SI9010607A - Pharmacologically active cns compounds - Google Patents
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THE WELLCOME FOUNDATION LIMITEDTHE WELLCOME FOUNDATION LIMITED
Farmakološko aktivne CNS spojinePharmacologically active CNS compounds
Predloženi izum se nanaša na razred pirimidinskih spojin, ki so uporabne za zdravljenje bolezni in motenj centralnega živčnega sistema (CNS = central nervous system), kot je poškodba zaradi cerebralne ishemije, na farmacevtske pripravke, ki jih vsebujejo, na njihovo uporabo v zdravljenju takšnih bolezni in na postopke za njihovo pripravo.The present invention relates to a class of pyrimidine compounds useful for the treatment of diseases and disorders of the central nervous system (CNS = central nervous system), such as damage due to cerebral ischemia, to pharmaceutical preparations containing them, for their use in the treatment of such diseases and the procedures for preparing them.
Glutamat je ekscitativna aminokislina, ki deluje kot nevrotransmiter. Seveda pa, kadar je njegova zunajcelična koncentracija zadovoljujoče visoka, glutamat deluje kot močan nevrotoksin, ki lahko ubije nevrone v centralnem živčnem sistemu. (Rothman & Oliney (1986) Prog. Brain Res., 63, 69). Nevrotoksični učinek glutamata je vpleten v večje število motenj in bolezenskih stanj centralnega živčnega sistema, vključno s cerebralno ishemsko poškodbo, epilepsijo in kroničnimi degenerativnimi motnjami, kot so Alzheimerjeva bolezen, motnje motornega sistema in Huntingtonova koria, (Meldrum Clinical Science (1985) 68 113-122). Nadalje je glutamat vpleten v druge nevrološke motnje, kot so manična depresija, depresija, shizofrenija, nevrološki sindrom visokega tlaka, kronična bolečina, trigeminalna nevralgija in migrena.Glutamate is an excitatory amino acid that acts as a neurotransmitter. Of course, when its extracellular concentration is satisfactorily high, glutamate acts as a potent neurotoxin that can kill neurons in the central nervous system. (Rothman & Oliney (1986) Prog. Brain Res., 63, 69). The neurotoxic effect of glutamate has been implicated in a number of disorders and conditions of the central nervous system, including cerebral ischemic injury, epilepsy and chronic degenerative disorders such as Alzheimer's disease, disorders of the motor system and Huntington's measles (Meldrum Clinical Science (1985) 68 113- 122). Furthermore, glutamate is implicated in other neurological disorders such as manic depression, depression, schizophrenia, high pressure neurological syndrome, chronic pain, trigeminal neuralgia and migraine.
V evropski patentni prijavi št. 21121 je opisana skupina 3,5-diamino-6-(substituirani fenil)-l,2,4-triazinov, ki so aktivni v zdravljenju motenj CNS, npr. v zdravljenju epilepsije. Prikazano je, da ena opisana spojina v tej prijavi, 3,5-diamino-6-(2,3diklorofenil)-l,2,4-triazin, (lamotrigin), inhibira sproščanje ekscitativnih aminokislin, glutamata in asparaginata, (Leach et al, New anticonvulsant drugs, Ed. Meldrum and Porter 165-177,1987).In European patent application no. 21121 describes a group of 3,5-diamino-6- (substituted phenyl) -1,2,4-triazines that are active in the treatment of CNS disorders, e.g. in the treatment of epilepsy. One of the compounds described in this application, 3,5-diamino-6- (2,3dichlorophenyl) -1,2,4-triazine (lamotrigine), has been shown to inhibit the release of excitatory amino acids, glutamate and asparaginate, (Leach et al , New Anticonvulsant Drugs, Ed. Meldrum and Porter 165-177,1987).
Tukajšnji izumitelji so odkrili, da vrsta substituiranih pirimidinskih spojin, kot so definirane s formulo I, tvori močne inhibitorje sproščanja glutamata; te spojine soThe present inventors have discovered that a range of substituted pyrimidine compounds, as defined by Formula I, forms potent inhibitors of glutamate release; these compounds are
- 2uporabne za zdravljenje zgoraj omenjenih motenj in bolezenskih stanj centralnega živčnega sistema. Pirimidinske spojine s formulo I so prav tako inhibitorji sproščanja asparaginata.- 2 useful for the treatment of the aforementioned disorders and conditions of the central nervous system. Pyrimidine Compounds of Formula I are also asparaginate release inhibitors.
Tako je v prvem vidiku predloženega izuma zagotovljena uporaba spojine s formulo I ali njene adicijske soli s kislino v proizvodnji zdravila za zdravljenje ali preprečevanje poškodb ali bolezni CNS sesalcevThus, in a first aspect of the present invention, it is ensured the use of a compound of formula I or an acid addition salt thereof in the manufacture of a medicament for the treatment or prevention of damage or disease of a mammalian CNS
pri čemer sta v formuli Iwherein in formula I
Rj in R2 enaka ali različna in sta izbrana iz skupine, ki vsebuje vodik, halo, hidroksi, alkoksi, alkil, alkiltio in skupino NRH11, kjer sta R1 in R11 enaka ali različna in sta izbrana iz skupine, ki vsebuje vodik, alkil, aril in arilalkil ali skupaj z dušikovim atomom, na katerega sta vezana, tvorita ciklični obroč, ki je v danem primeru substituiran z eno ali več alkilnimi skupinami in v danem primeru vsebuje nadaljnji heteroatom;R 1 and R 2 are the same or different and are selected from the group consisting of hydrogen, halo, hydroxy, alkoxy, alkyl, alkylthio and the group NRH 11 , where R 1 and R 11 are the same or different and selected from the group containing hydrogen , alkyl, aryl and arylalkyl or together with the nitrogen atom to which they are attached form a cyclic ring which is optionally substituted by one or more alkyl groups and optionally contains a further heteroatom;
je R3 vodik, alkil, kije v danem primeru substituiran z enim ali več halo radikali, ali je amino, alkilamino, dialkilamino, ciano, nitro, halo, karbamoil, hidroksi, karboksi, alkoksi, alkiltio, alkiltioalkil, S(O)nalkil, di(alkiloksi)alkil, -C(R):NOH ali -COR ali -CO2R, kjer je R vodik ali alkil ali skupina CH2X, kjer je X hidroksi, alkoksi, ariloksi, arlalkiloksi, halo, ciano, -NRH11, kjer sta R1 in R11, kot je definirano zgoraj, S(O) alkil, kjer je n 1 ali 2, ali SC^NRH11;R 3 is hydrogen, alkyl optionally substituted by one or more halo radicals, or is amino, alkylamino, dialkylamino, cyano, nitro, halo, carbamoyl, hydroxy, carboxy, alkoxy, alkylthio, alkylthioalkyl, S (O) n alkyl, di (alkyloxy) alkyl, -C (R): NOH or -COR or -CO 2 R, where R is hydrogen or alkyl or a group CH 2 X, where X is hydroxy, alkoxy, aryloxy, arylalkyloxy, halo, cyano , -NRH 11 , where R 1 and R 11 , as defined above, are S (O) alkyl, where n is 1 or 2, or SC 4 NRH 11 ;
vsak od R4 do Rg je enak ali različen in vsak je izbran iz skupine, ki vsebuje vodik, halo, alkil, perhaloalkil, ciano, karbamoil, karboksi, COR, nitro, amino, alkilsulfonilamino, alkoksi, S(O)n-alkil, kjer je n 1 ali 2, ali SO^RH11; ali sta R4 in Rs, ali Rs in Rf> skupaj skupina -CH = CH-CH = CH- ali skupina -CH2-CH,-CH9-CH2-, pri čemer sta v tem primeru oba R? in R$ vodik;each of R 4 to R g is the same or different and each is selected from the group consisting of hydrogen, halo, alkyl, perhaloalkyl, cyano, carbamoyl, carboxy, COR, nitro, amino, alkylsulfonylamino, alkoxy, S (O) n - alkyl, wherein n is 1 or 2, or SO ^ RH 11 ; or R 4 and R s , or R s and R f> together are a group -CH = CH-CH = CH- or a group -CH 2 -CH, -CH 9 -CH 2 -, in which case both R ? and R $ is hydrogen;
in je v danem primeru eden od dušikovih atomov v pirimidinskem obroču lahko N alkiliran ali je lahko v danem primeru N oksid;and optionally one of the nitrogen atoms in the pyrimidine ring may be N alkylated or optionally N oxide;
pri čemer imajo predhodne alkilne skupine ali deli alkil-vsebujočih skupin 1 do 6 ogljikovih atomov, in imajo arilne skupine ali arilni deli aril-vsebujočih skupin 6 do 10 atomov ogljika.wherein the preceding alkyl groups or portions of the alkyl-containing groups have 1 to 6 carbon atoms, and the aryl groups or aryl moieties of the aryl-containing groups have 6 to 10 carbon atoms.
Določene spojine s formulo I so kiralne in jasno je, da v teh primerih formula I obsega tako racemno zmes, kot posamezne enantiomere takšnih spojin. Prav tako bo jasno, da lahko, kadar je eden ali več izmed Rp R2 in R3 hidroksi, obstajajo tudi v svoji tavtomerni obliki.Certain compounds of formula I are chiral, and it is clear that in these cases formula I comprises both a racemic mixture and the individual enantiomers of such compounds. It will also be clear that when one or more of R p is R 2 and R 3 is hydroxy, they may also exist in their tautomeric form.
Prednostni razred spojin s formulo I, ki so močni inhibitorji glutamata, so tiste, v katerih je eden od R3 in R2 amino in je drugi izbran iz skupine, ki vsebuje amino, hidroksi, halo, morfolino, piperazinil, N-alkil-piperazinil, Ν,Ν-dialkilamino, N-alkilamino ali alkiltio;A preferred class of compounds of formula I which are potent glutamate inhibitors are those in which one of R 3 and R 2 is amino and the other is selected from the group consisting of amino, hydroxy, halo, morpholino, piperazinyl, N-alkyl- piperazinyl, N, N-dialkylamino, N-alkylamino or alkylthio;
R3 je alkil, ki je v danem primeru substituiran z enim ali več alkilnimi radikali, ali je alkil, alkiltio, vodik, hidroksi, alkoksi, halo, karboksi, karbamoil ali skupina CH2X, kjer je X hidroksi, fenoksi benziloksi, alkoksi ali alkiltio;R 3 is alkyl, optionally substituted by one or more alkyl radicals, or alkyl, alkylthio, hydrogen, hydroxy, alkoxy, halo, carboxy, carbamoyl or a CH 2 X group, wherein X is hydroxy, phenoxy benzyloxy, alkoxy or alkylthio;
je eden od R4 in R5 halo in je drugi izbran iz skupine, ki vsebuje halo ali vodik;one of R 4 and R 5 is halo and the other is selected from the group consisting of halo or hydrogen;
je R6 halo, vodik, nitro ali amino;R 6 is halo, hydrogen, nitro or amino;
je R? vodik, halo, ciano, alkiltio, SO2NR1R11 alkil, nitro, amino ali metansulfonamido; in je Rg vodik ali halo.is R ? hydrogen, halo, cyano, alkylthio, SO 2 NR 1 R 11 alkyl, nitro, amino or methanesulfonamido; and R g is hydrogen or halo.
V predloženem izumu je Rj prednostno hidroksi, amino, N-alkilamino, Ν,Ν-dialkilamino, morfolino, piperazinil, N-alkilpiperazinil;In the present invention, R1 is preferably hydroxy, amino, N-alkylamino, N, N-dialkylamino, morpholino, piperazinyl, N-alkylpiperazinyl;
je R2 prednostno kloro, amino, Ν,Ν-dialkilamino ali piperidino;R 2 is preferably chloro, amino, N, N-dialkylamino or piperidino;
je R3 prednostno vodik, alkil, metoksimetil, trifluorometil, benziloksimetil, fenoksimetil ali metiltiometil;R 3 is preferably hydrogen, alkyl, methoxymethyl, trifluoromethyl, benzyloxymethyl, phenoxymethyl or methylthiomethyl;
so R4 do Rg prednostno izbrani iz skupine, ki vsebuje vodik in kloro. Prednostno vsebujejo alkilne skupine od 1 do 4 atome ogljika.R 4 to R g are preferably selected from the group consisting of hydrogen and chloro. Preferably, the alkyl groups contain from 1 to 4 carbon atoms.
V formuli I je primerno vsaj eden od Rj in R2 amino, in je drugi amino, piperazinil ali N-metilpiperazinil, N-alkilamino, Ν,Ν-dialkilamino; in je R3 vodik, metil, trifluorometil ali metoksimetil.In formula I, as appropriate, at least one of R and R 2 are amino, and the other is amino, piperazinyl or N-methylpiperazinyl, N-alkylamino, Ν, Ν-dialkylamino; and R 3 is hydrogen, methyl, trifluoromethyl or methoxymethyl.
Prednostna lastnost formule I je, da sta dva od R4, R5 in R7 kloro, zlasti prednostno je, da so vsi R4, R5 in R? kloro. Takšne spojine so zelo močni inhibitorji sproščanja glutamata. Prednostni primeri skupine NR^11 so amino, N-metilamino, N-etilamino, Ν,Ν-dimetilamino, piperazinil, N-metilpiperazinil, piperidinil in morfolino.An advantageous property of formula I is that two of R 4 , R 5 and R 7 are chloro, especially preferably all of R 4 , R 5 and R 7 being ? chloro. Such compounds are very potent inhibitors of glutamate release. Preferred examples of the group NR @ 11 are amino, N-methylamino, N-ethylamino, Ν, Ν-dimethylamino, piperazinyl, N-methylpiperazinyl, piperidinyl, and morpholino.
Posebno prednosten razred spojin znotraj formule I so tiste, v katerih je:A particularly preferred class of compounds within Formula I are those in which:
Rx izbran iz skupine, ki vsebuje amino, piperazinil, N-metilpiperazinil, N-morfolino, Ν,Ν-dimetilamino in N-etilamino;R x is selected from the group consisting of amino, piperazinyl, N-methylpiperazinyl, N-morpholino, N, N-dimethylamino and N-ethylamino;
jeR2 amino;R 2 is amino;
je R3 izbran iz skupine, ki vsebuje trifluorometil, vodik, metil, benziloksimetil, metoksimetil in metiltiometil;R 3 is selected from the group consisting of trifluoromethyl, hydrogen, methyl, benzyloxymethyl, methoxymethyl and methylthiomethyl;
je R4 kloro; in je vsaj eden od R5, R6 in R? kloro in je ostanek izbran iz skupine, ki vsebuje vodik, kloro in nitro; in jeRg vodik;R 4 is chloro; and is at least one of R 5 , R 6 and R ? chloro and the residue is selected from the group consisting of hydrogen, chloro and nitro; and R g is hydrogen;
ali sta R4 in Rg oba vodik, sta R5 in R? oba kloro in je R6 izbran iz skupine, ki vsebuje vodik, kloro in nitro.are R 4 and R g both hydrogen, R 5 and R ? both chloro and R 6 is selected from the group consisting of hydrogen, chloro and nitro.
Predloženi izum prav tako zagotavlja podrazred spojin s formulo I, ki, medtem ko so močni inhibitorji sproščanja glutamata, kažejo le slabe (t.j. imajo IC50 manjši od 20 ju,m) ali nepomembne inhibitome učinke za encim dehidrofolat reduktazo. Potemtakem so v prednostni izvedbi predloženega izuma zagotovljene spojine s formulo I, v kateri so Rj do Rg kot je tu definirano predhodno, pod pogojem, da kadar je R7 halo, potem jeThe present invention also provides a subclass of compounds of Formula I which, while potent glutamate release inhibitors, show only poor (i.e., IC 50 less than 20 µm) or insignificant inhibitory effects on the enzyme dehydrofolate reductase. Thus, in a preferred embodiment of the present invention are provided compounds of formula I, in which R to R g are as hereinbefore defined, provided that when R7 is halo, then
R3 vodik, perhaloalkil, metil ali metoksimetil in/ali jeR6 nitro in/ali je Rj N-alkilpiperazinil, morfolino, Ν,Ν-dimetilamino, piperazinil ali N-etilamino;R 3 is hydrogen, perhaloalkyl, methyl or methoxymethyl and / or R 6 is nitro and / or R 1 is N-alkylpiperazinyl, morpholino, N, N-dimethylamino, piperazinyl or N-ethylamino;
ali pod pogojem, da kadar jeor provided that when
R6 kloro, potem jeR 6 is chloro, then it is
R4 halo in je R3 vodik, perhaloalkil, metoksimetil, metil ali halo in/ali je Rt N-metilpiperazinil, piperazinil, morfolino ali Ν,Ν-dimetilamino ali N-etilamino.R 4 is halo and R 3 is hydrogen, perhaloalkyl, methoxymethyl, methyl or halo and / or R t is N-methylpiperazinyl, piperazinyl, morpholino or N, N-dimethylamino or N-ethylamino.
Spojine s formulo I lahko uporabljamo za zdravljenje in profilakso akutnih in kroničnih motenj centralnega živčnega sistema sesalcev. Akutno stanje obsega cerebralno ishemijo, ki lahko nastane zaradi različnih vzrokov, ki vključujejo kap, zaustavitev srca, by-pass operacijo, neonatalno anoksijo in hipoglikemijo; in prav tako fizično poškodbo ali travmo hrbteničnega mozga ali možgan. Kronične nevrodegenerativne motnje, ki jih lahko zdravimo, vključujejo Alzheimerjevo bolezen, Huntingtonovo korio, olivopontocerebralno atrofijo, motnje motornega sistema. Druga nevrološka stanja, ki jih lahko zdravimo s spojino s formulo I, vključujejo depresijo, manično depresijo, shizofrenijo, kronično bolečino, epilepsijo, trigeminalno nevralgijo in migreno.The compounds of formula I can be used for the treatment and prophylaxis of acute and chronic disorders of the mammalian central nervous system. The acute condition comprises cerebral ischemia, which can be caused by a variety of causes including stroke, cardiac arrest, by-pass surgery, neonatal anoxia, and hypoglycemia; and also physical injury or trauma to the spinal cord or brain. Chronic neurodegenerative disorders that can be treated include Alzheimer's disease, Huntington's chorea, olivopontocerebral atrophy, disorders of the motor system. Other neurological conditions that can be treated with the compound of Formula I include depression, manic depression, schizophrenia, chronic pain, epilepsy, trigeminal neuralgia, and migraine.
V nadaljnjem vidiku predloženi izum zagotavlja postopek za zdravljenje ali preprečevanje motenj ali bolezni CNS sesalcev, vključno človeka, ki obsega dajanje sesalcu netoksične učinkovite količine spojine s formulo I ali njene kislinske adicijske soli.In a further aspect, the present invention provides a method for treating or preventing disorders or diseases of a mammalian CNS, including a human, comprising administering to the mammal a non-toxic effective amount of a compound of formula I or an acid addition salt thereof.
Predloženi izum zlasti zagotavlja postopek za zdravljenje sesalca, ki je predisponiran za ali ima nevrotoksične zunajcelične nivoje glutamata centralnega živčnega sistema, ki obsega dajanje sesalcu netoksične učinkovite količine spojine s formulo I ali njene kislinske adicijske soli.The present invention particularly provides a method of treating a mammal that is predisposed to or has neurotoxic extracellular levels of central nervous system glutamate, comprising administering to the mammal a non-toxic effective amount of a compound of formula I or an acid addition salt thereof.
Znano je, da imajo določeni fenilpirimidini iz predloženega izuma antimalarično aktivnost. Glej npr. Brit. J. Pharmacol. 6, 185-200 (1951); JACS, 73, 3763-70, (1951). Drugi fenilpirimidini so znani iz Chem. Biol. Pteridines, 463-468, (1982) in Pharmacotherap. Budesinsky, str. 129-141 (1963), ed. Oldrich Hanc.Certain phenylpyrimidines of the present invention are known to have antimalarial activity. See, e.g. Brit. J. Pharmacol. 6, 185-200 (1951); JACS, 73, 3763-70, (1951). Other phenylpyrimidines are known from Chem. Biol. Pteridines, 463-468, (1982) and Pharmacotherap. Budesinsky, p. 129-141 (1963), ed. Oldrich Hanc.
Vsekakor so določene spojine predloženega izuma nove in potemtakem predloženi izum zagotavlja spojino s formulo I ali njeno kislinsko adicijsko sol, kjer so Rt do Rg kot je tu definirano predhodno, pod pogojem, da je vsaj eden od R4 do Rg različen od vodika in nadalje pod pogojem, da kadar sta Rj in R2 oba amino, ali kadar je R4 hidroksi in je R2 amino, in je R3 alkil ali vodik in je R? vodik, potem sta R4 in R5 oba halo.Certain compounds of the present invention are, however, novel and the present invention therefore provides a compound of formula I or an acid addition salt thereof, wherein R t to R g are as defined hereinbefore provided that at least one of R 4 to R g is different from and further provided that when R 1 and R 2 are both amino or when R 4 is hydroxy and R 2 is amino and R 3 is alkyl or hydrogen and R ? hydrogen, then R 4 and R 5 are both halo.
Druge nove spojine predloženega izuma so tiste, v katerih so Rt do R3 in Rg, kot je tu definirano predhodno in se eden od R4 ali R5 razlikuje od vodika in je R? halo, alkil, perhaloalkil, ciano, nitro, amino, alkiltio, S(O)n-alkil ali SOjNR^11.Other novel compounds of the present invention are those wherein R t to R 3 and R g are as hereinbefore defined and one of R 4 or R 5 is different from hydrogen and R ? halo, alkyl, perhaloalkyl, cyano, nitro, amino, alkylthio, S (O) n -alkyl or SOjNR ^ 11 .
Tretji razred novih spojin iz predloženega izuma so tiste spojine s formulo I, v katerih je RJ morfolino, piperazinil, N-alkilpiperazinil, Ν,Ν-dialkilamino, N-alkilamino ali alkiltio in so R2 do Rg kot je tu definirano predhodno.A third class of novel compounds of the present invention are those compounds of formula I wherein R 1 is morpholino, piperazinyl, N-alkylpiperazinyl, N, N-dialkylamino, N-alkylamino or alkylthio and are R 2 to R g as defined hereinbefore .
Četrti razred novih spojin iz predloženega izuma so tiste spojine s formulo I, kjer sta R4 in R2 kot je tu definirano predhodno;A fourth class of novel compounds of the present invention are those compounds of formula I wherein R 4 and R 2 are as hereinbefore defined;
in je R3 alkoksi, alkiltio ali alkil, kije substituiran z enim ali več halo radikali, ali je to skupina CH2X, kjer je X alkiltio, ariloksi, arilalkiloksi, alkiloksi ali hidroksi;and R 3 is alkoxy, alkylthio or alkyl substituted by one or more halo radicals, or is a CH 2 group X, wherein X is alkylthio, aryloxy, arylalkyloxy, alkyloxy or hydroxy;
so R4 do R6 enaki ali različni in je vsak izbran iz skupine, ki vsebuje vodik, halo, perhaloalkil, nitro, amino ali alkiltio;R 4 to R 6 are the same or different and are each selected from the group consisting of hydrogen, halo, perhaloalkyl, nitro, amino or alkylthio;
je R? halo, alkil, perhaloalkil, ciano, nitro, amino ali skupina SO2N(Rni), kjer je R111 alkil; in jeRg vodik ali halo.is R ? halo, alkyl, perhaloalkyl, cyano, nitro, amino or a group SO 2 N (R is not ) wherein R 111 is alkyl; and R g is hydrogen or halo.
Peti razred novih spojin predloženega izuma so tiste spojine s formulo I, kjer so Rt in R2 in R4 do Rg kot je tu definirano predhodno in je R3 alkoksi, ariloksi, arilalkiloksi ali alkiltio.The fifth class of novel compounds of the present invention are those compounds of formula I wherein R t and R 2 and R 4 to R g are as defined hereinbefore and R 3 is alkoxy, aryloxy, arylalkyloxy or alkylthio.
Prednostne nove spojine predloženega izuma vključujejo naslednje, pri čemer se številke nanašajo na primere, ki se pojavljajo v kasnejšem besedilu:Preferred new compounds of the present invention include the following, the numbers referring to the examples that appear later:
Primer št.Example no.
1. 4-amino-2-(4-metilpiperazin-l-il)-5-(2,3,5-triklorofenil)-6-trifluorometilpirimidin1. 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine
2. 2,4-diamino-5-(2,3,5-triklorofenil)-6-metoksimetilpirimidin2. 2,4-Diamino-5- (2,3,5-trichlorophenyl) -6-methoxymethylpyrimidine
3. 4-amino-2-(4-metilpiperazin-l-il)-5-(2,3,5-triklorofenil)-pirimidin3. 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -pyrimidine
4. 2,4-diamino-5-(2,3,5-triklorofenil)-6-trifluorometilpirimidin4. 2,4-Diamino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine
5. 2,4-diamino-5-(4-nitro-2,3,5-triklorofenil)pirimidin5. 2,4-Diamino-5- (4-nitro-2,3,5-trichlorophenyl) pyrimidine
6. 2,4-diamino-5-(2,3,5-triklorofenil)-6-metilpirimidin6. 2,4-Diamino-5- (2,3,5-trichlorophenyl) -6-methylpyrimidine
7. 4-amino-2-N-morfolino-5-(2,3,5-triklorofenil)-6-trifluorometilpirimidin7. 4-amino-2-N-morpholino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine
8. 4-ammo-2-N,N-dimetilamino-5-(2,3,5-triklorofenil)-6-trifluorometilpirimidin8. 4-amino-2-N, N-dimethylamino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine
9. 4-amino-2-morfolino-N-5-(2,3,5-triklorofenil)pirimidin9. 4-amino-2-morpholino-N-5- (2,3,5-trichlorophenyl) pyrimidine
10. 4-amino-2-N1N-dimetilamino-5-(2,3,5-triklorofenil)pirimidin10. 4-amino-2-N 1 N-dimethylamino-5- (2,3,5-trichlorophenyl) pyrimidine
11. 4-amino-6-metil-2-(4-meitlpiperazin-l-il);5-(2,3,5-triklorofenil)pirimidin11. 4-amino-6-methyl-2- (4-methylpiperazin-1-yl); 5- (2,3,5-trichlorophenyl) pyrimidine
14. 2,4-diamino-5-(2,3-diklorofenil)-6-trilluorometilpirimidin14. 2,4-Diamino-5- (2,3-dichlorophenyl) -6-trifluoromethylpyrimidine
15. 2,4-diamino-5-(2,3-diklorofenil)-6-metilpirimidin15. 2,4-Diamino-5- (2,3-dichlorophenyl) -6-methylpyrimidine
16. 2,4-diamino-5-(2,3-diklorofenil)-6-metoksimetilpirimidin16. 2,4-Diamino-5- (2,3-dichlorophenyl) -6-methoxymethylpyrimidine
25. 2,4-diamino-5-(2,4-diklorofenil)-6-triflourometilpirimidin25. 2,4-Diamino-5- (2,4-dichlorophenyl) -6-trifluoromethylpyrimidine
26. 6-benziloskimetil-2,4-diamino-5-(2,4-diklorofenil)pirimidin26. 6-Benzylosquimethyl-2,4-diamino-5- (2,4-dichlorophenyl) pyrimidine
27. 2-N-metilpiperazinil-4-amino-5-(2,4-diklorofenil)pirimidin27. 2-N-methylpiperazinyl-4-amino-5- (2,4-dichlorophenyl) pyrimidine
28. 2,4-diamino-5-(2,5-diklorofenil)-6-trifluorometilpirimidin28. 2,4-Diamino-5- (2,5-dichlorophenyl) -6-trifluoromethylpyrimidine
29. 2,4-diamino-5-(2,3,5-triklorofenil)pirimidin29. 2,4-Diamino-5- (2,3,5-trichlorophenyl) pyrimidine
36. 4-amino-5-(3,5-diklorofenil)-6-metil-2-(4-metilpiperazin-l-il)pirimidin 58. 4-amino-2-N-etilamino-5-(2,5-diklorofenil)pirimidin 79. 4-amino-2-N-metilamino-5-(2,3,5-triklorofenil)pirimidin ali njihova kislinska adicijska sol.36. 4-amino-5- (3,5-dichlorophenyl) -6-methyl-2- (4-methylpiperazin-1-yl) pyrimidine 58. 4-amino-2-N-ethylamino-5- (2,5 -dichlorophenyl) pyrimidine 79. 4-Amino-2-N-methylamino-5- (2,3,5-trichlorophenyl) pyrimidine or an acid addition salt thereof.
Primerne kislinske adicijske soli spojine s formulo I vključujejo tiste, ki se tvorijo z organskimi ali anorganskimi kislinami. Takšne kislinske adicijske soli bodo normalno farmacevtsko sprejemljive. Tako prednostne soli vključujejo tiste, ki se tvorijo iz klorovodikove, bromovodikove, žveplove, citronske, vinske, fosforne, mlečne, pirogrozdne, ocetne, jantarne, oksalne, fumarne, maleinske, oksalocetne, metansul8 fonske, etansulfonske, p-toluensulfonske, benzensulfonske in izetionske kisline. Te soli lahko pripravimo z reakcijo spojine v obliki proste baze z ustrezno kislino.Suitable acid addition salts of the compounds of formula I include those formed with organic or inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulfuric, citric, tartaric, phosphoric, milky, pyro-grape, acetic, amber, oxal, fumaric, maleic, oxalocet, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic, benzenesulfonic acid. These salts can be prepared by reaction of the compound in the form of the free base with the corresponding acid.
