Structure of 880468-89-3
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CAS No. : | 880468-89-3 |
Formula : | C16H24N2O4 |
M.W : | 308.37 |
SMILES Code : | O=C(OC(C)(C)C)N[C@H](COC)C(NCC1=CC=CC=C1)=O |
MDL No. : | MFCD16620517 |
InChI Key : | ZEWWJSJMNBJIKR-CYBMUJFWSA-N |
Pubchem ID : | 46223141 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 22 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.5 |
Num. rotatable bonds | 10 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 83.27 |
TPSA ? Topological Polar Surface Area: Calculated from |
76.66 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.84 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.66 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.69 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.25 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.84 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.86 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.34 |
Solubility | 1.41 mg/ml ; 0.00458 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.88 |
Solubility | 0.403 mg/ml ; 0.00131 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.32 |
Solubility | 0.0148 mg/ml ; 0.0000479 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.0 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
3.09 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | In hexane; chloroform; at 20 - 60℃; for 1h;Purification / work up; | The <strong>[880468-89-3](R)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide</strong> (C-937) solution prepared in example 3 above was evaporated in vacuo yielding crude C937 as an oily solid. The crude solid (2g) was dissolved in 10percent chloroform in hexane (30ml) at 60°C, cooled to room temperature and left stand for 1 hour at 0 this temperature. The resulting solids were isolated by filtration yielding crude C937 (1.1g). This crude solid was further recrystallised twice in 10 volumes of 10percent chloroform in hexane to yield (R)-N-benzyl-2-N-Boc-amino-3- methoxypropionamide (C-937) as a white crystalline solid (0.28g, 14percent). EPO <DP n="21"/>HPLC purity 97.3percent. Elemental analysis Calculated for C16H24N2O5 62.32percent C; 7.84percent H; 9.08percent N. Found 62.19percent C; 7.79percent H; 9.04percent N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride; water; In dichloromethane; at 0 - 30℃; for 2h; | To a solution of (R)-tert-butyl-(1-(benzylamino)-3-rnethoxy-1-oxopropan-2- yl)carbamate (9.0 g) in methylene chloride (90 mL) was added concentrated hydrochloric acid (18.5 mL) at 0-5°C and stirred at 25-30°C for 2 hrs. Reaction mixture was diluted with water (20 mL) at 0-5°C and stirred for half an hour. The aqueous layer was basified with 20percent aqueous sodium hydroxide solution at 0-5°C and the reaction mixture was extracted in methylene chloride. The combined organic layer was washed with water and concentrated under vacuum to obtain the title compound. Weight: 6.1g Yield: 100percent, |
100% | With hydrogenchloride; water; In dichloromethane; at 0 - 30℃; for 2h; | The above obtained Ic, (5.0g, 16.2mmol) was dissolved in dichloromethane (30mL) after which was added concentrated hydrochloric acid (3mL) at 0?5°C and stirred at 25?30°C for 2h. The reaction mixture was diluted with water (20mL), stirred for 10min and then both layers were separated. The aqueous layer pH was adjusted to 10 with 25percent NaOH, saturating with sodium chloride and extracted with dichloromethane (3×20mL). The organic layer was dried over Na2SO4, and evaporated under reduced pressure to yield (R)-2-amino-N-benzyl-3-methoxypropanamide Id as an oil (3.38g, 100percent). Compound Id was used directly in the next step without further purification. |
100% | With hydrogenchloride; In dichloromethane; water; at 0 - 10℃; for 1h; | The above prepared compound of formula IV (30.8g, 0 . 100mol) dissolved in dichloromethane (31 ml), cooled to 0 °C, and in 0-10 °C by adding 36percent hydrochloric acid (48.7g, 0 . 500mol), in 0-10 °C reaction 1 hour later by adding dichloromethane (62 ml) extraction layered. In the aqueous layer by adding dichloromethane (155 ml), and in 0-10 °C with 20percent sodium hydroxide alkalise to pH= 10-12, the compound V obtains the type water/methylene chloride mixed solution (yield according to the 100percent meter, HPLC purity 97.1percent). The compounds of formula V need not be isolated,The mixed solution was used directly in the next step. |
With hydrogenchloride; In dichloromethane; water; for 1h; | To the C937 solution prepared above was added 36percent HCI (46.5ml, 0.541 mol) and the mixture aged for 1 hour. Water (66ml) was added and the phases separated. The organic phase was extracted with water (22ml) and the aqueous layers combined. The aqueous was basified to pH 10-12 with 30percent sodium hydroxide at <35°C and sodium chloride (8.8g) added. The aqueous layer was extracted with methylene chloride (2x110ml) and the combined organic layers washed with water (44ml) yielding a methylene EPO <DP n="20"/>chloride solution of (R)-2-amino-N-benzyl-3-methoxypropionamide. | |
Intermediate 6: Preparation of methoxypropanamideTo a cold solution (5° C.) of 3.36 g of Intermediate 5, benzylamide in 40 mL of dichloromethane was added 6.02 mL of 36percent HCl. The reaction mixture was stirred at room temperature until no starting material was observed by TLC. The organic phase was washed with 1N HCl (2.x.30 mL) and the combined aqueous phase basified to 10-12 with 25percent NaOH. After saturating the aqueous phase with sodium chloride, it was extracted with dichloromethane (3.x.30 mL). The organic phase was dried and concentrated under vacuum yielding 2.01 g of a pale yellow oil. | ||
