CN109096136B - Erlotinib intermediate compound and refining method thereof - Google Patents
Erlotinib intermediate compound and refining method thereof Download PDFInfo
- Publication number
- CN109096136B CN109096136B CN201810978542.4A CN201810978542A CN109096136B CN 109096136 B CN109096136 B CN 109096136B CN 201810978542 A CN201810978542 A CN 201810978542A CN 109096136 B CN109096136 B CN 109096136B
- Authority
- CN
- China
- Prior art keywords
- intermediate compound
- methoxyethoxy
- amino
- stirring
- erlotinib
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to an erlotinib intermediate compound and a refining method thereof, belonging to the technical field of medicines. The erlotinib intermediate compound is 2-amino-4, 5-di (2-methoxyethoxy) ethyl benzoate hydrochloride. The refining method comprises 5 steps: 1. dissolving the intermediate compound crude product in water, adding alumina for adsorption after dissolving, and filtering to remove the alumina; 2. adding isopropyl acetate into the filtrate obtained in the step 1, adding solid alkali to adjust the pH value to 7-8, stirring, standing, and layering; 3. adding the organic phase obtained in the step 2 into active carbon for decoloring, precisely filtering the active carbon, and evaporating part of isopropyl acetate under reduced pressure; 4. adding methanol into the distillation residual liquid in the step 3, dropwise adding thionyl chloride, stopping dropwise adding when the pH value is detected to be qualified, and continuously stirring; 5. and (4) cooling, then carrying out suction filtration, leaching the organic solvent, and drying to obtain a target product. The refining method is scientific and reasonable, has high recovery rate and is easy for industrial production.
Description
Technical Field
The invention relates to an erlotinib intermediate compound and a refining method thereof, belonging to the technical field of medicines.
Background
Ethyl 2-amino-4, 5-bis (2-methoxyethoxy) benzoate hydrochloride is an important intermediate for the synthesis of the drug erlotinib. Erlotinib, co-developed by Genetech, OSI, Roche, a cancer treatment drug produced by Roche, is an innovative drug for the treatment of locally advanced or metastatic non-small cell lung cancer that fails at least one chemotherapy regimen. A plurality of clinical researches show that the traditional Chinese medicine composition has definite curative effect and small toxic and side effects, can obviously relieve the pain of patients, prolongs the service life of the patients, and also shows certain clinical application value in the treatment of advanced pancreatic cancer and head and neck malignant tumors.
In the process of synthesizing 2-amino-4, 5-bis (2-methoxyethoxy) ethyl benzoate hydrochloride, two impurities of A type and B type shown in the following structural formula are easy to appear, and because the two impurities are similar to the product structure and have similar physicochemical properties, the impurities are difficult to remove by the conventional refining method, so that the impurities are enriched in downstream products and are transferred to erlotinib finished products. The purity of 2-amino-4, 5-bis (2-methoxyethoxy) ethyl benzoate hydrochloride prepared by the prior art is generally about 98 percent and cannot meet the requirements of high-end customers, so that a refining method for preparing the high-purity 2-amino-4, 5-bis (2-methoxyethoxy) ethyl benzoate hydrochloride which is suitable for industrialization is necessary; the structures of the two impurities are as follows:
disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a method for refining an erlotinib intermediate compound, which has the advantages of simple process, scientific and reasonable property, high recovery rate and easy industrial production.
Meanwhile, the invention also provides a structural formula of the erlotinib intermediate compound.
The erlotinib intermediate compound is 2-amino-4, 5-di (2-methoxyethoxy) ethyl benzoate hydrochloride; the structural formula is as follows:
the method for refining the erlotinib intermediate compound comprises the following steps:
1) dissolving the crude product of ethyl 2-amino-4, 5-di (2-methoxyethoxy) benzoate hydrochloride in water according to the mass ratio of 1: 2.5-3.5, adding alumina for adsorption after dissolving, stirring and adsorbing for 2-2.5 h at a set temperature, and filtering to remove the alumina;
2) adding isopropyl acetate into the filtrate obtained in the step 1, adding solid alkali in batches under a stirring state to adjust the pH to 7-8, and controlling the temperature to be 10-15 ℃; stirring for 0.5h, standing for 0.5h, and layering;
3) adding activated carbon into the organic phase obtained in the step 2 at the temperature of 18-23 ℃ for decoloring for 30min, precisely filtering the activated carbon, and evaporating part of isopropyl acetate under reduced pressure;
4) adding methanol into the distillation residual liquid in the step 3, dropwise adding thionyl chloride at 10-15 ℃ under a stirring state, stopping dropwise adding when the pH value is detected to be qualified, and continuously stirring for 20 min;
5) and cooling to 5-8 ℃, carrying out suction filtration, leaching with an organic solvent, and drying to obtain a 2-amino-4, 5-di (2-methoxyethoxy) ethyl benzoate hydrochloride product with the purity of more than 99.8%.
