JPH0691837B2 - Process for producing optically active 4-hydroxy-2-cyclopentenones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention provides a compound of general formula (I) (In the formula, R is And XY is CH ₂ -CH ₂ or cis CH = CH, and R'is an alkyl group), and the optically active 4-hydroxy-2-cyclopentenones and its Regarding manufacturing method.

<Prior Art> Optically Active 4-Hydroxy-Represented by the General Formula (I)
The 2-cyclopentenones are novel compounds synthesized by the present inventors for the first time and are useful as intermediates for pharmaceuticals and the like.

For example, by transposing an optically active 4-hydroxy-2-cyclopentenone represented by the above general formula (I) while retaining a steric structure, the following general formula Is an optically active 2-substituted-4-hydroxy-2-
It can be cyclopentenone, and the compound can be used as an important intermediate of a prostaglandin derivative.

Furthermore, the optically active substance obtained by the above rearrangement is led to a sulfonic acid ester by, for example, paratoluenesulfonic acid chloride or methanesulfonic acid chloride, and then reacted with a base, or alternatively sodium acetate, sodium dichloroacetate, By reacting with sodium trichloroacetate or the like to form the corresponding ester and then hydrolyzing the resulting ester, 2-substituted 4- having a configuration that is opposite to the original configuration.
It can also be used by introducing it into hydroxy-2-cyclopentenone.

By the way, conventionally, nothing is known about the optically active 4-hydroxy-2-cyclopentenones represented by the above general formula (I), and Tetrahed only as a dl unit.
ron Letters 1131-1134 (1977),
The reference does not describe the configuration of the 4-position hydroxyl group and the 5-position substituent. Of course, there is no description about the optically active substance and its separation, and the possibility that the separated optically active substance undergoes rearrangement while maintaining the steric structure, or the obtained product by rearrangement while maintaining the steric property 2- The steric coordination of the substituted-4-hydroxy-2-cyclopentenones is not described, let alone the recognition.

On the other hand, the stereoisomer of the optically active 4-hydroxy-2-cyclopentenone represented by the general formula (I) as an isomer,
Acta Chemie Academiae Scientiarum Hungaricae, Tomu
The following method is described in s 102 (1), pp91-100 (1979).

However, the compound of formula (IV) is different in stereoconfiguration from the optically active 4-hydroxy-2-cyclopentenones represented by the general formula (I) of the present invention. The raw material (−)-cis-2-oxobicyclo [3.
3.0] -Octa-6-en-3-ol must be an optically active substance, requires a number of steps up to (IV), and is an intermediate which is always convenient for use as a raw material for prostaglandin. Not a body.

<Problems to be Solved by the Invention> From the above, a cyclopentenone-based intermediate that can be used as a raw material for prostaglandin, has a short number of manufacturing steps, and can be easily mass-produced industrially Development was strongly requested.

<Means for Solving Problems> In view of such circumstances, the present inventors have studied to develop a cyclopentenone-based intermediate for achieving the above object, and as a result, are represented by the general formula (I). Optically active 4-hydroxy-2-cyclopentenones are extremely useful as intermediates for prostaglandin, the number of steps leading to the compound is short, and industrially easy mass production is possible. Heading out, the present invention was reached.

Optically active 4-hydroxy- represented by the above general formula (I)
2-Cyclopentenones have the general formula (II) (In the formula, R has the same meaning as described above, R ₁ represents an acyloxy group, provided that the substituent R at the 5-position and the substituent R _{1 at the} 4-position are in trans-coordination). It can be easily produced by asymmetrically hydrolyzing dl-cyclopentenone esters using an esterase produced by a microorganism or an esterase derived from plants and animals.

Here, dl represented by the general formula (II) used as a raw material
-Cyclopentenone esters have the general formula (III) (In the formula, R has the same meaning as described above.)
It can be easily synthesized by reacting a 2-substituted-3-hydroxy-4-cyclopentenone with an organic carboxylic acid.

The dl-2-substituted-3-hydroxy-4-cyclopentenones can be easily obtained by rearranging furancarbinols, for example.

Examples of the organic carboxylic acids used herein include saturated or unsaturated organic carboxylic acid anhydrides and organic carboxylic acid halides, such as acetic anhydride, acetic acid chloride or bromide, propionic acid chloride or bromide, propionic anhydride, butyric acid. Lil chloride or bromide, caproyl chloride or bromide, caprylic chloride or bromide, stearin chloride or bromide Caprinoyl chloride or bromide, dodecanoin chloride or bromide, palmitoyl chloride or bromide, chloroacetyl chloride or bromide, dichloroacetyl chloride or Bromide etc. are illustrated.

