Gabapentin hydrochloride preparing process

Abstract
The gabapentin hydrochloride preparing process includes preparing 1, 5-diamino formyl-2, 4-dioxy-3-aza spiro[5, 5]hendecane with 1, 5-dicyano2, 4-dioxy-3-aza spiro[5, 5]hendecane at 65-85 deg.c in strong acid condition; and the subsequent Hoffman rearrangement under alkali condition.
The process has easy-to-obtain material, simple process, less intermediate purifying requirement, low production cost and high product purity.

Classifications
C07C227/22 Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones
or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
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CN1740161A
CN Application
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CN 200510041536
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CN100341856C (Grant)
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Priority date
2005-08-19
Filing date
2005-08-19
Publication date
2006-03-01
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Description
translated from Chinese
Gabapentin hydrochloride Preparation
TECHNICAL FIELD
The present invention pertains to a method for preparing gabapentin hydrochloride, in particular by Hofmann rearrangement process for the
preparation of gabapentin hydrochloride.
Background technique
Gabapentin hydrochloride is an important intermediate in the synthesis of antiepileptic drugs gabapentin, heretofore been reported in the patent
literature and a variety of synthetic methods reported in U.S. Patent Application 20040034248 cyclohexyl-1,1-diacetic acid monoamide carried out
Hofmann rearrangement . United States Patent Application 20040063997 been reported with 3,3-cyclopentyl glutarimide carried Hofmann
rearrangement.
SUMMARY

