JPS6022704B2 - Prostaglandin-like compound intermediate and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to intermediates for producing prostaglandin-like compounds.

More specifically, the general formula [wherein X is an ethylene group (i.e., 1 CQC day 2 -) or a cis-vinylene group (i.e.); RI represents a straight or branched alkyl group having 1 to 12 carbon atoms; R2 and R3 may be the same or different; R4 represents a sulfur atom or a selenium atom, R5 is a linear or branched alkyl group having 1 to 4 carbon atoms, or a group (in the group, R8 and R7 may be the same or different, but a hydrogen atom, a chlorine represents a trifluoromethyl group, a methoxy group, or a nitro group].

The object compound of the present invention is a prostaglandin-like compound, especially a compound with a single side chain cleavage, and a compound in which a trans single double bond is introduced between C2-C3 of prostanoic acid represented by the formula. It is extremely important as an intermediate in the process.

Method for producing secondary intermediates [Refer to Tokukan Sho 53-149955, Tokkoku Sho 52-36646 and Tokkan Sho 52-85151, or Tokkan Sho 52-64013]
According to the above, since a double bond is introduced between C2-C3 in the previous step, there is a drawback that side reactions are likely to occur when the reaction is carried out under basic conditions.

The present inventors have conducted research to eliminate these difficulties through industrially easy operations, and as a result, have obtained the present compound and completed the present invention.

The present invention is directed to all compounds represented by the general formula (1), that is, optically active "natural type" or their enantiomers or mixtures thereof (particularly racemic compounds consisting of a mixture of equal amounts of "natural type" and their enantiomers). ) regarding.

Preferred RIs in general formula (1) include straight-chain or branched-chain alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isoprobyl, n-butyl, isobutyl, Sec- Butyl group and rt-butyl group are mentioned, and R5 is preferably a group (in the group, R and R7 have the same meanings as above), such as phenyl group, 2
-nitrophenyl group, 4-nitrophenyl group, 4-chlorophenyl group, 2-trifluoromethylphenyl group, 3
Examples thereof include -trifluoromethylphenyl group, 2-trifluoromethyl-4-nitrophenyl group, and 4-methoxyphenyl group.

As the protecting group for the hydroxyl group represented by R2 and R3, any group may be used as long as it does not affect other parts of the compound upon removal and can be easily removed under mild conditions.

Examples of such protecting groups include ○}tetrahydropyran-2-yl group, “tetrahydrofuran-2-yl group,
a double ring group such as a tetrahydrothiopyran-2-yl group,
[2'Acyl groups such as acetyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, propionyl group, benzoyl group, p-phenylbenzoyl group, naphthyloyl group (3} 1- Ether groups such as ethoxyethyl group, 1-methoxy-1-methylethyl group, 1-〆toxycyclohexyl group, 1-methoxy-1-phenylethyl group, {4} trimethylsilyl group, triethylsilyl group, tri-n-butylsilyl group, t-butyldimethyl Trisubstituted silyl groups such as silyl groups, tribenzylsilyl groups, and triphenylsilyl groups,
'5) Trityl group etc. can be mentioned.

