6372
J. Org. Chem. 1991,56,5372-5375
Practical Chemoenzymatic Synthesis of Both Enantiomers of Propranolol H. S. Bevinakatti* and A. A. Banerji Alchemie Research Centre, ZCZ India Limited Site, Thane-Belapur Road, Thane-400 601,Maharashtra, India
Received February 6, 1991
Synthesis of (R)-and (S)-propranolol in high optical and chemical yields was achieved starting from I-naphthol and epichlorohydrin. Lipase-catalyzed kinetic m l u t i o n of key intermediatea l-chlom3-( l-naphthyloxy)-2-propanol and its 0-acetyl ester l-chloro-2-acetoxy-3-( 1-naphthy1oxy)propane was studied using four different approaches.
Introduction As stereochemistry in a drug molecule governs ita biological activity,' chirality is emerging as a key issue in pharmaceutical research.2 0-Blockers of the 3-(aryloxy)-l-(alkylamino)-2-propanoltype, e.g., propranolol (11, are one such class of drugs where the activity resides mainly in the S isomer^.^" Moreover, (R)-1 is known to act as a contraceptive. One of the important ways of meeting the growing needs of the f u t w chiral drug market is predicted to be through "environmentally friendly" biotransformation^.'*^ The ability of enzymes to work in organic solvents! especially lipases,l0due to their low cost and stability, now offers an attractive route for industrial exploitation. In continuation of our work on lipase catalysis," we report herein efficient syntheses, of S and R isomers of propranolol via lipase-catalyzed kinetic resolution of key (1)(a) Wainer, I. W., Drayer, D. E., Eds. Drug Stereochemistry; Marcel Dekker: New York, 1988. (b) Sriens, E.J. Med. Res. Reus. 1986, 6,451. (c) Simonyi, M. Med. Res. Reus. 1984,4,369.(d) Witiak, D. T.; Inbasekaran, M. N. In Kirk-Othmer Encyclopedia of Chem. Tech. 3rd ed.; Wiley-Interscience: New York, 1982;Vol. 17,p 311. (e) Ariens, E. J., Sondijn, W., Timmermans, P. B. M. W. M. Eds. Stereochemistry and Biological activity; Blackwell Scientific Publications: Amsterdam,1982. (f) Ariens, E. J. In Chiral Separations by HPLC; Applications to Pharmaceutical Compounds; Krstulovic,A. M., Ed.; Ellis Horwood La.: Chichater, 1989; p 31. (2)Borman, S. Chem. Eng. News 1990,68(28),9. (3)Nelaon, W. L.; Burke, T. R. J. Org. Chem. 1978,43,3641. (b) Howe, R.; Rao, B. S. J. Med. Chem. 1968,II,1118. (4)For recently reported preparations of (23)-propranolol and related compounds by nonenzymatic asymmetric synthesis, see: (a) Takahashi, H.; Sakuraba, S.;Takeda, H.; Achiwa, K. J. Am. Chem. Soc. 1990,112, 5876. (b) Klunder, J. M.; KO,S. Y.; Sharplese, K. B. J. Org. Chem. 1986, 52, 3710 and references cited therein. (5)For the synthesis of (S)-propranolol utilizing enzyme technology, we: (a) Wang, Y.-F.; Chen, S.T.; Liu, K. K.-C; Wong, C.-H. Tetrahedron Lett. 1989,30,1917.(b) Terao, Y.; Murata, M.; Achiwa, K.; Nuhino, T.; Akamatau, M.; Kamimura, M. Tetrahedron Lett. 1988,29,5173. (c) Matauo, M.; Ohno, N. Tetrahedron Lett. 1981,26,5533and references cited therein. (6)For the synthesia of chiral &blockers wing chiral building blocka, e.&, mu"anito1, we: J u r d , J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42,447and references cited therein. (7)(a) Sheldon, R.Chem. Ind. (London) 1990,7,212.(b) Roberta,S.; Turner, N. New Sci. 1990,126(1713),38. (8) For general reviews on biotransformations, see: (a) Jones, J. B. Tetrahedron 1986,42,3361.(b) Whiteaides, G.M.; Wong, C.-H. Angew. Chem., Int. Ed. Engl. 1981,24, 617. (c) Kieslich, K., Vol. Ed. Biotrans/ormations;Biotechnology; Rehm, H., Reed, H., Eds.; Verlag Chemie: Weinheim, 1984; Vol. 6A. (9) For some recent review, see: (a) Klibanov, A. M. Acc. Chem. Res. 1990,23,114.(b) Wong, C.-H. Science 1989,244,1146.(c) Akiyama, A.; Bednarski, M.; Kim, M. J.; Simon, E. S.; Waldmann, H.; Whiteaides, G. M. CHEMTECH 1988,16,640. (d) Yamada, H.; Shimizu, S. Angew. Chem., Int. Ed. En& 1988,27,622. (10)For reviews on the application of lipases alone, see: (a) Chen, C.-S.; Sih, C. J. Angew. Chem., Int. Ed. Engl. 1989,28,695.(b)Sih, C. J.; Wu, S.-H. In Topic8 in Stereochemistry; Eliel, E. L., Wilen, S. H., W.; John Wilry and Sons: New York, 1989;Vol. 19,pp 63-125. (c) Schneider, M. Perform. Chemicals 1990,5(3),19. (d) Ibid. 1989,4(4),28. (11)(a) Bevinakatti, H. S.; Banerji, A. A. Biotechnol. Lett. 1988,10, 397. (b) Bevinakatti, H. S.; Banerji, A. A.; Newadkar, R. V. J. Org. Chem. 1989,54,2453.(c) Bevinakatti, H. S.; Newadkar, R. V. Biotechnol. Lett. 1989,Jl, 785. (d) Bevinakatti, H. S.; Newadkar, R. V.; Banerji, A. A. J. Chem. Soc., Chem. Commun. 1990, 1091. (e) Bevinakatti, H. S.;Newadkar, R. V. Tetrahedron Asym. 1990,583. (f) Bevinakatti, H. S.; Banerji, A. A.; Newadkar, R. V.; Mukesh, D. Biocatalysis, in press.