The present invention is a preparation process for the development of raw materials, simple preparation process, low production cost, high
product purity obtained gabapentin.
The present invention provides the following technical solutions.
One kind of method for preparing gabapentin hydrochloride, which comprises the steps of: a) a 1,5-dicyano-2,4-dioxo-3-azaspiro [5,5] undecane
acid at 65 ~ 85 under conditions to generate 1,5-dioxo-2,4-diamine-formyl-3-aza-spiro [5,5] undecane; 2) step 1) to give 1,5-diamine formyl 2,4-dioxo-3-aza-spiro [5,5] undecane under alkaline conditions Hofmann rearrangement, acidification with hydrochloric acid was hydrochloric
gabapentin.
The preparation of gabapentin hydrochloride in step 1) of 1,5-dicyano-2,4-dioxo-3-aza-spiro [5,5] undecane with cyclohexanone and ethyl
cyanoacetate in ethanol and / or methanol, a solvent with ammonia and / or ammonia in the system. Preferred method of preparation is after 1
mol of cyclohexanone and 2 to 2.5 mol of ethyl cyanoacetate in ethanol and / or methanol solvent is reacted with 3-5 moles of ammonia reacted
at -5 ~ 5 condition 36 hours incubated at room temperature 36 hours, acidified with hydrochloric PH2 ~ 3, collected by filtration, 1,5-dicyano2,4-dioxo-3-azaspiro [5,5] undecane; or 1 mole of the cyclohexanone, 2 to 2.5 mol of ethyl cyanoacetate in ethanol and / or methanol solvent with
a reaction equivalent to 3-5 moles of ammonia in the ammonia, after the reaction at -5 ~ 10 24 hours and allowed to warm to 20 ~ 25 stirred
for 24 hours, then heated to 60 , water was added, adjusted with sulfuric acid pH2 ~ 3, cooling to 5 , collected by filtration, 1,5-dicyano-2,4dioxo-3-azaspiro [5,5] undecane.
Gabapentin hydrochloride prepared in the above process, step 1) at a temperature of 65 ~ 85 conditions, 1,5-dicyano-2,4-dioxo-3-azaspiro
[5,5] undecane batch was added a small amount of 80 to 90% sulfuric acid was added during 2.5 - 3.5 hours time required; 1,5-dicyano-2,4-dioxo3-aza-spiro [5,5] undecane and sulfuric acid liquid weight ratio is 1:3 to 5 parts; the 80 to 90% sulfuric acid solution of sulfuric acid and
water. Preferably at a temperature of 78 ~ 82 conditions, 1,5-dicyano-2,4-dioxo-3-azaspiro [5,5] undecane was added in small portions of 88%
sulfuric acid solution, when the mixture clarified; added process requires time three hours, 1,5-dicyano-2,4-dioxo-3-azaspiro [5,5] undecane and
the parts by weight ratio of sulfuric acid is 1:3.2 completion of the reaction; the reaction supernatant liquid was poured into ice water, collected by
filtration formyl-1,5-diamine, 2,4-dioxo-3-azaspiro [5,5] undecane, washed with water and dried.
The method of preparation of gabapentin hydrochloride in step 2), 1 mole of 1,5-dioxo-2,4-diamine-formyl-3-aza-spiro [5,5] undecane was
dissolved in 3 to 6 moles of 20 ~ 50% sodium hydroxide or potassium hydroxide solution, refluxed for 2.5 to 3.5 hours, the lye to stand for 24
hours at 25 ~ 30 , control the temperature at -5 ~ 5 condition, which was added to the solution of sodium hypochlorite thoroughly mixed,
35 to 45% was added sodium hydroxide or potassium hydroxide solution, mixed, warmed to 45 ~ 70 for 1 to 2 hours, acidified with
hydrochloric pHl 2, the resulting acidic solution was allowed to cool, collected by filtration, , dried to yield gabapentin hydrochloride. The method of
preparation of the gabapentin hydrochloride is preferably, 1 mol of 2,4-dioxo-1,5-diamine-formyl-3-aza-spiro [5,5] undecane was dissolved in 3 to
6 moles of 20 to 50% sodium hydroxide or potassium hydroxide solution, refluxed for 2.5 to 3.5 hours, at 70 ~ 80 with concentrated
hydrochloric acid adjusted to pH1 ~ 2, at 78 ~ 82 extracted with toluene, the toluene extract was washed with 15 ~ 25% sodium or potassium
hydroxide solution was basified with toluene lye after delamination to remove toluene (to remove impurities, purification of the product), placed in
the lye 25 ~ 30 24 hours, and the temperature controlled at -5 ~ 5 after remained, which was added to the sodium hypochlorite solution,
thoroughly mixed, and 35 to 45% sodium hydroxide or potassium hydroxide solution, mixed, warmed to 45 ~ 70 stirring for 1 to 2 hours,
acidified with hydrochloric ~ pHl 2, the resulting acidic solution was allowed to cool, the precipitate was collected by filtration and dried to yield
gabapentin hydrochloride. More preferred methods of preparation are 1 mole of the 1,5-dioxo-2,4-diamine-formyl-3-aza-spiro [5,5] undecane was
dissolved in 540 mol% potassium hydroxide solution and refluxed after 3 hours at 70 ~ 80 with concentrated hydrochloric acid and adjusted to
pH1 ~ 2, was refluxed for 1 hour, at 80 extracted with toluene, the toluene extract washed with 3mol 20% potassium hydroxide solution was
basified with toluene lye points after the layers, the toluene was removed lye left for 24 hours at 25 ~ 30 , at 0 temperature control
conditions, it is added to 1.2mol of 8% to 10% sodium hypochlorite solution, stirred for 30 minutes, was added 40 3mol after% potassium
hydroxide solution, stirred for 30 minutes, warmed to 45 ~ 50 stirring for 1 to 2 hours, acidified with hydrochloric pHl 2, the resulting acidic
solution was allowed to cool with toluene to remove impurities, precipitate was collected by filtration, dried and secondary butanol or isopropanol
recrystallized hydrochloric gabapentin.

