CA2016300C - Prostaglandin i analogue - Google Patents
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- CA2016300C CA2016300C CA002016300A CA2016300A CA2016300C CA 2016300 C CA2016300 C CA 2016300C CA 002016300 A CA002016300 A CA 002016300A CA 2016300 A CA2016300 A CA 2016300A CA 2016300 C CA2016300 C CA 2016300C
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Abstract
The present invention relates to new prostaglandin I
analogous compounds represented by the following formula (I) and (II).
(see formula I) (see formula II) wherein R1 is a hydrogen atom or alkyl group, at least one of R2 and/or R2' is a halogen atom, an alkyl group, a group containing an aromatic group, a hydroxyl group or an alkoxy group provided that R2 and R2' are not simultaneously hydrogen atoms or a salt thereof. The compounds of the present invention are suitable for use as hypotensives.
analogous compounds represented by the following formula (I) and (II).
(see formula I) (see formula II) wherein R1 is a hydrogen atom or alkyl group, at least one of R2 and/or R2' is a halogen atom, an alkyl group, a group containing an aromatic group, a hydroxyl group or an alkoxy group provided that R2 and R2' are not simultaneously hydrogen atoms or a salt thereof. The compounds of the present invention are suitable for use as hypotensives.
Description
2016~~~
PROST'AGLANDI:N I ANAhOGUE
- The present invention relates to a novel compound, a prostaglandin I analogue, which is referred to as PGI simply _ hereinafter.
It has been well known that PGIZ has a platelet _- aggregation controlling effect and a hypotensive activity, but it simultaneously has some side effects, e.g. increasing of pulse rate, hot flushes;, abdmoninalgia and the like (S.M.M. ', :Karim et al, PG. Med., 9, 307(1982)).
Japanese Patent Application KOKAI No. 61-78734 discloses an effectiveness of tri.carbonyl-aromatic-group VIB metals complex as a catalyst for reduction of a,l3-unsaturated ' carbonyl compounds, and the production of {(1S,2R,3R,5S)-(E)-7-(4-carbomethoxybutyli.dene)-2-(3-oxooctyl)-3-tetrahydro-pyranyloxy-bicyclo[3.3.0]octane} by the reaction of ' {(1S,5S,6S,7R)-3-(4-carbomethoxy-1(EZ)-butenyl)-6-(3-oxo-(E)- ', 1-octenyl)-7-tetrahydropyranyloxy-bicyclo(3.3.0]octane} in Example 7 of the above-noted reference. Further, Japanese Patent Application KOKF~I No. 61-37740 discloses the same compounds as those refE:rred to in the above noted Example 7.
However, the prior art does not disclose the PGIs (I) and (II) of the present invention, or any uses for these compounds.
The present invention, provides a novel compound of PGIs represented by the following formulae-(I) and (II):
C00R1 a -chain s a_..~~ ~ I ~
''.
R R 2' .
1a 12 1 is lz is cu-chain ~.1!4 16 18 20 .=COOR1 a -chain 9a 6 9 B' R2 R2 1~ 12 m-chain 1.~l.4 15 1B 1~ 18 ig 20 wherein R1 is a hydrogen ai=om or a C:L-C4 alkyl group, R2 in the formula (I) is a halogen atom, RZ in the formula (II) is a fluorine atom, R2' is a hydrogen atom, a halogen atom, a C~-Cz alkyl group, a phenyl group or a benzyl group or pharmaceutically acceptable salts thereof.
The PGIs represented by the formula (I) are generally named as 15-keto-16-subst:itute~:l-9 (0) -methano-~6~9"~-PGIls or 13, 14-dihydro-15-ketc-16-subst itut=ed-9 (0) -methano-o6~9<'~ -PGIls; and the PGIs represented by the formula (II) are generally named as 15-1o keto-16-substituted-9(O)-m.ethano-PGIz or 13,14-dihydro-15-keto-16-substituted-9(O)-methano.-PGI2s.
The PGIs of the present invention are characterized by a bicyclic ring in the molecu:Lar skeleton and by one or two specific substi.tuents at the 16-position. Such substituents contribute to blood pressure hypotension, and a reduction in side effects, e.g. i.ncrease of pulse rate, and other pharmaceutical or physiological activities of PGIs.
Groups represented bar the R2 and R2' include a halogen atom, e.g. a fluorine atom, a ch.l.orine atom and the like; an alkyl 2o group, e.g. met:hyl and etr,y:l; a group containing an aromatic group, e.g. phenyl and ber..~.yl; a hydroxyl group; an alkoxy group, e.g. methoxy and ethoxy. Une or both of Rz and/or R2' being a halogen atom, especially a. f:Luorine atom are most preferred.
R1 in the present invention is a hydrogen atom or alkyl group. As the alkyl group methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl group and the like are included. When Rl is a hydrogen atom, corresponding carboxyl group may form a suitable salt. When the compound of: the present invention is used for a pharmaceutical composition, the salt may be a physiologically 3o acceptable one. Such an alkali forming salt typically includes an alkaline metal, e.g. sodium, potassium and the like, an alkaline earth metal, e.g. calcium, magnesium and the like, ammonia, alkylamine, alkanolamine, e.g. monoethanolamine, diethanolamine, triethanol.am.ine, propanolamine and the like, 3s alkylalkanolamine and the like.
The 13,14-dihydro-PGI-s represented by (I) and saturated at the C13-C14 bond can be prepared, for instance, according to 20i b300 the Synthetic Scheme [I]. That is, commercially available (1S,5S,6R,7R)-6-(triaJLkylsiloxymethyl)-3-formyl-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (aldehyde compound (1)) is reaci~ed with ylide which is separately prepared from (3-carboxypropyl)triphenylphosphine bromide and _- potassium t-butoxide, and then the resultant product is reacted with diazomethane to give an ester (2). The ester (2) is reacted with tetra n-butylammonium fluoride to remove the silyl group to yield ithe alcohol (3). This alcohol (3) is subjected to Collins oxidation to give the aldehyde (4), which is then reacted with an anion prepared from dimethyl(2-oxo-3-substituted-heptyl)phosphonates and sodium hydride so as to introduce an w-chain. The double bond in the w-chain is hydrogenated with pal:ladium/carbon and the like under hydrogen atmosphere. In this process a double bond in the cu-chain, if there is one, is hydrogenated, but a double bond in the ring is not. The tetrahyd:ropyranyl group, a protective group, is removed with an acid ~to give an ester (7) of the objective compound (I). An acid corresponding to the ester (7) can be obtained by hydrolysis of the ester (7) according to a usual work-up. Though as a:n example of phosphonates which can be used to introduce the ~-chain one having a fluorine atom at the 3-position as a substituent is illustrated in Example 1, this substituent may be a halogen, e.g. a chlorine atom; or others, e.g. a methyl, ethyl, phenyl, benzyl, hydroxyl, methoxy or ethoxy group and the like.
PGI~s represented by the formula (I) and having a double bond between C~3-C~4 can be prepared according to a process illustrated by the Synthetic Scheme [II]. In this process the ester (2) which can be prepared according to the same manner as in the Scheme [I] is hydrogenated using palladium/carbon under hydrogen atmosphere to give 4-carbomethoxybutyl compounds (2'). This compound (2') is subjected to treatment with tetra n-butylammonium fluoride to remove the silyl group to yield the alcohol (3'). This alcohol (3') is subjected to ' Collins oxidation to give the aldehyde (4'), which is then reacted with an anion which is prepared from _. 4 _ zc~z ~~oo dimethyl(2-oxo-3-subst:ituted-heptyl)phosphonates and sodium hydride to introduce an o-chain to give the 15-keto compound (5'). The tetrahydropyranyl group, a protective group, is _ removed with an acid to give an ester (7') of the objective compound [I]. An acid corresponding to the ester (7') can be _- obtained by hydrolysis of the ester (7') according to a usual work-up. Though as an example of the phosphonates which can be used to introduce t:he c~-chain one having a fluorine atom at the 3-position as a su:bstituent is illustrated in Example 4, this substituent may be a halogen atom, e.g. a chlorine atom;
or other groups, e.g. a methyl, ethyl, phenyl, benzyl, hydroxyl, methoxy or ethoxy group and the like.
16,16-Difluoro compound (9) can be prepared by reacting '.
an anion derived from dimethyl(2-oxo-3,3-difluoroheptyl) phosphonate with the aldehyde (4') as illustrated in the Synthetic Scheme [III].
13,14-Dihydro-PGI2s represented by the formula (II) can be prepared according to the Synthetic Scheme [IV]. The compound (5) which can be prepared according to the same manner as illustrated in Scheme [I] can be hydrogenated using tricarbonyl chromium methyl benzoate complex (refer to Japanese Patent Application KOKAI No. 61-37740) (in this case the two double bonds on the a-chain and in the ring, which conjugate each other are also hydrogenated to one double bond between the carbon atoms bonding the ring and the a-chain).
The obtained compound is treated with an acid to remove the tetrahydropyranyl group to yield an ester (15') of the objective compound (II). Alternatively, the compound (11) obtained in the above process is reduced with sodium borohydride to alcohol, and then the alcohol is hydrolyzed with an alkali to give a carboxylic acid (13). The objective carboxylic acid (15) can be obtained by removing the tetrahydropyranyl group by hydrolysis after Jones oxidation.
In the Scheme [IV] a fluorine atom is shown as a substituent on the carbon atom adjacent to the carbonyl group, but another substituent as explained hereinbefore may be used.
PGIs represented by the formula (II) can be prepared from ', u'~~
_ 5 _ the compound (5) which. can be obtained according to the processes illustrated by the Synthetic Scheme [V]. The carbonyl group of the compound (5) is reduced using sodium _ borohydride to give a 15-hydroxy compound (5"), which compound (5") is then hydrogenated using tricarbonyl chromium benzoic _- acid methyl complex (~;ee Japanese Patent Application KOKAI No.
61-37740) (in this canoe two double bonds on the a-chain and in the ring, which conjugate each other are also hydrogenated to one double bond between the carbon atoms bonding the ring and the a-chain).
The obtained compound (12) was hydrolysed with alkali to an acid (13'), which acid (13') is then oxidized by Jones oxidation to give a keaone (14'). The tetrahydropyranyl group is removed from the kE~tone (14') by an acid to yield the objective carboxylic acid (15'). The substituents on the carbon atom adjacent t:o the carbonyl group may be other atom ( s ) or group ( s ) a:~ of orementioned .
16,16-Difluoro compound (21) can be prepared by reacting an anion derived from dimethyl(2-oxo-3,3-difluoroheptyl) phosphonate with aldehyde (4) as illustrated in the Synthetic Scheme [VI].
The PGIs of the present invention may include isomers or mixture of isomers. As isomers there are exemplified a keto-hemiacetal tautomer between hydroxyl group at 11-position and carbonyl group at 15-position and optical isomers, geometric isomers and the like.