Particularly preferred R2 is an acetyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, or tetrahydropyran-2-yl group, and particularly preferred R3 is a tetrahydropyran-2-yl group. Preferred compounds represented by the general formula (1) included in the present invention include, for example, mIQ-acetoxy-2Q-(6-phenylselenol 6
-methoxycarbonylhex-2-enyl)-3
8-formyl-4Q-(tetrahydropyran-2-yloxy)cyclobentane, [2) IQ-acetoxy-2
Q-(6-phenylselen-6-methoxycarbonylhexyl)-38-formyl-4Q-(tetrahydropyran-2-yloxy)cyclobentane, glue IQ-chloroacetoxy 2Q-(6-phenylselen 6-methoxycarbonylhexyl)-2 -enyl)-38-formyl-4Q-(tetrahydropyran-2-yloxy)
Cyclobentane, '4) IQ-chloroacetoxy-2Q
-(6-phenylseleno-6-methoxycarbonylhexyl)-38-formyl-4Q-(tetrahydropyran-2-yloxy)cyclobentane, (5)IQ-dichloroacetoxy-2Q-(6-phenylselen 6-methoxycarbonylhexyloxy) 2-enyl)-38-formyl-4Q-(tetrahydropyran-2-yloxy)cyclobentane, t6)IQ-dichloroacetoxy-2Q-(6-phenylseleno-6-methoxycarbonylhexyl)-38-formyl-4Q-(tetrahydropyran-2-yloxy) ) cyclobentane, [7}IQ
-Trichloroacetoxy-2Q-(6-phenylseleno-6-methoxycarbonylhexacys-2-enyl)
-38-formylu-4Q-(tetrahydropyran-2-
yloxy)cyclobentane, '8) IQ-trichloroacetoxy-2Q-(6-phenylseleno-6-methoxycarbonylhexyl)-38-formyl-4Q-(tetrahydropyran-2-yloxy)cyclobentane,
{9lIQ. 4Q-pis(tetrahydropyran-2-yloxy)-2Q-(6-phenylselenol-6-methoxycarbonylhex-2-enyl)-38-formylcyclobentane, OQIQ.4Q-bis(tetrahydropyran-2-yloxy)-2q-(6 -Phenylselenol 6-methoxycarponylhexyl)-38-formylcyclobentane, (11) IQ-acetoxy 2
Q-(6-phenylthio-6-methoxycarbonylhex-cis-2-enyl)-38-formyl-4Q-(tetrahydrobyrasol-2-yloxy)cyclobentane,
(12) IQ-acetoxy 2Q-(6-phenylthio 6-methoxycarbonylhexyl)-38-formyl-4Q-(tetrahydropyran-2-yloxy)cyclobentane, (13) IQ-chloroacetoxy 2Q-(6-phenylthio 6-methoxycarbonyl) hexcis-2-enyl)-33-formyl-4Q-(tetrahydropyran-2-yloxy)cyclobentane, (1
4) IQ-chloroacetoxy 2Q-(6-phenylthio-6-methoxycarbonylhexyl)-33-formyl-4Q-(tetrahydropyran-2-yloxy)cyclobentane, (15) IQ-dichloroacetoxy 2
Q-(6-phenylthio-6-methoxycarbonylhex-2-enyl)-33-formyl-4Q-(tetrahydropyran-2-yloxy)cyclobentane,
(16) IQ-dichloroacetoxy-2Q-(6-phenylthio-6-methoxycarbonylhexyl)-33-
Formyl-4Q-(tetrahydropyran-2-yloxy)cyclobentane, (17)IQ-trichloroacetoxy-2Q-(6-phenylthio-6-methoxycarbonylhex-cis-2-enyl)-38-formyl-4
Q-(tetrahydropyran-2-yloxy)cyclobentane, (18)IQ-trichloroacetoxy-2Q-(6-phenylthio-6-methoxycarponylhexyl)-38-formyl-4Q-(tetrahydropyran-2
-yloxy)cyclobentane, (19) IQ. 4Q-bis(tetrahydropyran-2-yloxy)-2Q-(6-phenylthio-6-methoxycarbonylhexcis-2-phenyl)-38-formylcyclobentane, (20)IQ・4Q-pis(tetrahydropyran-2
-yloxy)-2Q-(6-phenylthio-6-methoxycarbonylhexyl)-38-formylcyclobentane and the like.

According to the present invention, the compound represented by the general formula (1) has the general formula [wherein all symbols have the same meanings as above]
Hydroxymethyl group (1C ratio OH) of the compound shown by
It can be obtained by subjecting it to an oxidation reaction to convert it into a formyl group (mono-CHO).

Oxidation under mild, neutral conditions converting hydroxymethyl groups to formyl groups converts dimethylsulfide-N-chlorosuccinimide, thioanisole-N-chlorosuccinimide, dimethylsulfide-chloride, thioanisole- Chlorine Sudoku [Journal of the American Chemical Society]
the American ChemicalS ratio
V), 9 Kameson, 7 Spots 6 pages (1972 Wang)] or dicyclohexylcarbodiimide dimethyl sulfoxide cage [Journal of the American Chemical Society, Vol. 87, p. 5661 (1960)
Reference]. The reaction using chloride is
Usually in chloroform, halogenated hydrocarbons such as methylene chloride or carbon tetrachloride, or toluene as a solvent,
The reaction is carried out at a temperature between room temperature and 130 o'clock, followed by treatment with triethylamine. The reaction using dicyclohexylcarbodimidodimethylsulfoxide rust is usually carried out in excess dimethylsulfoxide at room temperature in the presence of an acid catalyst such as phosphoric acid, head phosphoric acid, cyanoacetic acid, pyridine phosphate or trifluoroacetic acid. The compound represented by the general formula (m) is
No. 53-1499 or the method described in the specification of JP-A-53-1499.

