CN112341346B - Synthesis method of Orientinib intermediate - Google Patents
Synthesis method of Orientinib intermediate Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 238000001914 filtration Methods 0.000 claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000000543 intermediate Substances 0.000 claims abstract description 21
- 239000000047 product Substances 0.000 claims abstract description 20
- BKYHMDNLFGUECN-UHFFFAOYSA-N 1-fluoro-5-methoxy-2,4-dinitrobenzene Chemical compound COC1=CC(F)=C([N+]([O-])=O)C=C1[N+]([O-])=O BKYHMDNLFGUECN-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000010438 heat treatment Methods 0.000 claims abstract description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 16
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 15
- MFJNOXOAIFNSBX-UHFFFAOYSA-N 1-fluoro-3-methoxybenzene Chemical compound COC1=CC=CC(F)=C1 MFJNOXOAIFNSBX-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 11
- 239000005457 ice water Substances 0.000 claims abstract description 11
- FYSIGSQCZXQTIH-UHFFFAOYSA-N 4-fluoro-2-methoxy-5-nitroaniline Chemical compound COC1=CC(F)=C([N+]([O-])=O)C=C1N FYSIGSQCZXQTIH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 9
- 239000007858 starting material Substances 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000010791 quenching Methods 0.000 claims abstract description 5
- 230000000171 quenching effect Effects 0.000 claims abstract description 5
- 238000005406 washing Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 3
- 239000012043 crude product Substances 0.000 claims abstract description 3
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical group [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 9
- PLUKVDOZEJBBIS-UHFFFAOYSA-N N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide Chemical compound C(C=C)(=O)NC1=C(C=C(C(=C1)NC1=NC=CC(=N1)C1=C2N(C3=CC=CC=C13)CCCC2)OC)N(C)CCN(C)C PLUKVDOZEJBBIS-UHFFFAOYSA-N 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000006396 nitration reaction Methods 0.000 description 5
- 238000004537 pulping Methods 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 4
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 3
- 108010016076 Octreotide Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 3
- 229960002700 octreotide Drugs 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- BNRRMRUVYDETQC-UHFFFAOYSA-N 4-fluoro-2-methoxyaniline Chemical compound COC1=CC(F)=CC=C1N BNRRMRUVYDETQC-UHFFFAOYSA-N 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940121647 egfr inhibitor Drugs 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- NDEMNVPZDAFUKN-UHFFFAOYSA-N guanidine;nitric acid Chemical compound NC(N)=N.O[N+]([O-])=O.O[N+]([O-])=O NDEMNVPZDAFUKN-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000001546 nitrifying effect Effects 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- VILFTWLXLYIEMV-UHFFFAOYSA-N 1,5-difluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC([N+]([O-])=O)=C(F)C=C1F VILFTWLXLYIEMV-UHFFFAOYSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 206010071975 EGFR gene mutation Diseases 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010059282 Metastases to central nervous system Diseases 0.000 description 1
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- 229960001686 afatinib Drugs 0.000 description 1
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 229940121645 first-generation egfr tyrosine kinase inhibitor Drugs 0.000 description 1
- 229950007440 icotinib Drugs 0.000 description 1
- QQLKULDARVNMAL-UHFFFAOYSA-N icotinib Chemical compound C#CC1=CC=CC(NC=2C3=CC=4OCCOCCOCCOC=4C=C3N=CN=2)=C1 QQLKULDARVNMAL-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229940121644 second-generation egfr tyrosine kinase inhibitor Drugs 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 229940121646 third-generation egfr tyrosine kinase inhibitor Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a synthesis method of an oritinib intermediate, which comprises the following steps: 1. taking 3-fluoroanisole as a starting material, adding the starting material into concentrated sulfuric acid, dropwise adding concentrated nitric acid in a low-temperature environment, heating and stirring for the first time after the dropwise adding is finished, injecting the system into ice water for quenching, heating and stirring for the second time, and filtering to obtain a product 3-fluoro-4, 6-dinitroanisole; 2. adding the compound 3-fluoro-4, 6-dinitroanisole obtained in the first step into water, adding alkali, heating, adding a weak reducing agent in batches, stirring at a constant temperature to a reaction end point, filtering to obtain a crude product, washing, recrystallizing with methanol, crystallizing at a low temperature, filtering, and drying to obtain the 4-fluoro-2-methoxy-5-nitroaniline. The invention solves the problems of high raw material price, difficult market acquisition, complex process and low yield existing in the synthesis method of the Ornitinib intermediate in the prior art.
