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CAS No. : | 99189-60-3 |
Formula : | C10H17NO3 |
M.W : | 199.25 |
SMILES Code : | O=C(O)CC1(CC(N)=O)CCCCC1 |
MDL No. : | MFCD02181086 |
InChI Key : | QJGSJXLCJRXTRY-UHFFFAOYSA-N |
Pubchem ID : | 665664 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.8 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 52.49 |
TPSA ? Topological Polar Surface Area: Calculated from | 80.39 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 1.17 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 1.17 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 1.29 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 0.76 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 1.16 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 1.11 |
Log S (ESOL):? ESOL: Topological method implemented from | -1.55 |
Solubility | 5.64 mg/ml ; 0.0283 mol/l |
Class? Solubility class: Log S scale | Very soluble |
Log S (Ali)? Ali: Topological method implemented from | -2.45 |
Solubility | 0.701 mg/ml ; 0.00352 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -1.31 |
Solubility | 9.67 mg/ml ; 0.0485 mol/l |
Class? Solubility class: Log S scale | 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 | -6.68 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 | 1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat | 0.56 |
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) | 1.78 |
* 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 |
---|---|---|
Synthesis of 1.1-cvclohexane diacetic acid monoamide25.7 kg (19.3 1) of electrolytic soda were charged in reactor C by means of meteringpump.The temperature was brought to about 95°C and it was maintained until the completedissolution of the solid, then the mixture was brought to reflux (101-105°C).Reflux was maintained for about six hours, then the reaction check was carried outAt the completion of the reaction, the solution was cooled to about 20°C withprecipitation of a solid white flocculate, then, at temperature 45.0 kg (57.3) ofisopropanol were charged and subsequently in about one hour, maintainingtemperature below 25°C, about 125 kg (107.7 1) of synthetic hydrochloric acid werecharged until reaching a pH of 6.5 +/- 0.2, measured with pH meter.Once the desired pH was reached, the suspension was heated to 35-40°C and it wasmaintained at this temperature until dissolution of the solid.At the completion of the dissolution, the solution was transferred into reactor E andsubsequently 20 kg of demineralised water were charged in the reactor.The washing was kept under stirring for 5-10 minutes, then it was transferred intoreactor E.The internal temperature of reactor E was regulated to about 35-40°C then, maintaining temperature, 40 kg (34.5 1) of synthetic hydrochloric acid were added in about one hour until reaching a pH of 4.0-4.5, measured with paper. The pH of the suspension was checked to be stable for at least 10-15 minutes, then the internal temperature of reactor E was brought to about 50°C and it was maintained for about 30 minutes.In about one and one half hours the suspension was cooled to about 15-20°C andafter about one hour several centrifuging operations were carried out. The panel waswashed twice with a mixture formed by isopropanol and water.In total, 23.6 kg (30 k) of isopropanol and 30 kg of demineralised water were used.After one washing with the alcoholic mixture, the panel was subjected to sixwashings with water.In total, 270 kg of demineralised water were indicatively used.78.0 kg of humid product were obtained, which after drying at about 50°C undervacuum yield about 59.0 kg of the desired dry product. | ||
