CN101085770B - Method for preparing t-butyl (3R, 5S)-3,5,6-trihydroxy-hexanoate - Google Patents
Method for preparing t-butyl (3R, 5S)-3,5,6-trihydroxy-hexanoate Download PDFInfo
- Publication number
- CN101085770B CN101085770B CN2006100273470A CN200610027347A CN101085770B CN 101085770 B CN101085770 B CN 101085770B CN 2006100273470 A CN2006100273470 A CN 2006100273470A CN 200610027347 A CN200610027347 A CN 200610027347A CN 101085770 B CN101085770 B CN 101085770B
- Authority
- CN
- China
- Prior art keywords
- benzyloxy
- hydroxyl
- butyl ester
- hecanoic acid
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention relates to a method for preparing (3R, 5S) - 3, 5, 6- trihydroxy- butylacetic acic tertbutyl ester, belonging to medical intermediate preparation technique. It comprises following steps: taking ethyl chloroacetate as raw material, oxides it with benzyl, catalyzing and hydrogenizing with RuCl2[(R)-BINAP] and getting(3S)- 3- hydroxy- 4- benzyloxy butyl acetate, employing methoxy benzyl to protect hydroxy, carryingout condensation reaction with Claisen ester to increase carbon chain, catalyzing and hydrogenizing the carbonyl at No. 3 carbon with RuCl2[(R)-BINAP] and getting (3R, 5S)- 5- p-methoxy benzyloxy- 6- benzyloxy- 3- hydroxy- butylacetic acic tertbutyl ester; removing p-methoxy benzyloxy with ammonium cerous nitrate, protecting with acetone, removing benzyl and getting (3R, 5S)- 6- hydroxy- 3, 5- 0- isopropylidene- 3, 5- dihydroxy butylacetic acic tertbutyl ester. The total productivity is 39.5%, d, e value is 99%. The cost is low and it is easy to industrialization.
Description
Technical field
The present invention relates to that a kind of (3R, 5S)-3,5, the preparation method of 6-trihydroxy--hecanoic acid t-butyl ester belongs to the medicine intermediate preparing technical field.
Background technology
Statins is a kind with fastest developing speed in the whole cardiovascular agent, occupies an leading position in blood lipid regulation medicine market.(3R, 5S)-3,5,6-trihydroxy--hecanoic acid t-butyl ester contains two chiral centres, and its constitutional features is following:
R
1Be hydrogen or benzyl, R2 is the ethyl or the tertiary butyl, and R is the protection base of hydrogen or alcohol, or is 1,3-glycerol protection base, and it is the important intermediate of preparation statins antilipemic drugs.
U.S. Pat 5399722 provide a kind of preparation (3R, 5S)-3,5, the method for 6-trihydroxy--hecanoic acid t-butyl ester.This method does not adopt blocking group, and as starting raw material, benzyloxyization is used RuCl again with chloroacetyl acetacetic ester in elder generation
2[(R)-BINAP] catalytic hydrogenation contracts and increases carbochain through the claisen ester, with the hydroxyl on No. 3 carbon of asymmetric reduction reagent triethyl-boron reduction, acetonylidene protection 3; 5 hydroxyl is sloughed benzyl with palladium carbon again, obtains (the 3R of acetonylidene protection; 5S)-3,5,6-trihydroxy--hecanoic acid t-butyl ester.Triethyl-boron reagent asymmetric reduction be reflected at that (-60 ℃) carry out under the very low temperature.The selectivity of reaction temperatures affect asymmetric reduction.When suitability for industrialized production, because reacting liquid temperature is inhomogeneous, caused product d, the e value is not high.Except d, the e value is not high cause of poor quality outside, this method requires to cause the high shortcoming of production cost to very low temperature (-60 ℃).
