JPS6259258A - Punaglandin compound and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is 1-10C alkyl; R<2> is OH- protecting group or H; A is H and B is OH or A and B together form a bond; *represents optically active or inactive C atom). USE:A carcinostatic agent and antiviral agent. It exhibits strong proliferation- inhibiting activity against L1210 leukemia cell and has proliferation-inhibiting action also against herpes simplex virus. PREPARATION:The compound of formula I can be produced by the aldol conden sation reaction of the cyclopentenone compound of formula II (R<20> is OH- protecting group) with the aldehyde of formula III in the presence of lithium diisopropylamide in a solvent such as ether at -100-+50 deg.C.

Description

[Detailed description of the invention] <Industrial application field> TECHNICAL FIELD The present invention relates to punagrangins and a method for producing the same.

More specifically, the present invention has excellent anticancer effects.

This invention relates to a compound with a punaglandin-like structure that has pharmacological effects such as antiviral effects, and a method for producing the same.

<Prior art> In recent years, punaglandin, a purustabrangin related substance expressed by the following formula, was isolated from Teleato riisei, which grows epiphytically on the bottom of a boat collected on Oahu (Monthly Yakuji 24141). 1982)
, Scheuer et al., The Journal
Chemical Engineering 107, 2976 (1985
)] is known to have a strong anticancer effect [Fukushima Zohei et al., Abstracts of the 43rd Japanese Cancer Society 905 (19
84)].

On the other hand, since prostaglandin A strongly suppresses DNA synthesis, the possibility of prostaglandin A as an antitumor agent has been reported [Biochemical &amp;
Piofuphysical Research Communications (
Biochem, Biophys, Res, Commu
n, ) t 87 +795*1979; W. A. Turner et al.
Prosta-grandins Re1at,
Lipids L 2 + 365-8 (1982)].

In addition, prostaglandin related compounds represented by the following formula are found in Okinawa corals [Okinawa soft coral: Gragrarif viridis].
clavularia viridis)), and is known to have pharmacological anti-inflammatory and anticancer effects [Etchi Kikuchi (1, Ki
kuchi) et al., Tetrahedron Letters (Tez
rahadron Lett, ), 23 *517
1 (1982); M. Kobayashi (M.

Tetrahedron Lett, ) + Q
+5331 (1982); see Fukushima Zohei, Cancer and Chemotherapy, 10°1930 (1983)]. In addition, this prostaglandin analog compound has also been synthesized [E. J. Corey et al.

Journal of the American Chemical Society (J, Am, Chem, Soc, ), 1
06 +3384 (1984)].

<Object of the Invention> These above-mentioned compounds are isolated from natural resources, and it is difficult to secure sufficient quantities for use as pharmaceuticals. The present inventors focused on this point and conducted intensive research with the aim of chemically synthesizing punaglandins that exhibit strong anticancer activity. The present invention was achieved based on the discovery that punaglandins can be obtained industrially advantageously by subjecting them to fulldol condensation.

Therefore, an object of the present invention is to provide punaglandins having excellent anticancer and antiviral effects, and an industrially advantageous method for producing the same.

<Disclosure of the Invention> The present invention relates to punagrandins represented by the following formula [I] and a method for producing the same.

In the above formula CI], R1 represents an alkyl group having 1 to 10 carbon atoms.

Examples of the unsubstituted furkyl group having 1 to 10 carbon atoms include methyl, ethyl, n-propyl, inpropyl, n-
Butyl, formula - butyl.

t-7'tyl, n-pentyl, n-hexyl.

Linear or branched ones such as n-heptyl, n-ocnal, n-nonyl 9n-decyl and the like can be mentioned.

In the above formula (1'), C and R1 represent a hydrogen atom or a hydroxyl group-protecting group.
Examples include a 77 syl group, a tri(C, to C?) hydrocarbon-silyl group, or a group that forms a 7 cetal bond with the oxygen atom of a hydroxyl group.

