CN1385409A - Optical resolution method for recemic diphenol - Google Patents

Abstract

The present invention relates to an optical resolution method for racemic biphenols including 1,1'-biphenol, 1,1'-binaphthol and derivatives thereof. Ground and racemic 1,1'-bidiphenol, 1,1'-binaphthol and one of its derivatives are combined to form molecular crystals, and the product is released after being treated with an organic solvent. Optically active 1,1'-diphenol, 1,1'-binaphthol and derivatives thereof can be obtained after post-treatment. The mother liquor is treated with an organic solvent to obtain another configuration of optically active 1,1'-biphenol, 1,1'-binaphthol and its derivatives. The method is simple to operate, high in efficiency, and good in repeatability. The method is economical and the chiral source is easy to obtain, the resolution reagent is easy to prepare, the price is cheap, and it is easy to recover. The high-efficiency optical resolution of the racemate is realized, and it is suitable for large-scale preparation.

Description

Optical Resolution Method of Racemic Bidiphenol

technical field

The invention relates to a new method for splitting optical isomers in chiral technology.

Background technique

In recent years, the application of optically active 1,1'-biphenol, 1,1'-binaphthol and its derivatives (1-4) in asymmetric synthesis has attracted more and more attention. Its application ranges from being a chiral ligand in an asymmetric catalytic reaction to a host compound for molecular recognition and enantiomer resolution, and then it can also be used as an important intermediate in the synthesis of chiral materials. For example, Cram uses the crown ether of chiral 1,1'-binaphthol unit to have chiral recognition for organic amines and amino acid derivatives, develops guest-of-host chemistry, and makes a "machine" for amino acid resolution. (CramD.J., Helv.Chim.Acta., 1979, 101, 5843; J.Org.Chem., 1977, 42, 4173; Acc., Chem., Res., 1978, 11, 8). Noyori utilizes The metal hydride complex formed by 1,1'-binaphthol and lithium aluminum hydride can induce the asymmetric reduction of aromatic ketone carbonyl to obtain high-yield alcohols, and is used in the synthesis of insect pheromones and prostaglandins. (Noyori R., Pure Appli.Chem., 1981, 53, 2315), utilizing 1,1'-binaphthol and titanium tetraisopropoxide to form a reagent for the alkylation of aromatic aldehydes (Olivero A.G. , Helv.Chim.Acta., 1981, 64, 2485) and Grignard reaction (Wang J.T., Synthesis, 1989, 291). Fuji has carried out asymmetric alkylation reaction (Fuji K., Tetra.Lett., 1989, 30, 2825) as chiral auxiliary agent. Tanaka used 1,1'-binaphthol as a chiral source for the asymmetric synthesis of amino acids (Tanaka K., Mija Ahn, Watanade Y., Fuji K., Tetra.Asymm., 1996, 7, 1771). Especially in recent years, the use of optically pure 1,1'-binaphthol and metal reagents to form a complex as a catalyst for asymmetric catalytic reactions has achieved a series of excellent results. These include the 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), allyl tin addition reaction (Keck, G.E.; Tatbet, K.H.; Geraci, L.S.J.Am.Chem.Soc.1993,115,8467), ene reaction (Mikami, K. Pure Appl. Chem. 1996, 68, 639), Diels-Alder reaction (Mikami, K.; Motoyama, Y.; Terada, M.J. Am. Chem. Soc. 1994, 116, 2812) and the like.

At present, the means of obtaining optically pure 1,1'-binaphthol and its derivatives (1-4) include: a) using the characteristics of the functional group of BINOL to react with photoactive reagents to obtain diastereoisomers, and then pass The means of crystallization can be separated. For example, the two hydroxyl groups of 1,1'-binaphthol and its derivatives (1-4) have good reactivity, and can be formed by ester or ether, or with chiral amine Effect, directly or indirectly interact with chiral groups to form diastereoisomers, and use their differences in properties to achieve the purpose of resolution. (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.; ; Hu, B.J.Org.Chem.1995, 60, 7364-7265; Fabbri, D.; Deloga, G.; De Lucchi, O.J.Org.Chem. .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.; , 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: Asymmetry 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) Using optically pure host compounds and their enantioselective formation of clathrates, this method is based on the principle of supramolecular chemistry, using the mutual complementarity between host (HOST) molecules and guest (GUEST) molecules in three-dimensional space and the weak interaction between the groups, the two selectively form stable molecular crystals through molecular recognition, thereby realizing the optical resolution of the racemate, such as the use of tartaric acid derivatives for racemic 1,1'-linked Resolution of binaphthol and its derivatives (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.; ; Periasamy, M.; Prasad, A.S.B.; Kanth, J.V.B.; Reddy, Ch.K. Tetrahedron: Asymmetry 1995, 6, 341-344; 62, 4302-4306.); c) Enzyme-catalyzed hydrolysis of its ester derivatives, such as the use of pig liver enzymes to hydrolyze the diester of racemic BINOL to obtain optically active BINOL. (Kazkausjas, R.J.J.Am.Chem.Soc., 1989,111,4953); direct asymmetric coupling of 2-naphthol derivatives, such as utilizing metal complexes of photoactive compounds, for stereoselective oxidative coupling, Photoactive BINOL can be obtained (Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S.J. Org. Chem. 1999, 64, 2264-2271 and references 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; , 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.). Among them, using optically active host compound molecules to enantioselectively generate clathrates with 1,1'-binaphthol and its derivatives (1-4) is the most practical means, because this method has the characteristics of high efficiency, and Racemic BINOL is very easy to prepare. However, the existing resolution methods have one or more of the following defects: (1) chiral sources are expensive; (2) resolution reagents are used in large quantities and are difficult to prepare; (3) the resolution process is complicated; (4) The resolution reagent is difficult to reclaim; (5) resolution efficiency is low etc.

Contents of the invention

In order to solve the problems of the above-mentioned resolution means, the present invention provides a simple and efficient method for racemic biphenols including 1,1'-biphenol, 1,1'-binaphthol and derivatives thereof. A new method for resolution of optical isomers.

According to the principle of supramolecular chemistry, the present invention utilizes the mutual complementarity between the host (HOST) molecules and the guest (GUEST) molecules in three-dimensional space and the weak interaction between the groups, and the two selectively form stable molecules through molecular recognition. Molecular crystals, thus achieving high-efficiency optical resolution of racemates.

