CN103923030B - Synthesis method of key intermediate of anacetrapib - Google Patents

Synthesis method of key intermediate of anacetrapib Download PDF

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CN103923030B
CN103923030B CN201410118643.6A CN201410118643A CN103923030B CN 103923030 B CN103923030 B CN 103923030B CN 201410118643 A CN201410118643 A CN 201410118643A CN 103923030 B CN103923030 B CN 103923030B
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compound
key intermediate
dissolved
reduced pressure
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CN103923030A (en
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冯汝洁
吴毅武
贝荣丙
陈海龙
施涯邻
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TUOBIN PHARMACENTICAL FACTORY SHANTOU ECOMOMIC SPECIAL ZONE
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    • 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
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms

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Abstract

The invention discloses a synthesis method of a key intermediate of anacetrapib. The synthesis method comprises the steps: making 3,5-bi(trifluoromethyl) benzaldehyde as a raw material perform a witting reaction with ethyltriphenylphosphonium bromide to obtain a mixture, performing inversion of configuration on the mixture under the illumination in the presence of an iodine elementary substance of a catalytic amount to obtain a transform product (I-2); performing Shi-dissymmetry epoxidation on the transform product (I-2) to obtain a compound (I-3); performing hydrolysis and ring opening on the compound (I-3) under an acidic condition, and then reacting under an alkaline condition to obtain a transform product (I-4); substituting the compound (I-4) by sodium azide, and performing inversion of configuration, performing hydrogenation reduction in the presence of Pd/C into an amino group, salifying with a feasible acid to obtain a compound (I-5); and performing ring closing on the compound (I-5) and triphosgene to obtain the key intermediate of anacetrapib. The synthesis method has the advantages of simplicity in operation, availability in raw materials, no need of purification of the intermediate, high yield, and environmental friendliness, and is easy to post-process, and suitable for large-scale production.

Description

The synthetic method of the key intermediate that a kind of Ansai is bent
Technical field
The invention belongs to chemosynthesis technical field, particularly one synthesis Ansai bent (Anacetrapib) and the method for intermediate.
Background technology
Bent of Ansai, English name: Anacetrapib, chemical name is (4S, 5R)-5-[3,5-bis-(trifluoromethyl) phenyl]-3-[[2-(the fluoro-2-methoxyl group of 4--5-third-2-base phenyl)-5-(trifluoromethyl) phenyl] methyl]-4-methyl isophthalic acid, 3-oxazolidine-2-ketone), (CAS No:875446-37-0), molecular formula: C 30h 25f 10nO 3, molecular weight: 637.51, structural formula is as follows:
Bent (Anacetrapib) is the orally active small molecules (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides selectivity CETP inhibitor researched and developed by Merck company in Ansai, is used for the treatment of atherosclerosis, coronary heart disease etc.Show with the clinical study that healthy volunteer and hyperlipemic patients are object, the lipid level of bent of Ansai (Anacetrapib) energy safety, effectively adjustment coronary heart disease and coronary heart disease high-risk patient, and to untoward reaction patient tolerance.Cardiovascular and cerebrovascular diseases is the disease of a class serious harm human health.In recent years, along with people's living habit and the change of dietary structure, the quickening of work rhythm, the sickness rate of cardiovascular and cerebrovascular diseases and case fatality rate are all in the situation that significantly rises.Atherosclerosis is the main pathological basis of cardiovascular and cerebrovascular diseases, causes the factor of atherosclerosis and coronary heart disease a lot, wherein lipid metabolism disorders particularly outstanding and the earliest be familiar with by people.Adjustment blood lipid level can slow down the process of coronary heart disease, obviously reduces Incidence of CHD.A series of extensive prospective clinical trial research confirms, application lipid-regulation medicine reduces total plasma cholesterol or LDL-C (LDL-C), significantly can reduce sickness rate and the case fatality rate of atherosclerosis and coronary heart disease.Adjust fat to have multiple method, pharmacological agent is one of most important means.Lipid lowering agent is of a great variety, can be divided into cholic acid integrated agent (QUESTRAN, cholestipol, divistyramine etc.), hydroxy-methyl-glutaryl coenzyme A reductase inhibitor (statins), nicotinic acid and derivative (Olbetam) thereof, the special class (fenofibrate, gemfibrozil etc.) of shellfish by chemical structure.At present, reduce LDL and remain the essential therapeutic arsenals reducing cardiovascular disorder harm.HMG CoA reductase inhibitor effectively can reduce LDL, but it exists the high risk drawback of cardiovascular event, makes patient be difficult to accept.Dysregulation blood fat new mechanism has been found in the research to lipid metabolism approach---cholesteryl ester transfer protein (CETP) inhibitor.CETP is a kind of plasma proteins, can promote exchange and the transhipment of lipid between each lipoprotein, completes and promotes to act as important role in reverse cholesterol process.
Patent WO2006014413 reports the route that is linearly synthesized Ansai bent (Anacetrapib), and total recovery is low; Other documents and patent mainly synthesize bent of Ansai with convergence type, and comprise the synthesis of crucial segment A and segment B, synthetic route is as follows:
Convergence type synthesis as described in WO2007005572, synthetic route is as follows, and be shown as best synthetic method, wherein segment B is prepared from 1-(the fluoro-4-p-methoxy-phenyl of 2-) ethyl ketone (1), need the method for three steps, obtain the bromo-4-of 1-fluoro-5-sec.-propyl-2-anisole (5):
Wherein the multiple method of the synthesis of Segment A sees bibliographical information.As described in WO2007005572, the synthesis of Segment A for starting raw material, obtains acid amides (8) with the condensation of weinreb amine hydrochlorate with CBZ-L-L-Ala (7), with 3, two (trifluoromethyl) bromobenzene of 5-is through grignard reaction, then in aluminum isopropylate reduction and cyclisation obtains segment A, synthetic route is as follows:
Although this synthetic method is simple, in its 3rd step reductive cyclization step, there is racemize oxazolone product to produce, cause yield on the low side.
As [1] such as Takanori Ogawa, with the neodymium/sodium asymmetric catalyst being carried on CNT (carbon nano-tube), asymmetry catalysis Henry reacts, and obtains trans product with e.e>99% highly selective.From 3,5-diiodo-benzene formaldehyde (10) sets out, obtain trans product (11) with nitroethane through asymmetric Henry reaction, close ring by triphosgene under zinc powder reduction, alkaline condition and obtain oxazolone (12), then trimethylammonium trifluoromethyl silane substituted obtains Segment A, synthetic route is as follows, there is following shortcoming in this synthetic method, catalyzer does not have commercialization, not easily obtains, and react at lesser temps (-60 DEG C), yield is lower, is difficult to realize industrialization.
As [2] such as Cameron J. Smith, with 3, two (trifluoromethyl) phenyl aldehyde (13) of 5-is starting raw material, racemic product (14) is obtained by reacting through Henry with nitroethane, Raney's nickel hydrogenation is amino nitroreduction, phosgene closes ring and obtains racemize oxazolone product (16) repeatedly, and separate cis and trans two by column chromatography and reflect isomer (17 and 18) to correspondence, synthetic route is as follows:
From the above mentioned, currently available technology not easily meets the intermediate of preparation high purity synthetic cholesterol transesterify albumen (CETP) inhibitor such as Ansai bent (Anacetrapib), so need development one new technology to overcome above-mentioned shortcoming.
