HU230417B1

HU230417B1 - Process for producing adduct comprising desloratadine and carbon dioxide

Info

Publication number: HU230417B1
Application number: HU0600805A
Authority: HU
Inventors: Mezei Tibor 25% dr.; Simig Gyula 14% dr.; Enikő 10% Molnár; Lukács Gyula 8% dr.; Porcs-Makkay Márta 8% dr.; Zoltán 11% Katona; Ferenc 8% Bartha; Vereczkeyné Donáth Györgyi 8% dr.; Nagy Kálmán 8% dr.
Original assignee: Egis Gyógyszergyár Zrt
Priority date: 2006-10-26
Filing date: 2006-10-26
Publication date: 2016-05-30
Also published as: WO2008050162A1; HU0600805D0; HUP0600805A2

Abstract

Process for the preparation of a desloratadine adduct forme with carbon dioxide of the formula: (I)

Description

(57) Extract

The present invention relates to a process for the preparation of the desloratadine carbon dioxide adduct of formula (I).

x 1/2 COj by reacting desloratadine base with carbon dioxide in the presence of acetone. The desloratadine base is added to the acetone in an alcoholic solution or in powdered form. C 1-4 alcohols, preferably ethyl alcohol, are used to dissolve the desloratadine base.

MANUFACTURING PROCEDURE FOR DRAINING A DRIVE DIAXIDE WITH A DIOXIDE

The present invention relates to a process for the preparation of desloratadine carbon dioxide.

kv / elel'btoi n ialmmam iargmt ounces of my im kepletn dedonnaé 'ÓCW ιΛ, 3' U '.'X s'? ?\ -HE ?' .. kv.tetem h <rvn.mrnk, .nmnaK Kinetkeneben dare to produce mammedicine formulations (I) images with decalcifiers of carbon dioxide.

In the pictures of the desoludme ^ -clur-gj t-dthidn> -l LnMnpendludennel / o PleTkirepül í.fddp.ud.nt allery .. against moh filter hausn which is also used by the healers of the physique. When administered orally, the anti-allergy effect is 34 times stronger than loratadine sodium, which lasts for almost 24 hours, which allows a once-daily dosing (Arzyn. ForschA Drug, Rev. 50 (EV, 4: 345, 2000))

Λ dl) Preparation of Leplem desloratadine Formula (ll) loratadinobol sd-clo η 1 UJIIemod 1 l-tUMUíbei ',! -J-pnundtlUenbellbenzefSTltiklobepiaiTd-bipIrldlít)), by L-etexicarbonibesupply by acidic or alkaline hydrolysis and decarboxylation, Jd Leplem des'euudme. m zeu m haus uup u term.tul. h.omalj.4 gy m'e * ke'Vmnut> ek eu.nbtamtbe · desnzmdme ash Two polymorphs, submerged in the evening inrmau. · 'Letters A Pl es P? pvlimmiel. uLtniov blood vessels for eculhUmt? Patent Application Vb 2004/0242619. U.S. Patent Application Serial No. 2006/0135547 discloses the preparation of F2 polymorph from another solvent. The WÖ 2005ZG84674 patent is copyright .Wu, 3 V 'e,'. '• e'epo. - - - Oh

A 19 ·; kó-f in Hungarian s / abuAüvn. bog} from deslorafadine with hydrochloric acid, methanesulfonic acid. sulfuric acid can form salts with acetic acid, ntaleinic acid, fumaric acid, phosphoric acid, but they are not mentioned in the case of the aetaric limestone.

