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I will list all the general procedures that I ever did over here. My colleagues told me that organic synthesis is another way of cooking. After so many year of "cooking", I generalized some common "recipes" for common reactions. Hopefully it will help you, the process of organizing this "recipes" definitely helped me.

Reaction set up:

Acylations

Alkylations

Condensations

Decarboxylations

Halogenations

 Hydrolysis

Hydrogenations

Oxidations

Rearrangements

Reductions

Reactions on heterocycle ring

Substitutions

NMR & MS

EDAC/HOBT Coupling.

 

J. Med. Chem. 1998, 41, 4288-4300

A soulution of 3.42 g (15.00 mmol) 2-phenyl-4-hydroymethylbenzoic acid in 30 mL of DMF was treated sequentially with 2.20 g (16.30 mmol) of HOBT, 3.12 g (16.30 mmol) of EDAC, and 3.90 g (19.50 mmol) of L-methionine methyl ester hydrochloride. The suspension was stirred for 15 min, 4.00 mL (27.00 mmol) of TEA was added, and the mixture stirred for 24 hours. The reaction was quenched by pouring into 300 mL of ethyl acetate and extracting with 3 portions of 1 N aqueous HCl, 2 portion of water, 1 portion of brine, 1 portion of saturated aqueous NaHCO3, and a portion of brine. The solution was then dried over Na2SO4, filter, and concentrated. The residue was purified by column chromatography on silica gel (120 g, 70:30 ethyl acetate/hexanes) to provide 4.4 g (79%) of product as an oil that solidified upon standing.

A Grignard reaction.

 

Org. Process Res. Dev., 11 (2), 206 -209, 2007.

Synthetic Procedure for 1-(1H-Imidazol-4(5)-yl)-2-methylpropan-1-one (9). A solution of 4(5)-cyanoimidazole (42.7 g, 0.458 mol) in THF (500 mL) was added dropwise over 30 min to a solution (1.4 L, 1.47 mol) of 1.1 M isopropylmagnesium bromide in THF below 10 oC under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 h. Water (430 mL) and 10% aqueous sulfuric acid solution (860 mL) were added dropwise, and the mixture was stirred at 30 min and titrated to pH 8 with 30% aqueous sodium hydroxide solution. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate (300 mL × 2). The organic layers were combined, and the mixture was washed with aqueous sodium hydrogen carbonate and brine and concentrated under reduced pressure. The crystals formed were collected by filtration and washed with isopropyl ether (300 mL). The crystals were dried in vacuo (40 oC) to give 1-(1H-imidazol-4(5)-yl)-2-methylpropan-1-one  (51.9 g, yield 82%).

 

Aldol Condensation:

 

Org. Process Res. Dev., 11 (1), 13 -18, 2007.

7-[3-(4-Fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoic acid-1,1-dimethylethylester. In a suitable reactor charged with nitrogen, sodium hydride (60% in paraffin oil, 6.0 g, 0.15 mol) was mixed with THF (120 mL) to form a suspension at 20-25 oC. tert-Butyl acetoacetate (23.7 g, 0.15 mol) was added within 30 min maintaining the temperature at 20-25 oC and the mixture was further stirred for 15 min. After cooling to 0 oC, butyllithium (1.6 M in hexane, 97.5 mL, 0.15 mol) was added within 60 min, maintaining the temperature at 0 oC. The reaction mixture was stirred at this temperature for a further 30-45 min. A solution of starting material (38.5 g, 0.125 mol) dissolved in THF (100 mL) was added to the reaction mixture, maintaining the temperature at 0 oC. After 60 min stirring at 0 C, the reaction mixture was quenched with acetic acid (22.6 g, 0.38 mol) and then with water (43.5 mL). The reaction mixture was extracted twice with saturated sodium chloride solution (100 mL) and once with water (50 mL). After removal of the solvents at 30-50 oC and 30 mbar pressure, the evaporation residue containing 57.5 g of product (98.8%) was diluted in THF (75 mL) and kept at 0-5 oC (storage solution of product).

Knoevenagel Condensation.

 

Org. Process Res. Dev., 11 (2), 190 -199, 2007.

Preparation of 5-[4-(2-{[6-(4-Methoxyphenoxy)pyrimidin-4-yl]methylamino}ethoxy)benzylidene]thiazolidine-2,4-dione. To a dry, nitrogen-purged 70-L reactor (Buchi) with a mechanically stirred solution of starting material aldehyde (1.8 kg, 4.8 mol) in 30 L of toluene were successively added 2,4-thiazolidinedione (0.48 kg, 4.8 mol), acetic acid (70 mL, 1.44 mol), and piperidine (0.12 L, 1.4 mol), and then the reaction mixture was stirred at reflux temperature for 5 h with a Dean-Stark water trap (the amount of condensed water was about 86 mL). The disappearance of the starting material was detected by monitoring HPLC (HPLC retention time; starting 7: 12.5 min, product 10: 13.5 min). Once the reaction was completed, the mixture was cooled to room temperature, and the precipitates formed were collected by filtration and washed twice with fresh anhydrous toluene.

Reformatsky Reaction.

 

Organic Process Research & Development 2005, 9, 216-218

The trick of Reformatsky reaction is that the Zn metal must be activated in order to let the Zn react with haloester smoothly. The Zn metal could be activated by heating it with TMSCl, I2, MeMgBr, 1, 2-dibromoethane, CuCl and CuI.

Procedure: CuCl (1.2 kg, 12 mol, 0.2 equiv) was charged into a 250 L alloy 59 vessel. THF (40.0 kg) was added at 20oC. To this solution, Zn powder (US-Zinc, 7.1 kg, 106 mol, 1.7 equiv) was added, followed again by THF (48.8 kg). Concentrated sulfuric acid (1.1 kg, 12 mol, 0.2 equiv) was added, and the mixture was heated to 45 oC. When the target temperature was reached, a solution of indanone (9.8 kg, 60 mol) in THF (88 kg) was added. The latter solution was prepared prior to the reaction and tempered at 45oC. After addition of the indanone solution, bromoester (13.4 kg, 73 mol, 1.2 equiv) was dosed over approximately 15 min. The pump and pipes were rinsed with THF (2 kg). The reaction mixture was stirred with a jacket temperature of 45oC for 1.5 h and subsequently cooled to 20oC. Diluted sulfuric acid (c =20%, 33.3 kg) was added, and the mixture was stirred at 20oC for 10 h. The mixture was transfered via a filter nutsche to 650 L alloy 59 vessel. The first vessel, the filter nutsche, and all pipes were rinsed with toluene (64.8 kg). The mixture was concentrated in vacuo (150 mbar) by distilling off THF (90 kg). Water (3 X 30 kg) was added, and the layers were separated. The aqueous layers were disposed of. THF and toluene (97 kg) were distilled off in vacuo (150 mbar), resulting in a solution of product in toluene (32.7 kg, 41.9 wt % of product), corresponding to an assay-corrected yield of 92% (13.70 kg of product).

Wittig Horner reaction

 

Org. Process Res. Dev., 11 (2), 200 -205, 2007

(5E,7E,22E)-(1S,3R)-1,3-Bis(tert-butyldimethylsilyloxy)-24-oxo-25-(5-butyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen . To 4.84 g of sodium hydride (121 mmol, 60% of a dispersion in paraffine) in 100 mL of THF at 0 oC were added slowly 42 g (133 mmol) of starting material aldehyde dissolved in 250 mL of THF. The solution was stirred for 1 h at rt, and then 65.9 g (115 mmol) of (5E,7E)-(1S,3R)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-secopregna-5,7,10(19)-triene-20-carbaldehyde dissolved in 400 mL of THF were added. The solution was stirred 1 h at 20 C and 19 h at 50 C. The reaction was monitored by thin layer chromatography (TLC) on SiO2 plates (eluent ethyl acetate/hexane 1:9 v/v), Rf = 0.15 (product), Rf = 0.53 (educt 4). 6 g (100 mmol) of acetic acid in 50 mL of THF were added for workup followed by 1 L of water, with citric acid used to adjust pH to 7. The product was extracted twice with 500 mL of methyl tert-butylether and evaporated to dryness. The crude material was purified by chromatography on silica gel by elution with hexanes and an increasing gradient of ethyl acetate (0-15%). The evaporation of the fractions gave 79.5 g of product in 90% yield.

