CN101058571A - A process for the preparation of pyridine compounds - Google Patents

A process for the preparation of pyridine compounds Download PDF

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CN101058571A
CN101058571A CN 200710104432 CN200710104432A CN101058571A CN 101058571 A CN101058571 A CN 101058571A CN 200710104432 CN200710104432 CN 200710104432 CN 200710104432 A CN200710104432 A CN 200710104432A CN 101058571 A CN101058571 A CN 101058571A
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P·阿莱格里尼
M·拉斯帕瑞尼
G·拉泽蒂
R·罗西
G·文蒂米利亚
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Dipharma Francis SRL
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Abstract

A process for the preparation of a compound of formula (I) or a salt thereof, both as the isomeric mixture and the individual isomers, wherein Q is =CR 8 - or =N-; each R 1 , R 2 , R 3 and R 4 is independently selected from hydrogen, halogen, hydroxy; nitro; C 1 -C 6 alkyl optionally substituted with hydroxy; alkylthio C 1 -C 6 ; C 1 -C 6 alkoxy optionally substituted with halogen or C 1 -C 6 alkoxy; phenyl-C 1 -C 6 alkyl; phenyl-C 1 -C 6 alkoxy; and - N(RaRb) wherein each Ra and Rb is independently hydrogen or C 1 -C 6 alkyl or Ra and Rb, taken together with the nitrogen atom they are linked to, form a saturated heterocyclic ring; and each R 5 , R 6 , R 7 and R 8 is independently selected from hydrogen, halogen, hydroxy; C1-C6 alkyl optionally substituted with hydroxy; alkylthio C 1 -C 6 ; C 1 -C 6 alkoxy optionally substituted with halogen; C 1 -C 6 alkyl-carbonyl, C 1 -C 6 alkoxy-carbonyl, and oxazol-2-yl; comprising converting a compound of formula (IV), or a salt thereof, wherein Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above, to said compound of formula (I), or a salt thereof, in the presence of a catalyst, if necessary in an organic solvent; and, if desired, converting a compound of formula (I) to a salt thereof to another compound of formula (I); and/or, if desired, resolving an isomeric mixture of a compound of formula (I) in the individual isomers.

Description

The method for preparing pyridine compounds
Invention field
The present invention relates to prepare and be used for the treatment of, particularly treat the novel method that increases relevant pathological pyridine compounds with gastric secretion.
Technical background
Sulfinyl compound as proton pump inhibitor is used to treat and the relevant pathology of gastric secretion increase.These examples for compounds that are called as " drawing azoles " are omeprazole, esomeprazole, pantoprazole, rabeprazole, lansoprazole, tenatoprazole and Hydroxyomeprazole.
The synthetic of these products carries out according to the schema that this paper reported basically, wherein R 1-R 7For example has defined implication in the present disclosure with Q.
Obviously, their preparation method needs the step of many complexity.In addition, the committed step in the currently known methods be with thioether (S-) intermediate oxidation, thus obtain corresponding sulfinyl (SO-) derivative.The normally preferred oxygenant of hydrogen peroxide and clorox.But the secure context that a large amount of hydrogen peroxide are handled the operator relates to very big danger.In addition, because simultaneous over oxidation process, (S-) oxidization of intermediates also may produce undesirable sulfone (SO that must remove to thioether 2-) derivative.This relates to, and productive rate reduces and the aftertreatment time is longer.Therefore, the method that needs the other favourable described compound of preparation.
Summary of the invention
Had been found that the novel method of the pyridine compounds of preparation formula (I) now, this method has overcome above-mentioned technical problem and to be equal to or higher than pyridine derivate or its salt that 99.5% purity has obtained formula (I).
