CN1765892A - Orlistat preparation method - Google Patents

Orlistat preparation method Download PDF

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CN1765892A
CN1765892A CN 200510110413 CN200510110413A CN1765892A CN 1765892 A CN1765892 A CN 1765892A CN 200510110413 CN200510110413 CN 200510110413 CN 200510110413 A CN200510110413 A CN 200510110413A CN 1765892 A CN1765892 A CN 1765892A
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formula
compound
preparation
orlistat
tetrahydrofuran
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CN1321114C (en
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陈卫平
杨琍苹
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Argus Pharmaceuticals, Ltd.
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East China Normal University
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Abstract

The invention relates to a preparation method for oleanstada, which comprises: on catalyst action, using enolsiliconether and lauraldehyde to condense directly and obtain chiral hydroxyl hexadeketo ester; after eight steps contained protecting hydroxyl group, reducing and cyclization, obtaining the objective product with chemical formula as (I) for efficient fat-reducing. This method needs low cost.

Description

A kind of preparation method of orlistat
Technical field
The present invention relates to a kind of preparation method of orlistat, belong to field of medicine preparing technology.
Background technology
Orlistat is a lipase inhibitor unique in the present diet pill, and it mainly acts on is the activity that select to suppress gi tract lipase, is absorbed by the body and reaches the purpose of fat-reducing by blocking about 30% dietary fat.Different with other diet pill, its biggest advantage is not act on neural system, does not enter blood, and more than 100 the country's listings in the whole world of depress appetite not, this medicine account for 2/3 of diet pill market, the world.
Chinese patent ZL97109732.1 provides a kind of method of fermentative production fat statin.The fat statin can be separated from nutrient solution and obtained, and the fat statin can be reduced to tetrahydrochysene fat statin.The microorganism of the generation fat statin described in this patent is other bacterial strain of poison three plain streptomycete or derivatives thereofs.The yield of microorganism that fermentation produces the fat statin is lower, and through 138 hours fermentation culture, 1 liter substratum only contained the fat statin of 0.15g, thereby makes the production cost height of orlistat.
The method of the production delta-lactone that the patent ZL01111916.0 that the Flax Huffmun-Laroqie Co., Ltd of Switzerland obtains in China provides a kind of enantiomorph to have to select.By to 5, the selecting property reduction of 6-dihydropyrane-2-ketone structure is carried out the chirality delta-lactone that generates ring-opening reaction then and is separated the intermediate that obtains orlistat under alkaline condition.But the synthetic route that this patent provides long (reaction of 12 steps is arranged) improves the beta-hydroxy esters production cost of (being used for synthesizing the important intermediate of orlistat).The chirality agents useful for same of controlling 5 hydroxyls in addition is relatively more expensive, and economical and practical value is lower.
Summary of the invention
It is short to the objective of the invention is to disclose a kind of synthetic route, the preparation method of the orlistat that production cost is low.
In order to achieve the above object, the present invention finds silyl enol ether and lauryl aldehyde under several chiral catalyst effects through studying for a long period of time, and a direct condensation of step gets 5-position chiral hydroxyl group hexadecyl β-oxo keto ester, the protection hydroxyl, use the chiral diphosphine ligand selective reduction, introduce hexane; By hydrolysis, Cheng Huan, protecting group, under the Mitsunobu condition, obtain the target product orlistat as shown in the formula (I) with low cost through protecting hydroxyl, reduction and becoming to encircle at last with N-formyl radical-S-leucine reaction.Concrete technology was undertaken by following eight steps:
Figure A20051011041300071
The first step. under catalyst action, with lauryl aldehyde and structural formula (II) or silyl enol ether (III) the asymmetry catalysis aldol reaction taking place respectively, obtains (5R)-5-hydroxyl-3-oxo methyl palmitate (IV):
R is an alkyl in formula (II), the formula (III); R 1And R 2Be alkyl or trialkyl silyl; R 3Be alkyl or trialkyl silyl; R 4And R 5Be alkyl or (CH 2) n, n=3 to 9.
