Concise Synthesis of (±)-Clopidogrel via Carboxylation of Benzylamine with CO2

Abstract A concise and efficient synthesis of (±)-clopidogrel, an antithrombotic agent, is achieved by inserting CO2 at the benzylic position as the key reaction without using any toxic transition metals. The overall yield of the synthetic process is 38% and the salient features include operationally simple process chemistry and fewer steps. GRAPHICAL ABSTRACT


INTRODUCTION
(S)-Methyl-2-(2-chlorophenyl)-2- (6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate, also known as (S)-clopidogrel (1a), is marketed as hydrogen sulfate salt. It is a potent antiaggregant and antithrombotic drug demonstrated in several experimental models of thrombosis [1] and was the second top-selling drug worldwide in 2005 with the commercial trade name of Plavix. It was marketed and licensed by Sanofi in 1986. The drug was launched on the market following a successful clinical evaluation [2] and studies, which has shown that it tends to block the platelet aggregation more than aspirin 2 and ticlopidine 3, even at much lower dosage. [3] Clopidogrel (1a) has an absolute S configuration [4] and the corresponding R enantiomer is totally devoid of antiaggregating activity. Because of the high biological activity of (S)-clopidogrel, many organic chemists are interested in synthesizing it via chiral or resolution pathway.
There are mainly two kinds of strategies known for its synthesis, such as (i) substitution reaction of 2-chlorophenylglycine or derivatives of 2-chloromandelic acid and (ii) attack of nitrogen nucleophile onto a-halogen substituted phenyl acetonitrile or phenyl acetate, both involving S N 2 substitution reaction. Many other recent methods are known for the synthesis of clopidogrel such as S N 2 displacement, [5] stereoselective hydrogenation, [6] Mannich-type multicomponent reaction, [7] Cu(II)-catalyzed oxidative coupling reaction, [8] and patented methods, [9] involving the resolution of (AE)-clopidogrel using 10-L-camphorsulfonic acid (L-CSA) or its precursor a-amino ester using D-or L-tartaric acid. Some of these intermediates in turn were obtained via simple S N 2 displacement reactions and NaCN addition on imines. [9a] Some of these reported methods do utilize highly poisonous cyanide as nucleophile and highly expensive toxic transition metals as catalyst in existing methods of its synthesis. Thus, there is a need for an efficient synthesis of (AE)-clopidogrel (AE)-1 with one carbon homologation using insertion of CO 2 at the benzylic position, [10] and this strategy has not been reported previously.

RESULTS AND DISCUSSION
CO 2 insertion for an alternative energy sources is a topic of current interest because of the constant rise in global warming and atmospheric CO 2 concentrations. [11] Because it is an attractive one-carbon source for organic synthesis, due to its low cost, low toxicity, and ease of handling, we were interested in its utility in some of organic transformations to synthesize the various substituted cyclic carbonates and propargylic acids. [12] Herein, we present a concise synthesis of (AE)-clopidogrel (AE)-1 by insertion of CO 2 at the benzylic position as the key reaction from readily available and cheap starting materials.
Retrosynthetic analysis of (AE)-clopidogrel (AE)-1 reveals that a -amino ester 7 could be visualized as the key intermediate, which in turn can be obtained from the insertion of CO 2 at the benzylic position in Boc-protected benzylamine 8 derived from 2-chlorobenzaldehyde (4).

