CN108239040A - Nitric acid 2-（4- methylthiazol -5- bases）The preparation method of carbethoxy hydrochloride - Google Patents
Nitric acid 2-（4- methylthiazol -5- bases）The preparation method of carbethoxy hydrochloride Download PDFInfo
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The present invention provides a kind of preparation method of nitric acid 2 (4 methylthiazol, 5 base) carbethoxy hydrochloride, feature includes the following steps：(1) using 4 methyl, 5 (2 ethoxy) thiazole as starting material nitric acid 2 (4 methylthiazol, 5 base) ethyl ester is obtained through nitration reaction；(2) nitric acid 2 (4 methylthiazol, 5 base) ethyl ester reacts in a solvent with hydrochloric acid is made nitric acid 2 (4 methylthiazol, 5 base) carbethoxy hydrochloride crude product；(3) nitric acid 2 (4 methylthiazol, 5 base) carbethoxy hydrochloride crude product is carried out being recrystallized to give qualified products.This method is easy to operate, reaction condition is mild, high income, good product purity, is suitble to large-scale industrial production.
Description
Technical field
The present invention relates to technical field prepared by compound, specifically nitric acid 2- (4- methylthiazol -5- bases) ethyl esters
The preparation method of salt.
Background technology
Compound nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride is recorded in document Journal of
Alzheimer’s Disease 2004,6,S75–S84；Current Alzheimer Research,2006,3,237–245；
Neuropsychopharmacology,2007,32,505–513；Pharmacology,Biochemistry and
Behavior 2009,91,495–502；ACS Medicinal Chemistry Letter,2011,2,656–661；
US20090252704；WO2014013338.Code name is GT-1061, molecular formula C to the compound in the literature6H9ClN2O3S, point
Son amount is 224.66, and structural formula is as follows.Document report shows that nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride has
There is anti-senile dementia (AD) effect.
GT-1061 document WO2000054756, WO2001049275, WO2005105065, US6310052,
Pharmaceutical Chemistry Journal, 1999,33,41-44 report nitric acid 2- (4- methylthiazol-5- bases) second
The synthetic method of ester, it is as follows.
Document WO2000054756, WO2001049275, WO2005105065, US6310052 are using condition 1 as nitrification item
Part, yield are relatively low.Document Pharmaceutical Chemistry Journal, 1999,33,41-44 with condition 2 be synthesis nitre
The method of sour 2- (4- methylthiazol -5- bases) ethyl ester does not provide specific test details in document and has been merely given as reaction and receives
Rate is 82%.
The present inventor verifies literature method, specific as shown in table 1.
The method that table 1. verifies document nitric acid synthesis 2- (4- methylthiazol -5- bases) ethyl ester
It summarizes：
(1) actual recovery of the ethyl ester in verification test 1 is 56% by nitric acid 2- (4- methylthiazol -5- bases), higher than document
45%；And in verification test 2, actual recovery is 48%.
(2) in verification test 1, hydroxy ethylthiazole can not the reaction was complete by raw material 4- methyl -5-, this causes reaction to need column
Chromatographic purifying, while yield is relatively low.
(3) in verification test 2, although the reaction was complete for raw material 4- methyl -5- hydroxy ethylthiazoles, yield is relatively low, simultaneously
Experimentation is related to heating and cools down two kinds of temperature control process, cumbersome to be unfavorable for mass production；Raw materials used urea needs dry
Dry processing also increases production difficulty and cost.
Meanwhile also reported the nitrification of 4- methyl -5- hydroxy ethylthiazole analogs in document US6310052, this method is
Using concentrated nitric acid and acetic anhydride as nitrating agent, raw material inventory is 0.3g, yield only 32%.
The present inventor verifies the method using 4- methyl -5- hydroxy ethylthiazoles as raw material, with concentrated nitric acid and acetic acid
Acid anhydride is as nitrating agent, and using reaction condition and post processing mode identical in document, raw material 4- methyl -5- hydroxy ethylthiazoles are thrown
Doses is 1.08g.Result of the test shows that raw material reaction is incomplete, and product needs column chromatography to purify, cumbersome, and yield is low only
Have 23%.Therefore, which is not particularly suited for preparing nitric acid 2- (4- methylthiazol -5- bases) ethyl ester.
