Concise Preparation of a Stable Cyclic Sulfamidate Intermediate in

Article pubs.acs.org/OPRD

Concise Preparation of a Stable Cyclic Sulfamidate Intermediate in the Synthesis of a Enantiopure Chiral Active Diamine Derivative Jean-Francois Rousseau,* Isaac Chekroun, Vincent Ferey, and Jean Robert Labrosse Sanofi Recherche, Chemistry and Biotechnologies Development, 371 av Pr. J. Blayac, 34184 Montpellier, France ABSTRACT: A classical resolution was studied and developed from 2-benzoyl-pyridine in order to prepare SSR504734, a novel antipsychotic derivative. The key step of this route is the substitution of a sulfamidate derivative by a benzamide anion with complete inversion of configuration. The sulfamidate is prepared in a two-step procedure by reacting erythro phenyl-piperidine2-yl-methanol derivative with thionyl chloride followed by oxidation with ruthenium oxide. This sulfamidate is an easily scalable intermediate that produce a diamine intermediate with the expected configuration.

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INTRODUCTION The glutamate hypothesis of the cause of schizophrenia postulates that the positive, negative, and cognitive symptoms of this devastating disease originate at least in part from faulty glutamatergic signaling via NMDA receptors, This article extends an earlier process research study in order to produce the first kilogram of SSR504734, the lead compound discovered by Sanofi that shows promise as a novel potential antipsychotic agent by improving NMDA signaling.1

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SECOND GENERATION PROCESS

The intent was to prepare the amino alcohol from a cheap and available raw material, and so the study was focused on 2benzoyl-pyridine 15, which could be easily hydrogenated into a mixture of erythro 16 and threo 17 amino alcohols (Scheme 3).4 This new potential route could be very interesting if the main erythro enantiomer could be used directly. In order to obtain the desired diastereomer, it was necessary to perform a SN2 displacement at the carbon bearing the alcohol function. Under these conditions, the absolute configuration (S,S) may be obtained from an erythro amino-alcohol (R,S) 5 (Scheme 4). This SN2 displacement becomes possible only when the protecting group of the piperidine does not allow the formation of an aziridinium intermediate. During the literature searching, a very interesting article was found where the authors demonstrated that the attack of a nucleophile on a sulfamidate type compound 20 was regioselective and stereoselective, with total inversion of configuration on the carbon bearing oxygen (Scheme 5).5 So, taking into account this regioselective and stereoselective advantage, it was hypothesized that a cyclic sulfamidate derived from the amino-alcohol 5 could produce the desired product with good stereoselectivity. Thus, it was planned to use the cyclic sulfamidate to simultaneously protect the piperidine, activate the benzylic alcohol, and realize nucleophilic displacement at the benzylic position with inversion of configuration. Starting from 2-benzoyl-pyridine, we developed the synthesis of SSR504734 via a sulfamidate intermediate (Scheme 6) by performing a reduction of the ketone followed by resolution, which was estimated to give the cheapest process.

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DISCOVERY ROUTE The discovery route starts with the pipecolic acid 1 derivative (Scheme 1). The (L)-N-Boc pipecolic acid is first activated to a Weinreb derivative in order to introduce the phenyl moiety at low temperature via the selective addition of phenyl lithium at −30 °C. The ketone is then selectively reduced into the corresponding alcohol using L-selectride and, after removing the N-Boc protecting group, the expected amino alcohol 5 is obtained after crystallization with good enantiomeric excess (up to 98%).2 The key step of this synthesis is the nucleophilic substitution of the alcohol by ammonia with retention of configuration (Scheme 2). An allyl protection is used in order to allow the introduction of the amine function, but during this amine introduction an azepine 9 impurity is always observed in the reaction mixture. This ring expansion is a well-known reaction described by Cossy et al.3 The formation of expected compound 8 and the azepine 9 byproduct (around 10% detected) could be explained by the formation of an aziridinium intermediate 7. This byproduct is difficult to eliminate; at lab scale, several chromatographic purifications must be performed in order to eliminate it after the coupling with the aryl acid chloride. The final deprotection is performed by using soluble palladium catalyst. The 10 step discovery route used to prepare SSR504734 presents numerous drawbacks related to industrial scale up, especially when considering that the targeted production should be several metric tons per year: − Availability and price of the (L)-N-Boc pipecolic raw material at metric ton scale; − Low temperature required in two different steps; © XXXX American Chemical Society

