GB2063863A - Nitrogen-containing prostaglandin/prostacyclin synthones and processes for their preparation - Google Patents
Nitrogen-containing prostaglandin/prostacyclin synthones and processes for their preparation Download PDFInfo
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- 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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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention provides a compound of the general formula <IMAGE> in which R<1> denotes a protecting group which can be split off under neutral or basic conditions and R<2> denotes a hydrogen atom, a straight-chain or branched alkyl radical having up to 8 carbon atoms, an unsubstituted or alkyl- substituted cycloalkyl or unsubstituted or alkyl-substituted cycloalkylalkyl radical each having from 3 to 8 carbon atoms in the cycloalkyl moiety and up to 8 carbon atoms in the or each alkyl moiety, or a phenyl or phenylalkyl radical having up to 8 carbon atoms in the alkyl moiety, wherein each of the phenyl and phenylalkyl radicals is unsubstituted or substituted in the benzene ring by 1 to 3 of the same or different substituents selected from halogen atoms, (C1 to C4)alkyl radicals and (C1 to C4)alkoxy radicals, and a process for its preparation. Compounds of the general formula I can be used as starting materials for N-containing prostaglandins and prostacyclins which in turn can be used as medicaments.
Description
SPECIFICATION
Nitrogen-containing prostaglandinlprostacyclin synthones and processes for their preparation
Prostaglandins are a group of fatty acids which occur in numerous tissues and organs of humans and animals. The basic skeleton of the naturally occurring prostaglandins consists of 20 carbon atoms which are arranged in the form of a five-membered ring and two adjacent linear side chains.
The pharmacological effects of prostaglandins extend, inter alia, over the fields of reproduction, bronchial muscle tone, blood pressure and gastroenterology. The pharmacological properties of naturally occurring prostaglandins are the subject of numerous review articles, for example N.H. Andersen and P.W. Ramwell in
Arch. Internal Med. 133, 30 (1974); R.L. Jones in Pathobiology Ann. 1972,359; J. Pike in Scient. American 225, 84 (1971) or M.P.L. Caton in Progress in Med. Chem. volume 8, ed: Butterworth, London, 1971.
The synthesis of prostanoic analogues which are not naturally occurring and in which the large number of pharmacological actions of the naturally occurring prostaglandins are differentiated is becoming of increasing importance.
The present invention provides a compound of the general formula
in which R1 denotes a protecting group which can be split off under neutral or basic conditions, preferably easily, and R2 denotes a hydrogen atom, a straight-chain or branched alkyl radical having up to 8 carbon atoms, an unsubstituted or alkyl-substituted cycloalkyl or unsubstituted or alkyl-substituted cycloalkylalkyl radical each having from 3 to 8 carbon atoms in the cycloalkyl moiety and up to 8 carbon atoms in the or each alkyl moiety, or a phenyl or phenylalkyl radical having up to 8 carbon atoms in the alkyl moiety, wherein each of the phenyl and phenylalkyl radicals is unsubstituted or substituted in the benzene ring by 1 to 3 of the same or different substituents selected from halogen atoms, (C1 to C4) alkyl radicals and (C1 to C4) alkoxy radicals.
Preferably R2 denotes a hydrogen atom, a straight-chain or branched alkyl radical having up to 8 carbon atoms, a cycloalkyl radical having 3 to 8 carbon atoms or a phenyl radical, each of the above radicals being unsubstituted or substituted by 1 to 3 of the same or different substituents selected from halogen atoms, (C1 to C4)alkyl radicals and (C1 to C4)alkoxy radicals, preferably unsubstituted or mono-, di- ortri-substituted by halogen, (C1-C4)alkyl or (C1-C4)alkoxy.
Preferably R' represents an aliphatic (C1 to C4)-acyl radical, especially acetyl or propionyl, or an acyl radical containing an aromatic group which is unsubstituted or substituted in the nucleus or nuclei by one or more of the same or different substituents, usually one or more of the same substituents, selected from (C1 to
C4)alkyl radicals, phenyl groups, preferably one such group, and nitro groups, especially benzoyl, 3-methyl-benzoyl, 4-phenyl benzoyl, 2,4-diethylbenzoyl, 2-nitro-benzoyl, 1 -naphthoyl or 2-naphthoyl.
Preferably R2 represents a hydrogen atom, a straight-chain (C1 to C6)alkyl radical, especially methyl, ethyl, n-propyl, n-butyl or n-hexyl, a branched (C2 to C6)alkyl radical, especially 2-propyl or 2-butyl, a (C3 to
C6)-cycloalkyl radical, especially cyclopentyl or cyclohexyl, a phenyl group, a phenyl group which is substituted by one or two of the same of different halogen atoms, especially by chlorine, for example 2-chlorophenyl or 2,6-dichlorophenyl, a phenyl group which is mono-, di- ortrisubstituted by methyl, especially 2,3-dimethylphenyl or 2,4,6-trimethylphenyl, or phenyl which is mono-, di- ortri-substituted by methoxy, especially 2,4-di-methoxyphenyl.
