EP2001839A1 - Improvements in the preparation of intermediates leading to [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-(4-bromo-3-methyl-5-propoxy-thiophen-2yl)-methanone hydrochloride - Google Patents

Improvements in the preparation of intermediates leading to [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-(4-bromo-3-methyl-5-propoxy-thiophen-2yl)-methanone hydrochloride

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Publication number
EP2001839A1
EP2001839A1 EP07759555A EP07759555A EP2001839A1 EP 2001839 A1 EP2001839 A1 EP 2001839A1 EP 07759555 A EP07759555 A EP 07759555A EP 07759555 A EP07759555 A EP 07759555A EP 2001839 A1 EP2001839 A1 EP 2001839A1
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EP
European Patent Office
Prior art keywords
condensing
compound
formula
solvent
methyl
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EP07759555A
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German (de)
French (fr)
Inventor
Adam W. Sledeski
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Sanofi Aventis France
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Sanofi Aventis France
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/22—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides

Definitions

  • This invention is directed to improvements. in the preparation of intermediates leading to [4-(5- aminomethyl-2-fluoropheryl)-piperidin-1-yl] -(4-bromo-3-methyl-5-propoxy-thiophen -2-yl)- methanone hydrochloride.
  • Mast cell mediated inflammatory conditions are a growing public health concern. Asthma is frequently characterized by progressive development of hyper-responsiveness of the trachea and bronchi t ⁇ both immunospecific allergens and generalized chemical or physical stimuli, which lead to the onset of chronic inflammation.
  • Leukocytes containing IgE receptors notably mast cells and basophils, are present in the epithelium and underlying smooth muscle tissues of bronchi. These leukocytes initially become activated by the binding of specific inhaled antigens to the IgE receptors and then release a number of chemical mediators. For example, degranulation of mast cells leads to the release of proteoglycans, peroxidase, urylsulfatase B. chymase, and tryptase, which results in bronchiole constriction.
  • Tryptase is stored in the mast cell secretory granules and is the major secretory protease of human mast cells. Tryptase has been implicated in a variety of biological processes, including degradation of vasodilating and bronchorelaxing neuropeptides (Caughey. et al., J. Pharmacol Exp. Ther, 1988. 244, pages 133-137; Franconi. et al., J. Pharmacol. Exp. Ther., 1988. 248. pages 947-951: und Tam, et al.,
  • tryptase inhibitors may be useful as anti-inflammatory agents ( K Rice, P.A. Sprengler, Current Opinion in Drug Discovery and Development, 1999, 2(5), pages 463 -474) particularly in the treatment of chronic asthma (M.Q. Zhang, H. Timmerman, Mediators inflamm., 1997. 112, pages 311- 317 ), and may also be useful in treating or preventing allergic rhinitis (S. J. Wilson et al, Clin. Exp.
  • tryptase has been shown to be a potent mitogen for fibroblasts, suggesting its involvement in the pulmonary fibrosis in asthma and interstitial lung diseases (Ruoss et al., J. Clin. Invest., 1991 , 88, pages 493-499).
  • tryptase inhibitors may be useful in treating or preventing fibrotic conditions (I.A, Cairns and A.F, WaIIs, J. Clin, invest., 1997. 99. pages 1313- 1321 ) for example, fibrosis, secleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas and hypertrophic scars.
  • fibrotic conditions I.A, Cairns and A.F, WaIIs, J. Clin, invest., 1997. 99. pages 1313- 1321 .
  • tryptase inhibitors may be useful in treating or preventing myocardial infarction, stroke, angina and other consequences of atherosclerotic plaque rupture (M. Jeziorska et al, J. Pathol.. 1997. 182, pages 115-122 ).
  • Tryptase has also been discovered to activate prostromelysin that in turn activates collagenase, thereby initiating the destruction of cartilage and periodontal connective tissue, respectively.
  • tryptase inhibitors could be useful in the treatment or prevention of arthrisis, periodontal disease, diabetic retinopathy, and tumor growth (WJ. Beil et al. Exp. Hematol., (1998) 26, pages 158- 169). Also, tryptase inhibitors may be useful in the treatment of anaphylaxis, ( L.B. Schwarz et al. J. Clin. Invest., 1995, 96. pages 2702-2710), multiple sclerosis (M. Steinhoff et al Nat Med. (N. Y.), 2000, 6(2), pages 151 -158), peptic ulcers and syncytial viral infections .
  • the compound of forrmila I is particularly useful for treating a patient suffering tram conditions thai can ht; ameliorated by ihe administration of an inhibitor of trypia ⁇ , e.g., mast cell mediated inflammatory conditions, inflammation, and diseases or disorders related to the- degradation of vasodilating and broi ⁇ :horehixin2 neuropeptides.
  • an inhibitor of trypia ⁇ e.g., mast cell mediated inflammatory conditions, inflammation, and diseases or disorders related to the- degradation of vasodilating and broi ⁇ :horehixin2 neuropeptides.
  • Ths present isvcniioa is dir ⁇ eied to impr ⁇ vensefits in the method of preparing insermediaic c.”;ii?poyi>d 13.
  • Additionaily, ihe me ⁇ h(.»d is focused on improving safety and industrial hygiene advasujiscs that would efiniirune ihe need for using earb ⁇ n disulfide and potassium hydride in the reaction.
