CN103936651B - Intermediate III of anti-hepatitis C medicine Boceprevir and its preparation method and application - Google Patents
Intermediate III of anti-hepatitis C medicine Boceprevir and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to the preparation method technical field for anti-hepatitis C medicine Boceprevir。Compound F-2 structural formula provided by the invention is as follows。The preparation of this compounds, easy and simple to handle, yield is higher。Using this compounds to can be used for the synthesis of anti-hepatitis C medicine Boceprevir, this is that the synthesis of anti-hepatitis C medicine Boceprevir provides new thinking and method。And convenient with the detection of ultraviolet chromophoric group more original synthetic method in such compound molecule, additionally on hydroxyl, the introducing of benzyl avoids the side reaction caused in condensation step because of hydroxyl nucleophilicity, has certain advantage compared with existing synthetic method。
Description
Technical field
The present invention relates to the preparation method technical field for anti-hepatitis C medicine Boceprevir。
Background technology
In global range, the infection rate of hepatitis C virus (hepatitisCvirus, HCV) is about 3%, and the total number of persons of infection is about 200,000,000。Due to the high infection rate of HCV and may result in potential complication as serious in liver cirrhosis, hepatocarcinoma etc., thus HCV is the serious threat that human life is healthy。According to Simmonds nomenclature, HCV can be divided into 6 main genotypes and I-VI, various can be divided into again several hypotypes (such as Ia, Ib, IIa, IIb, IIIa, IIIb etc.)。The HCV infection person of China about 40,000,000, and wherein 69% infects (based on Ib type) for I type。The method treating chronic hepatitis c at present is mainly Peg-IFN alpha-2b (PEG-IFN α) and ribavirin (RBV) drug combination, this kind of therapy patient of about 50% in HCVI type 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 kind HCV-Ab IgG drug candidates or granted to carry out clinical trial at present。In these medicines, Victrelis (boceprevir) is approved by the FDA in the united states on May 13rd, 2011 and treats Adult chronic's hepatitis C with Peg-IFN alpha-2b and ribavirin coupling。
Boceprevir(structure is as above) it is by the chronic hepatitis c curative of Schering Plough company of U.S. exploitation, it it is a kind of orally active HCVNS3 protease inhibitor, it it is the micromolecular inhibitor amino acid residue on a kind of 11 peptides having high NS3 inhibitory activity being carried out systematicness truncate and modification and finding, the serine of NS3 active site can be caught, on its keto-amide, carbonyl carbon is combined formation covalent adduct with this serine, thus causing NS3 inactivation。The research being published in " New England Journal of Medicine " shows, for previously untreated chronic hcv genotype I type infected patient, Peg-IFN alpha-2b-ribavirin standard therapy basis add with Boceprevir, compared with simple standard care, continued viral response rate can be dramatically increased。
The synthesis strategy of Boceprevir mainly has two kinds, and patent WO02/08244A2 and J.Med.Chem.2006,49,6074-6086 reports three fragments and is once hydrolyzed last oxidized side chain hydroxyl through twice condensation and obtains the synthesis strategy of Boceprevir。Specific as follows:
Patent WO2008/079216 reports the synthesis strategy of the Boceprevir of initial oxidation pendant hydroxyl group condensation again, specific as follows:
Other relevant patents or document are all the optimization and improvement (specifically can referring to US2004/018914, US2006/043950, US2007/025804 etc.) that carry out on the basis of both the above synthesis strategy。But all there is a same problem in existing synthetic method: control comparatively to bother owing to the structure of each intermediate being all absent from obvious chromophoric group therefore reaction detection and intermediate。Additionally there is exposed hydroxyl in a tactful condensation step, inevitably result in side reaction and occur, in the process of practical operation also just so。The present inventor successfully solves detection difficult and the problem of condensation step side reaction by introducing substituted or unsubstituted benzyl in a certain intermediate, simultaneously taking account of the importance of hepatitis C virus (" HCV ") protease inhibitor, the novel intermediate preparing this inhibitor is interesting all the time。
Summary of the invention
The purpose of the present invention solves Problems existing in above-mentioned existing synthesis Boceprevir method exactly, it is provided that a kind of new midbody compound, it is possible to the preparation Boceprevir of simple and effective or this compounds。
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
Following general formula compound F-2:
R is the optional position substituent group of phenyl ring, and R is hydrogen, alkyl or alkoxyl。Preferred R is in para-position；Preferred R is the alkyl of hydrogen or C1-C3, more preferably hydrogen。
Above-mentioned new general formula compound F-2, it is possible to for preparing hepatitis C (HCV) the protease inhibitor Boceprevir being structured with
The compound of formula F-2 can prepare Boceprevir through reaction path shown below:
A) in organic solvent, alkali and under condensing agent existence condition, make compound F-2 and compound G-3 condensation obtain formula 1 compound
B) compound 1 hydro-reduction is obtained compound 2, then aoxidize and obtain final goal product Boceprevir
Can referring to patent US2006/043950, WO02/08244A2, J.Med.Chem.2006,49,6074-6086, US8188137B2 by the method for formula (2) preparation of compounds of formula (3) compound Boceprevir。
