CN109912434B - Synthesis method of phenylethanolamine beta receptor agonist - Google Patents
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- ULSIYEODSMZIPX-UHFFFAOYSA-N phenylethanolamine Chemical compound NCC(O)C1=CC=CC=C1 ULSIYEODSMZIPX-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 102000012740 beta Adrenergic Receptors Human genes 0.000 title claims abstract description 29
- 108010079452 beta Adrenergic Receptors Proteins 0.000 title claims abstract description 29
- 239000000018 receptor agonist Substances 0.000 title claims abstract description 28
- 229940044601 receptor agonist Drugs 0.000 title claims abstract description 28
- 229950006768 phenylethanolamine Drugs 0.000 title claims abstract description 14
- 238000001308 synthesis method Methods 0.000 title description 9
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 20
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims abstract description 16
- -1 phenethyl alcohol amine Chemical class 0.000 claims abstract description 13
- GPRYKVSEZCQIHD-UHFFFAOYSA-N 1-(4-aminophenyl)ethanone Chemical compound CC(=O)C1=CC=C(N)C=C1 GPRYKVSEZCQIHD-UHFFFAOYSA-N 0.000 claims abstract description 11
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims abstract description 10
- 238000007336 electrophilic substitution reaction Methods 0.000 claims abstract description 9
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 7
- 230000009467 reduction Effects 0.000 claims abstract description 4
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-Phenylethanol Natural products OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000005893 bromination reaction Methods 0.000 claims abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 7
- 239000006227 byproduct Substances 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- 229940117803 phenethylamine Drugs 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 17
- 239000000126 substance Substances 0.000 abstract description 9
- 238000001514 detection method Methods 0.000 abstract description 7
- 235000013305 food Nutrition 0.000 abstract description 7
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 abstract description 6
- 238000010189 synthetic method Methods 0.000 abstract description 5
- 239000003054 catalyst Substances 0.000 abstract description 4
- 229910052751 metal Inorganic materials 0.000 abstract description 4
- 239000002184 metal Substances 0.000 abstract description 4
- 150000005171 halobenzenes Chemical class 0.000 abstract description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 description 41
- 238000003756 stirring Methods 0.000 description 25
- STJMRWALKKWQGH-UHFFFAOYSA-N clenbuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 STJMRWALKKWQGH-UHFFFAOYSA-N 0.000 description 19
- 229960001117 clenbuterol Drugs 0.000 description 19
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 16
- 238000001914 filtration Methods 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 239000005457 ice water Substances 0.000 description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
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- 241001465754 Metazoa Species 0.000 description 8
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- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 8
- BUXRLJCGHZZYNE-UHFFFAOYSA-N 2-amino-5-[1-hydroxy-2-(propan-2-ylamino)ethyl]benzonitrile Chemical compound CC(C)NCC(O)C1=CC=C(N)C(C#N)=C1 BUXRLJCGHZZYNE-UHFFFAOYSA-N 0.000 description 7
- 229950010971 cimaterol Drugs 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- JLPKZJDZXIKSCP-UHFFFAOYSA-N 1-(4-amino-3,5-dichlorophenyl)ethanone Chemical compound CC(=O)C1=CC(Cl)=C(N)C(Cl)=C1 JLPKZJDZXIKSCP-UHFFFAOYSA-N 0.000 description 5
- ASMVJBACZFHISI-UHFFFAOYSA-N 1-(4-amino-3-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=C(N)C(Br)=C1 ASMVJBACZFHISI-UHFFFAOYSA-N 0.000 description 5
- JEJMPSCCDHCPIT-UHFFFAOYSA-N 2-[4-[(4-nitrophenyl)methyl]piperazin-1-yl]ethanol Chemical compound C1CN(CCO)CCN1CC1=CC=C([N+]([O-])=O)C=C1 JEJMPSCCDHCPIT-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
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- 238000005303 weighing Methods 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
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- 239000000273 veterinary drug Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- PLFUBWPEUSILSL-UHFFFAOYSA-N 1-(4-amino-3,5-dibromophenyl)-2-(tert-butylamino)ethanol Chemical compound CC(C)(C)NCC(O)C1=CC(Br)=C(N)C(Br)=C1 PLFUBWPEUSILSL-UHFFFAOYSA-N 0.000 description 2
- UPAZHKPTSFKLPQ-UHFFFAOYSA-N 1-bromobut-1-en-1-ol Chemical compound CCC=C(O)Br UPAZHKPTSFKLPQ-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
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- 230000000171 quenching effect Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- QRRLMJRIOPVBCX-UHFFFAOYSA-N 6-chloro-2-n,4-n-diethyl-1,3,5-triazine-2,4-diamine;1h-1,2,4-triazol-5-amine Chemical compound NC1=NC=NN1.CCNC1=NC(Cl)=NC(NCC)=N1 QRRLMJRIOPVBCX-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- 239000013067 intermediate product Substances 0.000 description 1
- 235000020997 lean meat Nutrition 0.000 description 1
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- 230000007246 mechanism Effects 0.000 description 1
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- 125000002560 nitrile group Chemical group 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- GTSHREYGKSITGK-UHFFFAOYSA-N sodium ferrocyanide Chemical class [Na+].[Na+].[Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] GTSHREYGKSITGK-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- XOGGUFAVLNCTRS-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide Chemical class [K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] XOGGUFAVLNCTRS-UHFFFAOYSA-N 0.000 description 1
