JPH02237954A - Production of 4-hydroxy-2-cyclopentenone derivative - Google Patents

Abstract

PURPOSE:To advantageously obtain the subject substance which is a synthetic intermediate for prostaglandin-based medicines by reacting optically pure and active 3-hydroxy-4-pentenoic acid derivative which can be readily synthesized with a lower a alkyl-lithium and then tert-butyl-lithium. CONSTITUTION:An optically active 3-hydroxy-4-pentanoic acid derivative expressed by formula I or II [X is Cl, Br, I or tri(lower alkyl)tin group; R' is protecting group of hydroxyl group) which is an optically pure and active allyl alcohol derivative as a starting material is reacted with a lower alkyl- lithium (use of tert-butyl-lithium is optimum) at -60 to -90 deg.C preferably under anhydrous conditions and then tert-butyl-lithium at -60 to -90 deg.C to afford a compound expressed by formula III or IV (R is H or protecting group of hydroxyl group). The lower alkyl-lithium is used in an amount of preferably 1-1.5mol equiv. based on the compound expressed by formula I or II and the tert-butyl-lithium is used in an amount of preferably 2-3.5mol equiv. based on the compound expressed by formula I or II.

Description

[Detailed Description of the Invention] Industrial Benefits The present invention provides compounds of the following general formula (
m) or (IV) Saliva] [■] (However, in the formula, R is a hydrogen atom or a hydroxyl group-protecting group.
) relates to a method for producing an optically active 4-hydroxy-2-cyclopentenone derivative. As methods for synthesizing optically active 4-hydroxy-2-cyclopentenone derivatives, the following methods 1 to 2 have been known. Φ Method of selectively oxidizing the hydroxyl group at one end of optically active 3,5-dihydroxy-cyclopentene (Tanaka, Kurosumi et al., Tetrahedron Lett., 32
．． 1713 (1976) etc.). ■ A method in which racemic 4-hydroxy-2-cyclopentenone is obtained by a rearrangement reaction of a furan derivative, and then acylated and asymmetrically hydrolyzed with enzymes (Japanese Patent Laid-Open No. 57-6223
No. 6, Publication No. 63-109797, etc.).

■ A method of selectively isomerizing the racemic form of 4-hydroxy-2-cyclopentenone with an asymmetric rhodium catalyst and kinetically resolving it (Noyori et al., Tetrahedron ett., 28, 4719 (1987))
.

■ A method of combining the racemic form of 4-hydroxy-2-cyclopentenone with an optical resolving agent to separate diastereomers, and then removing the optical resolving agent to obtain an optically active form (JP-A-57-159777 Publications, etc.).

(2) A method for separating the racemic form of 4-hydroxy-2-cyclopentenone by optical resolution liquid chromatography (JP-A-61-267536, etc.).

However, the optical purity of the 4-hydroxy-2-cyclopentenone obtained by method (2) above is not fully satisfactory. In addition, in the methods ① to ② above, it is necessary to perform the optical splitting operation at the end.
-The disadvantage is that more than half of the hydroxy-2-cyclopentenone is wasted.Moreover, method (2) uses an enzyme and is therefore a water-based reaction;
Hydroxy-2-cyclopentenone is an extremely water-soluble and unstable compound, so it is difficult to remove it from the reaction solution, and methods The carrier used is expensive and economically disadvantageous. Furthermore, method (2) requires three steps just for optical resolution and requires an equimolar amount of optical resolving agent, making the process cumbersome and uneconomical. There is also a problem.

The present invention thus aims to provide a novel method for producing optically active 4-hydroxy-2-cyclopentenone derivatives, which has been difficult to produce industrially advantageously in a short process using conventional methods. purpose.

