WO2012172119A2 - Procédé de préparation de médétomidine - Google Patents

Procédé de préparation de médétomidine Download PDF

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Publication number
WO2012172119A2
WO2012172119A2 PCT/EP2012/070870 EP2012070870W WO2012172119A2 WO 2012172119 A2 WO2012172119 A2 WO 2012172119A2 EP 2012070870 W EP2012070870 W EP 2012070870W WO 2012172119 A2 WO2012172119 A2 WO 2012172119A2
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WO
WIPO (PCT)
Prior art keywords
reaction
compound
formula
acid
reagent
Prior art date
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PCT/EP2012/070870
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English (en)
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WO2012172119A3 (fr
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 KR1020147029915A priority Critical patent/KR101530506B1/ko
Priority to PL12784296T priority patent/PL2847173T3/pl
Priority to JP2015510660A priority patent/JP5779297B2/ja
Priority to NZ700640A priority patent/NZ700640B2/en
Priority to HRP20160215T priority patent/HRP20160215T1/hr
Priority to DK12784296.1T priority patent/DK2847173T3/en
Priority to MYPI2014002563A priority patent/MY166058A/en
Priority to AU2012285675A priority patent/AU2012285675B2/en
Priority to HK15102124.8A priority patent/HK1201532B/xx
Priority to ES12784296.1T priority patent/ES2563816T3/es
Priority to US14/386,054 priority patent/US9045433B2/en
Priority to PCT/EP2012/072796 priority patent/WO2013011155A2/fr
Priority to CN201280072266.6A priority patent/CN104245679B/zh
Priority to HUE12784296A priority patent/HUE027384T2/en
Priority to EP12784296.1A priority patent/EP2847173B1/fr
Priority to IN7983DEN2014 priority patent/IN2014DN07983A/en
Priority to CA2866424A priority patent/CA2866424A1/fr
Priority to SG11201405606RA priority patent/SG11201405606RA/en
Priority to EA201400940A priority patent/EA025950B1/ru
Publication of WO2012172119A2 publication Critical patent/WO2012172119A2/fr
Publication of WO2012172119A3 publication Critical patent/WO2012172119A3/fr
Priority to TW102116032A priority patent/TWI529164B/zh
Priority to CL2014002905A priority patent/CL2014002905A1/es
Anticipated expiration legal-status Critical
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
    • C07D233/58—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 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C07C1/20—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms
    • C07C1/24—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms by elimination of water
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/18—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part
    • C07C33/20—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part monocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
    • C07C45/58—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in three-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/228—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing six-membered aromatic rings, e.g. phenylacetaldehyde
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/04—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • C07C2531/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • C07C2531/025—Sulfonic acids

Definitions

  • the invention discloses a method for the preparation of medetomidine starting from 1-bromo 2,3-dimethylbenzene and acetone.
  • 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
  • salicylaldehyde derivative with ethylene diamine or with a substituted ethylene diamine
  • the method comprises a 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 ⁇ , ⁇
  • 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.
  • 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.
  • 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, Na 2 C0 3 and mixtures thereof;
  • compound (M) is NaCN or ammonia.
  • 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.
  • 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.
  • the reaction time of reaction (Ml) is from 30 min to 72 h, more preferably from 1 h to 48 h, even more preferably from 2 h 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;
  • the temperature may be modified continuously during the reaction.
  • 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 (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).
  • the amount of solvent (M) is from 0.5 to 20 fold, more preferably from 1 to 10 fold, even more preferably of from 2 to 5 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 (M-acid detrit) 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 steps, a step (Ml-Al-1) and a 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) and in a 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
  • mol equivalents Preferably from 1 to 10 mol equivalents, more preferably from 1 to 5 mol equivalents, even more preferably from 1 to 3 mol equivalents of compound (M) are used in reaction (Ml- Al-2), the mol equivalents being based on the mol of compound of formula (XXI).
  • M1-A2 comprises two steps, a step (M1-A2-1) and a 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 a 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 (XXI).