− Azepine byproduct formation; − Final Palladium deprotection with subsequent residual palladium (up to 100 ppm) in the final API which required several crystallizations to eliminate palladium.

Received: August 18, 2014

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DOI: 10.1021/op500264v Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Organic Process Research & Development Scheme 1

Scheme 2

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RESULTS AND DISCUSSION

is only 2.5 volumes with regard to the mass of reagent. In addition, the 2.5% w/w platinum oxide necessary for the hydrogenation does not suffer from scale-up conditions. Only 2 h were required to hydrogenate 10 kg of 2-benzoylpyridine.

The 2-benzoylpyridine 15 was hydrogenated in acetic acid using 2.5% platinum oxide at 3.5 bar in 2 h (Scheme 6). This step is very productive because the quantity of acetic acid used B


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Scheme 4

combination of DMAP and thionyl chloride forms a much more reactive intermediate, resulting in a better selectivity without formation of numerous byproducts. A study of various bases used for the sulfamidite 22 substitution allowed replacement of triethylamine by the combination of pyridine/DMAP, which gave better results. The choice of the mixture of these two bases arose from two results: − When pyridine/DMAP was used, the product could be isolated as a white solid with a good yield (90%) and a very good purity (95%). − When pyridine alone was used, the product was isolated as a brownish solid with a good yield (90%) and a good purity (90%), but with the concomitant presence of tar. The slow addition of thionyl chloride allowed control of the exothermicity, enabling a total conversion directly at the end of addition. Finally, the synthesis of the erythro sulfamidite (R,S) 22 could be realized by the addition of thionyl chloride in the presence of pyridine and DMAP (10% w/w) in dichloromethane at −5 °C. The product was isolated as a mixture of two diastereomers (due to the presence of chiral sulfoxide) with a 92% yield and 98.7% purity. Furthermore, various trials showed that this sulfamidite could be synthesized in no more than five volumes of dichloromethane and in a temperature range between 5 and 10 °C. The oxidation into sulfamidate (R,S) 23 was initially realized by the combination of RuCl3/NaIO4 in an acetonitrile/water mixture.8 This effective method was used during the synthesis of the first batch of SSR504734 and allowed the isolation of the erythro sulfamidate (R,S) with a 96% yield and 97.3% purity. Other oxidizing systems are effective.9 The replacement of sodium periodate by NaOBr3 or NaOCl in the presence of ruthenium trichloride in an acetonitrile/water mixture also permits the conversion into the sulfamidate with good yield and purity. Acetonitrile can be replaced by dichloromethane to avoid a further change of solvent. Finally, oxidation was also possible using bleach only, without ruthenium, but during scale up, the percentage of various impurities was significantly higher. Therefore, further work focused on the combination RuCl3/ NaOCl in dichloromethane. After several trials at different temperatures and with different amounts of RuCl3 and NaOCl,