Detailed Description Of The Invention
Target of the present invention is the method for formula (I) compound or its salt of preparation isomer mixture form or single isomeric forms,
Figure A20071010443200061
Wherein
Q is=CR 8-or=N-;
R 1, R 2, R 3And R 4Be selected from hydrogen, halogen, hydroxyl independently of one another; Nitro; The optional C that is replaced by hydroxyl 1-C 6Alkyl; C 1-C 6Alkylthio; Optional by halogen or C 1-C 6The C that alkoxyl group replaces 1-C 6Alkoxyl group; Phenyl-C 1-C 6Alkyl; Phenyl-C 1-C 6Alkoxyl group; And wherein Ra and Rb are hydrogen or C independently of one another 1-C 6Alkyl or Ra and Rb with the nitrogen-atoms that they linked to each other form saturated heterocyclic-N (RaRb); And
R 5, R 6, R 7And R 8Be selected from hydrogen, halogen, hydroxyl independently of one another; The optional C that is replaced by hydroxyl 1-C 6Alkyl; C 1-C 6Alkylthio; The optional C that is replaced by halogen 1-C 6Alkoxyl group; C 1-C 6Alkyl-carbonyl, C 1-C 6Alkoxyl group-carbonyl and  azoles-2-base; This method is included under the existence of catalyzer, if desired, in organic solvent formula (IV) compound or its salt is changed into described formula (I) compound or its salt,
Figure A20071010443200062
Wherein Q, R 1, R 2, R 3, R 4, R 5, R 6And R 7As above definition, and if desired, formula (I) compound is changed into its salt or another kind of formula (I) compound; And/or, if desired, the isomer mixture of formula (I) compound is split into single isomer.
Formula (IV) compound also can be shown below
Figure A20071010443200071
Wherein Q and R 1-R 7As above definition.
Formula (I) or (IV) the salt preferred acid or the base addition salt of compound, preferred pharmacologically acceptable salt.
The isomer of formula (I) compound can be for example geometrical isomer or optically active isomer, preferred (R)-or (S)-enantiomer.
R in above definition 1-R 8Alkyl in one of substituting group can be a straight or branched, preferred C 1-C 4Alkyl, particularly methyl, ethyl, propyl group, sec.-propyl, butyl or the tertiary butyl, more preferably methyl, ethyl or propyl group.
Halogen is fluorine, chlorine, bromine or iodine, preferred fluorine, chlorine or bromine.
The C that hydroxyl replaces 1-C 6The C that alkyl is preferably replaced by one or two hydroxyl 1-C 4Alkyl, particularly-CH 2OH.
The C that is replaced by halogen 1-C 6Alkoxyl group is preferably by one, two or three halogen atoms, the more preferably C that is replaced by two or three fluorine atoms 1-C 4Alkoxyl group, particularly-OCHF 2Or-OCH 2CF 3
By C 1-C 6The C that alkoxyl group replaces 1-C 6Alkoxyl group is preferably by C 1-C 4The C that alkoxyl group replaces 1-C 4Alkoxyl group, particularly C 1-C 3Alkoxyl group-OCH 3
The preferred amino of-N (RaRb) group, methylamino, ethylamino, propyl group amino, dimethylamino.When Ra formed saturated heterocyclic with Rb with the nitrogen-atoms that they linked to each other, it can be optional 5-or the 6-unit heterocycle that comprises other nitrogen or Sauerstoffatom.Described examples of groups is pyrrolidino, piperidino-(1-position only), Piperazino and morpholino.
Especially preferred formula I compound as defined above, wherein:
Q is=CH-or=N-;
R 2Be hydrogen or the optional C that is replaced by hydroxyl 1-C 4Alkyl;
R 3Be optional by C 1-C 4The C that alkoxy or halogen replaces 1-C 4Alkoxyl group;
R 4Be C 1-C 4Alkyl or C 1-C 4Alkoxyl group;
R 6Be hydrogen, the optional C that is replaced by halogen 1-C 4Alkoxyl group;
R 7Be hydrogen or C 1-C 4Alkoxyl group;
R 1And R 5Be hydrogen;
Or its salt.
The particular example of formula (I) compound is:
2-(3,4-dimethoxy-pyridine-2-yl) methylsulfinyl-5-difluoro-methoxy-1H-benzoglyoxaline (pantoprazole);
2-(4-chloro-3-Methoxy Pyridine-2-yl) methylsulfinyl-5-difluoro-methoxy-1H-benzoglyoxaline;
5-methoxyl group-2-{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline (omeprazole);
5-methoxyl group-2-{[(4-methoxyl group-3-methyl-5-hydroxymethyl-2-pyridyl)-and methyl] sulfinyl }-1H-benzoglyoxaline (Hydroxyomeprazole);
2-{[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline (lansoprazole);
2-{[3-methyl-4-(3-methoxyl group-propoxy-)-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline (rabeprazole); With
5-methoxyl group-2-{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-imidazo [4,5-b] pyridines (tenatoprazole);
And their salt.
