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(±)-Nipecotic acid is an inhibitor of GABA uptake with IC50 values of 8, 106 and 2370 mM for hGABA T-1, hGABA T-3 and hBGT-1 respectively.
Synonyms: (±)-β-Homoproline; Hexahydronicotinic acid; DL-Piperidine 3-Carboxylic Acid
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CAS No. : | 498-95-3 |
Formula : | C6H11NO2 |
M.W : | 129.16 |
SMILES Code : | O=C(C1CNCCC1)O |
Synonyms : |
(±)-β-Homoproline; Hexahydronicotinic acid; DL-Piperidine 3-Carboxylic Acid
|
MDL No. : | MFCD00005992 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
82% | With sodium hydroxide; | C. 1,3-Piperidinedicarboxylic acid, 1-(phenylmethyl)ester Benzyl chloroformate (4 mL) was added dropwise to a cooled (0-5 C.), stirred solution of piperidine-3-carboxylic acid (1.03 g, 8 mmol) in 1 N aqueous NaOH solution (25 mL). During the twenty minute addition, the pH was maintained between 8 and 9 by addition of 1 N NaOH solution. After addition was complete, the mixture was stirred cold for an additional hour, maintaining the pH thoughout this period. The reaction mixture was then extracted with ether (2*40 mL). The ether extracts were discarded and the aqueous layer was acidified with 1 N HCl solution. The acidified aqueous layer was then extracted with dichloromethane (2*40 mL). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give title acid as a viscous oil (1.73 g, 82%). |
113% | In diethyl ether; water; | Example 437A N-Benzyloxycarbonyl nipecotic acid To a solution of nipecotic acid 10 g, 63.6 mmol) in 1 N NaOH (2.5 g in 64 mL water, 63.6 mmol) at 0 C. was alternately added benzyloxycarbonyl chloride (10.9 mL, 76.5 mmol) in diethyl ether (50 mL) and 1 N NaOH (5 g in 128 mL water, 127.2 mmol) in five portions. The reaction mixture was stirred at 0 C. for 2 hours, and at ambient temperature for 24 hours. Then this was made acidic with 10% HCl and the solid formed was filtered and dried (vacuum oven, 45 C.) to obtain the title compound (18.9 g, 113%). MS (ESI) m/e 264 (M+H)+. |
Example 153 A1-(benzyloxycarbonyl)piperidine-3-carboxylic acid; To the solution of piperidine-3-carboxylic acid (1.3 g, 10 mmol) in water (20 mL) was added sodium hydroxide (1.6 g, 40 mmol). Then benzyloxycarbonyl chloride (2.02 g, 12 mmol) was added dropwise at 0 C. The mixture was stirred at 0 C. for 2 h. The resulting mixture was treated with 5N hydrochloric acid to pH=6 and extracted with ethyl acetate, the solvent was removed under reduced pressure and dried in vacuum. 2.2 g of solid of 1-(benzyloxycarbonyl)piperidine-3-carboxylic acid was obtained. LC-MS (ESI) m/z: 264 (M+1)+. |
[1246] To a solution of nipecotic acid (10 g, 63.6 mmol) in 1 N NaOH (2.5 g in 64 mL water, 63.6 mmol) at 0 C. was alternately added benzyloxycarbonyl chloride (10.9 mL, 76.5 mmol) in diethyl ether (50 mL) and 1 N NaOH (5 g in 128 mL water, 127.2 mmol) in five portions. The reaction mixture was stirred at 0 C. for 2 h, and at ambient temperature for 24 h. Then this was made acidic with 10% HCl and the solid formed was filtered and dried (vacuum oven, 45 C.) to obtain the title compound (18.9 g, 113%). MS (ESI) m/e 264 (M+H)+. | ||
EXAMPLE 15 ()-BENZYL 3- (6-METHOXY-2-METHYL-1-OXO-4-PHENYL-1, 2-DIHYDROISOQUINOLIN-3-YL) PIPERIDINE-1- carboxylate; Step A: ()-L-F (BENZYLOXY) CARBONYLLPIPERIDINE-3-CARBOXYLIC ACID; To an ice cooled solution of nipecotic acid (10.0 g, 77.5 mmol), sodium hydroxide (3.4 g, 85 mmol), and tetrahydrofuran (50 ML) in water (100 ML) was added by simultaneous dropwise addition benzylchloroformate (13.3 ML, 93 mmol) in tetrahydrofuran (50 ML) and sodium hydroxide (3.4 g, 85 mmol) in water (50 mL). Warmed slowly to room temperature. After 24 hours tetrahydrofuran was removed in vacuo and the resulting aqueous mixture acidified with 3 N hydrochloric acid and extracted with dichloromethane (3X). The combined organic portions were dried with anhydrous magnesium sulfate. Filtration followed by evaporation of the filtrate in vacuo gave the titled COMPOUND. HNMR (CHCIS, 300MHZ) Q 7.45-7. 20 (m, 5H) ; 5.14 (m, 2H); 4.21 (br S, 1H) ; 3.96 (m, 1H), 3.15 (br s, 1H) ; 2.93 (m, 1H) ; 2.51 (m, 1H) ; 2.09 (m, 1H); 1.80-1. 60 (m, 2H); 1.50 (m, 1H) ppm | ||
