CN115433117A - Roebecoxib intermediate and synthesis method of Roebecoxib - Google Patents
Roebecoxib intermediate and synthesis method of Roebecoxib Download PDFInfo
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- CN115433117A CN115433117A CN202210772928.6A CN202210772928A CN115433117A CN 115433117 A CN115433117 A CN 115433117A CN 202210772928 A CN202210772928 A CN 202210772928A CN 115433117 A CN115433117 A CN 115433117A
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- HFFLGKNGCAIQMO-UHFFFAOYSA-N trichloroacetaldehyde Chemical compound ClC(Cl)(Cl)C=O HFFLGKNGCAIQMO-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002994 raw material Substances 0.000 claims abstract description 18
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000297 Sandmeyer reaction Methods 0.000 claims abstract description 10
- 239000000126 substance Substances 0.000 claims abstract description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 51
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 32
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 17
- 238000000967 suction filtration Methods 0.000 claims description 16
- 238000001291 vacuum drying Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 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 claims description 11
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 11
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical group Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 claims description 7
- 229960002327 chloral hydrate Drugs 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 229940029273 trichloroacetaldehyde Drugs 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims 2
- 238000001035 drying Methods 0.000 claims 1
- NXPHCVPFHOVZBC-UHFFFAOYSA-N hydroxylamine;sulfuric acid Chemical compound ON.OS(O)(=O)=O NXPHCVPFHOVZBC-UHFFFAOYSA-N 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000002085 irritant Substances 0.000 abstract description 3
- 231100000021 irritant Toxicity 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- -1 5-ethyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione Chemical compound 0.000 description 63
- 239000000543 intermediate Substances 0.000 description 38
- 238000003756 stirring Methods 0.000 description 32
- 239000000243 solution Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000001816 cooling Methods 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 8
- ZEXGDYFACFXQPF-UHFFFAOYSA-N robenacoxib Chemical compound OC(=O)CC1=CC(CC)=CC=C1NC1=C(F)C(F)=CC(F)=C1F ZEXGDYFACFXQPF-UHFFFAOYSA-N 0.000 description 8
- FMBNMGDVELSOJQ-UHFFFAOYSA-N n-(4-ethylphenyl)-2,3,5,6-tetrafluoroaniline Chemical compound C1=CC(CC)=CC=C1NC1=C(F)C(F)=CC(F)=C1F FMBNMGDVELSOJQ-UHFFFAOYSA-N 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 238000004321 preservation Methods 0.000 description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 description 3
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 3
- DZTYHNMGAJRMOV-UHFFFAOYSA-N 5-ethyl-1-(2,3,5,6-tetrafluorophenyl)-3h-indol-2-one Chemical compound O=C1CC2=CC(CC)=CC=C2N1C1=C(F)C(F)=CC(F)=C1F DZTYHNMGAJRMOV-UHFFFAOYSA-N 0.000 description 3
- 238000007171 acid catalysis Methods 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 229960000205 robenacoxib Drugs 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthesis method of a robecoxib intermediate, which comprises the following steps
The raw material is subjected to sandmeyer reaction with chloral and hydroxylamine to obtain the intermediate of the robekoxib; the chemical formula of the intermediate of the robecoxib is as follows:
Description
Technical Field
The invention belongs to the technical field of drug synthesis, relates to a synthetic method of a non-steroidal anti-inflammatory drug, and particularly relates to a synthetic method of a robecoxib intermediate and robecoxib.
Background
Robecoxib (CAS number: 220991-32-2, english name: robenacoxib), also known as 2- (5-ethyl-2- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) acetic acid, is a novel non-steroidal anti-inflammatory drug, has various excellent properties, including rapid onset of action, and can be used for injections, oral preparations, and inflammation, pain and body temperature rise of cats and dogs. Compared with non-selective non-steroidal anti-inflammatory drugs, the compound has high selectivity on COX-2 inhibition, and has quick effect and higher safety in the blood-brain barrier of cats and dogs.
