US20030219880A1 - Method for preparing (2s,3r,4s)-4-hydroxyisoleucine and analogues thereof - Google Patents

Method for preparing (2s,3r,4s)-4-hydroxyisoleucine and analogues thereof Download PDF

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US20030219880A1
US20030219880A1 US10/239,194 US23919402A US2003219880A1 US 20030219880 A1 US20030219880 A1 US 20030219880A1 US 23919402 A US23919402 A US 23919402A US 2003219880 A1 US2003219880 A1 US 2003219880A1
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Jamal Ouazzani
Pierre Potier
Nobumichi-Andre Sasaki
Qian Wang
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    • 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
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
    • C07C255/26—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups, amino groups and singly-bound oxygen atoms bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02—Sulfinic acids; Derivatives thereof
    • C07C313/06—Sulfinamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers

Definitions

  • the present invention relates to methods for preparing ⁇ -amino acids.
  • group R 1 represents a hydrogen atom, a group protecting the amine group or a group of formula —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group, an aryl or aralkyl group.
  • group R 1 represents a group protecting the amine group or a group of formula —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group
  • an aryl or aralkyl group having never been synthesized are therefore novel and also form part of the invention.
  • the present invention therefore relates to a method for synthesizing compounds of general formula (2S)-I in which the group R 1 represents a hydrogen atom, a group protecting the amine group or a group of formula —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group, an aryl or aralkyl group.
  • group protecting the amine group is understood to mean, for the purposes of the present invention, any C 1 -C 6 alkyl group, any aryl or aralkyl group and in particular any labile group protecting the amine functional group and well known to persons skilled in the art, in particular of the benzyl, (S)-(+)-p-toluenesulfino
  • C 1 -C 6 alkyl group is understood to mean, for the purposes of the present invention, any substituted or unsubstituted, linear or branched C 1 -C 6 alkyl group, in particular the methyl, ethyl or t-butyl groups.
  • aryl group is understood to mean, for the purposes of the present invention, one or more aromatic rings having 5 to 8 carbon atoms, which may be condensed or fused, substituted or unsubstituted.
  • the aryl groups may be phenyl or naphthyl groups.
  • aralkyl group is understood to mean, for the purposes of the present invention, aryl groups as defined above, linked via an alkyl group as defined above.
  • an aralkyl group is a benzyl group.
  • This method comprises in particular the steps of:
  • enantiomeric excess of at least about 85%, advantageously of at least about 90%, and a diastereomeric excess (de) of at least about 90%, advantageously of at least about 95%.
  • the de is determined by gas chromatography (GC) analysis and the ee is estimated by the 1 H and 13 C NMR spectra of the ethyl (S)-lactate of 3.
  • the diastereo- and enantioselective reduction is carried out using an enzyme, still more advantageously using a microorganism containing this enzyme, in particular Geotrichum candidum (Buisson et al. Tetrahedron Lett. 1987, 28, 3939-3940 and Kawai et al.
  • the enzyme used may be isolated in particular from Geotrichum candidum (deposited at the Collection Nationale de Culture de Microorganismes on Dec. 8, 1999 with the registration number: I-2366) and used in powdered form or attached to a support.
  • group protecting the OH group is understood to mean any group known as such by persons skilled in the art, in particular the benzyl (Bn), t-butyl or tetrahydropyran (THP) groups.
  • the reduction may be carried out by any method well known to persons skilled in the art, in particular using LiAlH 4 or diisobutylaluminum hydride (DIBAL).
  • DIBAL diisobutylaluminum hydride
  • the oxidation may be carried out by any method well known to persons skilled in the art and in particular by treating with a pyridine/sulfur trioxide (Py.SO 3 ) complex in dimethyl sulfoxide (DMSO), by Swern oxidation or by treating with 2,2,6,6-tetramethyl-1-piperidinyloxy containing a free radical (TEMPO) using NaOCl as reducing agent in the presence of NaBr/NaHCO 3 /H 2 O.
  • DMSO dimethyl sulfoxide
  • TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy containing a free radical
  • the first route of synthesis (method A) is an asymmetric approach and comprises the following steps e 1 ) to h 1 ):
  • the group Y represents a group protecting the OH group and the group R4 represents a C 1 -C 6 alkyl, aryl or aralkyl group.