Scheme 5

The expected phenyl-piperidine-2-yl-methanol was isolated as a mixture of diastereomers (erythro/threo: 80/20) with 95% yield and 99.4% purity by HPLC. The product contains approximately 5% of a fully hydrogenated impurity 25 (Scheme 6), which was measured only by LC-MS analysis. The phenyl-piperidine-2-yl-methanol isomer required for the synthesis of SSR504734 via the “sulfamidate” process is the erythro diastereomer (R,S) 5. To obtain this product, the threo diastereoisomer must be eliminated and the erythro racemic mixture resolved. An important property of this amino-alcohol (16/17) allowed the separation of both diastereomers: the hydrochloride erythro salt is less soluble than the threo salt. Therefore, a crystallization of the hydrochloride salt as a mixture of erythro/threo 80:20 in hydrochloric isopropanol/isopropyl ether produced the erythro amino-alcohol (16) with a good yield but a moderate diastereomeric purity (2.5% of threo). After displacement of the hydrochloride salt, a direct separation of the enantiomers of the enriched erythro phenyl-piperidine-2-ylmethanol 16 was tried. Crystallization of the erythro base 16 in a mixture of ethanol/water (80/20) in the presence of 0.25 equiv of (+)-(D)-di-p-toluoyl tartaric acid was successful. After displacement of the tartaric salt, the amino-alcohol erythro (R,S) enantiomer 5 was isolated in 40% yield and 99% e.e. The synthesis of sulfamidate 23 was first envisaged from the amino-alcohol in the presence of sulfuryl chloride which might avoid an oxidation step.6 Unfortunately, the trials were not satisfactory due to the fact that low yield and numerous degradation products were observed. The next attempt was to generate the sulfamidite 22 derivative by thionyl chloride addition followed by triethylamine in dichloromethane.7 However, this reaction was not reproducible and product was isolated as an oil with a deep purple color and a considerable amount of tar. Morever, the C


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batch. The NaOCl oxidation need further study due to its easier industrial handling and lower price compared to NaIO4. Afterwards, the sulfamidate 23 was not isolated but used directly as a solution in NMP, after solvent exchange with dichloromethane, for the subsequent step. The 2-chloro-3-trifluorobenzamide 24 is obtained from the 2-chloro-3-trifluoro benzoic acid 10 via the corresponding acid chloride with a 84% yield and 99.3% purity.10 Even after trying numerous bases, solvents and temperatures, SN2 displacement of sulfamidite 22 was unsuccessful, so it was mandatory to use the more reactive sulfamidate 23. In the literature,11 the coupling of sulfamidates with nucleophiles is mainly performed in the presence of NaH in DMF. These conditions are not scalable due to safety issues. Thus, the influence of various bases, solvents and temperatures were studied instead. Some trials were performed under phase transfer conditions. The anion of 2-chloro-3-trifluorobenzamide 24 is obtained by reaction of sodium tert-amylate in THF. The sodium tertamylate could be used as a solid or in solution in THF with no impact on yield. The anion of compound 24 was slowly added to the sulfamidate 23 solution in NMP. After hydrolysis of the sulfamic acid intermediate by sulfuric acid, the 2-chloro-N-[(S)phenyl[-(2S piperidine-2-yl]-methyl]-3-trifluoromethyl) benzamide, SSR504734, was isolated with 85% crude yield. A recrystallization in 20 volumes of methyl cyclohexane and 0.2

the sulfamidate was obtained in good yield (up to 95%) and with good purity (up to 97%). An important point remained to study: the elimination of the ruthenium tetroxide and dioxide as byproducts of the oxidation. The presence of RuO2 darkens the organic phase black. Diverse trials to wash the crude with reducing aqueous media such as sodium thiosulfate or sodium metabisulfite, followed by several aqueous washes, gave no reproducible results. Indeed, the treated organic phase often returned to a black color, meaning that some residual ruthenium tetroxide is still present in the organic layer. The alternative was to reduce completely the ruthenium tetroxide to ruthenium dioxide. When studying the reaction in dichloromethane in order to solve this problem, a stoichiometric amount (0.17 equiv) of isopropanol with respect to the amount of ruthenium was added. The metal oxidizes isopropanol into acetone and is reduced into ruthenium dioxide. After filtration, a clear and colorless organic phase was obtained with less than 10 ppm of residual ruthenium (Scheme 7). It is therefore possible to perform the oxidation of sulfamidite 22 into sulfamidate 23 by using 0.75% w/w of RuCl3 in the presence of 3 equiv of NaOCl (1 M) in 5 volumes of dichloromethane at room temperature followed by treatment with isopropanol. But because the NaOCl oxidation process was not reproducible, NaIO4 was used to scale up the first D


