CN105085264A - Asymmetric synthesis method for tanshinol ester derivative - Google Patents
Asymmetric synthesis method for tanshinol ester derivative Download PDFInfo
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Abstract
The invention discloses an asymmetric synthesis method for a tanshinol ester derivative. The method comprises: carrying out direct reaction on (R)- or (S)-sodium tanshinol (the formula is shown in the description) and halogenated hydrocarbon, sulphonate, sulphate or carbonic ester to obtain an (R)- or (S)-tanshinol ester derivative (the formula is shown in the description) with high optical activity, wherein R is C1-C7 alkyl or bornyl. The method disclosed by the invention is free of complex separation steps in the whole course, is simple in preparation process, does not pass through chromatographic column, is low in production cost, and is quite suitable for industrialized batch production.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to a kind of method of asymmetric synthesis of Salvianic acidA ester derivative.
Background technology
Salvianic acidA has vasodilation, increases coronary flow, anti-myocardial ischemina, antithrombus formation and improve the effects such as microcirculation, in treatment coronary heart disease and stenocardia, there is unique curative effect, being the effective constituent of Radix Salviae Miltiorrhizae drop pill, Radix Salviae Miltiorrhizae Tabellae, Radix Salviae Miltiorrhizae Injection etc., is one of the critical treatment for cardiovascular and cerebrovascular diseases and maintenance medicine at present with clear and definite curative effect.But the hydroxy-acid group of the large polarity contained in Salvianic acidA structure, makes Salvianic acidA water-soluble too strong, is difficult to enter the cytolemma be made up of lipid bilayer, thus causes absolute bioavailability when administered orally very low.In addition, exposed carboxyl is easy to combine with the bioactive molecule in human body and cause the reduction of Salvianic acidA availability.These all significantly limit the clinical application of Salvianic acidA.Carrying out that esterification derives to the hydroxy-acid group of Salvianic acidA is one of effective ways of solving the problem.As 2004, Zhang Qunzheng and Zheng Xiaohui etc. develop the Salvianic acidA isopropyl ester of racemization, research show its have vasodilation, anti-cerebral ischemia and inside and outside anti-oxidant, protect heart and brain and treatment diabetes draw the physiological actions (CN200410026205.3) such as its ischemic cardiac muscle infarction.2006, Zheng Xiaohui etc. developed the tanshinol borneol ester of racemization, in the treatment and prevention of cardiovascular and cerebrovascular, have obvious drug effect (CN200610042787.3).2009, Sun Xiaoli etc. developed the Salvianic acidA Ismo 20 of racemization, and research shows that it can significantly alleviate ischemia/reperfusion myocardial damage, improve Ischemic Heart function (Journal of the Fourth Military Medical University, 2009,30 (14), 1257).
The traditional preparation method of Salvianic acidA is by extracting from the cinnabar Salvia japonica Thunb. of redness and the root of the red sage root, but this extraction process is comparatively complicated, only can obtain natural (R) configuration, and chemical purity is not high, easily causes the untoward reaction in use of its injection formulations.These problems constrain the synthesis of Salvianic acidA ester derivative and follow-up clinical application thereof too.The clinical study of Salvianic acidA ester derivative simultaneously also needs the isomers obtaining all configurations.So the research of the efficient method of asymmetric synthesis of Salvianic acidA ester derivative seems particularly important.But up to now, the research about the method for asymmetric synthesis of Salvianic acidA ester derivative is considerably less, only there are Asymmetrical dihydroxylation route (Tetrahedron:Asymmetry2011,22,4 of the reports such as Zheng Xiaohui and Jiang Ru; China's pharmaceutical chemistry magazine, 2012,22 (2), 113; CN201110371392.9), be shown below:
Although above-mentioned route can synthesize the Salvianic acidA ester derivative of required (R) or (S) configuration smoothly, but Sharpless bishydroxy catalyst system environment used in asymmetric dihydroxylation is unfriendly, will limit the industrial applications of this technique.
The present invention, just based on above-mentioned research background, have developed one becomes ester reaction technology Salvianic acidA ester derivative synthesis technique based on asymmetric rhodium catalysis hydrogenation technology and simple carboxylic acid sodium salt.
