CN1370767A - Synthesis of optically pure R-and S-2-hydroxyl-4-aryl butyric acid - Google Patents
Synthesis of optically pure R-and S-2-hydroxyl-4-aryl butyric acid Download PDFInfo
- Publication number
- CN1370767A CN1370767A CN 01107195 CN01107195A CN1370767A CN 1370767 A CN1370767 A CN 1370767A CN 01107195 CN01107195 CN 01107195 CN 01107195 A CN01107195 A CN 01107195A CN 1370767 A CN1370767 A CN 1370767A
- Authority
- CN
- China
- Prior art keywords
- acid
- hydroxyl
- butyric acid
- aryl butyric
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a process of the synthesis of optically pure R-and S-2-hydroxyl-4-aryl butyric acid. Through hydroxy protected reaction of dewatering to form anhydride and further reaction of, L- or D-malic acid as feedstock R- or S-2-hydroxyl-4-oxy-4-aryl butyric acid or R- or S-2-acetoxy 4-oxy-4-aryl butyric acid is prepared. R- or S-2-hydroxyl-4-oxy-4-aryl butyric acid is reduced and hydrolyzed to obtain R- or S-2-hydroxyl-4-aryl butyric acid; or R- or S-2 acetoxyl-4-oxy-4-aryl butyric acid is reduced, hydrogenolyzed and hydrolyzed to obtain R- or S-2-hydroxyl-4-aryl butyric acid. The present invention is simple and general, has high selectivity, high yield, low cost and is easy to realize in industry.
Description
The invention belongs to technical field of organic synthesis, particularly about the synthetic method of optical purity R-and S-2-hydroxyl-4-aryl butyric acid.
Optical purity R-and S-2-hydroxyl-4-aryl butyric acid are the non-natural alpha hydroxy acid of a class, such alcohol acid and ester thereof or have different physiologically actives or synthetic have the medicine of physiologically active, an important intermediate of agricultural chemicals.As R-and S-2-hydroxy-4-phenyl ethyl butyrate is the important intermediate of nervous plain converting enzyme inhibitor (ACEI) class treatment hypertension of synthetic vessel and congestive heart failure (CHF) medicine.Especially for synthesizing of enalapril (enalapril), Zinadril Briem (benazepril), delapril (delapril), quinapril (quinapril), lisinopril (lisinopril), Yipingshu (cilazapril), Ramipril (ramipril), moexipril (moexipril) and angiotensin-convertion enzyme inhibitors (ACEI) such as imidapril, spirapril, indolapril and alacepril.
The 2-hydroxy-4-phenyl butyric acid of Japanese Patent (JP04200391) report in 1992 racemization splits through lipase and can get R-2-hydroxy-4-phenyl butyric acid and S-2-hydroxy-4-phenyl butyric acid, yield 19%, and optical purity reaches 97%.Nineteen ninety-five Chadha, people such as A. be at Tetrahedron Lett.1995, and 6 (3), the 2-hydroxy-4-phenyl butyric acid of also reporting racemization on 651 pages splits through lipase and can get R-2-hydroxy-4-phenyl butyric acid and S-2-hydroxyl 4-phenylbutyric acid, and optical purity reaches 99%.1992, Japanese Patent (JP05335886) uses the enzyme Leuconostoc that is produced by L.Dextranicum IFO 27310 in the presence of NADPH, in phosphate buffered saline buffer, asymmetric reduction 2-oxo-4-phenylbutyric acid is a R-2-hydroxy-4-phenyl butyric acid, yield 68%.The Japanese Patent in the same year (JP0471494) is a R-2-hydroxy-4-phenyl butyric acid with enzyme process reductase 12-oxo 4-phenylbutyric acid also, and optical purity reaches 100%, yield 95%.1993, world patent (WO9313215) was a R-2-hydroxy-4-phenyl butyric acid with serum lactic dehydrogenase reductase 12-oxo-4-phenylbutyric acid, and optical purity reaches 97%.The Japanese Patent in the same year (JP05192190) gets R-2-hydroxy-4-phenyl butyric acid with the 2-hydroxy-4-phenyl