In view of the above circumstances, the inventors of the present invention have made extensive efforts using various optically active allyl alcohol derivatives in order to industrially advantageously synthesize optically active 4-hydroxy-2-cyclopentenone derivatives in short steps. As a result of repeated consideration, we found that the present inventor had previously filed Japanese Patent Application No. 189234/1982, and also Japanese Patent Application No. 1983
-170299, the following general formula (CI) or the general formula (
n) [However, in the formula, X is a chlorine atom, a bromine atom, an iodine atom, or a tri(lower alkyl)tin group, and R' is a hydroxyl group-protecting group. ] The optically active 3-hydroxy-4-pentenoic acid derivative represented by is treated with lower alkyl lithium, and then t-
By acting with butyllithium, the following general formula [
[■] Or an optically active 4-hydroxy-2-cyclopentenone represented by the general formula (II) ξ OR or the general formula (IV) n (wherein, R represents a hydrogen atom or a hydroxyl group retention fl.iit) The present inventors have discovered that derivatives can be industrially advantageously synthesized in a short process and without optical resolution operations, leading to the present invention. The present invention will be explained in more detail below. As mentioned above, in the production method of the present invention, an optically active 3-hydroxy-4-pentenoic acid derivative represented by the following general formula [I] is reacted with a lower alkyl lithium, and then t-
By reacting with butyllithium, an optically active 4-hydroxy-2-cyclopentenone derivative represented by the following general formula [■] n or general formula (IV) is obtained. Here, in the compounds of formula (1) and formula (II) used as starting materials in the method of the present invention, X in the formula is a chlorine atom, a bromine atom, an iodine atom, or a tri(lower alkyl)tin group. In addition,
Examples of the tri(lower alkyl)tin group include those having a lower alkyl group having 1 to 5 carbon atoms, such as a trimethyltin group and a triethyltin group.

Further, R' in formulas [I) and [II] above is a hydroxyl group-protecting group, and R in [III) and CTVE formula is a hydrogen atom or a hydroxyl group-protecting group. Here, specific examples of hydroxyl protecting groups include trialkylsilyl groups (e.g. trimethylsilyl group, t-butyldimethylsilyl group, phenyldimethylsilyl group), alkoxyalkyl groups (e.g. methoxymethyl group, ethoxyethyl group, tetrahydropyranyl group), Examples include aralkyloxyalkyl groups (eg, penzyloxymethyl group), trityl groups, and acyl groups (eg, acetyl group, P-nitrobenzoyl group). In the present invention, the 3-hydroxy-4-pentenoic acid derivative of formula (13 or ) The terminal carbonyl group of the 3-hydroxy-4-pentenoic acid derivative of the formula is converted into a lithium salt.

In this case, the lower alkyl lithium has a carbon number of 1
~5 lower alkyllithium, such as methyllithium,
Ethyllithium, n-butyllithium, t-butyllithium, etc. are preferably used, and it is optimal to use t-butyllithium, which is common to the second stage reaction described later, as the lower alkyllithium. In addition, it is preferable that the lower alkyl lithium is allowed to act on the compound of formula (1) or [I[] under anhydrous conditions, and it is desirable to reduce the amount of moisture in the system in advance in advance, but It is quite conceivable that some of the lower alkyl lithium is consumed by the mixed moisture. Therefore,
The amount of lower alkyl lithium used is [1) or (11)
1 to 1.5 molar equivalents per mole of the compound of formula are suitable. If the amount of lower alkyl lithium used is less than 1 molar equivalent, the reaction may not proceed sufficiently, and if it is more than 1.5 molar equivalent, the excess amount will be wasted and the economic merit will decrease.

Next, in the present invention, following the reaction of lower alkyllithium with the 3-hydroxy-4-pentenoic acid derivative of formula [■] or (II), as a second step, t-butyllithium is applied. . This second step reaction consists of an anion (
Including the formation of lithium salt by the first stage reaction, this is a process for forming dianion) and vinyllithium.

Here, the amount of t-butyllithium used is not particularly limited, but 1 mole of the compound of formula CI) or [II)
．． 5 to 4 molar equivalents, particularly 2 to 3.5 molar equivalents are preferred; if the amount used is less than 1.5 molar equivalents, the reaction may not proceed sufficiently; if it is more than 4 molar equivalents, the excess amount will be wasted; Economic benefits are reduced.

Furthermore, it is preferable to carry out the first and second step reactions in an organic solvent, and examples of the organic solvent include ethers such as diethyl ether, and non-reactive organic solvents that do not directly participate in the reaction of the present invention with these ethers. Solvent (e.g. hexane,
Mixed solvents with hydrocarbons (such as pentane, etc.) are preferably used. Note that it is preferable to use a sufficiently dried organic solvent.

