Synthesis of intermediates useful in preparing tricyclic...

Details Synthesis of intermediates useful in preparing tricyclic... Synthesis of intermediates useful in preparing tricyclic...

2002-06-18

2004-06-15

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S079000

Reexamination Certificate

active

06750347

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention provides an improved process for preparing intermediates useful in the preparation of tricyclic compounds that are antihistamines. In particular, the compounds of this invention are useful in the preparation of antihistamines such as those disclosed in U.S. Pat. Nos. 4,282,233 and 5,151,423, especially loratadine and azatadine.
PCT Publication No. WO98/42676, published Oct. 1, 1998, discloses the following process for preparing tricyclic intermediates:
wherein R, R
1
, R
2
, R
3
and R
4
are independently selected from hydrogen or halo, R
5
and R
6
are independently selected from hydrogen, alkyl, aryl or heteroaryl, wherein R
5
and R
6
are not both hydrogen, and R
7
is Cl or Br. This process has some undesirable aspects, including the fact that carbon monoxide, a poisonous gas, must be used under high pressure to prepare the amide compound 2, and the fact that an expensive palladium catalyst must be used. The present invention provides an efficient process for preparing the tricyclic ketone that avoids these undesirable aspects.
SUMMARY OF THE INVENTION
This invention provides a process for preparing a compound having the formula
comprising:
(a) reacting a compound having the formula
 with an isocyanate having the formula R
1
NCO to produce a compound having the formula
(b) optionally hydrolyzing the compound of formula (III) to form an amide having the formula
(c) reacting the compound of formula (III) or the amide of formula (IV) with a compound having the formula
 in the presence of a strong base to produce a compound having the formula
(d) cyclizing the compound of formula (VI) to obtain the compound of formula (I),
wherein R is H or Cl; M is selected from the group consisting of Li, Na, K, MgX, ZnR
A
, and Al(R
A
)
2
; R
A
is alkyl; X is halo; R
1
is selected from the group consisting of alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl; and L is a leaving group.
This invention further provides a process for preparing a compound having the formula
comprising reacting a compound having the formula
with CO
2
and a protonating agent to obtain the compound of formula (VIII), wherein M is selected from the group consisting of Li, Na, K, MgX, ZnR
A
, and Al(R
A
)
2
, wherein R
A
is alkyl and X is halo.
DETAILED DESCRIPTION
As used herein, the term “alkyl” means straight or branched hydrocarbon chains of 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, optionally substituted by one or more substituents selected from C
1
to C
6
alkoxy, halo, or CF
3
.
“Alkoxy” means a group having the formula —O-alkyl.
“Halo” refers to fluorine, chlorine, bromine or iodine radicals.
“Aryl” means phenyl or a polyaromatic ring (e.g., napthyl) optionally substituted by one or more substituents selected from the group consisting of C
1
to C
6
alkyl, C
1
to C
6
alkoxy, halo, or CF
3
.
“Aralkyl” means a group having the formula —R-aryl, wherein R is alkyl;
“Heteroaryl” means a 5- or 6-membered aromatic ring having one or two nitrogen atoms (e.g., pyridyl, pyrimidyl, imidazolyl or pyrrolyl), optionally substituted by one or more substituents selected from the group consisting of C
1
to C
6
alkyl, C
1
to C
6
alkoxy, halo, or CF
3
;
“Heteroaralkyl” means a group having the formula —R-heteroaryl, wherein R is alkyl;
“Cycloalkyl” means a non-aromatic carbocyclic ring of from 3 to 6 carbon atoms, optionally substituted by one or more substituents selected from the group consisting of C
1
to C
6
alkyl, C
1
to C
6
alkoxy, halo, or CF
3
;
“Cycloalkylalkyl” means a group having the formula —R-cycloalkyl, wherein R is alkyl;
“Heterocycloalkyl” means a 3 to 6 membered non-aromatic ring having from 1 to 3 heteroatoms selected from O, S and N, wherein the remaining members of the ring are carbon atoms, optionally substituted by one or more substituents selected from the group consisting of C
1
to C
6
alkyl, C
1
to C
6
alkoxy, halo, or CF
3
;
“Heterocycloalkylalkyl” means a group having the formula —R-heterocycloalkyl, wherein R is alkyl.
