CN105924406B - A kind of preparation method of acotiamide hydrochloride trihydrate - Google Patents
A kind of preparation method of acotiamide hydrochloride trihydrate 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
- C07D277/32—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a kind of method of new preparation acotiamide hydrochloride trihydrate (Acotiamide hydrochloride).The preparation method comprises the following steps：(1) 2 [N (2 are taken; 4; 5 trimethoxybenzoys) amino] 4 ethoxy carbonyls 1; 3 thiazoles (type I compound), di-n-butylamine, N; N dimethylformamides react to obtain 2 [N (2 hydroxyls 4; 5 Dimethoxybenzoyls) amino] 4 (ethoxy carbonyl) 1,3 thiazole (compound of formula II) crude product；(2) by the crude compound of formula II made from step (1), N, the obtained compound of formula II of in the mixed solvent of N dimethylformamides and acetic acid are added；(3) the above-mentioned compound of formula II and N, N diisopropyl ethylenediamine are reacted and the glutinous thick liquid of rufous is made；(4) ethanol, concentrated hydrochloric acid are added, reaction obtains acotiamide hydrochloride trihydrate crude product；(5) acotiamide hydrochloride trihydrate crude product is through being recrystallized to give refined acotiamide hydrochloride trihydrate.This method has the advantages of energy-conserving and environment-protective, production cost are low, product quality is high.
Description
Technical field
The present invention relates to a kind of process for preparing medicine, and in particular to a kind of preparation side of acotiamide hydrochloride trihydrate
Method.
Background technology
Acotiamide hydrochloride hydrate, chemical name：N-2- [(double isopropylaminos) ethyl] -2- [(2- hydroxyl -4,5- dimethoxys
Benzoyl) amino] thiazole -4-carboxamide hydrochloride trihydrate, CAS：773092-05-0, structural formula are as follows：
Acotiamide hydrochloride hydrate (Z-338) is by Japan (Zeria) new drug Co., Ltd. original is ground in damp a kind of new M1, M2
Receptor antagonist, treatment functional dyspepsia FD (FD) was approved in Japan in 2 months 2013, being mainly used in, which improves stomach, moves
Power obstacle, delayed gastric emptying, so as to improve FD symptoms, including post-prandial fullness, big belly, early satiety etc..
With 2- hydroxyls -4,5- dimethoxybenzoic acid and phosphorous triphenyl phosphate in the preparation method of patent (CN101006040B)
Ester is raw material, using toluene as solvent, using the concentrated sulfuric acid as catalyst back flow reaction, obtains intermediate 2- hydroxyl -4,5- dimethoxies
Yl benzoic acid phenyl ester.Above-mentioned intermediate and thiazolamine -4- methyl formates are placed in toluene afterwards, add triphenyl boric acid
Ester reacts, post-treated to obtain 2- [(2- hydroxyls -4,5- dimethoxybenzoyl) amino] -1,3-thiazoles -4- carboxylate methyl esters, most
It is made afterwards with N, N- diisopropyl ethylenediamines after being reacted in toluene into salt.This method operation is relatively tired, and needs to add triphenyl
For borate as reaction promoter, this reagent price is expensive, is unfavorable for industrialized production.
The preparation method of patent application (CN201210145398.9 and CN201210145399.3) is with 2- hydroxyls -4,5-
Dimethoxybenzoic acid is that the reaction under pyridine catalysis obtains intermediate 6,7- dimethoxies to raw material with phosgene, surpalite or triphosgene
Base-benzo [d] [1,3] dioxine -2,4- diketone (steps 1), directly reacts with thiazolamine -4- formic acid first (second) ester afterwards
Obtain 2- [(2- hydroxyls -4,5- dimethoxybenzoyl) the amino]-carboxyl of 1,3-thiazoles -4 first (second) ester (step 2), then its
With N, it is made after the reaction of N- diisopropyl ethylenediamines with HCl into salt.Phosgene, the surpalite severe toxicity used in this method step 1,
Low temperature control is more strict when having larger danger in industrial application, and reacting, and is unfavorable for industrialized production.