C! -C, acyl groups include, for example, acetyl, propionyl, n-styryl, ingtyryl, n-vanlyl, invaleryl, caproyl, ena/toyl, be/diyl, and the like. Among these, sC2~C
8Aliphatic 7syl groups such as acetyl, n-butyryl or imbutyryl, caproyl or benzoyl are preferred. Tri(C5-C?) hydrocarbon silyl group and 1° C. include tri(C+-C4) alkylsilyl group such as trinotylsilyl, triethylsilyl, t-butyldimethylsilyl group; t-7' tyldiphenylsilyl group Preferred examples include diphenyl(CI-C4)alkylsilyl or tribenzylsilyl groups such as.

An example of a group that forms a 7-cetal bond with the oxygen atom of a hydroxyl group is methoxymethyl.

1-Eng)-? diethyl, 2-methoxy 2-p-vir,
3 ,1,
Mention may be made of the 03hex-4-yl group.

Among these, 2-tetrahydropyranyl.

2-tetrahydrofuranyl, 1-ethoxyethyl, 2-
Methoxy-2-propyl, (2-methoxye)dFshi)
Methyl or 6,6-dimethyl-3-oxa-2-oquine-bicyclo[3°1.0]hex-4-yl group is preferred. Among these, hydrogen atoms and trimethylsilyl groups are particularly preferred.

A and B are a hydrogen atom and B a hydroxyl group, or A and B are KM mutually and represent one bond.

In other words, the punagrandins represented by the above formula (1) are A.

According to the definition of B, it represents a punaglandin represented by the following formula (la) and a punaglandin represented by the following formula (Ib).

These bunagransifs represented by the above formulas (Im) and (Ib) have stereoisomers derived from the chirality of the carbon atoms indicated by the bone marks, but in the present invention, any of these stereoisomers or a mixture thereof in any proportion.

The Bunagra/gins of the present invention are produced by the following method. That is, cyclobentenones represented by the following formula (n) are subjected to an aldol reaction with aldehydes represented by the following formula, and if necessary, ``Production method of punagrandins produced by the following formula CIaJ and the following formula (I
The following formula (l) is characterized in that the punaglandins represented by
b) This is a method for producing punagrandins represented by:

In the above formula (Ia'), R'' represents a hydroxyl group-protecting group, and specific examples of such Rlo include those similar to those exemplified as the hydroxyl group-protecting group of R2, in particular)
IJ (C, -C, hydrocarbon) silyl group is preferably used.

The starting material (II) can be produced by a route as shown in reaction scheme A below using a method separately proposed by the present inventors.

Scheme A The aldehyde represented by the above formula (III) can be obtained by a route as shown in reaction scheme B below.

Scheme B (III) The compound of the above formula (II) and the aldehyde of the above formula (I[I) are subjected to a fuldol condensation reaction.

The reaction is carried out in a solvent in the presence of a basic compound. As a reaction solvent for basic compounds 2, Toeha Literature: Eng., Chi., Nielsev (A, T.

N1elaen), W. J. Houlinan, Orkaninck
React 7 (Org, React,), I 6
, 1 (196B);
, House ), 'Modern 5ynthetic Reactions
na), '2ndEd,, <Njamiy
(Benjamin) (1972).

p629; New Experimental Chemistry Course-j4. + II 73
6 + ff1851 etc. are selected. The fuldol condensation reaction is preferably carried out using cyphthylboron trifluoromethanesulfonic acid in the presence of metal amides such as lithium diimpropylamide, lithium diethylamide, lithium bistrimethylsilylamide; or tertiary amide 7 such as triethylamine, diisopropylethylamine, and triglythyl 7mine. Sialgyl boron trifluorometa/sulfonic acids such as the following are used.

When the aldol condensation reaction is carried out using metal amides, the amount used is 0.5 to 30 equivalents, preferably 0.9 to 10 equivalents, relative to the cyclobentenone of formula (II) above. As the reaction solvent, ethers such as ether and tetrahydrofuran; hydrocarbons such as petroleum ether, hexane, and pentane are used.

The reaction temperature is preferably in the range -100°C to 50°C, particularly preferably -80°C to 0°C.