Catalyzer
Figure A20051011041300074
Used chiral catalyst can be above three kinds of form metal complexs, and organic ligand mainly is the dinaphthalene part, and the coordinate atom can be oxygen, phosphorus, nitrogen, and metal can be the transition metal that Ti, Cu, Zr etc. have strong coordination ability.Preferred catalyst is:
Figure A20051011041300081
Catalyzer/the formula used in this step (II) or mol ratio (III) are 1/2000～1/100000, are preferably 1/2000～1/4000.The enantiomorph (formula IV) that the asymmetric aldol reaction that this catalyzer provides provides is excessive, greater than 97%.
Second step. the formula (IV) that obtains is protected with protective material, got formula V::
P is a protecting group, as:
Figure A20051011041300083
Figure A20051011041300086
R 6, R 7, R 8, R 9, R 10, R 11It is alkyl or trimethyl silicon based.
The 3rd step. carry out asymmetric catalytic hydrogenation with following two kinds of chiral diphosphine metal complexs, obtain formula (VI):
Chiral diphosphine ligand
Figure A20051011041300091
Wherein X is a halogen, as chlorine, and bromine or iodine.R 1, R 2, R 3, R 4Independently be H, C 1-C6 alkyl or C 1-C 6Alkoxyl group, M are metal Ru, rhodium or palladium.
Figure A20051011041300092
Wherein X is a halogen, as chlorine, and bromine or iodine.R 5, R 6Independently be H, C 1-C6 alkyl or C 1-C 6Alkoxyl group, M are metal Ru, rhodium or palladium.The mol ratio of the title complex/substrate that uses in this step is 1/2000～1/100000, is preferably 1/2000～1/4000.The diastereomeric excess that the asymmetric induction reduction reaction that this catalyzer provides provides is greater than 92%.
The 4th step. the tetrahydrofuran solution of formula (VI) and n-BuLi/ diisopropylamine-10～-90 ℃ of reactions, is introduced n-hexyl, and is subjected to C3 on the alpha-carbon of ester group, the influence of C5 chirality can stereoselectively obtain (VII) temperature of reaction preferably at-78 ℃.Reaction provides the amount of diastereomer relevant with temperature of reaction.The amount of the low more diastereomer of temperature is few more.
Figure A20051011041300093
The 5th step. compound (VII) hydrolysis in KOH/ methyl alcohol provides the condition of alkalescence to comprise NaOH or KOH.Solvent can be the pure solution or the mixing solutions of methyl alcohol, ethanol or tetrahydrofuran (THF), and temperature of reaction can obtain compound (VIII) easily at 0～50 ℃:
Figure A20051011041300101
The 6th step. compound (VIII) with the TsCl effect of 1.5 times～3 times equivalents (mol ratio), forms asymmetric lactone (IX) in 10～30 hours intramolecular dehydrations of-5～10 ℃ of reactions under the pyridine effect:
Figure A20051011041300102
The 7th step. under the Pd-C10% effect, the protecting group of above-mentioned lactone can be sloughed, and obtains compound formula (X).
Figure A20051011041300103
The 8th the step. compound (X) again with N-formyl radical-leucine, triphenylphosphine, azo two carbonate reactions, can get target molecule orlistat (I) behind the purifying.
Figure A20051011041300104
Advantage of the present invention is as follows:
1. because the present invention adopts silyl enol ether and lauryl aldehyde as the raw material production orlistat, therefore, the synthetic route of comparing with existing method shortens into 8 from 12 steps and goes on foot, and is convenient to industrialization, has the higher utility of ratio.
2. because the present invention adopts the low price of chirality control reagent, obtaining easily, is that production cost has had bigger decline therefore.