Čeprav je možno, da spojine s formulo I dajemo kot surovo kemikalijo, je želeno, da jih formuliramo kot farmacevtsko formulacijo. Formulacije iz predloženega izuma obsegajo novo spojino s formulo I, kot je definirana zgoraj, ali njeno farmacevtsko sprejemljivo sol, skupaj z enim ali več farmacevtsko sprejemljivimi nosilci za te snovi in, v danem primeru, z drugimi terapevtskimi sestavinami. Nosilec(i) mora(jo) biti sprejemljiv(i) v smislu, da so kompatibilni z drugimi sestavinami formulacije in da niso škodljivi za njihovega prejemnika.Although it is possible to administer compounds of formula I as a crude chemical, it is desirable to formulate them as a pharmaceutical formulation. The formulations of the present invention comprise a novel compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers for these substances and, optionally, other therapeutic ingredients. The carrier (s) must be acceptable in the sense that they are compatible with the other components of the formulation and are not harmful to their recipient.
Formulacije vključujejo tiste, ki so primerne za oralno, parenteralno (vključno subkutano, intradermalno, intramuskularno in intravenozno), rektalno in lokalno (vključno dermalno, bukalno in sublingualno) dajanje, čeprav je najprimernejši način lahko odvisen, npr. od stanja in motnje pacienta. Formulacije lahko primerno formuliramo v obliki dozirne enote in pripravimo jih lahko s katerimkoli od dobro znanih postopkov iz farmacije. Vsi postopki vključujejo fazo privedbe v povezavo spojine s formulo I ali njene farmacevtsko sprejemljive kislinske adicijske soli (aktivne sestavine) z nosilcem, ki tvori eno ali več pomožnih sestavin. V glavnem pripravimo formulacije z enkratno in homogeno privedbo v povezavo aktivne sestavine s tekočimi nosilci ali fino porazdeljenimi trdnimi nosilci ali z obemi in nato, če je potrebno, z oblikovanjem produkta v želeno formulacijo.Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), rectal, and topical (including dermal, buccal, and sublingual) administration, although the preferred route may be dependent, e.g. from the condition and disorder of the patient. The formulations can be suitably formulated in the form of a dosage unit and can be prepared by any of the well-known methods of pharmacy. All processes involve the step of coupling a compound of formula I or a pharmaceutically acceptable acid addition salt (active ingredient) with a carrier to form one or more auxiliary ingredients. Generally, formulations are prepared by uniquely and homogeneously coupling the active ingredient to liquid carriers or finely divided solid carriers or both, and then, if necessary, forming the product into the desired formulation.
Tableto lahko naredimo s stiskanjem ali kalupljenjem, v danem primeru z eno ali več pomožnimi sestavinami. Stisnjene tablete lahko pripravimo s stiskanjem aktivne sestavine v takšni prosto tekoči obliki, kot je prah ali granule, ki je v danem primeru zmešana z nekim vezivnim sredstvom, mazivom inertnim razredčilom, mazivnim sredstvom, površinsko aktivnim sredstvom ali sredstvom za dispergiranje, v nekem primernem stroju. Kalupljene tablete lahko pripravimo s kalupljenjem zmesi uprašene omočene spojine z nekim inertnim tekočim razredčilom v nekem primernem stroju. Tablete lahko v danem primeru prevlečemo ali izmerimo in lahko jih formuliramo tako, da zagotovimo zagotovimo počasno in nadzorovano sproščanje aktivne sestavine iz njih.The tablet may be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets may be prepared by compressing the active ingredient in such a free-flowing form, such as powder or granules, optionally mixed with a binder, an inert diluent, a lubricant, a surfactant or a dispersing agent, in some suitable machine. . Molded tablets can be prepared by molding a mixture of a powdered wetted compound with an inert liquid diluent in a suitable machine. The tablets can optionally be coated or measured and can be formulated to ensure a slow and controlled release of the active ingredient from them.
Formulacije za parenteralno dajanje vključujejo vodne in nevodne sterilne raztopine za injekcije, ki lahko vsebujejo antioksidante, pufre, bakteriostate in topljence, ki naredijo formulacijo izotonično glede na kri nameravanega pacienta; in vodne in nevodne sterilne suspenzije, ki lahko vključujejo sredstva za suspendiranje in sredstva za zgoščevanje. Formulacije lahko formuliramo v dozirno enoto ali v večdozirne vsebnike, npr. zataljene ampule in fiole, in skladiščimo jih lahko liofiliziranem stanju, ki zahteva samo dodajanje sterilnega tekočega nosilca, npr. vode za injekcije, neposredno pred uporabo. Raztopine in suspenzije za injekcije lahko pripravimo v kateremkoli trenutku iz sterilnih praškov, granul in tablet predhodno opisane vrste.Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic to the intended patient's blood; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations can be formulated into a dosage unit or into multi-dose containers, e.g. sealed ampoules and vials, and can be stored in a lyophilized state that only requires the addition of a sterile liquid carrier, e.g. water for injection, just before use. Injectable solutions and suspensions may be prepared at any time from sterile powders, granules and tablets of the species previously described.
Formulacije za rektalno dajanje lahko formuliramo kot svečke z običajnimi nosilci, kot sta kakavovo maslo ali polietilenglikol.Formulations for rectal administration can be formulated as suppositories with conventional carriers such as cocoa butter or polyethylene glycol.
Formulacije za lokalno dajanje v usta, npr. bukalno ali sublingualno, vključujejo pastile, ki obsegajo aktivno sestavino v aromatizirani osnovi, kot so saharoza in akacija ali tragakant, in pastile, ki obsegajo aktivno sestavino v takšni osnovi, kot sta želatina in glicerin ali saharoza in akacija.Formulations for topical oral administration, e.g. buccal or sublingual include lozenges comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth and lozenges comprising the active ingredient in such a base as gelatin and glycerin or sucrose and acacia.
Prednostne enotske dozirne formulacije so tiste, ki vsebujejo učinkovito dozo aktivne sestavine, kot je ponazorjena predhodno ali njen ustrezni del.Preferred unit dosage formulations are those that contain an effective dose of the active ingredient as previously illustrated or a corresponding portion thereof.
Biti mora jasno, da lahko formulacije v smislu izuma poleg sestavin, ki so tu posebej omenjene, vključujejo tudi druga konvencionalna sredstva iz tehnike, odvisno od tipa zadevne formulacije, npr. tiste, ki so primerne za oralno dajanje, lahko vključujejo aromatizima sredstva.It should be clear that the formulations of the invention may include, in addition to the ingredients specifically mentioned herein, other conventional agents of the art, depending on the type of formulation concerned, e.g. those suitable for oral administration may include flavoring agents.
Tablete ali druge oblike za formuliranje, ki so zagotovljene kot posamezne enote, lahko vsebujejo količino spojine s formulo I, ki je učinkovita v takšni dozi ali večkratni zmnožek le-te, npr. enote, ki vsebujejo 5 mg do 500 mg, običajno okoli 10 mg do 250 mg.Tablets or other formulations provided as individual units may contain an amount of a compound of formula I that is effective at such a dose or multiple product thereof, e.g. units containing 5 mg to 500 mg, usually about 10 mg to 250 mg.
Spojine s formulo I prednostno uporabljamo za zdravljenje motenj ali bolezni CNS z oralnim dajanjem ali injiciranjem (intraperitonealnim ali subkutanim). Natančno količino spojine, ki se daje pacientu, določi zdravnik. Vendar pa bo uporabljena doza odvisna od večjega števila faktorjev, ki vključujejo starost in spol pacienta, natančno motnjo, ki jo zdravimo in njeno resnost. Tako bo npr., kadar zdravimo pacienta z epilepsijo, dozirni interval verjetno znatno nižji kot takrat, kadar zdravimo pacienta po kapi, da ublažimo cerebralno ishemsko poškodbo. Prav tako bo način dajanja verjetno variiral od stanja in njegove resnosti.The compounds of formula I are preferably used to treat CNS disorders or diseases by oral administration or injection (intraperitoneal or subcutaneous). The exact amount of compound administered to a patient is determined by the doctor. However, the dose used will depend on a number of factors including the age and gender of the patient, the exact disorder being treated and its severity. Thus, for example, when treating a patient with epilepsy, the dosage interval will likely be significantly lower than when treating a patient after a stroke to alleviate cerebral ischemic injury. Likewise, the route of administration is likely to vary with the condition and its severity.
Spojine s formulo I lahko dajemo oralno ali z injekcijo v dozi od 0,1 do 30 mg/kg dnevno. Dozirni interval za odrasle ljudi je v glavnem od 8 do 2400 mg/dan in prednostno 35 do 1050 mg/dan. Ker so določene spojine s formulo I dolgo-delujoče, je lahko primerno, da dajemo začetno dozo 70 do 2400 mg prvi dan, in nato nižjo dozo 20 do 1200 mg kasnejše dni.The compounds of formula I can be administered orally or by injection at a dose of 0.1 to 30 mg / kg per day. The dosing interval for adults is generally 8 to 2400 mg / day and preferably 35 to 1050 mg / day. Because certain compounds of formula I are long acting, it may be appropriate to administer an initial dose of 70 to 2400 mg on the first day and then a lower dose of 20 to 1200 mg later in the day.
Primeri takšnih dolgo-delujočih spojin so:Examples of such long-acting compounds are:
2.4- diamino-5-(2,3,5-triklorofenil)-6-trifluorometilpirimidin;2,4-diamino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine;
4-amino-2-(4-metilpiperazin-l-il)-5-(2,3,5-triklorofenil)-pirimidin; in4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -pyrimidine; and
4-amino-2-(4-metilpiperazin-l-il)-5-(2,3,5-triklorofenil)-pirimidin.4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -pyrimidine.
Dolgo-delujoče spojine so na klinikah primerne zato, ker je rokovanje z njimi lažje. V kronični situaciji jih lahko dajemo brez infuzije in obstaja minimum neposredne zdravniške intervencije; prav tako je v akutnih pogojih pacient ohrabren z minimiranjem dnevnega doziranja. Nasprotno pa kratko delujoče spojine, kot je:Long-acting compounds are appropriate in clinics because they are easier to handle. In a chronic situation, they can be given without infusion and there is a minimum of direct medical intervention; also, in acute conditions, the patient is encouraged by minimizing daily dosing. In contrast, short-acting compounds such as:
2.4- diamino-5-(2,3,5-triklorofenil)-6-metoksimetilpirimidin omogočajo kliničnemu zdravniku, da kontrolira farmakološki učinek spojine z veliko natančnostjo, saj se bodo takšne spojine hitro eliminirale iz centralnega živčnega sistema (CNS).2.4-Diamino-5- (2,3,5-trichlorophenyl) -6-methoxymethylpyrimidine allow the clinician to control the pharmacological action of the compound with great precision, since such compounds will be rapidly eliminated from the central nervous system (CNS).
Spojine predloženega izuma lahko pripravimo na način, ki je znan iz tehnike za analogne spojine (npr., JACS vol 73 (1951) 3763-70).The compounds of the present invention can be prepared in a manner known in the art for analogous compounds (e.g., JACS vol 73 (1951) 3763-70).
Predloženi izum prav tako zagotavlja postopek za pridobivanje spojine s formulo I ali njene kislinske adicijske soli, ki obsega reakcijo spojine s formulo II:The present invention also provides a process for the preparation of a compound of formula I or an acid addition salt thereof, comprising the reaction of a compound of formula II:
f?5 lo i f, «3f? 5 lo if, «3
II v kateri so R3 do Rg, kot je tu definirano predhodno, je L odhodna skupina in je Y ciano ali karboksi, karbonil ali alkoksikarbonil, s spojino ali njeno soljo s formulo III:II in which R 3 to R g , as defined hereinbefore, L is a leaving group and Y is cyano or carboxy, carbonyl or alkoxycarbonyl, with a compound or a salt thereof of formula III:
NHNH
H2N - C - R1 IH v kateri je Rj kot je tu definirano, in izolacijo spojine s formulo I v obliki proste baze ali njene kislinske adicijske soli, in v danem primeru, pretvorbo baze v njeno kislinsko adicijsko sol ali v drugo kislinsko adicijsko sol, ali v drugo spojino s formulo I ali njeno kislinsko adicijsko sol.H 2 N - C - R 1 IH in which R 1 is as defined herein, and isolating the compound of formula I in the form of a free base or its acid addition salt, and optionally converting the base into its acid addition salt or to another acidic salt an addition salt, or to another compound of formula I, or an acid addition salt thereof.
Jasno bo, da določene spojine s formulo III, npr. v katerih je Rj hidroksi, obstajajo v ustrezni tavtomemi obliki (npr. kot karbamid).It will be appreciated that certain compounds of formula III, e.g. in which R1 is hydroxy, exist in an appropriate tautomic form (eg as carbamide).
Kot primeri notranje konverzije spojin s formulo I, kadar je v produktu gornjega postopka eden od Rp R2 ali R3 hidroksi, lahko spojino halogeniramo, npr. z uporabo Wilsmeier-Haackovega reagenta ali fosforjevega oksiklorida (POC13), v ustrezno halo spojino. To spojino lahko nadalje prevedemo v spojino s formulo I, v kateri je Rj, R2 ali R3 alkiltio, z reakcijo z ustreznim alkiltiolatom ali z ustrezno amino spojino (Rj, R2 ali R3 je NR^11) z reakcijo z ustrezno amino spojino v nekem takšnem ustreznem topilu, kot je alkanol, npr. etanol, ali jo prevedemo v spojino, v kateri je Rj, R2 ali R3 alkoksi, z reakcijo z ustreznim alkoksidom.As examples of the internal conversion of compounds of formula I, when in the product of the above process one of R p is R 2 or R 3 is hydroxy, the compound may be halogenated, e.g. using a Wilsmeier-Haack reagent or phosphorus oxychloride (POC1 3 ) into the corresponding halo compound. This compound may be further converted to a compound of formula I in which Ri, R 2 or R 3 alkylthio by reaction with the appropriate alkylthiolate or to the appropriate amino compound of (R i, R 2 or R 3 is NR 11) by reaction with an appropriate an amino compound in some such suitable solvent as alkanol, e.g. ethanol, or converted to a compound in which R, R 2 or R 3 alkoxy, by reaction with the appropriate alkoxide.
Če je potrebno, da izdelamo spojino s formulo I, v kateri je eden od R4 do Rg nitro, lahko to naredimo iz ustrezne spojine s formulo I, kjer je eden od R4 do Rg vodik, z uporabo standardnih pogojev za nitriranje, npr. žveplene kisline in kalijevega nitrata, in nato nadalje prevedemo s standardnim reducirnim sredstvom v ustrezno amino spojino, npr. z uporabo PtO2, AcOH, H2.If it is necessary to produce a compound of formula I in which one of R 4 to R g is nitro, this can be done from a suitable compound of formula I wherein one of R 4 to R g is hydrogen, using standard nitration conditions , e.g. sulfuric acid and potassium nitrate, and then further converted by standard reducing agent to the corresponding amino compound, e.g. using PtO 2 , AcOH, H 2 .
Jasno bo, da lahko amino ali halo spojine nadalje prevedemo v R4 do Rg, kot je definirano tukaj, s standardno notranjo konverzijo, npr. preko diazonijevih soli. Kadar je R3 alkil, lahko le-tega prevedemo v perhaloalkil ali halogenirano alkilno skupino z reakcijo z ustreznim halogenom ali N-halosukcinimidom (NXS) v nekem takšnem primernem topilu, kot je ocetna kislina.It will be appreciated that the amino or halo compounds can be further converted to R 4 to R g as defined herein by standard internal conversion, e.g. over diazonium salts. When R 3 is alkyl, it can be converted to a perhaloalkyl or halogenated alkyl group by reaction with the corresponding halogen or N-halosuccinimide (NXS) in some suitable solvent such as acetic acid.
Spojine, v katerih je R3 CH(OEt)2, lahko prevedemo v ustrezen aldehid s hidrolizo z razredčeno(nimi) kislino(ami) in nato z redukcijo v ustrezen alkohol s standardnim reducirnim sredstvom (npr. natrijevim borohidridom NaBH4), ali ga prevedemo v ustrezen oksim (hidroksilamin hidroklorid v etanolu), ki ga nato lahko prevedemo v ustrezno ciano spojino z uporabo npr. trifluoroacetanhidrida (TFAA) in nato v ustrezno amido spojino z uporabo koncentrirane žveplene kisline. Alternativno lahko aldehid oksidiramo s KMnO4 (kalijevim permanganatom), tako da dobimo ustrezno kislino, ki jo zopet lahko presnovimo z alkoholom, tako da dobimo ustrezen ester.Compounds containing R 3 CH (OEt) 2 may be converted to the corresponding aldehyde by hydrolysis with dilute acid (s) and then reduced to the corresponding alcohol by a standard reducing agent (eg NaBH 4 sodium borohydride), or it is converted to the corresponding oxime (hydroxylamine hydrochloride in ethanol) which can then be converted to the corresponding cyano compound using e.g. of trifluoroacetic anhydride (TFAA) and then to the corresponding amido compound using concentrated sulfuric acid. Alternatively, the aldehyde can be oxidized with KMnO 4 (potassium permanganate) to give the corresponding acid, which can again be reacted with alcohol to give the corresponding ester.
Kadar je v produktu gornjega postopka R3 skupina CH2OR, kjer je R alkil ali arilalkil, lahko produkt prevedemo v CH2X z reakcijo z ΗΧ (X = halo) v npr. ocetni kislini in le-tega lahko nadalje prevedemo v ustrezno ciano spojino, npr. z obdelavo z natrijevim cianidom in DMF ali v fluorometil z obdelavo z npr. cezijevim fluoridom (CsF) ali v skupino CH^R11 z reakcijo z ustreznim aminom. Alternativno lahko skupino CH2OR dealkiliramo, tako da dobimo ustrezen alkohol, npr. z Me3SiJ in letega nadalje prevedemo v fluorometil z dietilaminožveplovim trifluoridom (DAST).When in the product of the above process R 3 is a CH 2 OR group, where R is alkyl or arylalkyl, the product can be converted to CH 2 X by reaction with ΗΧ (X = halo) in e.g. acetic acid and this can be further converted to the corresponding cyano compound, e.g. by treatment with sodium cyanide and DMF or into fluoromethyl by treatment with e.g. cesium fluoride (CsF) or to a group CH? R 11 by reaction with an appropriate amine. Alternatively, the CH 2 OR group can be dealkylated to give the corresponding alcohol, e.g. with Me 3 SiJ and fly is further converted to fluoromethyl with diethylamino sulfur trifluoride (DAST).
Kadar R3 do Rg vsebujejo alkiltio skupino, lahko le-to oksidiramo v ustrezen sulfoksid in sulfolon z uporabo, npr. MCPBA (metakloroperbenzojske kisline).When R 3 to R g contain an alkylthio group, it can be oxidized to the corresponding sulfoxide and sulfolone using, e.g. MCPBA (metachloroperbenzoic acid).
Jasno bo, da lahko izvedemo druge notranje konverzije, kot zahtevajo strokovnjaki v stroki, z uporabo standardnih metologij.It will be clear that we can perform other internal conversions, as required by those skilled in the art, using standard methodologies.
Primeri primernih odhodnih skupin (L) vključujejo R14 alkoksi, halo, NRxRn, kot je definirano tukaj, npr. anilino, morfolino, Cb4 alkilamino, benzilamino ali alkiltio. Prednostno je v formuli III Rj hidroksi, alkoksi, alkiltio ali skupina NR^11, kot je tukaj definirano. Primerno je R4 amino, alkilamino, dialkilamino, piperazinil ali N-metilpiperazinil.Examples of suitable leaving groups (L) include R 14 alkoxy, halo, NR x R n , as defined herein, e.g. anilino, morpholino, Cb4 alkylamino, benzylamino or alkylthio. Preferably, in formula III, R is hydroxy, alkoxy, alkylthio or a group NR 11 as defined herein. R4 is amino, alkylamino, dialkylamino, piperazinyl or N-methylpiperazinyl.
Prednostno reakcijo spojine s formulo I in II izvedemo v nevodnem topilu, npr. nekem alkanolu, npr. etanolu pri zvišanih temperaturah (npr. med 50 in 110°C) v neki bazi, prednostno nekem alkanoksidu, prednostno pod refluksom z uporabo natrijevega etoksida kot baze.Preferably, the reaction of the compounds of formula I and II is carried out in a non-aqueous solvent, e.g. to some alkanol, e.g. ethanol at elevated temperatures (e.g., between 50 and 110 ° C) in a base, preferably an alkanoxide, preferably under reflux using sodium ethoxide as the base.
Alternativno lahko spojino s formulo I ali njeno kislinsko adicijsko sol pripravimo tudi z reakcijo spojine s formulo III s spojino s formulo IV:Alternatively, a compound of formula I or an acid addition salt thereof may also be prepared by reacting a compound of formula III with a compound of formula IV:
OOh
IV v kateri so R3 do Rg in Y, kot je tu definirano. Reakcijo prednostno izvedemo v nekem nevodnem topilu, npr. alkanolih, kot je etanol, in pri povišanih temperaturah, prednostno pod refluksom.IV in which R 3 to R g and Y are as defined herein. The reaction is preferably carried out in a non-aqueous solvent, e.g. alkanols such as ethanol and at elevated temperatures, preferably under reflux.
Spojine s formulo IV lahko pripravimo z znanimi postopki iz tehnike (JACS, 1951, 73, 3763-3770).The compounds of formula IV can be prepared by known techniques in the art (JACS, 1951, 73, 3763-3770).
Spojine s formulo II lahko pripravimo z znanimi postopki iz tehnike (JACS zgoraj), npr. z reakcijo spojine s formulo IV z diazometanom ali z alkilortoestri (JACS, 1952, 74,1310-1313) ali s kondenzacijo z aminom.The compounds of formula II can be prepared by known techniques in the art (JACS above), e.g. by reaction of a compound of formula IV with diazomethane or alkylorthoesters (JACS, 1952, 74, 1310-1313), or by condensation with an amine.
V formuli III, kadar je R1 piperazinil ali alkilpiperazinil, lahko le-te pripravimo s standardnimi postopki, npr. z reakcijo znane spojine s formulo II, kjer je R1 alkiltio z ustreznim aminom, npr. N-metilpiperazinom. To reakcijo prednostno izvedemo pri sobni temperaturi v vodi.In Formula III, when R 1 is piperazinyl or alkylpiperazinyl, they can be prepared by standard procedures, e.g. by reacting a known compound of formula II, wherein R 1 is alkylthio with the corresponding amine, e.g. N-methylpiperazine. This reaction is preferably carried out at room temperature in water.
Spojine s formulo I lahko prav tako pripravimo z reakcijo spojine s formulo V:Compounds of formula I can also be prepared by reaction of a compound of formula V:
OOh
O v kateri sta Y in R3, kot je definirano predhodno in sta R10 in Rn alkil ali skupaj tvorita skupino (CR2)n, kjer je n 2 do 4 in je R H ali alkil, s spojino s formulo III. Najbolj prednostno je Rj amino, piperazinil ali metilpiperazinil. Prednostno reakcijo izvedemo v nekem nevodnem topilu, npr. etanolu, pod refluksom ob uporabi natrijevega etoksida kot baze.O in which Y and R 3 are as previously defined and R 10 and R n are alkyl or together form a group (CR 2 ) n , wherein n is 2 to 4 and is RH or alkyl, with a compound of formula III. Most preferably, R1 is amino, piperazinyl or methylpiperazinyl. The preferred reaction is carried out in a non-aqueous solvent, e.g. ethanol under reflux using sodium ethoxide as a base.
Spojine s formulo I lahko pripravimo tudi iz ustreznega dihidropirimidina z uporabo standardnih pogojev za dehidrogeniranje (npr. JCS, 1956,1019).The compounds of formula I may also be prepared from the corresponding dihydropyrimidine using standard conditions for dehydrogenation (e.g., JCS, 1956,1019).
Takšen dihidropirimidin lahko izdelamo z reakcijo spojine s formulo II, kjer so R3 do Rg kot je definirano in je L vodik, s spojino s formulo III.Such dihydropyrimidine can be prepared by reacting a compound of formula II, wherein R 3 to R g are as defined and L is hydrogen, with a compound of formula III.
V primerih iz izuma, ki so prikazani nižje, so uporabljene kemijske in druge okrajšave standardne v tehniki in imajo naslednje pomene:In the examples of the invention shown below, chemical and other abbreviations used are standard in the art and have the following meanings:
ch2ci2 ch 2 ci 2
Et3NEt 3 N
MeNH2 MeNH 2
NH4OHNH 4 OH
SOC12 SOC1 2
THF:THF:
NaHNaH
CCLCCL
DHFRDHFR
PtO2 PtO 2
NXS:NXS:
\\
TFAATFAA
CsFCsF
Me3SiJMe 3 SiJ
DASTDAST
MCPBAMCPBA
AIBN diklorometan trietilamin metilamin amonijev hidroksid tionil klorid tetrahidrofuran natrijev hidrid ogljikov tetraklorid dihidrofolat reduktaza platinov oksid (Adamsov katalizator)AIBN dichloromethane triethylamine methylamine ammonium hydroxide thionyl chloride tetrahydrofuran sodium hydride carbon tetrachloride dihydrofolate reductase platinum oxide (Adams catalyst)
N-halo-sukcinimid halogen trifluoroacetanhidrid cezijev fluorid trimetilsililjodid dietilaminožveplov trifluorid metakloroperbenzojska kislina α,α’-azoizobutironitril (2,2’-azobis(2-metilpropionitril)N-halo-succinimide halogen trifluoroacetic anhydride cesium fluoride trimethylsilyliodide diethylamino sulfur trifluoride metachloroperbenzoic acid α, α′-azoisobutyronitrile (2,2′-azobis (2-methylpropionitrile)
Primer 1Example 1
Pridobivanje 4-amino-2-(4-metilpiperazin-l-il)-5-(2,3,5-triklorofenil)-6-trifluormetilpirimidinaPreparation of 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine
1. Pridobivanje N-metilpiperazinoformamidin hidrojodida1. Preparation of N-methylpiperazinoformamidine hydroiodide
Tiokarbamid (10,8 g) raztopimo v acetonu (250 ml) pri 50°C. Dodamo jodometan (10 ml) in reakcijo mešamo pri 50°C 4 h. Po ohlajanju raztopino razredčimo z etrom (1 liter) in metiljodidno sol filtriramo, speremo z etrom in posušimo v vakuumu, 29,2 g, 113-115°C. Metiljodidno sol (5 g) raztopimo v vodi (30 ml) in dodamo N-metilpiperazin. Raztopino mešamo, prepihavamo z dušikom pri sobni temperaturi 24 h. Raztopino koncentriramo v vakuumu, 4,98 g, tal.230-242°C.Thiocarbamide (10.8 g) was dissolved in acetone (250 ml) at 50 ° C. Iodomethane (10 ml) was added and the reaction was stirred at 50 ° C for 4 h. After cooling, the solution was diluted with ether (1 liter) and the methyl iodide salt filtered, washed with ether and dried in vacuo, 29.2 g, 113-115 ° C. The methyl iodide salt (5 g) was dissolved in water (30 ml) and N-methylpiperazine was added. The solution was stirred, purged with nitrogen at room temperature for 24 h. The solution was concentrated in vacuo, 4.98 g, mp 230-242 ° C.
2. Pridobivanje 2,3,5-triklorobenzilalkohola2. Preparation of 2,3,5-trichlorobenzylalcohol
K raztopini 2,3,5-triklorobenzilaldehida (Aldrich, 50 g) v etanolu (1,0 1) pri sobni temperaturi dodamo NaBH4 (7,00 g) in dobljeno zmes mešamo 3,5 h. Reakcijo prekinemo z vodo in topilo uparimo v vakuumu pred porazdelitvijo ostanka med CHC13 in nasičeno raztopino NaHCO3. Organsko fazo speremo s slanico, posušimo preko MgSO4, filtriramo in topilo uparimo v vakuumu, da ostane bela trdna snov. 43,00 g, tal. 90-93°C.To a solution of 2,3,5-trichlorobenzylaldehyde (Aldrich, 50 g) in ethanol (1.0 L) at room temperature was added NaBH 4 (7.00 g) and the resulting mixture was stirred for 3.5 h. The reaction is quenched with water and the solvent evaporated in vacuo before distribution of the residue between CHC1 3 and a saturated solution of NaHCO third The organic phase was washed with brine, dried over MgSO 4 , filtered and the solvent was evaporated in vacuo to leave a white solid. 43.00 g, m.p. 90-93 ° C.
3. Pridobivanje 2,3,5-triklorobenzilbromida3. Preparation of 2,3,5-trichlorobenzyl bromide
K raztopini alkohola v benzenu (400 ml) dodamo PBr3 (126,58 g) pod dušikom in zmes mešamo na 55-60°C 3,5 h. Po ohlajanju zmes vlijemo na zdrobljen led (2 1) in odloči se benzenski sloj. Vodno fazo speremo z benzenom (x 3) in združene benzenske ekstrakte speremo z nasičeno raztopino NaHCO3 in vodo, posušimo preko MgSO4, filtriramo in topilo odparimo, da ostane rjavkasta tekočina, ki se ob stanju strjuje, 37,53 g, tal. 40-42°C.To the solution of alcohol in benzene (400 ml) was added PBr 3 (126.58 g) under nitrogen and the mixture was stirred at 55-60 ° C for 3.5 h. After cooling, the mixture is poured onto crushed ice (2 L) and the benzene layer precipitated. The aqueous phase was washed with benzene (x 3) and the combined benzene extracts washed with saturated NaHCO 3 solution and water, dried over MgSO 4 , filtered and the solvent was evaporated to leave a brownish, solidifying liquid, 37.53 g, m.p. 40-42 ° C.