The structural formula of the racemic biphenol involved in the resolution of the present invention is as follows, wherein R ₁ , R ₂ , R ₃ , and R ₄ are respectively H, C ₁ -C ₆ linear or branched chain alkane group, aryl group, halogen atom (F, Cl, Br, I), hydroxyl group, formyl group, C ₁ -C ₆ straight chain or branched alkoxy group or SPh, etc., R ₁ , R ₂ , R _3. R ₄ is the same or different: (1) 1,1'-binaphthol derivatives

(2) 5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthol derivatives

(3) 5,6,7,8-tetrahydro-1,1'-binaphthol derivatives

(4) Biphenol derivatives

In an organic solvent, the optically pure resolution reagent 5 is combined with the (R) or (S) isomer in the racemic biphenol to form a molecular crystal, and the optically pure resolution reagent 5 is added to the racemic The molar ratio of bidiphenol is 0.5-3: 1, and the molar ratio of 0.5: 1 is enough for the resolution reagent to be added. However, adding more resolution reagents generally does not hinder the reaction. The reaction temperature is 0-150 ° C, and the reaction time is 1-12 hours.

Described optically pure resolution reagent 5 is 5 (R) or 5 (S), and its structural formula is as follows: In the formula, n=0, 1 or 2; A is N or O, and when A is oxygen, there is no R"; R, R' or R" is H, C ₁ -C ₇ linear or branched alkyl , C ₁ -C ₇ straight or branched chain alkanoyl, 5-7 membered cycloalkyl, A 5-7-membered heterocyclic substituent containing nitrogen, oxygen, and sulfur, said R ₅ ═H, C ₁ -C ₇ linear or branched chain alkyl, halogen, C ₁ -C ₅ alkoxy, Nitro, acyl, cyano, hydroxyl; and when A is nitrogen, R', R", and A can be 5-7 membered rings.

The following is the structural formula of the recommended resolution reagent 5 (the configuration is R, and the corresponding resolution reagent of the S configuration is also used for resolution):

The yield of molecular crystals obtained by the above reaction is generally 70-90%, and the enantiomeric excess (ee) is generally 70-80%. After the mother liquor is concentrated, it is added to an organic solvent, heated to reflux, cooled and filtered, the insoluble matter is a resolution reagent, the mother liquor is concentrated, and recrystallized in an organic solvent to obtain optically pure bisphenol isomers (R or S configuration ), the yield is generally 40-60%. The resulting molecular crystals are added to an organic solvent, heated to reflux, cooled and filtered, the insoluble matter is a resolution reagent, the mother liquor is concentrated, and recrystallized to obtain an optically pure bisphenol isomer in another configuration. The yield is generally between 40-50%. The resolution reagent 5 can recover 85-95%. The structures of the obtained optically pure isomers are as follows:

The above-mentioned organic solvents include: dichloromethane, chloroform, benzene, toluene, ether, tetrahydrofuran, methanol, ethanol, isopropanol, n-hexane, acetonitrile, N,N-dimethylformamide (DMF), acetone or the above solvents A mixture of two solvents.

The present invention uses easy-to-get resolution reagents to resolve racemic BINOL, which has the following advantages compared with reported resolution methods or preparation methods:

1. According to the principle of supramolecular chemistry, this method utilizes the mutual complementarity between the host molecule and the guest molecule in the three-dimensional space and the weak interaction between the groups, and the two selectively form stable molecular crystals through molecular recognition, thereby A high-efficiency optical resolution of the racemate was achieved.

2. The chiral source used is a natural chiral compound, such as L-glutamic acid, which is cheap and easy to obtain.

3. The resolution reagent is easy to prepare, cheap, and has never been used as a resolution reagent before.

4. The method is economical, only 0.5-3 moles of chiral resolution reagent 5 can be used for optical resolution of 1 mole of racemate, and the chiral resolution reagent is easy to recover (recovery rate > 90%) and can be repeated It is used without affecting the resolution efficiency, so the consumption of resolution reagents is very low.

5. The separation efficiency is high. Due to the high molecular recognition ability, the separated isomers have high optical purity (70-80% ee). After recrystallization, the enantiomeric excess of chiral 1 can reach >99%, the total yield reaches 40-60%. Moreover, after the mother liquor is treated, an optical isomer of another configuration can be obtained.

6. Easy to operate, the operations involved in the method of the present invention, such as filtration, recrystallization, etc., all belong to simple operations in organic synthesis.

7. Good repeatability, can be prepared in large quantities. The scale-up test results show that the yield and optical purity of the product are not affected by the size of the test scale, so it is suitable for large-scale preparation.

Description of drawings

Figure 1 is a reaction process starting from 5a and racemic 1a.

Detailed ways

The following examples help to understand the present invention, but do not limit the present invention.

      Example 1 Preparation of Resolution Reagent

在500ml的圆底烧瓶内加入L-谷氨酸60g(0.4mol)，苯胺350Ml。装上分水器。加热至195-200度搅拌30分钟后，混合液变澄清。继续搅拌4小时，所生成的水通过共沸蒸馏带出体系。过量的苯胺在减压条件下除去。所得油状物中加入250mL丙酮，析出棕色固体，过滤，固体用甲醇重结晶，得白色针状晶体69g，收率85％。Mp 189.0℃[α]²⁰ _D+18.0(c＝1.0甲醇)¹H NMR(300MHz，DMSO-d₆)δ2.00(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-d₆)δ25.3，29.2，56.4，119.3，123.5，128.8，138.8，171.3，177.5 Anal.Calcd for C₁₁H₁₂N₂O₂：C，64.70，H，5.88，N，13.72.found：C，64.85，H，5.74，N，13.46.Preparation of Resolution Reagent 5a

Add 60 g (0.4 mol) of L-glutamic acid and 350 Ml of aniline into a 500 ml round bottom flask. Install the water separator. After heating to 195-200 degrees and stirring for 30 minutes, the mixed solution became clear. Stirring was continued for 4 hours, and the generated water was taken out of the system by azeotropic distillation. Excess aniline was removed under reduced pressure. 250 mL of acetone was added to the obtained oil, and a brown solid was precipitated. After filtration, the solid was recrystallized with methanol to obtain 69 g of white needle-like crystals, with a yield of 85%. Mp 189.0°C[α] ²⁰ _D +18.0 (c=1.0 Methanol) ¹ H 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) ¹³ C NMR (25.18MHz, DMSO-d ₆ ) δ25. 3, 29.2, 56.4, 119.3, 123.5, 128.8, 138.8, 171.3, 177.5 Anal. Calcd for C ₁₁ H ₁₂ N ₂ O ₂ : C, 64.70, H, 5.88, N, 13.72. Found: C, 64.85, H, 5.74, N, 13.46.

