METHODS OF MANUFACTURING BENZOQUINOLINE COMPOUNDS

Abstract

The present invention relates to new methods of manufacturing benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), and intermediates thereof.

##STR00001##

Claims

1. A process of preparing a compound of Formula IV: ##STR00030## or a salt thereof, comprising: a step of reacting a compound of Formula II or a salt thereof with a compound of Formula III: ##STR00031## in the presence of a base; wherein: R.sub.7-R.sub.12 and R.sub.15 are independently selected from the group consisting of hydrogen and deuterium; and Y.sub.1 is selected from the group consisting of acetoxy, alkoxy, halogen, haloalkoxy, perhaloalkoxy, heteroalkoxy, and aryloxy, any of which may be optionally substituted.

Description

EXAMPLE 1

N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide

[0227] ##STR00019##

Step 1

[0228] ##STR00020##

Optimization of Reaction Conditions

[0229] General Procedure:

[0230] Dopamine hydrochloride is suspended in ethyl formate at 25-30 C. The suspension is cooled to 10-15 C. and sodium tert-butoxide is added portionwise maintaining the same temperature. The reaction mixture is warmed to 50-55 C. for 12 hours. After completion of the reaction, ethanol is added to the reaction mass and the temperature is maintained for 2 hours. The reaction mass is filtered and washed with 2 volumes of ethanol. The filtrate is concentrated under vacuum and water (0.5 volumes) is added to the residue and stirred for 1 hour at 25-30 C. The solid is filtered and washed with water (0.25 volumes) and dried in an hot air oven at 55-60 C. for 8 hours.

TABLE-US-00001 TABLE 1 Optimization of reaction conditions by varying equivalents of sodium tert-butoxide Exp. Batch Product Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1 250 g Ethyl formate (10 eq) 151 g 63% 98.2% Sodium tert-butoxide (2 eq) Ethanol (5 vol) 50-55 C., 12 hours 2 250 g Ethyl formate (10 eq) 175 g 73% 92.7% Sodium tert-butoxide (1.6 eq) Ethanol (5 vol) 50-55 C., 12 hours 3 50 g Ethyl formate (10 eq) 18.5 g 38% 96.8% Sodium tert-butoxide (1.3 eq) Ethanol (5 vol) 50-55 C., 12 hours 4 50 g Ethyl formate (10 eq) 32.6 g 68% 94.4% Sodium tert-butoxide (1.8 eq) Ethanol (5 vol) 50-55 C., 12 hours

Representative ExampleStep 1

N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide

[0231] Dopamine hydrochloride (250.0 g, 1.323 mol, 1.0 eq) was suspended in ethyl formate (2.5 L, 10.0 vol) at 25-30 C. The suspension was cooled to 10-15 C. and sodium tert-butoxide (202 g, 2.12 mol, 1.60 eq) was added portionwise maintaining the same temperature. The reaction mixture was warmed to 55-60 C. for 12 hours and then concentrated under reduced pressure. To the remaining residue, water (125 mL, 0.5 vol) was added and stirred for 15 minutes. The volatile organic solvents were distilled under vacuum whereupon the product precipitated. The suspension was cooled to 25-30 C. and purified water (500 mL, 2.0 vol) was added. The solid was filtered and washed with water (125 mL, 0.5 vol) and dried in an oven at 55-60 C. for 8 hours to afford the title compound as abrown powder (203 g, yield=84.5%). .sup.1H NMR (300 MHz, CDCl.sub.3), 8.72 (s, broad, 2H), 7.96 (s, 1H), 6.548-6.630 (dd, 2H. J=8.1), 6.407-6.441 (d, 1H, J=2.1), 3.169-3.237 (q, 2H, J=6.9), 2.485-2.535 (t, 2H, J=7.8); LC-MS: m/z=181.92 (MH).sup.+.

EXAMPLE 2

d.SUB.6.-6,7-Dimethoxy-3,4-dihydroisoquinoline Hydrochloride

[0232] ##STR00021##

Step 1

[0233] ##STR00022##

Optimization of Reaction Conditions

[0234] General Procedure:

[0235] N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide is charged with solvent, base, phase transfer catalyst if any, and d.sub.3-methyl iodide (CD.sub.3I) at 25-30 C. The reaction temperature is set and maintained for the specified time. The reaction is filtered, the filtrate distilled under reduced pressure, and the crude product partitioned between dichloromethane (6.0 vol) and water (4.0 vol). The layers are separated and the organic layer is washed twice with 3% aqueous NaOH solution (24.0 vol) followed by water (4.0 vol). The organic layer is distilled under reduced pressure to give crude d.sub.6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide.

TABLE-US-00002 TABLE 2 Optimization of reaction conditions by varying solvent Exp. Batch Product Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1 50 g K.sub.2CO.sub.3 (3 eq) 50 g 86.6% 93.9% CH.sub.3I (2.2 eq) Acetone (8 vol) Tetrabutylammonium bromide (0.05 eq) 38-42 C., 36 hours 2 25 g K.sub.2CO.sub.3 (3 eq) 21 g 75% CH.sub.3I (2.2 eq) Acetonitrile (8 vol) Tetrabutylammonium bromide (0.05 eq) 38-42 C., 36 hours 3 50 g K.sub.2CO.sub.3 (3 eq) Not CH.sub.3I (2.2 eq) isolated 2-Methyl-tetrandrofuran (8 vol) Tetrabutylammonium bromide (0.05 eq) 38-42 C., 36 hours

TABLE-US-00003 TABLE 3 Optimization of reaction conditions by varying solvent volume Exp. Batch Product Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1 20 g K.sub.2CO.sub.3 (3 eq) 22 g 95.3% CH.sub.3I (3 eq) Acetone (6 vol) 18-crown-6 (0.05 eq) 38-42 C., 12 hours 2 100 g K.sub.2CO.sub.3 (3 eq) 116 g ~100% 92.4% CH.sub.3I (3 eq) Acetone (8 vol) 18-crown-6 (0.05 eq) / 38-42 C., 12 hours

