DE4302155A1 - New 1-amino-2-carboxy-cyclopentane derivs. - Google Patents

Abstract

Cyclopentane- or cyclopentene-beta-aminoacid derivs. of formula (I) and their isomers, acid addn. salts and metal salt complexes are new: A, B, D, E, G, L, M, T = H (but not all H), halogen, benzyl, OH or 1-8C alkyl (opt. substd. by 1 or 2 of halogen, OH, K, benzyloxy, COOH, 1-6C alkoxy, up to 6C acyl, 2-6C alkoxycarbonyl or -NR4R5); or (i) B+D, E+G or L+M = =CR6R7 or =N-OH; (ii) E+G and/or B+D = O or S; or (iii) B+E or E+M = additional bond, provided that if B+E = bond then D and G are not both H; R4,R5 = H, phenyl or 1-6C alkyl; R6,R7 = H, halogen, 1-8C alkyl, 1-8C alkoxy, up to 8C oxyacyl, benzyl or phenyl; R2 = H; amino-protecting gp.; 1-8C alkyl (opt. substd. by 1 or 2 of OH, CHD, up to 6C acyl, phenyl and benzoyl, the last two themselves opt. substd. by 1 or 2 of halogen, NO2, CN and 1-6C alkyl); up to 8C acyl; benzoyl (opt. substd. as above); -SO2R8; phenyl (opt. susbtd. by 1-3 of halogen, OH, NO2, CF3, OCF3, 1-6C alkyl, up to 6C acyl, 1-6C alkoxy, up to 6C alkoxycarbonyl, NR4R5 or SO2R8); or -COCHR9NHR10; R8 = 1-8C alkyl, or benzyl or phenyl (both opt. substd. by 1-3 of halogen, OH, NO2, CN, CF3, OCF3, 1-6C alkyl, 1-6C alkoxy, up to 6C alkoxycarbonyl, COOH or -NR4R5); R9 = 3-8C cycloalkyl, 6-10C aryl, H or 1-8C alkyl (opt. substd. by CN, MeS, OH, SH, guanidyl, NR11R12, -COR13, 3-8C cycloalkyl or 6-10C aryl (itself opt. substd. by OH, NO2, 1-8C alkoxy, halogen or NR11R12)); R11,R12 = H, 1-8C alkyl or Rh; R13 = OH, benzyloxy, 1-6C alkoxy or -NR10R11 (sic); R10 = H or amino-protecting gp.; R3 = H or 1-8C alkyl (opt. substd. by phenyl); or R2+R3 = =CHR14; R14 = H or 1-8C alkyl (opt. substd. by halogen, OH, Rh, COOH, 1-6C alkoxy or up to 6C alkoxycarbonyl); V = O, S or NH; R1 = H or 1-8C or phenyl (both opt. substd. by 1-3 of OH, halogen, NO2, CN, COOH, CF3, OCF3, 1-6C alkoxy, NR4R5, SO2R8 or (for phenyl only) 1-6C alkyl, up to 6C acyl or up to 6C alkoxycarbonyl); if V = NH, then R1 can also be SO2R8.

Description

The invention relates to the use of cyclopentane and -pentene-β-amino acids, process for their preparation and their use as antibacterial drugs.

Aminopentenecarboxylic acid derivatives are known from J 63 287-754 A. Furthermore are from the publication Chem. Ber. 106 (12), 2788-95, 2-oxo-4,5-diphenyl-3,5- Cyclopentadiene-1,3-dicarboxylates known.

It has now been found that the cyclopentane and pentene β-amino acids of general formula (I)

in which
A, B, D, E, G, L, M and T are the same or different and represent hydrogen, halogen, hydroxyl or straight-chain or branched alkyl having up to 8 carbon atoms, which may be 1 to 2 times the same or different is substituted by halogen, hydroxy, phenyl, benzyloxy, carboxy or by straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula -NR ⁴ R ⁵ , in which
R ⁴ and R ^{5 are} identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
or each B and D, E and G or L and M together for a radical of the formula

stand in what
R ⁶ and R ^{7 are the} same or different and are hydrogen, halogen or straight-chain or branched alkyl, alkoxy or oxyacyl each having up to 8 carbon atoms, benzyl or phenyl, or
E and G and / or B and D together represent the rest of the formula = O or = S, or
B, D, E and G or E, G, L and M each together form a radical of the formula

form,
wherein
D 'and G' have the meaning of D and G given above, but do not mean hydrogen at the same time
and
G and L have the meaning given above
R ² for hydrogen or
represents an amino protecting group, or
stands for straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted 1 to 2 times identically or differently by hydroxyl, formyl or by straight-chain or branched acyl having up to 6 carbon atoms or by phenyl or benzoyl, which is optionally up to 2 times the same or different are substituted by halogen, nitro, cyano, or by straight-chain or branched alkyl having up to 6 carbon atoms, or
for straight-chain or branched acyl with up to 8 carbon atoms, or
represents benzoyl, which is optionally substituted as described above, or
represents a group of the formula -SO ₂ R ⁸ ,
wherein
R ⁸ denotes straight-chain or branched alkyl having up to 8 carbon atoms, benzyl or phenyl, the latter optionally up to 3 times the same or different by halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl are each substituted with up to 6 carbon atoms, carboxy or by the group -NR ⁴ R ⁵ listed above,
wherein
R ⁴ and R ^{5 have} the meaning given above,
represents phenyl, which is optionally up to 3 times the same or different by halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula -NR ⁴ R ⁵ or -SO ₂ R ^{8 is} substituted,
wherein
R ⁴ , R ⁵ and R ^{8 have} the meaning given above,
or
for an amino acid residue of the formula

stands in what
R ⁹ denotes cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms or hydrogen, or
means straight-chain or branched alkyl having up to 8 carbon atoms,
where the alkyl is optionally substituted by cyano, methylthio, hydroxy, mercapto, guanidyl or by a group of the formula -NR ¹¹ R ¹² or R ¹³ -OC-,
wherein
R ¹¹ and R ¹² independently of one another represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, and
R ¹³ denotes hydroxy, benzyloxy, alkoxy with up to 6 carbon atoms or the group -NR ¹⁰ R ¹¹ listed above,
or the alkyl is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in turn is substituted by hydroxyl, halogen, nitro, alkoxy having up to 8 carbon atoms or by the group -NR ¹¹ R ¹² ,
wherein
R ¹¹ and R ^{12 have} the meaning given above, and
R ^{10 represents} hydrogen or an amino protecting group
R ^{3 represents} hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl, or
R ² and R ³ together represent the rest of the formula = CHR ¹⁴ ,
wherein
R ¹⁴ denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by halogen, hydroxy, phenyl, carboxy or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,
V represents an oxygen or sulfur atom or the -NH group,
R ^{1 represents} hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, the latter optionally up to 3 times the same or different by hydroxy, halogen, nitro, cyano, carboxy, trifluoromethyl, trifluoromethoxy, by straight-chain or branched alkoxy in the case of phenyl also substituted by alkyl, acyl or alkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula -NR ⁴ R ⁵ or -SO ₂ R ⁸ ,
wherein
R ⁴ , R ⁵ and R ^{8 have} the meaning given above,
or in the event that V represents the -NH group,
R ^{1 represents} the group of the formula -SO ₂ R ⁸ ,
wherein
R ^{8 has} the meaning given above,
optionally in an isomeric form, and their acid addition salts and metal salt complexes,
Surprisingly show a strong antibacterial effect and are therefore suitable for use in the prophylaxis and chemotherapy of local and systemic infections.

The compounds according to the invention can also be present in the form of their salts. In general, here are salts with organic or inorganic bases or Called acids.

The acids that can be added preferably include halogen carbons hydrochloric acids such as B. the hydrochloric acid and the hydrogen bromide Acid, especially hydrochloric acid, also phosphoric acid, nitric acid, Sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as B. acetic acid, maleic acid, malonic acid, oxalic acid, gluconic acid, amber acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid Acid and sulfonic acids, such as. B. p-toluenesulfonic acid, 1,5-naphthalenedisulfone acid or camphorsulfonic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group own, be. Z are particularly preferred. As sodium, potassium, magnesium or Calcium salts, as well as ammonium salts, which are derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or Triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, Ethylenediamine or phenethylamine.  

Amino protecting groups in the context of the invention are the usual ones in the Peptide chemistry used amino protecting groups.  

These preferably include: benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxy benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 2-nitro- 4,5-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxy carbonyl, allyloxycarbonyl, vinyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5- Trimethoxybenzyloxycarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tri chloro-tert-butoxycarbonyl, menthyloxycarbonyl, 4-nitrophenoxycarbonyl, fluorine enyl-9-methoxycarbonyl (Fmoc), formyl, acetyl, propionyl, plyaloyl, 2-chlorine acetyl, 2-bromoacetyl, 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, benzoyl, benzyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or Benzyloxymethylene, 4-nitrobenzyl, 2,4-dinitrobenzyl, 4-nitrophenyl or 2-nitro phenylsulfenyl.

The compounds according to the invention can exist in stereoisomeric forms, for example, either like image and mirror image (enantiomers), or which are not behave like image and mirror image (diastereomers), or as Diastereomer mixture or as pure cis or trans isomers. The The invention relates to both the antipodes, racemic forms and mixtures of diastereomers as well as the pure isomers. The racemic shapes can be just like that Diastereomers in a known manner into the stereoisomerically uniform constituents separate [cf. E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962]. The separation into the stereoisomerically uniform compounds takes place for example via a chromatographic resolution of diastereoisomers Esters and amides or on optically active phases. Besides, one is Crystallization of diastereomeric salts possible.

Compounds of the general formula (I) are preferably used
in which
A, B, D, E, G, L, M and T are the same or different and represent hydrogen, fluorine, chlorine, bromine, benzyl, hydroxyl or straight-chain or branched alkyl having up to 6 carbon atoms, which may be replaced by halogen, Benzyloxy, hydroxy, is substituted by straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 4 carbon atoms or by a group of the formula -NR ⁴ R ⁵ ,
wherein
R ⁴ and R ^{5 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
or each B and D, E and G or L and M together for a radical of the formula

stand in what
R ⁶ and R ^{7 are the} same or different and are hydrogen, fluorine, chlorine, bromine, or straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, or
E and G and / or B and D together represent the rest of the formula = O or = S, or
B, D, E and G or E, G, L and M each together form a radical of the formula

form,
wherein
D 'and G' have the meaning of D and G given above, but are not simultaneously hydrogen and
G and L have the meaning given above,
R ² for hydrogen or
represents Boc, benzyl, benzyloxycarbonyl allyloxycarbonyl or 9-fluorenyl methyloxycarbonyl (Fmoc), or
represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl, formyl or by straight-chain or branched acyl having up to 4 carbon atoms or by phenyl or benzoyl, which is optionally substituted by halogen, nitro, cyano, or by straight-chain or branched alkyl are substituted with up to 4 carbon atoms, or
for straight-chain or branched acyl with up to 6 carbon atoms or
represents benzoyl, which is optionally substituted as described above, or
represents a group of the formula -SO ₂ R ⁸ ,
wherein
R ⁸ denotes straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or benzyl, the latter optionally having up to 2 times the same or different by halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy in each case up to 4 carbon atoms or is substituted by the group of the formula -NR ⁴ R ⁵ listed above,
wherein
R ⁴ and R ^{5 have} the meaning given above,
represents phenyl, which is optionally up to 2 times identical or different by halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms or by a group of the formula -NR ⁶ R ⁷ or -SO ₂ R ^{8 is} substituted,
wherein
R ⁶ , R ⁷ , R ^{8 have} the meaning given above, or
for an amino acid residue of the formula

stands in what
R ^{9 is} hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or benzyl and
R ^{10 is} hydrogen, benzyloxycarbonyl, Fmoc or tert. Butoxy carbonyl means
R ^{3 represents} hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or benzyl, or
R ² and R ³ together represent the rest of the formula = CHR ¹⁴ , wherein
R ^{14 is} hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by halogen, hydroxy, or by straight-chain or branched alkoxy or alkoxycarbonyl, each having up to 4 carbon atoms,
V represents an oxygen or sulfur atom or the -NH group,
R ^{1 represents} hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, the latter optionally up to 2 times the same or different by hydroxy, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, by straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 4 carbon atoms or substituted by a group of the formula -NR ⁴ R ⁵ or -SO ₂ R ⁸ , in which
R ⁴ , R ⁵ and R ^{8 have} the meaning given above,
or in the event that V represents the -NH group,
R ^{1 represents} the group of the formula -SO ₂ R ⁸ , wherein
R ^{8 has} the meaning given above,
optionally in an isomeric form and their acid addition salts and metal salt complexes in the prophylaxis and chemotherapy of local and systemic infections.