In prior art, carboxylate salt under triethylamine or triethylamine and sodium iodide exist can directly and halohydrocarbon carry out esterification.Compared with prior art, special feature is to solve the selecting response sex chromosome mosaicism caused because of substrate singularity (containing the phenolic hydroxyl group, alcoholic extract hydroxyl group etc. with similar reactive behavior in Sodium Danshensu molecule) in the present invention.Up to now all do not have (R)-or (S)-Sodium Danshensu, halohydrocarbon or sulphonate to be obtained by reacting Salvianic acidA ester derivative, even there is no the above-mentioned reaction of racemization Sodium Danshensu yet; Its reason is that this reaction exists higher technical difficulty in reaction preference and raw material acquisition.Present invention employs special reaction conditions (to comprise directly using and there is optically active Sodium Danshensu, lower temperature of reaction and shorter reaction times can be adopted, avoid the racemization problem of other side reaction and raw material and product), successfully synthesize Salvianic acidA ester derivative with high yield.With esterification reacting phase ratio, the method have simple to operate, productive rate is high, good selective.
For achieving the above object, the technical solution used in the present invention is:
The present invention relates to a kind of method of asymmetric synthesis of Salvianic acidA ester derivative, described method comprises: (R)-or (S)-Sodium Danshensu
(R)-or (S)-Salvianic acidA ester derivative of high optical activity is obtained with halohydrocarbon, sulphonate, sulfuric ester or carbonic ether direct reaction
wherein, R is alkyl or the bornyl of C1 ~ C7.
Reaction formula is as follows:
Compound after the halohydrocarbon that the present invention the mentions hydrogen atom referred in hydrocarbon molecule is replaced by halogen atom, as methyl iodide, monobromethane, iodoethane, 2 cbloropropane isopropyl chloride, 2-N-PROPYLE BROMIDE, 2-iodopropane, bromocyclohexane, iodocyclohexane, benzyl chlorine, benzyl bromine, benzyl iodine or cyclohexyl bromide, the compound that sulphonate is formed after referring to sulfonic acid and dehydration of alcohols, as methyl mesylate, methyl benzenesulfonate, methyl tosylate, Methyl triflate, ethyl methane sulfonate, ethyl benzenesulfonat, ethyl p-toluenesulfonate, trifluoromethanesulfonic acid ethyl ester, isopropyl mesylate, isopropyl benzene sulfonate, tosic acid isopropyl ester, trifluoromethanesulfonic acid isopropyl ester, methylsulfonic acid cyclohexyl, Phenylsulfonic acid cyclohexyl, tosic acid cyclohexyl, trifluoromethanesulfonic acid cyclohexyl, methylsulfonic acid benzyl ester, Phenylsulfonic acid benzyl ester, tosic acid benzyl ester, trifluoromethanesulfonic acid benzyl ester, methylsulfonic acid norbornene ester, Phenylsulfonic acid norbornene ester, tosic acid norbornene ester or trifluoromethanesulfonic acid norbornene ester, the compound that sulfuric ester is formed after referring to sulfuric acid and two molecule dehydration of alcohols, as methyl-sulfate, the compound that carbonic ether is formed after referring to carbonic acid and dehydration of alcohols, as methylcarbonate, the alkyl of C1 ~ C7 mainly comprises methyl, ethyl, sec.-propyl, cyclohexyl or benzyl, bornyl refers to
Preferably, described reaction is carried out under organic solvent existent condition, and temperature of reaction is 0 ~ 189 DEG C, and the reaction times is 1 ~ 24 hour.
Preferably, the mol ratio of described (R)-or (S)-Sodium Danshensu and halohydrocarbon, sulphonate, sulfuric ester or carbonic ether is 1.0: 1.0 ~ 1.0: 2.0.
Preferably, described organic solvent is the mixing of one or more in methylene dichloride, acetone, methyl alcohol, tetrahydrofuran (THF), ethyl acetate, ethanol, Virahol, dioxane, toluene, chlorobenzene, methyl-sulphoxide, DMF.
Preferably, described (R)-or (S)-Sodium Danshensu synthesize by following steps: (R)-or (S)-tyrosine
via carboxylic acid salify synthesis described (R)-or (S)-Sodium Danshensu after acetylize, the replacement of diazotization hydroxyl, oxydrolysis.Reaction formula is as follows:
Preferably, described (R)-or (S)-tyrosine synthesize by following steps: α-dehydroamino acid or ester
be hydrolyzed after asymmetric rhodium catalysis hydrogenation, obtain final product; Wherein, R1 is hydrogen or ethanoyl, R
2for hydrogen or methyl.Reaction formula is as follows:
* marked is chiral carbon atom.