In the step 1, the mass ratio of the added alumina to the crude product of the 2-amino-4, 5-bis (2-methoxyethoxy) ethyl benzoate hydrochloride is 0.3-0.6: 1.
In the step 1, the temperature of stirring and adsorption is 15-18 ℃.
In the step 2, the addition amount of the isopropyl acetate is 5-8 times of the weight of the crude product of the ethyl 2-amino-4, 5-bis (2-methoxyethoxy) benzoate hydrochloride.
In the step 2, the solid alkali is one or more of ammonium carbonate, sodium carbonate and sodium bicarbonate.
In the step 3, the mass of the distilled isopropyl acetate accounts for 30-45% of the addition amount.
In the step 3, a filter membrane made of polytetrafluoroethylene is adopted for precise filtration; the aperture is 2.2 um; the vacuum degree is controlled between-0.07 MPa and-0.09 MPa.
In the step 4, the weight ratio of the added methanol to the crude product of the ethyl 2-amino-4, 5-bis (2-methoxyethoxy) benzoate hydrochloride is 1: 6-8.
In the step 4, the qualified value of the pH value is 2-2.7.
In the step 5, the leaching solvent is one or more of acetone, butanone or cyclohexanone; adding leaching solvent
The volume ratio of the water to the added water is 1: 4-10.
In the step 5, the drying temperature is 55-60 ℃.
Compared with the prior art, the invention has the following beneficial effects:
1. the purity of the 2-amino-4, 5-bis (2-methoxyethoxy) ethyl benzoate hydrochloride is as high as 99.8 percent and is much higher than 98 percent of the prior level;
2. the raw materials used in the invention are all common raw materials, the price is low, the process is simple, and the method is suitable for industrial production;
3. the invention adopts thionyl chloride for acid adjustment and crystallization, which not only can ensure the formation of hydrochloride, but also can reduce the dissolution loss of water to the product; meanwhile, the chromatographic content of the A-type impurity and the B-type impurity is controlled to be below 0.05 percent, so that the occurrence of side reactions in subsequent steps is reduced, and the difficulty in purifying subsequent products is reduced.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
A method for refining an erlotinib intermediate compound comprises the following steps:
1) adding 35.0g of crude 2-amino-4, 5-bis (2-methoxyethoxy) ethyl benzoate hydrochloride and 87.5g of water into a 250ml reaction bottle, stirring to dissolve, adding 12.4g of alumina, stirring at 15 ℃ for adsorption for 2 hours, and filtering to remove the alumina;
2) adding 175.8g of isopropyl acetate into the filtrate obtained in the step 1, adding sodium carbonate in portions while stirring to adjust the pH value to 7.34, and controlling the temperature to be 10 ℃; stirring for 0.5h, standing for 0.5h, and layering;
3) adding activated carbon into the organic phase obtained in the step 2 at 19 ℃ for decoloring for 30min, filtering with a polytetrafluoroethylene filter membrane with the aperture of 2.2 mu m, precisely filtering to remove the activated carbon, and evaporating 63.3g of isopropyl acetate under reduced pressure;
4) adding 5.2g of methanol into the distillation residual liquid in the step 3, dropwise adding 20.1g of thionyl chloride at 10 ℃ under a stirring state, stopping dropwise adding when the pH value is detected to be 2.37, and continuously stirring for 20 min;
5) cooling to 8 ℃, filtering, leaching with 10ml acetone, drying at 55 ℃ to obtain 33.1g of 2-amino-4, 5-di (2-methoxyethoxy) ethyl benzoate hydrochloride product with the purity of 99.82 percent.
Example 2
A method for refining an erlotinib intermediate compound comprises the following steps:
1) adding 2-amino-4, 5-bis (2-methoxyethoxy) ethyl benzoate hydrochloride crude product 60.0g and water 150g into a 250ml reaction bottle, stirring to dissolve, adding alumina 36g, stirring at 17 ℃ for adsorption for 2h, and filtering to remove the alumina;
2) adding 300g of isopropyl acetate into the filtrate obtained in the step 1, adding ammonium carbonate in batches under a stirring state to adjust the pH value to 7.52, and controlling the temperature to be 14 ℃; stirring for 0.5h, standing for 0.5h, and layering;
3) adding activated carbon into the organic phase obtained in the step 2 at 22 ℃ for decoloring for 30min, filtering with a polytetrafluoroethylene filter membrane with the aperture of 2.2 mu m, precisely filtering to remove the activated carbon, and evaporating 230.4g of isopropyl acetate under reduced pressure;
4) adding 10g of methanol into the distillation residual liquid in the step 3, dropwise adding 20.9g of thionyl chloride at 15 ℃ under a stirring state, stopping dropwise adding when the pH value is detected to be 2.57, and continuously stirring for 20 min;
5) cooling to 5 ℃, filtering, leaching with 30ml cyclohexanone, drying at 60 ℃ to obtain 59.928g of 2-amino-4, 5-di (2-methoxyethoxy) ethyl benzoate hydrochloride product with the purity of 99.88 percent.
