Name: 64744-50-9|2-Azaspiro[4.5]decan-3-one|95%
Brand: Ambeed
SKU: A125052
Price: 7.0 USD
Availability: InStock
Rating: 90 (30 reviews)

Yield	Reaction Conditions	Operation in experiment
99.9%		E E) E) Preparation of Compound (V) 2-aza-spiro[4.5]decan-3-one A 1.8 1 autoclave equipped with electric manometer, continuous recording thermocouple and muffle heating, is loaded at room temperature with 130 g (0.768 m) of compound (IV), 1300 ml of methanol and 10 g of nickel Raney. After washing with nitrogen, stirring is started, while thermostating at 80° C., and hydrogen is fed under 40 bars. After hydrogenating for 3 hours, the hydrogen pressure is discharged, washing three times with nitrogen, and the autoclave is discharged washing with 500 ml of methanol. The catalyst is filtered off and the mixture is evaporated to dryness, to obtain 109.8 g of the title compound (HPLC: 99.9%)
	Imid (E-1), NaOH/H2O;
	Imid (E-1), EtONa;

		Mother liquor B obtained from the Example 1 is concentrated under vacuum to a volume of 150 ml at less than 85 degrees and mother liquor A obtained from the Example 1 is added to the concentrated mass. The mixture is treated with 10% sodium hydroxide (100 ml) and heated to 80-85 degrees for 2 hr. It is extracted at about 50 degrees with toluene (200 ml) and the toluene layer is separated. The aqueous layer is again heated at 80-85 degrees for 2 hr and extracted with a second lot of toluene (200 ml). The combined toluene layers are treated with charcoal (2 g) at room temperature and filtered through a bed of hyflo. The filtrate is shaken with water (2×50 ml). The toluene solution is then evaporated to dryness in vacuo to give gabalactam (40 g). The recovered lactam is then converted to gabapentin hydrochloride by the known methods and gabapentin isolated from the same as per the process described above. The recovery of gabapentin from the hydrochloride thus works out to be 77% on recycling.
		Variant B Variant B 6.75 g. N-Benzene-sulphonyloxy-1,1-cyclohexane-diacetic acid imide was introduced portionwise, while stirring, into an alcoholic solution of sodium ethylate, prepared by dissolving 460 mg. sodium in 50 ml. absolute ethanol and heated under reflux for 2 hours. After cooling, the suspension was poured into water and extracted wit methylene chloride. The organic phase was dried and evaporated to a syrup, crystallization of which from diisopropyl ether gave 1-aminomethyl-1-cyclohexane-acetic acid lactam (m.p. 89°-90° C.), which was then converted into the free amino acid in Variant A.

Yield	Reaction Conditions	Operation in experiment
	With ammonia Zersetzen des Ammoniumsalzes mit 1.1 Mol 10%iger Natronlauge, Behandeln des Reaktionsprodukts mit alkal.Kaliumhypobromit-Loesung, zuletzt bei 70-75grad, und Eindampfen mit Salzsaeure;

3
2-(dimethylamino)-2-azaspiro[4.5]decan-3-one [ No CAS ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
39 mg	With magnesium monoperoxyphthalate hexahydrate In methanol at 20℃; for 3h;

Reference： [1]Bryans, Justin S.; Chessum, Nicola E.A.; Huther, Nathalie; Parsons, Andrew F.; Ghelfi, Franco [Tetrahedron, 2003, vol. 59, # 33, p. 6221 - 6231]

4
[ 608532-82-7 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
83%	With ammonium cerium(IV) nitrate In water; acetonitrile at 20℃;

Reference： [1]Bryans, Justin S.; Chessum, Nicola E.A.; Huther, Nathalie; Parsons, Andrew F.; Ghelfi, Franco [Tetrahedron, 2003, vol. 59, # 33, p. 6221 - 6231]

5
(+/-)-(5R,6S)-2-(benzoylamino)-4,4,6-trichloro-3-oxo-2-azaspiro[4.5]decane [ No CAS ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With nickel In ethanol at 110℃; for 21h;

Reference： [1]Cagnoli, Rita; Ghelfi, Franco; Pagnoni, Ugo M.; Parsons, Andrew F.; Schenetti, Luisa [Tetrahedron, 2003, vol. 59, # 50, p. 9951 - 9960]

6
(1-nitromethylcyclohex-1-yl)ethanoic acid polyglyceryl ester [ No CAS ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
58%	With hydrogenchloride; zinc In ethanol Heating;

Reference： [1]Roller, Sebastian; Siegers, Conrad; Haag, Rainer [Tetrahedron, 2004, vol. 60, # 39, p. 8711 - 8720]

7
[ 99189-60-3 ]
[ 64744-50-9 ]

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.

Reference： [1]Patent: US2007/287861,2007,A1 .Location in patent: Page/Page column 3-4
[2]Patent: US2007/287861,2007,A1 .Location in patent: Page/Page column 3-4
[3]Organic Process Research and Development,2016,vol. 20,p. 1828 - 1832
[4]Organic Process Research and Development,2016,vol. 20,p. 1828 - 1832

8
[ 64744-50-9 ]
[ 24424-99-5 ]
[ 898552-75-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With dmap In acetonitrile at 25℃;	Preparation of 2-{1-[2-(4-Chloro-phenyl)-6-oxo-4-thioxo-6H-1-oxa-3b,5-diaza-cyclopenta[a]pentalen-5-ylmethyl]-cyclohexyl}-N,N-diethyl-acetamide (Compound 24) 4,4-Pentamethylene-2-pyrrolidinone (765 mg, 5 mmol) was dissolved in acetonitrile (10 ml) and 4-dimethylamino-pyridine (DMAP; 61 mg, 0.5 mmol, 0.1 molequivalents) was added thereto. A solution of di-t-butyl dicarbonate (BOC2O; 1.308 g, 6 mmol, 1.2 molequivalents) in acetonitrile (10 ml) was thereafter added dropwise during 30 minutes, and the resulting mixture was stirred at 25° C., while monitoring the reaction by TLC, using ethyl acetate as eluent and KMNO4 and heating for developing the TLC plate. Stirring was ceased once complete consumption of the pyrrolidinone and appearance of a less polar spot near the front were observed (after about 4 hours). Thereafter, most of the solvent was evaporated under reduced pressure, chloroform was added to the residue and the resulting solution was then washed with 1M HCl, dried over Na2SO4 and the solvents were evaporated under reduced pressure to give 3-oxo-2-aza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.168 grams, 92% yield) as an off-white solid.

Reference： [1]Current Patent Assignee: YOSEF KLEIN; INSIGHT BIOPHARMACEUTICALS - US2008/39456, 2008, A1 Location in patent: Page/Page column 50

9
[ 1192-88-7 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: CH₂Cl₂ / 20 °C 2.1: DMAB; methanesulfonic acid / diethyl ether / 3 h / 0 °C 2.2: 81 percent / pyridine / CH₂Cl₂ / 0 °C 3.1: 77 percent / CuCl; TMEDA / acetonitrile / 20 h / 60 °C 4.1: 90 percent / Raney-Ni / ethanol / 21 h / 110 °C

Reference： [1]Cagnoli, Rita; Ghelfi, Franco; Pagnoni, Ugo M.; Parsons, Andrew F.; Schenetti, Luisa [Tetrahedron, 2003, vol. 59, # 50, p. 9951 - 9960]

10
1-cyclohexen-1-carboxaldehyde benzoylhydrazone [ No CAS ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: DMAB; methanesulfonic acid / diethyl ether / 3 h / 0 °C 1.2: 81 percent / pyridine / CH₂Cl₂ / 0 °C 2.1: 77 percent / CuCl; TMEDA / acetonitrile / 20 h / 60 °C 3.1: 90 percent / Raney-Ni / ethanol / 21 h / 110 °C

Reference： [1]Cagnoli, Rita; Ghelfi, Franco; Pagnoni, Ugo M.; Parsons, Andrew F.; Schenetti, Luisa [Tetrahedron, 2003, vol. 59, # 50, p. 9951 - 9960]

11
[ 651311-40-9 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 77 percent / CuCl; TMEDA / acetonitrile / 20 h / 60 °C 2: 90 percent / Raney-Ni / ethanol / 21 h / 110 °C

Reference： [1]Cagnoli, Rita; Ghelfi, Franco; Pagnoni, Ugo M.; Parsons, Andrew F.; Schenetti, Luisa [Tetrahedron, 2003, vol. 59, # 50, p. 9951 - 9960]

12
[ 219915-83-0 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: toluene / 1 h / 0 - 20 °C 1.2: 798 mg / triethylamine / toluene / 2 h / 0 - 20 °C 2.1: 26 percent / tributyltin hydride 3.1: 55 percent / triethylsilane; trifluoroacetic acid / CH₂Cl₂ / 0.5 h / 20 °C 4.1: 83 percent / cerium(IV) ammonium nitrate / acetonitrile; H₂O / 20 °C
	Multi-step reaction with 5 steps 1.1: toluene / 1 h / 0 - 20 °C 1.2: 798 mg / triethylamine / toluene / 2 h / 0 - 20 °C 2.1: 2,2'-bipyridine; copper(I) chloride / toluene / 11 h / Heating 3.1: 68 mg / AIBN; tributyltin hydride; water / toluene / 0.75 h / Heating 4.1: 55 percent / triethylsilane; trifluoroacetic acid / CH₂Cl₂ / 0.5 h / 20 °C 5.1: 83 percent / cerium(IV) ammonium nitrate / acetonitrile; H₂O / 20 °C

Reference： [1]Bryans, Justin S.; Chessum, Nicola E.A.; Huther, Nathalie; Parsons, Andrew F.; Ghelfi, Franco [Tetrahedron, 2003, vol. 59, # 33, p. 6221 - 6231]
[2]Bryans, Justin S.; Chessum, Nicola E.A.; Huther, Nathalie; Parsons, Andrew F.; Ghelfi, Franco [Tetrahedron, 2003, vol. 59, # 33, p. 6221 - 6231]

13
[ 2043-61-0 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: toluene / Heating 2.1: toluene / 1 h / 0 - 20 °C 2.2: 798 mg / triethylamine / toluene / 2 h / 0 - 20 °C 3.1: 26 percent / tributyltin hydride 4.1: 55 percent / triethylsilane; trifluoroacetic acid / CH₂Cl₂ / 0.5 h / 20 °C 5.1: 83 percent / cerium(IV) ammonium nitrate / acetonitrile; H₂O / 20 °C
	Multi-step reaction with 6 steps 1.1: toluene / Heating 2.1: toluene / 1 h / 0 - 20 °C 2.2: 798 mg / triethylamine / toluene / 2 h / 0 - 20 °C 3.1: 2,2'-bipyridine; copper(I) chloride / toluene / 11 h / Heating 4.1: 68 mg / AIBN; tributyltin hydride; water / toluene / 0.75 h / Heating 5.1: 55 percent / triethylsilane; trifluoroacetic acid / CH₂Cl₂ / 0.5 h / 20 °C 6.1: 83 percent / cerium(IV) ammonium nitrate / acetonitrile; H₂O / 20 °C

Reference： [1]Bryans, Justin S.; Chessum, Nicola E.A.; Huther, Nathalie; Parsons, Andrew F.; Ghelfi, Franco [Tetrahedron, 2003, vol. 59, # 33, p. 6221 - 6231]
[2]Bryans, Justin S.; Chessum, Nicola E.A.; Huther, Nathalie; Parsons, Andrew F.; Ghelfi, Franco [Tetrahedron, 2003, vol. 59, # 33, p. 6221 - 6231]

14
[ 608532-87-2 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Raney nickel; water / ethanol / 110 °C 2: 39 mg / magnesium monoperoxyphthalate hexahydrate / methanol / 3 h / 20 °C

Reference： [1]Bryans, Justin S.; Chessum, Nicola E.A.; Huther, Nathalie; Parsons, Andrew F.; Ghelfi, Franco [Tetrahedron, 2003, vol. 59, # 33, p. 6221 - 6231]

15
[ 608532-81-6 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 55 percent / triethylsilane; trifluoroacetic acid / CH₂Cl₂ / 0.5 h / 20 °C 2: 83 percent / cerium(IV) ammonium nitrate / acetonitrile; H₂O / 20 °C

Reference： [1]Bryans, Justin S.; Chessum, Nicola E.A.; Huther, Nathalie; Parsons, Andrew F.; Ghelfi, Franco [Tetrahedron, 2003, vol. 59, # 33, p. 6221 - 6231]

