CN113754554A - Method for synthesizing paracetamol by one-step hydrogenation - Google Patents
Method for synthesizing paracetamol by one-step hydrogenation Download PDFInfo
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- CN113754554A CN113754554A CN202110871378.9A CN202110871378A CN113754554A CN 113754554 A CN113754554 A CN 113754554A CN 202110871378 A CN202110871378 A CN 202110871378A CN 113754554 A CN113754554 A CN 113754554A
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- catalyst
- autoclave
- nitrophenol
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- paracetamol
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 31
- 229960005489 paracetamol Drugs 0.000 title claims abstract description 24
- 238000005984 hydrogenation reaction Methods 0.000 title claims abstract description 14
- 230000002194 synthesizing effect Effects 0.000 title claims description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 79
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 claims abstract description 41
- 230000008569 process Effects 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims description 82
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- 235000019439 ethyl acetate Nutrition 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 10
- 239000002184 metal Substances 0.000 claims description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 10
- 229910002844 PtNi Inorganic materials 0.000 claims description 8
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 3
- 229940090181 propyl acetate Drugs 0.000 claims description 3
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 3
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- 238000011068 loading method Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 abstract description 19
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- 239000012043 crude product Substances 0.000 description 41
- 238000010438 heat treatment Methods 0.000 description 33
- 238000001816 cooling Methods 0.000 description 29
- 239000000047 product Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 238000011084 recovery Methods 0.000 description 15
- 238000011049 filling Methods 0.000 description 14
- 238000004811 liquid chromatography Methods 0.000 description 14
- 238000005070 sampling Methods 0.000 description 14
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 12
- 208000029618 autoimmune pulmonary alveolar proteinosis Diseases 0.000 description 11
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 238000007112 amidation reaction Methods 0.000 description 6
- MQRWBMAEBQOWAF-UHFFFAOYSA-N acetic acid;nickel Chemical compound [Ni].CC(O)=O.CC(O)=O MQRWBMAEBQOWAF-UHFFFAOYSA-N 0.000 description 4
- 230000009435 amidation Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000002431 foraging effect Effects 0.000 description 4
- 229940078494 nickel acetate Drugs 0.000 description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 229940059260 amidate Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000007056 transamidation reaction Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical compound OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 1
- BVZSQTRWIYKUSF-UHFFFAOYSA-N 4-(N-hydroxy-C-methylcarbonimidoyl)phenol Chemical compound ON=C(C)C1=CC=C(O)C=C1 BVZSQTRWIYKUSF-UHFFFAOYSA-N 0.000 description 1
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 description 1
- 229940073735 4-hydroxy acetophenone Drugs 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical group CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000012345 acetylating agent Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- -1 amidate amines Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- XAYGUHUYDMLJJV-UHFFFAOYSA-Z decaazanium;dioxido(dioxo)tungsten;hydron;trioxotungsten Chemical compound [H+].[H+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.[O-][W]([O-])(=O)=O.[O-][W]([O-])(=O)=O.[O-][W]([O-])(=O)=O.[O-][W]([O-])(=O)=O.[O-][W]([O-])(=O)=O.[O-][W]([O-])(=O)=O XAYGUHUYDMLJJV-UHFFFAOYSA-Z 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N phenyl acetate Chemical compound CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910052594 sapphire Inorganic materials 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing paracetamol by one-step hydrogenation of p-nitrophenol. The catalytic reaction process is simple and efficient, the product is easy to separate, and the catalyst is easy to recycle. The yield of the paracetamol can reach more than 90 percent, the solvent can be distilled and separated to directly obtain a crude paracetamol product, and the product can be recrystallized once to obtain a high-purity product. The one-step method for preparing paracetamol has good industrial application prospect.
Description
Technical Field
The invention relates to synthetic paracetamol, in particular to a method for synthesizing paracetamol through one-step hydrogenation.
