JP2586897B2 - Process for producing optically active cis-cyclopentene-3,5-diol monoester - Google Patents

Description

The present invention relates to a method for producing optically active cis-cyclopentene-3,5-diol monoester.

More specifically, the present invention relates to the general formula (Wherein, R represents a lower alkyl group) A general formula, wherein a cyclopentene-3,5-diol diester represented by the following formula is transesterified using an enzyme in an organic solvent containing an aliphatic alcohol: (Wherein R has the above-mentioned definition), and an optically active cis-cyclopentene-3,5-
A method for producing a diol monoester is provided.

Prostaglandins (there is a prostaglandin E ₁ as an example of .PG which hereinafter referred to as PG, listed the chemical structural formula below) has a modulating effect of lowering blood pressure, various biological functions such as smooth muscle contraction It is a substance group. Due to the interesting biological activity exhibited by PG or its synthetic analogs, an easy and economical method for synthesizing optically active compounds has been demanded and sought.

(3S, 5R) -cis-5 represented by the following formula (IIa)
-Acetoxy-1-cyclopenten-3-ol (+)
-(IIa) is an excellent raw material for synthesizing optically active PGs, and the present inventor has determined that the optically active cis-cyclopentene-3,5-diol monoester represented by the general formula (II) can be efficiently used. As a result of various studies on a production method for obtaining a good result, the present invention succeeded in providing an excellent production method.

Heretofore, there have been various research reports that a diester represented by the general formula (I) is partially hydrolyzed using an enzyme to obtain a monoester represented by the general formula (II).

For example, Takano, Ogasawara et al., Which is a kind of Bacillus subtilis Baci
The above hydrolysis was carried out using llus subtilis var niger to obtain a monoester (-)-(II) (J. Chem. So
c. Chem. Commun., p. 189 (1976)).

Sih et al. Obtained monoesters (-)-(II) using pig liver esterase (Pig Liver Esterase, hereinafter referred to as PLE) in a phosphate buffered aqueous solution of pH 7.0 (J. Am. Che.
m. Soc., 106: 3695 (1984)).

Schneider et al. Describe a diester of general formula (I) (substrate)
The above partial hydrolysis is carried out using enzymes of various origins such as animals or microorganisms (Tetrahedron Letters,
25, p. 5875 (1984)). In addition, in the hydrolysis using pig pancreatic lipase (hereinafter referred to as PPL), the stereoselectivity was completely opposite to that using PLE, and the obtained monoester was (+)-(IIa). (See J. Chem. Soc. Chem. Commun. 1298 (1986)).

Deardorff et al. Performed a reaction in a pH 6.85 phosphate buffer aqueous solution using a commercially available acetylcholinesterase (ACE) derived from electric eel as an enzyme, and found that (+)-(IIa ) Was obtained (see Tetrahedron Letters, Vol. 27, p. 1255 (1986)).

Each of these methods is a method in which partial hydrolysis is carried out by using an enzyme with water as a solvent. In such a method using water as a solvent, an organic solvent and an aqueous layer used for extracting the produced target substance from the aqueous layer often become emulsified, and the separation of the two layers is considerable. Needs time.
In addition, at the time of hydrolysis, a part is hydrolyzed to a diol, but this diol body remains in an aqueous layer because it is easily water-soluble, and cannot be extracted with an organic solvent. It will not be collected.

The inventor of the present invention has found that a highly efficient optically active cis-cyclopentene-3,5-diol is obtained by subjecting a cyclopentene-3,5-diol diester to a transesterification reaction using an enzyme in an organic solvent containing an aliphatic alcohol. It has been found that monoesters can be produced. The present invention has been made based on such findings.

 Hereinafter, the present invention will be described in detail.

The diester represented by the general formula (I), which is a raw material of the method of the present invention, is a corresponding diol (the following formula [III])
Can be produced by various methods in addition to the acylation (Tetrahedron Letters, vol. 26).
5615 (1985), Synthesis, 867 (1974)).

formula, The diol of the above formula (III) can be produced, for example, by a method starting from cyclopentadiene (see Synthesis, p. 876 (1974)), and a cis form or a mixture of a cis form and a trans form is used.

The enzyme used in the method of the present invention may be appropriately selected from enzymes conventionally used in this type of reaction, and may be used. PPL, lipase P (derived from the genus Pseudomonas), A (As
pergillus), F-AP (from Rhizopus), M (M
and the like can be suitably used.

As the organic solvent, an organic solvent that can contain an aliphatic alcohol, for example, a saturated aliphatic hydrocarbon solvent such as pentane, hexane, and heptane is used. As the aliphatic alcohol to be contained therein, lower aliphatic alcohols such as methanol, ethanol and isopropyl alcohol are preferably used.

The amount of aliphatic alcohol used generally speaking,
The ratio is at least equimolar to 1 mol of the starting diester.

In order to efficiently obtain the desired monoester, various conditions such as the type of the enzyme and the amount used, the temperature of the transesterification reaction, the reaction time, the type of the aliphatic alcohol to be used and the amount used are appropriately determined. It is necessary to make a choice.

In the method of the present invention, not only a batch method but also a continuous production method can be adopted. That is, the enzyme powder is previously filled in a column, maintained at an appropriate temperature, and a mixed solution prepared by mixing the raw material diester, the aliphatic alcohol, and the organic solvent is repeatedly flowed through the column at an appropriate flow rate. As a result, a means of continuously producing monoesters can be employed.

FIG. 1 schematically shows the method for continuous production.

According to the transesterification method of the present invention described in detail above, the following advantages are obtained as compared with the above-mentioned monoester production method by a hydrolysis method using an enzyme.

Acquisition of the target product is extremely simple and very advantageous.

Even if the diol form is generated, it can be efficiently recovered.
Raw material loss can be prevented (the diol form can be reused as a raw material by diacylation).

