CN105753844A - Novel method for synthesizing dimethyl dicarbamate dihydrochloride compound - Google Patents
Novel method for synthesizing dimethyl dicarbamate dihydrochloride compound Download PDFInfo
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- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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Abstract
The invention relates to a novel method for synthesizing N,N'[[1,1'-biphenyl]4, 4'-diyl bis[1H-imidazole-5,2-diyl-(2S)-2,1-pyrrolidinediyl[(1S)-1-(1-ethylmethyl)-2-oxo-2,1-ethanediyl]]] dimethyl dicarbamate dihydrochloride. According to the novel method disclosed by the invention, an intermediate [1,1'-biphenylyl]-4,4'-bis(2-carbonylethyl-2, 1-bis)-(S)-bis((methoxycarbonyl)-L-valino-L-proline) is obtained by synthesizing a dipeptide key intermediate MOC-L-valino-L-proline of MOC-L-valine and L-proline and then reacting the dipeptide intermediate with 4,4'-bis(2-bromoacetyl)biphenyl, and then a target product is obtained by carrying out ring closing and salifying. According to the method, a convergent reaction strategy and a shorter synthetic route are adopted, such that the yield is promoted remarkably.
Description
Technical field
The present invention relates to pharmaceutical formulating art, specifically, the present invention provides a kind of synthesis N, N '-[[1,1 '-biphenyl]-4,4 '-diyl double [1H-imidazoles-5,2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] new method of diamino acid dimethyl ester dihydrochloride.
Technical background
N, N '-[[1, 1 '-biphenyl]-4, double [the 1H-imidazoles-5 of 4 '-diyl, 2-diyl-(2S)-2, 1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2, 1-ethane diyl]]] diamino acid dimethyl ester dihydrochloride (Daclatasvir) is the hepatitis medicine of BM Squibb company exploitation, the most respectively in the U.S., Europe and Japan's listing, this product combination oral with Suo Feibuwei (Sofosbuvir) hepatitis cure rate clinically can be more than 90%, listed in most important necessary base therapy list of substance by WHO, there are good result for the treatment of and market prospects；It can act on 1,2,3,4 type hepatitis as a kind of novel anti-hepatitis medicine, and during with other anti-hepatitis drug combinations, clinical cure rate is up to 89%-100%.
US7728027B2 discloses synthesis N, N '-[[1,1 '-biphenyl]-4, double [the 1H-imidazoles-5 of 4 '-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] conventional method of diamino acid dimethyl ester dihydrochloride, see formulas below.Traditional synthetic method is that acetyl biphenyl A1 bromination is obtained 4; 4'-bis-(2-acetyl bromide) biphenyl A2; the L-PROLINE A3 reaction of A2 and protection obtains intermediate A 4; intermediate A 4 cyclization under conditions of ammonium acetate obtains intermediate A 5; intermediate A 5 obtains A6 through deprotection; intermediate A 6 obtains A8 with MOC-L-valine A7 reaction again, then becomes salt to obtain end product A9.
It is above conventional synthesis N, N '-[[1,1 '-biphenyl]-4, double [the 1H-imidazoles-5 of 4 '-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] reaction equation of the method for diamino acid dimethyl ester dihydrochloride.This tradition reaction method is linear synthetic route, be through overprotection and the step of deprotection, and gross production rate is relatively low.And the A2 compound molecule utilization ratio that cost accounting is bigger is relatively low, only about about 20%.
Summary of the invention
nullIt is an object of the invention to provide a kind of brand-new synthesis N,N’-[[1,1 '-biphenyl]-4,Double [the 1H-imidazoles-5 of 4 '-diyl,2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] method of diamino acid dimethyl ester dihydrochloride，Different from conventional method，The method of the present invention does not use the step of protection and deprotection，But by synthesis MOC-L-valine and the two peptide prod key intermediate MOC-L-valine bases-L-PROLINE (the most hereinafter referred to as: dipeptides) of L-PROLINE，Subsequently，By described dipeptides intermediate and 4,The reaction of 4'-bis-(2-acetyl bromide) biphenyl obtains intermediate [1,1'-xenyl]-4,Double (the 2-carbonyl second class-2 of 4'-,1-bis-)-(S)-bis-((methoxycarbonyl)-Valine base-L-PROLINEs)，Eventually pass cyclization and become salt to obtain target product N,N’-[[1,1 '-biphenyl]-4,Double [the 1H-imidazoles-5 of 4 '-diyl,2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] diamino acid dimethyl ester dihydrochloride hydrochloride，The shortcoming that described method overcomes conventional method，Use and converge response strategy and shorter synthetic route，Yield is made to be obviously improved.
