Processes to produce brivaracetam

Abstract

The present invention provides a scalable synthesis of enantiomerically pure brivaracetam, and related derivatives.

Claims

1. A stereoselective process of making a compound of formula XII (brivaracetam) comprising converting a compound of formula X to the compound of formula XII: ##STR00019## wherein the converting comprises at least one of the following synthetic routes I and II: I. reacting the compound of formula X with (S)-2-aminobutanamide or its salt to produce a compound of formula XI; isolating the compound of formula XI, and converting the isolated compound of formula XI to the compound of XII (brivaracetam) ##STR00020## II. reacting the compound of Formula X with alkyl (S)-2-aminobutanoate to produce a compound of formula XI-a; isolating the compound of formula XI-a; converting the isolated compound of formula Xl-a to a compound of XII-a; isolating the compound of formula XII-a; and then converting the isolated compound of XII-a to the compound of formula XII ##STR00021## wherein R is NH.sub.2 or C1-C20 alkoxyl; if R is NH.sub.2, then XI-a is XI, and XII-a is XII; and wherein the process is free of a step of conducting chiral column chromatography purification or chiral HPLC separation of the compound of formula XII.

2. The process of claim 1, wherein the converting comprises the synthetic route I.

3. The process of claim 1, wherein the converting comprises the synthetic route II.

4. The process of claim 1 further comprising a step of converting a compound of formula VI to the compound of formula X ##STR00022##

5. The process of claim 4, wherein the step of converting the compound of formula VI to the compound of formula X comprises reacting the compound of VI with SOCl.sub.2 and a Lewis acid catalyst to produce the compound of formula X.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) In the drawings:

(2) FIG. 1 depicts process routes to produce key intermediate VI, which are embodiments of the present invention. The processes use a commercial available and inexpensive chiral pool starting material (compound I). Compound IV and Compound IV are new compounds.

(3) FIG. 2 depicts process routes to produce brivaracetam from the key intermediate VI, which are also embodiments of the present invention. Our synthesis (Route A) to brivaracetam comprises the making of intermediates of Compound VII and Compound IX, which are both novel. The Br in compound VII may also be another halogen, such as Cl or I, or OMs, OTs, ONs. The Et group in VII and IX may be H or C1-20 alkyl or C1alkyl-unsubstituted or substituted aryl.

(4) FIG. 3 depicts process routes to produce brivaracetam from the key intermediate VI, which are also embodiments of the present invention. Route B and Route C are our alternative synthesis to brivaracetam. Intermediate Compound X and Compound XI are new compounds. Route D may be conducted at high temperature and high pressure.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

Examples

Example 1

Preparation of (1S,5R)-ethyl 2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate (III)

(5) A mixture of sodium methoxide (2.05 g, 38 mmol) and diethyl malonate (6.3 mL, 42 mmol) in ethanol (80 mL) was stirred at 0° C. for 10 min. (R)-(-)-epichlorohydrin (2.7 mL, 35 mmol) was added dropwise (over 20 min) at room temperature. The reaction mixture was then heated to reflux for 18 h. Upon reaction completion, the solvent was evaporated. The residue was dissolved in water (100 mL) and extracted with ethylacetate (3×100 mL). The organic layers were combined and dried over Na2SO.sub.4. Filtration and evaporation of the solvent afforded crude material, which was purified by vacuum distillation to obtain the title compound (1S,5R)-ethyl 2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate as a viscous colorless oil. Yield 55%, ee 98%.

(6) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ4.33 (1H, dd), 4.23 (2H, q), 4.16 (1H, d), 2.73-2.75 (1H, m), 2.05 (1H, dd), 1.35 (1H, t), 1.28 (3H,t).

Example 2

Preparation of (4R)-ethyl 4-propyl-2-oxotetrahydrofuran-3-carboxylate (IV)

(7) To a stirred suspension of CuI (9.5 g, 50 mmol) in anhydrous THF at −30° C. was added ethyl magnesium bromide in THF (1.0 M, 300 mL, 300 mmol) dropwise. Stir at the same temperature for 1 h. A solution of compound III (20 g, 117 mmol) in anhydrous THF was added to the solution via cannula at −30° C. After stirred for 30 min, the reaction mixture was warmed to −15° C. and quenched with saturated ammonium chloride solution. The mixture was added water (1 L) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na.sub.2SO.sub.4. Filteration and evaporation afforded crude product IV, which was purified by silica gel column chromatography using Petroleum ether/Ethylacetate (10:1) to obtain the title compound IV.