  • 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)
  • reaction (Ml- A2-2) Preferably from 1 to 10 mol equivalents, more preferably from 1 to 5 mol equivalents, even more preferably from 1 to 3 mol equivalents of compound (M) are used in reaction (Ml- 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 with reagent (M-A) in a 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 10 mol equivalents, more preferably from 1 to 5 mol equivalents, even more preferably from 1 to 3 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.
  • the volatile components of the reaction mixture are removed by evaporation under reduced pressure.
  • 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_s 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 (M-acid) is preferably selected from the group consisting of oxalic acid, citric acid, maleic acid, fumaric acid, tartaric acid, NH 4 C1, HCl, HBr, H 2 S0 4 , H 3 PO 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,
  • 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
  • a 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);
  • base is selected from the group consisting of NaHC0 3 , Na 2 C0 3 , NaOH and mixtures thereof.
  • base (M-basify) 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 .
  • 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 (Mcryst).
  • compound of formula (XXI) is prepared in a step (N);
  • step (N) comprises a reaction (N);
  • reaction (N) is a reaction of 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
  • 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 is aluminosilicates.
  • the acidic ion exchange resin 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, with which the carbon was treated is selected from the group consisting of HC1, H 2 S0 4 and HN0 3 .
  • the 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 , aluminosilicates, acidic ion exchange resins, carbon treated with HC1, H 2 S0 4 or FiN0 3 , and mixtures thereof; more preferably, the 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 , aluminosilicates
  • reaction (N) is done in a solvent (N);
  • solvent (N) is selected from the group consisting of water, tert-butanol, isopropanol,
  • acetonitrile preferably from water, acetonitrile, propionitrile, THF, 2-methyl-THF, 1,2-dimethoxyethane, dichloromethane, 1 ,2-dichloroethane, chloroform, toluene, cyclohexane, ethyl acetate, acetic acid, formic acid and mixtures thereof;
  • 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 :20 to 1 : 1, especially from 1 : 10 to 1 :2.
  • the 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 2 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.
  • 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).
  • compound of formula (XXII) is prepared in a step (O) or in two steps, the two steps are step (01) and step (02);
  • step (O) comprises a reaction (O);
  • reaction (O) is a reaction of compound of formula (XXIII), with a reagent (O);
  • reagent (O) is selected from the group consisting of peracetic acid, trifluoroperacetic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid, dimethyldioxirane, tert- butylhydroperoxide, dibenzoyl peroxide, cumenehydroperoxide, oxygen, air, sodium hypochlorite, oxone, KHSO 5 , Na 2 0 2 , aqueous H 2 0 2 , H 2 0 2 dissolved in acetic acid, H 2 0 2 dissolved in trifluoroacetic acid, and mixtures thereof; step (01) comprises a reaction (01);
  • reaction (01) is a reaction of compound of formula (XXIII) with water and with a compound
  • step (02) comprises a reaction (02);
  • reaction (02) is a reaction of the reaction product from reaction (01) with a base (02);
  • base (02) is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide and mixture thereof.
  • reagent (O) is selected from the group consisting of peracetic acid, tert- butylhydroperoxide, oxygen, air, sodium hypochlorite, aqueous H 2 0 2 , H 2 0 2 dissolved in acetic acid, H 2 0 2 dissolved in trifluoroacetic acid, and mixtures thereof;
  • reagent (O) is aqueous H 2 0 2 .
  • reaction (O) is done in a solvent (O);
  • solvent (O) is selected from the group consisting of water, aqueous solutions of NaHC0 3 , Na 2 C0 3 , (NH 4 )HC0 3 , (NH 4 ) 2 C0 3 , KHC0 3 or K 2 C0 3 , benzene, toluene, NMP, dioxane, acetone, ethyl acetate, methylethylketone, tert-butanol, acetonitrile, chloroform, dichloromethane and mixtures thereof;
  • aqueous solutions of NaHC0 3 , Na 2 C0 3 , KHC0 3 or K 2 C0 3 , toluene, dioxane, acetone, ethyl acetate, methylethylketone, tert-butanol, acetonitrile,
  • Reaction (O) can be done in the presence of a catalyst (O);
  • catalyst (O) is selected from the group consisting of trifluoroacetic acid, trifluoroacetone, Mn(salen) complex, aldehydes, N-methylmorpholine N-oxide, 2,2,6, 6-tetramethylpiperidine 1-oxyl and mixtures thereof;
  • aldehydes are preferably isobutyraldehyde or benzaldehyde.
