FI56373C - SAOSOM MELLANPRODUKTER VID FRAMSTAELLNING AV PROSTAGLANDINER ELLER PROSTAGLANDINLIKNANDE FOERENINGAR ANVAENDBARA BICYKLO (2,2,1) HEPT-2-EN-7-SYN-KARBALDEHYDER - Google Patents

Description

r-, ADVERTISEMENT ¢: ^ - 57-¾

JffÄ B (11) UTLÄGGNINGSSKRIFT 30J / J

C (45) Patent granted 10 01 1930 Patent meddelat ^ ^ (51) Kv.ik. * / Int.ci. * c 07 0 121/48 C 07 0 69/74 C 07 C 103/19 C 07 C 177/00 ENGLISH NN LAN D (21) P »t * nttlh» k * mu * - Pxt «Mtn * öknlng 10UU / J2 (22) Htk« ml * p »lvl - Antöknlnpdag 13.OU.T2 (23) Alkupilvf —Giltighetsdtg 13.0U.T2 (41) Tullut JulklMluI - Bllvlt off «otll | IU. 10.72

Patent, ji registry board ....,,. .....

_ * (44) Date of issue and date of publication. -

Patent- och reglsterstyrelsen Anaökan utiagd och utl. «Krtft * n pubiieand 28.09. T9 (32) (33) (31) Requested «tuolkeui — Begird prlorltet 13.0U.T1 16.12.Tl England-England (GB) 9223 / T1,

58UOO / TI

(Tl) Imperial Chemical Industries Limited, Imperial Chemical House,

Millbank, London S.W.1, England-England (GB) (T2) Edward Douglas Brown, Macclesfield, Cheshire, Timothy John Leeney, Macclesfield, Cheshire, Graham Ernest Robinson, Macclesfield,

Cheshire, England-England (GB) (TU) Oy Kolster Ab (5U) Bicyclohexyl 2, 1,7hept-2-ene ~ T-syn-carbaldehydes used as intermediates in the manufacture of prostaglandins and prostaglandin-like compounds The present invention relates to bicyclo / 2,2,17hept-2-ene-T-syn for the preparation of prostaglandins and prostaglandin-like compounds for use as intermediates in the preparation of intermediates. -carbaldehydes, which are valuable intermediates in the preparation of prostaglandins and prostaglandin-like compounds.

In the known synthesis of prostaglandins and prostaglandin-like compounds, the following initial steps are carried out: a) cyclopentadienyl sodium is added to chloromethyl methyl ether to give 5-methoxymethyl-1,3-cyclopentadiene P, which is subjected to b) Diels-Alder reaction with 2-chloroacryl.

2 bb373 c) The bicyclic chloronitrile II thus formed is hydrolysed to give the corresponding bicyclic ketone III, which is subjected to d) Baeyer-Villiger oxidation to bicyclic lactone IV.

e) The lactone is saponified and iodinated to give a rearranged iodolactone V in the conversion reaction, which

f) acetylation, and the acetoxy-lactone VI formed

g) deiodination to obtain methoxymethyl lactone VII.

h) Methoxymethyl lactone VII is demethylated to hydroxymethyl lactone VIII, which i) is oxidized to aldehyde lactone IX.

ch2och3 1 ^ 1 Na ® + CH30CH2C1 -> J_ [I * CH OCH H 1

J A CH OCH

A - Ä

Ill II ^ CN

CH3OCK2 J.H

> _H

IV 1 '^^ A.CH2OCH3

HO

0 V I

/ s J

\ / °.

»_ * _ ^ 1 O ^ CH2OCH3 1 O CH2OCH3 1 1 CH CO.O VII CH C0.0

0, 5 VI

A A

_j, '*,' i / CH2OH ch0 CH3CO.0 VI11 CH3CO.0 ix 3 & 63 '/ 3 This known reaction chain is unsuitable for the large-scale preparation of prostaglandins and prostaglandin-like compounds for several reasons, the three most important of which are: 1) 5-methoxymethyl- 1,3-Cyclopentadiene is prone to readily isomerized to 1-methoxymethyl-1,3-cyclopentadiene, which is unusable for the purposes of this synthesis. This isomerization can be minimized by carrying out the reaction of cyclopentadienyl sodium with chloromethyl methyl ether at low temperatures, about -55 ° C, but such temperatures are inappropriate and uneconomical in large scale production.

2) The Diels-Alder reaction yields a mixture of bicyclic chloronitrile isomers II together with an equal amount of other isomers, mainly 5-chloro-5-cyano-1-methoxymethylbicyclo [2.2.1] hept-2-ene. The desired isomers II must be isolated from the other isomers present by column chromatography, preparative gas-liquid chromatography or distillation, and the presence of isomeric reaction products unusable for the purposes of this synthesis reduces the total yield of isomers II after purification from about 25% sodium cyclopentadiene.

3) Demethylation of methoxymethyl lactone VII requires the use of boron tribromide, a reagent which, due to its general hazard, is unsuitable for large scale use.

