CN115322105A - Method for synthesizing Iguratimod key intermediate - Google Patents
Method for synthesizing Iguratimod key intermediate Download PDFInfo
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- CN115322105A CN115322105A CN202110508388.6A CN202110508388A CN115322105A CN 115322105 A CN115322105 A CN 115322105A CN 202110508388 A CN202110508388 A CN 202110508388A CN 115322105 A CN115322105 A CN 115322105A
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- Prior art keywords
- iguratimod
- phenoxyanisole
- key intermediate
- reaction
- ammonium formate
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- 238000000034 method Methods 0.000 title claims abstract description 30
- ANMATWQYLIFGOK-UHFFFAOYSA-N Iguratimod Chemical compound CS(=O)(=O)NC1=CC=2OC=C(NC=O)C(=O)C=2C=C1OC1=CC=CC=C1 ANMATWQYLIFGOK-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229950003909 iguratimod Drugs 0.000 title claims abstract description 17
- 230000002194 synthesizing effect Effects 0.000 title claims description 6
- UOGZDMKXQVZVGO-UHFFFAOYSA-N 5-methoxy-2-phenoxyaniline Chemical compound NC1=CC(OC)=CC=C1OC1=CC=CC=C1 UOGZDMKXQVZVGO-UHFFFAOYSA-N 0.000 claims abstract description 21
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims abstract description 21
- QVCYQPIZAWIRIP-UHFFFAOYSA-N 4-methoxy-2-nitro-1-phenoxybenzene Chemical compound [O-][N+](=O)C1=CC(OC)=CC=C1OC1=CC=CC=C1 QVCYQPIZAWIRIP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims abstract description 11
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000006722 reduction reaction Methods 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 abstract description 4
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 238000011946 reduction process Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 10
- 239000002994 raw material Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
- 230000001502 supplementing effect Effects 0.000 description 4
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- -1 formamido Chemical group 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- ILFDRUFFPZTDRV-UHFFFAOYSA-N C1=CC(=C(C=C1COCC2=CC(=C(C=C2)Cl)[N+](=O)[O-])[N+](=O)[O-])Cl Chemical compound C1=CC(=C(C=C1COCC2=CC(=C(C=C2)Cl)[N+](=O)[O-])[N+](=O)[O-])Cl ILFDRUFFPZTDRV-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Images
Classifications
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- 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
-
- 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
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a preparation method of a key intermediate 3-amino-4-phenoxyanisole of Iguratimod, and the chemical reaction formula of the method is shown as follows. Reducing 3-nitro-4-phenoxyanisole (2) into 3-amino-4-phenoxyanisole (1) by taking ammonium formate as a hydrogen source and palladium hydroxide carbon as a catalyst. The structure of the target product is subjected to HPLC, 1 H-NMR and MS etc. The improved reduction process avoids special hydrogenation and pressurization reaction, reduces safety risk and production cost, and has high commercial value.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a synthetic method of a key intermediate 3-amino-4-phenoxyanisole of iguratimod.
Background
Iguratimod, chemical name of N- [3- (formamido) -4-oxygen-6-phenoxy-4H-1-benzopyran-7-yl ] -methane sulfonamide, is a novel non-steroidal anti-inflammatory drug for selectively inhibiting cyclooxygenase-2 (COX-2), and has antipyretic, analgesic, anti-arthritis and immunoregulatory effects.
The synthesis route of iguratimod is mainly 3, wherein the route is shortest and the process is relatively mature, and the synthesis route reported by Inaba T et al in chem. Pharm. Bull: 4-chloro-3-nitrobenzyl ether is taken as a raw material, and subjected to condensation, nitro reduction, mesylation, gattmann-Koch, formylation, methoxy hydrolysis and cyclization for 7 steps to finally prepare the Iguratimod.
The nitro reduction reaction in the route has been reported in 3 methods, specifically as follows:
(1) Iron powder reduction: reducing the compound (2) into the compound (1) in hydrochloric acid by taking iron powder as a reducing agent, wherein the yield is 83%; the method is easy to generate a large amount of iron oxide mud, contains aromatic primary amine, is difficult to recover and treat and pollutes the environment.
(2) And (3) hydrogenation reduction: indian patent 1507/MUM/2014 discloses that hydrogen is introduced into a reaction system under the pressure condition by taking nickel as a catalyst to obtain a compound (1), and the yield is 97%; the process is a special process, a hydrogenation reaction kettle is needed for realizing commercial production, and the investment and safety risk of production cost are increased to a certain extent.