The invention furthermore provides a process for the preparation of a compound of the general formula I, which comprises a) converting the aldehyde of the formula
into an acetal of the general formula
in which R3 and R4 are the same or different and each represents a straight-chain alkyl radical having 1 to 5 carbon atoms, or in which R3 and R4 together denote a (CH2)n group, in which n represents 2,3 or 4, b) converting the acetal of the general formula Ill into a hydroxy-acetal of the general formula
in which R3 and R4 have the meanings given above, c) protecting the hydroxyl group in the hydroxyacetal of the general formula IV by a group which can easily be split off under acid conditions, to give a compound of the general formula
in which R3 and R4 have the meanings given above and R5 represents a protecting group which can easily be split off under acid conditions, d) subjecting the acetal of the general formula V thus obtained to aminolysis with an amine of the general formula
R2-NH2 VI in which R2 has the meaning given above, to give a hydroxy-amide of the general formula
in which R2, R3, R4 and R5 have the meanings given above, e) oxidising the hydroxy-amide of the general formula VII thus obtained to give the keto-amide of the general formula
in which R2, R3, R4 and R5 have the meanings given above, f) if desired, converting the keto-amide of the general formula VIII into its isomeric hydroxy-lactam of the general formula
in which R2, R3, R4 and R5 have the meanings given above, g) reacting the hydroxy-lactam of the general formula IX, the keto-amide of the general formula VIII or a mixture of the keto-amide of the general formula VIII and the hydroxy-lactam of the general formula IX with a mercaptan of the general formula HS-R6 X in which R6 denotes an alkyl radical having 1 to 5 carbon atoms or a phenyl radical, to give a thioether of the general formula
in which R2, R3, R4, R5,,d R6 have the meanings given above, h) reducing the thioether of the general formula Xl to give the lactam of the general formula
in which R2, R3, R4 and R5 have the meanings given above, i) splitting off the hydroxy-protecting group from the lactam of the general formula XII by gentle selective acid hydrolysis, to give a hydroxy-acetal of the general formula
in which R2, R3 and R4 have the meanings given above, j) protecting the hydroxyl group in the hydroxy-acetal of the general formula XIII by a group which can be split off again under neutral or basic conditions, to give an acetal of the general formula
in which R1, R2, R3 and R4 have the meanings given above, and k) converting the lactam of the general formula XIV into an aldehyde of the formula I in which R1 and R2 have the meanings given above by acid-catalysed hydrolysis.
The invention also provides a process for the preparation of a compound of the general formula I by step (k) above.
The aldehyde II used as the starting material in the process according to the invention can be prepared by a process analogous to the process described in J. Am. Chem. Soc. 97,5675(1969).
Acetalisation of a compound of the general formula II may be carried out, for example, in an inert solvent, such as, for example, benzene, toluene or carbon tetrachloride, with a mono-alcohol or diol, with the addition of a catalytic amount of acid. Suitable acids are, for example, dilute mineral acids and organic acids, such as, for example, p-toluenesulphonic acid, oxalic acid and acetic acid. However, it is also possible to react a compound of the formula II with an ortho-alkanoic acid ester in the corresponding alcohol and to catalyse the reaction by boron trifluoride etherate.
The hydroxy-protecting group in the acetal of the general formula Ill can be split off, for example, in an alcoholic solvent at 0-30"C under base catalysis. Suitable bases are, for example, sodium carbonate, potassium carbonate and alkali metal hydroxides.
The hydroxy group thus liberated is then protected by a group which can be split off under acid conditions.
Especially preferred groups represented by R5 are trimethylsilyl t-butyldimethylsilyl, phenyldimethylsilyl and tetrahydropyranosyl.
To introduce the silyl protective groups, the alcohol of the general formula IV may be reacted with silyl chloride and a base in an inert solvent, such as, for example, chloroform, methylene chloride ortoluene, at 0-30"C. Suitable bases are, for example, triethylamine, pyridine and 1 ,5-diazabicyclo-[5,4.0]-undec-5-ene (DBU).
To prepare the tetrahydropyranosyl ether, dihydropyran may be added to the alcohol of the general formula IV in the presence of an acid catalyst, such as, for example,p-toluenesulphonic acid. The reaction may be carried out in an inert solvent, such as, for example, methylene chloride, diethyl ether or toluene.
In general, it is at this point advantageous to purify the resulting protected acetal of the general formula V by chromatography.
The compound of the general formula V is reacted with an amine of the general formula VI to give a hydroxy-amide of the general formula VII. This reaction may be carried out in the corresponding amine as the solvent or in an inert solvent, for example an alcohol, water, tetrahydrofuran, dioxan or xylene, at a temperature of 30 to 180"C. In the case of low-boiling amines, it is expedient to carry out the reaction in an autoclave.