在500ml的圆底烧瓶内加入L-谷氨酸60g(0.4mol)，邻甲基苯胺350Ml。装上分水器。加热至195-200度搅拌30分钟后，混合液变澄清。继续搅拌4小时，所生成的水通过共沸蒸馏带出体系。过量的邻甲苯胺在减压条件下除去。所得油状物中加入250mL丙酮，析出棕色固体，过滤，固体用水重结晶，得白色针状晶体69.2g，收率81％。Mp 148℃[α]²⁰ _D+16.9(c＝1.0乙醇)¹H NMR(300MHz，DMSO-d₆)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)，7.00-7.90(m，4H)，10.06(s，1H)Calcd for C₁₂H₁₄N₂O₂：C，66.04，H，6.47，N，12.84.found：C，65.85，H，6.32，N，12.90.Preparation of Resolution Reagent 5b

Add 60 g (0.4 mol) of L-glutamic acid and 350 Ml of o-methylaniline into a 500 ml round bottom flask. Install the water separator. After heating to 195-200 degrees and stirring for 30 minutes, the mixed solution became clear. Stirring was continued for 4 hours, and the generated water was taken out of the system by azeotropic distillation. Excess o-toluidine was removed under reduced pressure. 250 mL of acetone was added to the obtained oil, and a brown solid was precipitated. After filtration, the solid was recrystallized with water to obtain 69.2 g of white needle-like crystals, with a yield of 81%. Mp 148°C[α] ²⁰ _D +16.9(c=1.0 ethanol) ¹ H 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), 7.00-7.90(m, 4H), 10.06(s, 1H) Calcd for C ₁₂ H ₁₄ N ₂ O ₂ : C, 66.04, H, 6.47, N, 12.84. Found: C, 65.85, H, 6.32, N, 12.90.

在500ml的圆底烧瓶内加入L-谷氨酸60g(0.4mol)，间氯苯胺350Ml。装上分水器。加热至195-200度搅拌30分钟后，混合液变澄清。继续搅拌4小时，所生成的水通过共沸蒸馏带出体系。过量的苯胺在减压条件下除去。所得油状物中加入250mL丙酮，析出棕色固体，过滤，固体用甲醇重结晶，得晶体78g，收率82％。Mp 120℃[α]²⁰ _D+12.8(c＝1.0乙醇)¹H NMR(300MHz，DMSO-d₆)δ2.08(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 C₁₁H₁₁ClN₂O₂：C，55.36，H，4.65，N，14.85.found：C，55.44，H，4.66，N，14.74.Preparation of Resolution Reagent 5c

Add 60 g (0.4 mol) of L-glutamic acid and 350 Ml of m-chloroaniline into a 500 ml round bottom flask. Install the water separator. After heating to 195-200 degrees and stirring for 30 minutes, the mixed solution became clear. Stirring was continued for 4 hours, and the generated water was taken out of the system by azeotropic distillation. Excess aniline was removed under reduced pressure. 250 mL of acetone was added to the obtained oil, and a brown solid was precipitated. After filtration, the solid was recrystallized with methanol to obtain 78 g of crystals, with a yield of 82%. Mp 120°C[α] ²⁰ _D +12.8(c=1.0 ethanol) ¹ H NMR (300MHz, DMSO-d ₆ )δ2.08(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 ₁₁ H ₁₁ ClN ₂ O ₂ : C, 55.36, H, 4.65, N, 14.85. Found: C, 55.44, H, 4.66, N, 14.74.

Preparation of Resolution Reagent 5d Add 60 g (0.4 mol) of L-glutamic acid, 20 ml of isopropylamine and 100 mL of toluene into a 500 ml round bottom flask. Install the water separator. Heat to 120 degrees and stir for 4 hours, and the generated water is taken out of the system through azeotropic distillation. Excess isopropylamine and toluene were removed under reduced pressure. 200 mL of acetone was added to the obtained oil, and a solid was precipitated, filtered, and the solid was recrystallized with methanol to obtain 65 g of white crystals, with a yield of 82%. Mp140°C ¹ H 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 ₈ H ₁₄ N ₂ O ₂ : C, 54.65, H, 8.29, N, 16.46.found: C, 54.36, H, 8.32, N, 16.51.

在250ml的圆底烧瓶内加入L-谷氨酸30g(0.2mol)，吡咯烷40ml甲苯100mL。装上分水器。加热至120度搅拌搅拌4小时，所生成的水通过共沸蒸馏带出体系。过量的吡咯烷和甲苯在减压条件下除去。所得油状物中加入200mL丙酮，析出固体，过滤，固体用甲醇重结晶，得白色晶体29g，收率80％。Mp 111℃[α]²⁰ _D-40.5(c＝1.0，水)¹H NMR(300MHz，CDCl₃)δ1.8-2.5(m，11H)，2.8(m，1H)，4.5(t，J＝14.6Hz，1H)；Calcd for C₉H₁₄N₂O₂：C，59.32，H，7.74，N，15.37.found：C，59.36，H，7.52，N，15.51.Preparation of Resolution Reagent 5e

Add 30 g (0.2 mol) of L-glutamic acid, 40 ml of pyrrolidine, and 100 mL of toluene into a 250 ml round bottom flask. Install the water separator. Heat to 120 degrees and stir for 4 hours, and the generated water is taken out of the system through azeotropic distillation. Excess pyrrolidine and toluene were removed under reduced pressure. 200 mL of acetone was added to the obtained oil, and a solid was precipitated, filtered, and the solid was recrystallized with methanol to obtain 29 g of white crystals, with a yield of 80%. Mp 111°C [α] ²⁰ _D -40.5 (c=1.0, water) ¹ H NMR (300 MHz, CDCl ₃ ) δ1.8-2.5 (m, 11H), 2.8 (m, 1H), 4.5 (t, J= 14.6Hz, 1H); Calcd for C ₉ H ₁₄ N ₂ O ₂ : C, 59.32, H, 7.74, N, 15.37.found: C, 59.36, H, 7.52, N, 15.51.

在500ml的圆底烧瓶内加入L-谷氨酸60g(0.4mol)，β-萘胺42g(04mol)，200mL甲苯。装上分水器。加热至120度搅拌10小时，所生成的水通过共沸蒸馏带出体系。在减压条件下除去甲苯。所得油状物中加入200mL丙酮，析出1色固体，过滤，固体用乙醇重结晶，得白色晶体80g，收率71％。Mp 207℃ ¹H NMR(300MHz，DMSO-d₆)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 C₁₅H₁₄N₂O₂：C，70.85，H，5.55，N，11.02.Found：C，79.01，H，5.52，N，10.92。Preparation of Resolution Reagent 5f

Add 60 g (0.4 mol) of L-glutamic acid, 42 g (0.4 mol) of β-naphthylamine, and 200 mL of toluene into a 500 ml round bottom flask. Install the water separator. Heat to 120 degrees and stir for 10 hours, and the generated water is taken out of the system through azeotropic distillation. Toluene was removed under reduced pressure. 200 mL of acetone was added to the obtained oil, and a 1-color solid was precipitated, which was filtered, and the solid was recrystallized from ethanol to obtain 80 g of white crystals, with a yield of 71%. Mp 207°C ¹ H 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 ₁₅ H ₁₄ N ₂ O ₂ : C, 70.85, H, 5.55, N, 11.02. Found: C, 79.01, H, 5.52, N, 10.92.