The present invention provides a kind of synthesis N, N '-[[1,1 '-biphenyl]-4, double [the 1H-imidazoles-5 of 4 '-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] method of diamino acid dimethyl ester dihydrochloride, it is characterized in that, described reaction equation is as follows:
First acetyl biphenyl B1 bromination is become 4,4'-bis-(2-acetyl bromide) biphenyl B2；Under the effect of condensing agent and alkali, direct and unprotected for MOC-L-valine B3 L-PROLINE is reacted, prepare intermediate MOC-L-valine base-L-PROLINE B4；Subsequently by 4; 4'-bis-(2-acetyl bromide) biphenyl B2 and MOC-L-valine base-L-PROLINE B4 occurs SN2 to react prepared [1 in the basic conditions; 1'-xenyl]-4; double (2-carbonylethyl-2,1-two)-(S)-bis-((the methoxycarbonyl)-Valine base-L-PROLINEs) of 4'-；Carry out cyclization subsequently and salt-forming reaction obtains target product N, N '-[[1,1 '-biphenyl]-4, double [the 1H-imidazoles-5 of 4 '-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] diamino acid dimethyl ester dihydrochloride hydrochloride.
Described alkali is triethylamine, N-diisopropylethylamine, DMAP, pyridine, N-methyl horse coffee quinoline, NaOH, potassium carbonate, sodium carbonate or sodium acid carbonate；Preferably alkali is NaOH.
Above-mentioned alkalescence condition is the alkaline condition by being formed in the presence of triethylamine, N-diisopropylethylamine, DMAP, pyridine, N-methyl horse coffee quinoline, NaOH, potassium carbonate, sodium carbonate or sodium acid carbonate；Preferably formed in the presence of potassium carbonate.
Described condensing agent is 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI), I-hydroxybenzotriazole (HOBT), 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (HATU), O-BTA-tetramethylurea hexafluorophosphate (HBTU), 1-hydroxyl-7-azepine BTA (HABT), hexafluorophosphoric acid BTA-1-base-epoxide tripyrrole alkyl phosphorus (PyBOP), ethyl chloroformate and homologue thereof, N, one or more in N'-carbonyl dimidazoles (CDI) or dicyclohexylcarbodiimide (DCC)；More preferably the composition of 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI) and I-hydroxybenzotriazole (HOBT) is as condensing agent, and wherein the two weight ratio is 1:1.
Preferably, during the reaction of above-mentioned MOC-L-valine B3 direct and unprotected L-PROLINE, adopt and use water as solvent, to replace other organic solvents to participate in reaction, reduce it to the pollution in terms of environment.Here other organic solvents refer to current normally used dichloromethane, acetonitrile, N,N-dimethylformamide, acetone, dimethyl sulfoxide or oxolane.
Additionally, above-mentioned intermediate MOC-L-valine base-L-PROLINE B4 can also use following traditional method to prepare:
The reaction of MOC-L-valine and shielded L-PROLINE being reacted, hydrolysis subsequently removes protection group and obtains intermediate MOC-L-valine base-L-PROLINE.
Unlike the prior art; as raw material 4; 4'-bis-(2-acetyl bromide) biphenyl is only involved in 3 step reactions; and in traditional synthetic route 4; 4'-bis-(2-acetyl bromide) biphenyl participates in 5 step reactions; therefore in the present invention 4, the loss of 4'-bis-(2-acetyl bromide) biphenyl is the least, and its utilization rate is high.
Beneficial effect:
Compare the present invention with prior synthesizing method and there is following several advantage:
1). and N; N '-[[1; 1 '-biphenyl]-4; double [the 1H-imidazoles-5 of 4 '-diyl; 2-diyl-(2S)-2; 1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2; 1-ethane diyl]]] diamino acid dimethyl ester dihydrochloride hydrochloride conventional synthesis route compares; the present invention first synthesizes dipeptide compounds; then with raw material 4; 4'-bis-(2-acetyl bromide) biphenyl is etherified last cyclization and obtains product, and gross production rate, is significantly improved to 71% than former route by 31% original raising；
2). when synthesizing key intermediate MOC-L-valine base-L-PROLINE, it is to avoid the step of protection and deprotection, reduce operating procedure, increase economic efficiency further；
3) method provided by the present invention make that cost accounting is bigger 4,4'-bis-(2-acetyl bromide) biphenyl molecule utilization ratio is greatly improved, and utilization rate is promoted to 75% by original 20%.