Background
Paracetamol (acetaminophen, APAP) is a commonly used antipyretic analgesic. Currently, the widely used production process is to prepare p-aminophenol (PAP) by hydrogenation of p-nitrophenol, followed by further acetylation to obtain APAP. In the process, acetyl chloride or acetic anhydride is used for acylating the p-aminophenol, hydrochloric acid or acetic acid needs to be released, amino and phenolic hydroxyl groups are acylated at the same time, and acetyl on the phenolic hydroxyl group needs to be removed. Moreover, the process requires more separation steps, resulting in a poor overall yield. In 2017, Li Hong Juan et Al take Pt/alpha-Al2O3Adding nitrobenzene as a raw material into a mixed solution of acetic acid and zinc acetate to obtain APAP (ammonium paratungstate) by a one-pot method for serving as a hydrogenation catalystChemical reaction engineering and process, 2017,33(3):249-254,283), which realizes the one-pot synthesis of APAP but has lower yield of APAP. Meanwhile, the addition of acetic acid has high requirements on a reaction vessel, and the stability of the catalyst is also influenced. The one-step process also has a problem of multiple product separation steps. The traditional two-step method for producing paracetamol comprises the following steps:
in recent years, selective amidation reactions have been studied more extensively. Zyrui et al directly amidate amines with unactivated esters without solvents and transition metals by using sodium t-butoxide as a base (Green chem.,2021,23, 3972-3982). However, high purity PAP is difficult to obtain, so that APAP is abundant in impurities and difficult to purify. Chenxing spring et al in 2005 catalyzed acetylation of phenol and acetic anhydride with HF to obtain 4-hydroxyacetophenone, oximation with hydroxylamine sulfate to obtain p-hydroxyacetophenone oxime, and finally in SOCl2The APAP is obtained by rearrangement in ethyl acetate solvent under catalysis (applied chemical industry, 2005,34(11): 719-720). The synthesis process of the APAP has the advantages of high yield and high purity, and has the defects of large amount of acid and alkali used in the synthesis process, certain potential safety hazard and complex process steps. And nitrobenzene or nitrophenol is used as a raw material, and the problems of insufficient PAP purity and complicated operation can be avoided by combining reduction and amidation in the same reactor.
Chi Wai Cheung et al used nickel (II) chloride dimethyl ether complex Ni (glyme) Cl as catalyst, 1, 10-phenanthroline as ligand, Zn as reducing agent, trimethylchlorosilane as additive to directly amidate nitroarenes with unactivated esters in 2017 to give the corresponding amide product in 94% yield (Nat Commun 8,14878 (2017)). But the silyl ether, zinc chloride and silicon oxide are produced as by-products, and the production cost is high. The subsequent tertiary amide transamidation (J.Am.chem.Soc.2018,140,22, 6789-6792) using manganese metal as a reducing agent and a promoter and using nitroarene as a nitrogen source, and the direct amidation (org.chem.Front.2019, 6,756-761) of ester and nitroarene avoid using additional catalysts or ligands, but the organic solvent used in the synthesis process is not environment-friendly. Michael Fairley et al used lithium amide as a metal precursor to obtain various related synthetic carboxamides (chem.Sci.,2020,11,6500-6509) by ester amidation or amide transamidation with good yields. However, the lithium reagent is dissolved in the reaction system and is not easy to recover.
Therefore, the catalyst which is easy to recycle is used, and a process method which is one-step synthesized, safe and environment-friendly is developed, so that the method has good industrial prospect. The paracetamol is synthesized by using acetate (such as ethyl acetate) as an acetylating agent in a one-step method, better acetylation yield can be obtained under specific conditions, and only ethanol is released in an acylation reaction to be beneficial to being removed together with the ethyl acetate. Meanwhile, ethyl acetate can be directly used as a solvent, is relatively convenient to remove and is beneficial to product purification. Since the amide group is relatively stable, acylation of the phenol can be substituted in situ to give the amide. Generally, from the stability point of view, the acetamide group > ethyl acetate > acetyl phenol, so that the one-step method for synthesizing paracetamol can obtain higher selectivity.
Disclosure of Invention
The invention provides a process method for synthesizing paracetamol by one-step hydrogenation, aiming at improving the defects of the prior art. The paracetamol is prepared by catalyzing p-nitrophenol by controlling reaction conditions. The method has the advantages of directly carrying out amidation reaction without PAP separation, realizing one-step synthesis of APAP, having good catalytic effect, being easy to recover and reuse, being capable of completely reacting to generate the product paracetamol in the reaction process, and having good industrial application prospect.
