JPH0466552A - New phenylethylene derivative, its production and synthetic intermediate therefor - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is phenyl, fluorophenyl, methoxyphenyl, thienyl, oxopyrrolidinyl or pyridyl), esters, amides, lactones or salts thereof. EXAMPLE:trans-(E)-6-[4,4-Bis(4-fluorophenyl)-3-(2-furyl)-1,3-but--adie nyl]-3,4,5,6- tetrahydro-4-hydroxy-2H-pyran-2-one. USE:An antihyperlipemic agent having excellent inhibitory action on 3-hydroxy-3- methylglutaryl-coenzyme A, especially a preventive and treating agent for hypercholesterolemia. PREPARATION:A compound expressed by formula II is reacted with a compound expressed by formula III (R<2> is H or carboxyl-protecting group) to provide a compound expressed by formula IV, which is then reduced and the protecting group, as desired, is removed. The resultant product, as necessary, is further converted into an ester, amide, lactone or salt to afford the objective compound expressed by formula I, the aforementioned esters, amides, lactones or salts thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a novel phenylethylene derivative useful as an antilipemic agent.

(Prior art) Hyperlipidemia is considered to be one of the main causes of arteriosclerosis, an adult disease, and is caused by inhibition of absorption of cholesterol and bile acids, and very low density lipoprotein (VLDL). As a drug that treats and prevents hyperlipidemia by inhibiting the synthesis and secretion of
Name: 2-(4-chlorophenoxy)-2-methylpropanoic acid ethyl ester], probucol [chemical name = 4.4
° -[(1-methylethylidene)bis(thio)]bis[2°6-bis(1,1-dimethylethyl)phenol] and the like are used.

On the other hand, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) is an enzyme that catalyzes the biosynthetic system in which 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) becomes mevalonic acid, the precursor of choretyol. Enzyme A reductase (
Based on the idea that cholesterol biosynthesis can be inhibited by inhibiting HMG-Co A'J,-ductase, there is a desire to develop antilipidemia agents based on such a mechanism of action. Example Eva, 9,9-bis(4-fluorophenyl)3,5-dihydroxy-8-isopropyl-68
-Sodium nonagenate and the like are known.

(Structure and effects of the invention) The present invention is represented by the general formula ((8L, R' represents a phenyl group, a fluorophenyl group, a methoxyphenyl group, a thienyl group, a furyl group, an oxopyrrolidinyl group, or a pyridyl group). phenylethylene derivatives or pharmacologically acceptable esters, amides, lactones or salts thereof.

The object (1) of the present invention is an excellent HMG-C.

It is a pharmaceutical compound that has an A-reductase inhibitory effect and is useful as an antilipidemic agent, especially as a preventive/therapeutic agent for hypercholesterolemia.

The object (I) of the present invention can be used for pharmaceutical purposes in any form of free carboxylic acid, pharmacologically acceptable ester, amide, lactone or salt thereof. Specific examples of esters include lower alkyl esters and phenyl lower alkyl esters; specific examples of amides include:
Examples include unsubstituted amide, mono-lower alkyl amide, and di-lower alkyl amide. Further, as the object of the present invention, those of the general formula 5S) type are particularly preferable as medicines, and in the case of the lactone type object (I-a), the (4R,6S) type is particularly preferable.

The object (1) of the present invention is, for example, - binding margin (however, - R
1 has the same meaning as above. ) is also included. Examples of pharmacologically acceptable salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, heavy metal salts such as zinc salts, ammonium salts, triethylamine salts, Examples include organic amine salts such as pyridine salts, ethanolamine salts, and basic amino acid salts.

The object of the present invention includes all four types of optical isomers based on two asymmetric carbon atoms and mixtures thereof, and in the case of non-lactone object (I), (3RK゛ (However, R1 is have the same meaning as above) and an acetoacetic acid compound represented by the general formula % [) (wherein -COOR2 represents an optionally protected carboxyl group) or a salt thereof. The resulting intermediate (rv') represented by the general formula (wherein R1 and -cooR" have the same meanings as above) or a salt thereof is reduced, and C0OR" is a protected carboxyl group. If desired, the protective group can be removed for production.

As the protecting group for the carboxyl group of the acetoacetic acid compound (III) and the intermediate (■), any protecting group that can be easily removed by conventional treatments such as hydrolysis, reduction, solvolysis, and acid treatment may be used. I can do it. With such a protecting group (-, for example, lower alkyl group, substituted or unsubstituted phenyl lower alkyl group (e.g., Hensyl group, p-
methoxybendiPvM, p-nitrohenzyl group, etc.), henschtyl group, etc.

Aldehyde compound It (II) and acetoacetic acid compound (■)
or a salt thereof is preferably carried out in the presence of a suitable base. As such a base, an alkali metal hydride, lower alkyl lithium (e.g. n-butyl lithium), lithium diisopropylamide, etc. can be used as appropriate. It can also be subjected to the reaction as a salt with a base or an inorganic base. This reaction is carried out under cooling.
Preferably it is carried out at room temperature.

