Processes for making modulators of cystic fibrosis transmembrane conductance regulator

Abstract

The disclosure provides processes for synthesizing compounds for use as CFTR modulators. ##STR00001##

Claims

1. A compound selected from: ##STR00145## ##STR00146## and salts thereof.

2. A process for the preparation of compound 1: ##STR00147## comprising: a) converting compound 12: into compound 11A: ##STR00148## ##STR00149## wherein the conversion of compound 12 into compound 11A is performed in the presence of KNO.sub.3 and/or NaNO.sub.3, AlCl.sub.3, and optionally one or more of trimethylsilyl chloride and TiCl.sub.4; b) converting compound 11A into compound 4: ##STR00150## c) reacting compound 3: ##STR00151## with compound 4 to produce compound 5: ##STR00152## and d) converting compound 5 into compound 1; wherein the methyl (Me) of the —OCO.sub.2Me of each of compounds 4, 5, 11A, and 12 is optionally replaced by a group selected from aliphatic, heteroaliphatic, heterocyclic, haloaliphatic, aryl, and heteroaryl.

3. A process for the preparation of compound 11A: ##STR00153## comprising converting compound 12: ##STR00154## into compound 11A; wherein the conversion of compound 12 into compound 11A is performed in the presence of KNO.sub.3 and/or NaNO.sub.3, AlCl.sub.3, and optionally one or more of trimethylsilyl chloride and TiCl.sub.4; and wherein the methyl (Me) of the —OCO.sub.2Me of each of compounds 11A and 12 is optionally replaced by a group selected from aliphatic, heteroaliphatic, heterocyclic, haloaliphatic, aryl, and heteroaryl.

4. The process of claim 2 or 3, wherein the conversion of compound 12 into compound 11A is performed in the presence of KNO.sub.3, AlCl.sub.3, and trimethylsilyl chloride.

5. The process of claim 2 or 3, wherein the conversion of compound 12 into compound 11A is performed in the presence of KNO.sub.3 and AlCl.sub.3.

6. The process of claim 2 or 3, wherein the conversion of compound 12 into compound 11A is performed in the presence of NaNO.sub.3 and AlCl.sub.3.

7. The process of claim 2 or 3, wherein the conversion of compound 12 into compound 11A is performed in the presence of a solvent.

8. The process of claim 7, wherein the solvent is CH.sub.2Cl.sub.2.

9. The process of claim 2 or 3, wherein compound 12 is produced by converting compound 13: ##STR00155## into compound 12.

Description

III. EXAMPLES

Example 1

Synthesis of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (1)

(1) The overall scheme of the synthesis of compound 1 is shown below.

(2) ##STR00102## ##STR00103##

(3) Compounds 12, 4, 5, and 1, can be prepared as disclosed in PCT Publication No. WO 2010/108162.

(4) The investigation of a procedure to synthesize compound 11A is shown below.

Investigation of Nitration Reaction Conditions—Nitration Reaction of Compound 12 with H.SUB.2.SO.SUB.4 .and NaNO.SUB.3 .or KNO.SUB.3 .to form 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate (11A)

(5) TABLE-US-00001 TABLE 1 04 05 06 nitration ratio of purity at end of reaction.sup.1 11A:11B:11C isolated yield isolated purity entry —NO.sub.2 source acid (% 11A) (unpurified) (%) (%) 1 HNO.sub.3 H.sub.2SO.sub.4 21 47:39:14 37 73 2 HNO.sub.3 H.sub.2SO.sub.4 17 41:41:17 — — 3 KNO.sub.3 H.sub.2SO.sub.4 18 43:40:17 — — 4 KNO.sub.3 H.sub.2SO.sub.4 17 41:43:16 — — .sup.1HPLC purity of 11A in the reaction mixture once the reaction is completed, prior to any workup or isolation step.
Procedure for Nitration Reaction (Table 1, entry 1)

(6) 100 ml of 96% sulfuric acid were charged in reactor 1 and cooled to 0° C. 50 g of 2,4-di-tert-butylphenyl methyl carbonate (12) were added over the sulfuric acid maintaining the temperature below 10° C. Then the reactor was cooled to −5° C. To another reactor (reactor 2) 50 ml of 96% sulfuric acid and 14.4 ml of 65% nitric acid were charged, and the resulting mixture was cooled to −5° C. The contents of reactor 2 were added into reactor 1 maintaining the temperature below 0° C. The mixture was stirred at 0/−5° C. for 4 hours. The crude of reaction reaction was quenched by adding it slowly over a mixture formed by 200 ml of DCM and 353 ml of water at 0° C. Then the mixture was heated to 20° C. and stirred for 1 hour. The phases were separated and the aqueous phase was washed with 100 ml of DCM. The combined organic phases were washed with 123 ml of water first and then with 160 ml of a 13% sodium chloride solution in water. The resulting organic solution was then concentrated under vacuum to 55 ml to obtain an oil that precipitated. The solid was dissolved with 155 ml of methanol at 65° C. The solution was distilled at atmospheric pressure until 155 ml. 20 ml of methanol were added and the solution was cooled to 25/30° C. in 2 hours and stirred at this temperature for 1 hour. The solids were filtered and washed with 11.5 ml of methanol to yield 24.06 g of 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate (11A) as wet solid with a 10.6% of methanol. Yield: 37% HPLC purity: 73%.

