WO1987003278A1 - Procedes de synthese pour obtenir des derives d'acide cyclopentanecarboxylique - Google Patents

Procedes de synthese pour obtenir des derives d'acide cyclopentanecarboxylique

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Publication number
WO1987003278A1
WO1987003278A1 PCT/EP1986/000678 EP8600678W WO8703278A1 WO 1987003278 A1 WO1987003278 A1 WO 1987003278A1 EP 8600678 W EP8600678 W EP 8600678W WO 8703278 A1 WO8703278 A1 WO 8703278A1
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formula
acid
reaction
preparing
independently
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PCT/EP1986/000678
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English (en)
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WO1987003278A3 (fr
WO1987003278A2 (fr
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Laurence John Nummy
H. Glenn Corkins
Louis S. Scarano
Dennis P. Byrne
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Schering Aktiengesellschaft Berlin Und Bergkamen
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Publication of WO1987003278A1 publication Critical patent/WO1987003278A1/fr
Publication of WO1987003278A2 publication Critical patent/WO1987003278A2/fr
Publication of WO1987003278A3 publication Critical patent/WO1987003278A3/fr
Priority to DK390787A priority Critical patent/DK390787A/da

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  • This invention relates to the synthesis of intermediates useful in the manufacture of a variety of compounds useful, e.g., as constituents of or intermediates in preparations of fragrances and fragrant compounds, flavoring agents and/or enhancers and especially of synthetic sweetening agents.
  • synthetic sweeteners that certain branched alkyl and alkylated cycloalkylamines, alcohols and carboxylic acids when incorporated into a moiety which is bonded to the amide nitrogen atom, e.g., of L-aspartamide, possess unique ability to impart intense sweetness to these molecules. Examples of such amines, alcohols and acids are found, for instance, in U.S.
  • 2,2,5,5-tetramethylcyclopentane- carboxylic acid is of interest in this connection; see W.D. Fuller, M. Goodman and M.S. Verlander, J. Am. Chem. Soc., 107, 5821, 1985.
  • R 1 , R 2 , R 3 and R 4 independently is H
  • R 5 and R 6 independently is H, or optionally substituted alkyl, aryl or aralkyl or together R 5 and R 6 form a fused ring, comprising condensing the corresponding compound of the formula
  • each of R 7 and R 8 independently is alkyl, in the presence of Nao or Ko to form the corresponding cyclic acyloin, and then in situ oxidizing the latter product with an effective oxidizing agent to form the diketone; and a process for preparing a hydrazone of the formula
  • each of R 1 , R 2 , R 3 and R 4 independently is H, or optionally substituted alkyl, aryl or aralkyl and each of R 5 and R 6 independently is H, or optionally substituted alkyl, aryl or aralkyl, or together R 5 and R 6 form a fused ring, comprising reacting the corresponding diketone of the formula with hydrazine in the presence of an effective acid catalyst at a pH of 5-11 and, preferably without any special means to remove H 2 O; and a process for preparing a cyclopentanecarboxamide of a primary or secondary amine of the formula
  • each of R 1 , R 2 , R 3 and R 4 independently is H, or optionally substituted alkyl, aryl or aralkyl and each of R 5 and R 6 independently is H, or optionally substituted alkyl, aryl or aralkyl, or together R 5 and R 6 form a fused ring, comprising reacting the corresponding diazoketone of the formula
  • a preferred intermediate for use in these synthetic reactions is the diketone 4, inter alia. It is useful especially in the preparation of new hydrazone 5.
  • this invention also provides a process for preparing a cyclopentane carboxylic acid of the formula
  • each of R 1 , R 2 , R 3 and R 4 independently is H, or optionally substituted alkyl, aryl or aralkyl and each of
  • R 5 and R 6 independently is H, or optionally substituted alkyl, aryl or aralkyl or together R 5 and R 6 form a fused ring, comprising treating the corresponding diazoketone of the formula
  • R 1 -R 4 is alkyl and most preferably, all four are alkyl groups.
  • R 5 and R 6 are generally non-critical to the successful carrying out of the various process steps as long as they are reaction-compatible, e.g., do not interfere with the underlying chemical reactions. Such interfering groups will be readily recognizable to those of skill in the art.