16
[ 608532-79-2 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 26 percent / tributyltin hydride 2: 55 percent / triethylsilane; trifluoroacetic acid / CH₂Cl₂ / 0.5 h / 20 °C 3: 83 percent / cerium(IV) ammonium nitrate / acetonitrile; H₂O / 20 °C
	Multi-step reaction with 4 steps 1: 2,2'-bipyridine; copper(I) chloride / toluene / 11 h / Heating 2: 68 mg / AIBN; tributyltin hydride; water / toluene / 0.75 h / Heating 3: 55 percent / triethylsilane; trifluoroacetic acid / CH₂Cl₂ / 0.5 h / 20 °C 4: 83 percent / cerium(IV) ammonium nitrate / acetonitrile; H₂O / 20 °C

Reference： [1]Bryans, Justin S.; Chessum, Nicola E.A.; Huther, Nathalie; Parsons, Andrew F.; Ghelfi, Franco [Tetrahedron, 2003, vol. 59, # 33, p. 6221 - 6231]
[2]Bryans, Justin S.; Chessum, Nicola E.A.; Huther, Nathalie; Parsons, Andrew F.; Ghelfi, Franco [Tetrahedron, 2003, vol. 59, # 33, p. 6221 - 6231]

17
[ 608532-80-5 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 68 mg / AIBN; tributyltin hydride; water / toluene / 0.75 h / Heating 2: 55 percent / triethylsilane; trifluoroacetic acid / CH₂Cl₂ / 0.5 h / 20 °C 3: 83 percent / cerium(IV) ammonium nitrate / acetonitrile; H₂O / 20 °C

Reference： [1]Bryans, Justin S.; Chessum, Nicola E.A.; Huther, Nathalie; Parsons, Andrew F.; Ghelfi, Franco [Tetrahedron, 2003, vol. 59, # 33, p. 6221 - 6231]

18
1-(aminomethyl)cyclohexaneacetic acid hydrochloride [ No CAS ]
mother liquor A [ No CAS ]
mother liquor B [ No CAS ]
[ 64744-50-9 ]
impurity [ No CAS ]
[ 60142-96-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; pyrographite In water at 5 - 75℃; for 8h;	1 Example 1 Gabapentin hydrochloride (267g) ; is dissolved in chloride free demineralized water (375 ML) at 50 degrees. The solution is treated with charcoal at the same temperature and filtered through a bed of hyflo. The bed is washed with demineralized water (150 ML). The filtrate is cooled to 10DEG and neutralized with sodium lye (llOg of 50% w/w sodium hydroxide solution) with the temperature kept strictly below 15 degrees. The neutralized mixture is heated to 70-75 degrees over a period of 3 hours to get a clear solution, then cooled TO 5-10 degrees over a period of 4 hours and kept at that temperature range for 1 hr and filtered (mother liquor A). The product is suck dried thoroughly to give moist gabapentin (about 195 g) having water content of 14%. This is dissolved in a mixture of methanol (570 ml) and water (60 ml) at about 70 degrees. The solution is treated with activated charcoal (5 g) and filtered through a bed of hyflo. The bed is washed with a mixture of methanol (80 ml) and water (16 ML). To the combined filtrates is added isopropanol (815 ml). The mixture is cooled to 0-5 degrees and maintained for 1 hr, when pure white gabapentin crystallizes out, the mixture is centrifuged; the product is spin-dried for 45 min (mother liquor B) and dried to yield gabapentin (125 g) with 1. Chloride 40ppm, 2. Gabalactam, 0.01%, 3. Impurity WITH RF 0.5 relative to gabapentin NIL 4. Any other individual impurity less than 0. 1 % 5. Total impurties 0.032%

Reference： [1]Current Patent Assignee: THE KALYANI GROUP - WO2004/46085, 2004, A1 Location in patent: Page 17

19
1-(aminomethyl)cyclohexaneacetic acid hydrochloride [ No CAS ]
mother liquor B [ No CAS ]
[ 64744-50-9 ]
impurity [ No CAS ]
[ 60142-96-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; pyrographite In water at 0 - 70℃; for 6h;	2 Example 2 Gabapentin. hydrochloride (100G) is dissolved in chloride free demineralised water (290ML) at 50-60 deg. The solution is treated with charcoal at the same temperature and filtered through a bed of hyflo. The bed is washed with demineralised water (lOml). The filtrate is cooled to 0-lOdeg C and neutralized with 43g of around 45% w/w sodium hydroxide solution at the same temperature and maintained for half an hour. Then the reaction mixture is heated to 60-65 deg C over a period of 2 hours and then cooled to 0-5 deg C over a period of 3 hours, maintained at 0-5 deg for 1 hr. The precipitated gabapentin is filtered, the product suck dried to give moist gabapentin (60g), having water content of 15%. THIS is dissolved in a mixture of methanol (192 M .) and water (L L ML) at about 70 degrees. The solution is treated with activated charcoal (1 g) and filtered through a bed of hyflo. The bed is washed with a mixture of methanol (27 ml) and water (3 ML). TO THE COMBINED FILTRATES is added isopropanol (275 ml). The mixture is cooled to 0 - 5 degrees and maintained FOR 1 HR. when pure white gabapentin crystallizes out, the mixture is centrifuged; the product is spin-dried FOR 45 MIN (MOTHER LIQUOR B) and dried to yield gabapentin (35g) with 1. Chloride 50 ppm, 2. Gabalactam 0.03%, 3. Impurity with RF 0.5 relative to gabapentin 0.05%, 4. Any other individual impurity not more than 0. 1% 5. Total impurties 0.3% (excluding 3)
	With sodium hydroxide; pyrographite In water at 10 - 80℃; for 11.5h;	8 Example 8 Gabapentin. hydrochloride (100G) is dissolved in chloride free demineralised water (120ML) at 50-60 deg. The solution is treated with charcoal at the same temperature and filtered through a bed of hyflo. The filtrate is cooled to around 10-15DEG and neutralized with 45g of 40% w/w sodium hydroxide solution at the same temperature and maintained for half an hour. Then the reaction mixture is heated to 70-80 deg over a period of 1 hr and then cooled to around 15DEG over a period of 2 hrs, maintained at around 15 deg for 8 hrs. The precipitated gabapentin is filtered, the product suck dried to give moist gabapentin (72G) having water content of 18%. This is dissolved in a mixture of methanol (260 ml) and water (36 ml) at about 70 degrees. The solution is treated with activated charcoal (1 g) and filtered through a bed of hyflo. The bed is washed with a mixture of methanol (36ML) and water (9 ml). To the combined filtrates is added isopropanol (260 ml). The mixture is cooled to 0-5 degrees and maintained for 1 hr, when pure white gabapentin crystallizes out, the mixture is centrifuged; the product is spin-dried for 45 min (mother liquor B) and dried to yield gabapentin (41 g) 1. Chloride 90ppm, 2. Gabalactam 0.04%, 3. Impurity with RF 0.5 relative to gabapentin 0.085%, 4. Any other individual impurity not more than 0. 1 % 5. Total impurtie 0.4% excluding 3
	With sodium hydroxide; pyrographite In water at 5 - 75℃; for 11.5h;	7 Example 7 Gabapentin. hydrochloride (300g) is dissolved in chloride free demineralised water (525ml) at 50-60 deg. The solution is treated with charcoal at the same temperature and filtered through a bed of hyflo. The filtrate is cooled to around 10-15DEY and neutralized with 120G of 43% w/w sodium hydroxide solution at the same temperature and maintained for half an hour. Then the reaction mixture is heated to 70-75 deg over a period of 3 hrs and then cooled to 5-15 deg over a period of 2.5 hrs, maintained at 5-15 deg for 6 hr. The precipitated gabapentin is filtered, the product suck dried to give moist gabapentin (210G), having water content of 16%. This is dissolved in a mixture of methanol (625 ml) and water (50 ml) at about 70 degrees. The solution is treated with activated charcoal (3 g) and filtered through a bed of hyflo. The bed is washed with a mixture of methanol (86 ml) and water (13 ml). To the combined filtrates is added isopropanol (500 ml). The mixture is cooled to 0-5 degrees and maintained for 1 hr, when pure white gabapentin crystallizes out. The mixture is centrifuged; the product is spin-dried for 45 min (mother liquor B) and dried to yield gabapentin (120 g), with 1. Chloride 70 PPM, 2. Gabalactam 0. 045%, 3. Impurity with RF 0.5 relative to gabapentin 0.08%, 4. Any other individual impurity not more than 0.1% 5. Total impurties 0.35%, excluding 3

