DK175127B1 - New crystalline gabapentin mono:hydrate - Google Patents
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- DK175127B1 DK175127B1 DK200200056A DKPA200200056A DK175127B1 DK 175127 B1 DK175127 B1 DK 175127B1 DK 200200056 A DK200200056 A DK 200200056A DK PA200200056 A DKPA200200056 A DK PA200200056A DK 175127 B1 DK175127 B1 DK 175127B1
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Description
DK 175127 B1DK 175127 B1
Gabapentin er en generisk betegnelse, der anvendes tit at identificere den kemiske forbindelse (l-aminomethyl)-l-cyclohexaneddikesyre.Gabapentin is a generic term used to identify the chemical compound (1-aminomethyl) -1-cyclohexane acetic acid.
h2n-ch2-c-ch2-cooh / \ (!) /(ch2)5) /h2n-ch2-c-ch2-cooh / \ (!) / (ch2) 5) /
Gabapentin er nyttigt ved behandling af bestemte cerebrale sygdomme såsom visse former for epilepsi, besvimelsesanfald, hypokinesi og 10 kraniale traumer. U.S. patentskrifterne nr. 4.024.175 og nr. 4.087.544 angår forbindelsen og dens anvendelser. Der beskrives også et syresalt, nemlig gabapentin, hydrochloridhydrat i forholdet 4:4:1 og et natriumsalt af gabapentinhydrat i forholdet 2:1. Disse patentskrifter er hermed inkorporeret ved henvisning.Gabapentin is useful in the treatment of certain cerebral diseases such as certain types of epilepsy, fainting seizures, hypokinesia and cranial trauma. U.S. U.S. Patent Nos. 4,024,175 and 4,087,544 relate to the compound and its uses. Also described are an acid salt, namely gabapentin, hydrochloride hydrate in the ratio 4: 4: 1 and a sodium salt of gabapentin hydrate in the ratio 2: 1. These patents are hereby incorporated by reference.
15 Patentskrifterne beskriver forskellige fremgangsmåder til frem stillingen af denne og lignende forbindelser med den almene formel, H.N-CH.-C-CH.-COOR,The patent documents describe various methods of preparing this and similar compounds of the general formula, H.N-CH.-C-CH.-COOR,
AA
20 } (CH2)J20} (CH2) J
hvor Rj er et hydrogenatom eller en lavere al kyl gruppe, og n er 4, 5, eller 6 og de farmaceutisk acceptable salte deraf, hvilke gør brug af kendte fremgangsmåder anvendt til fremstillingen af primære aminer eller 25 aminosyrer.wherein R 1 is a hydrogen atom or a lower alkyl group and n is 4, 5, or 6 and the pharmaceutically acceptable salts thereof, which use known methods used for the preparation of primary amines or 25 amino acids.
Alle eksempler på synteserne standser ved et isocyanat eller en urethan, som let kan omdannes til den ønskede (l-aminomethyl)-l-cyclo-hexaneddikesyre ved sur hydrolyse (foretrukket) til opnåelse af en syre eller basisk hydrolyse til opnåelse af et basisk salt, eller efterfulgt 30 af syretilsætning til opnåelse af et syresalt.All examples of the syntheses are stopped by an isocyanate or urethane which can be readily converted to the desired (1-aminomethyl) -1-cyclohexane acetic acid by acid hydrolysis (preferred) to give an acid or basic hydrolysis to give a basic salt , or followed by acid addition to obtain an acid salt.
Den foreliggende opfindelse tilvejebringer krystallinsk gabapentin, monohydrat, et hidtil ukendt, meget rent stof med rimelig rumvægt, der er egnet til formulering i de ønskede former såsom kapsler eller tabletter. Dets egenskaber er dem, der søges i et farmaceutisk 35 produkt. Den foreliggende opfindelse tilvejebringer en fremgangsmåde til fremstilling af gabapentin, monohydrat i både lille og stor -målestok.The present invention provides crystalline gabapentin, monohydrate, a novel, very pure, reasonable bulk substance suitable for formulation in the desired forms such as capsules or tablets. Its properties are those sought in a pharmaceutical product. The present invention provides a process for the preparation of gabapentin, both small and large scale monohydrate.
