CN118026860A - Preparation method of 3- [1- (dimethylamino) ethyl ] phenol - Google Patents
Preparation method of 3- [1- (dimethylamino) ethyl ] phenol Download PDFInfo
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- CN118026860A CN118026860A CN202410161223.XA CN202410161223A CN118026860A CN 118026860 A CN118026860 A CN 118026860A CN 202410161223 A CN202410161223 A CN 202410161223A CN 118026860 A CN118026860 A CN 118026860A
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- GQZXRLWUYONVCP-UHFFFAOYSA-N 3-[1-(dimethylamino)ethyl]phenol Chemical compound CN(C)C(C)C1=CC=CC(O)=C1 GQZXRLWUYONVCP-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- DWLZULQNIPIABE-UHFFFAOYSA-N 1-ethyl-3-methoxybenzene Chemical compound CCC1=CC=CC(OC)=C1 DWLZULQNIPIABE-UHFFFAOYSA-N 0.000 claims abstract description 12
- HMNKTRSOROOSPP-UHFFFAOYSA-N 3-Ethylphenol Chemical compound CCC1=CC=CC(O)=C1 HMNKTRSOROOSPP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- -1 3- [1- (dimethylamino) ethyl ] anisole compound Chemical class 0.000 claims description 13
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- YGBWEVLCLQXBKI-UHFFFAOYSA-N 1-(1-bromoethyl)-3-methoxybenzene Chemical compound COC1=CC=CC(C(C)Br)=C1 YGBWEVLCLQXBKI-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical group N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 8
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 6
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 5
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 claims description 5
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 239000012022 methylating agents Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 238000006193 diazotization reaction Methods 0.000 abstract description 6
- 238000006396 nitration reaction Methods 0.000 abstract description 6
- 238000006722 reduction reaction Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 230000011987 methylation Effects 0.000 abstract description 2
- 238000007069 methylation reaction Methods 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 12
- 239000000243 solution Substances 0.000 description 9
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 229960004136 rivastigmine Drugs 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- KFKCIWQNLGOHOA-UHFFFAOYSA-N 1-(3-methoxyphenyl)-n,n-dimethylethanamine Chemical compound COC1=CC=CC(C(C)N(C)C)=C1 KFKCIWQNLGOHOA-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 108010053652 Butyrylcholinesterase Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102100032404 Cholinesterase Human genes 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000002932 cholinergic neuron Anatomy 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- FPLYNRPOIZEADP-UHFFFAOYSA-N octylsilane Chemical group CCCCCCCC[SiH3] FPLYNRPOIZEADP-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000016978 synaptic transmission, cholinergic Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 3- [1- (dimethylamino) ethyl ] phenol, which comprises the steps of reacting 3-ethylphenol with a methylation reagent to obtain 3-ethylanisole; the invention avoids the steps of nitration, diazotization, reduction reaction and the like with great industrialization difficulty, and the 4-step reaction is generally milder and easier to realize industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemical industry, and in particular relates to a preparation method of a key intermediate 3- [1- (dimethylamino) ethyl ] phenol of a medicine for treating Alzheimer dementia, namely rivastigmine.
Background
Rivastigmine is a reversible acetylcholinesterase inhibitor and is used clinically mainly for treating symptoms of dementia of the light and moderate Alzheimer's type. Rivastigmine is an inhibitor of acetyland butyrylcholinesterase selectively acting on the brain and promoting cholinergic neurotransmission by delaying the degradation of acetylcholine released by intact cholinergic neurons. Currently, the method is marketed in Europe and America, china, india, japan and south America.
