WO2012172121A1 - Procédé de préparation de médétomidine à partir de chloro-acétone - Google Patents

Procédé de préparation de médétomidine à partir de chloro-acétone Download PDF

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Publication number
WO2012172121A1
WO2012172121A1 PCT/EP2012/070875 EP2012070875W WO2012172121A1 WO 2012172121 A1 WO2012172121 A1 WO 2012172121A1 EP 2012070875 W EP2012070875 W EP 2012070875W WO 2012172121 A1 WO2012172121 A1 WO 2012172121A1
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Prior art keywords
reaction
compound
formula
reagent
group
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PCT/EP2012/070875
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English (en)
Inventor
Florencio Zaragoza Doerwald
Anna KULESZA
Stephan Elzner
Robert BUJOK
Zbigniew WROBEL
Krzysztof Wojciechowski
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Lonza AG
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Lonza AG
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Priority to EP12787007.9A priority Critical patent/EP2867211B1/fr
Priority to CN201510621358.0A priority patent/CN105218453B/zh
Priority to EA201400939A priority patent/EA027921B1/ru
Priority to NZ700642A priority patent/NZ700642B2/en
Priority to SG11201405609WA priority patent/SG11201405609WA/en
Priority to HUE12787007A priority patent/HUE027382T2/en
Priority to AU2012285677A priority patent/AU2012285677B2/en
Priority to CA2866437A priority patent/CA2866437C/fr
Priority to MYPI2014002579A priority patent/MY165218A/en
Priority to PCT/EP2012/072798 priority patent/WO2013011157A1/fr
Priority to DK12787007.9T priority patent/DK2867211T3/en
Priority to HK15102120.2A priority patent/HK1201530B/xx
Priority to PL12787007T priority patent/PL2867211T3/pl
Priority to IN7984DEN2014 priority patent/IN2014DN07984A/en
Priority to ES12787007.9T priority patent/ES2565066T3/es
Priority to HRP20160216T priority patent/HRP20160216T1/hr
Priority to US14/385,797 priority patent/US9156793B2/en
Priority to CN201280072210.0A priority patent/CN104245678B/zh
Priority to JP2015510662A priority patent/JP5777841B2/ja
Priority to KR1020147029607A priority patent/KR101560116B1/ko
Publication of WO2012172121A1 publication Critical patent/WO2012172121A1/fr
Priority to TW105114874A priority patent/TWI560182B/zh
Priority to TW102122683A priority patent/TWI543970B/zh
Priority to CL2014002907A priority patent/CL2014002907A1/es
Anticipated expiration legal-status Critical
Priority to US14/813,681 priority patent/US9434694B2/en
Priority to HK16101923.2A priority patent/HK1213893B/xx
Priority to CL2016001664A priority patent/CL2016001664A1/es
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms

Definitions

  • the invention discloses a method for the preparation of medetomidine starting from 1-bromo 2,3-dimethylbenzene and chloroacetone.
  • Medetomidine is the compound of formula (XX) and is an alpha2 adrenergic agonist, which is currently being used as veterinary sedative and analgesic and is evaluated as anesthetic.
  • Medetomidine is a 4-alkylimidazole.
  • 4-Alkylimidazoles without additional substituents at the nitrogen moiety are usually mixtures of two tautomers.
  • two tautomeric forms represented by compound of formula (XX) and compound of formula (XX-T) will usually interconvert if medetomidine is dissolved or in a non-crystalline state.
  • formula (XX) is used for medetomidine, and is meant to comprise both tautomeric forms as well as their mixture.
  • US 2010/0048915 A discloses a method for the preparation of medetomidine by reaction of halogenated imidazoles with 2,3-dimethylbenzaldehyde using Grignard reagents.
  • WO 00/42851 A discloses the use of medetomidine for inhibition of marine bio fouling on surfaces.
  • the known methods of preparation of compound of formula (XX) often use protecting groups, for example triphenylmethyl (trityl) residues, which entails high material
  • halogen means F, CI, Br or I, preferably CI, Br or I;
  • alkyl means linear, branched, cyclic or cyclo alkyl; if not otherwise stated.
  • alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, and the like;
  • cyclic alkyl or “cyclo alkyl” are intended to include cyclo aliphatic, bicyclo aliphatic and tricycle aliphatic residues;
  • OTf trifluoromethanesulfonate also known as triflate
  • Subject of the invention is a method for preparation of compound of formula (XX); the method comprises four steps, the four steps are a step (Ql), a step (Q2), a step (N) and a step (Ml); compound of formula (XX) is prepared in step (Ml);
  • step (Ml) comprises a reaction (Ml);
  • reaction (Ml) is a reaction between a compound of formula (XXI),
  • reagent (M) is selected from the group consisting of p-toluenesulfonylmethyl isocyanide, trifluoromethanesulfonylmethyl isocyanide, methanesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide, 4-acetamidobenzenesulfonylmethyl isocyanide and mixtures thereof;
  • reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, p- toluenesulfonamide, benzenesulfonamide, 4-acetamidobenzenesulfonamide, tritylamine, formamide, urea, urotropine, ethyl carbamate, acetamide and mixtures thereof;
  • solvent (M) is selected from the group consisting of ⁇ , ⁇
  • reaction (N) is a reaction of a compound of formula (XXII) with a catalyst (N);
  • catalyst (N) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
  • camphorsulfonic acid HC1, HBr, H 2 S0 4 , HN0 3 , H 3 P0 4 , HC10 4 , BC1 3 , BBr 3 , BF 3 OEt 2 , BF 3 SMe 2 , BF 3 THF, MgCl 2 , MgBr 2 , Mgl 2 , A1C1 3 , Al(0-alkyl) 3 , SnCl 4 , TiCl 4 , Ti(0- alkyl) 4 , ZrCl 4 , Bi 2 0 3 , BiCl 3 , ZnCl 2 , PbCl 2 , FeCl 3 , ScCl 3 , NiCl 2 , Yb(OTf) 3 , Yb(Cl) 3 , GaCl 3 , AlBr 3 , Ce(OTf) 3 , LiCl, Cu(BF 4 ) 2 , Cu(OTf) 2 , NiBr 2 (PP
  • reaction (Ql) is a reaction of compound of formula (XXV) with a reagent (Ql);
  • Rl is Br, CI, or I
  • reagent (Ql) is selected from the group consisting of lithium, magnesium, aluminum, zinc, calcium, propylmagnesium chloride, propylmagnesium bromide, butyllithium and mixtures thereof; step (Q2) comprises a reaction (Q2);
  • reaction (Q2) is a reaction of the reaction product of reaction (Ql) with chloroacetone; compound of formula (XXII) is prepared by the reaction (Q2).
  • reagent (M) is selected from the group consisting of p-toluenesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide and mixtures thereof;
  • reagent (M) is p-toluenesulfonylmethyl isocyanide.
  • reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, p- toluenesulfonamide, benzenesulfonamide, 4-acetamidobenzenesulfonamide, tritylamine, formamide and mixtures thereof;
  • reagent (M-A) is selected from the group consisting of ammonia, p- toluenesulfonamide, benzenesulfonamide, formamide, 4- acetamidobenzenesulfonamide, tritylamine and mixtures thereof;
  • reagent (M-A) is selected from the group consisting of ammonia, p- toluenesulfonamide, formamide, and mixtures thereof;
  • reagent (M-A) is ammonia or formamide.
  • reaction (Ml) is done in the presence of a compound (M), compound (M) is
  • compound (M) is selected from the group consisting of ammonia, tritylamine,
  • compound (M) is selected from the group consisting of ammonia, NaCN, KCN, piperidine, tBuOK, tBuONa, K 2 C0 3 , Na 2 C0 3 , KF and mixtures thereof;
  • compound (M) is selected from the group consisting of ammonia, NaCN, K 2 C0 3 , tBuOK, tBuONa, Na 2 C0 3 and mixtures thereof;
  • compound (M) is selected from the group consisting of ammonia, NaCN, tBuOK, tBuONa, K 2 C0 3 , Na 2 C0 3 and mixtures thereof;
  • compound (M) is K 2 C0 3 , Na 2 C0 3 ,NaCN or ammonia;
  • compound (M) is Na 2 C0 3i NaCN or ammonia.
  • solvent (M) is selected from the group consisting of N,N-dimethylformamide, methanol, ethanol, n-propanol, isopropanol, butanol, pentanol, hexanol, water, formamide, 1 ,2-dimethoxyethane, NMP, toluene, acetonitrile, propionitrile, ethyl carbamate, ⁇ , ⁇ -dimethylacetamide, acetamide and mixtures thereof;
  • solvent (M) is selected from the group consisting of N,N- dimethylformamide, methanol, ethanol, ethyl carbamate, formamide, acetamide and mixture thereof.
  • the reagent (M-A) can be used as such or in form of a solution in a solvent (M-A).
  • Solvent (M-A) is identical or different from solvent (M), preferably identical, and comprises the same group of solvents as solvent (M), also with respect to all of the preferred embodiments of solvent (M).
  • reagent (M-A) is ammonia
  • reagent (M-A) is preferably used in form of a solution, preferably in form of a solution in methanol or ethanol.
  • reagent (M-A) can be identical with solvent (M) and can be used as solvent (M).
  • reaction temperature of reaction (Ml) is from -10 to 250 °C, more preferably from 0 to 200 °C, even more preferably from 10 to 180 °C.
  • the reaction (Ml) can be done in a system, that is closed or open to the atmosphere;
  • reaction (Ml) is done in a closed system.
  • the pressure depends mainly on the boiling point of the solvent (M), on the amount of ammonia used, and on the reaction temperature of reaction (Ml);
  • the reaction (Ml) is done at a pressure of from atmospheric pressure to 20 bar, more preferably of from atmospheric pressure to 10 bar, even more preferably of from atmospheric pressure to 5 bar.
  • reaction time of reaction (Ml) is from 30 min to 72 h, more preferably from 30 min to 48 h, even more preferably from 30 min to 24 h.
  • Reaction (Ml) may be conducted at a constant temperature, or the temperature may be modified during the progress of the reaction. For instance, the reaction may be run for a certain time at first temperature, and then for a given time at second temperature different from the first temperature; alternatively, the temperature may be modified continuously during the reaction.
  • reagent (M) Preferably, from 0.5 to 10 mol equivalents, more preferably from 0.5 to 5 mol equivalents, even more preferably from 0.5 to 3 mol equivalents of reagent (M) are used, the mol equivalents being based on the mol of compound of formula (XXI).