Hydratet af den frie aminosyre har den fordel, at det er mindre kostbart at fremstille end den kendte form af gabapentin. Fremgangsmåden har den 2 DK 175127 B1 fordel at den kun efterlader svagt detekterbare rester af opløsningsmidler såsom 2-propanol. Der efterlades ingen detekterbare rester af methanol eller ethanol. Fremgangsmåden til fremstilling af hydratet tilvejebringer også et ekstra oprensningstrin, selvom der fortsættes til frem-5 stilling af det vandfri materiale. Hydratet sparer 12-13% af det totale udbytte af gabapentin ved eliminering af de tab, der opstår ved den sidste omkrystallisation. Hydratet sparer ligeledes omkostningerne ved opløsningsmidler, arbejdstimer og redskaber, der anvendes ved den sidste omkrystallisation. Produktet er en meget smuk krystal, der er stabil ved 10 omgivelsestemperaturer (20-25°C).The hydrate of the free amino acid has the advantage that it is less expensive to prepare than the known form of gabapentin. The process has the advantage of leaving only weakly detectable residues of solvents such as 2-propanol. No detectable residues of methanol or ethanol are left. The process of preparing the hydrate also provides an additional purification step, although preparation of the anhydrous material is continued. The hydrate saves 12-13% of the total yield of gabapentin by eliminating the losses caused by the last recrystallization. The hydrate also saves the cost of solvents, working hours and tools used in the last recrystallization. The product is a very beautiful crystal that is stable at 10 ambient temperatures (20-25 ° C).
Den foreliggende opfindelse er en hidtil ukendt form af gabapentin, nemlig krystallinsk gabapentin, monohydrat med følgende specifikke røntgendi ffraktionsegenskaber.The present invention is a novel form of gabapentin, namely crystalline gabapentin, monohydrate having the following specific X-ray diffraction properties.
15 Mellemrum 'd' Relative Intensiteter 14,255 99 7,196 99 5,438 4 20 4,848 99 4,575 7 4,291 7 3,633 99 3,376 21 25 3,220 9 2,903 28 2,771 23 2,356 7 2,344 12 30Spaces 'd' Relative Intensities 14,255 99 7,196 99 5,438 4 20 4,848 99 4,575 7 4,291 7 3,633 99 3,376 21 25 3,220 9 2,903 28 2,771 23 2,356 7 2,344 12 30
Krystallinsk gabapentin, monohydrat har en densitet i.området fra 0,35 til 0,9 g/cm . Den observerede densitet er fra 0,35 til 0,49 g/cm + eller - 0,02. Krystallerne opnås i meget ren tilstand. De har en rimelig rumvægt. Udtrykket "rimelig" henfører til en densitet over 0,4 35 g/cm . Disse karakteristika lader sig let bruge til farmaceutiske formuleringsoperationer.Crystalline gabapentin monohydrate has a density in the range of 0.35 to 0.9 g / cm. The observed density is from 0.35 to 0.49 g / cm + or - 0.02. The crystals are obtained in a very pure state. They have a reasonable room weight. The term "reasonable" refers to a density above 0.4 35 g / cm. These characteristics are readily applicable to pharmaceutical formulation operations.
Den foreliggende opfindelse tilvejebringer også en fremgangsmåde til fremstilling af gabapentin, monohydrat i lille målestok. Denne frem- 3 DK 175127 B1 gangsmåde angår fremstilling af en forbindelse med formlen M-ch*-c-ch9-cooh h,o 2 y x2 2 f\ 11 5 / (CH2)'5 hvilken fremgangsmåde omfatter, at man (a) hælder en IN opløsning af et syresalt af (l-aminomethyl)-cy-clohexaneddikesyre på en ionbyttersøjle på den basiske form og eluerer 10 søjlen med deioniseret vand; (b) opsamler og analyserer fraktioner fra trin (a) for ion og produkt; (c) koncentrerer fraktionerne indeholdende produkt fra trin (b) til en opslæmning; 15 (d) blander opslæmningen fra trin (c) med alkohol til dannelse af en suspension og efter afkøling; (e) frafiltrerer det ønskede produkt, vasker det med kold alkohol og tørrer det i vakuum.The present invention also provides a process for the preparation of small-scale gabapentin monohydrate. This process relates to the preparation of a compound of the formula M-ch * -c-ch9-cooh h, o 2 y x 2 2 f \ 11 5 / (CH 2) '5, which process comprises: ) pours an IN solution of an acid salt of (1-aminomethyl) -cyclohexane acetic acid on an ion exchange column of the basic form and elutes the column with deionized water; (b) collecting and analyzing fractions from step (a) for ion and product; (c) concentrating the product-containing fractions from step (b) into a slurry; (D) mixing the slurry of step (c) with alcohol to form a suspension and after cooling; (e) filtering the desired product, washing it with cold alcohol and drying it in vacuo.
