PROCESS FOR THE FORMATION OF INTERMEDIATES USEFUL FOR THE PREPARATION OF PHARMACEUTICALS

Abstract: The invention relates to a synthetic chemical process for forming an intermediate useful in manufacturing certain known nerve growth stimulatory and neuroprotective compounds and certain known multidrug resistance inhibitors.

Description: PROCESS FOR THE FORMATION OF INTERMEDIATES USEFUL FOR THE PREPARATION OF PHARMACEUTICALS TECHNICAL FIELD OF THE INVENTION The invention relates to a synthetic chemical process for forming an intermediate useful in manufacturing certain known nerve growth stimulatory and neuroprotective compounds and certain known multidrug resistance inhibitors. BACKGROUND OF THE INVENTION The synthesis of subsets of compounds described in United States Patents 5,543,423, 5,620,971, 5,723,459, 5,744,485, and PCT publications O96/40633, O97/16190, 097/18828 and 098/13355 may utilize 3-pentanol, 3- heptanol, 3-aminopentane or 3-aminoheptane each of which is terminally substituted at both ends of the alkyl chain by a carbocyclic or heterocyclic group. The synthesis schemes set forth in each of the above-identified documents require either multiple steps to obtain the above-described intermediate and/or expensive reagents. Moreover, the intermediate is often produced together with contaminants resulting from unwanted side reactions. Those contaminants can only be removed during later synthesis steps and therefore cause a reduced yield of the desired product. It would be desirable to identify a method of producing these required intermediates in higher yields, purer forms and for less cost, particularly if the desired product is going to be produced in commercial quantities . SUMMARY OF THE INVENTION The present invention solves this problem by providing a high-yielding, low cost method of producing compounds of the formula: I), wherein each D is the same and is selected from hydrogen, or a 5 to 7-membered carbocyclic or heterocyclic ring optionally comprising one or more substituents independently selected from halogen, hydroxyl, nitro, -S0 3 H, trifluoromethyl, trifluoromethoxy, (Cι-C 5 ) -straight or branched alkyl, (C 2 - C 6 ) -straight or branched alkenyl, 0- [ (Cι-C 6 ) -straight or branched alkyl], 0- [ (C 2 -Ce) -straight or branched alkenyl], O-benzyl, 0-phenyl, 1, 2-methylenedioxy, -N(R 1 ) (R 2 ) , carboxyl, N- (Cι-C 5 -straight or branched alkyl or C 2 -C5-straight or branched alkenyl) carboxamides, N,N- di- (Cι-C 5 -straight or branched alkyl or C 2 -Cs-straight or branched alkenyl) carboxamides, N- (Cι-C 5 -straight or branched alkyl or C 2 -Cs-straight or branched alkenyl) sulfonamides, N, N-di- (Cι-C 5 -straight or branched alkyl or C 2 -C5-straight or branched alkenyl) sulfonamides, orpholinyl, piperidinyl, O-Z, CH 2 - (CH 2 ) q -Z, 0-(CH 2 ) q -Z, (CH 2 ) q -Z-0-Z, or CH=CH-Z; wherein R 1 and R 2 are independently selected from (Ci-Cβ) -straight or branched alkyl, (C 2 -C 6 ) - straight or branched alkenyl or alkynyl, hydrogen or benzyl; or wherein Ri . and R 2 are taken together with the nitrogen atom to which they are bound to form a 5-7 membered heterocyclic ring; Z is selected from 4-methoxyphenyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5- di ethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, or pyrimidyl; and q is 0, 1 or 2; and wherein D is optionally benzofused; each n is the same and is selected from 1 or 2; and A is selected from 0, or -N(R), wherein R is selected from D, (Cι-C 6 ) -straight or branched alkyl, (C 2 - C 6 ) -straight or branched alkenyl or alkynyl, (Cι-C 6 )- straight or branched alkyl substituted with D, or (C 2 - C 6 ) -straight or branched alkenyl or alkynyl substituted with D. The resulting compounds are particularly useful as intermediates in the synthesis of compounds useful in stimulating nerve growth, inhibiting nerve degeneration and inhibiting multi-drug resistance. DETAILED DESCRIPTION OF THE INVENTION The invention provides a method of synthesizing a compound of formula (I) by combining compounds (1) and (2) : (1) (2) wherein: each D is the same and is selected from hydrogen, or a 5 to 7-membered carbocyclic or heterocyclic ring optionally comprising one or more substituents independently selected from halogen, hydroxyl, nitro, - S0 3 H, trifluoromethyl, trifluoromethoxy, (d-C 6 ) -straight or branched alkyl, (C 2 -C 6 ) -straight or branched alkenyl, 0- [ (Cι-C 6 ) -straight or branched alkyl], 0-[(C 2 -C 6 )- straight or branched alkenyl], O-benzyl, O-phenyl, 1,2- methylenedioxy, -NtR 1 ) (R 2 ) , carboxyl, N- (Cι-C 5 -straight or branched alkyl or C 2 -C 5 -straight or