Description
Technical Field
The invention relates to a synthesis method of an oritinib intermediate, belonging to the technical field of synthesis of drug intermediates.
Background
Lung cancer is the first killer in the first 10 cancers in the world, the number of lung cancer in China reaches 80 ten thousand in 2017, the number of death is 70 ten thousand, and the death of the lung cancer accounts for one fourth of the death of all cancers. By 2025, the death cause of China is estimated to be 100 tens of thousands of people per year. Wherein non-small cell lung cancer accounts for 80% of lung cancer.
EGFR positive mutations are more common in non-small cell lung cancer, and EGFR inhibitors have accordingly emerged. Is a targeted therapeutic drug.
A first generation EGFR-TKI inhibitor drug: reversibly binding EGFR, mainly including gefitinib, erlotinib, and icotinib; second-generation EGFR-TKI drug: most of the small molecule drugs with multiple targets can form covalent bonds with EGFR tyrosine to form irreversible binding, and simultaneously generate inhibitory activity on other members of ErbB family (such as ErbB-2 and ErbB-4). Mainly comprises afatinib and dacatinib; third generation EGFR-TKI drug: highly selective T790M mutant small molecule inhibitors, mainly comprising octenib and ametinib.
The three-generation EGFR inhibitor has been developed under great demands and attention, the countless Orditini powder which is born in 2015 is remarkably well-accepted by industry, and the research and development code 9291 is popular in industry. Oritinib was able to address the T790M mutation drug resistance mutation; EGFR gene mutations (including 18, 19, 21 mutations) can also be targeted, acting as a primary inhibitor; meanwhile, the octreotide has better selectivity, weak effect on wild EGFR protein and smaller side effects such as rash; most critical, it is also effective for brain metastases. The traditional Chinese medicine composition has the advantages of small side effect, obvious curative effect, accurate target crowd and effectiveness on brain metastasis, and the three problems of the first-generation inhibitors such as gefitinib are perfectly solved by the octreotide.
The chemical name of the Ornitinib intermediate is 4-fluoro-2-methoxy-5-nitroaniline, and the synthesis method of the Ornitinib intermediate is reported to mainly comprise the following steps:
the method comprises the following steps: dissolving 4-fluoro-2-methoxyaniline in concentrated sulfuric acid at the temperature of minus 15 ℃ to enable the solid in the mixed solution to be completely dissolved, slowly adding a potassium nitrate solution dissolved in the concentrated sulfuric acid, continuously stirring for 2 hours at the temperature, pouring the reaction solution into ice water, adding NaOH, adjusting the pH value to 8.0-9.0, vigorously stirring to separate out the solid, and carrying out suction filtration to obtain yellow solid 4-fluoro-2-methoxy-5-nitroaniline, wherein the reaction equation is as follows:
the method has the main defects of high price of the main raw material, easy oxidation of amino during nitration, low yield, high purification difficulty and high cost.
The second method is as follows: dissolving 4-fluoro-2-methoxy aniline in ethyl acetate, adding concentrated sulfuric acid, and then adding guanidine nitrate for reaction to obtain a product, wherein the reaction equation is as follows:
the method has little influence on the amino group of the main raw material, so the yield is higher than that of the first method, but the production cost is high because the main raw material is expensive and the guanidine nitrate is not low.
And a third method: 4, 6-difluoro-1, 3-dinitrobenzene is taken as a raw material, reacts with methanol to generate 4-fluoro-6-methoxy-1, 3-dinitrobenzene, and then sodium dithionite is used for reducing nitro on the 1-position to obtain a product, wherein the reaction equation is as follows:
the method has more expensive raw materials and is not easy to obtain in the market.