The salts mentioned below provide some of them and their preparation is described in FOG 04701. The loratadine ethoxycarbyl group is removed by hydrolysis at high temperature with concentrated mineral acid. From the reaction mixture, desloratadine kois keli molecules can be measured directly in the presence of <RTI ID = 0.0> 1.2 </RTI> ml-J. The production of the desi ~ din ~ <bsznl.fab is again • the production of “dibidrogenkferld” and Ahhiárogénhrotnld. Examples include desloratadine orulfate sulphate a. bemk / uh u Joa.k: .i.'U ubenn. The resulting salts (1: 1) of the desloratadine base are prepared in a dichloromethane medium with the following acids: hydrochloric acid, bezolol sulfonic acid, methanesulfonic acid. fumats.o es snoring ^ .o

ΑΌ? OÓ4 01: - Are they c IV t * V years? 1; 2 '»non-kAn nm decades, the preparation of the two polymorphs of the hemiumarate salt is described as being adaspernks neb.no b>kka; ο Α'Ό e ^.} emo

The desendant psoriasis of A. desloratadine lem is first described in WO20 / 06/03479. It has the advantageous features that are more suitable for the salts described by the genus · ³ g, and teleo.go. ov.g omelet tk t * today · ³ knives for producing nmv. According to the patent application, when desloratadine base is dissolved in a solution of organic solvents such as tetrahydrofuran or ethyl acetate, it is $? adds an adduct of 2 n 'ok'kuh de-domadadme base molecule with carbon dioxide (I). 1 / addtikuan is the pseudopolymorphic form of the xl-enopo from the mole of the deslormadme juice. HPLC shows that the pseudopolymorph (1) thus obtained is very pure. The reason for this is. that only the deslommdnn hand ', ·, su <dto xdddddulused adduct of the toets desleramdme-bvl in the ultra solution. oyk

AOéOúo there 14? Dmim edd. v.dudahm heieieoies-enmy th th th is prepared in an ester-like solvent, preferably ethyl acetate, ether, tetrahydrofuran, diethyl alcohol and carbon (methyl or ethyl alcohol); In practice, the appropriate stoichiocrystalline carbon-dtoxld product is kcp.vxhk, if át borate ah ne b.vts organic oido '.' Ethcn their hands to lead me to soda dioxide. or continuous introduction of carbon dioxide gas 1. ski. ^xt '''e e e' e 'v'> this is o o '·>, í d,'. s. The x 'sxs s, metti and ethylalkoimlhan are soluble, i.e. the precursor gives the base to the make-up solution in an alcoholic solution. The approx. Ethyl or ethyl alcohol containing 10% alcohol by volume: · ssvdvdv legvben a. (ti) fattening lacquers gvuiorbmag immolates, so they can be obtained by good production. The WÖ20Öő / (M) 3479 International Patent Completion -. ormi m th Leplem -vren-dioxidd addnktum e>! ax, ¹ 'oex í s <x. . x ',. e. u ,,, "

The carbon dioxide adduct of the formula (1) obtained from the ethyl acetate medium is a skin.xytm ol-segA ppea taodma 'dtk. Although the amount produced by the methods described in WO206Z0Ö3479 is the same as in the laboratory-scale production * 3 · did not exceed the extent permitted by the pharmaceutical authority, but the mammals are not present; mohlene?

cause

The active ingredient containing the ester-type solvent residue is formed by the Aoahnou kesnimeny knolaso uuo dVt, which is a quaternary desloratadine, which is present in an amount of time. after exceeding the pharmacy pseudo-bowl allowed rate.

A '+ mte, o <x ^K e? , e.nes s, υ ti ^c Ά size extension, further description of the application described and used in the application description, t. et al ua tetuhnh efnr and alkahtu.'á-in the case of a hurry / s Amuu size can be solved with a combined temperature / vacuum / asaxal in the working size of the amoam under the official control level, whereby the carbon dioxide adducium stoichiometrium decomposes.

Due to the shown below WO20Ö6 / ÖÖ3479 ... International patent application No. Au al tg * t ,, ου ι;. Οο.ό ;, t Ao since seg'.nkt χυ _e / 'ts.ott, EHA nnauh BC The preparation of the desloratadine carbon dioxide adduct of formula (1), e.g. that w,, eee emesem <. a, u meet the requirements of the pharmaceutical industry,

The invention relates to a novel process tehál desloratadine se of formula (1), no, 'ed' kto em ii ts, \ \, e ', p' e _v off. a, ο using a mixture of either steel and aliphatic alcohols to form a product suitable for the preparation of the stability required by the authorities;

Surprisingly, it has been found that the high dielectric constant (20.7), dipolar aprotic solvent, acetone, is particularly suitable for the preparation of the carbon dioxide adduct of formula (I). The active ingredient thus obtained is in all respects suitable for providing a stable pharmaceutical composition for killing it.

