JPH02178252A - Novel prostaglandin is - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I or II [R1 is H or alkyl; R2 and R2' are H, halogen, alkyl, aromatic-containing group, OH or alkoxy (except that both are H)] or salt thereof. EXAMPLE:16(RS)-Fluoro-15-keto-9-(O)-methano- <6(9alpha)>-PGI1 methyl ester. USE:A hypotensive agent, characterized in that the molecular skeleton has a bicyclo ring therein and capable of reducing other pharmacological and physiological actions, such as an increase in pulse rate, possessed by PGIs by the presence of substituent groups thereof. PREPARATION:For example, a 6-(trialkylsiloxymethyl)-3-formyl-7- tetrahydropyranyloxy-bicyclo[3.3.0]oct-2-ene expressed by formula III as a raw material is passed through routes according to the reaction formulas to afford a compound expressed by formula IV which is the exemplified compound.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention provides novel glosstaglandins I (hereinafter referred to as PC
(referred to as Category I).

Conventional technology PCI is known to have a strong platelet aggregation inhibiting effect and blood pressure lowering effect, but it is also known to have side effects such as increased pulse rate, facial flushing, and abdominal pain (
Written by S., M., Karim et al., PG.

Med, 9.307 (1982)).

On the other hand, in JP-A-61-78734, a polycyclic aromatic tricarbonyl metal (Vl-B) compound has σ.

It is stated that it is useful as a catalyst for the reduction of β-unsaturated carbonyl compounds, and Example 7 shows (3(E)-(4)
'-methoxycarbonylbutylidene)-6(S)-(3
'-oxo-trans-1'-octenyl)-7(R)
-Tetrahydropyranyloxy-(IS,5S)-cis-bicyclo[3,3,0]octane) is reduced to (3
(E)-(4'-methoxycarbonylbutylidene)-6
(R)-(3'-oxooctyl)-7-(R)-tetrahydropyranyloxy-(IS.

5S)-cis-bicyclo[3,3,0]octane) is shown. Furthermore, JP-A-61-3774
The same compound is also described in Example 7 of Publication No. 0.

However, in any of the prior art, the general formula [I] of the present invention
There is no disclosure regarding the compounds represented by (II) and no disclosure whatsoever regarding the usefulness of the aforementioned compounds.

Problems to be Solved by the Invention The object of the present invention is to provide novel PGIs that are expected to be useful as antihypertensive agents.

Means for Solving the Problems The present invention provides general formula (1) or [II]: [wherein R,
represents a hydrogen atom or an alkyl group, and R2 and R2'' each independently represent a hydrogen atom, a halogen atom, an alkyl group, an aromatic group, a hydroxyl group, or an alkoxy group (however, R
2 and R, I are both hydrogen atoms)
] The present invention relates to prostaglandins represented by ■ or salts thereof.

The PGIs represented by the general formula (I) of the present invention are 15-keto-
16-substituted-9(○)-methano-△6(”・)-PG
I, and the PGIs represented by the general formula (II) are 15-keto-16-substituted-9(○)-methano-PCl3
It is a kind.

A characteristic part of the present invention is that it has a bicyclo ring in its molecular skeleton. Furthermore, the presence of this substituent contributes to the blood pressure lowering effect of PGIs, and is considered useful in reducing other pharmacological and physiological effects of PGIs, such as increased pulse rate.

Groups represented by R2 and R, l include halogen atoms such as fluorine and chlorine; alkyl groups such as methinoethyl; aromatic groups such as phenyl and benzyl; hydroxyl groups; methoxy,
Examples include alkoxy groups such as ethoxy. Preferably one or both are halogen atoms, especially fluorine atoms.

R is a hydrogen atom or an alkyl group. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl. When R is a hydrogen atom, it may form a salt with a suitable alkali,
In particular, when the present invention is used as a medicine, physiologically acceptable salts, such as salts derived from alkali metals, alkaline earth metals, ammonia, alkylamines, alkanolamines, alkylalkanolamines, etc. are exemplified.