Thus, there is an urgent need for a method for synthesizing an intermediate of octreotide that overcomes the above-mentioned technical problems.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a method for synthesizing an oriatinib intermediate, which solves the problems of high raw material price, difficult market acquisition, complex process and low yield in the method for synthesizing the oriatinib intermediate in the prior art.
The invention discloses a synthesis method of an oritinib intermediate, which is characterized by comprising the following steps of:
1) Taking 3-fluoroanisole as a starting material, adding the starting material into concentrated sulfuric acid, dropwise adding concentrated nitric acid in a low-temperature environment, heating and stirring for the first time after the dropwise adding is finished, injecting the system into ice water for quenching, heating and stirring for the second time, and filtering to obtain the 3-fluoro-4, 6-dinitroanisole (intermediate 1), wherein the reaction equation is as follows:
the concentration of the concentrated sulfuric acid is 95-98 percent, and the concentration of the concentrated nitric acid is 65-98 percent
The mass ratio range of the 3-fluoroanisole, the concentrated sulfuric acid and the concentrated nitric acid is as follows: 1: (4.8-6.5): (1.1-1.8);
dropwise adding concentrated nitric acid in a low-temperature environment, wherein the low-temperature environment is-20-10 ℃;
the first heating and stirring is to heat to 20-25 ℃ and stir for 3-5 hours;
after the temperature is raised and stirred, controlling the temperature to be 10-20 ℃, and injecting the system into ice water for quenching;
the second heating and stirring is controlled to be carried out at 30-35 ℃ for 2-3 hours;
2) Adding the compound 3-fluoro-4, 6-dinitroanisole obtained in the first step into water, adding alkali, heating, adding a weak reducing agent in batches, stirring at a constant temperature to a reaction end point, filtering to obtain a crude product, washing, recrystallizing with methanol, crystallizing at a low temperature, filtering, and drying to obtain 4-fluoro-2-methoxy-5-nitroaniline, wherein the reaction equation is as follows:
the temperature rise in the step 2) is raised to 40-50 ℃;
the weak reducing agent in the step 2) is any one of sodium dithionite, sodium thiosulfate and sodium sulfite;
the washing in the step 2) adopts pure water at 40-50 ℃ to stir and wash the product for three times;
the methanol recrystallization in the step 2) is carried out after the thermal dissolution at 50-55 ℃;
the low-temperature crystallization in the step 2) is performed for three hours at the temperature of 10-15 ℃.
The mass ratio range of the 3-fluoro-4, 6-dinitroanisole, water, alkali and weak reducing agent is as follows: 1: (5-6): (0.8-1.2): (1.6-2.5)
The method is used for preparing the intermediate of the Ornitinib.
The invention discloses a synthesis method of an oritinib intermediate, which has the following beneficial effects:
1. the starting material of the synthesis intermediate 1 is 3-fluoroanisole, no sensitive group exists in the nitration process, and the nitration reaction is thorough due to the good positioning effect of the group;
2. the solvent in the step 1) is preferably concentrated sulfuric acid, which is an excellent nitration reaction solvent, so that the nitration reaction of the initial raw materials in the solvent is thoroughly carried out, and the reaction is effectively promoted;
3. the nitrifying reagent in the step 1) is selected to be concentrated nitric acid, so that the cost is low, the nitrifying effect is relatively good, the reaction time is short, and the yield is relatively high;
4. the solvent in the step 2) is preferably water, the water has excellent solubility on the reducing agent sodium dithionite, the raw materials have good solubility in the water, and the reaction is effectively promoted;
5. the reducing agent in the step 2) is sodium dithionite, the sodium dithionite is reduced more stably, and the selectivity is good;
6. the recrystallization solvent in the step 2) is methanol, the methanol has high yield of the recrystallization solvent, the cost of the methanol is low, the solubility of the product at high temperature is good, the solubility at low temperature is poor, and the impurity removing effect of the methanol serving as the recrystallization solvent of the product is good.
