CN103524494A - Sulfydryl imidazole derivative comprising picoline group and synthetic method - Google Patents
Sulfydryl imidazole derivative comprising picoline group and synthetic method Download PDFInfo
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- CN103524494A CN103524494A CN201310547332.7A CN201310547332A CN103524494A CN 103524494 A CN103524494 A CN 103524494A CN 201310547332 A CN201310547332 A CN 201310547332A CN 103524494 A CN103524494 A CN 103524494A
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract
The invention discloses a sulfydryl imidazole derivative comprising a picoline group and a synthetic method. According to the structure general formula of the sulfydryl imidazole derivative, R1 is a hydrogen atom or methyl, R2 is C1-6 alkyl or chlorine/fluoro alkyl, and R3 is methyl or ethyl or p-chlorophenyl or p-methylphenyl or p-methoxyphenyl or p-nitrophenyl. The sulfydryl imidazole derivative is used for replacing a benzimidazole derivative in a pantozol medicine structure, imidazole-derivative-replacing pyridyl sulfoxide compounds are synthesized, the compounds have the similarity with the pantozol medicine structure and have the same effective group, and medicine active molecules which have better curative effect and lower toxic and side effect than an existing proton pump inhibitor does can be screened from the compounds.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of mercaptoimidazole analog derivative that has latent effect in preparing preventing/treating digestive ulcer medicament.
Background technology
As the azole drug that draws of acid inhibitor, the effort through numerous scientific research personnel, has developed into a huge family, as: omeprazole, lansoprazole, rabeprazole, esomeprazole etc.Although through improvement for many years, proton pump inhibitor effect has obvious lifting, but still unavoidably there is unsatisfactory place,, even in some case, can there is gastric mucosal cell hyperplasia and atrophic gastritis in the side effects such as indivedual colonies still can produce as diarrhoea, headache, feel sick, stomachache, flatulence, constipation, fash, dizzy, drowsiness and insomnia.The people such as Per Lindberg, Peter Nordberg and Tomas Alminger are at J. Med. Chem., 1986,29 (8), 1327 have proved the drug mechanism of the proton pump inhibitors such as omeprazole in detail, pyridine nitrogen atom can obtain a proton and carry out protonated for the first time, then pass through the series reaction such as prototropy, the interior covalency of molecule, rearrangement, the-sulfinic acid compounds of formation is combined with proton pump involved enzyme, thereby has realized the inhibition of proton pump.Jai Moo Shin, Young Moon Cho and George Sachs be at J. Am. Chem. Soc., this mechanism of action done to checking and further research in 2004,126 (25), 7800, and drawn the calculation formula of medicine inhibition strength.The important research from above two authoritys, the mother nucleus structure that the pyridyl sulfoxide compound that benzoglyoxaline replaces forms is the common feature that draws azole drug, is also to play the inhibiting main group of proton pump.The a series of azole drug that draws is all to make certain chemically modified around this mother nucleus structure, to retain or to strengthen original curative effect of medication, thereby reduces the untoward reaction of original medicine.The present invention is as starting point, with mercaptoimidazole derivative, replaces and draws the benzimidizole derivatives in azole drug structure, synthesizes the pyridyl sulfoxide compound that imdazole derivatives replaces, and so far there are no reported for this compounds.Based on this type of novel compound with draw the similarity of azole drug structure and possess identical effective group, we have very large hope can therefrom filter out the pharmaceutical activity molecule that has better curative effect and lower toxic side effect than existing proton pump inhibitor.At present, the oxidation that the most effective synthetic method of sulfoxide compound is sulfide compound, the present invention introduces the pyridyl sulfide compound high-efficiency synthesis method that novel imidazole derivatives replaces, and carries out medicinal design prepare for sulfoxide synthetic.
Summary of the invention
Object of the present invention is exactly the problem existing for prior art, and a kind of proton pump inhibitor precursor that has better curative effect and lower toxic side effect than existing proton pump inhibitor is provided---containing the mercaptoimidazole analog derivative of picoline group.
Another object of the present invention is to provide the synthetic method containing the mercaptoimidazole analog derivative of picoline group.
For realizing above-mentioned purpose of the present invention, the present invention containing the mercaptoimidazole analog derivative of picoline group by the following technical solutions.
The present invention containing the general structure of the mercaptoimidazole analog derivative of picoline group is:
Wherein: R
1for hydrogen atom or methyl, R
2for C
1 ~ 6alkyl or chlorine/fluoro-alkyl, R
3for methyl, ethyl, rubigan, p-methylphenyl, p-methoxyphenyl or p-nitrophenyl.
Preferred compound is: R
1for hydrogen atom or methyl, R
2for C
1 ~ 3alkyl or chlorine/2,2,2-trifluoroethyl, R
3for methyl, ethyl, rubigan, p-methylphenyl or p-nitrophenyl.