The present invention utilizes the asymmetric hydrogenation of chiral diphosphine-Rhodium Complexes Catalyzed to obtain D-Tyrosine, replace via acetylize, diazotization hydroxyl, after oxydrolysis carboxylic acid salify and and halohydrocarbon, sulphonate, sulfuric ester or carbonate reaction finally can synthesize Salvianic acidA ester derivative with lower cost and environmental cost.
Compared with prior art, the beneficial effect that the present invention has is: route of the present invention have employed and becomes ester technology with the diverse carboxylic acid sodium salt of technology before this, and more efficiently, enantioselectivity is higher, and the esterification more easily carrying out multiple group derives.In addition, whole process of the present invention is without the need to complex separations step, and technique is simple, without the need to crossing chromatography column, and utilizing rhodium catalysis asymmetric hydrogenation technology can reduce reactions steps further, reducing production cost, be very applicable to industrialized mass production.Adopt the Salvianic acidA ester derivative purity >99% that aforesaid method is obtained, enantioselectivity >98%.The method also more environmental protection higher, more economical with the method phase specific efficiency reported before this, is therefore more suitable for suitability for industrialized production.
Summary of the invention
The object of the invention is to for the social demand of above-mentioned existing Salvianic acidA ester derivative in the urgent need to a kind of efficient asymmetric synthesis technique, provide a kind of method of asymmetric synthesis of Salvianic acidA ester derivative, specifically a kind of synthetic method becoming the optical activity Salvianic acidA ester derivative of ester reaction technology based on asymmetric rhodium catalysis hydrogenation technology and simple carboxylic acid sodium salt.The method has the advantages such as route is short, enantioselectivity is high, good economy performance, environmental protection, so be very suitable for suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.Following examples will contribute to those skilled in the art and understand the present invention further, but not limit the present invention in any form.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, some distortion and improvement can also be made.These all belong to protection scope of the present invention.
the acrylic acid asymmetric rhodium catalysis oxidation of embodiment 1, (Z)-2-acetylaminohydroxyphenylarsonic acid 3-(4-hydroxy phenyl)
(Z)-2-acetylaminohydroxyphenylarsonic acid 3-(4-hydroxy phenyl) vinylformic acid is added in 10mL reaction tube; catalyzer [Rh ((R; R)-QuinoxP*) (cod)] SbF6 (consumption is 1/10000 of dehydroamino acid molar equivalent); vacuumize and change hydrogen 3 times; then add under hydrogen shield degassed after MeOH (2mL), finally hydrogen pressure to be transferred to after 20atm vigorous stirring 48 hours.Reaction end removes MeOH under reduced pressure and namely obtains (R)-2-acetylaminohydroxyphenylarsonic acid 3-(4-hydroxy phenyl) propionic acid.
1HNMR(CD
3OD，400MHz)：δ7.25(d，J＝8.6Hz，2H)，7.02(d，J＝8.6Hz，2H)，4.65(dd，J＝9.2Hz，5.2Hz，1H)，3.20(dd，J＝13.8Hz，5.2Hz，1H)，2.96(dd，J＝13.8Hz，9.2Hz，1H)，2.25(s，3H)，1.91(s，3H).
HPLC is (with (CH
3)
3siCHN
2measure after esterification): DaicelCHIRALCELOD-H, 1.0mL/min, 2-propanol/hexane=10/90,210nm.Rt (major)=15.4min, Rt (minor)=19.5min.
the asymmetric rhodium catalysis hydrogenation of embodiment 2, (Z)-2-acetylaminohydroxyphenylarsonic acid 3-(4-acetyl oxygen phenyl) methyl acrylate
(Z)-2-acetylaminohydroxyphenylarsonic acid 3-(4-acetyl oxygen phenyl) methyl acrylate is added in 10mL reaction tube; catalyzer [Rh ((S; S)-QuinoxP*) (cod)] SbF6 (consumption is 1/10000 of dehydroamino acid molar equivalent); vacuumize and change hydrogen 3 times; then add under hydrogen shield degassed after MeOH (2mL), finally hydrogen pressure to be transferred to after 5atm vigorous stirring 20 hours.Reaction end removes MeOH under reduced pressure and namely obtains (S)-2-acetylaminohydroxyphenylarsonic acid 3-(4-acetyl oxygen phenyl) methyl propionate.
