IE20060358A1 - A process for preparing gabapentin - Google Patents
A process for preparing gabapentinInfo
- Publication number
- IE20060358A1 IE20060358A1 IE20060358A IE20060358A IE20060358A1 IE 20060358 A1 IE20060358 A1 IE 20060358A1 IE 20060358 A IE20060358 A IE 20060358A IE 20060358 A IE20060358 A IE 20060358A IE 20060358 A1 IE20060358 A1 IE 20060358A1
- Authority
- IE
- Ireland
- Prior art keywords
- acid
- aminomethyl
- cyclohexaneacetic
- gabapentin
- cyclohexaneacetic acid
- Prior art date
Links
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 229960002870 gabapentin Drugs 0.000 title claims description 23
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- YGFXLCAKCKPSQQ-UHFFFAOYSA-N 2-(1-cyanocyclohexyl)acetic acid Chemical compound OC(=O)CC1(C#N)CCCCC1 YGFXLCAKCKPSQQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000005580 one pot reaction Methods 0.000 claims abstract description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000011065 in-situ storage Methods 0.000 claims abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 49
- 230000008569 process Effects 0.000 claims description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 40
- CGWVBPMMLKULCR-UHFFFAOYSA-N acetic acid;cyclohexylmethanamine Chemical compound CC(O)=O.NCC1CCCCC1 CGWVBPMMLKULCR-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 14
- MRYZGCDTKUSBFA-UHFFFAOYSA-N ethyl 2-(1-cyanocyclohexyl)acetate Chemical compound CCOC(=O)CC1(C#N)CCCCC1 MRYZGCDTKUSBFA-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 10
- 238000005984 hydrogenation reaction Methods 0.000 claims description 9
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 210000003169 central nervous system Anatomy 0.000 claims description 6
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 229910052759 nickel Inorganic materials 0.000 claims description 5
- 206010015037 epilepsy Diseases 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 208000018152 Cerebral disease Diseases 0.000 claims description 2
- 208000012661 Dyskinesia Diseases 0.000 claims description 2
- 208000023105 Huntington disease Diseases 0.000 claims description 2
- 208000006083 Hypokinesia Diseases 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 208000012902 Nervous system disease Diseases 0.000 claims description 2
- 208000025966 Neurological disease Diseases 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 230000001773 anti-convulsant effect Effects 0.000 claims description 2
- 230000001663 anti-spastic effect Effects 0.000 claims description 2
- 239000001961 anticonvulsive agent Substances 0.000 claims description 2
- 229960003965 antiepileptics Drugs 0.000 claims description 2
- 230000008499 blood brain barrier function Effects 0.000 claims description 2
- 210000001218 blood-brain barrier Anatomy 0.000 claims description 2
- 230000002490 cerebral effect Effects 0.000 claims description 2
- 208000002173 dizziness Diseases 0.000 claims description 2
- 230000004064 dysfunction Effects 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 230000003483 hypokinetic effect Effects 0.000 claims description 2
- 230000006872 improvement Effects 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 208000014674 injury Diseases 0.000 claims description 2
- 231100000053 low toxicity Toxicity 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 208000020016 psychiatric disease Diseases 0.000 claims description 2
- 201000000980 schizophrenia Diseases 0.000 claims description 2
- 230000005062 synaptic transmission Effects 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 231100000027 toxicology Toxicity 0.000 claims description 2
- 230000008733 trauma Effects 0.000 claims description 2
- MESNBSCCFMELNF-UHFFFAOYSA-N 2-[3-(aminomethyl)cyclohexyl]acetic acid Chemical compound NCC1CCCC(CC(O)=O)C1 MESNBSCCFMELNF-UHFFFAOYSA-N 0.000 claims 1
- -1 cyclic amino acids Chemical class 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 abstract 1
- 229910052700 potassium Inorganic materials 0.000 abstract 1
- 239000011591 potassium Substances 0.000 abstract 1
- 229910052708 sodium Inorganic materials 0.000 abstract 1
- 239000011734 sodium Substances 0.000 abstract 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- AIPKMNGCAXYDJB-UHFFFAOYSA-M potassium;2-(1-cyanocyclohexyl)acetate Chemical compound [K+].[O-]C(=O)CC1(C#N)CCCCC1 AIPKMNGCAXYDJB-UHFFFAOYSA-M 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 229910000564 Raney nickel Inorganic materials 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- LJOODBDWMQKMFB-UHFFFAOYSA-N cyclohexylacetic acid Chemical compound OC(=O)CC1CCCCC1 LJOODBDWMQKMFB-UHFFFAOYSA-N 0.000 description 4
- 238000005292 vacuum distillation Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 description 2
- CYMZDPHCBAWUHZ-UHFFFAOYSA-N 1-(cyanomethyl)cyclohexane-1-carbonitrile Chemical compound N#CCC1(C#N)CCCCC1 CYMZDPHCBAWUHZ-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A one pot process for preparing 1-(aminomethyl)-cyclohexaneacetic acid or pharmaceutically acceptable salts thereof comprises the steps of hydrolysing 1-cyanocyclohexaneacetic acid ethl ester with a potassium, sodium or lithijm hydroxide to form a salt of 1-cyanocyclohexaneacetic acid; in-situ hydrogenating the salt of 1-cyanocyclohexaneacetic acid in the presence of catalyst to form the salt of 1-(aminomethly)-cyclohexaneacetic acid; isolating 1-(aminomethyl)- cyclohexaneacetic acid.
