PROCESS FOR THE PRODUCTION OF SUBSTITUTED 2-[2-(PHENYL)ETHYLAMINO]ALKANEAMIDE DERIVATIVES

Abstract

The present invention refers to a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein R is (C.sub.3-C.sub.10)alkyl, or ω-trifluoro(C.sub.3-C.sub.10)alkyl; R.sub.1 and R.sub.2 are, independently, hydrogen, hydroxy, (C.sub.1-C.sub.8) alkoxy, (C.sub.1-C.sub.8) alkylthio, halo, trifluoromethyl or 2,2,2-trifluoroethyl; or one of R.sub.1 and R.sub.2 is in ortho position to the R—O— group and, taken together with the same R—O—, represents a Formula (A) group where R.sub.0 is (C.sub.2-C.sub.9)alkyl; R.sub.3 and R.sub.4 are, independently, hydrogen, (C.sub.1-C.sub.4)alkyl; or R.sub.4 is hydrogen and R.sub.5 is a group selected from —CH.sub.2—OH, —CH.sub.2—O—(C.sub.1-C.sub.6)alkyl, —CH(CH.sub.3)—OH, —(CH.sub.2).sub.2—S—CH.sub.3, benzyl and 4-hydroxybenzyl; or R.sub.4 and R.sub.5, taken together with the adjacent carbon atom, form a (C.sub.3-C.sub.6)cycloalkyl residue; R.sub.5 and R.sub.6 are independently hydrogen or (C.sub.1-C.sub.6)alkyl; or taken together with the adjacent nitrogen atom form a 5-6 membered monocyclic saturated heterocycle, optionally containing one additional heteroatom chosen among —O—, —S— and —NR.sub.7— where R.sub.7 is hydrogen or (C.sub.1-C.sub.6) alkyl; and wherein optionally one or more hydrogen atom in the groups R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6, preferably in the R group, can be substituted by a deuterium atom.

##STR00001##

Claims

1. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR00030## wherein R is (C.sub.3-C.sub.10)alkyl, or ω-trifluoro(C.sub.3-C.sub.10)alkyl; R.sub.1 and R.sub.2 are, independently, hydrogen, hydroxy, (C.sub.1-C.sub.8)alkoxy, (C.sub.1-C.sub.8) alkylthio, halo, trifluoromethyl or 2,2,2-trifluoroethyl; or one of R.sub.1 and R.sub.2 is in ortho position to the R—O— group and, taken together with the same R—O—, represents a ##STR00031## group where R.sub.0 is (C.sub.2-C.sub.9)alkyl; R.sub.3 and R.sub.4 are, independently, hydrogen, (C.sub.1-C.sub.4)alkyl; or R.sub.4 is hydrogen and R.sub.5 is a group selected from —CH.sub.2—OH, —CH.sub.2—O—(C.sub.1-C.sub.6)alkyl, —CH(CH.sub.3)—OH, —(CH.sub.2).sub.2—S—CH.sub.3, benzyl and 4-hydroxybenzyl; or R.sub.4 and R.sub.5, taken together with the adjacent carbon atom, form a (C.sub.3-C.sub.6)cycloalkyl residue; R.sub.5 and R.sub.6 are independently hydrogen or (C.sub.1-C.sub.6)alkyl; or taken together with the adjacent nitrogen atom form a 5-6 membered monocyclic saturated heterocycle, optionally containing one additional heteroatom chosen among —O—, —S— and —NR.sub.7— where R.sub.7 is hydrogen or (C.sub.1-C.sub.6) alkyl; and wherein optionally one or more hydrogen atom in the groups R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 can be substituted by a deuterium atom; said process comprising the steps of: a) reacting a compound of formula (II): ##STR00032## wherein R, R.sub.1 and R.sub.2 are as above defined with a compound of formula (III):
[(R.sub.9).sub.3P CH.sub.2OR.sub.8].sup.+X.sup.−  (III) wherein R.sub.9 is aryl or a (C1-C6) alkyl; X is Cl, Br or I; R.sub.8 is (C.sub.1-C.sub.6) alkyl; in the presence of a strong base to obtain a compound of formula (IV): ##STR00033## wherein R, R.sub.1, R.sub.2 and R.sub.8 are as above defined and b) hydrolyzing the obtained compound of formula (IV) to obtain a compound of formula (V): ##STR00034## wherein R, R.sub.1 and R.sub.2 are as above defined and c) reacting the obtained compound of formula (V) with a compound of formula (VI) or a salt thereof: ##STR00035## wherein R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as above defined and G is hydrogen or a protecting group of the amino group, to obtain a condensation compound; d) reducing the obtained condensation compound to obtain the compound of formula (I) or alternatively c′) directly reacting the compound of formula (IV) as above defined with the compound of formula (VI) as above defined and reducing the obtained condensation compound to obtain the compound of formula (I); and e) optionally converting the obtained compound of formula (I) into a pharmaceutically acceptable salt thereof.

