CN109503319B - Synthesis method of chiral compound R- (+) -2-methyl-3-phenyl-1-propanol - Google Patents
Synthesis method of chiral compound R- (+) -2-methyl-3-phenyl-1-propanol Download PDFInfo
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- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/095—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of organic acids
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- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
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- C07C29/141—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of a —CHO group with hydrogen or hydrogen-containing gases
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- C07C29/88—Separation; Purification; Use of additives, e.g. for stabilisation by treatment giving rise to a chemical modification of at least one compound
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Abstract
The invention discloses a method for synthesizing a chiral compound R- (+) -2-methyl-3-phenyl-1-propanol. The method comprises the following steps of (1) synthesizing (+/-) -2-methyl-3-phenyl-1-propanol by using alpha-methyl cinnamaldehyde as a raw material through a catalytic hydrogenation reaction; then the monoester is formed by esterification reaction with phthalic anhydride; then the product is reacted with S- (-) -alpha-phenylethylamine through acid and alkali to form salt; then separating and purifying the single chiral isomer through crystallization and recrystallization; then obtaining R- (+) -2-methyl-3-phenyl-1-propanol and hydrolysis by-products through hydrolysis reaction; and finally, separating and purifying to remove hydrolysis byproducts to obtain R- (+) -2-methyl-3-phenyl-1-propanol.
Description
Technical Field
The invention relates to the field of chiral compound synthesis, in particular to a method for synthesizing a chiral compound R- (+) -2-methyl-3-phenyl-1-propanol.
Background
The chiral alcohol compound is an important intermediate for synthesizing chiral liquid crystal monomers, chiral drugs and alkaloid chiral chemicals.
The method for obtaining the non-natural chiral alcohol compound generally comprises the steps of firstly synthesizing by a chemical method; however, after chemical synthesis, only a mixture of isomers having two opposite chiralities (usually called racemic mixture) is obtained at the same time. Therefore, after chemical synthesis, separation and purification of two chiral isomers are often carried out.
The separation and purification method of chiral isomers mainly comprises a chemical resolution method, a chromatography method, an extraction method and the like. The chromatography has small treatment capacity and low efficiency, and can not be industrialized, so that the practicability is greatly limited; the extraction method can be applied only to substances having a large difference in physical properties between the two optical isomers; however, the two optical isomers of the compound of the present invention have almost no difference in physical properties, and thus the extraction method is not suitable.
For the chiral compound R- (+) -2-methyl-3-phenyl-1-propanol related to the present invention, no complete synthetic method study was seen before the present invention. There are only a few academic documents relating to the synthesis of the compound (±) -2-methyl-3-phenyl-1-propanol; however, none of these documents has been further investigated to obtain the single chiral isomer R- (+) -2-methyl-3-phenyl-1-propanol.
Disclosure of Invention
The invention aims to invent a method for synthesizing a chiral compound R- (+) -2-methyl-3-phenyl-1-propanol capable of realizing industrial production
In order to achieve the purpose, the invention adopts the technical scheme that: 1. A method for synthesizing chiral compound R- (+) -2-methyl-3-phenyl-1-propanol is characterized in that the following processes of synthesis, separation and purification are adopted:
step 1: carrying out catalytic hydrogenation on alpha-methyl cinnamaldehyde serving as a raw material and hydrogen to obtain (+/-) -2-methyl-3-phenyl-1-propanol; the reaction formula is as follows:
step 2: taking (+/-) -2-methyl-3-phenyl-1-propanol as a raw material, and carrying out esterification reaction with phthalic anhydride to obtain (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester; the reaction formula is as follows:
；
and step 3: the method comprises the following steps of (1) carrying out acid-base salt forming reaction on (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester serving as a raw material and S- (-) -alpha-phenylethylamine to obtain (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenylethylamine salt; the reaction formula is as follows:
and 4, step 4: purifying and separating (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt through crystallization and recrystallization to obtain (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt; the reaction formula is as follows:
and 5: carrying out hydrolysis reaction by using (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt as a raw material to obtain a mixture containing R- (+) -2-methyl-3-phenyl-1-propanol, phthalic acid and S- (-) -alpha-phenethylamine,the reaction formula is as follows:
step 6: phthalic acid and S- (-) -alpha-phenylethylamine were separated and removed by a conventional chemical or physical separation method to give R- (+) 2-methyl-3-phenyl-1-propanol.