Reduction of hydrazine hydrate: CN107021891A discloses that ferric trichloride is used as a catalyst, hydrazine hydrate is used to complete reduction reaction, and the yield is 68%; the method has low yield, and hydrazine hydrate has genotoxicity, so that the method is not suitable for drug production.
Disclosure of Invention
The invention aims to solve the problems in the prior art and find a process which is green, safe, high in yield and suitable for industrial production. The method takes 3-nitro-4-phenoxyanisole (2) as a raw material and ammonium formate (3) as a hydrogen source, and prepares the 3-amino-4-phenoxyanisole (1) under the catalytic condition of palladium hydroxide carbon.
The chemical reaction formula is as follows:
the invention adopts the following technical scheme:
the method comprises the following steps: adding 3-nitro-4-phenoxyanisole (2) into a solvent, and carrying out reduction reaction with ammonium formate (3) under the catalysis of palladium hydroxide carbon to obtain a compound (1), 3-amino-4-phenoxyanisole;
2. process for the synthesis of key intermediate (1) in iguratimod according to claim 1, characterized in that the molar ratio of formula (2) to ammonium formate (3) in step (i) is 1.5 to 3.0, more preferably 1.
3. The process for synthesizing key intermediate (1) in iguratimod according to claim 1, wherein the reaction solvent in step (a) is at least one of ethanol, isopropanol, and acetonitrile, and more preferably ethanol.
4. The process for the synthesis of key intermediate (1) in iguratimod according to claim 1, wherein the weight ratio of formula (2) to palladium hydroxide on carbon in step (i) is 1: 5% -10%, more preferably 1.
5. The process for the synthesis of key intermediate (1) in iguratimod according to claim 1, characterized in that the reaction temperature in step is comprised between 60 ℃ and 85 ℃, more preferably 85 ℃; the reaction time is 4 to 6 hours, more preferably 4 hours.
Compared with the prior art, the method has the following technical advantages:
(1) The method accords with the concept of green process, the product has high purity, almost no inorganic salt and no generation of solid waste which is difficult to treat;
(2) The invention abandons high-pressure equipment such as a hydrogenation kettle and the like, and reduces the requirements of the process on the equipment;
(3) The quality of the medicine is met by the design principle, and a genotoxic reagent hydrazine hydrate is not used.
Drawings
In order to more clearly illustrate the embodiments of the present invention, the drawings that are required to be used in the description of the embodiments will be briefly described below.
3-amino-4-phenoxyanisole (1) prepared in inventive example 1: FIG. 1 is an HPLC chromatogramFIG. 2 is 1 H-NMR spectrum, and FIG. 3 is MS spectrum.
Detailed Description
The new preparation method of the 3-amino-4-phenoxyanisole (1) comprises the following steps:
example 1
Adding 25.00 g of 3-nitro-4-phenoxyanisole (2) (1.0 eq) into a 100mL three-necked flask, adding 65mL of ethanol, stirring for dissolving, sequentially adding 9.64 g of ammonium formate (1.5 eq) and 2.50 g of palladium hydroxide carbon (10%), heating and stirring, supplementing 9.64 g of ammonium formate after the reaction is stable, continuously refluxing for 4h, and monitoring the reaction endpoint of the raw materials by TLC. Filtering to obtain filtrate, cooling to 10-20 ℃, separating out a large amount of solids, and carrying out suction filtration to dryness to obtain the compound (1) (20.98 g, 95.6%) with the purity of 99.4%. 1 H-NMR（500 MHz, DMSO-d6）δ：3.68(3H, s), 4.90(2H, s), 6.13～6.16 (1H, dd), 6.40 (1H, d), 6.74～6.76 (1H, d), 6.85～6.87 (2H, d), 6.98～7.01 (1H, t), 7.27～7.31 (2H, t)；ESI-MS m/z：215.9 [M+H] + 。
Example 2
Adding 25.00 g of 3-nitro-4-phenoxyanisole (2) (1.0 eq) into a 100mL three-necked flask, adding 65mL of ethanol, stirring for dissolving, sequentially adding 9.64 g of ammonium formate (1.5 eq) and 2.50 g of palladium hydroxide carbon (10%), heating, stirring for refluxing, keeping the temperature for 4 hours, monitoring by TLC, filtering to obtain a filtrate, cooling to 10-20 ℃, precipitating a large amount of solid, and performing suction filtration to dryness to obtain a compound (1) (18.32 g, 83.5%).