2. The process according to claim 1 for obtaining a compound of formula (I′): ##STR00036## wherein R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined in claim 1.

3. The process according to claim 1 for obtaining a compound of formula (I) wherein: R is (C.sub.4-C.sub.6)alkyl or CD.sub.3-CD.sub.2-(C.sub.2-C.sub.4)alkyl; R.sub.1 and R.sub.2 are, independently, hydrogen or halo; R.sub.3 and R.sub.4 are both hydrogen; and R.sub.5 and R.sub.6 are, independently, hydrogen or (C.sub.1-C.sub.3)alkyl.

4. The process according to claim 1 for obtaining a compound of formula (I) wherein R is n-butyl or CD.sub.3-CD.sub.2-CH.sub.2—CH.sub.2— and R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are hydrogen.

5. The process according to claim 1 wherein the strong base of step a) is selected in the group consisting of alkyl lithium, lithium hexamethylsilazide, lithium isopropylamide and potassium tert-butoxide.

6. The process according to claim 5 wherein the strong base is lithium hexamethylsilazide.

7. The process according to claim 1, wherein the side product (R.sub.9).sub.3 P formed in step a), wherein R.sub.9 is as defined in claim 1, is oxidized to (R.sub.9).sub.3 PO and removed.

8. The process according to claim 7 wherein (R9)3 PO is removed by filtration.

9. The process according to claim 7 wherein the obtained product (IV) is purified by chromatography.

10. The process according to claim 1, wherein the hydrolysis of step b) is carried out in aqueous acidic conditions.

11. The process according to claim 10 wherein the hydrolysis of step b) is carried out in acetonitrile and aqueous hydrochloric acid.

12. The process according to claim 1, wherein G in the compound of formula (VI) is hydrogen.

13. The process according to claim 1, wherein G in the compound of formula (VI) is a protecting group of the amino group selected from the group consisting of a carbamate N-carboxy alkyl group, N-t-butyl carbamate (BOC), N-benzyl carbamate (Cbz), bromobenzyl carbamate, p-chlorobenzylcarbamate and 9-fluorenylmethyl carbamate (Fmoc).

14. The process according to claim 1, wherein the reducing agent used in step d) is selected from the group consisting of sodium borohydride, sodium triacetoxyborohydride (STAB-H), Pd/H.sub.2, and NaBH3CN.

15. The process according to claim 1, wherein the reducing agent used in step d) is sodium triacetoxyborohydride (STAB-H).

16. The process according to claim 1, wherein step b), step c) and step d) are carried out without isolating the intermediate products.

17. The process according to claim 16 wherein step b), step c) and step d) are carried out in acetonitrile and aqueous hydrochloric acid.

18. The process according to claim 1, wherein the pharmaceutically acceptable acid of step e) is selected from the group consisting of HCl, HBr, CH.sub.3SO.sub.3H, paratoluenesulfonic acid and phosphoric acid.

19. The process according to claim 1 wherein the compound of formula (II) wherein R, R.sub.1 and R.sub.2 are as defined in claim 1 is prepared by alkylation of a compound of formula (II) wherein R is hydrogen by reaction with a compound of formula RY wherein R is as defined in claim 1 and Y is a leaving group.

20. The process according to claim 19 wherein Y is selected from the group consisting of chloride, bromide, mesylate, para-toluenesulphonate, brosylate, nosylate and phosphate.