Compound (IV) or its salt can approximately-10 ℃ carry out to the scope of the reflux temperature of solvent or reaction mixture to the conversion of compound (I) or its salt.
Catalyzer has the metal catalyst of avidity typically to oxygen, this catalyzer is based on being selected from following metal: Ti (II), Ti (IV), V (II), V (III), V (V), Cr (II), Cr (III), Mn (III), Mn (IV), Fe (II), Fe (III), Nb (III), Mo (II), Mo (III), Mo (IV), Mo (V), W (II), W (III), W (IV), Tc (III), Re (III), Re (V), Ru (II), Ru (III), Ru (IV), Os (II), Os (III), Os (IV), Os (VI), Pd (II), Hf (IV), Pt (II) or Hg (II) or two or more the mixture in them, preferably two kinds mixture in them, and this catalyzer is selected from following part by 1 to 8 and replaces: halogenide (for example muriate or bromide), oxyhydroxide, C 1-C 6Alkoxide; carboxylate salt (for example acetate or tartrate); carbonate; supercarbonate; inorganic acid salt (for example vitriol or phosphoric acid salt); prussiate; cyanate; thiocyanate-; two thiolate (ethane-1 for example; 2-two thiolate); thiocarbamate dialkyl (for example dithiocarbamic acid diethyl ester); enolate (for example acetyl-pyruvate); phosphine (for example triphenylphosphine or tricyclohexyl phosphine); (for example BINAP (2 for the chirality phosphine; 2 '-two (diphenylphosphino)-1; 1 '-dinaphthalene); cyclopentadienyl anion; carbon monoxide; alkene (ethene and 1; the 4-cyclooctadiene); aromatic hydrocarbons (benzene); carbene (benzylidene (benzylidene)); heterocyclic carbene (inferior imidazolinyl (imidazolinidene)); the peptide cyanines; porphyrin (in-tetraphenylporphyrin); amine (for example triethylamine and piperidines); (for example quadrol and azepine-big ring is as 1 for chelating amine; 4; 7; the 10-tetraazacyclododecanand); heterocyclic ligand (for example 1; the 10-phenanthroline; 8-hydroxyl or thiooxine or 2; 2 '-dipyridyl); ethylenediamine tetraacetic acid (EDTA) and salt thereof; nitrilo acetate and salt thereof; glyoxylic acid oxime ester (glyoxylic acid oxime dimethyl esters) and two-imine ligand (Salens ((R for example; R)-N; N '-two (3; 5-two-tertiary butyl salicylidene)-1, the 2-cyclohexane diamine)); tartrate and acid amides.
Catalyzer is preferred as defined above based on being selected from a kind of of following metal: V (II), V (III), V (V), Mo (II), Mo (III), Mo (IV), Mo (V), W (II), W (III), W (IV), Re (III), Re (V) and Ru (II), Ru (III), Ru (IV), or two or more the mixture in them, preferably two kinds mixture in them, and this catalyzer is selected from following part by 1 to 8 and replaces: halogenide (for example muriate and bromide), C 1-C 4Alkoxide, carbonate, ethylenediamine tetraacetic acid (EDTA) and salt thereof (for example sodium salt) and two-imine ligand (Salens ((R, R)-N, N '-two (3,5-two-tertiary butyl salicylidene)-1,2-cyclohexane diamine)) for example.
Described catalyzer can prepare respectively or in-situ preparing according to known method.
The typical amount of described catalyzer is 0.5% mole to 20% mole of compound (IV) amount, preferred 1% mole to 10% mole.
Organic solvent can be protonic solvent or aprotic solvent, typically is ether, for example tetrahydrofuran (THF), two  alkane, ether; Chlorated solvent, for example methylene dichloride, ethylene dichloride, zellon, chlorobenzene or dichlorobenzene; C 1-C 6Alkanol, for example methyl alcohol, ethanol or Virahol; Aliphatic series or aromatic hydrocarbon, for example toluene; Or ester, for example ethyl acetate or butylacetate; Dipolar aprotic solvent, for example acetonitrile, dimethyl formamide, N,N-DIMETHYLACETAMIDE or dimethyl sulfoxide (DMSO); Or the mixture of two or more described solvents, the particularly mixture of 2 kinds or 3 kinds described solvents.