The present invention provides a method for synthesizing PCl represented by the general formula [I], for example, as shown in the synthesis chart [II].
Commercially available 6-(trialkylsiloxymethyl)-3-formyl-7-titrahydrobilanyloxy-bicyclo[3
, 3,01 oct-2-ene (aldehyde form (1)) is used as a raw material, and it is reacted with a ylide prepared from (3-carboxypropyl)triphenylphosphine bromide and potassium t-butoxide to form diazomethane. The ester compound (2) is obtained by reacting with the ester compound (2), which is reduced using palladium carbon to obtain the 4-carbomethoxybutyl compound (3), which is then reacted with n-butylammonium 70 lid, etc.
The alcohol compound (4) is obtained by desilylation. This was subjected to Collins oxidation to obtain an aldehyde (5), and an anion prepared from dimethyl (2-oxo-3-substituted-hebutyl)phosphonate having a desired substituent and sodium hydride was added to this aldehyde (5). React to introduce ω chain, 1
5-keto monolith (6) is obtained. Next, the protecting group, the tetrahydropyranyl group, is removed using an acid to obtain the desired ester (7) of the compound [1]. A carboxylic acid type target compound can be obtained by hydrolysis using a conventional method. Example 1 shows an example in which the substituent at the 3-position of the phosphonate used for introducing the ω chain is a fluorine atom. , methoxy group,
It may be an ethoxy group.

PCI represented by general formula (II) is commercially available 6-(trialkylsiloxymethyl)-3-formyl-7-titrahydrobyranyloxy-bicyclo[3,3,0 ] Using oct-2-ene (aldehyde form (1)) as a raw material, reacting it with a ylide prepared from (3-carboxypropyl)triphenylphosphine bromide and potassium t-butoxide, and further reacting with diazomethane, Obtain ester body (2),
Using n-butylammonium 70lide, etc.,
The alcohol compound (4') is obtained by desilylation. This was subjected to Collins oxidation to obtain an aldehyde compound (5'), and the carbonyl group of the compound (10) into which an ω chain was introduced was reduced with sodium borohydride in the same manner as in the case of P CI , 15 -Hydroxy compound (11) is obtained, and this is reduced using a tricarbonyl chromium benzoate methyl complex (for example, JP-A-61-37740), and in this case, the double bond of the α chain conjugated with the endocyclic double bond is reduced to form a structure in which the ring and the α chain are bonded by a double bond), which is hydrolyzed with an alkali to obtain the free acid (13), and further Jones oxidized to obtain the ketone (14), which By removing the tetrahydropyranyl group with an acid, the desired ester (15) of [I[] can be obtained. The substituent on the carbon adjacent to the carbonyl group of the compound obtained above is in this case a fluorine atom, but may be another substituent.

The PCIs of the present invention also include isomers and mixtures of isomers. Examples of these isomers include the keto-hemiacetal tautomer between the hydroxyl group at the 11th position and the carbonyl group at the 15th position, optical isomers, and geometric isomers.

Hereinafter, the present invention will be explained based on examples.

In the examples, in order to indicate the compounds, except for the final target compound, names are given according to IUPAC nomenclature, and the carbon numbers of the bicyclo rings are as follows.

Example 1 12 (I S, 5 S, 6 S, 7 R)-6-(
t-Butyldimethylsiloxymethyl)-3-[4-carbomethoxy-1(EZ)-butenyl]-7-titrahydropyranyloxy-bicyclo[3,3,0]oct-2
Synthesis of -ene (2): Commercially available (ls, 5s, 6s, 7R)-6-(t-butyldimethylsiloxymethyl)-3-formyl-7-titrahydrobylanyloxy-bicyclo[3,3゜0 ] Oct-2-ene (1,oog) (1) in THF (3-
(carboxypropyl) triphenylphosphine bromide and a ylide prepared from potassium t-butoxide. A crude carboxylic acid was obtained by treatment in a conventional manner. This was reacted with an ethereal solution of diazomethane. The crude product obtained by conventional treatment was purified by column chromatography (hexane/ethyl acetate 10:l) to give (ls, 5S, 6S, 7R)-6-(t-butyldimethylsiloxymethyl) as a colorless oil. )-3-[4-carbomethoxy-1(
EZ)-butenyl]-7-titrahydrobilanyloxy-bicyclo[3,3,0]oct-2-ene (2) was obtained. Yield 0.85g (67%).

'HNMR (CDCIs)' 80.05 (6H.

S), 0.90 (9H, s), 1.05-1.95
(1OH, m), 2.10-3.13 (7H, m),
3.27-4.22 (5H, m), 3.63 (3H
,s), 4°45~4.69 (IH,m), 5-
05-5.65 (2H, m), 5.97 (0,67H
, d, J-12Hz), 6.22 (0,33H, d,
J-16Hz).