1HNMR(CD
3OD，400MHz)：δ7.23(d，J＝8.6Hz，2H)，7.02(d，J＝8.6Hz，2H)，4.87(s，3H)，4.66(dd，J＝8.8Hz，5.8Hz，1H)，3.14(dd，J＝14.0Hz，5.8Hz，1H)，2.97(dd，J＝14.0Hz，8.8Hz，1H)，2.56(s，3H)，1.91(s，3H).
HPLC：DaicelCHIRALCELOD-H，1.0mL/min，2-propanol/hexane＝10/90，210nm.Rt(major)＝15.3min，Rt(minor)＝19.9min.
the synthesis of embodiment 3, (R)-tyrosine
In 500ml single port bottle, add (R)-2-acetylaminohydroxyphenylarsonic acid 3-(4-hydroxy phenyl) propionic acid, hydrochloric acid, stirring and dissolving, reflux.TLC plate monitoring reaction, after 3 hours, raw material point disappears, and stops heating.Hydrolyzed solution is added ammoniacal liquor and adjust solution ph to 3.5, add 1% gac, stir and boil 10min, in 90 DEG C of stirring in water bath insulation 30min, filtered while hot, active carbon layer distilled water wash 3 times, filtrate and washing lotion merge.Be placed in less than 10 DEG C and quietly put 24h, i.e. crystallization (R)-tyrosine (ee>99%).
1HNMRofhydrochloridesaltof5(D
2O，400MHz)：δ7.13(d，J＝8.4Hz，2H)，6.83(d，J＝8.4Hz，2H)，4.23(dd，J＝7.6Hz，5.6Hz，1H)，3.21(dd，J＝14.4Hz，5.6Hz，1H)，3.09(dd，J＝14.4Hz，7.6Hz，1H).
HPLC：DaicelCHIRALCELCR(+)，0.8mL/min，pH＝2.0HC1O4aq.，200nm.Rt(major)＝5.4min，Rt(minor)＝7.8min.
the synthesis of embodiment 4, (S)-tyrosine
In 500ml single port bottle, add (S)-2-acetylaminohydroxyphenylarsonic acid 3-(4-acetyl oxygen phenyl) methyl propionate, hydrochloric acid, stirring and dissolving, reflux.TLC plate monitoring reaction, after 3 hours, raw material point disappears, and stops heating.Hydrolyzed solution is added ammoniacal liquor and adjust solution ph to 3.5, add 1% gac, stir and boil 10min, in 90 DEG C of stirring in water bath insulation 30min, filtered while hot, active carbon layer distilled water wash 3 times, filtrate and washing lotion merge.Be placed in less than 10 DEG C and quietly put 24h, namely crystallization (v)-tyrosine (ee>99%).
1HNMRofhydrochloridesaltof5(D
20，400MHz)：δ7.12(d，J＝8.4Hz，2H)，6.82(d，J＝8.4Hz，2H)，4.21(dd，J＝7.6Hz，5.6Hz，1H)，3.23(dd，J＝14.4Hz，5.6Hz，1H)，3.05(dd，J＝14.4Hz，7.6Hz，1H).
HPLC：DaicelCHIRALCELCR(+)，0.8mL/min，pH＝2.0HC104aq.，200nm.Rt(minor)＝5.3min，Rt(major)＝7.7min.
the synthesis of embodiment 5, (R)-or (S)-Sodium Danshensu
Take 14.5g (0.08mol) (R)-or (v)-tyrosine is dissolved in 350mL oil of mirbane, add 42.4g aluminum trichloride (anhydrous), homogeneous phase is stirred at 25 DEG C, then 7.2mL (0.1mol) Acetyl Chloride 98Min. is added, at 100 DEG C of reaction 6h, reaction solution is poured in 500g ice and 80mL concentrated hydrochloric acid, and separatory, aqueous phase is extracted with ethyl acetate three times.Then vacuum rotary steam is to 250mL, puts into refrigerator crystallization, filters to obtain 15.5g (R)-or (S)-β-(3-ethanoyl-4-hydroxyl) phenyl-α-amido propionic salt hydrochlorate.
Take that 7g (0.03mol) (R)-or (S)-β-(3-ethanoyl-4-hydroxyl) phenyl-α-amido propionic salt hydrochlorate is dissolved in 140mL water, under cryosel bath condition, adds Sodium Nitrite.Room temperature reaction 24h; reaction solution is extracted with ethyl acetate; vacuum rotary steam obtains crude product; by normal hexane and re-crystallizing in ethyl acetate (volume ratio 1: 5); then add methylene dichloride to stir; precipitation obtains jonquilleous pulverous solid 4.5g, i.e. (R)-or (S)-β-(3-ethanoyl-4-hydroxyl) phenyl-alpha-hydroxypropionic acid.