Description
wherein Ri is a hydrogen atom or a lower alkyl iadical,-and n is 4, 5 or 6 and the pharmacologically compatible salts thereof.
The compounds disclosed in the above United States patents are useful for the therapy of certain cerebral diseases, for example, they can be used for the treatment of certain forms of epilepsy, faintness attacks, hypokinesia, and cranial traumas. Additionally, they bring about an improvement of cerebral functions, and thus are useful in treating geriatric patients. Particularly valuable is 1(aminomethyl)-cyclohexaneacetic acid (gabapentin).
Gamma-aminobutyric acid (GABA) is an inhibitory amino acid found in the mammalian central nervous system (CNS). It has been reported that dysfunction with GABA neurotransmission in the CNS may contribute or even cause psychiatric and neurological diseases such as epilepsy, schizophrenia, Parkinson’s disease, Huntington’s Chorea, and dyskinesia (Saletu B., et al,.
International Journal of Clinical Pharmacology, Therapy and Toxicology.
1986;24:362-373). Gabapentin was designed as a GABA analog that would cross the blood-brain barrier. Gabapentin was found to have anticonvulsant and antispastic activity with extremely low toxicity in man.
United States Patent Numbers 5,132,451, 5,319,135, 5,362,833, 5,091,567, 5,068,413, 4,956,473, 4,958,044, 5,130,455, 5,095,148, 5,136,091, 5,149,870 and
IE Ο ϋ Ο 3 68
,693,845 disclose additional processes and intermediates for preparing gabapentin. These processes require a number of steps and in some cases utilise large uneconomic quantities of reagents and hazardous solvents.
There is a need for an improved process for preparing gabapentin more efficiently on a large scale.
Statements of Invention
According to the invention there is provided a one pot process for preparing 1(aminomethyl)-cyclohexaneacetic acid or pharmaceutically acceptable salts thereof comprising the steps ofthydrolysing 1-cyanocyclohexaneacetic acid ethyl ester with a potassium, sodium or lithium hydroxide to form a salt of 1-cyanocyclohexaneacetic acid;
in-situ hydrogenating the salt of 1-cyanocyclohexaneacetic acid in the presence of a catalyst to form the salt of l-(aminomethyl)20 cyclohexaneacetic acid; and isolating l-(aminomethyl)-cyclohexaneacetic acid.
In one embodiment of the invention the process is carried out in an aqueous environment.
In one embodiment of the invention after hydrolysis the solution is washed with a water immiscible solvent. Preferably the water immiscible solvent is toluene or MTBE
In one embodiment of the invention hydrolysis is carried out at a temperature of about 80°C for approximately 3 hours.
If Ο 6 ϋ 3 5 β
Hydrolysis may be carried out at room temperature.
In one embodiment of the invention hydrogenation is carried out at approximately 30°C for up to 20 hours. Preferably hydrogenation is carried out for approximately 14 hours.
In one embodiment of the invention the catalyst is Raney nickel.
In another embodiment of the invention the solution is filtered to remove the 10 catalyst.
