synthesis organic farmacs

3
Indian Journal of Chemistry Vol. 44B, March 2005, pp. 615-617 Note Synthesis of triphenylmethane derivative: necessary to purify the product. To prevent the Bisacodyl formation of the ortho-condensation products, pyridine-Zaldehyde was made to react with halo Hari Babu Mereyala* & Kalyani Sambaru substituted phenol in both or in a single ortho- Speciality & Gas-based Chemicals and Processes Division, Indian position, reductive dehalOgenatiOn with Rane~ Ni Institute of Chemical Technology, Hyderabad 500 007, India afforded the desired product in high yield7. Email: [email protected] t_l Received 24 March 2004; accepted (revised) 19 July 2004 A new method for the synthesis of bisacodyl 1 is described. The key step involves migration of Zpyridacyl group of phenyl pyridine-2-carboxylate 4 in AlC13 at 160 OC to yield the intermediate Chydroxyphenyl (Zpyridyl) ketone 5a. The reaction of 5a with phenol using H3PO4 gives 1. This method has advantage over the existing literature methods because easily available pyridine-2-carboxylic acid is used as a starting material instead of the less stable pyridine-2-carboxaldehyde. $- IPC: 1nt.cL7C 07 C 15/14 The substituted diphenyl(2-pyridy1)methane deri- vatives have been reported to possess laxative activity, prominent among them is bisacodyl 1 (ref. 1). In the course of investigations, on the relationship between chemical structure and laxative activity several of their derivatives have been synthesized2. Condensation of aromatic aldehyde and phenol was reported for their preparation by use of one of the acidic dehydrating agents or a combination ' of them [e.g. conc. HCI, HC~ (gas), conc. HZSO~, anhydrous ZnClz, Sn(IV)Cl, anhy. AlC13] to give the corresponding triphenylmethane derivatives3. Alter- natively condensation of p-methoxyphenyl(2-pyridyl) carbinol with various phenols by use of conc. H2S04 has been reported to obtain diphenyl(2-pyridy1)- methanes along with the formation of undesired by- products4.The a,a-disubstituted 2-pyridinemethanols were synthesized by reaction of (i) RMgX or RLi with pyridine-2-carboxylate, (ii) 2-pyridylphenyl ketone with RMgX or RLi and 2-pyridyl lithium or pyridyne with Al/ HgClz reaction with ketones, (iii) reaction of pyridine and ketone in the presence of Al, HgC12 or 2- lithiopyridine5. Condensation of phenol with pyridine- 2-carboxaldehyde has been shown to give 4',4"- dihydroxydiphenyl(2-pyridy1)methane together with 24-29% of its isomer 2',4"-dihydroxydiphenyl(2- P- pyridyl)methane6. Repeated crystallizations were We herein, report a new method for the synthesis of 4',4"-dihydroxydiphenyl(2-pyridy1)methane starting from pyridine-2-carboxylic acid 2. Reaction of 2 in benzene/SOC12 at 0°C resulted in the isolation of the corresponding acid chloride 3 in 60% yield which, on further reaction with phenol in presence of Et3N at 0°C resulted in the isolation of phenyl picolinate 4 in 60% overall yield as a crystalline solid, m.p. 78 "C (Scheme I). The phenyl ester 4 was subjected to migration of the 2-pyridacyl group by pulverizing with AlC13 and heating to 160°C for 4 hr to give 4- hydroxyphenyl(2-pyridyl) ketone 5a in 56% yield along with the corresponding ortho-isomer 5b in 28% yield. The pyridyl ketone 5a on reduction with NaBH4 gave the corresponding pyridyl phenyl methanol 6 in 95% yield. Condensation of 6 with phenol was performed with 85% aq. H3PO4 at RT for 1.5 hr and at 100°C for 30 min to give 7 in 69% yield as a white solid, m.p. 238-40°C (lit4. m.p. 240°C). Compound 7 was acetylated with Ac20/pyridine to afford bisacodyl 1 in quantitative yield as a white crystalline solid, m.p. 133-34°C (lit4.m.p. 134°C). In summary, a new synthesis of 4',4"-dihydroxy- diphenyr(2-pyridy1)methane is described by demon- strating facile migration of 2-pyridacyl group of 4-hydroxyphenyl(2-pyridyl) ketone to form the key intermediate phenyl(2-pyridyl) ketone by a new method. Experimental Section General. All the products were characterized by 'H NMR spectroscopy. 'H NMR spectra were recorded on an FT NMR; Varian 200 MHz spectrometer. The solvents and other chemicals used for the reactions were purified andlor dried as per the standard literature methods. Phenyl pyridine-2-carboxylate 3. To a solution of 2 (25 g, 200 m o l e s ) in benzene (150 mL) was added SOClz (10 rnL, 0.15 mole) at 0°C and then refluxed