  • Suitable R 5 and R 6 groups when present, include alkyl groups of 1-8 carbon atoms. All of the details discussed above with respect to R 1 -R 4 alkyl groups apply here also. All of these alkyl groups R 1 -R 6 can be the same, all can be different, or some can be the same and some different.
  • Suitable aryl groups as R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are of, e.g., 6-10 C atoms and include hydrocarbons, e.g., phenyl, 1-naphthyl, 2-naphthyl, etc.
  • Heterocycles are equivalents thereof, e.g., of 1 or more fused rings (e.g., 1-3) typically of 4 to 7 ring members each, containing about 1-3 heteroatoms each, e.g., 0, N and/or S, e.g.. thiophenyl, furanyl, imidazolyl, indolyl, pyrrolyl, etc.
  • R 5 /R 6 form a fused ring of, e.g., 4 to 6 members, usually all C-atoms but also optionally including 1 to 3 hetero atoms, e.g., 0, N or S, preferably 5,6-benzo.
  • the substituent R 1 -R 6 must be reaction compatible, e.g., any rings must be sufficiently electron rich that they will not be reduced during the Na°/K° reaction.
  • Aralkyl groups include those, e.g., of 6-10 C-atoms in the aryl portion and 1-8 C-atoms in the alkyl portion, e.g., combinations of the aforementioned alkyl and aryl moieties.
  • the aryl groups and fused rings can be substituted by a group such as alkyl (e.g., of 1-8 C atoms), carboxyl, hydroxy, alkoxy of 1-8 C atoms, alkylsulfonyl, amino, etc.
  • alkyl groups can also be similarly substituted to form equivalent groups. Again the substituent must not interfere with the subject reaction(s) or must be conventionally protected.
  • esterifying moieties R 7 and R 8 will generally also be alkyl groups of 1-8 C atoms, straight chain or branched. Again, all of the details regarding these alkyl groups discussed above with respect to R 1 -R 4 apply here.
  • cyclohexane precursors are in turn more readily accessible from inexpensive commercially available substances than are the cyclopentanes.
  • adipate 3 to diketone 4 is achieved by acyloin condensation followed by in situ oxidation of the resultant cyclic acyloin to form the desired diketone.
  • Acyloin condensations per se are known and discussed, e.g., in the Annales Academiae reference cited above as well as in many standard organic texts, e.g., J. March, "Advanced Organic Chemistry," Third Edition, 1985, p. 1113.
  • the reaction can be conducted using sodium or potassium metal, preferably sodium metal in an inert solvent. Reaction temperatures are suitable which allow the reduction to proceed at a reasonable rate. Typically, temperatures of 25-120° C are used. Typical reaction times are about 1-48 hours.
  • Suitable solvents are well known and include diethylether, tetrahydrofuran, benzene, toluene, xylene or other solvents compatible with sodium.
  • the preferred oxidizing agent is thionyl chloride.
  • many other oxidizing agents are suitable, including oxygen, chlorine, sulfuryl chloride, manganese dioxide, iodobenzene diacetate,
  • N-bromosuccinimide N-chlorosuccinimide, chloroisocyanuric acid, chlorinated amines, hypochlorites and hypobromites.
  • chlorinated amines including those of t-butyl, sodium, calcium, etc., sodium persulfate, diphenyl disulfide, elemental sulfur, etc.
  • the in situ oxidation step is generally carried out at temperatures of -10 to 140°C in the same solvents utilized in the first step, using about 1-8 equivalents of oxidizing agent. Typical oxidation times are less than one to 24 hours.
  • Preferred conditions for the cyclization step involve the use of about 1.1 equivalents of sodium in toluene at about 50°C for about 24 hours.
  • Preferred oxidation conditions involve cooling the reaction medium resulting from the first step to about 0°C, adding the oxidizing agent and then warming to a reaction temperature of about 64° for about 4 hours.
  • Overall yields for the cy ⁇ lization/oxidation are very high, e.g., in the range of 90-100%, typically about 95%.
