WO2013120257A1 - 一种左旋对羟基苯甘氨酸类化合物的合成方法 - Google Patents
一种左旋对羟基苯甘氨酸类化合物的合成方法 Download PDFInfo
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- WO2013120257A1 WO2013120257A1 PCT/CN2012/071159 CN2012071159W WO2013120257A1 WO 2013120257 A1 WO2013120257 A1 WO 2013120257A1 CN 2012071159 W CN2012071159 W CN 2012071159W WO 2013120257 A1 WO2013120257 A1 WO 2013120257A1
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- 229930014626 natural product Natural products 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- RBCYCMNKVQPXDR-UHFFFAOYSA-N phenoxysilane Chemical compound [SiH3]OC1=CC=CC=C1 RBCYCMNKVQPXDR-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- NWZYYCVIOKVTII-UHFFFAOYSA-N ureidoglycolic acid Chemical compound NC(=O)NC(O)C(O)=O NWZYYCVIOKVTII-UHFFFAOYSA-N 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
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- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C07C231/00—Preparation of carboxylic acid amides
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
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- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
- C07B37/02—Addition
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- C07B53/00—Asymmetric syntheses
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- the present invention relates to the field of chemical synthesis, and in particular to a method for synthesizing a L-p-hydroxyphenylglycine compound. Background technique
- L-p-hydroxyphenylglycine abbreviated as D-HPG, has a chemical name of D- ⁇ -amino-p-hydroxyphenylacetic acid, and its structural formula is as shown in Formula I.
- L-p-hydroxyphenylglycine is an important pharmaceutical intermediate mainly used for semi-synthetic ⁇ -lactam antibiotics. There is no natural product of L-p-hydroxyphenylglycine, which must be obtained by artificial synthesis.
- the synthesis methods are roughly divided into two categories: one is biological enzyme catalysis, selective synthesis of D-HPG, which has high selectivity and short route, but The problem of biological bacteria cultivation, as well as the production of a large amount of high-concentration phenol-containing wastewater in the production of p-hydroxyphenylhydantoin, has made it difficult to promote large-scale industrial production; the other is chemical synthesis, such as: WO2009/127446, EP0530879A1, EP0450684A1,
- CN200810054625.0, CN92102863.6, CN2006100251 97.X discloses a method of synthesizing and splitting DL-HPG.
- the chemical synthesis method has the advantages of simple production process and low cost, and is a commonly used method for industrial production of D-HPG in China.
- the method first prepares DL-HPG, and then splits it to obtain D-HPG.
- L-HPG does not have much application value at present. After the racemization treatment, the part is transformed into D-HPG, which has the disadvantages of long process route and cumbersome operation. Summary of the invention
- the present invention provides a method for synthesizing a L-p-hydroxyphenylglycine compound.
- the method eliminates the subsequent steps such as splitting and racemization, simplifies the operation steps, and the final product has a high ee (enantiomeric excess) value.
- the present invention provides the following technical solutions:
- the invention provides a method for synthesizing a L-p-hydroxyphenylglycine compound, comprising the following steps:
- Step 1 In a first solvent, a compound of the formula II is subjected to a nucleophilic addition reaction with a compound of the formula III to form a compound of the formula IV; the first solvent is selected from the group consisting of an ether solvent, an ester solvent, and a surface. Alkane solvent, C 5 ⁇ C 1Q hydrocarbon solvent, nitrile solvent, ketone solvent;
- the first solvent is selected from the group consisting of an ether solvent, an ester solvent, a surface alkane solvent,
- the ether solvent is selected from the group consisting of diethyl ether, dipropyl ether, 1,4-dioxane, and tetrahydrofuran.
- the ester solvent is selected from the group consisting of ethyl acetate, decyl acetate, propyl acetate, t-butyl acetate, and ethyl decanoate.
- the surface paraffinic solvent is selected from the group consisting of dichlorodecane, trichlorodecane and 1,2-dichloroethane.
- the C 5 -C 1Q hydrocarbon solvent is selected from the group consisting of benzene, toluene and dinonylbenzene.
- the nitrile solvent is selected from the group consisting of acetonitrile or propionitrile.
- the ketone solvent is acetone.
- the first solvent is preferably one of or a mixture of two or more of toluene, decyl acetate, propyl acetate, ethyl acetate, chloroform, dichlorosilane, acetone;
- Step 2 in a second solvent, using an acid as a catalyst, a compound of the formula IV and a compound of the formula V undergo a similar Friedel-Craft reaction to form the L-p-hydroxyphenylglycine compound, the structure is as shown in Formula VI;
- the second solvent is selected from the group consisting of a nitrile solvent, a surface paraffin solvent, a C 5 -C 1Q hydrocarbon solvent;
- the acid is a chiral acid or an achiral acid, and the chiral acid is selected from D-tartaric acid, L-tartaric acid, D-camphorsulfonic acid, L-camphorsulfonic acid, L-valine, D-valine, chiral phosphoric acid,
- the achiral acid is selected from the group consisting of sulfonic acid, p-toluenesulfonic acid, Trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid;
- the surface paraffinic solvent is selected from the group consisting of dichlorodecane, trichlorodecane and 1,2-dichloroethane.
- the C 5 -C 1Q hydrocarbon solvent is selected from the group consisting of benzene, toluene and dinonylbenzene.
- the nitrile solvent is selected from the group consisting of acetonitrile or propionitrile.
- an optically active compound of the formula VI will be formed, and if a achiral acid is used as a catalyst, a compound of the formula VI will be formed as a racemate.
- the chiral phosphoric acid is selected from the group consisting of a compound of the formula VII, a compound of the formula ring, a compound of the formula IX, a compound of the formula X, and a compound of the formula XI.
- Ar is selected from the group consisting of H, Ph, 2,4,6-(-Pr) 3 C 6 H 2 , 3,5-(CF 3 ) 2 C 6 H 3 , -Nap, SiPh 3 , 9-anthryL 4-biphenyL 4-N0 2 -C 6 H 4 , 9-phenanthryl, p-MeOC 6 H 4 , p-N0 2 C 6 H 4 , ie
- Ar is selected from the group consisting of hydrogen, phenyl, 2,4,6-triiso Propylphenyl, 3,5-ditrifluorodecylphenyl, -naphthyl, triphenylsilyl, 9-fluorenyl, 4-biphenylyl, 4-nitrophenyl, 9-phenanthryl, 4-decyloxyphenyl, 4-nitrophenyl.
- R 1 is selected from the group consisting of acetyl, benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, decanoyl, pivaloyl;
- R 2 is selected from the group consisting of decyl, ethyl, isopropyl, t-butyl, benzyl
- R 3 is selected from the group consisting of hydrogen, fluorenyl, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl.
- R 1 is selected from the group consisting of acetyl, benzoyl, tert-butoxycarbonyl, pivaloyl.
- the compound of formula II in step 1 is selected from the group consisting of acetamide, benzoquinone, tert-butyl aminoguanate, benzyl aminoguanate, and urea.
- the compound of formula II in step 1 is selected from the group consisting of acetamide, benzoxamide, t-butyl aminoguanate, and benzyl aminoguanate.
- the molar ratio of the compound of the formula II to the compound of the formula III in the step 1 is 1:0.5 ⁇
- the molar ratio of the compound of the formula II to the compound of the formula III in the step 1 is 1:1.05.
- the temperature of the nucleophilic addition reaction in the step 1 is 25 to 110.6 ° C, and the time of the nucleophilic addition reaction is 0.5 to 144 h.
- the temperature of the nucleophilic addition reaction in the step 1 is 28 to 110.6 ° C, and the time of the nucleophilic addition reaction is 0.5 to 144 h.
- the molar ratio of the compound of the formula IV to the compound of the formula V in the step 2 is 1:0.2 ⁇
- the molar ratio of the compound of the formula IV or the compound of the formula V in the step 2 to the catalyst is from 1 to 200:1.
- the temperature similar to the Friedel-Craft reaction in the step 2 is 40 to 82 ° C, and the time of the similar Friedel-Craft reaction is 13.5 to 96 h.
- the temperature similar to the Friedel-Craft reaction in the step 2 is 40 to 80 ° C, and the time similar to the Friedel-Craft reaction is 23.5 to 69 h.
- the present invention also provides a method for synthesizing L-p-hydroxyphenylglycine as shown in Formula I, comprising the following steps:
- Step 1 nucleophilic addition of a compound of formula II to a compound of formula III in a first solvent Reaction to form a compound of the formula IV;
- the first solvent is selected from the group consisting of an ether solvent, an ester solvent, an alkane solvent, a C 5 -C 1Q hydrocarbon solvent, a nitrile solvent, a ketone solvent;
- Step 2 in a second solvent, using an acid as a catalyst, a compound of the formula IV and a compound of the formula V undergo a similar Friedel-Craft reaction to form the L-p-hydroxyphenylglycine compound, the structure is as shown in Formula VI;
- the second solvent is selected from the group consisting of a nitrile solvent, a surface paraffin solvent, a C 5 -C 1Q hydrocarbon solvent;
- the acid is a chiral acid or an achiral acid, and the chiral acid is selected from D-tartaric acid, L-tartaric acid, D-camphorsulfonic acid, L-camphorsulfonic acid, L-valine, D-valine, chiral phosphoric acid,
- the achiral acid is selected from the group consisting of sulfonic acid, p-toluenesulfonic acid, Trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid;
- R 1 is selected from the group consisting of acetyl, benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, decanoyl, pivaloyl;
- R 2 is selected from the group consisting of decyl, ethyl, isopropyl, t-butyl, benzyl ;
- R 3 is hydrogen;
- Step 3 In a mixed solution of alcohol and water or water, the piHi ⁇ 2 is adjusted with an acid, and the compound represented by Formula VI is hydrolyzed and neutralized with a base to a pH of 5.2 to 5.6;
- the alcohol solvent in the step 3 is selected from the group consisting of decyl alcohol, ethanol, and isopropanol.
- the temperature of the hydrolysis reaction in the step 3 is from 60 to 100 °C.
- the temperature of the hydrolysis reaction in the step 3 is 60 to 80 °C.
- the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, sulfonic acid, and three Fluorine sulfonic acid.
- the concentration of the acid in step 3 is IN ⁇ 12N.
- the base is selected from the group consisting of sodium hydroxide, sodium hydrogencarbonate, sodium carbonate, potassium hydroxide, and ammonia.
- the concentration of the base in step 3 is from 2 to 12 N.
- Ee (enantiomeric excess) value ie optical purity
- the enantiomeric composition of a compound sample can be described by the term "enantiomeric excess” or "ee%", which means one enantiomer to another
- the present invention provides a synthesis method which eliminates the steps of resolution and racemization in the conventional synthesis method, and the optical purity of the L-p-hydroxyphenylglycine compound can be 88.1 to 98.0%.
- the invention provides a method for synthesizing a L-p-hydroxyphenylglycine compound, which omits the subsequent steps such as resolution and racemization, and simplifies the operation steps; in the second step, an organic small molecular acid is selected as a catalyst, Not only is it beneficial to achieve industrial production, but also the ee value of the final product is 88.1 ⁇ 98.0% through the determination of catalyst, reaction solvent, reaction material, reaction temperature and reaction time; non-aqueous solvent is used in the second step reaction to avoid The discharge of phenol-containing wastewater reduces environmental pollution.