	With sodium hydroxide; pyrographite In water at 15 - 80℃; for 4.5h;	9 Example 9 Gabapentin. hydrochloride (110G) is dissolved in chloride free demineralised water (110ML) at 50-60 deg. The solution is treated with charcoal at the same temperature and filtered through a bed of hyflo. The filtrate is cooled to 15-20deg and neutralized with 41G of 40% w/w sodium hydroxide solution at the same temperature and maintained for half an hour. Then the reaction mixture is heated to around 80 deg over a period of 2 hrs and then cooled to around 15 deg over a period of 2 hrs, maintained at 5-10 deg for 3 hr. The precipitated gabapentin is filtered, the product suck dried to give moist gabapentin (74g) having water content of 16%. This is dissolved in a mixture of methanol (370 ml) and water (45 ml) at about 70 degrees. The solution is treated with activated charcoal (1 g) and filtered through a bed of hyflo : The bed is washed with a mixture of methanol (52 ml) and water (12 ml). To the combined filtrates is added isopropanol (370ml). The mixture is cooled to 0-5 degrees and maintained for 1 hr, when pure white gabapentin crystallizes out, the mixture is centrifuged; the product is spin-dried for 45 min (mother liquor B) and dried to yield gabapentin. (46 g) with 1. Chloride 90ppm, 2. Gabalactam 0.045%, 3. Impurity with RF 0.5 relative to gabapentin 0.09%, 4. Any other individual impurity not more than 0.1 %, 5. Total impurties 0. 4%, excluding 3
	With sodium hydroxide; pyrographite In water at 0 - 70℃; for 4h;	3 Example 3 Gabapentin. hydrochloride (100g) is dissolved in chloride free demineralised water (250ML) at 50-60 deg. The solution is treated with charcoal at the same temperature and filtered through a bed of hyflo. The filtrate is cooled to around 15deg and neutralized with 44g of 40% w/w sodium hydroxide solution at the same temperature and maintained for half an hour. Then the reaction mixture is heated to 65-70 deg over a period of one and half hours and then cooled to 5-10 deg over a period of 2 hrs, maintained at 5-10 deg for 2 hr. The precipitated gabapentin is filtered, the product suck dried to give moist gabapentin (61g) having water content of 14%. This is dissolved in a mixture of methanol (145 ML) and water (23 ml) at about 70 degrees. The solution is treated with activated charcoal (1 g) and filtered through a bed of hyflo. The bed is washed with a mixture of methanol (20 ml) and water (6 ml). To the combined filtrates is added isopropanol (174 ml). The mixture is cooled to 0-5 degrees and maintained for 1 hr, when pure white gabapentin crystallizes out, the mixture is centrifuged ; the product is spin-dried for 45 min (mother liquor B) and dried to yield gabapentin (38 g) with 1. Chloride 60ppm, 2. Gabalactam 0. 02%, 3. Impurity with RF 0.5 relative to gabapentin 0.07%, 4. Any other individual impurity not more than 0.1% 5. Total impurities less than 0.4%, excluding 3
	With sodium hydroxide; pyrographite In water at 0 - 80℃; for 5.5h;	4 Example 4 Gabapentin. hydrochloride (100G) is dissolved in chloride free deminaralized water (150ML) at 50-60 deg. The solution is treated with charcoal at the same temperature and filtered through a bed of hyflo. The filtrate is cooled to 0-lOdeg and neutralized with 43g of 45% w/w sodium hydroxide solution at around 15deg and maintained for half an hour. Then the reaction mixture is heated to 70-80 deg over a period of 3 hrs and then cooled to around 15deg over a period of 1.5 hrs, maintained at 15 deg for half an hour. The precipitated gabapentin is filtered, the product suck dried to give moist gabapentin ( 70g) having water content of 12%. This is dissolved in a mixture of methanol (240 ml) and water (30 ml) at about 70 degrees. The solution is treated with activated charcoal (1 g) and filtered through a bed of hyflo. The bed is washed with a mixture of methanol (33 ml) and water (8 ml). To the combined filtrates is added isopropanol (360 ml). The mixture is cooled to 0-5 degrees and maintained for 1 hr, when pure white gabapentin crystallizes out, the mixture is centrifuged ; the product is spin-dried for 45 min (mother liquor B) and dried to yield gabapentin (41 g), 1. Chloride 90ppm, 2. Gabalactam 0.04% 3. Impurity with RF 0.5 relative to gabapentin 0.09% 4. Any other individual impurity not more than, 0. 1 %, 5. Total impurties 0.4%, excluding 3
	With sodium hydroxide; pyrographite In water at 15 - 90℃; for 5.5h;	10 Example 10 Gabapentin. hydrochloride (200g) is dissolved in chloride free demineralised water (150ML) at 50-60 deg. The solution is treated with charcoal at the same temperature and filtered through a bed of hyflo. The filtrate is cooled to around 20deg and neutralized with 84g of 50% w/w sodium hydroxide solution at the same temperature and maintained for half an hour. Then the reaction mixture is heated to 80-90 deg over a period of 2.5 hrs and then cooled to around 15deg over a period of 2 hrs, maintained at 15 deg for half an hour. The precipitated gabapentin is filtered, the product suck dried to give moist gabapentin (135g) having water content of 17%. This is dissolved in a mixture of methanol (450 ml) and water (105 ml) at about 70 degrees. The solution is treated with activated charcoal (2 g) and filtered through a bed of hyflo. The bed is washed with a mixture of methanol (63 ml) and water (27 ML). To the combined filtrates is added isopropanol (600 ml). The mixture is cooled to 0-5 degrees and maintained for 1 hr, when pure white gabapentin crystallizes out, the mixture is centrifuged; the product is spin-dried for 45 min (mother liquor B) and dried to yield gabapentin (79 g) with 1. Chloride 95ppm, 2. Gabalactam 0.04%, 3. Impurity with RF 0.5 relative to gabapentin 0.095%, 4. Any other individual impurity not more than 0.1% 5. Total impurties 0.45%, excluding 3
	With sodium hydroxide; pyrographite In water at 0 - 70℃; for 8.5h;	5 Example 5 Gabapentin. hydrochloride (100G) is dissolved in chloride free demineralised water (200ML) at 50-60 deg. The solution is treated with charcoal at the same temperature and filtered through a bed of hyflo. The filtrate is cooled to 0-lOdeg and neutralized with 45G of 50% w/w sodium hydroxide solution at the same temperature and maintained for half an hour. Then the reaction mixture is heated to 65-70 deg over a period of 2 hrs and then cooled to 5-10 deg over 2. 5hrs, maintained at 5-10 deg for 4 hr. The precipitated gabapentin is filtered, the product suck dried to give moist gabapentin (65g) having water content of 17%. This is dissolved in a mixture of methanol (174 ml) and water (20 ml) at about 70 degrees. The solution is treated with activated charcoal (1 g) and filtered through a bed of hyflo. The bed is washed with a mixture of methanol (25 ml) and water (5 ML). To the combined filtrates is added isopropanol (116 ml). The mixture is cooled to 0-5 degrees and maintained for 1 hr, when pure white gabapentin crystallizes out, the mixture is centrifuged ; the product is spin-dried for 45 min (mother liquor B) and dried to yield gabapentin (39 g), 1. Chloride 50ppm, 2. Gabalactam 0 : 04%, 3. Impurity with RF 0.5 relative to gabapentin NIL, 4. Any other individual impurity not more than 0. 1%, 5. Total impurties 0.3%, excluding 3
	With sodium hydroxide; pyrographite In water at 0 - 70℃; for 8.5h;	6 Example 6 Gabapentin. hydrochloride (100G) is dissolved in chloride free demineralised water (180ML) at 50-60 deg. The solution is treated with charcoal at the same temperature and filtered through a bed of hyflo. The filtrate is cooled to around LODEG and neutralized with 45G of 50% w/w sodium hydroxide solution at the same temperature and maintained for half an hour. Then the reaction mixture is heated to 65-70 deg over a period OF 2. 5 HRS and then cooled to around 10 deg over a period of 2. 5 hrs, maintained at around 10 deg for 4 hr. The precipitated gabapentin is filtered, the product suck dried to give moist gabapentin (63g) having water content of 15%. This is dissolved in a mixture of methanol (360 ml) and water (21 ml) at about 70 degrees. The solution is treated with activated charcoal (1 G) and filtered through a bed of hyflo. The bed is washed with a mixture of methanol (50 ml) and water (5.5 ml). To the combined filtrates is added isopropanol (360 ml). The mixture is cooled to 0-5 degrees and maintained for 1 hr, when pure white gabapentin crystallizes out, the mixture is centrifuged; the product is spin-dried for 45 min (mother liquor B) and dried to yield gabapentin (40 g), 1. Chloride 60ppm, 2. Gabalactam 0. 04% « 3. Impurity with RF 0.5 relative to gabapentin 0. 08%, 4. Any other individual impurity not more than 0. 1% 5. Total impurties 0.28% excluding 3

Reference： [1]Current Patent Assignee: THE KALYANI GROUP - WO2004/46085, 2004, A1 Location in patent: Page 17-18
[2]Current Patent Assignee: THE KALYANI GROUP - WO2004/46085, 2004, A1 Location in patent: Page 21-22
[3]Current Patent Assignee: THE KALYANI GROUP - WO2004/46085, 2004, A1 Location in patent: Page 21
[4]Current Patent Assignee: THE KALYANI GROUP - WO2004/46085, 2004, A1 Location in patent: Page 22
[5]Current Patent Assignee: THE KALYANI GROUP - WO2004/46085, 2004, A1 Location in patent: Page 18-19
[6]Current Patent Assignee: THE KALYANI GROUP - WO2004/46085, 2004, A1 Location in patent: Page 19
[7]Current Patent Assignee: THE KALYANI GROUP - WO2004/46085, 2004, A1 Location in patent: Page 23
[8]Current Patent Assignee: THE KALYANI GROUP - WO2004/46085, 2004, A1 Location in patent: Page 19-20
[9]Current Patent Assignee: THE KALYANI GROUP - WO2004/46085, 2004, A1 Location in patent: Page 20

20
[ 137307-65-4 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
72.8%	Stage #1: With sodium hydroxide; bromine In water at -10 - 0℃; for 1.25 - 2h; Stage #2: 1-carbamoyl-cyclohexanecarboxylic acid In water at -10 - 98℃; for 11 - 20h;	1; 2; 3; 4 Example-1 Bromine (0.824 kg, 5.15 mole) is added to a solution of sodium hydroxide (1 kg) in water (7 1) at-5 to 0 degrees C over 45-90 min and the solution stirred for an additional 30 min at the same temperature. Cyclohexane-1, 1-diacetic acid monoamide of the formula 3 (1 KG, 5.02 mole) is added to the above solution in portions over a period of 3 hrs at-5 to 0 degrees and the mixture stirred at the same temperature for 1 hr. The reaction mass is heated to 80-85 degrees C slowly over a period of 4 hrs and stirred for another 6 hrs at the same temperature. It is then extracted with toluene after cooling the reaction mixture to 40 degree C twice. The aqueous layer is again heated at 80-85 degrees C, aged for 6 hrs at the same temperature, cooled to 40deg C and extracted with toluene twice. The toluene layers are combined, treated with charcoal and filtered. The filtrate is washed with water twice and evaporated at a temperature of 60- 65 deg C under vacuum to give white crystals of gabalactam of the formula 1 (0.62 kg, 80.7%), m. p. 88-90 degree C; purity (area % by HPLC greater than 99). Example-2 Bromine 42g (0.257 mole) is added to a solution of potassium hydroxide (80g/80% purity) in water (350ML) at-5 to 0 degrees C over 60 min and the solution stirred for an additional 30 min at the same temperature. CYCLOHEXANE-L, L-DIACETIC acid monoamide of the formula 3 50g (0.251 mol) is added to the above solution in portions over a period of 2 hrs at- 10 to 0 degrees C and the mixture stirred at the same temperature for 2 hrs. The reaction mass is heated to 90-98 degrees C slowly over a period of 4 hr and stirred for another 5 hrs at the same temperature. It is then extracted with ethylene dichloride twice, after cooling the reaction mixture to 30 degrees C. The aqueous layer is again heated at 90-98 degrees C and extracted with ethylene dichloride after cooling the reaction mixture to 30 degrees C, twice. The ethylene dichloride layers are combined, treated with charcoal and filtered. The filtrate is washed with water and evaporated under reduced pressure to give brownish white crystals of gabalactam of the formula 1 (28g, 72.8%) m. p. 88-90 degree; purity (area % by HPLC 98). Example-3 Bromine 45g (0.257 mole) is added to a solution of sodium hydroxide (45G) in water (350ML) at-10 to 0 degrees C over 45-90 min and the solution stirred for an additional 30 min at the same temperature. Cyclohexane-1, 1-DIACETIC acid monoamide of the formula 3 (50g, 0.251 mole) is added to the above solution in portions over a period of 1 hr at-5 to 0 degrees C and the mixture stirred at the same temperature for 1 hr. The reaction mass is heated to 80-90 degrees slowly over a period of 6 hrs and stirred for another 8 hrs at the same temperature. It is then extracted with methylene dichloride twice, after cooling the reaction mixture to 30 degrees C. The aqueous layer is again heated at 80-90 degrees and extracted with methylene dichloride after cooling the reaction mixture to 30 degrees, twice. The methylene dichloride layers are combined, treated with charcoal and filtered. The filtrate is washed with water and evaporated under reduced pressure to give white crystals of gabalactam of the formula 1 (28g 72.8%) m. p. 88-90 degree; purity (area % by HPLC 99). Example 4 Bromine 50g (0.285 mole) is added to a solution of sodium hydroxide (55g) in water (300ML) at-10 to 0 degrees C over 45-90 min and the solution stirred for an additional 30 min at the same temperature. Cyclohexane-1, l-acetic acid monoamide of the formula 3 (50g, 0.251 mole) is added to the above solution in portions over a period of 1.5 hrs at - 10 to 0 degrees C and the mixture stirred at the same temperature for 1 hr. The reaction mass is heated to 85-95 degrees slowly over a period of 5 hrs and stirred for another 7 hrs at the same temperature. It is then extracted with toluene twice, after cooling the reaction mixture to 50 degrees C. The aqueous layer is again heated at 85-95 degrees C and extracted with toluene after cooling the reaction mixture to 50 degrees C, twice. The toluene layers are combined, treated with charcoal and filtered. The filtrate is washed with water and evaporated under reduced pressure to give white crystals of gabalactam of the formula 1 (29. 5g 76.7%) m. p. 88-90 degree C; purity (area % by HPLC 98).

Reference： [1]Current Patent Assignee: THE KALYANI GROUP - WO2004/46108, 2004, A1 Location in patent: Page 9-12

21
mother liquor A [ No CAS ]
mother liquor B [ No CAS ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; pyrographite In water at 80 - 85℃; for 2h;	Recovery of gaba lactam from mother liquors Mother liquor B obtained from the Example 1 is concentrated under vacuum to a volume of 150 ml at less than 85 degrees and mother liquor A obtained from the Example 1 is added to the concentrated mass. The mixture is treated with 10% sodium hydroxide (100ML) and heated to 80-85 degrees for 2 hr. It is extracted at about 50 degrees with toluene (200 ML) and the toluene layer is separated. The aqueous layer is again heated at 80-85 degrees for 2 hr and extracted with a second lot of toluene (200 ml). The combined toluene layers are treated with charcoal (2 g) at room temperature and filtered through a bed of hyflo. The filtrate is shaken with water (2 x 50 ml). The toluene solution is then evaporated to dryness in vacuo to give gabalactam (40 g). The recovered lactam is then converted to gabapentin hydrochloride by the known methods and gabapentin isolated from the same as per the process described above. The recovery of gabapentin from the hydrochloride thus works out to be 77 % on recycling. The process can be scaled up to a charge of 400 kg of gabapentin hydrochloride to afford gabapentin in 75-80% yield after recycling the mother liquors as described herein.