Example 8; Synthesis of cyclohexanediacetic acid monoamide (V); 9g of 2, 4-dioxo-3-azaspiro [5,5] undecane and 30 g of 10percent NaOH are placed in a 250 ml flask equipped with mechanical agitator, thermometer and condenser. The mixture is heated under reflux for 1 hour, cooled to 25°C and acidified with 36percent HCI to pH 5. The precipitate formed is filtered off, washed with water and dried under vacuum. 6.4 g of cyclohexanediacetic acid monoamide are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Water (380 mL), 324 g of NaOH solution (30percent) were added to a 2000 mL reaction flask. The solution was cooled to 10-15° C. Cyclohexane 1,1-diacetic acid monoamide (II) (160 g) was added. The mixture was stirred until all solid dissolved, and the cooled to 0-5° C. NaClO solution (557 g, 11.3percent) was added dropwise at 0-5° C. The mixture was further stirred for 1.5 h at 5-10° C. The temperature was slowly raised to 35-40° C. in an hour and stirred at this temperature for 2 h. Sodium bisulfite (2-5 g) was added to destroy remaining NaClO. The pH was adjusted to 8.5+/-0.3 with HCl solution recycled from the hydrolysis of 3,3-pentamethylenebutyrolactam (IV). The mixture was reflux (100-105° C.) for 3 hours and then cooled to 60-65° C. The pH again was adjusted with 31percent HCl to 8.5+/-0.5. The mixture was extracted with toluene (400 mL.x.2). Toluene layer was evaporated to dryness, to obtain white crystalline 3,3-pentamethylenebutyrolactam (IV), 129 g, Yield: 104.8percent (due to the use of recycled HCl, which contained some 3,3-pentamethylenebutyrolactam (IV), the yield is higher than 100percent); purity, 99.9percent (HPLC). | |
93.8 - 95.9% | 3,3-Pentamethylenebutyrolactam (IV). Water (380 mL), 324 g of NaOH solution (30percent) were added to a 2000 mL reaction flask. The solution was cooled to 10-20° C. Cyclohexane 1,1-diacetic acid monoamide (II) (160 g) was added. The mixture was stirred until all solid dissolved, and the cooled to 0-15° C. NaClO solution (557 g, 11.3percent) was added dropwise. The temperature was slowly raised to 40-50° C. and stirred at this temperature for 3 h. Sodium bisulfite was added to destroy remaining NaClO. The pH was adjusted to 11 to 12 with 31percent aqueous HCl solution. The mixture was refluxed (100-105° C.) for 3 hours and then cooled to 50-60° C. The mixture was extracted with toluene. Toluene layer was evaporated to dryness to afford white crystalline 3,3-pentamethylenebutyrolactam (IV), 118 g, Yield: 95.9percent; purity, 99.65percent (HPLC); 3,3-Pentamethylenebutyrolactam (IV). Water (420 L) and 420 kg of NaOH solution (30percent) were added to a 2000 L reaction vessel. The solution was cooled to 10-20° C. Cyclohexane 1,1-diacetic acid monoamide (II) (160 kg) was added. The mixture was stirred until all solid dissolved, and the cooled to 0-15° C. NaClO solution (630 kg, 11.3percent) was added dropwise at 0-5° C. The temperature was slowly raised to 40-50° C. and stirred at this temperature for 3 h. Sodium bisulfite was added to destroy remaining NaClO and starch-KI paper was used to assure that the excess NaClO was all destroyed. The pH was adjusted to 11 to 12 with 30percent aqueous HCl solution. The mixture was refluxed for 3 hours and then distilled and 300 to 400 L of water was distilled. The mixture was cooled to 0-5° C. and centrifuged. White crystalline product was obtained after toluene layer was evaporated the product was dried in vacuo, 115.5 kg, yield: 93.8percent; purity, 99.7percent, mp: 90-92° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Sodium hydroxide (51 g) is dissolved in sodium hypochlorite solution (6.25percent, 625 G) and cooled to 10°C. The solution is stirred for 10 - 15 min, and further cooled to -5°C. In a separate flask, <strong>[99189-60-3]1,1-cyclohexane diacetic acid monoamide</strong> (100 g) is dissolved in 4N Sodium hydroxide solution (150 ml) at 15°C - 20°C. The amide solution is slowly added to the sodium hypochlorite solution at temperature -5°C to -3°C. The solution is then maintained at about 0°C for 2 hrs. The temperature is gradually raised over 3 hrs to 20°C -25°C and then maintained at this temperature for 4 hrs. Sodium meta bisulphite solution (5 g in 10 ml water) is then added to the solution. The reaction mass