  • the sulfinamides having the configuration (S) (+) which may be used are in particular those for which the group R4 represents the t-butyl, 2-methoxy-1-naphthalenyl, 2-[1-(t-butylcarbonylamino)ethyl]benzyl or p-toluene group.
  • (S)-(+)-p-toluenesulfinamide may be easily prepared from (1R,2S,5R)-( ⁇ )-menthyl-(S)-p-toluenesulfinate and from lithium 1,1,1,3,3,3-hexamethyldisiloxane (LiHMDS).
  • the group Y represents a group protecting the OH group and the group R4 represents a C 1 -C 6 alkyl, aryl or aralkyl group.
  • lactone salt is understood to mean the salts obtained following the treatment with the inorganic acid, in particular chlorides or bromides. It is also possible, by another variant method, to obtain aminonitriles in step f 1 ) and lactones in step g 1 ) of good configurations by an asymmetric synthesis using chiral amines for the asymmetric induction at the C 2 position of the compounds of general formula II.
  • h 1 alkaline hydrolysis, in particular with LiOH, of the salt of the lactone of formula 9 in order to obtain the compound of general formula (2S)-I in which the group R 1 represents a hydrogen atom.
  • This compound may be purified, if necessary, by ion-exchange resin Dowex 50WX8 (H+ form), by neutralizing with an organic acid, in particular formic acid or acetic acid, and crystallization from an alcohol, in particular from isopropanol, propanol or ethanol, or by any other method known to persons skilled in the art.
  • the second route of synthesis (method B) from the compound of general formula II comprises the following steps e 2 ) to h 2 ):
  • the group Y represents a group protecting the OH group and the group R 3 represents a group protecting the amine group.
  • the compound of general formula II is preferably treated with benzylamine hydrochloride and KCN, preferably in an equimolar quantity, or still more preferably with benzylamine and trimethylsilyl cyanide (TMSCN).
  • TMSCN trimethylsilyl cyanide
  • the aminonitrile obtained is a racemic mixture of diastereomers (1S) and (1R), in particular with an (1S):(1R) ratio of 55:45.
  • the compound of general formula III in which the group R 3 represents the group (—CH(CH 3 )Ph) it is possible to treat the compound of general formula II preferably with (S)—NH 2 CH(CH 3 )Ph and TMSCN or the salt of (S)—NH 2 CH(CH 3 )Ph and KCN.
  • the aminonitrile obtained is a mixture of diastereomers with in particular a (1S):(1R) ratio of 3.5:1 to 4:1.
  • Step f 2 may be followed by an additional step f 2.1 ) of treatment of the lactone of general formula VI in order to obtain the lactone of the following general formula VII:
  • the group R 2 represents a C 1 -C 6 alkyl group, an aryl or aralkyl group.
  • This treatment of the lactone of general formula VI is carried out in a known manner by persons skilled in the art and in particular using hydrogen in the presence of a catalyst, advantageously containing palladium and still more advantageously with the Pd—C catalyst, and a compound A containing a group —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group, and aryl or aralkyl group.
  • the compound A is (COOCH 3 ) 2 O, in that where the group R 2 represents a t-butyl group, the compound A is di-tert-butyl bicarbonate and in that where the group R 2 represents the benzyl group, the compound A is benzyloxycarbonyl chloride.
  • step g 2 diastereoselective hydrolysis of the lactone of general formula VI or VII in order to obtain the compound of general formula (2S)-I.
  • This step g 2 ) may in particular consist of three variants.
  • the first variant g 2.1 ) relates only to the lactones of general formula VII or the lactones of general formula VI in which the group R 3 represents a group protecting an amine group. It then consists in the steps g 2.1.1 ) to g 2.1.3 ):
  • the group R 1 represents a group protecting the amine group or a group of formula —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group, an aryl or aralkyl group.
  • This mixture preferably comprises a 7:3 ratio in favor of the (2S) isomer.
  • This hydrolysis may be monitored by thin-layer chromatography (TLC) until it is complete and can be carried out, with stirring, for 1 hour at room temperature.