TABLE-US-00004 TABLE 4 Optimization of reaction conditions by varying molar equivalents of methyl iodide Exp. Batch Product Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1 50 g K.sub.2CO.sub.3 (3 eq) 44.3 g 76.7% 94.2% CH.sub.3I (2.2 eq) Acetone (8 vol) 28-35 C., 36 hours 2 50 g K.sub.2CO.sub.3 (3 eq) 47.6 g 82.4% 90.9% CH.sub.3I (2.4 eq) Acetone (8 vol) 28-35 C., 36 hours 3 50 g K.sub.2CO.sub.3 (3 eq) 48 g 83.0% 93.5% CH.sub.3I (2.6 eq) Acetone (8 vol) 28-35 C., 36 hours

TABLE-US-00005 TABLE 5 Optimization of reaction conditions by varying reaction temperature Exp. Batch Product Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1 200 g K.sub.2CO.sub.3 (3 eq) 198.9 g 83.7% 93.1% CD.sub.3I (2.2 eq) Acetone (8 vol) 28-35 C., 36 hours 2 25 g K.sub.2CO.sub.3 (3 eq) 21 g 72.9% 95.8% CH.sub.3I (2.2 eq) Acetone (8 vol) 38-40 C., 36 hours

TABLE-US-00006 TABLE 6 Optimization of reaction conditions by varying phase transfer catalyst and methyl iodide equivalents Phase Exp. Batch Transfer CH.sub.3I Base Solvent/ No. Size Catalyst (eq) (eq) (eq) Conditions Result 1 10 g Tetrabutyl 3 K.sub.2CO.sub.3 Acetone Worked well ammonium (3.0) 35-45 C., bromide 45 hours (0.05) 2 10 g Tetrabutyl 3 K.sub.2CO.sub.3 Acetone Worked well ammonium (3.0) 35-45 C., bromide 45 hours (0.08) 3 10 g None 2.2 Cs.sub.2CO.sub.3 Acetone 1.5% Formanide (2.0) 35-45 C., methylation, 5% 20 hours monomethylated phenol remaining 4 10 g None 2.5 Cs.sub.2CO.sub.3 Acetone 2% Formanide (2.0) 35-45 C., methylation, 3% 20 hours monomethylated phenol remaining 5 10 g Tetrabutyl 2.2 K.sub.2CO.sub.3 Acetone Worked well ammonium (3.0) 35-45 C., bromide 20 hours (0.05) 6 10 g Tetrabutyl 2.5 K.sub.2CO.sub.3 Acetone Worked well ammonium (3.0) 35-45 C., bromide 20 hours (0.05)

TABLE-US-00007 TABLE 7 Optimization of reaction conditions by varying phase transfer catalyst Exp. Batch Product Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1 30 g K.sub.2CO.sub.3 (3 eq) 28 g 82.3% CH.sub.3I (2.2 eq) Acetone (8 vol) Tetrabutyl ammonium bromide (0.05) 38-42 C., 36 hours 2 25 g K.sub.2CO.sub.3 (3 eq) 24 g 81% CH.sub.3I (2.2 eq) Acetone (8 vol) 18-Crown-6 (0.1) 38-42 C., 36 hours 3 25 g K.sub.2CO.sub.3 (3 eq) 23 g 79.8% 83.4% CH.sub.3I (2.2 eq) Acetone (8 vol) Tetrabutyl ammonium iodide (0.05) 38-42 C., 36 hours

TABLE-US-00008 TABLE 8 Optimization of reaction conditions by varying phase transfer catalyst quantity Exp. Batch Product Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1 50 g K.sub.2CO.sub.3 (3 eq) 50 g 86.6% 93.9% CH.sub.3I (2.2 eq) Acetone (8 vol) Tetrabutyl ammonium bromide (0.05) 38-42 C., 36 hours 2 25 g K.sub.2CO.sub.3 (3 eq) 22 g 76.3% 90.78% CH.sub.3I (2.2 eq) Acetone (8 vol) Tetrabutyl ammonium bromide (0.01) 38-42 C., 36 hours 3 25 g K.sub.2CO.sub.3 (3 eq) 21 g 72.9% 95.85% CH.sub.3I (2.2 eq) Acetone (8 vol) Without tetrabutyl ammonium bromide 38-42 C., 36 hours

Representative ExampleStep 1

d.SUB.6.-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide

[0236] N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide (190 g, 1.049 mol, 1.00 eq) was charged with acetone (1.52 L, 8.0 vol), followed by K.sub.2CO.sub.3 (434 g, 3.149 mol, 3.00 eq) at 25-30 C. CD.sub.3I (334 g, 2.309 mol, 2.20 eq) was added to the reaction mixture over 1 hour at 25-30 C. The reaction temperature was maintained for 36 hours at 25-35 C. The reaction was filtered, the filtrate was distilled under reduced pressure, and the crude product was partitioned between dichloromethane (1.14 L, 6.0 vol) and water (760 mL, 4.0 vol). The layers were separated and the organic layer was washed twice with 3% aqueous NaOH solution (2760 mL, 24.0 vol) followed by water (760 mL, 4.0 vol). The organic layer was distilled under reduced pressure to give 158 g crude d.sub.6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide.

Step 2

[0237] ##STR00023##

Optimization of Reaction Conditions

[0238] General Procedure:

[0239] N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide is charged with solvent and POCl.sub.3 at 10-15 C. The mixture is heated to an elevated temperature for 1 or 2 hours and then is cooled to ambient temperature, after which a quenching solvent (for example, a protic solvent such as an alcohol) is added and the mixture is stirred for 1 hour followed by addition of an anti-solvent if applicable. In some cases, d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride precipitates in the form of a salt directly from the reaction mixture. In others, d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinoline is isolated after acid-base workup.

TABLE-US-00009 TABLE 9 Optimization of reaction conditions by varying the solvent Exp. Batch Reaction Quenching/ Product Product HPLC No. Size Conditions Anti-Solvent Quantity Yield Purity 1 93 g POCl.sub.3 (1 eq) None 49 g 57.6% 90.0% Acetonitrile (10 vol) 80-85 C., 2 hours 2 200 g POCl.sub.3 (1 eq) None 112 g 61.5% 84.6% Toluene (2 vol) 90-95 C., 1 hours 3 20 g POCl.sub.3 (1 eq) None sticky MTBE* (4 vol) mass 0-30 C. 4 20 g POCl.sub.3 (1 eq) None sticky DCM* (2 vol) mass 0-30 C. *DCM = Dichloromethane; MTBE = Methyl tert-butyl ether.