is filtered remove any un-dissolved material. pH of the filtrate is adjusted to around 9.0 by the addition of hydrochloric acid at temperature 20°C - 25°C. n-Butanol (200 ml) is added arid the pH is further adjusted to 1.5 with hydrochloric acid and stirred for 10 - 15 min. The reaction mass is allowed to settle with separation of the layers. The aq. Layer is extracted with n-Butanol (200 ml). The organic is dried over anhydrous sodium sulphate (15 g ). Di isopropyl ether (1200 ml) is slowly added to the dried organic layer at room temperature over 30 - 45 min and maintained for about 1 hr under stirring. The system is cooled to 5°C and stirred for 1 hr at 0°C - 5°C.Product is filtered, washed with di iso propyl ether (50 ml) and dried at 45°C - 50°C to constant weight and finally crystallized from tertiary butanol - Diisopropyl ether to get the pure hydrochloride.The dry wt of the hydrochloride salt is 80.0 g (Yield: 75.0percent) | |
Example 4 Preparation of Gabapentin Hydrochloride (Crude) In a 1 litre flask, 350 ml water, 98.5 g (2.46 moles) sodium hydroxide flakes were mixed to get a clear solution. Then it was cooled to -8° C., and 28.6 ml (0.554 moles) liquid bromine was added drop-wise over a period of 40 minutes. To this a solution of <strong>[99189-60-3]1,1-cyclohexanediacetic acid monoamide</strong> in aqueous sodium hydroxide solution was added slowly with vigorous stirring. After addition the mixture was maintained at -8 to -5° C. for 1 hour under stirring, then allowed the temperature to rise to room temperature and further maintained at 35-40° C. for 1 hour. The mixture then cooled to 15-20° C. and the pH of the mixture adjusted to 5 and washed with dichloromethane. The pH of the aqueous layer further adjusted to 2 using conc. HCl and stirred for 4 hours. The precipitate obtained was filtered and dried to obtain 95 gm Gabapentin hydrochloride salt (crude). | ||
The 3,3-cyclopentanepentamic acid was added to a 15percent sodium hydroxide solution at a concentration of 20percent100 parts of sodium chlorate, heating to carry out reaction, adding 100 parts of benzene, heating to 100 ° C for dehydration condensation reaction 4h, separation of benzene layer andWater phase, to the benzene layer by adding hydrochloric acid concentration of 30percent, at 95 ° C for hydrolysis reaction 3h, separated from the organic phase, concentratedCondensing the dry phase to dryness to give gabapentin hydrochloride; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.8% | Sodium hypochlorite solution (6.25percent, 625 g) is cooled to 10°C and sodium hydroxide flakes (51 g) is dissolved in it by stirring for 10 - 15 min. at 10°C - 15°C. The mass is further cooled to -5°C. In a separate flaskl, 1-cyclohexane diacetic acid monoamide (lOOg) is dissolved in 4N sodium hydroxide solution (150 ml) at 15°C - 20°C. The amide solution is slowly added to sodium hypochlorite solution at temperature -5°C to -3°C over 3hrs and then maintained at about 0°C for 2 hrs. The temperature is slowly raised to 20°C -25°C over 3 hrs and maintained for 4 hrs at 20°C - 25°C. Sodium metabisulphite solution (5 g in 10 ml water) is then added. The reaction mass is filtered to remove any undissolved material. pH of the filtrate is adjusted to 9.0 by the addition of 1:1 dilute sulphuric acid attemperature 20°C - 25°C. n-Butanol (200 ml) is added and the pH id further adjusted to 1.5 with dilute sulphuric acid. The reaction mass is stirred for 10 - 15 min. and then allowed to settle. The layers are separated. The aqueous layer is extracted with n-Butanol (200 ml). The combined extract is dried over anhydrous sodium sulphate (15 g). Di isopropyl ether (1200 ml) is slowly added at room temperature over 30 - 45 min to the dried extracted layer. The reaction mass is stirred for 1 hr and then cooled to 5°C and stirred for 1 hr at about 0°C - 5°C. The product is filtered, washed with di isopropyl ether (50 ml) and dried at 45°C - 50°C to constant weight.The yield