CN103833546B - The method of asymmetric synthesis of optical purity danshensu and its derivatives - Google Patents

The method of asymmetric synthesis of optical purity danshensu and its derivatives Download PDF

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CN103833546B
CN103833546B CN201410064677.1A CN201410064677A CN103833546B CN 103833546 B CN103833546 B CN 103833546B CN 201410064677 A CN201410064677 A CN 201410064677A CN 103833546 B CN103833546 B CN 103833546B
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alpha
phase
acid compounds
optical purity
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CN103833546A (en
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陈福欣
王兰
龚频
周安宁
李刚
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Xian University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/42—One oxygen atom attached in position 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention discloses a kind of method of asymmetric synthesis of optical purity danshensu and its derivatives, with phenyl aldehyde or benzaldehyde derivative for starting raw material, through Knoevenagel condensation, hydrolysis obtains pyruvic acid compounds, again through asymmetric reduction reaction, and simple functional group conversions obtains optical purity danshensu and its derivatives, the method raw material is easy to get, chiral, secondary alcohols construction cost is low, stereoselectivity is good, simple to operate and environmental protection, be applicable to large-scale production, there is productive rate and selectivity is higher, simple to operate, the technical superiority that chirality construction cost is relatively low.

Description

The method of asymmetric synthesis of optical purity danshensu and its derivatives
Technical field
The invention belongs to pharmaceutical synthesis, organic synthesis field, relate to a kind of method of asymmetric synthesis of optical purity danshensu and its derivatives.
Background technology
Salvianic acidA is the primary medicinal component in the labiate red sage root (SalviamiltiorrhizaBge), there is physiological pharmacology widely active, be applied to coronary artery dilator, anticoagulant and apoptosis of cardiac muscle, antithrombotic and the immunity of atherosclerosis, liver protecting, anti-inflammatory and enhancing body etc. clinically.
Large quantity research shows, (±)-Salvianic acidA of chemosynthesis and natural (R)-Salvianic acidA pharmacology, drug effect and medicine in obviously different, even show contrary activity.Meanwhile, according to the standard that new drug is declared, require that the different isomerization body (comprising enantiomer and diastereomer) distinguishing compound is different chemical entities.Therefore, the such class of Salvianic acidA is only had to the compound of a chiral centre, (R)-Salvianic acidA and (S)-Salvianic acidA are two kinds of different chemical entities.
(R) in-Salvianic acidA, the structure of chiral hydroxyl group is the difficult point in whole building-up process, also be the part that in synthesis technique, cost is the highest, therefore, the construction process of the chiral hydroxyl group of R and D high yield, highly selective, low cost is the key of Salvianic acidA class medicament research and development.
The method of existing this chiral centre of structure mainly contains the fractionation of racemic modification, the specificity of enzyme is reduced, the methods such as the catalyzer hydrogenation of chiral centre and styrene compound introduced by raw material.Equivalent (R) and (S)-Salvianic acidA mixture are obtained single (R)-Salvianic acidA by chiral environment by racemate resolution method, and this can waste general raw material undoubtedly; Enzyme specificity reduction method can obtain higher optical purity, but poor to the adaptability of substrate; Chiral centre introduced by raw material is lower-cost synthetic method, but easily occurs racemization in building-up process, and namely optical purity is lower; Catalyzer hydride process generally needs higher reaction pressure and comparatively harsh reaction conditions, is not suitable for a large amount of synthesis.
Summary of the invention
The object of the present invention is to provide a kind of method of asymmetric synthesis of optical purity danshensu and its derivatives.
For achieving the above object, present invention employs following technical scheme:
This synthetic method comprises the following steps:
1) phenyl aldehyde or benzaldehyde derivative are obtained pyruvic acid compounds through Knoevenagel condensation and hydrolysis successively;
2) pyruvic acid compounds is obtained alpha-hydroxypropionic acid compounds through asymmetric reduction reaction synthesis, or pyruvic acid compounds is first carried out esterification with alcohol, then carry out asymmetric reduction reaction and obtain alpha-alcohol ketone acid esters compound.
