common reaction procedures.pdf

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

Reaction set up:

The chemicals that you take out from refrigerator or freezer should be keep closed for a couple hours untilthe temperature of the chemical you want reach to room temperature. A couple hours' waiting might saveyou several days suffering, especially you are doing water sensitive reactions.The concentration of the reaction sometimes is critical, even though most time does not make hugedifference. When your reaction is intra molecular reaction, you should keep your reaction very diluted toprevent the inter molecular side reaction.Larger stir bar is highly necessary for two phase reactions, like Schotten-Baumann acylation or Suzukicoupling (two phases). Because you need to stir the hell of it to have good yield. For large scale, or mixturewith high viscosity, or semi-solid reactions, needless to say mechanical stirring is needed. I added lowboiling point solvent (heating) to my reaction once to help the agitation.

Acylations

EDCI (DCC) /DMAP (HOBT) coupling. The carboxylic acid (1 equiv.), amine (1 equiv.), EDCI or DCC (1.1 equiv.), and DMAP or HOBT (0.3 equiv.) were dissloved into methylene chloride. The resulting mixturewas stirred at room temperature with N2 inlet for 12 hours. The resulting mixture was poured into brine.The organic layer was separated, dried, and concentrated under vacuo. The resulting residue was separatedby silica gel column.Weinreb amide formation. To a solution of amine in toluene or DCE was added AlMe3. The mixture wasstirred for 20 min at room temperature. The ester solution of toluene or DCE was added to the mixture. Theresulting mixture was heated to 80oC for 6 hours. The resulting mixture was diluted with ethyl acetate andwashed with brine. The organic layer was dried and concentrated. The residue was purified by silica gelcolumn.Schotten-Baumann acylation. The amine (1 equiv.) was dissolved into methylene chloride . 2 M NaHCO3aqueous solution was added into the solution. The mixture was stirred vigorously, and then acid chloride(1.5 equiv.) in methylene chloride was added into the mixture slowly. The mixture was stirred for 2 hours.The organic layer was separated, and washed with Na2CO3 aqueous solution three times. The resultingorganic layer was dried, and concentrated. The resulting residue was separated by silica gel column.Schotten-Baumann reaction is very good for the acylation of unreactive amine. Weak bases, like RCOOKalso could catalyze the acylation between acid chloride and unreactive amine.

Alkylations

0.1 to 0.2 Equiv. of KI could promote your reaction, when your alkylation reagent is not active enough. It iscalled Finkelstein reaction.The mono-alkylation of betaketoester or malonate ester. The starting material, beta-ketoester or malonateester, (1 equiv.) was dissolved into DMF with Li2CO3 (4equiv.). MeI, or EtI, or BnBr (2 equiv.) was addedinto the mixture. The resulting mixture was heated to 65oC for 12 hours. GS-MS was used to check thereaction process. The reaction mixture was poured into brine, and ethyl was used to extract the product from

common reaction procedures http://www.ecompound.com/Reaction reference/Lab rat procedures.htm

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aqueous layer. The organic layer was dried and concentrated by vacuo. The resulting mixture was easilypurified by silica gel column to afford high yield mono-alkylation product. Sometimes LiH is used insteadof Li2CO3.The alkylation of substituted malonate or ethyl cyanoacetate. The starting material (1 equiv.) was dissolvedinto DMF, and RBr (1.5 equiv.) was added into the mixture. K2CO3 (15 equiv.) was added into the resultingmixture in portion. The resulting mixture was stirred at 80oC for 6 hours. The resulting mixture was dilutedby ethyl acetate, and washed with brine. The ethyl acetate solution was dried and concentrated. Theresulting residue was separated by silica gel column.Borch reductive amination or alkylation. The amine (1equiv.) and ketone or aldehyde (1.5 equiv.) weredissolved into CH2Cl2 or dichloroethane. The mixture was stirred for 3 hours at 60oC. The resultingmixture was cooled to room temperature, and then acetic acid (2.5 equiv.) and NaBH3CN or NaBH(OAc)3(3equiv.) was added into the mixture. The resulting mixture was stirred for another 8 hours. Ethyl acetatewas used to dilute the mixture, and brine was sued to wash the organic layer. The organic layer was driedand concentrated . The resulting residue was purified by silica gel column to afford 70% product. Click hereto learn more. This reaction is similar to Eschweiler-Clarke reaction, in which formaldehyde is used, andformic acid is used as hydrogen donor.The alkylation of amine with alkyl bromide. The amine (1 equiv.) and alkyl bromide (1.1 equiv.) weredissolved into DMF with TEA (3 equiv.). The mixture was stirred for 8 hours at 80oC. The resultingmixture was diluted with ethyl acetate, and washed with brine. The organic layer was dried andconcentrated under vacuo. The resulting residue was separated by silica gel column. The common sidereaction was over alkylation, or elimination of alkyl bromide.

Condensations

Knoevenagel condensation 1. The ketone (1 equiv.) or aldehyde, ethyl cyanoacetate (2 equiv.), ammoniumacetate (5 equiv.), and acetic acid (10 equiv.) were mixed into toluene. The resulting mixture was heated toreflux for 48 hours. The resulting mixure was diluted with ethyl acetate and washed with brine. The organiclayer was dried and concentrated. The resulting residue was purified by silica gel column.Knoevenagel condensation 2. The ketone (1 equiv.) or aldehyde, diethyl malonate(2 equiv.) were dissolvedinto THF. TiCl4 (2 equiv.) was added into the mixture dropwise with a N2 inlet at 0oC. Pyridine (4 equiv.)was added into the mixture also at 0oC. The resulting mixture was stirred for 12 hours at room temperature.The resulting mixture was filtered, the filtrate was diluted with ethyl acetate and washed with brine. Theorganic layer was dried and concentrated. The resulting residue was purified by silica gel column.Mukaiyama aldole condensation. The starting material, ketone (1 equiv.), was dissolved in THF, andcooled to -78oC. TiCl4 (2 equiv.) was added into the mixture dropwise. TMS enol or enolate (1.3 equiv.) inTHF was added into the mixture dropwise. The resulting mixture was stirred for 4 hour at roomtemperature, and then 50oC for 2 hours. The resulting mixture was diluted with ethyl acetate, and washedwith brine. The ethyl acetate solution was dried and concentrated. The residue was purified by silica gelcolumn.Reformatsky reaction. The starting materials, ketone (1equiv.), alpha-bromoester (1.5 equiv.), and Zinc (2equiv.) activated by TMSCl, were dissolved into THF. The resulting mixture was heated to 60oC for 12hours with a N2 inlet. The resulting mixture was filtered. To the filtrate, 2 N HCl was added and stirred foranother 2 hours. The resulting mixture was diluted with ethyl acetate and washed with brine. The organiclayer was dried, concentrated, and the residue was purified by silica gel column to yield alpha, betaunsaturated ester.

