EP1651627A2 - Verfahren zur herstellung von oxetan-2-one - Google Patents

Verfahren zur herstellung von oxetan-2-one

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Publication number
EP1651627A2
EP1651627A2 EP04743966A EP04743966A EP1651627A2 EP 1651627 A2 EP1651627 A2 EP 1651627A2 EP 04743966 A EP04743966 A EP 04743966A EP 04743966 A EP04743966 A EP 04743966A EP 1651627 A2 EP1651627 A2 EP 1651627A2
Authority
EP
European Patent Office
Prior art keywords
formula
oxetan
acid
ether
group
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.)
Withdrawn
Application number
EP04743966A
Other languages
English (en)
French (fr)
Inventor
Yatendra Kumar
Mohan Prasad
Keshav Deo
Anand Pandey
Kilol Patel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of EP1651627A2 publication Critical patent/EP1651627A2/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
    • C07D305/12—Beta-lactones

Definitions

  • the present invention relates to a process for the preparation of diastereomerically and enantiomerically pure oxetan-2-ones.
  • the present invention also relates to a process for the preparation of ester derivatives of oxetan-2-ones.
  • FORMULA I wherein R 1 is undecyl or 2Z,5Z-undecadienyl have been reported.
  • Such oxetan-2-ones are useful intermediates for the preparation of lipstatin, tetrahydrolipstatin, esterastin, tetrahydroesterastin, and structurally related compounds, which are useful as pancreatic lipase-inhibiting agents, as well as for the prevention and treatment of obesity and hyperlipaemia.
  • Several processes have been reported for the preparation of oxetan-2-ones of Formula I.
  • FORMULA I which provides improvements over prior methods of synthesis.
  • Such oxetan-2-ones are useful as enzyme inhibitors. More particularly, there is provided a process for preparing an oxetan-2-one of Formula I,
  • FORMULA I comprising the steps of: reacting an aldehyde of Formula II
  • R is phenoxy or 1-benzotriazolyl and M is lithium, MgBr, ZnCl or Ti(OR) 3 wherein R is alkyl.
  • the reaction of the aldehyde of Formula II with the metal enolate of Formula III is performed in an inert organic solvent.
  • the inert organic solvent can be diethyl ether, dibutyl ether, methyl tert-butyl ether, dioxane or tetrahydrofuran (THF).
  • the reaction of the aldehyde of Formula II with the metal enolate of Formula HI is carried out at a temperature of from about - 120 °C to about -70 °C. In one particular embodiment, this reaction step is carried out at a temperature from about -100 °C to about -80 °C.
  • the reaction of the aldehyde of Formula II with the metal enolate of Formula III can be quenched by addition of an acid or a salt solution and the compound of Formula IV can be recovered by extraction.
  • the acid can be hydrochloric acid and the salt solution can be ammonium chloride.
  • the hydrolysis of the diastereomeric trans- oxetan-2-one of Formula IN is carried out in the presence of an acidic catalyst and a polar solvent.
  • the acidic catalyst can be an acid, a salt of a weak base, an acidic ion-exchange resin or acidic silica gel.
  • the acid can be hydrofluoric acid or hydrochloric acid and the salt of a weak base can be ammonium fluoride or pyridinium-4- toluenesulphonate.
  • the polar solvent can be an alcohol, a cyclic ether, a nitrile, a dipolar aprotic solvent, an ester, or a mixture thereof;
  • the alcohol can be methanol, ethanol or isopropanol;
  • the cyclic ether can be dioxane or tetrahydrofuran (THF);
  • the nitrile can be acetonitrile;
  • the dipolar aprotic solvent can be dimethylformamide, dimethyl sulfoxide, sulfolane or N-methylpyrrolidone;
  • the ester can be ethyl acetate, or isopropyl acetate.
  • the hydrolysis of the compound of Formula IN is carried out at a temperature from about -20 °C to about 120 °C. In one particular embodiment, the temperature is from about 0 °C to about 60 °C.
  • the diastereomerically pure oxetan-2-ones of Formula I are separated by crystallization from an aliphatic hydrocarbon solvent.
  • the aliphatic hydrocarbon solvent can be hexane, pentane, heptane, cyclohexane, or mixtures thereof.
  • the diastereomerically pure oxetan-2-ones of Formula I are separated by crystallization from a mixture of an aliphatic hydrocarbon solvent along with at least one of an aromatic hydrocarbon, an ether, a chlorinated hydrocarbon, an ester, a ketone.
  • the aromatic hydrocarbon can be toluene or xylene;
  • the ether can be diisopropyl ether, dibutyl ether, diethyl ether, methyl tert-butyl ether, dioxane or tetrahydrofuran;
  • the chlorinated hydrocarbon can be methylenedichloride or ethylenedichloride;
  • the ester can be ethyl acetate or isopropyl acetate;
  • the ketone can be acetone or methylisobutylketone.
  • the present invention also encompasses a process for preparing a compound of Formula N
