CN103508918B - With the Alpha-hydroxy beta-amino ester compound and preparation method thereof of cyclobutyl - Google Patents

With the Alpha-hydroxy beta-amino ester compound and preparation method thereof of cyclobutyl Download PDF

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CN103508918B
CN103508918B CN201210200429.6A CN201210200429A CN103508918B CN 103508918 B CN103508918 B CN 103508918B CN 201210200429 A CN201210200429 A CN 201210200429A CN 103508918 B CN103508918 B CN 103508918B
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alkyl
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ethyl
methyl
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CN103508918A (en
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姚旻
袁哲东
杨玉雷
胡雪峰
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Shanghai Institute of Pharmaceutical Industry
Chia Tai Tianqing Pharmaceutical Group Co Ltd
China State Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Abstract

The invention provides a kind of Alpha-hydroxy beta-amino ester compound with cyclobutyl, open novel formula (1) compound of the present invention: wherein R 1for alkyl, aryl or aralkyl, R 2for alkyl.The present invention also discloses the preparation method of described formula (1) compound.Described compound can be used for the synthesis of anti-third liver medicine Boceprevir.

Description

With the Alpha-hydroxy beta-amino ester compound and preparation method thereof of cyclobutyl
Technical field
The present invention relates to pharmaceutical synthesis field, be specifically related to new Alpha-hydroxy beta-amino ester compound with cyclobutyl and preparation method thereof.Described compound can be used for the synthesis of anti-third liver medicine Boceprevir intermediate.
Background technology
In global range, the infection rate of hepatitis C virus (hepatitis C virus, HCV) is about 3%, and the total number of persons of infection is about 200,000,000.Due to HCV high infection rate and potential complication as serious in liver cirrhosis, liver cancer etc. can be caused, thus HCV is the threat that of human life's health is serious.According to Simmonds naming system, HCV can be divided into 6 main genotypes and I-VI, variously can be divided into again several hypotypes (as Ia, Ib, IIa, IIb, IIIa, IIIb etc.).The HCV infection person about 4,000 ten thousand of China, wherein 69% is I type infection (based on Ib type).Method mainly Peg-IFN alpha-2b (PEG-IFN α) and ribavirin (RBV) drug combination of current treatment chronic hepatitis C, this kind of therapy in HCV I type patient about 50% patient can not produce continued viral response, and have untoward reaction, thus need the effective medicine of exploitation badly.Due to this needs, HCV-Ab IgG new drug development is very active, has more than 50 planting HCV-Ab IgG drug candidate or grantedly carry out clinical trial at present.In these medicines, Victrelis (boceprevir) is treated Adult chronic hepatitis C by U.S. FDA approval with Peg-IFN alpha-2b and ribavirin coupling on May 13rd, 2011.The FDA officer in charge that is correlated with thinks that Victrelis is that this serious disease for the treatment of third liver provides a kind of effective ways, brings hope for curing the third liver.
Boceprevir (structure as above) is the chronic hepatitis C curative developed by Schering Plough company of the U.S., it is a kind of orally active HCV NS3 proteinase inhibitor, that systemic brachymemma and modification are carried out and the micromolecular inhibitor found to the amino-acid residue on a kind of 11 peptides of tool height NS3 inhibit activities, the Serine of NS3 reactive site can be caught, carbonyl carbon Serine combination formation covalent adduct therewith on its keto-amide, thus cause NS3 inactivation.The research being published in " New England Journal of Medicine " shows, for the past untreated chronic hcv genotype I type infected patient, Peg-IFN alpha-2b-ribavirin standard therapy basis add with Boceprevir, compared with simple standard care, can significantly increase continued viral response rate.
Following three key intermediates are related in the synthetic method of Boceprevir disclosed in original chemical patent WO 02/08244 A2 of Boceprevir:
Wherein key intermediate 3 synthetic method report have two kinds, it is raw material through the method for 7 step Reactive Synthesis key intermediates 3 and hydrochloride thereof that WO2004/113272 reports with 2-((diphenylmethylene) amino) ethyl acetate.
WO2008/082486 is that raw material utilizes for twice Henry reaction through the hydrochloride of 9 step Reactive Synthesis key intermediates 3 with cyclobutanemethanol.
Consider the importance of hepatitis C virus (" HCV ") proteinase inhibitor, the intermediate of novel this inhibitor of preparation is interesting all the time.