butyronitrile of microbial hydrolytic racemization, and optical purity reaches 95%.European patent in 1989 (EP329156) splits the 2-hydroxy-4-phenyl butyric acid of racemization respectively with optical purity 1-p-methylphenyl ethamine and N-hydroxyethylbenzene ethamine, yield 61%, and optical purity reaches 99%.The 2-hydroxy-4-phenyl butyric acid that Spain's patent (ES2019241) in 1991 and Spain's patent (ES2035800) in 1993 all use cheap paraxin intermediate to split racemization gets R-2-hydroxy-4-phenyl butyric acid and S-2-hydroxy-4-phenyl butyric acid, but this method is difficult to repeat.2000, Backvall, people such as J-E be at Org.Lett.2000, and 2 (8), reported with chirality ruthenium complex kinetic resolution Alpha-hydroxy acid esters on 1037 pages, but this method is not suitable for the fractionation of 2-hydroxy-4-phenyl methyl-butyrate its optical purity only 18%.1987, Yamamoto, people such as H. are at J.Med.Chem.1987,30 (11), 1984 pages go up report with 2-oxo-4-phenyl-3-butenoic acid make chirality the Meng ester through the asymmetric synthetic R-2-hydroxy-4-phenyl butyric acid of reduction of leading of palladium carbon, three step total recoverys 25%, but the Meng, alcohol was more expensive.1993, Pedrosa, people such as R. be at Tetrahedron Lett.1993, and 34 (51), also report with the synthetic R-2-hydroxy-4-phenyl butyric acid of chiral induction on 8325 pages, yield 64%, optical purity reaches 98%.In the same year, the Blaser of vapour Bagong department, people such as H.U. are at Stud.Surf.Sci.Catal.1993, and 78,139 pages are gone up report is R-2-hydroxy-4-phenyl ethyl butyrate with heterogeneous catalysis hydro-reduction 2-oxo-4-phenylbutyrate, and optical purity only reaches 80%.Japanese Patent in 1992 (JP0418050) is in the presence of the L-proline(Pro), get R-2-hydroxy-4-phenyl-3-butenoic acid with sodium borohydride reduction 2-oxo-4-phenyl-3-butenoic acid, yield 73%, optical purity reaches 94%, and further shortening gets R-2-hydroxy-4-phenyl butyric acid.
The purpose of this invention is to provide a kind of simple general-purpose, simple operation, the selectivity height, yield is good, and cost is low, is easy to the synthetic method of industrialized optical purity R-and S-2-hydroxyl-4-aryl butyric acid.
The objective of the invention is to realize by the following technical solutions:
With L-or D-oxysuccinic acid is chiral source, through following step:
(a) carry out hydroxyl protection and be dehydrated into anhydride reactant with Acetyl Chloride 98Min. or diacetyl oxide, make S-or R-2-acetoxyl group Succinic anhydried (I);
(b) with I and benzene or other aromatic compounds carry out Fred-Kerafyrm now (Friedel-Crafts) select acylation reaction, S-or R-2-hydroxyl-4-oxo-4-aryl butyric acid (II) or S-or R-2-acetoxyl group-4-oxo-4-aryl butyric acid (III);
(c) II gets S-or R-2-hydroxyl-4-aryl butyric acid (IV) through the reduction hydrogenolysis;
Or (d) III through the reduction hydrogenolysis, S-or R-2-acetoxyl group-4-aryl butyric acid (V);
(e) V gets S-or R-2-hydroxyl-4-aryl butyric acid (IV) through acid or basic hydrolysis or reduction hydrogenolysis;
Or (f) III through acid or basic hydrolysis, S-or R-2-hydroxyl-4-oxo-4-aryl butyric acid (II).
In the such scheme, other aromatic compounds refer to benzene replacement or unsubstituted, naphthalene, furans, thiophene, pyrroles, and wherein substituting group is the alkyl of C1～C10, alkoxyl group, hydroxyl, halogen (F, Cl, Br, I), replacement or unsubstituted thin base, replacement or the unsubstituted amino of C1～C10.