The aldehydes (II) are Schiff I7/
</Tenones (0.5 to 10 violets to C, preferably 0
．． 8-2 equivalents are used.

The reaction time varies in degrees Celsius depending on the raw material compound used, the reagent 2 reaction solvent, etc., but is usually carried out in a range of 5 minutes to 1 day, preferably in a range of 10 minutes to 12 hours.

After completion of the reaction, the product is processed by conventional means such as extraction, washing with water,
It can be purified and fractionated by drying, chromatography, etc. The product is subjected to deprotection and -reaction at °C as necessary.

Deprotection of the hydroxyl protecting group can be carried out as follows. When the protecting group is a group that forms a 7-cetal bond with the oxygen atom of a hydroxyl group, use a pyridinium salt of niacetic acid, p-)luenesulfonic acid, or a cation exchange resin as a catalyst, such as water or tetrahydrofuran.

This reaction is preferably carried out using ethyl ether, dioxane, acetone, acetonitrile, or the like as a reaction solvent. The reaction is normally carried out at a temperature range of -78°C to +30°C for about 10 minutes to 3 days. In addition, the protecting group) IJ (C, ~
Cy) in the case of hydrocarbon-silyl groups, for example acetic acid.

The reaction is carried out in the presence of tetrabutyl 7/monium fluoride, cesium fluoride, etc. in a reaction solvent as described above at a similar temperature and for a similar period of time.

When the protecting group is a C1-C,7 syl group, deprotection can be carried out by a known hydrolysis reaction or an enzyme such as lipase.

In this way, bunagransifs represented by the above formula (Ia) are obtained.

The punagrandins represented by the above formula (Ib) of the present invention can be obtained by subjecting the protected bunagransifs represented by the above formula (Ia') to a dehydration reaction and, if necessary, subjecting it to a deprotection reaction.

The dehydration reaction is performed by reacting the protected punaglandins of formula (Ia') with a reactive derivative or an acid anhydride of an organic sulfonic acid in the presence of a basic compound to form a corresponding derivative, and By processing with
Implemented.

As the basic compound used when reacting the compound of formula (Ia') with the reactive derivative of organic sulfonic acid or acid anhydride, amines are preferable, and examples of such amines include pyridine, 4 -dimethylaminopyridine, triethylamine, diisopropylcyclohexylamine, 1,5-diazabicyclo(4,3,0)
Non-5-ene (hereinafter abbreviated as DBN) t l*S-diazabicyclo(5,4,0)undec-7-ene (hereinafter abbreviated as DBU), quinuclidine, triethylenediamine, isopropyl dimethylamine, silylable Examples include bilethylamine, especially pyridine, 4-
Dimethyl 7-minopyridine, DBU.

DBN is preferred.

Reactive derivatives of organic sulfonic acids include, for example, evamethanesulfonyl chloride, nitanesulfonylchloride, n-
/'Organic sulfonic acid ^rogenides such as methanesulfonyl chloride, t-butanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, p-)luenesulfonyl chloride: methanesulfonic anhydride, ethanesulfonic anhydride, m Water) Lifluoromethanesulfonic acid, benzenesulfonic anhydride, anhydride P-)
Examples include anhydrous organic sulfonic acids such as luenesulfonic acid. Examples of acid anhydrides include acetic anhydride and propionic anhydride.

As the solvent used, the basic compound itself was used.
For example, dichloromethane.

Riproform, 1! li! Genated hydrocarbons such as carbon chloride and dichloroethane; ethers such as ether and tetrachloride; benzene;

Hydrocarbons such as toluene, pentane, hexa/cyclohexane, etc. may also be used. Preferably, pyridine and dichloromethane are used.

The reaction is a reaction between the hydroxyl group on the furkyl group at the 5-position of the protected bunagransif represented by the general formula (Ia') and a reactive derivative of an organic sulfonic acid or an acid anhydride, and stoichiometrically, both The compounds react in equimolar amounts. To actually carry out the reaction, a reactive derivative of an organic sulfonic acid or an acid anhydride is usually used in an amount of 1 to 10 equivalents to the punaglandin protected by the general formula (Im').