Summary of the invention
The problem to be solved in the present invention is to provide a kind of Alpha-hydroxy beta-amino ester compound with cyclobutyl of novelty, and the method for this compounds of simple and effective ground preparation.
On the one hand, the invention provides a kind of Alpha-hydroxy beta-amino ester compound with cyclobutyl of novelty, it has following general formula (1):
R 1for alkyl, aryl or aralkyl, R 2for alkyl; Preferably, R 1, R 2respective is independently the alkyl of C1-C6, is more preferably the alkyl of C1-C4.
Second aspect, the invention provides the method for preparation formula (1) compound, described method comprises the steps:
(1) Compound C is made to be converted into Compound D through following methods one or method two,
Method one:
A) Compound C and Wittig reagent or Wittig-Horner reagent react is made to obtain Compound D-1 in organic solvent in the presence of a base,
B) in organic solvent by oxidizing Compound D-1 to obtain Compound D,
Method two:
A ') make Compound C and halogenated acetic acids ester react to obtain Compound D in organic solvent in the presence of a base,
(2) coupling obtain compound (1) after being hydrolyzed in the presence of a catalyst of Compound D and nitrile reagent is made in organic solvent,
Wherein R 1for alkyl, aryl or aralkyl, R 2for alkyl, X is halogen.
According to the present invention one preferred embodiment, wherein R 1, R 2for the alkyl of C1-C6, the more preferably alkyl of C1-C4.
According to the present invention one preferred embodiment, described step a) described alkali can be selected from metal alkoxide, lithium alkylide, metal cyanides, and wherein said metal can be sodium or potassium.
According to the present invention one preferred embodiment, step a) described in alkali can be sodium hydrogen.
According to the present invention one preferred embodiment, described Wittig reagent can be phosphine acyl acetic acid three ethyl.
According to the present invention one preferred embodiment, step b) described in oxygenant can be selected from metachloroperbenzoic acid, clorox, hydrogen peroxide, Urea Peroxide, Peracetic Acid or trifluoro Peracetic Acid.
According to the present invention one preferred embodiment, step a ') described in alkali can be selected from lithium alkylide, lithium diisopropylamine, two trimethyl silicon based Lithamide or two trimethyl silicon based sodium amide.
According to the present invention one preferred embodiment, step a ') described in halogenated acetic acids ester can be selected from ethyl bromoacetate, methyl bromoacetate, ethyl chloroacetate, methyl chloroacetate, ethyl iodoacetate or iodoacetic acid methyl esters.
According to the present invention one preferred embodiment, the nitrile reagent described in step (2) can be selected from acetonitrile, benzyl cyanide or positive propionitrile.
According to the present invention one preferred embodiment, described in step (2), catalyzer can be selected from boron trifluoride diethyl etherate, aluminum chloride, trifluoroacetic acid.
The third aspect, the invention provides intermediate formula (D) compound:
Wherein R 2represent alkyl, the alkyl of preferred C1-C6, more preferably the alkyl of C1-C4.
Fourth aspect, the invention provides intermediate formula (D-1) compound:
Wherein R 2represent alkyl, the alkyl of preferred C1-C6.
Compound C of the present invention is prepared by means known in the art by compd A:
I () makes compd A and cyanylation agent react to obtain compd B,
(ii) compd B and reductive agent is made to react to obtain Compound C,
Below describe preparation method of the present invention in detail, described preparation method can represent as following scheme I:
Scheme I
Described step 1 is methods known to those skilled in the art.
The method of step 1 is based on J.Med.Chem.2006,49,3448-3450, compd A and cyanating reagent react obtained compd B in organic solvent, relative to compd A, cyanating reagent can use to about 5 molar equivalents by about 1 molar equivalent usually, and preferably 1 molar equivalent to 3 molar equivalent uses, and more preferably 1.5 molar equivalents use.Available cyanating reagent comprises sodium cyanide, potassium cyanide etc., preferred sodium cyanide.Available solvent comprises ether solvent, as ether, THF, methyl tertiary butyl ether, THP etc.; Aliphatic solvents, such as, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; And esters solvent, such as ethyl acetate etc.; With other solvents, such as acetonitrile, DMF, DMSO etc. or its suitable mixture.Preferred solvent is other solvents, more preferably DMSO.
The reaction of step 1 can about-20 DEG C of-Yue 90 DEG C, preferably 20 DEG C-80 DEG C, more preferably from about carry out about 3h at the temperature of 70 DEG C-80 DEG C or until react completely.
Described step 2 is also methods known to those skilled in the art.