In the such scheme; the protection of hydroxyl and be dehydrated into anhydride reactant and be: with L-or D-oxysuccinic acid is chiral source; with the Acetyl Chloride 98Min. of 1～20 times of mole or a kind of reaction in the acetic anhydride; temperature of reaction is 15～120 ℃; reaction times is 0.5～48 hour; react in a kind of or miscellany between them in the Acetyl Chloride 98Min. of 1～100mL/g-L-or D-oxysuccinic acid, acetic anhydride, acetate, tetrahydrofuran (THF), dioxane, ethyl acetate, isopropyl ether, obtain I.
When I and benzene or other aromatic compounds carry out the selectively acylating reaction; catalyzer is the Phosphorus Oxychloride of 0.9～15 times of weight of I; polyphosphoric acid and Lewis acid (Lewis acid) are aluminum trichloride (anhydrous); FERRIC CHLORIDE ANHYDROUS; Zinc Chloride Anhydrous; anhydrous stannic chloride; anhydrous titanium tetrachloride; the consumption of benzene or aromatic compound is 0.5～25 times of weight of I; temperature of reaction is 0～100 ℃; reaction times is 0.5～48 hour; use benzene; oil of mirbane; Nitromethane 99Min.; methylene dichloride; trichloromethane; 1; a kind of or mixture between them in the 2-ethylene dichloride is a solvent, and solvent load is 4～20mL/g-I.
When II or III reduce hydrogenolysis, use catalytic hydrogenation, catalyzer is Ni-H
2, 5% or 10% Pd/C-H
2, solvent is with hydrochloric acid, acetic acid, formic acid, phosphoric acid, sulfuric acid or the water of 2～100 times of weight and the mixture between them; Catalyst levels was 0.1～20% of a substrate, and pressure is 0.1～5MPa, in 15～60 ℃ of reactions 2～48 hours; Or under the hydrochloric acid condition, reduce hydrogenolysis with zinc amalgam, the aluminium amalgam of 5～15 times of weight of substrate; Or earlier be reduced to S-or R-2 with the sodium borohydride (potassium) of 0.5～10 times of amount or Lithium Aluminium Hydride etc., and 4-dihydroxyl-4-aryl butyric acid (VI) or S-or R-2-acetoxyl group-4-hydroxyl-4-aryl butyric acid (VII), VI or VII get IV or V through above-mentioned catalytic hydrogenation again.
III and V be through acid or basic hydrolysis, refers under the effect of the mineral acid of 1～10 times of amount or organic acid, mineral alkali or organic bases, in 0～100 ℃ of reaction 0.5～48 hour.
Characteristics of the present invention are: with L-or D-oxysuccinic acid (2-hydroxy-butanedioic acid) is chiral source, uses commonly used and inexpensive reagent, by the reaction of Friedel-Crafts selectively acylating, need not split, and has synthesized to specificity S-or R-2-hydroxyl-4-aryl butyric acid.Simple general-purpose of the present invention, simple operation, the selectivity height, yield is good, and cost is low, is easy to industrialization, and optical purity of products is more than or equal to 99%, and chemical purity is more than or equal to 98%.
Be embodiments of the invention below:
Embodiment one
100 gram D-oxysuccinic acid are suspended in 10000 milliliters of acetic anhydrides,, boil off solvent in 15 ℃ of reactions 48 hours, add 95 gram benzene, add 930 gram FERRIC CHLORIDE ANHYDROUS, in batches in 50 ℃ of reactions 24 hours, in 3 kilograms of ice of impouring and the 1000 milliliters of hydrochloric acid, divide three extractions with 2.5 liters of ethyl acetate, united extraction liquid is washed with saturated common salt, anhydrous sodium sulfate drying, filter, boil off solvent, get R-2-hydroxyl-4-oxo-4-phenylbutyric acid.
Embodiment two
100 gram D-oxysuccinic acid are dissolved in 100 milliliters of Acetyl Chloride 98Min.s and the 3000 milliliters of tetrahydrofuran (THF)s,, boil off solvent in 65 ℃ of reactions 24 hours, add 1500 milliliters of benzene, the frozen water cooling adds 106 gram aluminum trichloride (anhydrous)s down in batches, stirring reaction is 48 hours in the ice-water bath, in 10 kilograms of ice of impouring and the 100 milliliters of hydrochloric acid, divides three extractions with 2.5 liters of ethyl acetate, united extraction liquid, with the saturated common salt washing, anhydrous sodium sulfate drying filters, boil off solvent, get R-2-acetoxyl group-4-oxo 4-phenylbutyric acid.