  • Reaction (O) can be done in the presence of a buffer (O);
  • buffer (O) is an aqueous buffer and is selected from the group consisting of K 2 C0 3 / EDTA-Na 2 buffer, phosphate buffer and other buffers known by the skilled person;
  • buffer (O) is an K 2 C0 3 / EDTA-Na 2 buffer.
  • reaction temperature of reaction (O) is from -20 to 100 °C, more preferably from -10 to 80 °C, even more preferably from 0 to 50 °C.
  • the reaction (O) can be done in a system, that is closed or open to the atmosphere.
  • the pressure depends on the boiling point of a solvent (O) and on the
  • 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. More preferably the reaction (O) is done in an open system.
  • reaction time of reaction (O) is from 30 min to 72 h, more preferably from 1 h to 48 h, even more preferably from 2 h to 24 h.
  • reaction (O) the 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.
  • reaction (01) and reaction (02) are conducted in solvent (O), with solvent (O) as defined above, also with all its preferred embodiments.
  • reaction temperatures of reaction (01) and of reaction (02) are identical or different and independently from each other from -20 to 100 °C, more preferably from -10 to 80 °C, even more preferably from 0 to 50 °C.
  • Reaction (01) and reaction (02) can independently from each other be done in systems, that are closed or open to the atmosphere.
  • the pressure depends on the boiling point of a solvent (O) and on the reaction temperature of reaction (01) and reaction (O) respectively.
  • reaction (01) and reaction (02) are independently from each other done at pressures 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 (01) and reaction (02) are done in a open system.
  • reaction times of reaction (01) and of reaction (02) are independently from each other from 30 min to 72 h, more preferably from 1 h to 48 h, even more preferably from 2 h to 24 h.
  • the reaction product of reaction (01) and the compound of formula (XXII) from reaction (02) can be isolated by standard methods such as evaporation of volatile components, extraction, washing, drying, concentration, filtration, crystallization, distillation,
  • reaction (01) and reaction (02) can be done consecutively without isolation of the reaction product of reaction (01), they can be done in one pot.
  • step (N) is done directly after step (O) or step (02) respectively in one pot.
  • catalyst (N) is simply added to the reaction mixture resulting from reaction (O) or from reaction (02) respectively.
  • compound of formula (XXIII) is prepared in a step (P);
  • step (P) comprises a reaction (P);
  • temperature (P) is from 5 to 200 °C, more preferably from 100 to 150 °C.
  • Reaction (P) can be done in a solvent (P);
  • solvent (P) is selected from the group consisting of benzene, toluene, xylene, hexane, heptane,
  • benzene preferably from benzene, toluene, xylene, dichloromethane and mixtures thereof.
  • reaction (P) is done in the presence of a catalyst (P);
  • catalyst (P) 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 , KOH, NaOH, KHS0 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 , 1 2 , A1 2 0 3 , SnCl 4 , TiCl 4 , Ti(0-alkyl) 4 , ZrCl 4 , Bi 2 0 3 , BiCl 3 , ZnCl 2 , PbCl 2 , FeCl 3 , Yb(OTf) 3 , Yb(Cl) 3 , GaCl 3 , AlBr 3 , Ce(OTf) 3 , LiCl, acidic insoluble inorganic solid, acidic
  • the Al(0-alkyl)3 and the Ti(0-alkyl)4 in the list of possible compounds for catalyst (P) are Al(0-Ci_ 4 alkyl) 3 and Ti(0-Ci_ 4 alkyl) 4 .