在500ml的圆底烧瓶内加入L-谷氨酸60g(0.4mol)，2，3-二氯苯胺350Ml。装上分水器。加热至195-200度搅拌30分钟后，混合液变澄清。继续搅拌4小时，所生成的水通过共沸蒸馏带出体系。过量的2，3-二氯苯胺在减压条件下除去。所得油状物中加入250mL丙酮，析出固体，过滤，固体用甲醇重结晶，得晶体78g，收率82％。Mp 210℃[α]²⁰ _D+-30.6(c＝1.0乙醇)¹H NMR(300MHz，DMSO-d₆)δ2.08(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 C₁₁H₁₀Cl₂N₂O₂：C，48.37，H，3.69，N，10.26.found：C，48.54，H，3.52，N，10.22。The preparation of resolution reagent 5g

Add 60 g (0.4 mol) of L-glutamic acid and 350 Ml of 2,3-dichloroaniline into a 500 ml round bottom flask. Install the water separator. After heating to 195-200 degrees and stirring for 30 minutes, the mixed solution became clear. Stirring was continued for 4 hours, and the generated water was taken out of the system by azeotropic distillation. Excess 2,3-dichloroaniline was removed under reduced pressure. 250 mL of acetone was added to the obtained oil, and a solid was precipitated, filtered, and the solid was recrystallized with methanol to obtain 78 g of crystals, with a yield of 82%. Mp 210°C[α] ²⁰ _D +-30.6 (c=1.0 ethanol) ¹ H NMR (300MHz, DMSO-d ₆ ) δ 2.08 (dd, J=9.0, 4.8Hz, 1H), 2.18(td, J= Calcd for C ₁₁ H ₁₀ Cl ₂ N ₂ O ₂ : C, 48.37, H, 3.69, N, 10.26. Found: C, 48.54, H, 3.52, N, 10.22.

在500ml的圆底烧瓶内加入L-谷氨酸60g(0.4mol)，甲醇192ml，，苯120Ml，浓硫酸4Ml，加热回流流搅拌15小时，冷却至室温，加入20％氢氧化纳水溶液，调PH＝6，浓缩后加入200毫升氯仿，过滤，母液浓缩，减压蒸出产物34g，收率75％Mp 21℃ ¹H NMR(300MHz，CDCl₃)δ2.35-2.48(m，1H)，3.2(s，3H)，4.4(t，J＝18.6Hz，1H)；Calcd for C₆H₉NO₃：C，50.35，H，6.34，N，9.79.found：C，50.12，H，6.48，N，9.66。Preparation of Resolution Reagent 5h

Add 60g (0.4mol) of L-glutamic acid (0.4mol) in a 500ml round bottom flask, methanol 192ml, benzene 120Ml, concentrated sulfuric acid 4Ml, heat and reflux and stir for 15 hours, cool to room temperature, add 20% sodium hydroxide aqueous solution, adjust PH=6, after concentration, add 200ml of chloroform, filter, concentrate the mother liquor, evaporate the product under reduced pressure to 34g, yield 75% Mp 21°C ¹ H NMR (300MHz, CDCl ₃ ) δ2.35-2.48 (m, 1H), 3.2(s, 3H), 4.4(t, J=18.6Hz, 1H); Calcd for C ₆ H ₉ NO ₃ : C, 50.35, H, 6.34, N, 9.79.found: C, 50.12, H, 6.48, N, 9.66.

在500ml的圆底烧瓶内加入L-谷氨酸60g(0.4mol)，α-氨基呋喃34g(0.4mol)，200mL甲苯。装上分水器。加热至120度搅拌12小时，所生成的水通过共沸蒸馏带出体系。在减压条件下除去甲苯。所得油状物中加入200mL丙酮，析出1色固体，过滤，固体用乙醇重结晶，得白色晶体80g，收率82％。Mp 129℃ ¹H NMR(300MHz，DMSO-d₆)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 C₉H₁₀N₂O₃：C，55.67，H，6.19，N，14.43.found：C，55.60，H，6.28，N，14.49。Preparation of Resolution Reagent 5i

Add 60 g (0.4 mol) of L-glutamic acid, 34 g (0.4 mol) of α-aminofuran, and 200 mL of toluene into a 500 ml round bottom flask. Install the water separator. Heat to 120 degrees and stir for 12 hours, and the generated water is taken out of the system through azeotropic distillation. Toluene was removed under reduced pressure. 200 mL of acetone was added to the obtained oil, and a 1-color solid was precipitated. After filtration, the solid was recrystallized from ethanol to obtain 80 g of white crystals, with a yield of 82%. Mp 129°C ¹ H 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 ₉ H ₁₀ N ₂ O ₃ : C, 55.67, H, 6.19, N, 14.43. Found: C, 55.60, H, 6.28, N, 14.49.

Preparation of resolution reagent 5 in (S) configuration

The raw material L-glutamic acid is changed to D-glutamic acid, and the other preparation methods are exactly the same as the preparation of (R) configuration 5 above. Example 2 The optical resolution and resolution of racemic 1,1'-diphenol, 1,1'-binaphthol and their derivatives

外消旋1，1’-联萘酚衍生物1的拆分1a的拆分Recovery of sub-reagents 1.