The basic compound is used in an amount of 1 equivalent or more, preferably 2 equivalents or more, based on the reactive derivative or acid anhydride of the organic sulfonic acid used.

The amount of solvent used is usually 1 to 1000 times the volume, preferably 5 to 100 times the volume of the protected bunaglanshiff of the above formula (Ia'). The reaction temperature varies depending on the raw material compound, basic compound, solvent, etc. used, but is usually in the range of -10°C to 50°C, preferably in the range of 0°C to 30°C. The reaction time is
Although it varies depending on the conditions, it is about 0.1 to 10 hours. The progress of the reaction is monitored by methods such as thin layer chromatography.

After the reaction is completed, the target compound can be purified and fractionated by conventional means.

The Bunagra/gins thus obtained are further subjected to the same debinding reaction as described above, if necessary.

In this way, punaglandins represented by the above formula (Ib) are obtained.

<Effects of the Invention> The above formula (Ia) or (lb) provided by the present invention
Bunagra/gins provided by ) exhibit strong antiproliferative activity against L1210 leukemia cells, such as IC.

showed 0.1μEl/M1 or more. ) It is expected to be an anti-cancer drug. In addition, Bunagra/Zin of the present invention also exhibits a growth-inhibiting effect on herpes simplex virus, for example: 1
It is expected to be an antiviral agent (1) which showed approximately 60% inhibitory activity at μ, 1//rd.

Furthermore, with the production method of the present invention, punaglandin, which was conventionally obtained only from natural sources, can not only be obtained by chemical synthesis (but also its optical isomers and its optically inactive form, punaglandin structural analogues, as punaglandins). It can be manufactured industrially and efficiently.

<Example> Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 Alcohol (1) (35,5■+1.28X10-'
mol) was weighed out into a 101 test tube, and after replacing the inside of the tube with argon, dry benzene (0.4ad) was added and dissolved. Continued ℃ dried dimethyl sulfo? (DMSO)
(0.43d, 6.01 x 10”mol),
Dry Pyridy (0,010ml!, 1.28X
l 0-' mol ) l ) Lifluoro vinegar 1!
(0,0049 iu.

6.40 × 10−5 mol), and finally dicyclohexylcarbodiimide CDCC)
.

Add 3.84X10-' mol)k and heat at 17°C.
Stir for hours. After adding benzene (2,4al), the cFjML and dicyclohexyl urea were removed through two glass filters.The f solutions were combined and washed three times with water (31). After drying, it was concentrated under reduced pressure.The concentrated solution was then subjected to column coomadography (Florisilν4,!
ethyl acetate-hexane) to form aldehyde (2)
(14,0~, 5.10X10-'mol, 40%)
I got it.

(2) Spectrum data IR (C6H6, Bei-1) 2900.1740.136511210'HNMR (
CDCl, +90 M) fz + rsys) δ1
．． 4-2.5 (m + 12, 0COCH5X 2
, CH,X 2 , andcH,c = on,
3.70 (8,3,0CH3), 4.8-5
．． 6(m+2+cH-OX2), 9.53(a, 1,
HC=O).

TLC temperature 10.21 (1:1 ethyl acetate-hexane) 25 - Example 2 W (4) Alcohol f31 (118119,0.49 mmol) was placed in a 20 iu eggplant flask that had been heat dried under reduced pressure.
, methylene chloride (8-) was added. After cooling to 0°C, diimpropylethylamine (0.42m, 2.43m
mol ), )limethylsilyltrifluoromethanesulfonate (0,12117, 0,6 mmol)
was added and stirred for about 30 minutes. Add methylene chloride (5mj) here.
).

Water (5 ml) was added and the mixture was stirred and then extracted with methylene chloride. After drying over IJum (anhydrous sulfuric acid), filtration, and column chromatography were performed using Merck silica gel 5.
,9. Zoo: 1 Hexane-ethyl acetate, fraction 4-18), and a product dinone body (4) were obtained. Yield 1
31～. Yield 86%; TLC+! ! lLO, 61 (5:
1 hexane-ethyl acetate).