Decarboxylations

The malonate derivative (1 equiv.) was dissolved into methanol, and 2 M KOH (5 equiv.) was added intothe solution. The resulting mixture was acidified using HCl to pH 2. The resulting mixture was stirred for


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another 2 hours. Ethyl acetate was used to extract the product from aqueous layer. The organic layer wasdried, concentrated, and the residue was purified by silica gel column to afford a mono acid.The diethyl malonate (1equiv.) was dissolved into DMSO, and LiCl (15 equiv.) was also added into themixture. The resulting mixture was heated to 190oC with N2 inlet for 4 hours. The resulting mixture wascooled to room temperature and diluted with ethyl acetate. After filtering, the filtrate was washed withbrine. The organic layer was dried and concentrated. The resulting residue was purified by silica gel columnto afford an ethyl ester.Reductive decyano group. To a THF solution of ethyl cyano acetate derivative (1equiv.) with HMPA (10%)was added SmI2 (2 equiv.). The resulting mixture was stirred for 8 hours at room temperature. The resultingmixture was filtered. The filtrate was diluted with ethyl acetate and washed with brine. The organic layerwas dried and concentrated. The residue was purified by silica gel column.

Halogenations

Chloronation of alcohol. The starting material, primary alcohol, (1equiv.) was dissolved into THF withBu4NCl (0.2 equiv.). Thionyl chloride was added into the solution very slowly under 0oC. The mixture wasstirred for 3 hours at room temperature. 2 M K2CO3 aqueous solution was added into the mixture to adjustthe pH to 8. Ethyl acetate was used to extract the product from aqueous solution. The organic layer wasdried and concentrated under vacuo. The residue was separated by silica gel column to afford 85% yield.Acid chloride from acid. The acid (1 equiv.) was dissolved into methylene chloride with 0.5 mL of DMF.Thionyl chloride or oxalyl chloride (2 equiv.) was added into the solution slowly. The mixture was stirred 1hour at room temperature, and then heated to 70oC for another 4 hours. The resulting mixture wasconcentrated. The residue was used as it without further purification. On certain extremely condition thionylchloride could be used as solvent.Chloronation of aromatic ring from hydroxyl group. The starting material, hydroxyl-heterocycle, (1 equiv.)was added into POCl3 (30 equiv.). TEA, or dimethylaniline, or pyridine (20 equiv.) was also added into themixture slowly. The resulting mixture was heated to 60oC for 4 hours. The resulting mixture was added intoice-water dropwise with strong stirring. The precipitate was collected, and crystallized to afford 60%product.Bromination of alcohol. The starting material, primary alcohol, (1 equiv.) and PPh3 (1.5 equiv.) weredissolved into THF at 0oC. Bromine (1.2 equiv.) was added into the mixture slowly. You would notice thecolor change. The resulting mixture was stirred for another 3 hours at room temperature. After filtering, thefiltrate was concentrated under vacuo. the resulting residue was good enough for next reaction.Radical bromination of benzylic position. The alkyl substituted aromatic system was dissolved into CCl4with AIBN (0.2 equiv.) and NBS (1.5 equiv.). The mixture was heated to 65oC for 4 hours. The resultingmixture was diluted with ethyl acetate, and washed with brine. The organic layer was dried andconcentrated. The residue was separated by silica gel column to give product with 70% of yield. CF3Phcould be used to replace CCl4 for higher temperature.Bromination through electrophilic substitution mechanism. The aromatic compound was dissolved intoacetic acid, and Br2 was added into the solution dropwise. The resulting mixture was heated to 70oC andstirred for 7 hours. The resulting mixture was diluted with ethyl acetate and washed with brine. The organiclayer was dried and concentrated. The residue was purified by silica gel column. NBS,dibromomethylhydatoin, and Br2/Fe could be used as bromo sourse. Polar solvent THF. dioxane are highlynecessary for the reaction.Bromination of aromatic ring through Sandmeyer reaction. To a dark solution of CuBr2 (3 equiv.) inCH3CN in a two necked bottle, was added t-butyl nitrite (1.3 equiv.) slowly. The resulting solution washeated to 60oC for 20 min. to above solution, was added CH3CN solution of aniline type of startingmaterial (1 equiv.) dropwise. The resulting mixture was heated to 60oC for 3 hours. The resulting mixturewas transferred to 1 M NaOH aqueous solution, and extracted with ethyl acetate. The organic layer wasdried, and concentrated. The residue was separated by silica gel column.


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Iodonation of aromatic ring. The electronic rich aromatic ring (1 equiv.), ZnCl2 (3 equiv.), andBnNMe3(ICl2) (1.5 equiv.) were dissolved into acetic acid. The mixture was stirred at room temperature for48 hours. The resulting mixture was poured into ice water, and extracted with ethyl acetate. The organiclayer was washed with brine, dried and concentrated under vacuo. The resulting residue was separated bysilica gel column.Iodonation by NIS. To a suspension of starting material (1 equiv.) in dry CH3CN was addedn-iodosuccinimide (1.1 equiv.), and the mixture was stirred at room temperature fror 1 hour. The reactionmixture was heated at reflux for 10 min and then cooled to room temperature. Methylene chloride wasadded into the reaction mixture and the organic phase was washed successively with NaOH 10%, sodiumthiosulfate, and brine. The resulting organic phase was driedover magnisum sulfate, filtered, andconcentrated to dryness under reduced pressure. The resulting residue was separated by silica gel column.Swarts fluoroalkane synthesis. A mixture of trichlorotoluene (1 equiv.) and SbF5 (1.1 equiv.) was heateduntil the reaction started. After completion of the reaction, the mixture was washed with HCl and dried. Theresidue was separated accordingly.

Hydrolysis

The ester (1equiv.) was dissolved into methanol, and KOH, or LiOH, or NaOH (20 equiv.) aqueous solutionwas added into the solution. THF was used to make reaction homogenous. The mixture was stirred for 40min. at room temperature. Acetic acid was used to adjust the pH to 5. Ethyl acetate was used to extract theproduct from aqueous layer. The organic layer was dried and concentrated. The residue was crystallized toafford 90% product.

