WO1999054297A1 - Procede de preparation de chloroalcools et de leurs intermediaires - Google Patents

Procede de preparation de chloroalcools et de leurs intermediaires Download PDF

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Publication number
WO1999054297A1
WO1999054297A1 PCT/JP1998/001755 JP9801755W WO9954297A1 WO 1999054297 A1 WO1999054297 A1 WO 1999054297A1 JP 9801755 W JP9801755 W JP 9801755W WO 9954297 A1 WO9954297 A1 WO 9954297A1
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group
amino
general formula
derivative
optionally substituted
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PCT/JP1998/001755
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English (en)
Japanese (ja)
Inventor
Masaya Ikunaka
Jun Matsumoto
Yoshito Fujima
Yoshihiko Hirayama
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Nagase & Company, Ltd.
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Priority to AU68529/98A priority Critical patent/AU6852998A/en
Priority to PCT/JP1998/001755 priority patent/WO1999054297A1/fr
Publication of WO1999054297A1 publication Critical patent/WO1999054297A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a compound that inhibits the activity of a virus-derived protease and a method for producing an intermediate compound useful for synthesizing the same. More specifically, formulas [XI] useful as therapeutics for HIV-related diseases
  • Bu l is ⁇ - butyl group
  • P h is phenyl group
  • the present invention also relates to a novel compound useful for producing the above compound [XI].
  • novel compounds can be used not only for producing the above compound [XI] but also for producing various compounds.
  • BACKGROUND ART The above compound [XI] is known as an HIV protease inhibitor (W095Z09843). Conventionally, this compound has been produced through an extremely large number of steps including a carbohydrate reaction with serine as a starting material and a stereoselective carbonyl group reduction reaction. However, these conventional manufacturing methods are expensive In addition to the need for raw materials, it was extremely complicated and inefficient, requiring low-temperature reaction conditions.
  • WO 97/1193 7 and WO 97/1193 38 use, 1, —2-butenediol as a raw material, and the key reaction is the epoxy ring-opening reaction with a chiral amine.
  • a method for producing the above compound [XI] is disclosed. This manufacturing method requires a large number of steps.
  • Dale L. Rieger J. Org. Chem. 1997, 62, 8546-8548 discloses a method for producing the above compound [XI] using serine as a starting material and dithianyl alcohol as a key intermediate. ing. This manufacturing method requires a low-temperature reaction step. As described above, the conventional methods for synthesizing the above compound [XI] have many problems that must be solved in order to implement them industrially.
  • An object of the present invention is to provide a method for efficiently producing the above compound [XI], which is useful as an HIV protease inhibitor.
  • An object of the present invention is to provide a novel intermediate compound useful for producing the above compound and a method for producing the same.
  • DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies in order to achieve the above object, and as a result, starting from a 5,3R) -4-hydroxy xy-2,3-epoxybutanoic acid derivative as a starting material, the following formula [X]
  • the production method of the present invention comprises a step of curing a (2S, -3R) -4-hydroxy-2,3-epoxybutanoic acid derivative, a step of regioselectively opening an epoxy ring of the obtained derivative, A step of protecting the amino group of the obtained ring-opened derivative, a step of lactonizing the protected ring-opened derivative, a step of reducing the obtained lactone derivative, a step of protecting the 1,2-diol group of the obtained reduced derivative, protection Thioetherifying the reduced derivative thus obtained,
  • the method includes a step of removing a diol protecting group of the obtained thioether derivative and a step of selectively chlorinating a primary hydroxyl group of the obtained diol derivative.
  • the outline of the reaction scheme is shown below.
  • R 1 is [an alkyl group which may be substituted for S or an aryl group which may be substituted;
  • R 2 is an amino-protecting group of acyl or carbamate type;
  • R 3 and R 4 May be the same or different and are each a hydrogen atom, an optionally substituted alkyl group or an aryl group, or a cycloalkyl in which R 3 and R 4 are taken together with an adjacent carbon atom to form a ring
  • R 5 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group or an optionally substituted aralkyl group;
  • M ' is an alkali metal).
  • One aspect of the present invention is a novel intermediate compound obtained during the process of producing the compound represented by the formula [X] and a method for producing the same. More specifically, the following 1 to
  • R 1 is an alkyl group or an aryl group which may be substituted
  • R 1 including a step of curing a 2S, third-4-hydroxy-2,3-epoxybutanoic acid derivative, Method.
  • R 2 is an acyl or carbamate amino protecting group
  • R 2 is an acyl or carbamate amino protecting group
  • R 2 is an acyl- or carbamate-based amino protecting group
  • R 2 is an acyl- or carbamate-based amino-protecting group represented by (3R, 4S ⁇ ) dihydro-3-amino-4-hydroxy-2 (3W-furanone derivative Including the method.
  • R 3 and R 3 may be the same or different and are each a hydrogen atom, an optionally substituted alkyl group or an aryl group. Or a cycloalkyl group wherein R 3 and R 4 are taken together with adjacent carbon atoms to form a ring).