Oxane oxidation of the sulfide

 

Organic Process Research & Development 2006, 10, 512-517

ABT-963. A reactor was charged with 3.0 kg of Deloxan resin and 75 kg of acetone. The mixture was stirred under N2 for 1 h 50 min and then filtered. The resin was washed with 125 kg of acetone and blown dry with N2 to obtain 1.8 kg of dry resin. The dry resin, sulfide (3.0 kg, 6.94 mol) and acetone (19 kg), was charged to a reactor and mixed under N2 for 16 h. The resulting slurry was filtered and washed with acetone (5 kg). The filtrate was assayed by HPLC to determine the recovery of sulfide after Deloxan treatment. 2.80 kg (93.3%) of sulfide were present. A reactor was charged with Oxone monopersulfate compound (12.8 kg, 20.8 mol) and purged with N2. To this reactor were added the acetone/sulfide solution and acetone (4 kg). The reaction mixture was cooled to 5 °C, and then water (3.6 kg) was added at such a rate that the temperature of the reaction mixture did not exceed 12 °C. The mixture was stirred at 10 (5 °C until less than 0.5% of the sulfoxide intermediate remains by HPLC analysis. The reaction mixture was filtered through a filterpot, and the solids (excess Oxone and inorganic byproduct) were washed with acetone (10 kg). The wash and filtrate were combined and treated with 10% aqueous NaHSO3 solution (7.8 kg) maintaining a temperature at 18 °C. The mixture was stirred until a test sample showed that a less than 1 ppm peroxide is present with J.T. Baker “Testrips for Peroxide”. The mixture was filtered through a filterpot to remove salts. Salts were washed with acetone (4 kg). The wash and filtrate were combined and adjusted with 10% aqueous K2CO3 solution (14.6 kg) to a pH of about 8.0 as measured by a pH meter. Water (14.2 kg) was added slowly over 45 min. At this point the crystallization occurred and the slurry was stirred for 30 min. An additional amount of water (68.8 kg) was added over 2.25 h. The slurry was stirred at room temperature until the concentration of the product in the supernatant solution was less than 1 mg/mL. The slurry was filtered and washed with a 2:1 (v/v) mixture of acetone/water (11.2 kg) and then with water (50 kg). The wet product was dried under vacuum at 45 °C. The dry weight of product was 2.66 kg, and the potency adjusted yield was 85% (sulfide is 97% potent).

 

Swern Oxidation

 

1-(2-Oxo-hexylcarbamoyl)cyclopropanecarboxylic Acid Methyl Ester: A solution of 35.8 mL (0.5 mol) of DMSO in 100 mL of dichloromethane was cooled to -40 oC, and 19.8 mL (0.23 mol) of oxalyl chloride in 198 mL of dichloromethane (precooled to -40 oC) were slowly added. After 10 min of stirring, a solution of 51.6 g (0.18 mol) 1-(2-hydroxy-hexylcarbamoyl)cyclopropanecarboxylic acid methyl ester (crude, content 83%, dissolved in 198 mL of dichloromethane) was slowly added over a period of 40 min. The reaction was stirred for 30 min at -40 oC. Then 69.8 mL (0.5 mol) of triethylamine were added followed by 300 mL of water. Extraction with dichloromethane and evaporation of the solvent yielded 44.72 g (100% yield) of crude product as an oil.

Hydrogenation general procedure

 

Organic Process Research & Development 2006, 10, 493-499

4-(4-Aminobenzyl)morpholine. To a 1-L autoclave were charged 5% Pt/C (3.3 g, 50% water wet) and starting material (125 g, 563 mmol). THF (600 mL) was added and the mixture purged with nitrogen (3_) and then hydrogen (3_). The resulting mixture was stirred under hydrogen pressure (50 psig) at high rpm (>300) at 60-70 °C until the uptake of hydrogen stopped (about 2 h). The resulting mixture was cooled to room temperature and filtered. The filter cake was washed with THF (2 _ 200 mL), and the filtrate and rinses were charged to a 1-L, three-neck, round-bottom flask, fitted with mechanical stirring, thermocouple, and distillation head. The solution was vacuum distilled to a volume of 150 mL, and 600 mL of Isopar C was added. The mixture was concentrated to a volume of 200 mL and cooled to less than 20 °C. The resulting slurry was cooled to 0-5 °C and stirred for about 1 h. The slurry was filtered and washed with 100 mL of Isopar C. The product was dried in the vacuum oven at 50 °C and provided 99.4 g, 91% yield of desired product: mp 100.8- 102.2 °C. HPLC purity 98%.

Buchwald-Hartwig Amination Reaction

 

Organic Process Research & Development 2006, 10, 762-769

The classic solvents employed in the Buchwald-Hartwig amination reaction are nonpolar, aprotic solvents such as m-xylene and 1,4-dioxane. NMP, N,N-dimethylacetamide (DMAC) are used as polar solvents.

Preparation of the Reaction Mixtures. The reaction mixtures were prepared as follows: In a flask under nitrogen atmosphere and agitation at room temperature starting materials, Pd(dba)2, BINAP, and NaO-t-Bu were dissolved/suspended in the solvent. The solvent was previously purged for 10 min with nitrogen. The ratio between the reactants in this flask was as follows: 1.00 g (1.0 equiv) of bromotoluene, 0.555 g (1.1 equiv) and 1.11 g (2.2 equiv) of piperizine, 0.169 g (0.05 equiv) of Pd(dba)2, 0.274 g (0.075 equiv) of (()-BINAP, and 0.844 g (1.5 equiv) of NaO-t-Bu. The reactants were dissolved/suspended in 12 mL of solvent. The reaction mixture was distributed to a number of process vials. Each of the vials contained approximately 2 mL of the reaction mixture, was equipped with a magnetic stirring bar, and was purged with nitrogen prior to the sealing. Subsequently the reactors were loaded in an autosampler and reacted at 100 °C from 10 to 300 min. Initial investigation of the reaction mixtures left at room temperature for 24 h showed no conversion of the reactants.

 

Heck Coupling Jeffrey-type Condition

 

Organic Process Research & Development 2006, 10, 398-402

Preparation of 4,2¢-Difluoro-5¢-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)-biphenyl-2-carbonitrile. Under an atmosphere of nitrogen a well-stirred, degassed mixture of first starting material (5.0 g, 26.7 mmol), second startingmaterial (6.7 g, 26.7 mmol), Bu4NHSO4 (0.9 g, 2.7 mmol), Cs2CO3 (13.1 g, 40.1 mmol), XPhos (1.4 g, 2.9 mmol), and Pd(OAc)2 (0.3 g, 1.3 mmol) in 1,4-dioxane (140 mL) was heated at 90 °C for 8 h. The mixture cooled to ambient temperature, and desired product was isolated by quenching into water. The solid formed was isolated by filtration and washed with water (100 mL) and gave product (11.6 g, 80 wt % pure, 23.2 mmol) in 87% yield. Pure material was obtained by recrystallization from ethanol (95%).

 

palladium-catalyzed cyanation

 

Organic Process Research & Development 2006, 10, 881-886

(2S)-2-(N-tert-Butoxycarbonyl)-amino-N-cyclopentyl- 3-(4-cyanophenyl)-N-methylpropanamide. To a stirred mixture of Pd[(PPh)3]4 (7.01 g, 0.03 equiv), dppf (3.36 g, 0.03 equiv), zinc cyanide (14.25 g, 0.6 equiv), and starting material (100 g, 0.202 mol) was added DMF (500 mL) under nitrogen atmosphere. The mixture was heated at 80 °C for 4 h. The mixture was cooled to room temperature, and ethyl acetate (800 mL) and saturated sodium bicarbonate (500 mL) solution were added. After vigorous stirring for 30 min, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (300 mL). The combined organic layer was washed with brine and concentrated in vacuo. Column chromatography (hexane/ethyl acetate ) 7:3) afforded desired product (68.2 g, 91%) as a viscous oil.

