CN101643757B - Preparation method of optically pure N-substitute-morpholine-3-ketone-2-acetic acid - Google Patents
Preparation method of optically pure N-substitute-morpholine-3-ketone-2-acetic acid Download PDFInfo
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- CN101643757B CN101643757B CN200910102396XA CN200910102396A CN101643757B CN 101643757 B CN101643757 B CN 101643757B CN 200910102396X A CN200910102396X A CN 200910102396XA CN 200910102396 A CN200910102396 A CN 200910102396A CN 101643757 B CN101643757 B CN 101643757B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 239000004367 Lipase Substances 0.000 claims abstract description 32
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- 102000004882 Lipase Human genes 0.000 claims abstract description 32
- 235000019421 lipase Nutrition 0.000 claims abstract description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000003960 organic solvent Substances 0.000 claims abstract description 23
- 239000000758 substrate Substances 0.000 claims abstract description 21
- 230000003287 optical effect Effects 0.000 claims abstract description 17
- 238000006460 hydrolysis reaction Methods 0.000 claims description 19
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 8
- -1 styroyl Chemical group 0.000 claims description 8
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
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Abstract
The invention discloses a preparation method of optically pure N-substitute-morpholine-3-ketone-2-acetic acid, including the following steps: dl-N-substitute-morpholine-3-ketone-2-acetic ester substrate shown in formula (I) is hydrolyzed by resolution in water/organic solvent system by taking lipase as catalyst; and (R)-N-substitute-morpholine-3-ketone-2-acetic acid or (S)-N-substitute-morpholine-3-ketone-2-acetic acid shown in formula (II) is prepared through post processing. Enzymatic method adopted by the invention can control selectivity of hydrolysate by changing reaction condition, so as to realize controllable preparation of products in two configurations. Compared with other chemical synthesis methods, the method of the invention has the advantages that optical purity of product is high, side reaction is less, substrate product is easy to be separated, reaction condition is mild, and the method is environmentally friendly.
Description
Technical field
The present invention relates to the synthetic field of biocatalysis technology field and medicine, be specifically related to the preparation method of a kind of optical purity N-replacement-morpholine-3-ketone-2-acetate.
Background technology
α-zymoplasm of people is the serine stretch protein of a similar Regular Insulin, and it comprises two polypeptide chain A (containing 36 amino-acid residues) and B (259 amino-acid residues), plays Blood clotting in living things system.Zymoplasm performance Blood clotting has two approach: endogenous activated pathway and external source activated pathway usually.The external source activated pathway is when tissue injury, produces hemoglutinin, activates prothrombinase, finally causes forming zymoplasm; Endogenous activated pathway is because physiological equilibrium is broken, and activates thrombin, finally forms zymoplasm.These two kinds of approach all are stepped activation proenzymes, reassociate in producing the zymoplasm this point.Zymoplasm makes Fibrinogen be cross-linked to form scleroproein, and it is crosslinked with the activated thrombin again, forms clot at last.This process can be strengthened hematoblastic gathering again, and this coagulation process of positive regeeration quickens crosslinked action.Under normal physiological condition, endogenous activated blood coagulation system is by anticoagulation system and fibrinolytic system balance.But when cause of disease was brought out the destruction system balancing, anticoagulation system was in leading, causes hemorrhage; Blood coagulation system is leading, and the pipeline of blood circulation will form thrombus and a series of complication thereof, and these are priming factorses of cardiovascular and cerebrovascular disease.
Zymoplasm is in the final stage of blood coagulation crosslinking reaction, when thrombin inhibitors acts on mutually with of α-zymoplasm of people or all framework territories in certain proportion, thereby make the ability of zymoplasm forfeiture bound substrates, the catalysis activity of Trombin inhibiting, like this with regard to the proteic formation of barrier fibers, stop the hemostasis reaction of catalyzed by thrombin and the platelet activation reaction of thrombin induction, reach the purpose of the anti-bolt of anti-freezing.
