Process for preparation of 2-phenyl acetic acid derivatives

Details Process for preparation of 2-phenyl acetic acid derivatives Process for preparation of 2-phenyl acetic acid derivatives

2002-01-08

2003-03-11

Richter, Johann (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C562S406000, C562S496000

Reexamination Certificate

active

06531597

ABSTRACT:

FIELD OF INVENTION
The present invention is a process for the preparation of a compound of the formula
wherein
R
2a
, R
2b
are, independently selected from the group consisting of hydrogen, halogen, lower alkoxy, cyano, —COOH, lower alkoxy carbonyl, lower alkyl and lower alkyl substituted by halogen;
R
3a
, R
3b
are, independently selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl, or alternatively, R
3a
and R
3b
taken together, are —(CH
2
)
n
— wherein n=2, 3 or 5.
BRIEF SUMMARY OF THE INVENTION
The compounds of formula I are valuable intermediate products for the preparation of therapeutically active compounds of formula
wherein
R is hydrogen; lower alkyl; lower alkoxy; halogen; or trifluoromethyl;
(R
1
)
m
are, independently from each other, hydrogen or halogen; or
R and R
1
may be together —CH═CH—CH═CH—;
R
2a
, R
2b
, R
3a
, R
3b
have the meanings mentioned above;
R
4
is hydrogen; halogen; lower alkyl; lower alkoxy; —N(R
5
)
2
; —N(R
5
)S(O)
2
— lower alkyl; —N(R
5
)C(O)R
5
or a cyclic tertiary amine of the group
R
5
is, independently from each other, hydrogen; C
3-6
-cycloalkyl; benzyl; or lower alkyl;
R
6
is hydrogen; hydroxy; lower alkyl; —N(R
5
)CO— lower alkyl; hydroxy-lower alkyl; cyano; —CHO; or a 5- or 6 membered heterocyclic group, optionally bonded via an alkylene group;
Y is a single bond; —(CH
2
)
n
—; —O—; —S—; —SO
2
—; —C(O)—; or —N(R
5
)—;
X is ═N—; —CH═; or —C(Cl)═;
W is —CH═; or ═N—;
m is 0,1,2,3 or 4.
Examples of compounds of formula II can be found among the 4-phenyl-pyridine derivatives such as 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide and among the 4-phenyl pyrimidin derivatives such as 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-4-o-tolyloxy-pyrimidin-5-yl)-isobutyramide. It has been surprisingly found that the compounds of formula II are antagonists of the neurokinin-1 (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors.
Compounds of formula II are described e.g. in EP-A-1035115 and WO 00/50398.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term “lower alkyl” denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1 to 4 carbon atoms. A preferred “lower alkyl substituted by halogen” is trifluoromethyl.
The term “lower alkoxy” denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom.
The term “halogen” denotes chlorine, iodine, fluorine and bromine.
The term “cycloalkyl” denotes a saturated carbocyclic group, containing 3-7 carbon atoms.
The term “cyclic tertiary amine” denotes, for example, pyrrol-1-yl, imidazol-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, 1-oxo-thiomorpholin-4-yl or 1,1-dioxo-thiomorpholin-4-yl.
The term “5 or 6 membered heterocyclic group” denotes, for example pyridinyl, pyrimidinyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, piperazinyl or piperidyl.
The term “aryl” denotes 5 or 6 membered carbocyclic aromatic compounds or condensed carbocyclic aromatic compounds such as phenyl and naphthyl.
The compounds of formula II can be manufactured according to e.g. WO 00/50398, i.e. by converting a compound of formula
into the corresponding chloro or bromo acid halide, and by reacting the obtained halide with a compound of formula
to a compound of formula II, wherein the definition of the substituents is given above.
Compounds of general formula I can be manufactured, on their turn, by successively alkylating (twice) a compound of formula
with an R
3a
-halide (in the presence of a strong base such as BuLi) to a compound of general formula
and I, respectively.
This method for manufacturing the compounds of general formula I is high-yielding but requires the use of the expensive starting materials of formula IV. Furthermore, the dialkylated product of general formula I may contain rather high quantities of the mono alkylated intermediate V and/or of over alkylated compounds, e.g. at the benzene ring. These by-products are quite difficult to remove by crystallization and their concentration in the final product mixture strongly varies in accordance with the reaction conditions. Consequently the above process is unsuitable for scale-up.
Alternatively, the acid of formula IV can be converted into the corresponding ester of formula
wherein R
2a
, R
2b
, R
3a
, R
3b
have the significance given above and R
7
is lower alkyl. The ester of formula VI is then dialkylated and subsequently saponified (or hydrolyzed) to the compound of formula I.
The second variant of the state-of-the-art method allows to overcome the above purification problem, but it involves an additional esterification/saponification (hydrolysis) step, thus still increasing the costs and complexity of the whole manufacturing process.
The problem at the root of the present invention is therefore to provide a process for preparing the compounds of formula I which can overcome the disadvantages mentioned above.
This problem is solved, according to the invention, by a process for preparing the compounds of formula I comprising the steps of:
reacting a Grignard derivative of a compound of formula
 wherein X is Cl, Br or I, with a compound of formula
 to a compound of formula
 carbonylating the compound of formula IX in the presence of a strong acid, wherein the compound of formula I is obtained.
The process according to the present invention allows to obtain yields which are higher than those provided by the above described conventional process, no major side-products are observed and no complex purification operations are necessary.
Furthermore, the reactants used (formulae VII and VIII) are much cheaper than those applied in the above conventional processes (compounds of formula IV) and are easily available on the market, so that the overall manufacturing costs of compounds of formula I, and therefore also of compounds of formula II, are strongly decreased.
The process according to the present invention is therefore suitable for the scale-up production of the compounds of formula II.
According to a preferred embodiment of the present invention R
2a
, R
2b
are, independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkyl substituted by halogen, lower alkoxy, or cyano, and R
3a
, R
3b
are independently selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl or, alternatively, R
3a
and R
3b
taken together form —(CH
2
)
n
— with n=2,3 or 5.
According to another preferred embodiment of the present invention, R
2a
and R
2b
are independently selected from the group consisting of lower alkoxy; lower alkoxy carbonyl; lower alkyl and lower alkyl substituted by halogen; and R
3a
and R
3b
are independently lower alkyl or, alternatively, R
3a
and R
3b
taken together form —(CH
2
)
5
—.
According to a still more preferred embodiment of the invention, the process is applied for the manufacture of 2-(3,5-bis-trifluoromethyphenyl)-2-methyl-propionic acid.
The Grignard reaction (step a) takes place in an ether, such as diethyl ether, tetrahydrofuran, dipropyl ether, dibutyl ether and the like, or in a mixture of ethers and aromatic solvents such as toluene and xylene. The reaction is carried out at atmospheric pressure and at a temperature varying between about 15° C. and the boiling point o

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