It has now been found that the use of the new intermediates can avoid the three above-mentioned drawbacks in the above process so that 1) isomerization of the starting material is not possible, 2) no 1-substituted bicyclo / 2.2.1 / heptene derivative is formed in the Diels-Alder reaction, and 3) in the final step, the deprotection to form aldehyde IX is easily performed at room temperature and pressure without the use of hazardous reagents.

The bicyclo / 2,2,17hept-2-ene-7-syn-carbaldehyde intermediate used according to the invention has the formula

HCO H

p-R2 R1 k 563? i 1 ..2. .

wherein R is a halogen atom, R is a cyano or carbamoyl group or an alkoxycarbonyl group having up to 6 carbon atoms or an N-alkylcarbamoyl group having an alkyl group having 1 to 6 carbon atoms.

The wavy lines in Formula I indicate that either of the groups 1.2. .

R or R is in the exo position and the other group is in the endo position, i.e. the formula shows a mixture of compounds which are isomers on the carbon atom 5 · It is to be understood that the above and following formulas represent racemates which, however, can be resolved to give naturally occurring prostaglandins.

1 ..... .... 2 R is suitably, for example, a chlorine or bromine atom. R is, as the alkoxycarbonyl group, e.g. methoxycarbonyl, and the N-alkylcarbamoyl group is, e.g., N-methylcarbamoyl.

Preferred bicycloheptene-7-syn-carbaldehydes according to the invention are 5-chloro-7-syn-formylbicyclo [1,2,7] bept-2-ene-5-carbonitrile, 5-chloro-7-syn-formylbicyclo [2.2.17hept-2 -ene-5-carboxamide and methyl 5-chloro-7-syn-formylbicyclo / 2,2,17hept-2-ene-5-carboxylate.

Compounds of formula I may be prepared by a) hydrolysis with acid of GHOR3 eb> Y '• ·. . A compound according to 1 2, wherein in the compound R and R have the same meaning as above, and 3 .... .

R is an alkyl, alkanoyl, alkanesulfonyl or arenesulfonyl radical having up to 7 carbon atoms, under conditions and using an acid such that the initially formed

H ^^ CHO

The bicycloheptene-7-anti-carbaldehyde of R1 56373 1.2, wherein R and R are as defined above, is isomerized to the corresponding bicyclohepten-J-syn-carbaldehyde of formula I without substantial decomposition; or 1 2 b) reacting a compound of formula XII wherein R and R are 1 + 5. ...

same as above, to react in solution with an amine of the formula R R NH, wherein and R '* each represent hydrogen and / or an aryl radical which may contain up to 15 atoms.

3. .... .

R is suitably e.g. a t-butyl, acetyl, methanesulfonyl or toluene p-sulfonyl radical.

1.2.2 In process a) R is preferably chlorine, R is cyano and R is acetyl, and the acid used is preferably 2-hydrochloric acid (1 part) dioxane (U part) at about 85 ° C for about four days.

The isomerization of a compound of formula XII to a bicycloheptene of formula I can be conveniently monitored by NMR spectra by observing the presence of aldehyde proton signals at ε9> 50 and 9> 57.

In process b), the aldehyde reacts with the amine to form an aldehyde-amine adduct, for example a Schiff's base, which can be isolated or used without isolation in the isomerization reaction.

..... h 5. ....

Suitable amines R R NH are, for example, aromatic primary and secondary amines, e.g. aniline, p-chloroaniline, p-toluidine and N-methylaniline.

A suitable solvent is, for example, an alkanol, e.g. methanol, ethanol, isopropanol or tert-butanol, or a chlorinated aliphatic hydrocarbon, e.g. methylene dichloride.

The pH of the reaction mixture is suitably below 6, preferably 1 + -5, and is adjusted by the addition of an acid, e.g. an acidic acid such as glacial acetic acid.

. . . 1+ 5

The amine R R NH may be present in the reaction in 0.1-5.0 equivalents per equivalent of aldehyde of formula XII, but is preferably present in 0.5-2.0 equivalents per aldehyde equivalent.

The reaction should be continued until the isomerization is substantially complete, as can be seen from the doublet signal in the NMR spectrum of the reaction product at S9, 50 and 9.60. A typical reaction time is 16 to 21 hours.

The compounds of the formula XI which can be used as starting materials in the above-mentioned process a) are novel compounds

Compounds of formula XI may be prepared by reacting CHOR 3 0 6 56373 .... A fulvene derivative of formula 12 for reacting an olefin of formula CH: CR R 1.2. ^, wherein R and R have the same meaning as above.

The reactivity of the fulvene derivatives of formula XIII depends on the radical 3. . 12 The nature of R and the reactivity of the olefins of the formula CHp: CR R, respectively, depend on the nature of the radicals R and R. Thus, it is necessary to select a fulvene derivative and an olefin which react with each other under reasonable conditions in a suitable time. Suitable olefins include 2-chloroacryloyl chloride, 2-bromoacryloyl chloride and 2-chloroacrylonitrile. Fulven β-sulfonates and 6-methoxyful vein are not particularly stable and should therefore be reacted with the most reactive olefins.

The aldehydes of formula XII used in process b) are novel compounds.