Described alpha-hydroxypropionic acid compounds is for having the compound such as formula structure described in I-1, and alpha-alcohol ketone acid esters compound is for having the compound such as formula structure described in I-2:
, wherein, R 1for H, OH, OCH 3, OCOCH 3or OCOPh, R 2for H, OH, OCH 3, OCOCH 3or OCOPh, R 3for CH 3, Bn, BnCH 2, i-Pr, t-Bu or adamantyl.
Described R 1and R 2during for hydroxyl, described synthetic method is further comprising the steps of: before Knoevenagel condensation, to R 1and R 2protect.
Adopt cinchona alkaloid phase-transfer catalyst as chiral catalyst in described asymmetric reduction reaction, cinchona alkaloid phase-transfer catalyst is for having the compound such as formula structure described in II, the positively charged ion of cinchona alkaloid phase-transfer catalyst is the derivative of quinine, and the negatively charged ion of cinchona alkaloid phase-transfer catalyst is bromine negative ion or chlorine negative ion:
, in formula II, R 4for H, OH, OCH 3, OCOCH 3or OBn; R 5for OH, OCH 3, OCOCH 3, OBn or OCOPh; R 6for phenyl, menaphthyl, benzyl, substituted benzyl or 9-anthracene methyl.
Described asymmetric reduction reaction adopts two-phase or three-phase system, the reductive agent adopted is the alkali metal borohydride of alkali metal borohydride or replacement, the temperature range of reaction is-20 DEG C to 60 DEG C, reaction times is 2-24h, carry out product separation after having reacted, the step of separation comprises extraction successively, steams solvent and column chromatography.
Described two-phase system is liquid/liquid two-phase system, described three-phase system is solid-liquid/liquid tri-phase system, in two-phase or three-phase system, a liquid phase is water, and another liquid phase is arene, fat hydrocarbon, alicyclic hydrocarbon type, halogenated hydrocarbons, alcohols, ethers, ester class, ketone, diol, derivatives or acetonitrile.
Described reductive agent is sodium borohydride, lithium borohydride or POTASSIUM BOROHYDRIDE, or described reductive agent is sodium borohydride, lithium borohydride or POTASSIUM BOROHYDRIDE that cyano group or triacetoxyl group replace.
Described synthetic method is further comprising the steps of: alpha-hydroxypropionic acid compounds and alcohol are carried out esterification and obtains alpha-alcohol ketone acid esters compound.
Described esterification is carried out under Steglich esterification condition.
Described step 1) specifically comprises the following steps:
Phenyl aldehyde or benzaldehyde derivative are obtained oxazolone compounds through Knoevenagel condensation reaction, oxazolone compounds is hydrolyzed to olefinic amine compound in acetone/water system, olefinic amine compound is hydrolyzed further in hydrochloric acid and obtains pyruvic acid compounds.
Beneficial effect of the present invention is embodied in:
Compared with the conventional method, the present invention with the phenyl aldehyde of cheapness or benzaldehyde derivative for raw material, pyruvic acid compounds is obtained through Knoevenagel condensation and hydrolysis reaction, pyruvic acid compounds or the pyruvic acid compounds through over-churning, through the catalysis of golden pheasant soda class phase-transfer catalyst (chiral catalyst), under comparatively gentle condition, reduction obtains product, there is productive rate and selectivity is higher, simple to operate, the optical purity of gained danshensu and its derivatives is high, chiral hydroxyl group construction cost is relatively low, environmental friendliness, be applicable to the technical superiority of mass-producing synthesis.
The phase-transfer catalyst that the present invention adopts with golden pheasant soda (quinine, quinine set, cinchonine and cinchonine fixed) for raw material, according to existing reference, can the obtaining of high yield.Cinchona alkaloid phase-transfer catalyst of the present invention relative to polyethers, crown ether-like or season phosphine saline catalyst, make asymmetric reduction reaction have higher productive rate and selectivity.
The present invention is directed to R 1and R 2for have employed protection/deprotection steps during hydroxyl, overcome the deficiency that unprotected hydroxyl affects the productive rate of subsequent reactions.
