Process for preparing optically active 2-[6-(hydroxy-methyl)-1,3-dioxan-4-yl] acetic acid derivatives

Abstract

The present invention is to provide a production technology by which an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative, which are of value as pharmaceutical intermediates, can be produced from inexpensive and readily available starting materials without using any extraordinary equipment such as an ultra-low-temperature reactor. The present invention is a production process of an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative which comprises reacting an enolate, prepared by permitting a base or a 0-valent metal to act on an acetic acid ester derivative with (S)-β-hydroxy-γ-butyrolactone at a temperature not lower than −30° C. to give a dihydroxyoxohexanoic acid derivative, treating the same with an acylating agent in the presence of a base to produce a dihydroxyoxohexanoic acid monoacyl derivative, reducing this compound with a microorganism to produce a trihydroxyhexanoic acid monoacyl derivative, treating this compound with an acetal-forming reagent in the presence of an acid catalyst to produce an acyloxy-methyldioxanylacetic acid derivative, and finally, subjecting this compound to solvolysis in the presence of a base.

1 . An isolation/purification process 
 which comprises treating a compound contaminated with an impurity and represented by the following formula (V);                          in the formula, R 1  represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and R 4  represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms,    with an aliphatic hydrocarbon solvent to remove the impurity contaminating the compound represented by the above formula (V) and    obtaining the compound represented by the above formula (V) in a crystal form.    
   
   
       2 . The isolation/purification process according to  claim 1   wherein the impurity contaminating the compound of the above formula (V) is a compound represented by the following formula (XII);                          in the formula, R 1  and R 4  are as defined above.    
   
   
       3 . The isolation/purification process according to  claim 1   wherein the aliphatic hydrocarbon solvent is pentane, hexane, methylcyclohexane, heptane, octane, or isooctane.    
   
   
       4 . The isolation/purification process according to  claim 1   wherein the crystallization is carried out with additional use of an auxiliary solvent,    said solvent being used for a purpose of improving at least one of a solubility, yield, treatment concentration, effect of purification, and physical properties of obtainable crystals of the compound represented by the above formula (V).    
   
   
       5 . The isolation/purification process according to  claim 4   wherein the auxiliary solvent is used in such an amount that the weight ratio of said auxiliary solvent and the aliphatic hydrocarbon solvent (said auxiliary solvent/aliphatic hydrocarbon solvent) is not greater than 1 at completion of the procedure for crystallization.    
   
   
       6 . The isolation/purification process according to  claim 4   wherein the auxiliary solvent is at least one species selected from the group consisting of toluene, ethyl acetate, methyl tert-butyl ether and methylene chloride.    
   
   
       7 . The isolation/purification process according to  claim 1   wherein the compound represented by the above formula (V) is used,    said compound being produced by treating a compound represented by the following formula (IV);                          in the formula, R 1  is as defined above,    with an acylating agent in the presence of a base.    
   
   
       8 . The isolation/purification process according to  claim 7   wherein a compound represented by the following formula (XI);                          or a compound represented by the following formula (XVI);                          in the above formulas, R 4  represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms;    and Q represents a leaving group,    is used as the acylating agent.    
   
   
       9 . The isolation/purification process according to  claim 8   wherein Q of the acylating agent (XI) is a halogen atom.    
   
   
       10 . The isolation/purification process according to  claim 9   wherein the halogen atom is a chlorine atom.    
   
   
       11 . The isolation/purification process according to claims  7   wherein an amine is used as the base.    
   
   
       12 . The isolation/purification process according to  claim 11   wherein triethylamine or pyridine is used as the amine used in the acylation step.    
   
   
       13 . The isolation/purification process according to  claim 7   wherein the compound represented by the above formula (IV) is used,    said compound being produced by reacting an enolate prepared by permitting a base or a 0-valent metal to act on an acetic acid ester derivative represented by the following formula (II);      X 1 CH 2 CO 2 R 1   (II)    in the formula, R 1  is an defined above; and X 1  represents a hydrogen or a halogen atom,    with (S)-β-hydroxy-γ-butyrolactone represented by the formula (III);                          at a temperature not lower than −30° C.    
   
