CN104163786B - A kind of method preparing 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate - Google Patents
A kind of method preparing 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate Download PDFInfo
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- 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
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Abstract
A kind of method preparing 5 methyl 3 bromo methyl cycloheptapyridine bromates, including the step of preparation 5 methyinicotinate, 5 methylnicotinic acids and thionyl chloride are heated to reflux esterification, obtain 5 methyinicotinate；5 methyinicotinate in organic solvent with sodium borohydride generation reduction reaction, obtain 5 methyl 3 pyridinemethanols；The step of one preparation 5 methyl 3 pyridinemethanol hydrobromate, 5 methyl 3 pyridinemethanols and hydrobromic acid reaction obtain 5 methyl 3 pyridinemethanol hydrobromates；The step of one preparation 5 methyl 3 bromo methyl cycloheptapyridine hydrobromate, 5 methyl 3 pyridinemethanol hydrobromates react with hydrobromic acid in organic solvent, remove the water in reaction, obtain 5 methyl 3 bromo methyl cycloheptapyridine hydrobromates.The present invention obtains 5 methyl 3 bromo methyl cycloheptapyridine bromates by four step rule, and technique is simple, and yield is high.
Description
Technical field
The invention belongs to chemical field, particularly relate to a kind of pharmaceutical intermediate 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate,
A kind of method preparing 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate.
Background technology
5-methyl-3-bromo methyl cycloheptapyridine is a crucial pharmaceutical intermediate in new drug development.Rupatadine is one
Novel medicine, he produces with specific acceptor and interacts, is potential platelet activating factor (PAF) and histamine (H1)
Effectively antagonist.ES2042421 and WO2006114676 reports with Desloratadine and 5-methyl-3-bromo methyl cycloheptapyridine side
Method synthesizes the method for Rupatadine.WO2013000406 reports benzocyclohepta the thiophene having synthesized a series of antiallergic action
Fen derivative, including with the benzocyclohepta of 5-methyl-3-bromo methyl cycloheptapyridine alternatively base thiazole.Abnormal anti-
Should be a kind of world generality disease, therefore research and development improve effect and to reduce the antiallergic action medicament of side effect very urgent.
WO2012097196 report has synthesized pyrazolopyrimidine analog derivative, and this analog derivative can suppress multiple cancer cell
Growth, highly effective to treatment cancer, these components can also treat some with kinases (Aurora A, Aururo B,
Aurora C, cMet, JAK2 etc.) the relevant disease of dysregulation, research shows, when substituent is 5-methyl-3-bromomethyl
During pyridine, compound is the most notable to the inhibitory action of cMet.US20130274272 discloses pyridone-pyridine derivatives,
This compounds can effectively treat the disease relevant with P38 kinases, such as the disease such as lymthoma, auto-inflammatory.When with 5-methyl-3-
When bromo methyl cycloheptapyridine synthesizes compound, activity is more preferably.
For the synthesis of 5-methyl-3-bromo methyl cycloheptapyridine, document is it has been reported that several method.ES2042421 is with 3,
5-lutidines synthesizes 5-methyl-3-bromo methyl cycloheptapyridine by N-bromo-succinimide (NBS) bromination in carbon tetrachloride,
Yield is the lowest.It is possible to additionally incorporate azodiisobutyronitrile in WO2006114676 and participated in reaction, yield brings up to 67.66%.
WO2013000406 has continued to use above-mentioned synthetic method.But, use above two method raw material to react incomplete all the time, obtain
Being monosubstituted and disubstituted mixture, two kinds compound separation is the most more complicated and yield is low.Raw material NBS used is high poison
Property compound, azodiisobutyronitrile be height inflammable compound, reaction condition is the harshest.
