JPH05137586A - Selective production of 3-methyladipic acid mono ester - Google Patents

Abstract

PURPOSE:To simply obtain the subject highly pure compound useful as a raw material for medicines or agricultural chemicals in a good position selectivity by hydrolyzing a methyladipic acid diester in the presence of an enzyme having an ester-hydrolyzing activity. CONSTITUTION:A 3-methyladipic acid diester of formula I (R is hydrocarbon residue) in the presence of an enzyme having an ester-hydrolyzing activity (preferably a lipase or esterase obtained from microorganism such as Mucor niehei or Aspergillus oryzae) to obtain the objective compound of formula II. The pH of the reaction solution, the reaction temperature and the reaction time are preferably 5-8, 5-50 deg.C and 1-5 days, respectively. When a usual commercially available enzyme is used, the enzyme is preferably employed in an amount of 0.01-100g per mole of the diester of formula I.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for selectively producing 3-methyladipic acid monoester by hydrolyzing 3-methyladipic acid diester. 3-Methyladipic acid monoester is useful as a raw material for various chemical products, and particularly, an optically active one is a chiral compound having a methyl group on an asymmetric carbon as a raw material for medicines, agricultural chemicals and other physiologically active substances. It is also useful as a raw material for liquid crystal polymers.

[0002]

BACKGROUND OF THE INVENTION 3-Methyladipic acid monoester is
For example, it can be obtained by partially hydrolyzing 3-methyladipic acid diester with an alkali catalyst or the like. However, in this method, the reaction product essentially becomes a mixture of 3-methyladipic acid, a monoester and a diester of 3-methyladipic acid, and 3-methyladipic acid monoester cannot be selectively produced. Further, the regioselectivity of the monoester cannot be expected, and it is difficult to selectively produce only the 1-ester. Further, when optically active dimethyl 3-methyladipate is used as a substrate, racemization occurs, and optically active 3-methyladipic acid cannot be obtained.

On the other hand, as a method for regioselectively synthesizing 3-methyladipic acid monoester, particularly 1-ester, a method of reducing 3-methyl-2-hexenedioic acid-1-ester under a metal catalyst (J Chem. Soc., 3621, 1952)
It has been known. However, the monoester that can be produced by this method is racemic. Further, as a method for producing an optically active 3-methyladipic acid monoester, particularly a 1-ester, a method for producing (R)-(+)-citronellic acid ester by ozone oxidation (J. Am. Chem. Soc., 81 , 237,
1959) is known, but this method is costly in the process of ozone oxidation and is disadvantageous in industrial production.

[0004]

SUMMARY OF THE INVENTION The present invention provides a method for simply and selectively producing highly pure 3-methyladipic acid monoester.

[0005]

That is, the present invention provides the following general formula (1):

[0006]

[Chemical 3]

The 3-methyladipic acid diester represented by the formula (wherein R represents a hydrocarbon residue) is hydrolyzed using an enzyme having ester hydrolyzing activity to give the following general formula (2):

[0008]

[Chemical 4]

The present invention relates to a method for selectively producing 3-methyladipic acid monoester represented by: Where R
Represents a hydrocarbon residue, particularly preferably an alkyl group having 1 to 18 carbon atoms or an aralkyl group. As the alkyl group, a lower alkyl group, particularly one having 1 to 6 carbon atoms is particularly preferable, and examples thereof include a methyl group, an ethyl group, a propyl group and a butyl group. As the aralkyl group, those having 7 to 18 carbon atoms are used, and examples thereof include a phenyl lower alkyl group such as a benzyl group.

According to the present invention, the 1-ester can be selectively produced with a purity of 90% or more, preferably 95% or more. In the present invention, the optically active 3
When -methyladipic acid diester is used as a raw material, racemization is unlikely to occur, and a highly pure corresponding 1-ester having optical activity can be obtained.

The enzyme having ester-decomposing activity derived from a microorganism used in the present invention is preferably lipase or esterase, and these enzymes are preferably derived from a microorganism. Examples of microorganisms that produce these enzymes include, in filamentous fungi, the genus Mucor, the genus Aspergillus, the genus Rhizopus, the genus Penicillium, and the genus Geotrichum.
Genus, Trichoderma, Actinomycol
(Actinomucor) genus, Tritirachium (Tritirachium) genus,
Thermoanaerobium spp., Endomyces spp., Kluyveromyces spp.
Genus, genus Nadsonia,

Pachysolen genus, Rhodosporidium genus, Beauviria
Genus, genus Calonectrium, genus Coniochaetidium, Backusella
Genus, genus Cladobotryum, genus Chloridium, genus Corticium, genus Cunninghamella, genus Circine
Lla), Gliocephalotricum
Genus, Echinopodospora, Gelasinospora, Dichoto
momyces, Pycnoporus, Neosartorya, Thamnostylu
m) genus, Zygorhynchus genus, Monascus (Mon
ascus), Gliocladium (Gliocladium) genus, Sporidiobolus (Sporidiobolus) genus,