   
       14 . The isolation/purification process according to  claim 13   wherein X 1  of the acetic acid ester derivative (II) is a hydrogen atom and    a magnesium amide represented by the following formula (VIII);                          in the formula, R 5  and R 6  each independently represents an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms, or a silyl group; and X 2  represents a halogen atom,    is used as the base in preparing the enolate.    
   
   
       15 . The isolation/purification process according to  claim 14   wherein, of the magnesium amide (VIII), each of R 5  and R 6  is an isopropyl group and X 2  is a chlorine atom.    
   
   
       16 . The isolation/purification process according to  claim 13   wherein X 1  of the acetic acid ester derivative (II) is a halogen atom and    magnesium or zinc is used as the 0-valent metal in preparing the enolate.    
   
   
       17 . The isolation/purification process according to  claim 13   wherein the reaction of the enolate with (S)-β-hydroxy-γ-butyrolactone (III) is carried out in the presence of a polyether.    
   
   
       18 . The isolation/purification process according to  claim 17   wherein dimethoxyethane is used as the polyether.    
   
   
       19 . The isolation/purification process according to  claim 17   wherein the compound represented by the above formula (IV) is used,    said compound being produced by treating, in advance, (S)-β-hydroxy-γ-butyrolactone (III) with a Grignard reagent represented by the following formula (IX);      R 7 —Mg—X 3   (IX)    in the formula, R 7  represents an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and X 3  represents a halogen atom, and    reacting, at a temperature not lower than −30° C., with an enolate prepared by permitting a base or a 0-valent metal to act on an acetic acid ester derivative (II).    
   
   
       20 . The isolation/purification process according to  claim 19   wherein, of the Grignard reagent (IX), R 7  is a tert-butyl group and X 3  is a chlorine atom.    
   
   
       21 . The isolation/purification process according to  claim 7   wherein the compound represented by the above formula (IV) is used,    said compound being produced by treating, in advance, (S)-β-hydroxy-γ-butyrolactone (III) with a base and a magnesium compound, and    reacting, at a temperature not lower than −30° C., with an enolate prepared by permitting a base or a 0-valent metal to act on an acetic acid ester derivative (II).    
   
   
       22 . The isolation/purification process according to  claim 21   wherein the base is sodium hydride, lithium diisopropylamide, or chloromagnesium diisopropylamide.    
   
   
       23 . The isolation/purification process according to  claim 21   wherein the magnesium compound is magnesium chloride or magnesium bromide.    
   
   
       24 . The isolation/purification process according to  claim 19   wherein X 1  of the acetic acid ester derivative (II) is a hydrogen atom and    a lithium amide represented by the following formula (X);                          in the formula, R 8  and R 9  each independently represents an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms, or a silyl group,    is used as the base in preparing the enolate.    
   
   
       25 . The isolation/purification process according to  claim 24   wherein, of the lithium amide (X), each of R 8  and R 9  represents an isopropyl group.    
   
   
       26 . The isolation/purification process according to  claim 19   wherein X 1  of the acetic acid ester derivative (II) is a halogen atom and    magnesium or zinc is used as the 0-valent metal in preparing the enolate.    
   
   
       27 . The isolation/purification process according to  claim 1   wherein R 1  is a tert-butyl group.    
   
   
       28 . The isolation/purification process according to  claim 1  to 
 wherein R 4  is a phenyl group.    
   