(8) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ4.52 (1H, dd), 4.27 (2H, q), 3.92 (1H, dd), 3.23 (1H, d), 2.96-3.03 (1H, m), 1.49-1.56 (2H, m), 1.27-1.35 (5H, m), 0.95 (3H,t).
[α].sup.23.sub.D=+22.6 (C=10, CHCl.sub.3)

Example 3

Preparation of (R)-4-propyldihydrofuran-2(3H)-one (VI)

(9) The crude compound IV (about 117 mmol) and LiCl (14.7 g, 350 mmol) in DMSO/H2O (400 mL/20 mL) was heated for 18 h at 140° C. After the reaction was complete, water (400 mL) was added to the solution at room temperature. The solution was extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvent, the residue was purified by vacuum distillation to afford the title compound (R)-4-propyldihydrofuran-2(3H)-one (50% yield, yield for 2 steps) as a colorless oil.

(10) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ4.42 (1H, dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40-1.47 (2H, m), 1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H,t).
[α].sup.23.sub.D=+3.9 (C=10, CHCl.sub.3)

Example 4

Preparation of ethyl (R)-3-(bromomethyl)hexanoate (VII)

(11) TMSBr (3.1 mL, 24 mmol) was added to a solution of the compound VI (1.1 g, 7.8 mmol) and 2.5 ml ethanol in dry DCM (40 mL) at 0° C. The solution was stirred at room temperature overnight. The reaction mixture was added Na.sub.2S.sub.2O.sub.3 solution and water (50 mL) and was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvent, the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (20:1) to afford the title compound VII, ethyl (R)-3-(bromomethyl)hexanoate as a colorless oil, yield 87%.

(12) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ 4.16 (q, 2H), 3.58 (dd, 1H), 3.55 (dd, 1H), 2.51 (dd, 1H), 2.36 (dd, 1H), 2.15-2.30 (m, 1H), 1.25-1.51 (m, 7H), 0.94 (t, 3H).
[α].sup.23.sub.D=−3.8 (C=10, CHCl.sub.3)

Example 5

Preparation of ethyl (R)-3-((((S)-1-amino-1-oxobutan-2-yl)amino)methyl)hexanoate (IX)

(13) Compound (S)-2-aminobutanamide hydrochloride (3.4 g, 24.5 mmol), compound VII (2.83 g, 20.4 mmol), Na.sub.2CO.sub.3 (7.78 g, 73.4 mmol), and NaI (1.83 g, 12.2 mmol) were added to DMF (60 ml). The solution was stirred for 18 h at 90° C. After the reaction was complete, water (100 mL) was added to the solution at room temperature. The solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of the solvent afforded the crude product, which was purified by silica gel column chromatography using DCM/MeOH/TEA (100/1/1) to afford the title compound IX ethyl (R)-3-((((S)-1-amino-1-oxobutan-2-yl)amino)methyl)hexanoate (40% yield) as a yellow oil.

(14) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.03 (brs, 1H), 5.86 (brs, 1H), 4.13 (q, 2H), 2.96 (t, 1H), 2.54 (dd, 1H), 2.33 (dd, 1H), 1.78-2.10 (m, 1H), 1.56-1.75 (m, 2 H), 1.24-1.48 (m, 7 H), 0.85-1.03 (m, 6H).

Example 6

Preparation of Brivaracetam (XII)

(15) Compound IX (120 mg, 0.46 mmol) and HOBt (63 mg, 0.46 mmol) were added to toluene (1 ml). The solution was stirred for 3 h at 90° C. After the reaction was complete, saturated Na.sub.2CO.sub.3 solution (50 mL) was added to the reaction mixture at room temperature. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of the solvent afforded the crude product, which was purified by silica gel column chromatography using EA/TEA (100/1) to afford the title compound XII brivaracetam (41% yield, 98% ee) as a white solid.

(16) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ 6.42 (brs, 1H), 5.69 (brs, 1H), 4.46 (dd, 1H), 3.50 (dd, 1H), 3.05 (dd, 1H), 2.57 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 7

Preparation of Brivaracetam (XII)

(17) Compound IX (435 mg, 1.73 mmol) and 2-hydroxypyridine (82 mg, 0.86 mmol) were added to toluene (4 ml). The solution was stirred for 3 h at 90° C. After the reaction was complete, saturated Na.sub.2CO.sub.3 solution (50 mL) was added to the reaction mixture at room temperature. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of the solvent afforded the crude product, which was purified by silica gel column chromatography using PE/EA/TEA (50/50/1) to afford the title compound XII brivaracetam (58% yield, 98% ee) as a white solid.