Embodiment three
100 gram L MALIC ACIDs are suspended in 5000 milliliters of acetic anhydrides, and back flow reaction 0.5 hour boils off solvent, add 2950 milliliters of benzene, disposable adding 1770 gram polyphosphoric acid are warming up to 100 ℃ of reactions 0.5 hour, in 3 kilograms of ice of impouring and the 500 milliliters of hydrochloric acid, divide three extractions with 2.5 liters of ethyl acetate, close extracting solution, wash with saturated common salt, anhydrous sodium sulfate drying, filter, boil off solvent, get S-2-hydroxyl-4-oxo-4-phenylbutyric acid.
Embodiment four
90 gram R-2-hydroxyl-4-oxo-4-phenylbutyric acids (embodiment one) are dissolved in 150 milliliters of Glacial acetic acid, add 0.09 gram, 10% palladium-carbon catalyst, in 5MPa, 15 ℃ of hydrogenations 2 hours filter, and boil off solvent, R-2-hydroxy-4-phenyl butyric acid.
Embodiment five
90 gram S-2-hydroxyl-4-oxo-4-phenylbutyric acids (embodiment three) are dissolved in the hydrochloric acid of 7500 milliliters of 0.1N, add 18 grams, 5% palladium-carbon catalyst, in 0.1MPa, 40 ℃ of hydrogenations 48 hours filter, and boil off solvent, S-2-hydroxy-4-phenyl butyric acid.
Embodiment six
90 gram R-2-acetoxyl group-4-oxo-4-phenylbutyric acids (embodiment two) are dissolved in 3800 milliliters of Glacial acetic acid, add 7.5 grams, 10% palladium-carbon catalyst, in 1MPa, hydrogenation is 25 hours under the room temperature, filter, boil off solvent, get R-2-acetoxyl group-4-phenylbutyric acid.
Embodiment seven
30 gram R-2-acetoxyl group-4-phenylbutyric acids (embodiment six) are dissolved in 300 milliliter 10% the sodium hydroxide solution, in ice-water bath, stir hydrolysis 48 hours, adding hydrochloric acid transfers pH to acid, with ethyl acetate extraction three times, united extraction liquid is washed to neutrality with saturated common salt, anhydrous sodium sulfate drying, filter, boil off solvent, get R-2-hydroxy-4-phenyl butyric acid.
Embodiment eight
30 gram R-2-acetoxyl group-4-phenylbutyric acids (embodiment six) are dissolved in the solution of 3 milliliters of concentrated hydrochloric acids and 30 ml waters, back hydrolysis 0.5 hour, with ethyl acetate extraction three times, united extraction liquid, be washed to neutrality with saturated common salt, anhydrous sodium sulfate drying filters, boil off solvent, get R-2-hydroxy-4-phenyl butyric acid.
Embodiment nine
90 gram R-2-acetoxyl group-4-oxo-4-phenylbutyric acids (embodiment two) are dissolved in 150 milliliters of triethylamines and 150 ml waters, in 60 ℃ of reactions 24 hours, adding hydrochloric acid transfers pH to acid, with ethyl acetate extraction three times, united extraction liquid is washed to neutrality with saturated common salt, anhydrous sodium sulfate drying, filter, boil off solvent, get R-2-hydroxyl-4-oxo-4-phenylbutyric acid.
Embodiment ten
90 gram R-2-hydroxyl-4-oxo-4-phenylbutyric acids are dissolved in 1500 milliliters of ethanol, add 900 gram sodium borohydrides in stirring at room reaction 24 hours, add hydrochloric acid and transfer pH, use ethyl acetate extraction three times, united extraction liquid to acid, be washed to neutrality with saturated common salt, anhydrous sodium sulfate drying filters, and boils off solvent, get (2R)-2,4-dihydroxyl-4-phenylbutyric acid.
Embodiment 11
With 80 gram (2R)-2,4-dihydroxyl-4-phenylbutyric acid (embodiment ten) is dissolved in 1500 milliliters of Glacial acetic acid, adds 8 grams, 10% palladium-carbon catalyst, and in 0.5MPa, 25 ℃ of hydrogenations 2 hours filter, and boil off solvent, R-2-hydroxy-4-phenyl butyric acid.