The aldehyde of formula XII may be prepared by hydrolysis of a compound of formula XI, e.g. by heating with a mineral acid such as hydrochloric acid, or by treatment with alcoholic ammonia, e.g. methanolic ammonia.

The compounds of formula I are valuable intermediates for use in the synthesis of prostaglandins and prostaglandin-like compounds. Prostaglandins can be prepared from the compounds of formula I by a variety of methods using standard reactions known in organic chemistry. The following reaction scheme shows an alternative starting from a compound of formula I, 5-chloro-5-cyanobicyclo / 2,2,1-7hept-2-ene-7-carbaldehyde, which is reacted with trimethyl orthoformate or methanol and concentrated hydrochloric acid to give dimethyl acetal. To obtain XIVa, which is reacted with 1,2-xylene-*, * * · 'diol to give the corresponding acetal XIVV. The acetal XIVb is hydrolyzed with potassium hydroxide in dimethyl sulfoxide to the ketone XVb, which is subjected to Bayer-Villiger oxidation with m-chloroperbenzoic acid to the lactone XVIb. Lactone XVIb is saponified with sodium hydroxide, neutralized with acetic acid, and the product is treated with potassium triiodide to give iodohydrin XVIIb, which is reacted with p-phenylbenzoyl chloride to give ester XVIIIb. Ester XVIIIb is treated with tributyltin hydride to give deiodated lactone XlXb, which is hydrogenated to remove the acetal group to give aldehyde XX (R 1 = p-phenylbenzoyl).

g

The aldehyde XX (R 1 = p-phenylbenzoyl) is then converted to the prostaglandin F 1 E 4 by a known method used to convert the aldehyde XX (R 2 = acetyl) to F 2.

In a variation of this reaction sequence, dimethyl acetal XIVa is hydrolyzed to ketone XVa, which is converted to lactone XIIIa via lactone XVIa, iodohydrin XVIIa, and ester XVIIIa according to the above reaction sequence. Lactone X1Xa is then selectively hydrolyzed in a two-phase system of chloroform and concentrated hydrochloric acid so that the dimethyl acetal group is removed, leaving the lactone intact to give aldehyde XX.

7 56373

Potassium triiodide may, of course, be replaced by other known halogenating agents, e.g. chlorine, bromine or N-halosuccinimide in an aqueous reaction medium or a hypochlorous acid derivative, e.g. Similarly, known reducing agents other than tributyltin hydride can be used to convert esters XVIII to deiodinated lactones XIX, e.g. sodium borohydride or sodium cyanoborohydride (Na.BH 2 CN) in dimethylsulfoxide, dimethylformamide, sulphanamide, sulfolane or hexamethyl or hexamethyl.

Y = CH H

Y = CH 2 H

"Äa, -> -, j ^ Q> xv

XIV

$ - -¾ T xvi

HO

XVII

0 Q / o /! H -> M.

CH = Y Y ^ CH = Y

R6i r6 ° I XIX

XVIII Ψ a) Y = (CH30) 2 = ίϊ? / b) Y “I ano CH2 ° - 'Λ

= p-phenylbenzoyl XX

8 56373

An alternative reaction sequence starts from 7-acetyl-ethylene-5-chlorobicyclo-12 / 2,2,1,7-hept-2-ene-5-carbonyl chloride (XI, R = chlorine, R = chloroformyl, R = acetoxy), treated with a methanolic amine, e.g. methanolic ammonia, followed by acid treatment to give anti-aldehyde XII via 12.12 (R = chlorine, R = carbamoyl) primary amide XI (R = chlorine, R = carbamoyl). This anti-aldehyde is converted to ketone XVa by the method described above via the syn-aldehyde and its dimethyl acetal.

An alternative reaction sequence starts from methyl 7-acetoxymethylene-5-chloro-12 ribicyclo / 2,2,1- / hept-2-ene-5 'carboxylate (XI, R = chlorine, R * methoxy-3 carbonyl, R = acetoxy), which is hydrolyzed as described above to anti-12 aldehyde XII (R = chlorine, R = methoxycarbonyl), which is isomerized to the corresponding syn-aldehyde I (R = chlorine, R = methoxycarbonyl). This syn-aldehyde is protected as dimethyl acetal and the methoxycarbonyl group is converted by treatment with ammonia to an amide which is hydrolyzed as described above to ketone XVa. The invention is illustrated by the following examples:

Example 1 7-Acetoxymethylene-5-chlorobicyclo [2.2.1] hept-2-ene-5-carbonitrile (XI, R = chlorine, R = cyano, R = acetyl), (35.8 g, 0.16 mol) dissolved in dioxane (360 mL, purified by filtration, through a r0 "basic alumina plate, and purged with argon) and added to 2N hydrochloric acid (80 mL, 0.16 mol, purged by purging with argon before use) to give a pale yellow solution. Argon was bubbled into the solution for 30 minutes and heated under argon in an oil bath to maintain the temperature at 85 ° C to 3 ° C. The dioxane was evaporated under reduced pressure and the remaining liquid was basified with saturated aqueous sodium bicarbonate solution (120 ml) of water (200 ml) and methylene chloride. was added and the resulting suspension was filtered through celite The organic layer was removed and the remaining aqueous solution was extracted with methylene chloride (U x 50 mL) The organic layers were combined and dried, and the solvent was evaporated off under reduced pressure. The residue was dried under high vacuum to give 5-chloro-7-syn-formyl-bicyclo [2.2.1] hept-2-ene-5-carbonitrile (I, R = chlorine, R = cyano) as a brown oil. Thin layer chromatography of the aldehyde mixture on Merck 0.25 mm silica gel plates using methylene chloride as eluent gave two spots, Rj = 0.2 and 0.3. Spots were developed by spraying cerium IV sulfate onto the plates and heating the plates. The n.m.r. spectrum of mixed aldehydes in deuterium chloroform showed the following values (£ values): 1.79 and 2.26, 1H, doublets, J = 1U Hz, endohydrogen at C-6. 2.1 + 8 and 2.81+, 1H, double doublets, J = 11+ and 6 Hz, exo hydrogen at C-6. 2.85 and 3.07, 1H, singlet, hydrogen at C-7. 3.1 + 2, 1H, broad singlet, bridgehead hydrogen. 3.66 and 3.80, 1H, broad singlet, bridged. 6.0-6.6, 2H, complex multiplets, olefinic hydrogens. 9.50 and 9.57, 1H, doublets, J = 1 Hz, hydrogen aldehyde.

Example 2 3

Crude of -acetoxyfulvene (XIII, R = acetyl) (61 g, 0.1 + 5 moles) was dissolved in benzene (1 + 50 mL, dried with 1 + A molecular sieves) and freshly distilled 2-chloroacrylonitrile (235 g, 2.68 moles) and hydroquinone (250 mg) were added.

"The resulting solution was heated to reflux for 21 hours under argon.

The solvent was evaporated under reduced pressure to give a dark brown oil which was purified by passing through a Florisil column (1 kg) using methylene chloride as eluent to give 7-acetoxymethylene-5-chlorobicyclo [b, 1,2 '] hept-2-ene. -5_carbonitrile as a pale yellow oil, R „= 0.1+ in thin layer chromatography on Merck silica gel plates using methylene chloride as eluent. The n.m.r. spectrum of the product in deuterium chloroform showed the following values (in Jarvos): 1.7-2.9, 2H, complex, protons at C-6. 2.08 and 2.09, 3H, complex, methyl protons. 3.3-1 +, 2, 2H, complex, ring olefinic protons. 6.81 and 6.82, 1H, complex, acetoxymethylene olefinic proton.

Example 3 5-Chloro-7-syn-formylbicyclo [2.2.1] hept-2-ene-5-carbonitrile (i, R1 = 2 chlorine, R = cyano) (15 g, 0.08 mol), trimethyl orthoformate (26 g, 0.25 mol) and toluene-p-sulfonic acid (710 mg, 1+ mmol) were dissolved in methanol (500 ml) and the solution was heated at reflux for 20 hours. The solvents were evaporated off under reduced pressure, and the residual oil was dried under high vacuum using an oil pump to give a epime mixture of dimethyl acetal XIVa.

The crude dimethyl acetal mixture was dissolved in benzene (550 mL, dried on a 1 + A molecular sieve), and 1,2-xylenediol (11 g, 0.08 μmol) and toluene-p-sulfonic acid (560 mg) were added to the solution. The solution was heated for 13 hours, allowing the benzene to slowly distill off and keeping the volume constant by the addition of dried benzene. The solution was cooled, washed with saturated aqueous sodium bicarbonate solution (100 ml), dried and the solvent removed under reduced pressure. The residue was purified by chromatography on Florisil (1 + 20 g) using methylene chloride as eluent to give 1,2-xylene-o-α-diylacetal (XIVb) as a pale yellow solid, Rf = 0.3 in thin layer chromatography 56373 10

On Merck silica gel plates using methylene chloride as eluent. The n.m.r. spectrum (XIVb) of the acetal mixture in deuterium chloroform showed the following values (in J value) 1.6-2.8, 3H, multiplet signals, C-6 and C-T hydrogens. 3> 10, 1H, broad singlet, C-1 hydrogen. 3.36 and 3.50, 1H, broad singlet, C-4 hydrogen. 4.6-5.0, 5H, multiplet, CH-O-. 6.0-6.5, 2H, multiplet, olefinic, 7.14, 4h, singlet, aromatic.

Acetal (XIVb) (19.4 g, 0.06 mol) was dissolved in dimethyl sulfoxide (100 mL, purified by distillation from calcium hydride and stored over a molecular sieve) and argon was bubbled into the solution for 4 hours. At the same time, a solution of potassium hydroxide (13 g) in water (10 ml) was heated to 50 ° C and purified by purging with argon for 4 hours. The potassium hydroxide solution was then added to the acetal solution with stirring, and the mixture was stirred under argon at room temperature for 20 hours, during which time a white solid separated. The reaction mixture was poured into 1N hydrochloric acid (500 ml), and the mixture was extracted with methylene chloride (1+ x 200 ml). The combined organic layers were dried and the solvent evaporated under reduced pressure to give the ketone (XVb) as a white solid, R f = 0.25 Γ by thin layer chromatography on Merck silica gel plates using ethyl acetate / methylene chloride (3:97) as eluent. The nmr spectrum of the ketone (XVb) in deuterium chloroform showed the following features (in Jarvos): 1.99 »2H, singlet + doublet, -CH 2 CO 2, 2.48, 1H, doublet, J = 8 Hz, C-7 hydrogen . 3.12 and 3.72, 2H, multi-Pletit, bridged. 4.7-5.0, 5H, multiplet j> CH.CO-, 6.0 and 6.5, 2H, multiplets, olefinic 7.15, 4h, singlet, aromatic.