The existing synthesis method of the robecoxib has long steps, uses a large amount of Lewis acid catalysts, has large pollution and low yield, and simultaneously requires anhydrous conditions in the reaction process, thereby bringing certain difficulties to the safety and the convenience of operation in the industrial production process.
There are two main routes reported in the literature for the synthesis of robesicoxib:
the first synthetic route, for example, the chinese patent application discloses a method for preparing an acid (publication No. CN 109694330A), which comprises the steps of performing two acylation reactions on N- (4-ethylphenyl) -2,3,5, 6-tetrafluoroaniline as a raw material and oxalyl chloride to obtain an intermediate 5-ethyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione, and performing two reactions of hydrolysis and reduction to obtain robucoside, wherein the reaction requires 4 steps. The reaction equation is as follows:
The second synthetic route, for example, the chinese patent with publication number CN1140500C, the chinese patent application with publication number CN112679410A, the chinese patent application with publication number CN109503399B, the chinese patent application with publication number CN102311355B and the chinese patent application with publication number CN107721901A, uses N- (4-ethylphenyl) -2,3,5,6-tetrafluoroaniline as a raw material to perform two acylation reactions with chloroacetyl chloride to obtain an intermediate 5-ethyl-1- (2,3,5,6-tetrafluorophenyl) indolin-2-one, and then performs a hydrolysis reaction to obtain robucoside. The reaction equation is as follows:
For another example, chinese patent application publication No. CN111807978A provides a preparation method of robecoxib, in which synthesis of an intermediate 5-ethyl-1- (2,3,5,6-tetrafluorophenyl) indolin-2-one takes indolinone as a raw material, and is obtained by acylation, reduction, and N-alkylation, and 5-ethyl-1- (2,3,5,6-tetrafluorophenyl) indolin-2-one is further hydrolyzed to obtain robecoxib. Compared with the method, the method only has different synthesis modes of intermediates, but still uses a large amount of aluminum trichloride, has special reduction reagent during reduction reaction, requires anhydrous conditions for reaction, and has harsh conditions.
Therefore, a method for synthesizing the robecoxib which is easy to industrially produce is needed.
Disclosure of Invention
The invention aims to solve the problems and provides a robesib intermediate and a synthesis method of robesib.
The invention creatively provides a synthetic method of a Roebixib intermediate, which comprises the following steps
Is prepared from trichloroacetaldehyde and hydroxylamine through proportional mixingThe sandmeyer reaction is used for synthesizing and obtaining the intermediate of the robecoxib; the chemical formula of the intermediate of the robecoxib is as follows:
The invention adopts the sandmeyer reaction to prepare the intermediate of the Roebricoxib, does not use toxic and irritant raw materials such as aluminum trichloride and the like in the whole reaction process, does not require anhydrous conditions, has the advantages of less pollution and easy production, has low requirements on reaction conditions, and can obviously reduce the industrial production cost.
Further, the sandmeyer reaction comprises:
a. the raw materials, trichloroacetaldehyde and hydroxylamine are subjected to a first-step reaction under an acidic condition to obtain a primary intermediate, and the reaction equation is as follows:
b. and then carrying out a second-step reaction under acid catalysis to obtain a Roebecoxib intermediate, wherein the reaction equation is as follows:
namely, the raw material is 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethan-1-one or N- (4-ethylphenyl) -2,3,5, 6-tetrafluoroaniline; the primary intermediate is N- (4-acetylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide or N- (4-ethylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide; the intermediate of the robuximab is 5-acetyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione or 5-ethyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione.
In the synthesis method of the intermediate of the Roebeckib, in the step a, the molar ratio of the raw material, the chloral and the hydroxylamine is 0.66-1.
In the synthesis method of the intermediate of the Robecoxib, the chloral is chloral hydrate or anhydrous chloral, and the hydroxylamine is hydroxylamine hydrochloride or hydroxylamine sulfate.