Accompanying drawing illustrates:
Accompanying drawing 1: the N synthesized by the present invention, N '-[[1,1 '-biphenyl]-4, double [the 1H-imidazoles-5 of 4 '-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] diamino acid dimethyl ester dihydrochloride 1HNMR collection of illustrative plates.
Detailed description of the invention
Further illustrating the present invention below in conjunction with embodiment, the cited case is not construed as limiting the scope of the invention.Unreceipted concrete experimental technique in embodiment, generally according to the condition described in normal condition and laboratory manual；Used equipment, material, reagent etc., if no special instructions, be commercial sources and be commercially available.
Embodiment 1
Adding 4 in tri-mouthfuls of reaction bulbs of 500mL, 4'-bis-(2-acetyl bromide) biphenyl 20g, N-BOC-L-proline 22.8g and 200mL acetonitrile, 20 degree of lower DIPEA 18.2mL that add, liter high-temperature is to 25 degree, and stirring 3 hours at this temperature.Reaction clarification, organic phase 13% saline solution 100mL washing 3 times, acetonitrile solution also toluene replacement to ethane nitrile content is less than 0.5vol%.
In above-mentioned toluene solution, add 78g ammonium acetate and be heated to 95-100 degree, keeping this temperature to stir 15 hours.When, after reaction completely, reaction system is cooled to 70-80 degree, in system, add 7mL acetic acid, 40mL n-butanol and the acetic acid aqueous solution of 80mL5%.50 degree of lower split-phases.Organic phase is washed with the acetic acid solution of 5%, and organic phase is poured in methanol solution, filters, and filter cake volume ratio is the methylbenzene methanol solution washing of 10:3, and 70 degree lower dry, obtains 19.8g product, productivity 63%.
250mL reaction bulb adds 25g di-t-butyl-N, N'-[[1,1'-biphenyl]-4, double [the 1H-imidazoles-5 of 4'-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] double carbamic acid C, C'-dimethyl ester is dissolved in 250mL methyl alcohol, adds 32.85mL6M hydrochloric acid solution.Stirring 5 hours under 50 degree.It is cooled to room temperature, and is stirred at room temperature 18 hours.Filtering, filter cake 100mL90% methanol aqueous solution washed once and 100mL methyl alcohol washes twice.It is dried to obtain 18.12g product, productivity 79.4% for 50 times.By recrystallizing methanol, the rate of recovery 82.6%.
Weigh MOC-L-valine 15.07g, I-hydroxybenzotriazole 13.69g, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate 16.46g is dissolved in 200mL acetonitrile, stirring one hour under 20 degree.Then in reaction system, add 20.4g di-t-butyl-N, N'-[[1,1'-biphenyl]-4,4'-diyl double [1H-imidazoles-5,2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] double carbamic acid C, C'-dimethyl ester hydrochloride and DIPEA 18.47g, stirring 12 hours under 15 degree.Wash 2 times with 0.5N sodium hydroxide solution 240mL after reaction completely.13% saline solution 120mL washes twice.Organic phase is poured in isopropyl acetate solution, concentrates, and filters.Filtrate adds ethanol solution and is concentrated into 140mL.50 degree of lower addition 1.24M ethanol solution hydrochloride 66.4mL.Add after stirring 3 hours under crystal seed, 50 degree, be cooled to be stirred at room temperature 22 hours.Filtering, the acetone ethanol solution washing of filter cake 2:1, solid is dried to obtain 22.15g product, productivity 76.3% under 70 degree, and total recovery is 31%.
Embodiment 2
Weigh MOC-L-valine 100g in three mouthfuls of reaction bulbs of 2L, add 600mL water, mechanical agitation.1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate 111.61g is added under ice bath, stir about 5 minutes, I-hydroxybenzotriazole 39.33g is added in system, about 1h is stirred under ice bath, having thick white thing to separate out in system, this thick white thing is reactive intermediate.
