CN1385409A - Optical resolution method for recemic diphenol - Google Patents
Optical resolution method for recemic diphenol Download PDFInfo
- Publication number
- CN1385409A CN1385409A CN02111829A CN02111829A CN1385409A CN 1385409 A CN1385409 A CN 1385409A CN 02111829 A CN02111829 A CN 02111829A CN 02111829 A CN02111829 A CN 02111829A CN 1385409 A CN1385409 A CN 1385409A
- Authority
- CN
- China
- Prior art keywords
- diphenol
- resolution reagent
- resolution
- yield
- recemic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present ivnention relates to an optical resolution method of racemic diphenol, including 1,1'-diphenol, 1,1'-dinaphthol and its derivative. It is characterized by that it uses optical pure resolution reagent to selectively combine with one enantiomorph being in racemic 1,1'-diphenol, 1,1'-dinaphthol and its derivative to form molecualr crystal and dissolve out, after having been treated by organic solvent the product can be released out, after final treatment the 1,1'-diphenol, 1,1'-dinaphthol and its derivative with optical activity can be obtained. The mother liquor is treated by organic solvent, the 1,1'-diphenol, 1,1'-dinaphthol and its derivative with another configuration and optical activity also can be obtained.
Description
Technical field
The present invention relates to the optical isomer new method for splitting in the chiral technology.
Optically active in recent years 1,1 '-biphenyl phenol, 1,1 '-binaphthol and derivative thereof (1-4) application in asymmetric synthesis more and more comes into one's own.Its range of application arrives the host compound that molecular recognition and enantiomer split from as the chiral ligand the asymmetric catalysis, then can also be as the important intermediate of synthesis of chiral material.Use chirality 1 as Cram, the unitary crown ether of 1 '-binaphthol is to organic amine, and amino acid derivative has the chiral recognition effect, has developed guest of honour's chemistry, has made by " machine " that amino acid splits.(CramD.J., Helv.Chim.Acta., 1979,101,5843; J.Org.Chem., 1977,42,4173; Acc., Chem., Res., 1978,11,8) .Noyori utilizes 1, the metal hydride complex compound that 1 '-binaphthol and lithium aluminum hydride form, can induce the aromatic ketone carbonyl to carry out asymmetric reduction, obtain the alcohol of high yield, and be used for the synthetic of insect pheromone and prostaglandin(PG).(Noyori R., Pure Appli.Chem., 1981,53,2315), utilize 1, the reagent that 1 '-binaphthol and the four different third oxygen titaniums form is used for alkylated reaction (Olivero A.G., the Helv.Chim.Acta. of aromatic aldehyde, 1981,64,2485) and grignard reaction (Wang J.T., Synthesis, 1989,291).Fuji utilizes and has carried out asymmetric alkylation reaction (Fuji K., Tetra.Lett., 1989,30,2825) as chiral auxiliary(reagent).Tanaka utilizes 1, and 1 '-binaphthol is that chiral source has been carried out amino acid whose asymmetric synthesis (Tanaka K., Mija Ahn, Watanade Y., Fuji K., Tetra.Asymm., 1996,7,1771).Particularly in recent years, utilize optically pure 1,1 '-binaphthol and metal reagent effect, the complex compound of formation is used for asymmetric catalysis as catalyzer, has obtained a series of outstanding results.Comprising nitro aldol reaction (Shibayaki, M.; Sasai, H.; Arai, T.Angew.Chem., Int.Ed.Engl.1997,36,1236; Mikami, K; Matsukawa, S..J.Am.Chem.Soc.1994,116,4077), the addition reaction of allyl group tin (Keck, G.E.; Tatbet, K.H.; Geraci, L.S.J.Am.Chem.Soc.1993,115,8467), alkene reaction (Mikami, K.Pure Appl.Chem.1996,68,639), Diels-Alder reacts (Mikami, K.; Motoyama, Y.; Terada, M.J.Am.Chem.Soc.1994,116,2812) etc.
Obtain optically pure 1 at present, 1 '-binaphthol and derivative thereof (1-4) means comprise: the characteristic of a) utilizing the functional group of BINOL, obtain diastereomer with the photolytic activity reagent react, separated by the crystalline means again, as 1 of utilization, two hydroxyls of 1 '-binaphthol and derivative thereof (1-4) have good reactivity, can be by becoming ester or becoming ether, perhaps with the Chiral Amine effect, directly or indirectly with the chiral radicals effect, form diastereomer, utilize their qualitative difference, reach the purpose of fractionation.(Jacques, J.; Fouquey, C.; Viterbo, R.Tetrahedron Lett.1971,7,4617-4620; Jacques, J.; Fouquey, C.Org.Synth.1988,67,1-12; Gong, B.; Chen, W.; Hu, B.J.Org.Chem.1991,56,423-425; Brunel, J.M.; Buono, G.J.Org.Chem.1993,58,7313-7314; Wang, M.; Liu, S.; Hu, B.J.Org.Chem.1995,60,7364-7265; Fabbri, D.; Deloga, G.; De Lucchi, O.J.Org.Chem.1995,60,6599-6601; Pakulski, Z.; Zamojski, A.Tetrahedron:Asymmetry 1995,6,111-115; Chow, H.F.; Wan, C.W.; Ng, M.K.J.Org.Chem.1996,61,8712-8714; Kim, H.C.; Choi, S.; Kim, H.; Ahn, K.H.; Koh, J.H.; Park, J.Tetrahedron Lett.1997,38,3959-3962; Shan, Z.; Xiong, Y.; Zhao, D.Tetrahedron 1999,55,3893-3896; Shan, Z.; Wang, G.; Duan, B.; Zhao, D.Tetrahedron:Asymme try 1996,7,2847-2850; Shan, Z.; Cheng, F.; Huang, S.; Zhao, D.; Jing, Z.Tetrahedron:Asymmetry 1997,8,1175-1177; Periasamy, M.; Venkatraman, L.; Sivakumar, S.; Sampathkumar, N.; Ramanathan, C.R.; J.Org.Chem.1999,64,7643-7645.); B) utilize optically pure host compound and its enantioselectivity ground to generate the inclusion crystal, this kind method is according to the supramolecular chemistry principle, utilize the weak interaction between the additional mutually and group on the three-dimensional space between main body (HOST) molecule and object (GUEST) molecule, the two optionally forms stable molecular crystal by molecular recognition, thereby realized optical resolution to racemic modification, as utilize tartaric acid derivatives to racemize 1, the fractionation of 1 '-binaphthol and derivative thereof (1-4) etc.