Resolution of racemic 1,1'-binaphthol derivative 1 1a split

在一装有回流冷凝管的25毫升烧瓶内加入(±)1a 1.544克(4mmol)，拆分试剂5a 0.418克(2mmol)，加入四氢呋喃，乙醇混合溶剂5-10ml，加热回流使固体完全溶解，冷却到室温，析出晶体，过滤，得包结晶体0.85克收率78％，70％ee。将母液浓缩，溶于丙酮，加热回流，过滤，不溶物为拆分试剂，母液浓缩用有机溶剂苯重结晶，得(S)-1a，收率41％，100％ee。将包结晶体加入到丙酮中，加热回流，冷却过滤。母液浓缩，用苯重结晶结晶得(R)-1a收率45％，100％ee。不溶物为拆分试剂，回收0.4g，回收率为92％。所得分子晶体的数据如下：MP.157-158℃ 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 C₃₁H₂₆N₂O₄：C，75.90，H，5.34，N，5.71.found：C，75.76，H，5.44，N，5.46.Split using 5a

In a 25 milliliter flask equipped with a reflux condenser, add (±) 1a 1.544 grams (4mmol), resolution reagent 5a 0.418 grams (2mmol), add tetrahydrofuran, ethanol mixed solvent 5-10ml, heat to reflux to make the solid dissolve completely, After cooling to room temperature, crystals were precipitated and filtered to obtain 0.85 g of clathrates, yield 78%, 70% ee. The mother liquor was concentrated, dissolved in acetone, heated to reflux, filtered, the insoluble matter was the resolution reagent, and the concentrated mother liquor was recrystallized with organic solvent benzene to obtain (S)-1a with a yield of 41%, 100% ee. Add crystals to acetone, heat to reflux, cool and filter. The mother liquor was concentrated and recrystallized from benzene to obtain (R)-1a in a yield of 45%, 100% ee. The insoluble matter is a resolution reagent, 0.4 g is recovered, and the recovery rate is 92%. The data of the obtained molecular crystals are as follows: MP.157-158°C ¹ H 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 ₃₁ H ₂₆ N ₂ O ₄ : C, 75.90, H, 5.34, N, 5.71.found: C, 75.76, H, 5.44, N, 5.46.

Split using 5b' Add (±) 1a 1.544g (4mmol) and resolution reagent 5b' 0.436g (2mmol) in a 25ml flask equipped with a reflux condenser, add ether, ethanol mixed solvent 5-10ml, heat to reflux to dissolve the solid completely , cooled to room temperature, precipitated crystals, and filtered to obtain 0.92 g of cladding crystals, yield 80%, 68% ee. The mother liquor was concentrated, dissolved in dichloromethane, heated to reflux, filtered, the insoluble matter was the resolution reagent, the mother liquor was concentrated and recrystallized with toluene to obtain (R)-1a with a yield of 40%, 100% ee. The clathrates were added to dichloromethane, heated to reflux, cooled and filtered. The mother liquor was concentrated and recrystallized from toluene to obtain (S)-1a in a yield of 51%, 100% ee. The insoluble matter was the resolution reagent 5b, 0.4 g was recovered, and the recovery rate was 91%. The data of the obtained molecular crystals are as follows: MP.122°C ¹ H NMR (CDCL3, ppm) δ7.82-7.90 (m, 4H), 7.62 (d, J=8.1Hz, 2H), 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 ₃₂ H ₂₈ N ₂ O ₄ : C, 76.17, H, 5.59, N, 5.55.found: C, 75.96, H, 5.48, N, 5.56.

Split with 5c Add (±) 1a 1.544 grams (4mmol) in a 25 milliliter flask equipped with a reflux condenser, resolution reagent 5c 0.476 grams (2mmol), add tetrahydrofuran, methanol mixed solvent 5-10ml, heat to reflux to make the solid dissolve completely, After cooling to room temperature, crystals were precipitated and filtered to obtain 0.82 g of clathrates with a yield of 67%. The mother liquor was concentrated, dissolved in acetone, heated to reflux, filtered, the insoluble matter was the resolution reagent, the mother liquor was concentrated and recrystallized with benzene to obtain (S)-1a with a yield of 46%, 100% ee. Add crystals to acetone, heat to reflux, cool and filter. The mother liquor was concentrated and recrystallized from benzene to obtain (R)-1a in a yield of 42%, 100% ee. The insoluble matter was the resolution reagent 5c, 0.42 g was recovered, and the recovery rate was 86%. . The data of the obtained molecular crystals are as follows: MP.108°C ¹ H NMR (CDCL3, ppm) δ7.76-7.80 (m, 4H), 7.60 (d, J=8.0Hz, 2H), 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 ₃₁ H ₂₅ ClN ₂ O ₄ : C, 70.92, H, 4.80, N, 5.34.found: C, 70.89, H, 4.77, N, 5.24.

在一装有回流冷凝管的25毫升烧瓶内加入(±)-1a 1.544克(4mmol)，拆分试剂5j 0.284克(2mmol)，加入乙醚5-10Ml，加热回流使固体完全溶解，冷却到室温，析出晶体，过滤，得包结晶体0.66克收率70％。将母液浓缩，溶于甲苯，加热回流，过滤，不溶物为拆分试剂，母液浓缩用苯重结晶，得(S)-1a，收率42％，100％ee。将包结晶体加入到甲苯中，加热回流，冷却过滤。母液浓缩，用苯重结晶结晶得(R)-1a收率46％，100％ee。不溶物为拆分试剂5j，回收0.26g，回收率为91％。所得分子晶体的数据如下：MP.132℃ ¹H NMR(CDCL3，ppm)δ7.82-7.90(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)，δ4.4(t，J＝16.7Hz，1H)，2.8(s，3H)，2.4-2.5(m，1H)；Calcd for C₂₆H₂₄N₂O₄：C，72.88，H，5.65，N，6.54.found：C，72.96，H，5.62，N，6.57.Split with 5j

Add (±)-1a 1.544g (4mmol) and resolution reagent 5j 0.284g (2mmol) into a 25ml flask equipped with a reflux condenser, add ether 5-10Ml, heat to reflux to dissolve the solid completely, and cool to room temperature , precipitated crystals, and filtered to obtain 0.66 g of cladding crystals with a yield of 70%. The mother liquor was concentrated, dissolved in toluene, heated to reflux, filtered, the insoluble matter was the resolution reagent, the mother liquor was concentrated and recrystallized with benzene to obtain (S)-1a with a yield of 42%, 100% ee. The clathrate crystals were added to toluene, heated to reflux, cooled and filtered. The mother liquor was concentrated and recrystallized from benzene to obtain (R)-1a in a yield of 46%, 100% ee. The insoluble matter was the resolution reagent 5j, 0.26 g was recovered, and the recovery rate was 91%. The data of the obtained molecular crystals are as follows: MP.132°C ¹ H NMR (CDCL3, ppm) δ7.82-7.90 (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), δ4.4(t, J=16.7Hz, 1H), 2.8(s, 3H), 2.4-2.5( m, 1H); Calcd for C ₂₆ H ₂₄ N ₂ O ₄ : C, 72.88, H, 5.65, N, 6.54.found: C, 72.96, H, 5.62, N, 6.57.

