GB2030144A - Keto-bicyclooctanes - Google Patents

Keto-bicyclooctanes Download PDF

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GB2030144A
GB2030144A GB7935144A GB7935144A GB2030144A GB 2030144 A GB2030144 A GB 2030144A GB 7935144 A GB7935144 A GB 7935144A GB 7935144 A GB7935144 A GB 7935144A GB 2030144 A GB2030144 A GB 2030144A
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hydroxy
bicyclo
endo
compound
trans
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
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    • C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
    • C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
    • C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
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    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/385—Saturated compounds containing a keto group being part of a ring
    • C07C49/487—Saturated compounds containing a keto group being part of a ring containing hydroxy groups
    • C07C49/507—Saturated compounds containing a keto group being part of a ring containing hydroxy groups polycyclic
    • C07C49/513—Saturated compounds containing a keto group being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system
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    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/743—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups having unsaturation outside the rings, e.g. humulones, lupulones
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
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    • C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
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Abstract

The invention concerns a keto- bicyclooctane compound of the formula, <IMAGE> wherein R2 is hydrogen or C4-7 alkyl, R3 is hydrogen or C1-4 alkyl, and X is optionally present and is ethylene or vinylene. Such compounds are useful as intermediates in the preparation of pharmaceutical products.

Description

1
GB 2 030 144 A
1
SPECIFICATION Keto-bicyclooctanes
5 The present invention relates to novel keto-bicyclooctane compounds. 5
Such compounds can be employed as intermediates in the preparation of bicyclooctane compounds of the formula (I);
R,00C-A
10 10
. xvS ®
R4O or5
15 wherein A is optionally present and is ^.4 alkylene, Rt is hydrogen or C^ alkyl, R2 is hydrogen orC4.7 alkyl, 15 R3 is hydrogen or Cn.4 alkyl, X is optionally present and is ethylene orvinyleneand R4and R5are each, independently of one another, hydrogen or a hydroxy-protecting group; or a non-toxic salt of such a compound wherein Rt is hydrogen. Such bicyclooctane compounds (I) are described and claimed in our copending U.K. Application No. 79.08169 and are useful medicines.
20 The present invention provides a keto-bicyclooctane compound of the formula; 20
25 CCv_„/Rz 25
X-C'
HO iH R3 ^
wherein R2 is hydrogen or C4.7 alkyl, R3 is hydrogen or C-i_4 alkyl and X is absent, or is vinylene or ethylene, and when X is vinylene and R2 is n-pentyl, R3 is C^ alkyl.
30 The term "C1.4 alkyl" means a straight or branched alkyl group having from 1 to 4 carbon atoms inclusive 30 (e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl); and "C4_7 alkyl" means a straight or branched alkyl group having from fourto seven carbon atoms inclucive (e.g., n-butyl, n-pentyl, a-methyl-n-pentyl, a,a01-dimethyl-n-pentyl).
A bicyclooctane compound within the formula [I] and specifically of the formula [Ic], 35 35
RjOOC-A
(ic)
40 J hT* 40
wherein R1( R2, R3, X and A are as defined above, can be prepared by reacting a keto-bicyclooctane compound of the formula [II]' 45 „ 45
50 R40 R50 50
wherein R2, R3 and X are as defined above and R4 and R5 are each hydrogen (in which case, the keto-bicyclooctane compount (II)' is specifically of the formula (II), given and defined above) or hydroxy-protecting group, with a compound of the formula [Ilia] 55 55
(R')3P=CH-A-COOM [Ilia]
wherein A is defined above, R' is an aryl and M is an alkali metal or C-i_4 alkyl and, if R4 and R5 are hydroxy-protecting groups, such as tetrahydropyranyl, or alkoxyalkyl, hydrolyzing the resulting product.
60 When A is propylene in [Ilia], M is preferably an alkali metal. 60
Among the bicyclooctane compounds [I] thus obtained, the carboxylic acid compound (R-|=H) can be transformed to its ester derivative by a conventional procedure.
Moreover, the carboxylic acid compound (R-]=H) can be transformed to its pharmacologically acceptable salt form.
65 The pharmaceutical^ acceptable salts of these bicyclooctane compounds may be any of those with 65
2
GB 2 030 144 A
2
pharmaceutically acceptable metal cations such as, sodium, potassium, magnesium and calcium, ammonium or amine cations.
A compound of the formula (II)' can be prepared by the reaction and procedures described and exemplified hereinafter. (Chart A)
Chart A
£
(i)
H
C00H
CH20H
CHjCN
OH CH20H (4)
OH CH20C0C6H5 (5)
3^°"^ — Co>^Y^CH2CN
CH20C0C6H5 (6)
CHjOCOCgHj (7)
CHjCN
COOCHo r40
RcO
lxR,
(17)
^COOCHj cc r4O
cooch3
4°3
(18)
r^r-COOCHj
PC
r4o
X-C-I
RcO
/h txR,
(19)
hi *
R4O
r5o
CK)'
3
GB 2 030 144 A
3
wherein R2, R3, R4, R5 and X are as defined above.
