CN116199569A - Preparation method of antitumor drug Lin Zage key phenol intermediate - Google Patents
Preparation method of antitumor drug Lin Zage key phenol intermediate Download PDFInfo
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 20
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- BNRRMRUVYDETQC-UHFFFAOYSA-N 4-fluoro-2-methoxyaniline Chemical compound COC1=CC(F)=CC=C1N BNRRMRUVYDETQC-UHFFFAOYSA-N 0.000 claims abstract description 40
- 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 18
- 239000002994 raw material Substances 0.000 claims abstract description 11
- OULGLTLTWBZBLO-UHFFFAOYSA-N 4-fluoro-2-methoxyphenol Chemical compound COC1=CC(F)=CC=C1O OULGLTLTWBZBLO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 5
- 238000005979 thermal decomposition reaction Methods 0.000 claims abstract description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 146
- 239000000243 solution Substances 0.000 claims description 92
- 238000001816 cooling Methods 0.000 claims description 76
- 238000006243 chemical reaction Methods 0.000 claims description 42
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 38
- 239000007864 aqueous solution Substances 0.000 claims description 34
- 238000003756 stirring Methods 0.000 claims description 32
- 238000010438 heat treatment Methods 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 239000000543 intermediate Substances 0.000 claims description 20
- 235000010288 sodium nitrite Nutrition 0.000 claims description 19
- 239000011259 mixed solution Substances 0.000 claims description 18
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 17
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 17
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 16
- 238000001514 detection method Methods 0.000 claims description 16
- 238000000605 extraction Methods 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 238000000967 suction filtration Methods 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 3
- BQJTUDIVKSVBDU-UHFFFAOYSA-L copper;sulfuric acid;sulfate Chemical compound [Cu+2].OS(O)(=O)=O.[O-]S([O-])(=O)=O BQJTUDIVKSVBDU-UHFFFAOYSA-L 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 abstract description 16
- 239000003054 catalyst Substances 0.000 abstract description 5
- BMAAMIIYNNPHAB-UHFFFAOYSA-N 3-[5-[(2,3-difluoro-6-methoxyphenyl)methoxy]-2-fluoro-4-methoxyphenyl]-2,4-dioxo-1h-thieno[3,4-d]pyrimidine-5-carboxylic acid Chemical compound COC1=CC(F)=C(N2C(C3=C(C(O)=O)SC=C3NC2=O)=O)C=C1OCC1=C(OC)C=CC(F)=C1F BMAAMIIYNNPHAB-UHFFFAOYSA-N 0.000 abstract description 4
- 229940121296 linzagolix Drugs 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 12
- 238000005406 washing Methods 0.000 description 11
- 206010046798 Uterine leiomyoma Diseases 0.000 description 6
- PNYSELJBPNZNPD-UHFFFAOYSA-N 4-fluoro-2-methoxy-5-nitrophenol Chemical compound COC1=CC(F)=C([N+]([O-])=O)C=C1O PNYSELJBPNZNPD-UHFFFAOYSA-N 0.000 description 5
- 201000010260 leiomyoma Diseases 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 108700012941 GNRH1 Proteins 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- ADJBXDCXYMCCAD-UHFFFAOYSA-N (4-fluoro-2-methoxyphenyl)boronic acid Chemical compound COC1=CC(F)=CC=C1B(O)O ADJBXDCXYMCCAD-UHFFFAOYSA-N 0.000 description 1
- HLTBTUXAMVOKIH-UHFFFAOYSA-N 1-(4-fluoro-2-hydroxyphenyl)ethanone Chemical compound CC(=O)C1=CC=C(F)C=C1O HLTBTUXAMVOKIH-UHFFFAOYSA-N 0.000 description 1
- -1 4-fluoro-2-methoxy-5-nitroaniline sulfate Chemical compound 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 102000008238 LHRH Receptors Human genes 0.000 description 1
- 108010021290 LHRH Receptors Proteins 0.000 description 1
- 201000004458 Myoma Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002474 gonadorelin antagonist Substances 0.000 description 1
- 229940121381 gonadotrophin releasing hormone (gnrh) antagonists Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000004185 hypothalamic-pituitary-gonadal axis Effects 0.000 description 1
- 238000009802 hysterectomy Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal 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
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/20—Diazonium compounds
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of an antitumor drug Lin Zage key phenol intermediate, which takes 4-fluoro-2-methoxyaniline or 4-fluoro-2-methoxy-5-nitroaniline as a raw material, and obtains a target product 4-fluoro-2-methoxyphenol or 4-fluoro-2-methoxy-5-nitroaniline through diazotization reaction and thermal decomposition reaction in a microreactor. In the preparation method of the Linzagolix key phenol intermediate of the antitumor drug, no expensive catalyst or solvent is used, the post-treatment is simple, the product purity is high, and the cost is low; the use of continuous flow greatly improves the safety of diazotization reaction and plays a vital role in commercialization of products.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of an antitumor drug Lin Zage by utilizing key phenol intermediates (4-fluoro-2-methoxyphenol and 4-fluoro-2-methoxy-5-nitrophenol).