Description

EXPERIMENTAL PART

Example 1

Synthesis of 3-butoxybenzyaldehyde

[0096] ##STR00020##

[0097] A solution containing 3-hydroxybenzaldehyde 25 kg (204.7 mol), potassium carbonate 39.5 kg (285.8 mol), and 1-chlorobutane 28.5 kg (307.8 mol) in N,N-dimethylformamide 120 kg was heated to 115° C. and kept at this temperature until reaction completion (3-hydroxybenzaldehyde less than 1%). The mixture was cooled, diluted with water 325 kg and then concentrated under vacuum to about 325 L. The batch was diluted with water 126 kg and methyl tert-butyl ether 150 kg was added at about 20° C. The aqueous layer was discarded and the batch was washed sequentially with dilute sodium chloride solution and then water. The batch was concentrated under vacuum and residual methyl tert-butyl ether was replaced by tetrahydrofuran through a series of dilution and concentration under vacuum. The resulting tetrahydrofuran solution containing 33.5 kg (188.0 mol) (91% molar yield, purity 99.7%) of 3-butoxybenzaldehyde was used in the next step.

[0098] MS (M+1: 179.1); .sup.1H NMR is consistent with the given structure.

Example 2

Synthesis of 3-butoxybenzyaldehyde

[0099] ##STR00021##

[0100] A mixture containing 3-hydroxybenzaldehyde 3.95 kg (32.34 mol), 1-chlorobutane 4.49 kg (48.52 mol), and potassium carbonate 6.26 kg (45.28 mol) in N,N-dimethylformamide 19.75 L was heated to 115-118° C. and kept at this temperature until the reaction was complete (3-hydroxybenzaldehyde circa 0.1% area %). The reaction mixture was cooled to circa 20° C. The slurry was added with a mixture of tert-butyl methyl ether 32.4 L and water 52.9 L and stirred for 15 min. The two phases mixture was allowed to separate. The organic solution was washed with a sodium chloride aqueous solution. The batch was concentrated under reduced pressure at <50° C. to provide the oily product 3-butoxybenzaldehyde 5.57 kg in 96.6% molar yield.

Example 3

Synthesis of 1-Butoxy-3-(2-methoxyvinyl)benzene

[0101] ##STR00022##

[0102] A solution of lithium hexamethylsilazide (prepared from hexamethyldisilazane 53.4 kg (331 mol), n-butyl lithium (2.5 M) in N-Hexane 91 kg (328 mol) in tetrahydrofuran 83 kg at −25° C. to 0° C., was added to a solution of (methoxymethyl)triphenylphosphonium chloride 95.6 kg (279 mol) and tetrahydrofuran 290 kg at about −25° C. A pre-cooled tetrahydrofuran solution of 3-butoxybenzaldehyde 33.5 kg (188 mol) in THE solution, prepared in the previous step, was added and the batch was kept at about 0° C. until complete reaction. The reaction mixture was quenched with water 166 kg (pre-cooled to about 0° C.). The biphasic mixture was concentrated under vacuum to about 266 L. The batch was diluted with n-heptane 77 kg and filtered through Celite with a n-heptane rinse. The combined filtrate was allowed to settle, the aqueous layer was separated and extracted with n-heptane 115 kg. The combined organic layer was washed three times with water 166 kg each time. A solution containing hydrogen peroxide 6.05 kg in water 33 kg was added to the batch and stirred at about 20° C. for about 6 h. The batch was diluted with water 66 kg and then filtered through Celite with a n-heptane rinse. The combined filtrate was allowed to settle and the aqueous layer was discarded. The organic solution was washed three times with water, 100 kg each time. The solution was concentrated to about 66 L and purified on silica gel 160 kg; (200-300 mesh) using n-heptane as the eluent. Fractions containing the product were combined and concentrated under vacuum to about 66 L. The concentrated solution of E and Z 1-Butoxy-3-(2-methoxyvinyl)benzene 25 kg (121.2 mol), 64% molar yield, was used directly in the next step. MS (M+1: 207.2) and .sup.1H NMR (DMSO-d.sub.6) showed that it is a mixture of E- and Z-isomers. Based on the NMR integration, the ratio is 43:57 of the E:Z isomers.