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Images
Abstract
The invention discloses a synthetic method of a phenethyl alcohol amine beta receptor stimulant, which comprises the following steps: s1, dissolving 4-aminoacetophenone in an organic solvent, and performing halogenation reaction on a benzene ring with an electrophilic substitution reagent to generate a halogeno-benzene intermediate; the halobenzene intermediate and a cyaniding reagent are subjected to nucleophilic substitution reaction in an organic solvent or water under the catalysis of a metal catalyst to generate an acetophenone intermediate; s2: the acetophenone intermediate and copper bromide are subjected to carbonyl alpha bromination reaction in an organic solvent to generate an alpha-bromo acetophenone intermediate; s3: reacting the alpha-bromoacetophenone intermediate with tert-butylamine or isopropylamine in an organic solvent to generate an acetophenone amine intermediate; s4: reacting the acetophenone amine intermediate with a reduction hydrogenation reagent in an organic solvent to generate a phenylethanolamine beta receptor agonist; the synthetic method is simple and efficient, the raw materials are cheap and easy to obtain, the atom utilization rate is high, the chemical purity of the synthetic product is more than 99%, and the food safety detection requirement is met.
Description
Technical Field
The invention relates to the technical field of chemical engineering, in particular to a synthetic method of phenylethanolamine beta receptor agonist.
Background
With the continuous improvement of the living standard of human beings, people pay more and more attention to food safety, however, the food safety problem is not optimistic, especially the animal-derived food safety problem becomes a global issue, and veterinary drug residues are a main cause of the animal-derived food safety problem. Veterinary drug residues are one of the chemical risks which are not organoleptically identifiable by the consumer, and therefore enhancing the detection of veterinary drug residues is of great importance in protecting the health of humans.
Beta receptor agonists are clinically useful in the treatment of asthma-like conditions in humans and animals, phenylethanolamines which resemble epinephrine in chemical structure. In addition, the compound is added into feed, so that the lean meat quantity of animals can be increased, the feed use is reduced, and meat products are sold in the market early, so that the compound is commonly called as 'clenbuterol'. However, it is easily left in the animal body. After a person eats food containing higher beta receptor agonist, acute poisoning symptoms such as: nausea, vomiting, nervousness, tremors, increased heart rate, etc., and even life risks. In recent years, the detected clenbuterol beta receptor agonists include brombuterol, clenbuterol, cimaterol and salts thereof, and the safety of animal products is seriously harmed. The part of agriculture in China issued in 1997 announces that such drugs cannot be detected in all edible animal tissues, and application of clenbuterol to animal husbandry is prohibited.
At present, the synthetic method of the beta receptor agonist has less published documents, complex operation, higher cost and lower atom utilization rate, and is difficult to obtain various phenylethanolamine compounds by using a general route.
Disclosure of Invention
The invention aims to solve the technical problem of providing a synthetic method of phenylethanolamine beta receptor agonist, which has the advantages of simple route, cheap raw materials and high atom utilization rate.
The technical scheme adopted by the invention for solving the technical problems is to provide a synthesis method of phenylethanolamine beta receptor agonists, wherein the phenylethanolamine beta receptor agonists are shown as a general formula (IV):
the beta receptor agonist compounds are:
clenbuterol: r1＝Cl，R2R ═ Cl, R ═ tert-butylamine
Bromine Brottorotero: r1＝Br，R2Br, R tert-butylamine
Sibutrol: r1＝H，R2CN, R is tert-butylamine
Simatellor: r1＝H，R2CN, R is isopropylamine; or
Bromochlorobutiro: r is1＝Br，R2R ═ Cl, R ═ tert-butylamine
The method comprises the following steps: s1, dissolving 4-aminoacetophenone in an organic solvent, and performing halogenation reaction on a benzene ring with an electrophilic substitution reagent to generate a halogeno-benzene intermediate; the halobenzene intermediate and a cyaniding reagent are subjected to nucleophilic substitution reaction in an organic solvent or water under the catalysis of a metal catalyst to generate an acetophenone intermediate shown as a general formula (I); s2: the acetophenone intermediate shown in the general formula (I) and copper bromide are subjected to carbonyl alpha bromination reaction in an organic solvent to generate an alpha-bromo acetophenone intermediate shown in the general formula (II); s3: reacting the alpha-bromoacetophenone intermediate shown in the general formula (II) with tert-butylamine or isopropylamine in an organic solvent to generate an acetophenone amine intermediate shown in the general formula (III); s4: reacting the acetophenone amine intermediate shown in the general formula (III) with a reduction hydrogenation reagent in an organic solvent to generate a phenylethanolamine beta receptor agonist;
general formula (I), (II), (III)III) in R1、R2Are respectively and independently selected from one of hydrogen, chlorine, bromine and nitrile groups, and R is tert-butylamine or isopropylamine.
