CN112592307B - Preparation method of nintedanib intermediate - Google Patents
Preparation method of nintedanib intermediate Download PDFInfo
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- CN112592307B CN112592307B CN202110213208.1A CN202110213208A CN112592307B CN 112592307 B CN112592307 B CN 112592307B CN 202110213208 A CN202110213208 A CN 202110213208A CN 112592307 B CN112592307 B CN 112592307B
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
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Abstract
The invention relates to a preparation method of a nintedanib intermediate. The method has the advantages that the acetic anhydride and/or the solvent with proper equivalent and the dosage thereof are used, and the nintedanib intermediate is prepared from the 2-oxoindole-6-methyl formate, so that the method not only improves the product yield, but also can effectively control the content of impurities and ensure the medicine quality;
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, and particularly relates to a preparation method of a nintedanib intermediate.
Background
The chemical name of the ethanesulfonic acid nintedanib is 1H-indole-6-carboxylic acid, 2, 3-dihydro-3- [ [ [4- [ methyl [ (4-methyl-1-piperazinyl) acetyl ] methyl]Amino group]Phenyl radical]Amino group]Phenylmethylene]-2-oxo-, methyl ester, (3Z) -, ethanesulfonate (1: 1). The commodity name is as follows: vigat® / Ofev®The structural formula is as follows:
nintedanib ethanesulfonate is a triple vascular kinase inhibitor useful in the treatment of Idiopathic Pulmonary Fibrosis (IPF) and may act by inhibiting growth factor receptors associated with the pathogenesis of idiopathic pulmonary fibrosis.
At present, the methods for preparing the nifedipine ethanesulfonate have various international disclosures, wherein the compound of formula II or formula III is an important intermediate for synthesizing the nifedipine ethanesulfonate, and the methods for preparing the intermediate are reported in the following prior art:
1. a method for preparing a nintedanib intermediate and an analogue thereof is provided in Chinese patent CN1391557A published by Berlingger Engelham Famao in 2000, and 1-acetyl-3- (methoxy (phenyl) methylene) -2-oxoindoline-6-methyl formate is synthesized by a one-pot method. Prepared by reacting ethyl 2-oxoindole-6-carboxylate, triethyl orthobenzoate and 20.4 equivalents of acetic anhydride at 110 ℃ for 4 hours with a molar yield of 61%.
2. Gerald J. Roth et al in 2009 (J.Med.chem., 2009, 52, 4466-4480) proposed two methods for preparing Nintedanib intermediates and analogs thereof, first using a step-by-step process, i.e. first reacting methyl 2-oxoindole-6-carboxylate with 17.4 equivalents of acetic anhydride at 130 ℃ for 8 hours to isolate methyl 1-acetyl-2-oxoindole-6-carboxylate with a molar yield of 73%, then further reacting with trimethyl orthobenzoate in 20.4 equivalents of acetic anhydride at 120 ℃ for 6 hours to obtain methyl 1-acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate, but the molar yield of analogs thereof only reaches 56%.
In both of the above-mentioned preparation methods, excess acetic anhydride is used and the molar yield is low. Meanwhile, in the research process, the inventor finds that the contents of the impurity 1 and the impurity 2 in the sample prepared by the method are about 1% and about 5% respectively, the impurity content is high, and the quality of the medicine is influenced.
3. An improved process route is proposed in the 2016 published Chinese patent CN106748961A by Ruiyang pharmaceutical company, and the same one-pot method is adopted, 2-oxoindole-6-methyl formate is added into toluene, trimethyl orthobenzoate and 4.4 equivalents of acetic anhydride are added to react for 5 hours at the temperature of 120 ℃ and 125 ℃ to prepare the 1-acetyl-3- (methoxy (phenyl) methylene) -2-oxoindoline-6-methyl formate, and the molar yield is only 48.9%.
The process adopts toluene as a solvent, so that the consumption of acetic anhydride is correspondingly reduced, but the yield is obviously reduced, and therefore, a process route which can reduce the consumption of acetic anhydride and has good yield while ensuring the reduction of the content of impurities is required to be found.
