CN109020896A - The sodium salt of telmisartan with and preparation method thereof - Google Patents
The sodium salt of telmisartan with and preparation method thereof Download PDFInfo
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- CN109020896A CN109020896A CN201811066885.XA CN201811066885A CN109020896A CN 109020896 A CN109020896 A CN 109020896A CN 201811066885 A CN201811066885 A CN 201811066885A CN 109020896 A CN109020896 A CN 109020896A
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- telmisartan
- sodium salt
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
Abstract
The present invention relates to field of pharmaceutical engineering, in particular to a kind of the sodium salt of telmisartan with and preparation method thereof.The preparation method of the sodium salt of telmisartan, comprising the following steps: be mixed to get the sodium salt of telmisartan crude product with the first organic solvent again after mixing Telmisartan with alkaline solution；The sodium salt of telmisartan crude product is beaten stage by stage with the second organic solvent.Its is easy to operate, low energy consumption, solvent is recyclable, and loss of material is small, while the stability of product is good, not hygroscopic.
Description
Technical field
The present invention relates to field of pharmaceutical engineering, in particular to a kind of the sodium salt of telmisartan with and preparation method thereof.
Background technique
Telmisartan chemical name is 4'- [(1,4'- dimethyl -2'- propyl [bis- -1H- benzimidazole of 2,6'-] -1'-
Base) methyl]-[1,1'- dibiphenylyl] -2- carboxylic acid, molecular structural formula is as follows；
Its sterling be colourless to white crystallization, 261-263 DEG C of fusing point.4'- [(1,4'- dimethyl -2'- propyl [2,6'-
Two -1H- benzimidazoles] -1'- base) methyl]-[1,1'- dibiphenylyl] -2- carboxylic acid and its physiologically acceptable salt has
The pharmacological property of value.It is a kind of angiotensin-ii antagonist, can be used for treating high blood in view of its pharmacological property
Pressure and myocardial function be not complete, treats the peripheral circulation disease of ischaemic, myocardial ischaemia (colic pain).Due to 4'- [(1,4'-
Dimethyl -2'- propyl [bis- -1H- benzimidazole of 2,6'-] -1'- base) methyl]-[1,1'- dibiphenylyl] -2- carboxylic acid starting material's medicine
Solubility is smaller, and after being made into preparation, its dissolution rate is lower, therefore is made as soluble sodium salt.But prior art system
Loss of material is big, energy consumption is high, unstable product quality during standby the sodium salt of telmisartan, while the sodium salt of telmisartan prepared
Water imbibition is stronger, influences the stability and drug effect of drug.
Summary of the invention
It is easy to operate, low energy consumption, solvent is recyclable the present invention provides a kind of preparation method of the sodium salt of telmisartan,
Loss of material is small, while the stability of product is good, not hygroscopic.
The present invention also provides a kind of the sodium salt of telmisartan, which stablizes, and is not susceptible to water suction phenomenon.
The present invention is implemented as follows:
A kind of preparation method of the sodium salt of telmisartan, comprising the following steps:
The sodium salt of telmisartan crude product is mixed to get with the first organic solvent again after Telmisartan is mixed with alkaline solution；It will
The sodium salt of telmisartan crude product is beaten stage by stage with the second organic solvent.
A kind of the sodium salt of telmisartan is prepared by the preparation method of above-mentioned the sodium salt of telmisartan.
The beneficial effects of the present invention are: the preparation method of the sodium salt of telmisartan of the present invention is molten by mixing with alkaline solution
Solution, the mode being then precipitated again promote the generation of the sodium salt of telmisartan, while reducing production difficulty, while using first
Organic solvent and the second organic solvent can be reduced the yield of the three wastes, realize green production, be passed through with recycling and reusing
It is beaten stage by stage, significantly reduces the moisture content in the sodium salt of telmisartan, meanwhile, improve the stabilization of the sodium salt of telmisartan
Property, it effectively prevent the sodium salt of telmisartan to absorb water.Meanwhile each processing node of this method is convenient for control, convenient for guaranteeing product
Quality.