The thrombin inhibitors of clinical use has low-molecular-weight heparin and warfarin, but there are many weak points in they.The danger that low-molecular-weight heparin extended treatment causes osteoporosis takes place increases, can also cause " heparin-induced property thrombopenia ", heparin depends on intrinsic coagulation enzyme inhibitors antithrombin blood plasma level, and it can not make sludged blood bonded zymoplasm inactivation.The dvt that oral anticoagulant such as warfarin (a kind of vitamin K antagonist) can effectively reduce after the major operation forms, yet it has the danger that causes severe haemorrhage, the frequent laboratory Monitoring and Controlling that needs.
At present, existing low molecular weight thrombin inhibitor comprises low molecular peptide type, amino acid pattern and peptide analogs type thrombin inhibitors, and the molecule of these several compounds all has one to four peptide bond.Claesson is at Blood Coagul.Fibrinol. (1994) 5, introduced the early stage development of low molecular weight thrombin inhibitor in 411.As the parent division center of morpholone mai Thrombin-like enzyme inhibitor, the N-replacement-morpholine of isomorphism type-3-ketone-2-acetate not, its inhibition activity to zymoplasm significantly shows difference.People such as A.Dahlgren have reported in Bioorg.Med.Chem.10 (2002) 1829-1839 suc as formula (the R)-morpholone mai thrombin inhibitors shown in (III) and (S)-morpholone mai thrombin inhibitors, its synthetic method is to be set out by the optical purity substrate, obtain the optical purity target product, studies show that, (R)-morpholone mai thrombin inhibitors that the N-diphenyl methyl replaces suppresses the active morpholone mai thrombin inhibitors that replaces much larger than (S)-N-diphenyl methyl.Opposite, Jonas W. is in J.Med.Chem. (2003), and 46, think in the report of 3985-4001 that it is very high that morpholone mai thrombin inhibitors that (S)-N-(2, the 5-dimethoxy) benzsulfamide replaces suppresses activity.As seen, the configuration of morpholine ketone and its thrombin inhibitors suppress the active very big relation that has, and the method for the morpholone mai Thrombin-like enzyme inhibitor intermediate of research preparation particular configuration is significant.
Summary of the invention
The invention provides the preparation method of a kind of optical purity N-replacement-morpholine-3-ketone-2-acetate, utilize the catalytic selectivity of different lipase, N-replacement-morpholine-3-ketone-2-acetic ester substrate by resolution of racemic, can prepare (R)-N-replacement-morpholine-3-ketone-2-acetate and (S)-N-replacements-morpholine-3-ketone-2-acetate easily, for (R)-morpholone mai Thrombin-like enzyme inhibitor with (S)-preparation of morpholone mai Thrombin-like enzyme inhibitor provides a feasible approach.
The preparation method of a kind of optical purity N-replacement-morpholine-3-ketone-2-acetate comprises the steps:
With lipase is catalyzer, in water/organic solvent system, N-replacement-morpholine shown in the formula of hydrolysis resolution of racemic (I)-3-ketone-2-acetic ester substrate makes (the R)-N-replacement-morpholine shown in the formula (II)-3-ketone-2-acetate or (S)-N-replacement-morpholine-3-ketone-2-acetate through aftertreatment;
Wherein, described R is a diphenyl-methyl, (3 ', 4 '-dimethoxy) benzyl, (4 '-methoxyl group) benzyl, (4 '-chlorine) benzyl, (4 '-dimethylin) benzyl, styroyl, benzyl, phenyl, (2 ', 5 '-dimethoxy)-benzene sulfonamido, octyl group, sec.-propyl, ethyl or methyl.
Described R
1Be C
1～C
18Alkyl or C
1～C
18Thiazolinyl, preferred C
1～C
8Alkyl or C
1～C
8Thiazolinyl, more preferably octyl group, butyl, ethyl, methyl or vinyl.
The present invention can use immobilized lipase, also can use the free-fat enzyme.
As preferably, described lipase be antarctic candidia lipase (CAL-B:Candidaantarctica lipase B) or immobilization mucor miehei lipase (
Immobilized fromMucor miehei) time, in water/organic solvent system, N-replacement-morpholine shown in the above-mentioned formula (I) of hydrolysis resolution of racemic-3-ketone-2-acetic ester substrate makes (S) N-replacement-morpholine-3-ketone-2-acetate shown in the above-mentioned formula (II) through aftertreatment.