=26- Example 3 0S i (CHs )s O8i
(CHs) + enone compound obtained in Example 2 + 41 (115 da, 0.36 ml) was placed in a reaction tube heated and dried under reduced pressure.

Tetrahydrofuran (THF) (11d) was charged.

After cooling to -78°C, lithium diimpropylamide (approx.
．． 4M THF solution, 0.93d, 0.37mm
ol) was added. After 10 minutes, the aldehyde compound (2) obtained in Example 1 <1049. A solution of about 0.37 mmol) in THF (0.5aj) was added and stirred for 15 minutes.

Cool to -95°C and heat after 10 minutes with H7,4 phosphate buffer (0%
, 1M, 3d) was added. The organic layer was separated and the aqueous layer was extracted with ether. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (Merck silica gel!M/, 20:1 - hexane-ethyl acetate).

7 Luxion 1-4) (Raw material + 41.8011Q,
71% recovery). The product (5
) was collected. Next, this fraction was concentrated and subjected to thin layer P mudgraphy (Merek Kiese1ge16
0F'*s*+thickness 0.2511I11) Two kinds of Uv active parts (mixture of diastereomers) were separated.

Low polarity (Fi 27.2 da, yield 13%) TLC
fO, 37 (2:1 ethyl acetate/-ethyl acetate);'
HNMR (CDC1,) 60.0610.21 (fi
X 2, 9.

5t(CH,)3), 0.7-1.1 (brt I
31 CI,), 1.1-1.5(m t 6 t
cH,)? 1.5-1.8 (m t 41 C1(
, L 2.0612.09.2.13.2.15 (aX
4,6+0COCH,), 1.9-2.0(br,2
．． C1(,), 2.2-2.8(m+fzcH.

CH, OH), 3.67 (s, 3, OCR,
), 4.1-4.4 (m.

1 +CHO), 5.1-5.9(m+4 +vin
yl, CHOAc)+7.2917・32(sX2
e 1 +vinyl).

High polarity! (Yield 9.519. Yield 4%) TLC Kei 10
．． 30 (2:1 hexane-ethyl acetate);')l
NMR (CDCls) 0.15.0.18 (sX
2, 9.

81CCHs)s L O,7-1,1(brt j
3, CH,), 1.1-1.5 (m + 6
+ CHt) + 1.5 1.9 (m + 4
+CHt)+1.9-3.0 (m, 14.0COC
H,,CH,+CH+OH).

3.66 (s, 3.OCR,), 3.7-4.1 (br
i + CHO).

4.8-5.8(m+4 wv+nyl tcHOAc
), 7.31 (s +1, vinyl)
.

Example 4 Fuldol compound (
5) (approximately 5Q, 0.0085 mmol) and ethyl chloride ~/approximately III1 were added and cooled to 0°C. Anhydrous vinegar here #
l (approx.) Opl *approx. Q, 10 mmol) +
4-dimethyl 7minopyridine (about 151119.about 0
．． 12 mmol) at 0°C for 4 hours, then at 5°C for 9 hours.
Stir for hours.

Thereafter, it was cooled to θ°C, and methylene chloride and saturated saline were added thereto. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and I! I
It was concentrated and subjected to short column chromatography (Florisil: approx. 0.5.9.2:1 hexane-ethyl acetate) after removing the starting material, and then concentrated and subjected to column chromatography using 1 g of Merck silica gel, 8:1 to hexane-ethyl acetate. Ethyl acetate, fractions 1-9), product genone (6
) was obtained. Yield 1.8. Yield 37%.

TLC mature 10,53 (2:1 hexane-ethyl acetate).