Further preferred compound is: R
1for hydrogen atom or methyl, R
2for methyl, ethyl or trifluoroethyl, R
3for methyl, ethyl, p-methylphenyl or rubigan.
24 kinds of compounds below:
The present invention also provides the synthetic method of the above-mentioned mercaptoimidazole analog derivative containing picoline group, comprises following reaction process and reactions steps, condition:
1) reaction equation is:
2) reactions steps, condition: by 1.1, when content of starting materials 2 use dissolve with methanol, under room temperature, drip 1 ~ 3 equivalent methanol solution of sodium methylate, treat that mercaptan all changes into sodium mercaptides and drips 1 methanol solution when content of starting materials 1 again, dropwise rear temperature rising reflux; After reaction finishes, reclaim methyl alcohol, add a small amount of water dissolution inorganic salt, with dichloromethane extraction, organic phase is dry, evaporate to dryness obtains target compound---containing the mercaptoimidazole analog derivative of picoline group.
In above reaction formula, R
1, R
2and R
3as mentioned before.
The preparation of synthetic Raw 1 and raw material 2 is with reference to following methods:
The preparation of raw material 1:
I is mixed with glacial acetic acid, be warming up to 80 ~ 105 ℃, at this temperature, slowly drip 30% quantitative hydrogen peroxide, dropwising insulation reaction to raw material transforms completely, excessive hydrogen peroxide, with removing solvent acetic acid under reduced pressure after reductive agent reduction and water obtains crude product II, is not needed to process directly to enter nitration reaction; Crude product II is dripped to diluting concentrated sulfuric acid under ice bath, slowly be warming up to 80 ~ 95 ℃, at this temperature, slowly drip the nitration mixture of 65% concentrated nitric acid and the preparation of 98% vitriol oil, react completely reaction solution is cooling and pour in frozen water, with sodium carbonate, be neutralized to that weakly alkaline, organic solvent extraction, organic phase are dry, evaporate to dryness obtains crude product III, available ethyl alcohol recrystallization is to reach more high purity; III is dissolved in correspondent alcohol, in solution, adds quantitative salt of wormwood or sodium hydroxide, reflux, detection reaction completely after, pressure reducing and steaming solvent also reclaims, organic solvent extraction residue for, be dried, evaporate to dryness obtains IV; IV is dissolved with a small amount of acetic acid, drip wherein diacetyl oxide, temperature reaction is to completely, and acetic acid and diacetyl oxide are reclaimed in underpressure distillation, and residue is complete with 13%NaOH aqueous hydrolysis, neutralization, extraction, dry, the concentrated V that obtains; V is dissolved with methylene dichloride, the dichloromethane solution that drips sulfur oxychloride under ice bath carries out chlorination reaction, react completely underpressure distillation recovery part methylene dichloride and sulfur oxychloride obtains the concentrated solution of raw material 1, slowly drips wherein ethyl acetate and obtains white crystalline solid raw material 1.
The preparation of raw material 2:
Intermediate 2 be raw material 2 prepare reference literature Organic Syntheses., 1973,5,223. and document Synthetic Communications., 1997,27 (20), 3565..
The present invention is according to the medicine principle of proton pump inhibitor, with mercaptoimidazole derivative, replace and draw the benzimidizole derivatives in azole drug structure, the pyridyl sulfoxide novel cpd that the imdazole derivatives that synthesizes replaces with draw azole drug structure to have very large similarity and possess identical effective group, therefore must have certain proton pump restraining effect, compare proton pump inhibitor drug effect or enhancing or the reservation of listing or weaken, can filter out the pharmaceutical activity molecule with better curative effect and lower toxic side effect by bioassay.
Embodiment
For further describing the present invention, below by embodiment, the present invention is elaborated containing mercaptoimidazole analog derivative and the synthetic method of picoline group.
embodiment 1: the preparation of Compound I:
0.442g (2.1mmol) 2-sulfydryl-1-rubigan imidazoles is dissolved in 2mL methyl alcohol, drip the solution of 0.2g sodium methylate and 3mL methyl alcohol, until mercaptan, all convert to after sodium salt, drip 0.4443g (2mmol) 2-chloromethyl-4-methoxyl group-3, the 5mL methanol solution of 5-dimethyl pyrazole thiamine hydrochloride, backflow 3h detection reaction is complete, evaporated under reduced pressure methyl alcohol, after adding a small amount of water dissolution, use dichloromethane extraction, organic phase anhydrous sodium sulfate drying, evaporate to dryness obtains target product
i0.592g, productive rate 82.3%.