  • FORMULA V comprising the steps of: treating an oxetan-2-one of Formula I
  • R 5 can be benzyloxycarbonyl or p- nitrobenzyloxycarbonyl.
  • the alkanoylating agent can be an acid anhydride of R 4 -COOH or R 4 X wherein X is a halide.
  • Particular alkanoylating agents include formic acid anhydride, acetic anhydride, formyl halide or acetyl halide.
  • the treatment of oxetan-2-one of Formula I with the acid of Formula VI is performed in a solvent, where the solvent can be a hydrocarbon, a chlorinated hydrocarbon, an ether, an ester, a dipolar aprotic solvent, or mixtures thereof.
  • the hydrocarbon can be hexane, cyclohexane, toluene, or xylene;
  • the chlorinated hydrocarbon can be methylenedichloride or ethylenedichloride;
  • the ether can be diethyl ether, methyl tert-butyl ether, dioxane or tetrahydrofuran;
  • the ester can be ethyl acetate or isopropyl acetate;
  • the dipolar aprotic solvent can be dimethylformamide or dimethylacetamide.
  • the treatment of oxetan-2-one of Formula I with the acid of Formula NI is performed at a temperature from about -20°C to about 40°C.
  • R 5 is cleaved by hydrogenation in the presence of a hydrogenation catalyst and a solvent at a temperature from about 10 to about 75 °C.
  • the invention encompasses a compound prepared by a process comprising the steps of: a. reacting an aldehyde of Formula II
  • FORMULA I comprising the steps of: a. reacting an aldehyde of Formula II
  • a process for preparing a compound of Formula N comprises treating the oxetan-2-one of Formula I directly with an acid of Formula NI
  • R 5 can be an amino protecting group and R 3 can be isobutyl or carbamoylmethyl; followed by cleaving off the amino protecting group R 5 of the obtained ester of Formula VIII
  • R 1 can be undecyl or 2Z, 5Z-undecadienyl; and reacting the compound of Formula VIII with an alkanoylating agent containing an R 4 group to introduce R 4 to obtain the compound of Formula V.
  • the aryl part of the aryloxy and arylsulfonyl groups includes any aromatic mono- or polycyclic ring system, such as benzene, and naphthalene.
  • the heteroaryl group includes mono- or polycyclic heteroaromatic ring systems, such as pyridine and furan. Examples of R 2 include phenoxy or 1-benzotriazolyl.
  • Examples of M include Li, MgBr, ZnCl and Ti(OR) 3 , wherein R is alkyl.
  • the reaction of the aldehyde of Formula II with the metal enolate of Formula III may be performed in a suitable solvent.
  • suitable solvents for the reaction are inert organic solvents that do not change under the reaction conditions. Examples of such solvents include ethers, such as diethyl ether, dibutyl ether, methyl tert-butyl ether, dioxane and tetrahydrofuran (THF).
  • the reaction may be carried out at a temperature range from about
  • Lithium enolates of the Formula III may be prepared from the activated carboxylic acid derivative of Formula IX
  • R 2 can be phenoxy or 1-benzotriazolyl, by adding the activated carboxylic acid derivative of Formula IX to a solution of a strong base, such as lithium diisopropylamide or lithium hexamethyldisilazide, at an appropriate temperature, for example at about -70 °C.
  • a strong base such as lithium diisopropylamide or lithium hexamethyldisilazide
  • Other metal enolates of Formula III may be prepared from the corresponding lithium enolate by addition of metal salts, such as MgBr 2 , ZnCl 2 or Ti(OPr) 3 Cl.
  • Aldehyde of Formula II may be prepared by methods known in the art, such as those described in Synthesis, 1994, 1294-1300 for the corresponding R enantiomer.
  • acidic catalyst examples include an acid, such as hydrofluoric acid and hydrochloric acid; a salt of a weak base, such as ammonium fluoride and pyridinium-4- toluenesulphonate; an acidic ion-exchange resin, such as Dowex 20 ® (E. Merck), or acidic silica gel (obtained by treatment of silica gel with methanolic hydrochloric acid).
  • an acid such as hydrofluoric acid and hydrochloric acid
  • a salt of a weak base such as ammonium fluoride and pyridinium-4- toluenesulphonate
  • an acidic ion-exchange resin such as Dowex 20 ® (E. Merck)
  • acidic silica gel obtained by treatment of silica gel with methanolic hydrochloric acid.
  • polar solvents examples include alcohols, such as methanol, ethanol and isopropanol; cyclic ethers, such as dioxane and tetrahydrofuran (THF); nitriles, such as acetonitrile; dipolar aprotic solvents, such as dimethylformamide, dimethyl sulfoxide, sulfolane and N-methylpyrrolidone; esters, such as ethyl acetate and isopropyl acetate; and mixtures thereof.
  • alcohols such as methanol, ethanol and isopropanol
  • cyclic ethers such as dioxane and tetrahydrofuran (THF)
  • nitriles such as acetonitrile
  • dipolar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, sulfolane and N-methylpyrrolidone
  • esters such as ethyl acetate and iso