The present invention is illustrated by Examples, in which compounds are nominated according to IUPAC except the final objective compounds. The carbon number of the bicyclic ring is indicated as :Follows: .
d 1 i OH OH
tA
- 201 ~3~d Example 1 - Preparation of 13,14-dihydro-15-keto-16(RS)-fluoro-9(0)-methano-e6~9"~-PGI~ methyl ester:
1-1 Synthesis oj~ (1S,5S,6S,7R)-6-(t-butyldimethylsiloxy-methyl)-3-[4-carbomethoxy-1(EZ)-butenyl]-7-tetrahydro-pyranyloxy-bicyclo[3.3.0]octo-2-ene (2):
Commercially available (1S,5S,6S,7R)-6-(t-butyldimethyl-siloxymethyl)-3-formy:l-7-tetrahydropyranyloxy-bicyclo [3.3.0]octo-2-ene (1.00 g) (1) was reacted with ylide which was prepared from (3-carboxypropyl)triphenylphosphine bromide and potassium t-butox:ide. A crude carboxylic acid was obtained according to a usual work-up. The product was reacted with diazometJZane in ether. A crude product obtained after a usual work-up was purified using column chromatography (hexane/ethyl acetate = 10/1) to give (1S,5S,6S,7R)-6-(t-butyldimethylsiloxymethyl)-3-[4-carbomethoxy-1(EZ)-butenyl]-7-tetrahydropyranyloxy-'bicyclo[3.3.0]octo-2-ene (2) as a colourless oily product. Yield: 0.85 g (67a) ~H NMR (CDC13~ S 0.05 (6H,s), 0.90 (9H,s), 1.05 ~ 1.95 (lOH,m), 2.10 ~ 3.13 (7H,m), 3.27 ~ 4.22 (SH,m), 3.63 (3H,s), 4.45 ~ 4.69 (lH,m), 5.05 ~ 5"65 (2H,m), 5.97 (0.67H,d, J = 12 Hz), 6.22 (0.33H, d, J = 16 Hz) 1-2 Synthesis of (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-hydroxymet:hyl-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (3):
(1S,5S,6S,7R)-6-(t-Butyldimethylsiloxymethyl)-3-[4-carbomethoxy-1(EZ)-butenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (2) obtained in 1-1 (0.85 g) was dissolved in THF, into which tetra-n-butylammonium fluoride in THF (1.1 M, 6.43 ml) was added, and the mixture was stirred for 18 hours. A crude product obtained after a usual work-up was purified using column chromatography (hexane/ethyl acetate = 1 /1) to give (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo [3.3.0]octo-2-ene (3) as a colourless oily product.
Yield: 0.59 g (96 %) - 7 _ ~H NMR (CDC13)d 1.18 ~ 1.93 {lOH,m), 2.16 ~ 3.28 (BH,m), 3.42 - 4.07(SH,m), 3.6:3(3H,s), 4.55 - 4.64(0.5H,m), 4.66 -°
4.77(0.5H,m), 5.33(0.6'7H,dt, J = 7.5 Hz, J = 12.5 Hz), 5.42 5.67(1.33H,m), 5.99(0.67H,d, J = 12.5 Hz), 6.26(0.33H,d, J = 15.5 Hz).
1-3 Synthesis of (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluo:ro-3-oxo-(E)-1-octenyl]-7-tetrahydro-pyranyloxy-bicyclo[3.3.0]octo-2-ene (5):
(1S,5S,6S,7R)-3-[.4-carbomethoxy-1(EZ)-butenyl]-6-hydroxymethyl-7-tetrah:ydropyranyloxy-bicyclo[3.3.0]octo-2-ene (3) (0.240 g) was subjected to Collins oxidation in methylene chloride at 0 °C. Sodium hydrogen sulfonate was added into the reaction mixture which was then filtered. A crude aldehyde (4) obtained .after concentration under reduced pressure of the filtrate was dissolved in THF, and reacted with an anion which was prepared from dimethyl (2-oxo-3-fluoroheptyl) phosphonate (0.61 g) and sodium hydride with stirring at 50 °C for 5 hours. The reaction mixture was neutralized with acetic acid. A crude product obtained after a usual work-up was purified using column chromatography (hexane/ethyl acetate = 6/1) to give (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluoro-3-oxo(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5) as a pale yellow oily product.
Yield: 0.250 g (85%) ~H NMR(CDC13) b 0.70 -- 1.07 (3H, m) , 1.06 a 2.14 (lSH,m) , 2.15 ~ 4.16(llH,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= 11 Hz), 6.24(0.33H,d, J = 16 Hz), 6.36 - 6.73(lH,m), 6.83 ~ 7.23(lH,m).
1-4 Synthesis of (1S,5S,6R,7R)-3-(4-carbomethoxybutyl-6-[4(RS)-fluoro-3-oxo-octyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene {6):
(1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluoro-3-oxo-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5) (0.094 g) was dissolved in ethyl acetate, into which palladium (5 wt %)/carbon (0.0094 g) was r< .~I
added and stirred unds:r hydrogen atmosphere at 15 °C for 2 hours. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The obtained crude product was chromatographed using a silica gel treated with silver nitrate (15 wt ~) (hexane/ethyl acetate = 12/1 - 9/1) ,- to give (1S,5S,6R,7R)--3-(4-carbomethoxybutyl)-6-[4(RS)-fluoro-3-oxo-octyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (6) as a pale yellow oily product. Yield: 0.042 g (44 0) ~H NMR(CDC13) 8 0. X56 ~ 1.03 (3H,m) , 1.03 ~ 3.12 (3lH,m) , 3.24 ~ 4.02(3H,m), 3.63(3H,s), 4.27 ~ 4.53(0.5H,m), 4.50 ~
4.70(lH,m), 4.83 ~ 5.t)6(0.5H,m), 5.06 ~ 5.33(lH,m).
1-5 Synthesis oi: 13,14-dihydro-15-keto-16(RS)-fluoro-9 (O) -methano-e6~9a>-PGI~ methyl ester:
(1S,5S,6R,7R)-3-(4-carbomethoxybutyl)-6-[4(RS)-fluoro-3-oxo-octyl]-7-tetrahydr_opyranyloxy-bicyclo[3.3.0]octo-2-ene (6) (0.088 g) was dissolvsad in a mixture of acetic acid, water and THF (4 . 2 . 1) and stirred a.t 45 °C for 4 hours. The reaction mixture was <:oncentrated under reduced pressure, and the crude product obtained was purified using column chromatography (hexanEa/ethyl acetate = 6/1 - 4/1) to give 13 , 14-dihydro-15-keto--16 (RS ) -fluoro-9 (O) -methano-o6<9a~_pGI~
methyl ester (7) as a pale yellow product. Yield: 0.072 g (loo o) ~H NMR(CDC13) 8 0.'73 ~ 1. 05 (3H,m) , 1.05 ~ 3.15(25H,m), 3..46 ~ 4.04(lH,m), 3.63(3H,s), 4.33 ~ 4.56(0.5H,m), 4.48 ~ 5.07(0.5H,m), 5.07 ~ 5.36(lH,m).
Example 2 Preparation of 1:3,14-dihydro-15-keto-16(RS)-fluoro-9(O)-methano-PGIZ
2-1 Synthesis o:E (1S,2R,3R,5S)-7(E)-(4-carbomethoxy-butylidene)-2-[4-(RS)~-fluoro-3-oxo-octyl]-3-tetrahydro-pyranyloxy-bicyclo[3.:3.0]octane (11):
(1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluoro-3-oxo-(E)-1-ocltenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5) (0.109 g) was dissolved in acetone in an autoclave, into which a tricarbonyl chromium/methyl benzoate complex (0.023 g) was added. The _ g -mixture was degassed and the contents stirred under a hydrogen atmosphere (70 kg/cm2) at 125 °C for 20 hours. The reaction mixture was concentrated under reduced pressure. The crude _ product obtained was c:hromatographed (hexane/ethyl acetate = 10/1 - 7/1) to give (1S,2R,3R,5S)-7(E)-(4-carbo-_- methoxybutylidene)-2-[4(RS)-fluoro-3-oxo-octyl]-3-tetrahydro-pyranyloxy-bicyclo[3.3.0]octane (11) as a colourless oily product. Yield: 0.157 g (990) ~H NMR(CDC13) 6 0.',~6 - 1.05 (3H,m) , 1.05 ~ 2.91(3lH,m), 3.27 ~ 3.98(3H,m), 3.62(3H,s), 4.31 - 4.72(1.5H,m), 9:.79 - 5.32(1.5H,m).
2-2 Synthesis of (15,2R,3R,5S)-7(E)-(4-carbomethoxy-butylidene)-2-[4(RS)-f:luoro-3(RS)-hydroxy-octyl]-3-tetrahydro-pyranyloxy-bicyclo[3.3.0]octane (12):
(1S,2R,3R,5S)-7(E)-(4-carbomethoxybutylidene)-2-[4(RS)-fluoro-3-oxo-octyl]-3--tetrahydropyranyloxy-bicyclo[3.3.0]
octane (11) (0.197 g) was dissolved in methanol, to which a sodium borohydride (0..017 g) was added at 0 °C. The mixture was stirred for 30 minutes anal treated with a usual work-up.
The crude product obtained was chromatographed (hexane/ethyl acetate = 3/1) to glVE: (1S,2R,3R,5S)-7(E)-(4-carbomethoxy-butylidene)-2-[4(RS)-i:luoro-3(RS)-hydroxy-octyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (12).
Yield: 0.185 g (93 %) ~H NMR (CDC13)S 0.72 ~ 1.05(3H,m), 1.05 - 2.66(32H,m), 3..22 - 4.15(4.5H,m), 3.62(3H,s), 4.42 ~ 4.67(1.5H,m), 5.00 -- 5.31(lH,m).
2-3 Synthesis of (1S,2R,3R,5S)-7(E)-(4-carboxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxyoctyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (13):
(1S,2R,3R,5S)-7(E)-(4-Carbomethoxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-octyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (12) (0.185 g) was dissolved in methanol, to which an aqueous solution of 1N sodium hydroxide (6.5 ml) was added. The mixtu~__~e was stirred at room temperature for 4 hours. After a usual work-up a crude product (1S,2R,3R,5S)-7 (E) -(4-carboxybutyli<iene) -2-[4 (RS) -fluoro-3 (RS) -- 2~ ~ 630 hydroxyoctyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (13) was obtained. Yield 0.184 g.
2-4 Synthesis of (1S,2R,3R,5S)-7(E)-(4-carboxy butylidene)-2-[4(RS)-fluoro-3-oxooctyl]-3-tetrahydro pyranyloxy-bicyclo[3.3.0]octane (14):
(1S,2R,3R,5S)-7(E)-(4-Carboxybutylidene)-2-[4-(RS)-fluoro-3(RS)-hydroxyoctyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (13) (0.184 g) was oxidized with a Jones reagent between about -15 and -5 °C. After stirring for 40 minutes, isopropyl alcohol (0.43 ml) was added, and treated with a usual work-up. The obtained crude product was purified by column chromatography (hexane/ethyl acetate = 15/1 - 10/1) using silica gel treated with an acid (CC-4*: available from Mallineckrodt Co., Ltd.) to give (1S,2R,3R,5S)-7(E)-(4-carboxybutylidene)-2-[4(RS)-fluoro-3-oxooctyl]-3-tetrahydro-pyranyloxy-bicyclo[3.3.0]octane (14) as a colourless oily product. Yield: 0.072 g (40 0) ~H NMR(CDC13) d 0. T2 ~ 1.04 (3H,m) , 1.04 ~ 2.88(3lH,m), 3.20 ~ 3.98(3H,m), 4.20 ~ 4.68(1.5H,m), 4.75 ~ 5.33(1.5H,m), 6.52 ~ 8.52(lH,brs).
2-5 Preparation of 13,14-dihydro-15-keto-16(RS)-fluoro-9(O)-methano-PGIZ (15):
(1S,2R,3R,5S)-7(E~~)-4-Carboxybutylidene)-2-[4(RS)-fluoro 3-oxooctyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]-octane (14) (0.070 g) was dissolved in a mixture of acetic acid, water and THF (4 . 2 . 1) and starred at 45 °C for 3.5 hours. The reaction mixture was concentrated under reduced pressure. The crude product obtaineol was purified by column chromatography (hexane/ethyl acetate = 3.5/1) using a silica gel (CC-4) to give 13,14-dihydro-15-~keto-16(RS)-fluoro-9(O)-methano-PGI2 (15) as a colourless oily product. Yield: 0.048 g (84 0) ~H NMR(CDC13) 8 0. fi5 ~ 1.05 (3H,m) , 1.05 ~ 2.85(25H,m), 3.43 ~ 3.82(lH,m), 4.26 ~ 4.57(0.5H,m), 4.76 ~ 5.35(1.5H,m), °_..20 ~ 6.57(2H,brs).