Anvendelige syresalte er hydrobromid, sulfat, methansulfonat, hy- 20 drochlorid og lignende. Det foretrukne syresalt i trin (a) er hydrochlo-ridet.Useful acid salts are hydrobromide, sulfate, methanesulfonate, hydrochloride and the like. The preferred acid salt of step (a) is hydrochloride.
Der analyseres i trin (b) fortrinsvis for chlorid-ionen ved anvendelse af en sølvnitratopløsning, men andre analysemetoder for chlorid kan anvendes af en fagmand. Produktet testes ved tyndtlagskromatografi.Preferably, step (b) is analyzed for the chloride ion using a silver nitrate solution, but other methods of analysis for chloride may be employed by one of ordinary skill in the art. The product is tested by thin layer chromatography.
25 Fraktionerne i trin (c) koncentreres fortrinsvis på en rotations inddamper med et vakuum på ca. 29-31" ved en temperatur på ca. 25 til ca. 50°C til et volumen på ca. tre gange det teoretiske volumen-udbytte af 1:1 hydrat.The fractions in step (c) are preferably concentrated on a rotary evaporator with a vacuum of approx. 29-31 "at a temperature of about 25 to about 50 ° C to a volume of about three times the theoretical volume yield of 1: 1 hydrate.
Alkoholen i trin (d) er fortrinsvis 2-propanol, og suspensionen 30 afkøles i ca. 8 til ca. 20 timer.The alcohol of step (d) is preferably 2-propanol, and the suspension 30 is cooled for approx. 8 to approx. 20 hours.
Den foreliggende opfindelse tilvejebringer yderligere en fremgangsmåde til fremstilling af gabapentin, hydrat (1:1) i stor målestok, hvilken fremgangsmåde omfatter, at man fremstiller en forbindelse med formlen 35 H9N-CH.-C-CH9-C00H ΗΛ) t Λ ' <CHz>5 'The present invention further provides a process for the preparation of large-scale gabapentin hydrate (1: 1) which comprises preparing a compound of formula 35 H9N-CH.-C-CH9-C00H (t). CH 2> 5 '
------- I III------- I III
DK 175127 B1 4 ved, at man (a) hælder en opløsning af et syresalt af (l-aifiinomethyl)-cyclo-hexaneddikesyre i deioniseret vand på en ionbyttersøjle i den basiske form og eluerer søjlen med deioniseret vand; 5 (b) koncentrerer eluatet til dannelse af en opslæmning; (c) afkøler og tilsætter alkohol til opslæmningen fra trin (b); (d) afkøler og centrifugerer opslæmningen fra trin (c); og (e) tørrer det ønskede udfældede produkt.By (a) pouring a solution of an acid salt of (1-aliphinoomethyl) -cyclohexane acetic acid into deionized water on an ion exchange column in the basic form and eluting the column with deionized water; (B) concentrating the eluate to form a slurry; (c) cooling and adding alcohol to the slurry of step (b); (d) cooling and centrifuging the slurry from step (c); and (e) drying the desired precipitated product.
Anvendelige syresalte omfatter, men er ikke begrænset til hydro-10 bromid, sulfat, methansulfonat, hydrochlorid og lignende. Det foretrukne salt er hydrochloridet, og det foretrukne forhold er 4:4:1.Useful acid salts include, but are not limited to, hydrobromide, sulfate, methanesulfonate, hydrochloride and the like. The preferred salt is the hydrochloride and the preferred ratio is 4: 4: 1.
Det foretrukne syresalt af (l-aminomethyl)-cyclohexaneddikesyre er monohydrochloridhydratet i forholdet 4:4:1.The preferred acid salt of (1-aminomethyl) -cyclohexane acetic acid is the 4: 4: 1 monohydrochloride hydrate.
Foretrukne fremgangsmådebetingelser i trin (b) inkluderer, at elu-15 atet koncentreres i et glasforet destillationsapparat i vakuum ved ca.Preferred process conditions in step (b) include concentrating the eluate in a glass-lined distillation apparatus in vacuo at ca.