TABLE-US-00010 TABLE 10 Optimization of reaction conditions by varying quenching solvent and anti-solvent freaction solvent toluene) Exp. Batch Reaction Quenching/ Product HPLC No. Size Conditions Anti-Solvent Quantity Yield Purity 1 48 g POCl.sub.3 (1.8 eq) Ethanol Product Toluene (2 vol) (3.8 eq) not 90-95 C., MTBE* obtained 1 hour (4 vol) as a free solid 2 48 g POCl.sub.3 Ethanol 20.2 g 46% 91.9% (distilled,1.8 eq) (3.8 eq) Toluene (2 vol) MTBE* 90-95 C., (4 vol) 1 hour 3 50 g POCl.sub.3 (1 eq) Ethyl 35 g 76% Toluene (2 vol) Acetate 90-95 C., (2 vol) Ethyl Acetate/ 1 hour HCl (2 vol) 4 20 g POCl.sub.3 (distilled, Ethanol Product 1.8 eq) (2.4 eq) not Toluene (2 vol) MTBE* obtained 40-45 C., (4 vol) as a free 1 hour solid 5 50 g POCl.sub.3 (distilled, Ethanol Product 1.8 eq) (3.8 eq) not Toluene (2 vol) MTBE* obtained (4 vol) as a free 80-85 C., solid 1 hour, seeded with product 6 28 g POCl.sub.3 (1.8 eq) Ethanol 24 g >100% Isolated Toluene (2 vol) (3.8 eq) by 90-95 C., MTBE* acid- 2 hours (4 vol) base workup 7 25 g POCl.sub.3 (1.8 eq) IPA* 14.5 g 53.2% 80.2% Toluene (2 vol) (3.8 eq) (black 90-95 C., MTBE* solid) 2 hours (4 vol) 12 hours 8 25 g POCl.sub.3 (1.8 eq) 1-Butanol 20.1 g 73.5% 80.1% Toluene (2 vol) (3.8 eq) (black 90-95 C., MTBE* solid) 2 hours (4 vol) 12 hours 9 25 g POCl.sub.3 (1.8 eq) 1-Propanol Product Toluene (2 vol) (3.8 eq) not 90-95 C., Cyclohexane obtained 2 hours (4 vol) as a free 12 hours solid *IPA = Isopropyl alcohol; MTBE = Methyl tert-butyl ether.

TABLE-US-00011 TABLE 11 Optimization of reaction conditions by varying quenching solvent and anti-solvent freaction solvent acetonitrile) Exp. Batch Reaction Quenching/ Product HPLC No. Size Conditions Anti-Solvent Quantity Yield Purity 1 100 g POCl.sub.3 Ethanol 110 g 93.3% (1.8 eq) (3.8 eq) (hygro- Acetonitrile MTBE* scopic) (2 vol) (4 vol) 80-85 C., 12 hours, 1 hour seededwith product 2 25 g POCl.sub.3 IPA* 17 g 62.4% 87.1% (1.8 eq) (3.8 eq) (black Acetonitrile MTBE* solid) (2 vol) (4 vol) 80-85 C., 12 hours, 2 hours 3 25 g POCl.sub.3 1-Butanol 17.3 g 63.8% 95.6% (1.8 eq) (3.8 eq) (grey Acetonitrile MTBE* solid) (2 vol) (4 vol) 80-85 C., 12 hours 2 hours 5 25 g POCl.sub.3 t-Butanol Solid not (1.8 eq) (3.8 eq) isolated Acetonitrile MTBE* (2 vol) (4 vol) 80-85 C., 12 hours 2 hours 6 25 g POCl.sub.3 ( 1-Propanol 17 g 62.4% 88.8% 1.8 eq) (3.8 eq) (gray Acetonitrile MTBE* solid) (2 vol) (4 vol) 80-85 C., 12 hours 2 hours 7 25 g POCl.sub.3 1-Pentanol 13.4 g 49.2% Brown (1.8 eq) (3.8 eq) solid Acetonitrile MTBE* (2 vol) (4 vol) 80-85 C., 12 hours 2 hours 8 25 g POCl.sub.3 2-methyl 12.77 g 46.9% 87.6% (1.8 eq) propanol (gray Acetonitrile (3.8 eq) solid) (2 vol) MTBE* 80-85 C., (4 vol) 2 hours 12 hours *IPA = Isopropyl alcohol; MTBE = Methyl tert-butyl ether.

TABLE-US-00012 TABLE 12 Optimization of reaction conditions by varying anti-solvent (reaction solvent acetonitrile, 1-butanol as a quenching solvent) Exp. Batch Reaction Quenching/ Product Product HPLC No. Size Conditions Anti-Solvent Quantity Yield Purity 1 25 g POCl.sub.3 (1.8 eq) 1-butanol 13.3 g 48.8% 91.9% Acetonitrile (3.8 eq) (2 vol) Ethyl acetate 80-85 C., (4 vol) 2 hours 12 hours 2 25 g POCl.sub.3 (1.8 eq) 1-butanol 14.83 g 54.5% 94.4% Acetonitrile (3.8 eq) (2 vol) Isopropyl 80-85 C., acetate 2 hours (4 vol) 12 hours 3 25 g POCl.sub.3 (1.8 eq) 1-butanol 14.2 g 52.2% 93.3% Acetonitrile (3.8 eq) (2 vol) 2-methyl- 80-85 C., THF* 2 hours (4 vol) 12 hours 4 25 g POCl.sub.3 (1.8 eq) 1-butanol 13.0 g 47.7% 94.2% Acetonitrile (3.8 eq) (2 vol) Ethyl 80-85 C., acetate/HCl 2 hours (4 vol) 12 hours 5 25 g POCl.sub.3 (1.8 eq) 1-butanol 18.3 g 67.2% 93.5% Acetonitrile (3.8 eq) (2 vol) MTBE* 80-85 C., (4 vol) 2 hours 12 hours 6 25 g POCl.sub.3 (1.8 eq) 1-butanol 17.5 g 64.3% 91.3% Acetonitrile (3.8 eq) (2 vol) MTBE* 80-85 C., (8 vol) 2 hours 12 hours *MTBE = Methyl tert-butyl ether; 2-methyl-THF = 2-methyltetrahydrofuran (4 vol).