To a stirred solution of 3-piperidine carboxylic acid (1.48 g, 11.5 mmol) and saturated sodium bicarbonate (40 mL) in tetrahydrofuran (40 mL) at 0 C. was added benzylchloroformate (2.05 g, 12.0 mmol). The mixture was stirred in an ice-bath for 3 h, and then at room temperature for 16 h. The mixture was then cooled to 0 C. and the pH was reduced to ca. 1.0 with 6 M HCl. The mixture was extracted three times with ethyl acetate. The combined extracts were dried with magnesium sulfate, filtered, and concentrated to provide 10.0 g of the title compound as a colorless oil. | ||
Step 1. 1-(Benzyloxycarbonyl)piperidine-3-carboxylic; A 500-mL 4-necked round-bottom flask was charged with a solution of NaOH (8 g, 198.00 mmol, 1.00 equiv, 99%) in H2O (200 mL). To this was added piperidine-3-carboxylic acid (25.8 g, 197.75 mmol, 1.00 equiv, 99%), in small portions at 0 C. Then, a solution of benzyl carbonochloridate (39.2 g, 227.48 mmol, 1.15 equiv, 99%) in Et2O (50 mL) was added at 0 C. over 40 minutes. Then a solution of NaOH (12 g, 1.50 equiv) in H2O (300 mL) was added drop wise with stirring at 0-10 C. The resulting solution was allowed to stir overnight at room temperature. The reaction progress was monitored by TLC (EtOAc/PE=1/1). The pH adjusted to 3 with 10% aqueous HCl. The resulting solution was extracted with ethyl acetate (3×500 mL). Combined organic layers were dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator to afford 1-(benzyloxycarbonyl)piperidine-3-carboxylic acid (58 g) as white solid. | ||
With sodium hydroxide; In water; at 0 - 20℃; | Step 1: In a 100 ml three-necked flask, in a stream of nitrogen and under magnetic stirring the nipecotinic acid (3.7 g) was placed in solution in a 3N sodium hydroxide solution (30 ml). The solution was cooled over an ice bath to 0 C. Benzyl chloroformiate (5.8 ml) was added in fractions at 0 C. alternately with a 3N sodium hydroxide solution (9.3 ml) for a time of 45 min. After the addition time the reaction medium was pale yellow and the temperature 3 C. The ice bath was removed and the reaction medium left under stirring at ambient temperature overnight. The aqueous phase was then extracted once with ethyl ether, then acidified to pH 1 using a 3N hydrochloric acid solution. The acidified aqueous phase was extracted three times with ethyl ether. The ether extract phase was successively washed with 1N hydrochloric acid solution, then twice with saturated sodium chloride solution before being dried over magnesium sulphate, filtered then concentrated in vacuo. [0126] The yellow oil obtained (7.35 g, 98%) was used at the following step without any purification step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In water; | A. 2.5 g nipecotic acid was stirred with a solution of 2.67 g potassium carbonate in 20 ml of water to give a clear solution. To this solution wasadded 2.4 g <strong>[1184-90-3]aminoiminomethanesulfonic acid</strong> in small portions over a period of 10 minutes. The solution was allowed to stand overnight and the resulting precipitate recrystallized from water to give N-amidino-piperidine-3-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Cupriavidus sp. KNK-J915 strain (FERM BP-10739); at 30℃; for 35h;pH 7;Aqueous phosphate buffer; Enzymatic reaction;Product distribution / selectivity; | Example 3 Selective Hydrolysis of R-Enantiomer in Racemic <strong>[4138-26-5]Nipecotamide</strong>Cupriavidus sp. KNK-J915 strain (FERM BP-10739) was cultivated by the method of Example 1 to prepare a bacterial cell suspension. The bacterial cell suspension (0.1 ml) was mixed with 100 mM phosphate buffer containing 1.0 to 5.0percent of racemic <strong>[4138-26-5]nipecotamide</strong> (0.1 ml, pH 7.0), and the mixture was shaken at 30° C. for 35 hours. After completion of the reaction, solid substance such as bacterial cells