* Trade mark i ._ 11 Example 3 Preparation of 13,14-dihydro-15-keto-16(RS)-fluoro-9(O)-methano-PGIZ methyl ester (15'):
(1S,2R,3R,5S)-7(E)-(4-Carbomethoxybutylidene)-2-[4(RS)-fluoro-3-oxooctyl]-3-1=etrahydropyranyloxy-bicyclo[3.3.0]
octane (11) (0.070 g) was dissolved in a mixture of acetic acid, water and THF (4 . 2 . 1), and stirred at 45 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography (hexane/ethyl acetate = 3.5/1) to give 13,14-dihydro-15-keto~-16(RS)-fluoro-9(O)-methano-PGIZ methyl ester (15') as a colourless oily product. Yield: 0.038 g (670) ~H NMR(CDC13) 6 0. 75 ~ 1.05 (3H,m) , 1.05 ~ 2.87(26H,m), 3.37 -- 3.96(lH,m), 3.64(3H,s), 4.28 ~ 4.53(0.5H,m), 4.77 - 5.32(1.5H,m). ' Example 4 Preparation of 1y RS)-fluoro-15-keto-9(O1-methano-esc9«~-pGI~ methyl estez_ 4-1 Synthesis o:E (1S,5S,6S,7R)-6-(t-butyldimethyl- ', siloxymethyl)-3-[4-ca:rbomethoxy-1(EZ)-butenyl]-7-tetra-hydropyranyloxy-bicyc:Lo[3.3.0]octo-2-ene (2): ' According to the~same manner as in the Example 1, 1-1 the title compound (2) was prepared.
4-2 Synthesis o:f (1S,5S,6S,7R)-6-(t-butyldimethyl-siloxymethyl)-3-(4-ca:rbomethoxybutyl)-7-tetrahydropyranyloxy-bicyclo[3.3.o]octo-2-~ene (2'):
(1S,5S,6S,7R)-6-(t-Butyldimethylsiloxymethyl)-3-[4-carbomethoxy-1(EZ)-butenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-~ene (2) (0.214 g) was dissolved in methanol, to which palladium (10 %)/carbon (0.050 g) was added, and the mixture was stirred under hydrogen atmosphere at room temperature for 45 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. A crude product was chromatographed (hexane/ethyl acetate = 40/1 - 30/1) using silica gel treated with silver nitrate (10 wt. o) to give (1S,5S,6S,7R)-6-(t-butyldimethyl-~~~ ~~~o siloxymethyl)-3-(4-carbomethoxybutyl)-7-tetrahydropyranyloxy-- bicyclo[3.3.0]octo-2-ene (2') as a colourless oily product.
Yield: 0.151 g (70 ~N NMR(CDC13) 6 0.05 (6H, s) , 0.88 (9H, s) , 0.97 ~ 3.03(2lH,m), 3.23 ~ 4.15(SH,m), 3.62(3H,s), 4.45 ~ 4.69(lH,m), 5.10 ~ 5.33(lH,m).
4-3 Synthesis of (1S,5S,6S,7R)-3-(4-carbomethoxybutyl)-6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (3') (1S,5S,6S,7R)-6-(t-Butyldimethylsiloxymethyl)-3-(4-carbomethoxybutyl)-7-t.etrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (2') (0.294 g) was dissolved in THF into which tetra-n-butyl-ammonium fluoride solution in THF, (1.1 M, 2.2 ml) was added, and stirred at room temperature for 18 hours. A crude compound obtained after a usual work-up was purified by column chromatography (hexane:/ethyl acetate = 1/1) to give (1S,5S,6S,7R)-3-(4-carbomethoxybutyl)-6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (3') as a colourless oily produces. Yield: 0.228 g ~H NMR(CDC13~S 0.76 ~ 3.13 (22H,m) , 3.27 ~ 4.13(SH,m), 3.63(3H,s), 4.46 ~ 4.77(lH,m), 5.02 ~ 5.42(lH,m).
4-4 Synthesis of (1S,5S,6S,7R)-3-(4-carbomethoxybutyl)-6-[4(RS)-fluoro-3-oxo-~(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-E:ne (5'):
(1S,5S,6S,7R)-3-(4-Carbomethoxybutyl)-6-hydroxymethyl-7-tetrahydropyranyloxy-x>icyclo[3.3.0]octo-2-ene (3') (0.125 g) was dissolved in DMSO, to which a solution of triethylamine (0.93 ml) and sulfur t:rioxide/pyridine complex (0.504 g) in DMSO was added, and starred at room temperature for 1.5 hours.
A crude aldehyde (4') obtained after a usual work-up was dissolved in THF, and reacted at 50 °C with the anion prepared from dimethyl(2-oxo-3-~fluoroheptyl)phosphonate (0.341 g) and sodium hydride. After stirring for 3 hours, the reaction mixture was neutralizE:d with acetic acid. A crude product obtained according to a usual work-up was purified by column chromatography (hexane/ethyl acetate = 7/1) to give (1S,5S,6S,7R)-3-(4-carloomethoxybutyl)-6-[4(RS)-fluoro-3-oxo-- (E)-1-octenyl]-7-tetral'nydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5'). Yield: 0.088 g (56 %) ~H NMR(CDC13) E 0.75 ~ 1.06 (3H,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(lH,m), 6.80 -- 7.26 (lH,m) .
4-5 Synthesis of 16(RS)-fluoro-15-keto-9(O)-methano-n6c9a~-PGI~ methyl ester (7' ) (1S,5S,6S,7R)-3-(4-Carbomethoxybutyl)-6-[4(RS)-fluoro-3-oxo-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5') (0.088 g) was dissolved in a mixture of acetic acid, water and THF (4 . 2 . 1), and stirred at 45 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by ' column chromatography (hexane/ethyl acetate = 3/1) to give 16 (RS) -fluoro-15-keto-9 (O) -methano-e6<9a~-PGI~ methyl ester (7' ) .
Yield: 0.069 g (96 %) ~H NMR(CDC13) S 0.72 ~ 1.04 (3H,m) , 1.04 -- 3.18(22H,m), 3.62(3H,s), 3.70 ~ 4.12(lH,m), 4:43 - 4.63(0.5H,m), 4.98 - 5.23(0.5H,m), 5.18 - 5.35(lH,m), 6.53(lH,dd, J = 16 Hz, J = 3 Hz), 6.98(lH,dd, J = 16 Hz, J = 9 Hz) .
Example 5 Preparation of 16,16-difluoro-15-keto-9(O)-methano-~6(9a)-PGI~ methyl ester.:
5-1 Synthesis of (1S,5S,6S,7R)-3-(4-carbomethyoxybutyl)-6-[4,4-difluoro-3-oxo-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (8):
(1S,5S,6S,7R)-3-(4-Carbomethoxybutyl)-6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (3') (0.108 g) was dissolved in DMSO, to which a solution of triethylamine (0.90 ml) and sulfur trioxide/pyridine complex (0.488 g) in DMSO was added, and stirred at room temperature for 30 minutes. A usual work-up gave a crude aldehyde. The crude aldehyde was dissolved in THF, and reacted with an anion prepared from dimethyl(2-oxo-3,3-difluoroheptyl)phosphate A
(0.435 g) and sodium r~ydride. The mixture was heated for 48 hours under reflux, and then neutralized with acetic acid.
A crude product obtained after a usual work-up was purified by column chromatography (hexane/ethyl acetate = 7/1) to give (1S,5S,6S,7R)-3-(4-carbomethoxybutyl)-6-[4,4-difluoro-3-oxo _- (E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (8) as a colourless oily product. Yield: 0.091 g (64 %) ~H NMR(CDCi3~6 0.76 ~ 1.05 (3H,m) , 1. 05 -- 3 .17 (27H,m) , 3 ., 25 - 4. 15 (3H,m) , 3 . 63 (3H, s) , 4.35 ~ 4.75(lH,m), 5.09 - 5.37(lH,m), 6.56(lH,dd, J = 15 Hz, J = 6 Hz), 6.86 ~ 7.37(lH,m).
5-2 Synthesis oi= 16,16-difluoro-15-keto-9(O)-methano-n6c9a~-PGI~ methyl ester' ( 9 ) (1S,5S,6S,7R)-3-(4-Carbomethoxybutyl)-6-[4,4-difluoro-3-oxo-(E)-1-octenyl]-7-i~etrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (8) (0.091 g) w<~s dissolved in a mixture of acetic acid, water and THF (4 . 2 . 1), and stirred at 45 °C for 3 hours.
The reaction mixture was concentrated under reduced pressure, and a crude product was purified on column chromatography (hexane/ethyl acetate = 2/1) to give 16,16-difluoro-15-keto 9 (O) -methano-e6<9a>_pGl,i methyl ester (9) as a colourless oily product. Yield: 0.060 g (80 %) ~H NMR(CDC13) 6 0.76 ~ 1.05 (3H,m) , 1.05 - 3.21(22H,m), 3.62(3H,s), 3.73 - 4.17(lH,m), 5.09 ~ 5.43(lH,m), 6.:56(lH,dd, J = 15 Hz), 7.12(lH,dd, J = 15 Hz , J = 7 . 5 Hz ) .
Example 6 Preparation of 16(RS)-fluoro-15-keto-9(O)-methano-PGI2:
6-1 Synthesis of (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-hydroxymet:hyl-7-tetrahydropyranyloxy-bicyclo [3.3.0]octo-2-ene (5):
According to the same manner as in 1-2 of Example 1 the Compound (3) was prepared.
6-2 Synthesis of (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluoro-3-oxo-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5):
~p1 b3o0 According to the same manner as in 1-3 of Example 1 the above compound {5) was prepared.
6-3 Synthesis of (1S,5S,6S,7R)-3-(4-carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluoro-3(RS)-hydroxy (E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo(3.3.0)octo-2-ene (5"):
_- (1S,5S,6S,7R)-3-[4-Carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluoro-3-oxo-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5) (0.088 g) was dissolved in methanol, into which sodium borohydride (0.008 g) was added at 0 °C and stirred for 30 minutes. The reaction mixture was treated in a usual manner to give {1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-but.enyl]-6-[4(RS)-fluoro-3(RS)-hydroxy-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5") as a colourless oily product. Yield: 0.089 g 'H NMR(CDC13~6 0. 67 - 1.03 (3H,m) , 1.03 ~ 3.19(24H,m), 3.22 ~ 4.34(4.5H,m), 3.62(3H,s), 4.40 ~ 4.74(1.5H,m), 5.07 ~ 6.32(SH,m).
6-4 Synthesis of' (1S,2S,3R,5S)-(E)-7-(4-carbomethoxybutylidene:)-2-[4(RS)-fluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (12'):
(1S,5S,6S,7R)-3-[4-Carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluoro-3(RS)-hydroxy-('E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-E:ne (5") (0.089 g) was placed in an autoclave and dissolved in acetone, into which tricarbonyl chromium/methyl benzoate complex (0.011 g) was added, and then degassed. The mixture in the autoclave was stirred under a hydrogen pressure of 70 kg/cmz at 120 °C for 15 hours. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (hexansa/ethyl acetate = 2/1) to give (1S,2S,3R,5S)-(E)-7-(~6-carbomethoxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-I;E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (12') as a colourless oily product.