WO2012097196 reacts with 5-methyinicotinate and lithium aluminium hydride reduction after generating alcohol, then generates with hydrobromic acid reaction
5-methyl-3-bromo methyl cycloheptapyridine bromate.This kind of method lithium aluminium hydride reduction is expensive, and in reaction, heat release is violent, poor stability.I
Find when repeating the method, when 5-methyl-3-pyridinemethanol generates 5-methyl-3-bromo methyl cycloheptapyridine bromate, raw material is always
Can not react completely, reaction has impurity to generate, and the reaction time was up to 18 hours.
Summary of the invention
For defect present in above-mentioned prior art, the technical problem to be solved is to provide one and prepares 5-
The method of methyl-3-bromo methyl cycloheptapyridine hydrobromate, described this preparation method to solve preparation method of the prior art
Process is complicated, the technical problem that yield is low.
A kind of method preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate of the present invention, including a preparation 5-methylnicotinic acid
The step of methyl esters, in the described step preparing 5-methyinicotinate, 5-methylnicotinic acid and thionyl chloride are at organic solvent
In be heated to reflux occur esterification, obtain 5-methyinicotinate；One step preparing 5-methyl-3-pyridinemethanol,
In one step preparing 5-methyl-3-pyridinemethanol, 5-methyinicotinate occurs also with sodium borohydride in organic solvent
Former reaction, obtains 5-methyl-3-pyridinemethanol；One step preparing 5-methyl-3-pyridinemethanol hydrobromate, a system
In the step of standby 5-methyl-3-pyridinemethanol hydrobromate, 5-methyl-3-pyridinemethanol and hydrobromic acid reaction obtain 5-methyl-
3-pyridinemethanol hydrobromate；One step preparing 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, prepares 5-first at one
In the step of base-3-bromo methyl cycloheptapyridine hydrobromate, 5-methyl-3-pyridinemethanol hydrobromate is in organic solvent and hydrobromic acid
Reaction, removes the water in reaction, obtains 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate.
Further, in the described step preparing 5-methyinicotinate, first methyl alcohol is first measured, by first
Methyl alcohol joins in first reaction vessel, then measures 5-methylnicotinic acid, and 5-methylnicotinic acid with first methyl alcohol volume ratio is
1.0:3.0～10.0, is dissolved in 5-methylnicotinic acid in first methanol solvate, then measures thionyl chloride as catalyst, 5-first
Base nicotinic acid is 1.0:1.1～5.0 with the mol ratio of thionyl chloride, under nitrogen protection, is added by thionyl chloride in reaction vessel,
After dropping, 5-methylnicotinic acid and first methyl alcohol are heated to reflux esterification, are evaporated under reduced pressure and remove first methyl alcohol,
Adding frozen water, the volume of described frozen water is the 15～40% of reaction vessel volume, is neutralized to alkalescent with aqueous slkali, uses the
One organic solvent extraction, organic phase cleaning solution wash, are dried, and are evaporated under reduced pressure and remove the first organic solvent, obtain 5-methyl cigarette
Acid methyl esters.
Further, in a step preparing 5-methyl-3-pyridinemethanol, weigh sodium borohydride, 5-methylnicotinic acid
The mol ratio of methyl esters and sodium borohydride is 1.0:1.5～20.0, measures second batch methanol solvate simultaneously, second batch methanol solvate with
The volume ratio of 5-methyinicotinate is 1.0:5.0～15.0, is initially charged 5-methylnicotinic acid first in second reaction vessel
Ester and second batch methanol solvate, be heated to 25 DEG C～70 DEG C, adds sodium borohydride, after reaction completely, is slowly added to suitable quantity of water,
Until stopping during solution no longer bubbling adding water, being evaporated under reduced pressure and removing second batch methanol solvate, residue extracts with the second organic solvent,
Organic phase is dried, and removes the second organic solvent, obtains 5-methyl-3-pyridinemethanol.
In a step preparing 5-methyl-3-pyridinemethanol hydrobromate, measure and take first hydrobromic acid, 5-first
Base-3-pyridinemethanol and first hydrobromic mol ratio are 1.0:1.0～5.0, and 5-methyl-3-pyridinemethanol is at-15 DEG C～0
React with first hydrobromic acid at a temperature of DEG C, remove solvent, be filtrated to get 5-methyl-3-pyridinemethanol hydrobromate.