  • the acidic insoluble inorganic solid is acidic aluminosilicates or silica gel.
  • the inorganic acid, with which the carbon was treated is selected from the group consisting of HC1, H 2 S0 4 and HN0 3 .
  • the acidic ion exchange resin is selected from the group consisting of copolymers of styrene and divinylbenzene and of perfluorinated branched or linear polyethylenes, these polymers being functionalized with S0 3 H groups;
  • the acidic ion exchange resin is selected from the group consisting of
  • reaction (P) is done in the presence of a catalyst (P), temperature (P) is preferably from 0 to 200 °C, more preferably from 10 to 150 °C, even more preferably from 10 to 100 °C.
  • Reaction (P) can be done in gas phase by passing evaporated compound of formula (XXIV) through a heated tube, the heated tube can be charged with a catalyst (P).
  • step (Ql) comprises a reaction (Ql) by a reaction of compound of formula (XXV) with a reagent (Ql);
  • Q is Br, CI, or I
  • step (Q 1 ) is selected from the group consisting of lithium, magnesium, aluminum, zinc, calcium, isopropylmagnesium chloride, isopropylmagnesium bromide, butyllithium, sec- butyllithium and mixtures thereof; step (Q2) comprises a reaction (Q2);
  • reaction (Q2) is a reaction of the reaction product of reaction (Ql) with acetone; in step (Q3) comprises a reaction (Q3);
  • reaction (Q3) is a reaction of the reaction product of reaction (Q2) with a reagent (Q3); reagent (Q3) is selected from the group consisting of water, methanol, ethanol, oxalic acid, citric acid, NH 4 C1, HCl, HBr, HNO 3 , H 2 S0 4 , H 3 PO 4 , acetic acid, propionic acid, formic acid and mixtures thereof.
  • Q is Br.
  • reagent (Ql) is selected from the group consisting of lithium, magnesium, aluminum, isopropylmagnesium chloride, isopropylmagnesium bromide and mixtures thereof.
  • Reaction (Ql) can be catalyzed with a catalyst (Ql).
  • Catalyst (Ql) is selected from the group consisting of iodine, 1 ,2-dibromoethane, TiCl 4 ,
  • reagent (Q3) is water or aqueous NH 4 C1.
  • reaction (Ql) is performed in a solvent (Ql).
  • reaction (Q2) is performed in a solvent (Q2).
  • reaction (Q3) is performed in a solvent (Q3).
  • solvent (Ql), solvent (Q2) and solvent (Q3) are identical or different and
  • the solvent (Ql), solvent (Q2) and solvent (Q3) are identical.
  • the reaction temperatures of reaction (Ql), of reaction (Q2) and of reaction (Q3) are identical or different and idependently from each other preferably from -100 to 150 °C, more preferably from -60 to 100 °C, and even more preferably from -20 to 80 °C.
  • Reaction (Ql), reaction (Q2) and reaction (Q3) 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.
  • the reaction times of reaction (Ql), of reaction (Q2) and of reaction (Q3) are identical or different and idependently 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), of solvent (Q2) and of solvent (Q3) are are identical or different and idependently from each other preferably from 2 to 40 fold, more preferably from 3 to 10 fold, even more preferably from 5 to 7 fold, of the weight of compound of formula (XXV), of the weight of the reaction product of reaction (Ql) and of the weight of the reaction product of reaction (Q2) respectively.
  • 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 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 of acetone are used, the mol equivalents being based on the mol of compound of formula (XXV).
  • reagent Q3
  • the mol equivalents being based on the mol of compound of formula (XXV) or of the mol of the reaction product of reaction (Q2).
  • reaction (Ql), reaction (Q2) and reaction (Q3) are done at atmospheric pressure.
  • reaction (Ql), reaction (Q2) and reaction (Q3) are done under inert atmosphere.
  • the inert atmosphere is achieved by the use if an inert gas 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.