According to the preferred embodiment of the present invention, step a) can alkali include triethylamine, DIPEA, pyridine, N-methylmorpholine, it is preferable that N-methylmorpholine and DIPEA。Relative to compound F-2, the consumption of alkali can at 2 molar equivalents to 8 molar equivalents, it is preferable that 2 molar equivalents are to 5 molar equivalents, and more preferably 2 molar equivalents use to 4 molar equivalents。Available condensing agent includes EDCI, BOP, PyBOP, CDI, HATU, HBTU, DCC, it is preferable that EDCI, BOP, PyBOP, HATU, more preferably EDCI and HATU。Relative to compound F-2, the consumption of condensing agent can at 1 molar equivalent to 5 molar equivalents, it is preferable that 1 molar equivalent is to 3 molar equivalents, and more preferably 1 molar equivalent uses to 2 molar equivalents。For promoting that reaction carries out, it is also possible to adding additive, available additive includes HOBT, HOAT。Relative to compound F-1, the consumption of additive is at 0 to 5 molar equivalents, it is preferable that 1 molar equivalent is to 3 molar equivalents, and more preferably 1 molar equivalent uses to 2 molar equivalents。Relative to compound F-2, the consumption of compound G-3 can at 1 molar equivalent to 2 molar equivalents, it is preferable that 1 molar equivalent is to 1.5 molar equivalents, and more preferably 1 molar equivalent uses to 1.2 molar equivalents。Available solvent includes ether solvent, such as ether, oxolane, methyl tertiary butyl ether(MTBE), Pentamethylene oxide., dioxane etc.；Halogenated hydrocarbons, for instance, dichloromethane, chloroform, carbon tetrachloride, dichloroethanes etc.；Aromatic solvent, for instance toluene, benzene, dimethylbenzene, trimethylbenzene, chlorobenzene etc.；Esters solvent, for instance ethyl acetate etc., and other solvents, for instance DMF, DMSO, acetonitrile etc. or its suitable mixture。Preferred solvent is other solvents, more preferably DMF and acetonitrile。
The preparation method of general formula compound F-2 provided by the invention, the method is in organic solvent, makes the compound F-1 deprotection base of following formula, obtain compound F-2 under acid condition:
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl, and A is acid group。Preferred R is in para-position；Preferred R is the alkyl of hydrogen or C1-C3, more preferably hydrogen。
The acid that above-mentioned reaction uses includes hydrochloric acid, sulphuric acid, trifluoroacetic acid, it is preferable that hydrochloric acid。Relative to compound F-1, sour consumption can be 1 molar equivalent to 20 molar equivalents, it is preferable that 1 molar equivalent is to 10 molar equivalents, and more preferably 1 molar equivalent uses to 5 molar equivalents。Available solvent includes ether solvent, such as ether, THF, methyl tertiary butyl ether(MTBE), THP, dioxane etc.；Halogenated hydrocarbons, for instance, dichloromethane, chloroform, carbon tetrachloride, dichloroethanes etc.；Aromatic solvent, for instance toluene, benzene, dimethylbenzene, trimethylbenzene, chlorobenzene etc.；And esters solvent, for instance ethyl acetate etc. or its suitable mixture。Preferred solvent is ether solvent, more preferably dioxane。Reaction can at-25 DEG C～50 DEG C, it is preferable that-10 DEG C～25 DEG C, carry out about 1 hour or until react completely at the temperature of more preferably 0 DEG C～25 DEG C。
Compound F-1, can in organic solvent, alkali and under condensing agent existence condition, makes following formula: compound F and compound G-2 condensation obtain:
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl, and A is acid group。Preferred R is in para-position；Preferred R is the alkyl of hydrogen or C1-C3, more preferably hydrogen。
Above-mentioned condensation reaction can alkali include triethylamine, DIPEA, pyridine and N-methylmorpholine, it is preferable that N-methylmorpholine and DIPEA。Relative to compound F, the consumption of alkali can be 2 molar equivalents to 8 molar equivalents, it is preferable that 2 molar equivalents are to 5 molar equivalents, and more preferably 2 molar equivalents use to 4 molar equivalents。Available condensing agent is selected from 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI), BTA-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP), hexafluorophosphoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl (PyBOP), N, N'-carbonyl dimidazoles (CDI), 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (HATU), 2-(7-azo BTA)-tetramethylurea hexafluorophosphoric acid ester (HATU), >=99.5% (HPLC) (HBTU), N, N'-dicyclohexylcarbodiimide (DCC), preferred EDCI, BOP, PyBOP and HATU, more preferably EDCI and HATU。Relative to compound F, condensing agent consumption can be 1 molar equivalent to 5 molar equivalents, it is preferable that 1 molar equivalent is to 3 molar equivalents, and more preferably 1 molar equivalent uses to 2 molar equivalents。Step a) also can add additive, and additive includes 1-hydroxyl-7-azo BTA (HOAT), I-hydroxybenzotriazole (HOBT), >=99% (HPLC) etc.。Relative to compound F, additive amount can be 0 to 5 molar equivalent, it is preferable that 1 molar equivalent is to 3 molar equivalents, and more preferably from about 1 molar equivalent uses to 2 molar equivalents。Relative to compound F, compound G-2 generally can about 1 molar equivalent to about 2 molar equivalent, it is preferable that 1 molar equivalent is to 1.5 molar equivalents, and more preferably 1 molar equivalent uses to 1.2 molar equivalents。Available solvent includes ether solvent, such as ether, oxolane, methyl tertiary butyl ether(MTBE), Pentamethylene oxide., dioxane etc.；Halogenated hydrocarbons, for instance, dichloromethane, chloroform, carbon tetrachloride, dichloroethanes etc.；Aromatic solvent, for instance toluene, benzene, dimethylbenzene, trimethylbenzene, chlorobenzene etc.；Esters solvent, for instance ethyl acetate etc., and other solvents, for instance DMF, DMSO, acetonitrile etc. or its suitable mixture。Preferred solvent is other solvents, more preferably DMF and acetonitrile。Reaction can at-25 DEG C～50 DEG C, it is preferable that-10 DEG C～25 DEG C, carry out about 24 hours or until react completely at the temperature of more preferably 0 DEG C～25 DEG C。
Compound F, can by compound E in organic solvent, and under acid condition, deprotection base obtains:
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl。Preferred R is in para-position；Preferred R is the alkyl of hydrogen or C1-C3, more preferably hydrogen。
Available acid includes hydrochloric acid, sulphuric acid, trifluoroacetic acid, it is preferable that hydrochloric acid。Relative to compound E, sour that consumption can at 1 molar equivalent to 20 molar equivalents, it is preferable that 1 molar equivalent is to 10 molar equivalents, and more preferably 1 molar equivalent uses to 5 molar equivalents。Available solvent includes ether solvent, such as ether, oxolane, methyl tertiary butyl ether(MTBE), Pentamethylene oxide., dioxane etc.；Halogenated hydrocarbons, for instance, dichloromethane, chloroform, carbon tetrachloride, dichloroethanes etc.；Aromatic solvent, for instance toluene, benzene, dimethylbenzene, trimethylbenzene, chlorobenzene etc.；And esters solvent, for instance ethyl acetate etc. or its suitable mixture。Preferred solvent is ether solvent, more preferably dioxane。Reaction can at-25 DEG C～50 DEG C, it is preferable that-10 DEG C～25 DEG C, more preferably carry out at the temperature of 0～25 DEG C, about 1 hour or until react completely。