The present invention adopts the alkali metal borohydride of alkali metal borohydride or replacement as reductive agent, has comparatively suitable reducing power, can reductone carbonyl be chiral hydroxyl group, and can not reduce carboxyl or ester group, improves reaction efficiency.
The nonhomogeneous system that the present invention adopts depends on raw material, product and the catalyzer solubleness in organic phase and aqueous phase, has taken into account speed of reaction, productive rate and selectivity simultaneously.
Enzymatic synthesis condition dicyclohexylcarbodiimide of the present invention is as coupling reagent, and DMAP is catalyzer, and synthetic method is ripe, can high yield obtain corresponding Salvianic acidA ester derivative.
Accompanying drawing explanation
Fig. 1 is the synthetic route schematic diagram of optical purity danshensu and its derivatives of the present invention.
Embodiment
Below in conjunction with drawings and Examples, the present invention is elaborated.
Optical purity danshensu and its derivatives is a class chipal compounds, different optical isomers has different pharmacology, toxicological activity, and according to the requirements of customs declaration of national new drug, different optical isomers should be treated according to different chemical entities, therefore, chirality is very important in such medicine.
See Fig. 1, the method for asymmetric synthesis of above-mentioned optical purity danshensu and its derivatives comprises the following steps:
(1) with phenyl aldehyde or benzaldehyde derivative (compound 3) for starting raw material, obtain oxazolone compounds (compound 4) through Knoevenagel condensation reaction (gram Novi Na Gaier condensation or the condensation reaction of Ke's Nova promise lattice);
(2) oxazolone compounds (compound 4) is hydrolyzed to olefinic amine compound (compound 5) in acetone/water system;
(3) olefinic amine compound (compound 5) is hydrolyzed further and obtains pyruvic acid compounds (compound 6) in dilute hydrochloric acid;
(4) pyruvic acid compounds (compound 6) is reduced to alpha-hydroxypropionic acid compounds (compound 1) under condition of phase transition, and phase-transfer catalyst is cinchona alkaloid phase-transfer catalyst (PTCs);
(5) pyruvic acid compounds (compound 6) also can be reacted into alpha-keto ester compounds (compound 7) under Steglich esterification (DCC/DMAP) condition with alcohol;
(6) alpha-hydroxypropionic acid compounds (compound 1) is reacted into ester compound (compound 2) under Steglich esterification (DCC/DMAP) condition with alcohol;
(7) alpha-keto ester compounds (compound 7) is reduced to alpha-alcohol ketone acid esters compound (compound 2) under condition of phase transition, and phase-transfer catalyst is cinchona alkaloid phase-transfer catalyst.
In step (4) and step (7) reductive agent be sodium borohydride, lithium borohydride or POTASSIUM BOROHYDRIDE or cyano group, the triacetoxyl group sodium borohydride, lithium borohydride or the POTASSIUM BOROHYDRIDE that replace.
R 1and R 2during for hydroxyl, before Knoevenagel condensation, to R 1and R 2protect, conventional protecting group, as benzyl, silicon ether, alkoxyl group etc., to eliminate the issuable side reaction of reactive hydrogen.
Two-phase or the three-phase system (nonhomogeneous system) of step (4) and the middle use of step (7) are: liquid/liquid phase or solid-liquid/liquid phase, liquid phase solvent used comprises two classes: wherein a class is 1. arene (benzene, toluene, dimethylbenzene), 2. fat hydrocarbon (pentane, hexane, octane, sherwood oil), 3. alicyclic hydrocarbon type (hexanaphthene, pimelinketone, toluene pimelinketone), 4. halogenated hydrocarbons (chlorobenzene, dichlorobenzene, methylene dichloride), 5. alcohols (methyl alcohol, ethanol, Virahol etc.), 6. ethers (ether, propylene oxide), 7. ester class (ritalin, vinyl acetic monomer, propyl acetate), 8. ketone (acetone, espeleton, mibk), 9. diol, derivatives (ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether) or 10. other: acetonitrile, another kind of is water.