branched alkenyl) carboxamides, N,N-di- (Cι-C 5 -straight or branched alkyl or C-C 5 -straight or branched alkenyl) carboxamides, N- (Ci-Cs-straight or branched alkyl or C 2 -C 5 -straight or branched alkenyl) sulfonamides, N, N-di- (Cι-C 5 -straight or branched alkyl or C 2 -C 5 -straight or branched alkenyl) sulfonamides, morpholinyl, piperidinyl, O-Z, CH 2 - (CH 2 ) q -Z, 0-(CH 2 ) q -Z, (CH 2 ) q -Z-0-Z, or CH=CH-Z; wherein R 1 and R 2 are independently selected from (Cι-C 6 ) -straight or branched alkyl, (C 2 -C 6 ) - straight or branched alkenyl or alkynyl, hydrogen or benzyl; or wherein Ri and R 2 are taken together with the nitrogen atom to which they are bound to form a 5-7 membered heterocyclic ring; Z is selected from 4-methoxyphenyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5- dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, or pyrimidyl; and q is 0, 1 or 2; and wherein D is optionally benzofused; each n is the same and is selected from 1 or 2; and A is selected from 0, or -N(R), wherein R is selected from D, (Cχ-C δ ) -straight or branched alkyl, (C 2 - C 6 ) -straight or branched alkenyl or alkynyl, (Cι-C 6 ) - straight or branched alkyl substituted with D, or (C 2 - C 6 ) -straight or branched alkenyl or alkynyl substituted with D; M is selected from Li, Na, K, Mg, Zn, Zr, Pd, B or Al ; and L is a leaving group, preferably selected from Cl, Br, I, F, O-p-toluenesulfonate, O-methanesulfonate, or 0- trifluoromethanesulfonate . According to one preferred embodiment, M is Li. According to another preferred embodiment, L is halo. Even more preferred is when L is Br . The term "5 to 7-membered carbocyclic or heterocyclic ring", as used herein, includes saturated, partially saturated and unsaturated rings which contain from 0 to 4 heteroatoms independently selected from N, 0 or S. Examples of ring structure include, but are not limited to, cyclopentane, cyclopentenes, furans, thiophenes, pyrroles, pyrrolines, pyrrolidine, dioxalanes, oxazoles, thiazoles, imidazoles, imidazolines, imidazolidines, pyazoles, pyrazolines, pyrazolidines, isoxazoles, isothiazoles, oxadiazoles, triazoles, thiadiazoles, cyclohexane, cyclohexenes, cyclohexadienes, benzene, pyrans, pyridines, piperidines, dioxanes, morpholines, dithianes, thiomorpholines, pyridazines, pyrimidines, pyrazines, piperazines, triazines, trithianes, cycloheptane, and cycloheptenes . Additional heterocyclic structures falling within the above description may be found in A.R. Katritzky, and C.W. Rees, eds . "Comprehensive Heterocyclic Chemistry: Structure, Reactions, Synthesis and Use of Heterocyclic Compounds, Vol. 1-8, " Pergamon Press, NY (1984), the disclosure of which is herein incorporated by reference. The reaction depicted above is typically worked up using a strong acid, including, but not limited to, methanesulfonic acid, trifluoromethanesulfonic acid, p- toluenesulfonic acid, acetic acid, maleic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, oxalic acid, fumaric acid, formic acid, lactic acid, succinic acid, tartaric acid, mandelic acid, picric acid, camphor acid, alkyl-substituted acetic acid derivatives, aryl-substituted acetic acid derivatives, succinic acid, and tartaric acid. According to another embodiment, the reaction depicted above is utilized in the synthesis of a compound having the formula: (II) , wherein: A, D and n are as defined above, except that D is not hydrogen; J is selected from hydrogen, (Cι-C 6 ) -straight or branched alkyl, (C 2 -C 3 ) -straight or branched alkenyl or alkynyl, (Cι-C 6 ) -straight or branched alkyl substituted with D, or (C 2 -C 6 ) -straight or branched alkenyl or alkynyl substituted with D; K is selected from (Cι~C 6 ) -straight or branched alkyl, (C 2 -C 6 ) -straight or branched alkenyl or alkynyl, (Cι-C 6 ) -straight or branched alkyl substituted with D, or (C 2 -C 6 ) -straight or branched alkenyl or alkynyl substituted with D; wherein any one of the -CH 2 - groups of said alkyl, alkenyl or alkynyl chains in K is optionally replaced by -0-, -S-, -S(O)-, -S(0) 2 -, -NH-, -N (Cι-C 6 -straight or branched alkyl)-, or -N(C 2 -C 6 - straight or branched alkenyl or alkynyl)-; or J and K are taken together with the nitrogen and carbon atoms to which they are respectively bound to form a 5- to 7-membered heterocyclic ring; and X is selected from R 3 , -S (0) 2 -R 3 , -C (0) -C (0) -R 4 , -C(0)-C(=CHR 4 )-R 4 , -C(0)-N(R 3 ) (R 3 ) , -C (=S ) -N (R 3 ) (R 3 ) , -C(0)-0-R 3 , -C(=S)-0-R 3 , or -C(0)-C(0) -N(R 3 ) (R 3 ) , wherein each R 3 is independently selected from D, (Ci- C 6 ) -straight or branched alkyl, (C 2 -C6) -straight