Example 5 10 - Genone tri obtained in Example 4 in a test tube
(1,811kfi, 3.2 x 10-” mm
ol) yIl-cooled to oc'c. here 0
'C pre-cooled acetic acid-water to THF6:
Add 3:1 solution (approximately 1 d) and stir for 1 hour.
Stir for hours. After cooling to 0° C. and adding ether, a saturated aqueous solution of hydrogen carbonate (IJ) was slowly added dropwise to neutralize the mixture. The organic layer was separated and the aqueous layer was extracted with a needle. The organic layers were combined, dried over anhydrous sulfuric acid, filtered and concentrated, and subjected to column chromatography at °C (Merck
product (7a) was obtained from fraction 5-14 (yield: about 0.5jlp).

TLC temperature 0.2B 2:1 hexane-ethyl acetate). The product (7b) was obtained from 7Rexion 24-32 (approximately 0.8 my, TLC time (o, 2o 2:
1 hexane-ethyl acetate).

Spectral data of (7a): 500 MHz '1 (NMR (5olvent C
DCA'$) δ7,25 (s.

1, H-11), 6.37 (d, 1, J
=9.15+1zlH-7).

6.04 (dd, 1, J=9.00, 4.
4311z, H-6).

5.54-5.57 (dt, 1, H-15),
5.26-5.35 (m121H-5,14L
3.66 (l1310cH1) 13.01 (datl
+J=14.8 +9. OHz, H-13a).

2.67 (dd+1, J=14.8*7
．． 78Hz+H-13b).

2.27-2.3 (m12?H-2), 2.12 (s,
390COCH,), 1.99-2.05 (m
s 5 + 0COCH,? H-16), 1.6-1.
7(m+4.H-3,4), 1.2-1.4(m, 6t
H-17, +8.19), 0.9 (t+3+H-20)
.

Spectral data of (7b): 500 MHz 'HNMR (aolvent CDC
4) δ7.22 hl, H-11), 6.36 (dd,
1. J=7.94°3.67Hz, H-6), 6.
10 (d, 1 + J = 7.94h.

H-7), 5.60 (dt, 1, J = 10
．． 68, 7.63tlz+H-15), 5.24-
5.29 (m, 1, H-14).

5.20-5.24 (m, 1, H-5), 3.6
6(s, 3.

0CH8), 2.58 (dd, 1.J=14.49,
7.7811ztH-13m), 2.46(da, 1
, J=14.34°? , 33flz, H-13b),
2.35 (t+2.J=7.02Hz.

H-2), 2.11 (s, 3.0 COCH,), 2.
05(s, 3.

0COCHs), 1.99 (dt, 2, J”
"9.46 + 5.501 (z tH16), 1.
65 1.72 (m, 4+H3-4).

1.20-1.35 (m, 6.H-17, 18, 19)
.

o, 89 (t, 3.J=7.02Hz, H-20).

Reference Example 1 Dry methylene chloride (40Qm) Q was placed in an argon-substituted 11-size round bottom flask, and while stirring at -50°C, titanium tetraisopropoxide (Ti(0-1-Pr), (14,
88tnl, 50 mmol), D-(=
)-diethyl tartrate (1,0,31J+', 50mm
Add dry methylene chloride solution (201α)vk of olJ,
Stirred at =50°C for 5 minutes. Next, alcohol prisoners (
7,91,! Dry methychloride 1/7'llE (20 m) and t-butyl hydroperoxide (3,36 M t/g, 29,817°100 mmol) were added. After stirring at -50°C for 30 minutes, the temperature was raised to -200°C and stirred for 25.5 hours. and dimethyl sulfide (14,7 au.

200 mmol) was added thereto, and the mixture was stirred at -20°C for 40 minutes. Subsequently, the anti-inflammatory solution was added to the 5% NaF aqueous solution (Il) under stirring. After stirring for a while at 13°C, the mixture was filtered. Liquid f was transferred to separation liquid a-) and separated into an organic layer and an aqueous layer. After extracting the aqueous layer three times with methine chloride, the organic layers were combined and dried over anhydrous sulfuric acid. After adding a desiccant once, it was concentrated under reduced pressure and subjected to silica gel column chromatography (1:1 ethyl acetate-hexane).
(B) (3,8411,22 mmol, 44%)
I got it.