The oxidation of the hydroxy-amide of the general formula VII thus obtained to give the keto-amide of the general formula VIII may be carried out with an oxidising agent such, for example, as chromium trioxide/dimethyl sulphate, chromium trioxide/pyridine, pyridinium chlorochromate, pyridinium dichromate or chromium trioxide/sulphuric acid/water in an inert solvent, for example dimethylformamide, methylene chloride or acetone, at a temperature of from -30 to +400C. A preferred embodiment of the process consists in dissolving a compound of the general formula VII in dimethylformamide at 0 C, adding 2 to 3 equivalents of pyridinium dichromate and stirring the solution at room temperature. It is expedient to purify the keto-amides of the general formula VIII by chromatography.
The keto-amide of the general formula VIII is in tautomeric equilibrium with its cyclic isomer, that is to say the hydroxy-lactam of the general formula IX. Such equilibria are known from the literature, for example
Chem. Ber. 703,3205 (1970).
If the keto-amide of the general formula VIII is dissolved in an inert solvent, for example acetone, methanol, ethanol, tetrahydrofuran, chloroform or methylene chloride, and the solution is left to stand at 20 to 400C, a hydroxy-lactam of the formula IX is generally obtained after 2 hours to 4 weeks.
The hydroxy-iactam of the general formula IX, the keto-amide of the general formula XIII our a mixture of the two may then be reacted with a mercaptan of the general formula X and chlorotrimethylsilane in an inert solvent, such as, for example, methylene chloride, chloroform, toluene or dimethoxyethane, to give a thioether of the general formula XI. The reaction may be carried out at 30 to 1 00'C, expediently in the presence of an organic base, such as, for example, pyridine, triethylamine or 1,4-diazabicyclo[4.3.01-non-5- ene (DBN).
The thioether of the general formula Xl can be reduced by reaction with a metal catalyst, such as, for example, Pd/C, Raney Ni or NiCI2/NaBH4, and hydrogen in a (C1-C6)-, preferably (C1-C4)-alkyl alcohol, such as, for example, methanol, ethanol, t-butanol or iso-propanol, or in acetone.
The lactam of the general formula XII can be obtained by warming the mixture to 50 to 90"C.
HR5 may be split off from the compound of the general formula XII, to form a compound of the formula XIII, by the action of an acid in an inert solvent, for example methanol, ethanol, chloroform, methylene chloride, tetrahydrofuran ortoluene, at 0 to 500C. Suitable acids are, for example, dilute aqueous mineral acids and organic acids, e.g. p-toluenesulphonic acid, oxalic acid or acetic acid.
The compounds of the general formula XIV can be prepared for example by reacting the alcohol of the general formula XIII either with an anhydride of the general formula R1 -O-R1 or with an acid chloride of the general formula R' -Cl, wherein R1 has the meaning given above. The reaction may be carried out without a solvent or, in the case of the reaction with an acid chloride of the general formula R1-CI, in an inert solvent, such as, for example, chloroform, methylene chloride, carbon tetrachloride, tetrahydrofuran or dioxan, in the presence of a base. Suitable bases are, for example, pyridine, triethylamine and 4-dimethylaminopyridine.
The acetal grouping in the compound of the general formula XIV can be removed either by transacetalisation in the presence of a large excess of a ketone in a manner which is in itself known, or by gentle acid-catalysed hydrolysis, for example in a (C-C6)-, preferably (C1-C4)-, alkanol/water mixture.
Suitable acids are, for example, mineral acids and organic acids, e.g. p-toluenesulphonic acid, oxalic acid or acetic acid.
In addition to the compounds mentioned in the examples, the following compounds, especially, can also be prepared by the process according to the invention:
TABLE A N-methyl-2-aza-3-oxo-7-biphenylcarbonyloxy-bicyclo-[3.3.Ojoctane-6-carbaldehyde,
N-ethyl-2-aza-3-oXo-7-biphenylcarbonyloxy-bicyclo[3.3.0]-octane-6-carbaldehyde,
N-propyl-2-aza-3-oxo-7-biphenylcarbonyloxy-bicyclo-[3.3.0]octane-6-carbaldehyde,
N-butyl-2-aza-3-oxo-7-biphenylcarbonyloxy-bicyclo[3.3.0]-octane-6-carbaldehyde,
