CN107382922A - The preparation method of high-transmittance ranitidine hydrochloride - Google Patents
The preparation method of high-transmittance ranitidine hydrochloride Download PDFInfo
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- CN107382922A CN107382922A CN201710656979.1A CN201710656979A CN107382922A CN 107382922 A CN107382922 A CN 107382922A CN 201710656979 A CN201710656979 A CN 201710656979A CN 107382922 A CN107382922 A CN 107382922A
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- ranitidine
- ranitidine hydrochloride
- methyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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Abstract
The invention discloses a kind of preparation method of high-transmittance ranitidine hydrochloride, comprise the following steps：（1）Preparing raw material solution；（2）Reaction prepares ranitidine；（3）Ranitidine purifies；（4）Prepare ranitidine hydrochloride；（5）Ranitidine hydrochloride purifies.A kind of preparation method of high-transmittance ranitidine hydrochloride of the present invention, pass through rational process modification, it is combined by the control of the drop rate of temperature control, stir speed (S.S.) control with crystallizing solvent absolute ethyl alcohol, and vacuum reaction condition, effectively increase the yield and purity of ranitidine hydrochloride, the exploitativeness of its production process is high, it is easy to industrialized production, products obtained therefrom has higher light transmittance and printing opacity stability, and the crystalline form of product is good, good fluidity, combination property is more excellent, and there is important practical application and the market development to be worth.
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly to a kind of preparation method of high-transmittance ranitidine hydrochloride.
Background technology
Ranitidine hydrochloride（Ranitidine Hydrochloride）It is H2- receptor antagonists, it is to physiological and five
Gastric acid secretion caused by peptide gastrin etc. has obvious inhibiting effect, for alleviating stomachache caused by hyperhydrochloria, heartburn（Burn
The heart）, acid reflux, while to benign gastric ulcer, duodenal ulcer, marginal ulcer, reflux esophagitis, Zhuo-Emhorn syndrome
Also there is good therapeutic effect, due to rapid with oral absorption, dosage is small, takes that number is few, and Small side effects, recurrence rate is low, easily
The characteristics of being accepted by patients, it is the indispensable medicine of each hospitalize disease of digestive system, national base is classified as by the Ministry of Public Health of China
This medicine.
At present, prior art is for preparing ranitidine hydrochloride, and its complex steps, yield are relatively low, processing cost is higher, and
It is not suitable for producing in enormous quantities.Further, since the factor in terms of the materialization of ranitidine hydrochloride product itself so that its stability is deposited
Gap be present in terms of some problems, the stability of product batches, light transmittance is poor.
The content of the invention
, can the present invention solves the technical problem of a kind of preparation method of high-transmittance ranitidine hydrochloride is provided
Solves above mentioned problem existing for existing ranitidine hydrochloride production.
In order to solve the above technical problems, one aspect of the present invention is：A kind of high-transmittance hydrochloric acid thunder is provided
Buddhist nun replaces the preparation method of fourth, comprises the following steps：
（1）Preparing raw material solution：By 2- [[[5- (dimethylamino) methyl -2- furans] methyl] sulfenyl] ethamine and N- methyl -
1- methyl mercapto -2- nitroethylenes amine is configured to the aqueous solution of same molar ratio with purified water respectively；
（2）Reaction prepares ranitidine：Under stirring, by step（1）Two kinds of solution of middle preparation are added dropwise with identical volume
Mixing, drop finish, are allowed to react under vacuum heating conditions, after reaction terminates, when reducing reacting liquid temperature and constant temperature and stirring one section
Between, crystallisation by cooling fully separates out, and is filtrated to get crude product ranitidine；
（3）Ranitidine purifies：By step（2）In obtained crude product ranitidine be dissolved in excessive methyl-isobutyl copper solvent
In, under vacuum condition, distillation azeotropic dehydration to distillate to there is no water, then adds 0.5~1g activated carbon decolorizings, filters, filtrate
Crystallize and separate out under stirring, low temperature, vacuum condition, filter, be dried to obtain white ranitidine solid；
（4）Prepare ranitidine hydrochloride：To step（3）In in obtained ranitidine after purification with 5~8ml/min speed
Absolute ethyl alcohol is added dropwise, dissolves ranitidine with 80~100r/min stir speed (S.S.) stirring when being added dropwise, is added at 0~3 DEG C
Salt forming agent adjusts pH value to 6.3~6.8, is then transferred in vacuum environment, constant temperature stirring separates out ranitidine hydrochloride, and vacuum subtracts
Pressure suction filtration obtains crude product ranitidine hydrochloride；
（5）Ranitidine hydrochloride purifies：To step（4）In in obtained crude product ranitidine hydrochloride with 5~8ml/min speed
Ethanol is added dropwise, dissolves ranitidine hydrochloride with 80~100r/min stir speed (S.S.) stirring when being added dropwise, low temperature crystallization, takes out
Filter, repeats the above steps 2~3 times, is finally dried in vacuo filtered solid, the ranitidine hydrochloride purified.