or branched alkenyl or alkynyl, (Cχ-C 5 ) -straight or branched alkyl substituted with D, or (C 2 -C 6 )- straight or branched alkenyl or alkynyl substituted with D, or, when two R 3 are bound to the same nitrogen atom, both R 3 are taken together with the nitrogen atom to which they are bound to form a 5- to 7-membered heterocyclic ring; and R 4 is R 3 or 0-R 3 ; wherein any one of the -CH 2 - groups of said alkyl, alkenyl or alkynyl chains in R 3 is optionally replaced by -0-, -S-, -S(0)-, -S(0) 2 -, -NH-, -N(Cι-C 6 -straight or branched alkyl)-, or -N(C 2 -C 6 - straight or branched alkenyl or alkynyl)-; Preferably, in formula II, D is 3-pyridyl, 4- pyridyl or phenyl, A is -NR, J and K are not taken together to form a ring and X is -C (0) -C (0) -R 3 . Even more preferred is when D is 4-pyridyl, n is 1, A is -N- benzyl, J is methyl, K is 4-chloro-benzyl and X is -C(0)- C (0) -3, 4, 5-trimethoxyphenyl . Compounds of formula II are typically synthesized by combining a compound of formula I with an appropriately protected amino acid of the formula (3) : produce an intermediate of formula (4), wherein P is a protecting group and J and K are defined as set forth above. The bottom portion of a compound of formula II (represented by X in formula II) is then added by combining a deprotected form of intermediate (4) with an activated compound of the formula (5) or (5') : X-OH (5) or X-L (5' ) , wherein L is a leaving group as defined above. Of course when X is hydrogen in a compound of formula II, removal of the protecting group, P, is all that is necessary to create that compound. Protected alpha-amino acids of formula (3) are well known in the art and many are commercially available. For example, common protecting groups and convenient methods for the protection of amino acids are described in T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Chemistry, 2nd Ed., John Wiley and Sons, New York (1991) . Alkoxycarbonyl groups are preferred for protection of the nitrogen atom in compounds of formula (3), with t-butoxycarbonyl (Boc) , benzyloxycarbonyl (Cbz) , allyloxycarbonyl (Alloc) , and trimethylsilylethoxycarbonyl (Teoc) being more preferred. After the coupling, compounds of formula (3) are deprotected under suitable deprotection conditions (see Greene, supra) , and the resulting free amino group is then combined with X using a compound of formula (5) or (5' ) . In order that this invention may be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way. EXAMPLE 1 Synthesis of Compound 9 Compound 9 was synthesized by the scheme depicted below: A. Preparation of a Compound of Formula I Toluene Two equivalents of picoline in THF (O.lg/ml) at -20°C were slowly mixed with two equivalents of n- butylLithium so as to avoid the temperature of the solution rising above 0°C . Following the addition of the n-butylLithium, the solution was stirred for one hour at 0°C . We then added 1 equivalent of epibromohydrin, warmed the solution to room temperature and stirred overnight. We then treated the solution with approximately 3 equivalents of HC1 dissolved in ethyl ether to precipitate out the desired product, collected the product by filtration and dried the material under vacuum. This produced the alcohol in about 75% crude yield. To an excess of DMSO in 1 volume methylene chloride at -78°C was mixed with 1.5 equivalents of oxalyl chloride. The reaction was stirred for 20 minutes at -60°C followed by the addition of the alcohol (1 equivalent) dissolved in 3 equivalents triethylamine and 1 volume methylene chloride. The reaction was stirred for 2 days and resulted in production of the ketone. To the ketone (975 g, 4.06 moles) in toluene (7500 mL) was added benzylamine (540 mL, 4.8 moles). The solution was heated at reflux while water was azeotropically remixed. The formation of the imine was typically complete in 22-26 hours (as followed by NMR) . The solvent was removed in vacuo at a bath temperature of less than 45°C. The crude product was dissolved in isopropanol (6340 mL) and sodium borohydride (166 g, 4.38 moles) was added portionwise. The reaction was stirred at 12-20°C for 16-20 hours. The volume of solvent was reduced to approximately 3900 mL in vacuo at a bath temperature of less than 35°C. The reaction mixture was then poured into a 3M aqueous HC1 solution (4990 mL) which has been pre-cooled to between -5 and +5°C, keeping -li¬ the temperature during addition below +10°C. To the resultant solution was added 50% aqueous NaOH solution (1110 mL) , which had been pre-cooled to between -5 and +5°C, until the pH of the solution was between 10-12. The reaction