CN114853619A - Preparation method of N-methyltyramine hydrochloride suitable for industrial production - Google Patents
Preparation method of N-methyltyramine hydrochloride suitable for industrial production Download PDFInfo
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- CN114853619A CN114853619A CN202210552860.0A CN202210552860A CN114853619A CN 114853619 A CN114853619 A CN 114853619A CN 202210552860 A CN202210552860 A CN 202210552860A CN 114853619 A CN114853619 A CN 114853619A
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- CN
- China
- Prior art keywords
- methyltyramine
- reaction
- industrial production
- hydrochloride
- hydroxyphenylethylamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- JNZSSRZVHCKFLK-UHFFFAOYSA-N 2-(4-hydroxyphenyl)ethyl-methylazanium;chloride Chemical compound Cl.CNCCC1=CC=C(O)C=C1 JNZSSRZVHCKFLK-UHFFFAOYSA-N 0.000 title claims abstract description 33
- AXVZFRBSCNEKPQ-UHFFFAOYSA-N N-Methyltyramine Natural products CNCCC1=CC=C(O)C=C1 AXVZFRBSCNEKPQ-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000009776 industrial production Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000001914 filtration Methods 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 23
- DZGWFCGJZKJUFP-UHFFFAOYSA-N tyramine Chemical compound NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 17
- 230000022244 formylation Effects 0.000 claims abstract description 15
- 238000006170 formylation reaction Methods 0.000 claims abstract description 15
- 239000002841 Lewis acid Substances 0.000 claims abstract description 13
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000001816 cooling Methods 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 10
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 238000002386 leaching Methods 0.000 claims abstract description 8
- 239000007789 gas Substances 0.000 claims abstract description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 7
- 230000018044 dehydration Effects 0.000 claims abstract description 4
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 4
- 239000000706 filtrate Substances 0.000 claims abstract description 4
- 239000007788 liquid Substances 0.000 claims abstract description 4
- 239000012044 organic layer Substances 0.000 claims abstract description 4
- 239000000047 product Substances 0.000 claims abstract description 4
- 238000010791 quenching Methods 0.000 claims abstract description 4
- 230000000171 quenching effect Effects 0.000 claims abstract description 4
- 238000000926 separation method Methods 0.000 claims abstract description 4
- 239000007787 solid Substances 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000003786 synthesis reaction Methods 0.000 claims description 14
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- -1 N- (4-hydroxybenzylethyl) formamide Chemical compound 0.000 claims description 6
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical group COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- CHNLPLHJUPMEOI-UHFFFAOYSA-N oxolane;trifluoroborane Chemical compound FB(F)F.C1CCOC1 CHNLPLHJUPMEOI-UHFFFAOYSA-N 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 229910004664 Cerium(III) chloride Inorganic materials 0.000 claims description 3
- 239000012448 Lithium borohydride Substances 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 3
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 230000003321 amplification Effects 0.000 abstract description 2
- ZRAJFHFOIYKZPF-UHFFFAOYSA-N n-[2-(4-hydroxyphenyl)ethyl]formamide Chemical compound OC1=CC=C(CCNC=O)C=C1 ZRAJFHFOIYKZPF-UHFFFAOYSA-N 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 230000006837 decompression Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 6
- JCDWXESTXVUQNR-UHFFFAOYSA-N n-[(4-hydroxyphenyl)methyl]formamide Chemical compound OC1=CC=C(CNC=O)C=C1 JCDWXESTXVUQNR-UHFFFAOYSA-N 0.000 description 5
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- XQXPVVBIMDBYFF-UHFFFAOYSA-N 4-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- HPOIPOPJGBKXIR-UHFFFAOYSA-N 3,6-dimethoxy-10-methyl-galantham-1-ene Natural products O1C(C(=CC=2)OC)=C3C=2CN(C)CCC23C1CC(OC)C=C2 HPOIPOPJGBKXIR-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- LPCKPBWOSNVCEL-UHFFFAOYSA-N Chlidanthine Natural products O1C(C(=CC=2)O)=C3C=2CN(C)CCC23C1CC(OC)C=C2 LPCKPBWOSNVCEL-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 239000002537 cosmetic Substances 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
