HRP20220733T1 - Neprekidni postupak za proizvodnju trazodona - Google Patents

Neprekidni postupak za proizvodnju trazodona Download PDF

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HRP20220733T1
HRP20220733T1 HRP20220733TT HRP20220733T HRP20220733T1 HR P20220733 T1 HRP20220733 T1 HR P20220733T1 HR P20220733T T HRP20220733T T HR P20220733TT HR P20220733 T HRP20220733 T HR P20220733T HR P20220733 T1 HRP20220733 T1 HR P20220733T1
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chlorophenyl
piperazine
group
continuous
flow reactor
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HRP20220733TT
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Tommaso Iacoangeli
Leonardo Mario MORO
Giuliano Caracciolo Torchiarolo
Claudia CAVARISCHIA
Guido Furlotti
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Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
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    • B01J19/18—Stationary reactors having moving elements inside
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00002—Chemical plants
    • B01J2219/00027—Process aspects
    • B01J2219/00029—Batch processes
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00002—Chemical plants
    • B01J2219/00027—Process aspects
    • B01J2219/00033—Continuous processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00788—Three-dimensional assemblies, i.e. the reactor comprising a form other than a stack of plates
    • B01J2219/00792—One or more tube-shaped elements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00801—Means to assemble
    • B01J2219/0081—Plurality of modules
    • B01J2219/00813—Fluidic connections
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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    • B01J8/24—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes with fluidised particles according to "fluidised-bed" technique

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Claims (25)

