CN104844524A - Synthetic method of ambrisentan - Google Patents
Synthetic method of ambrisentan Download PDFInfo
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- CN104844524A CN104844524A CN201510252569.1A CN201510252569A CN104844524A CN 104844524 A CN104844524 A CN 104844524A CN 201510252569 A CN201510252569 A CN 201510252569A CN 104844524 A CN104844524 A CN 104844524A
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- RQJWOLFMWKZKCJ-UHFFFAOYSA-N COC(C(C(O)=O)O)(c1ccccc1)c1ccccc1 Chemical compound COC(C(C(O)=O)O)(c1ccccc1)c1ccccc1 RQJWOLFMWKZKCJ-UHFFFAOYSA-N 0.000 description 1
- 0 COC([C@@](*)O)(c1ccccc1)c1ccccc1 Chemical compound COC([C@@](*)O)(c1ccccc1)c1ccccc1 0.000 description 1
- ZHPSNGCLCHWTRG-UHFFFAOYSA-N Cc1nc(S(C)(=O)=O)nc(C)c1 Chemical compound Cc1nc(S(C)(=O)=O)nc(C)c1 ZHPSNGCLCHWTRG-UHFFFAOYSA-N 0.000 description 1
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
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- C07D239/34—One oxygen atom
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Abstract
The invention relates to a synthetic method of ambrisentan and belongs to the technical field of medicine chemistry. The method comprises the steps of taking a racemoid 1 as a reactant, performing L-proline methyl ester hydrochloride resolution on a compound 1 to obtain a crude product of compound 2, performing nucleophilic reaction on the crude product of the compound 2 and a compound 3 to obtain compound 4. After an enantiomer of the compound 2 of compound 1 is filtered our by resolution, methyl tertiary butyl ether phase obtained by extracting hydrochloric acid free filtrate is used for drying a solvent through distillation to obtain the crude product of the compound 2 which is directly subjected to nucleophilic reaction with the compound 3, a qualified compound 4 is obtained by a subsequent process purifying treatment (comprising decoloration and salifying), the process operation is simplified, process stability is enhanced, loss of the compound 2 caused by crystallization of methylbenzene or crystallization for multiple times is avoided, and cost of process materials is greatly reduced. Lithium amide and sodium-hydrogen are innovatively substituted by lithium hydrate, safety is higher, cost is lower, lithium hydrate is proper in alkalinity, and a reaction system has few impurity points and is suitable for industrialized amplification production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, relate to a kind of synthetic method of ambrisentan.
Background technology
Ambrisentan, formal name used at school is (+)-(2S)-2-[(4,6-dimethyl pyrimidine-2-base) oxygen base]-3-methoxyl group-3,3-diphenyl-propionic acid, in 2007 through U.S. FDA approval listing, be used for the treatment of pulmonary hypertension, to improve the motor capacity of patient, improve quality of life.This medicine is less to liver untoward reaction, has a wide range of applications sight.Therefore, the technique study on the synthesis tool of this medicine is of great significance.
Patent WO9841206 discloses the enantiomer utilizing L-PROLINE methyl ester hydrochloride to carry out splitting elimination compound 2, and filtrate is dissociated and obtained very pure compound 2 (ee. is not less than 99%) through toluene crystallization, and splitting total recovery is 35%.The ee value (mapping excessive value) that in splitting step, final crystallization goes out compound 2 affects very large by system cooling process, technological operation has certain unstable.
Patent CN103086877 discloses when the reactions steps utilizing L-PROLINE methyl esters to carry out the fractionation of 2 hydroxy propanoic acid class racemic mixture is amplified to 100kg, toluene needs crystallization repeatedly just can obtain optically pure compound 2, certainly will cause the growth of process costs and increase complex process degree.
Patent DE202009009917U1, WO2011114338 are reported in follow-up nucleophilic reaction, and compound 2 finally obtains ambrisentan and compound 4 with compound 3 nucleophilic under Lithamide or the effect of sodium hydrogen, and report yield is about 61%.And Lithamide or this quasi-alkali of sodium hydrogen extremely responsive to aqueous vapor, amplification produce in certainly will there is certain potential safety hazard.
Patent CN102276536 discloses a kind of preparation method of optically pure (+)-ambrisentan, and the method synthesis step is complicated, and the reagent participating in reaction is many, and productive rate is low, can not scale operation.
Summary of the invention
In order to overcome the deficiencies in the prior art, the invention provides a kind of synthetic method of ambrisentan, the method is easy and simple to handle, productive rate is high, operational safety.
The invention provides following technical scheme:
A synthetic method for ambrisentan, with racemoid 1 for reactant, compound 1 splits to obtain compound 2 crude product through L-PROLINE methyl ester hydrochloride, and compound 2 crude product and compound 3 nucleophilic reaction occur under the effect of alkali and obtain compound 4,
Described synthetic method is reacted according to following route:
The whole operating process of synthetic method of the present invention is equivalent to one kettle way, need not with solvent as compound 2 crude product be refined by toluene further, and gained compound 2 crude product need not take out oven dry from conversion unit, but directly add nucleophilic reaction solvent after solvent evaporate to dryness and compound 3 carries out nucleophilic reaction under alkali effect.It is 137:225 that the consumption of L-PROLINE methyl ester hydrochloride is preferably with the mass ratio of compound 1.
In such scheme preferably, described nucleophilic reaction alkali used is lithium hydroxide or lithium hydroxide monohydrate.
The present invention uses lithium hydroxide or lithium hydroxide monohydrate to replace Lithamide and sodium hydrogen innovatively, and security is higher, and cost is lower, and lithium hydroxide basic is moderate, and reaction system impurity is little, is more suitable for industrial amplification production.
In above-mentioned either a program preferably, there is nucleophilic reaction with compound 3 after described compound 2 crude product removing solvent seasoning.
In above-mentioned either a program preferably, the consumption of described alkali is 3.5 ~ 5 equivalents of compound 2 crude product removing solvent seasoning after product.
Described alkali consumption I haven't seen you for ages cause reaction cannot transform completely, consumption is excessive certainly will be wasted and compound 3 can be caused to decompose.
In above-mentioned either a program preferably, the consumption of described alkali is preferably 4 equivalents of compound 2 crude product removing solvent seasoning after product.
In above-mentioned either a program preferably, the solvent of described nucleophilic reaction is tetrahydrofuran (THF) (THF) or DMF (DMF).
As long as nucleophilic reaction use the consumption of solvent to control organic raw material to be dissolved into, reaction can occur.Wherein the consumption of tetrahydrofuran (THF) is preferably the volume mass ratio removing solvent seasoning after product with described compound 2 crude product is 5.7ml:1g; It is 4ml:1g that the consumption of DMF is preferably the volume mass ratio removing solvent seasoning after product with described compound 2 crude product.Both ensure that reaction efficiency, can not process costs be increased again.
Because little polar solvent is limited to material dissolution degree, nucleophilic reaction difficulty transforms, and above-mentioned two kinds of solvent polarities are comparatively large, and be beneficial to the carrying out of nucleophilic reaction, wherein the effect of DMF is more excellent, and raw material and mineral alkali lithium hydroxide all have certain solubleness, and reaction efficiency is higher.