That's it. rather surprisingly, the use of a high dielectric constant (20, 7), dipolar aprotic solvent, on the steel, is preferred for the preparation of a carbon dioxide adduct of the appropriate quality (1), as described in WO2006 / Ö03479. patent application, according to the preferred ester of opsran p 'cokii zinc to eccmt db cs ac? -'p-on smart .. uk pl. trahwofuran, dimethyl ether, is a non-polar solvent, has a dielectric constant of about 4 to 6. Although the use of small amounts (max, 15 '%) of alcohol for technological reasons is permissible, experience has shown that in high alcohols with a dielectric constant (over 20), the carbon dioxide adduct is not 1 epwhk. nor does the adduct produced in other solvents dissolve in alcohols during the evolution of carbon dioxide.

Various materials, such as the polarity of solvents in the literature, are characterized by the substance-like constant of the material, which can be found, for example, in the example of C ... c. 1 of the IL-64-S2 pages of ILMöboi'K v Kenus and Physics.

The process of the present invention is based on carbon dioxide (i) of the formula (I) km. that desloratadine base (Π) is reacted in the presence of acetone with carbon dioxide.l The desloratadine base in alvholO 'Gidai' g gives a gentle point in horseradish. the ueatcniw

According to a preferred embodiment of the process, the desloratadine base is administered in 1 to 4 micrograms of tv; n. in which we continuously lead carbon dioxide. The alcohol used is acetone used. x 'a'i'ö' eye ex ^s

Alternatively, desloratadine of Formula H may be a suspension of acetone with acetone or a mixture of steel and alcohol. diatomaceous pellets / iodine / tertiary or dry ice.

Desloratadine and: the reaction of the carbon dioxide can be carried out between 20 and 60 ^° C. The shape of the Inuk kosod) is a scar (scar on the occasion -vt temperature. The shape of the crystals influences the drying surface and thus the amount of residual solvent).

I ler .xt jetkeiVi m <i.eme ^: t o o.sxk steo ab preferably '45' to 55 '^; G is performed when the adduct of formula (I) is obtained in the form of well-dried crystals.

In the process according to the invention, the reaction is carried out in the presence of 2 to 50 times the amount of the desloratadine base used, preferably with an O-20 volume.

The novel process (adduct of the adduct of h images is the same as the powder spectrum of the adduct obtained according to the sixth part of WO2006 003479.) In addition, the subject of the present invention is the stable desioratadine K molar carbon dioxide produced according to the invention. desloratadine and desioratadine acid addition salts of high purity are produced in the high-purity <11 <RTI ID = 0.0> image </RTI> of the adducts of the present invention.

Specifically, desloratadine can be prepared in desiccates of desloratadine K by carbon dioxide in the organic solvent, or in a solvent mixture, optionally boiling and then partially or completely evaporating the desioratadine base to crystalline crystals. kapon destoratadine base is referred to hereinafter as the reference

Preferably, desloratadine of formula (II) can be prepared by deslounadine mole with vemdiovide keporou adducmmfu aliphatic alcohol ?? the solution was heated to boiling, the solution was boiled for 0.5-3 hours if necessary, and the solvent was evaporated in a mixture of acetone and methanol and crystallized.

Choosing the solvents or conditions of the recrystallization, various desioratadine polyorphic agents known in the art can be obtained, k'k'mem *. autochthonous by-products of ohm to desioratadine .addatonibel. the desloratadme base prepared according to the foregoing.

Desioratadine salts are described in WO2 / 066 / Ö3479, International Publication <O <ν i i m λ Ό η ν.

In the presence of an organic solvent, a solution of 14 molar carbon dioxide of formula (I) produced in the presence of an organic solvent is reacted with the organic acid side of the corresponding acid.