Embodiment
Embodiment 1
The preparation of the first step (5R)-5-hydroxyl-3-oxo methyl palmitate (IV)
Under the nitrogen effect, (458mg, tetrahydrofuran solution 1.6mmol) add to Ti (OPr-i) with (S)-(-)-BINOL 4(455mg, 1.6mmol) in.Solution at room temperature stirred 20 minutes, then with lauryl aldehyde (14.75g, 80mmol), lithium chloride (1.10g, 0.026mol) and N, N, N ', (6.14g 0.053mol) adds N '-tetramethyl-ethyl diamines.Mixture at room temperature stirred 20 minutes, and again with 1, (48.7g 187mmol) dropwise adds two (the trimethylsiloxy group)-1-methoxyl group-1,3-butadienes of 3-, at room temperature stirs 4 hours.Reaction finishes the back and adds NaHCO 3The aqueous solution, organic layer is handled with ethyl acetate, gets compound formula (IV).
Second the step (5R)-5-right-methoxyl group benzyloxy base-3-oxo methyl palmitate, prepare as formula V
(5.18g, ethereal solution 37.5mmol) add under room temperature in the ether of NaH (90mg, 3.75mmol, 60% mineral/oil) with 4-methoxyl group benzylalcohol.With this solution stirring 1 hour, be chilled to 0 ℃.(3.76ml, 5.42g 37.5mmol) stirred 5 minutes in the adding mixture, at room temperature stirred 20 minutes again with Trichloroacetonitrile.Add the 50ml ether, use saturated NaHCO again 3Solution and salt water washing, drying gets the yellow oil intermediate.The intermediate that this is thick is dissolved in the methylene dichloride, and with (5R)-5-hydroxyl-3-oxo methyl palmitate (IV) (25.0mmol) and PPTS (276mg 0.049mmol) adds, and mixture was stirred 22 hours, forms white solid simultaneously.Use NaHCO 3Solution and salt water washing, the anhydrous MgSO of solution 4Dry, suction filtration obtain the semi-solid mixture after the removal of solvent under reduced pressure, use 1: 1 hexane and methylene dichloride to handle again, boil off behind the solvent again through dodging column purification.
The 3rd step (3S, 5R)-3-hydroxyl-5-is right-methoxyl group benzyloxy base methyl palmitate, and suc as formula (VI)
Under the nitrogen effect with (RuCl (C 6H 6)) 2(10.5mg, 0.21mmol) and (S)-(26.7mg 0.43mmol) stirred ten minutes in 100 ℃ at the solution of DMF (2ml) Binap, in the room temperature cooling, obtained catalyst solution.Again with (5R)-5-right-methoxyl group benzyloxy base-3-oxo methyl palmitate (V) (40mmol) is dissolved in the 100ml methyl alcohol, in autoclave, logical H 2To 50atm, mixture is chilled to room temperature in 100 ℃ of stirrings 8 hours.With the reaction mixture concentrating under reduced pressure, residuum is dissolved in the normal hexane, suction filtration, and solution decompression concentrates, and obtains compound (VI).
The 4th step (2S, 3S, 5R)-2-hexyl-3-hydroxy-5-is to methoxyl group benzyloxy base methyl palmitate (VII)
Under the nitrogen effect, (5.63g, tetrahydrofuran solution 56mmol) (50ml) are cooled to-20 ℃, and (2.5M, 21.6ml 54mmol) dropwise add in the above-mentioned solution, and stir 30 minutes at-30 to-20 ℃ with the n-BuLi/ hexane solution with Diisopropylamine.Reaction mixture is cooled to-78 ℃, with compound VI (3S, 5R)-3-hydroxyl-5-is right-(7.61g 18mol) splashes in this solution in-78 ℃ methoxyl group benzyloxy base methyl palmitate.Mixture stirred 1 hour at-70 ℃, and be warming up to-10 ℃ 1.5 hours.Again mixture is cooled to-40 ℃, with 1-iodohexane (11.4g, 54mmol) and HMPA (5.0ml 27mmol) splashes in-40 ℃ ,-40 ℃ stir 2 hours after, mixture is warmed to room temperature, and in stirring at room 20 hours, reacts saturated NH 4The Cl aqueous solution (60ml) stops, and with ethyl acetate handle compound (VII).
