WO2000027786A1 - Stereoselective process for preparing (cyclo)alkyl phenylglycolic acids - Google Patents

Stereoselective process for preparing (cyclo)alkyl phenylglycolic acids Download PDF

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Publication number
WO2000027786A1
WO2000027786A1 PCT/US1999/025587 US9925587W WO0027786A1 WO 2000027786 A1 WO2000027786 A1 WO 2000027786A1 US 9925587 W US9925587 W US 9925587W WO 0027786 A1 WO0027786 A1 WO 0027786A1
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Prior art keywords
phenyl
dioxolan
acid
alkyl
process according
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PCT/US1999/025587
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English (en)
French (fr)
Inventor
Chris H. Senanayake
Paul T. Grover
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Sepracor Inc.
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Filing date
Publication date
Application filed by Sepracor Inc. filed Critical Sepracor Inc.
Priority to AU13343/00A priority Critical patent/AU765158B2/en
Priority to EP99956816A priority patent/EP1127043A1/en
Priority to JP2000580968A priority patent/JP2002529437A/ja
Priority to CA002349209A priority patent/CA2349209A1/en
Publication of WO2000027786A1 publication Critical patent/WO2000027786A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D317/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/54—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings and other rings

Definitions

  • the invention relates to a chemical process for preparing ⁇ - alkylphenylglycolic acids and to intermediates in that process.
  • Cyclohexylphenyl glycolic acid (also referred to herein as "CHPGA") is used as a starting material for manufacturing compounds that have important biological and therapeutic activities.
  • Such compounds include, for example, oxphencyclimine, oxyphenonium bromide, oxypyrronium bromide, oxysonium iodide, oxybutynin (4- diethylamino-2-butynyl phenylcyclohexylglycolate) and its metabolites, such as desethyloxybutynin (4-ethylamino-2-butynyl phenylcyclohexylglycolate).
  • Racemic CHPGA is generally prepared by one of two methods: (1) selective hydrogenation of phenyl mandelic acid or of phenyl mandelate esters, as shown in Scheme 1 ; or (2) cyclohexyl magnesium halide addition to phenylglyoxylate as shown in Scheme 2.
  • R is hydrogen or lower alkyl.
  • a more efficient and economic method for producing ⁇ -alkylphenylglycolic acids, particularly single enantiomers of ⁇ -alkylphenylglycolic acids, on an industrial scale is therefore desirable.
  • Such a method should provide high purity compounds in high chemical yields with few processing steps.
  • the substituted acetaldehyde is pivaldehyde
  • the alkyl ketone is cyclohexanone
  • the mandelic acid is (S)-(+)-mandelic acid or (R)- (-)-mandelic acid and cyclohexylphenylglycolic acid enriched in either the S or the R enantiomer, respectively, is produced.
  • the invention relates to a process for preparing a racemic alkyl phenylgly colic acid, comprising a first step of:
  • the condensation of the acetaldehyde, symmetrical dialkyl ketone or substituted acetaldehyde with mandelic acid may be accomplished in the presence of an acid catalyst; the condensation of the 5-phenyl-l,3-dioxolan-4-one with an alkyl ketone or aldehyde may be accomplished under basic conditions.
  • the invention relates to a compound chosen from the group consisting of:
  • R 1 is alkyl of 1 to 10 carbons or substituted alkyl of 4 to 20 carbons in total.
  • the compounds are novel intermediates in the synthesis of CHPGA.
  • enantiomeric excess is related to the older term “optical purity” in that both are measures of the same phenomenon.
  • the value of ee will be a number from 0 to 100, zero being racemic and 100 being pure, single enantiomer.
  • a compound which in the past might have been called 98% optically pure is now more precisely described as 96% ee.; in other words, a 90% e.e. reflects the presence of 95% of one enantiomer and 5% of the other in the material in question.
  • p and q are diastereomers, and 90% de reflects 95% of p and 5% of q.
  • the diastereomeric excess is a measure of the diastereoselectivity of a reaction or process.
  • Substituted acetaldehyde means acetaldehyde in which one or more hydrogens is replaced so as to provide an aldehyde which, when incorporated into the dioxolone ring, is base-inert.
  • base-inert aldehyde For syntheses in which enantioselectivity is important, a bulky, base-inert aldehyde is needed.