Further, the molar ratio of the 4-aminoacetophenone to the electrophilic substitution reagent in the step S1 is 1 (1-2.5), the reaction temperature is 0-40 ℃, and the reaction time is 0.5-5 hours; the molar ratio of the halobenzene intermediate to the metal catalyst to the cyaniding reagent is 1 (0.01-0.05): 0.3-0.8), the reaction temperature is 80-120 ℃, and the reaction time is 4-24 hours.
Further, the electrophilic substitution reagent used in step S1 is selected from the group consisting of: NBS, NCS, Br2And Cl2At least one of; the cyanating reagent is selected from: one of sodium ferrocyanide salt, potassium ferrocyanide salt or hydrate thereof; the metal catalyst is palladium tetratriphenylphosphine.
Further, the main product and the by-products obtained by different charge ratios of 4-aminoacetophenone and electrophilic substitution reagent in the step S1 can be used as raw materials for synthesizing different phenethylamine beta-receptor agonists.
Further, in step S1, DBU is further added, and the molar ratio of the halophenyl intermediate to DBU is 1: (0.25-0.5).
Further, in the step S2, the molar ratio of the acetophenone intermediate to the copper bromide is 1: 1.5-2.5; the reaction temperature is 55-75 ℃, and the reaction time is 2-3 hours.
Further, in step S3, the molar ratio of the α -bromoacetophenone intermediate to tert-butylamine or isopropylamine is 1: 1.5-2.5, the reaction temperature is 0-60 ℃, and the reaction time is 2-5 hours.
Further, in the step S4, the molar ratio of the acetophenone amine intermediate to the reduction hydrogenation reagent is 1: 1-2.5, the reaction temperature is 0-40 ℃, and the reaction time is 6-16 hours.
Further, the reductive hydrogenation reagent used in step S4 is selected from: at least one of sodium borohydride, potassium borohydride, and lithium aluminum hydride.
Further, the organic solvent used in the steps S1-S4 is selected from: at least one of acetonitrile, ethyl acetate, dichloromethane, ethanol, tetrahydrofuran, methanol, chloroform and t-butanol.
Compared with the prior art, the invention has the following beneficial effects: the synthesis method of the phenylethanolamine beta receptor agonist provided by the invention is simple and efficient, the raw materials are cheap and easy to obtain, the atom utilization rate is high, and the phenylethanolamine beta receptor agonist can be prepared through electrophilic substitution, nucleophilic substitution and reduction reaction. The invention can be used for synthesizing various phenethyl alcohol amine beta receptor agonists, the chemical purity of the synthetic product is more than 99 percent, and the invention can fully meet the forbidden veterinary drug residue detection and the metabolic mechanism research of clenbuterol and the like in the food safety field.
Drawings
FIG. 1 is a NMR spectrum of clenbuterol; obtained by Bruke-400M nuclear magnetic resonance instrument with DMSO as solvent.
FIG. 2 is a NMR spectrum of Brombutol; by CD3OD was solvent and was obtained by Bruke-400M NMR instrument.
FIG. 3 is a NMR spectrum of sibutrol; by CD3OD was solvent and was obtained by Bruke-400M NMR instrument.
FIG. 4 is a NMR spectrum of cimaterol; by CD3OD was solvent and was obtained by Bruke-400M NMR instrument.
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of bromochlorobuterol; by CD3OD was solvent and was obtained by Bruke-400M NMR instrument.
Fig. 6 is a high performance liquid chromatogram of clenbuterol.
FIG. 7 is a high performance liquid chromatogram of bromobuterol.
FIG. 8 is a high performance liquid chromatogram of sibutrol.
Fig. 9 is a high performance liquid chromatogram of cimaterol.
FIG. 10 is a high performance liquid chromatogram of bromochlorobuterol.
Detailed Description
The invention is further described in connection with the following figures and examples, which should not be construed as limiting the invention.
Example 1
Synthesis method of 4-amino-3, 5-dichloroacetophenone (clenbuterol)
7.9g (59.2mmol) of NCS was weighed into a 250ml three-necked flask, 60ml of MeCN was added, the mixture was dissolved by stirring, 4-aminoacetophenone (4g,29.6mmol) dissolved in 50ml of acetonitrile was slowly dropped into the reaction apparatus through a constant pressure dropping funnel, the dropping was completed for half an hour, and the mixture was stirred at room temperature for 3 hours. Most of the solvent is evaporated, ethyl acetate is added, stirring and dissolving are carried out, 50ml of pure water is used for washing 3 times each time, and an organic phase is collected and dried by anhydrous sodium sulfate. Filtering, and spin-drying the solvent to obtain 4.8g of a main product acetophenone intermediate 4-amino-3, 5-dichloroacetophenone with a yield of 80%; meanwhile, 0.9g of by-product 4-amino-3-chloroacetophenone is obtained, the yield is 18%, and the by-product can be used as a raw material for preparing bromochlorobuterol in example 5.