- 150000002148 esters Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- BHEQMFPTERNULE-UHFFFAOYSA-N formamide;oxolane Chemical compound NC=O.C1CCOC1 BHEQMFPTERNULE-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- BGLNUNCBNALFOZ-WMLDXEAASA-N galanthamine Natural products COc1ccc2CCCC[C@@]34C=CCC[C@@H]3Oc1c24 BGLNUNCBNALFOZ-WMLDXEAASA-N 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- IYVSXSLYJLAZAT-NOLJZWGESA-N lycoramine Natural products CN1CC[C@@]23CC[C@H](O)C[C@@H]2Oc4cccc(C1)c34 IYVSXSLYJLAZAT-NOLJZWGESA-N 0.000 description 1
- 239000000203 mixture Substances 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
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- 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
- C07C213/08—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 not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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 N-methyltyramine hydrochloride suitable for industrial production, which comprises the following preparation steps: reacting 4-hydroxyphenylethylamine with a formylation reagent in a closed system, cooling to room temperature after the 4-hydroxyphenylethylamine completely reacts, adding N-heptane, carrying out solvent replacement by decompression concentration to separate out a solid, filtering, leaching and drying to obtain N- (4-hydroxyphenylethyl) formamide; heating the obtained N- (4-hydroxybenzene ethyl) formamide, a reducing reagent, a solvent and Lewis acid for reaction, and adding water for quenching after the reaction is completed; adjusting the pH value to 7.5-8.5, then carrying out salt filtration, carrying out liquid separation and washing on the filtrate, concentrating an organic layer, carrying out azeotropic dehydration by using isopropanol, and introducing hydrogen chloride gas to form salt; continuously adding N-heptane, crystallizing at low temperature, filtering, leaching and drying to obtain the product N-methyltyramine hydrochloride; through the mode, the method is convenient to operate, the cost is obviously reduced, meanwhile, the pollution is small, and the method is suitable for industrial amplification.
Description
Technical Field
The invention relates to the technical field of preparation of organic synthesis intermediates, in particular to a preparation method of N-methyltyramine hydrochloride suitable for industrial production.
Background
N-methyltyramine hydrochloride is widely applied to the direction of additives of foods or cosmetics, and is also an intermediate for synthesizing a drug galanthamine, and the structural formula of the N-methyltyramine hydrochloride is shown as follows:
the synthesis method of N-methyltyramine hydrochloride in the prior art mainly comprises the following steps:
1. the synthesis method disclosed in the patent (publication No. CN103755576A) is as follows:
in the synthesis method, noble metal palladium is needed to be used as a catalyst, and high-pressure hydrogenation reaction is involved, so that high requirements on equipment and safety are met.
2. The synthetic route adopted in the patent (International publication No.: WO2008127560A1) is as follows:
according to the method, after hydrobromic acid is adopted for bromination, methylamine is adopted for nucleophilic substitution, but the hydrobromic acid has strong irritation, an intermediate bromide is sensitive to skin, a reaction product contains methylamine bromide hydrogen salt and is difficult to remove, and the cost of the whole synthesis process is slightly high.
3. The synthesis method disclosed in the patent (publication number: CN106977411A) is as follows:
the method takes 4-hydroxy-phenylacetic acid as a raw material, prepares acyl chloride by thionyl chloride, condenses with methylamine to form amide, and reduces by metal borohydride under the catalysis of Lewis acid, and the thionyl chloride used in the preparation of the amide in the route has large corrosion to equipment.
The preparation of the N-methyltyramine hydrochloride has high cost, high equipment requirement, or existence of solvents with strong irritation or corrosiveness, and has great challenges for industrial scale-up production and difficult popularization.
Disclosure of Invention
The invention mainly solves the technical problem of providing a preparation method of N-methyltyramine hydrochloride suitable for industrial production, which is convenient to operate, obviously reduces the cost, has small pollution and is suitable for industrial amplification.