The derivative that the positively charged ion of the cinchona alkaloid phase-transfer catalyst used in step (4) and step (7) is quinine, the negatively charged ion of cinchona alkaloid phase-transfer catalyst is bromine negative ion or chlorine negative ion.
The derivative (see formula II) of quinine: R 4for H, OH, OCH 3, OCOCH 3, OBn; R 5for (R) or (S) OH, OCH 3, OCOCH 3, OBn, OCOPh; R 6for phenyl, menaphthyl (α-menaphthyl, β-menaphthyl), benzyl, substituted benzyl (e.g., benzyl methyl (o-CH 3-Bn, m-CH 3-Bn, p-CH 3-Bn), t-butylbenzyl (o-C (CH 3) 3-Bn, m-C (CH 3) 3-Bn, p-C (CH 3) 3-Bn), isopropyl benzyl (o-iPr-Bn, m-iPr-Bn, p-iPr-Bn), three trifluoromethyl benzyls (o-C (CF 3) 3-Bn, m-C (CF 3) 3-Bn, p-C (CF 3) 3-Bn)) or 9-anthracene methyl.
Embodiment 1
1) protection (R of 3,4-Dihydroxy benzaldehydes 1=R 2=OH)
Be furnished with to 500mL in the there-necked flask of constant pressure funnel and reflux condensing tube and add 200mLN, dinethylformamide, 17.22g(0.126mol) 3,4-Dihydroxy benzaldehyde, 86.8g(0.63mol) salt of wormwood, add 36.3mL(0.315mol in constant pressure funnel) benzyl bromine; Be warming up to 65 DEG C, slowly instillation benzyl bromine (about 30min), drip off rear continuation reaction 6h.TLC detection reaction, has reacted rear suction filtration, and filtrate decompression distillation is except DMF, and residuum imports in frozen water, obtains pale yellow precipitate, and suction filtration is dry obtains yellow solid (structure is shown in formula 1) 38.3g, productive rate 96%.Fusing point, 1hNMR, MS data are consistent with bibliographical information.
2) 4-(3,4-methylenedioxyphenyl)-2-methyl oxazolone (compound 4, R 1=R 2=OBn) synthesis
In 250mL there-necked flask, add 31.8g(0.1mol) compound, the 14.4g(0.125mol of formula 1 structure) acetyl glycine, 10.4g(0.125mol) sodium acetate, anhydrous, 50mL Glacial acetic acid, slowly be heated to backflow, backflow 1h, pour into after cooling in 100g trash ice, stir simultaneously, obtain pale yellow precipitate, suction filtration, with frozen water washing, dry, yellow solid 32.1g, productive rate 80%.Fusing point, 1hNMR, MS data are consistent with bibliographical information.
3) α-acetamido β-(3,4-methylenedioxyphenyl) vinylformic acid (compound 5, R 1=R 2=OBn) synthesis
16g(40mmol is added in 500mL there-necked flask) step 2) obtained compound 4,80mL water and 120mL acetone, backflow 3h, activated carbon decolorizing, filtered while hot, filtrate as refrigerating chamber, to be crystallized completely after suction filtration, obtain faint yellow solid 11.6g, productive rate 70%.Fusing point, 1hNMR, MS data are consistent with bibliographical information.
4) β-(3,4-methylenedioxyphenyl) pyruvic acid (compound 6, R 1=R 2=OBn) synthesis
8.34g(20mmol is added in 100mL there-necked flask) hydrochloric acid of compound 5 that step 3) obtains and 50mL3M, be slowly heated to backflow, backflow 8h, activated carbon decolorizing, filtered while hot, filtrate is as refrigerating chamber, completely rear suction filtration to be crystallized, obtains faint yellow solid 5.26g, productive rate 70%.Fusing point, 1hNMR, MS data are consistent with bibliographical information.