Compounds of the general formula (I) in which
A, B, D, E, G, L, M and T are the same or different and are for hydrogen, fluorine, chlorine, bromine, benzyl, hydroxy or
stand for straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxy or benzyloxy,
or each B and D, E and G or L and M together for a radical of the formula

stand in what
R ⁶ and R ^{7 are the} same or different and are hydrogen, fluorine, chlorine, bromine or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, or
E and G and / or B and D together represent the rest of the formula = O or = S, or
B, D, E and G or E, G, L and M each together form a radical of the formula

form what
D 'and G' have the meaning of D and G given above, but do not simultaneously represent hydrogen
G and L are the same or different and are hydrogen or methyl,
R ^{2 represents} hydrogen, allyloxycarbonyl, benzyl, Boc or Fmoc, or
represents straight-chain or branched alkyl having up to 4 carbon atoms, or
represents straight-chain or branched acyl having up to 4 carbon atoms or a group of the formula -SO ₂ R ⁸ , in which
R ⁸ denotes straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or benzyl, the latter optionally being substituted by hydroxy, fluorine, chlorine, bromine, nitro, cyano, methyl, ethyl or methoxy, or
for an amino acid residue of the formula

stands in what
R ^{9 is} hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or benzyl and
R ^{10 is} hydrogen, tert. Butoxycarbonyl or Fmoc means
R ^{3 represents} hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or
R ² and R ³ together represent the rest of the formula = CHR ¹⁴ , wherein
R ¹⁴ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
V represents an oxygen or a sulfur atom or the -NH group,
R ^{1 represents} hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, the latter optionally by fluorine, chlorine, bromine, nitro, cyano, methoxy, ethoxy or by a group of the formula -NR ⁴ R ⁵ or -SO ₂ R ^{8 are} substituted, wherein
R ⁴ and R ^{5 are the} same or different and are hydrogen, methyl or ethyl and
R ^{8 has} the meaning given above,
or in the case that V stands for the -NH group,
R ^{1 represents} the group of the formula -SO ₂ R ⁸ , wherein
R ^{8 has} the meaning given above,
optionally in an isomeric form, and their acid addition salts and metal salt complexes in the prophylaxis and chemotherapy of local and systemic infections.

We have also found processes for the preparation of the compounds of the general formula (I) according to the invention, characterized in that
[A] compounds of the general formula (II)

in which
A, B, D, L, M and T have the meaning given above,
in organic solvents, preferably dioxane, first with (C ₁ -C ₃ ) -trialkylsilylazides, then with ethers, in the presence of water, into the compounds of the general formula (III)

in which
A, B, D, L, M and T have the meaning given above,
convicted,
and in a next step with acids, preferably hydrochloric acid, with ring opening to give the compounds of the general formula (Ia)

in which
A, B, D, L, M and T have the meaning given above,
implements
and optionally an elimination with acids, preferably hydrochloric acid, or
[B] Compounds of the general formula (IV)

in which
A, B, D, E, L, M and T have the meaning given above, first by converting chlorosulfonyl isocyanate into the compounds of the general formula (V)

in which
A, B, D, E, L, M and T have the meaning given above,
transferred and then released with acids, preferably hydrochloric acid, with ring opening the amine and carboxy function, or
[C] compounds of the general formula (VI)

in which
B, D, E, G, L, M and T have the meaning given above, and
R ^{15 represents} C ₁ -C ₄ alkyl,
by reaction with amines of the general formula (VII)

H ₂ NR ¹⁶ (VlI)

in which
R ^{16 represents} benzyl, which is optionally halogen, NO ₂ , cyano or C ₁ -C ₄ alkyl or the rest of the formula -CH (C ₆ H ₄ -pOCH ₃ ) ₂ ,
in organic solvents, optionally in the presence of a base, into the compounds of the general formula (VIII)

in which
B, D, E, G, L, M, R ¹⁵ and R ^{16 have} the meaning given above,
convicted,
and then first reducing the double bond by double hydrogenation, then releasing the amine function and in a last step saponifying the carboxylic acid ester with acids,
and in principle the substituents AT, optionally derivatized with the blocking of the amine function beforehand by reaction of the protective groups by customary methods, for example by oxidation, reduction or alkylation,
and in the case of acids, the esters are saponified by conventional methods
and in the case of the other definitions given for V and R ¹ above, likewise derivatized by customary processes, such as, for example, amidation, sulfonation or sulfoamidation, if appropriate in the presence of auxiliaries such as catalysts and dehydrating agents, starting from the corresponding carboxylic acids, if appropriate with prior activation,
and, in the case of the pure enantiomers, carries out a resolution.

The method according to the invention can be exemplified by the following formula are explained:  

Come as solvents for the individual steps of processes [A], [B] and [C] Water and all inert organic solvents in question, which are among the Do not change reaction conditions. These preferably include alcohols such as Methanol, ethanol, propanol, isopropanol, ethers such as diethyl ether, dioxane, diiso propyl ether, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or chlorinated hydrocarbons, such as chloroform or methylene chloride, or Amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric acid triamid, or glacial acetic acid, dimethyl sulfoxide, acetonitrile or pyridine. Are preferred for the individual steps diisopropyl ether, diethyl ether, dioxane, methanol, Ethanol and dichloromethane.

The reaction temperatures can be varied over a wide range. in the generally one works between -78 ° C and + 150 ° C, preferably between -10 ° C and + 100 ° C.  

The reactions can be carried out at normal pressure, but also at elevated or low pressure (e.g. 0.5 to 80 bar). Generally you work at normal pressure or at an increased pressure of 3 to 80 bar.

When carrying out process variants [A], [B] and [C] according to the invention the ratio of the substances involved in the reaction is arbitrary. In general however, one works with molar amounts of the reactants. The isolation and Reini supply of the substances according to the invention is preferably carried out in such a way that the Solvent is distilled off in vacuo and, if necessary, only after ice cooling crystalline residue obtained recrystallized from a suitable solvent. In In some cases it may be necessary to use the compounds of the invention to be purified by chromatography.

Examples of suitable oxidizing agents are hydrogen peroxide and sodium per iodate, peracids such as m-chloroperbenzoic acid or potassium permanganate. Prefers are hydrogen peroxide, m-chloroperbenzoic acid and sodium periodate.

Organic amines (trialkyl (C1-C6) amines) such as, for example, are suitable as bases Triethylamine or heterocycles such as pyridine, methylpiperidine, piperidine or Morpholine. Triethylamine is preferred.

Mineral acids are generally used as acids for the ring opening (V) puts. Hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid or mixtures of the acids mentioned. Hydrochloric acid is preferred.

Suitable acids for deblocking (III) are C ₁ -C ₆ carboxylic acids such as acetic acid or propionic acid. Acetic acid is preferred.

The acid is generally used in an amount of 2 mol to 30 mol, preferably from 5 mol to 15 mol, in each case based on 1 mol of the compounds of the general Formulas (III) and (V) used.  

The saponification of the carboxylic acid esters is carried out by customary methods, by the esters are treated with customary bases in inert solvents, the first being resulting salts are converted into the free carboxylic acids by treatment with acid can be.

The saponification of the carboxylic acid esters can also be carried out using one of the above Acids are carried out.

The usual inorganic bases are suitable as bases for the saponification. For this preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as Sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali carbonates such as Sodium or potassium carbonate or sodium hydrogen carbonate, or alkali alcohol latex such as sodium ethanolate, sodium methoxide, potassium ethanolate, potassium methoxide or potassium tert-butoxide. Sodium hydroxide or is particularly preferred Potassium hydroxide used.

Suitable solvents for saponification are water or those for saponification usual organic solvents. These preferably include alcohols such as methanol, Ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or Dioxane, or dimethylformamide or dimethyl sulfoxide. Particularly preferred who alcohols such as methanol, ethanol, propanol or isopropanol are used. As well it is possible to use mixtures of the solvents mentioned.

The saponification is generally in a temperature range from 0 ° C to + 100 ° C, preferably from + 20 ° C to + 80 ° C.

The saponification is generally carried out at normal pressure. It is also possible to work at negative or excess pressure (e.g. from 0.5 to 5 bar).

When carrying out the saponification, the base or the acid in general in an amount of 1 to 3 mol, preferably from 1 to 1.5 mol based on 1 mol of the Esters used. Molar amounts of the reactants are particularly preferably used the.  

When carrying out the reaction, the salts of the invention are formed in the first step Compounds as intermediates that can be isolated. The acids of the invention are obtained by treating the salts with conventional ones inorganic acids. These preferably include mineral acids such as, for example Hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. It has proven advantageous in the production of the carboxylic acids basic reaction mixture of saponification in a second step without isolation acidification of the salts. The acids can then be isolated in the usual way become.

Examples of the derivatization options listed above are the Amidation and sulfonation or sulfonamidation are explained.

The amidation is generally carried out in inert solvents in the presence of a Base and a dehydrating agent.

Inert organic solvents, which are among the Do not change reaction conditions. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichlor ethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, Dimethylformamide, acetonitrile or hexamethylphosphoric triamide. Likewise it is possible to use mixtures of the solvents. Dichlor is particularly preferred methane.

The usual basic compounds are suitable as bases for the amidation. These preferably include alkali and alkaline earth metal hydroxides such as lithium hydroxide, Sodium hydroxide, potassium hydroxide or barium hydroxide, alkali hydrides such as Na triumhydride, alkali or alkaline earth carbonates such as sodium carbonate, potassium carbonate, or alkali alcoholates such as sodium methoxide or ethanolate, Potassium methoxide or ethanolate or potassium tert.buylate, or organic amines  such as benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, pyridine, Triethylamine or N-methylpiperidine.

The amidation is generally in a temperature range from 0 ° C to 150 ° C, preferably at 25 ° C to 40 ° C, carried out.

The amidation is generally carried out at normal pressure. But it is also possible to carry out the process under negative pressure or under positive pressure (e.g. in a range from 0.5 to 5 bar).

Suitable dehydration reagents are carbodiimides such as Di isopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) - N'-ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldi imidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfonate or propane phosphoric anhydride or isobutyl chloroformate or Benzotriazolyloxy-tris (dimethylamino) phosphonium hexyfluorophosphat- or Phosphonic acid diphenyl ester amide or methanesulfonic acid chloride, optionally in Presence of bases such as triethylamine or N-ethylmorpholine or N-Methylpi peridine or dicyclohexylcarbodiimide and N-hydroxysuccinimide [cf. J.C. Sheehan, S.L. LEdis, J. Am. Chem. Soc. 95: 875 (1973); F.E. Frerman et al., J. Biol. Chem. 225, 507 (1982) and N.B. Benoton, K. Kluroda, Int Pept. Prot. Res. 13, 403 (1979), 17, 187 (1981)].

The sulfonation or sulfoamidation takes place in the inert solutions mentioned above medium, if necessary using the bases and De also listed above hydrating agents.

The sulfonation and sulfoamidation are generally carried out at normal pressure carried out. However, it is also possible to use the vacuum or overpressure method pressure (e.g. in a range from 0.5 to 5 bar).

The sulfonation and sulfoamidation is generally carried out in a tempera tur range from 0 ° C to + 150 ° C, preferably from + 25 ° C to + 40 ° C.  

The commercially available literature are generally suitable for amidation Amines and their derivatives [cf. Houben-Weyl, "Methods of Organic Chemistry ", Bad. XI / 1 and XI / 2].

The sulfonation and sulfoamidation generally also take place with the usual sulfonic acids and their activated derivatives [cf. Houben-Weyl, "Methods der organic chemistry ", Volume IX, S 407 ff; Beilstein 11, 26].

The esterification of the acids is carried out according to the usual method, by taking the acids optionally in one of the solvents listed above in the presence of a Reacts catalyst with the appropriate alcohols. This is preferred Alcohol is also used as a solvent.

Inorganic acids such as sulfuric acid can be used as catalysts or inorganic acid chlorides, such as thionyl chloride, or p-Toluenesulfonic acid can be used.

In general, 0.01 to 1, preferably 0.05 to 0.5, mol of catalyst is used based on 1 mol of reactant.

Both the esterification and the amidation can optionally via acti fourth stages of the carboxylic acids, such as acid halides, from the corresponding acid by reaction with thionyl chloride, phosphorus trichloride, Phosphorus pentachloride, phosphorus tribromide or oxalyl chloride can be produced can run.

The acid addition salts of the compounds of formula (I) can in simpler Way according to usual salt formation methods, e.g. B. by loosening a connection Formula (I) in a suitable solvent and adding the acid, e.g. B. chlorine hydrochloric acid can be obtained and in a known manner, for. B. by filtering, isolated and optionally by washing with an inert organic solvent be cleaned.  

The amino protective groups are split off in a manner known per se [cf. Th. Greene, "Protective Groups in Organic Synthesis", 1st ed. J. Wiley & Sons, New York 1981 and Houben-Weyl "Methods of Organic Chemistry, Volume XV / 1 and 1].

Double bonds are converted into carbonyl functions by owno lysis and reduction of the ozonides with reducing agents such as, for example, dimethyl sulfoxide, zinc or (C ₁ -C ₃ ) -trialkylphophine.

The reduction of alkoxycarbonyl compounds or aldehydes to the equivalent Alcohols generally use hydrides such as sodium borohydride or sodium borohydride, preferably with sodium borohydride in inert solvents such as Ethers, hydrocarbons or alcohols or mixtures thereof, preferably in Ethers such as diethyl ether, tetrahydrofuran or dioxane, or Alcohols such as ethanol, in the case of the ketones and aldehydes preferably with sodium borohydride in ethanol, in a temperature range from 0 ° C to + 150 ° C, preferred from + 20 ° C to + 100 ° C, at normal pressure.

