Processes for the preparation of peripheral opioid...

Details Processes for the preparation of peripheral opioid... Processes for the preparation of peripheral opioid...

2002-08-08

2004-09-21

Desai, Rita (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S331000, C546S236000

Reexamination Certificate

active

06794510

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel processes for the preparation of peripheral opioid antagonist compounds, as well as intermediates thereof.
BACKGROUND OF THE INVENTION
The trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines are an important class of compounds which exhibit opioid antagonist activity as a result of the 3-methyl substituent. Alvimopan (i.e., (+)-2-[(S)-benzyl-3-[4(R)-(3-hydroxyphenyl)-3(R),4-dimethylpiperidin-1-yl]propionamidolacetic acid), shown below, represents an example of this class of opioid antagonists. This compound is a peripherally-active antagonist which has a high affinity for the &mgr;-opioid receptor in the lining of the gastrointestinal tract and is useful in the treatment of gastrointestinal motility disorders. See, e.g., U.S. Pat. Nos. 5,270,328; 5,250,542; 5,159,081; and 5,434,171.
A synthesis of Alvimopan, partially outlined in
FIG. 1
, has been described in Werner et al.,
J. Org. Chem.,
1996, 61, 587. The drug product was prepared in 12 steps and 6.2% yield from 1,3-dimethyl-4-piperidone as starting material. The synthesis includes the preparation of a (3R,4R)-3,4-dimethyl-4-(3-hydroxyphenyl)-piperidine nucleus (A), which was achieved in seven steps and 14.4% overall yield. While the next step, involving the Michael addition of (A) to methyl acrylate to produce intermediate (B), proceeds in good yield (96%), alkylation of the dianion of (B) with benzyl bromide proceeds with poor diastereoselectivity (47:53 mixture of the (3R,4R,&agr;S)- and (3R,4R,&agr;R)-isomers of the alkylation products, respectively). Consequently, the diastereomers require separation by recrystallization of their hydrochloride salts from methanol, resulting in low yields of intermediate (C) (34%). The poor diastereoselectivity of the alkylation step contributes to the low overall yield for the synthesis of Alvimopan.
In view of the importance of Alvimopan and related trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine derivatives and intermediates in the treatment of gastrointestinal motility disorders and other conditions involving &mgr;-opioid receptors, improved syntheses are needed. Such improvements may include, for example, one or more of the following: enhanced diastereoselectivity of individual reaction steps, increased product yields, use of lower cost starting materials, lowered energy consumption (e.g., avoidance of reactions conducted at very high or low temperatures or pressures), reduction in the number of synthetic steps, improved scale up conditions, and the like. The methods and compositions of the present invention are directed to these, as well as other important needs.
SUMMARY OF THE INVENTION
Accordingly, the present invention is directed, in part, to novel processes for preparing Alvimopan and related trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine derivatives and intermediates thereto. Specifically, in one embodiment, there are provided processes for preparing a compound of Formula IIa, a compound of Formula IIb, or a mixture thereof:
wherein:
each R
1
is, independently, H, alkyl, aryl, aralkyl, heteroaryl, or heterocyclyl;
each R
2
is independently, H or a hydroxyl protecting group;
each R
A
is, independently, halo, alkyl, halo-substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, OR, C(O)R, C(O)OR, OC(O)R, NHC(O)R, NHSO
2
R, SO
2
NRR, aminocarbonyl, amino, nitro, cyano, or SR, wherein each R is, independently, H, alkyl, aryl, aralkyl, heteroaryl, or heterocyclyl; and
n is 0 to 5;
or a salt thereof;
comprising contacting a compound of Formula III:
with a compound of Formula IVa:
for a time and under conditions effective to provide said compound of Formula IIa, compound of Formula IIb, or mixture thereof.
Another embodiment relates to processes for preparing a compound of Formula Va, a compound of Formula Vb, or a mixture thereof:
wherein:
each R
1
is, independently, H, alkyl, aryl, aralkyl, heteroaryl, or heterocyclyl;
each R
2
is, independently, H or a hydroxyl protecting group;
each R
A
is, independently, halo, alkyl, halo-substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, OR, C(O)R, C(O)OR, OC(O)R, NHC(O)R, NHSO
2
R, SO
2
NRR, aminocarbonyl, amino, nitro, cyano, or SR, wherein each R is, independently, H, alkyl, aryl, aralkyl, heteroaryl, or heterocyclyl; and
n is 0 to 5;
or a salt thereof;
comprising providing a compound of Formula IIa, a compound of Formula IIb, or a mixture thereof:
substituting the secondary hydroxyl group of said compound of Formula IIa, said compound of Formula IIb, or said mixture thereof with hydrogen to provide the compound of Formula Va, the compound of Formula Vb, or the mixture thereof.
Still another embodiment relates to processes for preparing a compound of Formula IIc, a compound of Formula IId, or a mixture thereof:
wherein:
each R
1
is, independently, H, alkyl, aryl, aralkyl, heteroaryl, or heterocyclyl;
each R
2
is, independently, H or a hydroxyl protecting group;
each R
A
is, independently, halo, alkyl, halo-substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, OR, C(O)R, C(O)OR, OC(O)R, NHC(O)R, NHSO
2
R, SO
2
NRR, aminocarbonyl, amino, nitro, cyano, or SR, wherein each R is, independently, H, alkyl, aryl, aralkyl, heteroaryl, or heterocyclyl; and
n is 0 to 5;
or a salt thereof;
comprising contacting a compound of Formula III:
with a compound of Formula IVb:
for a time and under conditions effective to provide the compound of Formula IIc, the compound of Formula IId, or the mixture thereof.
Yet another embodiment relates to processes for preparing a compound of Formula Va, a compound of Formula Vb, or a mixture thereof:
wherein:
each R
1
is, independently, H, alkyl, aryl, aralkyl, heteroaryl, or heterocyclyl;
each R
2
is, independently, H or a hydroxyl protecting group;
each R
A
is, independently, halo, alkyl, halo-substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, OR, C(O)R, C(O)OR, OC(O)R, NHC(O)R, NHSO
2
R, SO
2
NRR, aminocarbonyl, amino, nitro, cyano, or SR, wherein each R is, independently, H, alkyl, aryl, aralkyl, heteroaryl, or heterocyclyl; and
n is 0 to 5;
or a salt thereof;
comprising providing a compound of Formula IIc, a compound of Formula IId, or a mixture thereof:
substituting the secondary hydroxyl group with hydrogen to provide the compound of Formula Va, the compound of Formula Vb, or the mixture thereof.
Another embodiment relates to processes for preparing a compound of Formula VIIa, a compound of Formula VIIb, or a mixture thereof:
wherein:
each R
1
is, independently, H, alkyl, aryl, aralkyl, heteroaryl, or heterocyclyl;
each R
2
is, independently, H or a hydroxyl protecting group;
each R
4
, R
5
, and R
N
is, independently, H, alkyl, or aralkyl;
each R
A
is, independently, halo, alkyl, halo-substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, OR, C(O)R, C(O)OR, OC(O)R, NHC(O)R, NHSO
2
R, SO
2
NRR, aminocarbonyl, amino, nitro, cyano, or SR, wherein each R is, independently, H, alkyl, aryl, aralkyl, heteroaryl, or heterocyclyl; and
n is 0 to 5;
or a salt thereof;
comprising contacting a compound of Formula III:
with a compound of Formula VIIIa:
for a time and under conditions effective to provide said compound of Formula VIIa, said compound of Formula VIIb, or said mixture thereof.
Yet another embodiment relates to processes for preparing a compound of Formula IXa, a compound of Formula IXb, or a mixture thereof:
wherein:
each R
1
is, independently, H, alkyl, aryl, aralkyl, heteroaryl, or heterocyclyl;
each R
2
is, independently, H or a hydroxyl protecting group;
each R
4
, R
5
, and R
N
is, independently, H, alkyl, or aralkyl;
each R
A
is, independently, halo, alkyl, halo-substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, OR, C(O)R, C(O)OR, OC(O)R, NHC(O)R, NHSO
2
R, SO
2
NRR, aminocarbonyl, amino, nitro, cyano, or SR, wherein each R is, independently, H, alkyl, aryl, aralkyl, heteroaryl, or heterocyclyl; and
n is 0 to 5;
or a salt thereof;
comprising providing a compound of Formula VIIa, a compound of For

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