Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-03-28
2002-05-14
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C560S029000
Reexamination Certificate
active
06388134
ABSTRACT:
FIELD OF THE INVENTION
The present invention refers to novel 6-(4-phenyl-butoxy)hexylamine derivatives of the general formula (I) as well as to a process for the obtention thereof. The invention also refers to a process for the obtention of Salmeterol from said novel derivatives.
The novel 6-(4-phenylbutoxy)hexylamine derivatives are represented by the general formula (I):
wherein:
R
1
is CHO or CHOR
3
OR
4
, where R
3
and R
4
independently are C
1
-C
6
alkyl, aralkyl or they form 5 or 6 membered cyclic acetals; and
R
2
is H, benzyl or an alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or acyl group.
Said derivatives are useful as intermediates in the synthesis of Salmeterol.
BACKGROUND OF THE INVENTION
It is known the use of Salmeterol in the therapeutical field and specially for the treatment of asthma because of its properties as a bronchodilator. Several references may be found in the literature which describe processes for the obtention of Salmeterol.
Thus, Patent FR 2545482 discloses the following procedures for the obtention of Salmeterol:
By alkylation of an amine of the general formula 1 with an alkylating agent of the general formula 2:
where R
3
, R
5
and R
6
each represent a hydrogen atom or a protecting group, and L a leaving group as chlorine, bromine, iodine, mehanesufonyloxy or p-toluenesulfonyloxy and further removal of the eventually present protecting groups.
Alternatively, alkylation may be carried out by reductive amination of aldehyde 3 with amine 1 (R
3
=H or a group convertible into H under the reaction conditions).
By reduction of a compound of the general formula 4:
wherein R
5
is a hydrogen atom or a protecting group, and at least one of the X, X
1
, X
2
, X
3
and X
4
radicals is a reducible group; and further removal of the eventually present protecting groups.
Suitable reducible groups are:
X : COOH or COOR
7
(where R
7
is H, alkyl, aryl or aralkyl), and CHO.
X
1
: C═O.
X
2
: CH
2
NY (where Y is convertible into H by hydrogenation), CH═N and CONH.
X
3
: CO(CH
2
)
5
, CH═CH—(CH
2
)
4
, CH
2
CH═CH(CH
2
)
3
, etc.
X
2
—X
3
: CH
2
N═CH (CH
2
)
5
.
X
4
: CH═CH(CH
2
)
2
, CH
2
CH═CHCH
2
, etc.
By reaction of epoxide 5 or halohydrine 6 with the amine 7:
where Y
1
is H or a group convertible into hydrogen by hydrogenation; and further removal of the eventually present protecting groups.
On the other hand, Patent WO 9824753 discloses an asymmetric synthesis of amine 10 and its application to the synthesis of optically active Salmeterol.
The asymmetric addition of nitromethane to the aldehyde 8 affords the optically active nitroderivative 9, the reduction of which leads to amine 10.
where R
1
and R
2
are suitable protecting groups.
However, these procedures described in the prior art present some drawbacks. The starting compounds are highly functionalized low-molecular weight intermediates, whereby its obtention involves considerably complex reactions, specially at industrial level, mainly due to the formation of undesirable byproducts which, moreover, decrease the yield of the reaction.
Thus, for example, the obtention of said compound 1 (GB 1200886) comprises many steps, among them, a bromination reaction and a chloromethylation, with the ensuing possibility of formation of dibrominated derivatives and isomers, respectively.
On the other hand, halohydrine 6 is a very slightly stable compound and it is difficult to isolate due to its tendency to convert into epoxide 5 under basic conditions. Reactions for obtention of epoxides are neither simple, the use of epoxide 5 also presenting the additional drawback that the obtention of Salmeterol is effected by opening of the epoxide, which reaction is little advisable because of the obtention of many byproducts (Randall et al.,
Tetrahedron Letters,
(1986), 2451-2454).
The present invention provides novel 6-(4-phenylbutoxy)hexylamine derivatives which are useful as starting compounds in a new procedure of obtention of Salmeterol. Said new derivatives are easily obtained from industrially available compounds by means of simple reactions such as hydrolysis or alkylation of alcohols or amines.
