EP1233939A1 - Procede relatif a l'elaboration d'acides alpha-hydroxy optiquement actifs, y compris leurs derives - Google Patents

Procede relatif a l'elaboration d'acides alpha-hydroxy optiquement actifs, y compris leurs derives

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Publication number
EP1233939A1
EP1233939A1 EP99961901A EP99961901A EP1233939A1 EP 1233939 A1 EP1233939 A1 EP 1233939A1 EP 99961901 A EP99961901 A EP 99961901A EP 99961901 A EP99961901 A EP 99961901A EP 1233939 A1 EP1233939 A1 EP 1233939A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
formula
unsubstituted
hept
diisopropyl
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Withdrawn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
EP99961901A
Other languages
German (de)
English (en)
Other versions
EP1233939A4 (fr
Inventor
Biing-Jiun 4F No. 2 UANG
Jia-Wen No. 25 CHANG
Der-Pin No. 64 JANG
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.)
Scinopharm Singapore Pte Ltd
Original Assignee
Scinopharm Singapore Pte 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 Scinopharm Singapore Pte Ltd filed Critical Scinopharm Singapore Pte Ltd
Publication of EP1233939A1 publication Critical patent/EP1233939A1/fr
Publication of EP1233939A4 publication Critical patent/EP1233939A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a process for preparing optically active cc-hydroxy acids and derivatives thereof.
  • ⁇ -Hydroxy acids are important intermediates for synthesis of organic compounds in pharmaceutical and industrial applications. More particularly, the present invention relates to an enantioselective synthesis for cc-hydroxy acids by employing 10-camphorsulfonamide as a chiral auxiliary through 1,3-dioxolanones.
  • Optically active ⁇ -hydroxy acids are structural subunits of many natural products, such as motuportin. integerrimine, monocrotaline, and eremantholide A.
  • ⁇ -Hydroxy acids and their derivatives are important intermediates for the synthesis of organic compounds in pharmaceutical and industrial applications.
  • a number of useful synthetic methods for the preparation of enantiomertically pure ⁇ -branched ⁇ -hydroxy acids have been developed.
  • optically active ⁇ -hydroxy acids are obtained through microbial methods, enzymatic syntheses and enantioselective syntheses using chiral auxiliaries.
  • Microbial methods utilizes microorganism to convert the precursors of ⁇ -hydroxy acids, such as oxo- or hydroxy-containing compounds, to produce ⁇ -hydroxy acids and derivatives thereof.
  • U.S. Patent No. 5,326,702 discloses a process for biologically producing an ⁇ -hydroxyamide or an ⁇ -hydroxy acid, comprising reacting an ⁇ -hydroxynitrile or an aldehyde with a microorganism which produces an amide or acid from the corresponding ⁇ -hydroxynitrile, in the presence of a sulfite ion, a disulfite ion or a dithionite ion.
  • the related prior art such as U.S. Patent Nos.
  • 5,371,014, 5,508,181, 5,756,306 and 5,273,895 can also be incorporated herein for reference.
  • microbial methods it is difficult to isolate the product from the fermentation broth.
  • the purification for the product is complex and very expensive.
  • the fermentation process usually generates a large amount of waste effluent which harm the environment. An additional treatment process is required and it is not economical.
  • U.S. Patent No. 5,098,841 discloses a process for the preparation of the enantiomers of 2-hydroxy-4-phenylbutyric acid, comprising reducing 2-oxo-4-phenyl-butyric acid with the enzyme lactate dehydrogenases in the presence of an electron donor and an
  • U.S. Patent Nos. 5,488,131 discloses a method for synthesis of compounds of predetermined chirality that are useful in asymmetric synthesis, comprising the acylation of an enantiomer of pseudoephedrine and then the alkylation of the ⁇ -carbon of the adduct, wherein the alkylation proceeds in a stereoselective manner and is directed by the chiral auxiliary pseudoephedrine.
  • the related prior art utilizing enantioselective syntheses using chiral auxiliary, such as U.S. Patent Nos.