The method for synthesizing the oritinib intermediate-4-fluoro-2-methoxy-5-nitroaniline is simple, the reaction flow is short, the initial materials are low in price and easy to obtain in the market, after simple purification, the pure product is obtained, the reaction time is short, the process is simple, the reaction condition is mild, the control is convenient, no organic solvent is used in both steps of reaction, the cost is low, the yield of both steps is high, no larger impurity exists in the product, and the purity is high.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
1) Preparation of 3-fluoro-4, 6-dinitroanisole (intermediate 1)
Adding 792g of 98% concentrated sulfuric acid into a 1L reaction bottle, adding 160g of 3-fluoroanisole in batches under stirring, cooling to-10 ℃ to-5 ℃ after stirring uniformly, dropwise adding 183g of concentrated nitric acid (98%) at the temperature of-10 ℃ to-0 ℃ under control, stirring for 10 minutes after dropwise adding, heating to the normal temperature of 20-25 ℃, and stirring for 3 hours. And (3) a dot plate (developing agent: ethyl acetate: petroleum ether=2:1), after the reaction is finished, slowly dripping the system into 1500mL of ice water, controlling the temperature to be less than 20 ℃, and after the dripping is finished, controlling the temperature to be 30-35 ℃ and stirring for 3 hours. Filtering, leaching the filter cake with a small amount of water, and drying to obtain 246.9g of a earthy yellow product. Purity 98.5% and yield 90%.
2) Preparation of 4-fluoro-2-methoxy-5-nitroaniline
Adding 300mL of water into a 1L reaction bottle, adding 60g of 3-fluoro-4, 6-dinitroanisole under stirring, adding 68g of concentrated ammonia water, adding 96.7g of sodium dithionite under stirring in three batches, controlling the temperature to be 45-50 ℃, stirring for three hours, then spotting a plate, (developing agent: ethyl acetate: petroleum ether=2:1), filtering after the reaction is finished, pulping a filter cake with 100g of 3 purified water at 40-50 ℃ for three times, and filtering. Recrystallizing with 500g of methanol, dissolving at 50-55 ℃, crystallizing at 10-15 ℃ for three hours, filtering, and drying to obtain 43.9g of refined product with the yield of 85% and the purity of 99.6%.
Example 2
1) Preparation of 3-fluoro-4, 6-dinitroanisole (intermediate 1)
Adding 792g of 98% concentrated sulfuric acid into a 1L reaction bottle, adding 160g of 3-fluoroanisole in batches under stirring, cooling to-10 ℃ to-5 ℃ after stirring uniformly, dropwise adding 210g of concentrated nitric acid (95%) at-10 ℃ to-0 ℃ under controlled temperature, stirring for 10 minutes after dropwise adding, heating to normal temperature of 20-25 ℃, and stirring for 3 hours. And (3) a dot plate (developing agent: ethyl acetate: petroleum ether=2:1), after the reaction is finished, slowly dripping the system into 1500mL of ice water, controlling the temperature to be less than 20 ℃, and after the dripping is finished, controlling the temperature to be 30-35 ℃ and stirring for 3 hours. Filtering, leaching the filter cake with a small amount of water, and drying to obtain 230g of a earthy yellow product. Purity 97.8% and yield 83.8%.
2) Preparation of 4-fluoro-2-methoxy-5-nitroaniline
Adding 300mL of water into a 1L reaction bottle, adding 60g of 3-fluoro-4, 6-dinitroanisole under stirring, adding 75mL of concentrated ammonia water, adding 96.7g of sodium dithionite under stirring in three batches, controlling the temperature to be 45-50 ℃, stirring for three hours, then spotting a plate, (developing agent: ethyl acetate: petroleum ether=2:1), filtering after the reaction is finished, pulping a filter cake three times with 100g of 3 purified water at 40-50 ℃, and filtering. Recrystallizing with 500g of methanol, dissolving at 50-55 ℃, crystallizing at 10-15 ℃ for three hours, filtering, and drying to obtain 42.3g of refined product with the yield of 82% and the purity of 99.5%.
