CN109734650A - The synthetic method of Carprofen and its intermediate - Google Patents
The synthetic method of Carprofen and its intermediate Download PDFInfo
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- CN109734650A CN109734650A CN201910135332.3A CN201910135332A CN109734650A CN 109734650 A CN109734650 A CN 109734650A CN 201910135332 A CN201910135332 A CN 201910135332A CN 109734650 A CN109734650 A CN 109734650A
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Abstract
A kind of synthetic method of Carprofen: (1) 4- chloroiodobenzone and the chloro- 5- bromaniline reaction of 2- generate compound shown in M-1.(2) compound shown in formula M-1 generates compound shown in M-2 by reaction.(3) compound shown in formula M-2 is by reaction, compound shown in production M-3.(4) compound shown in formula M-3 is by compound shown in reaction production M-4.(5) compound shown in formula M-4 is by compound shown in reaction production M-5.(6) compound shown in formula M-5 is by Carprofen shown in reaction production A.
Description
Technical field
The invention belongs to medicine and its intermediate synthesis fields more particularly to the synthesis side of a kind of Carprofen and its intermediate
Method.
Background technique
Carprofen is propionic non-steroid antiphlogistic, its chemical name is: 2- (the chloro- 9H- carbazole -2- base of 6-) propionic acid is changed
Structure is learned as shown in formula A:
With the application development of Carprofen in practice, the synthetic method for developing new Carprofen is necessary.
Summary of the invention
The present invention provides the synthetic methods of a kind of new Carprofen and its intermediate:
(1) 4- chloroiodobenzone and the chloro- 5- bromaniline reaction of 2-, generate the bromo- 2- of 5- chloro- N- (4- chlorphenyl) aniline shown in M-1.
The chloro- N- of the bromo- 2- of 5- shown in formula M-1 (4- chlorphenyl) aniline generates the chloro- N- of 5- ethyl -2- shown in M-2 by reaction
(4- chlorphenyl) aniline.
(3) the chloro- N- of 5- ethyl -2- shown in formula M-2 (4- chlorphenyl) aniline is by reaction, N- (2- shown in production M-3
Chloro- 5- ethylphenyl)-N- (4- chlorphenyl) acetamide.
(4) (the chloro- 5- ethylphenyl of 2-)-N- (4- chlorphenyl) acetamide of N- shown in formula M-3 is by reaction production M-4 institute
Show 2- (the chloro- 3- of 4- (N- (4- chlorphenyl) acetylamino) phenyl) ethyl propionate.
(5) (the chloro- 3- of 4- (N- (4- chlorphenyl) acetylamino) phenyl) ethyl propionate of 2- shown in formula M-4 is generated by reaction
2- shown in formula M-5 (3- ((4- chlorphenyl) amino) -4- chlorphenyl) propionic acid.
(6) (3- ((4- chlorphenyl) the amino) -4- chlorphenyl) propionic acid of 2- shown in formula M-5 is by card shown in reaction production A
Ibuprofen, i.e.,2- (the chloro- 9H- carbazole -2- base of 6-) propionic acid.
Meanwhile the present invention also provides compound shown in formula M-1 and its applications in Carprofen synthesis.
On the other hand, the present invention also provides compound shown in formula M-2 and its applications in Carprofen synthesis.
On the other hand, the present invention also provides compound shown in formula M-3 and its applications in Carprofen synthesis.
On the other hand the present invention also provides compound shown in formula M-4 and its applications in Carprofen synthesis.
The present invention has the beneficial effect that:
The present invention provides the synthetic methods of new Carprofen.
Specific embodiment
According to the present invention, the optional factor that the preparation method of Carprofen shown in formula A provides is more, right according to the present invention
It is required that different embodiments can be combined into, embodiment is only used for that the present invention is described further, not to structure of the present invention
At limitation.The present invention is further detailed below in conjunction with embodiment.
The synthesis of Carprofen shown in 1 formula A of embodiment:
(1) 4- chloroiodobenzone and the chloro- 5- bromaniline reaction of 2-, generate the bromo- 2- of 5- chloro- N- (4- chlorphenyl) aniline shown in M-1.