DESCRIPTION OF THE INVENTION
The present invention refers to novel 6-(4-phenylbutoxy)hexylamine derivatives of the general formula (I):
wherein:
R
1
is CHO or CHOR
3
OR
4
, where R
3
and R
4
independently are C
1-C
6
alkyl, aralkyl, or they form 5 or 6 membered cyclic acetals; and
R
2
is H, benzyl or an alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or acyl group.
When R
1
is CHO, R
2
preferably is alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, or an acyl group.
Preferably, R
2
is tert-butoxycarbonyl, benzyloxycarbonyl or ethoxycarbonyl, acetyl, benzoyl or trifluoroacetyl; and R
3
and R
4
independently are methyl, ethyl, benzyl, or they form 1,2-dioxolanes or 1,3-dioxanes.
It is also an object of the present invention a process for the obtention of said 6-(4-phenylbutoxy)hexylamine derivative compounds. Said process is outlined in Scheme I below.
(R
1
═CHO, R
2
=alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, or an acyl group)
where:
R
3
and R
4
have the same meaning as described above;
Z
1
an Z
2
are each different and the same as L or NHR
2
, L being a leaving group such as chlorine, bromine, iodine, methanesufonyloxy or p-toluenesulfonyloxy, preferably bromine; and R
2
is H or benzyl.
The process of obtention of said 6-(4-phenylbutoxy)hexylamine derivatives of the general formula (I) is carried out according to the following steps:
(i) Alkylation of an amine by reaction of a compound of the formula (11) with a compound of the formula (12) to yield a compound of the formula (I), with R
1
=CHOR
3
OR
4
, R
2
=H or benzyl:
wherein:
R
3
and R
4
independently are C
1
-C
6
alkyl, aralkyl, or they form 5 or 6 membered cyclic acetals;
Z
1
and Z
2
are each different and the same as L or NHR
2
, where L is a leaving group such as chlorine, bromine, dine, methanesulfonyloxy or p-toluenesulfonyloxy; and R
2
H or benzyl;
in an inert solvent in the presence of an organic o organic base at a temperature ranging from 25° C. to 110° C., preferably from 80° C. to 100° C., to yield the compound of the general formula (I):
wherein R
1
=CHOR
3
OR
4
and R
3
=H or benzyl.
The inert solvent may be a high boiling-point aprotic solvent such as, for example, N,N-dimethylformamide, N-methylpirrolidone or dimethylsulfoxide, an halogenated solvent such as methylene chloride or chloroform, an ether such as tetrahydrofuran or dioxane, or an aromatic hydrocarbon such as benzene, toluene or xylene.
The organic base may be a tertiary amine such as, for example, triethylamine or diisopropylethylamine, an aromatic amine such as N,N-dimethylaniline, or a heterocyclic amine such as pyridine. The inorganic base may be a carbonate or a bicarbonate.
(ii) Protection of the amino group of a compound (I) obtained in step (i) with a suitable reagent, prior to hydrogenation when R
2
is benzyl, which leads to the obtention of compounds of the formula (I), with R
1
=CHOR
3
OR
4
, R
2
alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, or an acyl group.
Referring to compounds of the formula (I) (when R
1
=CHCOR
3
OR
4
, R
2
=alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, or an acyl group), R
2
, R
3
and R
4
must be chosen so that it should exist the possibility of removing R
3
and R
4
without affecting R
2
.
Protection of the amino group with the alkyloxycarbonyl, aryloxycarbonyl and aralkyloxycarbonyl residues is carried out by reaction of a compound of the formula (I), wherein R
1
=CHOR
3
OR
4
, R
2
=H, with a chloroformate such as, for example, ethyl chloroformate, tert-butyl chloroformate or benzyl chloroformate; a dicarbonate such as di-tert-butyl dicarbonate or dibenzyl dicarbonate; or specific reagents such as N-(benzyloxycarbonyl)succinimide. Protection with acyl groups is performed with conventional reagents such as acid chlorides or anhydrides.
The protecti
Barjoan Pere Dalmases
Bessa Bellmunt Jordi
Marquillas Olondriz Francisco
Barts Samuel
Steinberg & Raskin, P.C.
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