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Synlett 2007(8): 1289-1293  
DOI: 10.1055/s-2007-977458
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Novel Approach for the Conversion of Primary Amides into Tetrazoles by Using Tributyltin Chloride and Sodium Azide in the Presence of DMF

Korrapati V. V. Prasada Raoa, Ramesh Dandala*a, Vijay K. Handaa, Inti V. Subramanyeswara Raoa, Ananta Rania, Sripelly Shivashankara, Andra Naidub
a APL Research Center, Aurobindo Pharma Ltd., Bachupally, Hyderabad 500072, India
b Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500072, India
Fax: +91(40)23042932; e-Mail: rdandala@aurobindo.com;
Further Information

Publication History

Received 20 February 2007
Publication Date:
08 May 2007 (online)

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Abstract

A novel and efficient one-pot synthesis of tetrazole ­derivatives such as Irbesartan and its analogues has been described from the primary acid amide derivatives. Thus 2-alkyl-3-[p-(o-amidophenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one derivatives or 4-[α-(acylamino)cyclopentamidomethyl]-2′-carboxamidobi­phenyl derivatives were treated with tributyltin chloride and sodium azide in o-xylene in the presence of DMF to afford irbesartan and its analogues without generation of nitriles. The synthesis of these new starting materials is also described, and two of the derivatives have been used as new intermediates in the preparation of ­irbesartan.

Key words

primary acid amides - tributyltin chloride - sodium azide - o-xylene - DMF - irbesartan

    References and Notes

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11

Solvents and reagents were obtained from commercial sources and used without purification. Melting points were determined on a Polmon melting point apparatus. All melting points are uncorrected. The 1H NMR and 13C NMR spectra were recorded on a Bruker 300 spectrometer at 300 MHz and 75 MHz, respectively. The chemical shifts are reported in δ (ppm) relative to TMS. The mass spectra were recorded on a API 2000 Perkin Elmer PE-SCIEX mass spectrometer.
Synthesis of 2-(4-Aminomethylphenyl)benzamide Hydrochloride (2): 2-(4-Aminomethylphenyl)benzonitrile hydrochloride (150 g, 0.614 mol) was neutralized in a mixture of CH2Cl2 (750 mL) and H2O (300 mL) at 15-20 °C by the addition of NaOH (25.90 g, 0.647 mol). The organic layer was separated and washed with H2O and concentrated. The concentrated mass was dissolved in t-BuOH (450 mL) and heated to 65 °C. Freshly prepared KOH powder (48.52 g, 85%, 0.736 mol) was added and heated to reflux for 7 h. The reaction mixture was cooled to r.t. and diluted with CH2Cl2 (750 mL) followed by H2O (600 mL). The aqueous layer was separated and extracted with CH2Cl2 (750 mL). The combined CH2Cl2 extract was washed with H2O (300 mL) and dried over anhyd Na2SO4. The pH was adjusted to 1.2-1.4 with HCl acid at 2-5 °C over a period of 60 min and stirring was continued for another 60 min. The precipitate obtained was collected by filtration and dried to afford the title compound (135 g, 83.8%) as a white crystalline powder; mp 140-142 °C (Lit.3 182 °C). 1H NMR (300 MHz, DMSO-d 6): δ = 4.03 (br s, 2 H), 7.33-7.57 (m, 10 H), 8.66 (br s, 3 H). 13C NMR (75 MHz, DMSO-d 6): δ = 42.7, 128.1, 128.4, 129.3, 129.7, 130.1, 130.7, 133.8, 138.2, 139.1, 141.4, 171.9. MS: m/z = 227.2 [M+].