Hydrogenations

Parr Shaker. The starting material (1 equiv.) in ethanol or methanol with 5-10% of Pd-C [Pd(OH)2 oncarbon, Pearlman reagent, is a good choice also] was put onto parr shaker. The regular pressure is from 20to 60 psi. You should pay a little extra attention on mechanic problems besides flushing the bottle with H2.Filter the mixture, Pd catalyst was collected into special container with water, and filtrate was concentrated.The residue was separated by silica gel column.Transfer hydrogenation. The starting material (1 equiv.) was dissolved into methanol with HCO2NH4 orNH2NH2 (20 equiv.). Pd-C 5% was added into the mixture. The resulting mixture was heated to 80oC withN2 inlet for several hours until TLC showed no starting material left. Work up is similar to that of Parrshaker.Ionic hydrogenation (Kursanov-Parnes reaction). The CH2Cl2 solution of starting material, ArCOAr' (1equiv.), was put into ice-NaCl bathe. CF3SO3H (1 equiv.) and triethylsilane (1equiv.) was added into themixture sequentially. The mixture was stirred for 20 min, and another 2 equiv. of CF3SO3H andtriethylsilane was added. The resulting mixture was stirred at room temperature for 12 hours. The resultingmixture was poured into ice-water with sodium carbonate. The product was extracted from aqueous layer.The organic layer was dried and concentrated under vacuo. The residue was separated by silica gel columnto afford product (70%). This reaction is very good for base sensitive compound reduction.

Oxidations

Dess-Martin oxidation. The primary alcohol (1 equiv.) was dissolved into methylene chloride, and thenDess-Martin periodinane (1.1 equiv.) was added into the solution. The resulting mixture was stirred at roomtemperature for 12 hours. Saturated NaHCO3 aqueous solution with sodium thiosulfate was then added tothe mixture. The resulting mixture was stirred at 40oC for 30 min. The organic layer was washed withbrine, separated, dried, and concentrated. The resulting residue was purified by silica gel column. Sodiumthiosulfate was used to reduce extra of Dess-Martin reagent.Swern oxidation. The alcohol (1 equiv.) was dissolved into THF with DMSO (1.5 equiv.). The resulting


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mixture was cooled to -78oC. Oxalyl chloride (1.5 equiv.) was added into the mixture. The mixture wasstirred for 30 min at -78oC. TEA (2 equiv.) was added into the mixture dropwise. The resulting mixture wasstirred 1 hour at -78oC, and 2 hours at room temperature. The resulting mixture was diluted with ethylacetate and washed with brine. The organic layer was dried and concentrated. The resulting residue wasseparated by silica gel column.

Rearrangements

Claisen rearrangement. The allyl phenol in a flask with N2 inlet was heated to 200oC for 16 hours. TLCshowed trace amount of starting material. The flask was cooled to room temperature. The resulting residuewas purified by silica gel column. Dimethylaniline could be used as solvent in this reaction.

Reductions

LAH ester reduction: The starting material (ester or amide1 equiv.) was dissolved into THF, and LAH (solidor in THF) was added into the solution at -78oC. The mixture was stirred for 1 hour at -78oC, and then themixtrue was stirred for another 2 hours at room temperature. KOH 10% in water or Rochelle's salt wasadded into the mixture slowly. Ethyl acetate was used to extract the product (alcohol from ester or aminefrom amide) from aqueous solution. The organic layer was dried, concentrated. The resulting residue wasseparated by silica gel column to give 70% yield.NaBH4 ketone reduction. The staring material, ketone, was dissolved into methanol, and NaBH4 (2 equiv.)was added into the mixture by portion. The mixture was stirred for 2 hours. The resulting mixture wasdiluted by ethyl acetate, and washed with brine. The organic layer was dried and concentrated. The residuewas separated by silica gel column.DIBAL reduction ester to aldehyde. The ester (1 equiv.) was dissolved into CH2Cl2. The temperature of thesolution was coole to -78oC. DIBAL in THF (1.2 equiv.) was added into the solution dropwise with a N2inlet. The resulting mixture was stirred at -78oC for 1 hour. Methanol was added into the mixture slowly,and then brine was added into the mixture. The organic layer was separated, dried, and concentrated. Theresidue was purified by silica gel column.

Reactions on heterocycle ring

The choice of base or acid to do the cyclization. If the leaving group of cyclization is hydroxyl or aminegroup, acid have to be used, because only protonated amine or hydroxyl group could become leaving group.If the leaving group is alcohol, base has to be used. If nucleophile has to be activated, using base, otherwise,using acid.

Substitutions

Azide substitution. Alkyl bromide (1 equiv.) and sodium azide were dissolved into DMF. The mixture washeated up to 80oC for 12 hours. To the resulting mixture, were added PPh3 (3 equiv.) and H2O (30 equiv.)at room temperature. The resulting mixture was stirred at room temperature for 12 hours. A primary amine(75%) was made after work up and purification. The second part of this reaction is called Staudinger azidereduction.Aromatic substitution 1. 4-Hydroxylcoumarin (1 equiv.) and aniline (50 equiv.) were mixed together with aN2 inlet. The mixture was stirred for 2 hours under reflux. The resulting mixture was dissolved intomethanol. 0.1 M NaOH aqueous solution was added into the methanol solution slowly. The yellowprecipitate was collected, and washed by water.Halogen substitution from an electronic deficient aromatic ring. The halo-aromatic ring (1 equiv.), amine oralcohol (2 equiv.), and base (TEA, or diisopropylethylamine 2 equiv.) were mixed into DMF. The mixturewas stirred at 95oC for 8 hours with a N2 inlet. Ethyl acetate was used to dilute the resulting mixture. The


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resulting mixture was washed with brine. The organic layer was dried, concentrated, and the residue waspurified by silica gel column.Floride substitution from an electronic rich aromatic ring.Substitution of MsOR. Step 1, making MsOR. The alcohol (1 equiv.) was dissolved into THF with TEA(1.5 equiv.). MsCl (1.2 equiv.) was added into the solution slowly at 0oC. The mixture was stirred for 3hours. The resulting mixture was diluted with ethyl acetate, and washed with brine. The organic solutionwas dried, and concentrated. The resulting residue was used in next step without further purification. Step2, substitution. The amine (1.3 equiv.) was added into the acetonitrile solution of the product of step 1. TEA(1.5 equiv.) was also added into the mixture. The resulting mixture was stirred at room temperature for 12hours. The resulting mixture was diluted by ethyl acetate, and washed with brine. The organic solution wasdried, and concentrated. The resulting residue was separated by silica gel column. The common sidereaction is elimination.Mitsunobu reaction. The phenol (1.2 equiv.), primary alcohol (1.0 equiv.), Dead or ADDP (1.5 equiv.), andPPh3 (1.5 equiv.) were dissolved into THF with N2 inlet. The resulting mixture was stirred for 3 hours, andprecipitate was formed. The mixture was stirred for another 2 hours. The mixture was filtered, and filtratewas directly loaded to silica gel column. Precipitate (OPPh3) formation is a good sign for Mitsunobureaction. And the common side reaction is elimination. Intramolecular Mitsunobu reaction is much fasterthan inter molecular Mitsunobo. Sometimes, high concentration helps this reaction.

