Process for the synthesis of substituted 1-benzyl-3-(1-(isoxazol-4-ylmethyl)-1h-pyrazol-4-yl)imidazolidine-2,4-diones

Patent metadata

Field	Value
Publication number	US-9936723-B2
Application number	US-201514619458-A
Country	US
Kind code	B2
Filing date	Feb 11, 2015
Priority date	Feb 12, 2014
Publication date	Apr 10, 2018
Grant date	Apr 10, 2018

Abstract

The present invention relates to processes and intermediates for the preparation of compounds of formula (I):

or a salt or oxide thereof, wherein Alk, M1, M2, R1, R2, R3, R4, R5, R6, R7, and n are as described herein. The present invention also relates to compounds of formula (I) and composition comprising a compound of formula (I). Also disclosed is a method of altering or improving the taste of a composition that includes adding to the composition at least one compound of formula (I), in an amount effective to obtain a modified composition having altered or improved taste relative to an otherwise identical composition lacking said compound.

First claim

What is claimed:

1. A process for the preparation of a compound of formula (I):

or a salt or oxide thereof,
wherein Alk is an alkyl group;
M 1 is N or CR 8 , wherein R 8 is H or substituted or unsubstituted alkyl;
M 2 is N or CR 9 , wherein R 9 is H or substituted or unsubstituted alkyl;
R 1 is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, and substituted or unsubstituted alkylaryl;
R 2 is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, and substituted or unsubstituted alkylaryl;
R 3 and R 4 are, the same or different from one another and are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroalkyl, or R 3 and R 4 , together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl group;
R 5 is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkylaryl, —OH, and —OPG;
R 6 is independently selected at each location from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkylaryl, —OH, and —OPG;
R 7 is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkylaryl, —OH, and —OPG;
or R 4 and R 7 can combine to form —(CH 2 ) m —;
PG is any protecting group;
n is 0, 1, 2, or 3; and
m is 0 or 1;
said process comprising:
treating a first intermediate compound of formula (II) wherein LG is a leaving group, and Alk, M 1 , M 2 , R 1 , and R 2 are defined supra:

under conditions effective to form the compound of formula (I).

2. The process according to claim 1 , wherein R 1 and R 2 are methyl.

3. The process according to claim 1 , wherein treating comprises:
reacting the first intermediate with a second intermediate of formula (III):

wherein R is selected from the group consisting of H, alkyl, heteroalkyl, aryl, and heteroaryl and R 3 , R 4 , R 5 , R 6 , R 7 , and n are the same as defined in claim 1 .

4. The process according to claim 3 , wherein the second intermediate has a formula (IIIa):

wherein R is selected from the group consisting of H, alkyl, heteroalkyl, aryl, and heteroaryl and R 3 , R 5 , R 6 , m, and n are the same as defined in claim 1 .

5. The process according to claim 1 further comprising:
treating a third intermediate of formula (IV) or a salt thereof of formula (V):

wherein Alk, M 1 , M 2 , R 1 , and R 2 are the same as defined in claim 1 ,
under conditions effective to form the first intermediate compound.

6. The process according to claim 1 wherein the third intermediate compound is of formula (IV):

wherein Alk, M 1 , M 2 , R 1 , and R 2 are the same as defined in claim 1 , is treated with at least one acid to form a compound of formula (V):

wherein Alk, M 1 , M 2 , R 1 , and R 2 are the same as defined in claim 1 .

7. The process according to claim 6 , wherein the acid or acids are independently selected from the group consisting of hydrochloric acid (HCl), hydrobromic acid (HBr), sulfuric acid (H 2 SO 4 ), and trifluoroacetic acid (TFA).

8. The process according to claim 5 further comprising reacting:

wherein X is selected from the group consisting of halogen and —OH and R 1 and R 2 are the same as defined in claim 1 , under conditions effective to form a fourth intermediate of formula (VI):

wherein Alk, M 1 , M 2 , R 1 , and R 2 are the same as defined in claim 1 and treating the fourth intermediate compound with at least one reducing agent under conditions effective to form the third intermediate compound.

9. The process according to claim 8 , wherein the at least one reducing agent is selected from the group consisting of hydrogen in the presence of Pd/C, Pd/C-Et 3 SiH, SnCl 2 , and Fe.

10. The process of claim 1 , wherein the compound of formula (I) is selected from the group consisting of compound of formula (Ia):

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n are the same as defined in claim 1 ,
compound of formula (Ib):

wherein R 1 , R 2 , R 3 , R 4 , R 6 , and n are the same as defined in claim 1 ,
compound of formula (Ic):

and compound of formula (Id):

wherein R 1 , R 2 , R 3 , R 5 , R 6 , m, and n are the same as defined in claim 1 .

11. The process according to claim 3 , further comprising:
providing a compound of formula (VII):

wherein R 5 , R 6 , R 7 , and n are the same as defined in claim 1 ;
providing a compound of formula (VIII):

wherein R 3 and R 4 are the same as defined in claim 1 , and R is selected from the group consisting of H, alkyl, heteroalkyl, aryl, and heteroaryl; and
reacting the compound of formula (VII) with the compound of formula (VIII) under conditions effective to form a second intermediate of said formula (III).

12. The process according to claim 11 further comprising:
reacting the compound of formula (VIIa):

wherein R 5 , R 6 , R 7 , and n are as the same as defined in claim 1 , with the proviso that one or more of the R 5 , R 6 , or R 7 is OH;
with a protecting group introducing agent (PG-Y) under conditions effective to form a compound of formula (VII).

13. The process according to claim 3 further comprising reacting the compound of formul

Assignees

• Senomyx Inc

Inventors

• Fotsing Joseph R

Classifications

• A23L27/2056

  having at least two different hetero atoms, at least one being a nitrogen atom · CPC title

• A23L27/2054 Primary

  having nitrogen as the only hetero atom · CPC title

• C07D309/12

  only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers · CPC title

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title