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V. VENKATARAMASUBRAMANIAN AND A. SUDALAI at room temperature provided the corresponding imine. The subsequent reduction of imine using NaBH 4 in methanol at 0°C gave the N-substituted-2-chlorobenzylamine 5, which was then protected as Boc-carbamate 6 by treating it with (Boc) 2 O in CH 3 CN at room temperature. (The 1 H NMR spectrum of 6 showed the presence of rotameric proton signals at d 1.41 (brs, 4H), and 1.49 (brs, 5H) as two broad singlets for nine Boc-methyl protons and at d 4.45 (brs, 1H) and 4.55 (brs, 1H) as two broad singlets for two benzylic protons. Its 13 C NMR spectrum also displayed the presence of rotameric carbon signals at d 155.3, and 155.6 for carbonyl carbon present in the Boc group.) Insertion of CO 2 at benzylic position of carbamate 6 was achieved by using n-BuLi as a strong base with the bubbling of CO 2 at À 78°C in dry tetrahydrofuran (THF) to provide the a -amino acid as its lithium salt, as indicated by the formation of turbid pale yellow solution after 3 h. Subsequently, a -amino acid salt was treated with NaHCO 3 and MeI in dimethylformamide (DMF), which gave the a -amino ester 7 in 65% yield. To make this process in an asymmetric fashion, CO 2 was bubbled to a solution containing carbamate 6, (þ)-sparteine (1 equiv), [13] and n-BuLi at À 78°C. However, we ended up with the a -amino ester 7 in only 3% ee. The Boc group in a -amino ester 7 was deprotected using trifluoroacetic acid in CH 2 Cl 2 at 25°C, followed by electrophilic aromatic cyclization (Pictet-Spengler type) on the thiophene ring was achieved, on treatment with paraformaldehyde in one pot at 10°C. It was then quenched with saturated NaHCO 3 solution, which furnished the (AE)-clopidogrel free base, (AE)-1, in 68% yield and whose spectral data are in complete agreement with those reported in the literature. [5] CONCLUSION In conclusion, a concise synthesis of (AE)-clopidogrel with an overall yield of 38% is described. The key reaction employed here is the insertion of CO 2 at the benzylic position, which has been unprecedented for its synthesis. The salient features include fewer steps and avoiding the use of toxic transition metals.

EXPERIMENTAL
All reactions were carried out under a nitrogen atmosphere. Unless otherwise stated, all the chemicals and reagents were obtained commercially. Dry solvents were prepared by the standard procedures. Analytical thin-layer chromatography (TLC) was done on precoated silica-gel plates (Kieselgel 60 F 254 , Merck). Column chromatographic purifications were done with 230-to 400-mesh silica gel. NMR spectra were recorded in CDCl 3 on AV 200 and AV 400 MHz Bruker NMR spectrometers.  (2), and ticlopidine (3).

SYNTHESIS OF (±)-CLOPIDOGREL
All chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane (TMS), and peak multiplicities are referred to as singlet (s), doublet (d), quartet (q), and multiplet (m). Elemental analyses were performed on an Elmentar-Vario-EL (Heraeus Company Ltd., Germany). Infrared (IR) spectra were recorded in CHCl 3 using Shimadzu FTIR-8400 spectrophotometer. Liquid chromatography-mass spectrometry (LC-MS) was carried out on a Thermo Finnigan Surveyor MSQ LC-MS instrument.
Methyl-2-((tert-butoxycarbonyl) (2-(thiophen-2-yl)ethyl)amino)-2-(2chlorophenyl)acetate (7) n-BuLi (2.96 mL, 4.7 mmol) was added dropwise to a stirred solution of carbamate 6 (1.5 g, 4.3 mmol) in dry THF, at À 78°C under N 2 atmosphere for 15 min. CO 2 (1 atm) gas was bubbled through the reaction mixture and allowed to stir for 3 h until it formed a pale yellow turbid solution. This was followed by the addition of NaHCO 3 (540 mg, 6.39 mmol) and MeI (1.5 g, 10.65 mmol) in DMF and stirred for further 3 h at 25°C. The reaction mixture was quenched with saturated NH 4 Cl solution, and the solvent was evaporated under reduced pressure. The obtained crude mixture was extracted with EtOAc (3 × 15 mL) and washed with brine (3 × 10 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 and concentrated. Silica-gel column chromatographic purification of the crude product using petroleum ether = EtOAc (90:10) as eluent gave a -amino ester 7 (1.13 g) as a colorless liquid.