Alkylation with an alkyl fluoroalkyl sulfonate

Patent metadata

Field	Value
Publication number	US-2016130280-A1
Application number	US-201414895523-A
Country	US
Kind code	A1
Filing date	Jun 18, 2014
Priority date	Jun 20, 2013
Publication date	May 12, 2016
Grant date	—

Abstract

The present invention discloses a process for preparing a chemical compound comprising reacting a nucleophile with an alkyl fluoroalkyl sulfonate in the presence of a base of formula NR1R2R3, wherein R1 and R2 are independently 2-methyipropyl or isopropyl and R3 is —CH(R4)(R5), wherein R4 and R5 are identical or different alkyls that are optionally connected to form a ring. The invention also relates to a process for preparing an alkyl fluoroalkyl sulfonate. The invention further relates to a use of the base in a chemical reaction comprising an alkyl fluoroalkyl sulfonate. The process and uses are suitable for preparing chemical compounds, reactants or intermediates thereof, and in particular for preparing API or reactants, like for example everolimus or reactants for its preparation.

First claim

1 . A process for preparing a chemical compound comprising reacting rapamycin with an alkyl fluoroalkyl sulfonate in the presence of a base, wherein the base is of formula NR1R2R3:
R1 and R2 are independently 2-methylpropyl or isopropyl; and R3 is —CH(R4)(R5), wherein R4 and R5 are identical or different alkyls that are optionally connected to form a ring.

2 . A process for preparing a chemical compound comprising reacting rapamycin with an alkyl fluoroalkyl sulfonate according to claim 1 , wherein the fluoroalkyl sulfonate part of the alkyl fluoroalkyl sulfonate comprises C1-C4 alkyl substituted by at least one fluoride, preferably the alkyl fluoroalkyl sulfonate being alkyl trifluoromethylsulfonate, alkyl trifluoroethylsulfonate or alkyl nonafluorobutylsulfonate, especially is alkyl trifluoromethanesulfonate.

3 . The process for preparing a chemical compound according to claim 1 , wherein the alkyl part of the alkyl fluoroalkyl sulfonate is substituted with a functional group, wherein the functional group is protected with a protecting group.

4 . The process of preparing a chemical compound according to claim 1 , wherein the nucleophile has a functional group —OH, —NH2 or —SH, preferably —OH.

5 . The process for preparing a chemical compound according to claim 1 , wherein the alkyl fluoroalkyl sulfonate is a compound of formula (2):

wherein
PG is protecting group; and
LG is fluoroalkyl sulfonate.

6 . The process for preparing a chemical compound according to claim 1 , wherein the fluoroalkyl sulfonate part of the alkyl fluoroalkyl sulfonate is trifluoromethylsulfonate, trifluoroethylsulfonate or nonafluorobutylsulfonate, particularly the fluoroalkyl sulfonate is trifluoromethylsulfonate.

7 . The process for preparing a chemical compound according to claim 3 , further comprising a step of removing the protecting group.

8 . A process for preparing an alkyl fluoroalkyl sulfonate by reacting an alcohol with a fluoroalkylsulfonic acid anhydride in the presence of a base, wherein the base is of formula NR1R2R3:
R1 and R2 are independently 2-methyipropyl or isopropyl; and R3 is —CH(R4)(R5), wherein R4 and R5 are identical or different alkyls that are optionally connected to form a ring.

9 . A process for preparing an alkyl fluoroalkyl sulfonate according to claim 8 , wherein a compound of formula (2) is prepared, the process comprising the step of reacting a compound of formula (3)

PG being a protecting group;
with fluoroalkylsulfonic acid anhydride, preferably with trifluoromethylsulfonic acid anhydride.

10 . The process for preparing a compound of formula (2) according to claim 9 , wherein the molar ratio of the compound of formula (3) to the base is between 0.5 and 2, preferably is between 0.80 and 1, more preferably is around 0.9.

11 . The process for preparing a compound of formula (2) according to claim 9 at a temperature between −10° C. and 25° C., preferably around 0° C.