Specific embodiment
It in order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below will be in the embodiment of the present invention
Technical solution be clearly and completely described.The person that is not specified actual conditions in embodiment, according to normal conditions or manufacturer builds
The condition of view carries out.Reagents or instruments used without specified manufacturer is the conventional production that can be obtained by commercially available purchase
Product.
Below to the sodium salt of telmisartan of the embodiment of the present invention with and preparation method thereof be specifically described.
A kind of preparation method of the sodium salt of telmisartan, comprising the following steps:
S1, at salt:
Telmisartan is mixed with alkaline solution, so that Telmisartan is dissolved in alkaline solution, obtains mixed alkali liquor.
The molar ratio of Telmisartan and the alkaline solution neutral and alkali substance is 1:1.1~1.5.It will be replaced using aforementioned proportion
Meter Sha Tan is mixed with alkaline solution, can guarantee that the inorganic base in alkaline solution can fully be reacted with Telmisartan,
Obtain telmisartan sodium salting liquid.
Specifically, Telmisartan and alkaline solution are carried out under conditions of 20~45 DEG C that 15~60 points of dissolution is mixed
Clock is dissolved using above-mentioned condition, can guarantee that Telmisartan is substantially dissolved in alkaline solution, and guarantee that it is molten with alkalinity
Liquid sufficiently reacts, and then guarantees the quality of the sodium salt of telmisartan.
Further, the alkaline matter in alkaline solution used for alkaline sodium salt, preferably sodium hydroxide, sodium carbonate or
Any one in person's sodium bicarbonate.
S2, precipitation:
It dissolves and is simultaneously mixed to get the sodium salt of telmisartan crude product with the first organic solvent again after reaction, specifically, 0~
Mixed alkali liquor is added dropwise in first organic solvent under conditions of 25 DEG C, is then stirred 4~10 hours, by mixed base drop
It adds in the first organic solvent, the sodium salt of telmisartan does not dissolve in the first organic solvent, can be precipitated out of first organic solvent.
And 0~25 DEG C is used, it is the appropriate precipitation for reducing environment temperature and being conducive to the sodium salt of telmisartan, guarantees yield.It simultaneously will mixing
It is precipitation efficiency in order to further enhance the sodium salt of telmisartan that lye, which is added dropwise in the first organic solvent, reduces telmisartan sodium
Impurity in salt, while guaranteeing yield.
Further, every 10 grams of Telmisartans are corresponding uses 18~22 milliliter of first organic solvent, using aforementioned proportion, energy
Enough guarantee the precipitation of the sodium salt of telmisartan crude product, while reducing impurity.
Mixed alkali liquor is added dropwise to the drop rate control of the first organic solvent in 1.5~1.9 ml/mins, and control is added dropwise
Rate advantageously ensures that the precipitation of the sodium salt of telmisartan, prevents the precipitation of impurity, while guaranteeing the quality of the sodium salt of telmisartan, mentions
Rise the stability of the sodium salt of telmisartan.
Further, the first organic solvent is selected from alcohols solvent or saturation ketone solvent,
It is preferred that the alcohols solvent is monohydric alcohol, more preferably ethyl alcohol, most preferably dehydrated alcohol or 94~96% second
Alcohol；
It is preferred that the saturation ketone solvent is C1-C10 saturated ketone, more preferably acetone.Use above-mentioned solvent organic for first
Solvent can not only guarantee the precipitation of the sodium salt of telmisartan, but also can recycle to solvent, and reduction prepares the sodium salt of telmisartan mistake
Pollution on the environment in journey.It is filtered after being precipitated completely, obtains the sodium salt of telmisartan crude product and the first filtrate.
S3, mashing:
The sodium salt of telmisartan crude product is beaten stage by stage with the second organic solvent.Stage by stage mashing be will be described
The sodium salt of telmisartan crude product carries out first time mashing after mixing with second organic solvent under conditions of 10~20 DEG C, then
Centrifugation obtains filter cake；
It carries out being beaten for second under conditions of 0~5 DEG C after then the filter cake is mixed with second organic solvent.