In the preparation method of patent (CN1084739C), 2- [N- (2- hydroxyls -4,5- Dimethoxybenzoyl) amino] -
4- (ethoxy carbonyl) -1,3-thiazoles is recrystallized using the dioxane of Isosorbide-5-Nitrae -, and the dioxane of Isosorbide-5-Nitrae-is the solvent of two classes, dirty to environment
Contaminate bigger；It is found by experiment that 1,4- dioxanes to 2- [N- (2- hydroxyl -4,5- Dimethoxybenzoyls) amino] -4-
(ethoxy carbonyl) -1,3-thiazoles can not be completely dissolved, and it is yellowish-brown to obtain intermediate 2, thus be not suitable for doing recrystallize it is molten
Agent；In the step of synthesizing Acotiamide crude product, because the solvent used is has the DMA of pollution to environment,
Cause the complete N of unreacted, N- diisopropyl ethylenediamines can not reclaim；And the temperature of reaction is higher, be not suitable for industrialized production.
In the preparation method of patent (CN1063442C), 2- [N- (2,4,5- trimethoxybenzoy) amino] -4- (second
Epoxide carbonyl) -1,3-thiazoles existing for pyridine hydrochloride and pyridine situation occur demethylation, then tied again with acetic acid
Crystalline substance, obtains 2- [N- (2- hydroxyls -4,5- Dimethoxybenzoyl) amino] -4- (ethoxy carbonyl) -1,3-thiazoles, then with N,
N- diisopropyl ethylenediamines react to obtain Acotiamide, it has been investigated that, acetic acid is to 2- [N- (2- hydroxyl -4,5- dimethoxy benzenes
Formoxyl) amino] -4- (ethoxy carbonyl) -1,3-thiazoles can not be completely dissolved, therefore it is yellowish-brown to obtain intermediate 2, and
This method is cumbersome, and cost is higher, is only applicable to prepare compound, is not suitable for industrialized production.
In the preparation method of patent (CN102040515A, CN103237781A, CN103387552A), with 4,5- dimethoxies
The acid of base -2 synthesizes 2- [N- (2- hydroxyl -4,5- Dimethoxybenzoyls) amino] -4- (ethoxy carbonyl) -1 for initiation material,
3- thiazoles, solvent is done using toluene or the dioxane of Isosorbide-5-Nitrae-, may because toluene and the dioxane of Isosorbide-5-Nitrae-are two class solvents, and in toluene
Containing a kind of solvent benzol, so environmental pollution is bigger；When forming acotiamide hydrochloride hydrate, the solvent used is higher for price
Isopropanol, cost is higher, is unfavorable for industrialized production.
The content of the invention
For deficiency of the prior art, the invention provides a kind of new acotiamide hydrochloride trihydrate preparation side
Method, this method have the advantages of energy-conserving and environment-protective, production cost are low, product quality is high.
Specifically, the preparation method of acotiamide hydrochloride trihydrate provided by the invention, comprises the following steps：
(1) 2- [N- (2,4,5- trimethoxybenzoys) amino] -4- ethoxy carbonyl -1,3- thiazole (chemical combination of formula I is taken
Thing) 1mol, di-n-butylamine 3mol, DMF 2V/W (compound of formula I), be stirred at reflux (153 DEG C) reaction (8h)；
Room temperature is cooled to, adds 10% aqueous hydrochloric acid solution, separates out pale solid, after stirring (4h), centrifugation, water washing filter cake；80
DEG C~90 DEG C, under -0.095Mpa, it is dried to obtain 2- [N- (2- hydroxyls -4,5- Dimethoxybenzoyl) amino] -4- (ethoxies
Base carbonyl) -1,3-thiazoles (compound of formula II) crude product, yield reaches 83%-88%；
Compound of formula I structural formula：
Formula II structural formula of compound：
(2) by the crude compound of formula II made from step (1), the mixing for adding DMF and acetic acid is molten
Agent, it is heated to being completely dissolved, adds activated carbon, stirs (30 minutes) at this temperature；Filtering, filtrate stirring natural cooling analysis
Crystalline substance, centrifugation, at 80 DEG C~90 DEG C, under -0.095Mpa, is dried to obtain 2- [N- (2- hydroxyls -4,5- Dimethoxybenzoyl) ammonia
Base] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II) yield reaches 81%-89%, purity 99.05-99.8%.
(3) N is taken, N- diisopropyl ethylenediamines, is heated to 70 DEG C~75 DEG C, above-mentioned formula is added in four batches (in 3 hours)
II compound, 95 DEG C~105 DEG C are warming up to, after stirring (10h), is cooled to 30 DEG C, obtained rufous and stick thick liquid.
