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Rivastigmine International Journal of Organic Chemistry, 2011, 1, 26-32 doi:10.4236/ijoc.2011.12005 Published Online June 2011 (http://www.SciRP.org/journal/ijoc) A Simple and Highly Efficient Enantioselective Synthesis of (S)-Rivastigmine Veera R. Arava1*, Laxminarasimhulu Gorentla1, Pramod K. Dubey2 1R&D Laboratory, Suven Life Sciences Ltd., Hyderabad, India 2Department of Chemistry, J. N. T. University, Hyderabad, India E-mail: [email protected] Received April 1, 2011; revised May 17, 2011; accepted May 28, 2011 Abstract A highly efficient and convenient procedure for the enantioselective synthesis of (S)-Rivastigmine, a cho- linergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson’s disease, is accomplished by the treatment of versatile, readily accessible (S)-(-)-2-methyl- 2-propanesulfinamide with 3-hydroxyacetophenone. This protocol provides high yield and excellent enan- tiomeric excess in short step synthesis. Keywords: Cholinergic Agent, Enantioselective, Highly Efficient, (S)-(-)-2-Methyl-2-Propane Sulfinamide, (S)-Rivastigmine 1. Introduction hibits the desired cholinesterase inhibition, which re- quires the drug in enantiomerically pure form. Alzheimer’s disease (AD) is the most common form of The insertion of chiral amine functionality through dementia, a severe human health threat with more than N-sulfinylimines is a major breakthrough endeavor due 30 million sufferers worldwide [1]. Rivastigmine, (S)-3- to the exceptional behavior of the chiral sulfinyl group in [1-(dimethylamino)ethyl] phenyl ethyl (methyl) car- N-sulfinylimines, as an activator, chiral controller and bamate 1, is the first USFDA approved drug in the form useful protective group and finally recyclability [8] of capsules and patches for the treatment of mild to makes the sulfinamides extremely versatile chiral re- moderate dementia of the Alzheimer’s type [2-5] and for agents (Figure 2) [9]. mild to moderate dementia related to Parkinson’s disease [6]. In the year 2006, it has been used in more than 6 2. Results and Discussion million patients worldwide. Rivastigmine works by in- hibiting both butyrylcholinesterase (BuChE) and acetyl- Our research group has been interested in utilization of cholinesterase (AChE) with the same potency, unlike these sulfinamides in industrial perspective for the de- donepezil 2 (which selectively inhibits acetylcholines- velopment of facile chemical processes for active phar- terase), mimantine 3 and galanthamine 4. Its pharmacol- maceutical ingredients (API’s) [10]. Although several ogical effect is selectively on the central nervous system, methods for the synthesis of rivastigmine and phenyl- preferentially on the monomeric G1 isoform of AChE carbamate derivatives have been reported (Scheme 1), (selectivity for different isoforms of BuChE have not yet these methods suffer from limitations. Initial approaches been investigated). The metabolism of rivastigmine is by have been developed via resolution of recemate using the enzyme cholinesterase and do not depend on the chiral acids [11-14] and transition metal catalysis [15,16]. P450 system in the liver, which reduces the risk of inter- Recent approaches are based on lipase catalyzed kinetic actions with other medications [7]. The other stigmine resolution [17-19], chemoenzymatic asymmetric synthe- products are pyridostigmine 5, physostigmine 6 and neo- sis [20] and asymmetric transfer hydrogenation [21]. stigmine 7 (Figure 1). In order to circumvent these difficulties and provide Rivastigmine has one chiral center with amine func- access to feasible industrial process, we have devised a tionality. Therefore, attention needs to be paid to the highly efficient enantioselective synthetic route based on synthesis of the correct enantiomer. (S)-enantiomer ex- the report that enantiopure tert-butane-sulfinamides take Copyright © 2011 SciRes. IJOC V. R. ARAVA ET AL. 27 O H CH3 H N N O N O H3C N O CH3 N N N O N CH3 CH3 O O N H O (S)-Rivastigmine. 1 Pyridostigmine. 5 Physostigmine. 6 Neostigmine. 7 O O OH H2N O O N H CO N 3 CH3 Donepezil. 2 Mimantine. 3 Galanthamine. 4 Figure 1. Acetylcholinesterase inhibitors. O O S S NH2 NH2 (R)-tert-butanesulfinamide (S)-tert-butanesulfinamide. 