Further, in a step preparing 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, the 3rd is measured organic molten
Agent, the 3rd organic solvent is 1.0:3.0～10.0 with the volume ratio of 5-methyl-3-pyridinemethanol hydrobromate, then measures second
Criticizing hydrobromic acid, 5-methyl-3-pyridinemethanol hydrobromate and the hydrobromic mol ratio of second batch are 1.0:5.0～20.0,5-first
Base-3-pyridinemethanol hydrobromate reacts with second batch hydrobromic acid in the 3rd organic solvent, is heated to reflux, and subtracts after reaction completely
Pressure evaporation, removes solvent, obtains brown solid, adds the 4th organic solvent, solid and the 4th organic solvent volume in solid
Ratio is 1.0:3.0～10.0, ultrasonic 0.5～2 hour, filters, obtains 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate.
Further, in the described step preparing 5-methyinicotinate, the first organic solvent used is acetic acid
Any one in ethyl ester, dichloromethane, chloroform, DMAC N,N' dimethyl acetamide, methyl tertiary butyl ether(MTBE), ether, dimethyl sulfoxide
Kind or more than one combination；Heating-up temperature is 65～150 DEG C.
Further, in the described step preparing 5-methyinicotinate, described neutralization alkali lye is unsaturated carbonate
Any one in sodium, sodium acid carbonate, potassium carbonate or saleratus, described cleaning solution is saturated sodium-chloride, saturated chlorination
Any one of potassium or saturated ammonium chloride, the reaction time is 3～6 hours.
Further, in a step preparing 5-methyl-3-pyridinemethanol, the second organic solvent be dichloromethane,
Any one in chloroform, ether, methyl tertiary butyl ether(MTBE), ethyl acetate, DMA, dimethyl sulfoxide, during reaction
Between be 0.5～6 hour.
Further, in a step preparing 5-methyl-3-pyridinemethanol hydrobromate, reaction temperature is-15 DEG C
～0 DEG C, the reaction time is 0.5～1.5 hour.
Further, in a step preparing 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, used the 3rd is organic
Solvent is ethyl acetate, petroleum ether, ether, chloroform, carbon tetrachloride, dichloromethane, toluene, dimethylbenzene, paraxylene, adjacent diformazan
Any one in benzene or nitrobenzene, reaction temperature is 100 DEG C～210 DEG C, removes second batch hydrogen bromine with water knockout drum in reaction
The water produced in water in acid and reaction, the reaction time is 4～8 hours.
Further, in a step preparing 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, used the 4th is organic
Solvent is alcohols solvent, oxolane, trifluoroacetic acid, acetone, butanone, acetonitrile, ethylene glycol diethyl ether, ethylene glycol, 1,4-bis-
Any one in oxygen six ring, pyridine, ethylenediamine, N,N-dimethylformamide, dimethyl sulfoxide.
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 described step preparing 5-methyinicotinate, the first preferred second of organic solvent used
Acetoacetic ester；Heating-up temperature preferably 65 DEG C；Neutralize the preferred saturated sodium carbonate solution of alkali lye；The preferred saturated nacl aqueous solution of cleaning solution；
Preferably 4 hours reaction time.
In the described step preparing 5-methyinicotinate, 5-methylnicotinic acid is preferred with first methyl alcohol volume ratio
Mol ratio for 1.0:5.0,5-methylnicotinic acid Yu thionyl chloride is preferably 1.0:3.0, and the volume of described frozen water is preferably anti-
Answering the 20% of vessel volume, second batch methanol solvate is preferably 1.0:10.0. with the volume ratio of 5-methyinicotinate
In a step preparing 5-methyl-3-pyridinemethanol, the second organic solvent ethyl acetate used；Instead
Answer temperature preferably 55 DEG C；Preferably 1 hour reaction time；5-methyinicotinate: the preferred 1.0:3.5 of mol ratio of sodium borohydride.