NMR & MS

NMR, chemical shifts of deuterated solvents could come from proton in trace of amount of non-deuteratedsolvent, proton exchanged with trace amount of water in the solvent if you have a polar solvent, and waterproton when water make hydrogen bond with the solvent. These chemical shifts will change withtemperature and in some case they change with percentage of water in the solvent. The chemical shiftslisted in my table are obtained at room temperature (22oC).

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 treatedsequentially with 2.20 g (16.30 mmol) of HOBT, 3.12 g (16.30 mmol) of EDAC, and 3.90 g (19.50 mmol) ofL-methionine methyl ester hydrochloride. The suspension was stirred for 15 min, 4.00 mL (27.00 mmol) of TEAwas added, and the mixture stirred for 24 hours. The reaction was quenched by pouring into 300 mL of ethylacetate and extracting with 3 portions of 1 N aqueous HCl, 2 portion of water, 1 portion of brine, 1 portion ofsaturated aqueous NaHCO3, and a portion of brine. The solution was then dried over Na2SO4, filter, andconcentrated. The residue was purified by column chromatography on silica gel (120 g, 70:30 ethylacetate/hexanes) to provide 4.4 g (79%) of product as an oil that solidified upon standing.

A Grignard reaction.


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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 of4(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 mixturewas stirred at room temperature for 3 h. Water (430 mL) and 10% aqueous sulfuric acid solution (860 mL) wereadded dropwise, and the mixture was stirred at 30 min and titrated to pH 8 with 30% aqueous sodium hydroxidesolution. 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 andbrine and concentrated under reduced pressure. The crystals formed were collected by filtration and washed withisopropyl 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:


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, 0.15mol) 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, maintainingthe temperature at 0 oC. The reaction mixture was stirred at this temperature for a further 30-45 min. A solution ofstarting material (38.5 g, 0.125 mol) dissolved in THF (100 mL) was added to the reaction mixture, maintainingthe 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 sodiumchloride solution (100 mL) and once with water (50 mL). After removal of the solvents at 30-50 oC and 30 mbarpressure, the evaporation residue containing 57.5 g of product (98.8%) was diluted in THF (75 mL) and kept at0-5 oC (storage solution of product).

Knoevenagel Condensation.


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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 weresuccessively added 2,4-thiazolidinedione (0.48 kg, 4.8 mol), acetic acid (70 mL, 1.44 mol), and piperidine (0.12L, 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 bymonitoring HPLC (HPLC retention time; starting 7: 12.5 min, product 10: 13.5 min). Once the reaction wascompleted, the mixture was cooled to room temperature, and the precipitates formed were collected by filtrationand 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 haloestersmoothly. The Zn metal could be activated by heating it with TMSCl, I2, MeMgBr, 1, 2-dibromoethane, CuCl andCuI.

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 at20oC. To this solution, Zn powder (US-Zinc, 7.1 kg, 106 mol, 1.7 equiv) was added, followed again by THF (48.8kg). Concentrated sulfuric acid (1.1 kg, 12 mol, 0.2 equiv) was added, and the mixture was heated to 45 oC. Whenthe target temperature was reached, a solution of indanone (9.8 kg, 60 mol) in THF (88 kg) was added. The lattersolution 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 rinsedwith THF (2 kg). The reaction mixture was stirred with a jacket temperature of 45oC for 1.5 h and subsequentlycooled 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 allpipes 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. THFand 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


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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 inparaffine) in 100 mL of THF at 0 oC were added slowly 42 g (133 mmol) of starting material aldehyde dissolvedin 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 THFwere added. The solution was stirred 1 h at 20 C and 19 h at 50 C. The reaction was monitored by thin layerchromatography (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 citricacid used to adjust pH to 7. The product was extracted twice with 500 mL of methyl tert-butylether andevaporated to dryness. The crude material was purified by chromatography on silica gel by elution with hexanesand an increasing gradient of ethyl acetate (0-15%). The evaporation of the fractions gave 79.5 g of product in90% yield.

Oxane oxidation of the sulfide


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 andthen 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 andwashed 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 (3.6kg) 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 untilless than 0.5% of the sulfoxide intermediate remains by HPLC analysis. The reaction mixture was filtered through a filterpot, and thesolids (excess Oxone and inorganic byproduct) were washed with acetone (10 kg). The wash and filtrate were combined and treated with10% aqueous NaHSO3 solution (7.8 kg) maintaining a temperature at 18 °C. The mixture was stirred until a test sample showed that aless 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) toa 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 occurredand 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 roomtemperature until the concentration of the product in the supernatant solution was less than 1 mg/mL. The slurry was filtered and washed


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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. Thedry 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) ofDMSO in 100 mL of dichloromethane was cooled to -40 oC, and 19.8 mL (0.23 mol) of oxalyl chloride in 198mL 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 for30 min at -40 oC. Then 69.8 mL (0.5 mol) of triethylamine were added followed by 300 mL of water. Extractionwith dichloromethane and evaporation of the solvent yielded 44.72 g (100% yield) of crude product as an oil.

Hydrogenation general procedure


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, 563mmol). THF (600 mL) was added and the mixture purged with nitrogen (3_) and then hydrogen (3_). The resulting mixture was stirredunder hydrogen pressure (50 psig) at high rpm (>300) at 60-70 °C until the uptake of hydrogen stopped (about 2 h). The resultingmixture was cooled to room temperature and filtered. The filter cake was washed with THF (2 _ 200 mL), and the filtrate and rinses werecharged to a 1-L, three-neck, round-bottom flask, fitted with mechanical stirring, thermocouple, and distillation head. The solution wasvacuum 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 andcooled 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 with100 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


The classic solvents employed in the Buchwald-Hartwig amination reaction are nonpolar, aprotic solvents such as m-xylene and1,4-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 andagitation at room temperature starting materials, Pd(dba)2, BINAP, and NaO-t-Bu were dissolved/suspended in the solvent. The solventwas previously purged for 10 min with nitrogen. The ratio between the reactants in this flask was as follows: 1.00 g (1.0 equiv) ofbromotoluene, 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 wasdistributed to a number of process vials. Each of the vials contained approximately 2 mL of the reaction mixture, was equipped with a


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magnetic stirring bar, and was purged with nitrogen prior to the sealing. Subsequently the reactors were loaded in an autosampler andreacted at 100 °C from 10 to 300 min. Initial investigation of the reaction mixtures left at room temperature for 24 h showed noconversion of the reactants.