(4) ethanol is added into aforesaid liquid, is stirred (1h), dissolving obtains dark brown solution, continuously adds ethanol, is added dropwise
Concentrated hydrochloric acid, temperature is no more than 50 DEG C in control, stirs (5h), separates out white solid, stands (1h), and centrifugation obtains acotiamide hydrochloride hydrate
Trihydrate crude product.
(5) by acotiamide hydrochloride trihydrate crude product made from step (4), the mixed of a certain proportion of second alcohol and water is added
Bonding solvent, heating stirring are completely dissolved, and are added activated carbon, heat filtering, filtrate Temperature fall, after white solid is separated out, are centrifuged,
Acotiamide hydrochloride trihydrate after being refined, purity 99.94-99.99%.
In the step (2), the DMF of mixed solvent and the volume ratio of acetic acid are 1：99~99：1；It is excellent
Select 1:2~20:1；Most preferably 10：1.
The step (3) uses solvent-free reaction.
In the step (4), the hydrogen cloride concentration of concentrated hydrochloric acid is 36%.
Step (1)-(4) are carried out under nitrogen protection.
In the step (5), the ethanol of mixed solvent and the volume ratio of water are 1：9~9：1；It is preferred that 4：1.
In the prior art, 2- [N- (2- hydroxyls -4,5- Dimethoxybenzoyl) amino] -4- (ethoxy carbonyl) -
When 1,3-thiazoles (compound of formula II) carries out recrystallization purifying, it is impossible to be completely dissolved or consume substantial amounts of solvent, lead to not
The color of the compound of removal formula II causes yield to reduce, therefore inventor develops DMF and acetic acid group
Into mixed solvent, the compound of formula II is dissolved completely in the in the mixed solvent when carrying out recrystallization purifying, and add work
Property carbon carry out decolorization filtering, obtain the compound of formula II of white high-purity, its purity can reach 99.8%, wherein the mixing
The volume ratio of DMF and acetic acid in solvent is 1：99~99：1；It is preferred that 1:2~20:1；More preferably 10：1.
And in the prior art, N, N- diisopropyl ethylenediamines and 2- [N- (2- hydroxyl -4,5- dimethoxybenzoyls
Base) amino] -4- (ethoxy carbonyl) -1,3-thiazoles reacts in organic solvent, caused the discharge of multi-pollutant；Therefore originally
Invention, without using the method for solvent, has the advantages of energy-conserving and environment-protective using the two is directly reacted.Wherein N, N- diisopropyl
Base ethylenediamine rubs with 2- [N- (2- hydroxyl -4,5- Dimethoxybenzoyls) amino] -4- (ethoxy carbonyl) -1,3- thiazoles
You are than being more than 2：1；It is preferred that 3：1.
The present invention can reclaim N, N- after Acotiamide is generated by the way of being evaporated under reduced pressure or directly distilling
Diisopropyl ethylenediamine；Ethanol and hydrochloric acid can also be directly added into salt.
Acotiamide hydrochloride trihydrate it is refined during, document uses isopropanol and hydrochloric acid, due to isopropanol
Boiling point be 82.6 DEG C, and ethyl alcohol boiling point is 78.4 DEG C, and in recycling design, the energy consumption of ethanol consumption significantly reduces, and ethanol
Price it is cheaper than isopropanol, production cost can be reduced；Isopropanol or methanol are substituted using ethanol, solvent can also be reduced
Toxicity；Refined method is mixed using second alcohol and water, the purity for obtaining product is higher than isopropanol.
In addition, present invention also offers the process for purification of acotiamide hydrochloride trihydrate crude product, comprise the following steps：
(1) by 2- [N- (2- hydroxyl -4,5- Dimethoxybenzoyls) amino] -4- (ethoxy carbonyl) -1,3- thiazoles
(compound of formula II) crude product：
Formula II structural formula of compound：
The mixed solvent of DMF and acetic acid is added, is heated to being completely dissolved, adds activated carbon, it is warm herein
Degree is lower to be stirred；Filtering, filtrate stirring natural cooling crystallization, centrifugation, at 80 DEG C~90 DEG C, under -0.095Mpa, is dried to obtain 2-
[N- (2- hydroxyls -4,5- Dimethoxybenzoyl) amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II) is pure
Spend for 99.05-99.8%.
