Process for preparing acylated amphetamine derivatives

1. A process for preparing a compound of Formula (IV), the process comprising:

(a) forming a reaction mixture comprising a solvent and a compound of Formula (I), the solvent being an alkyl tetrahydrofuran;

(b) adding a compound of Formula (II) to the reaction mixture, thereby forming an intermediate compound of Formula (III);

(c) phase extracting the reaction mixture after step (b) with (i) a water wash; (ii) an acid wash having a pH of <3.0, (iii) an alkaline wash having a pH of >12.0, and (iv) one or more additional water washes to remove the compounds of Formulas (I) and (II) and reaction by-products, thereby forming a purified mixture comprising the intermediate compound of Formula (III); and

(d) contacting the purified mixture comprising the intermediate compound of Formula (III) with an acid to form the compound of Formula (IV);

wherein:

R is hydrocarbyl or substituted hydrocarbyl;

LG is a leaving group chosen from N-hydroxysuccinimidyl or halo;

PG is a protecting group; and

A is an anion.

2. The process of claim 1 , wherein R is an amino acid side chain chosen from —(CH 2 ) 4 —NH 2 , —(CH 2 ) 3 —NH—C(NH)—NH 2 , —(CH 2 ) 4 —NH—C(NH)—NH 2 , —CH 2 —C(O)—NH 2 , —(CH 2 ) 2 —C(O)—NH 2 , —CH 2 —SH, —CH 2 —OH, CH(OH)—CH 3 , —CH 2 -Ph-OH, —CH2-C(O)—OH, or —(CH 2 ) 2 —C(O)—OH; and PG is tert-butyloxycarbonyl, triphenylmethyl, dimethyl-3,5-dimetheoxybenzyloxycarbonyl, 2-(4-biphenyl)isopropoxycarbonyl, 2-nitropheylsulfenyl, 2-chlorobenzyloxycarbonyl, or 4-methyltriphenymethyl.

3. The process of claim 1 , wherein the alkyl tetrahydrofuran and the compound of Formula (I) are present in the reaction mixture at a weight ratio of about 5:1 to about 15:1; steps (b) and (c) are conducted at room temperature; the acid at step (d) is methanesulfonic acid, hydrochloric acid, or oxalic acid; and step (d) is conducted at a temperature from about 40° C. to about 70° C.

4. The process of claim 1 , further comprising azeotropically drying the purified mixture comprising the intermediate compound of Formula (III) after step (c) until it has a water content of less than about 2% by weight.

5. The process of claim 1 , further comprising isolating the compound of Formula (IV) after step (d) by filtration.

6. The process of claim 5 , further comprising recrystallizing the compound of Formula (IV).

7. The process of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ia):

the compound of Formula (II) is a compound of Formula (IIa):

the intermediate compound of Formula (III) is a compound of Formula (IIIa),

and

the compound of Formula (IV) is a compound of Formula (IVa):

8. The process of claim 7 , wherein the alkyl tetrahydrofuran at step (a) is 2-methyl tetrahydrofuran.

9. The process of claim 8 , wherein 2-methyl tetrahydrofuran and the compound of Formula (Ia) are present in the reaction mixture at a weight ratio of about 6:1 to about 10:1.

10. The process of claim 9 , wherein the compound of Formula (IIa) is prepared from a salt of a compound of Formula (IIa) by contacting the salt of the compound of Formula (IIa) with an alkali metal or alkaline earth metal hydroxide, followed by one or more extractions with 2-methyl tetrahydrofuran.

11. The process of claim 7 , wherein steps (a) and (b) are conducted at room temperature; and step (d) is conducted at a temperature from about 50° C. to about 60° C.

12. The process of claim 7 , wherein step (c) comprises sequential contact with a water solution, a solution of hydrochloric acid having a pH of less than about 3, a solution of sodium hydroxide having a pH of greater than about 12, and one or more additional water solutions.

13. The process claim 7 , further comprising azeotropically drying the purified mixture comprising the intermediate compound of Formula (IIIa) after step (c) until it has a water content of less than about 1% by weight.

14. The process of claim 7 , further comprising isolating the compound of Formula (IVa) by filtration after step (d).

15. The process of claim 14 , further comprising recrystallizing the compound of Formula (IVa).

16. The process of claim 15 , wherein the recrystallizing is conducted in the presence of a mixture of isopropanol and water.

17. The process of claim 15 , further comprising washing the crystallized compound of Formula (IVa) with isopropanol.