U.S. Pat 5286883 has proposed a kind of more simple and effective preparation method.This method is a starting raw material with the chloroacetyl acetacetic ester, through benzyloxyization, uses Ru
2X
4[(R)-R
3-BINAP]
2N (CH
2CH
3)
3Catalytic hydrogenation, and newly-generated hydroxyl protected with tetrahydropyrans (THP) protection base.Continue to use Ru
2X
4[(R)-R
3-BINAP]
2N (CH
2CH
3)
3Do second chiral carbon of Preparation of Catalyst.When sloughing the basic tetrahydropyrans of protection, get up with the hydroxyl protection of acetonylidene 3,5, again with benzyl slough obtain acetonylidene protection (3R, 5S)-3,5,6-trihydroxy--hecanoic acid t-butyl ester.After this patent is found to have only the hydroxyl protection on No. 5 carbon is got up, the selectivity of asymmetric catalytic hydrogenation height just for the second time.Selected several kinds of blocking groups therebetween, found that at last reaction effect is best when blocking group is tetrahydropyrans, its reaction underlying condition and result are as shown in the table: the shortcoming of this method is productive rate and d, and the e value is not high, and especially productive rate is not high.Can find out that from following table at d, the e value is at 98% o'clock, productive rate has only 59%.And when productive rate has 70%, d, the e value has only 82%.
*In temperature, H
2Pressure is under reaction times, the substrate condition identical with catalyst ratio
Summary of the invention
The objective of the invention is to disclose a kind of (3R, 5S)-3,5, the preparation method of 6-trihydroxy--hecanoic acid t-butyl ester.With this method make (3R, 5S)-3,5, the overall yield of 6-trihydroxy--hecanoic acid t-butyl ester can reach 39.5%, and d, the e value is up to 99%.
According to U.S. Pat 5286883, have only behind the hydroxyl protection on No. 5 carbon, with the d of ruthenium reagent asymmetric catalytic hydrogenation, the e value just can be high.The present invention has found a kind of new blocking group.This blocking group is to methoxy-benzyl.Use on No. 5 carbon of methoxy-benzyl protection during hydroxyl, use catalyzer RuCl again
2Carbonyl on No. 3 carbon of catalytic hydrogenation of [(R)-BINAP] makes that (3R, 5S)-5-is to methoxyl group benzyloxy base-6-benzyloxy-3-hydroxyl-hecanoic acid t-butyl ester, its single step productive rate can reach more than 90%, d, e value 99%.
Concrete technology is following: comprising the first step, is starting raw material with the ethyl chloroacetate earlier, after benzyloxyization, makes the benzyloxy methyl aceto acetate.
In second step, use RuCl
2[(R)-and BINAP] catalytic hydrogenation, make (3S)-3-hydroxyl-4-benzyloxy ethyl n-butyrate.Be characterized in:
The 3rd step; Second (3S)-3-hydroxyl-4-benzyloxy ethyl n-butyrate of making of step used methoxy-benzyl (PMB) is protected as blocking group; Adopt GPF (General Protection False technology, the hydroxyl protection on its No. 5 carbon is made (3S)-3-to methoxyl group benzyloxy base-4-benzyloxy ethyl n-butyrate.
In the 4th step, process claisen ester contracts and reacts, and increases carbochain, makes (5S)-5-to methoxyl group benzyloxy base-6-benzyloxy-3-carbonyl-hecanoic acid t-butyl ester.
In the 5th step, use RuCl
2[(R)-BINAP] made catalyzer, the carbonyl on No. 3 carbon of catalytic hydrogenation make (3R, 5S)-5-is to methoxyl group benzyloxy base-6-benzyloxy-3-hydroxyl-hecanoic acid t-butyl ester.
In the 6th step, (CAN) will slough methoxy-benzyl with ceric ammonium nitrate, make (3R, 5S)-6-benzyloxy-3,5-dihydroxyl-hecanoic acid t-butyl ester.
The 7th step, with acetonylidene 3,5 hydroxyl of the 6th step product is protected, make (3R, 5S)-6-benzyloxy-3,5-O-isopropylidene-3,5-dihydroxyl hecanoic acid t-butyl ester.
The 8th step, with palladium carbon benzyl is sloughed, obtain at last (3R, 5S)-6-hydroxyl-3,5-O-isopropylidene-3,5-dihydroxyl hecanoic acid t-butyl ester.
Synthetic route chart is following:
Advantage of the present invention is following:
1. because the present invention has selected methoxy-benzyl not use blocking group to compare as blocking group with U.S. Pat 5399722, the present invention avoids the use of triethyl-boron, but continues to use RuCl
2Carbonyl on [(R)-BINAP] No. 3 positions of catalysis, and the 5th step productive rate can reach more than 90%, d, the e value is up to 99%.