Negishi Coupling

 

Org. Process Res. Dev., 11 (2), 237 -240, 2007

2-Chloro-5-(pyridin-2-yl) Pyrimidine. A 2-L flask was charged with tetrahydrofuran (130 mL) and purged with nitrogen. The mixture was cooled to -70 oC, and a solution of hexyllithium in hexanes (175 mL 2.5molar, 0.436 mol) was added dropwise at such a rate that the inner temperature remained below -50 oC. On completion of the addition the mixture was cooled to -65 oC, and 2-bromopyridine (65.7 g, 0.416 mol) was added at such a rate that the inner temperature remained below -65 oC. Subsequently, a solution of ZnCl2 (57.8 g, 0.416 mol) in tetrahydrofuran (268 mL) was added below -55 oC. Upon completion of the addition, the mixture was allowed to warm to approx 22 C. After stirring for another 2 h, Pd(PPh3)4 (4.8 g, 0.004 mol) was added. Subsequently, a solution of 5-iodo-2-chloropyrimidine (50 g, 0.2 mol) in tetrahydrofuran (160 mL) was added at such a rate that the temperature remained below 30 oC. After stirring for another hour, a 0.39 M aqueous solution of EDTA·3Na (1 L) and dichloromethane (100 mL) were added, and the mixture was stirred vigorously for 15 min. The layers were separated, and from the organic layer the solvents were evaporated under reduced pressure, leading to a black oily residue. The residue was dissolved in dichloromethane (300 mL), and to the solution were added Kieselgel 60 (66 g) and thiol-modified silica (6.1 g).The mixture was stirred for 20 min and filtered. The solid collected was washed with dichloromethane (3 aliquots of 230 mL). From the filtrate the solvents were evaporated until the residual volume reached approx 350 mL. After cooling to approx 22 oC the residue was washed with a 2 N hydrochloric acid solution (2 aliquots of 350 mL). The combined aqueous layers were treated with Norit A Supra (1.4 g). After filtration the filtrate was neutralized with aqueous ammonia (pH 6-7). The resulting precipitate was collected by filtration and dried in vacuo at 40 oC, yielding 25.6 g (67%) of the title compound.

Sonogashira coupling reaction

 

Org. Process Res. Dev., 11 (2), 246 -250, 2007

To a 1 L round-bottom flask were added THF (250 mL), 4-(butyn-3-yl)benzonitrile (49.38 g, 0.318 mol), TEA (250 mL, 1:1 TEA/THF), bromopyridine (33.3 mL, 0.35 mol), Pd (PPh3)2Cl2 (4.47 g, 6.0 mmol), and CuI (1.21 g, 6.0 mmol). The reaction mixture was stirred at 60 oC for 2 h. The reaction was then cooled to room temperature and quenched with water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and washed with water (50 mL) and brine (30 mL), dried over sodium sulfate, and concentrated in vacuo to give a brown solid, which was subsequently washed with heptane (2 × 50 mL) to afford 4-(4-(pyridin-2-yl)butyn-3-yl)benzonitrile as an off-white solid (58.73 g, 79.6%) with a purity of 98.4% (HPLC, 230 nm).

Reductive carbonylation

 

Org. Process Res. Dev., 11 (1), 39 -43, 2007.

General Procedure for the Reductive Carbonylation of 4-Bromotoluene (Method A). To 4-bromotoluene (0.616 g, 3.6 × 10-3 mol), [PdCl2(dppp)] (0.053 g, 9 × 10-5 mol), and Na2CO3 (0.381 g, 3.6 × 10-3 mol) were added DMF (5 mL), mesitylene (0.25 mL, 1.8 × 10-3 mol) as reference, and Et3SiH (1.166 mL, 7.2 × 10-3 mol). Once sealed inside the reactor the system was purged with CO several times. The temperature was raised to 90 C, and the reactor was charged with 3 bar of CO. The reaction was stirred under these conditions for 18 h after which the reactor was allowed to cool. The reaction was filtered, and the filtrate was analysed by GC-MS to determine the conversion and yield of aldehyde.

General Procedure for the Reductive Carbonylation of 4-Bromobenzonitrile (Method B). To 4-bromobenzonitrile (0.655 g, 3.6 × 10-3 mol) and [PdCl2(dtbpf)] (0.065 g, 9 × 10-5 mol) were added THF (5 mL), mesitylene (0.25 mL, 1.8 × 10-3 mol) as reference, Et3N (0.504 mL, 3.6 × 10-3 mol), and Et3SiH (1.166 mL, 7.2 × 10-3 mol). Once sealed inside the reactor the system was purged with CO several times. The temperature was raised to 90 C, and the reactor was charged with 3 bar of CO. The reaction was stirred under these conditions for 18 h after which the reactor was allowed to cool. The reaction was filtered, and the filtrate was analysed by GC-MS to determine the conversion and yield of aldehyde.

General Procedure for the Reductive Carbonylation of 4-Bromoanisole (Method C). To [Pd(PtBu3)2] (0.046 g, 9 × 10-5 mol) were added dioxane (5 mL), mesitylene (0.25 mL, 1.8 × 10-3 mol) as reference, 4-bromoanisole (0.451 mL, 3.6 × 10-3 mol), Et(iPr)2N (0.658 mL, 3.6 × 10-3 mol), and Et3SiH (1.166 mL, 7.2 × 10-3 mol). Once sealed inside the reactor the system was purged with CO several times. The temperature was raised to 120 C, and the reactor was charged with 3 bar of CO. The reaction was stirred under these conditions for 18 h, after which the reactor was allowed to cool. The reaction was filtered, and the filtrate was analysed by GC-MS to determine the conversion and yield of aldehyde.

 

Chloronation Reaction

 

Org. Process Res. Dev., 11 (2), 237 -240, 2007

2-Chloro-5-iodo-pyrimidine. A 3-L flask was charged successively with 2-hyroxy-5-iodo-pyrimidine (100 g, 0.45 mol), acetonitrile (540 mL), and phosphorous oxychloride (82.9 g, 0.54 mol). Diisopropylethylamine (29.1 g, 0.23 mol) was added dropwise. Upon addition, the mixture was heated to reflux and kept under the same heating conditions for 20 h. After the mixture was cooled to 40 C, water (900 mL) was added over 20 min. The formed black precipitate was extracted with ethyl acetate (1130 mL). The extract was washed with an aqueous solution of sodium sulfite (150 g in 570 mL). The extract was transferred into a 2-L flask, and water (270 mL) was added. The mixture was heated to reflux, and about 600 mL of solvent was distilled off, and another portion of water (540 mL) was added. Solvent evaporation was continued until the inner temperature reached 85 oC. The mixture was cooled to approx 22 oC and filtered. The precipitate washed with water (100 mL) and dried at 40 oC in vacuo yielding 78.4 g (72%) of the title compound

 

Nenitzescu reaction

 

Org. Process Res. Dev., 11 (2), 241 -245, 2007

1-(4-Fluorophenyl)ethyl 5-Hydroxy-2-methyl-1H-indole-3-carboxylate. A 20-L jacketed vessel was charged with 2-propanol (10 L), acetic acid (700 mL), and 1,4-benzoquinone (850 g, 7.87 mol). The mixture was heated, and reflux was obtained after 1 h (IT 85 oC). A solution of 1-(4-fluorophenyl)ethyl 3-aminobut-2-enoate (1.569 g, 7.04 mol) in 2-propanol (3 L) was added over 25 min, and heating was continued. A sample was taken after 30 min and concentrated, and NMR analysis indicated the reaction was complete. After an additional 10 min, the mixture was cooled to 20 oC over 1 h. The mixture was concentrated, taken up in dichloromethane (8 L), and washed with 10% aqueous potassium carbonate (2 × 6 L). The aqueous layers were combined and extracted with dichloromethane (2 L). The organic layers were combined, dried with magnesium sulfate (700 g), filtered, and concentrated to approximately 7.5 L total volume.

Mannich reaction

 

Org. Process Res. Dev., 11 (2), 241 -245, 2007

1-(4-Fluorophenyl)ethyl 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate Hydrochloride. A 20-L jacketed vessel was charged with dichloromethane (7.5 L) and N,N,N',N'-tetramethylmethylenediamine (1.25 L, 9.16 mol) and was cooled to IT 0 oC. Acetyl chloride (625 mL, 8.79 mol) was added over 30 min, causing the internal temperature to rise to 20 oC (jacket reaching -25 oC). After 35 min, potassium carbonate (1.31 kg, 9.48 mol) was added (IT 0 oC), the mixture was stirred for 5 min more, and 1-(4-fluorophenyl)ethyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate (7.32 mol in 7.5 L of dichloromethane) was added over 10 min causing the IT to rise to 8 oC. The mixture was warmed to 20 oC over 30 min and stirred at this temperature. The reaction was monitored by 1H NMR using concentrated aliquots. After stirring at 20 oC for 100 min, water (5 L) was added and the mixture stirred vigorously for 10 min and allowed to settle. The layers were separated, and the organic phase was washed with an additional portion of water (5 L). The aqueous layers were combined and extracted with dichloromethane (2.5 L). The organic layers were combined, dried with magnesium sulfate (824 g), filtered, and concentrated. The residue was taken up in ethanol (4.5 L) and transferred to a 10-L round-bottomed vessel with overhead anchor stirring. A solution of HCl in ethanol was prepared by addition of acetyl chloride (657 mL, 9.24 mol) to ethanol (1.5 L) with cooling. This solution was added over 85 min to the Mannich product, using an ice bath to control the IT < 35 oC. Precipitation was observed before the addition was complete. The mixture was stirred at ambient temperature for 2.5 days. The mixture was then cooled in an ice-water bath for 30 min (IT 6 C) before dividing into two portions and filtering. The cakes were washed with ice cold ethanol (2 × 500 mL each) and dried in a vacuum oven at ambient for 23 h to give 1.375 kg, as a light-purple solid.

