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    US8048876B2

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    Pingol Pham
    Patent

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    © All Rights Reserved
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    2) United States Patent 6a 03) ow o ey @ (86) n 63) (60) 6) (2) 68) Bosch I Llad6 et al PROCESS FOR PREPARING QUETIAPINE AND QUETIAPINE FUMARATE, Inventors: Jordl Bosch I Lladé, Girona (ES); Maria Carmen Burgarolas Montero, ‘Santa Maria de Palastordera (ES): Tolunda Chamorro Gutiérrez, Santa Coloma de Famers (F Assignee: Medichem S.A., Barcelona (ES) Notice: Subject to any disclaimer, the team ofthis pateat is extended or adjusted under 35 US. 154(b) by 719 days. Appl.No: 11911,898 PCT Filed: Ape. 21,2006 PCT Nos PETAR 2006,002286 $371 (0,0), (2),(4) Date: Ang. 8, 2008 PCT Pub, Nos WO2006/117700 PCT Pub, Date: Nov. 9, 2006 Prior Publication Data US 200910076262.A1 Mar. 19,2000 Related Application Data Provisional aplication No, 601673,373, fled on Ape: 21, 2008, provisional application No. 60V730.864, filed on Oct 28, 2005, Int Cl. AGLP 2508 (2006.01) AGIK 31554 (2006.01) AGIK 9/14 (2006.01) Co7D 281/16 (2006.01) vs.C1 S14/211.13; 5400551 Field of Classification Search S14/211.13 ‘ce application file for complete se ‘USOO8048876B2 (10) Patent No.: US 8,048,876 B2 (35) Date of Patent: Nov. 1, 2011 66) References Cited US. PATENT DOCUMENTS 5.286.722 421994 Cairaset al 2oosiooi001 AL 1/2005 Yanupucht ta 2vetoeso27 AL* 32006 Faint al sansst POREIGN PATENT DOCUMENTS ep 024028 A 1011987 wo 1217 A 3.2001 wo oDazie A 112009 WO —_woosbsposs AL 102003 WO — WO3on6O0I6I9 AL 12006 OTHER PUBLICATIONS Intemational Search Report dated Nov. 21,2006 or Intemational Pateat Application No, CT/1B2006 002286, Warowa tal. "Behviowal Aproech o Nondnskintic Dopamine ‘Anogonsts: enicoron of Seog”, 1. Med. Chem, vl 4, whee 239) : Schmae, e¢ al. 729. Uber iv selling amino-substte Dibencob fl Iethacepine und -ocaepine elveticn Chimica Ata vol 30,1967 pp SAS254 Kichne etal. "Rede of Amides and Lactams by Amines by Resets with Phoyphwour Chordata erode 161 Chem, 042.0 12,17 20822087 * cited by examiner Primary Examiner — Brena Coleman (14) Attorney, Agen, oF Firm — Coven O'Connor on ABSTRACT The invention comprises @ process for preparing quetiapine andr its sas, ineluding, quetiapine fimarate. The process tdenorlly comprises reacting dibenzothiazepinone (ibenza {bill s]thiazepin-11(10H)-one) with phosphorous oxychlo- Fide inthe presence of triethylamine in an afomatie organic Solvent such as toluene or, preferably, xylene at reflux tem- perature fo oblain an aromatic hydrocarbon solution of Techloro-dibenzo[bialiazepine, Thereafter, the -chloro-dibenzo[bfLA}hiazepine is reacted with 2-(2- pipervin-L-ylethoxy}-elbanol 10 yield, Following several processing steps, quetiapine, Compound Ian then be further reacted with fmarie acid at elevated temperature To yield (quetiapine famamte. The resulting quetiapine Fumarate ‘blained is suitable for use in pharmacentical preparitions. 19 Claims, 1 Drawing Sheet U.S, Patent Nov. 1, 2011 US 8,048,876 B2 i ® Tree. PVTEVEETEV EPP e ibe eri renee US 8,048,876 B2 1 PROCESS FOR PREPARING QUETIAPINE "AND QUETIAPINE FUMARATE, (CROSS REFERENCE TO RELATED "APPLICATIONS, plication claims priority under 95 US.C. §371 to International Application No, PCT/182006002286 (filed Apr. 21, 2006), which claims priority to US. Provisional Application Nos. 60673,373 (filed Apr. 21, 2008) and 60/730,864 (ied Oct. 28, 2005), all three of whieh appl tions are expressly incorporated herein by elerence in their ‘entirety, BACKGROUND OF THE INVENTION 1. Field ofthe Invention “The invention relates toa process for preparing quetiapine and its salts(e quetiapine fumarate). The invention further Jnchidesformelating uetipine andor its salts (eg. ,quetian- ine fumarate) (collectively, “the compounds of the inven- tion”) into readily usable dosage units forthe therapeutic treatment (including prophylactic treatment) of mammals including humans. 