4. Pridobivanje 2,3,5-triklorofenilacetonitrila4. Preparation of 2,3,5-trichlorophenylacetonitrile
Bromid suspendiramo v DMF (130 ml)/voda (86,67 ml) pri 0°C in po deležih dodamo KCN (12,99 g). Po mešanju 3 h na 30-35°C suspenzijo razredčimo z vodo in ekstrahiramo z Et2O. Združene etrske ekstrakte speremo z vodo, posušimo preko MgSO4, fitriramo in topilo uparimo v vakuumu. S kromatografijo na silikagelu z eluacijo s heksanom do 20% eter-heksana dobimo želen produkt kot belo trdno snov, 18,52 g, tal. 60-62°C.The bromide was suspended in DMF (130 ml) / water (86.67 ml) at 0 ° C and KCN (12.99 g) was added portionwise. After stirring for 3 h at 30-35 ° C, the suspension was diluted with water and extracted with Et 2 O. The combined ether extracts were washed with water, dried over MgSO 4 , filtered and the solvent was evaporated in vacuo. Chromatography on silica gel eluting with hexane to 20% ether-hexane gave the desired product as a white solid, 18.52 g, m.p. 60-62 ° C.
5. Pridobivanje 2-(2.3,5-triklorofenil)-4,4,4-trifluoro-3-okso-butironitrila5. Preparation of 2- (2,3,5-trichlorophenyl) -4,4,4-trifluoro-3-oxo-butyronitrile
K raztopini NaOEt (iz 1,04 g Na) v EtOH (60 ml) pri sobni temperaturi pod dušikom dodamo nitril (8,40 g) in nato etil trifluoroacetat (6,57 g) in zmes mešamo pri refluksu 5 h. Po ohlajanju topilo odločimo v vakuumu, ostanek pa raztopimo v vodi. Vodno fazo speremo z Et2O (zavržemo), nakisamo s H2SO4 in ekstrahiramo z Et2O. Združene Et2O ekstrakte speremo z vodo, posušimo preko MgSO4, filtriramo in topilo uparimo v vakuumu, tako da ostane olje. Le-to obdelamo s petroletrom in trdno snov odfiltriramo in posušimo. Trdno snov azeotropiramo s toluenom (x5), 4,89 g, tal. 160-163°C.To a solution of NaOEt (from 1.04 g Na) in EtOH (60 ml) at room temperature under nitrogen was added nitrile (8.40 g) and then ethyl trifluoroacetate (6.57 g) and the mixture was refluxed for 5 h. After cooling, the solvent was removed in vacuo and the residue dissolved in water. The aqueous phase was washed with Et 2 O (discarded), acidified with H 2 SO 4 and extracted with Et 2 O. The combined Et 2 O extracts were washed with water, dried over MgSO 4 , filtered and the solvent was evaporated in vacuo to leave an oil. It is treated with light petroleum and the solid is filtered off and dried. The solid was azeotroped with toluene (x5), 4.89 g, m.p. Mp 160-163 ° C.
6. Pridobivanje 2-(2,3,5-triklorofenil)-4.4.4-trifluoro-3-metoksibut-2-enonitrila6. Preparation of 2- (2,3,5-trichlorophenyl) -4.4.4-trifluoro-3-methoxybut-2-enonitrile
K raztopini trifluorometilketona v Et2O (39,62 ml) pri sobni temperaturi dodamo diazometan (iz 8,55 g Diazald-a) v Et2O (79,62 ml) in nastalo zmes pustimo stati pri sobni temperaturi preko noči. Prebitek diazometana nato odstranimo v vakuumu v AcOH, ostanek pa raztopimo v Et2O, posušimo preko MgSO4, filtriramo in topilo uparimo v vakuumu, tako da ostane rjavkasto olje, 5,20 g.To a solution of trifluoromethyl ketone in Et 2 O (39.62 ml) at room temperature was added diazomethane (from 8.55 g Diazald-a) in Et 2 O (79.62 ml) and the resulting mixture was allowed to stand at room temperature overnight. The excess of diazomethane was then removed in vacuo in AcOH and the residue was dissolved in Et 2 O, dried over MgSO 4 , filtered and the solvent was evaporated in vacuo to leave a brownish oil, 5.20 g.
7. Pridobivanje 4-amino-2-i4-metilpiperazin-l-il)-5-(2.3,5-triklorofeniD-6-trifluoro metil-pirimidina7. Preparation of 4-amino-2-4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl-6-trifluoro methyl-pyrimidine
K raztopini NaOEt (iz 0,144 g Na) v EtOH (12,5 ml) dodamo N-metilpiperazinoformamidin hidrojodid (1,39 g). Po mešanju 10 minut na sobni temperaturi dodamo raztopino gornjega intermediata (0,85 g) v EtOH (2,5 ml) in dobljeno zmes mešamo pri refluksu 4,5 h. Po ohladitvi suspenzijo filtriramo in filtrat uparimo do suhega v vakuumu. Kromatografija na silikagelu, z eluiranjem z CHC134% MeOH/CHCl3 da želen produkt, ki ga obdelamo s petroletrom (vrel. 40-60°C) in posušimo v vakuumu, 0,56 g, tal. 127-129°C.To a solution of NaOEt (from 0.144 g Na) in EtOH (12.5 ml) was added N-methylpiperazinoformamidine hydroiodide (1.39 g). After stirring for 10 minutes at room temperature, a solution of the above intermediate (0.85 g) in EtOH (2.5 ml) was added and the resulting mixture was stirred at reflux for 4.5 h. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel, eluting with CHCl 3 4 4% MeOH / CHCl 3 gave the desired product, which was treated with petroleum ether (boiling point 40-60 ° C) and dried in vacuo, 0.56 g, m.p. 127-129 ° C.
8. 4-amino-2-(4-metilpiperazin-l-il)-5-(2,3,5-triklorofenil)-6-trifluorometil pirimidin-metansulfonat8. 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine methanesulfonate
Fenilpirimidinsko bazo (9,6 g) raztopimo v absolutnem etanolu, ohladimo na 0°C in nato dodamo metansulfonsko kislino. Po mešanju na sobni temperaturi 2 uri raztopino uparimo do suhega in ostanek obdelamo z Et2O, filtriramo in posušimo v vakuumu, tako da ostane trdna snov bež barve. Le-to raztopimo v vodi (500 ml) in liofiliziramo, tako da dobimo trdno snov rumeno rjave barve. Metansulfonatno sol lahko nadalje prečistimo z obdelavo s tBuOH (30 ml), filtriranjem, raztapljanjem v vodi in ponovnim sušenjem s pomočjo liofilizacije, tako da dobimo naslovno spojino v obliki belkaste trdne snovi.The phenylpyrimidine base (9.6 g) was dissolved in absolute ethanol, cooled to 0 ° C and then methanesulfonic acid was added. After stirring at room temperature for 2 hours, the solution was evaporated to dryness and the residue was treated with Et 2 O, filtered and dried in vacuo to leave a solid beige. This was dissolved in water (500 ml) and lyophilized to give a yellow-brown solid. The methanesulfonate salt can be further purified by treatment with tBuOH (30 ml), filtration, dissolution in water and repeated drying by lyophilization to give the title compound as a whitish solid.
8,33 g, tal. 145-147°C.8.33 g, m.p. 145-147 ° C.
Primer 2Example 2
Pridobivanje 2.4-diamino-5-(2,3,5-triklorofenill-6-metoksimetil pirimidinaPreparation of 2,4-diamino-5- (2,3,5-trichlorophenyl-6-methoxymethyl pyrimidine
A. 2-(2,3,5-triklorofenil)-4-metoksi-3-okso-butironitrilA. 2- (2,3,5-Trichlorophenyl) -4-methoxy-3-oxo-butyronitrile
K mešani refluktirani raztopini natrijevega etoksida (iz 1,38 g natrija) v etanolu (25 ml) dodamo tekom 5 minut zmes 2,3,5-triklorofenilacetonitrila (11 g) in etil metoksiacetata (8,85 g) v suhem DME (25 ml). Po 4 h zmes ohladimo na ledu in nakisamo z dokapavanjem ocetne kisline (okoli 6 ml), razredčimo z ledeno vodo (150 ml) in nato ekstrahiramo z diklorometanom (2 x 100 ml). Diklorometanski ekstrakt speremo z vodo, posušimo preko MgSO4 in koncentriramo, kar da rumeno trdno snov, ki jo obdelamo z malo etra in filtriramo. 8,6 g, homogen na osnovi TLC (19:1 CH2Cl:MeOH).A mixture of 2,3,5-trichlorophenylacetonitrile (11 g) and ethyl methoxyacetate (8.85 g) in dry DME (25) was added over 5 minutes to a stirred refluxed solution of sodium ethoxide (1.38 g sodium) in ethanol (25 ml). ml). After 4 h, the mixture was cooled on ice and acidified with acetic acid (about 6 ml), diluted with ice water (150 ml) and then extracted with dichloromethane (2 x 100 ml). The dichloromethane extract was washed with water, dried over MgSO 4 and concentrated to give a yellow solid which was triturated with a little ether and filtered. 8.6 g, homogeneous based on TLC (19: 1 CH 2 Cl: MeOH).
B. Pridobivanje 2,4-diamino-5-(2,3,5-triklorofenilj-6-metoksi-metilpirimidinaB. Preparation of 2,4-diamino-5- (2,3,5-trichlorophenyl-6-methoxy-methylpyrimidine
Suspenzijo surovega acilacetonitrila (8,5 g) v etru (100 ml) ohladimo na ledu, obdelamo s prebitkom brezalkoholnega diazometana v etru (0,035 M). Po eni uri TLC (19:1 CH2Cl2:MeOH) pokaže, da ni izhodnega materiala. To raztopino koncentriramo, da bi dobili rjavo voskasto trdno snov, ki jo uporabimo brez nadaljnjega čiščenja.A suspension of crude acylacetonitrile (8.5 g) in ether (100 ml) was cooled on ice, treated with an excess of non-alcoholic diazomethane in ether (0.035 M). After one hour, TLC (19: 1 CH 2 Cl 2 : MeOH) indicated that there was no starting material. Concentrate this solution to give a brown waxy solid, which is used without further purification.
K raztopini natrijevega etoksida (iz 0,76 g natrija) v etanolu (30 ml) dodamo gvanidin hidroklorid (2,9 g). Po 15 minutah dodamo raztopino surovega enolnega etra v etanolu (25 ml) in zmes refluktiramo ob mešanju tekom 4 h, ohladimo in koncentriramo. Ostanek zmešamo z 2M NaOH (150 ml) in nato temno trdno snov odfiltriramo, speremo z vodo, posušimo na zraku in rekristaliziramo iz etanola (150 ml). 5 g, tal. 214-216°C, TLC (1:9 MeOH:CHCl3) Rf okoli 0,35.To a solution of sodium ethoxide (from 0.76 g of sodium) in ethanol (30 ml) was added guanidine hydrochloride (2.9 g). After 15 minutes, a solution of crude enol ether in ethanol (25 ml) was added and the mixture was refluxed with stirring for 4 h, cooled and concentrated. The residue was mixed with 2M NaOH (150 ml) and then the dark solid was filtered off, washed with water, air-dried and recrystallized from ethanol (150 ml). 5 g, m.p. 214-216 ° C, TLC (1: 9 MeOH: CHCl 3 ) Rf about 0.35.
C. 2,4-diamino-5-(2,3,5-triklorofenil)-6-metoksimetilpirimidin etansulfatC. 2,4-Diamino-5- (2,3,5-trichlorophenyl) -6-methoxymethylpyrimidine ethanesulfate
K mešani suspenziji fenilpirimidina (2 g) v etanolu (75 ml) dodamo z dokapavanjem etansulfonsko kislino (0,67 g) v etanolu (10 ml). Po približno 30 minutah postane raztopina motna. Mešanje nadaljujemo še nadaljnjo 1,5 h in nato topilo koncentriramo dookoli 20 ml. Dodamo eter, trdno snov odfiltriramo in speremo z Et2O pred sušenjem v vakuumu. 2,17 g, tal. 265-268°C.Ethanesulfonic acid (0.67 g) in ethanol (10 ml) was added dropwise to a mixed suspension of phenylpyrimidine (2 g) in ethanol (75 ml). After about 30 minutes, the solution becomes cloudy. The stirring was continued for a further 1.5 h and then the solvent was concentrated to 20 ml. Ether was added, the solid was filtered off and washed with Et 2 O before drying in vacuo. 2.17 g, m.p. 265-268 ° C.
ITIT
Primer 3Example 3
Sinteza 4-amino-2-(4-metilpiperazin-l-il)-5-(2,3,5-triklorofenil)pirimidin mezilataSynthesis of 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine mesylate
1. Pridobivanje 2-(2,3,5-triklorofenil)-3-okso-propionitril natrijeve soli1. Preparation of 2- (2,3,5-trichlorophenyl) -3-oxo-propionitrile sodium salt
K raztopini NaOEt (iz 0,803 g natrija) v etanolu (55 ml), ki je ohlajena na ledu, pod dušikom dodamo 2,3,5-triklorofenil acetonitril (glej primer 1.4). Dodamo etilformiat (5,1 ml) in zmes mešamo na sobni temperaturi preko noči. Po mešanju naslednji 2,5 h na 50°C zmes ohladimo in filtriramo. Filtrat uparimo in ostanek obdelamo z dietiletrom, filtriramo in posušimo (6,82 g).To a solution of NaOEt (from 0.803 g sodium) in ice-cooled ethanol (55 ml), 2,3,5-trichlorophenyl acetonitrile was added under nitrogen (see Example 1.4). Ethylformate (5.1 ml) was added and the mixture was stirred at room temperature overnight. After stirring for the next 2.5 h at 50 ° C, the mixture was cooled and filtered. The filtrate was evaporated and the residue was treated with diethyl ether, filtered and dried (6.82 g).
2. Pridobivanje 2-(2,3,5-triklorofenil)-3-metoksi-akrilonitrila2. Preparation of 2- (2,3,5-trichlorophenyl) -3-methoxy-acrylonitrile
Gornjo trdno snov raztopimo v DMF (36 ml) in dodamo metiljodid (2 ml). Reakcijsko posodo zapremo in zmes mešamo na 40°C 3 h. Topilo nato odparimo. Ostanek porazdelimo med vodo in etilacetat. Organsko fazo speremo z vodo, posušimo (MgSO4)2 in topilo uparimo, tako da dobimo surov produkt rdeče-rjave barve, ki se ob stanju strjuje (5,04 g).The above solid was dissolved in DMF (36 ml) and methyl iodide (2 ml) added. The reaction vessel was closed and the mixture stirred at 40 ° C for 3 h. The solvent was then evaporated. The residue was partitioned between water and ethyl acetate. The organic phase was washed with water, dried (MgSO 4 ) 2 and the solvent was evaporated to give a crude product of a reddish-brown color, which solidified under condition (5.04 g).
3. Pridobivanje 4-amino-2-(4-metilpiperazin-l-if)-5-(2,3,5-triklorofenil)pirimidina3. Preparation of 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine
K raztopini NaOEt (iz 0,21 g natrija) v etanolu (20 ml) dodamo N-metilpiperazinoformamidin hidrojodid (2,06 g) (glej primer 1.1). Po mešanju 10 minut k zmesi dodamo spojino iz primera 3.2 (1 g) in vse skupaj mešamo pri refluksu 4 h. Zmes pustimo, da stoji preko noči na sobni temperaturi in jo nato filtriramo. Filtrat koncentriramo, ostanek pa prečistimo s kromatografijo na SiO2, z eluacijo s CHC13 do 4% MeOH/CHCl3, tako da dobimo naslovno spojino kot prosto bazo. 0,89 g, tal. 162-164°C.To a solution of NaOEt (0.21 g sodium) in ethanol (20 ml) was added N-methylpiperazinoformamidine hydroiodide (2.06 g) (see Example 1.1). After stirring for 10 minutes, the compound of Example 3.2 (1 g) was added to the mixture and stirred at reflux for 4 h. The mixture was allowed to stand at room temperature overnight and then filtered. The filtrate was concentrated and the residue purified by chromatography on SiO 2 , eluting with CHCl 3 to 4% MeOH / CHCl 3 to give the title compound as the free base. 0.89 g, m.p. Mp 162-164 ° C.
Prosto bazo (0,805 g) raztopimo v etanolu (35 ml) in ohladimo na ledeni kopeli. Dodamo metansulfonsko kislino (0,21 g) in reakcijo mešamo na sobni temperaturi 2The free base (0.805 g) was dissolved in ethanol (35 ml) and cooled in an ice bath. Methanesulfonic acid (0.21 g) was added and the reaction was stirred at room temperature 2
h. Topilo nato odparimo in ostanek obdelamo z dietiletrom, filtriramo, raztopimo v hladni vodi in liofiliziramo. Dobimo naslovno sol kot bledo zeleno trdno snov. 0,98 g, tal. 143-146°C.h. The solvent was then evaporated and the residue treated with diethyl ether, filtered, dissolved in cold water and lyophilized. We obtain the title salt as a pale green solid. 0.98 g, m.p. Mp 143-146 ° C.
Primer 4Example 4
Sinteza 2,4-diamino-5-f2,3,5-triklorofenil)-6-trifluorometil pirimidinaSynthesis of 2,4-diamino-5-f2,3,5-trichlorophenyl) -6-trifluoromethyl pyrimidine
K raztopini NaOEt (iz 0,88 g Na) v EtOH (82 ml) dodamo gvanidin hidroklorid (2,98 g). Dobljeno belo suspenzijo mešamo na sobni temperaturi 10 minut. Le-tej dodamo raztopino enolnega etra (primer 1.6) v etanolu (27 ml) in dobljeno zmes mešamo na refluksu 4,25 h. Po ohladitvi suspenzijo filtriramo in filtrat uparimo do suhega v vakuumu. Kromatografija na silikagelu z eluiranjem s CHC13 do 2% MeOH/CHCl3 da želeni produkt, ki ga obdelamo z Et2O in posušimo v vakuumu. 1,78 g, tal. 226227°C.To a solution of NaOEt (from 0.88 g Na) in EtOH (82 ml) was added guanidine hydrochloride (2.98 g). The resulting white suspension was stirred at room temperature for 10 minutes. To this was added a solution of enol ether (Example 1.6) in ethanol (27 ml) and the resulting mixture was refluxed for 4.25 h. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel eluting with CHC1 3 to 2% MeOH / CHCl 3 gave the desired product, which was treated with Et 2 O and dried in vacuo. 1.78 g, m.p. 226227 ° C.
Primer 5Example 5
Pridobivanje 2,4-diamino-5-(4-nitro-2,3,5-triklorofenil) pirimidinaPreparation of 2,4-diamino-5- (4-nitro-2,3,5-trichlorophenyl) pyrimidine
Spojino iz primera 29 raztopimo v koncentrirani žvepleni kislini (2,5 ml). Dodamo kalijev nitrat (25,8 mg) in raztopino mešamo 3 h. Raztopino nato vlijemo na led in naalkalimo z ION NaOH. Produkt ekstrahiramo z etilacetatom (x3), posušimo preko MgSO4, filtriramo in topilo uparimo. Kromatografija na silikagelu z eluiranjem z etilacetatom da želeni produkt. 40,7 mg, tal. 293-295°C.The compound of Example 29 was dissolved in concentrated sulfuric acid (2.5 ml). Potassium nitrate (25.8 mg) was added and the solution stirred for 3 h. The solution was then poured onto ice and basified with ION NaOH. The product was extracted with ethyl acetate (x3), dried over MgSO 4 , filtered and the solvent was evaporated. Chromatography on silica gel eluting with ethyl acetate gave the desired product. 40.7 mg, m.p. 293-295 ° C.
Primer 6Example 6
Pridobivanje 2,4-diamino-5-(2,3,5-triklorofenil)-6-metil pirimidinaPreparation of 2,4-diamino-5- (2,3,5-trichlorophenyl) -6-methyl pyrimidine
1. Pridobivanje 2-(2,3,5-triklorofenil)-3-oksobutironitrila1. Preparation of 2- (2,3,5-trichlorophenyl) -3-oxobutyronitrile
K raztopini NaOEt (iz 0,68 g natrija) v etanolu (20 ml) dodamo 2,3,5triklorofenilacetonitrila (5 g) in etilacetata (4,43 ml). Zmes segrevamo pod refluksom pod dušikom 2,5 ure. Zmes pustimo, da stoji pri sobni temperaturi preko noči. Zmes nato koncentriramo in ostanek raztopimo v vodi. Vodno fazo speremo z etrom, nakisamo s koncentrirano H2SO4 in ekstrahiramo z etrom. Ekstrakte zberemo, posušimo (MgSO4) in uparimo. 2,59 g, tal. 134-135°C.To a solution of NaOEt (from 0.68 g of sodium) in ethanol (20 ml) was added 2,3,5 trichlorophenylacetonitrile (5 g) and ethyl acetate (4.43 ml). The mixture was refluxed under nitrogen for 2.5 hours. The mixture was allowed to stand at room temperature overnight. The mixture was then concentrated and the residue dissolved in water. The aqueous phase was washed with ether, acidified with concentrated H 2 SO 4 and extracted with ether. The extracts were collected, dried (MgSO 4 ) and evaporated. 2.59 g, m.p. 134-135 ° C.
2. Pridobivanje (2-(2,3,5-triklorofenilj-3-metoksibut-2-enonitrila2. Preparation of (2- (2,3,5-trichlorophenyl-3-methoxybut-2-enonitrile)
K raztopini ketona v etru (100 ml) na sobni temperaturi dodamo diazometan (iz 5,43 Diazald-a) v etru (50 ml) in dobljeno zmes pustimo, da stoji pri sobni temperaturi preko noči. Eter nato oddestiliramo, tako da ostane želeni produkt. 2,45 g.To a solution of ketone in ether (100 ml) at room temperature was added diazomethane (from 5.43 Diazald-a) in ether (50 ml) and the resulting mixture was allowed to stand at room temperature overnight. The ether is then distilled off to leave the desired product. 2,45 g.
3. Pridobivanj e 2,4-diamino-5 - (2,3,5-triklorofenil) -6-metil-pirimidina3. Preparation of 2,4-diamino-5- (2,3,5-trichlorophenyl) -6-methyl-pyrimidine
Gvanidin hidroklorid (3,87 g) dodamo k raztopini natrijevega etoksida (iz 1,01 g natrija) v etanolu (80 ml). Dobljeno belo suspenzijo mešamo na sobni temperaturi 10 minut in jo nato dodamo k raztopini enolnega etra (Primer 6.2) (5,60 g) v etanolu (20 ml). Dobljeno zmes mešamo na refluksu 8 h pod dušikom. Po ohladitvi suspenzijo filtriramo in filtrat uparimo do suhega v vakuumu. Kromatografija na silikagelu ob eluiranju s CHC13 do 2% MeOH/CHCl3 da želeni produkt, ki ga obdelamo z etrom in posušimo v vakuumu. Dobitek 1,70 g, tal. 236-238°C.Guanidine hydrochloride (3.87 g) was added to a solution of sodium ethoxide (from 1.01 g sodium) in ethanol (80 ml). The resulting white suspension was stirred at room temperature for 10 minutes and then added to a solution of enol ether (Example 6.2) (5.60 g) in ethanol (20 ml). The resulting mixture was stirred at reflux for 8 h under nitrogen. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel eluting with CHC1 3 to 2% MeOH / CHCl 3 gave the desired product, which was treated with ether and dried in vacuo. Yield 1.70 g, m.p. 236-238 ° C.
Primer 7Example 7
Pridobivanje 4-amino-2-N-morfolino-5-(2,3,5-triklorofenil)-6-trifluorometilpirimidinaPreparation of 4-amino-2-N-morpholino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine
K raztopini NaOEt (iz 0,144 g Na) v EtOH (12,5 ml) dodamo morfolinoformamidin hidrobromid (1,08 g) (Lancaster Synthesis). Dobljeno belo suspenzijo mešamo pri sobni temperaturi 10 minut. Dodamo raztopino enolnega etra (0,85 g) (Primer 1.6) v EtOH (2,5 1) in dobljeno zmes mešamo pri refluksu 4,5 ure. Po ohlajanju suspenzijo filtriramo in filtrat uparimo do suhega v vakuumu. Kromatografija na silikagelu ob eluaciji s CHClj da želeni produkt, ki ga obdelamo s petroletrom (vrel. 40-60°C) in posušimo v vakuumu. 0,47 g, tal. 177-181°C.To a solution of NaOEt (from 0.144 g Na) in EtOH (12.5 ml) was added morpholinoformamidine hydrobromide (1.08 g) (Lancaster Synthesis). The resulting white suspension was stirred at room temperature for 10 minutes. A solution of enol ether (0.85 g) (Example 1.6) in EtOH (2.5 L) was added and the resulting mixture was stirred at reflux for 4.5 hours. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel eluting with CHCl3 afforded the desired product, which was treated with petroleum ether (boiling point 40-60 ° C) and dried in vacuo. 0.47 g, m.p. 177-181 ° C.
Primer 8Example 8
Pridobivanje 4-amino-2-fN,N-dimetiIamino)-5-(2,3,5-triklorofenil)-6-trifluorometilpirimidinaPreparation of 4-amino-2-fN, N-dimethylamino) -5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine
K raztopini NaOEt (iz 0,144 g Na) v EtOH (12,5 ml) dodamo 1,1-dimetilgvanidin sulfata (1,4 g) (Aldrich). Dobljeno belo suspenzijo mešamo pri sobni temperaturi 10 minut. Dodamo raztopino 2-(2,3,5-triklorofenil)-4,4,4-trifluoro-3-metoksibut-222 enonitrila (glej Primer 1.6) (0,85) v EtOH (2,5 ml) in dobljeno zmes mešamo pri refluksu 4,5 ure. Po ohlajanju suspenzijo filtriramo in filtrat uparimo do suhega v vakuumu. Kromatografija na silikagelu z eluiranjem s CHC13 da želeni produkt. 0,61 g, tal. 124-126°C.To a solution of NaOEt (from 0.144 g Na) in EtOH (12.5 ml) was added 1,1-dimethylguanidine sulfate (1.4 g) (Aldrich). The resulting white suspension was stirred at room temperature for 10 minutes. A solution of 2- (2,3,5-trichlorophenyl) -4,4,4-trifluoro-3-methoxybut-222 enonitrile (see Example 1.6) (0.85) in EtOH (2.5 ml) was added and the resulting mixture was stirred at reflux for 4.5 hours. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel eluting with CHCl 3 gave the desired product. 0.61 g, m.p. 124-126 ° C.
Primer 9Example 9
Sinteza 4-amino-2-N-morfolino-5-(2,3,5-triklorofenil)-pirimidinaSynthesis of 4-amino-2-N-morpholino-5- (2,3,5-trichlorophenyl) -pyrimidine
K raztopini NaOEt (iz 0,21 g natrija) v etanolu (20 ml) dodamo morfolinoformamidin hidrobrommid (1,6 g). Po mešanju 10 minut dodamo adukt iz primera 3.2 (1 g) in zmes mešamo na refluksu 4 ure. Zmes pustimo, da stoji pri sobni temperaturi preko noči in jo nato filtriramo. Filtrat koncentriramo. Ostanek prečistimo s kromatografijo na SiO2 in eluacijo s CHC13, tako da dobimo želeni produkt, 0,73 g, tal. 168-170°C.To a solution of NaOEt (from 0.21 g sodium) in ethanol (20 ml) was added morpholinoformamidine hydrobromide (1.6 g). After stirring for 10 minutes, the adduct of Example 3.2 (1 g) was added and the mixture was refluxed for 4 hours. The mixture was allowed to stand at room temperature overnight and then filtered. The filtrate was concentrated. The residue was purified by chromatography on SiO 2 and elution with CHCl 3 to give the desired product, 0.73 g, m.p. Mp 168-170 ° C.
Primer 10Example 10
Sinteza 4-amino-2-(N,N-dimetilaminol-5-(2.3,5-triklorofenil)-pirimidinaSynthesis of 4-amino-2- (N, N-dimethylaminol-5- (2,3,5-trichlorophenyl) -pyrimidine
K raztopini NaOEt (iz 0,21 g natrija) v etanolu (20 ml) dodamo 1,1-dimetilgvanidinsulfat (2,07 g). Po mešanju 10 minut dodamo adukt iz primera 3.2 (1 g) in zmes mešamo na refluksu 4 ure. Zmes pustimo, da stoji pri sobni temperaturi preko noči in jo nato filtriramo. Filtrat koncentriramo in ostanek prečistimo s kromatografijo na SiO2 in eluacijo s CHC^, da dobimo želeni produkt, 0,69 g, tal. 145-147°C.To a solution of NaOEt (0.21 g sodium) in ethanol (20 ml) was added 1,1-dimethylguanidinesulfate (2.07 g). After stirring for 10 minutes, the adduct of Example 3.2 (1 g) was added and the mixture was refluxed for 4 hours. The mixture was allowed to stand at room temperature overnight and then filtered. The filtrate was concentrated and the residue was purified by chromatography on SiO 2 and elution with CHCl 3 to give the desired product, 0.69 g, m.p. 145-147 ° C.
Primer 11Example 11
K raztopini NaOEt (iz 0,16 g natrija) v etanolu (15 ml) dodamo N-metilpiperazinoformamidin hidrojodida (1,6 g). Po mešanju 10 minut dodamo k raztopini enolnieter iz primera 6.2 (0,82 g) v etanolu (5 ml) in zmes mešamo na refluksu 5 ur. Zmes pustimo, da stoji pri sobni temperaturi preko noči in jo nato filtriramo. Filtrat koncentriramo. Ostanek prečistimo s kromatografijo na SiO2 gelu, z eluiranjem s CHC13 do 4% MeOH/CHCl3, tako da dobimo želeni produkt. 0,31 g, tal. 156-159°C.To a solution of NaOEt (0.16 g sodium) in ethanol (15 ml) was added N-methylpiperazinoformamidine hydroiodide (1.6 g). After stirring for 10 minutes, the enolniether of Example 6.2 (0.82 g) in ethanol (5 ml) was added to the solution and the mixture was refluxed for 5 hours. The mixture was allowed to stand at room temperature overnight and then filtered. The filtrate was concentrated. The residue was purified by chromatography on a SiO 2 gel, eluting with CHC1 3 to 4% MeOH / CHCl 3 to give the desired product. 0.31 g, m.p. Mp 156-159 ° C.