The present invention further comprises a method for preparing the intermediate gabapentin hydrochloride, comprising the steps of: 1,5-dicyano2,4-dioxo-3-azaspiro [5,5] undecane in formyl-1,5-diamine, 2,4-dioxo-3-azaspiro [5,5] undecane 65 ~ 85 under acidic conditions. Preferably at
a temperature of 65 ~ 85 conditions, 1,5-dicyano-2,4-dioxo-3-azaspiro [5,5] undecane was added in small portions of 80 to 90% sulfuric acid
solution added process takes time 2.5 to 3.5 hours; 1,5-dicyano-2,4-dioxo-3-aza-spiro [5,5] undecane and sulfuric acid weight ratio of parts: 1: 3
to 5 parts; the 80 to 90% sulfuric acid solution of sulfuric acid and water. Preferred methods to prepare intermediate gabapentin hydrochloride is
at a temperature of 78 ~ 82 conditions, 1,5-dicyano-2,4-dioxo-3-azaspiro [5,5] undecane points was added in small batches of 88% sulfuric
acid solution was added process requires time 3 hours, the weight of 1,5-dicyano-2,4-dioxo-3-azaspiro [5,5] undecane and sulfuric acid solution
parts ratio: 1:3.2; when the reaction was complete the mixture was clarified; the reaction was poured into ice water and the supernatant liquid
collected by filtration formyl-1,5-diamine, 2,4-dioxo-3-azaspiro [5, 5] undecane, washed with water and dried.
The present invention uses 1,5-dicyano-2,4-dioxo-3-azaspiro [5,5] undecane as starting material, 2-formyl-1,5-diamine under conditions of acid
hydrolysis, 4- dioxo-3-azaspiro [5,5] undecane. Formyl-1,5-diamine, 2,4-dioxo-3-aza-spiro [5,5] undecane under alkaline conditions Hofmann
rearrangement, acidified with hydrochloric acid was hydrochloric gabapentin, its craft Directions are as follows:
(I): 1,5- dicyano-2,4-dioxo-3-azaspiro [5,5] undecane (II): 1,5- dioxo-2,4-diamine carboxylic acid 3-aza-spiro [5,5] undecane (III): the present
invention gabapentin hydrochloride gabapentin hydrochloride preparation materials used readily available (for example: the starting material
cyclohexanone, ethyl acetate cyanide, ammonia or ammonia ), simple preparation process can be reduced for purification of intermediates, lower
production costs, the higher the resulting product purity.
detailed description
Commercial reagents used material specifications: Industrial cyclohexanone; ethyl cyanoacetate industry; concentrated aqueous ammonia 25%
(Example at a concentration of 25% calculated, but is not limited thereto concentration); industrial methanol; sulfuric acid industry.
Example a-dicyano-2,4-dioxo-1,1,5- 3-azaspiro [5,5] undecane is prepared (see: GB898692 ExampleStepA) Cyclohexanone 98 g (1mol) , ethyl
cyanoacetate 226 g (2mol) and 980 g of 95% ethanol mixed in a reaction flask and stirred at 98 g ammonia gas to control the temperature in the
range of insulation stirred -5 ~ 0 12 hours, and then at 0 ~ incubated for 24 hours in the range of 5 , then stand at room temperature for 48
hours, with concentrated hydrochloric acid to adjust the pH = 2-3, stirring was continued for 30 minutes, filtered, washed with water and dried to
give 1,5-cyano-2, 4- dioxo-3-azaspiro [5,5] undecane. Yield: 85% Melting point: dioxo-3-azaspiro [5,5] undecane (II) in the preparation of 202 ~
210 2,1,5- formyl-2,4-diamine Weigh 231 g of 1,5-dicyano-2,4-dioxo-3-aza-spiro [5,5] undecane (I) in the range of about 80 (controlled
within a range of 78-82 ), portionwise was added to a small amount of 739.2 g (weight / weight ratio, the sulfuric acid solution (I), 3.2) in 88%
sulfuric acid solution, added to the whole process takes about 3 hours. Until the reaction mixture was clarified supernatant, approximately 1 hour

