NADOLOL

Abstract: A process for making 5-{d-3-(tert-butylamino)-2-hydroxypropoxy}-1,2,3,4-tetrahydro-1-cis-2,3 naphthalenediol of formula (I), by reacting formula (II) in an essentially water free environment with (a) M'I03 wherein M' represents a suitable ion for forming the salt, (b) I2 (iodine), (c) CH3C00<->M''<+> wherein M'' represents a suitable ion for forming the salt, (d) glacial acetic acid and (e) ROH/M'''OH where R is alkyl and M''' is a suitable metal ion.

Description: TTTLE OF INVENTION NADOLOL F TF.T.F) OF INVENTION Thi s invent ion re lat e s to a proce s s fo manufacturing 5- [d-3- (tert-butylamino ) -2-hydroxypropoxy ] 1 , 2 , 3 , 4-tetrahydro-l-cis-2 , 3 naphthalenediol , (Nadolol) a β blocking agent having anti-arrhythmic activity and β-blockin activity . BACKGROUND QF THE INVENTION According to the Official Monograph of USP XXI, Nadolol is identified as follows: OCH2CHOHCH2NHC (CH3) 3 Formula C17H27NO4 M. . 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-l-naphthyl) oxy] -2-propanol [42200-33-9] . Nadolol contains not less than 98.0 percent and not more tha 101.5 percent of C17H27NO4, calculated on a dried basis. Nadolol is also made up of 4 cis isomers. Many processes have been proposed for the manufactur 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 i 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 makin 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 SUBSTITUTE SHEET 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 OH I Ari - O - CH 2 - CH - CH 2 - NH - Ri 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-l-cis-2,3 naphthalenediol in good yields. Canadian Letters Patent 882,705 discloses a process for the preparation of SUBSTITUTE SHEET Applicant is also aware of the following additional publications (a) "A Convenient Procedure for the Cis hydroxylation of Olefins" by L. Mangoni et al, Tetrahedro Letters No. 45, pp.4485-4486, 1973; and (b) " A Convenient Modification of the Woodward cis-hydroxylation of Olefins" L. Mangoni et al, Gazz. Chi . Ital. 1975, 105,377. Woodward in U.S. Patent 2,687,435 (1954) and at .Am. Chpm. So . 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 Chemistry (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. Che . Society (1963) 770 reported results as follows: "Cyclohexenes .- The Woodward procedure, reaction between 1, 2-dimethylcyclohexene and iodine and silver acetate in 'wet' acetic acid (1.5% of water), gave after vacuum-distillation of the product and its recrystallization a 1:1 molecular compound of the cis-and the trans-diol. Stereospecific cis-hydroxylation by this method has been reported previously. 3 Reaction in 'dry' acetic acid gave no 1, 2-diol. We therefore studied the oxidation of 1- methylcyclohexene by the Woodward procedure and obtained the cis-1, 2-diol . In agreement with other workers, we also obtained the cis-diόl from cyclohexene by the Woodward procedure and the 'trans-diol by using 'dry' acetic acid. Cyclopentenes . - The reaction between cyclopentene SUBSTITUTE SHEET and iodine and silver acetaic in 'wet' acetic acid is reported to give the cis-diol in a 48% yield. By this method we converted 1-methylcycloρentene into the cis- diol in 20% yield, but obtained no diol from 1,2- dimethylcyclopentene. " Subsequently Hauck in Canadian Letters Patent 1,041,544 attempted to separate- the four optical cis isomers of 2 3-cis-l.2.3.4-tetrahγdro-S- T2-hydroxy-3- (ter - butyla ino) propoxy]-2,3-naphthalenediol in order to determine the best of these isomers. The processes of manufacture (See pages 4, 5 and 6 of the Patent and example 4 at pages 18 and 19 of the patent) employ water. Crystallization of isomer product is from chloroform. In Hauck' s laboratory procedure resulting 1- (2, 3-epoxypropoxy) -5, 8- ' dihydronaphthalene is isolated and subsequently reacted with t-butylamine in a high pressure reactor. The resulting dl-1-(tert-butylamino) -3- (5, 8-dihydronaphthyl)oxyl-2-propanol is then cis hydroxylated with wet acetic acid, silver iodide, and the resulting acetoxy iodide is hydrolysed with base and finally subjected to catalytic hydrogenation to afford crude Nadolol. Mangoni et al in an article entitled "A convenient Modification of the Woodward cis-Hydroxylation of Olefins" (Gazz. Chem. Ital. 1975, 105, 377) discussed modifications of the Woodward procedure by subtituting for silver acetate. Wet acetic acid is still used; glacial acetic acid was also tried. No exceptional results are produced by the use of the