  • a "bulky, base-inert aldehyde” as the term is used herein refers to an aldehyde which meets two criteria: (1) it has sufficient steric bulk such that the approach of a ketone to the dioxolone anion 7 results in a product alcohol which is not a 1 : 1 mixture of enantiomers at the C-5 carbon; and (2) it contains
  • Aldehydes that meet these criteria are easily determined by the artisan by simply reacting the putative aldehyde with S-mandelic acid and then with cyclohexanone under the conditions described below and examining the ⁇ H NMR for the signal of the proton at C-2; if there is a single pair of signals of equal integrated signal strength between 5 and 6 ⁇ , the aldehyde fails criterion (1); if there is no signal between 5 and 6 ⁇ , the aldehyde fails criterion (2); if there is more than one signal of non-equal integrated signal strength between 5 and 6 ⁇ , the aldehyde meets the criteria; if there is only a single signal between 5 and 6 ⁇ , the aldehyde not only meets the criteria, but is preferred.
  • substituted acetaldehydes that are bulky and "base-inert” include pivaldehyde and diphenylacetaldehyde.
  • substituted acetaldehydes include acetaldehydes in which at least two hydrogens on the ⁇ -carbon are replaced by alkyl or aryl groups, although we have found that if the two alkyl groups are no more bulky than methyls (isobutyraldehyde), the resulting dioxolone does not have a sufficient directing effect at C-5 to allow high enantioselectivity.
  • Alkyl refers to saturated hydrocarbon residues containing twenty or fewer carbons in straight or branched chains, as well as monocyclic structures of 3 to 8 carbons and decalin.
  • Aryl includes phenyl, naphthyl, and phenyl substituted with one or more alkyl or alkoxyl.
  • Symmetrical dialkyl ketones include acetone and diethyl ketone. The person of skill will readily appreciate that an equivalent to the foregoing ketones and aldehydes would be the corresponding acetals, such as acetone dimethyl acetal (dimethoxypropane), which are often commercially available. These would be converted to the dioxolone under analogous conditions by alcohol exchange.
  • Schemes 4 and 5 depict the processes of the invention using cyclohexanone as the exemplary alkyl ketone.
  • Scheme 4 depicts the process in which the 5-cyclohexenyl-5-phenyldioxol-2-one 3 is first cleaved to ⁇ - cyclohexenylphenylglycolic acid 4 and then reduced;
  • Scheme 5 depicts the process in which the 5-cyclohexenyl-5-phenyldioxol-2-one 3 is first reduced to 5- cyclohexyl-5-phenyldioxol-2-one 5 and then reduced.
  • an aldehyde R'CHO is condensed with mandelic acid in the presence of an acid catalyst to provide a 5-phenyl-l,3-dioxolan-4-one 1.
  • the preferred aldehydes for enantioselective syntheses are pivaldehyde and diphenylacetaldehyde. Acetone is preferred when the racemic synthesis is followed.
  • the preferred acids for condensing aldehydes are sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and toluenesulfonic acid; if acetone is used, sulfuric acid may be employed.
  • the 5-phenyl-l,3-dioxolan-4-one 1 is condensed with an alkyl ketone or alkyl aldehyde, in this case cyclohexanone, in the presence of a base to provide a 5- (l-hydroxyalkyl)-5-phenyl-l,3-dioxolan-4-one 2.
  • a base is a lithium amide, such as lithium diethylamide or lithium bis(trimethylsilyl)amide. The best yields are obtained if the process is carried out below ambient temperature.
  • R-CHPGA Reactive hydrogenation phosphidelic acid
  • S-mandelic acid if one wished to obtain R-CHPGA, one could start with R-mandelic acid and carry out the aldol at -78° C or one could start with S-mandelic acid and carry out the aldol at 0°C.
  • the reaction is run in an inert solvent or solvent mixture having a freezing point below the desired temperature for the reaction.
  • Typical solvents include lower alkanes, ethers and mixtures thereof.
  • the 5-(l-hydroxyalkyl)-5-phenyl-l,3-dioxolan-4-one 2 is subjected to dehydrating conditions to provide a 5-(l-alkenyl)-5-phenyl-l,3-dioxolan-4-one 3.
  • dehydrating conditions are the sequential treatment with thionyl chloride and then pyridine, but any of the myriad of conditions known to persons in the art for converting alcohols to alkenes could be used.
  • Other dehydrating reactions that may be employed include: formic acid [Wang et al J. Chem. Soc. 1949. 2186]; potassium bisulfate [Cook et al J. Chem. Soc. 1938.
  • the dioxolan-4-one 3 may be first hydrolyzed and then reduced, as shown in Scheme 4, or first reduced and then hydrolyzed, as in Scheme 5.