(18) .sup.1HNMR (400 MHz, CDCl.sub.3) of the title compound: δ 6.42 (brs, 1 H), 5.69 (brs, 1 H), 4.46 (dd, 1H), 3.50 (dd, 1H), 3.05 (dd, 1H), 2.57 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 8

Preparation of Brivaracetam (XII)

(19) Compound (S)-2-aminobutanamide hydrochloride (4.35 g, 31.5 mmol), compound VII (5.0 g, 21.0 mmol), Na.sub.2CO.sub.3 (8.9 g, 84.0 mmol) and NaI (1.57 g, 10.5 mmol) were added to DMF (50 ml). The solution was stirred for 18 h at 90° C. After the reaction was complete, water (100 mL) was added to the reaction mixture at room temperature. The mixture was extracted with ethyl acetate (3×50 mL) The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The crude product and 2-hydroxypyridine (1.0 g, 10.5 mmol) were added to toluene (50 ml). The reaction mixture was stirred at 90° C. for 5 h. After the reaction was complete, saturated Na.sub.2CO.sub.3 solution (100 mL) was added to the reaction mixture at room temperature. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of the solvent afforded the crude product, which was purified by silica gel column chromatography using PE/EA/TEA (50/50/1) to afford the title compound XII brivaracetam (50% yield, 98% ee) as a white solid.

(20) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ 6.42 (brs, 1H), 5.69 (brs, 1H), 4.46 (dd, 1H), 3.50 (dd, 1H), 3.05 (dd, 1H), 2.57 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H)∘

Example 9

Preparation of (R)-3-(chloromethyl)hexanoyl chloride (X)

(21) A solution of thionyl chloride (20 mL), anhydrous ZnCl.sub.2 (2.5 g, 18.3 mmol), and the compound of formula VI (12.0 g, 93.7 mmol) was stirred under 55° C. After the reaction was complete, the solvents were evaporated in vacuo and the residue was purified by vacuum distillation to obtain the title compound X as a yellow oil. Yield 68%.

(22) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ3.67 (1H, dd), 3.59 (1H, dd), 2.58 (1H, dd), 2.40 (1H, dd), 2.20-2.31 (1H, m), 1.25-1.53 (4H, m), 0.93 (3H, t).
[α].sup.23.sub.D=+2.9 (C=10, CHCl.sub.3)

Example 10

Preparation of (R)-3-(chloromethyl)hexanoyl chloride (X)

(23) A solution of thionyl chloride (400 mL), anhydrous ZnCl.sub.2 (40 g, 0.29 mol), and the compound of formula VI (188 g, 1.47 mol) was stirred at 85° C. After the reaction was complete by GC, the solvent was evaporated in vacuo and the residue was purified by vacuum distillation to obtain the title compound X as a yellow oil. Yield 63.5%.

(24) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ3.67 (1H, dd), 3.59 (1H, dd), 2.58 (1H, dd), 2.40 (1H, dd), 2.20-2.31 (1H, m), 1.25-1.53 (4H, m), 0.93 (3H, t).
[α].sup.23.sub.D=+2.9 (C=10, CHCl.sub.3)

Example 11

Preparation of (R)-N-((S)-1-amino-1-oxobutan-2-yl)-3-(chloromethyl)hexanamide (XI)

(25) Compound (S)-2-aminobutanamide hydrochloride (1.67 g, 12 mmol) was added to DCM (60 ml). TEA (2.43 g, 24 mmol) was added to the solution at room temperature and stirred at room temperature for 30 min. Compound X (2.0 g, 10.8 mmol) was added to the solution. After the reaction was complete, water (30 ml) and ethanol (4 ml) was added to the solution. The mixture was extracted with DCM (2×40 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of the solvent afforded crude product of compound XI, yield 96.7%.

(26) The crude product was purified by silica gel column chromatography using ethyl acetate, .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: .sup.1H NMR (400 MHz, CDCl.sub.3) δ6.20-6.45 (2H, m), 5.69 (1H, brs), 4.46 (1H, dd), 3.61 (2H, d), 2.23-2.42 (3H, m), 1.85-1.97 (1H, m), 1.62-1.75 (1H, m), 1.23-1.53 (4H, m), 0.97 (3H, t), 0.91 (3H, t).
[α].sup.25.sub.D=−23.7 (C=3, CH.sub.3OH)

Example 12

Preparation of Brivaracetam (XII)

(27) The crude product of compound XI (10.0 g, 40 mmol) were added to anhydrous THF (150 ml). t-BuOK (5.6 g, 50 mmol) was added to the reaction and cooled to −30° C. till TLC showed no starting material remained. After the reaction was complete, The saturated NH.sub.4Cl solution (50 mL) was added to the solution. The solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of the solvent the crude product in 93% yield. Purified by recrystallization to afford the higher purity product (chiral HPLC>99.5%) as a white solid.