Yield: 0.078 g (87 %) ~H NMR(CDC13) 6 0.'70 ~ 1.04 {3H,m) , 1.04 -- 2.67(28H,m), 3..21 - 4.32(4.5H,m), 4.35 - 4.75(1.5H,m), 4.99 - 5.30(lH,m), 5.30 - 5.92(2H,m) di at 6-5 Synthesis of (1S,2S,3R,5S)-(E)-7-(4-Carboxy-butylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (13'):
(1S,2S,3R,5S)-(E)-7-(4-Carbomethoxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (12') (0.129 g) was dissolved in methanol, into which 1N aqueous solution of sodium hydroxide (2 ml) was added, and stirred at room temperature for 6 hours.
After a usual work-up (1S,2S,3R,5S)-(E)-7-(4-carboxy-butylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (13') was obtained as a colourless oily product. Yield: 0.140 g 1H NMR(CDC13)S 0. TO - 1.05(3H,m), 1.05 ~ 2.70(27H,m), 3.26 ~ 6.06(lOH,m).
6-6 Synthesis of (1S,2S,3R,5S)-(E)-7-(4-carboxybutylidene)-2-[4(RS)-fluoro-3-oxo-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (14'):
(1S,2S,3R,5S)-(E)-7-(4-Carboxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (13') (0.140 g) was subjected to Jones oxidation between -15 °C and -20 °C. The mixture was stirred for 30 minutes, isopropyl alcohol was added, and the resultant product was treated by a usual work-up. The obtained crude product was purified by column chromatography (hexane/ethyl acetate = 6/1 - 5/1) to give (1S,2S,3R,5S)-(E)-7-(4-carboxybutylidene)-2-[4(RS)-fluoro-3-oxo-(E)-1-octenyl]-3-tetrahydropyranyloxy-b~icyclo[3.3.0]octane (14') as a colourless oily product. Yield: 0.106 g (76%) ~H NMR (CDC13) 6 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(lH,m).
6-7 Synthesis of 16(RS)-fluoro-15-keto-9(O)-methano-PGI2 (15'):
(1S,2S,3R,5S)-(E)-7-(4-Carboxybutylidene)-2-[4(RS)-fluoro-3-oxo-(E)-1-oct.enyl]-3-tetrahydroxypanyloxy-bicyclo[3.3.0]octane (14') (0.106 g) was dissolved in a mixture of acetic acif., water and THF (4 . 2 . 1), and stirred ~~x~;~
2a~ ~~aa at 45 °C for 3.5 hours. The reaction mixture was concentrated under reduced pressurs:. The crude product was purified by column chromatography (hexane/ethyl acetate = 6/1 - 2/1) using a silica gel (CC-4: ava_Llable from Mailineckrodt Co., Ltd.) to give 16(RS)-fluoro-15--keto-9(O)-methano-PGI2 (15') as a colourless oily produces. Yield: 0.047 g (52 %) ~H NMR(CDC13) 8 0.'74 ~ 1. 04 (3H,m) , 1.04 ~ 2.80(2lH,m), 3..67 ~ 4.07(lH,m), 4.43 ~ 4.65(0.5H,m), ;
4.99 ~ 5.37(1.5H,m), 4.00 ~ 5.60(2H,brs), 6.51(lH,dd, J = 17 Hz, J = 4 Hz), 6.94(lH,dd, J = 17 Hz, J = 7 Hz).
Example 7 Preparation of 1~5,16-difluoro-15-keto-9(O)-methano-PGI2:
7-1 Synthesis o:E (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4,4-difluoro-3-oxo-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (16): ;
(1S,5S,6R,7R)-3-[4-Carbomethoxy-1(EZ)-butenyl]-6-hydroxymethyl-7-tetralzydropyranyloxy-bicyclo[3.3.0]octo-2-ene (3) (0.333 g) was subjected to Collins oxidation in methylene chloride at 0 °C. Af=ter 30 minutes sodium hydrogen sulfate was added to the reaction mixture. The mixture was filtered.
The filtrate was conc~antrated under reduced pressure to give crude aldehyde (4), which was dissolved in THF, and reacted at 70 °C with an anion prepared from dimethyl (2-oxo-3,3-difluoroheptyl)phosphonate (0.970 g) and sodium hydride.
After stirring for 17 hours, the reaction product was neutralized with acetic acid. A crude product obtained after a usual work-up was purified by column chromatography (hexane/ethyl acetate = 6/1) to give (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4,4-difluoro-3-oxo-(E)-1-octenyl]-7-tetrahydro~pyranyloxy-bicyclo[3.3.0]octo-2-ene (16) as a colourless oily product. Yield: 0.196 g (43 %) ~H NMR(CDC13) a 0.73 ~ 1.06 (3H,m) , 1.04 ~ 2.90(23H,m), 2.90 ~ 4.17(3H,m), 3.63(3H,s), 4.33 ~ 4.71(lH,m), 5.10 ~ 5.56(2H,m), 5.94(0.67H,dd, J = 12 Hz), 6.22(0.33:Ei,dd, J = 16.5 Hz), 6.57(lH,dd, J = lS Hz, J = 6 Hz), 6.86 ~ 7.33(lH,m).
- 18 _ 201 00 7-2 Synthesis of (1S,5S,6S,7R}-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4,4-difluoro-3(RS)hydroxy-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (17):
p (1S,5S,6S,7R)-3-[4-Carbomethoxy-1(EZ)-butenyl]-6-[4,4-difluoro-3-oxo-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo - [3.3.0]octo-2-ene (16) (0.196 g) was dissolved in methanol, to which sodium borohydride (0.015 g) was added at 0 °C, and stirred for 30 minutes. After a usual work-up (1S,5S,6S,7R)- ', 3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4,4-difluoro-3(RS)hydroxy-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (17) was obtained as a colourless oily product. ' Yield: 0.184 g (93 %).
~H NMR(CDC13) 6 0. TO ~ 1.03 (3H,m) , 1.03 - 2.72(24H,m), 2.85 - 3.23(lH,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(SH,m).
7-3 Synthesis of (1S,2S,3R,5S}-(E)-7-(4-carbomethoxy-butylidene)-2-[4,4-difluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (18):
(1S,5S,6S,7R)-3-[4-Carbomethoxy-1(EZ)-butenyl]-6-[4,4-difluoro-3(RS)hydroxy-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (17) (0.184 g) was dissolved in acetone and placed in an autoclave, into which tricarbonyl chromium/methyl benzoate complex (0.021 g) was added, and then degassed. The mixture in the autoclave was stirred under ' hydrogen pressure (70 kg/cm2) at 120 °C for l5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained crude prcduct was purified by column chromatography (hexane/ethyl acetate = 7/2 - 3/1) to give (1S,2S,3R,5S)-(E)-7-(4-carbomethoxybutylidene)-2-[4,4-difluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (18) as a colourless oily product.
Yield: 0.175 g (95 %) ~H NMR(CDC13) d O. i'5 ~- 1.05 (3H,m) , 1.05 ~ 2.63(28H,m), 3.23 - 4.00(3H,m), 3.62(3H,s), 4.00 ~ 4.40 (lH,m) , 4.48 -- 4.66 (lH,m} , 5.03 -- 5.32 (lH,m) , 5.33 -- 6.05(2H,m).
7-4 Synthesis of (1S,2S,3R,5S)-(E)-7-{4-carboxy-- butylidene)-2-[4,4-difluoro-3{RS)-hydroxy-{E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (19):
(1S,2S,3R,5S)-{E)-7-(4-Carbomethoxybutylidene)-2-[4,4-difluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-.- bicyclo[3.3.0]octane {18) (0.175 g) was dissolved into methanol, to which 1N aqueous solution of sodium hydroxide was added. The mixture was stirred until the mixture became completely clear. After a usual work-up a crude product, (1S,2S,3R,5S)-(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: 0.172 g ~H NMR(CDC13) d 0. TO ~ 1.03 (3H,m) , 1.03 ~ 2.73(27H,m), 3.22 ~ 4.39(4H,m), 4.40 ~ 4.72(lH,m), 4.98 ~ 5.35(lH,m), 5.35 ~ 6.03(2H,m), 3.22 ~ 6.13(2H,brs).
7-5 Synthesis of {1S,2S,3R,5S)-(E)-7-{4-carboxybutylidene)-2-[4,4-difluoro-3-oxo-(E)-1-octenyl]-3-tetrahydropyranyloxy-b~icyclo[3.3.0]octane (20):
(1S,2S,3R,5S)-(E)-7-(4-Carboxybutylidene)-2-[4,4-difluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane {19) (0.172 g) was subjected to Collins oxidation at room temperature. The mixture was stirred for minutes, sodium hydrogen sulfonate was added, and then filtered. The filtrate was concentrated. The obtained crude 25 product was purified on column chromatography (hexane/ethyl acetate = 20/1 - 10/1) using a silica gel (CC-4) to give (1S,2S,3R,5S)-(E)-7-(4-carboxybutylidene)-2-[4,4-difluoro-3-oxo-(E)-1-octenyl]-3-t.etrahydropyranyloxy-bicyclo[3.3.0]octane (20) . Yield: 0.050 g (30 %) .
30 ~H NMR(CDC13) s 0. Ei6 -y 1.03 (3H,m) , 1.03 ~ 2.75(27H,m), 3.24 ~ 4.08{3H,m}, 4.36 ~ 4.68(lH,m), 5.07 ~ 5.36(lH,m), 6.52(lH,dd, J = 15 Hz, J = 6 Hz), 6.83 ~ 7.30(lH,m), 7.20 ~ 8.20{lH,brs).
7-6 Synthesis of 16,16-difluoro-15-keto-9(O)-methano-PGIZ ( 21 ) -~ 20 -(1S,2S,3R,5S)-(E)-7-(4-Carboxybutylidene)-2-[4,4-difluoro-3-oxo-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane ('20) (0.050 g) was dissolved in a mixture of acetic acid, water and THF (4 . 2 . 1), and stirred at 45 °C for 3.5 hours. Ths~ reaction mixture was concentrated under _- reduced pressure, and the obtained crude product was purified by column chromatography (hexane/ethyl acetate = 4/1) using a silica gel {CC-4) to dive 16,16-difluoro-15-keto-9(O)-methano-PGIZ (21) as a colourless oily product. Yield: 0.033 g (80 %) ~H NMR(CDC13) 8 0.'70 ~ 1.05 (3H,m) , 1.05 ~ 2.90(2lH,m), 3.65 ~ 4.20(lH,m), 5.05 ~ 5.40(lH,m), 4.80 -- 5.95 (2H,brs) , Ei.53 (lH,dd, J = 16 Hz) , 7.07 (lH,dd, J = 16 Hz, J = 7.5 Hz) .
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PROST'AGLANDI:N I ANAhOGUE
- The present invention relates to a novel compound, a prostaglandin I analogue, which is referred to as PGI simply _ hereinafter.
It has been well known that PGIZ has a platelet _- aggregation controlling effect and a hypotensive activity, but it simultaneously has some side effects, e.g. increasing of pulse rate, hot flushes;, abdmoninalgia and the like (S.M.M. ', :Karim et al, PG. Med., 9, 307(1982)).
Japanese Patent Application KOKAI No. 61-78734 discloses an effectiveness of tri.carbonyl-aromatic-group VIB metals complex as a catalyst for reduction of a,l3-unsaturated ' carbonyl compounds, and the production of {(1S,2R,3R,5S)-(E)-7-(4-carbomethoxybutyli.dene)-2-(3-oxooctyl)-3-tetrahydro-pyranyloxy-bicyclo[3.3.0]octane} by the reaction of ' {(1S,5S,6S,7R)-3-(4-carbomethoxy-1(EZ)-butenyl)-6-(3-oxo-(E)- ', 1-octenyl)-7-tetrahydropyranyloxy-bicyclo(3.3.0]octane} in Example 7 of the above-noted reference. Further, Japanese Patent Application KOKF~I No. 61-37740 discloses the same compounds as those refE:rred to in the above noted Example 7.