Indolizine Synthesis

 

3-(4-Cyanobenzoyl)indolizine. To a solution of 4-acetylbenzonitrile (34 g, 235 mmol) in EtOAc (320 mL) was added Br2 (neat, 11.9 mL, 320 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After the solvent was removed under reduced pressure, the resulting residue was dissolved in CH3CN (210 mL). To it was added picoline (50 mL, 500 mmol). After the reaction mixture was stirred for 2 h at room temperature and then 0.5 h at 0 C, EtOAc (70 mL) was added to the mixture. The resulting precipitates were collected by filtration and washed with EtOAc to give 2-methyl-1-(4-cyano)phenacylpyridinium bromide (60 g, 88%) which was used directly in the next step. 1H NMR (300 MHz, DMSO-d6) (ppm) 9.05-8.03 (m, 8H), 6.78 (s, 2H), 2.74 (s, 3H). To a stirred suspension of the above picolinium salt (50 g, 120 mmol) in DMF (500 mL) was added DMF-Me2SO4 (400 mL) (pre-prepared in a separate reaction flask by stirring a mixture of equal mole equivalents of DMF and Me2SO4 at 60-80 C for 3 h, then cooled to room temperature). After the addition, the reaction mixture was stirred at room temperature for 15 min. To it was then added Et3N (500 mL) while the inner temperature was kept between 25 and 40 C. After stirring at room temperature for 2 h, the reaction mixture was charged with ice water (2000 mL) with stirring which led to the formation of slurry. The precipitates were collected, washed with water, and dried under a vacuum to give 29 g (76%) of 3-(4-cyanobenzoyl)indolizine. Rf 0.3 (10% ethyl acetate in hexanes); mp 156-157 C (recrystallized from ethyl acetate).

Shi Epoxidation

Org. Process Res. Dev., 11 (1), 44 -51, 2007.

 

The potassium trans-alkenoate solution from the Suzuki cross-coupling was adjusted to pH 10.5 with 25% aqueous H2SO4. The solution was cooled to between -5 to 5 oC and D-Epoxone (4.3 g, 0.017 mol), as a solution in acetonitrile (20 mL) was added. While the mixture was stirred with vigorous agitation, Oxone (45.3 g, 0.074 mol) in water (160 mL) was added to the mixture. The temperature was maintained below 10 oC by control of the Oxone solution charge rate, and the pH was maintained at 10.0-11.0 by the addition of 20% KOH as necessary. After the addition was complete, the mixture was held at 10-15 oC for 1 h. The mixture was adjusted to pH 2 with 25% H2SO4. Toluene (233 mL) was added, the mixture was heated to 75-80 oC, and the layers were separated. The organic layer was filtered and concentrated until the pot volume was approximately 100 mL. The solution was cooled to 20-30 oC, and heptane (67 mL) was added over approximately 1 h to crystallise the product. The solids were filtered, washed with cold heptane (~15 mL), and dried at 35-40 oC to afford a 55% yield of hydroxylactone in 86%.

 

3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one Synthesis

 

Representative Procedure To a solution of LiOH (17.25 g, 1.5 equiv) in anhydrous methanol (600 mL) was added cyanoacetamide (63 g, 1.5 equiv) under nitrogen atmosphere. The resulting mixture was stirred for 20 min at room temperature. To this was added a solution of phthalimidoacetone (101.5 g, 0.5 mol) in 700 mL of THF (anhydrous) over a period of 30 min. The resulting reaction mixture was stirred for 2 h at room temperature and then heated at 55 oC for 1 h. To this was added sodium methoxide solution (25% solution, 172 mL, 1.5 equiv) at 55 oC over a period of 40 min. After 3 h HPLC/MS indicated starting material and intermediates were converted to the pyrrole. A crude sample of pyrrole was obtained by extractive aqueous workup. To the above reaction mixture was added ethyl formate (200.8 mL, 5 equiv) over a period of 20 min followed by sodium methoxide (25% solution, 324 g, 3 equiv). The resulting reaction mixture was heated for 7 h at 55 oC at which time HPLC/MS indicated that the pyrrole was converted to the pyrrolopyrimidinone. The reaction mixture was diluted with 1.5 L water, heated at 60 oC for 1 h, and then concentrated to small volume (~1.5 L). Solution assay indicated that pyrrolopyrimidinone was formed in 75% solution yield. This solution was neutralized to pH 7.5 with 6 N aq HCl, cooled to about 5 oC, and held at this temperature for 30 min. Solids were filtered, washed with water, dried at 50 oC under vaccum overnight to give the pyrrolopyrimidinone as a light brown solid (45.8 g, 61% yield, purity: 99.0% by HPLC area).

quinolone synthesis

Organic Process Research & Development 2006, 10, 493-499

Ethyl 8-Iodo-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline- 3-carboxylate. Preparation  of Eaton’s Reagent. To a 250-mL, three-neck, round-bottom flask fitted with mechanical stirring thermocouple and nitrogen inlet, was charged phosphorus pentoxide dimer (23.3 g, 82 mmol). The stirring was started briefly to distribute the solids, and the stirrer was raised above the solids in the flask. Methanesulfonic acid (178 g, 120 mL, 1852 mmol) was added and the mixture warmed to 90 °C until all the phosphorus pentoxide dimer was dissolved. The resulting solution was cooled to less than 30 °C.

Cyclization Reaction. To a 500-mL, three-neck, round bottom flask fitted with mechanical stirring, thermocouple, and nitrogen inlet, was charged starting material (20 g, 41 mmol) followed by Eaton’s reagent. There was an exotherm to about 47 °C. The resulting dark-red solution was heated to 90 °C for at least 4 h. The reaction was checked by TLC (about 0.5 mL of reaction was quenched into 3-4 g of ice and the pH adjusted to 7-8 by addition of 50% NaOH, 2 mL of methylene chloride were added, and the lower layer was spotted and eluted with 5% methanol/95% methylene chloride). When completed, the reaction was cooled to less than 30 °C and poured into 200 g of ice. A solution of 50% NaOH (180 g, 2258 mmol) in 150 mL of water was slowly added until the pH was 5-6. Methylene chloride (200 mL) was added, and the addition of NaOH solution was resumed until the pH was 7-8, keeping the temperature less than 30 °C (use an ice bath if needed). The phases were separated, and the aqueous was washed with methylene chloride (1 _ 100 mL). The combined organic phases were filtered through 5 g of silica gel, and the cake was washed with 300 mL of methylene chloride. The filtrates were concentrated on the rotovap to about 150-mL volume. Methanol (200 mL) was added and the solution concentrated to about 50-mL volume. Methanol (100 mL) was added and the mixture again concentrated to about 50-mL volume. The slurry was cooled to 0 °C, filtered, and washed with 50 mL of methanol. The product was dried in the vacuum oven at 50 °C overnight to provide 11.0 g (61% yield) of desired product.

 

Shestopalov pyridine ring construction

 

Organic Process Research & Development 2006, 10, 1157-1166

Knoevenagel condensation of aldehyde with methyl cyanoacetate, Michael addition of the pyridinium yield to the condensation product, and cyclization of the Michael adduct.

5¢-Cyano-1¢,2¢,3¢,4¢-tetrahydro-6¢-hydroxy-4¢-(2-methylphenyl)- 2¢-oxo-1,3¢-bipyridinium, Inner Salt .  A 3000 mL four-necked flask (with a 250 mL pressure equilibrating addition funnel/dry N2 adapter, septum with a Teflon-coated thermocouple, Teflon paddle stirrer/glass shaft, and stopper) is charged with 115.6 mL (120.15 g, 1.0 mol) of o-tolualdehyde, 87.9 mL (99.09 g, 1.0 mol) of methyl cyanoacetate, the suspension of 172.61 g (1.0 mol) of pyridinium salt in 300 mL of isopropanol , and 1.7 L of methanol. The addition funnel is charged with 153.3 mL (111.3 g, 1.1 mol) of triethylamine. The amine is added over 24 min at 170 rpm and 20-25 °C (intermittent ice-water bath). The resulting mixture is stirred at 25-30 °C for 24 h. The precipitate is suction filtered, washed with 500 mL of 25 °C methanol, 500 mL of 25 °C toluene, and 500 mL of 25 °C hexanes, and then air-dried 18 h at 25 °C to afford 284.69 g (93.2%) of product as a bright yellow solid.