ExampIe-33: Preparation of (R)-N-benzyl-2-amino-3-methoxypropionamide compound of formula-8; Concentrated hydrochloric acid (175 ml) was added to a reaction mixture containing (R)-2-tert-butyl l-(benzylamino)-3-methoxy-l-oxopropan-2-yl carbonate (280 ml) obtained in example-32 at 0-5°C and stirred for 3 hrs. The organic and aqueous layers were separated. Aqueous layer was basified with sodium hydroxide and the reaction mixture extracted into methylene chloride. The methylene chloride layer containing the title compound used directly in the next step without any further isolation or purification. | ||
Step 3:Production of (R)-2-amino-N-benzyI-3-methoxypropionamide.; <strong>[880468-89-3](R)-N-Benzyl-2-N-Boc-amino-3-methoxypropionamide</strong> solution in methylene chloride was concentrated till the solution volume was half of the original volume at 35-40°C under reduced pressure. Hydrochloric acid (36percent, 55 ml, 0.6137 mol) was added at 25-30°C and the resulting mixture was aged for 60-90 min at 25-30°C. Water (60 ml) was added and the phases were separated. The aqueous phase was washed with methylene chloride (50 ml). The aqueous layer was basified to pH 10-1 1 with 30percent sodium hydroxide at 25-30°C and saturated with sodium chloride (-20.0 g). The aqueous layer was extracted with methylene chloride (2 x 100 ml) . and the combined organic layer was dried over anhydrous sodium sulfate. Methylene chloride was distilled off at 35-40°C under diminished pressure to get oily mass. Yield: 40.0 g, HPLC purity: -94percent, Chiral purity: > 98percent. | ||
3. Lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropionamide (I)) In a 1 L flask with overhead stirrer, condenser, thermometer and dropping funnel were combined 40 g (0.13 mol) (R)-boc-2-amino-N-benzyl-3-methoxy-propionamide (IV) and 400 ml dichloromethane. To this was carefully added 51.3g (0.52 mol) 37percent w/w hydrochloric acid in water. The reaction was stirred at 25 °C for 3 hours, at which time a sample showed >99percent hydrolysis of the boc protecting group. To the reaction was added 112 g water. The solution was then cooled on ice to 4-6 °C. With good mixing 75 g (0.62 mol) 33percent w/w sodium hydroxide solution in water was then slowly added maintaining the temperature between 4-8 °C. At completion of addition, 17.3 g (0.17 mol) acetic acid anhydride was slowly added. The reaction was allowed to come to room temperature and stirred for a further 1 hour. The phases were separated and the aqueous phase extracted with 100 ml dichloromethane. The dichloromethane phases were combined and washed with 25 ml water. The dichloromethane was then exchanged for toluene and lacosamide crystallised from a mixture of 460 ml toluene plus 10 ml methanol by warming until all solids were in solution and then slowly cooling to 4-8 °C. The lacosamide was filtered and washed 2 times with 50 ml toluene. Yield 24.8 g (76.4percent), purity by HPLC 99.9percent, ee >99.9percent, 1H NMR conforms. ee is enantiomeric excess and is calculated by determining the percentage of each separate enantiomer of a given chiral compound, such that the sum of the (R) and (S) enantiomers is 100percent, and subtracting one from the other. | ||
3. Lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropionamide (I))In a 1 L flask with overhead stirrer, condenser, thermometer and dropping funnel were combined 40 g (0.13 mol) (R)-boc-2-amino-N-benzyl-3-methoxy-propionamide (IV) and 400 ml dichloromethane. To this was carefully added 51.3 g (0.52 mol) 37percent w/w hydrochloric acid in water. The reaction was stirred at 25° C. for 3 hours, at which time a sample showed >99percent hydrolysis of the boc protecting group. To the reaction was added 112 g water. The solution was then cooled on ice to 4-6° C. With good mixing 75 g (0.62 mol) 33percent w/w sodium hydroxide solution in water was then slowly added maintaining the temperature between 4-8° C. At completion of addition, 17.3 g (0.17 mol) acetic acid anhydride was slowly added. The reaction was allowed to come to room temperature and stirred for a further 1 hour. The phases were separated and the aqueous phase extracted with 100 ml dichloromethane. The dichloromethane phases were combined and washed with 25 ml water. The dichloromethane was then exchanged for toluene and lacosamide crystallised from a mixture of 460 ml toluene plus 10 ml methanol by warming until all solids were in solution and then slowly cooling to 4-8° C. The lacosamide was filtered and washed 2 times with 50 ml toluene. Yield 24.8 g (76.4percent), purity by HPLC 99.9percent, ee >99.9percent, 1H NMR conforms. | ||
To the above solution of (i?)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide in dichoromethane was added cone, hydrochloric acid and stirred at ambient temperature for 1 hour. Water was then added to the mixture, stirred and separated the product containing aqueous layer. Basified the aqueous layer to pH 10-12 and extracted with dichloromethane to obtain a solution of ( ?)-2-amino-N-benzyl-3- methoxypropionamide in dichloromethane | ||
Preparation of (R)-2-amino-N-benzyl-3-methoxypropionamide(R)-N-Benzyl-2-((tert-butoxy)carbonylamino)-3-methoxypropionamide (116 gm) as obtained example 5 was dissolved in methylene chloride (1000 ml) and then added hydrochloric acid (36percent, 203 ml). The contents were maintained for 1 hour at room temperature and then added water (190 ml). The pH of the separated aqueous layer was adjusted to 10 to 11 with sodium hydroxide solution (30percent) and then extracted with methylene chloride. The solvent was distilled off to obtain a residual solid of (R)-2- amino-N-benzyl-3 -methoxypropionamide (62 gm). | ||