of dry wt of hemisulphate hemihydrate is 85 g (Yield: 73.8percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1; 3246 kg (3748 1) of toluene and in nitrogen flow and under stirring 1874 kg of 1,1- cyclohexanediacetic acid were charged in a reactor. A dense suspension was obtained. The suspension was heated at 80°C and 1146 kg (1064 1) of acetic anhydride were added thereto in 2-3 hours. The addition was slightly endothermic. During the addition the inner temperature was kept at about 80°C. Upon proceeding with the addition the reaction mixture fluidifie until complete dissolution. The mixture was left under stirring for about 30 min. at about 80°C inside, then it was gradually vacuum-placed and it was distilled by keeping the inner temperature below 80°C until a residue volume of about 2600 1. About 3800 kg of a mixture, about 25/75 w/w acetic acid/toluene, which were sent to the incinerator, were distilled. The distillation residue crystallized at a temperature of about 40-50°C, then it was kept dissolved at the temperature of 50-60°C. In the meantime in a second reactor an ammoniacal solution was prepared by charging 656 kg of demineralized water and 1500 kg (1670 1) of an ammonia solution, about 28percent, were added thereto. By keeping the inner temperature at 10-25°C the distillation residue previously obtained and kept dissolved at 50-60°C (the addition was exothermic) was added. The pH was controlled which have to remain higher than a value of 8 during and at the end of the addition. The obtained biphasic solution was stirred for about 20 minutes at 20-30°C, then it was left to decant for one hour. The lower aqueous phase was separated, at room temperature, whereas the toluenic phase was sent to the incenerator. The aqueous phase was gradually vacuum-placed to remove possible toluene and ammonia traces. To the aqueous solution 3000 kg of demineralized water were added and the inner temperature was brought to 40-45°C. Then, by keeping the inner temperature at 40-45°C, about 1596 kg (1386 1) of hydrochloric acid in solution were added. It was left under stirring by still keeping the inner temperature of 40-45°C until obtaining pH 3.8-4. 2. At the end of the addition it was stirred for about 20 minutes and the pH was controlled again. By keeping the temperature at 40-45°C it was filtered and each filtration washed with four washings each one constituted by about 255 kg of demineralized water. About 2000 kg of wet product were obtained which was sent to the drying. The process yield was higher than 95percent. The titre of the reaction product evaluated by means of the HPLC method was greater than 99percent (total unknown impurities lower than 0.1percent). The resultant 1, 1-cyclohexanediacetic acid monoamide was transformed into gabapentin through known methods, for example, by the Hofmann rearrangement, the acidification, extraction, purification of an aqueous solution of gabapentin hydrochloride on a strong cationic ion exchange resin followed by recrystallization as described in the International patent application WO 02/34709 in the name of the same applicant | ||
Example 1 Preparation of 1,1-Cyclohexanediacetic Acid Monoamide In 1.0 lit R B Flask charged water (135 ml), and ammonium chloride (161.6 g), under cooling. Aqueous sodium hydroxide solution (110 g in 200 ml water) was added drop wise under stirring maintaining temperature below 20° C. After complete addition the reaction mass was further maintained at 0-5° C. for 30 min. Charged 1,1-cyclohexane diacetic acid anhydride (100 gm) maintaining temperature below 5° C. Maintained the reaction mass for 2.0 hrs at about 0° C., then raised the temperature to 25-30° C. and maintained 2 hrs at room temperature. Adjusted pH of the solution to 2-3 with aqueous HCl. Cooled the reaction mass to 0° C., maintained for 1.0 hr, filtered the solid mass and washed with chilled water. Dried the wet cake to get 105 gm 1,1-Cyclohexanediacetic acid monoamide. | ||
