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 (cis)-d.sub.6-tetrabenazine having a diastereomeric purity of at least 99%, comprising: a) reacting d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinoline, or a salt thereof, ##STR00030## d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinoline with a salt of 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium: ##STR00031## 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium salt wherein X is halogen, alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkyloxonium, alkylphosphate, or alkyl carbonate; and an optional base; in the presence of one or more solvents; for a period of time and at a temperature sufficient to produce crude (cis)-d.sub.6-tetrabenazine; and b) recrystallizing the crude (cis)-d.sub.6-tetrabenazine from ethanol to produce the (cis)-d.sub.6-tetrabenazine having a diastereomeric purity of at least 99%.

2. The process of claim 1, wherein the (cis)-d.sub.6-tetrabenazine having a diastereomeric purity of at least 99%, has a deuterium enrichment of no less than about 20%.

3. The process of claim 1, wherein the (cis)-d.sub.6-tetrabenazine having a diastereomeric purity of at least 99%, has a deuterium enrichment of no less than about 50%.

4. The process of claim 1, wherein the (cis)-d.sub.6-tetrabenazine having a diastereomeric purity of at least 99%, has a deuterium enrichment of no less than about 70%.

5. The process of claim 1, wherein the (cis)-d.sub.6-tetrabenazine having a diastereomeric purity of at least 99%, has a deuterium enrichment of no less than about 80%.

6. The process of claim 1, wherein the (cis)-d.sub.6-tetrabenazine having a diastereomeric purity of at least 99%, has a deuterium enrichment of no less than about 90%.

7. The process of claim 1, wherein the (cis)-d.sub.6-tetrabenazine having a diastereomeric purity of at least 99%, has a deuterium enrichment of no less than about 98%.

8. The process of claim 1, wherein the one or more solvents comprise water and methanol.

9. The process of claim 8, wherein the solvents comprise a 3:1 ratio of methanol to water.

10. The process of claim 1, wherein the process is carried out in the presence of a base.

11. The process of claim 9, wherein the base is K.sub.2CO.sub.3.

12. The process of claim 1, wherein the salt form of d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinoline is d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride.

13. The process of claim 11, wherein the process is carried out in the presence of a base.

14. The process of claim 12, wherein the base is K.sub.2CO.sub.3.

15. The process of claim 1, wherein X is halogen.

16. The process of claim 1, wherein X is iodide.

17. The process of claim 1, wherein in step b), the diastereomeric purity of (cis)-d.sub.6-tetrabenazine is at least 99.1%.

18. The process of claim 1, wherein in step b), the diastereomeric purity of (cis)-d.sub.6-tetrabenazine is about 99.1%-99.9/o.

19. The process of claim 1, wherein in step b), the diastereomeric purity of (cis)-d.sub.6-tetrabenazine is about 99.2%.

20. The process of claim 1, wherein in step b), the diastereomeric purity of (cis)-d.sub.6-tetrabenazine is about 99.5%.

21. The process of claim 1, wherein in step b), the diastereomeric purity of (cis)-d.sub.6-tetrabenazine is about 99.6%.

22. The process of claim 1, wherein in step b), the diastereomeric purity of (cis)-d.sub.6-tetrabenazine is about 99.9%.

23. (cis)-d.sub.6-Tetrabenazine having a diastereomeric purity of at least 99% produced by the process of claim 1.

24. (cis)-d.sub.6-Tetrabenazine having a diastereomeric purity of at least 99% produced by the process of claim 8.