Investigation of Nitration Reaction Conditions—Nitration Reaction of Compound 12 with Trimethylsilylchloride, AlCl.SUB.3., and KNO.SUB.3 .to form 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate (11A)

(7) TABLE-US-00002 TABLE 2 07 08 09 nitration ratio of KNO.sub.3 TMSCI AlCl.sub.3 purity at end of reaction.sup.1 11A:11B:11C entry (equiv) (equiv) (equiv) T (° C.) (% 11A) (unpurified) 1 1.5 2.0 3.0 0 55 85:5:10 2 1.5 2.0 3.0 0 43 82:4:14 3 1.5 2.0 3.0 0 57 89:6:4  4 1.1 2.5 3.3 0 47 87:9:4  5 1.1 2.5 3.3 20 42 64:30:6 6 1.1 2.5 4.5 20 36 88:0:12 7 1.2 2.0 3.0 0 46 66:34:0 8 1.5 2.0 3.0 −15 53 91:6:3  9 1.5 2.0 3.0.sup.2 −15 21 48:46:6 .sup.1HPLC purity of 11A in the reaction mixture once the reaction is completed, prior to any workup or isolation step.
Procedure for Nitration Reaction (Table 2, entry 1)

(8) 1.15 g of potassium nitrate and 14.6 ml of dichloromethane were charged into a reactor. The suspension was cooled to 0° C. 1.95 ml of chloromethylsilane were added at 0° C. and then 2.0 g of 2,4-di-tert-butylphenyl methyl carbonate (12) and 2 ml of dichloromethane. 3.03 g of aluminum trichloride were added slowly at 0° C. and the mixture was stirred then at this temperature for 20 hours. The reaction was then quenched by adding 20 ml of water maintaining the temperature below 30° C. 15 ml of dichloromethane were charged and the mixture was heated to 25° C. The two phases were separated and the aqueous phase was washed with 20 ml of dichloromethane. The combined organic phases were washed with 20 ml of water two times and the resulting organic phase was concentrated to dryness to yield 2.044 g (87.4%) of 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate (11A). HPLC purity: 55%.

Investigation of Nitration Reaction Conditions—Nitration Reaction of Compound 12 with AlCl.SUB.3./NaNO.SUB.3 .to form 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate (11A)

(9) TABLE-US-00003 TABLE 3 0 nitration ratio of NaNO.sub.3 AlCl.sub.3 purity at end of reaction.sup.1 11A:11B:11C isolated yield isolated purity entry (equiv) (equiv) T (° C.) (% 11A) (unpurified) (%) (%) 1 1.2 3.0 −15 88 96:3:1 87 99.3 2 1.2 3.0 −15 89 96:3:1 87 99.6 .sup.1HPLC purity of 11A in the reaction mixture once the reaction is completed, prior to any workup or isolation step.
Procedure for Nitration Reaction (Table 3, entry 2)

(10) 143.75 g of aluminum trichloride and 789 ml of methylene chloride were charged to a 1 liter reactor. The mixture was cooled to 0° C. and 36.65 g of sodium nitrate were added. The crude of reaction was stirred at 0° C. for 3 hours. Then the reactor was cooled to −20° C. and 95 g of 2,4-di-tert-butylphenyl methyl carbonate (12) dissolved in 76 ml of methylene chloride were added while maintaining the temperature at −15° C. The mixture was then stirred for twenty hours at −15° C. In another reactor 665 ml of 2M hydrochloric acid were charged and cooled to 3° C., then the crude of reaction was quenched slowly over the hydrochloric solution at 10° C. The mixture was heated to 20° C. and stirred for 1 hour at this temperature before separating both layers. The aqueous phase was washed with 190 ml of methylene chloride that were combined with the initial organic phase. The two combined organic phases were washed three times with 510 ml of sodium chloride solution containing 475 ml of water and 95 g of sodium chloride each. The resulting organic phase was concentrated under vacuum to 190 ml and then 618 ml of methanol were added. The mixture was concentrated again to a final volume of 570 ml and heated to 64° C. 190 ml of methanol are added to the mixture while maintaining 64° C. to obtain complete dissolution of the solids. Then the mixture was cooled to 55° C. and maintained at this temperature for 1 hour. Later it was cooled to 2° C. in 2 hours and stirred at this temperature for 2 additional hours before filtering the solid. The wet cake was washed twice with 47.5 ml of cold methanol and the wet solids were dried at 45° C. under vacuum to yield 96.15 g (86.5%) of 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate (11A). HPLC purity: 99.6%

Synthesis of 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate (11A)

(11) ##STR00113##

(12) Methylene chloride (3091 L) was charged into a reactor and cooled to −5-5° C., then aluminum trichloride (564 kg) and sodium nitrate (144 kg) were added. The mixture was stirred at −1-5° C. for not less than 3 hours and then further cooled to −20-−12° C. A solution of 2,4-di-tert-butylphenyl methyl carbonate (373 kg) in methylene chloride (300 L) was added while maintaining the temperature at −20-−12° C. After the addition, the mixture was maintained at −21-−15° C. The completeness of the reaction was measured by HPLC with in-process control sample taken after 2 hours. The reaction was considered complete when the peak area of 2,4-di-tert-butylphenyl methyl carbonate was less than 4.5%.

(13) In another reactor 2N hydrochloric acid solution was prepared (526 kg of concentrated HCl in 1864 L of water) and cooled to 0±5° C. The reaction mixture was then added slowly to the hydrochloric solution at not more than 20° C. to quench the reaction. The mixture temperature was heated to 15-21° C. and stirred for 1 hour before separating both layers. The aqueous phase was washed with methylene chloride (745 L, 2.0 vol) at 15 to 21° C. The combined organic phase was washed three times with 16.7% sodium chloride aqueous solution (prepared by the dissolution of NaCl (298 kg) in water (1491 L) at 15 to 21° C.). The resulting organic phase was then concentrated to 746 L at not more than 45° C., and methanol (3169 L) was added. The resulting mixture was concentrated to 2237 L at not more than 65° C. and then additional methanol (373 L) was added. The mixture was concentrated again to 2237 L at not more than 65° C. and then heated to reflux (˜65° C.) to dissolve any solids present. If any solids were still present, methanol (373 L) was added while maintaining the temperature at reflux. This procedure was repeated until all solids were dissolved. At this point the solution was cooled to 45-55° C. until crystallization was observed and maintained at this temperature for 1 hour. The resulting slurry was cooled at −5-5° C. in 2-5 hours and stirred at this temperature for one additional hour before filtration. The filter cake was washed twice with cold methanol (298 L).

