CN115611752A - Synthetic refining method of lubabylon intermediate - Google Patents
Synthetic refining method of lubabylon intermediate Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000007670 refining Methods 0.000 title claims abstract description 10
- BVJSUAQZOZWCKN-UHFFFAOYSA-N p-hydroxybenzyl alcohol Chemical compound OCC1=CC=C(O)C=C1 BVJSUAQZOZWCKN-UHFFFAOYSA-N 0.000 claims abstract description 30
- QEFUZHZUCRVJLK-UHFFFAOYSA-N 4-(2-methyl-2-nitropropyl)phenol Chemical compound [O-][N+](=O)C(C)(C)CC1=CC=C(O)C=C1 QEFUZHZUCRVJLK-UHFFFAOYSA-N 0.000 claims abstract description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 24
- DQFAEBUKXCRWHR-UHFFFAOYSA-N 4-(2-amino-2-methylpropyl)phenol Chemical compound CC(C)(N)CC1=CC=C(O)C=C1 DQFAEBUKXCRWHR-UHFFFAOYSA-N 0.000 claims abstract description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 12
- FGLBSLMDCBOPQK-UHFFFAOYSA-N 2-nitropropane Chemical compound CC(C)[N+]([O-])=O FGLBSLMDCBOPQK-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000006482 condensation reaction Methods 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 8
- 239000003208 petroleum Substances 0.000 claims abstract description 8
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims abstract description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 8
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000004440 column chromatography Methods 0.000 abstract description 3
- 239000003513 alkali Substances 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000010494 dissociation reaction Methods 0.000 abstract 1
- 230000005593 dissociations Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 150000001721 carbon Chemical group 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000007605 air drying Methods 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102100034159 Beta-3 adrenergic receptor Human genes 0.000 description 1
- SQHYABIWYKZVHS-UHFFFAOYSA-N CC(C)(CC1=CC=CC(CC(N=CC=C2)=C2C#N)=C1)NCC(COC(C=CC=C1)=C1C1=CC=CS1)O Chemical compound CC(C)(CC1=CC=CC(CC(N=CC=C2)=C2C#N)=C1)NCC(COC(C=CC=C1)=C1C1=CC=CS1)O SQHYABIWYKZVHS-UHFFFAOYSA-N 0.000 description 1
- 102000015779 HDL Lipoproteins Human genes 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 108040005346 beta3-adrenergic receptor activity proteins Proteins 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 230000010243 gut motility Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 238000002531 positive electrospray ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- 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
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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- 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 synthesis and refining method of a lubabylon intermediate, wherein p-hydroxybenzyl alcohol and 2-nitropropane are subjected to condensation reaction in potassium hydroxide, tetrabutylammonium bromide and toluene to obtain a crude product of 4- (2-methyl-2-nitropropyl) phenol; recrystallizing with ethyl acetate and petroleum ether to obtain intermediate 1; and then palladium-carbon is catalyzed and hydrogenated to obtain an intermediate 2 hydrogenation reaction liquid, 4- (2-amino-2-methylpropyl) phenol generated in the process is salified with acetic acid, and high-purity 4- (2-amino-2-methylpropyl) phenol can be obtained through alkali dissociation. The method can reduce the production cost of the product, and simultaneously provides a refining method of an intermediate to replace the refining method of column chromatography in the prior art, simplifies the operation mode, and is more suitable for commercial production.
Description
Technical Field
The invention relates to the technical field of chemical preparation, in particular to a synthetic refining method of a lubabylon intermediate.
Background
Lu Babei, chemically known as 2- (3- (2- ((2-hydroxy-3- (2- (thiophen-2-yl) phenoxy) propyl) amino) -2-methylpropyl) benzyl) nicotinonitrile, is a β 3 adrenoceptor agonist with increased intracellular lipolysis and energy expenditure, and can be used to lower triglyceride levels and cholesterol levels, or to increase high density lipoprotein levels or to reduce gut motility, and thus can be used to treat type II diabetes or obesity, and in addition, the compound can be used to reduce neuroinflammation, or can be used as an antidepressant.
In the prior art, diethylene glycol dimethyl ether and potassium tert-butoxide are needed to be used for synthesizing the intermediate 4- (2-methyl-2-nitropropyl) phenol, so that the cost is high, the safety is poor, and raw materials which are more utilized for industrial production need to be selected.
The prior art adopts a column chromatography method for purifying 4- (2-methyl-2-nitropropyl) phenol, and is not suitable for industrial production.