A method for synthesizing chiral compound R- (+) -2-methyl-3-phenyl-1-propanol is characterized in that:
step 1: using alpha-methyl cinnamaldehyde as raw material, adding catalyst, carrying out catalytic hydrogenation with hydrogen at a certain temperature and pressure to obtain (+/-) -2-methyl-3-phenyl-1-propanol,
the catalyst in the step 1 is various catalysts capable of catalyzing aldehydes to be hydrogenated into alcohol, and is one or a mixture of more of palladium carbon, Raney nickel, platinum carbon, ruthenium carbon and rhodium carbon, the dosage of the catalyst is 0.1-40% of the weight ratio of the raw materials,
the reaction temperature in the step 1 is 0 ℃ to 150 ℃,
the reaction pressure in the step 1 is 0.1MPa-5 MPa;
step 2: the method comprises the following steps of (1) taking (+/-) -2-methyl-3-phenyl-1-propanol as a raw material, adding a certain amount of solvent, catalyst and phthalic anhydride, heating and raising the temperature to perform esterification reaction; after reacting for a certain time, obtaining (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester,
the solvent in the step 2 is one or more of toluene, tetrahydrofuran, methyl cyclopentyl ether, methyl tert-butyl ether, petroleum ether and cyclohexane, and the dosage of the solvent is 100-1000% of the weight ratio of the raw materials;
the catalyst in the step 2 is a catalyst commonly used for esterification reaction of acid anhydride, and is one or more of pyridine, triethylamine and 2, 6-dimethylpyridine;
the (+/-) -2-methyl-3-phenyl-1-propanol in the step 2: phthalic anhydride: the molar ratio of the catalyst = 1: 1.0-1.2: 0.01-0.05,
the reaction temperature in the step 2 is 0-130 ℃, and the reaction time is 5-30 hours;
and step 3: taking (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester as a raw material, adding a certain amount of solvent and S- (-) -alpha-phenylethylamine, heating and reacting for a certain time to obtain (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenylethylamine salt,
the solvent in the step 3 is selected from common organic solvents which do not participate in the reaction, and is one or more of toluene, tetrahydrofuran, methyl cyclopentyl ether, methyl tert-butyl ether, petroleum ether, cyclohexane and ethyl acetate, and the dosage of the solvent is 50-1000% of the weight ratio of the raw materials;
the reaction temperature in the step 3 is 0-110 ℃, the reaction time is 1-20 hours,
the (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester in step 3: s- (-) - α -phenylethylamine at a molar ratio = 1: 1-3;
and 4, step 4: selecting a proper amount of solvent, crystallizing and recrystallizing (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt to obtain (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt,
the solvent in the step 4 is a solvent with chemical stability to the substrate, and is one or a mixture of water, methanol, ethanol, isopropanol, toluene, tetrahydrofuran, methyl cyclopentyl ether, petroleum ether, cyclohexane and ethyl acetate, wherein the dosage of the solvent is 100-1000% of the weight ratio of the raw materials;
and 5: taking (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt as a raw material, adding a certain amount of solvent, catalyst and water, maintaining a certain temperature for hydrolysis reaction, and obtaining a mixture containing R- (+) -2-methyl-3-phenyl-1-propanol, phthalic acid, S- (-) -alpha-phenethylamine, solvent and water after a period of time,
the solvent in the step 5 is selected from a solvent which does not participate in the reaction and can partially dissolve the raw materials, and is one or a mixture of more of ethanol, isopropanol, toluene, tetrahydrofuran, methyl cyclopentyl ether, petroleum ether and cyclohexane, the dosage of the solvent is 50-1000% of the weight ratio of the raw materials,
the catalyst in the step 5 is selected from a catalyst commonly used for ester hydrolysis, which is one or a mixture of more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide and ammonia water, the dosage of the catalyst is 100-200% of the mass ratio of the raw materials when an acidic catalyst is used, and 200-300% of the mass ratio of the raw materials when an alkaline catalyst is used,
the hydrolysis reaction temperature in the step 5 is 0-110 ℃, and the reaction time is 3-30 hours;
step 6: phthalic acid and S- (-) -alpha-phenylethylamine were separated and removed by a conventional chemical or physical separation method to give R- (+) 2-methyl-3-phenyl-1-propanol.