Heck Coupling Jeffrey-type Condition


Preparation of 4,2¢-Difluoro-5¢-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)-biphenyl-2-carbonitrile. Under an atmosphere ofnitrogen 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 intowater. 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


(2S)-2-(N-tert-Butoxycarbonyl)-amino-N-cyclopentyl- 3-(4-cyanophenyl)-N-methylpropanamide. To a stirred mixture ofPd[(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 roomtemperature, and ethyl acetate (800 mL) and saturated sodium bicarbonate (500 mL) solution were added. After vigorous stirring for 30min, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (300 mL). The combined organic layer waswashed 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


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2-Chloro-5-(pyridin-2-yl) Pyrimidine. A 2-L flask was charged with tetrahydrofuran (130 mL) and purged withnitrogen. The mixture was cooled to -70 oC, and a solution of hexyllithium in hexanes (175 mL 2.5molar, 0.436mol) was added dropwise at such a rate that the inner temperature remained below -50 oC. On completion of theaddition the mixture was cooled to -65 oC, and 2-bromopyridine (65.7 g, 0.416 mol) was added at such a rate thatthe 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 towarm to approx 22 C. After stirring for another 2 h, Pd(PPh3)4 (4.8 g, 0.004 mol) was added. Subsequently, asolution of 5-iodo-2-chloropyrimidine (50 g, 0.2 mol) in tetrahydrofuran (160 mL) was added at such a rate thatthe 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 layerswere separated, and from the organic layer the solvents were evaporated under reduced pressure, leading to ablack oily residue. The residue was dissolved in dichloromethane (300 mL), and to the solution were addedKieselgel 60 (66 g) and thiol-modified silica (6.1 g).The mixture was stirred for 20 min and filtered. The solidcollected was washed with dichloromethane (3 aliquots of 230 mL). From the filtrate the solvents were evaporateduntil the residual volume reached approx 350 mL. After cooling to approx 22 oC the residue was washed with a 2N hydrochloric acid solution (2 aliquots of 350 mL). The combined aqueous layers were treated with Norit ASupra (1.4 g). After filtration the filtrate was neutralized with aqueous ammonia (pH 6-7). The resultingprecipitate was collected by filtration and dried in vacuo at 40 oC, yielding 25.6 g (67%) of the title compound.

Sonogashira coupling reaction


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 temperatureand quenched with water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and washed withwater (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 asan off-white solid (58.73 g, 79.6%) with a purity of 98.4% (HPLC, 230 nm).

Reductive carbonylation


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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 whichthe reactor was allowed to cool. The reaction was filtered, and the filtrate was analysed by GC-MS to determinethe conversion and yield of aldehyde.

General Procedure for the Reductive Carbonylation of 4-Bromobenzonitrile (Method B). To4-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 temperaturewas raised to 90 C, and the reactor was charged with 3 bar of CO. The reaction was stirred under these conditionsfor 18 h after which the reactor was allowed to cool. The reaction was filtered, and the filtrate was analysed byGC-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, andthe reactor was charged with 3 bar of CO. The reaction was stirred under these conditions for 18 h, after which the


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reactor was allowed to cool. The reaction was filtered, and the filtrate was analysed by GC-MS to determine theconversion and yield of aldehyde.

Chloronation Reaction


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 heatingconditions for 20 h. After the mixture was cooled to 40 C, water (900 mL) was added over 20 min. The formedblack precipitate was extracted with ethyl acetate (1130 mL). The extract was washed with an aqueous solution ofsodium 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 mixturewas cooled to approx 22 oC and filtered. The precipitate washed with water (100 mL) and dried at 40 oC in vacuoyielding 78.4 g (72%) of the title compound

Nenitzescu reaction


1-(4-Fluorophenyl)ethyl 5-Hydroxy-2-methyl-1H-indole-3-carboxylate. A 20-L jacketed vessel was chargedwith 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 30min and concentrated, and NMR analysis indicated the reaction was complete. After an additional 10 min, themixture was cooled to 20 oC over 1 h. The mixture was concentrated, taken up in dichloromethane (8 L), andwashed with 10% aqueous potassium carbonate (2 × 6 L). The aqueous layers were combined and extracted withdichloromethane (2 L). The organic layers were combined, dried with magnesium sulfate (700 g), filtered, andconcentrated to approximately 7.5 L total volume.

Mannich reaction


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1-(4-Fluorophenyl)ethyl 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylateHydrochloride. 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, and1-(4-fluorophenyl)ethyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate (7.32 mol in 7.5 L of dichloromethane) wasadded over 10 min causing the IT to rise to 8 oC. The mixture was warmed to 20 oC over 30 min and stirred atthis temperature. The reaction was monitored by 1H NMR using concentrated aliquots. After stirring at 20 oC for100 min, water (5 L) was added and the mixture stirred vigorously for 10 min and allowed to settle. The layerswere separated, and the organic phase was washed with an additional portion of water (5 L). The aqueous layerswere combined and extracted with dichloromethane (2.5 L). The organic layers were combined, dried withmagnesium sulfate (824 g), filtered, and concentrated. The residue was taken up in ethanol (4.5 L) and transferredto a 10-L round-bottomed vessel with overhead anchor stirring. A solution of HCl in ethanol was prepared byaddition of acetyl chloride (657 mL, 9.24 mol) to ethanol (1.5 L) with cooling. This solution was added over 85min to the Mannich product, using an ice bath to control the IT < 35 oC. Precipitation was observed before theaddition was complete. The mixture was stirred at ambient temperature for 2.5 days. The mixture was then cooledin an ice-water bath for 30 min (IT 6 C) before dividing into two portions and filtering. The cakes were washedwith ice cold ethanol (2 × 500 mL each) and dried in a vacuum oven at ambient for 23 h to give 1.375 kg, as alight-purple solid.