In above-mentioned either a program preferably, the temperature of reaction of described nucleophilic reaction is 25 ~ 50 DEG C.
Nucleophilic reaction temperature too low namely lower than 25 DEG C time, reaction is reacted very slowly or hardly, and temperature too high (more than 50 DEG C) reaction is very fast, but can produce more impurity in system or compound 3 is decomposed more, makes reaction yield on the low side.
In above-mentioned either a program preferably, resolved product, without separation, is directly used in nucleophilic reaction.
Without the need to being separated resolved product after the present invention splits, can be directly used in nucleophilic reaction, easy to operate, process is simple.
In above-mentioned either a program preferably, the mass ratio that described compound 3 and described compound 2 crude product remove solvent seasoning after product is at least 96.8:115.
The consumption of described compound 3 is to ensure that compound 2 can transform complete, is at least 1 equivalent.
In above-mentioned either a program preferably, the ee value of described compound 2 crude product removing solvent seasoning after product is 75 ~ 85%.
In above-mentioned either a program preferably, described building-up reactions also comprises the aftertreatment purge process to nucleophilic product.
In above-mentioned either a program preferably, described aftertreatment purge process comprises the decolorization and salification process of carrying out successively.
Described decolorization can be decoloured to nucleophilic product, separately also can the raceme of elimination compound 4 optical purity of 4 be significantly improved; Described salification process is refining further compound 4, finally can control impurity and be no more than 0.10%.
In above-mentioned either a program preferably, the decolouring solvent that described decolorization uses is methyl alcohol.
In above-mentioned either a program preferably, the consumption of described methyl alcohol is 8 ~ 10 with the volume mass ratio (ml/g) of nucleophilic product, is preferably 9.
In above-mentioned either a program preferably, the decolouring solvent that described decolorization uses is ethyl acetate.
In above-mentioned either a program preferably, the consumption of described ethyl acetate is 25 ~ 30 with the volume mass ratio (ml/g) of nucleophilic product, is preferably 26.
In above-mentioned either a program preferably, the decolouring solvent that described decolorization uses is acetone.
In above-mentioned either a program preferably, the consumption of described acetone is 15 ~ 20 with the volume mass ratio (ml/g) of nucleophilic product, is preferably 15.
The selection of above-mentioned decolouring solvent species and consumption can make required optically pure compound 4 all dissolve, and the raceme as impurity is then insoluble.
In above-mentioned either a program preferably, the temperature of described decolorization is 20 ~ 35 DEG C.
The temperature of described decolorization controls at room temperature, avoids low temperature or high temperature, easy and simple to handle, is easy to control.
In above-mentioned either a program preferably, described decolorization uses gac to decolour.
In above-mentioned either a program preferably, the consumption of described gac is preferably 0.1 times of nucleophilic product quality.
In above-mentioned either a program preferably, described methyl alcohol continues the one-tenth salt solvent that uses as described salification process.
In above-mentioned either a program preferably, described ethyl acetate continues the one-tenth salt solvent that uses as described salification process.
In above-mentioned either a program preferably, the one-tenth salt solvent that described salification process uses is methyl alcohol.
In above-mentioned either a program preferably, the consumption of described methyl alcohol is 8 ~ 10 with the volume mass ratio (ml/g) of nucleophilic product, is preferably 9.
In above-mentioned either a program preferably, the one-tenth salt solvent that described salification process uses is ethyl acetate.
In above-mentioned either a program preferably, the consumption of described ethyl acetate is 25 ~ 30 with the volume mass ratio (ml/g) of nucleophilic product, is preferably 26.
When the decolouring solvent that decolorization uses is for methyl alcohol or ethyl acetate, the methyl alcohol added or ethyl acetate continue as becoming salt solvent to use, without the need to additionally adding into salt solvent in salification process.And when the decolouring solvent that decolorization uses is for acetone, because acetone, with ammonia, chemical reaction can occur, needs filtrate evaporate to dryness, after then adding new ethyl acetate or methyl alcohol, carry out salification process again.
The product that the material obtained after above-mentioned nucleophilic product all refers to nucleophilic reaction obtains after drying, i.e. compound 4 crude product.
In above-mentioned either a program preferably, the positively charged ion form of salify is ammonium ion.
In the present invention, salification process generates the positively charged ion form of salt is ammonium ion, and relative to use organic amine (as p-nitrophenyl ethamine) salify, cost is lower, has obvious advantage.
In above-mentioned either a program preferably, the salt-forming reagent feed postition of salt system is become to be directly pass into dry ammonia.
In above-mentioned either a program preferably, become the salt-forming reagent feed postition of salt system for instillation ammonia organic solvent solution.
Described ammonia organic solvent solution is the solution that ammonia and organic solvent are formed, and the organic solvent of use is preferably methyl alcohol or ethanol.The organic solvent used can not with ammonia generation chemical reaction.
In above-mentioned either a program preferably, the temperature of reaction becoming salt system is 20 ~ 35 DEG C.
The temperature of described salification process controls at room temperature, avoids low temperature or high temperature, easy and simple to handle, is easy to control.
In above-mentioned either a program preferably, the reaction product of described salification process mixes with methyl alcohol and methyl tertiary butyl ether after desolventizing.
The volume ratio of described methyl alcohol and methyl tertiary butyl ether is 1:10, and the consumption of described methyl alcohol and the volume mass of nucleophilic product are than being 10ml:1g.
The object of above-mentioned steps is the solubleness of ammonium salt in system in order to utilize methyl alcohol and methyl tertiary butyl ether to reduce compound 4, improves yield.
In above-mentioned either a program preferably, in described compound 4, the content of single contaminant (comprising optical isomer) is no more than 0.10%.
In the compound 4 that the present invention finally obtains, the content of arbitrary impurity is no more than 0.10%.
In the present invention, compound 1 is after splitting the enantiomer of elimination compound 2, utilizing hydrochloric acid, free (in split process, in compound 1, carboxyl forms salt with amino in L-PROLINE methyl esters, need to add hydrochloric acid and compound 2 is formed free state, dissociate by the salt in above-mentioned, form carboxyl freely) methyl tertiary butyl ether (MTBE) the phase solvent evaporated of filtrate extraction gained obtain compound 2 crude product directly and compound 3 nucleophilic, qualified compound 4 is obtained again through subsequent technique purification process (comprising decolouring and salify), Simplified flowsheet operates, technical process is short, enhance the stability of technique, avoid because of toluene crystallization or repeatedly crystallization cause the loss of compound 2, greatly reduce process stream cost.Meanwhile, in the nucleophilic reaction process of compound 2 and 3, the present invention uses lithium hydroxide to replace Lithamide and sodium hydrogen innovatively, and security is higher, and cost is lower, and lithium hydroxide basic is moderate, and the assorted point of reaction system seldom, is more suitable for industrial amplification production.There is no document first-hand report at present uses lithium hydroxide or lithium hydroxide monohydrate to carry out nucleophilic reaction.The whole operating process of synthetic method of the present invention is equivalent to one kettle way, polystep reaction is simplified, and aftertreatment is simple, easy to operate, and reaction conditions is gentle, and productive rate is high, and cost is low.