Background
Both 4-fluoro-2-methoxyphenol and 4-fluoro-2-methoxy-5-nitrophenol are key phenolic intermediates for the preparation of antitumor drug Lin Zage (Linzagolix). Uterine Fibroids (UF) are common benign tumors of uterine musculature affecting women of childbearing age, and myomas are of unequal size, from which no large mass can be found. Many female patients with hysterectomy are receiving hysteromyoma each year due to few long-term medical procedures. Uterine fibroids have a wide range of symptoms including severe menstrual bleeding, anemia, pelvic pressure and distension, frequent urination and pain, which are extremely debilitating and have a significant impact on quality of life. The new drug Linzagolix is the first and only oral GnRH antagonist that provides flexible dosage regimens, including add-back therapy (ABT) with and without the use of hormones. Linnogolix is a selective non-peptide gonadotrophin releasing hormone (GnRH) receptor antagonist that modulates hypothalamic-pituitary-gonadal axis by competing for inhibition of GnRH receptor binding in endogenous GnRH signaling pituitary glands for use in treating moderate to severe symptoms associated with Uterine Fibroids (UF) in adult women of gestational age (. Gtoreq.18 years).
The preparation method of the linagole phenol intermediates reported in the literature, such as 4-fluoro-2-methoxyphenol, mainly comprises the following steps:
1) 4-fluoro-2-methoxyphenylboronic acid is taken as a starting material, and is subjected to catalytic oxidation to obtain 4-fluoro-2-methoxyphenol (chemistry select 2020,5,2419-2423), wherein the reaction formula is as follows:
the method has the advantages of expensive raw materials, use of a series of relatively expensive catalysts and solvents, no great advantage of yield and inapplicability to commercialization of the product.
2) The 4-fluoro-2-methoxyphenol (J.Am.chem.Soc.2016, 138, 13493-13496) is obtained by catalytic reaction from 5-fluoro-2-anisole as starting material, and has the following reaction formula:
the raw materials of the method are not easily available, a series of relatively expensive catalysts and solvents are also used, and the intermediate has no great process advantage.
3) Patent US 6110956 provides a method for preparing 4-fluoro-2-methoxyphenol from 4-fluoro-2-hydroxyacetophenone by the steps of methyl, oxidation and deprotection, wherein the reaction formula is as follows:
the method has the advantages of difficult acquisition of raw materials, relatively high cost, long operation steps, and unsuitable industrial amplification due to the use of the mCPBA oxidant, and is more unfavorable for commercialization of the intermediate.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides a preparation method of an antitumor drug Lin Zage key phenol intermediate (4-fluoro-2-methoxyphenol and 4-fluoro-2-methoxy-5-nitrophenol) which has the advantages of simple operation, cheap raw materials, easily available catalyst, small reaction pollution and low cost.
The preparation method of the antitumor drug Lin Zage by utilizing key phenol intermediates takes 4-fluoro-2-methoxyaniline or 4-fluoro-2-methoxy-5-nitroaniline as a raw material, and the target product 4-fluoro-2-methoxyphenol or 4-fluoro-2-methoxy-5-nitroaniline is obtained through diazotization reaction and thermal decomposition reaction in a microreactor.
Preferably, the micro-reactor comprises a front-stage precooling device, a cooling pipe reactor and a heating pipe reactor.
