CN102993116A - Preparation method of benzoxazine excitant - Google Patents
Preparation method of benzoxazine excitant Download PDFInfo
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- CN102993116A CN102993116A CN2012105125305A CN201210512530A CN102993116A CN 102993116 A CN102993116 A CN 102993116A CN 2012105125305 A CN2012105125305 A CN 2012105125305A CN 201210512530 A CN201210512530 A CN 201210512530A CN 102993116 A CN102993116 A CN 102993116A
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Abstract
The invention discloses a preparation method of a benzoxazine excitant, which belongs to the technical field of protein coupling receptors. An object compound is synthesized through seven-step reaction by taking 2-nitryl resorcinol as a raw material. The preparation method disclosed by the invention is easy and convenient to operate, prevents the poisonous reagent from being used and can be used for preparing a larger amount of BI-167107 and similar compounds thereof.
Description
Technical field
The present invention relates to a kind of benzo oxazinyl β
2The synthetic method of-AR agonist BI-167107 belongs to the protein linked receptor technical field.
Background technology
G protein coupled receptor (G-protein-coupled receptor, GPCR) is the transmembrane protein acceptor that a class has 7 transbilayer helixs.The constitutional features of GPCR and the vital role in the signal conduction have determined that it can be used as good drug targets.The functional disorder of GPCR can cause the generation of numerous disease, such as Alzheimer's disease, parkinsonism, nanism, colour blindness disease, retinitis pigmentosa and asthma etc.By regulating the illnesss such as all right Cure of depression of signal conduction, schizophrenia, insomnia hypertension, weakness, impatience, anxiety, renal failure, cardiovascular and cerebrovascular diseases and inflammation of relevant GPCR mediation.Most of medicine can reach by targeting the effect for the treatment of in GPCR, it is activator (agonist) or the antagonist (antagonist) of GPCR that 1/3rd small-molecule drug is arranged on world's pharmaceutical market at present, and this illustrates that this receptoroid and their aglucon occupy extremely important status in drug development and design.Wherein, β
2Adrenergic receptor (β
2-AR) agonist and antagonist are important GPCR class medicines.β
2Adrenoceptor agonists causes bronchiectasic effect owing to having, so be used for the treatment of asthma and chronic obstructive pulmonary disease (COPD).As New-type long-acting β
2Receptor stimulant, benzoxazinones β
2Adrenoceptor agonists is high to receptor-selective aspect expansion bronchus, releasing symptoms of asthma, and successful is the ideal medicament for the treatment of bronchial asthma, trachitis, chronic obstructive pulmonary disease, has shown good prospect.BI-167107 is the long-acting beta that German Boehringer Ingelheim company develops
2Receptor stimulant (long-acting β
2Agonists, LABA), contain benzoxazinone female ring and side chain amido in its structure.As far as we know, in the document of having published, also there are not the specific descriptions about the BI-167107 synthetic method.
The chemical structure of BI-167107
Summary of the invention
The present invention provides the preparation method of a kind of BI-167107 in order to overcome above-mentioned deficiency of the prior art.
Its reaction equation is as follows:
The synthetic route of BI-167107
A kind of benzo oxazinyl β
2The preparation method of-AR agonist BI-167107, carry out according to following step:
(1) 2-nitro-resorcinol and diacetyl oxide react under the aluminum chloride effect, with about 5 hours of heating in oil of mirbane, generate 2,4-dihydroxyl-3-nitro-acetophenone (2);
(2) during room temperature, 2,4-dihydroxyl-3-nitro-acetophenone (2) carries out alkylation with the benzyl bromine in dimethyl formamide DMF under the alkali effect, generates 2-hydroxyl-3-nitro-4-benzyloxy methyl phenyl ketone (3);
(3) 2-hydroxyl-3-nitro-4-benzyloxy methyl phenyl ketone (3) is reduced the agent reduction in acetic acid, generates 2-hydroxyl-3-amino-4-benzyloxy methyl phenyl ketone (4);
(4) 2-hydroxyl-3-amino-4-benzyloxy methyl phenyl ketone (4) reacts under the alkali effect with chloroacetyl chloride, generates 5-benzyloxy-8-ethanoyl-2H-benzo [Isosorbide-5-Nitrae] oxazine-3 (4H) ketone (5);
(5) 5-benzyloxy-8-ethanoyl-2H-benzo [1,4] oxazine-3 (4H) ketone (5) react with oxidizer system in dimethyl sulfoxide (DMSO), generate 5-benzyloxy-8-(2,2-dihydroxyl ethanoyl)-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-3 (4H)-ketone (6);
(6) under the room temperature, 5-benzyloxy-8-(2,2-dihydroxyl ethanoyl)-2H-benzo [b] [1,4] oxazines-3 (4H)-ketone (6) and 2-methyl isophthalic acid-(o-tolyl) propyl group-2-amine reaction, then, through the reductive agent reduction, generate 5-benzyloxy-8-(1-hydroxyl-2-((2-methyl isophthalic acid-(o-tolyl) third-2-yl) amino) ethyl)-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-3 (4H)-ketone (7);
(7) 5-benzyloxy-8-(1-hydroxyl-2-((2-methyl isophthalic acid-(o-tolyl) third-2-yl) amino) ethyl)-2H-benzo [b] [1,4] oxazines-3 (4H)-ketone (7) is dissolved in the methyl alcohol, in the presence of catalyzer, through catalytic hydrogenation, generate 5-hydroxyl-8-(1-hydroxyl-2-((2-methyl isophthalic acid-(o-tolyl) third-2-yl) amino) ethyl)-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-3 (4H)-ketone (BI-167107).