12 . The process for preparing a compound of formula (2) according to claim 9 , wherein the solvent used for the process is an aprotic organic solvent.

13 . The process for preparing a chemical compound comprising reacting a nucleophile with an alkyl fluoroalkyl sulfonate in the presence of a base according to claim 1 , or the process for preparing an alkyl fluoroalkyl sulfonate according to any one of claims 8 to 12 , wherein the process is done in a solvent selected from a group consisting of toluene, trifluoromethyltoluene, xylenes, dichloromethane, heptane, pentane, acetonitrile and tert-butylmethyl ether, preferably the solvent is toluene.

14 . The process for preparing a chemical compound according to claim 1 , the process comprising the steps:
(a) reacting rapamycin with the compound of formula (2) in the presence of the base

wherein
PG is protecting group; and
LG is fluoroalkyl sulfonate,

(b) removing the protecting group to obtain everolimus.

15 . The process for preparing a chemical compound according to claim 14 , wherein the LG is trifluoromethylsulfonate, trifluoroethylsulfonate or nonafluorobutylsulfonate, specifically the LG is trifluoromethylsulfonate.

16 . The process for preparing a chemical compound according to claim 14 , further comprising a step of preparing the compound of formula (2).

17 . The process for preparing a chemical compound according to claim 16 , wherein the compound of formula (2) is prepared according to claim 9 .

18 . The process for preparing a chemical compound according to claim 1 at a temperature between 25° C. and 70° C., preferably between 40° C. and 50° C., particularly at 45° C.

19 . The process for preparing a chemical compound according to claim 14 , wherein rapamycin in step (a) is reacted at the temperature between 25° C. and 70° C.

20 . The process for preparing a chemical compound according to claim 1 , wherein rapamycin is reacted in an organic aprotic solvent, preferably is selected from the group consisting of toluene, trifluoromethyltoluene, xylenes, dichloromethane, heptane, pentane and mixtures thereof, particularly is toluene.

21 . The process for preparing a chemical compound according to claim 7 , wherein the protecting group is removed with an acid.

22 . The process of preparing a chemical compound according to claim 7 , wherein the protecting group is removed with an agent selected from the group consisting of HF.pyridine, ammonium fluoride, HF.triethylamine, hexafluoroisopropanol, acetic acid, trifluoroacetic acid, hydrochloric acid, and sulfuric acid.

23 . The process for preparing a chemical compound according to claim 7 , wherein the protecting group is removed in a solvent selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, acetone, heptane, methanol, acetonitrile and hexafluoroisopropanol.

24 . The process for preparing a chemical compound according to claim 7 , wherein the protecting group is removed at the temperature between −78° C. and 70° C.

25 . The process for preparing a chemical compound according to claim 3 , wherein the protecting group is selected from the group consisting of triisopropylsilyl, tert-butyldimethylsilyl, dimethyltert-hexylsilyl, tert-butyldiphenylsilyl, trityl, benzhydryl, dimethoxyltrityl and diphenylmethyl.

26 . The process according to claim 1 , wherein a solvent used in the process is selected from the group consisting of free of N,N-dimethylformamide, 1,2-diethoxyethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, Bis(2-methoxyethyl) ether and 1-methyl-2-pyrrolidine.

27 . Use of a base having formula NR1R2R3 in preparing everolimus, wherein:
R1 and R2 are independently 2-methylpropyl or isopropyl; and R3 is —CH(R4)(R5), wherein R4 and R5 are identical or different alkyls that are optionally connected to form a ring;
in a chemical reaction comprising an alkyl fluoroalkyl sulfonate.

28 . (canceled)

29 . (canceled)

30 . (canceled)

31 . (canceled)

32 . (canceled)

Assignees

• Novartis Ag

Inventors

• Acemoglu Murat
• Veitch Gemma

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• C07C303/28

  by reaction of hydroxy compounds with sulfonic acids or derivatives thereof · CPC title

• C07F7/1804

  Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896) · CPC title

• C07D498/18 Primary

  Bridged systems · CPC title