149541-62-8

This report discloses an industrially feasible and cost efficient process for the preparation of the compound [(3R, 4R)-3-(3,4-dimethyl-4-piperidinyl)- phenol] (1), which is used as the key intermediate for preparation of the opioid drug Alvimopan. The overall yield in this process is increased from 15 to 30%, mainly due to the improvement in yield from 26 to 53% for intermediate 7.

Isolation of all possible diastereomers of alvimopan 1 was found to be challenging. In order to perform cut off studies during analytical method development, it was mandatory to synthesize and characterize all the diastereomeric impurities. Here in, our efforts toward the synthesis and isolation of alvimopan (1) diastereomers are discussed.

Compositions containing opioid antagonists are disclosed, particularly alvimopan and its active metabolite in solid dosage forms, where the drug is uniformly distributed, achieves the desired bioavailability, and is stable. Methods of preparing and using the compositions containing opioid antagonists are also disclosed. The results are achieved by a combination of processing techniques and component selection.

(3R)-7-Hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1- piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3- isoquinolinecarboxamide (JDTic) was identified as a potent and selective κ opioid receptor antagonist. Structure-activity relationship (SAR) studies on JDTic analogues revealed that the 3R,4R stereochemistry of the 3,4-dimethyl-4-(3-hydroxy-phenyl)piperidine core structure, the 3R attachment of the 7-hydroxy-1,2,3,4-tetrahydroisoquinoline group, and the 1S configuration of the 2-methylpropyl (isopropyl) group were all important to its κ potency and selectivity. The results suggest that, like other κ opioid antagonists such as nor-BNI and GNTI, JDTic requires a second basic amino group to express potent and selective κ antagonist activity in the [35S] GTPγS functional assay. However, unlike previously reported κ antagonists, JDTic also requires a second phenol group in rigid proximity to this second basic amino group. The potent and selective κ antagonist properties of JDTic can be rationalized using the "message-address" concept wherein the (3R,4R)-3,4-dimethyl-4-(hydroxyphenyl)piperidinyl group represents the message, and the basic amino and phenol group in the N substituent constitutes the address. It is interesting to note the structural commonality (an amino and phenol groups) in both the message and address components of JDTic. The unique structural features of JDTic will make this compound highly useful in further characterization of the κ receptor.

Improved syntheses of two trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists from 1,3-dimethyl-4-piperidinone are described. The 1,3-dimethyl-4-arylpiperidinol 23 was selectively dehydrated in a two step process to the 1,3-dimethyl-4-aryl-1,2,3,6-tetrahydropyridine 26 by the cis-thermal elimination of the corresponding alkyl carbonate derivative at 190°C. In the presence of a basic nitrogen, the success of the elimination was found to be critically dependent upon the nature of the carbonate alkyl group, with Et, i-Bu, and i-Pr being preferred (90% yield). Alkylation of the metalloenamine, formed by deprotonation of 26 with n-BuLi, proceeded regio- and stereospecifically to give the trans-3,4-dimethyl-4-aryl-1,2,3,4-tetrahydropyridine 27, which was converted in three steps to the common intermediate, (3R,4R)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine. LY255582, a centrally-active opioid antagonist, and LY246736-dihydrate, a peripherally-active opioid antagonist, were prepared from 1,3-dimethyl-4-piperidinone in 11.8% yield (8 steps) and 6.2% yield (12 steps), respectively.

A process for preparing certain 1,3,4,4-tetrasubstituted-1,2,3,4-tetrahydropyridines is provided as well as certain 4-carbonate-1,3,4-trisubstituted-piperidines.