The intermediate 4- (2-amino-2-methyl propyl) phenol is synthesized by reducing nitro into amino, and the prior art does not relate to a high-pressure hydrogenation process, so that a high-efficiency and safe hydrogenation process needs to be developed.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the defects in the prior art, the invention discloses a synthetic refining method of a lubabylon intermediate. This patent uses toluene and potassium hydroxide system, can be better realize above-mentioned requirement, simultaneously, this patent provides a convenient simple easy industrial production's refined scheme.
The technical scheme is as follows: the invention provides a method for synthesizing and refining a Lu Babei clone intermediate, which comprises the following steps:
step (1): carrying out condensation reaction on p-hydroxybenzyl alcohol and 2-nitropropane in potassium hydroxide, tetrabutylammonium bromide and toluene to obtain a crude product of 4- (2-methyl-2-nitropropyl) phenol;
step (2): recrystallizing the 4- (2-methyl-2-nitropropyl) phenol crude product by ethyl acetate and petroleum ether to obtain an intermediate 1;
and (3): 4- (2-methyl-2-nitropropyl) phenol is hydrogenated under the catalysis of palladium carbon to obtain an intermediate 2 hydrogenation reaction solution;
and (4): adding acetic acid into the hydrogenation reaction liquid of the 4- (2-amino-2-methylpropyl) phenol to refine to obtain the 4- (2-amino-2-methylpropyl) phenol.
Specifically, in the step (1), the condensation reaction of 4- (2-methyl-2-nitropropyl) phenol is firstly carried out at 100-110 ℃ for reflux and water diversion reaction.
Specifically, in the step (1), the weight ratio of 4-hydroxybenzyl alcohol, 2-nitropropane, toluene and tetrabutylammonium bromide in the condensation reaction is 1:2 to 6:4 to 12:0.01 to 0.05. The preferable weight ratio is 1:4: 8:0.02.
specifically, in the step (1), the molar ratio of 4-hydroxybenzyl alcohol and potassium hydroxide in the condensation reaction is 2:0.8 to 1.2. The preferred molar ratio is 2:1.
specifically, in the step (1), 4- (2-methyl-2-nitropropyl) phenol is refined, and the weight ratio of 4-hydroxybenzyl alcohol, ethyl acetate and petroleum ether is 1:1 to 2:10 to 20. The preferred weight ratio is 1:1:10.
specifically, in the step (2), the weight ratio of 4- (2-methyl-2-nitropropyl) phenol, methanol and palladium carbon in the hydrogenation reaction is 1:5 to 15:0.05 to 0.2. The preferable weight ratio is 1:10:0.1.
specifically, in the step (2), 4- (2-amino-2-methylpropyl) phenol is purified, and the molar ratio of the intermediate 2 to acetic acid is 1:1.
has the advantages that: the synthesis method of Lu Babei intermediate 4- (2-amino-2-methylpropyl) phenol provided by the invention can reduce the production cost of the product, and meanwhile, the purification method of the intermediate is provided to replace the purification method of column chromatography in the original process, so that the operation mode is simplified, and the method is more suitable for commercial production.
Drawings
FIG. 1 shows NMR carbon spectrum of 4- (2-amino-2-methylpropyl) phenol
FIG. 2 is a hydrogen nuclear magnetic resonance spectrum of 4- (2-amino-2-methylpropyl) phenol
FIG. 3 is a mass spectrum of 4- (2-amino-2-methylpropyl) phenol
FIG. 4 is a liquid phase spectrum of 4- (2-amino-2-methylpropyl) phenol
Detailed Description
The following examples illustrate the invention in more detail, without limiting the scope of the invention to the examples.
Example 1:
condensation of p-hydroxybenzyl alcohol with 2-nitropropane
Adding 1g of p-hydroxybenzyl alcohol, 40g of 2-nitropropane, 80g of toluene, 4.5g of potassium tert-butoxide and 0.2g of tetrabutylammonium bromide into a reaction bottle, installing a reflux water separator, heating the mixture to 100 ℃, starting reflux and separating hands, stopping heating after 5 hours, cooling to room temperature, and adding 60g of water; adjusting the pH value to 6-7 by hydrochloric acid; separating, washing the organic phase with 60g of water, drying the organic phase with anhydrous sodium sulfate, and performing decompression and desolventizing to obtain a crude product of the 4- (2-methyl-2-nitropropyl) phenol.
