Process for synthesis of Eliglustat and intermediate compounds thereof

Abstract

The present invention relates to a process for synthesis of Eliglustat and intermediate compounds thereof. In particular, the present invention relates to a process for synthesis of Eliglustat and pharmaceutically acceptable salts thereof, and relates to the intermediate compounds in the process and a process for preparation of the intermediate compounds.

Claims

1. A process for preparation of Eliglustat or a pharmaceutically acceptable salt thereof, ##STR00097## the process comprising the following steps: (a-3) reducing Compound VII by catalytic hydrogenation with a metal catalyst or reducing Compound VII with organophosphorus reagent, to give Compound VIII, ##STR00098## wherein R.sub.5 is hydrogen or a hydroxy-protecting group selected from the group consisting of alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, acyl and silyl protective group, (a-4) amidation reaction of Compound VIII with Compound IX to give Compound X, ##STR00099## wherein R.sub.6 is selected from the group consisting of hydroxy, halogen and succimidyloxy, and wherein R.sub.5 is either hydrogen, whereby Compound X is Eliglustat, or R.sub.5 is the hydroxy-protecting group and the process further comprises the following step: (a-5) deprotecting Compound X to remove the hydroxy-protecting group to give Eliglustat ##STR00100## wherein the process comprises the following steps before step (a-3): (a-1) sulfonylation reaction of Compound V to give Compound VI, ##STR00101## wherein M is alkyl, aryl, substituted aryl or substituted alkyl, (a-2) reacting Compound VI with pyrrolidine to give Compound VII, ##STR00102## and wherein the process comprises the following steps before step (a-1): (c-1) coupling reaction of Compound I with Compound II in the presence of Lewis acid, deacid reagent and coordination agent, to give Compound III, ##STR00103## wherein each of R.sub.1, R.sub.2 and R.sub.4, independent of each other, is selected from the group consisting of hydrogen, alkyl, aryl and aralkyl, (c-2) optionally, reacting Compound III with a hydroxy-protecting reagent in the presence of base to give Compound IV, ##STR00104## and (c-3) preparing the compound of formula V by one of the following steps: (c-3.1a) reducing Compound III to obtain Compound V wherein R.sub.5 is hydrogen ##STR00105## or (c-3.1b) reducing Compound IV to obtain Compound V wherein R.sub.5 is the hydroxy-protecting group ##STR00106## or (c-3.2a) oxidizing Compound III to give Compound XI-1, and reducing Compound XI-1 to obtain Compound XI wherein R.sub.5 is hydrogen ##STR00107## or (c-3.2b) oxidizing Compound IV to give Compound V-1, and reducing Compound V-1 to obtain Compound V wherein R.sub.5 is the hydroxy-protecting group ##STR00108##

2. The process according to claim 1, wherein in step c-1, the Lewis acid is titanium tetrachloride or tin dichloride, the deacid reagent is an organic base, and the coordination agent is N-methyl pyrrolidone; wherein in optional step c-2, the reaction solvent is an organic aprotic solvent or solvents; wherein in each of steps c-3.1(a) and (b), the reducing is carried out with an reducing agent selected from the group consisting of sodium borohydride, potassium borohydride, boron trifluoride etherate, boranes, and a mixture of any two or more thereof; and wherein in each of steps c-3.2(a) and (b), the oxidizing is carried out with an oxidizing agent that is a peroxide or a manganese-containing salt with or without catalysis of a base selected from the group consisting of alkali metal, alkaline earth metal hydroxide and alkaline earth metal carbonate, and the reducing is carried out with a reducing agent selected from the group consisting of sodium borohydride, potassium borohydride, boron trifluoride etherate, boranes, and a mixture of any two or more thereof.

3. The process according to claim 1, wherein R.sub.6 is chloro or succimidyloxy.

4. The process according to claim 1, wherein in step (a-1), the sulfonylation reaction is carried out with sulfonyl halide without a catalyst or with a suitable amount of acylation catalyst.

5. The process according to claim 1, wherein in step (a-2), the pyrrolidine is reacted with the sulfonate of formula VI in an organic aprotic solvent or solvents.

6. The process according to claim 1, wherein in step (a-3), Compound VII is reduced by catalytic hydrogenation with the metal catalyst, wherein the metal catalyst is a Pd catalyst or a Ni catalyst.

7. The process according to claim 1, wherein R.sub.6 is hydroxy and the amidation reaction of Compound VIII with Compound IX is carried out under catalysis of a coupling agent for amidation to give Compound X.

8. The process according to claim 1, wherein R.sub.6 is chloro or succimidyloxy, and the amidation reaction of Compound VIII with Compound IX yields Compound X.