Specifically, the sodium salt of telmisartan crude product and the second organic solvent are mixed to get for meter Sha under conditions of 10~20 DEG C
The solid suspension of smooth sodium salt crude product contains free alkali due to being precipitated in the sodium salt of telmisartan crude product, so that the sodium salt of telmisartan
The pH of crude product is excessively high, while being also easy water suction, is unfavorable for the stabilization of the sodium salt of telmisartan crude product, the sodium salt of telmisartan crude product is consolidated
Liquid suspension can dissolve free alkali, remove free alkali, promote the stability of the sodium salt of telmisartan crude product.
Corresponding addition the second organic solvent of 9~11ml of every 10 grams of Telmisartans, is mixed, Neng Goubao using aforementioned proportion
Demonstrate,prove the removal effect of free alkali.
It then stirs 0.5~3 hour, can then guarantee the removal effect of free alkali.
It is then centrifuged, obtains filter cake and third filtrate.
It carries out being beaten for second under conditions of 0~5 DEG C after then filter cake is mixed with second organic solvent.Second
Secondary mashing is prevented from forming crystalline hydrate when the later period is dry, then be mentioned to remove the moisture in the sodium salt of telmisartan crude product
The stability of high the sodium salt of telmisartan.
Specifically operate, by filter cake 0~5 DEG C condition in the second organic solvent be mixed 0.5~3 hour, then
It is centrifuged to obtain the 4th filtrate and the sodium salt of telmisartan wet product.
Further, the second organic solvent is selected from alcohols solvent or saturation ketone solvent,
It is preferred that the alcohols solvent is monohydric alcohol, more preferably ethyl alcohol, most preferably dehydrated alcohol or 94~96% second
Alcohol；
It is preferred that the saturation ketone solvent is C1~C10 saturated ketone, more preferably acetone.
Its removal effect to free alkali and moisture can be guaranteed using above-mentioned solvent, while being convenient for recycling design, reduced
Influence of the solvent to environment.
S4, drying:
The sodium salt of telmisartan wet product that second of mashing centrifugation obtains is dried, drying process is replaced described
Meter Sha Tan sodium salt wet product dries 3~6 hours in the environment of 50~70 DEG C of normal pressure, then in vacuum degree≤- 0.08Mpa, 60~
It is 6~12 hours dry under conditions of 80 DEG C.The pressure of drying at a temperature of 50~70 DEG C is normal pressure, and what normal pressure indicated is not formed
The pressure of negative pressure, usually external atmospheric pressure, the step mainly remove moisture content and organic solvent, and the later period is prevented to be dried in vacuo
Under the conditions of, material discoloration.Then drying can further remove combination under conditions of vacuum degree≤- 0.08Mpa, 60~80 DEG C
Water and organic solvent, so that the moisture content of the sodium salt of telmisartan is lower than 1.0%.
It is then pulverized and sieved, the mesh number of sieving is 80~100 mesh, obtains the sodium salt of telmisartan.
S5, solvent and Telmisartan recycling:
The third filtrate being obtained by filtration in S3- pulping process and the 4th filtrate are mixed to get the second filtrate, in the S1
After first filtrate and second filtrate mix, first air-distillation then carries out rectification process to fraction again, obtains qualification
Organic solvent.And to the raffinate of distillation, appropriate purified water is added, then adjusts pH value of solution at 0~10 DEG C, obtains white crystal
As Telmisartan.Specifically, operation is that 50ml purified water stirring 30min is added in raffinate, then in 0~10 DEG C of condition
Under, hydrochloric acid is added dropwise, the pH of solution is adjusted to 2~4, white crystal is precipitated, 0.5~3h is then stirred under conditions of 0~5 DEG C,
Centrifugation, obtains filter cake i.e. Telmisartan and waste water.
It is returned again it should be noted that the recycling of the first filtrate body and the second filtrate can be after first mixing the two
It receives, or again mixes material after the recovery after being recycled respectively.