In order to solve the technical problems, the invention adopts a technical scheme that: provides a preparation method of N-methyltyramine hydrochloride suitable for industrial production, which comprises the following preparation steps:
1. synthesis of N- (4-hydroxybenzylethyl) formamide:
(a) reacting 4-hydroxyphenylethylamine with a formylation reagent in a closed system, detecting complete reaction of the 4-hydroxyphenylethylamine by HPLC, and cooling;
(b) after the temperature is reduced to room temperature, adding N-heptane, performing solvent replacement through reduced pressure concentration to separate out solid, then filtering, leaching and drying to obtain N- (4-hydroxybenzene ethyl) formamide;
2. synthesis of N-methyltyramine hydrochloride:
(c) adding the N- (4-hydroxybenzene ethyl) formamide obtained in the step (b) into a reaction bottle at a low temperature, simultaneously adding a reducing reagent, a solvent and Lewis acid, heating for reaction, detecting the reaction by HPLC, and adding water for quenching;
(d) adjusting the pH value to 7.5-8.5, then carrying out salt filtration, carrying out liquid separation and washing on the filtrate, concentrating an organic layer, carrying out azeotropic dehydration by using isopropanol, and introducing hydrogen chloride gas to form salt;
(e) continuously adding N-heptane, crystallizing at low temperature, filtering, leaching and drying to obtain the product N-methyltyramine hydrochloride;
the reaction principle of the above process is as follows:
preferably, after the 4-hydroxyphenylethylamine and the formylation reagent are added into the closed system in the step (a), the temperature of the system is raised to 50-80 ℃ for reaction, the reaction time is 12-16 h, and the reaction pressure is 0.1-0.5 Mpa.
Preferably, the formylation reagent is any one or combination of formic acid and C1-4 formate.
Preferably, the formylation reagent is methyl formate or ethyl formate, and the molar amount of the formylation reagent is 1-10 times of that of the raw material 4-hydroxyphenylethylamine.
Preferably, the reducing agent in the step (c) is any one or a combination of more than one of sodium borohydride, potassium borohydride and lithium borohydride, and the molar amount of the reducing agent is 1-4 times that of the raw material 4-hydroxyphenylethylamine.
Preferably, the solvent in the step (c) is any one or combination of toluene, tetrahydrofuran and ethylene glycol dimethyl ether.
Preferably, in the step (c), the lewis acid is one or a combination of more of anhydrous zinc chloride, ferric trichloride, anhydrous aluminum trichloride, cerium trichloride, boron trifluoride diethyl etherate and boron trifluoride tetrahydrofuran, and the molar amount of the lewis acid is 0.5-4 times of that of the raw material 4-hydroxyphenylethylamine.
Preferably, the reaction temperature in the step (c) is-5 to 40 ℃, and the reaction time is 2 to 12 hours.
Preferably, the pH adjustment process in the step (d) is to adjust the pH to 2-3 by using 37% hydrochloric acid and stir for 1h, and then adjust the pH to 7.5-8.5 by using 15% sodium hydroxide solution.
Preferably, the salt filtering process in the step (d) is to add saturated salt solution, stir for 1-2 h, add diatomite and filter.
The invention has the beneficial effects that:
according to the preparation method of the N-methyl tyramine hydrochloride suitable for industrial production, provided by the invention, 4-hydroxy phenethylamine with low price is taken as a starting material, Lewis acid is added into metal borohydride for reduction after formylation, and hydrogen chloride gas is used for acidification to form salt, so that the operation is convenient, the cost is obviously reduced, the cost of the currently marketed N-methyl tyramine hydrochloride is 1200 yuan/kg, the preparation cost is only 600-700 yuan/kg through the preparation method, the production cost is effectively reduced, meanwhile, the method is low in pollution, the blank of the preparation method of the N-methyl tyramine hydrochloride suitable for industrial production in the market is effectively filled up, and the preparation method has good market popularization value.
Detailed Description
The following detailed description of the preferred embodiments of the present invention is provided to enable those skilled in the art to more readily understand the advantages and features of the present invention, and to clearly and unequivocally define the scope of the present invention.
