Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-03-09
2003-05-20
O'Sullivan, Peter (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
Reexamination Certificate
active
06566510
ABSTRACT:
The invention provides a novel method for synthesising Morphine-6Glucuronide (M6G) and intermediates therefor.
Synthesis of M6G from 3-acetylmorphine and methyl 2-&agr;-bromo-3,4,5-tri-O-acetylglucuronate is described by Lacy, C., et al. (
Tetrahedron Letters,
36 (22), (1995), 3949-3950).
Hidetoshi, Y. et al., (
Chemical and Pharmaceutical Bulletin,
JP, TOKYO, 16 (11), (1968), 2114-2119) describe synthesis of M6G by reaction of 3-acetyl-morphine with a bromo derivative of glucuronic acid to form a Methyl[3-acetylmorphin-6yl-2,3,4-tri-O-acetyl-&bgr;-D-glucopyranosid]uronate intermediate which is subsequently hydrolysed to M6G.
WO 93/05057 discloses preparation of M6G by reaction of 3-acetyl morphine with methyl 1&agr;-bromo, 1-deoxy, 2,3,4-tri-O-acetyl D glucopyranuronate and subsequently hydrolysing the resulting intermediate to M6G.
In order to synthesise M6G the major problem to overcome is to obtain the glycoside linkage with very high &bgr;-selectivity since prior methods produce the &agr;-anomer.
One method for obtaining high &bgr;-selectivity is to use trichloroimidate as the leaving group, as shown in WO 93/03051:
FIG. 1
(Salford Ultrafine Chemicals and Research Limited).
Orthoesters are simple to synthesise from their respective bromides
1
. There is a reaction reported in the literature
2
between the glucuronate orthoester (2) and the sugar derivative (3) catalysed by lutidinium perchlorate
3
(4) (Scheme 1).
When this reaction was repeated with the t-butyl orthoacetate (5) and cyclohexanol (6 equivalents), the desired product (6) was isolated in 9% yield. Two other products also suggested that they were the desired product, but with the loss of one acetyl group, isolated in a combined yield of 43% (Scheme 2).
When 1.2 equivalents of 4-tert-butylcyclohexanol was used, the desired compound (7) was obtained in 17% yield. Other compounds obtained from the reaction also appeared to contain the desired peaks in the nmr, but after further examination proved to be the product of transorthoesterification (8) (Scheme 3).
Reaction of Orthoester (5) with Protected Morphine
Initially, 1.2 equivalents of 3-TBS protected morphine and the orthoester (5) were dissolved in chlorobenzene and half of the solvent was distilled off before 0.1 equivalents of lutidinium perchlorate (4) in chlorobenzene was added. The solvent was continuously distilled off while fresh solvent was added, and after 2.5 h another compound was formed with similar tlc properties to the protected morphine. Workup and chromatography gave a compound which corresponded to trans-orthoesterified material (9). None of the desired material was obtained (Scheme 4).
This product (9) was resubmitted to the reaction conditions (0.1 equivalents of lutidinium perchlorate and protected morphine in refluxing chlorobenzene) with no new products formed after 4 h. Two further reactions were attempted using two equivalents of orthoester (5) and 0.2 equivalents of lutidinium perchlorate and 1 equivalent of orthoester (5) and 1.2 equivalents of lutidinium perchlorate, but both gave varying yields of orthoester (9).
We have concluded that a different, more bulky, alkyl group was needed on the orthoester to hinder attack there. Initially, the isopropyl group was examined. However, the initial reaction, perisobutyrylation, failed to give a compound which recrystallised from petrol, so the &agr; and &bgr; anomers could not be separated. Therefore, attention focussed on the pivaloyl group.
REFERENCES:
patent: WO 93/03051 (1993-02-01), None
patent: WO 93/05057 (1993-03-01), None
patent: WO 96/28451 (1996-09-01), None
“An improved synthesis of &bgr;-Glucosiduronic acid derivates”, Jontscho Vlahov et al., Liebigs Ann. Chem. (1983), (4), 570-4, XP002123583, p. 571.
“Synthesis of oligosaccharides related to the HNK-1 antigen. .actopyranoside” Kornilov A.V. et al., Russ. J. Bioorg. Chem., vol. 23, No. 8, 1997, pp. 655-656, XP000856215.
“Synthesis, Opioid Receptor Affinity, and Enzymatic Hydrolysis of Sterically Hindered Morphine 3-Esters”, Christian Mignat et al., J. Pharm. Sci. (1996), 85(7), 690-694, XP002123584, see table 1, compound 10.
“A comparison of acid-base properties of substituted pyridines and their N-oxides in propylene carbonate”, Alicja Wawrzynow et al., J. Chem. Thermodyn (1998), 30(6), 713-722, XP000856067.
“A Synthesis of Morphine-6-Glucuronide”, C. Lacy et al., Tetrahedron Letters, vol. 36, No. 22, 1995, pp. 3949-3950, XP000616116, ISSN: 0040-4039, p. 3949, p. 3950, compound 1.
“Metabolism of Drugs. LX.1). The Synthesis of Codeine and Morphine Glucuronides 2)”, Hidetoshi Yoshimura et al., Chemical and Pharmaceutical Bulletin, JP, Tokyo, vol. 16, No. 11, 1968, pp. 2114-2119, XP000614807.
Ewin Richard Andrew
Parsons Philip James
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Genes Limited
O'Sullivan Peter
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