Synthesis of 4-amino-3, 5-dichloro bromoacetophenone from 4-amino-3, 5-dichloroacetophenone
4.8g (23.7mmol) of 4-amino-3, 5-dichloroacetophenone are weighed into a 250ml round-bottom flask, 60ml of EA (ethyl acetate), 60ml of CHCl are added3And 20ml CH3CH2OH solvent, and stirring and dissolving at the reflux temperature. 7.8g (35mmol) of copper bromide was weighed into the reaction apparatus and reacted for 2 hours. Vacuum filtering while hot, using 20ml of CH each time2Cl2The filter cake was washed 3 times, the filtrate was transferred to a separatory funnel, the filtrate was washed with 50ml of pure water 3 times, the organic phase was collected, and anhydrous sodium sulfate was added to dry. Filtering, spin-drying the solvent, and recrystallizing with 5.0g of 75% ethanol by mass to obtain 4-amino-3, 5-dichloro bromoacetophenone.
Synthesis of clenbuterol from 4-amino-3, 5-dichloro bromoacetophenone
5.0g (17.8mmol) of 4-amino-3, 5-dichlorobromoacetophenone were weighed into a 250ml round-bottom flask, 50ml of Tetrahydrofuran (THF) and 50ml of ethanol (CH) were added3CH2OH), putting the mixture into an ice-water bath, stirring and dissolving the mixture, deoxidizing the mixture by using a device, and N2And (3) under the protection of gas, sucking 3.8ml (35.6mmol) of tert-butylamine by using a syringe after 20min, slowly adding into a reaction device, and continuously reacting for 3h at the temperature of 0 ℃ and reacting for 1h at normal temperature.
The reaction apparatus was then placed in an ice-water bath and 1.5g (28mmol) of KBH was weighed4Slowly adding into the reaction device, removing ice bath after 2h, measuring 50ml methanol (CH)3OH) is added into a reaction device, stirred for 16 hours at normal temperature, most of solvent is removed by rotary evaporation, 30ml of water is added for quenching reaction, and dichloromethane is extracted for three times. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration the solvent was removed and column chromatography gave 1.7g clenbuterol in 35% yield.
FIG. 1 is a NMR spectrum of clenbuterol; obtained by Bruke-400M nuclear magnetic resonance instrument with DMSO as solvent. Chemical shifts δ 7.20(2H, s),5.35(2H, s),4.41-4.37(1H, m),2.57-2.55(2H, m),1.01(9H, s).
Fig. 6 is a high performance liquid chromatogram of clenbuterol, the sample is dissolved in mobile phase, and the mixture is extracted from acetonitrile: 0.01MKH2PO4The mobile phase was 20:80 (PH 3), the high performance liquid chromatogram of clenbuterol was obtained by passing a liquid phase column (CNWAthena C18-WP 4.6 × 250mm,5um (LAEQ-462572)) at a column temperature of 30 ℃ at a flow rate of 1.0mL/min, and a DAD (213nm) detector, and as can be seen from fig. 6, the sample purity was 99% or more.
Example 2
Synthesis method of 4-amino-3, 5-dibromoacetophenone (bromobutol)
Weighing 11.6g,65.1mmol N-bromosuccinimide (NBS) in a 250ml three-neck flask, adding 60ml MeCN, stirring for dissolving, slowly dripping 4g,29.6mmol 4-aminoacetophenone dissolved in 50ml acetonitrile into a reaction device by a constant pressure dropping funnel, after half an hour of dripping, stirring for 3 hours at room temperature. Most of the solvent is evaporated, ethyl acetate is added and stirred to dissolve, 50ml of pure water is used for washing for 3 times, and an organic phase is collected and dried by anhydrous sodium sulfate. Filtering, and spin-drying the solvent to obtain 6.9g of 4-amino-3, 5-dibromoacetophenone as the main intermediate product of acetophenone, with a yield of 80%; simultaneously, 1.2g of the by-product 4-amino-3-bromoacetophenone was obtained with a yield of 20%, which was used in examples 3 and 4 as starting material for the preparation of sibutrol and simetrol.
Synthesis of 4-amino-3, 5-dibromo-bromoacetophenone from 4-amino-3, 5-dibromo-acetophenone
6.9g (23.7mmol) of 4-amino-3, 5-dibromoacetophenone were weighed into a 250ml round-bottomed flask, and 60ml of EA, 60ml of CHCl were added3And 20ml CH3CH2OH solvent, and stirring and dissolving at the reflux temperature. 10.5g (47.4mmol) of copper bromide was weighed into the reaction apparatus and reacted for 2 hours. Vacuum filtering while hot, using 20ml CH each time2Cl2The filter cake was washed 3 times, the filtrate was transferred to a separatory funnel, the filtrate was washed 3 times with 50ml of pure water each time, the organic phase was collected, and anhydrous sodium sulfate was added to dry. After filtration, the solvent was spin-dried, and ethanol was recrystallized to obtain 6.3g of 4-amino-3, 5-dibromobromoacetophenone, the yield was 71%.