2. selected methoxy-benzyl as blocking group, in conjunction with RuCl owing to the present invention
2Therefore the use of [(R)-BINAP] catalyzer is that tetrahydropyrans (THP) catalyzer is Ru with the blocking group that U.S. Pat 5286883 is used
2X
4[(R)-R
3-BINAP]
2N (CH
2CH
3)
3Compare, remove d, e value is up to beyond 99%, and productive rate has improved about 30%, so has reduced production cost.
3. because the temperature of reaction of asymmetric reduction of the present invention is 100 ℃, compare with-60 ℃ of the U.S. Pat of not using blocking group 5399722, more help process of industrialization.
Embodiment
The preparation of the first step benzyloxy methyl aceto acetate (II)
(7.35g 55%-60%) hydrogenation receive (168-184mmol) be suspended in the 100ml toluene, ice bath cooling, (15.5ml 150mmol) slowly splashes into wherein with 16.2g benzylalcohol in 30 minutes.Stirring at room 2 hours forms white soup compound.The ice bath cooling splashes into 12.5g chloroacetyl acetacetic ester (76mmol) wherein then, drips complete ambient temperature overnight reaction 19 hours.Add the 75.5ml2N Hydrocerol A, separatory, water extracted in toluene twice merges organic phase, drying, rotary evaporation is with (2 * 10ml) heptane wash resistatess.The resistates underpressure distillation obtains 15g benzyloxy methyl aceto acetate (II), productive rate 84%.
The preparation of second step (3S)-3-hydroxyl-4-benzyloxy ethyl n-butyrate (III)
Preparation of catalysts: 36mg (R)-(+)-BINAP, 14mg dimerization phenyl ruthenium chloride are joined through the distillation and the 1mlN of argon-degassed again; In N-N (DMF); Stirred 15 minutes, in 100 ℃ of oil baths, continue then reaction got final product in 10 minutes catalyzer RuCl
2The DMF solution of [(R)-BINAP], whole process needs argon shield.
In the 100ml reaction kettle, add 20g (84.6mmol) benzyloxy methyl aceto acetate (II), 20ml ethanol, argon-degassed.Under argon shield, in the catalyzer adding reaction kettle with above-mentioned preparation, regulate hydrogen pressure to 4 normal atmosphere then, spend the night in 100 ℃ of stirring reactions.Be cooled to room temperature, reaction solution is transferred in the beaker, the washing with alcohol reaction kettle.At suction funnel middle berth layer silica gel, suction filtration reaction solution.Ethanol boils off in will filtrating, and gained oily matter is placed the refrigerator crystallization, gets 19.4g (3S)-hydroxyl-4-benzyloxy ethyl n-butyrate (III), productive rate 96%, e, e value 98.4%.
The 3rd step (3S)-3-is to the preparation of methoxyl group benzyloxy base-4-benzyloxy ethyl n-butyrate (IV)
With 11.9g (50mmol) (3S)-hydroxyl-4-benzyloxy ethyl n-butyrate (III) joins in the mixed solvent of methylene dichloride (50ml) and normal hexane (100ml); Add 1.2g (5mmol) camphorsulfonic acid, drip commercially available 20.7g (10mmol) imido that is dissolved in the 20ml normal hexane then and pursue the solution of acetate methoxy benzyl ester.Normal-temperature reaction 36h adds saturated ammonium chloride, adds methylene dichloride 100ml again, separatory, and organic phase is used the saturated common salt water washing, uses anhydrous sodium sulfate drying again, revolves inspissation and contracts.Add normal hexane 100ml, separate out solid, filter.Revolve dried, 13.4g (3S)-3-to methoxyl group benzyloxy base-4-benzyloxy ethyl n-butyrate (IV), productive rate 75%.
