CN106083833A - A kind of purification process of trityl olmesartan medoxomil - Google Patents
A kind of purification process of trityl olmesartan medoxomil Download PDFInfo
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- CN106083833A CN106083833A CN201610533492.XA CN201610533492A CN106083833A CN 106083833 A CN106083833 A CN 106083833A CN 201610533492 A CN201610533492 A CN 201610533492A CN 106083833 A CN106083833 A CN 106083833A
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- olmesartan medoxomil
- trityl olmesartan
- purification process
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- crude product
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- 0 CCCCCC*(CC1=CC2=C(CC(C(*(C=*)N)=*)=C)[C@]2C=C11)*C1[O+]C[C@@](C)(C(C)O1)OC1=O Chemical compound CCCCCC*(CC1=CC2=C(CC(C(*(C=*)N)=*)=C)[C@]2C=C11)*C1[O+]C[C@@](C)(C(C)O1)OC1=O 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Abstract
The invention provides the purification process of a kind of trityl olmesartan medoxomil, the method is by trityl olmesartan medoxomil dissolving crude product in the sodium carbonate liquor mixed liquor with acetonitrile, then uses the method for cooling crystallize to obtain high-purity trityl olmesartan medoxomil.The present invention not only single feature that batch processing amount is big, refining effect good, yield is high, and equipment requirements is low, easy and simple to handle, and crystallization solvent is also with recovery, environmentally friendly, and waste water produces few, beneficially industrialized great production.
Description
Technical field
The invention discloses the purification process of a kind of trityl olmesartan medoxomil, i.e. a kind of hypertension therapeutic medicine Aomei
The purification process of the intermediate of husky smooth ester (Olmesartan Medoxomil), belongs to field of medicaments.
Background technology:
Trityl olmesartan medoxomil chemical name: 4-(1-hydroxyl-1-Methylethyl)-2-propyl group-1-{4-[2-(2-triphen
Methyl tetrazolium-5-base) phenyl] phenyl } Methylimidazole .-5-carboxylic acid (5-methyl-2-oxo-1,3-Dioxol-4-yl)
Methyl ester.
Olmesartan medoxomil is prodrug, through gastrointestinal absorption after being administered orally, is hydrolyzed to bioactive product Aomei husky
Smooth, be U.S. FDA approval listing the 7th for treating the angiotensin ii receptor antagonist of hypertension, these product are in 1991
Year is succeeded in developing by Sankyo commercial firm of Japan, and various hypertension is all had good therapeutic effect, and its outstanding feature is long half time, takes
Dosage is little, rapid-action.And trityl olmesartan medoxomil is the important intermediate of olmesartan medoxomil.
The route that patent 92102075.9 disclosed in Japanese Sankyo commercial firm provides trityl olmesartan medoxomil to synthesize is such as
Under:
The method utilizes compound 4 and DMDO-Br (4-bromomethyl-5-methyl-1,3-dioxy heterocyclic pentene-2-ketone) at DMAc (N, N-
Dimethyl acetylamide) when making to occur esterification to generate trityl olmesartan medoxomil under solvent condition, impurity trityl is difficult to understand
Modal impurity when Mei Shatan acid is to produce trityl olmesartan medoxomil.Aomei is prepared in trityl olmesartan
During husky smooth ester, trityl olmesartan acid can be changed into Olmesartan acid, it is difficult to removes.Trityl olmesartan acid structure
Formula is as follows:
Prepare trityl olmesartan medoxomil impurity level by above method higher, not only operate complexity, and need
Column chromatography purification, need to can obtain trityl olmesartan medoxomil through 3 crystallize purification, and total yield of products loss is serious,
Thus it is unfavorable for industrialized production.
The open a kind of trityl olmesartan medoxomil purification process of CN102206208A, is by trityl olmesartan medoxomil
Dissolving crude product in acetone, obtains trityl olmesartan medoxomil at cooling crystallization.
The trityl that the method when trityl olmesartan acid content is relatively low, can only can be only achieved higher degree is difficult to understand
Mei Shatan ester, but when trityl olmesartan acid content is higher, its purification effect is inconspicuous, or need repeatedly purification, and
Acetone is as recrystallisation solvent, and product yield is the highest.
Therefore exploitation one just can obtain height through single treatment in the case of trityl olmesartan medoxomil purity is the highest
The purification process of pure trityl olmesartan medoxomil, significant.Instant invention overcomes the various of prior art existence to lack
Fall into, the method mild condition, simple to operate, it is only necessary to just can remove the trityl olmesartan of more than 15% through 1 crystallization
Acid, and yield is high, with short production cycle, the trityl olmesartan medoxomil purity simultaneously prepared reaches more than 99%, is suitable for industrialization
Produce.