The compound (2) is obtained from the compound (1) (Japanese Patent (unexamined) publication No. 51-131871) by reduction. The compound (3) is obtained from the compound (2) by a sequence of mesylation and cyanation. The transformations of the compound (3) to the compound (6) are conducted by reduction, 5 benzoylation and oxidation. Acetalization of the compound (6) followed by hydrolysis affords the compound 5 (8). The transformations of the compound (8) to the compound (10) are conducted by oxidation and epimerization. The compound (13a) is obtained from the compound (10) by reduction (R2=H) or alkylation (R2=C4_7 alkyl) [U.S.P. No. 4,073,933]. In an alternative route, the compound (12) is obtained from the compound (10) by Wittig reaction [U.S.P. 4,073,933], and, if necessary, reduction of the double bond. 10 Oxidation of the compound (13a) affords the compound (12a). The compound (13) is obtained from the 10
compound (12) by reduction (R3=H) or alkylation (R3=C1.4 alkyl). The transformations of the compound (15)
from the compound (13) are conducted by deacetalization, oxidation and, if necessary, protection of the hydroxy group. The compound (17) is obtained from the compound (15) by methanolysis and, if necessary, protection of the hydroxy group. The transformations of the compound (17) to a compound within the 15 formula (II)' are conducted by hydrolysis, esterification, Dieckmann condensation and decarbomethoxyla- 15 tion.
When the compound (II)' is a 2(3-hydroxymethylbicyclo-[3.3.0]octan-7-one[a compound of the formula (20) and within the formula (II) in which X is absent and R2 and R3 are each hydrogen], This compound (20) can be transformed into another compound within the formula (II) by the following procedures (Chart B).
20 Chart B 20
0
CW0H_ Jy _ yp
D.n V^CHO V^X-C-I
25 RA V^CHO 25
R40 r4° 0
(20) (21) x; -CH=CH- (22)
-CH2CH2- (23)
30 ^ 30
njS 0
& <*> V^x-c(R2 CU<Ri
35 W' H(TR3 H0NR3 35
(24) (H)
(wherein R2, R3, R4, R5 and X are as defined above.)
The compound (20) is subjected to acetalization, followed by oxidation on the hydroxymethyl moiety to 40 afford the formyl compound (21). Wittig reaction of the compound (21) affords the enone compound (22), 40 which can be transformed into the dihydro compound (23) by catalytic hydrogenation. Hydride reduction or Grignard reaction on the compound (22) or on the compound (23) affords the compound (24), from which the desired compound within the formula (II) can be obtained by deacetalization.
The following Examples are given for the purpose of illustration of (1) the preparation of starting materials 45 from which compounds of the formula (II) can be prepared in accordance with methods represented by the 45 above charts (Examples 1 to 12), (2) the preparation of compounds embodying the invention in accordance with methods represented by the above charts (Examples 13 to 15), and (3) the conversion of compounds within the formula (II)' given and defined above to compounds within the formula (Ic) given and defined above (Examples 16 to 20).
50 50
Example 1
Into a solution of bicyclo[2.2.1 )heptan-endo-2,3-dicarboxy-endo-5-hydroxy-Y-lactone (5.8 g) in dry tetrahydrofuran (THF, 110 ml), was added a solution of diborane in THF at 0°C.
The reaction solution was stirred for 2 hours (hrs) at same temperature and excess diboran was quenched 55 with water and the mixture was concentrated under reduced pressure. This residue was diluted with 55
chloroform, washed with water, dried and then evaporated to afford an oily bicyclo[2.2.1]heptan-endo-2-hydroxymethyl-endo-3-carboxy-endo-5-hydroxy-y-lactone (4.8 g).
, IRuJjim; 3450,2960,2880,1780,1360,1170,1040,1020.
60 MS m/e: 168,150,139,138. 60
Example 2
Into a solution of bicyclo[2.2.1]heptan-endo-2-hydroxymethyl-endo-3-carboxy-endo-5-hydroxy-Y-lactone (Example 1,4g) in pyridine, was added a solution of mesylchloride (2.85 g) in dry benzene (5 ml) under 65 cooling. After stirring for several hrs, the reaction mixture was diluted with benzene and washed with 10% 65
4
GB 2 030 144 A
4
hydrochloric acid, aqueous sodium bicarbonate and aqueous sodium chloride.
The organic layer was dried and evaporated to afford the desired mesylate. The mesylate obtained above in dimethylsulfoxide (DMSO, 25 ml) was treated with sodium cyanide (2 g) at 90-105°Cfor2 hrs to afford an oily bicyclo[2.2.1]heptan-endo-2-cyanomethyl-endo-3-carboxy-endo-5-hydroxy-y-lactone (3.6 g).
5
IRufe 2250,1780,1360,1170,1040.
MS m/e; 178,177,149,133,105.
Example 3
10 Into a solution of lithium borohydride (15 mmole) in diglyme, was added a solution of bicyclo[2.2.1]-heptan-endo-2-cyanomethyl-endo-3-carboxy-endo-5-hydroxy-Y-lactone (1.7 g) in diglyme under ice cooling. The reaction mixture was stirred for 30 min at room temperature and further for 2 hrs at80°Cand excess lithium borohydride was quenched with acetone. The mixture was poured onto saturated aqueous ammonium chloride, and extracted with chloroform. The chloroform layer was dried and evaporated to 15 afford an oily endo-2-cyanomethyl-endo-3-hydroxymethyl-endo-5-hydroxy-bicyclo[2.2.1]heptane (1.25 g).
IFhjfjim; 3350,2250,1460,1430,1140,1120,1060.
Example 4
20 Into a solution of endo-2-cyanomethyl-endo-3-hydroxymethyl-endo-5-hydroxy-bicyclo[2.2.1]heptane (Examples, 3.6 g) in pyridine (10 ml), was added a solution of benzoyl chloride (2.8 g) in benzene (10 ml) under cooling. The reaction mixture was stirred for 3 hrs at same temperature and further for several hours and ethyl acetate and 10% hydrochloric acid was added. The organic layer was separated, washed with brine, dried and then evaporated to afford the desired endo-2-cyanomethyl-endo-3-benzoyloxymethyl-endo-5-25 hydroxy-bicyclo[2.2.1]heptane (4.1 g) mp. 141-143°C (from ether)