- Fig. 1 is a view showing a single crystal of D-2-acetylamino-2-(4-hydroxyphenyl)acetate obtained in Example 1. detailed description
- the invention discloses a method for synthesizing a L-p-hydroxyphenylglycine compound, and those skilled in the art can learn from the contents of the present article and appropriately improve the process parameters. It is to be noted that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
- the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
- Step 1 In a first solvent, a compound of the formula II is subjected to a nucleophilic addition reaction with a compound of the formula III to form a compound of the formula IV; the first solvent is selected from the group consisting of an ether solvent, an ester solvent, and a surface. Alkane solvent, C 5 ⁇ C 1Q hydrocarbon solvent, nitrile solvent, ketone solvent;
- the first solvent is selected from the group consisting of an ether solvent, an ester solvent, a surface alkane solvent,
- the ether solvent is selected from the group consisting of diethyl ether, dipropyl ether, 1,4-dioxane, and tetrahydrofuran.
- the ester solvent is selected from the group consisting of ethyl acetate, decyl acetate, propyl acetate, tert-butyl acetate, and ethyl decanoate.
- the surface paraffinic solvent is selected from the group consisting of dichlorodecane, trichlorodecane and 1,2-dichloroethane.
- the C 5 -C 1Q hydrocarbon solvent is selected from the group consisting of benzene, toluene and dinonylbenzene.
- the nitrile solvent is selected from the group consisting of acetonitrile or propionitrile.
- the ketone solvent is acetone.
- the first solvent is preferably one of or a mixture of two or more of toluene, decyl acetate, propyl acetate, ethyl acetate, chloroform, dichlorosilane, acetone;
- Step 2 in a second solvent, using an acid as a catalyst, a compound of the formula IV and a compound of the formula V undergo a similar Friedel-Craft reaction to form the L-p-hydroxyphenylglycine compound, the structure is as shown in Formula VI;
- the second solvent is selected from the group consisting of a nitrile solvent, a surface paraffin solvent, a C 5 -C 1Q hydrocarbon solvent;
- the acid is a chiral acid or an achiral acid, and the chiral acid is selected from D-tartaric acid, L-tartaric acid, D-camphorsulfonic acid, L-camphorsulfonic acid, L-valine, D-valine, chiral phosphoric acid,
- the achiral acid is selected from the group consisting of sulfonic acid, p-toluenesulfonic acid, Trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid;
- the surface paraffinic solvent is selected from the group consisting of dichlorodecane, trichlorodecane and 1,2-dichloroethane.
- the C 5 -C 1Q hydrocarbon solvent is selected from the group consisting of benzene, toluene and dinonylbenzene.
- the nitrile solvent is selected from the group consisting of acetonitrile or propionitrile.
- an optically active compound of the formula VI will be formed, and if a achiral acid is used as a catalyst, a compound of the formula VI will be formed as a racemate.
- the chiral phosphoric acid is selected from the group consisting of a compound of the formula VII, a compound represented by the formula ring, a compound of the formula IX, a compound of the formula X, and a compound of the formula XI.
- Ar is selected from the group consisting of H, Ph, 2,4,6-(-Pr) 3 C 6 H 2 , 3,5-(CF 3 ) 2 C 6 H 3 , - Nap, SiPh 3 , 9-anthryL 4- biphenyL 4-N0 2 -C 6 H 4 , 9-phenanthryl, p-MeOC 6 H 4 , p-N0 2 C 6 H 4 , ie, Ar is selected from hydrogen, phenyl, 2,4,6-triisopropyl Phenyl, 3,5-ditrifluorodecylphenyl, -naphthyl, triphenylsilyl, 9-fluorenyl, 4-biphenyl, 4-nitrophenyl, 9-phenanthryl, 4- Alkoxyphenyl, 4-nitrophenyl.
- Formula II Formula II
- R 1 is selected from the group consisting of acetyl, benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, decanoyl, pivaloyl;
- R 2 is selected from the group consisting of decyl, ethyl, isopropyl, t-butyl, benzyl
- R 3 is selected from the group consisting of hydrogen, fluorenyl, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl.
- R 1 is selected from the group consisting of acetyl, benzoyl, tert-butoxycarbonyl, pivaloyl.
- the compound of formula II in step 1 is selected from the group consisting of acetamide, benzoquinone, tert-butyl aminoguanate, benzyl aminoguanate, and urea.
- the molar ratio of the compound of the formula II in the step 1 to the compound of the formula III is from 1:0.5 to 1:2.1.
- the molar ratio of the compound of the formula II to the compound of the formula III in the step 1 is 1:1.05.
- the temperature of the nucleophilic addition reaction in the step 1 is 25 to 110.6 ° C, and the time of the nucleophilic addition reaction is 0.5 to 144 h.
- the temperature of the nucleophilic addition reaction in the step 1 is 28 to 110.6 ° C, and the time of the nucleophilic addition reaction is 0.5 to 144 h.
- nucleophilic addition reaction described in the step 1 may be:
- the synthesis method of 2-ureido-2-hydroxyacetic acid was as follows: Urea (3.01 g, 50 mmol), ethyl glyoxylate (50% benzene solution, 11.22 g, 55) was sequentially added to a 250 mL eggplant bottle. Mg), acetone, 150 mL, reaction at 28 ° C for 74 hours, at 0 ° C for 12 hours, a white precipitate was precipitated, filtered, and the filter cake was washed twice with 10 mL of acetone and vacuumed for 1 hour to give a white solid 3. lg, filtrate The mixture was dried with EtOAc (EtOAc m.).
- the nucleophilic addition reaction in the step 1 may also be:
- hydrazine, hydrazine-bis(2-hydroxyethyl acetate) urea is as follows: 3.0 g (50 mmol) of urea, ethyl glyoxylate (50% benzene solution, 21.42 g, is sequentially added to a 250 mL round bottom flask. 105 mmol), acetone 150 mL, reacted at 28 ° C for 6 days, a large amount of white precipitate precipitated in the reaction solution, and the reaction was stopped. After suction filtration, the filter cake was dried under vacuum at 30 ° C for 12 hours to give a white solid, 9.18 g, yield 69.5%.
- the molar ratio of the compound of the formula IV to the compound of the formula V in the step 2 is 1:0.2 ⁇
- the molar ratio of the compound of the formula IV or the compound of the formula V in the step 2 to the catalyst is from 1 to 200:1.
- the temperature similar to the Friedel-Craft reaction in the step 2 is 40 to 82 ° C, and the similar Fu- The reaction time is 13.5 ⁇ 96h.
- the temperature similar to the Friedel-Craft reaction in the step 2 is 40 to 80 ° C, and the time similar to the Friedel-Craft reaction is 23.5 to 69 h.
- the present invention also provides a method for synthesizing L-p-hydroxyphenylglycine as shown in Formula I, comprising the following steps:
- Step 1 In a first solvent, a compound of the formula II is subjected to a nucleophilic addition reaction with a compound of the formula III to form a compound of the formula IV; the first solvent is selected from the group consisting of an ether solvent, an ester solvent, and a surface. Alkane solvent, C 5 ⁇ C 1Q hydrocarbon solvent, nitrile solvent, ketone solvent;
- Step 2 in a second solvent, using an acid as a catalyst, a compound of the formula IV and a compound of the formula V undergo a similar Friedel-Craft reaction to form the L-p-hydroxyphenylglycine compound, the structure is as shown in Formula VI;
- the second solvent is selected from the group consisting of a nitrile solvent, a surface paraffin solvent, a C 5 -C 1Q hydrocarbon solvent;
- the acid is a chiral acid or an achiral acid, and the chiral acid is selected from D-tartaric acid, L-tartaric acid, D-camphorsulfonic acid, L-camphorsulfonic acid, L-valine, D-valine, chiral phosphoric acid,
- the achiral acid is selected from the group consisting of sulfonic acid, p-toluenesulfonic acid, Trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid;
- R 1 is selected from the group consisting of acetyl, benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, decanoyl, pivaloyl;
- R 2 is selected from the group consisting of decyl, ethyl, isopropyl, t-butyl, benzyl ;
- R 3 is hydrogen;
- Step 3 In a mixed solution of alcohol and water or water, the piHi ⁇ 2 is adjusted with an acid, and the compound represented by the formula VI is hydrolyzed and neutralized with a base to a pH of 5.2 to 5.6; the third solvent is selected. Self-water, alcohol solvent; Formula I.
- the alcohol solvent in the step 3 is selected from the group consisting of decyl alcohol, ethanol, and isopropanol.
- the temperature of the hydrolysis reaction in the step 3 is from 60 to 100 °C.
- the temperature of the hydrolysis reaction in the step 3 is 60 to 80 °C.
- the acid is selected from the group consisting of hydrochloric acid, acid, sulfonic acid, and trifluoroanthracenesulfonic acid.
- the concentration of the acid in the hydrolysis reaction in step 3 is 1N ⁇
- the base is selected from the group consisting of sodium hydroxide, sodium hydrogencarbonate, sodium carbonate, potassium hydroxide, and ammonia.
- the concentration of the base in step 3 is from 2 to 12 N.
- the invention provides a method for synthesizing a L-p-hydroxyphenylglycine compound, which omits the subsequent steps such as resolution and racemization, and simplifies the operation steps; in the second step, an organic small molecular acid is selected as a catalyst, Not only beneficial to industrial production, but also through the determination of catalyst, reaction solvent, reaction material, reaction temperature and reaction time, the ee value of the final product is 88.1 ⁇ 99.0%; in the second step, non-aqueous solvent is used to avoid The discharge of phenol-containing wastewater reduces environmental pollution.
- the reagents used in the synthetic methods provided by the present invention are commercially available.
- Example 1 The present invention will be further illustrated below in conjunction with the embodiments: Example 1
- Acetamide (11.81 g, 0.20 mol), ethyl glyoxylate (50%) was added to a 500 mL eggplant bottle.
- the white solid was obtained in 28.0 g,yield: 87%, m.p.: 88-89.
- 2-acetamido-2-hydroxyacetic acid ethyl ester ( 1.932 g, 12 mmol) was added to a 100 mL three-necked flask equipped with a constant pressure dropping funnel and a thermometer.
- the catalyst chiral phosphoric acid was 0.1 mmol (wherein Ar was selected from hydrogen, Phenyl, 2,4,6-triisopropylphenyl, 3,5-ditrifluorodecylphenyl, -naphthyl, triphenylsilyl, 9-fluorenyl, 4-biphenyl, 4 -Nitrophenyl, 9-phenanthryl, 4-decyloxyphenyl, 4-nitrophenyl), phenol (0.94 g, 10 mmol), acetonitrile 50 mL, reaction at 81 ° C for 34 hours, stop reaction.
- FIG. 1 A single crystal of D-2-acetylamino-2-(4-hydroxyphenyl)acetate is shown in Fig. 1.