(28) The .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound as follow: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 13

Preparation of Brivaracetam (XII)

(29) To a solution of crude product of compound XI (10.0 g, 40 mmol) in DCM (150 ml), TBAC (2.3 g, 10 mmol) and anhydrous Na.sub.2SO.sub.4 (5.6 g, 40 mmol) were added. KOH (4.2 g, 75 mmol) was added at −10° C. After the reaction was complete, saturated NH.sub.4Cl solution (50 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of the solvent afforded crude brivaracetam in 96% yield. The crude product was purified by recrystallization to afford high purity product (chiral HPLC>99.5%) as a white solid.

(30) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 14

Preparation of (R)-N-((S)-1-amino-1-oxobutan-2-yl)-3-(chloromethyl)hexanamide (XI)

(31) Compound (S)-2-aminobutanamide hydrochloride (5.0 g, 36 mmol) and TEA (7.3 g, 72 mmol) were added to THF (100 ml) at room temperature. After 30 min, compound X (6.0 g, 32.5 mmol) was added. After the reaction was complete, water (100 ml) was added. The reaction mixture was extracted with EA (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of the solvent afforded crude product of compound XI, which was purified by silica gel column chromatography using ethyl acetate as the eluent.

(32) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ6.20-6.45 (2H, m), 5.69 (1H, brs), 4.46 (1H, dd), 3.61 (2H, d), 2.23-2.42 (3H, m), 1.85-1.97 (1H, m), 1.62-1.75 (1H, m), 1.23-1.53 (4H, m), 0.97 (3H, t), 0.91 (3H, t).
[α].sup.25.sub.D=−23.7 (C=3, CH.sub.3OH)

Example 15

Preparation of Brivaracetam (XII)

(33) To a solution of the crude product of compound XI from example 14 in anhydrous THF (100 ml), t-BuOK (4.8 g, 43.2 mmol) was added. The solution was stirred for at 0° C. After the reaction was complete, saturated NH.sub.4Cl solution (50 mL) was added. The reaction mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of the solvent afforded crude brivaracetam, which was purified by recrystallization in IPAc to afford pure product (chiral HPLC>99.5%) as a white solid, yield 49% for 2 steps.

(34) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 16

Preparation of (R)-4-propyldihydrofuran-2(3H)-one (VI)

(35) To a solution of sodium methoxide (2.05 g, 38 mmol) in ethanol (80 mL) at 0° C., diethyl malonate (6.3 mL, 42 mmol) was added. The mixture was stirred at the same temperature for 10 min. (R)-(-)-epichlorohydrin (2.7 mL, 35 mmol) was added dropwise (over 20 min) at room temperature. The reaction mixture was heat to refluxed for 18 h. After the reaction was complete, the solvent was evaporated. The residue was added water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na.sub.2SO.sub.4. Filtration and evaporation of solvent afforded the crude product, which was purified by vacuum distillation to obtain the compound III (1S,5R)-ethyl 2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate as a viscous colorless oil. Yield 55%, ee 98%.

(36) To a stirred suspension of CuI (9.5 g, 50 mmol) in anhydrous THF at −30° C. was added ethyl magnesium bromide in THF (1.0 M, 300 mL, 300 mmol) dropwise. After 1 h, a solution of compound III (20 g, 117 mmol) in anhydrous THF was added via cannula at −30° C. The reaction mixture was warmed to −15° C. before quenched with saturated ammonium chloride solution. The mixture was added water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na.sub.2SO.sub.4. Filtration and evaporation of solvent afforded the crude product IV.

(37) The crude product of compound IV (about 117 mmol) and LiCl (14.7 g, 350 mmol) in DMSO/H.sub.2O (400 mL/20 mL) was heated for 18 h at 140° C. After the reaction was complete, water (400 mL) was added to the solution at room temperature. The reaction mixture was extracted with ethyl acetate (3×400mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of the solvent afforded the crude product, which was purified by vacuum distillation to afford the title compound VI (R)-4-propyldihydrofuran-2(3H)-one (50% yield, yield for 2 steps) as a colorless oil.

