Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/10—Spiro-condensed systems
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• Growth hormone which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing.
• growth hormone is known to have the following basic effects on the metabolic processes of the body: (1) Increased rate of protein synthesis in all cells of the body; (2) Decreased rate of carbohydrate utilization in cells of the body; (3) Increased mobilization of free fatty acids and use of fatty acids for energy.
• a deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
• growth hormone Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone- releasing hormone or all of these.
• L-DOPA L-3,4-dihydroxyphenylalanine
• GRF growth hormone releasing factor
• certain spiro compounds are disclosed in PCT Patent Publication WO 94/13696 as being non-peptidal growth hormone secretagogues. These compounds have the ability to stimulate the release of natural or endogenous growth hormone and thus may be used to treat conditions which require the stimulation of growth hormone production or secretion such as in humans with a deficiency of natural growth hormone or in animals used for food or wool production where the stimulation of growth hormone will result in a larger, more productive animal.
• PCT Patent Publication WO 94/13696 discloses several methods for preparing these spiro compounds. Some of these methods employ as an intermediate the spiroindoline sulfonamide of the formula:
• L is hydrogen or an amino protecting group.
• Additional references related to the use of the Fisher indole synthesis include: (a) Robinson, B. The Fischer Indole Synthesis; Wiley: New York, 1982, e.g. 632-672; (b) Ungematch, F.; Cook, J.M. Heterocycles, 1978, 9, 1089-1119; (c) Wang, T.S.T. Tetrahedron Lett.., 1975, 19, 1637- 1638; (d) Heacock, R. A. ; Kasparek, S. The Indole Grignard Reagents, in vol 10 of Advances in Heterocyclic Chemistry; Katritsky, A.R.; Boulton, A.J.
• L is hydrogen or an amino protecting group.
• spiroindoline sulfonamides may be used to prepare certain spiro compounds which have the ability to stimulate the release of natural or endogenous growth hormone. These spiro compounds may be used to treat conditions which require the stimulation of growth hormone production or secretion such as in humans with a deficiency of natural growth hormone or in animals used for food or wool production where the stimulation of growth hormone will result in a larger, more productive animal. DESCRIP ⁇ ON OF THE INVENTION
• the present invention is directed to a novel process for the preparation of a spiroindoline sulfonamide compound of the formula:
• L is hydrogen or an amino protecting group.
• the instant process provides the desired spiroindoline sulfonamide from readily available inexpensive and environmentally acceptable starting materials reagents and solvents.
• the process does not use any chromatographic purifications, and it is possible to produce the spiroindoline sulfonamide without isolation of any of the intermediates.
• a Fischer indole condensation provides the spiroindolenine of the formula:
• the spiroindolenine is then reduced in-situ to the spiroindoline of the formula:
• Catalytic agents suitable for the Fischer indole reaction of the present invention are generally strong acids. Catalytic agents appropriate for this process include: trifluoroacetic acid; hydrogen fluoride; hydrogen chloride; hydrogen bromide; hydrogen iodide; chlorotrimethylsilane; trifluoromethanesulfonic acid; methanesulfonic acid; camphorsulfonic acid; sulfuric acid; phosphoric acid; and arylsulfonic acids, such as benzenesulfonic acid, p-toluenesulfonic acid, and p-chlorobenzene-sulfonic acid.
• Preferred catalytic agents include: trifluoroacetic acid; methanesulfonic acid; camphorsulfonic acid; benzenesulfonic acid, p-toluenesulfonic acid; and p-chlorobenzene- sulfonic acid.
• the most preferred catalytic agent is trifluoroacetic acid.
• Solvents appropriate for this processes include: acetonitrile; propionitrile; chlorinated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, ortho- dichlorobenzene; benzene; toluene; xylenes; and the like; and mixtures thereof.
• Preferred solvents include: dichloromethane; chloroform; mixtures of toluene-acetonitrile (4:1 to 100:1 v/v); mixtures of chlorobenzene-acetonitrile (4:1 to 100:1 v/v); and mixtures of ortho- dichlorobenzene-acetonitrile (4:1 to 100:1 v/v).