9. The process according to claim 1, wherein R.sub.5 is the silyl protective group, and the reaction of step a-5 is carried out in the presence of an acid, a fluorine-containing salt or a base selected from the group consisting of alkali metal, alkaline earth metal hydroxide and alkaline earth metal carbonate.

10. The process according to claim 1, wherein R.sub.5 is an alkyl, haloalkyl, alkoxyalkyl or an allyl protective group and the reaction of step a-5 is carried out in the presence of an acid.

11. The process according to claim 1, wherein R.sub.5 is the aralkyl protective group and the reaction of step a-5 is carried out under catalytic hydrogenation with metal catalyst, wherein the metal catalyst is a Pd catalyst or a Ni catalyst.

12. The process according to claim 1, wherein R.sub.5 is p-methoxybenzyl and the reaction of step a-5 is carried out in the presence of an oxidizing agent.

13. The process according to claim 1, wherein R.sub.5 is an acyl protective group and the reaction of step a-5 removes the acyl from the acyl protective group.

14. The process according to claim 1, wherein R.sub.5 is hydrogen, and the process consists of reaction steps (a-1), (a-2), (a-3) and (a-4).

15. A compound of formula V: ##STR00109## wherein R.sub.5 is hydrogen or a hydroxy-protecting group selected from the group consisting of alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, acyl and silyl protective group.

16. The compound according to claim 14, having the structure of formula XI: ##STR00110##

17. A compound of formula VII: ##STR00111## wherein R.sub.5 is hydrogen or a hydroxy-protecting group selected from the group consisting of alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, acyl and silyl protective group.

18. The compound according to claim 16, having the structure of formula XII ##STR00112##

Description

EXAMPLES

(1) The embodiments of the present invention will be further illustrated by the following examples. It should be understood that the following examples are provided to help further understand the present invention, not intended to limit the scope of the present invention in any manner.

Example 1: Preparation of 3-((2S,3R)-2-azido-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxypropanoyl)-4-phenyloxazolidin-2-one (Compound III-1)

(2) ##STR00076##

(3) 10 mmol Compound I (wherein R.sub.1 and R.sub.2 are hydrogen, R.sub.4 is phenyl) was dissolved in 100 ml dichloromethane, to which 12 mmol titanium tetrachloride was added dropwise at ?78? C. After the mixture was stirred for 20 minutes, 15 mmol DIPEA was added. After the mixture was further stirred for 3 hours, 20 mmol N-methyl pyrrolidone was added. After the addition was completed, the reaction mixture was stirred for 30 minutes, and then 15 mmol 2,3-dihydrobenzo[b][1,4]dioxin-6-formaldehyde was added. After the addition was completed, the reaction mixture was maintained for 30 minutes. The reaction mixture was warmed to ?20 to 30? C. and maintained for 2 hours at the temperature. Subsequently, saturated ammonium chloride aqueous solution was added to quench the reaction. The reaction mixture was extracted with dichloromethane twice. The organic phases were combined, washed with water, dried and concentrated to give 2.5 g of the product Compound III-1.

(4) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.40-7.26 (m, 5H), 6.99 (d, 1H), 6.91 (dd, 1H), 6.84 (d, 1H), 5.33 (dd, 1H), 5.18 (d, 1H), 5.15-5.13 (m, 1H), 4.59 (t, 1H), 4.25 (dd, 1H), 4.22 (s, 4H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 168.06, 153.28, 143.56, 143.49, 138.15, 132.56, 129.31, 129.20, 128.96, 126.05, 125.81, 119.24, 117.29, 115.32, 73.70, 70.65, 65.69, 64.35, 64.29, 57.90; HR-MS (ESI) calcd for C.sub.20H.sub.19O.sub.6N.sub.4(M+H).sup.+: 411.1305, found 411.1312.

Example 2: Preparation of (S)-3-((2S,3R)-2-azido-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-((trimethylsilyl)oxy)propanoyl)-4-phenyloxazolidin-2-one (Compound IV, wherein R1 and R2 are hydrogen, R4 is phenyl, R5 is trimethylsilyl)

(5) ##STR00077##

(6) 10 mmol Compound III-1 (wherein R.sub.1 and R.sub.2 are hydrogen, R.sub.4 is phenyl, R.sub.5 is hydrogen) was dissolved in 200 ml dichloromethane, to which 12 mmol triethylamine was added at 0? C., and then 11 mmol trimethylsilyl chloride was added slowly. After the addition was completed, the reaction was maintained for 3 hours. The reaction mixture was quenched by adding water. Organic phase was dried and concentrated to give 4.3 g of Compound IV (wherein R.sub.1 and R.sub.2 are hydrogen, R.sub.4 is phenyl, R.sub.5 is trimethylsilyl).