2. Discussion of the Related An ‘Quetapine (Compound I) isthe common name for 22-4 Dibetzofh 1, 4Iibiazepin-1-ylpiperain-|-yDethoxy] ‘ethanol Cempount ar ine fumarate (Compound Il) is a commercially mar- kKeted pharmaceutically aetive substance useful forthe treat ment of schizophrenia. Compound Il may be made by & variety of methods. Ccompou US. Pat, No. 4879,288 and its equivalent EP 240 228 “disclose three general processes for preparing quetiapine and ‘quetiapine fumarate, According to US. Pat. No. 4,879,288 and EP 240 228, and asillustrated in Schome | (below, one mole of Compound I] (ie, dibenzothiazepinone, dibenzo[b. fl Althiazepino-11 (1OiD-0ne) is combined with 14.8 moles of phosphorous ‘oxychloride and 0.6 moles of N.N-dimethylanifine and the ‘mixtures refixed for about Ghours, Theexcess phosphorots ‘oxyellorde can then be removed under vacuum to yield 8 2 brown reside, which ean then be dissolved in toluene and ‘weated With an ice-water mixture, The toluene layer is thea separated, washed twice wth Water and dried with anbydrous ‘magnesium sulphate, After removal ofthe drying agent by 5 filtration, the filtrate ean be concentrated under vacuum to give 2 92.6% yield of Compound IV {ic 11-chlorodisenzn ball .¢thiacepine. ‘Compound IV ean then be combined with 2.58 | of xylene and 2 mot of Compound V (ie.,242-Piperazin-I-yithoxy)- thao!) and refluxed for approximately 30 hours. Thereater, the mixture is subjected to a complex. work-up, which ‘includes using diethylether, in which Compound I (ie.,qne- ‘iapine) is extracted 2s a dichloromethanie solution, Com- pound Is then concentrated under vai to yield a viscous Amber oil whichis purified by fash chromatography using a silica gel column and dichloromethane as eluent. The yildof Compound I following purification is 77.79% (overall yield=71.0%6), ‘Compound I (1 mole) is then optionally trated with 1.04 smo of famarie acid in 3.6 ml of ethanol ta yield 49.63% of Compound II (Le, quetiapine fumarate) (overall yield of Jnewsating agents such as corn starch and its derivatives, ‘rosspovidne, erosscannellose andor algenie acid: binding ‘agents such as starch and pregelatinized stare; lubricating fgens such as magnesium stearate, stearic acid or tales pre- servative agents sich as sodium benzos, ethyl or props p-tydeoxybenzoste; andl anti-oxidants, such as ascorbic ci. Tablet formulations may be uncoated or coated either {0 modify thir disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, o& © improve their stability and/or appearance, in either case, using conventional coating. agents and procedures well known inthe a. Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient i mix with ‘an inect solid diluent, for example, calcium carbonate, cal ‘cium phosphate, kaolin or cellose, «disintegrating agent such & com starch and its derivatives, cosspovidone and ‘rossearmellose, or as soft gelatin capsules in which the ‘sete ingredient is mixed with water or an ol suc as peanut cil, liquid paralln, olive ol or glyceryl oleate derivatives Aqueous suspensions generally contain the active ingred ‘ent in finely powdered form together with one or more sus- pending agents, such as sodium carboxymethyleetilose, methylcellulose. hydroxypropylmethylcellulose, sodium alginate, polyvinyl -pyrmlidone, gum tragacanth and gum acacia; dispersing or wetting agents such a lecithin or con- ‘densation products of an alkylene oxide with fatty acs (for ‘example polyoxethylene stearate), or condensation product ‘of ethylene oxide with long chain aliphatic alcohols, for ‘example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a extol such as polyoxyethylene sorbitol ‘monooleate, or condensation products of ethylene oxide with partial estes derived from Fatty acids and hexitol anlydrdes, Jor example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such asthe sodium salt of benzoic acid, ethyl or propyl p-hydroxy- benzoate), anti-oxidants (Sueh as ascorbic acid), coloring agents, lavoring agents, and/or swostening agents (such as suerose, saccharine or aspartame), (ily suspensions may be formulated by suspending the ‘active ingredient in a vegetable ol (uch 2s arachis ol, olive 10 cil, sesame vil or coconut il) or in a mineral oil (uch as Iiquid paraffin). The oily stwpensions may also contain a ‘thickening agent such as beeswax, hart paraffin or cetyl aleo- hol. Swostening agents such as those set out above, and Tavoring agents may be added wo provide a palatable oral preparation. These compositions may he preserved by the Addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation ‘of an aqueous suspension by the ation of water generally contain the active ingredient topether with a dispersing or wetting agent, suspending agent and one or more preserva tives. Suitable dispersing or wetting ageats and suspending ‘agents are exemplified by those already mentioned above, ‘Additional excipients such as sweetening, flavoring and col- fring agents, may also be preset The pharmaceutical compositions of the invention may also be in the Form of oil-in-water emulsions. The ily pase ‘may be a vegetable oil, such as olive ol or arachis oi, or a ‘mineral, suchas forexample liquid partfinor amixtireot ‘any of these. Suitable emulsifying’ agents may be, for ‘example, naturally-occurring gums such as gum acacia or gum teagacant, naturally-oecuring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan ‘monooleate) and condensation products of the said partial testers with ethylene oxide such as polyoxyethylene sorbitan :monooleate. The emulsions may also contsin sweetening, Flavoring and preservative agents Syrups and elixirs may be formulated with sweetening agents suchas glycerol. propylene glycol, sorbitol, aspartame fr sucrose and may also contain a demulcent, preservative, ‘Navoring andor coloring agent. ‘The amount of a compound of this invention that is com bined with one or more excipients to produce a single dosage ‘orm will necessarily vary depending upon the host treated fand the paticular route of administration, For example, a tormulation intended for oral administration to humans may contain, for example, from 0.5 mg to 2 of active ingredient jeompounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 08 percent by weight ofthe total composition, Dosage unit forms will genenlly contain about 1 mg 10 about SO mg of an active ingredient “Table I usrats a representative pharmaceutical compo sition (et granulation) containing quetiapine: TABLE L Gusts Famaet Mencowaline x Solin Sach Giese Raine ea gia 3 of icp ‘The representative pharmaceutical composition described in Table T was prepared by mixing a portion ofthe microe~ -ystaline cellulose, lactose monohydrate and sodium starch alyeolate with quetiapine ina high shear mixer. These com- ponents were granulated using an aqueous polyvinylpyrra ‘done solution. The obtained granules were dried in Md bed US 8,048,876 B2 u ‘and sieved through a 1 mm mesh, The sieved pranules were then mixed with the extagranular excipients, which included the remaining part of the intragranular excipients, and the dlbasic calcium phosphate ina suitable blender. Thereafer, the obtained blend was further blended with magnesivm stearate. The resulting ready to press blend was compressed jn rotary tabletting machine 6 produce suitably sized tab- Jets. After the compression process, the cores were fim ‘outed to give them ther final sppearance, “The sie of the dose for therapeutic or prophyltic pur- poses of the compounds of the invention