In 1000 milliliters of there-necked flasks, under nitrogen protection, 500 milliliters of DMF (n,N-Dimethylformamide) are added, are added 23.8
Then gram (0.1mol) 4- chloroiodobenzone, 20.6 grams of chloro- 5- bromanilines of (0.1mol) 2- are slowly added to 6.72 grams of (0.12mol) hydrogen
Potassium oxide stirs 30 minutes, 10 grams of cuprous oxide is then added, be to slowly warm up to 100 DEG C, reacts 60 hours, be then down to room
Water and methylene chloride liquid separation are added into obtained mother liquor for temperature, filtering, and organic layer is washed to neutrality, after sodium sulphate is dry, concentration
To doing, with recrystallizing methanol, 8.8 grams of aniline of the chloro- N- of the bromo- 2- of 5- shown in formula M-1 (4- chlorphenyl), yield 27.8% are obtained.
Mass Spectrometer Method has been carried out to product shown in obtained formula M-1, has obtained the m/e:317 of product.
Nuclear-magnetism detection is carried out to product shown in obtained formula M-1, obtained nuclear-magnetism parsing data are as follows:
1HNMR (500MHz, CDCl3): δ 7.70 (m, 2H), δ 7.31 (m, 2H), δ 7.25 (m, 2H), δ 7.16 (m, 1H), δ
6.66 (s, 1H).
(2) the chloro- N- of the bromo- 2- of 5- shown in formula M-1 (4- chlorphenyl) aniline generates 5- ethyl -2- shown in M-2 by reaction
Chloro- N- (4- chlorphenyl) aniline.
100 milliliters of tetrahydrofurans, chemical combination shown in 3.17 grams of (0.01mol) M-1 is added in 500 milliliters of there-necked flasks, nitrogen protection
Object, 0.54 gram of (0.001mol) Ni (dppp) Cl2(1,3- bis- (diphenylphosphine propane) Nickel Chlorides) control temperature 10~15
DEG C, the tetrahydrofuran solution of the 1M of 50 milliliters of (0.05mol) ethylmagnesium bromides is slowly added dropwise, finishes and is to slowly warm up to 50 DEG C of reactions
4 hours, cooling was slowly added to 10 ml methanols, and ammonium chloride solution is then added, and stirred 30 minutes.Add water and dichloromethane
Alkane liquid separation, organic layer is washed to neutrality, after sodium sulphate is dry, silica gel column chromatography separation, and petroleum ether: ethyl acetate=5: 1 (volume
Than) elution, obtain 1.6 grams of aniline of the chloro- N- of 5- ethyl -2- shown in formula M-2 (4- chlorphenyl), yield 60.1%.
Mass Spectrometer Method has been carried out to product shown in obtained formula M-2, has obtained the m/e:265 of product.
Nuclear-magnetism detection is carried out to product shown in obtained formula M-2, obtained nuclear-magnetism parsing data are as follows:
1HNMR (500MHz, CDCl3): δ 7.68 (m, 2H), δ 7.38 (d, 1H), δ 7.31 (m, 2H), δ 7.22 (d, 1H), δ
6.86 (m, 1H), δ 6.47 (s, 1H), δ 2.73 (m, 2H), δ 1.19 (m, 3H).
(3) the chloro- N- of 5- ethyl -2- shown in formula M-2 (4- chlorphenyl) aniline is by reaction, N- (2- shown in production M-3
Chloro- 5- ethylphenyl)-N- (4- chlorphenyl) acetamide.
250 milliliters of there-necked flasks, are added 100 milliliters of methylene chloride, compound shown in 2.66 grams of (0.01mol) formula M-2, and 1.5
Gram (0.015mol) triethylamine controls 20~25 DEG C of temperature, 0.94 gram of (0.012mol) chloroacetic chloride is slowly added dropwise, finishes and is warming up to
Reflux is reacted 4 hours, and cooling, water washing to neutrality is concentrated to dryness, recrystallizing methanol obtains after organic layer sodium sulphate is dry
N- shown in formula M-3 (the chloro- 5- ethylphenyl of 2-) 2.76 grams of acetamide of-N- (4- chlorphenyl), yield 89.6%.