Weigh L-PROLINE 69.01g in conical flask, add water 120mL dissolving, and transfer in constant pressure funnel, weigh 28.7% sodium hydrate aqueous solution 192g in another constant pressure funnel.Above two solution is added drop-wise in reaction system simultaneously.Within about 1 hour, drip complete.Keeping system temperature during dropping is 0-5 degree.Continue reaction to active ester content less than 0.5%.After completion of the reaction system there is White Flocculus to separate out.
Reaction uses the salt acid for adjusting pH of 2.4N to 1-2 after terminating, filter after separating out a large amount of solid.Filtrate extracts 3 times with dichloromethane.Organic phase is concentrated to give product MOC-L-valine base-L-PROLINE 150g, productivity 96%.
Weigh 30g compound 4, 4'-bis-(2-acetyl bromide) biphenyl is in 1L there-necked flask, 180mL acetone respectively, 47g compound MOC-L-valine base-L-PROLINE, 25g potassium carbonate, 30 degree stirring 2 hours after HPLC detection, with diluted ethyl acetate after after raw material reaction, rotation is evaporated off acetone, organic phase washed with water 200mL washs 2 times, 1N hydrochloric acid 200mL washs 2 times, 13% NaCl 1 time, organic phase anhydrous sodium sulfate is dried, filter, concentrate, obtain 56.6g product [1, 1'-xenyl]-4, double (the 2-carbonyl second class-2 of 4'-, 1-bis-)-(S)-bis-((methoxycarbonyl)-Valine base-L-PROLINEs), productivity 96%.
Weigh 56.6g compound [1; 1'-xenyl]-4; double (the 2-carbonyl second class-2 of 4'-; 1-bis-)-(S)-bis-((methoxycarbonyl)-Valine base-L-PROLINEs) are dissolved in 360mL toluene; ammonium acetate 67g is added in system; under nitrogen protection, 85 degree are stirred overnight.HPLC detects, and after raw material reaction, rotation is evaporated off toluene, with diluted ethyl acetate, separatory after 1N sodium hydrate regulator solution pH=7-8.Organic phase washed with water 200mL washs 2 times, 1N hydrochloric acid 100mL washs 1 time, 13% saline solution 100mL washs 1 time, organic phase anhydrous sodium sulfate is dried, filter, it is concentrated to give 48g thick product N, N'-[[1,1'-biphenyl]-4, double [the 1H-imidazoles-5 of 4'-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] double carbamic acid C, C'-dimethyl ester, purity 91%, productivity 90%.
Weigh 48g compound N, N'-[[1,1'-biphenyl]-4, double [the 1H-imidazoles-5 of 4'-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] double carbamic acid C, C'-dimethyl ester is in tri-mouthfuls of reaction bulbs of 500mL, add ethanol 300mL so that it is be completely dissolved, in system, under 55 degree, drip the ethanol solution hydrochloride 19g of 36%, after keeping this temperature to continue stirring 3 hours, natural cool overnight.System separates out a large amount of solids, filters, and filter cake ethanol washs 2 times, drying obtains end product N, N'-[[1,1'-biphenyl]-4, double [the 1H-imidazoles-5 of 4'-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] double carbamic acid C, C'-dimethyl ester dihydrochloride 40g, productivity 86%, gross production rate 71%.Analysis of spectra data see accompanying drawing 1, specific as follows: 1H NMR (400MHz, DMSO-d6): 15.12 (2H), 8.17 (s, 2H), 8.04 (d, 4H), 7.93 (d, 4H), 7.30 (d, 2H), 5.21 (t, 2H), 4.13 (t, 2H), (4.033-4.012 m, 2H), 3.86-3.81 (m, 2H), 3.46-3.42 (m, 4H), (2.5-2.35 m, 2H), 2.22-2.17 (m, 4H), 2.13-2.08 (m, 2H), 2.03-1.97 (m, 2H), 0.84 (d, 6H), 0.76 (d, 6H).
Embodiment 3
Weigh MOC-L-valine 100g in three mouthfuls of reaction bulbs of 2L, add 600mL dichloromethane, stirring.1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate 111.61g is added under ice bath, stir after being completely dissolved to it (about 5min), in system, add I-hydroxybenzotriazole 78.67g, stir under ice bath and be completely dissolved (about 1h) to it.The content continuing to react to raw material MOC-L-valine is less than 0.5%.After it has reacted, washing twice (500mL*2) with water 500mL, 13% saline solution (300mL) washed once.Organic phase is directly transferred in tri-mouthfuls of reaction bulbs of 2L without being dried.