Embodiment 12
30 gram R-2-acetoxyl group-4-phenylbutyric acids are dissolved in 200 milliliters of tetrahydrofuran (THF)s, add 15 gram Lithium Aluminium Hydrides in stirring at room reaction 2 hours, adding hydrochloric acid transfers pH to acid, with ethyl acetate extraction three times, united extraction liquid is washed to neutrality with saturated common salt, anhydrous sodium sulfate drying, filter, boil off solvent, get (2R)-2-acetoxyl group-4-hydroxy-4-phenyl butyric acid.
Embodiment 13
20 gram (2R) 2-acetoxyl group-4-hydroxy-4-phenyl butyric acid are dissolved in 50 milliliters of acetic anhydrides, back flow reaction 4 hours, the pressure reducing and steaming solvent, add 20 milliliters of hydrochloric acid and 2 grams, 10% palladium-carbon catalyst, in 0.1MPa, 40 ℃, logical hydrogen hydrogenation 15 hours, filter, boil off solvent, get R-2-hydroxy-4-phenyl butyric acid.
Embodiment 14
100 gram D-oxysuccinic acid are suspended in 8000 milliliters of acetic anhydrides,, boil off solvent in 15 ℃ of reactions 36 hours, add 78 gram furans, add 930 gram FERRIC CHLORIDE ANHYDROUS, in batches in 50 ℃ of reactions 24 hours, in 3 kilograms of ice of impouring and the 1000 milliliters of hydrochloric acid, divide three extractions with 2.5 liters of ethyl acetate, united extraction liquid is washed with saturated common salt, anhydrous sodium sulfate drying, filter, boil off solvent, get R-2-hydroxyl-4-oxo-4-(2-furyl) butyric acid.
Embodiment 15
100 gram D-oxysuccinic acid are suspended in 1000 milliliters of Acetyl Chloride 98Min.s,, boil off solvent in 85 ℃ of reactions 15 hours, add 2500 gram naphthalene and 5000 milliliters of Nitromethane 99Min.s, add 2900 gram anhydrous stannic chlorides, in batches in 100 ℃ of reactions 40 hours, in 5 kilograms of ice of impouring and the 1500 milliliters of hydrochloric acid, divide three extractions with 3.5 liters of ethyl acetate, united extraction liquid is washed with saturated common salt, anhydrous sodium sulfate drying, filter, boil off solvent, get R-2-hydroxyl-4-oxo-4-(1-naphthyl) butyric acid.
Embodiment 16
100 gram D-oxysuccinic acid are suspended in 200 milliliters of acetic anhydrides and the 200 milliliters of anhydrous isopropyl ethers, and back flow reaction 8 hours boils off solvent, add 1500 gram methyl-phenoxides, add the anhydrous zinc dichloride of 700 grams, in batches in 100 ℃ of reactions 24 hours, in 3 kilograms of ice of impouring and the 1000 milliliters of hydrochloric acid, divide three extractions with 2.5 liters of ethyl acetate, united extraction liquid is washed with saturated common salt, anhydrous sodium sulfate drying, filter, boil off solvent, get R-2-hydroxyl-4-oxo-4-(4-methoxyl group) phenylbutyric acid.
Embodiment 17
100 gram D-oxysuccinic acid are suspended in 5000 milliliters of acetic anhydrides, and back flow reaction 2 hours boils off solvent, add 600 gram Acetanilides and 300 milliliter 1, the 2-ethylene dichloride adds the anhydrous titanium tetrachloride of 700 grams in batches, in 0 ℃ of reaction 48 hours, in 3 kilograms of ice of impouring and the 1000 milliliters of hydrochloric acid, divide three extractions with 2.5 liters of ethyl acetate, united extraction liquid, with the saturated common salt washing, anhydrous true sour sodium drying is filtered, boil off solvent, get R-2-hydroxyl-4-oxo-4-(4-kharophen) phenylbutyric acid.