The method of step 2 is based on J.Med.Chem.2006,49,3448-3450, compound obtains Compound C through going back original reagent effect in organic solvent, relative to compd B, reductive agent can use by about 1 molar equivalent-Yue 5 molar equivalent usually, preferably 1 molar equivalent-3 molar equivalent, and more preferably from about 1 molar equivalent-1.2 molar equivalent uses.Available reductive agent comprises DIBAL-H.Available solvent comprises ether solvent, as ether, THF, methyl tertiary butyl ether, THP etc.; Aliphatic solvents, such as, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; And esters solvent, such as ethyl acetate etc.; With other solvents, such as acetonitrile, DMF, DMSO etc. or its suitable mixture.Preferred solvent is aliphatic solvents, more preferably methylene dichloride.
The reaction of step 2 can about-78 DEG C of-Yue 50 DEG C, preferably-78 DEG C-25 DEG C, more preferably from about carry out about 5h at the temperature of-15 DEG C-0 DEG C or until react completely.
The step 3 of the inventive method:
Described step 3 comprises, in organic solvent, under alkali existent condition, and Compound C and Wittig reagent
Or Wittig-Horner reagent
(EtO) 2P(O)CH 2COOR 2
Be obtained by reacting Compound D-1.
Preferred R in available reagent 2for ethyl, more preferably reagent is phosphine acyl acetic acid three ethyl (Triethyl phosphonoacetate).Spendable alkali comprises butyllithium, LDA, LiHMDS, NaHMDS, NaH, potassium tert.-butoxide etc., preferred butyllithium and NaH, more preferably NaH.Relative to Compound C, available reagent can use to about 5 molar equivalents by about 1 molar equivalent usually, preferably 1 molar equivalent to 3 molar equivalent, and more preferably from about 1 molar equivalent to 1.2 molar equivalent uses.
Relative to Compound C, available bases can use to about 5 molar equivalents by about 1 molar equivalent usually, preferably 1 molar equivalent to 3 molar equivalent, and more preferably from about 1 molar equivalent to 1.1 molar equivalent uses.Available solvent comprises ether solvent, as ether, THF, methyl tertiary butyl ether, THP etc.; Aliphatic solvents, such as, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; And esters solvent, such as ethyl acetate etc.; With other solvents, such as acetonitrile, DMF, DMSO etc. or its suitable mixture.Preferred solvent is ether solvent, more preferably THF.
Step 3 is reacted can about-78 DEG C of-Yue 50 DEG C, preferably-40 DEG C of-Yue 30 DEG C, carry out about 4 hours or until react completely at the temperature of more preferably from about-15 DEG C of-Yue 30 DEG C.
The step 4 of the inventive method:
Step 4 comprises, and in organic solvent, Compound D-1 obtains Compound D under the effect of oxygenant.Available oxygenant comprises hydrogen peroxide, metachloroperbenzoic acid, Peracetic Acid, trifluoro Peracetic Acid, t-butyl hydroperoxide, hypochlorite, Urea Peroxide etc., preferred hypochlorite and metachloroperbenzoic acid, more preferably metachloroperbenzoic acid.Relative to Compound D-1, oxygenant can use to about 5 molar equivalents by about 1 molar equivalent usually, preferably 1 molar equivalent to 3 molar equivalent, and more preferably from about 1 molar equivalent to 1.5 molar equivalent uses.Available solvent comprises ether solvent, as ether, THF, methyl tertiary butyl ether, THP etc.; Aliphatic solvents, such as, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; And esters solvent, such as ethyl acetate etc.; With other solvents, such as acetonitrile, DMF, DMSO etc. or its suitable mixture.Preferred solvent is aliphatic solvents, more preferably methylene dichloride.
Step 4 reaction can about-20 DEG C of-Yue 80 DEG C, and preferably 0 DEG C-50 DEG C are reacted about 18h or until react completely.
The step 5 of the inventive method:
Step 5 comprises in organic solvent, under having alkali existent condition, obtains compound 1 after the acetate esters reagent of compound 2 and halo carries out condensation.Spendable alkali comprises butyllithium, LDA, LiHMDS, NaHMDS, NaH, potassium tert.-butoxide etc., preferred LDA and LiHMDS, more preferably LiHMDS.Available halogenated acetic acids ester class reagent comprises ethyl chloroacetate, methyl chloroacetate, ethyl bromoacetate, methyl bromoacetate, ethyl iodoacetate, iodoacetic acid methyl esters, preferred ethyl bromoacetate
The compound of formula 1 can obtain 3-(amino)-3-cyclobutyl-2-hydroxy-propanamide or its salt through reaction path as follows, and the latter is the key intermediate of Boceprevir.