When described lipase is fold lipase from candida sp (CRL:Candida rugosa lipase) or cylindric lipase from candida sp (CCL:lipase from Candida cylindracea), in water/organic solvent system, N-replacement-morpholine shown in the above-mentioned formula (I) of hydrolysis resolution of racemic-3-ketone-2-acetic ester substrate makes (R) N-replacement-morpholine-3-ketone-2-acetate shown in the above-mentioned formula (II) through aftertreatment.
N-replacement-morpholine shown in the described formula (the I)-3-ketone-concentration of 2-acetic ester in water/organic solvent system is 5～100g/L; Too high concentration of substrate causes reaction system to present heterogeneous attitude easily and influences the result of fractionation.
Because too high lipase concentration can not further improve the enzymatic reaction activity, therefore consuming cost that but can corresponding increase reaction raw materials considers that from the angle of saving cost the concentration of described lipase in water/organic solvent system is preferably 5～50g/L.
Described hydrolysis splits preferably in rotating speed is the shaking table of 100～200r/min to be carried out, and temperature of reaction is 5～60 ℃, and the reaction times is 1～50 hour; Preferable reaction temperature is 10～30 ℃, and the reaction times is 1～50 hour.This preferred temperature of reaction can be kept the higher hydrolytic activity of enzyme, on the other hand rationally the control hydrolysis reaction times then can so that hydrolysis conversion near 50% theoretical value, thereby obtain best split result.
Hydrolysis resolution reaction of the present invention does not have special requirement to pressure, gets final product under normal pressure.
Described aftertreatment is after hydrolysis splits end, centrifugal removal lipase, and filtrate is used saturated NaHCO
3-ethyl acetate extraction obtains optical purity (R)-N-replacement-morpholine-3-ketone-2-acetate or (S)-N-replacement-morpholine-3-ketone-2-acetate after being spin-dried for.
Described water/organic solvent system is the mixture of water and organic solvent, wherein organic solvent can be selected the general hydrophilic organic solvent in this area for use, as dimethyl sulfoxide (DMSO), N, dinethylformamide, dioxane, acetonitrile, acetone, a kind of in the tertiary amyl alcohol, also can select the general hydrophobic organic solvent in this area for use, as methyl tertiary butyl ether, Di Iso Propyl Ether, ether, butyl ether, methyl-phenoxide, phenylate, normal hexane, octane-iso, hexanaphthene, toluene, a kind of in the methylene dichloride, preferred hydrophobic methyl tertiary butyl ether, Di Iso Propyl Ether, methyl-phenoxide or normal hexane.Hydrophobic organic solvent is owing to have higher LogP value, a little less than the polarity, can be as the easy necessary water of depriving the enzyme molecular surface of intensive polar solvent, therefore, easier being kept of activity of enzyme in the system that preferred non-polar organic solvent (being hydrophobic organic solvent) and water are formed, thus good fractionation effect guaranteed, and also the lipase in the system can recycle and reuse, as using immobilized lipase, it is reused number of times and can reach 10 times.
The volumn concentration of water is 0.5%～100% in described water/organic solvent system, is preferably 0.5%～20%.Because water is one of reaction raw materials in the hydrolysis reaction, the too high hydrolysis reaction that causes easily of water-content is too fast, thereby make (R)-N-replacements-morpholine-3-ketone-2-acetic ester and (S)-all rapid hydrolysis of N-replacements-morpholine-3-ketone-two kinds of substrates of 2-acetic ester, the fractionation effect is relatively poor.And in the water/organic solvent system with higher organic solvent concentration, the adding of organic solvent has suppressed the hydrolyzation catalysis activity of enzyme to a certain extent, (R)-N-replacement-morpholine-3-ketone-2-acetic ester and (S)-N-replacement-morpholine-3-ketone-two kinds of substrates of 2-acetic ester different binding site in the three-dimensional cavity of enzyme catalysis will determine the difference of its hydrolytic activity at this moment, thus make (R)-N-replacement-morpholine-3-ketone-2-acetic ester with (S)-N-replacement-morpholine-3-ketone-two kinds of substrates of 2-acetic ester are split to come.
