Process for the preparation of gemcitabine-[phenyl(benzoxy-L-alaninyl)] phosphate

Patent metadata

Field	Value
Publication number	US-9834577-B2
Application number	US-201515411409-A
Country	US
Kind code	B2
Filing date	Jul 22, 2015
Priority date	Jul 22, 2014
Publication date	Dec 5, 2017
Grant date	Dec 5, 2017

Abstract

The present invention provides a process for the preparation of gemcitabine-[phenyl(benzoxy-L-alaninyl)] phosphate of Formula I in high yield and purity.

First claim

The invention claimed is:

1. A process for the preparation of gemcitabine-[phenyl(benzoxy-L-alaninyl)]phosphate of Formula I,

the process comprising:
a) reacting protected gemcitabine derivative of Formula IV

wherein
P 1 is a hydroxy protecting group independently selected from the group consisting of optionally substituted —Si(C 1-6 alkyl) 3 , optionally substituted —C(O)—C 1 -C 6 -alkyl, optionally substituted —C(O)-aryl, optionally substituted —C(O)—OC 1 -C 6 -alkyl, —C(O)—O-allyl, —C(O)—O—CH 2 -fluorenyl, optionally substituted —CH(aryl) 3 , optionally substituted —(C 1 -C 3 -alkylene)-aryl, optionally substituted —C(O)OCH 2 -aryl, and —C 1 -C 4 -alkyl-O—C 1 -C 4 -alkyl;
P 2 represents an amine protecting group independently selected from the group consisting of —C(O)OC 1 -C 6 -alkyl, optionally substituted —C(O)OCH 2 -aryl, —C(O)—O-allyl, —C(O)—O—CH 2 -fluorenyl, optionally substituted —CH(aryl) 3 , optionally substituted —(C 1 -C 3 -alkylene)-aryl, optionally substituted —C(O)—C 1 -C 6 -alkyl, optionally substituted —C(O)-aryl, —S(O) 2 —C 1 -C 6 -alkyl, optionally substituted —S(O) 2 -aryl, and optionally substituted —Si(C 1-6 alkyl) 3 ; and
P 3 represents a hydrogen or an amine protecting group independently selected from the group consisting of —C(O)OC 1 -C 6 -alkyl, optionally substituted —C(O)OCH 2 -aryl, —C(O)—O-allyl, —C(O)—O—CH 2 -fluorenyl, optionally substituted —CH(aryl) 3 , optionally substituted —(C 1 -C 3 -alkylene)-aryl, optionally substituted —C(O)—C 1 -C 6 -alkyl, optionally substituted —C(O)-aryl, —S(O) 2 —C 1 -C 6 -alkyl, optionally substituted —S(O) 2 -aryl, and optionally substituted —Si(C 1-6 alkyl) 3 ;
with ProTide intermediate of Formula III, wherein “X” is a leaving group,

to obtain protected phosphoramidate of Formula II

b) deprotecting the protected phosphoramidate of Formula II to obtain gemcitabine-[phenyl(benzoxy-L-alaninyl)]phosphate by exposing the phosphoramidate of Formula II to a reagent selected from the group consisting of a Bronsted acid; a Lewis acid; a base; a fluorine source; H 2 and a catalyst an oxidizing agent (PPh 3 ) 4 Pd; and piperidine.

2. The process of claim 1 , wherein X is selected from the group consisting of Cl, Br, I, tosylate, mesylate, trifluoroacetate, triflurosulfonate.

3. The process of claim 1 , wherein step a) is conducted in the presence of a base.

4. The process of claim 3 , wherein the base is tBuMgCl.

5. A process for the preparation of gemcitabine-[phenyl(benzoxy-L-alaninyl)]phosphate of Formula I,

comprising:
a) deprotecting a protected phosphoramidate of Formula II to obtain gemcitabine-[phenyl(benzoxy-L-alaninyl)]phosphate of Formula I by exposing the phosphoramidate of Formula II to a reagent selected from the group consisting of a Bronsted acid; a Lewis acid; a base; a fluorine source; H 2 and a catalyst an oxidizing agent (PPh 3 ) 4 Pd; and piperidine;