  • a process for producing a 1,2,4-butanetriol derivative comprising:
  • R 2 is an acyl-based or carbamate-based amino-protecting group
  • R 3 and R 4 may be the same or different and are each a hydrogen atom, an optionally substituted alkyl group or an aryl group. Or R 3 and R 4 are cycloalkyl groups formed together with adjacent carbon atoms to form a ring
  • R 2 is an acyl-based or carbamate-based amino-protecting group
  • R 2 is an acyl-based or carbamate-based amino-protecting group
  • a method comprising reacting an acetalizing agent in the presence of a catalyst and a dehydrating agent to protect the 1,2-diol group of the derivative.
  • R 2 is an acyl- or bamate-based amino-protecting group
  • R 3 and R 4 may be the same or different and each is a hydrogen atom, an optionally substituted alkyl group or an aryl group.
  • R 3 and R 4 are a cycloalkyl group which forms a ring together with adjacent carbon atoms
  • R 5 is a hydrogen atom, an optionally substituted alkyl group, or a substituted
  • a process for producing a 4--4-mercapto-i, 2-butanediol derivative comprising:
  • R 2 is an acyl-based or carbamate-based amino-protecting group
  • R 3 and R 4 may be the same or different and each is a hydrogen atom, an optionally substituted alkyl group or an aryl group.
  • R 3 and R 4 are a cycloalkyl group which forms a ring together with adjacent carbon atoms
  • R 5 is a hydrogen atom, an optionally substituted alkyl group, An alkenyl group which may be substituted, an aryl group which may be substituted or an aralkyl group which may be substituted
  • R 3 and R 4 may be the same or different and each is a hydrogen atom, an optionally substituted alkyl group or an aryl group, Or R 3 and R 4 are a cycloalkyl group which forms a ring together with adjacent carbon atoms)
  • R 2 is an acyl-based or carbamate-based amino-protecting group
  • R 5 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group Or an aralkyl group which may be substituted
  • alkali metal includes sodium, potassium, lithium, rubidium, cesium and francium, preferably sodium, potassium or lithium.
  • alkyl group embraces both straight-chain and branched-chain alkyl groups, preferably having 1 to 6 carbons.
  • Preferable alkyl groups in the present invention include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, and di-pentyl group.
  • hexyl group isohexyl group, neohexyl group and the like.
  • Preferred alkyl groups are "lower alkyl groups" having 1 to 4 carbon atoms, and specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, f-butyl and the like. It is.
  • optionally substituted 'alkyl group refers to an alkyl group substituted with one or more substituents that does not affect the reaction.
  • This substituent may be a hydroxyl group; a halogen atom such as fluorine, chlorine, bromine, or iodine; an amino group; a nitro group; a mono- to mono-carbon group having 1 to 6 carbon atoms, such as Or a dialkylamino group; a cyano group; a cycloalkyl group having 3 to 7 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a cycloheptyl group; a methoxy group, an ethoxy group, a propoxy group, or a butoxy group Alkoxy group having 1 to 6 carbon atoms such as a pentoxy group, a pentoxy group, a pentoxy group,
  • aryl group includes aromatic groups such as phenyl, naphthyl, biphenyl and the like, and is preferably phenyl '.
  • optionally substituted aryl group means an aryl group substituted with one or more substituents that do not affect the reaction.
  • This substituent includes the substituents described in the above “optionally substituted alkyl group”, and further includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and an s-butyl group.
  • An alkyl group having 1 to 6 carbon atoms such as a monobutyl group, a pentyl group, an isopentyl group, a neopentyl group, a dipentyl group, a hexyl group, an isohexyl group, a neohexyl group; a vinyl group, an aryl group,
  • An alkenyl group having 2 to 6 carbon atoms such as a butenyl group, a pentenyl group, and a hexenyl group; Include.
  • Preferred substituents are an alkyl group, a hydroxyl group, a halogen atom, an amino group, a nitro group, an alkoxy group, and an acyloxy group, and more preferred are an alkyl group, a hydroxyl group, a halogen atom, an alkoxide group, and an acyloxy group.
  • substitution position and number of the above substituents on the aryl group are not particularly limited,
  • acyl- or carbamate-based amino-protecting group refers to rumyl, acetyl, propionyl, butyryl, bivaloyl, 2-crocoacetyl, 2-bromoacetyl, 2-bromoacetyl, 2,2.
  • aryloxycarbonyl groups such as phenoxycarbonyl group; benzyloxycarbonyl group, 4-bromobenzyloxycarbonyl group, 2-hydroxybenzyloxycarbonyl group Group, 3-chlorobenzyloxycarbonyl group, 3,5-dimethylbenzylcarbonyl group, 4-methoxybenzylcarbonyl group, 2-nitrobenzyloxycarbonyl group, 4-nitrobenzyloxycarbonyl group,
  • aralkyloxycarbonyl groups such as 2,2-troth 4,5-dimethoxybenzyloxycarbonyl group, 3,4,5-trimethoxybenzyloxycarbonyl group, phenethyloxycarbonyl group A methylthiocarbonyl group, an ethylthiocarbonyl group, a butylthiocarbonyl group, a t-butylthioca Including and base Nji thiocarbonyl optionally substituted ⁇ Lal key Lucio carbonylation Le
  • a preferred "amino group of an acyl or carbamate type" is an aralkyloxycarbonyl group, more preferably a benzyloxycarbonyl group.