However, the prior art does not disclose the PGIs (I) and (II) of the present invention, or any uses for these compounds.
The present invention, provides a novel compound of PGIs represented by the following formulae-(I) and (II):
C00R1 a -chain s a_..~~ ~ I ~
''.
R R 2' .
1a 12 1 is lz is cu-chain ~.1!4 16 18 20 .=COOR1 a -chain 9a 6 9 B' R2 R2 1~ 12 m-chain 1.~l.4 15 1B 1~ 18 ig 20 wherein R1 is a hydrogen ai=om or a C:L-C4 alkyl group, R2 in the formula (I) is a halogen atom, RZ in the formula (II) is a fluorine atom, R2' is a hydrogen atom, a halogen atom, a C~-Cz alkyl group, a phenyl group or a benzyl group or pharmaceutically acceptable salts thereof.
The PGIs represented by the formula (I) are generally named as 15-keto-16-subst:itute~:l-9 (0) -methano-~6~9"~-PGIls or 13, 14-dihydro-15-ketc-16-subst itut=ed-9 (0) -methano-o6~9<'~ -PGIls; and the PGIs represented by the formula (II) are generally named as 15-1o keto-16-substituted-9(O)-m.ethano-PGIz or 13,14-dihydro-15-keto-16-substituted-9(O)-methano.-PGI2s.
The PGIs of the present invention are characterized by a bicyclic ring in the molecu:Lar skeleton and by one or two specific substi.tuents at the 16-position. Such substituents contribute to blood pressure hypotension, and a reduction in side effects, e.g. i.ncrease of pulse rate, and other pharmaceutical or physiological activities of PGIs.
Groups represented bar the R2 and R2' include a halogen atom, e.g. a fluorine atom, a ch.l.orine atom and the like; an alkyl 2o group, e.g. met:hyl and etr,y:l; a group containing an aromatic group, e.g. phenyl and ber..~.yl; a hydroxyl group; an alkoxy group, e.g. methoxy and ethoxy. Une or both of Rz and/or R2' being a halogen atom, especially a. f:Luorine atom are most preferred.
R1 in the present invention is a hydrogen atom or alkyl group. As the alkyl group methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl group and the like are included. When Rl is a hydrogen atom, corresponding carboxyl group may form a suitable salt. When the compound of: the present invention is used for a pharmaceutical composition, the salt may be a physiologically 3o acceptable one. Such an alkali forming salt typically includes an alkaline metal, e.g. sodium, potassium and the like, an alkaline earth metal, e.g. calcium, magnesium and the like, ammonia, alkylamine, alkanolamine, e.g. monoethanolamine, diethanolamine, triethanol.am.ine, propanolamine and the like, 3s alkylalkanolamine and the like.
The 13,14-dihydro-PGI-s represented by (I) and saturated at the C13-C14 bond can be prepared, for instance, according to 20i b300 the Synthetic Scheme [I]. That is, commercially available (1S,5S,6R,7R)-6-(triaJLkylsiloxymethyl)-3-formyl-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (aldehyde compound (1)) is reaci~ed with ylide which is separately prepared from (3-carboxypropyl)triphenylphosphine bromide and _- potassium t-butoxide, and then the resultant product is reacted with diazomethane to give an ester (2). The ester (2) is reacted with tetra n-butylammonium fluoride to remove the silyl group to yield ithe alcohol (3). This alcohol (3) is subjected to Collins oxidation to give the aldehyde (4), which is then reacted with an anion prepared from dimethyl(2-oxo-3-substituted-heptyl)phosphonates and sodium hydride so as to introduce an w-chain. The double bond in the w-chain is hydrogenated with pal:ladium/carbon and the like under hydrogen atmosphere. In this process a double bond in the cu-chain, if there is one, is hydrogenated, but a double bond in the ring is not. The tetrahyd:ropyranyl group, a protective group, is removed with an acid ~to give an ester (7) of the objective compound (I). An acid corresponding to the ester (7) can be obtained by hydrolysis of the ester (7) according to a usual work-up. Though as a:n example of phosphonates which can be used to introduce the ~-chain one having a fluorine atom at the 3-position as a substituent is illustrated in Example 1, this substituent may be a halogen, e.g. a chlorine atom; or others, e.g. a methyl, ethyl, phenyl, benzyl, hydroxyl, methoxy or ethoxy group and the like.
PGI~s represented by the formula (I) and having a double bond between C~3-C~4 can be prepared according to a process illustrated by the Synthetic Scheme [II]. In this process the ester (2) which can be prepared according to the same manner as in the Scheme [I] is hydrogenated using palladium/carbon under hydrogen atmosphere to give 4-carbomethoxybutyl compounds (2'). This compound (2') is subjected to treatment with tetra n-butylammonium fluoride to remove the silyl group to yield the alcohol (3'). This alcohol (3') is subjected to ' Collins oxidation to give the aldehyde (4'), which is then reacted with an anion which is prepared from _. 4 _ zc~z ~~oo dimethyl(2-oxo-3-subst:ituted-heptyl)phosphonates and sodium hydride to introduce an o-chain to give the 15-keto compound (5'). The tetrahydropyranyl group, a protective group, is _ removed with an acid to give an ester (7') of the objective compound [I]. An acid corresponding to the ester (7') can be _- obtained by hydrolysis of the ester (7') according to a usual work-up. Though as an example of the phosphonates which can be used to introduce t:he c~-chain one having a fluorine atom at the 3-position as a su:bstituent is illustrated in Example 4, this substituent may be a halogen atom, e.g. a chlorine atom;
or other groups, e.g. a methyl, ethyl, phenyl, benzyl, hydroxyl, methoxy or ethoxy group and the like.
16,16-Difluoro compound (9) can be prepared by reacting '.
an anion derived from dimethyl(2-oxo-3,3-difluoroheptyl) phosphonate with the aldehyde (4') as illustrated in the Synthetic Scheme [III].
13,14-Dihydro-PGI2s represented by the formula (II) can be prepared according to the Synthetic Scheme [IV]. The compound (5) which can be prepared according to the same manner as illustrated in Scheme [I] can be hydrogenated using tricarbonyl chromium methyl benzoate complex (refer to Japanese Patent Application KOKAI No. 61-37740) (in this case the two double bonds on the a-chain and in the ring, which conjugate each other are also hydrogenated to one double bond between the carbon atoms bonding the ring and the a-chain).
The obtained compound is treated with an acid to remove the tetrahydropyranyl group to yield an ester (15') of the objective compound (II). Alternatively, the compound (11) obtained in the above process is reduced with sodium borohydride to alcohol, and then the alcohol is hydrolyzed with an alkali to give a carboxylic acid (13). The objective carboxylic acid (15) can be obtained by removing the tetrahydropyranyl group by hydrolysis after Jones oxidation.
In the Scheme [IV] a fluorine atom is shown as a substituent on the carbon atom adjacent to the carbonyl group, but another substituent as explained hereinbefore may be used.
PGIs represented by the formula (II) can be prepared from ', u'~~
_ 5 _ the compound (5) which. can be obtained according to the processes illustrated by the Synthetic Scheme [V]. The carbonyl group of the compound (5) is reduced using sodium _ borohydride to give a 15-hydroxy compound (5"), which compound (5") is then hydrogenated using tricarbonyl chromium benzoic _- acid methyl complex (~;ee Japanese Patent Application KOKAI No.
61-37740) (in this canoe two double bonds on the a-chain and in the ring, which conjugate each other are also hydrogenated to one double bond between the carbon atoms bonding the ring and the a-chain).
The obtained compound (12) was hydrolysed with alkali to an acid (13'), which acid (13') is then oxidized by Jones oxidation to give a keaone (14'). The tetrahydropyranyl group is removed from the kE~tone (14') by an acid to yield the objective carboxylic acid (15'). The substituents on the carbon atom adjacent t:o the carbonyl group may be other atom ( s ) or group ( s ) a:~ of orementioned .
16,16-Difluoro compound (21) can be prepared by reacting an anion derived from dimethyl(2-oxo-3,3-difluoroheptyl) phosphonate with aldehyde (4) as illustrated in the Synthetic Scheme [VI].
The PGIs of the present invention may include isomers or mixture of isomers. As isomers there are exemplified a keto-hemiacetal tautomer between hydroxyl group at 11-position and carbonyl group at 15-position and optical isomers, geometric isomers and the like.
The present invention is illustrated by Examples, in which compounds are nominated according to IUPAC except the final objective compounds. The carbon number of the bicyclic ring is indicated as :Follows: .
d 1 i OH OH
tA
- 201 ~3~d Example 1 - Preparation of 13,14-dihydro-15-keto-16(RS)-fluoro-9(0)-methano-e6~9"~-PGI~ methyl ester:
1-1 Synthesis oj~ (1S,5S,6S,7R)-6-(t-butyldimethylsiloxy-methyl)-3-[4-carbomethoxy-1(EZ)-butenyl]-7-tetrahydro-pyranyloxy-bicyclo[3.3.0]octo-2-ene (2):
Commercially available (1S,5S,6S,7R)-6-(t-butyldimethyl-siloxymethyl)-3-formy:l-7-tetrahydropyranyloxy-bicyclo [3.3.0]octo-2-ene (1.00 g) (1) was reacted with ylide which was prepared from (3-carboxypropyl)triphenylphosphine bromide and potassium t-butox:ide. A crude carboxylic acid was obtained according to a usual work-up. The product was reacted with diazometJZane in ether. A crude product obtained after a usual work-up was purified using column chromatography (hexane/ethyl acetate = 10/1) to give (1S,5S,6S,7R)-6-(t-butyldimethylsiloxymethyl)-3-[4-carbomethoxy-1(EZ)-butenyl]-7-tetrahydropyranyloxy-'bicyclo[3.3.0]octo-2-ene (2) as a colourless oily product. Yield: 0.85 g (67a) ~H NMR (CDC13~ S 0.05 (6H,s), 0.90 (9H,s), 1.05 ~ 1.95 (lOH,m), 2.10 ~ 3.13 (7H,m), 3.27 ~ 4.22 (SH,m), 3.63 (3H,s), 4.45 ~ 4.69 (lH,m), 5.05 ~ 5"65 (2H,m), 5.97 (0.67H,d, J = 12 Hz), 6.22 (0.33H, d, J = 16 Hz) 1-2 Synthesis of (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-hydroxymet:hyl-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (3):
(1S,5S,6S,7R)-6-(t-Butyldimethylsiloxymethyl)-3-[4-carbomethoxy-1(EZ)-butenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (2) obtained in 1-1 (0.85 g) was dissolved in THF, into which tetra-n-butylammonium fluoride in THF (1.1 M, 6.43 ml) was added, and the mixture was stirred for 18 hours. A crude product obtained after a usual work-up was purified using column chromatography (hexane/ethyl acetate = 1 /1) to give (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo [3.3.0]octo-2-ene (3) as a colourless oily product.
Yield: 0.59 g (96 %) - 7 _ ~H NMR (CDC13)d 1.18 ~ 1.93 {lOH,m), 2.16 ~ 3.28 (BH,m), 3.42 - 4.07(SH,m), 3.6:3(3H,s), 4.55 - 4.64(0.5H,m), 4.66 -°
4.77(0.5H,m), 5.33(0.6'7H,dt, J = 7.5 Hz, J = 12.5 Hz), 5.42 5.67(1.33H,m), 5.99(0.67H,d, J = 12.5 Hz), 6.26(0.33H,d, J = 15.5 Hz).
