CN1389459A - Optical breaking process of d1-trans-4-phenyl-5-O-chlorobenzyl pyrrolidone-2 - Google Patents
Optical breaking process of d1-trans-4-phenyl-5-O-chlorobenzyl pyrrolidone-2 Download PDFInfo
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Abstract
The present invention provides a method for optical-cutting compound dl-trans-4-phenyl-5-o-chlorobenzylpyrrolidone-2-(KMBZ-009) which possesses the actions of improving dysmnesia, improving sequal of cerebrovascular disease, raising learning memory and curing senile dementia by using enzymatic reaction. Said method includes: placing the KMBZ-009 in formaldehyde aqueous solution, under the action of potassium carbonate stirring to produce reaction at room temp. to obtain nitrogen formaldehyde compound; under the action of acetic anhydride/pyridine converting nitrogen formaldehyde compound into acetylated compound; making said intermediate acetylated compound undergo the process of enzymatic catalysis action and forming acetylated compound with optical activity and desacetyl product.
Description
Technical field: the invention belongs to the synthetic field of organic chemistry, belong to particularly utilize enzymatic reaction split dl-trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 is left-handed and the dextrorotation monomer methods.
Background technology: the pyrrolidone-2 compounds is considered to a unique not class of dispute and has the active compound of short intelligence, as patent medicine listing, be mainly used in and improve brain function, especially for treatment senile dementia, the behavior of cerebrovascular sequelae and the medicine piracetam and the Anixidan of mental disorder.The applicant designs, synthetic and filtered out one to neurocyte have the compound d l-of highly selective calcium antagonistic activity trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 (KMBZ-009), and associated visceras such as its synthetic method, route, structure and application have been applied for three of patents of invention and have all obtained certificate (patent No. ZL 94 1 04879.9, ZL 97 123417.5 and ZL 97 1 23419.1).Be pharmacology, drug effect and the clinical study of further carrying out this target compound, with dl-trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 splits left-handed and the dextrorotation monomer is necessary.Up to the present, utilizing enzymatic reaction to come the pyrrolidone-2 compounds is carried out optical segmentation is effective means [Bruno Jouglet and GerardRousseau, Tetrahedron Letters, 34 (14), 2307-2310,1993], still, method and route according to prior art do not obtain expected result.
Summary of the invention: the object of the present invention is to provide a kind of with dl-trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 is split as left-handed and dextrorotation monomeric compound, approach unlike the prior art, different katalaze enzymes and the different methods that removes auxiliary base.
For achieving the above object, the invention provides following technical scheme:
Optical segmentation dl-is trans-method of 4-phenyl-5-o-chlorobenzyl pyrrolidone-2 compound (being called for short KMBZ-009), enantiomorph dl-is trans-and 4-phenyl-5-o-chlorobenzyl pyrrolidone-2 (KMBZ-009) is in formalin, under the effect of salt of wormwood, the stirring at room reaction generates n-formyl sarcolysine hydroformylation thing 1; Under the effect of aceticanhydride/pyridine, n-formyl sarcolysine hydroformylation thing 1 is converted into acetylate 2; Intermediate acetylate 2 forms and to have optically active acetylate 3 and deacetylate product 4 after the katalysis of enzyme, just obtains corresponding left-handed and dextrorotation monomeric compound after auxiliary base is handled through removing again:
According to described method, formolation is measured salt of wormwood (K with trans dl-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 (KMBZ-009) at 1.5 times
2CO
3) effect under, with 30-40% formalin (20 times of-40 times of amounts), stirring reaction is 4 hours under the room temperature condition, n-formyl sarcolysine hydroformylation thing (formula 1).
According to described method, acetylize adopt n-formyl sarcolysine aldehyde cpd 1 at room temperature, dry pyridine solvent and three normal aceticanhydrides reaction generation acetylates (formula 2).
According to described method; enzymatic reaction is at 10-25 ℃; small amount of methanol or ethanol or propyl carbinol exist down; 1: 1 isopropyl ether: in normal hexane/t-butyl methyl ether solvent; enzyme reagent Triacylglylcerol lipase (EC 3.1.1.3 from porcine pancreas; type II Crude) catalyzing acetylization product generation hydrolysis reaction, acetylate and enzyme reagent weight ratio are 1: 6, generate to have optically active compound 3 and 4 (formula 3 and formula 4).