  • the method is focused such as so be snore amenable for the manufacture of Sarps-scale pharmaceutical aj ⁇ iousts of the compound of formula L
  • the method would sJso eliminate three chr ⁇ mniographic reparation steps and reduce ihe rota] reaction time of she thr ⁇ c-step proeedure,
  • T he present invention is directed to improvements in ihe preparation of 3-oxo- l -propo ⁇ y-bat-l - c»yLs «Ha ⁇ >'1)-acc!ic acid methyl ester (coxnpOLi ⁇ d of formula 13) and S-oso-thiobstyriv acid O-pf ⁇ py] ester icornpoiind of formaia 8 ⁇ . which are useful im ⁇ rsed ⁇ afes lor the preparation of the compound of forrnuia I.
  • Furtivsmiorc « she present iuvention is directed to a method for preparing a compound or fo ⁇ nula
  • rhc present invention is directed to a method for preparing a compound of formula .13
  • Trcaunsnt or “treating” includes prophylactic therapy as v.dJ AS trea.? ⁇ v ⁇ :m of an establish condition.
  • tbi* present invention is dwrcietl to UK: meiluxi for ptvparing a cor»pr>unJ of l ' o ⁇ nul ⁇ 8 comprising condensing the c ⁇ .> « ⁇ po ⁇ i ⁇ l of formula 7 with acetone, wlicrein five cor ⁇ 5ersir.g i ⁇ carried out in the presence of an iprotic organic s ⁇ lxxnt >cLxfcd fi ⁇ m an ethcrual solvent and u hy ⁇ 3rucarlx>D snlvctrt.
  • invcniion is directed to having an ethef-S ⁇ ! ⁇ oiv ⁇ nt sciocicd from te».-abydri%fiicin. 2-methyUelfaiiydrofuran MkJ ten-Suiy! methyl c.her.
  • Another pdrticuljr eirixxiitjvsnt of ihal iiivvuikni is directed to condensing ⁇ t ⁇ tetnoexatyre froci aKiit 25 v C to ubo «»t 45 o C
  • Anotiier partkuiar embodinxitf of that invention is directed to corateming Ht « id- ⁇ ct'Uturc of about
  • Another p* ⁇ ticulur «:mhodimcrtt of that invention is directed to condensing in the presence ⁇ f an organic metal base.
  • Anotljcr particular embodiment of ll ⁇ t hivcolioti is wherein the organic metal base is selected tnun an alkali :ncw! amide bivo and an alk.au nteial hydride.
  • the alkali metal amide base is sekxied iron) ikhksin diisop ⁇ opylamide, lithium dieyeloh ⁇ xyiaifiiiie. lithium (bis ⁇ trirneth>isifyi amide, sodium (hsslinmethyixsly) arnsde arid potassium (bis)trin ⁇ cthybijyj amide,
  • alkali metas axriide base is s ⁇ dii ⁇ s (hls)tnmethyisilvf amkk.
  • Another p&rticiiW ersshodirnem of that invention is wherein she alkali metaJ hydride is selected from from lithium hydride. sodium hydride and frictioniiun hydride.
  • the present invention is directed ED the method for preparing a compoinui of formula 13 compriss ⁇ g alkylating a coinpnund of fo ⁇ ntsla 8 usjns raethy! bromoacciaie. wherein the alkylating is carried out in the presence of ts.n aprotic organic soh-em, u. mixture of apre ⁇ ic organic solvents, or in fhe presence of ' a mixture contsining a polar upraise solvers! snd nn ethereal solvent.
  • she aprotic organic soiveftS is? selected from a polar aproik solvent arsd a chlorinated hydrsxarbon solvent.
  • tliaS iiive ⁇ tion is wherein ⁇ hc ethereal ?olvem is selected IVO ⁇ ⁇ ctrahydrofunin, 2-methyketyahydrofuran and tert -butyl methyl e?her.
  • the present, invention is directed to r&vini: dichioroniedusne &i a chforhu ⁇ ted hydrixarbon solvent.
  • Another particular embodiment of that invention is diseeted to alkylating ai a temperature, fvam ahout 0 v C ⁇ O about 50 ;! C.
  • panks.i ⁇ r embodiment of rMt invention is direcied to alkylating st a temps rafujre from about 5 ⁇ ! C; Jo about 40" C.
  • Another particular embodiment of that invention is directed to alkylating txi a temperature from about S" C lo ab ⁇ i!t 35" C.
  • Anoihcr partk'ular embodiment of tKat invention is directed to alkylating in theuiteixe of an ulkvlaminr haix ⁇ .
  • cmHo ⁇ Jme ⁇ t of that invention is «/ltcrein the ⁇ iikylan ⁇ inc base is ⁇ ckxtcd front trieihylamine ami diisopropyieUijlainine.
  • the compo ⁇ nd of the present invention is ait athiral ⁇ )n ⁇ (Ain ⁇ J whose preparatioa ⁇ ctHnprised of the stepwise procedures that culminate in the prepa ⁇ uioo cit thiocartsuiaic D. as shewa in ⁇ kberoe J.
  • Scheme II below lhcn shows the s « ⁇ pwi ⁇ e pixxodurcs that result from reac-iag the ihiocdrb ⁇ miite compound 13, to eutmiruite in UK prrpaira» ⁇ »n of the cvrrtpound of fiKmula ia.
  • ⁇ * hich is Uw hydrochloride buil f ⁇ xrn of ihc cinnpcnind of fo ⁇ nula I. discussed stipnr.
  • i .i Mhiocarb ⁇ yidiimidazoic is e ⁇ nvt ⁇ ttfd to compound 7 by reacting i-pjxjp ⁇ no! in the presence of an etherea! soh"er»t.
  • arotriatic l ⁇ >drv ⁇ arb(in y.»ivcnt ⁇ v ⁇ ester solvent, inch x ⁇ inwhyl len-bmy! rucr (MTIiE). to yield mioeurbjtnato compound 7.