The synthesis route of the key intermediate 3- [1- (dimethylamino) ethyl ] phenol of rivastigmine described in the prior document CN106242957a and "improvement of the synthesis method of rivastigmine" (16 th edition 20 of journal of new medicine in china 2007) is as follows:
The disadvantage of this reaction scheme is that the final step is carried out at 150℃for a long period of time by nitration, reduction, diazotization. The nitration reaction produces a large amount of waste acid and waste water, the waste water amount is large, the danger is high, and batch or semi-batch kettle nitration processes are classified as obsolete processes. The nitro reduction and diazotization are dangerous processes, and the diazotization generates nitric oxide gas and special equipment oxidizes and absorbs tail gas, so that the synthetic route is not friendly to environment, has special requirements on reaction equipment, and is high in safety risk and unfavorable for industrial production.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a novel synthesis method of 3- [1- (dimethylamino) ethyl ] phenol, compared with the prior art, the method avoids the steps of nitration, diazotization, reduction reaction and the like with great industrialization difficulty, and the reaction is generally milder and is easier to realize industrial production.
In order to achieve the above purpose, the present invention is realized by the following technical scheme:
a process for the preparation of 3- [1- (dimethylamino) ethyl ] phenol comprising the steps of:
(1) Reacting the 3-ethyl phenol compound II with a methylating agent to obtain a 3-ethyl anisole compound III;
(2) Brominating the 3-ethyl anisole compound III obtained in the previous step to obtain a 3- (1-bromoethyl) anisole compound IV;
(3) Condensing the 3- (1-bromoethyl) anisole compound IV obtained in the previous step with dimethylamine hydrochloride to obtain a 3- [1- (dimethylamino) ethyl ] anisole compound V;
(4) The 3- [1- (dimethylamino) ethyl ] anisole compound V obtained in the previous step is hydrolyzed to obtain 3- [1- (dimethylamino) ethyl
A radical ] phenol compound I;
The chemical reaction flow is as follows:
The chemical reaction flow is as follows:
Further, the methylation reagent in the step (1) is dimethyl sulfate.
Further, the brominating reagent in the step (2) is N-bromosuccinimide (NBS for short), and the catalyst is azobisisobutyronitrile (AIBN for short).
Further, the reaction solvent in the step (3) is dimethylformamide, and the acid binding agent is sodium carbonate.
Further, the reaction solvent in the step (4) is hydrobromic acid aqueous solution.
More specifically, a process for the preparation of 3- [1- (dimethylamino) ethyl ] phenol comprising the steps of:
(1) Reacting a 3-ethyl phenol compound II with dimethyl sulfate in the presence of sodium hydroxide and tetrabutylammonium hydroxide, and extracting with dichloromethane after the reaction is finished to obtain a 3-ethyl anisole compound III;
(2) In the presence of N-bromosuccinimide, azodiisobutyronitrile and chloroform solvent, carrying out bromination reaction on a 3-ethyl anisole compound III to obtain a 3- (1-bromoethyl) anisole compound IV;
(3) Condensing 3- (1-bromoethyl) anisole compound IV with dimethylamine hydrochloride in the presence of dimethylformamide and sodium carbonate, adding water after the reaction, adjusting the pH value to 1.0, extracting with ethyl acetate to remove impurities, adjusting the pH value of the reaction solution to 10.0, extracting with ethyl acetate, drying and concentrating to obtain 3- [1- (dimethylamino) ethyl ] anisole compound V;
(4) Dissolving 3- [1- (dimethylamino) ethyl ] anisole compound V in hydrobromic acid for reflux reaction, extracting with ethyl acetate to remove impurities after the reaction is finished, adjusting the pH value of a water layer to 10.0, extracting with ethyl acetate, drying, filtering, concentrating to dryness, and recrystallizing with ethyl acetate to obtain 3- [1- (dimethylamino) ethyl ] phenol compound I;
The chemical reaction flow is as follows:
compared with the synthesis method of 3- [1- (dimethylamino) ethyl ] phenol reported in the prior literature, the invention has the main advantages that: the method avoids the steps of nitration, diazotization, reduction reaction and the like with great industrialization difficulty, and the reaction is generally milder and is easier to realize industrial production.