In a preferred embodiment of the present invention, the step（1）In, 2- [[[5- (dimethylamino) methyl -2-
Furans] methyl] sulfenyl] and ethylamine solution and N- methyl isophthalic acids-methyl mercapto -2- nitroethylene amine aqueous solutions molal volume concentration it is equal
For 3.5~4.0mol/L.
In a preferred embodiment of the present invention, the step（2）In, the dropwise addition mode of described two solution is：By 2-
[[[5- (dimethylamino) methyl -2- furans] methyl] sulfenyl] ethylamine solution is first added drop-wise to N- with 3~5mL/min speed
In methyl isophthalic acid-methyl mercapto -2- nitroethylene amine aqueous solutions, while stirred with 200~260r/min speed, then again with 1.5
~2mL/min speed is added dropwise, while is stirred with 60~150r/min speed.
In a preferred embodiment of the present invention, the step（2）In, the condition of the reaction is：Vacuum 0.01~
0.03MPa, 38~42 DEG C of temperature, 5~7h of time；The temperature that the crystallization separates out is 1~3 DEG C, and the time is 6~12h, stirring speed
Rate is 30~50r/min.
In a preferred embodiment of the present invention, the step（3）In, the vacuum of the vacuum condition for 0.01~
0.03MPa, vapo(u)rizing temperature are 90~95 DEG C；The condition that precipitation is crystallized in the filtrate is：0.01~0.03MPa vacuum
Under, 40~50 DEG C first are cooled to 10~15 DEG C/min under 100~150r/min stir speed (S.S.), then in identical stirring
15~20 DEG C are cooled to 5~10 DEG C/min speed under speed, constant temperature keeps 2~3h, finally in 30~60r/min stirring
Under speed, 0~5 DEG C is cooled to 5~10 DEG C/min speed, constant temperature keeps 3~5h.
In a preferred embodiment of the present invention, the step（4）In, the salt forming agent is that volumetric concentration is 20~25%
Ethanol solution of hydrogen chloride；The vacuum condition is 0.03~0.05MPa of vacuum, and the stir speed (S.S.) is 20~30r/min.
In a preferred embodiment of the present invention, the step（5）In, the recrystallization temperature is 0~3 DEG C, the vacuum
Drying condition is：0.1~0.12MPa of vacuum, circulating cooling water management drying temperature be 55~60 DEG C, drying time be 2~
3h。
The beneficial effects of the invention are as follows：A kind of preparation method of high-transmittance ranitidine hydrochloride of the present invention, by reasonable
Process modification, be combined by temperature control, stir speed (S.S.) control with the control of drop rate of crystallization solvent absolute ethyl alcohol,
And vacuum reaction condition, the yield and purity of ranitidine hydrochloride are effectively increased, the exploitativeness of its production process is high, just
In industrialized production, products obtained therefrom has higher light transmittance and printing opacity stability, and the crystalline form of product is good, mobility
Good, combination property is more excellent, and there is important practical application and the market development to be worth.