5) (R)-β-(3,4-methylenedioxyphenyl)-alpha-hydroxypropionic acid (compound 1, R 1=R 2=OBn) synthesis
3.76g(10mmol is added in 150mL there-necked flask) obtained compound 6, the 0.38g(10mmol of step 4)) sodium borohydride, 0.495g(1mmol) chiral catalyst N-benzylquininium bromine, 30mL benzene, 50mL water, room temperature (20 DEG C) stirs 4h, TLC detection reaction, after having reacted, be separated organic phase, aqueous phase ethyl acetate 3*20mL extraction, merges organic phase, anhydrous sodium sulfate drying, underpressure distillation goes out solvent, 200-300 order silica gel column chromatography is separated, and obtains white solid 2.55g, productive rate 68%.Fusing point, 1hNMR, MS data are consistent with bibliographical information; Chiral HPLC analyzes, ee%=96%.
6) synthesis (deprotection) of (R)-Salvianic acidA
1.52g(4mmol is added in 50mL there-necked flask) obtained compound 1, the 0.3g(0.4mmol of step 5)) 10%Pd/C, 10mL methyl alcohol, pass into H under normal pressure 2, stirring at room temperature 4h.TLC detection reaction, after having reacted, filter, filtrate decompression is distilled, and 200-300 order silica gel column chromatography is separated, and obtains pale solid 0.713g, productive rate 90%.Fusing point: 85-87 DEG C, ESI-MS:198, 1hNMR (D 2o): 2.82 (1H, dd); 3.05 (1H, dd); 4.27 (1H, dd); 6.83 (1H, dd); 6.97 (1H, d), 6.92 (1H, d).[α] 20.5 d=+34 ° of (c=1, H 2o), consistent with bibliographical information.
Embodiment 2
Step 1) is identical with embodiment 1 to step 5);
6) (R)-β-(3,4-methylenedioxyphenyl)-alpha-hydroxypropionic acid isopropyl ester (compound 2, R 1=R 2=OBn) synthesis
1.88g(5mmol is added in 100mL there-necked flask) obtained compound 1, the 2.06g(10mmol of step 5)) N, N'-dicyclohexylcarbodiimide (DCC), 0.732g(6mmol) DMAP (DAMP), 1.5mL Virahol, 40mL methylene dichloride, stirring at room temperature 24h.TLC detection reaction, after having reacted, filters, add 50mL water, after vigorous stirring, be separated organic phase, aqueous phase ethyl acetate 3*20mL extracts, merge organic phase, anhydrous sodium sulfate drying, underpressure distillation desolventizes, and 200-300 order silica gel column chromatography is separated, obtain white solid (structure is shown in formula III) 1.94g, productive rate 94%.Fusing point, 1hNMR, MS data are consistent with bibliographical information.
7) synthesis (deprotection) of (R)-Salvianic acidA isopropyl ester
1.68g(4mmol is added in 50mL there-necked flask) obtained compound 2, the 0.168g(0.4mmol of step 6)) 10%Pd/C, 20mL methyl alcohol, pass into H under normal pressure 2, stirring at room temperature 2h.TLC detection reaction, after having reacted, filter, filtrate decompression is distilled, and 200-300 order silica gel column chromatography is separated, and obtains pale white solid 0.864g, productive rate 90%.Fusing point: 80-82 DEG C, ESI-MS:241 [M+1], 1hNMR (DMSO-d6): δ: 6.56 ~ 6.76 (m, 3H), 4.91 ~ 4.98 [m, 1H]; 4.23 [m, 1H], 2.86 ~ 2.91 (m, 1H); 2.75 ~ 2.80 (m, 1H), 1.11 ~ 1.29 (m, 6H); .[α] 20.5 D=-9.7°(c=1,MeOH)。Consistent with bibliographical information.
Embodiment 3
Step 1) is identical with embodiment 1 to step 4);
5) β-(3,4-methylenedioxyphenyl)-pyruvic acid isopropyl ester (compound 7, R 1=R 2=OBn) synthesis
1.83g(4.82mmol is added in 100mL there-necked flask) obtained compound 6, the 1.94g(9.6mmol of step 4)) N, N'-dicyclohexylcarbodiimide (DCC), 0.71g(5.78mmol) DMAP (DAMP), 1.5mL Virahol, 40mL methylene dichloride, stirring at room temperature 24h.TLC detection reaction, after having reacted, filters, add 50mL water, after vigorous stirring, be separated organic phase, aqueous phase ethyl acetate 3*20mL extracts, merge organic phase, anhydrous sodium sulfate drying, underpressure distillation desolventizes, and 200-300 order silica gel column chromatography is separated, obtain faint yellow solid (structure is shown in formula IV) 1.93g, productive rate 95%.Fusing point, 1hNMR, MS data are consistent with bibliographical information.