IRt®1? 3450,2250,1710,1600.
Into a solution of the benzoyloxymethyl derivative (4.1 g) obtained above in acetone (41 ml), was added 30 Jone's reagent [prepared with Cr03 (10.3 g), conc. H2S04 (8.7 ml) and H20 (30 ml) under ice cooling. The reaction mixture was treated with isopropyialochol and then extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated to afford the desired endo-2-cyanomethyi-endo-3-benzoyloxymethyl-bicyclo[2.2.1]heptan-5-one (4.0 g). mp. 119-121.5°C (from ether)
35 IR<ujx01; 2250,1740,1720,1600,1580,1340,1330,1320,1310,1280.
MSm/s: 284,283,161,105.
Example 5
A solution of endo-2-cyanomethyl-endo-3-benzoyloxymethylbicyclo[2.2.1]heptan-5-one (Example 4,4 g), 40 ethyleneglycol (4.4 g), methyl orthoformate (1.1 g) and p-toluenesulfonicacid (100 mg) was warmed at70°C for 3 hrs.
The reaction mixture was neutralized with aqueous sodium bicarbonate and extracted with chloroform. The chloroform layer was dried and evaporated to afford the desired endo-2-cyanomethyl-endo-3-benzoyloxymethyl-bicyclo[2.2.1]heptan-5-one ethylene glycol acetal (4.1 g). mp. 129-132°C (from isopropyl-45 alcohol).
IRUma!?'; 2950,2250,1720,1600,1450,1350,1280,1100.
Example 6
50 A solution of endo-2-cyanomethyl-endo-3-benzoyloxymethyl-bicyclo[2.2.1]heptan-5-one-ethylene glycol acetal (Example 5,4.1 g) in methanol was treated with anhydrous K2C03 for 5 hrs and evaporated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The organic layer was dried and evaporated to afford an oily endo-2-cyanomethyl-endo-3-hydroxymethyl-bicyclo[2.2.1]heptan-5-one ethylene glycol acetal (2.5 g).
55
IRufjiny 3450,2950,2250,1090.
MS m/e; 223 (M+), 192.
Example 7
60 A chilled dichloromethane solution of endo-2-cyanomethyl-endo-3-hydroxymethyl-bicyclo[2.2.1]heptan-5-one ethylene glycol acetal (Example 6,2.5 g) was added into the Collins reagent prepared with anhydrous chromium trioxide (9 g) and pyridine (14.3 g) in dichloromethane. Benzene was added and the mixture was filtered and washed with benzene. The filtrate was concentrated under reduced pressure to afford endo-2-cyanomethyl-endo-3-formyl-bicyclo[2.2.1]heptan-5-one ethylene glycol acetal. 65 The endo-aldehyde obtained above was dissolved in benzene (100 ml) and 5 drops of acetic acid and 5
5
10
15
20
25
30
35
40
45
50
55
60
65
5
GB 2 030 144 A
5
drops of piperidine were added. The mixture was refluxed under nitrogen for 2 hrs to give the exo-aldehyde. This aldehyde thus obtained was added into a tetrahydrofuran solution of ylid prepared with dimethyl 2-oxoheptylphosphonate (440 mg) and sodium hydride (50 % mineral oil dispersion, 96 mg) and the mixture was stirred for 2 hrs at room temperature. Evaporation of the solvent gave an oily residue, to which benzene 5 and water was added. The benzene layer was separated and dried over magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel to afford endo-2-cyanomethyl-exo-3-(3'-oxo-trans-1'-octenyl)bicyclo[2.2.1]heptan-5-one ethylene glycol acetal (500 mg) as an oil.
IRVSISR; 2950, 2250,1700,1670,1620,1330,1180.
10
NMR (CCL4)5: 6.6 (IH.d.d), 6.0 (1 H.d), 0.9 (3H.t).
Following the same procedures, but replacing the Wittig reagent (dimethyl 2-oxo-heptyl phosphonate) with other Wittig reagents [J.Am. Chem. Soc.,S7 5675 (1969) and Chem. Rev., 7487, e.q. dimethyl 15 2-oxo-3-methyl heptyl phosphonate and dimethyl 2-oxo-3,3-dimethyl heptyl phosphonate], there were obtained the following compounds: endo-2-cyanomethyl-exo-3-(3'-oxo-4'-methyM'-trans-octenyl)-bicyclo[2.2.1]-heptan-5-one ethylene glycol acetal, as oily substance,
IRufe 2950,2250,1695,1675,1620,1460,1430,1120,1040.
20
NMR (CCL4)5; 6.8 (1H, d.d), 6.25 (1H, d), 1.1 (3H, d); endo-2-cyanomethyl-exo-3-(3'-oxo-4',4'-dimethyl-1'-trans-octenyl)bicyclo[2.2.1]heptan-5-one ethylene glycol acetal as an oil.
IRufjlgy 2950,2250,1680,1620,1460,1445,1430,1120,1040.
25
NMR (CCI4)6; 6.8 (1H, d.d), 6.25 (H, d), 1.05 (6H, s).
Example 8
A methanolic solution of endo-2-cyanomethyl-exo-3-(3'-oxo-trans-1'-octenyl)-bicyclo[2.2.1]heptan-5-one 30 ethylene glycol acetai (Example 7,200 mg) was hydrogenated with 5% Pd-C under atmospheric pressure. The mixture was filtered to remove the catalyst, and the filtrate was concentrated to afford an oily endo-2-cyanomethyl-exo-3-(3'-oxo-octyl)-bicyclo[2.2.1]-heptan-5-one ethylene glycol acetal (200 mg).
IRufHgy 2950,2250,1715,1460,1320,1120,1040.
35
NMR (CDCI3)S; 3.90 (4H, s), 0.9 (3H, s).
Example 9
Into a solution of endo-2-cyanomethyl-exo-3-(3'-oxo-trans-1'-octenyl)-bicyclo[2.2.1]heptan-5-one ethylene 40 glycol acetal (Example 7,500 mg) in dry methanol (30 ml) was added sodium borohydride (500 mg) with ice cooling.
Stirring was continued for 1.5 hrs and excess reducing agent was quenched with acetone, and then the mixture was concentrated under reduced pressure. To the residue thus obtained was added aqueous ammonium chloride and extracted with eth'yl acetate.
45 The organic layer was dried and evaporated to give an oily endo-2-cyanomethyl-exo-3-(3'-hydroxy-trans-1'-octenyl)-bicyclo[2.2.1]heptan-5-one ethylene glycol acetal (450 mg):
IRugls; 3450,2950,2925, 2250,1470,1450,1280,1160,1020.
50 NMR (CDCI3)5; 5.4-5.6 (2H), 3.9 (4H.s), 0.9 (3H.t).