In another embodiment of the invention the filtered catalyst is re-used.
In one embodiment of the invention the product is isolated by.15 adding a weak acid; and isolating l-(aminomethyl)-cyclohexaneacetic acid.
Preferably the weak acid is acetic acid.
In one embodiment of the invention after addition of the acid, the solution is seeded with gabapentin.
o
Preferably the process includes the step of stirring the product at 0 at 10C for approximately 4 hours.
In one embodiment of the invention the isolated l-(aminomethyl)cyclohexaneacetic acid is washed with an alcohol. Preferably the alcohol is isopropyl alcohol (IPA).
In one embodiment of the invention the the l-(aminomethyl)-cyclohexaneacetic acid is recrystallised.
IE Ο fi 0 3 5 β ln one embodiment of the invention the 1 -(aminomethyl)-cyclohexaneacetic acid is dissolved in methanol and water.
In another embodiment of the invention the l-(aminomethyl)-cyclohexaneacetic acid is dissolved in methanol and water, isopropyl alcohol is added and the solution distilled under vacuum.
In a further embodiment of the invention the product is washed with isopropyl alcohol and dried under vacuum.
The invention also provides the compound l-(aminomethyl)-cyclohexaneacetic acid potassium salt.
The invention further provides l-(aminomethyl)-cyclohexaneacetic acid containing less than 0.01% by weight of potassium acetate.
Detailed description
We have developed an improved process for the preparation of gabapentin. The process comprises a one pot reaction involving fewer unit operations than previous preparation methods. The reaction takes place in water resulting in an environmentally friendly process with a high product yield. The process is illustrated in scheme 1 below
Scheme 1 *E Ο 6 Ο 3 5 8
The process of the invention has a number of advantages over known processes for preparing gabapentin as follows:The isolation of the intermediate cyano acid (1-cyanocyclohexaneacetic acid) is not required. This offers major advantages over existing routes as this material is labile and requires refrigerated storage. The hydrogenation step is conducted in a purely aqueous medium with concomitant reduction in costs of solvents and environmental burden. In addition the Raney Nickel catalyst may be removed at the end of the process and directly reused in a subsequent process.
The process doubles the throughput in comparison to current known processes for preparing gabapentin.
The 1-cyanocyclohexaneacetic acid ethyl ester is heated to high temperatures (about 80°C) with potassium hydroxide during the hydrolysis step (approximately 3 hours). This has been found to result in very reproducible hydrogenations and provides a very efficient process overall. Reproducibility is a very important factor when preparing gabapentin on a large plant scale. The process may however also be carried out at room temperature.
Because the cyano acid potassium salt is hydrogenated (in comparison to the free cyano acid as used in other processes), at least 50% less Raney Nickel is used in comparison to other processes for preparing gabapentin. In some instances approximately 60% less Raney Nickel may be used in comparison to other processes. This results in a safer process which is more environmentally friendly.
A major problem encountered in current processes for preparing gabapentin is the generation of impurities in the form of secondary amines. Typically ammonia is added to suppress these impurities. The use of the potassium salt as in the process of the invention appears to inhibit the formation of secondary amine impurities and therefore no ammonia is required to be added to suppress such impurities; a significant environmental advantage.
^ 060358
The absence of ammonia also appears to prevent the leaching of nickel by complexation with ammonia. As a result there is no longer a requirement for ion exchange resins post hydrogenation to remove solubilised nickel resulting in a significantly streamlined batch process.
The process of the invention provides an improved process for the production of Gabapentin which is substantially free of chloride ions. Chloride ions affect the stability of gabapentin drug substance, increasing the propensity towards lactam formation.
Overall the process of the invention is a more environmentally friendly process as all reactions take place in water. Reaction concentrations are high, thus maximising energy consumption and minimising waste processing. Only one hydrocarbon (toluene) is used in impurity extraction. The toluene used is fully recyclable.
The invention will be more clearly understood by the following examples.