Can compound (I) be changed into another kind of compound (I) or its salt with known method is optional, and the isomer mixture of compound (I) is split into single isomer.
Compound (IV) or its salt can be as reporting among the ES 2063705, for example by with formula (II) compound and compound (III) or its salt in the presence of alkaline reagents and reaction at room temperature prepare,
Figure A20071010443200101
R wherein 1, R 2, R 3And R 4As above definition, X is a leavings group,
Figure A20071010443200102
Wherein Q, R 5, R 6And R 7As above definition.
If desired, by method of the present invention, need not from reaction mixture, to separate promptly and thus obtained compound (IV) or its salt can be transformed an accepted way of doing sth (I) compound or its salt.
If desired, according to known method, need not from reaction mixture, to separate promptly and compound (IV) or its salt can be changed into another kind of compound (IV) or its salt.
Formula (II) and (III) compound and salt thereof are known and can be according to known method preparation that wherein some is commercially available.
Formula (II) or (III) the salt preferred acid or the base addition salt of compound, preferred pharmacologically acceptable salt.
Have been noted that, according to ES 2063705, by also (S-) intermediate is oxidized to sulfoxide and (SO-) compound (IV) can be changed into lansoprazole with thioether subsequently with the reduction of N-oxide groups, but, it relates to simultaneous over oxidation process, and this process causes undesirable sulfo group (SO 2-) generation of derivative.
R wherein 3Be-O (CH 2) 3-OCH 3, R 4Be CH 3, R 1, R 2And R 5-R 7Be that hydrogen and Q are=CH-; And R 3And R 4Be OCH 3R 6Be-OCHF 2, R 1, R 2, R 5And R 7Be hydrogen and Q be=compound and the salt thereof of the formula (IV) of CH-is new compound and is another target of the present invention.
Method of the present invention to be to be equal to or higher than 99.5%, and typically being higher than 99.9% purity provides pyridine derivate or its salt of formula (I), thereby has satisfied the adjusting needs.Therefore, obviously formula (I) compound or its salt of gained does not contain or does not contain substantially undesirable sulfo group (SO 2-) derivative.
Following examples are used for illustrating the present invention.
Embodiment 1
2-(4-chloro-3-Methoxy Pyridine-2-yl) methylsulfinyl-5-difluoro-methoxy-1H-benzoglyoxaline
In being installed, magnetic stirring apparatus, reflux exchanger and the three neck round-bottomed flasks of the 50mL in nitrogen atmosphere add RuCl 3(63.1mg, 0.30mmol), THF (2.0mL) and 1,4-two  alkane (2.0mL).Then, the aqueous solution (the 0.13M that adds the ETDA trisodium, 2.37mL, 0.30mmol), (about 80 ℃) drip 2-(4-chloro-3-methoxyl group-1-oxygen yl pyridines-2-ylmethyl sulfane base)-5-difluoro-methoxy-1H-benzoglyoxaline (1.178g under refluxing then, 3.05mmol) 1, the solution in the 4-two  alkane (12mL).After 1 hour, with mixture cooling, vaporising under vacuum remove desolvate and by flash chromatography with required product purification.
1H NMR (300MHz, CDCl 3): δ 8.12 (1H, d, J=5.0Hz), 7.54 (1H, d, J=8.7Hz), 7.33 (1H, s), 7.25 (1H, d, J=5.0Hz), 7.08 (1H, dd, J=8.7,2.4Hz), 6.52 (1H, t, J=74.1Hz), 4.87 ﹠amp; 4.78 (2 * 1H, the AB system, J=13.2Hz), 3.85 (3H, s).
According to identical method, 1-oxygen yl pyridines derivative separately begins certainly, can obtain following compound:
5-methoxyl group-2-{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline;
5-methoxyl group-2-{[(4-methoxyl group-3-methyl-5-hydroxymethyl-2-pyridyl)-and methyl] sulfinyl }-the 1H-benzoglyoxaline;
2-{[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline;
2-{[3-methyl-4-(3-methoxyl group-propoxy-)-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline; With
5-methoxyl group-2-{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-imidazo [4,5-b] pyridine.