Embodiment
In order to understand technical characteristic of the present invention further, below in conjunction with specific embodiment, the present invention is set forth in detail.Embodiment only has exemplary effect to the present invention, and does not have any restrictive effect, the amendment of any unsubstantiality that those skilled in the art makes on basis of the present invention, all should belong to protection scope of the present invention.
Embodiment 1: a kind of synthetic method of ambrisentan
Under room temperature (20 ~ 25 DEG C), 137g L-PROLINE methyl ester hydrochloride is mixed in 130ml methyl alcohol (MeOH), control temperature is no more than 25 DEG C, the solution that dropping 44.7g sodium methylate and 132ml MeOH are made into, 4800ml methyl tertiary butyl ether (MTBE) and 225g compound 1 is added after being added dropwise to complete, after stirring half an hour, normal pressure boils off MTBE/MeOH mixed solvent about 2680ml, distillation temperature is 50 ~ 55 DEG C, still-process probably continues 2 ~ 3 hours, after be naturally down to 20 ~ 25 DEG C, filtration under diminished pressure removes system solid.Filtrate decompression steams extremely about 900ml (can adopt water pump underpressure distillation, temperature is generally-5 ~ 5 DEG C), add water 1000ml, adjust system PH to acid (can control ph be 1 ~ 4) with concentrated hydrochloric acid, leave standstill branch vibration layer, aqueous phase 400ml MTBE back extraction, merge MTBE, dried over sodium sulfate, filters, and evaporated under reduced pressure MTBE obtains solid 115.0g (it is 83% that HPLC shows ee).Add DMF (DMF) 458ml, decompression is steamed to 50 DEG C, makes compound 2 crude product clearly molten simultaneously; add Lithium Hydroxide Monohydrate 74g after system being as cold as room temperature, argon replaces is protected, and adds 96.8g compound 3 in batches; 1h/ time, add for totally 6 times, after ambient temperature overnight.HPLC detection next day starting compound 2 is no more than 1%, otherwise add minority specioz 3 and corresponding ratio Lithium Hydroxide Monohydrate, after having reacted, system slowly instills in 2200ml water, with concentrated hydrochloric acid regulation system PH to acid (can control ph be 1 ~ 4), filters after stirring half an hour, solid washed with water is to neutral, obtain wet product 486.4g, can obtain dry product 157.8g after 50 DEG C of forced air dryings, crude product total recovery is 50.5%.This crude product is mixed in 1420ml MeOH and adds gac 15.8g after room temperature making beating 2h, stirs after 5 minutes and filters.Filtrate goes in reaction flask and passes into dry ammonia to system PH is alkalescence (can control ph be 8 ~ 9), and stir 15 minutes, repetition measurement system PH is constant, stir half an hour, evaporated under reduced pressure MeOH, adds new MeOH158ml, MTBE1580ml, stirring to pulp spends the night.Filter gained wet product next day and obtain dry product after 50 DEG C of forced air dryings, it is molten clearly in the mixed solvent of 1580ml acetone and 1580ml purified water, drip 3M HCl to system PH to acid (can control ph be 1 ~ 4), stir after 2 hours and filter, gained wet product 1580ml water filters after pulling an oar 10 minutes and washes filter cake with water to neutral, forced air drying, obtains dry product 101.4g, and total recovery is 32.4%.Gained sample HPLC purity is not less than 99.8%, and single contaminant is no more than 0.1%, and optical purity is not less than 99.9%, and enantiomer is no more than 0.1%.Product chromatogram analysis data: m.p.:182.7 ~ 183.6.1H NMR(400MHz，DMSO-d6):δ:2.32(s，6H)，3.36(s，3H)，6.13(s，1H)，6.93(s，1H)，7.19～7.33(m，10H)，12.54(s，1H)。
Embodiment 2:
Under room temperature (20 ~ 25 DEG C), 137g L-PROLINE methyl ester hydrochloride is mixed in 130ml MeOH, control temperature is no more than 25 DEG C, the solution that dropping 44.7g sodium methylate and 132ml MeOH are made into, adds 4800ml MTBE and 225g compound 1 after being added dropwise to complete, after stirring half an hour, normal pressure boils off MTBE/MeOH mixed solvent about 2680ml, distillation temperature is 50 ~ 55 DEG C, still-process probably continue 2 ~ 3 hours, after be naturally down to 20 ~ 25 DEG C, filtration under diminished pressure removes system solid.Filtrate decompression steams extremely about 900ml (can adopt water pump underpressure distillation, temperature is generally-5 ~ 5 DEG C), add water 1000ml, adjust system PH to acid (can control ph be 1 ~ 4) with concentrated hydrochloric acid, leave standstill branch vibration layer, aqueous phase 400ml MTBE back extraction, merge MTBE, dried over sodium sulfate, filter, evaporated under reduced pressure MTBE obtains solid 115.6g (HPLC ee is 81%).Add DMF458ml, decompression steam to 50 DEG C, make compound 2 crude product clearly molten simultaneously, after system being as cold as room temperature, add Lithium Hydroxide Monohydrate 74g, argon replaces protect, add 96.8g compound 3,1h/ time in batches, add for totally 6 times, after ambient temperature overnight.HPLC detection next day starting compound 2 is no more than 1%, otherwise add minority specioz 3 and corresponding ratio Lithium Hydroxide Monohydrate, after having reacted, system slowly instills in 2200ml water, with concentrated hydrochloric acid regulation system PH to acid (can control ph be 1 ~ 4), filters after stirring half an hour, solid washed with water is to neutral, obtain wet product 492g, can obtain dry product 155.8g after 50 DEG C of forced air dryings, crude yield is 49.8%.This crude product is mixed in 4000ml ethyl acetate and adds gac 15.6g after room temperature making beating 2h, stirs after 5 minutes and filters.Filtrate goes in reaction flask and passes into dry ammonia to system PH to alkalescence (can control ph be 8 ~ 9), and stir 15 minutes, repetition measurement system PH is constant, stir half an hour, evaporated under reduced pressure ethyl acetate, adds MeOH156ml, MTBE1560ml, making beating is spent the night.Filter gained wet product next day and obtain dry product after 50 DEG C of forced air dryings, it is molten clearly in the mixed solvent of 1560ml acetone and 1560ml purified water, drip 3M HCl to system PH to acid (can control ph be 1 ~ 4), stir after 2 hours and filter, gained wet product 1560ml water filters after pulling an oar 10 minutes and washes filter cake with water to neutral, forced air drying, obtains dry product 95.7g, and total recovery is 30.6%.Gained sample HPLC purity is not less than 99.8%, and single contaminant is no more than 0.1%, and optical purity is not less than 99.9%, and enantiomer is no more than 0.1%.