(7) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.40-7.26 (m, 5H), 6.99 (d, 1H), 6.91 (dd, 1H), 6.83 (d, 1H), 5.24 (dd, 1H), 5.12 (d, 1H), 5.05 (d, 1H), 4.51 (t, 1H), 4.29-4.26 (m, 1H), 4.24 (s, 4H), 0.07 (s, 9H); .sup.13C NMR (101 MHz, CDCl.sub.3) 167.86, 153.04, 143.34, 143.28, 138.11, 133.37, 129.30, 128.96, 125.78, 119.41, 116.98, 115.48, 75.30, 70.46, 66.08, 64.33, 64.30, 57.90, ?0.29; HR-MS (ESI) calcd for C.sub.23H.sub.27O.sub.6N.sub.4 (M+H).sup.+: 483.1700, found 483.1717.

Example 3: Preparation of (S)-3-((2S,3R)-2-azido-3-((tert-butyldimethylsilyl)oxy)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propanoyl)-4-phenyloxazolidin-2-one (Compound IV, wherein R1 and R2 are hydrogen, R4 is phenyl, R5 is tert-butyldimethylsilyl)

(8) ##STR00078##

(9) 10 mmol Compound III-1 (wherein R.sub.1 and R.sub.2 are hydrogen, R.sub.4 is phenyl, R.sub.5 is hydrogen) was dissolved in 200 ml dichloromethane, to which 12 mmol triethylamine was added at 0? C., and then 11 mmol tert-butyldimethylsilyl chloride was added slowly. After the addition was completed, the reaction was maintained for 3 hours. The reaction mixture was quenched by adding water. Organic phase was dried and concentrated to give 4.8 g of Compound IV (wherein R.sub.1 and R.sub.2 are hydrogen, R.sub.4 is phenyl, R.sub.5 is tert-butyldimethylsilyl).

(10) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.33-7.22 (m, 3H), 7.20-7.13 (m, 3H), 6.97 (d, 1H), 6.90 (d, 1H), 5.67 (ddt, 1H), 5.44 (dt, 1H), 4.47-4.40 (m, 2H), 4.28-4.17 (m, 4H), 4.10 (dd, 1H), 0.85 (s, 7H), ?0.06 (s, 4H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 171.90, 154.26, 143.28, 143.18, 137.83, 133.03, 128.25, 128.02, 127.45, 120.01, 114.41, 112.33, 76.73, 69.67, 63.72, 63.26, 63.20, 57.36, 25.61, 17.98, ?4.77; HR-MS (ESI) calcd for C.sub.26H.sub.32O.sub.6N.sub.4Si (M+H).sup.+: 524.2091, found 524.2084.

Example 4: Preparation of (1R,2R)-2-azido-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propane-1,3-diol (Compound XI)

(11) ##STR00079##

(12) 7 mmol Compound III-1 was dissolved in a mixed solvent of 60 ml tetrahydrofuran and 10 ml water, to which 35 mmol sodium borohydride was added at 0? C. After the addition was completed, the reaction mixture was warmed to 25? C. and maintained for 3 hours at the temperature. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate twice. The combined organic phases were washed with sodium bicarbonate solution, dried and concentrated to give 1.7 g of Compound XI.

(13) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 6.80-6.89 (m, 3H), 4.66 (d, J=6.8 Hz, 1H), 4.25 (m, 4H), 3.59-3.66 (m, 2H), 3.50-3.57 (m, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 143.4, 133.5, 118.9, 117.7, 114.8, 74.1, 68.8, 64.0, 62.9; HR-MS (ESI) calcd for C.sub.11H.sub.14O.sub.4N.sub.3 (M+H).sup.+: 252.0984, found 252.0988.

Example 5: Preparation of (2R,3R)-2-azido-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-((trimethylsilyl)oxy)propane-1-ol (Compound V, wherein R5 is trimethylsilyl)

(14) ##STR00080##

(15) 7 mmol Compound IV was dissolved in a mixed solvent of 60 ml tetrahydrofuran and 10 ml water, to which 35 mmol sodium borohydride was added at 0? C. After the addition was completed, the reaction mixture was warmed to 25? C. and maintained for 3 hours at the temperature. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate twice. The combined organic phases were washed with sodium bicarbonate solution, dried and concentrated to give 2.5 g of Compound V.

