CN118146206A - Olmesartan medoxomil impurity and preparation process thereof - Google Patents
Olmesartan medoxomil impurity and preparation process thereof Download PDFInfo
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- CN118146206A CN118146206A CN202410328882.8A CN202410328882A CN118146206A CN 118146206 A CN118146206 A CN 118146206A CN 202410328882 A CN202410328882 A CN 202410328882A CN 118146206 A CN118146206 A CN 118146206A
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- 239000012535 impurity Substances 0.000 title claims abstract description 38
- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical compound C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 title claims abstract description 33
- 229960001199 olmesartan medoxomil Drugs 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 46
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 42
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 38
- 235000019270 ammonium chloride Nutrition 0.000 claims description 19
- 239000005457 ice water Substances 0.000 claims description 16
- 239000000706 filtrate Substances 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- LZTRCELOJRDYMQ-UHFFFAOYSA-N triphenylmethanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1=CC=CC=C1 LZTRCELOJRDYMQ-UHFFFAOYSA-N 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000007670 refining Methods 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 238000001514 detection method Methods 0.000 abstract description 2
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical group OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 abstract 1
- 208000032825 Ring chromosome 2 syndrome Diseases 0.000 abstract 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 230000001066 destructive effect Effects 0.000 abstract 1
- 230000014759 maintenance of location Effects 0.000 abstract 1
- 238000001819 mass spectrum Methods 0.000 abstract 1
- 238000004886 process control Methods 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- 230000001276 controlling effect Effects 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 238000002425 crystallisation Methods 0.000 description 14
- 230000008025 crystallization Effects 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 238000004090 dissolution Methods 0.000 description 11
- 230000007062 hydrolysis Effects 0.000 description 11
- 238000006460 hydrolysis reaction Methods 0.000 description 11
- 239000002994 raw material Substances 0.000 description 11
- 238000000967 suction filtration Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 238000000990 heteronuclear single quantum coherence spectrum Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to the technical field of chemistry, and particularly relates to an olmesartan medoxomil impurity and a preparation process thereof. Olmesartan medoxomil chemical name: 2, 3-dihydroxy-2-butenyl-4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- (2-1H-tetrazol-5-phenyl) benzyl ] imidazole-5-carboxylate ring-2, 3-carbonate. In the EP detection method, the retention time RT is about 21min (RRT 1.66), an unknown impurity is sometimes generated, the content is about 0.11%, the removal rate is about 20% lower in the refining process, and the risk of exceeding the standard exists. According to the method, impurity enrichment and purification, mass spectrum nuclear magnetic resonance identification, impurity structure judgment, destructive test preparation of an impurity standard substance, determination of impurity generation source, process control and product quality improvement are carried out.
Description
Technical Field
The invention belongs to the technical field of chemistry, and particularly relates to an olmesartan medoxomil impurity and a preparation process thereof.
Background
The unknown impurity of RRT1.66 appears in the EP method detection of the olmesartan medoxomil crude product, the content is about 0.11 percent, the removal rate is about 20 percent lower in the refining process, and the risk of exceeding the standard exists. The literature is referred to without this impurity related information. The impurity is inferred to be a reaction solvent-generating impurity by the reaction route and is reacted with olmesartan medoxomil derivative to generate the RRT1.66 impurity, and no related synthetic route is introduced.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of an unknown impurity of olmesartan medoxomil.
In order to achieve the purpose, the invention adopts the following technical scheme:
An olmesartan medoxomil impurity having the structure:
OLM-IM-RRT1.66。
the preparation process and synthesis route of the olmesartan medoxomil impurity are as follows:
Mainly comprises the following steps:
1) Adding OLM01 into acetone, adding a reagent 1, controlling the temperature to be 30+/-5 ℃ for reaction for 2.5-3.5 hours, filtering to remove triphenylmethanol, and taking filtrate;
2) And (3) dropwise adding a reagent 3 into the filtrate, controlling the temperature, adjusting the pH, reacting, adding ice water, stirring, centrifuging, and obtaining white solid OLM-IM-RRT1.66 impurities.
Preferably, reagent 1 is ammonium chloride; reagent 3 is triethylamine.
Preferably, the solid-to-liquid ratio of OLM01 to acetone in step 1) is 1 (4-6) (M/V); the molar ratio of OLM01 to ammonium chloride is 1: (1.5-2.0).
Preferably, in the step 1), the reaction condition is that the temperature is 15-35 ℃ and the reaction time is 2-12 h; preferably, the reaction is carried out at 30℃for 3h.
Preferably, in the step 2), triethylamine is used for adjusting the pH value to be 8.0-9.0, and the reaction is carried out for 1.5-3.5 hours at the temperature of 25-35 ℃; preferably, ph=8.5 is adjusted and reacted at 30 ℃ for 2h.