Embodiment 3:
Under room temperature (20 ~ 25 DEG C), 137g L-PROLINE methyl ester hydrochloride is mixed in 130ml MeOH, control temperature is no more than 25 DEG C, the solution that dropping 44.7g sodium methylate and 132ml MeOH are made into, adds 4800ml MTBE and 225g compound 1 after being added dropwise to complete, after stirring half an hour, normal pressure boils off MTBE/MeOH mixed solvent about 2680ml, distillation temperature is 50 ~ 55 DEG C, still-process probably continue 2 ~ 3 hours, after be naturally down to 20 ~ 25 DEG C, filtration under diminished pressure removes system solid.Filtrate decompression steams extremely about 900ml (can adopt water pump underpressure distillation, temperature is generally-5 ~ 5 DEG C), add water 1000ml, adjust system PH to acid (can control ph be 1 ~ 4) with concentrated hydrochloric acid, leave standstill branch vibration layer, aqueous phase 400ml MTBE back extraction, merge MTBE, dried over sodium sulfate, filter, evaporated under reduced pressure MTBE obtains solid 113.2g (HPLC ee is 83%).Add DMF458ml, decompression steam to 50 DEG C, make compound 2 crude product clearly molten simultaneously, after system being as cold as room temperature, add Lithium Hydroxide Monohydrate 74g, argon replaces protect, add 96.8g compound 3,1h/ time in batches, add for totally 6 times, after ambient temperature overnight.HPLC detection next day starting compound 2 is no more than 1%, otherwise add minority specioz 3 and corresponding ratio Lithium Hydroxide Monohydrate, after having reacted, system slowly instills in 2200ml water, with concentrated hydrochloric acid regulation system PH to acid (can control ph be 1 ~ 4), filters after stirring half an hour, solid washed with water is to neutral, obtain wet product 493.4g, can obtain dry product 159.8g after 50 DEG C of forced air dryings, crude yield is 51.1%.This crude product is mixed in backflow making beating in 2400ml acetone and adds gac 16.0g after half an hour, stirs after 5 minutes and filters.Filtrate goes to evaporated under reduced pressure acetone in reaction flask and adds 1420ml MeOH to pass into dry ammonia to system PH be alkalescence (can control ph be 8 ~ 9), stir 15 minutes, repetition measurement system PH is constant, stir half an hour, evaporated under reduced pressure MeOH, add new MeOH158ml, MTBE1580ml, making beating is spent the night.Filter gained wet product next day and obtain dry product after 50 DEG C of forced air dryings, it is molten clearly in the mixed solvent of 1580ml acetone and 1580ml purified water, drip 3M HCl to system PH to acid (can control ph be 1 ~ 4), stir after 2 hours and filter, gained wet product 1580ml water filters after pulling an oar 10 minutes and washes filter cake with water to neutral, forced air drying, obtains dry product 98.4g, and total recovery is 31.5%.Gained sample HPLC purity is not less than 99.8%, and single contaminant is no more than 0.1%, and optical purity is not less than 99.9%, and enantiomer is no more than 0.1%.
Embodiment 4:
Under room temperature (20 ~ 25 DEG C), 137g L-PROLINE methyl ester hydrochloride is mixed in 130ml MeOH, control temperature is no more than 25 DEG C, the solution that dropping 44.7g sodium methylate and 132ml MeOH are made into, adds 4800ml MTBE and 225g compound 1 after being added dropwise to complete, after stirring half an hour, normal pressure boils off MTBE/MeOH mixed solvent about 2680ml, distillation temperature is 50 ~ 55 DEG C, still-process probably continue 2 ~ 3 hours, after be naturally down to 20 ~ 25 DEG C, filtration under diminished pressure removes system solid.Filtrate decompression steams extremely about 900ml (can adopt water pump underpressure distillation, temperature is generally-5 ~ 5 DEG C), add water 1000ml, adjust system PH to acid (can control ph be 1 ~ 4) with concentrated hydrochloric acid, leave standstill branch vibration layer, aqueous phase 400ml MTBE back extraction, merge MTBE, dried over sodium sulfate, filter, evaporated under reduced pressure MTBE obtains solid 115g (HPLC ee is 83%).Add Lithium Hydroxide Monohydrate 74g after adding THF650ml, argon replaces protect, add 96.8g compound 3,1h/ time in batches, add for totally 6 times, after room temperature 48h.HPLC detects starting compound 2 and is no more than 1%, otherwise add minority specioz 3 and corresponding ratio Lithium Hydroxide Monohydrate, after having reacted, system slowly instills in 2200ml water, with concentrated hydrochloric acid regulation system PH to acid (can control ph be 1 ~ 4), filters after stirring half an hour, solid washed with water is to neutral, obtain wet product 471g, can obtain dry product 154.5g after 50 DEG C of forced air dryings, crude yield is 49.4%.This crude product is mixed in 1420ml MeOH and adds gac 15.5g after room temperature making beating 2h, stirs after 5 minutes and filters.Filtrate goes in reaction flask and passes into dry ammonia to system PH is alkalescence (can control ph be 8 ~ 9), and stirs 15 minutes, repetition measurement system PH is constant, stirring half an hour, and evaporated under reduced pressure MeOH, adds new MeOH158ml, MTBE1580ml, and making beating is spent the night.Dry product is obtained after filtering the 50 DEG C of forced air dryings of gained wet product next day, it is molten clearly in the mixed solvent of 1580ml acetone and 1580ml purified water, drip 3M HCl to system PH to acid (can control ph be 1 ~ 4), stir after 2 hours and filter, gained wet product 1580ml water filters after pulling an oar 10 minutes and washes filter cake with water to neutral, forced air drying, obtains dry product 91.3g, and total recovery is 29.2%.Gained sample HPLC purity is not less than 99.8%, and single contaminant is no more than 0.1%, and optical purity is not less than 99.9%, and enantiomer is no more than 0.1%.