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vol of N-methylpyrrolidinone produced a final SSR504734 in high purity (up to 98%). Finally, SSR504734 was obtained starting from 2-benzoylpyridine through the synthesis of an original sulfamidate 23 intermediate as shown in Scheme 8. This robust and scalable process resulted in the expected SSR504734 in seven steps with 15% overall yield, compared with 10% via the discovery route. The process was optimized later on in order to produce kilogram quantities of SS504734 for first GMP batches.

wavelength, 220 nm; mobile phase CH3CN/phosphate buffer pH = 3, gradient 20/80 increasing to 80/20 over a 20 min period. 1H and 13C NMR spectra were recorded on a Varian NMR 400 MHz spectrometer operating at 399.9 MHz in DMSO-d6 for 1H NMR. The chemical shifts, δ, were recorded relative to tetramethylsilane as an internal standard; all coupling constants, J, are reported in Hz. Preparation of Phenyl-piperidine-2-yl-methanol (16/ 17). A solution of 10.061 kg (54.915 mol) of 2-benzoylpyridine (15) in 20 L (2 volumes) of acetic acid was loaded in a 40 L hydrogenator followed by the addition of 250 g (2.5 wt %) platinum oxide (PtO2) suspended in 5 L (0.5 volumes) of acetic acid. The reaction media was shaken at 20 °C under 50 psi (3.5 bar) of hydrogen. Beginning with the agitation under pressure, the internal temperature increases to 45 °C. The flow of hydrogen is then controlled so as to maintain the temperature around 35 °C. After reacting for approximately 3−4 h, the addition of hydrogen was stopped and the reaction worked up. The acetic acid solution was filtered on Celite (Clarcel) to eliminate the catalyst and the cake is washed with 2 × 8 L (0.8 volumes) of water. The filtrate was then concentrated, 40 L (4 volumes) of water was added, and pH of the mixture was adjusted to 14 using concentrated aqueous NaOH (30%). The precipitate was filtered, washed using 2 × 10 L (1 volume) of water, and then dried at 50 °C under vacuum. Phenylpiperidine-2-yl-methanol (16/17) was isolated as a racemic mixture of diastereomers (erythro/threo: 80/20) with a yield of 95% (9 970 g), 99.4% purity, and 100% assay. The product

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EXPERIMENTAL SECTION General Considerations. All reagents were purchased from commercial sources and used without any additional purification. All experiments were carried out under a nitrogen atmosphere to maintain anhydrous conditions. The reaction profiles were followed quantitatively by HPLC on a Varian series 9000 machine used for Method 1: Modulo-Cart QS Uptisphere 120A 5 μm NEC 250 × 4.6, column at 30 °C; flow rate, 0.8 mL/min; injection volume, 10 μL; detection wavelength, 215 nm; mobile phase CH3CN/sodium heptanesulfonate buffer pH = 3, gradient 20/80 increasing to 80/20 over a 25 min period. Method 2: Chiral method used for phenyl-piperidine-2-yl-methanol: AGP 150 × 4.0 chiral AGP 5 μm column at 30 °C; flow rate, 0.8 mL/min; injection volume, 5 μL; detection wavelength, 210 nm; mobile phase MeOH/ KH2PO4 buffer pH = 6.5, 5/95:7.7 min: erythro SR, 8.7 min: erythro RS; 9.7 min: threo RR; 10.5 min: threo SS. Method 3: YMC Pack ODS AQ, 150 × 4.6 mm, 5 mm, 12 mm column at 30 °C; flow rate, 1 mL/min; injection volume, 5 μL; detection E