(B) Spectrum data IR (CHCA!s, crn-') 3600-3
200.2930.1735°'HNMR (CDC4,
90M) lz, fermentation) δ1.4 2.1 (m+4.cH
tX2), 2.23 (br, m+1 +OH), 2.
4] (L, J=6,6[1z+2tcH1
c=o).

2.9-3.3 (m, 2, CH-OX2),
3.69 (1.

3, OCR,), 3.5-3.9 and 4.2-
4.7 (m + 2 *C)I! 0).

[α)! + + 2. s°(c 1.o 41 (lH
c4) TLC, -R(0,i 4 (1: 1 hexane-ethyl acetate) Reference example 2 Epoxy alcohol (B) (21* 1,15X]0
-"mol) was weighed into a 2004 eggplant flask, and 0.
5 N NaOHfa g (5: I H, O-t
-Burn) 1001 was added and stirred. After stirring at 60°C for 25 hours, INHcl aqueous solution 50117
was added to neutralize it. After removing H2O with a vacuum pump, add 20% of ethanol, mix well, and add ether bath solution of diazometha. After confirming esterification with TLC, concentrate under reduced pressure and perform silica gel column chromatography. (1:10 methyl alcohol-ethyl acetate) to separate the triol form (C) (672
,1iy.

3.50 × 10-' mol, 30%) was obtained.

(Spectral data of q I R (CHCl5, 儂-') 3700-3100.292011730.1360'
HNMR (CDCl 1.90 MHz, pP) δ1
．． 4-2.0 (m*4*CH,X2),
2.38 (t.

J=6.8Hzw2*CH,C=0), 3.
0-4.0 (m*7tCH-OX2,C
H,0 and 0HX3), 3.68 (s + 3
tOCH,).

(a)” + 6.4° (c O, 62e CHCl,
) D-TLC temperature, 51 (1:5 methyl alcohol-ethyl acetate) Reference example 3 Trit-tyl (Q (36,8 m
g.

1.91 x 10"-' mol) was weighed out, the inside of the tube was replaced with argon, and then dried 1) MF (0.5 m
) was added. After cooling to 0°C and stirring, imidazole (2
6,1! , 3.83 X 10-' mol) and t-butyldiphenylchlorosilane (52,611 Ig
, 1.91×10-' mol) was added. 1
After stirring at 7°C for 30 minutes, the reaction solution was directly subjected to silica gel column chromatography (1:1 #: acid-ethylhexane) to obtain the silyl compound ([J (80,4#)
.

1.87 x 10-' mol, 98%) was obtained.

Spectral data of (6) IR (CHCl5, prepared-') 3600 3300t
2920t2860.1735.1670.1100 HNMR (CDCA', , 90MHz, u
) δ1.07(s*9s(CH,),C)+1.3
−2.0 (m.

4, CH, X2), 2.35 (t, 21CH1C=O)
.

2.7-2.9 (m, 2.0)lX2), 3
．． 4-3.8 (m.

4, CH,0 and CHOX2), 3.67
(s + 3 + OCR,), 7.4-7.8 (m
*10, phenyl) (a cap + 0.71
°(cO,675t CHCl5)TLCdanfO,
41 (1:1 ethyl acetate-hexane) Reference Example 4 - (g) 1011j test'ifK! J Le body (Di (8o
, 4"9+1.87 X 10-' mol) was weighed out and dissolved in dry ethyl chloride/(l m ), and then acetic anhydride (0,046 m, 4.67 X 1 G
−' mol) was added.

After cooling to 0°C and stirring at 0°C, dimethyl 7-minobiridine (68
. Add saturated aqueous solution of 7/monium chloride (a < 1oy) to the reaction solution, shake well, and separate into an organic layer and an aqueous layer.The aqueous layer contains methine chloride/monium chloride.
After extraction with (3X1011j).

The organic layers were combined and washed with water (2×101aj).

The organic layer was dried over anhydrous sulfuric acid, concentrated under reduced pressure, and subjected to silica gel column chromatography (1:5
diacetate (I
tl (81,'1■, 1.70X10 first mo+, 91
%) was obtained.