• the most preferred solvents include: dichloromethane; mixtures of toluene-acetonitrile (9: 1 to 100:1 v/v); mixtures of chlorobenzene-acetonitrile (9:1 to 100:1 v/v); and mixtures of ortho-dichlorobenzene-acetonitrile (4:1 to 100:1 v/v).
• the preferable reaction temperature range is between -40 and 150 ⁇ C, and the most preferable range is between 35 and 55 ⁇ C If the piperidine starting material is not protected (L is hydrogen) it is preferred that such compound be present as its acid addition salt, i.e.
• an inorganic or organic acid such as hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methanesulfonic acid and the like.
• a reducing agent such as a hydride reducing agent or by catalytic reduction.
• a reducing agent such as a hydride reducing agent or by catalytic reduction.
• a reducing agent such as a hydride reducing agent or by catalytic reduction.
• hydride reducing agents include sodium borohydride, lithium borohydride, lithium aluminum hydride, di- isobutylaluminum hydride, bis(2-methoxyethoxy)aluminum hydride, triacetoxy borohydride, borane or carboxylates thereof, and other reducing agents which are known in the art to reduce imines.
• the preferred reducing agent is sodium borohydride or lithium borohydride. If sodium borohydride or lithium borohydride is employed as a reducing agent, it is prefered that the reduction is conducted in the presence of an alcohol, such as methanol, ethanol, or isopropanol.
• the introduction of the sulfonyl group may be accomplished by use of a sulfonylating agent, such as methanesulfonyl chloride, methanesulfonic anhydride, methanesulfonic acid in the presence of a suitable dehydrating agent, or various sulfonylating agents known in the art, in which methanesulfonyl chloride and methane ⁇ sulfonic anhydride are preferred, and in which methanesulfonyl chloride is more preferred.
• a sulfonylating agent such as methanesulfonyl chloride, methanesulfonic anhydride, methanesulfonic acid in the presence of a suitable dehydrating agent, or various sulfonylating agents known in the art, in which methanesulfonyl chloride and methane ⁇ sulfonic anhydride are preferred, and in which methanesulfonyl chlor
• This reaction is generally conducted in the presence of an amine base, such as di-isopropylethylamine, triethylamine, dimethylaminopyridine, l,8-diazabicyclo[5.4.0]undec-7-ene, or other amine bases known in the art, in which di-isopropylethylamine is preferred.
• an amine base such as di-isopropylethylamine, triethylamine, dimethylaminopyridine, l,8-diazabicyclo[5.4.0]undec-7-ene, or other amine bases known in the art, in which di-isopropylethylamine is preferred.
• the entire process may be outlined as follows:
• the starting materials used in the Fischer indole condensation are: (1) a piperidine-4-carboxaldehyde ⁇ such as piperidine-4-carboxaldehyde or one of its acid addition salts, an N-protected piperidine-4-carboxaldehyde of the formula:
• L is a CBZ protecting group, an _V-acetylpiperidine-4- carboxaldehyde, or another suitably TV-protected piperidine-4- carboxaldehyde ⁇ ; and (2) a phenylhydrazine (such as phenylhydrazine, 2,3, or 4-bromophenylhydrazine, 2,3, or 4-chloro-phenylhydrazine, or ar salt thereof).
• a phenylhydrazine such as phenylhydrazine, 2,3, or 4-bromophenylhydrazine, 2,3, or 4-chloro-phenylhydrazine, or ar salt thereof.
• the _V-protected piperidine carboxaldehydes are readily available from the corresponding piperidine carboxylic acids via acid chloride formation and Rosenmund reduction.
• amino protecting group is intended to indicate the presence of an appropriate protecting group for amino, such as those described in Greene, T.W., Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991.
• An appropriate protecting group will be able to withstand the reaction conditions of intermediate processes, prior to being removed when desired.