  • group R 1 represents a group protecting the amine group or a group of formula —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group, an aryl or aralkyl group, into a lactone of the following general formula (3R)-VIII:
  • group R 1 represents a group protecting the amine group or a group of formula —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group, an aryl or aralkyl group.
  • the recyclization may be monitored by high-performance liquid chromatography (HPLC).
  • group R represents a hydrogen atom, a group protecting the amine group or a group of formula —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group, an aryl or aralkyl group,
  • Step g 2 may be followed by an additional step h 2 ) in the case where the group R 1 of the compound of general formula (2S)-1 represents a group protecting the amine group or a group of formula —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group, an aryl or aralkyl group allowing the production of (2S,3R,4S)-4-hydroxyisoleucine 1.
  • group R 1 of the compound of general formula (2S)-1 represents a group protecting the amine group or a group of formula —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group, an aryl or aralkyl group allowing the production of (2S,3R,4S)-4-hydroxyisoleucine 1.
  • This additional step consists in a catalytic hydrogenolysis, in particular using a palladium-based catalyst, still more particularly using the Pd/C catalyst, of the compound of formula (2S)-I in which the group R 1 represents a group protecting the amine group or a group of formula —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group, an aryl or aralkyl group.
  • the third variant g 2.3 ) relates only to the lactones of general formula VI in which the group R 3 represents a group protecting the amine group, in particular a group (—CH(CH 3 )Ph). It then consists of the steps g 2.3.1 ) to g 2.3.3 ):
  • the method B of synthesis of (2S,3R,4S)-4-hydroxyisoleucine 1 may have the following reaction scheme:
  • the method B of synthesis of (2S,3R,4S)-4-hydroxyisoleucine 1 may also have the following reaction scheme:
  • the present invention also relates to the synthesis intermediates.
  • the latter are in particular lactones of the following general formula VIII:
  • the group R 1 represents a group of formula —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group, an aryl or aralkyl group.
  • These compounds may be present in free form or in the form of salts of acids, in particular inorganic acids of the HCl or HBr type. They may also be present in the form of a mixture, in particular a racemic mixture, of diastereomers (3S) and (3R) or in their optically pure form (3S) or (3R).
  • these compounds may be present in the form of a mixture of diastereomers with a (3S)/(SR) ratio of 4:1.
  • the present invention also relates to the aminonitriles of the following general formula III:
  • the group Y represents a group protecting the OH group and the group R 3 represents a group protecting the amine group. They may be present in the form of a mixture, in particular a racemic mixture, of the diastereomers (2S) and (2R) or in their optically pure (2S) or (2R) form.
  • the group R 3 represents the group —CH(CH 3 )Ph
  • these compounds may be present in the form of a mixture of diastereomers with a (2S)/(2R) ratio of 4:1.
  • the aminonitriles according to the present invention may be represented by the following general formula V:
  • the group Y represents a group protecting the OH group and the group R4 represents a C 1 -C 6 alkyl, aryl or aralkyl group.
  • the present invention also relates to the compounds of the following general formula IV:
  • the group Y represents a group protecting the OH group and the group R4 represents a C 1 -C 6 alkyl, aryl or aralkyl group.
  • the present invention also relates to the compounds of the following general formula I:
  • the group R 1 represents a group of formula —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group, an aryl or aralkyl group. They may be present in the form of a mixture, in particular a racemic mixture, of the diastereomers (2S) and (2R) or in their optically pure (2S) or (2R) form. In particular, in the case where the group R 1 represents the group —CH(CH 3 )Ph, these compounds may be present in the form of a mixture of diastereomers with a (2S)/(2R) ratio of 4:1.
  • the present invention also relates to the compounds of general formula (2S)-I in which the group R 1 represents a group protecting the amine group or a group of formula —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group, an aryl or aralkyl group as a medicine, in particular intended for the treatment of noninsulin-dependent diabetes mellitus or as an insulinotropic agent and its use for the manufacture of a medicine, in particular for the treatment of noninsulin-dependent diabetes mellitus.