Primer 12Example 12
Sinteza 2,4-diamino-6-metil-5-(2,3,5-trikloro-4-nitrofenil) pirimidinaSynthesis of 2,4-diamino-6-methyl-5- (2,3,5-trichloro-4-nitrophenyl) pyrimidine
2,4-diamino-6-metil-5-(2,3,5-triklorofenil)pirimidin (0,152 g) (primer 6) raztopimo v koncentrirani žvepleni kislini in nato dodamo kalijev nitrat (50 mg). Raztopino mešamo pri sobni temperaturi preko noči in nato vlijemo na led in naalkalimo z 0,880 amoniaka. Produkt ekstrahiramo v etilacetat, zberemo, posušimo (MgSO4) in uparimo. Ostanek prečistimo s kromatografijo na SiO2 gelu, z eluracijo s ETOAc do 8% MeOH/EtOAc, da dobimo želeni produkt. 0,13 g, tal. 313-315°C.2,4-Diamino-6-methyl-5- (2,3,5-trichlorophenyl) pyrimidine (0.152 g) (Example 6) was dissolved in concentrated sulfuric acid and then potassium nitrate (50 mg) was added. The solution was stirred at room temperature overnight and then poured onto ice and basified with 0.880 ammonia. The product was extracted into ethyl acetate, collected, dried (MgSO 4 ) and evaporated. The residue was purified by chromatography on SiO 2 gel, eluting with ETOAc to 8% MeOH / EtOAc to give the desired product. 0.13 g, m.p. 313-315 ° C.
Primer 13Example 13
Sinteza 4-amino-2-(N,N-dimetilamino)-6-metil-5-(2,3,5-triklorofenil)-pirimidinaSynthesis of 4-amino-2- (N, N-dimethylamino) -6-methyl-5- (2,3,5-trichlorophenyl) -pyrimidine
K raztopini NaOEt (iz 0,16 g natrija) v etanolu (15 ml) dodamo 1,1-dimetilgvanidinsulfat (1,6 g). Po mešanju 10 minut dodamo enolni eter iz primera 6.2 (0,82 g) v etanolu (5 ml) in zmes mešamo pri refluksu 5 ur. Zmes pustimo, da stoji pri sobni temperaturi preko noči in jo nato filtriramo. Filtrat koncentriramo in ostanek prečistimo s kromatografijo na SiO2 gelu, eluiramo s CHC^, tako da dobimo želeni produkt, 54 mg, tal. 151-153°C.To a solution of NaOEt (0.16 g sodium) in ethanol (15 ml) was added 1,1-dimethylguanidinesulfate (1.6 g). After stirring for 10 minutes, the enol ether of Example 6.2 (0.82 g) in ethanol (5 ml) was added and the mixture was refluxed for 5 hours. The mixture was allowed to stand at room temperature overnight and then filtered. The filtrate was concentrated and the residue was purified by chromatography on SiO 2 gel, eluting with CHCl3 to give the desired product, 54 mg, m.p. Mp 151-153 ° C.
Primer 14Example 14
Sinteza 2,4-diamino-5-(2,3,-diklorofenil)-6-trifluorometil-pirimidinaSynthesis of 2,4-diamino-5- (2,3, -dichlorophenyl) -6-trifluoromethyl-pyrimidine
1. Priprava 2,3-diklorobenzilalkohola1. Preparation of 2,3-dichlorobenzylalcohol
V raztopino 2,3-diklorobenzaldehida (Aldrich, 50 g) v alkoholu (800 ml) pri sobni temperaturi dodamo NaBH4 (8,54 g) in dobljeno zmes mešamo 1,5 ure. Reakcijo pogasimo z vodo in topilo uparimo v vakuumu pred porazdelitvijo ostanka med CHC13 in nasičeno raztopino NaHCOr Organsko fazo speremo s slanico soli, posušimo preko MgSO4, filtriramo in topilo uparimo v vakuumu, tako da ostane bela trdna snov, 48,38 g, tal. 87-87,5°C.To a solution of 2,3-dichlorobenzaldehyde (Aldrich, 50 g) in alcohol (800 ml) at room temperature was added NaBH 4 (8.54 g) and the resulting mixture was stirred for 1.5 hours. The reaction was quenched with water and the solvent was evaporated in vacuo before partitioning the residue between CHCl 3 and saturated NaHCO 3 solution . The organic phase was washed with brine, dried over MgSO 4 , filtered and the solvent was evaporated in vacuo to leave a white solid, 48.38 g. , tal. 87-87.5 ° C.
2. Priprava 2,3-diklorobenzilbromida2. Preparation of 2,3-dichlorobenzyl bromide
V raztopino alkohola v benzenu (500 ml) pod N2 dodamo PBr3 (167,8 g) in zmes mešamo na 55-60°C 3,5 ure. Po ohladitvi zmes vlijemo na zdrobljen led (21) in odloči se benzenski sloj. Vodno fazo speremo z benzenom (x3) in združene benzenske ekstrakte speremo z nasičeno raztopino NaHCO3 in vodo, posušimo preko MgSO4, filtriramo in topilo uparimo, tako, da ostane rjavkasta tekoča snov, ki se s stanjem stijuje. 37,53 g, tal. 31-32°C.To the solution of alcohol in benzene (500 ml) under N 2 was added PBr 3 (167.8 g) and the mixture was stirred at 55-60 ° C for 3.5 hours. After cooling, the mixture is poured onto crushed ice (21) and the benzene layer is decided. The aqueous phase was washed with benzene (x3), and the combined benzene extracts were washed with saturated NaHCO 3 solution and water, dried over MgSO 4 , filtered and the solvent was evaporated to leave a brownish liquid substance which was in contact with the liquid. 37.53 g, m.p. 31-32 ° C.
3. Priprava 2,3-diklorofenilacetonitrila3. Preparation of 2,3-dichlorophenylacetonitrile
Bromid suspendiramo v DMSO (155 ml/vodi (105 ml) pri 0°C in dodamo KCN (20,24 g) po delih. Po mešanju na 30-35°C 2 uri suspenzijo razredčimo v vodi in ekstrahiramo z Et2O. Združene etrske ekstrakte speremo z vodo, posušimo preko MgSO4, filtriramo in topilo uparimo v vakuumu, tako da ostane bela trdna snov, 27,52 g, tal. 64-67°C.The bromide was suspended in DMSO (155 ml / water (105 ml) at 0 ° C and KCN (20.24 g) was added in parts. After stirring at 30-35 ° C for 2 hours, the suspension was diluted in water and extracted with Et 2 O. The combined ether extracts were washed with water, dried over MgSO 4 , filtered and the solvent was evaporated in vacuo to leave a white solid, 27.52 g, mp 64-67 ° C.
4. Priprava 2-(2,3-diklorofenil)-4,4,4-trifluoro-3-okso-butironitrila4. Preparation of 2- (2,3-dichlorophenyl) -4,4,4-trifluoro-3-oxo-butyronitrile
V raztopino NaOEt (iz 1,48 g Na) v EtOH (25 ml) na sobni temperaturi pod N2 dodamo nitril (10,0 g) in nato etiltrifluoroacetat (9,3 g) in zmes mešamo na refluksu 5 ur. Po ohladitvi topilo odločimo v vakuumu in ostanek raztopimo v vodi. Vodno fazo speremo z Et2O (zavržemo), nakisamo z H2SO4 in ekstrahiramo z Et2O. Združene Et2O ekstrakte speremo z vodo, posušimo preko MgSO4, filtriramo in topilo upparimo v vakuumu, tako da ostane olje. Le-to trituriramo s petroletrom in trdno snov odfiltriramo in posušimo. 9,56 g, tal. 74-75°C.To a solution of NaOEt (from 1.48 g Na) in EtOH (25 ml) at room temperature below N 2 was added nitrile (10.0 g) and then ethyltrifluoroacetate (9.3 g) and the mixture was refluxed for 5 hours. After cooling, the solvent was removed in vacuo and the residue dissolved in water. The aqueous phase was washed with Et 2 O (discarded), acidified with H 2 SO 4 and extracted with Et 2 O. The combined Et 2 O extracts were washed with water, dried over MgSO 4 , filtered and the solvent evaporated in vacuo to leave an oil. This is triturated with petroleum ether and the solid is filtered off and dried. 9.56 g, m.p. 74-75 ° C.
5. Priprava 2-(2,3-diklorofenil)-4,4,4-trifluoro-3-metoksibut-2-enonitrila5. Preparation of 2- (2,3-dichlorophenyl) -4,4,4-trifluoro-3-methoxybut-2-enonitrile
V raztopino trifluorometilketona v Et2O (90 ml) na sobni temperaturi dodamo diazometan (iz 19,35 g Diazald-a) v Et2O (180 ml) in dobljeno zmes pustimo, da stoji na sobni temperaturi preko noči. Višek diazometana nato v vakuumu odločimo v AcOH in ostanek raztopimo v Et2O, posušimo preko MgSO4, filtriramo in topilo odparimo v vakuumu, tako da ostane rjavkasta trdna snov, 6,44 g.To a solution of trifluoromethyl ketone in Et 2 O (90 ml) at room temperature was added diazomethane (from 19.35 g Diazald-a) in Et 2 O (180 ml) and the resulting mixture was allowed to stand at room temperature overnight. The excess diazomethane was then removed in vacuo in AcOH and the residue dissolved in Et 2 O, dried over MgSO 4 , filtered and the solvent evaporated in vacuo to leave a brownish solid, 6.44 g.
6. Priprava 2,4-diamino-5-(2,3-diklorofeniI)-6-trifIuorometiI-pirimidina6. Preparation of 2,4-diamino-5- (2,3-dichlorophenyl) -6-trifluoromethyl-pyrimidine
V raztopino gornjega enolnega etra v etanolu (33 ml) dodamo gvanidinhidroklorid (1,92 g) in nato raztopino NaOEt (iz 540 mg Na) v EtOH (90 ml) in dobljeno zmes mešamo pri refluksu 3 ure. Po ohladitvi suspenzijo filtriramo in filtrat uparimo do suhega v vakuumu. Kromatografija na silikagelu z eluacijo s CHC13 do 2% MeOHCHC13 je dala želen produkt, ki ga obdelamo z Et2O in posušimo v vakuumu, 673 mg, tal. 218-9°C.To a solution of the above single ether in ethanol (33 ml) was added guanidine hydrochloride (1.92 g) and then a solution of NaOEt (from 540 mg Na) in EtOH (90 ml) and the resulting mixture was refluxed for 3 hours. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel eluting with CHC1 3 to 2% MeOHCHC1 3 gave the desired product, which was treated with Et 2 O and dried in vacuo, 673 mg, m.p. 218-9 ° C.
7. 2,4-diamino-5-(2,3-diklorofenil)-6-trifluorometilpirimidin-metansulfonat7. 2,4-Diamino-5- (2,3-dichlorophenyl) -6-trifluoromethylpyrimidine-methanesulfonate
V suspenzijo proste baze (100 mg) v etanolu dodamo metansulfonsko kislino (30 mg) in dobljeno bistro raztopino mešamo pri sobni temperaturi 2 uri. Raztopino uparimo do suhega in dobljeno trdno snov trituriramo z etrom, filtriramo in posušimo v vakuumu, 107 mg, tal. 253-256°C.To the free base suspension (100 mg) in ethanol was added methanesulfonic acid (30 mg) and the resulting clear solution was stirred at room temperature for 2 hours. The solution was evaporated to dryness and the resulting solid was triturated with ether, filtered and dried in vacuo, 107 mg, m.p. 253-256 ° C.
8.2,4-diamino-5-(2,3-diklorofenil)-6-trifluorometilpirimidin-hidroklorid8.2,4-diamino-5- (2,3-dichlorophenyl) -6-trifluoromethylpyrimidine hydrochloride
V raztopino proste baze (150 mg) v metanolu dodamo etrski vodikov klorid. Po mešanju topilo upparimo do suhega in dobljeno trdno snov trituriramo z etrom, filtriramo in posušimo v vakuumu, 160 mg, tal. 233-236°C.Ether hydrogen chloride was added to a solution of free base (150 mg) in methanol. After stirring, the solvent was evaporated to dryness and the resulting solid was triturated with ether, filtered and dried in vacuo, 160 mg, m.p. 233-236 ° C.
Primer 15Example 15
Sinteza 2,4-diamino-5-(2,3-diklorofenil)-6-metilpirimidinaSynthesis of 2,4-diamino-5- (2,3-dichlorophenyl) -6-methylpyrimidine
To spojino pripravimo na analogen način s spojino iz primera 6 iz 2,3dikloroacetonitrila, tal. 245-247°C.This compound was prepared in an analogous manner with the compound of Example 6 of 2,3dichloroacetonitrile, m.p. 245-247 ° C.
Primer 16Example 16
Sinteza 2,4-diamino-5-(2,3-diklorofenil)-4-metoksi-3-okso-butironitrilaSynthesis of 2,4-diamino-5- (2,3-dichlorophenyl) -4-methoxy-3-oxo-butyronitrile
1. Priprava 2-(2,3-diklorofenil)-4-metoksi-3-okso-butironitrila1. Preparation of 2- (2,3-dichlorophenyl) -4-methoxy-3-oxo-butyronitrile
V mešano refluktirajočo raztopino NaOEt (iz 1,38 g Na) v EtOH (25 ml) dodamo zmes etilmetoksiacetata (8,85 g) in 2,3-diklorofenilacetonitrila (Primer 14.3) (9,3 g) raztopljenega v DME (20 ml) v teku 5 minut. Po 5 urah se pojavi oborina (natrijeva sol produkta). Zmes ohladimo in filtriramo, filtrat uparimo do suhega v vakuumu in ostanek porazdelimo med eter in vodo (etrsko fazo zavržemo). Vodni ostanek nakisamo z 2N H2SO4 in ekstrahiramo z etrom (2x). Združene Et2O ekstrakte speremo z vodo, posušimo preko MgSO4, filtriramo in uparimo v vakuumu, tako da dobimo rumeno trdno snov (a). Natrijevo sol (zgoraj) raztopimo v vodi in raztopino ekstrahiramo z etrom in zavržemo. Vodno raztopino nakisamo z 2N H2SO4 in ekstrahiramo z etrom. Etrski ekstrakt speremo z vodo, posušimo preko MgSO4, filtriramo in uparimo v vakuumu, tako da dobimo belo trdno snov (b).A mixture of ethylmethoxyacetate (8.85 g) and 2,3-dichlorophenylacetonitrile (Example 14.3) (9.3 g) dissolved in DME (20 ml) was added to a stirring reflux solution of NaOEt (from 1.38 g Na) in EtOH (25 ml). ) within 5 minutes. After 5 hours a precipitate appears (sodium salt of the product). The mixture was cooled and filtered, the filtrate was evaporated to dryness in vacuo and the residue was partitioned between ether and water (discarded ether phase). The aqueous residue was acidified with 2N H 2 SO 4 and extracted with ether (2x). The combined Et 2 O extracts were washed with water, dried over MgSO 4 , filtered and evaporated in vacuo to give a yellow solid (a). The sodium salt (above) was dissolved in water and the solution was extracted with ether and discarded. The aqueous solution was acidified with 2N H 2 SO 4 and extracted with ether. The ether extract was washed with water, dried over MgSO 4 , filtered and evaporated in vacuo to give a white solid (b).
Gornja produkta (a) in (b) združimo, tako da dobimo dobitek 10,4 g, ki ga uporabimo brez nadaljnjega čiščenja. En madež s pomočjo TLC (19:1 CH2C12 : MeOH) Rf0,35.The above products (a) and (b) were combined to give a yield of 10.4 g, which was used without further purification. One stain using TLC (19: 1 CH 2 C1 2 : MeOH) Rf0.35.
2. Priprava 2-(2,3-diklorofenil)-3,4-dimetoksibut-2-enonitrila2. Preparation of 2- (2,3-dichlorophenyl) -3,4-dimethoxybut-2-enonitrile
V mešano raztopino gornjega nitrila (9,4 g) v etru dodamo po delih diazometan (0,4-0,45 M) v etru. Na začetku se pojavi močno penjenje in po nadaljnjem dodajanju ne nastaja trenutna reakcija. Zmes pustimo, da se meša pri sobni temperaturi 3 ure in jo uparimo v vakuumu v AcOH, tako da dobimo enolni eter.Diazomethane (0.4-0.45 M) in ether was added portionwise to a mixed solution of the above nitrile (9.4 g) in ether. Strong foaming occurs initially and no further reaction is generated after further addition. The mixture was allowed to stir at room temperature for 3 hours and evaporated in vacuo in AcOH to give a single ether.
3. Priprava 2,4-diamino-5-(2.3-diklorofenil)-6-metoksimetilpirimidina3. Preparation of 2,4-diamino-5- (2,3-dichlorophenyl) -6-methoxymethylpyrimidine
V raztopino NaOEt (iz 0,92 g Na) v EtOH (40 ml) dodamo gvanidin-hidroklorid (3,44 g). Dodamo raztopino enolnega etra (gornjega) v EtOH (30 ml) iz zmes refluktiramo okoli 3 ure. Po ohladitvi topilo uparimo v vakuumu in ostanek obdelamo s 5N NaOH (okoli 50 ml). Rdečo trdno snov filtriramo, raztopimo v AcOH (okoli 20 ml), razredčimo z vodo (40 ml), obdelamo z ogljem in filtriramo. Filtrat (rumeno raztopino) naalkalimo z 2N NaOH in belo oborino filtriramo, posušimo in prekristaliziramo iz EtOH, 4,39 g, tal. 237-240°C.To a solution of NaOEt (from 0.92 g Na) in EtOH (40 ml) was added guanidine hydrochloride (3.44 g). A solution of enol ether (above) in EtOH (30 ml) was added from the mixture to reflux for about 3 hours. After cooling, the solvent was evaporated in vacuo and the residue was treated with 5N NaOH (about 50 ml). The red solid was filtered, dissolved in AcOH (about 20 ml), diluted with water (40 ml), treated with charcoal and filtered. The filtrate (yellow solution) was basified with 2N NaOH and the white precipitate was filtered, dried and recrystallized from EtOH, 4.39 g, m.p. 237-240 ° C.
Primer 17Example 17
Priprava 2,4-diamino-5-(l-naftil)pirimidinaPreparation of 2,4-diamino-5- (1-naphthyl) pyrimidine
V raztopino NaOEt (iz 1,45 g Na) v etanolu (60 ml) pri sobni temperaturi pod N2 dodamo 1-naftilacetonitril (Aldrich, 10,02 g). Po mešanju 10 minut dodamo etilfor27 miat (8,88 g) in zmes mešamo pri refluksu 5 ur. Zmes ohladimo, topilo upparimo in ostanek trituriramo z Et2O pred filtracijo in sušenjem trdne snovi v vauumu (6,86 g).To a solution of NaOEt (from 1.45 g Na) in ethanol (60 ml) at room temperature below N 2 was added 1-naphthylacetonitrile (Aldrich, 10.02 g). After stirring for 10 minutes, ethylfor 27 miate (8.88 g) was added and the mixture was stirred at reflux for 5 hours. The mixture was cooled, the solvent was evaporated and the residue triturated with Et 2 O before filtration and drying of the solid in vacuo (6.86 g).
Gornjo snov raztopimo v DMF (45 ml) dodamo metiljodid (5,4 g) in reakcijsko posodo zapremo pred mešanjem vsebine na 40°C 4 ure. Topilo nato odločimo v vakuumu in ostanek porazdelimo med EtOAc in vodo. Organsko fazo speremo z vodo, posušimo preko MgSO4, filtriramo in topilo uparimo v vakuumu, tako da ostane surov produkt kot viskozno rdečkasto olje (5,4 g).The above was dissolved in DMF (45 ml), methyl iodide (5.4 g) was added and the reaction vessel was closed before stirring the contents at 40 ° C for 4 hours. The solvent was then removed in vacuo and the residue partitioned between EtOAc and water. The organic phase was washed with water, dried over MgSO 4 , filtered and the solvent was evaporated in vacuo to leave the crude product as a viscous reddish oil (5.4 g).
V raztopino NaOEt (iz 1,19 g Na) v etanolu (80 ml) dodamo gvanidinhidroklorid (4,94 g). Po mešanju nadaljnjih 5 minut dodamo zgornji intermediat v etanolu in nastalo zmes mešamo pri refluksu 3,5 ure. Po ohladitvi topilo odstranimo v vakuumu in ostanek porazdelimo med CHCL^ in vodo. Organsko fazo speremo z vodo, posušimo preko MgSO4, filtriramo in topilo uparimo, da ostane bledo rumeno trdno snov. Kromatografija na SiO2 z eluacijo z do 4% CHC13 v zmesi CHCl3:MeOH in nato rekristalizacija iz etanola da ta želeni produkt kot belo snov. 2,82 g, tal. 171-3°C.To a solution of NaOEt (from 1.19 g Na) in ethanol (80 ml) was added guanidine hydrochloride (4.94 g). After stirring for a further 5 minutes, the above intermediate in ethanol was added and the resulting mixture was stirred at reflux for 3.5 hours. After cooling, the solvent was removed in vacuo and the residue partitioned between CHCl3 and water. The organic phase was washed with water, dried over MgSO 4 , filtered and the solvent evaporated to leave a pale yellow solid. Chromatography on SiO 2 eluting with up to 4% CHC1 3 in CHCl 3 : MeOH and then recrystallization from ethanol gives this desired product as a white substance. 2.82 g, m.p. 171-3 ° C.
Primer 18Example 18
Priprava 2,4-diamino-5-(2,3-diklorofenil)-6-fluorometil-pirimidinaPreparation of 2,4-diamino-5- (2,3-dichlorophenyl) -6-fluoromethyl-pyrimidine
1- 2,4-diamino-5-(2,3-diklorofenil)-6-(dietoksimetil)-pirimidin1- 2,4-Diamino-5- (2,3-dichlorophenyl) -6- (diethoxymethyl) -pyrimidine
V mešano refluktirajočo raztopino NaOEt (iz 1,38 g Na) v etanolu (25 ml) dodamo teku 5 minut zmes etildietoksiacetata (13,21 g; 75 mmola) in (Primer 14.3) 2,3diklorofenilacetonitrila (9,3 g; 50 mmola) v suhem dimetoksietanu (20 ml). Po 4 urah se ohladi in upari v vakuumu. Ostanek porazdelimo med vodo (100 ml) in eter (100 ml), etrsko fazo zavržemo in vodni ostanek nakisamo z IN H2SO4. Ekstrakcija z CH2C12 da acilacetonitril (13,47 g), ki ga uporabimo brez nadaljnjega čiščenja.To a stirring reflux solution of NaOEt (from 1.38 g Na) in ethanol (25 ml) was added over a 5 minute period a mixture of ethyldiethoxyacetate (13.21 g; 75 mmol) and (Example 14.3) 2,3 dichlorophenylacetonitrile (9.3 g; 50 mmol) ) in dry dimethoxyethane (20 ml). After 4 hours, it was cooled and evaporated in vacuo. The residue was partitioned between water (100 ml) and ether (100 ml), the ether phase discarded and the aqueous residue acidified with IN H 2 SO 4 . Extraction with CH 2 C1 2 gave acylacetonitrile (13.47 g), which was used without further purification.
V mešano raztopino gornjega acilacetonitrila v etru (100 ml), ki je ohlajena na ledu, dodamo po deležih raztopino diazometana (okoli 3 g) v etru. Po 2 urah raztopino uparimo v vakuumu, tako da dobimo želeni enolni eter kot olje, ki ga uporabimo brez nadaljnjega čiščenja.A solution of diazomethane (about 3 g) in ether was added portionwise to a stirred solution of the above acylacetonitrile in ether (100 ml), which was cooled on ice. After 2 hours the solution was evaporated in vacuo to give the desired enol ether as an oil which was used without further purification.
V raztopino NaOEt (iz 1,4 g natrija) v etanolu (50 ml) dodamo gvanidin hidroklorid (4,8 g; 50 mmol). Dodamo raztopino gornjega enolnega etra v etanolu (20 ml) in zmes refluktiramo 4 ure, ohladimo in koncentriramo v vakuumu, tako da dobimo temno vijolično trdno snov, ki jo filtriramo, raztopimo v CH2C12, speremo z vodo, posušimo preko MgSO4 in uparimo v vakuumu. Ostanek trituriramo z etanolom (50 ml) in filtrriramo, da dobimo želeni produkt (8,4 g), ki ga uporabimo brez nadaljnjega prečiščevanja, (tal. 214-217°C).To a solution of NaOEt (1.4 g sodium) in ethanol (50 ml) was added guanidine hydrochloride (4.8 g; 50 mmol). A solution of the above single ether in ethanol (20 ml) was added and the mixture was refluxed for 4 hours, cooled and concentrated in vacuo to give a dark purple solid which was filtered, dissolved in CH 2 C1 2 , washed with water, dried over MgSO 4 and evaporated in vacuo. The residue was triturated with ethanol (50 ml) and filtered to give the desired product (8.4 g), which was used without further purification (mp 214-217 ° C).
2. 2,4-diamino-5-(2,3-diklorofenil)pirimidin-6-karboksaldehid2. 2,4-Diamino-5- (2,3-dichlorophenyl) pyrimidine-6-carboxaldehyde
Zmes gornjega acetala (7 g) in 0,4M HC1 (150 ml) refluktiramo ob mešanju 1 uro, ohladimo na ledu in nevtraliziramo z 2M NaOH. Zmes filtriramo, speremo z vodo in sušimo na zraku, tako da dobimo želeni produkt (6,2 g), ki ga uporabimo brez nadaljnjega čiščenja.The mixture of the above acetal (7 g) and 0.4M HCl (150 ml) was refluxed with stirring for 1 hour, cooled on ice and neutralized with 2M NaOH. The mixture was filtered, washed with water and air-dried to give the desired product (6.2 g), which was used without further purification.
3.2.4- diamino-5-(2,3-diklorofenil)-6-hidroksimetilpirimidin3.2.4-Diamino-5- (2,3-dichlorophenyl) -6-hydroxymethylpyrimidine
V mešano raztopino gornjega aldehida (2,8 g; 10 mmol) v zmesi dimetoksietana (15 ml) in etanola (15 ml) dodamo po deležih natrijev borohidrid (110 mg; 3 mmol). Po 30 minutah raztopino obdelamo z vodo (50 ml) in dodamo nekaj kapljic ocetne kisline, da uničimo prebitni borohidrid. Ekstrahiramo z diklorometanom (2 x 50 ml), speremo z vodo in ekstrakt nato posušimo preko MgSO4. Uparitev topila v vakuumu da roza trdno snov, ki jo trituriramo z etrom, fitriramo in posušimo (1,6 g). Rekristalizacija iz metanola (50 ml) da želeni produkt kot fine brezbarvne kristale 0,65 g, tal. 173-6°C.Sodium borohydride (110 mg; 3 mmol) was added to a stirred solution of the above aldehyde (2.8 g; 10 mmol) in a mixture of dimethoxyethane (15 ml) and ethanol (15 ml). After 30 minutes, the solution was treated with water (50 ml) and a few drops of acetic acid were added to destroy excess borohydride. It was extracted with dichloromethane (2 x 50 ml), washed with water and the extract was then dried over MgSO 4 . Evaporation of the solvent in vacuo gave a pink solid, which was triturated with ether, filtered and dried (1.6 g). Recrystallization from methanol (50 ml) gave the desired product as fine colorless crystals 0.65 g, m.p. 173-6 ° C.
4.2.4- diamino-5-(2,3-diklorofenil)-6-fluorometilpirimidin4.2.4-Diamino-5- (2,3-dichlorophenyl) -6-fluoromethylpyrimidine
V mešano suspenzijo 2,4-diamino-5-(2,3-diklorofenil)-6-hidroksimetilpirimidina (185 mg; 1 mmol) v suhem diklorometanu (25 ml) dodamo pod dušikom na -70°C z dokapavanjem dietilaminožveplov trifluorid (263 μ\; 2 mmol). Zmes pustimo, da se segreje na 0°C in jo vzdržujemo na tej temperaturi 4 ure. Po ohladitvi na -70°C zmes pogasimo z vodnim natrijevim bikarbonatom, ekstrahiramo z diklorometanom (2 x 50 ml), speremo z nasičeno slanico in posušimo (MgSO4). Koncentriranje da brezbarvno gumo (0,2 g). Kromatografija na silikagelu, z eluiranjem z zmesjo 0,01:1:19 Et3N:MeOH:CH2Cl2 da želeni produkt, ki ga trituriramo s CC14 in posušimo v vakumu. 111 mg, tal. 224-6°C.To a stirred suspension of 2,4-diamino-5- (2,3-dichlorophenyl) -6-hydroxymethylpyrimidine (185 mg; 1 mmol) in dry dichloromethane (25 ml) was added under nitrogen at -70 ° C by dropwise addition of diethylamine sulfur trifluoride (263 μ \; 2 mmol). The mixture was allowed to warm to 0 ° C and maintained at this temperature for 4 hours. After cooling to -70 ° C, the mixture was quenched with aqueous sodium bicarbonate, extracted with dichloromethane (2 x 50 ml), washed with saturated brine and dried (MgSO 4 ). Concentration gave a colorless gum (0.2 g). Chromatography on silica gel, eluting with a mixture of 0.01: 1: 19 Et 3 N: MeOH: CH 2 Cl 2 gave the desired product, which was triturated with CCl 4 and dried in vacuo. 111 mg, m.p. 224-6 ° C.