N-heXyl-2-aza-3-oXo-7-biphenylcarbonyloxy-bicyclo[3.3.0]-octane-6-carbaldehyde,
N-iso-propyl-2-aza-3-oxo-7-biphenylcarbonyloxy-bicyclo-t3.3.Ojoctane-6-carbaldehyde,
N-iso-butyl-2-aza-3-oxo-7-biphenylcarbonyloxy-bicyclo-[3.3.0]octane-6-carbaldehyde,
N-cyclopentyl-2-aza-3-oXo-7-biphenylcarbonyloxy-bicyclo-[3.3.0]octane-6-carbaldehyde,
N-cyclohexyl-2-aza-3-oxo-7-biphenylcarbonyloxy-bicyclo-[3.33.0]octane-6-carbaldehyde,
N-phenyl-2-aza-3-oxo-7-biphenylcarbonyloxy-bicyclo-[3.3.Ojoctane-6-carbaldehyde,
N-(2-chlorophenyl)-2-aza-3-oxo-7-biphenylcarbonyloxy-bicyclo[3.3.0]octane-6-carbaldehyde,
N-(2,6-dich Iorophenyl)-2-aza-3-oxo-7-biphenylcarbonyloxy-bicyclo [3.3.0]octane-6-carbaldehyde,
N-(2,3-dimethylphenyl)-2-aza-3-oxo-7-biphenylcarbonyloxy-bicyclo[3.3.Ojoctane-6-carbaldehyde,
N-(2,4,6-trimethylphenyl)-2-aza-3-oXo-7-biphenylcarbonyloxy-bicyclo[3.3.0]octane-6-carbaldehyde,
N-(2,4-dimethoxyphenyl)-2-aza-3-oXo-7-biphenylcarbonyloxy-bicyclo[3.3.0]octane-6-carbaldehyde,
N-methyl-2-aza-3-oxo-7-acetoxy-bicyclo[3.3.0]-octane-6-carbaldehyde,
N-ethyl-2-aza-3-oxo-7-acetoxy-bicyclo [3.3.Ojoctane-6-carbaldehyde,
N-propyl-2-aza-3-oxo-7-acetoxy-bicyclo [3.3.Ojoctane-6-carbaldehyde,
N-butyl-2-aza-3-oxo-7-acetoxy-bicyclo [3.3.0]octane-6-carbaldehyde,
N-hexyl-2-aza-3-oxo-7-acetoxy-bicyclo [3.3.0]octane-6-carbaldehyde,
N-iso-propyl-2-aza-3-oxo-7-acetoxy-bicyclo [3.3.0]octane-6-carbaldehyde,
N-iso-butyl-2-aza-3-oxo-7-acetoxy-bicyclo[3.3.0]octane-6-carbaldehyde,
N-cyclopentyl-2-aza-3-oxo-7-acetoxy-bicyclo[3.3.Ojoctane-6-carbaldehyde,
N-cyclohexyl-2-aza-3-oxo-7-acetoxy-bicyclo[3.3.0]octane-6-carbaldehyde,
N-phenyl-2-aza-3-oXo-7-acetoxy-bicyclo[3.3.0]octane-6-carbaldehyde,
N-(2-chlorophenyl )-2-aza-3-oxo-7-acetoxy-bicyclo[3.3.0]octane-6-ca rbaldehyde,
N-(2,6-dichlorophenyl)-2-aza-3-oXo-7-acetoxy-bicyclo[3.3.0]octane-6-carbaldehyde,
N-(2,3-dimethylphenyl)-2-aza-3-oXo-7-acetoxy-bicyclo[3.3.0]octane-6-carbaldehyde, N-(2,4,6-trimethylphenyl)-2-aza-3-oxo-7-acetoxy-bicyclo[3.3.0]octane-6-carbaldehyde, and
N-(2,4-dimethoxyphenyl )-2-aza-3-oXo-7-acetoxy-bicyclo[3.3.01octane-6-carbaldehyde.
The process according to the invention is distinguished by a hitherto unknown gentle method of converting a lactone grouping into a lactam grouping.
The compounds prepared in the process according to the invention can be used as starting materials for
N-containing prostaglandins and prostacyclins, which in turn can be used as medicaments.
The following Examples illustrate the invention.
EXAMPLE 1 2-0xa-3-oxo-6-dimethoxymethyl-7-biphen ylcaronyloxy-bicycl0[3. 3. 01octane 73 g (0.208 mole) of aldehyde II are dissolved in 300 ml of methanol. 35.6 g (0.335 mole) of trimethyl ortho-formate and, as the catalyst, 2 ml of boron trifluoride etherate are added at room temperature. The mixture is stirred at room temperature overnight. Most of the acetal precipitates during the reaction. The solution is cooled, the precipitate is filtered off and the mother liquor is evaporated to dryness. The residue is dissolved in hot methanol, the solution is clarified with charcoal and filtered and the filtrate is again concentrated to dryness. The residue is recrystallized from methanol.
Yield: 77.6 g (93.8%)
Melting point: 109-1100C NMR (CDC13): b ppm: 7.2-8.2, m, 9H (aryl), 5.3-5.5, m, 1H (O=C-O-C-H), 4.9-5.2, m, 1H (PB-O-C-H), 4.35, d, 1H (CH-(OCH3)2) and 2.4, d, 6H (OCH3)
IR (KBr): cam~1: 1765 (C=O lactone) and 1700 (C=O aryl ester)
EXAMPLE 2 2-Oxa-3-oxo-6-dimethoxymethyl-7-hydroxy-bicyclo[3.3. 01-octane 77.6 g (0.196 mole) of acetal (Example 1) are stirred with 30.4 g of finely powdered K2CO3 in 350 ml of dry
methanol at room temperature overnight. The solution is cooled to 0 C and acidified to pH 4-5 with saturated citric acid solution.The potassium salts which have precipitated and the biphenylcarboxylate ester are filtered off and washed with ice-cold methanol. The filtrate is concentrated to about 100 ml in a rotary evaporator at 25"C, 50 - 80 ml of saturated NaCI solution are added and the mixture is extracted with ethyl acetate. The extracts are washed with saturated NaCI solution, dried over MgSO4 and evaporated.
