Process for the preparation of gabapentin
Inventors
Divi, Satchandra Kiran • Rao, Mysore AswathaNarayana • NUTHI, Surendra Kalyan
Assignees
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Publication Number
US-10399926-B1
Publication Date
2019-09-03
Expiration Date
Abstract
The present invention relates to an improved process for the preparation of Gabapentin. The process also relates to a new process for the preparation of 1, 1-cyclohexane diaceitic acid monoamide (CDMA), which is a key intermediate for the preparation of Gabapentin.
Core Innovation
The document addresses problems in an improved gabapentin manufacturing route in which gabapentin is produced via a Hofmann reaction from 1,1-cyclohexane diacetic acid monoamide (CDMA, IV), an intermediate that had previously been obtained from cyclohexane diacetic acid (CDA) and its anhydride under highly concentrated sulfuric acid. During decarboxylation and neutralization, problematic CO2 foaming is discussed as a key practical problem in the prior route.
The document proposes starting from a different precursor: a diimide VI derived from dinitrile V, followed by alkaline decarboxylation and hydrolysis to yield CDMA (IV) directly. In this approach, isolation of CDA and the anhydride intermediate is avoided, while still enabling conversion to gabapentin through a Hofmann reaction.
In the claimed process, spiro[cyclohexane-1,9′-(3,7-diazabicyclo-[3.3.1]nonane)]-2′,4′,6′,8′-tetraone (VI) is reacted with an alkali to obtain CDMA (IV). The resulting compound IV is then converted to gabapentin by Hofmann reaction using alkali hypo halite, and the described route is positioned as reducing foaming by relocating CO2 liberation primarily to room-temperature neutralization while also eliminating organic solvents and bypassing CDA (II) and intermediate III.
Claims Coverage
The document provides one independent claim covering a two-stage gabapentin preparation (formation of CDMA from a specified spiro-tetraone followed by Hofmann conversion). Dependent claims further specify the alkali identity, alkali concentration, reaction timing and reflux conditions for the CDMA-forming stage, and the preparation of the tetraone precursor using sulfuric acid strength and temperature range.
Spiro-tetraone to CDMA via alkali decarboxylation/hydrolysis
Reacting spiro[cyclohexane-1,9′-(3,7-diazabicyclo-[3.3.1]nonane)]-2′,4′,6′,8′-tetraone of the formula VI with an alkali to obtain 1,1-cyclohexane diacetic acid monoamide of the formula IV.
Hofmann conversion of CDMA using alkali hypo halite
Converting the compound IV obtained to gabapentin I by Hofmann reaction using alkali hypo halite.
Selectable alkali for the CDMA-forming step
Carrying out the step-a reaction using an alkali chosen from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide, or potassium tert-butoxide.
Alkali concentration range for step-a
Using an alkali concentration within the range of 5% to 50% (w/v) at step-a.
Reflux temperature and time window for step-a
Carrying out the reaction at reflux temperature for 6 to 24 hours at step-a.
Narrow time subset at step-a
Performing the reaction at step-a for a time period of 15 to 20 hours.
Preparation of the tetraone precursor from dinitrile V using 50% to 70% sulfuric acid
Preparing the compound of formula VI by reacting 2,4-dioxo-3-aza-spiro[5.5]undecane-1,5-dicarbonitrile (formula V) with a 50% to 70% sulfuric acid solution at 90°C to 110°C.
Overall, the claim set focuses on using a specified spiro-tetraone (VI) to generate CDMA (IV) through reaction with an alkali, followed by Hofmann reaction of CDMA to form gabapentin using alkali hypo halite. Dependent claims narrow the process by specifying alkali selection, alkali concentration, reflux and time conditions for the CDMA-forming stage, and conditions for preparing the tetraone precursor (VI) from dinitrile V using 50% to 70% sulfuric acid at 90°C to 110°C.
Stated Advantages
Reduces CO2 foaming by making CO2 liberated mainly during room-temperature neutralization.
Eliminates organic solvents.
Improves economy by bypassing CDA and intermediate III.
Enables about 80% yield and more than 99% purity for CDMA under alkali reflux conditions.
Documented Applications
Manufacturing gabapentin using a route in which gabapentin is obtained via a Hofmann reaction from CDMA formed by alkaline decarboxylation and hydrolysis of a spiro-tetraone precursor.
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