(Tanaka, K.; Okada, T.; Toda, F.Angew.Chem., Int.Ed.Engl.1993,32,1147-1148; Toda, F.; Tanaka, K.; Stein, Z.; Goldberg, I.J.Org.Chem.1994,59,5748-5751; Toda, F.; Tanaka, K.Chem.Commun.1997,1087-1088; Cai, D.W.; Hughes, D.L.; Verhoeven, T.R.; Reider, P.J.Tetrahedron Lett.1995,36,7991-7994.Hu, Q.S.; Vitharana, D.; Pu, L.Tetrahedron:Asymmetry 1995,6,2123-2126.Wang, Y.; Sun, J.; Ding, K.Tetrahedron 2000,56,4447-4451; Kawashima, M.; Hirayama, A.; Chem.Lett.1990,2299-2300; Kawashima, M.; Hirata, R.Bull.Chem.Soc.Jpn.1993,66,2002-2005; Periasamy, M.; Prasad, A.S.B.; Kanth, J.V.B.; Reddy, Ch.K.Tetrahedron:Asymmetry 1995,6,341-344; Periasamy, M.; Venkatraman, L.; Thomas, K.R.J.J.Org.Chem.1997,62,4302-4306.); C) utilize its ester derivative of enzymatic hydrolysis, as utilize of the two fat hydrolysis of pork liver enzyme, obtain optical activity BINOL racemize BINOL.(Kazkausjas, R.J.J.Am.Chem.Soc., 1989,111,4953); Direct asymmetric coupling beta naphthal derivative, as utilize the metal complex of Photoactive compounds, carry out the stereoselectivity oxidative coupling, can obtain photolytic activity BINOL (Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S.J.Org.Chem.1999,64,2264-2271 and thereferences 3 and 4 cited therein; Smrcina, M.; Palakova, J.; Vyskocil, S.; Kocovsky, P.J.Org.Chem.1993,58,4534-4537; Feringa, B.; Wynberg, H.Bioorg.Chem.1979,7,397-408; Brussee, J.; Groenendijk, J.L.G.; Te Koppele, J.M.; Jansen, A.C.A.Tetrahedron 1985,41,3313-3319; Li, X.L.; Yang, J.; Kozlowski, M.C.Org.Lett.2001,3,1137-1140.).Wherein utilize optical activity host compound molecule and 1, it is practical means the most that 1 '-binaphthol and derivative thereof (1-4) enantioselectivity ground generates the inclusion crystal, because this method has characteristics of high efficiency, and racemic BINOL is very easy to preparation.Yet the fractionation means that exist exist following one or more defectives now: (1) chiral source costs an arm and a leg; (2) the resolution reagent usage quantity is big, is difficult to preparation; (3) split process complexity; (4) resolution reagent is difficult to reclaim; (5) it is low or the like to split efficient.
Summary of the invention
In order to solve the problem that above-mentioned fractionation means exist, the invention provides a kind of recemic diphenol and comprise 1,1 '-biphenyl phenol, 1, easy, the optical isomer new method for splitting efficiently of 1 '-binaphthol and derivative thereof.
The present invention is according to the supramolecular chemistry principle, utilize the weak interaction between the additional mutually and group on the three-dimensional space between main body (HOST) molecule and object (GUEST) molecule, the two optionally forms stable molecular crystal by molecular recognition, thereby has realized the high-level efficiency optical resolution to racemic modification.
It is as follows that the present invention splits the structural formula of related recemic diphenol, R in the formula
1, R
2, R
3, R
4Be respectively H, C
1-C
6Straight chain or have alkyl, aryl, halogen atom (F, Cl, Br, I), hydroxyl, formyl radical, the C of side chain
1-C
6Straight chain or have the alkoxyl group of side chain or SPh etc., R
1, R
2, R
3, R
4Identical or different: (1) 1,1 '-binaphthol derivative
(2) 5,5 ', 6,6 ', 7,7 ', 8,8 '-octahydro-1,1 '-binaphthol derivative
(3) 5,6,7,8-tetrahydrochysene-1,1 '-binaphthol derivative
(4) 2,2 '-biphenol derivative
In organic solvent, (R) in optically pure resolution reagent 5 and the recemic diphenol or (S) isomer be combined into the molecule crystal, the molar ratio that wherein adds optically pure resolution reagent 5 and recemic diphenol is 0.5-3: 1, resolution reagent add mol ratio be 0.5: 1 just enough, but adding resolution reagent does not generally hinder reaction, temperature of reaction is 0-150 ℃, and the reaction times is 1-12 hour.
Described optical purity resolution reagent 5 is 5 (R) or 5 (S), and its structural formula is as follows:
N=0,1 or 2 in the formula; A is N or O, and when A is oxygen, no R "; R, R ' or R " be H, C
1-C
7Straight or branched alkyl, C
1-C
7Straight or branched alkyloyl, 5-7 person's cycloalkyl,
Nitrogenous, oxygen, the 5-7 element heterocycle substituting group of sulphur, described R
5=H, C
1-C
7Straight or branched alkyl, halogen, C
1-C
5Alkoxyl group, nitro, acyl group, cyano group, hydroxyl; And when A is nitrogen, R ', R ", A three can be 5-7 person's ring.
Below be the structural formula (be configured as R, the resolution reagent of corresponding S configuration also is applied to split) of the resolution reagent 5 of recommendation:
The yield of the molecular crystal that above-mentioned reaction obtains is generally at 70-90%, and enantiomeric excess (ee) is generally at 70-80%.Mother liquor is added in the organic solvent after concentrating, reflux, and cold filtration, insolubles are resolution reagent, and mother liquor concentrates, and recrystallization in organic solvent can obtain optically pure di-phenol isomer (R or S configuration), and yield is generally at 40-60%.The gained molecular crystal is added in the organic solvent, reflux, cold filtration, insolubles are resolution reagent, and mother liquor concentrates, and recrystallization can get the optically pure di-phenol isomer of another configuration, and yield is generally at 40-50%.Resolution reagent 5 recyclable 85-95%.The structure example of gained optically pure isomer is as follows:
Above-mentioned organic solvent comprises: methylene dichloride, chloroform, benzene, toluene, ether, tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol, normal hexane, acetonitrile, N, dinethylformamide (DMF), the mixing of two kinds of solvents in acetone or the above-mentioned solvent.
The present invention uses the resolution reagent that is easy to get that racemize BINOL is split, and method for splitting of having reported more or preparation method have following advantage:
1. present method is according to the supramolecular chemistry principle, utilize the weak interaction between the additional mutually and group on the three-dimensional space between host molecule and the guest molecule, the two optionally forms stable molecular crystal by molecular recognition, thereby has realized the high-level efficiency optical resolution to racemic modification.