Reference： [1]Current Patent Assignee: THE KALYANI GROUP - WO2004/46085, 2004, A1 Location in patent: Page 23-24

22
[ 460711-33-5 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: ethyl 2-(1-formylcyclohexyl)acetate With ammonia In ethanol at 20℃; for 48h; Stage #2: With hydrogen; acetic acid at 80 - 100℃; for 3h;	3.1 Example 3; Synthesis of Gabapentin by Method A; Step 1: Preparation of the lactam, 2-aza-spiro[4,5]decan-3-one.; The ethyl (1-formylcyclohexyl)acetate from Example 1, Step 1 (6 g) was dissolved in 100 mL of ethanol saturated with ammonia. The reaction mixture was allowed to stand two days at room temperature. The removal of excess ammonia and ethanol gave the intermediate amidol (5.8 g), which was dissolved in 100 mL of acetic acid. The hydrogenation was carried out in the presence of 5.5 g of Pd-C (5%, dry) at 80-100° C. for 1 hour. Hydrogenation was continued for another two hours at 55 psi hydrogen pressure. The reaction product was isolated after filtration and evaporation. Trituration with methyl t-butyl ether (MTBE) followed by ether gave 1.7 g of the desired lactam 6. 1H NMR (CDCl3) δ 6.6-6.4 (bs, 1H), 3.15 (s, 2H), 2.18 (s, 2H), 1.80-1.30 (m, 10H) 13C NMR (CDCl3) d 178.6, 54.0, 43.5, 39.6, 37.0, 25.9, 23.1.

Reference： [1]Current Patent Assignee: Gopal, Damodaragounder - US2005/148792, 2005, A1 Location in patent: Page/Page column 4

23
[ 460711-34-6 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen; acetic acid at 80℃; for 6h;	5.2 Step 2: Preparation of gabapentin hydrochloride.; A solution of the oxime prepared in Step 1 (2.15 g) was dissolved in acetic acid, and hydrogenated at 80° C., 50 psi using 5% Pd-C (4.0 g) for 6 hours. The reaction mixture was filtered and evaporated in vacuo. The residue was treated with 60 mL of 50% concentrated HCl and heated under reflux for 14 hours. Thereafter, the solution was co-evaporated with 50 mL of n-butanol. Trituration with THF and MTBE gave 0.67 g of gabapentin hydrochloride

Reference： [1]Current Patent Assignee: Gopal, Damodaragounder - US2005/148792, 2005, A1 Location in patent: Page/Page column 4

24
[ 64744-50-9 ]
1-(aminomethyl)cyclohexaneacetic acid hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.9%	With hydrogenchloride In water at 80 - 90℃; for 5h; Heating / reflux;	3 3,3-Pentamethylenebutyrolactam (IV) (250 g), concentrated HCl (1500 g) and water (300 g) was refluxed for 5 h and cooled to 80-90° C. The mixture was cooled to -5 to 5° C. to precipitate the crude product. The solid was filtered to provide wet gabapentin HCl salt (III), equivalent to 308 g of dry gabapentin HCl salt (the water content was measured with Karl-Fisher method and discounted); yield: 90.9%, purity, 98.5% (HPLC); 3,3-pentamethylenebutyrolactam (IV) content, 0.4%. The HCl concentration of filtrate is about 15-16%, which can be used to neutralize NaOH in the previous step or its HCl concentration can be raised to 22% by adding 36% HCl and reused in this step. 3,3-Pentamethylenebutyrolactam (IV) may also be recovered from this HCl solution (see Example 7).
90%	With hydrogenchloride; water for 24h; Reflux;
90%	With hydrogenchloride; water at 100℃; for 10h;

77%	With hydrogenchloride In water for 24h; Reflux; Inert atmosphere;
	With hydrogenchloride; water for 14 - 16h; Heating / reflux;	3.2; 5.2 Step 2: Preparation of gabapentin hydrochloride.; The lactam (23 g, prepared according to Step 1) and concentrated hydrochloric acid (500 mL) are heated under reflux for 16 hours. Water and excess HCl are removed by evaporation in vacuo to give crude gabapentin hydrochloride, which is purified by crystallization from butanol/ether; Step 2: Preparation of gabapentin hydrochloride.; A solution of the oxime prepared in Step 1 (2.15 g) was dissolved in acetic acid, and hydrogenated at 80° C., 50 psi using 5% Pd-C (4.0 g) for 6 hours. The reaction mixture was filtered and evaporated in vacuo. The residue was treated with 60 mL of 50% concentrated HCl and heated under reflux for 14 hours. Thereafter, the solution was co-evaporated with 50 mL of n-butanol. Trituration with THF and MTBE gave 0.67 g of gabapentin hydrochloride
	With hydrogenchloride In water	1 Gabapentin hydrochloride EXAMPLE 1 Gabapentin hydrochloride 150.0 g (0.976 mols) of 2-aza-spiro[4.5]decan-3-one are placed in a 2000 ml round-bottom flask and water (330 ml) is added. The mixture is heated to 60° C., then a 30% hydrochloric acid solution (910 g-7.488 mols) is added in 15 minutes under stirring. Temperature raises from 60° C. to 65° C. during the addition. The mixture is refluxed for 4 hours, then heating is stopped and the mixture is left to cool overnight. After this time, temperature is 23° C. The precipitated product is cooled to 10° C., keeping this temperature for an hour. The product is filtered, washing the filter with acetone.
	With hydrogenchloride In water at 70 - 100℃; for 21h; Industry scale;	3 Example 3; Hydrolysis of gabalactam to gabapentin hydrochloride. A mixture of 800 Kg (5229 mol) of gabalactam and 880 litres (10120 mol) of concentrated hydrochloric acid are heated in a steam jacketed vessel at 95-100ºC for about 15 hours under vigorous stirring. The reaction mass is cooled to 70-75ºC during 6 hours. 1050 litres of toluene are charged into the vessel. The reaction mass is cooled to about 45ºC and kept at that temperature for 30 minutes. It is then filtered through a Nutsch filter using nitrogen pressure. 1600 Kg of acetone are charged to the filter and the agitated mass is heated to 30 to 35ºC for 30 min and filtered. Gabapentin hydrochloride is sucked free of water and acetone in nitrogen atmosphere. 800 Kg of gabapentin hydrochloride containing about 4.25% water of crystallization (corresponding to hemihydrate) and traces of acetone are obtained, lactam content about 0.2%.
	With hydrogenchloride; water for 24h; Reflux;
	With hydrogenchloride; water for 4h; Reflux;	2.5. Preparation of 1 Lactam 4 (15.3 g), water (50 mL) and hydrochloric acid (50 mL) were added to a 250-mL round bottomed flask with a mechanical stirrer, and refluxed for 4 h at 150 rpm. The mixture was then cooled to room temperature, and washed twice with dichloromethane (50 mL each). The organic phases were combined, dried by CaCl2 and filtered. The resulting filtrate was evaporated to remove the organic, and the starting material 4 was recovered. The aqueous phase was cooled to 0-4 °C. After 1 h, a white crystalline solid was collected by filtration. The solid was dried at 40 °C to obtain gabapentin hydrochloride. 36.4 g of gabapentin hydrochloride and 50 mL water were added to a 250-mL round bottomed flask. The mixture was stirred at 40 °C to dissolve the gabapentin hydrochloride, 12.5 mL of methylbenzene was added and the pH was adjusted to 7.5 with 200 g/L sodium carbonate aqueous solution. After 30 min, the mixture was cooled to 4 °C for a few hours. The solid was separated, and flushed with methylbenzene. The crude gabapentin was obtained. After crystallization by methanol/isopropanol, the pure 1 was obtained. The mother liquors were reused in next reaction.

Reference： [1]Current Patent Assignee: ZHEJIANG SHOUXIN PHARMACEUTICAL - US2007/287861, 2007, A1 Location in patent: Page/Page column 4
[2]Moriyama, Katsuhiko; Ishida, Kazuma; Togo, Hideo [Chemical Communications, 2012, vol. 48, # 68, p. 8574 - 8576]
[3]Katuri, Jashuva V. P.; Ekkundi, Vadiraj S.; Nagarajan, Kuppuswamy [Organic Process Research and Development, 2016, vol. 20, # 10, p. 1828 - 1832]
[4]Budny, Marcin; Nowak, Magdalena; Wojtczak, Andrzej; Wolan, Andrzej [European Journal of Organic Chemistry, 2014, vol. 2014, # 29, p. 6361 - 6365]
[5]Current Patent Assignee: Gopal, Damodaragounder - US2005/148792, 2005, A1 Location in patent: Page/Page column 4
[6]Current Patent Assignee: PROCOS SPA - US6518456, 2003, B1
[7]Current Patent Assignee: THE KALYANI GROUP - WO2010/23694, 2010, A2 Location in patent: Page/Page column 17
[8]Niphakis, Micah J.; Turunen, Brandon J.; Georg, Gunda I. [Journal of Organic Chemistry, 2010, vol. 75, # 20, p. 6793 - 6805]
[9]Xue, Ya-Ping; Wang, Ying-Peng; Xu, Zhe; Liu, Zhi-Qiang; Shu, Xin-Rui; Jia, Dong-Xu; Zheng, Yu-Guo; Shen, Yin-Chu [Catalysis Communications, 2015, vol. 66, p. 121 - 125]

25
[ 64744-50-9 ]
[ 797762-15-3 ]