Compound E, the compound D of available following formula in organic solvent, under alkali existence condition, are directly obtained by reacting with strong aqua ammonia after reacting with ethyl chloroformate
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl。Preferred R is in para-position；Preferred R is the alkyl of hydrogen or C1-C3, more preferably hydrogen。
The alkali that above-mentioned reaction can use includes triethylamine, DIPEA, pyridine, N-methylmorpholine, Lithium hydrate, sodium hydroxide, potassium hydroxide, it is preferable that triethylamine, DIPEA and N-methylmorpholine, more preferably triethylamine。Relative to compound D, the consumption of alkali is recommended as 1 molar equivalent to 5 molar equivalents, it is preferable that 1 molar equivalent is to 3 molar equivalents, and more preferably 1 molar equivalent uses to 2.5 molar equivalents。Relative to compound D, the consumption of ethyl chloroformate can be 1 molar equivalent extremely about 5 molar equivalent, it is preferable that 1 molar equivalent is to 3 molar equivalents, and more preferably 1 molar equivalent uses to 2.5 molar equivalents。Relative to compound D, strong aqua ammonia consumption can be 1 molar equivalent to 8 molar equivalents, it is preferable that 1 molar equivalent is to 5 molar equivalents, and more preferably 1 molar equivalent uses to 3 molar equivalents。Available solvent includes ether solvent, such as ether, oxolane, methyl tertiary butyl ether(MTBE), Pentamethylene oxide. etc.；Halogenated hydrocarbons, for instance, dichloromethane, chloroform, carbon tetrachloride, dichloroethanes etc.；Aromatic solvent, for instance toluene, benzene, dimethylbenzene, trimethylbenzene, chlorobenzene etc.；And esters solvent, for instance ethyl acetate etc. or its suitable mixture。Preferred solvent is ether solvent, more preferably oxolane。Reaction can at-25 DEG C～50 DEG C, it is preferable that-10 DEG C～25 DEG C, carry out at the temperature of more preferably 0 DEG C～25 DEG C, about 2 hours or until react completely。
Compound D, it is possible in organic solvent, under alkali effect, makes compound C hydrolysis obtain:
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl。Preferred R is in para-position；Preferred R is the alkyl of hydrogen or C1-C3, more preferably hydrogen。
Said hydrolyzed is reacted, and available alkali includes potassium hydroxide, sodium hydroxide, Lithium hydrate, it is preferable that sodium hydroxide and Lithium hydrate, more preferably Lithium hydrate。Relative to compound C, the consumption of alkali can be 1 molar equivalent to 10 molar equivalents, it is preferable that 1 molar equivalent is to 5 molar equivalents, and more preferably 1 molar equivalent uses to 4 molar equivalents。Available solvent includes ether solvent, such as ether, oxolane, methyl tertiary butyl ether(MTBE), Pentamethylene oxide. etc.；Halogenated hydrocarbons, for instance, dichloromethane, chloroform, carbon tetrachloride, dichloroethanes etc.；Aromatic solvent, for instance toluene, benzene, dimethylbenzene, trimethylbenzene, chlorobenzene etc.；And esters solvent, for instance ethyl acetate etc.；Proton solvent, for instance methanol, ethanol, water etc. or its suitable mixture。Preferred solvent is mixed solvent, more preferably oxolane/methanol mixed solvent。This reaction can at 0 DEG C～60 DEG C, it is preferable that 0～40 DEG C, carry out at the temperature of more preferably 10 DEG C～25 DEG C, about 4 hours or until react completely。
Compound C by the compound B of following formula, in organic solvent, under catalyst action, can obtain then through hydrazine hydrate effect after reacting with Bis(tert-butoxycarbonyl)oxide:
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl。Preferred R is in para-position；Preferred R is the alkyl of hydrogen or C1-C3, more preferably hydrogen。
Available catalyst can be DMAP, triethylamine, butyl lithium, sodium hydroxide etc., it is preferable that DMAP and triethylamine, more preferably DMAP。Relative to compound B, the consumption of catalyst generally can at 0.2 molar equivalent to 3 molar equivalents, it is preferable that 0.2 molar equivalent is to 1 molar equivalent, and more preferably 0.2 molar equivalent uses to 0.5 molar equivalent。Relative to compound B, the consumption of Bis(tert-butoxycarbonyl)oxide generally can at 1 molar equivalent to 5 molar equivalents, it is preferable that 1 molar equivalent is to 3 molar equivalents, and more preferably 1 molar equivalent uses to 2 molar equivalents。Relative to compound B, the consumption of hydrazine hydrate generally can at 2 molar equivalents to 10 molar equivalents, it is preferable that 2 molar equivalents are to 5 molar equivalents, and more preferably 2 molar equivalents use to 4 molar equivalents。During with Bis(tert-butoxycarbonyl)oxide effect can solvent include ether solvent, such as ether, oxolane, methyl tertiary butyl ether(MTBE), Pentamethylene oxide. etc.；Halogenated hydrocarbons, for instance, dichloromethane, chloroform, carbon tetrachloride, dichloroethanes etc.；Aromatic solvent, for instance toluene, benzene, dimethylbenzene, trimethylbenzene, chlorobenzene etc.；And esters solvent, for instance ethyl acetate etc. or its suitable mixture。Preferred solvent is ether solvent, more preferably oxolane。During hydrazinolysis can solvent include ether solvent, such as ether, oxolane, methyl tertiary butyl ether(MTBE), Pentamethylene oxide. etc.；Halogenated hydrocarbons, for instance, dichloromethane, chloroform, carbon tetrachloride, dichloroethanes etc.；Aromatic solvent, for instance toluene, benzene, dimethylbenzene, trimethylbenzene, chlorobenzene etc.；Proton solvent, for instance methanol, ethanol, water etc. or its suitable mixture。Preferred solvent is mixed solvent, more preferably the mixed solvent of oxolane/methanol。The reaction of compound B and Bis(tert-butoxycarbonyl)oxide can under 25 DEG C～reflux temperature, it is preferable that 50 DEG C～reflux temperature, more preferably carry out under reflux temperature, about 8 hours or until react completely；Hydrazinolysis reaction can at-25 DEG C～50 DEG C, it is preferable that-10 DEG C～about 25 DEG C, carry out at the temperature of more preferably 10 DEG C～25 DEG C, about 4 hours or until react completely。