Synthesis of bromobutenol from 4-amino-3, 5-dibromobromoacetophenone
6.3g (16.8mmol) of 4-amino-3, 5-dibromobromoacetophenone were weighed into a 250ml round-bottomed flask, 50ml of THF and 50ml of CH were added3CH2Putting the mixture into an OH solvent in an ice-water bath, stirring and dissolving the mixture, removing oxygen by a device, and adding N2And (3) under the protection of gas, sucking 2.7ml (25.2mmol) of tert-butylamine by using a syringe after 20min, slowly adding into a reaction device, and continuously reacting for 3h at the temperature of 0 ℃ and reacting for 1h at normal temperature.
The reaction apparatus was then placed in an ice-water bath and 1.5g (28mmol) of KBH was weighed4Slowly adding into the reaction device, removing ice bath after 2h, measuring 50ml CH3And adding OH into a reaction device, stirring for 16 hours at normal temperature, removing most of solvent by rotary evaporation, adding 30ml of water, quenching for reaction, and extracting with dichloromethane for three times. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was removed and column chromatography gave 2.0g of bromobutenol in 33% yield.
FIG. 2 is a NMR spectrum of Brombutol; by CD3OD was solvent and was obtained by Bruke-400M NMR instrument. Chemical shifts delta 7.43(2H, s),4.57-4.54(1H, m),2.74-2.64(2H, m),
1.15(9H,s)。
FIG. 7 is a high performance liquid chromatogram of Brombuterole, the detection method is similar to that of clenbuterol, and it can be seen from FIG. 7 that the purity of the sample reaches more than 99%.
Example 3
Synthesis method of 4-amino-3-bromoacetophenone (sibutrol)
4g (29.6mmol) of 4-aminoacetophenone is weighed into a 250ml three-neck flask, 40ml of MeCN is added and dissolved by stirring, 5.8g (32.6mmol) of NBS dissolved in 50ml of acetonitrile is slowly dripped into a reaction device by a constant pressure dropping funnel, after dripping is finished for half an hour, and stirring is carried out for 3 hours at room temperature. Most of the solvent is evaporated, ethyl acetate is added, stirring and dissolving are carried out, 50ml of pure water is used for washing 3 times each time, and an organic phase is collected and dried by anhydrous sodium sulfate. Filtering, and spin-drying the solvent to obtain 4.5g of 4-amino-3-bromoacetophenone intermediate main product, wherein the yield is 71%; simultaneously, 1.2g of by-product 4-amino-3, 5-dibromoacetophenone is obtained with a yield of 14 percent, which can be used in example 2 as a raw material for synthesizing bromobrethreo.
Synthesis of 4-amino-3-cyanoacetophenone from 4-amino-3-bromoacetophenone
Weighing 4.5g (21mmol) of 4-amino-3-bromoacetophenone, 3.6g (8.5mmol) of potassium ferrocyanide trihydrate and 0.45g (0.42mmol) of tetratriphenylphosphine palladium in a three-necked flask, measuring 35ml of tert-butyl alcohol, adding 35ml of pure water into a reaction device, adding 0.8ml of 1, 8-diazabicyclo [5.4.0 ] by using a syringe]Undec-7-ene (DBU), N after deoxygenation of the reaction apparatus2And reacting for 16 hours at reflux temperature under protection. And after the reaction is finished, carrying out suction filtration, collecting filtrate, extracting for 3 times by using 20ml of dichloromethane each time, collecting an organic phase, adding anhydrous sodium sulfate for drying, carrying out suction filtration and spin drying to obtain 2.8g of 4-amino-3-cyanoacetophenone, wherein the yield is 85%.
Synthesis of 4-amino-3-cyano bromo acetophenone from 4-amino-3-cyano acetophenone
2.8g (17.5mmol) of 4-amino-3-cyanoacetophenone were weighed into a 250ml round-bottomed flask, and 60ml of EA and 60ml of CHCl were added3And 20ml CH3CH2OH solvent, and stirring and dissolving at the reflux temperature. Weighing 7.8g (35mmol) of copper bromide, adding the copper bromide into a reaction device, performing reflux reaction for 2 hours, performing suction filtration while the copper bromide is hot, collecting filtrate, washing the filtrate with 20ml of water for 3 times each time, collecting an organic phase, adding anhydrous sodium sulfate for drying, and performing suction filtration and spin drying on a solvent to obtain 3.4g of 4-amino-3-cyano bromo acetophenone, wherein the yield is 80%.
Synthesis of sibutrol from 4-amino-3-cyano bromoacetophenone
3.4g (14mmol) of 4-amino-3-cyanoboroacetophenone were weighed into a 250ml round-bottom flask, 50ml of THF and 50ml of CH were added3CH2And (3) placing the OH solvent in an ice water bath, stirring for dissolving, sucking 3ml (28mmol) of tert-butylamine by using a syringe after 20min, slowly adding into a reaction device, continuously reacting for 3h at 0 ℃, and reacting for 1h at normal temperature.