Embodiment 18
100 gram D-oxysuccinic acid are suspended in 5000 milliliters of acetic anhydrides, and back flow reaction 2 hours boils off solvent, add 2950 gram dodecylbenzenes, add 1500 gram aluminum trichloride (anhydrous)s, in 25 ℃ of reactions 48 hours, in 3 kilograms of ice of impouring and the 1000 milliliters of hydrochloric acid in batches, divide three extractions with 2.5 liters of ethyl acetate, united extraction liquid with the saturated common salt washing, is transferred about pH to 9 with saturated sodium bicarbonate, use water extraction, combining water layer transfers pH to acid, divides three extractions with 1 liter of ethyl acetate again, united extraction liquid, with the saturated common salt washing, anhydrous sodium sulfate drying filters, boil off solvent, get R-2-hydroxyl-4-oxo-4-(4-dodecyl) phenylbutyric acid.
Embodiment 19
50 gram R-2-hydroxyl-4-oxo-4-(2-furyl) butyric acid (embodiment 14) are dissolved in 5000 milliliter of 1% hydrochloric acid, add 5 grams, 10% palladium-carbon catalyst, in 2MPa, finish at 40 ℃ of following hydrogenations, filter, boil off solvent, get R-2-hydroxyl-4-(2-furyl) butyric acid.
Embodiment 20
60 gram R-2-hydroxyl-4-oxo-4-(1-naphthyl) butyric acid (embodiment 15) are dissolved in 5000 milliliter of 1% sulfuric acid, add 12 grams, 10% palladium-carbon catalyst, in 0.1MPa, finish at 60 ℃ of following hydrogenations, filter, boil off solvent, get R-2-hydroxyl-4-(1-naphthyl) butyric acid.
Embodiment 21
50 gram R-2-hydroxyl-4-oxo-4-(4-methoxyl group) phenylbutyric acids (embodiment 16) are dissolved in 2500 milliliters of Glacial acetic acid, add 5 grams, 10% palladium-carbon catalyst, in 2MPa, the room temperature hydrogenation finishes, filter, boil off solvent, get R-2-hydroxyl-4-(4-methoxyl group) phenylbutyric acid.
Embodiment 22
50 gram R-2-hydroxyl-4-oxo-4-(4-kharophen) phenylbutyric acids (embodiment 17) are dissolved in 2500 milliliters of Glacial acetic acid, add 5 grams, 5% palladium-carbon catalyst, in 5MPa, hydrogenation finishes under the room temperature, filter, boil off solvent, get R-2-hydroxyl-4-(4-kharophen) phenylbutyric acid.
Embodiment 23
50 gram R-2-hydroxyl-4-oxo-4-(4-dodecyl) phenylbutyric acids (embodiment 18) are dissolved in 2500 milliliters of Glacial acetic acid, add 5 grams, 10% palladium-carbon catalyst, in 2MPa, hydrogenation finishes under the room temperature, filter, boil off solvent, get R-2-hydroxyl-4-(4-dodecyl) phenylbutyric acid.
Claims (6)
1, the synthetic method of optical purity R-and S-2-hydroxyl-4-aryl butyric acid is characterized in that with L-or D-oxysuccinic acid be chiral source, through following step:
(a) carry out hydroxyl protection and be dehydrated into anhydride reactant with Acetyl Chloride 98Min. or acetic anhydride, make S-or R-2-acetoxyl group Succinic anhydried (I);
(b) with I and benzene or other aromatic compounds carry out Fred-Kerafyrm now (Friedel-Crafts) select acylation reaction, S-or R-2-hydroxyl-4-oxo-4-aryl butyric acid (II) or S-or R-2-acetoxyl group-4-oxo-4-aryl butyric acid (III);
(c) II gets S-or R-2-hydroxyl-4-aryl butyric acid (IV) through the reduction hydrogenolysis;
Or (d) III through the reduction hydrogenolysis, S-or R-2-acetoxyl group-4-aryl butyric acid (V);
(e) V gets S-or R-2-hydroxyl-4-aryl butyric acid (IV) through acid or basic hydrolysis or reduction hydrogenolysis;
Or (f) III through acid, basic hydrolysis, S-or R-2-hydroxyl-4-oxo-4-aryl butyric acid (II).