(14) The crude product (402 kg), methylene chloride (804 L) and methanol (804 L) were charged into a reactor. The mixture was heated to 40-45° C. until all solids completely dissolved. The solution was treated with activated carbon for not less than 1 hour at 40-45° C. After the filtration, methanol (804 L) was added. The solution was concentrated to 804 L under vacuum at not more than 45° C. Methanol (804 L) was added and the resulting slurry was concentrated to 804 L under vacuum at not more than 45° C. Methanol (804 L) was added again. The slurry was cooled at −10-0° C. in 2-5 hours and then stirred at this temperature for minimum 3 hours before filtration. The filter cake was washed twice with cold methanol (402 L).

(15) The wet cake was dried at not more than 50° C. under vacuum until residual methanol and methylene chloride contents were less than 5000 ppm. A light yellow solid, 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate (11A), was obtained (364.9 kg, 99.9% purity measured by HPLC analysis) with 83.6% yield.

Example 2

N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (2)

(16) The overall scheme of the synthesis of compound 2 is shown below, followed by the procedure for the synthesis of each intermediate.

(17) ##STR00114## ##STR00115##

Procedure for the Synthesis of 4-(tert-butyl)phen-2,6-d2-ol-d (19)

(18) ##STR00116##

(19) To a 5 L round bottom flask equipped with overhead stirrer was charged 4-tert-butylphenol (14, 503.2 g), K.sub.2CO.sub.3 (46.3 g), D.sub.2O (1949 g, 1761 mL, 3.5 vol), and MeOD (409 g, 503 mL, 1.0 vol). The mixture was heated to reflux under a nitrogen atmosphere. The reaction mixture was aged at reflux for 16 hours. The reaction mixture was cooled to room temperature and sampled for conversion (% D incorporation). The reaction was cooled to 5° C. and 35% DCl solution (90 g, 71.2 mL) was added. The reaction mixture was aged at 5° C. for 2 hours. The resultant slurry was filtered and the cake washed with D.sub.2O (836 g, 755 mL, 1.5 vol). This process was repeated until the target % D incorporation is met (normally two exchanges required). The wet cake is dried in a vacuum oven with a nitrogen bleed at 40° C. until a constant weight is obtained. Yield of 4-(tert-butyl)phen-2,6-d2-ol-d (19) is 506 g of a white solid (98%) with a purity of 99.6% and % D incorporation of 99.3%.

Procedure for the Synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phen-6-d-ol-d and 4-(tert-butyl)-2,6-bis(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol-d (18)

(20) ##STR00117##

(21) 4-(tert-butyl)phen-2,6-d2-ol-d (19) (101.8 g, 0.66 mol, 1.0 equiv.) was dissolved in CH.sub.2Cl.sub.2 (400 mL) in a 2 L reactor. tert-Butanol-d.sub.10 (43.0 g, 0.51 mol, 0.77 equiv.) was dissolved in CH.sub.2Cl.sub.2 (100 mL) in a 250 mL flask. The solution of tert-butanol-d.sub.10 was charged to the 2 L reactor at room temperature. The reaction mixture was cooled to −5° C. D.sub.2SO.sub.4 (51.1 g, 0.51 mol, 0.77 equiv.) was charged dropwise via an addition funnel while maintaining a temperature range of −4 to −2° C. The reaction mixture was stirred at −2° C. for 3-4 hours. Upon complete conversion the reaction was quenched by adding water (28 mL) and warmed to 18-20° C. The bottom aqueous layer was drained and discarded. The CH.sub.2Cl.sub.2 layer was treated with sat. aq. NaHCO.sub.3 solution (approximately 200 mL), adjusting the pH to 6-8. NaCl (sat.) solution (400 mL) was charged to the mixture. The resulting solution was stirred for 5 min, and settled for 5 min. The lower CH.sub.2Cl.sub.2 layer was drained into a 1 L flask. The aqueous layer was discarded. The CH.sub.2Cl.sub.2 solution was concentrated to minimal volume and n-heptane (200 mL) was charged. The solution was concentrated to minimal volume and n-heptane charged to a final volume of 800 mL. 0.5 N NaOH solution 600 mL (6 vol) was charged to the reactor and the resulting mixture was stirred for 5 min, and settled for at least 5 min. The aqueous layer was drained and discarded. 1.0 N NaOH solution 300 mL (3 vol) was charged to the reactor and the resulting mixture was stirred for 5 min, and settled for at least 5 min. The aqueous layer was drained and discarded. 1.0 N NaOH solution 300 mL (3 vol) was charged to the reactor and the resulting mixture was stirred for 5 min, and settled for at least 5 min. The aqueous layer was drained and discarded. The remaining n-heptane solution was concentrated to dryness to afford the desired product, 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phen-6-d-ol-d (18) as a clear oil, 104.5 g, which was carried forward into the next step without further purification.

Procedure for the Synthesis of 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol (17)

(22) ##STR00118##

(23) 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phen-6-d-ol-d (18) (100 g, 0.462 mol, 1.0 equiv.) was dissolved in CH.sub.2Cl.sub.2 (800 mL, 7 vol) in a 2 L reactor and the solution was stirred. The batch was cooled down to 0±3° C. To the batch was charged portion-wise N-bromosuccinimide (84.4 g, 0.462 mol, 1.0 equiv) over 30 min. The batch was stirred at 0±2° C. for at least 30 minutes. The batch was then heated to 20±2° C. over a period of 2 hours, and stirred at 20±2° C. for at least 12 hours. Upon complete conversion, sat. aq. NaHCO.sub.3 solution (500 mL, 5 vol) was charged and the batch stirred for at least 10 minutes. The agitation was stopped to allow the phases to separate for at least 5 minutes and the CH.sub.2Cl.sub.2 layer was drained, followed by removal of the aqueous layer. The CH.sub.2Cl.sub.2layer was charged back to the vessel. To the batch was charged sat. aq. NaHCO.sub.3 bicarbonate solution (500 mL, 5 vol), and the batch was stirred for at least 10 minutes. The agitation was stopped to allow the phases to separate for at least 5 minutes and the CH.sub.2Cl.sub.2 layer was drained, followed by removal of the aqueous layer. The CH.sub.2Cl.sub.2 layer was charged back to the vessel and diluted with an additional CH.sub.2Cl.sub.2 (300 mL, 3 vol). The batch was distilled (removal of 300 ml) and checked by KF to achieve dryness. The resulting clear yellow solution of 17 was carried forward into the next step without further purification.