Preferably, the preparation method of the antitumor drug Lin Zage by utilizing the key phenol intermediates comprises the following steps:
(1) Adding water, sulfuric acid and 4-fluoro-2-methoxyaniline or 4-fluoro-2-methoxy-5-nitroaniline into a reactor, and uniformly stirring to obtain a sulfuric acid solution of sulfate of 4-fluoro-2-methoxyaniline or 4-fluoro-2-methoxy-5-nitroaniline;
(2) The sulfuric acid solution in the first step enters a micro-reactor, a pre-cooling device in the front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-10 ℃, then the solution enters a cooling pipe reactor, sodium nitrite aqueous solution is introduced into the cooling pipe reactor at a certain speed V1, the temperature is maintained at-5-15 ℃, after the reaction is finished, the mixed solution enters a heating pipe reactor, copper sulfate sulfuric acid solution is introduced at a certain speed V2, the temperature is raised for reaction, the temperature is maintained at 60-110 ℃, and finally, the reaction solution is obtained, and the finished product is obtained through post treatment.
Preferably, in step (1), the ratio of the amount of 4-fluoro-2-methoxyaniline or 4-fluoro-2-methoxy-5-nitroaniline to the amount of sulfuric acid species is 1:2 to 8.
Preferably, in step (2), 4-fluoro-2-methoxyaniline or 4-fluoro-2-methoxy-5-nitroaniline sulfate: sodium nitrite: copper sulfate: the ratio of the amount of sulfuric acid substance is 1: 1-2: 0.14 to 0.3:0.1 to 0.22.
Preferably, in the step (2), the precooling temperature is-5-0 ℃, the cooling tube reactor temperature is maintained at 0-5 ℃, and the heating tube reactor temperature is maintained at 90-100 ℃.
Preferably, in the step (2), the rate V1 is 5.8-11.7 mL/min, and the rate V2 is 3-6 mL/min.
Preferably, in the step (2), when the raw material is 4-fluoro-2-methoxyaniline, liquid separation and rectification are adopted in the post-treatment; when the raw material is 4-fluoro-2-methoxy-5-nitroaniline, suction filtration and recrystallization are adopted for the post-treatment.
Preferably, the preparation method of the antitumor drug Lin Zage by utilizing the key phenol intermediates specifically comprises the following steps:
(1) 444g of water and 296g of sulfuric acid are added into a reactor, 70g of 4-fluoro-2-methoxyaniline is added in batches under stirring, and a sulfuric acid solution of sulfate of the 4-fluoro-2-methoxyaniline is obtained after uniform stirring;
(2) In the first step, sulfuric acid solution enters a micro-reactor, a pre-cooling device at the front section is started for circulation and cooling, solution temperature is detected, the temperature is stabilized at-5-0 ℃, the solution enters a cooling tube reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution is introduced into the cooling tube reactor at the weight ratio of 6mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, the mixed solution enters a heating tube reactor, 4.5mL/min of aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid is introduced into the heating tube reactor, the temperature is maintained at 90-100 ℃, finally reaction solution is obtained, and the finished product is obtained through extraction, separation and rectification.
The invention has the beneficial effects that:
(1) In the preparation method of the Linzagolix key phenol intermediate of the antitumor drug, no expensive catalyst or solvent is used, the post-treatment is simple, the product purity is high, and the cost is low;
(2) The use of continuous flow greatly improves the safety of diazotization reaction and plays a vital role in commercialization of products.
Drawings
FIG. 1 is a schematic flow diagram of a microreactor according to the invention;
FIG. 2 is a nuclear magnetic spectrum of 4-fluoro-2-methoxy-5-nitrophenol prepared in accordance with the present invention.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto. Those skilled in the art can and should appreciate that any simple changes or substitutions based on the true spirit of the invention should fall within the scope of the invention as hereinafter claimed.
The experimental methods described in the examples, unless otherwise specified, are all conventional; the related percentages are mass percentages unless specified otherwise; the reagents and materials, unless otherwise specified, are commercially available.
Example 1
The preparation method of the antitumor drug Lin Zage by utilizing the key phenol intermediates, the device flow is shown in figure 1, and the preparation method specifically comprises the following steps:
(1) 444g of water and 296g of sulfuric acid are added into a 1000mL reactor, 70g of 4-fluoro-2-methoxyaniline are added in portions by stirring, and after the mixture is stirred uniformly by a material mixer, a sulfuric acid solution of sulfate of 4-fluoro-2-methoxyaniline is obtained.