Example 3 Preparation of 1,1-Cyclohexanediacetic Acid Monoamide In 1.0 lit R B Flask charged 600 ml 12-14percent ammonia solution in isopropyl alcohol and cooled to 0° C. Slowly charged 1,1-cyclohexanediacetic acid anhydride (100 g) maintaining temperature below 5° C. Stirred 1.0 hr after complete addition and raised the temperature to room temperature. Then cooled to 15-20° C. and adjusted the pH to 2-3 with aq. HCl solution. The reaction mass was stirred further for about 15 hrs, Filtered and washed the solid with chilled water. Dried the wet cake to get 95 g 1,1-Cyclohexanediacetic acid monoamide. The filtrate was further concentrated to recover second crop 7 g. |
Example 2 Preparation of 1,1-Cyclohexanediacetic Acid Monoamide In 1.0 lit R B Flask charged Toluene (500 ml) and 1,1-cyclohexanediacetic acid anhydride (100 gm). Heated the reaction mixture to 35-40° C. and charged slowly ammonium carbonate (47 g). Raised the temperature gradually to 70° C. and maintained for 6-8 hrs at ~70° C. Cooled the reaction mass to 0° C. and filtered the same. The solid obtained was taken in water and adjusted the pH to 2-3 with conc. HCl. The solution was cooled to 0° C. and maintained 2-3 hrs, filtered and washed with chilled water. | ||
The 1,1-cyclohexanediacetic anhydride was added to 120 parts of benzene solvent, heated to 105 ° C, and the concentration of 20percent ammonia80 parts of water at 25 ° C ammoniation reaction 5h, cooling, separation of benzene solvent, add hydrochloric acid acidification to pH 4, heated to 55 ° C Stir1.5h, cooling, centrifugal filtration, the system 3,3-cyclopentane acid amide; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.6% | With sodium carbonate; In benzyl alcohol;pH 7 - 7.5;Product distribution / selectivity; | EXAMPLE-6 Cyclohexane diaceticacid monoamide (20 g, 0.1 mol) was dissolved in 4 N NaOH solution (30 ml) at 15-20 C. To this 100 ml of a solution of 7-8% sodium hypochlorite and 10.2 g sodium hydroxide were added and stirred for 5 h. Excess hypochlorite was neutralized by 1 g sodium metabisulphite solution. The solution was acidified to pH 2 by HCl. The aqueous solution was extracted with benzyl alcohol (40 ml×2). The organic layer was dried over anhydrous Na2SO4. Finely powdered sodium carbonate (10.65 g, 0.1 mol) was added and the reaction mixture was stirred until the solution pH reaches 7.0 to 7.5. It will take about 2 to 3 hours. The suspension was filtered and the residue washed with about 5 ml benzyl alcohol. The clear filtrate was cooled to 0-5 C. and 160 ml of methyl tert.butyl ether (MTBE) was added. The solution was stirred for one hour and the precipitated gabapentin filtered. The crude gabapentin was washed with MTBE and stirred in ethanol to remove traces of benzyl alcohol to obtain pure gabapentin. Yield: 11.8 g (68.6% based on <strong>[99189-60-3]CDMA</strong>), HPLC: 99.6%. |
With sodium hydroxide; sodium hypochlorite; In water; at -10 - 20℃; for 8h; | In a 1 1 flask under nitrogen atmosphere, 147.2 g of 30% sodium hydroxide solution (equal to 1.106 moles ; 1. 10 eq.) and 147. 2 g of demineralised water were charged. The solution was cooled up to 0C and 200.0 g of 1, 1-cyclohexanediacetic acid monoamide (equal to 1.005 moles; 1.00 eq. ) were charged in portions. After charging about two thirds of the monoamide, the additions were continued letting the temperature rise to facilitate dissolution, without ever exceeding 20C. Separately, in a 2 1 reactor under nitrogen atmosphere, 628.0 g of 12.5% sodium hypochlorite solution (equal to 1.055 moles; 1.05 eq. ) containing 1.03% sodium hydroxide (equal to 0.162 moles; 0.16 eq.) and 125.8 g of 30% sodium hydroxide solution (equal to 0.944 moles; 0.94 eq. ) were added. The solution was cooled to-10C and 494.0 g of 1, 1-cyclohexanediacetic acid monoamide solution in soda were added, maintaining the temperature at-10C. At the end, the reaction mixture was maintained at-10C for further two hours, then the temperature was brought from-10C to 20C in four hours, taking care to control any exothermic situations. The reaction mixture was maintained at 20C for further two hours, then the presence of oxidising power was checked with an amido-iodide paper and any excess oxidising power was eliminated adding 0. 