Take that 4g (0.018mol) (R)-or (S)-β-(3-ethanoyl-4-hydroxyl) phenyl-alpha-hydroxypropionic acid is dissolved in 5mol/LNaOH solution, in cryosel bath, add 30%H
2o
2, be warming up to 40 DEG C, reaction half hour.Acidifying, extraction into ethyl acetate, vacuum rotary steam obtains crude product, and hexanaphthene and propyl acetate (volume ratio 1: 8) recrystallization obtain Salvianic acidA 2.0g.
Above-mentioned Salvianic acidA is dissolved in 5mL methyl alcohol, adds the methanol solution of 2mol/LNaOH, pH=6.7, cryopreservation crystallization.Filter to obtain white crystalline solid Sodium Danshensu 2.2g.
1HNMR(D
2O，400MHz)：δ6.83-6.77(m，2H)，6.71-6.66(m，1H)，4.15(dd，J＝7.6Hz，4.4Hz，1H)，2.93(dd，J＝14.0Hz，4.0Hz，1H)，2.71(dd，J＝14.4Hz，8.0Hz，1H)；
13CNMR(D20，100MHz)：δ180.9，143.7，142.4，130.9，121.9，117.2，116.2，73.5，39.7.
HPLC (acidifying measures after becoming Salvianic acidA): DaicelCHIRALCELOD-H, 0.5mL/min, 2-propanol/hexane/TFA=20/80/1,254nm.Rt (minor)=17.0min, Rt (major)=21.9min.
the synthesis of embodiment 6, (R)-2-hydroxyl-3-(4-hydroxy phenyl) isopropyl propionate
(R)-Sodium Danshensu 9.6g (43.5mmol) is placed in 250mL twoport round-bottomed flask, add 160mL tetrahydrofuran (THF) again, be stirred to homogeneous phase, add 2-iodopropane (8.7mL, 87.0mmol, 2eq.), be heated to 66 DEG C, reaction 24h, cooling, be transferred in 500mL beaker, add saturated aqueous common salt (200mL), stir, extraction, revolve steaming, obtain red thick product, yellow oily liquid i.e. (R)-2-hydroxyl-3-(4-hydroxy phenyl) isopropyl propionate 3.7g (15.4mmol) is obtained through column chromatography purification, productive rate 35% (ee>98%).
1HMNR(DMSO-d6，400MHz)：δ8.61-8.70(d，2H)，6.41-6.60(m，3H)，5.37-5.39(d，1H)，4.80-4.89(m，1H)，4.03-4.08(m，1H)，2.61-2.74(dq，2H)，1.09-1.17(dd，6H).
HPLC：DaicelCHIRALCELOD-H，254nm，temp.25℃，0.5mL/min，2-propanol/hexane＝5/95，，59.0min(minor)，65.5min(major)。
the synthesis of embodiment 7, (S)-2-hydroxyl-3-(4-hydroxy phenyl) isopropyl propionate
(S)-Sodium Danshensu 9.6g (43.5mmol) is placed in 250mL twoport round-bottomed flask, add 160mL tetrahydrofuran (THF) again, be stirred to homogeneous phase, add isopropyl mesylate (87.0mmol, 2eq.), be heated to 66 DEG C, reaction 24h, cooling, be transferred in 500mL beaker, add saturated aqueous common salt (200mL), stir, extraction, revolve steaming, obtain red thick product, yellow oily liquid i.e. (R)-2-hydroxyl-3-(4-hydroxy phenyl) isopropyl propionate 4.1g (17.0mmol) is obtained through column chromatography purification, productive rate 39% (ee>98%).
1HMNR(DMSO-d6，400MHz)：δ8.62-8.71(d，2H)，6.42-6.61(m，3H)，5.35-5.36(d，1H)，4.81-4.88(m，1H)，4.01-4.09(m，1H)，2.62-2.76(dq，2H)，1.04-1.15(dd，6H).