12

Typical Experimental Procedure for the Synthesis of 4-[α-( n -Acylamino)cyclopentamidomethyl]-2′-carbox-amidobiphenyls 3a-e: Compound 2 (115 g, 0.438 mol) was added to a mixture of dicyclohexylcarbodiimide (DCC; 99.36 g, 0.482 mol) in CH2Cl2 (2300 mL) followed by compound 1a 10 (93.38 g, 0.438 mol) at 25-30 °C. Thereafter, N-hydroxybenzotriazole (11.85g, 0.087 mol) was added followed by diisopropylethylamine (62.70 g, 0.482 mol) and heated to reflux for 6 h. The reaction mixture was cooled to 25 °C and the salts were filtered. The filtrate was washed with H2O (230 mL) followed by sat. Na2CO3 solution (575 mL) and concentrated to a 1200-mL volume. The slurry obtained was cooled to 10-15 °C and stirred for 1 h. The solid was filtered and washed with precooled CH2Cl2 (230 mL) and dried to afford compound 3b as a white powder; mp 100-101 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 0.83-0.88 (t, J = 7.41 Hz, 3 H), 1.22-1.29 (m, 2 H), 1.45-1.50 (m, 2 H), 1.60-2.00 (m, 4 H), 1.87-2.07 (m, 4 H), 2.11-2.16 (t, J = 7.41 Hz, 2 H), 4.28-4.30 (d, J = 6.04 Hz, 2 H), 7.22-7.48 (m, 8 H), 7.27, 7.62 (2 × br s, 2 H), 7.89 (s, 1 H), 8.02-8.06 (t, J = 6.04 Hz, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 14.7, 22.7, 24.8, 28.2, 36.1, 37.1, 42.9, 67.1, 127.3, 127.7, 128.9, 130, 130.7, 138.2, 139.4, 139.6, 139.8, 171.1, 173.4, 174.7. MS: m/z = 422.2 [M+]. Anal. Calcd for C25H31N3O3: C, 71.23; H, 7.41; N, 9.97. Found: C, 71.01; H, 7.41; N, 9.99.
4-[α-( n -Hexanoylamino)cyclopentamidomethyl]-2′-carboxamidobiphenyl (3a): mp 137-138 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 0.82-0.86 (t, J = 7.41 Hz, 3 H), 1.24-1.28 (m, 2 H), 1.47-1.52 (m, 2 H), 1.61-1.63 (m, 4 H), 1.88-2.07 (m, 8 H), 2.10-2.15 (t, J = 7.41 Hz, 2 H), 4.29-4.30 (d, J = 6.04 Hz, 2 H), 7.22-7.48 (m, 8 H), 7.27, 7.62 (2 × br s, 2 H), 7.89 (s, 1 H), 8.02-8.06 (t, J = 6.04 Hz, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 14.8, 22.8, 24.8, 25.7, 31.8, 36.3, 37.1, 42.8, 67.1, 127.3, 127.7, 128.3, 128.9, 130.0, 130.6, 138.2, 139.4, 139.5, 139.8, 172.1, 173.4, 174.7. MS: m/z = 434.2 [M-]. Anal. Calcd for C26H33N3O3: C, 71.70; H, 7.64; N, 9.65. Found: C, 71.44; H, 7.65; N, 9.67.
4-[α-( n -Butanoylamino)cyclopentamidomethyl]-2′-carboxamidobiphenyl (3c): mp 108-109 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 0.82-0.85 (t, J = 7.41 Hz, 3 H), 1.47-1.52 (m, 2 H), 1.60-1.62 (m, 4 H), 1.88-2.03 (m, 4 H), 2.08-2.13 (t, J = 7.41 Hz, 2 H), 4.28-4.30 (d, J = 6.04 Hz, 2 H), 7.22-7.46 (m, 8 H), 7.25, 7.45 (2 × br s, 2 H), 7.88 (s, 1 H), 8.01-8.05 (t, J = 6.04 Hz, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 14.5, 19.4, 24.8, 37.1, 38.3, 39.5, 42.8, 67.1, 127.3, 127.7, 128.3, 128.9, 130.0, 138.2, 139.4, 139.5, 139.8, 172.1, 173.2, 174.7. MS: m/z = 406.3 [M-]. Anal. Calcd for C24H29N3O3: C, 70.74; H, 7.17; N, 10.31. Found: C, 71.00; H, 7.16; N, 10.31.
4-[α-( n -Propylamino)cyclopentamidomethyl]-2′-carboxamidobiphenyl (3d): mp 189-190 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 0.96-1.00 (t, J = 7.41 Hz, 3 H), 1.62-1.64 (m, 4 H), 1.86-2.10 (m, 4 H), 2.13-2.18 (t, J = 7.41, 2 H), 4.28-4.30 (d, J = 6.04 Hz, 2 H), 7.22-7.49 (m, 8 H), 7.32, 7.61 (2 × br s, 2 H), 7.86 (s, 1 H), 8.03-8.07 (t, J = 6.04 Hz, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 10.5, 24.9, 29.4, 37.2, 42.8, 67, 127.3, 127.7, 128.3, 130, 130.7, 138.2, 139.4, 139.5, 139.9, 172.1, 174, 174.7. MS: m/z = 392.2 [M-]. Anal. Calcd for C23H27N3O3: C, 70.21; H, 6.92; N, 10.68. Found: C, 70.50; H, 6.91; N, 10.70.
4-[α-( n -Formyloxyamino)cyclopentamidomethyl]-2′-carboxamidobiphenyl (3e): mp 87-88 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 1.65-1.67 (m, 4 H), 1.90-2.11 (m, 4 H), 4.29-4.31 (d, J = 6.04 Hz, 2 H), 7.22-7.48 (m, 8 H), 7.26, 7.61 (2 × br s, 2 H), 7.96 (s, 1 H), 8.20-8.24 (t, J = 6.04 Hz, 1 H), 8.27 (s, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 24.8, 38.0, 42.9, 66.7, 127.3, 127.7, 128.3, 129.0, 129.1, 130.0, 130.7, 138.2, 139.4, 139.5, 139.7, 162.1, 165.4, 172.1, 174.1. MS: m/z = 434.2 [M-]. Anal. Calcd for C21H23N3O3: C, 69.02; H, 6.34; N, 11.50. Found: C, 69.11; H, 6.34; N, 11.51.