(38) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ4.42 (1H, dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40-1.47 (2H, m), 1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H,t).
[α].sup.23.sub.D=+3.9 (C=10, CHCl.sub.3)

Example 17

Preparation of (1S,5R)-ethyl 2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate (III)

(39) Sodium methoxide (2.0 kg, 37.03 mol) was dissolved in ice cold ethanol (44.5 kg) and stirred for 15 min. The resulting mixture was added diethyl malonate (6.0 kg, 37.46 mol) at 10° C. and was stirred at the same temperature for 10 min. (R)-(-)-epichlorohydrin (3.3 mL, 35.67 mol) was added dropwise (over 20 min) at the room temperature. After refluxing for 2 h, the solvent was evaporated. The residue was added water (19.3 kg) and was extracted with ethyl acetate twice (17.0 kg and 12.0 kg). The combined organic layers were dried over Na.sub.2SO.sub.4. Filtration and evaporation of solvent afforded the crude product, which was purified by vacuum distillation to obtain the title compound III as a viscous colorless oil. Yield 50%, ee 98.5%

(40) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: .sup.1H NMR (400 MHz, CDCl.sub.3): δ4.33 (1H, dd), 4.23 (2H, q), 4.16 (1H, d), 2.73-2.75 (1H, m), 2.05 (1H, dd), 1.35 (1H, t), 1.28 (3H, t).

Example 18

Preparation of (4R)-ethyl 4-isobutyl-2-oxotetrahydrofuran-3-carboxylate (IV)

(41) CuI (108.3 g, 0.57 mol) was added to a stirred suspension of ethyl magnesium bromide in 2-Me-THF (1.29 mol/kg, 2.44 kg, 3.14 mol) at −20 to −30° C. After 0.5 h, a solution of compound III (434 g, 2.55 mol) in anhydrous 2-Me-THF was added at −30° C. After 30 min, the reaction mixture was quenched with saturated ammonium chloride solution. Layers separation afforded a solution of the crude compound IV in 2-Me-THF. Yield 64%.

(42) The crude product was purified by silica gel column chromatography using petroleum ether/ethyl acetate (10:1) to obtain the title compound IV.

(43) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ4.52 (1H, dd), 4.27 (2H, q), 3.92 (1H, dd), 3.23 (1H, d), 2.96-3.03 (1H, m), 1.49-1.56 (2H, m), 1.27-1.35 (5H, m), 0.95 (3H,t).
[α].sup.23.sub.D=+22.6 (C=10, CHCl.sub.3)

Example 19

Preparation of (4R)-ethyl 4-isobutyl-2-oxotetrahydrofuran-3-carboxylate (IV)

(44) CuI (2.22 g, 11.70 mmol) was added to a stirred suspension of ethyl magnesium bromide in 2-Me-THF (1.29 mol/kg, 63.51 g, 81.93 mmol) at −20 to −30° C. After 0.5 h, a solution of compound III (10.0 g, 58.52 mol) in anhydrous 2-Me-THF was added at −30° C. After 30 min, the reaction was quenched with saturated ammonium chloride solution then the residue was stirred for 30 min. Layers separation afforded a solution of the crude compound IV in 2-Me-THF. Yield 87%.

(45) The crude product was purified by silica gel column chromatography using petroleum ether/ethyl acetate (10:1) to obtain the title compound IV.

(46) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ4.52 (1H, dd), 4.27 (2H, q), 3.92 (1H, dd), 3.23 (1H, d), 2.96-3.03 (1H, m), 1.49-1.56 (2H, m), 1.27-1.35 (5H, m), 0.95 (3H,t).
[α].sup.23.sub.D=+22.6 (C=10, CHCl.sub.3)

Example 20

Preparation of (4R)-2-oxo-4-propyltetrahydrofuran-3-carboxylic acid

(47) To a suspension of crude product of compound IV in 2-Me-THF (from example 19) at 25 to 30° C., NaOH/H.sub.2O (255 g/640 ml) was added. After 2 h, the mixture was wash with ethyl acetate (1 L). The pH of the mixture was adjusted to pH=1 with concentrated HCl, and was extracted with 2-Me-THF (2×1 L). The combined organic layers were concentrated to give the crude product. Yield 99%.

(48) The crude product was purified by silica gel column chromatography using 100% ethyl acetate.

(49) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ10.57 (1H, brs), 64.54 (1H, dd), 3.95 (1H, dd), 3.30 (1H, d), 2.96-3.03 (1H, m), 1.39-1.76 (2H, m), 1.27-1.35 (2H, m), 0.95 (3H, t).

Example 21

Preparation of (R)-4-propyldihydrofuran-2(3H)-one (VI)

(50) The crude product of (4R)-2-oxo-4-propyltetrahydrofuran-3-carboxylic acid (from example 20) in toluene was heated at 120° C. for 2 h. After the reaction was complete, the mixture was purified by vacuum distillation to afford the title compound (R)-4-propyldihydrofuran-2(3H)-one (99% yield).