Double bonds are generally introduced by converting the alcohols into the corresponding mesylates, tosylates, bromides, iodides or arylselenyl compounds, preferably with 2-nitrophenylselenyl cyanide and tri-n-butylphosphine, and then eliminating the leaving groups with bases, preferably with one of the above organic amines, or by eliminating the selenyl groups by oxidation, preferably with H ₂ O ₂ in H ₂ O / THF.

Conventional organic solvents which are suitable as solvents for the alkylation are: do not change under the reaction conditions. These preferably include Ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or Hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, Carbon tetrachloride, dichlorethylene, trichlorethylene or chlorobenzene, or vinegar  ester, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexa methylphosphoric triamide, acetonitrile, acetone or nitromethane. It is the same possible to use mixtures of the solvents mentioned. Dichlor is preferred methane.

The alkylation is carried out in the solvents listed above at temperatures of 0 ° C to + 150 ° C, preferably at room temperatures up to + 100 ° C, at normal pressure carried out.

The hydrogenations (reductions, splitting off of protective groups) are generally carried out in one of the solvents listed above, such as alcohols, for example methanol, ethanol or propanol, in the presence of a noble metal catalyst such as platinum, platinum / C, palladium, palladium on charcoal or Raney nickel , in the case of the double bond of the general formula (VIII) preferably with H ₂ / platinum or with H ₂ / palladium.

Acids are generally used as catalysts. This includes before adds inorganic acids such as hydrochloric acid or sulfuric acid, or organic sulfonic or carboxylic acids such as methanesulfonic acid, Ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, acetic acid or propion acid.

The hydrogenations can be carried out at normal, elevated or reduced pressure (e.g. 0.5-5 bar).

The catalysts and bases are generally in an amount from 0 mol to 10 mol, preferably from 1.5 mol to 3.5 mol, in each case based on 1 mol of the verbin The general formulas (IV), (V), (VI) and (VIII) are used.

The acid is generally used in an amount of 2 mol to 30 mol, preferably from 5 mol to 15 mol, in each case based on 1 mol of the compounds of the general Formulas (IV), (V), (VI) and (VIlI) used.  

The compounds of general formula (II) are largely new and can can be prepared, for example, by using compounds of the general Formula (IX)

in which
A, B, D, L, M and T have the meaning given above
first releases the corresponding dicarboxylic acids by basic saponification, preferably using lithium hydroxide / H ₂ O in one of the solvents listed above, preferably tetrahydrofuran, and then reacting it with propionic anhydride.

The compounds of the general formula (IX) are known per se or can can be prepared by customary methods (cf. H.J. Gals, J. Org. Chem. 1989, 54, 5115).

The compounds of the general formulas (V) and (VIII) are new and can can be produced by the method listed above.

The compounds of the general formula (IV) are known per se or can be produced according to the usual method.  

The compounds of the general formula (VI) are largely known or can be produced according to methods known from the literature [cf. Soc. 1983, 48, 5364; JACS, 1951, 73, 4286; JACS, 1978 100, 6728].

The amines of the general formula (VII) are known and are customary Methods can be produced or purchased.

The compounds of general formula (Ia) are new and can according to the above listed procedures are produced.

The pure enantiomers can be obtained by starting from the race mat, first the amine function with a protective group, preferably Fmoc, blocked, then after reaction with chiral amines, such as Phenethylamine or (-) - quinine, preferably with phenethylarine the corresponding diastereomeric salts crystallized and in a last step the protective group, for example with liquid ammonia.

The method can be illustrated using the following formula scheme:  

The above manufacturing processes are given for illustration only ben. The preparation of the compounds of general for Meln (I) and (Ia) is not limited to these methods, any modification of them The method can be used in the same way for the production.

A logarithinically growing S. aureus 133 culture was diluted with physiological saline so that - 1 × 10 ⁸ bacteria in 0.25 ml could be injected intraperitoneally into the mice. The infected animals were treated 0.5 and 3 hours after infection. The survival of the mice was recorded up to the 6th day after infection.

Example 32 shows a dose-dependent one compared to the untreated infection control therapeutic effect.

The compounds according to the invention show an unforeseeable, valuable pharmacological spectrum of action.

They are antibacterial with low toxicity against gram-positive germs, especially against those germs that are resistant to various Antibiotics such as B. penicillins, cephalosporins, tetracyclines, macrolides, Quinolones.  

These valuable properties enable them to be used as chemotherapeutic agents in medicine and as substances for preservation of inorganic and organic materials, especially organic Materials of all kinds, e.g. B. polymers, lubricants, paints, fibers, leather, paper and wood, food and water.

With the help of the compounds according to the invention, gram-positive bacteria fights and prevents the diseases caused by these pathogens, be improved and / or cured. They are therefore particularly good for prophylaxis and Chemotherapy of local and systemic infections in human and Suitable veterinary medicine, which are caused by these pathogens.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically acceptable excipients one or more Contain compounds of the invention or those of one or more Active substances according to the invention exist, and methods for producing them Preparations.

The active ingredient (s) may optionally be present in one or more of the above specified carrier substances are also present in microencapsulated form.

The preferred pharmaceutical preparations are tablets, dragees, capsules, Pills, granules, suppositories, solutions, suspensions and emulsions, pastes, Called ointments, oils, creams, lotions, powders and sprays.

The therapeutically active compounds are listed in the above pharmaceutical preparations preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95% by weight of the total mixture to be available.

The pharmaceutical preparations listed above can in addition to the inventions Compounds according to the invention also contain other active pharmaceutical ingredients.  

In general, it has been found in both human and veterinary medicine proven advantageous, the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg body weight each 24 hours, possibly in the form of several individual doses, to achieve the to deliver the desired results. A single dose contains the Active ingredients according to the invention preferably in amounts of about 1 to about 80, especially 3 to 30 mg / kg body weight.  

Output connections Example I 1,2-cis-4-methylene-cyclopentane-1,2-dicarboxylic acid

To dissolve diethyl 1,2-cis-4-methylene-cyclopentane-1,2-dicarboxylate (19.0 g; 84 mmol) in 100 ml THF, a solution of LiOH × H ₂ O (7, 8 g; 18 5mmol) in 150 ml water. The resulting solution is stirred at room temperature for 20 h, the THF is stripped off in vacuo and the residue is extracted once with 40 ml of ether. The aqueous phase is brought to pH 2 with 10% hydrochloric acid and extracted three times with 200 ml of ethyl acetate. The combined ethyl acetate phases are dried over Na ₂ SO ₄ and the solvent is stripped off in vacuo.
Yield: 13.4 g (93% of theory)
M.p .: 116-120 ° C
C ₈ H ₁₀ O ₄ (170.2).

Example II 1,2-cis-4-methylene-cyclopentane-1,2-dicarboxylic acid anhydride

A solution of the compound from Example I (13.0 g; 76.5 mmol) in 65 ml of propionic anhydride is heated under reflux for 3 h. The solvent is stripped off at 60 ° C./0.5 torr and the residue is distilled.
Yield: 10.0 g (86% of theory)
Bp .: 130-140 ° C / 0.1 Torr
M.p .: 47-49 ° C
C ₈ H ₈ O ₃ (152.1)

Example III 6-methylene-cyclopentano [3,4-d] oxazin-2,4- (1H) -dione

A solution of the compound from Example II (8.8 g, 58 mmol) and trimethylsilyl azide (7.9 g, 69 mmol) in 60 ml of dioxane is heated to 80 ° C. for 2 h. The solvent is removed in vacuo, the residue is taken up in 80 ml of ether and H ₂ O (0.52 g, 29 mmol) is added. The mixture is stirred vigorously for 5 minutes and stored at 6 ° C. for 2 days. Precipitated product is filtered off and washed with diethyl ether.
Yield: 4.2 g (43% of theory)
M.p .: 145 ° C (decomposition)
C ₈ H ₉ NO ₃ (167.2)

Example IV 1,2-cis-2-N- (tert-butyloxycarbonyl) amino-4- (2-nitrophenyl) - selenyl-cyclopentane-1-carboxylic acid methyl ester

A solution of the compound from Example 63 (3.30 g, 12.7 mmol) in 50 ml of THF is dissolved at room temperature under argon with 2-nitrophenylselencyanide (3.46 g, 15.2 mmol) and then with tri-n-butylphosphine (3 , 08 g, 15.2 mmol) was added. The mixture is stirred at room temperature for 1 h, the solvent is stripped off in vacuo and the residue is chromatographed on silica gel (ether: petroleum ether = 2: 1).
Yield: 4.45 g (79% of theory)
Diastereomer ratio D ₁ : D ₂ = 3: 1
R _f = 0.28 and 0.39 (ether / petroleum ether = 2: 1)
C ₁₈ H ₂₄ N ₂ O ₆ Se (443.4)

General procedure A for 2-benzylamino-cyclopent-1-ene-carbon acid methyl ester

A solution of the substituted 2-benzylamino-cyclopent-1-ene-carboxylic acid methyl ester (160 mmol) and benzylamine (34.2 g, 320 mmol) in 540 ml Dichloromethane is mixed with p-toluenesulfonic acid (200 mg) and 108 g molecular sieve (4th A) added and heated under reflux on a water separator for 24 h. The mixture is filtered and the filtrate is concentrated in vacuo. The residue is on silica gel chromatographed.

Example V 2-Benzylamino-4,4-dimethyl-cyclopent-1-ene-carboxylic acid methyl ester

In analogy to working instruction A, the title connection is established.
Yield: 30.0 g (72% of theory)
R _f = 0.49 (petroleum ether / ethyl acetate = 3: 1)
C ₁₆ H ₂₁ NO ₃ (259.3)

Example VI 2-Benzylamino-5-methyl-cyclopent-1-ene-carboxylic acid methyl ester

In analogy to working instruction A, the title connection is established.
Yield: 27.9 g (71% of theory)
R _f = 0.42 (ether / petroleum ether = 5: 1)
C ₁₅ H ₁₉ NO ₂ (245.3)

Example VII 2-Benzylamino-3-methyl-cyclopent-1-ene-carboxylic acid methyl ester

The title link is established in analogy to the working procedure.
Yield: 20.0 g (51% of theory)
R _f = 0.45 (ether / petroleum ether 1: 5)
C ₁₅ H ₁₉ NO ₂ (245.3)

Example VIII 4-Ethylidene-cyclopentane-1,2-dicarboxylic acid diethyl ester

Ethyl triphenylphosphonium bromide (100 g, 270 mmol) is added at room temperature under argon to the solution of potassium t-butanolate (24.8 g, 220 mmol) in 1,000 ml of diethyl ether and the mixture is stirred for 20 h at room temperature. A solution of diethyl 4-cyclopentanone-1,2-dicarboxylate (15.8 g, 69 mmol) in 120 ml of diethyl ether is added dropwise at 0 ° C. and the mixture is stirred at 0 ° C. for 1 h. 300 ml of water are added, the organic phase is washed with saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and the solvent is evaporated down i. Vac. from. The residue is chromatographed on silica gel (petroleum ether / ether = 2: 1).
Yield: 13.1 g (79%) of a cis / trans diastereomer mixture
¹ H NMR (CDCl ₃ ): 8 = 1.23 (t, 6H), 1.58 (m, 3H), 2.3-2.6 (m, 4H), 3.0-3.22 ( m, 2H), 4.17 (q, 4H), 5.35 (cm, 1H)
C ₁₃ H ₂₀ O ₄

Example IX 4-ethylidene-cyclopentane-1,2-dicarboxylic acid

A solution of LiOH.H ₂ O (5.1 g, 120 mmol) in 130 ml of water is added dropwise to the solution of the compound from Example VIII (13.1 g, 54.5 mmol) in 70 ml of THF at 0 ° C. The solution is stirred for 20 h at room temperature, the THF i. Vac. pulled off and the residue extracted once with 40 ml of ether. The aqueous phase is brought to pH 2 with 10% hydrochloric acid and extracted three times with 200 ml of ethyl acetate. The combined ethyl acetate phases are dried over Na ₂ SO ₄ and the solvent is evaporated down i. Vac. deducted.
Yield: 9.0 g (90%) of a mixture of diastereomers
M.p .: 170 ° C
C ₉ H ₁₂ O ₄ (1 84.2)

Example X 1,2-cis-4-ethylidene-cyclopentane-1,2-dicarboxylic anhydride

A solution of the compound from Example IX (8.25 g, 44.7 mmol) in 37 ml of propionic anhydride is heated under reflux for 3 h. The solvent is stripped off at 60 ° C./0.5 torr and the residue is distilled.
Yield: 2.0 g (27%)
M.p .: 150 ° C / 0.1 Torr (Kugelrohr distillation)
C ₉ H ₁₈ O ₂ (166.2)

Example XI 6-ethylidene-cyclopentanol [3,4-d] oxazin-2,4- (1H) -dione

A solution of the compound from Example X (2.0 g, 12.0 mmol) and trimethylsilyl azide (1.66 g, 14.4 mmol) in 12 ml of dioxane is heated to 80 ° C. for 2 h. The solvent is i. Vac. stripped off, the residue is taken up in 13 ml of ether and water (0.22 g, 12 mmol) is added. The mixture is stirred vigorously for 5 minutes and stored at 6 ° C. for 3 hours. Precipitated product is filtered off and washed with ether.
Yield: 0.48 g (22%) of a diastereomer mixture
M.p .: <250 ° C (dec.)
C ₉ H ₁₁ NO ₃ (181.2)