Compound B by the compound A of following formula, in organic solvent, under alkali existence condition, can be obtained by reacting with substituted or unsubstituted benzyl halide:
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl。Preferred R is in para-position；Preferred R is the alkyl of hydrogen or C1-C3, more preferably hydrogen。
In above-mentioned substituted or unsubstituted benzyl halide, X can be chlorine or bromine, it is preferable that X is bromine；R can be hydrogen, C1-C6 alkyl or C1-C6 alkoxyl, it is preferable that R is hydrogen or C1-C3 alkyl；R can in any unsubstituted position of phenyl ring, it is preferable that R is in para-position。Relative to compound A, the consumption of substituted or unsubstituted benzyl halide generally can at 1 molar equivalent to 5 molar equivalents, it is preferable that 1 molar equivalent is to 3 molar equivalents, and more preferably 1 molar equivalent uses to 1.3 molar equivalents。Available alkali includes potassium tert-butoxide, sodium hydride, hydrofining, double; two (trimethyl silicon based) Lithamide., double; two (trimethyl silicon based) Sodamide., double; two (trimethyl silicon based) potassamide, lithium diisopropylamine, butyl lithium, preferred potassium tert-butoxide, sodium hydride, double; two (trimethyl silicon based) Lithamide., more preferably sodium hydride。Relative to compound A, alkali generally can at 1 molar equivalent to 5 molar equivalents, it is preferable that 1 molar equivalent is to 3 molar equivalents, and more preferably 1 molar equivalent uses to 1.5 molar equivalents。Available solvent includes ether solvent, such as ether, oxolane, methyl tertiary butyl ether(MTBE), Pentamethylene oxide. etc.；Aromatic solvent, for instance toluene, benzene, dimethylbenzene, trimethylbenzene, chlorobenzene etc.；And esters solvent, for instance ethyl acetate etc. or its suitable mixture。Preferred solvent is ether solvent, more preferably oxolane。Reaction can at-25 DEG C～25 DEG C, it is preferable that-10 DEG C～10 DEG C, carry out at the temperature of more preferably-5 DEG C～0 DEG C, about 2 hours or until react completely。
Compound A of the present invention can be prepared by means known in the art, referring particularly to Chinese patent application 201210200429.6。
The invention provides a kind of new compound F-2, the preparation of this compounds, operation is easy, and yield is higher。Using this compounds to can be used for the synthesis of anti-hepatitis C medicine Boceprevir, this is that the synthesis of anti-hepatitis C medicine Boceprevir provides new thinking and method。And convenient with the detection of ultraviolet chromophoric group more original synthetic method in such compound molecule, additionally on hydroxyl, the introducing of benzyl avoids the side reaction caused in condensation step because of hydroxyl nucleophilicity, has certain advantage compared with existing synthetic method。
Detailed description of the invention
The reactions steps below related to for the preferred embodiment of the present invention, outside indicating, all of chemicals of the present invention and solvent all obtain from commercial channel, without being further purified before using。
Embodiment 1-9:R is the preparation of formula 1 compound of hydrogen
Embodiment 1: the preparation of compound B
Compound A (5g, 20.6mmol) is dissolved in 40mlDMF and adds to there-necked flask, be cooled to-5 DEG C；It is dividedly in some parts NaH (60%, 1.1g, 26.8mmol) stir 1h afterwards, 40mlBnBr (4.2g is dripped at-5 DEG C, 24.7mmo) DMF solution, dropwise stirring 2h at this temperature, add frozen water cancellation reaction, with extraction into ethyl acetate, on a small quantity repeatedly, merge organic facies, dry and be evaporated off solvent with anhydrous sodium sulfate after saturated common salt water washing and obtain yellow oil, it is white solid that column chromatography obtains 6.2g compound B, yield 90.4%, m/z (MH+) 334.16, 1HNMR (400MHz, CDCl3) δ 1.31 (t, 3H), 1.41-1.57 (m, 4H), 1.64-1.74 (m, 2H), 1.77 (s, 3H), 1.96-2.06 (m, 2H), 2.25-2.29 (m, 1H), 3.95 (d, 1H), 4.19-4.25 (m, 3H), 4.28 (d, 1H), 4.81 (d, 1H), 5.63 (d, 1H), 7.30-7.35 (m, 5H)。
Embodiment 2: the preparation of compound C
Compound B (5g, 15mmol), DMAP (0.37g, 3mmol) are dissolved in 60mlTHF, add (Boc)2O (6.88ml, backflow it is warming up to after 30mmol), reflux and be down to room temperature after about 8h and add 60ml methanol and hydrazine hydrate (3g, 200ml dchloromethane is added after 60mmol) stirring 4h, reactant liquor is successively with 1NHCl, copper-bath, saturated sodium bicarbonate solution and saturated common salt water washing, anhydrous sodium sulfate is dried, solvent is evaporated off and obtains yellow oil, it is white solid that column chromatography obtains 4.4g compound C, yield 75.0%, m/z (MNa+) 414.06, 1HNMR (400MHz, CDCl3) δ 1.32 (t, 3H), 1.44 (s, 9H), 1.48-1.68 (m, 4H), 1.78-1.87 (m, 2H), 2.02-2.11 (m, 2H), 2.33-2.37 (m, 1H), 3.98 (m, 1H), 4.20-4.32 (m, 3H), 4.43 (d, 1H), 4.65 (d, 1H), 4.81 (d, 1H), 7.30-7.37 (m, 5H)。
Embodiment 3: the preparation of compound D
Compound C (2g, 5mmol) it is dissolved in 20mlMeOH/THF (v/v1:1) solution, add 20ml1MLiOH solution, 4h is stirred at room temperature, add 1M potassium hydrogen sulfate solution and regulate PH to 2, with dichloromethane extraction, merging organic facies, organic facies uses saturated sodium bicarbonate and saturated common salt water washing successively, and anhydrous sodium sulfate obtains compound D after drying and be evaporated off solvent be white solid 1.91g, yield 100%, m/z (MNa+) 386.13。
Embodiment 4: the preparation of compound E
Compound D (1.91g, 5mmol) it is dissolved in the anhydrous THF of 30ml and is cooled to 0 DEG C, add triethylamine (1.9ml, 12.5mmol) add ethyl chloroformate (1.2ml afterwards, 11mmol), ammonia (the 2ml of 30% is added after stirring 15min at 0 DEG C, 13.5mmol) and at 0 DEG C, stir 30min, 20min is stirred after adding ethyl acetate 50ml, sucking filtration removes solid, filtrate is successively with 1M potassium acid sulfate, saturated sodium bicarbonate and saturated common salt solution washing, anhydrous sodium sulfate dries, white solid is obtained after solvent is evaporated off, it is a white solid that column chromatography obtains 3.30g compound E, yield 71.2%。M/z (MNa+) 385.16,1HNMR (400MHz, CDCl3) δ 1.44 (s, 9H), 1.61-1.70 (m, 4H), 1.76-1.90 (m, 2H), 2.03-2.10 (m, 2H), 2.34-2.40 (m, 1H), 3.80-3.98 (m, 1H), 4.47 (s, 1H), 4.60-4.67 (m, 2H), 5.50 (s, 1H), 6.46 (s, 1H), 7.28-7.41 (m, 5H)。