1-2 (Is, 5S, 6S, 7R)-6-Q-butyldimethylsiloxymethyl)-3-(4-carbomethoxybutyl)-7-titrahydrobilanyloxy-bicyclo[3,3,0]octo- Synthesis of 2-ene (3): (lS,5S,6S,7R)-6-Q-butyldimethylsiloxymethyl)-3-[4-carbomethoxy-1(
F-Z)-butenyl]-7-titrahydrobilanyloxy-bicyclo[3,3,0]oct-2-ene (2X0
．． 214g) Dissolved in methanol, added 10% palladium on carbon (0,050g), and heated at room temperature under hydrogen atmosphere for 45 minutes.
Stir for a minute. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure.

The obtained crude product was immersed in silica gel treated with silver nitrate (low
Column chromatography (hexane/ethyl acetate 40:1 to 30:l) using (IS, 5S) as a colorless oil.

6S,7R)-6-(L-butyldimethylsiloxymethyl)-3-(4-carbomethoxybutyl)-7-titrahydrobilanyloxybicyclo[3,3°0]oct-2-ene (3) Obtained. Yield 0.151g<70%)
.

'HNMR (CDCI,) δ 0.05 (6H.

S), 0.88 (9H, s), 0.97-3.03
(2IH, m), 3.23-4-15 (5H, m), 3
．． 62 (3H, s), 4.45-4.69 (LH,
m), 5°10-5.33 (l H, m).

1-3 (IS, 5S, 65,7R)-3-(4-carbomethoxybutyl)-6-hydroxymethyl-7-tetrahydrobyranyloxy-bicyclo[3,3,0]oct-2-ene(4 ) synthesis: (lS, 5S, 6S, 7
R)-6-(t-butyldimethylsiloxymethyl)-3
-(4-Carbomethoxybutyl)-7-titrahydrobilanyloxy-bicyclo[3,3,0]oct-2-ene (3) (0,294 g) was dissolved in THF, and n-butylammonium fluoride was dissolved in the solution. THF solution (ilM, 2.2
mL) and stirred at room temperature for 18 hours. The crude product obtained by conventional treatment was purified by column chromatography (hexane/ethyl acetate 1:1) to give (IS, 5S, 6S, 7R)-3-(4- Carbomethoxybutyl-6-hydroxymethyl-7-tetrahydrobilanyloxy-bicyclo[3°3.0]oct-2-ene (4) was obtained. Yield: 0°228g (quantitative).

'HNMR (CDClS) 80.76-3.13 (22
H, m), 3.27-4.13 C5H, m), 3゜6
3 (3H, s), 4.46-4.77 (I H, m
), 5.02-5.42 (l H, m).

(lS, 5S, 6S, 7R)-3-(4-carbomethoxybutyl)-6-[4(R5)-fluoro-3
-oxo-(E)-1-octenyl]-7-titrahydrobilanyloxy-bicyclo[3,3.

Synthesis of 01 oct-2-ene (6): (ls, 5s, 6s, 7R)-3-(4-carbomethoxybutyl)-6-hydroxymethyl-7-tetrahydrobilanyloxy-bicyclo[3,3, O] Octo-2-
Ene (4) (0,125g) was dissolved in DMS○,
A DMSO solution of triethylamine (0.93 mL) and sulfur trioxide/pyridine complex (0.504 g) was added, and the mixture was stirred at room temperature for 1.5 hours.

A crude aldehyde (5) was obtained by treatment in a conventional manner. This was dissolved in THF and reacted at 50°C with an anion prepared from dimethyl (2-oxo-3fluoroheptyl)phosphonate (0,341 g) and sodium hydride. 3
The mixture was stirred for an hour and neutralized by adding acetic acid. The crude product obtained by conventional treatment was purified by column chromatography (hexane/ethyl acetate 7:l) to give (l S, 5S, 6S, 7
R)-3-(4carbomethoxybutyl)-6-[4(R
5)-Fluoro-3-oxo-(E)-1-octenyl 1-7-titrahydrobilanyloxy-bicyclo[3,
3°01oct-2-ene (6) was obtained. Yield 0.08
8g (56%).

'HNMR (CDCI 3) 80.75-1.06 (3
H, m), 1.05-3.14 (27H, m), 3
．． 26-4.13 (3H, m), 3.63 (3H,
s), 4.38-4.71 (1,5H, m), 5
．． 01~5゜43 (1,5H, m), 6.26~6
．． 68 (IH.

m), 6.80 to 7.26 (LH, m).