Reference:
[1]. Angew. Chem. Int. Ed. 2013, 52, 6196 –6201；
[2]. J. Med. Chem. 2011, 54, 4880–4895。
Summary of the invention
The object of the invention is the above-mentioned shortcoming overcoming prior art, provide that a kind of operation is simple, raw material is easy to get, intermediate product without the need to purifying, aftertreatment is easy, productive rate is high, be suitable for the method for the key intermediate of the Ansai of suitability for industrialized production bent (Anacetrapib).
A synthetic method for the key intermediate that Ansai is bent, this key intermediate is 5-[3,5-bis-(trifluoromethyl) phenyl]-4-methyl isophthalic acid, 3-azoles alkane-2-ketone (A) comprise the following steps: with 3, two (trifluoromethyl) phenyl aldehyde (I-1) of 5-is raw material, there is witting with ethyltriphenylphosphonium bromide phosphine to react, because obtaining cis-trans isomerism than the mix products for 15:85, by the elemental iodine of mixture at catalytic amount, configuration reversal under illumination, high yield obtain compound (I-2); Compound (I-2), through Shi-asymmetric Epoxidation, obtains product (2R, 3S)-2-(two (trifluoromethyl) phenyl of 3,5-)-3-methyl cyclopropane (I-3) with e.e>99%; In acid condition, hydrolysis, then obtains trans product (I-4) with 4-Nitrobenzenesulfonyl chloride, methylsulfonyl chloride or p-methyl benzene sulfonic chloride to compound (I-3) in the basic conditions; Compound (I-4) is replaced by sodiumazide, and configuration reversal, be amino in Pd/C catalytic hydrogenating reduction, with feasibility acid salify, obtain (1R, 2S)-1-(3, two (trifluoromethyl) phenyl of 5-)-2-amino-1-propyl alcohol acid salt (I-5); Compound (I-5) and triphosgene close the key intermediate A that ring obtains bent of Ansai:
。
The concrete steps of the synthetic method of the key intermediate that above-mentioned Ansai is bent are:
Step a: reference literature CN 101029070, prepare triphenyl ethyl phosphonium bromide phosphine, for subsequent use, get triphenyl ethyl phosphonium bromide phosphine and be dissolved in quality and volume ratio (wherein, quality is in g, volume is in ml) be the anhydrous aprotic solvent a of 5 ~ 15 times, be cooled to-5 ~ 5 DEG C, add potassium tert.-butoxide, wherein avoid very exothermic, at being placed in 0 ~ 35 DEG C, stir, obtain dark red solution, holding temperature, be added dropwise to the anhydrous aprotic solvent a that the quality of compound (I-1) and volume ratio are 5 ~ 10 times, wherein compound (I-1): triphenyl ethyl phosphonium bromide phosphine: the mass ratio of potassium tert.-butoxide is 1:1.5 ~ 3.0:0.5 ~ 1.0, react complete, shrend is gone out reaction, organic solvent b extracts, organic layer uses water successively, saturated NaCl washing, dry, concentrating under reduced pressure, products therefrom is dissolved in the mixed solvent c that mass volume ratio is 5 ~ 15, add the iodine of catalytic amount again, configuration conversion under illumination, HPLC detects E/Z>99, then sodium thiosulfate solution process is used, organic layer is washed, saturated NaCl washing, dry, concentrating under reduced pressure obtains compound (I-2), this compound (I-2) is colorless oil,
；
Step b: in reactor, add compound (I-2), sodium borate buffer liquid, the tetrabutyl ammonium sulfate of catalytic amount and the Shi catalyzer of D-Fructose that step a obtains successively, wherein compound (I-2): the amount of substance of the shi-catalyzer of D-Fructose is than being 1:2.0, compound (I-2) is 1:40 ~ 100 with the mass volume ratio of sodium borate buffer liquid, is cooled to-5 ~ 5 DEG C.Drip concentration 0.13g/mL containing the sodium borate buffer liquid of Oxone and the wet chemical of concentration 0.12g/mL simultaneously, keep rate of addition consistent, wherein containing the sodium borate buffer liquid of Oxone and wet chemical volume and compound (I-2) than being 25 ~ 35, control rate of addition, react complete, normal heptane cancellation, organic solvent b extracts, and merges organic layer, washing, dry, concentrating under reduced pressure, gained compound (I-3), product is oily matter, directly drops into next step reaction;
；
Step c: above-claimed cpd (I-3) is dissolved in the mixed solvent d of 5 ~ 15 times of volumes, adding with the mass ratio of compound (I-3) under room temperature is the vitriol oil of 0.05 ~ 0.15, stirring reaction, complete, in mixture, add organic solvent b extract, organic layer 5 ~ 10% sodium bicarbonate aqueous solutions wash, washing, dry, concentrating under reduced pressure, residuum is dissolved in dry organic solvent e, be cooled to-10 DEG C ~ 0 DEG C, add triethylamine, stir and lower drip methylsulfonyl chloride or Tosyl chloride or to nitrosulfonyl chloride, dropwise, stir at 0 ~ 5 DEG C again, TLC detection reaction is complete, use 0.5M hydrochloric acid successively, water, 5 ~ 10% sodium bicarbonate aqueous solution washings, dry, concentrating under reduced pressure, residuum mixed solvent f recrystallization, obtaining product is white solid, i.e. compound (I-4),
；
Steps d: previous step gained compound (I-4) is dissolved in the organic solvent g of 5 ~ 20 times of volumes, add sodiumazide, wherein the quality of sodiumazide and the mass ratio of compound (I-4) are 0.14 ~ 0.30:1.0, be warming up to 40 ~ 50 DEG C of stirring reactions, react complete, add organic solvent b to extract, organic layer uses water successively, 5 ~ 10% sodium bicarbonate aqueous solutions, saturated NaCl washing, then the organic layer after washing is dry, concentrating under reduced pressure, residuum is dissolved in methyl alcohol, and use 10%pd/C catalysis, under 15 ~ 45psi, 35 ~ 45 DEG C of hydrogenating reductions, react complete, cross filtering pd/C, residuum concentrating under reduced pressure, obtain colorless oil, again colorless oil is dissolved in anhydrous organic solvent h, sour L equimolar with compound (I-4) is added under room temperature, stirring is spent the night, refilter collection solid, obtain the compound (I-5) of white crystals,
；
Step e: previous step gained compound (I-5) is dissolved in the organic solvent j of 10 ~ 50 times of volumes; be cooled to 0 ~ 5 DEG C; under argon shield; add diisopropyl ethyl amine and triphosgene successively; wherein compound (I-5): diisopropyl ethyl amine: mass ratio=1:1.0 ~ 3.0:0.3 ~ 0.5 of triphosgene keeps temperature; react complete; be evaporated to 1/2 of original volume; this mixture dilute with water; organic solvent b extracts, and merges organic layer, dry concentrating under reduced pressure; residuum mixed solvent k recrystallization, obtains key intermediate A:
。
Further, in described step a, aprotic solvent a is tetrahydrofuran (THF) or ether or dioxane or methylene dichloride, preferentially selects tetrahydrofuran (THF); Mixing solutions c be in normal hexane, heptane, ether, tetrahydrofuran (THF) any two or more, preferred normal hexane and ether mixtures, its ratio be 12 ~ 21, preferably 32.