- the ethyl D-2-acetamido-2-(4-hydroxyphenyl)acetate obtained by the method of the present invention was prepared as L-p-hydroxyphenylglycine hydrochloride, and the synthesis route was as follows:
- Phenyl amide 7.21 g, 60 mmol
- ethyl glyoxylate was added to a 250 mL eggplant bottle in turn.
- 2-tert-butoxyamido-2-hydroxyacetic acid (0.44 g, 2 mmol), and chiral phosphoric acid 0.2 mmol
- Ar was selected from hydrogen, phenyl, 2,4,6-three Isopropylphenyl, 3,5-ditrifluorodecylphenyl, naphthyl, triphenylsilyl, 9-fluorenyl, 4-biphenylyl, 4-nitrophenyl, 9-phenanthryl, 4-decyloxyphenyl, 4-nitrophenyl), phenol (0.23 g, 2.4 mmol), acetonitrile 10 mL, refluxed at 81.6 ° C for 12 hours and 15 min, and then quenched.
- 2-acetamido-2-hydroxyacetic acid ethyl ester ( 1.932 g, 12 mmol) was added to a 100 mL three-necked flask equipped with a constant pressure dropping funnel and a thermometer.
- the catalyst chiral phosphoric acid was 0.1 mmol (wherein Ar was selected from hydrogen, Phenyl, 2,4,6-triisopropylphenyl, 3,5-ditrifluorodecylphenyl, -naphthyl, triphenylsilyl, 9-fluorenyl, 4-biphenyl, 4 -Nitrophenyl, 9-phenanthryl, 4-nonyloxyphenyl, 4-nitrophenyl), phenol (0.94 g, 10 mmol), acetonitrile 50 mL, and the reaction mixture was reacted at 81 ° C for 34 hours.
- 2-acetamido-2-hydroxyacetic acid ethyl ester ( 1.932 g, 12 mmol) was added to a 100 mL three-necked flask equipped with a constant pressure dropping funnel and a thermometer.
- the catalyst chiral phosphoric acid was 0.1 mmol (wherein Ar was selected from hydrogen, Phenyl, 2,4,6-triisopropylphenyl, 3,5-ditrifluorodecylphenyl, -naphthyl, triphenylsilyl, 9-fluorenyl, 4-biphenyl, 4 -Nitrophenyl, 9-phenanthryl, 4-nonyloxyphenyl, 4-nitrophenyl), phenol (0.94 g, 10 mmol), acetonitrile 50 mL, and the reaction mixture was reacted at 81 ° C for 34 hours.
- 2-acetamido-2-hydroxyacetic acid ethyl ester ( 1.932 g, 12 mmol) was added to a 100 mL three-necked flask equipped with a constant pressure dropping funnel and a thermometer.
- the catalyst chiral phosphoric acid was 0.1 mmol (wherein Ar was selected from hydrogen, Phenyl, 2,4,6-triisopropylphenyl, 3,5-ditrifluorodecylphenyl, -naphthyl, triphenylsilyl, 9-fluorenyl, 4-biphenyl, 4 -Nitrophenyl, 9-phenanthryl, 4-nonyloxyphenyl, 4-nitrophenyl), phenol (0.94 g, 10 mmol), acetonitrile 50 mL, and the reaction mixture was reacted at 81 ° C for 34 hours.
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Abstract
提供一种左旋对羟基苯甘氨酸类化合物的合成方法，其包括：（1）使胺化合物与乙醛酸酯化合物发生亲核加成反应；（2）使步骤（1）的产物与苯酚化合物在手性酸或非手性酸的存在下发生类似傅-克反应，生成左旋对羟基苯甘氨酸类化合物。该方法具有终产物的ee值高、污染少、无需拆分和消旋化处理的优点。
Description
一种左旋对羟基苯甘氨酸类化合物的合成方法 技术领域
本发明涉及化学合成领域，特别涉及一种左旋对羟基苯甘氨酸类化合物的 合成方法。 背景技术
左旋对羟基苯甘氨酸， 简称 D-HPG, 化学名为 D-α-氨基对羟基苯乙酸， 其结构式如式 I所示。
式 I
左旋对羟基苯甘氨酸是一种重要的医药中间体，主要用于半合成 β-内酰胺 类抗生素。 左旋对羟基苯甘氨酸没有天然产物， 必须通过人工合成方法得到， 其合成方法大致分两类： 一类是生物酶催化法， 选择性合成 D-HPG, 该法选 择性高， 路线短， 但因生物菌培养问题， 以及原料对羟基苯海因生产过程会产 生大量高浓度含酚废水，使其大规模工业化生产推广遇到困难； 另一类是化学 合成法， 如： WO2009/127446、 EP0530879A1 , EP0450684A1 ,
CN200810054625.0, CN92102863.6, CN2006100251 97.X公开了 DL-HPG的 合成和拆分方法。 化学合成法具有生产工艺简单、 成本低等优点， 是目前中国 工业化生产 D-HPG普遍釆用的方法， 该方法先制备 DL-HPG, 再对其进行拆 分得到 D-HPG。 但 L-HPG目前并没有太大的应用价值， 经消旋化处理后， 部 分又转化 D-HPG, 存在工艺路线长、 操作繁瑣等缺点。 发明内容
有鉴于此， 本发明提供一种左旋对羟基苯甘氨酸类化合物的合成方法。该 方法省去了拆分、 消旋化处理等后续工序， 简化了操作步骤， 终产物的 ee (对 映体过量）值较高。
为了实现上述发明目的， 本发明提供以下技术方案：
本发明提供了一种左旋对羟基苯甘氨酸类化合物的合成方法，包括如下步 骤：
步骤 1 : 在第一溶剂中， 式 II所示化合物与式 III所示化合物发生亲核加成 反应， 生成式 IV所示化合物； 所述第一溶剂选自醚类溶剂、 酯类溶剂、 面代烷 烃类溶剂、 C5 ~ C1Q烃类溶剂、 腈类溶剂、 酮类溶剂；
作为优选， 所述第一溶剂选自醚类溶剂、 酯类溶剂、 面代烷烃类溶剂、
C5 ~ C1Q烃类溶剂、 腈类溶剂。
作为优选， 所述醚类溶剂选自乙醚、 二丙醚、 1,4-二氧六环、 四氢呋喃。 作为优选， 所述酯类溶剂选自乙酸乙酯、 乙酸曱酯、 乙酸丙酯、 乙酸叔丁 酯和曱酸乙酯。
作为优选，所述面代烷烃类溶剂选自二氯曱烷、三氯曱烷和 1,2-二氯乙烷。 作为优选， 所述 C5 ~ C1Q烃类溶剂选苯、 曱苯和二曱苯。
作为优选， 所述腈类溶剂选自乙腈或丙腈。
作为优选， 所述酮类溶剂为丙酮。
优选地， 第一溶剂优选为曱苯、 乙酸曱酯、 乙酸丙酯、 乙酸乙酯、 氯仿、 二氯曱烷、 丙酮中的一种或两种以上的混合物；
步骤 2: 在第二溶剂中， 以酸为催化剂， 式 IV所示化合物与式 V所示化合 物发生类似傅-克反应， 生成所述左旋对羟基苯甘氨酸类化合物， 结构如式 VI 所示； 所述第二溶剂选自腈类溶剂、 面代烷烃类溶剂、 C5-C1Q烃类溶剂； 所述 酸为手性酸或非手性酸， 所述手性酸选自 D-酒石酸、 L-酒石酸、 D-樟脑磺酸、 L-樟脑磺酸、 L-脯氨酸、 D-脯氨酸、 手性磷酸， 所述非手性酸选自曱磺酸、 对 曱苯磺酸、 三氟曱磺酸、 硫酸、 盐酸；
作为优选，所述面代烷烃类溶剂选自二氯曱烷、三氯曱烷和 1,2-二氯乙烷。 作为优选， 所述 C5 ~ C1Q烃类溶剂选苯、 曱苯和二曱苯。
作为优选， 所述腈类溶剂选自乙腈或丙腈。
如果用手性酸催化，将生成具有光学活性的式 VI所示化合物，如果用非手 性酸做催化剂将生成外消旋体的式 VI所示化合物。
所述手性磷酸选自式 VII所示化合物、 式環所示化合物、 式 IX所示化合物、 式 X所示化合物、 式 XI所示化合物。
式 XI 其中， Ar选自 H、 Ph、 2,4,6-( -Pr)3C6H2、 3,5-(CF3)2C6H3、 - Nap、 SiPh3、 9-anthryL 4-biphenyL 4-N02-C6H4、 9-phenanthryl、 p-MeOC6H4、 p-N02C6H4, 即 Ar选自氢、 苯基、 2,4,6-三异丙基苯基、 3,5-二三氟曱基苯基、 -萘基、 三 苯基硅基、 9-蒽基、 4-联苯基、 4-硝基苯基、 9-菲基、 4-曱氧基苯基、 4-硝基苯 基。
0
- NH2
0 式 II 式 III
其中， R1选自乙酰基、 苯曱酰基、 叔丁氧羰基、 苄氧羰基、 曱酰胺基、 新戊酰基； R2选自曱基、 乙基、 异丙基、 叔丁基、 苄基； R3选自氢、 曱基、 三曱基硅基、 叔丁基二曱基硅基、 三异丙基硅基。
作为优选， R1选自乙酰基、 苯曱酰基、 叔丁氧羰基、 新戊酰基。
作为优选， 步骤 1中式 II所示化合物选自乙酰胺、 苯曱酰胺、 氨基曱酸叔 丁酯、 氨基曱酸苄酯、 尿素。
