CN1126728C - Preparation of S-Ibuprofen - Google Patents
Preparation of S-Ibuprofen Download PDFInfo
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- CN1126728C CN1126728C CN 01106592 CN01106592A CN1126728C CN 1126728 C CN1126728 C CN 1126728C CN 01106592 CN01106592 CN 01106592 CN 01106592 A CN01106592 A CN 01106592A CN 1126728 C CN1126728 C CN 1126728C
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- ibuprofen
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- HEFNNWSXXWATRW-JTQLQIEISA-N dexibuprofen Chemical compound CC(C)CC1=CC=C([C@H](C)C(O)=O)C=C1 HEFNNWSXXWATRW-JTQLQIEISA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 229960001680 ibuprofen Drugs 0.000 claims description 5
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 229960005091 chloramphenicol Drugs 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000013507 mapping Methods 0.000 claims 4
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 claims 1
- 239000006227 byproduct Substances 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000001117 sulphuric acid Substances 0.000 claims 1
- 235000011149 sulphuric acid Nutrition 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 11
- 230000003287 optical effect Effects 0.000 abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 6
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000001728 carbonyl compounds Chemical class 0.000 description 4
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 238000011914 asymmetric synthesis Methods 0.000 description 3
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- HCFAJYNVAYBARA-UHFFFAOYSA-N 4-heptanone Chemical compound CCCC(=O)CCC HCFAJYNVAYBARA-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000005185 salting out Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- BTANRVKWQNVYAZ-BYPYZUCNSA-N (2S)-butan-2-ol Chemical compound CC[C@H](C)O BTANRVKWQNVYAZ-BYPYZUCNSA-N 0.000 description 1
- SDOFMBGMRVAJNF-SLPGGIOYSA-N (2r,3r,4r,5s)-6-aminohexane-1,2,3,4,5-pentol Chemical compound NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO SDOFMBGMRVAJNF-SLPGGIOYSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- -1 (S)-ibuprofen amine salt Chemical class 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000013626 chemical specie Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
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- 239000012452 mother liquor Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种(S)-布洛芬的制备方法，将外消旋布洛芬与拆分剂发生对映选择性成盐反应，经纯化、非对映盐析解即得所需(S)-布洛芬。本发明工艺简单，制取(S)-布洛芬的收率高、成本低，所得(S)-布洛芬的光学纯度为89～98%ee。The present invention relates to a kind of preparation method of (S)-ibuprofen, racemic ibuprofen and resolving agent take place enantioselective salt-forming reaction, obtain desired ( S) - ibuprofen. The process of the invention is simple, the yield of preparing (S)-ibuprofen is high and the cost is low, and the optical purity of the obtained (S)-ibuprofen is 89-98% ee.
Description
本发明描述非甾体广谱抗炎手性药物(S)-布洛芬的制备新方法，属于手性药物制备化学领域。The invention describes a new method for preparing non-steroidal broad-spectrum anti-inflammatory chiral drug (S)-ibuprofen, which belongs to the field of chiral drug preparation chemistry.
布洛芬，是α-芳基丙酸类药物中应用最广的品种之一。早在二十世纪六十年代由Boots公司首先开发成功。长期以来，在国际市场上一直以外消旋形式(两种对映体R和S的等量混合物)销售。由于外消旋药物中的两种对映体常常表现出不同的生理活性，服用外消旋药物具有极大潜在危险性。Adams等的研究表明，在活体外(S)-布洛芬对前列腺合成酶的抑制能力比其(R)-异构体强160倍(J.Pharm.Pharakol，28，257)。Jamali等也指出布洛芬的两种对映体在药理动力学和生物转化作用方面也不同(Pharmac.Res.1988，5，44)。所以，国际上一些厂家已经或正在把(S)-布洛芬推向市场，以替代外消旋布洛芬。Ibuprofen is one of the most widely used varieties of α-arylpropionic acid drugs. As early as the 1960s, it was first successfully developed by the Boots company. For a long time, it has been sold in the racemic form (equal mixture of two enantiomers R and S) in the international market. Because the two enantiomers in racemic drugs often exhibit different physiological activities, taking racemic drugs is potentially dangerous. Studies by Adams et al. have shown that in vitro (S)-ibuprofen has a 160-fold stronger inhibitory effect on prostate synthase than its (R)-isomer (J.Pharm.Pharakol, 28, 257). Jamali et al. also pointed out that the two enantiomers of ibuprofen are also different in pharmacokinetics and biotransformation (Pharmac. Res. 1988, 5, 44). Therefore, some manufacturers in the world have or are introducing (S)-ibuprofen to the market to replace racemic ibuprofen.