4. The Fermi company proposed a preparation method for improving the yield of the process route in Chinese patent CN111465594A published in 2018, which comprises adding 2-oxoindole-6-methyl formate into xylene, adding 9 equivalents of acetic anhydride, heating to 130 ℃, supplementing xylene after 5 hours, adding trimethyl orthobenzoate at 120 ℃ for reaction, and finally obtaining 1-acetyl-3- (methoxy (phenyl) methylene) -2-oxoindoline-6-methyl formate, wherein the molar yield reaches 79.29%, but the purity is not high, and is only 93.20%.
Acetic anhydride has strong acetic acid smell and has great harm to human body, so that a process route which can reduce the consumption of acetic anhydride, improve the product yield and reduce the impurity content is found and is very important for preparing the ethanesulfonic acid nintedanib.
The invention adopts a one-pot method for synthesis, and greatly reduces the contents of impurities 1 and 2 to below 0.5% by adjusting the using amount of acetic anhydride, the types of solvents and the using amount of the solvents, and the molar yield of the prepared product is greatly improved, while the using amount of the acetic anhydride is obviously reduced, so that the preparation method is environment-friendly and is more suitable for industrial application.
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of a nintedanib intermediate, which can effectively control the contents of impurities 1 and 2 while obtaining higher yield by controlling the consumption of acetic anhydride and combining with the screening of a solvent. The method is simple to operate and suitable for industrial production.
In order to achieve the purpose, the invention provides a preparation method of an ethanesulfonic acid nintedanib intermediate, which comprises the following steps: reacting a compound of formula I, a trialkyl orthobenzoate and acetic anhydride in an organic solvent, wherein the trialkyl orthobenzoate is selected from trimethyl orthobenzoate or triethyl orthobenzoate, R1 is selected from methyl or ethyl, and the molar ratio of the compound of formula I to acetic anhydride is 1:2 to 1: 4;
in the present invention, the molar ratio of the compound of formula I to acetic anhydride is from 1:2 to 1:3, preferably 1: 3.
In the invention, the reaction temperature is 60-130 ℃, preferably 100-130 ℃, and more preferably 110-120 ℃.
In the present invention, the organic solvent is selected from one or more of xylene, dimethyl sulfoxide, tetrahydrofuran, N-dimethylformamide, acetone and isopropyl ether; preferably, the organic solvent is selected from one or more of xylene, N-dimethylformamide and isopropyl ether, more preferably xylene and/or N, N-dimethylformamide, and further preferably xylene.
In the present invention, the mass-to-volume ratio of the compound of formula I to the organic solvent is 1:5 to 1:20, preferably 1:7 to 1:15, more preferably 1:10 to 1:15, and still more preferably 1: 10.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
(1) the one-pot method is adopted to prepare the nintedanib intermediate, so that the process route is shortened, and the operation steps are simplified;
(2) the consumption of acetic anhydride is reduced, and the harm of the reagent to a human body in the production process is reduced;
(3) the method realizes the improvement of the yield of the nintedanib intermediate by screening acetic anhydride and/or a solvent and the using amount thereof through a great deal of creative labor;
(4) greatly reduces the generation of impurities 1 and 2 and ensures the quality of the medicine.
Drawings
FIG. 1 is a HPLC chromatogram of the compound of formula III prepared in example 1.
FIG. 2 is a HPLC detection spectrum of impurity 1 in examples 1 to 12.
FIG. 3 is a HPLC detection spectrum of impurity 2 in examples 1 to 12.
FIG. 4 is a HPLC chromatogram of the compound of formula III prepared in example 3.
FIG. 5 is a HPLC chromatogram of the compound of formula II prepared in example 12.
Detailed Description
For a better understanding of the present invention, the present invention is further described below with reference to specific examples, but the scope of the present invention is not limited to the specific examples.
The liquid phase detection method of the nintedanib intermediate is shown in table 1 below:
TABLE 1
EXAMPLE 11 preparation of methyl acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate
Adding 2-oxoindole-6-methyl formate (15 g, 78.5 mmol), triethyl orthobenzoate (49.5 g, 220.7 mmol) and acetic anhydride (150 ml, 1.59 mol) into a reaction bottle in sequence, heating to 110 ℃, preserving heat for reaction for 4 hours, cooling, separating out a solid, filtering, and vacuum drying at 50 ℃ for 16 hours to obtain 22g, wherein the mass yield is 146.7%, and the molar yield is 76.8%. HPLC purity 93.35%, impurity 10.82%, impurity 24.9%.
