CN105315272B - A kind of preparation method of thiamine hydrochloride crystal product - Google Patents
A kind of preparation method of thiamine hydrochloride crystal product Download PDFInfo
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- CN105315272B CN105315272B CN201510679360.3A CN201510679360A CN105315272B CN 105315272 B CN105315272 B CN 105315272B CN 201510679360 A CN201510679360 A CN 201510679360A CN 105315272 B CN105315272 B CN 105315272B
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses a kind of preparation methods preparing thiamine hydrochloride crystal.Thiamine mononitrate is distributed in solvent, the suspension of the thiamine mononitrate of a concentration of 0.05~0.2g/mL is obtained, is heated to 50~70 DEG C.Chlorosulfonic acid is instilled in concentrated hydrochloric acid and generates hydrogen chloride gas, gas is passed through drying in the concentrated sulfuric acid, and the suspension of middle thiamine mononitrate is passed through under stirring action.After the completion of hydrogen chloride gas is passed through, 15~30min is kept the temperature, is then cooled to 10 DEG C, rate of temperature fall is 0.1 DEG C/min~0.5 DEG C/min, and through being filtered, washed, drying, thiamine hydrochloride crystal is made.Crystal is rhabdolith, and angle of repose is 31 °~36.4 °, and heap density is 0.50~0.608g/mL.Good fluidity.The present invention avoids being initially formed thiamine hydrochloride methanol solvate compound, and the process that re-dry removes methanol reduces cost and dissolvent residual to reduce environmental pollution.It is applicable to large-scale production.
Description
Technical field
The invention belongs to medical crystallization technique fields, and in particular to a kind of preparation method of thiamine hydrochloride crystal.
Background technology
Thiamine hydrochloride, vitamin B1Hydrochloride also known as thiamine hydrochloride, English name thiamine
Hydrochloride, molecular formula C12H17ClN4OSHCl, molecular weight 337.27, CAS 67-03-8, the entitled chlorination 3- of chemistry
[(4- amino-2-methyl -5- pyrimidine radicals)-Jia Ji ]- 5- (2- hydroxyethyls) -4- methylthiazols, molecular structure are as follows.
Thiamine hydrochloride is vitamin B1A kind of existence form, be commonly used for nutritional supplement.Vitamin B1Be by pyrimidine ring and
The compound that thiazole ring is combined into, due to containing sulphur and amine, again name thiamine in molecule.Vitamin B1It is naturally occurring in rice
In the foods such as chaff, wheat bran, lean meat, shelled peanut, sterling is usually prepared by chemical synthesis, is a kind of nutrition necessary to humans and animals
Substance.Vitamin B1 participates in the intermediate supersession of carbohydrate in vivo.Vitamin B1 is insufficient in body, and cocarboxylase activity declines, sugar
Metabolism is obstructed, to influence entire organism metabolism process.Wherein acetone decarboxylation is obstructed, and cannot be entered tricarboxylic acid cycle, not continued
Oxidation, accumulates in the tissue.At this moment, nerve fiber energy supply is insufficient, then may occur in which corresponding neuromuscular symptom, such as multiple
Neuritis, muscular atrophy and oedema can also influence the function of cardiac muscle and brain tissue when serious.
1935-1936, Williams synthesize vitamin B first1, it is domestic then started in 1964 produce thiamine hydrochloride.
Currently, thiamine hydrochloride is at home and abroad mainly prepared with chemical synthesis, the raw material for synthesizing initial stage is acrylonitrile.The system of thiamine hydrochloride
It is for technique：Generally first nitric acid synthesis thiamines, then thiamine hydrochloride is converted by thiamine mononitrate, detailed process is to drip chlorosulfonic acid
It is added to the hydrogen chloride equipped with hydrochloric acid to occur in kettle, the hydrogen chloride of generation is passed through in the methanol suspension of thiamine mononitrate, by nitric acid
Thiamines is converted into thiamine hydrochloride.The crystal that the technique is prepared is thiamine hydrochloride methanol solvate compound, passes through drying process
The methanol in lattice is removed, but waste of the pollution and methanol of environment can be caused during this, while there is also dissolvent residuals
Risk.In addition, the product that is prepared of the technique is flat crystal, there are product poor fluidity, heap density is low, product is easily tied
The problem of block.
In Chinese patent CN103387573 A, a kind of preparation process of thiamine hydrochloride, the area with traditional handicraft are disclosed
Be not that the patent generates hydrogen chloride gas using the method for heating concentrated hydrochloric acid, can to avoid using hazardous chemical chlorosulfonic acid,
But by the technique be prepared be equally thiamine hydrochloride methanol solvate compound, by drying process remove methanol, together
When product be still flat crystal, there are product poor fluidity, easily caking the problem of.
