Skip to main content

Advertisement

Improved one-pot synthesis of N, N-diisopropyl-3-(2-Hydroxy-5-methylphenyl)-3-phenyl propanamide; a key intermediate for the preparation of racemic Tolterodine

Article metrics

Abstract

An improved, cost effective process for the synthesis of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide; a key intermediate for the preparation of Tolterodine and its related substances were described. The process features one pot synthesis employing inexpensive reagents.

Introduction

Tolterodine is chemically known as (R)-N,N-disiopropyl-3-(2-hydroxy-5-methyl phenyl)-3-phenyl propyl amine. Tolterodine acts as a muscarinic receptor antagonist. It is useful in the treatment of urinary incontinence [1]. Tolterodine tartrate acts by relaxing the smooth muscle tissues in the walls of the bladder by blocking cholinergic receptors [2]. Tolterodine tartrate [3] is marketed by Pharmacia & Upjohn in the brand name of Destrol®.

The present invention relates to a novel process for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4); a key intermediate for the preparation of Tolterodine (1). Some different approaches have been published [48] for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4). These methods involve multistep synthesis using hazardous, expensive reagents and some of the methods [6] involve activators like Grignard reagents, LDA, n-butyl lithium, Lewis acids. Hence there is a need to develop an alternative, plant friendly procedure for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4) from 3,4-dihydro-6-methyl-4-phenylcoumarin (2) (Figure 1).

Figure 1
figure1

Tolterodine (1), Methyl 3-(2-hydroxy-5-methylphenyl)-3-phenylpropanoate (3) and N,N -diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4).

Results and discussion

Ring opening reactions of dihydrocoumarins are well known in literature [911]. But in the present invention, we have described a new methodology (Scheme 1 & Scheme 2) for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4) by using inexpensive and commercially vailable starting materials like 3, 4-dihydro-6-methyl 4-phenylcoumarin (2), which was synthesized from p-cresol and trans-cinnamic acid [12].

Scheme 1
scheme1

N,N -diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide 4.

Scheme 2
scheme2

N -Isopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide 5.

3,4-Dihyhydro-6-methyl 4-phenylcoumarin (2) reacts with diisopropylamine (6) in presence of acetic acid gives N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4) at room temperature. This process of compound 4 is very useful for commercialization of Tolterodine 1 in plant.

In order to optimize the yields, this reaction was studied in different solvents like Dichloromethane, Tetrahydrofuran, Acetonitrile, Toluene, Ethanol, Methanol and Diisopropylether. The reaction parameters are tabulated in Table 1. In methanol, methyl 3-(2-hydroxy-5-methylphenyl)-3-phenylpropanoate (3) was observed as an intermediate, which is not completely converted to amide (4). Hence the yield was found low. Among, diisopropylether was found to be the best suitable solvent for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4), which results maximum yields of 53%.

Table 1 Screening of solvent for the synthesis of compound 4

In our continuous research, this reaction was further studied with acetic acid as a catalyst in diisopropylether. The experiments details are tabulated in Table 2. Based on the results, we observed the yield of compound 4 was increased to 75%, when 4 mole equivalents of acetic acid was used. But our attempts to increase the yield of compound 4 further by adding more equivalents of acetic acid were not successful. With lesser equivalents of acetic acid, we observed lower yields of compound 4.

Table 2 Screening of catalyst for the synthesis of compound 4

Compound 4 is known in literature [412]. Compounds 4a-4c and 5-5c are novel. These compounds upon reduction [412] with LiAlH4, Vitride, Sodium borohydride gives corresponding amines, which are useful in the synthesis of Tolterodine and its related compounds.

Conclusion

An efficient, synthesis of N,N-diisopropyl-3-(2-hydroxy-6-methylphenyl)-3-phenylpropanamide was achieved by one pot synthesis between 3,4-dihydro-6-methyl-4-phenylcoumarin and diisopropylamine.

Experimental

Solvents and reagents were obtained from commercial source and used without purification. The IR spectra (ϑmax, cm-1) were recorded in solid state KBr dispersion using Perkin Elmer FT-IR spectrometer. The 1H NMR and 13C NMR spectra were recorded on Bruker-Avance 300 MHz spectrometer. The chemical shifts were reported in δ/ ppm relative to TMS. The mass spectra were recorded on API 2000 Perkin Elmer PE-Sciex mass spectrometer. The reactions were monitored by Thin–layer chromatography (TLC). Melting points were determined by polman melting point apparatus (Model No MP96), open capillary method and are uncorrected.