mixture was extracted with CH 2 C1 2 (1950 mL) and then with ethyl acetate (975 mL) . The combined organic phases were dried over sodium sulfate (975 g) , filtered and the filter cake washed with EtOAc (975 mL) . The solvent was removed in vacuo, at a bath temperature below 45°C, to afford an orange red oil. The oil was dissolved in methanol (4680 mL) and the mixture was heated to reflux. A solution of oxalic acid (800 g, 8.88 moles) in methanol (1755 mL) was added over a period of 15-30 minutes. The solution was cooled to between +5 and -5°C and stirred at this temperature for 1.75-2.5 hours. The solid was removed by filtration and the filter cake washed with methanol (1950 mL) . The solid is dried to constant weight in vacuo at 50-60°C. The dried solid is dissolved in water (4580 mL) and EtOAc (1560 L) and solid K 2 C0 3 was added until the pH is greater than 10. The layers were separated and the aqueous layer extracted with ethyl acetate (975 mL) . The combined organic layers were dried over sodium sulfate (975 g) for 25-35 minutes, filtered and the filter cake washed with EtOAc (975 mL) . The solvent was removed in vacuo at a bath temperature below 45°C to afford the product as a red-brown oil (809 g - 1073 g; yields 60-80% of theory; 83-110% w/w) . B . Preparation of a Protected Amino Acid of Formula 3 The reaction vessel was purged with nitrogen for 10 minutes prior to adding sodium hydride (60% dispersed in oil; 261 g, 6.50 moles). THF (4090 mL) was added and the resulting suspension was cooled to between -5 and +5°C. (L) -N-Boc-4-chlorophenylalanine (615 g, 2.05 moles) was added portionwise at such a rate as to ensure the internal reaction temperature did not exceed +10°C. The nitrogen flow was stopped and the reaction was stirred at below +10°C until the evolution of hydrogen ceases (0.5-2 hours) . Iodomethane (738 mL, 11.8 moles) was added dropwise at such a rate as to maintain the internal reaction temperature below +10°C. The reaction mixture was allowed to warm to between +10 and +20°C and stirring was continued until the reaction was complete, as analyzed by HPLC . A 5.2% w/v aqueous citric acid solution was added in small quantities to obtain a pH < 4.0. The two layers were separated and the aqueous layer extracted with EtOAc (2 x 1540 mL) . The organic phases were combined and then washed with a 35% w/v aqueous sodium chloride solution (1540 mL) . The organic phase was dried with sodium sulphate (154 g) , filtered and the filter cake washed with EtOAc (615 mL) . The solvent was removed in vacuo keeping the bath temperature below 42°C. Hexane (1540 mL) was added to the residue and this was stirred for 1-1.5 hours. The solid was filtered, washed with hexane (615 mL) , dissolved in toluene (770 mL) and heated to reflux. The solution was allowed to cool to between +10 and + 20°C and stirred at this temperature for 12-18 hours. The reaction mixture was cooled to between +5 and -5°C and stirred at this temperature for 3-5 hours. The resulting solid was isolated by vacuum filtration and washed with hexane (2 x 310 mL) . The solid was dried in a vacuum oven below 42°C until the solvent has been removed to afford the product as an off-white solid (387 g - 547 g; yields 60-85% of theory; 63-89% w/w) . C. Preparation of a Compound of Formula 5 We mixed 2 , 6-dimethoxyphenol ( 28 . 0 kg, 182 moles ) and water ( 28 L ) , followed by potass ium hydroxide solution (30.5 kg of KOH, 544 moles, in 224 L demineralized water) , maintaining the internal temperature below 25°C. Water (28 L) was used as a line rinse. Glyoxylic acid solution (27.0 kg, 264 moles in 54 L water) was added over 20-40 minutes, maintaining the internal temperature below 30°C. The solution was stirred at 20-25°C and analyzed by HPLC at 5 hour intervals until the reaction was complete (expected reaction time was 15-20 hours) . The solution was cooled to 0-5°C and concentrated hydrochloric acid (33 L) was added (keeping the reaction at 0-10°C) to acidify the mixture to a pH of 0-1. This produced a thick, white precipitate. The mixture was cooled to 0-5°C and stirred at this temperature for between 0.5 and 2.25 hours, before the solid was collected by filtration. The filter cake was slurry-washed with water (70 L) followed by washing with water (2 x 28 L) . The filter cake was dried in vacuo at up to 25 °C to obtain a water content of not more than 50%. The filter cake was then dried in vacuo at approximately 40°C to a water content of < 30 w/w%, to yield the initial carboxylic acid as a white solid (28.0 kg - 36.4 kg; yields 68 - 88% of theory; 100 - 130% w/w) . Potassium carbonate (32.7 kg, 