Example 3
A method for refining an erlotinib intermediate compound comprises the following steps:
1) adding 40g of crude 2-amino-4, 5-bis (2-methoxyethoxy) ethyl benzoate hydrochloride and 120g of water into a 250ml reaction bottle, stirring to dissolve, adding 20g of alumina, stirring and adsorbing at 18 ℃ for 2.5h, and filtering to remove the alumina;
2) adding 240g of isopropyl acetate into the filtrate obtained in the step 1, adding sodium bicarbonate in portions while stirring to adjust the pH to 7.14, and controlling the temperature to be 12 ℃; stirring for 0.5h, standing for 0.5h, and layering;
3) adding activated carbon into the organic phase obtained in the step 2 at 19 ℃ for decoloring for 30min, filtering with a polytetrafluoroethylene filter membrane with the aperture of 2.2 mu m, precisely filtering to remove the activated carbon, and evaporating 150.4g of isopropyl acetate under reduced pressure;
4) adding 5.7g of methanol into the distillation residual liquid in the step 3, dropwise adding 19.6g of thionyl chloride at 13 ℃ under the stirring state, stopping dropwise adding when the pH value is detected to be 2.57, and continuously stirring for 20 min;
5) cooling to 6 ℃, filtering, leaching with 20ml acetone, drying at 58 ℃ to obtain 39.96g of 2-amino-4, 5-di (2-methoxyethoxy) ethyl benzoate hydrochloride product with the purity of 99.90 percent.
Claims (9)
1. A method for refining an erlotinib intermediate compound is characterized by comprising the following steps:
the method comprises the following steps:
1) dissolving the crude product of ethyl 2-amino-4, 5-di (2-methoxyethoxy) benzoate hydrochloride in water according to the mass ratio of 1: 2.5-3.5, adding alumina for adsorption after dissolving, stirring and adsorbing for 2-2.5 h at a set temperature, and filtering to remove the alumina;
2) adding isopropyl acetate into the filtrate obtained in the step 1, adding solid alkali in batches under a stirring state to adjust the pH to 7-8, and controlling the temperature to be 10-15 ℃; stirring for 0.5h, standing for 0.5h, and layering;
3) adding activated carbon into the organic phase obtained in the step 2 at the temperature of 18-23 ℃ for decoloring for 30min, precisely filtering the activated carbon, and evaporating part of isopropyl acetate under reduced pressure;
4) adding methanol into the distillation residual liquid in the step 3, dropwise adding thionyl chloride at 10-15 ℃ under a stirring state, stopping dropwise adding when the pH value is detected to be qualified, and continuously stirring for 20 min;
5) cooling to 5-8 ℃, carrying out suction filtration, leaching with an organic solvent, and drying to obtain a 2-amino-4, 5-di (2-methoxyethoxy) ethyl benzoate hydrochloride product with the purity of more than 99.8%;
the erlotinib intermediate compound is 2-amino-4, 5-di (2-methoxyethoxy) ethyl benzoate hydrochloride; the structural formula is as follows:
2. the method for purifying an erlotinib intermediate compound according to claim 1, wherein: in the step 1, the mass ratio of the added alumina to the crude product of the 2-amino-4, 5-di (2-methoxyethoxy) ethyl benzoate hydrochloride is 0.3-0.6: 1.
3. The method for purifying an erlotinib intermediate compound according to claim 1, wherein: in the step 1, the temperature of stirring and adsorption is 15-18 ℃.
4. The method for purifying an erlotinib intermediate compound according to claim 1, wherein: in the step 2, the addition amount of the isopropyl acetate is 5-8 times of the weight of the crude product of the ethyl 2-amino-4, 5-bis (2-methoxyethoxy) benzoate hydrochloride.
5. The method for purifying an erlotinib intermediate compound according to claim 1, wherein: the solid alkali used in the step 2 is one or more of ammonium carbonate, sodium carbonate and sodium bicarbonate.
6. The method for purifying an erlotinib intermediate compound according to claim 1, wherein: in the step 4, the weight ratio of the added amount of the methanol to the crude product of the ethyl 2-amino-4, 5-bis (2-methoxyethoxy) benzoate hydrochloride is 1: 6-8.
7. The method for purifying an erlotinib intermediate compound according to claim 1, wherein: in step 4, the pH value is 2-2.7.