Further, in described step a, b, c, d, e, organic solvent b is ethyl acetate or methylene dichloride or toluene, preferentially selects ethyl acetate, methylene dichloride.
Further, in described step b, containing 0.05M borax solution in sodium borate buffer liquid, 4 × 10 -4m Na 2eDTA.
Further, in described step c, mixing solutions d be in Isosorbide-5-Nitrae-diepoxy six alkane, water, tetrahydrofuran (THF) any two or more, the mixture of preferred Isosorbide-5-Nitrae-diepoxy six alkane and water, its ratio be 21 ~ 61, preferably 41; Mixed solvent f be in ethyl acetate, normal heptane, sherwood oil, Virahol any two or more, ethyl acetate and normal heptane, its ratio is 1/10 ~ 1/1, preferably 1/5.
Wherein, in described step c, organic solvent e is methylene dichloride or ethyl acetate or tetrahydrofuran (THF) or acetonitrile, preferred methylene dichloride.
Further, organic solvent g is DMF or dimethyl sulfoxide (DMSO), preferred DMF; Organic solvent h is methyl alcohol or ethanol or Virahol or methylene dichloride, particular methanol, ethanol; Acid L is the one in hydrochloric acid or sulfuric acid or oxalic acid or formic acid or acetic acid.
Further, in described step e, organic solvent j is methylene dichloride or ethyl acetate or tetrahydrofuran (THF) or acetonitrile, preferred methylene dichloride; Mixed solvent k be in methyl alcohol, ethanol, Virahol, hexane, normal heptane arbitrary two or more, preferred Virahol and normal heptane, its ratio is 1/10 ~ 1/1, preferably 1/4.
Further, in described step a, b, c, d, e, drying means is with anhydrous sodium sulphate, anhydrous magnesium sulfate drying.
The present invention compared with prior art, has following advantage and beneficial effect:
1, select raw material cheap and easy to get, cost is lower;
2, adopt chiral catalysis, target product can be obtained compared with highly selective, improve pharmaceutical purity;
3. operational path is more easy, and the more existing technique of production cost is low, can create significant economic worth.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
In following embodiment, nucleus magnetic resonance is by Bruker AMX-400 type nmr determination, and TMS is interior mark, and chemical shift unit is ppm; High performance liquid phase (HPLC) is detected by Agilent 1100; TLC silica-gel plate GF254 is that Haiyang Chemical Plant, Qingdao produces, and adopts ultraviolet lamp colour developing; If do not particularly point out working method in embodiment, described concentrating under reduced pressure refers to be steamed by the solvent prepared in compound solution with Rotary Evaporators; Described drying refers to anhydrous sodium sulphate or magnesium sulfate, and described vacuum-drying refers to prepare compound with vacuum-drying in vacuum drying oven.
Embodiment one
Step a:
Ph 3the preparation of PEtBr
Triphenylphosphine (200g, 0.76mol), is dissolved in toluene (600mL), adds monobromethane (200mL, 2.66mol), and then in 70 DEG C of stirring reactions 48 hours, gained solid petroleum ether, obtains white solid (240g, 85%) through vacuum-drying;
The preparation of I-2
The triphenyl ethyl phosphonium bromide phosphine (74.25g, 0.20mol) taking above-mentioned preparation is dissolved in anhydrous tetrahydro furan 375mL, is cooled to 0 DEG C, adds potassium tert.-butoxide (24g, 0.21mol), avoids very exothermic.Transposition stirred at ambient temperature 0.5 hour, obtains dark red solution.Be added dropwise to the anhydrous tetrahydrofuran solution 250mL containing two (trifluoromethyl) phenyl aldehyde (I-1) (36.3g, 0.15mol) of 3,5-under stirring, dropwise, stirring at room temperature, TLC monitoring reaction is complete, about 40 minutes.Under cooling, to go out reaction with 200mL shrend, to reacting not very exothermic.500mL × 3 extraction into ethyl acetate, merges organic layer, washs successively, anhydrous sodium sulfate drying with 300mL water, saturated aqueous common salt 300mL.Concentrating under reduced pressure, obtains oily matter, carries out next step out without purification.(oily matter detects Z/E=15/85 through HPLC.）
Gained oily matter is dissolved in normal hexane/ether (3/2) 500mL, adds 50mg iodine (catalytic amount), stir under illumination condition.Monitored by HPLC and be less than 1/99 to Z/E, in mixture, add sodium thiosulfate solution 150mL cancellation reaction.Separate organic layer, 200mL washing, the saturated NaCl washing of 200mL, anhydrous sodium sulfate drying.Concentrating under reduced pressure, obtains title compound, is colourless water oily matter 33g, yield 87%;
ESI -MS: [M+H] +=255.1
Nuclear magnetic resonance data: 1h-NMR (CDCl 3, 400MHz): δ (ppm)=7.53-7.50 (m, 3H), 6.42 (d, 1H, J=12.00Hz), 6.0 (q, 1H), 1.72 (d, 3H, J=4.2Hz);
Step b:
Preparation (2R, 3S)-2-(two (trifluoromethyl) phenyl of 3,5-)-3-methyl cyclopropane (I-3) (pH=10) is oxidized I-2;
In there-necked flask, add I-2(25.4g, 0.1mol successively), sodium borate buffer solution (0.05M borax solution, 4 × 10 -4m Na 2eDTA, 1L), 4-butyl ammonium hydrogen sulfate (1.35g, 4.0mmol), ketone D(51.6g, 0.2mol) (Shi's D-fructosederived catalyst) is cooled to 0 DEG C, is instilled sodium borate buffer solution (concentration 0.13g/ml) 700mL and K of Oxone by two constant pressure funnels in system simultaneously 2cO 3the aqueous solution (0.12g/mL) 700mL.The drop rate of two dropping funnels will be consistent and pH maintains 10, and controlling drop rate is drip off for 1.5 hours.Drip and namely react end.Skellysolve A 100mL cancellation is reacted, 3 × 500mL dichloromethane extraction, merges organic layer, washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, and products therefrom, without the need to purifying, directly carries out next step reaction.
ESI -MS: [M+H] +=271.1
Nuclear magnetic resonance data: 1h-NMR (CDCl 3, 400MHz): δ (ppm)=7.60 (m, H), 7.40 (m, 2H), 3.85 (d, 1H, J=8.60Hz), 3.09 (q, 1H), 1.32 (d, 3H, J=5.6Hz);
Step C
The preparation of I-4
(2R, 3S)-2-(3,5-two (trifluoromethyl) phenyl)-3-methyl cyclopropane (I-3) (51.3g, 0.19mol) is dissolved in Isosorbide-5-Nitrae-diepoxy six rings/water (4/1) 500mL, under room temperature, adds the dense H of 5mL 2sO 4, mixture is placed in stirred at ambient temperature, and TLC monitoring reaction is complete, about 30 minutes.In mixture, add 1L ethyl acetate, organic layer washs with 5% sodium bicarbonate 200mL, water 200mL successively, anhydrous sodium sulfate drying, concentrating under reduced pressure.Products therefrom directly carries out next program without purification.