237 moles) and TBAB (tetra-n-butyl ammonium bromide, 1.7 kg, 5.3 moles) were added to the reaction vessel, followed by acetone (49 L) . The carboxylic acid produced as described above (24.6 kg, 108 moles) was added to a make-up vessel, followed by sufficient water to give a mixture containing 30% w/w water. Acetone (148 L) was added to the make-up vessel and the contents stirred to produce a slurry. The slurry was added to the reaction vessel maintaining the temperature between 20 and 30°C throughout, followed by a line rinse of acetone (24.6 L) . Dimethyl sulfate (DMS; 27.3 kg, 216 moles) was added to the reaction vessel, followed by a line rinse of acetone (24.6 L) . The mixture was heated to reflux and stirred for 1.5-1.75 hours before analysis. The reaction was analyzed using TLC and DMS test strips. When all of the DMS has been consumed, the mixture was cooled to 0-5°C, stirred at this temperature for 30-60 minutes, then filtered to remove inorganic material. The filter cake was washed with acetone (3 x 74 L) . The filtrate was retained and the solid was discarded. The filtrate was concentrated to 74 L by vacuum distillation, keeping the internal temperature not more than 40°C. Methanol (123 L) was charged, and the remaining acetone was removed by atmospheric distillation, during which time further methanol was added to maintain a constant internal volume of 197 L. The solution was concentrated to a volume of 74 L at an internal temperature of 60-70°C. Water (197 L) was charged, the mixture was cooled to 0-5°C, and stirred for 1-2 hours at this temperature. The solid was collected by filtration and washed with water (2 x 25 L) . The product was dried in vacuo at 20-25°C to yield the hydroxy ester as an off-white solid containing up to 7.5% w/w water (16.4 kg - 21.9 kg; yields 60 -80% of theory; 67 - 89% w/w) . We next mixed potassium permanganate (15.4 kg, 97.4 moles) and dichloromethane (DCM; 44 L) . The internal temperature was adjusted to between 20 and 25 °C . To this was added a solution of the hydroxy ester (16.7 kg, 65.2 moles) and tetra-n-butylammonium bromide (TBAB; 534 g, 1.66 moles) in DCM (155 L) at a temperature of 20-25°C, followed by a line rinse of DCM (17 L) . The reaction mixture was stirred at 20-25°C until complete by TLC, which typically requires 16-22 hours. The mixture was filtered to remove manganese dioxide and the filter cake washed with DCM (4 x 22 L) . The filtrate was mixed with sodium metabisulphite solution (15 kg dissolved in 51 L of water) , keeping the temperature below 25°C, followed by a line rinse with water (5 L) . This was stirred at 15-25°C until the purple coloration disappeared (approximately 3 hours) . The phases were allowed to separate and the organic phase removed and retained. The aqueous phase was extracted with DCM (2 x 44 L) , then the combined organic phases were washed with water (2 x 33 L) . The combined water washes were then extracted with DCM (44 L) , and all organic phases combined. The solution was concentrated to approximately 50 L by atmospheric distillation. Then the DCM was solvent-exchanged for THF at atmospheric pressure, maintaining the reaction volume at approximately 67 L by gradually adding approximately 67-150 L THF. The endpoint was determined by a stable internal temperature being established at 62-66°C. The concentrate was cooled to 20°C and discharged into a container followed by a line rinse of THF (8.4 L) . The resulting methyl ester was assayed and carried on to the next stage (10.7 kg - 15.7 kg; yields 65 - 85% of theory; 64 - 94% w/w). A reaction vessel was purged with nitrogen and charged with a solution of the methyl ester (27.7 kg, 109 moles) in THF (approximately 97 L) followed by a line rinse of THF (14 L) . The volume of the solution was then adjusted to 110 L, either by addition of THF or concentration at atmospheric pressure. A 2M solution of NaOH was added as needed to adjust the pH to ≥ 11, while maintaining an internal temperature of 20-25°C. The reaction was stirred at 20-25°C for 30-60 minutes and then checked for absence of starting material by TLC . If starting material was still present, the reaction mixture was stirred for a further 30-45 minutes. Water (55 L) and DCM (112 L) were added and the layers separated. The aqueous layer was extracted with DCM (2 x 111 L) . The final DCM extract was checked by proton NMR for the absence of TBAB. If necessary, extraction of the aqueous phase with DCM (111 L) was repeated until NMR analysis indicates TBAB was essentially absent from the DCM extract. The DCM phases were discarded. Methyl ethyl ketone (MEK; 139 L) was