##STR00023##

[0103] The .sup.1H NMR (400 MHz) assignments are tabulated as below:

TABLE-US-00001 Position δ.sub.H (ppm) 1, 2, 3, 4 7.22-6.96 (m, 2H), 6.89-6.74 (m, 1H), 6.73-6.57 (m, 1H) 5’ & 5 5.79 (d, J = 13.0 Hz, 0.57H) & 5.18 (d, J = 7.1 Hz, 0.43H) 6’ & 6 δ 7.28 (d, J = 13.0 Hz, 0.57H) & 6.28 (d, J = 7.0 Hz, 0.43H) 7’ & 7 3.85-3.68 (m, 1.29H), 3.65-3.51 (m, 1.71H) 8 4.10-3.85 (m, 2H) 9 1.85-1.57 (m, 2H) 10 1.57-1.32 (m, 2H) 11 1.04-0.82 (m, 3H)

Example 4

Synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide

[0104] ##STR00024##

[0105] A solution of 1-butoxy-3-(2-methoxyvinyl)benzene; 20.7 kg (25.8 kg×80.2% assay, 100.3 mol; 1 equivalent), 2N aqueous hydrochloric acid (7.3 kg) and acetonitrile 278 kg was kept at about 0° C. until reaction completion (1-butoxy-3-(2-methoxyvinyl)benzene <3%). This was added to a mixture containing 2-amino-N,N-dimethylacetamide hydrochloride; 15.5 kg (16.6 kg×93.3% assay) (111.7 mol), water 6.2 kg and acetonitrile 93 kg at about 10° C., warmed to and held at 40° C. until reaction completion. The temperature of the batch was adjusted to about 0° C., and a solution of sodium triacetoxyborohydride 44.3 kg (99% assay, 207 mol) in acetonitrile 93 kg at about 5° C. After complete reaction (<2% residual quantity of 3-n-butoxy-phenylacetaldehyde), the batch was quenched with water 207 kg and the biphasic mixture was concentrated under vacuum at about 40° C. to about 90 L. The batch was diluted with methyl tert-butyl ether 104 kg and the layers were separated. The organic layer was washed with water twice (about 133 kg each time). The combined aqueous layers were extracted with methyl tert-butyl ether 104 kg, and the separated organic layer was washed with water 62 kg. The pH of the combined aqueous layers was adjusted to about 9 using 30% aqueous sodium hydroxide solution and extracted with methyl tert-butyl ether twice (104 kg each time). The combined organic layer was concentrated under vacuum, using a series of dilution with methyl tert-butyl ether (20 kg each time) and concentrated, to a final volume of about 20 L. The batch was further azeotropically dried by a series of dilution with methyl isobutyl ketone 25 kg and concentrated under vacuum to a final volume of 40 L, providing 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide free base 20.1 kg (72.1 mol, 72% molar yield) as a concentrated solution in methyl isobutyl ketone. The identity of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide (free base) was consistent with MS (M+1=279.0), with 400 MHz .sup.1H NMR and elemental analysis.

Example 5

Synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide

[0106] 3-butoxyphenylacetaldehyde 1.95 g (1 equiv.) and 2-amino-N,N-dimethylacetamide 5.18 g (5 equiv.) were dissolved in anhydrous THE 340 mL. To this reaction mixture acetic acid 3.47 mL (6 equiv.) was added drop wise and the resulting solution was stirred for 5 minutes. To this solution STAB-H 8.6 g (4 equiv.) was added in portions and stirred for 2.5 hours. After the reaction was complete, Na.sub.2CO.sub.3 aqueous solution was added and the organic layer was separated. The aqueous layer was extracted twice with DCM 200 mL. The organic layers were combined, dried and concentrated. A flash column chromatography performed on crude material (8% ethyl acetate in heptanes) yielded 1.66 g (59% molar yield of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide free base).