Procedure for the Synthesis of 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (16)

(24) ##STR00119##

(25) To a clean reactor was charged the CH.sub.2Cl.sub.2 solution of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phen-6-d-ol-d (17) (136 g, 0.462 mol, 1.0 equiv.) followed by additional CH.sub.2Cl.sub.2 (130 mL, 1 vol), and this solution was stirred. To the batch was charged 4-(dimethylamino)pyridine (2.8 g, 0.023 mol, 0.05 equiv) and triethylamine (70.1 g, 0.693 mol, 1.5 equiv). The batch was cooled to 0±3° C. To the batch was charged drop-wise methyl chloroformate (48.0 g, 0.508 mol, 1.1 equiv) over 40 minutes while maintaining a batch temperature ≤5° C. The batch was stirred at 3±2° C. for at least 30 minutes, and then warmed to 20±2° C. over a period of 1 hour. Upon complete conversion, 1 N HCl (400 mL, 3 vol) was charged. The batch was stirred for at least 10 minutes, and then the layers were allowed to separate for at least 5 minutes. The lower organic layer was drained followed by the aqueous layer (1.sup.st aqueous layer). The organic layer was charged back to the reactor, along with 1 N HCl solution (400 mL, 3 vol). The batch was stirred for at least 10 minutes, and then the layers were allowed to separate for at least 5 minutes. The lower organic layer was drained. The 1.sup.st aqueous layer was charged to the reactor, along with CH.sub.2Cl.sub.2 (300 mL, 2.2 vol). The batch was stirred for at least 10 minutes, and then the layers were allowed to separate for at least 5 minutes. The lower organic layer was drained and combined with the 1.sup.st organic layer, followed by removal of the aqueous layer. Charge the vessel with the contents of both organic layers. The reactor was charged with water (500 mL, 3.7 vol). The batch was stirred for at least 10 minutes, and then the layers were allowed to separate for at least 5 minutes. The lower organic layer was drained, followed by the aqueous layer. The organic layer was charged back to the reactor, along CH.sub.2Cl.sub.2 (400 mL, 3 vol). The batch was distilled to remove 800 ml and checked by KF to ensure dryness. The resulting clear yellow solution of 16 was telescoped into the next step without further purification.

Procedure for the Synthesis of 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-3-nitrophenyl methyl carbonate (15)

(26) ##STR00120##

(27) To a reactor was charged 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (16) and then the solution was cooled to 0° C. Sulfuric acid (4.9 equiv) and nitric acid (100%, 2.0 equiv) was charged while maintaining a temperature of not more than 5° C. The reaction was stirred at 0° C. for 2 hours until complete conversion. The reaction was then quenched with water (8.8 vol) and diluted with CH.sub.2Cl.sub.2 (1.7 vol). The layers were separated and the upper aqueous layer was extracted with CH.sub.2Cl.sub.2 (2.8 vol). After separating the layers, the organic layers were combined, returned to the reactor, and washed with sodium bicarbonate (7.4% w/w, 6.8 vol). After separating the layers, the organic layer was returned to the reactor and washed with sodium chloride (23% w/w, 3.8 vol). After separating the layers, the organic layer was returned to the reactor and concentrated to minimal volume. Methanol (1.2 vol) was charged, followed by concentration to minimal volume. Methanol (1.2 vol) was charged, followed by concentration to minimal volume. Methanol (1.7 vol) was charged, and the slurry was heated to reflux for 30 min and then cooled slowly over 4 hours to 5° C. The solid product (15) was filtered and the cake washed with cold methanol (1.0 vol). The solid 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-3-nitrophenyl methyl carbonate (15) was dried under vacuum at 40-50° C. to yield an off-white solid, 99.9% purity and 99% D incorporation.

Procedure for the Synthesis of 5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (7)

(28) ##STR00121##

(29) Charge 5 wt % (50-65 wt % wet, JM Type 37) of 5% Pd/C to a reactor. Charge (4.0 vol) Methanol. Close the system. Purge with N.sub.2 (g) at 2.0 Bar. Activate with H.sub.2 (g) at 2.0 Bar. Charge the vessel to 2.0 Bar with H.sub.2 (g) at 25° C.+/−5° C. Stir for not less than 2 hours while maintaining a temperature of 25° C.+/−5° C. Vent and purge with N.sub.2 (g) at 2.0 Bar. Charge compound 15 (1.0 eq) to a reactor, together with Na.sub.2HPO.sub.4 (2.3 eq). Charge (11.0 vol) Methanol. Close the system. Purge with N.sub.2 (g) at 2.0 Bar. Activate with H.sub.2 (g) at 2.0 Bar. Charge the vessel to 2.0 Bar with H.sub.2 (g) at 25° C.+/−5° C. Stir for about 24 hours while maintaining a reaction temperature of 25° C.+/−5° C. Upon complete conversion, dilute reaction mixture by adding 7.7 vol of MeOH. Heat reaction mixture to 35.0° C.+/−5° C. Filter off catalyst and Na.sub.2HPO.sub.4. Wash the reactor and filter cake with Methanol (4.0 vol), and filter, combining with the initial filtrate. Check Pd content and if needed perform resin treatment (resin treatment is: Charge SPM-32 resin (5 wt %). Stir the resin treated solution for not less than 3 hours at 35.0° C.+/−5° C. Filter off resin. Wash the reactor and filter cake with Methanol (2.0 vol), and filter, combining with the initial filtrate). Charge Norit CASP active carbon (3 wt %,). Stir for not less than 3 hours at 35.0° C.+/−5° C. Filter off active carbon. Wash the reactor and filter cake with Methanol (2.0 vol), and filter, combining with the initial filtrate. Distill under vacuum at not more than 50° C. to 8.0 vol. Charge water (2.0 vol) while maintaining a temperature of 45° C.+/−5° C. Cool the resultant slurry to 0° C.+/−5° C. over 2 hours. Hold and stir the slurry at 0° C.+/−5° C. for not less than 1 hour. Filter and wash the cake with 2.0 volumes Methanol/Water (8:2) at 0° C.+/−5° C. Dry 5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (7) under vacuum at not more than 40° C. to give a yield of a white solid, >99.5% purity.