优选地， 步骤 1中式 II所示化合物选自乙酰胺、 苯曱酰胺、 氨基曱酸叔丁 酯、 氨基曱酸苄酯。
作为优选，步骤 1中式 II所示化合物与式 III所示化合物的摩尔比为 1:0.5 ~
1:2.1。
优选地， 步骤 1中式 II所示化合物与式 III所示化合物的摩尔比为 1: 1.05。 作为优选， 步骤 1中所述亲核加成反应的温度为 25 ~ 110.6°C , 所述亲核 加成反应的时间为 0.5 ~ 144h。
优选地， 步骤 1中所述亲核加成反应的温度为 28 ~ 110.6°C , 所述亲核加 成反应的时间为 0.5 ~ 144h。
作为优选，步骤 2中式 IV所示化合物与式 V所示化合物的摩尔比为 1 :0.2 ~
1:5。
作为优选，步骤 2中式 IV所示化合物或式 V所示化合物与所述催化剂的摩 尔比为 1 ~ 200:1。
作为优选， 步骤 2中所述类似傅-克反应的温度为 40 ~ 82 °C , 所述类似傅- 克反应的时间为 13.5 ~ 96h。
优选地， 步骤 2 中所述类似傅-克反应的温度为 40 ~ 80°C , 所述类似傅- 克反应的时间为 23.5 ~ 69h。
本发明还提供了一种结构如式 I所示左旋对羟基苯甘氨酸的合成方法，包 括如下步骤：
步骤 1 : 在第一溶剂中， 式 II所示化合物与式 III所示化合物发生亲核加成
反应， 生成式 IV所示化合物； 所述第一溶剂选自醚类溶剂、 酯类溶剂、 面代烷 烃类溶剂、 C5 ~ C1Q烃类溶剂、 腈类溶剂、 酮类溶剂；
步骤 2: 在第二溶剂中， 以酸为催化剂， 式 IV所示化合物与式 V所示化合 物发生类似傅-克反应， 生成所述左旋对羟基苯甘氨酸类化合物， 结构如式 VI 所示； 所述第二溶剂选自腈类溶剂、 面代烷烃类溶剂、 C5-C1Q烃类溶剂； 所述 酸为手性酸或非手性酸， 所述手性酸选自 D-酒石酸、 L-酒石酸、 D-樟脑磺酸、 L-樟脑磺酸、 L-脯氨酸、 D-脯氨酸、 手性磷酸， 所述非手性酸选自曱磺酸、 对 曱苯磺酸、 三氟曱磺酸、 硫酸、 盐酸；
其中， R1选自乙酰基、 苯曱酰基、 叔丁氧羰基、 苄氧羰基、 曱酰胺基、 新戊酰基； R2选自曱基、 乙基、 异丙基、 叔丁基、 苄基； R3为氢；
步骤 3: 在醇类与水的混合溶液或水中， 用酸调节 piHi < 2, 式 VI所示化 合物发生水解反应， 用碱中和至 pH值为 5.2 ~ 5.6即得；
作为优选， 步骤 3中所述醇类溶剂选自曱醇、 乙醇、 异丙醇。
作为优选， 步骤 3中所述水解反应的温度为 60 ~ 100°C。
优选地， 步骤 3中所述水解反应的温度为 60 ~ 80°C。
作为优选， 步骤 3所述水解反应中， 所述酸选自盐酸、 硫酸、 曱磺酸、 三
氟曱磺酸。
在本发明的一些实施例中， 步骤 3中所述酸的浓度为 IN ~ 12N。
作为优选， 步骤 3中， 所述碱选自氢氧化钠、 碳酸氢钠、 碳酸钠、 氢氧化 钾 、 氨水。
在本发明的一些实施例中， 步骤 3中所述碱的浓度为 2 ~ 12 N。
ee (对映体过量）值， 即光学纯度， 化合物样品的对映体组成可用术语 "对映体过量（enantiomeric excess) "或" e.e.% "来描述，它表示一个对映体对 另一个对映体的过量； 本发明提供的合成方法， 省去了现有合成方法中拆 分、 消旋化处理等工序， 制得的左旋对羟基苯甘氨酸类化合物的光学纯度能够 达到 88.1 ~ 98.0%。
本发明提供了一种左旋对羟基苯甘氨酸类化合物的合成方法， 省去了拆 分、 消旋化处理等后续工序， 简化了操作步骤； 在第二步反应中选用有机小分 子酸作为催化剂， 不仅有利于实现工业化生产， 而且通过催化剂、 反应溶剂、 反应物质、 反应温度和反应时间的确定， 使得终产物的 ee值为 88.1 ~ 98.0%; 在第二步反应中使用了非水溶剂， 避免了含酚废水的排放， 减少了环境污染。 附图说明
图 1示实施例 1中制得的 D -2-乙酰氨基 -2-(4-羟基苯基）乙酸乙酯单晶图。 具体实施方式
本发明公开了一种左旋对羟基苯甘氨酸类化合物的合成方法，本领域技术 人员可以借鉴本文内容， 适当改进工艺参数实现。 特别需要指出的是， 所有类 似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本 发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能 在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当 变更与组合， 来实现和应用本发明技术。
步骤 1 : 在第一溶剂中， 式 II所示化合物与式 III所示化合物发生亲核加成 反应， 生成式 IV所示化合物； 所述第一溶剂选自醚类溶剂、 酯类溶剂、 面代烷 烃类溶剂、 C5 ~ C1Q烃类溶剂、 腈类溶剂、 酮类溶剂；
作为优选， 所述第一溶剂选自醚类溶剂、 酯类溶剂、 面代烷烃类溶剂、
C5 ~ C1Q烃类溶剂、 腈类溶剂。
作为优选， 所述醚类溶剂选自乙醚、 二丙醚、 1,4-二氧六环、 四氢呋喃。
作为优选， 所述酯类溶剂选自乙酸乙酯、 乙酸曱酯、 乙酸丙酯、 乙酸叔丁 酯和曱酸乙酯。
作为优选，所述面代烷烃类溶剂选自二氯曱烷、三氯曱烷和 1,2-二氯乙烷。 作为优选， 所述 C5 ~ C1Q烃类溶剂选苯、 曱苯和二曱苯。
作为优选 所述腈类溶剂选自乙腈或丙腈。
作为优选， 所述酮类溶剂为丙酮。
优选地， 第一溶剂优选为曱苯、 乙酸曱酯、 乙酸丙酯、 乙酸乙酯、 氯仿、 二氯曱烷、 丙酮中的一种或两种以上的混合物；
步骤 2: 在第二溶剂中， 以酸为催化剂， 式 IV所示化合物与式 V所示化合 物发生类似傅-克反应， 生成所述左旋对羟基苯甘氨酸类化合物， 结构如式 VI 所示； 所述第二溶剂选自腈类溶剂、 面代烷烃类溶剂、 C5-C1Q烃类溶剂； 所述 酸为手性酸或非手性酸， 所述手性酸选自 D-酒石酸、 L-酒石酸、 D-樟脑磺酸、 L-樟脑磺酸、 L-脯氨酸、 D-脯氨酸、 手性磷酸， 所述非手性酸选自曱磺酸、 对 曱苯磺酸、 三氟曱磺酸、 硫酸、 盐酸；
作为优选，所述面代烷烃类溶剂选自二氯曱烷、三氯曱烷和 1,2-二氯乙烷。 作为优选， 所述 C5 ~ C1Q烃类溶剂选苯、 曱苯和二曱苯。
作为优选， 所述腈类溶剂选自乙腈或丙腈。
如果用手性酸催化，将生成具有光学活性的式 VI所示化合物，如果用非手 性酸做催化剂将生成外消旋体的式 VI所示化合物。
所述手性磷酸选自式 VII所示化合物、 式環所示化合物、 式 IX所示化合物、 式 X所示化合物、 式 XI所示化合物。
其中， Ar选自 H、 Ph、 2,4,6-( -Pr)3C6H2、 3,5-(CF3)2C6H3、 - Nap、 SiPh3、 9-anthryL 4-biphenyL 4-N02-C6H4、 9-phenanthryl、 p-MeOC6H4、 p-N02C6H4, 即 Ar选自氢、 苯基、 2,4,6-三异丙基苯基、 3,5-二三氟曱基苯基、 -萘基、 三 苯基硅基、 9-蒽基、 4-联苯基、 4-硝基苯基、 9-菲基、 4-曱氧基苯基、 4-硝基苯 基。
式 II 式 III
其中， R1选自乙酰基、 苯曱酰基、 叔丁氧羰基、 苄氧羰基、 曱酰胺基、 新戊酰基； R2选自曱基、 乙基、 异丙基、 叔丁基、 苄基； R3选自氢、 曱基、 三曱基硅基、 叔丁基二曱基硅基、 三异丙基硅基。
作为优选， R1选自乙酰基、 苯曱酰基、 叔丁氧羰基、 新戊酰基。 作为优选， 步骤 1中式 II所示化合物选自乙酰胺、 苯曱酰胺、 氨基曱酸叔 丁酯、 氨基曱酸苄酯、 尿素。
作为优选，步骤 1中式 II所示化合物与式 III所示化合物的摩尔比为 1:0.5 ~ 1:2.1。
优选地， 步骤 1中式 II所示化合物与式 III所示化合物的摩尔比为 1: 1.05。 作为优选， 步骤 1中所述亲核加成反应的温度为 25 ~ 110.6°C , 所述亲核 加成反应的时间为 0.5 ~ 144h。
优选地， 步骤 1中所述亲核加成反应的温度为 28 ~ 110.6°C , 所述亲核加 成反应的时间为 0.5 ~ 144h。
具体的， 步骤 1中所述亲核加成反应可以为：
2-脲基 -2-羟基乙酸乙酯的合成方法如下： 向 250 mL茄型瓶中依次加入尿 素 (3.01 g, 50 mmol),乙醛酸乙酯 ( 50%曱苯溶液, 11.22g, 55 mmol ) , 丙酮 150 mL, 28°C反应 74小时， 在 0°C放置 12小时， 析出白色沉淀， 过滤， 用 10mL 丙酮洗滤饼 2次， 抽真空 1小时， 得白色固体 3. lg, 滤液旋干， 用乙酸乙酯重 结晶， 又得到白色固体 1.63g, 两次总收率 58.4%, 熔点： 103-104 °C。 ^ NMR [400 MHz, DMSO]:5 6.77 (d, J = 9.2 Hz ,1H), 6.31 (d, J = 6.4 Hz, 1H), 5.78 (s, 2H), 5.34 (dd, J= 9.6,6.8 Hz , 1H), 4.11(q, J= 6.8 Hz 2H), 1.21 (t, J= 7.2 Hz, 3H); 13C NMR [100MHz, DMSO]: δ 170.3, 157.2, 72.0, 60.6, 14.0。
具体的， 步骤 1中所述亲核加成反应还可以为：
Ν，Ν-二 ( 2-羟基乙酸乙酯）脲的合成方法如下： 向 250mL圓底烧瓶中依 次加入尿素 3.0g ( 50 mmol ), 乙醛酸乙酯（ 50%曱苯溶液， 21.42g, 105 mmol ) , 丙酮 150 mL, 28°C反应 6天， 反应液析出大量白色沉淀， 停止反应。 抽滤， 滤饼在 30°C真空干燥 12小时，得白色固体 9.18克，收率 69.5%。 ^ NMR [400 MHz, DMSO]:5 7.16-7.10 (m ,2H), 6.53-6.40 (m,2H), 5.50-5.40(m, 2H), 4.15-4.10 (m, 4H), 1.23-1.19(m, 6H); 13C NMR [100MHz, DMSO]: 5170.0, 155.2, 71.9, 60.7, 13.9。
作为优选，步骤 2中式 IV所示化合物与式 V所示化合物的摩尔比为 1 :0.2 ~
1:5。
作为优选，步骤 2中式 IV所示化合物或式 V所示化合物与所述催化剂的摩 尔比为 1 ~ 200:1。
作为优选， 步骤 2中所述类似傅-克反应的温度为 40 ~ 82 °C , 所述类似傅-
克反应的时间为 13.5 ~ 96h。
优选地， 步骤 2 中所述类似傅-克反应的温度为 40 ~ 80°C , 所述类似傅- 克反应的时间为 23.5 ~ 69h。