  • the present invention relates to a process for p r eparing optically active ⁇ -hydroxy acids and derivatives thereof through 1,3-dioxolanones by employing 10- camphorsulfonamide as a chiral auxiliary.
  • the 1,3-dioxolanones are prepared by the catalyzed condensation of a dialkoxy acetal which is derived from the chiral auxiliary, 10- camphorsulfonamide, by treating with ⁇ -hydroxy acids.
  • the 1,3-dioxolanones are enantioselective and therefore can be further used to produce optically active compounds such as ⁇ -hydroxy acids and derivatives thereof.
  • the 1,3-dioxolanones are subjected to alkylation and then either to alcoholysis or to hydrolysis to produce mono- and disubstituted ⁇ -hydroxy acids and derivatives thereof and 10-camphorsulfonamide. 10- camphorsulfonamide can be easily recovered.
  • the present invention relates to an enantioselective synthesis for ⁇ -hydroxy acids through 1,3-dioxolanones by employing 10-camphorsulfonamide as a chiral auxiliary.
  • the process of the present invention for preparing optically active ⁇ -hydroxy acids comprises steps of
  • R, and R 2 are the same or different and are each independently H or
  • R, and R 2 are the same or different and are each independently H or
  • C,. 6 alkyl, R 3 and R are the same or different and are each independently C alkyl;
  • R 5 is H, C,. 16 alkyl, or unsubstituted or substituted phenyl, to form 1,3-dioxolanones of formula III
  • R, and R 2 are the same or different and are each independently H or C, .6 alkyl, and R 5 is H, C 6 alkyl, or unsubstituted or substituted phenyl;
  • R, and R 2 are the same or different and are each independently H or C I-6 alkyl, R 5 is H, C,. 16 alkyl, or unsubstituted or substituted phenyl, and R ⁇ is C 1-8 alkyl, C 2-7 alkenyl or unsubstituted or substituted benzyl; (d) subjecting the alkylated 1,3-dioxolanones of formula IV to either
  • R 7 is C 1-6 alkyl, and R ⁇ 5 is C 1-8 alkyl, C 2 . 7 alkenyl or unsubstituted or substituted benzyl, or
  • R 5 is H, C 1-16 alkyl, or unsubstituted or substituted phenyl, and R ⁇ is C s alkyl, C 2 . 7 alkenyl or unsubstituted or substituted benzyl.
  • the starting material, 10-camphorsulfonamid-* of formula I, for the process of the present invention is generally known and available in the art.
  • step (a) the 10-camphorsulfonamide of formula I reacts with alkoxy-substituted alkane to form a dialkoxy acetal of formula II.
  • the reaction can be conducted in the absence or presence of catalysts and solvents known to persons skilled in the art. Catalysts such as p-toluene sulfonic acid (p-TSA) and solvents such as alcohols, for example, methanol, are commonly used.
  • p-TSA p-toluene sulfonic acid
  • solvents such as alcohols, for example, methanol
  • the alkoxy-substituted alkane used is (CH 3 O) 3 CH.
  • step (b) the dialkoxy acetal of formula II produced from step (a) is subjected to Lewis acid-catalyzed condensation with an ⁇ -hydroxy acid having the formula R 5 C(OH)COOH, wherein R 5 is H, C 6 alkyl, or unsubstituted or substituted phenyl, to produce 1,3-dioxolanones of formula III.
  • the reaction conditions for Lewis acid-catalyzed condensation is known in the state of art. Reference can be made to sources such as Farines, M.; Soulier, J. Bull. Soc. Chim. Fr. 1970, 332; Petasis, N. A.; Lu, S.-P. J. Am. Chem. Soc.
  • the dialkoxy acetal is reacted with ⁇ -hydroxy acid, preferably, glycolic acid, lactic acid and mandelic acid, under an inert gas, at a temperature from about -35 °C to about -60 °C, in the presence of ethers as the solvent.
  • ⁇ -hydroxy acid preferably, glycolic acid, lactic acid and mandelic acid
  • the Lewis acid used in the preferred embodiment of the present invention is BF 3 » OEt 2 .
  • the product 1,3-dioxolanones of formula III are also enantioselective. Therefore, the enantioselective 1,3-dioxolanones of formula III is very useful to prepare optically active compounds such as ⁇ -hydroxy acids and derivatives thereof.
  • step (b) may produce a small amount of by-product of 1,3-dioxolanones having formula Ilia
  • R, and R 2 are the same of different and are each independently H or C,_ 6 alkyl.