Procedure for the Synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate (8)

(30) ##STR00122##

(31) The procedure for the conversion of compound 7 into compound 8 may be performed according to the analogous procedure for compound 5.

Procedure for the Synthesis of N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (2)

(32) ##STR00123##

(33) The procedure for the conversion of compound 8 into compound 2 may be performed according to the analogous procedure for the synthesis of compound 1.

Example 3

Synthesis of 5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (7)

(34) An alternative overall scheme of the synthesis of compound 7 is shown below, followed by the procedure for the synthesis of each synthetic intermediate.

(35) ##STR00124## ##STR00125##

Procedure for the Synthesis of 4-(tert-butyl)phen-2, 6-d2-ol-d (19)

(36) ##STR00126##

(37) To a clean and dry 500-mL reactor was charged 4-tert-butylphenol (14) (24.6 g, 0.162 mmol, 1.00 equiv), CH.sub.2Cl.sub.2 (64 mL, 2.6 vol), and heptane (64 mL, 2.6 vol), and this mixture was warmed to 25° C. and stirred until all solids dissolved. To this solution was charged deuterium chloride (35% w/w in deuterium oxide, 25 mL, 1.0 vol), and this mixture was agitated for at least 3.5 hours. The agitation was stopped and the phases were allowed to separate, and then the aqueous layer (bottom) was drained from the reactor. To the reactor was charged deuterium chloride (35% w/w in deuterium oxide, 25 mL, 1.0 vol), and this mixture was agitated for at least 3.5 hours. The agitation was stopped and the phases were allowed to separate, and then the aqueous layer (bottom) was drained from the reactor. To the reactor was charged deuterium chloride (35% w/w in deuterium oxide, 25 mL, 1.0 vol), and this mixture was agitated for at least 3.5 hours. The agitation was stopped and the phases were allowed to separate, and then the aqueous layer (bottom) was drained from the reactor. The resulting solution was sampled and confirmed to be at least 99% of the desired deuterium incorporation product 4-(tert-butyl)phen-2,6-d2-ol-d (19) relative to starting material 4-tert-butylphenol. The solution in the reactor was carried on to the next step described below.

Procedure for the Synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phen-6-d-ol (18)

(38) ##STR00127##

(39) To the methylene chloride solution containing the reaction mixture of 4-(tert-butyl)phen-2,6-d2-ol-d (19) was charged CH.sub.2Cl.sub.2 (125 mL, 5 vol). Approximately 125 mL of the reaction solution was distilled from the reactor using a distillation head and heating the reactor to 60° C. To the reactor was charged CH.sub.2Cl.sub.2 (125 mL, 5 vol). Approximately 100 mL of the reaction solution was then distilled from the reactor, and at this time the solution was sampled to confirm water content (KF) was less than 300 ppm and determine the CH.sub.2Cl.sub.2 and heptane content. After measuring the batch volume, CH.sub.2Cl.sub.2 (8 mL, 0.24 vol) was charged to adjust the total CH.sub.2Cl.sub.2 content to 3 vol and heptane (68 mL, 2.8 vol) was charged to adjust the heptane content to 4.5 vol. To the solution was charged tert-butyl acetate-d9 (30.2 g, 1.46 equiv), and the resulting solution was cooled to 0° C. To the solution was charged sulfuric acid-d2 (8.12 g, 0.49 equiv) over at least 15 min, and the solution was agitated for 2 hours while maintaining the temperature at 0-5° C. After this time, the temperature was set to ramp up to 20° C. over two hours and the solution was agitated for another 14 hours. The solution was sampled to confirm 4-tert-butylphenol (14) or 4-(tert-butyl)phen-2,6-d2-ol-d (19) were present at less than 3%. To the reactor was charged CH.sub.2Cl.sub.2 (58 mL, 2.4 vol) and heptane (90 mL, 3.7 vol), and the solution was cooled to 0-5° C. before charging water (125 mL, 5 vol). The mixture was agitated for 15 min before agitation was stopped and the phases were allowed to separate. After the aqueous phase (bottom) was drained from the reactor, 0.5 N aqueous NaOH (125 mL, 5 vol) was charged and the temperature was adjusted to 20° C. The mixture was agitated for 20 min before agitation was stopped and the phases were allowed to separate. The organic phase (top) was sampled to confirm 4-tert-butylphenol (14) or 4-(tert-butyl)phen-2,6-d2-ol-d (18) were present at less than 0.5%. The aqueous phase (bottom) was drained from the reactor. The solution in the reactor was carried on to the next step described below.

Procedure for the Synthesis of 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol (17)

(40) ##STR00128##

(41) After the agitated solution of the alkylation reaction to produce 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phen-6-d-ol-d (18) was brought to 0-5° C., bromine (38.4 g, 1.45 equiv) was charged over at least 1 hour, maintaining the temperature below 5° C. The solution was sampled to confirm 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phen-6-d-ol was present at less than 1%. To the solution was charged sodium metabisulfite (20% w/w aqueous solution, 147 g, 0.95 equiv) over at least 1 hour, maintaining the temperature below 10° C. After adjusting the temperature to 20° C., the mixture was agitated for another 1 hour. Agitation was stopped and the phases were allowed to separate. The aqueous phase (bottom) was drained from the reactor, and water (125 mL, 5 vol) was charged to the reactor. The mixture was agitated for 15 min before stopping agitation and allowing the phases to separate. The aqueous phase (bottom) was drained from the reactor. The solution of 17 in the reactor was carried on to the next step described below.