By a upper program products therefrom (28.8g, 0.10mol) be dissolved in dry methylene dichloride 600mL, be cooled to-10 DEG C, slowly add triethylamine (18mL, 0.10mol), then 4-Nitrobenzenesulfonyl chloride (17.7g is dripped under stirring, 0.08mol), dropwise, in 0-5 DEG C of stirring reaction, TLC monitoring reaction is complete, about 2 hours.Successively with 0.5M hydrochloric acid 150mL, water 200mL, saturated sodium bicarbonate solution washing, organic layer anhydrous sodium sulfate drying.Concentrating under reduced pressure, the solution 500mL recrystallization of residuum ethyl acetate/normal heptane=1/5, obtains product 21.2g, yield 56%;
ESI -MS: [M+H] +=474.0
Nuclear magnetic resonance data: 1h-NMR (DMSO, 400MHz): δ (ppm)=8.55 (d, 2H, J=3.8Hz), 8.20 (d, 2H, J=4.2Hz), 7.56 (m, H), 7.39 (m, 2H), 5.45 (q, 1H), 4.61 (d, 1H, J=8.60Hz), 1.50 (d, 3H, J=8.0Hz);
Steps d
Preparation 2-amino-1-[3,5-bis-(trifluoromethyl) phenyl] third-1-alcohol oxalate (I-5)
By I-4(61.5g, 0.13mol) be dissolved in DMF 1L900mL, add NaN 3(11.4g, 0.175mol).Be warming up to 45 DEG C of stirrings, TLC monitors, and reacts complete, adds 2L ethyl acetate, washs successively, organic over anhydrous dried over sodium sulfate with 1L water 2 times, 5% sodium bicarbonate 1L, saturated aqueous common salt 1L.Concentrating under reduced pressure, residuum is dissolved in 800mL methyl alcohol, adds 10% pd/C 3.0g, and under 15Psi hydrogen, 40 DEG C are stirred 2 hours.React complete, cross filtering pd/C, residuum concentrating under reduced pressure, obtains colorless oil.Be dissolved in 580mL acetonitrile, add 11.7g oxalic acid under room temperature, stirring is spent the night.Collecting by filtration crystal, obtains title compound I-5, is white crystals 26.4g, yield 53.8%;
ESI -MS: [M+H] +=288.0
Nuclear magnetic resonance data: 1H-NMR (CDCl3,400MHz): δ (ppm)=7.78 (brs, 3H), 4.36 (br s, 1H), 3.23 (br s, 1H), 2.60 (br s, 3H), 0.83 (d, J=6.1Hz, 3H)
Step e
Preparation 5-[3,5-bis-(trifluoromethyl) phenyl]-4-methyl isophthalic acid, 3-azoles alkane-2-ketone A
Get 2-amino-1-[3,5-bis-(trifluoromethyl) phenyl] third-1-alcohol oxalate (I-5) (22.6g, 0.06mol) to be dissolved in anhydrous methylene chloride 1L, be cooled to 0 DEG C.Under argon shield, add diisopropylethylamine (62g, 0.48mol) and triphosgene (8.9g, 0.03mol) successively, by this reaction 0 DEG C of stirring.TLC monitoring reaction is complete, about 1 hour.Then vacuum concentration is to the volume of about 500mL.This mixture use water (2L) is diluted, extracts with EtOAc (3 × 1L).Merge organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure, gained crude product, with 200mL (Virahol/heptane=1/4) solution weight crystallization, obtaining title compound 14.0g, is white solid.Yield 75%;
ESI -MS: [M+H] +=314.1
Nuclear magnetic resonance data: 1h-NMR (CDCl 3, 400MHz): δ (ppm)=7.92 (brs, 1H), 7.80 (brs, 2H), 5.82 (d, J=8.0Hz, 1H), 5.36 (brs, 1H), 4.32 (br, J=7.0Hz, 1H), 0.82 (d, J=6.6Hz, 1H).
Embodiment two
Step a:
Ph 3the preparation of PEtBr
Triphenylphosphine (150g, 0.57mol), is dissolved in toluene (450mL), adds monobromethane (150mL, 2.0mol), and then in 70 DEG C of stirring reactions 48 hours, gained solid petroleum ether, obtains white solid (200g, 94%) through vacuum-drying;
The preparation of I-2
The triphenyl ethyl phosphonium bromide phosphine (37.1g, 0.10mol) taking above-mentioned preparation is dissolved in anhydrous tetrahydro furan 200mL, is cooled to 0 DEG C, adds potassium tert.-butoxide (13.5g, 0.12mol), avoids very exothermic.Transposition stirred at ambient temperature 50 minutes, obtains dark red solution.Be added dropwise to the anhydrous tetrahydrofuran solution 121mL containing two (trifluoromethyl) phenyl aldehyde (I-1) (24.2g, 0.10mol) of 3,5-under stirring, dropwise, stirring at room temperature, TLC monitoring reaction is complete, about 30 minutes.Under cooling, to go out reaction with 150mL shrend, to reacting not very exothermic.200mL × 3 extraction into ethyl acetate, merges organic layer, washs successively, anhydrous sodium sulfate drying with 100mL water, saturated aqueous common salt 100mL.Concentrating under reduced pressure, obtains oily matter, carries out next step out without purification.(oily matter detects Z/E=13/87 through HPLC.）
Gained oily matter is dissolved in normal hexane/ether (3/2) 200mL, adds 30mg iodine (catalytic amount), stir under illumination condition.Monitored by HPLC and be less than 1/99 to Z/E, in mixture, add sodium thiosulfate solution 100mL cancellation reaction.Separate organic layer, 100mL washing, the saturated NaCl washing of 100mL, anhydrous sodium sulfate drying.Concentrating under reduced pressure, obtains title compound, is colourless water oily matter 19g, yield 74.8%.
Structural identification data consistent with Example one
Step b:
Preparation (2R, 3S)-2-(two (trifluoromethyl) phenyl of 3,5-)-3-methyl cyclopropane (I-3) (pH=10) is oxidized I-2;
In there-necked flask, add I-2(15.2g, 0.06mol successively), sodium borate buffer solution (0.05M borax solution, 4 × 10 -4m Na 2eDTA, 1L), 4-butyl ammonium hydrogen sulfate (814mg, 2.4mmol), ketone D(31g, 0.12mol) (Shi's D-fructosederived catalyst) is cooled to 0 DEG C, is instilled sodium borate buffer solution (concentration 0.13g/ml) 532mL and K of Oxone by two constant pressure funnels in system simultaneously 2cO 3the aqueous solution (0.12g/mL) 532mL.The drop rate of two dropping funnels will be consistent and pH maintains 10, and controlling drop rate is drip off for 1.5 hours.Drip and namely react end.Skellysolve A 100mL cancellation is reacted, 3 × 300mL dichloromethane extraction, merges organic layer, washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, and products therefrom, without the need to purifying, directly carries out next step reaction.