Embodiment 2
2-(3,4-dimethoxy-pyridine-2-yl) methylsulfinyl-5-difluoro-methoxy-1H-benzoglyoxaline (pantoprazole)
In being installed, magnetic stirring apparatus, reflux exchanger and the three neck round-bottomed flasks of the 25mL in nitrogen atmosphere add RuCl 3(27.0mg, 0.13mmol), THF (1.0mL), H 2O (0.05mL), ETDA three sodium hydrates (46.7mg, 0.13mmol).Then, drip 2-(3,4-dimethoxy-1-oxygen yl pyridines-2-ylmethyl sulfane base)-5-difluoro-methoxy-1H-benzoglyoxaline (500.0mg, 1.30mmol) 1, the solution in the 4-two  alkane (6mL) and with this mixture heating up to reflux (about 80 ℃).After 1 hour, with mixture cooling, vaporising under vacuum remove desolvate and by flash chromatography with required product purification.
1H NMR (300MHz, d6-DMSO+NaOD) δ 8.23 (1H, d, J=5.4Hz), 7.46 (1H.d, J=8.7Hz), 7.26 (1H, d, J=4.8Hz), 7.08 (1H, d, J=5.7Hz), 7.03 (1H, t, JHF=84Hz), 6.74 (1H, dd, J=5.7,2.4Hz), 4.63 ﹠amp; 4.38 (2 * 1H, the AB system, J=12Hz), 3.90 (3H, s), 3.78 (3H, s).
Embodiment 3
2-(4-chloro-3-Methoxy Pyridine-2-yl) methylsulfinyl-5-difluoro-methoxy-1H-benzoglyoxaline
In being installed, magnetic stirring apparatus, reflux exchanger and the three neck round-bottomed flasks of the 100mL in nitrogen atmosphere are incorporated in the 4-chloro-2-chloromethyl-3-Methoxy Pyridine N-oxide compound (8.9g among the 40mL THF, 43mmol), then, add 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline (9.3g, 43mmol) and triethylamine (13g, 128mmol) the solution in 20mL THF keeps its temperature to be lower than 40 ℃.After 3 hours, add entry (30mL), obtain clear soln, and add 10%HCl to pH=5.
Then, add ETDA three sodium-hydrates (1.54g, 4.3mmol) and RuCl 3(0.9g).With mixture heating 8 hours under 60 ℃, nitrogen, remove by diatomite filtration and vaporising under vacuum and to desolvate.Residue is also passed through purification by flash chromatography with ethyl acetate extraction, thereby obtain title compound.
According to identical method, can obtain following compound:
5-methoxyl group-2-{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline;
5-methoxyl group-2-{[(4-methoxyl group-3-methyl-5-hydroxymethyl-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline;
2-{[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline;
2-{[3-methyl-4-(3-methoxyl group-propoxy-)-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline; With
5-methoxyl group-2-{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-imidazo [4,5-b] pyridine.
Embodiment 4
2-(4-(2,2, the 2-trifluoro ethoxy)-3-picoline-2-yl) methylsulfinyl-1H-benzoglyoxaline (lansoprazole)
In magnetic stirring apparatus, reflux exchanger and the three neck round-bottomed flasks of the 25mL in nitrogen atmosphere are installed, add Ru[(EDTA) H] Cl}NaH 2O (100mg, 0.21mmol), water (20mL).With this mixture heating up to 50 ℃.Then, under identical temperature, add 2-(4-(2,2, the 2-trifluoro ethoxy)-3-methyl isophthalic acid-oxygen yl pyridines-2-yl) methyl sulfane base-1H-benzoglyoxaline (1.79g, 4.84mmol) solution in ethanol (50mL).Stir after 1 hour, with the mixture cooling, and 2-(4-(2,2, the 2-trifluoro ethoxy)-3-picoline-2-yl) methylsulfinyl-1H-benzoglyoxaline is precipitated out.Product is filtered and drying under vacuum.Productive rate: 50%.
1H NMR (300MHz, d6-DMSO) δ 8.29 (1H, d), 7.62 (2H.m, broad peaks), 7.28 (2H, d), 7.07 (1H, d), 4.88 (2H, dd), 4.76 (2H, dd), 2.16 (3H, s).