Indolizine Synthesis

3-(4-Cyanobenzoyl)indolizine. To a solution of 4-acetylbenzonitrile (34 g, 235 mmol) in EtOAc (320 mL) wasadded Br2 (neat, 11.9 mL, 320 mmol) at room temperature. The reaction mixture was stirred at room temperaturefor 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 roomtemperature and then 0.5 h at 0 C, EtOAc (70 mL) was added to the mixture. The resulting precipitates werecollected 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) wasadded DMF-Me2SO4 (400 mL) (pre-prepared in a separate reaction flask by stirring a mixture of equal moleequivalents 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 innertemperature was kept between 25 and 40 C. After stirring at room temperature for 2 h, the reaction mixture was


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charged with ice water (2000 mL) with stirring which led to the formation of slurry. The precipitates werecollected, washed with water, and dried under a vacuum to give 29 g (76%) of 3-(4-cyanobenzoyl)indolizine. Rf0.3 (10% ethyl acetate in hexanes); mp 156-157 C (recrystallized from ethyl acetate).

Shi Epoxidation


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 solutionin acetonitrile (20 mL) was added. While the mixture was stirred with vigorous agitation, Oxone (45.3 g, 0.074mol) in water (160 mL) was added to the mixture. The temperature was maintained below 10 oC by control of theOxone 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 with25% 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 solutionwas cooled to 20-30 oC, and heptane (67 mL) was added over approximately 1 h to crystallise the product. Thesolids were filtered, washed with cold heptane (~15 mL), and dried at 35-40 oC to afford a 55% yield ofhydroxylactone 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) wasadded cyanoacetamide (63 g, 1.5 equiv) under nitrogen atmosphere. The resulting mixture was stirred for 20 minat 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 andthen heated at 55 oC for 1 h. To this was added sodium methoxide solution (25% solution, 172 mL, 1.5 equiv) at55 oC over a period of 40 min. After 3 h HPLC/MS indicated starting material and intermediates were convertedto the pyrrole. A crude sample of pyrrole was obtained by extractive aqueous workup. To the above reactionmixture 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


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HPLC/MS indicated that the pyrrole was converted to the pyrrolopyrimidinone. The reaction mixture was dilutedwith 1.5 L water, heated at 60 oC for 1 h, and then concentrated to small volume (~1.5 L). Solution assayindicated that pyrrolopyrimidinone was formed in 75% solution yield. This solution was neutralized to pH 7.5with 6 N aq HCl, cooled to about 5 oC, and held at this temperature for 30 min. Solids were filtered, washed withwater, 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


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 dimerwas 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, wascharged starting material (20 g, 41 mmol) followed by Eaton’s reagent. There was an exotherm to about 47 °C. The resulting dark-redsolution 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 iceand the pH adjusted to 7-8 by addition of 50% NaOH, 2 mL of methylene chloride were added, and the lower layer was spotted andeluted with 5% methanol/95% methylene chloride). When completed, the reaction was cooled to less than 30 °C and poured into 200 g ofice. 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 (200mL) was added, and the addition of NaOH solution was resumed until the pH was 7-8, keeping the temperature less than 30 °C (use anice bath if needed). The phases were separated, and the aqueous was washed with methylene chloride (1 _ 100 mL). The combinedorganic phases were filtered through 5 g of silica gel, and the cake was washed with 300 mL of methylene chloride. The filtrates wereconcentrated on the rotovap to about 150-mL volume. Methanol (200 mL) was added and the solution concentrated to about 50-mLvolume. 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


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


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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 witha 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 (1.0mol) of pyridinium salt in 300 mL of isopropanol , and 1.7 L of methanol. The addition funnel is charged with153.3 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 suctionfiltered, washed with 500 mL of 25 °C methanol, 500 mL of 25 °C toluene, and 500 mL of 25 °C hexanes, andthen air-dried 18 h at 25 °C to afford 284.69 g (93.2%) of product as a bright yellow solid.

Tisler triazolopyrimidine cyclization


(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 intoluene (ca. 20%, 2.6mL, ca. 4.9 mmol). The reaction was stirred at this temperature for 40 min at which timeHPLC analysis indicated 15% of hydroxyguanidine remained. After stirring an additional 30 min HPLC analysisindicated 15% of hydroxyguanidine still remained. Additional phosgene/toluene (0.25 mL) was added and thereaction 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 analysisindicated that 9% of oxadiazolone remained. The white slurry was warmed to 35 °C and was held there for 30 minat which time HPLC indicated the cyclization was complete. The slurry was cooled to room temperature and thentreated with water (15 mL). The pH was adjusted to 2 by dropwise addition of concentrated HCl. The volatileswere removed on the rotary evaporator (35 °C/25 mmHg), leaving a white slurry. The solid was collected byfiltration and washed with a little water to give 2.74 g of crude wet material. HPLC analysis of the wet materialrevealed 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 constantweight (80 °C/ 25 mmHg), providing the product as a white solid (1.84 g). A 1.0 g sample was dissolved inboiling CH3OH/CH3CN (60 mL/10 mL) and then concentrated to a total volume of 15 mL. The mixture wascooled in an ice bath, and the resulting crystals were collected and washed with a little CH3OH. The material wasdried 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 ofcrude 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


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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) wasadded. After the atmosphere was displaced with N2 followed by H2, the mixture was stirred for 15 h at rt underatmospheric pressure of H2. After the atmosphere was replaced with N2, aqueous NH3 (_14%, 20 mL) wasadded. The following workup operations were conducted under N2. After stirring for 20 min, the mixture wasfiltered to remove the catalyst, which was washed with THF (50 mL). The combined solutions were extractedwith toluene (50 mL). The organic layer obtained was washed with aqueous citric acid (10%, 50 g), aqueoussodium 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 combinedtoluene solutions were analyzed by HPLC (3.22 assay g, 94% yield), and then concentrated in vacuo. The residualsolids were suspended in toluene (5 mL) and heptane (13 mL) and heated to 90 °C to dissolve the solids. Thehomogeneous solution was cooled to 63 °C, followed by seeding with a crystal of indole to form a seed bed. Theslurry formed was stirred for 1 h at 60-65 °C, heptane (37 mL) was added over a period of 2 h, and the solutionwas 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 colorlesscrystals (2.94 g, 86% yield with 99.9 area % purity by HPLC).

