CN104163786A - Method for preparing 5-methyl-3-bromomethylpyridine hydrobromide - Google Patents

Method for preparing 5-methyl-3-bromomethylpyridine hydrobromide Download PDF

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CN104163786A
CN104163786A CN201410254204.8A CN201410254204A CN104163786A CN 104163786 A CN104163786 A CN 104163786A CN 201410254204 A CN201410254204 A CN 201410254204A CN 104163786 A CN104163786 A CN 104163786A
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methyl
piconol
organic solvent
cycloheptapyridine
hydrobromate
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CN104163786B (en
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鲁彦
王进
郭建宇
黄敏飞
熊蕾
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Shanghai Institute of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals

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  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a method for preparing 5-methyl-3-bromomethylpyridine hydrobromide. The method comprises a step of preparing methyl 5-methyl nicotinate; a step of preparing 5-methyl-3-pyridinemethanol; a step of preparing 5-methyl-3-pyridinemethanol hydrobromide; and a step of preparing 5-methyl-3-bromomethylpyridine hydrobromide. In the step of preparing methyl 5-methyl nicotinate, esterification of 5-methyl nicotinic acid and thionyl chloride is carried out under heating reflux to obtain methyl 5-methyl nicotinate; in the step of preparing 5-methyl-3-pyridinemethanol, a reduction reaction of methyl 5-methyl nicotinate and sodium borohydride is carried out in an organic solvent to obtain 5-methyl-3-pyridinemethanol; in the step of preparing 5-methyl-3-pyridinemethanol hydrobromide, 5-methyl-3-pyridinemethanol reacts with hydrobromic acid to obtain 5-methyl-3-pyridinemethanol hydrobromide; and in the step of preparing 5-methyl-3-bromomethylpyridine hydrobromide, 5-methyl-3-pyridinemethanol hydrobromide reacts with hydrobromic acid in an organic solvent and water is removed from the reaction system to obtain 5-methyl-3-bromomethylpyridine hydrobromide. According to the method, 5-methyl-3-bromomethylpyridine hydrobromide is obtained by four steps; the process is simple; and yield is high.

Description

A kind of method of preparing 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate
Technical field
The invention belongs to chemical field, relate in particular to a kind of pharmaceutical intermediate 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, is a kind of method of the 5-of preparation methyl-3-bromo methyl cycloheptapyridine hydrobromate specifically.
Background technology
5-methyl-3-bromo methyl cycloheptapyridine is a crucial pharmaceutical intermediate in new drug development.Rupatadine is a novel medicine, and he produces and interact with specific acceptor, is potential platelet activating factor (PAF) and effective antagonist of histamine (H1).ES2042421 and WO2006114676 have reported the method for synthesizing Rupatadine by Desloratadine and 5-methyl-3-bromo methyl cycloheptapyridine method.WO2013000406 has reported the Benzocycloheptathiopcompounds derivative that has synthesized a series of anti-allergics, comprising using 5-methyl-3-bromo methyl cycloheptapyridine as substituent benzocyclohepta thiazole derivative.Transformation reactions is a kind of world ubiquity disease, therefore researches and develops the anti-allergic medicament that improves effect and reduce side effect very urgent.
WO2012097196 report has synthesized pyrazolopyrimidine analog derivative, this analog derivative can suppress the growth of multiple cancer cells, very effective to treatment cancer, these components also can be treated some and kinases (Aurora A, Aururo B, Aurora C, cMet, JAK2 etc.) the relevant disease of dysregulation, research shows, when substituting group is 5-methyl-3-bromo methyl cycloheptapyridine, compound is the most remarkable to the restraining effect of cMet.US20130274272 has announced pyridone-pyridine derivatives, and this compounds can effectively be treated the disease relevant with P38 kinases, as diseases such as lymphoma, self inflammation.When carrying out synthetic compound with 5-methyl-3-bromo methyl cycloheptapyridine, active better.