Embodiment 5
2-{[3-methyl-4-(3-methoxy propoxy)-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline (I) (rabeprazole)
In magnetic stirring apparatus, reflux exchanger and the three neck round-bottomed flasks of the 25mL in nitrogen atmosphere are installed, add 2-{[3-methyl-4-(3-methoxy propoxy)-1-oxygen base-2-pyridyl) methyl] the sulfane base }-the 1H-benzoglyoxaline (0.4g, 1.1mmol), acetonitrile (10mL), Quilonum Retard (75mg), RuCl 3(18mg, 0.1mmol) and NaVO 3(15mg, 0.12mmol).Analyze with this mixture heating up backflow 2 hours and by HPLC, show to obtain 2-{[3-methyl-4-(3-methoxy propoxy)-2-pyridyl of 5%] methyl } sulfinyl }-the 1H-benzoglyoxaline.
Embodiment 6
5-methoxyl group-2-{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline (omeprazole)
In being installed, magnetic stirring apparatus, reflux exchanger and the three neck round-bottomed flasks of the 50mL in nitrogen atmosphere add RuCl (PPh 3) (SALEN) (SALEN=salicylic aldehyde (salycilaldehyde)-ethylenediamine adduct) (0.77mg, 0.0028mmol), 5-methoxyl group-2-{[(4-methoxyl group-3,5-dimethyl-1-oxygen base-2-pyridyl) methyl] the sulfane base }-the 1H-benzoglyoxaline (100mg, 0.289mmol) and methylene dichloride (3.0mL).Iodobenzene of adding and 0.5mg AgOAc also stir this solution and spend the night under refluxing in thus obtained solution.Then, evaporation remove desolvate and by flash chromatography with the residue purifying, obtain the 10mg omeprazole.
1H NMR (300MHz, CDCl 3): δ 8.24 (1H, s), 7.58 (1H, m, broad peaks), 7.08 (1H, m, broad peaks), 6.96 (1H, dd), 4.78 ﹠amp; (4.60 2 * 1H, AB system), 3.87 (3H, s), 3.72 (3H, s), 2.25 (3H, s), 2.23 (3H, s).
According to identical method, 1-oxygen yl pyridines derivative separately begins certainly, can obtain following compound:
5-methoxyl group-2-{[(4-methoxyl group-3-methyl-5-hydroxymethyl-2-pyridyl)-and methyl] sulfinyl }-the 1H-benzoglyoxaline;
2-(4-chloro-3-Methoxy Pyridine-2-yl) methylsulfinyl-5-difluoro-methoxy-1H-benzoglyoxaline;
2-{[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline;
2-{[3-methyl-4-(3-methoxyl group-propoxy-)-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline; With
5-methoxyl group-2-{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-imidazo [4,5-b] pyridine.

Claims (11)

1. the method for preparing formula (I) compound or its salt of isomer mixture form or single isomeric forms,
Wherein
Q is=CR 8-or=N-;
R 1, R 2, R 3And R 4Be selected from hydrogen, halogen, hydroxyl independently of one another; Nitro; The optional C that is replaced by hydroxyl 1-C 6Alkyl; C 1-C 6Alkylthio; Optional by halogen or C 1-C 6The C that alkoxyl group replaces 1-C 6Alkoxyl group; Phenyl-C 1-C 6Alkyl; Phenyl-C 1-C 6Alkoxyl group; And wherein Ra and Rb are hydrogen or C independently of one another 1-C 6Alkyl or Ra and Rb with the nitrogen-atoms that they linked to each other form saturated heterocyclic-N (RaRb); And
R 5, R 6, R 7And R 8Be selected from hydrogen, halogen, hydroxyl independently of one another; The optional C that is replaced by hydroxyl 1-C 6Alkyl; C 1-C 6Alkylthio; The optional C that is replaced by halogen 1-C 6Alkoxyl group; C 1-C 6Alkyl-carbonyl, C 1-C 6Alkoxyl group-carbonyl and  azoles-2-base; This method is included under the existence of catalyzer, if desired, in organic solvent formula (IV) compound or its salt is changed into described formula (I) compound or its salt,
Figure A2007101044320002C2
Wherein Q, R 1, R 2, R 3, R 4, R 5, R 6And R 7As above definition, and if desired, formula (I) compound is changed into its salt or another kind of formula (I) compound; And/or, if desired, the isomer mixture of formula (I) compound is split into single isomer.