Embodiment
Presently preferred embodiments of the present invention is described in detail below so that advantages and features of the invention can be easier to by
It will be appreciated by those skilled in the art that apparent clearly defined so as to be made to protection scope of the present invention.
The embodiment of the present invention includes：
Embodiment 1
（1）Preparing raw material solution：443g 2- [[[5- (dimethylamino) methyl -2- furans] methyl] sulfenyl] ethamine is weighed to put
In the reactor of hot tail gas absorption plant, 590ml purified waters are added thereto, it is 3.5 mol/ that stirring, which is configured to molar concentration,
The L aqueous solution；
307g N- methyl isophthalic acids-methyl mercapto -2- nitroethylene amine is weighed to be placed in the reactor of another hot tail gas absorption plant,
590ml purified water purified waters are added thereto, are configured to the 3.5 mol/L aqueous solution；
（2）Reaction prepares ranitidine：First under 200r/min speed stirring, by 2- [[[5- (dimethylamino) methyl -2-
Furans] methyl] sulfenyl] ethylamine solution is added drop-wise to N- methyl isophthalic acids-methyl mercapto -2- nitroethylene aqueous amines with 3mL/min speed
In solution, then continue again under 60r/min speed stirring by 2- [[[5- (dimethylamino) methyl -2- furans] methyl]
Sulfenyl] ethylamine solution is added drop-wise in N- methyl isophthalic acids-methyl mercapto -2- nitroethylene amine aqueous solutions with 1.5mL/min speed, drips
Finish, be allowed to react 7h to 38 DEG C in 0.01~0.03MPa heating under vacuum, after reaction terminates, reduce reacting liquid temperature be 1~
3 DEG C, 12h is stirred with 30r/min speed constant temperature, crystallization is fully separated out, is filtrated to get crude product ranitidine；
（3）Ranitidine purifies：By step（2）In obtained crude product ranitidine be dissolved in excessive methyl-isobutyl copper solvent
In, under 0.01~0.03MPa vacuum condition, it is heated to 90~95 DEG C of distillation azeotropic dehydrations to distillate to there is no water, Ran Houjia
Enter 0.5~1g activated carbon decolorizings, filter, filtrate is under 0.01~0.03MPa vacuum, first in 100r/min stir speed (S.S.)
Under with 10 DEG C/min be cooled to 40 DEG C, be then cooled to 15 DEG C under identical stir speed (S.S.) with 5 DEG C/min speed, constant temperature is protected
2h is held, finally under 30r/min stir speed (S.S.), is cooled to 0~5 DEG C with 5 DEG C/min speed, constant temperature keeps 3h, makes crystal
All crystallization separates out, and filters, obtains white ranitidine solid after purification；
（4）Prepare ranitidine hydrochloride：To step（3）In dripped with 5ml/min speed in obtained ranitidine after purification
Add absolute ethyl alcohol, dissolve ranitidine with 80r/min stir speed (S.S.) stirring when being added dropwise, volumetric concentration is added at 0~3 DEG C
For 20% ethanol solution of hydrogen chloride as salt forming agent, regulation pH value to 6.3, be then transferred to 0.03~0.05MPa vacuum environment
In, 0~3 DEG C of constant temperature, separate out ranitidine hydrochloride with 20r/min speed stirring, vacuum decompression filters to obtain crude product hydrochloric acid
Ranitidine；
（5）Ranitidine hydrochloride purifies：To step（4）In dripped with 5ml/min speed in obtained crude product ranitidine hydrochloride
Add ethanol, dissolve ranitidine hydrochloride with 80r/min stir speed (S.S.) stirring when being added dropwise, 0~3 DEG C of crystallization, filter, weight
Filtered solid, is finally dried in vacuo, the ranitidine hydrochloride purified by multiple above-mentioned washing step 2~3 times, described true
Empty drying condition is：0.1~0.12MPa of vacuum, circulating cooling water management drying temperature are 55 DEG C, drying time 2h.