For synthesizing of 5-methyl-3-bromo methyl cycloheptapyridine, document has been reported several method.ES2042421 synthesizes 5-methyl-3-bromo methyl cycloheptapyridine by N-bromo-succinimide (NBS) bromination with 3,5-lutidine in tetracol phenixin, and yield is very low.In WO2006114676, added in addition Diisopropyl azodicarboxylate to participate in reaction, yield brings up to 67.66%.WO2013000406 has continued to use above-mentioned synthetic method.But, adopt above-mentioned two kinds of method raw materials to react all the time not exclusively, what obtain is monosubstituted and disubstituted mixture, two kinds of compound separation also more complicated and yield low.Raw material NBS used is high toxicity compound, and Diisopropyl azodicarboxylate is height inflammable compound, and reaction conditions is also harsher.
WO2012097196 generates after alcohol with 5-methylnicotinic acid methyl esters and lithium aluminum hydride reaction, then reaction generates 5-methyl-3-bromo methyl cycloheptapyridine bromate with Hydrogen bromide.This kind of method lithium aluminum hydride is expensive, in reaction heat release violent, poor stability.When we repeat this method, find, when 5-methyl-3-piconol generates 5-methyl-3-bromo methyl cycloheptapyridine bromate, raw material always can not complete reaction, and reaction has impurity to generate, and the reaction times reaches 18 hours.
Summary of the invention
For the defect existing in above-mentioned prior art, technical problem to be solved by this invention is to provide a kind of method of the 5-of preparation methyl-3-bromo methyl cycloheptapyridine hydrobromate, it is complicated that described this preparation method will solve preparation method's process of the prior art, the technical problem that yield is low.
A kind of method of preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate of the present invention, the step that comprises a preparation 5-methylnicotinic acid methyl esters, in the step of described preparation 5-methylnicotinic acid methyl esters, 5-methylnicotinic acid and sulfur oxychloride be reflux generation esterification in organic solvent, obtains 5-methylnicotinic acid methyl esters; The step of preparation 5-methyl-3-piconol, in the step of preparation 5-methyl-3-piconol, 5-methylnicotinic acid methyl esters in organic solvent and sodium borohydride generation reduction reaction, obtains 5-methyl-3-piconol; The step of preparation 5-methyl-3-piconol hydrobromate, in the step of preparation 5-methyl-3-piconol hydrobromate, 5-methyl-3-piconol and Hydrogen bromide reaction obtain 5-methyl-3-piconol hydrobromate; The step of preparation 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, in the step of preparation 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, 5-methyl-3-piconol hydrobromate reacts with Hydrogen bromide in organic solvent, water except in dereaction, obtains 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate.
Further, in the step of described preparation 5-methylnicotinic acid methyl esters, first measure first methyl alcohol, first methyl alcohol is joined in first reaction vessel, measure again 5-methylnicotinic acid, 5-methylnicotinic acid and first methyl alcohol volume ratio are 1.0:3.0～10.0, 5-methylnicotinic acid is dissolved in first methanol solvate, measure again sulfur oxychloride as catalyzer, the mol ratio of 5-methylnicotinic acid and sulfur oxychloride is 1.0:1.1～5.0, under nitrogen protection, sulfur oxychloride is added in reaction vessel, after dropwising, 5-methylnicotinic acid and first methyl alcohol reflux generation esterification, reduction vaporization is removed first methyl alcohol, add frozen water, the volume of described frozen water is 15～40% of reaction vessel volume, with alkaline solution, be neutralized to weakly alkaline, adopt the first organic solvent extraction, organic phase is washed with washings, dry, reduction vaporization is removed the first organic solvent, obtain 5-methylnicotinic acid methyl esters.