Weigh L-PROLINE 69.01g in conical flask, add water 120mL dissolving, and transfer in constant pressure funnel, weigh 73.77g DIPEA in another constant pressure funnel.Above two solution is added drop-wise in reaction system simultaneously.Within about 1 hour, drip complete.Keeping system temperature during dropping is 0-5 degree.Continue reaction to active ester content less than 0.5%.
Reaction uses the salt acid for adjusting pH of 2.4N to 1-2 after terminating, filter after separating out a large amount of solid.Filter cake 200mL water washs 2 times.Filtrate is layered, and organic phase 1N hydrochloric acid 200mL washs 2 times, and 200mL water washed once, and 13% saline solution 200mL washed once, and anhydrous sodium sulfate is dried, and filters, is concentrated to give MOC-L-valine base-L-PROLINE 140g, productivity 90%.
Weigh 30g compound 4, 4'-bis-(2-acetyl bromide) biphenyl is in 1L there-necked flask, 180mL acetone respectively, 47g compound MOC-L-valine base-L-PROLINE, 25g potassium carbonate, 30 degree stirring 2 hours after HPLC detection, with diluted ethyl acetate after after raw material reaction, rotation is evaporated off acetone, organic phase washed with water 200mL washs 2 times, 1N hydrochloric acid 200mL washs 2 times, 13% NaCl 1 time, organic phase anhydrous sodium sulfate is dried, filter, concentrate, obtain 56.6g product [1, 1'-xenyl]-4, double (the 2-carbonyl second class-2 of 4'-, 1-bis-)-(S)-bis-((methoxycarbonyl)-Valine base-L-PROLINEs), productivity 96%.
Weigh 56.6g compound [1; 1'-xenyl]-4; double (the 2-carbonyl second class-2 of 4'-; 1-bis-)-(S)-bis-((methoxycarbonyl)-Valine base-L-PROLINEs) are dissolved in 360mL toluene; ammonium acetate 67g is added in system; under nitrogen protection, 85 degree are stirred overnight.HPLC detects, and after raw material reaction, rotation is evaporated off toluene, with diluted ethyl acetate, separatory after 1N sodium hydrate regulator solution pH=7-8.Organic phase washed with water 200mL washs 2 times, 1N hydrochloric acid 100mL washs 1 time, 13% saline solution 100mL washs 1 time, organic phase anhydrous sodium sulfate is dried, filter, it is concentrated to give 48g thick product N, N'-[[1,1'-biphenyl]-4, double [the 1H-imidazoles-5 of 4'-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] double carbamic acid C, C'-dimethyl ester, purity 91%, productivity 90%.
Weigh 48g compound N, N'-[[1,1'-biphenyl]-4, double [the 1H-imidazoles-5 of 4'-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] double carbamic acid C, C'-dimethyl ester is in tri-mouthfuls of reaction bulbs of 500mL, add ethanol 300mL so that it is be completely dissolved, in system, under 55 degree, drip the ethanol solution hydrochloride 19g of 36%, after keeping this temperature to continue stirring 3 hours, natural cool overnight.System separates out a large amount of solids, filters, and filter cake ethanol washs 2 times, drying obtains end product N, N'-[[1,1'-biphenyl]-4, double [the 1H-imidazoles-5 of 4'-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] double carbamic acid C, C'-dimethyl ester dihydrochloride 40g, productivity 86%, gross production rate 66%.
Embodiment 4
Adding 5g Moc-L-valine, oxolane 25mL, DIPEA 7.37g in 100mL there-necked flask, stirring makes it be completely dissolved.Under ice bath, in system, drip 2.83g methylchloroformate, drip complete follow-up continuous stirring 1 hour, reaction system separates out a large amount of solid.It is filtered to remove the solid of precipitation.In filtrate systems, add 3.45g L-PROLINE under ice bath, be stirred overnight.Adding 1N hydrochloric acid solution in the HPLC detection complete backward system of intermediate reaction, and regulate pH to 1,50mL ethyl acetate extracts 3 times, and organic layer anhydrous sodium sulfate is dried, and filtering and concentrating obtains crude product 7.67g, productivity 85%.