A kind of new method preparing thiamine hydrochloride with thiol thiamines is disclosed in Chinese patent CN1459449 A, for dimension
Raw element B1 intermediate thiol thiamines is raw material, and thiamine hydrochloride is generated through hydrogen peroxide oxidation, and barium chloride is added and reacts, directly complete
At the conversion from sulfuric acid thiamine to thiamine hydrochloride, hydrochloric acid methanol is recycled to carry out conversion of the thiamine mononitrate to thiamine hydrochloride, still
Barium ions is introduced in conversion process, this more difficult removing in the subsequent process, purity is unqualified, and a large amount of nothings of entire technology utilization
Machine compound carry out in and/or salt-forming reaction, can not recovery, cause process costs to improve, it is complex for operation step.
China is vitamin big producer and trade exports big country, solves the above problem of thiamine hydrochloride, develops hydrochloric acid sulphur
The new production technology of amine is of great significance.
By replacing recrystallisation solvent, the anhydride or hydrate of thiamine hydrochloride are directly obtained, and control crystallization process and change
Become its crystalline substance to practise, make its become it is blocky or it is rodlike be one of the feasible program for solving problem above.
Invention content
It is an object of the invention to overcome the prior art, a kind of new method preparing thiamine hydrochloride crystal is provided.
This method does not have to methanol as recrystallisation solvent, uses new solvent instead, by the duration of ventilation, speed of agitator, the knot that control hydrogen chloride
Thiamine hydrochloride non-stoichiometric hydrate is prepared in the conditions such as brilliant temperature, saves the mistake that methanol is removed using drying means
Journey, it is environmental-friendly, reduce cost, at rodlike or blocky, mobility is preferable for the thiamine hydrochloride crystal of gained.
The above-mentioned advantageous effect of the present invention is achieved through the following technical solutions.
A method of thiamine hydrochloride crystal being prepared, the method includes the steps as follows：
(1) thiamine mononitrate is distributed in solvent, obtains the suspension of the thiamine mononitrate of a concentration of 0.05~0.2g/mL,
It is heated to 50~75 DEG C；
(2) chlorosulfonic acid is instilled in concentrated hydrochloric acid and generates hydrogen chloride gas, gas is passed through in the concentrated sulfuric acid dry, stirring action
Under, it is passed through the suspension of thiamine mononitrate in step (1), chlorosulfonic acid is 1 with thiamine mononitrate mass ratio:1；The time for adding of chlorosulfonic acid
For 60~180min；
(3) after the completion of hydrogen chloride gas is passed through, 15~30min is kept the temperature, 10 DEG C are then cooled to, through being filtered, washed, doing
It is dry, thiamine hydrochloride crystal is made.
Solvent described in step (1) is selected from ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, Ethyl formate, methyl acetate, acetic acid
The mixture of one or more of ethyl ester, butyl acetate.According to《Impurity：Residual solvent guideline》In solvent classes,
Solvent methanol used in traditional handicraft is two class solvents, has certain toxicity, and limitation in the formulation uses.Institute in this method
The solvent of use is three classes solvent, has higher safety.
A concentration of 0.05~the 0.25g/mL, preferably 0.1~0.2g/mL of thiamine mononitrate suspension in the step (1).
Suspension concentration is too low, and yield is relatively low, and solvent dosage is larger.When suspension concentration is excessively high, crystallization degree of supersaturation is higher, while brilliant
Body is crushed serious caused by the factors such as collision.
The time for adding of chlorosulfonic acid is 60~180min in the step (2).The time for adding of chlorosulfonic acid affects crystallization
The degree of supersaturation of process, when time for adding is shorter, solution crystallization process degree of supersaturation is higher, and crystal is smaller.
Rate of temperature fall is 0.1 DEG C/min~0.5 DEG C/min in the step (3).Rate of temperature fall is lower, and crystal size is bigger,
But crystallizing cycle is elongated simultaneously.
Thiamine hydrochloride crystal prepared by the method for the invention is rodlike, and scanning electron microscope (SEM) photograph as shown in Figure 1, be with methanol
The scanning electron microscope (SEM) photograph of the thiamine hydrochloride product that traditional crystallization processes of recrystallisation solvent obtain is fragile as shown in Fig. 2, be flat crystal
It is broken.This method prepare thiamine hydrochloride product good fluidity, angle of repose be 31 °~36.4 °, heap density be 0.50~
0.608g/mL.The sheet thiamine hydrochloride mobility prepared using methanol as solvent is poor, 60.5 ° of angle of repose, and heap density is
0.301g/mL.Comparison is it is found that the obtained crystal of this patent the method is with the obvious advantage.In addition, the hydrochloric acid that this method is prepared
Thiamines crystal is its non-stoichiometric hydrate, and X-ray powder diffraction pattern is as shown in Figure 3.