 

Tisler triazolopyrimidine cyclization

 

Organic Process Research & Development 2006, 10, 1167-1171

(3-(2-Methoxy-4-trifluoromethyl)-N-(5,7-dimethoxy-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)pyridinesulfonamide). Hydroxyguanidine (2.0 g, 4.4 mmol) was slurried in CH3CN (20 mL) and cooled to -5 °C under N2.Potassium carbonate (1.38 g, 10 mmol) was added, followed by dropwise addition of phosgene in toluene (ca. 20%, 2.6mL, ca. 4.9 mmol). The reaction was stirred at this temperature for 40 min at which time HPLC analysis indicated 15% of hydroxyguanidine  remained. After stirring an additional 30 min HPLC analysis indicated 15% of hydroxyguanidine  still remained. Additional phosgene/toluene (0.25 mL) was added and the reaction stirred at -5 °C for 30 min at which time HPLC indicated that less than 2% of hydroxyguanidine  remained. The white slurry was warmed to room temperature and allowed to stir overnight. HPLC analysis indicated that 9% of oxadiazolone remained. The white slurry was warmed to 35 °C and was held there for 30 min at which time HPLC indicated the cyclization was complete. The slurry was cooled to room temperature and then treated with water (15 mL). The pH was adjusted to 2 by dropwise addition of concentrated HCl. The volatiles were removed on the rotary evaporator (35 °C/25 mmHg), leaving a white slurry. The solid was collected by filtration and washed with a little water to give 2.74 g of crude wet material. HPLC analysis of the wet material revealed three major peaks: (1) rt 3.07 min, 7.9%; HRMS indicated this impurity is an isomer of desired product; (2) rt 3.52 min, 79.5% desired product; (3) rt 5.84 min, 10.9%, toluene. The wet solid was dried to a constant weight (80 °C/ 25 mmHg), providing the product as a white solid (1.84 g). A 1.0 g sample was dissolved in boiling CH3OH/CH3CN (60 mL/10 mL) and then concentrated to a total volume of 15 mL. The mixture was cooled in an ice bath, and the resulting crystals were collected and washed with a little CH3OH. The material was dried to a constant weight (5 mmHg/room temperature) providing desired product as white needles (944 mg, 91.1% purity via external standard HPLC analysis, 83% yield based on recrystallization of all of the 1.84 g of crude material). This sample contained 2.3 area % of an isomer of desired product and 6.6 wt % CH3CN.

Leimgruber-Batcho indole synthesis for 6-benzyloxyindole

 

Organic Process Research & Development 2006, 10, 1178-1183

Laboratory Procedure of Hydrogenation to Obtain the Indole. To a mixture of enamine (5.00 g, 15.4 mmol), iron(II) acetate (28 mg, 0.154 mmol), and 5% Rh/C (317 mg, 0.154 mmol), tetrahydrofuran (THF) (100 mL) was added. After the atmosphere was displaced with N2 followed by H2, the mixture was stirred for 15 h at rt under atmospheric pressure of H2. After the atmosphere was replaced with N2, aqueous NH3 (_14%, 20 mL) was added. The following workup operations were conducted under N2. After stirring for 20 min, the mixture was filtered to remove the catalyst, which was washed with THF (50 mL). The combined solutions were extracted with toluene (50 mL). The organic layer obtained was washed with aqueous citric acid (10%, 50 g), aqueous sodium bicarbonate (5%, 50 g), and brine (20%, 50 g). The yield of the target indole was determined by HPLC (3.30 assay g, 96% yield). The solution was concentrated in vacuo. The residue was dissolved in toluene (100 mL) and filtered through a pad of SiO2 (5 g), and the silica gel was washed with toluene (100 mL). The combined toluene solutions were analyzed by HPLC (3.22 assay g, 94% yield), and then concentrated in vacuo. The residual solids were suspended in toluene (5 mL) and heptane (13 mL) and heated to 90 °C to dissolve the solids. The homogeneous solution was cooled to 63 °C, followed by seeding with a crystal of indole to form a seed bed. The slurry formed was stirred for 1 h at 60-65 °C, heptane (37 mL) was added over a period of 2 h, and the solution was gradually cooled to rt. After standing overnight, the slurry was filtered, washed with heptane-toluene (10:1) (5.5 mL) and heptane (5.5 mL), and dried in vacuo at 40 °C overnight. The target indole was obtained as colorless crystals (2.94 g, 86% yield with 99.9 area % purity by HPLC).

Knorr Cyclization Pyrrole

 

Organic Process Research & Development 2006, 10, 899-904

3-(4-Bromophenyl)-4-cyano-5-ethyl-1H-pyrrole-2-carboxylic Acid Ethyl Ester. Preparation of enolate: Under a nitrogen atmosphere, potassium tert-butoxide (13.097 kg, 117.29 mol) was dissolved in THF (68.2 L) at 20 °C. To the resulting mixture, a mixture of ethyl propionate 12.2 L, 106.63 mol) and acetonitrile (6.68 L) was added over 0.75 h at 18 to 21 °C and stirred for 1 h at this temperature (NMR (10 íL of reaction mixture in 1 mL of DMSO-d6) indicated no ester remaining). Preparation of pyrrole: In a separate reactor under a nitrogen atmosphere, R-isonitroso-â-ketoester (12.8 kg, 42.65 mol) was dissolved in EtOH (110 L) at 20 °C. The solution was cooled to 1 °C, and zinc (6.429 kg, 98.01 mol) was added portionwise over 0.5 h. A solution of acetic acid (19.5 L), water (2.5 L), and EtOH (11.5 L) was prepared. About 1 to 2% of the ethanolic aqueous acetic acid solution was added to the mixture of R-isonitroso-â-ketoester and zinc in EtOH at 0 °C to give a slight exotherm and initiate the reduction. The rest of the ethanolic aqueous acetic acid solution was added to the mixture of R-isonitroso-â-ketoester and zinc in EtOH over 1.5 h between -2 to 2 °C. The suspension was cooled to -5 °C and stirred for 0.25 h (HPLC indicated 98.3% conversion of R-isonitroso-â-ketoester). The potassium enolate suspension was added over 0.5 h to the zinc suspension at -9 to -2 °C. The reaction was stirred at -4 °C for 3.0 h, warmed to 20 °C over 10 h, and stirred at 20 °C for 3.0 h (HPLC indicated a complete conversion of intermediate). The suspension was filtered, and the filter cake washed with EtOH (6 L). The mother liquor was distilled under reduced pressure at 55 °C to 28% of its original volume. IPA (66 L) was added followed by water (128 L) at 35 to 38 °C and the resulting suspension cooled to 10 °C over 6.0 h and stirred for 6.0 h. The suspension was filtered and washed with water (51 L). The filter cake was dried under a constant flow of nitrogen for 48.0 h to afford pyrrole (12.49 kg, 84% yield) as pale yellow crystals (HPLC 99.73 area%).

 

Magnesium-halogen exchange for generation of Grignard

 

Organic Process Research & Development 2006, 10, 1258-1262

General Procedure for Magnesium-Iodine Exchange. A nitrogen-purged flask with magnetic stir bar was charged with i-PrMgCl solution (20.0 mL, 40.0 mmol, 2.0 M in THF). The reaction mixture was cooled to an internal temperature of 0 °C, and starting material (9.4 g, 40.0 mmol) was added over 10 min, keeping internal temperature between 0 and 10 °C. The reaction mixture was stirred at 10 °C for 45 min, at which time HPLC analysis (aliquot into MeOH) showed 95% consumption of starting material. A 10 mL sample was withdrawn for thermal safety analysis.

 

Lawesson’s reagent

 

4(R)-[1¢(S)-[tert-(Butoxycarbonyl)amino]ethyl]pyrrolidinone- 2-thione. A slurry of starting material (254 g, 1.114 mol) in THF (2.285 L) in a 5-L reaction flask under nitrogen was treated with Lawesson’s Reagent (225 g, 0.557 mol, 0.5 equiv) in three portions over a 15-min period. The reaction was stirred at room temperature for 4 h. The solid was collected by filtration and washed with toluene (200 mL). The collected solid was dried (45 °C, 35 mmHg) to give 173 g of desired product, (HPLC1) ) 3.03 min, 96.71 by area %. The filtrates were combined and held at -10 °C for 2 days, solid was collected by filtration, washed with toluene (50 mL), and dried as before to give 70 g of product, 89.6% total yield, (HPLC1) ) 2.96 min, 92.35 area %.