1-3 Synthesis of (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluo:ro-3-oxo-(E)-1-octenyl]-7-tetrahydro-pyranyloxy-bicyclo[3.3.0]octo-2-ene (5):
(1S,5S,6S,7R)-3-[.4-carbomethoxy-1(EZ)-butenyl]-6-hydroxymethyl-7-tetrah:ydropyranyloxy-bicyclo[3.3.0]octo-2-ene (3) (0.240 g) was subjected to Collins oxidation in methylene chloride at 0 °C. Sodium hydrogen sulfonate was added into the reaction mixture which was then filtered. A crude aldehyde (4) obtained .after concentration under reduced pressure of the filtrate was dissolved in THF, and reacted with an anion which was prepared from dimethyl (2-oxo-3-fluoroheptyl) phosphonate (0.61 g) and sodium hydride with stirring at 50 °C for 5 hours. The reaction mixture was neutralized with acetic acid. A crude product obtained after a usual work-up was purified using column chromatography (hexane/ethyl acetate = 6/1) to give (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluoro-3-oxo(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5) as a pale yellow oily product.
Yield: 0.250 g (85%) ~H NMR(CDC13) b 0.70 -- 1.07 (3H, m) , 1.06 a 2.14 (lSH,m) , 2.15 ~ 4.16(llH,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= 11 Hz), 6.24(0.33H,d, J = 16 Hz), 6.36 - 6.73(lH,m), 6.83 ~ 7.23(lH,m).
1-4 Synthesis of (1S,5S,6R,7R)-3-(4-carbomethoxybutyl-6-[4(RS)-fluoro-3-oxo-octyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene {6):
(1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluoro-3-oxo-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5) (0.094 g) was dissolved in ethyl acetate, into which palladium (5 wt %)/carbon (0.0094 g) was r< .~I
added and stirred unds:r hydrogen atmosphere at 15 °C for 2 hours. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The obtained crude product was chromatographed using a silica gel treated with silver nitrate (15 wt ~) (hexane/ethyl acetate = 12/1 - 9/1) ,- to give (1S,5S,6R,7R)--3-(4-carbomethoxybutyl)-6-[4(RS)-fluoro-3-oxo-octyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (6) as a pale yellow oily product. Yield: 0.042 g (44 0) ~H NMR(CDC13) 8 0. X56 ~ 1.03 (3H,m) , 1.03 ~ 3.12 (3lH,m) , 3.24 ~ 4.02(3H,m), 3.63(3H,s), 4.27 ~ 4.53(0.5H,m), 4.50 ~
4.70(lH,m), 4.83 ~ 5.t)6(0.5H,m), 5.06 ~ 5.33(lH,m).
1-5 Synthesis oi: 13,14-dihydro-15-keto-16(RS)-fluoro-9 (O) -methano-e6~9a>-PGI~ methyl ester:
(1S,5S,6R,7R)-3-(4-carbomethoxybutyl)-6-[4(RS)-fluoro-3-oxo-octyl]-7-tetrahydr_opyranyloxy-bicyclo[3.3.0]octo-2-ene (6) (0.088 g) was dissolvsad in a mixture of acetic acid, water and THF (4 . 2 . 1) and stirred a.t 45 °C for 4 hours. The reaction mixture was <:oncentrated under reduced pressure, and the crude product obtained was purified using column chromatography (hexanEa/ethyl acetate = 6/1 - 4/1) to give 13 , 14-dihydro-15-keto--16 (RS ) -fluoro-9 (O) -methano-o6<9a~_pGI~
methyl ester (7) as a pale yellow product. Yield: 0.072 g (loo o) ~H NMR(CDC13) 8 0.'73 ~ 1. 05 (3H,m) , 1.05 ~ 3.15(25H,m), 3..46 ~ 4.04(lH,m), 3.63(3H,s), 4.33 ~ 4.56(0.5H,m), 4.48 ~ 5.07(0.5H,m), 5.07 ~ 5.36(lH,m).
Example 2 Preparation of 1:3,14-dihydro-15-keto-16(RS)-fluoro-9(O)-methano-PGIZ
2-1 Synthesis o:E (1S,2R,3R,5S)-7(E)-(4-carbomethoxy-butylidene)-2-[4-(RS)~-fluoro-3-oxo-octyl]-3-tetrahydro-pyranyloxy-bicyclo[3.:3.0]octane (11):
(1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluoro-3-oxo-(E)-1-ocltenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5) (0.109 g) was dissolved in acetone in an autoclave, into which a tricarbonyl chromium/methyl benzoate complex (0.023 g) was added. The _ g -mixture was degassed and the contents stirred under a hydrogen atmosphere (70 kg/cm2) at 125 °C for 20 hours. The reaction mixture was concentrated under reduced pressure. The crude _ product obtained was c:hromatographed (hexane/ethyl acetate = 10/1 - 7/1) to give (1S,2R,3R,5S)-7(E)-(4-carbo-_- methoxybutylidene)-2-[4(RS)-fluoro-3-oxo-octyl]-3-tetrahydro-pyranyloxy-bicyclo[3.3.0]octane (11) as a colourless oily product. Yield: 0.157 g (990) ~H NMR(CDC13) 6 0.',~6 - 1.05 (3H,m) , 1.05 ~ 2.91(3lH,m), 3.27 ~ 3.98(3H,m), 3.62(3H,s), 4.31 - 4.72(1.5H,m), 9:.79 - 5.32(1.5H,m).
2-2 Synthesis of (15,2R,3R,5S)-7(E)-(4-carbomethoxy-butylidene)-2-[4(RS)-f:luoro-3(RS)-hydroxy-octyl]-3-tetrahydro-pyranyloxy-bicyclo[3.3.0]octane (12):
(1S,2R,3R,5S)-7(E)-(4-carbomethoxybutylidene)-2-[4(RS)-fluoro-3-oxo-octyl]-3--tetrahydropyranyloxy-bicyclo[3.3.0]
octane (11) (0.197 g) was dissolved in methanol, to which a sodium borohydride (0..017 g) was added at 0 °C. The mixture was stirred for 30 minutes anal treated with a usual work-up.
The crude product obtained was chromatographed (hexane/ethyl acetate = 3/1) to glVE: (1S,2R,3R,5S)-7(E)-(4-carbomethoxy-butylidene)-2-[4(RS)-i:luoro-3(RS)-hydroxy-octyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (12).
Yield: 0.185 g (93 %) ~H NMR (CDC13)S 0.72 ~ 1.05(3H,m), 1.05 - 2.66(32H,m), 3..22 - 4.15(4.5H,m), 3.62(3H,s), 4.42 ~ 4.67(1.5H,m), 5.00 -- 5.31(lH,m).
2-3 Synthesis of (1S,2R,3R,5S)-7(E)-(4-carboxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxyoctyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (13):
(1S,2R,3R,5S)-7(E)-(4-Carbomethoxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-octyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (12) (0.185 g) was dissolved in methanol, to which an aqueous solution of 1N sodium hydroxide (6.5 ml) was added. The mixtu~__~e was stirred at room temperature for 4 hours. After a usual work-up a crude product (1S,2R,3R,5S)-7 (E) -(4-carboxybutyli<iene) -2-[4 (RS) -fluoro-3 (RS) -- 2~ ~ 630 hydroxyoctyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (13) was obtained. Yield 0.184 g.
2-4 Synthesis of (1S,2R,3R,5S)-7(E)-(4-carboxy butylidene)-2-[4(RS)-fluoro-3-oxooctyl]-3-tetrahydro pyranyloxy-bicyclo[3.3.0]octane (14):
(1S,2R,3R,5S)-7(E)-(4-Carboxybutylidene)-2-[4-(RS)-fluoro-3(RS)-hydroxyoctyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (13) (0.184 g) was oxidized with a Jones reagent between about -15 and -5 °C. After stirring for 40 minutes, isopropyl alcohol (0.43 ml) was added, and treated with a usual work-up. The obtained crude product was purified by column chromatography (hexane/ethyl acetate = 15/1 - 10/1) using silica gel treated with an acid (CC-4*: available from Mallineckrodt Co., Ltd.) to give (1S,2R,3R,5S)-7(E)-(4-carboxybutylidene)-2-[4(RS)-fluoro-3-oxooctyl]-3-tetrahydro-pyranyloxy-bicyclo[3.3.0]octane (14) as a colourless oily product. Yield: 0.072 g (40 0) ~H NMR(CDC13) d 0. T2 ~ 1.04 (3H,m) , 1.04 ~ 2.88(3lH,m), 3.20 ~ 3.98(3H,m), 4.20 ~ 4.68(1.5H,m), 4.75 ~ 5.33(1.5H,m), 6.52 ~ 8.52(lH,brs).
2-5 Preparation of 13,14-dihydro-15-keto-16(RS)-fluoro-9(O)-methano-PGIZ (15):
(1S,2R,3R,5S)-7(E~~)-4-Carboxybutylidene)-2-[4(RS)-fluoro 3-oxooctyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]-octane (14) (0.070 g) was dissolved in a mixture of acetic acid, water and THF (4 . 2 . 1) and starred at 45 °C for 3.5 hours. The reaction mixture was concentrated under reduced pressure. The crude product obtaineol was purified by column chromatography (hexane/ethyl acetate = 3.5/1) using a silica gel (CC-4) to give 13,14-dihydro-15-~keto-16(RS)-fluoro-9(O)-methano-PGI2 (15) as a colourless oily product. Yield: 0.048 g (84 0) ~H NMR(CDC13) 8 0. fi5 ~ 1.05 (3H,m) , 1.05 ~ 2.85(25H,m), 3.43 ~ 3.82(lH,m), 4.26 ~ 4.57(0.5H,m), 4.76 ~ 5.35(1.5H,m), °_..20 ~ 6.57(2H,brs).
* Trade mark i ._ 11 Example 3 Preparation of 13,14-dihydro-15-keto-16(RS)-fluoro-9(O)-methano-PGIZ methyl ester (15'):
(1S,2R,3R,5S)-7(E)-(4-Carbomethoxybutylidene)-2-[4(RS)-fluoro-3-oxooctyl]-3-1=etrahydropyranyloxy-bicyclo[3.3.0]
octane (11) (0.070 g) was dissolved in a mixture of acetic acid, water and THF (4 . 2 . 1), and stirred at 45 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography (hexane/ethyl acetate = 3.5/1) to give 13,14-dihydro-15-keto~-16(RS)-fluoro-9(O)-methano-PGIZ methyl ester (15') as a colourless oily product. Yield: 0.038 g (670) ~H NMR(CDC13) 6 0. 75 ~ 1.05 (3H,m) , 1.05 ~ 2.87(26H,m), 3.37 -- 3.96(lH,m), 3.64(3H,s), 4.28 ~ 4.53(0.5H,m), 4.77 - 5.32(1.5H,m). ' Example 4 Preparation of 1y RS)-fluoro-15-keto-9(O1-methano-esc9«~-pGI~ methyl estez_ 4-1 Synthesis o:E (1S,5S,6S,7R)-6-(t-butyldimethyl- ', siloxymethyl)-3-[4-ca:rbomethoxy-1(EZ)-butenyl]-7-tetra-hydropyranyloxy-bicyc:Lo[3.3.0]octo-2-ene (2): ' According to the~same manner as in the Example 1, 1-1 the title compound (2) was prepared.