Example 3
1) Preparation of 3-fluoro-4, 6-dinitroanisole (intermediate 1)
Adding 900g of 95% concentrated sulfuric acid into a 1L reaction bottle, adding 160g of 3-fluoroanisole in batches under stirring, cooling to-10 ℃ to-5 ℃ after stirring uniformly, dropwise adding 280g of concentrated nitric acid (65%) at-10 ℃ to-0 ℃ under controlled temperature, stirring for 10 minutes after dropwise adding, heating to normal temperature of 20-25 ℃, and stirring for 3 hours. And (3) a dot plate (developing agent: ethyl acetate: petroleum ether=2:1), after the reaction is finished, slowly dripping the system into 1500mL of ice water, controlling the temperature to be less than 20 ℃, and after the dripping is finished, controlling the temperature to be 30-35 ℃ and stirring for 3 hours. Filtration gave 216g of a earthy yellow solid with a purity of 97.5% and a yield of 78.7%.
2) Preparation of 4-fluoro-2-methoxy-5-nitroaniline
360mL of water is added into a 1L reaction bottle, 60g of 3-fluoro-4, 6-dinitroanisole is added under stirring, 50g of potassium carbonate is added, 120g of sodium sulfite is added under stirring in three batches, the temperature is controlled to be 45-50 ℃, the stirring is performed for three hours, a plate is arranged after stirring, (developing agent: ethyl acetate: petroleum ether=2:1), the reaction is finished, the filtration is performed, 100g of purified water with the temperature of 40-50 ℃ is used for pulping the filter cake for three times, and the filtration is performed. Recrystallizing with 500g of methanol, dissolving at 50-55 ℃, crystallizing at 10-15 ℃ for three hours, filtering, and drying to obtain 40.8g of refined product with the yield of 79% and the purity of 99.1%.
Example 4
1) Preparation of 3-fluoro-4, 6-dinitroanisole (intermediate 1)
Adding 400mL of 98% concentrated sulfuric acid into a 1L reaction bottle, adding 160g of 3-fluoroanisole in batches under stirring, cooling to-10 ℃ to-5 ℃ after uniform stirring, dropwise adding 183g of concentrated nitric acid (98%) at the temperature of 0-10 ℃ under control, stirring for 10 minutes after dropwise adding, heating to the temperature of 20-25 ℃ under normal temperature, and stirring for 3 hours. And (3) a dot plate (developing agent: ethyl acetate: petroleum ether=2:1), after the reaction is finished, slowly dripping the system into 1500mL of ice water, controlling the temperature to be less than 20 ℃, and after the dripping is finished, controlling the temperature to be 30-35 ℃ and stirring for 3 hours. The mixture was filtered, and the filter cake was rinsed with a small amount of water and dried to give 239g of a dark brown slightly tacky product. Purity 90%, yield 87%.
2) Preparation of 4-fluoro-2-methoxy-5-nitroaniline
Adding 300mL of water into a 1L reaction bottle, adding 60g of 3-fluoro-4, 6-dinitroanisole under stirring, adding 75mL of concentrated ammonia water, adding 108g of sodium thiosulfate under stirring in three batches, controlling the temperature to be 45-50 ℃, stirring for three hours, then spotting a plate, (developing agent: ethyl acetate: petroleum ether=2:1), after the reaction is finished, filtering, pulping a filter cake three times with 100g of 3 purified water at 40-50 ℃, and filtering. Recrystallizing with 500g of methanol, dissolving at 50-55 ℃, crystallizing at 10-15 ℃ for three hours, filtering, and drying to obtain 33g of refined product with the yield of 63.9% and the purity of 98.5%.