In the reaction system of the present invention, can also add other organic or inorganic additive, as add the tensio-active agent tween 80 and can be used for the emulsification substrate and make more homodisperse of substrate and enzyme, add the water activity that inorganic salt/salt hydrate such as Disodium sulfate decahydrate/sodium sulfate etc. can be used for the conditioned reaction system, to improve the selectivity and the activity of lipase.
With CAL-B, CRL is example, and hydrolysis of the present invention splits and can realize with the represented course of following formula:
Reaction process detects chromatographic column with HPLC (Shimadzu SPD-10AVP): and Shim-PackVP-ODS (150 * 4.6mm), analysis condition: methanol (volume ratio)=40/60, flow velocity: 1ml/min.
Enantiomeric excess value detects with HPLC (Shimadzu SPD-10AVP), chiral chromatographic column: Chiralcel AS-H (250 * 4.6mm, Daicel Co., Japan), analysis condition: normal hexane/Virahol/acetate (volume ratio)=55/45/0.1, flow velocity: 0.4ml/min.
The reaction product optical purity is estimated by mapping excessive value (ee%), and the enantio-selectivity of reaction is estimated with E.The corresponding calculated formula is as follows, wherein ee
pBe meant the ee value of product, ee
sBe meant the enantiomeric excess percentage of substrate, c is a reaction conversion ratio.[(S)-acid], [(R)-acid], [Intial vinyl ester] refer to the concentration of reaction S configuration hydrolysis acid product when finishing, the concentration of R configuration hydrolysis acid product, the starting point concentration of substrate respectively.
The present invention has following beneficial effect:
The present invention screen the lipase CAL-B that obtained highly-solid selectively,
Obtain optical purity (S)-N-replacement-morpholine-3-ketone-2-acetate in order to selective hydrolysis (S)-N-replacement-morpholine-3-ketone-2-acetic ester, the product enantiomeric excess value is up to 99%, yield is 40%～53%, obtains (S)-morpholone mai thrombin inhibitors by final conversion; Adopt lipase CRL, then selecting property hydrolysis of CCL (R)-N-replacement-morpholine-3-ketone-2-acetic ester to obtain optical purity (R)-N-replacement-morpholine-3-ketone-2-acetate, the product enantiomeric excess value is up to 98.3%, yield is 41%～47%, obtains (R)-morpholone mai thrombin inhibitors by final conversion.The inventive method can be regulated and control the selectivity of hydrolysate by changing reaction conditions, realizes the controlled preparation of two kinds of configuration products;
The enzymatic means that the present invention adopts and other chemical method be synthetic compares that product optical purity height, side reaction are few, substrate and product is easily separated, reaction conditions is gentle, environmentally friendly.
The inventive method for further synthetic (R)-morpholone mai thrombin inhibitors and (S)-the morpholone mai thrombin inhibitors provides a kind of effective route.
Embodiment
Embodiment 1
Get 500mg 4-(3 ', 4 '-dimethoxy-benzyl) morpholine-3-ketone-2-vinyl-acetic ester and place the 100ml reaction flask, with the dissolving of 25ml methyl tertiary butyl ether.Adding distil water 500 μ l again, 500mg CAL-B, the shaking table temperature is controlled at 25 ℃, and shaking speed is 200r/min, stirring reaction 30h.After reaction finishes, reacting liquid filtering is reclaimed enzyme with recycling.Product in the filtrate (S)-4-(3 ', 4 '-dimethoxy-benzyl) morpholine-3-ketone-2-acetate and unreacted (R)-4-(3 ', 4 '-dimethoxy-benzyl) morpholine-3-ketone-2-vinyl-acetic ester detect with HPLC.Product yield is 48.9%, and the ee value is 98.1%.