(16) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.09-7.00 (m, 2H), 6.88 (d, 1H), 4.73-4.68 (m, 1H), 4.28-4.17 (m, 4H), 3.62-3.53 (m, 1H), 3.42-3.31 (m, 2H), 2.68 (t, 1H), 0.16 (s, 7H).; .sup.13C NMR (101 MHz, CDCl.sub.3) ? 143.14, 143.12, 133.45, 119.83, 114.35, 112.44, 76.61, 68.15, 63.63, 63.60, 62.78, ?0.26; HR-MS (ESI) calcd for C.sub.14H.sub.21O.sub.4N.sub.3Si (M+H).sup.+: 323.1301, found 323.1321.

Example 6: Preparation of (2R,3R)-2-azido-3-((tert-butyldimethylsilyl)oxy)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propane-1-ol (Compound V, wherein R5 is tert-butyldimethylsilyl)

(17) ##STR00081##

(18) 7 mmol Compound IV was dissolved in a mixed solvent of 60 ml tetrahydrofuran and 10 ml water, to which 35 mmol sodium borohydride was added at 0? C. After the addition was completed, the reaction mixture was warmed to 25? C. and maintained for 3 hours at the temperature. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate twice. The combined organic phases were washed with sodium bicarbonate solution, dried and concentrated to give 2.8 g of Compound V.

(19) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.09-7.02 (m, 2H), 6.88 (d, 1H), 4.85-4.80 (m, 1H), 4.28-4.17 (m, 4H), 3.69 (ddd, 1H), 3.60 (td, 1H), 3.50 (ddd, 1H), 2.68 (t, 1H), 0.84 (s, 6H), 0.02 (s, 4H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 143.14, 143.14, 133.42, 119.89, 114.34, 112.39, 76.07, 68.60, 63.47, 63.44, 62.45, 25.59, 18.00, ?4.76; HR-MS (ESI) calcd for C.sub.17H.sub.27O.sub.4N.sub.3Si (M+H).sup.+: 365.1771, found 365.1782.

Example 7: Preparation of (1R,2S)-2-azido-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxo-3-((S)-2-oxo-4-phenyloxazolidin-3-yl)propyl benzoate (Compound IV, wherein R1 and R2 are hydrogen, R4 is phenyl, R5 is benzoyl)

(20) ##STR00082##

(21) 10 mmol Compound III-1 (wherein R.sub.1 and R.sub.2 are hydrogen, R.sub.4 is phenyl, R.sub.5 is hydrogen) was dissolved in 200 ml dichloromethane, to which 12 mmol triethylamine was added at 0? C., and then 11 mmol benzoyl chloride was added slowly. After the addition was completed, the reaction was maintained for 3 hours. The reaction mixture was quenched by adding water. Organic phase was dried and concentrated to give 4.9 g of Compound VI (wherein R.sub.1 and R.sub.2 are hydrogen, R.sub.4 is phenyl, R.sub.5 is benzoyl).

(22) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.17-8.07 (m, 2H), 7.62-7.56 (m, 1H), 7.49-7.45 (m, 2H), 7.40-7.33 (m, 3H), 7.30-7.27 (m, 2H), 7.13 (s, 1H), 7.06 (dd, 1H), 6.89 (d, 1H), 6.62 (d, 1H), 5.30-5.27 (m, 2H), 4.80 (t, 1H), 4.35 (dd, 1H), 4.25 (s, 4H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 167.55, 165.53, 153.74, 143.86, 143.58, 138.17, 134.56, 133.66, 130.56, 130.03, 129.28, 129.19, 128.96, 128.94, 128.88, 128.61, 125.91, 119.49, 117.54, 115.48, 74.88, 70.88, 68.31, 64.42, 64.34, 64.30, 58.11; HR-MS (ESI) calcd for C.sub.27H.sub.23O.sub.7N.sub.4 (M+H).sup.+: 515.1567, found 515.1558.

Example 8: Preparation of (1R,2R)-2-azido-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propane-1,3-diol (Compound XI)

(23) ##STR00083##

(24) 7 mmol Compound XI-1 was dissolved in 60 ml tetrahydrofuran, to which 14 mmol sodium borohydride and 8 mmol boron trifluoride etherate were added at 0? C. After the addition was completed, the reaction mixture was stirred for 3 hours while the temperature was maintained. After the reaction was completed, dilute hydrochloric acid was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate twice. The combined organic phases were washed with sodium bicarbonate solution, dried and concentrated to give 1.4 g of Compound XI.

(25) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 6.80-6.89 (m, 3H), 4.66 (d, J=6.8 Hz, 1H), 4.25 (m, 4H), 3.59-3.66 (m, 2H), 3.50-3.57 (m, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 143.4, 133.5, 118.9, 117.7, 114.8, 74.1, 68.8, 64.0, 62.9; HR-MS (ESI) calcd for C.sub.11H.sub.14O.sub.4N.sub.3 (M+H).sup.+: 252.0984, found 252.0988.