The filter cake that the step obtains again with the alkaline solution, first organic solvent and second organic solvent into
Row processing.I.e. the obtained filter cake of the step is Telmisartan, can with circulating repetition preparation method provided in an embodiment of the present invention, or
The filter cake is added in the Telmisartan of the step 1 of embodiment provided by the invention by person, carries out subsequent operation.
The embodiment of the present invention also provides a kind of the sodium salt of telmisartan, passes through the preparation method of above-mentioned the sodium salt of telmisartan
It is prepared.
Feature and performance of the invention are described in further detail with reference to embodiments.
Embodiment 1
Firstly, the usage amount for each material that the present embodiment uses is referring to table 1.
Table 1
| Title | Weight or volume | Molar ratio |
| Telmisartan | 50g | 1 |
| Sodium hydroxide | 4.3g | 1.1 |
| Water | 60g | —— |
| First organic solvent-dehydrated alcohol | 1000ml | —— |
| Second organic solvent-dehydrated alcohol | 500ml | —— |
| Second organic solvent-dehydrated alcohol | 500ml | —— |
The present embodiment provides a kind of preparation methods of the sodium salt of telmisartan, comprising the following steps:
S1, at salt:
At 25 DEG C, successively into the four-hole boiling flask of 100ml, purified water 60g, sodium hydroxide 4.3g stirring and dissolving 15 are put into
Minute, after dissolution clarification, investment, Telmisartan 50g, stirring and dissolving 15min dissolve complete.
S2, precipitation:
Under the conditions of 25 DEG C, mixed alkali liquor is added drop-wise in 1000ml dehydrated alcohol, 25 DEG C of stirring 4h, centrifugation is replaced
Meter Sha Tan sodium salt crude product and the first filtrate.Wherein, drop rate is about 1.7 ml/mins.
S3, mashing:
Under the conditions of 10 DEG C, the sodium salt of telmisartan crude product and dehydrated alcohol 500ml carry out first time mashing, specifically mix
0.5h is stirred, then centrifugation obtains filter cake and third filtrate.
Under the conditions of 0 DEG C, filter cake and dehydrated alcohol 500ml carry out second and are beaten, specifically mixing 0.5h, then
Centrifugation, is obtained by filtration the 4th filtered fluid and the sodium salt of telmisartan wet product.
S4, drying:
The sodium salt of telmisartan wet product is dried, in the dry 3h of 50 DEG C of heated-air circulation ovens, then is transferred to vacuum baking
It is 12 hours dry under conditions of 60 DEG C ,≤- 0.08Mpa in case.The solid obtained to the step detects, and detection includes
Weighing, content detection, moisture content detection, dissolvent residual detection and pH value detection.
S5, solvent and Telmisartan recycle:
The third filtrate being obtained by filtration in S3- pulping process and the 4th filtrate are mixed to get the second filtrate, described first
After filtrate and second filtrate mix, first air-distillation then carries out rectification process to fraction again, obtains the organic of qualification
Solvent.And to the raffinate after distillation, 50ml purified water is added and stirs 30min, salt acid for adjusting pH is then added dropwise at 10 DEG C to 4,
Obtaining white crystal is Telmisartan.0.5h then is stirred under conditions of 0 DEG C, is centrifuged, filter cake is obtained, filter cake repeats above-mentioned
Step.
The present embodiment also provides a kind of the sodium salt of telmisartan, is prepared by the preparation method of above-mentioned the sodium salt of telmisartan
It arrives.
Embodiment 2
The preparation for the sodium salt of telmisartan that the preparation method and embodiment 1 for the sodium salt of telmisartan that embodiment 2 provides provide
The operation of method is almost the same, and difference is that operating condition changes.
Alkaline matter is sodium carbonate, dosage 7.95g, and the molar ratio of Telmisartan and alkaline matter is 1:1.5, first
Organic solvent and the second organic solvent are 95% ethyl alcohol.