Example 6

2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride

[0107] ##STR00025##

[0108] A solution containing gaseous hydrogen chloride (about 4 kg) in methyl tert-butyl ether (about 36 Kg) is added to a solution of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide free base 13.5 kg (48.5 mol) in methyl isobutyl ketone at about 25° C. The resulting suspension was filtered at about 0-5° C., and the filter cake was washed with cold methyl isobutyl ketone. The collected solid was suspended in methyl isobutyl ketone 68 kg at 35-40° C. for several hours, and then filtered at about 20° C. The filter cake was washed with methyl isobutyl ketone 14 kg. The collected solid was dissolved in a mixture of water 1.4 kg and methyl isobutyl ketone 54 kg and polished filtered. The filtrate was azeotropically dried, with a series of dilution with methyl isobutyl ketone and concentrated, to a final volume of about 81 L. The precipitated solids were filtered at 30-35° C. The collected solid was washed with methyl isobutyl ketone 14 kg, and then dried at about 40° C. under vacuum. The dried solid was sieved to provide 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride 10.64 kg, (33.8 mol) in 69.7% molar yield. The identity of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride is confirmed by elemental analysis (theoretical vs found: C, 61.04% vs 61.3±0.2 wt %; H, 8.64% vs 8.7±0.1 wt %; N, 8.90% vs 8.9±0.1 wt %; O 10.16% vs 10.17±0.1 wt %; Cl 11.26% vs 10.2±0.5 wt %) (MS (M+1: 279.0), and 300 MHz .sup.1H NMR Spectrum in DMSO Bruker Avance 300 at 20° C.:

TABLE-US-00002 [00026] Chemical Shift [ppm] Multiplicity Number of Hydrogen Assignment 0.94 t 3 16 (CH.sub.3) 1.35-1.53 m 2 15(CH.sub.2) 1.62-1.77 m 2 14 (CH.sub.2) 2.90 s 3 12a (CH.sub.3) 2.94 s 3 12b (CH.sub.3) 2.97-3.05 m 2 7 (CH.sub.2) 3.08-3.22 m 2 8 (CH.sub.2) 3.95 t 2 13 (CH.sub.2) 4.05 s 2 10 (CH.sub.2) 6.75-6.88 m 3 2 (CH), 4 (CH), 6 (CH) 7.18-7.30 m 1 5 (CH) 9.26 bs 2 —NH.sub.2+—

[0109] Bruker Avance 300 .sup.13C-NMR Spectrum in DMSO at 20° C.

TABLE-US-00003 [00027] Chemical Shift [ppm] Kind of Carbon Atom Assignment 14.57 CH.sub.3 16 19.62 CH.sub.2 15 31.64 CH.sub.2 14 32.13 CH.sub.2 7 35.77 CH.sub.3 12a, b 36.54 CH.sub.3 47.67 CH.sub.2 10 48.68 CH.sub.2 8 67.85 CH.sub.2 13 113.53 CH 115.57 CH 2, 4, 6 121.47 CH 130.55 CH 5 139.70 C 159.76 C 1, 3, 11 165.89 C

Example 7

Synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride

[0110] 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide free base 8.10 g (29 mmol; 1 equiv.) grams was dissolved in diethyl ether 15 mL. To this solution HCl in ether solvent 46 mL (2 mmol) was added and vigorously stirred. The residue formed was scratched at 0° C. to produce a white precipitate of crude 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride. This precipitate was further purified by trituration in ethyl acetate hydrochloride 40 mL 6.66 g (21.1 mmol; 72% yield).

Example 8

Synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride

[0111] A solution of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide free base 5.4 Kg(19.40 mol) in methyl isobutyl ketone solution 35 L was added to 37% hydrochloric acid 2.03 kg. The mixture was dried azeotropically by repeated cycles of dilution with methyl isobutyl ketone and then concentrated under vacuum at <45° C. to about 27 L residual volume. The precipitated solid was filtered and was washed sequentially with methyl isobutyl ketone 10.95 kg and heptanes 18.70 kg. The wet product was dried at 40° C., to give 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride 4.91 Kg (15.59 mol) as a white solid in 80.3% yield. Spectral data (.sup.1H NMR) of the solid are consistent with the assigned structure of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride.

Example 9

Synthesis of 2-[2-(3-butoxy-3,3,4,4,4-d.SUB.5.-phenyl)-ethylamino]-N,N-dimethylacetamide

[0112] ##STR00028##

[0113] Phenylacetaldehyde-3-butoxy-3,3,4,4,4-d.sub.5 2 g (10.1 mmol; 1 equiv.) and 2-amino-N,N-dimethylacetamide 5.18 g (5 equiv.) were dissolved in anhydrous tetrahydrofuran 340 mL in an oven dried round ball flask. To this reaction mixture, acetic acid 3.47 mL (6 equiv.) was added drop wise and the resulting solution was stirred for 5 minutes. To this solution sodium triacetoxyborohydride (STAB-H) 8.6 g (4 equiv.) was added in portions and stirred for 2.5 hours. After the reaction was complete, sodium carbonate aqueous solution was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane (200 mL). The organic layers were combined, dried and concentrated. A flash column chromatography performed on crude material (8% ethyl acetate in heptanes) yielded 1.7 g (6.0 mmol) of 2-[2-(3-butoxy-3,3,4,4,4-d.sub.5-phenyl)-ethylamino]-N,N-dimethylacetamide (59.4% yield). .sup.1H-NMR is reported in FIG. 1.