(42) Surprisingly, this bromination reaction significantly improved the selectivity of the nitration reaction. Another unexpected advantage to this process was that bromination converted the mixture of compound 18 and 4-(tert-butyl)-2,6-bis(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol to the same desired product (17). This significantly improved the overall yield.

Procedure for the Synthesis of 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (16)

(43) ##STR00129##

(44) To the solution of the bromination reaction to produce 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol (17) was charged CH.sub.2Cl.sub.2 (125 mL, 5 vol). Approximately 125 mL of the reaction solution was distilled from the reactor using a distillation head and heating the reactor to 60° C. To the reactor was charge CH.sub.2Cl.sub.2 (125 mL, 5 vol). Approximately 125 mL of the reaction solution was distilled from the reactor. To the reactor was charged CH.sub.2Cl.sub.2 (125 mL, 5 vol). Approximately 125 mL of the reaction solution was then distilled from the reactor, and at this time the solution was sampled to confirm water content (KF) was less than 300 ppm and determine the CH.sub.2Cl.sub.2 and heptane content. After measuring the batch volume, CH.sub.2Cl.sub.2was charged to adjust the total CH.sub.2Cl.sub.2 content to 5.3 vol and heptane was charged to adjust the heptane content to 8 vol. To the solution was charged triethylamine (31.7 g, 1.91 equiv), and the solution was cooled to 0-5° C. To the solution was charged methyl chloroformate (24.1 g, 1.56 equiv) over at least 1 hour, maintaining the temperature below 10° C. The solution was agitated for 1 hour, and a sample of the solution was taken to confirm 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol (17) was present at less than 1%. To the solution was charged 1 N aqueous hydrochloric acid (125 mL, 0.76 equiv) over at least 30 min, maintaining the temperature below 10° C. The temperature was then adjusted to 20° C., and agitation was stopped and the phases were allowed to separate. After the aqueous phase (bottom) was drained from the reactor, water (125 mL, 5 vol) was charged to the reactor. The mixture was agitated for 15 min before agitation was stopped and the phases were allowed to separate. After the aqueous phase (bottom) was drained from the reactor, water (125 mL, 5 vol) was charged to the reactor. The mixture was agitated for 15 min before agitation was stopped and the phases were allowed to separate. The aqueous phase (bottom) was drained from the reactor. The solution of 16 in the reactor was carried on to the next step described below.

Procedure for the Synthesis of 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-3-nitrophenyl methyl carbonate (15)

(45) ##STR00130##

(46) To the solution of the protection reaction to produce 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (16) was charged CH.sub.2Cl.sub.2 (125 mL, 5 vol). Approximately 125 mL of the reaction solution was distilled from the reactor using a distillation head and heating the reactor to 60° C. To the reactor was charged CH.sub.2Cl.sub.2 chloride (125 mL, 5 vol). Approximately 125 mL of the reaction solution was distilled from the reactor. To the reactor was charged CH.sub.2Cl.sub.2 (125 mL, 5 vol). To the reactor was charged CH.sub.2Cl.sub.2 (125 mL, 5 vol). Approximately 125 mL of the reaction solution was distilled from the reactor. Approximately 125 mL of the reaction solution was then distilled from the reactor, and at this time the solution was sampled to confirm water content (KF) was less than 300 ppm and determine the CH.sub.2Cl.sub.2 and heptane content. After measuring the batch volume, CH.sub.2Cl.sub.2 was charged to adjust the total CH.sub.2Cl.sub.2 content to 6 vol and heptane was charged to adjust the heptane content to 9 vol. After cooling the solution to 0-5° C., sulfuric acid (172 g, 10.3 equiv) was charged over at least 30 min, maintaining the temperature below 5° C. To the mixture was charged nitric acid (70% w/w, 19.1 g, 1.31 equiv) over at least 30 min, maintaining the temperature below 10° C. After agitating the mixture for 1 hour, a sample was taken and analyzed to confirm 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (16) was present at less than 1%. To the mixture was charged water (100 mL, 4 vol) over at least 1 hour, maintaining the temperature below 10° C. Agitation was stopped and the phases were allowed to separate, and the aqueous phase (bottom) was drained from the reactor. After resuming agitation, sodium bicarbonate (8% w/w aqueous solution, 100 mL, 4 vol, 0.62 equiv) was charged over at least 10 min, maintaining the temperature below 10° C. The temperature was adjusted to 20° C., agitation was stopped, and the phases were allowed to separate. After draining the aqueous phase (bottom) from the reactor, water (100 mL, 4 vol) was charged to the reactor and the mixture was agitated for 15 min. Agitation was stopped, the phases were allowed to separate, and the aqueous phase (bottom) was drained from the reactor. To the mixture was charged water (100 mL, 4 vol), and this mixture was agitated for 15 min. Agitation was stopped, the phases were allowed to separate, and the aqueous phase (bottom) was drained from the reactor. After marking the solvent level on the reactor, a distillation head was attached and the temperature was set to 80° C. To the solution was charged methanol (570 mL, 23 vol) while distilling at the same time, matching the addition rate to the distillation rate by keeping the solvent level at the mark. Distillation was continued until the batch volume was approximately 264 mL (11 vol) and approximately 1.10 kg of distillate had been removed. The mixture was sampled and analyzed to confirm heptane was present at less than 1% v/v. The temperature was adjusted to 0° C. over 4 hours. The mother liquor was sampled and analyzed to determine the concentration of 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-3-nitrophenyl methyl carbonate (15), and the mixture was filtered. To the reactor was charged methanol (51.1 mL, 2 vol), and this was agitated until the temperature reached 0-5° C. This solution was used to wash the filter cake, and the filter cake was then dried by suction for at least 1 hour. The solid was then submitted to vacuum drying to produce 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-3-nitrophenyl methyl carbonate (15) as 41.5 g of an off-white solid (98.4% pure w/w, 63% yield after purity correction).

