CN116924936A - Preparation method of dabigatran intermediate compound p-aminobenzonitrile - Google Patents
Preparation method of dabigatran intermediate compound p-aminobenzonitrile Download PDFInfo
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- dabigatran etexilate
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 title claims description 14
- 229960003850 dabigatran Drugs 0.000 title description 4
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 21
- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960000288 dabigatran etexilate Drugs 0.000 claims abstract description 14
- 229940126214 compound 3 Drugs 0.000 claims description 27
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 24
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 229940125782 compound 2 Drugs 0.000 claims description 17
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 16
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 14
- SRRKNRDXURUMPP-UHFFFAOYSA-N sodium disulfide Chemical compound [Na+].[Na+].[S-][S-] SRRKNRDXURUMPP-UHFFFAOYSA-N 0.000 claims description 14
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 claims description 8
- 235000017281 sodium acetate Nutrition 0.000 claims description 8
- 229940087562 sodium acetate trihydrate Drugs 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 claims description 2
- 238000007333 cyanation reaction Methods 0.000 claims description 2
- ALUKVDZZOIZELC-UHFFFAOYSA-N OC(C1=CC=CC=C1)=O.OC(C1=CC=CC=C1)=O.OC(C1=CC=CC=C1)=O.P Chemical compound OC(C1=CC=CC=C1)=O.OC(C1=CC=CC=C1)=O.OC(C1=CC=CC=C1)=O.P ALUKVDZZOIZELC-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 30
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 230000008569 process Effects 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 229910052979 sodium sulfide Inorganic materials 0.000 description 9
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000002912 waste gas Substances 0.000 description 3
- 239000002351 wastewater Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- XDJWZONZDVNKDU-UHFFFAOYSA-N 1314-24-5 Chemical compound O=POP=O XDJWZONZDVNKDU-UHFFFAOYSA-N 0.000 description 1
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 1
- NKJIFDNZPGLLSH-UHFFFAOYSA-N 4-nitrobenzonitrile Chemical compound [O-][N+](=O)C1=CC=C(C#N)C=C1 NKJIFDNZPGLLSH-UHFFFAOYSA-N 0.000 description 1
- ZPTVNYMJQHSSEA-UHFFFAOYSA-N 4-nitrotoluene Chemical compound CC1=CC=C([N+]([O-])=O)C=C1 ZPTVNYMJQHSSEA-UHFFFAOYSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 150000008359 benzonitriles Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- VSAISIQCTGDGPU-UHFFFAOYSA-N phosphorus trioxide Inorganic materials O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of organic synthesis, in particular to the technical field of medical synthesis, and more particularly relates to a preparation method of a dabigatran etexilate intermediate compound. The synthesis cost is obviously reduced, the whole synthesis process is simple to operate, the safety is high, and the environment friendliness is high. Meanwhile, the reaction yield is high, the product purity is high, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis, in particular to the technical field of medical synthesis, and more particularly relates to a preparation method of a dabigatran etexilate intermediate compound p-aminobenzonitrile.
Background
Dabigatran is a reversible strong thrombin inhibitor, can prevent thrombosis, can be used for preventing stroke and embolism of partial atrial fibrillation patients, and the like. Para-aminobenzonitrile is an important intermediate compound in the synthesis of dabigatran.
The method for synthesizing the p-aminobenzonitrile disclosed in the prior art mainly comprises the following steps:
1. the para-halogenated aniline cyanidation method, however, the method needs to use the cyanide of the highly toxic substance, and has great potential safety hazard;
2. the method for aminating the halogenated benzonitrile has the advantages that the catalyst used in the method is difficult to recover and the production cost is high;
3. the p-nitrobenzonitrile reduction process, however, the noble metal catalysts used in this process are expensive;
4. the method is a common method for domestic current industrial production, uses low-cost aminobenzamide as a main raw material, and adopts the processes of dehydration reaction under the action of phosphorus pentoxide, phosphorus oxychloride or phosphorus pentachloride, acidification, decolorization, alkali washing and refining to obtain the product, and the raw material used by the process is cheap and easily available, but can produce a large amount of phosphorus-containing wastewater and waste gas, so that the wastewater and waste gas are difficult to treat and pollute the environment.