Although method shown in table 1 can realize the synthesis of nitric acid 2- (4- methylthiazol -5- bases) ethyl ester, exist apparent
Deficiency, if hydroxy ethylthiazole can not the reaction was complete by raw material 4- methyl -5- in verification test 1, product needs column chromatography purifying etc.；It tests
Operation is cumbersome in confirmatory test 2, and one of raw material urea needs dry pretreatment etc..The preparation method of comprehensive literature report, has
There is the problems such as preparation amount is small, operation is complicated, yield is low and economy is poor, therefore above-mentioned literature procedures are not suitable for industrializing
Produce nitric acid 2- (4- methylthiazol -5- bases) ethyl ester.And the preparation of nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride has no
Document report.
Invention content
The technical problem to be solved by the present invention is to provide a kind of preparations of nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride
Method.This method is industrially prepared with scale suitable for repeating, and the product produced can meet wanting for pharmaceutical quality standard
It asks, and improves operability, yield and improve Environmental compatibility.
To achieve these goals, the technical solution adopted by the present invention is as follows：
A kind of preparation method for preparing nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride, its main feature is that, including as follows
Step：
Step (1)：Using 4- methyl -5- (2- ethoxys) thiazoles as starting material nitric acid 2- (4- first is obtained through nitration reaction
Base thiazole -5- bases) ethyl ester.Nitrating agent in reaction is selected from fuming nitric aicd and acetic anhydride, and reaction temperature is at -10~10 DEG C, instead
At 1~5 hour between seasonable, reaction dissolvent is selected from ethyl acetate, acetone, butanone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform,
The mixed solvent formed including above-described single solvent or two kinds and multi-solvents.
Wherein, preferable reaction temperature is -10~5 DEG C；Further preferably, reaction temperature is 0~5 DEG C；
Preferred reaction time is 1~4 hour；Further preferably, the reaction time is 1.5~2.5 hours；
It is preferred that reaction dissolvent is selected from ethyl acetate, acetone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform；
Further preferably, the solvent is selected from dichloromethane, chloroform.
Step (2)：Nitric acid 2- (4- methylthiazol -5- bases) ethyl ester is reacted with hydrochloric acid prepares nitric acid 2- (4- methylthiazols -5-
Base) carbethoxy hydrochloride.Reaction temperature is at -10~10 DEG C, and the reaction time, hydrochloric acid source was selected from concentrated hydrochloric acid, salt at 0.5~5 hour
Acid/ethanol solution, hydrochloric acid/ethyl acetate solution, chloroacetic chloride/ethanol system.Solvent used is selected from methanol, ethyl alcohol, acetone, first
Benzene, ethyl acetate, n,N-Dimethylformamide (DMF), tetrahydrofuran, acetonitrile, dichloromethane, chloroform, including above-described
The mixed solvent of single solvent or two kinds and multi-solvents composition.
Wherein, preferable reaction temperature is 0~5 DEG C；
Preferred reaction time is 0.5~2 hour；
It is preferred that hydrochloric acid source is selected from hydrochloric acid/ethyl acetate solution, chloroacetic chloride/ethanol system；
It is preferred that solvent used is selected from ethyl acetate, dichloromethane, chloroform.
Step (3)：Nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride carries out being recrystallized to give sterling in a solvent.
The recrystallization temperature is 0~30 DEG C, and solvent used is selected from ethyl acetate, acetone, butanone, tetrahydrofuran, acetonitrile, anhydrous second
Alcohol, absolute methanol, isopropanol, methyl tertiary butyl ether(MTBE) etc., including above-described single solvent or two kinds and multi-solvents composition
Mixed solvent.
Wherein, preferably recrystallization temperature is 0~20 DEG C；Further preferred recrystallization temperature is 0~10 DEG C；
It is preferred that the solvent is acetone, ethyl acetate, absolute ethyl alcohol；It is further preferred that the solvent is absolute ethyl alcohol.
The advantage of the invention is that：
(1) nitric acid 2- (4- methylthiazol -5- bases) ethyl ester directly reacts hydrochloric acid salt after preparation without concentration, behaviour
Make risk of explosion that is simple and convenient, while avoiding nitrate compound.
(2) nitric acid 2- (4- methylthiazol -5- bases) ethyl ester product salt is directly precipitated from solvent, and purity is high, avoids
Complicated column chromatography separating purification.