  • alkenyl group embraces straight-chain and branched alkenyl groups, preferably having 2 to 6 carbons. Arke preferred in the present invention: Examples of ⁇ groups include A vinyl group, an aryl group, a crotyl group, a 2-pentenyl group, a 3-pentenyl group, a 2-hexenyl group, a 3-hexenyl group and the like. More preferred alkenyl groups are alkenyl groups having 2 to 4 carbon atoms, and are a vinyl group, an aryl group and a crotyl group.
  • optionalally substituted alkenyl group means an alkenyl group substituted with one or more substituents that do not affect the reaction. This substituent includes the substituents described above for the “optionally substituted alkyl group”. The substitution position and the number of substituents on the alkenyl group are not particularly limited.
  • aralkyl group is composed of the above aryl group (phenyl group, naphthyl group, biphenyl group, etc.) and the above alkyl group (alkyl group having 1 to 6 carbon atoms), such as benzyl group, phenethyl group, phenylpropyl group. Group, phenylbutyl group, phenylhexyl group and the like.
  • a preferred aralkyl group comprises a phenyl group and an alkyl group having 1 to 4 carbon atoms.
  • optionally substituted aralkyl group means an aralkyl group substituted with one or more substituents that does not affect the reaction.
  • This substituent includes the substituents described in the above “optionally substituted alkyl group”, and further includes a haloalkyl group having 1 to 6 carbon atoms such as a chloromethyl group, a chloroethyl group and a chlorobutyl group. I do.
  • the “optionally substituted aralkyl group” includes a benzyl group, a halogen-substituted benzyl group, an alkyl-substituted benzyl group, an alkoxy-substituted benzyl group, a phenethyl group, a halogen-substituted phenyl group, an alkyl-substituted phenyl group, and an alkoxy-substituted group.
  • It includes a phenyl group, a phenylpropyl group, a halogen-substituted phenylpropyl group, an alkyl-substituted phenylpropyl group, an alkoxy-substituted phenylpropyl group and the like, and is preferably a benzyl group or a phenethyl group.
  • the substitution position and the number of the above substituents with respect to the aralkyl group are not particularly limited, but 1 to 3 substituents are preferable.
  • cycloalkyl group preferably includes a cycloalkyl group having 3 to 7 carbon atoms, and includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like. More preferably, it is a cycloalkyl group having 4 to 6 carbon atoms, including a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • Esterification of ester-Compound (I) can be prepared, for example, by 1) Dunigan, J .; Weigel, L. 0. J. Org. Chew. 1991, 56, 6225, 2) Weigel, manufactured according to the method described in USP 5, 097, 04.
  • compound (II) is obtained by dissolving compound (I) in a suitable alcoholic solvent at a predetermined temperature and reacting with a predetermined amount of a suitable base.
  • a suitable base sodium hydroxide, potassium hydroxide, lithium hydroxide can be used, preferably sodium hydroxide.
  • Suitable alcoholic solvents include, for example, methanol, ethanol, pucopropyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, s_butyl alcohol;; -butyl alcohol, etc., preferably methanol, Ethanol, isopropyl alcohol and more preferably methanol are used.
  • the amount of the salt group to be used is 1 equivalent to 2 equivalents, preferably 1.0 equivalent to 1.2 equivalents, relative to compound (I).
  • the reaction temperature is suitably from ⁇ 20 to 50, preferably from 0 to 2 (TC. Usually, the reaction of the compound (I) is completed in a reaction time of 5 to 15 hours, and the compound (II) Step (2): Regioselective ring opening of the epoxy ring with ammonia
  • the epoxy ring of the compound (II) is opened using a predetermined amount of ammonia in a suitable solvent at a predetermined temperature to obtain a compound (II).
  • Suitable solvents include, for example, alcohol solvents such as methanol, ethanol, propyl alcohol, isopropyl alcohol,] -butyl alcohol, isobutyl alcohol, s-butyl alcohol, and t-butyl alcohol; benzene, toluene, hexane, xylene, etc. Hydrocarbon solvents; ether solvents such as getyl ether, 1,2-dimethoxyethane, tetrahydrofuran and diglyme; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc. Or a polar solvent such as N, N-dimethylformamide, acetonitrile, acetone, or water; or a mixed solvent thereof, and preferably water.
  • alcohol solvents such as methanol, ethanol, propyl alcohol, isopropyl alcohol,] -butyl alcohol, isobutyl alcohol, s-butyl alcohol, and
  • Ammonia is usually used in the form of an aqueous solution, and its use amount is 5 to 40 equivalents, preferably 10 to 25 equivalents, relative to compound (II).