glacial acetic acid. The cis-diol steroid product is produced with both procedures - in a slightly lesser percentage return using glacial acetic acid than a solution of acetic acid and water. It is therefore another object of this invention to provide improved processes for the manufacture of Nadolol which unexpectedly yielded Nadolol in a minimal number of process steps, in good yields and Nadolol of substantial purity. Further and other objects of this invention will be realized by those skilled in the art from the followin summary of invention and detailed description of an embodimen thereof. SUBSTITUTE SHEET SUMMARY OF THE TNVENTTON Unexpectedly, according to one aspect of the invention, there is provided a process for making very pure 5- [d-3- (tert-butylamino) -2-hydroxypropoxy]-1,2,3, 4-tetrahydro-l- cis-2,3 naphthalenediol of the formula OH (I) I • 0 - CH2 - CH - CH 2 - NH - C(CH3) 3 by reacting (ID OH 0 - CH 2 - CH - CH 2 - NH - C(CH 3 ) 3 SUBSTITUTE SHEET in an essentially water free environment with (a) M' IO3 for example KIO 3 (potassium iodate) or other suitable salt wherein M' represents a suitable ion for forming the salt (for example Na + ,K + , etc); (b) I 2 (iodine) -a solid; (c) CH3C00 ~ M , ,+ for example CH3C00 " K + (potassium acetate) or other suitable salt wherein M' ' represents a suitable ion for forming the salt (for example Na + , K + , etc.) (d) glacial acetic acid and (e) ROH/M''OH where R may be an alkyl radial (for example CH3) and M' ' ' is a suitable metal ion (for example Na + , K + , etc.) . This solution may then be evaporated and the residue treated with a solvent for example toluene, chloroform or a ketone of the formula R1COR2, wherein Ri may be CH3 and R2 may be a higher alkyl group for the recovery of 5-[d.-3- (tert- butylamino)-2-hydroxypropoxy] -1, 2, 3, 4 -tetrahydro-1- cis- 2, 3naphthalenediol. Compound II (shown at page 5 herein) may be made in accordance with the teachings of Canadian Letters Patent 882,705 (which involves isolation of intermediates and the use of a high pressure reactor at 50 psi) or any other suitable process including a process developed by the Applicant according to the following flow diagram in which isolation of the intermediates and the use of high pressure reactors are avoided: SUBSTITUTE SHEET HO CL OIHVIftONftPHTHOL (EPOMIOE) < TERTIARY - BUTVIAMINE) H2N-C(CM 3 ) 3 SUBSTITUTE SHEET Thus a Production Scheme for Nadolol in one vessel (not a high pressure reactor) may comprise the following [without isolation of any intermediates] : OIHVORONflPHTOL (CHLOROHVORIN) (CPOKIOC) to which has been added (A) (GLACIAL ACETIC ACID) WATER FREE ENVIRONMENT " IS SUBSTITUTE SHEET A more detailed Production Scheme is as follows (EPOHIOE) 30 (THEN EUHPORATE ADD 0R6ANIC SOLUENT TO RECOVER CIS-I SOMER NADOLOL (C IS-ISOMER ONLY) OF NADOLOL) 35 SUBSTITUTE SHEET The entire process may be carried out in one reaction vessel not a high pressure reactor. Thus Applicant's process may be employed without isolating the epoxide, without using a high pressure reactor, without using silver acetate and without catalytic hydrogenation to produce 5-[ .-3-(tert- butylamino) -2-hydroxypropoxy]-1,2,3, 4-tetrahydro-l-cis-2 ,3 naphthalenediol. [Wet acetic acid is to be avoided]. Whereas U.S.P. Nadolol is stated to be 99.4-5% pure, Applicant's invention produces exceptionally pure Nadolol (in the order of at least 99.7% purity) which was found using an in house HPLC method, to exceed U.S.P. specification. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THF, INVENTION ( PROTECT FROM LIGHT) 1.46 kg 5, 8-dihydronaphthol ' 80% pure (10 mol) is suspended in 9.4 L epichlorohydrin ( [9.4/92.53] 1.183=12 mol) . Purge with nitrogen and add 368 inL tetraethylammonium hydroxide (5 mol%) . Heat the reaction to 80° C and maintain for 2.5 hours. Distill epichlorohydrin completely under vacuum. Add 80gm methanol, 50gm water and then 1.5kg t- butylamine (CAUTION: EXOTHERMIC) . Reflux for 6 hours and stir at Room Temperature ove night. Distill off solvent under vacuum. To the thick oil add 3 L chloroform, 2 L water and 0.3 L of a 50% solution of NaOH. Agitate vigorously for 10 minutes and separate. Wash the organic layer with 2 L water. Dry the organic layer over sodium sulfate and evaporate chloroform completely at 80°C under vacuum. To the thick brown oil in an essentially water free environment add 12.5 L glacial acetic acid, heat to 60°C and add 473 g. potassium iodate under nitrogen with good stirring. Add 1.15 