will naturally Vary oconding to the nature and severity ofthe conditions the age ‘and sex of the animal or patient, and the route of adainista- 1, according to well known principles of medicine. For ‘example, the method may comprise at least one of an hourly administration, a daily administration, a weokly administa- tion, or 3 monthly administration of One oF more com tions described herein According othe invention, suitable methods of adminis tering the therapeutic composition of the invention to 2 patient include any route of in vivo administration that is ‘uitable for delivering the composition into a patient. The prefered coutes of administration willbe apparent wo thse of ill in the ar, depending on the type of condition to be prevented or tested, andor the target cell population. Twill be apparent to those skilled inthe art that various ‘modifications and variations eanbe made in the invention and specific examples provided herein without departing fom the spirit or scope ofthe invention. Thus, i is intended thatthe vention cavers the modifications and variations of this invention that come within the seope of any elaims and their ‘equivalents, Specie Examples ‘The following examples are for illustrative purposes only and are not intended, nor should they be interpreted t, limit the scope ofthe invention ‘Gencral Experimental Conditions i, HPLC Method. Chromatographie separation was earied out in a Symme- ey C8, $ ym, 25 em4.6mm LD. columnat room temperature (-20.25°C), ‘The mobile phase was prepared by mixing 700 volumes of 50 mM HCIO, (pH-2.5, adjusted with SO% KOH) with 300 volumes of scetonitile, The solution was then mixed and ‘ered through 0.22 um nylon fer under vacuum ‘The chromatograph was equipped with a 210 nm detector ‘andthe low rate was 1. mi. per minute. Test samples (~20 UL) were prepared by dissolving a sulicent quantity of ‘ample inorder to obtain a mg per mi. concentration in the mobile phase fi, Particle Size Measurements and Distribution ‘The particle size for quetiapine fumarate was measured using a Malvem MastersizerS particle size analyzer with an (MSI Sima Valume Reciteulating unitattached. A 300RF mm Jens and a beam length of 2.4 mm was used. Samples for analysis were prepared by dispersing a weighed amount of ‘quetigpine fumarate (0.1 p) in 20 mL of toluene. The result Ing suspension was sonicated for approximately 1 minuteand delivered drop-wise to background corrected measuring, previously filled with toluene until the obscuration reached the desired level Volume disieibusions were obtained for throe times. Upon measurement completion, the sample ell was empiied and cleaned, refilled with suspending medivm and the sampling procedure repented again Por characteriza- tion, the values of Dp, Dyy and Day (By volume) were spe- 0 o 12 cifically listed, each one being the mean of the six values available for each characterization parameter. ili. Method for Determining Residual Solvents ‘GC method: The chromatographic separation iscaried ot in a VOCOL capillary column of 3 yun film thickness, 105 ‘mx0.53 mm il-column andat room temperature (20-25° C) ‘The chromatograph is equipped with @ FID detector and @ ead Space injection suiliary devi. “The oven temperature is programmed as follows: Initial (0-16 minutes, 70° C.; the temperature is then raised with a ramp rateof 25°C /minute to 180° C, and maintained at 150° CC for 3 minutes; the temperature is then raised with a ramp eof 30°C./minute to 240°C. an eitaned t 240° C. for 10 minutes ‘The injector and detector temperatures are set at 220° C and 280° C., respectively. Helium is used as cartier gas (20 psi) and a split flow of 50 mL /minute is used. Samples are heated for 30 minvtes at 100°C. in the head space device. After heating, the vials are pressurized with heim (18 psi), {or 0.3 mines, The sample loop is thea