Example XII 4-Benzylidene-cyclopentane-1,2-dicarboxylic acid diethyl ester

The solution of potassium t-butanolate (22.0 g, 196 mmol) in 1200 ml of diethyl ether is added at room temperature under argon, benzyl triphenylphosphonium chloride (95.4 g, 245 mmol) and the mixture is stirred for 4 h at room temperature. A solution of diethyl 4-cyclopentanone-1,2-dicarboxylate (14.0 g, 61.3 mmol) is then added dropwise at 0 ° C. and the mixture is heated under reflux for 8 d. Further processing is carried out in analogy to the regulation of Example VIII.
Yield: 15.9 g (86%), cis / trans isomers
R _f = 0.37, 0.43 (petroleum ether / ether = 5: 1)
¹ H-NMR (CDCl ₃ ): δ = 1.25 (2t, 6H), 2.70-3.35 (m, 6H), 4.17 (q, 4H), 6.38 (cm, 1H) , 7.12-7.40 (m, 5H).
C ₁₈ H ₂₂ O ₄ (302.37)

Example XIII 4-benzylidene-cyclopentane-1,2-dicarboxylic acid

The title compound is prepared in analogy to the procedure of Example IX.
Yield: 12.8 g (100%)
M.p .: 172 ° C
C ₁₄ H ₁₄ O ₄ (246.26)

Example XIV 1,2-cis-4-difluoromethylene-cyclopentane-1,2-dicarboxylic acid diethyl ester -

To dissolve diethyl 1,2-cis-4-cyclopentanone-1,2-dicarboxylate (20.0 g, 87.6 mmol) and dibromodifluoromethane (36.8 g, 175 mmol) in THF (400 ml) are added dropwise at 0 ° C under argon within 30 min tris (dimethylamino) phosphine (57.1 g, 350 mmol). The mixture is allowed to warm up slowly to room temperature and stirred at this temperature for a further 1 h. Triethylamine (17.6 g, 175 mmol) is added and the mixture is stirred at room temperature for 15 h. After adding 500 ml of water, the reaction mixture is extracted with diethyl ether (3 × 500 ml) and the combined org. Phases are with sat. Washed NaCl solution (2 × 300 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue is chromatographed on silica gel (petroleum ether / diethyl ether = 1: 1).
Yield: 5.93 g (27%)
¹ H NMR (CDCl ₃ ): δ = 1.28 (t, 6H), 2.55-2.90 (4H), 3.17 (dt, 2H), 4.17 (q, 4H)
C ₁₂ H ₁₆ F ₂ O ₄ (262.4)

Example XV 1,2-cis-4-difluoromethylene-cyclopentane-1,2-dicarboxylic acid

The title compound is prepared in analogy to the procedure of Example IX.
Yield: 3.86 g (85%)
M.p .: 147-149 ° C
C ₈ H ₈ F ₂ O ₄ (206.1)

Example XVI 4-difluoromethylene-cyclopentane-1,2-dicarboxylic acid anhydride

The title compound is prepared in analogy to the procedure of Example X.
Yield: 2.25 g (65%)
M.p .: 140-145 ° C / 0.05 mbar (Kugelrohr distillation)
C ₈ H ₆ F ₂ O ₃ (188.1)

Example XVII 6-difluoromethylene-cyclopentano [3,4-d] oxazin-2,4- (1H) -dione

The title compound is prepared in analogy to the procedure of Example XI.
Yield: 1.40 g (59%)
M.p .: 130 ° C (dec.)
C ₈ H ₇ F ₂ NO ₃ (203.1)

Example XVIII 4,4-difluorocyclopentane-1,2-dicarboxylic acid diethyl ester

Diethylaminosulfur trifluoride (11.28 g, 70 mmol) is added dropwise at 0 ° C. to the solution of diethyl 4-cyclopentanone-1,2-dicarboxylic acid (6.43 g, 28.2 mmol) in 100 ml of toluene and the mixture is left for 5 d Stir room temperature. The solution is poured onto ice water, extracted with ethyl acetate (2 × 200 ml), the organic phase is dried (Na ₂ SO ₄ ) and the solvent is removed in vacuo. The residue is chromatographed on silica gel (petroleum ether / diethyl ether = 1: 1).
Yield: 3.79 g (56%) of a mixture of diastereomers
R _f = 0.65 (petroleum ether / diethyl ether = 1: 1)
¹ H NMR (CDCl ₃ ): δ 1.28 (t, 6H), 2.52 (cm, 4H), 3.29 (cm, 2H), 4.18 (q, 4H)
C ₁₁ H ₁₆ O ₄ F ₂ (250.2)

Example XIX 4,4-difluorocyclopentane-1,2-dicarboxylic acid

The title compound is prepared in analogy to the procedure of Example XI.
Yield: 4.40 g (77%)
M.p .: 128 ° C
C ₇ H ₈ O ₄ F ₂ (194.1)

Example XX 4,4-difluorocyclopentane-1,2-dicarboxylic anhydride

The title compound is prepared in analogy to the procedure of Example X.
Yield: 2.90 g (75%)
Sdp .: 150 ° C / 0.15 mbar (Kugelrohr distillation)
C ₇ H ₆ F ₂ O ₃ (176.12)

Example XXI 6,6-difluoro-cyclopentano- [3,4-d] oxazin-2,4- (1H) -dione

The title compound is prepared in analogy to the procedure of Example XI.
Yield: 2.33 g (74%)
M.p .: 116 ° C (dec.)
C ₇ H ₇ F ₂ NO ₃ (191.1)

Example XXII 3-Benzyloxymethyl-cyclopentan-2-one-1-carboxylic acid ethyl ester

A solution of 2-benzyloxymethyl-cyclopentan-2-one (23.5 g, 115 mmol, produced according to Murata S., Tetrahedron Letters) is added dropwise at -78 ° C. under argon to dissolve lithium diisopropylamide (138 mmol) in 300 ml THF , 1980, 2527) in 100 ml THF and allowed to stir for 30 min at -78 ° C and 10 min at -40 ° C. At -78 ° C, 1,3-dimethyltetrahydro-2- (1H) -pyrimidone (14.7 g, 115 mmol) is added dropwise, and the solution thus prepared is finally added dropwise at -78 ° C to the solution of ethyl cyanoformate (22, 8 g, 230 mmol). After 10 min, the reaction mixture is poured onto 200 ml of water, the THF is stripped off in vacuo and the residue is taken up in 1100 ml of diethyl ether. The organic phase is washed with water (3 × 100 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue is chromatographed on silica gel (petroleum ether / diethyl ether = 2: 1).
Yield: 19.3 g (61%)
R _f = 0.34 (petroleum ether / diethyl ether = 2: 1)
C ₁₆ H ₂₀ O ₄ (276.3)

Example XXIII 2-Benzylamino-3-benzyloxymethyl-cyclopent-1-en-1-carboxylic acid ethyl ester

The title compound is prepared in analogy to the procedure of Example V starting from Example XXII.
Yield: 14.2 g (54%)
R _f = 0.62 (petroleum ether / diethyl ether = 2: 1)
C ₂₄ H ₂₇ NO ₃ (377.48)

Manufacturing examples Example 1 1,2-cis-2-amino-4-methylene-cyclopentane-1-carboxylic acid ethyl ester hydrochloride

Acetyl chloride (3.01 g, 38.4 mmol) is added dropwise to dissolve the compound from Example III (3.90 g, 23.3 mmol) in 48 ml EtOH. The solution is stirred for 20 h at room temperature and the solvent is removed in vacuo.
Yield: 4.79 g (100%)
R _f = 0.48 (ether: acetonitrile: conc. NH3 / 10: 1: 0.1)
C ₉ H ₁₅ NO ₂ × HCl (169.2 × 36.5)

Example 2 1,2-cis-2-amino-4-methylene-cyclopentane-1-carboxylic acid hydrochloride

A solution of the compound from Example III (0.500 g, 3.00 mmol) in 30 ml 0.1 N HCl (3.00 mmol) is stirred for 4 h at room temperature. The solvent is removed in vacuo at 30 ° C. and the residue is dried for 12 hours at 30 ° C./0.1 torr.
Yield: 0.513 g (96%)
M.p .: 190 ° C
C ₇ H ₁₁ NO ₃ × HCl (141.2 × 36.5)

Example 3 1,2-cis-2-N- (tert-butyloxycarbonyl) amino-4-methylene-cyclopentane-1-carboxylic acid ethyl ester

A solution of the compound from Example 1 (15.4 g, 75.0 mmol) and triethylamine (22.8 g, 225 mmol) in 225 ml CH ₂ Cl ₂ is dissolved at 0 ° C with di-tert-butyldicarbonate (24, 8 g, 112 mmol) were added and the mixture was stirred at room temperature for 4 h. The solvent is removed in vacuo and the residue is chromatographed on silica gel (ether / petroleum ether = 1: 3).
Yield: 18.0 g (91%)
R _f = 0.29 (ether / petroleum ether = 1: 3)
C ₁₄ H ₂₃ NO ₄ (269.3)

Example 4 1,2-cis-2-N- (tert-butyloxycarbonyl) amino-4-oxo-cyclopentane-1-carboxylic acid ethyl ester

By dissolving the compound from Example 3 (18.0 g, 67.0 mmol), ozone is passed at -70 ° C. until it turns blue and then oxygen until it is decolorized. Dimethyl sulfide (24.8 g, 0.40 mol) is added, the mixture is allowed to warm to room temperature and stirred for a further 2 h at this temperature. The solvent is removed in vacuo, the residue is stirred with diisopropyl ether, suction filtered and washed with diethyl ether.
Yield: 15.1 g (83%)
M.p .: 132 ° C
C ₁₃ H ₂₁ NO ₅ (271.3)

Example 5 1,2-cis-2-amino-4-oxo-cyclopentane-1-carboxylic acid ethyl ester hydrochloride

A solution of the compound from Example 4 (0.980 g, 3.60 mmol) in 5 ml of 4N HCl in dioxane is stirred for 3 h at room temperature. The solvent is removed in vacuo and the residue is dried at 50 ° C./0.1 torr for 20 h.
Yield: 0.734 g (98%)
¹ H NMR (DMSO-d ₆ ): δ = 1.24 (t, J = 7 Hz, 3H); 2.14-2.80 (m, 4H); 3.49-3.62 (m, 1H), 402-4.28 (m, 3H); 8.53 (s, broad, 3H).
C ₈ H ₁₃ NO ₃ × HCl (171.2 × 36.5)

Example 6 1,2-cis-2-amino-4-oxo-cyclopentane-1-carboxylic acid hydrochloride

A solution of the compound from Example 5 (0.500 g, 2.41 mmol) in 40 ml of 3N HCl is heated to 80 ° C. for 2 h. The solvent is removed in vacuo and the residue is dried at 50 ° C./0.1 torr for 20 h.
Yield: 0.432 g (100%)
¹ H NMR (DMSO-d ₆ ): δ = 2.42-2.76 (m, 4H); 3.42-3.56 (m, 1H); 4.08 (s, broad, 1H); 8.45 (s, broad, 3H).
C ₆ H ₁₃ NO ₃ × HCl / (141.3 × 36.5)

Example 7 1,2-cis-2-N- (tert-butyloxycarbonyl) amino-4-hydroxy-cyclopentane-carboxylic acid ethyl ester

A solution of the compound from Example 6 (5.00 g, 18.5 mmol) in 150 ml of MeOH is mixed with NaBH ₄ (0.345 g, 9.0 mmol) at 5 ° C. and stirred for 1 hour at room temperature. The solvent is removed in vacuo, the residue is taken up in water and extracted with CH ₂ Cl ₂ . The organic phase is dried over Na ₂ SO ₄ and the solvent is removed in vacuo.
Yield: 4.9 g (97%)
Diastereomer ratio D ₁ : D ₂ = 3: 1
R _f = 0.42 and 0.48 (ether)
C ₁₃ H ₂₃ NO ₅ (273.3)

Example 8 1,2-cis-2-amino-4-hydroxy-cyclopentanecarboxylic acid ethyl ester hydrochloride

A solution of the compound from Example 7 (1.10 g, 4.0 mmol) in 6 ml of 4N HCl in dioxane is stirred at room temperature for 1 h. The solvent is removed in vacuo and the residue is dried at 50 ° C./0.1 torr for 20 h.
Yield: 0.82 g (97%)
Diastereomer ratio D ₁ : D ₂ = 3: 1
MS (DEI): m / z = 174 (M + H).
C ₈ H ₁₅ NO ₃ × HCl (173.2 × 36.5)

Example 9 1,2-cis-2-amino-4-hydroxy-cyclopentane-1-carboxylic acid hydrochloride

A solution of the compound from Example 8 (210 mg, 1.0 mmol) in 13 ml of 3N HCl is stirred at 80 ° C. for 2 h. The solvent is removed in vacuo and the residue is dried at 50 ° C./0.1 torr for 20 h.
Yield: 151 mg (83%)
Diastereomer ratio D ₁ : D ₂ = 3: 1
MS (DEI): m / z = 146 (M + H)
C ₆ H ₁₁ NO ₃ × HCl (145.2 × 36.5)