In the above synthesis method of the intermediate of robecoxib, step a specifically includes: adding water and raw materials into a first container, and adding a hydrochloric acid solution or a sulfuric acid solution while stirring to provide an acidic condition for later use;
adding water and anhydrous sodium sulfate into a second container, heating to 70-80 ℃, adding trichloroacetaldehyde, stirring, keeping the temperature for 0.5 hour, adding the mixture in the first container into the second container, adding hydroxylamine, heating to 80-85 ℃, reacting for 2 hours, cooling to 20 ℃, performing suction filtration, washing for 2 times, and performing vacuum drying to obtain a primary intermediate.
In the synthesis method of the robecoxib intermediate, in the step b, 90-98% of sulfuric acid solution or polyphosphoric acid is adopted for the acid catalysis reaction, and the dosage of the 90-98% of sulfuric acid solution or polyphosphoric acid is 2.5-5 times of that of the primary intermediate; the reaction temperature is 50-230 ℃, the temperature is kept for reaction, then the reaction product is cooled to room temperature, washed by water and dried in vacuum to obtain the intermediate of Roebixib.
Preferably, the amount of the 90% -98% sulfuric acid solution or polyphosphoric acid is 2.85-3.8 times of the amount of the primary intermediate.
In the synthesis method of the intermediate of the robekoxib, the step b is specifically as follows: adding 90-98% sulfuric acid solution or polyphosphoric acid and a primary intermediate into a third container, slowly heating to 50-230 ℃ under stirring, and reacting for 2 hours in a heat preservation way; and cooling the reaction solution to room temperature, adding water, stirring for 30min, performing suction filtration, washing with water, and performing vacuum drying to obtain the intermediate of the Roebricoxib.
The invention also provides a synthesis method of the Robecoxib, which comprises the following steps:
1) Preparing a robesite intermediate using the synthesis method of the robesite intermediate of claims 1-6;
2) And reducing the intermediate of the robecoxib to obtain the robecoxib.
Preferably, in one of the above methods for the synthesis of rofecoxib,
the chemical formula of the intermediate of the robuximab is as follows:
namely R is acetyl and the raw material is 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethane-1-ketone.
Then, in the synthesis method of the robecoxib, in the step 1), 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethane-1-ketone, chloral and hydroxylamine are subjected to sandmeyer reaction to obtain 5-acetyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-diketone;
in the step 2), the 5-acetyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-diketone is reduced and then regulated to be acid to obtain the robecoxib.
Thus, in the reduction process, the reduction of the carbonyl on the acetyl of the robesib intermediate and the reduction of the carbonyl on the 2, 3-position of indoline are completed in one step, so that the invention can directly adopt 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethane-1-ketone as a raw material, omit the step of reducing the 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethane-1-ketone into N- (4-ethylphenyl) -2,3,5, 6-tetrafluoroaniline, and improve the total yield of the robesib (the yield can reach 95%).
Further, the synthesis method of the robecoxib comprises the following steps:
1) Synthesis of intermediate of robecoxib
Reacting 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethane-1-ketone with chloral and hydroxylamine under an acidic condition to obtain N- (4-acetylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide, wherein the reaction equation is as follows:
reacting N- (4-acetylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide at a certain temperature by acid catalysis to obtain 5-acetyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-diketone, wherein the reaction equation is as follows:
2) Synthesis of Robecoxib
Reducing 5-acetyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-diketone by hydrazine hydrate under alkaline condition, and then adjusting acid to obtain the robecoxib, wherein the reaction equation is as follows:
in the synthesis method of the Roebeckib, in the step 2), the Roebeckib intermediate and diethylene glycol are subjected to hydrazine hydrate heating distillation to remove water under an alkaline condition, the reaction is carried out under a heat preservation condition, then the reaction product is cooled to room temperature, the pH value is adjusted to 2.9-3.1, and the Roebeckib is obtained through stirring, suction filtration, water washing and vacuum drying.
Further, 300 to 550mL of diethylene glycol and 35 to 70g of 85% hydrazine hydrate are added to each 100g of the intermediate of Roebesib for reaction. Further, the alkaline condition in the step 3) means that the pH is 12 to 14.