  • the hydrolysis may be carried out at a temperature range from about -20 °C to about 120 °C, at a temperature range from about 0 °C to about 60 °C, or even at a temperature range from about 10 °C to about 40 °C.
  • the diastereomerically pure oxetan-2-one of the Formula I is obtained from the diastereomeric mixture by crystallization from a suitable solvent(s).
  • suitable solvents include aliphatic hydrocarbons, such as hexane, pentane, heptane, cyclohexane, and mixtures thereof.
  • Aliphatic hydrocarbons can be used in a mixture with other solvents, including aromatic hydrocarbons, such as toluene, and xylene; ethers, such as diisopropyl ether, dibutyl ether, diethyl ether, methyl tert-butyl ether, dioxane and tetrahydrofuran (THF); chlorinated hydrocarbons, such as methylenedichloride and ethylenedichloride; esters, such as ethyl acetate and isopropyl acetate; ketones, such as acetone and methylisobutylketone (MD3K); and any combinations thereof.
  • aromatic hydrocarbons such as toluene, and xylene
  • ethers such as diisopropyl ether, dibutyl ether, diethyl ether, methyl tert-butyl ether, dioxane and tetrahydrofuran (THF)
  • the oxetan-2-one of Formula I may be converted to a compound of Formula V, by methods known in the art, such as those described in U.S. Patent No. 4,983,746 and U.S. Patent No. 5,175,186, which are incorporated herein by reference; as well as in Helv. Chim. Ada, 1987, 70, 1412-1418; and/. Org. Chem. 1988, 53, 1218-1221.
  • the acid anhydride of an acid of Formula VI, or a mixed anhydride thereof is used for esterification of the oxetan-2-one of Formula I; followed by cleaving off the amino protecting group R 5 of the ester of Formula VIII so obtained; and reacting with an alkanoylating agent, which introduces the group R 4 to obtain the compound of Formula V.
  • the compound of Formula V can be prepared by directly esterifying the oxetan-2-one of Formula I with an acid anhydride of an acid of Formula VII, or a mixed anhydride thereof, wherein R 3 and R 4 are as defined in Formula V.
  • lower yields maybe obtained with this process (J. Org. Chem. 1991, 56, 4716; Chem.
  • the compounds of Formula V, wherein R is undecyl may also be prepared by hydrogenating a compound of Formula V, wherein R 1 is 2Z,5Z-undecadienyl.
  • Examples of amino protecting group R 5 include benzyloxycarbonyl and p- nitrobenzyloxycarbonyl.
  • the acid anhydrides may be obtained by reacting an acid of Formula VI or Formula VII, with dicyclohexylcarbodumide orN-ethyl-N'-(3-dimethylaminopropy ⁇ )- carbodiimide.
  • the preparation of this acid anhydride may be carried out in a suitable solvent such as methylene chloride while cooling, for example to a temperature from about 0 °C to about 5 °C.
  • a suitable solvent such as methylene chloride
  • the dicyclohexylurea byproduct is filtered off and the subsequent esterification can be carried out in a solvent such as dimethylformamide in the presence of dimethylaminopyridme at room temperature.
  • the mixed acid anhydride may be obtained by reacting an acid of Formula VI or Formula VII, with a suitable acid halide (such as pivaloyl chloride) in a solvent (such as dimethylformamide) while cooling, for example to a temperature from about -5 °C to about 0 °C, and the subsequent esterification can be carried out in the same solvent at the same temperature.
  • a suitable acid halide such as pivaloyl chloride
  • a solvent such as dimethylformamide
  • the cleavage of amino protecting group R 5 may be carried out by hydrogenation in a solvent, for example, ethers, such as dioxane and tetrahydrofuran; chlorinated hydrocarbons, such as methylenedichloride and ethylenedichloride; and esters, such as ethyl acetate and isopropyl acetate in the presence of a hydrogenation catalyst, such as palladium-on-carbon, at a temperature of about 10 °C to about 75 °C.
  • the hydrogenation may be carried out at normal pressure, or at elevated pressure. In general, it may be carried out at a hydrogen pressure range from 1 to 2 atmospheres.
  • an undecadienyl group present in Formula V can be hydrogenated to the undecyl group during the hydrogenolytic cleavage of the amino protecting group.
  • the alkanoylating agent may be an acid anhydride, such as formic acid anhydride or acetic acid anhydride; a mixed acid anhydride, such as formic acid/acetic acid anhydride; or an acid halide, such as acetyl chloride.
  • the alkanoylation may be carried out in a suitable solvent, for example, ethers, such as dioxane and tetrahydrofuran, and chlorinated hydrocarbons, such as methylenedichloride and ethylenedichloride, at room temperature.
  • a base such as triethylamine, may be added in cases where an acid halide is used.
  • An improved process for preparing a compound of Formula V is provided, which involves treating the oxetan-2-one of Formula I directly with an acid of Formula VI, and dicyclohexylcarbodumide, followed by deprotection of the amino protecting group and alkanoylation as above.
