CN1045773C - Preparation method of pyridine derivant - Google Patents
Preparation method of pyridine derivant Download PDFInfo
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- CN1045773C CN1045773C CN94110342A CN94110342A CN1045773C CN 1045773 C CN1045773 C CN 1045773C CN 94110342 A CN94110342 A CN 94110342A CN 94110342 A CN94110342 A CN 94110342A CN 1045773 C CN1045773 C CN 1045773C
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Abstract
The present invention relates to a new method for preparing a compound with the following molecular formula. The medicine is an H(+), K(+)-ATP enzyme inhibitor and has effects on preventing and treating digestive system ulcer (such as gastric ulcer and duodenal ulcer) and gastritis. The pyridine system compound has the structure that 1, when the R1 is hydrogen, the R2 is methyl, and the R3 is 2, 2, 2-trifluoroethyl; when the R1 is difluoromethoxy, the R2 is methoxy, the R3 is methyl, and the represents 0 or 1.
Description
The present invention relates to a kind of preparation method who has been used to prevent and treat the active drug-pyridine derivate of digestive system and ulcer and gastritis, it is suitable for suitability for industrialized production.
At present, some have the useful pyridine derivate of antiulcer activity by known, and this is from disclosed patent documentation US4, and 188,486, US4,255,431, US4,472,409, obtain narration among EP0166287, the CN85106134.And instability of the physicochemical property aspect that exists at these known compounds and the shortcoming that is easy to decompose have produced existing gastric acid inhibitory secretion, and the pyridine derivate of enhancing gastric mucosal protective effect is arranged again.Two compound 2-[[4-(2 that the present invention relates to have been comprised in the above-mentioned pyridine derivate; 2; the 2-trifluoro ethoxy)-and 3-picoline-2-yl] methylsulfinyl]-1H-benzimidazolyl and 5-difluoro-methoxy-2-[(3,4-dimethoxy-pyridine-2-yl] methylsulfinyl]-the 1H-benzimidazolyl.Known preparation method is different, a kind of docking calculation is the method that adopts benzimidazolyl ring and the butt joint of pyridine ring two-part structure, its butt joint synthesis yield is lower, about 70-80%, the synthetic general dithiocarbonic anhydride that uses of mercaptobenzoimidazole, by product sulfuration argon pollutes environment, and this method comprises and with chemical structural formula is
Compound (R herein
1Be H or difluoro-methoxy), with structural formula be
Compound reaction, generate compound (I) (R herein
2Be methyl or methoxy, R
3Be methyl or 2,2,2-trifluoroethyl, X
1And X
2One of them is SH, and another is a kind of leavings group).Another kind of docking calculation is to carry out the butt joint that ring-closure reaction is realized two-part structure with O-Phenylene Diamine and mercapto formic acid, and this method comprises and with chemical structural formula is
Compound (R herein
1Be H or difluoro-methoxy), with structural formula be
Compound reaction, generate compound (I) (R herein
2Be methyl or methoxy, R
3Be methyl or 2,2, the 2-trifluoroethyl).Generally in acidic aqueous solution, because product is unstable in acidic aqueous solution, so quality product is bad for operation condition.
The preparation method who the purpose of this invention is to provide a kind of improved pyridine derivate, it adopts O-Phenylene Diamine, and symphysis becomes the method for benzimidazolyl to realize the butt joint of two-part structure with mercapto formic acid alicyclic ring, synthesis yield is more than 90%, sulfydryl is to introduce by the thiocarbamide reaction in the structure, do not produce sulfuration argon gas body, effectively prevent the pollution of the environment.
The object of the present invention is achieved like this: this pyridine derivate has the structure of structure formula I
Wherein, work as R
1During for argon, R
2Be methyl, R
3Be 2,2, the 2-trifluoroethyl.Work as R
1During for difluoro-methoxy, R
2Be methoxyl group, R
3Be methyl, and n represents 0 or 1.
The preparation method of this compound comprises the compound reaction of the compound that makes following structural (II) and structure formula III, in case of necessity, resultant of reaction is carried out oxidation.
(R herein
2And R
3Identical with above-mentioned definition, R
4Alkyl for C1-C4).
Pyridine derivate of the present invention (I) (n=0) can be used the method preparation of compound (II) and compound (III) reaction, and wherein compound ii is free alkali or its salt, preferred free alkali, the R of compound III
4Be low alkyl group.
This is reflected under the neutrallty condition and carries out, and reaction solvent is arene (a for example benzene,toluene,xylene).Temperature of reaction is in 0 ℃ usually extremely near between the solvent boiling point, and preferred 80-120 ℃, the reaction times is 0.5-36 hour, preferred 20-25 hour.Product (I) (n=0) is slightly soluble in toluene, and corresponding formula II and formula III all are soluble in the toluene, therefore, (n=0) easily separated purification of the product that this method produces (I), good product quality, yield is higher, and general yield is more than 90%.