Embodiment 5
Under room temperature (20 ~ 25 DEG C), 137g L-PROLINE methyl ester hydrochloride is mixed in 130ml methyl alcohol (MeOH), control temperature is no more than 25 DEG C, the solution that dropping 44.7g sodium methylate and 132ml MeOH are made into, 4800ml methyl tertiary butyl ether (MTBE) and 225g compound 1 is added after being added dropwise to complete, after stirring half an hour, normal pressure boils off MTBE/MeOH mixed solvent about 2680ml, distillation temperature is 50 ~ 55 DEG C, still-process probably continues 2 ~ 3 hours, after be naturally down to 20 ~ 25 DEG C, filtration under diminished pressure removes system solid.Filtrate decompression steams extremely about 900ml (can adopt water pump underpressure distillation, temperature is generally-5 ~ 5 DEG C), add water 1000ml, adjust system PH to acid (can control ph be 1 ~ 4) with concentrated hydrochloric acid, leave standstill branch vibration layer, aqueous phase 400mlMTBE back extraction, merge MTBE, dried over sodium sulfate, filters, and evaporated under reduced pressure MTBE obtains solid 114.3g (it is 83% that HPLC shows ee).Add DMF (DMF) 458ml, decompression is steamed to 50 DEG C, makes compound 2 crude product clearly molten simultaneously; add Lithium Hydroxide Monohydrate 74g after system being as cold as room temperature, argon replaces is protected, and adds 96.8g compound 3 in batches; 1h/ time, add for totally 6 times, after ambient temperature overnight.HPLC detection next day starting compound 2 is no more than 1%, otherwise add minority specioz 3 and corresponding ratio Lithium Hydroxide Monohydrate, after having reacted, system slowly instills in 2200ml water, with concentrated hydrochloric acid regulation system PH to acid (can control ph be 1 ~ 4), filters after stirring half an hour, solid washed with water is to neutral, obtain wet product 486.4g, can obtain dry product 157.8g after 50 DEG C of forced air dryings, crude product total recovery is 50.5%.This crude product is mixed in 1420ml MeOH and adds gac 15.8g after room temperature making beating 2h, stirs after 5 minutes and filters.Filtrate goes in reaction flask, the methanol solution (10%) dripping ammonia is alkalescence (can control ph be 8 ~ 9) to system PH, stir 15 minutes, repetition measurement system PH is constant, stir half an hour, evaporated under reduced pressure MeOH, adds new MeOH158ml, MTBE1580ml, stirring to pulp spends the night.Filter gained wet product next day and obtain dry product after 50 DEG C of forced air dryings, it is molten clearly in the mixed solvent of 1580ml acetone and 1580ml purified water, drip 3M HCl to system PH to acid (can control ph be 1 ~ 4), stir after 2 hours and filter, gained wet product 1580ml water filters after pulling an oar 10 minutes and washes filter cake with water to neutral, forced air drying, obtains dry product 101.2g, and total recovery is 32.3%.Gained sample HPLC purity is not less than 99.8%, and single contaminant is no more than 0.1%, and optical purity is not less than 99.9%, and enantiomer is no more than 0.1%.
Embodiment 6
Under room temperature (20 ~ 25 DEG C), 137g L-PROLINE methyl ester hydrochloride is mixed in 130ml methyl alcohol (MeOH), control temperature is no more than 25 DEG C, the solution that dropping 44.7g sodium methylate and 132ml MeOH are made into, 4800ml methyl tertiary butyl ether (MTBE) and 225g compound 1 is added after being added dropwise to complete, after stirring half an hour, normal pressure boils off MTBE/MeOH mixed solvent about 2680ml, distillation temperature is 50 ~ 55 DEG C, still-process probably continues 2 ~ 3 hours, after be naturally down to 20 ~ 25 DEG C, filtration under diminished pressure removes system solid.Filtrate decompression steams extremely about 900ml (can adopt water pump underpressure distillation, temperature is generally-5 ~ 5 DEG C), add water 1000ml, adjust system PH to acid (can control ph be 1 ~ 4) with concentrated hydrochloric acid, leave standstill branch vibration layer, aqueous phase 400ml MTBE back extraction, merge MTBE, dried over sodium sulfate, filters, and evaporated under reduced pressure MTBE obtains solid 115.7g (it is 83% that HPLC shows ee).Add DMF (DMF) 458ml, decompression is steamed to 50 DEG C, makes compound 2 crude product clearly molten simultaneously; add anhydrous lithium hydroxide 43g after system being as cold as room temperature, argon replaces is protected, and adds 96.8g compound 3 in batches; 1h/ time, add for totally 6 times, after ambient temperature overnight.HPLC detection next day starting compound 2 is no more than 1%, otherwise add minority specioz 3 and corresponding ratio Lithium Hydroxide Monohydrate, after having reacted, system slowly instills in 2200ml water, with concentrated hydrochloric acid regulation system PH to acid (can control ph be 1 ~ 4), filters after stirring half an hour, solid washed with water is to neutral, obtain wet product 489.1g, can obtain dry product 157.8g after 50 DEG C of forced air dryings, crude product total recovery is 50.5%.This crude product is mixed in 1420ml MeOH and adds gac 15.8g after room temperature making beating 2h, stirs after 5 minutes and filters.Filtrate goes in reaction flask and passes into dry ammonia to system PH is alkalescence (can control ph be 8 ~ 9), and stir 15 minutes, repetition measurement system PH is constant, stir half an hour, evaporated under reduced pressure MeOH, adds new MeOH158ml, MTBE1580ml, stirring to pulp spends the night.Filter gained wet product next day and obtain dry product after 50 DEG C of forced air dryings, it is molten clearly in the mixed solvent of 1580ml acetone and 1580ml purified water, drip 3M HCl to system PH to acid (can control ph be 1 ~ 4), stir after 2 hours and filter, gained wet product 1580ml water filters after pulling an oar 10 minutes and washes filter cake with water to neutral, forced air drying, obtains dry product 102.5g, and total recovery is 32.8%.Gained sample HPLC purity is not less than 99.8%, and single contaminant is no more than 0.1%, and optical purity is not less than 99.9%, and enantiomer is no more than 0.1%.
In above-described embodiment 1-6, the consumption of the alkali that nucleophilic reaction uses all is preferably 4 equivalents, and practical application any number in 3.5 ~ 5 scopes can be selected all can to realize the present invention according to practical situation; It is 9 that the consumption of decolouring solvent methanol is preferably with the volume mass ratio of compound 4 crude product, and practical application any number in 8 ~ 10 scopes can be selected all can to realize the present invention according to practical situation; It is 26 that the consumption of decolouring solvent ethyl acetate is preferably with the volume mass ratio of compound 4 crude product, and practical application any number in 25 ~ 30 scopes can be selected all can to realize the present invention according to practical situation; It is 15 that the consumption of decolouring solvent acetone is preferably with the volume mass ratio of compound 4 crude product, and practical application any number in 15 ~ 20 scopes can be selected all can to realize the present invention according to practical situation; The situation of salify solvent methanol and ethyl acetate is also in like manner.
