Stereoselective synthesis of metyrosine

1. A process for the synthesis of Metyrosine, comprising contacting a compound of Formula I:

with a compound of Formula IA

or an acid addition salt thereof,

to give a product comprising a compound of Formula II:

or an acid addition salt thereof,

wherein:

the contacting takes place in a methanol:water solution comprising about 1:2 methanol:water (vol:vol) in the presence of cyanide (CN);

the product comprising the compound of Formula II or acid addition salt thereof selectively precipitates from the methanol:water solution; and

the product comprising the compound of Formula II or acid addition salt thereof that precipitates from the methanol:water solution includes the compound of Formula II in about 80% yield and at least about 95% diastereomeric purity.

2. The process of claim 1 further comprising contacting the compound of Formula II or an acid addition salt thereof with a hydrolyzing agent selected from the group consisting of an acid, a base, a hydroperoxide, and an enzyme to provide a compound of Formula III

or an acid addition salt thereof.

3. The process of claim 2 , wherein the hydrolyzing agent is a a Bronsted acid.

4. The process of claim 2 , further comprising hydrogenolyzing the compound of Formula III or an acid addition salt thereof to provide a compound of Formula V:

or an acid addition salt thereof.

5. The process of claim 4 , further comprising contacting the compound of Formula V or an acid addition salt thereof with an acid to provide Metyrosine:

or an acid addition salt thereof.

6. A process for the synthesis of Metyrosine, comprising contacting a compound of Formula I:

with a compound of Formula IA

or an acid addition salt thereof,

to give a product comprising a compound of Formula II:

or an acid addition salt thereof,

wherein:

the contacting takes place in a methanol:water solution comprising about 1:2 methanol:water (vol:vol) in the presence of cyanide (CN − );

the product comprising the compound of Formula II or acid addition salt thereof selectively precipitates from the methanol:water solution; and

the product comprising the compound of Formula II or acid addition salt thereof that precipitates from the methanol:water solution includes the compound of Formula II in at least about 95% diastereomeric purity.

7. The process of claim 6 , wherein the product comprising the compound of Formula II or acid addition salt thereof that precipitates from the methanol:water solution includes the compound of Formula II in at least about 60% yield.

8. The process of claim 7 , wherein the product comprising the compound of Formula II or acid addition salt thereof that precipitates from the methanol:water solution includes the compound of Formula II in at least about 75% yield.