In addition, it is desirable that the reaction temperature is low for both the first and second stage reactions; the first stage reaction is -30 to -90°C, especially -60 to -90°C, and the second stage reaction is -60 to -90°C. 90℃
The range of 1 and 2 is preferable from the viewpoint of ease of operation.
Preferably, the reaction is carried out through the steps at -70 to -80°C.

In the 4-hydroxy-2-cyclopentenone derivative thus obtained, R is a hydroxyl protecting group (R'), but this can be removed by a conventional method if necessary, and R is a hydrogen atom. This can lead to optically active 4-hydroxy-2-cyclopentenone.

In addition, the general formula (13,
The optically active 3-hydroxy-4-pentenoic acid derivative of formula (n) is disclosed in Japanese Patent Application No. 62-189 previously filed by the present inventor.
No. 234, as well as Japanese Patent Application No. 170299/1983, No. 62
It can be easily produced from an optically active furyl alcohol derivative that can be synthesized in an optically pure manner by the method proposed in Japanese Patent No. 238169.

That is, the following general formula (V) OH [wherein R1 is a carbon number of 1 to 10 Substituted or unsubstituted Here, R", R", and R" represent a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted phenyl group, and may be the same or different from each other. trans-type allyl alcohol having a silyl group or stannyl group at the γ-position and containing optically active allyl alcohol represented by the following general formula (VI) and [■] 0H as a racemate or a mixture. is oxidized with hydroperoxide in the presence of titanium tetraalkoxide and optically active tartaric acid diester, and the optically active allyl alcohol derivative (VI) or ゛[■] is given priority depending on the optical activity of the optically active tartaric acid diester. The above-mentioned optically active allyl alcohol derivative [■] or (VI) can be synthesized in an optically pure manner by reacting the above-mentioned optically active allyl alcohol derivative [■] or (VI). Using the obtained optically pure allyl alcohol, for example, as shown in the reaction formula below, the following formula (
Hydrolyzing the ester moiety of the optically active allyl alcohol in i), followed by an iodolactonization reaction using iodine, and treating the resulting lactone [] with 'Eu4NF yields droxycarboxylic acid [■]. and then add this to t
B u M e, Si (J is used to form a disilyl compound, and then K2C○, is applied to selective deprotection to yield a 3-hydroxy-4-pentenoic acid derivative of the formula [I']. It can be easily manufactured by a method that can be easily obtained.

(i) ILZυ9 As explained above, according to the production method of the present invention, the following general formula [■] or ( rV)
The optically active 4-hydroxy-2-cyclobentenone derivative represented by can be industrially advantageously produced in a short process and without the need for an optical resolution step.

The present invention will be specifically explained below with reference to Reference Examples and Examples, but the present invention is not limited to the following Examples. In addition, in the following examples, Me is a methyl group, "Bu is a t
-butyl group, nBu is n-butyl group, iPr is isoprobyl group, Et20 is diethyl ether, THF is tetrahydrofuran, DMF is . Indicates N,N-dimethylformamide.