Further, in the step of preparation 5-methyl-3-piconol, take sodium borohydride, the mol ratio of 5-methylnicotinic acid methyl esters and sodium borohydride is 1.0:1.5～20.0, measure second batch methanol solvate simultaneously, the volume ratio of second batch methanol solvate and 5-methylnicotinic acid methyl esters is 1.0:5.0～15.0, in second reaction vessel, first add 5-methylnicotinic acid methyl esters and second batch methanol solvate, be heated to 25 ℃～70 ℃, add again sodium borohydride, after reacting completely, slowly add suitable quantity of water, until solution no longer stops adding water during bubbling, reduction vaporization is removed second batch methanol solvate, residue the second organic solvent extraction, organic phase is dry, remove the second organic solvent, obtain 5-methyl-3-piconol.
In the step of preparation 5-methyl-3-piconol hydrobromate, measure and get first Hydrogen bromide, 5-methyl-3-piconol and first hydrobromic mol ratio are 1.0:1.0～5.0,5-methyl-3-piconol reacts with first Hydrogen bromide at the temperature of-15 ℃～0 ℃, except desolventizing, filter and obtain 5-methyl-3-piconol hydrobromate.
Further, in the step of preparation 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, measure the 3rd organic solvent, the volume ratio of the 3rd organic solvent and 5-methyl-3-piconol hydrobromate is 1.0:3.0～10.0, measure again second batch Hydrogen bromide, 5-methyl-3-piconol hydrobromate and the hydrobromic mol ratio of second batch are 1.0:5.0～20.0, 5-methyl-3-piconol hydrobromate reacts with second batch Hydrogen bromide in the 3rd organic solvent, reflux, reduction vaporization after reacting completely, except desolventizing, obtain brown solid, in solid, add the 4th organic solvent, solid and the 4th organic solvent volume ratio are 1.0:3.0～10.0, ultrasonic 0.5～2 hour, filter, obtain 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate.
Further, in the step of described preparation 5-methylnicotinic acid methyl esters, the first organic solvent used is any one or more than one the combination in ethyl acetate, methylene dichloride, trichloromethane, N,N-dimethylacetamide, methyl tertiary butyl ether, ether, methyl-sulphoxide; Heating temperature is 65～150 ℃.
Further, in the step of described preparation 5-methylnicotinic acid methyl esters, in described and alkali lye be any one in saturated sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus, described washings is any one of saturated sodium-chloride, saturated Repone K or saturated ammonium chloride, and the reaction times is 3～6 hours.
Further, in the step of preparation 5-methyl-3-piconol, the second organic solvent is any one in methylene dichloride, chloroform, ether, methyl tertiary butyl ether, ethyl acetate, N,N-dimethylacetamide, methyl-sulphoxide, and the reaction times is 0.5～6 hour.
Further, in the step of preparation 5-methyl-3-piconol hydrobromate, temperature of reaction is-15 ℃～0 ℃, and the reaction times is 0.5～1.5 hour.
Further, in the step of preparation 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, the 3rd organic solvent used is any one in ethyl acetate, sherwood oil, ether, chloroform, tetracol phenixin, methylene dichloride, toluene, dimethylbenzene, p-Xylol, o-Xylol or oil of mirbane, temperature of reaction is 100 ℃～210 ℃, in reaction, with water trap, remove the water producing in water in second batch Hydrogen bromide and reaction, the reaction times is 4～8 hours.
Further, in the step of preparation 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, the 4th organic solvent used is alcoholic solvent, tetrahydrofuran (THF), three fluoro acetic acid, acetone, butanone, acetonitrile, ethylene glycol diethyl ether, ethylene glycol, 1, any one in 4-dioxane, pyridine, quadrol, DMF, methyl-sulphoxide.
Further, the volume of the first described organic solvent is 0.5 ~ 5 times of the front liquor capacity of extraction.
Further, the volume of the second described organic solvent is 0.5 ~ 5 times of the front liquor capacity of extraction.
Further, in the step of described preparation 5-methylnicotinic acid methyl esters, the first organic solvent ethyl acetate used; Preferably 65 ℃ of Heating temperatures; In and the preferred saturated sodium carbonate solution of alkali lye; The preferred saturated nacl aqueous solution of washings; Preferably 4 hours reaction times.