Mass Spectrometer Method has been carried out to product shown in obtained formula M-3, has obtained the m/e:307 of product.
(4) (the chloro- 5- ethylphenyl of 2-)-N- (4- chlorphenyl) acetamide of N- shown in formula M-3 is by reaction production M-4 institute
Show 2- (the chloro- 3- of 4- (N- (4- chlorphenyl) acetylamino) phenyl) ethyl propionate.
In 500 milliliters of autoclaves, compound shown in 3.08 grams of (0.01mol) formula M-3 of addition, 50 milliliters of dehydrated alcohols,
1.72 grams of (0.01mol) metachloroperbenzoic acids, 0.058 gram (0.0001mol)
Xantphos (4,5- bis- diphenylphosphine -9,9- xanthphos), 0.0177 gram of (0.0001mol) palladium chloride,
Fill CO to 1MPa, be warming up to 100 DEG C react 12 hours, cooling, release CO, reaction solution filtering after be concentrated, obtained solid without
Further purification, obtains the production containing 2- shown in formula M-4 (the chloro- 3- of 4- (N- (4- chlorphenyl) acetylamino) phenyl) ethyl propionate
Object, directly progress the next step.
(5) (the chloro- 3- of 4- (N- (4- chlorphenyl) acetylamino) phenyl) ethyl propionate of 2- shown in formula M-4 is generated by reaction
2- shown in formula M-5 (3- ((4- chlorphenyl) amino) -4- chlorphenyl) propionic acid.
500 milliliters of there-necked flasks, step is prepared not purified containing the 2- (chloro- 3- (N- of 4- shown in formula M-4 in addition
(4- chlorphenyl) acetylamino) phenyl) product of ethyl propionate adds 50 milliliters of dioxane, 5.6 grams of (0.1mol) KOH, and 3
Milliliter water, back flow reaction 12 hours, water and methylene chloride liquid separation, organic layer was added with 10% hydrochloric acid tune pH value to 3 in cooling
Neutrality is washed to be concentrated to dryness after sodium sulphate is dry, with recrystallizing methanol, obtain (3- ((4- chlorphenyl) ammonia of 2- shown in formula M-5
Base) -4- chlorphenyl) 2.4 grams of propionic acid, above (4), (5) two steps add up to total recovery 77.4%.
Mass Spectrometer Method has been carried out to product shown in obtained formula M-5, has obtained the m/e:309 of product.
Nuclear-magnetism detection is carried out to product shown in obtained formula M-5, obtained nuclear-magnetism parsing data are as follows:
1HNMR (500MHz, CDCI3): δ 11.13 (s, 1H), δ 7.67 (m, 2H), δ 7.49 (d, 1H), δ 7.35 (d, 1H),
δ 7.31 (m, 2H), δ 7.10 (m, 1H), δ 6.67 (m, 1H), δ 3.20 (s, 1H), δ 1.46 (d, 3H).
(6) (3- ((4- chlorphenyl) the amino) -4- chlorphenyl) propionic acid of 2- shown in formula M-5 is by card shown in reaction production A
Ibuprofen, i.e.,2- (the chloro- 9H- carbazole -2- base of 6-) propionic acid.
Under nitrogen protection, 2- (3- ((4- chlorphenyl) ammonia shown in 3.1 grams of (0.01mol) M-5 is added in 500 milliliters of there-necked flasks
Base) -4- chlorphenyl) propionic acid, 100 milliliters of DMF (n,N-Dimethylformamide), 2.88 grams of (0.03mol) sodium tert-butoxides, 1.05 grams
(0.004mol) triphenyl phosphorus, 0.17 gram of (0.001mol) PdCl2, 0.13 gram of (0.001mol) NiCl2, it is to slowly warm up to 100 DEG C
Reaction 10 hours, is down to room temperature, and 10 grams of glacial acetic acid are added, and stirs 10 minutes, and water and methylene chloride liquid separation, organic layer water is added
It washes, organic layer is concentrated to dryness, and ethyl alcohol and petroleum ether mixed solvent crystallization obtain 2.4 grams of Carprofen shown in formula A, yield 87.9%.