   
       29 . A production process of a compound represented by the following formula (VI);  
     
       
         
         
             
             
         
       
     
     in the formula, R 1  represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and R 4  represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms, 
 which comprises reducing a compound represented by the following formula (V);  
                     
 in the formula, R 1  and R 4  are as defined above,  
 with a microorganism, wherein the microorganism is selected from among genera and species of microorganisms from the group consisting of  Ashbya, Botryoascus, Brettanomyces, Citeromyces, Clavispora, Cryptococcus, Dekkera, Dipodascus, Galactomyces, Geotrichum, Hanseniaspora, Hormoascus, Hyphopichia, Issatchenkia, Kluyveromyces, Komagataella, Lipomyces, Metschnikowia, Nakazawaea, Ogataea, Pachysolen, Pichia, Rhodotorula, Rhodsporidium, Saccharomyces, Saccharomycodes, Saccharomycopsis, Saturnospora, Schizoblastosporion, Schizosaccharomyces, Schwanniomyces, Sporidiobolus, Sporobolomyces, Torulaspora, Torulopsis, Trichosporon, Willopsis, Yamadazyma, Zygosaccharomyces, Acidiphilium, Aerobacter, Alcaligenes, Arthrobacter, Aureobacterium, Bacillus, Brevibacterium, Buttiauxella, Cedecea, Cellulomonas, Citrobacter, Clostridium, Comamonas, Corynebacterium, Enterobacter, Erwinia, Escherichia, Flavobacterium, Klebsiella, Luteococcus, Microbacterium, Micrococcus, Ochrobactrum, Proteus, Providencia, Pseudomonas, Rhodococcus, Sarcina, Serratia, Sphingobacterium, Tsukamurella, Absidia, Acremonium, Aegerita, Agrocybe, Amylostereum, Aspergillus, Byssochlamys, Chaetomidium, Chaetosartorya, Cladosporium, Coprinus, Crinipellis, Endophragmia, Flavolus, Fomitopsis, Fusarium, Ganoderma, Glomerella, Laetiporus, Lentinus, Lenzites, Macrophoma, Monascus, Mortierella, Paecilomyces, Penicillium, Phialophora, Pholiota, Pleurotus, Scopulariopsis, Sehizophyllum, Sporotrichum, Zygorhynchus, Microtetraspora , and  Streptomyces.    
 
   
   
       30 . The production process according to  claim 29   wherein a culture broth, cells or processed cells of the microorganism is used.    
   