For the reaction of the dl-2-substituted-3-hydroxy-4-cyclopentenone and the organic carboxylic acid, ordinary esterification conditions are applied, and the reaction is performed using a catalyst in the presence or absence of a solvent. It is carried out by

When a solvent is used in this reaction, the solvent may be, for example, tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, hexane or the like. Solvents such as aromatic hydrocarbons, ethers and halogenated hydrocarbons, which are inert to the reaction, may be used alone or as a mixture. The amount used can be used without particular limitation.

The organic carboxylic acid used in the reaction needs to be 1 equivalent or more with respect to the starting material dl-2-substituted-3-hydroxy-4-cyclopentenone, and the upper limit is not particularly limited, but it is preferably 4 equivalents. .

Examples of the catalyst include organic or inorganic basic substances such as triethylamine, tri-n-butylamine, pyridine, picoline, sodium carbonate, sodium methylate and potassium hydrogencarbonate. The amount used is not particularly limited, but is usually 1 to dl-cyclopentenones.
It is 5 equivalents.

When an organic amine is used as a solvent, the amine may act as a catalyst.

Further, acids such as toluene sulfonic acid, methane sulfonic acid and sulfuric acid can also be used as a catalyst.

The reaction temperature is usually -20 ° C to 150 ° C, preferably -1
It is in the range of 0 ° C to 120 ° C.

The reaction time is not particularly limited.

By such a reaction, the general formula (II) which is the raw material of the present invention
The dl-cyclopentenone ester represented by
Obtained in good yield, these can be easily isolated from the reaction mixture by conventional separation means such as extraction, separation, concentration, chromatography and the like.

Such asymmetric hydrolysis of dl-cyclopentenone esters is carried out by causing an esterase produced by a microorganism or an esterase derived from animals and plants to hydrolyze one of the optically active substances of the starting dl-cyclopentenone esters. Done.

The esterase-producing microorganism used in this reaction may be any microorganism that produces an esterase having the ability to asymmetrically hydrolyze the dl-cyclopentenone esters represented by the general formula (II), and is not particularly limited. It is not something that will be done.

The esterase in the present invention means an esterase in a broad sense including lipase. Specific examples of such microorganisms include, for example, Enterobacter, Arthrobacter, Brevibacterium, and Cydomonas,
Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus, Lactobacillus, Trichoderma,
Candida, Saccharomyces, Rhodotorula, Cryptococcus, Torrlopsis, Pichia, Penicillium, Aspergillus, Rhizopus, Mucor, Aureobasidium, Actinomucor, Nocardia, Streptomyces, Hansenula Genus, microorganisms belonging to the genus Achromobacter are exemplified, more specifically, Rhodotorula minuta IFO-0387, IFO-0412, Rhodotorul
a rubra IFO-0870, Rhodotolura minuta var texensis
IFO-0879, Trichoderma longibrachiatum IFO-4847,
Candida krusei out−6007, Candida cylindracea, Ca
ndida tropicalis PK 233, Candida utilus IFO-1086,
Pseudomonas fragi IFO−3458, Pseudomonas putida I
FO-12996, Pseudomonas fluorescens IFO-3903, Pseu
domonas aeruginosa IFO-3080, Bacillus cereus IFO
−3466, Bacillus subtilis ATCC-6638, Bacillus pul
milus IFO−12092, Bacillus subtilis var niger IFO
−3108, Nocardia uniformis subtsuyanarenus ATCC−2
1806, Nocardia uniformis IFO−13072, Chromobacteri
um chocolatum IFO-3758, Chromobacterium iodinum I
FO-3558, Flavobacterinm arbonescens IFO-3750, Fl
avobacterium heparinum IFO-12017, Rizopus chinens
is IFO−4768, Mucor javanicus IFO−4572, Aspergill
us niger ATCC−9642, Alcaligenes faecalis IFO−126
69, Torulopsis candida IFO-0768, Corynebacterium
sepedonicum IFO−13763, Saccaromyces rouxii IFO−0
505, Arthrobacter simplex IFO-3530, Streptomyces
grisens IFO-3356, Brevibacterium ammoniagenes IFO
−12072, Brevibacterium divaricarum ATCC−14020, M
icrococcus varians IFO−3765, Micrococcus luteus I
FO-3066, Enterobacter cloacae IFO-3320, Coryneba
cterium equi ATCC−7699, Lacto bacillus casei IFO
−3322, Cryptococcus albidus IFO−0378, Pihia poli
morpha IFO-1166, Penicillium frequentans IFO-569
2, Aureobasidium pullulans IFO−4464, Actinomucor
elegans IFO-4022, Hansenula anomala var ciferrii
out 6095, Hansenula anomala IFO−0118, Achromobact
er parvuius IFO-13181, Achromobacter sinplex IFO
-12069 and the like are exemplified.