Example 5
1) Preparation of 3-fluoro-4, 6-dinitroanisole (intermediate 1)
Adding 400mL of 98% concentrated sulfuric acid into a 1L reaction bottle, adding 160g of 3-fluoroanisole in batches under stirring, cooling to-10 ℃ to-5 ℃ after uniform stirring, dropwise adding 183g of concentrated nitric acid (98%) at the temperature of-10 ℃ to-0 ℃ under control, stirring for 10 minutes after dropwise adding, heating to the normal temperature of 20-25 ℃, and stirring for 3 hours. And (3) a dot plate (developing agent: ethyl acetate: petroleum ether=2:1), after the reaction is finished, slowly dripping the system into 1500mL of ice water, controlling the temperature to be less than 20 ℃, and after the dripping is finished, controlling the temperature to be 30-35 ℃ and stirring for 3 hours. Filtering, leaching the filter cake with a small amount of water, and drying to obtain 246.9g of a earthy yellow product. Purity 98.5% and yield 90%.
2) Preparation of 4-fluoro-2-methoxy-5-nitroaniline
Adding 300mL of water into a 1L reaction bottle, adding 60g of 3-fluoro-4, 6-dinitroanisole under stirring, adding 75mL of concentrated ammonia water, adding 120g of sodium dithionite under stirring in three batches, controlling the temperature to be 45-50 ℃, stirring for three hours, then spotting a plate, (developing agent: ethyl acetate: petroleum ether=2:1), after the reaction is finished, filtering, pulping a filter cake three times with 100g of 3 purified water at 40-50 ℃, and filtering. Recrystallizing with 500g of methanol, dissolving at 50-55 ℃, crystallizing at 10-15 ℃ for three hours, filtering, and drying to obtain 36g of refined product with the yield of 69.7% and the purity of 96%.
The method for synthesizing the oritinib intermediate-4-fluoro-2-methoxy-5-nitroaniline is simple, the reaction flow is short, the initial materials are low in price and easy to obtain in the market, after simple purification, the pure product is obtained, the reaction time is short, the process is simple, the reaction condition is mild, the control is convenient, no organic solvent is used in both steps of reaction, the cost is low, the yield of both steps is high, no larger impurity exists in the product, and the purity is high.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (1)
1. The method for synthesizing the Ornitinib intermediate is characterized by comprising the following steps of:
1) Taking 3-fluoroanisole as a starting material, adding the starting material into concentrated sulfuric acid, dropwise adding concentrated nitric acid in a low-temperature environment, heating and stirring for the first time after the dropwise adding is finished, injecting the system into ice water for quenching, heating and stirring for the second time, and filtering to obtain the 3-fluoro-4, 6-dinitroanisole, wherein the reaction equation is as follows:
2) Adding the compound 3-fluoro-4, 6-dinitroanisole obtained in the first step into water, adding alkali,
heating, adding a weak reducing agent in batches, stirring at a constant temperature to a reaction end point, filtering to obtain a crude product, washing, recrystallizing with methanol, crystallizing at a low temperature, filtering, and drying to obtain 4-fluoro-2-methoxy-5-nitroaniline, wherein the reaction equation is as follows:
the mass ratio range of the 3-fluoroanisole, the concentrated sulfuric acid and the concentrated nitric acid in the step 1) is as follows: 1: (4.8-6.5): (1.1-1.8); the concentration of the concentrated sulfuric acid in the step 1) is 95-98%, and the concentration of the concentrated nitric acid is 95-98%;
dropwise adding concentrated nitric acid in the low-temperature environment in the step 1), wherein the low-temperature environment is-20-10 ℃;
the first heating and stirring in the step 1) is to heat to 20-25 ℃ and stir for 3-5 hours; the second heating and stirring is controlled to be carried out at 30-35 ℃ for 2-3 hours;
after the temperature is raised and stirred in the step 1), controlling the temperature to be 10-20 ℃, and injecting the system into ice water for quenching;
in the step 2), the temperature is raised to 40-50 ℃, and the weak reducing agent is sodium dithionite; the alkali is strong ammonia water; in the step 2), the washing adopts pure water at 40-50 ℃ to stir and wash the product for three times; the low-temperature crystallization is crystallization for three hours at the temperature of 10-15 ℃;
in the step 2), the mass ratio range of the 3-fluoro-4, 6-dinitroanisole, water, alkali and weak reducing agent is as follows: 1: (5-6): (0.8-1.2): (1.6-2.5).
