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

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 [4-8] 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) (Fig1).

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

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

 

 

Ring opening reactions of dihydrocoumarins are well known in literature[9-11]. But in the present invention, we have described a new methodology (Scheme 1 & Scheme2) for the preparation ofN,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
N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide 4.

Scheme 2
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.

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).

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)⁺].

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

Garaga Srinivas^12*, Ambati V Raghava Reddy¹, Koilpillai Joseph Prabahar¹, Korrapati venkata vara Prasada Rao¹, Paul Douglas Sanasi² and Raghubabu Korupolu²

• *Corresponding author: Garaga Srinivas srinivasgaraga@yahoo.com

¹Chemical Research and Development Department, Aurobindo Pharma Ltd, Survey No:71&72, Indrakaran Village, Sangareddy Mandal, Medak district, Hyderabad 502329, Andhra Pradesh, India

²Engineering Chemistry Department, AU college of Engineering, Andhra University, Visakhapatnam 530003, Andhra Pradesh, India

Sustainable Chemical Processes 2014, 2:2  doi:10.1186/2043-7129-2-2

The electronic version of this article is the complete one and can be found online at:http://www.sustainablechemicalprocesses.com/content/2/1/2
http://www.sustainablechemicalprocesses.com/content/2/1/2/additional

Srinivas garaga

scientist at Aurobindo Pharma

Chemical Research and Development Department, Aurobindo Pharma Ltd

 

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Anti-inflammatory Properties of an Active Sesquiterpene Lactone and its Structure-Activity Relationship

A sesequiterpenoid, 2α-hydroxyl-3β-angeloylcinnamolide (HAC) was isolated from the Chinese medicinal herb Polygonum jucundum Lindex. (Polygonaceae) with anti-inflammatory activities in vivo. In the present study, we investigated the anti-inflammation effects of HAC on lipopolysaacharide (LPS)-induced murine RAW264.7 cells. As the results, we found that HAC dose-dependently decreased NO over-production with IC50 value of 17.68 μM but showed very weak inhibition on TNF-α release with IC50 value of 98.66 μM. Meanwhile, eight novel derivatives modified at C-2 position of HAC were synthesized to further explore the structure-activity relationships (SARs) of HAC on antiinflammation effects. Compound PJH-1, an acetyl easer of HAC, showed better inhibition on over-production of NO and TNF-α (IC50, 7.31 and 3.38 μM, respectively). Furthermore, we demonstrated that HAC and PJH-1 attenuates the mitogen-activated protein kinases (MAPK) signaling pathways through blocking the phosphorylation of ERK, p38, JNK/MAPK. We also found that the structure of PJH-1 are more stable than that of HAC in cell medium, these finding are useful to develop in vitro molecular mechanism research of HAC. In a conclusion, our studies enhance the understanding of anti-inflammation activities of HAC and lead to the discovery of novel derivatives as potential antiinflammation agents.