HPLC：DaicelCHIRALCELOD-H，254nm，temp.25℃，0.5mL/min，2-propanol/hexane＝5/95，，58.1min(major)，64.3min(minor)。
the synthesis of embodiment 8, (R)-2-hydroxyl-3-(4-hydroxy phenyl) benzyl propionate
(R)-Sodium Danshensu 9.6g (43.5mmol) is placed in 250mL twoport round-bottomed flask, add 160mL methylene dichloride again, be stirred to homogeneous phase, add benzyl bromine (5.2mL, 43.5mmol, 1eq.), be cooled to 0 DEG C, reaction 24h, rise to room temperature, be transferred in 500mL beaker, add saturated aqueous common salt (200mL), stir, extraction, revolves steaming, obtains red thick product, yellow oily liquid i.e. (R)-2-hydroxyl-3-(4-hydroxy phenyl) benzyl propionate 6.7g (23.3mmo1) is obtained, productive rate 53% through column chromatography purification.
1HMNR(CDCl
3，400MHz)：δ7.58-6.60(m，8H)，5.15(dd，2H)，4.43(q，1H)，3.07(q，1H)，2.80(q，1H).
the synthesis of embodiment 9, (S)-2-hydroxyl-3-(4-hydroxy phenyl) benzyl propionate
(S)-Sodium Danshensu 9.6g (43.5mmol) is placed in 250mL twoport round-bottomed flask, add 160mL methylene dichloride again, be stirred to homogeneous phase, add tosic acid benzyl ester (43.5mmol, 1eq.), be cooled to 0 DEG C, reaction 24h, rises to room temperature, be transferred in 500mL beaker, add saturated aqueous common salt (200mL), stir, extraction, revolve steaming, obtain red thick product, obtain yellow oily liquid i.e. (R)-2-hydroxyl-3-(4-hydroxy phenyl) benzyl propionate 6.6g (23.2mmol) through column chromatography purification, productive rate 51%.
1HMNR(CDCl
3，400MHz)：δ7.56-6.64(m，8H)，5.17(dd，2H)，4.45(q，1H)，3.06(q，1H)，2.80(q，1H).
the synthesis of embodiment 10, (S)-2-hydroxyl-3-(4-hydroxy phenyl) cyclohexyl propionate
(S)-Sodium Danshensu 9.6g (43.5mmol) is placed in 250mL twoport round-bottomed flask, add 160mL tetrahydrofuran (THF) again, be stirred to homogeneous phase, add cyclohexyl bromide (4.7mL, 43.5mmol, 1eq.), be warming up to 80 DEG C, reaction 16h, rise to room temperature, be transferred in 500mL beaker, add saturated aqueous common salt (200mL), stir, extraction, revolves steaming, obtains red thick product, yellow oily liquid i.e. (S)-2-hydroxyl-3-(4-hydroxy phenyl) cyclohexyl propionate 8.4g (29.1mmol) is obtained, productive rate 67% through column chromatography purification.
1HMNR(CDCl
3，400MHz)：δ7.58-6.60(m，8H)，4.70(m，1H)，4.43(q，1H)，3.05(q，1H)，2.77(q，1H)，2.50-1.10(m，1OH).
the synthesis of embodiment 11, (R)-2-hydroxyl-3-(4-hydroxy phenyl) ethyl propionate
(R)-Sodium Danshensu 9.6g (43.5mmol) is placed in 250mL twoport round-bottomed flask, add 160mLN again, dinethylformamide, be stirred to homogeneous phase, add monobromethane (4.9mL, 65.3mmol, 1.5eq.), be warming up to 80 DEG C, reaction 18h, cooling, be transferred in 500mL beaker, add saturated aqueous common salt (200mL), stir, extraction, revolve steaming, obtain red thick product, obtain yellow oily liquid i.e. (R)-2-hydroxyl-3-(4-hydroxy phenyl) ethyl propionate 6.6g (29.1mmol) through column chromatography purification, productive rate 67%.
1HMNR(CDCl
3，400MHz)：δ6.72(m，2H)，6.60(d，1H)，4.40(q，1H)，3.44(m，2H)，3.00(q，1H)，2.85(q，1H)，2.05～1.50(s，3H).
the synthesis of embodiment 12, (R)-2-hydroxyl-3-(4-hydroxy phenyl) methyl propionate
(R)-Sodium Danshensu 9.6g (43.5mmol) is placed in 250mL twoport round-bottomed flask, add 160mL toluene again, be stirred to homogeneous phase, add methyl-sulfate (5.9mL, 62.3mmol, 1.5eq.), be warming up to 111 DEG C, reaction 12h, cooling, is transferred in 500mL beaker, adds saturated aqueous common salt (200mL), stir, extraction, revolves steaming, obtains red thick product, yellow oily liquid i.e. (R)-2-hydroxyl-3-(4-hydroxy phenyl) methyl propionate 7.3g (34.3mmol) is obtained, productive rate 78% through column chromatography purification.