Temperature when sodium carbonate to be dissolved in water to obtain alkaline solution, alkaline solution and Telmisartan mixed dissolution is 40
DEG C, and the time of stirring and dissolving is 20 minutes.
When precipitation, temperature is 10 DEG C, and mixing time 6h is added drop-wise in 95% ethyl alcohol, and the amount of 95% ethyl alcohol is 900ml.
Wherein, drop rate is about 1.5 ml/mins.
When mashing, the temperature of mashing is 20 DEG C for the first time, and the amount of 95% ethyl alcohol used is 550ml, mixing time 1h,
The temperature of second of mashing is 5 DEG C, and the amount of 95% ethyl alcohol used is 550ml, mixing time 1.5h.
When dry, normal pressure is dried 5 hours in the environment of 60 DEG C, then dry 10 under conditions of≤- 0.08Mpa, 80 DEG C
Hour, the solid matter then obtained to post-processing detects.
Recycling:
1 solvent recovery: according to the operating method of example 1.
The recycling of 2 Telmisartans: the temperature that hydrochloric acid is added dropwise is 5 DEG C, and pH is adjusted to 3, then stirs 2 hours under the conditions of 5 DEG C.
Embodiment 3
Alkaline matter is sodium hydroxide, dosage 4.69g, and the molar ratio of Telmisartan and alkaline matter is 1:1.2, the
One organic solvent and the second organic solvent are acetone.
Temperature when being dissolved in water to obtain alkaline solution, alkaline solution and Telmisartan mixed dissolution for sodium hydroxide is
45 DEG C, and the time of stirring and dissolving is 30 minutes.
When precipitation, temperature is 0 DEG C, and mixing time 5h is added drop-wise in acetone, and the amount of acetone is 1100ml, wherein is added dropwise
Rate is about 1.7 ml/mins.
When mashing, the temperature of mashing is 15 DEG C for the first time, and the amount of the acetone used is 450ml, mixing time 2h, second
The temperature of secondary mashing is 2 DEG C, and the amount of the acetone used is 450ml, mixing time 3h.
When dry, normal pressure is dried 4 hours in the environment of 70 DEG C, and then vacuum is dry under conditions of≤- 0.08Mpa, 70 DEG C
Dry 6 hours, the solid matter then obtained to post-processing detected.
Recycling:
1 solvent recovery: according to the operating method of example 1.
The recycling of 2 Telmisartans: the temperature that hydrochloric acid is added dropwise is 0 DEG C, and pH is adjusted to 2, then stirs 3 hours under the conditions of 2 DEG C.
Embodiment 4
Alkaline matter is sodium carbonate, dosage 6.7g, and the molar ratio of Telmisartan and alkaline matter is 1:1.3, first
Organic solvent and the second organic solvent are 94% ethyl alcohol.
Temperature when sodium carbonate to be dissolved in water to obtain alkaline solution, alkaline solution and Telmisartan mixed dissolution is 20
DEG C, and the time of stirring and dissolving is 60 minutes.
When precipitation, temperature is 15 DEG C, and mixing time 10h is added drop-wise in 94% ethyl alcohol.The amount of 94% ethyl alcohol is
1050ml, the rate of dropwise addition are about 1.8 ml/mins.
When mashing, the temperature of mashing is 13 DEG C for the first time, and the amount of 94% ethyl alcohol used is 475ml, mixing time 3h,
The temperature of second of mashing is 3 DEG C, and the amount of 94% ethyl alcohol used is 475ml, mixing time 2h.
When dry, dried in the environment of 55 DEG C 6 hours, it is then 8 hours dry under conditions of≤- 0.8Mpa, 75 DEG C, and
The solid matter obtained afterwards to post-processing detects.
Recycling:
1 solvent recovery: according to the operating method of example 1.
The recycling of 2 Telmisartans: the temperature that dilute hydrochloric acid is added dropwise is 3 DEG C, and pH is adjusted to 3, then stirs 1 hour under the conditions of 4 DEG C.