Comparative example 1:
Under room temperature (20 ~ 25 DEG C), 137g L-PROLINE methyl ester hydrochloride is mixed in 130ml MeOH, control temperature is no more than 25 DEG C, the solution that dropping 44.7g sodium methylate and 132ml MeOH are made into, adds 4800ml MTBE and 225g compound 1 after being added dropwise to complete, after stirring half an hour, normal pressure boils off MTBE/MeOH mixed solvent about 2680ml, distillation temperature is 50 ~ 55 DEG C, still-process probably continue 2 ~ 3 hours, after be naturally down to 20 ~ 25 DEG C, filtration under diminished pressure removes system solid.Filtrate decompression steams extremely about 900ml (can adopt water pump underpressure distillation, temperature is generally-5 ~ 5 DEG C), add water 1000ml, adjust system PH to acid (can control ph be 1 ~ 4) with concentrated hydrochloric acid, leave standstill branch vibration layer, aqueous phase 400ml MTBE back extraction, merge MTBE, dried over sodium sulfate, filter, evaporated under reduced pressure organic phase obtains solid 115.0g (HPLC ee is 81%).Add DMF458ml, decompression steam to 50 DEG C, make compound 2 crude product clearly molten simultaneously, after system being as cold as room temperature, add Lithium Hydroxide Monohydrate 74g, argon replaces protect, add 96.8g compound 3,1h/ time in batches, add for totally 6 times, after ambient temperature overnight.HPLC detection next day starting compound 2 is no more than 1%, otherwise add minority specioz 3 and corresponding ratio Lithium Hydroxide Monohydrate, with concentrated hydrochloric acid regulation system PH to acid (can control ph be 1 ~ 4), filter after stirring half an hour, after having reacted, system slowly instills in 2200ml water, solid washed with water is to neutral, obtain wet product 486.4g, can obtain dry product 158.0g after 50 DEG C of forced air dryings, crude yield is 50.5%.This crude product is mixed in 1000ml methyl alcohol and adds gac 15.8g after room temperature making beating 2h, stirs after 5 minutes and filters.Filtrate goes in reaction flask and passes into dry ammonia to system PH is alkalescence (can control ph be 8 ~ 9), and stir 15 minutes, repetition measurement system PH is constant, stir half an hour, evaporated under reduced pressure MeOH, adds new MeOH158ml, MTBE1580ml, stirring to pulp spends the night.Filter gained wet product next day and obtain dry product after 50 DEG C of forced air dryings, it is molten clearly in the mixed solvent of 1580ml acetone and 1580ml purified water, drip 3M HCl to system PH to acid (can control ph be 1 ~ 4), stir after 2 hours and filter, gained wet product 1580ml water filters after pulling an oar 10 minutes and washes filter cake with water to neutral, forced air drying, obtains dry product 85.0g, and total recovery is 27.2%.Gained sample HPLC purity is not less than 99.8%, and single contaminant is no more than 0.1%, and optical purity is not less than 99.9%, and enantiomer is no more than 0.1%.
Comparative example 1 compares with embodiment 1, and the consumption of methyl alcohol adopted when difference is to decolour in comparative example 1 is 6 with the volume mass ratio (ml/g) of nucleophilic product, is less than the ratio of embodiment 1.And experimental result contrast shows, the productive rate of comparative example 1 is lower than embodiment 1, and therefore, the consumption of methyl alcohol and the volume mass ratio (ml/g) of nucleophilic product are 8 ~ 10, and experimental result is better.
Comparative example 2:
Under room temperature (20 ~ 25 DEG C), 137g L-PROLINE methyl ester hydrochloride is mixed in 130ml MeOH, control temperature is no more than 25 DEG C, the solution that dropping 44.7g sodium methylate and 132ml MeOH are made into, the tertiary ether of 4800ml first and 225g compound 1 is added after being added dropwise to complete, after stirring half an hour, normal pressure boils off MTBE/MeOH mixed solvent about 2680ml, distillation temperature is 50 ~ 55 DEG C, still-process probably continues 2 ~ 3 hours, after be naturally down to 20 ~ 25 DEG C, filtration under diminished pressure removes system solid.Filtrate decompression steams extremely about 900ml (can adopt water pump underpressure distillation, temperature is generally-5 ~ 5 DEG C), add water 1000ml, adjust system PH to acid (can control ph be 1 ~ 4) with concentrated hydrochloric acid, leave standstill branch vibration layer, aqueous phase 400ml MTBE back extraction, merge MTBE, dried over sodium sulfate, filter, evaporated under reduced pressure MTBE obtains solid 115.4g (HPLC ee is 82%).Add DMF458ml, decompression steam to 50 DEG C, make compound 2 crude product clearly molten simultaneously, after system being as cold as room temperature, add Lithium Hydroxide Monohydrate 74g, argon replaces protect, add 96.8g compound 3,1h/ time in batches, add for totally 6 times, after ambient temperature overnight.HPLC detection next day starting compound 2 is no more than 1%, otherwise add minority specioz 3 and corresponding ratio Lithium Hydroxide Monohydrate, after having reacted, system slowly instills in 2200ml water, with concentrated hydrochloric acid regulation system PH to acid (can control ph be 1 ~ 4), filters after stirring half an hour, solid washed with water is to neutral, obtain wet product 492g, can obtain dry product 155.8g after 50 DEG C of forced air dryings, crude yield is 49.8%.This crude product is mixed in 3000ml ethyl acetate and adds gac 15.6g after room temperature making beating 2h, stirs after 5 minutes and filters.Filtrate goes in reaction flask and passes into dry ammonia to system PH is alkalescence (can control ph be 8 ~ 9), and stir 15 minutes, repetition measurement system PH is constant, stir half an hour, evaporated under reduced pressure ethyl acetate, adds MeOH156ml, MTBE1560ml, making beating is spent the night.Dry product is obtained after filtering the 50 DEG C of forced air dryings of gained wet product next day, it is molten clearly in the mixed solvent of 1560ml acetone and 1560ml purified water, drip 3M HCl to system PH to acid (can control ph be 1 ~ 4), stir after 2 hours and filter, gained wet product 1560ml water filters after pulling an oar 10 minutes and washes filter cake with water to neutral, forced air drying, obtains dry product 72.4g, and total recovery is 23.2%.Gained sample HPLC purity is not less than 99.8%, and single contaminant is no more than 0.1%, and optical purity is not less than 99.9%, and enantiomer is no more than 0.1%.
Comparative example 2 compares with embodiment 2, and the consumption of ethyl acetate adopted when difference is to decolour in comparative example 2 is 19 with the volume mass ratio (ml/g) of nucleophilic product, is less than the ratio of embodiment 1.And experimental result contrast shows, the productive rate of comparative example 1 is lower than embodiment 1, and therefore, the consumption of ethyl acetate and the volume mass ratio (ml/g) of nucleophilic product are 25 ~ 30, and experimental result is better.