Summary of the invention:
The present invention can effectively remove trityl olmesartan acid and bring into when trityl olmesartan medoxomil produces
Other impurity, solve the industrially prepared purification of trityl olmesartan medoxomil problem.
For solving above-mentioned problem, the present invention adopts the following technical scheme that the method is by trityl olmesartan medoxomil
Crude product i.e. 4-(1-hydroxyl-1-Methylethyl)-2-propyl group-1-{4-[2-(2-trityl tetrazole-5-base) phenyl] phenyl
It is molten that Methylimidazole .-5-carboxylic acid (5-methyl-2-oxo-1,3-Dioxol-4-yl) crude methyl ester is dissolved in sodium carbonate
In the mixed solvent of liquid and acetonitrile, then the method for cooling crystallize is used to prepare.
The quality ratio range that the invention reside in trityl olmesartan medoxomil crude product and acetonitrile is 1:2～1:5, is preferably
1:3；Trityl olmesartan medoxomil crude product is 1:1～1:3, preferably 1:2 with the quality ratio range of water；Trityl Aomei
Husky smooth ester crude product is 15:1～30:1, preferably 25:1 with the quality ratio range of sodium carbonate.
The configuration of mixed solvent is first to be dissolved in the water by sodium carbonate, then is mixed with acetonitrile by sodium carbonate liquor, stirs 5
～15 minutes.
Trityl olmesartan medoxomil crude product whipping temp in mixed solvent is 40～80 DEG C, it is ensured that trityl is difficult to understand
Mei Shatan ester crude product is completely dissolved.
Trityl olmesartan medoxomil crude product stirs 10～30 minutes after dissolving in mixed solvent.
The present invention is dissolved and is used the method for low temperature crystallize to obtain product after stirring terminates, and recrystallization temperature is-5～10 DEG C, excellent
Elect 0～5 DEG C as；The crystallize time is 0～10 hour, preferably 3～4 hours.
Purification process according to the present invention obtains 4-(1-hydroxyl-1-Methylethyl)-2-propyl group-1-{4-[2-(2-triphen
Methyl tetrazolium-5-base) phenyl] phenyl } Methylimidazole .-5-carboxylic acid (5-methyl-2-oxo-1,3-Dioxol-4-yl)
Methyl ester purity is not less than 98.5%, and up to 99.6%.
After the present invention uses Crystallization method to obtain product, mother solution is through the most recyclable acetonitrile of simple distillation, to product matter
Amount is without impact.
The present invention compared with prior art has the advantage that
1) operation simplifies, low for equipment requirements；
2) single batch processing amount is big, improves production capacity；
3) good yield and high purity product: the trityl olmesartan medoxomil crude product purity that the present invention uses is
80.2%, trityl olmesartan acid is 17.0%, after single treatment, trityl olmesartan medoxomil purity >=
98.5%, up to 99.6%, it is ensured that product can meet the prescription of various medicine intermediate.
4) crystallization solvent can be applied mechanically through simple distillation, lowers industrialization cost, reduces ambient pressure.
Detailed description of the invention
Below the preferred embodiment of the invention is described, but it is to be understood that these describe simply for furtherly
Bright the features and advantages of the present invention rather than limiting to the claimed invention.
Olmesartan medoxomil quality testing specifies olmesartan medoxomil detection analysis side with analyzing to use in European Pharmacopoeia EP7.4
Method.
Embodiment 1:
Trityl olmesartan medoxomil synthesis is provided according to patent CN92102075.9 disclosed in Sankyo commercial firm of Japan
Route trityl olmesartan medoxomil crude product purity is 80.2%, and wherein trityl olmesartan acid is 17.0%.
Adding 1.2g sodium carbonate, 60g water, stirring at normal temperature 15 minutes in 500ml four-hole bottle, sodium carbonate adds after being completely dissolved
90g acetonitrile, stirs 5 minutes.Add 30g trityl olmesartan medoxomil crude product, be to slowly warm up to 75 ± 5 DEG C, continue stirring 30
Minute.After material is completely dissolved, it is slowly dropped to 20～30 DEG C of stirring stirrings 1 hour.Continuing to be down to 0～5 DEG C, stirring and crystallizing 4 is little
Time, sucking filtration is dried and is obtained trityl olmesartan medoxomil white solid powder 22.7g, yield 75.7%.HPLC analyzes, and purity is
99.6%, acid miscellaneous 0.09%, other unknown single miscellaneous equal ＜ 0.1%.
Embodiment 2:
Trityl olmesartan medoxomil synthesis is provided according to patent CN92102075.9 disclosed in Sankyo commercial firm of Japan
Route trityl olmesartan medoxomil crude product purity is 80.2%, and wherein trityl olmesartan acid is 17.0%.