  • the total amount of substances different from ammonia, formamide and ethyl carbamate used as reagent (M-A) is preferably from 1.0 to 10 mol equivalents, more preferably from 1.1 to 5 mol equivalents, even more preferably from 1.1 to 3 mol equivalents, the mol equivalents being based on the mol of compound of formula (XXI).
  • reagent (M-A) When ammonia, formamide, ethyl carbamate or mixtures thereof are used as reagent (M-A), preferably from 1.0 to 100 mol equivalents, more preferably from 1.1 to 50 mol equivalents, even more preferably from 1.1 to 30 mol equivalents of ammonia, formamide, ethyl carbamate or mixtures thereof are used, the mol equivalents being based on the mol of compound of formula (XXI).
  • the given amounts for ammonia, formamide and ethyl carbamate, and the given amounts for the one or more substances different from ammonia, formamide and ethyl carbamate add up to the total amount of reagent (M-A);
  • the total amount of reagent (M-A) is preferably from 1.0 to 100 mol equivalents, more preferably from 1.1 to 50 mol equivalents, even more preferably from 1.1 to 30 mol equivalents, the mol equivalents being based on the mol of compound of formula (XXI).
  • mol equivalents Preferably from 0.01 to 15 mol equivalents, more preferably from 0.02 to 10 mol equivalents, even more preferably from 0.02 to 5 mol equivalents of compound (M) are used, the mol equivalents being based on the mol of compound of formula (XXI).
  • reagent (M-A) is not one or more substances selected from the group ammonia, formamide and ethyl carbamate, then preferably from 1 to 15 mol equivalents, more preferably from 1 to 10 mol equivalents, even more preferably from 1 to 5 mol equivalents of compound (M) are used, the mol equivalents being based on the mol of compound of formula (XXI).
  • the amount of solvent (M) is from 0.5 to 20 fold, more preferably from 1 to 20 fold, even more preferably of from 2 to 20 fold, of the weight of compound of formula (XXI).
  • reaction (Ml) is done under inert atmosphere.
  • the product of reaction (Ml) may be N-trityl medetomidine and the trityl residue would have to be removed.
  • the method for preparation of compound of formula (XX) comprises a further step (M2); step (M2) is done after step (Ml); step (M2) comprises a reaction (M2); reaction (M2) is the treatment of the product of reaction (Ml) with an acid (M-acid detrit).
  • Acid is preferably selected from the group consisting of acetic acid, propionic acid, formic acid, HC1 or mixtures thereof.
  • Acid (M-acid detrit) can be used as an aqueous solution.
  • reaction (M) Any sequence of the reaction of reagent (M) and of reagent (M-A) with the compound of formula (XXI) in reaction (Ml) can be used:
  • compound of formula (XXI) can first be reacted with reagent (M) and then reagent (M-A) added;
  • compound of formula (XXI) can first be reacted with reagent (M-A) and then reagent (M) added;
  • compound of formula (XXI) can simultaneously be reacted with reagent (M) and with reagent (M-A), this embodiment is preferably suited for the case that reagent (M-A) and solvent (M) are identical and are formamide, ethyl carbamate or acetamide; preferably formamide.
  • compound of formula (XXI) is first reacted with reagent (M) and then reagent (M- A) added;
  • Step (Ml) can therefore be done in three alternatives, the three alternatives are alternative (Ml-Al), alternative (M1-A2) and alternative (M1-A3).
  • Alternative (Ml-Al) comprises two consecutive steps, a first step (Ml-Al-1) and a second step (Ml-Al-2);
  • step (Ml-Al-1) comprises a reaction (Ml-Al-1);
  • reaction (Ml-Al-1) is a reaction of compound of formula (XXI) with reagent (M) in the presence of compound (M) in solvent (M);
  • step (Ml-Al-2) comprises a reaction (Ml-Al-2);
  • reaction (Ml-Al-2) is a reaction of the reaction product of reaction (Ml-Al-1) with reagent
  • reaction temperature of reaction (Ml-Al-1) is from -10 to 250 °C, more
  • reaction temperature of reaction (Ml-Al-2) is from 20 to 250 °C, more
  • reaction (Ml-Al-1) Preferably from 0.01 to 1 mol equivalents, more preferably from 0.02 to 1 mol equivalents, even more preferably from 0.02 to 1 mol equivalents of compound (M) are used in reaction (Ml-Al-1), the mol equivalents being based on the mol of compound of formula (XXI).
  • Reaction (Ml-Al-2) can be done in the presence of compound (M).
  • reagent (M-A) is not one or more substances selected from the group ammonia
  • reaction (Ml-Al-2) is preferably done in the presence of compound (M); preferably from 1 to 15 mol equivalents, more preferably from 1 to 10 mol equivalents, even more preferably from 1 to 5 mol equivalents of compound (M) are used, the mol equivalents being based on the mol of compound of formula (XXI).
  • reaction product of reaction (Ml-Al-1) can be isolated by standard methods such as hydrolysis, filtration, evaporation of the volatile components, extraction, washing, drying, concentration, crystallization, distillation, chromatography and any combination thereof, which are known per se to the person skilled in the art.
  • reaction product of reaction (Ml-Al-1) is the compound of formula (XXIII); (XXIII)
  • R2 is 4-tolyl, phenyl, 4-acetamidophenyl, methyl or trifluoromethyl;
  • R2 is 4-tolyl, which is compound of formula (23).