13

Typical Experimental Procedure for the Synthesis of 2-Alkyl-3-[ p -( o -amidophenyl)benzyl]-1,3-diaza-spiro[4.4]non-1-en-4-ones 4a-e: Trifluoroacetic acid (15.5 g, 0.136 mol) was added to a preheated suspension of 4-[α-(n-pentanoylamino)cyclopentamidomethyl]-2′-carbox-amidobiphenyl (3b; 50 g, 0.124 mol) in o-xylene (500 mL) over a period of 30 min. Thereafter, the mixture was heated to reflux for 18 h. Xylene was distilled off and a mixture of EtOAc (750 mL) and H2O (250 mL) was added at 55 °C and the reaction mixture was cooled to r.t. The pH was adjusted to 9.0-9.5 with aq NH3 and stirred for 5 min. The organic layer was separated and washed with H2O (250 mL). The organic layer was concentrated to a volume of about 250 mL and cooled to 0-5 °C. The slurry obtained was stirred for 30 min to complete the crystallization. The solid obtained was filtered and washed with precooled EtOAc (50 mL) and dried to afford 2-(n-butyl)-3-[p-(o-amidophenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one (4b) as a white crystal-line powder; mp 146-147 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 0.79-0.83 (t, J = 7.41 Hz, 3 H), 1.20-1.29 (m, 2 H), 1.48-1.51 (m, 2 H), 1.67-1.85 (m, 8 H), 2.32-2.37 (t, J = 6.04 Hz, 2 H), 4.71 (s, 2 H), 7.15-7.50 (m, 8 H), 7.30, 7.66 (2 × br s, 2 H). 13C NMR (75 MHz, DMSO-d 6): δ = 14.5, 22.4, 26.3, 27.5, 28.4, 37.7, 43.2, 76.7, 127.0, 127.9, 128.4, 129.6, 130.1, 130.7, 131.9, 136.8, 138.2, 139.2, 140.5, 162.0, 172.0, 186.6. MS: m/z = 404.5 [M+]. Anal. Calcd for C25H29N3O2: C, 74.41; H, 7.24; N, 10.41. Found: C, 74.70; H, 7.25; N, 10.43. 2-(n -Pentyl)-3-[ p -( o -amidophenyl)benzyl]-1,3-diaza-spiro[4.4]non-1-en-4-one (4a): mp 142-144 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 0.78-0.82 (t, J = 7.41 Hz, 3 H), 1.20-1.23 (m, 2 H), 1.25-1.85 (m, 10 H), 2.31-2.36 (t, J = 6.04 Hz, 2 H), 4.71 (s, 2 H), 7.15-7.49 (m, 8 H), 7.30, 7.65 (2 × br s, 2 H). 13C NMR (75 MHz, DMSO-d 6): δ = 14.7, 22.6, 25.1, 26.3, 28.6, 31.5, 37.7, 43.2, 76.7, 127.0, 127.9, 128.4, 129.6, 130.1, 130.7, 136.8, 138.2, 139.2, 140.4, 162.0, 171.9, 186.6. MS: m/z = 418.0 [M+]. Anal. Calcd for C26H31N3O2: C, 74.79; H, 7.48; N, 10.06. Found: C, 75.00; H, 7.48; N, 10.11.
2-(n -Propyl)-3-[ p -( o -amidophenyl)benzyl]-1,3-diaza-spiro[4.4]non-1-en-4-one (4c): mp 182-184 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 0.85-0.90 (t, J = 7.41 Hz, 3 H), 1.53-1.58 (m, 2 H), 1.60-1.99 (m, 10 H), 2.30-2.35 (t, J = 6.04 Hz, 2 H), 4.78 (s, 2 H), 7.08-7.50 (m, 8 H), 7.30, 7.65 (2 × br s, 2 H). 13C NMR (75 MHz, DMSO-d 6): δ = 14.3, 18.8, 26.3, 30.5, 37.7, 43.1, 76.7, 127.0, 127.9, 128.4, 129.6, 130.1, 136.8, 138.2, 139.2, 140.4, 161.8, 172.0, 86.6. MS: m/z = 390.3 [M+]. Anal. Calcd for C24H27N3O2: C, 74.01; H, 6.99; N, 10.79. Found: C, 74.20; H, 7.00; N, 10.80.
2-Ethyl-3-[ p -( o -amidophenyl)benzyl]-1,3-diaza-spiro[4.4]non-1-en-4-one (4d): mp 102-104 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 0.95-0.99 (t, J = 7.41 Hz, 3 H), 1.60-1.63 (m, 8 H), 2.20-2.25 (t, J = 6.04 Hz, 2 H), 4.78 (s, 2 H), 7.18-7.40 (m, 8 H), 7.30, 7.65 (2 × br s, 2 H). 13C NMR (MHz, DMSO-d 6): δ = 14.3, 19.8, 24.3, 37.2, 38.5, 39.4, 42.1, 76.7, 127.4, 127.9, 128.4, 129.6, 130.1, 138.2, 139.2, 139.9, 161.7, 172.0, 186.5. MS: m/z = 376.1 [M+]. Anal. Calcd for C23H25N3O2: C, 73.57; H, 6.71; N, 11.90. Found: C, 73.61; H, 6.70; N, 11.91.
3-[ p -( o -Amidophenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one (4e): mp 152-154 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 1.67-1.84 (m, 8 H), 4.67 (s, 2 H), 7.23-7.50 (m, 8 H), 7.29, 7.66 (2 × br s, 2 H), 8.03 (s, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 26.2, 37.5, 44.2, 77.7, 127.7, 127.9, 128.0, 129.6, 130.1, 130.7, 136.6, 138.2, 139.2, 140.6, 153.3, 171.9, 185.6. MS: m/z = 390.3 [M+]. Anal. Calcd for C21H21N3O2: C, 72.60; H, 6.09; N, 12.10. Found: C, 72.70; H, 6.10; N, 12.11.