The 5th the step (2S, 3S, 5R)-2-hexyl-3-hydroxy-5-to methoxyl group benzyloxy base palmitic acid (VIII) with compound VI I (2S, 3S, 5R)-(7.15g 15mmol) adds tetrahydrofuran (THF) (30ml) to 2-hexyl-3-hydroxy-5-, and methyl alcohol (30ml) water to methoxyl group benzyloxy base methyl palmitate, (5ml) potassium hydroxide (30mmol, 1.68g) in the mixed solvent, mixture refluxed to be concentrated in 5 hours, added 50ml hexane and 10% hydrochloric acid (20ml), organic layer separates, anhydrous MgSO 4Dry, suction filtration, filtrate decompression concentrates, and residuum gets compound (VIII) through dodging post.
The 6th step (3S, 4S)-3-hexyl-4-(R-2-(to methoxyl group benzyloxy base) tridecyl)-2-oxo lactone (IX)
Under nitrogen, 0 ℃, dropwise with Tosyl chloride (3.81g, 20mmol), add compound VIII (2S, 3S, 5R)-(4.63g is in pyridine solution 10mmol) to methoxyl group benzyloxy base palmitic acid for 2-hexyl-3-hydroxy-5-.Stirred 20 hours down at 0 ℃, add water, mixture stirring at room 30 minutes boils off pyridine, with methyl tertiary butyl ether, 2N HCl, 5%NaHCO 3With the above-mentioned crystal slurry of 10%NaCL solution elder generation's after scouring shape solid, organic phase anhydrous Na 2SO 4Drying, activated carbon decolorizing, elimination siccative and gac, filtrate concentrate compound (IX).
The 7th step (3S, 4S)-3-hexyl-4-[R-2-hydroxyl tridecyl]-2-oxo lactone (X)
At Compound I X (3S, 4S)-3-hexyl-4-[R-2-(to methoxyl group benzyloxy base) tridecyl]-2-oxo lactone (4.45g, in tetrahydrofuran solution 10mmol), add 10%pd-C (250mg), hydrogenation is suction filtration after 18 hours, and hexane wash is used in the filtrate evaporation behind the residuum, dry (X), fusing point 61-62 ℃ of getting.
The preparation (I) of the 8th step orlistat
With compounds X (8.86g; 25mmol); N-formyl radical-S-leucine (5.17g; 33mmol) and triphenylphosphine (9.84g; 37.5mmol) be dissolved in the 100ml tetrahydrofuran (THF), stir, with azo Ue-5908 (7.26g; 41.7mmol) tetrahydrofuran solution dropwise add in the above-mentioned solution, be chilled to-10 ℃.Stirred n hour at-10 ℃, boil off solvent, with hexane and the washing of 70% methanol aqueous solution, resulting residuum is used anhydrous Na 2SO 4Drying, boil off behind the solvent crude product, this crude product is dissolved in the hexane, slowly be chilled to 5 ℃, separate out crystallization, use hexane wash, must orlistat (I).