The reduction reaction of intermediate (IV) is carried out using a reducing agent capable of selectively reducing the 1 to 2 moieties, such as an alkali metal borohydride, and a tri-lower alkyl boron (such as l-ethylboron, tri(n-butyl) ) boron), di-lower alkyl-lower alkoxy boron (for example, diethyl methoxy boron), etc., and a combination of an alkali metal boron hydride. When intermediate (IV) is a free carboxylic acid, it may be subjected to the reaction, for example, as an alkali metal salt. This reaction is preferably carried out in a suitable solvent (ether, tetrahydrofuran, dioxane or mixtures thereof) under cooling to room temperature.

When 4-coop2 is a protected carboxyl group, removal of the 3IM (R2) from the above-mentioned reduction reaction composition is carried out by conventional methods such as hydrolysis, reduction, vesicular decomposition, and acid treatment. be able to. For example, by hydrolyzing in the presence of a base and neutralizing with an acid, a free carboxylic acid type target product (r) can be obtained. As a base, alkali metal hydroxide,
Alkali metal carbonate, alkali metal hydrogen carbonate, etc. can be used as appropriate, and as the acid, mineral acids such as hydrochloric acid can be used as appropriate.

Moreover, this reaction is preferably carried out at room temperature or under heating.

Furthermore, the free carboxylic acid type target product (1
The esters, amides and lactones of (I) can be produced from the target compound (I) by conventional methods. For example, the ester can be used to combine the target product (1) with a lower alkanol, phenyl lower alkanol, etc. and an acid catalyst (e.g., hydrogen chloride, sulfuric acid, phenyl lower alkanol, etc.).
-Toluenesulfonic acid or strong acidic ion exchange resin, etc.)
The amide form thereof can be obtained by reacting with, for example, ammonia, lower alkylamine, or di-lower alkylamine. Lactone type object (1-a
) can be obtained by heat-treating the free carboxylic acid type target compound (1). These reactions are preferably carried out in a solvent such as alkanol or toluene.

Further, the target substance can be optically resolved into each optically active substance, if desired. As the resolving agent, there are known ones such as optically active 1-phenylethylamine, 1-(2-naphthyl)ethylamine, α-
Methyl-p-dil-lovenzylamine, 1-(1-naphthyl)ethylamine, etc. can be used. For example, (±)−
trans-(E)-6-C4.4-bis(4-fluorone-1-nyl)-3-(2-thienyl)-1.3-butadienyl)-3. 4. 5. 6-tetrapido-4-hydroxy-2H-bilan-2-one and (R)
- React with (→-)-1-phenylethylamine-
Then, the two diastereoisomers 7- formed are separated by column chromatography, and after hydrolysis, the corresponding optically active free carboxylic acid type target product can be obtained as an acidic substance. An optically active lactone type target product can be obtained by heat treatment.

The object (1) of the present invention or a pharmacologically acceptable ester, amide, lactone or salt thereof is an excellent HMG
-Has a CoA reductase inhibitory effect and is useful as an antilipidemic agent, such as for coronary artery disease, arteriosclerosis, hyperlipidemia, etc.
Familial hypercholesterolemia, xanthomas (xantoma)
It can be used for the treatment, alleviation and prevention of and similar diseases.

The object (1) of the present invention or its ester, amide, lactone, or salt can be administered orally or parenterally, and can be administered by conventional methods, such as tablets, granules, capsules, powders, and injections. It is used as an appropriate pharmaceutical preparation such as.

The dosage varies depending on the administration method, age, weight, and condition of the patient, but is usually about 0.05 to 10 mg per day.
/kg, particularly preferably about 0.1 to 5 mg/kg.

Note that the raw material compound (II) of the present invention is a new compound, for example, J, A, C, S, 73.2716 (195
A compound represented by the general formula (wherein R1 has the same meaning as above) is produced according to the method described in 1), and this is reacted with N-ethylidenecyclohexaneamine and lithium diisopropylamide, or Compound (V
) and 2-[bis(l-methylethoxy)phosphinylcoacetonitrile are reacted in the presence of sodium hydride and then reduced, or compound (■) and diethyl 2
It can be produced by reacting -(cyclohexylamino)vinylphosphonate in the presence of sodium hydride and treating with an acid.

Experimental Example A dimethyl sulfoxide solution of the specimen and "
C-11MGC-11 (substrate) was added. After incubating this solution for 10 minutes, 6N hydrochloric acid was added to stop the reaction, the solution was left at 37° C. for 15 minutes, and then centrifuged. The supernatant was analyzed by TLC (kieselge160F25
4, Merck) and developed with Jl/F:7 Seton-1:1. A 14 cm mevalonolactone spot was collected and the amount of isotope was measured using a scintillation counter (Type 4640 Tri
-Carb.

Paracard) to calculate the amount of mevalonolactone produced. The inhibition rate of II M GR activity by the specimen was calculated from the mevalonolactone amounts in the control group (no specimen added group) and the specimen added group. The results are shown in Table 1.