The ketone (XVb) (1U, 6 g, 57 mmol) was dissolved in methylene chloride (250 mL, purified by stirring over anhydrous sodium bicarbonate). Anhydrous sodium bicarbonate (9.35 g, 114 mmol) was added followed by m-chloroperbenzoic acid (12.5 g, 68 mmol) and the mixture was stirred for 20 hours at room temperature. The reaction mixture was diluted with methylene chloride (750 mL) and washed sequentially with saturated sodium sulfite solution (50 mL) and saturated sodium bicarbonate solution (2 x 50 mL). The separated organic solution was dried and the solvent evaporated to give the lactone (XVIb) as a white solid,

Rp = 0.25 by thin layer chromatography on Merck silica gel plates using ether / benzene (1: 3) as eluent.

The n.m.r. spectrum of lactone (XVIb) in deuterium chloroform showed the following values (in J): 2.48, 1H, doublet, J = 8 Hz, C-7 hydrogen. 2.4-2.9, 2H, multiplet, -CH 2 CO-. 3.0, 1H, broad singlet, bridgehead adjacent to C0. 1 +, 48, 1H, doublet, J = 8 Hz, -0. 4.80, 4h, singlet, -CHp.0-. 5.07, 1H, broad singlet, -O-CH- bridgehead adjacent to 0. 6.2-6.5, 2H, multiplet, olefinic.

11 563/3

Lactone (XVTb) (11 *, 6 g, mmol) was dissolved in dioxane (153 mL), and a solution of sodium hydroxide (6.5 g, 162 mmol) in water (68 mL) was added to the solution with stirring at room temperature. Stirring was continued for 6 hours, after which acetic acid was added to bring the pH of the solution to about 7.5. A solution of iodine (U0.8 g, 161 mol) and potassium iodide (82 g, 1 * 83 mmol) in water (181 ml) was added, and the mixture was stirred for 21 hours at room temperature. Solid sodium sulfite was then added to the stirred reaction mixture to scavenge excess iodine. The resulting suspension was filtered and the solids were washed with water (3 x 30 mL) and then acetone (3 x 25 mL). The solids were then dried in vacuo to give iodohydrin (XVITb) as a white solid, Rf = 0.1 * by thin layer chromatography on Merck silica gel plates using methanol / benzene (5:95) as eluent.

The n.m.r. spectrum of iodohydrin (XVIIb) in d-pyridine showed the following features (in Jarvos): 2.1 *, 1H, multiplet, C-k hydrogen. 2.73, 2H, doublet, J = 8 Hz, C-3 hydrogens. 3.03, 1H, multiplet, C ~ 3a hydrogen. 3.53, 1H, singlet, hydroxy.

1 *, 1 * 2, 2H, multiplet, 05 and 06 hydrogen, h, 82, 1 * H, multiplet, -CH 2 .-. 5.08, 1H, -? Multiplet, C-6a hydrogen. 5 »30, 1H, doublet, J = 1 * Hz, CH-. 1.13, 1H, singlet, -O 2 aromatic.

Iodohydrin (XVIIb) (16.3 g, 39 mmol) was dissolved in pyridine (60 mL) (dried over potassium hydroxide granules), p-phenylbenzoyl chloride (9.7 g, 1 + 1 * mmol) was added and the solution was heated to 50 ° C. at room temperature under argon for 27 hours. The solution was cooled to room temperature, water (0.2 ml) was added, and the mixture was stirred for 30 minutes at room temperature. The pyridine was evaporated off under reduced pressure, and the residue was dissolved in methylene chloride (500 ml). This solution was washed successively with 2N hydrochloric acid (3 x 100 mL), saturated sodium bicarbonate solution (3 x 100 mL) and water (100 mL). The organic layer was dried and the solvent was evaporated to give a white solid which was crystallized from a mixture of methylene chloride and ether to give p-phenylbenzoate ester (XVIIIb) as a white solid, R = 0.2 by thin layer chromatography on Merck silica gel eluting with silica gel. as the eluent.

The n.m.r. spectrum of p-phenylbenzoate ester (XVIIIb) in deuterium chloroform showed the following features (in Jarvo): 2.1 + 2, 1H, multiplet, C ~ 3a hydrogen. 2.72, 2H, singlet + doublet, C-3 hydrogen. 3.25, 1H, multiplet, C-1 + hydrogen. 1 +, 1 + 1, 1H, doublet, J = 3 and 5 Hz, C-6 hydrogen. 1 +, 72-1 +, 9, 1 + H, multiplet, -CH 2 -O-.