(2) The sulfuric acid solution in the step (1) enters a micro-reactor through a micro-pipeline, a pre-cooling device 1 at the front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-5-0 ℃, the solution enters a cooling pipe reactor 2 at the speed of 30mL/min, 25% sodium nitrite aqueous solution by weight ratio is introduced into the cooling pipe reactor 2 at the speed of 6mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, the mixed solution enters a heating pipe reactor 3, 4.5mL/min of aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid is introduced into the heating pipe reactor, the temperature is maintained at 90-100 ℃, finally, 200g of ethyl acetate is added for extraction, 50mL of aqueous washing is carried out once, the organic phase is separated, the solvent is removed, the product is obtained through reduced pressure rectification, the yield is 52.8g, and the GC purity is 99.6%.
Example 2
444g of water and 198g of sulfuric acid are added into a 1000mL reactor, 70g of 4-fluoro-2-methoxyaniline are added in portions by stirring, and after stirring uniformly, a sulfuric acid solution of the sulfate of 4-fluoro-2-methoxyaniline is obtained.
In the first step, sulfuric acid solution enters a micro-reactor through a micro-pipeline, a pre-cooling device at a front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-5-0 ℃, the solution enters a cooling pipe reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution by weight ratio is introduced into the cooling pipe reactor at the speed of 6mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, mixed solution enters a heating pipe reactor, 4.5mL/min of aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid is introduced into the heating pipe reactor, the temperature is maintained at 90-100 ℃, finally reaction solution is obtained, 200g of ethyl acetate is added for extraction, 50mL of water is used for washing once, organic phase is separated, the solvent is removed, the product is distilled under reduced pressure, the yield is 64.9%, and the GC purity is 99.2%.
Example 3
444g of water and 395g of sulfuric acid are added into a 1000mL reactor, 70g of 4-fluoro-2-methoxyaniline are added in portions by stirring, and after stirring uniformly, a sulfuric acid solution of the sulfate of 4-fluoro-2-methoxyaniline is obtained.
In the first step, sulfuric acid solution enters a micro-reactor through a micro-pipeline, a pre-cooling device at a front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-5-0 ℃, the solution enters a cooling pipe reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution by weight ratio is introduced into the cooling pipe reactor at the speed of 6mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, mixed solution enters a heating pipe reactor, 4.5mL/min of aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid is introduced into the heating pipe reactor, the temperature is maintained at 90-100 ℃, finally reaction solution is obtained, 200g of ethyl acetate is added for extraction, 50mL of water is used for washing once, organic phase is separated, the solvent is removed, the product is distilled under reduced pressure, the yield is 56.2%, and the GC purity is 98.3%.
Example 4
444g of water and 296g of sulfuric acid are added into a 1000mL reactor, 70g of 4-fluoro-2-methoxyaniline are added in portions by stirring, and after stirring uniformly, a sulfuric acid solution of sulfate of 4-fluoro-2-methoxyaniline is obtained.
In the first step, sulfuric acid solution enters a micro-reactor through a micro-pipeline, a pre-cooling device 1 at the front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-10 to-5 ℃, the solution enters a cooling pipe reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution by weight ratio is introduced into the cooling pipe reactor at the speed of 6mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, the mixed solution enters a heating pipe reactor, 4.5mL/min of aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid is introduced into the heating pipe reactor, the temperature is maintained at 90-100 ℃, finally reaction solution is obtained, 200g of ethyl acetate is added for extraction, 50mL of water is used for washing once, organic phase is separated, the solvent is removed, the yield is 71.3% and the GC purity is 99.1%.
Example 5
444g of water and 296g of sulfuric acid are added into a 1000mL reactor, 70g of 4-fluoro-2-methoxyaniline are added in portions by stirring, and after stirring uniformly, a sulfuric acid solution of sulfate of 4-fluoro-2-methoxyaniline is obtained.
In the first step, sulfuric acid solution enters a micro-reactor through a micro-pipeline, a pre-cooling device 1 at the front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-5-0 ℃, the solution enters a cooling pipe reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution by weight ratio is introduced into the cooling pipe reactor at the speed of 6mL/min, the temperature is maintained at 10-15 ℃, after the reaction is finished, mixed solution enters a heating pipe reactor, 4.5mL/min of aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid is introduced into the heating pipe reactor, the temperature is maintained at 90-100 ℃, finally reaction solution is obtained, 200g of ethyl acetate is added for extraction, 50mL of water is used for washing once, organic phase is separated, the solvent is removed, the yield is 65.7% and the GC purity is 98.6% after the rectification under reduced pressure is obtained.
Example 6
444g of water and 296g of sulfuric acid are added into a 1000mL reactor, 70g of 4-fluoro-2-methoxyaniline are added in portions by stirring, and after stirring uniformly, a sulfuric acid solution of sulfate of 4-fluoro-2-methoxyaniline is obtained.