(Note) The HMGR activity of microsomes is N, L, You.
ng et al.'s method [Method in Enzymology (M
methods in Enzymology), 71.
498 (1981)).

Table 1 HM GR inhibitory effect (%) Example 1 (1) (E)-5,5-bis(4-fluoropheny/l/)-4-phenyl-2,4-pentadienitrile 900 μ 1.5M in tetrahydrofuran 10d solution
Toluene solution of diisobutylaluminum hydride 7.0
ml and stir for 15 minutes at 0°C.

After adding 10% hydrochloric acid and extracting with ethyl acetate, the solvent was distilled off, and the residual aroma was purified by silica gel column chromatography (solvent: n~
Separate and purify with hexane:ethyl acetate-20:1) to obtain (E)-5,5-bis(4-fluorophenyl)-4
~600 mg of Fuuniru 2,4-pentagenal are obtained as yellow crystals.

Yield 66% m, p, 120-123°C MS (m/z): 346 (M”) (2) 60
% sodium hydride 130 mg, tetrahydrofuran 3
A mixture of 380 mg of mft and methyl acetoacetate is stirred for 10 minutes at room temperature under an argon atmosphere. After reaction-5
Cooled to ~0°C, added dropwise 2.0d of 1.6M n-methyllithium in hexane, stirred at 5°C for 15 minutes, and (E) -5,5-bis(4-fluorophenyl) −
A solution of 560 mg of 1-phenyl-2,4 pentadienal in 7 ml of tetrahydrofuran was added dropwise at 15°C for 15 minutes.
Stir for a minute.

After the reaction, ice and saturated ammonium chloride aqueous solution are added, extracted with ethyl acetate, and the solvent is distilled off. The residue was separated and purified by silica gel column chromatography (vehicle: anhexane:diyl acetate 2=1) to give (E)-9,9-bis(4-fluorophenyl)-5-hydroxy-3-oxo- Methyl 8-phenyl 6.8-nonadienoate 550
mg as a yellow oil.

Yield 74% MS (m/z): 462 (M”), 346IR
v (cm-'): 3500, 1740.
1710, 1590, 1500 (3) 520 mg of Motoichi, 4 ml of tetrahydrofuran, and 1.8 zl of IM triethylborane to tetrahydrobilane! The mixture is stirred at room temperature under an argon atmosphere, bubbled with 1 ml of air, and stirred at room temperature for 10 minutes.

Cool to -70°C, sodium borohydride 85+
Add ++g and 1.1 mfl of methanol and leave at the same temperature for 30 minutes.
Stir for a minute. Add 30% hydrogen peroxide solution little by little, stir at room temperature for 20 minutes, add water, extract with ethyl acetate, wash and dry, and then evaporate the solvent. The residue was separated and purified by silica gel column chromatography (vehicle; n-hequinane:ethyl acetate-1=1) to obtain (3R3,5SR)-(E
)-9,9-bis(4-fluorophenyl)-3,5-
430 ml of methyl dihydroxy-8-phenyl-6,8-nonadienoate is obtained as a colorless oil.

Yield 82% MS (m/z): 464 (M”), 20315
90, 1500 (4) A mixture of 410 mg of Honjima, 1 d of methanol, and 1.1 ml of jN aqueous sodium hydroxide solution was heated to 20 mL at room temperature.
Stir for a minute. After the reaction, the solvent was distilled off, and the residue was purified using column chromatography packed with a nonionic adsorption resin (product name: Diaion HP2O, manufactured by Mitsubishi Chemical Corporation) (solvent: methanol:
Water-1: 1) (3R3,5SR)-(E)-9,
Sodium 9-bis(4-fluorophenyl)-35-dihydroxy-8-phenyl-6,8-nonadienate 3
00 mg is obtained as a pale yellow powder.

Yield 72% FABMS (m/z): 495 (M'(-Na
), 473 (M"+1), 115 ■ [7v (cm-') +3360, 1
590.1570, 1500 Examples 2 to 6 (1) The products of Reference Examples 6 to 10 described below were converted to Example 1-(1)
The following treatment is carried out in the same manner as above to obtain the compounds listed in Table 2 below.

Table 2 (3) The product of (2) above is treated in the same manner as in Example 1-(3) to obtain the (3R3,5SR) type compounds listed in Table 4 below.

Table 4 (2) The product of (1) above is treated in the same manner as in Example 1-(2) to obtain the compounds listed in Table 3 below.

Table 3 (4) The product of (3) above is treated in the same manner as in Example 1-(4) to obtain the (3R3,5SR) type compounds listed in Table 5 below.