5.1, 2H, multiplet, C-6a hydrogen. 5.73, 1H, triplet, J = 5 Hz, C ~ 5 hydrogen.

7.0- 8.1, 13H, multiplet, aromatic.

A mixture of p-phenylbenzoate ester (XVIIIb) (11 +, 0 g, 21 + mmol) and benzene (500 mL, dried over a type 1 + A molecular sieve) was heated to reflux until complete dissolution. While boiling through the solution, argon was purged for 30 minutes, and then a solution of tri-n-butyltin hydride (8.6 g, 29 mmol) in benzene (10 mL) was added. The reaction mixture was heated to reflux for 20 hours, allowed to cool to room temperature and the benzene evaporated off under reduced pressure. The resulting solid was triturated with n-pentane (3 x 50 mL) and crystallized from a mixture of methylene chloride and ether to give the deionized ester (XlXb) as a white solid, m.p. 188-189 ° C, Rf = 0.3 by thin layer chromatography on Merck silica gel plates using a mixture of ethyl acetate and pentane (1: 1) as eluent. The nmr spectrum of the deionized ester (XlXb) in deuterium chloroform showed the following values (rare): 2.3-3.2, 6η, complex, C-3, 3a, k and 6 hydrogens, k, 86, 1 + H, multiplet, - CH ^ .O-.

5.05, 2H, multiplet, C-6a and hydrogen. 5.50, 1H, multiplet, C ~ 5 hydrogen.

-0-CH

7.1- 8.1, 13H, multiplet, aromatic.

The deodorized ester (XlXb) (li + 2 mg) was suspended in methanol (30 ml) containing 1 drop of concentrated perchloric acid. Palladium oxide (67 mg) was added, and the suspension was shaken under a hydrogen atmosphere for 2 L + hours. The reaction mixture was diluted with methylene chloride (100 mL) and filtered through celite. The filtrate was washed with saturated sodium bicarbonate solution (10 ml), the organic layer was separated and dried, and the solvent was removed by evaporation. The residue was purified by chromatography to give the aldehyde (XX), Rf = 0.5 by thin layer chromatography on Merck silica gel plates using a mixture of ethyl acetate and methylene chloride (1: 1) as eluent. The n.m.r. spectrum of the aldehyde in deuterium chloroform showed the following features (in Jarvo): 13 56373 1.9 “3.5, 6H, complex, C-3, 3a, 1+ and 6 hydrogens. 5.15 »1H, triplet, J * 6 Hz, C-6a hydrogen. Δ, Ί9, 1H, multiplet, C 5 5 hydrogen. 7.3-8.2, 9H, multiplet, aromatic. 9.81+, ih, singlet, aldehyde.

The aldehyde (XX) was identical in all respects to the sample prepared by previously known methods.

Example k 5-Chloro-5-cyanobicyclo [2.2.1] hept-2-ene-7-anti-carboxaldehyde (116.7 g) and p-chloroaniline (98.2 g) were dissolved in glacial acetic acid (116 ml) and in iso-propanol (950 ml) and the solution was stirred under nitrogen for 20 hours at room temperature. The solvents were removed by evaporation, 2-hydrochloric acid (500 ml) was added to the residue and the mixture was extracted twice (1 + 00 ml and 200 ml) with methylene chloride. The combined extracts were washed successively with 2N hydrochloric acid (250 ml), aqueous sodium bicarbonate acid free and water (2 x 300 ml) and dried over magnesium sulphate. The solvent was removed by evaporation to give a thick oil containing> 90% 5-chloro-7-syn-formylbicyclo / 2,2,1,7hept-2-ene-5 'carbonitrile which could be used without further purification.

Example 5

Using the procedure set forth in Example i +, but substituting 0.5 equivalents of p-toluidine for p-chloroaniline and carrying out the reaction for 18 hours, 90% isomerization to the syn-aldehyde was obtained, respectively.

Example 6

The procedure of Example k was repeated except that glacial acetic acid was omitted and using the amines and solvents shown to give the following results: 2.0 equivalents of N-methylaniline in methanol for 18 hours gave U0 # isomerization; 2.0 equivalents of N-methylaniline in ethanol for 18 hours gave 65% isomerization; 1.2 equivalents of aniline in isopropanol gave 75% isomerization in 16 hours; 2.0 equivalents of aniline in methanol for 16 hours gave 88 # isomerization; 2.0 equivalents of aniline in t-butanol for 20 hours gave> 90 # isomerization.

1U 56373

Example 7

5-Chloro-7-syn-dimethoxymethylbicyclo (2,2,1) hept-2-ene-5-carbonitrile (XIV) (k5.5 g) was dissolved in ethanol (1 x 50 ml) containing dimethyl sulfoxide (50 ml, dried over a UA molecular sieve), sodium hydroxide (16.8 g) was added and the solution was heated to reflux for 20 hours. The solution was then cooled, diluted with water (500 mL) and extracted with methylene chloride (U x 250 mL). The combined extracts were washed with water (U x 500 ml) and dried and the solvent removed under reduced pressure to give an oil which on crystallization from pentane gave the ketone (XVa) m.p. 1 * 5 ° C, »o, U (5 JK

ethyl acetate in methylene chloride). The n.m.r. spectrum of the ketone (XVa) in deuterio-chloroform showed the following characteristic features (<ε values): 1.96, 2H, multiplet, -CH 2 CO 2, 52, 1H, doublet, C-7 proton.