In the step of described preparation 5-methylnicotinic acid methyl esters, 5-methylnicotinic acid and first methyl alcohol volume ratio are preferably 1.0:5.0, the mol ratio of 5-methylnicotinic acid and sulfur oxychloride is preferably 1.0:3.0, the volume of described frozen water is preferably 20% of reaction vessel volume, and the volume ratio of second batch methanol solvate and 5-methylnicotinic acid methyl esters is preferably 1.0:10.0.
In the step of preparation 5-methyl-3-piconol, the second organic solvent ethyl acetate used; Preferably 55 ℃ of temperature of reaction; Preferably 1 hour reaction times; 5-methylnicotinic acid methyl esters: the preferred 1.0:3.5 of mol ratio of sodium borohydride.
In the step of preparation 5-methyl-3-piconol hydrobromate, preferably-10 ℃ of temperature of reaction; Preferably 0.5 hour reaction times; 5-methyl-3-piconol: the preferred 1.0:1.1 of first hydrobromic mol ratio, most preferably is 1.0:3.0.
In the step of preparation 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, need to isolate the moisture in Hydrogen bromide, to react, can thoroughly carry out the preferred dimethylbenzene of the 3rd organic solvent used; The volume ratio of the 3rd organic solvent and 5-methyl-3-piconol hydrobromate is 1.0:5.0; Preferably 140 ℃ of temperature of reaction; Reaction times is preferably 5 hours; 5-methyl-3-piconol hydrobromate: the preferred 1.0:15.0 of hydrobromic mol ratio.
In the step of preparation 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, revolve that to steam the brown solid obtaining impure, so with the ultrasonic purifying of the 4th organic solvent, the preferred acetone of the 4th organic solvent used; The 4th organic solvent and the preferred 1.0:5.0 of brown solid volume ratio; Ultrasonic time preferably 1 hour.
Further, the volume of the first described organic solvent is 0.5 ~ 5 times of the front liquor capacity of extraction.
Further, the volume of the second described organic solvent is 0.5 ~ 5 times of the front liquor capacity of extraction.
The method that the present invention prepares 5-methyl-3-bromo methyl cycloheptapyridine (1) by 5-methylnicotinic acid (2) is as follows:
Compound (1) is the key intermediate of synthetic Rupatadine and other macromolecular cpd, the medicine that contains specific examples of such components can be used for the treatment disease relevant with platelet activating factor (PAF), histamine and with kinases (Aurora A, Aururo B, Aurora C, cMet, JAK2 etc.) the relevant disease of dysregulation, cancer etc.It is raw material that 5-methylnicotinic acid (2) is take in the present invention, with succinct four-step reaction, has synthesized 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate.
5-methylnicotinic acid and excessive methanol generation esterification, esterification is a reversible reaction, the water producing in reaction can promote the carrying out of esterification reversed reaction, so drip sulfur oxychloride in reaction, sulfur oxychloride and water reaction generate nicotinic acid and sulfurous gas, promote esterification thoroughly to carry out, improve productive rate.5-methylnicotinic acid methyl esters generates 5-methyl-3-piconol with sodium borohydride generation reduction reaction in methanol solvate.Then, in 5-methyl-3-piconol, drip Hydrogen bromide, synthetic 5-methyl-3-piconol bromate, because 5-methyl-3-piconol is liquid, is difficult for purifying, and in fact this step is equivalent to the process of purifying 5-methyl-3-piconol.Last 5-methyl-3-piconol bromate generates target compound 5-methyl-3-bromo methyl cycloheptapyridine bromate with Hydrogen bromide generation substitution reaction in dimethylbenzene, and the effect of dimethylbenzene is to take the water in reaction out of as solvent, and reaction can thoroughly be carried out.