  • the present invention also relates to the pharmaceutical compositions comprising, as active ingredient, a compound of general formula (2S)-I in which the group R 1 represents a group protecting the amine group or a group of formula —COOR 2 in which the group R 2 represents a C 1 -C 6 alkyl group, an aryl or aralkyl group and an appropriate excipient.
  • These compositions may be formulated for administration to mammals, including humans. The dosage may vary according to the treatment and according to the condition in question. These compositions are produced so that they can be administered by the digestive or parenteral route.
  • the active ingredient may be administered in unit forms for administration, mixed with conventional pharmaceutical carriers, to animals or to human beings.
  • the appropriate unit forms for administration comprise the forms for oral administration such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, the forms for sublingual or buccal administration, the forms for subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and the forms for rectal administration.
  • the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. It is possible to coat the tablets with sucrose or other appropriate substances or alternatively it is possible to treat them such that they have a prolonged or delayed activity and they continuously release a predetermined quantity of active ingredient.
  • a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. It is possible to coat the tablets with sucrose or other appropriate substances or alternatively it is possible to treat them such that they have a prolonged or delayed activity and they continuously release a predetermined quantity of active ingredient.
  • a preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard gelatin capsules.
  • a preparation in syrup or elixir form may contain the active ingredient together with a sweetener, an antiseptic, as well as a taste enhancer and an appropriate coloring.
  • the water-dispersible powders or granules may contain the active ingredient in the form of a mixture with dispersing agents or wetting agents, or suspending agents, and with flavor correctors or sweeteners.
  • FIG. 1 represents the GC analysis of the mixture obtained after incubating compound 2 with Geotrichum candidum.
  • the carrier gas is helium with a pressure of 65 Kpa.
  • the column used is DB.5 with the dimensions 30 m ⁇ 0.32 mm.
  • the detection is carried out using a flame ionization detector (FID) with an isotherm at 60° C.
  • FID flame ionization detector
  • FIG. 1 a represents the GC analysis of the mixture after 30 hours of incubation of compound 2 with Geotrichum candidum.
  • FIG. 1 b represents the GC analysis of the mixture obtained after 48 hours of incubation of compound 2 with Geotrichum candidum.
  • FIG. 2 represents the HPLC analyses during the enzymatic hydrolysis of the lactone 11.
  • a and B correspond to (3R)-(11) and (3S)-(11), respectively.
  • the solvent used is a mixture of 35% acetonitrile and 0.2% triethylamine in water.
  • the detection is carried out by UV at 250 nm.
  • FIG. 2 a represents the analytical HPLC analysis.
  • the column used is a C 18 hypersil ODS having the dimensions 5 ⁇ m, 250 ⁇ 4.6 mm.
  • the flow rate is 1 ml/min.
  • FIG. 2 b represents the preparative HPLC analysis.
  • the column used is prep nova-pak.HR C 18 having the dimensions 6 ⁇ m 60 A 10 ⁇ 2.5 cm.
  • the flow rate is 6 ml/min.
  • FIG. 3 a represents a resolution obtained with a pig pancreas acetone powder after 48 hours of incubation.
  • a and B correspond to (3R)-(11) and to (3S)-(11), respectively.
  • FIG. 3 b represents a resolution obtained with a penicillum microbial strain after 48 hours of incubation.
  • a and B correspond to (3R)-(11) and (3S)-(11), respectively.
  • FIG. 4 represents the HPLC analyses of the mixture of diastereomers of formula N-Bn-1 during the treatment with TFA.
  • a and B correspond to (2S)-N-Bn-1 and to (2R)-N-Bn-1, respectively.
  • the solvent used is a mixture of 20% acetonitrile and 0.1% TFA in water.
  • the detection is carried out by UV at 250 nm.
  • the column used is a C 18 hypersil ODS having the dimensions 5 ⁇ m, 250 ⁇ 4.6 mm.
  • the flow rate is 1 ml/min.
  • FIG. 4 b represents the preparative HPLC analysis.
  • the column used is prep nova-pak.HR C 18 having the dimensions 6 ⁇ m 60 A 10 ⁇ 2.5 cm.
  • the flow rate is 6 ml/min.