Sulfonyl derivative of the present invention (I) (n=1) can be used oxygenated compound (I) method preparation (n=0), and the used oxygenant of this reaction is a peracid, for example metachloroperbenzoic acid, hydrogen peroxide.This reaction solvent for use comprises methylene dichloride and trichloromethane.The preferred amounts of used oxygenant is about monovalent or excessive slightly (n=0) for compound (I), promptly about 1-3 equivalent, more preferably use 1-1.3 equivalent oxygenant, temperature of reaction from-10 ℃ between the boiling point that uses solvent, usually reaction at room temperature, preferably-10-0 ℃ between, about 1-24 of reaction times hour, preferred 3-5 hour.
Raw material (II) adopts commercially available O-Phenylene Diamine
Compound (R wherein with molecular formula (VII)
2And R
3Identical with aforesaid definition) can with thiocarbamide reacting generating compound (VIII).This reaction solvent for use is ethanol, methyl alcohol or water, temperature of reaction 0-100 ℃, and preferred 80-100 ℃, reaction times 0.1-3 hour.
Compound (VIII) is carried out alkaline hydrolysis, generate compound (IX).This alkali is example with argon sodium oxide, argon potassium oxide, salt of wormwood.Reaction solvent is an example with the mixed solution of methyl alcohol, second alcohol and water, the common 0-100 of temperature of reaction ℃, and preferred 0-20 ℃, reaction times 0.1-20 hour, preferred 2-4 hour.
With compound (IX) and chloro-formic ester (ClCO2R
4, R
4Be the C1-C4 alkyl) reaction, generate compound (III), use solvent to be example with chloroform, methane dioxide and four argon furans, temperature of reaction 0-70 ℃, reaction times 1-24 hour.
The preparation of raw material [4-(2,2,2-trifluoro second argon base)-3-picoline-2-yl] methylthio group ethyl formate:
The first step:
With 2-chloromethyl-4-(2,2, the 2-trifluoro ethoxy)-3-picoline hydrochloride 27.6 grams, thiocarbamide 9.1 gram and 95% ethanol 120ml, add in the reaction flask successively, reflux 3 hours adds 2M argon aqueous solution of sodium oxide 120ml again after the cooling, stirred 5 hours under the room temperature, cooling, suction filtration, washing, drying, get white solid 4-(2,2, the 2-trifluoro ethoxy)-3-methyl-2-thiopurine methyltransferase pyridine 19.7 grams, mp126-8 ℃, NMR (CDCl
3) δ: 2.30 (3H, s), 4.35 (2H, q, J=7.5), 4.40 (2H, s), 5.9 (1H, s), 6.64 (1H, d, J=6), 8.44 (1H, d, J=6).
Second step:
With 4-(2,2, the 2-trifluoro ethoxy)-3-methyl-2-thiopurine methyltransferase pyridine 11.9 grams, be dissolved among the four argon furans 100ml, be cooled to 0 ℃, add Vinyl chloroformate 5.7ml and triethylamine 8.4ml, stirred 4 hours under the room temperature, suction filtration, mother liquor concentrate to be done, add acetic acid ethyl dissolution, wash once anhydrous magnesium sulfate drying, concentrating under reduced pressure gets yellow oil, and [4-(2,2, the 2-trifluoro ethoxy)-3-picoline-2-yl] methylthio group ethyl formate 14.7 grams, NMR (CDCl
3) δ: 1.30 (3H, t), 2.31 (3H, S), 4.10 (2H, q), 4.36 (2H, q, J=7.5), 4.45 (2H, S), 6,64 (1H, d, J=6), 8.42 (1H, d, J=6).
The preparation of raw material (3,4-dimethoxy-pyridine-2-yl) methylthio group ethyl formate:
The first step:
With 2-chloromethyl-3,4-dimethoxy pyridine hydrochloride 22.8 grams, thiocarbamide 9.1 grams and 95% ethanol 120ml add in the reaction flask successively, reflux 3 hours, cooling adds 2M argon potassium oxide aqueous solution 120ml again, stirred 10 hours under the room temperature, cooling, chloroform extraction, anhydrous magnesium sulfate drying, concentrating under reduced pressure, get white solid 2-thiopurine methyltransferase-3.4-dimethoxy pyridine hydrochloride 15.4 grams, mp113-5 ℃, NMR (CDCl
3) δ: 3.80 (3H, s), 3.82 (3H, s), 4.44 (2H, s), 5.50 (1H, s), 6.68 (1H, d, J=6), 8.10 (1H, d, J=6).
Second step:
With 2-thiopurine methyltransferase-3,4-dimethoxy-pyridine 9.5 grams, be dissolved among the methylene dichloride 100ml, be cooled to 0 ℃, add Vinyl chloroformate 5.7ml and triethylamine 8.4ml, stirring at room 5 hours, after the washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure get yellow oil (3,4-dimethoxy-pyridine-2-yl) methylthio group ethyl formate 11.8 grams, NMR (CDCl
3) δ: 1.32 (3H, t), 3.80 (3H, s), 3.83 (3H, s), 4.18 (2H, q), 4.45 (2H, s), 6.70 (1H, d, J=6), 8.12 (1H, d, J=6).
In the following example, will describe the preparation of compound (I) in detail.