Structural identification data consistent with Example one
Step C
The preparation of I-4
(2R, 3S)-2-(3,5-two (trifluoromethyl) phenyl)-3-methyl cyclopropane (I-3) (27g, 0.10mol) is dissolved in Isosorbide-5-Nitrae-diepoxy six rings/water (4/1) 300mL, under room temperature, adds the dense H of 2mL 2sO 4, mixture is placed in stirred at ambient temperature, and TLC monitoring reaction is complete, about 50 minutes.In mixture, add 1L methylene dichloride, organic layer washs with 5% sodium bicarbonate 100mL, water 100mL successively, anhydrous magnesium sulfate drying, concentrating under reduced pressure.Products therefrom directly carries out next program without purification.
By a upper program products therefrom (17.3g, 0.06mol) be dissolved in dry methylene dichloride 350mL, be cooled to-10 DEG C, slowly add triethylamine (10mL, 0.07mol), then Methanesulfonyl chloride (5.7g is dripped under stirring, 0.05mol), dropwise, in 0-5 DEG C of stirring reaction, TLC monitoring reaction is complete, about 3 hours.Wash with 0.5M hydrochloric acid 100mL, water 150mL, 5% sodium hydrogen carbonate solution 100mL successively, organic layer anhydrous sodium sulfate drying.Concentrating under reduced pressure, the solution 300mL recrystallization of residuum ethyl acetate/normal heptane=1/5, obtains product 11.0g, yield 60.0%;
ESI -MS: [M+H] +=367.1
Steps d
Preparation 2-amino-1-[3,5-bis-(trifluoromethyl) phenyl] third-1-alcohol oxalate (I-5)
By I-4(36.6g, 0.10mol) be dissolved in DMF 486mL, add NaN 3(9.7g, 0.15mol).Be warming up to 50 DEG C of stirrings, TLC monitors, and reacts complete, adds 1.6L ethyl acetate, washs successively, organic over anhydrous dried over sodium sulfate with 800mL water 2 times, 5% sodium bicarbonate 800mL, saturated aqueous common salt 800mL.Concentrating under reduced pressure, residuum is dissolved in 800mL ethanol, adds 10% pd/C 3.0g, and under 30Psi hydrogen, 40 DEG C are stirred 1 hour.React complete, cross filtering pd/C, residuum concentrating under reduced pressure, obtains colorless oil.Be dissolved in 560mL acetonitrile, add 9.0g oxalic acid under room temperature, stirring is spent the night.Collecting by filtration crystal, obtains title compound I-5, is white crystals 24.0g, yield 63.7%.
Structural identification data consistent with Example one
Step e
Preparation 5-[3,5-bis-(trifluoromethyl) phenyl]-4-methyl isophthalic acid, 3-azoles alkane-2-ketone (A)
Get 2-amino-1-[3,5-bis-(trifluoromethyl) phenyl] third-1-alcohol oxalate (I-5) (37.7g, 0.1mol) to be dissolved in anhydrous methylene chloride 1.8L, be cooled to-5 DEG C.Under argon shield, add diisopropylethylamine (103.4g, 0.8mol) and triphosgene (14.8g, 0.05mol) successively, by this reaction-5 DEG C of stirrings.TLC monitoring reaction is complete, about 1.5 hours.Then vacuum concentration is to the volume of about 1000mL.This mixture use water (3L) is diluted, extracts with EtOAc (3 × 1.5L).Merge organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure, gained crude product, with 400mL (Virahol/heptane=1/4) solution weight crystallization, obtaining title compound 23.0g, is white solid.Yield 73.4%.
Structural identification data consistent with Example one
Embodiment three
Step a:
Ph 3the preparation of PEtBr
Triphenylphosphine (300g, 1.14mol), is dissolved in toluene (900mL), adds monobromethane (300mL, 4.0mol), and then in 70 DEG C of stirring reactions 48 hours, gained solid petroleum ether, obtains white solid (370g, 87%) through vacuum-drying;
The preparation of I-2
The triphenyl ethyl phosphonium bromide phosphine (74.25g, 0.20mol) taking above-mentioned preparation is dissolved in anhydrous tetrahydro furan 1100mL, is cooled to 5 DEG C, adds potassium tert.-butoxide (29g, 0.26mol), avoids very exothermic.Transposition stirred at ambient temperature 1.0 hours, obtains dark red solution.Be added dropwise to the anhydrous tetrahydrofuran solution 322mL containing two (trifluoromethyl) phenyl aldehyde (I-1) (32.2g, 0.133mol) of 3,5-under stirring, dropwise, stirring at room temperature, TLC monitoring reaction is complete, about 60 minutes.Under cooling, to go out reaction with 200mL shrend, to reacting not very exothermic.500mL × 3 extraction into ethyl acetate, merges organic layer, washs successively, anhydrous sodium sulfate drying with 300mL water, saturated aqueous common salt 300mL.Concentrating under reduced pressure, obtains oily matter, carries out next step out without purification.(oily matter detects Z/E=17/83 through HPLC.）
Gained oily matter is dissolved in normal hexane/ether (3/2) 600mL, adds 60mg iodine (catalytic amount), stir under illumination condition.Monitored by HPLC and be less than 1/99 to Z/E, in mixture, add sodium thiosulfate solution 100mL cancellation reaction.Separate organic layer, 150mL washing, the saturated NaCl washing of 150mL, anhydrous sodium sulfate drying.Concentrating under reduced pressure, obtains title compound, is colourless water oily matter 29g, yield 85.7%.
Structural identification data consistent with Example one
Step b:
Preparation (2R, 3S)-2-(two (trifluoromethyl) phenyl of 3,5-)-3-methyl cyclopropane (I-3) (pH=10) is oxidized I-2;
In there-necked flask, add I-2(5.0g, 0.02mol successively), sodium borate buffer solution (0.05M borax solution, 4 × 10 -4m Na 2eDTA, 800mL), 4-butyl ammonium hydrogen sulfate (339mg, 1.0mmol), ketone D(10.3g, 0.04mol) (Shi's D-fructosederived catalyst) is cooled to 0 DEG C, is instilled sodium borate buffer solution (concentration 0.13g/ml) 150mL and K of Oxone by two constant pressure funnels in system simultaneously 2cO 3the aqueous solution (0.12g/mL) 150mL.The drop rate of two dropping funnels will be consistent and pH maintains 10, and controlling drop rate is drip off for 1.5 hours.Drip and namely react end.Skellysolve A 30mL cancellation is reacted, 3 × 100mL dichloromethane extraction, merges organic layer, washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, and products therefrom, without the need to purifying, directly carries out next step reaction.
Structural identification data consistent with Example one
Step C
The preparation of I-4
(2R, 3S)-2-(3,5-two (trifluoromethyl) phenyl)-3-methyl cyclopropane (I-3) (32.4g, 0.12mol) is dissolved in tetrahydrofuran (THF)/water (4/1) 500mL, under room temperature, adds the dense H of 4mL 2sO 4, mixture is placed in stirred at ambient temperature, and TLC monitoring reaction is complete, about 50 minutes.In mixture, add 750mL ethyl acetate, organic layer washs with 5% sodium bicarbonate 150mL, water 150mL successively, anhydrous sodium sulfate drying, concentrating under reduced pressure.Products therefrom directly carries out next program without purification.