Table 5 Example 7 (1) To a suspension of 0.76 g of 62.4% sodium hydride in 5 ml of tetrahydrofuran, add diethyl 2-
(cyclohexylamino)vinylphosphonate) 3.68
g of tetrahydrofuran (20 mh volume) was added dropwise, and the mixture was stirred for 20 minutes. To this, 2.2
Add 6 g of 15 ml of tetrahydrofuran solution and stir at room temperature for 1 hour and at 50°C for 1 hour. After distilling off the solvent from the reaction solution, ice water was added and the mixture was extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off and the residue was diluted with 50% terahydrofuran.
d. Add 25 ml of 5% hydrochloric acid and reflux for 45 minutes. The solvent was distilled off, water was added, and the mixture was extracted with chloroform. After washing and drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (vehicle: ethyl acetate: n-hexane-1:
1) to obtain 2.08 g of (E)-5,5-bis(4-fluorophenyl)4-(3-pyridyl)-2,4-pentagenal.

Yield 85% m, p, 129-130°C (recrystallized from ethyl acetate-n-hexano) MS (m/z): 347 (M'), 31B (2)
The main island was treated in the same manner as in Example 1-(2) (E) 9.9
-bis(4-fluorophenyl)-5hydroxy-3-
Methyl oxo-8-(3-pyridyl)6.8-nonadiene is obtained as an oil.

MS (m/Z): 463 (M'), 31
8(3) The main island was treated in the same manner as in Example 1-(3).
R3,5SR) (E)-9,9-bis(4-fur-5-dihydroxy-8-(orophenyl)-3°3-pyridyl)-6° methyl nonadenoate is obtained as an oil.

MS (m/z): 465 (M'), 318 (4)
The main purpose was processed in the same manner as in Example 1-(4) (3R3,5
SR) (E) 9.9-Bis(4-fluorophenyl)-3,5-dihydroxy-8-(3-pyridyl)-6,8-nonadiene acid is obtained as a powder.

FABMS (m/z): 496 (M'+Na) Example 8 (1) 3.3--bis(4-fluorophenyl)-2(
2-oxo-1-pyrrolidinyl)acrylicaldehyde was treated in the same manner as in Example 7-(1) to obtain (E) 5.5-bis(4-fluorophenyl)-4(2-oxo-1-pyrrolidinyl)- 2,4-pentadienal is obtained.

m, p, 153.5-155°C MS (m/z): 353 (M”) 324.268
(2) Treat the main island in the same manner as in Example 1-(2) (E)
9.9-Bis(4-fluorophenyl)-5hydroxy-3-oxo-8-(2-oxo-1pyrrolidinyl)-
Methyl 6,8-nonadienoate is obtained as an oil.

MS (m/z): 469 (M゛), 38417
20, 1680 (3) The main island was treated in the same manner as in Example 1-(3) (3R
3,5SR) -(E)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(2-oxo-1-pyrrolidinyl)-6,8-methyl nonadienate as an oil. obtain.

MS (m/z): 471 (M'), 386
(4) The main island was treated in the same manner as in Example 1-(4) (3R
3,5SR)-(E)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(2-oxo-
Sodium 1-pyrrolidinyl)-6,8-nonadienate is obtained as a powder.

FABMS (m/z): 502 (?vl”+Na
) 1600, 1575 Example 9 (1) (3R3,5SR)-(E)-9,9-bis(4-fluorophenyl)-3,5-dihydroxydi8
- Add 10% hydrochloric acid to a mixture of 2 g of sodium phenyl-6,8-nonadienate and 20 ml of ethyl acetate under water cooling, and stir at room temperature for 10 minutes. After separating the organic layer, the solvent was distilled off to give (3R3,5SR)-(E)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-
1.80 g of 8-phenyl 6,8-nonadiene acid are obtained as a foam.

Yield 99% MS (m/z): 450 (M”), 433 (2
) A mixture of 1.5 g of the main island and 50 ml of toluene was placed in a reflux dehydrator (Dean) filled with molecular sieves 4A.
5 tark) for 3 hours. After distilling off the solvent, the residue was recrystallized from a mixture of isopropyl ether and n-hexane to give (±)-trans-(E)6-C4,4-bis(
0.98 g of 4-fluorophenyl)3-phenyl-1,3-butadienyl]-3.5.6-tetrahydro-4-hydroxy-2H-pyran-2-one are obtained as colorless needles.

Yield 69% m, p, 135-137°C MS (m/z): 432 (M”), 317
Example 10 Sodium (3R3,5SR)-(E)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy8-(3-pyridyl)-6,8-nonadienate 482.5■
1 trdl of IN hydrochloric acid is added to a 15d aqueous solution of the mixture, and the mixture is extracted with chloroform. After drying and filtration, the solvent is distilled off. 50 d of toluene was added to the residue, and the mixture was heated in a reflux dehydrator (Dean 5tark) filled with 4A molecular sieves.
Reflux for an hour.

The reaction solution was washed, dried, filtered, the solvent was distilled off, and the residue was recrystallized from a mixture of ethyl acetate and -hexane to give (±)-trans-(E)-6-(4,4-bis( 4-fluorophenyl)-3-(3-pyridyl)-1,3-butadienyl)-3,4,5,6tetrahydro-4-hydroxy-
2H-pyran-2-one 341■ is obtained as light brown prismatic crystals.