2. used chiral source is natural chipal compounds, as L-L-glutamic acid etc., cheaply is easy to get.
3. resolution reagent is easy to preparation, low price, and never be used to as resolution reagent in the past.
4. method economy, chiral selectors 5 that need only the 0.5-3 mole can carry out optical resolution to 1 mole of racemic modification, and chiral selectors reclaims (rate of recovery>90%) easily, and is reusable and do not influence fractionation efficient, so the consumption of resolution reagent is very low.
5. it is higher to split efficient, because high molecule distinguishability is arranged, causes isolating isomer to have higher optical purity (70-80%ee), and through recrystallization, the enantiomeric excess of chirality 1 can reach>and 99%, total recovery reaches 40-60%.And mother liquor can obtain the optical isomer of another kind of configuration after treatment.
6. easy and simple to handle, the involved operation of the inventive method is as filtering, and recrystallization etc. all belong to the simple operations in the organic synthesis.
7. good reproducibility can prepare in a large number.Scale-up is the result show, therefore the be not put to the test influence of scale of the yield of product and optical purity is applicable to a large amount of preparations.
Description of drawings
Fig. 1 is to be the reaction method of raw material with 5a and racemize 1a.
Embodiment
Help to understand the present invention by following examples, but be not limited to the present invention.
The preparation of embodiment one resolution reagent
The preparation of resolution reagent 5a
In the round-bottomed flask of 500ml, add L-L-glutamic acid 60g (0.4mol), aniline 350Ml.Load onto water trap.Be heated to the 195-200 degree and stir after 30 minutes, mixed solution becomes clarification.Continue to stir 4 hours, the water that is generated is taken system out of by component distillation.Excessive aniline is removed under reduced pressure.Add 250mL acetone in the gained oily matter, separate out brown solid, filter, the solid recrystallizing methanol gets white needle-like crystals 69g, yield 85%.189.0 ℃ of Mp [α]
20 D+ 18.0 (c=1.0 methyl alcohol)
1H NMR (300MHz, DMSO-d
6) δ 2.00 (tdd, J=9.7,12.3,4.7Hz, 1H), 2.18 (td, J=9.7,14.4Hz, 2H), 2.31 (tdd, J=9.7,12.3 8.5Hz, 1H), 4.19 (dd, J=8.5,4.3Hz, 1H), 7.06 (t, J=7.5Hz, 1H) 7.32 (t, J=7.5Hz, 2H), 7.63 (d, J=7.5Hz, 2H), 7.92 (s, 1H), 10.06 (s, 1H)
13C NMR (25.18MHz, DMSO-d
6) δ 25.3,29.2,56.4,119.3,123.5,128.8,138.8,171.3,177.5 Anal.Calcd for C
11H
12N
2O
2: C, 64.70, H, 5.88, N, 13.72.found:C, 64.85, H, 5.74, N, 13.46.
The preparation of resolution reagent 5b
In the round-bottomed flask of 500ml, add L-L-glutamic acid 60g (0.4mol), o-toluidine 350Ml.Load onto water trap.Be heated to the 195-200 degree and stir after 30 minutes, mixed solution becomes clarification.Continue to stir 4 hours, the water that is generated is taken system out of by component distillation.Excessive Ortho Toluidine is removed under reduced pressure.Add 250mL acetone in the gained oily matter, separate out brown solid, filter, solid water recrystallization gets white needle-like crystals 69.2g, yield 81%.148 ℃ of Mp [α]
20 D+ 16.9 (c=1.0 ethanol)
1H NMR (300MHz, DMSO-d
6) δ 2.00 (dd, J=9.6,4.6Hz, 1H), 2.18 (td, J=9.7,14.4Hz, 2H), 2.20-2.30 (m, 4H), 4.19 (dd, J=8.5,4.3Hz, 1H), 7.00-7.90 (m, 4H), 10.06 (s, 1H) Calcd for C
12H
14N
2O
2: C, 66.04, H, 6.47, N, 12.84.found:C, 65.85, H, 6.32, N, 12.90.
The preparation of resolution reagent 5c
In the round-bottomed flask of 500ml, add L-L-glutamic acid 60g (0.4mol), m-chloro aniline 350Ml.Load onto water trap.Be heated to the 195-200 degree and stir after 30 minutes, mixed solution becomes clarification.Continue to stir 4 hours, the water that is generated is taken system out of by component distillation.Excessive aniline is removed under reduced pressure.Add 250mL acetone in the gained oily matter, separate out brown solid, filter, the solid recrystallizing methanol gets crystal 78g, yield 82%.120 ℃ of Mp [α]
20 D+ 12.8 (c=1.0 ethanol)
1H NMR (300MHz, DMSO-d
6) δ 2.08 (dd, J=9.0,4.8Hz, 1H), 2.18 (td, J=9.4,14.2Hz, 2H), 2.20-2.30 (m, 4H), 4.19 (dd, J=8.5,4.3Hz, 1H), 7.2-8.2 (m, 4H), 9.62 (s, 1H) Calcd for C
11H
11ClN
2O
2: C, 55.36, H, 4.65, N, 14.85.found:C, 55.44, H, 4.66, N, 14.74.
The preparation of resolution reagent 5d
In the round-bottomed flask of 500ml, add L-L-glutamic acid 60g (0.4mol), Isopropylamine 20ml toluene 100mL.Load onto water trap.Be heated to 120 degree and stirred 4 hours, the water that is generated is taken system out of by component distillation.Excessive Isopropylamine and toluene are removed under reduced pressure.Add 200mL acetone in the gained oily matter, separate out solid, filter, the solid recrystallizing methanol gets white crystal 65g, yield 82%.Mp140℃?
1H?NMR(300MHz,CDCl
3)δ2.2(d,J=12.6Hz,6H)2.4-2.5(m,1H),2.7(m,1H),4.4(t,J=16.0Hz,1H);Calcd?for?C
8H
14N
2O
2:C,54.65,H,8.29,N,16.46.found:C,54.36,H,8.32,N,16.51.
The preparation of resolution reagent 5e
In the round-bottomed flask of 250ml, add L-L-glutamic acid 30g (0.2mol), tetramethyleneimine 40ml toluene 100mL.Load onto water trap.Be heated to 120 degree and stirred 4 hours, the water that is generated is taken system out of by component distillation.Excessive tetramethyleneimine and toluene are removed under reduced pressure.Add 200mL acetone in the gained oily matter, separate out solid, filter, the solid recrystallizing methanol gets white crystal 29g, yield 80%.111 ℃ of Mp [α]
20 D-40.5 (c=1.0, water)
1H NMR (300MHz, CDCl
3) δ 1.8-2.5 (m, 11H), 2.8 (m, 1H), 4.5 (t, J=14.6Hz, 1H); Calcd for C
9H
14N
2O
2: C, 59.32, H, 7.74, N, 15.37.found:C, 59.36, H, 7.52, N, 15.51.