   
       31 . The production process according to  claim 29   wherein the microorganism is selected from the group consisting of  Ashbya gossypii, Botryoascus synnaedendrus, Brettanomyces custersianus, Citeromyces matritensis, Clavispora lusitaniae, Cryptococcus laurentii, Dekkera anomala, Dipodascus armillariae, Dipodascus ovetensis, Dipodascus tetrasperma, Galactomyces reessii, Geotrichum candidum, Geotrichum fermentans, Geotrichum fragrans, Geotrichum loubieri, Hanseniaspora guilliermondii, Hormoascus philentomus, Hormoascus platypodis, Hyphopichia burtonii, Issatchenkia orientalis, Issatchenkia terricola, Kluyveromyces lactis, Kluyveromyces marxianus, Kluyveromyces polysporus, Kluyveromyces thermotolerans, Komagataella pastoris, Lipomyces starkeyi, Metschnikowia bicuspidata, Metschnikowia pulcherrima, Nakazawaea holstii, Ogataea minuta  var.  minuta, Ogataea pini, Ogataea polymorpha, Ogataea wickerhamii, Pachysolen tannophilus, Pichia canadensis, Pichia farinose, Pichia jandinii, Pichia saitoi, Pichia toletana, Pichia triangularis, Pichia wickerhamii, Rhodotorula graminis, Rhodotorula minuta, Rhodsporidium diobovatum, Rhodsporidium toruloides, Saccharomyces bayanus, Saccharomyces pastorianus, Saccharomyces rosei, Saccharomyces sake, Saccharomyces steineri, Saccaromyces unisporus, Saccharomycodes ludwigii, Saccharomycopsis capsularis, Saccharomycopsis malanga, Saturnospora dispora, Schizoblastosporion kobayasii, Schizosaccharomyces pombe, Schwanniomyces occidentalis  var.  occidentalis, Sporidiobolus johnsonii, Sporobolomyces pararoseus, Sporobolomyces salmonicolor, Torulaspora delbrueckii, Torulopsis methanolevescens, Torulopsis osboenis, Torulopsis  sp.,  Torulopsis uvae, Trichosporon pullulans, Trichosporon  sp.  Willopsis saturnus  var.  mrakii, Willopsis saturnus  var.  saturnus, Yamadazyma farinosa, Yamadazyma haplophila, Zygosaccharomyces naniwensis, Zygosaccharomyces  sp.,  Acidiphilium cryptum, Aerobacter cloacae, Alcaligenes xylosoxidans, Alcaligenes xylosoxidans  subsp.  denitrificans, Arthrobacter globiformis, Arthrobacter protophormiae, Aureobacterium esteraromaticum, Bacillus badius, Bacillus sphaericus, Brevibacterium ammomiagenes, Buttiauxella agrestis, Cedecea davisiae, Cellulomonas  sp.,  Cellulomonas turbata, Citrobacter freundii, Clostridium cylindrosporum, Comamonas testosteroni, Corynebacterium acectoacidophilum, Corynebacterium ammoniagenes, Corynebacterium glutamicum, Corynebacterium glutamicus, Enterobacter aerogenes, Enterobacter cloacae, Erwinia carotovora  subsp.  carotovora, Escherichia coli, Flavobacterium flavesceus, Klebsiella planticola, Luteococcus japonicus, Microbacterium arborescens, Micrococcus flavus, Micrococcus luteus, Ochrobactrum  sp.,  Proteus inconstans, Proteus mirabilis, Proteus rettgeri, Proteus vulgaris, Providencia stuartii, Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas stutzeri, Rhodococcus equi, Sarcina lutea, Serratia plymuthicum, Serratia proteamaculans  subsp.  proteamaculans, Sphingobacterium spiritivorum, Tsukamurella paurometabolum, Absidia orchidis, Acremonium bacillisporum, Aegerita candida, Agrocybe cylindracea, Amylostereum areolatum, Aspergillus parasiticus, Aspergillus phoenicis, Byssochlamys fulva, Chaetomidium fimeti, Chaetosartorya stromatoides, Cladosporium resinae F. avellaneum, Coprinus cinereus, Coprinus lagopus, Coprinus  sp.,  Crinipellis stipitaria, Endophragmia alternata, Flavolus arcularius, Fomitopsis pubertatis, Fusarium merismoides, Ganoderma lucidum, Glomerella cingulata, Laetiporus sulphureus, Lentinus lepideus, Lenzites betulina, Macrophoma commelinae, Monascus purpureus, Mortierella isabellina, Paecilomyces varioti, Penicillium chermesinum, Penicillium chrysogenum, Penicillium expansum, Penicillium lilacinium, Phialophora fastigiata, Pholiota aurivella, Pholiota limonella, Pleurotus dryinus, Pleurotus ostreatus, Pleurotus porrigens, Scopulariopsis brevicaulis, Sehizophyllum commune, Sporotrichum aurantiacum, Zygorhynchus moelleri, Microtetraspora roseoviolacea, Streptomyces achromogenes  subsp.  rubradiris, Streptomyces  sp. and  Streptomyces aureus.      
   
   
       32 . The production process according to  claim 29   wherein R 1  is a tert-butyl group.    
   
   
       33 . The production process according to  claim 29   wherein R 4  is a phenyl group.    
   
   
       34 . A production process of a compound represented by the following formula (VII);  
     
       
         
         
             
             
         
       
     
     in the formula, R 1  represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; R 4  represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; R 2  and R 3  each independently represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and R 2  and R 3  may jointly form a ring, 
 which comprises treating a compound represented by the following formula (VI);  
                     
 in the formula, R 1  and R 4  are as defined above,  
 with an acetal-forming reagent using an amine salt composed of an acid and an amine as a catalyst.  
 
   
   
       35 . The production process according to  claim 34   wherein the amine salt is prepared and used in situ.    
   
   
       36 . The production process according to  claim 34   wherein the acid is hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid.    
   
   
       37 . The production process according to  claim 34   wherein the amine is a tertiary amine.    
   
   
       38 . The production process according to  claim 37   wherein the tertiary amine is triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, 2-methylpyridine, 3-methylpyridine, or imidazole.    
   