Transcript of synthesis organic farmacs

Page 1: synthesis organic farmacs

Indian Journal of Chemistry Vol. 44B, March 2005, pp. 615-617

Note

Synthesis of triphenylmethane derivative: necessary to purify the product. To prevent the

Bisacodyl formation of the ortho-condensation products, pyridine-Zaldehyde was made to react with halo

Hari Babu Mereyala* & Kalyani Sambaru substituted phenol in both or in a single ortho-

Speciality & Gas-based Chemicals and Processes Division, Indian position, reductive dehalOgenatiOn with R a n e ~ Ni Institute of Chemical Technology, Hyderabad 500 007, India afforded the desired product in high yield7.

Email: [email protected] t_l

Received 24 March 2004; accepted (revised) 19 July 2004

A new method for the synthesis of bisacodyl 1 is described. The key step involves migration of Zpyridacyl group of phenyl pyridine-2-carboxylate 4 in AlC13 at 160 O C to yield the intermediate Chydroxyphenyl (Zpyridyl) ketone 5a. The reaction of 5a with phenol using H3PO4 gives 1. This method has advantage over the existing literature methods because easily available pyridine-2-carboxylic acid is used as a starting material instead of the less stable pyridine-2-carboxaldehyde.

$- IPC: 1nt.cL7 C 07 C 15/14

The substituted diphenyl(2-pyridy1)methane deri- vatives have been reported to possess laxative activity, prominent among them is bisacodyl 1 (ref. 1). In the course of investigations, on the relationship between chemical structure and laxative activity several of their derivatives have been synthesized2. Condensation of aromatic aldehyde and phenol was reported for their preparation by use of one of the acidic dehydrating agents or a combination ' of them [e.g. conc. HCI, H C ~ (gas), conc. HZSO~, anhydrous ZnClz, Sn(IV)Cl, anhy. AlC13] to give the corresponding triphenylmethane derivatives3. Alter- natively condensation of p-methoxyphenyl(2-pyridyl) carbinol with various phenols by use of conc. H2S04 has been reported to obtain diphenyl(2-pyridy1)- methanes along with the formation of undesired by- products4. The a,a-disubstituted 2-pyridinemethanols were synthesized by reaction of (i) RMgX or RLi with pyridine-2-carboxylate, (ii) 2-pyridylphenyl ketone with RMgX or RLi and 2-pyridyl lithium or pyridyne with Al/ HgClz reaction with ketones, (iii) reaction of pyridine and ketone in the presence of Al, HgC12 or 2- lithiopyridine5. Condensation of phenol with pyridine- 2-carboxaldehyde has been shown to give 4',4"- dihydroxydiphenyl(2-pyridy1)methane together with 24-29% of its isomer 2',4"-dihydroxydiphenyl(2-

P- pyridyl)methane6. Repeated crystallizations were

We herein, report a new method for the synthesis of 4',4"-dihydroxydiphenyl(2-pyridy1)methane starting from pyridine-2-carboxylic acid 2. Reaction of 2 in benzene/SOC12 at 0°C resulted in the isolation of the corresponding acid chloride 3 in 60% yield which, on further reaction with phenol in presence of Et3N at 0°C resulted in the isolation of phenyl picolinate 4 in 60% overall yield as a crystalline solid, m.p. 78 "C (Scheme I). The phenyl ester 4 was subjected to migration of the 2-pyridacyl group by pulverizing with AlC13 and heating to 160°C for 4 hr to give 4- hydroxyphenyl(2-pyridyl) ketone 5a in 56% yield along with the corresponding ortho-isomer 5b in 28% yield. The pyridyl ketone 5a on reduction with NaBH4 gave the corresponding pyridyl phenyl methanol 6 in 95% yield. Condensation of 6 with phenol was performed with 85% aq. H3PO4 at RT for 1.5 hr and at 100°C for 30 min to give 7 in 69% yield as a white solid, m.p. 238-40°C (lit4. m.p. 240°C). Compound 7 was acetylated with Ac20/pyridine to afford bisacodyl 1 in quantitative yield as a white crystalline solid, m.p. 133-34°C (lit4. m.p. 134°C).