29-31" ved en temperatur på ca. 25°C til ca. 50°C til dannelse af en Opslæmning.29-31 "at a temperature of about 25 ° C to about 50 ° C to form a slurry.
Foretrukne fremgangsmådebetingelser i trin (c) inkluderer, at opslæmningen afkøles til ca. 25°C til ca. 45°C i ca. 1-3 timer, og den 20 tilsatte alkohol er 2-propanol.Preferred process conditions in step (c) include that the slurry is cooled to ca. 25 ° C to approx. 45 ° C for approx. 1-3 hours and the 20 added alcohol is 2-propanol.
Foretrukne fremgangsmådebetingelser i trin (d) inkluderer, at opslæmningen afkøles til ca. -10°C til ca. 0°C i ca. 12 til 16 timer.Preferred process conditions in step (d) include cooling the slurry to ca. -10 ° C to approx. 0 ° C for approx. 12 to 16 hours.
Foretrukne fremgangsmådebetingelser i trin (e) inkluderer, at bundfaldet tørres i vakuum ved ca. 25-35°C i ca. 8 til 24 timer.Preferred process conditions in step (e) include drying the precipitate in vacuo at ca. 25-35 ° C for approx. 8 to 24 hours.
25 Gabapentin, monohydratet tilvejebringer et ekstra oprensningstrin og kan anvendes til fremstilling af det vandfri materiale, der er omhandlet i de U.S. patentskrifter, der er inkorporeret heri ved henvisning.Gabapentin, the monohydrate provides an additional purification step and can be used to prepare the anhydrous material disclosed in U.S. Pat. patents incorporated herein by reference.
Den foreliggende opfindelse tilvejebringer yderligere en frem-30 gangsmåde til fremstilling, i stor målestok, af i det væsenlige vandfri gabapentin med samme krystalstruktur som fremstillet ved fremgangsmåderne beskrevet i de U.S. patentskrifter, der er inkorporeret heri ved henvisning. Denne fremgangsmåde til fremstilling af forbindelsen med formlen 35 M-CHo-C-CH,-C0oH f (CH2)5 5 DK 175127 B1 omfatter, at man (a) opløser ren gabapentin, monohydrat i methanol ved 50°C til 60°C; (b) fortynder opløsningen fra trin (a) med 2-propanol og afkøler 5 til 0°C til - 10°C, hvilket resulterer i en opslæmning; (c) centrifugerer opslæmningen fra trin (b) og tørrer bundfaldet af gabapentin.The present invention further provides a large-scale process for the preparation of substantially anhydrous gabapentin of the same crystal structure as prepared by the methods described in U.S. Pat. patents incorporated herein by reference. This process for the preparation of the compound of formula 35 M-CHo-C-CH, -COOH f (CH2) B1 comprises: (a) dissolving pure gabapentin monohydrate in methanol at 50 ° C to 60 ° C ; (b) diluting the solution of step (a) with 2-propanol and cooling 5 to 0 ° C to - 10 ° C, resulting in a slurry; (c) centrifuging the slurry from step (b) and drying the precipitate of gabapentin.
Foretrukne fremgangsmådebetingelser i trin (a) inkluderer, at gabapentin, monohydratet opløses i methanol i forholdet 0,141 kg 10 gabapentin, monohydrat til 1,00 kg vandfri methanol i temperaturområdet fra ca. 50°C til ca. 60°C.Preferred process conditions in step (a) include dissolving gabapentin, the monohydrate in methanol in the ratio of 0.141 kg of gabapentin, monohydrate to 1.00 kg of anhydrous methanol in the temperature range from ca. 50 ° C to approx. 60 ° C.
Foretrukne fremgangsmådebetingelser i trin (b) inkluderer, at opløsningen fortyndes med vandfri 2-propanol i forholdet 1 kg vandfri 2-propanol til 1 kg vandfri methanol, og opløsningen afkøles til 20°C til 15 25°C i 2 timer og derefter til -8°C til -10°C i 16 til 20 timer.Preferred process conditions in step (b) include diluting the solution with 1 kg of anhydrous 2-propanol to 1 kg of anhydrous methanol and cooling the solution to 20 ° C to 25 ° C for 2 hours and then to - 8 ° C to -10 ° C for 16 to 20 hours.