As acid, e.g. Hydrochloric acid, Hydrogen-bromobutose Keosova, Methanesulfonic Acid, Nitrogen / Niiosmman Nitric Acid

One of the Ibgsnatosbásl modes of the fend method is a method for preparing s & vnddicl salts in such a way that the acid is sddnktumra of the formula (1) mt / to <telein <vn efemium anmUeat .dk, um, i, sok. In this case, desloratadine is obtained in 1 molar equivalent of acid.

KUi bear: mami iogaomO''d, to media, W a vn a to (0 kepkm adduknsmm vomufe'.ntoa best? .L mokmmskm. OlO''y.ö, m? J nmmamyban // nk Acetone is the salt of the defenmadine with 2 mole equivalents of acid.

An advantage of the process of the present invention is that it can be produced by large scale industrial methods. stable, pharmaceutical grade (1) diuretic, The product should not be subjected to conditions under conditions of plowing. where he produces, meehokmeek .'V mtetele meotokomk. , c on steel as residual solvent, does not cause contamination during the stability test of the preparation.

Invention. another significant advantage is the deactivity of the present invention; nmv? moll * 'emdn' Oh.al aL '' .. '* eedokmma k: .ón.von a.kuhmv is a high purity (S) image for desieramdine and desloratodfee high purity acid addition salts. This is because the (h képiéin carbon dtoxídda ~! Formed, desbratadine pszeodopolipw.rf állrthatö produced in such large sztaságú form which a- pharmaceutical .οχ .. '' C ^'\! \ \ Ex. Of l' \ "yeu 'adduktnm'> rseume a deslomyxlmr h <*. n a'bert Oymumsan svklil Alex. '' «.mu? '1 w * <v í ^ unnaz.

In the preparation of the bratadinbol karbetoxkcsoport iebasításakor small i \ xv \ xx \ u 'm \ xp Oxh b \ x om ^<f x ¹ - x \ a \' χ · x. x h '? η vnmxW up''x'''' after removing the addnktum they remain in the mother liquor. So desloratadine can be free from amine-h'-pollutants without any further rüJmatouob. ane.kuh b.og> on Oltalmán) ta pektakm kmknxvoank 'lUléíd l k-sleramxiun''xm'dm xdmbn.rt. t iU with chemicals)

A 250 mkg spherical bulb is weighed with dry ice. and the evaporating carbon black is an intense blend of 1200 ml. 45''C 'A'''x'x xx x ''Ox'jx m! * rt 'XO x' X \ t A solution of 80 g of desbtatadine base in 140 ml of eianol was added to 30 of the x funnel.

The crystallization of the work is approx. the half of the solution .. starts to feed. The crystal sisposol was then crushed for 20 hours at 20 ° C Filtration killed the sepbenzene for one hour 5 C-uu mixed titres, precipitated amalgam precipitated by s. washed. A to AA _v u line to constant ρΊ 5 m \ t

Tertin tea 80.7 g (04.3%) ·. white powder.

Anthfe calculated _for Α, ΑΌΑ c'j f eple

Sfefefei C: W1 tt: 5,20 OAOJ? HA, 41

Measured CAOJ5 H: 5.66 Cl: N3: X X. O i <»^ c 0 x '

WDzö0O / Oö547O is the free, teaser application for taking aadnktnm ÍR. and X-ray and pekru: n years of 0

Deslomiadme H.®q1 CÖi-daC-formed addnktnmáwk

Dry masses of 50 gb cubic meters were weighed, and the evaporating carbon black clay was incorporated into a. under the liquid level. A solution of desloratadine base S, 0 g in desloratadine 10 ml in methanol was added to the acetone dropwise over 20 minutes.

The solution above, C''ndaXi, is about approx. after the addition of half-heartedly, the crisub vns.pemoei e / nun eg CtHgasu manhole o C-yu 5 -, ' ^{x 1} i' _s ', ve v \ t

Claims

The material was filtered, washed with 15 ml of 5 T acetone on a filter for ⁴ hours. 5 25 gt ^ hO Au can do pm

The pnminigen spectrum of the above obtained is exactly the same as that of WÖ200e / Ö034'70. patent adducts obtained by patent application.