  • the reaction temperature is suitably from 0 to 100, preferably from 40 to 70.
  • the epoxy ring of compound (II) is opened in a reaction time of 5 to 70 hours to obtain compound (III).
  • the compound (III) is added to a predetermined amount of an acid halide, a halogenated formate, an acid anhydride or a carbonate anhydride corresponding to a predetermined amount of R 2 in a suitable solvent at a predetermined temperature.
  • the amino group is protected with a protecting group (R 2 ) to give a lig compound (IV).
  • acyl-based or carbamate-based amino-protecting group (R 2 ) examples include an acyl group, an imide group, a phenoxycarbonyl group, an aralkyloxycarbonyl group, an alkylthiocarbonyl group, an aralkylthiocarbonyl group and the like.
  • an aralkyloxycarbonyl group, more preferably a benzyloxycarbonyl group may be used.
  • the acid anhydride corresponding to R 2 or carbonitrides anhydride is not particularly limited as long as it is a compound corresponding to R 2, e.g., acetic anhydride, di one f - butyl dicarbonate: di (2, 2, 2-trichloroethyl) dicarbonate or the like may be used.
  • Suitable solvents include, for example, alcohol solvents such as methanol, ethanol, propyl alcohol, isopropyl alcohol, monobutyl alcohol, isobutyl alcohol, s-butyl alcohol, and butyl alcohol; and carbonized solvents such as benzene, toluene, hexane, and xylene.
  • alcohol solvents such as methanol, ethanol, propyl alcohol, isopropyl alcohol, monobutyl alcohol, isobutyl alcohol, s-butyl alcohol, and butyl alcohol
  • carbonized solvents such as benzene, toluene, hexane, and xylene.
  • Hydrogen solvents Ether solvents such as jet ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, etc .: Halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc .; acetic acid Ester solvents such as ethyl, methyl acetate and butyl acetate; polar solvents such as ⁇ , ⁇ -methylformamide, acetonitrile, acetone, water and the like; or a mixed solvent thereof, preferably water or the above organic solvent. Mixture of solvent and water Can be used.
  • reaction temperature is suitably from 0 to 10 °, preferably from 0 to 50 °.
  • amino group of compound (III) is protected in a reaction time of 5 to 15 hours to obtain compound (IV).
  • the compound (V) is obtained by lactonizing the compound (IV) at a predetermined temperature in a suitable solvent in the presence of a predetermined amount of a suitable acid or a reagent that generates an acid in the reaction system. ).
  • a suitable alcoholic solvent for example, methanol, ethanol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, S-butyl alcohol, polyvinyl alcohol and the like, preferably methanol can be used.
  • inorganic acids such as sulfuric acid and hydrochloric acid
  • sulfonic acids such as methanesulfonic acid and ⁇ -toluenesulfonic acid
  • chlorotrimethylsilane, ⁇ -toluenesulfonyl chloride, methanesulfonyl chloride, benzyloxycarbonyl chloride, Acetyl chloride and the like can be used, and preferably chlorotrimethylsilane can be used.
  • the amount of the acid or the reagent that generates an acid in the reaction system to be used is 1 equivalent to 3 equivalents, preferably 1.0 equivalent to 1.5 equivalents, relative to compound (IV).
  • reaction temperature is suitably from 110 to 50, preferably from 0 to 30.
  • compound UV) is lactonized in a reaction time of 5 to 24 hours to obtain compound (V).
  • compound (IV) is directly lactonized at a predetermined temperature in a suitable solvent in the presence of an acid catalyst to obtain compound (V).
  • Suitable solvents include, for example, methanol, ethanol, propyl alcohol.
  • Alcohol solvents such as isopropyl alcohol, J2-butyl alcohol, isobutyl alcohol, s-butyl alcohol, t-butyl alcohol, etc .; -Ether solvents such as dimethoxyethane, tetrahydrofuran and diglyme; polar solvents such as N, N-dimethylformamide, acetonitrile, acetone and water; and mixed solvents thereof.
  • water is used.
  • Suitable acid catalysts include, for example, inorganic acids such as sulfuric acid and hydrochloric acid, and sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, and preferably p-toluenesulfonic acid.
  • the amount of the acid or the reagent that generates an acid in the reaction system to be used is 0.1 equivalent to 1.0 equivalent, preferably 0.3 equivalent to 0.6 equivalent, relative to compound (IV).
  • reaction temperature is suitably 0.50, and preferably 2030.
  • compound (IV) is lactonized in a reaction time of 524 hours to obtain compound (V).
  • compound (VI) is obtained by treating compound (V) with a predetermined amount of a suitable reducing agent in a suitable solvent at a predetermined temperature.
  • sodium borohydride, calcium borohydride, lithium borohydride, lithium triethylborohydride, borane, lithium aluminum hydride, alane, diisobutylaluminum hydride, sodium bis (2-methoxhetoxy) Aluminum hydride or the like can be used, preferably sodium borohydride, calcium borohydride, lithium borohydride, and more preferably calcium borohydride.