  • the strain Geotrichum candidum LCM is cultured in a sterile medium containing (per liter of distilled water): KH 2 PO 4 1 g, K 2 HPO 4 2 g, MgSO 4 0.5 g , FeSO 4 20 mg, KCl 0.5 g, NaNO 3 3 g, glucose 30 g, soluble corn extract 10 g.
  • the culture (6 liters) was placed in a rotary stirrer for 3 days (200 rpm, 27° C.). After growth, the mycelium was recovered by filtration, resuspended in distilled water (2 liters) and shaken for a further 24 hours (200 rpm, 27° C.).
  • the mycelium was filtered and was introduced into the reaction medium (2 liters) containing ethyl 2-methylacetate (2) (10 to 20 g/l ), glucose at 1.5% and NaCl at 1% (% relative to the substrate). The mixture was shaken (200 rpm, 27° C.), 1 ml samples were collected and they were analyzed from time to time by GC in order to determine the percentage conversion and the diastereomeric excess (de) (FIG. 1 a: after 30 hours). When the reaction was complete (after about 48 h: FIG.
  • TsOH.H 2 O (3.2 mg, 0.017 mmol,0.2%) was added at room temperature to a stirred solution of ethyl (2S,3S)-2-methyl-3-hydroxybutanoate (3) (1.22 g, 8.36 mmol) and dihydropyran (773 mg, 0.84 ml, 9.19 mmol) in toluene (17 ml). After stirring at the same temperature for 1 hour, the reaction was stopped by adding a saturated aqueous NaHCO 3 solution. The mixture was extracted with toluene.
  • the reaction is neutralized by means of the “Fieser treatment”; the reaction was treated by successively adding dropwise 2.7 ml of ice-cold water, 2.7 ml of a 15% aqueous NaOH solution, and 3 ⁇ 2.7 ml of ice-cold water. After having stirred for at least 30 minutes, the mixture is filtered on Celite. The precipitated aluminum salts were then washed with EtOAc.
  • the aqueous phase was separated and washed with Et 2 O (50 ml).
  • the combined organic phases were washed with a KI solution (80 mg) dissolved in aqueous 10% KHSO4 (20 ml), and then with a 10% aqueous sodium thiosulfate solution (10 ml), brine (20 ml), and dried (MgSO 4 ). Filtration and concentration under vacuum gave the desired aldehyde 6 (1.72 g, 92%) which was used for the next reactions without further purification.
  • Et 2 AlCN 1.0 M in toluene, 1.28 ml, 1.28 mmol, 1.5 eq.
  • isopropanol solution 56 mg, 72 ml, 0.94 mmol, 1.1 eq.
  • Et(OiPr)AlCN prepared above in THF at ⁇ 70° C. was added to a solution of (S)-N-[(2R,3S)-2-methyl-3-tetrahydropyranyloxybutylidene]-p-toluenesulfinamide (7) (275 mg, 0.85 mmol) in tetrahydrofuran (THF).
  • reaction mixture was brought to room temperature, it was stirred and the disappearance of the sulfinamide (22 hours) was monitored by TLC.
  • the reaction mixture was cooled to ⁇ 70° C. and it was neutralized by adding aqueous NaHCO 3 .
  • the suspension was diluted with EtOAc, it was filtered on Celite and diluted with water and the aqueous phase was extracted with EtOAc (2 ⁇ ). The combined organic phases were washed with brine, they were dried and evaporated.
  • Trifluoroacetic acid 200 ⁇ l was added to a solution of (2R)-N-Bn-1 (40 mg) in H 2 O (10 ml) and the solution was heated at 45° C. for 5 minutes. The solvent was evaporated using a rotary evaporator at 45° C. The residue was dissolved in EtOAc (10 ml), washed with a saturated NaHCO 3 solution, brine and dried over Na 2 SO 4 to give the lactone (3R)-11 (33 mg, 89%).
  • Trifluoromethanesulfonic acid (0.09 ml) was added drop wise to a solution of ethyl (2S,3S)-anti-2-methyl-3-hydroxybutanoate (3) (1.0 g, 6.85 mmol) and benzyl 2,2,2-trichloroacetimidate (4.32 g, 17.12 mmol) in cyclohexane (20 ml) and dichloromethane (10 ml).