Description

EXAMPLE 1

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

[0220] ##STR00019##

Step 1

[0221] ##STR00020##

Optimization of Reaction Conditions

[0222] General Procedure: 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 EXAMPLE—STEP 1

[0223] N-(2-(3,4-dihydroxy-phenyl)-ethyl)formamide: 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 a brown powder (203 g, yield=84.5%). .sup.1H NMR (300 MHz, CDCl.sub.3), δ 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

[0224] ##STR00021##

Step 1

[0225] ##STR00022##

Optimization of Reaction Conditions

[0226] General Procedure: 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 (2×4.0 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-tetrahdrofuran (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 Transfer Solvent/ Exp. Batch Catalyst CH.sub.3I Base Condi- No. Size (eq) (eq) (eq) tions 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 10g 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 10g 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 Product Pro- Exp. Batch Quan- duct HPLC No. Size Reaction Conditions tity 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) Tetrabutylammonium bromide (0.05) 38-42.sup.cC, 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) Tetrabutylammonium 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) Tetrabutylammonium 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 ) Tetrabutylammonium 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 tetrabutylammonium bromide 38-42° C., 36 hours

REPRESENTATIVE EXAMPLE—STEP 1

[0227] d.sub.6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide: 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. CD3I (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 (2×760 mL, 2×4.0 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

[0228] ##STR00023##

Optimization of Reaction Conditions

[0229] General Procedure: 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 Quen- ching/ Exp. Batch Reaction Anti- Product Product HPLC No. Size Conditions 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 (reaction solvent toluene) Batch Reaction Quenching/ Product HPLC Exp. No. Size Conditions Anti-Solvent Quantity Yield Purity 1 48 g POCl.sub.3 (1.8 eq) Ethanol (3.8 eq) Product not — — Toluene (2 vol) MTBE* (4 vol) obtained as 90-95° C., 1 hour a free solid 2 48 g POCl.sub.3 (distilled, Ethanol (3.8 eq) 20.2 g   46% 91.9% 1.8 eq) MTBE* (4 vol) Toluene (2 vol) 90-95° C., 1 hour 3 50 g POCl.sub.3 (1 eq) Ethyl Acetate   35 g   76% — Toluene (2 vol) (2 vol) 90-95° C., 1 hour Ethyl Acetate/ HCl (2 vol) 4 20 g POC1.sub.3 (distilled, Ethanol (2.4 eq) Product not — — 1.8 eq) MTBE* (4 vol) obtained as Toluene (2 vol) a free solid 40-45° C., 1 hour 5 50 g POCl.sub.3 (distilled, Ethanol (3.8 eq) Product not 1.8 eq) MTBE* (4 vol) obtained as Toluene (2 vol) 80-85° C., 1 hour, a free solid seeded with product 6 28 g POCl.sub.3 (1.8 eq) Ethanol (3.8 eq)   24 g >100% Isolated Toluene (2 vol) MTBE* (4 vol) by 90-95° C., acid- 2 hours base workup 7 25 g POCl.sub.3 (1.8 eq) IPA* (3.8 eq) 14.5 g 53.2% 80.2% Toluene (2 vol) MTBE* (4 vol) (black 90-95° C., 12 hours solid) 2 hours 8 25 g POCl.sub.3 (1.8 eq) 1-Butanol (3.8 20.1 g 73.5% 80.1% Toluene (2 vol) eq) (black 90-95° C., MTBE* (4 vol) solid) 2 hours 12 hours 9 25 g POCl.sub.3 (1.8 eq) 1-Propanol (3.8 Product not — — Toluene (2 vol) eq) obtained as 90-95° C., Cyclohexane (4 a free solid 2 hours vol) 12 hours *IPA = Isopropyl alcohol; MTBE = Methyl tert-butyl ether.