本发明还提供了一种结构如式 I所示左旋对羟基苯甘氨酸的合成方法，包 括如下步骤：
步骤 1 : 在第一溶剂中， 式 II所示化合物与式 III所示化合物发生亲核加成 反应， 生成式 IV所示化合物； 所述第一溶剂选自醚类溶剂、 酯类溶剂、 面代烷 烃类溶剂、 C5 ~ C1Q烃类溶剂、 腈类溶剂、 酮类溶剂；
步骤 2: 在第二溶剂中， 以酸为催化剂， 式 IV所示化合物与式 V所示化合 物发生类似傅-克反应， 生成所述左旋对羟基苯甘氨酸类化合物， 结构如式 VI 所示； 所述第二溶剂选自腈类溶剂、 面代烷烃类溶剂、 C5-C1Q烃类溶剂； 所述 酸为手性酸或非手性酸， 所述手性酸选自 D-酒石酸、 L-酒石酸、 D-樟脑磺酸、 L-樟脑磺酸、 L-脯氨酸、 D-脯氨酸、 手性磷酸， 所述非手性酸选自曱磺酸、 对 曱苯磺酸、 三氟曱磺酸、 硫酸、 盐酸；
其中， R1选自乙酰基、 苯曱酰基、 叔丁氧羰基、 苄氧羰基、 曱酰胺基、 新戊酰基； R2选自曱基、 乙基、 异丙基、 叔丁基、 苄基； R3为氢；
步骤 3: 在醇类与水的混合溶液或水中， 用酸调节 piHi < 2, 式 VI所示化 合物发生水解反应，用碱中和至 pH值为 5.2 ~ 5.6即得；所述第三溶剂选自水、 醇类溶剂；
式 I 。
作为优选， 步骤 3中所述醇类溶剂选自曱醇、 乙醇、 异丙醇。
作为优选， 步骤 3中所述水解反应的温度为 60 ~ 100°C。
优选地， 步骤 3中所述水解反应的温度为 60 ~ 80°C。
作为优选， 步骤 3所述水解反应中， 所述酸选自盐酸、 酸、 曱磺酸、 三 氟曱磺酸。
在本发明的一些实施例中， 步骤 3 中水解反应中所述酸的浓度为 1N ~
12N。
作为优选， 步骤 3中， 所述碱选自氢氧化钠、 碳酸氢钠、 碳酸钠、 氢氧化 钾 、 氨水。
在本发明的一些实施例中， 步骤 3中所述碱的浓度为 2 ~ 12 N。
本发明提供了一种左旋对羟基苯甘氨酸类化合物的合成方法， 省去了拆 分、 消旋化处理等后续工序， 简化了操作步骤； 在第二步反应中选用有机小分 子酸作为催化剂， 不仅有利于实现工业化生产， 而且通过催化剂、 反应溶剂、 反应物质、 反应温度和反应时间的确定， 使得终产物的 ee值为 88.1 ~ 99.0%; 在第二步反应中使用了非水溶剂， 避免了含酚废水的排放， 减少了环境污染。
本发明提供的合成方法中所用试剂均可由市场购得。
下面结合实施例， 进一步阐述本发明： 实施例 1
对比例：
2-乙酰胺基 -2-羟基乙酸乙酯的合成， 合成路线如下所示:
'剛 2
向 500 mL茄型瓶中依次加入乙酰胺（ 11.81 g, 0.20 mol ),乙醛酸乙酯（ 50%
曱苯溶液， 42.84 g, 0.21 mol), 曱苯 160 mL。 在 80°C反应 35h, 再在 60°C反 应 27h , 析出大量白色沉淀， 降至室温， 抽滤， 用曱苯洗滤饼两次， 40°C真 空干燥 24h。 得白色固体 28.0g,摩尔收率 87%, 熔点： 88-89°C。
ifiNMR [400MHz, CDC13]: δ 6.86 (s, 1H ), 5.58 (d, J = 7.6 Hz, 1H), 4.46 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 2.05 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR [100MHz, CDC13]; δ 171.3, 169.6, 72.4, 62.8, 23.3, 14.2。
DL-2-乙酰氨基 -2- ( 4-羟基苯基）乙酸乙酯的合成， 合成路线如下所示:
向 25 mL茄型瓶中依次加入 2-乙酰胺基 -2-羟基乙酸乙酯（ 0.48g, 3 mmol ) 苯酚 (0.33g, 3.60 mmol) TsOH (0.05g, 0.30 mmol) 二氯曱烷 10 mL。 室温反应 38h, 反应液为无色透明液体， 停止反应。
浓缩， 柱色谱分离， 用石油酸 /乙酸乙酯 =1 : 1 , 洗脱出邻位产物， 为白色固 体， 59.8 mg, 收率 8.4%, 熔点： 39-40°C。
lR NMR [400 MHz, CDC13]: δ 9.05(s, 1H ), 7.20 (td, J = 7.6, 1.2 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.01 (dd, J = 7.6, 1.2 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 5.70 (d, J = 7.6 Hz, 1H), 4.31-4.16(m, 2H), 2.02 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR [100MHz, CDC13]: δ 171.5, 171.2, 155.4, 130.4, 128.0, 124.0, 120.7, 118.6, 62.4, 52.5, 22.8, 14.1。
用石油酸 /乙酸乙酯 =1 :2,洗脱出对位产物，为白色固体， 60 mg,收率 8.4%, 熔点： 119-121 °C。
¾ NMR [400 MHz, CDC13]: δ 7.12 (d, J= 8.4 Hz, 2H ), 6.93 (d, J= 7.2 Hz, 1H), 6.72 (d, J= 8.8Hz, 2H), 5.42 (d, J= 6.8 Hz, 1H), 4.29-4.06 (m, 2H), 2.00 (s, 1H), 1.17 (t, J= 7.2 Hz, 3H); 13C NMR [100MHz, CDC13]: δ 171.5, 170.8, 157.2, 128.7, 127.4, 116.1, 62.1, 56.5, 23.0, 14.1。
本发明提供的合成方法：
2-乙酰胺基 -2-羟基乙酸乙酯的合成， 合成路线如下所示：
向 500 mL茄型瓶中依次加入乙酰胺（ 11.81 g, 0.20 mol ),乙醛酸乙酯（ 50% 曱苯溶液， 42.84 g, 0.21 mol), 曱苯 160 mL。 在 80°C反应 35h, 再在 60°C反 应 27, 析出大量白色沉淀， 降至室温， 抽滤， 用曱苯洗滤饼两次， 40°C真空 干燥 24h。 得白色固体 28.0g,摩尔收率 87%, 熔点： 88-89°C。
ifiNMR [400MHz, CDC13]: δ 6.86 (s, 1H ), 5.58 (d, J= 7.6 Hz, 1H), 4.46 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 2.05 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR [100MHz, CDC13]; δ 171.3, 169.6, 72.4, 62.8, 23.3, 14.2。
D -2-乙酰氨基 -2-(4-羟基苯基）乙酸乙酯的合成， 合成路线如下所示:
在装有恒压滴液漏斗和温度计的 lOOmL三口瓶中依次加入 2-乙酰胺基 -2- 羟基乙酸乙酯（ 1.932g , 12 mmol), 催化剂手性磷酸 0.1 mmol (其中 Ar选自 氢、 苯基、 2,4,6-三异丙基苯基、 3,5-二三氟曱基苯基、 -萘基、 三苯基硅基、 9-蒽基、 4-联苯基、 4-硝基苯基、 9-菲基、 4-曱氧基苯基、 4-硝基苯基）， 苯酚 (0.94g, 10 mmol ), 乙腈 50mL, 反应液在 81 °C反应 34小时， 停止反应。 加入 23ml水， 室温搅拌 4小时， 过滤出催化剂， 回收率 88.2%。 滤液旋干， 过硅 胶柱， 二氯曱烷溶解样品上样， 石油醚： 乙酸乙酯： 冰乙酸 =600:200: 16 过出 催化剂和苯酚， 石油醚： 乙酸乙酯 =3250:3250过出邻位和对位产品。 对位产品 1.47g, 收率 62%, 熔点： 147- 148°C , ee =90%。（HPLC条件： chiralPAK AD-H
5μιη, 4.6χ250ηιηι色谱柱， 正己烷 /异丙醇 =9: 1为流动相， 流速为 1.0 mL/min, 最大吸收波长为 229nm )。
¾ NMR [400 MHz, CDC13]: δ 7.17 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 6.58 (d, J= 6.4 Hz, 1H), 5.47 (d, J= 6.8 Hz, 1H), 4.27-4.10 (m, 2H), 2.04 (s 3H), 1.21 (t, J= 7.2 Hz, 3H); 13C NMR [100 MHz, CDC13]: δ 171.4, 170.0, 156.5, 128.7, 128.4, 116.1, 62.2, 56.3, 23.4, 14.2。
D -2-乙酰氨基 -2-(4-羟基苯基）乙酸乙酯单晶图如图 1所示。 将本发明提供的方法制得的 D -2-乙酰氨基 -2-(4-羟基苯基)乙酸乙酯制备 成左旋对羟基苯甘氨酸盐酸盐， 合成路线如下所示：
向 10 mL schlenk 管中依次加入 D-2-乙酰氨基 -2-(4-羟基苯基）乙酸乙酯 O. lg, 浓盐酸（ 12N盐酸） 2mL, 开启搅拌， 100°C回流 6.5h,停止反应， 反应 液旋干得浅黄色固体 81.1mg, 收率 95.1%[a]D 2Q= -90°(c = 1.0, 水)。
¾ NMR [400 MHz, D20]: 57.30 (d, J = 8.4 Hz, 2H ) , 6.90 (d, J = 8.8 Hz , 2H), 5.07 (s, 1H); 13C NMR [100MHz, D20]: δ 171.1, 157.0, 129.8, 123.2, 116.3, 56.1。 实施例 2
对比例：
2-苯曱酰胺基 -2-羟基乙酸乙酯的合成， 合成路线如下所示:
¾ NMR [400 MHz, CDC13]: 57.81 (d, J = 7.6 Hz, 2H ), 7.58-7.48 (m,2H), 7.44 (t, J= 7.6 Hz, 2H), 5.81 (d, J= 7.2 Hz, 1H), 4.57 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR [ 100MHz,CDCl3]: δ 169.7, 168.2, 133.1, 132.6, 128.9, 127.5, 72.9, 62.9, 14.3.