2. the described method of claim 1, its Chinese style (IV) compound or its salt approximately-10 ℃ is carrying out to the scope of the reflux temperature of solvent or reaction mixture to the conversion of formula (I) compound or its salt.
3. the described method of claim 1, wherein catalyzer is based on and is selected from a kind of in the following metal: V (II), V (III), V (V), Mo (II), Mo (III), Mo (IV), Mo (V), W (II), W (III), W (IV), Re (III), Re (V) and Ru (II), Ru (III), Ru (IV), or two or more the mixture in them, and described catalyzer is replaced by 1 to 8 part.
4. the described method of claim 3, wherein part is selected from halogenide, C 1-C 4Alkoxide, carbonate, ethylenediamine tetraacetic acid (EDTA) or its salt and two-imine ligand.
5. according to the process of claim 1 wherein that the amount of catalyzer is 0.5% mole to 20% mole of amount of formula (IV) compound.
6. the described method of claim 5, wherein the amount of catalyzer is 1% mole to 10% mole.
7. according to the process of claim 1 wherein that organic solvent is selected from ether, chlorated solvent, C 1-C 6Alkanol; Aliphatic series or aromatic hydrocarbon, ester solvent, dipolar aprotic solvent or two kinds of mixtures to four kinds of described solvents.
8. the described method of claim 7, wherein solvent is selected from tetrahydrofuran (THF), two  alkane, ether, methylene dichloride, ethylene dichloride, zellon, chlorobenzene, dichlorobenzene, methyl alcohol, ethanol, Virahol, toluene, ethyl acetate, butylacetate, acetonitrile, dimethyl formamide, N,N-DIMETHYLACETAMIDE and dimethyl sulfoxide (DMSO).
9. according to the process of claim 1 wherein in formula (I) compound
Q is=CH-or=N-;
R 2Be hydrogen or the optional C that is replaced by hydroxyl 1-C 4Alkyl;
R 3Be optional by C 1-C 4The C that alkoxy or halogen replaces 1-C 4Alkoxyl group;
R 4Be C 1-C 4Alkyl or C 1-C 4Alkoxyl group;
R 6Be hydrogen, the optional C that is replaced by halogen 1-C 4Alkoxyl group;
R 7Be hydrogen or C 1-C 4Alkoxyl group;
R 1And R 5Be hydrogen.
10. be selected from according to the formula of the process of claim 1 wherein (I) compound:
2-(3,4-dimethoxy-pyridine-2-yl) methylsulfinyl-5-difluoro-methoxy-1H-benzoglyoxaline;
2-(4-chloro-3-Methoxy Pyridine-2-yl) methylsulfinyl-5-difluoro-methoxy-1H-benzoglyoxaline;
5-methoxyl group-2-{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline;
5-methoxyl group-2-{[(4-methoxyl group-3-methyl-5-hydroxymethyl-2-pyridyl)-and methyl] sulfinyl }-the 1H-benzoglyoxaline;
2-{[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline;
2-{[3-methyl-4-(3-methoxyl group-propoxy-)-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline (rabeprazole); With
5-methoxyl group-2-{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-imidazo [4,5-b] pyridine; Or its salt.
11. formula (IV) compound or its salt,
Figure A2007101044320004C1
Wherein:
R 3Be-O-(CH 2) 3-OCH 3, R 4Be CH 3, Q is=CH-; And R 1, R 2And R 5-R 7Be hydrogen; Perhaps
R 3And R 4Be OCH 3R 6Be-OCHF 2, and Q is=CH-; And R 1, R 2, R 5And R 7Be hydrogen.
CN 200710104432 2006-04-21 2007-04-20 A process for the preparation of pyridine compounds Pending CN101058571A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103058997A (en) * 2012-12-25 2013-04-24 吉林修正药业新药开发有限公司 Synthesis method of thioether nitrogen oxides (2-{[4-(3-methoxy-propoxy)-3-methyl nitrogen-oxygen pyridine-2-group] methylmercapto}-1H-benzimidazole)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103058997A (en) * 2012-12-25 2013-04-24 吉林修正药业新药开发有限公司 Synthesis method of thioether nitrogen oxides (2-{[4-(3-methoxy-propoxy)-3-methyl nitrogen-oxygen pyridine-2-group] methylmercapto}-1H-benzimidazole)

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