3 g of sodium metabisulpbite. 3 g of activated charcoal were added to the solution, which was kept under stirring for 15 minutes, then filtered under vacuum on a celite bed with a height of about 1 cm. The resultant solution thus obtained (pH about 12. 5) was checked by HPLC titre (useful to predetermine the quantity of acid to be used) and it was ready for the acidification, isolation and crystallization step carried out operating according to what described in Example 1. | |
Example 4: Gabapentin synthesis in a continuous tubular reactor with a retention time of 12 minutes A solution of <strong>[99189-60-3][1-(2-amino-2-oxoethyl)cyclohexyl]acetic acid</strong> in aqueous sodium hydroxide consisting of 1675 g of amide with a 52% humidity and 1153.3 g of 16.7% NaOH, and a solution of sodium hypochlorite and sodium hydroxide consisting of 3161.5 g of 13.4% aqueous hypochlorite, 332.6 g of 100%NaOH and 278.4 g of H2O were fed into a glass reactor series consisting of a mixer with a volume of 25 ml, followed by a first tubular reactor with an internal diameter of 10 mm and a volume of 50 ml and then a second tubular reactor filled with glass beads, with a diameter of 3 cm and a free volume of 129 ml, and maintained at 40C. The total volume of the reaction system, also considering the joints between the various components, was 249 ml. The flow rates were 420 ml/h and 634 ml/h, respectively, and the retention time was 14 minutes. Sodium metabisulphite (in 24% aqueous solution) in proportions of 0.11 g/gram of crude reaction product was added to the product coming from the reactor to destroy the excess hypochlorite, using a flow rate sufficient to adjust the potential of the solution to values below 100 mV with reference to an Ag/AgCl electrode. After reaching the stationary state, the solution delivered contained 8.5% by weight of Gabapentin, corresponding to a yield of 96%. |
62 g | With sodium hypochlorite; sodium hydroxide; In water; at -10 - 20℃; for 6h; | Hofmann reaction and decarboxylation: 100 g of Gaba 1 (<strong>[99189-60-3]1,1-cyclohexanediacetic acid monoamide</strong>) were placed in a 1 litre reactor at room temperature, followed by addition of 76 g of demineralized water. While maintaining the temperature at about 20C, 74 g of a caustic sodium hydroxide solution were added. The mixture was stirred vigorously until dissolution was complete. In parallel, 70 g of a caustic sodium hydroxide solution and, then, 288 g of a 14% sodium hypochlorite solution were placed in a 2 litre reactor. The sodium hypochlorite solution was cooled to -10C and, when this temperature had been reached, the solution of Gaba 1 was added over about 2 hours, while maintaining the temperature at about -10C. The temperature was raised to about 20C over about 2 hours. This temperature was maintained for 2 hours and sodium metabisulfite was, then, added until the oxidizing power had completely disappeared. The basic pH of the reaction mixture was brought to 4.5-5 with a hydrochloric acid solution, while maintaining the temperature at about 20C. When this pH was reached, the solution was heated to about 40C. This temperature was maintained for 20-30 minutes and the solution was, then, cooled to about 20C. 150 g of ethyl acetate were added and the mixture was, then, stirred for 1 hour and then left to stand until the phases had separated. The upper organic phase was discarded and 150 g of ethyl acetate were added to the aqueous phase. The mixture was stirred for 1 hour and, then, left to stand until the phases had separated. The upper organic phase was discarded and the aqueous phase was brought to pH 7.2 with a caustic sodium hydroxide solution. Extraction with m-cresol and gabapentin isolation: 430 g of m-cresol were added to the gabapentin solution/suspension (crystallized gabapentin). The mixture was stirred for 1 hour and, then, left to stand until the phases had separated. The lower aqueous phase was discarded and the organic phase was distilled under vacuum to a constant water content in the cresol mixture. The solution was cooled to about 20C and the opalescent solution was, then, filtered through a filter system. 