Disclosure of Invention
The invention aims to solve the technical problems of providing a preparation method of a dabigatran etexilate intermediate compound, namely para-aminobenzonitrile, so as to solve the problems in the prior art, such as: the production cost is high, the reaction process discharges a large amount of wastewater and waste gas to pollute the environment, and toxic objects are extremely poisonous, so that the reaction safety is reduced, and the like.
In order to solve the technical problems, the invention discloses a preparation method of a dabigatran etexilate intermediate compound, namely para-aminobenzonitrile, which takes a compound 3 as a raw material to prepare the aminobenzonitrile through a cyanation reaction, wherein the synthesis route is as follows:
wherein (1) is oxalyl chloride and (2) is phosphorus oxychloride; or (1) potassium hydroxide and (2) dimethyl sulfoxide.
When (1) is oxalyl chloride and (2) is phosphorus oxychloride, the specific synthetic steps are as follows: firstly dissolving phosphorus oxychloride in ethyl acetate, and then adding oxalyl chloride into the solution to obtain a first reaction solution; then dissolving the compound 3 in ethyl acetate to obtain a second reaction solution; then the second reaction liquid is slowly added into the first reaction liquid, stirred and reacted, and the solvent is removed by reduced pressure distillation of the reactant, and then the compound 4 is obtained by purification.
Further preferably, the molar ratio of compound 3 to oxalyl chloride is 1:1-5, which may be, but is not limited to, 1:1, 1:1.5, 1:2.0, 1:2.5, 1:3.0, 1:3.5, 1:4.0, 1:4.5, 1:5.0, more preferably 1:3.0.
Further preferably, the molar ratio of compound 3 to phosphorus trioxide is from 1:0.05 to 0.5, which may be, but is not limited to, 1:0.05, 1:0.10, 1:0.15, 1:0.20, 1:0.25, 1:0.30, 1:0.35, 1:0.40, 1:0.45, 1:0.50, more preferably 1:0.10.
When (1) is potassium hydroxide and (2) is dimethyl sulfoxide, the specific synthesis steps are as follows: compound 3 and potassium hydroxide were added to dimethyl sulfoxide, and the mixture was stirred and heated in an autoclave to effect a reaction. The reaction mixture was washed with water, extracted with diethyl ether, dried over anhydrous sodium sulfate, and then distilled to obtain compound 4.
Further preferably, the molar ratio of compound 3 to potassium hydroxide is in the range of 1:0.05 to 0.5, which may be, but is not limited to, 1:0.05, 1:0.10, 1:0.15, 1:0.20, 1:0.25, 1:0.30, 1:0.35, 1:0.40, 1:0.45, 1:0.50, more preferably 1:0.1.
Further preferably, the feed ratio of compound 3 to dimethyl sulfoxide is 1:0.1-1mol/L, which may be, but is not limited to, 1:0.10mol/L, 1:0.15mol/L, 1:0.20mol/L, 1:0.25mol/L, 1:0.30mol/L, 1:0.35mol/L, 1:0.40mol/L, 1:0.45mol/L, 1:0.50mol/L, more preferably 1:0.5mol/L. The feed ratio expressed in mL here is the ratio of the molar amount of Compound 3 to the volume of dimethyl sulfoxide.
Further preferably, the autoclave high pressure reaction temperature is 120-160 ℃, which may be, but is not limited to 120 ℃, 125 ℃, 130 ℃, 135 ℃, 140 ℃, 145 ℃,150 ℃, 155 ℃,160 ℃, more preferably 140 ℃.
Further preferably, the autoclave is operated at a high pressure for a reaction time of 1 to 6 hours, which may be, but is not limited to, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, more preferably 3 hours.