In the synthesis method of the robecoxib, the step 2) is specifically as follows: adding diethylene glycol, the robecoxib intermediate, alkali and 85% hydrazine hydrate into a fourth container, heating while stirring, distilling to remove water until the reaction temperature is 200 ℃, and carrying out heat preservation reaction for 4 hours; and cooling the reaction liquid to room temperature, adding water, regulating the pH value to 3 by using a hydrochloric acid solution or a sulfuric acid solution, stirring for 30min, carrying out suction filtration, washing with water, and carrying out vacuum drying to obtain the Roebricoxib.
The alkali may be sodium hydroxide or potassium hydroxide.
Compared with the prior art, the invention has the advantages that:
1) The invention adopts the sandmeyer reaction to prepare the intermediate of the robekoxil, toxic and irritant raw materials such as aluminum trichloride and the like are not used in the whole reaction process, anhydrous conditions are not required, the invention has the advantages of less pollution and easy production, the requirement on the reaction conditions is low, and the industrial production cost can be obviously reduced; and then reducing the intermediate of the Roebecoxib to obtain the Roebecoxib.
2) The carbonyl reduction on the acetyl group of the robecoxib intermediate and the carbonyl reduction on the 2, 3-position of indoline are completed in one step, so that the method can directly adopt 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethane-1-ketone as a raw material, a step of reducing the 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethane-1-ketone into N- (4-ethylphenyl) -2,3,5, 6-tetrafluoroaniline is omitted, and the total yield of the robecoxib is improved.
Detailed Description
Further illustrated by the following specific examples;
in the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described herein, and thus the present invention is not limited to the specific embodiments disclosed below.
Example 1
100g of water and 56.6g (0.2 mol) of 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethan-1-one are placed in a 250mL beaker, and 25g of 30% hydrochloric acid are added with stirring for further use.
Adding 600mL of water and 170.4g (1.2 mol) of anhydrous sodium sulfate into a 1000mL three-necked bottle, heating to 80 ℃, adding 49.6g (0.3 mol) of chloral hydrate, stirring, keeping the temperature for 0.5 hour, adding the mixture in the beaker into the three-necked bottle, adding 20.9g (0.3 mol) of hydroxylamine hydrochloride, heating to 85 ℃, reacting for 2 hours, cooling to 20 ℃, carrying out suction filtration, washing for 2 times with water, and carrying out vacuum drying to obtain 70.2g of N- (4-acetylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide, wherein the yield is 99%.
250g of polyphosphoric acid and 70.2g of N- (4-acetylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide are added into a 500mL three-necked bottle, the temperature is slowly raised to 230 ℃ under stirring, and the temperature is kept for reaction for 2 hours. The reaction solution was cooled to room temperature, 200mL of water was added, and stirring was carried out for 30min, followed by suction filtration, water washing, and vacuum drying to obtain 66.1g of 5-acetyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione with a yield of 99%.
250mL of diethylene glycol, 66.1g of 5-acetyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione, 48.0g of sodium hydroxide and 45.2g of 85% hydrazine hydrate are added into a 500mL three-necked flask, the mixture is heated with stirring, distilled and dehydrated until the reaction temperature is 200 ℃, and the reaction is carried out for 4 hours under heat preservation. Cooling the reaction liquid to room temperature, adding 200mL of water and 30% hydrochloric acid to adjust the pH value to 3, stirring for 30min, carrying out suction filtration, washing with water, and carrying out vacuum drying to obtain 2- (5-ethyl-2- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) acetic acid with the yield of 95% (calculated on 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethane-1-ketone).
Example 2
150g of water and 85.0g (0.3 mol) of 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethan-1-one are placed in a 250mL beaker, and 30g of 98% sulfuric acid is added dropwise with stirring for further use.