Embodiment 2
（1）Preparing raw material solution：443g 2- [[[5- (dimethylamino) methyl -2- furans] methyl] sulfenyl] ethamine is weighed to put
In the reactor of hot tail gas absorption plant, 518ml purified waters are added thereto, it is 4.0mol/L that stirring, which is configured to molar concentration,
The aqueous solution；
307g N- methyl isophthalic acids-methyl mercapto -2- nitroethylene amine is weighed to be placed in the reactor of another hot tail gas absorption plant,
518ml purified water purified waters are added thereto, are configured to the 4.0mol/L aqueous solution；
（2）Reaction prepares ranitidine：First under 260r/min speed stirring, by 2- [[[5- (dimethylamino) methyl -2-
Furans] methyl] sulfenyl] ethylamine solution is added drop-wise to N- methyl isophthalic acids-methyl mercapto -2- nitroethylene aqueous amines with 5mL/min speed
In solution, then continue again under 150r/min speed stirring by 2- [[[5- (dimethylamino) methyl -2- furans] methyl]
Sulfenyl] ethylamine solution is added drop-wise in N- methyl isophthalic acids-methyl mercapto -2- nitroethylene amine aqueous solutions with 2mL/min speed, drips
Finish, be allowed to react 5h to 42 DEG C in 0.01~0.03MPa heating under vacuum, after reaction terminates, reduce reacting liquid temperature be 1~
3 DEG C, 6h is stirred with 50r/min speed constant temperature, crystallization is fully separated out, is filtrated to get crude product ranitidine；
（3）Ranitidine purifies：By step（2）In obtained crude product ranitidine be dissolved in excessive methyl-isobutyl copper solvent
In, under 0.01~0.03MPa vacuum condition, it is heated to 90~95 DEG C of distillation azeotropic dehydrations to distillate to there is no water, Ran Houjia
Enter 0.5~1g activated carbon decolorizings, filter, filtrate is under 0.01~0.03MPa vacuum, first in 150r/min stir speed (S.S.)
Under with 15 DEG C/min be cooled to 50 DEG C, be then cooled to 20 DEG C under identical stir speed (S.S.) with 10 DEG C/min speed, constant temperature
3h is kept, finally under 60r/min stir speed (S.S.), is cooled to 0~5 DEG C with 10 DEG C/min speed, constant temperature keeps 5h, makes crystalline substance
All crystallization separates out body, filters, obtains white ranitidine solid after purification；
（4）Prepare ranitidine hydrochloride：To step（3）In dripped with 8ml/min speed in obtained ranitidine after purification
Add ethanol, dissolve ranitidine when being added dropwise with 100r/min stir speed (S.S.) stirring, volumetric concentration is added at 0~3 DEG C is
25% ethanol solution of hydrogen chloride is as salt forming agent, regulation pH value to 6.8, is then transferred to 0.03~0.05MPa vacuum environment
In, 0~3 DEG C of constant temperature, separate out ranitidine hydrochloride with 30r/min speed stirring, vacuum decompression filters to obtain crude product hydrochloric acid
Ranitidine；
（5）Ranitidine hydrochloride purifies：To step（4）In dripped with 8ml/min speed in obtained crude product ranitidine hydrochloride
Add absolute ethyl alcohol, dissolve ranitidine hydrochloride with 100r/min stir speed (S.S.) stirring when being added dropwise, 0~3 DEG C of crystallization, take out
Filtered solid, is finally dried in vacuo, the ranitidine hydrochloride purified by filter, the above-mentioned washing step of repetition 2~3 times,
The vacuum drying condition is：0.1~0.12MPa of vacuum, circulating cooling water management drying temperature are 60 DEG C, and drying time is
3h。
The ranitidine hydrochloride that the above method obtains, reaction yield is more than 75%, and reaction condition is gentle, reaction raw materials are easy
；After tested, its minimum bulk density is up to 0.3g/ml, and light transmittance reaches more than 93%, and the solubility of product, fusing point, infrared
Light absorbs spectrogram, chemical reaction, the clarity of solution and color, acidity, relevant material, loss on drying, residue on ignition, a huge sum of money
The all technicals such as category, ethanol and assay all meet the standard of State Food and Drug Administration's approval issue
It is required that.