The preparation of resolution reagent 5f
In the round-bottomed flask of 500ml, add L-L-glutamic acid 60g (0.4mol), beta-naphthylamine 42g (04mol), 200mL toluene.Load onto water trap.Be heated to 120 degree and stirred 10 hours, the water that is generated is taken system out of by component distillation.Under reduced pressure, remove toluene.Add 200mL acetone in the gained oily matter, separate out 1 look solid, filter, the solid ethyl alcohol recrystallization gets white crystal 80g, yield 71%.Mp?207℃?
1H?NMR(300MHz,DMSO-d
6)δ2.00(dd,J=9.6,4.6Hz,1H),2.18(td,J=9.7,14.4Hz,2H),2.20-2.30(m,4H),4.19(dd,J=8.5,4.3Hz,1H),7.00-8.1(m,7H),9.89(s,1H);Calcd?for?C
15H
14N
2O
2:C,70.85,H,5.55,N,11.02.Found:C,79.01,H,5.52,N,10.92。
The preparation of resolution reagent 5g
In the round-bottomed flask of 500ml, add L-L-glutamic acid 60g (0.4mol), 2,3-dichlorphenamide bulk powder 350Ml.Load onto water trap.Be heated to the 195-200 degree and stir after 30 minutes, mixed solution becomes clarification.Continue to stir 4 hours, the water that is generated is taken system out of by component distillation.Excessive 2, the 3-dichlorphenamide bulk powder is removed under reduced pressure.Add 250mL acetone in the gained oily matter, separate out solid, filter, the solid recrystallizing methanol gets crystal 78g, yield 82%.210 ℃ of Mp [α]
20 D+-30.6 (c=1.0 ethanol)
1H NMR (300MHz, DMSO-d
6) δ 2.08 (dd, J=9.0,4.8Hz, 1H), 2.18 (td, J=9.4,14.2Hz, 2H), 2.20-2.30 (m, 4H), 4.19 (dd, J=8.5,4.3Hz, 1H), 7.2-8.2 (m, 3H), 9.68 (s, 1H); Calcd for C
11H
10Cl
2N
2O
2: C, 48.37, H, 3.69, N, 10.26.found:C, 48.54, H, 3.52, N, 10.22.
The preparation of resolution reagent 5h
In the round-bottomed flask of 500ml, add L-L-glutamic acid 60g (0.4mol), methyl alcohol 192ml, benzene 120Ml, vitriol oil 4Ml, reflux stream stirred 15 hours, be cooled to room temperature, add the 20% sodium hydroxid aqueous solution, transfer PH=6, concentrate the back and add 200 milliliters of chloroforms, filter, mother liquor concentrates, and decompression steams product 34g, 21 ℃ of yield 75%Mp
1H NMR (300MHz, CDCl
3) δ 2.35-2.48 (m, 1H), 3.2 (s, 3H), 4.4 (t, J=18.6Hz, 1H); Calcd for C
6H
9NO
3: C, 50.35, H, 6.34, N, 9.79.found:C, 50.12, H, 6.48, N, 9.66.
The preparation of resolution reagent 5i
In the round-bottomed flask of 500ml, add L-L-glutamic acid 60g (0.4mol), alpha-amino group furans 34g (0.4mol), 200mL toluene.Load onto water trap.Be heated to 120 degree and stirred 12 hours, the water that is generated is taken system out of by component distillation.Under reduced pressure, remove toluene.Add 200mL acetone in the gained oily matter, separate out 1 look solid, filter, the solid ethyl alcohol recrystallization gets white crystal 80g, yield 82%.Mp?129℃?
1H?NMR(300MHz,DMSO-d
6)δ2.00(dd,J=9.6,4.6Hz,1H),2.18(td,J=9.7,14.4Hz,2H),2.20-2.30(m,4H),4.19(dd,J=8.5,4.3Hz,1H),7.2-7.6(m,3H),8.62(s,1H);Calcd?for?C
9H
10N
2O
3:C,55.67,H,6.19,N,14.43.found:C,55.60,H,6.28,N,14.49。
(S) preparation of the resolution reagent 5 of configuration
Raw material L-L-glutamic acid is used D-L-glutamic acid instead, other preparation method and above-mentioned preparation (R) configuration 5 identical.Embodiment two racemizes 1,1 '-biphenyl phenol, 1, the optical resolution of 1 '-binaphthol and derivative thereof and tearing open
The recovery 1. that divides reagent
Racemize 1, the fractionation of 1 '-binaphthol derivative 1
The fractionation of 1a
Utilize 5a to split
Be equipped with one and add (±) 1a 1.544 grams (4mmol) in 25 ml flasks of reflux condensing tube, resolution reagent 5a 0.418 gram (2mmol), add tetrahydrofuran (THF), alcohol mixed solvent 5-10ml, reflux is dissolved solid fully, cool to room temperature, separate out crystal, filter, get inclusion crystal 0.85 gram yield 78%, 70%ee.Mother liquor is concentrated, be dissolved in acetone, reflux is filtered, and insolubles is a resolution reagent, and mother liquor concentrates uses the organic solvent-benzene recrystallization, gets (S)-1a, yield 41%, 100%ee.The inclusion crystal is joined in the acetone reflux, cold filtration.Mother liquor concentrates, and gets (R)-1a yield 45%, 100%ee with the crystallization of benzene recrystallization.Insolubles is a resolution reagent, reclaims 0.4g, and the rate of recovery is 92%.The data of gained molecular crystal are as follows: MP.157-158 ℃
1H NMR (CDCL3, ppm) δ 7.82-7.90 (m, 4H), 7.62 (d, J=8.1Hz, 2H), and 7.29-7.34 (m, 4H), 7.12-7.24 (m, 4H), 7.08 (t, J=7.5Hz, 1H), 6.92 (d, J=8.1Hz, 2H), 4.17-4.20 (m, 1H), 3.4 (s, 2H), 3.59 (t, J=6.0Hz, 1H), 1.99-2.34 (m, 4H); Calcd for C
31H
26N
2O
4: C, 75.90, H, 5.34, N, 5.71.found:C, 75.76, H, 5.44, N, 5.46.