Example 1 - Preparation of l-(aminomethyl)-cyclohexaneacetic acid
1-cyanocyclohexaneacetic acid ethyl ester (1) is prepared as described in LJS5693845, the entire contents of which are herein incorporated by reference Preparation of Ethyl 1-cvanocyclohexaneacetate (1) (or 1cyanocyclohexaneacetic acid ethyl ester)
A 1-L pressure flask is charged with 148 g (1 mol) of 1cyanocyclohexaneacetonitrile, 206 mL of ethanol, and 100 mL of toluene. The mixture is cooled to 5°C and evacuated. Anhydrous hydrogen chloride (148 g, 4.05 mol) is added to the evacuated flask, causing the pressure to rise to 10 pounds per square inch gauge (psig) while allowing the temperature to rise to 35°C. This temperature is maintained for 7 hours, during which time additional hydrogen chloride (25 g. 0.68 mol) is added to maintain a pressure of 5 pounds per square inch gauge (psig.). At the end of the 7-hour period, the excess
IE Ο 6 Ο 3 5 8 hydrogen chloride and ethanol are removed by vacuum distillation, maintaining the mixture at below 25°C. To the resulting slurry is added 200 mL of toluene, which is then removed by vacuum distillation. This procedure is repeated two more times with 150 mL of toluene. After the final distillation, 150 mL of toluene and 500 mL of ice water are added and the pH adjusted to four with aqueous sodium hydroxide solution. After stirring for 18 hours, the mixture is filtered, the filtrate layers separated, the aqueous layer washed with 100 mL of toluene, and then the combined toluene layers washed with 100 Ml of IN aqueous sodium hydroxide solution, followed by two water washes of 50 mL each. The toluene solution is then dried by azeotropic distillation, which is followed by vacuum distillation to remove the toluene. The residual yellow oil (166 g) is 91% ethyl 1-cyanocyclohexaneacetate. Further purification can be effected by vacuum distillation, collecting distillate with by 85°C to 95°C at 0.2 to 0.3 mm of Hg.
Preparation of l-(aminomethyl)-cyclohexaneacetic acid
1-cyanocyclohexaneacetic acid ethyl ester (1) is mixed with 34% w/w KOH (1.05 kg/kg 1) over lh. On complete addition the batch is heated to about 80°C and stirred for 3h. The solution is cooled to 20-25°C then washed with toluene (0.70 kg/kg 1). After separating the layers, the product rich aqueous stream comprising 1-cyanocyclohexaneacetic acid potassium salt (2) is forward processed to the hydrogenation reaction.
1-Cyanocyclohexaneacetic acid potassium salt (2) is hydrogenated over sponge
Nickel catalyst (12% active Nickel loading vs. 1) at 3.5 barg and 30°C for 14-16 hrs. The batch is cooled to ambient temperature and filtered to remove catalyst. The catalyst bed is washed with water (0.4kg/kg. 1) and the solution stored at 05°C. The catalyst bed is then washed with potassium hydroxide solution in preparation for re-use. This wash is disposed and the Raney Nickel stored under caustic solution.
The solution of l-(aminomethyl)cyclohexaneacetic acid potassium salt (3) (pH 13-14) is heated to about 40°C before pH adjustment to 7.1 (isoelectric point) by
If ο 6 Ο 3 5 8 addition of 80% acetic acid - (ca. 0.53kg/kg vs. 1). The 80% acetic acid is added at such a rate to maintain the temperature <55°C. The batch is cooled to 40°C and seeded by addition of gabapentin to the batch. The batch is then cooled to 0°C and stirred for a minimum of 4h. The batch is isolated, and washed with isopropyl alcohol (IPA) (1.56kg/kg 1). The IPA wet, l-(aminomethyl)cyclohexaneacetic acid (4) may be recrystallised using either of the crystallisation steps described in examples 2 or 3. Yield = 68-73% from active 1cyanocyclohexaneacetic ethyl ester.
Example 2 - Recrystallisation l-(aminomethyl)-cyclohexaneacetic acid (4) l-(Aminomethyl)-cyclohexaneacetic acid (4) as prepared in Example 1 is dissolved (ca. 65-67°C) in methanol (2.5 vol) and water (ca. 0.6 vol). Water is added in small portions until solution is achieved. Preheated IPA (5.0 vol) is added to the solution and the batch cooled to 0°C for isolation. The batch is washed with IPA (1.0 vol) and dried under vacuo at 50°C. Recovery: 88 to 92%.