Adding 700mL of water and 142.0g (1.0 mol) of anhydrous sodium sulfate into a 1000mL three-necked bottle, heating to 70 ℃, adding 49.6g (0.3 mol) of chloral hydrate, stirring and keeping the temperature for 0.5 hour, adding the mixture in the beaker into the three-necked bottle, adding 39.3g (0.3 mol) of hydroxylamine sulfate, heating to 80 ℃, reacting for 3 hours, cooling to 20 ℃, performing suction filtration, washing with water for 2 times, and performing vacuum drying to obtain 105.2g of N- (4-acetylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide with the yield of 99%.
300g of polyphosphoric acid and 105.2g of N- (4-acetylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide are added into a 500mL three-necked flask, and the temperature is slowly increased to 180 ℃ under stirring, and the reaction is kept for 5 hours. The reaction solution was cooled to room temperature, 200mL of water was added, and stirring was carried out for 30min, followed by suction filtration, water washing, and vacuum drying to obtain 101.2g of 5-acetyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione with a yield of 99%.
400mL of diethylene glycol, 101.2g of 5-acetyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione, 84.0g of potassium hydroxide and 67.1g of 85% hydrazine hydrate are added into a 1000mL three-necked bottle, the mixture is heated with stirring to distill off water until the reaction temperature is 200 ℃, and the temperature is kept for 4 hours for reaction. Cooling the reaction liquid to room temperature, adding 400mL of water, dropwise adding 98% sulfuric acid to adjust the pH value to 3, stirring for 30min, performing suction filtration, washing with water, and performing vacuum drying to obtain 87.4g of 2- (5-ethyl-2- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) acetic acid, wherein the yield is 89% (calculated on 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethane-1-ketone).
Example 3
50g of water and 28.3g (0.1 mol) of 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethan-1-one were added to a 250mL beaker, and 19.6g of 98% sulfuric acid was added dropwise with stirring for further use.
200mL of water and 14.2g (0.2 mol) of anhydrous sodium sulfate are added into a 500mL three-necked bottle, 16.5g (0.1 mol) of chloral hydrate is added after the temperature is raised to 75 ℃, the mixture is stirred and kept warm for 0.5 hour, the mixture in the beaker is added into the three-necked bottle, 13.1g (0.1 mol) of hydroxylamine sulfate is added, the temperature is raised to 85 ℃ for reaction for 2 hours, the temperature is lowered to 20 ℃, the mixture is filtered, washed for 2 times by suction and dried in vacuum, and 32.6g of N- (4-acetylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide is obtained, and the yield is 92 percent.
100g of 98% sulfuric acid and 32.6g of N- (4-acetylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide are added into a 500mL three-necked flask, and the temperature is slowly raised to 50 ℃ under stirring, and the temperature is kept for reaction for 6 hours. The reaction solution was cooled to room temperature, poured into 200mL of water, stirred for 30min, filtered, washed with water, and dried under vacuum to give 29.5g of 5-acetyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione with a yield of 95%.
100mL of diethylene glycol, 29.5g of 5-acetyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione, 12.0g of sodium hydroxide and 11.3g of 85% hydrazine hydrate are added into a 500mL three-necked bottle, the mixture is heated under stirring to distill off water until the reaction temperature is 200 ℃, and the reaction is carried out for 4 hours under heat preservation. The reaction solution is cooled to room temperature, 200mL of water and 30% hydrochloric acid are added to adjust the pH value to 3, stirring is carried out for 30min, suction filtration, water washing and vacuum drying are carried out, and 26.2g of 2- (5-ethyl-2- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) acetic acid is obtained, and the yield is 80% (calculated on 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethane-1-ketone).
Example 4
150g of water and 85.0g (0.3 mol) of 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethan-1-one were added to a 250mL beaker, and 37.0g of 30% hydrochloric acid was added dropwise with stirring for further use.
Adding 500mL of water and 127.8g (0.9 mol) of anhydrous sodium sulfate into a 1000mL three-necked bottle, heating to 70 ℃, adding 57.9g (0.35 mol) of chloral hydrate, stirring, keeping the temperature for 0.5 hour, adding the mixture in the beaker into the three-necked bottle, adding 24.3g (0.35 mol) of hydroxylamine hydrochloride, heating to 80 ℃, reacting for 3 hours, cooling to 20 ℃, carrying out suction filtration, washing for 2 times with water, and carrying out vacuum drying to obtain 105.2g of N- (4-acetylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide, wherein the yield is 99%.