Utilize 5b ' to split
Be equipped with one and add (±) 1a 1.544 grams (4mmol) in 25 ml flasks of reflux condensing tube, resolution reagent 5b ' 0.436 gram (2mmol), add ether, alcohol mixed solvent 5-10ml, reflux is dissolved solid fully, cool to room temperature, separate out crystal, filter, get inclusion crystal 0.92 gram yield 80%, 68%ee.Mother liquor is concentrated, be dissolved in methylene dichloride, reflux is filtered, and insolubles is a resolution reagent, and mother liquor concentrates uses the toluene recrystallization, gets (R)-1a, yield 40%, 100%ee.The inclusion crystal is joined in the methylene dichloride reflux, cold filtration.Mother liquor concentrates, and gets (S)-1a yield 51%, 100%ee with the crystallization of toluene recrystallization.Insolubles is resolution reagent 5b, reclaims 0.4g, and the rate of recovery is 91%.The data of gained molecular crystal are as follows: MP.122 ℃
1H NMR (CDCL3, ppm) δ 7.82-7.90 (m, 4H), 7.62 (d, J=8.1Hz, 2H), and 7.29-7.34 (m, 3H), 7.12-7.24 (m, 4H), 7.08 (t, J=7.5Hz, 1H), 6.92 (d, J=8.1Hz, 2H), 4.17-4.20 (m, 1H), 3.4 (s, 2H), 3.59 (t, J=6.0Hz, 1H), 1.99-2.34 (m, 7H); Calcd for C
32H
28N
2O
4: C, 76.17, H, 5.59, N, 5.55.found:C, 75.96, H, 5.48, N, 5.56.
Utilize 5c to split
Be equipped with one and add (±) 1a 1.544 grams (4mmol) in 25 ml flasks of reflux condensing tube, resolution reagent 5c 0.476 gram (2mmol), add tetrahydrofuran (THF), methanol mixed solvent 5-10ml, reflux is dissolved solid fully, and cool to room temperature is separated out crystal, filter, get inclusion crystal 0.82 gram yield 67%.Mother liquor is concentrated, be dissolved in acetone, reflux is filtered, and insolubles is a resolution reagent, and mother liquor concentrates uses the benzene recrystallization, gets (S)-1a, yield 46%, 100%ee.The inclusion crystal is joined in the acetone reflux, cold filtration.Mother liquor concentrates, and gets (R)-1a yield 42%, 100%ee with the crystallization of benzene recrystallization.Insolubles is resolution reagent 5c, reclaims 0.42g, and the rate of recovery is 86%.。The data of gained molecular crystal are as follows: MP.108 ℃
1H NMR (CDCL3, ppm) δ 7.76-7.80 (m, 4H), 7.60 (d, J=8.0Hz, 2H), and 7.27-7.34 (m, 3H), 7.12-7.24 (m, 4H), 7.08 (t, J=6.5Hz, 1H), 6.76 (d, J=8.4Hz, 2H), 4.17-4.20 (m, 1H), 3.35 (s, 2H), 3.62 (t, J=6.4Hz, 1H), 1.99-2.38 (m, 4H); Calcd for C
31H
25ClN
2O
4: C, 70.92, H, 4.80, N, 5.34.found:C, 70.89, H, 4.77, N, 5.24.
Utilize 5j to split
Be equipped with one and add (±)-1a 1.544 grams (4mmol) in 25 ml flasks of reflux condensing tube, resolution reagent 5j 0.284 gram (2mmol) adds ether 5-10Ml, reflux is dissolved solid fully, and cool to room temperature is separated out crystal, filter, get inclusion crystal 0.66 gram yield 70%.Mother liquor is concentrated, be dissolved in toluene, reflux is filtered, and insolubles is a resolution reagent, and mother liquor concentrates uses the benzene recrystallization, gets (S)-1a, yield 42%, 100%ee.The inclusion crystal is joined in the toluene reflux, cold filtration.Mother liquor concentrates, and gets (R)-1a yield 46%, 100%ee with the crystallization of benzene recrystallization.Insolubles is resolution reagent 5j, reclaims 0.26g, and the rate of recovery is 91%.The data of gained molecular crystal are as follows: MP.132 ℃
1H NMR (CDCL3, ppm) δ 7.82-7.90 (m, 4H), 7.62 (d, J=8.1Hz, 2H), 7.12-7.24 (m, 4H), 7.08 (t, J=7.5Hz, 1H), 6.92 (d, J=8.1Hz, 2H), δ 4.4 (t, J=16.7Hz, 1H), 2.8 (s, 3H), 2.4-2.5 (m, 1H); Calcd for C
26H
24N
2O
4: C, 72.88, H, 5.65, N, 6.54.found:C, 72.96, H, 5.62, N, 6.57.
Utilize 5d to split
Be equipped with one and add (±) 1a 1.544 grams (4mmol) in 25 ml flasks of reflux condensing tube, resolution reagent 5d 0.340 gram (2mmol) adds chloroform 5-10ml, reflux is dissolved solid fully, and cool to room temperature is separated out crystal, filter, get inclusion crystal 0.64 gram yield 70%.Mother liquor is concentrated, be dissolved in ether, reflux is filtered, and insolubles is a resolution reagent, and mother liquor concentrates uses the benzene recrystallization, gets (S)-1a, yield 40%, 100%ee.The inclusion crystal is joined in the benzene reflux, cold filtration.Mother liquor concentrates, and gets (R)-1a yield 51%, 100%ee with the crystallization of benzene recrystallization.Insolubles is resolution reagent 5d, reclaims 32g, and the rate of recovery is 94%.The data of gained molecular crystal are as follows: MP.120 ℃
1H NMR (CDCL3, ppm) δ 7.82-7.90 (m, 4H), 7.62 (d, J=8.1Hz, 2H), 7.12-7.24 (m, 4H), 7.08 (t, J=7.5Hz, 1H), 6.92 (d, J=8.1Hz, 2H), δ 4.4 (t, J=16.2Hz, 1H), 2.7 (m, 1H), 2.4-2.5 (m, 1H), 2.2 (d, J=12.0Hz, 6H); Calcdfor C
28H
28N
2O
4: C, 73.66, H, 6.18, N, 6.14.found:C, 73.84, H, 5.32, N, 6.17.