Example 3 - Recrystallisation of l-(aminomethvl)-cyclohexaneacetic acid (4) l-(Aminomethyl)-cyclohexaneacetic acid (4) as prepared in Example 1 is dissolved (ca. 65-67°C) in methanol (2.5 vol) and water (ca. 0.6 vol). The solution is added to preheated IPA (5.0 vol). The solution is then distilled to remove up to 70% of the batch volume. The batch is cooled to 0°C for isolation. The batch is washed with IPA (l.Ovol) and dried under vacuo at 50°C. Recovery: 88 to 95%.
Example 4 - Preparation of l-(aminomethyl)-cyclohexaneacetic acid (41 using recovered Nickel catalyst
1-cyanocyclohexaneacetic acid ethyl ester (1) is mixed with 34% w/w KOH (1.05 kg/kg 1) over lh. On complete addition the batch is heated to about 80°C and stirred for 3h. The solution is cooled to 20-25°C then washed with toluene (0.70 kg/kg 1). After separating the layers the product rich aqueous stream comprising 1-cyanocyclohexaneacetic acid potassium salt (2) is forward processed to the hydrogenation reaction.
IE Ο 6 Ο 3 5 β
I -Cyanocyclohexaneacetic acid potassium salt (2) is hydrogenated over the recovered sponge Nickel catalyst from Example 1 (12% active Nickel loading vs.
1) at 3.5 barg and 30°C for 14-16 hrs. The batch is cooled to ambient temperature and filtered to remove catalyst. The catalyst bed is washed with water (0.4kg/kg
1) and the solution stored at 0-5°C.
The solution of l-(aminomethyl)cyclohexaneacetic acid potassium salt (3) (pH 13-14) is heated to about 40°C before pH adjustment to 7.1 (isoelectric point) by addition of 80% acetic acid - (ca. 0.53kg/kg vs. 1). The 80% acetic acid is added at such a rate to maintain the temperature <55°C. The batch is cooled to 40°C and seeded by addition of gabapentin to the batch. The batch is then cooled to 0°C and stirred for a minimum of 4h. The batch is isolated, and washed with isopropyl alcohol (IPA) (1.56kg/kg 1). The IPA wet, l-(aminomethyl)15 cyclohexaneacetic acid (4) can be recrystallised using either of the crystallisation steps described in examples 2 or 3. Yield = 68-73% from active 1cyanocyclohexaneacetic ethyl ester.
The invention is not limited to the embodiments hereinbefore described which may be varied in detail.
Claims (20)
1. A one pot process for preparing 1 -(aminomethyl)-cyclohexaneacetic acid or pharmaceutically acceptable salts thereof comprising the steps of:5 hydrolysing 1-cyanocyclohexaneacetic acid ethyl ester with a potassium, sodium or lithium hydroxide to form a salt of 1cyanocyclohexaneacetic acid;
2. A process as claimed in claim 1 wherein the process is carried out in an aqueous environment.
3. A process as claimed in claim 1 or 2 wherein after hydrolysis the solution 20 is washed with a water immiscible solvent.
4. A process as claimed in claim 3 wherein the water immiscible solvent is toluene or MTBE. 25 5. A process as claimed in any of claims 1 to 4 wherein hydrolysis is carried out at a temperature of about 80°C for approximately 3 hours.
5. Nickel.
6. A process as claimed in any of claims 1 to 4 wherein hydrolysis is carried out at room temperature. t
7. A process as claimed in any of claims 1 to 6 wherein hydrogenation is carried out at approximately 30°C for up to 20 hours. 60358
8. A process as claimed in claim 7 wherein hydrogenation is carried out for approximately 14 hours.
9. A process as claimed in any of claims 1 to 8 wherein the catalyst is Raney
10. A process as claimed in any of claims 1 to 9 wherein the solution is filtered to remove the catalyst. 10 in-situ hydrogenating the salt of 1-cyanocyclohexaneacetic acid in the presence of a catalyst to form the salt of 1-(aminomethyl)cyclohexaneacetic acid; and isolating 1-(aminomethyl)-cyclohexaneacetic acid.
11. A process as claimed in claim 10 wherein the filtered catalyst is re-used.
12. A process as claimed in any of claims 1 to 11 wherein the product is isolated by:15 adding a weak acid; and isolating 1-(aminomethyl )-cyclohexaneacetic acid.