  • Compound 7 is convem.* ⁇ to compound 8 by condensing compound 7 with acetone i» tru* pivseiwe trf an ethereal ⁇ ivent or aronutic hydrocarlxM solvent, soch «s oflhydmus tefrohydtofur.'m (TW) and adding the apjaopriato r»ase to ) ⁇ e!d ihc keto ⁇ iioc»ier pr»xi ⁇ t. , Lc UK compound of f;>nwtu JJ.
  • Compound B is convened u> compound 9 by ustng an alkylating ager.t mch as mcih ⁇ l rraimoacciale. iu the pr ⁇ kentc o ⁇ ' a eliiurnwted (jydrocarbon sovJcnu polar aprotk solvent w a niixtitfv of poljr apriHic ioiv ⁇ iitb, )>uch a* dimcmylfo ⁇ rtfimidc (OMF 4 '). to yield the S-alkyiatcd prtvim-t. i.e.. tix r . con ⁇ pouad intermediate o; formula 13.
  • the staj fi ⁇ L; rfi ⁇ t-rials and ⁇ k-i ⁇ ned ⁇ k> may be prc
  • T ⁇ o frcsc ⁇ s hAeisfi- ni is dho discoied ⁇ > some fntctnvdiaios in thx ahtne scru ⁇ nix ⁇ ,.i-xl > ss nicK ihc processes described h « ⁇ vin for their pa-parytiod ctms ⁇ l ⁇ tc futihor features of ihc prcv ⁇ s irssrnrio ⁇ Exampitfs
  • the present sswn ⁇ n may be better understood by reference Io the ihlhwing son-HroJfm" Examples, which arc provided as exemplary of the invention.
  • the f ⁇ llcsvvmg examples are presented iss order to more fully j lhi ⁇ tr&te particular embodiments of lhe invention. They should in no way be conxmscd. however, as iln ⁇ iflrig the broad scope of the mverUion.
  • Tiie organic phase is wash;* ⁇ with saturated sodium bicarbonate sohJliojt (50 ml.), water (75 mL> and brine (50 ml.). It is dried over rodium sulfate, tlien it is cv>i ⁇ emr»ted on iociry evaporator : ⁇ t an lumber ml, comr ⁇ it;nd 8 ( I 8.. * J g. 70% cn ⁇ k yickJj. a jn cuol-keUmc mixture. MS (EI) tii'r. 160 (M+). 1 H N'MR (300 MfIr, CDCJ... ketone ! cno!
  • the aqucouk pl ⁇ i ⁇ e is ttxt ⁇ ctcd wilh MTBE ⁇ 3 x KM) mL).
  • the combined cr ⁇ anics arc wnsJied witK water (IW ml..), brine C75 ml.) ami then are coucenlraJed oo a rotary cvapo ⁇ tor to l l .S g ot ⁇ )dkr-v oiL
  • the antic nuucrul is allowed to stand over-night at room tcn ⁇ cr ⁇ turv. atUsr which it is turned into a mixture of crystalline solid and semi-solid material.
  • the pr ⁇ seru roves ⁇ on is not to he limited in scope by the speci fic c ⁇ ilxxli ⁇ je ⁇ ts describe herein, fndeed, various modificafioss of the i?ive ⁇ iti ⁇ R in uddslion to rhose described herein will become apparent to thost- skilled in ihe an from the foregoing dascr sption and tb ⁇ accoiDpasying ilgyres.
  • Such iTXTi ⁇ ficarions are mt ⁇ ndcd to CaO within the scope of the appended claims.

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Abstract

The present invention is directed (i) to a method for the preparation of a compound of formula (8) by condensing the compound of formula (7) with acetone and (ii) to a method for the preparation of a compound of formula (13) by alkylating the compound of formula (8) using methyl bromoacetate. The compounds of formula (7,8) and (13) useful intermediates for the preparation of the compound of formula (I).

Description

IMPROVEMENTS IN THE PREPARATION OF INTERMEDIATES LEADING TO [4-(5-AMINOMETHYL-2- FLUORO-PHENYL)-PIPERIDIN-1-YL]-(4-BROMO-3-METHYL-5-PROPOXY-THIOPHEN-2-YL)- METHANONE HYDROCHLORIDE
FIELD OF THE INVENTION
This invention is directed to improvements. in the preparation of intermediates leading to [4-(5- aminomethyl-2-fluoropheryl)-piperidin-1-yl] -(4-bromo-3-methyl-5-propoxy-thiophen -2-yl)- methanone hydrochloride.
BACKGROUND OF THE INVENTION
Mast cell mediated inflammatory conditions, in particular asthma, are a growing public health concern. Asthma is frequently characterized by progressive development of hyper-responsiveness of the trachea and bronchi tυ both immunospecific allergens and generalized chemical or physical stimuli, which lead to the onset of chronic inflammation. Leukocytes containing IgE receptors, notably mast cells and basophils, are present in the epithelium and underlying smooth muscle tissues of bronchi. These leukocytes initially become activated by the binding of specific inhaled antigens to the IgE receptors and then release a number of chemical mediators. For example, degranulation of mast cells leads to the release of proteoglycans, peroxidase, urylsulfatase B. chymase, and tryptase, which results in bronchiole constriction.