Examples 1-2, the results of which are shown in Table 1.
Table 1: molar ratio of Compound (2) to ammonium Formate (3)
Example 3
Adding 25.00 g of 3-nitro-4-phenoxyanisole (2) (1.0 eq) into a 250 mL three-necked bottle, adding 80 mL of isopropanol, stirring for dissolving, sequentially adding 9.64 g of ammonium formate (1.5 eq) and 2.50 g of palladium hydroxide carbon (10%), heating and stirring until the reaction is stable, supplementing 9.64 g of ammonium formate, continuously refluxing for 4h, and monitoring the reaction endpoint of the raw materials by TLC. After filtration, the filtrate was cooled to 10 to 20 ℃ to precipitate a large amount of solid, which was then suction-filtered to dryness to obtain Compound (1) (20.12g, 91.7%).
Example 4
Adding 25.00 g of 3-nitro-4-phenoxyanisole (2) (1.0 eq) into a 250 mL three-necked flask, adding 100mL of acetonitrile, stirring for dissolving, sequentially adding 9.64 g of ammonium formate (1.5 eq) and 2.50 g of palladium hydroxide carbon (10%), heating and stirring until the reaction is stable, supplementing 9.64 g of ammonium formate, continuously refluxing for 4h, and monitoring the reaction end point of the raw materials by TLC. After filtration, the filtrate was cooled to 10 to 20 ℃ and a large amount of solid precipitated and was suction filtered to dryness to obtain compound (1) (19.40 g, 88.4%).
Examples 3-4, results of the experiments are given in Table 2.
Table 2: screening of solvents
Example 5
Adding 25.00 g of 3-nitro-4-phenoxyanisole (2) (1.0 eq) into a 100mL three-necked flask, adding 65mL of ethanol, stirring for dissolving, sequentially adding 9.64 g of ammonium formate (1.5 eq) and 1.25 g of palladium hydroxide carbon (5%), heating and stirring until the reaction is stable, supplementing 9.64 g of ammonium formate, continuously refluxing for 6h, and monitoring the end point of the raw material reaction by TLC. After filtration, the filtrate was cooled to 10-20 ℃ and a large amount of solid precipitated and was suction filtered to dryness to give compound (1) (19.20 g, 87.5%).
The results of the experiments are shown in Table 3.
Table 3: catalyst inventory screening
The method for synthesizing the key intermediate 3-amino-4-phenoxyanisole (1) of iguratimod provided by the invention is described in detail above. The embodiments and preferred conditions of the invention are explained herein using specific examples, which are described to help understand the method and core concept of the invention.
Claims (5)
1. A method for synthesizing a key intermediate (1) of Iguratimod is characterized in that the reaction equation is as follows:
the method comprises the following specific steps:
the method comprises the following steps: adding 3-nitro-4-phenoxyanisole (2) into a solvent, and carrying out reduction reaction with ammonium formate (3) under the catalysis of palladium hydroxide carbon to obtain a compound (1), 3-amino-4-phenoxyanisole.
2. Process for the synthesis of key intermediate (1) in iguratimod according to claim 1, characterized in that the molar ratio of formula (2) to ammonium formate (3) in step (i) is 1.5 to 3.0, more preferably 1.
3. The process for synthesizing key intermediate (1) in iguratimod according to claim 1, wherein the reaction solvent in step (a) is at least one of ethanol, isopropanol, and acetonitrile, and more preferably ethanol.
4. The process for the synthesis of key intermediate (1) in iguratimod according to claim 1, wherein the weight ratio of formula (2) to palladium hydroxide on carbon in step (i) is 1: 5% -10%, more preferably 1.
5. The process for the synthesis of key intermediate (1) in iguratimod according to claim 1, characterized in that the reaction temperature in step is comprised between 60 ℃ and 85 ℃, more preferably 85 ℃; the reaction time is 4 to 6 hours, more preferably 4 hours.
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2021
- 2021-05-11 CN CN202110508388.6A patent/CN115322105A/en active Pending
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| WO2001062736A1 (en) * | 2000-02-25 | 2001-08-30 | Pfizer Products Inc. | Aryl fused azapolycyclic compounds |
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