4-2 Synthesis o:f (1S,5S,6S,7R)-6-(t-butyldimethyl-siloxymethyl)-3-(4-ca:rbomethoxybutyl)-7-tetrahydropyranyloxy-bicyclo[3.3.o]octo-2-~ene (2'):
(1S,5S,6S,7R)-6-(t-Butyldimethylsiloxymethyl)-3-[4-carbomethoxy-1(EZ)-butenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-~ene (2) (0.214 g) was dissolved in methanol, to which palladium (10 %)/carbon (0.050 g) was added, and the mixture was stirred under hydrogen atmosphere at room temperature for 45 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. A crude product was chromatographed (hexane/ethyl acetate = 40/1 - 30/1) using silica gel treated with silver nitrate (10 wt. o) to give (1S,5S,6S,7R)-6-(t-butyldimethyl-~~~ ~~~o siloxymethyl)-3-(4-carbomethoxybutyl)-7-tetrahydropyranyloxy-- bicyclo[3.3.0]octo-2-ene (2') as a colourless oily product.
Yield: 0.151 g (70 ~N NMR(CDC13) 6 0.05 (6H, s) , 0.88 (9H, s) , 0.97 ~ 3.03(2lH,m), 3.23 ~ 4.15(SH,m), 3.62(3H,s), 4.45 ~ 4.69(lH,m), 5.10 ~ 5.33(lH,m).
4-3 Synthesis of (1S,5S,6S,7R)-3-(4-carbomethoxybutyl)-6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (3') (1S,5S,6S,7R)-6-(t-Butyldimethylsiloxymethyl)-3-(4-carbomethoxybutyl)-7-t.etrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (2') (0.294 g) was dissolved in THF into which tetra-n-butyl-ammonium fluoride solution in THF, (1.1 M, 2.2 ml) was added, and stirred at room temperature for 18 hours. A crude compound obtained after a usual work-up was purified by column chromatography (hexane:/ethyl acetate = 1/1) to give (1S,5S,6S,7R)-3-(4-carbomethoxybutyl)-6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (3') as a colourless oily produces. Yield: 0.228 g ~H NMR(CDC13~S 0.76 ~ 3.13 (22H,m) , 3.27 ~ 4.13(SH,m), 3.63(3H,s), 4.46 ~ 4.77(lH,m), 5.02 ~ 5.42(lH,m).
4-4 Synthesis of (1S,5S,6S,7R)-3-(4-carbomethoxybutyl)-6-[4(RS)-fluoro-3-oxo-~(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-E:ne (5'):
(1S,5S,6S,7R)-3-(4-Carbomethoxybutyl)-6-hydroxymethyl-7-tetrahydropyranyloxy-x>icyclo[3.3.0]octo-2-ene (3') (0.125 g) was dissolved in DMSO, to which a solution of triethylamine (0.93 ml) and sulfur t:rioxide/pyridine complex (0.504 g) in DMSO was added, and starred at room temperature for 1.5 hours.
A crude aldehyde (4') obtained after a usual work-up was dissolved in THF, and reacted at 50 °C with the anion prepared from dimethyl(2-oxo-3-~fluoroheptyl)phosphonate (0.341 g) and sodium hydride. After stirring for 3 hours, the reaction mixture was neutralizE:d with acetic acid. A crude product obtained according to a usual work-up was purified by column chromatography (hexane/ethyl acetate = 7/1) to give (1S,5S,6S,7R)-3-(4-carloomethoxybutyl)-6-[4(RS)-fluoro-3-oxo-- (E)-1-octenyl]-7-tetral'nydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5'). Yield: 0.088 g (56 %) ~H NMR(CDC13) E 0.75 ~ 1.06 (3H,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(lH,m), 6.80 -- 7.26 (lH,m) .
4-5 Synthesis of 16(RS)-fluoro-15-keto-9(O)-methano-n6c9a~-PGI~ methyl ester (7' ) (1S,5S,6S,7R)-3-(4-Carbomethoxybutyl)-6-[4(RS)-fluoro-3-oxo-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5') (0.088 g) was dissolved in a mixture of acetic acid, water and THF (4 . 2 . 1), and stirred at 45 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by ' column chromatography (hexane/ethyl acetate = 3/1) to give 16 (RS) -fluoro-15-keto-9 (O) -methano-e6<9a~-PGI~ methyl ester (7' ) .
Yield: 0.069 g (96 %) ~H NMR(CDC13) S 0.72 ~ 1.04 (3H,m) , 1.04 -- 3.18(22H,m), 3.62(3H,s), 3.70 ~ 4.12(lH,m), 4:43 - 4.63(0.5H,m), 4.98 - 5.23(0.5H,m), 5.18 - 5.35(lH,m), 6.53(lH,dd, J = 16 Hz, J = 3 Hz), 6.98(lH,dd, J = 16 Hz, J = 9 Hz) .
Example 5 Preparation of 16,16-difluoro-15-keto-9(O)-methano-~6(9a)-PGI~ methyl ester.:
5-1 Synthesis of (1S,5S,6S,7R)-3-(4-carbomethyoxybutyl)-6-[4,4-difluoro-3-oxo-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (8):
(1S,5S,6S,7R)-3-(4-Carbomethoxybutyl)-6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (3') (0.108 g) was dissolved in DMSO, to which a solution of triethylamine (0.90 ml) and sulfur trioxide/pyridine complex (0.488 g) in DMSO was added, and stirred at room temperature for 30 minutes. A usual work-up gave a crude aldehyde. The crude aldehyde was dissolved in THF, and reacted with an anion prepared from dimethyl(2-oxo-3,3-difluoroheptyl)phosphate A
(0.435 g) and sodium r~ydride. The mixture was heated for 48 hours under reflux, and then neutralized with acetic acid.
A crude product obtained after a usual work-up was purified by column chromatography (hexane/ethyl acetate = 7/1) to give (1S,5S,6S,7R)-3-(4-carbomethoxybutyl)-6-[4,4-difluoro-3-oxo _- (E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (8) as a colourless oily product. Yield: 0.091 g (64 %) ~H NMR(CDCi3~6 0.76 ~ 1.05 (3H,m) , 1. 05 -- 3 .17 (27H,m) , 3 ., 25 - 4. 15 (3H,m) , 3 . 63 (3H, s) , 4.35 ~ 4.75(lH,m), 5.09 - 5.37(lH,m), 6.56(lH,dd, J = 15 Hz, J = 6 Hz), 6.86 ~ 7.37(lH,m).
5-2 Synthesis oi= 16,16-difluoro-15-keto-9(O)-methano-n6c9a~-PGI~ methyl ester' ( 9 ) (1S,5S,6S,7R)-3-(4-Carbomethoxybutyl)-6-[4,4-difluoro-3-oxo-(E)-1-octenyl]-7-i~etrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (8) (0.091 g) w<~s dissolved in a mixture of acetic acid, water and THF (4 . 2 . 1), and stirred at 45 °C for 3 hours.
The reaction mixture was concentrated under reduced pressure, and a crude product was purified on column chromatography (hexane/ethyl acetate = 2/1) to give 16,16-difluoro-15-keto 9 (O) -methano-e6<9a>_pGl,i methyl ester (9) as a colourless oily product. Yield: 0.060 g (80 %) ~H NMR(CDC13) 6 0.76 ~ 1.05 (3H,m) , 1.05 - 3.21(22H,m), 3.62(3H,s), 3.73 - 4.17(lH,m), 5.09 ~ 5.43(lH,m), 6.:56(lH,dd, J = 15 Hz), 7.12(lH,dd, J = 15 Hz , J = 7 . 5 Hz ) .
Example 6 Preparation of 16(RS)-fluoro-15-keto-9(O)-methano-PGI2:
6-1 Synthesis of (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-hydroxymet:hyl-7-tetrahydropyranyloxy-bicyclo [3.3.0]octo-2-ene (5):
According to the same manner as in 1-2 of Example 1 the Compound (3) was prepared.
6-2 Synthesis of (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluoro-3-oxo-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5):
~p1 b3o0 According to the same manner as in 1-3 of Example 1 the above compound {5) was prepared.
6-3 Synthesis of (1S,5S,6S,7R)-3-(4-carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluoro-3(RS)-hydroxy (E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo(3.3.0)octo-2-ene (5"):
_- (1S,5S,6S,7R)-3-[4-Carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluoro-3-oxo-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5) (0.088 g) was dissolved in methanol, into which sodium borohydride (0.008 g) was added at 0 °C and stirred for 30 minutes. The reaction mixture was treated in a usual manner to give {1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-but.enyl]-6-[4(RS)-fluoro-3(RS)-hydroxy-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (5") as a colourless oily product. Yield: 0.089 g 'H NMR(CDC13~6 0. 67 - 1.03 (3H,m) , 1.03 ~ 3.19(24H,m), 3.22 ~ 4.34(4.5H,m), 3.62(3H,s), 4.40 ~ 4.74(1.5H,m), 5.07 ~ 6.32(SH,m).
6-4 Synthesis of' (1S,2S,3R,5S)-(E)-7-(4-carbomethoxybutylidene:)-2-[4(RS)-fluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (12'):
(1S,5S,6S,7R)-3-[4-Carbomethoxy-1(EZ)-butenyl]-6-[4(RS)-fluoro-3(RS)-hydroxy-('E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-E:ne (5") (0.089 g) was placed in an autoclave and dissolved in acetone, into which tricarbonyl chromium/methyl benzoate complex (0.011 g) was added, and then degassed. The mixture in the autoclave was stirred under a hydrogen pressure of 70 kg/cmz at 120 °C for 15 hours. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (hexansa/ethyl acetate = 2/1) to give (1S,2S,3R,5S)-(E)-7-(~6-carbomethoxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-I;E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (12') as a colourless oily product.
Yield: 0.078 g (87 %) ~H NMR(CDC13) 6 0.'70 ~ 1.04 {3H,m) , 1.04 -- 2.67(28H,m), 3..21 - 4.32(4.5H,m), 4.35 - 4.75(1.5H,m), 4.99 - 5.30(lH,m), 5.30 - 5.92(2H,m) di at 6-5 Synthesis of (1S,2S,3R,5S)-(E)-7-(4-Carboxy-butylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (13'):
(1S,2S,3R,5S)-(E)-7-(4-Carbomethoxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (12') (0.129 g) was dissolved in methanol, into which 1N aqueous solution of sodium hydroxide (2 ml) was added, and stirred at room temperature for 6 hours.
After a usual work-up (1S,2S,3R,5S)-(E)-7-(4-carboxy-butylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (13') was obtained as a colourless oily product. Yield: 0.140 g 1H NMR(CDC13)S 0. TO - 1.05(3H,m), 1.05 ~ 2.70(27H,m), 3.26 ~ 6.06(lOH,m).
6-6 Synthesis of (1S,2S,3R,5S)-(E)-7-(4-carboxybutylidene)-2-[4(RS)-fluoro-3-oxo-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (14'):
(1S,2S,3R,5S)-(E)-7-(4-Carboxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (13') (0.140 g) was subjected to Jones oxidation between -15 °C and -20 °C. The mixture was stirred for 30 minutes, isopropyl alcohol was added, and the resultant product was treated by a usual work-up. The obtained crude product was purified by column chromatography (hexane/ethyl acetate = 6/1 - 5/1) to give (1S,2S,3R,5S)-(E)-7-(4-carboxybutylidene)-2-[4(RS)-fluoro-3-oxo-(E)-1-octenyl]-3-tetrahydropyranyloxy-b~icyclo[3.3.0]octane (14') as a colourless oily product. Yield: 0.106 g (76%) ~H NMR (CDC13) 6 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(lH,m).