In summary, a new synthesis of 4',4"-dihydroxy- diphenyr(2-pyridy1)methane is described by demon- strating facile migration of 2-pyridacyl group of 4-hydroxyphenyl(2-pyridyl) ketone to form the key intermediate phenyl(2-pyridyl) ketone by a new method.

Experimental Section

General. All the products were characterized by 'H NMR spectroscopy. 'H NMR spectra were recorded on an FT NMR; Varian 200 MHz spectrometer. The solvents and other chemicals used for the reactions were purified andlor dried as per the standard literature methods.

Phenyl pyridine-2-carboxylate 3. To a solution of 2 (25 g, 200 moles ) in benzene (150 mL) was added SOClz (10 rnL, 0.15 mole) at 0°C and then refluxed

Page 2: synthesis organic farmacs

616 uuumn J. CHEM., SEC B, MARCH 2005

TI2 hr, v) phenoV8i Sch

i) S O C l f i ~ d t e f l w d l 2 hr, ii) C H C I g ~ t g 1 p n e n o W 3 nr, m) A I L I ~ ~ O U -

iv) NaBH&leOWR j%H3PO4 r. vi) Ah( C/4 hr,

" for 12 hr. Thionyl chloride and benzene were removed by distillation to obtain the corresponding acid chloride 3 in 60% yield. A solution of phenol (6.66 g, 70.8 mrnoles) in CH2C12 (20 mL) was added to 3 in CH2C12 (20 mL) and the mixture cooled under N2 atmosphere. To the reaction mixture was added triethylamine (18 mL, 140 rnmoles) dropwise at 0°C and brought to RT and stirred for 3 hr. After completion of the reaction, the reaction mixture was concentrated, diluted with water (250 mL) and extracted into CH2C12 (2 x 150 mL). The organic phase was separated, washed with water, dried (Na2S04) and concentrated to a residue and crystallized from CH2C12/hexane to obtain the title compound 4 as a light brown solid in 60% yield (8.4 g), m.p. 78°C; 'H NMR (CDC13, 200 MHz): 6 7.20- 7.48 (m, 5H, Ar-H), 7.5 (dd, lH, H-5), 7.80 (dd, lH, H-4), 8.25 (dd, lH, H-3), 8.81 (d, lH, H-6); EIMS: rnlz 199 (W). Anal. Calcd for C12H9N02: C, 72.35; H, 4.55; N, 7.03. Found: C, 72.55; H, 4.59; N, 7.13%.

4-Hydroxyphenyl(2-pyridyl) ketone 5a. A mixture of 4 (10 g, 50.25 mrnoles) and AlC13 (21 g, 157.75 mmoles) were grinded to a fine powder in a mortar and heated at 160 "C for 4 hr. The reaction mixture was cooled to RT, treated with 3N. HCl and extracted the compound into CH2C12 (2 x 100 mL). The organic layer was separated, washed with water, dried (Na2S04), concentrated to a residue and

chromatographed [silica gel (60-120 mesh)] eluted with hexane-ethyl acetate (7:3) to isolate the title compound 5a in 56% yield (5.6 g) as a light yellow syrup followed by the ortho-isomer 2-hydroxy- phenyl(2-pyridyl) ketone 5b in 28% yield (2.8 g) as a syrup. 'H NMR (CDC13, 200 MHz): 6 7.20-7.48 (m, 5H, ArH), 7.50 (dd, lH, H-5'), 7.80 (dd, lH, H-4'), 8.25 (dd, lH, H-30, 8.81 (d, IH, H-6'); EIMS: m/z 199 (M'). Anal. Calcd for CI2H9NO2: C, 72.35; H, 4.55; N, 7.03; 0 , 16.06. Found: C, 72.55; H, 4.61; N, 7.1 1%.

