Process for making amino acid compounds

Patent metadata

Field	Value
Publication number	US-9278917-B2
Application number	US-201314401095-A
Country	US
Kind code	B2
Filing date	May 17, 2013
Priority date	May 17, 2012
Publication date	Mar 8, 2016
Grant date	Mar 8, 2016

Abstract

The invention provides new processes for making and purifying amino acid compounds, which are useful in the preparation of AKT inhibitors used in the treatment of diseases such as cancer, including the compound (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one.

First claim

I claim:

1. A process comprising reducing a compound of formula II, or a salt thereof:

wherein:
R 1 and R 2 are independently hydrogen, C 1 -C 12 alkyl or an amino protecting group to form a compound of formula I:

or a salt thereof.

2. The process of claim 1 , further comprising hydrolyzing a compound of formula III, or salt thereof:

wherein:
R 3 is optionally substituted C 1 -C 12 alkyl, to form a compound of formula II.

3. The process of claim 2 , further comprising reacting a compound of formula IV, or a salt or tautomer thereof:

with —NHR 1 R 2 or a salt thereof, to form a compound of formula III, or a salt thereof.

4. The process of claim 3 , wherein NHR 1 R 2 is —NH(isopropyl).

5. The process of claim 3 further comprising contacting a compound of formula V or a salt thereof:

with HCO 2 R 4 , wherein R 4 is optionally substituted C 1 -C 12 alkyl, or a salt thereof, under basic conditions, to form a compound of formula IV, or a salt thereof.

6. The process of claim 5 , wherein said basic conditions comprise a base selected from hydroxide or alkoxide base.

7. The process of claim 1 , wherein R 1 is an amino protecting group.

8. The process of claim 1 , wherein said amino protecting group is selected from acetyl, trifluoroacetyl, phthalimide, benzyl, triphenylmethyl, benzylidenyl, p-toluenesulfonyl, p-methoxybenzyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and carbobenzyloxy.

9. The process of claim 1 , wherein R 1 is tert-butyloxycarbonyl and R 2 is isopropyl.

10. The process of claim 1 , wherein said reducing comprises contacting a compound of formula II, or a salt thereof, with a metal catalyst and hydrogen gas.

11. The process of claim 10 , wherein said metal catalyst is a ruthenium, rhodium, or palladium catalyst.

12. The process of claim 10 , wherein said metal catalyst is [(S)—BINAPRuCl(benzene)]Cl.

13. The process of claim 1 , wherein R 2 is an amino protecting group.

14. The process of claim 1 , wherein R 2 is C 1 -C 12 alkyl.

15. The process of claim 1 , wherein R 2 is isopropyl.

16. The process of claim 1 , wherein said reducing comprises reducing a compound of formula IIb, or a salt thereof:

to form said compound of formula I or a salt thereof.

17. A compound of formula VI:

or salt thereof, wherein:
R 1 is hydrogen, acetyl, trifluoroacetyl, phthalimide, benzyl, triphenylmethyl, benzylidenyl, p-methoxybenzyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or carbobenzyloxy;
R 2 is C 1 -C 12 alkyl; and
R 5 is hydrogen or C 1 -C 12 alkyl.

18. The compound of claim 17 , wherein R 1 is hydrogen; R 2 is isopropyl; and R 5 is hydrogen or ethyl.

19. The compound of claim 17 , having the formula VIb:

or a salt thereof wherein R 1 is hydrogen or t-butyloxycarbonyl.

20. The compound of claim 17 , wherein R 1 is t-butyloxycarbonyl.

21. A compound of formula VIb:

or a salt thereof wherein R 1 is hydrogen or an amino protecting group.

Assignees

• Genentech Inc

Inventors

• Remarchuk Travis

Classifications

• C07C271/22

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• C07C229/34

  the carbon skeleton containing six-membered aromatic rings · CPC title

• C07C227/32

  by stereospecific synthesis · CPC title

• C07C67/313

  by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups · CPC title

• C07C269/04

  from amines with formation of carbamate groups · CPC title