Yield: 33.7 g (80%)
NMR (CDCl3): b ppm: 4.8-5.2, m, 1H (O=C-O-C-H), 4.25, d, 1H (I-6Hz, CH-(OCH3)2), 4.2, qu, 1H (I-7Hz, H-C-OH) and 3.4, d, 6H (OCH3)
IR (film): cam~1: 3200-3600 (broad, OH) and 1755 (C=O lactone)
EXAMPLE 3 2-0xa-3-oxo-6-dimethoxymethyl-7-tetrah ydrop yranosyloxy-icyclo[3. 3. O]ocfane 14 g (0.164 mole) of dihydropyran and 0.2 g ofp-toluenesulfonic acid are added to 33.7 g (0.156 mole) of alcohol (Example 2) in 500 ml of methylene chloride. An exothermic reaction takes place. The solution is stirred at room temperature for a further few hours. It is stirred vigorously with 20 ml of bicarbonate solution in order to neutralize the acid catalyst and the organic phase is separated off, dried over MgSO4 and concentrated.
Yield: 42.9 g (92%)
NMR (CDC13): 8 ppm: 4.85-5.15, m, 1 H (O=C-O-C-H), 4.55-4.75, m, 1H (O-CH-O), 4.1-4.3, m, 1H (CH-(OCH3)2) and 3.3, d, 6H (OCH3)
IR (film): cam~1: 1760 (C=O lactone)
EXAMPLE 4 (1- Tetrahydrop yranosyloxy-2-dimethoxymethyl-4-hydroxy-cyc!opent-3-yI)-acetamide 10 g of lactone (Example 3) are dissolved in 100 ml of methanol and the solution is heated with 100 ml of liquid ammonia to 1300C in an autoclave for 20 hours. After cooling, the ammonia is allowed to evaporate and the mixture is concentrated in a Rotavapor.The residue is chromatographed on silica gel (running agent: methylene chloride/methanol 20:1).
1.15 g of unreacted lactone is isolated again as the first fraction.
Yield: 5.4 g (57.6%, based on the conversion)
NMR (CDC13): 6 ppm: 6.0-6.3, 2H (NH), 4.6,s (broad), 1 H (O-CH-O), 4.0-4.3, m, 3H (CH-OH, CH(O-CH3)2), 3.5-4.0, m, 2H (O-CH2), 3.35, d, 6H (OCH3) and 1.7-2.9, m, 1.6, s (broad)
IR (film) cam~1: 3400 (broad) O-H, 3200 N-H and 1665 N-C=O
Analysis: C10H18NO4 (216.262): calculated: C 55.54 H 8.39 N 6.48 found:C 55.2 H 8.6 N 6.0
EXAMPLE 5 (1-Oxo-3-dimethoxymethyl-4-tetrahydropyranosyloxy-cyclopent-2-yl)-acetamide
1.1 g (3.17 mmoles) of hydroxy-amide (Example 4) are dissolved in 5 ml of dimethylformamide and the solution is cooled to 0 C. 3.57 g of pyridinium dichromate are added to this solution and the mixture is stirred at 0 C for 30 minutes. The cooling is then removed and stirring is continued at room temperature for 5 hours.
5 ml of water are added to the solution and the mixture is extracted several times with ethyl acetate. The extracts are washed with saturated sodium chloride solution, dried and concentrated. The keto-amide can be purified by chromatography on silica gel (running agent: ethyl acetate/methanol 8:1).
Yield: 750 mg (69%)
Melting point: 120-121"C (acetone/hexane)
NMR (CDCl3): h ppm: 5.9, s (broad), 2H (NH2), 3.9-4.7, m, 3H (CH-(OR)2, CH-OR), 3.2-3.9, m, 2H (CH2-O), 3.35, m, 6H (O-CH3), 2.55, s (broad), 6H and 1.5, s (broad), 6H.
IR (KBr): cm1: 3200 (broad NH), 1740 (C=Ofive-membered ring) and 1675 (C=O amide)
EXAMPLE 6
1-Hydroxy-2-aza-3-oxo-6-dimethoxymethyl-7-tetrahydropyranosyloxy-bicyclo[3.3.0]octane
700 mg of keto-amide (Example 5) are dissolved in 5 ml of methanol and the solution is left to stand at room temperature. The methanol is stripped off and the residue is crystallized from acetone/hexane.