1HMNR(CDCl
3，400MHz)：δ6.74(m，2H)，6.61(d，1H)，4.41(q，1H)，3.74(s，3H)，3.02(q，1H)，2.86(q，1H).
the synthesis of embodiment 13, (S)-2-hydroxyl-3-(4-hydroxy phenyl) methyl propionate
(S)-Sodium Danshensu 9.6g (43.5mmol) is placed in 250mL twoport round-bottomed flask, add 160mL dioxane again, be stirred to homogeneous phase, add methylcarbonate (10.3mL, 87.0mmol, 2eq.), be heated to 101 DEG C, reaction 8h, cooling, is transferred in 500mL beaker, adds saturated aqueous common salt (200mL), stir, extraction, revolves steaming, obtains red thick product, yellow oily liquid i.e. (v)-2-hydroxyl-3-(4-hydroxy phenyl) methyl propionate 6.5g (30.8mmol) is obtained, productive rate 70% through column chromatography purification.
1HMNR(CDCl
3，400MHz)：δ6.71(m，2H)，6.62(d，1H)，4.45(q，1H)，3.73(s，3H)，3.00(q，1H)，2.89(q，1H).
the synthesis of embodiment 14, (R)-2-hydroxyl-3-(4-hydroxy phenyl) propionic acid norbornene ester
(R)-Sodium Danshensu 9.6g (43.5mmo1) is placed in 250mL twoport round-bottomed flask, add 160mL methyl-sulphoxide again, be stirred to homogeneous phase, add tosic acid norbornene ester (43.5mmo1,1eq.), be heated to 105 DEG C, reaction 9h, cooling, be transferred in 500mL beaker, add saturated aqueous common salt (200mL), stir, extraction, revolve steaming, obtain red thick product, obtain yellow oily liquid i.e. (R)-2-hydroxyl-3-(4-hydroxy phenyl) propionic acid norbornene ester 8.4g (25.2mmol) through column chromatography purification, productive rate 58%.
1HMNR(CDCl
3，400MHz)：δ6.75-6.60(m，3H)，4.85(t，1H)，4.43-4.39(m，1H)，3.03-2.98(m，1H)，2.91-2.87(m，1H)，2.30-1.15(m，7H)，1.00-0.83(m，9H).
the synthesis of embodiment 15, (S)-2-hydroxyl-3-(4-hydroxy phenyl) propionic acid norbornene ester
(S)-Sodium Danshensu 9.6g (43.5mmol) is placed in 250mL twoport round-bottomed flask, add 160mL methyl-sulphoxide again, be stirred to homogeneous phase, add trifluoromethanesulfonic acid norbornene ester (43.5mmol, 1eq.), be heated to 115 DEG C, reaction 20h, cooling, be transferred in 500mL beaker, add saturated aqueous common salt (200mL), stir, extraction, revolve steaming, red thick product, obtain yellow oily liquid i.e. (v)-2-hydroxyl-3-(4-hydroxy phenyl) propionic acid norbornene ester 9.0g (26.9mmol) through column chromatography purification, productive rate 62%.
1HMNR(CDCl
3，400MHz)：δ6.75-6.61(m，3H)，4.82(t，1H)，4.45-4.37(m，1H)，3.04-2.98(m，1H)，2.91-2.85(m，1H)，2.33-1.14(m，7H)，1.04-0.85(m，9H).
In addition, from chemical sense, the activity of halohydrocarbon and sulphonate is mainly by steric influence, and embodiment listed by the present invention has comprised steric hindrance less primary alkyl halohydrocarbon, sulphonate and steric hindrance relatively large secondary halogenated alkyl hydrocarbon, sulphonate, so above-described embodiment is enough to straight chain, the branched-chain alkyl of C1 ~ C7 that other are described, the cycloalkyl etc. of phenyl, tolyl, C3 ~ C7 is all applicable to reaction of the present invention.
In sum, essence of the present invention there is provided a kind of method of asymmetric synthesis and technique of D-Tyrosine of more economical more environmental protection newly, and achieves the synthesis of Salvianic acidA ester derivative with shorter route and economic processing condition as intermediate.The method has the advantages such as route is short, enantioselectivity is high, good economy performance, environmental protection, so be very suitable for suitability for industrialized production.