6) (R)-β-(3,4-methylenedioxyphenyl)-alpha-hydroxypropionic acid isopropyl ester (compound 2, R 1=R 2=OBn) synthesis
4.18g(10mmol is added in 150mL there-necked flask) obtained compound 7, the 0.38g(10mmol of step 5)) sodium borohydride, 0.552g(1mmol) chiral catalyst N-benzylquininium bromine, 30mL benzene, 50mL water, stirring at room temperature 4h, TLC detection reaction, after having reacted, be separated organic phase, aqueous phase ethyl acetate 3*20mL extraction, merges organic phase, anhydrous sodium sulfate drying, underpressure distillation goes out solvent, 200-300 order silica gel column chromatography is separated, and obtains white solid 2.75g, productive rate 66%.ESI-MS:421[M+1]; 1HNMR(DMSO-d6)δ:7.34～7.47(m,10H),6.81～7.32(m,3H),5.08(s,4H),4.82～4.90[m,1H],4.39[t1H,],2.80～2.82(m,1H),2.75～2.78(m,1H),1.07～1.18(m,6H)。
7) identical with the step 7) of embodiment 2.
Embodiment 4
Step 1) to step 4) and step 6) identical with embodiment 1;
5) (R)-β-(3,4-methylenedioxyphenyl)-alpha-hydroxypropionic acid (compound 1, R 1=R 2=OBn) synthesis
3.76g(10mmol is added in 150mL there-necked flask) obtained compound 6, the 0.63g(10mmol of step 4)) sodium cyanoborohydride, 0.496g(1mmol) chiral catalyst N-naphthyl quinine chlorine, 30mL methylene dichloride, 50mL water, stirring at room temperature 6h, TLC detection reaction, after having reacted, be separated organic phase, aqueous phase ethyl acetate 3*20mL extraction, merges organic phase, anhydrous sodium sulfate drying, underpressure distillation goes out solvent, 200-300 order silica gel column chromatography is separated, and obtains white solid 2.52g, productive rate 67%.Fusing point, 1hNMR, MS data are consistent with bibliographical information; Chiral HPLC analyzes, ee%=94%.
Embodiment 5
Step 1) to step 4) and step 6) identical with embodiment 1;
5) (R)-β-(3,4-methylenedioxyphenyl)-alpha-hydroxypropionic acid (compound 1, R 1=R 2=OBn) synthesis
3.76g(10mmol is added in 150mL there-necked flask) obtained compound 6, the 2.12g(10mmol of step 4)) sodium triacetoxy borohydride; 0.635g(1mmol) chiral catalyst N-is to t-butylbenzyl-O-ethanoyl cinchonine bromine; 30mL ether, 50mL water; stirring at room temperature 24h; TLC detection reaction; after having reacted; be separated organic phase; aqueous phase ethyl acetate 3*20mL extraction, merges organic phase, anhydrous sodium sulfate drying; underpressure distillation goes out solvent; 200-300 order silica gel column chromatography is separated, and obtains white solid 2.13g, productive rate 57%.Fusing point, 1hNMR, MS data are consistent with bibliographical information; Chiral HPLC analyzes, ee%=90%.
Embodiment 6
Step 1) to step 4) and step 6) identical with embodiment 1;
5) (R)-β-(3,4-methylenedioxyphenyl)-alpha-hydroxypropionic acid (compound 1, R 1=R 2=OBn) synthesis
3.76g(10mmol is added in 150mL there-necked flask) obtained compound 6, the 0.54g(10mmol of step 4)) POTASSIUM BOROHYDRIDE; 0.744g(1mmol) chiral catalyst N-is to three trifluoromethyl benzyl-O-benzyl base-O-ethanoyl-quinine bromines; 30mL hexanaphthene, 50mL water; stirring at room temperature 8h; TLC detection reaction; after having reacted; be separated organic phase; aqueous phase ethyl acetate 3*20mL extraction, merges organic phase, anhydrous sodium sulfate drying; underpressure distillation goes out solvent; 200-300 order silica gel column chromatography is separated, and obtains white solid 2.24g, productive rate 60%.Fusing point, 1hNMR, MS data are consistent with bibliographical information; Chiral HPLC analyzes, ee%=91%.