 

CBS Reduction/ BH3/THF

 

Organic Process Research & Development 2006, 10, 893-898

2-Chloro-1-phenylethanol. A 75-mL jacketed reaction flask equipped with an addition port, reflux condenser and a magnetic stir bar was first purged with argon for 10 min and then charged with a solution of 0.025 mmol of CBS reagent in 5 mL of THF. A BH3âTHF solution containing 4.8 mmol of BH3 (10 mL) was added portionwise over 10 min. The reaction flask was heated to 30 °C and a solution of 1.24 g (8 mmol) of starting material ketone in 10 mL of THF was added via syringe pump at a rate of 0.15 mL/min. After the addition was complete, the reaction mixture was stirred for 45 min and cooled to ambient, and the remaining hydride was decomposed by the addition of 2 mL of dry methanol. The reaction mixture was passed through a short bed of SiO2 and the solvent evaporated giving the chloro alcohol, desired product, in 95% yield; HPLC purity >95%, HPLC ee ) 95%.

Noyori hydrogenation

 

Organic Process Research & Development 2006, 10, 893-898

(S)-2-Succinimido-1-phenylethanol. Twenty mmol (4.34 g) of starting material was placed in a 250-mL jacketed, glass reactor vessel,14 and the air in the reactor was completely replaced by argon using multiple fill/release cycles. Degassed methanol (250 mL) was added to the reactor via cannula and the mixture stirred at 30 °C to dissolve the ketone. Four milliliters of the Noyori catalyst solution (8 ímol of Ru) and 12 mL of the K-OtBu solution (3 mmol) were injected into the reactor using gastight syringes. The argon in the reactor was replaced with hydrogen (fill/release cycles) and the reactor pressurized to 60 psig with hydrogen. The reaction mixture was stirred at 1000 rpm overnight at 30 °C with the hydrogen uptake recorded as described previously. The reaction mixture was passed through a short alumina column and the solvent removed to give desired product, with an HPLC ee of 99% at 100% conversion. HPLC purity >97%.

Asymmetric Hydrogenation of a beta-Enamine Amide

 

Organic Process Research & Development 2006, 10, 723-726

Hydrogenation of Enamine Amide. Methanol (230 mL)is charged to a reactor with 25 g of enamine amide. Theresulting slurry is degassed followed by the addition of 0.003mol equiv (0.046 g) of [(COD)RhCl]2 dimer and 0.0031 molequiv (0.104 g) of Josiphos SL-J002-1 ligand (Solvias). The reaction mixture is heated to 50 °C and hydrogenated at 100 psig (or 115 psi). After 16 h at temperature and under hydrogen pressure, the batch is cooled to 20 °C and sampled to analyze for percent conversion and enantiomeric excess.

Transsulfamoylation Reaction

 

Organic Process Research & Development 2006, 10, 770-775

Typical Operating Procedure for Synthesis of Sulfamide. A 100-L glass-lined reactor was charged with acetonitrile (17.8 kg) and 4-methylsulfonylaniline hydrochloride (3.36 kg, 16.2 mol) under stirring at room temperature. Triethylamine (4.5 kg, 44.47 mol) and 2-oxooxazolidine- 3-sulfonic acid isopropylamide (3.70 kg, 17.77 mol, 1.1 equiv) were then added at the same temperature. The reaction mixture was heated to reflux and stirred at the same temperature for a minimum of 6 h. The solution was then slowly cooled to room temperature and kept agitated overnight. Water was slowly added over 40 min, and the reactor was placed under vacuum to distill as much as possible of acetonitrile (27.8 kg of distillate) while maintaining the reaction temperature below 40 °C. The suspension was cooled to room temperature and stirred for a minimum of 2 h before filtering the product. The cake was rinsed with water (16.2 kg) and dried under vacuum at about 50 °C for a minimum of 16 h to yield the 1-isopropylamino- 1-sulfonic acid (4-methanesulfonylphenyl)amide

Heck Reaction

 

Organic Process Research & Development 2006, 10, 776-783

(E)-ä-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-7- (cyanomethoxy)-1H-indole-1-pentanenitrile. The indole (655 mg, 3.75 mmol) and NaH (60% dispersion in oil; 153 mg, 3.75 mmol) were charged into a dry, 250-mL roundbottom flask. The mixture was maintained at room temperature, and DMSO (33 mL) was carefully added. After stirring for 40 min the solution of the chloride starting material (969 mg, 2.5 mmol) in DMSO (14 mL) was added over 10 min. The reaction was monitored at different times (0, 0.5, 1, 2, 4, 6, 24 h) byHPLC analysis of aliquots. After 24 h, water (50 mL) and acetic acid (0.635 mL) were added with stirring, and the mixture was extracted with CH2Cl2 (55 mL). The organic layer was washed with water (3 _ 50 mL), dried with MgSO4 (9 g), filtered, and concentrated under vacuum as an oil. The oil was purified by chromatography on silica gel (80 g) using toluene (500 mL), followed by a mixture toluene/ethyl  acetate/CH2Cl2 90/5/5 (600 mL) as eluent to afford product (375 mg, 29% molar yield).

Hantzsch pyridine synthesis

 

In a typical process, 3-cyanobenzaldehyde (1 equiv) and ammonium acetate (2.5 equiv) are slurried together in ethanol (18 rel vols). A solution of dione (0.9 equiv) in ethanol (6 rel vols) is added slowly, followed by allyl ester (1.1 equiv) and more ammonium acetate (2.5 equiv) in ethanol (11 rel vols). The mixture is heated to reflux for 3.5 h, and then excess ethanol is removed by distillation under vacuum until 18 rel vols remains. Water (24 rel vols) is added to precipitate the product, which is isolated by filtration and washed with water (6 rel vols) and MTBE (6 rel vols, twice).

Reductive alkylation

 

Organic Process Research & Development 2006, 10, 814-821

(R)-2-(4-(2-(2-Cyclopentyl-5-((5,7-dimethyl-[1,2,4]triazolo[ 1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-6-oxo-3,6-dihydro- 2H-pyran-2-yl)ethyl)-2-fluorophenyl)-2-methylpropanenitrile. A 100-gal reactor was charged with aldehyde (6.5 kg, 36.9 mol). A separate 50-gal reactor was charged with beta-ketoester (9.1 kg, 24.5 mol), BH3/NMe3 (2.7 kg, 37 mol), MeOH (7 gal), and THF (5 gal). The solution in the 50-gal reactor was transferred to the 100-gal reactor, and a slight exotherm was observed to 28 °C. The mixture was allowed to stir at room temperature for 30 min and was then charged with concentrated aqueous HCl (0.25 gal). The reactor was charged with water (13.7 kg) and then seeded with 1 (2 g) to initiate crystallization. The mixture was stirred for 20 h and then was filtered; the cake rinsed with THF (4 gal) and then water (7 gal). The wet cake was transferred to a clean reactor and charged with water (18 gal) and stirred for 2 h. The slurry was filtered, washed with water (12 gal), and dried at 50 °C for 5 days to provide 7.3 kg (56%) of desired product as a white crystalline solid (purity 90% by HPLC analysis).

Beta-ketoester synthesis

 

Organic Process Research & Development 2006, 10, 814-821

(R)-Ethyl 7-(4-(2-cyanopropan-2-yl)-3-fluorophenyl)- 5-cyclopentyl-5-hydroxy-3-oxoheptanoate. A 100-gal reactor was charged with CDI (9.70 kg, 59.8 mol), DMAP (244 g, 2.00 mol), and MTBE (6 gal). An MTBE solution of acid (13.85 kg, 39.87 mol, _15 gal) was added to the stirred mixture over a 30-min period. The line was rinsed with THF (2 gal), and the mixture was stirred for 75 min to complete formation of the acylimidazole intermediate. A separate 200- gal tank was charged with ethyl magnesium malonate (17.1 kg, 59.66 mol) and THF (9 gal). The stirred mixture was heated to 46 °C, and the acylimidazole solution was slowly added to the ethyl magnesium malonate mixture. Stirring was continued at 48 °C for 2 h. The solution was cooled to room temperature and charged with IPE (18 gal) and 1 M HCl (32 gal), the mixture was stirred well, and the phases were separated. The organic phase was washed with H2O (1 gal), the phases were separated, and the organic layer was distilled to 12 gal to remove water (K-F titration) 0.18%). The solution of desired product was used directly in the next step.

aza Diels-Alder reaction

 

Organic Process Research & Development 2006, 10, 464-471

cis-(2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)carbamic Acid Benzyl Ester. To a 1-L flask under nitrogen atmosphere charged with aniline (27.66 g, 156 mmol, 1.0 equiv) were added dry toluene (500 mL), 7 (50.0 g, 156 mmol, 1.0 equiv), and p-toluenesulfonic acid monohydrate (297 mg, 1.56 mmol, 0.01 equiv). The mixture was heated to 70 °C. After 2 h, the mixture was cooled to room temperature and transferred to a separatory funnel. Ethyl acetate (500 mL) was added. The mixture was washed 1 _ 200 mL of 1 N NaOH, 1 _ 200 mL of H2O, 1 _ 200 mL of brine, and dried (MgSO4). The mixture was filtered, and the solids were washed 1 _ 50 mL of ethyl acetate. The filtrate was concentrated to _250 mL; 500 mL of toluene was added, and the mixture was concentrated to _500 mL. Five hundred milliliters of n-heptane was added, the slurry was stirred 1 h and filtered through a Buchner funnel and dried. Desired product was isolated as a white powder (45.04 g, 76%).