Adding 1.2g sodium carbonate, 60g water, stirring at normal temperature 15 minutes in 500ml four-hole bottle, sodium carbonate adds after being completely dissolved
150g acetonitrile, stirs 5 minutes.Add 30g trityl olmesartan medoxomil crude product, be to slowly warm up to 75 ± 5 DEG C, continue stirring 30
Minute.After material is completely dissolved, it is slowly dropped to 20～30 DEG C of stirring stirrings 1 hour.Continuing to be down to 0～5 DEG C, stirring and crystallizing 4 is little
Time, sucking filtration is dried and is obtained trityl olmesartan medoxomil white solid powder 25.5g, yield 85.0%.HPLC analyzes, and purity is
99.6%, acid miscellaneous 0.08%, other unknown single miscellaneous equal ＜ 0.1%.
Embodiment 3:
The road providing trityl olmesartan medoxomil to synthesize according to patent 92102075.9 disclosed in Japanese Sankyo commercial firm
Line trityl olmesartan medoxomil crude product purity is 80.2%, and wherein trityl olmesartan acid is 17.0%.
Adding 1.2g sodium carbonate, 90g water, stirring at normal temperature 15 minutes in 500ml four-hole bottle, sodium carbonate adds after being completely dissolved
90g acetonitrile, stirs 5 minutes.Add 30g trityl olmesartan medoxomil crude product, be to slowly warm up to 75 ± 5 DEG C, continue stirring 30
Minute.After material is completely dissolved, it is slowly dropped to 20～30 DEG C of stirring stirrings 1 hour.Continuing to be down to 5～10 DEG C, stirring and crystallizing 4 is little
Time, sucking filtration is dried and is obtained trityl olmesartan medoxomil white solid powder 25.8g, yield 86.0%.HPLC analyzes, and purity is
99.5%, acid miscellaneous 0.07%, other unknown single miscellaneous equal ＜ 0.1%.
Embodiment 4:
The road providing trityl olmesartan medoxomil to synthesize according to patent 92102075.9 disclosed in Japanese Sankyo commercial firm
Line trityl olmesartan medoxomil crude product purity is 80.2%, and wherein trityl olmesartan acid is 17.0%.
Adding 2.0g sodium carbonate, 90g water, stirring at normal temperature 15 minutes in 500ml four-hole bottle, sodium carbonate adds after being completely dissolved
90g acetonitrile, stirs 5 minutes.Add 30g trityl olmesartan medoxomil crude product, be to slowly warm up to 75 ± 5 DEG C, continue stirring 30
Minute.After material is completely dissolved, it is slowly dropped to 20～30 DEG C of stirring stirrings 1 hour.Continuing to be down to 5～10 DEG C, stirring and crystallizing 4 is little
Time, sucking filtration is dried and is obtained trityl olmesartan medoxomil white solid powder 25.5g, yield 85.0%.HPLC analyzes, and purity is
99.4%, acid miscellaneous 0.06%, other unknown single miscellaneous equal ＜ 0.1%.
Embodiment 5:
The road providing trityl olmesartan medoxomil to synthesize according to patent 92102075.9 disclosed in Japanese Sankyo commercial firm
Line trityl olmesartan medoxomil crude product purity is 80.2%, and wherein trityl olmesartan acid is 17.0%.
Adding 1.0g sodium carbonate, 30g water, stirring at normal temperature 15 minutes in 500ml four-hole bottle, sodium carbonate adds after being completely dissolved
90g acetonitrile, stirs 5 minutes.Add 30g trityl olmesartan medoxomil crude product, be to slowly warm up to 75 ± 5 DEG C, continue stirring 30
Minute.After material is completely dissolved, it is slowly dropped to 20～30 DEG C of stirring stirrings 1 hour.Continuing to be down to 5～10 DEG C, stirring and crystallizing 4 is little
Time, sucking filtration is dried and is obtained trityl olmesartan medoxomil white solid powder 25.4g, yield 84.7%.HPLC analyzes, and purity is
99.4%, acid miscellaneous 0.09%, other unknown single miscellaneous equal ＜ 0.1%.
Comparative example 1:
Trityl olmesartan medoxomil synthesis is provided according to patent CN92102075.9 disclosed in Sankyo commercial firm of Japan
Route trityl olmesartan medoxomil crude product purity is 80.2%, and wherein trityl olmesartan acid is 17.0%.
500ml four-hole bottle adds 150g acetonitrile, 30g trityl olmesartan medoxomil crude product, is to slowly warm up to 75 ± 5
DEG C, continue stirring 30 minutes.After material is completely dissolved, it is slowly dropped to 20～30 DEG C of stirring stirrings 1 hour.Continue to be down to 0～5
DEG C, stirring and crystallizing 4 hours, sucking filtration is dried and is obtained trityl olmesartan medoxomil white solid powder 26.3g, yield 87.7%.