[0114] Phenylacetaldehyde-3-butoxy-3,3,4,4,4-d.sub.5 used as starting material in the above synthesis was prepared according to the process reported in Example 1 or 2 starting from 3-hydroxybenzaldehyde by using 1-chlorobutane-3,3,4,4,4-d.sub.5 instead of 1-chlorobutane and subsequent Wittig reaction.

Example 10

Synthesis of 2-[2-(3-butoxy-4,4,4,3,3-d.SUB.5.-phenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride

[0115] ##STR00029##

[0116] 2-[2-(3-butoxy-4,4,4,3,3-d.sub.5-phenyl)-ethylamino]-N,N-dimethylacetamide free base 8.25 g (29.1 mmol; 1 equiv.) was dissolved in diethylether 15 mL. To this solution a 2M HCl solution in diethylether (46 mL) was added and vigorously stirred. The gummy residue formed was scratched at 0° C. to produce a white precipitate of crude of 2-[2-(3-butoxy-3,3,4,4,4-d.sub.5-phenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride. This precipitate was further purified by trituration in ethyl acetate (40 mL). The resultant precipitate was filtered and dried under nitrogen to yield pure 2-[2-(3-butoxy-3,3,4,4,4-d.sub.5-phenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride 6.77 g (21.17 mmol, 73 yield).

[0117] .sup.1H NMR-spectrum is reported in FIG. 1;

[0118] LC-MS:

TABLE-US-00004 m/z Abundance 283.30 4.5 284.30 100.0 285.30 12.7 286.30 1.8 305.80 0.5 306.25 7.1 307.25 0.8

Example 11

Synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride

[0119] A mixture of 1-butoxy-3-(2-methoxyvinyl)benzene; 20.7 kg (25.8 kg×80.2% assay, 100.3 mol=1 equivalent), 2N aqueous hydrochloric acid (7.3 kg) and acetonitrile 278 kg was kept at about 0° C. until reaction completion (1-butoxy-3-(2-methoxyvinyl)benzene <3%). This was added to a mixture containing 2-amino-N,N-dimethylacetamide hydrochloride (VI) (15.5 kg (16.6 kg×93.3% assay) (111.7 mol), water 6.2 kg and acetonitrile 93 kg at about 10° C., warmed to and held at 40° C. until reaction completion. The temperature of the batch was adjusted to about 0° C., and a solution of sodium triacetoxyborohydride 46.0 kg (99% assay, 215 mol) in acetonitrile 93 kg at about 5° C. was added. After complete reaction (<2% residual quantity of 3-n-butoxy-phenylacetaldehyde), the batch was quenched with water 207 kg and the biphasic mixture was concentrated under vacuum at about 40° C. to about 90 L. The batch was extracted with methyl tert-butyl ether (104 kg). The organic layer was washed with water twice (about 133 kg each time). The combined aqueous layers were extracted with methyl tert-butyl ether 104 kg, and the separated organic layer was washed with water 62 kg. The pH of the combined aqueous layers was adjusted to about 9 using 30% aqueous sodium hydroxide solution and extracted with methyl tert-butyl ether twice (104 kg each time). The combined organic layer was concentrated under vacuum, using a series of dilution with methyl tert-butyl ether (20 kg each time) and concentrated, to a final volume of about 20 L. The batch was further azeotropically dried by a series of dilution with methyl isobutyl ketone 25 kg and concentrated under vacuum to a final volume of 40 L, providing 2-[2-(3-butoxyphenyl)-ethylamine]-N,N-dimethylacetamide free base 20.1 kg (72.1 mol, 72% molar yield).