TABLE-US-00013 TABLE 13 Optimization of reaction conditions by varying equivalents of 1-butanol (reaction solvent acetonitrile, 1-butanol as a quenching solvent) Exp. Batch Reaction Quenching/ Product Product HPLC No. Size Conditions Anti-Solvent Quantity Yield Purity 1 25 g POCl.sub.3 1-butanol 14.7 g 54% 84.1% (1.8 eq) (6.0 eq) Acetonitrile MTBE* (2 vol) (4 vol) 80-85 C., 12 hours 2 hours 2 28 g POCl.sub.3 1-butanol 21.3 g 70% 94.6% (1.8 eq) (3.8 eq) Acetonitrile MTBE* (2 vol) (4 vol) 80-85 C., 12 hours 2 hours *MTBE = Methyl tert-butyl ether;

TABLE-US-00014 TABLE 14 Optimization of reaction conditions by using methyl tert-butyl ether as reaction solvent and varying the quenching solvent Exp. Batch Reaction Quenching/ Product Product HPLC No. Size Conditions Anti-Solvent Quantity Yield Purity 1 25 g POCl.sub.3 (1.8 eq) Ethanol Solid not MTBE* (4 vol) (3.8 eq) isolated 55-60 C., 12 hours 2 hours 2 25 g POCl.sub.3 (1.8 eq) 1-butanol 10.5 g 38.5% 74.4% MTBE* (4 vol) (3.8 eq) (brown 45-50 C., 12 hours solid) 2 hours *MTBE = Methyl tert-butyl ether;

TABLE-US-00015 TABLE 15 Optimization of reaction conditions by varying the equivalents of POCl.sub.3 used Exp. Batch Reaction Quenching/ Product Product HPLC No. Size Conditions Anti-Solvent Quantity Yield Purity 1 50 g POCl.sub.3 (0.5 eq) 1-butanol Product Acetonitrile (3.8 eq) obtained (2 vol) MTBE* as a 80-85 C., (4 vol) gummy 2 hours 12 hours solid 2 50 g POCl.sub.3 (1.0 eq) 1-butanol Product Acetonitrile (3.8 eq) obtained (2 vol) MTBE* as a 80-85 C., (4 vol) gummy 2 hours 12 hours solid 3 25 g POCl.sub.3 (1.8 eq) 1-butanol 17.3 g 63.8% 98.6% Acetonitrile (3.8 eq) (2 vol) MTBE* 80-85 C., (4 vol) 2 hours 12 hours

Representative ExampleStep 2

d.SUB.6.-6,7-Dimethoxy-3,4-dihydroisoquinoline Hydrochloride

[0240] To the crude d.sub.6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide from step 1, (158 g, 0.734 mol, 1.00 eq), acetonitrile (316 mL, 2.0 vol) was added followed by POCl.sub.3 (202 g, 1.322 mol, 1.80 eq) at 10-15 C. The reaction mixture was heated to reflux for 2 hours and then cooled to 25-35 C. The temperature was maintained for 12 hours after which it was quenched with n-butanol (255 mL, 2.79 mol, 3.8 eq) and methyl ter-butyl ether (1.26 L, 8.0 vol). The precipitated product was filtered, washed with ethyl acetate (632 mL, 4.0 vol), and dried under vacuum. The crude product was further purified by slurrying in 10%/Ethanol in MTBE (944 mL, 8.0 vol) whereupon an orange brown product (108 g, yield=44.0%) was obtained after drying. .sup.1H NMR (300 MHz, CDCl.sub.3), 14.456 (br s, 1H), 9.105-9.133 (d, 1H, J 8.4), 7.497 (s, 1H), 6.806 (s, 1H), 3.951-4.000 (t, 2H, J=7.5), 3.089-3.144 (t, 2H, J=8.4); LC-MS: m/z=198.06 (MH).sup.+.

Step 3Optional Purification of d.SUB.6.-6,7-dimethoxy-3,4-dihydroisoguinoline Hydrochloride

[0241] To increase the purity of d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride various purification procedures were attempted.

TABLE-US-00016 TABLE 16 Recrystallization of d.sub.6-6,7-dimethoxy- 3,4-dihydroisoquinoline hydrochloride Exp. Batch Product Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1 5 g 6,7-Dimethoxy-3,4- 2.1 g 42% 94.5% dihydroisoquinoline hydrochloride (1 eq) Ethanol (3 vol) 60-65 C., 1 hour Cooled and filtered at 25-30 C. 2 5 g 6,7-Dimethoxy-3,4- 1.4 g 28.0% 89.0% dihydroisoquinoline hydrochloride (1 eq) Ethanol (8 vol) 75-80 C., 16 hours Cooled and filtered at 25-30 C. 3 5 g 6,7-Dimethoxy-3,4- 1.02 g 20.4% 84.8% dihydroisoquinoline hydrochloride (1 eq) 1-Propanol (8 vol) 95-100 C., 16 hours Cooled and filtered at 25-30 C. 4 5 g 6,7-Dimethoxy-3,4- 0.85 g 17.0% 76.0% dihydroisoquinoline hydrochloride (1 eq) 1-Butanol (8 vol) 115-120 C., 16 hours Cooled and filtered at 25-30 C. 5 5 g 6,7-Dimethoxy-3,4- 1.19 g 23.8% 85.7% dihydroisoquinoline hydrochloride (1 eq) 1-Pentanol (8 vol) 135-140 C., 16 hours Cooled and filtered at 25-30 C.