Yield 79% m, p, 172-172.5°C MS (m/z): 433 (M”), 318 Examples 11-12 Example 2-(31 or 5-(3+) product 1
(4) and treated in the same manner as in Example 9 to obtain the trans-type compounds listed in Table 6 below.

Table 6 Example 13 (1)(±)-trans-(E)-6(4,4bis(4
-fluorophenyl) -3-(2-thienyl)-1,
3-butadienyl)-3,4,5゜6-tetrahydro-
21.93 g of 4-hydroxy-2H-pyran-2-one
and R-(+)-1 phenylethylamine 10.46
g of toluene 1 LOP! The solution is heated to reflux for 3 hours. After the reaction, 10% hydrochloric acid was added while cooling with water, and the mixture was extracted with ethyl acetate. After washing, drying and filtering the ethyl acetate layer, the solvent was distilled off,
The residue was subjected to silica gel column chromatography (solvent: ethyl acetate: n-hexane = 2:1), and the fraction eluted first had the following physical property values (3R"5S")
-(E)-N-((R)-1 phenylethyl l-9,9
20.28 g of -bis(4-fluorophenyl)-3,5-dihydroxy-8-(2thienyl)-6,8-nonadienamide (hereinafter referred to as the compound) are obtained as a colorless caramel.

Yield 37% [α) +38.2 (c・1.0.chloroform) MS (m/z): 559 (M”) Next, the fraction eluted later had the following physical properties:
(5R′″, 3S″)-(E)-N-((R)■-phenylethyl)-9,9-bis(4-fluorophenyl)
-3,5-dihydroxydi8(2-thienyll-6,8
-Nonadienic acid amide (hereinafter referred to as compound B) 11
．． 52 g are obtained as colorless caramel.

Yield 41% [α) +37.6 (c=1.0.chloroform) MS (m/z): 559 (M”)
(2) Compound vIJA 10. 28 gnoIri/-ru1
30m! 8g of sodium hydroxide in a solution of 30ml of water1?8
The mixture was heated under reflux for 112 hours under an argon atmosphere. After the reaction, the solvent was distilled off, diluted with ice water, acidified with 10% hydrochloric acid, and extracted with ethyl acetate. After washing, drying, and filtering the ethyl acetate layer, the solvent was distilled off, and 200% of toluene was added to the residue.
ean 5 tark) for 7 hours under reflux. After cooling, ethyl acetate was added, washed, dried, filtered, and dried under reduced pressure. The residue was subjected to silica gel column chromatography (solvent;
Purified with ethyl acetate:n hexane-1:3) and recrystallized from a mixture of ethyl acetate and isopropyl ether (+)
-trans-(E)-6-(4,4-bis(4-fluorophenyl)-i (2-thienyl)1,3-butadienyl) -3,4,5,6-tetrahydro-4-hydroxy-2H 3.59 g of pyran-2one are obtained as colorless needles.

Yield 44% m, p, 159-161.5°C [α) +98.6 (cm1.chloroform) MS (m/z): 438 (M”)I
Rv (cm-'): 3480. 170
5゜Compound B735■ was also treated in the same manner to give ()-trans-(E)-6-(4,4-bis(4fluorophenyl)-,3-(2-thienyl)1,3-butadienyl. )-3,4,5,6-tetrahydro-4-hydroxy-
360 ml of 2H-pyra-7-2-one is obtained as colorless needles.

Yield 62% m, p, 160.5-163°C (recrystallized from ethyl acetate-isopropyl ether mixture) [α) -97,7 (c 1.0.chloroform) M
S (m/z): 438 (M”) Example 14 (+)-trans-(E)-6-(4,4-bis(4-
Fluorophenyl'I-3-(2-thienyl)-1,
3-butadienyl)-3,4,5,6tetrahydro4
-Hydroxy-2H-pyran-2-one 2.4 g of ethanol-1 was added to a 30 ml solution of 1 liter of IN=sodium hydroxide aqueous solution, and the mixture was returned to room temperature and stirred for 0.5 hour. After distilling off the ethanol, the residue is treated with a nonionic adsorption resin (product name:
Diaion HP-20, manufactured by Mitsubishi Kasei Co., Ltd.) was purified using packed column chromatography (solvent: methanol:water - 3:2).
+)-(3R",5S")-(E)-9.9-bis(4-fluorophenyl)-3.5-dihydroxy-8
2.42 g of sodium -(2-thienyl)-6,8-nonadienate are obtained as a pale yellow powder.

Yield 92% [α]+11.1 (cm1.0, methanol)F
ABMS (m/z): 5 0 1 (M”10N
a) IRv (cm-'): 338
0. 1600(-)-) Lance-(E)-6-(4
,4-bis(4-fluorophenyl)-3(2-thienyl)-1,3-butadienyl)-3.4.5.6tetrahydro-4-hydroxy-2H-pyran-2-one 3
60 ■ in the same way (-) - (3R", 5S
”)-(E)-9.9-bis(4fluorophenyl)-3.5-dihydroxy-8(2-thienyl)-6.
254 ml of sodium 8-nonadienate is obtained as a colorless powder.