Foretrukne fremgangsmådebetingelser i trin (c) inkluderer, at ga-bapentinet tørres i vakuum ved ca. 25°C til 45°C i ca. 8 til 48 timer.Preferred process conditions in step (c) include drying the gabapentin in vacuo at ca. 25 ° C to 45 ° C for approx. 8 to 48 hours.
Da forbindelsen med formel (II) kun udviser ekstrem lav toxicitet, kan den administreres enteralt eller parenteralt inden for vide dosisom-20 råder på flydende eller fast form. Som injektions-opløsning anvendes fortrinsvis vand, der indeholder de sædvanlige tilsætningsstoffer for injektionsopløsninger, såsom stabiliseringsmidler, opløsningsmidler og/eller puffere.Since the compound of formula (II) exhibits only extremely low toxicity, it can be administered enterally or parenterally within wide dose ranges in liquid or solid form. Preferably, water is used as injection solution containing the usual additives for injection solutions, such as stabilizers, solvents and / or buffers.
Tilsætningsstoffer af denne type inkluderer, fx tartrat og citrat, 25 puffere, ethanol., kompleks-dannende midler (såsom ethylendiamin-tetra-eddikesyre og de ikke-toksiske salte deraf), samt polymerer med høj molekylvægt (såsom flydende polyethylenoxid) for viskositetsregulering.Additives of this type include, for example, tartrate and citrate, buffers, ethanol, complexing agents (such as ethylenediamine-tetraacetic acid and the non-toxic salts thereof), and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity control.
Faste bærermaterialer inkluderer fx stivelse, lactose, mannitol, methyl-cellulose, talkum, stærkt dispergerede kisel syrer, fede syrer med høj 30 molekylvægt (såsom stearinsyre), gelatine, agaragar, calciumfosfat, mag-nesiumstearat, dyre- og plantefe.dtstoffer og faste polymerer med høj molekylvægt (såsom polyethylenglycol); præparater, der er egnede til oral administrering kan, om ønsket, også indeholde smagsstoffer og/eller sødemidler.Solid carriers include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silica, high molecular weight fatty acids (such as stearic acid), gelatin, agar agar, calcium phosphate, magnesium stearate, animal and plant feeds, and solids. high molecular weight polymers (such as polyethylene glycol); compositions suitable for oral administration may, if desired, also contain flavoring and / or sweetening agents.
35 Den individuelle dosis for forbindelserne ifølge den foreliggende opfindelse kan være fra 100 til 3000 mg/dag for en voksen, fortrinsvis fra 600 til 2400 mg/dag, og mest foretrukkent er dosen ca. 1200 mg/dag eller det, som skønnes nødvendigt af en læge.The individual dosage for the compounds of the present invention may be from 100 to 3000 mg / day for an adult, preferably from 600 to 2400 mg / day, and most preferably the dose is about 100 mg / day. 1200 mg / day or as deemed necessary by a physician.
Ul\ Ι/ΟΙέί Dl 6Ul \ Ι / ΟΙέί Dl 6
Den foreliggende opfindelse tilvejebringer således også farmaceutiske præparater af forbindelsen i blanding med en fast eller flydende farmaceutisk diluent eller bærer.Thus, the present invention also provides pharmaceutical compositions of the compound in admixture with a solid or liquid pharmaceutical diluent or carrier.
Fremstillingen af gabapentin, monohydrat er illustreret ved 5 følgende ikke-begænsende eksempler.The preparation of gabapentin monohydrate is illustrated by the following non-limiting examples.
EKSEMPEL 1EXAMPLE 1
Isolering af gabapentin, hydrat (1:1) i lille målestok ((1-aminomethyl)-10 cyclohexaneddikesyre H^O)Isolation of gabapentin, hydrate (1: 1) on a small scale ((1-aminomethyl) -10 cyclohexane acetic acid H 2 O)
En ionbyttersøjle fremstilles ved at fylde en glassøjle med 380mlAn ion exchange column is prepared by filling a glass column with 380ml
DD
Amberiite IRA-68. Harpiksen skylles med en fortyndet ammoniak-opløsning, 140 ml ammoniumhydroxid i 3 1 vand, efterfulgt af deioniseret vand 15 til neutral pH, (ca. 2 1). En IN opløsning af (1-aminomethyl)-cyclohexaneddikesyre, hydrochlorid fremstilles ved opløsning af 64,6 g (1-aminomethyl)-cyclohexaneddikesyre, hydrochloridhydrat (4:4:1) i 310 ml deioniseret vand. Denne opløsning filtreres gennem et filter til fjernelse af alt uopløseligt materiale eller ekstraheres med et organisk op-20 løsningsmiddel, såsom dichlormethan.Amberiite IRA-68. The resin is rinsed with a dilute ammonia solution, 140 ml of ammonium hydroxide in 3 L of water, followed by deionized water 15 to neutral pH, (about 2 L). An 1N solution of (1-aminomethyl) cyclohexane acetic acid hydrochloride is prepared by dissolving 64.6 g of (1-aminomethyl) cyclohexane acetic acid hydrochloride hydrate (4: 4: 1) in 310 ml of deionized water. This solution is filtered through a filter to remove all insoluble material or extracted with an organic solvent such as dichloromethane.