3.00, 1U, multiplet 3.10, 1H multiplet and * 3.21, 3H, singlet 3.30, 3H, singlet / 3.38, 1H, doublet, (CH3O) 2.CH- 5.96, m, multiplet! ol6finin proton 6, kU, 1H, multiplet /

Ketone (XVa) (111 g) was dissolved in ether (550 ml) and sodium hydroxide (39.7 ml of 10% aqueous solution) was added and the mixture was stirred and cooled to 0 ° C. Hydrogen peroxide (136 ml as a 2 E solution) was added dropwise to the stirred mixture, which was kept below 10 ° C. At the end of the addition, the mixture was stirred for 3 hours, the ether layer was removed and the aqueous layer was extracted with ether (2 x 100 ml). glacial acetic acid, cooled to 0 ° C and a solution of potassium iodide (887 g) and iodine (1 x 51 g) in water (1758 ml) was added, the mixture was stirred at 0 ° C for 20 hours and the excess iodine was then decomposed by the addition of solid sodium sulphite. The aqueous suspension was extracted with methylene dichloride (x 500 ml), the combined organic extracts dried and the solvent evaporated under reduced pressure to give iodohydrin (XVIIa) as an oil, Rf = 0.3 (5% ethyl acetate in methylene chloride). values): 3.39, 6η, singlet, methoxy.

U, 0.2H, multiplet, C-5 and C-6 protons MO, 1H, doublet, (CH3O) 2CH-U, 96, 1H, multiplet, C-6a proton.

15 5637 3

The procedure described in the second part of Example 3 was repeated using iodohydrin XVIIa instead of iodohydrin XVIIb to give the following intermediates: ester (XVIIIa), m.p. 139 DEG-11 DEG C., Rf = 0.6 (15% methanol in benzene) The Nmr spectrum in deuteriochloroform showed the following characteristics (cC values): 3.30 and 3.32, 6H, singlets, methoxy U, 1 * 1, 1H , quartet, C-6 proton i +, 6l, 1H, doublet, (CH 2 J 9 CH- 5.10, 1H, quartet, C-6a proton 5.62, 1H, triphet, C-5 proton 7, ^ - 6, 1.9H, multiplet, aromatic protons, deiodinated ester (XIX), mp 11-1-16 ° C, 0.3 (50% ethyl acetate in pentane) The NMR spectrum in deuterium chloroform showed the following characteristic features (<Required) : 3.3 and 3.1 * 1 »6h, syngetti, methoxy 1 *, 3! *, 1H, doublet, (CH 3 O) 2 CH = 5.0l *, 1H, multiplet, C-6a proton 5.1 * 2 , 1H, multiplet, C-5 proton 7.1 * -8.1, 9H, multiplet, aromatic protons.

Deiodatate ester (XlXa) (39.5 g) was dissolved in chloroform (1980 ml) containing 2 L of isopropanol. Concentrated hydrochloric acid (1 x 95 ml) was added and the resulting two-phase system was stirred at room temperature for 1 1/2 hours. The chloroform layer was then removed and the aqueous layer was extracted with chloroform (2 x 50 mL). The combined extracts were washed with saturated sodium bicarbonate solution (50 ml) and the organic solvent was removed by evaporation under reduced pressure in the presence of sodium bicarbonate solution (50 ml). The resulting suspension was then extracted with ethyl acetate (3 x 50 ml), the combined extracts dried and the solvent removed by evaporation under reduced pressure until crystallization began. The solution was allowed to crystallize to completion and the product was filtered off and dried, yielding 2,3,3α, β, β-tetrahydro-η 5 - (p-phenylbenzoyloxy) β-octocyclopentenoyl-furan-γ-carbaldehyde (XX), which was identical in all respects to the sample prepared according to the previously known method.

Example 8

A solution of 5% of 5-chloro-7-anti-formylbicyclo (2.2.1) hept-2-12 ene-5-carboxamide (XII, R-chloro, R * carbamoyl) in methylene dichloride 16 56373 containing 1, 5 equivalents of p-chloroaniline were stirred overnight, washed twice with 3N hydrochloric acid and filtered and the solvent removed by evaporation. The residue was dissolved in ethyl acetate and the solution was filtered through silica gel to remove low H 2 impurities. Evaporation of the solvent gave 5-chloro-7-syn-formylbicyclo (2,2,1) hept-2-ene-5-carboxamide (X, R1 * chlorine, R2 carbamoyl). The N.m.r. spectrum in deuterium chloroform showed a doublet at ό * 9.6 (J = 2 Hz), which is characteristic of the 7-syn-formyl group.