Utilize 5e to split
Be equipped with one and add (±)-1a 1.544 grams (4mmol) in 25 ml flasks of reflux condensing tube, resolution reagent 5e 0.364 gram (2mmol), add methylene dichloride 5-10ml, reflux is dissolved solid fully, cool to room temperature, separate out crystal, filter, get inclusion crystal 0.73 gram yield 72%.Mother liquor is concentrated, be dissolved in ether, reflux is filtered, and insolubles is a resolution reagent, and mother liquor concentrates uses the benzene recrystallization, gets (S)-1a, yield 41%, 100%ee.The inclusion crystal is joined in the ether reflux, cold filtration.Mother liquor concentrates, with there being the crystallization of benzene recrystallization to get (R)-1a yield 49%, 100%ee.Insolubles is resolution reagent 5e, reclaims 0.31g, and the rate of recovery is 86%.The data of gained molecular crystal are as follows:
MP.90℃?
1H?NMR(CDCL3,ppm)δ7.82-7.90(m,4H),7.62(d,J=8.1Hz,2H),7.29-7.34(m,4H),7.12-7.24(m,4H),7.08(t,J=7.5Hz,1H),6.92(d,J=8.1Hz,2H),4.5(t,J=14.6Hz,1H),2.8(m,1H)1.8-2.5(m,11H);Calcdfor?C
29H
28N
2O
4:C,74.34,H,6.02,N,5.98.found:C,74.42,H,5.92,N,6.17.
Utilize 5f to split
Be equipped with one and add (±)-1a 11.544 grams (4mmol) in 25 ml flasks of reflux condensing tube, resolution reagent 5f 0.508 gram (2mmol), add tetrahydrofuran (THF), alcohol mixed solvent 5-10ml, reflux is dissolved solid fully, and cool to room temperature is separated out crystal, filter, get inclusion crystal 0.74 gram yield 68%.Mother liquor is concentrated, be dissolved in acetone, reflux is filtered, and insolubles is a resolution reagent, and mother liquor concentrates uses the benzene recrystallization, gets (S)-1a, yield 40%, 100%ee.The inclusion crystal is joined in the acetone reflux, cold filtration.Mother liquor concentrates, with there being the crystallization of benzene recrystallization to get (R)-1a yield 52%, 100%ee.Insolubles is resolution reagent 5f, reclaims 0.45, and the rate of recovery is 90%.The data of gained molecular crystal are as follows:
MP.180℃?
1H?NMR(CDCL3,ppm)δ7.82-7.90(m,4H),7.62(d,J=8.1Hz,2H),7.29-7.34(m,4H),7.12-7.24(m,4H),7.08(t,J=7.5Hz,1H),6.92(d,J=8.1Hz,2H),4.17-4.20(m,1H),3.4(s,2H),3.59(t,J=6.0Hz,1H),1.99-2.34(m,4H);Calcd?for?C
35H
28N
2O
4:C,77.76,H,5.22,N,5.18.found:C,77.48,H,5.42,N,5.17
Utilize 5g to split
Be equipped with one and add (±)-1a 1.544 grams (4mmol) in 25 ml flasks of reflux condensing tube, resolution reagent 5g 0.544 gram (2mmol), add tetrahydrofuran (THF), isopropyl alcohol mixed solvent 5-10ml, reflux is dissolved solid fully, and cool to room temperature is separated out crystal, filter, get inclusion crystal 0.40 gram yield 71%.Mother liquor is concentrated, be dissolved in acetone, reflux is filtered, and insolubles is a resolution reagent, and mother liquor concentrates uses the benzene recrystallization, gets (S)-1a, yield 39%, 100%ee.The inclusion crystal is joined in the acetone reflux, cold filtration.Mother liquor concentrates, and gets (R)-1a yield 50%, 100%ee with the crystallization of benzene recrystallization.Insolubles is resolution reagent 5g, reclaims 0.5g, and the rate of recovery is 92%.。The data of gained molecular crystal are as follows:
MP.131℃?
1H?NMR(CDCL3,ppm)δ7.0-8.0(m,19H)4.17-4.20(m,1H),4.4(T,2H),3.59(t,J=6.0Hz,1H),1.99-2.34(m,4H);Calcd?for?C
31H
24Cl
2N
2O
4:C,66.55,H,4.32,N,5.01.found:C,66.48,H,4.42,N,5.18
Utilize 5h to split
Be equipped with one and add (±)-1a 1.544 grams (4mmol) in 25 ml flasks of reflux condensing tube, resolution reagent 5h 0.290 gram (2mmol), add acetone, ether mixed solvent 5-10ml, reflux is dissolved solid fully, and cool to room temperature is separated out crystal, filter, get inclusion crystal 0.52 gram yield 60%.Mother liquor is concentrated, be dissolved in methylene dichloride, reflux is filtered, and insolubles is a resolution reagent, and mother liquor concentrates uses the toluene recrystallization, gets (S)-1a, yield 41%, 100%ee.The inclusion crystal has been joined in the methylene dichloride reflux, cold filtration.Mother liquor concentrates, and gets (R)-1a yield 45%, 100%ee with the crystallization of toluene recrystallization.Insolubles is resolution reagent 5h, reclaims 0.2g, and the rate of recovery is 69%.The data of gained molecular crystal are as follows:
MP.89℃?
1H?NMR(CDCL3,ppm)δ7.82-7.90(m,4H),7.62(d,J=8.1Hz,2H),7.29-7.34(m,4H),7.12-7.24(m,2H),4.4(t,J=18.6Hz,1H),3.2(s,3H),2.35-2.48(m,1H);Calcd?for?C
26H
23NO
5:C,72.71,H,5.40,N,3.26.found:C,72.67,H,5.49,N,3.16
Utilize 5i to split
Be equipped with one and add (±)-1a 1.544 grams (4mmol) in 25 ml flasks of reflux condensing tube, resolution reagent 5i 0.384 gram (2mmol), add tetrahydrofuran (THF), alcohol mixed solvent 5-10ml, reflux is dissolved solid fully, and cool to room temperature is separated out crystal, filter, get inclusion crystal 0.672 gram yield 70%.Mother liquor is concentrated, be dissolved in acetone, reflux is filtered, and insolubles is a resolution reagent, and mother liquor concentrates uses the benzene recrystallization, gets (S)-1a, yield 41%, 100%ee.The inclusion crystal is joined in the acetone reflux, cold filtration.Mother liquor concentrates, and gets (R)-1a yield 50% with the crystallization of benzene recrystallization,
MP.102℃?
1H?NMR(CDCL3,ppm)δ7.82-7.90(m,4H),7.62(d,J=8.1Hz,2H),7.29-7.34(m,4H),7.12-7.24(m,4H),6.92(d,J=8.1Hz,1H),4.17-4.20(m,1H),3.4(s,2H),3.59(t,J=6.0Hz,1H),1.99-2.34(m,4H);Calcd?for?C
29H
24N
2O
5:C,72.49,H,5.03,N,5.83.found:C,72.31,H,5.27,N,5.15
Utilize the resolution reagent 5 of (S) configuration to split
Resolution reagent 5 fractured operation steps of utilization (S) configuration and the resolution reagent 5 of above-mentioned (R) configuration are identical.