Following the same procedures, there were obtained the following compounds: endo-2-cyanomethyl-exo-3-(4'-methyl-3'-hydroxy-trans-1'-octenyl)-bicyclo[2.2.1]heptan-5-one ethylene glycol acetal as an oil.
55
IRvfiim; 3500,2960,2250,1470,1430,1340,1100,1020.
NMR (CDCI3)6; 5.4-5.6 (2H,m), 3.9 (4H,s), 0.9 (3H,t);
endo-2-cyanomethyl-exo-3-(4',4'-dimethyl-3'-hydroxy-trans-1'-octenyl)-bicyclo[2.2.1]heptan-5-one ethylene 60 glycol acetal as an oil.
IRi^iny 3500,2960, 2250,1470,1440,1340,1100,1020.
NMR (CDCI3)6; 5.7-5.5 (2H,m) 3.9 (4H,s), 0.9 (9H,m); 65 endo-2-cyanomethyl-exo-3-(3'-hydroxy-octyl)-bicyclo[2.2.1]heptan-5-one ethylene glycol acetal as an oil
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GB 2 030 144 A
6
(starting material was obtained by the method of Example 8).
3450,2960,2250,1470,1450,1340,1100,1020.
5 NMR (CDCI3)§; 3.9 (4H,s), 0.9 (3H,t). 5
Example 10.
Following the procedures of Example 9, endo-2-cyanomethyl-exo-e-formyl-bicyclo[2.2.1]heptan-5-one ethylene glycol (obtained by the method of Example 7) was subjected to reduction to give an oily 10 endo-2-cyanomethyl-exo-3-hydroxymethyl-bicyclo[2.2.1]heptan-5-one ethylene glycol acetal. 10
IFtofe 3480,2950,2250,1450,1330,1105,1020.
Example 11.
15 Into a solution of endo-2-cyanomethyl-exo-3(3'-oxo-trans-1'-octenyl)-bicyclo[2.2.1]heptan-5-one ethylene 15 glycol acetal (Example 7,200 mg) in dry ether was added a solution of methylmagnesium iodide (1.1. eq) in dry ether at — 10~0°C. After being stirred at same temperature for 2 hrs, the mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo.
20 The residue was chromatograhed on silica gel using benzene ethyl acetate (10:1) to afford an oily 20
endo-2-cyanomethyl-exo-3-(3'-methyl-3'hydroxy-trans-1'-octenyl)-bicyclo[2.2.1]heptan-5-one ethylene glycol acetal (155 mg).
IRufe 3450, 2940, 2250,1120,1020. 25 : 25
NMR (CDCI3)6; 5.7-5.5 (2H,m), 3.9 (4H,s), 1.25 (3H,s).
Example 12
The foregoing endo-2-cyanomethyl-exo-3-(3'-hydroxy-trans-1'-octenyl)-bicyclo[2.2.1]heptan-5-one 30 ethylene glycol acetal (Example 9,450 mg) was dissolved in a solution of aqueous acetaic acid [5 ml, acetic 30 acid/water, 3:7 (v/v)] and heated at 90°C for 2 hrs.
The reaction mixture was evaporated in vacuo. The residue was diluted with ethyl acetate, washed with brine, dried and then evaporated to afford an oily endo-2-cyanomethyl-exo-3-(3'-hydroxy-trans-1'-octenyl)-bicyclo[2.2.1]heptan-5-one (350 mg). 35 35
IRufilS; 3450, 2950, 2250,1740,1460,1410,1160.
NMR (CDCI3)5; 5.7-5.5 (2H,m), 0.9 (3H,t).
40 The bicycloheptanone (350 mg) thus obtained was dissolved in acetic acid (3 ml) and sodium acetate (500 40 mg) and 30% hydrogen peroxide (2 ml). The mixture was stirred for 24 hrs at room temperature. After addition of 10% aqueous sodium hydrogen sulfite, the mixture was extracted with chloroform. The chloroform layer was washed with water and aqueous sodium bicarbonate, dried and then evaporated to afford an oily 2a-cyanomethyl-3|3-(3'-hydroxy-trans-1'-octenyl)-4a-hydroxy-cyclopentan-1a-acetic acid 6-45 lactone (300 mg). 45
•Rufe 3450, 2950, 2250,1740,1470,1380,1240,1040.
The lactone (300 mg) thus obtained was dissloved in methanol and was treated with anhydrous potassium 50 carbonate (200 mg) with stirring for 4 hrs. The reaction mixture was concentrated, and extracted with 50
chloroform. Evaporation of the solvent afforded an oily 1a-hydroxy-2(3-(3'-hydroxy-trans-1'-octenyl)-3a-cyanomethyl-4a-methoxycarbonylmethyl-cyciopentane (210 mg).
IRu{ji&; 3450, 2950, 2250,1740,1440,1220,1180. 55 55
NMR (CDCI3)6; 5.7-5.4 (2H,m), 3.70 (3H,s), 0.9 (3H,t).
The hydroxy-cyclopentane (210 mg) thus obtained was dissolved in dichloromethane (15 ml) and treated with 2,3-dihydropyran (150 mg) and pyridinium p-toluene-sulfqnic acid (20 mg) with stirring for 4 hrs at room 60 temperature. A solution of aqueous sodium bicarbonate was added and the dichloromethane layer was 60 separated.
Evaporation of the solvent gave 1a-tetrahydropyranyloxy-2p-(3'-tetrahydropyranyloxy-trans-1'-octenyl)-3a-cyanomethy!-4a-methoxycarbonylmethyl-cyclopentane (300 mg) as an oil.
65 IFhjfjim; 2940,2250,1740,1470,1450,1440,1355,1260,1200,1075,1020. 65
7
GB 2 030 144 A
7
NMR (CCI4)S; 5.65-5.3 (2H,m), 4.7-4.4 (2H,m), 3.67 (3H,s), 0.9 (3H,t).
The tetrahydropyranyl ether (460 mg) obtained as described above was dissolved in ethanol (4 ml) and treated with 12N potassium hydroxide solution (2 ml) with refluxing for 15 hrs.
5 The reaction mixture was concentrated under reduced pressure, and carefully acidified with 2N potassium hydrogen sulfate and then extracted well with ethyl acetate. The organic layer was treated with an eythereal solution of diazomethaneto afford an oily 1cx-tetrahydropyranyloxy-2p-(3'-tetrahydropyranyloxy-trans-1'-octenyl)- 3a,4a-bis(methoxycarbonylmethyl)-cyclopentane (425 mg).
10 IRuglgy 2950,1740,1440,1260,1160,1140,1020.
NMR (CCI4)5; 5.6-5.3 (2H,m), 4.7-4.4 (2H, m), 3.60 (6H, s), 0.9 (3H, t).
A benzene solution (15 ml) of the 3,4-bis-(methoxycarbonylmethyl)-cyclopentane (425 mg) obtained above 15 was treated with potassium t-butoxide (130 mg) with refluxing for 4 hrs. After cooling, acetic acid (90 mg) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and then evaporated to afford a mixture of 2|3-(3'-tetrahydropyranyloxy-trans-1'-octenyl)-3a-tetrahydropyranyloxy-6-methoxycarbonyl-bicyclo[3.3.0]octan-7-one and 2(3-tetrahydropyranyloxy-trans-1'-octenyl)-3a-tetrahydropyranloxy-8-methoxy-carbonyl-bicyclo[3.3.0]octan-7-one (320 mg).