Example 9: Preparation of (2R,3R)-2-azido-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-((trimethylsilyl)oxy)propyl 4-methylbenzenesulfonate (Compound VI, wherein R5 is trimethylsilyl)

(26) ##STR00084##

(27) 9 mmol Compound V (wherein R.sub.5 is trimethylsilyl) was dissolved in 200 ml dichloromethane, to which 12 mmol triethylamine and 10 mg DMAP were added at 0? C. 10 mmol p-toluenesulfonyl chloride was added slowly. After the addition was completed, the reaction was maintained for 3 hours. The reaction mixture was quenched by adding water. Organic phase was dried and concentrated to give 3.7 g of Compound VI (wherein R.sub.5 is trimethylsilyl).

(28) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.75-7.73 (m, 2H), 7.34-7.32 (m, 2H), 6.78-6.76 (m, 2H), 6.68 (dd, 1H), 4.58 (d, 1H), 4.24 (s, 4H), 3.93 (dd, 1H), 3.71 (dd, 1H), 3.55-3.51 (m, 1H), 2.44 (s, 3H), 0.00 (s, 9H); .sup.13C NMR (101 MHz, cdcl.sub.3) ? 145.07, 143.56, 143.49, 133.13, 132.44, 129.88, 127.97, 119.43, 117.30, 115.32, 74.63, 68.37, 65.95, 64.29, 64.27, 26.89, ?0.12; HR-MS (ESI) calcd for C.sub.21H.sub.28O.sub.6N.sub.3SSi (M+H).sup.+: 478.1468, found 478.1463.

Example 10: Preparation of (2R,3R)-2-azido-3-((tert-butyldimethylsilyl)oxy)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propyl 4-methylbenzenesulfonate (Compound VI, wherein R5 is tert-butyldimethylsilyl)

(29) ##STR00085##

(30) 9 mmol Compound V (wherein R.sub.5 is tert-butyldimethylsilyl) was dissolved in 200 ml dichloromethane, to which 12 mmol triethylamine and 10 mg DMAP were added at 0? C. 10 mmol p-toluenesulfonyl chloride was added slowly. After the addition was completed, the reaction was maintained for 3 hours. The reaction mixture was quenched by adding water. Organic phase was dried and concentrated to give 4.2 g of Compound VI (wherein R.sub.5 is tert-butyldimethylsilyl).

(31) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.75-7.69 (m, 2H), 7.48 (dq, 2H), 7.12 (dd, 1H), 6.95 (d, 1H), 6.90 (d, 1H), 4.74 (d, 1H), 4.28-4.17 (m, 5H), 3.96 (dd, 1H), 3.61 (q, 1H), 2.37 (d, 3H), 0.85 (s, 7H), ?0.06 (s, 4H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 143.59, 143.21, 143.16, 134.03, 133.24, 129.69, 128.09, 120.03, 114.38, 112.44, 76.17, 68.10, 66.52, 63.59, 63.56, 25.61, 21.53, 17.98, ?4.80; HR-MS (ESI) calcd for C.sub.24H.sub.33O.sub.6N.sub.3SSi (M+H): 519.1859, found 519.1866.

Example 11: Preparation of (2R,3R)-2-azido-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxypropyl 4-methylbenzenesulfonate (Compound VI, wherein R5 is hydrogen)

(32) ##STR00086##

(33) 9 mmol Compound XI (wherein R.sub.5 is hydrogen) was dissolved in 200 ml dichloromethane, to which 12 mmol triethylamine and 10 mg DMAP were added at 0? C. 10 mmol p-toluenesulfonyl chloride was added slowly. After the addition was completed, the reaction was maintained for 3 hours. The reaction mixture was quenched by adding water. Organic phase was dried and concentrated to give 3.5 g of Compound VI (wherein R.sub.5 is hydrogen).

(34) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.81 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 6.75-6.87 (m, 3H), 4.60 (d, J=6.4 Hz, 1H), 4.28 (s, 4H), 4.11 (dd, J=3.6 Hz, 10.4 Hz, 1H), 3.90 (dd, J=7.2 Hz, 10.4 Hz, 1H), 3.67-3.71 (m, 1H), 2.45 (s, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 145.5, 144.2, 143.9, 132.1, 129.7, 128.3, 119.0, 117.9, 114.8, 73.1, 69.1, 65.7, 64.1; HR-MS (ESI) calcd for C.sub.18H.sub.20O.sub.6N.sub.3S (M+H).sup.+: 406.1037, found 406.1035.