Primer 19Example 19
2,4-diamino-5-(2,3-diklorofenil)-6-fenoksimetilpirimidin2,4-Diamino-5- (2,3-dichlorophenyl) -6-phenoxymethylpyrimidine
V mešano raztopino NaOEt (iz 1,38 g natrija), v etanolu (70 ml) pri refluksu, dodamo v teku 10 minut zmes 2,3-diklorofenilacetonitrila (9,3 g) in etilfenoksiacetata (13,5 g) v suhem dimetoksietanu (50 ml). Po mešanju pri refluksu 3 ure zmes ohladimo, filtriramo in topila uparimo v vakuumu. Ostanek raztopimo v vodi, speremo z etrom (zavržemo), nakisamo z 2N klorovodikovo kislino in ekstrahiramo z diklorometanom. Združene ekstrakte speremo s slanico, posušimo (MgS04) in uparimo v vakuumu, da ostane rumeno rjavo obarvana trdna snov (8 g), ki jo uporabimo brez nadaljnjega čiščenja.A mixture of 2,3-dichlorophenylacetonitrile (9.3 g) and ethylphenoxyacetate (13.5 g) in dry dimethoxyethane was added over 10 minutes to a stirred solution of NaOEt (from 1.38 g sodium) in ethanol (70 ml) at reflux. (50 ml). After stirring at reflux for 3 hours, the mixture was cooled, filtered and the solvents were evaporated in vacuo. The residue was dissolved in water, washed with ether (discarded), acidified with 2N hydrochloric acid and extracted with dichloromethane. The combined extracts were washed with brine, dried (MgSO 4 ) and evaporated in vacuo to leave a yellow-brown solid (8 g) which was used without further purification.
V suspenzijo surovega acilacetonitrila (8 g) v etru (150 ml) dodamo po delih prebitek raztopine diazometana v etru. Po mešanju 1 uro na sobni temperaturi raztopino koncentriramo v vakuumu, tako da dobimo enolni eter, ki ga uporabimo brez nadaljnjega čiščenja.To a suspension of crude acylacetonitrile (8 g) in ether (150 ml) was added in part the excess solution of diazomethane in ether. After stirring for 1 hour at room temperature, the solution was concentrated in vacuo to give a single ether, which was used without further purification.
V raztopino natrijevega etoksida (iz 0,63 g natrija) v etanolu (25 ml) dodamo pri sobni temperaturi gvanidin-hidroklorid (2,39 g). Po 15 minutah dodamo raztopino zgornjega enolnega etra v etanolu (25 ml) in zmes mešamo pri refluksu 4 ure. Po ohladitvi topilo uparimo v vakuumu. Ostanek suspendiramo v 2N NaOH (75 ml), filtriramo, speremo z vodo, posušimo na zraku in prekristaliziramo iz etanola, tako da dobimo želeni produkt kot brezbarvno trdno snov. 3,82 g, tal. 211-213°C.Guanidine hydrochloride (2.39 g) was added at room temperature to a solution of sodium ethoxide (0.63 g sodium) in ethanol (25 ml). After 15 minutes, a solution of the above enol ether in ethanol (25 ml) was added and the mixture was refluxed for 4 hours. After cooling, the solvent was evaporated in vacuo. The residue was suspended in 2N NaOH (75 ml), filtered, washed with water, air-dried and recrystallized from ethanol to give the desired product as a colorless solid. 3.82 g, m.p. 211-213 ° C.
Primer 20Example 20
2,4-diamino-5-f2,3-diklorofenil)-6-metiltiometilpirimidin2,4-diamino-5-f2,3-dichlorophenyl) -6-methylthiomethylpyrimidine
V mešano raztopino NaOEt (iz 1,38 g natrija), v etanolu (25 ml) pri refluksu dodamo tekom 5 minut zmes 2,3-diklorofenilacetonitrila (9,3 g) in etilmetiltioacetata (10,07 g) v suhem dimetoksietanu (20 ml). Po mešanju 5 ur na refluksu zmes ohladimo na ledu, nakisamo z ocetno kislino (5 ml), vlijemo v ledeno vodo in ekstrahiramo z diklorometanom. Združene ekstrakte speremo z vodo, posušimo (MgS04) in koncentriramo, tako da dobimo rumeno olje, ki ga uporabimo brez nadaljnjega čiščenja.A mixture of 2,3-dichlorophenylacetonitrile (9.3 g) and ethylmethylthioacetate (10.07 g) in dry dimethoxyethane (20) was added over 5 minutes to a stirred solution of NaOEt (from 1.38 g of sodium) in ethanol (25 ml). ml). After stirring for 5 hours at reflux, the mixture was cooled on ice, acidified with acetic acid (5 ml), poured into ice water and extracted with dichloromethane. The combined extracts were washed with water, dried (MgSO 4 ) and concentrated to give a yellow oil which was used without further purification.
Surovi acilacetonitril segrevamo pod N2 s trietilortoformiatom (40 ml) na 140-150°C 4 ure in oddestiliramo material z nizkim vreliščem. Po hlajenju zmes koncentriramo v vakuumu, tako da ostane temno olje (15,2 g). Olje raztopimo v etanolu (20 ml) in ga dodamo v zmes gvanidin-hidroklorida (4,8 g) in natrijevega etoksida (iz 1,38 g natrija) v etanolu (50 ml). Po mešanju na refluksu 4 ure zmes ohladimo in koncentriramo v vakuumu. Ostanek stresamo s 5M NaOH, tako da dobimo temno olje, ki ga ekstrahiramo z diklorometanom, speremo z vodo in posušimo (MgSOJ. Koncentriranje v vakuumu pusti temno gumasto snov. Želeni produkt kristaliziramo iz etanola (20 ml) kot svetlo rumeno rjavo trdno snov, 0,57 g, tal. 205-7°C.The crude acylacetonitrile was heated under N 2 with triethylorthoformiate (40 ml) to 140-150 ° C for 4 hours and the material was distilled off at low boiling point. After cooling, the mixture was concentrated in vacuo to leave a dark oil (15.2 g). The oil was dissolved in ethanol (20 ml) and added to a mixture of guanidine hydrochloride (4.8 g) and sodium ethoxide (from 1.38 g sodium) in ethanol (50 ml). After stirring at reflux for 4 hours, the mixture was cooled and concentrated in vacuo. The residue was shaken with 5M NaOH to give a dark oil, which was extracted with dichloromethane, washed with water and dried (MgSOJ. Concentration in vacuo left a dark gum. The desired product was crystallized from ethanol (20 ml) as a light yellow brown solid. 0.57 g, mp 205-7 ° C.
Primer 21AExample 21A
Priprava 2,4-diamino-5-(2,3-diklorofenil)pirimidinaPreparation of 2,4-diamino-5- (2,3-dichlorophenyl) pyrimidine
a. 2-(2,3-diklorofenil)-3-okso-propionitrila. 2- (2,3-Dichlorophenyl) -3-oxo-propionitrile
V raztopino NaOEt (iz 3,63 g Na) v etanolu (500 ml) dodamo 2,3diklorofenilacetonitril (primer 14.3) v etanolu (150 ml). Nato dodamo etilformiat (16,67 g) in zmes mešamo pri 80°C 45 minut predno dodamo nadaljnje količine etilformiata (2,78 g). Po mešanju na 80°C Še 1,5 ure oborino odfiltriramo in posušimo v vakuumu. Trdno snov raztopimo v vodi, filtriramo, nakisamo s koncentrirano klorovodikovo kislino in oborino filtriramo in posušimo v vakuumu, 14,35 g, 45%-ni dobitek.To a solution of NaOEt (from 3.63 g Na) in ethanol (500 ml) was added 2,3 dichlorophenylacetonitrile (Example 14.3) in ethanol (150 ml). Ethylformate (16.67 g) was then added and the mixture was stirred at 80 ° C for 45 minutes before further volumes of ethylformate (2.78 g) were added. After stirring at 80 ° C, the precipitate was filtered off and dried under vacuum for 1.5 hours. The solid was dissolved in water, filtered, acidified with concentrated hydrochloric acid and the precipitate filtered and dried in vacuo, 14.35 g, 45% yield.
b. Raztopino gornjega produkta, etilenglikola (9,19 g) in p-toluensulfonske kisline (8,9 g) v toluenu (100 ml) mešamo pri refluksu pri čemer se voda ki se zbira v Dean in Stark-ovi pasti. Po ohladitvi raztopino speremo z vodo, z IN NaOH in vodo pred sušenjem preko MgSO4. Uparitev topila da olje (20,17 g), ki ga raztopimo v EtOH (70 ml). Po stanju 1 uro kremno oborino odfiltriramo in posušimo v vakuumu (10,44 g)·b. A solution of the above product, ethylene glycol (9.19 g), and p-toluenesulfonic acid (8.9 g) in toluene (100 ml) was stirred at reflux with water collected in Dean and Stark traps. After cooling, the solution was washed with water, 1N NaOH and water before drying over MgSO 4 . Evaporation of the solvent gave an oil (20.17 g) which was dissolved in EtOH (70 ml). After 1 hour, the cream precipitate was filtered off and dried in vacuo (10.44 g).
c. V raztopino NaOMe (5,1 g) v etanolu (75 ml) dodamo gvanidin hidroklorid (8,2 g). Po mešanju 30 minut filtriramo NaCl, dodamo gornji acetal in zmes mešamo na refluksu 1 uro. Topilo nato koncentriramo in produkt odfiltriramo. Rekristalizacija iz etanola da produkt kot belo trdno snov, 7,67 g, 70%-ni dobitek, tal. 212,5-214°C.c. To a solution of NaOMe (5.1 g) in ethanol (75 ml) was added guanidine hydrochloride (8.2 g). After stirring for 30 minutes, NaCl was filtered, the above acetal was added and the mixture was stirred at reflux for 1 hour. The solvent was then concentrated and the product filtered off. Recrystallization from ethanol gave the product as a white solid, 7.67 g, 70% yield, m.p. 212.5-214 ° C.
Diamino pirimidin (6,12 g) raztopimo v etanolu (250 ml), dodamo koncentrirano klorovodikovo kislino (2,07 ml) in suspenzijo močno ohlajamo 2 uri. Oborino nato odfiltriramo in posušimo, da dobimo hidrokloridno sol, 5,52 g.The diamino pyrimidine (6.12 g) was dissolved in ethanol (250 ml), concentrated hydrochloric acid (2.07 ml) was added and the suspension was cooled vigorously for 2 hours. The precipitate was then filtered off and dried to give the hydrochloride salt, 5.52 g.
Primer 21BExample 21B
a. 2,3-diklorofenilocetna kislinaa. 2,3-Dichlorophenylacetic acid
Koncentrirano klorovodikovo kislino (100 ml) vlijemo na zdrobljen led (150 ml), raztopino dodamo k 2,3-diklorofenilacetonitrilu (30,6 g) in zmes refluktiramo 3 ure. Po ohladitvi zmes razredčimo z vodo (500 ml), ekstrahiramo z EtOAc (600 ml) in organsko fazo speremo s slanico pred sušenjem preko MgSO4. Uparitev topila pusti belo trdno snov, 31,3 g.The concentrated hydrochloric acid (100 ml) was poured onto crushed ice (150 ml), the solution was added to 2,3-dichlorophenylacetonitrile (30.6 g) and the mixture was refluxed for 3 hours. After cooling, the mixture was diluted with water (500 ml), extracted with EtOAc (600 ml) and the organic phase was washed with brine before drying over MgSO 4 . Evaporation of the solvent left a white solid, 31.3 g.
b. Etil-2,3-diklorofenilacetatb. Ethyl 2,3-dichlorophenyl acetate
K suspenziji kisline v etanolu (200 ml) dodamo koncentrirano H2SO4 (1 ml) in zmes mešamo pri refluksu 3 ure. Po ohladitvi topilo uparimo in ostanek obdelamo s koncentriranim NH4OH (3 ml) v vodi (50 ml). Organsko fazo ekstrahiramo v CE^C^, posušimo preko MgSO4 in topilo uparimo, da ostane bistra tekočina, 19,88 g.To the acid suspension in ethanol (200 ml) was added concentrated H 2 SO 4 (1 ml) and the mixture was stirred at reflux for 3 hours. After cooling, the solvent was evaporated and the residue was treated with concentrated NH 4 OH (3 ml) in water (50 ml). The organic phase was extracted into CE? C ?, dried over MgSO 4 and the solvent evaporated to leave a clear liquid, 19.88 g.
c. Etil 2,3-diklorofenilacetatc. Ethyl 2,3-dichlorophenyl acetate
V zmes estra, morfolina (40,7 g) in etilortoformiata (69,24 g) dodamo acetanhidrid (0,5 ml) in nastalo bledo rumeno raztopino mešamo pri refluksu 3 ure. Po ohladitvi zmes koncentriramo v vakuumu. Tvoriti se začne bela oborina in le-to odfiltriramo predno filtrat nadalje koncentriramo, da dobimo rjavkasto bistro olje. Stanje preko noči v vakuumu da rumeno trdno snov, 34,34 g.Acetane anhydride (0.5 ml) was added to a mixture of ester, morpholine (40.7 g) and ethylorthoformate (69.24 g) and the resulting pale yellow solution was stirred at reflux for 3 hours. After cooling, the mixture was concentrated in vacuo. A white precipitate begins to form and is filtered off before concentrating the filtrate to give a brownish clear oil. The overnight condition in vacuo gave a yellow solid, 34.34 g.
d. 5-(2,3-diklorofenil)izocitozind. 5- (2,3-Dichlorophenyl) isocytosine
V gornji ester dodamo gvanidin-hidroklorid (26,6 g) suspendiran v natrijevem-2metoksietoksidu (iz 6,6 g Na) v 2-metoksietanolu (150 ml) in zmes mešamo pri refluksu preko noči. Po ohladitvi zmes koncentriramo v vakuumu, razredčimo z vodo (100 ml) in nato speremo z Et2O (200 ml). Vodno fazo nakisamo z AcOH in oborino prefiltriramo in speremo z EtOH in nato z Et2O pred sušenjem v vakuumu, 13,48 g.Guanidine hydrochloride (26.6 g) suspended in sodium 2-methoxyethoxide (from 6.6 g Na) in 2-methoxyethanol (150 ml) was added to the above ester and the mixture was stirred at reflux overnight. After cooling, the mixture was concentrated in vacuo, diluted with water (100 ml) and then washed with Et 2 O (200 ml). The aqueous phase was acidified with AcOH and the precipitate filtered and washed with EtOH and then with Et 2 O before drying in vacuo, 13.48 g.
e. N1-(4-kloro-5-(2,3-diklorofenil)-2-pirimidinill-N-.N-dimetilformamidine. N 1- (4-chloro-5- (2,3-dichlorophenyl) -2-pyrimidinyl-N-N-dimethylformamidine
V zmes gornjega izocitozina (14,4 g), v CH2C12 (200 ml) dodamo z dokapavanjem tekom 30 minut svež Vilsmeier-Haack-ov reagent (iz 2,75 ekvivalenta SOC12 in 2,58 ekvivalenta DMF) in zmes refluktiramo 6 ur. Po ohladitvi dodamo počasi IN NaOH (250 ml). Vodno fazo speremo s CH2C12 in združene organske ekstrakte speremo s slanico pred sušenjem preko MgSO4. Uparitev topila in kromatografija na SiO2 gelu ob eluaciji z EtOAc da 13,6 g, tal. 113-115°C.To the mixture of the above isocytosine (14.4 g), in CH 2 C1 2 (200 ml), a fresh Vilsmeier-Haack reagent (from 2.75 equivalents of SOCl 2 and 2.58 equivalents of DMF) was added dropwise over 30 minutes and the mixture reflux for 6 hours. After cooling, slowly add IN NaOH (250 ml). The aqueous phase was washed with CH 2 Cl 2 and the combined organic extracts were washed with brine before drying over MgSO 4 . Solvent evaporation and chromatography on SiO 2 gel eluting with EtOAc gave 13.6 g, m.p. 113-115 ° C.
f. 2-amino-4-kloro-5-(2.3-diklorofenil)pirimidinf. 2-amino-4-chloro-5- (2,3-dichlorophenyl) pyrimidine
V formamidin v EtOH (50 ml) dodamo etanolni MeNH2 (8 ekv.) v EtOH (50 ml) in zmes zapremo v Parr-ovo reakcijsko posodo pred mešanjem na sobni temperaturi 5ur. Reakcijsko zmes nato koncentriramo v vakuumu, ostanek zmešamo z IN NaOH (75 ml), filtriramo, speremo z vodo in posušimo v vakuumu, 11,2 g, tal. 228-30°C.To formamidine in EtOH (50 ml) was added ethanol MeNH 2 (8 eq) in EtOH (50 ml) and the mixture was sealed in a Parr reaction vessel before stirring at room temperature for 5 h. The reaction mixture was then concentrated in vacuo, the residue was stirred with 1N NaOH (75 ml), filtered, washed with water and dried in vacuo, 11.2 g, m.p. 228-30 ° C.
g. 2,4-diamino-5-(2,3-diklorofenil)pirimidinMr Rücker 2,4-Diamino-5- (2,3-dichlorophenyl) pyrimidine
V 2-amino-4-kloro-5-(2,3-diklorofenil)pirimidin (6,73 g) dodamo etanolni amoniak (30 ekv. v 50 ml EtOH) in zmes zapremo v Parr-ovo reakcijsko posodo in segrevamo na 125°C 38 ur. Po ohladitvi zmes koncentriramo v vakuumu in ostanek zmešamo z IN NaOH (75 ml), filtriramo, speremo z vodo in posušimo v vakuumu, 6,14 g, tal. 208-211°C.To 2-amino-4-chloro-5- (2,3-dichlorophenyl) pyrimidine (6.73 g) was added ethanol ammonia (30 eq in 50 ml EtOH) and the mixture was sealed in a Parr reaction vessel and heated to 125 ° C 38 hours After cooling, the mixture was concentrated in vacuo and the residue was stirred with 1N NaOH (75 ml), filtered, washed with water and dried in vacuo, 6.14 g, m.p. Mp 208-211 ° C.
Primer 22Example 22
Sinteza 2,4-diamino-5-(2-klorofenil)-pirimidinaSynthesis of 2,4-diamino-5- (2-chlorophenyl) -pyrimidine
To spojino pripravimo po JACS, (1951), 73, 3763-70, tal. 225°C.This compound was prepared according to JACS (1951), 73, 3763-70, m.p. 225 ° C.
Primer 23Example 23
Sinteza 2,4-diamino-5-i2-klorofenil)-6-metil-pirimidinaSynthesis of 2,4-diamino-5-yl-chlorophenyl) -6-methyl-pyrimidine
To spojino pripravimo po JACS, (1951), 73, 3763-70, tal. 125-8°C.This compound was prepared according to JACS (1951), 73, 3763-70, m.p. 125-8 ° C.
Primer 24Example 24
Sinteza 2,4-diamino-5-f2-klorofeniB-6-etilpirimidinaSynthesis of 2,4-diamino-5-f2-chlorophenyl-6-ethylpyrimidine
Pripravimo kot za primer 22, razen da etilpropionat zamenja etilacetat, tal. 197-8°C.Prepare as in Example 22 except that ethyl propionate replaces ethyl acetate, m.p. 197-8 ° C.
Primer 25Example 25
Sinteza 2.4-diamino-5-(2,4-diklorofenil)-6-trifluorometil-pirimidinaSynthesis of 2,4-diamino-5- (2,4-dichlorophenyl) -6-trifluoromethyl-pyrimidine
To spojino pripravimo na analogen način kot spojino iz primera 14 iz 2,4diklorofenilacetonitrila (Aldrich); tal.: 220,5-221°C.This compound was prepared in an analogous manner as the compound of Example 14 from 2,4-dichlorophenylacetonitrile (Aldrich); mp: 220.5-221 ° C.
Primer 26Example 26
Sinteza 6-benziloksimetil-2,4-diamino-5-(2,4-diklorofeniljpirimidinaSynthesis of 6-benzyloxymethyl-2,4-diamino-5- (2,4-dichlorophenylpyrimidine
To spojino pripravimo na analogen način kot spojino iz primera 16 iz 2,4diklorofenilacetata in etilbenziloksiacetata, 3,77 g, tal. 171-172°C.This compound was prepared in an analogous manner as the compound of Example 16 from 2,4 dichlorophenyl acetate and ethylbenzyloxyacetate, 3.77 g, m.p. 171-172 ° C.
Primer 27Example 27
2-(4-metilpiperazin-l-ilj-4-amino-5-(2.4-diklorofenil)pirimidin2- (4-methylpiperazin-1-yl-4-amino-5- (2,4-dichlorophenyl) pyrimidine
A) Pripravimo raztopino 55,7 g (0,4 ekv.) S-metilizotiokarbamidnega sulfata v 280 ml vode in rahlo segrevamo na parni kopeli ob mešanju. Nato v raztopino počasi dokapavamo 40 g (0,4 mola) N-metil-piperazina ob prepihavanju bučke z dušikom. Razvite pline zberemo v nekaj deležih raztopine 132 g živosrebrovega klorida v 400 ml etanola, kar je povzročilo, da se je razviti metilmerkaptan oboril kot metilživosrebrov klorid. Ko je dodajanje N-metilpiperazina končano, reakcijo nadaljujemo, dokler se metilživosrebrov klorid ne neha obarjati. Reakcijsko zmes nato koncentriramo v vakuumu in močno ohladimo, kar povzroči, da kristalizira N-metilN’-amidinopiperazin-sulfat; zberemo 50,79 g.A) Prepare a solution of 55.7 g (0.4 eq.) Of S-methylisothiocarbamide sulfate in 280 ml of water and heat gently on a steam bath with stirring. Then, 40 g (0.4 mol) of N-methyl-piperazine are slowly added to the solution by blowing the flask with nitrogen. The developed gases were collected in a few portions of a solution of 132 g of mercuric chloride in 400 ml of ethanol, which caused the developed methylmercaptan to precipitate as methyl mercuric chloride. When the addition of N-methylpiperazine is complete, the reaction is continued until methyl mercuric chloride has ceased to precipitate. The reaction mixture was then concentrated in vacuo and cooled strongly, causing it to crystallize N-methylN′-amidinopiperazine sulfate; we collect 50.79 g.
B) Zmes 76,3 g (0,356 mola) alfa-formil-2,4-diklorofenilacetonitrila, 63,7 g izoamilalkohola, 0,36 g p-toluensulfonske kisline, 895 ml toluena in 10 kapljic koncentrirane žveplene kisline segrevamo pod refluksom 20 ur v prisotnosti Dean &B) A mixture of 76.3 g (0.356 mol) of alpha-formyl-2,4-dichlorophenylacetonitrile, 63.7 g of isoamylalcohol, 0.36 g of p-toluenesulfonic acid, 895 ml of toluene and 10 drops of concentrated sulfuric acid is refluxed for 20 hours in the presence of Dean &
Stark pasti, da odstranimo vodo, ki se tvori v reakciji. Nato dodamo enak delež i-amilalkohola in nekaj kapljic žveplene kisline in reakcijo segrevamo nadaljnjih 20 ur, dokler ne zberemo teoretične količine vode. Raztopina se močno ohladi.Stark traps to remove the water that forms in the reaction. An equal proportion of i-amylalcohol is then added and a few drops of sulfuric acid are added and the reaction is heated for a further 20 hours until the theoretical amount of water is collected. The solution is strongly cooled.
C) 8,2 g velik kos natrija raztopimo v 500 ml abs. etanola in dodamo 50 g N-metilN’-amidinopiperazin-sulfata. Zmes pustimo mešati 10 minut. Le-to nato dodamo na raztopino B. Zmes mešamo ob refluksu 6 ur, pustimo, da stoji preko noči in v vakuumu odstranimo topilo. Ostanek nato ekstrahiramo z razredčeno klorovodikovo kislino, ki raztopi večino ostanka. Raztopino trikrat ekstrahiramo z etrom in nato vodno frakcijo nevtraliziramo, kar obori gumo, ki se strdi preko noči; masa 30 g. To snov ponovno kristaliziramo iz 50%-nega etanola s pomočjo oglja za razbarvanje. Da bi se tvorili kristali je bilo potrebno zelo počasno ohlajanje,; tal. 137°C.C) Dissolve 8.2 g of a large piece of sodium in 500 ml abs. ethanol and 50 g of N-methylN'-amidinopiperazine sulfate were added. The mixture was allowed to stir for 10 minutes. This was then added to solution B. The mixture was stirred at reflux for 6 hours, allowed to stand overnight and the solvent removed in vacuo. The residue is then extracted with dilute hydrochloric acid, which dissolves most of the residue. The solution is extracted three times with ether and then the aqueous fraction is neutralized, which precipitates the rubber which hardens overnight; weight 30 g. This substance was recrystallized from 50% ethanol using decolorizing charcoal. Very slow cooling was required to form crystals; m.p. 137 ° C.
Anal. izrač. za C15H17C12N5 Anal. calcd. for C 15 H 17 C1 2 N 5
C, 53,27; H, 5,14; N, 20,21;C, 53.27; H, 5.14; N, 20.21;
Ugotovljeno: C, 53,58; H, 5,14; N, 20,40.Found: C, 53.58; H, 5.14; N, 20.40.
Primer 28Example 28
Sinteza 2.4-diamino-5-(2,5-diklorofenil)-6-trifluorometilpirimidinaSynthesis of 2,4-diamino-5- (2,5-dichlorophenyl) -6-trifluoromethylpyrimidine
To spojino pripravimo na analogen način kot spojino iz primera 14 iz 2,5diklorobenzilalkohola (Lancaster Synthesis, 48,26 g), tako da dobimo naslovno spojino v dobitku 3,85 g, tal. 215-217°C.This compound was prepared in an analogous manner as the compound of Example 14 from 2,5 dichlorobenzyl alcohol (Lancaster Synthesis, 48.26 g) to give the title compound in a yield of 3.85 g, m.p. Mp 215-217 ° C.
Primer 29Example 29
Priprava 2,4-diamino-5-(2,3,5-triklorofenil)pirimidinaPreparation of 2,4-diamino-5- (2,3,5-trichlorophenyl) pyrimidine
Gvanidin-hidroklorid (3,20 g) dodamo v raztopino natrijevega etoksida (iz 848 mg natrija) v etanolu (52 ml). Dobljeno belo suspenzijo mešamo pri sobni temperaturi 10 minut. Dodamo enolni eter iz primera 3.2 (4,40 g) in dobljeno zmes mešamo pod refluksom 3,5 ure. Po ohladitvi suspenzijo filtriramo in filtrat uparimo do suhega v vakuumu. Kromatografija na silikagelu ob eluaciji s CHC13 do 3% MeOH-CHCl3 da želeni produkt, ki ga trituriramo z etrom in posušimo v vakuumu. Dobitek = 2,01 g, tal. 246-249°C.Guanidine hydrochloride (3.20 g) was added to a solution of sodium ethoxide (from 848 mg sodium) in ethanol (52 ml). The resulting white suspension was stirred at room temperature for 10 minutes. The enol ether of Example 3.2 (4.40 g) was added and the resulting mixture was stirred under reflux for 3.5 hours. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel eluting with CHC1 3 to 3% MeOH-CHCl 3 gave the desired product, which was triturated with ether and dried in vacuo. Yield = 2.01 g, m.p. 246-249 ° C.
Primer 30Example 30
Sinteza 4-amino-5-(3-bromofenil)-6-metil-2-(4-metilpiperazin-l-il)-pirimidinaSynthesis of 4-amino-5- (3-bromophenyl) -6-methyl-2- (4-methylpiperazin-1-yl) -pyrimidine
V raztopino NaOEt (iz 0,92 g natrija) v etanolu (75 ml) dodamoTo a solution of NaOEt (from 0.92 g of sodium) in ethanol (75 ml) was added
3-bromofenilacetonitril (aldrich, 7,85 g) in etilacetat (3,52 g). Zmes segrevamo pod refluksom 6 ur. Po ohladitvi zmes koncentriramo in ostanek raztopimo v vodi. Vodno fazo speremo z etrom, nakisamo z 2N HC1 in ekstrahiramo z etrom. Ekstrakte zberemo, posušimo (MgSO4) in uparmo, 3,8 g, tal. 97-103°C.3-bromophenylacetonitrile (aldrich, 7.85 g) and ethyl acetate (3.52 g). The mixture was refluxed for 6 hours. After cooling, the mixture was concentrated and the residue dissolved in water. The aqueous phase was washed with ether, acidified with 2N HCl and extracted with ether. The extracts were collected, dried (MgSO 4 ) and boiling point, 3.8 g, m.p. 97-103 ° C.
Dobljeni keton (3,7 g), etilenglikol (5 ml) in p-toluensulfonsko kislino (100 mg) segrevamo pod refluksom v toluenu (100 ml) v Dean & Stark aparatu 3,5 ure. Zmes ohladimo, koncentriramo in na ostanek dodamo vodo. Produkt ekstrahiramo z etrom in ekstrakte zberemo, posušimo (MgSO4) in uparimo, 4,03 g, tal. 68-71°C.The resulting ketone (3.7 g), ethylene glycol (5 ml) and p-toluenesulfonic acid (100 mg) were refluxed in toluene (100 ml) in a Dean & Stark apparatus for 3.5 hours. The mixture was cooled, concentrated and water was added to the residue. The product was extracted with ether and the extracts were collected, dried (MgSO 4 ) and evaporated, 4.03 g, m.p. 68-71 ° C.
V raztopino NaOEt (iz 0,28 g natrija) v etanolu (30 ml) dodamo N-metilpiperazinoformamidin-hidrojodid (2,7 g). Po mešanju 10 minut dodamo ketal (1,41 g) in zmes mešamo pod refluksom 4 ure. Po ohladitvi suspenzijo filtriramo in filtrat koncentriramo. Ostanek prečistimo s kromatografijo na SiO2 gelu, z eluiranjem z 10% MeOH/CHClg, da dobimo želeni produkt, 0,48 g, tal. 120-122°C.To a solution of NaOEt (0.28 g sodium) in ethanol (30 ml) was added N-methylpiperazinoformamidine hydroiodide (2.7 g). After stirring for 10 minutes, ketal (1.41 g) was added and the mixture was refluxed for 4 hours. After cooling, the suspension was filtered and the filtrate was concentrated. The residue was purified by chromatography on a SiO 2 gel, eluting with 10% MeOH / CHCl2 to give the desired product, 0.48 g, m.p. 120-122 ° C.