Then the reaction device is placed in an ice-water bath1.5g (28mmol) of KBH are weighed out4Slowly adding into the reaction device, removing ice bath after 2h, measuring 50ml CH3And adding OH into a reaction device, stirring for 16h at normal temperature (the reaction is carried out overnight), removing most of solvent by rotary evaporation, adding 30ml of water to quench the reaction, and extracting with dichloromethane for three times. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was removed, and column chromatography was performed to give 1.0g of sibutrol, 30% yield.
FIG. 3 is a NMR spectrum of sibutrol; by CD3OD was solvent and was obtained by Bruke-400M NMR instrument. Chemical shifts δ 7.38-7.34(2H, m),6.83(1H, d),4.58(1H, dd),2.72(2H, ddd),1.16(9H, s).
Fig. 8 is a high performance liquid chromatogram of sibutrol, the detection method is similar to that of clenbuterol, and it can be seen from fig. 8 that the purity of the sample reaches more than 99%.
Example 4
The synthesis route of 4-amino-3-cyano bromo acetophenone (simatrol) was the same as the synthesis method of example 3.
Synthesis of cimaterol from 4-amino-3-cyano bromo-acetophenone
3.4g (14mmol) of 4-amino-3-cyanoboroacetophenone were weighed into a 250ml round-bottom flask, 50ml of THF and 50ml of CH were added3CH2And (3) placing the OH solvent in an ice-water bath, stirring for dissolving, sucking 3ml (28mmol) of isopropylamine by using a syringe after 20min, slowly adding into the reaction device, continuously reacting for 3h at the temperature of 0 ℃, and reacting for 1h at normal temperature.
The reaction apparatus was then placed in an ice-water bath and 1.5g (28mmol) of KBH was weighed4Slowly adding into the reaction device, removing ice bath after 2h, measuring 50ml CH3And adding OH into a reaction device, stirring for 16h at normal temperature (the reaction is carried out overnight), removing most of solvent by rotary evaporation, adding 30ml of water to quench the reaction, and extracting with dichloromethane for three times. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was removed and column chromatography gave 1.0g of cimaterol in 30% yield.
FIG. 4 is a NMR hydrogen spectrum of cimaterol; by CD3OD was solvent and was obtained by Bruke-400M NMR instrument. Chemical shifts δ 7.37-7.33(2H, m),6.83(1H, d),4.63(1H, dd),2.89(1H, dd),2.78-2.68(2H, m),1.11(6H, dd).
Fig. 9 is a high performance liquid chromatogram of cimaterol, the detection method is similar to that of clenbuterol, and it can be seen from fig. 9 that the purity of the sample reaches more than 99%.
Example 5
Synthesis method of 4-amino-3-chloroacetophenone (bromochlorobuterol)
5g (37mmol) of 4-aminoacetophenone are weighed into a 250ml round-bottom flask, 60ml of MeCN is added and dissolved by stirring, then 5.4g (40.4mmol) of NCS are weighed and dissolved into 50ml of MeCN and slowly dripped into the reaction device by a constant pressure dropping funnel, after dripping is finished for half an hour, stirring is carried out for 4 hours at room temperature. Most of the solvent is evaporated, ethyl acetate is added, stirring and dissolving are carried out, 50ml of pure water is used for washing 3 times each time, and an organic phase is collected and dried by anhydrous sodium sulfate. Filtering, and spin-drying the solvent to obtain 3g of 4-amino-3-chloroacetophenone as an acetophenone intermediate main product, wherein the yield is 45%; meanwhile, 1.5g of 4-amino-3, 5-dichloroacetophenone is obtained as a byproduct, the yield is 20%, and the method can be used as a raw material for synthesizing clenbuterol in example 1.
Synthesis of 4-amino-3-bromo-5-chloroacetophenone from 4-amino-3-chloroacetophenone
Weighing 3g (17.6mmol) of 4-amino-3-chloroacetophenone in a 250ml round-bottom flask, adding 50ml of MeCN, stirring for dissolving, then weighing 3.5g (40.4mmol) of NBS, dissolving in 50ml of MeCN, slowly dropping the NBS into a reaction device by using a constant pressure dropping funnel, stirring for 1.5h at room temperature after half an hour of dropping is finished, evaporating most of solvent in a rotary way, adding ethyl acetate, stirring for dissolving, washing with 50ml of pure water for 3 times each time, collecting an organic phase, and drying by using anhydrous sodium sulfate. After filtration, the solvent was spin-dried to obtain 3.5g of acetophenone intermediate, 4-amino-3-bromo-5-chloroacetophenone, in a yield of 80%.