在一装有回流冷凝管的25毫升烧瓶内加入(±)1a 1.544克(4mmol)，拆分试剂5d 0.340克(2mmol)，加入氯仿5-10ml，加热回流使固体完全溶解，冷却到室温，析出晶体，过滤，得包结晶体0.64克收率70％。将母液浓缩，溶于乙醚，加热回流，过滤，不溶物为拆分试剂，母液浓缩用苯重结晶，得(S)-1a，收率40％，100％ee。将包结晶体加入到苯中，加热回流，冷却过滤。母液浓缩，用苯重结晶结晶得(R)-1a收率51％，100％ee。不溶物为拆分试剂5d，回收32g，回收率为94％。所得分子晶体的数据如下：MP.120℃ ¹H NMR(CDCL3，ppm)δ7.82-7.90(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)，δ4.4(t，J＝16.2Hz，1H)，2.7(m，1H)，2.4-2.5(m，1H)，2.2(d，J＝12.0Hz，6H)；Calcdfor C₂₈H₂₈N₂O₄：C，73.66，H，6.18，N，6.14.found：C，73.84，H，5.32，N，6.17.Use 5d to split

In a 25 ml flask equipped with a reflux condenser, add (±) 1a 1.544 g (4 mmol), resolution reagent 5d 0.340 g (2 mmol), add chloroform 5-10 ml, heat to reflux to dissolve the solid completely, cool to room temperature, Crystals were precipitated and filtered to obtain 0.64 g of clathrates with a yield of 70%. The mother liquor was concentrated, dissolved in ether, heated to reflux, filtered, the insoluble matter was the resolution reagent, the mother liquor was concentrated and recrystallized with benzene to obtain (S)-1a with a yield of 40%, 100% ee. Add crystals to benzene, heat to reflux, cool and filter. The mother liquor was concentrated and recrystallized from benzene to obtain (R)-1a in a yield of 51%, 100% ee. The insoluble matter was the resolution reagent 5d, 32 g was recovered, and the recovery rate was 94%. The data of the obtained molecular crystals are as follows: MP.120°C ¹ H NMR (CDCL3, ppm) δ7.82-7.90 (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), δ4.4(t, J=16.2Hz, 1H), 2.7(m, 1H), 2.4-2.5( m, 1H), 2.2 (d, J=12.0Hz, 6H); Calcd for C ₂₈ H ₂₈ N ₂ O ₄ : C, 73.66, H, 6.18, N, 6.14.found: C, 73.84, H, 5.32, N , 6.17.

Split using 5e Add (±)-1a 1.544g (4mmol) and resolution reagent 5e 0.364g (2mmol) in a 25ml flask equipped with a reflux condenser, add 5-10ml of dichloromethane, heat to reflux to dissolve the solid completely, cool At room temperature, crystals were precipitated and filtered to obtain 0.73 g of clathralized crystals with a yield of 72%. The mother liquor was concentrated, dissolved in ether, heated to reflux, filtered, the insoluble matter was the resolution reagent, the mother liquor was concentrated and recrystallized with benzene to obtain (S)-1a with a yield of 41%, 100% ee. The clathrate crystals were added to ether, heated to reflux, cooled and filtered. The mother liquor was concentrated and recrystallized with benzene to obtain (R)-1a in a yield of 49%, 100% ee. The insoluble matter was the resolution reagent 5e, 0.31 g was recovered, and the recovery rate was 86%. The data of the obtained molecular crystals are as follows:

MP.90°C ¹ H 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 ₂₉ H ₂₈ N ₂ O ₄ : C, 74.34, H, 6.02, N, 5.98.found: C, 74.42, H, 5.92, N, 6.17.

在一装有回流冷凝管的25毫升烧瓶内加入(±)-1a 11.544克(4mmol)，拆分试剂5f 0.508克(2mmol)，加入四氢呋喃，乙醇混合溶剂5-10ml，加热回流使固体完全溶解，冷却到室温，析出晶体，过滤，得包结晶体0.74克收率68％。将母液浓缩，溶于丙酮，加热回流，过滤，不溶物为拆分试剂，母液浓缩用苯重结晶，得(S)-1a，收率40％，100％ee。将包结晶体加入到丙酮中，加热回流，冷却过滤。母液浓缩，用有苯重结晶结晶得(R)-1a收率52％，100％ee。不溶物为拆分试剂5f，回收0.45，回收率为90％。所得分子晶体的数据如下：Split using 5f

Add (±)-1a 11.544g (4mmol) and resolution reagent 5f 0.508g (2mmol) in a 25ml flask equipped with a reflux condenser, add tetrahydrofuran, ethanol mixed solvent 5-10ml, heat to reflux to dissolve the solid completely , cooled to room temperature, crystals were precipitated, and filtered to obtain 0.74 g of cladding crystals with a yield of 68%. The mother liquor was concentrated, dissolved in acetone, heated to reflux, filtered, the insoluble matter was the resolution reagent, the mother liquor was concentrated and recrystallized with benzene to obtain (S)-1a with a yield of 40%, 100% ee. Add crystals to acetone, heat to reflux, cool and filter. The mother liquor was concentrated and recrystallized with benzene to obtain (R)-1a in a yield of 52%, 100% ee. The insoluble matter is the resolution reagent 5f, the recovery is 0.45, and the recovery rate is 90%. The data of the obtained molecular crystals are as follows:

MP.180°C ¹ H 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=6.0 Hz, 1H), 1.99-2.34 (m, 4H); Calcd for C ₃₅ H ₂₈ N ₂ O ₄ : C, 77.76, H, 5.22, N, 5.18.found: C, 77.48, H, 5.42, N, 5.17

在一装有回流冷凝管的25毫升烧瓶内加入(±)-1a 1.544克(4mmol)，拆分试剂5g 0.544克(2mmol)，加入四氢呋喃，异丙醇混合溶剂5-10ml，加热回流使固体完全溶解，冷却到室温，析出晶体，过滤，得包结晶体0.40克收率71％。将母液浓缩，溶于丙酮，加热回流，过滤，不溶物为拆分试剂，母液浓缩用苯重结晶，得(S)-1a，收率39％，100％ee。将包结晶体加入到丙酮中，加热回流，冷却过滤。母液浓缩，用苯重结晶结晶得(R)-1a收率50％，100％ee。不溶物为拆分试剂5g，回收0.5g，回收率为92％。。所得分子晶体的数据如下：Split with 5g

Add (±)-1a 1.544 grams (4mmol) in a 25 milliliter flask equipped with a reflux condenser, resolution reagent 5g 0.544 grams (2mmol), add tetrahydrofuran, isopropanol mixed solvent 5-10ml, heat to reflux to make the solid Completely dissolved, cooled to room temperature, precipitated crystals, filtered to obtain 0.40 g of clathrates with a yield of 71%. The mother liquor was concentrated, dissolved in acetone, heated to reflux, filtered, the insoluble matter was the resolution reagent, and the mother liquor was concentrated and recrystallized with benzene to obtain (S)-1a with a yield of 39%, 100% ee. Add crystals to acetone, heat to reflux, cool and filter. The mother liquor was concentrated and recrystallized from benzene to obtain (R)-1a with a yield of 50% and 100% ee. The insoluble matter was 5 g of the resolution reagent, 0.5 g was recovered, and the recovery rate was 92%. . The data of the obtained molecular crystals are as follows:

MP.131°C ¹ H 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 ₃₁ H ₂₄ Cl ₂ N ₂ O ₄ : C, 66.55, H, 4.32, N, 5.01. Found: C, 66.48, H, 4.42, N, 5.18

Split using 5h Add (±)-1a 1.544g (4mmol) to a 25ml flask equipped with a reflux condenser, split reagent 5h 0.290g (2mmol), add acetone, ether mixed solvent 5-10ml, heat to reflux to dissolve the solid completely , cooled to room temperature, precipitated crystals, and filtered to obtain 0.52 g of cladding crystals with a yield of 60%. The mother liquor was concentrated, dissolved in dichloromethane, heated to reflux, filtered, the insoluble matter was the resolution reagent, the mother liquor was concentrated and recrystallized with toluene to obtain (S)-1a with a yield of 41%, 100% ee. Add the clathrate to dichloromethane, heat to reflux, cool and filter. The mother liquor was concentrated and recrystallized from toluene to obtain (R)-1a in a yield of 45%, 100% ee. The insoluble matter was the resolution reagent for 5 hours, 0.2 g was recovered, and the recovery rate was 69%. The data of the obtained molecular crystals are as follows:

MP.89°C ¹ H 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 ₂₆ H ₂₃ NO ₅ : C, 72.71, H, 5.40, N, 3.26.found: C, 72.67, H, 5.49, N, 3.16

在一装有回流冷凝管的25毫升烧瓶内加入(±)-1a 1.544克(4mmol)，拆分试剂5i 0.384克(2mmol)，加入四氢呋喃，乙醇混合溶剂5-10ml，加热回流使固体完全溶解，冷却到室温，析出晶体，过滤，得包结晶体0.672克收率70％。将母液浓缩，溶于丙酮，加热回流，过滤，不溶物为拆分试剂，母液浓缩用苯重结晶，得(S)-1a，收率41％，100％ee。将包结晶体加入到丙酮中，加热回流，冷却过滤。母液浓缩，用苯重结晶结晶得(R)-1a收率50％，Split with 5i

Add (±)-1a 1.544 g (4 mmol) and resolution reagent 5i 0.384 g (2 mmol) in a 25 ml flask equipped with a reflux condenser, add tetrahydrofuran, ethanol mixed solvent 5-10 ml, heat to reflux to dissolve the solid completely , cooled to room temperature, precipitated crystals, and filtered to obtain 0.672 g of clathrates, yield 70%. The mother liquor was concentrated, dissolved in acetone, heated to reflux, filtered, the insoluble matter was the resolution reagent, the mother liquor was concentrated and recrystallized with benzene to obtain (S)-1a with a yield of 41%, 100% ee. Add crystals to acetone, heat to reflux, cool and filter. The mother liquor was concentrated and recrystallized from benzene to obtain (R)-1a with a yield of 50%.

MP.102°C ¹ H 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 ₂₉ H ₂₄ N ₂ O ₅ : C, 72.49, H, 5.03, N, 5.83.found: C, 72.31, H, 5.27, N, 5.15

          Using the (S)-configured resolution reagent 5 for resolution

The resolution operation steps using the resolution reagent 5 in the (S) configuration are exactly the same as the above-mentioned resolution reagent 5 in the (R) configuration. The resolution of: Utilize resolution reagent 5a to carry out resolution

The operation is the same as using the resolution reagent 5a to resolve 1a, and the yield of (R)-1b is 52%, 100% ee (S)-1b yield is 42%, 100% ee, and the recovery rate of the resolution reagent is 92%. The resolution of: Utilize resolution reagent 5a to carry out resolution

The operation was the same as the resolution of 1a using the resolution reagent 5a, and the yield of (R)-1c was 48%, 100% ee (S)-1c yield was 42%, 100% ee, and the recovery rate of the resolution reagent was 89%. The resolution of: Utilize resolution reagent 5a to carry out resolution

的拆分：利用拆分试剂5a进行拆分操作如同利用拆分试剂5a拆分1a，得到(R)-1e  收率51％，100％ee(S)-1e收率45％，100％ee，拆分试剂回收率91％。

的拆分：利用拆分试剂5a进行拆分The operation was the same as the resolution of 1a using the resolution reagent 5a, and the yield of (R)-1d was 47%, 100% ee (S)-1b yield was 41%, 100% ee, and the recovery rate of the resolution reagent was 90%.

Resolution: The resolution operation using the resolution reagent 5a is the same as the resolution of 1a using the resolution reagent 5a to obtain (R)-1e yield 51%, 100% ee (S)-1e yield 45%, 100% ee , The recovery rate of the resolution reagent was 91%.

The resolution of: Utilize resolution reagent 5a to carry out resolution

的拆分：利用拆分试剂5a进行拆分The operation is the same as the resolution of 1a by using the resolution reagent 5a to obtain (R)-1f yield of 56%, 100% ee (S)-1f yield of 60%, 100% ee, and the resolution reagent recovery rate of 88%.

The resolution of: Utilize resolution reagent 5a to carry out resolution

The operation was the same as the resolution of 1a using the resolution reagent 5a, and the yield of (R)-1g was 52%, the yield of (S)-1g was 45%, 100% ee, and the recovery rate of the resolution reagent was 90%. The resolution of: Utilize resolution reagent 5a to carry out resolution

The operation was similar to the resolution of 1a using the resolution reagent 5a, and the yield of (R)-1h was 51%, the yield of (S)-1h was 38%, 100% ee, and the recovery rate of the resolution reagent was 91%. The resolution of: Utilize resolution reagent 5a to carry out resolution

5，5’，6，6’，7，7’，8，8’-八氢-1，1’-联萘酚衍生物2的拆分利用5a进行拆分

的拆分：The operation was the same as the resolution of 1a using the resolution reagent 5a, and the yield of (R)-li was 53%, 100% ee (S)-li yield was 39%, 100% ee, and the recovery rate of the resolution reagent was 86%. 2.

Resolution of 5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthol derivative 2 using 5a

The split of:

的拆分：The operation was the same as the resolution of 1a using the resolution reagent 5a, and the yield of (R)-2a was 57%, 100% ee (S)-2a yield was 42%, 100% ee, and the recovery rate of the resolution reagent was 85%.