  • Compound of formula (XXIII) can be isolated after reaction (Ml-Al-1) by addition of water to the reaction mixture as obtained from reaction (Ml-Al-1). The addition of water precipitates compound of formula (XXIII). Compound of formula (XXIII) can then be isolated by filtration, followed preferably by washing and drying. Compound of formula (XXIII) can be further purified by crystallization.
  • the volume of water used for this precipitation is preferably from 0.01 to 5 fold, more preferably from 0.05 to 2 fold, of the volume of solvent (M).
  • M1-A2 comprises two consecutive steps, a first step (M1-A2-1) and second step (M1-A2-2);
  • step (M1-A2-1) comprises a reaction (M1-A2-1);
  • reaction (M1-A2-1) is a reaction of compound of formula (XXI) with reagent (M-A) in solvent (M);
  • step (M1-A2-2) comprises a reaction (M1-A2-2).
  • reaction (M1-A2-2) is a reaction of the reaction product of reaction (M1-A2-1) with reagent
  • reaction temperature of reaction (M1-A2-1) is from 0 to 250 °C, more
  • reaction temperature of reaction (M1-A2-2) is from -10 to 250 °C, more
  • reaction (M1-A2-1) can be done in the presence of an acid (M1-A2-1); acid (M1-A2-1) is selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid and benzenesulfonic acid; preferably from 0.01 to 1 mol equivalents, more preferably from 0.05 to 0.5 mol equivalents, even more preferably from 0.1 to 0.3 mol equivalents of acid (M1-A2-1) are used in reaction (M1-A2-1), the mol equivalents being based on the mol of compound of formula
  • Reaction (M1-A2-1) can be done in the presence of compound (M).
  • reagent (M-A) is not one or more substances selected from the group ammonia
  • reaction (M1-A2-1) is preferably done in the presence of compound (M); preferably from 1 to 15 mol equivalents, more preferably from 1 to 10 mol equivalents, even more preferably from 1 to 5 mol equivalents of compound (M) are used, the mol equivalents being based on the mol of compound of formula (XXI).
  • reaction (M1-A2-2) Preferably from 0.01 to 1 mol equivalents, more preferably from 0.02 to 1 mol equivalents, even more preferably from 0.02 to 1 mol equivalents of compound (M) are used in reaction (M1-A2-2), the mol equivalents being based on the mol of compound of formula (XXI).
  • step (M1-A3-1) comprises a reaction (M1-A3-1);
  • reaction (M1-A3-1) is a reaction of compound of formula (XXI) with reagent (M) and with reagent (M-A) in solvent (M).
  • reaction temperature of reaction (M1-A3-1) is from 0 to 250 °C, more
  • Reaction (M1-A3-1) can be done in the presence of compound (M); preferably from 1 to 15 mol equivalents, more preferably from 1 to 10 mol equivalents, even more preferably from 1 to 5 mol equivalents of compound (M) are used in reaction (M1-A3-1), the mol equivalents being based on the mol of compound of formula (XXI).
  • reagent (M), reagent (M-A), compound (M) and solvent (M) are as defined herein, also with all their preferred embodiments.
  • the compound of formula (XX) can be isolated by standard methods such as evaporation of volatile components, extraction, washing, drying, concentration, filtration, crystallization, distillation, chromatography and any combination thereof, which are known per se to the person skilled in the art.
  • the volatile components of the reaction mixture are removed by evaporation under reduced pressure.
  • the reaction mixture resulting from reaction (Ml) or the reaction mixture resulting from reaction (M2) can be extracted with a solvent (M-extract),
  • solvent (M-extract) is preferably selected from the group consisting of water, toluene, benzene, xylene, chlorobenzene, dichloromethane, chloroform, acetic acid Ci_8 alkyl ester and combinations thereof;
  • the acetic acid Ci_8 alkyl ester is preferably an acetic acid Ci_ 4 alkyl ester, more preferably selected from the group consisting of ethyl acetate, isopropyl acetate and butyl acetate;
  • solvent (M-extract) is selected from the group consisting of toluene,
  • dichloromethane ethyl acetate, isopropyl acetate and mixtures thereof.
  • the extraction can be followed by filtration and concentration of the extract.
  • the extract resulting from the extraction with solvent can be extracted with an aqueous solution of an acid (M- acid).
  • Acid is preferably selected from the group consisting of oxalic acid, citric acid, maleic acid, fumaric acid, tartaric acid, NH 4 C1, HC1, HBr, H 2 S0 4 , 3 ⁇ 4 ⁇ 0 4 and mixtures thereof.
  • the extract resulting from the extraction with an aqueous solution of acid (M-acid) can be washed with a solvent (M-wash).
  • solvent (M-wash) is selected from the group consisting of toluene, benzene, xylene, chlorobenzene, dichloromethane, chloroform, acetic acid Ci_s alkyl ester and mixtures thereof; the acetic acid Ci_8 alkyl ester is preferably an acetic acid Ci_ 4 alkyl ester, more preferably selected from the group consisting of ethyl acetate, isopropyl acetate and, butyl acetate.
  • the product can be isolated by concentration of the extract that was washed with solvent (M- wash).
  • reaction mixture resulting from reaction (Ml) or the reaction mixture resulting from reaction (M2) can be, without above mentioned extraction with solvent (M-extract), acidified by mixing with an aqueous solution of acid (M-acid).