For the culture of the above-mentioned microorganisms, a liquid culture is usually obtained by performing liquid culture according to a standard method.

For example, sterilized liquid medium (malt extract / yeast extract medium for molds and yeasts (peptone 5 g in water 1 g, glucose 10 g, malt extract 3 g, yeast extract 3 g, yeast extract 3
Dissolve g to pH 6.5), for bacteria use sweetened broth medium (1 g water with 10 g glucose, 5 g peptone, 5 meat extract)
g, Nacl3g is dissolved, and the pH is adjusted to 7.2)], and the culture is generally carried out by reciprocal shaking culture at 20 to 40 ° C. for 1 to 3 days. Good.

Some of these esterases originating from microorganisms are commercially available and can be easily obtained. Specific examples of commercially available esterases include the followings.

Lipase of the genus Cichudomonas (manufactured by Amano Pharmaceuticals) Lipase of the genus Aspergillus [lipase AP (manufactured by Amano Pharmaceuticals)], lipase AP of the genus Mucor (manufactured by Amano Pharmaceuticals)], Candida
Cylindracee lipase [Lipase MY (Meito Sangyo)], Alcaligenes lipase [Lipase PL (Meito Sangyo)], Achromobacter lipase [Lipase AL (Meito Sangyo)], Arthrobacter Lipase (manufactured by Shin Nippon Chemical Co., Ltd.), lipase of Chromobacterium sp. ].

Animal / plant esterases can also be used, and specific esterases thereof include the following.

Steapsin, pancreatin, pig liver esterase, Wheat Gevm esterase.

As the esterase used in this reaction, an enzyme obtained from animals, plants, or microorganisms is used, and its usage forms include purified yeast, crude enzyme, enzyme-containing material, microbial culture solution, culture, fungus body, and culture medium. It can be used in various forms such as a liquid and a product obtained by treating them as needed, and an enzyme and a microorganism can also be used in combination. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterium immobilized on a resin or the like.

The asymmetric hydrolysis reaction of the present invention is usually carried out by vigorously stirring a mixture of the starting dl-4-cyclopentenone esters and the above enzyme or microorganism in a buffer solution.

As the buffer solution, a commonly used buffer solution of an inorganic acid salt such as sodium phosphate or potassium phosphate, a buffer solution of an organic acid salt such as sodium acetate or sodium citrate, etc. is used, and its pH is an alkalophilic bacterium. PH of 8 to 11 for the culture solution and alkaline esterase, and for the culture solution of microorganisms that are not alkalophilic and esterase that does not have alkali tolerance
A pH of 5-8 is preferred. The concentration is usually 0.05 to 2M, preferably
It is in the range of 0.05 to 0.5M.

The reaction temperature is usually 10 to 60 ° C, and the reaction time is generally
10 to 70 hours, but not limited to this.

By such a reaction, one of the optically active dl-cyclopentenone esters is hydrolyzed to produce optically active 4-hydroxy-2-cyclopentenone represented by the general formula (I). On the other hand, the optically active 2-substituted-3-acyloxy-4-cyclopentenone in which the substituent R ₁ which is the other optically active substance in the raw material compound is an acyloxyl group remains as a hydrolysis residue as it is. Consequently, in the method of the present invention, the above two kinds of optically active compounds are simultaneously obtained as a hydrolysis product and a hydrolysis residue.

In addition, at the time of hydrolysis, in addition to the buffer solution, it is possible to use an organic solvent which is inert to the reaction such as toluene, chloroform, methyl isobutyl ketone, and dichloromethane, and by using these, asymmetric hydrolysis is advantageously carried out. be able to.

After the completion of such a hydrolysis reaction, in order to separate the hydrolysis product and the hydrolysis residue from the reaction solution, the hydrolysis reaction solution is treated with, for example, methyl isobutyl ketone, ethyl acetate,
Extraction treatment with a solvent such as ethyl ether, the solvent is distilled off from the organic layer and then the concentrated residue is further distilled, or it is carried out by a method such as column chromatography.
As a result, the optically active 2-substituted-indicated by the general formula (I)
3-hydroxy-4-cyclopentenone and optically active 2
The -substituted-3-acyloxyl-4-cyclopentenones can be separated.