The technical scheme of the invention is as follows: the one-step process of synthesizing paracetamol through hydrogenation features that metal catalyst is added into high pressure reactor, p-nitrophenol and acetate are filled into the high pressure reactor, hydrogen is filled into the high pressure reactor, and catalytic hydroamidation is carried out at specific reaction temperature to obtain paracetamol product. Stopping heating, cooling to room temperature, and detecting the conversion rate of p-nitrophenol and the selectivity of APAP. The basic reaction of the invention is:
preferably, the hydrogenation metal catalyst is Ni/C, Pd/C, Pt/C, Ir/C, Raney Ni or PtNi/C and the like; Pd/C, Pt/C, Ir/C, Raney Ni and the like are commercially available metal catalysts; wherein the metal loading in the Ni/C, Pd/C, Pt/C, Ir/C or PtNi/C catalyst is 5-55% of the carrier mass; the Ni/C and PtNi/C catalysts can also be prepared on the basis of the literature (ACS Catal.2021,11,8197-8210), and the specific preparation method is as follows:
the Ni/C catalyst containing 50% Ni is prepared by dissolving 24.8g nickel acetate in 500ml ethylene glycol solution, adding 5.8g activated carbon, heating to 165 deg.C, slowly adding 800ml water solution containing 21.3g sodium carbonate dropwise under vigorous stirring, maintaining 165 deg.C for aging for 1h, filtering, washing, and drying.
The PtNi/C catalyst containing 5% of Pt and 50% of Ni is prepared by dissolving 1.04g of chloroplatinic acid and 16.5g of nickel acetate in ethylene glycol solution, adding 3.5g of activated carbon, heating to 165 ℃, slowly dropwise adding 500ml of aqueous solution containing 14.1 g of sodium carbonate under vigorous stirring, maintaining the temperature at 165 ℃ for aging for 1h after dropwise adding, filtering, washing and drying.
Preferably, the acetate is ethyl acetate, methyl acetate, propyl acetate, butyl acetate, isopropyl acetate or tert-butyl acetate.
Preferably, the dosage of the hydrogenation metal catalyst is 1.0-35.0% of the mass of the p-nitrophenol; the mass of the p-nitrophenol is 1 to 50 percent of the mass of the acetic ester.
Preferably, the hydrogen is charged in an amount of 5 to 20 atmospheres; the reaction temperature is 120-180 ℃, and the reaction time is 2-10 h.
Has the advantages that:
the preparation method of the catalyst provided by the invention is simple, and the paracetamol is prepared by catalyzing p-nitrophenol by controlling the reaction conditions. APAP is synthesized by one-step hydrogenation and amidation of p-nitrophenol, and the process is simple and efficient. The catalyst has high activity for catalyzing p-nitrophenol and has selectivity of more than 99% for paracetamol, is easy to recycle, and is very suitable for industrial production. The product paracetamol is easy to separate and purify. The solvent is distilled to obtain a crude product of paracetamol, and a high-purity product can be obtained through one-step recrystallization.
Detailed Description
Example 1:
the Ni/C catalyst containing 50% Ni is prepared by dissolving 24.8g nickel acetate in 500ml ethylene glycol solution, adding 5.8g activated carbon, heating to 165 deg.C, slowly adding 800ml water solution containing 21.3g sodium carbonate dropwise under vigorous stirring, maintaining 165 deg.C for aging for 1h, filtering, washing, and drying, and is hereinafter referred to as Ni/C-0.5.
In the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated to dryness under reduced pressure to give a crude product (crude product yield 97%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (93%). The filtered catalyst was washed with acetonitrile, dried 5 times and reused, and the catalyst recovery is shown in table 1.
Example 2:
in the autoclave, 13.9g of p-nitrophenol, 0.39g of a commercial Pt/C catalyst containing 5% Pt and 34.7g of methyl acetate were charged. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated to dryness under reduced pressure to give a crude product (yield 85%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (79%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.
Example 3:
in the autoclave, 13.9g of p-nitrophenol, 0.38g of a commercially available Ir/C catalyst containing Ir 5% and 46.3g of propyl acetate were charged. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (yield of crude product 84%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (75%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.
Example 4:
in the autoclave were charged 13.9g of p-nitrophenol, 0.213g of a commercial Pd/C catalyst containing 5% Pd and 69.5g of butyl acetate. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (yield of crude product 86%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (80%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.