By a upper program products therefrom (28.8g, 0.10mol) be dissolved in dry methylene dichloride 800mL, be cooled to-5 DEG C, slowly add triethylamine (27mL, 0.15mol), then p-methyl benzene sulfonic chloride (19.0g is dripped under stirring, 0.10mol), dropwise, in 5 DEG C of stirring reactions, TLC monitoring reaction is complete, about 3.5 hours.Successively with 0.5M hydrochloric acid 250mL, water 300mL, saturated sodium bicarbonate solution washing, organic layer anhydrous sodium sulfate drying.Concentrating under reduced pressure, the solution 450mL recrystallization of residuum ethyl acetate/normal hexane=1/5, obtains product 33g, yield 74.6%;
ESI -MS: [M+H] +=443.1
Steps d
Preparation 2-amino-1-[3,5-bis-(trifluoromethyl) phenyl] third-1-alcohol oxalate (I-5)
By I-4(20g, 45.2mmol) be dissolved in DMF 300mL, add NaN 3(2.94g, 45.2mmol).Be warming up to 40 DEG C of stirrings, TLC monitors, and reacts complete, about 2 hours.In mixture, add 500mL ethyl acetate, wash with 300mL water 2 times, 5% sodium bicarbonate 300mL, saturated aqueous common salt 300mL successively, organic over anhydrous dried over sodium sulfate.Concentrating under reduced pressure, residuum is dissolved in 200mL methyl alcohol, adds 10% pd/C 1.0g, and under 30Psi hydrogen, 45 DEG C are stirred 3 hours.React complete, cross filtering pd/C, residuum concentrating under reduced pressure, obtains colorless oil.Be dissolved in 128mL acetonitrile, add 4.0g oxalic acid under room temperature, stirring is spent the night.Collecting by filtration crystal, obtains title compound I-5, is white crystals 8.5g, yield 49.8%.
Structural identification data consistent with Example one
Step e
Preparation 5-[3,5-bis-(trifluoromethyl) phenyl]-4-methyl isophthalic acid, 3-azoles alkane-2-ketone (A)
Get 2-amino-1-[3,5-bis-(trifluoromethyl) phenyl] third-1-alcohol oxalate (I-5) (30.2g, 0.08mol) to be dissolved in anhydrous methylene chloride 1.5L, be cooled to 5 DEG C.Under argon shield, add diisopropylethylamine (83g, 0.64mol) and triphosgene (11.8g, 0.04mol) successively, this is reacted on 5 DEG C of stirrings.TLC monitoring reaction is complete, about 2 hours.Then vacuum concentration is to the volume of about 750mL.This mixture use water (1.5L) is diluted, extracts with EtOAc (3 × 1L).Merge organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure, gained crude product, with 300mL (Virahol/heptane=1/4) solution weight crystallization, obtaining title compound 18.0g, is white solid.Yield 71.8%.
Structural identification data consistent with Example one.
Embodiment four
A synthetic method for the key intermediate that Ansai is bent, comprises the following steps:
Step a: get triphenyl ethyl phosphonium bromide phosphine and be dissolved in the dioxane that quality and volume ratio are 5 times, wherein, quality is in g, volume is in ml, be cooled to-5 DEG C, add potassium tert.-butoxide, wherein avoid very exothermic, at being placed in 0 DEG C, stir, obtain dark red solution, holding temperature, be added dropwise to the dioxane that the quality of compound (I-1) and volume ratio are 5 times, wherein compound (I-1): triphenyl ethyl phosphonium bromide phosphine: the mass ratio of potassium tert.-butoxide is 1:1.5:0.5, react complete, shrend is gone out reaction, dichloromethane extraction, organic layer uses water successively, saturated NaCl washing, dry, concentrating under reduced pressure, products therefrom is dissolved in the heptane that mass volume ratio is 5, add the iodine of catalytic amount again, configuration conversion under illumination, HPLC detects E/Z>99, then sodium thiosulfate solution process is used, organic layer is washed, saturated NaCl washing, dry, concentrating under reduced pressure obtains compound (I-2), this compound (I-2) is colorless oil,
；
Step b: in reactor, add successively compound (I-2) that step a obtains, sodium borate buffer liquid (containing 0.05M borax solution in sodium borate buffer liquid, 4 × 10 -4m Na 2eDTA), the tetrabutyl ammonium sulfate of catalytic amount and the Shi catalyzer of D-Fructose, wherein compound (I-2): the amount of substance of the shi-catalyzer of D-Fructose is than being 1:2.0, compound (I-2) is 1:40 with the mass volume ratio of sodium borate buffer liquid, is cooled to-5 DEG C.Drip concentration 0.13g/mL containing the sodium borate buffer liquid of Oxone and the wet chemical of concentration 0.12g/mL simultaneously, keep rate of addition consistent, wherein containing the sodium borate buffer liquid of Oxone and wet chemical volume and compound (I-2) than being 25, control rate of addition, react complete, normal heptane cancellation, dichloromethane extraction, merges organic layer, washing, dry, concentrating under reduced pressure, gained compound (I-3), product is oily matter, directly drops into next step reaction;
；
Step c: above-claimed cpd (I-3) is dissolved in 1 of 5 times of volumes, 4-diepoxy six alkane, water, in tetrahydrofuran (THF) mixed solution, adding with the mass ratio of compound (I-3) under room temperature is the vitriol oil of 0.05, stirring reaction, complete, dichloromethane extraction is added in mixture, organic layer 7% sodium bicarbonate aqueous solution washs, washing, dry, concentrating under reduced pressure, residuum is dissolved in dry ethyl acetate, be cooled to 0 DEG C, add triethylamine, stir and lower drip methylsulfonyl chloride or Tosyl chloride or to nitrosulfonyl chloride, dropwise, stir at 2 DEG C again, TLC detection reaction is complete, use 0.5M hydrochloric acid successively, water, 7% sodium bicarbonate aqueous solution washing, dry, concentrating under reduced pressure, residuum ethyl acetate, the mixed solution recrystallization of normal heptane, obtaining product is white solid, i.e. compound (I-4),
；
Steps d: previous step gained compound (I-4) is dissolved in the dimethyl sulfoxide (DMSO) of 5 times of volumes, add sodiumazide, wherein the quality of sodiumazide and the mass ratio of compound (I-4) are 0.14:1.0, be warming up to 45 DEG C of stirring reactions, react complete, add dichloromethane extraction, organic layer uses water successively, 7% sodium bicarbonate aqueous solution, saturated NaCl washing, then the organic layer after washing is dry, concentrating under reduced pressure, residuum is dissolved in methyl alcohol, and use 10%pd/C catalysis, under 15 ~ 45psi, 35 DEG C of hydrogenating reductions, react complete, cross filtering pd/C, residuum concentrating under reduced pressure, obtain colorless oil, again colorless oil is dissolved in anhydrous isopropyl alcohol, add under room temperature and compound (I-4) equimolar oxalic acid, stirring is spent the night, refilter collection solid, obtain the compound (I-5) of white crystals,
；
Step e: previous step gained compound (I-5) is dissolved in the ethyl acetate of 10 times of volumes; be cooled to 2 DEG C; under argon shield; add diisopropyl ethyl amine and triphosgene successively; wherein compound (I-5): diisopropyl ethyl amine: the mass ratio=1:1.0:0.3 of triphosgene keeps temperature; react complete; be evaporated to 1/2 of original volume; this mixture dilute with water; dichloromethane extraction, merges organic layer, dry concentrating under reduced pressure; residuum ethanol, Virahol mixed solution recrystallization, obtain key intermediate A:
。
In above-mentioned a, b, c, d, e, drying means is for using anhydrous sodium sulfate drying.