to complete the reaction. The supernatant was poured into the 10-fold amount (w / w) of ice-water, stirred for 30 minutes, precipitate was filtered,
the filter cake washed with water, and dried to give 1,5-formyl-2,4-diamine oxo-3-aza-spiro [5,5] undecane. Yield: 95% Melting point:> 300 .
3. Preparation of gabapentin hydrochloride (III) of the above product 1mol i.e. formyl-1,5-diamine, 2,4-dioxo-3-azaspiro [5,5] undecane was
dissolved in 243 g of 40 5mol % potassium hydroxide solution and, after refluxed for 3 hours, at 70 ~ 75 control with concentrated hydrochloric
acid to about pH = 1 ~ 2, heated at reflux for 1 hour, at about 80 degrees (low temperature will precipitate) with toluene extraction, the toluene
layer was 3mol 20% potassium hydroxide solution was basified, the toluene was removed, placed in a lye 25 ~ 30 24 hours. At 0 containing
1.2mol added dropwise 10% sodium hypochlorite solution, stirred for 30 minutes, was added 3mol of 40% potassium hydroxide solution, stirred
for 30 minutes, warmed to 45 ~ 50 stirred for 1 hour, neutralized with hydrochloric acid and to about pH = 1 ~ 2, toluene after extracting the
impurities allowed to cool, filtered, dried and recrystallized from butanol. Yield: 50% Melting point: 116 ~ 125 Second Embodiment 1,1,5-dicyano-2,4-dioxo-3-azaspiro [5,5] undecane A solution of 1mol cyclohexyl ketone 98 g, 2mol ethyl cyanoacetate 226 g and 392 g of 96%
methanol mixed in a reaction flask, 272 g of ammonia was added dropwise with stirring (equivalent 4mol ammonia). Aqueous ammonia was
added concrete steps are: first lowered to the range of -5 ~ 0 , dropped a predetermined amount of 3/4 of ammonia at -5 ~ 0 incubated for
12 hours, after which the temperature was raised to 5 ~ 10 incubated for 12 hours after the addition was complete the remaining 1/4 of the
ammonia. Warmed to 20 ~ 25 incubated for 24 hours. Heated to 60 , methanol was added an equal amount of water that is 980 grams of
water. Sulphuric acid was dropped pH2 ~ 3 and then cooled to below 5 , rejection filter cake was washed with water until PH = 6 ~ 7, drying,
into the drying room. Obtained 1,5-dicyano-2,4-dioxo-3-aza-spiro [5,5] undecane. Yield: 85% Melting point: dioxo-3-azaspiro [5,5] undecane (II) in
the preparation of 202 ~ 210 2,1,5- formyl-2,4-diamine at a temperature of 78 at ~ 82 conditions, 231 g of 1,5-dicyano-2,4-dioxo-3-azaspiro
[5,5] undecane was added in small portions of 88% sulfuric acid solution of 739.2 g added process takes time three hours, 1,5-dicyano-2,4-dioxo3-azaspiro [5,5] undecane and the parts by weight ratio of sulfuric acid is 1:3.2. Stirred for 1 hour mix till the completion of the reaction mixture
was clarified to give supernatant. The supernatant was poured into 10 times the amount (w / w) of ice-water, stirred for 30 minutes, precipitate
was filtered, the filter cake washed with water, and dried to give 2,4-dioxo-1,5-diamine carboxylic acid 3-azaspiro [5,5] undecane. Yield: 95%
Melting point:> 300 .
3. Preparation of gabapentin hydrochloride (III) of the above product 1mol i.e. formyl-1,5-diamine, 2,4-dioxo-3-azaspiro [5,5] undecane was
dissolved in 243 g of 40 5mol % potassium hydroxide solution and, after refluxed for 3 hours, at 75 ~ 80 control with concentrated hydrochloric
acid to about pH = 1 ~ 2, heated at reflux for 1 hour, at about 80 degrees (low temperature will precipitate) with toluene extraction, the toluene
layer was 3mol 20% potassium hydroxide solution was basified, the toluene was removed, placed in a lye 25 ~ 30 24 hours. At 0 added
dropwise containing 1.2mol of 8% sodium hypochlorite solution, stirred for 30 minutes, was added 3mol of 40% potassium hydroxide solution,
stirred for 30 minutes, warmed to 45 ~ 50 stirring for 1 to 2 hours, hydrochloric acid to about pH = 1 ~ 2, toluene after extracting the impurities