Scheme I"
OH
0
O Y -
-3
2
1
Industrial production of (*)-propranolol. Scheme 11"
r
1
-4
5
'Key: (a) epichlorohydrin, pyridine, rt 24 h; (b) HC1, 0-5 OC, 94%; (c) CHSCOCl,0-5 OC,rt, 3 h, 93%; (d) AQO-E~N,80-90 OC, 1 h. 92%. Table I. Effect of Base Concentration and Temperature on the Product Distribution Ratio ( 3 4 ) in the Condensation of I-Naphthol (2) with Epichlorohydrino
mol base pyridine
%
1.25 2.5 10
aqueous KzCOt
25 25 50 100 250
,
temp ("'2) 100 100 rt 60 rt rt rt rt
time (h) 10 6 24 2 16 24 24 24
product distribution 3:4
4555 61:39 23:ll 65:35 3263 2218 57:43 100:00
Reactions were carried out with %:epichlorohydrin molar ratio = 15. *In presence of 5 mol % of TEBAC (with respect to 2).
intermediates l-chlor0-3-(l-napthyloxy)-2-propanol(4)and its 0-acetyl ester l-chloro-2-acetoxy-3-(l-naphthyloxy)propane (5). Results and Discussion While direct resolution of propranolol was reported to be un~uccessful,1~ successfu1preparation of (a-propranolol via lipase-catalyzed hydrolysis/ transesterification of glycerol derivativessband cyanohydrin intermediates& was recently r e p ~ r t e d .In ~ spite of the excellent selectivity shown by lipase toward the intermediates used, these methods do not show any promise for industrial exploitation because of several disadvantages like multisteps (12) Kirchner, G.; Scollar, M. P.; Klibanov, A. M. J. Am. Chem. Soc. 1986,107,7072.
0022-3263/91/1956-5372$02.50/0 0 1991 American Chemical Society
J. Org. Chem., Vol. 56, No. 18, 1991 5373
Synthesis of Both Enantiomers of Propranolol
Table 11. Lipam-Catalyzed Kinetic Resolution of Acetate 5 and Chlorohydrin 4 O -OH (4) [al%D
convn sub. 5
lipase PPLd CCU LPSA"
4
PPL LPSA
reaction medium BuOH-DIPE' BuOH HZ0 BuOH-DIPE OctOH-DIP@ BuOH-DIPE BuOH HZOi
time 20d 14 d 51 h 2d 3d 5d 9d 5d 52 h
VAi VA VA' AcZO-DIPE'
2d 46 h 13 d 41 h
-0Ac (5)
(1-5%. EtOHj +3.3 t3.2 +4.2 -5.0 -3.6 -3.4 +9.0 +9.0 +8.7
(%)
26 22 16 41 58 58 50 47 48
-
47 50 51
-8.1
-8.7 -8.3
eeb
[a]%D
isomer
(%I
S S S
S S S
37 35 47 56 40 38 >95 >95 >95
(1-5%, EtOH) -2.8 -2.2 -1.7 +8.2 +11.8 +10.8 -19.9 -18.0 -17.5
R R R
90 >95 92
+19.1 +18.5 +17.5
R R R
el? isomer
(%)
S S S
S S S
14 11 9 41 59 54 >95 90 88
3 3 3 6 4 4 >loo >loo >lo0
R R R
>95 93 88
>lo0
R R R
>loo
53
a Reactions were carried out on 5-25-mmol scale of substrate 5 or 4 at ambient temperature. Unless otherwise mentioned, the ratio used for substrate-solvent (DIPE or BuOH or HzO or VA)-lipase was 5 mmoLl0 mL:500 mg. bSee ref 21. CSeeref 20. dPorcine pancreatic lipase. 10 mmol of 1-BuOH in 10 ,mL of DIPE. 'Lipase from C. cylindracea. 10 mmol of 1-OctOH in 10 mL of DIPE. Lipase PS 'Amano" isolated from P.cepacia. Substratdipase = 5 mmoL100 mg. 1 Vinyl acetate. 10 mmol of AczO in 10 mL of DIPE. J
(more than six steps), low overall yields (less than lo%), use of hazardous and expensive reagents like sodium cyanide, lithium aluminium hydride, sodium borohydride, etc., and lastly, noncompatibility with the existing industrial process for racemic propranolol13(Scheme I). To overcome these drawbacks, our obvious choices of the key intermediates for lipase-catalyzed studies were 4 and 5, which not only can be obtained in a single step from 1-naphthol (2) and epichlorohydrin but can also be converted easily to propranolol. Condensation of 2 with epichlorohydrin, following known procedure," in presence of 2.5 M % pyridine at 100 "C yielded a mixture of chlorohydrin 4 and glycidyl 1naphthyl ether (3) in ca. 4060 ratio. Treatment of this mixture with HCl at room temperature, however, yielded the required 4 contaminated with 2-3% of the unwanted regiomer 2-chloro-3-(l-naphthyloxy)-l-propanol, Cl&,OCH2CH(C1)CH20H;4a (detected only by GC) obviously was generated after the ring opening of epoxide 3. This was confirmed by treatment of pure glycidyl 1-naphthyl etherls separately with HCl to give 5 and 2.5% of 4a at room temperature and