DL -2-苯曱酰氨基 -2-(4-羟基苯基）乙酸乙酯的合成， 合成路线如下所示：
具体操作步骤如下：
向 50 mL茄形瓶中依次加入 2-苯曱酰胺基 -2-羟基乙酸乙酯 （2.23 g, 10 mmol), TsOH ( 0.35g, 2 mmol ) , PhOH (1.14 g, 12 mmol), CH3CN lOmL, 开 启搅拌， 开始加热， 当温度升至 48°C时， 反应液由悬浊液变为无色透明液体。 继续加热， 回流 13.5h后停止反应。 柱色谱分离， 用石油酸 /乙酸乙酯 =3: 1 , 洗 脱出对位产物， 为白色固体， 0.66 g, 收率 22.2%, 熔点： 156-157°C。
¾ NMR [400 MHz, MeOD]: δ 8.78 (d, J= 6 .OHz, 1H ), 7.84 (d, J = 7.2 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 8.8 Hz , 2H), 6.81 (d, J = 8.8 Hz, 2H), 5.60-5.50(m, 1H), 4.24-4.15 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR [100MHz, MeOD]: δ 172.7, 170.2, 158.9, 135.1, 132.8, 130.4, 129.5, 128.6, 127.9, 116.6, 62.6, 58.7, 14.4。
本发明提供的合成方法：
2-苯曱酰胺基 -2-羟基乙酸乙酯的合成， 合成路线如下所示:
向 250 mL茄形瓶中依次加入苯曱酰胺（ 7.21 g, 60 mmol ) , 乙醛酸乙酯
( 50%曱苯溶液， 10.32g, 50 mmol), 乙酸乙酯 55 mL, 开启搅拌， 开始加热， 当温度升至 53 °C时， 反应液由悬浊液变为无色透明液体。 继续加热， 77.06°C 回流反应 13h, 停止加热， 室温搅拌一夜， 析出白色沉淀， 抽滤， 用 3x5 mL 乙酸乙酯泡洗滤饼， 在 40°C真空干燥， 得白色固体 7.08g, 收率 63.5%, 熔点： 114-115°C。
¾ NMR [400 MHz, CDC13]: 57.81 (d, J = 7.6 Hz, 2H ), 7.58-7.48(m, 2H), 7.44 (t, J= 7.6 Hz, 2H), 5.81 (d, J= 7.2 Hz, 1H), 4.57 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR [ 100MHz,CDCl3]: δ 169.7, 168.2, 133.1, 132.6, 128.9, 127.5, 72.9, 62.9, 14.3.
D -2-苯曱酰氨基 -2-(4-羟基苯基）乙酸乙酯的合成， 合成路线如下所示：
向 lO mL schlenk管中依次加入 2-苯曱酰胺基 -2-羟基乙酸乙酯 （0.223 g, 1 mmol), 手性磷酸（0.1 mmol ) (其中， Ar选自氢、 苯基、 2,4,6-三异丙基苯基、 3,5-二三氟曱基苯基、 -萘基、 三苯基硅基、 9-蒽基、 4-联苯基、 4-硝基苯基、 9-菲基、 4-曱氧基苯基、 4-硝基苯基）， PhOH (0.112 g, 1.2 mmol), CH3CN 2mL,
开启搅拌， 开始加热， 81.6°C回流 23.5h后停止反应。 加入 1.2mL水， 析出催 化剂， 过滤， 滤液旋干， 柱色谱分离， 用石油酸 /乙酸乙酯 =5: 1 , 洗脱出苯酚 和剩余的催化剂， 用石油酸 /乙酸乙酯 =3: 1 , 洗脱出对位产品， 为白色固体， 40mg,收率 13.4%。 ee = 88.1% (HPLC条件： ChiralCEL OD-H 5μιη, 4.6x250 mm 色语柱， 正己烷 /异丙醇 =90: 10为流动相， 流速为 1.0 mL/min, 最大吸收波长 为 229
¾ NMR [400 MHz, CDC13]: δ 7.83 (d, J = 6.8 Hz, 2H ), 7.62-7.52 (m, 1H), 7.44 (t, J= 7.6 Hz, 2H), 7.23 (d, J= 8.8 Hz, 2H), 6.70 (d, J= 8.4 Hz , 2H), 6.41 (s, 1H), 5.64 (d, J= 6.8 Hz, 1H), 4.32-4.13 (m, 2H), 1.23 (t, J= 7.2 Hz, 3H); 13C NMR [lOOMHz, CDC13]: δ 171.5, 167.1, 156.7, 133.7, 132.2, 128.9, 128.7, 128.2, 127.4, 116.2, 62.3, 56.7, 14.2。 实施例 3
对比例：
2—叔丁氧酰胺基 -2-羟基乙酸乙酯的合成， 合成路线如下所示：
向 50 mL茄形瓶中依次加入 Boc-NH2 (6.15 g, 52.5 mmol), 乙醛酸乙酯 ( 50%曱苯溶液， 10.29 g, 50 mmol ), CHC13 15 mL, 开启搅拌， 反应液为无 色透体明液体， 61.70°C回流反应 60h, 停止反应。 柱色语分离， 用石油酸 /乙 酸乙酯 =8: 1 , 洗脱出目标产物， 为得白色固体， 8.02 g, 收率 73.2%, 熔点： 54-56。C。
ifiNMR [400 MHz, CDC13]: δ 5.89 (d, J= 8.0 Hz, 1H ), 5.39 (s, 1H), 4.38 (s, 1H), 4.30-4.21 (m, 2H), 1.43 (s, 9H), 1.30 (t, J= 7.2 Hz, 3H); 13C NMR [lOOMHz, CDC13]: δ 169.8, 155.1, 81.1, 73. 6, 62. 6, 28.4, 14.2.
DL -2-叔丁氧酰氨基 -2-(4-羟基苯基）乙酸乙酯的合成 ,合成路线如下所示:
具体操作步骤如下：
向 25 mL茄形瓶中依次加入 2-叔丁氧酰胺基 -2-羟基乙酸乙酯（ 423.3 mg, 1.93 mmoD TsOH (33.9 mg, 0.19 mmol), PhOH ( 218.0 mg, 2.32 mmol ), CHC13 2.5 mL, 回流反应 l lh, 停止反应。 柱色谱分离， 用石油酸 /乙酸乙酯 =6: 1洗脱 出对位产物， 为类白色固体， 85.4mg,收率 15%。
¾ NMR [400 MHz, CDC13]:5 7.12 (d, J= 8.0 Hz, 2H ) , 6.70 (d, J= 7.6 Hz, 2H), 5.66 (d, J= 6.4 Hz , 1H), 5.17 (d, J= 6.8 Hz, 1H), 4.16-4.07 (m,2H), 1.42 (s: 9H), 1.16 (t, J = 6.8 Hz, 3H); 13C NMR [100MHz, CDC13]:5 171.7, 156.8, 155.3, 128.5, 128.1, 116.0, 80.7, 62.0, 57.4, 28.4, 14.1. 本发明提供的合成方法：
2—叔丁氧酰胺基 -2-羟基乙酸乙酯的合成， 合成路线如下所示:
具体操作步骤如下：
向 50 mL茄形瓶中依次加入 Boc-NH2 (6.15 g, 52.5 mmol), 乙醛酸乙酯 ( 50%曱苯溶液， 10.29 g, 50 mmol ), CHC13 15 mL, 开启搅拌， 反应液为无 色透体明液体， 61.70°C回流反应 60h, 停止反应。 柱色语分离， 用石油酸 /乙 酸乙酯 =8: 1 , 洗脱出目标产物， 为得白色固体， 8.02 g, 收率 73.2%, 熔点： 54-56。C。
ifiNMR [400 MHz, CDC13]: δ 5.89 (d, J = 8 Hz, 1H ), 5.39 (s, 1H), 4.38 (s, 1H), 4.30-4.21 (m, 2H), 1.43 (s, 9H), 1.30 (t, J= 7.2 Hz, 3H); 13C NMR [100MHz, CDC13]: δ 169.8, 155.1, 81.1, 73. 6, 62. 6, 28.4, 14.2.
D -2-叔丁氧酰氨基 -2-(4-羟基苯基）乙酸乙酯的合成， 合成路线如下所示:
向 25mL 两口瓶中依次加入 2-叔丁氧酰胺基 -2-羟基乙酸乙酯（0.44 g, 2 mmol ), 手性磷酸 0.2 mmol ( Ar选自氢、 苯基、 2,4,6-三异丙基苯基、 3,5- 二三氟曱基苯基、 萘基、 三苯基硅基、 9-蒽基、 4-联苯基、 4-硝基苯基、 9- 菲基、 4-曱氧基苯基、 4-硝基苯基）， 苯酚（0.23 g, 2.4 mmol ), 乙腈 10 mL, 81.6°C回流反应 12小时零 15分钟， 停止反应。 柱色谱分离， 用石油酸 /乙酸乙 酯 /冰乙酸 =70: 10:5洗脱出对位产物 0.10 g, 为类白色固体， 收率 16.9%。 ee = 93.6% (HPLC条件： ChiralCEL OD-H 5μιη, 4.6x250 mm 色谱柱， 正己烷 /异丙 醇 =92.5:7.5为流动相， 流速为 0.5 mL/min, 最大吸收波长为 229 nm)。
¾ NMR [400 MHz, CDC13]: δ 7.14 (d, J= 7.6 Hz, 2H ) , 6.72 (d, J= 8.4 Hz, 2H), 5.62 (d, J = 6 Hz, 1H), 5.18 (d, J = 6.8 Hz, 1H), 4.20-4.09 (m, 2H), 1.43 (s, 9H), 1.18 (t, J= 6.8 Hz, 3H); 13C NMR [100MHz, CDC13]:5 171.8, 156.6, 155.4, 128.6, 128.3, 116.0, 80.7, 62.0, 57.4, 28.5, 14.2。 实施例 4
三曱基苯氧基硅的合成， 合成路线如下所示:
具体操作步骤如下：
向 lOOmL茄形瓶中依次加入苯酚 1.88g ( 20mmol ), 咪唑 1.63g(24mmol), 二氯曱烷 30mL, 三曱基氯硅烷 3.1 mL(24 mmol), 40 °C回流反应 46小时， 停 止反应。 把反应液旋干， 过硅胶柱， 用纯石油醚过出产品 0.56g, 为无色油状 液体， 收率 17%。
ifiNMR [400 MHz, CDC13]:57.31-7.27 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 0.34 (s, 9H); 13C NMR [100MHz, CDC13]: δ 155.4, 129.6, 121.6, 120.3, 0.4。
2-乙酰胺基 -2-羟基乙酸乙酯的合成， 合成路线如下所示:
具体操作步骤如下：
向 50 mL茄型瓶中依次加入乙酰胺（ 1.47 g, 25mmol )，乙酸 S史乙酯（50% 曱苯溶液， 5.35 g, 26.25mmol), 乙酸乙酯 20 mL。 77.06°C回流反应 45h后， 降至温至 25°C , 析出大量白色沉淀， 抽滤， 45°C真空干燥 l lh。 得白色固体 2.48g,摩尔收率 62%。
ifiNMR [400MHz, CDC13]: δ 6.99 (d, J = 6.4 Ηζ,ΙΗ ), 5.65-5.50 (m, ' ΙΗ), 4.69 (d, J= 5.6 Hz, 1H), 4.27 (q, J= 7.2 Hz, 2H), 2.04 (s, 3H), 1.31 (t, J= 7.2 Hz, 3H)。
D -2-乙酰 -2- 4-羟基苯基）乙酸乙酯的合成， 合成路线如下所示:
具体操作步骤如下：
向 0=5mm, 7=180mm的核磁管中依次加入 2-乙酰胺基 2-羟基乙酸乙酯
16.1mg ( O. lmmol ), 催化剂手性磷酸 O.Olmmol ( Ar选自氢、 苯基、 2,4,6-三异 丙基苯基、 3,5-二三氟曱基苯基、 萘基、 三苯基硅基、 9-蒽基、 4-联苯基、 4- 硝基苯基、 9-菲基、 4-曱氧基苯基、 4-硝基苯基）， 三曱基苯氧基硅 20mg ( 0.12mmol ), CD3CN 0.6mL,在 60°C反应 29小时， 再在 80°C反应 19小时， 结束反应。 反应液旋干， 硅胶柱分离， 用石油醚： 乙酸乙酯 =4: 5洗脱出产品