1. Neprekidni postupak za proizvodnju trazodon baze (IV), naznačen time, da proizlazi iz N-(3-klorofenil)-N'-(3-kloropropil)-piperazina (II) i s-triazolo-[4,3-a]-piridin-3-ona (III), u skladu s reakcijskom shemom 2: [image] , pri čemu obuhvaća neprekidno miješanje alkalne vodene otopine od s-triazolo-[4,3-a]-piridin-3-ona (III), i organske otopine od N-(3-klorofenil)-N'-(3-kloropropil)-piperazina (II), u protočnom reaktoru, i neprekidno dobivanje trazodon baze (IV).
2. Neprekidni postupak prema patentnom zahtjevu 1, naznačen time, da obuhvaća sljedeće korake: (i) neprekidna opskrba prvog kanala protočnog reaktora s vodenom otopinom od s-triazolo-[4,3-a]-piridin-3-ona (III), i najmanje jednim bazičnim spojem; (ii) neprekidna opskrba drugog kanala spomenutog protočnog reaktora s organskom otopinom od N-(3-klorofenil)-N'-(3-kloropropil)-piperazina (II), u najmanje jednom organskom otapalu; (iii) neprekidna reakcija navedenog s-triazolo-[4,3-a]-piridin-3-ona (III) s navedenim N-(3-klorofenil)-N'-(3-kloropropil)-piperazinom (II), pomoću neprekidnog miješanja navedene alkalne vodene otopine i navedene organske otopine u spomenutom protočnom reaktoru, na temperaturi od najmanje 90 °C; i (iv) neprekidno sakupljanje navedene reakcijske emjese iz spomenutog protočnog reaktora, te izoliranje dobivenog proizvoda trazodon baze (IV).
3. Postupak prema bilo kojem od patentnih zahtjeva 1-2, naznačen time, da se trazodon baza (IV) dobiva s iskoristivim prinosom od najmanje 70% putem HPLC.
4. Postupak prema bilo kojem od patentnih zahtjeva 1-3, naznačen time, da trazodon baza (IV) posjeduje čistoću od najmanje 90% putem HPLC.
5. Postupak prema bilo kojem od patentnih zahtjeva 2-4, naznačen time, da vrijeme boravka neprekidne reakcije u skladu s korakom iii), iznosi od 70 do 300 sekundi.
6. Postupak prema bilo kojem od patentnih zahtjeva 2-5, naznačen time, da temperatura neprekidne reakcije u skladu s korakom iii), iznosi od 130 °C do 160 °C.
7. Postupak prema bilo kojem od patentnih zahtjeva 2-6, naznačen time, da je bazični spoj u skladu s korakom i) anorganska baza odabrana iz skupine koju čine natrijev hidroksid, kalijev hidroksid, natrijev hidrid, natrijev amid, natrijev karbonat, kalijev karbonat, natrijev bikarbonat, kalijev bikarbonat, natrijev fosfat, kalijev fosfat, amonijev hidroksid, magnezijev oksid, i njihove mješavine.
8. Postupak prema patentnom zahtjevu 7, naznačen time, da se anorganska baza bira iz skupine koju čine natrijev hidroksid, kalijev hidroksid, natrijev karbonat, i njihove mješavine.
9. Postupak prema bilo kojem od patentnih zahtjeva 2-8, naznačen time, da je bazični spoj u skladu s korakom i) organska baza odabrana iz skupine koju čine alifatski i aromatski amini, i njihove mješavine.
10. Postupak prema patentnom zahtjevu 9, naznačen time, da se navedeni amini biraju iz skupine koju čine: trimetilamin, trietilamin, N,N-diizopropiletilamin, trietanolamin, N,N-dimetiletanolamin, N-metiletanolamin, i njihove mješavine.
11. Postupak prema bilo kojem od patentnih zahtjeva 2-10, naznačen time, da je organsko otapalo u skladu s korakom ii) polarno aprotično otapalo odabrano iz skupine koju čine: dimetilformamid, dimetil sulfoksid, aceton, tetrahidrofuran, acetonitril, dioksan; ili je nepolarno otapalo odabrano iz skupine koju čine: toluen, dietil eter; ili je polarno protično otapalo odabrano iz skupine koju čine: metanol, etanol, propanol, izopropanol, butilni alkohol, izobutilni alkohol, benzilni alkohol.
12. Postupak prema patentnom zahtjevu 11, naznačen time, da se organsko otapalo bira iz skupine koju čine: izobutilni alkohol, izopropanol, dioksan, i acetonitril.
13. Postupak prema bilo kojem od patentnih zahtjeva 1-12, naznačen time, da nadalje obuhvaća korak v) u kojem se trazodon baza (IV) pretvara u trazodon hidroklorid (V) i izolira, u skladu s reakcijskom shemom 3: [image] .
14. Neprekidni postupak prema bilo kojem od patentnih zahtjeva 1-13, naznačen time, da nadalje obuhvaća predreakciju m-klorofenil-piperazina (I) i 1-bromo-3-kloropropana, u N-(3-klorofenil)-N'-(3-kloropropil)-piperazin (II), u skladu s reakcijskom shemom 4: [image] .
15. Postupak prema patentnom zahtjevu 14, naznačen time, da m-klorofenil-piperazin (I) i 1-bromo-3-kloropropan, reagiraju na neprekidan način.