  • M-acid aqueous solution of acid
  • the mixture, that is thereby obtained, can be washed with solvent (M-wash), and the product can be isolated by concentration.
  • a suspension or solution of the salt of medetomidine preferably an aqueous suspension or solution of the salt of
  • medetomidine can be basified by addition of a base (M-basify) or of an aqueous solution of base (M-basify);
  • preferably base (M-basify) is selected from the group consisting of NaHCC"3, Na 2 C03, NaOH and mixtures thereof.
  • base is added in such an amount, that the pH of the resulting mixture is from 7 to 12, more preferably from 8 to 10, even more preferably from 8 to 9.
  • an aqueous phase can be extracted with solvent (M- extract), followed by isolation of the product by concentration of the extract.
  • any washing of any organic phase after reaction (Ml) or after reaction (M2) can be done with water, with base (M-basify), with an aqueous solution of base (M-basify) or with brine.
  • any extraction of any aqueous phase after reaction (Ml) or after reaction (M2) is done with solvent (M-extract).
  • the reaction mixture after reaction (Ml) or after reaction (M2) is first concentrated under reduced pressure, then diluted with water and acidified with acid (M-acid) as described above, washed with solvent (M-wash), preferably solvent (M-wash) is toluene, basified with base (M-basify), preferably base (M-basify) is an aqueous solution of NaHC0 3 , and then extracted with solvent (M-extract), preferably solvent (M-extract) is selected from the group consisting of toluene, dichloromethane, isopropyl acetate and ethyl acetate; followed by isolation of the product by concentration of the extract.
  • compound of formula (XX) is purified after reaction (Ml) or after reaction (M2) by chromatography.
  • Any organic phase can be dried, preferably over MgS0 4 or Na 2 S0 4 .
  • Any concentration is preferably done by distillation, preferably under reduced pressure.
  • the compound of formula (XX) can be purified, preferably by crystallization or distillation under reduced pressure, more preferably by crystallization from a mixture of cyclohexane and toluene, even more preferably from cyclohexane : toluene 99 : 1 v/v .
  • the compound of formula (XX) may also be converted into a salt by mixing with an acid (M- acid salt), acid (M-acid salt) is preferably used as aqueous solution, acid (M-acid salt) is preferably selected from the group consisting of acetic acid, oxalic acid, HC1 and H 2 S0 4 ; then it can be isolated by filtration and purified by recrystallization in a solvent (M-cryst), solvent (M-cryst) is preferably selected from the group consisting of water, ethanol, methanol, isopropanol, acetonitrile, hexane, cyclohexane, heptane, toluene, ethyl acetate and mixtures thereof; recrystallization can be repeated using a different solvent (M-cryst).
  • the Al(0-alkyl) 3 and the Ti(0-alkyl) 4 in the list of possible compounds for catalyst (N) are Al(0-Ci_ 4 alkyl) 3 and Ti(0-Ci_ 4 alkyl) 4 .
  • the acidic inorganic solid substance in the list of possible compounds for catalyst (N) is aluminosilicate.
  • the acidic ion exchange resin in the list of possible compounds for catalyst (N) is selected from the group consisting of copolymers of styrene and divinylbenzene and of perfluorinated branched or linear polyethylenes, these polymers being functionalized with SO 3 H groups;
  • the acidic ion exchange resin is selected from the group consisting of
  • the inorganic acid in the list of possible compounds for catalyst (N), with which the carbon was treated is selected from the group consisting of HC1, H 2 S0 4 and HN0 3 .
  • catalyst (N) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, HC1, HBr, H 2 S0 4 , H 3 P0 4 , BCI 3 , BF 3 OEt 2 , MgCl 2 , MgBr 2 , A1C1 3 , ZnCl 2 , Cu(BF 4 ) 2 , aluminosilicate, acidic ion exchange resin, carbon treated with HC1, H 2 S0 4 or FiN0 3 ,and mixtures thereof; more preferably, catalyst (N) is selected from the group consisting of acetic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, HC1, H 2 S0 4 , BF 3 OEt 2 , Cu(BF 4 ) 2 , aluminosilicate, acidic i
  • catalyst (N) is selected from the group consisting of methanesulfonic acid, p-toluenesulfonic acid, H 2 S0 4 , BF 3 OEt 2 , Cu(BF 4 ) 2 , aluminosilicate, acidic ion exchange resin, and mixtures thereof;
  • catalyst (N) is selected from the group consisting of methanesulfonic acid, p- toluenesulfonic acid, H 2 S0 4 , BF 3 OEt 2 and mixtures thereof.
  • reaction (N) is done in a solvent (N).
  • Solvent (N) is preferably selected from the group consisting of water, tert-butanol,
  • trifluoroacetic acid and mixtures thereof more preferably from water, acetonitrile, propionitrile, THF, 2-methyl-THF, 1,2- dimethoxyethane, dichloromethane, 1 ,2-dichloroethane, chloroform, toluene,
  • the catalyst (N) can be used in a pure form or as hydrate.
  • the catalyst (N) can be used as a solution in solvent (N).
  • the molar ratio between catalyst (N) and compound of formula (XXII) is from 1 : 1000 to 10: 1, more preferably from 1 : 100 to 5 : 1 , even more preferably from 1 : 50 to 1 : 1, especially from 1 :25 to 1 :2.
  • reaction temperature of reaction (N) is from -20 to 200 °C, more preferably from 0 to 150 °C, even more preferably from 10 to 100 °C.