The thiamine hydrochloride crystal that the method for the invention is prepared meets follow-up preparation process requirement.The present invention relative to
The prior art has the following advantages and advantageous effect：
1, it avoids being initially formed thiamine hydrochloride methanol solvate compound, re-dry removes the process of methanol, to reduce environment
Pollution, reduces cost and dissolvent residual.
2, the thiamine hydrochloride crystal being prepared is prevented from caking at rodlike, good product mobility, be conducive to storage and it is follow-up plus
Work requirement.
Learn that the technique that thiamine hydrochloride is prepared in embodiment is equally being given birth on a large scale by the research of further amplification test
The effect consistent with lab scale embodiment scale is shown as when production, it is known that corresponding technique is equally applicable to large-scale production.
Description of the drawings
Fig. 1：1 gained thiamine hydrochloride crystal stereoscan photograph of embodiment；
Fig. 2：The thiamine hydrochloride crystal stereoscan photograph that comparative example 1 obtains；
Fig. 3：Thiamine hydrochloride X-ray powder diagram；
Specific implementation mode
With reference to embodiment and attached drawing, the present invention is described in further detail, but the embodiment invented is not limited to
This.
It is the specific implementation mode of the present invention below：
Embodiment 1.
(1) 30g thiamine mononitrates are added in 150mL ethyl acetate, are stirred, and be heated to 60 DEG C；
(2) 30g concentrated hydrochloric acids are weighed to be put into more mouthfuls of crystallizers, are stirred, 30g chlorosulfonic acids is weighed and instills in concentrated hydrochloric acid, control
Time for adding processed is 60min, and the hydrogen chloride gas of generation is passed into drying in the concentrated sulfuric acid, and the gas after drying is passed into step
(1) in the suspension in, speed of agitator 300r/min；
(3) after the completion of hydrogen chloride gas is passed through, 20min is kept the temperature, is then cooled to 10 DEG C with 0.1 DEG C/min, filtering is washed
It washs, is dried to obtain thiamine hydrochloride crystal.
Products obtained therefrom is rodlike, and scanning electron microscope (SEM) photograph is as shown in Figure 1, X-ray powder diffraction figure is as shown in Figure 3.
Embodiment 2.
(1) 20g thiamine mononitrates are added in 190mL Ethyl formates, are stirred, and be heated to 50 DEG C；
(2) 20g concentrated hydrochloric acids are weighed to be put into more mouthfuls of crystallizers, are stirred, 20g chlorosulfonic acids is weighed and instills in concentrated hydrochloric acid, control
Time for adding processed is 90min, and the hydrogen chloride gas of generation is passed into drying in the concentrated sulfuric acid, and the buffered bottle of gas after drying is passed through
Into the suspension in step (1), speed of agitator 600r/min；
(3) after the completion of hydrogen chloride gas is passed through, 15min is kept the temperature, is then cooled to 10 DEG C with 0.3 DEG C/min, filtering is washed
It washs, is dried to obtain thiamine hydrochloride crystal.
Gained crystal is thiamine hydrochloride non-stoichiometric hydrate, and it is rodlike that crystalline substance, which is practised,.
Embodiment 3.
(1) 20g thiamine mononitrates are added in 190mL normal propyl alcohols, are stirred, and be heated to 75 DEG C；
(2) 20g concentrated hydrochloric acids are weighed to be put into more mouthfuls of crystallizers, are stirred, 20g chlorosulfonic acids is weighed and instills in concentrated hydrochloric acid, control
Time for adding processed is 90min, and the hydrogen chloride gas of generation is passed into drying in the concentrated sulfuric acid, and the buffered bottle of gas after drying is passed through
Into the suspension in step (1), speed of agitator 600r/min；
(3) after the completion of hydrogen chloride gas is passed through, 30min is kept the temperature, is then cooled to 10 DEG C with 0.5 DEG C/min, filtering is washed
It washs, is dried to obtain thiamine hydrochloride crystal.
Gained crystal is thiamine hydrochloride non-stoichiometric hydrate, and it is rodlike that crystalline substance, which is practised,.
Embodiment 4.
