Diastereoselective synthesis of phosphate derivatives

Patent metadata

Field	Value
Publication number	US-10774104-B2
Application number	US-201616060681-A
Country	US
Kind code	B2
Filing date	Dec 9, 2016
Priority date	Dec 11, 2015
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

Disclosed is a method for the preparation of intermediates useful in the synthesis of gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate. Also disclosed is a method of preparing gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate.

First claim

The invention claimed is:

1. A process for the preparation of gemcitabine-[phenyl (benzoxy-L-alaninyl)] phosphate (Formula I) having a diastereoisomeric purity of greater than about 95%:

the process comprising steps a) to d), and optionally step e):
a) suspending or dissolving the (R)-diastereoisomer of a compound of Formula II or a mixture of the (R)- and (S)-diastereoisomers of the compound of Formula II in a solvent (S2);
b) treating the solution or suspension with a base (B2) to obtain the (S)-diastereoisomer having a diastereoisomeric purity of greater than about 95%;
c) isolating the (S)-diastereoisomer of Formula II, having a diastereoisomeric purity of greater than about 95%;
d) reacting the compound of Formula II, having a diastereoisomeric purity of greater than about 95%; wherein R 1 represents an electron withdrawing group and a is an integer from 1 to 5, with a compound of Formula III in presence of a base (B1) to provide the (S)-diastereoisomer of a compound of Formula IV having a diastereoisomeric purity of greater than about 95%; wherein P 1 , P 2 and P 3 each independently represents hydrogen or a protecting group:

and
e) where any one or more of P 1 , P 2 and P 3 are protecting groups, optionally removing the protecting groups P 1 , P 2 and P 3 from the compound of formula IV to provide gemcitabine-[phenyl (benzoxy-L-alaninyl)] phosphate having a diastereoisomeric purity of greater than about 95%.

2. The process of claim 1 , wherein P 1 is —C(O)OC 1 —C 6 -alkyl or optionally substituted —C(O)OCH 2 -aryl.

3. The process of claim 2 , wherein P 1 is —C(O)O t Bu.

4. The process of claim 3 , wherein step e) is achieved by reacting the product of step d) with a mixture of a C 1 -C 4 -alcohol and water.

5. The process of claim 1 , wherein P 2 is H.

6. The process of claim 1 , wherein P 3 is H.

7. The process of claim 1 , wherein B 1 is a Grignard reagent.

8. The process of claim 7 , wherein B 1 is t BuMgCl.

9. The process of claim 1 , wherein step d) is conducted in an ether solvent.

10. The process of claim 9 , wherein step d) is conducted in THF.

11. The process of claim 1 , wherein the compound of Formula II is a compound selected from:

and *represents chiral center.

12. The process of claim 1 , wherein the compound of formula II is:

13. The process of claim 1 , wherein the compound of formula II is:

14. A process for the diastereoisomeric enrichment of a compound of Formula II, comprising the steps of:
a) suspending or dissolving the (R)-diastereoisomer of the compound of Formula II or a mixture of the (R)- and (S)-diastereoisomers of the compound of Formula II in a solvent (S2),
b) treating the solution or suspension with a base (B2) to obtain the (S)-diastereoisomer having a diastereoisomeric purity of greater than about 95%, and
c) isolating the (S)-diastereoisomer of Formula II.

15. The process of claim 14 , further comprising
forming the compound of Formula II as a mixture of the (R)- and (S)-diastereoisomers; and
wherein step a) comprises suspending or dissolving the mixture of the (R)- and (S)-diastereoisomers of the compound of Formula II in the solvent (S2).

16. The process of claim 1 , wherein B2 is a tertiary amine.

17. The process of claim 16 , wherein B2 is triethylamine.

18. The process of claim 1 , wherein S2 is a hydrocarbon or a mixture comprising a hydrocarbon.

19. The process of claim 18 , wherein S2 is hexane or heptane.

20. The process of claim 18 wherein S2 is a mixture of hexane or heptane and a polar organic solvent, and the mixture comprising over 50% by volume hexane or heptane.

21. The process of claim 20 , wherein S2 is a mixture of heptane or hexane and ethyl acetate, and the mixture comprises over 50% by volume heptane or hexane.

22. The process of claim 1 , wherein step b) comprises stirring the mixture of the compound of formula II and the base B2 for 6 h or longer.

23. The process of claim 14 , wherein step b) comprises stirring the mixture of the compound of formula II and the base B2 at a temperature from 0 to 50° C.

24. The process of claim 14 , wherein the compound of Formula II is a compound selected from:

and * represents chiral center.

25. The process of claim 14 , wherein the compound of formula II is:

26. The process of claim 14 , wherein the compound of formula II is:

Assignees

• NuCana plc
• Laurus Labs Private Ltd

Inventors

• Kotala Mani Bushan
• Dammalapati Venkata Lakshmi Narasimha Rao

Classifications

• C07H19/10

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

• C07H1/02 Primary

  Phosphorylation · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07H19/06 Primary

  Pyrimidine radicals · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title