The invention relates to a preparation method of N-methyltyramine hydrochloride suitable for industrial production, which comprises the following preparation steps:
first, synthesis of N- (4-hydroxyphenylethyl) formamide:
(a) reacting 4-hydroxyphenylethylamine with a formylation reagent in a closed system, raising the temperature of the system to 50-80 ℃ for reaction, wherein the reaction time is 12-16 h, the reaction pressure is 0.1-0.5 Mpa, completely reacting the 4-hydroxyphenylethylamine by HPLC detection, and cooling;
the formylation reagent is any one or combination of formic acid and C1-4 formic esters, preferably methyl formate or ethyl formate, and the molar amount of the formylation reagent is 1-10 times of that of the raw material 4-hydroxyphenylethylamine.
(b) And after the temperature is reduced to room temperature, adding N-heptane, carrying out solvent replacement through reduced pressure concentration, precipitating a solid, filtering, leaching and drying to obtain the N- (4-hydroxybenzyl ethyl) formamide.
Secondly, synthesis of N-methyltyramine hydrochloride:
(c) adding the N- (4-hydroxybenzene ethyl) formamide obtained in the step (b) into a reaction bottle at a low temperature, simultaneously adding a reducing reagent, a solvent and Lewis acid, heating for reaction, detecting the reaction by HPLC, and adding water for quenching;
wherein: the reducing reagent is any one or combination of more of sodium borohydride, potassium borohydride and lithium borohydride; the solvent is any one or combination of more of toluene, tetrahydrofuran and ethylene glycol dimethyl ether, and further, the molar amount of the reducing reagent is 1-4 times that of the raw material 4-hydroxyphenylethylamine; the Lewis acid is one or a combination of more of anhydrous zinc chloride, ferric trichloride, anhydrous aluminum trichloride, cerium trichloride, boron trifluoride diethyl etherate and boron trifluoride tetrahydrofuran; the reaction temperature range is-5-40 ℃, the reaction time is 2-12 h, and furthermore, the molar amount of the Lewis acid is 0.5-4 times of that of the raw material 4-hydroxyphenylethylamine.
(d) Adjusting the pH value to 7.5-8.5, then carrying out salt filtration, carrying out liquid separation and washing on the filtrate, concentrating an organic layer, carrying out azeotropic dehydration by using isopropanol, and introducing hydrogen chloride gas to form salt;
further, the pH is adjusted to 2-3 by using 37% hydrochloric acid and stirred for 1h, then the pH is adjusted to 7.5-8.5 by using 15% sodium hydroxide solution, the salt filtering process is to add saturated salt solution and stir for 1-2 h, and then diatomite is added for filtering.
(e) And (3) continuously adding N-heptane, crystallizing at low temperature, filtering, leaching and drying to obtain the product N-methyltyramine hydrochloride.
The reaction principle of the invention is as follows:
two groups of examples are given below for the synthesis of N- (4-hydroxybenzyl) formamide in step 1 and the synthesis of N-methyltyramine hydrochloride in step 2, respectively, wherein the yield of each group of examples is calculated as the ratio of the actual synthesis amount to the theoretical synthesis amount.
Synthesis of N- (4-hydroxybenzylethyl) formamide:
example 1:
adding 4-hydroxyphenylethylamine (55g, 0.4mol) and ethyl formate (152g, 2.5mol) into a reaction bottle, heating to 77 ℃ under a closed system, reacting under the pressure of 0.138Mpa, stirring for 12h, and cooling to 25 ℃ after complete reaction through HPLC detection;
adding N-heptane (165ml), concentrating under reduced pressure to 110ml, filtering, rinsing with N-heptane (55ml), and vacuum drying at 45 deg.C to obtain 59.7g of N- (4-hydroxybenzyl) formamide with a yield of 90.5%.
Example 2:
adding 4-hydroxyphenylethylamine (6g, 0.44mol) and ethyl formate (16.5g, 0.28mol) into a reaction bottle, heating to 50 ℃ under a closed system, reacting under the pressure of 0.11Mpa, stirring for 16h, and cooling to 25 ℃ after complete reaction through HPLC detection;
adding N-heptane (18ml), concentrating under reduced pressure to 12ml, filtering, rinsing with N-heptane (6ml), and vacuum drying at 45 deg.C to obtain 6.96g of N- (4-hydroxybenzyl) formamide with a yield of 96.4%.