R is preferably Cl.
M is preferably selected from Li, Na, K, and MgX.
R
1
is preferably alkyl or aryl. R
1
is most preferably t-butyl, phenyl or 4-chlorophenyl.
Examples of suitable leaving groups, L, include, but are not limited to Cl, Br, I, alkyl sulfonates, aryl sulfonates, dialkyl phosphates, diaryl phosphates and R
B
OC(O)O—, wherein R
B
is alkyl or aryl. L is preferably selected from Cl, Br, mesylate, tosylate, brosylate, triflate, and —OP(OC
2
H
5
)
2
.
Certain substituents, solvents and reagents are referred to herein by the following abbreviations: lithium dilsopropylamide (LDA); n-butyl lithium (n-BuLi); tetrahydrofuran (THF); and phenyl (Ph).
The compounds of formula (I) prepared by the present process are useful as intermediates in the procedures described in U.S. Pat. No. 5,151,423 to obtain the desired compounds wherein the piperidinyl ring is N-substituted. Using those procedures, the compounds of formula (I) may be reacted with a substituted piperidine of the formula
wherein L
1
is Cl or Br, to obtain a compound of the formula
This compound is converted to the corresponding piperidylidene, the nitrogen is deprotected, and the compound is reduced to the piperidyl form. The piperidinyl nitrogen can then be reacted with a variety of compounds, e.g., an acyl compound such as an ester or acyl chloride to form the desired amide.
The compound of formula (VIII) produced in accordance with our invention can be used to prepare the amide of formula (IV) by reacting it with an organic base, e.g., triethylamine, followed by an acid chloride, e.g., pivaloyl chloride or a chloroformate, e.g., C
2
H
5
OCOCl in a suitable solvent such as dichloromethane at a temperature of about −30° C. to 0° C. to give a mixed anhydride, and reacting the mixed ahydride with an amine of the formula NH
2
R
1
at a temperature of −30° C. to 0° C. to form the amide of formula (IV).
Those skilled in the art will recognize that the compound represented by formula (III) exhibits resonance as shown below:
As used herein, the compound of formula (III) is intended to represent both of these resonance structures, as well as the resonance hybrid of these structures.
The starting compounds of formula (II) are either known in the art, or can be readily prepared by one skilled in the art, using conventional methods. Preferably, the starting compounds of formula (II) are prepared in situ from a 2-halo 3-methyl pyridine, e.g., 2-bromo 3-methyl pyridine. For example, when M is Li, Na, or K, the compound of formula (II) can be prepared by reacting 2-bromo 3-methyl pyridine with an alkyl or aryl lithium, sodium or potassium compound, preferably an n-butyl lithium, sodium or potassium. When M is MgX, the compound of formula (II) can be prepared by reacting 2-bromo 3-methyl pyridine with an alkyl or aryl Grignard. When M is ZnR
A
or Al(R
A
)
2
, the compound of formula (II) can be prepared by reacting 2-bromo 3-methyl pyridine with Zn(R
A
)
2
or Al(R
A
)
3
.
In step (a) of the present process, the compound of formula (II) is reacted with an isocyanate having the formula R
1
NCO to produce the compound of formula (III). Preferably, the amount of isocyanate used in step (a) is 1.0 to 2.0 equivalents, more preferably, 1.0 to 1.5 equivalents, most preferably 1.0 to 1.1 equivalents. The reaction of step (a) is preferably carried out in an organic solvent, more preferably an aprotic organic solvent. Examples of suitable solvents, include, but are not limited to THF, ethylene glycol dimethyl ether, diethyl ether, methyl t-butyl ether, N,N, N′,N′-tetramethylethylenediamine, and mixtures thereof. THF, N,N, N′,N′-tetramethylethylenediamine, and mixtures of THF and ethylene glycol dimethyl ether are particularly preferred. Step (a) is preferably carried out at a temperature of −110 to −40° C., more preferably −90 to −60° C., most preferably −80 to −70° C.
Optionally, the compound of for

Affiliated with

Also associated with

Rating

Synthesis of intermediates useful in preparing tricyclic... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Synthesis of intermediates useful in preparing tricyclic..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Synthesis of intermediates useful in preparing tricyclic... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3306549