(2) N is taken, N- diisopropyl ethylenediamines, is heated to 70 DEG C~75 DEG C, above-mentioned formula is added in four batches (in 3 hours)
II compound, 95 DEG C~105 DEG C are warming up to, after stirring (10h), is cooled to 30 DEG C, obtained rufous and stick thick liquid.
(3) ethanol is added into aforesaid liquid, is stirred (1h), dissolving obtains dark brown solution, continuously adds ethanol, is added dropwise
Concentrated hydrochloric acid, temperature is no more than 50 DEG C in control, stirs (5h), separates out white solid, stands (1h), and centrifugation obtains acotiamide hydrochloride hydrate
Trihydrate crude product.
(4) by acotiamide hydrochloride trihydrate crude product made from step (4), the mixed of a certain proportion of second alcohol and water is added
Bonding solvent, heating stirring are completely dissolved, and are added activated carbon, heat filtering, filtrate Temperature fall, after white solid is separated out, are centrifuged,
Acotiamide hydrochloride trihydrate after being refined, purity 99.94-99.99%.
The DMF of above-mentioned mixed solvent and the volume ratio of acetic acid are 1：99~99：1；It is preferred that 1:2~20:
1；Most preferably 10：1.
In the step (3), the hydrogen cloride concentration of concentrated hydrochloric acid is 36%.
Step (2)-(3) are carried out under nitrogen protection.
In the step (4), the ethanol of mixed solvent and the volume ratio of water are 1：9~9：1；It is preferred that 4：1.
Embodiment
The technical scheme of the present invention is described in detail below in conjunction with the embodiment of the present invention, but following examples
Only it is to understand the present invention, and the present invention can not be limited, a variety of differences that the present invention can be defined by the claims and cover
Mode is implemented.
Embodiment 1
Under nitrogen protection, 2- [N- (2,4,5- trimethoxybenzoy) amino] -4- second is added into 20L reactors
Epoxide carbonyl -1,3-thiazoles (type I compound, 2kg), di-n-butylamine 2.12kg, DMF 4L, is stirred at reflux
(153 DEG C) reaction 8h.Room temperature is cooled to, adds 10% aqueous hydrochloric acid solution 13.9kg, pale solid separates out, after stirring 4h, from
The heart, 5L water washing filter cakes；At 80 DEG C~90 DEG C, under -0.095Mpa, 2- [N- (2- hydroxyl -4,5- dimethoxy benzenes are dried to obtain
Formoxyl) amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II) crude product 1.7kg, yield 88%, purity
99.55%.
The hydrogen nuclear magnetic resonance modal data parsing of the compound of formula II prepared by above-mentioned steps is as follows：
δ 1.31ppm (t, 3H), δ 3.78ppm (s, 3H), δ 3.83ppm (s, 3H),
δ 4.30ppm (q, 2H), δ 6.62ppm (s, 1H), δ 7.65ppm (s, 1H),
δ 8.13ppm (s, 1H), δ 11.76ppm (s, 1H), δ 12.42ppm (s, 1H),
The above is visible, and sample confirms the structure and 2- [N- (2- hydroxyl -4,5- diformazans of sample through proton nmr spectra
Epoxide benzoyl) amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II) structure is consistent, the chemical combination of meeting formula II
The architectural feature of thing.
Under nitrogen protection, the crude compound 1.7kg of formula II, DMF are added into 20L reactors
5.6L, acetic acid 0.56L, it is heated to being completely dissolved, then adds 0.1kg activated carbon, stirs 30 minutes at this temperature；Filtering,
Filtrate stirs natural cooling crystallization, centrifugation, at 80 DEG C~90 DEG C, under -0.095Mpa, is dried to obtain 2- [N- (2- hydroxyls -4,5-
Dimethoxybenzoyl) amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II) 1.5kg, yield 89%, purity
For 99.8%.
Under nitrogen protection, N, N- diisopropyl ethylenediamine 1.536kg are added into 20L reactors, be heated to 70 DEG C~
75 DEG C, then added the 1.5kg compound of formula II (0.4+0.4+0.4+0.3kg) in four batches in 3 hours, then heat to 95
DEG C~105 DEG C, after stirring 10h, 30 DEG C are cooled to, rufous is obtained and sticks thick liquid.2.34L second is added into aforesaid liquid
Alcohol, 1h is stirred, dissolving obtains dark brown solution, continuously adds 6.3L ethanol, and 2.16kg concentrated hydrochloric acids (36%), control is then added dropwise
Interior temperature is no more than 50 DEG C, stirs 5h, separates out white solid, stands 1h, and centrifugation obtains acotiamide hydrochloride trihydrate crude product
1.9kg。
In 20L reactors, 1.9kg acotiamide hydrochloride trihydrate crude products, ethanol (13.2L) and water are added
(3.3L), 80 DEG C~90 DEG C, after stirring and dissolving are warming up to, obtain brown solution, add activated carbon 100g, heat filtering, filtrate is certainly
So cooling, after white solid is separated out, centrifugation, refined acotiamide hydrochloride trihydrate 1.7kg is obtained, purity is
99.99%.