According to described method, time of enzymatic reacting is 3-5 days; Reaction process is detected by silica gel thin-layer chromatography (TLC), and development system is 3: 1 petrol ether/ethyl acetate; Reaction product 3 and 4 weight ratios through silica gel and sample are 50: 1, and elution system is with the silica gel column chromatography of 1: 1 petrol ether/ethyl acetate gradient elution to separate at 5: 1.
Can reach the 100%ee value through mixed solvent petroleum ether-ethyl acetate recrystallization again according to described method by the compound 4 that enzymatic reaction generates; Compound 3 can be enough to satisfy the optically active body 3 greater than 70%ee that gets the 100%ee final product after next step operation through obtaining purity behind three enzymolysis again.
The compound 3 greater than 70%ee that obtains according to described method can further be dissolved in the anhydrous methanol, under 0-5 ℃ of condition, with 3 normal KOH or NaOH reaction, generate dextrorotation optically active body (+)-KMBZ-009, after the petroleum ether-ethyl acetate recrystallization is handled, get 100%ee (+)-KMBZ-009 (dextrorotatory form) again; 100%ee compound 4 can be further through Ac
2O/Pyr. after the acetylize; under 0-5 ℃ of condition; with 3 normal KOH or NaOH reaction, generate dextrorotation optically active body (+)-KMBZ-009, after handling, the petroleum ether-ethyl acetate recrystallization gets left-handed monomeric compound (-)-KMBZ-009 (levo form) of 100%ee again.
The compound 3 that obtains according to described method and 4 and the detection method of the %ee value of (+)-KMBZ-009 and (-)-KMBZ-009 be usefulness chirality column type (Daicel Chiralcel AD), eluent 10% Virahol/normal hexane, flow velocity 1ml/min., detect wavelength 230nm, in be designated as the raceme of their correspondences HPLC detect their optical purity.
Compared with prior art, beneficial effect of the present invention is:
1. adopted the new enzymatic reaction that utilizes to split the approach of enantiomorph for optically active body; the acetylate that is n-formyl sarcolysine hydroformylation thing is a substrate; under the effect of lytic enzyme; reach the purpose of fractionation; rather than existing document [Bruno Jouglet and Gerard Rousseau, TetrahedronLetters, 34 (14); 2307-2310,1993] report is the optical segmentation that substrate carries out with n-formyl sarcolysine hydroformylation thing in.
2. enzyme reagent Triacylglylcerol lipase (the EC 3.1.1.3 fromporcine pancreas of Shi Yonging, type II Crude) is document [Bruno Jouglet and GerardRousseau, Tetrahedron Letters, 34 (14), 2307-2310,1993] not do not adopt in, and than the enzyme reagent of reporting in the document more be effective in split dl-trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 is left-handed and the dextrorotation monomeric compound.
3. adopted the new method that removes auxiliary base on the nitrogen-atoms, promptly the acetylate that acts on n-formyl sarcolysine hydroformylation thing at highly basic (KOH or NaOH)-methyl alcohol can a step be converted into the pyrrolidone-2 compound, and is more more convenient, more effective than prior art.
Description of drawings:
Fig. 1 be optical segmentation dl-of the present invention trans-method flow diagram of 4-phenyl-5-o-chlorobenzyl pyrrolidone-2.
Embodiment: followingly further illustrate technical scheme of the present invention, but content of the present invention is not limited thereto with embodiments of the invention.
Embodiment 1:
The preparation of n-formyl sarcolysine hydroformylation thing 1:
0.84g (its preparation method is seen patent of invention: patent No. ZL 97 123419.1, international monopoly Main classification number: C07D207/26) under the room temperature and K for dl-KMBZ-009
2CO
3(1.5 equivalent) and 40 equivalent formalins reaction 4 hours is filtered, washing get final product raceme compound (2) 0.88g (95%).
Colourless column crystallization (AcOEt),
1H-NMR (400MHz, CDCl
3) δ ppm:6.90-7.35 (m, 9H), 4.99 (d, J=11.0Hz, 1H), 4.73 (d, J=11.0Hz, 1H), 4.16 (m, 1H), 3.71 (w, 1H), 3.38 (dd, J=5.0,13.8Hz, 1H), 2.83-2.97 (m, 2H), 3.24 (m, 1H), 2.42 (dd, J=4.2,17.6Hz, 1H).
13C-NMR (400MHz, CDCl
3) δ ppm:175.3 (s), 143.5 (s), 134.8 (s), 134.4 (s), 131.4 (d), 129.8 (d), 128.82 (d), 128.4 (d), 127.0 (d), 126.8 (d), 126.4 * 2 (d), 66.0 (t), 65.2 (d), 41.9 (d), 38.4 (t), 37.9 (t).
