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  • 11 712 359 Mono Nitration of Aromatic Co

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    Omar Sánchez Antonio
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    The present invention relates to the nitration of substrates that contain at least one basic nitrogen atom. Further the process includes the formation and isolation of nitrate salts formed from the substrates and nitric acid. The present invention also relates to a process for the preparation of 4-morpholino-2-nitroanisole.

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    11_712_359_Mono_nitration_of_aromatic_co

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    The present invention relates to the nitration of substrates that contain at least one basic nitrogen atom. Further the process includes the formation and isolation of nitrate salts formed from the substrates and nitric acid. The present invention also relates to a process for the preparation of 4-morpholino-2-nitroanisole.

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    22 vistas14 páginas

    11 712 359 Mono Nitration of Aromatic Co

    Cargado por

    Omar Sánchez Antonio
    The present invention relates to the nitration of substrates that contain at least one basic nitrogen atom. Further the process includes the formation and isolation of nitrate salts formed from the substrates and nitric acid. The present invention also relates to a process for the preparation of 4-morpholino-2-nitroanisole.

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    Attribution Non-Commercial (BY-NC)
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    'US 20070255057A1 cu») United States 2) Patent Application Publication co) Pub. No.: US 2007/0255057 A1 oy 6) (60) Ce lote et al. MONO-NITRATION OF AROMATIC COMPOUNDS VIA NITRATE SALTS Inventors: Miall Cedilote, Plorence, SC (US), Thomas Patrick Cleary, Florence SC (US); Pingsheng Zhang, Florence, SC Comespondence Address: HOFFMANS-LA ROCHE IN PATENT LAW D 340 KINGSLAND. NUTLEY, NI 07110 Appl. Nos 712,359 Filed: Feb. 27, 2007 Related U.S. Application Data Provisional application No, 60/795,431, filed on Apr. 27, 2006, (43) Pub. Date: Nov. 1, 2007 Publication Classification ca) (200601), CTD 23300 (2005.01), CTD 268/30 (2006.01), (2) USC. S44/107. 544/160: $4800 564/306: 564/301: 564/304 on ABSTRACT A method of nttating a compound seleted from the group consisting of is provided US 2007/0255057 Al MONO-NITRATION OF AROMATI COMPOUNDS VIA NITRATE SALTS, PRIORITY TO RELATED APPLICATIONS [0001] This application claims the benefit of U:S. Provi sional Application ‘No. 60795,431, fled Apr. 27, 200, Which is Rereby incorporated by reference in is entirety FIELD OF THE INVENTION 0002} The present invention relates © the nitration of Substrates that contain at least one basic nitrogen alam. Further the process includes the fonmation and isolation of nitrate sltsTormed from the substrates and nitric acid and thereat the aitation of the salts under aeidie conditions In general therefore, the present invention relates. 10 3 tener method for mono-altration of sromatie compounds bearing a Basic nitrogen atom and ina more specific embod ment toa process forthe preparation of #mompbetin-2 BACKGROUND OF THE INVENTION Nitraton of aromatic ancleus is one of the most 0003) buasie reactions in organic chemistry und is widely used for preparing nitro aromatic compounds, However, the reaction Js notorious for several reasons and most pharsceutical manufacturers are discouraged wo cay out lage seale Iitationinshoue. Safty sues ate the primary concer ‘Two major factors contbute to the salty aspect of the reaction The fist fs the reaction ise. The most commonly ted nitating reagent isa mintureof concentsted nti ack td sulfur set, Both of thom are stong oxidizers Atoogh there ae alternative nitating reagents, the major: iy of them generate nic ack! or other highly reactive ittemeditesin sit. The nation reactions usally bighy ‘exothermic and has high sk of runaway fo explosion upon mishandling of the process of equipment failures, ‘The Second is the nitrated prodiets. Most of them have 1 thn ans nor bin nd he ge gy ‘energy upon decomposition (or instance, TNT iol tne, 19 a power explosive. As esl, ex precutons fave tobe taken when lraton is cared out wich ined Special equipment (eq, bnkered rectors) and intensive taining of personne. Besides safety problems, side reac- thas are anbiher concern, For iste, cvertation could fccur whenever the niating reagents are_overcharged Repoitomer formation and reactions at side-chains are Nov. 1, 2007 ‘common, Therefore the development of new nitration meth- fd that Lead to safer nitration processes and better como of chemistry is sil an important research poal SUMMARY OF THE INVENTION 0004} In accordance with this invention, it has been discovered that this process is applicable 10 a variety of compounds. In theory, any aromatics that can be nitrated ‘under conventional conditions and contain a baie nitrogen ‘tom can be nitrated using tis protocol. Some examples are Tisted in Table 1 through Table 4, For al the examples listed i tables I through 4, the nitration was curried out by adding 4 solution or suspension of the nitrate salt approximately 10 equivalents of concentrated sulfuric acid. The substrates an he covered ia this invention are simmarized inthe {allowing groups [005] "A. Aniline derivatives tht have general structures ‘Of'6, where Aris nittable aromatic ring, Ry and R, are hhydrogen, alkyl or aromatic groups. Some examples are listed in Table 1. RL e [0006] _B. Aromatic compounds have ener structure of 7, where Arisa nitraable aromatic ring, R. Ra, Ry, and Ry are hydrogen, alkyl or aromatic groups, and is an integer from I fo 12. Some examples are listed in Table 2 Boe BOR 0007] C. Aromatic compounds have general structure of | 8, where Ar is a ailatable aromatic ring, G are suitable aiomis of groups (e CR\R, O, S, SO, SOs, ete), Ris @ hheteroeyelic ring or other groups bearing a Basic nitrogen atom, Some examples are listed in Table 3 AHHR s [0008] _D. Fosed-ring aromatic compounds have general structure of 9, where the benzene ring is fused swith a heterocyclic ring that bears & hast nitrogen atom, Ry. R and Ry can be hydrogen or other groups thst can toleraie ‘conventional nitration conditions, Some examples ie listed in Table 4 TABLE Yi Set Yi ‘Src of Ninos roms Nite ca IK aN st “I US 2007/0255057 Al Nov. 1, 2007 TABLE 1-continued es i [> x - aN aK 2 Mv Lv oa 405 tN on oP sess ai . . ans y 7 wn som ee 7. _ NL NOs Li ait US 2007/0255057 Al Nov. 1, 2007 3 oe of, : eS eee Cy ‘NSE “NO; “7 Ns No 1 <2 ve eo a 2 eC ae ae p os De a - mia [ t, ae t. = Nas | fod Paci elon: poor S do 46: do: US 2007/0255057 Al Nov. 1, 2007 ‘ar wa my Soe Pre ‘oe or O 8S & TO ‘So @ sunewe of Nita oma Nw Coos OS o> . mew vs I> or co sa y erap.nbs 10009] ‘The salts of the substrates of tables 1-4 could be generally prepared by adding 1.0 eq, of 70% nite acid to & olution of the substrate at <20° C. TAME was sed as reaction solvent for the substrates soluble in it. For the ‘Substrates that were less soluble in TAME, a second solvent was added to help the solubility. The solvent combinations Used forthe reaction ineluded TBMEVTHF, TBMB/acetoni- tile, TBMBlethy acetate, ete. For the salts that precipitated ‘out of te solutions daring the salt formation, the isolation was achieved by filation and drying under vacuum at ‘ambient temperature, For the salts tht did not completely precipitate out from the solution, acetonitrile was added Tumi! homogeneous solutions were formed. The solutions ‘wore then dried over MeS0,, filtered, and concentrated t0 Alford the solid salts [0010] The station ofa salt was carted out by adding 2 Solution or suspension of the salt t0 excess amount of sulfuric acid at <10° C, Solvents used for the reaction included dichloromethane, nitrometbane, and others that are inert 0 the reaction mixture. Upon the completion of the reaction the mixture was died by adding the acid layer to ‘Water at <20° C. The diluted mixture was then basitied to pl 6-II by adding a base, such as aqueous ammonia solution, aqueous potassium carbonate, agueous sodium carbonate, oF aqueous sodium bicarbonate, ete. In most ofthe cases, the product precipitated out at this point, The solid produet was fikered, washed with water, and dried under vacuum at ‘around 50° C. overnight to give the nitrated product, Inthe teases in which the product precipitated out as an oil, the mixture was extracted with a solvent (e. dichloromethane, ethyl acotate, et.) The organic solution was thon washed with water, dried over MgSO,, filtered, and concentrate 10 aive the erude product. US 2007/0255057 Al [0011] Application ofthe nitration method resulted in a invention of new process for the preparation of 4-Mor- pholino-2-nitroansole (4), a key intermediate for a drug ‘candidate currently being developed to eat depression (WO (01/9786). The process is summarized in Scheme 1 10012] There are several major advantages of the new process over the original one dislosed in the above appli- ‘ation, which include: 10013] 1) Asimplifed process. With the precipitation of $

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