 

Nuceophilic substitution

 

Organic Process Research & Development 2006, 10, 493-499

 

4-(4-Nitrobenzyl)morpholine To a 2-L, three-neck, round-bottom flask, fitted with mechanical stirring, thermocouple, 250-mL addition funnel, and nitrogen inlet were charged 4-nitrobenzylbromide (100 g, 463 mmol) (Caution. Strong irritant and lachrymator! Weigh in hood with door down and transport in stoppered flask!) and 500 mL of toluene. A solution of morpholine (121 g, 1389 mmol) in 100 mL of toluene was added dropwise, keeping the temperature less than 50 °C. The solution was rinsed in with 50 mL of toluene. The resulting solution was stirred at less than 50 °C until the reaction was complete. TLC analysis; add 1 mL of reaction mixture to 1 mL of water, spot upper layer and elute with 1:1 ethyl acetate/heptane, visualize with UV. When complete, 500 mL of water was added, and the phases were separated. The organic phase was washed with 500 mL of saturated sodium bicarbonate. The organic phase was concentrated to less than 150 mL volume on the rotovap with a 60-70 °C bath. Isopar C (500 mL) was added to crystallize the product. The slurry was stirred at 20-25 °C for 30 min, filtered, and washed with 100 mL of Isopar C. The product was dried at 45 °C in a vacuum oven overnight. The yield was 96.0 g, 93%, of desired product: mp 80.3-82.1 °C. HPLC purity 95%.

mild conversion of a quinoline N-oxide to a 2-aminoquinoline

 

Organic Process Research & Development 2006, 10, 534-538

2-Amino-quinoline-6-carboxylic Acid Benzyl Ester. To a solution of 1-oxy-quinoline-6-carboxylic acid benzyl ester (4.1 kg, 14.7 mol) in methylene chloride (20 L) was added p-toluenesulfonyl chloride (3.9 Kg, 21 mol) under nitrogen, and the mixture was stirred for 45 min at 22-25 °C. This solution was added very slowly (400 mL/min) to a suspension of ammonium chloride (2.4 kg, 44 mol) in methylene chloride (12 L) and triethylamine (6.8 L, 48 mol) while keeping the temperature at 25-30 °C. The reaction mixture was stirred for an additional hour at 22-25 °C before cooling to -5 °C for 1 h and filtered. The filtered solids were rinsed with pre-cooled methanol (4.5 L) at -5 °C. This solid material was then triturated in water (45 L) for 20 min at 20-25 °C, filtered, and washed with precooled methanol (9 L) at -5 °C. The product was dried in a vacuum oven at 35-40 °C for 24 h to yield 1.85 kg (45.1%) of the title compound.

 

Transfer alkylation

 

Organic Process Research & Development 2006, 10, 198-202

D-6-Propyl-8â-hydroxymethylergoline. Into a stainless steel 800-L vessel containing NMP (40 L) under nitrogen, were sequentially added 9.3 kg of 9,10-dihydrolysergic acid (34.4 mol), 8.67 kg of sodium bicarbonate (103.0 mol), and 30.4 kg of n-propyl iodide (178.9 mol). The mixture was heated to 80 °C. After complete conversion of 9,10-dihydrolysergic acid into aminium, monitored by HPLC, the solution was cooled to 45 °C. Five kilograms (45.1 mol) of CaCl2 and 6.5 kg (172 mol) of NaBH4 were added and monitored by reverse phase HPLC (the same method for all the analyses: Hypersil- C18 4.6 mm _ 250 mm column, 50/50 pH 7 phosphate buffer/acetonitrile, 1.5 mL/min, 280 nm). After complete conversion of aminium into alcohol, 20.6 kg of NaOH (514 mol) and 40.4 kg of HO-CH2CH2-SH (516 mol) were sequentially added, and then the mixture was heated at 75 °C. After 12 h the conversion of alcohol into desired product was completed, and 600 L of water was added. The mixture was cooled to 5 °C and filtered in a centrifuge and washed extensively with water until the test for chloride was negative, affording 17.5 kg of wet desired product.

Curtius rearrangement

 

Organic Process Research & Development 2006, 10, 262-271

Ethyl(1R, 2R)-2-(Benzyloxycarbonylamino)cyclohexanecarboxylate. CAUTION! Although diphenyl phosphoryl azide (DPPA) is widely utilized in multi-kilogram quantities,11 prudent safety practices for its use are clearly indicated. DPPA itself is thermally stable and is often purified by vacuum distillation (137 °C, 0.2 Torr). However, adventitious moisture might hydrolyze the reagent, forming volatile (bp 37 °C) anhydrous hydrazoic acid. At least in principle, HN3 could collect in a cool region of the reactor and present an explosion hazard. A scrutiny of the literature did not reveal any incidents based on this eventuality. However, several sensible measures were taken to circumvent any potential problems. (1) Karl Fischer titration was used to monitor water levels, and these were kept below 0.1%. (2) Excess triethylamine was employed. Any traces of strongly acidic hydrazoic acid should be retained in solution as the triethylammonium salt. (3) Cooling to the reactor condenser was not turned on to maximize the likelihood of HN3 vapor being flushed from the system.

To a 100-gal vessel were charged (1R,2R)-cyclohexane- 1,2-carboxylic acid monoethyl ester, (R)-(+)-R-methylbenzyl- amine salt ( 55.0 kg, 172 mol), water (77.0 L), and toluene (119 kg). To the above suspension was added a 37% aqueous solution of HCl (22.0 kg). The phases were cut, and the toluene solution was distilled to a volume of about 120 L to remove water to under 1000 ppm. The solution was cooled to 20 °C, and triethylamine (26.0 kg, 257 mol) was added. The mixture was heated to 85 °C. A solution of diphenylphosphoryl azide (DPPA, 45.4 kg, 165 mol) in toluene (44.0 kg) was added to the mixture at a rate to maintain the temperature at 83-87 °C. The reaction was stirred for 30 min after the addition was complete and after a sample showed the reaction was complete (>98% conversion by HPLC, analysed as N-benzyl urea derivative of the isocyanate). To the above mixture was added benzyl alcohol (17.7 kg, 164 mol), and the mixture was heated to reflux at 110 °C for 5 h. When the reaction was complete, it was cooled to 20-25 °C and washed with water (50 L) and then twice with 10% brine (50 L). The toluene solution was solvent switched first to 2-propanol and then to n-heptane by vacuum distillation (to an end-point of less than 2% IPA in the n-heptane in the pot). The mixture was cooled to 50 °C, seeded with 200 g of desired product suspended in n-heptane (300 mL), and then cooled to 20 °C at 0.2 °C/min. After 8 h at this temperature the mixture was cooled further to -5 °C and filtered on a 36-in. Nutsche. The cake was washed with n-heptane and dried in a vacuum oven. The yield of product was 44.7 kg (80%).

LAH reduction

 

Organic Process Research & Development 2006, 10, 262-271

3-(4-Fluorobenzyl)piperidine. A solution of (S)-3-(4-fluorobenzyl)-2-piperidone (6.4 kg, 30.8 mol) in 120 L of toluene was cooled to 10 °C. Lithium aluminum hydride bis(tetrahydrofuran) solution in toluene (1.0 M, 27.8 kg, 31.8 L, 31.8 mol) was added at a temperature below 15 °C. The batch was heated to 40 °C and stirred for 3 h. The batch was quenched by slow addition to a Rochelle salt solution (16.4 kg in 90 L of water) and stirred for 15 min. The organic phase was washed with 10% brine followed by water. The toluene solution was concentrated by vacuum distillation to a volume of about 60 L. The resultant solution contained product (5.0 kg, 25.9 mol, 84%).