Embodiment 5
Alkaline matter is sodium bicarbonate, dosage 11.42g, and the molar ratio of Telmisartan and alkaline matter is 1:1.4,
First organic solvent and the second organic solvent are 96% ethyl alcohol.
Temperature when being dissolved in water to obtain alkaline solution, alkaline solution and Telmisartan mixed dissolution for sodium bicarbonate is
35 DEG C, and the time of stirring and dissolving is 35 minutes.
When precipitation, temperature is 20 DEG C, and mixing time 8h is added drop-wise in 96% ethyl alcohol, and the amount of 96% ethyl alcohol is 950ml,
The rate of dropwise addition is about 1.9 ml/mins.
When mashing, the temperature of mashing is 17 DEG C for the first time, and the amount of 96% ethyl alcohol used is 525ml, and mixing time is
1.5h, the temperature of second of mashing are 1 DEG C, and the amount of 96% ethyl alcohol used is 525ml, mixing time 2.5h.
When dry, dried in the environment of 65 DEG C 4.5 hours, then drying 9 is small under conditions of≤- 0.08Mpa, 65 DEG C
When, the solid matter then obtained to dry reason detects.
Recycling:
1 solvent recovery: according to the operating method of example 1.
The recycling of 2 Telmisartans: the temperature that hydrochloric acid is added dropwise is 7 DEG C, and pH is adjusted to 4, then stirs 1.5 hours under the conditions of 3 DEG C.
Embodiment 6
Alkaline matter is sodium hydroxide, dosage 5.1g, and the molar ratio of Telmisartan and alkaline matter is 1:1.3, the
One organic solvent and the second organic solvent are 95% ethyl alcohol.
Temperature when being dissolved in water to obtain alkaline solution, alkaline solution and Telmisartan mixed dissolution for sodium hydroxide is
30 DEG C, and the time of stirring and dissolving is 25 minutes.
When precipitation, temperature is 5 DEG C, and mixing time 7h is added drop-wise in 95% ethyl alcohol, and the amount of 95% ethyl alcohol is 1000ml,
The rate of dropwise addition is 1.5 ml/mins.
When mashing, the temperature of mashing is 11 DEG C for the first time, and the amount of 95% ethyl alcohol used is 500ml, and mixing time is
2.5h, the temperature of second of mashing are 4 DEG C, and the amount of 95% ethyl alcohol used is 500ml, mixing time 1h.
When dry, dried in the environment of 68 DEG C 5.5 hours, then drying 7 is small under conditions of≤- 0.08Mpa, 72 DEG C
When, the solid matter then obtained to post-processing detects.
Recycling:
1 solvent recovery: according to the operating method of example 1.
The recycling of 2 Telmisartans: being added dropwise plus the temperature of dilute hydrochloric acid is 8 DEG C, and pH is adjusted to 4, then stirs 2.5 under the conditions of 1 DEG C
Hour.
Embodiment 7
Alkaline matter is sodium hydroxide, dosage 4.71g, and the molar ratio of Telmisartan and alkaline matter is 1:1.2, the
One organic solvent and the second organic solvent are dehydrated alcohol.
Temperature when being dissolved in water to obtain alkaline solution, alkaline solution and Telmisartan mixed dissolution for sodium hydroxide is
32 DEG C, and the time of stirring and dissolving is 50 minutes.
When precipitation, temperature is 22 DEG C, and mixing time 9h is added drop-wise in dehydrated alcohol, and the amount of dehydrated alcohol is 980ml,
The rate of dropwise addition is about 1.7 ml/mins.
When mashing, the temperature of mashing is 16 DEG C for the first time, and the amount of the dehydrated alcohol used is 535ml, mixing time 2h,
The temperature of second of mashing is 3 DEG C, and the amount of the dehydrated alcohol used is 535ml, mixing time 3h.
When dry, dried in the environment of 53 DEG C 3.5 hours, then drying 9.5 is small under conditions of≤0.08Mpa, 79 DEG C
When, the solid matter then obtained to post-processing detects.
Recycling:
1 solvent recovery: according to the operating method of example 1.