added to the aqueous layer, which was then acidified to pH < 1 with concentrated HCl (22 L) while maintaining the internal temperature at 20-25°C. The layers were separated and the aqueous layer extracted with MEK (2 x 139 L) ensuring the pH remains ≤ 1 with additional HCl as necessary. The combined MEK layers were then washed with water (2 x 55 L) and the water washes were extracted with MEK (55 L) . The MEK layers were combined, followed by a line rinse of MEK (14 L) and concentrated at atmospheric pressure to 55 L. Fresh MEK (139 L) was added and the mixture was concentrated to 55 L. Continue drying by azeotropic distillation until the internal temperature was ≥ 65°C (approximately 2 repetitions) at which point a sample of the solution was removed for water determination by Karl-Fischer analysis. If the water content was > 2%, MEK (139 L) was added and the mixture was concentrated at atmospheric pressure to 55 L. The reaction was then diluted with toluene (139 L) and the mixture heated to 85-90°C, as necessary, in order to achieve complete dissolution. The reaction was cooled to 70°C and then further cooled from 70°C to 20°C over approximately 1 hour and then to 0-5°C before stirring for 1-3 hours. The final carboxylic acid product was collected by filtration and washed with cool (0-5°C) toluene (28-55L) . The solid was dried in vacuo at no more than 35°C (15.2 kg - 23.5 kg; yields 58 - 89% of theory; 55-85% w/w) . D. Assembly_of_Comrjound_9 Compound 9 *CDI = l .l '-Carbonyldiimidazole We mixed the protected amino acid from Step B (880 g, 2.80 moles) and CH 2 C1 2 (6290 mL) . N-N- diisopropylethylamine (1634 mL, 9.380 moles) was then added and the reaction mixture was stirred at 14-20°C until a solution was achieved. The reaction mixture was cooled to between -10 and -20°C and trimethylacetyl chloride (352 mL, 2.86 moles) was added keeping the temperature below -10°C. The mixture was stirred at this temperature for 1.75-2.25 hours. A solution of the amine produced in step A (679 g, 1.90 moles) in CH 2 C1 2 (630 mL) was added and the reaction mixture was allowed to warm to between 14 and 20°C with stirring. The reaction mixture was stirred at this temperature until the reaction was complete, as analyzed by 1 H NMR (12-20 hours) . The reaction mixture was washed with 10% w/v aqueous citric acid solution (3100 mL) and the solvent was removed in vacuo at a bath temperature of less than 45°C. The residue was dissolved in EtOAc (3150 L) and the organic phase was washed with 10% w/v aqueous K 2 C0 solution (2 x 940 mL) . The organic phase was dried over Na 2 S0 4 (630 g) , filtered and the filter cake washed with EtOAc (630 mL) . The solvent was removed in vacuo at a bath temperature of less than 45°C. The residue was dissolved in MeOH (1510 mL) and EtOAc (7550 mL) and the solution was cooled to between -5 and +5°C. HCl gas was bubbled through the solution for 40-50 minutes with vigorous stirring, keeping the temperature below 10°C. The reaction mixture was stirred for 55-75 minutes allowing the temperature to rise to between 14 and 20°C while checking for reaction completion, as analyzed by λ E NMR. The solvent was removed in vacuo at a bath temperature of less than 45°C. The residue was dissolved in EtOAc (7550 mL) and water (8170 mL) . Solid KC0 (approximately 1 kg) was added until the pH of the aqueous phase was greater than 12. The layers were separated and the aqueous phase was extracted with EtOAc (2 x 3150 mL) . The organic phase was dried over NaS0 4 (630 g) , filtered and the filter cake washed with EtOAc (630 mL) . The solvent was removed in vacuo at a bath temperature below 45°C. The residue was dissolved in isopropyl acetate (630 mL) at 50°C while the flask was still on the rotary evaporator. The flask was removed and the solution was cooled to between -5 and +5°C, with stirring. The reaction mixture was kept at this temperature for 0.5-2 hours. The crystalline solid was filtered and washed with isopropyl acetate (630 mL) . The solid was dried in vacuo at 14-20°C to afford the intermediate product as a white to off-white solid (528 g - 986 g; yields 35-65% of theory; 60-112% w/w) . The carboxylic acid produced in step C (230 g, 1.03 moles) and tetrahydrofuran (2500 mL) were mixed. Carbonyl diimidazole (160 g, 0.99 moles) was added and the reaction mixture was stirred at 14-20°C for 12-20 hours. The intermediate product described directly above (500 g, 0.95 moles) was added and stirring was continued until the reaction was complete, as analyzed by l U NMR (16-24 hours) . The solvent was removed in vacuo at a bath temperature below 45°C. The residue