The present invention compares with prior art, and its technical progress is significant.At ester, be reduced in the process of alcohol, bibliographical information is used lithium aluminum hydride as reductive agent mostly, or will use metal chloride or lewis acid as catalyzer with sodium borohydride during as reductive agent.Front a kind of method lithium aluminum hydride is expensive, and in reaction, produce a large amount of hydrogen and emit large calorimetric, very easily blast, severe reaction conditions, rear a kind of method reaction is more complicated, and aftertreatment is also complicated.The present invention, in the preparation process of 5-methyl-3-piconol, uses sodium borohydride as reductive agent, and without any need for other catalyzer, reaction is simple, and raw material is cheap and easy to get, and aftertreatment is simple.While 5-methyl-3-piconol being substituted by 5-methyl-3-bromo methyl cycloheptapyridine bromate by literature method, the direct and Hydrogen bromide reaction with alcohol.But we repeat this kind of method, find that alcohol can not be converted into bromide completely and have impurity to generate.The water resistance that this phenomenon can be interpreted as producing in reaction has hindered the generation of substitution reaction, therefore adds dimethylbenzene that the water in reaction is taken out of, the results show, and alcohol can generate bromine substituent completely.
Embodiment
embodiment 1
Compound ( 3) synthetic:
In 1000mL four-hole bottle, add compound ( 2) 5-methylnicotinic acid (100.0g, 0.73mol) and 500mL methyl alcohol, under nitrogen protection, dripping sulfur oxychloride (110mL, 1.5mol), temperature remains on 20～25 ℃.After dropwising, reflux 4h, reduction vaporization is removed methyl alcohol, adds 200mL frozen water, with saturated sodium carbonate solution, is neutralized to weakly alkaline (pH 7 ~ 10), be extracted with ethyl acetate, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure, obtain white solid (108.2g, 98.2%).
Melting Point: 44.9-45.4℃. MS(ESI, M+H) +: 151.95. 1H NMR(400Hz, CDCl 3) δ 9.03(1H, s), 8.60(1H, s), 8.11(1H, s), 3.95(3H, s), 2.40(3H, s). IR(KBr, cm -1): 3417.26, 3054.58, 2957.35 1721.15, 1579.13, 1438.89, 1383.87, 1320.42, 1296.30, 1219.72, 1109.99, 768.29. Anal. Calcd. for C 8H 9NO 2: C: 63.56; H: 6.00; N: 9.27. Found: C:63.57; H: 6.01; N: 9,30.
Compound ( 4) synthetic:
In 100mL there-necked flask, add step product ( 3) 5-methylnicotinic acid methyl esters (5.0g, 0.033mol) and 50mL methyl alcohol, be heated to 55 ℃, add on a small quantity sodium borohydride (4,4g, 0.12mol) in batches, solution is from the colourless yellow that becomes, and generates a large amount of bubbles.At 55 ℃, react 1h, TLC demonstration reacts completely.Add suitable quantity of water, reduction vaporization is removed methyl alcohol, and residue is extracted with ethyl acetate, and can produce a large amount of white precipitates, and when adding saturated common salt water washing, white precipitate all dissolves.Organic phase anhydrous sodium sulfate drying, revolves and steams except desolventizing, obtains yellow liquid (4.2g), need not be further purified, and is directly used in the next step.
Compound ( 5) synthetic:
In 100mL single port bottle, add step product, under condition of ice bath, drip Hydrogen bromide (5mL, 40%, 0.036mol), after dropwising, revolve and steam except desolventizing, obtain brown solid, add appropriate tetrahydrofuran solution (object that adds tetrahydrofuran solution is that product is not attached on wall of container), stir half an hour, filter, obtain white solid (5.7g, 84.4%, above step note productive rate)
Melting Point: 126.8-128.4℃. MS(ESI, M-HBr+H) +: 123.95. 1H NMR(400Hz, DMSO) δ 8.76(1H, s), 8.70(1H, s), 8.41(1H, s), 4.69(2H, s), 2.50(3H, s). IR(KBr, cm -1): 3312.58, 3172.37, 3027.90, 2687.47, 2064.43, 1623.11, 1557.39, 1442.26, 1404.98, 1330.52, 1059.22, 862.78, 680.94. Anal. Calcd. for C 7H 10BrNO: C: 41.20; H: 4.94; Br: 39.16, N: 6.86. Found: C: 41.20; H: 4.94; Br: 39.12, N: 6.85.