  • a suitable solvent is selected depending on the reducing agent used, and examples thereof include hydrocarbon solvents such as benzene, toluene, hexane, and xylene; getyl ether, 1,2-dimethyloxetane, tetrahydrofuran, diglyme, and the like.
  • Ether solvents such as dichloromethane, chloroform, carbon tetrachloride, and halogen solvents such as 1,2-dichlorobenzene; methanol, ethanol, propyl alcohol, isopropyl alcohol, ⁇ -butyl alcohol, isobutyl alcohol, Alcohol solvents such as s-butyl alcohol and ⁇ -butyl alcohol can be used.
  • a preferable solvent is an alcohol solvent or an ether solvent, and more preferably methanol.
  • the amount of the reducing agent to be used is 1 equivalent-3 equivalents, preferably 1.5 equivalents-2.0 equivalents, relative to compound (V).
  • the reaction temperature is suitably from 0 to 100, preferably from 0 to 50.
  • the compound (V) is reduced in a reaction time of 3 to 10 hours to obtain the compound (VI).
  • the compound (VI) is reacted with a predetermined amount of an acetalizing agent in a suitable solvent at a predetermined temperature in the presence of a predetermined amount of an acid catalyst or in the presence of an acid catalyst and a dehydrating agent.
  • the compound (VI I) is obtained by protecting the 1,2-diol group.
  • the solvent is appropriately selected depending on the kind of the acylating agent to be used, and suitable solvents include, for example, hydrocarbon solvents such as benzene, toluene, hexane and xylene; dimethyl ether, 1,2-dimethoxy Ether solvents such as ethane, tetrahydrofuran, and diglyme; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; and ester solvents such as ethyl acetate, methyl acetate, and butyl acetate. : ⁇ , ⁇ -dimethylformamide, acetonitrile, acetone, dime W
  • a polar solvent such as tylsulfoxide: or a mixed solvent thereof can be used.
  • acetalizing agent examples include carbonyl compounds such as benzaldehyde, acetone, getyl ketone, methyl ethyl ketone, acetophenone, cyclopentynone, cyclohexanone; dimethoxymethane, 1,1-dimethoxyacetoaldehyde, benzaldehyde dimethyl Ge dialkoxy compounds such as acetal, 2,2-dimethoxypropane and cyclohexanone dimethyl acetate; or methyl vinyl ether, ethyl vinyl ether, 2-methoxypropene, 2-ethoxypropene, A vinyl ether compound such as 1-methoxycyclohexene or the like can be used, preferably a carbonyl compound or an e-dialkoxy compound, more preferably acetone or 2,2-dimethoxypropane.
  • carbonyl compounds such as benzaldehyde, acetone, getyl ketone, methyl eth
  • the amount of the acetalizing agent to be used is 1 equivalent to 10 equivalents, preferably 1 equivalent to 3 equivalents, relative to compound (VI). However, in the case of acetone, a large excess is used as a solvent.
  • the acid catalyst is appropriately selected depending on the type of acetalizing agent used. Suitable catalysts include, for example, inorganic acids such as hydrochloric acid and sulfuric acid; sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid; A salt of a sulfonic acid and an organic amine such as a pyridinium salt of toluenesulfonic acid may be used, and a salt of a sulfonic acid and an organic amine is preferably used, and a pyridinium salt of toluenesulfonic acid is more preferably used.
  • inorganic acids such as hydrochloric acid and sulfuric acid
  • sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid
  • a salt of a sulfonic acid and an organic amine such as a
  • the amount of the acid catalyst to be used is 0.01 equivalent to 0.5 equivalent, preferably 0.05 equivalent to 0.2 equivalent, relative to compound (VI).
  • phosphorus oxychloride molecular sieves, magnesium sulfate, etc. can be used, and molecular sieves are preferably used.
  • the amount of the dehydrating agent to be used is 0.1 to 30 times, preferably 1 to 5 times, by weight, relative to compound (VI).
  • the reaction temperature is suitably from 0 to 100 ° C., preferably from 0 to 5 (TC. Usually, the reaction time of 10 to 24 hours allows the 1,2-diol group of the compound (V i) to be formed.
  • the compound (VII) is reacted with a predetermined amount of a halogenating agent or a sulfonylating agent in a suitable solvent at a predetermined temperature and in the presence of a predetermined amount of a suitable base to form a hydroxyl group. Is replaced with a suitable leaving group, and after isolation or without isolation, in the presence of a predetermined amount of a suitable base, a predetermined amount of the desired R 5 SH (where R 5 is The compound (VI II) is obtained by reacting with a mercaptan represented by the formula:
  • Suitable solvents for carrying out the halogenation or sulfonylation of hydroxyl groups include, for example, hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc .; ethyl ether, 1,2-dimethoxyquinone, tetrahydrofuran : Ether solvents such as diglyme; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; A polar solvent such as N-dimethylformamide, acetonitrile, acetone, dimethyl sulfoxide; or a mixed solvent thereof can be used.