(1) 10g thiamine mononitrates are added in 200mL methyl acetates, are stirred, and be heated to 70 DEG C；
(2) 10g concentrated hydrochloric acids are weighed to be put into more mouthfuls of crystallizers, are stirred, 10g chlorosulfonic acids is weighed and instills in concentrated hydrochloric acid, control
Time for adding processed is 180min, and the hydrogen chloride gas of generation is passed into drying in the concentrated sulfuric acid, and the buffered bottle of gas after drying is logical
Enter into the suspension in step (1), speed of agitator 500r/min；
(3) after the completion of hydrogen chloride gas is passed through, 20min is kept the temperature, is then cooled to 10 DEG C with 0.5 DEG C/min, filtering is washed
It washs, is dried to obtain thiamine hydrochloride crystal.
Gained crystal is thiamine hydrochloride non-stoichiometric hydrate, and it is rodlike that crystalline substance, which is practised,.
Embodiment 5.
(1) 15g thiamine mononitrates are added in 200mL n-butanols, are stirred, and be heated to 60 DEG C；
(2) 15g concentrated hydrochloric acids are weighed to be put into more mouthfuls of crystallizers, are stirred, 15g chlorosulfonic acids is weighed and instills in concentrated hydrochloric acid, control
Time for adding processed is 100min, and the hydrogen chloride gas of generation is passed into drying in the concentrated sulfuric acid, and the buffered bottle of gas after drying is logical
Enter into the suspension in step (1), speed of agitator 400r/min；
(3) after the completion of hydrogen chloride gas is passed through, 30min is kept the temperature, is then cooled to 10 DEG C with 0.5 DEG C/min, filtering is washed
It washs, is dried to obtain thiamine hydrochloride crystal.
Gained crystal is thiamine hydrochloride non-stoichiometric hydrate, and it is rodlike that crystalline substance, which is practised,.
Embodiment 6.
(1) 20g thiamine mononitrates are added to 100mL methyl acetates with the mixed liquor of 100mL ethyl acetate, stirred, and
It is heated to 65 DEG C；
(2) 20g concentrated hydrochloric acids are weighed to be put into more mouthfuls of crystallizers, are stirred, 20g chlorosulfonic acids is weighed and instills in concentrated hydrochloric acid, control
Time for adding processed is 120min, and the hydrogen chloride gas of generation is passed into drying in the concentrated sulfuric acid, and the buffered bottle of gas after drying is logical
Enter into the suspension in step (1), speed of agitator 300r/min；
(3) after the completion of hydrogen chloride gas is passed through, 20min is kept the temperature, is then cooled to 10 DEG C with 0.5 DEG C/min, filtering is washed
It washs, is dried to obtain thiamine hydrochloride crystal.
Gained crystal is thiamine hydrochloride non-stoichiometric hydrate, and it is rodlike that crystalline substance, which is practised,.
Embodiment 7.
(1) 15g thiamine mononitrates are added in 80mL ethyl acetate, are stirred, and be heated to 60 DEG C；
(2) 15g concentrated hydrochloric acids are weighed to be put into more mouthfuls of crystallizers, are stirred, 15g chlorosulfonic acids is weighed and instills in concentrated hydrochloric acid, control
Time for adding processed is 90min, and the hydrogen chloride gas of generation is passed into drying in the concentrated sulfuric acid, and the buffered bottle of gas after drying is passed through
Into the suspension in step (1), speed of agitator 600r/min；
(3) after the completion of hydrogen chloride gas is passed through, 30min is kept the temperature, is then cooled to 10 DEG C with 0.3 DEG C/min, filtering is washed
It washs, is dried to obtain thiamine hydrochloride crystal.
Gained crystal is thiamine hydrochloride non-stoichiometric hydrate, and it is rodlike that crystalline substance, which is practised,.
Comparative example 1.
(1) 30g thiamine mononitrates are added in 150mL methanol, are stirred, and be heated to 60 DEG C；
(2) 30g concentrated hydrochloric acids are weighed to be put into more mouthfuls of crystallizers, are stirred, 30g chlorosulfonic acids is weighed and instills in concentrated hydrochloric acid, control
Time for adding processed is 80min, and the hydrogen chloride gas of generation is passed into drying in the concentrated sulfuric acid, and the buffered bottle of gas after drying is passed through
Into the suspension in step (1), speed of agitator 300r/min；
(3) after the completion of hydrogen chloride gas is passed through, 20min is kept the temperature, is then cooled to 10 DEG C with 0.1 DEG C/min, filtering is washed
It washs, is dried to obtain thiamine hydrochloride crystal.
Products obtained therefrom is sheet, and scanning electron microscope (SEM) photograph is as shown in Fig. 2, X-ray powder diffraction figure is as shown in Figure 3.