Preferably, in the step 2), the volume ratio of acetone to ice water is 1: (0.8-1.2).
The invention has the beneficial effects that:
1. Provides a synthesis method of unknown impurities of olmesartan medoxomil RRT 1.66. The method has the advantages of simple steps, less side reaction and high purity.
2. The post-treatment controls the ratio of acetone to water, and the volume ratio of acetone to ice water is 1: (0.8-1.2), direct crystallization, high refining yield and high refining purity (more than 99 percent) reaching the requirements of impurity standard substances.
3. Ammonium chloride is used, the reaction temperature is controlled to be 25-35 ℃, so that the OLM01 can be thoroughly hydrolyzed; and (3) regulating the pH value to be about 8.5 by using organic base triethylamine, controlling the temperature to be 25-35 ℃, and reacting acetone under the condition to obtain an impurity intermediate and continuously carrying out derivatization reaction on the impurity intermediate and OLM to obtain a target product. The reaction mechanism is as follows:
Drawings
FIG. 1 HPLC chromatogram of olmesartan medoxomil RRT 1.66;
LCMS profile 1 of olmesartan medoxomil RRT1.66 of fig. 2;
LCMS profile 2 of olmesartan medoxomil RRT1.66 of fig. 3;
FIG. 4 1 H-NMR spectrum of olmesartan medoxomil RRT 1.66;
FIG. 5 is a 13 C-NMR chart of olmesartan medoxomil RRT 1.66;
FIG. 6 is a 1H-1 HCOSY map of olmesartan medoxomil RRT 1.66;
FIG. 7 DEPT135 pattern of olmesartan medoxomil RRT 1.66;
FIG. 8 HMBC pattern of olmesartan medoxomil RRT 1.66;
figure 9 HSQC spectrum of olmesartan medoxomil RRT 1.66.
Detailed Description
The invention will be further illustrated with reference to specific examples. The present invention will be described in further detail with reference to examples, but is not limited to these examples.
EXAMPLE 1 Synthesis of olmesartan medoxomil EP RRT1.66 impurity
OLM01 g (12.7 mmol), 50ml acetone is added for dissolution, 1.35g (25.5 mmol) ammonium chloride is added, the temperature is controlled at 15 ℃, the reaction is carried out for 3 hours, and the central control hydrolysis is incomplete; filtering to remove the triphenylmethanol, adding triethylamine into the filtrate, adjusting the pH to be 9, controlling the temperature to be 30 ℃, and reacting for 2 hours; the reaction solution was slowly dropped into 50ml of ice water, stirred for crystallization, and suction filtration was performed to obtain 6.4g of a white solid, with a yield of 77% and a purity of 98.9%.
EXAMPLE 2 Synthesis of olmesartan medoxomil EP RRT1.66 impurity
OLM01 g (12.7 mmol), 50ml acetone is added for dissolution, 1.35g (25.5 mmol) ammonium chloride is added, the temperature is controlled to 30 ℃, the reaction is carried out for 3 hours, and the central control hydrolysis is complete; filtering to remove triphenylmethanol, adding triethylamine into the filtrate, adjusting pH to be 9, controlling the temperature to be 30 ℃, reacting for 2 hours, and performing central control to finish the reaction of the raw materials; the reaction solution was slowly dropped into 50ml of ice water, stirred for crystallization, and suction filtration was performed to obtain 7.3g of a white solid with a yield of 88% and a purity of 99.1%.
EXAMPLE 3 Synthesis of olmesartan medoxomil EP RRT1.66 impurity
OLM01 g (12.7 mmol), 50ml acetone is added for dissolution, 1.35g (25.5 mmol) ammonium chloride is added, the temperature is controlled to 30 ℃, the reaction is carried out for 3 hours, and the central control hydrolysis is complete; filtering to remove triphenylmethanol, adding triethylamine into the filtrate, adjusting pH to be 9, controlling the temperature to be 30 ℃, reacting for 5 hours, and performing central control to finish the reaction of the raw materials; the reaction solution was slowly dropped into 50ml of ice water, stirred for crystallization, and suction filtration was performed to obtain 6.8g of a white solid, with a yield of 82% and a purity of 95.2%.
EXAMPLE 4 Synthesis of olmesartan medoxomil EP RRT1.66 impurity
OLM01 g (12.7 mmol), 50ml acetone is added for dissolution, 1.35g (25.5 mmol) ammonium chloride is added, the temperature is controlled to 30 ℃, the reaction is carried out for 3 hours, and the central control hydrolysis is complete; filtering to remove triphenylmethanol, adding triethylamine into the filtrate, adjusting pH to be 7, controlling the temperature to be 30 ℃, reacting for 16 hours, and controlling the reaction time by TLC (thin layer chromatography), wherein the raw materials are unreacted; the reaction solution was slowly dropped into 50ml of ice water, stirred for crystallization, and suction filtration was performed to obtain 5.7g of a white solid with a yield of 68% and a purity of 72%.