Synthesis of 4-amino-3-bromo-5-chlorobromoacetophenone from 4-amino-3-bromo-5-chloroacetophenone
3.5g (17.6mmol) of 4-amino-3-bromo-5-chloroacetophenone were weighed into a 250ml round-bottomed flask, and 60ml of EA and 60ml of CHCl were added3And 20ml CH3CH2OH solvent, reflux temperature, stirring and dissolving. 6.5g (29mmol) of cupric bromide were weighed and reacted for 2h under reflux. Vacuum filtering while hot, using 20ml CH each time2Cl2The filter cake was washed 3 times, the filtrate was transferred to a separatory funnel, the filtrate was washed 3 times with 50ml of pure water each time, the organic phase was collected, and anhydrous sodium sulfate was added to dry. After filtration, the solvent was spin-dried, and ethanol was recrystallized to obtain 3.5g of 4-amino-3-bromo-5-chlorobromoacetophenone, the yield was 75%.
Synthesis of bromochlorobutirole from 4-amino-3-bromo-5-chlorobromoacetophenone
3.5g (10.7mmol) of 4-amino-3-bromo-5-chlorobromoacetophenone were weighed into a 250ml round-bottom flask, 30ml of THF and 30ml of CH were added3CH2Placing OH solvent in ice water bath, stirring for dissolving, sucking 2.3ml (22mmol) of tert-butylamine by using a syringe after 20min, slowly adding into a reaction device, and removing oxygen N by using the reaction device2And (4) protecting, continuing to react for 3 hours at the temperature of 0 ℃, and reacting for 1 hour at normal temperature.
The reaction apparatus was then placed in an ice-water bath and 1.19g (22mmol) of KBH was weighed4Slowly adding into the reaction device, removing ice bath after 2h, measuring 30ml CH3OH is added into the reaction device. Adding 20ml pure water to quench the reaction, evaporating most of the solvent by rotary evaporation, transferring the rest into a separating funnel, and adding 50ml CH each time2Cl2:H2Washing with O (volume ratio 2:1) for 3 times, collecting organic phase, adding anhydrous sulfuric acidAnd (4) drying sodium. Column chromatography gave 1.3g of bromochlorobuterol in 37% yield.
FIG. 5 is a NMR spectrum of bromochlorotetraol; by CD3OD was solvent and was obtained by Bruke-400M NMR instrument. Chemical shifts δ 7.36-7.35(1H, m),7.24-7.23(1H, m),4.53-4.51(1H, m),2.71-2.59(2H, m),1.12-1.11(9H, m).
FIG. 10 is a high performance liquid chromatogram of bromochlorobuterol, the detection method is similar to that of clenbuterol, and it can be seen from FIG. 10 that the purity of the sample reaches more than 99%.
Although the present invention has been described with respect to one or more embodiments thereof, it will be understood by those skilled in the art that the foregoing and various other changes, omissions and deviations in the form and detail thereof may be made without departing from the scope of this invention.
Claims (7)
1. A method for synthesizing phenylethanolamine beta receptor agonists, wherein the phenylethanolamine beta receptor agonists are represented by a general formula (IV):
the beta receptor agonist compounds are:
bromochlorobuterol: r1=Br，R2= Cl, R = tert-butylamine
The method is characterized by comprising the following steps:
s1, dissolving 4-aminoacetophenone in an organic solvent, and performing halogenation reaction on a benzene ring with an electrophilic substituent reagent to generate an acetophenone intermediate shown as a general formula (I);
s2: the acetophenone intermediate shown in the general formula (I) and copper bromide are subjected to carbonyl alpha bromination reaction in an organic solvent to generate an alpha-bromo acetophenone intermediate shown in the general formula (II);
s3: reacting the alpha-bromo acetophenone intermediate shown in the general formula (II) with tert-butylamine in an organic solvent to generate an acetophenone amine intermediate shown in the general formula (III);
s4: reacting the acetophenone amine intermediate shown in the general formula (III) with a reduction hydrogenation reagent in an organic solvent to generate a phenylethanolamine beta receptor agonist;
in the general formulae (I), (II) and (III) R1=Br，R2= Cl, R is tert-butylamine;
in the step S1, the molar ratio of the 4-aminoacetophenone to the electrophilic substitution reagent is 1 (1-2.5), the reaction temperature is 0-40 ℃, and the reaction time is 0.5-5 hours;
in the step S1, main products and byproducts obtained by different charge ratios of the 4-aminoacetophenone and the electrophilic substitution reagent are used as raw materials for synthesizing the phenylethanolamine beta receptor agonist.
2. The method of synthesizing a phenethylamine beta receptor agonist according to claim 1, wherein the electrophilic substitution reagent used in step S1 is selected from the group consisting of: NBS, NCS, Br2And Cl2At least one of (1).
3. The method for synthesizing phenethyl alcohol amine beta receptor agonist according to claim 1, wherein in step S2, the molar ratio of acetophenone intermediate to copper bromide is 1: 1.5-2.5; the reaction temperature is 55-75 ℃, and the reaction time is 2-3 hours.
4. The method for synthesizing phenethylamine beta receptor agonist according to claim 1, wherein in step S3, the molar ratio of the α -bromoacetophenone intermediate to tert-butylamine is 1: 1.5-2.5, the reaction temperature is 0-60 ℃, and the reaction time is 2-5 hours.