Comparative example 3:
Under room temperature (20 ~ 25 DEG C), 137g L-PROLINE methyl ester hydrochloride is mixed in 130ml MeOH, control temperature is no more than 25 DEG C, the solution that dropping 44.7g sodium methylate and 132ml MeOH are made into, adds 4800ml MTBE and 225g compound 1 after being added dropwise to complete, after stirring half an hour, normal pressure boils off MTBE/MeOH mixed solvent about 2680ml, distillation temperature is 50 ~ 55 DEG C, still-process probably continue 2 ~ 3 hours, after be naturally down to 20 ~ 25 DEG C, filtration under diminished pressure removes system solid.Filtrate decompression steams extremely about 900ml (can adopt water pump underpressure distillation, temperature is generally-5 ~ 5 DEG C), add water 1000ml, adjust system PH to acid (can control ph be 1 ~ 4) with concentrated hydrochloric acid, leave standstill branch vibration layer, aqueous phase 400ml MTBE back extraction, merge MTBE, dried over sodium sulfate, filter, evaporated under reduced pressure MTBE obtains solid 115.0g (HPLC ee is 82%).Add DMF458ml, decompression steam to 50 DEG C, make compound 2 crude product clearly molten simultaneously, after system being as cold as 0 ~ 5 DEG C, add Lithium Hydroxide Monohydrate 74g, argon replaces protect, add 96.8g compound 3,1h/ time in batches, add for totally 6 times, after ambient temperature overnight.TLC detection next day starting compound 2 content is obviously very large, add Lithium Hydroxide Monohydrate 37g, and add 48.4g compound 3 in batches, add for three times and continued at 0 ~ 5 DEG C of argon shield reaction and spend the night, next day, TLC detected, raw material 2 still clearly, system rises to 10 ~ 15 DEG C, and add Lithium Hydroxide Monohydrate 14.8g, add 19.3g compound 3 simultaneously in batches, add for twice, after in 10 ~ 15 DEG C of incubated overnight, HPLC detection next day raw material still has 6%, add Lithium Hydroxide Monohydrate 7.4g and 9.7g compound 3, after, in 10 ~ 15 DEG C of reactions spend the night next day HPLC to detect starting compound 2 content residue qualified, system slowly instills in 2200ml water, with concentrated hydrochloric acid regulation system PH to acid (can control ph be 1 ~ 4), filter after stirring half an hour, solid washed with water is to neutral, obtain wet product 420.1g, dry product 147.1g can be obtained after 50 DEG C of forced air dryings, crude yield is 47.0%.This crude product is mixed in 1323ml methyl alcohol and adds gac 14.8g after room temperature making beating 2h, stirs after 5 minutes and filters.Filtrate goes in reaction flask and passes into dry ammonia to system PH is alkalescence (can control ph be 8 ~ 9), and stirs 15 minutes, repetition measurement system PH is constant, stirring half an hour, and evaporated under reduced pressure MeOH, adds new MeOH147ml, MTBE1470ml, and making beating is spent the night.To filter next day after the 50 DEG C of forced air dryings of gained wet product dry product is molten clearly in the mixed solvent of 1470ml acetone and 1470ml purified water, drip 3M HCl to system PH to acid (can control ph be 1 ~ 4), stir after 2 hours and filter, gained wet product 1470ml water filters after pulling an oar 10 minutes and washes filter cake with water to neutral, forced air drying, obtain dry product 75.6g, total recovery is 24.2%.Gained sample HPLC purity is not less than 99.8%, and single contaminant is no more than 0.1%, and optical purity is not less than 99.9%, and enantiomer is no more than 0.1%.
Comparative example 3 compares with embodiment 1, difference be the temperature of nucleophilic reaction in comparative example 3 be first set as 0 ~ 5 DEG C, after be set as 10 ~ 15 DEG C, nucleophilic reaction is all incomplete, and productive rate is low.Therefore, nucleophilic reaction temperature is set as 25 ~ 50 DEG C, and experimental result is better.
Comparative example 4:
Under room temperature (20 ~ 25 DEG C), 137g L-PROLINE methyl ester hydrochloride is mixed in 130ml MeOH, control temperature is no more than 25 DEG C, the solution that dropping 44.7g sodium methylate and 132ml MeOH are made into, adds 4800ml MTBE and 225g compound 1 after being added dropwise to complete, stirring normal pressure half an hour boils off MTBE/MeOH mixed solvent about 2680ml, distillation temperature is 50 ~ 55 DEG C, still-process probably continue 2 ~ 3 hours, after be naturally down to 20 ~ 25 DEG C, filtration under diminished pressure removes system solid.Filtrate decompression steams extremely about 900ml (can adopt water pump underpressure distillation, temperature is generally-5 ~ 5 DEG C), add water 1000ml, adjust system PH to acid (can control ph be 1 ~ 4) with concentrated hydrochloric acid, leave standstill branch vibration layer, aqueous phase 400ml MTBE back extraction, merge MTBE, dried over sodium sulfate, filter, evaporated under reduced pressure MTBE obtains solid 115.7g (HPLC ee is 81%).Add DMF458ml, decompression is steamed to 50 DEG C, makes compound 2 crude product clearly molten simultaneously; add Lithium Hydroxide Monohydrate 74g after system being risen to 80 DEG C of insulations, argon replaces is protected, and adds 96.8g compound 3 in batches; 1h/ time, add for totally 6 times, after be incubated and spend the night in 80 ~ 85 DEG C.HPLC detection next day starting compound 2 is no more than 1%, system slowly instills in 2200ml water, with concentrated hydrochloric acid regulation system PH to acid (can control ph be 1 ~ 4), filter after stirring half an hour, solid washed with water is to neutral, obtain wet product 495.1g, can obtain dry product 156.2g after 50 DEG C of forced air dryings, crude yield is 50.0%.This crude product is mixed in 1420ml methyl alcohol and adds gac 15.6g after room temperature making beating 2h, stirs after 5 minutes and filters.Filtrate goes in reaction flask and passes into dry ammonia to system PH is alkalescence (can control ph be 8 ~ 9), and stirs 15 minutes, repetition measurement system PH is constant, stirring half an hour, and evaporated under reduced pressure MeOH, adds new MeOH156ml, MTBE1560ml, and making beating is spent the night.Dry product is obtained after filtering the 50 DEG C of forced air dryings of gained wet product next day, it is molten clearly in the mixed solvent of 1560ml acetone and 1560ml purified water, drip 3M HCl to system PH to acid (can control ph be 1 ~ 4), stir after 2 hours and filter, gained wet product 1560ml water filters after pulling an oar 10 minutes and washes filter cake with water to neutral, forced air drying, obtains dry product 81.9g, and total recovery is 26.2%.Gained sample HPLC purity is not less than 99.8%, and single contaminant is no more than 0.1%, and optical purity is not less than 99.9%, and enantiomer is no more than 0.1%.
Comparative example 4 compares with embodiment 1, and difference is that the temperature of nucleophilic reaction in comparative example 4 is set as 80 DEG C, although HPLC next day detects starting compound 2 be no more than 1%, the productive rate of finalization compound 4 is very low.Explanation has part of compounds 2 to be converted into other materials, causes the loss of compound 2, affects experimental result.Therefore, nucleophilic reaction temperature is set as 25 ~ 50 DEG C, and experimental result is better.