Example 10 1,2-cis-2-benzylamino-4,4-dimethyl-cyclopentane-1-carboxylic acid methyl ester

A solution of the compound from Example VI (8.15 mmol) in 70 ml EtOH is mixed with 1 g platinum (5% on activated carbon) and hydrogenated at 35 ° C. and 80 bar H _{2 for} 20 h. The catalyst is filtered off, the filtrate is concentrated in vacuo and the residue is chromatographed on silica gel.
Yield: 2.13 g (51%)
R _f = 0.49 (ethyl acetate / petroleum ether = 1: 2)
C ₁₆ H ₂₃ NO ₂ (261.3)

Example 11 1,2-cis-2-benzylamino-5-methyl-cyclopentane-1-carboxylic acid methyl ester

The title compound is prepared in analogy to the procedure of Example 10.
Yield: diastereomer D ₁ : 0.67 g (33%)
R _f = 0.49 (ethyl acetate / petroleum ether = 1: 2)
Diastereomer D ₂ = 0.59 (29%)
R _f = 0.34 (ethyl acetate / petroleum ether = 1: 2)
C ₁₅ H ₂₁ NO ₂ (247.34)

Example 12 1,2-cis-2-benzylamino-3-methyl-cyclopentane-1-carboxylic acid methyl ester

The title compound is prepared in analogy to the procedure of Example 10.
Yield: 1.41 g (71%)
2 diastereomers D ₁ : D ₂ = 4: 1
R _f = 0.49 and 0.31 (ethyl acetate / petroleum ether = 1: 4)
C ₁₅ H ₂₁ NO ₂ (247.34)

Example 13 1,2-cis-2-amino-4,4-dimethyl-cyclopentane-1-carboxylic acid methyl ester hydrochloride

A solution of the compound from Example 10 (7.70 mmol) in 77 ml 0.1 N HCl (7.70 mmol), 80 ml H ₂ O and 110 ml EtOH is mixed with 710 mg palladium (10% on activated carbon) and Hydrogenated for 20 h at room temperature and 3 bar H ₂ . The catalyst is filtered off, the filtrate is concentrated in vacuo and the residue is dried at 50 ° C./0.1 torr for 12 h.
Yield: 1.52 g (95%)
M.p .: 148 ° C
C ₉ H ₁₇ NO ₂ × HCl (171.2 × 36.5)

Example 14 1,2-cis-2-amino-5-methyl-cyclopentane-1-carboxylic acid methyl ester hydrochloride

The title compound is obtained in analogy to the procedure of Example 10.
Yield: Diastereomer A: 1.43 g (96%)
M.p .: 169 ° C
Diastereomer B: 1.46 g (98%)
M.p .: 64 ° C
C ₈ H ₁₅ NO ₂ × HCl (157.2 × 36.5)

Example 15 1,2-cis-2-amino-3-methyl-cyclopentane-1-carboxylic acid methyl ester hydrochloride

The title compound is obtained in analogy to the procedure of Example 10.
Yield: 1.50 g (100%)
2 diastereomers: D ₁ : D ₂ = 4: 1
R _F = 0.45 (ether / acetonitrile / conc. NH ₃ = 10: 1: 0.1)
C ₈ H ₁₅ NO ₂ × HCl (157.2 × 36.5)

Example 16 1,2-cis-2-amino-4,4-dimethyl-cyclopentane-1-carboxylic acid hydrochloride

A solution of the compound from Example 13 (4.20 mmol) in 70 ml of 3N HCl is heated under reflux for 2 h. The solvent is removed in vacuo, the residue is washed with THF and dried at 50 ° C./0.1 Torr for 20 h.
Yield: 0.81 g (100%)
M.p .: 190 ° C (dec.)
C ₈ H ₁₅ NO ₂ × HCl (157.2 × 36.5)

Examples 17a and 17b 1,2-cis-2-amino-5-methyl-cyclopentane-1-carboxylic acid hydrochloride

The title compound is prepared in analogy to the procedure of Example 16.
Yield: Diastereomer A: 0.61 (81%) (Example 17a)
M.p .: 134 ° C
Diastereomer B: 0.73 g (97%) (Example 17b)
M.p .: 200 ° C (dec.)
C ₇ H ₁₃ NO ₂ × HCl (143.2 × 36.5)

Example 18 1,2-cis-2-amino-3-methyl-cyclopentane-1-carboxylic acid hydrochloride

The title compound is prepared in analogy to the procedure of Example 16.
Yield: 0.68 g (90%)
Diastereomer ratio D ₁ : D ₂ = 4: 1
M.p .: 206 ° C
C ₇ H ₁₃ NO ₂ × HCl (143.2 × 36.5)

Example 19 1,2-cis-2-amino-2-methyl-cyclopentane-1-carboxylic acid hydrochloride

15 g (0.12 mol) of 2-methyl-6-azabicyclo [3.2.0] heptan-7-one [cf. T. Sasaki et al., Tetrahedron 32, 437 (1976)] are suspended in portions in 100 ml of concentrated hydrochloric acid, and the suspension is stirred at 40 ° C. until the clear point. The solution is extracted 1 × with diethyl ether and the aqueous phase is evaporated to dryness. After drying under high vacuum, 20.7 g (96%) of a white solid are obtained.
M.p .: 194 ° C
C ₇ H ₁₃ NO ₂ × HCl (143 × 36.5)

Example 20 1,2-cis-2-amino-4-methyl-cyclopentane-1-carboxylic acid

3 g (0.024 mol) of 4Methyl-6-azabicyclo [3.2.0] heptan-7-one [presentation: T. Sasaki et al., Tetrahedron 32, (1976)] together with 15 ml of conc. Hydrochloric acid stirred for 2 h at room temperature. After etherification of the solution, the mixture is evaporated to dryness. The residue is dried at 40 ° C in a high vacuum.
Yield: 2.9 g (67%)
M.p .: 188.5 ° C
C ₇ H ₁₃ NO ₂ × HCl (143 × 36.5)

Example 21 1,2-cis-2-N- (9-fluorenylmethyloxycarbonyl) amino-4-methylene-cyclo pentane-1-carboxylic acid

A solution of N- (9-fluorenylmethyloxycarbonyloxy) -succinimide (0.995 g, 1 g) is added dropwise at 0 ° C. to the solution of Example 2 (0.500 g, 2.81 mmol) in 20 ml of 10% aqueous Na ₂ CO ₃ solution. 2.95 mmol) in 10 ml of dioxane. The mixture is stirred at room temperature for 12 h and extracted three times with 10 ml of ether each time. The aqueous phase is concentrated at 0 ° C. Hydrochloric acid adjusted to pH 2 and extracted twice with 40 ml ether each. The ether phases are dried over Na ₂ SO ₄ and the solvent removed in vacuo.
Yield: 0.940 g (92%)
M.p .: 137 ° C
C ₂₂ H ₂₁ NO ₄ (363.4)

Example 22 and Example 23 1,2-cis-2-N- (9-fluorenylmethyloxycarbonyl) - amino-4-methyl-cyclopent-3-en-1-carboxylic acid (Example 22) 1,2-cis-2-N- (9-fluorenylmethyloxycarbonyl) - amino-4-methyl-cyclopent-4-en-1-carboxylic acid (Example 23)

A solution of the compound from Example 2 (0.870 g, 4.90 mmol) in 20 ml of 10% hydrochloric acid is stirred at room temperature for 20 h and then i. Vac. evaporated. The residue is dissolved in 25 ml of 10% Na ₂ CO ₃ solution and a solution of N- (9-fluorenylmethyloxycarbonyloxy) succinimide (1.65 g, 4.30 mmol) in 15 ml of dioxane is added at 0 ° C. . The mixture is stirred for 48 h at room temperature, 50 ml of H ₂ O are added and the mixture is extracted twice with 20 ml of ether each time. The aqueous phase is adjusted to pH 2 at 0 ° C. and extracted twice with 50 ml of ether each time. The ether phases are dried over Na ₂ SO ₄ , the solvent is removed in vacuo and the residue is chromatographed on silica gel (methylene chloride / methanol = 20: 1).
Yield: 0.211 g (12%) (Example 22)
R _f = 0.31 (methylene chloride / methanol 20: 1) (Example 22)
Yield: 0.187 g (11%) (Example 23)
R _f = 0.28 (methylene chloride / methanol = 20: 1) (Example 23)
C ₂₂ H ₂₁ NO ₄ (363.4)

Example 24 1,2-cis-2-amino-4-methyl-cyclopent-4-en-1-carboxylic acid

A solution from Example 2 (0.870 g, 4.90 mmol) in 20 ml of 10% hydrochloric acid is stirred for 20 h at room temperature and then evaporated in vacuo. The residue is dissolved in 8 ml of ethanol, mixed with 15 ml of ether and left to stand at 5 ° C. for 5 d. Precipitated product is filtered off and washed with ether.
Yield: 0.246 g (28%)
M.p .: 196 ° C
C ₇ H ₁₁ NO ₂ × HCl (141.2 × 36.5)

Example 25 1,2-cis-2-amino-4-methyl-cyclopent-4-en-1-carboxylic acid

A solution from Example 23 (0.380 g, 1.05 mmol) in 30 ml of liquid ammonia is stirred for 10 h. The ammonia is allowed to evaporate, 50 ml of ether are added, the mixture is stirred for 1 h at room temperature, filtered and the residue is washed with 20 ml of ether. The residue is taken up in 5 ml of water and stirred for 10 min. It is filtered, washed with 3 ml of water and the filtrate is concentrated in vacuo. The residue is recrystallized from 80% aqueous ethanol.
Yield: 0.082 g (55%)
M.p .: 190 ° C
C ₇ H ₁₁ NO ₂ (141.2)

Example 26 1,2-cis-2-amino-4-methyl-cyclopent-3-en-1-carboxylic acid

A solution from Example 22 (0.410 g, 1.13 mmol) in 30 ml of liquid ammonia is stirred for 10 h. The ammonia is allowed to evaporate, 50 ml of ether are added, the mixture is stirred for 1 h at room temperature, filtered and the residue is washed with 20 ml of ether. The residue is taken up in 5 ml of water and stirred for 10 min. It is filtered, washed with 3 ml of water and the filtrate is concentrated in vacuo. The residue is recrystallized from 80% aqueous ethanol.
Yield: 0.112 g (70%)
M.p .: 221 ° C
C ₇ H ₁₁ NO ₂ (141.2)

Example 27 1,2-cis-2-amino-4-methyl-cyclopent-3-en-1-carboxylic acid hydrochloride

The compound from Example 2 (0.110 g, 0.78 mmol) is dissolved in 7.80 ml (0.78 mmol) 0.1 N HCl. The solution is then evaporated in vacuo.
Yield: 0.138 g (100%)
M.p .: 188 ° C (dec.)
C ₇ H ₁₁ NO ₂ × HCl (141.2 × 36.5)

Example 28 (+) - 1,2-cis-2- (9-fluorenylmethyloxycarbonyl) amino-4-methylene-cyclope-ntan-1-car bonic acid (R) -phenethylammonium salt

A solution from Example 21 (10.0 g, 27.5 mmol) in 4.5 ml of tert-butyl methyl ether and 15 ml of EtOH is mixed with (R) - (+) - phenethylamine (3.33 g, 27.5 mmol ) offset. The mixture is heated under reflux and about 80 ml of EtOH are added dropwise until a clear solution is formed. The mixture is allowed to cool slowly slowly to room temperature overnight, the crude product which has precipitated is filtered off and washed with 20 ml of tert-butyl methyl ether / EtOH ( 3 : 1). The crude product is then recrystallized again from 30 ml of tert-butyl methyl ether and 70 ml of ethanol.
Yield: 3.49 g (26%)
M.p .: 163 ° C [α] = + 17.1 (c = 1, MeOH)
C ₂₀ H ₂₁ NO ₄ × C ₈ H ₁₁ N (363.4 × 121.2)

Example 29 (-) - 1,2-cis-2- (9-fluorenylmethyloxycarbonyl) amino-4-methylene-cyclope-ntan-1-car bonic acid (S) -phenethylammonium salt

The preparation was carried out analogously to that described in Example 28 with (S) -phenethylamine instead of (R) -phenethylamine.
Yield: 3.48 g (26%)
M.p .: 165 ° C [α] = -17.8 (c = 0.73, MeOH)
C ₂₀ H ₂₁ NO ₄ × C ₈ H ₁₁ N (363.4 × 121.2)

Example 30 (-) - 1,2-cis-2- (9-fluorenylmethyloxycarbonyl) amino-4-methylene-cyclope-ntan-1-car bonic

Example 29 (3.49 g, 7.20 mmol) is suspended in 40 ml of water and 40 ml of ethyl acetate. 1N HCl is added to pH 2, the phases are separated and the aqueous phase is extracted twice with 40 ml of ethyl acetate each time. The combined organic phases are dried over Na ₂ SO ₄ and the solvent is evaporated down i. Vacuum removed.
Yield: 2.46 g (94%) [α] = -18.8 (c = 1, MeOH)
M.p .: 137 ° C
Enantiomeric excess ee = 99.5% (HPLC, Chiralpak AS)
C ₂₂ H ₂₁ NO ₄ (363.4)