Filtrate is used saturated NaHCO
3The each 25ml back extraction of the aqueous solution 3 times, water is regulated pH to 7 with rare HCl, with ethyl acetate water is extracted again, is spin-dried for ethyl acetate and obtains optically pure (S)-4-(3 ', 4 '-dimethoxy-benzyl) morpholine-3-ketone-2-acetate at last.Its structural formula is as follows:
Embodiment 2
Get 500mg 4-(3 ', 4 '-dimethoxy-benzyl) morpholine-3-ketone-2-vinyl-acetic ester and place the 100ml reaction flask, with the dissolving of 25ml hexanaphthene.Adding distil water 500 μ l again, 500mg CRL, the shaking table temperature is controlled at 25 ℃, and shaking speed is 200r/min, stirring reaction 36h.After reaction finishes, reacting liquid filtering is reclaimed enzyme with recycling.Product in the filtrate (R)-4-(3 ', 4 '-dimethoxy-benzyl) morpholine-3-ketone-2-acetate and unreacted (S)-4-(3 ', 4 '-dimethoxy-benzyl) morpholine-3-ketone-2-vinyl-acetic ester detect with HPLC.Product yield is 47.5%, and the ee value is 97.3%.
Filtrate is used saturated NaHCO
3The each 25ml back extraction of the aqueous solution 3 times, water is regulated pH to 7 with rare HCl, with ethyl acetate water is extracted again, is spin-dried for ethyl acetate and obtains optically pure (R)-4-(3 ', 4 '-dimethoxy-benzyl) morpholine-3-ketone-2-acetate at last.Its structural formula is as follows:
Embodiment 3
Except the enzymically hydrolyse substrate is selected 4-(4 '-benzyl chloride base) morpholine-3-ketone-2-ethyl acetate for use, all the other operations are with embodiment 1, make the optical purity shown in the following formula (S)-4-(4 '-benzyl chloride base) morpholine-3-ketone-2-acetate, transformation efficiency is 48.2%, and the ee value is 97.5%.
Embodiment 4
Except the enzymically hydrolyse substrate is selected 4-(4 '-benzyl chloride base) morpholine-3-ketone-2-ethyl acetate for use, all the other operations are with embodiment 2, make the optical purity shown in the following formula (R)-4-(4 '-benzyl chloride base) morpholine-3-ketone-2-acetate, transformation efficiency is 45.8%, and the ee value is 98.3%.
Embodiment 5
Getting 2.5g 4-(2 ', 5 '-dimethoxy-benzene sulfonamido) morpholine-3-ketone-2-butylacetate places the 100ml reaction flask, uses the 25ml acetone solution.Adding distil water 6.2ml (volume content 20%) again, 1250mg immobilization mucor miehei lipase
The shaking table temperature is controlled at 60 ℃, and shaking speed is 200r/min, stirring reaction 24h.After reaction finishes, reacting liquid filtering is reclaimed enzyme with recycling.Product in the filtrate (S)-4-(2 ', 5 '-dimethoxy-benzene sulfonamido) morpholine-3-ketone-2-acetate and unreacted (R)-4-(2 ', 5 '-dimethoxy-benzene sulfonamido) morpholine-3-ketone-2-butylacetate detect with HPLC.Product yield is 52.8%, and the ee value is 95.4%.
Filtrate is spin-dried for the saturated NaHCO in back
3The each 25ml washing of the aqueous solution 3 times, water is regulated pH to 7 with rare HCl, with ethyl acetate water is extracted again, is spin-dried for ethyl acetate and obtains (S)-4-(2 ', 5 '-dimethoxy-benzene sulfonamido) morpholine-3-ketone-2-acetate at last.Its structural formula is as follows:
Embodiment 6
Except catalyzer is selected cylindric lipase from candida sp (CCL) for use, solvent is selected 25ml hexanaphthene and 150ul water (volume content 0.5%) for use, outside the reaction times 50h, all the other operations are with embodiment 5, make the optical purity shown in the following formula (R)-4-(2 ', 5 '-dimethoxy-benzene sulfonamido) morpholine-3-ketone-2-acetate, transformation efficiency is 41.4%, the ee value is 97.3%.
Embodiment 7
Getting 160mg 4-(2 ', 5 '-dimethoxy-benzene sulfonamido) morpholine-3-ketone-2-butylacetate places the 100ml reaction flask, uses the 25ml acetone solution.Adding distil water 6.2ml (volume content 20%) again, 160mg immobilization mucor miehei lipase
The shaking table temperature is controlled at 60 ℃, shaking speed is 200r/min, stirring reaction 1h, all the other operations are with embodiment 5, hydrolysate (S)-4-(2 ' wherein, 5 '-dimethoxy-benzene sulfonamido) transformation efficiency of morpholine-3-ketone-2-acetate is 40.4%, and the ee value is 99.0%, and its structural formula is shown in embodiment 5.
