PROCESS FOR THE PREPARATION OF 3-AMINO-3-CYCLOPROPYLPROPANOATE ESTERS

Abstract: Disclosed is a process for preparing 3-amino-3-cyclopropylpropanoate esters, i.e., beta -cyclopropylalanine esters ( beta -CPA esters) including racemic and substantially enantiomerically-pure <i>R</i> or (<i>S</i>)- beta -CPA esters. The process comprises reacting cyclopropanecarboxaldehyde (CPCA) with a phosphonate reagent to obtain an alpha , beta -unsaturated ester which is reacted with an enantiomerically-enriched lithium amide to produce an arylalkyl-amino ester compound; and then removing the arylalkyl residue from the amino group by hydrogenolysis to give the beta -CPA ester.

Description: PROCESS FOR THE PREPARATION OF 3-AMINO-3-CYCLOPROPYLPROPANOATE ESTERS Introduction This invention pertains to a process for preparing 3-amino-3-cyclo- propylpropanoate esters, i.e., esters of 3-amino-3-cyclopropylpropanoic acid (β-cyclopropylalanine esters or β-CPA esters) including racemic and substantially enantiomerically pure (R) or (S)- β-CPA esters. More specifically, this invention pertains to a process for the preparation of β-CPA esters by a 3-step process wherein cyclopropanecarboxaldehyde (CPCA) is reacted with a phosphonate reagent to obtain an α,β-unsaturated ester which is reacted with an enantiomerically-enriched lithium amide to produce an arylalkyl-amino ester compound; and the arylalkyl residue is removed from the amino group by hydrogenolysis to give the β-CPA ester. The present invention also includes certain of the individual process steps and intermediate compounds. β-Amino acids are an important class of organic compounds and often are found in physiologically active compounds. See, for example, Suffness, Ed., Taxot ® Science and Applications (CRC, Boca Raton, FL, 1995) and Plattner, in Annual reports in Medicinal Chemistry, J. A. Bristol, Ed (Academic Press, San Diego, 1994), vol 29, pp. 113-22. Similarly, the cyclopropyl fragment also is found in pharmaceutical products. See, for example, British Patent Publication GB 1 ,136,214, U.S. Patent 3,433,791 , Published PCT Patent Application WO 9304047, Spanish Patent ES 539110, U.S. Patent 4,863,918, Czech Patent CZ 279821 and European Patent Publication EP 0380312 A1. Only one reference to an ester of a β-amino acid substrate of this type can be found in the literature and concerns the use of ethyl 3-amino-3- cyclopropylpropanoate in the synthesis of a platelet aggregation inhibitor, Published PCT Patent Application WO 9307867 A1 930429 (Application: WO 92-US8512). The racemic form of ethyl 3-amino-3-cyclopropyl- propanoate was prepared by the action of diazomethane and palladium acetate on the corresponding vinyl compound, the preparation of which is not trivial, The use of enantiomerically enriched lithium amides in the preparation of β-amino acids has been reported in, for example, Tetrahedron, 50, 3975 (1994), Synlett, 461 (1993) and Tetrahedron: Asymmetry, 2, 183 (1991). None of these published procedures employs a cyclopropyl- carbonyl substrate. Brief Summary of the Invention We have developed a process for the preparation of both racemic and substantially enantiomerically pure (R) or (S)-β-CPA esters beginning with CPCA. Our novel process comprises the steps of: (1) contacting CPCA with a phosphonate having the formula (I): in the presence of a base and an inert solvent to obtain an α,β-unsaturated ester having the formula (II): (2) contacting the α,β-unsaturated ester of formula (II) with a lithium amide of formula (III): in the presence of an inert solvent to obtain an amino ester compound having the formula (IV): and (3) contacting the amino ester compound of formula (IV) with hydrogen in the presence of a hydrogenation catalyst and an inert solvent to obtain an amino ester of the formula (V): wherein R 1 is an alkyl radical, e.g., unsubstituted or substituted Ci - C 8 alkyl; R 2 and R 3 are independently selected from alkyl radicals; R 4 is an unsubstituted or substituted Ci - C 8 alkyl, carbocyclic aryl, or arylalkyl radical; and R 5 is a carbocyclic aryl radical. The use of substantially enantiomerically pure (R) or (S) lithium amide (III) gives the corresponding substantially enantiomerically pure β-CPA ester whereas the use of racemic or achiral lithium amide (III) gives racemic β-CPA. As used herein, "substantially enantiomerically pure" refers to a compound possessing greater than 95% enantiomeric excess [ee] wherein enantiomeric excess is defined as the percent of one enantiomer minus the percent of the other enantiomer. Another embodiment of the invention comprises process step (2) described above wherein a substantially enantiomerically pure lithium amide is used to produce a substantially enantiomerically pure amino ester having formula (IV). The invention also includes the novel intermediate compounds produced and utilized in the above-described process, i.e., arylalkyl-amino esters (IV). In step (1) of the process, a phosphonate having the formula is reacted with CPCA in the presence of a base in an inert solvent to produce an α,β-unsaturated ester having the formula The alkyl radicals which R 1 , R 2 and R 3 represent may be unsubstituted or substituted, unbranched or branched, alkyl containing up to 8 carbon atoms. Examples of unsubstituted alkyl include methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, and 2-ethylhexyl. Examples of the substitutents which may be present on the substituted alkyl radicals include alkoxy, halogen such as chloro and bromo, alkylthio, and aryl, e.g., phenyl and substituted phenyl. R 2 and R 3 preferably represent lower alkyl, e.g. alkyl of up to 4 carbon atoms. The base employed in step (1) may be an alkali metal or alkaline earth metal hydride, alkoxide or hydroxide, preferably sodium hydride. The amount of base employed normally will give a base:CPCA mole ratio in the range of 0.5:1 to 10:1 , preferably 0.8:1 to 1.5:1. The inert solvent employed in the first step preferably is an ether, e.g., a dialkyl ether containing 2 to 8 carbon atoms or tetrahydrofuran; a hydrocarbon, e.g., an aliphatic hydrocarbon containing 6 to 12 carbon atoms, a cycloaliphatic hydrocarbon containing 5 to 7 carbon atoms or an aromatic hydrocarbon containing 6 to 12 carbon atoms such as benzene and alkyl-substituted benzene, e.g., toluene, the xylenes and diisopropylbenzene; or a dipolr aprotic solvent such as an N,N-dialkylformamide, N,N-dialkylacetamide or N-alkylpyrrolidinone wherein the alkyl groups contain up to 4 carbon atoms. The inert solvent preferably is an ether such as tetrahydrofuran The first step may be carried out at a temperature in the range of -25°C up to the boiling point of the solvent, e.g., -25 to 50°C, preferably at a temperature of -10 to 20°C. The mole ratio of CPCAphosphonate (I) normally will be 0.75:1 to1.25:1. α,β-Unsaturated ester (II) produced in step (1) may be isolated, e.g., by standard extraction techniques known in the art and can be used directly in the next step. The second step of the process comprises contacting α,β-unsat- urated ester (II) obtained from the first step with a lithium amide reactant having the formula: in the presence of an inert solvent to obtain an amino ester compound having the formula: in the presence of an inert solvent, such as an ether, hydrocarbon or mixture thereof wherein R 4 represents an alkyl radical, a carbocyclic aryl radical or a an arylalkyl radical; and R 5 is a carbocyclic aryl radical. Examples of the alkyl radicals which R 4 may represent are set forth above in the description of R 1 , R 2 and R 3 . The carbocyclic aryl radical represented by R 4 and R 5 may be unsubstituted or substituted phenyl or naphthyl. Examples of the substituents which may be present on the phenyl and naphthyl radicals which R 4 and R 5 may represent include alkyl, e.g., Ci - C alkyl; alkoxy, e.g., Ci - C 4 alkoxy; halogen, e.g., chloro and bromo; nitro; hydroxy; and the like. Normally, the phenyl and naphthyl radicals will not be substituted by more than 2 of any such substituents. R 4 preferably is a carbocyclic arylalkyl containing 7 to 10 carbon atoms, most preferably α- methylbenzyl, and R 5 preferably is phenyl. The inert solvent employed in the second step may be selected from dialkyl ethers, cyclic ethers, hydrocarbons or a mixture thereof, e.g., the ether and hydrocarbon solvents described above for step (1). The second step may be carried out at a temperature in the range of -80°C up to the boiling point of the solvent, preferably at a temperature of -70 to -40°C The mole ratio of lithium amide (III): α,β-unsaturated ester (II) normally will be 0.75:1 to 1.5:1. When lithium amide (III) is a substantially enantiomerically pure compound, i.e., (R) or (S) lithium amide (III) wherein R 4 is arylalkyl, the process of step 2 is observed to proceed with >20:1 diastereoselectivity. For example, when R 1 is tetτ-butyl and R 4 is α-methylbenzyl, the addition of lithium amide reactant (III) to α,β-unsaturated ester (II) is observed to provide arylalkyl-amino ester (IV) in a 97:1 ratio of diastereomers. The major diastereomer possesses either the (R,S) configuration [starting with the (R)-lithium amide] as shown in (IVa) or the (S,R) configuration [starting with the (S)-lithium amide] as shown in (IVb). The minor diastereomer possesses the (R,R) or (S,S) configuration as shown in (IVc) and (IVd), respectively. This diastereoselectivity is advantageous for the preparation of substantially enantiomerically pure β-CPA esters. (IVa) (IVb) In the third step of our novel process, the amino ester of formula (IV) from step (2) is subjected to a hydrogenolysis treatment to remove the arylalkyl and R 4 substituents, thereby producing the amino ester of formula (V). The hydrogenolysis treatment of step (3) comprises contacting a solution of arylalkyl-aminoester (IV) in an inert solvent, preferably an alkanol, e.g., an alkanol containing 1 to 4 carbon atoms, water or an alkanol/water mixture, with hydrogen or a suitable hydrogen donor such as formic acid and a hydrogenation catalyst. The hydrogenation catalyst may be selected from the metals of Group VIII and compounds thereof, e.g., nickel, palladium, platinum and the like. The catalyst preferably comprises a supported palladium or platinum catalyst, e.g., catalysts comprising 2 to 20 weight percent, preferably 5 to 10 weight percent, palladium or platinum deposited on a catalyst support material. Palladium and palladium hydroxide on carbon are particularly preferred hydrogenation catalysts. The process described herein may be carried out at ambient pressures. However, pressures moderately below or above ambient pressure may be used in one or more of the steps of the process. For example, increased pressure may permit the use of higher reaction temperatures and/or may provide for enhanced contact of process materials, e.g., hydrogen contact in the hydrogenolysis of step (3). In particular, hydrogen pressures for step (3) can be in the range of 1 to 100 atmospheres, preferably 1 to 30 atmospheres. The amino ester of formula (V) may be hydrolyzed to the corresponding β-cyclopropylpropanoic acid (β-CPA) having the formula by means of conventional hydrolysis procedures using an aqueous acid or base in a solvent comprising an ether, hydrocarbon, acetone, water or a mixture thereof. Examples of suitable acids include mineral acids such as hydrohalic acids such as hydrochloric and hydrobromic acids; sulfuric acid; phosphoric acid; alkyl- and arylsulfonic acids such as methanesulfonic, benzenesulfonic and toluenesulfonic acids. The acid preferably is hydrochloric acid. The acid:amino ester (V) mole ratio is in the range of 1 :1 to 10:1. The base may comprise an alkali metal or alkali earth metal hydroxide in a base:amino ester (V) mole ratio of 1 :1 to 10:1. The hydrolysis may be carried out at a temperature of room temperature to the boiling point of the solvent, preferably at the boiling point of the solvent. The reaction product produced by the hydrolysis normally is the acid addition salt of β-CPA (VI), e.g., the hydrochloride or sulfate of β-CPA (VI). A second embodiment of the process of the present invention comprises process step (2) described above wherein a substantially enantiomerically pure lithium amide is used to produce a substantially enantiomerically pure amino ester having formula (IV). This second embodiment comprises contacting an α,β-unsaturated ester having the formula: with a substantially enantiomerically pure lithium amide having the formula: in the presence of an inert solvent to obtain the amino ester having the formula: wherein R 1 , R 4 and R 5 are defined above and amino ester (IV) comprises a mixture of diastereomers with the ratio of major to minor diastereomers of greater than 20:1 , preferably greater than 97:1. The major diastereomer possesses either the (R,S) configuration [starting with the (R)-lithium amide] as shown in (IVa) or the (S,R) configuration [starting with the (S)-lithium amide] as shown in (IVb). The minor diastereomer possesses the (R,R) configuration as shown in (IVc) and (S,S) configuration (IVd), respectively. The operation of the process and preparation of the novel compounds provided by our invention are further illustrated by the following examples. The identities of the products obtained were confirmed by nuclear magnetic resonance spectrometry, mass spectrometry and infra-red spectrometry. The percentages specified in the examples are by weight unless otherwise specified. EXAMPLE 1 To NaH (42.8 g of a 60% dispersion in oil, 1.07 mol) was added THF (500 mL, 10 vol) with stirring. The reaction mixture was then cooled to 0°C, and a solution of diethyl te/f-butyloxycarbonylmethylphosphonate (180.0 g, 0.7 mol) in THF (350 mL, 7 vol) was added over 0.5 hours such that the temperature was maintained below 10°O This mixture then was allowed to stir for 15 minutes and a solution of CPCA (50.0 g, 0.7 mol) dissolved in tetrahydrofuran (THF) (150 mL, 3 vol) was added over 45 minutes. During the addition of the CPCA solution the temperature of the reaction mixture never exceeded 10°C The resulting solution then was allowed to warm to room temperature, and was stirred a further 0.5 hours. Water (500 mL, 10 vol) was added whereupon the reaction mixture became clear. The THF then was removed in vacuo after which the oily residue was transferred to a separating funnel. Tertiary butyl methyl ether (TBME, 400 mL, 8 vol) was added, and the two-phase system was mixed thoroughly. The organic layer was separated and the aqueous phase was again washed with TBME (400 mL, 8 vol). The combined organic extracts were washed with brine (600 mL, 6 vol), dried over magnesium sulfate and filtered after which the solvent was removed under reduced pressure. The resulting oil then was distilled under reduced pressure (2 mbar) at 80°C (still head temperature = 66 - 68°C) through a vigreux column to give the desired α,β-unsaturated ester (91.62 g, 76% of theory) as a colourless oil. A stirring solution of jb/s-[(R,RJ-α-methylbenzyl]amine (1.61g, 7.14 mmol) in dimethoxyethane (DME, 7.5 mL, 7.5 vol) was cooled to 0°C To this solution n-BuLi (4.61 ml of a 1.6 M solution in hexanes, 7.14 mmol) was added, and stirred for 30 minutes maintaining the temperature at < 5°O The resulting heterogeneous reaction mixture then was cooled to -63°C, and a solution of the α,β-unsaturated ester from the procedure of the preceding paragraph (1.00 g, 5.95 mmol) in DME (7.5 mL, 7.5 vol) was added over 30 minutes, ensuring that the temperature of the reaction mixture did not exceed -60°C After 4 hours at this temperature the deep purple reaction mixture was warmed to -40°C, and quenched with saturated ammonium chloride solution (2 mL, 2 vol). From the now yellow solution, the DME was removed under reduced pressure to give a yellow oil to which water (10 mL, 10 vol) , and TBME (10 mL, 10 vol) was added. From a separating funnel the aqueous phase was removed, and the resulting organic layer was washed with concentrated citric acid (2 x 10 mL, 2 x 10 vol), followed by saturated sodium bicarbonate solution (10 mL, 10 vol), and finally brine (10 mL, 10 vol). The resulting organic phase then was dried (magnesium sulfate), and the TBME was removed under reduced pressure to give the desired crude Michael adduct ((Sj-configuration at the new chiral center, 1.89 g, 81% of theory) as a colourless oil. Ethanol (70 mL, 3.5 vol) was added to 5 weight percent palladium on carbon (3.0 g, 15% w/w) under nitrogen with stirring. To this ethanol/catalyst mixture was added the crude N-protected amino ester prepared according to the preceding paragraph (20.0 g, 50.9 mmol) in ethanol (80 mL, 4 vol), followed by the addition of formic acid (8.0 g, 175.0 mmol). The resulting mixture was heated to reflux for 23 hours. After cooling to room temperature, the catalyst was removed by filtration. The filtrate was concentrated in vacuo to give a colourless oil which was dissolved in TBME (100 mL, 5 vol). This solution was cooled to 0°C and 1M HCI in ether (50.9 mL, 50.9 mmol) was added drop-wise. The resulting slurry was allowed to stir for 5 minutes and then the white precipitate was filtered off, and washed with TBME (2 x 50 m, 2 x 2.5 vol). The white solid then was dried giving the HCI salt of (S)-fett-butyl 3-amino-3-cyclopropyl- propanoate (7.9 g, 70% of theory, >98% ee by GC). The HCI salt of the (S)-amino ester (3.0 g, 13.5 mmol) was dissolved in 4M HCI in dioxane (15 mL, 5 vol), and heated to 50°C with stirring for 16 hours. The dioxane was removed under reduced pressure, and acetone (30 mL, 10 vol) was added. The resulting milky slurry then was stirred vigorously for 15 minutes and then filtered. The filter cake was then washed with acetone (2 x 15 ml, 2 x 5 vol), and dried to give the HCI salt of (S)-D-CPA (2.0 g, 91% of theory) as a fine white powder.

Claims: CLAIMS We claim: 1. Process which comprises the steps of: (1) contacting cyclopropanecarboxaldehyde (CPCA) with a phosphonate having the formula: in the presence of a base and an inert solvent to obtain an α,β-unsaturated ester having the formula: (2) contacting the α,β-unsaturated ester of formula (II) with a lithium amide of formula (III): in the presence of an inert solvent to obtain an amino ester compound having the formula: and (3) contacting the amino ester compound of formula (IV) with hydrogen or hydrogen donor in the presence of a hydrogenation catalyst and an inert solvent to obtain an amino ester of the formula (V): wherein R 1 is an alkyl radical; R 2 and R 3 are independently selected from alkyl radicals; R 4 is an alkyl radical, a carbocyclic aryl radical, or an arylalkyl radical; and R 5 is a carbocyclic aryl radical. 2. Process according to Claim 1 wherein R 1 , R 2 and R 3 are independently selected from Ci - Cs alkyl. 3. Process according to Claim 2 wherein step (1) is carried out at a temperature of -25 to 50°C in the presence of a base selected from alkali metal and alkaline earth metal hydrides and alkoxides; step (2) is carried out at a temperature of -70 to -40°C; and step (3) comprises contacting the amino ester compound of formula (IV) with hydrogen or formic acid in the presence of a hydrogenation catalyst selected from nickel, palladium or platinum hydrogenation catalysts and an inert solvent selected from an alkanol containing 1 to 4 carbon atoms, water or a mixture thereof. 4. Process according to Claim 3 wherein R 4 is a carbocyclic arylalkyl radical containing 7 to 10 carbon atoms and R 5 is phenyl. 5. Process which comprises the steps of: (1) contacting cyclopropanecarboxaldehyde (CPCA) with a phosphonate having the formula: at a temperature of -10 to 20°C in the presence of sodium hydride and an inert solvent selected from ethers, hydrocarbons or mixture thereof to obtain an α,β-unsaturated ester having the formula: (2) contacting the α,β-unsaturated ester of formula (II) with a lithium amide having the formula: at a temperature of -70 to -40°C in the presence of an inert solvent selected from ethers, hydrocarbons or mixture thereof to obtain an amino ester compound having the formula: and (3) contacting the amino ester compound of formula (IV) with hydrogen or formic acid in the presence of a hydrogenation catalyst comprising 2 to 20 weight percent palladium or platinum deposited on a catalyst support material and an inert solvent selected from an alkanol containing 1 to 4 carbon atoms, water or a mixture thereof, to obtain an amino ester of the formula (V): wherein R 1 , R 2 and R 3 are independently selected from Ci - C 8 alkyl; R 4 is α-methylbenzyl, and R 5 is phenyl. 6. A compound having the formula wherein R 1 is an alkyl radical; R 4 is an alkyl radical, a carbocyclic aryl radical, or an arylalkyl radical; and R 5 is a carbocyclic aryl radical. 7. A compound according to Claim 6 wherein R 1 is Ci - C 8 alkyl; R 4 is a carbocyclic arylalkyl radical containing 7 to 10 carbon atoms; and R 5 is phenyl. 8. A compound according to Claim 7 wherein R is α-methylbenzyl. 9. Process which comprises contacting an ,β-unsatu rated ester having the formula: with a substantially enantiomerically pure lithium amide having the formula: in the presence of an inert solvent to obtain the amino ester having the formula: wherein R 1 is an alkyl radical; R 4 is an alkyl radical, a carbocyclic aryl radical, or an arylalkyl radical; and R 5 is a carbocyclic aryl radical; and amino ester (IV) comprises a mixture of diastereomers with the ratio of major to minor diastereomers of greater than 20:1. 10. Process according to Claim 9 carried out at a temperature of -70 to -40°C wherein R 1 is Ci - C 8 alkyl; R 4 is a carbocyclic arylalkyl radical containing 7 to 10 carbon atoms; R 5 is phenyl; and amino ester (IV) comprises a mixture of diastereomers with the ratio of major to minor diastereomers of greater than 97:1.

Inventors: BAYSTON DANIEL JOHN, GRIFFIN JONATHAN LUKE WILLIAM, POLYWKA MARIO EUGENIO COSIMINO, SCOTT RONALD MICHAEL, BAYSTON, DANIEL, JOHN, GRIFFIN, JONATHAN, LUKE, WILLIAM, POLYWKA, MARIO, EUGENIO, COSIMINO, SCOTT, RONALD, MICHAEL
Applicants: EASTMAN CHEM CO, EASTMAN CHEMICAL COMPANY
Application year: 2000
Main classification: C07C229
IPC codes: C07C227, C07C229