Yield 64% [α) -11.0 (cm1.0, methanol) FABMS (m/z): 501 (M
"10Na) Example 15 (1)(±)-trans-(E)-6-(4,4bis(4-fluorophenyl)-3-(2-furyl)-
After treating 1.68 g of 1.3-butadienyl)-3.4,5.6tetrahydro-4-hydroxy-2H-pyran-2-one in the same manner as in Example If-(11), silica gel column chromatography (solvent: ethyl acetate) :n-hexane-2=3), and the fraction eluted first has the following physical property values (3R", 5S")-(E)-N-(
(R)-1 phenylethyl)-9.9-bis(4-fluorophenyl)-3.5-dihydroxy-8-(2furyl)-6.8-nonadienamide (hereinafter, compound C
660 mg (referred to as ) are obtained as a pale yellow foam.

Yield 30% MS (m/z): 543 (M”) Next, the fraction eluted later had the following physical property values (5
R",3S")-(E)-N-((R)-1-phenylethyl19.9-bis(4-fluorophenyll-3,
950 mg of 5-dihydroxy-8(2-furyl)-6,8-nonadienic acid amide (hereinafter referred to as Compound Ri) are obtained as a pale yellow foam.

Yield: 44% MS (m/z): 543 (M”) (2) 630 mg of compound C was treated in the same manner as in Example 13-(2) to obtain (±)-1-lance-(E)-6-C4゜4-bis(
4-fluorophenyl) -3-(2furyl)-1,3
-butadienyl)-3,4,56-te]-rahydro4
330 mg of -hydroxy-28-bilan-2-one are obtained as pale yellow crystals.

Yield 67% m, p, 160-162°C (recrystallized from ethyl acetate-n-hexane mixture) [α) +102.5' (c=1.09.chloroform) MS (m/z): 422 (M
”) In addition, 920 mg of compound D was treated in the same manner to give ()-
trans-(E)-6-(4,4-bis(4fluorophenyl)-3-(2-furyl)-13-butadienyl)
-3,4,5,6-tetrahydro-4-hydroxy-2
4-40 mg of I-(-bilan-2-one are obtained as a pale yellow foam.

Yield 62% (α'J -98,5 (c=1.12 r-to
Porum) MS (m/z): 422 (
M”) Example 16 (11-1-lance (E) [4,4 Hes(4-fluorophenyl)-3-(2-furyl 1-1
．． 3-butadienyl]-3.4,5.6tetrahydro-4-hydroxy-21(-pyran-2-one (310 mg) was treated in the same manner as in Example 14 to obtain (-)-(3R", 5S
“)-(E)-9,9bis(4-fluorophenyl)
-3,5-dihydroxy-8-(2-furyl)-6,8
- Obtain 280 mg of sodium nonagenate as a colorless powder.

Yield: 83% [α) -8,0° (c=1.0.water) (350 mg of sodium 2-furyl-6,8-nonadienate is obtained as a colorless powder.

Yield 74% [α) +7.8° (C・1.0.water)(-)-trans-(E)-6-(4,4-bis(4-fluorophenyl)-3-(2- Furyl 1-1,3-butadienyl)-3,4,5,6tetrahydro 4-hydroxy-
430 mg of 2H-pyran-2-one was treated in the same manner to give (10)-(3R(1,531″)-(E)-9,9-bis(
4-fluorophenyl l-3,5-dihydroxy-8 [
Production of raw material compounds] Reference example 1 (1) 1.9 g of benzyl chloride, 0 magnesium
．． 37 g of ether 13- and a trace amount of iodine are stirred, and a solution of 2.18 g of 4,4'-difluorobenzophenone in ether 10 mfi-tetrahydrofuran 5 Wi is added dropwise to the mixture under water cooling. 10 at room temperature after dropping
After stirring for a minute, the mixture was cooled to 0°C, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. After washing and drying the extract, the solvent was distilled off to obtain 3.36 g of 1,1-bis(4-fluorophenyl)-2-phenylethyl alcohol as an oil.

Add 400 μl of Honjima nitoluene and 400 μl of p-toluenesulfonic acid monohydrate, and reflux for 1 hour to dehydrate. After the reaction, water was added and the mixture was extracted with ethyl acetate, washed and dried, and the solvent was distilled off to obtain 3.04 g of 1.1-bis(4-fluorophenyl)-2-phenylethylene.

m, p, 88-90℃ (2) Keep 3.0g of the main island and 20d of acetic acid below 40℃ and drop 1.88g of bromine. After the completion of the dropwise addition, water is added, and after extraction with ethyl acetate, the solvent is distilled off. . The obtained crude crystals are
- recrystallized from hexane to 1-bromo-2,2-bis(
4-fluorophenyl)-1-phenylethylene 2.6
5 g are obtained as pale brown needles.

m, p, 103-103.5°C Reference Examples 2-3 (4-fluorophenyl)methyl chloride or (4-methoxyphenyl)methyl chloride is treated in the same manner as in Reference Example 1 to obtain the following compounds in Table 7.