[Reference Example 1] [Tech'] ((RS)-3) Diisopropylamine (30-Omle 214mmo
f! ) was cooled to 0° C. in THF (200 mil).
”BuLi (1 1 1 mQ, 1 70 mmo
l! , 1.53M in hexane) was added dropwise and stirred for 20 minutes at 0°C. This solution was cooled to -70°C, and butyl acetate (1) (19.8 uQ, 1 5 0+++ moR) was slowly added dropwise, and after stirring for 20 minutes, (E)-3-trimethylsilyl-2-propenal (2) (16 .64g, 1
28m++on) was slowly added dropwise at -70°C, and the mixture was stirred at that temperature for 20 minutes. Next, the reaction solution was poured into an ice-cooled NH4G2 saturated aqueous solution (700ml), the organic layer was separated, and the aqueous layer was separated into hexane-diethyl ether (5:1
) was extracted several times. Wash the extract with saturated saline and dry (
After MgSO4), the solvent was distilled off under reduced pressure, and the resulting oil was distilled (110-124℃/0.4IIv+Hg).
Then, compound ((RS)-3) (yield: 24.19g
, yield: 77%) was obtained. <Characteristic values of compound ((RS)-3)>"HNMR (CCL) δ: 0.14 (S, 9H), 1.16-1.93 (
my 4}1), 2.43(d, J==6.0Hz
, 2H), 3.25 (brs, IH), 4.
05Dr J=6.0Hz, 2H), 4.26-4
．． 57 (a+, IH), 5.82 (d, J=1
9.0Hz, 18), 6.02 (dd, J=1
9.0, 3.0Hz, LH) I R (neat): 3450, 3000,
1720, 1245,835 (an-') bp: 11.0-124°C/0.4 mmHg [Reference Example 2] ((RS)-3) ((R)-3) Orthotitanic acid isopropoxide (Ti Add L-(+
) Diisoprobyl monotartrate (L-(+)-DI PT
, 8.80ml, 41. 8:3+mofl
) was added dropwise and stirred for 10 minutes, and then the compound [(RS)-3) obtained in Reference Example 1 (5.67 g, 2 3 . 2 4
A dichloromethane solution (15 mQ) of MmoJi) was added dropwise and stirred for 20 minutes at -20'C. Next, a dichloromethane solution (8.05 ml, 34.86 mmofi, of anhydrous t-butylic hydroxide (TBHP) in methylene chloride was added dropwise and stirred for 20 minutes at -20'C. After slowly dropping 4.33M), -20'
Stirred at C for 18 hours. Furthermore, dimethyl sulfide (4
mQ, 5 4. 5mmoff) and -20
After stirring at ℃ for 1 hour, this reaction solution was poured into a mixture of 10% tartaric acid solution (22 ndl) and ethyl ether (200 ntQ), and after stirring at room temperature for 10 minutes, celite (Log) and sodium fluoride (2 ndl) were poured into the mixture. 0 g) and stirred at room temperature for 30 minutes. The extract was passed through a Celant furnace;
The residue was washed several times with ethyl ether. After concentrating the furnace liquid,
The resulting oily substance was purified by silica gel chromatography to obtain compound ((R)-3) (yield: 2.495g, yield: 44%) as a pale yellow oily substance. <Compound(
Characteristic value of (R)-3)〉 ((!) ”,' +6. 1 3゜(c 1.63.
CH(j!z) was converted to the corresponding MTPA ester (optically active form of α-methoxy α-trifluoromethylphenyl WPa) and confirmed to be >99% ee by HNMR analysis. HNMR, IR The data agreed with the data of the racemate (compound ((RS)-3)) of Reference Example 1. [Reference Example 3
] ((R)-3) [4] Compound obtained in Reference Example 2 ((R)-3) (9 7
6rrz, 4. 0mmof) of THF (5mQ
)-Et,O (5mu)-MeOH (2
．． 5 d) Add 3N aqueous sodium hydroxide solution (1.
5d) was added and stirred at room temperature overnight. After adding an aqueous sodium bicarbonate solution (10 mQ) to this and cooling the reaction mixture to 0°C, Step 2 (1.52 g, 5.99 mmoffi) was added.
) and stirred at 0° C. for 1 hour. The reaction solution was poured into a saturated aqueous solution of sodium thiosulfate (50d), the mixture was extracted with ether-ethyl acetate (200aQX3), the extract was dried (M g S 04), and the solvent was distilled off under reduced pressure to give an oily substance ( 1.llg) was obtained.