Example 31 (+) - 1,2-cis-2- (9-fluorenylmethyloxycarbonyl-) amino-4-methylene-cyclopentan-1-car bonic

The preparation is carried out as described for Example 30.
Yield: 2.46 g (94%) [α] = + 18.4 (c = 0.48 MeOH)
M.p .: 137 ° C
Enantiomeric excess ee = 99.0% (HPLC, Chiralpak AS)
C ₂₂ H ₂₁ NO ₄ (363.4)

Example 32 (-) - 1,2-cis-2-amino-4-methylene-cyclopentane-1-carboxylic acid hydrochloride

100 ml of liquid ammonia are added to Example 31 (1.35 g, 3.71 mmol), the mixture is stirred for about 10 h and then the ammonia is evaporated. The residue is mixed with 120 ml of ether and the mixture is stirred at room temperature for 1 h. It is filtered and the residue is taken up in 5 ml of water, filtered again, the residue is washed with 3 ml of water and the filtrate is evaporated down i. Vac. a. The residue is recrystallized from 80% aqueous ethanol. IN HCl (31.9 ml, 3.19 mmol) is added to the free amino acid obtained (0.451 g, 3.19 mmol) and the resulting solution is concentrated in vacuo and the residue is dried in vacuo at 50 ° C./0ITorr.
Yield: 0.567 g (86%), mp: 184 ° C, [α] = -11.6 (c = 1, H ₂ O)
C ₇ H ₁₁ NO ₂ × HCl (141.2 × 36.5)

Example 33 (+) - 1,2-cis-2-amino - 4-methylene-cyclopentane-1-carboxylic acid hydrochloride

The preparation is carried out analogously to that described for Example 32.
Yield: 0.566 g (86%)
M.p .: 186 ° C [α] = + 11.4 (c = 1.04, H ₂ O)
C ₇ H ₁₁ NO ₂ × HCl (141.2 × 36.5)

Example 34 1,2-cis-2-amino-4-ethylidene-cyclopentane-1-carboxylic acid hydrochloride

0.1 N HCl (16.6 mmol, 1.66 mmol) is added to the compound from Example XI (0.30 g, 1.66 mmol). The mixture is stirred for 5 hours until a clear solution has formed. The solvent is i. Vac. stripped at 30 ° C and the residue dried at 30 ° C / 0.1 Torr for 12 h.
Yield: 0.32 g (100%) of a mixture of diastereomers
M.p .: 188 ° C
C ₈ H ₁₃ NO ₂ × HCl (155.2 × 36.5)

Example 35 (-) - 1,2-cis-2- (t-butyloxycarbonyl) amino-4-methylene-1-carboxylic acid

A solution of the compound from Example 32 (2.0 g, 11.3 mmol) in 20 ml of dioxane is mixed with 16.8 ml of a 1 M Na ₂ CO ₃ solution and at 0 ° C. with di-tert-butyldicarbonate (2nd , 68 g, 12.3 mmol) was added. The mixture is stirred at room temperature for 20 h, 30 ml of ethyl acetate are added and the solution is brought to pH 2 with 10% hydrochloric acid. The aqueous phase is extracted twice with 30 ml of ethyl acetate. The united org. Phases are with sat. Washed NaCl solution, dried over Na ₂ SO ₄ and i. Vac. constricted.
Yield: 2.73 g (100%) [α] = -41.3 (c = 0.72, CH ₃ OH)
C ₁₂ H ₁₉ NO ₄ (241.3)

Example 36 (-) 1,2-cis-2- (tert-butyloxycarbonyl) amino-4-methylene-cyclopentane-1-c-arbon acid ethyl ester

To dissolve the compound from Example 35 (2.73 g, 11.3 mmol), 4-dimethylamino pyridine (0.14 g, 1.1 mmol) and methanol (1.09 g, 34 mmol) in 30 ml of dichloromethane a solution of dicydohexylcarbodumide (2.57 g, 12.5 mmol) in 10 ml of dichloromethane at 0 ° C. The mixture is allowed to stir at room temperature for 2 h, the precipitated dicyclohexylurea is filtered off with suction and washed with 50 ml of dichloromethane. The filtrate is saturated with 30 ml 0.1 NHCl and 30 ml. NaHCO ₃ solution, washed over Na ₂ SO ₄ and concentrated in vacuo. The residue is chromatographed on silica gel (petroleum ether / ethyl acetate = 3: 1)
Yield: 2.36 g (82%)
M.p .: 64 ° C [α] = -86.8 (c = 1.02, CH ₃ OH)
C ₁₃ H ₂₁ NO ₄

Example 37 (-) - 1,2-cis-2-amino-4-methylene-cyclopentane-1-carboxylic acid methyl ester Hydrochloride

To dissolve the compound from Example 36 (2.10 g, 8.20 mmol) and 2,6-lutidine (1.76 g, 16.5 mmol) in 50 ml of dichloromethane, trifluoromethanesulfonic acid (tert. -butyldimethyl) silylester (3.27 g, 12.3 mmol). The mixture is stirred for 15 min, 100 ml of sat. NH ₄ Cl solution and extracted twice with 100 ml ether. The org. Phases are with sat. Washed NaCl solution, dried over MgSO ₄ and in vacuo. constricted. The residue is dissolved in 50 ml of THF and water (0.30 g, 16.5 mmol) and tetrabutyl ammonium fluoride (1.1 M solution in THF, 7.5 ml, 8.2 mmol) are added at 0 ° C. The mixture is stirred at 0 ° C. for 1 h, 100 ml of water are added, the solution is brought to pH 9 with conc. NH ₃ , add 15 g NaCl and extract three times with 80 ml ethyl acetate. The org. Phases are dried over MgSO ₄ and in vac. constricted. The residue is chromatographed on silica gel (ether / acetonitrile / conc. NH ₃ = 10: 1: 0.1).
Yield: 1.15 g (73%)
M.p .: 146 ° C / [α] = -4.2 (c = 1.23, H ₂ O)
C ₈ H ₁₃ NO ₂ × HCl (155.2 × 36.5)

Example 38 (-) - 1,2-cis-2- (N- (tert-butyloxycarbonyl) glycinyl) amino-4-methylene - cyclopentane 1-carboxylic acid methyl ester

To dissolve the compound from Example 36 (0.40 g, 2.09 mmol), 1-hydroxy-1H-benzotriazole × H ₂ O (0.282 g, 2.09 mmol), N-ethylmorpholine (0.261 g, 2.09 mmol) and N- (tert-butyloxycarbonyl) glycine (0.366 g, 2.09 mmol) in 18 ml THF, a solution of dicyclohexylcarbodiimide (0.430 g, 2.09 mmol) in 2 ml THF is added dropwise under argon at 0 ° C . The mixture is stirred at 0 ° C. for 1 h and at room temperature for 20 h, filtered, washed with 10 ml of THF and the filtrate is evaporated down i. a. The residue is dissolved in 40 ml of ethyl acetate, saturated with 20 ml. NaHCO ₃ solution and 20 ml sat. Washed NaCl solution, dried over Na ₂ SO ₄ and i. Vac. constricted.
Yield: 0.585 g (100%)
¹ H-NHR (d ₆ -DMSO): α = 1.38 (s, 5H), 2.18-2.73 (m, 4H), 3.08 (dt, 1H), 3.18 and 3, 46 (AB from ABX, 2H), 3.57 (s, 3H), 4.40 (ddt, 1H), 4.90 (m, 2H), 6.88 (X from ABX, 1H), 7.71 (d, 1H)
C ₁₅ H ₂₄ N ₂ O ₅ (3 12.4)

Example 39 (-) - 1,2-cis-2- (N- (tert-butyloxycarbonyl) - (S) -alanyl) amino-4-methylene-cyc-lopentane 1-carboxylic acid methyl ester

The title compound is prepared analogously to the procedure in Example 38.
Yield: 0.630 g (86%)
¹ H NMR (d ₆ -DMSO): α = 1.09 (d, 3H), 1.36 (s, 9H), 2.22-2.72 (m, 4H), 3.10 (dt, 1H), 3.52 (s, 3H), 3.95 (dq, 1H), 4.40 (ddt, 1H), 4.90 (cm, 2H), 6.78 (d, 1H) 7.83 (d, 1H)
C ₁₆ H ₂₆ N ₂ O ₅ (326.4)

Example 40 (-) - 1,2-cis-2- (N-glycinyl) amino-4-methylene-cyclopentane-1-carboxylic acid methyl ester Hydrochloride

To dissolve the compounds from Example 38 (0.52 g, 1.66 mmol) and 2,6-lutidine (0.59 g, 5.50 mmol) in 10 ml of dichloromethane, trifluoromethanesulfonic acid ( tert-butyldimethyl) silylester (1.10 g, 4.15 mmol) and allowed to stir at room temperature for a further 20 h. 20 ml of sat. NH ₄ Cl solution, extracted twice with 50 ml ether each, the org. Phase with total NaCl solution dries over MgSO ₄ and draws the solvent in vacuo. from.

The residue is taken up in 10 ml of THF, water (0.06 g, 3.3 mmol) is added and a 1.1 M solution in tetrabutylammonium fluoride in THF (3.0 ml, 3.3 mmol) is at 0 ° C. dripped. The mixture is stirred at 0 ° C. for 1 h, 20 ml of water are added and the solution is brought up with conc. NH ₃ to pH 9. 4 g of NaCl are added, extracted three times with 20 ml of ethyl acetate, the org. Phases with sat. Washed NaCl solution, dried over MgSO ₄ and i. Vac. constricted. The residue is chromatographed on silica gel (ethyl acetate / MeOH conc. NH ₃ = 10: 0.1). The free base thus obtained is taken up in 10 ml of 0.1 N HCl and the solvent is evaporated down i. Vac. deducted. The residue is dried at 30 ° C / 0.1 Torr for 12 h.
Yield: 0.202 g (49%).
¹ H NMR (DMSO): α = 2.25-2.72 (m, 4H), 3.12 (dt, 1H), 3.40-3.62 (m, 2H), 3.59 (s , 3H), 4.49 (ddt, 1H), 4.92 (cm, 2H), 8.05 (s, broad, 3H), 8.42 (d, 1H)
C ₁₀ H ₁₆ N ₂ O ₃ x HCl (212.2 x 36.5).

Example 41 (-) - 1,2-cis-2- (N- (S) -alanyl) amino-4-methylene-cyclopentane-1-carboxylic acid remethyl ester hydrochloride

The title compound is prepared in analogy to the procedure of Example 40.
Yield: 0.249 g (57%) [α] = -66.3 (c = 1.1 H ₂ O)
C ₁₁ H ₁₈ H ₂ O ₃ × HCl

Example 42 (-) - 1,2-cis-2- [N- (9-fluorenylmethyloxycarbonyl) - (S) -norvalinyl] amino - 4- methylene-cyclopentane-1-carboxylic acid

To dissolve the compound from Example 32 (3.00 g, 16.9 mmol) and NaHCO ₃ (2.84 g, 33.8 mmol) in 60 ml of water, a solution of FMOC-norvaline-O-succinimide (7th , 38 g, 16.9 mmol) in dimethoxyethane (72 ml) and allowed to stir overnight at room temperature. THF (180 ml) is added and the solution is brought to pH 2 with 10% hydrochloric acid. The mixture is extracted with ether (3 × 300 ml), the combined ether phases are washed with water (100 ml) and sat. NaCl solution (100 ml) and dries over Na ₂ SO ₄ . The solvent is removed in vacuo and the residue is chromatographed on silica gel (dichloromethane / methanol = 10: 1).
Yield: 4.58 g (59%)
M.p .: 124 ° C
R _f = 0.43 (CH ₂ Cl ₂ / MeOH = 10: 1)
C ₂₇ H ₃₀ N ₂ O ₅ (462.54)

Example 43 (-) - 1,2-cis-2- [N- (9-fluorenylmethyloxycarbonyl) - (S) -norleucyl] amino4 - me ethylene-cyclopentane-1-carboxylic acid

The title compound is prepared analogously to the procedure in Example 42.
Yield: 4.97 g (74%)
M.p .: 151 ° C
R _f = 0.45 (CH ₂ Cl ₂ / MeOH = 10: 1)
C ₂₈ H ₃₂ N ₂ O ₅ (476.57)

Example 44 (-) - 1,2-cis-2- [N- (9-fluorenylmethyloxycarbonyl) - (S) - leucyl] amino-4-methylene-cyclopentane-1-carboxylic acid

The title compound was prepared in analogy to the procedure of Example 42.
Yield: 3.17 g (47%) [α] = -28.3 (c = 1.24, MeOH)
R _f = 0.21 (CH ₂ Cl ₂ / MeOH = 20: 1)
C ₂₈ H ₃₂ N ₂ O ₅ (476.57)

Example 45 (-) - 1,2-cis-2- (N- (S) -Norvalinyl) amino-4-methylene-cyclopentane-1-carbonic acid Hydrochloride