Table 7 Reference Example 4 fl) 10.9 g of 4,4-difluorobenzophenone,
A small amount of iodine is added to a mixture of 16.7 g of ethyl bromoacetate, 8.2 g of zinc powder, and 80 g of a benzene-toluene (1:1 v/v) mixture, and the mixture is refluxed. After 45 minutes, the reaction solution was poured into an ice-diluted sulfuric acid mixture, filtered, extracted with ethyl acetate, washed, dried, filtered, and the solvent was distilled off. To the obtained yellow solid were added 10 g of ethanol 150-1 hydroxide and 40141 water and refluxed for 1 hour. After the reaction, the solvent was distilled off, water was added, and after washing with ether, the mixture was poured into an ice-dilute sulfuric acid mixture.

The precipitated crystals were collected by filtration and dried to obtain 12.8 g of a light brown solid.

The main island was dissolved in 200 ml of ethanol, and 25 d of thionyl chloride was added dropwise while cooling with water. After stirring at the same temperature for 1 hour, stirring at room temperature for 1 hour, and refluxing for another 1 hour, the solvent was distilled off and the residue was purified by silica gel column chromatography (solvent: ethyl acetate: n-hexane - 1:15). Separation and purification yields 12.8 g of ethyl 3.3-bis(4-fluorophenyl)acrylate as a pale yellow solid.

m, p, 5(] to 61° C. (2) The main island is treated in the same manner as in Reference Example 1-12) to obtain ethyl 2-furomo-3.3-bis(4-fluorophenyl)acrylate.

m, p, 73-79°C Reference Example 5 (1) ■-Flomo 2,2-bis(4-fluorophenyl)-1-phenylethylene 2.8 g and ether 28
The mixture of PRIl was stirred at -50°C, a solution of 1.6M n-butyllithium in n-hexane was added, and the mixture was stirred at the same temperature.
Stir for 0 minutes. Dimethylformamide 8 is added to the reaction mixture.
After adding 20 nw, a saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate. After evaporating the solvent, the residue was separated and purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate = 15:l), and ethyl acetate-n
- Recrystallized from a hexane mixture to produce 3.3-bis(4-fluorophenyl)-2-phenylacrylaldehyde.2.
12 g are obtained as pale yellow needles.

m, p, 147.5-148°C (A mixture of 187 mg of 2160% sodium hydride and tetrahydrofuran 14- was cooled with ice, and diisopropyl cyanomethyl phosphate 94511N of tetrahydrofuran 3
Add solution d dropwise and stir at room temperature for 20 minutes. The reaction mixture was cooled on ice again and 3,3-bis(4fluorophenyl)-
A solution of 1.23 g of 2-phenylacrylaldehyde in 3 ml of tetrahydrofuran is added dropwise. Stir for 5 minutes at room temperature, add shallow water, and extract with ethyl acetate. After evaporating the solvent, the residue was separated and purified using silica gel column chromatography (solvent: n-hexane:ethyl acetate-20:1) to obtain (E)-5.
,5-bis(4-fluorophenyl)-4-phenyl-
1.2 g of 2,4-pentadienitrile are obtained as colorless needles.

m, p, 130-133°C Reference Example 6 (1) 4.98 g of ethyl 2-bromo-3,3-bis(4-fluorophenyl)acrylate, 6.07 g of 2-tri(n-butyl)stannylpyridine, A mixture of 375 ml of bis(triphenylphosphine)palladium(n) chloride and 20 m2 of dioxane is refluxed for 18 hours. After the reaction, an aqueous potassium fluoride solution is added, and the mixture is extracted with ethyl acetate. After filtration, the mixture is washed and dried. After filtration, the solvent is distilled off. The residue was separated and purified using silica gel column chromatography (solvent: ethyl acetate:n-hexane-1:9) to obtain 4.14 g of ethyl 3,3-bis(4-fluorophenyl)-2-(2-thienyl)acrylate. is obtained as a yellow solid.

m, p, 77.5-80°C (2) Main island 1.0g, methylene chloride 10PnE and 1.
A mixture of 5.4 mN of 5M diisobutylaluminum hydride in toluene is stirred at Q'c for 10 minutes.

After the reaction, 10% hydrochloric acid and then water were added, followed by extraction with ethyl acetate. The solvent was distilled off to give 3,3-bis(4-fluorophenyl)-2-(2-thienyl)allylic alcohol 770 μ
is obtained as colorless crystals.

m,, p, 108-110°C (3) 2.31 g of the main island, 2.3 g of pyridinium chlorochromate, and 23111 g of methylene chloride. After stirring the mixture at room temperature for 40 minutes, ether was added and the mixture was decanted. The organic layer was separated, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate-5=1) to obtain 3.3-bis(4-fluorophenyl)- 1.75 g of 2(2-thienyl)acrylaldehyde are obtained as yellow leaves.

m, p, 143-145°C (4) Treat the main island in the same manner as in Reference Example 5i2) ()E)
5.5-bis(4-fluorophenyl)-1-(2--
ffnyl)-2,4-pentadienitrile is obtained.

m, p, 167-169°C Reference Examples 7-10 The corresponding starting compounds were treated in the same manner as in Reference Example 5 or 6 to obtain the compounds listed in Table 8 below.