Yield	Reaction Conditions	Operation in experiment
59.27%	With water; hydrogen bromide at 0 - 114℃; for 6 - 24h; Heating / reflux;	1; 1.1; 2.1; 3.1; 4; 5.1; 6.1; 7.1; 8 Step 1: A 15 liter reactor was purged with nitrogen and charged with 1.0 kg of gabapentin lactam (2-azaspiro[4,5]decan-3-one or 1-aminomethyl-l-cyclohexane-acetic acid lactam) (6.527 mol, 1.0 molar equivalent), 2.130 kg of water (18.13 molar equivalents) and 6.60 kg of hydrobromic acid 48% aqueous solution (4.40 L of HBr 48%, 3.168 kg of HBr 100%, 39.16 mol, 6.0 molar equivalents). The resulting colorless, transparent solution was heated to -100-108° C over 4 hours and stirred for 6 hours at reflux temperature. The solution was then cooled to -0-5° C over an 8 hour period and stirred at that temperature for 6 hours. The solution was then filtered to produce 1.07 kg of wet gabapentin HBr5 which corresponded to 0.94 kg of dry material. EPO The same reactor was next charged with the filtrate (7.97 kg) from the previous step. The filtrate solution was heated to reflux (~108° C) over 4 hours and stirred for 6 hours at reflux temperature. The solution was then cooled to -40 +/- 2° C and seeded with 1 g of gabapentin HBr from the previous step. Thereafter, the solution was further cooled to ~0-5° C over 5 hours and stirred at this temperature for 8 hours. The solution was then filtered and dried under suction to produce an additional 0.30 kg of moist gabapentin HBr.The first and second yields of gabapentin HBr were combined and charged into the same reactor with 0.944 kg of isopropyl alcohol (1.21 L). The suspension was cooled and maintained at -0-5° C for 2 hours and then filtered. The resulting solid was washed with 0.079 kg isopropyl alcohol to yield 1.334 kg of moist gabapentin HBr (loss on drying 25.05%; yield: 60.74%). Example 2: Step 1: A 2 L reactor was purged with nitrogen and charged with 150 g of gabapentin lactam (0.979 mol, 1.0 molar equivalent), 164.3 g of water and 500.1 g of hydrobromic acid 48.31% aqueous solution (333.4 mL of HBr 48.31%, 241.6 g of HBr 100%, 2.986 mol, 3.05 molar equivalents). The resulting transparent, slightly yellow solution was heated to ~108-114° C and stirred for 6 hours at reflux temperature. The solution was then cooled to -0-5° C and stirred at that temperature for 6 hours. The solution was then filtered to yield 217.9 g of wet gabapentin HBr.The same reactor was then charged with the filtrate from the previous step, heated to reflux (-108-114° C) and stirred for 6 hours at reflux temperature. The solution was then cooled to ~0-5° C and stirred at this temperature for 9 hours. After filtration, the product was dried under suction to give an additional 52.5 g of moist gabapentin HBr.The first and second yields of the gabapentin HBr were combined (266.7 g of wet gabapentin HBr, which corresponded to 200.7 g of the dry material) and charged into the same reactor with 270 g of methylethylketone (336 mL). The suspension was cooled and maintained at -0-5° C for 2 hours and then filtered. The resulting solid was washed with 27 g of methylethylketone to yield 178.3 g of moist gabapentin HBr (loss on drying5.53%; yield: 69.20%). Example 3:Step 1: A 1 L reactor was charged with 75 g of gabapentin lactam (0.4895 mol, 1.0 molar equivalent), 82.15 mL of water and 250.0 g of hydrobromic acid 48.31 % aqueous solution (166.7 mL of HBr 48.31%, 120.79 g of HBr 100%, 1.493 mol, 3.05 molar equivalents). The resulting transparent, slightly yellow solution was heated to reflux (~108-l 14° C) and stirred for 6 hours at reflux temperature. The solution was cooled to -0-5° C and stirred at that temperature for 6 hours. The solution was then filtered to yield 107.7 g of wet gabapentin HBr.The filtrate was analyzed to determine the gabapentin lactam and HBr content. The same reactor was then charged with 75% of the filtrate and sufficient quantities of gabapentin lactam, HBr and water (72.0 g of gabapentin lactam, 123.O g of aqueous HBr 48.31%, 25 mL of H2O, respectively) to achieve the initial reaction conditions. The solution was heated to reflux (~108-l 14° C) and stirred for 6 hours. The solution was EPO then cooled to -0-5° C and stirred at this temperature for 6 hours. After filtration, the product was dried under suction to yield 135.2 g of moist gabapentin HBr.The filtrate was then again analyzed for gabapentin lactam and HBr content. Thereafter, 75% of the filtrate was charged to the reactor with 67.4 g of gabapentin lactam, 140.0 g of HBr 48.31% and 24.6 g of water. The solution was heated to reflux(-108-114° C) and stirred for 6 hours. The solution was then cooled to 0-5° C and stirred at that temperature for 5 hours. After filtration, the product was dried under suction to give 122.0 g of moist gabapentin HBr.Next, 75% of the filtrate from the previous step was charged to the reactor with 64.1 g of gabapentin lactam, 19.5 mL of water and 132 g hydrobromic acid 48.31% aqueous solution to give the initial reaction conditions. The mixture was heated to reflux for 6 hours, cooled and stirred at -0-5° C for 6 hours. After filtration, 127.8 g of moist gabapentin HBr was obtained. A 2 L reactor was charged with the four (4) combined crops of gabapentin HBr (485.0 g of moist gabapentin HBr, which corresponded to 351.1 g of dry material) and610 mL of methylethylketone. The suspension was cooled and maintained at ~0-5° C for 2 hours and filtered. The resulting solid was washed with 50 mL of methylethylketone to yield 320.3 g of moist gabapentin HBr (loss on drying 9.29%; yield: 64.3%). Example 4: Gabapentin HBr Analytical SampleStep 1: A 2 L reactor was purged with nitrogen and charged with 200 g of gabapentin lactam (1.305 mol, 1.0 molar equivalent), 438 g of water and 1293 g of hydrobromic acid 49.02% aqueous solution (862 mL of HBr 49.02%, 633.68 g of HBr 100%, 7.832 mol, 6 molar equivalents). The resulting transparent, slightly yellow solution was heated to -108-114° C and stirred for 6 hours at reflux temperature. The solution was then cooled to -0-5° C and stirred for 15-16 hours at this temperature. The solution was then filtered to yield 251.3 g of wet gabapentin HBr.The filtrate from the previous step was charged to the same reactor and then heated and stirred at reflux (-108-114° C) and for 6 hours. The solution was then cooled to between -10-20° C and stirred at this temperature for 15 hours. Precipitation began following seeding with a small portion of the gabapentin HBr obtained in the previous step. After stirring 3 hours at this temperature, the product was filtered and dried by suction to yield 69.7 g of moist gabapentin HBr. The first and second yields were then combined (321 g) in the same reactor with450.87 g of acetone (570 mL). The suspension was cooled and maintained at -0-5° C for 1.5 hours. The resulting solid was filtered and washed with 79.1 g of acetone (100 mL) to yield 238.24 g of moist gabapentin HBr (loss on drying 9.9 %, 214.7 g of dried product, yield: 65.24%). An analytical sample of gabapentin hydrobromide was obtained by suspending the obtained solid twice in isopropyl alcohol. The solid obtained was dried at -40° C under vacuum until a constant weight was obtained.Analytical data: Description: white crystalline solid; Assay (HClO4): 99.58%; Water content (KF method): 3.21%; Melting point: 116.4-116.9° C; Elemental analysis: C9H17NO2-HBr 0.5H2O (261.16 g/mol): C 41.30%, H 7.40%, N 5.34%, Br 30.90%Figure 2 illustrates the IR spectrum of the gabapentin HBr from Example 4 and Table 1 (below) identifies the IR peaks of the gabapentin HBr. EPO Table 1: IR (KBr) Peaks of Gabapentin HBr .Notes:1. Other Absorption Bands: 1624, 1578, 1519, 1461, 1447, 1437, 1429, 1405, 1388, 1310, 1279, 1253, 1199, 1141, 1126, 1085, 1053, 1004, 986, 853 and 683 cm"1.Figures 3 and 4 illustrate the 1H and 13C NMR spectra of the gabapentin HBr from Example 4 and Tables 2 and 3 (below) identify the chemical shifts and peak assignments of the gabapentin HBr.Table 2: 1H NMR of Gabapentin HBr (300 MHz, CD, OD)1Notes:1. The signal at δ 3.31 ppm corresponds to CD3OD.Table 3: 13C NMR of Gabapentin HBr (75.4 MHz, CD, OD)1Notes:1. The signal at δ 49.0 ppm corresponds to solvent.Figure 5 demonstrates the X-Ray powder diffraction pattern of the gabapentin HBr from Example 4 and Table 4 identifies the main diffraction peaks of the gabapentin HBr. EPO Table 4: X-Ray Diffraction Peaks of Gabapentin HBr 1,2Notes: 1. Intensities below 100 are not tabulated.2. Obtained using a SIEMENS D5000 X-ray powder diffractometer equipped with a vertical goniometer, graphite secondary monochromator and scintillation detector; Radiation source = Cu anode tube; Sample holder = glass; Scanning speed = 1 second per step with steps of 0.02 deg. Example 5:Step 1: A 500 mL, 3 -necked round bottom flask was purged with nitrogen and charged with 50 g of gabapentin lactam (0.326 mol, 1.0 molar equivalent), 54.75 g of water and 166.7 g of hydrobromic acid 48.31 % aqueous solution (111.1 mL of HBr EPO 48.31%, 80.53 g of HBr 100%,0.995 mol, 3.05 molar equivalent). The resulting transparent, slightly yellow solution was heated to reflux (-108-114° C) and stirred for 3 hours at reflux temperature. The solution was then cooled to -0-5° C and stirred at that temperature overnight. The solution was then filtered to yield 83.02 g of wet gabapentin HBr.The reactor was charged with the filtrate from the previous step and heated to reflux (-108-114° C) and stirred at that temperature for 3 hours. The solution was then cooled to -10-15° C and seeded with 0.2 g of gabapentin HBr from the previous step. Thereafter, the solution was further cooled to -0-5° C and stirred at this temperature overnight. After filtration, the product was dried under suction to yield 21.74 g of moist gabapentin HBr.The same reactor was then charged with the wet gabapentin HBr from the first and second crops (corresponding to 62.61 g of dry material) and 96.72 g of methylethylketone (120 niL). The suspension was cooled and maintained at -0-5° C for approximately 2 hours. The solution was then filtered and washed twice with 8.06 g of methylethylketone (10 mL) to yield 47.48 g of moist gabapentin HBr (loss on drying 6.73 %, yield: 59.27%). Example 6: Step 1: 274.0 kg of water and 828 kg of concentrated hydrobromic acid (48%) were mixed together. To the solution, 250 kg of gabapentin lactam was added with stirring. The mixture was then boiled under reflux (~110° C) for 3 hours. The reaction mixture was cooled to -0-5° C over 6-8 hours and stirred at this temperature for at least an additional 6 hours. The resulting precipitate was isolated by filtration. The filtrate was recovered and boiled under reflux (-110° C) for 3 hours. The reaction mixture was then cooled to -40° C over 8 hours. The cooled filtrate can optionally be seeded with gabapentin hydrobromide. The filtrate was further cooled to -0-5° C over 5 hours and stirred at this temperature for a minimum of 8 additional hours. The resulting precipitate was obtained by filtration. The two crops of gabapentin HBr were combined and stirred with 457 kg of methylethylketone for at least 2 hours at ~0-5° C. The resulting wet gabapentin HBr was isolated by filtration (yield: 63.2%). Example 7:Step 1: A 2 liter reactor was purged with nitrogen and charged with 297.7 g of gabapentin lactam (1.943 mol, 1.0 molar equivalent), 437 g of water and 1310 g of hydrobromic acid 48% aqueous solution (873 mL of HBr 48%, 628.8 g of HBr 100%, 7.77 mol, 4 molar equivalents). The resulting transparent, slightly yellow solution was heated to -108-114° C and stirred for 6 hours at reflux temperature. The solution was then cooled to ~0-5° C, stirred for 6 hours and filtered to yield 444.07 g of wet gabapentin HBr.The same reactor was charged with the filtrate from the previous step, heated to reflux (-108-114° C) and stirred for 6 hours at this temperature. The solution was then cooled to -0-5° C and stirred at this temperature overnight. The resulting product was isolated by filtration and suction dried to yield 96.02 g of moist gabapentin HBr. The same reactor was charged with the filtrate from the previous step, heated to reflux (-108-114° C) and stirred for 6 hours at this temperature. The solution was then cooled to -0-5° C and stirred at this temperature for two days. The resulting product was isolated by filtration and suction dried to yield 26.36 g of moist gabapentin HBr.A IL reactor was purged with nitrogen and charged with 558.7 g of the combined crops of gabapentin HBr (corresponding to 424.7 g of dry material) and 394.07 g of isopropyl alcohol (-502 mL). The suspension was cooled and maintained at 0-5° C for 2 hours and filtered. The resulting solid was washed twice with 15.7 g of isopropyl alcohol to yield 392.5 g of moist gabapentin HBr (loss on drying 17.1%, yield: 76.6%). Example 8: Synthesis of Gabapentin HBrStep 1: A 250 mL, 3 -necked round bottom flask was purged with nitrogen and charged with 20 g of gabapentin lactam (0.1305 mol, 1.0 molar equivalent), 28.3 g of water and 88.01 g of hydrobromic acid 48% aqueous solution (58.7 mL of HBr 48%, 42.25 g of HBr 100%, 0.522 mol, 4 molar equivalents). The resulting transparent, slightly yellow solution was heated to -108-114° C and stirred for 6 hours at reflux temperature. The solution was then cooled to 0-5° C, stirred for 8 hours and filtered to yield 22.9 g of wet gabapentin HBr.The same reactor was charged with the filtrate from the previous step, heated to reflux (-108-114° C) and stirred for 6 hours at this temperature. The solution was then cooled to -40° C and seeded with a small quantity of the solid obtained in the previous step. The seeded solution was then cooled to -0-5° C and maintained at this temperature overnight. The resulting precipitate was isolated by filtration and dried by suction to yield 6.56 g of moist gabapentin HBr.A 250 mL, 3 -necked round bottom flask was purged with nitrogen and charged with 28.52 g of the combined crops of gabapentin HBr (corresponding to 23.68 g of dry material) and 27.94 g of acetone (35.32 mL). The suspension was cooled and maintained at -0-5° C for 2 hours and filtered. The resulting solid was washed twice with 4 g of acetone to yield 21.19 g of moist gabapentin HBr (loss on drying 7.50%, yield: 62.06%). Tables 5-8 summarize the results of the foregoing examples. EPO Table 5: Summary of Step 1Notes:1. ML = Filtrate subjected to additional reaction cycle; MLR = Filtrate adjusted to initial reaction conditions and submitted to new reaction cycle.2. IPA = isopropyl alcohol; MEK = methylethylketone.3. Based on loss on drying data.Table 6: Summary of Step 2 ResultsNotes:1. IPA = isopropyl alcohol; MEK = methylethylketone; MeOH = methanol.2. DIE = diethylamine; TBA = tributylamine. EPO 3. Based on loss on drying data.Table 7 illustrates various neutralization pH values obtained using different amines and solvent conditions to neutralize gabapentin HBr.Table 7: Neutralization pH Values With Different Amines and SolventsNote:1. Based on loss on drying data.Table 8 summarizes the yields at each step and the overall yields for the specific examples described above.Table 8: Yield (%) of Each Step and Overall YieldNote:1. Based on loss on drying data.