In a step preparing 5-methyl-3-pyridinemethanol hydrobromate, reaction temperature preferably-10 DEG C；During reaction
Between preferably 0.5 hour；5-methyl-3-pyridinemethanol: the preferred 1.0:1.1 of first hydrobromic mol ratio, most preferably 1.0:
3.0。
In a step preparing 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, need the water isolating in hydrobromic acid
Point, in order to reaction can thoroughly be carried out, the 3rd preferred dimethylbenzene of organic solvent used；3rd organic solvent and 5-methyl-3-pyridine
The volume ratio of methyl alcohol hydrobromate is 1.0:5.0；Reaction temperature preferably 140 DEG C；Reaction time is preferably 5 hours；5-methyl-3-
Pyridinemethanol hydrobromate: the preferred 1.0:15.0 of hydrobromic mol ratio.
In a step preparing 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, it is impure that the brown solid obtained is steamed in rotation
Only, so with the 4th ultrasonic purifying of organic solvent, the 4th preferred acetone of organic solvent used；4th organic solvent and brown solid
The preferred 1.0:5.0 of 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 is prepared 5-methyl-3-bromo methyl cycloheptapyridine (1) by 5-methylnicotinic acid (2) is as follows:
Compound (1) is synthesis Rupatadine and the key intermediate of other macromolecular compound, containing specific examples of such components
Medicine can be used to treat the 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..The present invention with 5-methylnicotinic acid (2) as raw material,
5-methyl-3-bromo methyl cycloheptapyridine hydrobromate has been synthesized with succinct four-step reaction.
5-methylnicotinic acid and excessive methanol generation esterification, esterification is a reversible reaction, produces in reaction
Water can promote the carrying out of esterification back reaction, so dripping thionyl chloride in the reaction, thionyl chloride and water reaction generate cigarette
Acid and sulfur dioxide, promote that esterification is thoroughly carried out, improve productivity.5-methyinicotinate in methanol solvate with hydroboration
Sodium generation reduction reaction generates 5-methyl-3-pyridinemethanol.Then, in 5-methyl-3-pyridinemethanol, hydrobromic acid, synthesis are dripped
5-methyl-3-pyridinemethanol bromate, owing to 5-methyl-3-pyridinemethanol is liquid, not easy purification, this step is effectively equivalent to
Purify the process of 5-methyl-3-pyridinemethanol.Last 5-methyl-3-pyridinemethanol bromate occurs with hydrobromic acid in dimethylbenzene
Substitution reaction generates target compound 5-methyl-3-bromo methyl cycloheptapyridine bromate, and the solvent that functions as of dimethylbenzene is taken out of instead
Water in Ying, makes reaction thoroughly to carry out.
The present invention compares with prior art, and its technological progress is significant.During ester is reduced to alcohol, document is reported
Be used mostly lithium aluminium hydride reduction as reducing agent, or with sodium borohydride as metal chloride to be used during reducing agent or
Lewis acid is as catalyst.Former approach lithium aluminium hydride reduction is expensive, produces a large amount of hydrogen and release big calorimetric, pole in reaction
Explosive, severe reaction conditions, later approach reaction is more complicated, and post processing is also complicated.The present invention is in 5-methyl-3-pyridine first
In the preparation process of alcohol, use sodium borohydride is as reducing agent, and need not any other catalyst, and reaction is simple, and raw material is honest and clean
Valency is easy to get, and post processing is simple.By literature method, 5-methyl-3-pyridinemethanol is substituted by 5-methyl-3-bromo methyl cycloheptapyridine bromine
During hydrochlorate, directly react with hydrobromic acid with alcohol.But we repeat this kind of method, find that alcohol can not be fully converted to bromide
And have impurity to generate.The water that this phenomenon can be construed in reaction produce hinders the generation of substitution reaction, therefore adds diformazan
Water in reaction is taken out of by benzene, and the results show, alcohol can generate bromine substituent completely.