Table 8 Reference Example 11 Reference Example 6-(1) to (3) 3.3-bis(4-fluorophenyl)-2-(3-
pyridyl)acrylicaldehyde is obtained.

m, p, 118-120°C Reference Example 12 (1) ethyl 2-bromo-3,3-bis(4-fluorophenyl)acrylate 1 g and tetrahydrofuran 6
40 mL of a 1.5M toluene solution of diisobutylaluminum hydride at 0 to 5°C under an argon stream to a mixture of
After dropping, stir at room temperature for 30 minutes. The reaction mixture was poured into 10% hydrochloric acid-ice, the solvent was distilled off, and the mixture was extracted with ethyl acetate. The solvent was distilled off and 2-7'romo3,3-bis(4
-fluorophenyl)proper-2-ene-1-:t-)
9.77 g of this product was obtained as an oil.

(2) A mixture of 9.77 g of main island, 40-2-pyrrolidone, and 20 g of copper powder was heated to 55% at 150°C under an argon stream.
After heating and stirring for a minute, and cooling, water and ethyl acetate are added, insoluble matter is filtered off, and the organic layer is separated. Distill the solvent,
The resulting residue was subjected to silica gel column chromatography (
Separation and purification using chloroform:methanol (solvent: 40:1) and recrystallization from a mixture of ethyl acetate and n-hexane yielded 3,3-bis(4-fluorophenyl)-2-(2-oxo-1-pyrrolidinyl). ) 7.16 g of prop-2-en-1ol are obtained as colorless needles.

m, p, 129 to 131°C (3) After refluxing a mixture of 6.5 g of main island, 21.2 g of manganese dioxide, and 65 g of methylene chloride for 2 hours, insoluble materials are filtered off and the solvent is distilled off. The residue was recrystallized from n-hexane to give 3,3-bis(4-fluorophenyl)-2-(2
-oxo-1-pyrrolidinyl)acrylicaldehyde6.
19 g are obtained as yellow needles.

m, p, 107-109℃

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 is a phenyl group, fluorophenyl group, methoxyphenyl group, thienyl group, furyl group, oxopyrrolidinyl group, or A phenylethylene derivative represented by (representing a pyridyl group) or a pharmacologically acceptable ester, amide, lactone or salt thereof. 2. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 represents a phenyl group, fluorophenyl group, methoxyphenyl group, thienyl group, furyl group, oxopyrrolidinyl group, or pyridyl group.) The compound according to claim 1, which is represented by: 3, trans-(E)-6-[4,4-bis(4-fluorophenyl)-3-(2-furyl)-1,3-butadienyl]-3,4,5,6-tetrahydro-4- Hydroxy-2H-pyran-2-one. 4, trans-(E)-6-[4,4-bis(4-fluorophenyl)-3-(2-thienyl)-1,3-butadienyl]-3,4,5,6-tetrahydro-4- Hydroxy-2H-pyran-2-one. 5. The compound according to claim 1, 2, 3 or 4, which is an optically active compound. 6. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 represents a phenyl group, fluorophenyl group, methoxyphenyl group, thienyl group, furyl group, oxopyrrolidinyl group, or pyridyl group, - COOR^2 represents an optionally protected carboxyl group.) By reducing the compound represented by or its salt, -COOR^
When 2 is a protected carboxyl group, the protecting group is optionally removed and, if necessary, the product is characterized in that it is a pharmacologically acceptable ester, amide, lactone or salt thereof. Process for producing phenylethylene derivatives represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (where R^1 has the same meaning as above) or its pharmacologically acceptable ester, amide, lactone, or salt . 7. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 represents a phenyl group, fluorophenyl group, methoxyphenyl group, thienyl group, furyl group, oxopyrrolidinyl group, or pyridyl group.) An aldehyde compound represented by the formula CH_3COCH_2COOR^2 (wherein -COOR^2 represents an optionally protected carboxyl group) is reacted with an acetoacetic acid compound or a salt thereof, and the general formula thus obtained is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, R^1 and -COOR^2 have the same meanings as above.) By reducing the compound or its salt, -
If COOR^2 is a protected carboxyl group,
General formulas ▲Mathematical formulas, chemical formulas, tables, etc., characterized in that, if desired, the protecting group is removed and, if desired, the product becomes its pharmacologically acceptable ester, amide, lactone or salt▼ (However, R^1 has the same meaning as above.) A method for producing a phenylethylene derivative or a pharmacologically acceptable ester, amide, lactone or salt thereof. 8. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 represents a phenyl group, fluorophenyl group, methoxyphenyl group, thienyl group, furyl group, oxopyrrolidinyl group, or pyridyl group.) An aldehyde compound represented by