Step II reaction mass (145 gm), dichloromethane (725 ml) and HCl (217.5 ml) were added at 27±3°C and stirred the reaction mass for 80-90 min. at 27±3°C. DM water was added 27±3°C and stirred for 5-10 min. at 27±3°C. The layers were separated. The organic layer was collected. The organic layer was washed with 10percent v/v HCl solution (29ml con HCl make 290 ml using DM water), stirred at 27±3°C for 5-10 min and allowed to settle. The combined aqueous layer was cooled to 0-5°C. Adjust pH 9-10 using 20percentw/v Sodium hydroxide solution at 0-15°C. Dichloromethane (725 ml) was added at 10-25°C and stirred for 5-10 min. at 27±3°C. The layers were separated. The organic layer was collected. The aqueous layer was extracted with dichloromethane (2x290 ml), stirred at 27±3°C and allowed to settle and layers were separated. Combined organic layers and sodium chloride solution (65.25 g in 435ml DM water) was added at 27±3°C and stirred for 10-15 min. at 27±3°C. The layers were separated. The organic layer (Product is in organic layer) was collected. | ||
With hydrogenchloride; In dichloromethane; water; at 20℃; for 1h; | To the above solution of <strong>[880468-89-3](R)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide</strong> in dichoromethane was added conc. hydrochloric acid and stirred at ambient temperature for 1 hour. Water was then added to the mixture, stirred and separated the product containing aqueous layer. Basified the aqueous layer to pH 10-12 and extracted with dichloromethane to obtain a solution of (R)-2-amino-N-benzyl-3-methoxypropionamide in dichloromethane. | |
40.0 g | With hydrogenchloride; In dichloromethane; water; at 25 - 40℃; | Step 3 Production of (R)-2-amino-N-benzyl-3-methoxypropionamide <strong>[880468-89-3](R)-N-Benzyl-2-N-Boc-amino-3-methoxypropionamide</strong> solution in methylene chloride was concentrated till the solution volume was half of the original volume at 35-40° C. under reduced pressure. Hydrochloric acid (36percent, 55 ml, 0.6137 mol) was added at 25-30° C. and the resulting mixture was aged for 60-90 min at 25-30° C. Water (60 ml) was added and the phases were separated. The aqueous phase was washed with methylene chloride (50 ml). The aqueous layer was basified to pH 10-11 with 30percent sodium hydroxide at 25-30° C. and saturated with sodium chloride (?20.0 g). The aqueous layer was extracted with methylene chloride (2*100 ml) and the combined organic layer was dried over anhydrous sodium sulfate. Methylene chloride was distilled off at 35-40° C. under diminished pressure to get oily mass. Yield: 40.0 g, HPLC purity: ?94percent, Chiral purity: >98percent. |
With hydrogenchloride; In dichloromethane; water; at 20℃; for 1h; | Dichloromethane (625 L) was charged at room temperature, Lacosamide stage III product (130 kg), 30percent concentrated hydrochloric acid (195 L) and water (260 L), reaction for 1 hour, extracted with 10percent dilute hydrochloric acid solution (320 L), cool to 5 °C. The pH was adjusted to 9.5 with sodium hydroxide 2 solution. Extraction with dichloromethane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | To a solution of acid (R)-9 (0.7 g, 3.2 mmol) in dry THF was added N-methylmorpholine (0.43 mL, 3.8 mmol) at -78 °C under an argon atmosphere. After 5 min, isobutyl chloroformate (0.5 mL, 3.8 mmol) was added and stirred for another 5 min. To this reaction mixture benzylamine (0.4 mL, 3.8 mmol) was added at -78 °C after which the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was filtered, and washed with ethylacetate. The solvent was removed under reduced pressure and the crude product was subjected to column chromatography (silica gel, petroleum ether/acetone, 85:15) to yield (R)-10 as a colorless solid (0.9 g, 90percent); mp 63-64 °C; (c 0.9, CHCl3); IR (CHCl3, cm-1): numax 3683, 3431, 3020, 2931, 2401, 1714, 1523, 1496, 1368, 1165, 1119, 928, 758, 669; 1H NMR (200 MHz, CDCl3): deltaH 1.43 (s, 9H), 3.37 (s, 3H), 3.47-3.54 (dd, J = 9.2, 6.1 Hz, 1H), 3.82 (dd, J = 9.3, 3.7 Hz, 1H), 4.27 (m, 1H), 4.47 (d, J = 5.1 Hz, 1H), 5.41 (br s, 1H), 6.77 (m, 1H), 7.22-7.37 (m, 5H); 13C NMR (50 MHz, CDCl3): deltaC 170.3 (CO), 155.5 (CO), 137.9 (C), 128.7 (CH, 2 carbons), 127.5 (CH, 3 carbons), 80.4 (C), 72.1 (CH2), 59.1 (CH3), 54.0 (CH), 43.5 (CH2), 28.3 (CH3, 3 carbons); MS: m/z 331 [M+Na]+. | |
90% | With 4-methyl-morpholine; isobutyl chloroformate; In tetrahydrofuran; at -78 - 30℃; for 1h;Inert atmosphere; | Example-5 Synthesis of (R)-tert-butyl 1-(benzylamino)-3-methoxy-1-oxopropan-2-ylcarbamate (R)-9 To a solution of acid (R)-8 (0.7 g, 3.2 mmol) in dry THF was added N-methylmorpholine (0.43 mL, 3.8 mmol) at -78° C. under argon atmosphere. After 5 min, isobutyl chloroformate (0.5 mL, 3.8 mmol) was added and stirred the content for another 5 min. To this reaction mixture benzylamine (0.4 mL, 3.8 mmol) was added at -78° C. and allowed the reaction mixture to stir at 30° C. for 1 h. After completion of the reaction, reaction mixture was filtered, washed with ethylacetate. The solvent was removed under reduced pressure and the crude product was subjected to column chromatography (silica gel, petroleum ether/acetone, 85:15) to yield (R)-9 as colorless solid (0.9 g, 90percent). m.p 63-64° C.; [alpha]25D=-20.5 (c 0.9, CHCl3); IR (CHCl3, cm-1): vmax 3683, 3431, 3020, 2931, 2401, 1714, 1523, 1496, 1368, 1165, 1119, 928, 758, 669; 1H NMR (200 MHz, CDCl3): deltaH 1.43 (s, 9H), 3.37 (s, 3H), 3.47-3.54 (dd, J=9.2, 6.1 Hz, 1H), 3.82 (dd, J=9.3, 3.7 Hz, 1H), 4.27 (m, 1H), 4.47 (d, J=5.1 Hz, 1H), 5.41 (bs, 1H), 6.77 (m, 1H), 7.22-7.37 (m, 5H); 13C NMR (50 MHz, CDCl3): deltaC 170.3 (CO), 155.5 (CO), 137.9 (C), 128.7 (CH, 2 carbons), 127.5 (CH, 3 carbons), 80.4 (C), 72.1 (CH2), 59.1 (CH3), 54.0 (CH), 43.5 (CH2), 28.3 (CH3, 3 carbons); MS: m/z 331 [M+Na]+. |