Inflammation is the first response of a tissue to injury, it can be classed as both acute and chronic inflammations. Chronic inflammation is a persistent one, which cause progressive damage to the body [1]. Macrophages play a key role in the specific and non-specific immune responses during the inflammation process, after macrophages are activated by LPS, large amounts of the cytokines and inflammatory mediators will be released [2-4]. Among the many pro-inflammatory mediators, NO is a key one in inflammation reactors [5] which is a free radical produced from L-argine by nitric oxide synthases (NOS) and is known to regulate various physiological functions in many tissues [6], however, excessive NO has been implicated in various pathological processes. The inhibition of NO overproduction has been suggested to be an important therapeutic approach for treatment of inflammation [7,8]. Expression of the iNOS in macrophages is regulated mainly at the induction of transcription factors through mitogen-activated protein kinases (MAPKs).
The aerial parts of Polygonum jucundum Lindex. (Polygonaceae) is used as traditional Chinese herbs for inhibiting inflammation, lowering serum cholesterol levels, and treating rheumatism [9-11]. In our previous study, a drimane-type sesquiterpenoid, 2α- hydroxyl - 3β – angeloyl -cinnamolide (HAC) from P. jucundum, was identified with anti-inflammatory effects by oral administration effects by oral administration at dose of 50-200mg/kg in mouse, and a sensitive and rapid LC-MS method was developed to study its pharmacokinetics and distribution in rats [12-14]. Up to now, some natural sesquiterpenoids were shown to possess significant inhibitions on pro-inflammation mediator production [15-17]. The drimane-type sesquiterpenoids has been identified with anti-inflammatory properties [18]. Therefore, in this study, we investigated the effects of HAC on the release of LPS-induced pro-inflammatory mediators and explored the molecular mechanism in terms of inflammatory signaling pathways. Meanwhile, eight novel derivatives modified at carbon-2 position of HAC were synthesized (Scheme 1) to further explore structure-activity relationships (SARs) of HAC on LPS-activated RAW264.7 cells. These studies also lead to a better understanding of the structure-activity relationship for the sesquiterpene lactones family and the discovery of novel derivatives as potential anti-inflammation agents.
2α- acetoxy- 3β- angeloylcinnamolide (PJH-1 C₂₂H₃₀O₆):
To a solution of HAC (200 mg, 0.574 mmol) in di-chloromethane (20 mL) was added DMAP (60 mg) and acetic anhydride (0.54 mL, 1.7 mmol). The reaction mixture was stirred at room temperature for 3 h (TLC monitoring). The crude product was chromatographed on a silica gel column using the elution (petroleum ether: acetyl acetate=1:1) to afford PJH-1 (83% yield) as a white needle crystal. Yield: 83%; white needle crystal. [α]²⁰_D=-0.73° (c 0.3, CH₂Cl₂). ¹H-NMR (CDCl₃, 500 MHz): δ2.02 (1H, dd, J=4.5, 12.5 Hz, H-1β), 1.46 (1H, t, J=12.1, 12.1 Hz, H-1α), 5.16 (1H, m, H-2), 4.94 (1H, d, J=9.0 Hz, H-3), 1.62 (1H, q, J=5.5 Hz, H-5), 2.47 (1H, m, H-6α), 2.25 (1H, m, H-6β), 6.90 (1H, m, H-7), 2.90 (1H, m, H-9), 4.39 (1H, t, J=9.0 Hz, H-11α), 4.05 (1H, t, J=9.0 Hz, H-11β), 1.26 (3H, s, H-13), 1.08 (3H, s, H-14), 0.97 (3H,s, H-15), angelica acyl: δ6.09 (1H, ddd, J=1.5, 1.5, 14.5 Hz, H-3'), 1.98 (3H, dd, J=1.5, 7.5 Hz, 3'-CH₃), 1.89 (3H, t, J=1.5 Hz, 2'-CH₃), Acetyl: 1.96 (3H, s, H-2'). ¹³C-NMR (CDCl₃, 75 MHz): δ42.6 (C-1), 66.7 (C- 2), 79.2(C-3), 39.2(C-4), 48.9(C-5), 24.7(C-6), 135.7(C-7), 126.9(C-8), 50.6(C-9), 35.1(C-10), 68.6(C-11), 167.4(C-12), 17.1(C-13), 28.1(C- 14), 14.3(C-15), angelica acyl: 167.4(C-1'), 127.7(C-2'), 138.4(C-3'), 20.9(2'-CH₃), 15.7(3'-CH₃), acetyl: 167.4(C-1''), 20.5(2'-CH₃).
Anti-inflammatory Properties of an Active Sesquiterpene Lactone and its Structure-Activity Relationship
Yang Hu¹, Fei Zhang², Chaofeng Zhang^1* and Mian Zhang^1
1State Key Laboratory of Natural Medicines, Research Department of Pharmacognosy, China Pharmaceutical University, Longmian Road 639, Nanjing 211198, PR China
²Jiangsu Simcere Pharmaceutical Group Ltd., Xuanwu Avenue No. 699-18, Nanjing 210042, PR China
Chaofeng Zhang
State Key Laboratory of Natural Medicines
Research Department of Pharmacognosy
China Pharmaceutical University
Longmian Road 639, Nanjing 211198
PR China
Tel/Fax: (86)-25-86185140

E-mail: njchaofeng@126.com
Citation: Hu Y, Zhang F, Zhang C, Zhang M (2015) Anti-inflammatory Properties of an Active Sesquiterpene Lactone and its Structure-Activity Relationship. Med chem 5:354-360. doi: 10.4172/2161-0444.1000286

Mian Zhang - China Pharmaceutical University.