  • the hydrolysis is preferably carried out using aqueous alkali metal hydroxide in an alcoholic or polar aprotic solvent, for example, potassium hydroxide in methanol-water.
  • Reduction is preferably accomplished by exposure to hydrogen gas in the presence of a noble metal catalyst.
  • the hydrogen may be provided as gaseous hydrogen or may be derived by metathesis from a hydrogen source such as ammonium formate.
  • the catalyst is preferably palladium on a solid support such as carbon, but one may also use other noble metal catalysts such as platinum and rhodium catalysts.
  • the reaction mixture was allowed to stir for 0.5 hours at -78° C, after which ccylohexanone (5.07 mL, 46.7 mmol) was added. After stirring for a further 2 hours at -78 °C, a solution of saturated NH 4 C1 solution (8.0 mL) was added. The reaction mixture was poured into a separatory funnel containing saturated NH 4 C1 solution (300 mL). The aqueous layer was separated and washed with ethyl acetate (2 x 300 mL). The combined organic layers were dried (NajSO , filtered and concentrated in vacuo to provide 12.01 g of crude aldol product (85%) as a white solid. !
  • (S)-CHPGA To a solution of (S)-Cyclohexenyl phenyl glycolic acid (1.1 lg, 4.78 mmol) in methanol (16 mL) was added 10% Pd/C (0.11 g). The reaction was subjected to 1 ATM of Hydrogen and was allowed to stir for 18 h. the reaction mixture was filtered through a plug of celite and concentrated in vacuo to provide 1.01 g of (S)-CHPGA (91%, 98.3% e.e.).
  • Cis-(2S,5S)-2-(tert-butyl)-5-phenyl-l,3-dioxolan-4-one (SS)-l To a suspension of (S)-(+)-mandelic acid (10. Og, 65.7 mmol) in pentane (150 mL) was added pivaldehyde (8.56 mL, 78.8 mmol), followed by addition of methanesulfonic acid (213 ⁇ L, 3.2 mmol) at rt. To the reaction flask was added a dean-stark trap. The mixture was warmed to 65 ° C and allowed to reflux for 5.5 h.
  • reaction mixture was allowed to cool to rt, ethyl acetate was added (200 mL) and the solution was washed with said NaHCO 3 solution (150 mL) and concentrated in vacuo to provide a white solid.
  • the crude material was dissolved in 50 mL of hot ethyl acetate and allowed to cool to 0° C. The solids formed were collected by filtration and dried to give 9.95 g (69%) of product.
  • (S)-Cyclohexenyl phenyl glycolic acid (S)-4 To a -78° C solution of lithium bis- (trimethylsilyl)-amide (147.6 mL, 147.6 mmol, 1.0M in hexanes) was added Cis- (2S,5S)-2-(tert-butyl)-5-phenyl-l,3-dioxolan-4-one (S,S)-1 (25.0 g, 113.5 mmol, dissolved in 172 mL THF). The reaction mixture was allowed to stir for 0.5h at - 78° C, followed by the addition of cyclohexanone (16.47 mL, 158.9 mmol).
  • the solvent was distilled to a volume of 20 mL, after which 40 mL of toluene was added, this was repeated 3 times, with the last distillation resulting in 11 mL final volume of solvent (toluene).
  • the mixture was warmed to 65 ° C and 12.9 mL of heptane was added to it.
  • the mixture was slowly cooled to rt, then 0° C for 2 h. the crystals were collected via filtration and dried to provide 2.11 g of pure (S)-CHPGA (87%, 99% e.e.).
  • the bottom layer (aqueous) was removed and the top layer (organic) was treated with KOH (29.1 g, 520 mmol) in 120 mL of water.
  • the reaction mixture was distilled to remove 300 mL of solvent. MeOH (60 mL) was added and the reaction was allowed to reflux for 2 hours at 95° C.
  • the white precipitate was collected via filtration and dried to provide 21.5 g of (S)-4 (93%, 99.96% e.e.).
  • 2-(Dimethyl)-5-phenyl-5-(cyclohexyl-l-ol)-l,3-dioxolan-4-one To a -78°C solution of lithium bis-(trimethylsilyl)amide (2.98 mL, 2.98 mmol, 1.0M in hexanes) in 16 mL of dry THF was added 2-(dimethyl)-5 -phenyl- 1, 3 -dioxolan-4-one (0.50 g, 2.84 mmol) dissolved in 3 mL of THF. The reaction mixture was allowed to stir for 0.5h at -78 °C, followed by the addition of cyclohexanone (0.32 mL, 3.2 mmol).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
PCT/US1999/025587 1998-11-06 1999-10-29 Stereoselective process for preparing (cyclo)alkyl phenylglycolic acids WO2000027786A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU13343/00A AU765158B2 (en) 1998-11-06 1999-10-29 Stereoselective process for preparing (cyclo)alkyl phenylglycolic acids
EP99956816A EP1127043A1 (en) 1998-11-06 1999-10-29 Stereoselective process for preparing (cyclo)alkyl phenylglycolic acids
JP2000580968A JP2002529437A (ja) 1998-11-06 1999-10-29 （シクロ）アルキルフェニルグリコール酸の立体選択的調製プロセス
CA002349209A CA2349209A1 (en) 1998-11-06 1999-10-29 Stereoselective process for preparing (cyclo)alkyl phenylglycolic acids