Example 5:
in the autoclave, 13.9g of p-nitrophenol, 1.173g of Raney Ni catalyst and 139 g of isopropyl acetate were charged. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (crude yield 88%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (83%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.
Example 6:
the PtNi/C catalyst containing 5% of Pt and 50% of Ni is prepared by dissolving 1.04g of chloroplatinic acid and 16.5g of nickel acetate in ethylene glycol solution, adding 3.5g of activated carbon, heating to 165 ℃, slowly dropwise adding 500ml of aqueous solution containing 14.1 g of sodium carbonate under vigorous stirring, maintaining the temperature at 165 ℃ for aging for 1h after dropwise adding, filtering, washing and drying.
In an autoclave, 13.9g of p-nitrophenol, 0.39g of PtNi/C catalyst and 1390g of tert-butyl acetate were charged. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (yield of crude product 92%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (86%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.
Example 7:
in the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 120 ℃ for reaction for 5 hours, taking the autoclave out after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 93%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (crude product yield 76%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (71%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.
Example 8:
in the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 150 ℃ for reaction for 5 hours, taking the autoclave out after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (yield of crude product 87%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (83%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.
Example 9:
in the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 180 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated to dryness under reduced pressure to give a crude product (crude product yield 96%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (91%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.
Example 10:
in the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 5 atmospheres, putting the autoclave into a heating kettle sleeve with the temperature of 160 ℃ for reaction for 5 hours, taking the autoclave out after the reaction is finished, cooling the autoclave to the room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 96%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (yield of crude product 81%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (74%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.
Example 11:
in the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling 20 atmospheres of hydrogen, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking the autoclave out after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated to dryness under reduced pressure to give a crude product (yield of crude product 94%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (91%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.
Example 12:
in the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve with the temperature of 160 ℃ for reaction for 2 hours, taking the autoclave out after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 91%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated to dryness under reduced pressure to give a crude product (crude product yield 75%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (70%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.
Example 13:
in the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve with the temperature of 160 ℃ for reaction for 10 hours, taking the autoclave out after the reaction is finished, cooling the autoclave to the room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated to dryness under reduced pressure to give a crude product (crude product yield 97%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (90%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.
Example 14:
in the autoclave, 13.9g of p-nitrophenol, 4.70gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (crude product yield 93%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (89%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.
The catalyst of example 1 was filtered and washed with acetonitrile, dried and reused. The process flow is identical to that of example 1, and the catalyst recovery and use conditions are as follows:
TABLE 1
Claims (5)
1. The one-step process of synthesizing paracetamol through hydrogenation features that metal catalyst is added into high pressure reactor, p-nitrophenol and acetate are filled into the high pressure reactor, hydrogen is filled into the high pressure reactor, and catalytic hydroamidation is carried out at specific reaction temperature to obtain paracetamol product.
2. The process of claim 1 wherein the hydrogenation metal catalyst is Ni/C, Pd/C, Pt/C, Ir/C, Raney Ni or PtNi/C; wherein the metal loading mass in the Ni/C, Pd/C, Pt/C, Ir/C or PtNi/C catalyst is 5-55% of the carrier mass.
3. The process of claim 1, wherein the acetate is ethyl acetate, methyl acetate, propyl acetate, butyl acetate, isopropyl acetate, or tert-butyl acetate.
4. The method of claim 1, wherein the amount of the hydrogenation metal catalyst is 1.0-35.0% of the mass of the p-nitrophenol; the mass of the p-nitrophenol is 1 to 50 percent of the mass of the acetic ester.
5. The method according to claim 1, wherein the hydrogen gas is charged in an amount of 5 to 20 atmospheres; the reaction temperature is 120-180 ℃, and the reaction time is 2-10 h.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102060729A (en) * | 2010-12-28 | 2011-05-18 | 刘瑞平 | Method for continuously and efficiently preparing p-acetamidophenol |
| WO2017154024A1 (en) * | 2016-03-08 | 2017-09-14 | Reddy G Pratap | A process for synthesis of paracetamol |
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| CN102060729A (en) * | 2010-12-28 | 2011-05-18 | 刘瑞平 | Method for continuously and efficiently preparing p-acetamidophenol |
| WO2017154024A1 (en) * | 2016-03-08 | 2017-09-14 | Reddy G Pratap | A process for synthesis of paracetamol |
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