59.27%	With water; hydrogen bromide at 0 - 114℃; for 24 - 45h; Heating / reflux;	1.1; 2.1; 3.1; 4.1; 5.1; 6.1; 7.1; 8.1 A 15 liter reactor was purged with nitrogen and charged with 1.0 kg of gabapentin lactam (2-azaspiro[4,5]decan-3-one or 1-aminomethyl-1-cyclohexane-acetic acid lactam) (6.527 mol, 1.0 molar equivalent), 2.130 kg of water (18.13 molar equivalents) and 6.60 kg of hydrobromic acid 48% aqueous solution (4.40 L of HBr 48%, 3.168 kg of HBr 100%, 39.16 mol, 6.0 molar equivalents). The resulting colorless, transparent solution was heated to 100-108° C. over 4 hours and stirred for 6 hours at reflux temperature. The solution was then cooled to 0-5° C. over an 8 hour period and stirred at that temperature for 6 hours. The solution was then filtered to produce 1.07 kg of wet gabapentin HBr, which corresponded to 0.94 kg of dry material.The same reactor was next charged with the filtrate (7.97 kg) from the previous step. The filtrate solution was heated to reflux (108° C.) over 4 hours and stirred for 6 hours at reflux temperature. The solution was then cooled to 40+/-2° C. and seeded with 1 g of gabapentin HBr from the previous step. Thereafter, the solution was further cooled to 0-5° C. over 5 hours and stirred at this temperature for 8 hours. The solution was then filtered and dried under suction to produce an additional 0.30 kg of moist gabapentin HBr.The first and second yields of gabapentin HBr were combined and charged into the same reactor with 0.944 kg of isopropyl alcohol (1.21 L). The suspension was cooled and maintained at 0-5° C. for 2 hours and then filtered. The resulting solid was washed with 0.079 kg isopropyl alcohol to yield 1.334 kg of moist gabapentin HBr (loss on drying 25.05%; yield: 60.74%); A 2 L reactor was purged with nitrogen and charged with 150 g of gabapentin lactam (0.979 mol, 1.0 molar equivalent), 164.3 g of water and 500.1 g of hydrobromic acid 48.31% aqueous solution (333.4 mL of HBr 48.31%, 241.6 g of HBr 100%, 2.986 mol, 3.05 molar equivalents). The resulting transparent, slightly yellow solution was heated to 108-114° C. and stirred for 6 hours at reflux temperature. The solution was then cooled to 0-5° C. and stirred at that temperature for 6 hours. The solution was then filtered to yield 217.9 g of wet gabapentin HBr.The same reactor was then charged with the filtrate from the previous step, heated to reflux (108-114° C.) and stirred for 6 hours at reflux temperature. The solution was then cooled to 0-5° C. and stirred at this temperature for 9 hours. After filtration, the product was dried under suction to give an additional 52.5 g of moist gabapentin HBr.The first and second yields of the gabapentin HBr were combined (266.7 g of wet gabapentin HBr, which corresponded to 200.7 g of the dry material) and charged into the same reactor with 270 g of methylethylketone (336 mL). The suspension was cooled and maintained at 0-5° C. for 2 hours and then filtered. The resulting solid was washed with 27 g of methylethylketone to yield 178.3 g of moist gabapentin HBr (loss on drying 5.53%; yield: 69.20%); A 1 L reactor was charged with 75 g of gabapentin lactam (0.4895 mol, 1.0 molar equivalent), 82.15 mL of water and 250.0 g of hydrobromic acid 48.31% aqueous solution (166.7 mL of HBr 48.31%, 120.79 g of HBr 100%, 1.493 mol, 3.05 molar equivalents). The resulting transparent, slightly yellow solution was heated to reflux (108-114° C.) and stirred for 6 hours at reflux temperature. The solution was cooled to 0-5° C. and stirred at that temperature for 6 hours. The solution was then filtered to yield 107.7 g of wet gabapentin HBr.The filtrate was analyzed to determine the gabapentin lactam and HBr content. The same reactor was then charged with 75% of the filtrate and sufficient quantities of gabapentin lactam, HBr and water (72.0 g of gabapentin lactam, 123.0 g of aqueous HBr 48.31%, 25 mL of H2O, respectively) to achieve the initial reaction conditions. The solution was heated to reflux (108-114° C.) and stirred for 6 hours. The solution was then cooled to 0-5° C. and stirred at this temperature for 6 hours. After filtration, the product was dried under suction to yield 135.2 g of moist gabapentin HBr.The filtrate was then again analyzed for gabapentin lactam and HBr content. Thereafter, 75% of the filtrate was charged to the reactor with 67.4 g of gabapentin lactam, 140.0 g of HBr 48.31% and 24.6 g of water. The solution was heated to reflux (108-114° C.) and stirred for 6 hours. The solution was then cooled to 0-5° C. and stirred at that temperature for 5 hours. After filtration, the product was dried under suction to give 122.0 g of moist gabapentin HBr.Next, 75% of the filtrate from the previous step was charged to the reactor with 64.1 g of gabapentin lactam, 19.5 mL of water and 132 g hydrobromic acid 48.31% aqueous solution to give the initial reaction conditions. The mixture was heated to reflux for 6 hours, cooled and stirred at 0-5° C. for 6 hours. After filtration, 127.8 g of moist gabapentin HBr was obtained.A 2 L reactor was charged with the four (4) combined crops of gabapentin HBr (485.0 g of moist gabapentin HBr, which corresponded to 351.1 g of dry material) and 610 mL of methylethylketone. The suspension was cooled and maintained at 0-5° C. for 2 hours and filtered. The resulting solid was washed with 50 mL of methylethylketone to yield 320.3 g of moist gabapentin HBr (loss on drying 9.29%; yield: 64.3%); A 2 L reactor was purged with nitrogen and charged with 200 g of gabapentin lactam (1.305 mol, 1.0 molar equivalent), 438 g of water and 1293 g of hydrobromic acid 49.02% aqueous solution (862 mL of HBr 49.02%, 633.68 g of HBr 100%, 7.832 mol, 6 molar equivalents). The resulting transparent, slightly yellow solution was heated to 108-114° C. and stirred for 6 hours at reflux temperature. The solution was then cooled to 0-5° C. and stirred for 15-16 hours at this temperature. The solution was then filtered to yield 251.3 g of wet gabapentin HBr.The filtrate from the previous step was charged to the same reactor and then heated and stirred at reflux (108-114° C.) and for 6 hours. The solution was then cooled to between 10-20° C. and stirred at this temperature for 15 hours. Precipitation began following seeding with a small portion of the gabapentin HBr obtained in the previous step. After stirring 3 hours at this temperature, the product was filtered and dried by suction to yield 69.7 g of moist gabapentin HBr.The first and second yields were then combined (321 g) in the same reactor with 450.87 g of acetone (570 mL). The suspension was cooled and maintained at 0-5° C. for 1.5 hours. The resulting solid was filtered and washed with 79.1 g of acetone (100 mL) to yield 238.24 g of moist gabapentin HBr (loss on drying 9.9%, 214.7 g of dried product, yield: 65.24%).An analytical sample of gabapentin hydrobromide was obtained by suspending the obtained solid twice in isopropyl alcohol. The solid obtained was dried at 40° C. under vacuum until a constant weight was obtained.Analytical data: Description: white crystalline solid; Assay (HClO4): 99.58%; Water content (KF method): 3.21%; Melting point: 116.4-116.9° C.; Elemental analysis: C9H17NO2.HBr.0.5H2O (261.16 g/mol): C 41.30%, H 7.40%, N 5.34%, Br 30.90%FIG. 2 illustrates the IR spectrum of the gabapentin HBr from Example 4 and Table 1 (below) identifies the IR peaks of the gabapentin HBr. TABLE 1 IR (KBr) Peaks of Gabapentin HBr1 Frequency, ν (cm-1) Assignment 3600-2300 O-H (Maxima at 3383, 3058, 2933, 2615, 2502) C-H (stretch) NH3+(stretch) 1713 CO (stretch) Notes: 1Other Absorption Bands: 1624, 1578, 1519, 1461, 1447, 1437, 1429, 1405, 1388, 1310, 1279, 1253, 1199, 1141, 1126, 1085, 1053, 1004, 986, 853 and 683 cm-1.FIGS. 3 and 4 illustrate the 1H and 13C NMR spectra of the gabapentin HBr from Example 4 and Tables 2 and 3 (below) identify the chemical shifts and peak assignments of the gabapentin HBr.FIG. 5 demonstrates the X-Ray powder diffraction pattern of the gabapentin HBr from Example 4 and Table 4 identifies the main diffraction peaks of the gabapentin HBr; A 500 mL, 3-necked round bottom flask was purged with nitrogen and charged with 50 g of gabapentin lactam (0.326 mol, 1.0 molar equivalent), 54.75 g of water and 166.7 g of hydrobromic acid 48.31% aqueous solution (111.1 mL of HBr 48.31%, 80.53 g of HBr 100%, 0.995 mol, 3.05 molar equivalent). The resulting transparent, slightly yellow solution was heated to reflux (108-114° C.) and stirred for 3 hours at reflux temperature. The solution was then cooled to 0-5° C. and stirred at that temperature overnight. The solution was then filtered to yield 83.02 g of wet gabapentin HBr.The reactor was charged with the filtrate from the previous step and heated to reflux (108-114° C.) and stirred at that temperature for 3 hours. The solution was then cooled to 10-15° C. and seeded with 0.2 g of gabapentin HBr from the previous step. Thereafter, the solution was further cooled to 0-5° C. and stirred at this temperature overnight. After filtration, the product was dried under suction to yield 21.74 g of moist gabapentin HBr.The same reactor was then charged with the wet gabapentin HBr from the first and second crops (corresponding to 62.61 g of dry material) and 96.72 g of methylethylketone (120 mL). The suspension was cooled and maintained at 0-5° C. for approximately 2 hours. The solution was then filtered and washed twice with 8.06 g of methylethylketone (10 mL) to yield 47.48 g of moist gabapentin HBr (loss on drying 6.73%, yield: 59.27%); 274.0 kg of water and 828 kg of concentrated hydrobromic acid (48%) were mixed together. To the solution, 250 kg of gabapentin lactam was added with stirring. The mixture was then boiled under reflux (110° C.) for 3 hours. The reaction mixture was cooled to 0-5° C. over 6-8 hours and stirred at this temperature for at least an additional 6 hours. The resulting precipitate was isolated by filtration.The filtrate was recovered and boiled under reflux (110° C.) for 3 hours. The reaction mixture was then cooled to 40° C. over 8 hours. The cooled filtrate can optionally be seeded with gabapentin hydrobromide. The filtrate was further cooled to 0-5° C. over 5 hours and stirred at this temperature for a minimum of 8 additional hours. The resulting precipitate was obtained by filtration.The two crops of gabapentin HBr were combined and stirred with 457 kg of methylethylketone for at least 2 hours at 0-5° C. The resulting wet gabapentin HBr was isolated by filtration (yield: 63.2%); A 2 liter reactor was purged with nitrogen and charged with 297.7 g of gabapentin lactam (1.943 mol, 1.0 molar equivalent), 437 g of water and 1310 g of hydrobromic acid 48% aqueous solution (873 mL of HBr 48%, 628.8 g of HBr 100%, 7.77 mol, 4 molar equivalents). The resulting transparent, slightly yellow solution was heated to 108-114° C. and stirred for 6 hours at reflux temperature. The solution was then cooled to 0-5° C., stirred for 6 hours and filtered to yield 444.07 g of wet gabapentin HBr.The same reactor was charged with the filtrate from the previous step, heated to reflux (108-114° C.) and stirred for 6 hours at this temperature. The solution was then cooled to 0-5° C. and stirred at this temperature overnight. The resulting product was isolated by filtration and suction dried to yield 96.02 g of moist gabapentin HBr.The same reactor was charged with the filtrate from the previous step, heated to reflux (108-114° C.) and stirred for 6 hours at this temperature. The solution was then cooled to 0-5° C. and stirred at this temperature for two days. The resulting product was isolated by filtration and suction dried to yield 26.36 g of moist gabapentin HBr.A 1 L reactor was purged with nitrogen and charged with 558.7 g of the combined crops of gabapentin HBr (corresponding to 424.7 g of dry material) and 394.07 g of isopropyl alcohol (502 mL). The suspension was cooled and maintained at 0-5° C. for 2 hours and filtered. The resulting solid was washed twice with 15.7 g of isopropyl alcohol to yield 392.5 g of moist gabapentin HBr (loss on drying 17.1%, yield: 76.6%); A 250 mL, 3-necked round bottom flask was purged with nitrogen and charged with 20 g of gabapentin lactam (0.1305 mol, 1.0 molar equivalent), 28.3 g of water and 88.01 g of hydrobromic acid 48% aqueous solution (58.7 mL of HBr 48%, 42.25 g of HBr 100%, 0.522 mol, 4 molar equivalents). The resulting transparent, slightly yellow solution was heated to 108-114° C. and stirred for 6 hours at reflux temperature. The solution was then cooled to 0-5° C., stirred for 8 hours and filtered to yield 22.9 g of wet gabapentin HBr.The same reactor was charged with the filtrate from the previous step, heated to reflux (108-114° C.) and stirred for 6 hours at this temperature. The solution was then cooled to 40° C. and seeded with a small quantity of the solid obtained in the previous step. The seeded solution was then cooled to 0-5° C. and maintained at this temperature overnight. The resulting precipitate was isolated by filtration and dried by suction to yield 6.56 g of moist gabapentin HBr.A 250 mL, 3-necked round bottom flask was purged with nitrogen and charged with 28.52 g of the combined crops of gabapentin HBr (corresponding to 23.68 g of dry material) and 27.94 g of acetone (35.32 mL). The suspension was cooled and maintained at 0-5° C. for 2 hours and filtered. The resulting solid was washed twice with 4 g of acetone to yield 21.19 g of moist gabapentin HBr (loss on drying 7.50%, yield: 62.06%).