150 g of demineralized water were added to the filtered solution. The mixture was stirred for about 15 minutes and, then, left to stand until the phases had separated. The aqueous phase was discarded and 894 g of ethyl acetate and 1167 g of demineralized water were added to the organic solution. The mixture was stirred for about 15 minutes and, then, left to stand until the phases had separated. The organic phase was discarded and 150 g of ethyl acetate were added to the aqueous phase. The mixture was stirred for about 15 minutes and, then, left to stand until the phases had separated. The organic phase was discarded and 3-4 g of Carbon L4S were added to the aqueous phase. The mixture was stirred, heated to 35-40C and, then, filtered. The filtered solution was concentrated under vacuum to a solid residue and the mixture was, then, cooled to about 20C and 61 g of methanol were added. This mixture was heated to 50-55C and maintained until homogenization of the solid was complete. The resulting mixture was cooled to about 25C and, once this temperature had been reached, 254 g of isopropanol were added. The resulting mixture was maintained at about 25C for about 20 minutes. It was cooled to -3 - -5C and, once at this temperature, was maintained for at least 1 hour and the mixture was, then, filtered. The product was washed on a filter twice with isopropanol. The wet product was dried under vacuum to constant weight. 62 g of "pure" gabapentin were obtained (titre: 100%). [HPLC analysis: m-cresol: 0.000%; max. single impurity: 0.003%>; total impurities: 0.003%>; chlorides: not detectable] |
With sodium hypochlorite;Alkaline conditions; | <strong>[99189-60-3]CDMA</strong> (IV) was treated with a solution of sodium hypochlorite in an alkaline medium and converted into gabapentin as described in the U.S. Pat. No. 8,431,739. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.98% | With sodium hypobromide; sodium hydroxide; In water; at 40 - 55℃;Flow reactor; | A solution of 304.66g of [l-(2-amino-2-oxoethyl)cyclohexyl] acetic acid (<strong>[99189-60-3]CAM</strong>) in 541.33g of 11.31percent aqueous sodium hydroxide and a solution of 2215g of 9.01percent aqueous sodium hypobromite, were fed into pinch tube reactor made of stainless steel AISI 316L with an internal diameter of 4.00mm and a length of 5000mm (5 metre), in which constrictions are formed along the length of the tube by pinching the tube so that its walls are internally separated by less than one third of their original separation. The principal radial axis of each constriction being at an angle 90° to that of its neighbour, to leave a free volume of 70.59ml, and maintained at 40+2°C (first 2m part of pinch tube). The remaining 3m part of pinch tube was maintained at 55+2°C. The flow rates were l l.lmL/min for <strong>[99189-60-3]CAM</strong> solution and 28.3mL/min for hypobromite solution respectively, and the retention time was 2.0min. The product outlet from pinch tube was collected at atmospheric temperature. After reaching the stationary state, the collected solution contained 7.87percent by weight of gabapentin(equivalent to 8.88percent gabapentin salt), corresponding to a yield of 91.98percent. The reaction mass was collected in three parts and confirmed reproducibility by HPLC analysis. |