(51) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ4.42 (1H, dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40-1.47 (2H, m), 1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H,t).
[α].sup.23.sub.D=+3.9 (C=10, CHCl.sub.3)

Example 22

Preparation of (R)-4-propyldihydrofuran-2(3H)-one (VI)

(52) The crude product of (4R)-2-oxo-4-propyltetrahydrofuran-3-carboxylic acid (from example 20) and toluene (2 vol) was heated at 120° C. for 8 h. After the reaction was complete, the mixture was purified by vacuum distillation to afford the title compound (R)-4-propyldihydrofuran-2(3H)-one (95% yield).

(53) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ4.42 (1H, dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40-1.47 (2H, m), 1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H,t).
[α].sup.23.sub.D=+3.9 (C=10, CHCl.sub.3)

Example 23

Preparation of (R)-3-(chloromethyl)hexanoyl chloride (X)

(54) A solution of thionyl chloride (200 mL), anhydrous ZnCl.sub.2 (10.6 g, 0.078 mol), and the compound of formula (VI) (100 g, 0.78 mmol) was heated to 85° C. After the reaction was complete, the solvents were evaporated in vacuo. The crude product was purified by vacuum distillation to obtain the title compound X as a yellow oil. Yield 79.7%.

(55) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ3.67 (1H, dd), 3.59 (1H, dd), 2.58 (1H, dd), 2.40 (1H, dd), 2.20-2.31 (1H, m), 1.25-1.53 (4H, m), 0.93 (3H, t).
[α].sup.23.sub.D=+2.9 (C=10, CHCl.sub.3)

Example 24

Preparation of (R)-N-((S)-1-amino-1-oxobutan-2-yl)-3-(chloromethyphexanamide (XI)

(56) To a mixture of (S)-2-aminobutanamide hydrochloride (10.0 g, 72.5 mmol) and K.sub.2CO.sub.3 (25 g, 181.3 mmol) in CH.sub.3CN (150 ml) at 0° C., the compound of formula (X) (14.6 g, 79.71 mmol) was added. After the reaction was complete by TLC, the solvents were evaporated in vacuo. DCM (150 ml), water (150 ml), and ethanol (10 ml) was added. Layers were separated. The aqueous layer was extracted with DCM (100 ml). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of the solvent afforded crude compound XI, yield 96%.

(57) The crude compound (XI) was purified by recrystallization to afford the high purity product as a white solid.

(58) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: 6.20-6.45 (2H, m), 5.69 (1H, brs), 4.46 (1H, dd), 3.61 (2H, d), 2.23-2.42 (3H, m), 1.85-1.97 (1H, m), 1.62-1.75 (1H, m), 1.23-1.53 (4H, m), 0.97 (3H, t), 0.91 (3H, t).
[α].sup.25.sub.D=−23.7 (C=3, CH.sub.3OH)

Example 25

Preparation of Brivaracetam (XII)

(59) To a solution of compound XI (2.0 g, 8 mmol) in anhydrous DMF (6 ml), KOH (670 mg, 12 mmol) was added portionwise at −15° C. to −10° C. After the reaction was complete by HPLC, the reaction was quenched with 1N HCl. Brine (24 ml) were added. The mixture was extracted with MTBE (4×20 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of the solvent gave crude brivaracetam, yield 95%. Recrystallization afforded pure product (chiral HPLC>99.5%) as a white solid.

(60) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 26

Preparation of Brivaracetam (XII)

(61) To a mixture of (S)-2-aminobutanamide hydrochloride (8.0 g, 58 mmol) and PEG400 (3.5 g, 8.7 mmol) in DCM (120 ml) at −10° C., compound X (11.7 g, 645 mmol) and KOH (17.9 g, 320 mmol) were added portionwise. The reaction was stirred at 2° C. reaction completion by TLC. A solution of half saturated NH.sub.4Cl was added. The mixture was extracted with DCM (3×40 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of solvent gave crude brivaracetam, yield 95%. Recrystallization afforded pure product (chiral HPLC>99%) as a white solid.

(62) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 27

Preparation of Brivaracetam (XII)

(63) To a mixture of (S)-2-aminobutanamide hydrochloride (2.5 g, 18 mmol) and TBAB (1.16 g, 3.6 mmol) in DCM (40 ml) at −10° C., compound X (3.66 g, 20 mmol) and KOH (4.53 g, 81 mmol) were added portionwise. The reaction was stirred at −2° C. till completion by TLC. A solution of half saturated NH.sub.4Cl was added. The mixture was extracted with DCM (3×40 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of solvent gave crude brivaracetam, yield 83%. Recrystallization afforded pure product (chiral HPLC>99%) as a white solid.