Yield: 700 mg (100%)
Melting point: 141-143"C (acetone/hexane) NMR (CDCl3): 5 ppm: 7.55,s, 1 H (NH), 5.15 (broad), 1 H (OH), 4.6,s (broad), 1 H (THP), 3.9-4.5, m, 2H (CH-(OR)2, CH-OR), 3.3-3.9, m, 2H (CH2-O), 1.8-3.0, m, 6H and 1.6, s (broad), 6H
IR (KBr): cm-: 3500-3000 (broad, NH, OH) and 1685 (C=O lactam)
EXAMPLE 7 I-Phenylthio-2-aza-3-oxo-6-dimethoxymeth yl-7-tetrah ydrop yranosyloxy-bicyclo[3. 3. O]octane 816 mg (7.5 mmoles, 0.95 ml) of trimethylchlorosilane are slowly added dropwise to a solution of 1.47 g (4.66 mmoles) of hydroxy-lactam (Example 6) and 550 mg (5 mmoles, 0.51 ml) of thiophenol in 10 ml of pyridine/methylene chloride (v:v 1:1) at room temperature. The solution is boiled under reflux for 40 hours (bath temperature: 700C). The pyridinium hydrochloride which has precipitated is filtered off and the filtrate is concentrated. The residue is taken up in ethyl acetate and the ethyl acetate mixture is washed with water, dried over MgSO4 and concentrated. The residue is chromatographed on silica gel (running agent: ethyl acetate/methanol 8:1).
Yield: 900 mg (47.4%)
NMR (CDCl3): 5 ppm: 7.7-7.9, m, 1 H (NH), 7.1-7.6, m, 5H (aryl), 4.45-4.65, m, 1 H (O-CH-O), 4.15-4.4, m, 1 H (CH-(OCH3)2) and 3.15-3.35, m, 6H (OCH3)
IR (film): cam~1: 3200 (broad, NH), 3070 (CH, aryl) and 1690 (C=O lactam)
EXAMPLE 8 2-Aza-3-oXo-6-dimethoxymethyl-7-tetrahydropyranosyloxy-bicyclo[3.3.0]octane 220 mg of thioether (Example 7) are boiled under reflux with about 3 g of Raney nickel in 10 ml of t-butanol for 30 minutes. The solution is filtered over celite, the residue is rinsed thoroughly with methanol and the filtrate is concentrated. The residue is filtered over a short column containing silica gel (running agent: methylene chloride/methanol 10:1).
Yield: 120 mg (75%)
NMR (CDCl3): 5 ppm: 6.75-6.95, m, 1 H (NH), 4.5-4.7, m, 1 H (O-CH-O), 3.8-4.3, m, 2H (CH-(OCH3)2, O=C-N-C-H) and 3.35, d, 6H (OCH3)
IR (film): cam~': 3250 (broad, NH) and 1690 (C=O lactam)
EXAMPLE 9 2-Aza-3-oXo-6-dimethoxymethyl-7-hydroxybicyclo[3.3.0]-octane 800 mg of tetrahydropyranosyl ether (Example 8) are stirred with 50 mg of p-toluenesulfonic acid in 5 ml of dry methanol at room temperature overnight. The solution is neutralized with 3 drops of pyridine and concentrated in a Rotavapor. The residue is chromatographed on silica gel (running agent: ethyl acetate/methanol 8:1).
Yield: 477 mg (83%)
Melting point: 104-105"C NMR (CDC13): 5 ppm: 6.4-6.6, m, 1 H (NH), 4.2, d, 1H H (CH-(OCH3)2), 3.7-4.1, m, 2H (O=C-N-C-H, CH-OH) and 3.4, d, 6H (OCH3)
IR (KBr): cam~1: 3400 (broad, NH) and 1660 (C=O lactam)
EXAMPLE 10 2-Aza-3-oXo-6-dimethoxymethyl-7-biphenylcarbonyloxy-bicyclo[3.3.01octane 430 mg of alcohol (Example 9) are dissolved in 10 ml of dry pyridine. 500 mg of p-phenylbenzoyl chloride are added, and the mixture is stirred, at room temperature until the starting material can no longer be detected in a thin layer chromatogram (running agent: ethyl acetate/methanol 8:1). The solvent is stripped off and the residue crystallizes.
Yield: 726 mg (92%)
NMR (CDCI3): 5 ppm: 7.3-8.3, m, 9H (aryl), 6.5-6.7, m, 1H (NH), 4.9-5.2, m, 1 H (H-C-O-CO-aryl), 4.3, d, 1H (CH-(OCH3)2), 3.7-4.0, m, 1 H (O=C-N-C-H) and 3.4, d, 6H (OCH3)
IR (KBr): cm-: 3200 (broad, NH), 1700 (C=O aryl) and 1660 (C=O lactam)
EXAMPLE 11 2-Aza-3-oxo-7-biphenylcarbonyloxy-bicyclo[3.3.0]octane-6-carbaldehyde
700 mg of acetal (Example 10) are stirred in 5 ml of chloroform and 0.5 ml of isopropanol with 0.2 ml of concentrated hydrochloric acid at room temperature. When the reaction has ended, 5 ml of water are added and the organic phase is separated off and washed with bicarbonate solution until neutral. The organic phase is dried over MgSO4 and concentrated. The residue is chromatographed on silica gel (running agent: ethyl acetate/methanol 8:1).