The present invention passes through the temperature control in preparation process, stir speed (S.S.) control and the dropwise addition speed of crystallization solvent absolute ethyl alcohol
The control of rate is combined, and with reference to vacuum reaction condition, effectively increases the yield and purity of ranitidine hydrochloride, products obtained therefrom tool
There are higher light transmittance and printing opacity stability.
Embodiments of the invention are the foregoing is only, are not intended to limit the scope of the invention, it is every to utilize this hair
The equivalent structure or equivalent flow conversion that bright description is made, or directly or indirectly it is used in other related technology necks
Domain, it is included within the scope of the present invention.
Claims (7)
1. a kind of preparation method of high-transmittance ranitidine hydrochloride, it is characterised in that comprise the following steps：
（1）Preparing raw material solution：By 2- [[[5- (dimethylamino) methyl -2- furans] methyl] sulfenyl] ethamine and N- methyl -
1- methyl mercapto -2- nitroethylenes amine is configured to the aqueous solution of same molar ratio with purified water respectively；
（2）Reaction prepares ranitidine：Under stirring, by step（1）Two kinds of solution of middle preparation are added dropwise with identical volume
Mixing, drop finish, are allowed to react under vacuum heating conditions, after reaction terminates, when reducing reacting liquid temperature and constant temperature and stirring one section
Between, crystallisation by cooling fully separates out, and is filtrated to get crude product ranitidine；
（3）Ranitidine purifies：By step（2）In obtained crude product ranitidine be dissolved in excessive methyl-isobutyl copper solvent
In, under vacuum condition, distillation azeotropic dehydration to distillate to there is no water, then adds 0.5~1g activated carbon decolorizings, filters, filtrate
Crystallize and separate out under stirring, low temperature, vacuum condition, filter, be dried to obtain white ranitidine solid；
（4）Prepare ranitidine hydrochloride：To step（3）In in obtained ranitidine after purification with 5~8ml/min speed
Absolute ethyl alcohol is added dropwise, dissolves ranitidine with 80~100r/min stir speed (S.S.) stirring when being added dropwise, is added at 0~3 DEG C
Salt forming agent adjusts pH value to 6.3~6.8, is then transferred in vacuum environment, constant temperature stirring separates out ranitidine hydrochloride, and vacuum subtracts
Pressure suction filtration obtains crude product ranitidine hydrochloride；
（5）Ranitidine hydrochloride purifies：To step（4）In in obtained crude product ranitidine hydrochloride with 5~8ml/min speed
Ethanol is added dropwise, dissolves ranitidine hydrochloride with 80~100r/min stir speed (S.S.) stirring when being added dropwise, low temperature crystallization, takes out
Filtered solid, is finally dried in vacuo, the ranitidine hydrochloride purified by filter, the above-mentioned washing step of repetition 2~3 times.
2. the preparation method of high-transmittance ranitidine hydrochloride according to claim 1, it is characterised in that the step
（1）In, 2- [[[5- (dimethylamino) methyl -2- furans] methyl] sulfenyl] ethylamine solutions and N- methyl isophthalic acids-first sulphur
The molal volume concentration of base -2- nitroethylene amine aqueous solutions is 3.5~4.0mol/L.
3. the preparation method of high-transmittance ranitidine hydrochloride according to claim 1, it is characterised in that the step
（2）In, the dropwise addition mode of described two solution is：By 2- [[[5- (dimethylamino) methyl -2- furans] methyl] sulfenyl] second
Amine aqueous solution is first added drop-wise in N- methyl isophthalic acids-methyl mercapto -2- nitroethylene amine aqueous solutions with 3~5mL/min speed, while with
200~260r/min speed stirring, is then added dropwise with 1.5~2mL/min speed again, while with 60~150r/min speed
Rate stirs.