[0120] The solution was diluted to circa with methyl isobutyl ketone (130 L). The solution was added to 36% hydrochloric acid (7.6 kg). The mixture was dried azeotropically by repeated cycles of dilution with methyl isobutyl ketone and then concentrated under vacuum at <45° C. to about 100 L residual volume. The precipitated solid was filtered and was washed sequentially with methyl isobutyl ketone 40 kg and heptanes 70 kg. The wet product was dried at 40° C., to give 2-[2-(3-butoxyphenyl)-ethylamine]-N,N-dimethylacetamide hydrochloride 18.7 kg (59.4 mol) as a white solid in 82% yield from 2-[2-(3-butoxyphenyl)-ethylamine]-N,N-dimethylacetamide free base.

Example 12

Synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride

[0121] 2-amino-N,N-dimethylacetamide hydrochloride; 15.5 kg (16.6 kg×93.3% assay) (111.7 mol), water 6.2 kg and acetonitrile 93 kg, was added at about 10° C. to a mixture of 1-butoxy-3-(2-methoxyvinyl)benzene; 20.7 kg (25.8 kg×80.2% assay, 100.3 mol=1 equivalent), 2N aqueous hydrochloric acid (7.3 kg) and acetonitrile 278 kg kept at about 0° C. until reaction completion (1-butoxy-3-(2-methoxyvinyl)benzene <3%). The thus obtained mixture was warmed to and held at 40° C. until reaction completion. The temperature of the stirred batch was adjusted to about 0° C. Acetonitrile 93 kg and sodium triacetoxyborohydride 44.3 kg (99% assay, 207 mol) were added to the stirred mixture kept at 5° C. After complete reaction (<2% residual quantity of 3-n-butoxy-phenylacetaldehyde), the batch was quenched with water 207 kg and the mixture was concentrated in vacuo under stirring at circa 40° C. to about 90 L. The batch was extracted with methyl tert-butyl ether (104 kg). The organic layer was washed with water twice (about 133 kg each time). The combined aqueous layers were extracted with methyl tert-butyl ether 104 kg, and the separated organic layer was washed with water 62 kg. The pH of the combined aqueous layers was adjusted to about 9 using 30% aqueous sodium hydroxide solution and extracted with methyl tert-butyl ether twice (104 kg each time). The combined organic layer was concentrated under vacuum, using a series of dilution with methyl tert-butyl ether (20 kg each time) and concentrated, to a final volume of about 20 L. The batch was further azeotropically dried by a series of dilution with methyl isobutyl ketone 25 kg and concentrated under vacuum to a final solution (40 L) of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide free base 20.1 kg (72.1 mol, 72% molar yield) which was diluted to circa 130 L with methyl isobutyl ketone and added with 37% hydrochloric acid (7.6 kg). The mixture was dried azeotropically by repeated cycles of dilution with methyl isobutyl ketone and then concentrated under vacuum at <45° C. to about 100 L residual volume. The precipitated solid was filtered and was washed sequentially with methyl isobutyl ketone 40 kg and heptanes 70 kg. The wet product was dried at 40° C., to give 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride 19.0 kg (60.3 mol) as a white solid in 84% yield from 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide free base.

Example 13

Synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride

[0122] A solution of 1-butoxy-3-(2-methoxyvinyl)benzene; 20.7 Kg (25.8 kg×80.2% assay, 100.3 mol=1 equivalent), 2N aqueous hydrochloric acid (7.3 Kg) and acetonitrile 278 Kg was kept at about 0° C. until reaction completion (1-butoxy-3-(2-methoxyvinyl)benzene <3%). This was added to a mixture containing 2-amino-N,N-dimethylacetamide hydrochloride (VI) (111.7 mol), (readily prepared in situ from N-Boc-2-amino-N,N-dimethylacetamide and hydrochloric acid) water 6.2 Kg and acetonitrile 93 kg at about 10°.