(64) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 28

Preparation of Brivaracetam (XII)

(65) To a solution of compound XI (2.5 g, 10 mmol) and TBAB (161 mg, 0.5 mmol) in anhydrous DCM (20 ml), KOH (730 mg, 12 mmol) was added in two portions. The reaction was stirred for at −15° C. to −10° C. till reaction completion by HPLC. A saturated NH.sub.4Cl solution was added. The mixture was extracted with DCM three times. The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of solvent gave crude brivaracetam, yield 68%. Recrystallization afforded pure product (chiral HPLC>99.5%) as a white solid.

(66) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 29

Preparation of Brivaracetam (XII)

(67) To a solution of compound XI (100 mg, 0.4 mmol) and PEG400 (24 mg, 0.06 mmol) in anhydrous DCM (1 ml), NaOH (32 mg, 0.8 mmol) was added. The reaction was stirred at −15° C. to −10° C. till reaction completion by HPLC. A saturated NH.sub.4Cl solution was added. The mixture was extracted with DCM three times. The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of solvent afforded brivaracetam, yield 87%.

(68) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 30

Preparation of Brivaracetam (XII)

(69) To a mixture of compound XI (100 mg, 0.4 mmol) and PEG400 (24 mg, 0.06 mmol) in anhydrous CH.sub.3CN (1 ml) was added KOH (45 mg, 0.8 mmol). The reaction was stirred at −15° C. to −10° C. till reaction completion by HPLC. A saturated NH.sub.4Cl solution was added. The mixture was extracted with DCM three times. The combined organic layer were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of solvent afforded brivaracetam, yield 86%.

(70) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 31

Preparation of Brivaracetam (XII)

(71) To a solution of compound XI (100 mg, 0.4 mmol) and PEG400 (24 mg, 0.06 mmol) in acetone (1 ml) was added KOH (45 mg, 0.8 mmol). The mixture was stirred at −15° C. to −10° C. till reaction completion by HPLC. A saturated NH.sub.4Cl solution was added. The mixture was extracted with DCM three times. The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of solvent afforded brivaracetam, yield 90%.

(72) The result of .sup.1HNMR (400 MHz, CDCl.sub.3) analysis of the title compound as follow: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 32

Preparation of (R)-4-propyldihydrofuran-2(3H)-one (VI)

(73) To a suspension of CuI (9.5 g, 50 mmol) in anhydrous THF at −30° C. was added ethyl magnesium bromide in THF (1.0 M, 300 mL, 300 mmol) dropwise. After 1 h, a solution of compound III (20 g, 117 mmol) in anhydrous THF was added via cannula at −30° C. After 30 min, the reaction mixture was warmed to −15° C. and quenched with saturated ammonium chloride solution. The mixture was added water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na.sub.2SO.sub.4. Filtration and evaporation of solvent afforded crude product (IV).

(74) The crude product of compound IV (about 117 mmol) and LiCl (14.7 g, 350 mmol) in DMSO/H.sub.2O (400 mL/20 mL) was heated at 140° C. for 18 h. After the reaction was complete, water (400 mL) was added at room temperature. The mixture was extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of solvent afforded crude product, which was purified by vacuum distillation to afford the title compound VI (50% yield, yield for 2 steps) as a colorless oil.

(75) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ4.42 (1H, dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40-1.47 (2H, m), 1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H,t).
[α].sup.23.sub.D=+3.9 (C=10, CHCl.sub.3)

Example 33

Preparation of (4R)-2-oxo-4-propyltetrahydrofuran-3-carboxylic acid

(76) CuI (2.24 g, 11.79 mmol) was added to a suspension of ethyl magnesium bromide in 2-Me-THF (1.36 mol/kg, 64.85 g, 88.2 mmol) at −20 to −30° C. After 0.5 h, a solution of compound III (10.0 g, 58.52 mol) in anhydrous 2-Me-THF was added at −30° C. After 30 min, the reaction was quenched with 3N HCl solution. The reaction mixture was heated to reflux for 24 h. The layers were separated after cooling down to room temperature. The organic layer contained the crude 4R)-2-oxo-4-propyltetrahydrofuran-3-carboxylic acid. Yield 74%.

(77) The crude 4R)-2-oxo-4-propyltetrahydrofuran-3-carboxylic acid was purified by silica gel column chromatography using 100% ethyl acetate

(78) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ10.57 (1H, brs), δ4.54 (1H, dd), 3.95 (1H, dd), 3.30 (1H, d), 2.96-3.03 (1H, m), 1.39-1.76 (2H, m), 1.27-1.35 (2H, m), 0.95 (3H, t).