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Synthesis of New Heterocyclic Compounds Derived From 5,10- dihydrophenophosphazine

Synthesis of New Heterocyclic Compounds Derived From 5,10- dihydrophenophosphazine
Suad M. Al – Araji., Moayad abood Gban*
Department of Chemistry, College of Science, University of Baghdad, Baghdad, Iraq.
*Email:moayad.kban@yahoo.com
Iraqi Journal of Science, 2015, Vol 56, No.1A, pp: 12-24
http://www.iasj.net/iasj?func=fulltext&aId=99208

Iraqi Journal of Science

المجلة العراقية للعلوم

 

 




Abstract:
This work comprises the synthesis of 18 new N- substituted 5,10- dihydrophenophosphazine.The diphenylamine was chosen as the starting material , which was reacted with phosphorus trichloride at elevated temperature (200-220)0C for 6 hrs, followed by treating the reaction mixture with water to yield 5,10- dihydrophenophosphazine-10-oxide(1), this was reacted with ethylchloroacetat to obtain ethyl(5,10-dihydrophenophosphazine-10- oxide)acetate(2). Compound (2) was converted to acid hydrazide by treating with hydrazine hydrate( 98% ) to obtain 5-(5,10-dihydrophenophosphazine) acetohydrazide-10-oxide (3). The acid hydrazid was used to react with phenylisocyanat , phenylthioisocyanat to give (4,7) respectively which were used to prepare different heterocyclic compounds. Compound (5) was performed by the intramolecular cyclization of (4) in the presence of NaOH(2N).Compound (8) was synthesized by interaction of (7) with NaOH(2N).Compound (6) and (9) were obtaind upon the reaction of semicarbazide (4) and thiosemicarbazide (7) with phosphoric acid at 1200C. Compound (3) undergoes the character condensation reaction with different aromatic aldehyde in ethanol gave the shiff bases (10-18).
5-N-Ethyl (5, 10-dihydrophenophosphazine-10-oxide) acetate (2)
Amixture of 5,10-dihydrophenophosphazine-10-oxide(1),(5g,0.027mol) ethylchloroacetate (3.5ml,0.027 mol) in dry acetone (5 ml) and anhydrous K2CO3 (0.5 g) was refluxed for 24 h, then cooled ,filtered and solvent removed under reduced pressure. The resulting solid was monitored by (T.L.C) and recrystallized from ethanol.

Result and discussion
5,10-dihydrophenophosphazine-10-oxide(1) was prepared by the reaction of diphenylamine and phosphorus trichloride at 2200C followed by hydrolysis of the mixture with hot water [11] show figure 1.Compound(1) was treated with ethylchloroacetate to give N- ethyl(5,10dihydrophenophosphazine- 10-oxide)acetate(2)which was characterized by T.L.C, m.p , 1HNMR and FTIR spectrum figure 2 showed stretching bands at (3186- 3093) cm -1 for aromatic (C-H)., 2977 cm-1 for aliphatic (C-H) ., 2322 cm-1 (P-H).,1751cm-1 for ester(C=O).,(1612-1591-1520) cm-1 for (C=C) aromatic and bending band at 1465 cm-1 for (N-H) [12-14] see table2.

 

 

Iraqi Journal of Science

المجلة العراقية للعلوم

University of Baghdad, College of Science, Department of Chemistry, Karada, Baghdad,








KARADA

A view above karrada - view is taken to Baghdad's Karrada over from a military plane,

- منظر ماخوذ لبغداد من فوق الكرادة من طائرة عسكرية

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