CN1940079B - Synthesis of (2S,3S)-2-benzoyl aminometh-3-hydroxy-butyrate ester series compound by asymmetric yeast cell - Google Patents
Synthesis of (2S,3S)-2-benzoyl aminometh-3-hydroxy-butyrate ester series compound by asymmetric yeast cell Download PDFInfo
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- 238000000034 method Methods 0.000 claims description 16
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- 238000002360 preparation method Methods 0.000 claims description 10
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000012153 distilled water Substances 0.000 claims description 2
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- 238000000711 polarimetry Methods 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- -1 (2S,3S)-2-benzoyl-aminomethyl-3-hydroxy-butyrate ester Chemical class 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 4
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- 239000012467 final product Substances 0.000 abstract 1
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
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- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
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- 238000005516 engineering process Methods 0.000 description 4
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- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- WFRNRWHEMQWFRH-IMJSIDKUSA-N (2S,3S)-2-(aminomethyl)-3-hydroxybutanoic acid Chemical compound C[C@H](O)[C@H](CN)C(O)=O WFRNRWHEMQWFRH-IMJSIDKUSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- HGGAKXAHAYOLDJ-FHZUQPTBSA-N 6alpha-[(R)-1-hydroxyethyl]-2-[(R)-tetrahydrofuran-2-yl]pen-2-em-3-carboxylic acid Chemical compound S([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1[C@H]1CCCO1 HGGAKXAHAYOLDJ-FHZUQPTBSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- TYMABNNERDVXID-DLYFRVTGSA-N Panipenem Chemical compound C([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1S[C@H]1CCN(C(C)=N)C1 TYMABNNERDVXID-DLYFRVTGSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
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- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
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- 229960000379 faropenem Drugs 0.000 description 1
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- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Synthesis of (2S,3S)-2-benzoyl-aminomethyl-3-hydroxy-butyrate ester series compound by yeast cell asymmetry is carried out by taking baker yeast as raw material and converting to obtain the final product by one-step biological method. It's effective and efficient and has better substrate percent conversion.
Description
Technical field
The present invention relates to shown in the formula (I) (2S, 3S)-the biological asymmetric synthesis of 2-benzoyl aminomethyl-3-butyric ester.Formula (I) compound of invention preparation is the key intermediate of industrial production formula (II) compound (abbreviating 4-AA as); Formula (II) compound can be used as intermediate (seeing formula 1) in carbapenem and penems medicine synthetic.
Background technology
Azetidinones 3R, 4R-3-[(1R)-tert-butyl dimethyl silica ethyl]-4-acetoxyl group-2-azetidinone (formula (II), abbreviate 4-AA as) be new and effective antibiotic medicine carbapenem and penems medicine synthetic key intermediate, as be used for synthesizing carbapenem microbiotic imipenum, meropenem, Faropenem and panipenem etc.
Formula (II) compound has 3 chiral centres, therefore has 8 steric isomers, and very big synthetic difficulty is arranged.About the existing literature review of the synthesis technique of (II), but most of technology all exists shortcomings such as synthetic route is long, total recovery is low, complex operation, cost height, thereby limited the suitability for industrialized production of formula (II) compound.Japan Takasago company adopts chiral catalyst (R)-BINAP-Ru asymmetry catalysis 2-benzene carbon amide ylmethyl-3-carbonyl butyric ester (formula (III)) preparation (2S, 3R)-and 2-benzene carbon amide ylmethyl-3-butyric ester (formula (IV)), thus preparation formula (II) compound.But this method needs at high pressure (100kg/cm
2) just can obtain under the situation highly-solid selectively (＞97%ee), formula (IV) compound (seeing formula 2) of high chemo-selective (94:6).