filled for 0.15 min- tes (loop volume=1 mi.) and injected for 0:5 minutes Procedure: The test solution is injected three times along wit the standard solution of methanol and isopropyl acetate i suitable vials for head space injection. The vals are sealed with suitable crimp caps and are analyzed by headspace using the deseribed conditions, ‘Standard Solutions ‘Methanol: Dilute quantitatively 13 pL. of methanol with 200 ml. of water to obtain solution containing 51.48 yq/ml. of methanol Isopropyl Acetate: Dilute quantitatively 12uL of isopropyl acetate wth 200 mi. of water to obtain a solution containing $52.26 upiml.of isopropyl acetate. ‘Methacol and Isopropyl Acetate Mixture: Dilute quanti tively 10 mL of methanol and 1.0 ml of isopropyl acetate with 100 mL of Water to obtain a solution containing $.1 Haiml. of methanol and 0-5 ya/ml. of isopropyl acetate Test solution: Approximately 25 mg of quetiapine accu rately weighed in ml. of water Example 1 Preparation of Quetiapine Fumarate Step 1: Formation of Compound IV (11-shloro-dibenzofh tI], sIthiazepine) Dibenzothiazepinone (Compound II 4.1 Kg, 18.04 mal) ‘was combined with 19.2 Kg (22.33 L) of xylene ina suitable reactor. To the solution was added 2.07 Kg. (13.50 mol, 1.26 L) of phosphorus oxychloride followed by 1-13 Kg (11.17 ‘mol, 1.55 L) of treliylamine. The molar ratio of Compound TL to phosphorous oxychloride to triethylamine to xylene is approximately 1 mol:0.7483 mo:0.6192 mol-.2378 L. The inital addition ofthe triethylamine causes a mildly exotber- ‘mie reaction and gas emission. Thos, during the addition of each of the components, care was taken to maintain the tem- perature of the reaction at approximately roo temperate (©20.25°C), ‘After combining the reactants, the reactor was heated to seflux (approximately 140° C.) with continuous string and ‘maintained ot that temperature for 4 hours. Thereater, the reactor contents were cool to room remperatute and 6.3 Kg (63 L) of deionized water was added with continuous si- ring. Nex, 1.70 Kp (21.25 mol, 1.11 1) of 50% aqueous sodium hydroxide was added with continoous stiring t0 adjust the pH to approximately 2.53.5 followed by the add US 8,048,876 B2 13 tionof0.20 Kgof Celie. The solution was then tered, The resulting aqueous and organie phases ofthe filtrate were then separated, and the organic phase was twice extracted with 2.S Kg of deionized water. Residual water in the organic phase was then removed by distillation under vacuum at tempera- ture that did not exceed 65°C. The resulting organic solation ‘a8 then cooled to mom temperature and tse in step 2. Step 2: Formation of Compound I(2-(2-(4-libenza [bei 4}thiazepin-1L-ylpiperazin-1-yhethoxy etha- nol) Tote xylenic solution of Compound IV obtained in step 1 is added 6.14 Kg (35.24 mol of 2-2-pipenszin-L-ylelhoxy)- ‘ethanol. The mixture is then heated to reflux Cappeoximately 141° C.) and stirred at this temperature for approximately 6 hours. The molar ratio of Compound IV t0 Compound V is approximately 1 mokI.95 mol. “The reactor contents were then cooled 10 room tempera ture, and 19.$ Kg of deionized water was ad with contina- ‘ous stiring. Next, 1.93 Kg (18.52 mol, 1.64 L) of hydrochlo~ Fic acid was added with sticring to adjust the pll to ‘approximately 4555, The mixture was then steed for aa ‘addtional 15 minutes. Thereafter, the aqueous and organic Phases were separated, and the aqueous phase was twice ‘exnicied with 4.7 Kg (5.46 L) of xylene. “The aqueons phase thus obtained was placed in a suitable reactor. and24.7 Kg 28.36 Jofisopropyl acetate was add. The pH of the aqueous phase was then adjusted to approxi rately 9-10 by theadditionof 3.8 Kg (47.5 mol,2481.)ofan aqucous sodium hydroxide solution (eg. 30% aqueous sodium hydroxide solution). The phases were then separated. and the aqueous phase was extracted with 6.4 Kg (7.35 L)oF ‘isopropyl acetate, Nex, the combined organic extracts Were treated with ative charcoal at room temperate For appeox mately | hour and filtered The isopropyl acetate was removed by distillation under vacuum 10 a final volume of approximately 15 1 without ‘excoedinga temperature of approximately 60°C. The isopro- pylaeetate was further removed by adding 21 Kg (26.51 L) of ‘methanol and continuing the distillation under vacuum to 8 final volume of approximately 15 L without exceeding @ temperature of approximately 60°C. Next, 13.5 Ke (17.04 L) ‘of methanol was aided, andthe reactor contents were cooled to room temperature. The resting organi solution of 2-(2- (4sdibenzo[b.1] lthiazepin-1L-slpiperazin-l-yethoxy] ‘ethanol was thes filtered, and a sample was titrated to assay atof242-(4-dibenzo[b.f[ 1 4thiazepin-I-ylpiper= siethoxy}ethanol Step 3: Formation of Compound I (2-[2-(4-dibenzo [ball1.4}thiszepin-1 Lylpiperazin-1-yethoxy ethae ‘ol Fustarate) ‘The organic solution containing $39 Ke (14.06 mol) of ‘Compound I obtained in step 2 was heated to approximately 50-55° C. Separately, 0.82 Ky of fumari acid (706 mol) and 8.1 Kg (10.23 L) of methanol were combined in a suitable reactor and’ were heated 0 approximately $0.55? C. and ‘maintained at this temperature with continuous string for approximately 15 minutes. The heated fumarie acid olution ‘a8 then poured into the solution containing Compound | ‘while maintaining the temperature at approximately 50-55” C. The mixture was maintained at $0-55° C. for approx ‘mately 30 minutes with continuous stiering, The reatoe Was then cnoled to room temperature and maintained at 20-28" C. {or approximately 5 hours and 20 minutes. 0 o 14 Thereafter, the suspension was filtered, and the collected wet solid was dried under vacuum at 60° C, until eoastant ‘weight to yield 5.7 Kg (12.91 mol, 91.85%) of quetiapine fumarate. The solid was then milled and sieved tough a 500 um sereen and blended for 2 hours. ‘Analytical data: HPLC purty: 99.72%; Residual solvents (os determined by gas chromatography): isopropyl acetate=100 ppm and methanol 903.15 ppm: Panicle size: 10% by volume ofthe panicles havea diameterbelow 4.61 um, ~S0% by volume ofthe particles have a diameter below 16.60 um, ~90%% by volume of the particles have a diameter below’ 33.70 ims Titration 99.26%, Example 2 Preparation of Quetiapine Fumarate Step 1: Formation of Compound IV (11-chloro-dibenzofb I sIhiazepine) Dibensothiazepinone (Compound Ill, 100 g, 0.440 mal) was combined with 600ml. ofxylenein 21 flask keptat vom temperature under nitrogen atmosphere. To the solution was ade 50.60 g (0.330 mo, 30.82 mL) of phosphorus oxychlo~ ride followed by 27.60 g (0.273 mol, 37.81 mL) of trethy- Jamine, The molar ratio of Compound IIT to phosphorous oxychloride to triethylamine to xylene is 1 mol:0.75 mol: (0.6205 mol 1.363 L. The initial action ofthe tiethylamine causes a mildly exothermic raetion and pas emission. Thus during theaddition of eachof the components, care was taken to maintain the temperature of the retetion at approximately oom temperature (-20-25° C.) “After combining the reactants, dhe resulting white suspen- sion was heated 10 appeoximately 140° C. sith eontianous Stirring and maintained at that temperature forapproximately 9.5 hours. Thereator, the reaetor contents were cooled 10 oom temperatureand 154g (154 ml.) of deionized water was ‘added with continuous tering for approximately 30 minutes. Next, 35.19 g (0-44 mol, 23 mL.) of 50% aqueous sodi hnydroxide was added with continuous siring toadjust the pH to approximately 2.5.35, followed by the aldition of § g of elite The sokation was then filtered. The resulting agve- ‘ousand organic phases ofthe irate were then separated, and the onganie phase was tice extracted with 61 g (6 mil.) of

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