先前，(S)-布洛芬的制备方法，概括起来可分为外消旋体拆分法和不对称合成法两大类。从理论上而言，不对称合成是最理想的制备方法，它可以由非手性分子在手性作用物的影响下直接合成目标产物。遗憾的是，现有的利用不对称合成技术制备(S)-布洛芬的方法要么需要昂贵的手性助剂或手性催化剂，要么制备路线长，涉及化学物种多，实现工业化生产并不经济。通过外消旋体拆分制备(S)-布洛芬已有许多途径。在这些方法中，人们用D-葡辛胺(Lodeuigk Eric et al，US.361767)，D-氯霉素碱(Blaschke Gottfried et al，Ger，D.E.3814887.0)，(S)-α-苯乙胺(Choudhary A.A.et al，PCT Int.Appl.WO9315039)，(S)-2-丁醇(AslamM.et al，US 434360)，(S)-赖氨酸(Tung，H.H.et al，Aiche.Symp.Ser.1991，87(264)，64；Bruzzese，T.et al，Ger.Offen.2508895；Bhattacharya A.et al，PCT Int.Appl.WO9412481)，酶等作拆分剂。由于这些手性作用物价格不菲，使得(S)-布洛芬的制备成本较高。Previously, the preparation methods of (S)-ibuprofen can be summarized into two categories: racemate resolution and asymmetric synthesis. In theory, asymmetric synthesis is the most ideal preparation method, which can directly synthesize target products from achiral molecules under the influence of chiral substrates. Unfortunately, the existing methods for preparing (S)-ibuprofen by using asymmetric synthesis technology either need expensive chiral auxiliary agents or chiral catalysts, or have long preparation routes and involve many chemical species, so it is difficult to realize industrial production. economy. There are many ways to prepare (S)-ibuprofen by racemate resolution. In these methods, people use D-glucamine (Lodeuigk Eric et al, US.361767), D-chloramphenicol base (Blaschke Gottfried et al, Ger, D.E.3814887.0), (S)-α-phenylethylamine (Choudhary A.A.et al, PCT Int.Appl.WO9315039), (S)-2-butanol (AslamM.et al, US 434360), (S)-lysine (Tung, H.H.et al, Aiche.Symp. Ser.1991, 87 (264), 64; Bruzzese, T.et al, Ger.Offen.2508895; Bhattacharya A.et al, PCT Int.Appl.WO9412481), enzymes etc. as resolving agent. Because these chiral substrates are expensive, the preparation cost of (S)-ibuprofen is relatively high.
本发明的目的就是提供一种以制药的手性“废料”为基本手性原料，经过适当分子修饰后用作拆分剂、廉价制备(S)-布洛芬的方法。The purpose of the present invention is to provide a method for preparing (S)-ibuprofen cheaply by using pharmaceutical chiral "waste" as the basic chiral raw material and using it as a resolution agent after appropriate molecular modification.
本发明的实施要点是：将工业制备氯霉素的手性“废料”L-(+)-2-氨基-1-对硝基苯基-1，3-丙二醇粗品纯化后，与羰基化合物缩合，用所得的缩合物为拆分剂，与外消旋布洛芬发生对映选择性成盐反应，经纯化、分离、非对映盐析解即得所需(S)-布洛芬。The implementation points of the present invention are: after purifying the chiral "waste" L-(+)-2-amino-1-p-nitrophenyl-1,3-propanediol crude product of industrial preparation of chloramphenicol, condense with carbonyl compound , using the obtained condensate as a resolving agent, enantioselective salt-forming reaction with racemic ibuprofen, purification, separation, and diastereomeric salting-out solution to obtain the desired (S)-ibuprofen.
按照本发明，拆分剂L-(+)-2-氨基-1-对硝基苯基-1，3-丙二醇与羰基化合物的缩合物可依00114346.8号专利申请(公开号CN1266847A)提供的方法制取。According to the present invention, the condensate of resolving agent L-(+)-2-amino-1-p-nitrophenyl-1,3-propanediol and carbonyl compound can be provided according to the method provided by No. 00114346.8 patent application (publication number CN1266847A) make.
按照本发明，制备拆分剂所用的羰基化合物由丙酮，丁酮，3-戊酮，4-庚酮，环戊酮，环己酮中选择。According to the present invention, the carbonyl compound used for preparing the resolving agent is selected from acetone, butanone, 3-pentanone, 4-heptanone, cyclopentanone and cyclohexanone.
按照本发明，外消旋布洛芬与拆分剂在有机溶剂中反应生成由(S)-布洛芬和拆分剂组成的非对映盐。According to the present invention, racemic ibuprofen reacts with a resolving agent in an organic solvent to form a diastereomeric salt composed of (S)-ibuprofen and a resolving agent.