14

Typical Experimental Procedure for the Synthesis of 2-Alkyl-3-[2′-(1 H -tetrazol-5-yl)(1,1′-biphenyl-4-yl)meth-yl]-1,3-diazaspiro[4.4]non-1-en-4-ones 5a-e: Sodium azide (16.20 g, 0.249 mol) was added to tributyltin chloride (81 g, 0.249 mol) at 25-30 °C under a nitrogen atmosphere and the contents were stirred for 30 min at the same temperature. Thereafter, DMF (13 g, 0.18 mol) was added at 25-30 °C and the stirring continued for 30 min at temperatures below 45 °C. o-Xylene (50 mL) was added followed by 2-(n-butyl)-3-[p-(o-amidophenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one (4b; 50 g, 0.124 mol). The temperature was raised to 150-155 °C and the stirring was continued for 60 h at the same temperature under nitrogen atmosphere. Thereafter, the reaction mixture was cooled to 25 °C and diluted with CH2Cl2 (200 mL), o-xylene (100 mL) and H2O (100 mL) at the same temperature. HCl acid (13 g, 35%) was added in 15 min at 25 °C and stirring was continued for 1 h at the same temperature. The precipitated solid was filtered and washed with a CH2Cl2 and o-xylene (1:1) mixture. The wet material was dried under reduced pressure at 65-70 °C to afford the compound 2b (54.5 g). It was dissolved in EtOH (1090 mL) at reflux temperature to get a cloudy solution and was cooled to 60 °C. Carbon (5 g) and hyflo (10 g) were added and the mixture was again refluxed for 15 min. Thereafter, the temperature was brought down to 60 °C and the mixture was filtered to remove carbon. The filtrate was concentrated to 500-mL volume under reduced pressure at 55-65 °C. The resulting suspension was cooled to 5-10 °C and stirred for 1 h at the same temperature. The solid was filtered and washed with precooled EtOH (100 mL) and dried under reduced pressure at 65-70 °C to afford the title compound, 2-(n-butyl)-3-[2′-(1H-tetrazol-5-yl)(1,1′-biphenyl-4-yl)methyl]-1,3-diaza-spiro[4.4]non-1-en-4-one [irbesartan (5b); 42.5 g, 80%)] as a white crystalline powder; mp 181-182 °C (Lit.3 182 °C). 1H NMR (300 MHz, DMSO-d 6): δ = 0.70-0.91 (t, J = 7.41 Hz, 3 H), 1.20-1.40 (sext, 2 H), 1.45-1.60 (quint, 2 H), 1.60-2.00 (m, 8 H), 2.20-2.40 (t, J = 6.04 Hz, 2 H), 3.00-3.60 (br s, 1 H), 4.60-4.80 (s, 2 H), 7.32-7.95 (m, 8 H). 13C NMR (75 MHz, DMSO-d 6): δ = 14.5, 22.4, 26.3, 27.4, 28.3, 37.7, 43.1, 76.7, 124.3, 127.1, 128.7, 130.1, 131.4, 131.9, 137.2, 139.2, 141.9, 155.9, 162.0, 186.5. MS: m/z = 429 [M+].