Further, the raw material (+/-) -2-methyl-3-phenyl-1-propanol of the step 2 is the product of the step 1; or the following steps: after a part of S- (-) -2-methyl-3-phenyl-1-propanol is separated and extracted by using (+/-) -2-methyl-3-phenyl-1-propanol as a raw material, the mother liquor separated and extracted is recycled, and the (+/-) -2-methyl-3-phenyl-1-propanol is obtained and recycled.
Further, the raw material (+/-) -2-methyl-3-phenyl-1-propanol of the step 2 is the product of the step 1; or the following steps: the method comprises the steps of taking (+/-) -2-methyl-3-phenyl-1-propanol as a raw material, separating and extracting a part of R- (+) -2-methyl-3-phenyl-1-propanol, then recycling mother liquor obtained by separation and extraction, and obtaining the (+/-) -2-methyl-3-phenyl-1-propanol.
Further, the conventional chemical separation method in step 6 is to add acid or alkali to the hydrolyzed mixture to generate salts from phthalic acid or S- (-) - α -phenylethylamine, precipitate the salts from the organic solvent, and filter the salts to remove the salts; or dissolving salt in acid solution or alkali solution, and washing to remove; or steam distillation is used to distill off the target product, but the salts of phthalic acid or S- (-) -alpha-phenylethylamine cannot.
Further, the physical separation method in step 6 is to adsorb and filter the hydrolyzed mixture by using a polar adsorbent, or to perform column chromatography, so that phthalic acid or S- (-) - α -phenylethylamine is adsorbed and removed.
Further, in the reaction process of the step 1, no reaction solvent is added; or adding solvent which does not participate in the reaction, wherein the solvent is one or a mixture of water, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, cyclohexane and petroleum ether, and the dosage of the solvent is not more than 1000 percent of the weight of the raw materials.
Further, the (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester product obtained in the step 2 is subjected to purification treatment and then put into the reaction of the next step, and the purification treatment process comprises concentration, crystallization and filtration.
Further, the amount of the solvent used in the step 3 is brought from the solution of the raw materials or is newly added or supplemented in a sufficient amount when the reaction is carried out.
The invention realizes the synthesis method of the complete chiral compound R- (+) -2-methyl-3-phenyl-1-propanol, and has industrial realizability. Prior to the present invention, no complete synthetic studies on the chiral compounds were found. Although there are few academic documents, the study of the synthesis of the compound (±) -2-methyl-3-phenyl-1-propanol is involved; however, none of these documents has been further investigated to obtain the single chiral isomer R- (+) -2-methyl-3-phenyl-1-propanol.
The method is not only pioneering in realizing the separation and purification of the racemic compound (+/-) -2-methyl-3-phenyl-1-propanol from the single chiral compound R- (+) -2-methyl-3-phenyl-1-propanol, but also adopts a chemical resolution method, and guarantees the feasibility of industrial amplification from the aspect of process productivity.
When the synthesis of the compound is realized, all selected raw materials, such as alpha-methyl cinnamaldehyde, hydrogen, a hydrogenation catalyst, phthalic acid, S- (-) -alpha-phenylethylamine and the like, are common chemical products which are fully supplied industrially and in the market, and the industrial realizability of the compound is ensured from the aspect of raw materials.
Detailed Description
The following examples illustrate the invention in detail: the embodiment is implemented on the premise of the technical scheme of the invention, and a detailed implementation mode and a specific operation process are given. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
The invention aims to provide a method for synthesizing a chiral compound R- (+) -2-methyl-3-phenyl-1-propanol, which comprises the following specific implementation modes:
example one
Step 1: the method comprises the steps of taking alpha-methyl cinnamaldehyde as a raw material, adding a proper catalyst, and carrying out catalytic hydrogenation with hydrogen at a certain temperature and pressure to obtain (+/-) -2-methyl-3-phenyl-1-propanol.
110g of alpha-methylcinnamaldehyde and 550g of isopropanol were charged into a 2L stainless steel autoclave, and after nitrogen substitution, 1.1g of palladium on carbon was added under nitrogen protection. Then replacing nitrogen for three times and replacing hydrogen for three times; keeping the temperature at 50-70 ℃ and continuously introducing 0.4MPa hydrogen, and stirring for reaction for 5 hours; then keeping the temperature at 130-150 ℃ and continuously introducing 0.6MPa hydrogen, and stirring for reaction for 5 hours. Stopping reaction, cooling, replacing with nitrogen for three times, taking out reaction liquid, filtering, and concentrating filtrate to obtain 111g of (+/-) -2-methyl-3-phenyl-1-propanol with gas chromatography purity of not less than 95%.