400g of 90% sulfuric acid and 105.2g of N- (4-acetylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide were added to a 500mL three-necked flask, and the mixture was slowly heated to 105 ℃ with stirring and then allowed to react for 5 hours while maintaining the temperature. The reaction solution was cooled to room temperature, poured into 400mL of water, stirred for 30min, filtered, washed with water, and dried under vacuum to give 95.1g of 5-acetyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione, yield 95%.
500mL of diethylene glycol, 95.1g of 5-acetyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione, 67.2g of potassium hydroxide and 45.2g of 85% hydrazine hydrate are added into a 1000mL three-necked flask, and the mixture is heated, distilled and dehydrated under stirring until the reaction temperature reaches 200 ℃, and is subjected to heat preservation reaction for 4 hours. Cooling the reaction liquid to room temperature, adding 400mL of water, dropwise adding 98% sulfuric acid to adjust the pH value to 3, stirring for 30min, performing suction filtration, washing with water, and performing vacuum drying to obtain 83.5g of 2- (5-ethyl-2- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) acetic acid, wherein the yield is 85% (calculated on 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethane-1-ketone).
Example 5
300g of water and 134.6g (0.5 mol) of N- (4-ethylphenyl) -2,3,5, 6-tetrafluoroaniline were added to a 1L beaker, and 60.8g of 30% hydrochloric acid was added dropwise with stirring for backup.
Adding 1L of water and 284.0g (2.0 mol) of anhydrous sodium sulfate into a 2L three-necked bottle, heating to 70 ℃, adding 99.3g (0.6 mol) of chloral hydrate, stirring, keeping the temperature for 0.5 hour, adding the mixture in the beaker into the three-necked bottle, adding 41.7g (0.6 mol) of hydroxylamine hydrochloride, heating to 80 ℃, reacting for 3 hours, cooling to 20 ℃, performing suction filtration, washing with water for 2 times, and performing vacuum drying to obtain 168.4g of N- (4-ethylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide with the yield of 99 percent.
700g of 90% sulfuric acid and 202.1g of N- (4-ethylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide are added into a 1L three-necked bottle, the temperature is slowly raised to 100 ℃ under stirring, and the temperature is kept for reaction for 5 hours. The reaction solution was cooled to room temperature, 1L of water was poured, stirred for 30min, filtered, washed with water, and dried under vacuum to give 155.2g of 5-ethyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione in 97% yield.
700mL of diethylene glycol, 155.2g of 5-ethyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione, 48.0g of sodium hydroxide and 37.7g of 85% hydrazine hydrate were added into a 2L three-necked flask, and the mixture was heated with stirring, distilled to remove water until the reaction temperature became 200 ℃ and reacted for 4 hours while maintaining the temperature. The reaction solution was cooled to room temperature, 700mL of water was added, 98% sulfuric acid was added dropwise to adjust the pH to 3, and the mixture was stirred for 30min, followed by suction filtration, water washing, and vacuum drying to obtain 144.0g of 2- (5-ethyl-2- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) acetic acid in 88% yield (based on N- (4-ethylphenyl) -2,3,5, 6-tetrafluoroaniline).
The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments, or alternatives may be employed, by those skilled in the art, without departing from the spirit or ambit of the invention as defined in the appended claims.
Although the terms 1- (4- ((2, 3,5, 6-tetrafluorophenyl) amino) phenyl) ethan-1-one, N- (4-acetylphenyl) -2- (hydroxyimino) -N- (2, 3,5, 6-tetrafluorophenyl) acetamide, 5-acetyl-1- (2, 3,5, 6-tetrafluorophenyl) indoline-2, 3-dione, robecco, chloral, hydroxylamine, sandmeyer reaction, and the like are used more often herein. These terms are used merely to more conveniently describe and explain the nature of the present invention and they are to be interpreted as any additional limitation in keeping with the spirit of the present invention.