2, the synthetic method of optical purity R-according to claim 1 and S-2-hydroxyl-4-aryl butyric acid, it is characterized in that described other aromatic compounds refer to benzene replacement or unsubstituted, naphthalene, furans, thiophene, pyrroles, wherein substituting group is the alkyl of C1～C10, alkoxyl group, hydroxyl, halogen (F, Cl, Br, I), replacement or unsubstituted thin base, replacement or the unsubstituted amino of C1～C10.
3, the synthetic method of optical purity R-according to claim 1 and S-2-hydroxyl-4-aryl butyric acid; it is characterized in that the protection of hydroxyl and be dehydrated into anhydride reactant being: with L-or D-oxysuccinic acid is chiral source; with the Acetyl Chloride 98Min. of 1～10 times of mole or a kind of reaction in the acetic anhydride; temperature of reaction is 15～120 ℃; reaction times is 0.5～48 hour; react in a kind of or miscellany between them in the Acetyl Chloride 98Min. of 1～100mL/g-L-or D-oxysuccinic acid, acetic anhydride, acetate, tetrahydrofuran (THF), dioxane, ethyl acetate, isopropyl ether, obtain I.
4; the synthetic method of optical purity R-according to claim 1 and S-2-hydroxyl-4-aryl butyric acid; when it is characterized in that I and benzene or other aromatic compounds carry out the selectively acylating reaction; catalyzer is the Phosphorus Oxychloride of 0.9～15 times of weight of I; polyphosphoric acid and Lewis acid (Lewis acid) are aluminum trichloride (anhydrous); FERRIC CHLORIDE ANHYDROUS; Zinc Chloride Anhydrous; anhydrous stannic chloride; anhydrous titanium tetrachloride; the consumption of benzene or aromatic compound is 0.5～25 times of weight of I; temperature of reaction is 0～100 ℃; reaction times is 0.5～48 hour; use benzene; oil of mirbane; Nitromethane 99Min.; methylene dichloride; trichloromethane; 1; a kind of or mixture between them in the 2-ethylene dichloride is a solvent, and solvent load is 4～20mL/g-I.
5, the synthetic method of optical purity R-according to claim 1 and S-2-hydroxyl-4-aryl butyric acid when it is characterized in that II or III reduce hydrogenolysis, is used catalytic hydrogenation, and catalyzer is Ni-H
2, 5% or 10% Pd/C-H
2, solvent is hydrochloric acid, acetic acid, formic acid, phosphoric acid, sulfuric acid or the water of 2～100 times of weight and the mixture between them; Catalyst levels was 0.1～20% of a substrate, and pressure is 0.1～5MPa, in 15～60 ℃ of reactions 2-48 hour; Or under the hydrochloric acid condition, reduce hydrogenolysis with zinc amalgam, the aluminium amalgam of 5～15 times of weight of substrate; Or earlier be reduced to S-or R-2 with the sodium borohydride (potassium) or the Lithium Aluminium Hydride of 0.5～10 times of amount, and 4-dihydroxyl-4-aryl butyric acid (VI) or S-or R-2-acetoxyl group-4-hydroxyl-4-aryl butyric acid (VII), VI or VII get IV or V through above-mentioned catalytic hydrogenation again.