150 ml of liquid ammonia are added to Example 42 (4.53 g, 9.80 mmol), the mixture is stirred for about 10 h and then the ammonia is evaporated. 200 ml of ether are added to the residue, and the mixture is stirred at room temperature for 1 h. It is filtered and the residue is taken up in 60 ml of water, filtered again, the residue is washed with 20 ml of water and the filtrate is evaporated down i. Vac. a. The residue is dissolved in 89 ml of 0.1 N hydrochloric acid, the solvent is evaporated down i. deducted and the residue is over P ₂ O ₅ i. Vac. dried.
Yield: 2.50 g (92%)
M.p .: 130-135 ° C [α] = -27.1 (c = 1.05, MeOH)
C ₁₂ H ₂₀ N ₂ O ₃ × HCl (240.3 × 36.5)

Example 46 (-) - 1,2-cis-2 (N- (S) -norleucyl) amino-4-methylene-cyclopentane-1-carboxylic acid Hydrochloride

The title compound is prepared in analogy to the procedure in Example 45.
Yield: 1.63 g (54%)
M.p .: 108 ° C [α] = -34.3 (c = 1.27, MeOH)
C ₁₃ H ₂₂ N ₂ O ₃ × HCl (254.3 × 36.5)

Example 47 (-) - 1,2-cis-2- (N- (S) -leucyl) amino-4-methylene-cyclopentane-1-carboxylic acid Hydrochloride

The title compound is prepared in analogy to the procedure in Example 45.
Yield: 1.82 g (96%)
M.p .: 70-80 ° C [α] = -21.5 (c = 1.4, MeOH)
C ₁₃ H ₂₂ N ₂ O ₃ × HCl (254.3 × 36.5)

Example 48 (-) - 1,2-cis-2- (N- (tert-butyloxycarbonyl) - (S) -leucyl) - amino-4-methylene-cyclopentane-1-carboxylic acid methyl ester

The title compound is prepared analogously to the procedure in Example 38.
Yield: 0.584 g (56%)
M.p .: 124 ° C
C ₁₈ H ₃₀ N ₂ O ₅ (354.5)

Example 49 (-) - 1,2-cis-2- (N- (S) -leucyl) amino-4-methylene-cyclo pentane-1-carboxylic acid methyl ester hydrochloride

The title compound is prepared in analogy to the procedure of Example 40.
Yield: 0.259 g (65%)
M.p .: 70 ° C [α] = -52.1 (c = 1.04, H ₂ O).
C ₁₄ H ₂₄ N ₂ O ₃ × HCl (268.4 × 36.5)

Example 50 1,2-cis-2-amino-4-benzylidene-cyclopentane-1-carboxylic acid hydrochloride

A solution of the compound from Example XIII (12.53 g, 50.9 mmol) in 43 ml of propionic anhydride is heated under reflux for 3 h. The solvent is stripped off at 60 ° C./0.5 torr, the residue is dried for 30 min at 100 ° C./0.1 torr and dissolved in 60 ml of dioxane. After adding trimethylsilyl azide (6.84 g, 59.4 mmol), the reaction mixture is heated to 80 ° C. for 2 h. The solvent is i. Vac. removed, the residue is taken up in 200 ml of ether and mixed with 0.78 g (43.4 mmol) of water. The mixture is stirred vigorously for 30 minutes and the mixture is kept at 5 ° C. for 2 days. The precipitate is filtered off and discarded. (The precipitation mainly consists of example XIII). The filtrate is concentrated to a volume of approximately 50 ml and cooled to 0 ° C. for 12 h, during which 6-benzylidene-cyclopentano [3,4] oxazine-2,4- (1H) -dione (2.52 g) crystallizes out the crystals are filtered off with suction, washed with a little ether and 103 ml of 0.1 N hydrochloric acid are added to the solid. The mixture is stirred at room temperature for 1 h, filtered and the filtrate is evaporated down i. Vac. a. The residue is over P ₄ O ₁₀ i. Vac. dried.
Yield: 0.95 g (7%) of a 5: 1 E / Z isomer mixture
M.p .: 234 ° C
¹ H-NMR (DMSO-d ₆ ): δ = 2.70-3.55 (m, 5H), 3.70 (cm, 1H), 6.48 (s, 1H), 7.12-7, 42 (m, 5H)
C ₁₃ H ₁₅ NO ₂ × HCl (217.3 × 36.5)

Example 51 1,2-cis-2-amino-4-difluoromethylene-cyclopentane-1-carboxylic acid hydrochloride

The title compound was prepared in analogy to the instructions in Example 17911 00070 552 001000280000000200012000285911780000040 0002004302155 00004 177922.
Yield: 1.26 g (96%)
M.p .: 215 ° C (dec.)
C ₇ H ₉ F ₂ NO ₂ × HCl (177.2 × 36.5)

Example 52 1,2-cis-2-amino-4,4-difluoro-cyclopentane-1-carboxylic acid hydrochloride

The title compound was prepared in analogy to the procedure of Example 2.
Yield: 1.85 g (83%)
M.p .: 222 ° C (dec.)
C ₆ H ₉ F ₂ NO ₂ × HCl (165.1 × 36.5)

Example 53 (-) 1,2-cis-2-amino-4-methyl-cyclopentane-1-carboxylic acid hydrochloride

A solution of Example 32 (400 mg, 2.25 mmol) in 30 ml EtOH and 5 ml H ₂ O is hydrogenated in the presence of 50 mg palladium on an active cavity (10%) at 3 bar and room temperature for 3 h. It is filtered through diatomaceous earth and the filtrate is concentrated in vacuo. The residue is dried at 25 ° C / 0.1 mbar for 12 h.
Yield: 396 mg (98%) of a 5: 1 mixture of diastereomers at C-4
M.p .: 156 ° C
C ₇ H ₁₃ NO ₂ × HCl (143.2 × 36.5)

Example 54 (-) 1,2-cis-2-amino-4-ethyl-cyclopentane-1-carboxylic acid hydrochloride

The title compound was prepared in analogy to the procedure of Example 53 starting from Example 34.
Yield: 140 g (93%) of a 16: 1 mixture of diastereomers
M.p .: 205 ° C (dec.)
C ₈ H ₁₅ NO ₂ × HCl (157.2 × 36.5)

Example 55 1,2-cis-2-amino-4-benzyl-cyclopentane-1-carboxylic acid hydrochloride

The title compound was prepared in analogy to the procedure of Example 53 starting from Example 50.
Yield: 198 mg (90%) of a 3: 1 mixture of diastereomers at C-4
M.p .: 104 ° C (dec.)
C ₁₃ H ₁₇ NO ₂ × HCl (219.3 × 36.5)

Example 56 1,2-cis-2-N- (tert-butyloxycarbonyl) amino-4-methylene-cyclopentane-1-ca-rbonic acid

A solution of the compound from Example 2 (30.0 g, 170 mmol) in 350 ml of dioxane and 252 ml of 1N Na ₂ CO ₃ solution is dissolved at 0 ° C. with di-tert-butyl dicarbonate (40.5 g, 185 mmol ) and stirred for 16 h at room temperature. The dioxane is removed in vacuo and 200 ml of ethyl acetate are added to the aqueous residue. The pH of the aqueous phase is adjusted to 2-3 by adding 1N aqueous KHSO ₄ solution. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate (2 × 200 ml). The combined organic phases are washed with water (2 × 100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo.
Yield: 38.3 g (93%)
¹ H-NMR (DMSO-d ₆ ): δ = 1.39 (s, 9H), 2.30-272 (m, 4H), 3.00 (dt, 1H), 4.12 (dt, 1H) , 4.85 (s, 2H), 6.78 (d, 1H), 12.08 (s, 1H)
C ₁₂ H ₁₉ NO ₄ (214.3)

Example 57 1,2-cis-2-N- (tert-butyloxycarbonyl) amino-4-methylene-cyclopentane-1-c-arbonic acid methyl ester

A solution of the compound from Example 56 (54.5 g, 226 mmol), methanol (21.8 g, 680 mmol) and 4- (N, N-dimethylarnino) pyridine (2.76 g, 22.6 mmol) in A solution of dicyclohexylcarbodiimide (51.4 g, 250 mmol) in 200 ml of CH ₂ Cl _{2 is} slowly added to 600 ml of CH ₂ Cl ₂ at 0 ° C. After stirring for 2 h at room temperature, the mixture is filtered, the filtrate is saturated with 0.1N HCl (300 ml). NaHCO ₃ solution (300 ml) and water (300 ml), washed, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue is chromatographed on silica gel (petroleum ether / ethyl acetate = 3: 1).
Yield: 42.0 g (73%)
M.p .: 55 ° C
R _f = 0.30 (petroleum ether / ethyl acetate = 3: 1)
C ₁₃ H ₂₁ NO ₄ (255.3)

Example 58 1,2-cis-2-N- (tert-butyloxycarbonyl) amino-4-oxo-cyclopentane-1-carboxylic acid methyl ester

The title compound is prepared in analogy to the procedure of Example 4 starting from Example 57.
Yield: 34.4 g (92%)
M.p .: 135 ° C
C ₁₂ H ₁₉ NO ₅ (257.3)

Example 59 1,2-cis-2-N- (tert-butyloxycarbonyl) amino-4-oximino-cyclopentan-1-car-bonic acid methyl ester

A solution of Example 58 (500 mg, 1.94 mmol), pyridine (0.80 ml, 9.80 mmol) and hydroxylamine hydrochloride (148 mg, 2.25 mmol) in 10 ml EtOH is heated under reflux for 20 h . The solvent is removed in vacuo, the residue is taken up in water (20 ml) and extracted with ether (3 × 20 ml). The combined ether phases are washed with water (1 × 10 ml), dried (Na ₂ SO ₄ and concentrated in vacuo. The residue is chromatographed on silica gel (diethyl ether).
Yield: 269 mg (51%)
R _f = 0.67 / 0.71 (diethyl ether)
C ₁₂ H ₂₀ N ₂ O ₅ (272.3)

Example 60 1,2-cis-2-amino-4-oximino-cyclopentane-1-carboxylic acid methyl ester hydrochloride

The title compound is prepared in analogy to the procedure of Example 5 starting from Example 59.
Yield: 103 mg (54%)
M.p .; 90-95 ° C (dec.)
C ₇ H ₁₂ N ₂ O ₃ × HCl (223.1 × 36.5)

Example 61 1,2-trans-2-N- (tert-butyloxycarbonyl) amino-4-methylene-cyclopentane-1 - carbon acid methyl ester

A solution of Example 57 (1.00 g, 3.9 mmol) and 1,8-diazabicyclo [5.4.0] - undec-7-ene (0.90 g, 5.9 mmol) in 20 ml MeOH becomes 12 h heated under reflux. The solvent is removed in vacuo, the residue is taken up in ethyl acetate (30 ml), washed with 1N HCl (10 ml) and water (10 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue is chromatographed on silica gel (petroleum ether / ethyl acetate = 3: 1).
Yield: 520 mg (52%)
M.p .: 140 ° C
R _f = 0.26 (petroleum ether / ethyl acetate = 3: 1)
C ₁₃ H ₂₁ NO ₄ (255.3)

Example 62 1,2-trans-2-amino-4-methylene-cyclopentane-1-carboxylic acid methyl ester

The title compound was prepared in analogy to the procedure of Example 37 starting from Example 61.
Yield: 141 mg (30%)
¹ H-NMR (DMSO): δ = 2.30-2.50, 2.67-2.90 (2m, 4H), 3.08 (dt, 1H), 3.68 (s, 3H), 3 , 72 (German, 1H), 4.95 (s, 2H), 8.40 (s, 3H)
C ₈ H ₁₃ NO ₂ × HCl (155.2 × 36.5)

Example 63 1,2-cis-2-N- (tert-butyloxycarbonyl) amino-4-hydroxy-cyclopentan-1-car-bonic acid methyl ester

The title compound is prepared in analogy to the procedure of Example 7 starting from Example 58.
Yield: 3.30 g (97%) of a 3: 1 mixture of diastereomers
¹ H NMR (CDCl ₃ ): δ = 1.45 (s, 9H), 3.14 and 3.32 (2dt, 1H), 3.68 and 3.70 (2s, 3H), 4.40 and 4.46 (2dt, 1H), 5.40 (d, 1H)
C ₁₂ H ₂₁ NO ₅ (259.3)

Example 64 1,2-cis-2-N- (tert-butyloxycarbonyl) amino-4-cyclopentene-1-carboxylic acid, methyl ester

A solution of Example IV (3.90 g, 8.80 mmol) in 87 ml THF is slowly mixed with 30% H ₂ O ₂ (5.23 g, 46.3 mmol) at 0 ° C. and for a further 3 h dissolved at room temperature. After adding 100 ml of ice water, the mixture is extracted with CH ₂ Cl ₂ (3 × 100 ml), the combined organic phases are washed with sat. NaCl solution (100 ml) washed, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue is chromatographed on silica gel (petroleum ether / diethyl ether = 2: 1, R _f = 0.33). 1.32 g (62%) of a 35:65 mixture of the title compound and the corresponding 3-cyclopentene isomer are obtained. After fractional crystallization from n-hexane (the title compound is in each case in the mother liquor), the title compound is obtained.
Yield: 142 mg (7%)
¹ H-NMR (CDCl ₃ ): δ = 1.48 (s, 9H), 2.37, 2.70 (AB part of an ABX system, 2H), 3.70 (s, 3H), 3, 71 (m, 1H), 4.62 (dt, 1H), 5.20 (d, 1H), 5.71 (m, 1H), 5.96 (m, 1H)
C ₁₂ H ₁₉ NO ₄ (241.3)