  • a hydrocarbon solvent for example, toluene is used.
  • Suitable leaving groups are, for example, halogens such as chlorine, bromine and iodine; methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, camphorsulfonyl And a sulfonyloxy group such as a oxy group, preferably a sulfonyloxy group, more preferably a methanesulfonyloxy group.
  • halogenating agent examples include ordinary halogenating agents such as phosphorus trichloride, phosphorus oxychloride, phosphorus tribromide, thionyl chloride, phosphorus pentachloride, etc. Combinations of carbon and trirefenylphosphine may be used.
  • sulfonylating agent examples include sulfonyl chlorides such as methanesulfonyl dichloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, camphorsulfonyl-chloride and the like: methanesulfonic anhydride, p- Sulfonic anhydrides such as toluenesulfonic anhydride and trifluoromethanesulfonic anhydride can be used, preferably sulfonyl chloride, more preferably methanesulfonyl chloride.
  • the amount of the dehalogenating agent or the sulfonylating agent to be used is 1 equivalent-2 equivalents, preferably 1.0 equivalent-1.2 equivalents, relative to compound (VII).
  • Suitable bases include, for example, pyridine, lutidine, picoline, triethylamine, diisopropylethylamine, 4- (N, N-dimethylamino) pyridine, 1,8-diazabicyclo [5,4,0] -7-indenecene
  • Organic bases such as (DBU), 1,5-diazabicyclo [4,3,0] -5-nonene (DBN), triethylenediamine (DAB C0), etc. may be used: preferably pyridine, trie Phenylamine, more preferably triethylamine.
  • the amount of the base to be used is 1 equivalent-2 equivalents, preferably 1.2 equivalents-1.7 equivalents, relative to compound (VII).
  • the reaction temperature of the halogenation or the sulfonylation is suitably from 0 to 100, preferably from 0 to 5 Ot :.
  • the hydroxyl group of compound (VII) is substituted in a reaction time of 30 minutes to 6 hours.
  • Suitable solvents used for the reaction with the desired mercapnones include, for example, hydrocarbon solvents such as benzene, toluene, hexane, and xylene; and ethers such as jetter ether, 1,2-dimethyloxetane, tetrahydrofuran, and diglyme.
  • Ether solvents halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane
  • ester solvents such as ethyl acetate, methyl acetate and butyl acetate
  • N N-dimethylformamide, acetonitrile, acetone , Dimethyl sulfoxide, etc.
  • a mixed solvent thereof preferably a polar solvent, for example, dimethyl sulfoxide, acetone, methyl ethyl ketone, N,>:-dimethylformamide.
  • the desired mercaptans may be any as long as they have a mercapto group, for example, optionally substituted aryl mercaptans such as thiophenol and toluene thiol; methyl mercaptan, ethyl mercaptan Alkyl mercaptans which may be substituted, such as propyl mercaptan, isopropyl mercaptan, butyl mercaptan, isobutyl mercaptan, s-butyl mercaptan, f-butyl mercaptan; benzyl mercaptan, phenethyl mercaptan, naphthyl
  • aralkyl mercaptans such as methyl mercaptan
  • substituted or unsubstituted aryl mercaptans such as vinyl mercaptan and aryl mercaptan
  • aryl mercaptans are optionally substituted ary
  • the amount of the mercap compound to be used is 1 equivalent-2 equivalents, preferably 1. ⁇ equivalent-1.2 equivalents, relative to compound (VII).
  • Suitable bases used for the reaction with the desired mercapnones include, for example, pyridine, lutidine, picoline, triethylamine, diisopropylethylamine, dimethylaminopyridine, 1,8-diazabicyclo [5,4, Organic bases such as 0] — 7-indene (DBU), 1,5-diazabicyclo [4,3,0] —5-nonene (DBN) and triethylenediamine (DABCO): lithium hydroxide, sodium hydroxide, water
  • Inorganic bases such as potassium oxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like can be used, and preferably, an inorganic base such as potassium carbonate is used.
  • the amount of the above base to be used is 1 equivalent to 3 equivalents, preferably 1.5 equivalents to 2.5 equivalents, relative to compound (VII).
  • reaction temperature with the desired mercapones is suitably 0 to 100 ° C, preferably 0 to 50.
  • the compound 'III) is obtained in a reaction time of 5 to 20 hours.
  • the compound is prepared in a suitable solvent at a predetermined temperature in the presence of a predetermined amount of a suitable acid.
  • Suitable solvents include, for example, alcoholic solvents such as methanol, ethanol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, s-butyl alcohol, and tert-butyl alcohol; or alcohol solvents and ether solvents.
  • Mixed solvent with polar solvent here, ether solvents include getyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, etc., and polar solvents include N, N-dimethylformamide, acetonitrile , Acetone, water, etc.