Further, the invention also discloses that the compound 3 is prepared from a compound 2 and hydroxylamine hydrochloride, and the synthetic route is as follows:
preferably, the compound 2 and hydroxylamine hydrochloride are reacted in the presence of sodium acetate trihydrate to prepare the compound 3, wherein preferably, the feeding molar ratio of the compound 2 to the hydroxylamine hydrochloride and sodium acetate trihydrate is 1:1-3:1-3, which can be but is not limited to 1:1:1, 1:1.5:1.5, 1:2:2, 1:2.5:2.5, and 1:3:3, and even more preferably, the feeding molar ratio of the compound 2 to the hydroxylamine hydrochloride and sodium acetate trihydrate is 1:2:2.
Further preferably, the reaction time of compound 2 with hydroxylamine hydrochloride is 12 to 20 hours, and may be, but not limited to, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, with a reaction time of 16 hours being more preferred.
Further, the invention also discloses a compound 2 which is formed by reducing a compound 1 under the action of sodium disulfide, and the synthetic route is as follows:
the preparation method of sodium disulfide comprises adding 20ml distilled water into glass jacketed bottle, introducing circulating water, heating, adding crystalline sodium sulfide, and stirring to dissolve sodium sulfide; after the sodium sulfide crystal is completely dissolved, stirring is continued, sulfur powder is added, and the reaction is stopped after the reaction is carried out for 1h at 55 ℃; and after the reaction is finished, carrying out suction filtration, wherein the filtrate is the sodium disulfide solution. Sodium disulfide in the above reaction needs to be prepared as it is.
The preparation method disclosed by the invention has mild overall process conditions, takes paranitrotoluene as a raw material, and synthesizes the paraaminobenzonitrile through three steps, so that the synthesis cost is obviously reduced, and the whole synthesis process is simple to operate, high in safety and high in environmental friendliness. Meanwhile, the reaction yield is high, the product purity is high, and the method is suitable for industrial production.
Detailed Description
For a better understanding of the present invention, we will further describe the present invention with reference to specific examples.
Unless otherwise specified, the reagents used in the examples of the present invention are all commercially available products.
Example 1
Firstly, preparing a sodium disulfide solution: 20ml of distilled water was added to a glass jacketed bottle, and the mixture was heated to 55℃by introducing circulating water, then 0.04mol of crystalline sodium sulfide was added thereto, and the mixture was dissolved by stirring. After the sodium sulfide crystal is completely dissolved, stirring is continued for 0.5h, then 0.048mol of sulfur powder is added, and the reaction is stopped after 1h at 55 ℃. And after the reaction is finished, carrying out suction filtration, wherein the filtrate is the sodium disulfide solution.
Then, to compound 1 (21.9 g,160 mmol) was added 80ml of ethanol and DMF (1.1 g,16 mmol), and the mixture was stirred well to dissolve completely. The sodium disulfide solution was added dropwise thereto at a temperature of 80℃and reacted for 4 hours. Distillation is carried out until the distillate is neutral. Cooling and crystallizing the raffinate in ice water bath, filtering, recrystallizing a filter cake with water, and drying in vacuum to obtain the compound 2 with the yield of 95.3%.
Example 2
To a solution of compound 2 (1.2 g,0.01 mol) in 66ml of a mixture of ethanol and water (10:1) was added hydroxylamine hydrochloride (1.39 g,0.02 mol), followed by sodium acetate trihydrate (2.72 g,0.02 mol), and the reaction mixture was stirred at room temperature under nitrogen for 16 hours. After completion of the reaction, concentration under reduced pressure gave a crude residue, which was dissolved in ethyl acetate, washed with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the desired compound 3, which was purified by column chromatography to give the purified compound 3 in 92.4% yield.
Examples 3 to 6 and comparative examples 1 to 4 were constructed by changing only part of the reaction conditions according to the preparation method and the reaction conditions disclosed in example 2, and the results are shown in table 1;
table 1:
example 7
To 500ml of ethyl acetate was added phosphorus oxychloride (1.57 g,5 mmol), and the mixture was stirred sufficiently to dissolve the phosphorus oxybenzene completely, oxalyl chloride (19.0 g,150 mmol) was added, and the mixture was stirred at room temperature for 20 minutes to obtain a reaction solution. Compound 3 (6.8 g,50 mmol) was dissolved in ethyl acetate (500 ml), and the reaction mixture was slowly added and stirred at room temperature for 2 hours. And (3) distilling under reduced pressure to remove the solvent, and purifying the obtained residue by using a column chromatography method to obtain the target product. The yield was 98.6% and the purity of the product was 99.57%.