  • reaction product of reaction (Ql), the reaction product of reaction (Q2) and compound of formula (XXIV) respectively can be isolated by standard methods such as evaporation of volatile components, extraction, washing, drying, concentration, crystallization, distillation, chromatography and any combination thereof.
  • reaction product of reaction (Ql) and the reaction product of reaction (Q2) are not isolated.
  • reaction (Ql), reaction (Q2) and reaction (Q3) are done consecutively; preferably, reaction (Ql), reaction (Q2) and reaction (Q3) are done in one pot.
  • reaction (Ql) and reaction (Q2) can be done in one pot by adding reagent (Ql) to a mixture of compound of formula (XXV) and acetone in a solvent (Ql); reaction (Q3) is done thereafter, preferably in the same pot.
  • Compound of formula (XXIV) is preferably isolated using conventional methods, such as evaporation of volatile components, hydrolysis and optional acidification of the higher- boiling residue, extraction, and distillation.
  • aqueous phase can be extracted, preferably the extraction is done with a solvent (Q- extract).
  • Solvent is benzene, toluene, ethyl acetate, or isopropyl acetate.
  • Any organic phase can be dried, preferably with magnesium sulphate.
  • Any concentration is preferably done by distillation, preferably under reduced pressure.
  • the compound of formula (XXIV) can be purified, preferably by crystallization or distillation under reduced pressure.
  • TLC Chromatography
  • any organic phase can be dried, preferably over MgS0 4 or Na 2 S0 4 , if not stated otherwise.
  • subject of the invention is compound of formula (XXI).
  • the whole carbon framework of compound of formula (XX) is built in few chemical steps, using cheap reagents only.
  • No protecting groups are needed and the overall amount of material used is therefore reduced, the batch size based on molar amounts is increased.
  • no trityl or acetal protection groups are used and no protection of the imidazoles is necessary.
  • the method has good yields.
  • EI Electron ionization mass spectra (70 eV), they were obtained on an AMD-604 spectrometer.
  • THF was distilled from sodium/benzophenone ketyl prior to use; the obtained anhydrous THF is called "dry THF" in the following text.
  • Example 1 2-(2,3-Dimethylphenyl)propan-2-ol, compound of formula (XXIV), prepared via an organomagnesium intermediate
  • the l-bromo-2,3- dimethylbenzene solution (1.0 mL) was added via a dropping funnel and the reaction was initiated by the addition of 1 ,2-dibromoethane (3 drops), and then the rest of the l-bromo-2,3- dimethylbenzene solution was added.
  • the content of the dropping funnel was added at such a rate to maintain slight reflux.
  • the mixture was refluxed for 1 h and then cooled to 0 °C.
  • a solution of dry acetone (4.2 mL, 58 mmol) in dry THF (15 mL) was added dropwise and the mixture was stirred at a temperature between 0 and 20 °C for 3 h.
  • a buffer was prepared by dissolving K 2 C0 3 (20.7 g) and EDTA-Na 2 (11.5 mg) in water (100 mL).
  • l,2-Dimethyl-3-(2-propenyl)benzene, compound of formula (XXIII), prepared according to example 3 (0.90 g, 6.16 mmol) was dissolved in a mixture of dichloromethane and acetonitrile (v/v 1 : 1 , 60 mL), and the buffer prepared as described above (9.3 mL) was added.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (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 d'acétone.