Nuclear magnetic data:1H-NMR：δ1.35(t, 3H)，2.44 (s, 3H)，3.87(s, 3H)，3.98-4.03 (q, 2H)，7.52-7.57 (m, 5H)，7.87-7.89(d, 1H)，8.07-8.09(d, 1H)， 8.73(s, 1H)。
wherein, the HPLC detection profile of the compound of formula III prepared in example 1 is shown in FIG. 1.
EXAMPLE 21 preparation of methyl acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate
Adding 2-oxoindole-6-methyl formate (20 g, 104.6 mmol), triethyl orthobenzoate (46.9 g, 209.2 mmol), acetic anhydride (32.0 g, 313.8 mmol) and 200mL of xylene into a reaction flask in sequence, heating to 110 ℃, carrying out heat preservation reaction for 4 hours, cooling to room temperature, filtering, and carrying out vacuum drying at 50 ℃ for 16 hours to obtain 30.9g, wherein the mass yield is 154.5%, the molar yield is 80.9%, the HPLC purity is 99.43%, the impurity is 10.03% and the impurity is 20.03%.
The structure was confirmed and analyzed, which revealed that the product obtained was the same as methyl 1-acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate in example 1.
EXAMPLE 31 preparation of methyl acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate
Adding 2-oxoindole-6-methyl formate (20 g, 104.6 mmol), triethyl orthobenzoate (46.9 g, 209.2 mmol), acetic anhydride (32.0 g, 313.8 mmol) and 200mL of xylene into a reaction flask in sequence, heating to 120 ℃, carrying out heat preservation reaction for 4 hours, cooling to room temperature, filtering, and carrying out vacuum drying at 50 ℃ for 16 hours to obtain 31.5g, wherein the mass yield is 157.5%, the molar yield is 82.4%, the HPLC purity is 99.75%, the impurity 1 is not detected, and the impurity 2 is less than 0.01%.
The structure was confirmed and analyzed, which revealed that the product obtained was the same as methyl 1-acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate in example 1.
Wherein, the HPLC detection profile of the compound of formula III prepared in example 3 is shown in FIG. 4.
EXAMPLE 41 preparation of methyl acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate
Adding 2-oxoindole-6-methyl formate (20 g, 104.6 mmol), triethyl orthobenzoate (57.2 g, 313.8 mmol), acetic anhydride (32.0 g, 313.8 mmol) and 200mL of xylene into a reaction bottle in sequence, heating to 130 ℃, carrying out heat preservation reaction for 4 hours, cooling to room temperature, filtering, and carrying out vacuum drying at 50 ℃ for 16 hours to obtain 31.1g, wherein the mass yield is 155.5%, the molar yield is 81.4%, the HPLC purity is 99.69%, the impurity 1 is less than 0.01%, and the impurity 2 is less than 0.01%.
The structure was confirmed and analyzed, which revealed that the product obtained was the same as methyl 1-acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate in example 1.
EXAMPLE 51 preparation of methyl acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate
Adding 2-oxoindole-6-methyl formate (20 g, 104.6 mmol), triethyl orthobenzoate (57.2 g, 313.8 mmol), acetic anhydride (21.4 g, 209.2 mmol) and 200mL of xylene into a reaction bottle in sequence, heating to 120 ℃, carrying out heat preservation reaction for 4 hours, cooling to room temperature, filtering, and carrying out vacuum drying at 50 ℃ for 16 hours to obtain 30.6g, wherein the mass yield is 153.0%, the molar yield is 80.1%, the HPLC purity is 99.67%, the impurity content is 10.01% and the impurity content is 20.02%.
The structure was confirmed and analyzed, which revealed that the product obtained was the same as methyl 1-acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate in example 1.