TABLE-US-00017 TABLE 17 Reslurry and washing of d.sub.6-6,7-dimethoxy- 3,4-dihydroisoquinoline hydrochloride Exp. Batch Product Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1 2 g 6,7-Dimethoxy-3,4- 1.75 g 83.3% 93.3% dihydroisoquinoline hydrochloride (1 eq) Acetone (3 vol) Stirred at 25-30 C. for 2 hours, then filtered and dried 2 2 g 6,7-Dimethoxy-3,4- 1.21 g 60% 94.5% dihydroisoquinoline hydrochloride (1 eq) Acetonitrile (2 vol) Stirred at 25-30 C. for 2 hours, then filtered and dried 3 2 g 6,7-Dimethoxy-3,4- 1.35 g 67.5% dihydroisoquinoline hydrochloride (1 eq) Ethanol/acetonitrile/acetone (1:1:8) (3 vol) Stirred at 25-30 C. for 2 hours, then filtered and dried 4 2 g 6,7-Dimethoxy-3,4- 1.78 g 89% dihydroisoquinoline hydrochloride (1 eq) Methanol/ethyl acetate (5:95) (3 vol) Stirred at 25-30 C. for 2 hours, then filtered and dried 5 2 g 6,7-Dimethoxy-3,4- 1.34 g 67% dihydroisoquinoline hydrochloride (1 eq) Methanol/ethyl acetate (5:95) (3 vol) Stirred at 25-30 C. for 1 hour, then filtered and dried 6 2 g 6,7-Dimethoxy-3,4- 1.46 g 73% dihydroisoquinoline hydrochloride (1 eq) Ethanol/acetone/ ethyl acetate (1:1:8) (3 vol) Stirred at 25-30 C. for 1 hour, then filtered and dried 7 1 g 6,7-Dimethoxy-3,4- 0.55 g 55% dihydroisoquinoline hydrochloride (1 eq) Ethanol/ethyl acetate (1:9) (3 vol) Stirred at 25-30 C. for 1 hour, then filtered and dried 8 5 g 6,7-Dimethoxy-3,4- 4.8 g 96.0% 93.5% dihydroisoquinoline hydrochloride (1 eq) Ethyl acetate (5 vol) Stirred at 28-32 C. for 16 hours, then filtered and dried 9 5 g 6,7-Dimethoxy-3,4- 4.87 g 97.4% 79.1% dihydroisoquinoline hydrochloride (1 eq) Methyl tert-butyl ether (5 vol) Stirred at 28-32 C. for 16 hours, then filtered and dried 10 5 g 6,7-Dimethoxy-3,4- 4.31 g 86.2% 94.1% dihydroisoquinoline hydrochloride (1 eq) Acetone (3 vol) Stirred at 28-32 C. for 16 hours, then filtered and dried 11 5 g 6,7-Dimethoxy-3,4- 1.63 g 32.6% 90.9% dihydroisoquinoline hydrochloride (1 eq) Acetonitrile (3 vol) Stirred at 28-32 C. for 16 hours, then filtered and dried 12 5 g 6,7-Dimethoxy-3,4- 3.4 g 68% 91.7% dihydroisoquinoline hydrochloride (1 eq) Methyl tert-butyl ether (6 vol) 50-55 C. 1-butanol (12 vol) Stirred at 28-32 C. for 16 hours, then filtered and dried 13 5 g 6,7-Dimethoxy-3,4- 4.3 g 86% 87.6% dihydroisoquinoline hydrochloride (1 eq) Methyl tert-butyl ether/ethanol (9:1) (6 vol) Stirred at 28-32 C. for 16 hours, then filtered and dried 14 150 g 6,7-Dimethoxy-3,4- 138 g 92% 99.0% dihydroisoquinoline hydrochloride (1 eq) Methyl tert-butyl ether/ethanol (9:1) (6 vol) Stirred at 28-32 C. for 16 hours, then filtered and dried

EXAMPLE 3

(RR, SS)-1,3,4,6,7-11b-Hexahydro-9,10-di(methoxy-d.SUB.3.)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one((+/)-d.SUB.6.-Tetrabenazine)

[0242] ##STR00024##

Step 1

[0243] ##STR00025##

Representative ExampleStep 1

2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium Iodide

[0244] 3-[(dimethylamino)methyl]-5-methyl-hexan-2-one (90 g, 0.526 mol, 1.00 eq) was charged with methyl tert-butyl ether (1.35 L, 15.0 vol) and cooled 0-10 C. Methyl iodide (171 g, 1.209 mol, 2.3 eq) was added slowly to the reaction mixture and stirred for 15 hours at 25-35 C. The reaction was warmed to 35-40 C. for 2 hours. The precipitated solid was filtered under nitrogen and was washed with methyl tert-butyl ether (900 mL, 10.0 vol). The crude product was further purified by slurrying in ethyl acetate (1.46 L, 10 vol) and filtered to give 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide (146 g) as a white solid.

Step 2

[0245] ##STR00026##

Optimization of Reaction Conditions

[0246] General Procedure:

[0247] 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide is charged to a suspension containing d.sub.6-6,7-dimethoxy-3, 4-dihydroisoquinoline (hydrochloride or freebase, 1.00 eq) and solvent. If d.sub.6-6,7-dimethoxy-3, 4-dihydroisoquinoline hydrochloride is used, a base is added to the reaction mixture at room temperature. The reaction mixture is stirred at the appropriate temperature, cooled, and water is added. The reaction mass is filtered and the solids are washed with water and dried to afford the title compound [The (RR, SS)-diastereomer of d.sub.6-tetrabenazine is the desired product].