  • the reaction (N) can be done in a system that is closed or open to the atmosphere.
  • the pressure depends mainly on the boiling point of a solvent (N) and on the reaction temperature of reaction (N).
  • the reaction (N) is done at a pressure of from 0.01 bar to 20 bar, more preferably of from 0.1 to 10 bar, even more preferably of from atmospheric pressure to 5 bar.
  • reaction (N) is done in an open system.
  • reaction time of reaction (N) is from 30 min to 72 h, more preferably from 1 h to 48 h, even more preferably from 1.5 h to 24 h.
  • reaction (N) can be done as a continuous gas-phase reaction by passing the evaporated compound of formula (XXII) over the catalyst (N).
  • This gas-phase reaction can be done in the presence of an inert gas, the inert gas is preferably selected from the group consisting of nitrogen, a noble gas and carbon dioxide.
  • compound of formula (XXI) can be isolated by standard methods such as evaporation of volatile components, extraction, washing, drying, concentration, filtration, crystallization, distillation, chromatography and any combination thereof, which are known per se to the person skilled in the art.
  • any volatile components of the reaction mixture or added or generated during work up can be removed by evaporation under reduced pressure.
  • the reaction mixture resulting from reaction (N) or any aqueous phase during the work up after reaction (N) can be extracted with solvent (M-extract), with solvent (M-extract) as defined above, also with all its preferred embodiments.
  • any washing of any organic phase after reaction (N) can be done with water, with a base (M-basify), with an aqueous solution of a base (M-basify), with an aqueous solution of an acid (M-acid) or with brine; with base (M-basify) and acid (M-acid) as defined above, also with all their preferred embodiments.
  • Any extraction or washing can be followed by filtration and concentration of the extract or of the washed mixture.
  • compound of formula (XXI) is purified after reaction (N) by chromatography. Any organic phase can be dried, preferably over MgS0 4 or Na 2 S0 4 .
  • Any concentration is preferably done by distillation, preferably under reduced pressure.
  • Compound of formula (XXI) can be obtained in step (N) as the aldehyde as depicted in formula (XXI), but also in form of its hydrate or hemiacetal.
  • the hemiacetal of compound of formula (XXI), which can result as product from step (N) can be the product of an addition reaction between the aldehyde as depicted in formula (XXI) and an alcohol selected from the group consisting of tert-butanol and isopropanol, or between the aldehyde as depicted in formula (XXI) and any alcohol which is used during the isolation after reaction (N). Therefore formula (XXI) for the purpose of this invention encompasses the aldehyde, hydrate and the hemiacetal.
  • reaction (N) in form of its hydrate or of a hemiacetal
  • the hydrate or the hemiacetale can be converted into the aldehyde by standard reactions known to the person skilled in the art.
  • formula (XXI) for the purpose of this invention encompasses the aldehyde, the hydrate of the aldehyde and the hemiacetale of the aldehyde.
  • compound (XXI) is not isolated after reaction (N).
  • reaction (N) and reaction (M) are done in the same pot. More preferably, after reaction (N) solvent (N) is removed by evaporation, and reaction (M) is done after
  • Rl is Br
  • reagent (Ql) is selected from the group consisting of lithium, magnesium,
  • reagent (Ql) is selected from the group consisting of lithium, magnesium, isopropylmagnesium chloride, isopropylmagnesium bromide, n-butyllithium and mixtures thereof.
  • Reaction (Ql) can be done in the presence of a catalyst (Ql);
  • catalyst (Ql) is selected from the group consisting of iodine, 1 ,2-dibromoethane, TiCl 4 , A1C1 3 , PbCl 2 , B1CI 3 , LiCl and mixtures thereof.
  • reaction (Ql) is performed in a solvent (Ql).
  • reaction (Q2) is performed in a solvent (Q2).
  • solvent (Ql) and solvent (Q2) are identical or different and independently from each other selected from the group consisting of THF, toluene, heptane,
  • heptane When heptane is used as solvent, it is often used as a mixture of isomeric heptanes.
  • solvent (Ql) is THF, hexane or a mixture thereof
  • solvent (Q2) is THF, hexane, toluene or a mixture thereof.
  • solvent (Ql) and solvent (Q2) are identical.
  • reaction temperatures of reaction (Ql) and of reaction (Q2) are identical or different and independently from each other preferably from -100 to 150 °C, more preferably from -90 to 100 °C, and even more preferably from -80 to 80 °C.
  • Reaction (Ql) and reaction (Q2) can be done at a constant temperature, or the temperature may be modified during the progress of the reactions. For instance, the reactions can run for a certain time at first temperature, and then for a subsequent time at a second temperature different from the first temperature. Alternatively, the temperature may be modified continuously during the reaction.
  • reaction times of reaction (Ql) and of reaction (Q2) are identical or different and independently from each other preferably from 30 min to 48 h, more preferably from 1 to 24 h, even more preferably from 2 to 12 h.
  • the amounts of solvent (Ql) and of solvent (Q2) are identical or different and independently from each other preferably from 2 to 40 fold, more preferably from 3 to 20 fold, even more preferably from 5 to 10 fold, of the weight of compound of formula (XXV) in case of solvent (Ql), and of the weight of the reaction product of reaction (Ql) in case of solvent (Q2).