Upper Nidan 16 (R3)--yluoro 15-keto-9
Synthesis of (0)-methano-△60"-PGI, methyl ester (7): (Is, 5S, 6S, 7R)-3-(4-carbomethoxybutyl)-6-[4(R5)-fluoro -3-oxo-(E)-1-octenyl]-7-titrahydrobilanyloxy-bicyclo[3,3,O]oct-2-ene (
6) (0,088g) was dissolved in a 4:2:l mixed solvent of acetic acid, water, and THF, and stirred at 450C for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (hexane/ethyl acetate 3:1) to give 16(RS)-fluoro-15 as a colorless oil.
-Keto-9(O)methanol-Δ8(!, l pQl, methyl ester (7) was obtained.

Yield: 0.069g (96%).

'HNMR (CDCI,) 80.72~1.04 (
3H, m), 1.04-3.18 (22H, m),
3.62 (3H,s), 3.70-4.12 (IH
, m), 4.43-4.63 ((L5H, m),
4.98-5゜23 (0.5H, m), 5.18-5
．． 35 (IH, m), 6.53 (IH, dd, J-
16Hz, J=3Hz), 6.98 (l H, dd,
J = 16Hz, J-9Hz).

Example 2 Composition: Suni (15,55,6S,7R)-3-(4-carbomethoxybutyl)-6-[4,4-difluoro-3-
Oxo-(E)-1-octenyl]-7-titrahydrobilanyloxy-bicyclo[3,3°01oct-2-
Synthesis of ene (8): (15,5S, 6S, 7R)
-3-(4-carbomethoxybutyl)-6-hydroxymethyl-7-tetrahydrobilanyloxy-bicyclo[
3,3,0]oct-2-ene (4) (0,10
8g) was dissolved in DMSO and triethylamine (0,9g) was dissolved in DMSO.
0 mL) and sulfur trioxide/pyridine complex (0,48
8 g) of DMSO solution was added and stirred in chamber I for 30 minutes.

A crude aldehyde (5) was obtained by treatment in a conventional manner.

This was dissolved in THF and dimethyl (2-oxo3.3-
Difluoroheptyl)phosphonate (0°435) was reacted with an anion prepared from sodium hydride.4
The mixture was heated under reflux for 8 hours and neutralized by adding acetic acid. The crude product obtained by conventional treatment was purified by column chromatography (hexane/ethyl acetate 7:1) as a colorless oil (Is.

5S, 6S, 7R)-3-(4-carbomethoxybutyl)-6-[4,4-difluoro-3-oxo,
-(E)-1-otatenyl]-7-titrahydrobilanyloxy-bicyclo[3,3,0]oct-2-ene (
8) was obtained.

Yield 0.091g (64%).

'HNMR (CDCI 3) 80.76-1.05 (3
H, m), 1.05-3.17 (27H, m), 3.
25-4.15 (3H, m), 3.63 (3H, s
), 4.35 to 4.75 (l H, m), 5.0
9-5.37 (IH, m), 6.56 (IH, dd,
J-15Hz, J=6Hz), 6.86-7.37
(LH, m).

Suni 2 16.16-difluoro-15-keto 9(0)
)9/-Δ4ft-1-PGII) Synthesis of chill x stel (9).

(is, 5S, 6S, 7R)-3-(4-carbomethoxybutyl)-6-[4,4-difluoro-3-oxo-
(E)-1-octenyl]-7-titrahydrobilanyloxy-bicyclo[3,3,0]oct-2-ene (
8) (0,091 g) was dissolved in a 4:2:l mixed solvent of acetic acid, water, and THF, and stirred at 45° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (hexane/ethyl acetate 2:l) to give 16.16-difluoro-15- as a colorless oil.
Keto-9(0)-methano-△@feel-pG■, methyl ester (9) was obtained. Yield 0.060g (80%
).

'HNMR (CDCIs) 80.76-1.05 (3H
, m), 1.05-3.21 (22H, m), 3.
62 (3H, s), 3.73-4.17 (IH, m
), 5.09-5.43 (IH, m), 6.56 (
IH.

d, J=15Hz), 7.12 (IH, dd, J
-15Hz, J=7.5Hz).

3-1 (IS, 5S, 6S, 7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-hydroxymethyl-7-tetrahydrobilanyloxy-bicyclo[3;3.0]oct Synthesis of -2-ene (4'): (lS, 5S, 6S, 7R)-6-(t-butyldimethylsiloxymethyl")-3-[4-carbomethoxy-l
(E Z)-butenyl]-7-titrahydrobilanyloxy-bicyclo[3,3,O]oct-2-ene(2
Dissolve 0.85 g of tetra-n-phthylammonium 70lide in THF and add
L) was added and stirred at room temperature for 18 hours.