TABLE-US-00018 TABLE 18 Optimization of the reaction by varying the solvent Exp. Batch Product Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1 30 g 6,7-Dimethoxy-3,4- 20.3 g 40.7% 98.8% dihydroisoquinoline 0.56% free base (1 eq) Dia- 2-acetyl-N,N,N,4- stereomer tetramethyl-1- impurity* pentanaminium iodide Water (6 vol) 100 C., 48 hour 2 10 g 6,7-Dimethoxy-3,4- 1.4 g 8.3% 97.8% dihydroisoquinoline 1.45% free base (1 eq) Dia- 2-acetyl-N,N,N,4- stereomer tetramethyl-1- impurity* pentanaminium iodide (0.75 eq) Methanol (6 vol) 65-70 C., 48 hour 3 10 g 6,7-Dimethoxy-3,4- 1.4 g 8.3% 98.1% dihydroisoquinoline 0.75% free base (1 eq) Dia- 2-acetyl-N,N,N,4- stereomer tetramethyl-1- impurity* pentanaminium iodide (0.75 eq) Ethanol (6 vol) 75-80 C., 48 hour 4 10 g 6,7-Dimethoxy-3,4- 6.8 g 40.8% 99.1% dihydroisoquinoline 0.04% free base (1 eq) 2-acetyl- Dia- N,N,N,4-tetramethyl-1- stereomer pentanaminium iodide impurity* (0.75 eq) Methanol/water (1:1) (6 vol) 45-50 C., 90 hour *The diastereomer impurity is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.
Tables 19 and 20in-Process HPLC Results

TABLE-US-00019 Ex. 2Methanol Ex. 3Ethanol Diaster- Diaster- Time SM* Product eomer* SM* Product eomer* 6 h 17.2% 12.5% 2.6% 3.3% 12.4% 3.0% 18 h 4.3% 17.1% 3.8% 0.2% 14.6% 3.9% 24 h 1.2% 16.8% 4.5% 0.1% 17.2% 5.2% 30 h 0.5% 14.0% 3.2% 0.3% 12.4% 3.3% 42 h 0.3% 12.3% 3.1% 0.2% 9.6% 2.6% 48 h 0.3% 12.1% 2.9% 0.2% 12.0% 2.9% Product 97.8% 1.4% 98.1% 0.75% Wt (g) 1.38 Wt (g) 1.38 Y (%) 8.3 Y (%) 8.3 *SM = Starting material[6,7-Dimethoxy-3,4-dihydro isoquinoline]; The diastereomer impurity is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.

TABLE-US-00020 Ex. 4-Methanol:Water (1:1) Time SM* Product Diastereomer* 6 h 18 h 3.1% 21% 0.7% 24 h 30 h 42 h 1.8% 23.9% 0.5% 48 h 90 h 28.1% 1.0% Product 99.1% 0.04% Wt (g) 6.78 g Y (%) 40.8 *SM = Starting material-[6,7-Dimethoxy-3,4-dihydro isoquinoline]; The diastereomer impurity is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.

TABLE-US-00021 TABLE 21 Optimization of the reaction by varying the reaction temperature Exp. Batch Product Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1 8 g 6,7-Dimethoxy-3,4-di- 8.3 g 74.5% 99.1% hydroisoquinoline hydro- 0.04% chloride (1 eq) 2-acetyl- Dia- N,N,N,4-tetramethyl- stereomer 1-pentanaminium impurity* iodide (1.08 eq) Methanol/water (1:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 63 hour 2 8 g 6,7-Dimethoxy-3,4-di- 8.5 g 76.7% 99.1% hydroisoquinoline hydro- 0.04% chloride (1 eq) 2-acetyl- Dia- N,N,N,4-tetramethyl- stereomer 1-pentanaminium impurity* iodide (1.08 eq) Methanol/water (1:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 25-30 C., 63 hour 3 8 g 6,7-Dimethoxy-3,4-di- 8.3 g 75% 99.1% hydroisoquinoline hydro- 0.1% chloride (1 eq) 2-acetyl- Dia- N,N,N,4-tetramethyl- stereomer 1-pentanaminium impurity* iodide (1.08 eq) Methanol/water (1:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 65-70 C., 63 hour *The diastereomer impurity is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.
Tables 22 and 23in-Process HPLC Results

TABLE-US-00022 Ex. 3Methanol:Water (1:1) 65-70 C. Ex. 2Methanol:Water (1:1) 45-50 C. Hours SM* Product Diastereomer* SM* Product Diastereomer* 15 h 0.8% 8.1% 0.5% 23.5% 0.1% 23 h 33.1% 0.5% 17.1% 0.2% 39 h 14.3% 0.4% 22.0% 0.1% 47 h 17.9% 0.5% 35.9% 0.3% 63 h 44.4% 0.8% 58.2% 0.4% Crude 88.6% 1.8% 92.3% 0.6% After 91.6% 1.3% 95.2% 0.6% EA Final 99.19% 0.1% 99.15% 0.04% Product Wt (g) 8.38 Wt (g) 8.32 Y (%) 75 Y (%) 74.5 *SM = Starting material[6,7-Dimethoxy-3,4-dihydro isoquinoline]; The diastereomer impurity is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.

TABLE-US-00023 Ex.1-Methanol:Water (1:1) 25-30 C. Hours SM* Product Diastereomer* 15 h 31.6% 0.2% 23 h 29.5% 0.2% 39 h 35.2% 0.2% 47 h 20.9% 0.1% 63 h 63.4% 0.3% Crude 95.7% 0.5% After 95.5% 0.4% EA* treat- ment Final 99.16% 0.04% Product Wt (g) 8.56 Y (%) 76.7 *SM = Starting material-[6,7-Dimethoxy-3,4-dihydro isoquinoline]; EA = Ethyl Acetate; The diastereomer impurity is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.

TABLE-US-00024 TABLE 24 Optimization of the reaction by varying the solvent mixture ratio Exp. Batch Product Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1 8 g 6,7-Dimethoxy-3,4- 8.5 g 76.9% 98.9% dihydroisoquinoline 0.09% hydrochloride (1 eq) undesired 2-acetyl-N,N,N,4- isomer tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/ water (1:3) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 63 hour 2 8 g 6,7-Dimethoxy-3,4- 8.6 g 77.1% 99.6% dihydroisoquinoline 0.03% hydrochloride (1 eq) undesired 2-acetyl-N,N,N,4- isomer tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/ water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 63 hour 3 10 g 6,7-Dimethoxy-3,4- 9.6 g 68.9% 99.3% dihydroisoquinoline off-white hydrochloride (1 eq) product 2-acetyl-N,N,N,4- tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/ water (4:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C, 63 hour 4 10 g 6,7-Dimethoxy-3,4- 7.6 g 54.4% 99.2% dihydroisoquinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4- tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 63 hour
Tables 25 and 26in-Process HPLC Results

TABLE-US-00025 Ex. 1Methanol:Water (1:3) Ex. 2Methanol:Water 45-50 C. (3:1) 45-50 C. Hours SM* Product Diatereomer* SM* Product Diastereomer* 24 h 44.7% 0.4% 18.6% 0.5% 48 h 54.8% 0.6% 18.9% 0.5% 63 h 70.0% 0.8% 16.0% 0.8% Crude 91.1% 1.3% 98.5% 0.4% After 92.6% 1.0% 98.7% 0.4% EA* treatment Final 98.98% 0.09% 99.64% 0.03% Product Wt(g) 8.59 8.61 Y (%) 76.9 77.1 *SM = Starting material[6,7-Dimethoxy-3,4-dihydro isoquinoline]; EA = Ethyl Acetate; The diastereomer impurity is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.

