2.0 equivalents), it is evaporated to 900ml. Gained slurry being cooled to 0 DEG C of crystallization and takes out filter collecting precipitation thing, at 50 DEG C, vacuum-drying obtains title compound, i.e. Linezolid crystallization 133.6g, receipts rate 88%, HPLC purity 99.8%.
Method B
General step according to method A also carries out nonessential change, but with (S)-5-{ [(4-oxyethyl group-benzylidene)-amino]-methyl }-3-(3-fluoro-4-morpholine-4-base-phenyl)-azoles alkane-2-ketone (embodiment 5) replacement (S)-5-{ [(4-methoxyl group-benzylidene)-amino]-methyl }-3-(the fluoro-4-morpholine-4-base-phenyl of 3-)-azoles alkane-2-ketone, obtain title compound.
Method C
General step according to method B also carries out nonessential change, but with (S)-5-{ [(4-isopropoxy-benzylidene)-amino]-methyl }-3-(3-fluoro-4-morpholine-4-base-phenyl)-azoles alkane-2-ketone (embodiment 7) replacement (S)-5-{ [(4-methoxyl group-benzylidene)-amino]-methyl }-3-(the fluoro-4-morpholine-4-base-phenyl of 3-)-azoles alkane-2-ketone, obtain title compound.
Method D
General step according to method C also carries out nonessential change, but with (S)-5-{ [(4-tert.-butoxy-benzylidene)-amino]-methyl }-3-(3-fluoro-4-morpholine-4-base-phenyl)-azoles alkane-2-ketone (embodiment 9) replacement (S)-5-{ [(4-methoxyl group-benzylidene)-amino]-methyl }-3-(the fluoro-4-morpholine-4-base-phenyl of 3-)-azoles alkane-2-ketone, obtain title compound.
The preparation of the chloro-3-of embodiment 4 (S)-1-[(4-oxyethyl group-E-benzylidene)-amino]-propyl-2-alcohol
4-ethoxy-benzaldehyde (30.0g is added successively to being equipped with in the 250ml tri-neck round-bottomed flask of mechanical stirring, reflux exchanger and heating in water bath pot, 0.20mol, 1.0 equivalents), THF(60ml), ammoniacal liquor (26.0wt%, 19.6g, 0.30mol, 1.5 equivalents), stir after 10 minutes, add S-epoxy chloropropane (18.5g, 0.20mol, 1.0 equivalents), it is heated to 40 DEG C. Stirring reaction 3 hours at the temperature of 35 ~ 40 DEG C, the S-epoxy chloropropane of now GC display residue 0.51 area %. To cumulative volume, mixture vacuum concentration being about 40ml, crystallisation by cooling, collecting precipitation thing, drying under reduced pressure solid 5 hours at the temperature of 40 DEG C, obtain the title compound 35.3g of white crystalline solid, receipts rate 73%.
Embodiment 5 (S)-5-{ [(4-oxyethyl group-benzylidene)-amino]-methyl } preparation of-3-(the fluoro-4-morpholine-4-base-phenyl of 3-)-azoles alkane-2-ketone
In (fluoro-4-morpholine-4 bases-phenyl of 3-)-benzyl carbamate (10g, 30.3mmol, 1.0eq.), add trimethyl carbinol lithium (7.3g, 91.2mmol, 3.0eq.), add MTBE(40ml afterwards), at room temperature it is uniformly mixed thing. In the suspension of gained, disposable adding is dissolved in MTBE(30ml) in the chloro-3-of (S)-1-[(4-oxyethyl group-E-benzylidene)-amino]-propyl-2-alcohol (14.6g, 60.4mmol, 2.0eq.). The dilute suspension of gained is heated to backflow (about 55 DEG C) keep 4 hours. After reaction solution is cooled to room temperature, washs organic layer with water (1 �� 50mL, 1 �� 30ml), then abandon these Aqueous wash things. Organic phase is dry by anhydrous sodium sulphate (2g), to filter, filtrate concentrates to dry. Add methyl alcohol (30ml), it is cooled to 0 ~ 5 DEG C of crystallization, filters out crystallization, then vacuum-drying at the temperature of 50 DEG C, obtain the title compound 10.6g of off-white color solid crystal powder, receipts rate 82%.1HNMR(500MHz,CDCl3)��1.32(t,J=2Hz,3H),3.05(t,J=4Hz,4H),3.87(t,J=4.5Hz,4H),3.90(s,1H),3.95(dd,J=13,5Hz,1H),4.04(m,1H),4.08(dd,J=2,4Hz,2H),4.12(t,J=8.5Hz,1H),4.93(dt,J=13.5,5.5Hz,1H),6.91(m,2H),6.94(s,1H),7.13(m,1H),7.45(dd,J=15,3Hz,1H),7.64(d,J=8Hz,2H),8.32(s,1H);13CNMR(500MHz,CDCl3)��14.80,48.47,51.20,63.39,64.60,67.12,72.09,107.60(d,J=104.5Hz),114.30,118.93,128.67,129.42,133.22,133.71,136.35(d,J=17.5Hz),154.74,156.64,162.20,163.02.��
The preparation of the chloro-3-of embodiment 6 (S)-1-[(4-isopropoxy-E-benzylidene)-amino]-propyl-2-alcohol
4-isopropoxide benzaldehyde (36.1g is added successively to being equipped with in the 250ml tri-neck round-bottomed flask of mechanical stirring, reflux exchanger and heating in water bath pot, 0.22mol, 1.1 equivalents), dehydrated alcohol (70ml), ammoniacal liquor (26.0wt%, 19.6g, 0.3mol, 1.5 equivalents), stir after 10 minutes, add S-epoxy chloropropane (18.5g, 0.20mol, 1.0 equivalents), it is heated to 40 DEG C. Stirring reaction 3 hours at the temperature of 35 ~ 40 DEG C, the S-epoxy chloropropane of now GC display residue 0.11 area %. To cumulative volume, mixture vacuum concentration being about 40ml, crystallisation by cooling, collecting precipitation thing, drying under reduced pressure solid 5 hours at the temperature of 40 DEG C, obtain the title compound 36.3g of off-white color crystalline solid, receipts rate 71%.
Embodiment 7 (S)-5-{ [(4-isopropoxy-benzylidene)-amino]-methyl } preparation of-3-(the fluoro-4-morpholine-4-base-phenyl of 3-)-azoles alkane-2-ketone
In (fluoro-4-morpholine-4 bases-phenyl of 3-)-benzyl carbamate (10g, 30.3mmol, 1.0eq.), add trimethyl carbinol lithium (5.6g, 70.0mmol, 2.3eq.), add methylene dichloride (40ml) afterwards, be at room temperature uniformly mixed thing. Disposable in the suspension of gained add the chloro-3-of (S)-1-[(4-isopropoxy-E-benzylidene)-the amino]-propyl-2-alcohol (10.1g, 39.5mmol, 1.3eq.) being dissolved in methylene dichloride (20ml). The dilute suspension of gained is heated to backflow (about 41 DEG C) keep 4 hours. After reaction solution is cooled to room temperature, washs organic layer with water (1 �� 50ml, 1 �� 30ml), then abandon these Aqueous wash things. Organic phase is dry by anhydrous sodium sulphate (3g), to filter, filtrate concentrates to dry. Add Virahol (30mL), it is cooled to 5 ~ 10 DEG C of crystallizations, filters out crystallization, then vacuum-drying at the temperature of 50 DEG C, obtain the title compound 11.4g of off-white color solid crystal powder, receipts rate 85%.1HNMR(500MHz,CDCl3)��1.34(d,J=2Hz,6H),3.05(t,J=4Hz,4H),3.86(t,J=4.5Hz,4H),3.88(s,1H),3.96(dd,J=13,5Hz,1H),4.02(m,1H),4.13(t,J=8.5Hz,1H),4.72(m,J=2Hz,1H),4.94(dt,J=13.5,5.5Hz,1H),6.91(m,2H),6.94(s,1H),7.14(m,1H),7.45(dd,J=15,3Hz,1H),7.62(d,J=8Hz,2H),8.36(s,1H);13CNMR(500MHz,CDCl3)��22.01,48.47,51.20,63.39,67.12,72.09,75.82,107.60(d,J=104.5Hz),114.30,118.93,128.67,129.42,133.22,133.71,136.35(d,J=17.5Hz),154.74,156.64,161.02,162.21��
The preparation of the chloro-3-of embodiment 8 (S)-1-[(4-tert.-butoxy-E-benzylidene)-amino]-propyl-2-alcohol
4-tert.-butoxy phenyl aldehyde (39.2g is added successively to being equipped with in the 1L tri-neck round-bottomed flask of mechanical stirring, reflux exchanger and heating in water bath pot, 0.22mol, 1.1 equivalents), THF(70ml), ammoniacal liquor (26.0wt%, 19.6g, 0.3mol, 1.5 equivalents), stir after 10 minutes, add S-epoxy chloropropane (18.5g, 0.20mol, 1.0 equivalents), it is heated to 40 DEG C. Stirring reaction 4 hours at the temperature of 35 ~ 40 DEG C, the S-epoxy chloropropane of now GC display residue 0.81 area %. To cumulative volume, mixture vacuum concentration being about 40ml, crystallisation by cooling, collecting precipitation thing, drying under reduced pressure solid 5 hours at the temperature of 40 DEG C, obtain the title compound 37.2g of off-white color crystalline solid, receipts rate 69%.