General procedure for the synthesis of compounds 4-4c & 5-5c

To a solution of 3,4-dihyhydro-6-methyl 4-phenylcoumarin 2 (10 g, 42 mmol) in diisopropylether (200 mL), N,N-diisopropylamine (33.95 g, 336 mmol) and acetic acid (10 g, 168 mmol) were added at room temperature. The suspension was stirred for 16 h at room temperature. The reaction mass was concentrated, the resulting residue was crystallized with D.M.Water (50 mL) and diisopropyl ether (50 mL) mixture to gave N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide 4 (10.6 g, 75% yield).

This methodology was extended to make similar analogues 4-4c and 5-5c of compound 4 and 5. The analogues were summarized in Tables 3 & 4.

Table 3 Novel analogues of compound 4
Table 4 novel analogues of compound 5 (Scheme 2 )

N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide 4

IR (KBr) cm-1: 3024 (Aromatic C-H, str.), 2949, 2904, 2869 (Aliphatic C-H, str.), 1630 (C═O, str.), 1609, 1555, 1510 (C═C, str.), 1469, 1459 (CH2 bending), 1270 (C-N, str.), 1072 (C-O, str.), 788, 769 (Aromatic CH Out-of-plane bend). 1H NMR (300 MHz, DMSO-d6) δ 1.04 (d, 12H), 2.089 (s, 3H), 2.79 (m, 2H), 3.037 (m, 2H), 4.702 (t, 1H), 6.6 (d, 1H), 6.75 (d, 2H), 7.127-7.246 (m, 5H). 13C NMR (125 MHz, DMSO-d6) δ 19.39, 20.36, 45.69, 115.33, 125.70, 127.20, 128.15, 130.60, 144.43, 152.23, 173.37. MS m/z: 340 [(M + H)+].

N-Isopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide 5

IR (KBr), cm-1: 3030 (Aromatic C-H, str.), 2977, 2932, 2872 (Aliphatic C-H, str.), 1628 (C═O, str.), 1605, 1556, 1509 (C═C, str.), 1496, 1453 (CH2 bending), 1270 (C-N, str.), 1081 (C-O, str.), 790,753 (Aromatic CH Out-of-plane bend). 1H NMR (300 MHz, DMSO-d6) δ 0.9 (m, 6H), 2.16 (s, 3H), 2.69 (m, 2H), 3.69 (m, 1H), 4.74 (t, 1H), 6.6 (d, 1H), 6.76 (d, 2H), 7.08-7.2 (m, 5H), 7.64 (d, 1H). 13C NMR (125 MHz, DMSO-d6) δ 20.37, 22.30, 39.17, 39.50, 39.70, 39.90, 40.00, 40.71, 114.98, 125.54, 126.91, 127.11, 127.81, 128.15, 130.11, 144.48, 152.21, 169.38. MS m/z: 298 [(M + H)+].

N,N-diisopropyl-3-(2-hydroxy-4-methylphenyl)-3-phenylpropanamide 4a

IR (KBr) cm-1: 3024 (Aromatic C-H, str.), 2984, 2950, 2863 (Aliphatic C-H, str.), 1625 (C═O, str.), 1567, 1493 (C═C, str.), 1470, 1427 (CH2 bending), 1282 (C-N, str.), 1072 (C-O, str.), 781,762 (Aromatic CH Out-of-plane bend). 1H NMR (300 MHz, DMSO-d6) δ 1.04 (d, 12H), 2.089 (s, 3H), 2.79 (m, 2H), 3.037 (m, 2H), 4.702 (t, 1H), 6.6 (d, 1H), 6.75 (d, 2H), 7.127-7.246 (m, 5H). 13C NMR (125 MHz, DMSO-d6) δ 20.18, 20.60, 39.0, 39.17, 39.34, 39.50, 39.67, 39.77, 39.84, 40.0, 42.59, 45.22, 116.72, 119.51, 125.41, 127.87, 129.41, 135.58, 145.47, 154.72, 174.71. MS m/z: 340 [(M + H)+].