EXAMPLE 61 preparation of acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylic acid methyl ester
Adding methyl 2-oxoindole-6-carboxylate (20 g, 104.6 mmol), triethyl orthobenzoate (57.2 g, 313.8 mmol), acetic anhydride (42.7 g, 418.4 mmol) and 200mL of xylene into a reaction flask in sequence, heating to 120 ℃, keeping the temperature for reaction for 4 hours, cooling to room temperature, filtering, and vacuum drying at 50 ℃ for 16 hours to obtain 30.1g, wherein the mass yield is 150.5%, the molar yield is 78.8%, the HPLC purity is 95.61%, the impurity content is 10.46% and the impurity content is 22.68%.
The structure was confirmed and analyzed, which revealed that the product obtained was the same as methyl 1-acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate in example 1.
Example 71 preparation of acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylic acid methyl ester
Adding 2-oxoindole-6-methyl formate (20 g, 104.6 mmol), triethyl orthobenzoate (57.2 g, 313.8 mmol), acetic anhydride (32.0 g, 313.8 mmol) and 200mL of toluene into a reaction bottle in sequence, heating to 120 ℃, carrying out heat preservation reaction for 4 hours, cooling to room temperature, filtering, and carrying out vacuum drying at 50 ℃ for 16 hours to obtain 23.1g, wherein the mass yield is 115.5%, the molar yield is 60.5%, the HPLC purity is 94.66%, the impurity is 10.56% and the impurity is 23.18%.
The structure was confirmed and analyzed, which revealed that the product obtained was the same as methyl 1-acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate in example 1.
Example 81 preparation of acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylic acid methyl ester
Adding 2-oxoindole-6-methyl formate (20 g, 104.6 mmol), triethyl orthobenzoate (57.2 g, 313.8 mmol), acetic anhydride (32.0 g, 313.8 mmol) and N, N-dimethylformamide 200mL into a reaction bottle in sequence, heating to 120 ℃, preserving heat for reaction for 4 hours, cooling to room temperature, filtering, and vacuum drying at 50 ℃ for 16 hours to obtain 30.3g, the mass yield is 151.5%, the molar yield is 79.3%, the HPLC purity is 99.38%, the impurity is 10.03% and the impurity is 20.05%.
The structure was confirmed and analyzed, which revealed that the product obtained was the same as methyl 1-acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate in example 1.
Example 91 preparation of acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylic acid methyl ester
Adding 2-oxoindole-6-methyl formate (20 g, 104.6 mmol), triethyl orthobenzoate (57.2 g, 313.8 mmol), acetic anhydride (32.0 g, 313.8 mmol) and 200mL isopropyl ether into a reaction bottle in sequence, heating to 120 ℃, carrying out heat preservation reaction for 4 hours, cooling to room temperature, filtering, and carrying out vacuum drying at 50 ℃ for 16 hours to obtain 27.1g, wherein the mass yield is 135.5%, the molar yield is 71.0%, the HPLC purity is 98.91%, the impurity is 10.04%, and the impurity is 20.09%.
The structure was confirmed and analyzed, which revealed that the product obtained was the same as methyl 1-acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate in example 1.
EXAMPLE 101 preparation of acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylic acid methyl ester
Adding 2-oxoindole-6-methyl formate (20 g, 104.6 mmol), triethyl orthobenzoate (57.2 g, 313.8 mmol), acetic anhydride (32.0 g, 313.8 mmol) and 140mL of xylene into a reaction bottle in sequence, heating to 120 ℃, carrying out heat preservation reaction for 4 hours, cooling to room temperature, filtering, and carrying out vacuum drying at 50 ℃ for 16 hours to obtain 30.0g, wherein the mass yield is 150.0%, the molar yield is 78.5%, the HPLC purity is 99.06%, the impurity content is 10.02% and the impurity content is 20.05%.
The structure was confirmed and analyzed, which revealed that the product obtained was the same as methyl 1-acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate in example 1.
EXAMPLE 111 preparation of acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylic acid methyl ester
Adding 2-oxoindole-6-methyl formate (20 g, 104.6 mmol), triethyl orthobenzoate (57.2 g, 313.8 mmol), acetic anhydride (32.0 g, 313.8 mmol) and 300mL of xylene into a reaction bottle in sequence, heating to 120 ℃, carrying out heat preservation reaction for 4 hours, cooling to room temperature, filtering, and carrying out vacuum drying at 50 ℃ for 16 hours to obtain 31.4g, wherein the mass yield is 150.0%, the molar yield is 82.2%, the HPLC purity is 99.37%, the impurity is 10.02% and the impurity is 20.03%.