Claims (10)
1. A method for synthesizing a robecoxib intermediate is characterized in that
The raw material is subjected to a sandmeyer reaction with chloral and hydroxylamine to synthesize the robecoxib intermediate, wherein the chemical formula of the robecoxib intermediate is as follows:
2. The method of synthesizing an intermediate of robesicoxib as claimed in claim 1 wherein said sandmeyer reaction comprises:
a. the raw materials, trichloroacetaldehyde and hydroxylamine are subjected to a first-step reaction under an acidic condition to obtain a primary intermediate, and the reaction equation is as follows:
b. and then carrying out a second-step reaction under the catalysis of acid to obtain the intermediate of the Robecoxib, wherein the reaction equation is as follows:
3. the method for synthesizing the intermediate of the robecoxib as claimed in claim 3, wherein in the step a, the molar ratio of the raw material, the chloral and the hydroxylamine is 0.66-1.
4. A process for the synthesis of a robecoxib intermediate as claimed in claim 3, wherein chloral is chloral hydrate or chloral anhydrous and hydroxylamine is hydroxylamine hydrochloride or hydroxylamine sulphate.
5. A method of synthesizing a robecoxib intermediate as claimed in claim 3, wherein: in the step a, water, raw materials and an acid solution are prepared into a mixture for later use, the water, anhydrous sodium sulfate, trichloroacetaldehyde and the mixture are mixed in a second container, hydroxylamine is added for mixing, the temperature is increased for reaction, then the temperature is reduced, suction filtration, water washing and drying are carried out, and a primary intermediate is obtained.
6. A method of synthesizing a robecoxib intermediate as claimed in claim 3, wherein: in the step b, 90-98% of sulfuric acid solution or polyphosphoric acid is adopted in the acid catalytic reaction, and the dosage of the 90-98% of sulfuric acid solution or polyphosphoric acid is 2.5-5 times of the mass of the primary intermediate; the reaction temperature is 50-230 ℃, the temperature is kept, the reaction is carried out, then the reaction product is cooled to the room temperature, and the intermediate of the Robecoxib is obtained through water washing and vacuum drying.
7. A synthesis method of the Roebeckib compound is characterized by comprising the following steps:
1) Preparing a robesite intermediate using the synthesis method of the robesite intermediate of claims 1-6;
2) And reducing the intermediate of the robecoxib to obtain the robecoxib.
8. The method of claim 8, wherein the intermediate of robekoxib has the formula:
9. the method for synthesizing robesib according to claim 8, wherein the robesib intermediate is reduced with diethylene glycol through hydrazine hydrate under alkaline conditions and then regulated to obtain robesib.
10. A method of synthesizing robecoxib as claimed in claim 9, wherein: adding 300-550 mL of diethylene glycol and 35-70g of 85% hydrazine hydrate into every 100g of the intermediate of the robekoxib for reaction; the alkaline condition is pH 12-14.
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| CN109694330A (en) * | 2017-10-24 | 2019-04-30 | 乳源瑶族自治县东阳光生物科技有限公司 | A kind of preparation method of acid |
| CN114634496A (en) * | 2022-02-27 | 2022-06-17 | 复旦大学 | Indolone substituted-1, 3-thiazolidone derivative and preparation method and application thereof |
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| CN109694330A (en) * | 2017-10-24 | 2019-04-30 | 乳源瑶族自治县东阳光生物科技有限公司 | A kind of preparation method of acid |
| CN114634496A (en) * | 2022-02-27 | 2022-06-17 | 复旦大学 | Indolone substituted-1, 3-thiazolidone derivative and preparation method and application thereof |
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| Title |
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| KURKIN, ALEXANDER V.等: "(2R)-Ethyl 2-(5-bromo-2, 3-dioxoindolin-1-yl)propanoate", 《KURKIN, ALEXANDER V.》, vol. 64, no. 8, 31 December 2008 (2008-12-31), pages 1448 * |
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