PCT/EP2012/070870 2012-05-08 2012-10-22 Procédé de préparation de médétomidine Ceased WO2012172119A2 (fr)

Priority Applications (21)

Application Number Priority Date Filing Date Title
PCT/EP2012/072796 WO2013011155A2 (fr) 2012-05-08 2012-11-15 Procédé de préparation de médétomidine
CN201280072266.6A CN104245679B (zh) 2012-05-08 2012-11-15 美托咪定的制备方法
JP2015510660A JP5779297B2 (ja) 2012-05-08 2012-11-15 メデトミジンの調製のための方法
NZ700640A NZ700640B2 (en) 2012-05-08 2012-11-15 Method for preparation of medetomidine
HRP20160215T HRP20160215T1 (hr) 2012-05-08 2012-11-15 Postupak za pripravu medetomidina
DK12784296.1T DK2847173T3 (en) 2012-05-08 2012-11-15 METHOD OF PRODUCING Medetomidine
MYPI2014002563A MY166058A (en) 2012-05-08 2012-11-15 Method for preparation of medetomidine
AU2012285675A AU2012285675B2 (en) 2012-05-08 2012-11-15 Method for preparation of medetomidine
HK15102124.8A HK1201532B (en) 2012-05-08 2012-11-15 Method for preparation of medetomidine
PL12784296T PL2847173T3 (pl) 2012-05-08 2012-11-15 Sposób wytwarzania medetomidyny
US14/386,054 US9045433B2 (en) 2012-05-08 2012-11-15 Method for preparation of medetomidine
KR1020147029915A KR101530506B1 (ko) 2012-05-08 2012-11-15 메데토미딘 제조 방법
EP12784296.1A EP2847173B1 (fr) 2012-05-08 2012-11-15 Procédé de préparation de médétomidine
ES12784296.1T ES2563816T3 (es) 2012-05-08 2012-11-15 Método de preparación de medetomidina
HUE12784296A HUE027384T2 (en) 2012-05-08 2012-11-15 A method for preparing medetomidine
IN7983DEN2014 IN2014DN07983A (fr) 2012-05-08 2012-11-15
CA2866424A CA2866424A1 (fr) 2012-05-08 2012-11-15 Procede de preparation de medetomidine
SG11201405606RA SG11201405606RA (en) 2012-05-08 2012-11-15 Method for preparation of medetomidine
EA201400940A EA025950B1 (ru) 2012-05-08 2012-11-15 Способ получения медетомидина
TW102116032A TWI529164B (zh) 2012-05-08 2013-05-06 製備美托咪啶之方法
CL2014002905A CL2014002905A1 (es) 2012-05-08 2014-10-27 Un metodo para la preparacion de medetomidina a partir de 1-bromo-2,3-dimetilbenceno y acetona, util como agente sedante y analgesico veterinario.

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US201261644284P 2012-05-08 2012-05-08
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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
JP2018505179A (ja) * 2015-01-30 2018-02-22 カンブレックス カルルスクーガ アクチ ボラケットＣａｍｂｒｅｘ Ｋａｒｌｓｋｏｇａ Ａｂ メデトミジンの合成に有用な３−アリールブタナールなどの化合物の調製方法
WO2018051964A1 (fr) 2016-09-14 2018-03-22 株式会社スクウェア・エニックス Dispositif, procédé et programme d'affichage vidéo
CN111903674A (zh) * 2020-08-05 2020-11-10 马保臣 一种质量均一稳定的过硫酸氢钾复合粉及其制备工艺
CN117384006A (zh) * 2023-12-08 2024-01-12 寿光市诚信盐业有限公司 一种溴苯的制备方法

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Cited By (10)

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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
JP2018505179A (ja) * 2015-01-30 2018-02-22 カンブレックス カルルスクーガ アクチ ボラケットＣａｍｂｒｅｘ Ｋａｒｌｓｋｏｇａ Ａｂ メデトミジンの合成に有用な３−アリールブタナールなどの化合物の調製方法
WO2018051964A1 (fr) 2016-09-14 2018-03-22 株式会社スクウェア・エニックス Dispositif, procédé et programme d'affichage vidéo
CN111903674A (zh) * 2020-08-05 2020-11-10 马保臣 一种质量均一稳定的过硫酸氢钾复合粉及其制备工艺
CN111903674B (zh) * 2020-08-05 2022-07-12 马保臣 一种质量均一稳定的过硫酸氢钾复合粉及其制备工艺
CN117384006A (zh) * 2023-12-08 2024-01-12 寿光市诚信盐业有限公司 一种溴苯的制备方法
CN117384006B (zh) * 2023-12-08 2024-04-19 寿光市诚信盐业有限公司 一种溴苯的制备方法

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