Embodiment 1
The first step:
With [[4-(2,2, the 2-trifluoro ethoxy)-3-picoline-2-yl] methyl] sulphur ethyl formate 14.0 restrains, O-Phenylene Diamine 5.4 gram and toluene 100ml, adds reaction flask successively, reflux 24 hours, be cooled to below 5 ℃, crystallization is separated out, suction filtration, toluene wash, dry white solid 2-[[4-(2,2, the 2-trifluoro ethoxy)-3-picoline-2-yl] methylthio group]-1H-benzimidazolyl 15.3 grams, mp149-150 ℃.NMR(CDCl
3)δ:2.30(3H,S),4.39(2H,q,J=7.5),4.40(2H,S),6.66(1H,d,J=6),7.05-7.65(4H,m),8.40(1H,d,J=6)。
Second step:
With 2-[[4-(2; 2; the 2-trifluoro ethoxy)-and 3-picoline-2-yl] methylthio group]-1H-benzimidazolyl 7.0 gram is dissolved among the chloroform 100ml; the ice-water bath cooling down; add metachloroperbenzoic acid 3.5 grams; stirring at room 5 hours; wash with 10% solution of potassium carbonate; washing back anhydrous magnesium sulfate drying, liquid contract crude product, the dehydrated alcohol recrystallization; get white solid 2-[[4-(2; 2, the 2-trifluoro ethoxy)-3-picoline-2-yl] methylsulfinyl]-1H-benzimidazolyl 6.2 grams, mp165-8 ℃ (dec).NMR(CDCl
3)δ:2.18(3H,S),4.33(2H,q,J=7.5),4.75(2H,m),6.63(1H,d,J=6),7.15-7.90(4H,m),8.32(1H,d,J=6)。
Embodiment 2
The first step:
With [(3,4-dimethoxy-pyridine-2-yl) methyl] sulphur ethyl formate 12.6 grams, 5-difluoro-methoxy O-Phenylene Diamine 12.4 gram and toluene 100ml add reaction flask successively, reflux 5 hours is cooled to below 5 ℃, and crystallization is separated out, suction filtration, toluene wash, dry white solid 5-dioxy methoxyl group-2-[(3, the 4-dimethoxy-pyridine-2-yl of getting) methylthio group]-1H-benzimidazolyl 16.2 grams, mp118-9 ℃, NMR δ: 3.92 (3H, S), 3.94 (3H, S), 4.40 (2H, S), 6.51 (1H, t, J=74.6), 6.86 (1H, d, J=6), and 6.98-7.62 (3H, m), 8,26 (1H, d, J=6), 12.5 (1H, br).
Second step:
With 5-difluoro-methoxy-2-[(3; 4-dimethoxy-pyridine-2-yl] methylthio group]-1H-benzimidazolyl 7.4 gram is dissolved among the methylene dichloride 100ml; the ice-water bath cooling down; add metachloroperbenzoic acid 3.5 grams; stirring at room 5 hours; wash with 10% wet chemical; washing back anhydrous magnesium sulfate drying gets crude product; the Virahol recrystallization; get white solid 5-difluoro-methoxy-2-[(3; 4-dimethoxy-pyridine-2-yl] methylsulfinyl]-1H-benzimidazolyl 7.0 grams, mp138-139 ℃ (dec), NMR (CDCl
3) δ: 3.90 (3H, S), 3.92 (3H, S), 4.47 (2H, S), 6.51 (1H, t, J=74.6), 6.86 (1H, d, J=6), 7.05-7.55 (3H, m), 8.26 (1H, d, J=6), 12.6 (1H, br).
Claims (1)
1, a kind of method for preparing pyridine derivate, this pyridine derivate structural formula is:
Wherein work as R
1During for argon, R
2Be methyl, R
3Be 2,2,2 one trifluoroethyls; Work as R
1During for difluoro-methoxy, R
2Be methoxyl group, R
3Be methyl, and n represents 0 or 1, comprising using following formula: compound
With compound
Reaction, in addition oxidation more in case of necessity, it is characterized in that this is reflected at carries out under the neutrallty condition, and reaction solvent is an arene, R in the formula
1, R
2, R
3Identical with above-mentioned definition, R
4Be the C1-C4 alkyl.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4472409A (en) * | 1981-11-05 | 1984-09-18 | Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung | 2-Pyridylmethyl thio(sulfinyl)benzimidazoles with gastric acid secretion inhibiting effects |
EP0166287A1 (en) * | 1984-06-16 | 1986-01-02 | Byk Gulden Lomberg Chemische Fabrik GmbH | Dialkoxyridines, process for their preparation, their application and medicaments containing them |
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1994
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4472409A (en) * | 1981-11-05 | 1984-09-18 | Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung | 2-Pyridylmethyl thio(sulfinyl)benzimidazoles with gastric acid secretion inhibiting effects |
EP0166287A1 (en) * | 1984-06-16 | 1986-01-02 | Byk Gulden Lomberg Chemische Fabrik GmbH | Dialkoxyridines, process for their preparation, their application and medicaments containing them |
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