In the first step, sulfuric acid solution enters a micro-reactor through a micro-pipeline, a pre-cooling device at a front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-5-0 ℃, the solution enters a cooling pipe reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution by weight ratio is introduced into the cooling pipe reactor at the speed of 6mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, mixed solution enters a heating pipe reactor, 4.5mL/min of aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid is introduced into the heating pipe reactor, the temperature is maintained at 80-90 ℃, finally reaction solution is obtained, 200g of ethyl acetate is added for extraction, 50mL of water is used for washing once, organic phase is separated, the solvent is removed, the product is distilled under reduced pressure, the yield is 53.3%, and the GC purity is 97.3%.
Example 7
444g of water and 296g of sulfuric acid are added into a 1000mL reactor, 70g of 4-fluoro-2-methoxyaniline are added in portions by stirring, and after stirring uniformly, a sulfuric acid solution of sulfate of 4-fluoro-2-methoxyaniline is obtained.
In the first step, sulfuric acid solution enters a micro-reactor through a micro-pipeline, a pre-cooling device 1 at the front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-5-0 ℃, the solution enters a cooling pipe reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution by weight ratio is introduced into the cooling pipe reactor at the speed of 6mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, mixed solution enters a heating pipe reactor, 4.5mL/min is introduced into an aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid, the temperature is maintained at 100-110 ℃, finally reaction solution is obtained, 200g ethyl acetate is added for extraction, 50mL of water is used for washing once, organic phase is separated, solvent is removed, the rectification is carried out under reduced pressure, the yield is 65%, and GC purity is 99%.
Example 8
444g of water and 296g of sulfuric acid are added into a 1000mL reactor, 70g of 4-fluoro-2-methoxyaniline are added in portions by stirring, and after stirring uniformly, a sulfuric acid solution of sulfate of 4-fluoro-2-methoxyaniline is obtained.
In the first step, sulfuric acid solution enters a micro-reactor through a micro-pipeline, a pre-cooling device 1 at the front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-5-0 ℃, the solution enters a cooling pipe reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution by weight ratio is introduced into the cooling pipe reactor at the speed of 5.8mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, the mixed solution enters a heating pipe reactor, 4.5mL/min is introduced into an aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid, the temperature is maintained at 90-100 ℃, finally, reaction solution is obtained, 200g of ethyl acetate is added for extraction, 50mL of water is used for washing once, organic phase is separated, the solvent is removed, the yield is 72.8% and the GC purity is 99.2%.
Example 9
444g of water and 296g of sulfuric acid are added into a 1000mL reactor, 70g of 4-fluoro-2-methoxyaniline are added in portions by stirring, and after stirring uniformly, a sulfuric acid solution of sulfate of 4-fluoro-2-methoxyaniline is obtained.
In the first step, sulfuric acid solution enters a micro-reactor through a micro-pipeline, a pre-cooling device 1 at the front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-5-0 ℃, the solution enters a cooling pipe reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution by weight ratio is introduced into the cooling pipe reactor at the speed of 8mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, mixed solution enters a heating pipe reactor, 4.5mL/min is introduced into an aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid, the temperature is maintained at 90-100 ℃, finally reaction solution is obtained, 200g ethyl acetate is added for extraction, 50mL of water is used for washing once, organic phase is separated, the solvent is removed, the yield is 37.3% and the GC purity is 86.8%.
Example 10
444g of water and 296g of sulfuric acid are added into a 1000mL reactor, 70g of 4-fluoro-2-methoxyaniline are added in portions by stirring, and after stirring uniformly, a sulfuric acid solution of sulfate of 4-fluoro-2-methoxyaniline is obtained.
In the first step, sulfuric acid solution enters a micro-reactor through a micro-pipeline, a pre-cooling device 1 at the front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-5-0 ℃, the solution enters a cooling pipe reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution by weight ratio is introduced into the cooling pipe reactor at the speed of 6mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, mixed solution enters a heating pipe reactor, 3mL/min is introduced into an aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid, the temperature is maintained at 90-100 ℃, finally, reaction solution is obtained, 200g ethyl acetate is added for extraction, extraction is carried out, 50mL water is washed once, organic phase is separated, solvent is removed, the product is decompressed and rectified, the yield is 65.4%, and GC purity is 98.8%.