Step 2: the method comprises the following steps of (1) taking (+/-) -2-methyl-3-phenyl-1-propanol as a raw material, adding a certain amount of solvent, catalyst and phthalic anhydride, heating and raising the temperature to perform esterification reaction; after reacting for a certain time, getting (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester.
To a 1L three-necked glass bottle was added 54g of (. + -.) -2-methyl-3-phenyl-1-propanol, 53.3g of phthalic anhydride, 0.8g of triethylamine, and 300g of toluene under nitrogen. Heating to 100 ℃, and maintaining the temperature of 100-110 ℃ to stir for 10 hours to obtain a toluene solution of (+/-) -2-methyl-3-phenyl-1-propanol-phthalic monoester, wherein the toluene solution contains 107g of a target product; the purity of the liquid chromatogram is more than or equal to 95 percent.
And step 3: the method comprises the steps of taking (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester as a raw material, adding a certain amount of solvent and S- (-) -alpha-phenylethylamine, heating and reacting for a certain time to obtain (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenylethylamine salt.
Under the protection of nitrogen, 107g of (+/-) -2-methyl-3-phenyl-1-propanol-phthalic monoester and a solution (reaction solution in the previous step) consisting of 300g of toluene were added into a 1L three-necked glass bottle; 43.6g of S- (-) -alpha-phenylethylamine was further added. Heating to 110 deg.c, and stirring at 100-110 deg.c for 1 hr. Cooling to room temperature and filtering. And drying the obtained filter cake to obtain 133g of (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt.
And 4, step 4: selecting a proper type and a proper amount of solvent, and crystallizing and recrystallizing (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt to obtain (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt.
100g of (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenylethylamine salt was added to a 500L three-necked glass bottle under nitrogen protection; and 100g of tetrahydrofuran. Heating until the solid is completely dissolved; then slowly cooling to-10 ℃ under stirring, and preserving the heat for 3 hours at-10 ℃. Carrying out suction filtration, and recrystallizing the obtained filter cake once by using tetrahydrofuran with the weight ratio of 1 time; after drying the filter cake of the secondary crystallization, 33g of (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt was obtained.
And 5: the method comprises the steps of taking (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt as a raw material, adding a certain amount of solvent, catalyst and water, maintaining a certain temperature for hydrolysis reaction, and obtaining a mixture containing R- (+) -2-methyl-3-phenyl-1-propanol, phthalic acid, S- (-) -alpha-phenethylamine, solvent and water after a period of time.
Step 6: phthalic acid and S- (-) -alpha-phenylethylamine were separated and removed by a conventional chemical or physical separation method to give R- (+) -2-methyl-3-phenyl-1-propanol.
To a 3L three-necked glass bottle was added 150g of (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenylethylamine salt under a nitrogen blanket. 200g of 40% aqueous sodium hydroxide solution and 1500g of petroleum ether were added. Stirring and reacting for 30 hours at the temperature of 0-10 ℃, and washing with water to remove the disodium phthalate; the organic layer was then passed through a column containing 200g of silica gel for chromatography to remove S- (-) - α -phenylethylamine by adsorption. The filtrate was concentrated again to remove the solvent by chromatography to obtain 38g of R- (+) -2-methyl-3-phenyl-1-propanol.
Example two
Step 1: the method comprises the steps of taking alpha-methyl cinnamaldehyde as a raw material, adding a proper catalyst, and carrying out catalytic hydrogenation with hydrogen at a certain temperature and pressure to obtain (+/-) -2-methyl-3-phenyl-1-propanol.
A2L stainless steel autoclave was charged with 800g of alpha-methyl cinnamaldehyde without solvent. After nitrogen substitution, 0.8g of platinum carbon was added under nitrogen protection. Then replacing nitrogen for three times, replacing hydrogen for three times, keeping the temperature at 0-20 ℃, continuously introducing 5MPa hydrogen, and stirring for reacting for 72 hours. Stopping the reaction, replacing the reaction solution with nitrogen for three times, taking out the reaction solution, filtering, and concentrating the filtrate to obtain 813g of (+/-) -2-methyl-3-phenyl-1-propanol with the purity of the gas chromatography being more than or equal to 99 percent.