5. The method for synthesizing phenethylamine beta receptor agonist according to claim 1, wherein in step S4, the molar ratio of the acetophenone amine intermediate to the reductive hydrogenation reagent is 1: 1-2.5, the reaction temperature is 0-40 ℃, and the reaction time is 6-16 hours.
6. The method of synthesizing phenethylamine beta receptor agonists according to claim 1, wherein the reductive hydrogenation reagent used in step S4 is selected from the group consisting of: at least one of sodium borohydride, potassium borohydride and lithium aluminum hydride.
7. The method for synthesizing phenethylamine beta receptor agonist according to claim 1, wherein the organic solvent used in steps S1-S4 is selected from: at least one of acetonitrile, ethyl acetate, dichloromethane, ethanol, tetrahydrofuran, methanol, chloroform and t-butanol.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0049728A2 (en) * | 1980-08-25 | 1982-04-21 | American Cyanamid Company | Method for enhancing the growth rate of meat-producing animals and for improving the lean meat to fat ratio thereof |
| US4404222A (en) * | 1980-08-25 | 1983-09-13 | American Cyanamid Company | Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and improving the efficiency of feed utilization thereby |
| US4501751A (en) * | 1980-12-22 | 1985-02-26 | American Cyanamid Company | Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and improving the efficiency of feed utilization thereby |
| EP0260400A2 (en) * | 1986-09-10 | 1988-03-23 | American Cyanamid Company | Method of treating diabetes with 5-[1-hydroxy-2-(isopropylamino)-ethyl]anthranilonitrile |
| US4754047A (en) * | 1979-08-16 | 1988-06-28 | American Cyanamid Company | Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and/or improving the efficiency of feed utilization thereby |
| CN87108295A (en) * | 1986-12-31 | 1988-07-13 | 藤泽药品工业株式会社 | New alkane sulfonyl aniline derivative and its medicinal compositions and preparation method |
| CN1120535A (en) * | 1995-04-03 | 1996-04-17 | 北京农业大学 | Method for synthesizing 5-[1-hydroxy-2-(isopropylamino)ethyl] aminobenzonitrile |
| CN104292061A (en) * | 2014-09-30 | 2015-01-21 | 上海市计量测试技术研究院 | Synthetic method of deuterium-labeled phenylethanolamine beta receptor stimulants |
| CN104478740A (en) * | 2014-11-19 | 2015-04-01 | 上海化工研究院 | Synthesis method of stable isotope-labeled beta receptor agonist type compound |
-
2017
- 2017-12-13 CN CN201711330975.0A patent/CN109912434B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4754047A (en) * | 1979-08-16 | 1988-06-28 | American Cyanamid Company | Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and/or improving the efficiency of feed utilization thereby |
| EP0049728A2 (en) * | 1980-08-25 | 1982-04-21 | American Cyanamid Company | Method for enhancing the growth rate of meat-producing animals and for improving the lean meat to fat ratio thereof |
| US4404222A (en) * | 1980-08-25 | 1983-09-13 | American Cyanamid Company | Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and improving the efficiency of feed utilization thereby |
| US4501751A (en) * | 1980-12-22 | 1985-02-26 | American Cyanamid Company | Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and improving the efficiency of feed utilization thereby |
| EP0260400A2 (en) * | 1986-09-10 | 1988-03-23 | American Cyanamid Company | Method of treating diabetes with 5-[1-hydroxy-2-(isopropylamino)-ethyl]anthranilonitrile |
| CN87108295A (en) * | 1986-12-31 | 1988-07-13 | 藤泽药品工业株式会社 | New alkane sulfonyl aniline derivative and its medicinal compositions and preparation method |
| CN1120535A (en) * | 1995-04-03 | 1996-04-17 | 北京农业大学 | Method for synthesizing 5-[1-hydroxy-2-(isopropylamino)ethyl] aminobenzonitrile |
| CN104292061A (en) * | 2014-09-30 | 2015-01-21 | 上海市计量测试技术研究院 | Synthetic method of deuterium-labeled phenylethanolamine beta receptor stimulants |
| CN104478740A (en) * | 2014-11-19 | 2015-04-01 | 上海化工研究院 | Synthesis method of stable isotope-labeled beta receptor agonist type compound |
Non-Patent Citations (5)
| Title |
|---|
| A New Chemoselective Synthesis of Brombuterol;Marcelo S. Nery;《SYNTHESIS》;20070205;第28卷(第6期);第1472页方案1 * |
| Synthesis of new amino-halogen-substituted phenylaminoethanols;Keck, J.等;《Arzneimittel-Forschung》;19721231;第22卷(第5期);第864-865页表3 * |
| SYNTHESIS OF NINADEUTERO-CLENBUTEROL;Lutz, Robert E.等;《Journal of Organic Chemistry》;19471231;第12卷;第681页第1段 * |
| 氨哮素的合成方法研究;陆绍荣;《合成化学》;20011231;第9卷(第1期);第86-87页反应式和第实验部分2-4节 * |
| 陆绍荣.氨哮素的合成方法研究.《合成化学》.2001,第9卷(第1期), * |
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