Comparative example 5:
Under room temperature (20 ~ 25 DEG C), 137g L-PROLINE methyl ester hydrochloride is mixed in 130ml methyl alcohol (MeOH), control temperature is no more than 25 DEG C, the solution that dropping 44.7g sodium methylate and 132ml MeOH are made into, 4800ml methyl tertiary butyl ether (MTBE) and 225g compound 1 is added after being added dropwise to complete, after stirring half an hour, normal pressure boils off MTBE/MeOH mixed solvent about 2680ml, distillation temperature is 50 ~ 55 DEG C, still-process probably continues 2 ~ 3 hours, after be naturally down to 20 ~ 25 DEG C, filtration under diminished pressure removes system solid.Filtrate decompression steams extremely about 900ml (can adopt water pump underpressure distillation, temperature is generally-5 ~ 5 DEG C), add water 1000ml, adjust system PH to acid (can control ph be 1 ~ 4) with concentrated hydrochloric acid, leave standstill branch vibration layer, aqueous phase 400mlMTBE back extraction, merge MTBE, dried over sodium sulfate, filter, evaporated under reduced pressure MTBE obtains solid 114.3g (it is 83% that HPLC shows ee), after adding toluene 650ml, system is heated to reflux and keeps 15 minutes, system naturally cools to room temperature (20 ~ 25 DEG C) and filters after being incubated half an hour, toluene wash filter cake, dry product 69.5g is obtained after the forced air drying of gained wet product, resolution yield is 31%.Above-mentioned dry product drops in reaction flask; add N; dinethylformamide (DMF) 278ml; stirring makes compound 2 crude product clearly molten, adds Lithium Hydroxide Monohydrate 45g after system being as cold as room temperature, and argon replaces is protected; add 58.9g compound 3 in batches; 1h/ time, add for totally 6 times, after ambient temperature overnight.HPLC detection next day starting compound 2 is no more than 1%, otherwise add minority specioz 3 and corresponding ratio Lithium Hydroxide Monohydrate, after having reacted, system slowly instills in 1340ml water, with concentrated hydrochloric acid regulation system PH to acid (can control ph be 1 ~ 4), filters after stirring half an hour, solid washed with water is to neutral, obtain wet product 301.5g, can obtain dry product 95.9g after 50 DEG C of forced air dryings, crude product total recovery is 30.7%.This crude product is mixed in 867ml MeOH and adds gac 9.6g after room temperature making beating 2h, stirs after 5 minutes and filters.Filtrate goes in reaction flask, the methanol solution (10%) dripping ammonia is alkalescence (can control ph be 8 ~ 9) to system PH, stir 15 minutes, repetition measurement system PH is constant, stir half an hour, evaporated under reduced pressure MeOH, adds new MeOH96ml, MTBE960ml, stirring to pulp spends the night.Filter gained wet product next day and obtain dry product after 50 DEG C of forced air dryings, it is molten clearly in the mixed solvent of 960ml acetone and 960ml purified water, drip 3M HCl to system PH to acid (can control ph be 1 ~ 4), stir after 2 hours and filter, gained wet product 960ml water filters after pulling an oar 10 minutes and washes filter cake with water to neutral, forced air drying, obtains dry product 74.2g, and total recovery is 23.7%.Gained sample HPLC purity is not less than 99.8%, and single contaminant is no more than 0.1%, and optical purity is not less than 99.9%, and enantiomer is no more than 0.1%.
In comparative example 5 before nucleophilic reaction, use toluene to carry out recrystallization to resolved product, and the productive rate of finalization compound 4 is lower, and the loss causing part of compounds 2 when recrystallization is described, have impact on final productive rate.
Comparative example 6 (WO2011114338)
400ml DMF and 50g compound 2 is dropped in 1L reaction flask, stir and slowly add sodium hydrogen 18.9g after 30 minutes, after reaction system in stirring at room temperature 1 hour, the DMF solution (47.8g compound 3 and 100ml DMF mix) of slow dropping compound 3, within about 45 ~ 60 minutes, be added dropwise to complete, stirred overnight at room temperature, after having reacted, system slowly adds 50ml methyl alcohol.System adds 600ml dilute hydrochloric acid after carrying out cancellation with 5L water again and is adjusted to acidity, organic phase is merged after system 500ml extraction into ethyl acetate twice, organic phase extracts with 1M sodium hydroxide again, gained aqueous phase 1M hydrochloric acid is adjusted to acid stirring after 2 hours and filters, gained wet product is dry that dry product 60g. dry product is dissolved in 900ml acetone in 60 ~ 65 DEG C, add 26.2g4-oil of mirbane ethamine and to stir after 30 minutes temperature rising reflux 1 ~ 2 hour, system progressively cools to room temperature and is incubated 16 ~ 18 hours, filter, and use 200ml washing with acetone, 60 ~ 70 DEG C of vacuum-dryings of gained wet product obtain this dry product of dry product 60g. and are dissolved in 3L water, stir 15 minutes, dripping 1M hydrochloric acid 500ml adjusts system PH to be 1 ~ 2, and stirring at room temperature 2 ~ 3 hours.Filter, water washing, wet product 60 ~ 70 DEG C of vacuum-dryings, obtaining dry product 42g. total recovery is 60.4%.
According to embodiment best in patent WO2011114338 in comparative example 6, carry out nucleophilic reaction with compound 2 raw material, the total recovery of final nucleophilic reaction is 60.4%.
In order to clearer contrast, preferred embodiment to carry out nucleophilic reaction according in patent WO2011114338 and DE202009009917 in following table 1, and fractionation productive rate compound 1 being obtained after splitting compound 2 is set as 35%, calculates the productive rate of compound 4.Ultimate yield is all low compared with the productive rate of compound in embodiments of the present invention 4, proves that the experiment effect of synthetic method of the present invention is excellent.
Claims (10)
1. the synthetic method of an ambrisentan, with racemoid 1 for reactant, compound 1 splits to obtain compound 2 crude product through L-PROLINE methyl ester hydrochloride, it is characterized in that: compound 2 crude product and compound 3 nucleophilic reaction occur under the effect of alkali and obtain compound 4
Described synthetic method is reacted according to following route:
。
2. synthetic method according to claim 1, is characterized in that: described nucleophilic reaction alkali used is lithium hydroxide or lithium hydroxide monohydrate.
3. synthetic method according to claim 1 and 2, is characterized in that: with compound 3, nucleophilic reaction occurs after described compound 2 crude product removing solvent seasoning.
4. synthetic method according to claim 3, is characterized in that: the consumption of described alkali is 3.5 ~ 5 equivalents of compound 2 crude product removing solvent seasoning after product.
5. synthetic method according to claim 1, is characterized in that: the solvent of described nucleophilic reaction is tetrahydrofuran (THF) or DMF.
6. synthetic method according to claim 1, is characterized in that: the temperature of reaction of described nucleophilic reaction is 25 ~ 50 DEG C.
7. synthetic method according to claim 1, is characterized in that: the mass ratio that described compound 3 and described compound 2 crude product remove solvent seasoning after product is at least 96.8:115.
8. synthetic method according to claim 1, is characterized in that: described building-up reactions also comprises the aftertreatment purge process to nucleophilic product.
9. synthetic method according to claim 8, is characterized in that: described aftertreatment purge process comprises the decolorization and salification process of carrying out successively.
10. synthetic method according to claim 9, is characterized in that: the decolouring solvent that described decolorization uses is methyl alcohol.
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| CN109705042A (en) * | 2017-10-26 | 2019-05-03 | 正大天晴药业集团股份有限公司 | A kind of preparation method of ambrisentan |
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| CN106699626A (en) * | 2015-11-13 | 2017-05-24 | 辽宁远大诺康生物制药有限公司 | Method for preparing 2-hydroxy-3-methoxy-3,3,-diphenyl propionate racemate |
| CN106699626B (en) * | 2015-11-13 | 2019-08-16 | 辽宁远大诺康生物制药有限公司 | A kind of preparation method of 2- hydroxy-3-methoxy -3,3- diphenylprop hydrochlorate raceme |
| CN109705042A (en) * | 2017-10-26 | 2019-05-03 | 正大天晴药业集团股份有限公司 | A kind of preparation method of ambrisentan |
| CN109705042B (en) * | 2017-10-26 | 2021-12-21 | 正大天晴药业集团股份有限公司 | Preparation method of ambrisentan |
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