TABLE-US-00011 TABLE 11 Optimization of reaction conditions by varying quenching solvent and anti-solvent (reaction solvent acetonitrile) Exp. Batch Reaction Quenching/ Product HPLC No. Size Conditions Anti-Solvent Quantity Yield Purity 1 100 g  POCl.sub.3 (1.8 eq) Ethanol (3.8 eq)  110 g — 93.3% Acetonitrile (2 vol) MTBE* (4 vol) (hygroscopic) 80-85° C., 1 hour 12 hours, seededwith product 2 25 g POCl.sub.3 (1.8 eq) IPA* (3.8 eq)   17 g 62.4% 87.1% Acetonitrile (2 vol) MTBE* (4 vol) (black 80-85° C., 2 hours 12 hours, solid) 3 25 g POCl.sub.3 (1.8 eq) 1-Butanol (3.8 17.3 g 63.8% 95.6% Acetonitrile (2 vol) eq) (grey 80-85° C., 2 hours MTBE* (4 vol) solid) 12 hours 5 25 g POCl.sub.3 (1.8 eq) t-Butanol (3.8 Solid not — — Acetonitrile (2 vol) eq) isolated 80-85° C., 2 hours MTBE* (4 vol) 12 hours 6 25 g POCl.sub.3 (1.8 eq) 1-Propanol (3.8   17 g 62.4% 88.8% Acetonitrile (2 vol) eq) (gray 80-85° C., 2 hours MTBE* (4 vol) solid) 12 hours 7 25 g POCl.sub.3 (1.8 eq) 1-Pentanol (3.8 13.4 g 49.2% Brown Acetonitrile (2 vol) eq) solid 80-85° C., 2 hours MTBE* (4 vol) 12 hours 8 25 g POCl.sub.3 (1.8 eq) 2-methyl 12.77 g  46.9% 87.6% Acetonitrile (2 vol) propanol (3.8 eq) (gray 80-85° C., 2 hours MTBE* (4 vol) solid) 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) Reaction Quenching/ Product Product HPLC Exp. No. Batch Size Conditions Anti-Solvent Quantity Yield Purity 1 25 g POCl.sub.3 (1.8 eq) 1-butanol (3.8 eq) 13.3 g 48.8% 91.9% Acetonitrile (2 Ethyl acetate vol) (4 vol) 80-85° C., 2 hours 12 hours 2 25 g POCl.sub.3 (1.8 eq) 1-butanol (3.8 eq) 14.83 g 54.5% 94.4% Acetonitrile (2 vol) Isopropyl acetate 80-85° C., 2 hours (4 vol) 12 hours 3 25 g POCl.sub.3 (1.8 eq) 1-butanol (3.8 eq) 14.2 g 52.2% 93.3% Acetonitrile (2 vol) 2-methyl-THF* 80-85° C., 2 hours (4 vol) 12 hours 4 25 g POCl.sub.3 (1.8 eq) 1-butanol (3.8 eq) 13.0 g 47.7% 94.2% Acetonitrile (2vol) Ethyl acetate/ 80-85° C., 2 hours HCl (4 vol) 12 hours 5 25 g POCl.sub.3 (1.8 eq) 1-butanol (3.8 eq) 18.3 g 67.2% 93.5% Acetonitrile (2 vol) MTBE* (4 vol) 80-85° C., 2 hours 12 hours 6 25 g POCl.sub.3 (1.8 eq) 1-butanol (3.8 eq) 17.5 g 64.3% 91.3% Acetonitrile (2 vol) MTBE* (8 vol) 80-85° C., 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) Reaction Quenching/ Product Product HPLC Exp. No. Batch Size Conditions Anti-Solvent Quantity Yield Purity 1 25 g POCl.sub.3 (1.8 eq) 1-butanol (6.0 eq) 14.7 g 54% 84.1% Acetonitrile (2 vol) MTBE* (4 vol) 80-85° C., 12 hours 2 hours 2 28 g POCl.sub.3 (1.8 eq) 1-butanol (3.8 eq) 21.3 g 70% 94.6% Acetonitrile (2 vol) MTBE* (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 Quench- ing/ Exp. Batch Reaction Anti- Product Product HPLC No. Size Conditions Solvent Quantity Yield Purity 1 50 g POCl.sub.3 (0.5 eq) 1-butanol — — Product Acetonitrile (2 (3.8 eq) obtained 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 (2 (3.8 eq) obtained 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 (2 (3.8 eq) vol) MTBE* 80-85° C., (4 vol) 2 hours 12 hours

REPRESENTATIVE EXAMPLE—STEP 2

[0230] d.sub.6-6,7-Dimethoxy-3,4-dihydroisoquinoline hydrochloride: 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 tert-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), δ 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 3—Optional purification of d.SUB.6.-6,7-dimethoxy-3,4-dihydroisoauinoline hydrochloride

[0231] To increase the purity of d.sub.6-6,7-dimethoxy-3,4-dihydroisoquinolmne hydrochloride various purification procedures were attempted.