Reductive Amination

 

Organic Process Research & Development 2006, 10, 262-271

 In a 100-gal glass reactor were warmed sodium triacetoxyborohydride (18.5 kg, 87.3 mol) and DMSO (71 kg) to 40 °C until homogeneous. The batch was cooled to 12 °C, and (S)-3-(4-fluorobenzyl)piperidine 2-(R)-mandelate salt (20.2 kg, 58.5 mol) was added. In a separate reactor, (1R,2R)-2-(benzyloxycarbonylamino)cyclohexanecarboxaldehyde (15.3 kg, 58.5 mol) and DMSO (33 kg) were mixed to give a homogeneous solution. The aldehyde solution was added over 2 h to the piperidine solution while keeping the temperature at 10-14 °C. After the addition the reaction was stirred for an additional hour and then quenched with 6 N aqueous HCl solution (8.4 kg) at 20-24 °C. To the quenched reaction mass were sequentially added iPrOAc (59 kg), water (67 kg), and 15% aqueous sodium hydroxide solution (50 kg). The mandelic acid was removed in the aqueous solution. The product was extracted into the iPrOAc, which was washed with 10% brine (40 kg) and water (45 kg). This iPrOAc solution containing (1R,2S)-1-(benzyloxycarbonyl) amino-2-{[3(S)-(4 fluorobenzyl)piperidinyl]methyl}-cyclohexane was used in next reaction without purification.

Imidazole synthesis from aldehyde

 

Organic Process Research & Development 2006, 10, 296-303

7-Chloro-2-(1H-imidazol-2-yl)thieno[3,2-b]pyridine. A 3-L flask was charged with aldehyde (110.07 g, 0.5569 mol) and MeOH (1250 mL). The slurry was stirred for _5 min followed by sequential charge of acetic acid (250 mL), glyoxal trimer dihydrate (117.34 g, 1.675 mol equiv glyoxal), and NH4OAc (258.07 g, 3.348 mol). The mixture was stirred at room temperature for 24 h. Water (625 mL) was slowly added via addition funnel over 30 min, and the resulting slurry was stirred an additional 15 min at room temperature. The slurry was filtered, and the smoothed cake was rinsed (2:1 MeOH/H2O, 2 _ 600 mL). After the filtration was pulled down to a smooth, packed cake, it was given a final rinse with CH2Cl2 (600 mL). The solids were dried to provide 78.33 g (60%) of desired product as a brown powder

Skraup quinoline synthesis

 

Org. Process Res. Dev., 10 (1), 36 -45, 2006

8-Bromo-6-methylquinoline. Sodium m-nitrobenzenesulfonate (2.67 kg, 11.8 mol) was added to methanesulfonic acid (10 L) at 20 C followed by iron sulfate heptahydrate (156.8 g, 0.564 mol). This addition is slightly exothermic and raised the temperature to 27 C. To the resulting mixture was added 2-bromo-4-methylaniline (3.50 kg, 18.8 mol) through an addition funnel with stirring over 30 min, flushed with methanesulfonic acid (0.5 L), and agitated until the solid dissolved (~15 min). The addition is exothermic, and the temperature reached ~60 C after the addition. The reaction mixture was heated to 118-125 C, and glycerol (4.33 kg, 47.0 mol) was added through an addition funnel over 4-8 h. After stirring at 125-133 C for 10-16 h, the mixture was cooled to ~80 C and diluted with cold DI water (10 L) keeping the temperature <90 C. After cooling to ~20 C with an ice bath, the mixture was neutralized with cold aqueous NaOH (10 M, 15.6 L). Solka floc (500 g) was added, and the mixture was further neutralized with 1 M aqueous NaHCO3 (1 M, 16 L). The mixture was cooled to 10-20 C, and MTBE (30 L) was added. After stirring for 4-6 h, the mixture was filtered through a centrifuge (10-m bag), and the phases were separated. The (top) MTBE layer was washed with 20 L of brine (95% saturation). The aqueous layers were back extracted with MTBE, and the organic phases were combined (3.97 kg of product as a 7-9 wt % MTBE solution in 95% yield). For characterization purposes, the hydrochloride salt of 8-bromo-6-methylquinoline can be prepared.

1,2,4-Oxadiazole Synthesis

 

Org. Process Res. Dev., 10 (1), 36 -45, 2006

3-Methyl-5-[4-(methylsulfonyl)benzyl]-1,2,4-oxadiazole. Hydroxybenzotriazole hydrate (2.06 kg, 13.4 mol) was suspended in acetonitrile (25 L), and 2.5 L was distilled off at 1 atm under nitrogen to azeotropically remove water. [CAUTION: Hydroxybenzotriazole will decompose, possibly violently, if heated above its melting point (155-160 C).] After cooling to 25-30 C, 4-methylsulfonylphenylacetic acid (2.5 kg, 11.67 mol) was added, followed by EDC hydrochloride (2.68 kg, 14.0 mol). The resulting mixture was stirred at 20-30 C for 30 min. Methylamidoxime (1.14 kg, 14.0 mol) was added to the slurry over 10 min. The resulting mixture was then heated at reflux for 12 h. The solution was solvent switched to ethyl acetate under reduced pressure (100-200 mBar, 40-50 C) by continuous distillation of ~40 L of ethyl acetate and concentrated to a final volume of ~27 L. After cooling to ~20 C, aqueous NaHCO3 (1 M, 20 L) was added slowly with vigorous stirring. The aqueous layer was removed, and the organic layer was washed with DI water (7.5 L). The aqueous solutions were back extracted with 17.5 L of ethyl acetate. The combined ethyl acetate solution was concentrated to ~7 L (100-200 mBar, 50-70 C) and diluted with 2-propanol (17.5 L). The solution was further concentrated to ~12.5 L. The solution was allowed to cool to 10-20 C, and the desired product precipitated. After stirring for 2 h the mixture was filtered; the solid was washed with 2 × 2.5 L of 2-propanol and then air-dried for 2 h. The solid was further dried in an oven at 30-35 C under vacuum (N2 sweep) to constant weight. Isolated yield: 2.6 kg, 88%.

Friedel-Crafts acetylations

 

Org. Process Res. Dev., 10 (1), 135 -141, 2006

N-(5-Acetyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide. Regioselective Friedel-Crafts Acetylation of starting material in Dichloromethane. A 1-L, four-necked, round-bottomed flask (rinsed with dichloromethane), equipped with a mechanical stirrer, digital thermometer, cooling bath, and nitrogen inlet-outlet, was charged with aluminum chloride (102.0 g, 765.0 mmol) and dichloromethane (280.0 mL) at 20-25 C. The slurry was cooled to an internal temperature at 0-5 C, and acetyl chloride (72.0 g, 917.0 mmol) was added over 20 min while maintaining the temperature at 0-5 C. The white suspension was stirred at 0-5 C for 15 min and N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (70.0 g, 305.0 mmol) was added in five equal portions (14.0 g each) at 5-min intervals (total time = 25 min) while maintaining the internal temperature at 0-7 C. Dichloromethane (20.0 mL) was added to wash off any solids sticking to the wall of the flask. The resulting tan solution was stirred at 0-5 C for 1 h and then added to 1 N HCl (500.0 mL, precooled to 0-5 C) in a 2-L, three-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, and a cooling bath, while maintaining the temperature at 0-25 C. The 1-L, round-bottomed flask and the transferring tube were rinsed with dichloromethane (40.0 mL) and the dichloromethane added to the reaction mixture. The biphasic reaction mixture was warmed to 20-25 C. The layers were separated, and the organic layer was washed with water (100.0 mL). The organic layer was transferred to a 2-L, four-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, addition funnel, nitrogen inlet-outlet, a reflux condenser, and a heating mantle. The solution was warmed to an internal temperature at 40 ± 3 C to achieve gentle refluxing. Heptane (1.2 L) was added slowly over a period of 50 min while maintaining the temperature at 40-55 C to maintain a gentle reflux. The resulting slurry was stirred at 55-58 C for an additional 30 min. The suspension was cooled to 20-25 C over a period of 30 min with efficient stirring and stirred at 20-25 C for an additional 2 h. The solids were collected by filtration, washed with a mixture of dichloromethane/heptane (2 × 100.0 mL, 20:80 v/v), and dried at 60-65 C in vacuo to afford N-(5-acetyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (73.4 g, 88.7%)

 


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