• Suitable protecting groups for amino include those groups well known in the art such as: benzyl, benzyloxymethyl, benzyloxycarbonyl (carbobenzyloxy), benzylsulfonyl, 2-bromoethyloxycarbonyl, t-butoxy- carbonyl, 2-chloro-benzyloxycarbonyl, 2-chloroethyloxycarbonyl, di-t- amyloxycarbonyl, 9-fluoroenylmethyloxycarbonyl, isopropoxycarbonyl, 4-methoxy-benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrophenyl- sulfonyl, phthaloyl, 2,2,2-trichloro-t-butyloxycarbonyl, trifluoroacetyl, - 16 -
• tirphenylmethane and vinyloxycarbonyl groups, and the like, in which the preferred ones include benzyloxycarbonyl (carbobenzyloxy), 2-chlorobenzyloxy-carbonyl, 4-methoxybenzyloxycarbonyl, and 4-nitrobenzyloxycarbonyl groups, and in which the most preferred one is the benzyloxycarbonyl (carbobenzyloxy) group.
• L is an amino protecting group
• it may be removed using well known procedures (Greene, T.W., Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991).
• Removal of benzyloxycarbonyl (carbobenzyloxy) groups may be achieved by a number of methods known in the art; for example, catalytic hydrogenation with hydrogen in the presence of a noble metal or its oxide such as palladium on activated carbon in a protic solvent such as ethanol.
• removal of benzyloxycarbonyl (carbobenzyloxy) groups may also be achieved by treatment with a solution of hydrogen bromide in acetic acid, or by treatment with a mixture of TFA and dimethylsulfide. Removal of t-butoxycarbonyl protecting groups may be carried out in a solvent such as methylene chloride or methanol or ethyl acetate, with a strong acid, such as trifluoroacetic acid or hydrochloric acid or hydrogen chloride gas.
• alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration and if two carbon atoms or more they may include a double or a triple bond.
• exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, propargyl, and the like .
• alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond.
• alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.
• halogen is intended to include the halogen atoms fluorine, chlorine, bromine, and iodine.
• aryl within the present invention, unless otherwise specified, is intended to include aromatic rings, such as carbocyclic and heterocyclic aromatic rings selected the group consisting of: phenyl, naphthyl, pyridyl, l-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrrazinyl, or isothiazolyl, which may be optionally substituted by 1 to 3 of Cl-C6 alkyl, 1 to 3 of halogen, 1 to 2 of -OR2, methylenedioxy, -S(0) m R 2 , 1 to 2 of -CF3, -OCF3, nitro, -N(R2)C(0)(R2), -C(0)OR2, -C(0)N(R2)(R2), -l,
• the amine compounds employed as starting materials for the process of the present invention may be present as their acid addition salts, such as the salts derived from using inorganic and organic acids.
• acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonic and the like.
• the compounds produced by the processes of the instant invention may be isolated in the form of their pharmaceutically acceptable acid addition salts.
• certain compounds containing an acidic function such as a carboxy can be in the form of their inorganic salt in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
• the preparation of compounds with the process of the present invention may be carried out in sequential or convergent synthetic routes. It is noted that in some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. In general, the process of the present invention is conducted in a sequential manner as presented herein.
• standard peptide coupling reaction conditions is intended to mean the coupling of a carboxylic acid with an amine using an acid activating agent such as EDC, DCC, and BOP in a inert solvent such as dichloromethane in the presence of a catalyst such as HOBT.
• an acid activating agent such as EDC, DCC, and BOP
• a inert solvent such as dichloromethane
• HOBT a catalyst
• protective groups for amine and carboxylic acid to facilitate the desired reaction and minimize undesired reactions are well documented. Conditions required to remove protecting groups which may be present and can be found in Greene, T, and Wuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, NY 1991.
• CBZ and BOC may be used extensively in the instant process, and conditions for their removal are known to those skilled in the art.
• removal of CBZ groups may be achieved by a number of methods known in the art; for example, catalytic hydrogenation with hydrogen in the presence of a nobel metal or its oxide such as palladium on activated carbon in a protic solvent such as ethanol.