Embodiment 5: the preparation of compound F
By compound E (422mg, 1.12mmol) it is dissolved in 5ml4NHCl/dioxane and stirs 1h, add 10ml dichloromethane after being evaporated by the volatile material of above-mentioned reactant liquor and continue concentration, repeating to obtain 350mg compound F for 4 times is a white solid, yield 100%, m/z (MH+) 263.13。
Embodiment 6: the preparation of formula 1 compound
G-1 (136mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) it is dissolved in 8mlDMF, ice-water bath cools down, add NMM (0.23mml, 1.56mmol), stirring 30min, compound F (117mg, 0.37mmol) add to 8mlDMF, this solution is added to the reaction solution of G-1, 0 DEG C is stirred 2 days, reactant liquor adds 50ml water, with extraction into ethyl acetate reactant liquor, organic facies is washed with 1N hydrochloric acid and saturated sodium bicarbonate solution successively, again with saturated common salt water washing, anhydrous sodium sulfate dries, solvent is evaporated off and obtains the grease of yellow, column chromatography obtains 177mg formula 1 compound, it it is a white solid, yield 78.0%, m/z (MNa+) 634.34, 1HNMR (400MHz, DMSO-d) δ 0.89 (m, 9H), 0.82-1.00 (m, 6H), 1.17 (s, 9H), 1.26 (m, 1H), 1.43 (m, 1H), 1.65-1.74 (m, 4H), 1.78-1.94 (m, 2H), 2.01-2.08 (m, 2H), 2.36-2.40 (m, 1H), 3.74-3.76 (m, 2H), 3.92-3.97 (m, 1H), 4.11 (d, 1H), 4.26 (s, 1H), 4.47 (s, 1H), 4.60-4.67 (m, 2H), 5.52 (s, 1H), 6.44 (s, 1H), 7.28-7.46 (m, 5H), 7.76-8.04 (br, 2H), 8.20-8.30 (s, 1H)。
Embodiment 7: the preparation of compound F-1
G-2 (94mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) are dissolved in 8mlDMF, and ice-water bath cools down, and add NMM (0.23mml, 1.56mmol), stir 30min；Compound F (120mg, 0.37mmol) adds to 8mlDMF, is added to the reaction solution of G-2 by this solution, and 0 DEG C is stirred 2 days；Reactant liquor adds 50ml water, with extraction into ethyl acetate reactant liquor, organic facies is washed with 1N hydrochloric acid and saturated sodium bicarbonate solution successively, again with saturated common salt water washing, anhydrous sodium sulfate dries, solvent is evaporated off and obtains the grease of yellow, column chromatography obtains 146mg compound F-1, it it is a white solid, yield 79.2%, m/z (MNa+) 522.30, 1HNMR (400MHz, DMSO-d) δ 0.92-1.03 (m, 6H), 1.23-1.26 (m, 1H), 1.44 (s, 9H), 1.46-1.50 (m, 1H), 1.64-1.74 (m, 4H), 1.75-1.92 (m, 2H), 2.03-2.08 (m, 2H), 2.38-2.44 (m, 1H), 3.54-3.72 (m, 2H), 3.91-3.97 (m, 1H), 4.13 (d, 1H), 4.49 (s, 1H), 4.60-4.69 (m, 2H), 5.52 (s, 1H), 6.44 (s, 1H), 7.25-7.49 (m, 5H)。
Embodiment 8: the synthesis of compound F-2
By compound F-1 (140mg, 0.28mmol) it is dissolved in 3ml4NHCl/dioxane and stirs 1h, add 10ml dichloromethane after being evaporated by the volatile material of above-mentioned reactant liquor and continue concentration, repeating to obtain 120mg compound F-2 for 4 times is a white solid, yield 100%, m/z (MH+) 400.30。
Embodiment 9: the preparation of formula 1 compound
G-3 (78mg, 0.34mmol), HATU (128mg, 0.34mmol) are dissolved in 8mlDMF, and ice-water bath cools down, and add DIEA (0.18mml, 1.00mmol), stir 30min；Adding to 8mlDMF in compound F-2 (120mg, 0.28mmol), added to the reaction solution of G-2 by this solution, 0 DEG C of stirring is overnight；Reactant liquor adds 50ml water, with extraction into ethyl acetate reactant liquor, organic facies is washed with 1N hydrochloric acid and saturated sodium bicarbonate solution successively, again with saturated common salt water washing, anhydrous sodium sulfate dries, and solvent is evaporated off and obtains the grease of yellow, and column chromatography obtains 118mg formula 1 compound, it is a white solid, yield 68.7%。
Embodiment 10-18:R is methyl and the R preparation at formula 1 compound of para-position
Embodiment 10: the preparation of compound B
Compound A (2g, 8.23mmol) it is dissolved in 10mlDMF to add to there-necked flask, it is cooled to-5 DEG C, it is dividedly in some parts NaH (60%, 0.43g, 10.70mmol) stir 1h afterwards, 10ml is dripped to methyl bromobenzyl (1.83g at-5 DEG C, DMF solution 9.88mmo), dropwise stirring 2h at this temperature, add frozen water cancellation reaction, with extraction into ethyl acetate, on a small quantity repeatedly, merge organic facies, dry with anhydrous sodium sulfate after saturated common salt water washing, solvent is evaporated off and obtains yellow oil, it is white solid that column chromatography obtains 2.4g compound B, yield 82.5%, 1HNMR (400MHz, CDCl3) δ 1.31 (t, 3H), 1.43-1.64 (m, 4H), 1.74-1.78 (m, 2H), 1.83 (s, 3H), 1.97-2.05 (m, 2H), 2.25-2.29 (m, 1H), 2.34 (s, 3H), 4.00 (d, 2H), 4.17-4.33 (m, 4H), 4.77 (d, 1H), 5.58 (d, 1H), 7.16 (d, 2H), 7.23 (d, 2H)。
Embodiment 11: the preparation of compound C
Compound B (1.8g, 5.19mmol), DMAP (0.13g, 1.04mmol) are dissolved in 20mlTHF, add (Boc)2O (2.4ml, 10.38mmol) after be warming up to backflow, reflux and be down to room temperature after about 8h and add 20ml methanol and hydrazine hydrate (1.04g, 20.76mmol) stirring 4h after add 100ml dchloromethane, reactant liquor is successively with 1NHCl, copper-bath, saturated sodium bicarbonate solution and saturated common salt water washing, anhydrous sodium sulfate is dried, solvent is evaporated off and obtains yellow oil, it is white solid that column chromatography obtains 1.34g compound C, yield 63.7%, m/z (MNa+) 428.06, 1HNMR (400MHz, CDCl3) δ 1.32 (t, 3H), 1.43 (s, 9H), 1.50-1.67 (m, 4H), 1.76-1.91 (m, 2H), 2.00-2.10 (m, 2H), 2.30-2.33 (m, 1H), 2.35 (s, 3H), 3.94-3.98 (m, 1H), 4.00 (d, 1H), 4.17-4.38 (m, 3H), 4.64 (d, 1H), 4.79 (d, 1H), 7.17 (d, 2H), 7.27 (d, 2H)。
Embodiment 12: the preparation of compound D
Compound C (1.2g, 2.96mmol) is dissolved in 20mlMeOH/THF (v/v1:1) solution, adds 20ml1MLiOH solution, 4h is stirred at room temperature, add 1M potassium hydrogen sulfate solution and regulate PH to 2, with dichloromethane extraction, merge organic facies, organic facies is successively with saturated sodium bicarbonate and saturated common salt water washing, anhydrous sodium sulfate dries and is evaporated off, and obtains compound D1.2g after solvent, for white solid, yield 100%, m/z (MNa+) 400.13。