67% | With sodium hydroxide; sodium hypobromide; In water; at 0 - 10℃; for 2 - 3h;Product distribution / selectivity; | Crude GBP sodium salt was prepared according to the method outlined in step 1 of Example 1, above, except the alkaline monoamide solution (from 0.5 mole, 100 g <strong>[99189-60-3]CDMA</strong>) was added at 0°C to a sodium hypobromite solution prepared in situ by dissolution of bromine (0.6 mole, 96 g) in cold (0°C) sodium hydroxide solution (20percent, 220 ml). Additional isolation and purification was performed as described in Example 1, to yield a white solid precipitate. [55] Yield : 271 g of crude, wet GBP-Na salt or 152 g on dry basis containing about 65 g of sodium salt (67percent yield, by HPLC analysis |
65 - 72% | With sodium hydroxide; sodium hypochlorite; In water; at 0 - 10℃; for 2 - 3h;Product distribution / selectivity; | A fresh solution of 1, 1-cyclohexanediacetic acid monoamide (<strong>[99189-60-3]CDMA</strong>) was prepared by slow addition of monoamide (<strong>[99189-60-3]CDMA</strong>, 0.5 mole, 100 g) into a solution (120 g, 107 ml) containing about 15percent of sodium hydroxide in water, while the temperature was kept below 15 ° C. At the same time, a suitable vessel was charged with a sodium hypochlorite 8-10percent solution (485 g) and cooled below 5 ° C. Sodium hydroxide pellets (100 g) were then added in small portions, while the temperature was kept below 10°C. The solution was then cooled below 0°C. [46] The thick syrupy <strong>[99189-60-3]CDMA</strong> solution was then added to the cooled hypochlorite solution with stirring, while the temperature was maintained at 0-10°C. After 2-3 hours of stirring at the same temperature, a saturated sodium thiosulfate pentahydrate solution was added to the cold mixture until negative to a potassium iodide-starch paper test. The reaction mixture was then heated to 60-70 ° C for about l/2 hour and cooled to room temperature. [47] The white solid precipitate was filtered in vacuo and washed with a small amount of isopropyl alcohol. [48] Yield: 203 g of crude, wet GBP-Na salt or 131 g on dry basis containing about 63 g of sodium salt (65percent yield, by HPLC analysis vs. gabapentin standard). The crude, wet salt is directly used in the next step. Example 3:Step 1 was carried out according to the method outlined in Step 1 of Example 1 using 100 g (0.5 mole) of monoamide. Example 4: Step 1 was carried out according to the method outlined in Step 1 of Example 1, using 50 g (0.25 mole) monoamide to give 138 g crude wet sodium salt of GBP. Example 5: Step 1. Preparation of crude gabapentin sodium salt: Sodium hydroxide pellets (1.5 kg) were added in small portions into a cold (0°C) sodium hypochlorite 10percent solution, keeping the inside temperature below 15°C. The solution obtained was further cooled to 0-5°C. [64] In a separate vessel, monoamide (<strong>[99189-60-3]CDMA</strong>, 1.5 kg, 7.5 mole) was added to a cold (0-5°C), dilute solution of sodium hydroxide prepared from sodium hydroxide 50percent (d=1.4 g/ml, 0.75 kg) in demineralized water, with stirring and cooling. [65] The <strong>[99189-60-3]CDMA</strong> suspension was slowly added to the alkaline sodium hypochlorite solution keeping the inside temperature below 10°C. The reaction mixture was stirred for 2-3 hours, and then a sodium thiosulfate 50percent solution was added until a negative test with a potassium iodide starch paper was achieved. The reaction mixture was then rapidly heated to 60-70°C, stirred for 1/2 hour and cooled to room temperature. [66] Filtration of the resulting suspension produced the crude sodium salt intermediate as off-white solid. Yield: 4.2 kg wet or 2.9 kg on dry basis (LOD 31 percent). Gabapentin content (HPLC, to) : 36percent, which is equivalent to 1.04 kg of sodium salt (72percent yield). Purity : lactam: 0.5percent related diacetic acid (CDAA): 0.2percent The crude, wet intermediate was used directly in the next step. |
Tags: 99189-60-3 synthesis path| 99189-60-3 SDS| 99189-60-3 COA| 99189-60-3 purity| 99189-60-3 application| 99189-60-3 NMR| 99189-60-3 COA| 99189-60-3 structure
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