was dissolved in ethyl acetate (3000 mL) and the organic phase was washed with 7% w/v aqueous sodium hydrogen carbonate solution (2 x 2000 mL) and 35% w/v aqueous sodium chloride solution (4 x 1250 mL) . The organic phase was dried over Na 2 Sθ (500 g) , filtered and the filter cake washed with EtOAc (500 mL) . The solvent was removed in vacuo at a bath temperature below 45°C. The residue was suspended in MeOH (1875 mL) and warmed to between 50 and 60°C until the solid has dissolved. The solution was cooled to between -5 and +5°C and stirred for 0.5-3 hours. The crystalline solid was filtered and washed with MeOH (250 mL) . The solid was suspended in MeOH (1875 mL) and warmed to between 50 and 60°C until the solid dissolved. The solution was cooled to between +5 and -5°C and stirred at this temperature for 0.5-3 hours. The crystalline solid was filtered, washed with MeOH (250 mL) and dried in vacuo at 14-20°C to afford the product as a white to off-white crystalline solid (131 g - 230 g; yields 40-70% of theory; 57-100% w/w) . Compound 9 may be converted to the more stable methyl sulfonate salt by treatment with MeS0 3 H in acetone/hexane . Other compounds of formula II can be produced by analogous steps . EXAMPLE 2 Alternate route to a Compound of Formula I The synthesis of a compound of formula I, depicted in Example 1, part A, above, may be replaced by an alternate, more direct synthesis depicted below: In this alternate scheme, two equivalents of picoline in THF (0.1 g/ml) at -20°C are slowly mixed with two equivalents of n-butylLithium so as to avoid the temperature of the solution rising above 0°C. Following the addition of the n-butylLithium, the solution is stirred for one hour at 0°C. One equivalent of bromoazoiridine is then added, the solution is warmed to room temperature and stirred overnight. The solution is then treated with approximately 3 equivalents of HCl dissolved in ethyl ether to precipitate out the desired product, which is then collected by filtration and dried the material under vacuum. The resulting product is then used as described in Example 1, part D. While we have hereinbefore presented a number of embodiments of this invention, it is apparent that our basic construction can be altered to provide other embodiments which utilize the methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the claims appended hereto rather than the specific embodiments which have been presented hereinbefore by way of example.

Claims: CLAIMS We claim: A method of producing a compound of the formula : D I), comprising the step of reacting a compound of the formula: D Λ-kn M ( ) w it a compound of the formula: (2) in the presence of a strong acid; wherein each D is the same and is selected from hydrogen, or a 5 to 7-membered carbocyclic or heterocyclic ring optionally comprising one or more substituents independently selected from halogen, hydroxyl, nitro, - S0 3 H, trifluoromethyl, trifluoromethoxy, (Cι-C 6 ) -straight or branched alkyl, (C 2 -C 6 ) -straight or branched alkenyl, 0-[ (Cι-C 6 ) -straight or branched alkyl], 0-[(C 2 -C 6 )- straight or branched alkenyl], O-benzyl, O-phenyl, 1,2- methylenedioxy, -NtR 1 ) (R 2 ) , carboxyl, N- (Ci-Cs-straight or branched alkyl or C 2 -Cs-straight or branched alkenyl) carboxamides, N, N-di- (Ci-Cs-straight or branched alkyl or C 2 -C 5 -straight or branched alkenyl) carboxamides, N- (Cι-C 5 -straight or branched alkyl or C 2 -C 5 -straight or branched alkenyl) sulfonamides, N, N-di- (Ci-Cs-straight or branched alkyl or C 2 -C 5 -straight or branched alkenyl) sulfonamides, morpholinyl, piperidinyl, O-Z, CH 2 - (CH 2 ) q -Z, 0-(CH 2 ) q -Z, (CH 2 ) q -Z-0-Z, or CH=CH-Z; wherein R 1 and R 2 are independently selected from (Cι-C 6 ) -straight or branched alkyl, (C 2 -C 6 )- straight or branched alkenyl or alkynyl, hydrogen or benzyl; or wherein Ri and R 2 are taken together with the nitrogen atom to which they are bound to form a 5-7 membered heterocyclic ring; Z is selected from 4-methoxyphenyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5- dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, or pyrimidyl; and q is 0, 1 or 2; and wherein D is optionally benzofused; each n is the same and is selected from 1 or 2; and A is selected from 0, or -N(R), wherein R is selected from D, (Ci-Cβ) -straight or branched alkyl, (C 2 - C 6 ) -straight or branched alkenyl or alkynyl, (Ci-Cβ)- straight or branched alkyl substituted with D, or (C 2 - C 6 ) -straight or branched alkenyl or alkynyl substituted with D; M is selected from Li, Na, K, Mg, Zn, Zr, Pd, B or Al ; and L is a leaving group. 