4. the preparation method of high-transmittance ranitidine hydrochloride according to claim 1, it is characterised in that the step
（2）In, the condition of the reaction is：0.01~0.03MPa of vacuum, 38~42 DEG C of temperature, 5~7h of time；The crystallization analysis
The temperature gone out is 1~3 DEG C, and the time is 6~12h, and stir speed (S.S.) is 30~50r/min.
5. the preparation method of high-transmittance ranitidine hydrochloride according to claim 1, it is characterised in that the step
（3）In, the vacuum of the vacuum condition is 0.01~0.03MPa, and vapo(u)rizing temperature is 90~95 DEG C；Analysis is crystallized in the filtrate
The condition gone out is：Under 0.01~0.03MPa vacuum, first under 100~150r/min stir speed (S.S.) with 10~15 DEG C/
Min's is cooled to 40~50 DEG C, is then cooled to 15~20 DEG C under identical stir speed (S.S.) with 5~10 DEG C/min speed, perseverance
Temperature keeps 2~3h, finally under 30~60r/min stir speed (S.S.), is cooled to 0~5 DEG C with 5~10 DEG C/min speed, perseverance
Temperature keeps 3~5h.
6. the preparation method of high-transmittance ranitidine hydrochloride according to claim 1, it is characterised in that the step
（4）In, the salt forming agent is the ethanol solution of hydrogen chloride that volumetric concentration is 20~25%；The vacuum condition is vacuum 0.03
~0.05MPa, the stir speed (S.S.) are 20~30r/min.
7. the preparation method of high-transmittance ranitidine hydrochloride according to claim 1, it is characterised in that the step
（5）In, the recrystallization temperature is 0~3 DEG C, and the vacuum drying condition is：0.1~0.12MPa of vacuum, circulating cooling water control
Drying temperature processed is 55~60 DEG C, and drying time is 2~3h.
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| CN201710656979.1A CN107382922A (en) | 2017-08-03 | 2017-08-03 | The preparation method of high-transmittance ranitidine hydrochloride |
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| CN201710656979.1A CN107382922A (en) | 2017-08-03 | 2017-08-03 | The preparation method of high-transmittance ranitidine hydrochloride |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114591274A (en) * | 2022-03-09 | 2022-06-07 | 河北海力香料股份有限公司 | Preparation method of ranitidine hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000029400A3 (en) * | 1998-11-19 | 2000-07-20 | Dd Zdravlje Farmaceutsko Hemij | Procedure for synthesis of n-[2[[[5- [(dialkilamino) methyl]-2- furanyl] methyl]thyo] ethyl]-n'- alkyl-2-nitro1,1 alkenediamines and their hydrochlorides |
| CN104817523A (en) * | 2015-05-26 | 2015-08-05 | 苗怡文 | Medicine ranitidine hydrochloride compound for treating stomach illness and preparation method of medicine ranitidine hydrochloride compound |
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2017
- 2017-08-03 CN CN201710656979.1A patent/CN107382922A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000029400A3 (en) * | 1998-11-19 | 2000-07-20 | Dd Zdravlje Farmaceutsko Hemij | Procedure for synthesis of n-[2[[[5- [(dialkilamino) methyl]-2- furanyl] methyl]thyo] ethyl]-n'- alkyl-2-nitro1,1 alkenediamines and their hydrochlorides |
| CN104817523A (en) * | 2015-05-26 | 2015-08-05 | 苗怡文 | Medicine ranitidine hydrochloride compound for treating stomach illness and preparation method of medicine ranitidine hydrochloride compound |
Non-Patent Citations (1)
| Title |
|---|
| 黄祥龙等: "盐酸雷尼替丁精制方法的改进", 《中国医药工业杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114591274A (en) * | 2022-03-09 | 2022-06-07 | 河北海力香料股份有限公司 | Preparation method of ranitidine hydrochloride |
| CN114591274B (en) * | 2022-03-09 | 2024-05-24 | 石家庄海力药业有限公司 | Preparation method of ranitidine hydrochloride |
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