Detailed description of the invention
Embodiment 1
The synthesis of compound (3):
In 1000mL four-hole bottle, add compound (2) 5-methylnicotinic acid (100.0g, 0.73mol) and 500mL methyl alcohol,
Under nitrogen protection, dropping thionyl chloride (110mL, 1.5mol), temperature is maintained at 20～25 DEG C.After dropping, heat back
Stream 4h, is evaporated under reduced pressure and removes methyl alcohol, adds 200mL frozen water, is neutralized to alkalescent (pH 7 ~ 10) with saturated sodium carbonate solution, uses
Ethyl acetate extracts, and organic phase saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and solvent removed by evaporation at reduced pressure obtains white
Solid (108.2g, 98.2%).
Melting Point: 44.9-45.4℃. MS(ESI, M+H)+: 151.95. 1H NMR(400Hz,
CDCl3) 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 C8H9NO2: C:
63.56; H: 6.00; N: 9.27. Found: C:63.57; H: 6.01; N: 9,30.
The synthesis of compound (4):
In 100mL there-necked flask, addition walks product (3) 5-methyinicotinate (5.0g, 0.033mol) and 50mL first
Alcohol, is heated to 55 DEG C, adds sodium borohydride (4,4g, 0.12mol) the most on a small quantity, and solution is from the colourless yellow that becomes, and generates big
Amount bubble.1h, TLC display reaction is reacted completely at 55 DEG C.Add suitable quantity of water, be evaporated under reduced pressure and remove methyl alcohol, residue acetic acid
Ethyl ester extracts, and can produce a large amount of white precipitate, and when adding saturated aqueous common salt washing, white precipitate all dissolves.Organic phase is used
Anhydrous sodium sulfate is dried, and rotation is evaporated off solvent, obtains yellow liquid (4.2g), need not be further purified, is directly used in lower step anti-
Should.
The synthesis of compound (5):
In 100mL single port bottle, addition walks product, under condition of ice bath drip hydrobromic acid (5mL, 40%,
0.036mol), after dropping, rotation is evaporated off solvent, obtains brown solid, adds appropriate tetrahydrofuran solution and (adds tetrahydrochysene
The purpose of tetrahydrofuran solution is to make product be not attached on chamber wall), stir half an hour, filter, obtain white solid (5.7g,
84.4%, above step note productivity)
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
C7H10BrNO: 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.
The synthesis of compound (1):
In 100mL single port bottle, addition walks product 5(5.0g, 0.025mol), hydrobromic acid (50mL, 40%, 0.34mol)
With dimethylbenzene 25mL, being heated to reflux, water knockout drum removes water until not having moisture to go out, and TLC display reaction is completely.It is evaporated under reduced pressure, removes
Remove solvent, obtain brown solid 8.6g, add acetone 45ml, 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 C7H9Br2N: 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
The synthesis of compound (3):
In 1000mL four-hole bottle, add compound (2) 5-methylnicotinic acid (100.0g, 0.73mol) and 500mL methyl alcohol,
Under nitrogen protection, dropping thionyl chloride (80mL, 1.1mol), temperature is maintained at 20～25 DEG C.After dropping, it is heated to reflux
4h, TLC display reaction is not complete, adds 30mL thionyl chloride, continues to be heated to reflux 4h, and reaction is completely.It is evaporated under reduced pressure and removes first
Alcohol, adds 200mL frozen water, is neutralized to alkalescent with saturated sodium carbonate solution, is extracted with ethyl acetate, organic phase saturated common salt
Water washs, and anhydrous sodium sulfate is dried, solvent removed by evaporation at reduced pressure, obtains white solid (104.6g, 94.8%).