Embodiment 9 (S)-5-{ [(4-tert.-butoxy-benzylidene)-amino]-methyl } preparation of-3-(the fluoro-4-morpholine-4-base-phenyl of 3-)-azoles alkane-2-ketone
In (fluoro-4-morpholine-4 bases-phenyl of 3-)-benzyl carbamate (10g, 30.3mmol, 1.0eq.), add trimethyl carbinol lithium (5.4.g, 67.5mmol, 2.2eq.), add methylene dichloride (40ml) afterwards, be at room temperature uniformly mixed thing. Disposable in the suspension of gained add the chloro-3-of (S)-1-[(4-tert.-butoxy-E-benzylidene)-the amino]-propyl-2-alcohol (9.8g, 36.3mmol, 1.2eq.) being dissolved in methylene dichloride (20ml). The dilute suspension of gained is heated to backflow (about 41 DEG C) keep 4 hours. After reaction solution is cooled to room temperature, washs organic layer with water (1 �� 50ml, 1 �� 30ml), then abandon these Aqueous wash things. Organic phase is dry by anhydrous sodium sulphate (3g), to filter, filtrate concentrates to dry. Add Virahol (30ml), it is cooled to 0 ~ 5 DEG C of crystallization, filters out crystallization, then vacuum-drying at the temperature of 50 DEG C, obtain the title compound 12.3g of off-white color solid crystal powder, receipts rate 89%.1HNMR(500MHz,CDCl3)��1.40(s,9H),3.05(t,J=4Hz,4H),3.86(t,J=4.5Hz,4H),3.90(s,1H),3.97(dd,J=13,5Hz,1H),4.04(m,1H),4.14(t,J=8.5Hz,1H),4.94(dt,J=13.5,5.5Hz,1H),6.91(m,2H),6.94(s,1H),7.13(m,1H),7.45(dd,J=15,3Hz,1H),7.64(d,J=8Hz,2H),8.38(s,1H);13CNMR(500MHz,CDCl3)��27.80,48.47,51.20,63.39,67.12,72.09,78.01,107.60(d,J=104.5Hz),114.30,118.93,128.67,129.42,133.22,133.71,136.35(d,J=17.5Hz),154.74,156.64,161.02,162.21��
Claims (12)
1. a compound, its structural formula is as shown in I:
Wherein R1For C1��C4Alkoxyl group.
2. compound as claimed in claim 1, it is (S)-5-{ [(4-methoxyl group-benzylidene)-amino]-methyl }-3-(the fluoro-4-morpholine-4-base-phenyl of 3-)-azoles alkane-2-ketone.
3. compound as claimed in claim 1, it is (S)-5-{ [(4-oxyethyl group-benzylidene)-amino]-methyl }-3-(the fluoro-4-morpholine-4-base-phenyl of 3-)-azoles alkane-2-ketone.
4. compound as claimed in claim 1, it is (S)-5-{ [(4-isopropoxy-benzylidene)-amino]-methyl }-3-(the fluoro-4-morpholine-4-base-phenyl of 3-)-azoles alkane-2-ketone.
5. compound as claimed in claim 1, it is (S)-5-{ [(4-tert.-butoxy-benzylidene)-amino]-methyl }-3-(the fluoro-4-morpholine-4-base-phenyl of 3-)-azoles alkane-2-ketone.
6. the preparation method of compound described in a claim 1, it is characterized in that, in the presence of an organic base, structural formula II compound and formula II I are obtained by reacting structural formula I in aprotic solvent, temperature of reaction is 0 ~ 100 DEG C, described organic bases is the organic bases that pKa is greater than 12, and synthetic route is as follows:
Wherein R1For C1��C4Alkoxyl group, R2For benzyl or C1-8Alkyl.
7. preparation method, wherein R as claimed in claim 62For benzyl or the tertiary butyl.
8. preparation method as claimed in claim 6, wherein the molar ratio of structural formula II compound and structural formula III compound is 0.1:1-10:1, and the molar ratio of organic bases and structural formula III compound is 0.1:1-10:1.
9. preparation method as claimed in claim 6, it is characterised in that the molar ratio of structural formula II compound and structural formula III compound is 1:1-2:1, and the molar ratio of organic bases and structural formula III compound is 2:1-3:1.
10. preparation method as claimed in claim 6, it is characterised in that described organic bases is trimethyl carbinol lithium.
11. preparation methods as claimed in claim 6, it is characterised in that described aprotic solvent is methyl tertiary butyl ether or methylene dichloride.
12. preparation methods as claimed in claim 6, it is characterised in that temperature of reaction is 40-55 DEG C.
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