Example 65 1,2-cis-2-amino-4-cyclopentene-1-carboxylic acid methyl ester hydrochloride

The title compound was prepared in analogy to the procedure of Example 5 starting from Example 64.
Yield: 93 mg (89%)
¹ H-NMR (d ₆ -DMSO): δ = 2.40-2.85 (m, 2H), 3.86 (m, 1H), 4.01 (dt, 1H), 5.76 (m, 1H), 5.97 (m, 1H), 8.10 (s, 3H)
C ₇ H ₁₁ NO ₂ × HCl (141.2 × 36.5)

Example 66 1,2-cis-2-benzylamino-3-benzyloxymethyl-cyclopentan-1-carboxylic acid ethyl ester

The title compound is prepared in analogy to the procedure of Example 10 starting from Example XXIII.
Yield: 8.38 g (76%)
M.p .: 215 ° C (dec.)
Deastereomer ratio D ₁ : D ₂ = 6: 1
R _f = 0.43 (D ₁ ), 0.34 (D ₂ ), (petroleum ether / diethyl ether = 1: 1)
C ₂₄ H ₂₉ O ₃ (379.50)

Example 67 1,2-cis-2-amino-3-hydroxymethyl-cyclopentane-1-carboxylic acid ethyl ester - hydro chloride

The title compound is prepared in analogy to the procedure of Example 13 starting from Example 66.
Yield: 3.14 g (97%)
Diastereomer ratio D ₁ : D ₂ = 6: 1
¹ H NMR (CDCl ₃ ): δ = 1.28, 1.29 (2t, 3H), 1.72-2.30 (m, 4H), 2.71 (D ₂ ) and 2.88 (D ₂ ) (2m, 1H), 3.06 (D ₂ ) and 3.27 (D ₂ ) (2m, 1H), 3.50-3.90 (m, 3H), 4.10-4.32 ( m, 3H), 8.40 (s, 3H)
C ₉ H ₁₇ NO ₃ × HCl (187.2 × 36.5)

Example 68 1,2-cis-2-N- (tert-butyloxycarbonyl) amino-3-hydroxymethyl-cyclopentane-1-carbon acid ethyl ester

The title compound was prepared in analogy to the procedure of Example 3 starting from Example 67.
Yield: 2.98 g (98%)
Diastereomer ratio D ₁ : D ₂ = 5: 1
¹ H NMR (CDCl ₃ ): 1.28 (2t, 3H), 1.45 (2s, 9H), 1.65-2.38 (m, 5H), 3.02 (D ₂ ), 3, 06 (D ₁ ) (2dt, 1H), 3.22-3.60 (m, 2H), 3.95-4.40 (m, 4H), 4.95 (D ₁ ), 5.61 (D ₂ ) (2d, 1H)
C ₁₄ H ₂₅ NO ₅ (287.4)

Example 69 1,2-cis-2-N- (tert-butyloxycarbonyl) amino-3-methylene-cyclopentane-1-ca-rbonic acid ethyl ester

2- nitrophenylselenocyanate (3.56 g, 15.7 mmol) and a solution of tri-n-butylphosphine ( 3.17 g, 15.7 mmol) in 20 ml THF. After stirring for 30 min, 30% H ₂ O ₂ (1.33 g, 39.2 mmol) is added dropwise and the mixture is stirred overnight at room temperature. After adding water (500 ml), the mixture is extracted with ethyl acetate (3 × 250 ml), the combined organic phases are washed with sat. NaHCO ₃ solution (200 ml), dried (MgSO ₄ ) and the solvent is removed in vacuo. The residue is chromatographed on silica gel (petroleum ether / diethyl ether = 2: 1)
Yield: 1.67 g (79%)
M.p .: 64 ° C
C ₁₄ H ₂₃ NO ₄ (269.3)

Example 70 1,2-cis-2-N- (tert-butyloxycarbonyl) amino-3-methylene-cyclopentane-1-c-arbonic acid

The title compound is prepared in analogy to the procedure of Example IX starting from Example 69.
Yield: 1.71 g (97%)
M.p .: 135 ° C
C ₁₂ H ₁₉ NO ₄ (241.3)

Example 71 1,2-cis-2-N- (tert-butyloxycarbonyl) amino-3-methylene-cyclopentane-1-c-arbonic acid methyl ester

The title compound is prepared analogously to the procedure of Example 57 starting from Example 70.
Yield: 1.59 g (91%)
M.p .: 44 ° C
C ₁₃ H ₂₁ NO ₄ (255.3)

Example 72 1,2-cis-2-amino-3-methylene-cyclopentane-1-carboxylic acid hydrochloride

To dissolve example 70 (500 mg, 2.07 mmol) and 2,6-lutidine (890 mg, 8.30 mmol) in 5 ml of CH ₂ Cl _2, dropwise trifluoromethanesulfonic acid (tert-butyldi methyl) silyl ester (1, 64 g, 6.21 mmol) at room temperature under argon. The mixture is stirred for 3 h, 10 ml of sat. NH ₄ Cl solution, extracted with ether (2 × 20 ml), the combined organic phases washed with sat. NaCl solution (10 ml), dries (Na ₂ SO ₄ ) and removes the solvent in vacuo. The residue is taken up in 20.7 ml of 0.1N hydrochloric acid and 20 ml of THF, the mixture is stirred for 20 h, the THF is removed in vacuo, the residue is washed with ether (10 ml) and the aqueous phase is concentrated in vacuo. The residue is dissolved in 7 ml of propene oxide and heated under reflux for 30 minutes. The precipitated solid is filtered off with suction, washed with ether and the residue (136 mg) is taken up in 9.6 ml of 0.1N hydrochloric acid. The solvent is removed in vacuo and the residue is dried in vacuo over P ₄ O ₁₀ .
Yield: 190 mg (52%)
M.p .: 208 ° C (dec.)
C ₇ H ₁₁ NO ₂ × HCl (141.2 × 36.5)

Example 73 1,2-cis-2-amino-3-methylene-cyclopentane-1-carboxylic acid methyl ester hydrochloride

The title compound was prepared in analogy to the procedure of Example 37 starting from Example 71.
Yield: 145 mg (39%)
M.p .: 143 ° C
C ₈ H ₁₃ NO ₂ (155.2 × 36.5)

Example 74 1,2-trans-2-N- (tert-butyloxycarbonyl) amino-3-methylene-cyclopentane-1 - carbon acid methyl ester

The title compound was prepared in analogy to the procedure of Example 61 starting from Example 71.
Yield: 410 mg (82%)
M.p .: 74 ° C
R _f = 0.43 (petroleum ether / ethyl acetate = 3: 1)
C ₁₃ H ₂₁ NO ₄ (255.3)

Example 75 1,2-trans-2-amino-3-methylene-cyclopentane-1-carboxylic acid methyl ester hydrochloride

The title compound was prepared in analogy to the procedure of Example 37 starting from Example 74.
Yield: 228 mg (82%)
M.p .: 166 ° C
C ₈ H ₁₃ NO ₂ × HCl (155.2 × 36.5)

Example 76 2-N- (tert-Butyloxycarbonyl) amino-cyclopentan-3-one-carboxylic acid methyl ester

The title compound was prepared in analogy to the procedure of Example 4 starting from Example 71.
Yield: 898 mg (89%),
2 diastereomers cis: trans = 2: 1
M.p .: 98 ° C
C ₁₂ H ₁₉ NO ₅ (257.3)

Example 77 2-Amino-cyclopentan-3-one-1-carboxylic acid methyl ester

The title compound was prepared in analogy to the procedure of Example 5 starting from Example 76.
Yield: 139 mg (92%)
2 diastereomers cis: trans = 2: 1
M.p .: 250 ° C
C ₇ H ₁₁ NO ₃ × HCl (157.2 × 36.5)

Example 78 2-N- (tert-Butyloxycarbonyl) amino-3,3-difluoro-cyclopentane-1-carboxylic acid methyl ester

The title compound was prepared in analogy to the procedure of Example XVIII starting from Example 76.
Yield: 176 mg (32%), cis: trans = 2: 1
¹ H NMR (CDCl ₃ ): δ = 1.46 (s, 9H), 2.10-2.42 (m, 2H), 2.49-2.70 (m, 2H), 2.72 ( dt, 2H), 3.72 (s, 3H), 4.30-4.52 (m, 1H), 4.85 (cis, s, 1H), 5.20 (trans, s, 1H)
C ₁₂ H ₁₉ F ₂ NO ₄ (279.3)

Example 79 2-Amino-3,3-difluoro-cyclopentane-1-carboxylic acid methyl ester

The title compound was prepared in analogy to the procedure of Example 5 starting from Example 78.
Yield: 61 mg (48%), cis / trans = 2: 1
M.p .: 118 ° C
C ₇ H ₁₁ F ₂ NO ₂ × HCl (176.2 × 36.5).

Claims (1)

Use of cyclopentane and pentene β-amino acids of the general formula (I) in which
A, B, D, E, G, L, M and T are the same or different and represent hydrogen, halogen, hydroxyl or straight-chain or branched alkyl having up to 8 carbon atoms, which may be 1 to 2 times the same or different by halogen, hydroxy, phenyl, benzyl oxy, carboxy or by straight-chain or branched alkoxy, acyl o-alkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula -NR ⁴ R ⁵ , wherein
R ⁴ and R ^{5 are} identical or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
or B and D, E and G or L and M together for a remainder of the or = N-OH,
wherein
R ⁶ and R ^{7 are the} same or different and are hydrogen, halogen or straight-chain or branched alkyl, alkoxy or oxyacyl each having up to 8 carbon atoms, benzyl or phenyl, or
E and G and / or B and D together represent the rest of the formula = O or = S, or
B, D, E and G or E, G, L and M each together form a radical of the formula form what
D 'and G' have the meaning of D and G given above, but do not simultaneously mean hydrogen and
G and L have the meaning given above
R ^{2 represents} hydrogen or an amino protecting group, or
stands for straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted 1 to 2 times identically or differently by hydroxyl, formyl or by straight-chain or branched acyl having up to 6 carbon atoms or by phenyl or benzoyl, which optionally up to 2 times the same or different by halogen, nitro, cyano, or by straight-chain or branched alkyl having up to 6 carbon atoms, or
for straight-chain or branched acyl with up to 8 carbon atoms, or
stands for benzoyl, which is optionally substituted as described above, or
represents a group of the formula -SO ₂ R ⁸ , wherein
R ⁸ denotes straight-chain or branched alkyl having up to 8 carbon atoms, benzyl or phenyl, the latter optionally being up to 3 times identical or different by halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl are each substituted with up to 6 carbon atoms, carboxy or by the group -NR ⁴ R ⁵ listed above, wherein
R ⁴ and R ^{5 have} the meaning given above,
represents phenyl, which is optionally up to 3 times the same or different by halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula -NR ⁴ R ⁵ or -SO ₂ R ^{8 is} substituted, wherein
R ⁴ , R ⁵ and R ^{8 have} the meaning given above, or
for an amino acid residue of the formula stands in what
R ⁹ denotes cycloalkyl with 3 to 8 carbon atoms or aryl with 6 to 10 carbon atoms or hydrogen, or straight-chain or branched alkyl with up to 8 carbon atoms,
wherein the alkyl is optionally substituted by cyano, methylthio, hydroxy, mercapto, guanidyl or by a group of the formula -NR ¹¹ R ¹² or R ¹³ -OC-, wherein
R ¹¹ and R ¹² independently of one another represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, and
R ¹³ denotes hydroxy, benzyloxy, alkoxy with up to 6 carbon atoms or the group -NR ¹⁰ R ¹¹ listed above,
or the alkyl is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in turn is substituted by hydroxyl, halogen, nitro, alkoxy having up to 8 carbon atoms or by the group -NR ¹¹ R ¹² , wherein
R ¹¹ and R ^{12 have} the meaning given above, and
R ^{10 represents} hydrogen or an amino protecting group
R ^{3 represents} hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl, or
R ² and R ³ together represent the rest of the formula = CHR ¹⁴ , wherein
R ¹⁴ denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by halogen, hydroxy, phenyl, carboxy or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,
V represents an oxygen or sulfur atom or the -NH group,
R ^{1 represents} hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, the latter optionally up to 3 times the same or different by hydroxy, halogen, nitro, cyano, carboxy, trifluoromethyl, trifluoromethoxy, by straight-chain or branched Alkoxy, in the case of phenyl also by alkyl, acyl or alkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula -NR ⁴ R ⁵ or -SO ₂ R ^{8 are} substituted, wherein
R ⁴ , R ⁵ and R ^{8 have} the meaning given above, or in the event that V represents the -NH group,
R ^{1 represents} the group of the formula -SO ₂ R ⁸ , wherein
R ^{8 has} the meaning given above,
optionally in an isomeric form, and their acid addition salts and metal salt complexes for the preparation of an antibacterial drug.