The compound of the present invention represented by the general formula (1) is an important new intermediate that can industrially produce a prostaglandin-like compound in which a trans single double bond is introduced between C2-C3 of prostanic acid.

For example, the process to trans-△2-prostaglandin F2Q was described by Wordsworth Emmons (Wa ship monh-Em
mo old) reactions, reduction reactions, protecting groups (i.e. R2 and R
3), followed by a reaction to eliminate the group -R4-R5 and introduce a trans double bond. Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.

In addition, "TLC", "nR" and "N" in Reference Examples and Examples
The symbols ``MR'' represent ``thin layer chromatography infrared absorption spectrum'' and ``nuclear magnetic resonance spectrum,'' respectively, and the proportion of solvent described in the section of separation by chromatography indicates the volume ratio. Reference example IQ-acetoxy-2Q-(6-phenylselenoid 6-
methoxycarbonylhex(2-enyl)-38
-Hydroxymethyl-4Q-(tetrahydropyran-2
-yloxy)cyclobentane 4.65% of diisopropylamine dissolved in 100% of tetrahydrofuran under a nitrogen atmosphere. 236' of n-hexane solution of Kosen-butyllithium was added dropwise at -78°C, and 196' of n-hexane solution was added at the same temperature.
Stir for a while.

2Q-(2Q-(
6-Methoxycarbonylhexercis-2-enyl)-138-(1-methoxy-1-methylethoxy)methyl-4Q-(tetrahydropyran-2-yloxy)cyclobentan-IQ-ol [Specification Examples of Tokukan Shobaraichi 1499 Mouse Publication Compound described in 1]5. Slowly drip 500 ml of acetate at -78°C, stir for 20 minutes at the same temperature, then add 69 ml of diphenyl diselenide (C6 public SeSeC 6 days 5) dissolved in 15 ml of tetrahydrofuran, and add 178 qo of
Stir for 20 minutes at room temperature, then for another 20 minutes at room temperature.

The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the extract was poured into a saturated aqueous solution of sodium bicarbonate,
After successively washing with saturated brine, drying over anhydrous magnesium sulfate, and concentrating under reduced pressure, 2Q-(6-
A crude product of phenylselenol (6-methoxycarbonylhexcis-2-enyl)-38-(1-methoxy1-methylethoxy)methyl-4Q-(tetrahydrapyran-2-yloxy)cyclobentan-IQ-ol was obtained. TLC (developing solvent, ethyl acetate:benzene=
1:3):Rna: ○-440 After dropping 2.14% of acetyl chloride at -20qo to the crude product of pyridine 108% dissolved in 60% methylene chloride and the selenium compound obtained previously, Stir at 0°C for 2 hours.

The reaction solution was diluted with diethyl ether, washed sequentially with hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain IQ-acetoxy 2Q-(6 -Phenylselenoid 6-Methoxycarbonylhexacysu2
A crude product of -enyl)-38-(1-methoxy-1-methylethoxy)methyl-4Q-(tetrahydropyran-2-yloxy)cyclobentane was obtained. TLC(
Developing solvent, ethyl acetate:benzene=1:3):Rna=0
The crude product obtained was dissolved in 80% of tetrahydrofuran and then diluted with 0.0% of tetrahydrofuran. Add 20% of hydrochloric acid and stir at 4°C for 4 minutes.

The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate solution, diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was used as a solvent in a mixed solvent of methylene chloride and ethyl acetate (4:1).
Purification by column chromatography on silica gel gave the title compound 5.3 with the following physical properties: TLC (developing solvent, benzene:ethyl acetate=3:・
): R na = 0.2 m (liquid film method): = 3450, 17
30, 1246, 1010 10NMR (CDC13
solution): 6=8.05-7.30 (field, m), 5.50
(crime, m), 5.16 (IH, m), 4.90-4,5
0 (IH, m), 3.72 (ga, s), 2.08 (group,
S).

Example 1 IQ-acetoxy 2 is 1 (6-phenyl selenol 6-
methoxycarbonylhex-2-enyl)-38
- Formyl-4Q-(tetrahydropyran-2-yloxy)cyclobentantoluene 70 N- suspended in the skin
Chlorosuccinimide 1.6 to dimethyl sulfide 1
．． Add 03M and stir at 400 for 3 minutes.