Compound ( 1) synthetic:
In 100mL single port bottle, add step product 5(5.0g, 0.025mol), and Hydrogen bromide (50mL, 40%, 0.34mol) and dimethylbenzene 25mL, and reflux, water trap is not except anhydrating until have moisture to go out, and TLC shows and reacts completely.Reduction vaporization, except desolventizing, obtains brown solid 8.6g, adds acetone 45ml, and ultrasonic 1 hour, filter, obtain white solid (5.2g, 79.5%).
Melting Point: 158.1-158.8℃. MS(ESI, M-HBr) +: 185.95. 1H NMR(400Hz, DMSO) δ 8.84(2H, s), 8.58(1H, s),, 4.88(2H, s), 2.50(3H, s). IR(KBr, cm -1): 3224.65, 3110.06, 3013.81, 2964.09, 2924.24, 2552.82, 2036.34, 1556.90, 1462.53, 1344.25, 1317.06, 1229.41, 1030.02, 861.84, 736.31, 680.93. Anal. Calcd. for C 7H 9Br 2N: C: 31.49; H: 3.40; Br: 59.86, N: 5.25. Found: C: 31.48; H: 3.40; Br: 59.81, N: 5.23.
embodiment 2
Compound ( 3) synthetic:
In 1000mL four-hole bottle, add compound ( 2) 5-methylnicotinic acid (100.0g, 0.73mol) and 500mL methyl alcohol, under nitrogen protection, dripping sulfur oxychloride (80mL, 1.1mol), temperature remains on 20～25 ℃.After dropwising, reflux 4h, TLC shows that reaction is incomplete, adds 30mL sulfur oxychloride, continues reflux 4h, reacts completely.Reduction vaporization is removed methyl alcohol, adds 200mL frozen water, with saturated sodium carbonate solution, is neutralized to weakly alkaline, be extracted with ethyl acetate organic phase saturated common salt water washing, anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure, obtains white solid (104.6g, 94.8%).
Compound ( 4) synthetic:
In 100mL there-necked flask, add step product ( 3) 5-methylnicotinic acid methyl esters (5.0g, 0.033mol) with 50mL methyl alcohol, under ice bath is cooling, add on a small quantity sodium borohydride (2.0g, 0.05mol), solution is from the colourless yellow that becomes in batches, and generate a large amount of bubbles, temperature is down to room temperature after rising to gradually 55 ℃, reaction 1h, and TLC shows that reaction is not exclusively.Be heated to 60 ℃ and react half an hour, still have raw material, at this temperature, add sodium borohydride 2.5g, react 1 hour, but TLC shows the impurity (boric acid ester) that reacts completely.Add suitable quantity of water, reduction vaporization is removed methyl alcohol, and residue is extracted with ethyl acetate, and can produce a large amount of white precipitates, and when adding saturated common salt water washing, white precipitate all dissolves.Organic phase anhydrous sodium sulfate drying, revolves and steams except desolventizing, obtains yellow liquid (4.0g), need not be further purified, and is directly used in the next step.