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-CH2-), 2.4−3.0 (3H, m, -NCH2-, -NCH-), 4.5 (1H, d, J = 5.1 Hz, -CHOH-), 7.1−7.3 (5H, m, -CH- phenyl). Preparation of erythro (R,S) Phenyl-piperidine-2-ylmethanol (5). A solution was prepared by dissolving 298 g (1.6 mol) of erythro phenyl-piperidin-2-yl-methanol (16) in 1.14 L (4 volumes) of an ethanol/water (80/20) mixture. To this solution was added 143.3 g (0.4 mol) (+)-(D)-di-p-toluoyl tartaric acid previously dissolved in 274 mL (2 volumes) of an ethanol/water (80/20) mixture. The reaction media was stirred at room temperature for 1 h and the precipitate was filtered, washed with 1 L of absolute ethanol, and dried under vacuum. The erythro (R,S) phenyl-piperidine-2-yl-methanol (5) was obtained as a (+)-(D)-di-p-toluoyl taratric acid salt in a ratio of 2:1 with a 40% yield (241 g). HPLC (Method 1): RT, 12.6 min. HPLC (Method 2): Diastereomeric purity: erythro 99%, threo 1%. Enantiomeric purity: erythro (R,S) 98.2%, (S,R) 0.8%, and threo (S,S) 0.8%. The salt was suspended in 1.25 L (5 volumes) of water and treated with 30% NaOH. The heterogeneous media was shaken for 16 h. After filtration, washing with 1 L of water, and drying under vacuum conditions, the enantiomer (R,S) of the erythro form (5) was isolated as a white powder with a 90% yield (108 g). The overall yield for these steps was 36%. HPLC (Method 1): RT, 12.6 min. HPLC (Method 2): diastereomeric purity, erythro 100%; enantiomeric purity, erythro (R,S) 100%, fully hydrogenated impurity 25 < 0.1% (GC-MS); mp 127.6 °C Preparation of Sulfamidite (3R,3aS)-3-Phenyl-hexahydro-[1,2,3]oxathiazolo[3,4-a]pyridine 1-Oxide (22). To a solution of 381 g (1.99 mol) of erythro (R,S) phenyl-piperidine2-yl-methanol (5), 480 mL (6 mol) of pyridine, and 38 g (10% w/w) of DMAP in 3 L (9.5 volumes) of dichloromethane, were

contained approximately 5% of a fully saturated impurity (25), which was not detected in HPLC but by GCMS. HPLC (Method 1): RT, 12.6 min; RT, 20.6 min (2-benzoylpyridine). TLC: dichloromethane/methanol 90/10, Rf = 0.2; mp 132.2 °C. 1H NMR (CDCl3) δ 1.0−1.8 (6H, m, -CH2-), 2.2−3.0 (3H, m, -NCH2-, -NCH-), 4.3 (0.2H, d, J = 6.3 Hz, -CHOH- threo), 4.5 (0.8H, d, J = 5.1 Hz, -CHOH- erythro), 7.1−7.4 (5H, m, -CH- phenyl). Purification of erythro Phenyl-piperidine-2-yl-methanol (16). In 1 L (2 volumes) of absolute ethanol, 500 g (2.61 mol) of the previous phenyl-piperidine-2-yl-methanol (16/17) erythro/threo racemic mixture 80:20 was dissolved and cooled at 0−5 °C followed by the addition of 363 mL (3.14 mol of HCl) of hydrochloric ethanol 8.66 M. The initially heterogeneous reaction media became homogeneous and then reprecipitated. Diethyl ether (6 L) was added, and the reaction medium was shaken for 4 h. The precipitate was filtered, washed with 2 L of diethyl ether, and dried under vacuum. The erythro amino-alcohol (16) was obtained as a hydrochloride salt with a 64% yield (382 g). Analysis: purity diastereomeric erythro 97.5%; threo 2.5%. The hydrochloride was finally suspended in 3.4 L (9 volumes) of water and basified with concentrated aqueous 30% NaOH. The heterogeneous reaction media was shaken for 16 h. After filtration, washing with 3 L of water, and drying under vacuum, the diastereoisomer erythro (16) was isolated as a white powder with a 93% yield (298 g). Overall yield for these steps was 59%. HPLC (Method 1): RT, 12.6 min; HPLC (Method 2): Diastereomeric purity: erythro 99%, threo 1,0%, HPLC purity 99,7%, fully hydrogenated impurity 25: 0.4% (GC-MS); mp 139.2 °C. 1H NMR (CDCl3) δ 1.0−1.8 (6H, m, F