(3) reaction condition is mild, at low cost, high income, suitable for industrialized production.
Specific embodiment
Be explained further the present invention with reference to embodiments, but embodiment protection scope of the present invention is not done it is any
The restriction of form.
Comparative example
1.04ml (16.60mmol) concentrated nitric acid is added dropwise in 8ml (84.66mmol) acetic anhydride, control temperature 25~
30 DEG C, drop finishes, and temperature is reduced to 0~5 DEG C, is added dropwise 1.08g (7.52mmol) 4- methyl -5- hydroxy ethylthiazoles, temperature 5 in maintenance
DEG C hereinafter, drop finish, stir 45min, add in 1.8ml water, stir 30min, concentration, residue saturated sodium bicarbonate aqueous solution
20ml is neutralized, and ethyl acetate extraction, dry, concentration, column chromatography purifies to obtain nitric acid 2- (4- methylthiazol -5- bases) ethyl ester
0.325g, yield：23%.
Embodiment 1
21.46g (0.15mol) 4- methyl -5- hydroxy ethylthiazoles are placed in 1000ml three-necked bottles, add in 210ml dichloros
Methane, ice salt bath cooling, interior 0 DEG C of temperature is hereinafter, add in 56.7ml (0.6mol) acetic anhydride, and 0 DEG C of temperature in maintenance is hereinafter, be added dropwise
25.4ml (0.6mol) fuming nitric aicd maintains 0~4 DEG C and reacts 2 hours after adding, the reaction was complete.100ml is added in into solution
Water, 0 DEG C of temperature in maintenance separate water layer, use dichloromethane hereinafter, 60%NaOH (about 120ml) aqueous solution tune pH ≈ 7~8 are added dropwise
It extracts (100ml × 2 time), merges organic layer, be washed with water (100ml × 2 time), saturated common salt washing (100ml × 1 time) is anhydrous
Sodium sulphate is dried, and is filtered, and concentration obtains nitric acid 2- (4- methylthiazol -5- bases) ethyl ester 26.33g, yield：93%.
Embodiment 2
7.15g (0.05mol) 4- methyl -5- hydroxy ethylthiazoles are placed in 500ml three-necked bottles, add in 70ml dichloromethanes
Alkane, ice salt bath cooling, interior 5 DEG C of temperature is hereinafter, add in 7.3ml (0.08mol) acetic anhydride, and 5 DEG C of temperature in maintenance is hereinafter, be added dropwise 8.5ml
(0.2mol) fuming nitric aicd, less than 5 DEG C of temperature is reacted 2 hours in maintenance after adding, and the reaction was complete, and 33ml water is added in into solution,
5 DEG C of temperature in maintenance separates water layer, (30ml × 2 is extracted with dichloromethane hereinafter, dropwise addition 60%NaOH aqueous solution tune pH ≈ 7~8
It is secondary), merge organic layer, be washed with water (30ml × 2 time), saturated common salt washing (30ml × 1 time), anhydrous sodium sulfate drying, and add
Enter 0.9g activated carbon decolorizings, filter, concentration obtains nitric acid 2- (4- methylthiazol -5- bases) ethyl ester 9.10g, yield：96.8%.
Embodiment 3
7.15g (0.05mol) 4- methyl -5- hydroxy ethylthiazoles are placed in 500ml three-necked bottles, add in 35ml dichloromethanes
Alkane, ice salt bath cooling, interior 5 DEG C of temperature is hereinafter, add in 7.6ml (0.08mol) acetic anhydride, and 5 DEG C of temperature in maintenance is hereinafter, be added dropwise 8.5ml
(0.2mol) fuming nitric aicd, less than 5 DEG C of temperature is reacted 3 hours in maintenance after adding, and the reaction was complete, and 5 DEG C of temperature in maintenance is hereinafter, be added dropwise
30%NaOH aqueous solution tune pH ≈ 7~8 (about 60ml), separate water layer, are extracted (30ml × 2 time) with dichloromethane, merge organic
Layer, is washed with water (30ml × 2 time), saturated common salt washing (30ml × 1 time), anhydrous sodium sulfate drying, and adds in 0.9g activated carbons
Decoloration is filtered, and concentration obtains nitric acid 2- (4- methylthiazol -5- bases) ethyl ester 8.94g, yield：95.1%.By gained nitric acid 2- (4-
Methylthiazol -5- bases) ethyl ester is dissolved in 55ml ethyl acetate, adds in 2.2g (47.5mmol) absolute ethyl alcohol, and ice salt bath cooling is interior
3.7g (47.5mmol) chloroacetic chloride is added dropwise hereinafter, stirring is lower in 5 DEG C of temperature, and solid is precipitated, and is stirred at room temperature 30 minutes and is dissipated completely to solid
It opens, filters, solid is washed with ethyl acetate, and infrared lamp is dried.Nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride 6.9g is obtained,
Yield：64.8%.