N-Isopropyl-3-(2-hydroxy-4-methylphenyl)-3-phenylpropanamide 5a

IR (KBr) cm-1: 3026 (Aromatic C-H, str.), 2977, 2934, 2874 (Aliphatic C-H, str.), 1627 (C═O, str.), 1610, 1589, 1543 (C═C, str.), 1492, 1449 (CH2 bending), 1245 (C-N, str.), 1074 (C-O, str.), 780,756 (Aromatic CH Out-of-plane bend). 1H NMR (300 MHz, DMSO-d6) δ 0.9 (m, 6H), 2.16 (s, 3H), 2.69 (m, 2H), 3.69 (m, 1H), 4.74 (t, 1H), 6.6 (d, 1H), 6.76 (d, 2H), 7.08-7.2 (m, 5H), 7.64 (d,1H). 13C NMR (125 MHz, DMSO-d6) δ 0.65, 22.30, 39.17, 39.33, 39.50, 39.67, 39.83, 40.0, 40.74, 115.76, 119.40, 125.51, 127.57, 127.78, 135.95, 144.60, 154.33, 169.42. MS m/z: 298 [(M + H)+].

N,N-diisopropyl-3-(2-hydroxy-3-methylphenyl)-3-phenylpropanamide 4b

IR (KBr), cm-1: 3030 (Aromatic C-H, str.), 2952, 2920, 2877 (Aliphatic C-H, str.),1629 (C═O, str.), 1592, 1548, 1495 (C═C, str.), 1466, 1418 (CH2 bending), 1265 (C-N, str.), 1067.7 (C-O, str.), 780, 769 (Aromatic CH Out-of-plane bend). 1H NMR (300 MHz, DMSO-d6) δ 1.04 (d, 12H), 2.089 (s, 3H), 2.79 (m, 2H), 3.037 (m, 2H), 4.702 (t, 1H), 6.6 (d, 1H), 6.75 (d, 2H), 7.127-7.246 (m, 5H). 13C NMR (125 MHz, DMSO-d6) δ 16.6, 16.81, 19.09, 19.14, 40.01, 43.93, 45.64, 118.75, 125.99, 127.66, 128.10, 133.33, 145.66, 153.17, 175.73. MS m/z: 340 [(M + H)].

N-Isopropyl-3-(2-hydroxy-3-methylphenyl)-3-phenylpropanamide 5b

IR (KBr): cm-1: 3024 (Aromatic C-H, str.), 2944, 2916, 2895 (Aliphatic C-H, str.), 1627 (C═O, str.), 1592, 1561 (C═C, str.), 1466, 1431 (CH2 bending), 1274 (C-N, str.), 1080 (C-O, str.), 779.8, 771 (Aromatic CH Out-of-plane bend). 1H NMR (300 MHz, DMSO-d6) δ 0.9 (m, 6H), 2.16 (s, 3H), 2.69 (m, 2H), 3.69 (m, 1H), 4.74 (t, 1H), 6.6 (d, 1H), 6.76 (d, 2H), 7.08-7.2 (m, 5H), 7.64 (d, 1H). 13C NMR (125 MHz, DMSO-d6) δ 16.78, 22.25, 39.0, 39.16, 39.33, 39.50, 39.59, 39.66, 39.83, 40.01, 41.04, 119.20, 124.58, 125.21, 125.62, 127.87, 128.36, 131.46, 144.53, 152.21, 169.60. MS m/z: 298 [(M + H)+].

N,N-diisopropyl-3-(2-hydroxy phenyl)-3-phenylpropanamide 4c

IR (KBr): cm-1: 3028 (Aromatic C-H, str.), 2944, 2871 (Aliphatic C-H, str.), 1627 (C═O, str.), 1557, 1497 (C═C, str.), 1469, 1452 (CH2 bending), 1270 (C-N, str.), 1073 (C-O, str.), 780,753 (Aromatic CH Out-of-plane bend). 1H NMR (300 MHz, DMSO-d6) δ 1.04 (d, 12H), 2.089 (s, 3H), 2.79 (m, 2H), 3.037 (m, 2H), 4.702 (t, 1H), 6.6 (d, 1H), 6.75 (d, 2H), 7.127-7.246 (m, 5H). 13C NMR (125 MHz, DMSO-d6) δ 20.25, 39.00, 39.17, 39.33, 39.50, 39.67, 39.83, 40.0, 42.53, 45.22, 116.14, 118.75, 125.51, 126.51, 127.97, 132.36, 145.25, 154.92, 174.56. MS m/z: 326 [(M + H)+].