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Organic Process Research & Development

380 g (1.5 mol) of sulfamidate (R,S) (3R,3aS)-3-phenylhexahydro-[1,2,3] oxathiazolo[3,4-a]pyridine 1,1-dioxide (23) in 1.9 L (5 volumes) of NMP was added over 2 h. At the end of the addition, the temperature of the reaction medium was maintained under reflux another 2 h. After cooling to 5 °C, 3.8 L of 20% H2SO4 solution and 6 L of MTBE were added to the reaction medium, which was stirred overnight at room temperature. After decantation, the aqueous phase was washed by 3 × 2 L of MTBE and then the pH was adjusted to 14 with concentrated (30%) NaOH (2.7 L) in the presence of 3 L of toluene. The reaction media was diluted with 15 L with water to solubilize all the sodium sulfate. The organic phase was then washed until neutral pH using 3 × 6 L of water. After concentration under vacuum of this organic phase, the threo SSR504734 (S,S) (14) was isolated as an off-white solid with a 85% yield (507 g). A recrystallization in 20 vol of methyl cyclohexane and 0.2 vol of N-methylpyrrolidinone produced a final SSR504734 in high purity (min. 98%). HPLC (Method 3): RT SSR504734, 12.2 min, 98% purity, enantiomeric purity e.e. = 99.9%. TLC: dichloromethane/methanol 95/5, Rf = 0.17; mp 146 °C. 1H NMR (CDCl3) δ 1.2−1.8 (6H, m, -CH2-), 2.2 (1H, td, J = 11.4/2.8 Hz, -NCH-), 2.8 (1H, m, -NCH2-), 5.1 (1H, dd, J = 7.2/1.7 Hz, -CHOH-), 7.1−7.8 (9H, m, -NHCO-, -CH- phenyl).