The crude product obtained by conventional treatment was purified by column chromatography (hexane/ethyl acetate 1:1) to give (IS, 5S, 6S, 7R)-3-[4-
Carbomethoxy-1(E Z')-butenyl]-〇-hydroxymethyl-7-titrahydrobilanyloxy-bicyclo[3,3,O]oct-2-ene (4') was obtained. Yield 0.59g (96%).

'HNMR (CDCI,) 81.18-1.93 (IO
H, m), 2.16-3.28 (8H, m), 3°4
2-4.07 (5H, m), 3-63 (3H, s)
, 4.5'5~4-64 (0.5H, m) , 4.6
6-4-77 (0,5H,m), 5.33 (0,6
7H, dt.

J=7.5Hz, J=12.5Hz), 5.42~5゜67 (1,33H, m), 5.99 (0,67H,
d.

J-12,5Hz), 6.26 (0,33H,d,
J=15.5Hz).

3-2 (15,55,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4(R
5)-Fluoro-3-oxo-(E)-1-octenyl]-7-titrahydrobilanyloxy-bicyclo[3,
Synthesis of 3,0]oct-2-ene (10): (lS,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl], -6-hydroxy Methyl-7-tetrahydrobilanyloxy-bicyclo[3,3,O]oct-2-ene (4″) (0,240
g) in methylene chloride at 0°C with Collins oxidation I;

Sodium hydrogen sulfate was added to the reaction solution, and the mixture was filtered.

The crude aldehyde (5') obtained by concentrating the filtrate under reduced pressure was dissolved in THF.
It was prepared from dimethyl (2-oxo-3-fluoroheptyl)phosphonate (0.61 g) and sodium hydride and reacted with the anion at 50 °C, stirred for 5 hours and neutralized by adding acetic acid. .

The crude product obtained by conventional treatment was purified by column chromatography (hexane/ethyl acetate 6:l) to give (IS, 5S, 6S, 7R)-3-[4-
Carbomethoxy-1(EZ)-butenyl]-6-[4(
RS)-Fluoro-3-oxo-(E)-1-octenyl]-7-titrahydrobilanyloxy-bicyclo[3
,3,0]oct-2-ene (10) was obtained.

Yield 0.250g (85%).

'HNMR (CDCIs) 8 0.70~1.07
(3H, m), 1.06-2.14 (15H, m)
, 2.15-4.16 (11H, m), 3.66
(3H.

S), 4.43=4.72 (1,5H,m), 4
．． 96-5.71 (2.5H, m), 5.95
(0,67H,d.

J=l 1Hz), 6.24 (0,33H,d,
J -16Hz), 6.36~6-73 (IH,
m), 6.83-7.23 (lH,m).

3-3 (15,55,6S,7R)-3-[4-carbomethoxy-1(E Z)-butenyl]-6-[4(
R5)-70o-3(R3)-hydroxy-(E)-
Synthesis of (is, 5S, 6S, 7R)-3-[4-carbomethoxy-1 (EZ )-butenyl]-6-[4(R3)-yroolo-3-oxo-(E)-1-octenyl1-7-titrahydrobilanyloxy-bicyclo[3°3.0]oct-2-ene ( 10) Dissolve (0,08By) in methanol and add sodium borohydride (0,0By) at 0°C.
08g) was added and stirred for 30 minutes. (IS, 5S, 6S, 7R)-3- as a colorless oil by conventional treatment.
[4-Carbomethoxy-1(EZ)-butenyl]-6-
[4(R3)-70o-3(RS)-hydroxy-(
E)-1-octenyl]-7-titrahydrobilanyloxy-bicyclo[3,3,0]oct-2-ene (1
1) was obtained. Yield 0.089g (quantitative).

'HNMR(CDC]s)80.67~1
．． 03 (3H, m), 1.03-3.19 (24H,
m), 3°22~4-34 (4,5H, m), 3.6
2 (3H, s), 4.40-4.74 (1,5H,
m), 5.07-6°32 (5H, m).

Nima (Is, 2S, 3R, 5S)-(E)-7-(4
-carbomethoxybutylidene)-2-[4(Rs)-fluoro-3(R3)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[
Synthesis of 3,3,0]octane (12): (IS, 5S, 6S, 7R)-3-[
4-Carbomethoxy-1(EZ)-butenyl]-6-[
4(R3)-70olor3(R5)-hydroxy-(E
)-1-octenyl1-7-titrahydrobilanyloxy-bicyclo[3,3,0]oct2-ene (11)
(0,089 g) was added and dissolved in acetone, and tricarbonylchromium/methyl benzoate complex (0,011 g) was added and degassed. Under hydrogen pressure (70 Jig/cm, l
Stirred at 20'O for 15 hours.