Embodiment 13: the preparation of compound E
Compound D (1.2g, 3.19mmol) it is dissolved in the anhydrous THF of 20ml and is cooled to 0 DEG C, add triethylamine (1.1ml, ethyl chloroformate (0.7ml is added after 7.98mmol), 7.02mmol), ammonia (the 1ml of 30% is added after stirring 15min at 0 DEG C, stir 30min 8.61mmol) and at 0 DEG C, 20min is stirred after adding ethyl acetate 50ml, sucking filtration removes solid, filtrate is successively with 1M potassium acid sulfate, saturated sodium bicarbonate and saturated common salt solution washing, anhydrous sodium sulfate dries, white solid is obtained after solvent is evaporated off, column chromatography obtains 831mg compound E, it it is a white solid, yield 69.3%, m/z (MNa+) 399.16, 1HNMR (400MHz, CDCl3) δ 1.43 (s, 9H), 1.60-1.71 (m, 4H), 1.77-1.93 (m, 2H), 2.00-2.10 (m, 2H), 2.35 (s, 3H), 2.36-2.40 (m, 1H), 3.83-3.98 (m, 1H), 4.50 (s, 1H), 4.62-4.69 (m, 2H), 5.50 (s, 1H), 6.47 (s, 1H), 7.18 (d, 2H), 7.25 (d, 2H)。
Embodiment 14: the preparation of compound F
By compound E (400mg, 1.06mmol) it is dissolved in 5ml4NHCl/dioxane and stirs 1h, add 10ml dichloromethane after being evaporated by the volatile material of above-mentioned reactant liquor and continue concentration, repeating to obtain 330mg compound F for 4 times is a white solid, yield 100%, m/z (MH+) 277.13。
Embodiment 15: the preparation of compound 1
G-1 (136mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) it is dissolved in 8mlDMF, ice-water bath cools down, add NMM (0.23mml, 1.56mmol), stirring 30min, compound F (120mg, 0.38mmol) add to 8mlDMF, this solution is added to the reaction solution of G-1, 0 DEG C is stirred 2 days, reactant liquor adds 50ml water, with extraction into ethyl acetate reactant liquor, organic facies is washed with 1N hydrochloric acid and saturated sodium bicarbonate solution successively, again with saturated common salt water washing, anhydrous sodium sulfate dries, solvent is evaporated off and obtains the grease of yellow, column chromatography obtains 173mg formula 1 compound, it it is a white solid, yield 72.7%, m/z (MNa+) 648.34, 1HNMR (400MHz, DMSO-d) δ 0.88-0.92 (m, 9H), 0.81-1.02 (m, 6H), 1.18 (s, 9H), 1.27 (m, 1H), 1.45 (m, 1H), 1.68-1.75 (m, 4H), 1.81-1.94 (m, 2H), 2.03-2.09 (m, 2H), 2.33-2.41 (m, 1H), 2.35 (s, 3H), 3.75-3.77 (m, 2H), 3.92-3.97 (m, 1H), 4.13 (d, 1H), 4.25 (s, 1H), 4.44 (s, 1H), 4.61-4.67 (m, 2H), 5.48 (s, 1H), 6.42 (s, 1H), 7.17 (d, 2H), 7.23 (d, 2H), 7.77-8.04 (br, 2H), 8.20-8.28 (s, 1H)。
Embodiment 16: the preparation of compound F-1
G-2 (94mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) it is dissolved in 8mlDMF, ice-water bath cools down, add NMM (0.23mml, 1.56mmol), stirring 30min, compound F (120mg, 0.38mmol) add to 8mlDMF, this solution is added to the reaction solution of G-2, 0 DEG C is stirred 2 days, reactant liquor adds 50ml water, with extraction into ethyl acetate reactant liquor, organic facies is washed with 1N hydrochloric acid and saturated sodium bicarbonate solution successively, again with saturated common salt water washing, anhydrous sodium sulfate dries, solvent is evaporated off and obtains the grease of yellow, column chromatography obtains 139mg compound F-1, it it is a white solid, yield 73.1%, m/z (MNa+) 536.30, 1HNMR (400MHz, DMSO-d) δ 0.90-1.03 (m, 6H), 1.22-1.26 (m, 1H), 1.44 (s, 9H), 1.48-1.51 (m, 1H), 1.62-1.71 (m, 4H), 1.75-1.92 (m, 2H), 2.03-2.08 (m, 2H), 2.34 (s, 3H), 2.37-2.44 (m, 1H), 3.54-3.70 (m, 2H), 3.90-3.97 (m, 1H), 4.13 (d, 1H), 4.52 (s, 1H), 4.60-4.69 (m, 2H), 5.52 (s, 1H), 6.44 (s, 1H), 7.18 (d, 2H), 7.23 (d, 2H)。
Embodiment 17: the synthesis of compound F-2
By compound F-1 (139mg, 0.27mmol) it is dissolved in 3ml4NHCl/dioxane and stirs 1h, add 10ml dichloromethane after being evaporated by the volatile material of above-mentioned reactant liquor and continue concentration, repeating to obtain 120mg compound F-2 for 4 times is a white solid, yield 100%, m/z (MH+) 414.30。
Embodiment 18: the preparation of formula 1 compound
G-3 (78mg, 0.34mmol), HATU (128mg, 0.34mmol) it is dissolved in 8mlDMF, ice-water bath cools down, add DIEA (0.18mml, 1.00mmol), stirring 30min, compound F-2 (120mg, 0.27mmol) add to 8mlDMF, this solution is added to the reaction solution of G-3, 0 DEG C of stirring is overnight, reactant liquor adds 50ml water, with extraction into ethyl acetate reactant liquor, organic facies is washed with 1N hydrochloric acid and saturated sodium bicarbonate solution successively, again with saturated common salt water washing, anhydrous sodium sulfate dries, solvent is evaporated off and obtains the grease of yellow, column chromatography obtains 102mg formula 1 compound, it it is a white solid, yield 60.2%。
Embodiment 19-27:R is methoxyl group and the R preparation at formula 1 compound of para-position
Embodiment 19: the preparation of compound B
Compound A (4g, 16.46mmol) is dissolved in 10mlDMF and adds to there-necked flask, be cooled to-5 DEG C；It is dividedly in some parts NaH (60%, 0.86g, 21.40mmol) and stirs 1h afterwards；At-5 DEG C, drip the 10ml DMF solution to methoxyl group benzyl chloride (3.08g, 19.75mmol), dropwise stirring 2h at this temperature；Add frozen water cancellation reaction, with extraction into ethyl acetate, on a small quantity repeatedly, merge organic facies, dry with anhydrous sodium sulfate after saturated common salt water washing and solvent is evaporated off obtains yellow oil；It is white solid that column chromatography obtains 2.3g compound B, yield 37.9%, m/z (MH+) 364.16
Embodiment 20: the preparation of compound C
Compound B (2.0g, 5.51mmol), DMAP (134mg, 1.10mmol) are dissolved in 20mlTHF, add (Boc)2O (2.5ml, 11.02mmol) after be warming up to backflow, reflux and be down to room temperature after about 8h and add 20ml methanol and hydrazine hydrate (1.10g, 22.04mmol) stirring 4h after add 100ml dchloromethane, reactant liquor is successively with 1NHCl, copper-bath, saturated sodium bicarbonate solution and saturated common salt water washing, anhydrous sodium sulfate is dried, solvent is evaporated off and obtains yellow oil, it is white solid that column chromatography obtains 1.51g compound C, yield 65.3%, (MNa+) 444.06。
Embodiment 21: the preparation of compound D
