Process for preparing substituted 3-(1-amino-2-methylpentane-3-yl)phenyl compounds

Patent metadata

Field	Value
Publication number	US-9850198-B2
Application number	US-201615157216-A
Country	US
Kind code	B2
Filing date	May 17, 2016
Priority date	Jun 15, 2010
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

Abstract

A process for the preparation of substituted 3-(1-amino-2-methylpentane-3-yl)phenyl compounds which has advantages over conventional processes with respect to higher conversions and yields, flexibility, a shorter overall route, environmentally acceptable conditions, influence of stereoselectivity such as diastereoselectivity in a targeted manner and at least partial suppression of the formation of undesired side-products and/or undesired stereoisomers, in particular undesired diastereomers.

First claim

The invention claimed is:

1. A method of preparing a compound according to formula (I)

wherein
R 1 , R 2 , and R 3 are each independently selected from H or C 1-4 aliphatic residues, or a physiologically acceptable acid addition salt thereof, said method comprising the steps of:
hydrogenating a compound according to formula (C—I)

wherein R 3 is defined above, to a compound a according to formula (C-II)

wherein R 3 is defined as above,
substituting at least one hydrogen atom of the primary amine group of the compound according to formula (C-II) with a C 1-4 aliphatic residue to form the compound according to formula (I), and
optionally converting the compound according to formula (I) into a physiologically acceptable acid addition salt thereof.

2. The method according to claim 1 , wherein said compound is in the form of an isolated stereoisomer.

3. The method according to claim 2 , wherein said compound is in the form of an isolated enantiomer or diastereomer.

4. The method according to claim 1 , wherein said compound is in the form of a mixture of stereoisomers in any mixing ratio.

5. The method according to claim 4 , wherein said compound is in the form of a racemic mixture of stereoisomers.

6. The method according to claim 1 , wherein the hydrogenation is effected by a homogeneous or heterogeneous catalyst in the presence of hydrogen.

7. The method according to claim 6 , wherein the homogenous catalyst is a transition metal complex.

8. The method according to claim 7 , wherein the transition metal complex includes rhodium, iridium or ruthenium, or rhodium with diphosphine ligands, wherein the diphosphine ligands.

9. The method according to claim 7 , wherein the homogeneous catalyst is rhodium (−)-DIPAMP [(R,R)-(+1,2-Bis[(2-methoxyphenyl)(phenyl)phosphino]ethane], rhodium (+)-DIPAMP [(S, S)-(+)-1,2-Bis[(2-methoxyphenyl(phenyl)phosphino]ethane], rhodium R-Solphos [R-(+)-N,N′-Dimethyl-7,7′-bis(diphenylphosphino)-3,3′,4,4′-tetrahydro-8,8′-bi-2H-1,4-benzoxazine ]or rhodium S-Solphos [S-(−)-N,N′-Dimethyl-7,7′-bis(diphenylphosphino)-3,3′,4,4′-tetrahydro-8,8′-bi-2H-1,4-benzoxazine].

10. The method according to claim 6 , wherein the heterogeneous catalyst is one or more transition metals, wherein the one or more transition metals is in the same or different oxidation states or in two or more different oxidation states.

11. The method according to claim 10 , wherein the heterogeneous catalyst is Raney nickel, palladium, palladium on carbon, platinum, platinum on carbon, ruthenium on carbon or rhodium on carbon.

12. The method according to claim 1 , wherein the compound according to formula (C-II) is optionally converted into a physiologically acceptable acid addition salt.

13. The method according to claim 1 , wherein the compound according to formula C-I is prepared according to the following steps:
desiylating a compound according to formula (C-0-I)

wherein R 3 is H or a C 1-4 aliphatic residue, and R a , R b , R c is C 1-8 aliphatic residue or aryl, to a compound according to formula (C-0-II)

and
dehydrating the compound according to formula (C-0-II) to the compound according to formula (I).

14. The method according to claim 13 , wherein the compound according to formula (C-0-I) and (C-0-II) are produced into the compound according to formula (I) without any isolation steps.

15. The method according to claim 13 , wherein the desilylating is acid catalyzed, acid promoted or performed in the presence of a fluoride source or optionally in the presence of a base when R a , R b , R c is each methyl.

16. The method according to claim 13 , wherein the desilylating is acid catalyzed in the presence of a catalytically effective or at least stoichiometric amount of an acid selected from formic acid, hydrochloric acid, acetic acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, phosphoric acid, or combinations thereof.

17. The method according to claim 13 , wherein the dehydrating is acid catalyzed or acid promoted in the presence of a catalytically effective or at least stoichiometric amount of an acid selected from formic acid, hydrochloric acid, acetic acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, phorphorous pentoxide, thionyl chloride, phosphoryl chloride, or combinations thereof.

18. The method according to claim 13 , wherein any one of the compounds according to formula (C-I), (C-II), (C-0I), (C-0-II), or (I), wherein R 3 is not hydrogen, undergoes deprotecting to produce a compound according to formula (Ib)

19. The method according to claim 18 , wherein the compound according to formula (C-I), (C-II), or (I) undergoes deprotecting.

20. The method according to claim 13 , wherein the compound according to formula (C-I) is produced according to the following steps:
reacting a compound according to formula (C-0-III)

wherein R 3 is a H or a C 1-4 aliphatic residue with a compound having a formula SiR a R b R c (CN), wherein R a , R b , R c are each independently selected from C 1-8 aliphatic residues or aryl, to produce a compound, according to formula (C-0-I).

21. The method according to claim 20 , wherein the compound according to formula SiR a R b R c (CN) is trimethylsilylcyanide, triethylsilylcyanide, tri-n-propylsilylcyanide or triisopropylsilylcyanide.

22. The method according to claim 1 , wherein
R 1 and R 2 of formula (I) are each selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;
R 3 of formula (I) is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

23. The method according to claim 1 , wherein R 1 and R 2 of formula (I) are each selected from H or methyl; and R 3 of formula (I) is selected from H or methyl.

Assignees

• Gruenenthal Gmbh

Inventors

• Buschmann Helmut Heinrich
• Holenz Joerg

Classifications

• C07C213/08 Primary

  by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups · CPC title

• C07C215/54

  linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring · CPC title

• C07C231/12

  by reactions not involving the formation of carboxamide groups · CPC title

• C07C217/62

  linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring · CPC title

• C07B2200/07

  Optical isomers · CPC title