The optically active 2-substituted-3-acyloxyl-4-cyclopentenone obtained here can be further hydrolyzed and used as a raw material for producing a symmetric body.

<Effects of the Invention> Thus, according to the method of the present invention, the optically active 4-hydroxy-2-cyclopentenones represented by the general formula (I) can be easily obtained, and the obtained optically active substance, for example, l
Rearrangement of 4-hydroxy-2-cyclopentenones with retention of steric form gives 2-substituted-4-hydroxy-2-cyclopentenones having R (+) coordination, which is a drug. It is extremely useful as an intermediate for prostaglandin derivatives.

<Examples> Hereinafter, the present invention will be described with reference to Examples.

Raw Material Production Example 1 A flask is charged with 1,000 ml of water and 0.2 g of 2 potassium hydrogen phosphate, and the pH is adjusted to 4.2 with 5% phosphoric acid.

To this, 20 g of 2- (ω-methoxycarbonylhexyl) -furfuryl alcohol is added, and the mixture is heated and stirred for 12 hours.

After completion of the reaction, extraction is performed twice with 200 ml of toluene. The organic layer is concentrated under reduced pressure to obtain a concentrated residue (19.8 g).

19.8 g of this concentrated residue are dissolved in 100 ml of dichloromethane and 30 ml of pyridine are added. 13.1 g of acetyl chloride is added over 2 hours while keeping the internal temperature at 0 to 10 ° C. After incubating at the same temperature for 1 hour, react at 25-30 ° C for 3 hours.

After completion of the reaction, the organic layer was washed with water, 1% dilute hydrochloric acid, 1% aqueous sodium hydrogen carbonate and water successively, dried over magnesium sulfate and concentrated under reduced pressure to obtain 23.1 g of a concentrated residue.

This was purified by silica gel column chromatography using a mixed solution of toluene: ethyl acetate (5: 2), and 4-acetoxy-5- (ω-methoxycarbonylhexyl)-
9.75 g of 2-cyclopentenone are obtained.

▲ n ²⁰ _D ▼ 1.4809 Example 1 100 ml of 0.3M phosphate buffer (pH 7.5), 4-acetoxy-5- (ω-methoxycarbonylhexyl) -2-cyclopentenone was placed in a flask equipped with a stirrer and a thermometer. Four
g, 2 ml of dichloromethane, and 240 mg of Pseudomonas lipase (amanolipase "P") were charged, and the mixture was kept at 30 ° C for 15
Stir vigorously for hours.

After completion of the reaction, the reaction solution is extracted twice with 40 ml of toluene.
The organic layers are combined and concentrated under reduced pressure.

The concentrated residue was purified by column chromatography using toluene: ethyl acetate (5: 2) to give l-4-hydroxy-5- (ω-methoxycarbonylhexyl) -2-cyclopentenone 1.
Get 27g.

▲ [α] ²⁰ _D ▼ -16.3 ° (C = 1, CHCl ₃ ) mp 48 ° C. Example 2 Example 1 except that 280 mg of Arthrobacter lipase (Nippon Kagaku Co., Ltd.) is used instead of Pseudomonas lipase. And treated in the same manner as in 1-4-hydroxy-5- (ω-
Methoxycarbonylhexyl) -2-cyclopentenone
Got 1.08g.

▲ [α] ²⁰ _D ▼ -15.6 ° (C = 1, CHCl ₃ ) mp 49 ° C

 ─────────────────────────────────────────────────── --Continued front page (56) References JP-A-60-78585 (JP, A) US Pat. No. 4,067,732 (1978) (US, A) Acta Chim. Acad. Sc i. Hung. , Vol. 102, No. 1, (1979), p. 91-100

Claims (1)

[Claims] 1. A general formula (In the formula, R ₁ represents an acyloxy group, In a substituent represented, the X-Y is CH ₂ -CH ₂ or cis CH = CH, R 'represents an alkyl group. However, the substituent R at the 5-position and the substituent R _{1 at the} 4-position are trans-coordinated), and the dl-cyclopentenone ester represented by Pseudomonas or Arthrobacter is used as the lipase derived from the microorganism. General formula characterized by asymmetric hydrolysis by (In the formula, R has the same meaning as described above.) A method for producing an optically active 4-hydroxy-2-cyclopentenone.