Weigh 30g compound 4, 4'-bis-(2-acetyl bromide) biphenyl is in 1L there-necked flask, 180mL acetone respectively, 47g compound MOC-L-valine base-L-PROLINE, 25g potassium carbonate, 30 degree stirring 2 hours after HPLC detection, with diluted ethyl acetate after after raw material reaction, rotation is evaporated off acetone, organic phase washed with water 200mL washs 2 times, 1N hydrochloric acid 200mL washs 2 times, 13% NaCl 1 time, organic phase anhydrous sodium sulfate is dried, filter, concentrate, obtain 56.6g product [1, 1'-xenyl]-4, double (the 2-carbonyl second class-2 of 4'-, 1-bis-)-(S)-bis-((methoxycarbonyl)-Valine base-L-PROLINEs), productivity 96%.
Weigh 56.6g compound [1; 1'-xenyl]-4; double (the 2-carbonyl second class-2 of 4'-; 1-bis-)-(S)-bis-((methoxycarbonyl)-Valine base-L-PROLINEs) are dissolved in 360mL toluene; ammonium acetate 67g is added in system; under nitrogen protection, 85 degree are stirred overnight.HPLC detects, and after raw material reaction, rotation is evaporated off toluene, with diluted ethyl acetate, separatory after 1N sodium hydrate regulator solution pH=7-8.Organic phase washed with water 200mL washs 2 times, 1N hydrochloric acid 100mL washs 1 time, 13% saline solution 100mL washs 1 time, organic phase anhydrous sodium sulfate is dried, filter, it is concentrated to give 48g thick product N, N'-[[1,1'-biphenyl]-4, double [the 1H-imidazoles-5 of 4'-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] double carbamic acid C, C'-dimethyl ester, purity 91%, productivity 90%.
Weigh 48g compound N, N'-[[1,1'-biphenyl]-4, double [the 1H-imidazoles-5 of 4'-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] double carbamic acid C, C'-dimethyl ester is in tri-mouthfuls of reaction bulbs of 500mL, add ethanol 300mL so that it is be completely dissolved, in system, under 55 degree, drip the ethanol solution hydrochloride 19g of 36%, after keeping this temperature to continue stirring 3 hours, natural cool overnight.System separates out a large amount of solids, filters, and filter cake ethanol washs 2 times, drying obtains 40g end product N, N'-[[1,1'-biphenyl]-4, double [the 1H-imidazoles-5 of 4'-diyl, 2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] double carbamic acid C, C'-dimethyl ester dihydrochloride, productivity 86%, gross production rate 63%.
1H NMR(400MHz,DMSO-d6):15.12(2H),8.17(s,2H),8.04(d,4H),7.93(d,4H),7.30(d,2H),5.21(t,2H),4.13(t,2H),4.033-4.012(m,2H),3.86-3.81(m,2H),3.46-3.42(m,
4H),2.5-2.35(m,2H),2.22-2.17(m,4H),2.13-2.08(m,2H),2.03-1.97(m,2H),0.84(d,6H),0.76(d,6H)。
As can be seen from the above-described embodiment, embodiment 1 uses existing preparation method, its productivity is 76.3%, gross production rate is 31%, and embodiment 2 is embodiments of the invention, its productivity is 86%, and gross production rate is more up to 71%, in addition embodiment 3 and embodiment 4 are optimized respectively on solvent and route, and it is also significantly larger than prior art on productivity and gross production rate.As can be seen here, the preparation method of the application has excellent technique effect.
A kind of synthesis N of the present invention, N '-[[1, 1 '-biphenyl]-4, double [the 1H-imidazoles-5 of 4 '-diyl, 2-diyl-(2S)-2, 1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2, 1-ethane diyl]]] new method of diamino acid dimethyl ester dihydrochloride is described by concrete example, those skilled in the art can use for reference present invention, suitably feed change, the links such as process conditions realize other purpose corresponding, its relevant change is all without departing from present disclosure, all similar replacements and change it will be apparent to those skilled in the art that, it is considered as being included within the scope of the present invention.