Primer 31Example 31
Sinteza 2,4-diamino-5-( l-naftil)-6-trifluorometilpirmidinaSynthesis of 2,4-diamino-5- (1-naphthyl) -6-trifluoromethylpyrimidine
To spojino pripravimo na analogen način kot spojino iz primera 14 iz 1-naftilacetonitrila (Aldrich, 10 g), tako da dobimo naslovno spojino v dobitku 0,69 g, tal. 224-226°C.This compound was prepared in an analogous manner as the compound of Example 14 from 1-naphthylacetonitrile (Aldrich, 10 g) to give the title compound in a yield of 0.69 g, m.p. 224-226 ° C.
Primer 32Example 32
Priprava 2-amino-5-(2.4-diklorofneil)-4,6-dikloropirimidinaPreparation of 2-amino-5- (2,4-dichlorophneyl) -4,6-dichloropyrimidine
1. Etil-2,4-diklorofenilacetat1. Ethyl-2,4-dichlorophenyl acetate
2,4-diklorofenilacetonitril (27,9 g, 150 mmol) suspendiramo v 2N NaOH (400 ml) in zmes refluktiramo 4 ure. Ohlajeno reakcijsko zmes ekstrahiramo z etrom (2 x 200 ml), nakisamo do pH 3 in trdno snov odfiltriramo in posušimo (22 g, 70%).2,4-Dichlorophenylacetonitrile (27.9 g, 150 mmol) was suspended in 2N NaOH (400 ml) and the mixture was refluxed for 4 hours. The cooled reaction mixture was extracted with ether (2 x 200 mL), acidified to pH 3 and the solid filtered off and dried (22 g, 70%).
Produkt (20 g) raztopimo v EtOH (300 ml) in previdno dodamo koncentrirano H2SO4 (5 ml). Zmes refluktiramo 7 ur. Ohlajeno reakcijsko zmes uparimo pod znižanim tlakom in preostanek porazdelimo med CH2C12 in vodo (po 30 ml vsakega). Organsko plast ekstrahiramo z nasičeno raztopino NaHCO3 (200 ml), speremo z vodo (100 ml) posušimo in uparimo v vakuumu, tako da dobimo etil-2,4diklorofenilacetat kot olje (22,2 g, 89,5%).The product (20 g) was dissolved in EtOH (300 ml) and concentrated H 2 SO 4 (5 ml) was carefully added. The mixture was refluxed for 7 hours. The cooled reaction mixture was evaporated under reduced pressure and the residue was partitioned between CH 2 Cl 2 and water (30 ml each). The organic layer was extracted with saturated NaHCO 3 solution (200 ml), washed with water (100 ml), dried and evaporated in vacuo to give ethyl-2,4dichlorophenyl acetate as an oil (22.2 g, 89.5%).
2. Dietil-2,4-diklorofenilmalonat2. Diethyl-2,4-dichlorophenylmalonate
Natrij (1,86 g, 0,081M) dodamo po delih v abs. etanol (150 ml) ob mešanju. Potem, ko se ves natrij raztopi, po kapljicah dodamo raztopino etil-2,4-diklorofenilacetata (20 g) v dietilkarbonatu (40 ml). Reakcijsko zmes segrevamo, dokler ne oddestiliramo EtOH. Hitrost dodajanja kontroliramo tako, da je enaka hitrosti destilacije. Po končanem dodajanju reakcijsko zmes segrevamo in destiliramo nadaljnje 4 ure. Ohlajeno reakcijsko zmes porazdelimo med vodo (300 ml) in EtOAc (300 ml) in organsko plast posušimo in uparimo v vakuumu, tako da dobimo rumeno olje (21 g, 85%).Sodium (1.86 g, 0.081M) was added portionwise into abs. ethanol (150 ml) with stirring. After all the sodium was dissolved, a solution of ethyl 2,4-dichlorophenyl acetate (20 g) in diethyl carbonate (40 ml) was added dropwise. The reaction mixture was heated until EtOH was distilled off. The rate of addition is controlled to be equal to the rate of distillation. After the addition is complete, the reaction mixture is heated and distilled for a further 4 hours. The cooled reaction mixture was partitioned between water (300 ml) and EtOAc (300 ml) and the organic layer was dried and evaporated in vacuo to give a yellow oil (21 g, 85%).
3. 2-amino-5-(2,4-diklorofenil)-4,6-dihidroksipirimidin3. 2-amino-5- (2,4-dichlorophenyl) -4,6-dihydroxypyrimidine
Natrij (4,52 g, 0,196 M) po delih dodamo v etanol (150 ml). Potem ko se ves natrij raztopi, dodamo gvanidin-hidroklorid (12,44 g, 0,13M) in nato dietil-2,4-diklorofenilmalonat (20 g, 0,0655M). Zmes refluktiramo 6 ur, EtOH ločimo pod znižanim tlakom in ostanek porazdelimo med 2N NaOH (400 ml) in EtOAc (400 ml). Vodno plast nakisamo s koncentrirano klorovodikovo kislino ob ohlajanju ter oborjeno snov filtriramo in posušimo (11 g, 62%).Sodium (4.52 g, 0.196 M) was added portionwise to ethanol (150 ml). After all the sodium was dissolved, guanidine hydrochloride (12.44 g, 0.13M) was added followed by diethyl-2,4-dichlorophenylmalonate (20 g, 0.0655M). The mixture was refluxed for 6 hours, the EtOH was separated under reduced pressure and the residue was partitioned between 2N NaOH (400 ml) and EtOAc (400 ml). The aqueous layer was acidified with concentrated hydrochloric acid upon cooling, and the precipitated material was filtered and dried (11 g, 62%).
4. 2-amino-5-(2,4-diklorofenil)-4,6-dikloropirimidin4. 2-amino-5- (2,4-dichlorophenyl) -4,6-dichloropyrimidine
Zmes 2-amino-5-(2,4-diklorofenil)-4,6-dihidroksipirimidina (10 g), fosforilklorida (100 ml) in dimetilanilina (1,5 ml) refluktiramo 6 ur. Ohlajeno reakcijsko zmes previdno dodamo na zdrobljen led in netopno trdno snov odfiltriramo in speremo z 2N HCl in nato z vodo. Trdno snov resuspendiramo v vodi, nevtraliziramo (0,88 NH4OH) ob ohlajanju in zmes pustimo preko noči na sobni temperaturi. Netopno snov filtriramo, posušimo in prečistimo s hitro kolonsko kromatografijo, tako da dobimo naslovno spojino (2,5 g, 22%), tal. 211-213°C. Mikroanaliza :A mixture of 2-amino-5- (2,4-dichlorophenyl) -4,6-dihydroxypyrimidine (10 g), phosphoryl chloride (100 ml) and dimethylaniline (1.5 ml) was refluxed for 6 hours. The cooled reaction mixture was carefully added to the crushed ice and the insoluble solid filtered off and washed with 2N HCl and then with water. The solid was resuspended in water, neutralized (0.88 NH 4 OH) under cooling, and the mixture was left overnight at room temperature. The insoluble material was filtered, dried and purified by flash column chromatography to give the title compound (2.5 g, 22%), m.p. 211-213 ° C. Microanalysis:
Izrač.:Calc .:
Ugot.:Found:
C, 38,83; H, 1,6; N, 13,59; C, 38,59; H, 1,53; N, 13,40.C, 38.83; H, 1.6; N, 13.59; C, 38.59; H, 1.53; N, 13.40.
Primer 33Example 33
Sinteza 2,4-diamino-6-kloro-5-(2,4-diklorofenil)pirimidinaSynthesis of 2,4-diamino-6-chloro-5- (2,4-dichlorophenyl) pyrimidine
Zmes 2-amino-4-kloro-5-(2,4-diklorofenil)-4-6-dikloropirimidina (0,5 g) (Primer 32), EtOH, ki je nasičen z amoniakom (20 ml) in bakra v prahu (0,05 g) segrevamo v avtoklavu pri 180°C 18 ur. Ohlajeno reakcijsko zmes filtriramo, uparimo in ostanek prečistimo s hitro kromatografijo na koloni, tako da dobimo naslovno spojino (0,12 g, 25%), tal. 219°C. Mikroanaliza:Mixture of 2-amino-4-chloro-5- (2,4-dichlorophenyl) -4-6-dichloropyrimidine (0.5 g) (Example 32), ammonia-saturated EtOH (20 ml) and copper powder (0.05 g) was heated in an autoclave at 180 ° C for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (0.12 g, 25%), m.p. 219 ° C. Microanalysis:
Izrač.: C, 40,82; H, 2,55; N, 19,05;Calcd: C, 40.82; H, 2.55; N, 19.05;
Ugot.: C, 41,27; H, 2,46; N, 18,74.Found: C, 41.27; H, 2.46; N, 18.74.
Primer 34Example 34
Sinteza 2-amino-4-kloro-5-(2,4-diklorofenil)-6-metiltiopirmidinaSynthesis of 2-amino-4-chloro-5- (2,4-dichlorophenyl) -6-methylthiopyrimidine
Zmes 2-amino-5-(2,4-diklorofenil)-4,6-dikloropirimidina (0,5 g) (Primer 32), THF (15 ml), natrijeve soli metantiola (0,113 g), bakra v prahu (0,05 g) in tris[2-(2metoksietoksi)etil]amina (0,1 g) segrevamo v avtoklavu pri 180°C 18 ur. Ohlajeno reakcijsko zmes filtriramo, uparimo in ostanek prečistimo s hitro kromatografijo na koloni, tako da dobimo naslovno spojino (0,262 g, 52%), tal. 201-202°C (se zmehča na 196°C). Mikroanaliza:Mixture of 2-amino-5- (2,4-dichlorophenyl) -4,6-dichloropyrimidine (0.5 g) (Example 32), THF (15 ml), methanethiol sodium salts (0.113 g), copper powder (0 , 05 g) and tris [2- (2methoxyethoxy) ethyl] amine (0.1 g) were heated in an autoclave at 180 ° C for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (0.262 g, 52%), m.p. 201-202 ° C (softens to 196 ° C). Microanalysis:
Izrač.:Calc .:
Ugot.:Found:
C, 41,19; H, 2,50; N, 13,10; C, 41,10; H, 2,52; N, 12,77.C, 41.19; H, 2.50; N, 13.10; C, 41.10; H, 2.52; N, 12.77.
Primer 35Example 35
Sinteza 2,4-diamino-5-(2,4-diklorofenil)-6-metiltiopirimidinaSynthesis of 2,4-diamino-5- (2,4-dichlorophenyl) -6-methylthiopyrimidine
Zmes 2-amino-4-kloro-5-(2,4-diklorofenil)-6-metiltiopirimidina (0,5 g) (Primer 32), EtOH, ki je nasičen z amoniakom (20 ml), bakra v prahu (0,05 g) in tris-[2-(2metoksietoksi)etil]amina (0,01 g) segrevamo v avtoklavu na 180°C 18 ur. Ohlajeno reakcijsko zmes filtriramo, uparimo in ostanek prečistimo s hitro kolonsko kromatografijo, tako da dobimo naslovno spojino (0,11 g, 23,5%), tal. 191-192°C. Mikroanaliza:Mixture of 2-amino-4-chloro-5- (2,4-dichlorophenyl) -6-methylthiopyrimidine (0.5 g) (Example 32), ammonia-saturated EtOH (20 ml), copper powder (0 , 05 g) and tris- [2- (2methoxyethoxy) ethyl] amine (0.01 g) were heated in an autoclave at 180 ° C for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (0.11 g, 23.5%), m.p. 191-192 ° C. Microanalysis:
Izrač.: za 0,2 hidrat: C, 43,33; H, 3,41; N, 18,38;Calcd for 0.2 hydrate: C, 43.33; H, 3.41; N, 18.38;
Ugot.: C, 43,37; H, 3,23; N, 18,33.Found: C, 43.37; H, 3.23; N, 18.33.
Primer 36Example 36
4-amino-5-(3,5-diklorofenil)-6-metil-2-f4-metilpiperazin-l-il)-pirimidin4-amino-5- (3,5-dichlorophenyl) -6-methyl-2-4-methylpiperazin-1-yl) -pyrimidine
a. 3,5-diklorofenilacetonitrila. 3,5-dichlorophenylacetonitrile
Zmes 3,5-diklorobenzilalkohola (Aldrich, 25 g), tionilklorida (100 ml) in DMF (0,5 ml) mešamo in refluktiramo 4 ure. Po ohladitvi zmes koncentriramo v vakuumu, ostanek zberemo v etru, speremo z nasičenim vodnim NaHCO3 in s slanico, posušimo (MgSO4) in koncentriramo v vakuumu, tako da dobimo 3,5-diklorobenzoilklorid kot svetlo rumeno trdno snov, ki jo uporabimo brez nadaljnjega čiščenja, 28 mg, tal. 3236°C.A mixture of 3,5-dichlorobenzyl alcohol (Aldrich, 25 g), thionyl chloride (100 ml) and DMF (0.5 ml) was stirred and refluxed for 4 hours. After cooling, the mixture was concentrated in vacuo, the residue collected in ether, washed with saturated aqueous NaHCO 3 and brine, dried (MgSO 4 ) and concentrated in vacuo to give 3,5-dichlorobenzoyl chloride as a light yellow solid, which was used without further purification, 28 mg, m.p. 3236 ° C.
V močno mešano raztopino 3,5-diklorobenzilklorida (28 g) v diklorometanu (150 ml) dodamo zmes KCN (27,5 g) in tetrabutilamonijevega bisulfata (2,38 g) v vodi (110 ml). Po mešanju na sobni temperaturi 22 ur zmes razredčimo z diklorometanom, organsko fazo speremo z vodo in koncentriramo v vakuumu, tako da ostane olje. Filtracija skozi silicijev dioksid s toluenom in nato koncentriranje in trituriranje s heksanom dajo želen produkt kot brezbarvno trdno snov. 15,8 g, tal. 31-32°C.To a strongly stirred solution of 3,5-dichlorobenzyl chloride (28 g) in dichloromethane (150 ml) was added a mixture of KCN (27.5 g) and tetrabutylammonium bisulfate (2.38 g) in water (110 ml). After stirring at room temperature for 22 hours, the mixture was diluted with dichloromethane, the organic phase was washed with water and concentrated in vacuo to leave an oil. Filtration through silica with toluene and then concentration and trituration with hexane give the desired product as a colorless solid. 15.8 g, m.p. 31-32 ° C.
b. 4-amino-5-(3,5-diklorofenil)-6-metil-2-(4-metilpiperazin-l-il)pirimidinb. 4-amino-5- (3,5-dichlorophenyl) -6-methyl-2- (4-methylpiperazin-1-yl) pyrimidine
V mešano raztopino NaOEt (iz 0,69 g natrija) v etanolu (25 ml) pri refluksu dodamo v teku 5 minut zmes 3,5-diklorofenilacetonitrila (9,3 g) in etilacetata (3,3 g) v suhem dimetoksietanu (10 ml). Po mešanju na refluksu 4 ure zmes ohladimo na ledu, nakisamo z ocetno kislino, vlijemo v hladno vodo in ekstrahiramo z diklorometanom. Združene ekstrakte speremo z vodo in koncentriramo, tako da dobimo olje. Trituracija s heksanom da 2-(3,5-diklorofenil)-3-oksobutironitril kot brezbarvno trdno snov (4,15 g).A mixture of 3,5-dichlorophenylacetonitrile (9.3 g) and ethyl acetate (3.3 g) in dry dimethoxyethane (10) was added over 5 minutes to a stirred solution of NaOEt (0.69 g sodium) in ethanol (25 ml). ml). After stirring at reflux for 4 hours, the mixture was cooled on ice, acidified with acetic acid, poured into cold water and extracted with dichloromethane. The combined extracts were washed with water and concentrated to give an oil. Trituration with hexane gave 2- (3,5-dichlorophenyl) -3-oxobutyronitrile as a colorless solid (4.15 g).
V raztopino acilacetonitrila (4,1 g) v etru (100 ml) dodamo po delih prebitek raztopine diazometana v etru. Po mešanju 2 uri na sobni temperaturi raztopino koncentriramo v vakuumu, tako da dobimo enolni eter.To a solution of acylacetonitrile (4.1 g) in ether (100 ml) was added in part the excess solution of diazomethane in ether. After stirring for 2 hours at room temperature, the solution was concentrated in vacuo to give a single ether.
V mešano raztopino NaOEt (iz 0,72 g natrija) v etanolu (25 ml) dodamo N-metilpiperazinoformamidin-hidrojodid (7,29 g). Po 10 minutah dodamo raztopino gornjega enolnega etra v etanolu (25 ml) in nato zmes mešamo in refluktiramo 4,5 ure. Po ohladitvi topilo uparimo v vakuumu in ostanek stresamo z 2N NaOH (50 ml). Snov odfiltriramo, speremo z vodo, posušimo na zraku in kromatografiramo (silicijev dioksid; 1:9 MeOH:CHCl3), tako da dobimo želeni produkt kot brezbarvno trdno snov, 1,6 g, tal. 164-166°C.To a stirred solution of NaOEt (0.72 g of sodium) in ethanol (25 ml) was added N-methylpiperazinoformamidine hydroiodide (7.29 g). After 10 minutes, a solution of the above enol ether in ethanol (25 ml) was added and the mixture was then stirred and refluxed for 4.5 hours. After cooling, the solvent was evaporated in vacuo and the residue was shaken with 2N NaOH (50 ml). The material was filtered off, washed with water, dried in air and chromatographed (silica; 1: 9 MeOH: CHCl 3 ) to give the desired product as a colorless solid, 1.6 g, m.p. Mp 164-166 ° C.
Primer 37Example 37
Priprava 2,4-diamino-5-(2,5-diklorofenil)-6-metilpirimidinaPreparation of 2,4-diamino-5- (2,5-dichlorophenyl) -6-methylpyrimidine
To spojino pripravimo na analogen način kot spojino iz primera 6 iz 2,5diklorobenzilalkohola (Lancaster Synthesis). Tal. 226-228°C:This compound was prepared in an analogous manner as the compound of Example 6 from 2,5 dichlorobenzyl alcohol (Lancaster Synthesis). Tal. 226-228 ° C:
TLC (SiO2:CHCl3/MeOH, 9:1) Rf = 0,24.TLC (SiO 2 : CHCl 3 / MeOH, 9: 1) Rf = 0.24.
Primer 38Example 38
Priprava 2,4-diamino-5-(3,4-diklorofenil)-6-trifluorometilpirimidinaPreparation of 2,4-diamino-5- (3,4-dichlorophenyl) -6-trifluoromethylpyrimidine
To spojino pripravimo na analogen način kot spojino iz primera 4, iz 3,4dikloroacetonitrila (Aldrich), tal. 252-254,5°C: TLC (SiO2; metanol/kloroform, 1:9) Rf = 0,38.This compound was prepared in an analogous manner as the compound of Example 4 from 3,4dichloroacetonitrile (Aldrich), m.p. 252-254.5 ° C: TLC (SiO 2 ; methanol / chloroform, 1: 9) Rf = 0.38.
Primer 39Example 39
Priprava 2,4-diamino-5-(2,3-diklorofenil-4-nitrofenil)-pirimidinaPreparation of 2,4-diamino-5- (2,3-dichlorophenyl-4-nitrophenyl) -pyrimidine
To spojino pripravimo na analogen način kot spojino iz primera 5, iz 2,4-diamino-5(2,3-diklorofenil)pirimidina (Primer 21). Reakcija je dala zmes 4-nitro in 5-nitro derivatov, iz katerih ločimo naslovno spojino s kromatografijo na koloni (SiO2, EtOAc), tal. 237-9°C. Prav tako na ta način ločimo 2,4-diamino-5-(2,3-dikloro-5nitrofenil)pirimidin, tal. 264-6°C.This compound was prepared in an analogous manner as the compound of Example 5 from 2,4-diamino-5 (2,3-dichlorophenyl) pyrimidine (Example 21). The reaction gave a mixture of 4-nitro and 5-nitro derivatives, from which the title compound was separated by column chromatography (SiO 2 , EtOAc), mp. 237-9 ° C. 2,4-diamino-5- (2,3-dichloro-5-nitrophenyl) pyrimidine is also separated in this way, m.p. 264-6 ° C.
Primer 40Example 40
Priprava 2,4-diamino-5-(2,4-diklorofenil)-6-(dietoksimetil)pirimidinaPreparation of 2,4-diamino-5- (2,4-dichlorophenyl) -6- (diethoxymethyl) pyrimidine
To spojino pripravimo na način, ki je analogen z 2,4-diamino-5-(2,3-diklorofenil)-6dietoksimetil)pirimidinom (Primer 18,1) iz 2,4-diklorofenilacetonitrila, tal. 225°C.This compound was prepared in a manner analogous to 2,4-diamino-5- (2,3-dichlorophenyl) -6diethoxymethyl) pyrimidine (Example 18,1) from 2,4-dichlorophenylacetonitrile, m.p. 225 ° C.
Primer 41Example 41
Priprava 2,4-diamino-5-(3,5-diklorofenil)-6-metilpirimidinaPreparation of 2,4-diamino-5- (3,5-dichlorophenyl) -6-methylpyrimidine
To spojino pripravimo na analogen način s spojino iz Primera 6 iz 3,5diklorofenilacetonitrila (Aldrich), tal. 242-244°C.This compound was prepared in an analogous manner with the compound of Example 6 from 3,5 dichlorophenylacetonitrile (Aldrich), m.p. 242-244 ° C.
Primer 42Example 42
Priprava 2,4-diamino-5-(2,3-diklorofenil)-6-trifluorometilpirimidina-N-oksidaPreparation of 2,4-diamino-5- (2,3-dichlorophenyl) -6-trifluoromethylpyrimidine-N-oxide
To spojino pripravimo iz spojine iz Primera 14 z reakcijo z MCPBA v CHC13 pri sobni temperaturi. Tal. 275-278°C.This compound was prepared from the compound of Example 14 by reaction with MCPBA in CHCl 3 at room temperature. Tal. 275-278 ° C.
Primer 43Example 43
Priprava 2,4-diamino-5-(2,3-diklorofenil)-6-tribromometilpirimidinaPreparation of 2,4-diamino-5- (2,3-dichlorophenyl) -6-tribromomethylpyrimidine
To spojino pripravimo iz spojine iz primera 15 z reakcijo s prebitnim bromom in natrijevim acetatom v ocetni kislini pri refluksu. Naslovno spojino ločimo iz zmesi spojin iz primera 75 s kromatografijo na koloni, tal. 210°C (razp.).This compound was prepared from the compound of Example 15 by reaction with excess bromine and sodium acetate in acetic acid at reflux. The title compound was separated from the mixture of compounds of Example 75 by column chromatography, m.p. 210 ° C (dec).
Primer 44Example 44
Priprava 2,4-diamino-5-(2,4-diklorofenil)-6-metoksimetilpirimidinaPreparation of 2,4-diamino-5- (2,4-dichlorophenyl) -6-methoxymethylpyrimidine
To spojino pripravimo na analogen način s primerom 2 iz 2,4-diklorofenilacetonitrila, tal. 183-185°C. En madež na TLC.This compound was prepared in an analogous manner to Example 2 from 2,4-dichlorophenylacetonitrile, m.p. 183-185 ° C. One stain on TLC.
Primer 45Example 45
Priprava 2,4-diamino-5-(2.6-diklorofenil)-6-metilpirimidinaPreparation of 2,4-diamino-5- (2,6-dichlorophenyl) -6-methylpyrimidine
To spojino pripravimo na analogen način s primerom 6 iz 2,6-diklorofenilacetonitrila (Aldrich), tal. 250°C.This compound was prepared in an analogous manner to Example 6 from 2,6-dichlorophenylacetonitrile (Aldrich), m.p. 250 ° C.
Primer 46Example 46
Priprava 2,4-diamino-5-(2.4-diklorofenil)-pirimidin-6-karboksaldehidaPreparation of 2,4-diamino-5- (2,4-dichlorophenyl) -pyrimidine-6-carboxaldehyde
To spojino pripravimo iz spojine iz primera 40 na analogen način kot spojino v primeru 18.2, tal. nad 350°C.This compound was prepared from the compound of Example 40 in an analogous manner as the compound of Example 18.2, m.p. above 350 ° C.
Primer 47Example 47
Priprava 2,4-diamino-5-(2,3-dikloro-4-nitrofenil)-6-metilpirimidinaPreparation of 2,4-diamino-5- (2,3-dichloro-4-nitrophenyl) -6-methylpyrimidine
To spojino pripravimo iz spojine iz primera 15 na analogen način kot spojino iz Primera 39, tal. nad 265°C. Prav tako s to reakcijo dobimo 2,4-diamino-5-(2,3dikioro-5-nitrofenil)-6-metilpirimidin.This compound was prepared from the compound of Example 15 in an analogous manner as the compound of Example 39, m.p. above 265 ° C. This reaction also yields 2,4-diamino-5- (2,3dichloro-5-nitrophenyl) -6-methylpyrimidine.
Primer 48Example 48
Priprava 2,4-diamino-5-(2,4-diklorofenil)-6-hidroksiiminometilpirimidinaPreparation of 2,4-diamino-5- (2,4-dichlorophenyl) -6-hydroxyiminomethylpyrimidine
To spojino pripravimo iz spojine iz primera 46 z reakcijo s hidroksilaminhidrokloridom v etanolu, tal. 260-5°C.This compound was prepared from the compound of Example 46 by reaction with hydroxylamine hydrochloride in ethanol, m.p. 260-5 ° C.
Primer 49Example 49
Priprava 2,4-diamino-5-(2,4-diklorofenil)-6-hidroksimetilpirimidinaPreparation of 2,4-diamino-5- (2,4-dichlorophenyl) -6-hydroxymethylpyrimidine
To spojino pripravimo iz spojine iz primera 46 na analogen način kot spojino iz primera 18.3, tal. 169-171°C.This compound was prepared from the compound of Example 46 in an analogous manner as the compound of Example 18.3, m.p. Mp 169-171 ° C.
Primer 50Example 50
Priprava 2,4-diamino-5-(2,3,4-triklorofenil)-6-metilpirimidinaPreparation of 2,4-diamino-5- (2,3,4-trichlorophenyl) -6-methylpyrimidine
To spojino pripravimo iz spojine iz primera 47 z redukcijo v amin (PtO2, H2, AcOH), s tvorbo diazonijeve soli (NaNO2, H2SO4) in z reakcijo le-te s CuCl (kot za Primer 57). Sublimira na 275°C. Homogeno na TLC (metanol/kloroform, 1:9) Rf=0,36.This compound was prepared from the compound of Example 47 by reduction to an amine (PtO 2 , H 2 , AcOH), by the formation of a diazonium salt (NaNO 2 , H 2 SO 4 ) and by reaction with CuCl (as for Example 57). Sublimates to 275 ° C. Homogeneous on TLC (methanol / chloroform, 1: 9) Rf = 0.36.
Primer 51Example 51
2,4-diamino-5-(2,6-diklorofenil)-6-metoksimetil-pirimidin2,4-Diamino-5- (2,6-dichlorophenyl) -6-methoxymethyl-pyrimidine
To spojino pripravimo na analogen način kot spojino iz primera 2 iz 2,6diklorofenilacetonitrila (Aldrich), tal. 204-207°C.This compound was prepared in an analogous manner as the compound of Example 2 from 2,6dichlorophenylacetonitrile (Aldrich), m.p. 204-207 ° C.
Primer 52Example 52
Priprava 2,4-diamino-5-(2,3,5-triklorofenil)-6-triklorometil-pirimidinaPreparation of 2,4-diamino-5- (2,3,5-trichlorophenyl) -6-trichloromethyl-pyrimidine
To spojino pripravimo iz spojine iz primera 6 z reakcijo z NCS v AcOH na 100°C (AIBN kot katalizator), tal. 226-227°C.This compound was prepared from the compound of Example 6 by reaction with NCS in AcOH at 100 ° C (AIBN as catalyst), m.p. 226-227 ° C.
Primer 53Example 53
2.4- diamino-5-(2,4-diklorofenil)-6-fluorometilpirimidin2,4-Diamino-5- (2,4-dichlorophenyl) -6-fluoromethylpyrimidine
1. 2,4-diamino-6-bromometil-5-(2,4-diklorofenil)pirimidin1. 2,4-Diamino-6-bromomethyl-5- (2,4-dichlorophenyl) pyrimidine
2.4- diamino-6-benziloksimetil-5-(2,4-diklorofenil)pirimidin (primer 25) (6,5 g) raztopimo v 47%-ni raztopini bromovodikove kisline v ocetni kislini (75 ml) in zmes mešamo in segrevamo na 100°C 6 ur. Po stanju na sobni temperaturi preko noči dihidrobromidno sol odfiltriramo, speremo z etrom in posušimo v vakuumu, 6 g. V mešano raztopino dihidrobromidne soli (0,43 g) v dimetilsulfoksidu (4 ml) dodamo z dokapanjem raztopino natrijevega bikarbonata (0,84 g) v vodi (10 ml). Po 30 minutah oborino odfiltriramo, speremo z vodo, nato z etrom in posušimo v vakuumu, 0,26 g, tal. nad 270°C (razpada).2.4-Diamino-6-benzyloxymethyl-5- (2,4-dichlorophenyl) pyrimidine (Example 25) (6.5 g) was dissolved in 47% hydrochloric acid in acetic acid (75 ml) and the mixture was stirred and heated to 100 ° C for 6 hours. At room temperature overnight, the dihydrobromide salt was filtered off, washed with ether and dried in vacuo, 6 g. To a stirred solution of the dihydrobromide salt (0.43 g) in dimethylsulfoxide (4 ml) was added dropwise a solution of sodium bicarbonate (0.84 g) in water (10 ml). After 30 minutes the precipitate was filtered off, washed with water, then with ether and dried in vacuo, 0.26 g, mp. above 270 ° C (decomposition).
