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US 2004/0006224 A1Published application
Synthesis of 2-alkyl amino acids
AssigneeGenzyme Corporation
InventorsMukund S. Chorghade, Mukund K. Gurjar, Bhanu M. Chanda
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Abstract
A method of preparing a 2-alkyl amino acid involves the aziridination of an alkylacrylate and the opening of the aziridine ring by addition of a side chain. This method can result in the preparation of enantiomeric excess of a 2-alkyl amino acid. The invention also discloses a method of preparing a class of iron chelating agents related to desferrithiocin, all of which contain a thiazoline ring. In this method, an aryl nitrile or imidate is condensed with cysteine, a 2-alkyl cysteine, or a cysteine ester.
Claims37
A method of preparing a compound represented by Structural Formula (I):
- 25
- or a salt thereof;
- wherein:
- R1 and R2 are, independently, —H or a substituted or unsubstituted alkyl group;
- R3 is —H, —(CH2)xS(CH2)yH, —(CH2)xO(CH2)yH, —(CH2)xNH(CH2)yH, —COOH, —CONH2, —NHC(NH)NH2, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloaliphatic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, wherein R3 optionally comprises a protecting group;
- x is an integer from 0-12;
- and
- y is an integer from 0-4;
- comprising the steps of:
- a.) reacting the compound represented by Structural Formula (III):
- 26
- wherein:
- L is a bond, a sulfoxide (—S(O)—), or a sulfone (—S(O)(O)—);
- and
- R4 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group;
- with a nucleophile of the formula A-R3, wherein A is —H, —Li, —MgCl, —MgBr, or —MgI, provided that A and R3 are not each —H, and R3 is as defined above;
- thereby forming a compound represented by Structural Formula (IV):
- 27
- b.) cleaving L-R4 and optionally the protecting group of R3 from the compound represented by Structural Formula (IV), thereby forming the compound represented by Structural Formula (I).
16 more elements
The method of claim 35, wherein the source of nitrogen is represented by Structural Formula (V):
- 28
- wherein M is an alkali metal, X is a halide, and R5 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group.
The method of claim 35, wherein the R1 and R2 are each methyl.
A method of preparing a compound represented by Structural Formula (VI):
- 32
- or a salt thereof;
- wherein:
- R6 and R7 are, independently, —H or a substituted or unsubstituted alkyl group;
- comprising the steps of:
- a.) aziridinating a compound represented by Structural Formula (VII):
- 33
- by reacting said compound with a source of nitrogen and an aziridination catalyst, thereby forming a compound represented by Structural Formula (VIII):
- 34
- wherein:
- L is a bond, sulfoxide (—S(O)—), or sulfone (—S(O)(O)—);
- R9 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group;
- and
- R6 and R7 are as defined above;
- b.) reacting the compound represented by Structural Formula (VIII) with a nucleophile, A-S-Z, wherein A is —H;
- and Z is —H or a protecting group;
- thereby forming a compound represented by Structural Formula (IX):
- 35
- c.) cleaving Z and L-R9 from the compound represented by Structural Formula (IX), thereby forming the compound represented by Structural Formula (VI).
16 more elements
A method of preparing a compound represented by Structural Formula (XI):
- 37
- or a salt thereof;
- wherein:
- R11 and R12 are, independently, —H or a substituted or unsubstituted alkyl group;
- R13 is —H, —(CH2)xSH, —(CH2)xOH, —(CH2)xNH2, —COOH, —CONH2, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group;
- and
- x is an integer from 0-12;
- comprising the steps of:
- a.) aziridinating a compound represented by Structural Formula (XII):
- 38
- by reacting said compound with a source of nitrogen and a stereospecifie aziridination catalyst, thereby forming a compound represented by Structural Formula (XIII):
- 39
- wherein:
- L is a bond, sulfoxide (—S(O)—), or sulfone (—S(O)(O)—);
- R14 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group;
- and
- R11 and R12 are as defined above;
- b.) reacting the compound represented by Structural Formula (XIII) with a nucleophile, A-R13, wherein A is —H, —Li, —MgCl, —MgBr, or —MgI, provided that A and R13 are not each —H;
- and R13 is as defined above;
- thereby forming a compound represented by Structural Formula (XIV):
- 40
- c.) cleaving L-R14 and optionally the protecting group of R13 from the compound represented by Structural Formula (XIV), thereby forming the compound represented by Structural Formula (XI).
19 more elements
A method of preparing a compound represented by Structural Formula (XVI):
- 42
- comprising the steps of:
- a) reacting the compound represented by Structural Formula (XVIII):
- 43
- wherein:
- L is a bond, sulfoxide (—S(O)—), or sulfone (—S(O)(O)—);
- and
- R17 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group;
- with a nucleophile, A-S-Z, wherein A is —H;
- and Z is —H or a protecting group;
- thereby forming a compound represented by Structural Formula (XIX):
- 44
- (XIX);
- and
- b) cleaving R16, Z, and L-R17 from the compound represented by Structural Formula (XIX), thereby forming 2-methylcysteine or a salt thereof;
- c) resolving the enantiomers of 2-methylcysteine or salts thereof;
- d) isolating (S)-2-methylcysteine or a salt thereof, and neutralizing the salt, if present;
- and
- e) coupling (S)-2-methylcysteine with 2,4-dihydroxybenzonitrile, thereby forming the compound represented by Structural Formula (XVI).
16 more elements
Dependencies are inferred from the claim text.