wherein
P 1 is a hydroxy protecting group independently selected from the group consisting of optionally substituted —Si(C 1-6 alkyl) 3 , optionally substituted —C(O)—C 1 -C 6 -alkyl, optionally substituted —C(O)-aryl, optionally substituted —C(O)—OC 1 -C 6 -alkyl, —C(O)—O-allyl, —C(O)—O—CH 2 -fluorenyl, optionally substituted —CH(aryl) 3 optionally substituted —(C 1 -C 3 -alkylene)-aryl, optionally substituted —C(O)OCH 2 -aryl, and —C 1 -C 4 -alkyl-O—C 1 -C 4 -alkyl;
P 2 represents an amine protecting group independently selected from the group consisting of —C(O)OC 1 -C 6 -alkyl, optionally substituted —C(O)OCH 2 -aryl, —C(O)—O-allyl, —C(O)—O—CH 2 -fluorenyl, optionally substituted —CH(aryl) 3 , optionally substituted —(C 1 -C 3 -alkylene)-aryl, optionally substituted —C(O)—C 1 -C 6 -alkyl, optionally substituted —C(O)-aryl, —S(O) 2 —C 1 -C 6 -alkyl, optionally substituted —S(O) 2 -aryl, and optionally substituted —Si(C 1-6 alkyl) 3 ; and
P 3 represents a hydrogen or an amine protecting group independently selected from the group consisting of —C(O)OC 1 -C 6 -alkyl, optionally substituted —C(O)OCH 2 -aryl, —C(O)—O-allyl, —C(O)—O—CH 2 -fluorenyl, optionally substituted —CH(aryl) 3 optionally substituted —(C 1 -C 3 -alkylene)-aryl, optionally substituted —C(O)—C 1 -C 6 -alkyl, optionally substituted —C(O)-aryl, —S(O) 2 —C 1 -C 6 -alkyl, optionally substituted —S(O) 2 -aryl, and optionally substituted —Si(C 1-6 alkyl) 3 .

6. The process of claim 5 , wherein P 1 is independently selected from the group consisting of optionally substituted —Si(C 1-6 alkyl) 3 , optionally substituted —C(O)—OC 1 -C 6 -alkyl, optionally substituted —C(O)OCH 2 -aryl, and —C(O)—O-allyl.

7. The process of claim 5 , wherein P 1 is C(O)—O-tBu.

8. The process of claim 5 , wherein P 2 is independently selected from the group consisting of —C(O)OC 1 -C 6 -alkyl, optionally substituted —C(O)OCH 2 -aryl, —C(O)—O-allyl, optionally substituted —CH(aryl) 3 , and optionally substituted —Si(C 1-6 alkyl) 3 .

9. The process of claim 5 , wherein P 2 is C(O)—O-tBu.

10. The process of claim 5 , wherein P 3 is H.

11. The process of claim 7 , wherein the deprotection step is conducted using a Bronsted acid.

12. The process of claim 11 , wherein the Bronsted acid is TFA.

13. A compound of formula II

wherein
P 1 is a hydroxy protecting group independently selected from the group consisting of optionally substituted —Si(C 1-6 alkyl) 3 , optionally substituted —C(O)—C 1 -C 6 -alkyl, optionally substituted —C(O)-aryl, optionally substituted —C(O)—OC 1 -C 6 -alkyl, —C(O)—O-allyl, —C(O)—O—CH 2 -fluorenyl, optionally substituted —CH(aryl) 3 , optionally substituted —(C 1 -C 3 -alkylene)-aryl, optionally substituted —C(O)OCH 2 -aryl, and —C 1 -C 4 -alkyl-O—C 1 -C 4 -alkyl;
P 2 represents an amine protecting group independently selected from the group consisting of —C(O)OC 1 -C6-alkyl, optionally substituted —C(O)OCH 2 -aryl, —C(O)—O-allyl, —C(O)—O—CH 2 -fluorenyl, optionally substituted —CH(aryl) 3 , optionally substituted —(C 1 -C 3 -alkylene)-aryl, optionally substituted —C(O)—C 1 -C 6 -alkyl, optionally substituted —C(O)-aryl, —S(O) 2 —C 1 -C 6 -alkyl, optionally substituted —S(O) 2 -aryl, and optionally substituted —Si(C 1-6 alkyl) 3 ; and
P 3 represents a hydrogen or an amine protecting group independently selected from the group consisting of —C(O)OC 1 -C 6 -alkyl, optionally substituted —C(O)OCH 2 -aryl, —C(O)—O-allyl, —C(O)—O—CH 2 -fluorenyl, optionally substituted —CH(aryl) 3 optionally substituted —(C 1 -C 3 -alkylene)-aryl, optionally substituted —C(O)—C 1 -C 6 -alkyl, optionally substituted —C(O)-aryl, —S(O) 2 —C 1 -C 6 -alkyl, optionally substituted —S(O) 2 -aryl, and optionally substituted —Si(C 1-6 alkyl) 3 .

14. The process of claim 9 , wherein the deprotection step is conducted using a Bronsted acid.

15. The process of claim 14 , wherein the Bronsted acid is TFA.

16. The process of claim 1 , wherein P 1 is C(O)—O-tBu.

Assignees

• Nucana Biomed Ltd
• Laurus Labs Private Ltd
• Laurus Labs Ltd

Inventors

• Dammalapati Venkata Lakshmi Narasimha Rao
• Kotala Mani Bushan
• Madhavaram Shankar

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07H19/10 Primary

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07H1/02

  Phosphorylation · CPC title