The synthetic method for preparing the N- (4-hydroxybenzene ethyl) formamide has the advantage that the yield range is kept above 90%.
Synthesis of N-methyltyramine hydrochloride:
example 3:
adding N- (4-hydroxybenzene ethyl) formamide (10g, 0.061mol), sodium borohydride (4.6g, 0.121mol) and tetrahydrofuran (80ml) into a reaction bottle, stirring and dissolving, cooling to 5 ℃, adding boron trifluoride tetrahydrofuran (17g, 0.121mol), heating to 40 ℃, stirring for 2 hours, detecting the reaction completion by HPLC, cooling to room temperature, adding water (5ml), adjusting the pH to 2.5 by using 37% hydrochloric acid, stirring for 1 hour by using a 15% sodium hydroxide solution, adding saturated saline (40ml), stirring for 1 hour, adding kieselguhr, filtering, separating, washing an organic phase by using saturated saline (40ml), and separating;
using isopropanol (40ml) to carry water twice until the water content of the organic phase is 1.5%, concentrating to 20ml, filtering, introducing hydrogen chloride gas until the reaction is complete, adding n-heptane (20ml), reducing the temperature to 0 ℃, stirring for 1h, filtering, drying n-heptane (6ml) at 40 ℃ to obtain 9.2g, wherein the yield is 81%.
Example 4:
adding boron trifluoride tetrahydrofuran (17g, 0.121mol), sodium borohydride (4.6g, 0.121mol) and tetrahydrofuran (20ml) into a reaction bottle, cooling to 5 ℃, adding N- (4-hydroxybenzoethyl) formamide (10g, 0.061mol) and tetrahydrofuran (60ml) into another reactor, stirring and dissolving, dropwise adding an N- (4-hydroxybenzoethyl) formamide tetrahydrofuran solution into a sodium borohydride reaction solution, heating to 40 ℃, stirring for 2h, detecting complete reaction by HPLC, cooling to room temperature, adding water (5ml), adjusting pH to 2.5 by using 37% hydrochloric acid, stirring for 1h, adjusting pH to 8 by using 15% sodium hydroxide solution, adding saturated saline (40ml), stirring for 1h, adding kieselguhr, filtering, separating, washing an organic phase by using saturated saline (40ml), and separating.
Using isopropanol (40ml) with water twice until the water content of the organic phase is about 1.5%, concentrating to 20ml, filtering, introducing hydrogen chloride gas until the reaction is complete, adding n-heptane (20ml), reducing the temperature to 0 ℃, stirring for 1h, filtering, washing with n-heptane (6ml), drying at 40 ℃ to obtain 10.2g, yield: 90 percent.
Example 3 and example 4 apart from the differences in formulation content, the sequence of addition of the lewis acid and N- (4-hydroxybenzyl) formamide, which has an effect on the yield of the end product, is different, wherein the yield of the synthetic process according to the invention for the preparation of N- (4-hydroxybenzyl) formamide remains in the range of more than 80%.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (10)
1. The preparation method of the N-methyltyramine hydrochloride suitable for industrial production is characterized by comprising the following preparation steps:
1. synthesis of N- (4-hydroxybenzylethyl) formamide:
(a) reacting 4-hydroxyphenylethylamine with a formylation reagent in a closed system, detecting complete reaction of the 4-hydroxyphenylethylamine by HPLC, and cooling;
(b) after the temperature is reduced to room temperature, adding N-heptane, carrying out solvent replacement through reduced pressure concentration, separating out a solid, then filtering, leaching and drying to obtain N- (4-hydroxybenzyl ethyl) formamide;
2. synthesis of N-methyltyramine hydrochloride:
(c) adding the N- (4-hydroxybenzene ethyl) formamide obtained in the step (b) into a reaction bottle at a low temperature, simultaneously adding a reducing reagent, a solvent and Lewis acid, heating for reaction, detecting the reaction by HPLC, and adding water for quenching;
(d) adjusting the pH value to 7.5-8.5, then carrying out salt filtration, carrying out liquid separation and washing on the filtrate, concentrating an organic layer, carrying out azeotropic dehydration by using isopropanol, and introducing hydrogen chloride gas to form salt;
(e) continuously adding N-heptane, crystallizing at low temperature, filtering, leaching and drying to obtain the product N-methyltyramine hydrochloride;
the reaction principle of the above process is as follows:
2. the method for preparing N-methyltyramine hydrochloride suitable for industrial production according to claim 1, wherein: after the 4-hydroxyphenylethylamine and the formylation reagent are added into the closed system in the step (a), the temperature of the system is raised to 50-80 ℃ for reaction, the reaction time is 12-16 h, and the reaction pressure is 0.1-0.5 Mpa.