• catalytic hydrogenation is contraindicated by the presence of other potentially reactive functionality
• removal of CBZ groups can also be achieved by treatment with a solution of hydrogen bromide in acetic acid, or by treatment with a mixture of TFA and dimethylsulfide.
• Removal of BOC protecting groups is carried out in a solvent such as methylene chloride or methanol or ethyl acetate, with a strong acid, such as trifluoroacetic acid or hydrochloric acid or hydrogen chloride gas.
• a solvent such as methylene chloride or methanol or ethyl acetate
• a strong acid such as trifluoroacetic acid or hydrochloric acid or hydrogen chloride gas.
• Isonipecotic acid (2) and K2CO3 were dissolved in 40.2 L of water in a 100 L 4 neck flask with mechanical stirring under N2 and the solution was cooled to 10 °C Benzyl chloroformate was added, maintaining the temperature between 9 and 14 °C, and the mixture was warmed up to 22 °C after the addition was complete and aged for 58 h.The addition was completed in 4 h at which point the pH was 9.0. After aging for 58 h there was no change in the pH.
• the aqueous phase was acidified with of 37% aqueous HCl to pH 1.8. Carbon dioxide was evolved during the addition of HCl, but gas evolution was easily controlled. The addition of HCl took ⁇ 1 h and required 10 L of cone. HCl.
• the aqueous phase was extracted with 3 x 66 L of toluene. The toluene extracts were dried with 2 kg of sodium sulfate and filtered through a pad of Solka-floc. The combined filtrates weighed 17.8 kg. The crude yield of carbamate 3 was 7.89 kg (97%) (as obtained by evaporation of weighed aliquots of the filtrates to dryness).
• the filtrates were transferred through a 10 ⁇ inline filter to a 100 L flask.
• the extracts were concentrated at 10 mbar at ⁇ 25 °C to a volume of 18 L.
• the final concentration of carbamate 3 was 440 g/L.
• the product was 99.1 area % pure with 0.9 area % benzyl alcohol as the only impurity.
• Toluene 12 L To the toluene solution of benzyl carbamate 3 from the preceding step was added 5 mL of DMF and 10 L of toluene. The oxalyl chloride was added over a period of 20 min. The reaction mixture was aged for 16 h at 18 °C under a slow stream of nitrogen.HPLC analysis of the reaction mixture showed that 1.3% of the carboxylic acid 3 still remained unreacted. The reaction mixture was warmed to 26 °C, and 5 mL of DMF were added. The mixture was aged for 2.5 h.
• the assay yield of aldehyde 3 was 94% by HPLC analysis.
• the crude aldehyde 5 solution from the previous step was transferred through a 10 ⁇ inline filter to a 100 L reactor equipped with Teflon coated copper coils for cooling or heating and a mechanical stirrer. Toluene (34.4 kg) and MeCN (7 L) were added, and the resulting solution was cooled to 0 °C Phenylhydrazine was added in portions and the temperature was maintained at -1 to 3 °C while nitrogen was continuously bubbled through the reaction mixture.
• the color change from green to orange corresponds very closely to reaction end point.
• the quantity of NaBH4 required to complete the reaction is heavily dependent on the temperature and rate of addition of NaBH4, but the yield and quality of the product is virtually unaffected provided that the reaction is complete.
• the reaction mixture was cooled to 5 °C over a period of 30 min.
• 8 L of 3% aqueous NH4OH ( 8 L) were added to bring the pH of the aqueous phase to 7.4, the mixture was agitated, and allowed to settle.
• the cloudy yellow lower aqueous phase was separated.
• the organic phase was washed with 4 L of 3% aqueous NH4OH, 2 x 4 L of water, and 2 x 4 L of brine.
• the weight of the organic phase after the washings was 53.5 kg, and the assay yield was 94%.
• the washed toluene solution was combined with the washed organic phases of two other similarly processed reactions.
• the total aldehyde used in the three reactions was 5.06 kg, (20.5 mol).
