Process for preparing aryl-iminomethyl-carbamino acid esters

Details Process for preparing aryl-iminomethyl-carbamino acid esters Process for preparing aryl-iminomethyl-carbamino acid esters

2001-01-09

2002-07-09

Richter, Johann (Department: 1621)

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

Organic compounds

Sulfonate esters

C560S027000

Reexamination Certificate

active

06417382

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a process for the production of compounds of general formula (I)
wherein the groups R
1
and R
2
may have the meanings given in the specification and claims.
BACKGROUND OF THE INVENTION
From International Patent Application WO 96/02497, benzamidines and aryl-iminomethylcarbamino acid esters are known which are highly effective as pharmaceutical compositions with an LTB
4
-antagonistic activity. Compounds of general formula (I) are of particular importance.
The problem of the present invention is to provide a process which can be used for industrial-scale synthesis of compounds of general formula(I) in high yields and with end products of high purity.
DETAILED DESCRIPTION OF THE INVENTION
To solve the problem mentioned above, the invention provides a process for preparing compounds of general formula (I)
wherein
R
1
denotes a group selected from among methyl, ethyl, propyl, cyclopentyl, cyclohexyl, phenyl, benzyl and —C(Me
2
)phenyl, each of which may be mono-, di- or trisubstituted by hydroxy;
R
2
denotes a group selected from among methyl, ethyl, propyl and benzyl, characterised in that a compound of general formula (II)
wherein
R
1′
denotes a group selected from among methyl, ethyl, propyl, cyclopentyl, cyclohexyl, phenyl, benzyl and —C(Me
2
)phenyl, each of which may be mono-, di- or trisubstituted by a group —O—PG, the group —O—PG denoting a protected hydroxyl function selected from among methoxymethyloxy, 2-methoxyethoxymethyloxy, 1-ethoxyethyloxy, 2-tetrahydropyranyloxy, 1-butoxyethyloxy, tert.-butyloxy, benzyloxy and 4-methoxybenzyloxy, is first reacted in an ethereal or aromatic solvent with an alkali metal hexaalkyldisilazane and is then treated with a compound of formula (III)
R
2
—O—COX′  (III)
wherein
R
2
is as hereinbefore defined and
X′ denotes chlorine, bromine or —O—R
2
, after working up using an acid of formula HY a compound of formula (IV)
wherein the groups R
1
and R
2
are as hereinbefore defined and Y denotes any desired acid group,
is isolated and from this the compound of formula (I) is liberated.
The compounds of formulae (I) and (IV) also include the corresponding tautomers of formulae (I-T) and (IV-T):
The term “alkali metal hexaalkyldisilazane” as used above and hereinafter to denote the reagent which is reacted with the compound of formula (II) generally designates a compound of formula (VIII)
wherein
Met denotes an alkali metal, preferably lithium, sodium or potassium, particularly lithium, and
R
3
independently in each case denotes a C
1-4
-alkyl group, preferably methyl or ethyl, especially methyl.
Most particularly preferred are lithium hexamethyldisilazane, sodium hexamethyldisilazane and potassium hexamethyldisilazane, particularly lithium hexamethyldisilazane.
The term “subsequent reaction” with a compound of formula (III) covers both procedures in which the product of the reaction of the compound of formula (II) with the alkali metal hexamethyldisilazane is reacted with the compound of formula (III) directly, without any further intermediate reaction, and also procedures in which the free amidine base is liberated in the mean time from the product formed. Preferably, the product of the reaction of the compound of formula (II) with the alkali metal hexamethyldisilazane is reacted with the compound of formula (III) directly, especially in a “one-pot synthesis”.
A preferred process for preparing compounds of general formula (I) is one wherein
R
1
denotes a group selected from among phenyl, benzyl and —C(Me
2
)phenyl, each of which may be mono- or disubstituted, preferably monosubstituted by hydroxy;
R
2
denotes a group selected from among ethyl, propyl and benzyl, characterised in that a compound of general formula (II)
wherein
R
1