The 4th step (5S)-5-is to the preparation of methoxyl group benzyloxy base-6-benzyloxy-3-carbonyl-hecanoic acid t-butyl ester (V)
The claisen ester contracts and reacts, and the step that increases carbochain is: in nitrogen protection, under 0 ℃; 60ml (61mmol) n-Butyl Lithium is splashed in the solution of 8.1ml Isopropylamine and 12ml THF composition; Stirred 30 minutes, and be cooled to-40 ℃, drip 7.7ml (57.4mmol) tert-butyl acetate again.React after 1 hour, with 10.75g (30mmol) (3S)-3-splashes in the above-mentioned mixed system the tetrahydrofuran solution of methoxyl group benzyloxy base-4-benzyloxy ethyl n-butyrate (IV) and 8ml, drips Bi Jixu-40 ℃ of reactions 1 hour down, react completely.20ml water is joined in the reaction mixture, and temperature rises to-15 ℃.Separatory, (2 * 15ml), the merging organic phase is used anhydrous sodium sulfate drying to water, and solvent revolves steaming, gets thick product, and column chromatography gets 10.9g (5S)-5-to methoxyl group benzyloxy base-6-benzyloxy-3-carbonyl-hecanoic acid t-butyl ester (V), productive rate 85% with extracted in toluene.
The 5th step (3R, 5S)-5-is to the preparation of methoxyl group benzyloxy base-6-benzyloxy-3-hydroxyl-hecanoic acid t-butyl ester (VI)
Preparation of catalysts: 18mg (R)-(+)-BINAP, 7mg dimerization phenyl ruthenium chloride are joined and heavily steam in the 1mlDMF of argon-degassed, stirred 15 minutes, in 100 ℃ of (in advance preheating) oil baths, continue then reaction got final product in 10 minutes catalyzer RuCl
2The DMF solution of [(R)-BINAP], whole process needs argon shield.
In the 100ml reaction kettle, add 17.14g (40mmol) (5S)-5-is to methoxyl group benzyloxy base-6-benzyloxy-3-carbonyl-hecanoic acid t-butyl ester (V), 20ml ethanol, argon-degassed.After the catalyzer of above-mentioned preparation joins in the reaction kettle under argon shield then, regulate hydrogen pressure 4.04X10
5Pa (4 normal atmosphere) spends the night at 100 ℃ of following stirring reactions.Be cooled to room temperature, reaction solution is transferred in the beaker, the washing with alcohol reaction kettle.At suction funnel middle berth layer silica gel, suction filtration reaction solution.Ethanol boils off in will filtrating, and gained oily matter is placed the refrigerator crystallization, 16.25g (3R, 5S)-5-is to methoxyl group benzyloxy base-6-benzyloxy-3-hydroxyl-hecanoic acid t-butyl ester (VI), productive rate 94%, d, e value 99.2%.
The 6th step (3R, 5S)-6-benzyloxy-3, the preparation of 5-dihydroxyl-hecanoic acid t-butyl ester (VII)
With 16.25g (37.7mmol) (3R, 5S)-5-is dissolved in the 150ml acetonitrile methoxyl group benzyloxy base-6-benzyloxy-3-hydroxyl-hecanoic acid t-butyl ester (VI), adds 15ml water; Add 41.4g (75.5mmol) ceric ammonium nitrate (CAN); React after 15 minutes, add ether 500ml, water (250ml) washing ether layer; Separatory, organic phase is used anhydrous sodium sulfate drying.Revolve dried, bullion through column chromatography purification, pure article 11.5g, productive rate 98%.
The 7th step (3R, 5S)-6-benzyloxy-3,5-O-isopropylidene-3, the preparation of 5-dihydroxyl hecanoic acid t-butyl ester (VIII)
Respectively with 7.35g (8.68ml; 69.2mmol) 2,2-Propanal dimethyl acetal, 0.68g tosic acid, 11.1g (35.8mmol), (3R, 5S)-dihydroxyl-6-benzyloxy hecanoic acid t-butyl ester (VII) joins in the 100ml acetone; Stirring at room reaction 4 hours, solution colour is flavescence gradually.Revolve the steaming reaction solution, add in the resistates in the 50ml ETHYLE ACETATE, with saturated sodium bicarbonate solution washing three times, saturated common salt water washing then, anhydrous sodium sulfate drying organic layer, suction filtration revolve and boil off solvent.Get faint yellow oily thing, bullion 11.8g, productive rate 96%.Need not further to handle again, can directly cast step reaction.