Embodiment 4
7.15g (0.05mol) 4- methyl -5- hydroxy ethylthiazoles are placed in 500ml three-necked bottles, add in 35ml dichloromethanes
Alkane, ice salt bath cooling, interior 10 DEG C of temperature is hereinafter, add in 7.6ml (0.08mol) acetic anhydride, and 10 DEG C of temperature in maintenance is hereinafter, be added dropwise
8.5ml (0.2mol) fuming nitric aicd, maintained after adding in less than 10 DEG C of temperature react 3 hours, the reaction was complete, in maintenance warm 10 DEG C with
Under, 30%NaOH aqueous solution tune pH ≈ 7~8 (about 60ml) are added dropwise, separates water layer, is extracted (30ml × 2 time) with dichloromethane, close
And organic layer, it is washed with water (30ml × 2 time), saturated common salt washing (30ml × 1 time), anhydrous sodium sulfate drying, and add in 0.9g
Activated carbon decolorizing filters, and concentration obtains nitric acid 2- (4- methylthiazol -5- bases) ethyl ester 8.6g yields：91.5%.By gained nitric acid
2- (4- methylthiazol -5- bases) ethyl ester is dissolved in 53ml ethyl acetate, adds in 2.5g (55.2mmol) absolute ethyl alcohol, and ice salt bath is cold
But, 4.3g (55.2mmol) chloroacetic chloride is added dropwise hereinafter, stirring is lower in interior 5 DEG C of temperature, and solid is precipitated, be stirred at room temperature 30 minutes it is complete to solid
It scatters, filters entirely, solid is washed with ethyl acetate, and infrared lamp is dried.Obtain nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride
8.5g, yield：96.1%.
1 present invention of table prepares nitric acid 2- (4- methylthiazol -5- bases) reaction temperatures of ethyl ester and the impact analysis of time：
| Embodiment | Raw material throwing amount g | Reaction temperature DEG C | Reaction time hr | Yield % |
| 1 | 21.5 | 0~4 | 2 | 93 |
| 2 | 7.15 | <5 | 2 | 96.8 |
| 3 | 7.15 | <5 | 3 | 95.1 |
| 4 | 7.15 | <10 | 3 | 91.5 |
The result shows that when using fuming nitric aicd/acetic anhydride as nitrating agent, reaction temperature is less than 10 DEG C, and reaction raw materials are thrown
Amount, reaction time influence less the yield of product, and the yield of nitric acid 2- (4- methylthiazol -5- bases) ethyl ester is more than 90%；
Embodiment 5
7.15g (0.05mol) 4- methyl -5- (2- ethoxys) thiazole is placed in 500ml three-necked bottles, adds in 46ml dichloros
Methane, stirring, the cooling of external application ice salt bath, interior temperature maintain 5 DEG C hereinafter, dropwise addition 7.6ml (0.08mol) acetic anhydride, is added dropwise 8.4ml
(0.2mol) fuming nitric aicd, finishes, and is reacted 1 hour below interior 5 DEG C of temperature, and the reaction was complete, and 5 DEG C of temperature in maintenance is hereinafter, be added dropwise 33ml
Water is added dropwise 60%NaOH aqueous solution tune reaction solution pH ≈ 11, separates water layer, extracted (20ml × 2) with dichloromethane, merges organic
Layer, is washed with water (120ml × 2), saturated common salt washing (20ml), anhydrous sodium sulfate drying, and adds in 0.9g activated carbon decolorizings, mistake
Filter, adds in 2.72g (0.059mol) absolute ethyl alcohol, ice salt bath cooling, and 4.63g is added dropwise hereinafter, stirring is lower in interior 5 DEG C of temperature
(0.059mol) chloroacetic chloride is precipitated solid, is stirred at room temperature 2 hours, filters, and solid washes (20ml × 2) with acetone, and infrared lamp is baked
It is dry, obtain nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride 7.82g, yield：69.6%.