按照本发明，外消旋布洛芬与拆分剂的摩尔比为1～3∶1。According to the present invention, the molar ratio of racemic ibuprofen to resolving agent is 1-3:1.
按照本发明，外消旋布洛芬与拆分剂的成盐反应在20-100℃进行。According to the present invention, the salt-forming reaction of racemic ibuprofen and resolving agent is carried out at 20-100°C.
按照本发明，成盐反应及非对映盐的结晶所用的介质由甲醇、乙醇、丙醇、异丙醇、丁醇、异丁醇、二氯甲烷、三氯甲烷、苯、甲苯、二甲苯、环己烷、甲基环己烷、乙醚、四氢呋喃、丙酮、乙腈中选择。According to the present invention, the medium used for the salt-forming reaction and crystallization of diastereomeric salts is composed of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, dichloromethane, chloroform, benzene, toluene, xylene , Cyclohexane, Methylcyclohexane, Diethyl ether, Tetrahydrofuran, Acetone, Acetonitrile.
按照本发明，生成的非对映盐可从反应体系中以沉淀析出，也可以从反应生成的均相溶液中获取。According to the present invention, the diastereomeric salts formed can be precipitated from the reaction system, and can also be obtained from the homogeneous solution formed by the reaction.
按照本发明，当生成的非对映盐不能从反应体系中以沉淀析出时，则采用蒸发溶剂并用萃取剂萃取残余物或向反应液中加入沉淀剂的办法，使盐与未反应的(R)-对映体分离；萃取剂或沉淀剂由石油醚、环己烷、甲基环己烷、乙醚中选取。According to the present invention, when the generated diastereomeric salt cannot be precipitated out from the reaction system, the method of evaporating the solvent and extracting the residue with an extractant or adding a precipitant to the reaction solution is used to make the salt and unreacted (R )-enantiomer separation; extractant or precipitant is selected from petroleum ether, cyclohexane, methylcyclohexane, ether.
按照本发明，由非对映盐析解出(S)-布洛芬采用两种方式进行：1.将非对映盐直接用稀盐酸或稀硫酸酸化，使(S)-布洛芬呈固体析出；2.将非对映盐先碱化、分出拆分剂，再酸化水溶液，析出(S)-布洛芬。According to the present invention, the (S)-ibuprofen is released in two ways by the diastereomer salting out: 1. the diastereomer salt is directly acidified with dilute hydrochloric acid or dilute sulfuric acid to make (S)-ibuprofen take the form of dilute hydrochloric acid or dilute sulfuric acid Solid precipitation; 2. Alkalinize the diastereomeric salt first, separate the resolving agent, and then acidify the aqueous solution to precipitate (S)-ibuprofen.
按照本发明，在利用先碱化、后酸化程序析解出(S)-布洛芬时，所用的碱由氢氧化钠、氢氧化钙、碳酸氢钠、碳酸钠、碳酸钾、氨水中选择。According to the present invention, when utilizing first alkalization and post-acidification procedures to separate out (S)-ibuprofen, the alkali used is selected from sodium hydroxide, calcium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, and ammonia .
按照本发明，(S)-布洛芬粗品纯化所用的溶剂由石油醚、环己烷或甲基环己烷以及异丙醇-水，乙醇-水中选择。According to the present invention, the solvent used for the purification of crude (S)-ibuprofen is selected from petroleum ether, cyclohexane or methylcyclohexane, isopropanol-water, and ethanol-water.
本发明以工业制备氯霉素的手性“废料”为基本手性原料与羰基化合物缩合，所得缩合物为拆分剂从外消旋布洛芬中拆分出(S)-布洛芬，因而本发明工艺简单，制取(S)-布洛芬的收率高，成本低，所得(S)-布洛芬的光学纯度89～98％ee。In the present invention, the chiral "waste" of industrial preparation of chloramphenicol is used as the basic chiral raw material to condense with the carbonyl compound, and the obtained condensate is used as a resolving agent to separate (S)-ibuprofen from racemic ibuprofen, Therefore, the process of the present invention is simple, the yield of preparing (S)-ibuprofen is high, the cost is low, and the optical purity of the obtained (S)-ibuprofen is 89-98% ee.
本发明由下面的实施例具体说明。The present invention is illustrated by the following examples.