  • reagent (Ql) from 1.0 to 10 mol equivalents, more preferably from 1.1 to 5 mol equivalents, even more preferably from 1.1 to 3 mol equivalents of reagent (Ql) are used, the mol equivalents being based on the mol of compound of formula (XXV).
  • mol equivalents from 1.0 to 10 mol equivalents, more preferably from 1.1 to 5 mol equivalents, even more preferably from 1.1 to 3 mol equivalents of chloroacetone are used, the mol equivalents being based on the mol of compound of formula (XXV).
  • reaction (Ql) and reaction (Q2) are done at atmospheric pressure.
  • reaction (Ql) and reaction (Q2) are done under inert atmosphere.
  • the inert atmosphere is achieved by the use if an inert gas preferably selected from the group consisting of argon, another noble gas, lower boiling alkane, nitrogen and mixtures thereof.
  • the lower boiling alkane is preferably a Ci_ 3 alkane, i.e. methane, ethane or propane.
  • compound of formula (XXII) can be isolated by standard methods such as evaporation of volatile components, extraction, washing, drying, concentration, crystallization, distillation, chromatography and any combination thereof, which are known per se to the person skilled in the art.
  • reaction product of reaction (Ql) is not isolated.
  • reaction (Ql) and reaction (Q2) are done consecutively.
  • reaction (Ql) and reaction (Q2) are done in one pot.
  • reaction (Ql) and reaction (Q2) can be done in one pot by adding reagent (Q l) to a mixture of compound of formula (XXV) and chloroacetone in a solvent (Ql).
  • reagent (Q3) is combined with the reaction mixture derived from reaction (Q2);
  • reagent (Q3) is selected from the group consisting of water, methanol, ethanol, oxalic acid, citric acid, NH 4 C1, HC1, HBr, HNO 3 , H 2 SO 4 , H 3 PO 4 , acetic acid, propionic acid, formic acid and mixtures thereof.
  • reagent (Q3) is water or aqueous NH 4 C1;
  • reagent (Q3) is water.
  • reagent (Q3) from 0.01 to 1000 mol equivalents, more preferably from 0.02 to 1000 mol equivalents, of reagent (Q3) are used, the mol equivalents being based on the mol of compound of formula (XXV).
  • Reagent (Q3) is used to neutralize any excess of reagent (Ql), therefore the amount of reagent (Q3) is adjusted with respect to the excess of reagent (Ql) used in reaction (Ql).
  • Compound of formula (XXII) is preferably isolated using conventional methods, such as evaporation of volatile components, hydrolysis and optional acidification of the higher- boiling residue, extraction, and distillation.
  • the compound of formula (XXII) can be purified, preferably by crystallization or distillation under reduced pressure.
  • Any extraction of an aqueous phase is done preferably with a solvent (Q-extract), solvent (Q- extract) is benzene, toluene, ethyl acetate or isopropyl acetate.
  • solvent Q- extract
  • Any organic phase can be dried, preferably with magnesium sulphate.
  • Any concentration is preferably done by distillation, preferably under reduced pressure.
  • compounds, and the formulae comprise any enantiomer as well as any mixture of enantiomers of the compounds of formula (XX), of formula (XX-T), of formula (XXI), of formula (XXII), of formula (XXIII) or of formula (23) respectively.
  • Enantiomers can be separated by conventional procedure known in organic chemistry, such as repeated crystallizations of the (+) tartaric acid salt in alcoholic media, as disclosed for compound of formula (XX) in Cordi et al, Synth. Commun. 1996, 26, 1585-1593.
  • Compounds of formula (XXV) are known compounds and can be prepared according to known methods.
  • the progress of any of the reactions (Ml), (N), (Ql) and (Q2) can be monitored by standard techniques, such as nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), High performance Liquid Chromatography (HPLC), Liquid Chromatography Mass Spectrometry (LCMS), or Thin Layer Chromatography (TLC), and work-up of the reaction mixture can start, when the conversion of the starting material exceeds 95%, or when no more starting material can be detected.
  • NMR nuclear magnetic resonance spectroscopy
  • IR infrared spectroscopy
  • HPLC High performance Liquid Chromatography
  • LCMS Liquid Chromatography Mass Spectrometry
  • TLC Thin Layer Chromatography
  • any organic phase can be dried, preferably over MgS0 4 or Na 2 S0 4 , if not stated otherwise.
  • Further subject of the invention is a compound of formula (XXI).
  • EI Electron ionization mass spectra (70 eV), they were obtained on an AMD-604 spectrometer.
  • Example 1 the THF was not dried with sodium. In example 2 NaH was used for this purpose.
  • Example 1 2-(2,3-Dimethylphenyl)methyloxirane, compound of formula (XXII), metallation with butyllithium in THF
  • Example 2 2-(2,3-Dimethylphenyl)methyloxirane, compound of formula (XXII), metallation with magnesium in THF

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de médétomidine à partir de 1-bromo 2,3-diméthylbenzène et de chloro-acétone.