Examples 8-11 and comparative examples 5-8 were constructed with only a partial change in the reaction conditions according to the preparation method and reaction conditions disclosed in example 7, and the results are shown in Table 2;
table 2:
example 12
0.07mol of Compound 3 and 0.007mol of potassium hydroxide were added to 35mL of dimethyl sulfoxide, and the mixture was heated in an autoclave at 140℃with stirring for 3 hours. The reaction mixture was washed with water, extracted with diethyl ether, dried over anhydrous sodium sulfate, and then distilled to give compound 4 with a purity of 99.65% and a yield of 97.5%.
Examples 13-18 and comparative examples 9-14 were constructed with only a partial change in the reaction conditions according to the preparation method and reaction conditions disclosed in example 12, and the results are shown in Table 3;
table 3:
example 19
Firstly, preparing a sodium disulfide solution: 20ml of distilled water was added to a glass jacketed bottle, and the mixture was heated to 55℃by introducing circulating water, then 0.04mol of crystalline sodium sulfide was added thereto, and the mixture was dissolved by stirring. After the sodium sulfide crystal is completely dissolved, stirring is continued for 0.5h, then 0.048mol of sulfur powder is added, and the reaction is stopped after 1h at 55 ℃. And after the reaction is finished, carrying out suction filtration, wherein the filtrate is the sodium disulfide solution.
Then, to compound 1 (21.9 g,160 mmol) was added 80ml of ethanol and DMF (1.1 g,16 mmol), and the mixture was stirred well to dissolve completely. The sodium disulfide solution was added dropwise thereto at a temperature of 80℃and reacted for 4 hours. Distillation is carried out until the distillate is neutral. Cooling and crystallizing the raffinate in ice water bath, filtering, recrystallizing a filter cake with water, and drying in vacuum to obtain the compound 2 with the yield of 95.3%.
To a solution of compound 2 (1.2 g,0.01 mol) in 66ml of a mixture of ethanol and water (10:1) was added hydroxylamine hydrochloride (1.39 g,0.02 mol), followed by sodium acetate trihydrate (2.72 g,0.02 mol), and the reaction mixture was stirred at room temperature under nitrogen for 16 hours. After completion of the reaction, concentration under reduced pressure gave a crude residue, which was dissolved in ethyl acetate, washed with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the desired compound 3, which was purified by column chromatography to give the purified compound 3 in 92.4% yield.
To 500ml of ethyl acetate was added phosphorus oxychloride (1.57 g,5 mmol), and the mixture was stirred sufficiently to dissolve the phosphorus oxybenzene completely, oxalyl chloride (19.0 g,150 mmol) was added, and the mixture was stirred at room temperature for 20 minutes to obtain a reaction solution. Compound 3 (6.8 g,50 mmol) was dissolved in ethyl acetate (500 ml), and the reaction mixture was slowly added and stirred at room temperature for 2 hours. And (3) distilling under reduced pressure to remove the solvent, and purifying the obtained residue by using a column chromatography method to obtain the target product. The yield was 98.6% and the purity of the product was 99.57%.
The total yield of the three steps of reaction is 86.8 percent.
Example 20
Firstly, preparing a sodium disulfide solution: 20ml of distilled water was added to a glass jacketed bottle, and the mixture was heated to 55℃by introducing circulating water, then 0.04mol of crystalline sodium sulfide was added thereto, and the mixture was dissolved by stirring. After the sodium sulfide crystal is completely dissolved, stirring is continued for 0.5h, then 0.048mol of sulfur powder is added, and the reaction is stopped after 1h at 55 ℃. And after the reaction is finished, carrying out suction filtration, wherein the filtrate is the sodium disulfide solution.