The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (hexane/ethyl acetate 2:l) to give a colorless oil (IS, 2S, 3R).

5S)-(E)-7-(4-carbomethoxybutylidene)-2-[4(R5)-fluoro-3(R3)-hydroxy-(E)-]-]otatenyl]-3-tetrahydropyranyl Oxybicyclo[3,3,0]octane (12
) was obtained.

Yield 0.0789 (87%).

'HNMR (CDC13) 80.70-1.04 (3H
, m), 1.04-2.67 (28H, m), 3°21-4-32 (4.5H, m), 4.36-4.7
5 (1,5H, m), 4.99-5.30 (L H
, m), 5°30-5.92 (2H, m).

3-5 (Is, 2S, 3R, 5S)-(E)-7-
(4-Carboxybutylidene)-2-[4(RS)-fluoro-3(R3)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[
Synthesis of 3,3,O]octane (13): (I S, 2
S,3R,5S)-(E)-7-(4-carbomethoxybutylidene)-2-[4(RS)-fluoro-3(R5
)-Hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3,3,0]octane (12) (0,1299) was dissolved in methanol and dissolved in an aqueous IN sodium hydroxide solution (2 mL). ) and stirred at room temperature for 6 hours. After treatment in a conventional manner, a colorless oil (1S, 2S, 3R) was obtained.

5S)-(E)-7-(4-carboxybutylidene)-
2-[4(R5)-Fluoro-3(R3)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3,3,0]octane (13) was obtained.

Yield 0.140g (quantitative).

'HNMR (CDCI 80.70-1.05 (3H,
m), 1.05-2.70 (27H, m), 3°26
~6.06 (l OH, m).

3-6 (is, 2S, 3R, 5S)-(E)-7-
(4-carboxybutylidene)-2-[4(R5)-fluoro-3-oxo-(E)-1-octenyl]-3-
Tetrahydropyranyloxy-bicyclo [3,3゜0]
Synthesis of octane (14): (ls,2s,3R,5S)-(E)-7-(4-carboxybutylidene)-2-[4(R5)-fluoro-3
(RS)-hydroxy-(E)-1-octenyl]-3
-tetrahydropyranyloxy-bicyclo[3,3,0
] Octane (13XO, 140g) at -15 to -20℃
Jones oxidized with. After stirring for 30 minutes, isopropyl alcohol was added and treated in a conventional manner. The obtained crude product was acid-treated with silica gel (Mallinkrodt, CC-
4) as a colorless oil by column chromatography (hexane/ethyl acetate 6:1-5:l).
(is, 2S.

3R,5S)-(E)-7-(4-carboxybutylidene)-2-[4(R5)-fluoro-3-oxo-(E
)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3,3,0]octane (14) was obtained.

Yield 0.106g (76%).

'HNMR(CDCl3)δ 0.75~1
．． 04 (3H, m), 1.04-2.78 (27H,
m), 3.23~4.14 (3H, m), 4.37~
4.73 (1°5H, m), 5.02~5.36 (1
,5H,m), 6°32~6-67 (lH,m),
6.73-7.26 (IH, m).

3-7 16(R3)-fluoro-15-keto-9(O
)-Methano-PGIz (15) synthesis: (IS,
2S,3R,5S)-(E)-7-(4-carboxybutylidene)-2-[4(R3)-fluoro-3-oxo-(E)-1-octenyl]-3-tetrahydropyranyloxy -bicyclo[3,3,0]octane (14)
(0,1069) in acetic acid, water, and THF 4:2:
1 of mixed solvent and stirred at 45°C for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified using silica gel (Mallinkrodt).

16(RS)-Fluoro-15-keto-9(0) was purified by column chromatography (hexane/ethyl acetate 6:1 to 2:1) using CC-4) as a colorless oil.
-, 'Tano PG I! (15) It's 4.

Yield 0.0479 (52%).

'HNMR (CDC13) 80.74-1.04 (3H
, m), 1.04-2.80 (21H, m), 3゜6
7-4.07 (IH, m), 4.43-4.65 (
0,5H,m), 4.99-5.37 (1,5H,m
), 4°00 ~ 5-60 (2H, brs), 6.5
t(iH, dd.

J-17Hz, J=4Hz), 6.94 (l H, d
d.

J=17Hz, J-7Hz).