2.2.4- diamino-5-(2,4-diklorofneil)-6-fluorometilpirimidin2.2.4- Diamino-5- (2,4-dichlorophenyl) -6-fluoromethylpyrimidine
V raztopino 2,4-diamino-6-bromometil-5-(2,4-diklorofenil)pirimidina (1,04 g) v tetrametilensulfonu (4,5 ml) dodamo cezijev fluorid (1 g). Zmes mešamo in segrevamo na 100°C 4 ure, ohladimo, razredčimo z vodo in ekstrahiramo s kloroformom. Združene ekstrakte speremo z vodo, posušimo (MgSO4) in koncentriramo v vakuumu. Ostanek kromatografiramo (silicijev dioksid; 19:1:0,1 diklorometan/metanol/trietilamin), tako da dobimo naslovno spojino, ki jo rekristalizramo iz etanola. 0,19 g, tal. 210-211°C.To a solution of 2,4-diamino-6-bromomethyl-5- (2,4-dichlorophenyl) pyrimidine (1.04 g) in tetramethylenesulfone (4.5 ml) was added cesium fluoride (1 g). The mixture was stirred and heated at 100 ° C for 4 hours, cooled, diluted with water and extracted with chloroform. The combined extracts were washed with water, dried (MgSO 4 ) and concentrated in vacuo. The residue was chromatographed (silica; 19: 1: 0.1 dichloromethane / methanol / triethylamine) to give the title compound, which was recrystallized from ethanol. 0.19 g, m.p. 210-211 ° C.
Primer 54Example 54
Priprava 2,4-diamino-5-[2-kloro-5-(N,N-dimetilsulfamoil)fenil]-6-metilpirimidinaPreparation of 2,4-diamino-5- [2-chloro-5- (N, N-dimethylsulfamoyl) phenyl] -6-methylpyrimidine
1.2.4- diamino-5-(2-kloro-5-nitrofneil)-6-metilpirimidin1.2.4- Diamino-5- (2-chloro-5-nitrophneyl) -6-methylpyrimidine
V raztopino 2,4-diamino-5-(2-klorofenil)-6-metilpirimidina (11,84 g) (primer 22) v koncentrirani ,H2SO4 (100 ml) dodamo kalijev nitrat (5,1 g). Po mešanju na sobni temperaturi 90 minut raztopino vlijemo na led in naalkalimo z 10N NaOH. Produkt ekstrahiramo z etilacetatom, zberemo, posušimo (MgSO4) in uparimo, 13,9 g, 23624G°C.To a solution of 2,4-diamino-5- (2-chlorophenyl) -6-methylpyrimidine (11.84 g) (Example 22) in concentrated H 2 SO 4 (100 ml) was added potassium nitrate (5.1 g). After stirring at room temperature for 90 minutes, the solution was poured onto ice and basified with 10N NaOH. The product was extracted with ethyl acetate, collected, dried (MgSO 4 ) and evaporated, 13.9 g, 23624G ° C.
2.2.4- diamino-5-(5-amino-2-klorofenil)-6-metilpirimidin2.2.4- Diamino-5- (5-amino-2-chlorophenyl) -6-methylpyrimidine
Raztopino 2,4-diamino-5-(2-kloro-5-nitrofenil)-6-metilpirimidina (13,9 g) v ocetni kislini reduciramo pod atmosfero vodika v prisotnosti PtO2 (0,28 g). Zmes filtriramo skozi hiflo in filtrat koncentriramo. Ostanek nevtraliziramo z nasičeno raztopino NaHCO3 in produkt ekstrahiramo z etilacetatom, zberemo, posušimo (MgSO4) in uparimo. Kromatografija na SiO2 gelu ob eluaciji s CHC13 do 40% MeOH/CHCLj da želeni produkt, 6 g, tal. 117-121°C.A solution of 2,4-diamino-5- (2-chloro-5-nitrophenyl) -6-methylpyrimidine (13.9 g) in acetic acid was reduced under a hydrogen atmosphere in the presence of PtO 2 (0.28 g). The mixture was filtered through hyflo and the filtrate was concentrated. The residue was neutralized with saturated NaHCO 3 solution and the product was extracted with ethyl acetate, collected, dried (MgSO 4 ) and evaporated. Chromatography on SiO 2 gel eluting with CHC1 3 to 40% MeOH / CHCl3 gave the desired product, 6 g, m.p. 117-121 ° C.
3. 2,4-diamino-5-(2-kloro-5-N.N-dimetilsulfamoilfenil)-6-metilpirimidin3. 2,4-Diamino-5- (2-chloro-5-N.N-dimethylsulfamoylphenyl) -6-methylpyrimidine
2.4- diamino-5-(5-amino-2-klorofenil)-6-metilpirimidin (0,25 g) raztopimo v vodi (0,8 ml) in koncentrirani HC1 (0,5 ml). V močno ohlajeno raztopino (pod 10°C) dodamo raztopino natrijevega nitrita (0,07 g) v vodi (0,5 ml). Po mešanju na sobni temperaturi 2 uri raztopino ohladimo na 5°C. Dodamo bakrov klorid (0,05 g) in 5,14M SO2 v ocetni kislini (0,97 ml) in reakcijo mešamo pri 5°C preko noči. Zmes filtriramo in speremo z vodo, tako da dobimo sulfonilklorid, 0,23 g.2.4-Diamino-5- (5-amino-2-chlorophenyl) -6-methylpyrimidine (0.25 g) was dissolved in water (0.8 ml) and concentrated HCl (0.5 ml). A solution of sodium nitrite (0.07 g) in water (0.5 ml) was added to a strongly cooled solution (below 10 ° C). After stirring at room temperature for 2 hours, the solution was cooled to 5 ° C. Copper chloride (0.05 g) and 5.14M SO 2 in acetic acid (0.97 ml) were added and the reaction was stirred at 5 ° C overnight. The mixture was filtered and washed with water to give sulfonyl chloride, 0.23 g.
Sulfonilklorid (0,16 g) raztopimo v THF (2 ml) in dodamo vodni dimetilamin (2 ml). Po mešanju preko noči raztopino razredčimo z vodo, ekstrahiramo z etilacetatom, zberemo, posušimo (MgSO4) in uparimo. Kromatografija na SiO2 gelu ob eluaciji z 2% MeOH/CHCL, da želeni produkt, 0,047 g tal. 283-285°C.The sulfonyl chloride (0.16 g) was dissolved in THF (2 ml) and aqueous dimethylamine (2 ml) was added. After stirring overnight, the solution was diluted with water, extracted with ethyl acetate, collected, dried (MgSO 4 ) and evaporated. Chromatography on SiO 2 gel eluting with 2% MeOH / CHCL gave the desired product, 0.047 g m.p. 283-285 ° C.
Primer 55Example 55
Priprava 2,4-diamino-(3,5-diklorofenil)-6-metoksimetilpirimidinaPreparation of 2,4-diamino- (3,5-dichlorophenyl) -6-methoxymethylpyrimidine
To spojino pripravimo na analogen način kot spojino v primeru 2 iz 3,5diklorofenilacetonitrila, tal. 228-230°C.This compound was prepared in an analogous manner as the compound of Example 2 from 3,5 dichlorophenylacetonitrile, m.p. Mp 228-230 ° C.
Primer 56Example 56
Priprava 2,4-diamino-5-(2,3-diklorofenil)-6-hidroksipirimidinaPreparation of 2,4-diamino-5- (2,3-dichlorophenyl) -6-hydroxypyrimidine
1. Etil-2-ciano-2-(2,3-diklorofenil)acetat1. Ethyl-2-cyano-2- (2,3-dichlorophenyl) acetate
Natrij (1,2 g) dodamo ob mešanju po delih k etanolu (50 ml). Potem, ko se natrij raztopi, dodamo z dokapanjem raztopino 2,4-diklorofenilacetonitrila (9,4 g) v dietilkarbonatu (25 ml). Reakcijsko zmes segrevamo, dokler ne oddestilira EtOH. Hitrost dodajanja kontroliramo tako, da je enaka hitrosti destilacije. Po končanem dodajanju reakcijsko zmes segrevamo in destiliramo še 4 ure. Ohlajeno reakcijsko zmes porazdelimo med vodo in EtOAc (po 300 ml vsakega). Organsko plast posušimo in uparimo v vakuumu in ostanek prečistimo s hitro kromatografijo na koloni, tako da dobimo naslovni produkt. (5 g, 39%).Sodium (1.2 g) was added portionwise to ethanol (50 ml). After dissolving sodium, a solution of 2,4-dichlorophenylacetonitrile (9.4 g) in diethyl carbonate (25 ml) was added dropwise. The reaction mixture was heated until it was distilled off with EtOH. The rate of addition is controlled to be equal to the rate of distillation. After the addition is complete, the reaction mixture is heated and distilled for another 4 hours. The cooled reaction mixture was partitioned between water and EtOAc (300 ml each). The organic layer was dried and evaporated in vacuo and the residue was purified by flash column chromatography to give the title product. (5 g, 39%).
2.2,4-diamino-5-(2,3-diklorofenil)-6-hidroksipirimidin2,2,4-diamino-5- (2,3-dichlorophenyl) -6-hydroxypyrimidine
Natrij (1,2 g, 0,52 mol) dodamo po delih v abs. etanol (50 ml) ob mešanju. Potem, ko se natrij raztopi, dodamo gvanidin hidroklorid (3,69 g, 0,039 mol) in nato etil-2ciano-2-(2,3-diklorofenil)acetat (5 g, 0,0195 mol). Zmes refluktiramo 8 ur, EtOH odločimo pod znižanim tlakom in ostanek porazdelimo med EtOAc in vodo. EtOAc plast ekstrahiramo z 2N NaOH in ekstrakt nevtraliziramo z 2N HC1 ob ohlajanju. Oborjeno snov odfiltriramo in posušimo, tako da dobimo naslovno spojino. (0,22 g, tal. 275°C). (razpad). Mikroanaliza:Sodium (1.2 g, 0.52 mol) was added portionwise into abs. ethanol (50 ml) with stirring. After dissolving sodium, guanidine hydrochloride (3.69 g, 0.039 mol) was added followed by ethyl 2cyano-2- (2,3-dichlorophenyl) acetate (5 g, 0.0195 mol). The mixture was refluxed for 8 hours, the EtOH was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was extracted with 2N NaOH and the extract was neutralized with 2N HCl upon cooling. The precipitated material was filtered off and dried to give the title compound. (0.22 g, mp 275 ° C). (breakup). Microanalysis:
Anal. izrač. za 0,25 hidrat:Anal. calcd. by 0.25 hydrate:
C, 43,56; H, 3,09; N, 20,33;C, 43.56; H, 3.09; N, 20.33;
C, 43,76; H, 3,09; N, 20,03.C, 43.76; H, 3.09; N, 20.03.
Primer 57Example 57
Sinteza 2,4-diamino-5-(2,4-trikIorofenil)-6-metilpirimidinaSynthesis of 2,4-diamino-5- (2,4-trichlorophenyl) -6-methylpyrimidine
a. Priprava 2-(2,4-diklorofenil)-3-okso-butironitrilaa. Preparation of 2- (2,4-dichlorophenyl) -3-oxo-butyronitrile
Raztopino 2,4-diklorofenilacetonitrila (30,0 g, 161 mmola) (Aldrich), v suhem etilacetatu (36 ml) dodamo ob dokapavanju v etanolno raztopino natrijevega etoksida, pripravljeno in situ iz kovinskega natrija (4,90 g, 213 mmola) in suhega etanola (60 ml). To reakcijsko zmes refluktiramo 2 uri, pustimo, da stoji preko noči na sobni temperaturi in etanol uparimo. Dobljeno rumeno snov raztopimo v vodi in dobljeno raztopino ekstrahiramo dvakrat z etrom. Vodno plast močno ohladimo in nakisamo s klorovodikovo kislino. Surovi produkt ekstrahiramo z etrom, tako da dobimo 23,31 g bele snovi.A solution of 2,4-dichlorophenylacetonitrile (30.0 g, 161 mmol) (Aldrich) in dry ethyl acetate (36 ml) was added dropwise to an ethanolic sodium ethoxide solution prepared in situ from metallic sodium (4.90 g, 213 mmol). and dry ethanol (60 ml). The reaction mixture was refluxed for 2 hours, allowed to stand at room temperature overnight and the ethanol was evaporated. The resulting yellow substance was dissolved in water and the resulting solution was extracted twice with ether. The aqueous layer was cooled strongly and acidified with hydrochloric acid. The crude product was extracted with ether to give 23.31 g of a white solid.
b. Priprava 2,4-diamino-5-(2,4-diklorofenil)-6-metilpirimidinab. Preparation of 2,4-diamino-5- (2,4-dichlorophenyl) -6-methylpyrimidine
Raztopino surovega 2-(2,4-diklorofenil)-3-okso-butironitrila (23,24 g) v suhem toluenu (400 ml) refluktiramo z etilenglikolom (280 ml) in p-toluensolfonsko kislino (8,00 g, 42 mmol) 4 ure ob uporabi Dean & Stark pasti. Po močnem ohlajanju organsko fazo speremo z nasičenim NaHCO3, posušimo preko MgSO4, in topilo uparimo, ta ostane trdna snov (24,0 g). Fino zmlet gvanidin hidroklorid (19,1 g, 200 mmol) dodamo v etanolno raztopino natrijevega etoksida, pripravljeno in situ iz kovinskega natrija (5,0 g, 218 mmol) v suhem etanolu (500 ml). Raztopino ketala (25,0 g, 92 mmol) v suhem etanolu (10 ml) dodamo na gvanidinsko raztopino. To zmes refluktiramo 2 uri in pustimo, da stoji preko noči pri sobni temperaturi. Etanol uparimo in surovi produkt prekristaliziramo iz vročega acetona, tako da dobimo 17,23 g produkta, tal. 222-222,5°C.A solution of crude 2- (2,4-dichlorophenyl) -3-oxo-butyronitrile (23.24 g) in dry toluene (400 ml) was refluxed with ethylene glycol (280 ml) and p-toluenesulfonic acid (8.00 g, 42 mmol) ) 4 hours using Dean & Stark traps. After vigorous cooling, the organic phase was washed with saturated NaHCO 3 , dried over MgSO 4 , and the solvent was evaporated to leave a solid (24.0 g). Finely ground guanidine hydrochloride (19.1 g, 200 mmol) was added to an ethanolic sodium ethoxide solution prepared in situ from metallic sodium (5.0 g, 218 mmol) in dry ethanol (500 ml). A solution of ketal (25.0 g, 92 mmol) in dry ethanol (10 ml) was added to the guanidine solution. The mixture was refluxed for 2 hours and allowed to stand at room temperature overnight. The ethanol was evaporated and the crude product was recrystallized from hot acetone to give 17.23 g of product, m.p. 222-222.5 ° C.
c. Priprava 2.4-diamino-5-(2,4-dikloro-5-nitrofenil)-6-metilpirimidinac. Preparation of 2,4-diamino-5- (2,4-dichloro-5-nitrophenyl) -6-methylpyrimidine
Fino zmlet kalijev nitrat (6,5 g, 64 mol) dodamo v raztopino 2,4-diamino-5-(2,4diklorofenil)-6-metilpirimidina (17,23 g, 64 mmol) v koncentrirani žveplovi kislini (150 ml). To zmes mešamo pri sobni temperaturi 90 minut. Reakcijsko zmes nato dodamo na natrijev bikarbonat in led. Produkt ekstrahiramo z etilacetatom. Potem, ko se etilacetat odloči, dobimo rumeno snov (30,86 g). Del tega surovega produkta (7,0 g) prepustimo skozi kolono silicijevega dioksida za hitro kromatografijo in eluiramo z etilacetatom, tako da dobimo čist produkt (4,81 g).Fine ground potassium nitrate (6.5 g, 64 mol) was added to a solution of 2,4-diamino-5- (2,4 dichlorophenyl) -6-methylpyrimidine (17.23 g, 64 mmol) in concentrated sulfuric acid (150 ml). . The mixture was stirred at room temperature for 90 minutes. The reaction mixture was then added to sodium bicarbonate and ice. The product was extracted with ethyl acetate. After ethyl acetate was determined, a yellow solid (30.86 g) was obtained. A portion of this crude product (7.0 g) was passed through a silica column for flash chromatography and eluted with ethyl acetate to give the pure product (4.81 g).
d. Priprava 2,4-diamino-5-(5-amino-2,4-diklorofenil)-6-metilpirimidinad. Preparation of 2,4-diamino-5- (5-amino-2,4-dichlorophenyl) -6-methylpyrimidine
2,4-diamino-5-(2,4-dikloro-5-nitrofenil)-6-metilpirimidin (4,80 g, 15 mmol) raztopimo v ledocetni kislini (18 ml). To raztopino in 10 mg Adamsovega katalizatorja mešamo pod atmosfero vodika pri sobni temperaturi 4 ure. Katalizator odfiltriramo in ocetno kislino uparimo. Dobljeno brezbarvno tekočino raztopimo v etilacetatu in speremo trikrat z vodo. Po uparitvi etilacetata dobimo belo snov (2,64 g, 9 mmol).2,4-Diamino-5- (2,4-dichloro-5-nitrophenyl) -6-methylpyrimidine (4.80 g, 15 mmol) was dissolved in glacial acetic acid (18 ml). This solution and 10 mg of Adams catalyst were stirred under a hydrogen atmosphere at room temperature for 4 hours. The catalyst was filtered off and the acetic acid was evaporated. The resulting colorless liquid was dissolved in ethyl acetate and washed three times with water. Evaporation of ethyl acetate gave a white solid (2.64 g, 9 mmol).
e. Priprava 2,4-diamino-5-(2A5-triklorofenil)-6-metilpirimidinae. Preparation of 2,4-diamino-5- (2A5-trichlorophenyl) -6-methylpyrimidine
2,4-diamino-5-(5-amino-2,4-diklorofenil)-6-metilpirimidin (1,95 g, 7 mmol) raztopimo v zmesi koncentrirane klorovodikove kisline (3,6 ml) in vode (6 ml). Temperatura se zniža na 10°C. Močno ohlajeno vodno raztopino (3,6 ml) natrijevega nitrita (0,50 g, 7 mmol) dodamo z dokapavanjem ob vzdrževanju temperature na 10°C. To zmes mešamo na sobni temperaturi 2 uri, nato jo močno ohladimo predno jo dodatmo z dokapavanjem v hladno raztopino bakrovega klorida (1,7 g, 17 mmol) v koncentrirani klorovodikovi kislini (50 ml). Obori se siva snov, ki jo odfiltriramo in posušimo. Surov produkt (2,30 g) raztopimo v etilacetatu in speremo dvakrat z raztopino amonijevega hidroksida in enkrat s slanico. Po uparitvi etilacetata dobimo belkasto snov (2,04 g). Po rekristalizaciji iz 10% metanola v kloroformu dobimo čist produkt (0,55 g, 2 mmol), tal. 262°C (razpad).2,4-Diamino-5- (5-amino-2,4-dichlorophenyl) -6-methylpyrimidine (1.95 g, 7 mmol) was dissolved in a mixture of concentrated hydrochloric acid (3.6 ml) and water (6 ml). . The temperature is lowered to 10 ° C. A strongly cooled aqueous solution (3.6 ml) of sodium nitrite (0.50 g, 7 mmol) was added dropwise while maintaining the temperature at 10 ° C. This mixture was stirred at room temperature for 2 hours, then cooled strongly before being added dropwise to a cold solution of copper chloride (1.7 g, 17 mmol) in concentrated hydrochloric acid (50 ml). The precipitate is grayed out, which is filtered off and dried. The crude product (2.30 g) was dissolved in ethyl acetate and washed twice with ammonium hydroxide solution and once with brine. Evaporation of ethyl acetate gave a whitish substance (2.04 g). Recrystallization from 10% methanol in chloroform gave the pure product (0.55 g, 2 mmol), m.p. 262 ° C (decomposition).
Primer 58Example 58
Sinteza 4-amino-2-(etilamino)-5-(2,3,5-triklorofenil)pirimidinaSynthesis of 4-amino-2- (ethylamino) -5- (2,3,5-trichlorophenyl) pyrimidine
K raztopini NaOEt (iz 0,1 g natrija v etanolu (10 ml) dodamo etilgvanidin-sulfat (1 g) (Aldrich). Po mešanju 10 minut dodamo enolni eter (primer 3.2) (0,486 g) in zmes mešamo na refluksu 4 ure. Zmes pustimo, da stoji preko noči na sobni temperaturi in jo nato filtriramo. Filtrat koncentriramo. Ostanek prečistimo s kromatografijo na SiO2 gelu, ob eluaciji s CHCLj, tako da dobimo želeni produkt. 0,11 g, tal. 149-152OC.Ethylguanidine sulfate (1 g) (Aldrich) was added to a solution of NaOEt (0.1 g of sodium in ethanol (10 ml). After stirring for 10 minutes, enol ether (Example 3.2) (0.486 g) was added and the mixture was refluxed for 4 hours The mixture was allowed to stand at room temperature overnight and then filtered, the filtrate was concentrated, the residue was purified by chromatography on SiO 2 gel, eluting with CHCl3 to give the desired product, 0.11 g, mp 149-152 O C.
Primer 59Example 59
2,4-diamino-5-(2,4-diklorofenil)-6-cianometil-pirimidin2,4-Diamino-5- (2,4-dichlorophenyl) -6-cyanomethyl-pyrimidine
To spojino dobimo iz 2,4-diamino-5-(2,4-diklorofenil)-6-bromometil-pirimidina (primer 53) z reakcijo z natrijevim cianidom v DMF pri sobni temperaturi. Tal. 249251°C.This compound was obtained from 2,4-diamino-5- (2,4-dichlorophenyl) -6-bromomethyl-pyrimidine (Example 53) by reaction with sodium cyanide in DMF at room temperature. Tal. 249251 ° C.
Primer 60Example 60
2.4- diamino-5-(2,4-diklorofenil)-6-dimetilaminometil-pirimidin2,4-diamino-5- (2,4-dichlorophenyl) -6-dimethylaminomethyl-pyrimidine
To spojino dobimo iz 2,4-diamino-5-(2,4-diklorofenil)-6-bromometil-pirimidina (primer 53) z reakcijo z dimetilaminom v etanolu pri sobni temperaturi. Tal. 170172°C.This compound was obtained from 2,4-diamino-5- (2,4-dichlorophenyl) -6-bromomethyl-pyrimidine (Example 53) by reaction with dimethylamine in ethanol at room temperature. Tal. 170172 ° C.
Primer 61Example 61
2.4- diamino-5-(2,4-diklorofenil)-6-ciano-pirimidin2,4-diamino-5- (2,4-dichlorophenyl) -6-cyano-pyrimidine
To spojino dobimo iz spojine iz primera 48 z reakcijo s trifluoroocetnim anhidridu v pirimidinu. Tal. 249°C.This compound is obtained from the compound of Example 48 by reaction with trifluoroacetic anhydride in pyrimidine. Tal. 249 ° C.
Primer 62Example 62
2.4- diamino-5-(2-kloro-4-fluorofenil)-6-metilpirimidin2.4-diamino-5- (2-chloro-4-fluorophenyl) -6-methylpyrimidine
To spojino dobimo na enak način kot spojino iz primera 15 iz 2-kloro-4fluorofenilacetonitrila, ki ga dobimo iz 2-kloro-4-fluorotoluena (Aldrich). Tal. 238°C.This compound was obtained in the same manner as the compound of Example 15 from 2-chloro-4fluorophenylacetonitrile obtained from 2-chloro-4-fluorotoluene (Aldrich). Tal. 238 ° C.
Primer 63Example 63
2.4- diamino-5-(3,4-diklorofenil)-6-metoksimetil pirimidin2,4-Diamino-5- (3,4-dichlorophenyl) -6-methoxymethyl pyrimidine
To spojino dobimo na analogen način kot spojino iz primera 2 iz 3,4diklorofenilacetonitrila (Aldrich). Tal. 204-206°C.This compound was obtained in an analogous manner as the compound of Example 2 from 3,4-dichlorophenylacetonitrile (Aldrich). Tal. 204-206 ° C.
Primer 64Example 64
2,4-diamino-5-(2,3-diklorofenil)-6-etil pirimidin2,4-Diamino-5- (2,3-dichlorophenyl) -6-ethyl pyrimidine
To spojino dobimo na analogen način kot spojino iz primera 15 iz etil-propionata. Tal. 228-230°C.This compound was obtained in an analogous manner as the compound of Example 15 from ethyl propionate. Tal. Mp 228-230 ° C.
Primer 65Example 65
2.4- diamino-5-(2,4-difluorofenil)-6-metil pirimidin2,4-Diamino-5- (2,4-difluorophenyl) -6-methyl pyrimidine
To spojino dobimo na analogen način kot spojino iz primera 6 iz 2,4difluorofenilacetonitrila (Aldrich). Tal. 291-296°C.This compound was obtained in an analogous manner as the compound of Example 6 from 2,4difluorophenylacetonitrile (Aldrich). Tal. 291-296 ° C.
Primer 66Example 66
2.4- diamino-5-(2-naftilj-6-metilpirimidin2,4-Diamino-5- (2-naphthyl-6-methylpyrimidine
To spojino dobimo na analogen način kot spojino iz primera 6 iz 2-naftilacetonitrila (Aldrich). Tal. 221-222°C.This compound was obtained in an analogous manner as the compound of Example 6 from 2-naphthylacetonitrile (Aldrich). Tal. Mp 221-222 ° C.
Primer 67Example 67
2.4- diamino-5-(l-naftil)-6-metilpirimidin2,4-Diamino-5- (1-naphthyl) -6-methylpyrimidine
To spojino dobimo na analogen način kot spojino iz primera 6 iz 1-naftilacetonitrila (Aldrich). Tal. 224-225°C.This compound was obtained in an analogous manner as the compound of Example 6 from 1-naphthylacetonitrile (Aldrich). Tal. 224-225 ° C.
Primer 68Example 68
2-hidroksi-4-amino-5-(2,3-diklorofenil)pirimidin2-hydroxy-4-amino-5- (2,3-dichlorophenyl) pyrimidine
To spojino dobimo iz spojine iz primera 21 z reakcijo z natrijevim nitritom v IN H2SO4 pri refluksu, tako da dobimo zmes naslovne spojine in spojine iz primera 21B.d. Naslovno spojino ločimo s kromatografijo na koloni. Tal. 330-334°C.This compound is obtained from the compound of Example 21 by reaction with sodium nitrite in IN H 2 SO 4 at reflux to give a mixture of the title compound and the compound of Example 21B.d. The title compound was separated by column chromatography. Tal. Mp 330-334 ° C.
Primer 69Example 69
2-amino-4-etoksi-5-(2,4-diklorofenil)-6-metiltiopirimidin2-amino-4-ethoxy-5- (2,4-dichlorophenyl) -6-methylthiopyrimidine
To spojino dobimo iz spojine iz primera 32.4 z reakcijo z metantiolnatrijevo soljo v etanolu. Tal. 123-124°C.This compound is obtained from the compound of Example 32.4 by reaction with the methanethiol sodium salt in ethanol. Tal. 123-124 ° C.
Primer 70Example 70
2.4- diamino-5-f2,3,5-triklorofenil)-6-hidroksimetilpirimidin2.4-diamino-5-f2,3,5-trichlorophenyl) -6-hydroxymethylpyrimidine
To spojino dobimo iz spojine iz primera 2 z reakcijo s trimetilsilil jodidom v sulfolanu na 80°C. Tal. 101-105°C.This compound is obtained from the compound of Example 2 by reaction with trimethylsilyl iodide in sulfolane at 80 ° C. Tal. 101-105 ° C.
Primer 71Example 71
2.4- diamino-5-(2,3,5-triklorofenil)-6-fluorometilpirimidin2,4-Diamino-5- (2,3,5-trichlorophenyl) -6-fluoromethylpyrimidine
To spojino dobimo na analogen način kot spojino iz primera 18 iz 2,4-diamino-5(2,3,5,-triklorofenil)-6-hidroksimetilpirimidina. Tal. 215-217°C.This compound was obtained in an analogous manner as the compound of Example 18 from 2,4-diamino-5 (2,3,5, -trichlorophenyl) -6-hydroxymethylpyrimidine. Tal. Mp 215-217 ° C.
Primer 72Example 72
2.4- diamino-5-(2,4-diklorofenil)-6-karbamoilpirimidin2,4-Diamino-5- (2,4-dichlorophenyl) -6-carbamoylpyrimidine
To spojino dobimo iz spojine iz primera 61 z reakcijo s koncentrirano žveplovo kislino pri sobni temperaturi. Tal. 298-299°C.This compound is obtained from the compound of Example 61 by reaction with concentrated sulfuric acid at room temperature. Tal. 298-299 ° C.
Primer 73Example 73
2.4- diamino-5-(2,4-diklorofenil)pirimidin-6-karboksilna kislina2,4-Diamino-5- (2,4-dichlorophenyl) pyrimidine-6-carboxylic acid
To spojino dobimo iz spojine iz primera 46 z reakcijo s kalijevim permanganatom. Tal. 227°C.This compound is obtained from the compound of Example 46 by reaction with potassium permanganate. Tal. 227 ° C.
Primer 74Example 74
Etil-2,4-diamino-5-(2,4-diklorofenil)pirimidin-6-karboksilatEthyl-2,4-diamino-5- (2,4-dichlorophenyl) pyrimidine-6-carboxylate
To spojino dobimo iz spojine iz primera 73 z refluktiranjem v etanolu v prisotnosti koncentrirane žveplene kisline. Tal. 177,5°C.This compound was obtained from the compound of Example 73 by refluxing in ethanol in the presence of concentrated sulfuric acid. Tal. 177.5 ° C.