  • the reaction mixture was stirred at room temperature for 24 hours. Saturated NaHCO 3 was added.
  • the organic layer was extracted with dichloromethane.
  • the organic extracts were combined, they were dried and concentrated. The resulting solid was filtered and it was washed with heptane.
  • (3R)-(11) was gradually hydrolyzed, while (3S)-(11) remained intact.
  • the latter was extracted with ethyl acetate and it was subjected to another (nonstereo-specific) enzymatic hydrolysis in order to obtain (2R,3R,4S)-N-benzyl-4-hydroxyisoleucine.
  • Catalytic hydrogenolysis of this N-protected amino acid gave (1).

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US10/239,194 2000-03-27 2001-03-23 Method for preparing (2s,3r,4s)-4-hydroxyisoleucine and analogues thereof Abandoned US20030219880A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060199853A1 (en) * 2005-02-18 2006-09-07 Charles Mioskowski Analogs of 4-hydroxyisoleucine and uses thereof
US20060223884A1 (en) * 2005-03-22 2006-10-05 Nicolas Chapal Compounds and compositions for use in the prevention and treatment of obesity and related syndromes
US20100048545A1 (en) * 2006-03-22 2010-02-25 Innodia Inc. Compounds and Compositions for Use in the Prevention and Treatment of Disorders of Fat Metabolism and Obesity
WO2012162507A1 (en) 2011-05-24 2012-11-29 Apicore, Llc Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof
CN105566136A (zh) * 2016-01-19 2016-05-11 天津科技大学 一种从发酵液中分离提取4-羟基异亮氨酸的方法

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003234146A1 (en) * 2002-04-22 2003-11-03 Experimental And Applied Sciences, Inc. Food supplements containing 4-hydroxyisoleucine and creatine
FR2854629B1 (fr) 2003-05-07 2005-06-17 Centre Nat Rech Scient Procede de synthese de la 4-hydroxyisoleucine et de ses derives
EP1657236A1 (de) * 2004-11-10 2006-05-17 Centre National De La Recherche Scientifique (Cnrs) Verfahren zur Herstellung von Diastereoisomeren von 4-Hydroxyisoleucin
CN104152505B (zh) * 2014-08-08 2016-11-23 江南大学 一种利用重组菌株转化制备4-羟基-l-异亮氨酸的方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2745718B1 (fr) * 1996-03-08 1998-05-07 Gestion Jouvenet Soc Civ De Composition antidiabetique a base de 4-hydroxyisoleucine

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060199853A1 (en) * 2005-02-18 2006-09-07 Charles Mioskowski Analogs of 4-hydroxyisoleucine and uses thereof
US20060223884A1 (en) * 2005-03-22 2006-10-05 Nicolas Chapal Compounds and compositions for use in the prevention and treatment of obesity and related syndromes
US20100048545A1 (en) * 2006-03-22 2010-02-25 Innodia Inc. Compounds and Compositions for Use in the Prevention and Treatment of Disorders of Fat Metabolism and Obesity
WO2012162507A1 (en) 2011-05-24 2012-11-29 Apicore, Llc Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof
US8748631B2 (en) 2011-05-24 2014-06-10 Apicore, Llc Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof
US9150511B2 (en) 2011-05-24 2015-10-06 Apicore Us Llc Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof
CN105566136A (zh) * 2016-01-19 2016-05-11 天津科技大学 一种从发酵液中分离提取4-羟基异亮氨酸的方法

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AU4663301A (en) 2001-10-08
FR2806726B1 (fr) 2003-01-03
FR2806726A1 (fr) 2001-09-28
EP1268397B1 (de) 2007-12-05
CA2404621A1 (fr) 2001-10-04
ATE380173T1 (de) 2007-12-15
US20050079587A1 (en) 2005-04-14
US7432087B2 (en) 2008-10-07
WO2001072688A2 (fr) 2001-10-04
CA2404621C (fr) 2012-11-20
DE60131733T2 (de) 2008-10-30
EP1268397A2 (de) 2003-01-02
DE60131733D1 (de) 2008-01-17
WO2001072688A3 (fr) 2002-04-11

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