4-Hydroxyphenyl(2-pyridyl) carbinol 6. To a solution of 5a (4 g, 20 mrnoles) in methanol (20 mL) was added NaBH4 (2.0 g, 50 mmoles) at 0°C and stirred the reaction mixture at RT for 2 hr. The reaction mixture neutralized with AcOH, removed MeOH on rotary evaporator, added H20 (20 mL) and extracted into CH2C12 (2 x 50 mL) to isolate the title compound in 94.5% yield (3.8 g) as a light brown syrup. 'H NMR (CDC13, 200 MHz): 6 5.95 (s, lH, CHOH), 7.18 (d, 2H, H-3',5'), 7.25 (d, 2H, H-2',6'), 7.40 (d, lH, H-5), 7.65 (dd, lH, H-4), 8.55 (d, lH, H- 3), 8.81 (d, IH, H-6), EIMS: mlz 202 (M+l)+. Anal. Calcd for C12HllN02: C, 71.63; H, 5.51; N, 6.96. Found: C, 71.53; H, 5.57; N, 6.88%.

4',4"-Dihydroxydiphenyl(2-pyridyl) methane 7. A mixture of 6 (2.36 g, 22.0 mmoles) and phenol (4.15 g, 44.15 mmole) were cooled to 0°C and 85%

Page 3: synthesis organic farmacs

NOTES 617

H3P04 (20 mL) was added with stirring. The reaction rnixture was stirred at RT for 1.5 hr and at 100°C for 3.l min. The reaction mixture was cooled to 15°C and neutralized with aq. 30% NaOH (20 rnL). The product formed was filtered on a Buchner funnel and washed with water, dried and crystallized from ethyl acetate to obtain the title compound as white solid in 69%(4.2 g) yield, m.p. 238-40°C; 'H NMR (CDC13, 200 MHz): 6 5.40 (s, IH, CH), 6.62-6.70 (d, 4H, H-2',2",6',6"), 6.78-7.0 (d, 4H, H-3',3",5',5"), 7.10-7.22 (m, 2H, H- 3,4), 7.70 (dd, lH, H-5), 8.50 (d, lH, H-6); EIMS: m/z 277 (M'). Anal. Calcd for Cl8Hl5No2: C, 77.96;

A H, 5.46; N, 5.05. Found: C, 77.67; H, 5.53; N, 5.11%. Bis-(4-acetoxypheny1)-2-pyridyl methane 1. To a

solution of 7 (1.25 g, 4.5 m o l e s ) in CH2C12 (10 mL) and pyridine (3.6 mL, 27.2 mmoles) at 0°C was added acetic anhydride (1.2 mL, 10.8 moles ) and the mixture stirred at RT for 2 hr. After completion of the reaction, the reaction mixture was poured into H20 (15 mL) and extracted into CH2C12 (2 x 20 mL). The organic layer was separated, washed with 4% aq. CuS04 (2 x 15 mL) and water. The organic layer was

Is- dried (Na2S04) and concentrated to obtain the title

compound as .white solid (1.4 g) in 88% yield, m.p. 133°C; 'H NMR (CDC13, 200 MHz): 6 2.10 (s, 6H, OAC), 5.55 (s, lH, C-H), 6.80-6.90 (d, 4H, H- 2',2",6',6"), 6.92-7.08 (d, 4H, H-3',3",5',Sn), 7.05- 7.15 (m, IH, H-3), 7.40-7.50 (m, 2H, H-4,5), 8.45 (brs, lH, H-6). Anal. Calcd for CZ2H2,N04: C, 72.71; H, 5.82; N, 3.85. Found: C, 72.87; H, 5.73; N, 3.91%.

Acknowledgement

One of the authors (KS) is thankful to the Director, .IICT for providing financial assistance in the form of a research fellowship.

eller L, An Christians

ch Pharm, en J , Acta

'2. i E & Bietl neck P, Er .-

ti G, Tetra1 wiek S &

References 1 Schmidt L, Arzneimittel Forsch, 3,1953, 19. 2 Schmidt L & Seeger E, Aruteimittel Forsch, 6,1956,22. 3 Schultz 0 E & G 288160, 1955,234. 4 Rubinstein K & Scandinavica,

12,1958,1274. 5 McCarty F J, Tiltord C H &c Van. Campen M G, J Am Chem

SOC, 79,1957,47 6 Pala G, Crescenz ,1967,619. 7 Nathan S, Dome /I, J Am Chem

SOC, 71,1949,88

bedron, 24. Sherlock It