N-Isopropyl-3-(2-hydroxy phenyl)-3-phenylpropanamide 5c

IR (KBr): cm-1: 3027 (Aromatic C-H, str.), 2933, 2874 (Aliphatic C-H, str.), 1626 (C═O, str.), 1557, 1505 (C═C, str.), 1496, 1456 (CH2 bending), 1271 (C-N, str.), 1081 (C-O, str.). 1H NMR (300 MHz, DMSO-d6) δ 0.9 (m.6H), 2.16 (s, 3H), 2.69 (m, 2H), 3.69 (m, 1H), 4.74 (t, 1H), 6.6 (d, 1H), 6.76 (d, 2H), 7.08-7.2 (m, 5H), 7.64 (d, 1H). 13C NMR (125 MHz, DMSO-d6) δ 22.26, 22.28, 38.99, 39.16, 39.33, 39.50, 39.66, 39.73, 39.83, 39.93, 40.0, 40.65, 115.11, 118.725, 125.60, 126.84, 127.79, 130.47, 144.36, 154.48, 169.36. MS m/z: 284 [(M + H)+].

Data of the compounds 4-4c,5-5c

Additional file 1 complete spectral data. This material can be found via the ‘Supplementary Content’ section of this article’s web page’.

References

  1. 1.

    Jonas U, Hoefner K, Madersbacher H, Holmdahl TH: World J Urol. 1997, 15: 144-151. 10.1007/BF02201987.

  2. 2.

    Nilvebrant I, Anderson KE, Gillberg PG, Stahl M, Sparf B: Eur J Pharmacol. 1997, 327: 195-207. 10.1016/S0014-2999(97)89661-6.

  3. 3.

    Tolterodine Tartrate (Destrol®): Physicians Desk Reference. 2012, LLC: Montvale, NJ: PDR Network, 2482-2489. 66

  4. 4.

    Gianolli E, Giannini E, Bigini L, Piccolo O, Holmberg P, Lundholm T: Process for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine and its salts. PCT Int Appl. 2012, 157: 294728-WO 2012098044 A1 20120726 CAN

  5. 5.

    Kobayashi K, Nishikata T, Yamamoto Y, Miyaura N: Stepwise palladium-catalyzed 1,4-addition of arylboronic acids to enones and regioselective Baeyer-Villiger oxidation for enantioselective synthesis of β -diaryl esters and (+)-(R)-tolterodine. Bull Chem Soc Jpn. 2008, 81 (8): 1019-1025. 10.1246/bcsj.81.1019. CAN 149:471296

  6. 6.

    Wang G, Zhang J, He X, Wang Y: Process for preparation of Tolterodine and tartrate. Faming Zhuanli Shenqing. 2009, CN 101445462 A 20090603 CAN 151: 77765-

  7. 7.

    Kompella A, Thungathuthy Srinivasa R, Adibhtla Kali S, Bhujanga R, Venkaiah C, Nannapaneni: Process for the preparation of an intermediate useful in the synthesis of tolterodine. Indian Pat Appl. 2005, IN 2003CH01028 A 20051230 CAN 147: 486225-

  8. 8.

    Razzetti G, Mantegazza S, Rossi R, Allegrini P: A process for the preparation of tolterodine. Eur Pat Appl. 2006, EP 1693361 A1 20060823 CAN 145: 271484-

  9. 9.

    Kelin L, Tunge JA: J Org Chem. 2008, 73: 8651-8653. 10.1021/jo801627z.

  10. 10.

    Li K, Tunge JAJ: J Comb Chem. 2008, 10: 170-174. 10.1021/cc700150q.

  11. 11.

    Bussolari JC, Rehborn DC, Combs DW: Tetrahedron Lett. 1999, 40: 1241-1244. 10.1016/S0040-4039(98)02598-2.

  12. 12.

    Jonsson N, Spart BA, Mikiver L, Moses P, Nilverbrant L, Glas G: U.S. Patent 5,382,600. 1995

Download references

Acknowledgements

The authors gratefully acknowledge the management of Aurobindo pharma limited for allowing to us carryout this research work.

Author information

Correspondence to Garaga Srinivas.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

All authors read and approved the final manuscript.

Electronic supplementary material

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Keywords

  • Coumarin
  • Diisopropylamine
  • Aceticacid
  • Amidation
  • Tolterodine