TABLE-US-00016 TABLE 16 Recrystallization of d.sub.6-6,7dimethoxy-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)

[0232] ##STR00024##

Step 1

[0233] ##STR00025##

REPRESENTATIVE EXAMPLE—STEP 1

[0234] 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide: 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

[0235] ##STR00026##

Optimization of Reaction Conditions

[0236] General Procedure: 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 Pro- duct Pro- Exp. Batch Quan- duct HPLC No. Size Reaction Conditions tity Yield Purity 1 30 g 6,7-Dimethoxy-3,4-dihydro 20.3 g 40.7% 98.8% isoquinoline free base (1 eq) 0.56% 2-acetyl-N,N,N,4-tetramethyl-1- Diastereo pentanaminium iodide (0.75 eq) mer Water (6 vol) impurity* 100° C., 48 hour 2 10 g 6,7-Dimethoxy-3,4-dihydro  1.4 g  8.3% 97.8% isoquinoline free base (1 eq) 1.45% 2-acetyl-N,N,N,4-tetramethyl-1- Diastereo pentanaminium iodide (0.75 eq) mer Methanol (6 vol) impurity* 65-70° C., 48 hour 3 10 g 6,7-Dimethoxy-3,4-dihydro  1.4 g  8.3% 98.1% isoquinoline free base (1 eq) 0.75% 2-acetyl-N,N,N,4-tetramethyl-1- Diastereo pentanaminium iodide (0.75 eq) mer Ethanol (6 vol) impurity* 75-80° C., 48 hour 4 10 g 6,7-Dimethoxy-3,4-dihydro  6.8 g 40.8% 99.1% isoquinoline free base (1 eq) 0.04% 2-acetyl-N,N,N,4-tetramethyl-1- Diastereo pentanaminium iodide (0.75 eq) mer Methanol/water (1:1) (6 vol) impurity* 45-50° C., 90 hour *The diastereomer impurity is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.

TABLE-US-00019 TABLES 19 and 20 In-process HPLC results Ex. 2 - Methanol Ex. 3 - Ethanol 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 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-00020 TABLE 21 Optimization of the reaction by varying the reaction temperature Pro- duct Pro- Exp. Batch Quan- duct HPLC No. Size Reaction Conditions tity Yield Purity 1 8 g 6,7-Dimethoxy-3,4-dihydroiso- 8.3 g 74.5% 99.1% quinoline hydrochloride (1 eq) 0.04% 2-acetyl-N,N,N,4-tetramethyl-1- Diastereo pentanaminium iodide (1.08 eq) mer Methanol/water (1.1) (6 vol) impurity* K.sub.2CO.sub.3 (1 eq) 45-50° C., 63 hour 2 8 g 6,7-Dimethoxy-3,4-dihydroiso- 8.5 g 76.7% 99.1% quinoline hydrochloride (1 eq) 0.04% 2-acetyl-N,N,N,4-tetramethyl-1- Diastereo pentanaminium iodide (1.08 eq) mer Methanol/water (1:1) (6 vol) impurity* K.sub.2CO.sub.3 (1 eq) 25-30° C., 63 hour 3 8 g 6,7-Dimethoxy-3,4-dihydroiso- 8.3 g   75% 99.1% quinoline hydrochloride (1 eq) 0.1% 2-acetyl-N,N,N,4-tetramethyl-1- Diastereo pentanaminium iodide (1.08 eq) mer Methanol/water (1:1) (6 vol) impurity* 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.