′ denotes a group selected from among phenyl, benzyl and —C(Me
2
)phenyl, each of which may be mono- or disubstituted, preferably monosubstituted by a group —O—PG, the group —O—PG denoting a protected hydroxyl function selected from among methoxymethyloxy, 2-methoxyethoxymethyloxy, 1-ethoxyethyloxy, 2-tetrahydropyranyloxy, 1-butoxyethyloxy, tert.-butyloxy, benzyloxy and 4-methoxybenzyloxy, preferably 2-tetrahydropyranyloxy,
is first reacted in an ethereal or aromatic solvent with an alkali metal hexaalkyldisilazane and then treated with a compound of formula (III)
R
2
—O—COX′  (III)
wherein
R
2
is as hereinbefore defined and
X′ denotes chlorine, bromine or —O—R
2
,
after working up with aqueous hydrochloric acid a compound of formula (IVA)
wherein the groups R
1
and R
2
are as hereinbefore defined is isolated and from this the compound of formula (I) is liberated.
Particularly preferred is a process for preparing compounds of general formula (I) wherein
R
1
denotes —C(Me
2
)phenyl which may optionally be monosubstituted by hydroxy and
R
2
denotes ethyl,
characterised in that a compound of general formula (II)
wherein
R
1′
denotes —C(Me
2
)phenyl, which may optionally be monosubstituted by a group —O—PG, the group —O—PG denoting a protected hydroxyl function selected from among methoxymethyloxy, 2-tetrahydropyranyloxy, 1-butoxyethyloxy, tert.-butyloxy, benzyloxy and 4-methoxybenzyloxy, preferably 2-tetrahydropyranyloxy,
is first reacted in an ethereal or aromatic solvent with an alkali metal hexaalkyldisilazane and then treated with a compound of formula (III)
R
2
—O—COX′  (III)
wherein
R
2
is as hereinbefore defined and
X′ denotes chlorine, bromine or —O—R
2
, preferably chlorine, after working up with aqueous hydrochloric acid a compound of formula (IVA) wherein the groups R
1
and R
2
are as hereinbefore defined is isolated and from this the compound of formula (I) is liberated.
In a particularly preferred embodiment of the process according to the invention, the compound of formula (II) is prepared in a process comprising the following steps:
(a) reacting C
1-4
-alkyl 3-halomethylbenzoates with 4-hydroxybenzonitrile in the manner of a Wilkinson ether synthesis;
(b) reductively converting the resulting alkyl 3-(4-cyano-phenoxy)benzoates of formula (VII)
wherein R′ denotes C
1-4
-alkyl, into a compound of formula (V)
wherein X denotes hydroxy;
(c) optionally treating the compound of formula (V) wherein X denotes hydroxy with a halogenating reagent or a sulphonic acid chloride;
(d) reacting the compound of formula (V) wherein X denotes hydroxy, chlorine, bromine, mesylate, triflate or tosylate, with a phenol derivative of formula (VI)
wherein R
1′
denotes a group selected from among methyl, ethyl, propyl, cyclopentyl, cyclohexyl, phenyl, benzyl and —C(Me
2
)phenyl, each of which is optionally mono-, di- or trisubstituted by a group —O—PG, the group —O—PG denoting a protected hydroxyl function selected from among methoxymethyloxy, 2-methoxyethoxymethyloxy, 1-ethoxyethyloxy, 2-tetrahydropyranyloxy, 1-butoxyethyloxy, tert.-butyloxy, benzyloxy and 4-methoxybenzyloxy,; optionally in the form of the corresponding sodium or potassium phenoxides, under basic reaction conditions, preferably in a polar organic solvent.
The hydrochlorides of formula (IVA) are of central importance in the process according to the invention for preparing the compounds of general formula (I). They are obtained directly in high yields as readily crystallising salts, from which by-products and/or impurities can easily be removed by crystallisation. Accordingly, one aspect of the present invention relates to intermediate products of general formula (IVA)
wherein the groups R
1
and R
2
may be as hereinbefore defined.
Of the compounds of general formula (IVA) the compound ethyl{[4-(3-{4-[1-(4-hydroxy-phenyl)-1-methyl-ethyl]-phenoxymethyl}-benzyloxy)-phenyl]-imino-methyl}-carbaminate hydrochloride is particularly preferred.
The compounds of general formula (II)
wherein R
1′
may be as hereinbefore defined are obtained according to the invention by reacting a compound of formula (V)
wherein X denotes hydroxy, chlorine, bromine, mes

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