CN101085770A - 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
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- CN101085770A CN101085770A CN 200610027347 CN200610027347A CN101085770A CN 101085770 A CN101085770 A CN 101085770A CN 200610027347 CN200610027347 CN 200610027347 CN 200610027347 A CN200610027347 A CN 200610027347A CN 101085770 A CN101085770 A CN 101085770A
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- benzyloxy
- hydroxyl
- butyl ester
- hecanoic acid
- benzyl
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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 as follows:
R
1Be hydrogen or benzyl, R2 is the ethyl or the tertiary butyl, and R is the protecting group 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) protecting group.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 protecting group tetrahydropyrans, get up with the hydroxyl protection of acetonylidene 3,5, again benzyl is sloughed 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 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.From following table as can be seen, at d, the e value is 98% o'clock, and 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, e value is just understood height.The present invention has found a kind of new blocking group.This blocking group is to methoxy-benzyl.With 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 as follows: 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 butyrate.Be characterized in:
The 3rd step; second (3S)-3-hydroxyl-4-benzyloxy ethyl 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 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] makees 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 as follows:
Advantage of the present invention is as follows:
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 using 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 5399722 of not using blocking group, 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 citric acid, separatory, water toluene extracting 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 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 the dinethylformamide (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 reactor, add 20g (84.6mmol) benzyloxy methyl aceto acetate (II), 20ml ethanol, argon-degassed.Under argon shield, in the catalyzer adding reactor 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 reactor.At suction funnel middle berth layer silica gel, suction filtration reaction solution.Ethanol in the filtrate is boiled off, and gained oily matter is placed the refrigerator crystallization, gets 19.4g (3S)-hydroxyl-4-benzyloxy ethyl 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 butyrate (IV)
With 11.9g (50mmol) (3S)-hydroxyl-4-benzyloxy ethyl 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 anhydrous sodium sulfate drying is used in organic phase saturated common salt water washing again, revolves inspissation and contracts.Add normal hexane 100ml, separate out solid, filter.Be spin-dried for, get 13.49 (3S)-3-methoxyl group benzyloxy base-4-benzyloxy ethyl 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 tetrahydrofuran (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 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 the toluene extraction.
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 reactor, 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 reactor under argon shield then, regulate hydrogen pressure 4.04 * 10
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 reactor.At suction funnel middle berth layer silica gel, suction filtration reaction solution.Ethanol in the filtrate is boiled off, 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 (VI I)
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), add 15ml water, add 41.4g (75.5mmol) ceric ammonium nitrate (CAN), react after 15 minutes, add ether 500ml, water (250ml) washing ether layer, separatory, the organic phase anhydrous sodium sulfate drying.Be spin-dried for, get crude product, get pure product 11.5g, productive rate 98% through column chromatography purification.
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 ethyl 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, crude product 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)
With 6.5g (18.5mmol) (3R, 5S)-6-benzyloxy-3,5-isopropylidene hecanoic acid t-butyl ester (VIII) is dissolved in 30ml methyl alcohol, is adding 0.64g (10%) palladium carbon Pd/C, normal temperature and pressure feeds H
2, stirring reaction 5 hours, TLC detect (ethyl acetate/petroleum ether=1: 1) tracking reaction and finish.Diatomite filtration is removed palladium carbon, revolve to steam filtrate, 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 ethyl chloroacetate, 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 butyrate;It is characterized in that:The 3rd step, the hydroxyl of second (the 3S)-3-hydroxyl-4-benzyloxy ethyl butyrate that goes on foot is protected with the blocking group methoxy-benzyl, adopt GPF (General Protection False technology, make (3S)-3-to methoxyl group benzyloxy base-4-benzyloxy ethyl 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] makees 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.
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Cited By (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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE59307409D1 (en) * | 1992-07-02 | 1997-10-30 | Hoechst Ag | Process for the preparation of (3R, 5S) 6-hydroxy-3,5-0-isopropylidene-3,5-dihydroxy-hexanoic acid tert-butyl ester |
| JP3076154B2 (en) * | 1992-08-13 | 2000-08-14 | 高砂香料工業株式会社 | (3R, 5S) -3,5,6-trihydroxyhexanoic acid derivative and method for producing the same |
-
2006
- 2006-06-07 CN CN2006100273470A patent/CN101085770B/en active Active
Cited By (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 |
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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 |
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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 |
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