Fractionation: utilize resolution reagent 5a to split
Operation obtains (R)-1b yield 52%, 100%ee (S)-1b yield 42%, 100%ee, the resolution reagent rate of recovery 92% as utilizing resolution reagent 5a to split 1a.
Fractionation: utilize resolution reagent 5a to split
Operation obtains (R)-1c yield 48%, 100%ee (S)-1c yield 42%, 100%ee, the resolution reagent rate of recovery 89% as utilizing resolution reagent 5a to split 1a.
Fractionation: utilize resolution reagent 5a to split
Operation obtains (R)-1d yield 47%, 100%ee (S)-1b yield 41%, 100%ee, the resolution reagent rate of recovery 90% as utilizing resolution reagent 5a to split 1a.
Fractionation: utilize resolution reagent 5a to carry out fractured operation, obtain (R)-1e yield 51%, 100%ee (S)-1e yield 45%, 100%ee, the resolution reagent rate of recovery 91% as utilizing resolution reagent 5a to split 1a.
Fractionation: utilize resolution reagent 5a to split
Operation obtains (R)-1f yield 56%, 100%ee (S)-1f yield 60%, 100%ee, the resolution reagent rate of recovery 88% as utilizing resolution reagent 5a to split 1a.
Fractionation: utilize resolution reagent 5a to split
Operation obtains (R)-1g yield 52%, 100%ee (S)-1g yield 45%, 100%ee, the resolution reagent rate of recovery 90% as utilizing resolution reagent 5a to split 1a.
Fractionation: utilize resolution reagent 5a to split
Operation obtains (R)-1h yield 51% as utilizing resolution reagent 5a to split 1a, 100%ee (S)-1h yield 38%, and 100%ee,, the resolution reagent rate of recovery 91%.
Fractionation: utilize resolution reagent 5a to split
Operation obtains (R)-li yield 53%, 100%ee (S)-li yield 39%, 100%ee, the resolution reagent rate of recovery 86% as utilizing resolution reagent 5a to split 1a.2.
5,5 ', 6,6 ', 7,7 ', 8,8 '-octahydro-1, the fractionation of 1 '-binaphthol derivative 2 utilizes 5a to split
Fractionation:
Operation obtains (R)-2a yield 57%, 100%ee (S)-2a yield 42%, 100%ee, the resolution reagent rate of recovery 85% as utilizing resolution reagent 5a to split 1a.
Fractionation:
Operation obtains (R)-2b yield 55%, 100%ee (S)-2b yield 40%, 100%ee, the resolution reagent rate of recovery 88% as utilizing resolution reagent 5a to split 1a.
Fractionation:
Operation obtains (R)-2c yield 52%, 100%ee (S)-2c yield 40%, 100%ee, the resolution reagent rate of recovery 89% as utilizing resolution reagent 5a to split 1a.
Fractionation:
Operation obtains (R)-2d yield 47%, 100%ee (S)-2d yield 40%, 100%ee, the resolution reagent rate of recovery 90% as utilizing resolution reagent 5a to split 1a.
Fractionation: operation is as utilizing resolution reagent 5a to split 1a, with the resolving agent 5a ' of (S) configuration
Fractionation obtains (S)-2e, yield 58%, 100%ee (R)-2e yield 41%, 100%ee, the resolution reagent rate of recovery 89%.
Fractionation:
Operation obtains (R)-2f yield 52%, 100%ee (S)-2f yield 38%, 100%ee, the resolution reagent rate of recovery 91% as utilizing resolution reagent 5a to split 1a.3.
5,6,7,8-tetrahydrochysene-1, the fractionation of 1 '-binaphthol derivative 3 utilizes 5a to split:
Fractionation:
Operation obtains (R)-3a yield 50%, 100%ee (S)-3a yield 40%, 100%ee, the resolution reagent rate of recovery 88% as utilizing resolution reagent 5a to split 1a.
Fractionation: operation obtains (R)-3b yield 47%, 100%ee (S)-3b yield 39%, 100%ee, the resolution reagent rate of recovery 90% as utilizing resolution reagent 5a to split 1a.
Fractionation:
Operation obtains (R)-3c yield 46%, 100%ee (S)-3a yield 32%, 100%ee, the resolution reagent rate of recovery 88% as utilizing resolution reagent 5a to split 1a.
Fractionation:
Operation obtains (R)-3a yield 43%, 100%ee (S)-3a yield 35%, 100%ee, the resolution reagent rate of recovery 88% as utilizing resolution reagent 5a to split 1a.
Fractionation: operation is as utilizing resolution reagent 5a to split 1a, with the 5c ' of resolving agent (S) configuration
Obtain (S)-3e yield 44%, 100%ee (R)-3a yield 30%, 100%ee, the resolution reagent rate of recovery 90%.
Fractionation:
Operation obtains (R)-3f yield 50%, 100%ee (S)-3f yield 40%, 100%ee, the resolution reagent rate of recovery 86% as utilizing resolution reagent 5a to split 1a.
4.
The fractionation of 2,2 '-biphenol derivative 4: utilize resolution reagent 5a to split:
Fractionation:
Operation obtains (R)-4a yield 48%, 100%ee (S)-4a yield 39%, 100%ee, the resolution reagent rate of recovery 85% as utilizing resolution reagent 5a to split 1a.
Fractionation:
Claims (7)
1. the method for optical resolution of a recemic diphenol, it is characterized in that in organic solvent, optically pure resolution reagent 5 optionally with recemic diphenol in (R) or (S) optical isomer be combined into the molecule crystal, wherein the mol ratio of resolution reagent and di-phenol is 0.5-3: 1,0-150 ℃ of reaction 1-12 hour, the molecular crystal that reaction obtains obtained optically pure di-phenol after handling with organic solvent; The mother liquor of reaction is handled the optically pure di-phenol that obtains another kind of configuration with organic solvent,
Described recemic diphenol comprises following structural formula:
R in the formula
1, R
2, R
3Or R
4Be H, C
1-C
6Alkyl, aryl, halogen atom, formyl radical, hydroxyl, the C of straight or branched
1-C
6The alkoxyl group or the SPh of straight or branched;
Described optical purity resolution reagent 5 comprises 5 (R) or 5 (S) of following structural formula:
N=0,1 or 2 in the formula; A is N or O, and when A is oxygen, no R ": R, R ' or R " be H, C
1-C
7Straight or branched alkyl, C
1-C
7Straight or branched alkyloyl, 5-7 person's cycloalkyl,
Nitrogenous, oxygen, the 5-7 element heterocycle substituting group of sulphur,
Described R
5=H, C
1-C
7Straight or branched alkyl, halogen, C
1-C
5Alkoxyl group, nitro, acyl group, cyano group, hydroxyl
Base; And when A is nitrogen, R ', R ", A three can be 5-7 person's ring.