Opløsningen hældes i søjlen, og der suges, til den når topniveauet for harpiksen. Søjlen elueres under anvendelse af deioniseret vand ved ca. 15 ml/min. Fraktioner på ca. 200-250 ml opsamles. De første fire fraktioner, ca. 1 1 totalt, indeholder alt produktet (TIC). Der analyse-25 res for chlorid under anvendelse af en sølvnitratopløsning. Der findes sædvanligvis ikke spor af chlorid i nogen af de opsamlede fraktioner.The solution is poured into the column and sucked until it reaches the top level of the resin. The column is eluted using deionized water at ca. 15 ml / min. Fractions of approx. Collect 200-250 ml. The first four fractions, ca. 1 1 in total, contains all the product (TIC). Chloride is analyzed using a silver nitrate solution. Traces of chloride are usually not found in any of the fractions collected.
De første fire fraktioner koncentreres på en roterinddamper med ca. 29-31" vakuum og temperaturen < 40°C til en opslæmning, ca. 150 ml.The first four fractions are concentrated on a rotary evaporator with approx. 29-31 "vacuum and the temperature <40 ° C to a slurry, about 150 ml.
Denne blandes med 288 ml 2-proponal, og suspensionen afkøles i et køle-30 skab natten over. Det hvide krystallinske (l-aminomethyl)-cyclohexan-eddikesyrehydrat (1:1) frafiltreres, vaskes med kold 2-propanol, og tørres i vakuum til opnåelse af 42,93 g.This is mixed with 288 ml of 2-proponal and the suspension is cooled in a refrigerator overnight. The white crystalline (1-aminomethyl) cyclohexane acetic acid hydrate (1: 1) is filtered off, washed with cold 2-propanol and dried in vacuo to give 42.93 g.
Analytiske data: HPLC: 89,27¾ vægt/vægt overfor tør analytisk standard 35 H20: 9,68% + 0,5 smp. 156-156,7°C (dek)Analytical data: HPLC: 89.27¾ w / w versus dry analytical standard 35 H2 O: 9.68% + 0.5 m.p. 156-156.7 ° C (dec)
Cl": 8,6 ppmCl ": 8.6 ppm
Da dette er et hydrat og smelter under sønderdeling, kan smelte DK 175127 B1 7 punktsområdet starte så lavt som 154°C og kan slutte så højt som 162°C.Since this is a hydrate and melts during decomposition, the melting point can start as low as 154 ° C and can end as high as 162 ° C.
EKSEMPEL 2 5 Isolering af gabapentinhydrat (1:1) i stor målestok ((l-aminomethyl)-cyclohexaneddikesyre, hydrat (1:1))EXAMPLE 2 Isolation of gabapentin hydrate (1: 1) on a large scale ((1-aminomethyl) -cyclohexane acetic acid, hydrate (1: 1))
En ionbyttersøjle (60" højt lag, 15" radius) påfyldes med 250 1An ion exchange column (60 "high layer, 15" radius) is charged with 250 l
DD
filtreret deioniseret vand efterfulgt af 700 1 (504 kg vådt) Amberiite 10 IRA-68 harpiks. Harpiksen tilbagevaskes med 2000 1 filtreret deioniseret vand. Harpiksen behandles med 3700 1 filtreret deioniseret vand, som er blandet med 60,6 kg koncentreret saltsyre. Syrebehandlingen gentages med frisk syre. Harpiksen vaskes med 6400 1 filtreret, deioniseret vand.filtered deionized water followed by 700 l (504 kg wet) Amberiite 10 IRA-68 resin. The resin is washed back with 2000 liters of filtered deionized water. The resin is treated with 3700 l of filtered deionized water which is mixed with 60.6 kg of concentrated hydrochloric acid. The acid treatment is repeated with fresh acid. The resin is washed with 6400 l of filtered deionized water.