TABLE-US-00026 Ex. 3 - Methanol:Water (4:1) 45-50 C. Ex. 4 - Methanol, 45-50 C. Hours SM* Product Diastereomer* SM* Product Diastereomer* 24 h 48 h 63 h 17.75% 2.57% 17.75% 2.57% Crude 97.97% 0.59% 97.97% 0.59% After EA* 98.15% 0.35% 98.15% 0.35% treatment Final 99.28% 0.03% 99.28% 0.03% 7.58 7.58 Product 54.4 54.4 *SM = Starting material - [6,7-Dimethoxy-3,4-dihydro isoquinoline ]; EA = Ethyl Acetate; The diastereomer impurity is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.

TABLE-US-00027 TABLE 27 Optimization of the reaction by varying the reaction time Exp. Batch Product Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1 10 g 6,7-Dimethoxy-3,4-dihydroiso- 8.5 g 61% 99.2% quinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 24 hour 2 10 g 6,7-Dimethoxy-3,4-dihydroiso- 9.4 g 67.4% 99.5% quinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 48 hour 3 10 g 6,7-Dimethoxy-3,4-dihydroiso- 9.2 g 66% 99.2% quinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 63 hour
Tables 28 and 29in-Process HPLC Results

TABLE-US-00028 Ex. 1Methanol:Water (3:1) 45-50 C., Ex. 2Methanol:Water (3:1) 45 C., 24 h 48 h Hours SM* Product Diastereomer* SM* Product Diastereomer* 24 h 1.52% 15.65% 1.38% 48 h 23.73% 0.66% 63 h Crude 92.1% 1.96% 91.83% 1.53% After 91.96% 1.17% 91.64% 1.57% EA* treatment Final 99.25% 0.08% 99.58% 0.03% Product Wt (g) 8.5 Wt (g) 9.4 Y (%) 61 Y (%) 67.4 *SM = Starting material[6,7-Dimethoxy-3,4-dihydro isoquinoline]; EA = Ethyl Acetate; The diastereomer impurity is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.

TABLE-US-00029 Ex. 3-Methanol:Water (3:1) 45C., 63 h Hours SM* Product Diastereomer* 24 h 48 h 63 h 13.63% 0.71% Crude 98.43% 0.34% After 98.24% 0.45% EA* treat- ment Final 99.29% 0.04% Product Wt (g) 9.2 Y (%) 66.0 *SM = Starting material-[6,7-Dimethoxy-3,4-dihydro isoquinoline]; EA = Ethyl Acetate; The diastereomer impurity is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.

TABLE-US-00030 TABLE 30 Comparison of d.sub.0-6,7-dimethoxy-3,4-dihydroiso-quinoline hydrochloride and d.sub.6-6,7- dimethoxy-3,4-dihydroiso-quinoline hydrochloride Exp. Batch Product Product HPLC No. Size Reaction Conditions Quantity Yield Purity 1 10 g d.sub.0-6,7-Dimethoxy-3,4-dihydro 9.4 g 67.4% 99.5% isoquinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 48 hours 2 10 g d.sub.6-6,7-Dimethoxy-3,4-dihydro 9.96 g 72.0% 99.9% isoquinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 48 hours 3 10 g d.sub.6-6,7-Dimethoxy-3,4-dihydro 9.4 g 68.3% 99.8% isoquinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 48 hours 4 125 g d.sub.6-6,7-Dimethoxy-3,4-dihydro 125.7 g 72.77% 99.64% isoquinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4-tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 48 hours

TABLE-US-00031 TABLE 31 Optimization by varying the purity of 6,7-dimethoxy-3,4- dihydro isoquinoline hydrochloride Batch Exp. Size Product Product HPLC No. (Purity) Reaction Conditions Quantity Yield Purity 1 10 g 6,7-Dimethoxy-3,4-dihydro 9.2 g 66% 99.5% (87.1%) isoquinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4- tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/ water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 63 hours 2 8 g 6,7-Dimethoxy-3,4-dihydro 8.61 g 77.1% 99.9% (90.3%) isoquinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4- tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/ water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 63 hours 3 4 g 6,7-Dimethoxy-3,4-dihydro 4.72 g 84.7% 99.8% (99.0%) isoquinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4- tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/ water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 63 hours 4 50 g 6,7-Dimethoxy-3,4-dihydro 59.7 g 85.6% 99.64% (99.0%) isoquinoline hydrochloride (1 eq) 2-acetyl-N,N,N,4- tetramethyl-1- pentanaminium iodide (1.08 eq) Methanol/ water (3:1) (6 vol) K.sub.2CO.sub.3 (1 eq) 45-50 C., 63 hours

Representative ExampleStep 2

(RR,SS)-1,3,4,6,7-11b-Hexahydro-9,10-di(methoxy-dj)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one

[0248] The 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide from step 1 (146 g) was charged to a suspension containing d.sub.6-6,7-dimethoxy-3, 4-dihydroisoquinoline hydrochloride (90 g, 0.385 mol, 1.00 eq), methanol (405 mL, 4.5 vol) and water (135 mL, 1.5 vol) at 25-30 C. To the reaction mixture K.sub.2CO.sub.3 (54 g, 0.385 mol, 1.00 eq) was added at 25-30 C. and stirred at 40-45 C. for 30 hours. The reaction mixture was cooled and water (270 mL, 3.0 vol) was added. The reaction mass was filtered and the solids were washed with water (270 mL, 3.0 vol) and dried in an oven for 12 hours at 50-55 C. to afford the crude title compound as alight brown powder (100 g, yield=80.6%). .sup.1H NMR (300 MHz, CDCl.sub.3), 6.62 (s, 1H), 6.55 (s, 1H), 3.54 (d, 1H, J=11.7), 3.31 (dd, 1H, J=11.4 and 6.3), 3.11 (m, 2H), 2.92 (dd, 11, J=13.5 and 3.3), 2.73 (m, 2H), 2.59 (m, 2H), 2.39 (t, 1H, J=11.7), 1.82 (m, 1H), 1.65 (m, 1H), 1.03 (m, 1H), 0.90 (m, 6H); LC-MS: m/z=324.18 (MH).sup.+.