16. Postupak prema patentnom zahtjevu 14, naznačen time, da m-klorofenil-piperazin (I) i 1-bromo-3-kloropropan, reagiraju na periodičan način.
17. Postupak prema patentnom zahtjevu 15, naznačen time, da obuhvaća sljedeće korake: (a) neprekidna opskrba prvog kanala protočnog reaktora s m-klorofenil-piperazinom (I) i vodenom otopinom od najmanje jednog bazičnog spoja, kako bi se omogućila alkalna vodena faza; (b) neprekidna opskrba drugog kanala spomenutog protočnog reaktora s organskom fazom od 1-bromo-3-kloropropana, opcionalno u kombinaciji s najmanje jednim organskim otapalom; (c) neprekidna reakcija navedenog m-klorofenil-piperazina (I) s navedenim 1-bromo-3-kloropropanom pomoću neprekidnog miješanja navedene alkalne vodene faze i navedene organske faze u spomenutom protočnom reaktoru, na temperaturi od najmanje 70 °C; i (d) neprekidno odstranjivanje navedene reakcijske smjese iz spomenutog protočnog reaktora i izoliranje dobivenog proizvoda N-(3-klorofenil)-N'-(3-kloropropil)-piperazina (II) koji se dalje miješa s najmanje jednim organskim otapalom; (i) neprekidna opskrba prvog kanala protočnog reaktora s vodenom otopinom od s-triazolo-[4,3-a]-piridin-3-ona (III) i najmanje jednog bazičnog spoja; (ii) neprekidna opskrba drugog kanala spomenutog protočnog reaktora s organskom otopinom od N-(3-klorofenil)-N'-(3-kloropropil)-piperazina (II) i najmanje jednog organskog otapala; (iii) neprekidna reakcija navedenog s-triazolo-[4,3-a]-piridin-3-ona (III) s navedenim N-(3-klorofenil)-N'-(3-kloropropil)-piperazinom (II) pomoću neprekidnog miješanja navedene alkalne vodene otopine i navedene organske otopine u spomenutom protočnom reaktoru, na temperaturi od najmanje 90 °C; i (iv) neprekidno odstranjivanje navedene reakcijske smjese iz spomenutog protočnog reaktora, i izoliranje dobivenog proizvoda trazodon baze (IV), u skladu s reakcijskom shemom 5: [image] .
18. Postupak prema bilo kojem od patentnih zahtjeva 14-17, naznačen time, da nadalje obuhvaća korak v) u kojem se trazodon baza (IV) pretvara u trazodon hidroklorid (V) i izolira, u skladu s reakcijskom shemom 3: [image] .
19. Postupak prema bilo kojem od patentnih zahtjeva 17-18, naznačen time, da temperatura neprekidne reakcije u skladu s korakom c), iznosi od 80 °C do 100 °C.
20. Postupak prema bilo kojem od patentnih zahtjeva 17-19, naznačen time, da je bazični spoj u koraku a) anorganska baza odabrana iz skupine koju čine natrijev hidroksid, kalijev hidroksid, natrijev karbonat, kalijev karbonat, natrijev bikarbonat, kalijev bikarbonat, natrijev fosfat, kalijev fosfat, amonijev hidroksid, magnezijev oksid, hidrazin, hidroksilamin, i njihove mješavine.
21. Postupak prema bilo kojem od patentnih zahtjeva 17-20, naznačen time, da je bazični spoj u koraku a) organska baza odabrana iz skupine koju čine: trimetilamin, trietilamin, N,N-diizopropiletilamin, trietanolamin, N,N-dimetiletanolamin, kinolin, piridin, morfolin, N-metilmorfolin, i njihove mješavine.
22. Postupak prema bilo kojem od patentnih zahtjeva 17-21, naznačen time, da je organsko otapalo u skladu s korakom b) polarno aprotično otapalo odabrano iz skupine koju čine: N-metilpirolidon, dimetilformamid, dimetil sulfoksid, aceton, etil acetat, tetrahidrofuran, i acetonitril; ili je nepolarno otapalo odabrano iz skupine koju čine: toluen, benzen, i dietil eter.
23. Postupak prema patentnom zahtjevu 22, naznačen time, da otapalo jest N-metilpirolidon.
24. Postupak prema bilo kojem od patentnih zahtjeva 1-23, naznačen time, da protočni reaktor je protočni reaktor s mikroprotočnim sustavom, mezoprotočnim sustavom ili s velikim protočnim sustavom, koji se bira iz skupine koju čine: mikročip protočni reaktori, mikrofluidni protočni reaktori, spiralni protočni reaktori, cijevni protočni reaktori, pločasti reaktori, šaržni reaktori s napunjenim slojem, reaktori s fluidiziranim slojem, reaktori s nepokretnim slojem i njihove kombinacije.
25. Postupak prema patentnom zahtjevu 24, naznačen time, da se reaktor bira iz skupine koju čine: mikrofluidni protočni reaktori, čip mezoprotočni reaktori, spiralni mezoprotočni reaktori, i protočni reaktori s velikim protočnim sustavom.
HRP20220733TT 2018-02-07 2019-02-05 Neprekidni postupak za proizvodnju trazodona HRP20220733T1 (hr)

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