Chemical synthesis of spirocyclic piperidines by double...

Details Chemical synthesis of spirocyclic piperidines by double... Chemical synthesis of spirocyclic piperidines by double...

2001-02-27

2003-02-04

Morris, Patricia L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06515126

ABSTRACT:

The present invention relates to spirocyclic piperidine compounds and to the preparation thereof. The spirocyclic piperidine compounds of the present invention are useful as intermediates in the synthesis of therapeutic agents. In particular the spirocyclic piperidine compounds of the present invention are useful as intermediates in the synthesis of certain neurokinin-1 (NK-1) receptor antagonists.
Compounds of formula (A) below, which are described in a number of published patent specifications (WO 97/49710, WO 98/13369, WO 98/49170 and WO 98/54187), are potent and selective NK-1 receptor antagonists.
wherein
Ar represents a group selected from:
R
1
represents hydrogen, hydroxy, C
1-6
alkyl, C
2-6
alkenyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkoxy, C
1-6
alkoxyC
1-4
alkyl, C
1-6
alkoxyC
1-4
alkoxy, fluoroC
1-6
alkoxyC
1-4
alkyl, C
2-6
alkenyloxy, C
3-7
cycloalkoxy, C
3-7
cycloalkylC
1-4
alkoxy, phenoxy, benzyloxy, cyano, halogen, NR
a
R
b
, SR
a
, SOR
a
, SO
2
R
a
or OSO
2
R
a
, where R
a
and R
b
each independently represent hydrogen, C
1-4
alkyl or fluoroC
1-4
alkyl;
R
1a
represents halogen, hydroxy, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, C
1-6
alkoxyC
1-4
alkyl, fluoroC
1-6
alkyl, fluoroC
1-6
alkoxy, fluoroC
1-6
alkylthio, fluoroC
1-6
alkoxyC
1-4
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, C
2-6
alkenyloxy, cyano, phenoxy, benzyloxy, NR
a
R
b
, SR
a
, SOR
a
, SO
2
R
a
, or OSO
2
R
a
, where R
a
and R
b
each independently represent hydrogen, C
1-4
alkyl or fluoroC
1-4
alkyl;
R
2
represents hydrogen, halogen, C
1-6
alkyl or C
1-6
alkoxy;
or when R
2
is adjacent to R
1
or R
1a
, they may be joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two oxygen atoms;
R
3
represents hydrogen, halogen, C
1-6
alkyl, fluoroC
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkoxy, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, cyano, SR
a
, SOR
a
, SO
2
R
a
, NR
a
R
b
, NR
a
COR
14
, NR
a
SO
2
R
14
, or C
1-4
alkyl substituted by cyano or CO
2
R
a
where R
a
and R
b
are as previously defined;
or R
3
represents a 5- or 6-membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which group is optionally substituted by one or two groups selected from C
1-6
alkyl, C
1-6
alkoxy, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, trifluoromethyl, OCF
3
, NO
2
, CN, SR
a
, SOR
a
, SO
2
R
a
, COR
a
, CO
2
R
a
, phenyl, —(CH
2
)
r
NR
a
R
b
, —(CH
2
)
r
NR
a
COR
b
, —(CH
2
)
r
CONR
a
R
b
, or CH
2
C(O)R
a
, where R
a
and R
b
are each independently hydrogen or C
1-4
alkyl and r is zero, 1 or 2;
R
4
represents hydrogen, halogen, C
1-6
alkyl, C
1-6
alkoxy, CF
3
, OCF
3
, NO
2
, CN, SR
a
, SOR
a
, SO
2
R
a
, CO
2
R
a
, CONR
a
R
b
, C
2-6
alkenyl, C
2-6
alkynyl or C
1-4
alkyl substituted by C
1-4
alkoxy, where R
a
and R
b
are as previously defined;
R
5
represents hydrogen, halogen, C
1-6
alkyl, CF
3
or C
1-6
alkoxy substituted by C
1-4
alkoxy;
R
6
represents hydrogen, COR
a
, CO
2
R
a
, COCONR
a
R
b
, COCO
2
R
a
, C
1-6
alkyl optionally substituted by a group selected from (CO
2
R
a
, CONR
a
R
b
, hydroxy, CN, COR
a
, NR
a
R
b
, C(NOH)NR
a
R
b
, CONHphenyl(C
1-4
alkyl), COCO
2
R
a
, CONHNR
a
R
b
, C(S)NR
a
R
b
, CONR
a
C
1-6
alkylR
12
, CONR
13
C
2-6
alkenyl, CONR
13
C
2-6
alkynyl, COCONR
a
R
b
, CONR
a
C(NR
b
)NR
a
R
b
, CONR
a
heteroaryl, and phenyl optionally substituted by one, two or three substituents selected from C
1-6
alkyl, C
1-6
alkoxy, halogen and trifluoromethyl);
or R
6
represents a group of the formula —CH
2
C≡CCH
2
NR
7
R
8
where R
7
and R
8
are as defined below;
or R
6
represents C
1-6
alkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms optionally substituted by ═O or ═S and optionally substituted by a group of the formula ZNR
7
R
8
where
Z is C
1-6
alkylene or C
3-6
cycloalkyl;
R
7
is hydrogen or C
1-4
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, or C
2-4
alkyl substituted by C
1-4
alkoxy or hydroxyl;
R
8
is hydrogen or C
1-4
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, or C
2-4
alkyl substituted by C
1-4
alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R
7
, R
8
and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy or C
1-4
alkoxy optionally substituted by a C
1-4
alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)
2
or a second nitrogen atom which will be part of a NH or NR
c
moiety where R
c
is C
1-4
alkyl optionally substituted by hydroxy or C
1-4
alkoxy;
or R
7
, R
8
and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Z, R
7
and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R
9
and R
10
each independently represent hydrogen, halogen, C
1-6
alkyl, CH
2
OR
e
, oxo, CO
2
R
a
or CONR
a
R
b
where R
a
and R
b
are as previously defined and R
e
represents hydrogen, C
1-6
alkyl or phenyl;
R
12
represents OR
a
, CONR
a
R
b
or heteroaryl;
R
13
represents hydrogen or C
1-6
alkyl;
R
14
represents C
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkyl or phenyl; and
p is zero or 1;
and pharmaceutically acceptable salts thereof.
The aforementioned patent specifications describe the synthesis of compounds of formula (A) by a variety of methods. In particular, two useful intermediates are compounds of formula (B) and (C)
Synthetic routes for the preparation of these compounds are described in the following reaction schemes:
Another useful intermediate in the synthesis of compounds of formula (A) are compounds of formula (D).
Compounds of formula (D) may be prepared, for example, by conversion of a stannane of formula (C) to the corresponding iodide by treatment with iodine at reduced temperature, for example, at about −78° C., in a suitable solvent such as dichloromethane. The iodine may then be displaced to give the compound of formula (D) by treatment with, for example, &agr;,&agr;′-azo-isobutyronitrile and tributyltin hydride in a suitable solvent, for example, toluene, at an elevated temperature, for example, at about 100° C.
Alternatively, compounds of formula (D) may be prepared by the cyclisation of a compound of formula (E)
using suitable dehydrating reagents, for example, methanesulfonyl chloride or benzenesulfonyl chloride in pyridine or triethylamine in an organic solvent such as dichloromethane, or using triphenylphosphine and diethylazodicarboxylate in a suitable solvent such as tetrahydrofuran.
The preferred compounds of formula (A) are reported to have a 5R, 6S stereochemistry, for example, as shown in formula (F)
Thus, for instance, International Patent Specification No. WO 97/49710 (cross-referring also to European Patent Publication No. 0 528 495-A) describes the synthesis of (5R, 6S)-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4,5]dec-3-ene in an eight step synthesis from methyl 4-nitrobutyrate and benzaldehyde (Scheme D):
We have now found a high yielding process for the rapid, stereocontrolled synthesis of functionalised spirocyclic piperidine compounds useful as intermediates in the synthesis of compounds such as those described in the aforementioned International Patent Specifications. The process utilises a multiple ring-closing metathesis (RCM) reaction to form the spirocycle, with relative stereochemistry being directed by the choice of substituent on the nitrogen atom. The reaction occurs under mild conditions and is tolerant of a wide range of functional groups. The products are amenable to further selective transformations.
A particular advantage of the process of the present invention i

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