Step 3Purification of (RR,SS)-1,3,4,6,7-11b-Hexahydro-9,10-di(methoxy-d.SUB.3.)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one

Representative Example

[0249] Crude (RR,SS)-1,3,4,6,7-11b-Hexahydro-9,10-di(methoxy-d.sub.3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one from step 2 (90 g) was charged into absolute ethanol (540 mL, 6.0 vol) and heated to 75-85 C. for 1 hour. The reaction mass was filtered through a Buchner funnel at 75-85 C. and the filter cake was washed with hot ethanol (45 mL, 0.5 vol). The filtrate was cooled to 25-30 C. over 4 hours and further cooled to 0-5 C. over 3-4 hours. The resulting solid was filtered, washed with cold ethanol (180 mL, 2.0 vol), and dried under vacuum to afford the title compound as a pale yellow crystalline powder (75 g, yield=83.3%). .sup.1H NMR (300 MHz, CDCl.sub.3), 6.62 (s, 1H), 6.55 (s, 1H), 3.54 (d, 1H, J=11.7), 3.31 (dd, 1H, J=11.4 and 6.3), 3.11 (m, 2H), 2.92 (dd, 1H, J=13.5 and 3.3), 2.73 (m, 2H), 2.59 (m, 2H), 2.39 (t, 1H, J=11.7), 1.82 (m, 1H), 1.65 (m, 1H), 1.03 (m, 1H), 0.90 (m, 6H); LC-MS: m/z=324.18 (MH).sup.+.

EXAMPLE 4

3-[(Dimethylamino)methyl]-5-methyl-hexan-2-one

[0250] ##STR00027##

Step 1

[0251] ##STR00028##

2-Acetyl-4-methylpentanoic Acid Ethyl Ester

[0252] To a solution of ethyl acetoacetate (500 g, 3.842 mol, 1.00 eq) in DMF (1.5 L, 3.0 vol), KI (63.7 g, 0.384 mol, 0.10 eq), tetrabutylammonium bromide (136 g, 0.422 mol, 0.11 eq) and K.sub.2CO.sub.3 (632 g, 4.572 mol, 1.19 eq) were charged at 25-35 C. The reaction mixture was heated to 40-50 C. and 1-bromo 2-methyl propane (579 g, 4.226 mol, 1.10 eq) was added over 1 hour. The reaction mixture was heated to 65-75 C. for 6 hours, cooled and quenched with water (5.0 L, 10.0 vol). The reaction mixture was extracted with toluene (22.0 L, 24.0 vol) and the combined organic layers were washed with water (21.5 L, 23.0 vol). The organic layer was evaporated under reduced pressure to obtain crude 2-acetyl-4-methylpentanoic acid ethyl ester.

Step 2

[0253] ##STR00029##

3-[(Dimethylamino)methyl]-5-methyl-hexan-2-one

[0254] The ester was hydrolyzed using potassium hydroxide (212 g, 3.78 mol, 1.1 eq) in water (3.84 L, 6.0 vol). After the hydrolysis, the reaction mixture was washed with methyl tert-butyl ether (22.56 L, 24.0 vol) and the pH of the reaction mixture was adjusted to 6.8-7.2 using concentrated HCl (96 mL, 0.15 vol). Dimethylamine hydrochloride solution (420 g, 5.16 mol, 1.50 eq dissolved in 0.224 L, 0.35 vol of purified water), and formaldehyde solution (0.428 L, 5.763 mol, 1.675 eq) and tetrabutylammonium bromide (110 g, 0.344 mol, 0.10 eq) were added to the reaction mixture, and the pH was adjusted to below 1 using concentrated HCl (0.352 L, 0.55 vol) over 1 hour at 25-35 C. The reaction mixture was stirred for 15 hours at 25-35 C. and the pH was adjusted to 12.0-13.0 using 20% aqueous KOH (3.20 L, 5.0 vol) solution at 25-35 C. and dimethylamine hydrochloride (420 g, 5.16 mol, 1.5 eq) was added. The reaction mixture was stirred for 36 hours at 25-35 C. and the pH of the reaction mixture was adjust to below 1 using concentrated HCl (0.84 L, 0.13 vol) at 25-35 C. over 1 h. The reaction mixture was washed with methyl tert-butyl ether (22.56 L, 24.0 vol) and the pH of the reaction mixture was adjusted to 9-10 by using 20% aqueous KOH solution (1.72 L, 2.68 vol) at 25-35 C. The product was extracted with ethyl acetate (22.56 L, 24.0 vol and 11.28 L, 12.0 vol) and the combined organic layers were washed sequentially with purified water (21.92 L, 23.0 vol) and 10% ammonium chloride solution (23.2 L, 25.0 vol). Activated carbon (32 g, 0.05% w/w) was added to the organic layer and the mixture was stirred for 30-45 minutes at 25-35 C. The organic layer was filtered through celite (106 g) and was washed with ethyl acetate (0.32 L, 0.5 vol). The filtrate was distilled under reduced pressure to afford the title compound as a pale yellow liquid (151 g, yield=22.3%). .sup.1H NMR (300 MHz, CDCl.sub.3), 2.7-2.85 (m, 1H), 2.56-2.6 (m, 1H), 2.16 (s, 7H), 2.13 (s, 3H), 1.12-1.55 (m, 3H), 0.92 (d, 3H), 0.89 (d, 3H); LC-MS: m/z=172.11 (MH).sup.+.

[0255] From the foregoing description, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.