Procedure for the Synthesis of 5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (7)

(47) ##STR00131##

(48) Charge 5 wt % (50-65 wt % wet, JM Type 37) of 5% Pd/C to a reactor. Charge (4.0 vol) Methanol. Close the system. Purge with N.sub.2 (g) at 2.0 Bar. Activate with H.sub.2 (g) at 2.0 Bar. Charge the vessel to 2.0 Bar with H.sub.2 (g) at 25° C.+/−5° C. Stir for not less than 2 hours while maintaining a temperature of 25° C.+/−5° C. Vent and purge with N.sub.2 (g) at 2.0 Bar. Charge compound 15 (1.0 eq) to a reactor, together with Na.sub.2HPO.sub.4 (2.3 eq). Charge (11.0 vol) Methanol. Close the system. Purge with N.sub.2 (g) at 2.0 Bar. Activate with H.sub.2 (g) at 2.0 Bar. Charge the vessel to 2.0 Bar with H.sub.2 (g) at 25° C.+/−5° C. Stir for about 24 hours while maintaining a reaction temperature of 25° C.+/−5° C. Upon complete conversion, dilute reaction mixture by adding 7.7 vol of MeOH. Heat reaction mixture to 35.0° C.+/−5° C. Filter off catalyst and Na.sub.2HPO.sub.4. Wash the reactor and filter cake with Methanol (4.0 vol), and filter, combining with the initial filtrate. Check Pd content and if needed perform resin treatment (resin treatment is: Charge SPM-32 resin (5 wt %). Stir the resin treated solution for not less than 3 hours at 35.0° C.+/−5° C. Filter off resin. Wash the reactor and filter cake with Methanol (2.0 vol), and filter, combining with the initial filtrate). Charge Norit CASP active carbon (3 wt %,). Stir for not less than 3 hours at 35.0° C.+/−5° C. Filter off active carbon. Wash the reactor and filter cake with Methanol (2.0 vol), and filter, combining with the initial filtrate. Distill under vacuum at not more than 50° C. to 8.0 vol. Charge water (2.0 vol) while maintaining a temperature of 45° C.+/−5° C. Cool the resultant slurry to 0° C.+/−5° C. over 2 hours. Hold and stir the slurry at 0° C.+/−5° C. for not less than 1 hour. Filter and wash the cake with 2.0 volumes Methanol/Water (8:2) at 0° C.+/−5° C. Dry 5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (7) under vacuum at not more than 40° C. to give a yield of a white solid, >99.5% purity.

Procedure for the Synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate (8)

(49) ##STR00132##

(50) The procedure for the conversion of compound 7 into compound 8 may be performed according to the analogous procedure for compound 5.

Procedure for the Synthesis of N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (2)

(51) ##STR00133##

(52) The procedure for the conversion of compound 8 into compound 2 may be performed according to the analogous procedure for the synthesis of compound 1.

Example 4

Synthesis of 5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (7)

(53) An alternative scheme of the synthesis of compound 7 is shown below, followed by the procedure for the synthesis of each synthetic intermediate.

(54) ##STR00134##

Procedure for the Synthesis of 5-(tert-butyl)-2-hydroxybenzoic acid (15)

(55) ##STR00135##

(56) nBuLi 1.6 M in hexanes (3.49 g) was added to a round bottom flask equipped with a magnetic stirbar, a thermocouple, and a N.sub.2 bubbler. The round bottom flask was cooled down to −20° C. and stirring started. A solution of 2-bromo-4-tert-butylphenol (26) (5.00 g) in MTBE (12.5 mL) was prepared, cooled to −20° C., and charged to the round bottom flask drop wise while maintaining the temperature at −20° C.+/−5° C. The reaction mixture was stirred at −20° C.+/−5° C. for 15 min then allowed to warm up to 23° C. The completeness of the lithiation was measured by .sup.1H NMR (200 μL reaction mixture diluted into 0.75 mL d4-MeOH) after 15 min at room temperature. The reaction was considered complete when less than 1% 2-bromo-4-tert-butylphenol was observed. The reaction mixture was cooled down to 0° C., dry ice (solid CO.sub.2) was added, and the reaction was stirred at room temperature for 45 min. Water (50.0 mL) was added to quench the reaction. The mixture was transferred into a separatory funnel, the phases were separated, and the organic phase was discarded. The aqueous phase was acidified to pH ˜2 with 1 M HCl (15.0 mL), then extracted with MTBE (25.0 mL) three times. The combined organic extracts were concentrated under reduced pressure to yield 5-(tert-butyl)-2-hydroxybenzoic acid (25) as a yellow solid (2.25 g, 53.15% yield); .sup.1H NMR (400 MHz, d4-MeOH): 7.86 (1H, d, J=2.6 Hz), 7.54 (1H, dd, J=8.7, 2.6 Hz), 6.85 (1H, d, J=2.7 Hz), 1.30 (9H, s).

Procedure for the Synthesis of methyl 5-(tert-butyl)-2-hydroxybenzoate (24)

(57) ##STR00136##

(58) This reaction may be performed according to a procedure disclosed in Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, #21, p. 4752-4756.