[α] D 20＝-9.5°(c＝1，CHCl 3)。
1H?NMR(CDCl 3)δ＝8.23(1H，s)，6.06(1H，d)，5.11(1H，m)，4.69(2H，m)，3.69(1H，m)，2.10～1.85(2H，m)，1.81～1.47(12H，m)，1.42～1.07(21H，m)，0.95(6H，d)，0.87(6H)。

Claims (9)

1. the preparation method of an orlistat is characterized in that: the orlistat with formula (I) expression obtains according to the following step:
Figure A2005101104130002C1
The first step. with lauryl aldehyde and silyl enol ether (II) the asymmetry catalysis aldol reaction taking place, obtains (5R)-5-hydroxyl-3-oxo methyl palmitate (IV)
Figure A2005101104130002C2
Second step. the formula (IV) that obtains is protected, got formula V:
Figure A2005101104130002C3
The 3rd step. carry out asymmetric catalytic hydrogenation with the chiral diphosphine metal complex and obtain (VI):
Figure A2005101104130002C4
The 4th step. the tetrahydrofuran solution of formula (VI) and n-BuLi/ diisopropylamine-10～-90 ℃ of preferred-78 ℃ of reactions, is introduced n-hexyl, and is subjected to C3 on the alpha-carbon of ester group, the C5 chirality influences, stereoselective obtaining (VII)
The 5th step. compound (VII) hydrolysis in KOH/ methyl alcohol obtains compound (VIII):
Figure A2005101104130003C1
The 6th step. compound (VIII) with the TsCl effect, forms asymmetric lactone (IX) in pyridine solution:
The 7th step. under the Pd-C effect, the protecting group of above-mentioned lactone can be sloughed, and obtains compound (X);
Figure A2005101104130003C3
The 8th step. compound (X) again with N-formyl radical-leucine, triphenylphosphine, azo two carbonate reactions, behind the purifying the orlistat of formula (I).
Figure A2005101104130003C4
2, the preparation method of a kind of orlistat according to claim 1 is characterized in that: wherein the structure of the silyl enol ether that adopts in the described compound formula of the first step (IV) preparation is formula (II) or formula (III)
Figure A2005101104130003C5
Wherein R is an alkyl; R1, R2 and R3 are alkyl or trialkyl silyl; R4 and R5 are alkyl or (CH 2) n, n=3～9; Used chiral catalyst:
Catalyzer
Figure A2005101104130004C1
(S)-BINOL-Ti(OPr-i) 2
Wherein X is halogens chlorine or bromine or iodine; Used chiral catalyst is the metal complex of above three kinds of forms, and organic ligand mainly is the dinaphthalene part, and the coordinate atom is oxygen, phosphorus, nitrogen, and metal is the transition metal that Ti, Cu, Zr have strong coordination ability; Preferred catalyst is following structural formula.
Figure A2005101104130004C2
3. the preparation method of a kind of orlistat according to claim 1 is characterized in that: wherein the blocking group P of the alcohol of described compound formula V of second step is following four kinds of forms.
4. the preparation method of a kind of orlistat according to claim 1 is characterized in that: wherein the chiral diphosphine ligand of described asymmetric hydrogenation of the 3rd step is the metal ligand of following two kinds of forms:
Figure A2005101104130004C4
Wherein X is halogens chlorine or bromine or iodine, R 1, R 2, R 3, R 4, R 5, R 6Independently be H or C 1-C6 alkyl or C 1-C 6Alkoxyl group, M are metal Ru or rhodium or palladium.
5. the preparation method of a kind of orlistat according to claim 1 is characterized in that: the compound formula (VII) in wherein said the 4th step prepare by following method: with the temperature of the tetrahydrofuran solution of formula (VI) and highly basic n-BuLi/ diisopropylamine, iodine hexane and HMPA is that low temperature time reacts between-10～-90 ℃.
6. the preparation method of a kind of orlistat according to claim 1, it is characterized in that: wherein the 5th described compound formula of step (VIII) prepares by following method: compound (VII) hydrolysis under alkaline condition, provide alkaline condition to comprise the pure solution or the mixing solutions of methyl alcohol, ethanol or the tetrahydrofuran (THF) of NaOH or KOH, temperature of reaction is at 0～50 ℃.
7. the preparation method of a kind of orlistat according to claim 1 is characterized in that: wherein the 6th described compound formula of step (IX) prepares by following method: compound (VIII) becomes lactone under the TsCl effect, solvent for use is a pyridine.