2-(n -Pentyl)-3-[2′-(1 H -tetrazol-5-yl)(1,1′-biphenyl-4-yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (5a): mp 184-185 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 0.78-0.83 (t, J = 7.41 Hz, 3 H), 1.19-1.21 (m, 4 H), 1.48-1.84 (m, 10 H), 2.25-2.30 (t, J = 6.04 Hz, 2 H), 3.00-3.60 (br s, 1 H), 4.67 (s, 2 H), 7.08-7.70 (m, 8 H). 13C NMR (75 MHz, DMSO-d 6): δ = 14.7, 22.6, 25.0, 26.3, 27.4, 28.6, 31.4, 37.7, 43.1, 76.7, 124.3, 127.1, 128.7, 130.1, 131.4, 131.5, 131.9, 137.2, 139.2, 141.9, 155.9, 162.0, 186.5. MS: m/z = 443.2 [M+]. Anal. Calcd for C26H30N6O: C, 70.56; H, 6.83; N, 18.99. Found: C, 70.71; H, 6.84; N, 19.00.
2-( n -Propyl)-3-[2′-(1 H -tetrazol-5-yl)(1,1′-biphenyl-4-yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (5c): mp 110-112 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 0.83-0.89 (t, J = 7.41 Hz, 3 H), 1.55-1.60 (quint, 4 H), 1.85-2.02 (m, 8 H), 2.72-2.77 (t, J = 6.04 Hz, 2 H), 3.20-3.80 (br s, 1 H), 7.10-7.20 (m, 4 H), 7.50-7.70 (m, 4 H). 13C NMR (75 MHz, DMSO-d 6): δ = 14.0, 19.0, 26.1, 29.8, 37.6, 44.2, 72.7, 124.4, 127.7, 128.8, 130.2, 131.4, 131.5, 131.9, 134.9, 139.9, 141.8, 155.9, 172.5, 180.4. MS: m/z = 413.2 [M-]. Anal. Calcd for C24H26N6O: C, 69.54; H, 6.32; N, 20.27. Found: C, 69.23; H, 6.32; N, 20.29.
2-Ethyl-3-[2′-(1 H -tetrazol-5-yl)(1,1′-biphenyl-4-yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (5d): mp 104-106 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 1.19-1.24 (t, J = 7.41 Hz, 3 H), 1.94-2.03 (m, 8 H), 2.76-2.78 (q, 2 H), 3.50 (br s, 1 H), 4.86 (s, 2 H), 7.20-7.30 (m, 4 H), 7.60-7.78 (m, 4 H). 13C NMR (75 MHz, DMSO-d 6): δ = 9.8, 22.3, 26.2, 37.5, 44.0, 73.5, 124.3, 127.7, 128.7, 130.2, 131.4, 131.5, 131.9, 135.3, 139.7, 141.8, 155.9, 171.6, 181.5. MS: m/z = 399.1 [M-]. Anal. Calcd for C23H24N6O: C, 68.98; H, 6.04; N, 20.99. Found: C, 69.11; H, 6.03; N, 21.00.
3-[2′-(1 H -Tetrazol-5-yl)(1,1′-biphenyl-4-yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (5e): mp 190-191 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 1.65-1.86 (m, 8 H), 4.65 (s, 2 H), 7.08-7.19 (m, 4 H), 7.54-7.71 (m, 4 H), 8.0 (s, 1 H), 16.37 (br s, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 26.2, 37.4, 44.1, 77.7, 124.3, 127.8, 128.7, 130.1, 131.5, 132.0, 137, 139.4, 141.9, 153.3, 155.9, 185.5. MS: m/z = 371.1 [M-]. Anal. Calcd for C21H20N6O: C, 67.73; H, 5.41; N, 22.57. Found: C, 67.91; H, 5.41; N, 22.60.