20 A mixture of the p-ketoester (320 mg) obtained above was dissolved in pyridine (15 ml) and treated with lithium iodide (600 mg) with refluxing for 5 hrs. After cooling, ether and water was added, and the organic layer was separated, washed with water, dried, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using benzene ethyl acetate (10:1) to afford an oiiy 2(M3'-tetrahydropyranyloxy-trans-1'-octenyl)-3a-tetrahydropyranyloxy-bicyclo[3.3.0]octan-7-one (200 mg).
25
IRuSlSi? 2940,1740,1470,1455,1445,1355,1260,1200,1130,1080,1020.
The tetrahydropyranyl ether (120 mg) thus obtained was mixed with acetic acid-water-terahydrofuran [3 ml, 3:1:1 (v/v)].
30 The mixture was stirred at 45°C for 4 hrs, and then concentrated under reduced pressure to afford an oily 2|3-(3'-hydroxy-trans-1'-octenyl)-3a-hydroxy-bicyclo-[3.3.0]octan-7-one (70 mg).
IRufji™; 3400, 2940,1740,1460,1410,1160,1090,1030.
35 The dio! thus obtained was chromatographed on silica-gel using benzene-ethyl acetate (5:1) to afford 2f5-(3'[3-hydroxy-trans-1'-octenyl)-3a-hydroxy-bicyclo[3.3.0]octan-7-one (23 mg) and 2(3-(3'a-hydroxy-trans-1'-octenyl)-3a-hydroxy-bicyclo[3.3.0]octan-7-one (26 mg) and their mixture (9 mg).
3'P-hydroxy isomer; Rf value (0.20) on TLC (silica gel, AcOEt)
40 IRufilgy 3400,2930,1740,1460,1410,1160,1080.
NMR(CDCI3)6; 5.60 (2H, m), 0.9 (3H, t).
3'a-hydroxy isomer; Rf value (0.12)
45 IRufiinv 3400, 2940,1740,1460,1410,1160,1100,1080.
NMR(CDCI3)6; 5.53 (2H, m), 0.9 (3H,t).
Example 13.
50 The foregoing endo-2-cyanomethyl-exo-3-hydroxymethyl-bicycio[2.2.1]heptan-5-one ethylene glycol acetal (2.0 g) obtained in Example 10 was treated with benzoyl chloride and pyridine according to the procedures of Example 4. The benzoyl derivative thus obtained was dissolved in aqueous acetic acid [acetic acid/water, 3/7 (v/v)], followed by deacetalization according to the procedures of Example 12, to afford a crystalline endo-2-cyanomethyl-exo-3-benzoyloxymethyl-bicyc!o[2.2.1]heptan-5-one (mp. 112-113°, 1.6g).
55
IRufiim; 2950, 2250,1750,1600,1580,1450,1270,1120.
An acetic acid solution (15 ml) of the bicyclo-heptanone (1.5 g) obtained above was treated with sodium acetate (2.25 g) and 30% hydrogen peroxide (7.5 ml) with stirring overnight at room temperature, and the 60 reaction mixture was worked up as described in Example 12 to afford a crystalline 2a-cyanomethyl-3|3-benzoyloxymethyl-4a-hydroxy-cyclopentane-1a-acetic acid S-lactone (1.48 g). mp 91-93°C
IRufiiny 2950,2250,1740,1720,1480,1400,1320.
65 A mixture of the d-lactone (1.0 g) obtained above, conc. hydrochloric acid (5 ml) and methanol (10ml) was
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GB 2 030 144 A
8
refluxedfor 15 hrs, concentrated under reduced pressure, and extracted with chloroform. The chloroform extract was concentrated under reduced pressure to afford an oily 1a-hydroxy-2p-hydroxymethyl-3a,4a-bis-(methoxycarbonylmethyl)-cyclopentane (0.65 g).
5lR<&" 3450,2950,1730,1440,1200,1160. 5
The hydroxy-cyclopentane (0.55 g) thus obtained was dissolved in dichloromethane (10 ml) and treated with 2,3-dihydropyran (400 mg), and p-toluene-sulfonic acid (10 mg) with stirring for 1 hr at room temperature. A solution of aqueous sodium bicarbonate was added and the dichloromethane layer was 10separated. 10
Evaporation of the solvent gave 1a-tetrahydropyranyloxy-2|3-tetrahydropyranyloxymethyl-3a-4a-bis-(methoxycarbonylmethyl)-cyclopentane (0.75 g) as an oil.
IRufe 1740,1440,1380,1360,1320,1260,1040. 15 15
A benzene solution (30 ml) of the 3,4-bis-(methoxycarbonylmethyl)cyclopentane (600 mg) obtained above was treated with potassium t-butoxide (180 mg) with refluxing for 2 hrs. After cooling, the reaction mixture was neutralized with 5% hydrochloric acid, and extracted with benzene.
The benzene extract was washed with water, dried and then evaporated to afford a mixture of 20 2p-tetrahydropyranyloxymethyl-3a-tetrahydropyranyloxy-6-methoxycarbonyi-bicyclo[3.3.0]octan-7-one and 20 2p-tetrahydropyranyloxymethyl-3a-tetrahydropyranyloxy-8-methoxycarbonyl-bicyclo[3.3.0]octan-7-one (360 mg) as an oil.
A mixture of the p-ketoester (360 mg) obtained above was dissolved in dimethylformamide (9 ml) and treated with calcium chloride (150 ml) with refluxing for 3 hrs. After cooling, ether and water was added, and 25 the organic layer was separated, washed with water, dried and evaporated to afford an oily 2p- 25
tetrahydropyranyloxymethyl-3a-tetrahydropyranyloxy-bicycio[3.3.0]-octan-7-one(250 mg).
IRuf"™; 2950,1740,1440,1360,1200,1140,1030.
30 The tetrahydropyranyl ether (200 mg) thus obtained was treated with aqueous acetic acid according to the 30 procedure described in Example 12 to give 2p-hydroxymethyl-3oc-hydroxy-bicyclo[3.3.0]octan-7-one as an oil (92 mg).
IRufe 3400, 2950,1740,1450,1410,1270,1080,1030. 35 35
The diol (330 mg) obtained as described above was dissolved in pyridine and reacted with trityl chloride (630 mg). The mixture was heated at 65°C for 5 hrs, and poured onto ice-water and then extracted with ethyl acetate. The organic layer was dried, and evaporated to afford an oily 2p-trityloxymethyl-1a-hydroxy-bicyclo[3.3.0]octan-7-one (750 mg). 40 40
IRufe 3450, 2920,1735,1595,1490,1450,1370,1240,1150,1040.