The structure was confirmed and analyzed, which revealed that the product obtained was the same as methyl 1-acetyl-3- (ethoxy (phenyl) methylene) -2-oxoindoline-6-carboxylate in example 1.
Example 121 preparation of acetyl-3- (methoxy (phenyl) methylene) -2-oxoindoline-6-carboxylic acid methyl ester
Adding 2-oxoindole-6-methyl formate (20 g, 104.6 mmol), trimethyl orthobenzoate (57.2 g, 313.8 mmol), acetic anhydride (32.0 g, 313.8 mmol) and 200mL of xylene into a reaction flask in sequence, heating to 120 ℃, carrying out heat preservation reaction for 4 hours, cooling to room temperature, filtering, and carrying out vacuum drying at 50 ℃ for 16 hours to obtain 31.1g, wherein the mass yield is 155.5%, the molar yield is 81.4%, the HPLC purity is 99.58%, the impurity 1 is less than 0.01%, and the impurity 2 is less than 0.01%.
Nuclear magnetic data: 1H-NMR: 2.44 (s, 3H), 3.80(s, 3H), 3.90(s, 3H), 7.50-7.56 (m, 5H), 7.85-7.88(d, 1H), 8.06-8.08(d, 1H), 8.73(s, 1H).
Wherein, the HPLC detection profile of the compound of formula II prepared in example 12 is shown in FIG. 5.
In examples 1 to 12, the HPLC detection spectrum of impurity 1 is shown in fig. 2, and the HPLC detection spectrum of impurity 2 is shown in fig. 3.
Claims (7)
1. A preparation method of a nintedanib intermediate comprises the following steps: reacting a compound of formula I, a trialkyl orthobenzoate and acetic anhydride in an organic solvent, wherein,
the trialkyl orthobenzoate is selected from trimethyl orthobenzoate or triethyl orthobenzoate,
R1is selected from the group consisting of methyl or ethyl,
the molar ratio of the compound of the formula I to the acetic anhydride is 1:2-1: 3;
the organic solvent is selected from xylene;
2. the process of claim 1, wherein the molar ratio of the compound of formula I to acetic anhydride is 1: 3.
3. The method according to claim 1, wherein the reaction temperature is 60 to 130 ℃.
4. The method according to claim 1, wherein the reaction temperature is 100 to 130 ℃.
5. The method according to claim 1, wherein the reaction temperature is 110 to 120 ℃.
6. The preparation method according to claim 1, wherein the mass-to-volume ratio of the compound of formula I to the organic solvent is 1g:5mL-1g:20 mL.
7. The preparation method according to claim 1, wherein the mass-to-volume ratio of the compound of formula I to the organic solvent is 1g:10 mL.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20150284327A1 (en) * | 2014-04-04 | 2015-10-08 | Auspex Pharmaceuticals, Inc. | Oxindole inhibitors of tyrosine kinase |
| CN111465594A (en) * | 2017-11-17 | 2020-07-28 | 费米有限公司 | Synthesis of 2-indolinones known as intermediates for the preparation of nintedanib |
| CN111848490A (en) * | 2020-08-24 | 2020-10-30 | 江西国药有限责任公司 | Preparation method of high-purity ethanesulfonic acid nintedanib |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150284327A1 (en) * | 2014-04-04 | 2015-10-08 | Auspex Pharmaceuticals, Inc. | Oxindole inhibitors of tyrosine kinase |
| CN111465594A (en) * | 2017-11-17 | 2020-07-28 | 费米有限公司 | Synthesis of 2-indolinones known as intermediates for the preparation of nintedanib |
| CN111848490A (en) * | 2020-08-24 | 2020-10-30 | 江西国药有限责任公司 | Preparation method of high-purity ethanesulfonic acid nintedanib |
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| "尼达尼布的合成工艺改进";杨怡 等;《江苏科技信息》;20190930(第26期);第63-66页 * |
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