allowed to cool, filtered, dried and recrystallized from butanol. Yield: 45% Melting point: 116 ~ 125 Third Embodiment 1,1,5--dicyano-2,4-dioxo3-azaspiro [5,5] undecane A solution of 1 mole of ring cyclohexanone 98 g, 2 moles of cyanide in 226 g ethyl acetate solvent of methanol and
ammonia gas is equivalent to 3 moles of aqueous ammonia 204 g of the reaction, after the reaction at -5 ~ 0 24 hours and allowed to warm to
20 ~ 25 stirred for 24 hours , then heated to 60 , methanol and the like by weight of water was added, adjusted with sulfuric acid pH2 ~ 3,
cooling to 5 , collected by filtration, 1,5-dicyano-2,4-dioxo -3- N azaspiro [5,5] undecane.
2,1,5-formyl-2,4-diamine dioxo-3-aza-spiro [5,5] undecane (II) is prepared at a temperature of 65 ~ 70 conditions, 231 g 1, 5-cyano-2,4-dioxo3-aza-spiro [5,5] undecane was added in small portions 762 g of 80% sulfuric acid was added during 2.5 hours required; 1,5 dicyano-2,4-dioxo-3azaspiro [5,5] undecane and the weight ratio of sulfuric acid solution is: 1:3 parts; the 80% solution of sulfuric acid and 20% sulfuric acid of 80 %
water. When the reaction was complete the mixture was clarified; supernatant liquid was poured into the reaction 10-fold amount (w / w) of icewater, stirred for 30 minutes, collected by filtration, 1,5-dioxo-2,4-diamine formyl -3- azaspiro [5,5] undecane, washed with water and
dried. Formyl-1,5-diamine obtained 2,4-dioxo-3-azaspiro [5,5] undecane. Yield: 90% Melting point:> 300 3, the preparation of gabapentin
hydrochloride (III), 1 mole of 1,5-dioxo-2,4-diamine-formyl-3-aza-spiro [5,5] undecane 243 grams was dissolved in 320 mole% sodium hydroxide
solution, and refluxed for 2.5 hours, at 70 ~ 75 with concentrated hydrochloric acid adjusted to pH1 ~ 2, was refluxed for 1 hour, at 78 ~ 82
extracted with toluene, the toluene the extract was washed 3mol 25% sodium hydroxide solution was made alkaline lye layered with toluene, the
toluene was removed, the lye left for 24 hours at 25 ~ 30 , control the temperature at -5 ~ 0 condition, which after 1.2mol 8% sodium
hypochlorite solution was added and stirred for 30 minutes, was added 3mol 45% sodium hydroxide solution, stirred for 30 minutes, warmed to 45
~ 50 stirring for 1 to 2 hours, acidified with hydrochloric pHl 2, the resulting acidic solution let cool, collected by filtration, dried to yield
gabapentin hydrochloride.
Fourth Embodiment 1,1,5--dicyano-2,4-dioxo-3-azaspiro [5,5] undecane A solution of 1 mole of cyclohexanone 98 g, 2.5 mole ethyl acetate
cyanide 282.5 g in ethanol and ammonia gas is equivalent to 5 moles of ammonia water 340 g of the reaction, after the reaction at 5 ~ 10 24
hours, and heated with stirring to 25 24 hours, and then heated to 60 , ethanol and the like by weight of water was added , adjusted with
sulfuric acid pH2 ~ 3, cooling to 5 , collected by filtration, 1,5-dicyano-2,4-dioxo-3-azaspiro [5,5] undecane.
2,1,5-formyl-2,4-diamine dioxo-3-aza-spiro [5,5] undecane (II) is prepared at a temperature of 80 ~ 85 conditions, 231 g 1, 5-cyano-2,4-dioxo3-aza-spiro [5,5] undecane was added in small portions 1129 g 90% sulfuric acid was added during 3.5 hours required time; 1,5 dicyano-2,4dioxo-3-azaspiro [5,5] undecane and sulfuric acid weight ratio of parts: parts 1:5; the 90% sulfuric acid solution by a 90% sulfuric acid and 10 %
water. When the reaction was complete the mixture was clarified; supernatant liquid was poured into the reaction 10-fold amount (w / w) of icewater, stirred for 30 minutes, collected by filtration, 1,5-dioxo-2,4-diamine formyl -3- azaspiro [5,5] undecane, washed with water and
dried. Formyl-1,5-diamine obtained 2,4-dioxo-3-azaspiro [5,5] undecane. Yield: 92% Melting point:> 300 3, the preparation of gabapentin
hydrochloride (III), 1 mole of 1,5-dioxo-2,4-diamine-formyl-3-aza-spiro [5,5] undecane 243 g of 50% potassium hydroxide was dissolved in a
solution of 6 moles refluxed for 3.5 hours, at 75 ~ 80 with concentrated hydrochloric acid adjusted to pH1 ~ 2, at 80 extracted with toluene,