90% | To a solution of acid 5 (0.985 g, 4.49 mmol) in dry THF (10ml) was added N-methylmorpholine (0.6 mL, 5.39 mmol) at -78 °C under an argon atmosphere.After 5 min, isobutyl chloroformate (0.7 mL, 5.39 mmol)was added and stirred for another 5 min. To this reaction mixture benzyl amine (0.6 mL, 5.39 mmol) was added at -78 °C andthe reaction mixture was allowed to come up to room temperature and stirred foranother 1 h. After completion of the reaction (TLC), the reaction mixture wasfiltered through a pad of celite, and washed with ethyl acetate (20 mL). Thesolvent was removed under reduced pressure and the crude reaction mixture wassubjected to flash chromatography (CombiFlash Rf 200i, Teledyne Isco) using RediSep silica gel column (12 g) eluting with petroleum ether?EtOAc (3:2,isocratic) to yield 6as a white solid (1.24 g, 90percent); Rf0.35 (40percent EtOAc inpetroleum ether); mp 63-64 °C [Lit.63-64 °C3]; [alpha]D26 -24.3 (c 1.04, CHCl3) [Lit. [alpha]D26-20.5 (c 0.9, CHCl3)3]; IR (CHCl3) umax:3428, 3345, 3017, 2933, 2405, 1708, 1671, 1493, 1365, 1220, 1167, 1116, 1075,1025, 922, 860, 762, 668 cm-1; 1H NMR (200 MHz, CDCl3) delta: 7.40-7.19 (m, 5H), 6.78 (brs, 1H),5.55-5.33 (m, 1H), 4.48 (d, J = 4.3 Hz, 2H), 4.27 (brs, 1H), 3.84 (dd, J= 3.9, 9.2 Hz, 1H), 3.50 (dd, J = 6.2, 9.1 Hz, 1H), 3.36 (s, 3H), 1.43(s, 9H); 13C NMR (50 MHz,CDCl3) delta: 170.3,155.5, 138.0, 128.7, 127.5, 80.4, 72.1, 59.1, 43.5, 28.3; HRMS (ESI): m/z calcdfor C16H24N2O4Na [M + Na]+331.1628; found: 331.1612. |
46.4% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h;Cooling with ice; | Synthesis of (R)-N-Benzyl-2-Boc-amino-3-methoxypropionamide[0157] (R)-2-N-Boc-amino-3-methoxypropanoic acid (15.0 g, 68.4 mmol), phenylmethanamine (7.33 g, 68.4 mmol), and DMAP (4.17 g, 34.2 mmol) were dissolved in DCM (150 mL). The solution was cooled in an ice-bath and EDC (21 .21 g, 137 mmol) was added dropwise to the solution. Once addition was complete, the reaction mixture stirred at warmed to room temperature and stirred for two hours. Then DCM (200 ml) was added to the mixture. The DCM organic phase was washed with H20 (200 mL x 1 ), 0.5 N HC1 (200 mL x 2), 5percent sodium bicarbonate (200 mL chi 2) and water (200 mL x 2). The organic phase was dried over sodium sulfate, filtered, and solvent removed under reduced pressure. The desired product was obtained as a colorless semi-solid with a purity >95percent (9.8 g, 46.4percent). NMR (500 MHz, CDC13) delta 1.46 (s, 9H), 3.38 (s, 3H), 3.51 (m, 1H), 3.86 (d, 1 H), 4.30 (br., 1H), 4.50 (s, 2H), 5.42 (br., 1H), 6.74 (br., 1H), 7.28 (m, 3H), 7.35 (m, 2H). LC-MS (m/z) , calculated. 308.2, found 309.1 [M + H]+, 331.1 [M + Naf. |
The C936 solution prepared as above in example 2 was cooled to <-10°C and isobutyl chloroformate (14.2ml, 0.107mol) at <-5°C. N-methylmorpholine (11.8ml, 0.17mol) was added at<-5°C and the mixture aged for 30 minutes at <-5O. A solution of benzylamine (12.2ml, 0.11mol) in methylene chloride was added at <-5°C and the mixture warmed to room temperature. After aging for 1 hour the mixture was washed with water (44ml), 1N HCI (44ml), 8percent sodium bicarbonate (44ml) and water (44ml) to yield a C937 solution in methylene chloride. | ||
Example-32: Preparation of (R)-2-tert-butyl l-(benzylamino)-3-methoxy-l- oxopropan-2-yl carbonate compound of formuIa-18:; Ethylchoroformate (49.3 g) followed by N-methylmorpholine (46 g) was added to a pre-cooled reaction mass of (R)-2-(tert-butoxycarbonylamino)-3-methoxy propionic acid (280 ml) obtained in example-31 at -10 to -15°C and stirred for 15 min at -15°C. Benzylamine (49 g) was added to the reaction mixture slowly at -10 to -15 °C and stirred for 1.5 hours. Reaction temperature was raised to 20-25°C and stirred for 1.5 hours. The reaction mixture was washed with dilute hydrochloric acid (100 ml), and further the organic layer was washed with sodium bicarbonate solution followed by washed with water. The reaction mixture containing title compound was directly used for next stage without any isolation and purification. | ||
Preparation of (R)-N-benzyl-2-((tert-butoxy)carbonylamino)-3- methoxypropionamide(R)-2-((Tert-butoxy)carbonylamino)-3-methoxypropanoic acid (92.5 gm) as obtained in example 2 was dissolved in methylene chloride (925 ml) and then cooled to - 10°C. To the solution was added isobutyl chloroformate (57 ml) and then added 4- methylmorpholine (46.5 ml). The reaction mass was maintained for 30 minutes at -5°C and then added a solution of benzyl amine (46 ml) in methylene chloride (46 ml). The temperature of the reaction mass was raised to room temperature and then added water (140 ml). The separated organic layer was dried with sodium sulfate and the solvent was distilled off to obtain a residual mass. To the residual mass was added n-hexane (1200 ml) and stirred for 2 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 116 gm of (R)-N-benzyl-2-((tert-butoxy)carbonylamino)-3- methoxypropionamide. |
Yield | Reaction Conditions | Operation in experiment |
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96.28% | With tetrabutylammomium bromide; sodium hydroxide; In water; toluene; at 0 - 30℃; for 1.5h; | Put toluene at room temperature (4.8L) with Lacosamide stage II product (1kg), cooled to 0 °C, put sodium hydroxide solution 1 (0.54kg), tetrabutylammonium bromide (0.186 kg) with dimethyl sulfate (0.86 kg), heated to 30 °C, stir for 90 minutes. Extracted with toluene, put 5percent sodium bicarbonate solution, separate the organic phase. Put cyclohexane, stirred for 10 minutes and concentrated at 50 °C under reduced pressure for 2 hours. Drying to obtain lacosamide stage III. Yield of about 96.28percent. |