Compound C (1g, 2.57mmol) it is dissolved in 20mlMeOH/THF (v/v1:1) solution, add 20ml1MLiOH solution, 4h is stirred at room temperature, add 1M potassium hydrogen sulfate solution and regulate PH to 2, with dichloromethane extraction, merging organic facies, organic facies is successively with saturated sodium bicarbonate and saturated common salt water washing, and anhydrous sodium sulfate dries that to obtain compound D950mg after solvent is evaporated off be white solid, yield 100%, m/z (MNa+) 416.13。
Embodiment 22: the preparation of compound E
Compound D (900mg, 2.29mmol) it is dissolved in the anhydrous THF of 20ml and is cooled to 0 DEG C, add triethylamine (0.8ml, ethyl chloroformate (0.5ml is added after 5.73mmol), 5.04mmol), ammonia (the 0.7ml of 30% is added after stirring 15min at 0 DEG C, stir 30min 8.61mmol) and at 0 DEG C, 20min is stirred after adding ethyl acetate 50ml, sucking filtration removes solid, filtrate is successively with 1M potassium acid sulfate, saturated sodium bicarbonate and saturated common salt solution washing, anhydrous sodium sulfate dries, white solid is obtained after solvent is evaporated off, it is a white solid that column chromatography obtains 587mg compound E, yield 65.4%, m/z (MNa+) 415.16。
Embodiment 23: the preparation of compound F
By compound E (950mg, 2.42mmol) it is dissolved in 5ml4NHCl/dioxane and stirs 1h, add 10ml dichloromethane after being evaporated by the volatile material of above-mentioned reactant liquor and continue concentration, repeating to obtain 795mg compound F for 4 times is a white solid, yield 100%, m/z (MH+) 293.13。
Embodiment 24: the preparation of compound 1
G-1 (136mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) it is dissolved in 8mlDMF, ice-water bath cools down, add NMM (0.23mml, 1.56mmol), stirring 30min, compound F (120mg, 0.37mmol) add to 8mlDMF, this solution is added to the reaction solution of G-1, 0 DEG C is stirred 2 days, reactant liquor adds 50ml water, with dichloromethane extraction reactant liquor, organic facies is washed with 1N hydrochloric acid and saturated sodium bicarbonate solution successively, again with saturated common salt water washing, anhydrous sodium sulfate dries, solvent is evaporated off and obtains the grease of yellow, column chromatography obtains 145mg formula 1 compound, it it is a white solid, yield 61.3%, m/z (MNa+) 664.34, 1HNMR (400MHz, DMSO-d) δ 0.87-0.92 (m, 9H), 0.82-1.02 (m, 6H), 1.18 (s, 9H), 1.28 (m, 1H), 1.44 (m, 1H), 1.66-1.75 (m, 4H), 1.82-1.94 (m, 2H), 2.03-2.09 (m, 2H), 2.33-2.41 (m, 1H), 3.75-3.77 (m, 2H), 3.83 (s, 3H), 3.92-3.97 (m, 1H), 4.13 (d, 1H), 4.25 (s, 1H), 4.44 (s, 1H), 4.61-4.67 (m, 2H), 5.48 (s, 1H), 6.42 (s, 1H), 6.90 (d, 2H), 6.99 (d, 2H), 7.77-8.04 (br, 2H), 8.20-8.28 (s, 1H)。
Embodiment 25: the preparation of compound F-1
G-2 (94mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) it is dissolved in 8mlDMF, ice-water bath cools down, add NMM (0.23mml, 1.56mmol), stirring 30min, compound F (120mg, 0.37mmol) add to 8mlDMF, this solution is added to the reaction solution of G-2, 0 DEG C is stirred 2 days, reactant liquor adds 50ml water, with extraction into ethyl acetate reactant liquor, organic facies is washed with 1N hydrochloric acid and saturated sodium bicarbonate solution successively, again with saturated common salt water washing, anhydrous sodium sulfate dries, solvent is evaporated off and obtains the grease of yellow, column chromatography obtains 126mg compound F-1, it it is a white solid, yield 64.6%, m/z (MNa+) 552.30, 1HNMR (400MHz, DMSO-d) δ 0.91-1.03 (m, 6H), 1.20-1.26 (m, 1H), 1.44 (s, 9H), 1.48-1.51 (m, 1H), 1.62-1.71 (m, 4H), 1.75-1.92 (m, 2H), 2.03-2.08 (m, 2H), 2.38-2.44 (m, 1H), 3.54-3.70 (m, 2H), 3.84 (s, 3H), 3.91-3.97 (m, 1H), 4.11 (d, 1H), 4.52 (s, 1H), 4.63-4.70 (m, 2H), 5.52 (s, 1H), 6.44 (s, 1H), 6.91 (d, 2H), 7.02 (d, 2H)。
Embodiment 26: the synthesis of compound F-2
By compound F-1 (120mg, 0.23mmol) it is dissolved in 3ml4NHCl/dioxane and stirs 1h, add 10ml dichloromethane after being evaporated by the volatile material of above-mentioned reactant liquor and continue concentration, repeating to obtain 105mg compound F-2 for 4 times is a white solid, yield 100%, m/z (MH+) 430.30。
Embodiment 27: the preparation of formula 1 compound
G-3 (30mg, 0.13mmol), HATU (50mg, 0.13mmol) it is dissolved in 8mlDMF, ice-water bath cools down, add DIEA (0.1ml, 0.57mmol), stirring 30min, compound F-2 (50mg, 0.11mmol) add to 8mlDMF, this solution is added to the reaction solution of G-2, 0 DEG C of stirring is overnight, reactant liquor adds 50ml water, with extraction into ethyl acetate reactant liquor, organic facies is washed with 1N hydrochloric acid and saturated sodium bicarbonate solution successively, again with saturated common salt water washing, anhydrous sodium sulfate dries, solvent is evaporated off and obtains the grease of yellow, column chromatography obtains 40mg formula 1 compound, it it is a white solid, yield 57.2%
Embodiment 28: with R formula 1 preparation of compounds of formula 2 compound being hydrogen
By formula 1 compound (50mg, 0.08mmol) it is dissolved in 20ml methanol, add the palladium carbon of 10mg10%, be placed on 40 DEG C, the hydrogen atmosphere of 0.7MP stir overnight, with filtered off through Celite palladium carbon, obtain formula (2) compound 39mg after the concentration of gained filtrate, be a white solid, yield 92.3%, m/z (MNa+) 544.42, HPLC shows that purity is 91.2%。
Embodiment 5
Embodiment 29: with R for formula 1 preparation of compounds of formula 2 compound in para-position of methyl and R
By formula 1 compound (50mg, 0.08mmol) it is dissolved in 20ml methanol, add the palladium carbon of 10mg10%, it is placed on 40 DEG C, the hydrogen atmosphere of 0.7MP stirs overnight, after concentrating with filtered off through Celite palladium carbon gained filtrate, obtain formula (2) compound 37mg, it it is a white solid, yield 89.5%, m/z (MNa+) 544.42, HPLC shows that purity is 90.3%。
Claims (27)
1. following general formula compound F-2:
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, the alkyl of C1-C3 or alkoxyl, and A is acid group。
2. general formula compound F-2 as claimed in claim 1, it is characterised in that: R is in para-position。
3. general formula compound F-2 as claimed in claim 1 or 2, it is characterised in that: R is the alkyl of hydrogen or C1-C3。
4. general formula compound F-2 as claimed in claim 3, it is characterised in that: R is hydrogen。