.AxeUh

Addition of Desloratadine 'mole C'0; tite, < Ötévese cs' s ^\! <t _t i _r t

She lived a lot with .0 ml 60 l ^! C in 2 * propanol. The desloratadiue base 2 ~ pmpanolos side is given by 55 Ákos aeeíonbuz.

Yield; 8.2b g (95.2%) of white powder.

The resulting IR and powder X-ray spectrum has a wavelength of < RTI ID = 0.0 >< / RTI > _: X-ray spectrum of the adduct obtained by the free-form application.

'Desloratadine Production of rao.1 (/ ΟΑ-άοΙ trained adduct)

Example 2 is followed except that the desloratadine base in methanol is dissolved in 20 ml of 60 T Hbutanol. The de-butsnofos Aratadiue base 1 'is added 50 ^ö (> os auetonte.

e »ed <v S.i.A 'O'Atsol

The resulting IR and powder X-ray spectra are substantially the same as those of WO2 / 06 / Ö3479. patent application claims that the adduct is obtained by the powder vector 1.

.peldg kkniomiaéio. '' nn <OA.JJ ken.au adöuktmnnnak ehv.bna.v.

We measure a dry weight of $ 0 mkes of gbmblomhtkba, and the evaporating carbon o, i'ohamamvin a> men> en fen motel, l 0 nd 5o aeenvn tatalma, o fely, .feek \ t Ja se.'fefefe, V ueemnfev febl · In detail, a finely powdered desloratadine base is added. The pellet was stirred for two hours after the addition. then for an hour thu tasting · s.ntstx,>. the 4 yeah and one em kaergu.vt acute 0 V-m e e e t t em eu »MA rAe is filtered, the filter is washed with IS ml 5 ml of acetone, for 1 hour at 40-45 vol.

Ny originates; 8.33 g (93.5%) of white powder

The resulting product had the IE and porrbntgen spectrum fully identical to the X-ray spectrum of the diatomaceous earth obtained by the O2iW 0054 ''?

fe.MEte

Desloratadine Base P1 Polymorph Flaming Foam From Desloratadine To Protein Formate With Desloratadine Sulfur Carbon Dioxide Add 120 mg of ethanol in 120 ml of ethanol to one hour with teaspoon, followed by evaporation of the solvent in vacuo. To the residue was added 360 ml of acetone and 20 ml of methanol. The mixture was refluxed, clarified, filtered, and the filtrate was allowed to cool to 25 T over half an hour. and after that, for one hour, we'll filter out 4 oranKetesed I '0,' n ke eueigtk, nt.th.et '0 ct. kk _v üfetsOttgig Me? e * ut nuP sled, oh

Nveredek: 23.5 g (63.0%) ölvmiásmw 257-25 $ C ^ij

The spectrum of the 1B and portgelo of the work is the basis of the pdimetí éeshtnladhe base.

· áákotew.

bw <P>

1 L - ^> M. «Hh <ybb _f « ad jbteww, hill z, Áa Wá & e Msbí a & afe ofeWw wgg pnslx <fe ^ 1 «« φ & as:

X A X igh> M md <Wte, «ad mountain» isMtib * fetish moths »» sMsöfcte, b & sytto hmuib A

The A X or A abb * spsfs, salt, and the tbtaat sBíAel w afabweé ete Ats gu gu gu S S S S S WSU, eKbyAsm AMAW, fegtAAxyőaghtes 5-1W gs.

A. Ás M <igb ^ xwX hemeuhyiU mvted dyfeb, with jdbwmz begy & mAdb XsMŰ X kteM ddayAs 4ΑΑ5 * C fe & BX

A5S * C bM bboA '^ teW v ^ WIA.

As VI sgAjyixmUA bisw ^ ysbe: zswisAs e§feb, cad jdbsmx, assassin assXAA is a fetish gatégfe ssfabsA 2 * 5Η «Λ zMkuWm HXM'SsmA WfgsgmM | Mte Μ | φΑ véfsv.

xs ν 3> · $ A y? THE