Embodiment 2
Under nitrogen protection, 2- [N- (2,4,5- trimethoxybenzoy) amino] -4- second is added into 20L reactors
Epoxide carbonyl -1,3-thiazoles (type I compound, 2kg), di-n-butylamine 2.12kg, DMF 4L, is stirred at reflux
(153 DEG C) reaction 8h.Room temperature is cooled to, adds 10% aqueous hydrochloric acid solution 13.9kg, pale solid separates out, after stirring 4h, from
The heart, 5L water washing filter cakes.At 80 DEG C, under -0.095Mpa, 2- [N- (2- hydroxyls -4,5- Dimethoxybenzoyl) are dried to obtain
Amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II) crude product 1.6kg, yield 84.6%.
The hydrogen nuclear magnetic resonance modal data parsing of the compound of formula II prepared by above-mentioned steps is as follows：
δ 1.33ppm (t, 3H), δ 3.76ppm (s, 3H), δ 3.82ppm (s, 3H),
δ 4.28ppm (q, 2H), δ 6.61ppm (s, 1H), δ 7.63ppm (s, 1H),
δ 8.16ppm (s, 1H), δ 11.71ppm (s, 1H), δ 12.45ppm (s, 1H),
The above is visible, and sample confirms the structure and 2- [N- (2- hydroxyl -4,5- diformazans of sample through proton nmr spectra
Epoxide benzoyl) amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II) structure is consistent, the chemical combination of meeting formula II
The architectural feature of thing.
Under nitrogen protection, the crude compound 1.6kg of formula II, DMF are added into 20L reactors
2.05L, acetic acid 4.1L, it is heated to being completely dissolved, then adds 0.1kg activated carbon, stirs 30 minutes at this temperature；Filtering,
Filtrate stir natural cooling crystallization, centrifugation, at 80 DEG C, under -0.095Mpa, be dried to obtain 1.34kg 2- [N- (2- hydroxyl -4,
5- Dimethoxybenzoyls) amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II), yield 83.9%, purity
For 99.34%.
Under nitrogen protection, N is added into 20L reactors, N- diisopropyl ethylenediamine 1.536kg, is heated to 70 DEG C, so
Added the 1.34kg compound of formula II (0.3+0.3+0.4+0.34kg) in four batches in 3 hours afterwards, then heat to 95 DEG C, stir
After mixing 10h, 30 DEG C are cooled to, rufous is obtained and sticks thick liquid.2.34L ethanol is added into aforesaid liquid, stirs 1h, dissolving
Dark brown solution is obtained, continuously adds 6.3L ethanol, 2.16kg concentrated hydrochloric acids (36%) are then added dropwise, temperature is no more than 50 in control
DEG C, 5h is stirred, separates out white solid, stands 1h, centrifugation obtains acotiamide hydrochloride trihydrate crude product 1.65kg.
In 20L reactors, 1.65kg acotiamide hydrochloride trihydrate crude products, ethanol (9.9L) and water are added
(1.1L), 80 DEG C, after stirring and dissolving are warming up to, obtain brown solution, add activated carbon 100g, heat filtering, filtrate Temperature fall,
After white solid is separated out, centrifugation, refined acotiamide hydrochloride trihydrate 1.17kg, purity 99.94% are obtained.
Embodiment 3
Under nitrogen protection, 2- [N- (2,4,5- trimethoxybenzoy) amino] -4- second is added into 20L reactors
Epoxide carbonyl -1,3-thiazoles (type I compound, 2kg), di-n-butylamine 2.12kg, DMF 4L, is stirred at reflux
(153 DEG C) reaction 8h.Room temperature is cooled to, adds 10% aqueous hydrochloric acid solution 13.9kg, pale solid separates out, after stirring 4h, from
The heart, 5L water washing filter cakes.At 84 DEG C, under -0.095Mpa, 2- [N- (2- hydroxyls -4,5- Dimethoxybenzoyl) are dried to obtain
Amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II) crude product 1.65kg, yield 86%.