The recycling of 2 Telmisartans: the temperature that hydrochloric acid is added dropwise is 2 DEG C, and pH is adjusted to 3.5, then stirs 1 hour under the conditions of 0 DEG C.
Comparative example 1: the preparation method of the sodium salt of telmisartan provided according to embodiment 1 prepares the sodium salt of telmisartan, distinguishes
Be that the operation being beaten for the first time is different, specifically operation is: the temperature of mashing is 0 DEG C for the first time, the dehydrated alcohol used
Amount is 500ml, mixing time 0.5h, and the temperature of second of mashing is 0 DEG C, and the amount of the dehydrated alcohol used is 500ml, stirring
Time is 0.5h.
Comparative example 2: the preparation method of the sodium salt of telmisartan provided according to embodiment 1 prepares the sodium salt of telmisartan, distinguishes
It is to use organic solvent difference, specifically operation is: the use of organic solvent is anhydrous methanol.
Comparative example 3: the preparation method of the sodium salt of telmisartan provided according to embodiment 1 prepares the sodium salt of telmisartan, distinguishes
Be that the operation of second of mashing is different, specifically operation is: the temperature of mashing is 10 DEG C for the first time, the dehydrated alcohol used
Amount is 500ml, mixing time 0.5h, and the temperature of second of mashing is 10 DEG C, and the amount of the dehydrated alcohol used is 500ml, is stirred
Mixing the time is 0.5h.
Detection test:
The sodium salt of telmisartan of embodiment 1-7 and comparative example 1-3 are detected, testing result is referring to table 2.
2 testing result of table
According to table 2, the moisture of the sodium salt of telmisartan provided in an embodiment of the present invention, solvent content are low, medicament contg
Height, and moisture residual volume obviously increases after changing operation, solvent residues amount also increases, and medicament contg reduces.
It in relative humidity is 40% by the sodium salt of telmisartan of embodiment 1-7 and comparative example 1-3, temperature is 45 DEG C of condition
Lower storage 12h, and storage 0h, 3h, 6h and 12h sample is taken to be detected respectively, the content of the sodium salt of telmisartan in test sample,
Moisture content and pH value, specific testing result is referring to table 3.
3 testing result of table
In conclusion the preparation method of the sodium salt of telmisartan of the present invention by with alkaline solution mixed dissolution, then analyse again
Mode out promotes the yield of the sodium salt of telmisartan, while reducing production difficulty, at the same the first organic solvent used and
Second organic solvent can be reduced the yield of waste, be realized green production with recycling and reusing, by being beaten stage by stage,
The moisture content in the sodium salt of telmisartan is significantly reduced, meanwhile, the stability of the sodium salt of telmisartan is improved, is prevented for meter Sha
Smooth sodium salt water suction.Meanwhile each processing node of this method is convenient for control, convenient for guaranteeing the quality of product.
The foregoing is merely the preferred embodiment of the present invention, are not intended to restrict the invention, for this field
For technical staff, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any
Modification, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of the sodium salt of telmisartan, which comprises the following steps:
The sodium salt of telmisartan crude product is mixed to get with the first organic solvent again after Telmisartan is mixed with alkaline solution；It will be described
The sodium salt of telmisartan crude product is beaten stage by stage with the second organic solvent.
2. the preparation method of the sodium salt of telmisartan according to claim 1, which is characterized in that the Telmisartan with it is described
The molar ratio of alkaline solution neutral and alkali substance is 1:1.1~1.5.
3. the preparation method of the sodium salt of telmisartan according to claim 2, which is characterized in that the sodium salt of telmisartan is thick
Product are that the Telmisartan and alkaline solution mixed dissolution under conditions of 20~45 DEG C are obtained mixed alkali liquor, then again
The mixed alkali liquor is added dropwise in first organic solvent under conditions of 0~25 DEG C, after then stirring 4~10 hours
The sodium salt of telmisartan crude product arrived.