In the production process of chipal compounds, bio-transformation is one of the most competitive means.Compare remarkable advantage such as that bio-transformation has is efficient, single-minded, mild condition with chemical process.Abroad begin one's study from the nineties in 20th century formula (III) compound is carried out biological asymmetric reduction research, biosynthesizing mainly refers to enzyme technology.But result of study shows that through bio-transformation, most of condition following formula (III) compound mainly is reduced to the formula V compound; The formula V compound is the steric isomer (seeing formula 3) of formula (IV) compound.
Studies show that in a large number, in optically active ester derivative synthetic, utilize bread yeast reduction 'beta '-ketoester to become the optics beta-hydroxy esters to become one of the most frequently used method.Because its cost is low, be easy to get and practicality, bread yeast is considered to the easier reagent of a kind of easy to handle.It is a kind of that US4927507 provides. utilize the method for bread yeast reduction α-benzoyl aminomethyl-methyl aceto acetate; its reaction product is (2S; 3S)-2-benzoyl aminomethyl-ethyl 3-hydroxybutanoate and (2R; 3S)-2-benzoyl aminomethyl-ethyl 3-hydroxybutanoate; the two carries out the purity detecting that after separating has carried out corresponding isomer by silica gel column chromatography; but it directly uses bread yeast; facts have proved; if directly use yeast, product separation usually can be very difficult, and use immobilized yeast; just can easy handling; and the product yield height, and do not provide (2R, 3S) the configuration by product is converted into (2S; 3S) the method for configuration product; cause the waste of a large amount of by products, contaminate environment increases production cost.
Summary of the invention
Defective in view of the synthetic method of present formula (II) compound exists the invention provides a kind of method of utilizing bread yeast catalysis formula (III) compound mainly to be converted into formula (I) compound with two chiral centres.This method operation steps is very simple, and product separation is easier to, and can be used for scale operation.By product after bread yeast transforms is the formula V compound; The present invention provides a kind of simultaneously the formula V compound chemistry is converted into the method (seeing formula 4) of formula (I) compound, and R is meant the saturated low alkyl group that contains 1～6 carbon atom in the formula.
This method may further comprise the steps:
(a) bread yeast bio-transformation;
(b) a is gone on foot the gained by product and carry out C
-2The position configuration reversal;
Adopt bread yeast to be free bread leaven matricyte or immobilization bread leaven matricyte among the step a, preferably adopting bread yeast is the immobilization bread leaven matricyte; The organic bases that is adopted among the step b is one or more in n-Butyl Lithium, isobutyl-lithium, tert-butyl lithium, potassium tert.-butoxide, sodium methylate, triethylamine or the pyridine; The solvent that adopts is ethers or halohydrocarbon, is specially in tetrahydrofuran (THF), ether, chloroform, the methylene dichloride one or more; Temperature of reaction is-100 ℃～50 ℃; Reaction times is 0.05～24 hour.
This method is biological asymmetric reduction, have that cost is low, yield is high, easy and simple to handle, reaction conditions is easy to realize and be suitable for advantage such as large-scale industrial production formula (I) compound.Compared with prior art, has bigger competitive edge.
The objective of the invention is to use bread yeast prepare have single polarimetry nature (2S, 3S)-2-benzoyl aminomethyl-3-hydroxybutyric acid ester series compound.Adopt this technology, with one step of bread yeast bio-transformation preparation (2S, 3S)-2-benzoyl aminomethyl-3-hydroxybutyric acid ester series compound, the chiral substrates transformation efficiency of diving can reach more than 90%, by product is few, target product (2S, 3S)-2-benzoyl aminomethyl-3-butyric ester accounts for more than 75% of gross product.The present invention provides the method that effectively the catalysis by product is converted into target product simultaneously.
Embodiment
Further elaborate preparation method of the present invention below by embodiment.
(2S, 3S)-2-benzoyl aminomethyl-ethyl 3-hydroxybutanoate be formula (I) compound, (2R, 3S)-2-benzoyl aminomethyl-ethyl 3-hydroxybutanoate is the preparation (R=Et) of formula V compound:
In 5 liters of three mouthfuls of round-bottomed flasks that bubbler and thermometer are housed, add tap water (2500ml), sucrose (600g), bread yeast (supermarket is bought for 100g, Angel Yeast) successively, with mixture gentle agitation (120r/min).