Embodiment 6
7.15g (0.05mol) raw material 4- methyl -5- (2- ethoxys) thiazole is placed in 500ml three-necked bottles, adds in 46ml
Dichloromethane, stirring, the cooling of external application ice salt bath, interior temperature maintain 5 DEG C hereinafter, dropwise addition 7.6ml (0.08mol) acetic anhydride, is added dropwise
8.4ml (0.2mol) fuming nitric aicd, finishes, and is reacted 5 hours below interior 5 DEG C of temperature, and the reaction was complete, and 5 DEG C of temperature in maintenance is hereinafter, be added dropwise
60%NaOH aqueous solution tune reaction solution pH ≈ 11 are added dropwise in 33ml water.Water layer is separated, is extracted (20ml × 2) with dichloromethane, is merged
Organic layer is washed with water (120ml × 2), saturated common salt washing (20ml), anhydrous sodium sulfate drying, and adds in 0.9g activated carbons and take off
Color, filtering add in 2.72g (0.059mol) absolute ethyl alcohol, ice salt bath cooling, and 4.63g is added dropwise hereinafter, stirring is lower in interior 5 DEG C of temperature
(0.059mol) chloroacetic chloride is precipitated solid, is stirred at room temperature 2 hours, filters, and solid washes (20ml × 2) with acetone, and infrared lamp is baked
It is dry, obtain nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride 7.48g, yield：66.6%.
Embodiment 7
7.15g (0.05mol) raw material 4- methyl -5- (2- ethoxys) thiazole is placed in 500ml three-necked bottles, adds in 46ml
Dichloromethane, stirring, the cooling of external application ice salt bath, interior temperature maintain 10 DEG C hereinafter, dropwise addition 7.6ml (0.08mol) acetic anhydride, is added dropwise
8.4ml (0.2mol) fuming nitric aicd, finishes, and less than 10 DEG C of temperature is reacted 2 hours in maintenance, and the reaction was complete, in maintenance warm 5 DEG C with
Under, 33ml water is added dropwise, 60%NaOH aqueous solution tune reaction solution pH ≈ 11 are added dropwise.Water layer is separated, extracted with dichloromethane (20ml ×
2), merge organic layer, be washed with water (120ml × 2), saturated common salt washing (20ml), anhydrous sodium sulfate drying, and add in 0.9g work
Property carbon decoloring, filtering adds in 2.72g (0.059mol) absolute ethyl alcohol, ice salt bath cooling, and interior 5 DEG C of temperature is hereinafter, stirring is lower is added dropwise
4.63g (0.059mol) chloroacetic chloride is precipitated solid, is stirred at room temperature 2 hours, filters, solid is washed (20ml × 2) with acetone, infrared
Lamp is dried, and obtains nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride 8.26g, yield：73.5%.
Embodiment 8
7.15g (0.05mol) raw material 4- methyl -5- (2- ethoxys) thiazole is placed in 500ml three-necked bottles, adds in 46ml
Dichloromethane, stirring, the cooling of external application ice salt bath, interior temperature maintain 5 DEG C hereinafter, dropwise addition 7.6ml (0.08mol) acetic anhydride, is added dropwise
8.4ml (0.2mol) fuming nitric aicd, finishes, and is reacted 2 hours below interior 5 DEG C of temperature, and the reaction was complete, and 5 DEG C of temperature in maintenance is hereinafter, be added dropwise
60%NaOH aqueous solution tune reaction solution pH ≈ 11 are added dropwise in 33ml water.Water layer is separated, is extracted (20ml × 2) with dichloromethane, is merged
Organic layer is washed with water (120ml × 2), saturated common salt washing (20ml), anhydrous sodium sulfate drying, and adds in 0.9g activated carbons and take off
Color, filtering, ice salt bath cooling, interior 5 DEG C of temperature is hereinafter, solid, room is precipitated to pH ≈ 2 in the lower hydrochloric acid/ethyl acetate solution that is added dropwise of stirring
Temperature stirring 2 hours, filtering, solid washes (20ml × 2) with acetone, and infrared lamp is dried, and obtains nitric acid 2- (4- methylthiazol -5- bases) second
Ester hydrochloride 7.96g, yield：70.9%.