13. A process as claimed in claim 12 wherein the weak acid is acetic acid.
14. A process as claimed in claim 12 or 13 wherein, after addition of the acid, the solution is seeded with gabapentin. 15. Examples. 23. l-(aminomethyl)-cyclohexaneacetic acid potassium salt. 24. l-(aminomethyl)-cyclohexaneacetic acid containing less than 0.01% by
15. A process as claimed in any of claims 12 to 14 including the step of 25 stirring the product at 0 C for approximately 4 hours.
16. A process as claimed in any of claims 12 to 15 wherein the isolated 1(aminomethyl)-cyclohexaneacetic acid is washed with an alcohol.
17. A process as claimed in claim 16 wherein the alcohol is isopropyl alcohol (IPA). θ β 0 J 5 8
18. A process as claimed in any of claims 1 to 17 wherein the 1(aminomethyl)-cyclohexaneacetic acid is recrystallised.
19. A process as claimed in claim 18 wherein the 1 -(aminomethyl)5 cyclohexaneacetic acid is dissolved in methanol and water. 20. A process as claimed in claim 18 wherein the l-(aminomethyl)cyclohexaneacetic acid is dissolved in methanol and water, isopropyl alcohol is added and the solution distilled under vacuum. 21. A process as claimed in claim 19 or 20 wherein the product is washed with isopropyl alcohol and dried under vacuum. 22. A process substantially as hereinbefore described with reference to the
20. Weight of potassium acetate. The following amended page lof the Specification was filed on 30th May2006 “A process for preparing gabapentin” The invention relates to an improved process for preparing gabapentin. United States Patent Numbers 4,024,175 and 4,087,544 disclose novel cyclic amino acids of Formula A H 2 N ch 2 CO 2 R, C (CH 2 ) n wherein R| is a hydrogen atom or a lower alkyl radical, and n is 4, 5 or 6 and the pharmacologically compatible salts thereof. The compounds disclosed in the above United States patents are useful for the therapy of certain cerebral diseases, for example, they can be used for the treatment of certain forms of epilepsy, faintness attacks, hypokinesia, and cranial traumas. Additionally, they bring about an improvement of cerebral functions, and thus are useful in treating geriatric patients. Particularly valuable is 1(aminomethyl)-cyclohexaneacetic acid (gabapentin). Gamma-aminobutyric acid (GABA) is an inhibitory amino acid found in the mammalian central nervous system (CNS). It has been reported that dysfunction with GABA neurotransmission in the CNS may contribute or even cause psychiatric and neurological diseases such as epilepsy, schizophrenia, Parkinson’s disease, Huntington’s Chorea, and dyskinesia (Saletu B., et al,. International Journal of Clinical Pharmacology, Therapy and Toxicology. 1986;24:362-373). Gabapentin was designed as a GABA analog that would cross the blood-brain barrier. Gabapentin was found to have anticonvulsant and antispastic activity with extremely low toxicity in man. United States Patent Numbers 5,132,451, 5,319,135, 5,362,833, 5,091,567, 5,068,413, 4,956,473, 4,958,044, 5,130,455, 5,095,148, 5,136,091, 5,149,870 and
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE20060358A IE20060358A1 (en) | 2006-05-05 | 2006-05-05 | A process for preparing gabapentin |
| JP2007118514A JP2007297386A (en) | 2006-05-05 | 2007-04-27 | Method for preparing gabapentin |
| TW096115882A TW200812939A (en) | 2006-05-05 | 2007-05-04 | A process for preparing gabapentin |
| ARP070101943A AR060856A1 (en) | 2006-05-05 | 2007-05-04 | IMPROVED PROCEDURE TO PREPARE GABAPENTINE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE20060358A IE20060358A1 (en) | 2006-05-05 | 2006-05-05 | A process for preparing gabapentin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE20060358A1 true IE20060358A1 (en) | 2007-11-14 |
Family
ID=38662989
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE20060358A IE20060358A1 (en) | 2006-05-05 | 2006-05-05 | A process for preparing gabapentin |
Country Status (1)
| Country | Link |
|---|---|
| IE (1) | IE20060358A1 (en) |
-
2006
- 2006-05-05 IE IE20060358A patent/IE20060358A1/en not_active IP Right Cessation
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