Drawings
Fig. 1: example 43 chemical purity of- [1- (dimethylamino) ethyl ] phenol (compound of formula i) HPLC detection chromatogram.
Detailed Description
The foregoing of the invention will be described in further detail by way of embodiments represented by the following specific examples, but it should not be construed that the scope of the above subject matter of the invention is limited to the following specific embodiments. All techniques based on the above-described experiments of the present invention are within the scope of the present invention.
Example 1: synthesis of 3-ethyl anisole (Compound of formula III)
200 G (5 mol) of sodium hydroxide is added into a three-necked flask, 1000 ml of aqueous solution of tetrabutylammonium hydroxide (0.1 mol/L) is added, stirring is started, 305 g (2.5 mol) of 3-ethylphenol (compound of formula II) and 500ml of water are prepared into a solution, the solution is slowly dropped into the three-necked flask, the reaction solution is cooled to 10-15 ℃,300 ml (3 mol) of dimethyl sulfate is slowly dropped, the solution is stirred for 2 hours at 10-15 ℃ after the dropping, the temperature is raised to 25-30 ℃ after the stirring is completed, the aqueous layer is extracted twice by 2000 ml of dichloromethane, the organic layer is dried by magnesium sulfate and then concentrated, and colorless oily substance 312 g (2.3 mol) is obtained, and the yield is 92%.
Example 2: synthesis of 3- (1-bromoethyl) anisole (Compound of formula IV)
In a three-necked flask, 312 g (2.3 mol) of 3-ethylanisole (compound of formula III) obtained in example 1, 3.8g (0.023 mol) of azobisisobutyronitrile (i.e., AIBN), 427 g (2.4 mol) of NBS were added, refluxed with 3000mL of chloroform for 1 hour, cooled and filtered, and the filtrate was washed with saturated sodium hydrogencarbonate and brine, and then dried over sodium sulfate and concentrated. 449 g of a mixture of 3- (1-bromoethyl) anisole and 3-ethylanisole was obtained, wherein the product (compound of formula IV) was about 75% and the starting material (compound of formula III) was about 25% and was used without further purification.
Example 3: synthesis of 3- [1- (dimethylamino) ethyl ] anisole (Compound of formula V)
In a three-necked flask, 346.5g (4.25 mol) of dimethylamine hydrochloride, (3200 mL) of DMF and 742g (7.0 mol) of sodium carbonate were added, stirring was started, 449 g (1.7 mol) of the compound of formula IV obtained in example 2 was added, the reaction system was stirred at 30 to 35℃for 7 hours, the solid salt was filtered off, the solvent was evaporated in vacuo, 1500 mL of water was added, concentrated hydrochloric acid was added dropwise to a pH value of 1.0, ethyl acetate (1000 mL. Times.3) was used to extract the aqueous layer, the organic layer was discarded, the aqueous layer was adjusted to a pH value of 10.0 with liquid alkali, ethyl acetate (1000 mL. Times.3) was used to extract, and the combined organic phase was washed sequentially with water (500 mL) and saturated brine (500 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 244 g (1.36 mol) of oily compound, the yield 80%.
Example 4: synthesis of 3- [1- (dimethylamino) ethyl ] phenol (Compound of formula I)
In a three-necked flask, 94g (0.52 mol) of 3- [1- (dimethylamino) ethyl ] anisole (compound of formula V) obtained in example 3 were dissolved in 284 ml of 48% hydrobromic acid, and the resulting solution was refluxed with stirring in a reflux condenser for 12 hours. During the reflux, the reaction mixture was darkened, hydrobromic acid was distilled off under vacuum, and the evaporated residue was dissolved in 200 ml of water. The solution was decolorized with 5g of active carbon, extracted with 100ml of acetic acid for 3 times, the aqueous layer was adjusted to pH 10.0 with liquid base, extracted with 300ml of ethyl acetate for 3 times, the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness and recrystallized with ethyl acetate to give 78.2 g (0.47 mol) of a white-like powder in 92% yield. The purity was 99.9%.