Reference： [1]Current Patent Assignee: MEDICHEM, S.A. - WO2006/90208, 2006, A1 Location in patent: Page/Page column title page; 3; 6-17; 1/6
[2]Current Patent Assignee: MEDICHEM, S.A. - US2009/43126, 2009, A1 Location in patent: Page/Page column 3-7

26
[ 133481-10-4 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	In water; isopropyl alcohol	1.F.A Step A: Step A: Preparation of 2-Azaspiro[4.5]decan-3-one Ethyl 1- cyanocyclohexaneacetate (29.3 g) is combined with isopropanol (75 mL) and sponge nickel catalyst (6 g, 50% water wet) and hydrogenated at 300 psig at 130° C. The reaction mixture is cooled and the catalyst is removed by filtration, and the liquors are concentrated. The lactam product can be isolated as a white solid, if desired, by the addition of heptane (150 mL) followed by filtration (yield 18.6 g, 81%).

Reference： [1]Current Patent Assignee: PFIZER INC - US5319135, 1994, A

27
[ 133938-45-1 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
91.6%	In palladium-carbon; ethanol	8.3 (Step 3) (Step 3) 190 g (0 82 mole) Ethyl 1-nitromethyl-1-cyclohexaneacetate in 3168 mL ethanol are hydrogenated for 4 hours at 125° C. in the presence of 62.9 g 10% palladium-carbon. At the end of the take up of hydrogen, the catalyst is filtered off and the colorless solution obtained is distilled to dryness in a vacuum. 116.2 g 2-Aza-spiro[4,5]decan-3-one in the form of a colorless crystallizate are obtained; yield 91.6% of theory. Content 97.1% (GC); m.p. 88° to 90° C.

Reference： [1]Current Patent Assignee: PFIZER INC - US5091567, 1992, A

Yield	Reaction Conditions	Operation in experiment
		1 1-Aminomethyl-1cyclohexane-acetic acid. ml. 20% hydrochloric acid. After cooling the solution, it is extracted three times with 100 ml. amounts of chloroform to remove the 1-amino-methyl-1-cyclohexane-acetic acid lactam formed as a by-product product and the aqueous hydrochloric acid solution evaporated in a vacuum, whereby 1-aminomethyl-1-cyclohexane-acetic acid crystallises as the hydrochloride; m.p. 117°-118° C., after recrystallisation from acetone/methanol/ether. After recrystallization from methanol/ether the melting point of the product is 129°-133° C.

29
[ 60142-96-3 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium chloride In water-d2 at 80℃;
	at 80℃; for 336h;	The cyclisation rate constants are detailed in Table 3 and show that decomposition of both drugs is significantly retarded through intercalation into LDHs, both at ambient and elevated temperatures. At 80 °C, decomposition of the pristine drugs in solution was significant over a two week period, whereas decomposition of the drugs within the intercalation compounds was only just measurable within experimental error, the cyclisation rate constant being reduced by a factor of 15.0 in the case of GBP, and 16.6 in the case of PGB. Similarly, at 20 °C measurable decomposition of the pristine drugs occurred within a four week period, whereas decomposition of the drugs within the nanohybrids was not sufficiently significant to be measurable.

Reference： [1]Zambon, Elena; Giovanetti, Roberto; Cotarca, Livius; Pasquato, Lucia [Tetrahedron, 2008, vol. 64, # 28, p. 6739 - 6743]
[2]Current Patent Assignee: UNIVERSITY OF OXFORD; Oxford University Innovation (in: Oxford University) - WO2017/89804, 2017, A1 Location in patent: Paragraph 00133-00135

30
[ 64744-50-9 ]
[ 176-66-9 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Reflux; Inert atmosphere;

Reference： [1]Location in patent: experimental part Wang, Jun; Cady, Sarah D.; Balannik, Victoria; Pinto, Lawrence H.; DeGrado, William F.; Hong, Mei [Journal of the American Chemical Society, 2009, vol. 131, p. 8066 - 8076]

31
[ 1130-32-1 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; sodium hydroxide; In water; at 0 - 85℃;Product distribution / selectivity;	b) In another flask equipped with stirrer and cooling facility is charged caustic lye (48%, 40Og, 22.2 mol) and heated to 5OºC. The reaction mixture obtained above from the condensation of diacid with urea is added to the caustic lye over a period of 1 hr so as to maintain the temperature below 65ºC. Once the addition is complete the mixture is stirred vigorously for another 1 hour and cooled to room temperature or 30 ºC. c) In another round bottomed flask caustic lye (300ml) and water (800 ml) are taken and cooled to 0-5ºC. The reaction mixture is stirred well and bromine (165g, 1.03 mol) is added slowly keeping the temperature of the reaction below 5ºC, Once the bromine addition is completed, the reaction mixture is stirred at this temperature for another 30- 45 min. d) To the hypobromite solution as obtained in step (c), is added the solution obtained in step (b) over a period of 2-3 hours maintaining the temperature of the reaction below 5ºC. Once the addition is complete, the reaction mass is stirred for another 1 hour.Slowly the temperature of the reaction mixture is raised to room temperature or up to 3OºC. The reaction mixture is heated to 80-85ºC and maintained at temperature for another 2-3 hours. The reaction mass is then cooled to 50-55ºC and toluene (33Og) is added to the mixture and stirred. The stirring is stopped and allowed to settle to separate into layers. The aqueous layer is extracted with toluene (2 times) and the organic layers are combined. Activated charcoal is added to the toluene layer and stirred at room temperature. Charcoal is removed by filtration and the organic layer is taken up for concentration under vacuum. The solvent is distilled off completely under vacuum to obtain gabalactam (Formula 3), m.p. 88-90ºC and above 99% purity (105-11Og, 68%- 72% or 0.525-0.55 w/w based on diacid input).

Reference： [1]Chemical Communications,2012,vol. 48,p. 8574 - 8576
[2]Patent: WO2010/23694,2010,A2 .Location in patent: Page/Page column 15-16

32
[ 64744-50-9 ]
[ 490-79-9 ]
C₇H₆O₄*C₉H₁₅NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water at 20℃; for 12h;

Reference： [1]Location in patent: experimental part Maheshwari, Chinmay; Andre, Vania; Reddy, Sreenivas; Roy, Lilly; Duarte, Teresa; Rodriguez-Hornedo, Nair [CrystEngComm, 2012, vol. 14, # 14, p. 4801 - 4811]

33
[ 64744-50-9 ]
[ 150-13-0 ]
C₇H₇NO₂*C₉H₁₅NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water at 20℃; for 12h;

Reference： [1]Location in patent: experimental part Maheshwari, Chinmay; Andre, Vania; Reddy, Sreenivas; Roy, Lilly; Duarte, Teresa; Rodriguez-Hornedo, Nair [CrystEngComm, 2012, vol. 14, # 14, p. 4801 - 4811]

34
[ 64744-50-9 ]
[ 110-17-8 ]
0.5C₄H₄O₄*C₉H₁₅NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water at 20℃; for 12h;

Reference： [1]Location in patent: experimental part Maheshwari, Chinmay; Andre, Vania; Reddy, Sreenivas; Roy, Lilly; Duarte, Teresa; Rodriguez-Hornedo, Nair [CrystEngComm, 2012, vol. 14, # 14, p. 4801 - 4811]

35
[ 64744-50-9 ]
[ 99-96-7 ]
C₇H₆O₃*C₉H₁₅NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water at 20℃; for 12h;

Reference： [1]Location in patent: experimental part Maheshwari, Chinmay; Andre, Vania; Reddy, Sreenivas; Roy, Lilly; Duarte, Teresa; Rodriguez-Hornedo, Nair [CrystEngComm, 2012, vol. 14, # 14, p. 4801 - 4811]

36
[ 64744-50-9 ]
[ 1809-20-7 ]
[ 1417780-49-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	With copper diacetate; potassium carbonate In toluene at 80℃; for 0.666667h; Molecular sieve;

Reference： [1]Jin, Xiongjie; Yamaguchi, Kazuya; Mizuno, Noritaka [Organic Letters, 2013, vol. 15, # 2, p. 418 - 421]

37
[ 133481-09-1 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
97.3%	Stage #1: (1-cyanocyclohexyl)-acetic acid With sodium hydroxide In water Stage #2: With hydrogen In water; toluene at 80 - 85℃; Inert atmosphere;	4.2 Example 4.2 2- Aza-spiro[4.5]decane-3-one (Gabalactam) Example 4.2 2- Aza-spiro[4.5]decane-3-one (Gabalactam) : A sodium salt solution of (l-cyano-cyclohexyl)-acetic (308.45 g; 1.84 moles) was prepared by dissolving in 3.0 v water and 1.1 eq. of sodium hydroxide. The resulting solution at pH 12 + was transferred into a two litre autoclave and Raney Nickel 17.5 g (5 % WAV) was added. The reaction mass was flushed two times with 5.0 Kg/cm pressure of nitrogen and then by hydrogen. The reaction mass was heated to ~80°C and subjected to 10.0 Kg/cm2 hydrogen pressure under stirring. The reaction was maintained at the same temperature and pressure till the starting material disappeared. The heating was stopped and the autoclave was allowed to come to room temperature. The reaction mass was filtered to recover catalyst. Wash recovered catalyst and separately stored it in water. To the filtrate toluene (1400 mL) was added and heat to 80 to 85°C for 2 hour. The organic layer was separated and the aqueous layer was transferred to the reaction flask and repeated the extraction with toluene at 80°C under stirring. This extraction operation was carried out for 5 to 7 times. Toluene layer was distilled and the solid obtained was dried at 45 to 50°C under vacuum in vacuum oven to give 275 g (97.3%) 2-aza-spiro[4.5]decane-3-one (Gabalactam); mp. 90 to 91 °C; NMR (CDC13) δ 1.53 (m, 1 OH), 2.18 (s, 2H), 3.15 (s, 2H), 6.49 (br, NH)
95.3%	With chromium-promoted Raney-nickel; hydrogen In water at 110℃; for 9h; Autoclave;	2.4. Preparation of 4 by hydrogenation Into a 500-mL stirred autoclave was added 150 mL of aqueous solution containing 2 and 10 wt.% catalyst (based on the weight of 2). After flushing the reactor with nitrogen, the mixture was stirred at 1000 rpm, 110 °C and 290 psig of hydrogen for 9 h. After hydrogenation, the pH of the mixture was increased due to the released ammonia. The mixture was cooled to 60 °C, and filtered to remove the catalyst. The filtrate was adjusted to pH 7.0 with 6 M HCl and sodium chloride was added to saturate the solution. The resulting solution was extracted with equivoluminal dichloromethane for three times. The organic phases were combined and then evaporated to obtain yellowish liquid. After cooling to - 20 °C for a few hours, a white crystalline solid was collected and dried at 40 °C, to obtain the compound 4.