Yield: 452 mg (70%) NMR (CDCl3): 5 ppm:10.2, d, 1 H (CHO), 7.3-8.3, m, 9H (aryl), 6.5-6.7, m, 1 H (NH), 4.9-5.2, m, 1H (H-C-O-CO-aryl) and 3.7-4.0, m, 1H (O=C-N-C-H)
IR (KBr): cm-: 3200 (broad, NH), 1740 (CHO), 1700 (C=O aryl) and 1660 (C=O lactam)
Claims (17)
1. A compound of the general formula
in which R1 denotes a protecting group which can be split off under neutral or basic conditions and R2 denotes a hydrogen atom, a straight-chain or branched alkyl radical having up to 8 carbon atoms, an unsubstituted or alkyl-substituted cycloalkyl or unsubstituted or alkyl-substituted cycloalkylalkyl radical each having from 3 to 8 carbon atoms in the cycloalkyl moiety and up to 8 carbon atoms in the or each alkyl moiety, or a phenyl or phenylalkyl radical having up to 8 carbon atoms in the alkyl moiety, wherein each of the phenyl and phenylalkyl radicals is unsubstituted or substituted in the benzene ring by 1 to 3 of the same or different substituents selected from halogen atoms, (C1 to C4)alkyl radicals and (C1 to C4)alkoxy radicals.
2. A compound as claimed in claim 1,wherein R' represents a (C-C4)aliphatic acyl radical, an aromatic acyl radical which is unsubstituted or substituted by one or more of the same or different substituents selected from (C1-C4)alkyl radical and phenyl and nitro groups.
3. A compound as claimed in claim 2, wherein R' represents an acetyl, propionyl, benzoyl, 3-methylbenzoyl, 4-phenylbenzoyl, 2,4-diethylbenzoyl, 2-nitro-benzoyl, 1-naphthoyl or 2-naphthoyl group.
4. A compound as claimed in claim 1 or claim 2, wherein R2 represents a hydrogen atom, a straight-chain (C1 to Ce)alkyl radical, a branched (C2 to C5)aIkyI radical, a (C3 to C6)cycloalkyl radical, a phenyl group, a phenyl group mono- or disubstituted by halogen, a phenyl group mono-, di-ortrisubstituted by methyl, or a phenyl group mono-, di- ortri-substituted by methoxy.
5. A compound as claimed in claim 4, wherein R2 represents a hydrogen atom or a methyl, ethyl, n-propyl, n-butyl, n-hexyl, 2-propyl, 2-butyl, cyclopentyl, cyclohexyl, phenyl, 2-chlorophenyl, 2,6- dichlorophenyl, 2,3-dimethyl phenyl, 2,4,6-trichlorophenyl or 2,4-dimethoxyphenyl group.
6. 2-Aza-3-oxo-7-biphenylcarbonyloxy-bicyclo[3.3.0]-octane-6-carbaldehyde.
7. A compound as claimed in claim 1, which is any one of those listed in Table A herein.
8. A process for the preparation of a compound claimed in claim 1,which comprises converting the acetal grouping in a lactam of the general formula
wherein R1 and R2 have the meanings given in claim 1, and R3 and R4 are the same or different and each denotes a straight-chain alkyl radical having 1 to 5 carbon atoms or together represent a -(CH2)n- group in which n represents 2,3 or 4, into an aldehyde group.
9. A process as claimed in claim 8, wherein the acetal grouping is converted into the aldehyde group by transacetalisation in the presence of an excess of a ketone or by means of acid-catalysed hydrolysis.
10. A process as claimed in claim 9, wherein the hydrolysis is carried out in a (C-C4) alkanol/water mixture in the presence of a mineral acid or an organic acid.