The reaction solution was cooled to -2.0 mm, and 4.37 mm of an alcohol (prepared in the reference example) dissolved in 30 mm of toluene was added and stirred at the same temperature for 2 hours. Reacted milk and triethylamine 2
．． Add 22 I and stir at room temperature for 10 minutes. The reaction solution was diluted with diethyl ether, washed successively with 0.1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was used as a diluting agent in a mixed solvent of cyclohexane and ethyl acetate (3
Purification by column chromatography on silica gel using 1) gave the title compound 314 with the following physical properties. TLC (developing solvent, benzene:ethyl acetate=
3:・):R〆=060.

m (liquid film method): Re=1735, 1730, 1240, 1
018NMR (CC14 solution): 8=10.06(I
H, m), 8.00-7.30 (group, m), 5.46 (
, m), 5.16 (IH, m), 4.77-4.20
(2 days, m), 3.75 (9 days, s), 2.07 (thin,
s).

Example 2 IQ. 4Q-bis(tetrahydropyran-2-yloxy)-2Q-(6-phenylselenol-6-methoxycarbonylhex-cis-2-enyl)-38-formylcyclobentane IQ. 2-yloxy)-2Q-(6
-Phenylselenol 6-methoxycarbonylhexercis-2-enyl)-133-hydroxymethylcyclobentane [compound described in Box 1 of Reference Example 1 of JP-A-52-25745] produced the following physical reaction with a yield of 84.3%. The title compound with the following properties was obtained.

TLC (developing solvent, cyclohexane: ethyl acetate = 2:
1): R〆=0.50 IR (liquid film method): R; 2950, 1733, 1440,
-10NMR of 1137, 1025 (CC14 solution):
6=9. Plaque (IH, m), 7. Group 7, 26 (spot, m)
, 5,45 (ga, m), 4.64 (ga, m), 3.67
(Aim, s).

Example 3 IQ-chloroacetoxy-2Q-(6-phenylselenose-6-methoxycarbonylhexyl)-38-formyl-4Q-(tetrahydropyran-2-yloxy)cyclobentaso In the same manner as in Example 1, IQ-chloro Acetoxy-2Q-(6-phenylcere/-6-methoxycarbonylhexyl)-38-hydroxymethyl-4Q-(
The title compound having the following physical properties was obtained in 100% yield from tetrahydropyran-2-yloxy)cyclobentane [the compound described in Example 4 of the specification of Hakamoseki Publication No. 53-1499].

TLC (developing solvent, benzene: methyl acetate = 4:.):
Rna = ○-5 also IR (liquid film method): R = 2950, 2870, 2725,
1760-172Q1580, 1438 1140, 1
080, 1040, 1028, 97fu 74 & 69 &
Power-1.

NMR (CDC13 solution): 6=102-100 (IH
, m), 80-7.3 (arc, m), 5.6-5.2 (I
H, m), 4.18 (2 days, s), 3.74 (9 days, s
).