  • the ester of Formula VIII is thus obtained in a single step, wherein the acid anhydride of Formula VI is formed in situ and simultaneously used up in esterification.
  • the process may be performed in a suitable solvent, optionally in the presence of dimethylaminopyridine.
  • suitable solvents include chlorinated hydrocarbons, such as methylenedichloride and ethylenedichloride; hydrocarbons, such as hexane, cyclohexane, toluene, and xylene; ethers, such as diethyl ether, methyl tert-butyl ether, dioxane and tetrahydrofuran (THF); dipolar aprotic solvents, such as dimethylformamide and dimethylacetamide; esters, such as ethyl acetate and isopropyl acetate; and mixtures thereof.
  • the reaction may be carried out at a temperature range from about -20 °C to about 40 °C.
  • the present invention also is directed to a compound prepared by the processes described herein. Examples hi the following section preferred embodiments are described by way of examples to illustrate the process. However, these are not intended in any way to limit the scope of the claims. Several variants of these examples would be evident to persons ordinarily skilled in the art.
  • Example 1 Preparation of methyl (S)-3-(tert-butyldimefhylsiloxy) tetradecanoate A solution of methyl (S)-3-hydroxytetra deaconate (100 g, 0387 mol) was added to dimethylformamide (150 mL), cooled to 5 °C to 10 °C, and imidazole (66.2 g, 0.972 mL) in dimethylformamide (150 mL) was added, followed by the drop- wise addition of tert-butyldimethylsilyl chloride (87.0 g, 0.577 mol) in dimethylformamide (150mL). The mixture was then stirred for 8 to 10 hours at room temperature.
  • Example 2 Preparation of (SV3-(tert-butyldimefhylsiloxy) tetradecanal A solution of methyl-(S)-3-(tert-butyldimethylsiloxy) tetradecanoate (155 g) in toluene (600 mL) was cooled to -80 °C. A solution of DIBAL-H (20% in toluene, 400 mL) was diluted with another 400 mL of toluene and added drop-wise at -80 °C during 2 to 3 hours under stirring. The mixture was stirred at -80 °C for 30 minutes. Methanol (50 mL) was added to the reaction at-70 °C to-80 °C.
  • Example 3 Preparation of 3-hexyl-4[(2s)-2-tert-butyldimethylsiloxytridecyl] oxetan-2- Lithium hexamethyldisilazide (20% THF, 400 L) was cooled to -95 °C and a solution of N-octanoylbenzotriazole (100 g in 350 mL THF) pre-cooled to -40 °C was added at a rate sufficient to maintain the temperature at -95 °C. After complete addition, the reaction mixture was stirred at -95°C for 30 minutes.
  • the combined hexane layer was washed with saturated sodium chloride solution (200 mL) followed by water (200 mL) and concentrated under reduce pressure until a thick mass was obtained.
  • Fresh hexane (600 mL) was added to the thick mass and stirred at room temperature for 1 hour.
  • the solid that precipitated out (benzotriazole) was filtered off and washed with hexane.
  • the combined hexane layer was concentrated under reduce pressure to get a thick residue, which was dissolved in ethylacetate:hexane (5:95 v/v) and passed through silica gel bed to get the title diastereomeric mixture (150 g).
  • Example 4 Preparation of (3S.4S)-3-hexyl-4[(2S)-2-hvdroxy1oxetan-2-one
  • a solution of the diastereomeric oxetanone mixture obtained in Example 3 (150 g) in acetonitrile (600 mL) was cooled to 10 °C to 15 °C.
  • Aqueous hydrofluoric acid (40%, 15 mL) was added drop- wise and the reaction mixture was stirred for 10 hours at room temperature.
  • the mixture was poured in water (3 L) and extracted with hexane (750 mL). The hexane layer was separated and the aqueous layer was re-extracted with hexane (250 mL).
  • 1,3-Dicyclohexylcarbodimide (90 g, 0.436 mol) in toluene (300 mL) was slowly added to the solution, followed by the addition of the product from Example 4 (100 g, 0J82 mol) and 4-(N, N-dimethylammo)pyridine (10 g).
  • the reaction mixture was stirred for 1 hour at 0 °C to 10 °C, the residual urea derivative was filtered off, and the filter cake was washed with toluene (100 mL).
  • the toluene filtrate was combined washed with aqueous hydrochloric acid, sodium bicarbonate and water.
  • Example 7 Preparation of ( SVN-formylleucine (SV1-IT(2S. 3SV3-hexyl-4-oxo-2- oxetanyl] methyl] dodecyl ester (Orlistaf) To the solution of the product from Example 6 (100 g, 0.214 mol) in dichloromethane (700 mL), formic acid/acetic anhydride reagent (245 g, obtained by mixing 157.6 g of formic acid in 87.4 g of acetic anhydride) was added slowly at about -5 °C to about 5 °C. The reaction was monitored by TLC (ethylacetate:hexane at 30:70 v/v, I 2 ).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epoxy Compounds (AREA)
EP04743966A 2003-07-15 2004-07-15 Verfahren zur herstellung von oxetan-2-one Withdrawn EP1651627A2 (de)