• the total weight of CBZ-indoline 9 assayed in the combined organic phases was 5.91 kg, (18.3 mol, 90% assay yield).
• the combined organic phases were dried with 5 kg of sodium sulfate, treated with 250 g of Darco G60 carbon for 30 min, and filtered through Solka-floc. The filtrates were vacuum concentrated at 10 mbar at ⁇ 25 °C until the residue was near dryness.
• the solvent switch was completed by slowly bleeding in 30 L of IPAC and reconcentrating to 14 L at 200 mbar at 50-60 °C The mixture was heated to reflux in order to obtain a clear homogeneous deep orange solution. iH NMR analysis indicated that the solution contained ca. 6 mol% of residual toluene after solvent switch.
• the solution was cooled to 68 °C and seeded with 4 g of crystalline CBZ-indoline 9.
• the solution was allowed to gradually cool to 26 °C over 6 h and aged for 9 h at 20-26 °C
• the slurry was cooled to 2 °C over 1 h and aged at 2 °C for lh.
• the product was isolated by filtration, and the filter cake was washed 2 X 2 L of 5 °C IPAC and 2 X 2 L of 5 °C MTBE.
• the product was dried in the vacuum oven at 30 °C under a nitrogen bleed to give 4.37 kg (74%) of the title compound 9 as a light tan crystalline powder.
• HPLC analysis of the product indicated 99.5 area % purity.
• reaction mixture was warmed to 18 °C and aged for 16 h. There was no change in the appearance of the reaction mixture, and HPLC profile between the end of the addition and after the 16 h age.
• the reaction mixture was slowly transferred over lh into a vigorously stirred solution of 30 L of water and 200 mL of 37% aqueous HCl in a 50 L flask. The temperature in the 50 L flask rose from 22 to 28 °C The product separated as a pale tan gummy solid which changed to a granular solid.
• the aqueous suspension was cooled to 22 °C and aged for 1 h. The suspension was filtered, and the filter cake was washed with 2 x 4 L of MeOH/water (50/50). HPLC analysis indicated that ⁇ 0.1% of the CBZ-Spiroindoline- methanesulfonamidel was in the mother liquors.
• the CBZ-aldehyde 5 was dissolved in dichloromethane in a 1 L flask equipped with Teflon coated magnetic stirring bar. The resulting solution was cooled to 0 °C Phenylhydrazine was added via a weighed syringe over 5 min and the temperature was maintained at -1 to 3 °C while nitrogen was continuously bubbled through the reaction mixture.
• HPLC conditions 25 cm Dupont Zorbax RXC8 column at 30 °C with 1.0 mL/min flow and detection at 254 nm; gradient schedule:
• reaction mixture was aged for 10 min at 0-2 °C, and TFA was added by syringe maintaining the temperature between 2 and 7 °CThe reaction mixture was warmed to 35 °C over 30 min, and maintained for 17 h. The nitrogen sparge through the reaction mixture was stopped and a slow stream of nitrogen was maintained over the reaction mixture. During the first hour at 35 °C the color gradually darkened to a rosy pink then to a deep green, and a relatively small amount of a white crystalline precipitate (ammonium trifluoroacetate) formed. After 17 h HPLC analysis (same conditions as above) indicated that the reaction mixture contained 93 area % indolenine 8 and ⁇ 0.5% of unreacted phenylhydrazone remained.
• a 2% (by volume) solution of MeCN in toluene was made up using 654 mL of toluene and 13.3 mL of MeCN.
• 617 ml of the above solution were degassed by passing a fine stream of nitrogen through the solution for 5 min. Phenylhydrazine and TFA were added to the mixture while still degassing.
• the CBZ-aldehyde 5 was dissolved in the rest of the solution prepared above (50 mL) and degassed by bubbling nitrogen through the solution while in the addition funnel.
