US 6,635,784 B2 · Process for the preparation of enantiomerically-enriched cyclopropylalanine derivates

Abstract

Disclosed are processes for the preparation of enantiomerically-enriched cyclopropylalanine derivatives by the hydrogenation of certain enamides in the presence of a catalyst comprising a transition metal and a substantially enantiomerically-pure bis-phosphine catalyst and certain novel enamide ester compounds which are intermediates in the processes. The processes include novel 2-step and 3-step processes for the preparation of enantiomerically-enriched cyclopropylalanine derivatives. The two-step process comprises the steps of reacting cyclopropanecarboxaldehyde with a substituted phosphorylglycine to afford an enamide ester which then is hydrogenated in the presence of a catalyst comprising a transition metal and a substantially enantiomerically-pure bis-phosphine catalyst. The three-step process comprises the steps of forming an azlactone from an N-acylglycine and cyclopropanecarboxaldehyde, converting the azlactone to the aforesaid enamide which then is hydrogenated in the presence of a catalyst comprising a transition metal and a substantially enantiomerically-pure bis-phosphine catalyst.

Claims17

Dependent claims

A process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having the formula

which comprises contacting an enamide having the formula
with hydrogen in the presence of a catalyst system comprising a transition metal and a substantially enantiomerically-pure bis-phosphine under hydrogenation conditions of pressure and temperature;
wherein R1 is hydrogen, substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C1 to C20 alkoxy, substituted or unsubstituted C3 to C8 cycloalkyl, substituted or unsubstituted C3 to C8 cycloalkoxy, substituted or unsubstituted carbocyclic C6 to C20 aryl, substituted or unsubstituted carbocyclic C6 to C20 aryloxy, substituted or unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen or substituted or unsubstituted C4 to C20 heteroaryloxy wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
R2 is hydrogen, unsubstituted or substituted C1 to C20 alkyl, substituted or unsubstituted C3 to C8 cycloalkyl, unsubstituted or substituted carbocyclic C6 to C20 aryl, or substituted or unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
and the bis-phosphine has the formula
wherein
R5 is selected from substituted and unsubstituted, branched- and straight-chain C1 to C20 alkyl, substituted and unsubstituted C3 to C8 cycloalkyl, substituted and unsubstituted C6 to C20 carbocyclic aryl, and substituted and unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
R6, R7, R8, R9, and R10 are independently selected from hydrogen, substituted and unsubstituted, branched- and straight-chain C1 to C20 alkyl, substituted and unsubstituted C3 to C8 cycloalkyl, substituted and unsubstituted C6 to C20 carbocyclic aryl, and substituted and unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
n is 0 to 3;
m is 0 to 5;
and
M2 is selected from the metals of Groups IVB, VB, VIB, VIIB and VIII.

9 more elements

A process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having formula 4 or 5

by the steps comprising
(1) contacting cyclopropanecarboxaldehyde (CPCA) with an N-acylglycine having the formula
in the presence of a carboxylic acid anhydride and a base at elevated temperature to produce an azlactone having the formula
(2) contacting azlactone 8 with an alcohol to produce an enamide having the formula
and (3) contacting enamide 6 with hydrogen in the presence of a catalyst system comprising a transition metal and a substantially enantiomerically-pure bis-phosphine under hydrogenation conditions of pressure and temperature;
wherein
R1 is hydrogen, substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C1 to C20 alkoxy, substituted or unsubstituted C3 to C8 cycloalkyl, substituted or unsubstituted C3 to C8 cycloalkoxy, substituted or unsubstituted carbocyclic C6 to C20 aryl, substituted or unsubstituted carbocyclic C6 to C20 aryloxy, substituted or unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen or substituted or unsubstituted C4 to C20 heteroaryloxy wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
and
R2 is hydrogen, substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C3 to C8 cycloalkyl, substituted or unsubstituted carbocyclic C6 to C20 aryl, or C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen.

6 more elements

A process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having the formula

by the steps comprising
(i) contacting cyclopropanecarboxaldehyde (CPCA) with an N-acylglycine having the formula
in the presence of a carboxylic acid anhydride and a base at elevated temperature to produce an azlactone having the formula
(ii) contacting azlactone 10 with an alcohol to produce an enamide having the formula
(iii) contacting enamide 11 with an acylating agent having the formula R4O—C(O)—O—C(O)—OR4 or R4O—C(O)—X wherein X is fluorine, chlorine, bromine, or iodine in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) and an inert organic solvent to produce an amido-carbamate having formula 12
(iv) contacting amido-carbamate 12 with a nucleophile in the presence of an inert organic solvent to produce a second enamide having formula 13
and (iv) contacting enamide 13 with hydrogen in the presence of a catalyst system comprising a transition metal and a substantially enantiomerically-pure bis-phosphine under hydrogenation conditions of pressure and temperature;
wherein
R2 is hydrogen, substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C3 to C8 cycloalkyl, substituted or unsubstituted carbocyclic C6 to C20 aryl, or substituted or unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, or oxygen;
and
R3 and R4 are independently selected from substituted and unsubstituted C1 to C20 alkyl, substituted and unsubstituted C3 to C8 cycloalkyl, substituted and unsubstituted carbocyclic C6 to C20 aryl, C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen.

8 more elements

A process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having formula 4 or 5

by the steps comprising
(a) contacting cyclopropanecarboxaldehyde with a phosphonate ester having the formula 19
in an inert solvent in the presence of a base to form an enamide having formula 6
and (b) contacting enamide 6 with hydrogen in the presence of a catalyst system comprising a transition metal and a substantially enantiomerically-pure bis-phosphine under hydrogenation conditions of pressure and temperature;
wherein
R1 is hydrogen, substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C1 to C20 alkoxy, substituted or unsubstituted C3 to C8 cycloalkyl, substituted or unsubstituted C3 to C8 cycloalkoxy, substituted or unsubstituted carbocyclic C6 to C20 aryl, substituted or unsubstituted carbocyclic C6 to C20 aryloxy, substituted or unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen or substituted or unsubstituted C4 to C20 heteroaryloxy wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
R2 is hydrogen, substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C3 to C8 cycloalkyl, substituted or unsubstituted carbocyclic C6 to C20 aryl, or substituted or unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
R16 is substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C3 to C8 cycloalkyl, substituted or unsubstituted carbocyclic C6 to C20 aryl, or substituted or unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
and
and the bis-phosphine has the formula
wherein
R5 is selected from substituted and unsubstituted, branched- and straight-chain C1 to C20 alkyl, substituted and unsubstituted C3 to C8 cycloalkyl, substituted and unsubstituted C6 to C20 carbocyclic awl, and substituted and unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
R6, R7, R8, R9, and R10 are independently selected from hydrogen, substituted and unsubstituted, branched- and straight-chain C1 to C20 alkyl, substituted and unsubstituted C3 to C8 cycloalkyl, substituted and unsubstituted C6 to C20 carbocyclic aryl, and substituted and unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
n is 0 to 3
m is 0 to 5;
and
M2 is selected from the metals of Groups IVB, VB, VIB, VIIB and VIII.

14 more elements

Dependencies are inferred from the claim text.

Process for the preparation of enantiomerically-enriched cyclopropylalanine derivates

Life of this patent

Process for the preparation of enantiomerically-enriched cyclopropylalanine derivates

Life of this patent

Abstract

Claims17