Preparation method of 3-aryl lactic acid derivatives

A technology of aryl lactic acid and aryl lactate, applied in the field of medicine, can solve the problems of narrow application range, complicated separation and purification, harsh conditions, etc., and achieve the effect of wide application range and high enantiopurity

Inactive Publication Date: 2011-11-09
上海博拉酶诺化学科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Utilize (+)-Ipc 2 BCl is an asymmetric reducing reagent that can prepare optically active I from ketoacids, but the reagent is expensive and must use stoichiometric reagents (Tetrahedron Lett.1998, 39, 5501)
[0012] Enzyme-catalyzed method (Arch.Pharm.(Weinheim) 1988,321,179) has shortcomings such as narrow scope of application, harsh conditions, complicated separation and purification

Method used

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  • Preparation method of 3-aryl lactic acid derivatives
  • Preparation method of 3-aryl lactic acid derivatives
  • Preparation method of 3-aryl lactic acid derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 1) Benzyl (2R,3S)-3-(3,4-dibenzyloxyphenyl)-3-hydroxylactate

[0038] 6.30 grams of 3-(3,4-dibenzyloxyphenyl) benzyl acrylate was dissolved in a mixed solvent of 34 milliliters of tert-butanol and 28 milliliters of dichloromethane, and 0.065 grams of (DHQ) were added successively at room temperature 2 -PHAL, 3.70 ml of 60% aqueous solution of N-methylmorpholine-N-oxide, and 0.010 g of K 2 OSo 2 (OH) 4 , stirred and reacted for 3 hours, TLC showed that the raw materials disappeared, added 2.50 g of sodium sulfite and 8 ml of water, stirred for 0.5 hours, filtered, washed the solid with dichloromethane, extracted the aqueous phase with ethyl acetate, combined the organic phases, washed with 1M hydrochloric acid , washed with brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel, washed with ethyl acetate / petroleum ether=1 / 6 to 1 / 1, to obtain 5.00 g of product, 74% yi...

Embodiment 2

[0048] 1) Methyl (2R,3S)-3-(3,4-propylidenedioxyphenyl)-3-hydroxylactate

[0049] According to step 1 of Example 1, it was prepared from 3-(3,4-propylidenedioxyphenyl)-methyl acrylate. white solid.

[0050] 1 H NMR (CDCl 3 )6.84(d, 1H, J=1.8Hz), 6.78(dd, 1H, J=8.2, 1.5Hz), 6.64(d, 1H, J=7.9Hz), 4.90(m, 1H), 4.30(m, 1H), 3.80(s, 3H), 3.28(m, 1H), 2.89(m, 1H), 1.67(s, 3H), 1.66(s, 3H).

[0051] 2) Cyclocarbonate

[0052] According to step 2 of Example 1, it was prepared from (2R,3S)-3-(3,4-propylidenedioxyphenyl)-3-hydroxylactate methyl ester. Colorless oil.

[0053] 1 H NMR (CDCl 3 )6.70-6.50(m, 3H), 6.15(d, 1H, J=5.7Hz), 5.41(d, 1H,, J=5.6Hz), 3.70(s, 3H), 1.70(s, 3H), 1.68 (s, 3H).

[0054] 3) Methyl (R)-3-(3,4-propylidenedioxyphenyl) lactate

[0055] According to the hydrogenolysis reaction operation in Step 3 of Example 1, it was prepared from the cyclocarbonate obtained in the previous step, and purified by flash column chromatography on silica gel. Colorless o...

Embodiment 3

[0063] A kind of preparation method of 3-aryl lactic acid derivative, this method comprises the following steps:

[0064] (1) Cinnamate, N-methylmorpholine-N-oxide, 1,4-(dihydroquinineoxy)benzodiazine ((DHQ) 2 PHAL), potassium osmate by weight ratio is 400: 200: 6.5: 1 is placed in double hydroxylation reaction solvent, stirs 3 hours, through asymmetric double hydroxylation, prepares chiral diol, double hydroxylation reaction solvent is A mixture of tert-butanol and deionized water in a volume ratio of 1:1:1;

[0065] (2) Place the obtained chiral diol, acylating agent ditrichloromethyl ester, and organic base pyridine in the solvent tetrahydrofuran in a weight ratio of 10:4:3, and stir and react at room temperature for 40 minutes to prepare cyclocarbonic acid ester, the resulting cyclocarbonate structure is as follows:

[0066]

[0067] Wherein, R is C4 linear hydrocarbon group, R 4 for H, R 3 for H;

[0068] (3) cyclocarbonate, 10wt% palladium carbon is used as catal...

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Abstract

The invention relates to a preparation method of 3-aryl lactic acid derivatives. The preparation method comprises the following steps: chiral diol is prepared through putting cinnamate, N-methylmorpholine-N-oxide, a chiral ligand and potassium osmate into a dihydroxylation solvent, and carrying out asymmetric dihydroxylation, and cyclic carbonate is obtained through mixing and stirring chiral diol, an acylation agent, and an organic base; and the 3-aryl lactic acid derivatives are obtained by putting cyclic carbonate, a catalyst, and an additive into a reaction solvent, and reacting with stirring in hydrogen atmosphere to allow benzyl carbonate in cyclic carbonate to be subject to hydrogenolysis and decarbonation. Compared with the prior art, the preparation method of the present invention, which utilizes Sharpless enantioselective dihydroxylation and cyclic carbonate hydrogenolysis as key reactions, is used to prepare the 3-aryl lactic acid derivatives and enantiomers thereof with high enantioselectivity, so obtained products have the advantages of high enantiopurity, and wide range of application, and can be used for treating cardio cerebrovascular diseases.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a preparation method of lactic acid derivatives, in particular to a preparation method of 3-aryl lactic acid derivatives. Background technique [0002] 3-Aryl lactic acid derivative I or its enantiomer ent-I are important compounds in organic synthesis, and are used as intermediates in the production of drugs and pesticides. [0003] Zheng et al. reported that in vivo experiments in animals, Ia (R = isopropyl, R 3 =OH,R 4 =H) is the main metabolite of the traditional Chinese medicine Danshen dripping pills, which has a higher concentration in the heart and has the effect of relaxing the myocardium. It is expected to be used as a drug for the treatment of cardiovascular and cerebrovascular diseases (D. 30, 851). However, the enantioselective preparation method of Ia has not been reported. [0004] As a further illustration of its use, free 3-phenyllactic acid or its salt II also has sign...

Claims

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Application Information

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IPC IPC(8): C07C67/317C07C69/734C07C69/732C07C51/41C07C59/52C07C59/64C07D317/46C07D307/86A61K31/216A61K31/36A61K31/343A61P9/00
Inventor 王竝孙智华范尔康
Owner 上海博拉酶诺化学科技有限公司
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