In yeast, Saccharomyce
s), Candida, Rhodotor
ula), Cryptococcus genus, Torulopsis genus, Pichia genus, Aureobasidium genus, Hansenula
Genus, Brettanomyces (Brettanomyces) genus, Saccharomycopsis (Saccharomycopsis) genus,

For bacteria, Chromobact
erium genus, Arthrobacter genus, Pseudomonas genus, Mycob
Acterium genus, Enterobacter genus, Brevibacterium genus, Alcaligenes
(Alcaligenes) genus, Micrococcus (Micrococcus) genus,
Microbacterium (Microbacterium) genus, Corynebacterium (Corynebacterium) genus, Bacillus (Bacillus) genus,
Lactobacillus genus, Propionibacterium (Propionibacterium) genus,

Streptomyces genus, Achromobacter genus, Streptococcus
(Streptococcus), Bifidoba
cterium, Thermus, Serratia
a) Genus, Rhodopseudomonas genus, Salmonella genus, Escherichia
Genus, Klebsiella, Nocardia
Examples thereof include microorganisms belonging to the genus dia, the genus Flavobacterium, and the like.

More specifically, Mucor Niehei (Muc
or niehei), Aspergillus o
ryzae), Aspergillus melle
us), Aspergillus niger, Aspergillus pulveru
lentus), Aspergillus sait
oi), Aspergillus sojae,
Aspergillus aureus, Aspergillus ficuum, Rhizopus niveus, Rhizopus delemar, Rhizopus delemar
zopus japonicus), Rhizopus
arrhizus), Rhizopus chinensis
sis),

Penicillium d
upontii), Penicillium f
uniculosum), Penicillium citrinum
citrinum), Penicillium frequentans (Penicil
lium frequentans), Penicillium yanchinerum (Pen
icillium janthinellum), Geotrichum candidum, Trichoderma vivide
choderma vivide), Trichoderma longibrakiatum
(Trichoderma longibrachiatum), actinom call
Elegance (Actinomucor elegans), tritillachium
Arubum (Tritirachium album), Samoanellobium
Brokie (Thermoanaerobium brockii),

Endomyces magnusi
nusii), Kluyveromyces f
ragilis), Kluyveromycesla
ctis), Nadsonia elongata
, Pachysolen tannophilus
us), Rhodosporidi
um toruloides), Beauveria Bassiana
bassiana), Calonectria hedea
rae), Coniochaetidium savory (Coniochaetid
ium savoryi), Backusella cir
cina), Cladobotryum
apiculatum), Chloridium chlamydosporis (Chl
oridium chlamydosporis), Corticium rolfsii, Canninghamera ethinulata
(Cunninghamella echinulata),

Circinella simplex
simplex), Gliocephalotricum cylindrosporum, Echinopodospora jamaicensi
s), Gelasinospora cere
alis), Dichotomomyces cej
pii), Pycnoporus coccine
us), Neosartorya aurat
a), Thamnostylumpirif
orme), Zygorhynchus moeller
i), Monascus anka, Gliocladium deliquescen
s), Sporidiobolus j
ohnsonii),

[0020] Saccharomyc
es rouxii), Candida utilis,
Candida cylindracea, Candida krusel, Candida tropicalis, Rhodotorula minuta
(Rhodotorula minuta), Rhodotoru
la rubra), Cryptococ
cus albidus), Torulopsis gropengyzeri (Torul
opsis gropengiesseri), Torlopsis candida (T
orulopsis candida), Pichia polymorpha (Pichia po
lymorpha), Aureo
basidium pullulans),

Hansenula anomala
a), Brettanomyces c
usterianus), Saccharomycopsis lipolytica (Sacch
aromycopsis lipolytica), Chromobacterium chocolatum, Chromobacterium iodinum, Chromobacterium viscosu
m), Arthrobacter simplex
simplex), Pseudomonas fragi
, Pseudomonas putida, Pseudomonas aeruginos
a), Pseudomonas fluescens
orescens),

Pseudomonas testosteroni (Pseudom
onas testosteroni), Enterobacter cloaca (Ent
erobacter cloacae), Enterobacter erogenes (E
nterobacter aerogenes), Brevibacterium ammoniagenes, Brevibacterium divaricatu
m), Alcaligenes faecali
s), Micrococcus varian
s), Micrococcus luteu
s), Corynebacteri sepedonicum (Corynebacteri
um sepedonicum),