The synthesis of compound (4):
In 100mL there-necked flask, addition walks product (3) 5-methyinicotinate (5.0g, 0.033mol) and 50mL first
Alcohol, under ice bath cooling, adds sodium borohydride (2.0g, 0.05mol) the most on a small quantity, and solution is from the colourless yellow that becomes, and generates big
Amount bubble, temperature is down to room temperature, is reacted 1h, TLC display reaction not exclusively after being gradually increased to 55 DEG C.It is heated to 60 DEG C of reactions half little
Time, still there is raw material, add sodium borohydride 2.5g at this temperature, react 1 hour, but TLC display reaction completely has impurity (boron
Acid esters).Adding suitable quantity of water, be evaporated under reduced pressure and remove methyl alcohol, residue with ethyl acetate extracts, and can produce a large amount of white precipitate, when adding
When entering saturated aqueous common salt washing, white precipitate all dissolves.Organic phase anhydrous sodium sulfate is dried, and rotation is evaporated off solvent, obtains
Yellow liquid (4.0g), need not be further purified, be directly used in the next step.
The synthesis of compound (5):
In 100mL single port bottle, addition walks product, under condition of ice bath drip excess hydrobromic acid (8mL, 40%,
0.036mol), after dropping, rotation is evaporated off solvent, obtains brown solid, adds the mixed liquor of appropriate oxolane and ethanol
Or tetrahydrofuran solution (purpose is to make product be not attached on chamber wall) stirs half an hour, filter, obtain white solid
(3.7g, 55.2%)
The synthesis of compound (1):
In 100mL single port bottle, addition walks product 5(5.0g, 0.025mol), hydrobromic acid (50mL, 40%, 0.34mol)
With dimethylbenzene 20mL, being heated to reflux, water knockout drum removes water until not having moisture to go out, and TLC display reaction is completely.It is evaporated under reduced pressure, removes
Remove solvent, obtain brown solid, add acetone, ultrasonic 1 hour, filter, obtain white solid (4.8g, 54.5%).
Claims (9)
1. the method preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate, it is characterised in that: include a preparation 5-methyl cigarette
The step of acid methyl esters, first measures first methyl alcohol, is joined by first methyl alcohol in first reaction vessel, then measure 5-first
Base nicotinic acid, 5-methylnicotinic acid and first methyl alcohol volume ratio are 1.0:3.0～10.0, and 5-methylnicotinic acid is dissolved in first methyl alcohol
In solvent, then measuring thionyl chloride as catalyst, 5-methylnicotinic acid is 1.0:1.1～5.0 with the mol ratio of thionyl chloride,
Under nitrogen protection, being added by thionyl chloride in reaction vessel, after dropping, 5-methylnicotinic acid is heated to reflux with first methyl alcohol
Esterification occurs, and heating-up temperature is 65～150 DEG C, is evaporated under reduced pressure and removes first methyl alcohol, adds frozen water, described frozen water
Volume is the 15～40% of reaction vessel volume, is neutralized to alkalescent with aqueous slkali, uses the first organic solvent extraction, organic phase
With cleaning solution washing, it is dried, is evaporated under reduced pressure and removes the first organic solvent, obtain 5-methyinicotinate；One preparation 5-methyl-
The step of 3-pyridinemethanol, weighs sodium borohydride, the mol ratio of 5-methyinicotinate and sodium borohydride be 1.0:1.5～
20.0, measure second batch methanol solvate simultaneously, the volume ratio of second batch methanol solvate and 5-methyinicotinate be 1.0:5.0～
15.0, second reaction vessel is initially charged 5-methyinicotinate and second batch methanol solvate, is heated to 25 DEG C～70
DEG C, add sodium borohydride, after reaction completely, be slowly added to suitable quantity of water, until stopping during solution no longer bubbling adding water, decompression is steamed
Sending out and remove second batch methanol solvate, residue extracts with the second organic solvent, and organic phase is dried, and removes the second organic solvent, obtains
5-methyl-3-pyridinemethanol；One step preparing 5-methyl-3-pyridinemethanol hydrobromate, measures and takes first hydrobromic acid,