Tryptase is stored in the mast cell secretory granules and is the major secretory protease of human mast cells. Tryptase has been implicated in a variety of biological processes, including degradation of vasodilating and bronchorelaxing neuropeptides (Caughey. et al., J. Pharmacol Exp. Ther, 1988. 244, pages 133-137; Franconi. et al., J. Pharmacol. Exp. Ther., 1988. 248. pages 947-951: und Tam, et al.,
AM. J. Respir. Cell MoI. Biol.. 1990, 3, pages 27-32) and modulation of bronchial responsiveness to bistamine (Sekizawa, et al., J. Clin. Invest., 1989. 83. pages 1)5- 179). As a result, tryptase inhibitors may be useful as anti-inflammatory agents ( K Rice, P.A. Sprengler, Current Opinion in Drug Discovery and Development, 1999, 2(5), pages 463 -474) particularly in the treatment of chronic asthma (M.Q. Zhang, H. Timmerman, Mediators inflamm., 1997. 112, pages 311- 317 ), and may also be useful in treating or preventing allergic rhinitis (S. J. Wilson et al, Clin. Exp. Allergy. 1998, 28, pages 220-227 ). inflammatory bowel disease (S. C. Bischoff et al, Histopathology, 1996, 28, pages 1- 13), psoriasis (A. Naukkarinen et al, Arch. Dermatol. Res., 1993. 285, pages 341- 346), conjunctivitis (A.A.Irani et al, J. Allergy Clin. Immunol., 1990, 86, pages 34-40), atopic dermatisis ( A. Jarvikallio et al, Br. J, Dermatol. 1997, 136. pages 87i -877), rheumatoid arthrisis (L.C Tetlov et al, Ann. Rheum, Dis.. 1998, 54, pages 549-555). osteoarthritis (M.G Buckley et al, J, Pathol., 1998. 186. pages 67-74), gouty arthrisis, rheumatoid spondylitis and diseases, of joint cartilage destruction.
In addition, tryptase has been shown to be a potent mitogen for fibroblasts, suggesting its involvement in the pulmonary fibrosis in asthma and interstitial lung diseases (Ruoss et al., J. Clin. Invest., 1991 , 88, pages 493-499).
Therefore, tryptase inhibitors may be useful in treating or preventing fibrotic conditions (I.A, Cairns and A.F, WaIIs, J. Clin, invest., 1997. 99. pages 1313- 1321 ) for example, fibrosis, secleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas and hypertrophic scars.
Additionally, tryptase inhibitors may be useful in treating or preventing myocardial infarction, stroke, angina and other consequences of atherosclerotic plaque rupture (M. Jeziorska et al, J. Pathol.. 1997. 182, pages 115-122 ).
Tryptase has also been discovered to activate prostromelysin that in turn activates collagenase, thereby initiating the destruction of cartilage and periodontal connective tissue, respectively.
Therefore, tryptase inhibitors could be useful in the treatment or prevention of arthrisis, periodontal disease, diabetic retinopathy, and tumor growth (WJ. Beil et al. Exp. Hematol., (1998) 26, pages 158- 169). Also, tryptase inhibitors may be useful in the treatment of anaphylaxis, ( L.B. Schwarz et al. J. Clin. Invest., 1995, 96. pages 2702-2710), multiple sclerosis (M. Steinhoff et al Nat Med. (N. Y.), 2000, 6(2), pages 151 -158), peptic ulcers and syncytial viral infections .
The compound of formula I,
asxl its preparation for u^e in the ireafmem of disease states capable of beirsg nuKHdated Hy the inhibition of tryplase, are encompassed by U.S. Piiiem No. 6.977.263 and WC)2{K)5/()i)7780. The compound of forrmila I is particularly useful for treating a patient suffering tram conditions thai can ht; ameliorated by ihe administration of an inhibitor of trypiaω, e.g., mast cell mediated inflammatory conditions, inflammation, and diseases or disorders related to the- degradation of vasodilating and broiκ:horehixin2 neuropeptides.
One method for preparing ihe compound of formula I" disclosed in Wθ2005/ϋ9??SO involves the preparation of she intermediate; compound 13, see Scheme 0, hi a thres-siep procedure in an overall approxiϊDate vield of 23%.
Ths present isvcniioa is dirεeied to imprøvensefits in the method of preparing insermediaic c.";ii?poyi>d 13. Additionaily, ihe meιh(.»d is focused on improving safety and industrial hygiene advasujiscs that would efiniirune ihe need for using earbπn disulfide and potassium hydride in the reaction. Furihsrsrsore, the method is focused such as so be snore amenable for the manufacture of Sarps-scale pharmaceutical ajϊiousts of the compound of formula L The method would sJso eliminate three chrαmniographic reparation steps and reduce ihe rota] reaction time of she thrεc-step proeedure,
SUMMARY GF I HE INVENTION
T he present invention is directed to improvements in ihe preparation of 3-oxo- l -propoκy-bat-l - c»yLs«Haπ>'1)-acc!ic acid methyl ester (coxnpOLiπd of formula 13) and S-oso-thiobstyriv acid O-pf^py] ester icornpoiind of formaia 8}. which are useful imεπrsedϊafes lor the preparation of the compound of forrnuia I.
Furtivsmiorc« she present iuvention is directed to a method for preparing a compound or foπnula
comprising condensing the compound of fornjula ' with αcrtone.
Furthermore, rhc present invention is directed to a method for preparing a compound of formula .13
comprising alk/lalitic a coinpc-und of fometla 8
ut.iny incUij l bromoeceuiie.
Aspects, failures and acvuntajfcs of the prvAcnt iκvcntioπ will he hetrcr ur«isrHcx>d from the fol!owh\g detailed descr.ptioov, all of which Jre given by v>ay of -Jlustπilictn only, and an: ret limitative of the present invention.