[0123] The thus obtained mixture was warmed to and held at 40° C. until reaction completion. The temperature of the stirred batch was adjusted to about 0° C. Acetonitrile 93 kg and sodium triacetoxyborohydride 44.3 kg (99% assay, 207 mol.) were added to the stirred mixture kept at 5° C. After complete reaction (<2% residual quantity of 3-n-butoxy-phenylacetaldehyde), the batch was quenched with water 207 kg and the mixture was concentrated in vacuo under stirring at circa 40° C. to about 90 L. The batch was extracted with methyl tert-butyl ether (104 kg). The organic layer was washed with water twice (about 133 kg each time). The combined aqueous layers were extracted with methyl tert-butyl ether 104 kg, and the separated organic layer was washed with water 62 kg. The pH of the combined aqueous layers was adjusted to about 9 using 30% aqueous sodium hydroxide solution and extracted with methyl tert-butyl ether twice (104 kg each time). The combined organic layer was concentrated under vacuum, using a series of dilution with methyl tert-butyl ether (20 kg each time) and concentrated, to a final volume of about 20 L. The batch was further azeotropically dried by a series of dilution with methyl isobutyl ketone 25 kg and concentrated under vacuum to a final solution(40 L) of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide free base 19.1 kg (68.5 mol, 68.4% molar yield) which was diluted to circa 130 L with methyl isobutyl ketone and added with 37% hydrochloric acid (7.6 kg). The mixture was dried azeotropically by repeated cycles of dilution with methyl isobutyl ketone and then concentrated under vacuum at <45° C. to about 100 L residual volume. The precipitated solid was filtered and was washed sequentially with methyl isobutyl ketone 40 kg and heptanes 70 kg. The wet product was dried at 40° C., to give 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride 18.2 kg (57.8 mol) as a white solid in 80% yield from 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide free base.

Example 14

Synthesis of 1-butoxy-3-phenylacetaldehyde (V)

[0124] A solution consisting of 1-butoxy-3-(2-methoxyvinyl)benzene (200 mg, 0.001 mol), of HCl gas (0.001 mol) in THE (0.4 ml) and of acetonitrile (10V) was stirred at 25° C. for 30′ to provide a solution of 1-butoxy-3-phenylacetaldehyde (V) in CH.sub.3CN. The obtained solution was added to a mixture containing 2-amino-N,N-dimethylacetamide hydrochloride as per example 4.

Example 15

Synthesis of 1-butoxy-3-phenylacetaldehyde (V)

[0125] A solution consisting of 1-butoxy-3-(2-methoxyvinyl) benzene (200 mg, 0.001 mol), of HCl gas (0.001 mol., 1 equivalent) in EA (1 ml) and of CH.sub.3CN (10V) was stirred at 0° C. for 30′ to provide a solution of 1-butoxy-3-phenylacetaldehyde (V) in CH.sub.3CN). The obtained solution was added to a mixture containing 2-amino-N,N-dimethylacetamide hydrochloride as per example 4.

Example 16

Synthesis of 1-butoxy-3-phenylacetaldehyde (V)

[0126] A solution consisting of 1-butoxy-3-(2-methoxyvinyl)benzene (206.29 g, 1 mol, 1 equivalent), of gas HCl (7.3 g, 0.2 equivalent) in MTBE (100 ml), H2O (18.0 g, 1 mol.) and of CH.sub.3CN (10V) was stirred at 0-5° C. for 2 h to provide a solution of 1-butoxy-3-phenylacetaldehyde (V). The so obtained solution was added to a mixture containing 2-amino-N,N-dimethylacetamide hydrochloride as per example 4.

Example 17

Synthesis of 1-butoxy-3-phenylacetaldehyde (V)

[0127] A solution consisting of 1-butoxy-3-(2-methoxyvinyl)benzene (206.29 g, 1 mol., 1 equivalent), of 3N aqueous HCl (67 ml, 0.2 equivalent) and of CH3CN (10V) was stirred at 0-5° C. for 30′ to provide a solution of 1-butoxy-3-phenylacetaldehyde (V). The obtained solution was added to a mixture containing 2-amino-N,N-dimethylacetamide hydrochloride as per example 4.

Example 18

Synthesis and isolation of 1-butoxy-3-phenylacetaldehyde (V)

[0128] A solution of 1-butoxy-3-(2-methoxyvinyl)benzene; 20.7 g, 2 N aqueous hydrochloric acid (7.3 g) and acetonitrile (278 g) was kept at about 0° C. until reaction completion (1-butoxy-3-(2-methoxyvinyl)benzene <3%). The reaction medium was made neutral by adding diluted sodium hydroxide. The batch was extracted with methyl tert-butyl ether and the solution was washed with water. Distillation of the solvent under reduced pressure provided 1-butoxy-3-phenylacetaldehyde (V) as residue.