Reference： [1]Current Patent Assignee: THE KALYANI GROUP - WO2013/190357, 2013, A1 Location in patent: Page/Page column 24
[2]Xue, Ya-Ping; Wang, Ying-Peng; Xu, Zhe; Liu, Zhi-Qiang; Shu, Xin-Rui; Jia, Dong-Xu; Zheng, Yu-Guo; Shen, Yin-Chu [Catalysis Communications, 2015, vol. 66, p. 121 - 125]

38
(1-cyanocyclohexyl)acetic acid sodium salt [ No CAS ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
91.9%	With Raney Nickel In water at 80℃; for 18h;	4.10 Example 4.10 2-Aza-spiro[4.5]decane-3-one (Gabalactam) from 1-Cyanomethyl- cyclohexanecarbonitrile: Example 4.10 2-Aza-spiro[4.5]decane-3-one (Gabalactam) from 1-Cyanomethyl- cyclohexanecarbonitrile: Sodium salt of cyano cyclohexane-1 -acetic acid solution (1500 g of 16% solution≡ 240g as 100% basis) in water (pH of solution 13.5) and is charged to pre-cleaned autoclave. Then 10% (24 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated at 80°C for 18 hours with a hydrogen pressure of 10 kg /cm2' The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The aqueous layer saturated with sodium chloride (245 g). Gabalactam is isolated by toluene extractions (3x 150 mL) at 50 to 70°C. The molar yield is 91.9% with purity of >99%.

Reference： [1]Current Patent Assignee: THE KALYANI GROUP - WO2013/190357, 2013, A1 Location in patent: Page/Page column 29

39
(1-cyanocyclohexyl)acetic acid barium salt [ No CAS ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogen In water at 80℃; for 20h;	4.11 Example 4.11 2-Aza-spiro[4.5]decane-3-one (Gabalactam) from 1-Cyanomethyl- cyclohexanecarbonitrile Example 4.11 2-Aza-spiro[4.5]decane-3-one (Gabalactam) from 1-Cyanomethyl- cyclohexanecarbonitrile: Barium salt of cyano cyclohexane- 1 -acetic acid (645 g of 15.5% solution≡ 100 g as 100% basis) in water (pH of solution 13.5) and is charged to pre-cleaned autoclave. Then 10% (10 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated at 80°C for 20 hours with a hydrogen pressure of 10 kg /cm . The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The aqueous layer saturated with sodium chloride (125 g). Gabalactam is isolated by toluene extraction (3 x300 mL) at 50°C. The molar yield of gabalactam is 90% with purity of >99%.

Reference： [1]Current Patent Assignee: THE KALYANI GROUP - WO2013/190357, 2013, A1 Location in patent: Page/Page column 29

40
[ 55568-06-4 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: water; methanol / 80 - 90 °C / Reflux 2.1: sodium hydrogencarbonate / aq. buffer / 28 h / 25 °C / pH 7.4 - 7.5 / Enzymatic reaction 2.2: 20 °C 2.3: Raney Nickel / 80 °C / 7500.75 Torr / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: water; methanol / 80 - 90 °C / Reflux 2.1: sodium hydrogencarbonate; water / aq. buffer / 24 h / 20 - 35 °C / pH 7.5 / Enzymatic reaction 3.1: sodium hydroxide / water / pH 12 3.2: Raney Nickel / 80 - 85 °C / 3750.38 - 7500.75 Torr / Inert atmosphere

Reference： [1]Current Patent Assignee: THE KALYANI GROUP - WO2013/190357, 2013, A1
[2]Current Patent Assignee: THE KALYANI GROUP - WO2013/190357, 2013, A1

41
[ 108-94-1 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: ammonium acetate / methanol / 65 - 95 °C 2.1: sodium hydrogencarbonate / aq. buffer / 28 h / 25 °C / pH 7.4 - 7.5 / Enzymatic reaction 2.2: 20 °C 2.3: Raney Nickel / 80 °C / 7500.75 Torr / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: ammonium acetate / cyclohexane; water / 7.5 h / 75 - 80 °C / Dean-Stark 2.1: water; methanol / 80 - 90 °C / Reflux 3.1: sodium hydrogencarbonate / aq. buffer / 28 h / 25 °C / pH 7.4 - 7.5 / Enzymatic reaction 3.2: 20 °C 3.3: Raney Nickel / 80 °C / 7500.75 Torr / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: ammonium acetate / methanol / 65 - 95 °C 2.1: sodium hydrogencarbonate; water / aq. buffer / 24 h / 20 - 35 °C / pH 7.5 / Enzymatic reaction 3.1: sodium hydroxide / water / pH 12 3.2: Raney Nickel / 80 - 85 °C / 3750.38 - 7500.75 Torr / Inert atmosphere

Multi-step reaction with 4 steps 1.1: ammonium acetate / cyclohexane; water / 7.5 h / 75 - 80 °C / Dean-Stark 2.1: water; methanol / 80 - 90 °C / Reflux 3.1: sodium hydrogencarbonate; water / aq. buffer / 24 h / 20 - 35 °C / pH 7.5 / Enzymatic reaction 4.1: sodium hydroxide / water / pH 12 4.2: Raney Nickel / 80 - 85 °C / 3750.38 - 7500.75 Torr / Inert atmosphere

Reference： [1]Current Patent Assignee: THE KALYANI GROUP - WO2013/190357, 2013, A1
[2]Current Patent Assignee: THE KALYANI GROUP - WO2013/190357, 2013, A1
[3]Current Patent Assignee: THE KALYANI GROUP - WO2013/190357, 2013, A1
[4]Current Patent Assignee: THE KALYANI GROUP - WO2013/190357, 2013, A1

42
[ 4172-99-0 ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
93.63%	Stage #1: (1-cyanocyclohexyl)acetonitrile With sodium hydrogencarbonate at 25℃; for 28h; Enzymatic reaction; Stage #2: With sodium hydroxide In water at 20℃; Stage #3: With hydrogen In water at 80℃; Inert atmosphere;	4.3 Example 4.3 2-Aza-spiro[4.5]decane-3-one (Gabalactam) from 1-Cyanomethyl- cyclohexanecarbonitrile Example 4.3 2-Aza-spiro[4.5]decane-3-one (Gabalactam) from 1-Cyanomethyl- cyclohexanecarbonitrile: (a) To a 30 litre reactor fitted with, pH meter and overhead mechanical stirrer and temperature probe, a solution of sodium bicarbonate (32 g, 0.38 mmol) was prepared in demineralised water (15.98 L) and pH was adjusted to 7.5 by adding IN hydrochloric acid or sodium bicarbonate as required. The total volume made up to 19.98 L using demineralised water. Finely powdered 1 -cyanomethyl-cyclohexanecarbonitrile (1.5 kg, 10.12 mol) was added into the buffer solution under stirring ( 140 to 150 Rotation Per Minute) at room temperature for 10 minutes. Again the pH was adjusted to 7.5 using IN hydrochloric acid or sodium bicarbonate and the mixture stirred for 10 minutes. The enzyme ( 1 1.0 g having 1.1 KU specific activity; enzyme load of 8.01 U / g of substrate) was added in the reaction mixture and stirred at 25°C for 28 hours. The pH of the reaction was maintained at 7.4 ± 0.2 by adding IN hydrochloric acid (-1.2 kg) or solid sodium bicarbonate. After 24 hours the reaction mixture was cooled to room temperature and filtered to remove any undissolved material. The filtrate was taken into 30 L reactor and chilled at 0 to 2°C and equipped with pH meter and acidified with concentrated hydrochloric acid (~ 1.23 kg) to pH 1 to 2. A white solid product precipitated out which was filtered and washed with water (2 L) and suck dried to get wet l-cyano-cyclohexyl)-acetic acid weighing 2.84 kg (moisture content 43.5%); 97% yield based on dry weight with a purity of 88.2% by GC. The wet cake was dissolved in water containing sodium hydroxide (486 g; 1215 mol) and the total solution was made up to 10.18 kg. The solution was kept at room temperature for several hours (4 to 8 hours) and filtered. The resulting solution showed HPLC assay of monoacid as 12.88%. (b) The above solution (5590 mL = 720 g of monoacid; 4.31 mol) was charged in a 10 L autoclave and Raney Nickel (43.2 g; 6% w/w) was added. The reaction mass was flushed two times with 5.0 Kg/cm pressure of nitrogen and then by hydrogen. The reaction mass was heated to -80 °C and applied 10.0 Kg/cm2 hydrogen pressure under stirring. Maintained the reaction at the same temperature and pressure till the starting material disappeared ( 10 hours). The heating was stopped and the autoclave was allowed to come to room temperature. The reaction mass was filtered to recover catalyst. Wash recovered catalyst and separately stored it in water. To the filtrate toluene (1500 mL) was added and heat to 80 to 85°C for 2 hours. The organic layer was separated and the aqueous layer was transferred to the reaction flask and repeated the extraction with toluene at 80°C under stirring. This extraction operation was carried out for 5 to 7 times. Toluene layer was distilled and the solid obtained was dried at 45 to 50°C under vacuum in vacuum oven to give 515 g (93.63%) 2-aza-spiro[4.5]decane-3-one (Gabalactam) with > 99.5% purity by GC.

Reference： [1]Current Patent Assignee: THE KALYANI GROUP - WO2013/190357, 2013, A1 Location in patent: Page/Page column 24-25

43
[ 64744-50-9 ]
4-bromo-2-tosyl-2-azaspiro[4.5]decan-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: -78 - 20 °C / Inert atmosphere 2.1: trimethylsilyl trifluoromethanesulfonate; triethylamine / dichloromethane / 1 h / -20 - 0 °C / Inert atmosphere 2.2: -78 - -40 °C / Inert atmosphere

Reference： [1]Kern, Nicolas; Felten, Anne-Sophie; Weibel, Jean-Marc; Pale, Patrick; Blanc, Aurlien [Organic Letters, 2014, vol. 16, # 23, p. 6104 - 6107]

44
[ 64744-50-9 ]
methyl 2-tosyl-2-azaspiro[3.5]nonane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: -78 - 20 °C / Inert atmosphere 2.1: trimethylsilyl trifluoromethanesulfonate; triethylamine / dichloromethane / 1 h / -20 - 0 °C / Inert atmosphere 2.2: -78 - -40 °C / Inert atmosphere 3.1: potassium carbonate / acetonitrile / 3 h / 60 °C

Reference： [1]Kern, Nicolas; Felten, Anne-Sophie; Weibel, Jean-Marc; Pale, Patrick; Blanc, Aurlien [Organic Letters, 2014, vol. 16, # 23, p. 6104 - 6107]

45
[ 64744-50-9 ]
[ 98-59-9 ]
2-tosyl-2-azaspiro[4.5]decan-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: gabapentin-lactam With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: p-toluenesulfonyl chloride In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere;

Reference： [1]Kern, Nicolas; Felten, Anne-Sophie; Weibel, Jean-Marc; Pale, Patrick; Blanc, Aurlien [Organic Letters, 2014, vol. 16, # 23, p. 6104 - 6107]

46
[ 64744-50-9 ]
[ 60142-96-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: hydrogenchloride; water / 4 h / Reflux 2: sodium carbonate / water; toluene / 0.5 h / pH 7.5

Reference： [1]Xue, Ya-Ping; Wang, Ying-Peng; Xu, Zhe; Liu, Zhi-Qiang; Shu, Xin-Rui; Jia, Dong-Xu; Zheng, Yu-Guo; Shen, Yin-Chu [Catalysis Communications, 2015, vol. 66, p. 121 - 125]

47
cyclohexanecarbaldehyde O-((perfluorophenyl)methyl)oxime [ No CAS ]
[ 64744-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium cyanoborohydride; hydrogenchloride / methanol; water / 20 °C / Inert atmosphere 2.1: toluene / Inert atmosphere; Reflux 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; 4-acetamidobenzenesulfonyl azide / tetrahydrofuran / 20 °C / Inert atmosphere 3.2: 20 °C / Inert atmosphere 4.1: dirhodium tetraacetate / tetrahydrofuran / 2 h / 20 °C / Inert atmosphere 5.1: samarium diiodide / tetrahydrofuran; water / 1 h / Inert atmosphere