DKTΛJI.KO in^cwrnoN OK TIΠ-: INM^-VΓION
The r>ff«n« invi'iritcm sviH he hotter apffccitβcd by nefcιeικe to (he follow me DctuiUxl I>eκ:ription
Dctinrtiony
As used alxivc. and thrnughiπil <l»c descriptitm of ilw inwrniiVi including the apftmled c!a«mχ. tho following aMvύviatiom and terms, unltfis otherwise indicated, an: Uiideivkxid to have the folbwing meaniogst
Co4n|\>un<i(S) υf th.c present invenuon". and equivalent exfav.isior.s, aiv nieaitl to embrace lhc imcrruwliϋtcv of fnrmuiβc 7. 8 atid 13, which arc useful iniernKdidt^ κ<r jhc preparation ol '.IK compotuid of formula 1. ax described herein. Reference :u inωmwdiaK'.'i, wlv^hcr at not they thcmseKc^ are claimed, is meant to embrace the salts, ami solvates, where the c<wU*xl so pcrmin For Jhβ sake of clenn , p*ιrt!col«r instances when lhc cuniuxt sr> permits ur« ^>meiimc« indicated in she text. but thetc inblaiKcs ur\? purely illimrati \* and they are ικ>t intended to exclude other imrancrs M lien the context so permits.
"Trcaunsnt" or "treating" includes prophylactic therapy as v.dJ AS trea.?τv<:m of an establish condition.
"Pauent" nwam> a human or other πtaπtmui.
"Effective irtVsunl" is rwant in describe an amount of « ecxnpound cflcclivo in pitiducirig the <ksired ifvrupetitic ef 'ect
I>afttcul8r Em^-xiimcπti!
In a purlieu lur t'ltiKxliment. tbi* present invention is dwrcietl to UK: meiluxi for ptvparing a cor»pr>unJ of l'oπnulβ 8 comprising condensing the c<.>«ιpoυiκl of formula 7 with acetone, wlicrein five corκ5ersir.g i∑ carried out in the presence of an iprotic organic sυlxxnt >cLxfcd fiυm an ethcrual solvent and u hy<3rucarlx>D snlvctrt.
In αnoCtwr particular embodiment, (be present invcniion is directed to having an ethef-Sβ! λoivυnt sciocicd from te».-abydri%fiicin. 2-methyUelfaiiydrofuran MkJ ten-Suiy! methyl c.her.
Another particular einKxlmttiit of tint invention U wherein the hydixxrarb.'K) solvent wrlectβd from tolusnϋ oixJ Iwpune.
ΛΛOther porticuiar eniJxxJiπicnt of thai invemUx* \\ direc1c<; «n αmdemiii}1 ut a ic.Tjpcrature f/vm about jy C lo arxwl SST.
Another pdrticuljr eirixxiitjvsnt of ihal iiivvuikni is directed to condensing ^t Ά tetnoexatyre froci aKiit 25v C to ubo«»t 45o C
Anotiier partkuiar embodinxitf of that invention is directed to corateming Ht « id-φct'Uturc of about
4ir c.
Another p*ιticulur «:mhodimcrtt of that invention is directed to condensing in the presence <τf an organic metal base.
Anotljcr particular embodiment of llωt hivcolioti is wherein the organic metal base is selected tnun an alkali :ncw! amide bivo and an alk.au nteial hydride. Another particular embodiment of that invention is wherein the alkali metal amide base is sekxied iron) ikhksin diisopϊopylamide, lithium dieyelohεxyiaifiiiie. lithium (bis}trirneth>isifyi amide, sodium (hsslinmethyixsly) arnsde arid potassium (bis)trinτcthybijyj amide,
Another particular embodiment of that invention is wherein the alkali metas axriide base is sαdiiϋϊs (hls)tnmethyisilvf amkk.
Another p&rticiiW ersshodirnem of that invention is wherein she alkali metaJ hydride is selected from from lithium hydride. sodium hydride and poussiiun hydride.
In another particular embodiment, the present invention is directed ED the method for preparing a compoinui of formula 13 comprissπg alkylating a coinpnund of foπntsla 8 usjns raethy! bromoacciaie. wherein the alkylating is carried out in the presence of ts.n aprotic organic soh-em, u. mixture of apre^ic organic solvents, or in fhe presence of' a mixture contsining a polar upraise solvers! snd nn ethereal solvent.
is another particular embodiment, the present invention is whereits she aprotic organic soiveftS is? selected from a polar aproik solvent arsd a chlorinated hydrsxarbon solvent.
Another particular ernbodinxnt of thai invention h wherein She polar aprr>ιie soiversi is selected frosn dimethyifbrma.mkl::\ l-met.byl-2-pyrroϋdoπe and dimeihyisuifoxidc.
Another particular embodiment of tliaS iiiveπtion is wherein \hc ethereal ?olvem is selected IVOΠΪ ϊctrahydrofunin, 2-methyketyahydrofuran and tert -butyl methyl e?her.
In smother particular embodiment, the present, invention is directed to r&vini: dichioroniedusne &i a chforhuϊted hydrixarbon solvent.
Another particular embodiment of that invention is diseeted to alkylating ai a temperature, fvam ahout 0v C ΪO about 50;! C.
Another panks.i^r embodiment of rMt invention is direcied to alkylating st a temps rafujre from about 5<! C; Jo about 40" C.
Another particular embodiment of that invention is directed to alkylating txi a temperature from about S" C lo abαi!t 35" C. Anoihcr partk'ular embodiment of tKat invention is directed to alkylating in the pieseixe of an ulkvlaminr haixΛ.
Another particular cmHoΛJmeαt of that invention is «/ltcrein the <iikylanιinc base is λckxtcd front trieihylamine ami diisopropyieUijlainine.