The 8th step (3R, 5S)-6-hydroxyl-3,5-O-isopropylidene-3, the preparation of 5-dihydroxyl hecanoic acid t-butyl ester (IX)
(3R, 5S)-6-benzyloxy-3,5-isopropylidene hecanoic acid t-butyl ester (VIII) is dissolved in 30ml methyl alcohol, adding 0.64g (10%) palladium carbon Pd/C, normal temperature and pressure feeds H with 6.5g (18.5mmol)
2, stirring reaction 5 hours, TLC detect (ethyl acetate/petroleum ether=1:1) follow the tracks of reaction to accomplish.Diatomite filtration is removed palladium carbon, revolve to steam filtrating, gained oily matter column chromatography, 4.2g (3R, 5S)-6-hydroxyl-3,5-O-isopropylidene-3,5-dihydroxyl hecanoic acid t-butyl ester (IX), productive rate 87%.
Claims (1)
- One kind prepare (3R, 5S)-3,5, the method for 6-trihydroxy--hecanoic acid t-butyl ester comprises:The first step is a starting raw material with the chloroacetyl acetacetic ester, after benzyloxyization, makes the benzyloxy methyl aceto acetate;In second step, use RuCl 2[(R)-and BINAP] catalytic hydrogenation, make (3S)-3-hydroxyl-4-benzyloxy ethyl n-butyrate;It is characterized in that:The 3rd step, the hydroxyl of (3S)-3-hydroxyl-4-benzyloxy ethyl n-butyrate in second step to be protected with the blocking group methoxy-benzyl, employing GPF (General Protection False technology makes (3S)-3-to methoxyl group benzyloxy base-4-benzyloxy ethyl n-butyrate;In the 4th step, process claisen ester contracts and reacts, and increases carbochain, makes (5S)-5-to methoxyl group benzyloxy base-6-benzyloxy-3-carbonyl-hecanoic acid t-butyl ester;In the 5th step, use RuCl 2[(R)-BINAP] made catalyzer, the carbonyl on No. 3 carbon of catalytic hydrogenation make (3R, 5S)-5-is to methoxyl group benzyloxy base-6-benzyloxy-3-hydroxyl-hecanoic acid t-butyl ester;The 6th step, will slough methoxy-benzyl with ceric ammonium nitrate, make (3R, 5S)-6-benzyloxy-3,5-dihydroxyl-hecanoic acid t-butyl ester;The 7th step, with acetonylidene 3,5 hydroxyl of the 6th step product is protected, make (3R, 5S)-6-benzyloxy-3,5-O-isopropylidene-3,5-dihydroxyl hecanoic acid t-butyl ester;The 8th step, with palladium carbon benzyl is sloughed, obtain at last (3R, 5S)-6-hydroxyl-3,5-O-isopropylidene-3,5-dihydroxyl hecanoic acid t-butyl ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100273470A CN101085770B (en) | 2006-06-07 | 2006-06-07 | Method for preparing t-butyl (3R, 5S)-3,5,6-trihydroxy-hexanoate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100273470A CN101085770B (en) | 2006-06-07 | 2006-06-07 | Method for preparing t-butyl (3R, 5S)-3,5,6-trihydroxy-hexanoate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101085770A CN101085770A (en) | 2007-12-12 |
| CN101085770B true CN101085770B (en) | 2012-07-04 |
Family
ID=38936961
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006100273470A Active CN101085770B (en) | 2006-06-07 | 2006-06-07 | Method for preparing t-butyl (3R, 5S)-3,5,6-trihydroxy-hexanoate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101085770B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570554A (en) * | 2013-10-26 | 2014-02-12 | 合肥禾味食品有限公司 | Application of Ru-Binap catalyst to catalyzing isomerization reaction of substrate with specific structure |
| CN104726506A (en) * | 2015-03-17 | 2015-06-24 | 苏州汉酶生物技术有限公司 | Preparation method of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate |
| CN107915715A (en) * | 2016-10-09 | 2018-04-17 | 北京阜康仁生物制药科技有限公司 | A kind of synthetic method of rosuvastatin calcium side chain key intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5286883A (en) * | 1992-08-13 | 1994-02-15 | Takasago International Corporation | (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative and production method thereof |
| US5399722A (en) * | 1992-07-02 | 1995-03-21 | Hoechst Aktiengesellschaft | Process for preparing tert-butyl (3R,5S)-6-hydroxy-3,5--O--isopropylidene-3,5-dihydroxyhexanoate |
-
2006