4. the method for optical resolution of recemic diphenol as claimed in claim 1, after it is characterized in that forming molecular crystal, mother liquor is handled the di-phenol that obtains optically pure S or R configuration with organic solvent.
5. the method for optical resolution of recemic diphenol as claimed in claim 1 is characterized in that the molecular crystal that forms handles with organic solvent, filter resolution reagent 5.
6. the method for optical resolution of recemic diphenol as claimed in claim 1, after it is characterized in that forming molecular crystal, mother liquor is handled with organic solvent, filter resolution reagent 5.
7. the method for optical resolution of recemic diphenol as claimed in claim 1 is characterized in that described organic solvent is the mixing of two kinds of solvents in methylene dichloride, chloroform, benzene, toluene, ether, tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol, normal hexane, acetonitrile, DMF, acetone or the above-mentioned solvent.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB021118299A CN1215028C (en) | 2002-05-24 | 2002-05-24 | Optical resolution method for recemic diphenol |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB021118299A CN1215028C (en) | 2002-05-24 | 2002-05-24 | Optical resolution method for recemic diphenol |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1385409A true CN1385409A (en) | 2002-12-18 |
CN1215028C CN1215028C (en) | 2005-08-17 |
Family
ID=4741773
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB021118299A Expired - Fee Related CN1215028C (en) | 2002-05-24 | 2002-05-24 | Optical resolution method for recemic diphenol |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN1215028C (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7718693B2 (en) | 2006-07-06 | 2010-05-18 | Glaxo Group Limited | Receptor antagonists and their methods of use |
CN101333221B (en) * | 2008-07-24 | 2011-01-19 | 武汉大学 | Stabilization method for annular L-proline anhydride configuration |
CN102439438A (en) * | 2009-04-30 | 2012-05-02 | 大赛璐化学工业株式会社 | Agent for resolution of optical isomer |
CN102675053A (en) * | 2012-05-30 | 2012-09-19 | 中南民族大学 | Method for preparing enantiopure (S)-1,1'-co-2-naphthol and enantiopure (R)-1,1'-co-2-naphthol conveniently and simply |
-
2002
- 2002-05-24 CN CNB021118299A patent/CN1215028C/en not_active Expired - Fee Related
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7718693B2 (en) | 2006-07-06 | 2010-05-18 | Glaxo Group Limited | Receptor antagonists and their methods of use |
US8048907B2 (en) | 2006-07-06 | 2011-11-01 | Glaxo Group Limited | Receptor antagonists and their methods of use |
CN101333221B (en) * | 2008-07-24 | 2011-01-19 | 武汉大学 | Stabilization method for annular L-proline anhydride configuration |
CN102439438A (en) * | 2009-04-30 | 2012-05-02 | 大赛璐化学工业株式会社 | Agent for resolution of optical isomer |
CN102675053A (en) * | 2012-05-30 | 2012-09-19 | 中南民族大学 | Method for preparing enantiopure (S)-1,1'-co-2-naphthol and enantiopure (R)-1,1'-co-2-naphthol conveniently and simply |
CN102675053B (en) * | 2012-05-30 | 2014-04-30 | 中南民族大学 | Method for preparing enantiopure (S)-1,1'-co-2-naphthol and enantiopure (R)-1,1'-co-2-naphthol conveniently and simply |
Also Published As
Publication number | Publication date |
---|---|
CN1215028C (en) | 2005-08-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8097738B2 (en) | Ruthenium (II) catalysts for use in stereoselective cyclopropanations | |
JP5214609B2 (en) | Recovery of bis (diarylphenol) ligands during the production of isopulegol | |
CN105330557A (en) | Preparation method of chiral alpha-amino acid | |
CN1887893A (en) | New-type spiro phosphonite and its application in the asymmetrical catalytic hydrogenation of enamine | |
CN1172910C (en) | Process for preparing VA derivative | |
CN1290818C (en) | Method for asymmetrical hydrogen transfer of alpha-imino keton for synthesizing chirality salbutamol | |
Pouliquen et al. | Chiral 3-aminopyrrolidines as a rigid diamino scaffold for organocatalysis and organometallic chemistry | |
CN1385409A (en) | Optical resolution method for recemic diphenol | |
CN101058532A (en) | Method of preparing chiral primary alcohol and secondary alcohol with chirality center at ortho position of hydroxyl group | |
CN1079960A (en) | Asymmetric hydrogenation | |
CN1166672C (en) | Metal complex of C2 uncymmetric chira biphosphine ligand, its synthesizing process and its application in unsymmetric catalytic hydrogenation of ketone | |
CN1163499C (en) | External compensation method of atropisomerism bis (phosphine oxide) compound | |
CN102746335B (en) | Preparation method of chiral phosphine oxide | |
CN1121383C (en) | Process for recycle of waste product of diltiazem synthesis | |
CN1186125C (en) | Chirality catalyst for oxygenized dinaphthol | |
CN109020788A (en) | The preparation method of optically pure 1,1 '-spiro indan -6,6 '-diol, derivatives | |
US9527800B2 (en) | Process for total synthesis of venlafaxine | |
CN111484522B (en) | Preparation method of optically pure cis-2- (diphenylphosphino) -1-cyclohexanecarboxylic acid | |
CN1219758C (en) | Process for preparing optical purity di-t-butyl thioester-sulfinate | |
CN115650824B (en) | Chiral diol and preparation method thereof, prepared catalyst and preparation method and application thereof | |
CN1176924C (en) | Chirality catalyst for oxidative coupling naphthol | |
CN1220674C (en) | Levodopa methyl ester hydrochloride purifying method | |
CN1511826A (en) | Process for synthesizing beta-amino acid using ketone as raw material | |
JP6281877B2 (en) | Method for synthesizing catalyst precursor and asymmetric chain compound | |
AU2005273649B2 (en) | Enantioselective synthesis of 13-oxotricyclo[8.2.1.0 3,8]trideca-3(8),4,6-triene-5-carboxylates |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20050817 Termination date: 20130524 |