Knorr Cyclization Pyrrole


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 ethylpropionate 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 undera nitrogen atmosphere, R-isonitroso-â-ketoester (12.8 kg, 42.65 mol) was dissolved in EtOH (110 L) at 20 °C. The solution was cooledto 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-ketoesterand zinc in EtOH at 0 °C to give a slight exotherm and initiate the reduction. The rest of the ethanolic aqueous acetic acid solution wasadded 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 °Cand stirred for 0.25 h (HPLC indicated 98.3% conversion of R-isonitroso-â-ketoester). The potassium enolate suspension was added over0.5 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 for3.0 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 andwashed 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%).


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Magnesium-halogen exchange for generation of Grignard


General Procedure for Magnesium-Iodine Exchange. A nitrogen-purged flask with magnetic stir bar was charged with i-PrMgClsolution (20.0 mL, 40.0 mmol, 2.0 M in THF). The reaction mixture was cooled to an internal temperature of 0 °C, and startingmaterial (9.4 g, 40.0 mmol) was added over 10 min, keeping internal temperature between 0 and 10 °C. The reaction mixture was stirredat 10 °C for 45 min, at which time HPLC analysis (aliquot into MeOH) showed 95% consumption of starting material. A 10 mL samplewas 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 overa 15-min period. The reaction was stirred at room temperature for 4 h. The solid was collected by filtration and washed with toluene (200mL). The collected solid was dried (45 °C, 35 mmHg) to give 173 g of desired product, (HPLC1) ) 3.03 min, 96.71 by area %. Thefiltrates were combined and held at -10 °C for 2 days, solid was collected by filtration, washed with toluene (50 mL), and dried as beforeto give 70 g of product, 89.6% total yield, (HPLC1) ) 2.96 min, 92.35 area %.

CBS Reduction/ BH3/THF


2-Chloro-1-phenylethanol. A 75-mL jacketed reaction flask equipped with an addition port, reflux condenser and a magnetic stir barwas 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 BH3âTHFsolution containing 4.8 mmol of BH3 (10 mL) was added portionwise over 10 min. The reaction flask was heated to 30 °C and a solutionof 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 theaddition was complete, the reaction mixture was stirred for 45 min and cooled to ambient, and the remaining hydride was decomposedby the addition of 2 mL of dry methanol. The reaction mixture was passed through a short bed of SiO2 and the solvent evaporated givingthe chloro alcohol, desired product, in 95% yield; HPLC purity >95%, HPLC ee ) 95%.

Noyori hydrogenation


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(S)-2-Succinimido-1-phenylethanol. Twenty mmol (4.34 g) of starting material was placed in a 250-mL jacketed, glass reactorvessel,14 and the air in the reactor was completely replaced by argon using multiple fill/release cycles. Degassed methanol (250 mL) wasadded to the reactor via cannula and the mixture stirred at 30 °C to dissolve the ketone. Four milliliters of the Noyori catalyst solution (8ímol of Ru) and 12 mL of the K-OtBu solution (3 mmol) were injected into the reactor using gastight syringes. The argon in the reactorwas replaced with hydrogen (fill/release cycles) and the reactor pressurized to 60 psig with hydrogen. The reaction mixture was stirred at1000 rpm overnight at 30 °C with the hydrogen uptake recorded as described previously. The reaction mixture was passed through ashort 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


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

Transsulfamoylation Reaction


Typical Operating Procedure for Synthesis of Sulfamide. A 100-L glass-lined reactor was charged with acetonitrile (17.8 kg) and4-methylsulfonylaniline hydrochloride (3.36 kg, 16.2 mol) under stirring at room temperature. Triethylamine (4.5 kg, 44.47 mol) and2-oxooxazolidine- 3-sulfonic acid isopropylamide (3.70 kg, 17.77 mol, 1.1 equiv) were then added at the same temperature. The reactionmixture was heated to reflux and stirred at the same temperature for a minimum of 6 h. The solution was then slowly cooled to roomtemperature and kept agitated overnight. Water was slowly added over 40 min, and the reactor was placed under vacuum to distill asmuch as possible of acetonitrile (27.8 kg of distillate) while maintaining the reaction temperature below 40 °C. The suspension wascooled to room temperature and stirred for a minimum of 2 h before filtering the product. The cake was rinsed with water (16.2 kg) anddried 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


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(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 maintainedat 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 wasextracted with CH2Cl2 (55 mL). The organic layer was washed with water (3 _ 50 mL), dried with MgSO4 (9 g), filtered, andconcentrated under vacuum as an oil. The oil was purified by chromatography on silica gel (80 g) using toluene (500 mL), followed by amixture 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). Asolution of dione (0.9 equiv) in ethanol (6 rel vols) is added slowly, followed by allyl ester (1.1 equiv) and more ammonium acetate (2.5equiv) in ethanol (11 rel vols). The mixture is heated to reflux for 3.5 h, and then excess ethanol is removed by distillation under vacuumuntil 18 rel vols remains. Water (24 rel vols) is added to precipitate the product, which is isolated by filtration and washed with water (6rel vols) and MTBE (6 rel vols, twice).

Reductive alkylation


(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). Aseparate 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


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allowed to stir at room temperature for 30 min and was then charged with concentrated aqueous HCl (0.25 gal). The reactor was chargedwith 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; thecake 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) andstirred 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 desiredproduct as a white crystalline solid (purity 90% by HPLC analysis).

Beta-ketoester synthesis


(R)-Ethyl 7-(4-(2-cyanopropan-2-yl)-3-fluorophenyl)- 5-cyclopentyl-5-hydroxy-3-oxoheptanoate. A 100-gal reactor was chargedwith 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 tocomplete 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 ethylmagnesium malonate mixture. Stirring was continued at 48 °C for 2 h. The solution was cooled to room temperature and charged withIPE (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 ofdesired product was used directly in the next step.

aza Diels-Alder reaction


cis-(2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)carbamic Acid Benzyl Ester. To a 1-L flask under nitrogenatmosphere 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), andp-toluenesulfonic acid monohydrate (297 mg, 1.56 mmol, 0.01 equiv). The mixture was heated to 70 °C. After 2 h, the mixture wascooled to room temperature and transferred to a separatory funnel. Ethyl acetate (500 mL) was added. The mixture was washed 1 _ 200mL 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