As is clear from comparison of example 2 and example 4, the alkalinity is too weak, the pH is less than 9, the reaction time is prolonged, the raw materials cannot fully react, and the pH of the reaction system is controlled to be about 9.
EXAMPLE 5 Synthesis of olmesartan medoxomil EP RRT1.66 impurity
OLM01 g (12.7 mmol), 50ml acetone is added for dissolution, 1.35g (25.5 mmol) ammonium chloride is added, the temperature is controlled to 30 ℃, the reaction is carried out for 3 hours, and the central control hydrolysis is complete; filtering to remove triphenylmethanol, adding triethylamine into the filtrate, adjusting the pH to be 8.5, controlling the temperature to be 30 ℃, reacting for 2 hours, and performing central control to finish the reaction of the raw materials; the reaction solution was slowly dropped into 50ml of ice water, stirred for crystallization, and suction filtration was performed to obtain 7.05g of a white solid with a yield of 85% and a purity of 99.8%.
As can be seen from comparison of the example 2 and the example 5, the reaction pH is controlled to be 8.5, the purity of the product can be improved to 99.8%, the yield is also improved to 85%, and impurities can be generated when the pH is too high to influence the quality of the product.
EXAMPLE 6 Synthesis of olmesartan medoxomil EP RRT1.66 impurity
OLM01 g (12.7 mmol), 50ml acetone is added for dissolution, 1.35g (25.5 mmol) ammonium chloride is added, the temperature is controlled to 30 ℃, the reaction is carried out for 3 hours, and the central control hydrolysis is complete; filtering to remove triphenylmethanol, adding triethylamine into the filtrate, adjusting the pH to be 8.5, controlling the temperature to be 40 ℃, reacting for 2 hours, and performing central control to finish the reaction of the raw materials; the reaction solution was slowly dropped into 50ml of ice water, stirred for crystallization, and suction filtration was performed to obtain 6.0g of a white solid, with a yield of 72% and a purity of 35.1%.
As can be seen from comparison of example 5 and example 6, the pH is controlled to 8.5, the temperature is increased to 40 ℃, the system undergoes side reaction, the purity of the product is reduced to 35.1%, and the high reaction temperature is unfavorable for the generation of the target product.
EXAMPLE 7 Synthesis of olmesartan medoxomil EP RRT1.66 impurity
OLM01 g (12.7 mmol), 50ml acetone is added for dissolution, 1.0g (19 mmol) ammonium chloride is added, the temperature is controlled to 30 ℃, the reaction is carried out for 3 hours, and the medium control hydrolysis is complete; filtering to remove triphenylmethanol, adding triethylamine into the filtrate, adjusting the pH to be 8.5, controlling the temperature to be 30 ℃, reacting for 2 hours, and performing central control to finish the reaction of the raw materials; the reaction solution was slowly dropped into 50ml of ice water, stirred for crystallization, and suction filtration was performed to obtain 6.6g of a white solid with a yield of 79% and a purity of 98.5%.
As can be seen from the comparison of example 5 and example 7, the amount of ammonium chloride is reduced to 1.5 equivalents, the purity of the target product is slightly reduced, and the purity of the target product is lower than 99%, and the ammonium chloride is less than 2 equivalents, which is unfavorable for the generation of the target product.
EXAMPLE 8 Synthesis of olmesartan medoxomil EP RRT1.66 impurity
OLM01 g (12.7 mmol), 50ml acetone is added for dissolution, concentrated hydrochloric acid 2.6g (25.5 mmol) is added, the temperature is controlled to 30 ℃, the reaction is carried out for 3 hours, and the central control hydrolysis is complete; filtering to remove triphenylmethanol, adding triethylamine into the filtrate, adjusting the pH to be 8.5, controlling the temperature to be 30 ℃, reacting for 2 hours, and performing central control to finish the reaction of the raw materials; the reaction solution was slowly dropped into 50ml of ice water, stirred for crystallization, and suction filtration was performed to obtain 6.2g of a white solid with a yield of 75% and a purity of 78%.
As can be seen by comparing the example 5 with the example 8, the ammonium chloride is replaced by the concentrated hydrochloric acid, other conditions are unchanged, the purity of the target product is greatly reduced to be lower than 80%, the concentrated hydrochloric acid can catalyze the target product, but the effect of catalyzing the ammonium chloride to generate the target product is better.