TABLE-US-00021 TABLES 22 and 23 In-process HPLC results Ex. 3 - Methanol:Water Ex. 2 - Methanol:Water (1:1) 65-70° C. (1:1) 45-50° C. Diaster- Diaster- Hours SM* Product eomer* SM* Product eomer* 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 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]; The diastereomer impurity is the (RS, SR) diastereomer of d.sub.6-tetrabenazine.

TABLE-US-00022 TABLE 24 Optimization of the reaction by varying the solvent mixture ratio Pro- duct Pro- Exp. Batch Quan- duct HPLC No. Size Reaction Conditions tity Yield Purity 1  8 g 6,7-Dimethoxy-3,4-dihydroiso- 8.5 g 76.9% 98.9% quinoline hydrochloride (1 eq) 0.09% 2-acetyl-N,N,N,4-tetramethyl-1- undesired pentanaminium iodide (1.08 eq) isomer 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-dihydroiso- 8.6 g 77.1% 99.6% quinoline hydrochloride (1 eq) 0.03% 2-acetyl-N,N,N,4-tetramethyl-1- undesired pentanaminium iodide (1.08 eq) isomer 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-dihydroiso- 9.6 g 68.9% 99.3% quinoline hydrochloride (1 eq) off-white 2-acetyl-N,N,N,4-tetramethyl-1- product 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-dihydroiso- 7.6 g 54.4% 99.2% quinoline 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

TABLE-US-00023 TABLES 25 and 26 In-process HPLC results Ex. 1 - Methanol: Ex. 2 - Methanol: Water (1:3) 45-50° C. Water (3:1) 45-50° C. Diaster- Diaster- Hours SM* Product eomer* SM* Product eomer* 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 Ex. 3 - Methanol: Ex. 4 - Water (4:1) 45-50° C. Methanol, 45-50° C. Diaster- Diaster- Hours SM* Product eomer* SM* Product eomer* 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% Product 7.58 7.58 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-00024 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 (l 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

TABLE-US-00025 TABLES 28 and 29 In-process HPLC results Ex. 1 - Methanol:Water Ex. 2 - Methanol:Water (3:1) 45-50° C., 24 h (3:1) 45° C., 48 h Diaster- Diaster- Hours SM* Product eomer* SM* Product eomer* 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* treat- ment Final — 99.25% 0.08% — 99.58% 0.03% Product Wt (g) 8.5 Wt (g) 9.4 Y (%) 61 Y (%) 67.4 Ex. 3 - Methanol:Water (3:1) 45° C., 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-00026 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 Pro- duct Pro- Exp. Batch Quan- duct HPLC No. Size Reaction Conditions tity 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 12.5 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-00027 TABLE 31 Optimization by varying the purity of 6,7-dimethoxy-3,4-dihydro isoquinoline hydrochloride Batch Product Pro- Exp. Size Quan- duct HPLC No. (Purity) Reaction Conditions tity 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 (l 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 EXAMPLE—STEP 2

[0237] (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: The 2-acetyl-ANNN,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 a light brown powder (100 g, yield=80.6%). .sup.1H NMR (300 MHz, CDCl.sub.3), δ 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.+.

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

[0238] Representative example: 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), δ 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

[0239] ##STR00027##

Step 1

[0240] ##STR00028##

[0241] 2-Acetyl-4-methylpentanoic acid ethyl ester: 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 (2×2.0 L, 2×4.0 vol) and the combined organic layers were washed with water (2×1.5 L, 2×3.0 vol). The organic layer was evaporated under reduced pressure to obtain crude 2-acetyl-4-methylpentanoic acid ethyl ester.

Step 2

[0242] ##STR00029##

[0243] 3-[(Dimethylamino)methyl]-5-methyl-hexan-2-one: 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 (2×2.56 L, 2×4.0 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 (2×2.56 L, 2×4.0 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 (2×2.56 L, 2×4.0 vol and 1×1.28 L, 1×2.0 vol) and the combined organic layers were washed sequentially with purified water (2×1.92 L, 2×3.0 vol) and 10% ammonium chloride solution (2×3.2 L, 2×5.0 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), δ 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.+.

[0244] 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.