Adding the crude 4- (2-methyl-2-nitropropyl) phenol, 10g of ethyl acetate and 100g of petroleum ether into a reaction bottle, heating to 55-60 ℃, stirring for 20 minutes, cooling, filtering, and forced air drying at 60 ℃ to obtain 13g of intermediate with the yield of 82.7 percent
Reduction of 4- (2-methyl-2-nitropropyl) phenol
Adding 10g of 4- (2-methyl-2-nitropropyl) phenol, 100g of methanol and 1g of palladium carbon into a hydrogenation reaction kettle, replacing gas, heating to 60 ℃, and reacting under the pressure of 0.04-0.05 MPa until the hydrogen pressure is not reduced; cooling, replacing with nitrogen, and filtering;
adding 3.1g of acetic acid into the mother liquor, stirring for 20 minutes, and then performing rotary evaporation to remove the solvent until the solvent is dry to obtain a white solid; the white solid was dissolved in 50g of water, adjusted to pH =9 with 10% sodium hydroxide solution and filtered with suction to give 7.2g with a yield of 85.1%.
Example 2:
condensation of p-hydroxybenzyl alcohol with 2-nitropropane
Adding 40g of p-hydroxybenzyl alcohol, 160g of 2-nitropropane, 320g of toluene and 0.8g of tetrabutylammonium bromide, namely 18g of potassium tert-butoxide into a reaction bottle, installing a reflux water separator, heating the mixture to 100 ℃, starting reflux and separating hands, stopping heating after 5 hours, cooling to room temperature, and adding 240g of water; adjusting the pH value to 6-7 by hydrochloric acid; and separating liquid, washing an organic phase by 240g of water, drying the organic phase by using anhydrous sodium sulfate, and performing decompression and desolventizing to obtain a crude product of the 4- (2-methyl-2-nitropropyl) phenol.
Adding the crude 4- (2-methyl-2-nitropropyl) phenol, 40g of ethyl acetate and 400g of petroleum ether into a reaction bottle, heating to 55-60 ℃, stirring for 20 minutes, cooling, filtering, and forced air drying at 60 ℃ to obtain 56.7g of an intermediate with the yield of 90.2 percent
Reduction of 4- (2-methyl-2-nitropropyl) phenol
Adding 50g of 4- (2-methyl-2-nitropropyl) phenol, 500g of methanol and 5g of palladium carbon into a hydrogenation reaction kettle, replacing gas, heating to 60 ℃, and reacting under the pressure of 0.04-0.05 MPa until the hydrogen pressure is not reduced; cooling, replacing with nitrogen, and filtering;
adding 15.5g of acetic acid into the mother liquor, stirring for 20 minutes, and performing rotary evaporation to remove the solution until the solution is dry to obtain a white solid; the white solid was dissolved in 200g of water, adjusted to pH =9 with 10% sodium hydroxide solution and filtered with suction to give 37.6g with a yield of 88.9%.
Example 3:
condensation of p-hydroxybenzyl alcohol with 2-nitropropane
80g of p-hydroxybenzyl alcohol, 320g of 2-nitropropane, 640g of toluene, 36g of potassium tert-butoxide and 1.6g of tetrabutylammonium bromide are added into a reaction bottle, a reflux water separator is arranged, the mixture is heated to 100 ℃, reflux is started for separating hands, the heating is stopped after 5 hours, the mixture is cooled to room temperature, and 480g of water is added; adjusting the pH value to 6-7 by hydrochloric acid; separating, washing the organic phase with 480g of water, drying the organic phase with anhydrous sodium sulfate, and performing decompression and desolventizing to obtain a crude product of the 4- (2-methyl-2-nitropropyl) phenol.
Adding the crude 4- (2-methyl-2-nitropropyl) phenol, 80g of ethyl acetate and 800g of petroleum ether into a reaction bottle, heating to 55-60 ℃, stirring for 20 minutes, cooling, performing suction filtration, and performing forced air drying at 60 ℃ to obtain 115.2g of an intermediate, wherein the yield is 91.6 percent
Reduction of 4- (2-methyl-2-nitropropyl) phenol
Adding 100g of 4- (2-methyl-2-nitropropyl) phenol, 1000g of methanol and 10g of palladium-carbon into a hydrogenation reaction kettle, replacing gas, heating to 60 ℃, and reacting under the pressure of 0.04-0.05 MPa until the hydrogen pressure is not reduced; cooling, replacing with nitrogen, and filtering;
adding 31g of acetic acid into the mother liquor, stirring for 20 minutes, and performing rotary evaporation to remove the solvent until the solvent is dry to obtain a white solid; the white solid was dissolved in 400g of water, adjusted to pH =9 with 10% sodium hydroxide solution, and filtered to obtain 78.6g with a yield of 92.9% and a purity of 99.84%.