Embodiment 9
7.15g (0.05mol) raw material 4- methyl -5- (2- ethoxys) thiazole is placed in 500ml three-necked bottles, adds in 46ml
Dichloromethane, stirring, the cooling of external application ice salt bath, interior temperature maintain 5 DEG C hereinafter, dropwise addition 7.6ml (0.08mol) acetic anhydride, is added dropwise
8.4ml (0.2mol) fuming nitric aicd, finishes, and is reacted 2 hours below interior 5 DEG C of temperature, and the reaction was complete, and 5 DEG C of temperature in maintenance is hereinafter, be added dropwise
60%NaOH aqueous solution tune reaction solution pH ≈ 11 are added dropwise in 33ml water.Water layer is separated, is extracted (20ml × 2) with dichloromethane, is merged
Organic layer is washed with water (120ml × 2), saturated common salt washing (20ml), anhydrous sodium sulfate drying, and adds in 0.9g activated carbons and take off
Color, filtering add in 2.72g (0.059mol) absolute ethyl alcohol, ice salt bath cooling, and 4.63g is added dropwise hereinafter, stirring is lower in interior 5 DEG C of temperature
(0.059mol) chloroacetic chloride is precipitated solid, is stirred at room temperature 5 hours, filters, and solid washes (20ml × 2) with acetone, and infrared lamp is baked
It is dry, obtain nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride 8.15g, yield：72.6%.
Embodiment 10
57.2g (0.4mol) raw material 4- methyl -5- (2- ethoxys) thiazole is placed in 2000ml three-necked bottles, is added in
370ml dichloromethane, stirring, the cooling of external application ice salt bath, interior temperature maintain 5 DEG C hereinafter, 60.5ml (0.64mol) acetic acid is added dropwise
Acid anhydride is added dropwise 67.4ml (1.6mol) fuming nitric aicd, finishes, reacted 2 hours below interior 5 DEG C of temperature, and the reaction was complete, 5 DEG C of temperature in maintenance
Hereinafter, 267ml water is added dropwise, 60%NaOH aqueous solution tune reaction solution pH ≈ 11 are added dropwise.Water layer is separated, is extracted with dichloromethane
(130ml × 2) merge organic layer, are washed with water (130ml × 2), saturated common salt washing (130ml), and anhydrous sodium sulfate drying adds
Enter 7.5g activated carbon decolorizings, filter, add in 21.8g (0.47mol) absolute ethyl alcohol, ice salt bath cooling, interior 5 DEG C of temperature is hereinafter, stirring
Lower dropwise addition 37.1g (0.47mol) chloroacetic chloride, for interior 5 DEG C of temperature hereinafter, stirring 2 hours, filtering, solid washes (100ml × 2) with acetone,
40 DEG C are dried in vacuo 10 hours, obtain nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride 65.8g, yield：73.4%.2, table
Invention prepares salt-forming reagent, reaction temperature and the impact analysis of time of nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride：
The result shows that in the preparation of nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride, nitric acid 2- (4- first is prepared
Base thiazole -5- bases) hydrochloric acid salt is directly reacted after ethyl ester without concentration, total recovery is more than 66%.Reaction temperature<When 10,
Salt-forming reagent and reaction time influence the yield of product little.
To sum up table 1,2 illustrates this reaction route condition maturity, stabilization, and product yield high, purity are high, and post-processes letter
It is single, it is suitble to industrialized production.
Embodiment 11
8.5g nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride is placed in 250ml eggplant type bottles, addition 128ml
EtOAc∶C2H5OH=3: 1 solvent is heated to reflux stirring, and solid all after dissolving, adds in 1.6g activated carbon decolorizings, and filtering is stirred
Crystallization is mixed, is filtered, solid is washed with ethyl acetate, dried, and obtains off-white color nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride
6.75g yield：79.4%.
Embodiment 12
11.1g nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride is placed in 500ml eggplant type bottles, add in 42ml without
Water-ethanol stirs, and reflux, solid all dissolves, and adds in 42ml ethyl acetate, and filtering adds in 84ml ethyl acetate, stirring analysis
Crystalline substance, filtering, solid washed 2 times (25ml+25ml) with ethyl acetate, and infrared lamp is baked 2 hours, in vacuum drying chamber 60 DEG C vacuumize it is dry
Dry 12 hours, obtain off-white color nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride 9.847g, yield：88.7%.