5mg, 收率 21.1%。 ee=97.4%。（HPLC条件： chiralPAKAD-H 5μιη, 4.6x250mm 色语柱， 正己烷 /异丙醇 =9: 1为流动相， 流速为 1.0 mL/min, 最大吸收波长为 229
¾ NMR [400 MHz, CDC13]: δ 7.17 (d, J= 8.4 Hz, 2H), 6.73 (d, J= 8.8 Hz, 2H), 6.56 (d, J= 6.4 Hz, 1H), 6.44(s,lH),5.46 (d, J= 6.8 Hz, 1H), 4.32-4.10 (m, 2H), 2.04 (s, 3H), 1.21 (t, J= 7.2 Hz, 3H)。 左旋对羟基苯甘氨酸盐酸盐的合成， 合成路线如下所示:
具体操作步骤如下：
向 10 mL schlenk 管中依次加入 D-2-乙酰氨基 -2-(4-羟基苯基）乙酸乙酯 99.3 mg ( 0.42mmol ) , 6N盐酸 2mL, 开启搅拌， 60°C反应 45h,停止反应， 反 应液旋干， 得白色固体 66.8 mg, 收率 95%。 [a]D 2Q= -99.7°(c = 1.0, 水)。
¾ NMR [400 MHz, D20]: 57.35 (d, J = 8.8 Hz, 2H ) , 6.96 (d, J = 8.8 Hz , 2H), 5.09 (s, 1H); 13C NMR [100MHz, D20]: δ 171.3, 157.1, 129.8, 123.4, 116.3, 56.2。 实施例 5
2-乙酰胺基 -2-羟基乙酸乙酯的合成， 合成路线如下所示：
向 50 mL茄型瓶中依次加入乙酰胺（ 1.47 g, 25mmol )，乙酸 S史乙酯（50% 曱苯溶液， 5.35 g, 26.25mmol), 丙酮 20 mL。 56.2°C回流反应 45h后， 降至温 至 25°C , 析出大量白色沉淀， 抽滤， 45°C真空干燥 llh。 得白色固体 1.76g,
摩尔收率 43.82%。
ifiNMR [400MHz, CDC13]: δ 6.82 (s, 1H ), 5.61-5.55 (m,，1H), 4.40-4.20 (m: 3H), 2.05 (s, 3H), 1.33 (t, J= 7.2 Hz, 3H)。 -2-乙酰氨基 -2-(4-羟基苯基）乙酸乙酯的合成， 合成路线如下所示:
具体操作步骤如下：
向 25mL茄型瓶中依次加入 2-乙酰胺基 2-羟基乙酸乙酯 161mg ( lmmol ), 催化剂手性磷酸 O.Olmmol ( Ar选自氢、 苯基、 2,4,6-三异丙基苯基、 3,5-二三 氟曱基苯基、 萘基、 三苯基硅基、 9-蒽基、 4-联苯基、 4-硝基苯基、 9-菲基、 4-曱氧基苯基、 4-硝基苯基）， 苯酚 423mg ( 4.5mmol ), CDC136mL,在 50°C反 应 42.5小时， 再在 62 °C反应 46.5小时,结束反应。反应液旋干， 过硅胶柱分离 产品， 用石油醚： 乙酸乙酯： 曱醇 =25:25:1洗脱出对位产品 16 mg , 收率 7%。 ee=93.1%。 （HPLC条件： chiralPAK AD-H 5μιη, 4.6x250mm色谱柱， 正己烷 / 异丙醇 =9: 1为流动相， 流速为 1.0 mL/min, 最大吸收波长为 229 nm )。
¾ NMR [400 MHz, CDC13]: δ 7.15 (d, J= 7.6 Hz, 2H ), 6.71 (d, J= 8.4 Hz, 2H), 6.59 (s, 1H), 5.46 (d, J= 6.8 Hz, 1H), 4.29-4.06 (m, 2H), 2.04 (s, 3H), 1.21 (t, J= 7.2 Hz, 3H) 左旋对羟基苯甘氨酸盐酸盐的合成， 合成路线如下所示:
向 10 mL schlenk 管中依次加入 D-2-乙酰氨基 -2-(4-羟基苯基）乙酸乙酯 99.6 mg ( 0.42mmol ) , IN盐酸 2mL, 开启搅拌， 60°C反应 45h, 升温至 80°C 反应 13.5h, 再升温至 99°C反应 llh, 停止反应， 反应液旋干， 得白色固体 70.0 mg, 收率 99%。 [a]D 2°= -85。(c = 1.0, 水)。
¾ NMR [400 MHz, D20]: 57.34 (d, J = 8.8 Hz, 2H ) , 6.95 (d, J = 8.4 Hz , 2H), 5.06 (s, 1H)。 实施例 6
2-乙酰胺基 -2-羟基乙酸乙酯的合成， 合成路线如下所示：
具体操作步骤如下：
向 50 mL茄型瓶中依次加入乙酰胺（ 1.47 g, 25mmol )，乙酸 S史乙酯（50% 曱苯溶液， 5.35 g, 26.25mmol), 氯仿 20 mL。 61.7°C回流反应 45h后， 降至温 至 25°C , 析出大量白色沉淀， 抽滤， 45°C真空干燥 llh。 得白色固体 2.00g, 摩尔收率 50%。
ifiNMR [400MHz, CDC13]: δ 6.84 (s, 1Η ), 5.65-5.50 (m, 1H), 4.38 (d, J= 5.6
Ηζ ,ΙΗ), 4.29 (q, J= 7.2 Hz, 2H), 2.05 (s, 3H), 1.33 (t, J= 7.2 Hz, 3H)。
D -2-乙酰氨基 -2-(4-羟基苯基）乙酸乙酯的合成， 合成路线如下所示:
¾ NMR [400 MHz, CDC13]: δ 7.17 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 6.58 (d, J= 6.4 Hz, 1H), 5.47 (d, J= 6.8 Hz, 1H), 4.27-4.10 (m, 2H), 2.04 (s: 3H), 1.21 (t, J= 7.2 Hz, 3H); 13C NMR [100 MHz, CDC13]: δ 171.4, 170.0, 156.5, 128.7, 128.4, 116.1, 62.2, 56.3, 23.4, 14.2。 左旋对羟基苯甘氨酸盐酸盐的合成， 合成路线如下所示:
具体操作步骤如下：
向 10 mL schlenk 管中依次加入 D-2-乙酰氨基 -2-(4-羟基苯基）乙酸乙酯 99.3 mg ( 0.42mmol ) , 6N盐酸 2mL, 开启搅拌， 60°C反应 45h,停止反应， 反 应液旋干， 得白色固体 66.8 mg, 收率 95%。 [a]D 2Q= -99.7°(c = 1.0, 水)。
¾ NMR [400 MHz, D20]: 57.35 (d, J = 8.8 Hz, 2H ) , 6.96 (d, J = 8.8 Hz ,
2H), 5.09 (s, 1H); 13C NMR [100MHz, D20]: δ 171.3, 157.1, 129.8, 123.4, 116.3, 56.2。 实施例 7
2-乙酰胺基 -2-羟基乙酸乙酯的合成， 合成路线如下所示：
具体操作步骤如下：
向 50 mL茄型瓶中依次加入乙酰胺（ 1.47 g, 25mmol )，乙酸 S史乙酯（50% 曱苯溶液， 5.35 g, 26.25mmol), 四氢呋喃 20 mL。 65 °C回流反应 45h后， 降 至温至 25°C ,析出大量白色沉淀，抽滤， 45°C真空干燥 l lh。得白色固体 1.85g, 摩尔收率 47.13%。
ifiNMR [400MHz, CDC13]: δ 6.83 (s, 1Η ), 5.65-5.50 (m, 1H), 4.45-4.21 (m, 3H), 2.05 (s, 3H), 1.33 (t, J= 7.2 Hz, 3H)。
D -2-乙酰氨基 -2-(4-羟基苯基）乙酸乙酯的合成， 合成路线如下所示：
在装有恒压滴液漏斗和温度计的 lOOmL三口瓶中依次加入 2-乙酰胺基 -2- 羟基乙酸乙酯（ 1.932g , 12 mmol), 催化剂手性磷酸 0.1 mmol (其中 Ar选自 氢、 苯基、 2,4,6-三异丙基苯基、 3,5-二三氟曱基苯基、 -萘基、 三苯基硅基、 9-蒽基、 4-联苯基、 4-硝基苯基、 9-菲基、 4-曱氧基苯基、 4-硝基苯基）， 苯酚 (0.94g, 10 mmol ), 乙腈 50mL, 反应液在 81 °C反应 34小时， 经过后处理纯化 出对位产品 1.67g, 收率 62%, 熔点： 147- 148 °C , ee =90%。 （HPLC条件： chiralPAK AD-H 5μιη, 4.6x250mm色谱柱， 正己烷 /异丙醇 =9: 1为流动相， 流速 为 1.0 mL/min, 最大吸收波长为 229nm )。
¾ NMR [400 MHz, CDC13]: δ 7.17 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz,
2H), 6.58 (d, J= 6.4 Hz, 1H), 5.47 (d, J= 6.8 Hz, 1H), 4.27-4.10 (m, 2H), 2.04 (s: 3H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR [100 MHz, CDC13]: δ 171.4, 170.0, 156.5, 128.7, 128.4, 116.1, 62.2, 56.3, 23.4, 14.2。 左旋对羟基苯甘氨酸的合成， 合成路线如下所示：
向 25 mL 茄形瓶加入 D-2-乙酰氨基 -2-(4-羟基苯基）乙酸乙酯 0.807g ( 3.4mmol ) , 6Ν盐酸 12mL, 开启搅拌， 60°C反应 14小时 40分钟， 停止反 应，反应液旋干，用 3N氢氧化钠调 pH为 5.5 ,得白色固体 ,0.245g, 收率 43.2%。
[a]D 20= -156.6°(c = 1.0, IN盐酸)。 ^ NMR [400 MHz, D20]: 57.20 (d, J= 8.4 Hz, 2H ) , 6.81 (d, J= 8.4 Hz , 2H), 5.00 (s, 1H)。 实施例 8
2-乙酰胺基 -2-羟基乙酸乙酯的合成， 合成路线如下所示:
向 50 mL茄型瓶中依次加入乙酰胺（ 1.47 g, 25mmol )，乙酸 S史乙酯（50% 曱苯溶液， 2.55 g, 12.5mmol), 曱苯 20 mL。 110.6°C回流反应 30分钟， 降温 至 20°C , 析出大量白色沉淀， 抽滤， 50°C真空干燥 6h。 得白色固体 1.73g, 摩尔收率 85.76%。
ifiNMR [400MHz, CDC13]: δ 7.30 (d, J = 6.8 Hz, 1H ), 5.58 (d, J = 7.6 Hz, 1H ), 5.40 (s, 1H), 4.27-4.21 (q, J = 7.2 Hz 2H), 2.02 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H)。
D -2-乙酰氨基 -2-(4-羟基苯基）乙酸乙酯的合成， 合成路线如下所示:
具体操作步骤如下：
在装有恒压滴液漏斗和温度计的 lOOmL三口瓶中依次加入 2-乙酰胺基 -2- 羟基乙酸乙酯（ 1.932g , 12 mmol), 催化剂手性磷酸 0.1 mmol (其中 Ar选自 氢、 苯基、 2,4,6-三异丙基苯基、 3,5-二三氟曱基苯基、 -萘基、 三苯基硅基、 9-蒽基、 4-联苯基、 4-硝基苯基、 9-菲基、 4-曱氧基苯基、 4-硝基苯基）， 苯酚 (0.94g, 10 mmol ), 乙腈 50mL, 反应液在 81 °C反应 34小时， 经过后处理纯化 出对位产品 1.47g, 收率 62%, 熔点： 147- 148 °C , ee =90%。 （HPLC条件： chiralPAK AD-H 5μιη, 4.6x250mm色谱柱， 正己烷 /异丙醇 =9: 1为流动相， 流速 为 1.0 mL/min, 最大吸收波长为 229nm )。