• the mixture was warmed to 20 °C, and 200 mL of 1M aqueous HCl was added. The mixture was warmed to 50 °C, and the aqueous phase was separated. The organic phase was washed sequentialy with 100 mL water, 100 mL 5% aqueous sodium bicarbonate, and 100 mL water. The organic phase was transferred to a 1 L 3 neck flask equipped for mechanical stirring and distillation.
• the mixture (ca 400 mL) was distilled at atmospheric pressure until 150 mL of distillate had been collected.
• the distillation was continued with continuous addition of n- propanol at such a rate as to maintain a constant volume (ca 350 mL) in the pot.
• the distillation was stopped when a total of 525 mL of n-PrOH had been added and a total of 800 mL of distillate had been collected.
• the temperature of both the head and pot rose from 94 °C to 98 °C during the solvent switch.
• the mixture was allowed to cool gradually to 20 °C over 3h and aged for 12 h.
• the mother liquor was found to contain 2% toluene and 4 mg/mL of sulfonamide.
• the solubility of the sulfonamide in various mixtures of toluene and n-PrOH has been determined by HPLC assay:
• the crystalline slurry was filtered and washed with 3 x 100 mL of n-PrOH.
• the product was dried in a vacuum oven at 50 °C with a nitrogen bleed for 16 h to furnish 65.5g (82 % from aldehyde 5) of 6 as a tan solid with 93.5 wt% purity.
• n-PrOH crystallized sulfonamide was dissolved in 134 mL of EtOAc at 60 °C and treated with 8.0 g of Darco G-60 carbon for 1 h at 60 °C After the addition of 2.0 g Solkafloc the slurry was filtered through a pad of 4.0 g Solkafloc, and the pad was washed with 90 mLof EtOAc at 60 °C Prior to the addition of the carbon the solution was a brown color. The filtration proceeded well without plugging to give a golden yellow filtrate.
• the filtrate was distilled at atmospheric pressure in a 500 mL flask (pot temperature 80-85 °C) until 100 g (100 mL) of residue remained. This solution was allowed to cool to 35 °C over 3 h. Over a 1 h period, 116 mL of cyclohexane was added with good agitation at 35 °C The mixture was cooled to 20 °C over 1 h and aged at 20 °C for 12 h. At 35°C much of the sulfonamide has crystallized out and the mixture is thick. Addition of cyclohexane at 20 °C makes agitation difficult. After the age the supernatant was found to contain 2.5 mg 1/g .
• the crystalline slurry was filtered and the cake was washed with 77 mL of 2: 1 cyclohexane-EtOAc and 2 x 77 mL of cyclohexane.
• the catalyst was suspended in 7 L of MeOH and transferred into the 5 gal autoclave followed by the solution of 8 in 8 L of THF.
• the mixture was hydrogenolyzed at 25 °C at 80 psi of H2. After 2.5 h the temperature was raised to 35 °C over 30 min.
• HPLC analysis indicated complete consumption of Cbz- spiroindohnc-mcthancsulfonamidc.
• HPLC conditions 25 cm Dupont Zorbax RXC8 column with 1.5 mlVmin flow and detection at 254 nm.
• Gradient Schedule 25 cm Dupont Zorbax RXC8 column with 1.5 mlVmin flow and detection at 254 nm.
• Hydrogen chloride diluted with about an equal volume of nitrogen was passed into the solution.
• the temperature rose to 60 °C over the course of 15 min, and a white precipitate of the hydrochloride salt formed. Diluting the HCl with nitrogen only avoids the reaction mixture sucking back and may not be necessary.
• the mixture was cooled in an ice bath, and the hydrogen chloride addition was continued for lh. The temperature gradually fell to 20 °C
• the suspension was aged for 2 h while the temperature was lowered to 10 °C.
• the crystalline product was isolated by filtration, and the filter cake was washed with 3 L of EtOAc.
• reaction conditions other than the particular conditions as set forth herein above may be applicable as a consequence of variations in the reagents or methodology to prepare the compounds from the processes of the invention indicated above.
• specific reactivity of starting materials may vary according to and depending upon the particular substituents present or the conditions of manufacture, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

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