8. The method for purifying an erlotinib intermediate compound according to claim 1, wherein: and 5, the leaching solvent used in the step 5 is one or more of acetone, butanone or cyclohexanone.
9. The method for purifying an erlotinib intermediate compound according to claim 1, wherein: in step 5, the drying temperature is 55-60 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810978542.4A CN109096136B (en) | 2018-08-27 | 2018-08-27 | Erlotinib intermediate compound and refining method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810978542.4A CN109096136B (en) | 2018-08-27 | 2018-08-27 | Erlotinib intermediate compound and refining method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109096136A CN109096136A (en) | 2018-12-28 |
| CN109096136B true CN109096136B (en) | 2020-11-03 |
Family
ID=64851101
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810978542.4A Active CN109096136B (en) | 2018-08-27 | 2018-08-27 | Erlotinib intermediate compound and refining method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109096136B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104193688A (en) * | 2014-09-04 | 2014-12-10 | 埃斯特维华义制药有限公司 | Synthetic method for erlotinib intermediate |
| CN104725327A (en) * | 2015-03-03 | 2015-06-24 | 山东大学 | Environment-friendly method for preparing high-yield erlotinib hydrochloride |
| CN108061765A (en) * | 2017-12-04 | 2018-05-22 | 重庆华邦制药有限公司 | HPLC method separation determination erlotinib Hydrochloride intermediates M1And its method of related impurities |
| CN108358798A (en) * | 2018-02-12 | 2018-08-03 | 黑龙江鑫创生物科技开发有限公司 | A kind of method of micro passage reaction synthesis Tarceva intermediate |
-
2018
- 2018-08-27 CN CN201810978542.4A patent/CN109096136B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104193688A (en) * | 2014-09-04 | 2014-12-10 | 埃斯特维华义制药有限公司 | Synthetic method for erlotinib intermediate |
| CN104725327A (en) * | 2015-03-03 | 2015-06-24 | 山东大学 | Environment-friendly method for preparing high-yield erlotinib hydrochloride |
| CN108061765A (en) * | 2017-12-04 | 2018-05-22 | 重庆华邦制药有限公司 | HPLC method separation determination erlotinib Hydrochloride intermediates M1And its method of related impurities |
| CN108358798A (en) * | 2018-02-12 | 2018-08-03 | 黑龙江鑫创生物科技开发有限公司 | A kind of method of micro passage reaction synthesis Tarceva intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109096136A (en) | 2018-12-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110041261B (en) | Preparation method of naphazoline hydrochloride | |
| CN104402838B (en) | The process for purification of valsartan | |
| CN106892950B (en) | Preparation method of high-content troxerutin | |
| CN112608283A (en) | Preparation method of nitrazepam | |
| CN105153004A (en) | Improved industrialization technology for preparing Vildagliptin | |
| CN109096136B (en) | Erlotinib intermediate compound and refining method thereof | |
| CN102180820B (en) | Purification method for preparing high-purity Fudosteine | |
| CN112645912B (en) | Preparation method of high-purity M2 crystal form meclofenol sodium | |
| CN113461580A (en) | N-acetyl-L-cysteine synthesis method | |
| CN113549031A (en) | Method for refining dipheny hydrochloride | |
| CN109134556B (en) | Hydrochloric acid crystallization separation and purification method of lincomycin | |
| CN102093250A (en) | Glutamine dipeptide compound and novel method thereof | |
| CN111548310B (en) | Levosimendan sodium crystal form and preparation method thereof | |
| CN116410161A (en) | Method for refining furosemide | |
| CN108440324B (en) | Ornithine aspartate and crystallization method thereof | |
| CN116348110A (en) | Paroxetine hydrochloride purification method | |
| CN109761858B (en) | Refining method of gabexate mesylate | |
| CN107759609A (en) | A kind of purification process of asenapine | |
| CN111748004A (en) | Crystal form of high-purity dapagliflozin intermediate and preparation method thereof | |
| CN113045611A (en) | Preparation method of high-purity lincomycin hydrochloride | |
| CN111848561A (en) | Method for purifying mycophenolic acid | |
| CN112142740A (en) | Process for the preparation of imipenem | |
| CN114957130B (en) | Purification method and application of high-purity 5-benzylidene hydantoin | |
| CN109305962B (en) | Refining method of dalatavir hydrochloride | |
| CN111349098A (en) | Preparation method of sitagliptin intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220318 Address after: 255314 building 12, No. 468, Suyuan Road, Zhoucun District, Zibo City, Shandong Province Patentee after: Shandong Jincheng Pharmaceutical Research Institute Co.,Ltd. Address before: 255129 No.288 Shengdi Road, Kunlun town, Zichuan District, Zibo City, Shandong Province Patentee before: SHANDONG JINCHENG MEDICINE CHEMICAL CO.,LTD. |
|
| TR01 | Transfer of patent right |