6, the synthetic method of optical purity R-according to claim 1 and S-2-hydroxyl-4-aryl butyric acid, it is characterized in that III and V are through acid, basic hydrolysis, refer under the effect of the mineral acid of 1～10 times of amount or organic acid, mineral alkali or organic bases, in 0～100 ℃ of reaction 0.5～48 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01107195 CN1370767A (en) | 2001-02-27 | 2001-02-27 | Synthesis of optically pure R-and S-2-hydroxyl-4-aryl butyric acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01107195 CN1370767A (en) | 2001-02-27 | 2001-02-27 | Synthesis of optically pure R-and S-2-hydroxyl-4-aryl butyric acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1370767A true CN1370767A (en) | 2002-09-25 |
Family
ID=4656145
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 01107195 Pending CN1370767A (en) | 2001-02-27 | 2001-02-27 | Synthesis of optically pure R-and S-2-hydroxyl-4-aryl butyric acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1370767A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101613279B (en) * | 2009-07-06 | 2012-06-06 | 杭州福斯特药业有限公司 | Method for preparing chiral compound of (R)-2-hydroxy-4-phenylbutyrate |
| CN101462947B (en) * | 2009-01-05 | 2012-07-25 | 上海柏鼎医药技术有限公司 | Preparation of (R) -4-phenyl-2-hydroxybutyrate |
| CN115108883A (en) * | 2021-03-17 | 2022-09-27 | 山东泰和水处理科技股份有限公司 | Preparation method of benzyl chloride |
-
2001
- 2001-02-27 CN CN 01107195 patent/CN1370767A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101462947B (en) * | 2009-01-05 | 2012-07-25 | 上海柏鼎医药技术有限公司 | Preparation of (R) -4-phenyl-2-hydroxybutyrate |
| CN101613279B (en) * | 2009-07-06 | 2012-06-06 | 杭州福斯特药业有限公司 | Method for preparing chiral compound of (R)-2-hydroxy-4-phenylbutyrate |
| CN115108883A (en) * | 2021-03-17 | 2022-09-27 | 山东泰和水处理科技股份有限公司 | Preparation method of benzyl chloride |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1705664A (en) | Process for the preparation of (S,S)-cis-2-benzhydryl-3-benzylaminoquinuclidine | |
| CN1183082C (en) | Process for preparation of (2R)-2-propyloctanoic acid | |
| Caron et al. | An optimized sequential kinetic resolution of trans-1, 2-cyclohexanediol | |
| CN1370767A (en) | Synthesis of optically pure R-and S-2-hydroxyl-4-aryl butyric acid | |
| CN1069629C (en) | Process for manufacture of alpha-beta-unsaturated organic carboxylic acids | |
| CN1316008A (en) | Process for preparing alpha-(1,4) linked oligosaccharide | |
| CN1680565A (en) | Preparation of chiral epichlorohydrin | |
| CN1765892A (en) | Orlistat preparation method | |
| Gramatica et al. | Decarboxylation of cinnamic acids by Saccharomyces cerevisiae | |
| CN101462947B (en) | Preparation of (R) -4-phenyl-2-hydroxybutyrate | |
| CN1710087A (en) | Method for producing optical homochiral amygdalic acid | |
| EP2626428B1 (en) | Method for enzymatic synthesis of (7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid or the esters thereof, and use for the synthesis of ivabradine and the salts thereof | |
| CN1119332C (en) | Intermediate of azepine | |
| CN1919846A (en) | Novel oriented synthesis method of voriconazole, medicinal salt and intermediate thereof | |
| CN1452603A (en) | Process for preparing (-) mentrol and similar compounds | |
| CN115304564A (en) | Preparation method of S-tetrahydrofuran formic acid | |
| CN1053437C (en) | Synthetic method for lisinopril | |
| CN101240303B (en) | Method for synthesizing natural tocopherol ester catalyzed by lipase | |
| CN1946854A (en) | Chemo-enzymatic process for preparing escitalopram | |
| CN101628894B (en) | Preparation method of 3-(S)-amino-2, 3,4, 5-tetrahydro-2-oxo-1H-1-benzoaza-1-tert-butyl acetate | |
| CN1172902C (en) | Synthesis of 2-(s)-amino-4-phenyl (substituted aryl) butanoic acid and its ester (hydrochloride) | |
| Drioli et al. | A facile route to (+)-and (–)-trans-tetrahydro-5-oxo-2-pentylfuran-3-carboxylic acid, precursors of (+)-and (–)-methylenolactocin | |
| CN1993472A (en) | Method for enantioselectively opening 3-substituted oxetan-2-ones under the action of lipases of candida antarctica or burkholderia plantarrii | |
| CN114921507B (en) | Resolution method of prostaglandin chiral intermediate 2-oxabicyclo- [3.3.0] oct-6-en-3-one | |
| CN1145604C (en) | Method for preparing acetic acid and/or methyl acetate by methyl formate isomerisation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C57 | Notification of unclear or unknown address | ||
| DD01 | Delivery of document by public notice |
Addressee: Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences Document name: Notification before expiration of term |
|
| C57 | Notification of unclear or unknown address | ||
| DD01 | Delivery of document by public notice |
Addressee: Sun Zhanwei Document name: Notification before expiration of term |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |