Processes for the production of buprenorphine with reduced impurity formation

1. A process for the preparation of a compound of Formula (VII) according to the following reaction scheme:

wherein:

R is an alkyl or substituted alkyl;

R 1 is selected from the group consisting of an alkyl, a substituted alkyl, a cycloalkyl, and a substituted cycloalkyl;

R 2 and R 3 are independently selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;

R 4 and R 5 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, {—}OH, {—}NH 2 , {—}SH, {—}SR 10 , and {—}OR 10 ;

R 6 and R 7 are independently selected from the group consisting of hydrogen, a protecting group, hydrocarbyl, and substituted hydrocarbyl;

R 8 , R 9 , and R 10 are independently selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;

M is selected from the group consisting of a metal cation having a charge of +1, and a metal cation group having a charge of +2;

X is oxygen; and

X 1 is a halogen;

the process comprising:

(a) contacting a compound of Formula (I) with a dienophile in the presence of a solvent comprising water to form a compound of Formula (II);

(b) contacting the compound of Formula (II) with an aprotic solvent and a catalyst that catalyzes hydrogen addition to form a compound of Formula (III);

(c) contacting the compound of Formula (III) with R 9 MgX 1 to form the compound of Formula (IV);

(d) contacting the compound of Formula (IV) with X 1 CN to form the compound of Formula (V);

(e) contacting the compound of Formula (V) with a hydrolysis agent to form the compound of Formula (VI); and

(f) contacting the compound of Formula (VI) with MCO 3 a catalytic additive, and R 1 X 1 , the amount of alkenyl impurity in R 1 X 1 being less than 0.15% by weight, and heating the reaction mixture to a temperature of less than 60° C. to form the compound of Formula (VII).

2. The process of claim 1 , wherein R, R 6 , R 7 , R 8 and R 9 are alkyl or substituted alkyl, and R 1 is cycloalkyl or substituted cycloalkyl.

3. The process of claim 2 , wherein R 2 , R 3 , R 4 , and R 5 are hydrogen.

4. The process of claim 1 , wherein R, R 6 , R 7 and R 8 are methyl, and R 1 is methylcyclopropyl.

5. The process of claim 1 , wherein R 9 is selected from tertiary butyl, alkyl, and substituted alkyl, provided that if R 9 is alkyl or substituted alkyl then X 1 is chloride or bromide.

6. The process of claim 1 , wherein in step (a) the solvent comprises alcohol, and from about 10% to 35% (v/v) of water; the dienophile is selected from the group consisting of methyl vinyl ketone, maleic anhydride, methyl acrylate, diethyl fumarate, benzoquinone, acetylene, 4-phenyl-1,2,4-triazolin-3,4-dione, and 2-methyl-propenal; and the reaction mixture is heated to a temperature of about 50° C. to about 100° C. for a period time that is sufficient for the conversion of a substantial portion of the compound of Formula (I) to the compound of Formula (II).

7. The process of claim 6 , wherein a seed material comprising a crystalline form of the compound of Formula (II) is added to the reaction mixture as the reaction mixture is cooled to a temperature of about 5° C.; the amount of α-epimer formed at C(7) is greater than about 99.5% by weight of the amount of compound of Formula (II), and the amount of β-epimer formed at C(7) is less than about 0.50% by weight of the amount of compound of Formula (II).

8. The process of claim 1 , wherein in step (b) the aprotic solvent comprises isopropyl acetate, the catalyst is a palladium catalyst adsorbed onto a carbon support, and the hydrogenation reaction is conduced at a temperature from about 65° C. to about 85° C.

9. The process of claim 8 , further comprising removal of at least a portion of the isopropyl acetate after the hydrogenation reaction is substantially complete followed by the addition of an alkane as the hydrogenation reaction is cooled to less than 20° C.

10. The process of claim 1 , wherein step (c) further comprises a reaction product that includes the compound of Formula (IV) and an amount of the compound of Formula (III) that is unreacted.

11. The process of claim 10 , comprising:

(a) quenching the reaction product of step (c);

(b) filtering the quenched reaction product of step (a) to form a filtrate comprising an amount of the compound of Formula (III) and an amount of the compound of Formula (IV); and

(c) recycling the filtrate of step (b) by combining the filtrate with the compound of Formula (III) and R 9 MgX 1 and repeating step 1(c).

12. The process of claim 11 , wherein the molar ratio of the compound of Formula (III) to R 9 MgX 1 is from about 1:1 to about 1:5; step 1(c) is conducted at a temperature of from about 15° C. to about 100° C. and in the presence of a solvent system comprising an aprotic solvent; the reaction of step 11(b) is cooled to a temperature of less than 20° C.; step 11(c) is repeated up to four times; and repeating step 11(c) four times increases the yield of the compound of Formula (IV) by at least 20% compared to when no recycling step 11(c) is performed.

13. The process of claim 1 , wherein step (e) further comprises a reaction product that includes the compound of Formula (VI) and an amount of the compound of Formula (VIb); and isolating the compound of Formula (VIb) and contacting it with a second hydrolysis to form additional amounts of the compound of Formula (VI), the compound of Formula (VIb) corresponding to the following structure:

wherein X, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are as described in claim 1 .

14. The process of claim 13 , wherein the first and second hydrolysis agents are each a compound having a pKa of greater than about 12.0.

15. The process of claim 14 , wherein the molar ratio of the compound of Formula (VI) to the first hydrolysis agent is from about 1:9 to about 1:15; and the molar ratio of the compound of Formula (VIb) to the second hydrolysis agent is from about 1:5 to about 1:9.

16. The process of claim 15 , wherein R 6 , R 7 , R 8 and R 9 are alkyl or substituted alkyl, and R 1 is cycloalkyl or substituted cycloalkyl.

17. The process of claim 16 , wherein R 2 , R 3 , R 4 , and R 5 are hydrogen; and R 9 is tertiary butyl.

18. The process of claim 17 , further comprising contacting compound (VII) with an agent to form a salt of compound (VII).

19. The process of claim 1 , wherein the optical activity of the compound of Formula (II), (III), (IV), (V), (VI), or (VII) is selected from the group consisting of (+), (−), and combinations thereof; the configuration of each of C5 and C6 is R; and the configuration of C7, C9, C13, and C14, respectively, is selected from the group consisting of may be RRSS, RSRR, SRSS, and SSRR, provided that the C15 and the C16 carbons are both either on the alpha face or the beta face of the molecule.

20. The process of claim 1 , wherein compound (VII) is (−)-buprenorphine.