Dl-is trans-and the nmr spectrum data of 4-phenyl-5-o-chlorobenzyl pyrrolidone-2 is:
1H-NMR(400MHz，CDCl
3)δppm：7.17-7.35(m，9H)，6.08(w，1H)，4.01(m，1H)，3.28(m，1H)，3.13(dd，J＝4，14Hz，1H)，2.83(dd，J＝9，14Hz，1H).2.76(dd，J＝9，17Hz，1H)，2.49(dd，J＝9，17Hz，1H).
13C-NMR(400MHz，CDCl
3)δppm：176.0(s)，141.4(s)，135.1(s)，134.1(s)，131.1-127.1(7×d)，61.2(d)，46.8(d)，39.2(t)，38.9(t).
Above data presentation: raw material dl-is trans-" NH " in 4-phenyl-5-o-chlorobenzyl pyrrolidone-2 (6.08ppm) fignal center disappear the " N-CH that nitrogen-atoms formaldehyde replaces in the product molecular structure
2-OH " group (4.99 and 4.73ppm) and 3.71ppm fignal center occur; Product
13CNMR has more a CH than raw material
2The carbon peak (66.0ppm) of group.Infer that thus product should be n-formyl sarcolysine hydroformylation thing.
The preparation of acetylate 2:
At room temperature, compound 2 (0.80g) and 3 equivalent Ac
2O (0.7mL) and 5 equivalent pyridines (1mL) mix stirring reaction and spend the night, and after well-established law was handled, column chromatography for separation got 0.90g acetylate 2 (100%) pure product.
Colorless oil,
1H-NMR (400MHz, CDCl
3) δ ppm:7.26-6.86 (m, 9H), 5.49 (d, J=10.4Hz, 1H), 5.27 (d, J=10.4Hz, 1H), 4.07 (m, 1H), 3.28 (m, 2H), 2.95 (m, 2H), 2.51 (d, J=4.0,17.6Hz, 1H), 2.01 (s, 3H).
13C-NMR (400MHz, CDCl
3) δ ppm:175.3 (s), 170.6 (s), 143.1 (s), 134.3 * 2 (s), 131.3 (d), 129.8 (d), 128.7 * 2 (d), 128.5 (d), 127.0 (d), 126.9 (d), 126.32 (d), 65.3 (t), 65.1 (d), 41.6 (d), 37.6 (t), 37.4 (t), 20.7 (q).
Above hydrogen proton N MR shows: product has more a unimodal (CH than intermediate feed formolation thing 1 at the 2.01ppm place
3CO-); In the carbon NMR of product, 170.6ppm (unimodal) and 20.7ppm (quartet) locate also to prove that the ethanoyl in the product molecule exists.Infer that thus product is an acetylate.
Enzymic catalytic reaction:
0.88g acetylate 2 is at immobilized enzyme 5.28g (Lipase; EC 3.1.1.3; Type II; Crude; from Porcine) (enzyme and sample quality ratio=6: 1) effect down; among the isopropylether (100mL)/Hexane (100mL)/Methanol (100 μ l); reacted under the room temperature 3～5 days; behind the elimination immobilized enzyme; reclaim solvent, gained medicinal extract after column chromatography for separation compound 4 (0.27g, 75%ee); compound 3 (0.65g; 22%ee) (AD column, 10%isopropyl ether/Hexane, 1ml/min.). behind compound 4 recrystallizations (AcOEt/petroleum ether); can get the monomeric compound 4 (150mg) of 100%ee, its
1H-NMR and
13C-NMR is identical with formolation thing 1.Compound 3 behind twice of the enzymolysis, can get 0.33g oily compound 3 (73%ee) again, its
1H-NMR and
13C-NMR is identical with acetylate 2.
Remove auxiliary radical reaction:
0.33g zymolyte 3 (73%ee) be through three equivalent KOH/MeOH hydrolysis, can get 200mg (+)-KMBZ-009 (100%ee) behind petroleum ether-ethyl acetate mixed solvent recrystallization, its
1H-NMR and
13C-NMR is identical with dl-KMBZ-009; The retention time of HPLC be 13.4min. (the HPLC condition: chirality AD post, 1ml/min, 10%iso-propanol/Hexane);
=+45.0 (c=1.0 in CHCl
3).Zymolyte 4 (79mg 100%ee) after the acetylize, through same operation, gets 64mg (-)-KMBZ-009 (100%ee), its
1H-NMR and
13C-NMR is identical with dl-KMBZ-009; The retention time of HPLC be 12.9min. (the HPLC condition: chirality AD post, 1ml/min, 10%iso-propanol/Hexane);
=-44.0 (c=1.0 inCHCl
3).