Above specific embodiments of the invention are described.It is to be appreciated that the present invention is not limited to above-mentioned particular implementation, those skilled in the art can make various distortion or amendment within the scope of the claims, and this does not affect flesh and blood of the present invention.
Claims (7)
1. a method of asymmetric synthesis for Salvianic acidA ester derivative, is characterized in that, described method comprises: (R)-or (S)-Sodium Danshensu
(R)-or (S)-Salvianic acidA ester derivative of high optical activity is obtained with halohydrocarbon, sulphonate, sulfuric ester or carbonic ether direct reaction
wherein, R is alkyl or the bornyl of C1 ~ C7.
2. the method for asymmetric synthesis of Salvianic acidA ester derivative according to claim 1, is characterized in that, described reaction is carried out under organic solvent existent condition, and temperature of reaction is 0 ~ 189 DEG C, and the reaction times is 1 ~ 24 hour.
3. the method for asymmetric synthesis of Salvianic acidA ester derivative according to claim 1, it is characterized in that, the mol ratio of described (R)-or (S)-Sodium Danshensu and halohydrocarbon, sulphonate, sulfuric ester or carbonic ether is 1.0: 1.0 ~ 1.0: 2.0.
4. the method for asymmetric synthesis of the Salvianic acidA ester derivative according to claim 1,2 or 3, it is characterized in that, described halohydrocarbon is methyl iodide, monobromethane, iodoethane, 2 cbloropropane isopropyl chloride, 2-N-PROPYLE BROMIDE, 2-iodopropane, bromocyclohexane, iodocyclohexane, benzyl chlorine, benzyl bromine, benzyl iodine or cyclohexyl bromide;
Described sulphonate is methyl mesylate, methyl benzenesulfonate, methyl tosylate, Methyl triflate, ethyl methane sulfonate, ethyl benzenesulfonat, ethyl p-toluenesulfonate, trifluoromethanesulfonic acid ethyl ester, isopropyl mesylate, isopropyl benzene sulfonate, tosic acid isopropyl ester, trifluoromethanesulfonic acid isopropyl ester, methylsulfonic acid cyclohexyl, Phenylsulfonic acid cyclohexyl, tosic acid cyclohexyl, trifluoromethanesulfonic acid cyclohexyl, methylsulfonic acid benzyl ester, Phenylsulfonic acid benzyl ester, tosic acid benzyl ester, trifluoromethanesulfonic acid benzyl ester, methylsulfonic acid norbornene ester, Phenylsulfonic acid norbornene ester, tosic acid norbornene ester or trifluoromethanesulfonic acid norbornene ester,
Described sulfuric ester is methyl-sulfate;
Described carbonic ether is methylcarbonate.
5. the method for asymmetric synthesis of Salvianic acidA ester derivative according to claim 2, it is characterized in that, described organic solvent is the mixing of one or more in methylene dichloride, acetone, methyl alcohol, tetrahydrofuran (THF), ethyl acetate, ethanol, Virahol, dioxane, toluene, chlorobenzene, methyl-sulphoxide, DMF.
6. the method for asymmetric synthesis of Salvianic acidA ester derivative according to claim 1, it is characterized in that, described raw material is optically active (R)-or (S)-Sodium Danshensu, and it synthesizes by following steps: (R)-or (S)-tyrosine
via carboxylic acid salify synthesis described (R)-or (S)-Sodium Danshensu after acetylize, the replacement of diazotization hydroxyl, oxydrolysis.
7. the method for asymmetric synthesis of Salvianic acidA ester derivative according to claim 6, is characterized in that, described (R)-or (S)-tyrosine synthesize by following steps: α-dehydroamino acid or ester
be hydrolyzed after asymmetric rhodium catalysis hydrogenation, obtain final product; Wherein, R
1for hydrogen or ethanoyl, R
2for hydrogen or methyl.
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| CN113968781A (en) * | 2021-11-11 | 2022-01-25 | 上海吉奉生物科技有限公司 | Synthesis method of (S) -2-hydroxy-3-o-methylpropanoic acid |
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| CN113968781A (en) * | 2021-11-11 | 2022-01-25 | 上海吉奉生物科技有限公司 | Synthesis method of (S) -2-hydroxy-3-o-methylpropanoic acid |
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