75.8% | With sodium hydroxide;tetra(n-butyl)ammonium hydrogensulfate; In dichloromethane; water; at 4 - 25℃;Inert atmosphere; | 2.(R)-boc-2-amino-N-benzyl-3-methoxy-propionamide (IV)In a 4 L flask with overhead stirrer, thermometer, dropping funnel and under nitrogen were combined 120 g (R)-boc-2-amino-N-benzyl-3-hydroxy-propionamide (III) (0.407 mol) and 1 kg dichloromethane.The reaction was cooled on ice to 4-8°C and 6.9 g tetrabutylammonium bisulfate (6.8 mmol) and 285 g of 20percent sodium hydroxide in water (0.475 mol) added.To the reaction was then added 154 g (1.22 mol) dimethyl sulfate and the reaction stirred at 4-8 °C for 4 hours and overnight at 20-25 °C.A sample showed greater than 98percent methylation of the starting (R)-boc-2-amino-N-benzyl-3-hydroxy-propionamide.The reaction was quenched by additing 330 g of 25percent ammonium hydroxide solution in water plus a further 330 g water and stirred for 2 hours.The phases were then separated and the aqueous phase extracted with 340 g dichloromethane.The combined dichloromethane phases were washed with 450 ml water, then the dichloromethane was exchanged for tert-butyl methyl ether (MTBE) and the product crystallised from 345 ml MTBE at 4 °C overnight. The crystals were filtered and washed 2 times with 45 ml MTBE and dried to yield 95.3 g (75.8percent yield), HPLC purity = 98.6percent, ee >99percent ,1H NMR conforms. |
75.8% | 2. (R)-boc-2-amino-N-benzyl-3-methoxy-propionamide (IV)In a 4 L flask with overhead stirrer, thermometer, dropping funnel and under nitrogen were combined 120 g (R)-boc-2-amino-N-benzyl-3-hydroxy-propionamide (III) (0.407 mol) and 1 kg dichloromethane. The reaction was cooled on ice to 4-8° C. and 6.9 g tetrabutylammonium bisulfate (6.8 mmol) and 285 g of 20percent sodium hydroxide in water (0.475 mol) added. To the reaction was then added 154 g (1.22 mol) dimethyl sulfate and the reaction stirred at 4-8° C. for 4 hours and overnight at 20-25° C. A sample showed greater than 98percent methylation of the starting (R)-boc-2-amino-N-benzyl-3-hydroxy-propionamide. The reaction was quenched by additing 330 g of 25percent ammonium hydroxide solution in water plus a further 330 g water and stirred for 2 hours. The phases were then separated and the aqueous phase extracted with 340 g dichloromethane. The combined dichloromethane phases were washed with 450 ml water, then the dichloromethane was exchanged for tert-butyl methyl ether (MTBE) and the product crystallised from 345 ml MTBE at 4° C. overnight. The crystals were filtered and washed 2 times with 45 ml MTBE and dried to yield 95.3 g (75.8percent yield), HPLC purity=98.6percent, ee >99percent, 1H NMR conforms. |
With tetrabutylammomium bromide; sodium hydroxide; In water; toluene; at 10℃; for 2h; | Intermediate 5: Preparation of tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamateTo a stirred solution of 3.2 g (0.01 mol) of Intermediate 4 in 50 mL of toluene was added 0.61 g of tetrabutylammonium bromide and 5 ml of water. The resulting mixture was cooled to 10° C. and a solution of 2.4 g of sodium hydroxide in 2.5 ml of water was added dropwise maintaining the temperature below 10° C. Then, 5.54 g of dimethylsulfate was added dropwise maintaining the temperature below 10° C. After stirring at 10° C. for 2 hours, water (80 mL) was added and the reaction stirred at room temperature overnight. The layers were separated and the aqueous layer was washed twice with dichloromethane (50 mL). The combined organic phase was washed with sodium bicarbonate solution (2.x.30 mL) and brine. The solvent was removed under vacuum yielding 3.36 g of a pale red-oil. The oil was not purified and used directly in the following step. | |
Step 2:Production of (R)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide.; (R)-N-Benzyl-2-N-Boc amino-3-hydroxy propionamide solution prepared as per the method b was cooled to < 5°C and potassium hydroxide (17.6 g, 0.3136 mol) was added at <5°C. The resulting suspension was aged for 5-10 min at <5°C and dimethyl sulfate (29.6 g, 0.2346 mol) was added at <5°C in 10- 15 min. The resulting mixture was aged for 3-5 h at <5°C. Water (80 ml) was added to the suspension and separated the phases. The organic layer was washed with a solution of citric acid (20.0 g) in DM water (80 ml) to produce (R)-N-benzyl-2-N-Boc- amino-3-methoxypropionamide solution in methylene chloride with HPLC purity (90percent), chiral 1 purity (98percent). The purity of the crude compound is optionally improved by crystallization from a mixture of hexane and ethyl acetate. | ||
With sodium hydroxide;tetrabutylammomium bromide; In dichloromethane; water; at 5 - 20℃; for 2h; | To the above solution of (i?)-N-benzyl-2-N-Boc-amino-3-hydroxypropionamide in dichloromethane was added 50percent w/w aqueous solution of sodium hydroxide 250 ml (4.75 mole) and tetrabutylammonium bromide 12.0 g (0.036 mole). Cooled to 5° C, added dimethyl sulfate 389.5 g (3.09 mole) and stirred at ambient temperature for 2 hrs. he aqueous layer was separated, and the organic layer was washed with water to obtain a solution of (j?)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide in dichoromethane | |