5-Chloro-7-anti-fornylbicyclo (2,2,1) hept-2-ene-5 “carboxamide used as a starting material in the above process can be prepared as follows: 7-Acetokeethylene-5-chlorobicyclo ) hept-2-ene-5 “carbonyl chloride (XI, R = chlorine, R» chloroformyl, RJ = * acetoce) was added to an excess of methanol saturated with ammonia. After half an hour the resulting solution was acidified with 3N hydrochloric acid and extracted with methylene chloride. The extract was evaporated to dryness, the residue was dissolved in a small amount of methylene chloride and the solution was stirred vigorously with 3N hydrochloric acid for 2 hours. The organic phase was isolated, filtered and evaporated to dryness to give crude 5-chloro-7-anti-formylbicyclo (2.2.1) hept-2-ene-5-carboxamide, Ry = 0.52 (ethyl acetate / silica gel) . The N.m.r. spectrum in deuterium chloroform showed a singlet at cf e 9.7, which is characteristic of the 7-anti-formyl group.

Example 9

The process described in Example 8 was repeated using methyl 5 "chloro-12,7-anti-formyl bicyclo (2,2,1) hept-2-ene-5" carboxylate (X, R * * chlorine, R methoxycarbonyl) 5-chloro- 7-Anti-formylbicyclo (2,2,1) -hept-2-ene-5-carbonitrile to give methyl 5-chloro-7-syn-formylbicyclo (2,2,1) -hept-2 -ene-5-carboxylate (X, R = chlorine R methoxycarbonyl), 0. 17U5 n SIU8 cm (membrane methyl ester). The N.m.r. spectrum in deuterium chloroform showed characteristic bands similar to the corresponding nitrile shown in Example 1, together with an additional 3 H singlet at <3 = 3.73 due to the methyl group of the ester.

Methyl 5-chloro-7-anti-formylbicyclo (2,2,1) hept-2-ene-5 “carboxylate used as a starting material can be prepared by the method described in the last part of Example 8 using methyl 7-acetoxymethylene-5- chlorobicyclo (2,2,1) hept-2-ene-5-carboxylate instead of 7-acetoxymethylene-5 ”chlorobicyclo (2,2,1) -hept-2-ene-5-carbonyl chloride.

1T 56373

Tgalmerlrki 1Π 2-chloroacryloyl chloride (2.75 g) was added to a solution of o-acetoxyfulvene (2.72 g) in cyclohexane (10 ml) and the mixture was stirred at room temperature for 1 * hour. The reaction mixture was filtered and the solvent removed by evaporation to give 7-acetoxymethylene-5-chlorobicyclo (2.2.1) hept-2-ene-5 'carbonyl chloride, which was used in the process described in the second part of Example 8 without further purification. The Nmr spectrum in deuterium chloroform showed the following characteristic features (<≤ * values): 2.07 and 2.10, 3H, singlet, methyl (2 isomers at C-5) '6.1-6.7, 2H, multiplet, ring olefinic protons.

6.67, 1H, singlet, acetoxymethylene-olefinic proton.

In a similar manner, using methyl 2-chloroacrylate instead of 2-chloroacryloyl chloride, methyl 7-acetoxymethylene-5-chlorobicyclo (2,2,1) -hept-2-ene-5-carboxylate was obtained. The N.m.r. spectrum in carbon tetrachloride showed similar characteristic bands as in the acid chloride spectrum shown above, as well as 3H singlets at 3.69 and 3.72 due to the ester methyl group (isomers at C-5).

Example 11

The process described in the first paragraph of Example 3 was repeated using 5-chloro-7-syn-formylbicyclo (2,2,1) hept-2-ene-5-carboxamide 5-chloro-7-syn-formylbicyclo (2.2, 1) -hept-2-ene-5-carbonitrile to give 5-chloro-7-syn- (dimethoxymethyl) bicyclo (2,2,1) hept-2-ene-5-carboxamide. The n.m.r. spectrum in deuterium chloroform showed characteristic additional bands at: 3.2-3.38, 6h, 2 methoxy U, 88, 1H, (CH 3 O) 2 CH-CH <. (J 9 Hz.

5-Chloro-7-syn- (dimethoxymethyl) bicyclo (2,2,1) hept-2-ene-5-carboxamide was hydrolyzed by the process described in the first part of Example 7 to give 7-syn-dimethoxymethylbicyclo. (2,2,1) -hept-2-en-5-one (XVa), which was identical to that prepared in Example 7.

Methyl 5-chloro-7-ene- (dimethoxymethyl) bicyclo (2,2,1) hept-2-ene-5-carboxylate was converted to ketone XVa in a similar manner.

Claims (2)

18. . 66373 Claim: Bicyclo / 2,2,1,7-hept-2-ene-7-syn-carbaldehydes used as intermediates in the preparation of therapeutic prostaglandins and prostaglandin-like compounds, characterized in that they have the formula HCO H r 1 R 2 R 51 1. . 2 wherein R is a halogen atom, R is a cyano or carbamoyl group, or at most An alkoxycarbonyl group having 6 carbon atoms or an N-alkylcarbamoyl group having an alkyl group containing 1 to 6 carbon atoms.