5-methyl-3-pyridinemethanol and first hydrobromic mol ratio are 1.0:1.0～5.0, and 5-methyl-3-pyridinemethanol is-15
DEG C～0 DEG C at a temperature of and first hydrobromic acid react, remove solvent, be filtrated to get 5-methyl-3-pyridinemethanol hydrobromate；
One step preparing 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, measures the 3rd organic solvent, the 3rd organic solvent and 5-first
The volume ratio of base-3-pyridinemethanol hydrobromate is 1.0:3.0～10.0, then measures second batch hydrobromic acid, 5-methyl-3-pyridine
Methyl alcohol hydrobromate and the hydrobromic mol ratio of second batch are 1.0:5.0～20.0, and 5-methyl-3-pyridinemethanol hydrobromate exists
Reacting with second batch hydrobromic acid in 3rd organic solvent, be heated to reflux, reaction temperature is 100 DEG C～210 DEG C, then uses a point water
Device removes water until not having moisture to go out, and is evaporated under reduced pressure after reaction completely, removes solvent, obtains brown solid, adds in solid
4th organic solvent, solid and the 4th organic solvent volume ratio for 1.0:3.0～10.0, ultrasonic 0.5～2 hour, filters, obtains
5-methyl-3-bromo methyl cycloheptapyridine hydrobromate.
A kind of method preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate, it is characterised in that:
In the described step preparing 5-methyinicotinate, the first organic solvent used is ethyl acetate, dichloromethane, three chloromethanes
Any one or more than one combination in alkane, DMAC N,N' dimethyl acetamide, methyl tertiary butyl ether(MTBE), ether, dimethyl sulfoxide.
A kind of method preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate, it is characterised in that:
In the described step preparing 5-methyinicotinate, described aqueous slkali be saturated sodium carbonate, sodium acid carbonate, potassium carbonate or
Any one in saleratus, described cleaning solution is any one of saturated sodium-chloride, saturated potassium chloride or saturated ammonium chloride
Kind, the reaction time is 3～6 hours.
A kind of method preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate, it is characterised in that:
In one step preparing 5-methyl-3-pyridinemethanol, the second organic solvent is dichloromethane, chloroform, ether, methyl tertbutyl
Any one in ether, ethyl acetate, DMA, dimethyl sulfoxide, the reaction time is 0.5～6 hour.
A kind of method preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate, it is characterised in that:
In one step preparing 5-methyl-3-pyridinemethanol hydrobromate, the reaction time is 0.5～1.5 hour.
A kind of method preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate, it is characterised in that:
In one step preparing 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, the 3rd organic solvent used is ethyl acetate, oil
Appointing in ether, ether, chloroform, carbon tetrachloride, dichloromethane, toluene, dimethylbenzene, paraxylene, ortho-xylene or nitrobenzene
Meaning one, removes the water produced in the water in second batch hydrobromic acid and reaction with water knockout drum in reaction, the reaction time is 4～8 little
Time.
A kind of method preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate, it is characterised in that:
In one step preparing 5-methyl-3-bromo methyl cycloheptapyridine hydrobromate, the 4th organic solvent used is alcohols solvent, tetrahydrochysene
Furans, trifluoroacetic acid, acetone, butanone, acetonitrile, ethylene glycol diethyl ether, 1,4-dioxane, pyridine, ethylenediamine, N, N-diformazan
Any one in base formamide, dimethyl sulfoxide.
8. a kind of method preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate as described in claim 1, its feature exists
In: in a step preparing 5-methyinicotinate, the volume of the first described organic solvent is liquor capacity before extraction
0.5 ~ 5 times.
9. a kind of method preparing 5-methyl-3-bromo methyl cycloheptapyridine bromate as described in claim 1, its feature exists
In: in a step preparing 5-methyl-3-pyridinemethanol, the volume of the second described organic solvent is solution body before extraction
Long-pending 0.5 ~ 5 times.
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| CN113930793B (en) * | 2021-11-25 | 2024-04-16 | 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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