Wherein compound 2 is obtained by the method by contriver, and the synthetic method of compound 3, at J.Med.Chem.2006, was reported in 49,6074-6086.
In sum, the invention provides a kind of Alpha-hydroxy beta-amino ester compound with cyclobutyl and synthetic method thereof.This compounds can be that raw material obtains through 5 steps or the reaction of 4 steps with Bromomethylcyclobutane, and operation is easy, and yield is higher.This compounds can be used for the synthesis of anti-third liver medicine Boceprevir key intermediate 3-(amino)-3-cyclobutyl-2-hydroxy-propanamide or its salt, for the synthesis of anti-third liver medicine Boceprevir key intermediate 3-(amino)-3-cyclobutyl-2-hydroxy-propanamide or its salt provides new thinking and countermeasure.
Formula (1) compound disclosed in the present invention may be used for synthesizing key intermediate 3, and concrete scheme is as follows:
Wherein compound 2 is obtained by the method by contriver, and the synthetic method of compound 3, at J.Med.Chem.2006, was reported in 49,6074-6086.
Embodiment
Further illustrate the present invention by embodiment below, but described embodiment does not form limitation of the scope of the invention.
Outside indicating, all chemical and solvent all obtain from commercial channel, without being further purified before using.Bromomethylcyclobutane is purchased from Shanghai Lan Ke medical sci-tech Development Co., Ltd; diisobutyl aluminium hydride is purchased from Shanghai Da Rui fine chemicals company limited; phosphine acyl acetic acid three ethyl is purchased from Shanghai Hanhong Chemical Industry Co., Ltd.; metachloroperbenzoic acid purchased from all the other reagent of Shanghai Bang Cheng Chemical Co., Ltd. and solvent all purchased from Chemical Reagent Co., Ltd., Sinopharm Group; anhydrous tetrahydro furan and methyl bromoacetate, more preferably ethyl bromoacetate.
Available solvent comprises ether solvent, as ether, THF, methyl tertiary butyl ether, THP etc.; Aliphatic solvents, such as, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; And esters solvent, such as ethyl acetate etc.; With other solvents, such as acetonitrile, DMF, DMSO etc. or its suitable mixture.Preferred solvent is ether solvent, more preferably THF.
Reaction can at about-78 DEG C about 50 DEG C, preferably-78 DEG C about 0 DEG C, more preferably from about carry out about 2 hours at the temperature of-78 DEG C about-30 DEG C or until react completely.
The step 6 of the inventive method:
Step 6 comprise make Compound D in organic solvent under catalyst with the coupling of nitrile reagent, subsequently in acid condition hydrolysis obtain formula (1) compound.Described catalyzer is Lewis acid or protonic acid, comprises aluminum chloride, boron trifluoride diethyl etherate, trifluoroacetic acid, sulfuric acid, oleum etc., preferred Lewis acids, more preferably boron trifluoride diethyl etherate.Available nitrile reagent comprises acetonitrile, propionitrile, benzyl cyanide etc., preferred acetonitrile.During hydrolysis can acid comprise hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid etc., preferred hydrochloric acid.Available solvent comprises ether solvent, as ether, THF, methyl tertiary butyl ether, THP etc.; Aliphatic solvents, such as, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; And esters solvent, such as ethyl acetate etc.; With other solvents, such as acetonitrile, DMF, DMSO etc. or its suitable mixture.Preferred solvent is other solvents, more preferably acetonitrile.
Reaction can about-25 DEG C of-Yue 50 DEG C, preferably-15 DEG C of-Yue 25 DEG C, carry out about 4 hours or until react completely at the temperature of more preferably from about 0 DEG C of-Yue 25 DEG C.
Formula of the present invention (1) compound may be used for preparing hepatitis C (HCV) proteinase inhibitor Boceprevir (1R with following structure, 2S, 5S)-3-azabicyclo [3,1,0] hexane-2-methane amide, N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxo propyl group]-3-[(2S)-2-[[[1,1-dimethyl ethyl] amino] carbonylamino]-3,3-dimethyl-1-oxo butyl]-6,6-dimethyl.
Gained is distilled after being refluxed by tetrahydrofuran (THF) and sodium.