Step 2: the method comprises the following steps of (1) taking (+/-) -2-methyl-3-phenyl-1-propanol as a raw material, adding a certain amount of solvent, catalyst and phthalic anhydride, heating and raising the temperature to perform esterification reaction; after reacting for a certain time, getting (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester.
To a 1L three-necked glass bottle was added 54g of (. + -.) -2-methyl-3-phenyl-1-propanol, 64g of phthalic anhydride, 1.38g of pyridine, and 540g of tetrahydrofuran under nitrogen. The reaction was stirred for 30 hours at 0 ℃ to 20 ℃ and concentrated to give 122g of crude product. Then using ethyl acetate as solvent to crystallize, obtaining 103g of (+/-) -2-methyl-3-phenyl-1-propanol-phthalic monoester, wherein the purity of liquid chromatogram is more than or equal to 98 percent.
And step 3: the method comprises the steps of taking (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester as a raw material, adding a certain amount of solvent and S- (-) -alpha-phenylethylamine, heating and reacting for a certain time to obtain (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenylethylamine salt.
To a 1L three-necked glass bottle was added 100g of (. + -.) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester, 132g of S- (-) -alpha-phenylethylamine, and 50g of tetrahydrofuran under a nitrogen blanket. Heating to 50 deg.C, maintaining at 50-55 deg.C, stirring, reacting for 5 hr, cooling to room temperature, and vacuum filtering. The obtained filter cake is dried to obtain 135g of (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt.
And 4, step 4: selecting a proper type and a proper amount of solvent, and crystallizing and recrystallizing (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt to obtain (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt.
100g of (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenylethylamine salt was added to a 1000L three-necked glass bottle under nitrogen protection; and 100g of ethyl acetate/300 g of a toluene mixed solvent. Heating until the solid is completely dissolved; then slowly cooling to-10 ℃ under stirring, and preserving the heat for 3 hours at-10 ℃. Performing suction filtration, and recrystallizing the obtained filter cake once again by using ethyl acetate/toluene mixed solution with the weight ratio of 3 times; after drying the filter cake of the secondary crystallization, 35g of (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt was obtained.
And 5: the method comprises the steps of taking (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt as a raw material, adding a certain amount of solvent, catalyst and water, maintaining a certain temperature for hydrolysis reaction, and obtaining a mixture containing R- (+) -2-methyl-3-phenyl-1-propanol, phthalic acid, S- (-) -alpha-phenethylamine, solvent and water after a period of time.
Step 6: phthalic acid and S- (-) -alpha-phenylethylamine were separated and removed by a conventional chemical or physical separation method to give R- (+) 2-methyl-3-phenyl-1-propanol.
150g of (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenylethylamine salt was added to a 1L three-necked glass bottle under a nitrogen atmosphere. Then, 50g of 31% hydrochloric acid, 20g of water and 500g of toluene were added thereto, and the temperature was raised to 105 ℃. After stirring and reacting for 3 hours at the temperature of 100-110 ℃, washing with water to remove hydrochloride of S- (-) -alpha-phenylethylamine; the organic layer was washed twice with 200g of 15% sodium hydroxide solution and 200g of 5% sodium hydroxide solution, respectively, to remove phthalic acid. Finally, the organic layer was washed with water to neutrality, and then concentrated to remove toluene, to obtain 36g of R- (+) -2-methyl-3-phenyl-1-propanol.
EXAMPLE III
Step 1: the method comprises the steps of taking alpha-methyl cinnamaldehyde as a raw material, adding a proper catalyst, and carrying out catalytic hydrogenation with hydrogen at a certain temperature and pressure to obtain (+/-) -2-methyl-3-phenyl-1-propanol.
A2L stainless steel autoclave was charged with 55g of α -methylcinnamaldehyde and 550g of tetrahydrofuran, and after nitrogen substitution, 22.0g of Raney nickel was added under nitrogen protection. Then replacing nitrogen for three times, replacing hydrogen for three times, keeping the temperature at 50-70 ℃, continuously introducing 0.1MPa hydrogen, and stirring for reacting for 20 hours. Stopping reaction, cooling, replacing with nitrogen for three times, taking out reaction liquid, filtering, concentrating filtrate to obtain 56g of (+/-) -2-methyl-3-phenyl-1-propanol, wherein the purity of the gas chromatography is more than or equal to 97%.