Embodiment 7
Take phenyl aldehyde as Material synthesis Danshensu derivatives
1) 4-phenyl-2-methyl oxazolone (compound 4, R 1=R 2=H) synthesis
In 250mL there-necked flask, add 10.6g(0.1mol) phenyl aldehyde, 14.4g(0.125mol) acetyl glycine, 10.4g(0.125mol) sodium acetate, anhydrous, 50mL Glacial acetic acid, slowly be heated to backflow, backflow 1.5h, pour into after cooling in 100g trash ice, stir simultaneously, obtain pale yellow precipitate, suction filtration, with frozen water washing, dry, yellow solid 10.4g, productive rate 80%.Fusing point, 1hNMR, MS data are consistent with bibliographical information.
2) α-acetamido beta-phenyl-vinylformic acid (compound 5, R 1=R 2=H) synthesis
In 500mL there-necked flask, add 7.5g(40mmol) obtained compound 4,80mL water and the 120mL acetone of step 1), backflow 3h, activated carbon decolorizing, filtered while hot, filtrate as refrigerating chamber, to be crystallized completely after suction filtration, obtain faint yellow solid 5g, productive rate 70%.Fusing point, 1hNMR, MS data are consistent with bibliographical information.
3) beta-phenyl-pyruvic acid (compound 6, R 1=R 2=H) synthesis
3.28g(20mmol is added in 100mL there-necked flask) step 2) hydrochloric acid of obtained compound 5 and 50mL3M, be slowly heated to backflow, backflow 8h, activated carbon decolorizing, filtered while hot, filtrate is as refrigerating chamber, completely rear suction filtration to be crystallized, obtains faint yellow solid 1.94g, productive rate 66%.Fusing point, 1hNMR, MS data are consistent with bibliographical information.
4) (R)-beta-phenyl-alpha-hydroxypropionic acid (compound 1, R 1=R 2=H) synthesis
1.64g(10mmol is added in 150mL there-necked flask) obtained compound 6, the 0.38g(10mmol of step 3)) sodium borohydride, 0.595g(1mmol) chiral catalyst N-anthracene methyl quinuclidine bromine, 30mL propyl acetate, 50mL water,-20 DEG C are stirred 24h, TLC detection reaction, after having reacted, be separated organic phase, aqueous phase ethyl acetate 3*20mL extraction, merges organic phase, anhydrous sodium sulfate drying, underpressure distillation goes out solvent, 200-300 order silica gel column chromatography is separated, and obtains white solid 0.97g, productive rate 59%.Chiral HPLC analyzes, ee%=95%.Fusing point: 119-120 DEG C, ESI-MS:167 [M+1], 1hNMR (DMSO-d6): δ: 7.2 (m, 5H), 5.82 [s, 2H], 4.21 [q, 1H], 2.86 ~ 3.02 (m, 2H).[α] 20.5 D=+16.2°(c=2,MeOH)。Consistent with bibliographical information.