Procedure for the Synthesis of methyl 2-((tert-butoxycarbonyl)oxy)-5-(tert-butyl)benzoate (23)

(59) ##STR00137##

(60) Di-tert-butyl carbonate (230.55 g) and CH.sub.2Cl.sub.2 (400 mL) were charged to a 1 L reactor and the mixture was stirred until the solids dissolved completely. (Dimethylamino)pyridine (0.587 g) was charged to the stirring solution along with methyl 5-(tert-butyl)-2-hydroxybenzoate (24) (200 g). The reaction mixture was stirred at 15-30° C. and the completeness measured by HPLC (method) with sample aliquots after 60 m. The reaction was considered complete when the peak area of 5-tert-butyl-2-hydroxybenzoate (24) was less than 1%. A half-saturated solution of ammonium chloride was prepared in a separate flask by diluting saturated aqueous ammonium chloride solution (200 mL) with water (200 mL). The reaction mixture was twice washed with half saturated aqueous ammonium chloride solution (200 mL each wash). During each wash, the mixture was stirred for 15 minutes and held for 15 minutes. The organic solution was subsequently washed twice with water (100 mL each wash). During each wash, the mixture was stirred for 15 minutes and held for 15 minutes. The organic solution was transferred to a 1 L round bottom flask and concentrated below 35° C. and under vacuum to yield a white solid (275.51 g and 99.46% purity as measured by HPLC analysis (method), a 93.0% yield of methyl 2-((tert-butoxycarbonyl)oxy)-5-(tert-butyl)benzoate (23)). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.01 (m, 1H); 7.57 (m, 1H); 7.11 (m, 1H); 3.89 (s, 3H); 1.58 (s, 9H); 1.33 (s, 9H).

Procedure for the Synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol (22)

(61) ##STR00138##

(62) THF (176 mL) was charged to a 500 mL jacketed reactor and cooled to 5° C. To the stirring solvent and at 0-35° C. was slowly charged a solution of (methyl-d3)magnesium iodide (60.5 g) in dibutyl ether (145 mL). The resulting slurry was brought to and maintained at 20-30° C. while a solution of 2-((tert-butoxycarbonyl)oxy)-5-(tert-butyl)benzoate (23) (22 g) in THF (44 mL) was charged over 4-6 hours. The reaction mixture was stirred at 20-30° C. and the completeness measured by HPLC with sample aliquots after 60 m. The reaction was considered complete when the peak area of 2-((tert-butoxycarbonyl)oxy)-5-(tert-butyl)benzoate (23) was less than 1%. A second reactor was charged with 6N aqueous hydrochloric acid (110 mL) and the stirring solution was cooled to 0-10° C. The reaction slurry was slowly transferred to the acid solution at 0-35° C. The phases were stirred for 15 m and held for 15 m before being separated. The aqueous phase was extracted with dibutyl ether (132 mL). During the extraction the phases were stirred for 15 m and held for 15 m before being separated. The combined organic phases were washed sequentially with water (2×77 mL), 5% sodium thiosulfate aqueous solution (77 mL), and water (77 mL). During each wash, the mixture was stirred 15 minutes and held 15 minutes. The organic solution was transferred to a round bottom flask and concentrated below 80° C. and under vacuum to yield 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol (22) as a crude oil (5.94 g and 83.8% purity as measured by HPLC analysis with 99.3% D9 isotopic purity by LC/MS analysis, a 84.9% yield of methyl 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol (23)). .sup.1H NMR (400 MHz, CD.sub.3OD): 7.22 (m, 1H); 7.00 (m, 1H); 6.65 (m, 1H); 1.26 (s, 9H).

(63) The Grignard reaction of compound 23 led to some deuterium incorporation in compound 22. To effect H/D exchange, the mixture was subjected to a series of HCl washes:

(64) ##STR00139##
Procedure for H/D Exchange

(65) Charge the deuterated analogs of compound 22 (1.00 equiv) to a reactor. Charge DCM (5 vol). Set jacket to 20° C. Agitate to dissolved solids. Charge 35% hydrochloric acid (5 vol). Agitate to mix the layers for not less than 6 hours. Stop agitation and let the layers settle at least 30 min. Drain the bottom layer (organic) from the reactor. Drain the aqueous layer from the reactor. Charge the organic portion back into the reactor. Repeat HCl wash sequence twice. Charge pre-mixed water (2.5 vol) and sat. aq. NaCl (2.5 vol). Agitate to mix the layers for 30 min. Stop agitation and let the layers settle at least 30 min. Drain the bottom layer (organic) from the reactor. Drain the aqueous from the reactor. Charge the organic portion back into the reactor. Charge water (5 vol). Agitate to mix the layers for 30 min. Stop agitation and let the layers settle at least 30 min. Drain the bottom layer (organic) from the reactor. Drain the aqueous from the reactor. Charge the organic portion back into the reactor. Distill the solvent under reduced pressure to minimal volume (a rotovap with 35° C. bath temperature was used). Charge DCM (5 vol). Distill the solvent under reduced pressure to minimal volume (a rotovap with 35° C. bath temperature was used). Charge DCM (5 vol). Sample the solution and measure water content by KF. Repeat until the water content is less than 300 ppm. Note: This solution was used directly for the next reaction, so the final amount of DCM should be whatever is needed for the alkoxyformylation reaction of compound 22.

Procedure for the Synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (21)

(66) ##STR00140##

(67) The procedure for the conversion of compound 22 into compound 21 may be performed according to the analogous procedure for compound 12.

Procedure for the Synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-5-nitrophenyl methyl carbonate (20)

(68) ##STR00141##

(69) The procedure for the conversion of compound 21 into compound 20 may be performed according to the analogous procedure for compound 11A.

Procedure for the Synthesis of 5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (7)

(70) ##STR00142##

(71) The procedure for the conversion of compound 20 into compound 7 may be performed according to the analogous procedure for compound 4.

Procedure for the Synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate (8)

(72) ##STR00143##

(73) The procedure for the conversion of compound 7 into compound 8 may be performed according to the analogous procedure for compound 5.

Procedure for the Synthesis of N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (2)

(74) ##STR00144##

(75) The procedure for the conversion of compound 8 into compound 2 may be performed according to the analogous procedure for the synthesis of compound 1.

(76) All publications and patents referred to in this disclosure are incorporated herein by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Should the meaning of the terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meaning of the terms in this disclosure are intended to be controlling. Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments of the present disclosure. One skilled in the art will readily recognize from such discussion and from the accompanying drawings and claims, that various changes, modifications, and variations can be made therein without departing from the spirit and scope of the disclosure as defined in the following claims.