The hydrogen nuclear magnetic resonance modal data parsing of the compound of formula II prepared by above-mentioned steps is as follows：
δ 1.34ppm (t, 3H), δ 3.77ppm (s, 3H), δ 3.81ppm (s, 3H),
δ 4.32ppm (q, 2H), δ 6.63ppm (s, 1H), δ 7.62ppm (s, 1H),
δ 8.11ppm (s, 1H), δ 11.73ppm (s, 1H), δ 12.43ppm (s, 1H),
The above is visible, and sample confirms the structure and 2- [N- (2- hydroxyl -4,5- diformazans of sample through proton nmr spectra
Epoxide benzoyl) amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II) structure is consistent, the chemical combination of meeting formula II
The architectural feature of thing.
Under nitrogen protection, the crude compound 1.65kg of formula II, DMF are added into 20L reactors
5.87L, acetic acid 0.29L, it is heated to being completely dissolved, then adds 0.1kg activated carbon, stirs 30 minutes at this temperature；Filtering,
Filtrate stir natural cooling crystallization, centrifugation, at 80 DEG C, under -0.095Mpa, be dried to obtain 1.44kg 2- [N- (2- hydroxyl -4,
5- Dimethoxybenzoyls) amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II), yield 87.2%, purity
For 99.6%.
Under nitrogen protection, N is added into 20L reactors, N- diisopropyl ethylenediamine 1.536kg, is heated to 72 DEG C, so
Added the 1.44kg compound of formula II (0.3+0.3+0.4+0.44kg) in four batches in 3 hours afterwards, then heat to 99 DEG C, stir
After mixing 10h, 30 DEG C are cooled to, rufous is obtained and sticks thick liquid.2.34L ethanol is added into aforesaid liquid, stirs 1h, dissolving
Dark brown solution is obtained, continuously adds 6.3L ethanol, 2.16kg concentrated hydrochloric acids (36%) are then added dropwise, temperature is no more than 50 in control
DEG C, 5h is stirred, separates out white solid, stands 1h, centrifugation obtains acotiamide hydrochloride trihydrate crude product 1.70kg.
In 20L reactors, 1.70kg acotiamide hydrochloride trihydrate crude products, ethanol (1.1L) and water are added
(9.9L), 80 DEG C, after stirring and dissolving are warming up to, obtain brown solution, add activated carbon 100g, heat filtering, filtrate Temperature fall,
After white solid is separated out, centrifugation, refined acotiamide hydrochloride trihydrate 1.25kg, purity 99.95% are obtained.
Embodiment 4
Under nitrogen protection, 2- [N- (2,4,5- trimethoxybenzoy) amino] -4- second is added into 20L reactors
Epoxide carbonyl -1,3-thiazoles (type I compound, 2kg), di-n-butylamine 2.12kg, DMF 4L, is stirred at reflux
(153 DEG C) reaction 8h.Room temperature is cooled to, adds 10% aqueous hydrochloric acid solution 13.9kg, pale solid separates out, after stirring 4h, from
The heart, 5L water washing filter cakes.At 88 DEG C, under -0.095Mpa, 2- [N- (2- hydroxyls -4,5- Dimethoxybenzoyl) are dried to obtain
Amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II) crude product 1.6kg, yield 84.6%.
The hydrogen nuclear magnetic resonance modal data parsing of the compound of formula II prepared by above-mentioned steps is as follows：
δ 1.30ppm (t, 3H), δ 3.73ppm (s, 3H), δ 3.84ppm (s, 3H),
δ 4.31ppm (q, 2H), δ 6.64ppm (s, 1H), δ 7.64ppm (s, 1H),
δ 8.13ppm (s, 1H), δ 11.72ppm (s, 1H), δ 12.41ppm (s, 1H),
The above is visible, and sample confirms the structure and 2- [N- (2- hydroxyl -4,5- diformazans of sample through proton nmr spectra
Epoxide benzoyl) amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II) structure is consistent, the chemical combination of meeting formula II
The architectural feature of thing.