Embodiment 13
10g nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride is placed in 1000ml eggplant type bottles, adds in 500ml third
Ketone, agitating and heating, solid still cannot all dissolve after reflux 30 minutes, add 100ml acetone, be stirred at reflux after ten minutes, Gu
Body all dissolves, and adds in 1g activated carbon decolorizings, filtering, and filtrate steams 200ml solvents, has a small amount of solid to be precipitated in solution, stirring
Crystallization, placement room temperature, about 3 hours.Filtering, solid are washed with acetone, dried, and obtain off-white color nitric acid 2- (4- methylthiazol -5- bases)
Carbethoxy hydrochloride 7.274g, yield 72.7%.
Embodiment 14
10g nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride is placed in 250ml eggplant type bottles, it is anhydrous to add in 70ml
Solid is precipitated after being placed at room temperature for one day in ethyl alcohol, outer 70 DEG C of temperature, stirring and dissolving, filtering, filters, and solid is washed with a small amount of absolute ethyl alcohol,
60 DEG C in vacuum drying chamber, 10 hours, drying is vacuumized.Obtain off-white color nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride
6.16g, yield 61.6%.
Embodiment 15
6.58g nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride is placed in 100ml eggplant type bottles, add in 46ml without
Water-ethanol, heating, outer 60 DEG C of temperature, stirring, solid all after dissolving, add in 0.66g activated carbon decolorizings, filtering, 0~10 DEG C of stirring
1 hour, solid, filtering is precipitated, solid is washed (10ml × 2) with acetone, and 40 DEG C are dried in vacuo 10 hours, obtain off-white powder
5.12g yield：77.8%.
Embodiment 16
6.58g nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride is placed in 100ml eggplant type bottles, add in 46ml without
Water-ethanol, heating, outer 60 DEG C of temperature, stirring, solid all after dissolving, add in 0.66g activated carbon decolorizings, filtering, 0~10 DEG C of stirring
3 hours, solid, filtering is precipitated, solid is washed (10ml × 2) with acetone, and 40 DEG C are dried in vacuo 10 hours, obtain off-white powder
5.35g yield：81.3%.
Embodiment 17
6.58g nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride is placed in 100ml eggplant type bottles, add in 46ml without
Water-ethanol, heating, outer 60 DEG C of temperature, stirring, solid all after dissolving, add in 0.66g activated carbon decolorizings, filtering, 0~10 DEG C of stirring
5 hours, solid, filtering is precipitated, solid is washed (10ml × 2) with acetone, and 40 DEG C are dried in vacuo 10 hours, obtain off-white powder
5.28g yield：80.2%.
Embodiment 18
65.8g nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride is placed in 1000ml eggplant type bottles, adds in 460ml
Absolute ethyl alcohol, heating, outer 60 DEG C of temperature, stirring, solid all after dissolving, add in 6.6g activated carbon decolorizings, filtering, 0~10 DEG C is stirred
It mixes 1.5 hours, solid, filtering is precipitated, solid is washed (70ml × 2) with acetone, and 40 DEG C are dried in vacuo 10 hours, obtain off-white powder
52.5g yield：79.8%, mp：112~114 DEG C, HPLC：99.826%.1H NMR(400MHz,DMSO-d6)δ:9.33(s,
1H), 4.68 (t, J=6.0Hz, 2H), 3.26 (t, J=6.0Hz, 2H), 2.37 (s, 3H) .HRMS (ESI):m/z[M-HCl+H
]+calcd for C6H9N2O3S:189.0328；found:189.0323.
In conclusion the synthetic method of the present invention is suitable for preparing nitric acid 2- (4- methylthiazol -5- bases) on an industrial scale
Carbethoxy hydrochloride disclosure satisfy that the requirement in terms of industrial production, improve operability, safety and yield, while product purity
It is high.
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any Spirit Essences away from the present invention with made under principle change, modification, replacement, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (10)
1. a kind of preparation method of nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride,
It is characterized in that, described method includes following steps：
(1) 4- methyl -5- (2- ethoxys) thiazoles obtain nitric acid 2- (4- methylthiazol -5- bases) ethyl ester through nitration reaction；Wherein,
The nitrating agent of reaction is selected from fuming nitric aicd and acetic anhydride；
(2) nitric acid 2- (4- methylthiazol -5- bases) ethyl ester reacts generation nitric acid 2- (4- methylthiazols -5- in solvent with hydrochloric acid
Base) carbethoxy hydrochloride.