  • an alcoholic solvent for example, methanol.
  • Suitable acids include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; carboxylic acids such as acetic acid, chloroacetic acid, trichloroacetic acid, and trifluoroacetic acid; sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid; Acids can be used, preferably inorganic acids, for example hydrochloric acid.
  • inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid
  • carboxylic acids such as acetic acid, chloroacetic acid, trichloroacetic acid, and trifluoroacetic acid
  • sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid
  • Acids can be used, preferably inorganic acids, for example hydrochloric acid.
  • the amount of the above acid to be used is 0.01 equivalent to 0.2 equivalent, preferably 0.05 equivalent to 0.1 equivalent, relative to compound (VIII).
  • reaction temperature is suitably from 0 to 100, preferably from 60 to 90.
  • the compound (IX) is obtained in a reaction time of 30 minutes to 2 hours.
  • the diol (IX) is reacted with a predetermined amount of sulfonyl chloride in a suitable solvent or without a solvent at a predetermined temperature in the presence of a predetermined amount of a suitable base.
  • the primary hydroxyl group of the diol is converted into a sulfonic acid ester, and then the sulfonic acid ester is further substituted with a chlorine atom in the same reaction system to obtain a compound (X).
  • the reaction can be carried out without a solvent, but it is preferable to carry out the reaction after diluting in an appropriate solvent.
  • Suitable solvents include, for example, hydrocarbon solvents such as benzene, toluene, hexane and xylene; ether solvents such as getyl ether, 1,2-dimethoxyethane, tetrahydrofuran and diglyme; dichloromethane; Halogen solvents such as form, carbon tetrachloride and 1,2-dichloromethane; ester solvents such as ether acetate, methyl acetate and butyl acetate; N, N-dimethylformamide, acetonitrile, acetone, A polar solvent such as dimethyl sulfoxide; or a mixed solvent thereof can be used, and an ester solvent, for example, ethyl acetate can be used.
  • hydrocarbon solvents such as benzene, toluene, hexane and xylene
  • ether solvents such as getyl ether, 1,2-dimethoxyethane, tetrahydro
  • the solvent examples include, for example, p-toluenesulfonyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, camphorsulfonyl chloride, and the like, and preferably p-toluenesulfonyl chloride.
  • the amount of the sulfonyl ester and the mouth lid to be used is 1 equivalent-2 equivalents, preferably 1.0 equivalent-1.5 equivalents, relative to compound (IX).
  • Suitable bases include, for example, pyridine, lutidine, picoline, triethylamine, diisopropylethylamine, dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] -7-indene (DBU), 1 Organic bases such as, 5-diazabicyclo [4,3,0] -5-nonene (DBN) and triethylenediamine (DABCQ) can be used, preferably pyridine, triethylamine or DABCO, more preferably Use pyridine.
  • DBN 5-diazabicyclo [4,3,0] -5-nonene
  • DABCQ triethylenediamine
  • the amount used is 1 equivalent to Compound '(IX).
  • the amount is from 5 to 5, preferably from 1.5 to 2.5 equivalents.
  • the reaction temperature is suitably from 0 to 100, preferably from 0 to 50 ° C.
  • the compound (X) is obtained in a reaction time of 6 to 30 hours.
  • a compound of formula (XI) useful as a therapeutic agent for HIV-related diseases can be synthesized, for example, by the method described in WO95 / 09843. Examples Hereinafter, the present invention will be described in detail with reference to Examples. The following examples are illustrative of the invention and the invention is not limited thereto.
  • the mixture was cooled to room temperature, and the mixture was filtered through Hyflo Super-Cel to remove activated carbon.
  • the used laboratory equipment and residues were thoroughly washed with warm water (10Q mix 5).
  • the filtrate and the washing solution were combined, and the pH was adjusted to 1 by adding a 5M HC1 aqueous solution (400 ml) while stirring at room temperature. At this time, since the foaming vigorously C0 Z gas generated, were added carefully until the first 100 ml.
  • the acidic solution was allowed to stand at room temperature, and then concentrated under reduced pressure at a bath temperature of 60 ° C.
  • the obtained white solid residue was extracted with boiling ethyl acetate (400 mix 6). That is, the solid residue was suspended in hot acetate (400 ml) and heated until boiling, then the supernatant was decanted and filtered through filter paper. This operation was repeated six times. The absence of the desired product in the sixth extract was determined by thin layer chromatography (TLC; ck Kieseigel 60, thickness 0.25 ran; developing solvent: ethyl acetate). The combined ethyl acetate extract was concentrated under reduced pressure to give an almost white solid (86.3 g).
  • Ice water was added until the precipitate was almost dissolved, and the mixture was poured into an ice water mixture (500 ml). The solid matter adhering to the used laboratory equipment was washed into the above ice-water mixture with water. In addition, ice water was added to bring the volume of the mixture to 90 Q mi. Precipitated solid The body was collected by filtration, washed once with water, pressed to remove water, and air-dried at room temperature to give a solid with a wet weight of 91.3 g.