Corynebacte Equi
riumequi), Bacillus subtilis
, Bacillus cereus, Bacillus macerans, Bacillus thermoproteolyti
cus rokko), Bacillus polymyx
a), Bacillus licheniform
is), Bacillus pumilus, Lactobacillus acidophilu
s), Lactobacillus casei
,

Propionibacterium cermanii (Pro
pionibacterium shermanii), Streptomyces caespitosus, Streptomyces griseus, Streptococcus faecalis, Streptococcus aureifbacterium, and Streptococcus aureus.
m), Thermus aquaticus, Serratia marcescens, Rhodopseudomonas sphe
roides), Salmonella typhimurium
typhimurium), Escherichia col
i), Klebsiella pneumoia
e), Nocardia uniformi
s), Flavobacterium heparinum
heparinum) can be exemplified.

Some of these microbial-origin enzymes are commercially available and can be easily obtained. Among commercially available enzymes, specific examples of lipase include Aspergillu
s niger lipase (lipase A “Amano”) (manufactured by Amano Pharmaceuticals), Pseudomonas sp. lipase (lipase P “Amano”) (the same), Mucor javanicus lipase (lipase M “Amano”) (the same), Rhizopus sp Lipase (Lipase F "Amano") (same), Aspergillus lipase (Lipase AP "Amano") (same), Rhizopus lipase (Lipase D "Amano") (same), Candida lipase (lipase) AY "Amano") (same), Candida lipase (Lipase L "Amano")
(The same), a lipase of the genus Penicillium (lipase G "Amano") (the same),

Penicillium lipase (lipase R
"Amano") (same as), Geotrichum genus lipase (lipase GC "Amano") (same as), Rhizopus lipase (lipase N "Amano") (same), Candida cylindrace
a lipase (lipase OF) (manufactured by Meito Sangyo), Candid
a cylindracea lipase (lipase MY) (same), Alcaligenes lipase (lipase PL) (same), Achromobacter lipase (lipase AL) (same),
Arthrobacter lipase (lipase joint BSL)
(Joint liquor purification), Chromobacterium lipase (Toyo Brewing),

Rhizopus delemar lipase (talipase) (manufactured by Tanabe Seiyaku), Rhizopus delemar lipase (manufactured by Seikagaku Corporation), Candida cylindracea lipase (manufactured by Sigma), Rhizopus arrhizus lipase (the same), Chromo
Pseudomonas s, lipase of bacterium viscosum
p. lipase (same), Geotrichum candidum lipase (same), Rhizopus japonicus lipase (lipase Saiken) (Osaka Bacterial Research Institute), lipolase (Novo
Manufactured by the company), and the like.

When the enzyme used in the method of the present invention is obtained by culturing the above-mentioned microorganism, the culture is usually carried out by liquid culture according to a conventional method to obtain a culture solution. For example, sterilized liquid medium (for molds and yeasts, malt extract / yeast extract medium [glucose 10 g, peptone 5 g, malt extract 3 g, yeast extract 3 g are dissolved in 1 L of water to dissolve pH.
Set to 6.5. ], For bacteria, sweetened broth medium [water 1
L to glucose 10 g, peptone 5 g, meat extract 5 g,
Dissolve 3 g of NaCl to bring the pH to 7.2. ]) Is inoculated with a microorganism, and it is usually carried out by performing reciprocating agitation culture at 20 to 40 ° C. for 1 to 8 days in an air or nitrogen atmosphere.
Moreover, you may perform solid culture as needed. In the present invention, those obtained by subjecting these enzymes having esterolytic activity obtained by culturing to various separation and purification treatments can be used.

When the enzyme agent is used in the method of the present invention, the form of use is as follows: purified enzyme, crude enzyme, enzyme-containing material, microbial culture solution, culture, fungus body, culture filtrate, and those obtained by treating them. It can be used in various forms as necessary, and an enzyme and a microorganism can be used in combination. Furthermore, the microorganisms and enzymes may be those supported on a solid.

When a culture or microbial cell is used, it can be carried out by culturing the above-mentioned microorganism in the presence of 3-methyladipic acid diester. When the enzyme or microorganism is allowed to act on the diester in the present invention, it is preferable to act the diester in a liquid reaction medium. As a reaction medium, ion-exchanged water or a buffer solution containing an inorganic salt such as sodium phosphate, an organic acid salt such as sodium acetate or sodium citrate, or a salt of an organic compound such as tris (hydroxymethyl) aminomethane is used. ..

Further, the culture medium of the microorganism can be used as it is as the reaction medium. The pH of the reaction solution is preferably 2-11, more preferably 5-8. When the pH is lowered by the carboxylic acid formed in the reaction solution, it is preferable to add a base such as sodium hydroxide or ammonia to maintain the pH range. If necessary, a suitable emulsifier can be added to disperse the substrate efficiently.