Embodiment 1
The preparation of Compound C:
At 20 DEG C, NaCN (21.2g is added in there-necked flask, 0.433mol), DMSO140ml, be warming up to 60 DEG C, drip Bromomethylcyclobutane (42.4g, 0.285mol), dropwise at reaction solution remains on 70-80 DEG C and stir 3h, stop heating, reaction solution is poured in 500ml frozen water, with MTBE (250ml*3) extractive reaction liquid, merge organic phase, organic phase 150ml water washing, organic phase is added in 150ml 1M HCl subsequently and stirs 30min, organic phase saturated sodium bicarbonate, saturated common salt water washing, anhydrous sodium sulfate drying steams and desolventizes to obtain the liquid of 24g yellowish, for crude compound B, need not directly drop into next step reaction by purifying.
N 2under protection, by compd B (10g, 0.105mol) and 80ml CH 2cl 2be added in reaction flask, stir and be cooled to about-10 DEG C, drip the toluene solution of the DIBAL-H of 110ml 1mol/L, dropwise, insulated and stirred 2h after being naturally warming up to 0 DEG C, is cooled to about-5 DEG C subsequently, drops to the saturated NH of 250ml 4in Cl solution, then drip the hydrogen chloride solution of 300ml 2N, stir 30min, with methylene dichloride (250ml*3) extraction, merge organic interdependent time and use saturated NaHCO 3, saturated common salt water washing, anhydrous sodium sulfate drying, obtains the toluene solution of C after removing methylene dichloride under reduced pressure, not purifying directly drop into next step reaction.
The preparation of Compound D-1:
NaH (0.9g, 22.4mmol) adds in there-necked flask, then adds the anhydrous THF of 15ml, is cooled to 0 DEG C, drip phosphine acyl acetic acid three ethyl (4.6g, 20.4mmol), dropwise, rise to stirring at room temperature 2h, be cooled to-15 DEG C subsequently, drip the toluene solution of 20g C; Dropwise and rise to room temperature, drip 10ml water and 10ml saturated ammonium chloride solution after stirring 2h, use ethyl acetate (20ml*3) to extract subsequently, merge organic phase, with water and saturated common salt water washing, anhydrous sodium sulfate drying, steam after desolventizing and obtain 3.1g yellow oil.Need not directly drop into next step reaction by purifying.It is a weak yellow liquid that column chromatography obtains analysis D-1, 1h NMR (400MHz, CDCl 3) δ 1.25 (t, 3H), 1.60-1.67 (m, 2H), 1.80-1.87 (m, 2H), 2.02-2.10 (m, 2H), 2.26 (t, 2H), 2.36-2.42 (m, 1H), 4.15 (q, 2H), 5.75 (d, 1H), 6.83-6.89 (m, 1H).
The preparation of Compound D:
D-1 (12g, 72mmol), CH is added successively in reaction flask 2cl 2(180ml) with m-CPBA (21g, 0.107mol), be heated to reflux and stir 40h, stopping heating, be cooled to about 0 DEG C and stir 1h, adularescent solid is separated out, and suction filtration, adds 100ml saturated potassium carbonate solution stirring 30min in filtrate, after separatory, aqueous phase ethyl acetate (50ml*3) extracts, merge organic phase, use saturated ammonium chloride and brine It successively, anhydrous sodium sulfate drying steams and desolventizes to obtain pale yellow oil.Yield about 65%.Need not directly drop into next step reaction by purifying.It is a weak yellow liquid that column chromatography obtains analysis Compound D, m/z (MH +) 185.16, 1h NMR (400MHz, CDCl 3) δ 1.29 (t, 3H), 1.64-1.78 (m, 4H), 1.78-1.92 (m, 2H), 2.08-2.14 (m, 2H), 2.44-2.51 (m, 1H), 3.07-3.10 (m, 1H), 3.16 (d, 1H), 4.18-4.25 (m, 2H).
The preparation of Compound D:
N 2by LiHMDS (10ml under protection; 10mmol) be added in reaction flask; be cooled to-78 DEG C; ethyl bromoacetate (1.8g; 10.5mmol) to be dissolved in 5ml THF and to drop in reaction flask, dropwising and keep-78 DEG C to continue to stir 10min, drip the toluene solutions of 4g C subsequently; stir 10min, naturally heat up and stir 30min.Reaction solution is dropped in 20ml frozen water, extract with ethyl acetate (20ml*3), merge organic phase and use dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt water washing successively, anhydrous sodium sulfate drying obtains yellow solution after removing solvent under reduced pressure, column chromatography obtains 0.8g Compound D, yield 42.8%.