With tetrabutylammomium bromide; sodium hydroxide; In water; toluene; at 2 - 27℃; | Reaction mass of Stage II (190 g), toluene (950 ml), NaOH (71 g in 380ml of process water) (~415ml) and tetrabutyl ammonium bromide (35.36 g) were added at 27±3°C. Cooled the reaction mass to 2±3°C and the solution was stirred for 5-10 min. at 2±3°C and dimethyl sulfate (162.8 g) was added at 2±3°C followed by stirring for 5-10 min. at 2±3°C. Raised the temperature of reaction mass to 27±3°C and then it was stirred for 90 min. at the same temperature. The layers were separated. The organic layer was collected. The aqueous layer was extracted with toluene (190 ml), stirred and allowed to settle. The combined organic layers were washed with 5percent w/v sodium bicarbonate solution (47.5 g in 950 ml). The organic layer was collected and distilled out toluene completely under vacuum at below 56°C to obtained residue. Cyclohexane (190 ml) was added to residue at below 56°C and distilled out cyclohexane completely under vacuum at below 56°C. Degas the residue for 1-2 hr under vacuum (720 mm/Hg) at below 56°C. Cyclohexane (380 ml) was added to residue at below 56°C. Cooled the reaction mass to 27±3°C and then it was stirred for 2-3 hr. at the same temperature. Solid was filtered and washed with cyclohexane (190 ml) at 27±3°C. The solid was dried under vacuum at 47±3°C. | |
With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; at 5 - 20℃; for 2h; | To the above solution of (R)-N-benzyl-2-N-Boc-amino-3-hydroxypropionamide in dichloromethane was added 50percent w/w aqueous solution of sodium hydroxide 250 ml (4.75 mole) and tetrabutylammonium bromide 12.0 g (0.036 mole). Cooled to 5° C., added dimethyl sulfate 389.5 g (3.09 mole) and stirred at ambient temperature for 2 hrs. The aqueous layer was separated, and the organic layer was washed with water to obtain a solution of (R)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide in dichoromethane. | |
Step 2 Production of (R)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide (R)-N-Benzyl-2-N-Boc amino-3-hydroxy propionamide solution prepared as per the method b was cooled to <5° C. and potassium hydroxide (17.6 g, 0.3136 mol) was added at <5° C. The resulting suspension was aged for 5-10 min at <5° C. and dimethyl sulfate (29.6 g, 0.2346 mol) was added at <5° C. in 10-15 min. The resulting mixture was aged for 3-5 h at <5° C. Water (80 ml) was added to the suspension and separated the phases. The organic layer was washed with a solution of citric acid (20.0 g) in DM water (80 ml) to produce (R)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide solution in methylene chloride with HPLC purity (90percent), chiral purity (98percent). | ||
With potassium hydroxide; In dichloromethane; at 10 - 20℃; | A solution of tert-butyl [(2R)-l-(benzylamino)-3-hydroxy-l-oxopropan-2-yl]carbamate (300 g, 1.019 mol) in methylene chloride (1500 ml) was cooled to 10-15 °C and potassium hydroxide (102.7 g, 1.834 mol) was added maintaining the temperature below 15 °C. Dimethyl sulfate (218.38 g, 1.733 mol) was added below 15 °C in 10-15 min. The resulting mixture was stirred for 3-5 h at room temperature and water (1200 ml) was added. The layers were separated and the organic layer was evaporated under reduced pressure to obtain tert-butyl [(2i?)-l-(benzylamino)-3-methoxy-l-oxopropan-2- yl]carbamate in oil form having HPLC purity more than 90percent. This material was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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0.207 g | To a solution of compound 6 (0.320 g, 1.03 mmol) in dichloromethane (4 mL) was addedtrifluoroacetic acid (1.6 mL) and the reaction mixture was stirred at roomtemperature overnight. After the completion of reaction (TLC), the solvent wasevaporated under reduced pressure. The crude reaction mixture was dissolved inanhydrous CH2Cl2 (7.5 mL) and slowly acetic anhydride(1.0 mL, 10.57 mmol) dissolved in anhydrous CH2Cl2 (1.5mL) and catalytic amount of DMAP (27 mg, 0.103 mmol) were added. The resultingreaction mixture was stirred at room temperature for further 4 h. The solvent was removedunder reduced pressure and the residue was purified by flashchromatography (CombiFlash Rf 200i, Teledyne Isco) using RediSep silica gel column (12 g) eluting with CHCl3-MeOH (95:5, isocratic) to afford pure 1 as a white solid (0.207 g, 80percent for 2steps); Rf0.4 (10percent MeOH in CH2Cl2); mp 140-141 °C [Lit. 140-141°C,4142-143°C,5 143-144 °C6]; [alpha]D25+15.9 (c 1.01, MeOH) [Lit. +16.2 (c 1, MeOH),4 +16.1 (c 1.2, MeOH),5 +16.1 (c 1, MeOH)6]; IR (CHCl3) umax:3671, 3421, 3304, 3015, 2933, 2404, 1657, 1515, 1456, 1376, 1218, 1115, 927,762, 668 cm-1; 1H NMR (400 MHz, CDCl3) delta:7.36-7.21 (m, 5H), 7.02 (brs, 1H), 6.66 (d, J = 6.1 Hz, 1H), 4.60 (dt, J= 4.4, 7.0 Hz, 1H), 4.51-4.37 (m, 2H), 3.77 (ddd, J = 1.7, 4.2, 9.2 Hz,1H), 3.46 (dd, J = 7.5, 8.7 Hz, 1H), 3.36 (s, 3H), 1.99 (s, 3H); 13CNMR (100 MHz , CDCl3)delta: 170.5, 170.0, 137.9, 128.7, 127.4,71.9, 59.1, 52.5, 43.5, 23.1; HRMS(ESI): m/z calcd for C13H18N2O3Na[M + Na]+ 273.1210; found: 273.1195;ee> 99.9percent [The ee of (R)-lacosamide(1)wasdetermined by chiral HPLC analysis: Chiralcel OD-H (0.46 cm X 25 cm), iso-propyl alcohol-nhexane-trifluoroacetic acid (30:70:0.1), flow rate 0.5mL/min; UV detection at 220 nm; tR= 10.5 min]. |
Yield | Reaction Conditions | Operation in experiment |