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Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4640707A (en) * | 1984-07-23 | 1987-02-03 | Sumitomo Chemical Company, Ltd. | Tetrahydrophthalimides and their herbicidal use |
| CN103333170A (en) * | 2013-06-14 | 2013-10-02 | 清华大学 | Benzimidazole compound and use thereof |
| CN103998433A (en) * | 2011-12-23 | 2014-08-20 | 巴斯夫欧洲公司 | Process for manufacturing benzoxazinones |
| CN104583186A (en) * | 2012-08-17 | 2015-04-29 | 巴斯夫欧洲公司 | Carbamat-benzoxazinones |
| CN104628572A (en) * | 2015-02-11 | 2015-05-20 | 利尔化学股份有限公司 | Synthetic method of 2-(5-fluoro-2,4-dinitrophenoxy)acetate |
| CN104761544A (en) * | 2014-01-03 | 2015-07-08 | 南京波尔泰药业科技有限公司 | Selectivity inhibitor of EGFR tyrosine kinase clinic important mutant |
| CN104817541A (en) * | 2015-05-11 | 2015-08-05 | 苏州东南药业股份有限公司 | Synthetic method of anti-tumor medicine |
| CN106366022A (en) * | 2016-08-19 | 2017-02-01 | 上海工程技术大学 | Intermediate used for AZD9291 preparation, and preparation method and application thereof |
| CN106883216A (en) * | 2017-04-06 | 2017-06-23 | 张家港威胜生物医药有限公司 | A kind of uncommon preparation method for Buddhist nun difficult to understand |
| CN108623567A (en) * | 2017-03-15 | 2018-10-09 | 上海赛诺克医药科技有限公司 | Ao Si replaces the preparation method of Buddhist nun |
| CN110698461A (en) * | 2018-07-09 | 2020-01-17 | 上海翰森生物医药科技有限公司 | Preparation method of third-generation EGFR inhibitor |
-
2020
- 2020-10-30 CN CN202011186284.XA patent/CN112341346B/en active Active
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4640707A (en) * | 1984-07-23 | 1987-02-03 | Sumitomo Chemical Company, Ltd. | Tetrahydrophthalimides and their herbicidal use |
| CN103998433A (en) * | 2011-12-23 | 2014-08-20 | 巴斯夫欧洲公司 | Process for manufacturing benzoxazinones |
| CN104583186A (en) * | 2012-08-17 | 2015-04-29 | 巴斯夫欧洲公司 | Carbamat-benzoxazinones |
| CN103333170A (en) * | 2013-06-14 | 2013-10-02 | 清华大学 | Benzimidazole compound and use thereof |
| CN104761544A (en) * | 2014-01-03 | 2015-07-08 | 南京波尔泰药业科技有限公司 | Selectivity inhibitor of EGFR tyrosine kinase clinic important mutant |
| CN104628572A (en) * | 2015-02-11 | 2015-05-20 | 利尔化学股份有限公司 | Synthetic method of 2-(5-fluoro-2,4-dinitrophenoxy)acetate |
| CN104817541A (en) * | 2015-05-11 | 2015-08-05 | 苏州东南药业股份有限公司 | Synthetic method of anti-tumor medicine |
| CN106366022A (en) * | 2016-08-19 | 2017-02-01 | 上海工程技术大学 | Intermediate used for AZD9291 preparation, and preparation method and application thereof |
| CN108623567A (en) * | 2017-03-15 | 2018-10-09 | 上海赛诺克医药科技有限公司 | Ao Si replaces the preparation method of Buddhist nun |
| CN106883216A (en) * | 2017-04-06 | 2017-06-23 | 张家港威胜生物医药有限公司 | A kind of uncommon preparation method for Buddhist nun difficult to understand |
| CN110698461A (en) * | 2018-07-09 | 2020-01-17 | 上海翰森生物医药科技有限公司 | Preparation method of third-generation EGFR inhibitor |
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