Under nitrogen protection, the crude compound 1.6kg of formula II, DMF are added into 20L reactors
0.06L, acetic acid 5.6L, it is heated to being completely dissolved, then adds 0.1kg activated carbon, stirs 30 minutes at this temperature；Filtering,
Filtrate stirs natural cooling crystallization, centrifugation, at 80 DEG C, under -0.095Mpa, is dried to obtain 1.3kg 2- [N- (2- hydroxyls -4,5-
Dimethoxybenzoyl) amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II), yield 82.3%, purity is
99.2%.
Under nitrogen protection, N is added into 20L reactors, N- diisopropyl ethylenediamine 1.536kg, is heated to 74 DEG C, so
Added the 1.3kg compound of formula II (0.3+0.3+0.3+0.4kg) in four batches in 3 hours afterwards, then heat to 102 DEG C, stir
After mixing 10h, 30 DEG C are cooled to, rufous is obtained and sticks thick liquid.2.34L ethanol is added into aforesaid liquid, stirs 1h, dissolving
Dark brown solution is obtained, continuously adds 6.3L ethanol, 2.16kg concentrated hydrochloric acids (36%) are then added dropwise, temperature is no more than 50 in control
DEG C, 5h is stirred, separates out white solid, stands 1h, centrifugation obtains acotiamide hydrochloride trihydrate crude product 1.53kg.
In 20L reactors, 1.53kg acotiamide hydrochloride trihydrate crude products, ethanol (13.2L) and water are added
(3.3L), 80 DEG C, after stirring and dissolving are warming up to, obtain brown solution, add activated carbon 100g, heat filtering, filtrate Temperature fall,
After white solid is separated out, centrifugation, refined acotiamide hydrochloride trihydrate 1.34kg, purity 99.97% are obtained.
Embodiment 5
Under nitrogen protection, 2- [N- (2,4,5- trimethoxybenzoy) amino] -4- second is added into 20L reactors
Epoxide carbonyl -1,3-thiazoles (type I compound, 2kg), di-n-butylamine 2.12kg, DMF 4L, is stirred at reflux
(153 DEG C) reaction 8h.Room temperature is cooled to, adds 10% aqueous hydrochloric acid solution 13.9kg, pale solid separates out, after stirring 4h, from
The heart, 5L water washing filter cakes.At 90 DEG C, under -0.095Mpa, 2- [N- (2- hydroxyls -4,5- Dimethoxybenzoyl) are dried to obtain
Amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II) crude product 1.59kg, yield 83%.
The hydrogen nuclear magnetic resonance modal data parsing of the compound of formula II prepared by above-mentioned steps is as follows：
δ 1.28ppm (t, 3H), δ 3.71ppm (s, 3H), δ 3.80ppm (s, 3H),
δ 4.30ppm (q, 2H), δ 6.60ppm (s, 1H), δ 7.60ppm (s, 1H),
δ 8.15ppm (s, 1H), δ 11.71ppm (s, 1H), δ 12.44ppm (s, 1H),
The above is visible, and sample confirms the structure and 2- [N- (2- hydroxyl -4,5- diformazans of sample through proton nmr spectra
Epoxide benzoyl) amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II) structure is consistent, the chemical combination of meeting formula II
The architectural feature of thing.
Under nitrogen protection, the crude compound 1.59kg of formula II, DMF are added into 20L reactors
5.6L, acetic acid 0.06L, it is heated to being completely dissolved, then adds 0.1kg activated carbon, stirs 30 minutes at this temperature；Filtering,
Filtrate stirs natural cooling crystallization, centrifugation, at 90 DEG C, under -0.095Mpa, is dried to obtain 1.3kg 2- [N- (2- hydroxyls -4,5-
Dimethoxybenzoyl) amino] -4- (ethoxy carbonyl) -1,3-thiazoles (compound of formula II), yield 81%, purity is
99.05%.
Under nitrogen protection, N is added into 20L reactors, N- diisopropyl ethylenediamine 1.536kg, is heated to 75 DEG C, so
Added the 1.3kg compound of formula II (0.3+0.3+0.3+0.4kg) in four batches in 3 hours afterwards, then heat to 105 DEG C, stir
After mixing 10h, 30 DEG C are cooled to, rufous is obtained and sticks thick liquid.2.34L ethanol is added into aforesaid liquid, stirs 1h, dissolving
Dark brown solution is obtained, continuously adds 6.3L ethanol, 2.16kg concentrated hydrochloric acids (36%) are then added dropwise, temperature is no more than 50 in control
DEG C, 5h is stirred, separates out white solid, stands 1h, centrifugation obtains acotiamide hydrochloride trihydrate crude product 1.43kg.