the toluene extract washed with 3mol 15% potassium hydroxide solution was basified with toluene lye after delamination, the toluene was
removed lye left for 24 hours at 25 ~ 30 , temperature control at 0 ~ 5 condition, it is added to 1.2mol 10% sodium hypochlorite the
solution was stirred for 30 minutes, was added 3mol 35% potassium hydroxide solution, stirred for 30 minutes, warmed to 65 ~ 70 after stirring
for 1 to 2 hours, acidified with hydrochloric pHl 2, the resulting acidic solution was allowed to cool, the precipitate was collected by filtration and
dried to yield gabapentin hydrochloride.

Claims (10)
translated from Chinese
CLAIMS 1. A method for the preparation of gabapentin hydrochloride, comprising the steps of: a) 1,5-dicyano-2,4-dioxo-3-aza-spiro [5,5]
undecane in 65 ~ 85 generates strongly acidic conditions at formyl-1,5-diamine, 2,4-dioxo-3-azaspiro [5,5] undecane; 2) step 1) to give 1,5carbamoyl-2,4-dioxo-3-aza-spiro [5,5] undecane under alkaline conditions Hofmann rearrangement, acidification with hydrochloric acid was
hydrochloric gabapentin.
Preparing a gabapentin hydrochloride 2. The method as claimed in claim wherein the step a) 1,5-dicyano-2,4-dioxo-3-aza-spiro [5,5] undecane is
cyclohexyl ethyl ketone and cyanide in ethanol and / or methanol solvent with ammonia and / or ammonia reaction.
2 Gabapentin hydrochloride 3. The preparation process as claimed in claim characterized in that 1 mol of cyclohexanone and 2-2.5 mol of ethyl
cyanoacetate in ethanol and / or methanol, a solvent and 3-5 moles of ammonia at -5 ~ after the reaction 36 hours at 5 , at room temperature,
with hydrochloric PH2 ~ 3, collected by filtration, 1,5-dicyano-2,4-dioxo-3-azaspiro [5,5] undecane alkyl; or, one mole of cyclohexanone, 2 to 2.5
mol of ethyl cyanoacetate in ethanol and / or methanol solvent, the reaction of ammonia with 3-5 equivalent moles of ammonia react at -5 ~ 10
24 hours , stirring was warmed to 20 ~ 25 24 hours, and then heated to 60 , water was added, adjusted with sulfuric acid pH2 ~ 3, cooling to
5 , collected by filtration, 1,5-dicyano-2,4- oxo-3-aza-spiro [5,5] undecane.
Claim a method for the preparation of gabapentin hydrochloride, wherein Step a) at a temperature of 65 ~ 85 conditions, 1,5-dicyano-2,4dioxo-3-azaspiro [5, 5] undecane was added in small portions of 80 to 90% sulfuric acid was added during 2.5 - 3.5 hours time required; 1,5dicyano-2,4-dioxo-3-azaspiro [5, 5] undecane and sulfuric acid weight ratio is 1:3 parts to 5 parts; the 80 to 90% sulfuric acid solution of sulfuric
acid and water.
4 Preparation of gabapentin hydrochloride claim, characterized in that, at a temperature of 70-80 conditions, 1,5-dicyano-2,4-dioxo-3-aza-spiro
[5,5] dec an alkoxy was added in small portions of 88% sulfuric acid was added process requires time 3 hours, 1,5-dicyano-2,4-dioxo-3-azaspiro
[5,5] undecane and sulfuric acid parts weight liquid ratio 1:3.2; when the reaction was complete the mixture was clarified; the reaction was poured
into ice water and the supernatant liquid collected by filtration formyl-1,5-diamine, 2,4-dioxo-3-azaspiro [ 5,5] undecane, washed with water and
dried.
Preparing a gabapentin hydrochloride The method of claim, wherein step 2), the 1 mole of 1,5-dioxo-2,4-diamine-formyl-3-aza-spiro [5,5]
undecane It was dissolved in 3-6 mol of 20-50% sodium hydroxide or potassium hydroxide solution, refluxed for 2.5 to 3.5 hours, and then placed
in a lye 25 ~ 30 24 hours at controlled temperature conditions -5 ~ 5 next, it is added to sodium hypochlorite solution, thoroughly mixed,
and 35 to 45% sodium hydroxide or potassium hydroxide solution, mixed, warmed to 45 ~ 70 stirring for 1 to 2 hours, acidified with
hydrochloric pHl 1-2, The resulting acidic solution was allowed to cool, the precipitate was collected by filtration and dried to yield gabapentin