Example 11
444g of water and 296g of sulfuric acid are added into a 1000mL reactor, 70g of 4-fluoro-2-methoxyaniline are added in portions by stirring, and after stirring uniformly, a sulfuric acid solution of sulfate of 4-fluoro-2-methoxyaniline is obtained.
In the first step, sulfuric acid solution enters a micro-reactor through a micro-pipeline, a pre-cooling device 1 at the front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-5-0 ℃, the solution enters a cooling pipe reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution by weight ratio is introduced into the cooling pipe reactor at the speed of 6mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, mixed solution enters a heating pipe reactor, 5.5mL/min is introduced into an aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid, the temperature is maintained at 90-100 ℃, finally reaction solution is obtained, 200g ethyl acetate is added for extraction, 50mL of water is used for washing once, organic phase is separated, the solvent is removed, the product is distilled under reduced pressure, the yield is 71.8%, and the GC purity is 99.6%.
Example 12
2220g of water, 1480g of sulfuric acid and 350g of 4-fluoro-2-methoxyaniline were added to a 5000mL reactor with stirring, and after stirring uniformly, a sulfuric acid solution of the sulfate salt of 4-fluoro-2-methoxyaniline was obtained.
In the first step, sulfuric acid solution enters a micro-reactor through a micro-pipeline, a pre-cooling device 1 at the front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-5-0 ℃, the solution enters a cooling pipe reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution by weight ratio is introduced into the cooling pipe reactor at the speed of 6mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, mixed solution enters a heating pipe reactor, 4.5mL/min is introduced into an aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid, the temperature is maintained at 90-100 ℃, finally reaction solution is obtained, 1000g of ethyl acetate is added for extraction, 250mL of water is used for washing once, organic phase is separated, the solvent is removed, the product 263.5g is obtained through rectification under reduced pressure, the yield is 74.7%, and the GC purity is 99.6%.
Example 13
444g of water and 296g of sulfuric acid are added into a 1000mL reactor, 92.3g of 4-fluoro-2-methoxy-5-nitroaniline are added in portions by stirring, and after stirring uniformly, a sulfuric acid solution of sulfate of 4-fluoro-2-methoxy-5-nitroaniline is obtained.
The sulfuric acid solution enters a micro-reactor through a micro-pipeline, a pre-cooling device 1 at the front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-5-0 ℃, the solution enters a cooling pipe reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution is introduced into the cooling pipe reactor at the weight ratio of 6mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, the mixed solution enters a heating pipe reactor, 4.5mL/min is introduced into an aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid, the temperature is maintained at 90-100 ℃, finally, the reaction solution is cooled to 5-10 ℃, suction filtration is carried out, 150g ethanol is added into the solid for recrystallization, suction filtration is carried out, the finished product is obtained after the drying, the yield is 73.2%, and the HPLC purity is 99.7%; the nuclear magnetic spectrum of the prepared 4-fluoro-2-methoxy-5-nitrophenol is shown in figure 2.
Example 14
2220g of water, 1480g of sulfuric acid and 461.5g of 4-fluoro-2-methoxy-5-nitroaniline are added in portions to a 5000mL reactor, and after stirring uniformly, a sulfuric acid solution of the sulfate salt of 4-fluoro-2-methoxy-5-nitroaniline is obtained.
In the first step, sulfuric acid solution enters a micro-reactor through a micro-pipeline, a pre-cooling device 1 at the front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-5-0 ℃, the solution enters a cooling pipe reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution by weight ratio is introduced into the cooling pipe reactor at the speed of 6mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, the mixed solution enters a heating pipe reactor, 4.5mL/min is introduced into an aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid, the temperature is maintained at 90-100 ℃, finally, reaction solution is obtained, the reaction solution is cooled to 5-10 ℃, suction filtration is carried out, 750g of ethanol is added into the solid, the solid is recrystallized, suction filtration is carried out, the finished product is obtained at 336.7g, the yield is 72.6%, and the HPLC purity is 99.7%.
Finally, it should be noted that the above list is merely a few specific embodiments of the present invention. Obviously, the invention is not limited to the above embodiments, but many variations are possible. All modifications directly derived or suggested to one skilled in the art from the present disclosure should be considered as being within the scope of the present invention.
Claims (8)
1. The preparation method of the antitumor drug Lin Zage key phenol intermediates is characterized by comprising the following steps of: 4-fluoro-2-methoxy aniline or 4-fluoro-2-methoxy-5-nitroaniline is used as a raw material, and target products 4-fluoro-2-methoxy phenol or 4-fluoro-2-methoxy-5-nitroaniline are obtained through diazotization reaction and thermal decomposition reaction in a microreactor.