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, X is an ethylene group (i.e. -CH_2CH_2
-) or cis-vinylene group (i.e. ▲ mathematical formula, chemical formula,
▼ ), R^1 represents a straight chain or branched alkyl group having 1 to 12 carbon atoms, and R^2 and R^3 may be the same or different, but are hydrogen atoms or hydroxyl groups. Represents a protecting group, R^
4 represents a sulfur atom or a selenium atom, and R^5 is a linear or branched alkyl group having 1 to 4 carbon atoms, or a group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the group, R^6 and R ^7 may be the same or different, but is a hydrogen atom,
A prostaglandin-like compound intermediate represented by the following formula: a chlorine atom, a trifluoromethyl group, a methoxy group, or a nitro group. 2. The compound according to claim 1, wherein R^1 is a straight or branched alkyl group having 1 to 4 carbon atoms. 3 Claim No. 3 in which R^5 is the group ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the group, R^6 and R^7 have the same meaning as stated in claim 1) Compound according to item 1. 4 1α-acetoxy-2α-(6-phenylseleno-
6-methoxycarbonylhex-cis-2-enyl)-
The compound according to claim 1, which is 3β-formyl-4α-(tetrahydropyran-2-yloxy)cyclopentane. 5 1α-acetoxy-2α-(6-phenylseleno-
6-methoxycarbonylhexyl)-3β-formyl-
The compound according to claim 1, which is 4α-(tetrahydropyran-2-yloxy)cyclopentane. 6 1α-chloroacetoxy-2α-(6-phenylseleno-6-methoxycarbonylhex-cis-2-enyl)-3β-formyl-4α-(tetrahydropyran-
2-yloxy)cyclopentane. 7 1α-chloroacetoxy-2α-(6-phenylseleno-6-methoxycarbonylhexyl)-3β-formyl-4α-(tetrahydropyran-2-yloxy)
The compound according to claim 1, which is cyclopentane. 8 1α-dichloroacetoxy-2α-(6-phenylseleno-6-methoxycarbonylhex-cis-2-enyl)-3β-formyl-4α-(tetrahydropyran-2-yloxy)cyclopentane Claim 1 Compounds described in Section. 9. The compound according to claim 1, which is 1α-dichloroacetoxy-2α-(6-phenylseleno-6-methoxycarbonylhexyl)-3β-formyl-4α-(tetrahydropyran-2-yloxy)cyclopentane. 10 1α-trichloroacetoxy-2α-(6-phenylseleno-6-methoxycarbonylhex-cis-2
2. The compound according to claim 1, which is (enyl)-3β-formyl-4α-(tetradropyran-2-yloxy)cyclopentane. 11 1α-trichloroacetoxy-2α-(6-phenylseleno-6-methoxycarbonylhexyl)-3β
The compound according to claim 1, which is -formyl-4α-(tetrahydropyran-2-yloxy)cyclopentane. 12 1α・4α-bis(tetrahydropyran-2-yloxy)-2α-(6-phenylseleno-6-methoxycarbonylhex-cis-2-enyl)-3β-formylcyclopetane according to claim 1 compound. 13 The compound according to claim 1, which is 1α·4α-bis(tetrahydropyran-2-yloxy)-2α-(6-phenylseleno-6-methoxycarbonylhexyl)-3β-formylcyclopentane. 14 1α-acetoxy-2α-(6-phenylthio-
6-methoxycarbonylhex-cis-2-enyl)-
The compound according to claim 1, which is 3β-formyl-4α-(tetrahydropyran-2-yloxy)cyclopentane. 15 1α-acetoxy-2α-(6-phenylthio-
6-methoxycarbonylhexyl)-3β-formyl-
The compound according to claim 1, which is 4α-(tetrahydropyran-2-yloxy)cyclopentane. 16 1α-chloroacetoxy-2α-(6-phenylthio-6-methoxycarbonylhex-cis-2-enyl)-3β-formyl-4α-(tetrahydropyran-
2-yloxy)cyclopentane. 17 1α-chloroacetoxy-2α-(6-phenylthio-6-methoxycarbonylhexyl)-3β-formyl-4α-(tetrahydropyran-2-yloxy)
The compound according to claim 1, which is cyclopentane. 18 1α-dichloroacetoxy-2α-(6-phenylthio-6-methoxycarbonylhex-cis-2-enyl)-3β-formyl-4α-(tetrahydropyran-2-yloxy)cyclopentane Claim 1 Compounds described in Section. 19 The compound according to claim 1, which is 1α-dichloroacetoxy-2α-(6-phenylthio-6-methoxycarbonylhexyl)-3β-formyl-4α-(tetrahydropyran-2-yloxy)cyclopentane. 20 1α-trichloroacetoxy-2α-(6-phenylthio-6-methoxycarbonylhex-cis-2-
The compound according to claim 1, which is cyclopentane)-3β-formyl-4α-(tetrahydropyran-2-yloxy)cyclopentane. 21 1α-trichloroacetoxy-2α-(6-phenylthio-6-methoxycarbonylhexyl)-3β-
The compound according to claim 1, which is formyl-4α-(tetrhydropyran-2-yloxy)cyclopentane. 22 1α・4α-bis(tetrahydropyran-2-yloxy)-2α-(6-phenylthio-6-methoxycarbonylhex-cis-2-enyl)-3β-formylcyclopentane according to claim 1 compound. 23 The compound according to claim 1, which is 1α·4α-bis(tetrahydropyran-2-yloxy)-2α-(6-phenylthio-6-methoxycarbonylhexyl)-3β-formylcyclopentane. 24 The hydroxymethyl group (-CH_2OH) of the compound represented by the general formula ▲ includes numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, all symbols have the same meanings as stated in claim 1]. A general formula ▲ mathematical formula characterized by subjecting it to an oxidation reaction to convert it into (-CHO),
There are chemical formulas, tables, etc. ▼ A method for producing a prostaglandin-like compound intermediate represented by [In the formula, all symbols have the same meanings as above].