2. The method according to claim 1, wherein L is selected from Cl, Br, I, F, O-p-toluenesulfonate, 0- methanesulfonate, or 0-trifluoromethanesulfonate . 3. The method according to claim 2, wherein L is selected from Cl, Br, I or F. The method according to claim 3, wherein L is Br . The method according to claim 1, wherein M is Li , 6. The method according to claim 1, wherein said strong acid is selected from methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, acetic acid, maleic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, oxalic acid, fumaric acid, formic acid, lactic acid, succinic acid, tartaric acid, mandelic acid, picric acid, camphor acid, alkyl substituted acetic acid derivatives, aryl substituted acetic acid derivatives, succinic acid, or tartaric acid. A method of producing a compound of the formula : (II), comprising the steps of: a. synthesizing a compound of the formula: D (I) uussiinng the method according to claim 1; b. reacting a compound of the formula; (3), with said compound of formula (I) to produce an intermediate of formula: c. deprotecting said compound of formula (4) by removing P to produce a free amine; and d. reacting the deprotected free amine produced in step c with a compound of the formula: X-OH (5) or X-L (5') to produce a compound of the formula ( II ) ; wherein: A, D, L and n are as defined in claim 1, except that D is not hydrogen; P is an amino protecting group; J is selected from hydrogen, (d-C 6 ) -straight or branched alkyl, (C2-C 6 ) -straight or branched alkenyl or alkynyl, (Cι-C 6 ) -straight or branched alkyl substituted with D, or (C 2 -C6) -straight or branched alkenyl or alkynyl substituted with D; K is selected from (Cχ-C 6 ) -straight or branched alkyl, (C-C 3 ) -straight or branched alkenyl or alkynyl, (Cι-C 6 ) -straight or branched alkyl substituted with D, or (C 2 -C 6 ) -straight or branched alkenyl or alkynyl substituted with D; wherein any one of the -CH 2 - groups of said alkyl, alkenyl or alkynyl chains in K is optionally replaced by -0-, -S-, -S(O)-, -S(0) 2 -, -NH-, -N (Cι-C 6 -straight or branched alkyl)-, or -N(C 2 -C 6 - straight or branched alkenyl or alkynyl)-; or J and K are taken together with the nitrogen and carbon atoms to which they are respectively bound to form a 5- to 7-membered heterocyclic ring; and X is selected from R 3 , -S(0) 2 -R 3 , -C (0) -C (0) -R 4 , -C(O) -C(=CHR 4 )-R 4 , -C(0)-N(R (R 3, -C(=S)-N(R- (R J -C(0)-0-R 3 , -C(=S)-0-R 3 , or -C (0) -C(O) -N(R 3 ) (R 3 ) , wherein each R 3 is independently selected from D, (Cι~ C 6 ) -straight or branched alkyl, (C 2 -C 6 ) -straight or branched alkenyl or alkynyl, (Cι-C 6 ) -straight or branched alkyl substituted with D, or { C 2 -Cβ) ~ straight or branched alkenyl or alkynyl substituted with D, or, when two R 3 are bound to the same nitrogen atom, both R 3 are taken together with the nitrogen atom to which they are bound to form a 5- to 7-membered heterocyclic ring; and R 4 is R 3 or 0-R 3 ; wherein any one of the -CH 2 - groups of said alkyl, alkenyl or alkynyl chains in R 3 is optionally replaced by -0-, -S-, -S(0)-, -S(0) 2 -/ -NH-, -N (Ci-Cβ-straight or branched alkyl)-, or -N(C 2 -C6~ straight or branched alkenyl or alkynyl)-. A method of producing a compound of the formula : D (II), comprising the steps of: synthesizing an alcohol of the formula ; ! ' ) using the method according to claim 1; b. oxidizing said alcohol of the formula (I') to produce a ketone of the formula: c . reacting said ketone produced in step b with an amine of the formula: H 2 N-R to produce a compound of the formula: d. reacting said compound of formula with a compound of the formula: 3), to produce an intermediate of formula; e. deprotecting said compound of formula (4) by removing P to produce a free amine; and f. reacting the deprotected free amine produced in step c with a compound of the formula: X-OH (5) or X-L (5') to produce a compound of the formula (II); wherein A, D, J, K, L, P, R, R 3 , R 4 and n are as defined in claim 7. 9. The method according to claim 7 or 8, wherein: each D is selected from 3-pyridyl, 4-pyridyl or phenyl; A is -NR; J and K are not taken together to form a ring; and X is -C(0)-C(0)-R 3 . 10. The method according to claim 9, wherein: each D is 4-pyridyl; each n is 1; A is -N-benzyl; J is methyl; K is 4-chloro-benzyl; and X is -C(O) -C(0)-3, 4, 5-trimethoxyphenyl.

Inventors: OLIVER PATRICIA ANN, OLIVER, PATRICIA, ANN
Applicants: OLIVER PATRICIA ANN, VERTEX PHARMA, OLIVER, PATRICIA, ANN, VERTEX PHARMACEUTICALS INCORPORATED
Application year: 2000
Main classification: C07D213
IPC codes: A61K31, C07D203, C07D213, C07D303