EXAMPLE 9 Synthesis of olmesartan medoxomil EP RRT1.66 impurity
OLM01 g (12.7 mmol), 50ml acetone is added for dissolution, 1.35g (25.5 mmol) ammonium chloride is added, the temperature is controlled to 30 ℃, the reaction is carried out for 3 hours, and the central control hydrolysis is complete; filtering to remove triphenylmethanol, adding potassium carbonate into the filtrate, adjusting the pH to be 8.5, controlling the temperature to be 30 ℃, reacting for 2 hours, and performing central control to finish the reaction of the raw materials; the reaction solution was slowly dropped into 50ml of ice water, stirred for crystallization, and suction filtration was performed to obtain 6.5g of a white solid, with a yield of 78% and a purity of 85%.
As is clear from the comparison between the example 5 and the example 9, the second step is to replace triethylamine with potassium carbonate, other conditions are unchanged, the purity of the target product is greatly reduced to less than 90%, the effect is poor, and the yield is low.
EXAMPLE 10 Synthesis of olmesartan medoxomil EP RRT1.66 impurity
OLM01 g (12.7 mmol), 50ml acetone is added for dissolution, 1.35g (25.5 mmol) ammonium chloride is added, the temperature is controlled to 30 ℃, the reaction is carried out for 3 hours, and the central control hydrolysis is complete; filtering to remove triphenylmethanol, adding triethylamine into the filtrate, adjusting the pH to be 8.5, controlling the temperature to be 30 ℃, reacting for 2 hours, and performing central control to finish the reaction of the raw materials; the reaction solution was slowly dropped into 40ml of ice water, stirred for crystallization, and suction filtration was performed to obtain 5.4g of a white solid, with a yield of 65% and a purity of 94%.
By comparing example 5 with example 10, it was found that the ratio of water was reduced in the case of drip crystallization, the yield of the product was low, and the purity was also reduced.
EXAMPLE 11 Synthesis of olmesartan medoxomil EP RRT1.66 impurity
OLM01 g (12.7 mmol), 50ml acetone is added for dissolution, 1.35g (25.5 mmol) ammonium chloride is added, the temperature is controlled to 30 ℃, the reaction is carried out for 3 hours, and the central control hydrolysis is complete; filtering to remove triphenylmethanol, adding triethylamine into the filtrate, adjusting the pH to be 8.5, controlling the temperature to be 30 ℃, reacting for 2 hours, and performing central control to finish the reaction of the raw materials; the reaction solution was slowly dropped into 60ml of ice water, stirred for crystallization, and suction filtration was performed to obtain 7.5g of a white solid with a yield of 90% and a purity of 85%.
By comparing example 5 with example 11, it was found that the yield of the product was improved by increasing the water ratio during drip crystallization, but the purity of the product was lower. The effect is best when the dripping amount and the acetone amount are controlled to be 1:1.
The above embodiments are merely preferred embodiments of the present application, and should not be construed as limiting the present application, and the embodiments and features of the embodiments of the present application may be arbitrarily combined with each other without collision. The protection scope of the present application is defined by the claims, and the protection scope includes equivalent alternatives to the technical features of the claims. I.e., equivalent replacement modifications within the scope of this application are also within the scope of the application.
Claims (7)
1. An olmesartan medoxomil impurity characterized in that the olmesartan medoxomil impurity has the structure:
2. the process for preparing olmesartan medoxomil impurity according to claim 1, wherein the synthetic route of the process is as follows:
Comprises the following steps:
1) Adding OLM01 into acetone, adding reagent 1, reacting, filtering to remove triphenylmethanol, and collecting filtrate;
2) And (3) dropwise adding a reagent 3 into the filtrate, controlling the temperature, adjusting the pH, reacting, adding ice water, stirring, centrifuging, and obtaining white solid OLM-IM-RRT1.66 impurities.
3. The preparation process according to claim 2, characterized in that: reagent 1 is ammonium chloride; reagent 3 is triethylamine.
4. The preparation process according to claim 2, characterized in that: the solid-to-liquid ratio of the OLM01 to the acetone in the step 1) is 1 (4-6) (M/V); the molar ratio of OLM01 to ammonium chloride is 1: (1.5-2.0).
5. The preparation process according to claim 2, characterized in that: in the step 1), the reaction condition is that the temperature is 15-35 ℃ and the reaction time is 2-12 h; preferably, the reaction is carried out at 30℃for 3h.
6. The preparation process according to claim 2, characterized in that: in the step 2), triethylamine is used for adjusting the pH value to be 8.0-9.0, and the reaction is carried out for 1.5-3.5 hours at the temperature of 25-35 ℃; preferably, ph=8.5 is adjusted and reacted at 30 ℃ for 2h.
7. The preparation process according to claim 2, characterized in that: in the step 2), the volume ratio of the acetone to the ice water is 1: (0.8-1.2).
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