Next, dissolve this oil in THF (10ntQ),
After cooling to 0°C, a THF solution of tetrabutylammonium chloride (6.0Ifi!Q, 4.02mm
all, 0.67 M in THF) was added dropwise. 30 at 0℃
Stir for a minute and pour into NH4CQ saturated aqueous solution (10d).
Dilute hydrochloric acid was added little by little until the pH of the aqueous layer reached 4, and the mixture was extracted with chloroform (20 ndl x 4). After drying this extract (M g S 04), the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in diethyl ether and filtered through silica gel, yielding compound [4] (yield: 720 cm,
Yield: 85%) was obtained. The methyl ester form of this compound [4] was found to be 95% 2-form by HNMR analysis, and compound [4] was used in the next reaction without further purification. <Characteristic values of compound [4]> ″HNMR (CDC et al.) δ: 258 (d, J=6, OHz, 2H), 4.5
0-4.90 (m, IH), 6.17-6.48
(m, 2H), 6.75 (brs, 2H). [
Reference Example 4] [4] [Work'] Compound (4) obtained in Reference Example 3 (720■, 3.
0 mmojl). tBuMa. SiCji
(1.36 g, 9 mmoj!)
, imidazole (8 1 6ffil 1 2++
A solution of u++offi) in DMF (5-) was stirred at room temperature overnight. After adding NaCΩ saturated aqueous solution (20m!) to this and extracting the mixture with hexane (20+1QX3),
The extract was washed with a saturated aqueous solution of NaCR and dried (MgSO
．． )L, the solvent was distilled off under reduced pressure to obtain an oily substance. next,
The obtained oil was dissolved in MeOH-THF-H,O (5:
2: 2.28 ml) and potassium carbonate (
415. , 3 mmon) and stirred at room temperature for 10 minutes. Pour the reaction solution into a buffer solution (30 mQ) with a pH of 5,
CHC Q. Extracted several times. This extract was dried (Mg
When the crude product obtained by distilling off the solvent under reduced pressure was purified using a silica gel column, the compound [Work']
(Yield: 820 cm, yield: 80%) was obtained as an oil.

<Characteristic values of compound [tech']>'HNMR (CDCL) δ: 0.07 & 0.11 (2s, 6}1), 0.86
(st 9H), 2.55 (d, J=4.8Hz
, 2H), 4.70-4.96 (01, IH)
, 6.16-6.38 (m, 2H). i3CNMR
(CDC) δ: 176.6, 142.9, 81.1, 72.7,
41.7, 25.7.1? ．． 9, -4.3, -4.
9. I R (neat): 2930, 1705,
1250, 1090,830 (am-”). [Example] Compound (I') obtained in Reference Example 4 (650 mg, 1
．． 8 2+++mofi) in ether solution (20ml
) was cooled to -72°C and Me Li (0.8 8
aQ, 1.8 2+mmon, E t, 2.08 in O
M) was added dropwise and stirred for 30 minutes at -78°C.-7
tB u Li (2.14 mQ, 3.
64rrrrmon, 1.70M in pentane) was added dropwise and stirring continued for an additional 20 minutes. Next, the reaction solution was poured into an ice-cooled mixture of a saturated aqueous solution of NH4Cl (40all) and diethyl ether (20all), and the mixture was extracted with diethyl ether (20mRX3). This extract was dried, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to yield compound (II') (yield:
288μ, yield: 75%) was obtained as white crystals.

<Characteristic values of compound [■']> m p: 28.5-29.5°C (recrystallized from pentane)* ((E) ”.' +6 7.1@(c O.82,
MeOH)”1HNMR (CDCfl3) δ: 0.11 & 0.12 (2S, 6H), 0.89
(S, 9H), 2.22(dd, J=2.3,
18.1Hz, 18), 2.69 (dd, J=6
．． 0, 18.1Hz, IH), 4.93-5.0
2 (m, IH), 6, 17 (dd, J=1.2
, 5.7Hz, IH), 7.44 (dd, J
=2.3, 5.7Hz, IH). 13CNMR (CDCQ3) δ: 206.9, 164.2, 134.7, 70.9
, 44.9, 25.6, 18.0, -4.9,

Claims (1)

[Claims] 1. The following general formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] Or general formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... -(II) [However, in the formula, X is a chlorine atom, a bromine atom, an iodine atom, or a tri(lower alkyl)tin group, and R' is a hydroxyl group-protecting group. ] The optically active 3-hydroxy-4-pentenoic acid derivative represented by is treated with lower alkyl lithium, and then t-
The following general formula [III] characterized by the action of butyllithium ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[III] Or general formula [IV] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・...[IV] (However, R is a hydrogen atom or a hydroxyl group-protecting group.) A method for producing an optically active 4-hydroxy-2-cyclopentenone derivative represented by the following.