And (3) product detection:
the 4- (2-amino-2-methylpropyl) phenol prepared in the embodiment 3 of the invention is respectively subjected to hydrogen spectrum analysis, carbon spectrum analysis and mass spectrum analysis, and the structure of the 4- (2-amino-2-methylpropyl) phenol is as follows:
according to the hydrogen spectrum: hydrogen spectrum 1HNMR (d 6-DMSO, d): 6.98-6.96 (m, 2H,), 6.70-6.68 (m, 2H,), 4.02 (s, s,2H,), 2.51-2.47 (m, 2H,), 0.97 (s, 6H,).
According to the carbon spectrum: 13CNMR (d 6-DMSO) 155.70 (carbon atom 7), 131.05 (carbon atom 3), 128.66 (carbon atom 2), 114.61 (carbon atom 1), 49.71 (carbon atom 4), 49.636 (carbon atom 6), 29.75 (carbon atom 5); the carbon atom in the product obtained in example 3 of the present invention is the same as that in 4- (2-amino-2-methylpropyl) phenol.
According to mass spectrum TOF MS ES +:166 (M + 1); the product obtained in the embodiment 3 of the invention has the same relative molecular mass with 4- (2-amino-2-methylpropyl) phenol.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application.
Claims (7)
1. A method for synthesizing and refining a lubabylon intermediate is characterized by comprising the following steps:
step (1): carrying out condensation reaction on p-hydroxybenzyl alcohol and 2-nitropropane in potassium hydroxide, tetrabutylammonium bromide and toluene to obtain a crude product of 4- (2-methyl-2-nitropropyl) phenol;
step (2): recrystallizing the crude product of 4- (2-methyl-2-nitropropyl) phenol by ethyl acetate and petroleum ether to obtain an intermediate 1;
and (3): 4- (2-methyl-2-nitropropyl) phenol is hydrogenated under the catalysis of palladium carbon to obtain an intermediate 2 hydrogenation reaction liquid;
and (4): adding acetic acid into the hydrogenation reaction liquid of the 4- (2-amino-2-methylpropyl) phenol to refine to obtain the 4- (2-amino-2-methylpropyl) phenol.
2. The method for synthesizing and purifying an intermediate Lu Babei as claimed in claim 1, wherein in step (1), the condensation reaction of 4- (2-methyl-2-nitropropyl) phenol is performed by reflux and water separation at 100-110 ℃.
3. The method for synthesizing and purifying Lu Babei long intermediate as claimed in claim 1, wherein in step (1), the weight ratio of 4-hydroxybenzyl alcohol, 2-nitropropane, toluene and tetrabutylammonium bromide in the condensation reaction is 1:2 to 6:4 to 12:0.01 to 0.05.
4. The method for synthesizing and purifying Lu Babei as claimed in claim 1, wherein in step (1), the molar ratio of 4-hydroxybenzyl alcohol and potassium hydroxide in the condensation reaction is 2:0.8 to 1.2.
5. The method for synthesizing and refining Lu Babei long intermediate as claimed in claim 1, wherein in step (1), 4- (2-methyl-2-nitropropyl) phenol is refined, and the weight ratio of 4-hydroxybenzyl alcohol, ethyl acetate and petroleum ether is 1:1 to 2:10 to 20.
6. The method for synthesizing and purifying Lu Babei as claimed in claim 1, wherein in step (2), the weight ratio of 4- (2-methyl-2-nitropropyl) phenol, methanol and palladium on carbon in hydrogenation reaction is 1:5 to 15:0.05 to 0.2.
7. The method for synthesizing and purifying an intermediate Lu Babei methyl according to claim 1, wherein in step (2), 4- (2-amino-2-methylpropyl) phenol is purified, and the molar ratio of intermediate 2 to acetic acid is 1:1.
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|---|---|---|---|---|
| US20020165234A1 (en) * | 1996-09-05 | 2002-11-07 | Crowell Thomas A. | Selective B3 adrenergic agonists |
| WO2001036412A1 (en) * | 1999-11-15 | 2001-05-25 | Eli Lilly And Company | Process for the preparation of aryloxy propanolamines |
| CN1390213A (en) * | 1999-11-15 | 2003-01-08 | 伊莱利利公司 | Aryloxy propanolamines for improving livestock production |
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| CN114380811A (en) * | 2021-12-29 | 2022-04-22 | 天和药业股份有限公司 | Synthetic method of lubaibailong |
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