Example 12: Preparation of 1-((2R,3R)-2-azido-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-((trimethylsilyl)oxy)propyl)pyrrolidine (Compound VII, wherein R5 is trimethylsilyl)

(35) ##STR00087##

(36) 5 mmol Compound VI (wherein R.sub.5 is trimethylsilyl) was dissolved in 50 ml DMF, to which 15 mmol pyrrolidine was added. The reaction was stirred at 60? C. for 10 hours. After the reaction was completed, water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate twice. The combined organic phases were washed with water, dried and concentrated to give 1.0 g of Compound VII (wherein R.sub.5 is trimethylsilyl).

(37) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 6.82-5.74 (m, 3H), 4.60 (d, 1H), 4.23 (s, 4H), 3.44-3.39 (m, 1H), 2.52-2.41 (m, 5H), 2.33 (dd, 1H), 1.75-1.72 (m, 4H), 0.03 (s, 9H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 160.05, 139.96, 128.98, 128.47, 125.97, 72.29, 64.26, 64.19, 56.28, 54.07, 23.45, 21.74, 0.09; HR-MS (ESI) calcd for C.sub.18H.sub.31O.sub.3N.sub.2Si (M+H).sup.+: 376.1931, found 376.1940.

Example 13: Preparation of (1R,2R)-2-azido-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propane-1-ol (Compound XII)

(38) ##STR00088##

(39) 5 mmol Compound VI (wherein R.sub.5 is hydrogen) was dissolved in 50 ml DMF, to which 15 mmol pyrrolidine was added. The reaction was stirred at 60? C. for 10 hours. After the reaction was completed, water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate twice. The combined organic phases were washed with water, dried and concentrated to give 1.1 g of Compound XII.

(40) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 6.82-6.92 (m, 3H), 4.93 (m, 1H), 4.24 (s, 4H), 4.10 (m, 1H), 3.15-3.19 (m, 1H), 3.07 (m, 4H), 2.81-2.87 (m, 1H), 1.96 (m, 4H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 143.7, 134.1, 119.8, 117.5, 115.9, 75.5, 64.1, 63.9, 56.7, 54.4, 23.8; HR-MS (ESI) calcd for C.sub.15H.sub.21O.sub.3 N.sub.4(M+H).sup.+: 305.1608, found 305.1611.

Example 14: Preparation of 1-((2R,3R)-2-azido-3-((tert-butyldimethylsilyl)oxy)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propyl)pyrrolidine (Compound XII)

(41) ##STR00089##

(42) 5 mmol Compound VI (wherein R.sub.5 is tert-butyldimethylsilyl) was dissolved in 50 ml DMF, to which 15 mmol pyrrolidine was added. The reaction was stirred at 60? C. for 10 hours. After the reaction was completed, water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate twice. The combined organic phases were washed with water, dried and concentrated to give 2.1 g of Compound XII.

(43) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.09-7.02 (m, 2H), 6.88 (d, 1H), 4.75-4.70 (m, 1H), 4.28-4.17 (m, 4H), 3.47 (q, 1H), 2.93-2.79 (m, 4H), 2.53 (dd, 1H), 2.02 (dd, 1H), 1.84 (hept, 4H), 0.84 (s, 7H), 0.02 (s, 4H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 143.18, 143.15, 132.60, 120.03, 114.34, 112.38, 78.23, 63.80, 63.78, 63.69, 59.99, 54.51, 25.61, 23.73, 18.03, ?4.78; HR-MS (ESI) calcd for C.sub.21H.sub.34O.sub.3N.sub.4Si (M+H).sup.+: 418.2400, found 418.2413.

Example 15: Preparation of (1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)-1-((trimethylsilyl)oxy)propan-2-amine (Compound VIII, wherein R5 is trimethylsilyl)

(44) ##STR00090##

(45) 4 mmol Compound VII (wherein R.sub.5 is trimethylsilyl) was dissolved in 200 ml methanol, to which 20 mg of 5% Pd/C was added. The reaction was carried out under 0.1 MPa of hydrogen pressure at 25? C. for 10 hours. After the reaction was completed, the reaction mixture was filtrated and concentrated to give 1.3 g of Compound VIII (wherein R.sub.5 is trimethylsilyl).

(46) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.15-7.10 (m, 1H), 7.07-7.00 (m, 1H), 6.88 (d, 1H), 4.46 (d, 1H), 4.28-4.17 (m, 4H), 3.59 (d, 2H), 3.25 (qt, 1H), 2.91-2.77 (m, 4H), 2.49 (dd, 1H), 2.40 (dd, 1H), 1.89-1.80 (m, 4H), 0.16 (s, 7H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 143.16, 142.99, 134.17, 120.00, 114.33, 112.41, 78.06, 63.52, 63.50, 61.58, 54.57, 53.62, 23.64, ?0.26; HR-MS (ESI) calcd for C.sub.18H.sub.30O.sub.3 N.sub.2Si (M+H).sup.+: 350.2026, found 350.2032.