Wherein R 1for methyl, R 2preparation for formula (1) compound of ethyl:
Compound D (1g, 5.4mmol) be dissolved in 18ml anhydrous acetonitrile, be cooled to 0 DEG C, drip boron trifluoride diethyl etherate (3.6ml, 27.8mmol), dropwise and rise to stirring at room temperature 4h, steaming desolventizes, 20ml diluted ethyl acetate is added in resistates, add 10ml saturated sodium bicarbonate and stir 30min, separatory, ethyl acetate (10ml*3) aqueous phase extracted, merge organic phase and wash twice with water, anhydrous sodium sulfate drying, after steaming desolventizes, add 20ml diluted ethyl acetate, and the dilute hydrochloric acid 20ml adding 0.5mol/L stirs 30min, add saturated sodium bicarbonate solution after stirring and regulate PH to 7, separatory with ethyl acetate (20ml*3) aqueous phase extracted, anhydrous sodium sulfate drying after merging organic phase brine It, steaming desolventizes to obtain orange red oily matter, it is a white solid that column chromatography obtains 0.9g compound 1, yield 68%.m/z(MH +)244.16， 1H NMR(400MHz，CDCl 3)δ1.31(t，3H)，1.50-1.63(m，3H)，1.71-1.88(m，2H)，1.96(s，3H)，1.98-2.09(m，2H)，2.24-2.32(m，1H)，3.39(s，1H)，4.21-4.30(m，3H)，5.77(d，1H)。
Embodiment 2
Wherein R 1for benzyl, R 2preparation for formula (1) compound of ethyl:
Compound D (0.5g, 2.7mmol) be dissolved in 10ml benzyl cyanide, be cooled to 0 DEG C, drip boron trifluoride diethyl etherate (3.6ml, 27.8mmol), dropwise and rise to stirring at room temperature 4h, remove solvent under reduced pressure, 10ml diluted ethyl acetate is added in resistates, add 10ml saturated sodium bicarbonate and stir 30min, separatory, ethyl acetate (10ml*3) aqueous phase extracted, merge organic phase and wash twice with water, anhydrous sodium sulfate drying, after steaming desolventizes, add 20ml methyl alcohol, and the dilute hydrochloric acid 20ml adding 0.5mol/L stirs 90min, add saturated sodium bicarbonate solution after stirring and regulate PH to 7, stirring is spent the night.Separatory with ethyl acetate (20ml*3) aqueous phase extracted, merge anhydrous sodium sulfate drying after organic phase brine It, steam and desolventize to obtain pale yellow oil, it is a white solid that column chromatography obtains 520mg compound 1, yield 59%, m/z (MNa +) 342.19, 1h NMR (400MHz, CDCl 3) δ 1.32 (t, 3H), 1.48-1.62 (m, 4H), 1.75-1.85 (m, 2H), 1.94-2.06 (m, 2H), 2.19-2.24 (m, 1H), 3.17 (s, 1H), 3.60 (s, 2H), 4.22-4.31 (m, 3H) 5.77 (d, 1H), 7.28-7.40 (m, 5H).