Another particular embodiment of that invention i* wherein the uikylamine base is rriethylamim;
Preparatory jA^y] l> Tlic intermediate of formula L? is prepared as described herein.
In the reactions Jesαibwi hereinafter it may be necessary io protect reactive functional groups, for eλamplc. amino group*, to avoid their unwanted participation in the reactions. Convctttioru-il protecting groups niuy be used in βccordancc *itb M.uκUrd practice, (at ι:ωiτiplc». see T.W Orβei« Jiul P.G.M.Wuta in Protective Orfπipi in Organic Chemistry " Mm Wiley and VSOON, 1991. In purticuJar, the eompounϋ of foπnula 1 may be pwpanai as shovvti in Schemes I-If. infra.
For υxuπφie, the compoβnd of the present invention is ait athiral α)nφ(Ain<J whose preparatioa ύ ctHnprised of the stepwise procedures that culminate in the prepaπuioo cit thiocartsuiaic D. as shewa in ϊkberoe J. Scheme II below, lhcn shows the s«<^pwi\e pixxodurcs that result from reac-iag the ihiocdrbβmiite compound 13, to eutmiruite in UK prrpaira»κ»n of the cvrrtpound of fiKmula ia. ^*hich is Uw hydrochloride buil f^xrn of ihc cinnpcnind of foπnula I. discussed stipnr. The preparaoor»s of thft present, inventions, xhe inrerπwdiates o\ the foτnκιlac 7. 8 and 13. are discussed in turn below.
i .i Mhiocarbυπyidiimidazoic is eυnvtπttfd to compound 7 by reacting i-pjxjpαno! in the presence of an etherea! soh"er»t. arotriatic lι>drvκarb(in y.»ivcnt ιv ΛΛ ester solvent, inch x< inwhyl len-bmy! rucr (MTIiE). to yield mioeurbjtnato compound 7.
Compound 7 is convem.*} to compound 8 by condensing compound 7 with acetone i» tru* pivseiwe trf an ethereal βϋivent or aronutic hydrocarlxM solvent, soch «s oflhydmus tefrohydtofur.'m (TW) and adding the apjaopriato r»ase to ) ιe!d ihc keto ϋiioc»ier pr»xiικt. , Lc UK compound of f;>nwtu JJ. Compound B is convened u> compound 9 by ustng an alkylating ager.t mch as mcih^l rraimoacciale. iu the prβkentc o\' a eliiurnwted (jydrocarbon sovJcnu polar aprotk solvent w a niixtitfv of poljr apriHic ioivβiitb, )>uch a* dimcmylfoπrtfimidc (OMF4'). to yield the S-alkyiatcd prtvim-t. i.e.. tixr. con^pouad intermediate o; formula 13.
The staj fiϋL; rfi^t-rials and Λk-iτnedύk> may be prc|XivU h> ϊhe dp|t]ic^ι1ϊ> >« or αddpiαUoπ of know n
Tπo frcscπs hAeisfi- ni is dho discoied κ> some fntctnvdiaios in thx ahtne scru\nixΛ ,.i-xl >ss nicK ihc processes described h«ιvin for their pa-parytiod ctmsύlαtc futihor features of ihc prcvπs irssrnrioα Exampitfs
The present sswnύυn may be better understood by reference Io the ihlhwing son-HroJfm" Examples, which arc provided as exemplary of the invention. The føllcsvvmg examples are presented iss order to more fully jlhiϋtr&te particular embodiments of lhe invention. They should in no way be conxmscd. however, as iln^iflrig the broad scope of the mverUion.
In the nuclear magnetic resonance spectra (NMR), reported >«/?■«, the rfsemicsi shifts are expressed is ppvn rabϊive 10 .etraϊrefhyisuane. Abbreviations have the following ss^Uicsnces.: br -~ broad, άά ~ di'iubla doubiet s ~ singles; m ~ mujtipiet.
EKAMn,K i
Preparation oπ.sπidazole-I -eadχ>thioic acid O-propyl ester
To the suspension of K ϊ '-thiαcai-tonyldiimidazole (3l .fi g, 177.3 jnmol) methyl tert-buϋyl eiher (MTBB, 95 rnL) at 25X is added ϊ -propanol ( I ! .7 g, 14.6 mi, 195 mmol j. Wiihi.n ! hour the reuction n-iixtυrc raphes 2ST and becoiiies a clear solution. TLC analysis (SiO2, EiOAc eluem, Rf of the pruduct. 0.75; Rf of the starting material, 0.15) shows \hsi the reaction is complete. Ti*.' reactsoR jiikfυrc is partis iosied between water (75 mL) and MTBE (25 inL). The organic phλtse is waskxi vsih wascf (75 ;ΏL), is »ai».in$t.cd sodium bicarhonaie soluiion (50 mt). brine (50 ?ϊiL.} and is conce trated OR a roSiis-y evaporate to an amber oil. compound 7 QS.5 g. 94% yield), AnaS. Calculated for C%HS!iN,OS: C 49.39; I L 5.92; N, 16.46. Found; C 49.47; H. 6.06: N, 16-50. JiPLC purity W..4K by area at 225 nrs (Rx -. 2.5 min). MS (ES+) m/x I T i <M+H,t. 1II NMR (300 MBK, QXIJ) δS.33 (n\, I H), 7.62 (m. I BJ, 7.02 {m, I H). 4.61 (ι, 2H), ! ,'λ) (ffi 2H), l.Oό [t, 3H). DSC; 1\Λ,, ,^ s)5ciC, i 5 /9 W / ks s. Nose: J he maicήal should be stored in refrigerator and nzed wsthht '"' days. tfpπJonged storage is necessary it is recommended u> keep it m a MTBE solution.