Example 16: Preparation of (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propane-1-ol (Compound VIII, wherein R5 is hydrogen)

(47) ##STR00091##

(48) 2 mmol Compound XII (wherein R.sub.5 is hydrogen) was dissolved in 100 ml methanol, to which 10 mg of 5% Pd/C was added. The reaction was carried out under 0.1 MPa of hydrogen pressure at 25? C. for 10 hours. After the reaction was completed, the reaction mixture was filtrated and concentrated to give 0.6 g of Compound VIII (wherein R.sub.5 is hydrogen).

(49) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 6.77-6.85 (m, 3H), 5.85 (d, J=7.2 Hz, 1H), 4.91 (d, J=3.6 Hz, 1H), 4.23 (s, 4H), 4.15-4.21 (m, 1H), 2.74-2.83 (m, 2H), 2.61-2.67 (m, 4H), 2.07-2.11 (m, 2H), 1.79-1.81 (m, 4H), 1.51-1.56 (m, 2H), 1.22-1.33 (m, 10H), 0.89 (t, J=6.8 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 174.1, 143.2, 142.7, 134.6, 119.2, 117.3, 115.1, 75.6, 64.5, 57.9, 55.1, 52.0, 36.5, 31.7, 29.5, 29.1, 25.8, 23.4, 22.7, 13.9. HR-MS (ESI) calcd for C.sub.23H.sub.37O.sub.4 N.sub.2(M+H).sup.+: 405.2748, found 405.2741.

Example 17: Preparation of (1R,2R)-1-((tert-butyldimethylsilyl)oxy)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-2-amine (Compound VIII, wherein R5 is tert-butyldimethylsilyl)

(50) ##STR00092##

(51) 2 mmol Compound XII (wherein R.sub.5 is tert-butyldimethylsilyl) was dissolved in 100 ml methanol, to which 10 mg of 5% Pd/C was added. The reaction was carried out under 0.1 MPa of hydrogen pressure at 25? C. for 10 hours. After the reaction was completed, the reaction mixture was filtrated and concentrated to give 1.1 g of Compound VIII (wherein R.sub.5 is tert-butyldimethylsilyl).

(52) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.14-7.09 (m, 1H), 7.03 (dd, 1H), 6.88 (d, 1H), 4.67 (dt, 1H), 4.28-4.17 (m, 4H), 3.59 (d, 2H), 3.24 (qt, 1H), 2.92-2.77 (m, 4H), 2.74 (dd, 1H), 2.40 (dd, 1H), 1.89-1.80 (m, 4H), 0.84 (s, 7H), 0.01 (s, 4H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 143.17, 143.04, 134.13, 120.03, 114.33, 112.46, 76.86, 63.55, 63.52, 61.53, 54.58, 53.69, 25.61, 23.74, 17.89, ?4.79; HR-MS (ESI) calcd for C.sub.21H.sub.36O.sub.3N.sub.2Si (M+H).sup.+: 392.2495, found 392.2483.

Example 18: Preparation of N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-((trimethylsilyl)oxy)-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (Compound X, wherein R5 is trimethylsilyl)

(53) ##STR00093##

(54) 1 mmol Compound VIII (wherein R.sub.5 is trimethylsilyl) was dissolved in 30 ml DMF, to which 1.5 mmol DIPEA and 1.2 mmol Compound IX (wherein R.sub.6 is succimidyloxy) were added. After the addition was completed, the reaction was maintained at 25? C. for 24 hours. After the reaction was completed, water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate twice. The combined organic phases were washed with water, dried and concentrated to give 0.5 g of Compound X.

(55) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 6.76-6.59 (m, 3H), 5.77 (d, 1H), 5.01 (d, 1H), 4.16 (s, 3H), 4.06 (q, 1H), 3.99 (dtd, 1H), 2.63 (dd, 1H), 2.58-2.38 (m, 4H), 2.24 (dd, 1H), 2.03 (td, 2H), 1.98 (s, 1H), 1.76-1.64 (m, 4H), 1.45 (p, 2H), 1.27-1.09 (m, 8H), 0.82 (t, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 172.55, 171.02, 142.91, 142.34, 135.90, 118.63, 116.57, 114.67, 71.33, 64.26, 64.18, 60.31, 56.47, 55.06, 54.26, 53.94, 36.76, 31.61, 29.03, 29.01, 25.64, 23.59, 22.59, 20.97, 14.14, 14.05, 1.36; HR-MS (ESI) calcd for C.sub.18H.sub.31O.sub.3N.sub.2Si (M+H).sup.+: 477.3149, found 477.3155.