Example 4 4-1 (IS, 5S, 63,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4゜4
-difluoro-3-oxo-(E)-1-octenyl]
-7-titrahydrobilanyloxy-bicyclo[3,3
,0] Synthesis of oct-2-ene (16): (15,5S
, 65.7 R)-3-[4-carbomethoxy-1(E
Z)-butenyl]-6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo[3,3,0]oct-2-ene (41X0.333 g) in methylene chloride,
Collins oxidation was performed at 0°C.

After 30 minutes, sodium hydrogen sulfate was added to the reaction solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain crude aldehyde (5''). The crude aldehyde (5') was dissolved in THF and dimethyl (2-
Oxo-3,3-sifu-o-oloheptyl)phosphonate (
0,970 g) and an anion prepared from sodium hydride at 70°C.

After stirring for 17 hours, acetic acid was added to neutralize. The crude product obtained by conventional treatment was purified by column chromatography (hexane/ethyl acetate 6:1) to give (IS, 5S, 6S, 7R)-3-[4-carpomethoxy- 1(EZ)-butenylco-6-[4,4-Schiff 0-year-old rho 3-oxo-(E)-1-octenyl]-7-
Titrahydrobilanyloxybicyclo[3,3,0]
Oct-2-ene (16) was obtained.

Yield 0.196g (43%).

'HNMR (CDCI 80.73-1.06 (3H,
m), 1.04-2.90 (23H, m), 2°90
~4.17 (3H, m), 3.63 (3H, s),
4.33-4.71 (IH, m), 5.10-5.
66 (2H, m), 5.94 (0,67H, d, J-
12H2), 6.22 (0,33H,d, J-16,
5Hz), 6.57 (LH, dd, J=15Hz, J
=6Hz), 6.86-7.33 (IH, m).

4-2 (is, 5S, 6S, 7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4゜4
-difluoro-3(R5)-hydroxy-(E)-1-
Synthesis of (lS,5S,63,7R)-3-[4-carbomethoxy-1( EZ)-butenyl]-6-[4,4-Schif0
Dissolve 3-oxo-(E)-1-octenyl]-7-titrahydrobilanyloxy-bicyclo[3°3.01oct-2-ene (16XO, l 969) in methanol and stir at 0 °C. Sodium borohydride (0,01
5g) was added and stirred for 30 minutes. (is, 5S, 6S, 7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4,4
-difluoro-3(R3)-hydroxy-(E)-1-
Octenyl]-7-titrahydrobilanyloxy-bicyclo[3,3,0]oct-2-ene (17) was obtained.

Yield 0.184g (93%).

'HNMR (CDCI,) 80.70-1.03 (3H
, m), 1.03-2.72 (24H, m), 2°8
5-3.23 (l H, m), 3.23-3.96
(2H, m), 3.63 (3H, s), 3.96-4
．． 35 (lH, m), 4.46-4.68 (lH,
m), 5.05-6.35 (5H, m).

Satnu (IS, 2S, 3R, 5S)-(E)-7-
(4-Carbomethoxybutylidene)-2-[4,4-difluoro-3(RS)-hydroxy-(E)-1-otatenyl]-3-tetrahydropyranyloxy-bicyclo[3,3,0]octane (IS, 5S, 6S, 7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4,4
-difluoro-3(R3)-hydroxy-(E)-1-
Octenyl 1-7-titrahydrobilanyloxy-bicyclo[3,3,0]oct-2-ene (17XO,18
4 g) was added and dissolved in acetone, and tricarbonylchromium/methyl benzoate complex (0,0219) was added and degassed. The mixture was stirred at 120°C for 15 hours under hydrogen pressure (70 kg/cm). The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (hexane/ethyl acetate 7:2
~3:l) and purified as a colorless oil (IS, 2S
, 3R,5S)-(E)-7-(4-carbomethoxybutylidene)-2-[4,4-difluoro-3(R3)-
Hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3,3,0]octane (18) was obtained.

Yield 0.175g (95%).

'HNMR (CDCIs) 80.75-1.05 (3H
, m), 1.05-2.63 (28H, m), 3-23
~4.00 (3H, m), 3.62 (3H, s
), 4°00~4.40 (L H, m), 4.48
~4.66 (IH, m), 5.03~5.32
(l H, m), 5.33-6.05 (2H, m)
.

l:4 (IS, 2S, 3R, 5S)-(E)-7
-(4-carboxybutylidene)-2-[4,4-difluoro-3(RS)-hydroxy-(E)-1-octenyl 1-3-tetrahydropyranyloxy-bicyclo[
Synthesis of 3,3,0]octane (19): (l S, 2S
, 3R,5S)-(E)-7-(4-carbomethoxybutylidene)-2-[4,4-difluoro-3(R9)-
Dissolve hydroxy-(E)-1-octenyl 1-3-tetrahydropyranyloxy-bicyclo[3,3,O]octane (18XO, 175 g) in methanol, add IN aqueous sodium hydroxide solution, and the raw material disappears. Stir until The crude product (l s, 2
S, 3 R, 55)-(E)-7-(4-carboxybutylidene)-2-[4.