  • the 1,3-dioxolanones of formulae III and Ilia are diastereomeric chiral compounds. Pure 1,3- dioxolanones of formula III can be obtained by recrystallization, or separated from their minor isomers of the 1,3-dioxolanones of formula Ilia by column chromatography. The conditions for recrystallization and column chromatography are well known to persons skilled in the art.
  • 1,3-dioxolanones of formula III are single products.
  • the stereochemistry of 1,3-dioxolanones can be confirmed by known methods commonly used in the art such as X-ray crystallographic analysis and nuclear overhauser effect (NOE) experiments.
  • 1,3-dioxolanones of formula III are reacted with alkylation reagents such as R ⁇ X wherein R ⁇ is C,-C 8 alkyl, C 2 -C 7 alkenyl or unsubstituted or substituted benzyl, and X is a leaving group, to form the alkylated 1,3-dioxolanones of formula IV.
  • alkylation reagent is a halide or sulfonate.
  • the alkylation is conducted under a temperature from -1 10°C to room temperature, preferably from -100°C to 0°C, more preferably from -100°C to -45°C, most preferably from -100°C to -78°C, in the presence of a strong base, such as lithium diisopropylamide (LDA), in the absence or presence of solvents.
  • a strong base such as lithium diisopropylamide (LDA)
  • LDA lithium diisopropylamide
  • the alkylated 1,3- dioxolanones of formulae IV have excellent diastereoselectivity.
  • the stereochemistry of the alkylated 1,3-dioxolanones of formulae IV can be detected by conventional manners such as X-ray crystallographic analysis.
  • step (d) the alkylated 1,3-dioxolanones of formula IV can be further subjected to alcoholysis or hydrolysis to produce ⁇ -hydroxy acids of formula VI and derivatives thereof of formula V.
  • R 5 is H
  • the alkylated products is subject to alcoholysis of step (i).
  • the alcoholysis is conducted by heating the alkylated 1,3-dioxolanones of formula IV with anhydrous hydrogen chloride in absolute alcohols with formula R 7 OH wherein R 7 is C,. 6 alkyl. such as ethanol.
  • the 10-camphorsulfonamide of formula I is also produced.
  • The, ⁇ -hydroxy acids derivatives of formula VI can be separated and purified by a conventional manner such as column chromatography. 10-Camphorsulfonamide can therefore be recovered.
  • the reaction scheme of step (d)(i) is shown as follows,
  • Rj and R 2 are the same or different and are each independently H or C,. 6 alkyl, R 5 is H, Rs is C 1-8 alkyl, C 2 . 7 alkenyl or unsubstituted or substituted benzyl, and R 7 is C,. 6 alkyl.
  • the alkylated 1,3-dioxolanones of formula IV are subject to the hydrolysis of step (ii).
  • the hydrolysis conditions are conventional in the state of the art.
  • the hydrolysis is conducted by reacting the alkylated 1,3-dioxolanones of formula IV with a strong base such as NaOH in the presence of alcohols, such as methanol, as the solvent.
  • a strong base such as NaOH
  • alcohols such as methanol
  • the 10-camphorsulfonamide of formula I is also produced, 10- Camphorsulfonamide can be separated by a conventional method such as extraction and recovered.
  • the purification of ⁇ -hydroxy acids can be conducted by concentration.
  • the reaction scheme of step (d)(ii) is shown as follows,
  • R t and R 2 are the same or different and ⁇ e each independently H or C 1-6 alkyl
  • R 5 is C 6 alkyl or unsubstituted or substituted phenyl
  • R ⁇ is C,. 8 alkyl, C 2 . 7 alkenyl or unsubstituted or substituted benzyl.
  • the ⁇ -hydroxy acids and derivatives thereof are important intermediates for synthesis of optically active organic compounds in pharmaceutical and industrial applications.
  • Me means methyl
  • Et means ethyl
  • Ac means COCH 3 .
  • Example 1 illustrates the preparation of the dialkoxy acetal of formula II from the 10-camphorsulfonamide of formula I. dRVN,N-Diisopropyl-(2.2-dimethoxy-7.7-dimethylbicvclor2.2.1 lhent- 1 -vH methanesulfonamide
  • Example 2a-d illustrates the preparation of the 1,3-dioxolanones of formula III and Ilia from the dialkoxy acetal of formula II by Lewis acid-catalyzed condensation.
  • General procedures for Lewis acid-catalyzed condensation of the dialkoxy acetal with ⁇ -hydroxy acids are as follows:
  • Example 2b riig.2RVN.N-Diisopropyl-r2-spiro-2'- ⁇ '-3'-dioxolane-4'-oneV7.7-dimethyl bicyclo[2.2. l ⁇
  • Example 2c ⁇ R.2S.5'S)-N.N-Diisopropyl-r2-spiro-2 , -r5'-methyl-l'.3 , -dioxolane-4 , -oneV
  • the title compound is prepared from the condensation of (li?)-N,N-diisopropyl-(2,2- dimethoxy-7,7-dimethylbicyclo[2.2.1]hept-l-yl) methanesulfonamide with r ⁇ c-mandelic acid (2.2 eq). 56% yield;
  • Example 3a-i illustrate the alkylation of 1,3-dioxolanones of formula III wherein R 5 is H.
  • LDA lithium diisopropylamide
  • THF tetrahydrofuran
  • HMPA hexamethyl phosphoramide
  • Example 3 a was repeated except that HMPA was not added and the reaction is conducted at temperature of -100°C increased to -78°C.
  • the title compound was produced with 84% yield and > 98% of diastereoselectivity.
  • Example 3 c
  • Example 3 a was repeated except that the reaction is conducted at temperature of -100°C increased to -78°C.
  • the title compound was produced with 86% yield and > 98% of diastereoselectivity.
  • LDA lithium diisopropylamide
  • THF tetrahydrofuran
  • Example 3d was repeated except that HMPA was added.
  • the title compound is produced with 76% yield and > 98% of diastereoselectivity .
  • Example 3f
  • Example 3f was repeated except that the reaction was conducted at the temperature of -100°C increased to -78°C.
  • the title compound is produced with 65% yield and > 98% of diastereoselectivity.
  • Example 3h riR.2S.5'RVNN-Diisopro ⁇ yl-[2-spiro-2 , -(5'-phenylmethyl-l'.-3'-dioxolane-4'-oneV7.7- dimethylbicvclo [2.2.1 ]hept- 1 -yl]methanesulfonamide
  • LDA lithium diisopropylamide
  • THF tetrahydrofuran
  • HMPA hexamethyl phosphoramide
  • Example 3h was repeated except that the reaction is conducted at the temperature of -100°C increased to -78°C.
  • the title compound is produced with 70% yield and > 98% of diastereoselectivity.
  • Example 4a-g
  • Example 4a-g illustrates the alkylation of 1,3-dioxolanones of formula III wherein R 5 is methyl or phenyl.
  • the general procedures for the alkylation are as follows:
  • the title compound was prepared by reacting (IR,2S,5'S)-N, N-diisopropyl- [2-spiro- 2'- (5'-methyl-r,3'-dioxolane-4'-one) -7,7-dimethyl-bicyclo[2.2.1]hept-l- yl] methanesulfonamide with ethyl halide according to the general procedures.
  • the title compound was prepared by reacting (li?,2S,5'S)-N,N-diisopropyl- [2-spiro- 2'- (5'-methyl-r,3'-dioxolane-4'-one) -7,7-dimethyl-bicyclo[2.2.1]hept-l- yljmethanesulfonamide with propyl halide according to the general procedures.
  • the title compound was prepared by reacting (lR,2S,5'S)-N,N-diisopropyl- [2-spiro- 2'- (5'-methyl-l',3'-dioxolane-4'-one) -7,7-dimethyl-bicyclo[2.2. l]hept-l - yl]methanesulfonamide with allyl halide according to the general procedures.
  • the diastereoselectivity of the produrt is > 98%.
  • the title compound was prepared by reacting (lR,2S,5'S)-N,N-diisopropyl- [2-spiro- 2 , - (5'-methyl-r,3'-dioxolane-4'-one) -7,7-dimethyl-bicyclo[2.2.1]hept-l- yl]methanesulfonamide with butyl halide according to the general procedures.
  • the title compound was prepared by reacting (lR,2S,5'S)-N,N-diisopropyl- [2-spiro- 2 , - (5'-methyl-l',3'-dioxolane-4'-one) -7,7-dimethyl-bicyclo[2.2.1]hept-l- yl]methanesulfonamide with benzyl halide according to the general procedures.
  • the title compound was prepared by reacting (lR,2S,5'S)-N,N-diisopropyl- [2-spiro- 2'- (5'-phenyl-l',3'-dioxolane-4'-one) -7,7- dimethyl-bicyclo[2.2.1]hept-l- yl]methanesulfonamide with methyl halide according to the general procedure.
  • the title compound was prepared by reacting (lR,2S,5'S)-N,N-diisopropyl- [2-spiro- 2'- (5'-phenyl-l',3'-dioxolane-4'-one) -7,7- dimethyl- bicyclo[2.2.1]hept-l- yljmethanesulfonamide with allyl halide according to the general procedure.
  • Example 5 illustrates the alcoholysis of the alkylated 1,3-dioxolanones of formula IV to form ⁇ -hydroxy acids derivatives of formula VI and 10-camphorsulfonamide of formula I.
  • Examples 6a-c illustrate the hydrolysis of the alkylated 1,3-dioxolanones of formula IV to form ⁇ -hydroxy acids of formula V and 10-camphorsulfonamide of formula I.
  • the general procedures of the hydrolysis Tie as follows:

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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)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)

Abstract

L'invention concerne un procédé relatif à l'élaboration d'acides α-hydroxy optiquement actifs, y compris leurs dérivés, qui consiste à soumettre à une alcoolyse ou à une hydrolyse les 1,3-dioxolanones alkylées de la formule (IV), dans laquelle R1 et R2 sont identiques ou différents et représentent chacun indépendamment H ou alkyle C1-6; R5 est H, alkyle C1-16, ou phényle substitué ou non; et R6 est alkyle C1-8, alcényle C2-7 ou benzyle substitué ou non, sachant que les 1,3-dioxolanones alkylées en question sont obtenues par utilisation de 10-camphorsulfonamide comme auxiliaire chiral.
EP99961901A 1999-12-02 1999-12-02 Procede relatif a l'elaboration d'acides alpha-hydroxy optiquement actifs, y compris leurs derives Withdrawn EP1233939A4 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1999/028440 WO2001040153A1 (fr) 1999-12-02 1999-12-02 PROCEDE RELATIF A L'ELABORATION D'ACIDES α-HYDROXY OPTIQUEMENT ACTIFS, Y COMPRIS LEURS DERIVES

Publications (2)

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EP1233939A1 true EP1233939A1 (fr) 2002-08-28
EP1233939A4 EP1233939A4 (fr) 2003-07-09

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EP99961901A Withdrawn EP1233939A4 (fr) 1999-12-02 1999-12-02 Procede relatif a l'elaboration d'acides alpha-hydroxy optiquement actifs, y compris leurs derives

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Country Link
EP (1) EP1233939A4 (fr)
JP (1) JP2003515576A (fr)
CN (1) CN1379748A (fr)
AU (1) AU1838900A (fr)
CA (1) CA2390815A1 (fr)
WO (1) WO2001040153A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102234255B (zh) * 2010-05-07 2013-05-08 国立清华大学 2-吗啉基异嵌烷-10-硫醇的制备方法及其所形成的中间物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHANG S-W ET AL: "Enantioselective synthesis of gamma-lactones from thioglycolic acid: Syntheses of (-)-muricatacin and 5-epi-(-)-muricatacin" TETRAHEDRON: ASYMMETRY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 9, no. 3, 13 February 1998 (1998-02-13), pages 521-529, XP004108202 ISSN: 0957-4166 *
See also references of WO0140153A1 *

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EP1233939A4 (fr) 2003-07-09
AU1838900A (en) 2001-06-12
CN1379748A (zh) 2002-11-13
WO2001040153A1 (fr) 2001-06-07
CA2390815A1 (fr) 2001-06-07
JP2003515576A (ja) 2003-05-07

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