This trityl ether (0.53 g) thus obtained was dissolved in dichloromethane (10 ml) and treated with 2,3-dihydropyran (0.2 g) and pyridinium p-toluene sulfonic acid (32 mg). The mixture was stirred for 2 days at 45 room temperature. Ether was added and the mixture was filtered and the filtrate was dried and evaporated to 45 afford an oily 2p-trityloxymethyl-1a-tetrahydropyranyloxy-bicyclo[3.3.0]octan-7-one (0.6 g).
NMR(CDCI3)S; 7.5-7.1 (15H, m), 4.7-4.4 (1h, m).
50 Example 14. 50
A mixture of 2p-hydroxymethyl-3a-hydroxy-bicyclo[3.3.0]octan-7-one (Example 13,1.9 g), ethylene glycol (2.7 g), methyl orthoformate (1.86 g) and p-toluene sulfonic acid (80 mg) was stirred for 16 hrs at room temperature. A solution of aqueous sodium bicarbonate was added and the mixture was extracted well with ethyl acetate. The organic layer was dried and evaporated.
55 The residue was purified by colum chromatography on silica gel using benzene-ethyl acetate (1:1) to 55
afford an oily 2p-hydroxymethyl-3a-hydroxy-bicyclo-[3.3.0]octane ethylene glycol acetal (2.1 g).
IRufe 3400, 2930,1460,1440,1330,1100,1030.
60 NMR (CDCI3)5; 3.9 (4H, s). 60
A solution of the diol obtained above (2.1 g) in dichloromethane was added to a suspension of pyridinium chloro chromate (PCC, 3,1 g, 1.2 eq) and sodium acetate (100 mg) in dichloromethane at 5° under nitrogen. Stirring was continued for 1 hr at 5° and ether was added. The mixture was filtered through Celite and 65 washed with ether. The filtrate was concentrated under reduced pressure to afford an oily 2p-formyl-3a- 65
9
GB 2 030 144 A
9
hydroxy-bicyclo-[3.3.0]octane ethylene glycol acetal (1.7 g).
3400,1710.
5 NMR (CDCI3)S; 9.42 (1H, s), 3.85 (4H, s).
The aldehyde thus obtained was treated with a tetrahydrofuran solution of the ylid obtained from dimethyl 2-oxo-heptyl phosphonate (1.7 g) and sodium hydride (310 mg, 60% mineral oil dispersion) (according to the procedures as described in Example 6).
10 The reaction was continued for 3 hrs at room temperature, and worked up in a similar manner as described in Example 6.
The crude enonethus obtained was chromatographed on silica gel using benzene-ethyl acetate (10:1) to afford 2|3-(3'-oxo-trans-1'-octenyl)-3a-hydroxy-bicyclo[3.3.0]octane ethylene glycol acetal (1.4 g).
15 IRufil™; 3400,2950,1670,1630,1470,1410,1250,1035.
NMR(CDCI3)6; 6.68 (1H, d,d), 6.03 (1H, d), 3.83 (4H, s).
The enonethus obtained was reduced with sodium borohydride according to the procedures as described 20 in Example 9 to afford 2(3-(3'-hydroxy-trans-1'-octenyl)-3a-hydroxy-bicyclo]3.3.0]octane ethylene glycol acetal (1.34 g).
IRuf"™; 3400, 2930,1460,1410,1330,1230,1040.
25 NMR(CDCI3)S; 5.7-5.4 (2H, m), 3.9 (4H, s).
The diol obtained above was treated with aqueous acetic acid for deacetalization according to the procedures described in Example 12 to afford an oily 2p-(3'-hydroxy-trans-1'-octenyl)-3a-hydroxy-bicyclo[3.3.0]octan-7-one (0.83 g), which was coincided with the bicyclo-octanone obtained in Example 12.
30
Example 15.
According to the procedures described in the previous examples, there were obtained the following compounds:
2|3-(4'-methyl-3'-tetrahydropyranyloxy-trans-1'-octenyl)-3a-tetrahydropyranyloxy-bicyclo[3.3.0]octan-7-35 one
(Rift; 2940,1740,1470,1450,1440,1360,1200,1130,1080,1020.
NMR(CDCI3)S; 5.7-5.4 (2H, m), 4.7-4.4 (2H, m), 0.9 (6H, m). 40 2(3-(4'-methyl-3'-hydroxy-trans-1'-octenyl)-3a-hydroxy-bicyclo[3.3.0]octan-7-one
I Rift; 3400, 2960, 2930,1740,1470,1410,1170,1100,1040.
NMR(CDCI3)6; 5.8-5.5 (2H, m), 0.9 (6H, m). 45 2j3-(3'-methyl-3'-hydroxy-trans-1'-octenyl)-3a-hydroxy-bicyclo[3.3.0]octan-7-one
IRufjigy 3400,2930,1740,1460,1410,1160,1100,1040.
NMR(CDCI3)S;5.7-5.5 (2H, m) 1.26 (3H, s), 0.9 (3H). 50 2(3-(3'-hydroxy-octyl)-3a-hydroxy-bicyclo[3.3.0]-octan-7-one
IR^mai; 3400,2930,1740,1470,1410,1160,1100,1040.
NMR(CDCl3)5;0.9 (3h, m).
55 2|3-(3'-hydroxy-trans-1'-propenyl)-3a-hydroxy-bicyclo[3.3.0]octan-7-one
IR^K?* 3400, 2930,1740,1455,1410,1250,1160,1090.
NMR(CDCI3)6;5.8-5.45 (2H, m), 4.2-3.7 (3H, m). 60 2|3-(4',4'-dimethyl-3'-hydroxy-trans-1'-octenyl)-3a-hydroxy-bicyclo[3.3.0]octan-7-one
IRufe 3400, 2950,1740,1470,1405,1250,1160,1090,1040.
NMR(CDCI3)8;5.8-5.55 (2H, m), 0.87 (9H, m).
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GB 2030144 A
10
Example 16
A suspension of 60% sodium hydride dispersion )80 mg) in dry dimethyl sulfoxide (2 ml) was stirred at 75°C for 1 hr under an atmosphere of nitrogen. The resultant blue green solution was cooled to room temperature and 4-carboxy butyltriphenyl phosphonium bromide (443 mg) was added. After 10 min, a 5 dimethyl sulfoxide solution (1 ml) of 2(3-(3'-tetrahydropyranyloxy-trans-1'-octenyl)-3a-tetrahydropyranyloxy-bicyclo[3.3.0]octan-7-one (50 mg) obtained as described in Example 12 was added to the above ylid solution. The reaction mixture was stirred at room temperature for 20 hrs.
The resultant solution was poured onto ice water and ether.
The organic layer was separated and the aqueous layer was carefully acidified by addition of 2N sodium 10 bisulfate and extracted with ethyl acetate. The ethyl acetate layer was treated with ethereal diazomethane and concentrated in vacuo. The residue was dissolved in a solution (1 ml) of acetic acid-water-tetrahydrofuran [3:1:1 (v/v)] and stirred for 4 hrs at 50°C.
The mixture was concentrated under reduced pressure, and then chromatographed on silica gel to afford an oily 2(3-(3'a-hydroxy-trans-1'octenyl)-3a-hydroxy-7-(4'-methoxycarbonyl butylidene)bicyclo[3.3.0]-octane 15 (5 mg).