6-7 Synthesis of 16(RS)-fluoro-15-keto-9(O)-methano-PGI2 (15'):
(1S,2S,3R,5S)-(E)-7-(4-Carboxybutylidene)-2-[4(RS)-fluoro-3-oxo-(E)-1-oct.enyl]-3-tetrahydroxypanyloxy-bicyclo[3.3.0]octane (14') (0.106 g) was dissolved in a mixture of acetic acif., water and THF (4 . 2 . 1), and stirred ~~x~;~
2a~ ~~aa at 45 °C for 3.5 hours. The reaction mixture was concentrated under reduced pressurs:. The crude product was purified by column chromatography (hexane/ethyl acetate = 6/1 - 2/1) using a silica gel (CC-4: ava_Llable from Mailineckrodt Co., Ltd.) to give 16(RS)-fluoro-15--keto-9(O)-methano-PGI2 (15') as a colourless oily produces. Yield: 0.047 g (52 %) ~H NMR(CDC13) 8 0.'74 ~ 1. 04 (3H,m) , 1.04 ~ 2.80(2lH,m), 3..67 ~ 4.07(lH,m), 4.43 ~ 4.65(0.5H,m), ;
4.99 ~ 5.37(1.5H,m), 4.00 ~ 5.60(2H,brs), 6.51(lH,dd, J = 17 Hz, J = 4 Hz), 6.94(lH,dd, J = 17 Hz, J = 7 Hz).
Example 7 Preparation of 1~5,16-difluoro-15-keto-9(O)-methano-PGI2:
7-1 Synthesis o:E (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4,4-difluoro-3-oxo-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (16): ;
(1S,5S,6R,7R)-3-[4-Carbomethoxy-1(EZ)-butenyl]-6-hydroxymethyl-7-tetralzydropyranyloxy-bicyclo[3.3.0]octo-2-ene (3) (0.333 g) was subjected to Collins oxidation in methylene chloride at 0 °C. Af=ter 30 minutes sodium hydrogen sulfate was added to the reaction mixture. The mixture was filtered.
The filtrate was conc~antrated under reduced pressure to give crude aldehyde (4), which was dissolved in THF, and reacted at 70 °C with an anion prepared from dimethyl (2-oxo-3,3-difluoroheptyl)phosphonate (0.970 g) and sodium hydride.
After stirring for 17 hours, the reaction product was neutralized with acetic acid. A crude product obtained after a usual work-up was purified by column chromatography (hexane/ethyl acetate = 6/1) to give (1S,5S,6S,7R)-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4,4-difluoro-3-oxo-(E)-1-octenyl]-7-tetrahydro~pyranyloxy-bicyclo[3.3.0]octo-2-ene (16) as a colourless oily product. Yield: 0.196 g (43 %) ~H NMR(CDC13) a 0.73 ~ 1.06 (3H,m) , 1.04 ~ 2.90(23H,m), 2.90 ~ 4.17(3H,m), 3.63(3H,s), 4.33 ~ 4.71(lH,m), 5.10 ~ 5.56(2H,m), 5.94(0.67H,dd, J = 12 Hz), 6.22(0.33:Ei,dd, J = 16.5 Hz), 6.57(lH,dd, J = lS Hz, J = 6 Hz), 6.86 ~ 7.33(lH,m).
- 18 _ 201 00 7-2 Synthesis of (1S,5S,6S,7R}-3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4,4-difluoro-3(RS)hydroxy-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (17):
p (1S,5S,6S,7R)-3-[4-Carbomethoxy-1(EZ)-butenyl]-6-[4,4-difluoro-3-oxo-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo - [3.3.0]octo-2-ene (16) (0.196 g) was dissolved in methanol, to which sodium borohydride (0.015 g) was added at 0 °C, and stirred for 30 minutes. After a usual work-up (1S,5S,6S,7R)- ', 3-[4-carbomethoxy-1(EZ)-butenyl]-6-[4,4-difluoro-3(RS)hydroxy-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (17) was obtained as a colourless oily product. ' Yield: 0.184 g (93 %).
~H NMR(CDC13) 6 0. TO ~ 1.03 (3H,m) , 1.03 - 2.72(24H,m), 2.85 - 3.23(lH,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(SH,m).
7-3 Synthesis of (1S,2S,3R,5S}-(E)-7-(4-carbomethoxy-butylidene)-2-[4,4-difluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (18):
(1S,5S,6S,7R)-3-[4-Carbomethoxy-1(EZ)-butenyl]-6-[4,4-difluoro-3(RS)hydroxy-(E)-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]octo-2-ene (17) (0.184 g) was dissolved in acetone and placed in an autoclave, into which tricarbonyl chromium/methyl benzoate complex (0.021 g) was added, and then degassed. The mixture in the autoclave was stirred under ' hydrogen pressure (70 kg/cm2) at 120 °C for l5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained crude prcduct was purified by column chromatography (hexane/ethyl acetate = 7/2 - 3/1) to give (1S,2S,3R,5S)-(E)-7-(4-carbomethoxybutylidene)-2-[4,4-difluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (18) as a colourless oily product.
Yield: 0.175 g (95 %) ~H NMR(CDC13) d O. i'5 ~- 1.05 (3H,m) , 1.05 ~ 2.63(28H,m), 3.23 - 4.00(3H,m), 3.62(3H,s), 4.00 ~ 4.40 (lH,m) , 4.48 -- 4.66 (lH,m} , 5.03 -- 5.32 (lH,m) , 5.33 -- 6.05(2H,m).
7-4 Synthesis of (1S,2S,3R,5S)-(E)-7-{4-carboxy-- butylidene)-2-[4,4-difluoro-3{RS)-hydroxy-{E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (19):
(1S,2S,3R,5S)-{E)-7-(4-Carbomethoxybutylidene)-2-[4,4-difluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-.- bicyclo[3.3.0]octane {18) (0.175 g) was dissolved into methanol, to which 1N aqueous solution of sodium hydroxide was added. The mixture was stirred until the mixture became completely clear. After a usual work-up a crude product, (1S,2S,3R,5S)-(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: 0.172 g ~H NMR(CDC13) d 0. TO ~ 1.03 (3H,m) , 1.03 ~ 2.73(27H,m), 3.22 ~ 4.39(4H,m), 4.40 ~ 4.72(lH,m), 4.98 ~ 5.35(lH,m), 5.35 ~ 6.03(2H,m), 3.22 ~ 6.13(2H,brs).
7-5 Synthesis of {1S,2S,3R,5S)-(E)-7-{4-carboxybutylidene)-2-[4,4-difluoro-3-oxo-(E)-1-octenyl]-3-tetrahydropyranyloxy-b~icyclo[3.3.0]octane (20):
(1S,2S,3R,5S)-(E)-7-(4-Carboxybutylidene)-2-[4,4-difluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane {19) (0.172 g) was subjected to Collins oxidation at room temperature. The mixture was stirred for minutes, sodium hydrogen sulfonate was added, and then filtered. The filtrate was concentrated. The obtained crude 25 product was purified on column chromatography (hexane/ethyl acetate = 20/1 - 10/1) using a silica gel (CC-4) to give (1S,2S,3R,5S)-(E)-7-(4-carboxybutylidene)-2-[4,4-difluoro-3-oxo-(E)-1-octenyl]-3-t.etrahydropyranyloxy-bicyclo[3.3.0]octane (20) . Yield: 0.050 g (30 %) .
30 ~H NMR(CDC13) s 0. Ei6 -y 1.03 (3H,m) , 1.03 ~ 2.75(27H,m), 3.24 ~ 4.08{3H,m}, 4.36 ~ 4.68(lH,m), 5.07 ~ 5.36(lH,m), 6.52(lH,dd, J = 15 Hz, J = 6 Hz), 6.83 ~ 7.30(lH,m), 7.20 ~ 8.20{lH,brs).
7-6 Synthesis of 16,16-difluoro-15-keto-9(O)-methano-PGIZ ( 21 ) -~ 20 -(1S,2S,3R,5S)-(E)-7-(4-Carboxybutylidene)-2-[4,4-difluoro-3-oxo-(E)-1-octenyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane ('20) (0.050 g) was dissolved in a mixture of acetic acid, water and THF (4 . 2 . 1), and stirred at 45 °C for 3.5 hours. Ths~ reaction mixture was concentrated under _- reduced pressure, and the obtained crude product was purified by column chromatography (hexane/ethyl acetate = 4/1) using a silica gel {CC-4) to dive 16,16-difluoro-15-keto-9(O)-methano-PGIZ (21) as a colourless oily product. Yield: 0.033 g (80 %) ~H NMR(CDC13) 8 0.'70 ~ 1.05 (3H,m) , 1.05 ~ 2.90(2lH,m), 3.65 ~ 4.20(lH,m), 5.05 ~ 5.40(lH,m), 4.80 -- 5.95 (2H,brs) , Ei.53 (lH,dd, J = 16 Hz) , 7.07 (lH,dd, J = 16 Hz, J = 7.5 Hz) .
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Claims (7)
1. A prostaglandin represented by the following formulae (I) and (II):
wherein R1 is a hydrogen atom or a C1-C4 alkyl group, R2 in the formula (I) is a halogen atom, R2 in the formula (II) is a fluorine atom, R2' is a hydrogen atom, a halogen atom, a C1-C2 alkyl group, a phenyl group, or a benzyl group, or a pharmaceutically acceptable salt thereof.
wherein R1 is a hydrogen atom or a C1-C4 alkyl group, R2 in the formula (I) is a halogen atom, R2 in the formula (II) is a fluorine atom, R2' is a hydrogen atom, a halogen atom, a C1-C2 alkyl group, a phenyl group, or a benzyl group, or a pharmaceutically acceptable salt thereof.
2. A prostaglandin as defined in Claim 1 in which R2 is a fluorine atom.
3. A prostaglandin as defined in Claim 1 or 2 in which R2' is a hydrogen atom or a fluorine atom.
4. A prostaglandin as defined in Claim 1 or 3 being a compound represented by the formula (I).
5. A prostaglandin as defined in Claim 1 being selected from the group consisting of 13,14-dihydro-15-keto-16(RS)-halo-9(O)-methano-.DELTA.6(9.alpha.)-PGI1, 16(RS)-halo-15-keto-9(O)-methano-.DELTA.6(9.alpha.)-PGI, 16,16-dihalo-15-keto-9(O)-methano-.DELTA.6(9.alpha.)-PGI1, an alkyl ester, or a pharmaceutically acceptable salt thereof.
6. A prostaglandin as defined in Claim 1 being selected from the group consisting of 13,14-dihydro-15-keto-16,16-difluoro-9(O)-methano-PGI2, an alkyl ester or a pharmaceutically acceptable salt thereof.
7. A prostaglandin as defined in Claim 1 being selected from the group consisting of 13,14-dihydro-15-keto-16(RS)-fluoro-9(0)-methano-.DELTA.6(9.alpha.) - PGI1, 13,14-dihydro-15-keto-16(RS)-fluoro-9(0)-methano-PGI2, 16(RS)-fluoro-15-keto-9(0)-methano-.DELTA.6(9.alpha.) - PGI1, 16,16-difluoro-15-keto-9(0)-methano-.DELTA.6(9.alpha.) - PGI1, 16(RS)-fluoro-15-keto-9(0)-methano-PGI2, 16,16-difluoro-15-keto-9(0)-methano-PGI2, an alkyl ester or a pharmaceutically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002016300A CA2016300C (en) | 1988-12-27 | 1990-05-08 | Prostaglandin i analogue |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63332219A JPH0791219B2 (en) | 1988-12-27 | 1988-12-27 | New prostaglandin I |
| CA002016300A CA2016300C (en) | 1988-12-27 | 1990-05-08 | Prostaglandin i analogue |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2016300A1 CA2016300A1 (en) | 1991-11-08 |
| CA2016300C true CA2016300C (en) | 2001-12-11 |
Family
ID=25674124
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002016300A Expired - Lifetime CA2016300C (en) | 1988-12-27 | 1990-05-08 | Prostaglandin i analogue |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2016300C (en) |
-
1990
- 1990-05-08 CA CA002016300A patent/CA2016300C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2016300A1 (en) | 1991-11-08 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed | ||
| MKEC | Expiry (correction) |
Effective date: 20121202 |