Left-handed KMBZ-009 crystal structure analysis:
Experiment adopts MAC DIP2030K face detection instrument, Moka radiation, graphite monochromator to collect the diffraction data of sample Samp4004 (left-handed KMBZ-009) respectively.Resolve and obtain their crystalline structure respectively with direct method (SHELX86).In molecular structure, contain 1 chlorion, because chlorion has the anomalous scattering effect for the Mo target, i.e. Δ f '=0.1, Δ f "=0.2, so can utilize the anomalous scattering effect of chlorion, by the R of more positive transoid
fValue is judged their absolute configuration.To adopting direct method to resolve the crystalline structure that obtains, consider the influence of anomalous scattering to atomic scattering, (r) value finally obtains their positive and negative types respectively to calculate and revise p (r) and p
R
fValue, as shown in table 1.As known from Table 1, the R of Samp4004 (left-handed KMBZ-009)
f(+) is greater than R
f(-), its difference is 0.0001, and the absolute configuration that tentatively can judge it is for providing the transoid of configuration, that is: and the absolute configuration most probable of 4,5 carbon atoms is the R configuration.Possible absolute configuration is as follows:
The left-handed KMBZ-009 crystal structure analysis of table 1 result
Claims (8)
1, optical segmentation dl-trans-method of 4-phenyl-5-o-chlorobenzyl pyrrolidone-2 compound (be called for short KMBZ-009), it is characterized in that KMBZ-009 in formalin, under the effect of salt of wormwood, the stirring at room reaction generates n-formyl sarcolysine hydroformylation thing 1; Under the effect of aceticanhydride/pyridine, n-formyl sarcolysine hydroformylation thing 1 is converted into acetylate 2; Intermediate acetylate 2 forms and to have optically active acetylate 3 and deacetylate product 4 after the katalysis of enzyme, just obtains corresponding left-handed and dextrorotation monomeric compound after auxiliary base is handled through removing again:
2, method according to claim 1, it is characterized in that formolation with trans dl-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 (KMBZ-009) at 1.5 times of amount salt of wormwood (K
2CO
3) effect under, with 30-40% formalin (20 times of-40 times of amounts), stirring reaction 4 under the room temperature condition
Hour, get n-formyl sarcolysine hydroformylation thing (formula 1).
3, method according to claim 1, it is characterized in that acetylize adopt n-formyl sarcolysine aldehyde cpd 1 at room temperature, dry pyridine solvent and three normal aceticanhydrides reaction generation acetylates (formula 2).
4, method according to claim 1, it is characterized in that enzymatic reaction is at 10-25 ℃, small amount of methanol or ethanol or propyl carbinol exist down, 1: 1 isopropyl ether: in normal hexane/t-butyl methyl ether solvent, and enzyme reagent Triacylglylcerol lipase (EC 3.1.1.3 from porcine
Pancreas, typ II Crude) catalyzing acetylization product generation hydrolysis reaction, acetylate and enzyme reagent weight ratio are 1: 6, generate to have optically active compound 3 and 4 (formula 3 and formula 4).
5,, it is characterized in that time of enzymatic reacting is 3-5 days according to claim 1 or 4 described methods; Reaction process is detected by silica gel thin-layer chromatography (TLC), and development system is 3: 1 petrol ether/ethyl acetate; Reaction product 3 and 4 weight ratios through silica gel and sample are 50: 1, and elution system is with the silica gel column chromatography of 1: 1 petrol ether/ethyl acetate gradient elution to separate at 5: 1.
6. according to claim 1 or 4 described methods, it is characterized in that to reach the 100%ee value through mixed solvent petroleum ether-ethyl acetate recrystallization again by the compound 4 that enzymatic reaction generates; Compound 3 can be enough to satisfy the optically active body 3 greater than 70%ee that gets the 100%ee final product after next step operation through obtaining purity behind three enzymolysis again.
7, according to claim 1 or 6 described methods, it is characterized in that further to be dissolved in the anhydrous methanol with the compound 3 that claim 6 obtains greater than 70%ee, under 0-5 ℃ of condition, with 3 normal KOH or NaOH reaction, generate dextrorotation optically active body (+)-KMBZ-009, after the petroleum ether-ethyl acetate recrystallization is handled, get 100%ee (+)-KMBZ-009 (dextrorotatory form) again; 100%ee compound 4 can be further through Ac
2O/Pyr. after the acetylize; under 0-5 ℃ of condition; with 3 normal KOH or NaOH reaction, generate dextrorotation optically active body (+)-KMBZ-009, after handling, the petroleum ether-ethyl acetate recrystallization gets left-handed monomeric compound (-)-KMBZ-009 (levo form) of 100%ee again.