IRufiim; 3600-3200,3010, 2950,1735,1440,1265,1170,1120,1075,1020.
NMR(CDCI3)6; 5.7-5.5 (2H, m), 5.5-5.25 (1H, m), 3.67 (3H, s).
20
Example 17.
A suspension of 65% sodium hydride dispersion (1.11 g) in dry dimethyl sulfoxide (15 ml) was stirred for 40 min at 65°-75°C under an atmosphere of nitrogen. After the cooled resultant blue green solution was added to 4-carboxy-butyltriphenyl phosphonium bromide (5.34 g) at 15°C-25°C,the reaction mixture was 25 stirred for 10mins at 20°C.
To the above ylid solution was added at 20° - 25°C a dimethyl sulfoxide (9 ml) solution of 2p-trityloxymethyl-1a-hydroxy-bicyclo[3.3.0]octan-7-one (1.8 g) obtained as described in Example 13.
After the stirring for an additional 21 hrs at room temperature, the resulting mixture was poured into water and washed with diethyl ether. The aqueous layer was acidified and extracted with ethyl acetate. 30 The ethyl acetate layer was washed with brine, dried and evaporated. This crude oil was chromatographed on silica gel to afford the desired 2(3-trityloxymethyl-3a-hydroxy-7E-(4'-carboxybutylidene)-bicyclo-[3.3.0]octane (0.8 g).
IRufe 2950, 2550,1700-1720,1060.
35
NMR(CDCI3)5; 4.9-5.4 (1H, broad).
The carboxylic acid obtained above was treated with diazomethane in ether, followed by hydrolysis to afford an oily 2(3-hydroxymethyl-3a-hydroxy-7E-(4'-methoxycarbonylbutylidene)-bicyclo[3.3.0]octane.
40
IRvfe 3300-3400,2920,1740,1440,1160.
NMR(CDCI3)6;3.66 (3H,s)
45 Example 18
Into a suspension of 60% sodium hydride (50 mg, mineral oil dispersion) in dry benzene (5 ml) was added a solution of methoxycarbonylmethyl diethylphosphonate (260 mg) in benzene (3 ml) under nitrogen at room temperature. After 1 hr, a solution of 2|3-(3'-tetrahydropyranyloxy-trans-1'-octenyl)-3a-tetrahydropyranyloxy-bicyclo[3.3.0]octan-7-one (Example 12,110 mg) in benzene (3 ml) was added at room 50 temperature. The mixture was stirred for 15 min at the same temperature and for 1 hr at 70°C. After addition of acetic acid, ether and water was added and the organic layer was separated. The organic layer was washed with brine and dried and then evaporated. The residue was treated with aqueous acetic acid and worked up according to the procedures of Example 12.
The oily product thus obtained was chromatographed on silica gel using benzene ethyl acetate (10:1) to 55 afford an oily 2[3-(3'-hydroxy-trans-1'-octenyl)-3a-hydroxy-7-methoxycarbonylmethyiidene-bicyclo[3.3.0]octan-7-one (45 mg).
IRufe 3400, 2920, 2850,1715,1655,1435,1360,1210,1130,1020.
60 NMR(CDCI3)5;5.8 (1H, m), 5.7-5.3 (2H, m), 3.7 (3H, s).
Example 19
A suspension of 65% sodium hydride (110 mg, mineral oil dispersion) in dimethylsulfoxide (DMSO, 3 ml) was heated at 75°C for 45 min and cooled to room temperature. The resultant solution was added to a 65 solution of 4-carboxy butyl triphenyl phosphonium bromide (534 mg) in DMSO at 20°C. After 30 min, into this
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GB 2 030 144 A
11
solution, a solution of 2|3-(3'a-tetrahydropyranyloxy-trans-1'-octenyl)-3a-tetrahydropyranyloxy-bicyclo[3.3.0]octan-7-one (80 mg, prepared with 2,3 dihydropyran and p-toluene soiufonic acid from 2|3-(3'a-hydroxy-trans-1'-octenyl)-3a-hydroxy-bicyclo[3.3.0]octan-7-one obtained as described in Example 12) was added at room temperature. The mixture was stirred for 20 hrs and poured onto ice-water. Ether was 5 added and ether layer was separated. The aqueous layer was acidified with 2N potassium bisulfate and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated. The residue was treated with aqueous acetic acid for removing the tetrahydropyranyl groups and worked up according to the procedures of Example 12.
The crude acid thus obtained was separated by column chromatographed on silica gei using ethyl acetate 10 to afford 2p-(3'a-hydroxy-trans-1'-octenyl)-3a-hydroxy-7E-(4'-carboxybutylidene)bicyclo[3.3.0]-octane (12 mg).
Rf. value (0.13) onTLC [silica gel, CHCI3-MeOH (10:1)]
15 NMR(CDCi3)5;5.6-5.5 (2H, m), 5.3-5.2 (1H, m).
The acid thus obtained was treated with ethereal solution of diazomethane to afford a methylester which was coincided wihthe bicyclooctane derivative obtained in Example 16.
20 Example 20
According to the procedures described in the previous examples, there were obtained the following compounds:
2(3-(4'-methyl-3'-hydroxy-trans-1'-octenyl)-3a-hydroxy-7-(4'-methoxycarbonylbutylidene)-bicyclo-25 [3.3.0]octane
IRift; 3400,2930,1740,1440,1380,1260,1200,1160,1075,1030
NMR(CDCI3)S; 5.8-5.5 (2H, m), 5.3-5.0 (1H, m), 3.67 (3H, s), 0.9 (6H, m)
30
2(3-(3'-hydroxy-trans-1'-propenyl(-3a-hydroxy-7-(4'-carboxybutylidene)-bicyclo[3.3.0]octane I Rife; 3300, 2920, 2600,1710,1440,1410,1245,1080.
35 NMR(CDCI3)6;5.7-5.43 (2H, m), 5.33-5.0 (1H, m)
2(3-(3'-hydroxy-octyl)-3a-hydroxy-7-(4'-methoxycarbonylbutylidene)-bicyclo[3.3.0]octane •Rift; 3400, 2930,1740,1440,1375,1320,1245,1200,1165,1080,1030
40
NMR(CDCI3)S;5.4-5.0 (1H, m), 3.66 (3H, s), 0.9 (3H, m)
2p-(3'-methyl-3'-hydroxy-trans-1'-octenyl)-3a-hydroxy-7-(4'-methoxycarbonylbutylidene)-bicyclo[3.3.0]-octane
45
I Rift 3400, 2950,1740,1440,1375,1260,1200,1160,1080,1030
NMR(CDCI3)6;5.8-5.5 (2H, m), 5.4-5.1 (1H, m), 3.63 (3H, s), 1.27 (3H, s), 0.9 (3H, m)
50 2p-(4',4'-dimethyl-3'-hydroxy-trans-1'-octenyl)-3a-hydroxy-7-(4'-methoxycarbonylbutylidene)-bicyclo-[3.3.0]octane
'Rift; 3400,2930,1740,1440,1260,1200,1160 55 NMR(CDCI3)6;5.8-5.5 (2H, m), 5.3-5.0 (1H, m), 0.9 (9H, m)