added 174 mL (2.39 mol) of thionyl chloride dissolved 160 mL (0.5 volumes) of dichloromethane over a period of 3 h. The temperature was maintained at −5 °C during the entire addition. The initial heterogeneous reaction medium became homogeneous, and then again heterogeneous. After 15 min at −5 °C, the reaction was complete and the reaction medium was returned to room temperature and hydrolyzed by 4 L of water. The organic phase was washed with 4 L of 1 M hydrochloric acid and by 3 × 4 L of water until the pH was neutral. After concentration in vacuo, the sulfamidite erythro (R,S) (22) was isolated as a white solid and a mixture of two diastereomers (due to the sulfoxide) with a 92% yield (436 g), a 98.7% purity, and a 100% assay. HPLC (Method 3): RT, 17.7 min. TLC: pure dichloromethane, Rf1 = 0.66, Rf2 = 0.46; mp 117.5 °C. 1H NMR (CDCl3) δ 0.5 (0.7H, qd, J = 11.4/2.7 Hz, -CH2-), 0.8−1.8 (5.3H, m, -CH2-), 2.6 (0.7H, td, J = 11.4/2.9 Hz, -NCH2-, -NCH-), 2.8−3.2 (0.3H, m, -NCH2-, -NCH-), 3.3−3.8 (2H, m, -NCH2-, -NCH-), 4.3 (0.3H, d, Dia1, J = 7.1 Hz, -CHOSO-), 5.8 (0.7H, d, Dia2, J = 6,3 Hz, -CHOSO-), 7.0−7.4 (5H, m, -CH- phenyl). Preparation of Sulfamidate (3R,3aS)-3-Phenyl-hexahydro-[1,2,3]oxathiazolo[3,4-a]pyridine 1,1-Dioxide (23). On a solution of 584 g (2.75 mol) of sodium periodate and 1.1 g (0.25% w/w/sulfamidite) of ruthenium trichloride in 4.3 L (10 volumes) of water and 1.3 L (3 volumes) of acetonitrile, are added, in 1 h, 435 g (1.83 mol) of erythro sulfamidite (R,S) (22) in a solution in 3 L (7 volumes) of acetonitrile. The temperature was maintained around +5 °C during the entire addition. After 15 min, the reaction was complete. The reaction media was filtered and the cake wass washed with 5 L of ethyl acetate. The organic phase was washed using 5 L of a 0.6 M sodium thiosulfate solution then by 2 × 5 L of water until neutral pH. After concentration in vacuo, the sulfamidate erythro (R,S) (23) was isolated as a white solid with a 96% yield (445 g), 97.3% purity, and 98.6% assay. HPLC (Method 3): the sulfamidate (23) and the sulfamidite (22) have the same retention time in the conditions used. TLC, pure dichloromethane, Rf = 0.60. Revelation with phosphomolybdic acid gave a black color for sulfamidate instead of the sulfamidite which turned brown; mp: 135.2 °C. 1H NMR (CDCl3) δ 0.7 (1H, qd, J = 11,4/4,6 Hz, -CH2-), 1.1−1.8 (5H, m, -CH2-), 2.6 (1H, td, J = 13.2/3.0 Hz, -NCH-), 3.5−3.8 (2H, m, -NCH2-), 5.6 (0.7H, d, Dia2, J = 6.3 Hz, -CHOSO2-), 7.3 (5H, m, -CHphenyl). Preparation of 2-Chloro-3-trifluoromethyl-benzamide (24). A solution of 898 g (4 mol) of 2-chloro-3-trifluorobenzoic̈ acid (10) in 4.5 L (5 volumes) of toluene was warmed to 80 °C before adding, over 2 h, 584 mL (8 mol) of thionyl chloride. The reaction medium was heated under reflux for 2 h and then concentrated. The obtained oil was added to 5 L of 20% w/w aqueous ammonia. After stirring for 16 h, the precipitate was filtered, washed with 1 L of water and dried room under vacuum. The 2-chloro-3-trifluoromethyl benzamide (24) was obtained as a white powder with a 84% yield (749 g) and a HPLC purity of 99.3%; HPLC (Method 3): RT, 9.9 min; mp 118.9 °C. 1H NMR (CDCl3) δ 7.2−8.2 (5H, m, CONH2 and phenyl CH-). Preparation of SSR504734: 2-Chloro-3-methyl-N-((S)phenyl-(S)-piperidin-2-yl-trifluoromethyl)-benzamide (14). To a solution of 502 g (2.25 mol) 2-chloro-3trifluoromethyl-benzamide (24) in 2.5 L (5 volumes) of THF was added 252.6 g (2.175 mol) of sodium tert-amylate. The reaction medium was heated to reflux. After 1 h, a solution of

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AUTHOR INFORMATION

Corresponding Author

*Telephone: +33 4 99 77 47 75. Fax: +33 4 99 77 68 03. Email: jean-francois.rousseau@sanofi.com. Notes

The authors declare no competing financial interest.

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ABBREVIATIONS API=active pharmaceutical ingredient DMAP=dimethylaminopyridin HPLC=high pressure liquid chromatography LC-MS=liquid chromatography−mass spectrometry NMDA=N-methyl-D-aspartate TLC=thin layer chromatography REFERENCES

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Concise Preparation of a Stable Cyclic Sulfamidate Intermediate in

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