4-difluoro-3(RS)-hydroxy-(E)-1
-octenyl]-3-tetrahydropyranyloxy-bicyclo[3,3,0]octane (19) was obtained.

Yield 0.172g (quantitative).

'HNMR (CDCI,) 80.70-1.03 (3H
, m), 1.03-2.73 (27H, m), 3゜2
2-4.39 (4H, m), 4.40-4.72 (
IH,m), 4-98-5.35 (IH,m), 5
．． 35-6.03 (2H, m), 3.22-6.13
(2H.

brs).

l:5 (ls, 2s, 3R, 5S)-(E)-7-
Synthesis of (4-carpoxybutylidene)-2-[4,4-difluoro-3-oxo-(E)-1-octenyl]-3tetrahydropyranyloxy-bicyclo[3,3°01 octane (20) : (IS, 2S, 3R, 5S)-(E)-7-(4-carboxybutylidene)-2-[4,4-difluoro-3
(R3)-hydroxy-(E)-1-octenyl]-3
-tetrahydropyranyloxy-bicyclo[3,3,0
] Octane (19) (0,1729) was subjected to Collins oxidation at room temperature. After stirring for 30 minutes, sodium hydrogen sulfate was added to the reaction solution, and the mixture was filtered. The crude product obtained by concentrating the filtrate was treated with acid-treated silica gel (Mallinkrodt, CC-4).
) to purify by column chromatography (hexane/ethyl acetate 20:1 to 10=1).
3R,5S)-(E) 7-(4-carboxybutylidene)-2-[4,4-difluoro-3-oxo-(E
)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3,3,O]octane (20) was obtained.

Yield 0.0509 (30%).

' HN M R (CD C13) δ 0.66-1.
03 (3H, m), 1.03-2.75 (27H, m
), 3°24~4.08 (3H, m), 4.36~4
．． 68 (IH, m), 5.07=5.36 (IH,
m), 6.52 (IH, dd, J=15Hz, J-6H
z), 6.83~7.30 (IH, m), 7.20~
8.20 (LH.

brs).

4-6 16.16-difluoro-15-keto-9(0
)-1ri/F'G1x (21) synthesis = (I
S, 2S, 3R, 5S)-(E)-7-(4-carboxybutylidene)-2-[4,4-difluoro-3-oxo-(E)-1-octenyl]-3-tetrahydropyranyl Oxy-bicyclo[3°3.0]octane (20
x0.050g) in acetic acid, water, and THF 4:2:
1. Dissolved in a mixed solvent and stirred at 45°C for 3°5 hours.

The reaction solution was concentrated under reduced pressure, and the resulting crude product was filtered onto silica gel (
16.16-difluoro-15-keto-
9(O)-methano-PGIz (21) was obtained.

Yield 0.033g (80%).

'HNMR (CDCI,) 80.70-1.05 (3H
, m), 1.05-2.90 (21H, m), 3゜6
5-4.20 (l H, m), 5.05-5.40
(IH, m), 4.80-5.95 (2H, brs)
, 6.53 (IH, d, J-16Hz), 7.0
7 (l H, dd.

J-16Hz, J-7,5Hz).

Synthesis Chart ■ (Continued) Effects of the Invention The present invention provides novel prostaglandin ■, namely 15
-keto-(16-substituted)-9(0)-methano-Δ6 f
! -1p Q II and 15-keto-(16-substituted)-9(0)-methano-PCI. These compounds are expected to be useful as blood pressure increasing agents.

Claims (1)

[Claims] 1. General formula [I] or [II]: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (α chain) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (ω chain) [ I ] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (α chain) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (ω chain) [II] [In the formula, R_1 is a hydrogen atom or an alkyl group and R_
2, R_2' each independently represents a hydrogen atom, a halogen atom, an alkyl group, an aromatic group, a hydroxyl group, or an alkoxy group (excluding cases where both R_2 and R_2' are hydrogen atoms)] Prostaglandin I or its salt. 2. Prostaglandin I according to item 1, wherein one or both of R_2 and R_2' is a halogen atom.