EXAMPLE 2
Preparation of 3-Qxo-Shiαb«i;yric acid O-propyϊ ester
To the solution of compound 7 (27.8 g. 163 mrnol) and acetone f2<6.(> g. 4S*7 rmnol; in anhydrous THF ( 164 ml.;, is added dropwise a 2M solution of Λodium <bu)lrimcthy!silyi 3inκk in TIiF ( 163 ΠJU 326 rnmoS) over 25 minutes, between room Urnψcrβturc mid 4(A - Following the e»d of addiiior. the reaction is complewd u$ determined by TlX and HPlX? analym. TLC (.SK)?. UtOAc / heptane i.2 clβcnt, Rf ot tw pruduct. 0.?ϋ: and R^ of the Λarting material, 028) The rvACtiυr; mixture is cooled to room trinpcraiur?. theii it ss quctjclκd with 200 ml. of %vaιer. The phavΛ arc separated and the orgunic ((op phase) is dinnnatcd. The aqueous phase is cooled to MTC and is acidified with aqueous 6N HO solution ω below pH 5. and it is extracted with Ml BE (2(Xl rnL). Tiie organic phase is wash;*} with saturated sodium bicarbonate sohJliojt (50 ml.), water (75 mL> and brine (50 ml.). It is dried over rodium sulfate, tlien it is cv>iκemr»ted on iociry evaporator :ςt an lumber ml, comrκit;nd 8 ( I 8..*J g. 70% cnπk yickJj. a jn cuol-keUmc mixture. MS (EI) tii'r. 160 (M+). 1H N'MR (300 MfIr, CDCJ... ketone ! cno! mJs»uα' aμprox 1.3) 8 1.1.6 fs, I H. πiol O-H). 5.6Λ (s. 1 M, cuot C--HV 4.4.' (t. J = 6.6 Hz, i H. ketone U-CH2). 4 .^5 (t. J^ 6.7 H/, JH. eπol 0-CH1). 3.90 ^s. JiL CS CH; CT>>. 2.2^ (*. 3H end). 2.03 (s, 3H. kcume). 1.90- 1.72 <m, 211 cnαl *aά hzume overlapping). 1.02-0.96 (l, Λ1 L αiwl and keuπie overlϋjiTrin^j.
EXAMPLE 3 rV'jpanrtion o! (i-Oxo- l-propixxy-hut-l ^πylsuifanyl^acetic acid mclh> l ester
To a chilled (80C) solution nf iceicMhiocster & ( J7.U g. 106 πrtnol) aiic! methyl Iwmoacctute (22,7 s. 148 nrmd> in I)MF { I ?5 ml.), triethylainine (15.0 g, 148 mrτκ)l) is adΛ«d portιonv,i«. The resufrtng cxothcrm *JΠHV up (be reaction mixture w 35"C aiwJ results in a thick fcβspension. 11Λ" analysis Ml minutes (Mowing the end of addition shuws tlκ reattiiwi tυ be complefc T\ .C (SiO., EtOΛc / heptane 1.2 elueiiL. K, of the proϋud. 0 15; Rt of the starting material. U.70). Thv* reaction tnixlufe is alto\\-«<. to cool to IIXKΓS icmporaturc o\er I hour, then it i* partitiOiicU between waxer (KX; mL; and MTBE (150 mL). The aqucouk plϋiβe is ttxtπέctcd wilh MTBE {3 x KM) mL). The combined crøanics arc wnsJied witK water (IW ml..), brine C75 ml.) ami then are coucenlraJed oo a rotary cvapo^tor to l l .S g ot β )dkr-v oiL The antic nuucrul is allowed to stand over-night at room tcnψcrαturv. atUsr which it is turned into a mixture of crystalline solid and semi-solid material. It is then trituimed mih heptane < I(K) niL) liv % hours, aικl then the solid is isolated by Buchncr ttlu*tioπ. The filler c&ke i.s washed with heptane (.10 nil.), lhen a is dried for 3 hours under vacuum, attouliog compound 9 (16.6 g, 67%> as a v-clJow solid: mp .- 54-srt. Anal. Calcd for C«HltO4.S: C. 51.71 ; H, 6.94. Found: C\ 51-68; II. 7.28. MS JESl) JiV? 233 (M+$ϊ). 'Il NMR (300 MHz, CDCi3) δ 5,72 {s, ! H), 3.92 U, J = 6.5 Hz. 2H). 3.72 <s. 3IiK 3.56 (s, 2H i. 2.16 (s, 3H), 1.82- 1.70 (m. 2B). UM U, J = 7.5 }-hj. ' 3C NMR f?S MHs, CDOO 5194-5 L 170.42, 169.33. 98.15, 73.24. 52. 1 O. 31.35, 30.14. 21.70, 10.22.
The prώseru rovesύon is not to he limited in scope by the speci fic cϋilxxliπjeαts describe herein, fndeed, various modificafioss of the i?iveτitiθR in uddslion to rhose described herein will become apparent to thost- skilled in ihe an from the foregoing dascr sption and tbε accoiDpasying ilgyres. Such iTXTiϋficarions are mtεndcd to CaO within the scope of the appended claims.
Various p!shlk:;.dinr,s arc cited herein, the disclosures of which are incorporated by refercr;ce in ϊhώis- t'nsϊrefitfs.

Claims

We Claim:
1. A method for preparing a compound of formula 8
comprising condensing the compound of formula 7
with acetone.