3. The method for preparing N-methyltyramine hydrochloride suitable for industrial production according to claim 1, wherein: the formylation reagent is any one or combination of formic acid and formic ether with 1-4 carbon atoms.
4. The method for preparing N-methyltyramine hydrochloride suitable for industrial production according to claim 3, wherein: the formylation reagent is preferably methyl formate or ethyl formate, and the molar amount of the formylation reagent is 1-10 times of that of the raw material 4-hydroxyphenylethylamine.
5. The method for preparing N-methyltyramine hydrochloride suitable for industrial production according to claim 1, wherein: the reducing agent in the step (c) is any one or combination of more of sodium borohydride, potassium borohydride and lithium borohydride, and the molar amount of the reducing agent is 1-4 times that of the raw material 4-hydroxyphenylethylamine.
6. The method for preparing N-methyltyramine hydrochloride suitable for industrial production according to claim 1, wherein: the solvent in the step (c) is any one or combination of more of toluene, tetrahydrofuran and ethylene glycol dimethyl ether.
7. The method for preparing N-methyltyramine hydrochloride suitable for industrial production according to claim 1, wherein: in the step (c), the Lewis acid is one or more of anhydrous zinc chloride, ferric trichloride, anhydrous aluminum trichloride, cerium trichloride, boron trifluoride diethyl etherate and boron trifluoride tetrahydrofuran, and the molar amount of the Lewis acid is 0.5-4 times of that of the 4-hydroxyphenylethylamine serving as the raw material.
8. The method for preparing N-methyltyramine hydrochloride suitable for industrial production according to claim 1, wherein: the reaction temperature in the step (c) is-5-40 ℃, and the reaction time is 2-12 h.
9. The method for preparing N-methyltyramine hydrochloride suitable for industrial production according to claim 1, wherein: the pH adjusting process in the step (d) is to adjust the pH to 2-3 by using 37% hydrochloric acid, stir for 1 hour, and then adjust the pH to 7.5-8.5 by using 15% sodium hydroxide solution.
10. The method for preparing N-methyltyramine hydrochloride suitable for industrial production according to claim 1, wherein: and (d) adding saturated salt water, stirring for 1-2 h, and adding diatomite for filtering.
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| US6017919A (en) * | 1996-02-06 | 2000-01-25 | Japan Tobacco Inc. | Compounds and pharmaceutical use thereof |
| CN101643470A (en) * | 2001-10-19 | 2010-02-10 | 富山化学工业株式会社 | Alkyl ether derivatives or salts thereof |
| CN106977411A (en) * | 2017-03-16 | 2017-07-25 | 苏州永健生物医药有限公司 | A kind of synthetic method of N methyltyramines hydrochloride |
| CN113735716A (en) * | 2021-11-08 | 2021-12-03 | 山东盛安贝新能源有限公司 | Preparation method of spermidine |
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|---|---|---|---|---|
| US6017919A (en) * | 1996-02-06 | 2000-01-25 | Japan Tobacco Inc. | Compounds and pharmaceutical use thereof |
| CN101643470A (en) * | 2001-10-19 | 2010-02-10 | 富山化学工业株式会社 | Alkyl ether derivatives or salts thereof |
| CN106977411A (en) * | 2017-03-16 | 2017-07-25 | 苏州永健生物医药有限公司 | A kind of synthetic method of N methyltyramines hydrochloride |
| CN113735716A (en) * | 2021-11-08 | 2021-12-03 | 山东盛安贝新能源有限公司 | Preparation method of spermidine |
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