Then, to compound 1 (21.9 g,160 mmol) was added 80ml of ethanol and DMF (1.1 g,16 mmol), and the mixture was stirred well to dissolve completely. The sodium disulfide solution was added dropwise thereto at a temperature of 80℃and reacted for 4 hours. Distillation is carried out until the distillate is neutral. Cooling and crystallizing the raffinate in ice water bath, filtering, recrystallizing a filter cake with water, and drying in vacuum to obtain the compound 2 with the yield of 95.3%.
To a solution of compound 2 (1.2 g,0.01 mol) in 66ml of a mixture of ethanol and water (10:1) was added hydroxylamine hydrochloride (1.39 g,0.02 mol), followed by sodium acetate trihydrate (2.72 g,0.02 mol), and the reaction mixture was stirred at room temperature under nitrogen for 16 hours. After completion of the reaction, concentration under reduced pressure gave a crude residue, which was dissolved in ethyl acetate, washed with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the desired compound 3, which was purified by column chromatography to give the purified compound 3 in 92.4% yield.
0.07mol of Compound 3 and 0.007mol of potassium hydroxide were added to 35mL of dimethyl sulfoxide, and the mixture was heated in an autoclave at 140℃with stirring for 3 hours. The reaction mixture was washed with water, extracted with diethyl ether, dried over anhydrous sodium sulfate, and then distilled to give compound 4 with a purity of 99.65% and a yield of 97.5%.
The total yield of the three steps is as follows: 85.86%.
What has been described above is a specific embodiment of the present invention. It should be noted that modifications and adaptations to the invention may occur to one skilled in the art without departing from the principles of the present invention and are intended to be within the scope of the present invention.
Claims (10)
1. The preparation method of the dabigatran etexilate intermediate compound p-aminobenzonitrile is characterized by comprising the following steps: the aminobenzonitrile is prepared by taking a compound 3 as a raw material through a cyanation reaction, and the synthetic route is as follows:
wherein (1) is oxalyl chloride and (2) is phosphorus oxychloride; or (1) potassium hydroxide and (2) dimethyl sulfoxide. .
2. The preparation method of the dabigatran etexilate intermediate compound p-aminobenzonitrile according to claim 1, which is characterized in that: the molar ratio of compound 3 to oxalyl chloride is 1:1-5, more preferably 1:3.
3. The preparation method of the dabigatran etexilate intermediate compound p-aminobenzonitrile according to claim 1, which is characterized in that: the feeding mole ratio of the compound 3 to the phosphorus tribenzoate is 1:0.05-0.5, and more preferably 1:0.1.
4. The preparation method of the dabigatran etexilate intermediate compound p-aminobenzonitrile according to claim 1, which is characterized in that: the molar ratio of compound 3 to potassium hydroxide is 1:0.05-0.5, more preferably 1:0.1.
5. The preparation method of the dabigatran etexilate intermediate compound p-aminobenzonitrile according to claim 1, which is characterized in that: the feed ratio of the compound 3 to the dimethyl sulfoxide is 1:0.1-1mol/L, and more preferably 1:0.5mol/L.
6. The preparation method of the dabigatran etexilate intermediate compound p-aminobenzonitrile according to claim 1, which is characterized in that: the compound 3 is prepared from a compound 2 and hydroxylamine hydrochloride, and the synthetic route is as follows:
7. the method for preparing the dabigatran etexilate intermediate compound p-aminobenzonitrile according to claim 6, which is characterized in that: compound 2 and hydroxylamine hydrochloride are reacted in the presence of sodium acetate trihydrate to prepare compound 3.
8. The method for preparing the dabigatran etexilate intermediate compound p-aminobenzonitrile according to claim 7, which is characterized in that: the molar ratio of the compound 2 to hydroxylamine hydrochloride and sodium acetate trihydrate is 1:1-3:1-3, preferably 1:2:2.
9. The method for preparing the dabigatran etexilate intermediate compound p-aminobenzonitrile according to claim 7, which is characterized in that: the reaction time of the compound 2 with hydroxylamine hydrochloride is 12 to 20 hours, preferably 16 hours.
10. The method for preparing the dabigatran etexilate intermediate compound p-aminobenzonitrile according to claim 6, which is characterized in that: the compound 2 is formed by reducing a compound 1 under the action of sodium disulfide, and the synthetic route is as follows:
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