In the present embodiment, structural identification data consistent with Example one.
Embodiment five
A synthetic method for the key intermediate that Ansai is bent, is characterized in that comprising the following steps:
Step a: get triphenyl ethyl phosphonium bromide phosphine and be dissolved in the dioxane that quality and volume ratio are 15 times, wherein, quality is in g, volume is in ml, be cooled to 3 DEG C, add potassium tert.-butoxide, wherein avoid very exothermic, at being placed in 35 DEG C, stir, obtain dark red solution, holding temperature, be added dropwise to the dioxane that the quality of compound (I-1) and volume ratio are 10 times, wherein compound (I-1): triphenyl ethyl phosphonium bromide phosphine: the mass ratio of potassium tert.-butoxide is 1:3.0:1.0, react complete, shrend is gone out reaction, toluene extracts, organic layer uses water successively, saturated NaCl washing, dry, concentrating under reduced pressure, products therefrom is dissolved in the ether that mass volume ratio is 15, tetrahydrofuran (THF) mixed solution, add the iodine of catalytic amount again, configuration conversion under illumination, HPLC detects E/Z>99, then sodium thiosulfate solution process is used, organic layer is washed, saturated NaCl washing, dry, concentrating under reduced pressure obtains compound (I-2), this compound (I-2) is colorless oil,
；
Step b: in reactor, add successively compound (I-2) that step a obtains, sodium borate buffer liquid (containing 0.05M borax solution in sodium borate buffer liquid, 4 × 10 -4m Na 2eDTA), the tetrabutyl ammonium sulfate of catalytic amount and the Shi catalyzer of D-Fructose, wherein compound (I-2): the amount of substance of the shi-catalyzer of D-Fructose is than being 1:2.0, compound (I-2) is 1:100 with the mass volume ratio of sodium borate buffer liquid, is cooled to 5 DEG C.Drip concentration 0.13g/mL containing the sodium borate buffer liquid of Oxone and the wet chemical of concentration 0.12g/mL simultaneously, keep rate of addition consistent, wherein containing the sodium borate buffer liquid of Oxone and wet chemical volume and compound (I-2) than being 35, control rate of addition, react complete, normal heptane cancellation, toluene extracts, and merges organic layer, washing, dry, concentrating under reduced pressure, gained compound (I-3), product is oily matter, directly drops into next step reaction;
；
Step c: above-claimed cpd (I-3) is dissolved in 1 of 15 times of volumes, 4-diepoxy six alkane, water, in tetrahydrofuran (THF) mixed solution, adding with the mass ratio of compound (I-3) under room temperature is the vitriol oil of 0.15, stirring reaction, complete, toluene extraction is added in mixture, organic layer 10% sodium bicarbonate aqueous solution washs, washing, dry, concentrating under reduced pressure, residuum is dissolved in dry tetrahydrofuran (THF), be cooled to 0 DEG C, add triethylamine, stir and lower drip methylsulfonyl chloride or Tosyl chloride or to nitrosulfonyl chloride, dropwise, stir at 5 DEG C again, TLC detection reaction is complete, use 0.5M hydrochloric acid successively, water, 10% sodium bicarbonate aqueous solution washing, dry, concentrating under reduced pressure, residuum sherwood oil, Virahol mixed solution recrystallization, obtaining product is white solid, i.e. compound (I-4),
；
Steps d: N previous step gained compound (I-4) being dissolved in 20 times of volumes, in dinethylformamide, add sodiumazide, wherein the quality of sodiumazide and the mass ratio of compound (I-4) are 0.30:1.0, be warming up to 50 DEG C of stirring reactions, react complete, add toluene extraction, organic layer uses water successively, 7% sodium bicarbonate aqueous solution, saturated NaCl washing, then the organic layer after washing is dry, concentrating under reduced pressure, residuum is dissolved in methyl alcohol, and use 10%pd/C catalysis, under 15 ~ 45psi, 45 DEG C of hydrogenating reductions, react complete, cross filtering pd/C, residuum concentrating under reduced pressure, obtain colorless oil, again colorless oil is dissolved in methylene dichloride, add under room temperature and compound (I-4) equimolar acetic acid, stirring is spent the night, refilter collection solid, obtain the compound (I-5) of white crystals,
；
Step e: previous step gained compound (I-5) is dissolved in the ethyl acetate of 50 times of volumes; be cooled to 3 DEG C; under argon shield; add diisopropyl ethyl amine and triphosgene successively; wherein compound (I-5): diisopropyl ethyl amine: the mass ratio=1:3.0:0.5 of triphosgene keeps temperature; react complete; be evaporated to 1/2 of original volume; this mixture dilute with water; toluene extracts, and merges organic layer, dry concentrating under reduced pressure; residuum Virahol, hexane mixed solution recrystallization, obtain key intermediate A:
。
In above-mentioned a, b, c, d, e, drying means is for using anhydrous magnesium sulfate drying.
In the present embodiment, structural identification data consistent with Example one.
Above the technical scheme that the embodiment of the present invention provides is described in detail, apply specific case herein to set forth the principle of the embodiment of the present invention and embodiment, the explanation of above embodiment is only applicable to the principle helping to understand the embodiment of the present invention; Meanwhile, for one of ordinary skill in the art, according to the embodiment of the present invention, embodiment and range of application all will change, and in sum, this description should not be construed as limitation of the present invention.