  • the mixture was diluted with toluene (50 ml) and ethyl acetate (100 ml), washed with water (50 ml), 0.5M aqueous solution of citric acid (50n), saturated aqueous NaHC03 (50 ml) and saturated saline (50 ml), and dried. (MgSO 4, followed by drying under reduced pressure to obtain white crystals (15.lg).

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention porte sur un procédé de préparation de composés de formule générale (X) comprenant les étapes suivantes. saponification d'un dérivé de l'acide (2S, 3R)-4-hydroxy-2,3-époxybutanoïque; ouverture sélective par région du cycle époxy du dérivé résultant pour obtenir un dérivé à cycle ouvert; protection du groupe amino du dérivé; lactonisation du dérivé protégé; réduction du dérivé lactonisé; protection des groupes hydroxy 1 et 2 du dérivé réduit; thioéthérification du dérivé protégé; extraction des groupes protecteurs du dérivé thioéthérifié; et chloration sélective du groupe hydroxy primaire du dérivé de diol. L'invention porte également sur les nouveaux composés intermédiaires obtenus intervenant dans le processus de production des composés (X), intermédiaires clefs de la préparation du composé de formule (XI) inhibiteur de la protéase du VIH.
PCT/JP1998/001755 1998-04-16 1998-04-16 Procede de preparation de chloroalcools et de leurs intermediaires WO1999054297A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU68529/98A AU6852998A (en) 1998-04-16 1998-04-16 Process for preparing chloro alcohol derivatives and intermediates
PCT/JP1998/001755 WO1999054297A1 (fr) 1998-04-16 1998-04-16 Procede de preparation de chloroalcools et de leurs intermediaires

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001226364A (ja) * 1999-12-06 2001-08-21 Ube Ind Ltd ３−ハロメチルオキセタン化合物の合成方法
WO2005040099A1 (fr) * 2003-10-23 2005-05-06 Ono Pharmaceutical Co., Ltd. Procedes destines a produire un derive d'acide (2r,3r)-2-(amino protege)-3-hydroxypropionique 3-substitue et produit intermediaire associe
JPWO2003057675A1 (ja) * 2001-12-28 2005-05-19 興和株式会社 環状ジアミン化合物又はその塩の製造法
JP2006508168A (ja) * 2002-12-02 2006-03-09 サーントル ナシオナル ドゥ ラ ルシェルシェ シャーンティフィク（セー．エンヌ．エール．エス．） ４−ヒドロキシイソロイシン及びその誘導体のジアステレオ異性体及びエナンチオマーの製造方法

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Publication number Priority date Publication date Assignee Title
JPS59106444A (ja) * 1982-12-10 1984-06-20 Takeda Chem Ind Ltd ４−ヒドロキシ−ｌ−アロスレオニンアミド類の製造法
WO1995009843A1 (fr) * 1993-10-07 1995-04-13 Agouron Pharmaceuticals, Inc. Inhibiteurs de la protease du vih
WO1997011938A1 (fr) * 1995-09-26 1997-04-03 Japan Tobacco Inc. Procede de production de derives amides et de leurs intermediaires
JPH09110809A (ja) * 1995-10-16 1997-04-28 L'oreal Sa ２−アミノアルカン−１，３，４−トリオールの製造方法

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JPS59106444A (ja) * 1982-12-10 1984-06-20 Takeda Chem Ind Ltd ４−ヒドロキシ−ｌ−アロスレオニンアミド類の製造法
WO1995009843A1 (fr) * 1993-10-07 1995-04-13 Agouron Pharmaceuticals, Inc. Inhibiteurs de la protease du vih
WO1997011938A1 (fr) * 1995-09-26 1997-04-03 Japan Tobacco Inc. Procede de production de derives amides et de leurs intermediaires
JPH09110809A (ja) * 1995-10-16 1997-04-28 L'oreal Sa ２−アミノアルカン−１，３，４−トリオールの製造方法

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001226364A (ja) * 1999-12-06 2001-08-21 Ube Ind Ltd ３−ハロメチルオキセタン化合物の合成方法
JP4507398B2 (ja) * 1999-12-06 2010-07-21 宇部興産株式会社 ３−ハロメチルオキセタン化合物の合成方法
JPWO2003057675A1 (ja) * 2001-12-28 2005-05-19 興和株式会社 環状ジアミン化合物又はその塩の製造法
JP2006508168A (ja) * 2002-12-02 2006-03-09 サーントル ナシオナル ドゥ ラ ルシェルシェ シャーンティフィク（セー．エンヌ．エール．エス．） ４−ヒドロキシイソロイシン及びその誘導体のジアステレオ異性体及びエナンチオマーの製造方法
WO2005040099A1 (fr) * 2003-10-23 2005-05-06 Ono Pharmaceutical Co., Ltd. Procedes destines a produire un derive d'acide (2r,3r)-2-(amino protege)-3-hydroxypropionique 3-substitue et produit intermediaire associe

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