was removed by centrifugal separation, and then a substrate and a product in the reaction mixture were reacted with benzyl chlorocarbonate for derivatization. The resulting derivative was analyzed by high performance liquid chromatography to determine the conversion rate (percent) and optical purity (ee percent). The results are listed in Table 3.High Performance Liquid Chromatographic Analysis ConditionsAnalysis of Conversion RateColumn: YMC-A303 (4.6 mm.x.250 mm, manufactured by YMC Inc., Eluent: 20 mM phosphoric acid aqueous solution (pH 2.5)/acetonitrile=7/3, Flow rate: 1.0 ml/minute, Column temperature: 35° C., Measuring wavelength: 210 nmAnalysis of Optical PurityColumn: CHIRALPAK AD-RH (4.6 mm.x.150 mm, manufactured by Daicel Chemical Industries, Ltd.), Eluent: 20 mM phosphate buffer (pH 2.5)/acetonitrile=7/3, Flow rate: 0.5 ml/minute, Column temperature: room temperature, Measuring wavelength: 210 nm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; at 30℃; for 60h;pH 7;Aqueous phosphate buffer; Enzymatic reaction; | Example 4Selective Hydrolysis of S-enantiomer in Racemic <strong>[4138-26-5]Nipecotamide</strong>Cupriavidus sp. KNK-J915 strain (FERM BP-10739) was cultivated by the method of Example 2 to obtain a 20-fold concentrated bacterial cell suspension. To the bacterial cell suspension (100 ml), racemic <strong>[4138-26-5]nipecotamide</strong> (19.9 g) was added. After the pH of the mixture was adjusted to 7 using NaOH, the mixture was shaken at 30° C. for 60 hours. After completion of the reaction, the reaction mixture was heat-treated at 70° C. for 30 minutes, and solid substance such as bacterial cells was removed by centrifugal separation. The substrate and product in the reaction mixture were analyzed by the method of Example 3; as a result, the conversion rate was 52.7percent, the optical purity of (R)-<strong>[4138-26-5]nipecotamide</strong> was 98.8percent ee and the optical purity of (S)-<strong>[4138-26-5]nipecotamide</strong> was 88.1percent ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With amidase from Cupriavidus sp. KNK-J915 (FERM BP-10739); water; In aq. phosphate buffer; at 30℃;pH 7;Enzymatic reaction; | General procedure: During the purification and characterization of amidase from Cupriavidus sp. KNK-J915, an enzyme assay was performed with (R,S)-BNPD as a substrate. The standard reaction mixture (0.2 mL) contained 100 mM potassium phosphate buffer (pH 7.0), 45.8 mM BNPD, and an appropriate amount of the enzyme. After the reaction was performed at 30°C for 0.5?1 h, the amount of BNPA was determined using HPLC. One unit of the enzyme was defined as the amount catalyzing the formation of 1 mol of BNPA per minute under the aforementioned condition. Protein content was determined by the Bradford method [11] with BSA as a standard using a kit from Bio-Rad Laboratories Ltd. (Tokyo, Japan). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With amidase from Cupriavidus necator JMP134; water; In aq. phosphate buffer; at 30℃;pH 7;Enzymatic reaction; | General procedure: During the purification and characterization of amidase from Cupriavidus sp. KNK-J915, an enzyme assay was performed with (R,S)-BNPD as a substrate. The standard reaction mixture (0.2 mL) contained 100 mM potassium phosphate buffer (pH 7.0), 45.8 mM BNPD, and an appropriate amount of the enzyme. After the reaction was performed at 30°C for 0.5?1 h, the amount of BNPA was determined using HPLC. One unit of the enzyme was defined as the amount catalyzing the formation of 1 mol of BNPA per minute under the aforementioned condition. Protein content was determined by the Bradford method [11] with BSA as a standard using a kit from Bio-Rad Laboratories Ltd. (Tokyo, Japan). |
Tags: Nipecotic acid | (±)-β-Homoproline | Neurotransmitter | Carboxylic Acids | Piperidines | Non-protein Amino Acid | Exosome | Organic Building Blocks | Small Molecule Positive Drugs | Amino Acids | Heterocyclic Building Blocks | 498-95-3
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