Applications Claiming Priority (2)

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IN900DE2003 2003-07-15
PCT/IB2004/002305 WO2005005403A2 (en) 2003-07-15 2004-07-15 Process for preparation of oxetan-2-ones

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Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006035296A1 (en) * 2004-09-27 2006-04-06 Ranbaxy Laboratories Limited Process for the preparation of an orlistat derivative useful as reference standard in the determination of the purity of orlistat and process for the preparation of orlistat
US20090171104A1 (en) * 2005-10-05 2009-07-02 Killol Patel Process for the preparation of orlistat
KR101504777B1 (ko) * 2007-06-06 2015-03-20 랜박시 래보러터리스 리미티드 오르리스타트의 제조 방법
CN112625009A (zh) * 2020-12-18 2021-04-09 植恩生物技术股份有限公司 一种奥利司他关键中间体的精制方法

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GB2023604B (en) * 1978-05-25 1982-07-28 Microbial Chem Res Found Physiologically active derivatives of esterastin and production thereof
CA1328881C (en) * 1984-12-21 1994-04-26 Pierre Barbier Process for the manufacture of oxetanones
CA1270837A (en) * 1984-12-21 1990-06-26 Hoffmann-La Roche Limited Oxetanones
AT398579B (de) * 1992-07-06 1994-12-27 Chemie Linz Gmbh Enzymatisches verfahren zur trennung racemischer gemische von delta-valerolactonen
DE19703713A1 (de) * 1997-01-23 1998-07-30 Hans Prof Dr Schick Verfahren für die Herstellung von Oxetan-2-onen und Zwischenprodukte
US6552204B1 (en) * 2000-02-04 2003-04-22 Roche Colorado Corporation Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one
US6392061B1 (en) * 2000-10-16 2002-05-21 Zpro Chemical, Inc. Process for making (2S, 3S, 5S) oxetanone derivatives

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