  • hydrazone 5 is prepared from diketone 4 by reaction of the latter at a pH of 5-11 with hydrazine in the presence of an acid catalyst. It has been discovered that the pH of the reaction solution is critical to the achievement of high yields.
  • the preferred pH range is 6-10, especially, 8-10.
  • reaction it has been discovered that it is not necessary to carry it out under conditions which achieve continuous removal of water from the reaction. A priori, it was expected that this would have been necessary. Surprisingly, not only can the reaction be conducted at room temperature or even lower temperatures, but it even can be conducted using aqueous hydrazine solutions as starting materials. Thus, the reaction can be conducted without heating, preferably in the temperature range of 10-40°C, most preferably at about room temperature. Of course, it is still possible to carry out the reaction at higher temperatures with continuous removal of water, but this is neither necessary nor economical.
  • the reaction can be conducted in the presence of any of a large number of weak acidic catalysts, typically those having pKa values in the range of about 1-6, e.g., benzoic acid, acetic acid, propionic acid, trifluoroacetic acid, phthalic acid, etc.
  • the dione is usually dissolved in a compatible solvent, typically an aromatic hydrocarbon solvent such as benzene, toluene or xylene in the presence of about 1-20 mole percent of the acid catalyst based on the amount of dione used.
  • a compatible solvent typically an aromatic hydrocarbon solvent such as benzene, toluene or xylene
  • an alcohol e.g., an alkanol of 1 to about 8 carbon atoms. The typical amounts of alcohol are 0-50%.
  • Typical amounts of hydrazine are about 1-10 equivalents, i.e., usually an excess.
  • the reaction time normally is from 2-24 hours. Reaction yields for this step are also high, e.g., in the range of about 90-100%, typically about 95%.
  • Particularly preferred conditions involve the use of ten equivalents of hydrazine in toluene containing acetic acid and ethanol.
  • Monohydrazones are reported to be the product of reactions of hydrazine with aryl ketones. Generally, in reacting hydrazine with alkyl ketones, no useful product can be isolated, or the remaining NH 2 group condenses with a second mole of carbonyl compound to give an azine, e.g.,
  • a diazoketone such as 6 is reacted with an amine directly to form the corresponding amide of the corresponding cyclopentane carboxylic acid.
  • This reaction is especially surprising since the effect of the amine during the ring contraction could not be anticipated in view of the prior art knowledge that such a contraction per se produces not only the desired ring contracted ketene, but also an undesired by-product, the corresponding ⁇ , ⁇ - unsaturated ketone. See Kaplan and Mitchell, supra.
  • direct reaction of the diazoketone with the amine under ring contraction condition produces very high yields of the desired ring contracted amide 12:
  • Suitable amines for use in this step of the invention include all compatible primary or secondary amines,e.g., ammonia, dimethylamine, methylamine, dibutylamine, aniline, phenylpropanolamine, etc. Such amines also include all of the important amino acids, including all of the naturally occuring amino acids as well as their optical isomers and racemates. Other amines correspond to the structures shown in U.S.P.
  • R 9 and R 10 moieties in the amines and resultant new amides generally include H and all of the alkyl, aryl, aralkyl, and alkaryl groups mentioned above or described in terms of alkyl or aryl components, as well as their substituted and equivalent counterparts. Many otherpossible amines are also equivalents for use in this invention as will readily be recognized by those of skill in the art.
  • Suitable solvents include benzene, toluene, xylene, chlorobenzene, chloroform, dichloromethane, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, acetonitrile, benzonitrile, etc.
  • the reaction is usually conducted at temperatures of 65-100 °C for times of 2-4 hours.
  • the amine reactant is unstable as a free base or is more conveniently available as an acid salt (e.g., the hydrochloride salt)
  • a second base such as a tertiary amine (e.g., triethylamine, N-ethylmorpholine, diazabicyclooctane, etc.) or an inorganic base such as the alkali metal carbonates or bicarbonates or alkaline earth metal oxides.
  • optical activity of the starting amine will be retained, e.g., where the amine is an optically active amino acid, e.g., a naturally occurring amino acid.
  • retention of optical configurational purity is important for maintenance of the desired end-use property e.g., sweetness.
  • Determination of optimal reaction conditions for retention of optical activity is routine and known, e.g., in the field of peptide bond formation.
  • the identity of the acid scavenger can be important in this regard, e.g., often a morpholine-based scavenger will lead to higher retention of optical activity than other conventional agents such as triethylamine.
  • ketene (8) can first be prepared as described below prior to addition of the optically active amine. The ketene (8) can then be converted to amide (12) under the mild reaction conditions discussed below. This avoids exposure of the optically active compounds to the more highly reactive conditions used to prepare the ketene thereby lessening the likelihood of racemization.
  • the reaction of the amine and the diazoketone is conducted in situ in the reaction solution which results after hydrazone 5 is used to prepare diazoketone 6.
  • Hydrazone 5 is converted to diazoketone 6 by oxidation.
  • the reaction can be carried out by stirring a solution of the hydrazone in an inert solvent. Any of the common solvents compatible with the reagents involved can be used, e.g., toluene and its equivalents described elsewhere herein and well known to those of skill in the art.
  • Suitable oxidizing agents are manganese (IV) dioxide, silver oxide, iodobenzene diacetate, etc.
  • the reaction is normally conducted at a temperature of about 0-50°C for times of about 1-24 hours. Typically, about 1-10 equivalents of the oxidizing agent is utilized. In a preferred aspect, this step is carried out in a toluene solution of hydrazone 5 while stirring it at 25°C with three molar equivalents of activated manganese dioxide for 2 hours.
  • Yields in this aspect of the process are also very high, e.g., in the range of 80-99% for both the reaction of the diazoketone with the amine and 90-100% for that of the hydrazone with the oxidizing agent. Typically, yields are around 95% for the hydrazone oxidation and, around 90% for the coupling of 6 with an amine.
  • the foregoing preferred reactions are performed sequentially, e.g., diester 3 is used to prepare diketone 4 which is then used to prepare hydrazone 5.
  • This sequence of reactions can then be extended whereby hydrazone 5 is used to prepare diazoketone 6; or, the sequence can begin with diketone 4 which is used to prepare hydrazone 5 which, in turn, is used to prepare diazoketone 6.
  • the sequences ending with diazoketone can be extended in a direct preparation of an amide of a desired amine, e.g., most preferably by reaction with alanine methyl ester.
  • the adipate (3) can be prepared by esterification of the corresponding acid (2) with an alcohol and an acid catalyst in such a way as to remove water as it is formed in the reaction.
  • Suitable aliphatic alcohols which provide satisfactory esters for this synthesis are represented by those containing C 1 -C 8 branched or straight hydrocarbon chains.
  • the acid catalyst can be sulfuric acid, an arylsulfonic acid such as toluene sulfonic acid, methane sulfonic acid or a polymeric resin sulfonic acid such as
  • Nafion-H R Temperatures usually are 75-120oC and reaction times 4-24 hours.
  • the esterification is typically carried out in a hydrocarbon solvent which forms an azeotrope with water. Examples include benzene, toluene or xylene. This, however, is not necessary when higher boiling alcohols that form azeotropes with water are used. An example is butanol.
  • Preferred conditions involve dissolving the diacid (2) in a mixture of sulfuric acid, ethanol and toluene and slowly distilling off a tertiary mixture of toluene, ethanol and water until the theoretical amount of water has been collected. It will be recognized by those skilled in the art that any of the well known literature procedures for preparing esters from carboxylic acids apply to the synthesis of (3) within the scope of this invention.
  • the adipic acid (2) can be prepared by one of several procedures known to the prior art.
  • the preferred method for the purpose of this invention involves a procedure which is based on but constitutes a significant improvement over that reported by D.D. Coffman, E.L. Jenner and R.D. Lipscomb, J. Amer. Chem. Soc. 80, 2864 (1958).
  • Pivalic acid is oxidatively dimerized by mixing with water and sulfuric acid. To this mixture is simultaneously added a solution of iron (II) sulfate in aqueous sulfuric acid and a solution of aqueous hydrogen peroxide. Temperatures usually are 25-100°C and reaction times 1-10 hours. Typically, from 1-10 molar equivalents each of hydrogen peroxide, ferrous sulfate and sulfuric acid are used, most preferably 1 equivalent each of hydrogen peroxide and ferrous sulfate and 1.3 equivalents of sulfuric acid.
  • Ionic surfactants can also be used including anionic and cationic ones.
  • Non-limiting examples of such surfactants include dialkylsulfosuccinates, e.g., a dioctylsulfosuccinate, long-chain alkylbenzene sulfonates, e.g., sodium dodecylbenzene sulfonate, etc.
  • Appropriate solvents for this transformation are those which have a boiling point equal to or greater than the temperatures necessary to bring about rearrangement and are otherwise reaction compatible. Some examples of solvents which satisfy the criteria for this reaction are tetrahydr ⁇ furan, dioxane, benzene; toluene, xylene, dichloroethane and chlorobenzene to name a few.
  • a practicable temperature range for ketene formation is 60° to 140°C Reaction times typically are 1-7 hours.
  • Preferred conditions employ toluene as solvent, at 90°C. Yields are excellent, e.g., 90-100%, typically around 95%.
  • An advantage of this approach is that the solution of the ketene produced can be used directly as an acylating agent.
  • ketenes due to their extremely high reactivity, allow the use of very mild reaction conditions.
  • ketene (8) can be hydrolyzed to the acid (7) or reacted with an amine such as those already described herein to produce amide (12) at a temperature in the range of -20°C to 25°C. Of course, higher temperatures are also effective.
  • Other reaction parameters are the same as those described for the analogous transformations beginning with the diazoketone (6).
  • a further advantage of this approach is revealed in the case where the amine being acylated is optically active and susceptible to racemization as discussed above. This function (high reactivity) can only be achieved alternatively by preparing and isolating acid (7) and then converting it to an activated form in a separate step.
  • the carboxylic acid (7) can also be produced from (6).
  • it can be accomplished by dissolving diazoketone (6) in aqueous alkaline media containing an organic co-solvent and then heating the homogeneous solution to a temperature sufficient to bring about rearrangement and hydrolysis. Typical temperatures are 65-100°C and reaction times 2-8 hours.
  • Compatible co-solvents are those which exhibit appreciable water solubility such as lower alcohols, ethylene glycol, acetonitrile, tetrahydrofuran, dioxane, dimethylsulfoxide, and the like.
  • a suitable aqueous alkali is sodium or potassium hydroxide solution.
  • a solvent which is substantially immiscible with water can be used in combination with a phase transfer catalyst such as tetra-n-butylammonium ion, 18-crown-6, etc., as is known.
  • a phase transfer catalyst such as tetra-n-butylammonium ion, 18-crown-6, etc.
  • the reaction can be performed successfully (albeit more slowly) in the absence of the alkaline reagent.
  • the preferred conditions for this reaction make use of ethanol as co-solvent mixed in a ratio of 3:1 with 18.75% (w/w) sodium hydroxide solution.
  • the reaction mixture is refluxed for two hours to afford (7).
  • the reaction of (6) to prepare (7) can also be carried out in situ of the reaction(s) used to prepare (6) from (5). See, e.g.. Example 10 below.
  • Another method of obtaining acid (7) from dione (4) is to convert the dione into the ring-contracted hydroxy-acid (9) or ester (10).
  • the reaction can be realized by treating (4) with sodium hydroxide or alkoxides in water or alcohol solvents. This reaction is run in a nitrogen atmosphere at a temperature of 65o-100°C for 1-18 hours. Alcohol/alk ⁇ xide combinations which are useful in this process are those containing one to eight carbon atoms in each component.
  • the acid (9) is produced, it can be converted to an ester in a separate step, e.g., a C 1 -8 -alkyl ester.
  • These esters, of which (10) is a representative example; are used to prepare the acylhydrazide (11).
  • the acid hydrazide prepared by this method can be used to synthesize acid (7) by an oxidative procedure.
  • the hydrazide is exposed to a reagent capable of converting the hydrazo moiety into the azo moiety.
  • this reaction results in splitting off water at the same time and consequently preparing the acid (7).
  • Many familiar oxidizing agents known in the prior art can be used. These can be employed stoichiometrically or in excess. Non-limiting examples of these include halogens such as chlorine or bromine, silver or mercury oxides, manganese dioxide and others.
  • the reaction is carried out in the temperature range of 0o-100°C in either water or organic solvents or mixtures of the two.
  • Acceptable organic solvents include those such as the C 1 -C 4 alcohols, glycols such as ethylene glycol or propylene glycol, ethers such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane.
  • Other useful solvents are acetonitrile and dimethylformamide.
  • a preferred mode of this reaction comprises adding a solution of sodium hypochlorite to an aqueous mixture containing the hydrazide (11) at a temperature of 0°C followed by warming to 25°C for one hour. Nitrogen gas is evolved, affording compound (7).
  • the product (7) formed in any of the ways described above can be used directly in many prior art reactions for preparation of many useful compounds.
  • the acid can fully conventionally be converted into any of its well-known functional equivalents such as any of the acid halides.
  • Use of the acid products of this invention to prepare the desired known prior art products is fully conventional. See Fuller, Goodman and Verlander, supra, and The Chemistry of Functional Groups Series, Saul Patai Editor, "The Chemistry of the Carboxyl Group,” Wiley Interscience, 1966.
  • the flask contents are cooled to 20°C and the crude 2,2,5,5-tetramethyladipic acid is isolated by filtration, washed with water and dried; weight 73.0 g.
  • the 73.0 g of diacid crystallized from 73 ml of methanol gives 44.0 g 2,2,5,5-tetramethyladipic acid, mp 181-184°C, neutralization equivalent 101; theory, 101.1.
  • Example 2 Diethyl-2,2,5,5-Tetramethyladipate (3) A total of 186.0 g (.92 mol) of 2,2,5,5-tetramethyladipic acid, 1350 ml toluene, 450 ml ethanol and 4.75 ml (0.09 mol) H 2 SO 4 is placed in a 3.0 1 flask equipped with a pot thermometer, vapor thermometer, stirrer, and condenser with Vigreux column and Dean-Stark tube. The flask is heated to gentle reflux to collect an azeotropic mixture of ethanol, toluene and water which distills at 74.2°-75°C.
  • 2,2,5,5-tetramethyladipate is isolated by vacuum distillation, b.p. 95-98°C at 2 torr. through a short Vigreux column. The yield is 196.0 g, 82.7% of theory.
  • Example 4 3,3,6, 6-Tetramethylcyclohexane-1,2-Dione ( 4 ) To a stirring solution of 68.0 g (.397 mol) of 2-hydroxy-3,3,6,6-tetramethylcyclohexanone, 67 ml dry pyridine and 520 ml dry toluene that has been cooled to 0 to 5°C under a N 2 atmosphere is slowly added 240 ml (3.3M) of thionyl chloride maintaining a temperature of 10°C or less. After addition of SOCl 2 , the reaction mixture is gently heated at 60-65°C for 12 hours. The reaction is cooled to 20°C and then slowly added to a stirring mixture of crushed ice and water (about 1,250 ml).
  • the layers are separated and the toluene layers washed with 500 ml saturated NaCl, two 500 ml portions of saturated NaHCO 3 , and finally with 500 ml saturated NaCl.
  • the toluene solution is dried over Na 2 SO 4 and concentrated by rotary evaporation to dryness. A 100-ml portion of cyclohexane is added to the residual yellow solid. The product is collected by filtration and washed with 10 ml cyclohexane. Yield is 54.0 g of
  • Diethyl 2,2,5,5-tetramethyladipate (25.8 g, 0.10 mol) is added to a vigorously stirred suspension of sodium (9.2 g, 0.40 mol) beads in toluene under a nitrogen atmosphere at 25 C. After complete addition, the temperature is brought to 50°C and maintained for 24 hours. The thick gelatinous mixture is then cooled in an ice bath and thionyl chloride is added drop-wise. Cooling is maintained but the temperature is allowed to rise to 65°C. This is maintained for 30 minutes. The excess thionyl chloride and toluene are then recovered by distillation and the residue is slurried two times with hexanes to remove diester. The residue (13.1 g, 0.078 mol) is composed of almost pure dione and represents a 78% yield.
  • Example 8 Preparation of Monohydrazone of 3,3,6,6- tetramethylcyclohexane-1,2-dione (5)
  • a 100-ml round-bottom flask equipped with magnetic stir bar is charged with the dione (4), 1.68 g (0.01 mole); toluene, 12.5 ml; ethanol, 7.5 ml and acetic acid, 2.5 mcl.
  • 64% (w/w) aqueous hydrazine, 5.50 g (0.11 mole) is added.
  • the resulting mixture is allowed to stir at ambient temperature. Reaction progress is monitored by thin layer chromatography (silica gel; 1% ethyl acetate in dichloromethane as eluent).
  • the crystalline hydrazone is further characterized by the following spectral properties: NMR - 60 MHz, CCl 4 solution ppm downfield from TMS: 1.10, S; 1.13, S (12 H); 1.68, S (4H); 9.1, br.s (2H)
  • 1,2-dione (26.10 g 0.14 mol) in benzene (23.49 g) solution is slurried with manganese dioxide (43.01 g, 0.49 mol) and the result stirred at room temperature for two hours.
  • the solids are filtered off and the filtrate concentrated to an oily residue.
  • This is dissolved in 4 ml ethanol and the solution added to the aqueous sodium hydroxide solution with stirring at 25°C.
  • the mixture is in two phases so an additional 2 ml ethanol is added to achieve homogeneity.
  • the solution is heated to reflux (gas evolution evident at 75°C) for two hours, upon cooling to 25 °C, the ethanol is removed in vacuo.
  • Example 12 (L)-Methyl-N-(2,2,5,5-tetramethylcyclopentane-1-carbonyl)- alaninate (Method 1) A solution of the diazoketone (6) (1.8 g, 10 mmol) in 5 ml of toluene is added to a stirring suspension of
  • Example 13 2 2,2,5,5-tetramethylcyclopentane-1-carboxylic acid amides
  • the procedure of Example 12 was followed using the following instead of L-alanine ester hydrochloride: methylamine hydrochloride, dimethylamine, aniline, di-n-butylamine and phenylpropanolamine hydrochloride.
  • the procedure also varied in that in the case of methylamine 3 equivalents each of the amine reactant and of triethylamine were used; and the dimethylamine was added as a 22% aqueous solution, i.e., a two-phase reaction ensued. Where the amines per se were used, triethylamine was not employed.
  • the following amides were obtained (% yield; m.p. (°C)), respectively: N-methyl-2,2,5,5-tetramethylcyclopentane-1-carboxamide, (84%; 170-173.5)
  • Example 15 Preparation of 2,2,5,5-Tetramethylcyclopent-1-ylidenone (8)
  • a solution of the diazoketone (6) (1.80 g, 10 mmol) in 10 ml dry toluene is heated at 90 °Cuntil its presence can no longer be detected by thin layer chromatography. This requires 3 to 4 hours.
  • the resulting solution upon cooling to ambient temperature is used directly to acylate primary and secondary amines or is hydrolyzed to acid (7).
  • Example 16 l-Hydroxy-2,2,5,5-tetramethylcyclopentanecarboxylic Acid (9) A total of 16.8 g (.1 mol) 3,3,6,6-tetraraethylcyclohexane-1,2-dione is added to 788 ml of 4 N NaOH in a 2.0 1 pressure bottle. The solution is saturated with N 2 and the agitated solution heated while maintaining a pressure of 5 psi of N 2 pressure at 110°C for 24 hours. The reaction mixture is cooled to 25°C and the alkaline solution extracted with two 100-ml portions of methylene chloride. The extracted solution is acidified with 285 ml of concentrated HCl.
  • the ester (10) is characterized by its NMR and IR spectral properties: NMR: 60 MHz, CDCl 3 solution ppm downfield from TMS: 0.92, s(6H); 1.1, s(6H); 1.75, br.s(4H); 3.37, s(1H); 3.8, s(3H)
  • Example 18 Preparation of l-Hydroxy-2,2,5,5-tetramethyl- cyclopentanecarboxylic Acid Hydrazide (11)
  • a mixture of the methyl ester (10) (2.0 g, 10 mmol), anhydrous hydrazine (1.28 ml, 40 mmol) and n-butanol (1.0 ml) is heated at 100°-105°C with stirring in a nitrogen atmosphere under a reflux condenser for 20 hours. The mixture is then allowed to cool to ambient temperature and the excess hydrazine and butanol is removed under vacuum. The product, a viscous oil, is partitioned between water and dichloromethane.
  • the phases are separated and the aqueous phase concentrated to a residual oil under vacuum.
  • This material is used directly in the oxidation step using sodium hypochlorite.
  • the hydrazide is characterized in this material by its NMR and IR spectral properties: NMR: 60 MHz, CD 3 OD solution ppm shift downfield from TMS: 1.1, br.s.(12H); 1.75, br.m(4H); 4.8, s.exch.
  • IR CHCl 3 solution (0.1g/cc) cm -1 : 3340, 3080, 3000-2900 br, 2860, 2800-2400 br, 2350, 1700-1500 br, 1455, 1375, 1335, 1150, 1075. It can be conventionally isolated and purified, e.g., using chromatographic techniques.
  • Example 19 Preparation of 2,2,5,5-tetramethylcyclopentane- carboxylic acid ( 7 ) 2 , 2 , 5 , 5-tetramethyl-1-hydroxycyclopentane carboxylic acid hydrazide (11) (0.035g, 0.18 mmol) is placed in a 5 ml round-bottom flash equipped with magnetic stir bar. A total of 100 mcl of water was added and the milky solution cooled by immersing the flask in an ice-water bath. While stirring the solution, an aqueous solution of sodium hypochlorite (8.37% w/w) (157 mcl, 0.176 mmol) was added dropwise. Vigorous gas evolution was noted and a precipitate formed.
  • the mixture was allowed to warm to ambient temperature. It was diluted with 100 mcl of water and the result (pH 7) extracted twice with ether.
  • the aqueous phase was acidified to a pH of less than 1.0 using concentrattd hydrochloric acid.
  • the solution which had become clear after ether extraction and prior to acidification again takes on a milky appearance. This was extracted twice with ether and the organic extract concentrated to dryness leaving 5.4 mg of residue.
  • the presence of the acid (7) was detected by thin layer chromatography by comparison with an authentic sample.

Abstract

Une méthode de contraction de cycles est appliquée à la préparation de dérivés de cyclopentane, notamment d'acide 2,2,5,5-tétraméthylcyclopentanecarboxylique à partir de composés de cyclohexane. Dans un aspect, une diazocétone de cyclohexane est mise en réaction avec une amine (par exemple un ester d'alanine) pour former l'amide correspondant d'acide de cyclopentane.
PCT/EP1986/000678 1985-11-27 1986-11-25 Procedes de synthese pour obtenir des derives d'acide cyclopentanecarboxylique WO1987003278A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DK390787A DK390787A (da) 1985-11-27 1987-07-27 Cyklopentancarboxylderivater og fremgangsmaade til fremstilling deraf

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US80248185A 1985-11-27 1985-11-27
US802,481 1985-11-27

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WO1987003278A1 true WO1987003278A1 (fr) 1987-06-04
WO1987003278A2 WO1987003278A2 (fr) 1987-06-04
WO1987003278A3 WO1987003278A3 (fr) 1987-07-02

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JP (1) JPS63501720A (fr)
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GB2476505A (en) * 2009-12-23 2011-06-29 Univ Reading Process for the production of diketones

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US3151986A (en) * 1962-05-02 1964-10-06 Monsanto Co Free-flowing fumaric and adipic acid compositions
CH522432A (de) * 1967-02-07 1972-06-30 Ciba Geigy Ag Verwendung von v-Triazolen als Schutzmittel für nichttextile organische Substrate gegen UV-Strahlen
US4571345A (en) * 1983-06-13 1986-02-18 Cumberland Packing Corp. 1,1-Diaminoalkane derived sweeteners
EP0196461A3 (fr) * 1985-03-01 1987-04-22 Kyowa Hakko Kogyo Co., Ltd. Dérivés de cyclopentane

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