1H NMR (CDCl
3, 400 MHz)
δ (ppm): 2.41 (s, 3H, C
H 3 in py), 2.43 (s, 3H, C
H 3 in py), 4.12 (s, 3H, -OC
H 3), 4.57 (s, 2H, -C
H 2S-), 6.68 (s, 1H,
H in imidazole）, 6.74 (s, 1H,
H in imidazole), 7.53 (d, J = 8.4Hz, 2H,
H in Ph), 7.75 (d, J = 8.4Hz, 2H,
H in Ph) , 8.12 (s, 1H,
H in py)。
embodiment 2: the preparation of Compound I I:
0.443g (2.1mmol) 2-sulfydryl-1-rubigan imidazoles is dissolved in 2mL methyl alcohol, drip the solution of 0.2g sodium methylate and 3mL methyl alcohol, until mercaptan, all convert to after sodium salt, drip 0.3994g (2mmol) 2-chloromethyl-4-oxyethyl group-3, the 5mL methanol solution of 5-dimethyl pyrazole thiamine hydrochloride, backflow 3h detection reaction is complete, evaporated under reduced pressure methyl alcohol, adds a small amount of water dissolution, dichloromethane extraction, organic phase anhydrous sodium sulfate drying, evaporate to dryness obtains target product
iI0.602g, productive rate 80.5%.
1H NMR (CDCl
3, 400 MHz)
δ (ppm): 1.52 (t, J = 8.4Hz, 3H, -OCH
2C
H 3), 2.39 (s, 3H, C
H 3 in py), 2.44 (s, 3H, C
H 3 in py), 4.29 (q, 2H, -OC
H 2CH
3), 4.58 (s, 2H, -C
H 2S-), 6.72 (s, 1H,
H in imidazole), 6.81 (s, 1H,
H in imidazole), 7.57 (d, J = 8.4Hz, 2H,
H in Ph), 7.70 (d, J = 8.4Hz, 2H,
H in Ph), 8.16 (s, 1H,
H in py)。
embodiment 3: the preparation of compound VI:
0.443g (2.1mmol) 2-sulfydryl-1-rubigan imidazoles is dissolved in 2mL methyl alcohol, the solution that drips 0.2g sodium methylate and 3mL methyl alcohol, all converts to after sodium salt until mercaptan, drips 0.552g (2mmol) 2-chloromethyl-4-(2,2, the 5mL methanol solution of 2-trifluoro ethoxy)-3-picoline hydrochloride, backflow 3h detection reaction is complete, evaporated under reduced pressure methyl alcohol, add a small amount of water dissolution, dichloromethane extraction, organic phase anhydrous sodium sulfate drying, evaporate to dryness obtains target product
vI0.7g, productive rate 84.5%.
1H NMR (CDCl
3, 400 MHz)
δ (ppm): 2.21 (s, 3H, C
H 3 in py), 4.39 (q, 2H, -OC
H 2CF
3), 4.50 (s, 2H, -C
H 2S-), 6.69 (d, J = 8.0Hz, 1H,
H in py), 6.78 (s, 1H,
H in imidazole), 6.84 (s, 1H,
H in imidazole), 7.49 (d, J = 8.0Hz, 2H,
H in Ph), 7.64 (d, J = 8.0Hz, 2H,
H in Ph), 8.26 (d, J = 8.0Hz, 1H,
H in py)。
embodiment 4: the preparation of compounds X II:
0.2512g (2.2mmol) 2-sulfydryl-1-Methylimidazole is dissolved in 2mL methyl alcohol, the solution that drips 0.2g sodium methylate and 3mL methyl alcohol, all converts to after sodium salt until mercaptan, drips 0.552g (2mmol) 2-chloromethyl-4-(2,2, the 5mL methanol solution of 2-trifluoro ethoxy)-3-picoline hydrochloride, backflow 4h detection reaction is complete, evaporated under reduced pressure methyl alcohol, add a small amount of water dissolution, dichloromethane extraction, organic phase anhydrous sodium sulfate drying, evaporate to dryness obtains target product
xII0.536g, productive rate 84.45%.
1H NMR (CDCl
3, 400 MHz)
δ(ppm): 2.18 (s, 3H, C
H 3 in py), 3.23 (s, 3H, C
H 3 in imidazole), 4.42 (q, 2H, -OC
H 2CF
3), 4.56 (s, 2H, -C
H 2S-), 6.62 (d, J = 5.6 Hz, 1H,
H in py), 6.81 (s, 1H,
H in imidazole), 6.92 (s, 1H,
H in imidazole), 8.30 (d, J = 5.6Hz, 1H,
H in py)。
embodiment 5: the preparation of compounds X IX:
0.400g (2.1mmol) 2-sulfydryl-1-p-methylphenyl imidazoles is dissolved in 2mL methyl alcohol, drip the solution of 0.2g sodium methylate and 3mL methyl alcohol, until mercaptan, all convert to after sodium salt, drip 0.4443g (2mmol) 2-chloromethyl-4-methoxyl group-3, the 5mL methanol solution of 5-dimethyl pyrazole thiamine hydrochloride, backflow 3h detection reaction is complete, evaporated under reduced pressure methyl alcohol, adds a small amount of water dissolution, dichloromethane extraction, organic phase anhydrous sodium sulfate drying, evaporate to dryness obtains target product
xIX0.638g, productive rate 94%.