After 1 hour, make the CO of generation
2Gas is overflowed with the speed of about 1～2 bubbles per second.(III 35g), stirs mixture 24 hours down at 33～36 ℃ to wherein adding 2-benzene carbon amide ylmethyl-3-carbonyl butyric ester then.
(150g) is dissolved in the 500ml tap water with sucrose, and joins in the reaction mixture, continue to stir down at 33～36 ℃, and with the TLC monitoring reaction to reacting completely about 72 hours.In reaction mixture, add diatomite (150g), and filter, remove solid with the diatomite packing layer.Filtrate is used ethyl acetate extraction (600ml * 6), and water (600ml), saturated brine (600ml) washing successively, the organic phase anhydrous sodium sulfate drying, after the filtration,, separate with silica gel column chromatography through concentrating under reduced pressure, obtain formula (I) compound (28.15g, 80%; Optical purity: 99.2%, HPLC); Formula V compound (7.05g, 20%; Optical purity: 98.6%, HPLC).
With the preparation of immobilized bread yeast (2S, 3S)-2-benzoyl aminomethyl-ethyl 3-hydroxybutanoate be formula (I) compound, (2R, 3S)-2-benzoyl aminomethyl-ethyl 3-hydroxybutanoate is formula V compound (R=Et):
A) bread yeast is immobilized:
With Angel Yeast (or the dry yeast bought of other supermarket, 20g), sodiun alginate (5g) slowly joins respectively in the 200ml tap water of quick stirring, is made into two solution.When two solution all become the homogeneous phase thick liquid, they are merged, be added drop-wise in calcium chloride (665ml, 10% (the mass volume ratio)) aqueous solution by dropping funnel then.The dropping liquid that splashes into forms the gel bead with after salts solution contacts, and the size of bead and shape can be controlled by rate of addition.
Bead washs with tap water (500ml * 5), and is used for the reduction of ketone immediately.
B) immobilized bread yeast is used for the reduction reaction of III:
The bead (about 200g) that preceding method makes is put into three mouthfuls of round-bottomed flasks of 2L.Add distilled water (700ml), sucrose (40g) successively, in 33～36 ℃ of following vigorous stirring said mixtures.After 3 hours, and adding 2-benzene carbon amide ylmethyl-3-carbonyl butyric ester (III, 6g).Continue vigorous stirring, TLC monitors to reacting completely.
The aqueous solution is poured on the diatomite in the B into suction filtration.The yeast filter cake that obtains is washed with ethyl acetate (100ml * 3); Water layer by diatomite filtration, is removed gel milk sap with the saturated back of sodium-chlor, and filtrate is washed with ethyl acetate (200ml * 3); Ethyl acetate is merged, water (200ml), saturated brine (200ml) washing successively, the organic phase anhydrous sodium sulfate drying after the filtration, through concentrating under reduced pressure, separates with silica gel column chromatography, obtains formula (I) compound (4.75g, 80%; Optical purity: 99.3%, HPLC); Formula V compound (1.20g, 20%; Optical purity: 98.8%, HPLC).
By (2R, 3S)-2-benzoyl aminomethyl-ethyl 3-hydroxybutanoate be the formula V compound (2S, 3S)-2-aminomethyl-3-hydroxybutyric acid is formula (I) compound (R=Et):
Under nitrogen protection, under-60 ℃ to (2R, 3S)-2-benzene carbon amide ylmethyl-ethyl 3-hydroxybutanoate V (R=Et) (5.30g, add 2.5M n-Butyl Lithium (28ml in anhydrous tetrahydro furan 20mmol) (100ml) solution, 70mmol), stirred 0.5 hour down at-60 ℃, be warmed up to room temperature naturally, at room temperature stirred two hours, add saturated ammonium chloride solution 30ml, continue then to stir after 0.5 hour, extract with ether (200ml * 3), successively water (100ml), saturated sodium-chloride water solution (100ml) washing, organic phase is after concentrating, separate with silica gel column chromatography, obtain formula (I) compound (4.52g, 85%; Optical purity: 99.0%, HPLC), and reclaim formula V compound (0.65g).