Step 2: the method comprises the following steps of (1) taking (+/-) -2-methyl-3-phenyl-1-propanol as a raw material, adding a certain amount of solvent, catalyst and phthalic anhydride, heating and raising the temperature to perform esterification reaction; after reacting for a certain time, getting (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester.
To a 500L three-necked glass bottle was added 54g of (. + -.) -2-methyl-3-phenyl-1-propanol, 58g of phthalic anhydride, 0.38g of 2, 6-lutidine, and 54g of xylene under nitrogen. Heating to 130 ℃, keeping the temperature between 120 ℃ and 130 ℃, stirring for reaction for 5 hours, and concentrating to obtain 115g of crude product. Then ethyl acetate is used as a solvent for crystallization, 102g of (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester is obtained, and the purity of liquid chromatography is more than or equal to 98 percent.
And step 3: the method comprises the steps of taking (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester as a raw material, adding a certain amount of solvent and S- (-) -alpha-phenylethylamine, heating and reacting for a certain time to obtain (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenylethylamine salt.
To a 2L three-necked glass bottle was added 100g of (. + -.) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester, 44g of S- (-) -alpha-phenylethylamine, and 1000g of petroleum ether under a nitrogen blanket. Cooling to 5 ℃, keeping the temperature of 0-10 ℃, stirring and reacting for 20 hours, and then carrying out suction filtration. And drying the obtained filter cake to obtain 138g of (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt.
And 4, step 4: selecting a proper type and a proper amount of solvent, and crystallizing and recrystallizing (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt to obtain (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt.
100g of (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenylethylamine salt was added to a 2000L three-necked glass bottle under nitrogen protection; and 300g of isopropanol/700 g of petroleum ether mixed solvent. Heating until the solid is completely dissolved; then slowly cooling to-10 ℃ under stirring, and preserving the heat for 3 hours at-10 ℃. Performing suction filtration, and recrystallizing the obtained filter cake once by using isopropanol/petroleum ether mixed solution with the weight ratio of 10 times; the filter cake from the second crystallization was dried to obtain 41g of (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt.
And 5: the method comprises the steps of taking (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt as a raw material, adding a certain amount of solvent, catalyst and water, maintaining a certain temperature for hydrolysis reaction, and obtaining a mixture containing R- (+) -2-methyl-3-phenyl-1-propanol, phthalic acid, S- (-) -alpha-phenethylamine, solvent and water after a period of time.
Step 6: phthalic acid and S- (-) -alpha-phenylethylamine were separated and removed by a conventional chemical or physical separation method to give R- (+) 2-methyl-3-phenyl-1-propanol.
150g of (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenylethylamine salt was added to a 1L three-necked glass bottle under a nitrogen atmosphere. 200g of 10% sulfuric acid and 75g of methanol were then added. Stirring and reacting for 10 hours at the temperature of between 30 and 40 ℃, and then carrying out steam distillation on the reaction liquid. Because the sulfate and the phthalic acid of the S- (-) -alpha-phenylethylamine cannot be evaporated; after the distillate was separated, the organic layer was R- (+) 2-methyl-3-phenyl-1-propanol (40 g).
Claims (9)
1. A method for synthesizing chiral compound R- (+) -2-methyl-3-phenyl-1-propanol is characterized in that the following processes of synthesis, separation and purification are adopted:
step 1: carrying out catalytic hydrogenation on alpha-methyl cinnamaldehyde serving as a raw material and hydrogen to obtain (+/-) -2-methyl-3-phenyl-1-propanol; the reaction formula is as follows:
step 2: taking (+/-) -2-methyl-3-phenyl-1-propanol as a raw material, and carrying out esterification reaction with phthalic anhydride to obtain (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester; the reaction formula is as follows:
and step 3: the method comprises the following steps of (1) carrying out acid-base salt forming reaction on (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester serving as a raw material and S- (-) -alpha-phenylethylamine to obtain (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenylethylamine salt; the reaction formula is as follows:
and 4, step 4: purifying and separating (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt through crystallization and recrystallization to obtain (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt; the reaction formula is as follows:
and 5: carrying out hydrolysis reaction by using (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt as a raw material to obtain a mixture containing R- (+) -2-methyl-3-phenyl-1-propanol, phthalic acid and S- (-) -alpha-phenethylamine,the reaction formula is as follows:
step 6: phthalic acid and S- (-) -alpha-phenylethylamine were separated and removed by a conventional chemical or physical separation method to give R- (+) 2-methyl-3-phenyl-1-propanol.