PCT/EP2012/070875 2012-06-28 2012-10-22 Procédé de préparation de médétomidine à partir de chloro-acétone Ceased WO2012172121A1 (fr)

Priority Applications (26)

Application Number Priority Date Filing Date Title
IN7984DEN2014 IN2014DN07984A (fr) 2012-06-28 2012-11-15
ES12787007.9T ES2565066T3 (es) 2012-06-28 2012-11-15 Método para la preparación de medetomidina con cloroacetona
EA201400939A EA027921B1 (ru) 2012-06-28 2012-11-15 Способ получения медетомидина с использованием хлорацетона
NZ700642A NZ700642B2 (en) 2012-06-28 2012-11-15 Method for preparation of medetomidine with chloroacetone
SG11201405609WA SG11201405609WA (en) 2012-06-28 2012-11-15 Method for preparation of medetomidine with chloroacetone
HUE12787007A HUE027382T2 (en) 2012-06-28 2012-11-15 A method for preparing medetomidine with chloroacetone
AU2012285677A AU2012285677B2 (en) 2012-06-28 2012-11-15 Method for preparation of medetomidine with chloroacetone
CA2866437A CA2866437C (fr) 2012-06-28 2012-11-15 Procede de preparation de medetomidine a partir de chloro-acetone
MYPI2014002579A MY165218A (en) 2012-06-28 2012-11-15 Method for preparation of medetomidine with chloroacetone
PCT/EP2012/072798 WO2013011157A1 (fr) 2012-06-28 2012-11-15 Procédé de préparation de médétomidine à partir de chloro-acétone
DK12787007.9T DK2867211T3 (en) 2012-06-28 2012-11-15 METHOD OF PREPARING MEDETOMIDINE WITH CHLORACETONE
HK15102120.2A HK1201530B (en) 2012-06-28 2012-11-15 Method for preparation of medetomidine with chloroacetone
PL12787007T PL2867211T3 (pl) 2012-06-28 2012-11-15 Sposób wytwarzania medetomidyny przy pomocy chloroacetonu
EP12787007.9A EP2867211B1 (fr) 2012-06-28 2012-11-15 Procédé de préparation de médétomidine à partir de chloro-acétone
US14/385,797 US9156793B2 (en) 2012-06-28 2012-11-15 Method for preparation of medetomidine with chloroacetone
KR1020147029607A KR101560116B1 (ko) 2012-06-28 2012-11-15 클로로아세톤을 이용한 메데토미딘의 제조 방법
HRP20160216T HRP20160216T1 (hr) 2012-06-28 2012-11-15 Postupak za pripremu medetomidina s kloracetonom
CN201280072210.0A CN104245678B (zh) 2012-06-28 2012-11-15 用氯丙酮制备美托咪定的方法
JP2015510662A JP5777841B2 (ja) 2012-06-28 2012-11-15 クロロアセトンを用いてメデトミジンを調製するための方法
CN201510621358.0A CN105218453B (zh) 2012-06-28 2012-11-15 用氯丙酮制备美托咪定的方法
TW105114874A TWI560182B (en) 2012-06-28 2013-06-26 Intermediate in method for preparation of medetomidine with chloroacetone
TW102122683A TWI543970B (zh) 2012-06-28 2013-06-26 藉氯丙酮製備美托定咪啶之方法
CL2014002907A CL2014002907A1 (es) 2012-06-28 2014-10-27 Método para la preparación de medetomidina con cloroacetona
US14/813,681 US9434694B2 (en) 2012-06-28 2015-07-30 Method for preparation of medetomidine with chloroacetone
HK16101923.2A HK1213893B (en) 2012-06-28 2016-02-22 Method for preparation of medetomidine with chloroacetone
CL2016001664A CL2016001664A1 (es) 2012-06-28 2016-06-29 Método para la preparación de medetomidina con cloroacetona

Applications Claiming Priority (6)

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US201261665510P 2012-06-28 2012-06-28
US61/665,510 2012-06-28
EP12174102 2012-06-28
EP12174102.9 2012-06-28
EP12188104.9 2012-10-11
EP12188104 2012-10-11

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JP2015517475A (ja) * 2012-06-28 2015-06-22 ロンザ・リミテッド クロロアセトンを用いて２−（２，３−ジメチルフェニル）−１−プロパナールを調製するための方法
JP2015517472A (ja) * 2012-05-08 2015-06-22 ロンザ・リミテッド メデトミジンの調製のための方法
JP2015517473A (ja) * 2012-05-08 2015-06-22 ロンザ・リミテッド ２−（２，３−ジメチルフェニル）−１−プロパナールを調製するための方法
JP2015517474A (ja) * 2012-06-28 2015-06-22 ロンザ・リミテッド クロロアセトンを用いてメデトミジンを調製するための方法

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EP1918282A1 (fr) * 2006-11-06 2008-05-07 "Joint Stock Company Grindeks" Procédé pour la préparation de medetomidine et ses sels
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EP1918282A1 (fr) * 2006-11-06 2008-05-07 "Joint Stock Company Grindeks" Procédé pour la préparation de medetomidine et ses sels
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015517472A (ja) * 2012-05-08 2015-06-22 ロンザ・リミテッド メデトミジンの調製のための方法
JP2015517473A (ja) * 2012-05-08 2015-06-22 ロンザ・リミテッド ２−（２，３−ジメチルフェニル）−１−プロパナールを調製するための方法
JP2015517475A (ja) * 2012-06-28 2015-06-22 ロンザ・リミテッド クロロアセトンを用いて２−（２，３−ジメチルフェニル）−１−プロパナールを調製するための方法
JP2015517474A (ja) * 2012-06-28 2015-06-22 ロンザ・リミテッド クロロアセトンを用いてメデトミジンを調製するための方法

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