实施例1Example 1
在一只100毫升的圆底烧瓶中加入0.04mol外消旋布洛芬和20ml乙醚，搅拌使其溶解。在搅拌下加入0.02mol L-(+)-2-氨基-1-对硝基苯基-1，3-丙二醇与环己酮的缩合物的20ml乙醚溶液并将反应温度控制在20～100℃。在加入过程中不断析出白色固体。搅拌一小时后，滤出生成的固体，用石油醚洗之，干燥，M.p.110-112℃；母液浓缩，又析出少量固体。总收率92.4％。将这种盐用2N的盐酸和石油醚搅拌处理，分出有机相，水相中通过加入2N的氢氧化钠溶液回收L-(+)-2-氨基-1-对硝基苯基-1，3-丙二醇。于有机溶液中加入40％的NaHSO4溶液，搅拌，分出石油醚层，用饱和NaCl溶液和水先后洗之，无水Na2SO3干燥，蒸发石油醚，得到白色(S)-布洛芬固体，m.p.52℃，收率：96％；[α]20 D＝+50.94(c＝1，C2H5OH)，89.4％ee.Add 0.04 mol of racemic ibuprofen and 20 ml of ether to a 100 ml round bottom flask and stir to dissolve. Add 0.02mol L-(+)-2-amino-1-p-nitrophenyl-1,3-propanediol and cyclohexanone condensate in 20ml ether solution under stirring and control the reaction temperature at 20～100℃ . A white solid continued to precipitate during the addition. After stirring for one hour, the resulting solid was filtered out, washed with petroleum ether, and dried, Mp 110-112°C; the mother liquor was concentrated, and a small amount of solid was precipitated. The total yield is 92.4%. Stir this salt with 2N hydrochloric acid and petroleum ether, separate the organic phase, and recover L-(+)-2-amino-1-p-nitrophenyl-1 by adding 2N sodium hydroxide solution to the aqueous phase , 3-propanediol. Add 40% NaHSO 4 solution to the organic solution, stir, separate the petroleum ether layer, wash it successively with saturated NaCl solution and water, dry it with anhydrous Na 2 SO 3 , evaporate the petroleum ether, and obtain white (S)-Buluo Fen solid, mp52°C, yield: 96%; [α] 20 D =+50.94 (c=1, C 2 H 5 OH), 89.4% ee.
实施例2Example 2
与上面的程序类似，将0.048mol的外消旋布洛芬和0.02molL-(+)-2-氨基-1-对硝基苯基-1，3-丙二醇与环己酮的缩合物在乙醚中反应，得到白色(S)-布洛芬固体，m.p.52℃，收率：96.4％；[α]20 D＝+54.9(c＝1，C2H5OH)，96.4％ee。实施例3Similar to the above procedure, the condensate of 0.048 mol of racemic ibuprofen and 0.02 mol of L-(+)-2-amino-1-p-nitrophenyl-1,3-propanediol and cyclohexanone in diethyl ether Reaction in medium to obtain white (S)-ibuprofen solid, mp52°C, yield: 96.4%; [α] 20 D =+54.9 (c=1, C 2 H 5 OH), 96.4% ee. Example 3
按照实施例2的程序制得非对映的(S)-布洛芬胺盐。在分离后，在固体中加入NaOH溶液和乙醚搅拌处理，分离有机相和水相，用乙醚萃取水相，合并有机相，无水Na2SO4干燥，由醚中回收拆分剂。将水相中加入2NHCl溶液和石油醚搅拌处理(调至酸性)，分出石油醚层，水洗，无水硫酸钠干燥，蒸发石油醚，得到白色(S)-布洛芬，熔点、收率、光学纯度与实施例2几乎相同。Following the procedure of Example 2, the diastereomeric (S)-ibuprofen amine salt was prepared. After separation, add NaOH solution and diethyl ether to the solid and stir, separate the organic phase and water phase, extract the water phase with diethyl ether, combine the organic phases, dry over anhydrous Na 2 SO 4 , and recover the resolving agent from ether. Add 2N HCl solution and petroleum ether to the water phase and stir (adjust to acidity), separate the petroleum ether layer, wash with water, dry over anhydrous sodium sulfate, evaporate petroleum ether to obtain white (S)-ibuprofen, melting point, yield , The optical purity is almost the same as in Example 2.
上述反应中外消旋布洛芬与拆分剂的摩尔比可在1～3∶1内选择。In the above-mentioned reaction, the mol ratio of racemic ibuprofen and resolving agent can be selected within 1～3:1.
上述成盐反应及非对映盐的结晶所用介质可在甲醇、乙醇、丙醇、异丙醇、丁醇、二氯甲烷、三氯甲烷、苯、甲苯、二甲苯、环己烷、甲基环己烷、乙醚、四氢呋喃、丙酮或乙腈中选择等。The medium used for the crystallization of the above-mentioned salt-forming reaction and diastereomeric salts can be in methanol, ethanol, propanol, isopropanol, butanol, methylene chloride, chloroform, benzene, toluene, xylene, cyclohexane, methyl Choose from cyclohexane, ether, tetrahydrofuran, acetone or acetonitrile, etc.
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