Test example 1
Stopping for 1 products obtained therefrom of Examples 1 to 2 and comparative example is detected using fixed funnel method and graduated cylinder hammering method respectively
Angle till and heap density, measurement result are as shown in the table：
As can be seen that the rhabdolith angle of repose obtained by Examples 1 to 2, generally between 31 °~36.4 °, comparison is implemented
The flat crystal angle of repose of 1 gained of example is higher, it is known that the mobility of gained rhabdolith is much better than lamellar morphology product；
Examples 1 to 2 heap density is much larger than lamellar morphology product, it is known that gained stick between 0.579~0.608g/mL
The electrostatic effect of shape crystal substantially reduces.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, it is other it is any without departing from the spirit and principles of the present invention made by changes, modifications, substitutions, combinations, simplifications,
Equivalent substitute mode is should be, is included within the scope of the present invention.
Claims (2)
1. a kind of preparation method of thiamine hydrochloride crystal, it is characterised in that include following step：
(1) thiamine mononitrate is distributed in solvent, obtains the suspension of the thiamine mononitrate of a concentration of 0.05~0.2g/mL, heated
To 50~70 DEG C；
(2) chlorosulfonic acid is instilled in concentrated hydrochloric acid and generates hydrogen chloride gas, gas is passed through in the concentrated sulfuric acid and dries, and under stirring action, leads to
Enter the suspension of thiamine mononitrate in step (1), chlorosulfonic acid is 1 with thiamine mononitrate mass ratio:1, the time for adding of chlorosulfonic acid is 60
~180min；
(3) after the completion of hydrogen chloride gas is passed through, 15~30min is kept the temperature, is then cooled to 10 DEG C, through being filtered, washed, drying, made
Obtain thiamine hydrochloride crystal；
The one kind or several of solvent in normal propyl alcohol, n-butanol, Ethyl formate, methyl acetate, ethyl acetate described in step (1)
The mixture of kind；Rate of temperature fall is 0.1 DEG C/min~0.5 DEG C/min in step (3)；The thiamine hydrochloride crystal is rodlike crystalline substance
Body, angle of repose are 31 °~36.4 °, and heap density is 0.50~0.608g/mL.
2. according to the method described in claim 1, it is characterized in that：Thiamine mononitrate suspension concentration is preferred in the step (1)
For 0.1~0.2g/mL.
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|---|---|---|---|---|
| EP0342482A2 (en) * | 1988-05-17 | 1989-11-23 | F. Hoffmann-La Roche Ag | Process for the preparation of pyrimidine derivatives |
| CN1459449A (en) * | 2002-05-22 | 2003-12-03 | 东北制药总厂 | New method of preparing ritamin B1 hydrochloride using thiohydrothiamine |
| WO2012090224A1 (en) * | 2010-12-29 | 2012-07-05 | Nutracryst Therapeutics Private Limited | Novel cocrystals / molecular salts of mesalamine to be used as improved anti-inflammatory drug |
| CN102952126A (en) * | 2012-12-03 | 2013-03-06 | 华中药业股份有限公司 | Novel method for synthesizing vitamin B1 hydrochloride |
| CN103387573A (en) * | 2012-05-08 | 2013-11-13 | 江苏兄弟维生素有限公司 | Preparation process for thiamine hydrochloride |
| CN104817551A (en) * | 2015-05-07 | 2015-08-05 | 常州大学 | New method of preparing vitamin B1 hydrochloride |
-
2015
- 2015-10-19 CN CN201510679360.3A patent/CN105315272B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0342482A2 (en) * | 1988-05-17 | 1989-11-23 | F. Hoffmann-La Roche Ag | Process for the preparation of pyrimidine derivatives |
| CN1459449A (en) * | 2002-05-22 | 2003-12-03 | 东北制药总厂 | New method of preparing ritamin B1 hydrochloride using thiohydrothiamine |
| WO2012090224A1 (en) * | 2010-12-29 | 2012-07-05 | Nutracryst Therapeutics Private Limited | Novel cocrystals / molecular salts of mesalamine to be used as improved anti-inflammatory drug |
| CN103387573A (en) * | 2012-05-08 | 2013-11-13 | 江苏兄弟维生素有限公司 | Preparation process for thiamine hydrochloride |
| CN102952126A (en) * | 2012-12-03 | 2013-03-06 | 华中药业股份有限公司 | Novel method for synthesizing vitamin B1 hydrochloride |
| CN104817551A (en) * | 2015-05-07 | 2015-08-05 | 常州大学 | New method of preparing vitamin B1 hydrochloride |
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