¾ NMR [400 MHz, CDC13]: δ 7.17 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 6.58 (d, J= 6.4 Hz, 1H), 5.47 (d, J= 6.8 Hz, 1H), 4.27-4.10 (m, 2H), 2.04 (s: 3H), 1.21 (t, J= 7.2 Hz, 3H); 13C NMR [100 MHz, CDC13]: δ 171.4, 170.0, 156.5, 128.7, 128.4, 116.1, 62.2, 56.3, 23.4, 14.2。 左旋对羟基苯甘氨酸盐酸盐的合成， 合成路线如下所示:
¾ NMR [400 MHz, D20]: 57.34 (d, J = 8.8 Hz, 2H ) , 6.95 (d, J = 8.4 Hz , 2H), 5.06 (s, 1H)。 以上对本发明所提供的一种左旋对羟基苯甘氨酸类化合物的合成方法进 以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。 应当指出， 对于本技术领域技术人员来说， 在不脱离本发明原理的前提下，还可以对本发 明进行若干改进和修饰， 这些改进和修饰也落入本发明权利要求的保护范围 内。
Claims
1、 一种左旋对羟基苯甘氨酸类化合物的合成方法， 其特征在于， 包括如 下步骤：
步骤 1 : 在第一溶剂中， 式 II所示化合物与式 III所示化合物发生亲核加成 反应， 生成式 IV所示化合物； 所述第一溶剂选自醚类溶剂、 酯类溶剂、 面代烷 烃类溶剂、 C5 ~ C1Q烃类溶剂、 腈类溶剂、 酮类溶剂；
步骤 2: 在第二溶剂中， 以酸为催化剂， 式 IV所示化合物与式 V所示化合 物发生类似傅-克反应， 生成所述左旋对羟基苯甘氨酸类化合物， 结构如式 VI 所示； 所述第二溶剂选自腈类溶剂、 面代烷烃类溶剂、 C5-C1Q烃类溶剂； 所述 酸为手性酸或非手性酸， 所述手性酸选自 D-酒石酸、 L-酒石酸、 D-樟脑磺酸、 L-樟脑磺酸、 L-脯氨酸、 D-脯氨酸、 手性碑 S , 所述非手性酸选自曱磺酸、 对 曱苯磺酸、 三氟曱磺酸、 硫酸、 盐酸；
式 II 式 III
2、 根据权利要求 1所述的方法， 其特征在于， 步骤 1中式 II所示化合物 与式 III所示化合物的摩尔比为 1 :0.5 ~ 1:2.1。
3、 根据权利要求 1所述的方法， 其特征在于， 步骤 1中所述亲核加成反 应的温度为 25 ~ 110.6°C , 所述亲核加成反应的时间为 0.5 ~ 144h。
4、 根据权利要求 1所述的方法， 其特征在于， 步骤 2中式 IV所示化合物 与式 V所示化合物的摩尔比为 1 :0.2 ~ 1:5。
5、 根据权利要求 1所述的方法， 其特征在于， 步骤 2中式 IV所示化合物 或式 V所示化合物与所述催化剂的摩尔比为 1 ~ 200:1。
6、 根据权利要求 其特征在于， 步骤 2中所述类似傅 -克反 应的温度为 40 ~ 82 °C , 所述类似傅-克反应的时间为 13.5 ~ 96h。
7、 一种结构如式 I所示左旋对羟基苯甘氨酸的合成方法， 其特征在于， 包括如下步骤：
步骤 1: 在第一溶剂中， 式 II所示化合物与式 III所示化合物发生亲核加成 反应， 生成式 IV所示化合物； 所述第一溶剂选自醚类溶剂、 酯类溶剂、 面代烷 烃类溶剂、 C5 ~ C1Q烃类溶剂、 腈类溶剂、 酮类溶剂；
步骤 2: 在第二溶剂中， 以酸为催化剂， 式 IV所示化合物与式 V所示化合 物发生类似傅-克反应， 生成所述左旋对羟基苯甘氨酸类化合物， 结构如式 VI 所示； 所述第二溶剂选自腈类溶剂、 面代烷烃类溶剂、 C5-C1Q烃类溶剂； 所述 酸为手性酸或非手性酸， 所述手性酸选自 D-酒石酸、 L-酒石酸、 D-樟脑磺酸、 L-樟脑磺酸、 L-脯氨酸、 D-脯氨酸、 手性碑 S , 所述非手性酸选自曱磺酸、 对 曱苯磺酸、 三氟曱磺酸、 硫酸、 盐酸；
0;
- NH2 式 II 式 III
步骤 3: 在醇类与水的混合溶液或水中， 用酸调节 piHi < 2, 式 VI所示化
合物发生水解反应， 用碱中和至 pH值为 5.2 ~ 5.6即得;
8、 根据权利要求 7所述的方法， 其特征在于， 步骤 3中所述水解反应的 温度为 60 ~ 100°C。
9、根据权利要求 7所述的方法， 其特征在于， 步骤 3中所述酸选自盐酸、 硫酸、 曱磺酸、 三氟曱磺酸。
10、 根据权利要求 7所述的方法， 其特征在于， 步骤 3中所述碱选自氢氧 化钠、 碳酸氢钠、 碳酸钠、 氢氧化钾、 氨水。
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| GB1308404.1A GB2503341B (en) | 2012-02-15 | 2012-02-15 | A method of synthesizing levorotatory p-hydroxyphenylglycine compounds |
| PCT/CN2012/071159 WO2013120257A1 (zh) | 2012-02-15 | 2012-02-15 | 一种左旋对羟基苯甘氨酸类化合物的合成方法 |
| JP2013558293A JP5767346B2 (ja) | 2012-02-15 | 2012-02-15 | 左旋性ｐ−ヒドロキシフェニルグリシン化合物の合成方法 |
| MX2013006993A MX342892B (es) | 2012-02-15 | 2012-02-15 | Un procedimiento para sintetizar compuestos de p-hidroxifenilglicina levorrotatoria. |
| ES201390067A ES2429431B2 (es) | 2012-02-15 | 2012-02-15 | Un procedimiento para sintetizar compuestos de P-Hidroxifenilglicina Levorrotatoria |
| CA2818094A CA2818094C (en) | 2012-02-15 | 2012-02-15 | A method of synthesizing levorotatory p-hydroxyphenylglycine compounds |
| US13/994,085 US8940928B2 (en) | 2012-02-15 | 2012-02-15 | Method of synthesizing levorotatory p-hydroxyphenylglycine compounds |
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| US5336805A (en) * | 1991-08-13 | 1994-08-09 | Dsm N.V. | Process for preparing an α-amino acid, the corresponding ester and amide |
| JPH10279541A (ja) * | 1997-04-02 | 1998-10-20 | Nippon Shokubai Co Ltd | ２−置換グリコール酸化合物及びその製造方法 |
| CN101362703A (zh) * | 2007-08-09 | 2009-02-11 | 谢建中 | 对羟基苯甘氨酸合成技术 |
| CN102603449A (zh) * | 2012-02-15 | 2012-07-25 | 河南新天地药业股份有限公司 | 一种左旋对羟基苯甘氨酸类化合物的合成方法 |
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| US3860631A (en) * | 1973-12-06 | 1975-01-14 | Smithkline Corp | Process for the preparation of n-acyl-2- and 4-hydroxyphenylglycines |
| NL7609939A (nl) * | 1975-09-12 | 1977-03-15 | Nobel Hoechst Chimie Societe A | Werkwijze voor de bereiding van n-acylhydroxyaryl- glycinen. |
| NL9000653A (nl) | 1990-03-21 | 1991-10-16 | Kessels Gerard | Werkwijze voor de bereiding van d-(-)-4-hydroxyfenylglycine en l-(+)-4-hydroxyfenylglycine, uitgaande van d.l.-4-hydroxyfenylglycine. |
| CN1072926A (zh) | 1992-11-19 | 1993-06-09 | 河北师范学院 | D-(-)-[4-r]-苯甘氨酸的制备方法 |
| CN100494165C (zh) | 2006-03-29 | 2009-06-03 | 宝山钢铁股份有限公司 | D-对羟基苯甘氨酸的制备方法 |
| CN100519514C (zh) | 2008-03-13 | 2009-07-29 | 河北宏源化工有限公司 | D-对羟基苯甘氨酸的制备方法 |
| WO2009127446A1 (en) * | 2008-04-17 | 2009-10-22 | Deretil, S.A. | METHOD FOR THE PREPARATION OF D-p-HYDROXYPHENYLGLYCINE |
| CN101613298A (zh) * | 2008-06-25 | 2009-12-30 | 河南新天地药业有限公司 | 水相拆分法生产d-(-)-对羟基苯甘氨酸技术 |
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| US5336805A (en) * | 1991-08-13 | 1994-08-09 | Dsm N.V. | Process for preparing an α-amino acid, the corresponding ester and amide |
| JPH10279541A (ja) * | 1997-04-02 | 1998-10-20 | Nippon Shokubai Co Ltd | ２−置換グリコール酸化合物及びその製造方法 |
| CN101362703A (zh) * | 2007-08-09 | 2009-02-11 | 谢建中 | 对羟基苯甘氨酸合成技术 |
| CN102603449A (zh) * | 2012-02-15 | 2012-07-25 | 河南新天地药业股份有限公司 | 一种左旋对羟基苯甘氨酸类化合物的合成方法 |
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| JP5767346B2 (ja) | 2015-08-19 |
| MX2013006993A (es) | 2013-12-06 |
| GB2503341B (en) | 2020-04-15 |
| MX342892B (es) | 2016-10-18 |
| CA2818094C (en) | 2016-11-08 |
| US8940928B2 (en) | 2015-01-27 |
| JP2014515733A (ja) | 2014-07-03 |
| GB201308404D0 (en) | 2013-06-19 |
| US20140350295A1 (en) | 2014-11-27 |
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