11. A process as claimed in claim 8, carried out substantially as described in Example 11 herein.
12. A process for the preparation of a compound as claimed in claim 1, which comprises a) converting the aldehyde of the formula
into an acetal of the general formula
in which R3 and R4 are the same or different and each represents a straight-chain alkyl radical having 1 to 5 carbon atoms, or in which R3 and R4 together denote a -(CH2),- group in which n represents 2,3 or 4, b) converting the acetal of the general formula III into a hydroxy-acetal of the general formula
in which R3 and R4 have the meanings given in the case of general formula III above, c) protecting the hydroxyl group in the hydroxy-acetal of the general formula IV by a group which can be split off under acid conditions, to give a compound of the general formula
in which R3 and R4 have the meanings given in the case of general formula III above and R5 represents a protecting group which can be split off under acid conditions, d) subjecting the acetal of the general formula Vthus obtained to aminolysis with an amine of the general formula
R2-NH2 VI in which R2 has the meaning given in the case of formula I in claim 1, to give a hydroxy-amide of the formula
VII
in which R2 has the meaning given in the case of general formula I in claim 1, R3 and R4 have the meanings given in the case of general formula III above, and R5 has the meaning given in the case of general formula V above, e) oxidising the hydroxy-amide of the general formula VII thus obtained to give the keto-amide of the general formula
in which R2 has the meaning given in the case of general formula I in claim 1, R3 and R4 have the meanings given in the case of general formula Ill above and R5 has the meaning given in the case of general formula V above, f) if desired, converting the keto-amide of the general formula VIII into its isomeric hydroxy-lactam of the general formula
in which R2 has the meaning given in the case of general formula I in claim 1, R3 and R4 have the meanings given in the case of general formula III above and R5 has the meaning given in the case of general formula V above, g) reacting the hydroxy-lactam of the general formula IX, the keto-amide of the general formula VIII or a mixture of the keto-amide of the general formula VIII and the hydroxy-lactam of the general formula IX with a mercaptan of the general formula HS-RG X in which R5 denotes an alkyl radical having 1 to 5 carbon atoms or a phenyl radical, to give a thioether of the general formula
in which R2 has the meaning given in the case of general formula I in claim 1, R3 and R4 have the meanings given in the case of general formula Ill above, R5 has the meaning given in the case of general formula V above and R6 has the meaning given in the case of general formula X above, h) reducing the thioether of the general formula XI to give the lactam of the general formula
in which R2 has the meaning given in the case of general formula I in claim 1, R3 and R4 have the meanings given in the case of general formula III above and R5 has the meaning given in the case of general formula V above, i) splitting off the protecting group on the alcohol group in the lactam of the general formula XII by selective acid hydrolysis, to give a hydroxy-acetal of the general formula
in which R2 has the meaning given in the case of general formula I in claim 1, and R3 and R4 have the meanings given in the case of general formula III above, j) protecting the hydroxyl group in the hydroxy-acetal of the general formula XIII by a group which can be split off again under neutral or basic conditions to give an acetal of the general formula
in which R1 and R2 have the meanings given in the case of general formula I in claim 1 and R3 and R4 have the meanings given in the case of general formula Ill above, and k) converting the acetal grouping in the lactam of the general formula XIV into an aldehyde group.
13. A process as claimed in claim 12, carried out substantially as described in Examples 1 to 11 herein.
14. A compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 8 to 13.
15. An N-containing prostaglandin or prostacyclin whenever prepared from a compound as claimed in any one of claims 1 to 7 and 14.
16. A compound of the general formula IX, Xl, XII, XIII or XIV as specified in claim 12.
17. A compound of the general formula III, IV orV, VII or VIII as specified in claim 12.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19792946756 DE2946756A1 (en) | 1979-11-20 | 1979-11-20 | PROSTAGLANDIN / PROSTACYCLIN SYNTHONE CONTAINING NITROGEN AND METHOD FOR THE PRODUCTION THEREOF |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2063863A true GB2063863A (en) | 1981-06-10 |
| GB2063863B GB2063863B (en) | 1983-09-21 |
Family
ID=6086444
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8037024A Expired GB2063863B (en) | 1979-11-20 | 1980-11-19 | Nitrogen-containing prostaglandin/prostacyclin synthones and processes for their preparation |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS5686158A (en) |
| DE (1) | DE2946756A1 (en) |
| FR (1) | FR2470122A1 (en) |
| GB (1) | GB2063863B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2505332A1 (en) * | 1981-05-11 | 1982-11-12 | Hoechst Ag | COMPOUNDS FOR THE SYNTHESIS OF PROSTAGLANDINS AND PROSTACYCLINS CONTAINING NITROGEN AND PROCESS FOR THEIR PREPARATION |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2416193C2 (en) * | 1974-04-03 | 1985-08-14 | Hoechst Ag, 6230 Frankfurt | Prostaglandin analogs, processes for their preparation and their use as cytoprotective agents |
| DE3006865A1 (en) * | 1980-02-23 | 1981-09-10 | Hoechst Ag, 6000 Frankfurt | HETERO-IMINO-PROSTACYCLINE |
-
1979
- 1979-11-20 DE DE19792946756 patent/DE2946756A1/en not_active Withdrawn
-
1980
- 1980-11-19 GB GB8037024A patent/GB2063863B/en not_active Expired
- 1980-11-20 JP JP16274780A patent/JPS5686158A/en active Pending
- 1980-11-20 FR FR8024622A patent/FR2470122A1/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2505332A1 (en) * | 1981-05-11 | 1982-11-12 | Hoechst Ag | COMPOUNDS FOR THE SYNTHESIS OF PROSTAGLANDINS AND PROSTACYCLINS CONTAINING NITROGEN AND PROCESS FOR THEIR PREPARATION |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2470122A1 (en) | 1981-05-29 |
| DE2946756A1 (en) | 1981-05-27 |
| FR2470122B1 (en) | 1983-08-12 |
| GB2063863B (en) | 1983-09-21 |
| JPS5686158A (en) | 1981-07-13 |
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