Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-11-26
1998-05-26
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D48908
Patent
active
057567450
DESCRIPTION:
BRIEF SUMMARY
Nalbuphine hydrochloride (C.sub.21 H.sub.27 NO.sub.4.HCl; CAS Registry No.:23277-42-2; IUPAC name: (-)-17-(cyclobutylmethyl)-4,5.alpha.-epoxymorphinan-3,6 .alpha., 14-triol hydrochloride) is a synthetic partial opiate agonist analgesic of the phenanthrene series. It is structurally related to naloxone and oxymorphone, but is pharmacologically similar to pentazocine and butorphanol. Nalbuphine hydrochloride is used as an analgesic in the treatment of moderate to severe pain such as that associated with acute and chronic medical disorders including cancer, orthopedic problems, renal or biliary colic, migraine or vascular headaches, and surgery. The drug is also used to provide preoperative sedation and analgesia and as a supplement to surgical anesthesia.
The synthesis of nalbuphine results in small quantities of the .beta.-epimer (diastereoisomer) of nalbuphine. The difference is the orientation of the hydroxyl moiety at the 6-position. Little is known about the pharmacological activity of the .beta.-epimer. In many countries, including the United States, regulatory authorities consider epimers of the desired compound to be impurities which must be minimized. The .beta.-epimer of nalbuphine can be reduced to very low levels by recrystallization. However, such recrystallizations are very time consuming and expensive. Further, because nalbuphine recrystallizations have high losses, and many recrystallizations (e.g.: 5 or 6) are required to reach low levels of .beta.-epimer, recrystallization results in unacceptably low yields.
The synthesis of nalbuphine hydrochloride is taught, for example, in U.S. Pat. No. 3,332,950 (Blumberg; Endo Laboratories; 1967). Blumberg teaches the LiAlH.sub.4 reduction of N,O.sup.3 -bis(cyclobutylcarbonyl)noroxymorphone to nalbuphine (see columns 3 and 4). The process of this patent produces nalbuphine with a weight ratio of nalbuphine to .beta.-epimer of about 6:1. Further processing yields slightly less than 10% .beta.-epimer.
L. J. Sargent, et al., Hvdroxvlated Codeine Derivatives, J. Org. Chem., 23, 1247-1251 (1958), shows several reactions of codeine derivatives, in particular, the stereospecific sodium borohydride reduction of 14-hydroxycodeinone to 14-hydroxycodeine.
A. C. Currie, et al., Some reactions of 14-Hydroxycodeine, J. Chem. Soc., 773-781 (1960) is similar to Sargent, et. al.
R. A. Olofson, et al., A New Reagent for the Selective, High-Yield N-Dealkylation of Tertiary Amines: Improved Syntheses of Naltrexone and Nalbuphine, J. Org. Chem., 49, 2081-2082 (1984), teaches a novel reagent, .alpha.-chloroethyl chloroformate, for the demethylation of tertiary amines to yield secondary amines. This reference, in the final paragraph, shows the use of this chemistry to synthesize nalbuphine from 14-hydroxydihydrocodeinone.
A. Benarab, et al., Utilisation du Groupment Cyanomethyle comme Motif Protecteur des Phenols, Amines et Carbamates, Tetrahedron Letters, 34, No. 47, 7567-7568 (1993), teaches the use of the cyanomethyl unit as a protecting group for phenols, primary and secondary amines, and carbamates. Optimized conditions for formation and hydrolysis of cyanomethyl in the presence of the other hydrogenolysis sensitive groups such as O- and N- benzyl groups are presented.
SUMMARY OF THE INVENTION
Briefly, the invention is a process for the synthesis of nalbuphine. The process is particularly useful for the synthesis of nalbuphine having very low levels of the undesirable .beta.-epimer.
DETAILED DESCRIPTION OF THE INVENTION
In this specification and claims, numerical values and ranges are not critical unless otherwise stated. That is, the numerical values and ranges may be read as if they were prefaced with the word "about" or "substantially".
The process of the invention begins with an N--R.sup.1,O.sup.3 --R.sup.2 - 14-hydroxynormorphinone, ##STR1## in which each of R.sup.1 and R.sup.2 is independently a protective group that may be removed by hydrolysis and/or hydrogenolysis. For instance, although not experimentally verified, and in any event not preferred, the pro
REFERENCES:
patent: 3332950 (1967-07-01), Blumberg
patent: 3393197 (1968-07-01), Pachter
patent: 4795813 (1989-01-01), Schwartz
patent: 5112975 (1992-05-01), Wallace
L. Sargent et al., J. Org. Chem., 23: pp. 1247-1251 (1958).
A. Currie et al., J. Chem. Soc., pp. 773-781 (1960).
R. Olofson et al., J. Org. Chem., 49: pp. 2081-2082 (1984).
A. Benarab et al., Tetrahedron Letters, 34, pp. 7567-7568 (1993).
Boone Jeffrey S.
Daus Donald G.
Lewis Linda
Mallinckrodt Medical Inc.
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