Through liquid chromatographic detection, wherein compound 99.8% shown in A containing formula.
Mass Spectrometer Method has been carried out to product shown in obtained formula A, has obtained the m/e:273 of product.
Nuclear-magnetism detection is carried out to product shown in obtained formula A, obtained nuclear-magnetism parsing data are as follows:
1HNMR (500MHz, CDCl3): δ 11.12 (s, 1H), δ 7.66 (d, 1H), δ 7.63 (m, 2H), δ 7.33 (m, 2H),
δ 7.21 (m, 1H), δ 7.13 (m, 1H), δ 4.00 (m, 1H), δ 1.45 (d, 3H).
Obviously, various changes and modifications can be made to the invention without departing from essence of the invention by those skilled in the art
Mind and range.In this way, if these modifications and changes of the present invention belongs to the range of the claims in the present invention and its equivalent technologies
Within, then the present invention is also intended to include these modifications and variations.
Claims (7)
1. a kind of synthetic method of Carprofen comprising the steps of:
(1) 4- chloroiodobenzone and the chloro- 5- bromaniline reaction of 2-, generate compound shown in M-1.
(2) the chloro- N- of the bromo- 2- of 5- shown in formula M-1 (4- chlorphenyl) aniline generates the chloro- N- of 5- ethyl -2- shown in M-2 by reaction
(4- chlorphenyl) aniline；
(3) the chloro- N- of 5- ethyl -2- shown in formula M-2 (4- chlorphenyl) aniline is by reaction, (the chloro- 5- of 2- of N- shown in production M-3
Ethylphenyl)-N- (4- chlorphenyl) acetamide；
(4) (the chloro- 5- ethylphenyl of 2-)-N- (4- chlorphenyl) acetamide of N- shown in formula M-3 is by 2- shown in reaction production M-4
(the chloro- 3- of 4- (N- (4- chlorphenyl) acetylamino) phenyl) ethyl propionate；
(5) (the chloro- 3- of 4- (N- (4- chlorphenyl) acetylamino) phenyl) ethyl propionate of 2- shown in formula M-4 is by reaction production M-
2- shown in 5 (3- ((4- chlorphenyl) amino) -4- chlorphenyl) propionic acid；
(6) (3- ((4- chlorphenyl) the amino) -4- chlorphenyl) propionic acid of 2- shown in formula M-5 passes through Carprofen shown in reaction production A,
I.e.2- (the chloro- 9H- carbazole -2- base of 6-) propionic acid；
2. compound shown in formula M-3:
3. compound shown in formula M-4:
4. application of the compound shown in formula M-3 described in claim 2 in synthesis Carprofen.
5. application of the compound shown in formula M-4 described in claim 3 in synthesis Carprofen.
6. the synthetic method of compound shown in formula M-3 described in claim 2:
Chloro- N- (4- chlorphenyl) aniline of 5- ethyl -2- shown in formula M-2 is by reaction, (the chloro- 5- ethyl of 2- of N- shown in production M-3
Phenyl)-N- (4- chlorphenyl) acetamide；
7. the synthetic method of compound shown in formula M-4 described in claim 3:
(the chloro- 5- ethylphenyl of 2-)-N- (4- chlorphenyl) acetamide of N- shown in formula M-3 is by 2- (4- shown in reaction production M-4
Chloro- 3- (N- (4- chlorphenyl) acetylamino) phenyl) ethyl propionate；
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114292230A (en) * | 2022-02-27 | 2022-04-08 | 桂林理工大学 | Palladium-catalyzed N-phenylpyridine-2-amine N-H carbonylation reaction taking DMF as methyl source |
-
2019
- 2019-02-21 CN CN201910135332.3A patent/CN109734650A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114292230A (en) * | 2022-02-27 | 2022-04-08 | 桂林理工大学 | Palladium-catalyzed N-phenylpyridine-2-amine N-H carbonylation reaction taking DMF as methyl source |
| CN114292230B (en) * | 2022-02-27 | 2023-11-17 | 桂林理工大学 | Palladium catalyzed N-H carbonylation of N-phenylpyridine-2-amine with DMF as methyl source |
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Application publication date: 20190510 |