Embodiment 8
Except temperature of reaction is 5 ℃, the reaction times is outside 24 hours, and all the other are operated with embodiment 7, hydrolysate (S)-4-(2 ' wherein, 5 '-dimethoxy-benzene sulfonamido) transformation efficiency of morpholine-3-ketone-2-acetate is 48.3%, and the ee value is 96.0%, and its structural formula is shown in embodiment 5.
Claims (7)
1. the preparation method of optical purity N-replacement-morpholine-3-ketone-2-acetate comprises the steps:
With lipase is catalyzer, in water/organic solvent system, N-replacement-morpholine shown in the formula of hydrolysis resolution of racemic (I)-3-ketone-2-acetic ester substrate makes (the R)-N-replacement-morpholine shown in the formula (II)-3-ketone-2-acetate or (S)-N-replacement-morpholine-3-ketone-2-acetate through aftertreatment;
Wherein, described R is diphenyl-methyl, (3 ', 4 '-dimethoxy) benzyl, (4 '-methoxyl group) benzyl, (4 '-chlorine) benzyl, (4 '-dimethylin) benzyl, styroyl, benzyl, phenyl or (2 ', 5 '-dimethoxy)-benzene sulfonamido;
Described R
1Be C
1～C
8Alkyl or C
1～C
8Thiazolinyl;
Described lipase is antarctic candidia lipase or immobilization mucor miehei lipase, makes (S)-N-replacement-morpholine-3-ketone-2-acetate;
Described lipase is fold lipase from candida sp or cylindric lipase from candida sp, makes (R)-N-replacement-morpholine-3-ketone-2-acetate.
2. preparation method as claimed in claim 1 is characterized in that: the described N-replacement-morpholine-3-ketone-concentration of 2-acetic ester substrate in water/organic solvent system is 5～100g/L.
3. preparation method as claimed in claim 1 is characterized in that: the concentration of described lipase in water/organic solvent system is 5～50g/L.
4. preparation method as claimed in claim 1 is characterized in that: the temperature of reaction that described hydrolysis splits is 5～60 ℃, and the reaction times is 1～50 hour.
5. preparation method as claimed in claim 1 is characterized in that: described aftertreatment is after hydrolysis splits end, centrifugal removal lipase, and filtrate is used saturated NaHCO
3-ethyl acetate extraction obtains optical purity (R)-N-replacement-morpholine-3-ketone-2-acetate or (S)-N-replacement-morpholine-3-ketone-2-acetate after being spin-dried for.
6. preparation method as claimed in claim 1, it is characterized in that: organic solvent is dimethyl sulfoxide (DMSO), N in described water/organic solvent system, dinethylformamide, dioxane, acetonitrile, acetone, tertiary amyl alcohol, methyl tertiary butyl ether, Di Iso Propyl Ether, ether, butyl ether, methyl-phenoxide, phenylate, normal hexane, octane-iso, hexanaphthene, toluene or methylene dichloride.
7. preparation method as claimed in claim 6 is characterized in that: the volumn concentration of water is 0.5%～20% in described water/organic solvent system.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251095A (en) * | 1997-03-26 | 2000-04-19 | 杜邦药品公司 | Lipase capalyzed dynamic resolution of isoxazoline thioester to isoxazoline carboxylic acids |
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2009
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251095A (en) * | 1997-03-26 | 2000-04-19 | 杜邦药品公司 | Lipase capalyzed dynamic resolution of isoxazoline thioester to isoxazoline carboxylic acids |
Non-Patent Citations (3)
| Title |
|---|
| Bokai Liu.Two lipase-catalyzed sequential synthesis of drug derivatives in organic media.《Enzyme and Microbial Technology》.2008,(第43期),375-380. * |
| 张媛媛等.脂肪酶催化外消旋对羟基苯甘氨酸甲酯水解制备对映体纯D2对羟基苯甘氨酸的新方法.《催化学报》.2005,第26卷(第2期),106-110. * |
| 肖咏梅等.反应介质对非水酶促反应中酶活性和选择性的影响.《郑州工程学院学报》.2004,第25卷(第3期),83-87. * |
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