2. the preparation method according to claim 1, it is characterised in that in step (1), 4- methyl -5- (2- ethoxys) thiazole
Molar ratio with fuming nitric aicd is 1:1~10, reaction temperature is -10~10 DEG C, and the reaction time is 1~5 hour, reaction dissolvent
Selected from ethyl acetate, acetone, butanone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, including above-described single solvent or two
The mixed solvent of kind and multi-solvents composition.
3. preparation method according to claim 2, which is characterized in that 4- methyl -5- (2- ethoxys) thiazoles and fuming nitric aicd
Molar ratio be 1:2~6, the reaction temperature is -10~5 DEG C, and the reaction time is 1~4 hour, and reaction dissolvent is selected from acetic acid
Ethyl ester, acetone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform.
4. preparation method according to claim 3, which is characterized in that 4- methyl -5- (2- ethoxys) thiazoles and smoke
The molar ratio of nitric acid is 1:2~6, reaction temperature is 0~5 DEG C, and the reaction time is 1.5~2.5 hours, and reaction dissolvent is selected from second
Acetoacetic ester, acetone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform.
5. the preparation method according to claim 1, it is characterised in that in step (2), nitric acid 2- (4- methylthiazol -5- bases)
The molar ratio of ethyl ester and hydrochloric acid is 1：1~5, reaction temperature is -10~10 DEG C, and the reaction time is 0.5~5 hour, hydrochloric acid source
Selected from concentrated hydrochloric acid, hydrochloric acid/ethanol solution, hydrochloric acid/ethyl acetate solution, chloroacetic chloride/ethanol system, solvent used is selected from first
Alcohol, ethyl alcohol, acetone, toluene, ethyl acetate, n,N-Dimethylformamide, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, including
The mixed solvent of above-described single solvent or two kinds and multi-solvents composition.
6. preparation method according to claim 5, which is characterized in that nitric acid 2- (4- methylthiazol -5- bases) ethyl esters and hydrochloric acid
Molar ratio be 1：1.1~2, the reaction temperature is 0~5 DEG C, and the reaction time is 0.5~5 hour, and hydrochloric acid source is selected from dense salt
Acid, hydrochloric acid/ethanol solution, hydrochloric acid/ethyl acetate solution, chloroacetic chloride/ethanol system, solvent used are selected from methanol, ethyl alcohol, third
Ketone, toluene, ethyl acetate, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dichloromethane, chloroform.
7. preparation method according to claim 6, which is characterized in that nitric acid 2- (4- methylthiazol -5- bases) ethyl esters and hydrochloric acid
Molar ratio be 1：1.1~1.5, the reaction time be 0.5~2 hour, hydrochloric acid source be selected from hydrochloric acid/ethyl acetate solution,
Chloroacetic chloride/ethanol system.Solvent used is selected from ethyl acetate, dichloromethane, chloroform.
8. preparation method described in claim 1, it is characterised in that nitric acid 2- (4- methylthiazol -5- bases) carbethoxy hydrochloride carries out
Decoloration is recrystallized to give sterling, and the recrystallization temperature is 0~30 DEG C, solvent used be selected from ethyl acetate, acetone, butanone,
Tetrahydrofuran, acetonitrile, absolute ethyl alcohol, absolute methanol, isopropanol, methyl tertiary butyl ether(MTBE) etc., including above-described single solvent
Or two kinds and multi-solvents composition mixed solvent.
9. preparation method according to claim 8, which is characterized in that the recrystallization temperature is 0~20 DEG C, and the solvent is
Ethyl acetate, acetone, butanone, tetrahydrofuran, acetonitrile, absolute ethyl alcohol, absolute methanol, isopropanol, methyl tertiary butyl ether(MTBE).
10. preparation method according to claim 9, which is characterized in that the recrystallization temperature is 0~10 DEG C, the solvent
For absolute ethyl alcohol.
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| CN117224483A (en) * | 2023-09-01 | 2023-12-15 | 山东京卫制药有限公司 | 2- (4-methylthiazol-5-yl) ethyl nitrate brain-targeted liposome applicable to heat assisted treatment |
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