Harpiksen behandles med 1770 1 4% opløsning af natriumhydroxid. Harpiks-15 en vaskes med 3200 1 deioniseret vand.The resin is treated with 1770 1 4% solution of sodium hydroxide. The resin-15 is washed with 3200 l of deionized water.
Harpiksen behandles med 3700 1 filtreret, deioniseret vand, som er blevet blandet med 60,6 kg koncentreret saltsyre. Syrebehandlingen gentages med frisk syre. Harpiksen vaskes med 6400 1 filtreret, deioniseret vand. Harpiksen behandles med 1770 1 4% opløsning af natriumhydroxid.The resin is treated with 3700 liters of filtered deionized water which has been mixed with 60.6 kg of concentrated hydrochloric acid. The acid treatment is repeated with fresh acid. The resin is washed with 6400 l of filtered deionized water. The resin is treated with 1770 1 4% solution of sodium hydroxide.
20 Harpiksen vaskes med 3200 1 deioniseret vand.The resin is washed with 3200 l of deionized water.
Harpiksen behandles med 37001 filtreret, deioniseret vand, som er blevet blandet med 60,6 kg koncentreret saltsyre. Syrebehandlingen gentages med frisk syre. Harpiksen vaskes med 6400 1 filtreret, deioniseret vand. Harpiksen behandles med en opløsning af 105 kg 28% ammonium-25 hydroxid i 1700 1 deioniseret vand. Harpiksen vaskes med 6400 1 deioniseret vand.The resin is treated with 37001 filtered deionized water which has been mixed with 60.6 kg of concentrated hydrochloric acid. The acid treatment is repeated with fresh acid. The resin is washed with 6400 l of filtered deionized water. The resin is treated with a solution of 105 kg of 28% ammonium hydroxide in 1700 liters of deionized water. The resin is washed with 6400 l of deionized water.
En opløsning af 122 kg (57,5 mol) l-(aminomethyl)-cyclohexan-eddikesyre, monohydrochloridhydrat (4:4:1) i 472 kg deioniseret vand filtreres til fjernelse af alt uopløseligt materiale eller ekstraheres 30 med et organisk opløsningsmiddel, såsom dichlormethan, og påføres der-• efter i toppen af ionbyttersøjlen og elueres med 3750 kg deioniseret vand. Tilstedeværelsen af chloridion analyseres ved anvendelse af sølvnitratopløsning, og tilstedeværelse af produktet analyseres ved anvendelse af tyndtlagskromatografi. Eluatet koncentreres i et 500 gallon 35 glasforet destillationsapparat ved ca. 29-31" vakuum og vægtemperatur < 50°C. En samlet mængde på 3500 kg vand fjernes. Den resulterende opslæmning afkøles til ca. 18-20°C og 248,5 kg 2-propanol tilsættes. Opslæmningen afkøles ved -12 til -8°C i 16 timer, centrifugeres og vaskes medA solution of 122 kg (57.5 mol) of 1- (aminomethyl) cyclohexane acetic acid, monohydrochloride hydrate (4: 4: 1) in 472 kg of deionized water is filtered to remove all insoluble material or extracted with an organic solvent such as dichloromethane, and then applied to the top of the ion exchange column and eluted with 3750 kg of deionized water. The presence of chloride ion is analyzed using silver nitrate solution and the presence of the product is analyzed using thin layer chromatography. The eluate is concentrated in a 500 gallon glass-lined distillation apparatus at ca. 29-31 "vacuum and wall temperature <50 ° C. A total amount of 3500 kg of water is removed. The resulting slurry is cooled to about 18-20 ° C and 248.5 kg of 2-propanol is added. The slurry is cooled at -12 to - 8 ° C for 16 hours, centrifuged and washed with
Vl\ I I V Ifal VIVl \ I I V Ifal VI
8 2-propanol. Bundfaldet tørres i vakuum ca. 29-31" ved 25-30°C til opnåelse af 86 kg l-(aminomethyl)-cyclohexaneddikesyrehydrat (1:1).8 2-propanol. The precipitate is dried in vacuo for approx. 29-31 "at 25-30 ° C to give 86 kg of 1- (aminomethyl) cyclohexane acetic acid hydrate (1: 1).