8. the preparation method of a kind of orlistat according to claim 1; it is characterized in that: wherein the 7th described compound formula of step (X) prepares by following method: compound (IX) is sloughed protecting group under the effect of palladium carbon; palladium carbon is 5%～10%; solvent for use is tetrahydrofuran (THF) or methyl alcohol or ethanol; hydrogen pressure 1atm is to 10atm, and the reaction times is 10～30 hours.
9. the preparation method of a kind of orlistat according to claim 1; it is characterized in that: wherein the 8th described formula of step (I) prepares by following method: compound (X) and N-formyl radical-leucine, triphenylphosphine, azo two carbonate reactions; solvent for use is a tetrahydrofuran (THF), and temperature of reaction is at-20～0 ℃.
CNB2005101104136A 2005-11-16 2005-11-16 Orlistat preparation method Expired - Fee Related CN1321114C (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009143664A1 (en) * 2008-05-26 2009-12-03 重庆植恩药业有限公司 The preparation method of (3s,4s)-3-hexyl-4-((r)-2-hydroxytridecyl)-oxetan-2-one and the product of that method
CN101066924B (en) * 2007-06-08 2011-01-12 中国科学院上海有机化学研究所 2-hexyl-3-hydroxy-5-R1Oxyhexadecanoic acid R2ester, preparation method and application thereof for preparing weight-reducing medicine orlistat
CN102070567A (en) * 2011-01-21 2011-05-25 天津市海德安科医药科技发展有限公司 Method for preparing high-purity orlistat by using reverse phase high-performance liquid chromatogram
CN103012240A (en) * 2012-12-11 2013-04-03 保定市龙瑞药物技术有限责任公司 Preparation method of atorvastatin calcium
CN108484536A (en) * 2018-05-22 2018-09-04 王晓季 A kind of synthetic method of slimming drugs orlistat intermediate
CN114560887A (en) * 2022-02-15 2022-05-31 安徽美致诚药业有限公司 Preparation method of intermediate for preparing orlistat

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101066924B (en) * 2007-06-08 2011-01-12 中国科学院上海有机化学研究所 2-hexyl-3-hydroxy-5-R1Oxyhexadecanoic acid R2ester, preparation method and application thereof for preparing weight-reducing medicine orlistat
WO2009143664A1 (en) * 2008-05-26 2009-12-03 重庆植恩药业有限公司 The preparation method of (3s,4s)-3-hexyl-4-((r)-2-hydroxytridecyl)-oxetan-2-one and the product of that method
US8431726B2 (en) 2008-05-26 2013-04-30 Chongqing Zhien Pharmaceutical Co., Ltd. Preparation method of (3S,4S)-3-hexyl-4-((R)-2-hydroxytridecyl)-oxetan-2-one and the product of that method
CN101939308B (en) * 2008-05-26 2013-10-23 重庆植恩药业有限公司 Preparation method of (3s,4s)-3-hexyl-4-((R)-2-hydroxytridecyl)-oxetan-2-one and product of that method
CN102070567A (en) * 2011-01-21 2011-05-25 天津市海德安科医药科技发展有限公司 Method for preparing high-purity orlistat by using reverse phase high-performance liquid chromatogram
CN103012240A (en) * 2012-12-11 2013-04-03 保定市龙瑞药物技术有限责任公司 Preparation method of atorvastatin calcium
CN103012240B (en) * 2012-12-11 2015-05-27 保定市龙瑞药物技术有限责任公司 Preparation method of atorvastatin calcium
CN108484536A (en) * 2018-05-22 2018-09-04 王晓季 A kind of synthetic method of slimming drugs orlistat intermediate
CN108484536B (en) * 2018-05-22 2021-02-02 东莞理工学院 Synthetic method of orlistat intermediate of weight-reducing drug
CN114560887A (en) * 2022-02-15 2022-05-31 安徽美致诚药业有限公司 Preparation method of intermediate for preparing orlistat
CN114560887B (en) * 2022-02-15 2024-01-26 安徽美致诚药业有限公司 Preparation method of orlistat intermediate

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