Compound ( 5) synthetic:
In 100mL single port bottle, add step product, under condition of ice bath, drip excessive hydrogen bromic acid (8mL, 40%, 0.036mol), after dropwising, revolve and steam except desolventizing, obtain brown solid, add mixed solution or the tetrahydrofuran solution (object is that product is not attached on wall of container) of appropriate tetrahydrofuran (THF) and ethanol to stir half an hour, filter, obtain white solid (3.7g, 55.2%)
Synthesizing of compound (1):
In 100mL single port bottle, add step product 5(5.0g, 0.025mol), and Hydrogen bromide (50mL, 40%, 0.34mol) and dimethylbenzene 20mL, and reflux, water trap is not except anhydrating until have moisture to go out, and TLC shows and reacts completely.Reduction vaporization, except desolventizing, obtains brown solid, adds acetone, and ultrasonic 1 hour, filter, obtain white solid (4.8g, 54.5%).

Claims (13)

1. a method of preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate, it is characterized in that: the step that comprises a preparation 5-methylnicotinic acid methyl esters, in the step of described preparation 5-methylnicotinic acid methyl esters, 5-methylnicotinic acid and sulfur oxychloride be reflux generation esterification in organic solvent, obtains 5-methylnicotinic acid methyl esters; The step of preparation 5-methyl-3-piconol, in the step of preparation 5-methyl-3-piconol, 5-methylnicotinic acid methyl esters in organic solvent and sodium borohydride generation reduction reaction, obtains 5-methyl-3-piconol; The step of preparation 5-methyl-3-piconol hydrobromate, in the step of preparation 5-methyl-3-piconol hydrobromate, 5-methyl-3-piconol and Hydrogen bromide reaction obtain 5-methyl-3-piconol hydrobromate; The step of preparation 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, in the step of preparation 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, 5-methyl-3-piconol hydrobromate reacts with Hydrogen bromide in organic solvent, water except in dereaction, obtains 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate.
2. a kind of method of preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate as claimed in claim 1, it is characterized in that: in the step of described preparation 5-methylnicotinic acid methyl esters, first measure first methyl alcohol, first methyl alcohol is joined in first reaction vessel, measure again 5-methylnicotinic acid, 5-methylnicotinic acid and first methyl alcohol volume ratio are 1.0:3.0～10.0, 5-methylnicotinic acid is dissolved in first methanol solvate, measure again sulfur oxychloride as catalyzer, the mol ratio of 5-methylnicotinic acid and sulfur oxychloride is 1.0:1.1～5.0, under nitrogen protection, sulfur oxychloride is added in reaction vessel, after dropwising, 5-methylnicotinic acid and first methyl alcohol reflux generation esterification, reduction vaporization is removed first methyl alcohol, add frozen water, the volume of described frozen water is 15～40% of reaction vessel volume, with alkaline solution, be neutralized to weakly alkaline, adopt the first organic solvent extraction, organic phase is washed with washings, dry, reduction vaporization is removed the first organic solvent, obtain 5-methylnicotinic acid methyl esters.
3. a kind of method of preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate as claimed in claim 1, it is characterized in that: in the step of preparation 5-methyl-3-piconol, take sodium borohydride, the mol ratio of 5-methylnicotinic acid methyl esters and sodium borohydride is 1.0:1.5～20.0, measure second batch methanol solvate simultaneously, the volume ratio of second batch methanol solvate and 5-methylnicotinic acid methyl esters is 1.0:5.0～15.0, in second reaction vessel, first add 5-methylnicotinic acid methyl esters and second batch methanol solvate, be heated to 25 ℃～70 ℃, add again sodium borohydride, after reacting completely, slowly add suitable quantity of water, until solution no longer stops adding water during bubbling, reduction vaporization is removed second batch methanol solvate, residue the second organic solvent extraction, organic phase is dry, remove the second organic solvent, obtain 5-methyl-3-piconol.
4. a kind of method of preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate as claimed in claim 1, it is characterized in that: in the step of preparation 5-methyl-3-piconol hydrobromate, measure and get first Hydrogen bromide, 5-methyl-3-piconol and first hydrobromic mol ratio are 1.0:1.0～5.0,5-methyl-3-piconol reacts with first Hydrogen bromide at the temperature of-15 ℃～0 ℃, except desolventizing, filter and obtain 5-methyl-3-piconol hydrobromate.