The amount of the diester charged into the reaction medium such as water, buffer solution or culture medium of microorganisms is not particularly limited, but generally 0.1 to 3,000 g per 1 L of the reaction medium,
It is preferably 1 to 1,000 g. The diester at this time can be added batchwise or continuously during the reaction, and the diester may be charged in a state of being suspended in water.

The optimum amount of the enzyme used at this time is determined depending on the activity of the enzyme to be used and the degree of purification of the enzyme.
For example, in the case of a general commercially available enzyme, 100 to 1000 units / mg of diester per mol of 0.00
It is 1 to 300 g, preferably 0.01 to 100 g.
On the other hand, when microbial cells are used as they are, the amount used is the amount of bacterial cells inoculated into the culture solution so that the reaction is sufficiently completed.
It is preferable to select it according to culture conditions.

The partial hydrolysis reaction of the diester may be carried out while stirring the diester or its solution or suspension, or may be carried out by circulating the reaction medium through a column packed with the immobilized enzyme or microorganism. .. The reaction temperature is 0 to 60 ° C, preferably 5 to 50 ° C. The reaction time is not particularly limited, but is 1 to 10 days, preferably 1 to 5 days.

The reaction product can be easily separated from the reaction solution by, for example, a solvent extraction method. As an example, the pH of the reaction solution may be adjusted to 7 after the hydrolysis reaction if necessary.
After adjusting to near, if necessary, unreacted 3-methyladipic acid diester is extracted and removed with a solvent such as methyl isobutyl ketone, ethyl acetate, and ethyl ether.
Next, the pH is adjusted to 4 or less and 3-methyladipic acid monoester is extracted with the same solvent. The 3-methyladipic acid monoester thus obtained can be obtained in a substantially pure form by distilling off the solvent and then distilling.

[0036]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. Example 1 To 12 mL of 0.1 M phosphate buffer (pH 7.0) was added 0.3 g of racemic dimethyl 3-methyladipate and 0.3 g of Candida cylindracea-derived lipase (manufactured by Sigma) 20 Reciprocal shaking was carried out at 60 ° C./minute for 72 hours to carry out the reaction.

The reaction solution was first extracted three times with 10 mL of ether to remove unreacted diester. Then with hydrochloric acid
After adjusting the pH to 3, the mixture was extracted 3 times with 20 mL of ethyl acetate. When the extract was dried and concentrated, 0.27 g of monoester was obtained. When this monoester was measured by gas chromatography, 1-ester was 97%,
The 6-ester was 3%. The optical purity of 1-ester measured by liquid chromatography was 2%.
It was ee (S).

Example 2 The present invention was carried out in the same manner as in Example 1 except that R-form (optical purity 96% ee) dimethyl 3-methyl adipate was used as the substrate. As a result, 0.26 g of monoester was obtained, which was 97% 1-ester and 3% 6-ester.
Met. The optical purity of 1-ester is 96% ee
(R).

Example 3 The present invention was carried out in the same manner as in Example 1 except that S-form (optical purity 99% ee) dimethyl 3-methyl adipate was used as the substrate. As a result, 0.27 g of monoester was obtained, 97% of 1-ester and 3% of 6-ester.
Met. The optical purity of 1-ester is 99% ee
It was (S).

Example 4 In 1.6 L of 0.1 M phosphate buffer (pH 7.0), 62 g of S-form dimethyl 3-methyladipate and Candida
Cylindracea-derived lipase (manufactured by Sigma) (21 g) was added, and 8N-NaOH was added dropwise at any time to maintain the pH at 7.0 and the reaction was carried out at 20 ° C. with stirring at 150 RPM for 72 hours. The reaction solution was adjusted to pH 3.0 with hydrochloric acid and then extracted 3 times with 1.5 L of ethyl acetate. When the extract was dried and concentrated, 50 g of monoester was obtained. The composition was 98% 1-ester and 2% 6-ester. The optical purity of 1-ester was 99% ee (S).

[0041]

Industrial Applicability According to the method of the present invention, 3-methyladipic acid diester can be hydrolyzed to selectively produce 3-methyladipic acid monoester, and optically active 3-methyladipic acid can be produced. Even when a diester is used, an optically active 3-methyladipic acid monoester can be produced in high purity without causing racemization.

Claims (2)

[Claims] 1. The following general formula (1): (Wherein R represents a hydrocarbon residue) 3
-Methyladipic acid diester is hydrolyzed with an enzyme having ester hydrolytic activity to give the following general formula (2): 3 wherein R has the meaning given above
-A method for selectively producing methyl adipic acid monoester. 2. An enzyme having ester hydrolysis activity,
The method according to claim 1, wherein the enzyme is an enzyme selected from lipase, protease and esterase.