8, according to claim 1 or 6 or 7 described methods, it is characterized in that compound 3 and 4 and the detection method of the %ee value of (+)-KMBZ-009 and (-)-KMBZ-009 be usefulness chirality column type (Daicel Chiralcel AD), eluent 10% Virahol/normal hexane, flow velocity 1ml/min., detect wavelength 230nm, in be designated as the raceme of their correspondences HPLC detect their optical purity.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101263113B (en) * | 2005-09-15 | 2012-06-13 | Ucb医药有限公司 | 4-substituted pyrrolidin-2-ones and their use |
| CN102491929A (en) * | 2011-12-08 | 2012-06-13 | 贵州省中国科学院天然产物化学重点实验室 | 1-hydroxy-2-ketopyrrolidine compound and preparation method and application thereof |
| CN103877080A (en) * | 2013-03-13 | 2014-06-25 | 贵州省中国科学院天然产物化学重点实验室 | New use of 4, 5-disubstituted-2-pyrrolidone compound |
| CN105420338A (en) * | 2015-12-21 | 2016-03-23 | 天台宜生生化科技有限公司 | Method for preparing L-valsartan by decomposing DL-valsartan ester through lipase |
| CN108997186A (en) * | 2018-09-05 | 2018-12-14 | 北京优和康生物医药科技有限公司 | The crystal form of trans- -4- phenyl -5- o-chlorobenzyl pyrrolidone-2 |
| CN111116445A (en) * | 2018-10-31 | 2020-05-08 | 北京优和康生物医药科技有限公司 | Novel crystal form of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 |
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2002
- 2002-07-04 CN CNB021334293A patent/CN1156444C/en not_active Expired - Lifetime
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101263113B (en) * | 2005-09-15 | 2012-06-13 | Ucb医药有限公司 | 4-substituted pyrrolidin-2-ones and their use |
| CN102491929A (en) * | 2011-12-08 | 2012-06-13 | 贵州省中国科学院天然产物化学重点实验室 | 1-hydroxy-2-ketopyrrolidine compound and preparation method and application thereof |
| CN102491929B (en) * | 2011-12-08 | 2014-04-30 | 贵州省中国科学院天然产物化学重点实验室 | 1-hydroxy-2-ketopyrrolidine compound and preparation method and application thereof |
| CN103877080A (en) * | 2013-03-13 | 2014-06-25 | 贵州省中国科学院天然产物化学重点实验室 | New use of 4, 5-disubstituted-2-pyrrolidone compound |
| CN103877080B (en) * | 2013-03-13 | 2016-01-27 | 贵州省中国科学院天然产物化学重点实验室 | 4,5-bis-replaces-medicinal usage of 2-Pyrrolidone compound |
| CN105420338A (en) * | 2015-12-21 | 2016-03-23 | 天台宜生生化科技有限公司 | Method for preparing L-valsartan by decomposing DL-valsartan ester through lipase |
| CN105420338B (en) * | 2015-12-21 | 2019-02-26 | 天台宜生生化科技有限公司 | A kind of method that lipase fractionation DL- Valsartan ester prepares L- Valsartan |
| CN108997186A (en) * | 2018-09-05 | 2018-12-14 | 北京优和康生物医药科技有限公司 | The crystal form of trans- -4- phenyl -5- o-chlorobenzyl pyrrolidone-2 |
| CN111116445A (en) * | 2018-10-31 | 2020-05-08 | 北京优和康生物医药科技有限公司 | Novel crystal form of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 |
| CN111116445B (en) * | 2018-10-31 | 2021-04-27 | 北京优和康生物医药科技有限公司 | Novel crystal form of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 |
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Effective date of registration: 20180119 Address after: 100176 building 7511, No. 2, courtyard No. 7, Beijing economic and Technological Development Zone, 7511 Co-patentee after: KUNMING INSTITUTE OF BOTANY, CHINESE ACADEMY OF SCIENCES Patentee after: BEIJING YOUHEKANG BIO-MEDICINE TECHNOLOGY CO.,LTD. Address before: 650204 Black dragon Pool, Kunming, Yunnan Province, Beijiao Patentee before: Kunming Institute of Botany, Chinese Academy of Sciences |
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