HPLC analyzes, and purity is 86.2%, acid miscellaneous 13.5%, other unknown single miscellaneous equal ＜ 0.1%.
Contrast experiment illustrates: only use acetonitrile is as solvent, and is added without sodium carbonate, and product purity is relatively low, sour miscellaneous content
Higher.
Comparative example 2:
Trityl olmesartan medoxomil synthesis is provided according to patent CN92102075.9 disclosed in Sankyo commercial firm of Japan
Route trityl olmesartan medoxomil crude product purity is 80.2%, and wherein trityl olmesartan acid is 17.0%.
500ml four-hole bottle adds 120g acetone, 30g trityl olmesartan medoxomil crude product, is to slowly warm up to 50 ± 5
DEG C, continue stirring 30 minutes.After material is completely dissolved, it is slowly dropped to 20～30 DEG C of stirring stirrings 1 hour.Continue to be down to 0～5
DEG C, stirring and crystallizing 4 hours, sucking filtration is dried and is obtained trityl olmesartan medoxomil white solid powder 20.9g, yield 69.7%.
HPLC analyzes, and purity is 90.0%, acid miscellaneous 10.7%, other unknown single miscellaneous equal ＜ 0.1%.
Contrast test illustrates: acetone has certain removal effect to trityl olmesartan acid, but inconspicuous.And product
Yield is the highest.
Claims (9)
1. its chemical name of the trityl olmesartan medoxomil as shown in formula I is 4-(1-hydroxyl-1-Methylethyl)-2-
Propyl group-1-{4-[2-(2-trityl tetrazole-5-base) phenyl] phenyl } Methylimidazole .-5-carboxylic acid (5-methyl-2-oxo-1,
3-Dioxol-4-yl) purification process of methyl ester, it is characterised in that trityl olmesartan medoxomil dissolving crude product is existed
In the mixed liquor of sodium carbonate liquor and acetonitrile, then the method for cooling crystallize is used to obtain trityl olmesartan medoxomil,
Purification process the most according to claim 1, it is characterised in that trityl olmesartan medoxomil crude product and the matter of acetonitrile
Amount ratio range is 1:2～1:5, preferably 1:3.
Purification process the most according to claim 1, it is characterised in that trityl olmesartan medoxomil crude product and the quality of water
Ratio range is 1:1～1:3, preferably 1:2.
Purification process the most according to claim 1, it is characterised in that trityl olmesartan medoxomil crude product and sodium carbonate
Quality ratio range is 15:1～30:1, preferably 25:1.
Purification process the most according to claim 1, it is characterised in that first sodium carbonate is dissolved in water, then mix with acetonitrile
Close stirring 5～15 minutes.
Purification process the most according to claim 1, it is characterised in that trityl olmesartan medoxomil dissolving crude product is at carbonic acid
Sodium solution is 40～80 DEG C with the mixed liquor whipping temp of acetonitrile.
Purification process the most according to claim 1, it is characterised in that recrystallization temperature is-5～10 DEG C, preferably 0～5 DEG C.
Purification process the most according to claim 1, it is characterised in that the crystallize time is 0～10 hour, preferably 3～4 is little
Time.
Purification process the most according to claim 1, it is characterised in that trityl olmesartan medoxomil is molten in mixed solution
Xie Houxu continues stirring 10～30 minutes.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110396084A (en) * | 2018-04-24 | 2019-11-01 | 连云港润众制药有限公司 | A method of preparing high-purity trityl olmesartan medoxomil |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011021224A2 (en) * | 2009-08-19 | 2011-02-24 | Msn Laboratories Limited | Process for (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate |
| CN103880825A (en) * | 2014-03-14 | 2014-06-25 | 浙江华海药业股份有限公司 | Preparation process of high-purity triphenyl methyl olmesartan medoxomil |
| CN104592213A (en) * | 2014-12-15 | 2015-05-06 | 山东新华制药股份有限公司 | Preparation method of olmesartan intermediate |
-
2016
- 2016-06-30 CN CN201610533492.XA patent/CN106083833B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011021224A2 (en) * | 2009-08-19 | 2011-02-24 | Msn Laboratories Limited | Process for (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate |
| CN103880825A (en) * | 2014-03-14 | 2014-06-25 | 浙江华海药业股份有限公司 | Preparation process of high-purity triphenyl methyl olmesartan medoxomil |
| CN104592213A (en) * | 2014-12-15 | 2015-05-06 | 山东新华制药股份有限公司 | Preparation method of olmesartan intermediate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110396084A (en) * | 2018-04-24 | 2019-11-01 | 连云港润众制药有限公司 | A method of preparing high-purity trityl olmesartan medoxomil |
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