hydrochloride.
Claim 6 The method of preparation of gabapentin hydrochloride, comprising reacting 1 mole of 2,4-dioxo-1,5-diamine-formyl-3-aza-spiro [5,5]
undecane was dissolved in 3 to 6 20 to 50% by mole of sodium or potassium hydroxide solution and refluxed for 2.5 to 3.5 hours, at 70 ~ 80 ~
2, at 78 ~ 82 extracted with toluene pHl with concentrated hydrochloric acid and adjusted, the toluene extracts were 15 to 25% with sodium
hydroxide or potassium hydroxide solution was basified with toluene lye after delamination to remove toluene, and then left for 24 hours at lye 25
~ 30 , controlling the temperature at -5 ~ 5 conditions next, it is added to sodium hypochlorite solution, thoroughly mixed, and 35 to 45%
sodium hydroxide or potassium hydroxide solution, mixed, warmed to 45 ~ 70 stirring for 1 to 2 hours, acidified with hydrochloric pHl 1-2, The
resulting acidic solution was allowed to cool, the precipitate was collected by filtration and dried to yield gabapentin hydrochloride.
7 Preparation of gabapentin hydrochloride claim, wherein 1 mole of the 1,5-dioxo-2,4-diamine-formyl-3-aza-spiro [5,5] undecane was dissolved in
5 mol of 40% potassium hydroxide solution, refluxed for 3 hours and at 80 deg.] C with concentrated hydrochloric acid and adjusted to pH1 ~ 2,
was refluxed for 1 hour, at 80 extracted with toluene, the toluene extracts were washed with 20% potassium hydroxide base solution 3mol of
lye layered with toluene, the toluene was removed, the lye left for 24 hours at 25 ~ 30 , at 0 temperature control conditions, added to 1.2mol
of 8% to 10% sodium hypochlorite solution, and stirred after 30 minutes, 3mol added 40% potassium hydroxide solution, stirred for 30 minutes,
warmed to 45 ~ 50 stirring for 1 to 2 hours, acidified with hydrochloric pHl 2, the resulting acidic solution with toluene to remove impurities
allowed to cool, collected by filtration The precipitate was dried and recrystallized from isopropanol or butanol yield gabapentin hydrochloride.
9. A method for the preparation of gabapentin hydrochloride intermediate, comprising the steps of: at a temperature of 65 ~ 85 conditions, 1,5dicyano-2,4-dioxo-3-azaspiro [5,5] undecane was added in small portions of 80 to 90% sulfuric acid was added during 2.5 - 3.5 hours time
required; 1,5-dicyano-2,4-dioxo-3-azaspiro [5,5] undecane and sulfuric acid weight ratio of parts: 5 parts 1:3 ~; 80 ~ 90% of the sulfuric acid
solution of sulfuric acid and water.
9 Preparation of the intermediate gabapentin hydrochloride claim, characterized in that, at a temperature of 70 ~ 80 conditions, 1,5-dicyano2,4-dioxo-3-azaspiro [5, 5] undecane was added in small portions of 88% sulfuric acid was added process requires time 3 hours, 1,5-dicyano-2,4dioxo-3-azaspiro [5,5] undecane alkyl sulfuric acid with a weight ratio of parts: 1:3.2; when the reaction was complete the mixture was clarified;
the reaction was poured into ice water and the supernatant liquid collected by filtration formyl-1,5-diamine, 2,4-dioxo -3- azaspiro [5,5] undecane,
washed with water and dried.

Cited By (3)Search Within Citing Patents

Publication numberPriority datePublication dateAssigneeTitle

CN102690207A *2012-05-312012-09-26 Gabapentin synthesizing method

CN104151180A *2014-08-282014-11-19 Preparation method of gabapentin hydrochloride
CN104230735A *2014-08-282014-12-24 Preparation method of gabapentin
* Cited by examiner, Cited by third party

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EP1939170A12008-07-02Application
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WO2007019752A12007-02-22Application
CN101296896A2008-10-29Application
US7667071B22010-02-23Grant

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