4. the preparation method of the sodium salt of telmisartan according to claim 1, which is characterized in that stage by stage mashing be will be described
The sodium salt of telmisartan crude product carries out first time mashing after mixing with second organic solvent under conditions of 10~20 DEG C, then
Centrifugation obtains filter cake；
It carries out being beaten for second under conditions of 0~5 DEG C after then the filter cake is mixed with second organic solvent.
5. the preparation method of the sodium salt of telmisartan according to claim 1, which is characterized in that first organic solvent and
Second organic solvent is selected from alcohols solvent or saturation ketone solvent,
It is preferred that the alcohols solvent is monohydric alcohol, more preferably ethyl alcohol, most preferably dehydrated alcohol or 94~96% ethyl alcohol；
It is preferred that the saturation ketone solvent is C1-C10 saturated ketone, more preferably acetone.
6. the preparation method of the sodium salt of telmisartan according to claim 1, which is characterized in that obtained after being beaten stage by stage
The sodium salt of telmisartan wet product be dried, then pulverized and sieved.
7. the preparation method of the sodium salt of telmisartan according to claim 6, which is characterized in that drying process is replaced described
Meter Sha Tan sodium salt wet product is dried 3~6 hours in the environment of 50~70 DEG C, then again in≤- 0.08Mpa, 60~80 DEG C of item
It is 6~12 hours dry under part.
8. the preparation method of the sodium salt of telmisartan according to claim 1, which is characterized in that by the Telmisartan, institute
The liquid being centrifuged after alkaline solution and first organic solvent mixing is stated to be collected to obtain the first filtrate；
The filtrate obtained after being beaten stage by stage is collected to obtain the second filtrate；
Organic solvent and solid matter are obtained after first filtrate and second filtrate are recycled again；
Recycle the obtained solid matter again with the alkaline solution, first organic solvent and second organic solvent
It is handled.
9. the preparation method of the sodium salt of telmisartan according to claim 8, which is characterized in that recycling is filtered described first
Liquid and second filtrate carry out air-distillation recycling, and water is added to the raffinate after distillation, then adjust pH, obtain white
Crystal.
10. a kind of the sodium salt of telmisartan, which is characterized in that it passes through telmisartan sodium described in any one of claim 1-9
The preparation method of salt is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811066885.XA CN109020896A (en) | 2018-09-13 | 2018-09-13 | The sodium salt of telmisartan with and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1548421A (en) * | 2003-05-22 | 2004-11-24 | 上海医药工业研究院 | Tilmisartan salt and its prepn |
| WO2006050921A2 (en) * | 2004-11-11 | 2006-05-18 | Lek Pharmaceuticals D.D. | Preparation of telmisartan salts with improved solubility |
| EP1719766A2 (en) * | 2005-05-03 | 2006-11-08 | Dipharma S.p.A. | A process for the preparation of telmisartan |
| CN101074213A (en) * | 2006-05-18 | 2007-11-21 | 上海科胜药物研发有限公司 | Synthesis of 2-n-propyl-4-methyl-6(1-methylbenzimidazole-2-radicle) benzimidazole and its use in synthesis of timishatan and its salts |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1548421A (en) * | 2003-05-22 | 2004-11-24 | 上海医药工业研究院 | Tilmisartan salt and its prepn |
| WO2006050921A2 (en) * | 2004-11-11 | 2006-05-18 | Lek Pharmaceuticals D.D. | Preparation of telmisartan salts with improved solubility |
| EP1719766A2 (en) * | 2005-05-03 | 2006-11-08 | Dipharma S.p.A. | A process for the preparation of telmisartan |
| CN101074213A (en) * | 2006-05-18 | 2007-11-21 | 上海科胜药物研发有限公司 | Synthesis of 2-n-propyl-4-methyl-6(1-methylbenzimidazole-2-radicle) benzimidazole and its use in synthesis of timishatan and its salts |
Non-Patent Citations (1)
| Title |
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| 赵临襄，等: "《化学制药工艺学》", 31 August 2015, 中国医药科技出版社 * |
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Application publication date: 20181218 |