(Eye spectrum data IR (CHCl3.儂-1) 2920.2860.1730, 1590.1370'
HNMR (CDC1, 90MHz, M) δ1.
04(B+9t(CH3)3C), 1.5 C7(m
, 4゜CM, X2), 2.04 (as 6.0
COCH,X2)t 2.2-2.4 (ml 2
, CH, C=O) 13.65 (8$ 310C) (
) 13.70 (d, J=5.27Hz, l
, CH,O), 5.0-5.3(m, 2+CH-O
X2), 7.3-7.7Cm, 10゜phenyl
2).

[α) IJ o, 61° (c O, 573, CHCl
l5) D-TLC temperature O162(]:l Ethyl acetate-hexane) Reference example 5 Diacetate (odor (81,89°1
．． 59 x 10-' mol) was weighed out, and 4°C of dry acetonitrile (IJ) was added thereto to dissolve it. After cooling to 0° C., HF-viridi/(0.3 m/) was added.

The cooling bath was removed and the mixture was stirred at 17.5°C for 2.5 hours.

The reaction solution was then added to a saturated potassium fluoride aqueous solution (2d) and stirred for a while, followed by a saturated aqueous solution of hydrogen carbonate (4d). After the generation of bubbles had stopped, ether (5d) was added and the mixture was thoroughly shaken and separated into an organic layer and an aqueous layer. After extracting the aqueous layer with ether (3X 5
d) The organic layers were combined and dried over anhydrous sodium sulfate. After filtration with a drying agent, it was concentrated under reduced pressure and the concentrated solution was subjected to silica gel column chromatography (1:1 ethyl acetate-hexane) to obtain alcohol (1) (4,1,
]j9. 1.49 X 10-9 mol,
94%) was obtained.

Spectrum data of il+ IR (CDCl51cm-') 3700-3200.2940.1730.1370'
HNMR (CDCl3.90 MHz, u) δ1
．． 5-1.7 (ml4+CH,X2), 2.1
1 (8161CH, C=OX2), 2.2-2.
8 (m, 3, CH, C=Oand 0w1)
, 3.67 (8,31ocu,), 3.6-4.
5 (m + 21 CH2-0L 4.9-5.3 (
m l 21 CH-Ox2)

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[I
] In the formula, R^1 represents an alkyl group having 1 to 10 carbon atoms,
R^2 represents a hydroxyl protecting group or a hydrogen atom. In A and B, A is a hydrogen atom and B is a hydroxyl group, or A and B are bonded to each other to represent one bond, and the * mark indicates that the carbon atom is optically active or optically inactive. Punagrandins represented by. 2. Punaglandins according to claim 1, wherein R^1 in the above formula [I] is a methyl group. 3. Claim 1 or 2, wherein R^2 in the above formula [I] is a hydrogen atom or a trimethylsilyl group
Punagrandins as described in section. 4. The following formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[II] It's the same. ] Cyclopentenones represented by the following formula [III] ▲ Numerical formula, chemical formula, table, etc.▼ [III] [In the formula, the definitions of R^1 and * mark are the same as above. ] The following formula [I a] is characterized by subjecting aldehydes represented by an aldol condensation reaction to a deprotection reaction if necessary [I a] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・〔I
a] [In the formula, the definitions of R^1, R^2, and * mark are the same as above. ] A manufacturing method for punagrandins represented by. 5. The method for producing punaglandins according to claim 4, wherein the aldol condensation reaction is carried out in the presence of lithium diisopropylamide. 6. The following formula [I a'] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I a'] [In the formula, the definitions of R^1, R^2^0 and * are the same as above. ] Punaglandins represented by the following formula [I
b] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・〔I
b] [In the formula, the definitions of R^1, R^2 and * are the same as above, and the symbol ■ indicates that the bond is E or Z with respect to the double bond.
or a mixture thereof in any proportion. ] A manufacturing method for punagrandins. 7. The method for producing punaglandins according to claim 6, wherein the dehydration reaction is carried out using acetic anhydride in the presence of a base.