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US09/187,832 1998-11-06
US09/187,832 US6180823B1 (en) 1998-11-06 1998-11-06 Stereoselective process for alkyl phenylglycolic acids

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EP (1) EP1127043A1 (und)
JP (1) JP2002529437A (und)
AU (1) AU765158B2 (und)
CA (1) CA2349209A1 (und)
WO (1) WO2000027786A1 (und)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2820045A1 (fr) 2001-01-29 2002-08-02 Chabunda Christophe Mwanza Dispositif bilina-imatron de stereoradiotherapie par acceleration et collision des particules des 2 faisceaux d'irriadiation synchrones associe a un dispositif de verification instantannee de delivrance des radiations
US6777576B2 (en) 2000-11-07 2004-08-17 Sumika Fine Chemicals Co., Ltd. Production method of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid intermediate therefor and production method thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6180823B1 (en) * 1998-11-06 2001-01-30 Sepracor Inc. Stereoselective process for alkyl phenylglycolic acids

Citations (1)

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EP0823423A1 (en) * 1995-04-28 1998-02-11 Banyu Pharmaceutical Co., Ltd. 1,4-disubstituted piperidine derivatives

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US6028177A (en) * 1991-10-04 2000-02-22 Washington University Methods of detecting single-chain forms of the glycoprotein hormone quartet
DE4142190A1 (de) * 1991-12-20 1993-06-24 Bayer Ag Verfahren zur herstellung von optisch aktiven (alpha)-hydroxycarbonsaeuren
PE92198A1 (es) 1996-08-01 1999-01-09 Banyu Pharma Co Ltd Derivados de 1,4-piperidina disustituida que contienen fluor
US6013830A (en) * 1998-03-30 2000-01-11 Sepracor Inc. Asymmetric grignard synthesis with cyclic 1,2 aminoalcohols
US5973182A (en) * 1998-10-22 1999-10-26 Sepracor Inc. Carbonate Intermediates useful in the preparation of optically active cyclohexylphenylglycolate esters
US6140529A (en) * 1998-10-22 2000-10-31 Sepracor Inc. Synthesis of optically active cyclohexylphenylglycolate esters
US6180823B1 (en) * 1998-11-06 2001-01-30 Sepracor Inc. Stereoselective process for alkyl phenylglycolic acids

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EP0823423A1 (en) * 1995-04-28 1998-02-11 Banyu Pharmaceutical Co., Ltd. 1,4-disubstituted piperidine derivatives

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PAILER M ET AL: "Derivate des 1,3-Dioxolan-4-ons und des 1,3-Oxathiolan-5-ons", MONATSHEFTE FÜR CHEMIE, vol. 99, no. 3, 1968, pages 891 - 901, XP002131338 *
SEEBACH D ET AL: "Enantioselective generation and diastereoselective reactions of chiral enolates derived from alpha-heterosubstituted carboxylic acids", HELVETICA CHIMICA ACTA, vol. 64, no. 8, 16 December 1981 (1981-12-16), pages 2704 - 8, XP002131337 *
VISSER T J ET AL: "Stereoselective synthesis and biodistribution of potent [11C]-labeled antagonists for positron emission tomography imaging of muscarinic receptors in the airways", JOURNAL OF MEDICINAL CHEMISTRY, vol. 40, no. 1, 3 January 1997 (1997-01-03), pages 117 - 24, XP002131336 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6777576B2 (en) 2000-11-07 2004-08-17 Sumika Fine Chemicals Co., Ltd. Production method of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid intermediate therefor and production method thereof
FR2820045A1 (fr) 2001-01-29 2002-08-02 Chabunda Christophe Mwanza Dispositif bilina-imatron de stereoradiotherapie par acceleration et collision des particules des 2 faisceaux d'irriadiation synchrones associe a un dispositif de verification instantannee de delivrance des radiations

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US6180823B1 (en) 2001-01-30
AU1334300A (en) 2000-05-29
AU765158B2 (en) 2003-09-11
US6376684B1 (en) 2002-04-23
EP1127043A1 (en) 2001-08-29
JP2002529437A (ja) 2002-09-10
CA2349209A1 (en) 2000-05-18

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