5. the application of any described compound F-2 of claim 1-4, it is characterised in that: for preparing the compound 2 of following formula
6. the application of compound F-2 as claimed in claim 5, it is characterised in that: the preparation process of compound 2 is as follows:
A) in organic solvent, alkali and under condensing agent existence condition, make compound F-2 and compound G-3 condensation obtain formula 1 compound
B) by compound 1 hydro-reduction
7. the application of compound F-2 as claimed in claim 6, it is characterised in that: the alkali that step a) uses is triethylamine, DIPEA, pyridine or N-methylmorpholine。
8. the application of compound F-2 as claimed in claim 6, it is characterised in that: the condensing agent that step a) uses is EDCI, BOP, PyBOP, CDI, HATU, HBTU or DCC。
9. the application of compound F-2 as claimed in claim 6, it is characterised in that: step a) is additionally added additive HOBT or HOAT。
10. the application of compound F-2 as claimed in claim 9, it is characterised in that: the consumption of additive is 0 to 5 times of moles of compound F-1。
11. the preparation method of the compound F-2 described in claim 1-4, it is characterised in that: compound F-2 is in organic solvent, makes following formula: compound F-1 deprotection base obtain under acid condition
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, the alkyl of C1-C3 or alkoxyl, and A is acid group。
12. the preparation method of compound F-2 as claimed in claim 11, it is characterised in that: the acid of use is hydrochloric acid, sulphuric acid or trifluoroacetic acid。
13. the preparation method of compound F-2 as claimed in claim 11, it is characterised in that: compound F-1 is in organic solvent, alkali and under condensing agent existence condition, makes compound F and compound G-2 condensation obtain:
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, the alkyl of C1-C3 or alkoxyl, and A is acid group。
14. the preparation method of compound F-2 as claimed in claim 13, it is characterised in that: the alkali of use is triethylamine, DIPEA, pyridine or N-methylmorpholine。
15. the preparation method of compound F-2 as claimed in claim 13, it is characterised in that: the condensing agent of use is EDCI, BOP, PyBOP, CDI, HATU, HBTU or DCC。
16. the preparation method of compound F-2 as claimed in claim 13, it is characterised in that: add additive HOBT or HOAT。
17. claim 13-16 arbitrarily as described in the preparation method of compound F-2, it is characterised in that: by compound E in organic solvent, under acid condition, deprotection base obtains compound F
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, the alkyl of C1-C3 or alkoxyl。
18. the preparation method of compound F-2 as claimed in claim 17, it is characterised in that: described acid is hydrochloric acid, sulphuric acid or trifluoroacetic acid。
19. the preparation method of compound F-2 as claimed in claim 17, it is characterised in that: compound E be compound D in organic solvent, under alkali existence condition, direct after react with ethyl chloroformate be obtained by reacting with strong aqua ammonia
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, the alkyl of C1-C3 or alkoxyl。
20. the preparation method of compound F-2 as claimed in claim 19, it is characterised in that: described alkali is triethylamine, DIPEA, pyridine, N-methylmorpholine, Lithium hydrate, sodium hydroxide or potassium hydroxide。
21. the preparation method of compound F-2 as claimed in claim 19, it is characterised in that: described strong aqua ammonia mass concentration is 28-35%。
22. the preparation method of compound F-2 as claimed in claim 19, it is characterised in that: compound D is in organic solvent, under alkali effect, makes compound C hydrolysis obtain
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, the alkyl of C1-C3 or alkoxyl。
23. the preparation method of compound F-2 as claimed in claim 22, it is characterised in that: described alkali is potassium hydroxide, sodium hydroxide or Lithium hydrate。
24. the preparation method of compound F-2 as claimed in claim 22, it is characterised in that: compound C is by the compound B of following formula, in organic solvent, under catalyst action, obtains then through hydrazine hydrate effect after reacting with Bis(tert-butoxycarbonyl)oxide:
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, the alkyl of C1-C3 or alkoxyl。
25. the preparation method of compound F-2 as claimed in claim 24, it is characterised in that: described catalyst is DMAP, triethylamine, butyl lithium or sodium hydroxide。
26. the preparation method of compound F-2 as claimed in claim 24, it is characterised in that: compound B is by the compound A of following formula, in organic solvent, under alkali existence condition, is obtained by reacting with substituted or unsubstituted benzyl halide
Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, the alkyl of C1-C3 or alkoxyl, and X is chlorine or bromine。
27. the preparation method of compound F-2 as claimed in claim 26, it is characterised in that: described alkali is potassium tert-butoxide, sodium hydride, hydrofining, double; two (trimethyl silicon based) Lithamide., double; two (trimethyl silicon based) Sodamide., double; two (trimethyl silicon based) potassamide, lithium diisopropylamine or butyl lithium。
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| WO2008079216A1 (en) * | 2006-12-20 | 2008-07-03 | Schering Corporation | Process for preparing (1r,2s,5s)-n-[(1s)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2s)-2-[[[(1,1-dimethylethyl)amino]-carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide |
| CN101291909A (en) * | 2005-08-19 | 2008-10-22 | 弗特克斯药品有限公司 | Processes and intermediates |
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2013
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101291909A (en) * | 2005-08-19 | 2008-10-22 | 弗特克斯药品有限公司 | Processes and intermediates |
| WO2008079216A1 (en) * | 2006-12-20 | 2008-07-03 | Schering Corporation | Process for preparing (1r,2s,5s)-n-[(1s)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2s)-2-[[[(1,1-dimethylethyl)amino]-carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide |
Non-Patent Citations (1)
| Title |
|---|
| A Potential Therapeutic Agent for the Treatment of Hepatitis C Infection;Srikanth Venkatraman,等;《J. Med. Chem.》;20060907;第49卷(第20期);第6084页制备方法以及第6080页表格5化合物70 * |
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