In 20L reactors, 1.23kg acotiamide hydrochloride trihydrate crude products, ethanol (13.2L) and water are added
(3.3L), 90 DEG C, after stirring and dissolving are warming up to, obtain brown solution, add activated carbon 100g, heat filtering, filtrate Temperature fall,
After white solid is separated out, centrifugation, refined acotiamide hydrochloride trihydrate 1.07kg, purity 99.96% are obtained.
Claims (9)
1. a kind of preparation method of acotiamide hydrochloride trihydrate, it is characterised in that the preparation method comprises the following steps：
(1) take 2- [N- (2,4,5- trimethoxybenzoys) amino] -4- ethoxy carbonyl -1,3- thiazoles (type I compound),
Di-n-butylamine, DMF, it is stirred at reflux reaction 8h；Room temperature is cooled to, adds 10% aqueous hydrochloric acid solution, separates out ash
White solid, after stirring 4h, centrifugation, water washing filter cake；At 80 DEG C~90 DEG C, under -0.095Mpa, 2- [N- (2- hydroxyls are dried to obtain
Base -4,5- Dimethoxybenzoyls) amino] -4- (ethoxy carbonyl) -1,3- thiazoles (compound of formula II) crude product；
(2) by the crude compound of formula II made from step (1), the mixed solvent of DMF and acetic acid is added, is added
Heat adds activated carbon to being completely dissolved, and stirs 30 minutes at this temperature；Filtering, filtrate stirring natural cooling crystallization, centrifugation,
At 80 DEG C~90 DEG C, under -0.095Mpa, 2- [N- (2- hydroxyls -4,5- Dimethoxybenzoyl) amino] -4- is dried to obtain
(ethoxy carbonyl) -1,3- thiazoles (compound of formula II)；
(3) N is taken, N- diisopropyl ethylenediamines are heated to 70 DEG C~75 DEG C, add the above-mentioned chemical combination of formula II in four batches in 3 hours
Thing, 95 DEG C~105 DEG C are warming up to, after stirring 10h, are cooled to 30 DEG C, obtained rufous and stick thick liquid；
(4) ethanol is added into aforesaid liquid, stirs 1h, dissolving obtains dark brown solution, continuously adds ethanol, dense salt is added dropwise
Acid, temperature is no more than 50 DEG C in control, stirs 5h, separates out white solid, stands 1h, and centrifugation obtains acotiamide hydrochloride hydrate crude product；
(5) by acotiamide hydrochloride hydrate crude product made from step (4), the mixed solvent of a certain proportion of second alcohol and water is added, is heated
Stirring is completely dissolved, and is added activated carbon, heat filtering, filtrate Temperature fall, after white solid is separated out, is centrifuged, after being refined
Acotiamide hydrochloride trihydrate.
2. preparation method as claimed in claim 1, it is characterised in that in the step (2), the N of mixed solvent, N- dimethyl
The volume ratio of formamide and acetic acid is 1：99~99：1.
3. preparation method as claimed in claim 2, it is characterised in that in the step (2), the N of mixed solvent, N- dimethyl
The volume ratio of formamide and acetic acid is 10：1.
4. preparation method as claimed in claim 1, it is characterised in that N in the step (3), N- diisopropyl ethylenediamines with
The mol ratio of 2- [N- (2- hydroxyl -4,5- Dimethoxybenzoyls) amino] -4- (ethoxy carbonyl) -1,3- thiazoles is more than 2：
1。
5. preparation method as claimed in claim 4, it is characterised in that N in the step (3), N- diisopropyl ethylenediamines with
The mol ratio of 2- [N- (2- hydroxyl -4,5- Dimethoxybenzoyls) amino] -4- (ethoxy carbonyl) -1,3- thiazoles is 3：1.
6. preparation method as claimed in claim 1, it is characterised in that the step (3) uses solvent-free reaction.
7. preparation method as claimed in claim 1, it is characterised in that step (1)-(4) are carried out under nitrogen protection.
8. preparation method as claimed in claim 1, it is characterised in that in the step (5), the ethanol of mixed solvent and water
Volume ratio is 1：9~9：1.
9. preparation method as claimed in claim 8, it is characterised in that in the step (5), the ethanol of mixed solvent and water
Volume ratio is 4：1.
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