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4-(4-Nitrobenzyl)morpholine To a 2-L, three-neck, round-bottom flask, fitted with mechanical stirring, thermocouple, 250-mL additionfunnel, and nitrogen inlet were charged 4-nitrobenzylbromide (100 g, 463 mmol) (Caution. Strong irritant and lachrymator! Weighin hood with door down and transport in stoppered flask!) and 500 mL of toluene. A solution of morpholine (121 g, 1389 mmol) in100 mL of toluene was added dropwise, keeping the temperature less than 50 °C. The solution was rinsed in with 50 mL of toluene. Theresulting solution was stirred at less than 50 °C until the reaction was complete. TLC analysis; add 1 mL of reaction mixture to 1 mL ofwater, spot upper layer and elute with 1:1 ethyl acetate/heptane, visualize with UV. When complete, 500 mL of water was added, and thephases were separated. The organic phase was washed with 500 mL of saturated sodium bicarbonate. The organic phase wasconcentrated 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 vacuumoven 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


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 45min at 22-25 °C. This solution was added very slowly (400 mL/min) to a suspension of ammonium chloride (2.4 kg, 44 mol) inmethylene chloride (12 L) and triethylamine (6.8 L, 48 mol) while keeping the temperature at 25-30 °C. The reaction mixture was stirredfor 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 precooledmethanol (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


D-6-Propyl-8â-hydroxymethylergoline. Into a stainless steel 800-L vessel containing NMP (40 L) under nitrogen, were sequentiallyadded 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 (178.9mol). The mixture was heated to 80 °C. After complete conversion of 9,10-dihydrolysergic acid into aminium, monitored by HPLC, thesolution 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 reversephase 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 productwas completed, and 600 L of water was added. The mixture was cooled to 5 °C and filtered in a centrifuge and washed extensively withwater until the test for chloride was negative, affording 17.5 kg of wet desired product.


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Curtius rearrangement


Ethyl(1R, 2R)-2-(Benzyloxycarbonylamino)cyclohexanecarboxylate. CAUTION! Although diphenyl phosphoryl azide (DPPA) iswidely utilized in multi-kilogram quantities,11 prudent safety practices for its use are clearly indicated. DPPA itself is thermally stable andis 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 explosionhazard. A scrutiny of the literature did not reveal any incidents based on this eventuality. However, several sensible measures were takento 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 triethylammoniumsalt. (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 ( 55.0kg, 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). Thephases were cut, and the toluene solution was distilled to a volume of about 120 L to remove water to under 1000 ppm. The solution wascooled to 20 °C, and triethylamine (26.0 kg, 257 mol) was added. The mixture was heated to 85 °C. A solution of diphenylphosphorylazide (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. Thereaction was stirred for 30 min after the addition was complete and after a sample showed the reaction was complete (>98% conversionby 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 withwater (50 L) and then twice with 10% brine (50 L). The toluene solution was solvent switched first to 2-propanol and then to n-heptaneby 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 with200 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 themixture 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


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 to10 °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 temperaturebelow 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 solutionwas 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



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In a 100-gal glass reactor were warmed sodium triacetoxyborohydride (18.5 kg, 87.3 mol) and DMSO (71 kg) to 40 °C untilhomogeneous. 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) weremixed to give a homogeneous solution. The aldehyde solution was added over 2 h to the piperidine solution while keeping thetemperature at 10-14 °C. After the addition the reaction was stirred for an additional hour and then quenched with 6 N aqueous HClsolution (8.4 kg) at 20-24 °C. To the quenched reaction mass were sequentially added iPrOAc (59 kg), water (67 kg), and 15% aqueoussodium 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


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 (1250mL). The slurry was stirred for _5 min followed by sequential charge of acetic acid (250 mL), glyoxal trimer dihydrate (117.34 g, 1.675mol equiv glyoxal), and NH4OAc (258.07 g, 3.348 mol). The mixture was stirred at room temperature for 24 h. Water (625 mL) wasslowly added via addition funnel over 30 min, and the resulting slurry was stirred an additional 15 min at room temperature. The slurrywas filtered, and the smoothed cake was rinsed (2:1 MeOH/H2O, 2 _ 600 mL). After the filtration was pulled down to a smooth, packedcake, 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 brownpowder

Skraup quinoline synthesis


8-Bromo-6-methylquinoline. Sodium m-nitrobenzenesulfonate (2.67 kg, 11.8 mol) was added tomethanesulfonic acid (10 L) at 20 C followed by iron sulfate heptahydrate (156.8 g, 0.564 mol). This addition isslightly 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 withmethanesulfonic acid (0.5 L), and agitated until the solid dissolved (~15 min). The addition is exothermic, and thetemperature 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, themixture was cooled to ~80 C and diluted with cold DI water (10 L) keeping the temperature <90 C. Aftercooling to ~20 C with an ice bath, the mixture was neutralized with cold aqueous NaOH (10 M, 15.6 L). Solkafloc (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 filteredthrough a centrifuge (10- m bag), and the phases were separated. The (top) MTBE layer was washed with 20 L ofbrine (95% saturation). The aqueous layers were back extracted with MTBE, and the organic phases werecombined (3.97 kg of product as a 7-9 wt % MTBE solution in 95% yield). For characterization purposes, thehydrochloride salt of 8-bromo-6-methylquinoline can be prepared.

1,2,4-Oxadiazole Synthesis


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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 removewater. [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 heatedat 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. Aftercooling 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 extractedwith 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 wasallowed 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 anoven at 30-35 C under vacuum (N2 sweep) to constant weight. Isolated yield: 2.6 kg, 88%.

Friedel-Crafts acetylations


N-(5-Acetyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide. Regioselective Friedel-Crafts Acetylation ofstarting 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 withaluminum chloride (102.0 g, 765.0 mmol) and dichloromethane (280.0 mL) at 20-25 C. The slurry was cooledto an internal temperature at 0-5 C, and acetyl chloride (72.0 g, 917.0 mmol) was added over 20 min whilemaintaining 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 geach) 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 tansolution 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, whilemaintaining the temperature at 0-25 C. The 1-L, round-bottomed flask and the transferring tube were rinsed withdichloromethane (40.0 mL) and the dichloromethane added to the reaction mixture. The biphasic reaction mixturewas 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 solutionwas warmed to an internal temperature at 40 ± 3 C to achieve gentle refluxing. Heptane (1.2 L) was added


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slowly over a period of 50 min while maintaining the temperature at 40-55 C to maintain a gentle reflux. Theresulting slurry was stirred at 55-58 C for an additional 30 min. The suspension was cooled to 20-25 C over aperiod of 30 min with efficient stirring and stirred at 20-25 C for an additional 2 h. The solids were collected byfiltration, washed with a mixture of dichloromethane/heptane (2 × 100.0 mL, 20:80 v/v), and dried at 60-65 C invacuo 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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