The split of:

The operation is the same as using the resolution reagent 5a to resolve 1a, and the yield of (R)-2b is 55%, 100% ee (S)-2b yield is 40%, 100% ee, and the recovery rate of the resolution reagent is 88%. The split of:

的拆分：The operation was the same as using the resolution reagent 5a to resolve 1a, and the yield of (R)-2c was 52%, 100% ee, and the yield of (S)-2c was 40%, 100% ee, and the recovery rate of the resolution reagent was 89%.

The split of:

的拆分：操作如同利用拆分试剂5a拆分1a，用(S)构型的拆分剂5a’

拆分得到(S)-2e，收率58％，100％ee(R)-2e收率41％，100％ee，拆分试剂回收率89％。的拆分：The operation was the same as using the resolution reagent 5a to resolve 1a, and the yield of (R)-2d was 47%, 100% ee, and the yield of (S)-2d was 40%, 100% ee, and the recovery rate of the resolution reagent was 90%.

The resolution of : the operation is the same as the resolution of 1a using the resolution reagent 5a, and the resolution reagent 5a' of the (S) configuration

The resolution yielded (S)-2e with a yield of 58%, 100% ee (R)-2e with a yield of 41%, 100% ee, and a resolution reagent recovery of 89%. The split of:

5，6，7，8-四氢-1，1’-联萘酚衍生物3的拆分利用5a进行拆分：的拆分：The operation was the same as the resolution of 1a using the resolution reagent 5a, and the yield of (R)-2f was 52%, 100% ee (S)-2f yield was 38%, 100% ee, and the recovery rate of the resolution reagent was 91%. 3.

Resolution of 5,6,7,8-tetrahydro-1,1'-binaphthol derivative 3 Using 5a for resolution: The split of:

的拆分：The operation is the same as the resolution of 1a using the resolution reagent 5a, and the yield of (R)-3a is 50%, 100% ee (S)-3a yield is 40%, 100% ee, and the recovery rate of the resolution reagent is 88%. Resolution: The operation is the same as using the resolution reagent 5a to resolve 1a, and the yield of (R)-3b is 47%, 100% ee (S)-3b yield is 39%, 100% ee, and the recovery rate of the resolution reagent is 90% .

The split of:

的拆分：The operation was the same as using the resolution reagent 5a to resolve 1a, and the yield of (R)-3c was 46%, 100% ee (S)-3a yield was 32%, 100% ee, and the recovery rate of the resolution reagent was 88%.

The split of:

的拆分：The operation was the same as the resolution of 1a using the resolution reagent 5a, and the yield of (R)-3a was 43%, 100% ee (S)-3a yield was 35%, 100% ee, and the recovery rate of the resolution reagent was 88%. Resolution: The operation is the same as the resolution of 1a using the resolution reagent 5a, and the configuration of 5c' with the resolution reagent (S) The yield of (S)-3e was 44%, the yield of (R)-3a was 30%, 100% ee, and the recovery rate of the resolution reagent was 90%.

The split of:

The operation is the same as using the resolution reagent 5a to resolve 1a, and the yield of (R)-3f is 50%, 100% ee, and the yield of (S)-3f is 40%, 100% ee, and the recovery rate of the resolution reagent is 86%.

联苯酚衍生物4的拆分：利用拆分试剂5a进行拆分：的拆分：4.

Resolution of biphenol derivative 4: Resolution using resolution reagent 5a: The split of:

的拆分：The operation was the same as the resolution of 1a using the resolution reagent 5a, and the yield of (R)-4a was 48%, the yield of (S)-4a was 39%, 100% ee, and the recovery rate of the resolution reagent was 85%.

The split of:

拆分得到(S)-4b  收率45％，100％ee(R)-4a收率37％，100％ee，拆分试剂回收率87％。The operation is the same as the resolution of 1a using the resolution reagent 5a, and the resolution reagent 5a' of the (S) configuration

The yield of (S)-4b was 45%, 100% ee (R)-4a was 37%, 100% ee, and the recovery of the resolution reagent was 87%.

Claims (7)

1. an optical resolution method of racemic biphenol, characterized in that in an organic solvent, optically pure resolution reagent 5 is selectively mixed with (R) or ( S) The optical isomers are combined into molecular crystals, wherein the molar ratio of the resolution reagent to bidiphenol is 0.5-3:1, reacted at 0-150°C for 1-12 hours, and the molecular crystals obtained after the reaction are treated with an organic solvent Obtain optically pure biphenol; the mother liquor of reaction obtains the optically pure biphenol of another configuration with organic solvent, The racemic biphenol includes the following structural formula: In the formula, R ₁ , R ₂ , R ₃ or R ₄ are H, C ₁ -C ₆ straight chain or branched alkyl, aryl, halogen atom, formyl, hydroxyl, C ₁ -C ₆ straight chain or branched alkoxy or SPh; The optically pure resolution reagent 5 includes 5(R) or 5(S) of the following structural formula: In the formula, n=0, 1 or 2; A is N or O, and when A is oxygen, there is no R": R, R' or R" is H, C ₁ -C ₇ linear or branched chain alkyl , C ₁ -C ₇ straight or branched chain alkanoyl, 5-7 membered cycloalkyl,

5-7 membered heterocyclic substituents containing nitrogen, oxygen, sulfur, The R ₅ =H, C ₁ -C ₇ linear or branched alkyl, halogen, C ₁ -C ₅ alkoxy, nitro, acyl, cyano, hydroxyl and when A is nitrogen, R', R", A three can be 5-7 membered rings. 2. The optical resolution method of racemic biphenol as claimed in claim 1, characterized in that the structural formula of the optically pure biphenol is as follows, wherein R ₁ , R ₂ , R ₃ , R ₄ As previously stated:

3. the optical resolution method of the biphenol of racemization as claimed in claim 1, it is characterized in that described resolution reagent structural formula is as follows:

4. The optical resolution method of racemic biphenol as claimed in claim 1, characterized in that after the formation of molecular crystals, the mother liquor is treated with an organic solvent to obtain optically pure biphenol of S or R configuration. 5. The optical resolution method of racemic biphenol as claimed in claim 1 is characterized in that the molecular crystal formed is treated with an organic solvent and filtered to obtain the resolution reagent 5. 6. The optical resolution method of the racemic biphenol as claimed in claim 1, characterized in that after the formation of molecular crystals, the mother liquor is treated with an organic solvent and filtered to obtain the resolution reagent 5. 7. the optical resolution method of the bidiphenol of racemization as claimed in claim 1 is characterized in that described organic solvent is methylene dichloride, chloroform, benzene, toluene, ether, tetrahydrofuran, methyl alcohol, ethanol, iso Propanol, n-hexane, acetonitrile, DMF, acetone or a mixture of two of the above solvents.

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