Embodiment 3
Wherein R 1for phenyl, R 2preparation for formula (1) compound of ethyl:
Compound D (0.5g, 2.7mmol) be dissolved in 9ml cyanobenzene, be cooled to 0 DEG C, drip boron trifluoride diethyl etherate (3.6ml, 27.8mmol), dropwise and rise to stirring at room temperature 4h, remove solvent under reduced pressure, 10ml diluted ethyl acetate is added in resistates, add 10ml saturated sodium bicarbonate and stir 30min, separatory, ethyl acetate (10ml*3) aqueous phase extracted, merge organic phase and wash twice with water, anhydrous sodium sulfate drying, after steaming desolventizes, add 20ml methyl alcohol, and the dilute hydrochloric acid 20ml adding 0.5mol/L stirs 90min, add saturated sodium bicarbonate solution after stirring and regulate PH to 7, stirring is spent the night.Separatory with ethyl acetate (20ml*3) aqueous phase extracted, anhydrous sodium sulfate drying after merging organic phase brine It, steam and desolventize to obtain pale yellow oil, it is a white solid that column chromatography obtains 560mg compound 1, yield 67.5%, m/z (MNa +) 328.14. 1H NMR(400MHz，CDCl 3)δ1.30(t，3H)，1.48-1.61(m，4H)，1.76-1.87(m，2H)，1.94-2.06(m，2H)，2.17-2.23(m，1H)，3.27(s，1H)，4.22-4.31(m，3H)，5.77(d，1H)，6.77-6.83(m，3H)，7.23-7.28(m，2H)。
Embodiment 4
Wherein R 1for butyl, R 2preparation for formula (1) compound of ethyl:
Compound D (0.5g, 2.7mmol) be dissolved in the positive valeronitrile of 9ml, be cooled to 0 DEG C, drip boron trifluoride diethyl etherate (3.6ml, 27.8mmol), dropwise and rise to stirring at room temperature 4h, remove solvent under reduced pressure, 10ml diluted ethyl acetate is added in resistates, add 10ml saturated sodium bicarbonate and stir 30min, separatory, ethyl acetate (10ml*3) aqueous phase extracted, merge organic phase and wash twice with water, anhydrous sodium sulfate drying, after steaming desolventizes, add 20ml methyl alcohol, and the dilute hydrochloric acid 20ml adding 0.5mol/L stirs 90min, add saturated sodium bicarbonate solution after stirring and regulate PH to 7, stirring is spent the night.Separatory with ethyl acetate (20ml*3) aqueous phase extracted, anhydrous sodium sulfate drying after merging organic phase brine It, steam and desolventize to obtain pale yellow oil, it is a white solid that column chromatography obtains 320mg compound 1, yield 41.5%, m/z (MNa +) 308.16. 1H NMR(400MHz，CDCl 3)δ0.92(t，3H)δ1.30(t，3H)，δ1.32-1.37(m，2H)，1.48-1.61(m，5H)，1.77-1.89(m，2H)，1.94-2.08(m，4H)，2.24-2.34(m，1H)，3.35(s，1H)，4.21-4.29(m，3H)，5.77(d，1H)。
Embodiment 5
With R 1for methyl, R 2for formula (1) compound of ethyl prepares compound 2:
Formula 1 compound (1g, 4.2mmol) be dissolved in 2.5ml methyl alcohol, add 6N hydrochloric acid 14ml, be heated to backflow, and keep backflow 16h, be cooled to 0-5 DEG C subsequently, regulate more than PH to 12,0.9g tert-Butyl dicarbonate to be dissolved in 5ml tetrahydrofuran (THF) and to be added in reaction solution, stirred overnight at room temperature.PH is adjusted to 2-3, ethyl acetate (20ml*3) extractive reaction liquid, merge organic phase, organic phase dryly obtains pale yellow oil to be concentrated into after saturated common salt water washing, and it is a white solid that oily matter ethyl acetate and normal hexane crystallization obtain formula 2 compound 740mg.m/z(MNa +)396.12， 1H NMR(400MHz，CDCl 3)δ1.45(s，9H)，1.58-1.91(m，6H)，2.03-2.11(m，2H)，2.33-2.38(m，1H)，2.19-2.24(m，1H)，3.81-3.88(m，1H)，4.27(d，1H)，4.81(s，1H)，5.71(br，1H)， 1H NMR(400MHz，CDCl 3+D 2O)δ1.45(s，9H)，1.58-1.91(m，6H)，2.03-2.11(m，2H)，2.33-2.38(m，1H)，2.19-2.24(m，1H)，3.81-3.88(m，1H)，4.27(d，1H).
Embodiment 6
With R 1for methyl, R 2for formula (1) compound of ethyl prepares compound 2:
Formula 1 compound (1g, 4.2mmol) be dissolved in 5ml methyl alcohol, add 5g NaOH and 15ml water, be heated to reflux and keep the 20h that refluxes, be cooled to 0-5 DEG C subsequently, add 15ml water, 0.9g tert-Butyl dicarbonate to be dissolved in 5ml dioxane and to be added in reaction solution, stirred overnight at room temperature.PH is adjusted to 2-3, ethyl acetate (30ml*3) extractive reaction liquid, merges organic phase, organic phase dryly obtains pale yellow oil to be concentrated into after saturated common salt water washing, and oily matter ethyl acetate and normal hexane crystallization obtain formula 2 compound 850mg.