2. The method for synthesizing the chiral compound R- (+) -2-methyl-3-phenyl-1-propanol according to claim 1, wherein the method comprises the following steps:
step 1: using alpha-methyl cinnamaldehyde as raw material, adding catalyst, carrying out catalytic hydrogenation with hydrogen at a certain temperature and pressure to obtain (+/-) -2-methyl-3-phenyl-1-propanol,
the catalyst in the step 1 is one or a mixture of more of palladium carbon, Raney nickel, platinum carbon, ruthenium carbon and rhodium carbon, the dosage of the catalyst is 0.1 to 40 percent of the weight ratio of the raw materials,
the reaction temperature in the step 1 is 0 ℃ to 150 ℃,
the reaction pressure in the step 1 is 0.1MPa-5 MPa;
step 2: the method comprises the following steps of (1) taking (+/-) -2-methyl-3-phenyl-1-propanol as a raw material, adding a certain amount of solvent, catalyst and phthalic anhydride, heating and raising the temperature to perform esterification reaction; after reacting for a certain time, obtaining (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester,
the solvent in the step 2 is one or more of toluene, tetrahydrofuran, methyl cyclopentyl ether, methyl tert-butyl ether, petroleum ether and cyclohexane, and the dosage of the solvent is 100-1000% of the weight ratio of the raw materials;
the catalyst in the step 2 is one or more of pyridine, triethylamine and 2, 6-dimethylpyridine;
the (+/-) -2-methyl-3-phenyl-1-propanol in the step 2: phthalic anhydride: the molar ratio of the catalyst = 1: 1.0-1.2: 0.01-0.05,
the reaction temperature in the step 2 is 0-130 ℃, and the reaction time is 5-30 hours;
and step 3: taking (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester as a raw material, adding a certain amount of solvent and S- (-) -alpha-phenylethylamine, heating and reacting for a certain time to obtain (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenylethylamine salt,
the solvent in the step 3 is one or more of toluene, tetrahydrofuran, methyl cyclopentyl ether, methyl tert-butyl ether, petroleum ether, cyclohexane and ethyl acetate, and the dosage of the solvent is 50-1000% of the weight ratio of the raw materials;
the reaction temperature in the step 3 is 0-110 ℃, the reaction time is 1-20 hours,
the (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester in step 3: s- (-) - α -phenylethylamine at a molar ratio = 1: 1-3;
and 4, step 4: selecting a proper amount of solvent, crystallizing and recrystallizing (+/-) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt to obtain (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt,
the solvent in the step 4 is one or a mixture of water, methanol, ethanol, isopropanol, toluene, tetrahydrofuran, methyl cyclopentyl ether, petroleum ether, cyclohexane and ethyl acetate, and the dosage of the solvent is 100-1000% of the weight ratio of the raw materials;
and 5: taking (+) -2-methyl-3-phenyl-1-propanol-phthalic acid monoester-S- (-) -alpha-phenethylamine salt as a raw material, adding a certain amount of solvent, catalyst and water, maintaining a certain temperature for hydrolysis reaction, and obtaining a mixture containing R- (+) -2-methyl-3-phenyl-1-propanol, phthalic acid, S- (-) -alpha-phenethylamine, solvent and water after a period of time,
the solvent in the step 5 is one or a mixture of more of ethanol, isopropanol, toluene, tetrahydrofuran, methyl cyclopentyl ether, petroleum ether and cyclohexane, the dosage of the solvent is 50-1000% of the weight ratio of the raw materials,
the catalyst in the step 5 is one or a mixture of more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide and ammonia water, 100-200% of the raw materials by mass ratio is required to be added when the acidic catalyst is used, 200-300% of the raw materials by mass ratio is required to be added when the alkaline catalyst is used,
the hydrolysis reaction temperature in the step 5 is 0-110 ℃, and the reaction time is 3-30 hours;
step 6: phthalic acid and S- (-) -alpha-phenylethylamine were separated and removed by a conventional chemical or physical separation method to give R- (+) 2-methyl-3-phenyl-1-propanol.