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80% | To a solution of compound (R)-10 (0.6 g, 1.9 mmol) in dichloromethane (7 mL) was added trifluoroacetic acid (3 mL) and the reaction mixture was stirred at room temperature overnight, after which the solvent was evaporated under reduced pressure. The residue was then dissolved in dry toluene after which Na2CO3 (0.6 g, 5.7 mmol) was added. The reaction mixture was cooled to 0 °C after which acetyl chloride (0.14 mL, 2.0 mmol) was slowly added and the solution stirred at 5 °C for 1 h. After completion of the reaction, the solid was filtered and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane/methanol, 95:05) to afford (R)-1 (Lacosamide) as a colorless solid (0.38 g, 80percent); Colorless solid; mp 139-40 °C (lit.refPreviewPlaceHolder7 143-44 °C); (c 1, MeOH) {lit.refPreviewPlaceHolder7 +16.4 (c 1, MeOH)}; IR (CHCl3): gamma 3685, 3421, 3020, 1663, 1523, 1426, 1118, 1030, 929 cm-1; 1H NMR (400 MHz, CDCl3): delta 2.05 (s, 3H, COCH3), 3.40 (s, 3H, OCH3), 3.45 (apparent t, J = 9.7, 8.0 Hz, 1H, OCH2), 3.83 (dd, J = 9.4, 3.4 Hz, 1H, OCH2), 4.50 (d, J = 4.5 Hz, 2H, CH2Ph), 4.52-4.58 (m, 1H), 6.48 (br s, 1H, NH), 6.78 (br s, 1H, NH), 7.26-7.38 (m, 5H, Ph);13C NMR (50 MHz, CDCl3): delta 170.7 (CO), 170.0 (CO), 137.7 (C), 128.6 (CH, 2 carbons), 127.4 (CH, 3 carbons), 71.8 (CH2), 59.1 (CH3), 52.6 (CH), 43.6 (CH2), 23.2 (CH3); MS: m/z 273 [M+Na]+; ee >98percent [The ee of 1 was determined by chiral HPLC analysis; Chiralcel OD-H (250 .x. 4.6 mm) column; eluent: pet. ether/isopropanol/trifluoroacetic acid (60:40:0.1); flow rate 0.5 mL/min; detector: 220 nm [(R)-isomer tR = 10.43 min; (S)-isomer tR = 11.8 min]. | |
80% | To a solution of compound (R)-9 (0.6 g, 1.9 mmol) in dichloromethane (7 mL) was added trifluoroacetic acid (3 mL) and the reaction mixture was stirred at 30° C. overnight (12 h), after which the solvent was evaporated under reduced pressure. Subsequently, the residue was dissolved in dry toluene and added Na2CO3 (0.6 g, 5.7 mmol). The reaction mixture was cooled to 0° C. and acetylchloride (0.14 mL, 2.0 mmol) was added slowly and stirred the content at 5° C. for 1 h. After completion of the reaction, filtered the solid and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane/methanol, 95:05) to afford (R)-1 (Lacosamide) as a colorless solid (0.38 g, 80percent). [0077] m.p 139-40° C. (Lit 143-44° C.); [alpha]D: +16.1 (c 1, MeOH) {Lit. +16.4 (c 1, MeOH)}; IR (CHCl3): gamma 3685, 3421, 3020, 1663, 1523, 1426, 1118, 1030, 929 cm?1; 1H NMR (400 MHz, CDCl3): delta 2.05 (s, 3H, COCH3), 3.40 (s, 3H, OCH3), 3.45 (apparent t, J=9.7, 8.0 Hz, 1H, OCH2), 3.83 (dd, J=9.4, 3.4 Hz, 1H, OCH2), 4.50 (d, J=4.5 Hz, 2H, CH2Ph), 4.52-4.58 (m, 1H), 6.48 (bs, 1H, NH), 6.78 (bs, 1H, NH), 7.26-7.38 (m, 5H, Ph); 13C NMR (50 MHz, CDCl3): delta 170.7 (CO), 170.0 (CO), 137.7 (C), 128.6 (CH, 2 carbons), 127.4 (CH, 3 carbons), 71.8 (CH2), 59.1 (CH3), 52.6 (CH), 43.6 (CH2), 23.2 (CH3); MS: m/z 273 [M+Na]+; (ee 98.3percent) ee>98percent [The ee of 1 was determined by chiral HPLC analysis; Chiralcel OD-H (250×4.6 mm) column; eluent: pet.ether/isopropanol/trifluoroacetic acid (60:40:0.1); flow rate 0.5 mL/min; detector: 220 nm [(R)-isomer tR=10.43 min; (S)-isomer tR=11.8 min]. |
Yield | Reaction Conditions | Operation in experiment |
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100% | In dichloromethane; at 20℃; for 2h; | Synthesis of (R)-2-amino-N-benzyl-3-methoxypropanamide[0159] (R)-N- benzyl-2-Boc-amino-3-methoxypropanamide (9.8 g, 31.8 mmol) was dissolved in 15 mL of DCM and then 15 mL of TFA was added to the solution. The mixture was stirred at room temperature for two hours. The solvent and TFA was removed by evaporation and a white solid was obtained (12.4, 100percent). Upon analysis, it was determined that on average each molecule contained 1.6 TFA. NMR (500 MHz, DMSO) delta 3.30 (s, 3H), 3.69 (m, 2H), 4.05 (m, 1H), 4.35 (m, 2H), 7.25 (m, 3H), 7.35 (m, 2H), 8.23 (br., 2H), 8,95 (m, 1H). LC-MS (m/z) calcd. 208.1 , found 209.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
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9 g | In tert-butyl methyl ether; at 60 - 65℃; | A mixture of (R)-tert-butyl-4-(methoxymethyl)-5-oxazolidinone (7.0 g), benzyl amine (6.5 g) and triethylamine (5.1 1 g) in methyl tert-butyl ether (15 mL) was stirred at 60- 65°C for 10- 12h. After completion of the reaction, methyl tert-butyl ether was added to reaction mixture and acidified with 20percent aqueous potassium hydrogen sulphate solution (~ 30 mL) at 10~15°C. The organic layer was washed with water (2x 15 mL) and concentrated under reduced pressure to get the title compound. Weight: 9.0 g Yield: 96.45percent |
Yield | Reaction Conditions | Operation in experiment |
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90.4% | at 20℃; for 3h; | A mixture of 2,4-dioxo-3-azaspiro[5.5]undecan-3-yl N-(tert-butoxycarbonyl)-O-methyl-d-serinate Ib (Scheme 5) (3.0g, 7.53mmol) and benzyl amine (0.97g, 9.05mmol) was vigorously stirred for 3h at ambient temperature. After completion of the reaction, methyl tert-butyl ether (20mL) was added and stirred at room temperature for 1h. The reaction mixture was filtered, and washed with methyl tert-butyl ether (5mL). The filtrate was washed with 5percent aq HCl solution (10mL), water (2×10mL), brine (10mL), dried over Na2SO4, and evaporated under reduced pressure. The crude product solidified while standing overnight at room temperature to yield tert-butyl (R)-(1-(benzylamino)-3-methoxy-1-oxopropan-2-yl) carbamate Ic as a colorless solid (2.1g, 90.4percent); mp 62?64°C (lit.23 63?64°C); [alpha]D25=?20.8 (c 0.9, CHCl3) [lit.23 ?20.5]; 97.68percent purity by HPLC (Method-d, Table 1); eepercent: 99.44percent (Method-j, Table 1) [(R)-isomer Rt=7.65min; (S)-isomer Rt=8.51min]. IR (KBr, cm?1): vmax 3326, 3030, 2971, 2950, 2927, 2852, 2824, 1684, 1650, 1528, 1496, 1453, 1393, 1364, 1351, 1317, 1284, 1252, 1227, 1171, 1115, 1095, 1046, 1021, 919, 870, 750, 697, 652; 1H NMR (300MHz, CDCl3): deltaH 1.43 (s, 9H), 3.36 (s, 3H), 3.47?3.52 (dd, J=9.3, 6.3Hz, 1H), 3.82?3.86 (dd, J=9.3, 3.9Hz, 1H), 4.27 (br, 1H), 4.48 (br s, 2H), 5.41 (br, 1H), 6.74 (br, 1H), 7.24?7.35 (m, 5H); 13C NMR (75MHz, CDCl3): deltaC 169.3, 154.5, 137.0, 127.5, 126.4, 79.2, 71.1, 58.0, 53.0, 42.3, 27.2; MS: m/z 331 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