1H NMR (CDCl
3, 400 MHz)
δ(ppm): 2.38 (s, 3H, C
H 3 in py), 2.40 (s, 3H, C
H 3 in py), 2.62 (s, 3H, C
H 3 in Ph), 4.08 (s, 3H, -OC
H 3), 4.57 (s, 2H, -C
H 2S-), 6.63 (s, 1H,
H in imidazole), 6.71 (s, 1H,
H in imidazole), 7.21 (d, J = 8.4Hz, 2H,
H in Ph), 7.34 (d, J = 8.4Hz, 2H,
H in Ph), 8.10 (s, 1H,
H in py)。
embodiment 6: the preparation of compounds X XIV:
0.400g (2.1mmol) 2-sulfydryl-1-p-methylphenyl imidazoles is dissolved in 2mL methyl alcohol, drip the solution of 0.2g sodium methylate and 3mL methyl alcohol, until mercaptan, all convert to after sodium salt, drip 0.552g (2mmol) 2-chloromethyl-4-(2,2, the 5mL methanol solution of 2-trifluoro ethoxy)-3-picoline hydrochloride, backflow 3h detection reaction is complete, evaporated under reduced pressure methyl alcohol, add a small amount of water dissolution, dichloromethane extraction, organic phase anhydrous sodium sulfate drying, evaporate to dryness obtains target product
xXIV0.718g, productive rate 91.2%.
1H NMR (CDCl
3, 400 MHz)
δ (ppm): 2.45 (s, 3H, C
H 3 in py), 2.59 (s, 3H, C
H 3 in Ph), 4.37 (q, 2H, -OC
H 2CF
3), 4.48 (s, 2H, -C
H 2S-), 6.67 (d, J = 8.0Hz, 1H,
H in py), 6.64 (s, 1H,
H in imidazole), 6.72 (s, 1H,
H in imidazole), 7.12 (d, J = 8.0Hz, 2H,
H in Ph), 7.23 (d, J = 8.0Hz, 2H,
H in Ph), 8.18(d, J = 8.0Hz, 1H,
H in py)。
Claims (4)
1. containing a mercaptoimidazole analog derivative for picoline group, it is characterized in that its general structure is:
Wherein: R
1for hydrogen atom or methyl, R
2for C
1 ~ 6alkyl or chlorine/fluoro-alkyl, R
3for methyl, ethyl, rubigan, p-methylphenyl, p-methoxyphenyl or p-nitrophenyl.
2. containing a mercaptoimidazole analog derivative for picoline group, it is characterized in that its general structure is:
Wherein: R
1for hydrogen atom or methyl, R
2for C
1 ~ 3alkyl or chlorine/2,2,2-trifluoroethyl, R
3for methyl, ethyl, rubigan, p-methylphenyl or p-nitrophenyl.
3. containing a mercaptoimidazole analog derivative for picoline group, it is characterized in that its general structure is:
Wherein: R
1for hydrogen atom or methyl, R
2for methyl, ethyl or trifluoroethyl, R
3for methyl, ethyl, p-methylphenyl or rubigan.
4. the synthetic method of a kind of mercaptoimidazole analog derivative containing picoline group as described in claim 1,2 or 3, is characterized in that comprising following reaction process and reactions steps, condition:
1) reaction equation is:
2) reactions steps, condition: by 1.1, when content of starting materials 2 use dissolve with methanol, under room temperature, drip 1 ~ 3 equivalent methanol solution of sodium methylate, treat that mercaptan all changes into sodium mercaptides and drips 1 methanol solution when content of starting materials 1 again, dropwise rear temperature rising reflux; After reaction finishes, reclaim methyl alcohol, add a small amount of water dissolution inorganic salt, with dichloromethane extraction, organic phase is dry, evaporate to dryness obtains target compound---containing the mercaptoimidazole analog derivative of picoline group.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101070315A (en) * | 2007-05-11 | 2007-11-14 | 江苏工业学院 | Method for preparing omeprazole |
| CN101230057A (en) * | 2002-10-18 | 2008-07-30 | 阿斯利康(瑞典)有限公司 | Method for the synthesis of a benzimidazole compound |
-
2013
- 2013-11-07 CN CN201310547332.7A patent/CN103524494A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101230057A (en) * | 2002-10-18 | 2008-07-30 | 阿斯利康(瑞典)有限公司 | Method for the synthesis of a benzimidazole compound |
| CN101070315A (en) * | 2007-05-11 | 2007-11-14 | 江苏工业学院 | Method for preparing omeprazole |
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Application publication date: 20140122 |