In the case of the hydrolysis reaction, since fatty acids such as acetic acid are generated, it is necessary to adjust the pH of the reaction system during the reaction, but since the method of the present invention is a transesterification reaction,
No acid formation is seen and therefore no pH adjustment is required.

Hereinafter, examples of the present invention will be described, and the present invention will be described more specifically.

Example 1 a) Production of Raw Diester (3,5-diacetoxycyclopentene) Using cyclopentadiene (33 g), J. Chem. Soc., 203
3,5-Dibromocyclopentene was prepared according to the method described on page 5 (1952). This is called Synthesis, page 867 (1
974), 3,5-diacetoxycyclopentene (mixture of cis- and trans-forms) (48 g, 5
2%).

b.p.74-75mm / 0.5mm.

▲ n ²³ _D ▼ 1.4521.

ν _max 1740 (s), 1235 (s), 1130 (s) cm ^-1 .

GLC (Column, PEG 2OM 2m, 90 ゜ +2 ゜ / min; N ₂ , 1.0kg / c
m ² ; hereinafter, all GLC analyzes were performed under these conditions): Rt15.4mi
n (trans form, 42.5%) 16.1 min (cis form, 57.5%). Signal derived from ¹ H NMR δ cis form: 1.73 (1H, dt, J = 15.
0,4.0Hz), 2.09 (6H, s), 2.89 (1H, dt, J = 15.0,7.5H
z), 5.55 (2H, ddd, J = 1.0, 4.0, 7.5 Hz), 6.13 (2H, d, J =
1.0Hz).

Signal from trans form: 1.29 (1H, br.s), 2.06 (6H,
s), 2.25 (1H, dd, J = 5.4,5.4Hz), 5.81 (2H, ddd, J = 0.
8,5.4,5.4Hz), 6.00 (2H, d, J = 0.8Hz).

MS m / z 124 (M ^<+>- AcOH, 23.1%).

b) Asymmetric transesterification using PPL (batch method) In a 1-liter four-necked flask, the cis-trans mixture (20 g) obtained in a) above, ethanol (32 m
l), n-hexane (400 ml) and PPL (40 g)
The mixture was stirred at 45 ° C. for 72 hours to perform a transesterification reaction.

The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude product 1.
8.2 g were obtained.

GLC: (crude product) Rt 15.4 min (transester diester, 4
5.8%), 16.1min (Diester cis form, 15.9%), 20.1min
(Monoester cis form, 31.6%), 22.3 min (monoester trans form, 6.7%).

The crude product is purified by silica gel column chromatography (90
g) to give a diester (9.7 g, 48.5%) and a crude monoester (5.3 g, 34%). The latter was recrystallized from n-pentane-ether (1: 1, 25 ml) to obtain a crystalline monoester cis form (cis-cyclopentene-3,5-diol monoester) (4.5 g).

Its mp was 47.5-48 ° C, which was consistent with the literature value. The specific rotation was ▲ [α] ²² _D ▼ + 75.0 ° (chloroform), which was slightly larger than the value 63-66 ° previously reported.

The optical purity of the recrystallized purified product was derived from its ester with optically active α-methoxy-α-trifluoromethylphenylacetic acid (MTPA). From its 500 MHz ¹ H NMR spectrum,
It was determined to be 00%.

Example 2 Asymmetric transesterification using PPL (column method) A column of a medium pressure column chromatograph was packed with PPL powder (40 g, diameter 2 cm × length 20 cm). The column was kept warm at 45 ° C., and the cis form obtained in Example 1a) was obtained.
A mixture of the trans-form mixture (20 g), ethanol (32 ml) and n-hexane (400 ml) was repeatedly flowed at 10-12 ml / min (see FIG. 1).

GLC (crude product after 72 hours) Rt 15.4 min (diester trans form, 49.5%), 16.1 min (diester cis form, 18.8)
%), 20.1min (monoester cis form, 26.5%), 22.3min
(Monoester trans form, 5.2%).

Physical properties and spectrum data of the (+)-monoester cis form after recrystallization: mp 47.5-48 ° C. [[α] ²² _D ▼ + 75.0 ゜ (c = 1.16, chloroform).

νmax 3450 (s.br), 3080 (w), 3000 (w), 2950
(W), 1725 (s), 1440 (m), 1415 (m), 1360
(M), 1320 (m), 1300 (m), 1270 (m), 1240
(S), 1180 (w), 1120 (w), 1090 (s), 1060
(S), 1025 (s), 980 (m), 970 (m), 910 (w), 88
0 (w), 840 (m), 795 (s) cm ^-1 . ^{1 H NMR δ 1.66 (1H,} dt, J = 15.0,4.0Hz), 2.08 (3H,
s), 2.79 (1H, dt, J = 15.0, 7.0Hz), 4.71 (1H, m), 5.50
(1H, m), 5.98 (1H, d, J = 7.0Hz), 6.12 (1H, d, J = 7H
z). The signal at 0H could not be identified due to the widened line width.

[Brief description of the drawings]

FIG. 1 is a diagram schematically showing a case where the method of the present invention is performed in a continuous manner.

Claims (3)

(57) [Claims] (1) General formula (Wherein, R represents a lower alkyl group) A general formula, wherein a cyclopentene-3,5-diol diester represented by the following formula is transesterified using an enzyme in an organic solvent containing an aliphatic alcohol: (Wherein R has the above-mentioned definition), and an optically active cis-cyclopentene-3,5-
Method for producing diol monoester. 2. The method according to claim 1, wherein said enzyme is porcine pancreatic lipase (PP).
The process for producing cis-cyclopentene-3,5-diol monoester according to claim 1, which is L). 3. The method according to claim 1, wherein R is a methyl group.