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100% | In dichloromethane; at 0 - 5℃; for 0.5h; | The above prepared compound of formula III (30.3g, 0 . 100mol) in the dichloromethane solution 0-5°C, added benzylamine (10.7g, 0 . 100mol) methylen chloride (22 ml) solution. In 0-5 °C reaction 30 minutes with water (88 ml), 10percent sodium hydroxide solution (88 ml), 0.6mol/L hydrochloric acid (88 ml), water (88 ml) washing the reactant, is distilled under reduced pressure to dry obtains the type compound IV 30.8g (yield 100percent, HPLC purity 93.0percent, chiral purity 95.8percent). |
Yield | Reaction Conditions | Operation in experiment |
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80% | With tetrabutylammomium bromide; potassium hydroxide; In toluene; at -1 - 2℃; | Toluene (820 mL), Intermediate III (50 g), methyl p-toluenesulfonate (63.5 g),Tetrabutylammonium bromide (5.4 g) was added and the mixture was cooled with stirring to -1 to 2 ° C. Potassium hydroxide aqueous solution (40 g / 34 mL) was added at -1 to 2 ° C, and the addition was completed in about 5 minutes. The addition was complete, continue to control the temperature at -1 ~ 2 reaction 4 ~ 4.5 hours (TLC detection or HPLC control) to stop the reaction. After completion of the reaction, water (400 mL) was added to separate the layers. Organic layer followed by 5percent phosphoric acid, saturated sodium bicarbonate, water each200mL wash. Decompression 40 ~ 45 ° C The solvent was evaporated to give an oil, the reaction was used directly for the next step. HPLC purity 95percent, chiral Purity 99.1percent. |
60.97g | With tetrabutylammomium bromide; potassium hydroxide; In water; toluene; at 20℃; for 3h; | Toluene (330 mL) was added sequentially to the 1 L reaction flask,The compound of formula II (20.00 g, 68 mmol)P-toluenesulfonic acid methyl ester (63.50 g, 340 mmol),Tetrabutylammonium bromide (2.63 g, 8.16 mmol),Stir evenly,An aqueous solution of potassium hydroxide (16.00 g of potassium hydroxide + 16 mL of water) was added at room temperature,Plus complete, room temperature reaction 3 hours.Reaction completed, adding water (160mL), stirring 5min, standing stratification, liquid separation,Organic layer followed by 5percent phosphoric acid(80 mL), water (160 mL x 2), and the organic layer was concentrated at 55 ° C under reduced pressure. The solvent was evaporated to give 60.97 g of an oil.The product of this example was the same as in Example 1 by isolation and identification. |
38.5 g | With tetrabutylammomium bromide; sodium hydroxide; In water; at 20℃; for 3h; | To a 1L reaction flask were sequentially added toluene (330 mL), Compound II (20.00 g, 68 mmol), methyl p-toluenesulfonate (38.10 g, 204 mmol), tetrabutylammonium bromide (2.63 g, 8.16 mmol), Stir well, add aqueous sodium hydroxide solution (16.00g of sodium hydroxide + 16mL of water) at room temperature, complete the addition, and react at room temperature for 3 hours. After the reaction is complete, add water (160 mL), stir for 5 min, stand for layering, separate the liquid, and use 5percent phosphoric acid in order for the organic layer.(80 mL) and water (160 mL×2) were washed. The organic layer was concentrated under reduced pressure at 55° C., and the solvent was evaporated to give 38.5 g of an oil. |
38.5 g | With tetrabutylammomium bromide; sodium hydroxide; In water; toluene; at 20℃; for 3h; | Toluene (330 mL) was added sequentially to a 1L reaction flask,Compound II (20.00 g, 68 mmol),Methyl p-toluenesulfonate (38.10 g, 204 mmol),Tetrabutylammonium bromide (2.63 g, 8.16 mmol),Stir well,An aqueous solution of sodium hydroxide (16.00 g of sodium hydroxide + 16 mL of water) was added at room temperature.After the addition, the reaction was carried out at room temperature for 3 hours.After the reaction is complete, add water (160 mL) and stir for 5 min.Static stratification, liquid separation,The organic layer was successively washed with 5percent phosphoric acid (80 mL) and water (160 mL×2), and the organic layer was concentrated under reduced pressure at 55° C.After the solvent was distilled off, 38.5 g of an oil was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; In methanol; at 50℃; for 2h; | A solution of tert-butyl [(2R)-l-(benzylamino)-3-methoxy-l-oxopropan-2-yl]carbamate (1.019 mol) obtained in Example 3 in methanol (300 ml) was heated at 50 °C with and Methanolic HCl (300 ml, 10percent) was added under stirring. The reaction mixture was stirred at 50 °C for 2 h, evaporated under reduced pressure. Methanol (300 ml) was added to the residue and evaporated under reduced pressure to provide HCl salt of O- methyl-N-benzyl-D-serinamide in oil form having HPLC purity more than 90percent. (0146) The above HCl salt of O-Methyl-N-benzyl-D-Serinamide (1.019 mol) was dissolved in methylene dichloride at room temperature and sodium acetate (125.4 g, 1.529 mol) was added under stirring. Acetic anhydride (127.05 g, 1.223 mol) was added slowly and stirred for 2-3 h. The reaction mass was washed with water (1200 ml) and the layers were separated. The organic layer was evaporated under reduced pressure and the residue was subjected to precipitation by dissolving in Ethyl acetate (2700 ml) and adding n-Heptane (3300 ml). The precipitated solid was filtered under reduced pressure to obtain crude Lacosamide having HPLC purity more than 98percent.. |