Claims (7)

1. a method of asymmetric synthesis for optical purity alpha-hydroxypropionic acid compounds or alpha-hydroxy propionic ester compounds, is characterized in that: this synthetic method comprises the following steps:
1) phenyl aldehyde or benzaldehyde derivative are obtained pyruvic acid compounds through Knoevenagel condensation and hydrolysis successively;
2) pyruvic acid compounds is obtained alpha-hydroxypropionic acid compounds through asymmetric reduction reaction synthesis, or pyruvic acid compounds is first carried out esterification with alcohol, then carry out asymmetric reduction reaction and obtain alpha-hydroxy propionic ester compounds;
Adopt cinchona alkaloid phase-transfer catalyst as chiral catalyst in described asymmetric reduction reaction, cinchona alkaloid phase-transfer catalyst is for having the compound such as formula structure described in II, the positively charged ion of cinchona alkaloid phase-transfer catalyst is the derivative of quinine, and the negatively charged ion of cinchona alkaloid phase-transfer catalyst is bromine negative ion or chlorine negative ion:
, in formula II, R 4for H, OH, OCH 3, OCOCH 3or OBn; R 5for OH, OCH 3, OCOCH 3or OBn; R 6for phenyl, menaphthyl, benzyl or 9-anthracene methyl;
Described alpha-hydroxypropionic acid compounds is for having the compound such as formula structure described in I-1, and alpha-hydroxy propionic ester compounds is for having the compound such as formula structure described in I-2:
, wherein, R 1for H, OH or OCH 3, R 2for H, OH or OCH 3, R 3for CH 3, i-Pr or t-Bu; The reductive agent used in described asymmetric reduction is sodium borohydride, lithium borohydride or POTASSIUM BOROHYDRIDE, or described reductive agent is sodium borohydride, lithium borohydride or POTASSIUM BOROHYDRIDE that cyano group or triacetoxyl group replace.
2. the method for asymmetric synthesis of a kind of optical purity alpha-hydroxypropionic acid compounds or alpha-hydroxy propionic ester compounds according to claim 1, is characterized in that: described R 1and R 2during for hydroxyl, described synthetic method is further comprising the steps of: before Knoevenagel condensation, to R 1and R 2protect.
3. the method for asymmetric synthesis of a kind of optical purity alpha-hydroxypropionic acid compounds or alpha-hydroxy propionic ester compounds according to claim 1, it is characterized in that: described asymmetric reduction reaction adopts two-phase or three-phase system, the temperature range of reaction is-20 DEG C to 60 DEG C, carry out product separation after having reacted, the step of separation comprises extraction successively, steams solvent and column chromatography.
4. the method for asymmetric synthesis of a kind of optical purity alpha-hydroxypropionic acid compounds or alpha-hydroxy propionic ester compounds according to claim 3, it is characterized in that: described two-phase system is liquid/liquid two-phase system, described three-phase system is solid-liquid/liquid tri-phase system, in two-phase or three-phase system, a liquid phase is water, and another liquid phase is arene, fat hydrocarbon, halogenated hydrocarbons, alcohols, ethers, ester class, ketone, diol, derivatives or acetonitrile.
5. the method for asymmetric synthesis of a kind of optical purity alpha-hydroxypropionic acid compounds or alpha-hydroxy propionic ester compounds according to claim 1, is characterized in that: described synthetic method is further comprising the steps of: alpha-hydroxypropionic acid compounds and alcohol are carried out esterification and obtains alpha-hydroxy propionic ester compounds.
6. the method for asymmetric synthesis of a kind of optical purity alpha-hydroxypropionic acid compounds or alpha-hydroxy propionic ester compounds according to claim 5, is characterized in that: described esterification is carried out under Steglich esterification condition.
7. the method for asymmetric synthesis of a kind of optical purity alpha-hydroxypropionic acid compounds or alpha-hydroxy propionic ester compounds according to claim 1, is characterized in that: described step 1) specifically comprise the following steps:
Phenyl aldehyde or benzaldehyde derivative are obtained oxazolone compounds through Knoevenagel condensation reaction, oxazolone compounds is hydrolyzed to olefinic amine compound in acetone/water system, olefinic amine compound is hydrolyzed further in hydrochloric acid and obtains pyruvic acid compounds.
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CN102924265A (en) * 2012-10-30 2013-02-13 中国人民解放军第四军医大学 Asymmetric synthesis method of (+)-tanshinol

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US4727183A (en) * 1983-12-23 1988-02-23 American Home Products Corporation Process for the asymmetric synthesis of chiral α-hydroxy-2-nitrobenzenepropanoic acid
CN102924265A (en) * 2012-10-30 2013-02-13 中国人民解放军第四军医大学 Asymmetric synthesis method of (+)-tanshinol

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