Claims (8)
1. a synthesis N, N '-[[1,1 '-biphenyl]-4,4 ' double [1H-imidazoles-5,2-diyl-(the 2S)-2,1-pyrrolidines two of-diyl
Base [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] method of diamino acid dimethyl ester dihydrochloride, its
Being characterised by, described reaction equation is as follows:
First acetyl biphenyl B1 bromination is become 4,4'-bis-(2-acetyl bromide) biphenyl B2；Under the effect of condensing agent and alkali,
Direct and unprotected for MOC-L-valine B3 L-PROLINE is reacted, prepares intermediate MOC-L-valine base
-L-PROLINE B4；Subsequently by 4,4'-bis-(2-acetyl bromide) biphenyl B2 and MOC-L-valine base-L-PROLINE B4
SN2 reaction is occurred to prepare double (2-carbonylethyl-2,1-two)-(S)-the bis-((first of [1,1'-xenyl]-4,4'-in the basic conditions
Epoxide carbonyl)-Valine base-L-PROLINE)；Carry out cyclization subsequently and salt-forming reaction obtains target product
N, N '-[[1,1 '-biphenyl]-4,4 ' double [1H-imidazoles-5,2-diyl-(2S)-2,1-pyrrolidines diyl [(1S)-1-(the 1-methyl of-diyl
Ethyl)-2-oxo-2,1-ethane diyl]]] diamino acid dimethyl ester dihydrochloride.
Synthesis N, N ' the most according to claim 1-[[1,1 '-biphenyl]-4,4 ' double [1H-imidazoles-5,2-diyl of-diyl
-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] diamino acid dimethyl ester
The method of dihydrochloride, it is characterised in that described alkali be triethylamine, N-diisopropylethylamine, DMAP,
Pyridine, N-methyl horse coffee quinoline, NaOH, potassium carbonate, sodium carbonate or sodium acid carbonate.
Synthesis N, N ' the most according to claim 2-[[1,1 '-biphenyl]-4,4 ' double [1H-imidazoles-5,2-diyl of-diyl
-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] diamino acid dimethyl ester
The method of dihydrochloride, it is characterised in that described alkali is preferably NaOH.
Synthesis N, N ' the most according to claim 1-[[1,1 '-biphenyl]-4,4 ' double [1H-imidazoles-5,2-diyl of-diyl
-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] diamino acid dimethyl ester
The method of dihydrochloride, it is characterised in that described alkalescence condition is by triethylamine, N-diisopropylethylamine, 4-
In the presence of dimethylamino naphthyridine, pyridine, N-methyl horse coffee quinoline, NaOH, potassium carbonate, sodium carbonate or sodium acid carbonate
The alkaline condition formed.
Synthesis N, N ' the most according to claim 1-[[1,1 '-biphenyl]-4,4 ' double [1H-imidazoles-5,2-diyl of-diyl
-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] diamino acid dimethyl ester
The method of dihydrochloride, it is characterised in that described condensing agent is 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimine
Hydrochloride, I-hydroxybenzotriazole, 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester, O-
BTA-tetramethylurea hexafluorophosphate, 1-hydroxyl-7-azepine BTA, hexafluorophosphoric acid BTA-1-base-
Epoxide tripyrrole alkyl phosphorus, ethyl chloroformate and homologue, N, N'-carbonyl dimidazoles or dicyclohexylcarbodiimide
In one or more.
Synthesis N, N ' the most according to claim 5-[[1,1 '-biphenyl]-4,4 ' double [1H-imidazoles-5,2-diyl of-diyl
-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] diamino acid dimethyl ester
The method of dihydrochloride, it is characterised in that described condensing agent is 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimine
The composition of hydrochloride and I-hydroxybenzotriazole is as condensing agent, and the two weight ratio is 1:1.
Synthesis N, N ' the most according to claim 1-[[1,1 '-biphenyl]-4,4 ' double [1H-imidazoles-5,2-diyl of-diyl
-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] diamino acid dimethyl ester
The method of dihydrochloride, it is characterised in that the described direct and unprotected L-PROLINE of MOC-L-valine B3 is anti-
At once, preferably by water as solvent.
8. according to synthesis N, N ' according to claim 1-[[1,1 '-biphenyl]-4,4 ' double [1H-imidazoles-5,2-two of-diyl
Base-(2S)-2,1-pyrrolidines diyl [(1S)-1-(1-Methylethyl)-2-oxo-2,1-ethane diyl]]] diamino acid diformazan
The method of ester dihydrochloride, it is characterised in that under described intermediate MOC-L-valine base-L-PROLINE B4 uses
Method of stating prepares:
The reaction of MOC-L-valine and shielded L-PROLINE being reacted, hydrolysis subsequently removes protection group and obtains centre
Body MOC-L-valine base-L-PROLINE.
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| CN106883138B (en) * | 2017-03-01 | 2018-07-10 | 郑州大学第一附属医院 | The preparation method of tiger element |
| CN107501243A (en) * | 2017-09-08 | 2017-12-22 | 安徽灵药业有限公司 | A kind of synthetic method of his Wei of Dacca |
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