Example 34

Preparation of (R)-4-propyldihydrofuran-2(3H)-one (VI)

(79) CuI (2.24 g, 11.79 mmol) was added to a suspension of ethyl magnesium bromide in 2-Me-THF (1.36 mol/kg, 64.85 g, 88.2 mmol) at −20 to −30° C. After 0.5 h, a solution of compound III (10.0 g, 58.52 mol) in anhydrous 2-Me-THF was added at −30° C. After 30 min, the reaction was quenched with saturated ammonium chloride solution (50 ml). The layers were separated. NaOH/H.sub.2O (7 g/18 ml) was added to the organic layer at 25 to 30° C. After 2 h, layers were separated. The aqueous was extracted with 2-Me-THF (50 mL). The combined organic layers were added concentrated HCl to pH=1. The mixture was extracted with 2-Me-THF twice. The organic layers were combined and the solvent was evaporated. The residue was heated to 105° C. for 10 h till reaction completion. Vacuum distillation afford the title compound (VI). (75% yield).

(80) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ4.42 (1H, dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40-1.47 (2H, m), 1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H,t).
[α].sup.23.sub.D=+3.9 (C=10, CHCl.sub.3)

(81) The following two Examples depict certain steps of the below scheme:

(82) ##STR00016##

(83) Alternatively, compound XII-a may be converted to XII by, for example, aminolysis and amide formation reaction.

Example 35

Preparation of methyl (S)-2-((R)-3-(chloromethyl)hexanamido)butanoate (XI-a)

(84) ##STR00017##

(85) To a mixture of methyl (S)-2-aminobutanoate hydrochloride (5.0 g, 32.6 mmol) and K.sub.2CO.sub.3 (11.2 g, 81.7 mmol) in acetone (100 ml) at 0° C., compound X (6.28 g, 34.3 mmol) was added. After the reaction was complete by TLC, the solvents were evaporated in vacuo. The residue was added DCM (50 ml) and water (50 ml). The layers were separated. The aqueous layer was extracted with DCM (50 ml). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of the solvent afforded crude compound XI-a (R=OMe), which was purified by silica gel column chromatography using PE/EA (20/1) to afford the title compound XI-a (R=OMe, 70% yield).

(86) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ 6.24 (1H, d), 4.54 (1H, ddd), 3.72 (3H, s), 3.61 (2H, d), 2.23-2.42 (3H, m), 1.85-1.95 (1H, m), 1.62-1.75 (1H, m), 1.23-1.53 (4H, m), 0.85-0.95 (6H, m).

Example 36

Preparation of methyl (S)-2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butanoate (XII-a, R=OMe)

(87) ##STR00018##

(88) To a solution of compound XI-a (R=OMe, 2.0 g, 7.6 mmol) in anhydrous DMF (6 ml), KOH (670 mg, 12 mmol) was added portionwise at −15° C. to −10° C. After the reaction was complete by HPLC, the reaction was quenched with 1N HCl. Brine (24 ml) were added. The mixture was extracted with MTBE (4×20 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Filtration and evaporation of the solvent gave crude compound XII-a, which was purified by silica gel column chromatography using PE/EA (15/1) to afford the title compound XII-a (65% yield).

(89) .sup.1H NMR (400 MHz, CDCl.sub.3) of the title compound: δ 4.67 (dd, 1H), 3.69 (s, 3H), 3.40 (dd, 1H), 3.12 (dd, 1H), 2.53 (dd, 1H), 2.32-2.40 (m, 1H), 2.05 (dd, 1H), 1.95-2.05 (m, 1H), 1.62-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.85-0.95 (m, 6H).

(90) The invention is not limited by the embodiments described above which are presented as examples only but can be modified in various ways within the scope of protection defined by the appended patent claims.

(91) Thus, while there have shown and described and pointed out fundamental novel features of the invention as applied to a preferred embodiment thereof, it will be understood that various omissions and substitutions and changes in the form and details of the devices illustrated, and in their operation, may be made by those skilled in the art without departing from the spirit of the invention. For example, it is expressly intended that all combinations of those elements and/or method steps which perform substantially the same function in substantially the same way to achieve the same results are within the scope of the invention. Moreover, it should be recognized that structures and/or elements and/or method steps shown and/or described in connection with any disclosed form or embodiment of the invention may be incorporated in any other disclosed or described or suggested form or embodiment as a general matter of design choice. It is the intention, therefore, to be limited only as indicated by the scope of the claims appended hereto.