2. The method according to claim 1 wherein the condensing is carried out in the presence of an aprotic organic solvent.
3. The method according to claim 2 wherein the aprotic organic solvent is selected from an ethereal solvent and a hydrocarbon solvent.
4. The method according to claim 3 wherein the ethereal solvent is selected from tetrahydrofuran, 2- methyltetrahydrofuran and tert-butyl methyl ether.
5. The method according to claim 3 wherein the hydrocarbon solvent is selected from toluene and heptane.
6. The method according to claim 1 wherein the condensing is carried out at a temperature from about 15° C to about 55°C.
7. The method according to claim 6 wherein the condensing is carried out at a temperature from about 25° C to about 45° C.
8. The method according to claim 7 wherein the condensing is carried out at a temperature of about 40°C.
9. The method according to claim 1 wherein the condensing is carried out in the presence of an organic metal base.
10. Tbc melhrxi according to ciaim 9 wherein the hose h selected from *n alkali rneta! nπritic bsuoc and at) alkali πtrtai hydride.
I ! . TJx: πtc!?κid according to claim U) wherein ihc βlkali mcul amide base is scicUcxi J'rυm h'.mun; ϋύsopropylainkk, lithium iJicyckihfxyJnmiik*. lithiinn ibi^rππcthyhilyJ aπ«dc, sodium (biOtrirTKlhybiiyl nruidc and potassium 'htsXritntlhylsilyl aπiύe.
JX TIw meUiod according io claim 11 \viκrcin lhc <!ikutt irinal amide twso is s«.iιϋutr. ( biiitritnclhyisilyl amide.
π. The mΛhϋd accoiding κ> clain? 10 wJvπrm t!κ alkali metal h>diitie is ru-'Ocu^! from liihinm itydruic, sodium hydride and potassium hydride.
14. A mdhod for pfcpoxing α conipιχ.nd of forrtrolϋ 13
wjmprising alkylaϋnj- fhc coi«ptiur.d < fonnui^ 8 prepared according io the nniruvi of c!«im 1 .wing methyl brυrooacetaie.
15. A nvthod for prcpariiiR a corπpoond of formula 13
comprijiinjj βUytating a compound of formula 8
using methyl broinoaccυste.
16 The method accordin to claim 14 or claim 15 furthe comprisin alkylatin in the pres en co f<. urjt'ojc ^rsynk solvent, u m'X-VK" of api otk > >)$:cmic ^oHonts, i1;' in *be psv^fce OΪ a mixusϊ • coii'o'iisϋg ,- ivM<« apκ".iv wJvciJ and jfi cϋioieai sohcrt.
17 He ruϋw -d αcv. M-Um^ K> claim ϊ» v hcivm Hv aprotic organs soKπsi io wdeϋed lr>^« a p^kr apr-.'ύc »s,<kcrt &nd J chi« »rinδted hydrocαibon juilsesn,
18 The rp«b«>>l uccordjjis to cUύm ! ? whctein the πolas vspn-^k ^oivcsa s^ icl^cteJ fu-sn d!Mxr;h> ;foπrun-κιk\ ' -"nϊtbyl-2-p \ Kolidonc atul dimc(h\ tsαih>\ !Jr.
19 The meShi^d acco(χ5tng to cLύm U? w berdπ 'he etherv^l soKsni !? ^\cfi^α sV^svs tcsrahjώiiiϋiviSK ^-mcbi iicirϋhydrv^uran aad Jv-u-butyi τnett>yl eihor.
20. TΪK sneιh><d accordlr.g fo cbim 17 v heu in ώo oh'ojin.«o-J hydKVvsri -^n s-^ive^? ^ JO "JotomdbiiK*
2 1 The ϊiieUϊod accoidiπg tα claim i4 or ciaiw i"1! w herein ϊii; ,Ϊ"Λ\ huiτ\g i* catriΛl oui ά\ ;s icj!(pcr,Jturc from ,3DfHn 0° C to aboiϋ 5(^ C,
.
22. Ts.c n^'Ksod acooϊdhsiε to cli'tm 21 v, herein the a&yiating is. o;jiτiod > -uι a£ .s Sei r permute i^^n
23 1 he nxnhod αtecrάim, u> ciatm 22 w ht-ieus the alkylating K o<ϊrnod oul as α ii'SΩperan:fc fs^^ about 'S'1 C )V> j bout 35° C.
24. Th^ motbod vϊccosdπψ M claim 14 oi v Ltim 1? uhorcni Ov αiU> UKin^. k= vajTk'ti out in fjv ,">κ\sctve ^l .ys ail v^nTnt.- ha so
25, TIv ;-!;odux! according to ciaiir 24 whciVin the alk^ laxniπc b<^e > sokvέed s'T-sv, mofru Luvήac <mύ Jii^opf-~»p\ loiin kmine
26. Ti ic s oϊhou .jccordi.ij' ?n ckiiin 25 t herein iiio a.lk\ lurøuso bα»e jj> u ic"Jn\aτr-m^.
EP07759555A 2006-03-29 2007-03-28 Improvements in the preparation of intermediates leading to [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-(4-bromo-3-methyl-5-propoxy-thiophen-2yl)-methanone hydrochloride Withdrawn EP2001839A1 (en)

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DOP2005000039A (en) * 2004-03-26 2005-10-31 Aventis Pharma Inc HYDROCHLORIDE OF [4- (5-AMINOMETIL-2-FLUORO-PHENYL) - PIPERIDIN-1-IL] - (4-BOMO-3-METHYL-5-PROPOXI-TIOFEN-2-IL) -METANONE AS AN INHIBITOR OF THE MASTOCYT TRIPTASE

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