Claims (2)

CLAIMS 0
1. A compound of the formula; r-4
& *
wherein R2 is hydrogen or C4.7 alkyl, R3 is hydrogen or C-^ alkyl and X is absent, or is vinylene or ethylene, 65 and when X is vinylene and R2 is n-pentyl, R3 is C^ alkyl.
5
10
15
20
25
30
35
40
45
50
55
60
65
12
GB 2 030 144 A
12
2. The compounds of the formula (II), given and defined in claim 1, which are specifically disclosed herein.
Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon Surrey, 1980. ^
Published by the Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.
GB7935144A 1978-03-09 1979-03-08 Keto-bicyclooctanes Expired GB2030144B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2733278A JPS54119441A (en) 1978-03-09 1978-03-09 Novel bicyclooctane derivative

Publications (2)

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GB2030144A true GB2030144A (en) 1980-04-02
GB2030144B GB2030144B (en) 1982-10-20

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GB7908169A Expired GB2019847B (en) 1978-03-09 1979-03-08 Bicyclooctanes processes for producing them and pharmaceutical compositions containing them
GB7935144A Expired GB2030144B (en) 1978-03-09 1979-03-08 Keto-bicyclooctanes

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AT (1) AT364097B (en)
AU (1) AU4493079A (en)
BE (1) BE874683A (en)
DE (1) DE2909088A1 (en)
DK (1) DK97179A (en)
ES (1) ES478384A1 (en)
FR (1) FR2419271A1 (en)
GB (2) GB2019847B (en)
IT (1) IT7948266A0 (en)
NL (1) NL7901818A (en)
SE (1) SE7902083L (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4552875A (en) * 1982-07-02 1985-11-12 Schering Aktiengesellschaft Novel carbacyclinamides, their preparation and use as medicinal agents
US4708963A (en) * 1980-12-19 1987-11-24 Schering Aktiengesellschaft Novel carbacyclins, their preparation and use

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2040928B (en) * 1978-01-26 1982-12-08 Erba Farmitalia Bicycloalkane derivatives useful as intermediates in preparing pg1 isosteres
DE2845770A1 (en) * 1978-10-19 1980-04-30 Schering Ag NEW PROSTACYCLINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF
CA1201712A (en) * 1980-02-28 1986-03-11 Paul A. Aristoff Carbacyclin analogs
DE3021895A1 (en) * 1980-06-06 1981-12-24 Schering Ag Berlin Und Bergkamen, 1000 Berlin NEW METHOD FOR PRODUCING CARBACYCLIN INTERMEDIATE PRODUCTS
DE3121155A1 (en) * 1981-05-22 1982-12-09 Schering Ag, 1000 Berlin Und 4619 Bergkamen NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS
US4689349A (en) * 1982-05-06 1987-08-25 Cbd Corporation Anti-tumor halo bicyclo alkanones
EP0107733B1 (en) * 1982-05-06 1988-10-19 Cbd Corporation Cycloaliphatic pharmaceutical compounds
US4689345A (en) * 1982-05-06 1987-08-25 Cbd Corporation Oxygenated alkyl substituted bicyclo alkanes

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5495552A (en) * 1978-01-06 1979-07-28 Sankyo Co Ltd Prostacyline derivative and its preparation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4708963A (en) * 1980-12-19 1987-11-24 Schering Aktiengesellschaft Novel carbacyclins, their preparation and use
US4552875A (en) * 1982-07-02 1985-11-12 Schering Aktiengesellschaft Novel carbacyclinamides, their preparation and use as medicinal agents

Also Published As

Publication number Publication date
NL7901818A (en) 1979-09-11
AU4493079A (en) 1979-09-13
AT364097B (en) 1981-09-25
FR2419271B1 (en) 1983-07-29
ES478384A1 (en) 1979-08-01
DE2909088A1 (en) 1979-09-20
JPS54119441A (en) 1979-09-17
SE7902083L (en) 1979-09-10
GB2030144B (en) 1982-10-20
FR2419271A1 (en) 1979-10-05
BE874683A (en) 1979-09-10
DK97179A (en) 1979-09-10
IT7948266A0 (en) 1979-03-08
ATA172179A (en) 1981-02-15
GB2019847B (en) 1982-10-13
GB2019847A (en) 1979-11-07

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