Embodiment 7
With R 1for phenyl, R 2for formula (1) compound of ethyl prepares compound 2:
Formula 1 compound (0.5g, 1.64mmol) be dissolved in 2ml methyl alcohol, add 6N hydrochloric acid 10ml, be heated to backflow, and keep backflow 16h, be cooled to 0-5 DEG C subsequently, regulate more than PH to 12,0.35g tert-Butyl dicarbonate to be dissolved in 5ml tetrahydrofuran (THF) and to be added in reaction solution, stirred overnight at room temperature.PH is adjusted to 2-3, ethyl acetate (20ml*3) extractive reaction liquid, merges organic phase, organic phase dryly obtains pale yellow oil to be concentrated into after saturated common salt water washing, and column chromatography obtains formula 2 compound 220mg.
Embodiment 8
With R 1for benzyl, R 2for formula (1) compound of ethyl prepares compound 2:
Formula 1 compound (0.5g, 1.58mmol) be dissolved in 2ml methyl alcohol, add 6N hydrochloric acid 10ml, be heated to backflow, and keep backflow 16h, be cooled to 0-5 DEG C subsequently, regulate more than PH to 12,0.34g tert-Butyl dicarbonate to be dissolved in 5ml tetrahydrofuran (THF) and to be added in reaction solution, stirred overnight at room temperature.PH is adjusted to 2-3, ethyl acetate (20ml*3) extractive reaction liquid, merges organic phase, organic phase dryly obtains pale yellow oil to be concentrated into after saturated common salt water washing, and column chromatography obtains formula 2 compound 270mg.

Claims (16)

1. the method for preparation formula (1) compound:
Wherein R 1for alkyl, aryl or aralkyl, R 2for alkyl,
Described method comprises the steps:
(1) Compound C is made to be converted into Compound D through following methods one or method two,
Method one:
A) Compound C and Wittig reagent or Wittig-Horner reagent react is made to obtain Compound D-1 in organic solvent in the presence of a base,
B) in organic solvent by oxidizing Compound D-1 to obtain Compound D,
Method two:
A ') make Compound C and halogenated acetic acids ester react to obtain Compound D in organic solvent in the presence of a base,
(2) coupling obtain compound (1) after being hydrolyzed in the presence of a catalyst of Compound D and nitrile reagent is made in organic solvent,
Wherein R 1, R 2as defined above, X is halogen.
2. the method for claim 1, wherein R 1, R 2respective is independently the alkyl of C1-C6.
3. method, wherein R as claimed in claim 2 1, R 2respective is independently the alkyl of C1-C4.
4. the method for claim 3, wherein step a) described in alkali be selected from metal alkoxide, lithium alkylide, metal cyanides or sodium hydrogen, wherein said metal is sodium or potassium.
5. the method for claim 4, wherein said alkali is sodium hydrogen.
6. the process of claim 1 wherein that the Wittig reagent described in step a) is phosphine acyl acetic acid three ethyl.
7. the process of claim 1 wherein step b) described in oxygenant be selected from metachloroperbenzoic acid, clorox, hydrogen peroxide, Urea Peroxide, Peracetic Acid or trifluoro Peracetic Acid.
8. the process of claim 1 wherein step a ') described in alkali be selected from lithium alkylide, lithium diisopropylamine, two trimethyl silicon based Lithamide or two trimethyl silicon based sodium amide.
9. the process of claim 1 wherein step a ') described in halogenated acetic acids ester be selected from ethyl bromoacetate, methyl bromoacetate, ethyl chloroacetate, methyl chloroacetate, ethyl iodoacetate or iodoacetic acid methyl esters.
10. the process of claim 1 wherein that the nitrile reagent described in step (2) is selected from acetonitrile, benzyl cyanide or positive propionitrile.
11. the process of claim 1 wherein that described in step (2), catalyzer is selected from boron trifluoride diethyl etherate, aluminum chloride, trifluoroacetic acid.
The method of 12. claims 4, wherein said organic solvent is selected from ether solvent, is selected from ether, THF, methyl tertiary butyl ether or THP; Halohydrocarbon, is selected from methylene dichloride, chloroform, tetracol phenixin or ethylene dichloride; Aromatic solvent, is selected from toluene, benzene, dimethylbenzene, Three methyl Benzene or chlorobenzene; And esters solvent, be selected from ethyl acetate; With other solvents, be selected from acetonitrile, DMF or DMSO or its suitable mixture.
13. formulas (D) compound:
Wherein R 2represent alkyl.
14. formula (D) compounds as claimed in claim 13, wherein R 2represent the alkyl of C1-C6.
15. formulas (D-1) compound:
Wherein R 2represent alkyl, and R 2it is not the tertiary butyl.
16. formula (D-1) compounds as claimed in claim 15, wherein R 2represent the alkyl of C1-C6.
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