HPLC detection method for 3- [1- (dimethylamino) ethyl ] phenol (compound of formula I)
The sample solution is taken in a proper amount, and is added with flow matching to prepare a solution containing about 0.3mg of the sample per 1ml, and the solution is uniformly shaken to be used as the sample solution.
The chromatographic conditions were followed by using a octyl silane bonded silica gel column (C8 5 mu.4.6X150 mm), methanol/water (7.16 g of disodium hydrogen phosphate dodecahydrate, 1000ml of water was added, pH was adjusted to 8.5) =50/50 (v/v) with dilute phosphoric acid as the mobile phase, column temperature was 35 ℃, flow rate was 1.0ml/min, detection wavelength was 215nm, sample injection amount was 10. Mu.l, and acquisition time was 25min.
Claims (6)
1. A process for the preparation of 3- [1- (dimethylamino) ethyl ] phenol, characterized by the steps of:
(1) Reacting the 3-ethyl phenol compound II with a methylating agent to obtain a 3-ethyl anisole compound III;
(2) Brominating the 3-ethyl anisole compound III obtained in the previous step to obtain a 3- (1-bromoethyl) anisole compound IV;
(3) Condensing the 3- (1-bromoethyl) anisole compound IV obtained in the previous step with dimethylamine hydrochloride to obtain a 3- [1- (dimethylamino) ethyl ] anisole compound V;
(4) Hydrolyzing the 3- [1- (dimethylamino) ethyl ] anisole compound V obtained in the previous step to obtain a 3- [1- (dimethylamino) ethyl ] phenol compound I;
The chemical reaction flow is as follows:
2. the method for producing 3- [1- (dimethylamino) ethyl ] phenol according to claim 1, wherein: the methylating agent in the step (1) is dimethyl sulfate.
3. The method for producing 3- [1- (dimethylamino) ethyl ] phenol according to claim 1, wherein: the brominating reagent used in the step (2) is N-bromosuccinimide, and the catalyst is azodiisobutyronitrile.
4. The method for producing 3- [1- (dimethylamino) ethyl ] phenol according to claim 1, wherein: the reaction solvent used in the step (3) is dimethylformamide, and the acid-binding agent is sodium carbonate.
5. The method for producing 3- [1- (dimethylamino) ethyl ] phenol according to claim 1, wherein: the reaction solvent used in the step (4) is an aqueous hydrobromic acid solution.
6. A process for the preparation of 3- [1- (dimethylamino) ethyl ] phenol, characterized by the steps of:
(1) Reacting a 3-ethyl phenol compound II with dimethyl sulfate in the presence of sodium hydroxide and tetrabutylammonium hydroxide, and extracting with dichloromethane after the reaction is finished to obtain a 3-ethyl anisole compound III;
(2) In the presence of N-bromosuccinimide, azodiisobutyronitrile and chloroform solvent, carrying out bromination reaction on a 3-ethyl anisole compound III to obtain a 3- (1-bromoethyl) anisole compound IV;
(3) Condensing 3- (1-bromoethyl) anisole compound IV with dimethylamine hydrochloride in the presence of dimethylformamide and sodium carbonate, adding water after the reaction, adjusting the pH value to 1.0, extracting with ethyl acetate to remove impurities, adjusting the pH value of the reaction solution to 10.0, extracting with ethyl acetate, drying and concentrating to obtain 3- [1- (dimethylamino) ethyl ] anisole compound V;
(4) Dissolving 3- [1- (dimethylamino) ethyl ] anisole compound V in hydrobromic acid for reflux reaction, extracting with ethyl acetate to remove impurities after the reaction is finished, adjusting the pH value of a water layer to 10.0, extracting with ethyl acetate, drying, filtering, concentrating to dryness, and recrystallizing with ethyl acetate to obtain 3- [1- (dimethylamino) ethyl ] phenol compound I;
The chemical reaction flow is as follows:
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