kg iodine (4.5 mol) and keep at 60-75° C for three hours. Add 1.01 kg potassium acetate and reflux for 1 hour. Evaporate acetic acid completely under vacuum. Add a solution of 3kg potassium hydroxide dissolved in 9 L methanol and reflux for 5 hours and stir overnight. Distill off the solvefit under vacuum. Cool to Room Temperature and add 7 L of toluene, chloroform or chosen ketone. Agitate vigorously for 15 minutes and separate. Wash the aqueous layer with 3 L chloroform, toluene or chosen SUBSTITUTE SHEET ketone. Wash the combined organic extracts with 2X1 L brine. Separate and evaporate the toluene, chloroform, or ketone as the case may be later completely under vacuum. Add 5 L acetone, seed with 5 g Nadolol, and stir for 4 hours. Add another 4 L acetone and stir overnight. Filter crude Nadolol and recrystallize from methanol-acetone and filter. Dissolve crude product in 5 L hot methanol and treat with 100 g active charcoal overnight. Filter and recrystallize from methanol- acetone. Filter and wash with 0.5 L acetone. The purity of the product obtained was 99.7% Unexpectedly, the elimination of water from the reaction solutions used to make Nadolol. from (I) (unlike the processes taught in Canadian Letters Patent 1,064,965 at pages 18 to 20) produces 5-[ d_-3- (tert-butylamino) 2 hydroxypropoxy ]-1,2,3, 4-tetrahydro-l-.c___Ls-.-2, 3 naphthalenediol. Unexpectedly the yields are high (greater than about 40%) and the purity of the final product exceeds the order of 99.7%. As many changes can be made to the embodiments without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense. SUBSTITUTE SHEET

Claims: THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE AS FOLLOWS: 1. A process for making 5-{d-3- (tert-butylamino) -2- hydroxypropoxy}-l, 2,3, 4-tetrahydro-l-cis-2, 3 naphthalenediol of the formula OH (I) I O CH 2 - CH - CH 2 - NH - C(CH3) 3 by reacting OH (II) i O - CH 2 CH CH 2 - NH - C(CH 3 ) 3 in an essentially water free environment with (a) 'Iθ3 wherein M" represents a suitable ion for forming the salt. (b) I 2 (iodine) (c) CH3C00 ~ M , ,+ wherein M' ' represents a suitable ion for forming the salt (d) glacial acetic acid and (e) ROH/M' * ' OH where R is alkyl and M' ' * is a suitable metal io . SUBSTITUTE SHEET 2. The process of claim 1 wherein M', M' ' and M" ' ' are each selected from potassium and sodium. 3. The process of claim 1 wherein R is CH3. The process of claim 2 wherein R is CH3. The process of claim 1 wherein OH (ID I 0 - CH 2 - CH - CH 2 - NH - C(CH 3 ) 3 is manufactured according to the following process tlMflilNAPNTIIOL (CHLOROHVOR I SI IEFOHI0E ) ITCRTIRRY- 8UTVLRMINC) SUBSTITUTE SHEET The process of Claim 2 wherein OH 0 - CH 2 - CH - CH 2 - NH - C (CH 3 ) 3 manufactured according to the following process HO CL IINYIRONNPNTHOL (CHLOROHYORISI lEPOMiOC) SUBSTITUTE SHEET The process of Claim 3 wherein OH O - CH 2 - CH - CH 2 - NH - C(CH 3 ) 3 is manufactured according to the following process HO CL OI to (CHLOROHVORINI IEP0HI0EI ITERTIRRY- BUTVLRMINEI SUBSTITUTE SHEET The process of Claim 4 wherein OH O - CH 2 - CH - CH 2 - NH - C(0.3)3 is manufactured according to the following process HO CL •IMVIRONAPNTNOL (CHLOROHYORISI / 0» XmmL IEFOHI0E) SUBSTITUTE SHEET 9. A process for directly making the cis-isomer of Nadolol, the process comprising carrying out the following steps : ICHLOROHYORINl IEPOKI0E) to which has been added (A) (GLACIAL ACETIC ACID) (B) ( IODINE) (C) (M* IO3 WHEREIN M' REPRESENTS A SUITABLE ION FOR FORMING THE SALT» WATER (D) (CH3COOM" WHEREIN M" REPRESENTS A SUITABLE ION FREE FOR FORMING THE SALT) ENVIRONMENT (E) ROH/M' ' 'OH WHEREIN R MAY BE AN ALKYL RADIAL AND M' * * A SUITABLE METAL ION FOR FORMING THE FINAL PRODUCT NADOLOL (CIS-ISOMER ONLY) SUBSTITUTE SHEET 10. The process of Claim 9 wherein M' , M' ' and M* ' ' are selected from K + and Na + . 11. The process of Claim 9 wherein R is methyl. 12. The process of Claim 10 wherein R is methyl. SUBSTITUTE SHEET 13. A process for directly making the cis-isomer of Nadolol, the process comprising carrying out the following steps: IEP0HI0C) (GLACIAL ACETIC ACID) (SOLID IODINE) (WATER FREE ENV IRONMENT) (POTASSIUM I00RTE) (POTRSSIUM ACETATE) EUAPORATE RNO RDO KOH RNO MeOH SUBSTITUTE SHEET 14. The cis isomer of Nadolol having a purity of at least 99.7%. SUBSTITUTE SHEET

Inventors: KARIMIAN KHASHAYAR, KARIMIAN, KHASHAYAR
Applicants: ACIC CANADA INC, ACIC (CANADA) INC.
Application year: 1990
Main classification: C07C217
IPC codes: C07C213, C07C217