2. The method for preparing the antitumor drug Lin Zage by using the key phenol intermediate according to claim 1, which is characterized in that: the micro-reactor comprises a front-stage precooling device, a cooling pipe reactor and a heating pipe reactor.
3. The method for preparing the antitumor drug Lin Zage by using the key phenol intermediate according to claim 1 or 2, which is characterized by comprising the following steps:
(1) Adding water, sulfuric acid and 4-fluoro-2-methoxyaniline or 4-fluoro-2-methoxy-5-nitroaniline into a reactor, and uniformly stirring to obtain a sulfuric acid solution of sulfate of 4-fluoro-2-methoxyaniline or 4-fluoro-2-methoxy-5-nitroaniline;
(2) The sulfuric acid solution in the step (1) enters a micro-reactor, a pre-cooling device at a front section is started for circulation and cooling, solution temperature detection is carried out, the temperature is stabilized at-10 ℃, then the solution enters a cooling pipe reactor, sodium nitrite aqueous solution is introduced into the cooling pipe reactor at a certain speed V1, the temperature is maintained at-5-15 ℃, after the reaction is finished, the mixed solution enters a heating pipe reactor, copper sulfate sulfuric acid solution is introduced at a certain speed V2, the temperature is raised for reaction, the temperature is maintained at 60-110 ℃, and finally, the reaction solution is obtained, and the finished product is obtained after the post treatment.
4. The method for preparing the antitumor drug Lin Zage by using the key phenol intermediate according to claim 1, which is characterized in that: in step (1), the ratio of the amount of 4-fluoro-2-methoxyaniline or 4-fluoro-2-methoxy-5-nitroaniline to the amount of sulfuric acid species is 1:2 to 8.
5. The method for preparing the antitumor drug Lin Zage by using the key phenol intermediate according to claim 1, which is characterized in that: in the step (2), the precooling temperature is-5-0 ℃, the cooling tube reactor temperature is maintained at 0-5 ℃, and the heating tube reactor temperature is maintained at 90-100 ℃.
6. The method for preparing the antitumor drug Lin Zage by using the key phenol intermediate according to claim 1, which is characterized in that: in the step (2), the speed V1 is 5.8-11.7 mL/min, and the speed V2 is 3-6 mL/min.
7. The method for preparing the antitumor drug Lin Zage by using the key phenol intermediate according to claim 1, which is characterized in that: in the step (2), when the raw material is 4-fluoro-2-methoxyaniline, liquid separation and rectification are adopted in the post-treatment; when the raw material is 4-fluoro-2-methoxy-5-nitroaniline, suction filtration and recrystallization are adopted for the post-treatment.
8. The method for preparing the antitumor drug Lin Zage by using the key phenol intermediate according to claim 3, which is characterized by comprising the following steps:
(1) 444g of water and 296g of sulfuric acid are added into a reactor, 70g of 4-fluoro-2-methoxyaniline is added in batches under stirring, and a sulfuric acid solution of sulfate of the 4-fluoro-2-methoxyaniline is obtained after uniform stirring;
(2) In the first step, sulfuric acid solution enters a micro-reactor, a pre-cooling device at the front section is started for circulation and cooling, solution temperature is detected, the temperature is stabilized at-5-0 ℃, the solution enters a cooling tube reactor at the speed of 30mL/min, 25% sodium nitrite aqueous solution is introduced into the cooling tube reactor at the weight ratio of 6mL/min, the temperature is maintained at 0-5 ℃, after the reaction is finished, the mixed solution enters a heating tube reactor, 4.5mL/min of aqueous solution containing 16.3% copper sulfate and 7.6% sulfuric acid is introduced into the heating tube reactor, the temperature is maintained at 90-100 ℃, finally reaction solution is obtained, and the finished product is obtained through extraction, separation and rectification.
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| CN108601781A (en) * | 2016-02-04 | 2018-09-28 | 广州必贝特医药技术有限公司 | As the 3,5- disubstituted pyrazoles of test point kinases 1 (CHK1) inhibitor and its preparation and application |
| CN109354570A (en) * | 2018-11-27 | 2019-02-19 | 常州大学 | A kind of preparation method of 2,4,5- trichlorophenol, 2,4,6,-T |
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