Analytiske data: HPLC: 89,4% vægt/vægt overfor tør referencestandard 5 H20(Karl Fischer): 9,69% ± 0,5 snip. 156-156,7°C (dek)Analytical data: HPLC: 89.4% w / w versus dry reference standard 5 H2 O (Karl Fischer): 9.69% ± 0.5 snip. 156-156.7 ° C (dec)
Cl”: 30 ppmCl ”: 30 ppm
Da dette er et hydrat og smelter under sønderdeling, kan smeltepunkts-området starte så lavt som 154°C og kan slutte så højt som 162°C.Since this is a hydrate and melts during decomposition, the melting point range can start as low as 154 ° C and can end as high as 162 ° C.
10 EKSEMPEL 3EXAMPLE 3
Isolering af vandfri l-(aminomethyl)-cyclohexaneddikesyre fra gabapen-tinmonohydrat i stor målestok ((1-aminomethyl)-cyclohexaneddikesyre 15 hydrat (1:1))Isolation of anhydrous 1- (aminomethyl) -cyclohexane acetic acid from gabapene-tin monohydrate on a large scale ((1-aminomethyl) -cyclohexane acetic acid hydrate (1: 1))
En opslæmning af 179 kg l-(aminomethyl)-cyclohexaneddikesyre, monohydrat og 1266 kg vandfri methanol opvarmes til 60°C til opnåelse af en fuldstændig opløsning. Opløsningen fortyndes med 1266 kg vandfri 2-20 propanol, og opløsningen afkøles til 20°C til 25°C i 2 timer og afkøles derefter til -8°C til -10°C i 20 timer. Den resulterende opslæmning centrifugeres, og bundfaldet tørres i vakuum ved 35°C i 48 timer til opnåelse af 145 kg hvidt, krystallinsk 1-(aminomethyl)-cyclohexaneddike-syre.A slurry of 179 kg of 1- (aminomethyl) -cyclohexane acetic acid, monohydrate and 1266 kg of anhydrous methanol is heated to 60 ° C to obtain a complete solution. The solution is diluted with 1266 kg of anhydrous 2-20 propanol, and the solution is cooled to 20 ° C to 25 ° C for 2 hours and then cooled to -8 ° C to -10 ° C for 20 hours. The resulting slurry is centrifuged and the precipitate is dried in vacuo at 35 ° C for 48 hours to give 145 kg of white crystalline 1- (aminomethyl) cyclohexane acetic acid.
25 Analytiske data: HPLC: 100,6% vægt/vægt overfor tør analytisk standard H20: 0,09% CH30H: 0,01% (CH3)2CHOH: 0,01% 30 CL": 22 ppmAnalytical data: HPLC: 100.6% w / w versus dry analytical standard H 2 O: 0.09% CH 3 OH: 0.01% (CH 3) 2 CHOH: 0.01% 30 CL ": 22 ppm
Smeltepunkt: 161,7 -162,6°C (sønderdeling)Melting point: 161.7 -162.6 ° C (dec.)
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK200200056A DK175127B1 (en) | 1988-05-02 | 2002-01-15 | New crystalline gabapentin mono:hydrate |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/188,819 US4894476A (en) | 1988-05-02 | 1988-05-02 | Gabapentin monohydrate and a process for producing the same |
| US18881988 | 1988-05-02 | ||
| DK212689 | 1989-05-01 | ||
| DK198902126A DK175400B1 (en) | 1988-05-02 | 1989-05-01 | Gabapentin, monohydrate |
| DK200200056A DK175127B1 (en) | 1988-05-02 | 2002-01-15 | New crystalline gabapentin mono:hydrate |
| DK200200056 | 2002-01-15 |
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| Publication Number | Publication Date |
|---|---|
| DK200200056A DK200200056A (en) | 2002-01-15 |
| DK175127B1 true DK175127B1 (en) | 2004-06-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK200200056A DK175127B1 (en) | 1988-05-02 | 2002-01-15 | New crystalline gabapentin mono:hydrate |
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| Country | Link |
|---|---|
| DK (1) | DK175127B1 (en) |
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2002
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| DK200200056A (en) | 2002-01-15 |
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