Process of making nadolol

Details Process of making nadolol Process of making nadolol

1991-05-20

1994-06-07

Raymond, Richard L.

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

Organic compounds

Amino nitrogen containing

C07C21300, C07C21738

Patent

active

053191412

DESCRIPTION:

BRIEF SUMMARY
FIELD OF INVENTION

This invention relates to a process for manufacturing 5-[d-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-1-cis-2,3 naphthalenediol, (Nadolol) a .beta.-blocking agent having anti-arrhythmic activity and .beta.-blocking activity.


BACKGROUND OF THE INVENTION

According to the Official Monograph of USP XXI, Nadolol is identified as follows: ##STR3##
Formula C.sub.17 H.sub.27 NO.sub.4 M.W. 309.41; 2,3-Naphthalenediol, 5-[-3(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,2,3,4-tetrahydro-, cis, 1-(tert-Butylamino)-3-[(5,6,7,8-tetrahydro-cis-6,7-dihydroxy-1-naphthyl)ox y]-2-propanol [42200-33-9]. Nadolol contains not less than 98.0 percent and not more than 101.5 percent of C.sub.17 H.sub.27 NO.sub.4, calculated on a dried basis. Nadolol is also made up of 4 cis isomers.
Many processes have been proposed for the manufacture of Nadolol from various intermediates. There are 4 cis isomers of Nadolol and because each cis isomer of Nadolol produced may have a number of impurities associated with it (from the manufacturing process). Also some of the impurities in the starting materials may themselves become involved in the reaction (the starting materials may only be 80%-85% pure and some of the impurities may be unknowns). Thus, the Official Monograph provides the specifications for Nadolol, and assay procedures for determination of its purity. The Monograph does-not include an HPLC method.
A number of proposals have been made for making Nadolol. See Canadian Letters Patent 979,912; 979,926; 1,000,287; 1,041,544; 1,059,147; 1,063,120; and 1,064,965. Hauck has also proposed processes for separation of the four cis isomers from one another. (See Canadian Letters Patent 1,041,544; 1,059,147 and 1,064,965.) However the processes led to very low yields and are therefore not commercially viable.
Canadian Letters Patent 1,132,560 (Ciba-Geigy) discloses a process for inverting the configuration in optically active compounds characterized in that an optically active compound of the formula ##STR4## having a R(+) or S(-) configuration is converted by treating with concentrated phosphoric acid or concentrated sulphuric acid or a chloride or bromide of such acids, into an optically active compound and the resulting compound is hydrolyzed to form a compound with a configuration opposite to that of the starting material used. This process is complex.
It is therefore an object of this invention to provide an improved process for manufacturing 5-[d-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-1-cis-2,3 naphthalenediol in good yields.
Canadian Letters Patent 882,705 discloses a process for the preparation of ##STR5##
Applicant is also aware of the following additional publications (a) "A Convenient Procedure for the Cis-hydroxylation of Olefins" by L. Mangoni et al, Tetrahedron Letters No. 45, pp.4485-4486, 1973; and (b) "A Convenient Modification of the Woodward cis-hydroxylation of Olefins" L. Mangoni et al, Gazz. Chim. Ital. 1975, 105,377.
Woodward in U.S. Pat. No. 2,687,435 (1954) and at J. Am. Chem. Soc. 80,209 (1958) with F. V. Brutcher taught the hydroxylation of an olefin with iodine and silver acetate in wet acetic acid to give cis-glycols. The process involves the "trans" addition of iodine and silver acetate to give a "trans" -iodo-acetoxy-derivative. The latter is hydrolyzed to a cis- mono-glycol acetate with acetic acid and water. Alkaline hydrolysis results in the final cis-glycol.
Brutcher and Evans reported in Journal of Organic
(1957) 23, 618, a modification to the process proposed by Woodward and Brutcher. This modification involved the interaction of an olefin with iodine, silver acetate, and wet acetic acid to give cis hydroxy acetate in one operation. Subsequent hydrolysis was purported to yield the free diol.
Bunton and Carr in an article "The hydroxylation of Cyclic Olefins by Iodine and Silver Acetate", J. Chem. Society (1963) 770 reported results as follows:
"Cyclohexenes.- The Woodward procedure, reaction between 1, 2-dimethylcyclohexene and iodine and silver acetate

REFERENCES:
patent: 2687435 (1954-08-01), Woodward
patent: 3935267 (1976-01-01), Hauck et al.
Mangoni et al, Tetrahedron Letters, No. 5 (1973) pp. 4485-4486.

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