   
       39 . The production process according to  claim 34   wherein the amine is used in an excess amount relative to the acid.    
   
   
       40 . The production process according to claims  34   wherein the acetal-forming reagent is 2,2-dimethoxypropane.    
   
   
       41 . The production process according to  claim 34   wherein R 1  is a tert-butyl group.    
   
   
       42 . The production process according to  claim 34   wherein R 4  is a phenyl group.    
   
   
       43 . The production process according to  claim 34   wherein each of R 2  and R 3  is a methyl group.    
   
   
       44 . An isolation/purification process 
 which comprises treating a compound represented by the following formula (VI);                          in the formula, R 1  represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and R 4  represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms,    with an acetal-forming reagent in the presence of an acid catalyst to thereby convert the same to a compound represented by the following formula (VII);                          in the formula, R 1  and R 4  are as defined above; R 2  and R 3  each independently represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and R 2  and R 3  may jointly form a ring,    treating the compound contaminated with an impurity and represented by the above formula (VII) with an aliphatic hydrocarbon solvent to remove the impurity contaminating the compound represented by the above formula (VII) and    obtaining the compound represented by the above formula (VII) in a crystal form.    
   
   
       45 . The isolation/purification process according to  claim 44   wherein the impurity contaminating the compound represented by the above formula (VII) is at least one compound selected from the group consisting of a compound represented by the following formula (XIII);                          in the formula, R 2 , R 3  and R 4  are as defined above; and R 10  represents a lower alkyl group and is different from R 1 ,    a diastereomer represented by the following formula (XIV);                          in the formula, R 1 , R 2 , R 3 , and R 4  are as defined above,    a compound represented by the following formula (XV);                          in the formula, R 4  is as defined above,    and a compound represented by the following formula (VI);                          in the formula, R 1  and R 4  are as defined above.    
   
   
       46 . The isolation/purification process according to  claim 44   wherein the aliphatic hydrocarbon solvent is pentane, hexane, methylcyclohexane, heptane, octane, or isooctane.    
   
   
       47 . The isolation/purification process according to  claim 44   wherein the crystallization is carried out with additional use of an auxiliary solvent,    said solvent being used for a purpose of improving at least one of a solubility, yield, treatment concentration, effect of purification, and physical properties of obtainable crystals of the compound represented by the above formula (VII).    
   
   
       48 . The isolation/purification process according to  claim 47   wherein the auxiliary solvent is used in such an amount that the weight ratio of said auxiliary solvent and the aliphatic hydrocarbon solvent (said auxiliary solvent/aliphatic hydrocarbon solvent) is not greater than 1 at completion of the procedure for crystallization.    
   
   
       49 . The isolation/purification process according to  claim 47   wherein the auxiliary solvent is at least one species selected from the group consisting of toluene, ethyl acetate, methyl tert-butyl ether and methylene chloride.    
   
   
       50 . The isolation/purification process according to  claim 44   wherein an amine salt composed of an acid and an amine is used as the acid catalyst.    
   
   
       51 . The isolation/purification process according to  claim 50   wherein the amine salt is prepared and used in situ.    
   
   
       52 . The isolation/purification process according to  claim 50   wherein the acid is hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid.    
   
   
       53 . The isolation/purification process according to  claim 50   wherein the amine is a tertiary amine.    
   
   
       54 . The isolation/purification process according to  claim 53   wherein the tertiary amine is triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, 2-methylpyridine, 3-methylpyridine, or imidazole.    
   
   
       55 . The isolation/purification process according to  claim 50   wherein the amine is used in an excess amount relative to the acid.    
   
   
       56 . The isolation/purification process according to  claim 44   wherein the acetal-forming reagent is 2,2-dimethoxypropane.    
   
   
       57 . The isolation/purification process according to  claim 44   wherein R 1  is a tert-butyl group and R 10  is a methyl group.    
   
   
       58 . The isolation/purification process according to  claim 44   wherein R 4  is a phenyl group.    
   
   
       59 . The isolation/purification process according to  claim 44   wherein each of R and R 3  is a methyl group.