Primer 75Example 75
2,4-diamino-5-(2,3-diklorofenil)-6-dibromometilpirimidin2,4-Diamino-5- (2,3-dichlorophenyl) -6-dibromomethylpyrimidine
To spojino dobimo iz spojine iz primera 15 z reakcijo z dvema ekvivalentoma NBS v CC14 in AIBN kot iniciatoijem. Naslovno spojino ločimo od zmesi s spojino iz Primera 43 s kromatografijo na koloni. Tal. 270°C (razpad).This compound is obtained from the compound of Example 15 by reaction with two equivalents of NBS in CC1 4 and AIBN as the initiator. The title compound was separated from the mixture with the compound of Example 43 by column chromatography. Tal. 270 ° C (decomposition).
Primer 76Example 76
2-dimetilamino-4-amino-5-(2,4-diklorofenil)pirimidin2-dimethylamino-4-amino-5- (2,4-dichlorophenyl) pyrimidine
To spojino dobimo na analogen način kot spojino iz primera 10 iz 2,4diklorofenilacetonitrila (Aldrich). Tal. 151°C.This compound was obtained in an analogous manner as the compound of Example 10 from 2,4-dichlorophenylacetonitrile (Aldrich). Tal. 151 ° C.
Primer 77Example 77
2-dimetilamino-4-amino-5-(3,4-diklorofenil)-6-metilpirimidin2-dimethylamino-4-amino-5- (3,4-dichlorophenyl) -6-methylpyrimidine
To spojino dobimo na analogen način kot spojino iz primera 13 iz 3,4diklorofenilacetonitrila.This compound was obtained in an analogous manner as the compound of Example 13 from 3,4-dichlorophenylacetonitrile.
Primer 78Example 78
2-N-pfperidil-4-amino-5-(2,4-diklorofenil)pirimidin2-N-Piperidyl-4-amino-5- (2,4-dichlorophenyl) pyrimidine
To spojino dobimo na analogen način kot spojino iz primera 76 izThis compound was obtained in an analogous manner as the compound of Example 76 from
1- piperidinkarboksamidin-sulfata (Bader). Tal. 169°C.1- piperidinecarboxamidine sulfate (Bader). Tal. 169 ° C.
Primer 79Example 79
2- metilamino-4-amino-5-(2,3,5-triklorofenil)pirimidin2-methylamino-4-amino-5- (2,3,5-trichlorophenyl) pyrimidine
To spojino dobimo na analogen način kot spojino iz primera 58 iz 1-metil-gvanidin hidroklorida (Aldrich). Tal. 155M57C.This compound was obtained in an analogous manner as the compound of Example 58 from 1-methyl-guanidine hydrochloride (Aldrich). Tal. 155M57C.
Primer 80Example 80
2.4- diamino-5-(2-kloro-5-bromofenil)-6-metilpirimidin2.4-diamino-5- (2-chloro-5-bromophenyl) -6-methylpyrimidine
To spojino dobimo na analogen način kot spojino iz primera 54 z reakcijo diazonijeve soli z bakrovim bromidom. Tal. 212°-216°C.This compound was obtained in an analogous manner as the compound of Example 54 by reaction of the diazonium salt with copper bromide. Tal. 212 ° -216 ° C.
Primer 81Example 81
2.4- diamino-5-(2-kloro-5-iodofenil)-6-metilpirimidm2,4-Diamino-5- (2-chloro-5-iodophenyl) -6-methylpyrimidine
To spojino dobimo na podoben način kot spojino iz primera 54 z reakcijo diazonijeve soli s kalijevim jodidom. Tal. 232°-234°C.This compound was obtained in a similar manner to the compound of Example 54 by reaction of the diazonium salt with potassium iodide. Tal. 232 ° -234 ° C.
Primer 82Example 82
2.4- diamino-5-(2-kloro-5-cianofenil)-6-metilpirimidin2.4-diamino-5- (2-chloro-5-cyanophenyl) -6-methylpyrimidine
To spojino dobimo na podoben način kot spojino iz primera 54 z reakcijo diazonijeve soli z bakrovim cianidom. Tal. 239°-241°C.This compound was obtained in a similar manner to the compound of Example 54 by reaction of the diazonium salt with copper cyanide. Tal. 239 ° -241 ° C.
Primer 83Example 83
2.4- diamino-5-(2-kloro-5-fluorofenil)-6-metilpirimidin2.4-diamino-5- (2-chloro-5-fluorophenyl) -6-methylpyrimidine
To spojino dobimo na podoben način kot spojino iz primera 54 s pomočjo diazonijeve tetrafluoroboratne soli. Tal. 195°-197°C.This compound was obtained in a similar manner to the compound of Example 54 using a diazonium tetrafluoroborate salt. Tal. 195 ° -197 ° C.
Primer 84Example 84
2,4-diamino-5-(2-kloro-5-metiltiofenil)-6-metilpirimidin2,4-Diamino-5- (2-chloro-5-methylthiophenyl) -6-methylpyrimidine
To spojino dobimo na podoben način kot spojino iz primera 54 z reakcijo diazonijeve soli z metantiolom v prisotnosti bakra v prahu. Tal. 194°-198°C.This compound was obtained in a similar manner to the compound of Example 54 by reaction of the diazonium salt with methanethiol in the presence of powdered copper. Tal. 194 ° -198 ° C.
Primer 85Example 85
2-amino-4.6-di-(metiltio)-5-(2.4-diklorofenil)pirimidin2-amino-4,6-di- (methylthio) -5- (2,4-dichlorophenyl) pyrimidine
To spojino dobimo iz spojine iz primera 32.4 z reakcijo z metantiolnatrijevo soljo v metanolu v prisotnosti tris[2-(2-metoksietoksi)etil]amina in bakra v prahu. Tal. 164°-165°C.This compound is obtained from the compound of Example 32.4 by reaction with the methanethiol sodium salt in methanol in the presence of tris [2- (2-methoxyethoxy) ethyl] amine and copper powder. Tal. 164 ° -165 ° C.
Primer 86Example 86
2.4- diamino-5-(2-kloro-5-metansulfonilaminofenil)-6-metilpirimidin2.4-diamino-5- (2-chloro-5-methanesulfonylaminophenyl) -6-methylpyrimidine
To spojino dobimo iz 2,4-diamino-5-(2-kloro-5-aminofeml)-6-metilpirimidina iz Primera 54 z reakcijo z metansulfonilkloridom v pirimidinu. Tal.: 234°-240°C.This compound was obtained from 2,4-diamino-5- (2-chloro-5-aminophenyl) -6-methylpyrimidine from Example 54 by reaction with methanesulfonyl chloride in pyrimidine. Melting point: 234 ° -240 ° C.
Primer 87Example 87
2.4- diamino-5-(2,3-diklorofenill-l-metilpirimidimieviodid2,4-Diamino-5- (2,3-dichlorophenyl-1-methylpyrimidimidioiodide
To spojino dobimo iz spojine iz primera 21 in metiljodida. Tal.: 280°-284°C.This compound is obtained from the compound of Example 21 and methyl iodide. M.p .: 280 ° -284 ° C.
Primer 88Example 88
2-amino-4-metilamino-5-(2,3-diklorofenil)pirimidin2-amino-4-methylamino-5- (2,3-dichlorophenyl) pyrimidine
To spojino dobimo na analogen način kot spojino iz primera 21B.g z reakcijo z metilaminom v etanolu. Tal.: 233°-237°C.This compound was obtained in an analogous manner as the compound of Example 21B.g by reaction with methylamine in ethanol. Melting point: 233 ° -237 ° C.
Primer 89Example 89
2-amino-4-dimetilamino-5-(2,3-diklorofenil)pirimidin klorohidrat2-amino-4-dimethylamino-5- (2,3-dichlorophenyl) pyrimidine chlorohydrate
To spojino dobimo na analogen način kot spojino iz primera 21B.g z reakcijo z dimetilaminom v etanolu in naknadno pretvorbo v hidrokloridno sol. Tal.: 295°300°C.This compound was obtained in an analogous manner as the compound of Example 21B.g by reaction with dimethylamine in ethanol and subsequent conversion to the hydrochloride salt. Melting point: 295 ° 300 ° C.
Primer 90Example 90
2-amino-4-kloro-5-(2,4-diklorofenil)pirimidin2-amino-4-chloro-5- (2,4-dichlorophenyl) pyrimidine
To spojino dobimo na analogen način kot spojino iz primera 21B.f iz 5-(2,4diklorofenil)izocitozina. Tal.: 215°-216°C.This compound was obtained in an analogous manner as the compound of Example 21B.f from 5- (2,4-dichlorophenyl) isocytosine. M.p .: 215 ° -216 ° C.
Primer 91Example 91
2-amino-4-metilamino-5-(2,4-diklorofenil)pirimidin2-amino-4-methylamino-5- (2,4-dichlorophenyl) pyrimidine
To spojino dobimo iz spojine iz primera 90 z reakcijo z metilaminom v etanolu. Tal.: 189°-190°C.This compound is obtained from the compound of Example 90 by reaction with methylamine in ethanol. M.p .: 189 ° -190 ° C.
Primer 92Example 92
2-amino-4-dimetilamino-5-(2.4-diklorofenil)pirimidin hidroklorid2-amino-4-dimethylamino-5- (2,4-dichlorophenyl) pyrimidine hydrochloride
To spojino dobimo iz spojine iz primera 90 z reakcijo z dimetilaminom v etanolu z naknadno pretvorbo v hidrokloridno sol. Tal.: 297°-301°C.This compound is obtained from the compound of Example 90 by reaction with dimethylamine in ethanol with subsequent conversion to the hydrochloride salt. M.p .: 297 ° -301 ° C.
Primer 93Example 93
2-amino-4-piperidino-5-(2,4-diklorofenil)pirimidin hidroklorid2-amino-4-piperidino-5- (2,4-dichlorophenyl) pyrimidine hydrochloride
To spojino dobimo iz spojine iz primera 90 z reakcijo s piperidinom v etanolu in naknadno pretvorbo v hidrokloridno sol. Tal.: 303°C (razp.).This compound is obtained from the compound of Example 90 by reaction with piperidine in ethanol and subsequent conversion to the hydrochloride salt. M.p .: 303 ° C (dec).
Med spojinami formule (I) so prednostni pirimidini predhodnih primerov 1,2,3,4,14 in 16 skupaj z njihovimi solmi (zlasti farmacevtsko sprejemljivimi solmi); te baze imajo naslednje ustrezne dvodimenzionalne strukture.Among the compounds of formula (I), the preferred pyrimidines of the preceding examples are 1,2,3,4,14 and 16 together with their salts (especially pharmaceutically acceptable salts); these bases have the following corresponding two-dimensional structures.
Primer 1Example 1
Primer 2Example 2
Primer 3Example 3
CICI
Primer 4Example 4
CICI
Primer 14Example 14
Tabela Ή NMR podatkov (δ)Table Ή NMR data (δ)
(dd,lH,07.5Hz), 7.64(dd,lH, 07.5, 1.0Hz)(dd, 1H, 07.5Hz), 7.64 (dd, 1H, 07.5, 1.0Hz)
DMSO-dg 4.43(d,lH,JllHz), 4.53(d,lH,JllHz),DMSO-dg 4.43 (d, 1H, JllHz), 4.53 (d, 1H, JllHz),
5.95(br.s,2H), 6.12(br.s,2H),5.95 (br.s, 2H), 6.12 (br.s, 2H),
6.7(m,2H), 6.85(dd,lH,J7Hz),6.7 (m, 2H), 6.85 (dd, 1H, J 7 Hz),
7.1-7.4(m,4H), 7.55(dd,IH,07,1Hz).7.1-7.4 (m, 4H), 7.55 (dd, 1H, 07.1Hz).
DMSO-dg 4.4(d,lH,012Hz,-CH2OPh), 4.52(d,lH,DMSO-dg 4.4 (d, 1H, 012Hz, -CH 2 OPh), 4.52 (d, 1H,
012Hz, -CH20Ph), 5.92(br.s,2H,-NH2), 6.12(br.s,2H, -NH2), 6.69(dd,IH,07.5, 1.0Hz,6'-H), 6.85(dd,IH,07.5Hz,5'-H), 7.10-7.35 (m,5H,-OPh), 7.55(dd,IH,07.5, 1.0Hz,4'-H)012Hz, -CH 2 0Ph), 5.92 (br.s, 2H, -NH 2 ), 6.12 (br.s, 2H, -NH 2 ), 6.69 (dd, 1H, 07.5, 1.0Hz, 6'-H) , 6.85 (dd, 1H, 07.5Hz, 5'-H), 7.10-7.35 (m, 5H, -OPh), 7.55 (dd, 1H, 07.5, 1.0Hz, 4'-H)
DMSO-dg 7.52(s,lH), 7.15-7.75(τη,3H),DMSO-dg 7.52 (s, 1H), 7.15-7.75 (τη, 3H),
6.02(br.s,4H,2x-NH2)6.02 (Nos, 4H, 2x-NH 2 )
DMSO-dg 6.07(s,2H), 6.25(s,2H), 7.25(d,lH),DMSO-dg 6.07 (s, 2H), 6.25 (s, 2H), 7.25 (d, 1H),
7.45(d,lH), 7.63(s,lH)7.45 (d, 1H), 7.63 (s, 1H)
DMSO-dg 3.88(d,lH,011Hz), 4.0(d,IH,011Hz),DMSO-dg 3.88 (d, 1H, 011Hz), 4.0 (d, 1H, 011Hz),
4.3(s,2H), 5.9(br.s,2H), 6.1(br.s,2H), 7.05-7.2(m,2H), 7.2-7.35(m,4H), 7.4(dd,lH,08,2.5Hz), 7.62(d,lH,02.5Hz)4.3 (s, 2H), 5.9 (br.s, 2H), 6.1 (br.s, 2H), 7.05-7.2 (m, 2H), 7.2-7.35 (m, 4H), 7.4 (dd, 1H, 08 , 2.5Hz), 7.62 (d, 1H, 02.5Hz)
DMSO-dg 6.25(s,2H), 6.50(s,2H), 7.30(s,lH),DMSO-dg 6.25 (s, 2H), 6.50 (s, 2H), 7.30 (s, 1H),
7.40(d,lH), 7.50(d,lH)7.40 (d, 1H), 7.50 (d, 1H)
DMSO-dg 5.85(s,2H), 6.1(s,2H), 7.25(s,lH),DMSO-dg 5.85 (s, 2H), 6.1 (s, 2H), 7.25 (s, 1H),
7.45(s,lH), 7.7(s,lH)7.45 (s, 1H), 7.7 (s, 1H)
CDC13 7.53-7.12(m,4H), 4.48-4.30(br.s,2H),CDC1 3 7.53-7.12 (m, 4H), 4.48-4.30 (br.s, 2H),
3.81(t,4H), 2.46(t,4H), 2.33(s,3H), 2.03(s,3H)3.81 (t, 4H), 2.46 (t, 4H), 2.33 (s, 3H), 2.03 (s, 3H)
CDC13 7.38(d,lH), 7.2(dd,lH), 7.08(d·,IH),CDCl 3 3 7.38 (d, 1H), 7.2 (dd, 1H), 7.08 (d ·, 1H),
8.2(br.s,2H)8.2 (No.s, 2H)
DMSO-dg 7.7(d,lH), 7.48(dd,lH), 7.29(d,lH),DMSO-dg 7.7 (d, 1H), 7.48 (dd, 1H), 7.29 (d, 1H),
6.45(br.s,2H), 6.2(br.s,2H)6.45 (no.s, 2H), 6.2 (no.s, 2H)
CDC13 7.5(d,lH), 7.35(dd,lH), 7.18(d,lH),CDCl 3 3 7.5 (d, 1H), 7.35 (dd, 1H), 7.18 (d, 1H),
5.25(br.s,2H), 2.44(s,3H)5.25 (br.s, 2H), 2.44 (s, 3H)
CDC13 7.52(d,lH), 7.32(dd,lH), 7.21(d,lH),CDCl 3 3 7.52 (d, 1H), 7.32 (dd, 1H), 7.21 (d, 1H),
5.08(br.s,2H), 4.66(br.s,2H), 2.42(s,3H)5.08 (br.s, 2H), 4.66 (br.s, 2H), 2.42 (s, 3H)
DMSO-dg 1.9(s,3H,6-CH3), 2.2(s,3H,N-Me),DMSO-d 1.9 (s, 3H, 6-CH 3), 2.2 (s, 3H, N-Me);
2.25-2.40(m,4H,-N N-), 3.55-3.75 (m,4H,-N N-), 5.85(2H,br.s,-NH2), 7.2(d,2H,J1.5Hz,2',6'-H), 7.52tdd,lH, J1.5Hz,4'-H)2.25-2.40 (m, 4H, -N N-), 3.55-3.75 (m, 4H, -N N-), 5.85 (2H, br.s, -NH 2 ), 7.2 (d, 2H, J1.5Hz , 2 ', 6'-H), 7.52tdd, 1H, J1.5Hz, 4'-H)
DMSO-dg 7.53(dd,lH), 7.45(dd,lH), 7.35(d,lH),DMSO-dg 7.53 (dd, 1H), 7.45 (dd, 1H), 7.35 (d, 1H),
7.24(br.s,lH), 3.35(br.s,2H), 3.96(br.s,2H)7.24 (br.s, 1H), 3.35 (br.s, 2H), 3.96 (br.s, 2H)
DMSO-dg 1.8(s,3H), 5.8(s,2H), 5.95(s,2H),DMSO-dg 1.8 (s, 3H), 5.8 (s, 2H), 5.95 (s, 2H),
7.53(s,lH), 7.92(s,lH)7.53 (s, 1H), 7.92 (s, 1H)
DMSO-dg 7.78(d,lH), 7.59(s,lH), 7.36(d,lH),DMSO-dg 7.78 (d, 1H), 7.59 (s, 1H), 7.36 (d, 1H),
6.60-6.47(br.t,lH), 6.25-6.03(br.s,2H), 3.25(q,2H), l.l(t,3H)6.60-6.47 (br.t, 1H), 6.25-6.03 (br.s, 2H), 3.25 (q, 2H), l.l (t, 3H)
V predhodni tabeli so uporabljene okrajšave kot sledi: s = singlet, d = dublet; dd = dublet dubleta; t = triplet; q = kvadriplet; m = multiplet; br.s = širok singlet; br.t = širok triplet.The preceding table uses abbreviations as follows: s = singlet, d = doublet; dd = doublet doublet; t = triplet; q = quadriplet; m = multiplet; br.s = wide singlet; br.t = wide triplet.
Farmakološka aktivnostPharmacological activity
Inhibiranie sproščanja glutamata in inhibiranie DHFR jeter podganInhibition of glutamate release and inhibition of rat DHFR
Spojine s formulo (I) testiramo na njihov učinek na sproščanje glutamata, ki je izzvano z veratrinom, iz rezin možgan podgan po protokolu, ki je opisan v Epilepisa 27(5): 490-497,1986. Protokol za inhibiranje DHFR aktivnosti je bil modifikacija tistega, kije prikazan v Biochemical Pharmacology Vol. 20 str. 561-574,1971.The compounds of formula (I) are tested for their effect on the release of veratrin-induced glutamate from rat brain slices according to the protocol described in Epilepis 27 (5): 490-497,1986. The protocol for inhibiting DHFR activity was a modification of the one shown in Biochemical Pharmacology Vol. 20 p. 561-574,1971.
Rezultati so podani v tabeli 1, pri čemer je IC50 koncentracija spojine, ki izzove 50% inhibiranje (a) sproščanja glutamata, ki je izzvano z veratrinom in (b) aktivnosti DHFR encima.The results are given in Table 1, with IC 50 being the concentration of a compound that causes 50% inhibition of (a) the release of glutamate induced by veratrin and (b) the activity of the DHFR enzyme.
TABELA 1TABLE 1
Toksikološki primerToxicological example
Spojino iz primera 1 dajemo intravenozno skupinam po Šest samcev in 6 samic Wistar podgan enkrat dnevno z doznimi nivoji do 15 mg/kg/dan. Doza neopaženega učinka je bila 2,5 mg/kg/dan.The compound of Example 1 was administered intravenously to groups of Six males and 6 Wistar rats once daily with dosage levels up to 15 mg / kg / day. The dose of the undetected effect was 2.5 mg / kg / day.
Spojino iz primera 2 testiramo tako na podganah kot na psih. Na podganah je bila doza neopaženega učinka 2,5 mg/kg/dan, na psih pa nismo opazili učinka doze pri 14 mg/kg/dan.The compound of Example 2 was tested in both rats and dogs. In rats, the dose of the observed effect was 2.5 mg / kg / day and no effect of the dose was observed in dogs at 14 mg / kg / day.
Primer farmacevtske formulacijeAn example of a pharmaceutical formulation
A: TABLETAA: TABLET
SESTAVINAINGREDIENT
Spojina iz primera 1 150 mg)Compound of Example 1 150 mg)
Laktoza 200 mg)Lactose 200 mg)
Koruzni škrob 50 mg)Corn starch 50 mg)
Polivinilpirolidon 4 mg)Polyvinylpyrrolidone 4 mg)
Magnezijev stearat 4 mg) ) = vsebina na tableto.Magnesium stearate 4 mg)) = content per tablet.
Zdravilo zmešamo z laktozo in škrobom in granuliramo z raztopino polivinilpirolidona v vodi. Dobljene granule posušimo, zmešamo z magnezijevim stearatom in stisnemo, tako da dobimo tablete.The product is mixed with lactose and starch and granulated with a solution of polyvinylpyrrolidone in water. The obtained granules were dried, mixed with magnesium stearate and pressed to give tablets.
B: INJEKCIJA (I)B: INJECTION (I)
Sol spojine s formulo I raztopimo v sterilni vodi za injekcije.The salt of the compound of formula I is dissolved in sterile water for injection.
FORMULACIJA ZA INTRAVENOZNO INJEKCIJO (II)FORMULATION FOR INTRAVENOUS INJECTION (II)
Aktivna sestavina 0,20 gActive ingredient 0.20 g
Sterilni fosfatni pufer brez pirogena (pH 9,0) do 10 mlSterile pyrogen free phosphate buffer (pH 9.0) up to 10 ml
Spojino iz primera 1 kot sol raztopimo v večinskem delu fosfatnega pufra pri 3540°C, nato dopolnimo do potrebnega volumna in filtriramo skozi sterilen mik64 roporozen filter v sterilne steklene fiole z 10 ml (Tip 1), ki jih zapremo s sterilnim zamaškom in zatalimo.The compound of Example 1 was dissolved as a salt in most of the phosphate buffer at 3540 ° C, then made up to volume and filtered through a sterile micro64 filter into 10 ml sterile glass vials (Type 1), sealed and sealed.
V naslednjih primerih je lahko aktivna spojina katerakoli spojina s formulo (I) ali njena farmacevtsko sprejemljiva sol.In the following cases, the active compound may be any compound of formula (I) or a pharmaceutically acceptable salt thereof.
C: FORMULACIJE KAPSULC: CAPSUL FORMULATIONS
Formulacija kapsule ACapsule Formulation A
Formulacijo A lahko pripravimo z mešanjem sestavin in polnjenjem dvodelnih trdih želatinskih kapsul r dobljeno zmesjo.Formulation A can be prepared by mixing the ingredients and filling the two-part hard gelatin capsules r the resulting mixture.
mg/kapsula (a) Aktivna sestavina (b) Laktoza B.P.mg / capsule (a) Active ingredient (b) Lactose B.P.
(c) Natrijev škrobni glikolat (d) Magnezijev stearat(c) Sodium starch glycolate (d) Magnesium stearate
250250
143143
420420
Formulacija kapsule B mg/kapsula (a) Aktivna sestavina (b) Macrogel 4000 BPCapsule Formulation B mg / capsule (a) Active ingredient (b) Macrogel 4000 BP
250250
350350
600600
Kapsule lahko pripravimo s taljenjem Macrogel-a 4000 BP, dispergiranjem aktivne sestavine v raztopini in polnjenjem dvodelnih trdih želatinskih kapsul.The capsules can be prepared by melting Macrogel 4000 BP, dispersing the active ingredient in solution, and filling two-part hard gelatin capsules.
Formulacija kapsule B (kapsula z nadzorovanim sproščanjem)Capsule B formulation (controlled release capsule)
Formulacijo kapsule z nadzorovanim sproščanjem lahko pripravimo z brizganjem mešanih sestavin (a) do (c) z uporabo brizgalnika, nato sferonizacijo in sušenjem ekstrudata. Sušene granule prevlečemo z etilacelulozo (d) kot membrano za nadzorovano sproščanje in jih napolnimo v dvodelne trde želatinske kapsule.The controlled release capsule formulation can be prepared by injection of mixed ingredients (a) to (c) using a syringe, then spheronization and drying of the extrudate. The dried granules were coated with ethylcellulose (d) as a controlled release membrane and filled into two-part hard gelatin capsules.
Formulacija sirupaSyrup formulation
Aktivna sestavina 0,2500 gActive ingredient 0.2500 g
Rraztopina sorbitola 1,5000 gSorbitol solution 1,5000 g
Glicerol 1,0000 gGlycerol 1,0000 g
Natrijev benzoat 0,0050 gSodium benzoate 0.0050 g
Aroma 0,0125 mlAroma 0.0125 ml
Prečiščena voda q.s. do 5,0 mlPurified water q.s. to 5,0 ml
Natrijev benzoat raztopimo v delu prečiščene vode in dodamo raztopino sorbitola. Dodamo in raztopimo aktivno sestavino. Dobljeno raztopino zmešamo z glicerolom in nato dopolnimo do potrebnega volumna s prečiščeno vodo.Dissolve the sodium benzoate in a portion of the purified water and add the sorbitol solution. The active ingredient is added and dissolved. The resulting solution was mixed with glycerol and then made up to volume with purified water.
Formulacija svečke mg/svečkaMg / spark plug formulation
Aktivna sestavina (63 μιη)* 250Active ingredient (63 μιη) * 250
Trda maščoba, BP (Witepsol H15 - Dynamit Nobel) 1770Hard Fat, BP (Witepsol H15 - Dynamit Nobel) 1770
2020 * Aktivno sestavino uporabimo kot prah, v katerem je vsaj 90% delcev s premerom 63 μιη ali manjšim.2020 * Use the active ingredient as a powder containing at least 90% of particles 63 μιη in diameter or smaller.
Eno petino Witepsol-a H15 raztopimo v ponvi s parnim plaščem pri največ 45°C. Aktivno sestavino sifoniramo skozi sito z 200 gm in dodamo na stopljeno osnovo ob mešanju z uporabo Siversona, ki je opremljen s sekalno glavo, dokler ne dobimo gladke disperzije. Vzdrževanje zmesi na 45°C nadaljujemo ob dodajanju preostalega Witepsol-a H15 v suspenzijo, ki jo mešamo, da zagotovimo homogeno mešanico. Celotno suspenzijo nato prepustimo skozi nerjavno jekleno sito z 250 μτη in ob kontinuirnem mešanju pustimo, da se ohladi na 40°C. Pri temperaturi 38-40°C napolnimo alikvote 2,02 g zmesi v primerne plastične kalupe in pustimo, da se svečke ohladijo na sobno temperaturo.Dissolve one-fifth of Witepsol H15 in a frying pan at a maximum of 45 ° C. The active ingredient was siphoned through a 200 gm sieve and added to the molten base while stirring using Siverson equipped with a chopping head until a smooth dispersion was obtained. Continue to maintain the mixture at 45 ° C while adding the remaining Witepsol H15 to the suspension, which was stirred to ensure a homogeneous mixture. The whole suspension was then passed through a stainless steel sieve of 250 μτη and allowed to cool to 40 ° C with continuous stirring. At 38-40 ° C, aliquots of 2.02 g of the mixture are filled into suitable plastic molds and allowed to cool to room temperature.
Claims (36)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB898908561A GB8908561D0 (en) | 1989-04-14 | 1989-04-14 | Pharmaceutically active cns compounds |
YU60790A YU47557B (en) | 1989-04-14 | 1990-03-28 | PROCEDURE FOR OBTAINING 5-PHENYLPYRIMIDINE COMPOUNDS AND THEIR SALTS |
Publications (2)
Publication Number | Publication Date |
---|---|
SI9010607A true SI9010607A (en) | 1997-06-30 |
SI9010607B SI9010607B (en) | 2006-06-30 |
Family
ID=10655105
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SI9010607A SI9010607B (en) | 1989-04-14 | 1990-03-28 | Pharmacologically active cns compounds |
Country Status (5)
Country | Link |
---|---|
CZ (1) | CZ287351B6 (en) |
GB (1) | GB8908561D0 (en) |
HR (1) | HRP940540B1 (en) |
SI (1) | SI9010607B (en) |
YU (1) | YU47557B (en) |
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1989
- 1989-04-14 GB GB898908561A patent/GB8908561D0/en active Pending
-
1990
- 1990-03-28 SI SI9010607A patent/SI9010607B/en not_active IP Right Cessation
- 1990-03-28 YU YU60790A patent/YU47557B/en unknown
-
1994
- 1994-09-16 HR HR940540A patent/HRP940540B1/en not_active IP Right Cessation
-
1998
- 1998-12-07 CZ CZ19984011A patent/CZ287351B6/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
HRP940540A2 (en) | 1996-08-31 |
YU47557B (en) | 1995-10-03 |
GB8908561D0 (en) | 1989-06-01 |
CZ287351B6 (en) | 2000-10-11 |
YU60790A (en) | 1994-04-05 |
SI9010607B (en) | 2006-06-30 |
HRP940540B1 (en) | 2000-12-31 |
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Legal Events
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IF | Valid on the event date | ||
OU02 | Decision according to article 73(2) ipa 1992, publication of decision on partial fulfilment of the invention and change of patent claims |
Effective date: 20060509 |
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KO00 | Lapse of patent |
Effective date: 20060525 |