Example 19: Preparation of N-((1R,2R)-1-((tert-butyldimethylsilyl)oxy)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (Compound X, wherein R5 is tert-butyldimethyl silyl)

(56) ##STR00094##

(57) 1 mmol Compound VIII (wherein R.sub.5 is tert-butyldimethylsilyl) was dissolved in 30 ml DMF, to which 1.5 mmol DIPEA and 1.2 mmol Compound IX (wherein R.sub.6 is succimidyloxy) were added. After the addition was completed, the reaction was maintained at 25? C. for 24 hours. After the reaction was completed, water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate twice. The combined organic phases were washed with water, dried and concentrated to give 0.9 g of Compound X.

(58) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.04 (ddd, 1H), 6.91-6.81 (m, 2H), 6.18 (d, 1H), 5.19 (d, 1H), 4.28-4.17 (m, 4H), 4.11 (dq, 1H), 2.91-2.83 (m, 2H), 2.86-2.76 (m, 2H), 2.59 (dd, 1H), 2.51 (dd, 1H), 2.26 (dt, 1H), 2.19 (dt, 1H), 1.83 (p, 4H), 1.63 (dt, 1H), 1.47 (dt, 1H), 1.39-1.14 (m, 7H), 0.94-0.84 (m, 3H), 0.85 (s, 6H), ?0.06 (s, 4H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 174.41, 143.16, 143.13, 134.01, 120.36, 114.37, 112.72, 76.42, 63.59, 63.56, 60.11, 54.61, 54.20, 35.54, 31.26, 28.68, 28.40, 25.62, 25.07, 23.79, 22.79, 17.98, 14.06, ?4.76; HR-MS (ESI) calcd for C.sub.29H.sub.50O.sub.4N.sub.2Si (M+H).sup.+: 518.3540, found 518.3549.

Example 20: Preparation of Eliglustat

(59) ##STR00095##

(60) 1 mmol Compound VIII (wherein R.sub.5 is hydrogen) was dissolved in 30 ml DMF, to which 1.5 mmol DIPEA and 1.2 mmol Compound IX (wherein R.sub.6 is succimidyloxy) were added. After the addition was completed, the reaction was maintained at 25? C. for 24 hours. After the reaction was completed, water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate twice. The combined organic phases were washed with water, dried and concentrated to give 0.3 g Eliglustat.

(61) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 6.72-6.90 (m, 3H), 5.83 (d, 1H), 4.89 (d, 1H), 4.25 (m, 4H), 4.15-4.19 (m, 1H), 2.71-2.77 (m, 2H), 2.56-2.70 (m, 4H), 2.10 (t, 2H), 1.73-1.82 (m, 4H), 1.46-1.57 (m, 2H), 1.15-1.30 (m, 8H), 0.88 (t, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 174.47, 143.25, 143.17, 135.21, 120.41, 114.34, 112.85, 74.96, 63.81, 63.60, 59.47, 54.48, 53.67, 35.86, 31.39, 28.44, 28.27, 25.39, 23.75, 22.71, 14.08. HR-MS (ESI) calcd for C.sub.23H.sub.37O.sub.2 N.sub.4 (M+H).sup.+: 405.2753, found 405.2760.

Example 21: Preparation of Eliglustat

(62) ##STR00096##

(63) 1 mmol Compound X (wherein R.sub.5 is trimethylsilyl) was dissolved in 30 ml THF, to which 20 ml of 2N HCl was added. After the addition was completed, the reaction was maintained at 25? C. for 2 hours. After the reaction was completed, water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate twice. Organic phases were combined, and washed with saturated sodium bicarbonate solution once. The resulting organic phase was dried and concentrated to give 0.4 g Eliglustat.

(64) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 6.72-6.90 (m, 3H), 5.83 (d, 1H), 4.89 (d, 1H), 4.25 (m, 4H), 4.15-4.19 (m, 1H), 2.71-2.77 (m, 2H), 2.56-2.70 (m, 4H), 2.10 (t, 2H), 1.73-1.82 (m, 4H), 1.46-1.57 (m, 2H), 1.15-1.30 (m, 8H), 0.88 (t, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 174.47, 143.25, 143.17, 135.21, 120.41, 114.34, 112.85, 74.96, 63.81, 63.60, 59.47, 54.48, 53.67, 35.86, 31.39, 28.44, 28.27, 25.39, 23.75, 22.71, 14.08. HR-MS (ESI) calcd for C.sub.23H.sub.37O.sub.2 N.sub.4(M+H).sup.+: 405.2753, found 405.2760.