- 2006-06-07 CN CN2006100273470A patent/CN101085770B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5399722A (en) * | 1992-07-02 | 1995-03-21 | Hoechst Aktiengesellschaft | Process for preparing tert-butyl (3R,5S)-6-hydroxy-3,5--O--isopropylidene-3,5-dihydroxyhexanoate |
| US5286883A (en) * | 1992-08-13 | 1994-02-15 | Takasago International Corporation | (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative and production method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 王颖.2006100273470.《STN检索记录》.2011, * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101085770A (en) | 2007-12-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Ohkuma et al. | Practical enantioselective hydrogenation of aromatic ketones | |
| CN102458659A (en) | Asymmetric hydrogenation catalyst | |
| Chen et al. | A highly effective phosphinite ligand derived from D-mannitol for Rh-catalyzed asymmetric hydrogenation | |
| CA2671830C (en) | Catalytic process for asymmetric hydrogenation | |
| CN101085770B (en) | Method for preparing t-butyl (3R, 5S)-3,5,6-trihydroxy-hexanoate | |
| CA2308415A1 (en) | Transition metal-catalyzed reactions based on chiral amine oxazolinyl ligands | |
| CA2658773C (en) | Asymmetric hydrogenation of 1,1,1-trifluoroacetone | |
| JPH09249677A (en) | Chiral ruthenium complex, its production and enantiomer selective transfer hydrogenation of prochiral ketone | |
| Faure et al. | Reactions of a Transient Carbonyl (chloro)(hydrido) ruthenium (ii) Complex with Ethylene, Alkynes, and CO; Chemistry of the New Anion [Ru2 (CO) 4Cl5]− | |
| JP2002037760A (en) | Method for producing optically active alcohol | |
| CN1579627A (en) | Chiral ligand metal complex catalyst system, and its preparation method and use | |
| WO2005007662A2 (en) | Biphosphine ruthenium complexes with chiral diamine ligande as catalysts | |
| CA2587726A1 (en) | Sulphonylated diphenylethylenediamines, method for their preparation and use in transfer hydrogenation catalysis | |
| US5239088A (en) | Process for the preparation of homoserine lactones | |
| CN111718250B (en) | Method for preparing R-citronellal | |
| CN111217809B (en) | Chiral nitrogen-containing diene ligand and preparation method and application thereof | |
| CN110128472B (en) | Synthesis and application of oxaspiro PNN type ligand | |
| Yin et al. | The synthesis of dendritic BINOL ligands and their applications in the asymmetric addition of diethylzinc to benzaldehyde | |
| JP4928798B2 (en) | Catalyst for asymmetric synthesis, ligand used therein, and method for producing optically active compound by asymmetric synthesis reaction using them | |
| CN109721630A (en) | A kind of synthetic method of Ugi ' s amine and its derivative | |
| CA2717039A1 (en) | Catalytic process for asymmetric hydrogenation | |
| CA2442934A1 (en) | Enantiomerically selective cyclopropanation | |
| CN101560184A (en) | N-chiral quaternary ammonium salt derived from amino acid and preparation method thereof | |
| CN115960007A (en) | Preparation method of sitagliptin intermediate by using nitrogen-containing formyl catalyst | |
| CN114524789A (en) | Method for enantioselectively synthesizing 3, 3-disubstituted isobenzofuran-1 (3H) -ketone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160512 Address after: 201424, Shanghai Fengxian District chemical industry zone, Fengxian District, Chu Hua Road, No. 7 Patentee after: Shanghai Qingsong Pharmaceutical Co., Ltd. Address before: 201424, Shanghai Fengxian District chemical industry zone, Fengxian District, Chu Hua Road, No. 7 Patentee before: Shanghai Qingsong Pharmaceutical Co., Ltd. Patentee before: East China Normal University |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation of N,N,N',N',-tetraacetyl-3,5,3',5'-tetrabromo(chloro)-4,4'-diaminodiphenyl methane Effective date of registration: 20160512 Granted publication date: 20120704 Pledgee: China Minsheng Banking Corp Shanghai branch Pledgor: Shanghai Qingsong Pharmaceutical Co., Ltd. Registration number: 2015990000388 |
|
| PLDC | Enforcement, change and cancellation of contracts on pledge of patent right or utility model |