Owing to described the present invention according to its special embodiment, some modification and equivalent variations are conspicuous and comprise within the scope of the invention for the those of ordinary skill in this field.
Claims (3)
1. compound that utilizes bread yeast biocatalysis following formula to represent, preparation have single polarimetry nature (2S, 3S)-method of 2-benzoyl aminomethyl-3-butyric ester,
R is meant the saturated low alkyl group that contains 1～6 carbon atom in the formula, it is characterized in that this method may further comprise the steps:
(a) in tap water or distilled water, utilize the preparation of bread yeast biocatalysis 2-benzoyl aminomethyl-3-carbonyl butyric ester (2S, 3S)-2-benzoyl aminomethyl-3-butyric ester, by product be (2R, 3S)-2-benzoyl aminomethyl-3-butyric ester;
(b) add organic bases in ethers or halohydrocarbon, a is gone on foot the gained by product, and (2R 3S)-2-benzoyl aminomethyl-3-butyric ester, carries out C
-2Position configuration reversal preparation (2S, 3S)-2-benzoyl aminomethyl-3-butyric ester, described organic bases is one or more in n-Butyl Lithium, isobutyl-lithium, tert-butyl lithium, potassium tert.-butoxide, sodium methylate, triethylamine or the pyridine, and ethers or halohydrocarbon are one or more in tetrahydrofuran (THF), ether, chloroform, the methylene dichloride.
2. method according to claim 1 is characterized in that adopting among the step a bread yeast to be free bread leaven matricyte or immobilization bread leaven matricyte.
3. method according to claim 2 is characterized in that adopting bread yeast among the step a is the immobilization bread leaven matricyte.
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| US11802299B2 (en) | 2021-06-08 | 2023-10-31 | Fudan University | Enzyme-catalyzed method for synthesizing (2S, 3R)-2-substituted aminomethyl-3-hydroxybutyrate |
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| CN103045504B (en) * | 2012-12-05 | 2014-06-04 | 浙江工业大学 | Microorganism catalysis prepared (2S,3R)-2-benzoyl aminomethyl-3-hydroxybutyric acid ester and bacterial strain |
| CN103373934A (en) * | 2013-06-14 | 2013-10-30 | 苏州汇和药业有限公司 | Catalytic synthesis method of chiral intermediate for carbapenem and penem medicaments |
| CN104846025B (en) * | 2015-03-31 | 2018-06-01 | 浙江大学 | A kind of method for preparing (2S, 3R) -2- benzoyl aminomethyls -3-hydroxybutyrate methyl esters |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4927507A (en) * | 1987-05-04 | 1990-05-22 | Ciba-Geigy Corporation | Novel process for the manufacture of 4-acyloxy-3-hydroxyethyl-azetidinones |
| US4981992A (en) * | 1988-11-15 | 1991-01-01 | Takasago International Corporation | Process for preparing optically active 3-hydroxybutanoic acid |
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|---|---|---|---|---|
| US4927507A (en) * | 1987-05-04 | 1990-05-22 | Ciba-Geigy Corporation | Novel process for the manufacture of 4-acyloxy-3-hydroxyethyl-azetidinones |
| US4981992A (en) * | 1988-11-15 | 1991-01-01 | Takasago International Corporation | Process for preparing optically active 3-hydroxybutanoic acid |
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| US 4981992 A,全文. |
| 第14-15栏实施例1. |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11802299B2 (en) | 2021-06-08 | 2023-10-31 | Fudan University | Enzyme-catalyzed method for synthesizing (2S, 3R)-2-substituted aminomethyl-3-hydroxybutyrate |
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