3. The process of claim 1 or 2 for the synthesis of the chiral compound R- (+) -2-methyl-3-phenyl-1-propanol, characterized by:
the raw material (+/-) -2-methyl-3-phenyl-1-propanol of the step 2 is the product of the step 1; or the following steps: after a part of S- (-) -2-methyl-3-phenyl-1-propanol is separated and extracted by using (+/-) -2-methyl-3-phenyl-1-propanol as a raw material, the mother liquor separated and extracted is recycled, and the (+/-) -2-methyl-3-phenyl-1-propanol is obtained and recycled.
4. The process of claim 1 or 2 for the synthesis of the chiral compound R- (+) -2-methyl-3-phenyl-1-propanol, characterized by:
the raw material (+/-) -2-methyl-3-phenyl-1-propanol of the step 2 is the product of the step 1; or the following steps: the method comprises the steps of taking (+/-) -2-methyl-3-phenyl-1-propanol as a raw material, separating and extracting a part of R- (+) -2-methyl-3-phenyl-1-propanol, then recycling mother liquor obtained by separation and extraction, and obtaining the (+/-) -2-methyl-3-phenyl-1-propanol.
5. The process of claim 1 or 2 for the synthesis of the chiral compound R- (+) -2-methyl-3-phenyl-1-propanol, characterized by: the conventional chemical separation method in the step 6 is to add acid or alkali into the hydrolyzed mixture to enable phthalic acid or S- (-) -alpha-phenylethylamine to generate salts, separate out the salts from the organic solvent, and filter and remove the salts; or dissolving salt in acid solution or alkali solution, and washing to remove; or steam distillation is used to distill off the target product, but the salts of phthalic acid or S- (-) -alpha-phenylethylamine cannot.
6. The process of claim 1 or 2 for the synthesis of the chiral compound R- (+) -2-methyl-3-phenyl-1-propanol, characterized by: the physical separation method in step 6 is to adsorb and filter the hydrolyzed mixture by using a polar adsorbent, or to perform column chromatography so that phthalic acid or S- (-) - α -phenylethylamine is adsorbed and removed.
7. The method for synthesizing chiral compound R- (+) -2-methyl-3-phenyl-1-propanol according to claim 2, which is characterized in that: in the reaction process of the step 1, no reaction solvent is added; or adding solvent which does not participate in the reaction, wherein the solvent is one or a mixture of water, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, cyclohexane and petroleum ether, and the dosage of the solvent is not more than 1000 percent of the weight of the raw materials.
8. The method for synthesizing chiral compound R- (+) -2-methyl-3-phenyl-1-propanol according to claim 2, which is characterized in that: and (3) purifying the (+/-) -2-methyl-3-phenyl-1-propanol-phthalic monoester product obtained in the step (2) to be fed into the next step, wherein the purification treatment process comprises concentration, crystallization and filtration.
9. The method for synthesizing chiral compound R- (+) -2-methyl-3-phenyl-1-propanol according to claim 2, which is characterized in that: the solvent dosage in the step 3 is brought from the solution of the raw materials or is newly added or supplemented with enough quantity when the reaction is carried out.
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| A molecular modelling approach to rationalize the stereochemical outcome of theBurkholderia cepacialipase-catalyzed transesterification of aromatic primary alcohols with vinyl esters with different chain lengths in chloroform;Giulio Vistoli et al.;《Tetrahedron:Asymmetry》;20090903;第20卷;第1833-1836页 * |
| Determination of the Absolute Configuration ofβ‑Chiral Primary Alcohols Using the Competing Enantioselective Conversion Method;Alexander S. Burns et al.;《Org. Lett.》;20170516;第19卷;第2953-2956页 * |
| Enantioselective Synthesis, Configurational Stability, and Reactivity of Lithium α-tert-Butylsulfonyl Carbanion Salts;Roland Scholz et al.;《Eur. J. Org. Chem.》;20100715;第4588-4616页 * |
| Enzyme recycling does not influence the enantioselectivity of the Pseudomonas cepacialipase-catalyzed acylation of a racemic alcohol in organic solvents;S. Casati et al.;《Biotechnology Techniques》;19971231;第11卷(第2期);第81-83页 * |
| 假单胞菌脂肪酶手性拆分研究进展;季青春;《化工进展》;20101231;第29卷(第4期);第722-729页 * |
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