Claims (10)

1. the synthetic method of the key intermediate of bent an of Ansai, this key intermediate is 5-[3,5-bis-(trifluoromethyl) phenyl]-4-methyl isophthalic acid, 3-azoles alkane-2-ketone (A), it is characterized in that: with 3, two (trifluoromethyl) phenyl aldehyde (I-1) of 5-is raw material, there is witting with ethyltriphenylphosphonium bromide phosphine to react, because obtaining cis-trans isomerism than the mix products for 15:85, by the elemental iodine of mixture at catalytic amount, configuration reversal under illumination, high yield obtain compound (I-2); Compound (I-2), through Shi-asymmetric Epoxidation, obtains product (2R, 3S)-2-(two (trifluoromethyl) phenyl of 3,5-)-3-methyl cyclopropane (I-3) with e.e>99%; In acid condition, hydrolysis, then obtains trans product (I-4) with 4-Nitrobenzenesulfonyl chloride to compound (I-3) in the basic conditions; Compound (I-4) is replaced by sodiumazide, and configuration reversal, be amino in Pd/C catalytic hydrogenating reduction, with feasibility acid salify, obtain (1S, 2R)-1-(two (trifluoromethyl) phenyl of 3,5-)-2-amino-1-propyl alcohol acid salt (I-5); Compound (I-5) and triphosgene close the key intermediate A that ring obtains bent of Ansai:
2. the synthetic method of the key intermediate of bent of a kind of Ansai according to claim 1, is characterized in that comprising the following steps:
Step a: get triphenyl ethyl phosphonium bromide phosphine and be dissolved in the anhydrous aprotic solvent a that quality and volume ratio are 5 ~ 15 times, wherein, quality is in g, volume is in ml, be cooled to-5 ~ 5 DEG C, add potassium tert.-butoxide, wherein avoid very exothermic, at being placed in 0 ~ 35 DEG C, stir, obtain dark red solution, holding temperature, be added dropwise to the anhydrous aprotic solvent a that the quality of compound (I-1) and volume ratio are 5 ~ 10 times, wherein compound (I-1): triphenyl ethyl phosphonium bromide phosphine: the mass ratio of potassium tert.-butoxide is 1:1.5 ~ 3.0:0.5 ~ 1.0, react complete, shrend is gone out reaction, organic solvent b extracts, organic layer uses water successively, saturated NaCl washing, dry, concentrating under reduced pressure, products therefrom is dissolved in the mixed solvent c that mass volume ratio is 5 ~ 15, add the iodine of catalytic amount again, configuration conversion under illumination, HPLC detects E/Z>99, then sodium thiosulfate solution process is used, organic layer is washed, saturated NaCl washing, dry, concentrating under reduced pressure obtains compound (I-2), this compound (I-2) is colorless oil,
Step b: in reactor, add the compound (I-2) that step a obtains successively, sodium borate buffer liquid, the tetrabutyl ammonium sulfate of catalytic amount and the Shi catalyzer of D-Fructose, wherein compound (I-2): the amount of substance of the shi-catalyzer of D-Fructose is than being 1:2.0, compound (I-2) is 1:40 ~ 100 with the mass volume ratio of sodium borate buffer liquid, be cooled to-5 ~ 5 DEG C, drip concentration 0.13g/mL containing the sodium borate buffer liquid of Oxone and the wet chemical of concentration 0.12g/mL simultaneously, keep rate of addition consistent, wherein containing the sodium borate buffer liquid of Oxone and wet chemical volume and compound (I-2) than being 25 ~ 35, control rate of addition, react complete, normal heptane cancellation, organic solvent b extracts, merge organic layer, washing, dry, concentrating under reduced pressure, gained compound (I-3), product is oily matter, next step reaction of direct input,
Step c: above-claimed cpd (I-3) is dissolved in the mixed solvent d of 5 ~ 15 times of volumes, adding with the mass ratio of compound (I-3) under room temperature is the vitriol oil of 0.05 ~ 0.15, stirring reaction, complete, in mixture, add organic solvent b extract, organic layer 5 ~ 10% sodium bicarbonate aqueous solutions wash, washing, dry, concentrating under reduced pressure, residuum is dissolved in dry organic solvent e, be cooled to-10 DEG C ~ 0 DEG C, add triethylamine, nitrobenzene sulfonyl chloride is dripped under stirring, dropwise, stir at 0 ~ 5 DEG C again, TLC detection reaction is complete, use 0.5M hydrochloric acid successively, water, 5 ~ 10% sodium bicarbonate aqueous solution washings, dry, concentrating under reduced pressure, residuum mixed solvent f recrystallization, obtaining product is white solid, i.e. compound (I-4),
Steps d: previous step gained compound (I-4) is dissolved in the organic solvent g of 5 ~ 20 times of volumes, add sodiumazide, wherein the quality of sodiumazide and the mass ratio of compound (I-4) are 0.14 ~ 0.30:1.0, be warming up to 40 ~ 50 DEG C of stirring reactions, react complete, add organic solvent b to extract, organic layer uses water successively, 5 ~ 10% sodium bicarbonate aqueous solutions, saturated NaCl washing, then the organic layer after washing is dry, concentrating under reduced pressure, residuum is dissolved in methyl alcohol, and use 10%pd/C catalysis, under 15 ~ 45psi, 35 ~ 45 DEG C of hydrogenating reductions, react complete, cross filtering pd/C, residuum concentrating under reduced pressure, obtain colorless oil, again colorless oil is dissolved in anhydrous organic solvent h, add under room temperature and compound (I-4) equimolar oxalic acid, stirring is spent the night, refilter collection solid, obtain the compound (I-5) of white crystals,
Step e: previous step gained compound (I-5) is dissolved in the organic solvent j of 10 ~ 50 times of volumes; be cooled to 0 ~ 5 DEG C; under argon shield; add diisopropyl ethyl amine and triphosgene successively; wherein compound (I-5): diisopropyl ethyl amine: mass ratio=1:1.0 ~ 3.0:0.3 ~ 0.5 of triphosgene keeps temperature; react complete; be evaporated to 1/2 of original volume; this mixture dilute with water; organic solvent b extracts, and merges organic layer, dry concentrating under reduced pressure; residuum mixed solvent k recrystallization, obtains key intermediate A:
3. the synthetic method of the key intermediate of bent of a kind of Ansai according to claim 2, to is characterized in that in described step a that aprotic solvent a is tetrahydrofuran (THF) or ether or dioxane or methylene dichloride; Mixing solutions c be in normal hexane, heptane, ether, tetrahydrofuran (THF) any two or more.
4. the synthetic method of the key intermediate of bent of a kind of Ansai according to claim 2, is characterized in that in described step a, b, c, d, e, and organic solvent b is ethyl acetate or methylene dichloride or toluene.
5. the synthetic method of the key intermediate of bent of a kind of Ansai according to claim 2, is characterized in that in described step b, containing 0.05M borax solution in sodium borate buffer liquid, and 4 × 10 -4m Na 2eDTA.
6. the synthetic method of the key intermediate of bent of a kind of Ansai according to claim 2, is characterized in that in described step c, mixing solutions d be in Isosorbide-5-Nitrae-diepoxy six alkane, water, tetrahydrofuran (THF) any two or more; Mixed solvent f be in ethyl acetate, normal heptane, sherwood oil, Virahol any two or more.
7. the synthetic method of the key intermediate of bent of a kind of Ansai according to claim 2, is characterized in that in described step c, and organic solvent e is methylene dichloride or ethyl acetate or tetrahydrofuran (THF) or acetonitrile.
8. the synthetic method of the key intermediate of bent of a kind of Ansai according to claim 2, it is characterized in that in described steps d, organic solvent g is DMF or dimethyl sulfoxide (DMSO); Organic solvent h is methyl alcohol or ethanol or Virahol or methylene dichloride.
9. the synthetic method of the key intermediate of bent of a kind of Ansai according to claim 2, is characterized in that in described step e, and organic solvent j is methylene dichloride or ethyl acetate or tetrahydrofuran (THF) or acetonitrile; Mixed solvent k be in methyl alcohol, ethanol, Virahol, hexane, normal heptane arbitrary two or more.
10. the synthetic method of the key intermediate of bent of a kind of Ansai according to claim 2, is characterized in that in described step a, b, c, d, e, drying means is for using anhydrous sodium sulphate, anhydrous magnesium sulfate drying.
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