8 Figure 2. Chiral tert-butanesulfinamides. O HO N O O O 10 9 re so P a lu a nd ti th B d t on A e n ra u th z o n s a y ti si in P l u tio g ta l n ch a o m ir c s e a re ta l a se l c a ic ca id p t ta s li e ly in sis k O H CH3 N H3C N O CH3 CH3 CH3 (S)-Rivastigmine. 1 c h P C r a e a e s m th h f y o at s m e D P an m n r e zy t t m ic n ri r io c a et t s ti a y c m en n m g th sy ro es a d i y s O h N S H3COH2CO O O 11 12 Scheme 1 part in the direct and enantioselective addition to alde- Initially we have synthesized 1 starting from 3-meth- hydes and ketones [9]. oxyacetophenone 13 [22] via four step synthesis. The Copyright © 2011 SciRes. IJOC 28 V. R. ARAVA ET AL. procedure includes, insitu preparation of N-sulfiny- mization of the reaction conditions and found great im- limine 11 from 13 and (S)-8 using Ti(OEt)4 as Lewis provement in yield and also achieved the excellent enan- acid and water scavenger in tetrahydrofuran. Imine on tiomeric excess of the desired product (100% ee). This reduction with sodium borohydride at –48˚C furnished time we chose 9 as starting material and synthesized 1 in 14. Hydrolysis of the sulfinyl group in 14 with dry two different routes. One is by condensing 1.25 equiv of methanolic hydrogen chloride gives the HCl salt 15 in N-ethyl-N-methylcarbamoyl chloride with 9 in the pres- pure form which on alkali treatment yields the chiral ence of K2CO3 (2.0 equiv) as base and ethyl acetate as amine intermediate 16 in 65% yield with > 99% ee. 16 solvent medium resulted 10 in 98.5% yield. 10 on con- was subjected to N,N-dimethylation using formic acid densation with 8 (S-isomer) furnished the imine interme- and formaldehyde results 17 in 90% isolated yield. De- diate 19 insitu, which was reduced with sodium boro- methylation of 17 in 48% aq.HBr proceeded in 87% hydride at –48˚C to get 20. Hydrolysis of the sulfinyl yield of 18. Finally treatment of 18 with N-ethyl-N- group in 20 and alkali treatment at room temperature methyl carbamoyl chloride in the presence of sodium afforded the desired chiral amine 21 in 81% yield methoxide furnished the free base of 1 in 93% isolated (Scheme 3). N,N-dimethylation of the amine with 98% yield with an enantiomeric excess of >99% (Scheme 2). formic acid and 35% formaldehyde solution liberates Still not satisfied with this yield and chiral purity, we free base of 1 in 95% yield with 100% ee (Scheme 4). set out to investigate the alternate possibilities for opti- And the other route proceeded by the treatment of 9 with O Ti(OEt)4 S NaBH4 H + NH2 N N H3CO THF H CO S 3 –-48°C48˚C H3CO S O reflux O O 13 8 (S)-tbs 11 14 CH HCl K CO 3 NH HCl 2 3 NH HCHO N H CO 2. H CO 2 H CO CH MeOH 3 65% 3 HCOOH 3 3 15 16 base 90% 17 O C O CH CH Cl N H 3 Aq.HBr 3 N N H3C N O CH3 HO CH3 87% NaOMe CH3 CH3 18 93% 1 Scheme 2 O O O N O N O N O O N O S HN S O O 1919 81% 98.5% 1010 2020 Route 1 O H HO NH H C N O 2 O 3 CH CH 9 Route 2 3 3 O 21 C 95% NaBH H Cl N H N 4 N O N HO HO S N O S S –-48°C48˚C K2CO3 22 O 23 O 20 O 76% Scheme 3. Current routes of asymmetric synthesis of 21 from 9. Copyright © 2011 SciRes. IJOC V. R. ARAVA ET AL. 29 O O CH H H 3 NH2 HCOOH N H3C N O H3C N O CH3 HCHO CH3 CH3 CH3 CH3 21 1 Scheme 4 8 (S-isomer) first, then reduction of the N-sulfinylimine Hz, ArH), 3.42 (q, 1H, J = 7.0 Hz, rotamer1 CH2), 3.37 22 followed by amido-ester formation with N-ethyl-N- (q, 1H, J = 7.0 Hz, rotamer2 CH2), 3.04 (s, 1.5H, ro- methyl carbamoyl chloride to afford 20 in 76% yield. tamer1 CH3), 2.95 (s, 1.5H, rotamer2 CH3), 2.55 (s, 3H, Hydrolysis of sulfinyl group with dry methanolic hydro- CH3), 1.21 (t, 1.5H, J = 7.0 Hz, rotamer1 CH3), 1.15 (t, 13 gen chloride and alkali treatment gives 21 base with 1.5H, J = 7.0 Hz, rotamer2 CH3); C NMR (100MHz, chiral purity > 94% in 95% yield (Scheme 3). Finally CDCl3): δC 197.08 (1C, C=O), 153.99 (d, J = 15.0 Hz, N,N-dimethylation of amine 21 with formic acid and 1C, C=O), 151.64 (Caryl), 138.19 (Caryl), 129.26 (Caryl), 35% formaldehyde solution furnished 1 (free base) with 126.57 (Caryl), 124.93 (Caryl), 121.47 (Caryl), 43.98 (1C, 98% chiral purity in 95% yield (Scheme 4). The chiral CH2 of carbamoyl), 34.14 (rotamer1 Mecarbamoyl), 33.70 purity is then improved to 100% by tartarate salt prepa- (rotamer2 Mecarbamoyl), 26.56 (1C, CH3), 13.10 (rotamer1 ration with L-(+)-tartaric acid.
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