5. a kind of method of preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate as claimed in claim 1, it is characterized in that: in the step of preparation 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, measure the 3rd organic solvent, the volume ratio of the 3rd organic solvent and 5-methyl-3-piconol hydrobromate is 1.0:3.0～10.0, measure again second batch Hydrogen bromide, 5-methyl-3-piconol hydrobromate and the hydrobromic mol ratio of second batch are 1.0:5.0～20.0, 5-methyl-3-piconol hydrobromate reacts with second batch Hydrogen bromide in the 3rd organic solvent, reflux, reduction vaporization after reacting completely, except desolventizing, obtain brown solid, in solid, add the 4th organic solvent, solid and the 4th organic solvent volume ratio are 1.0:3.0～10.0, ultrasonic 0.5～2 hour, filter, obtain 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate.
6. a kind of method of preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate as claimed in claim 2, it is characterized in that: in the step of described preparation 5-methylnicotinic acid methyl esters, the first organic solvent used is any one or more than one the combination in ethyl acetate, methylene dichloride, trichloromethane, N,N-dimethylacetamide, methyl tertiary butyl ether, ether, methyl-sulphoxide; Heating temperature is 65～150 ℃.
7. a kind of method of preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate as claimed in claim 2, it is characterized in that: in the step of described preparation 5-methylnicotinic acid methyl esters, in described and alkali lye be any one in saturated sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus, described washings is any one of saturated sodium-chloride, saturated Repone K or saturated ammonium chloride, and the reaction times is 3～6 hours.
8. a kind of method of preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate as claimed in claim 3, it is characterized in that: in the step of preparation 5-methyl-3-piconol, the second organic solvent is methylene dichloride, chloroform, ether, methyl tertiary butyl ether, ethyl acetate, N, any one in N-N,N-DIMETHYLACETAMIDE, methyl-sulphoxide, the reaction times is 0.5～6 hour.
9. a kind of method of preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate as claimed in claim 4, is characterized in that: in the step of preparation 5-methyl-3-piconol hydrobromate, the reaction times is 0.5～1.5 hour.
10. a kind of method of preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate as claimed in claim 5, it is characterized in that: in the step of preparation 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, the 3rd organic solvent used is any one in ethyl acetate, sherwood oil, ether, chloroform, tetracol phenixin, methylene dichloride, toluene, dimethylbenzene, p-Xylol, o-Xylol or oil of mirbane, temperature of reaction is 100 ℃～210 ℃, in reaction, with water trap, remove the water producing in water in second batch Hydrogen bromide and reaction, the reaction times is 4～8 hours.
11. a kind of methods of preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate as claimed in claim 5, it is characterized in that: in the step of preparation 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, the 4th organic solvent used is alcoholic solvent, tetrahydrofuran (THF), three fluoro acetic acid, acetone, butanone, acetonitrile, ethylene glycol diethyl ether, ethylene glycol, 1, any one in 4-dioxane, pyridine, quadrol, DMF, methyl-sulphoxide.
12. a kind of methods of preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate as claimed in claim 1, is characterized in that: the volume of the first described organic solvent is 0.5 ~ 5 times of the front liquor capacity of extraction.
13. a kind of methods of preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate as claimed in claim 1, is characterized in that: the volume of the second described organic solvent is 0.5 ~ 5 times of the front liquor capacity of extraction.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106560471A (en) * 2016-01-28 2017-04-12 平光制药股份有限公司 Rupatadine preparation proces
CN113200910A (en) * 2021-05-19 2021-08-03 北京嘉林药业股份有限公司 Preparation method of rupatadine fumarate intermediate 5-methyl nicotinate methanol solution
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CN113930793A (en) * 2021-11-25 2022-01-14 南京先进生物材料与过程装备研究院有限公司 Method for preparing 3-methyl-5-bromomethylpyridine bromate by using electrochemical microchannel reaction device
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