Wherein the mol ratio of the described 2-nitro-resorcinol of step (1) and diacetyl oxide is 1:1-5, preferred 1:1; The mol ratio of aluminum chloride and 2-nitro-resorcinol is 1:1-10, preferred 1:4; Described solvent is oil of mirbane, Nitromethane 99Min. or methylene dichloride, preferred oil of mirbane or Nitromethane 99Min..
Wherein step (2) is described 2, and the mol ratio of 4-dihydroxyl-3-nitro-acetophenone and benzyl bromine is 1:1-3, preferred 1:1; Wherein said alkali is trimethyl carbinol lithium, sodium tert-butoxide, potassium tert.-butoxide, sodium ethylate, sodium hydride or salt of wormwood, preferred tertiary butanols lithium or sodium hydride; Wherein said 2, the mol ratio of 4-dihydroxyl-3-nitro-acetophenone and alkali is 1:1-3, preferred 1:1; Wherein said solvent is dimethyl formamide, dimethyl sulfoxide (DMSO) and acetone, preferred dimethyl formamide.
Wherein the mol ratio of the described 2-hydroxyl of step (3)-3-nitro-4-benzyloxy methyl phenyl ketone and reductive agent is 1:1-10, preferred 1:3; Wherein said reductive agent is zinc powder, iron powder, tindichloride, preferred zinc powder and iron powder; Wherein said solvent is acetic acid, hydrochloric acid or sulfuric acid, preferred acetic acid; Wherein said temperature of reaction is 0 ° of C-80 ° of C, preferred 10 ° of C-30 ° of C.
Wherein the mol ratio of the described 2-hydroxyl of step (4)-3-amino-4-benzyloxy methyl phenyl ketone and chloroacetyl chloride is 1:1-5, preferred 1:1;
Wherein said alkali is sodium bicarbonate, cesium carbonate, trimethyl carbinol lithium, sodium tert-butoxide, potassium tert.-butoxide, sodium ethylate, sodium hydride or salt of wormwood, preferred sodium bicarbonate and cesium carbonate; The mol ratio of wherein said alkali and 2-hydroxyl-3-amino-4-benzyloxy methyl phenyl ketone is 1:1-5, preferred 1:2; Wherein said solvent is dimethyl formamide, dimethyl sulfoxide (DMSO) and acetone, preferred dimethyl formamide; Wherein said temperature of reaction is-10 ° of C-150 ° of C, preferred 20 ° of C-100 ° of C.
Wherein the described oxidizer system of step (5) is hydrobromic acid aqueous solution (commercially available content 40%-48%)/dimethyl sulfoxide (DMSO) system, tin anhydride, preferred hydrobromic acid aqueous solution/dimethyl sulfoxide (DMSO) system; [Isosorbide-5-Nitrae] oxazine-3 (4H) ketone and 48% hydrobromic mol ratio are 1:1-20 to wherein said 5-benzyloxy-8-ethanoyl-2H-benzo, preferred 1:3; Wherein said solvent is dimethyl formamide, dimethyl sulfoxide (DMSO), second alcohol and water, preferred dimethyl sulfoxide (DMSO); Wherein said temperature of reaction is 0 ° of C-150 ° of C, preferred 40 ° of C-70 ° of C.
Wherein [Isosorbide-5-Nitrae] oxazine-3 (4H)-ketone (6) is 1:1-3 with the mol ratio of 2-methyl isophthalic acid-(o-tolyl) propyl group-2-amine to the described 5-benzyloxy-8-of step (6) (2,2-dihydroxyl ethanoyl)-2H-benzo [b], preferred 1:1; [Isosorbide-5-Nitrae] oxazine-3 (4H)-ketone (6) is 1:2-6 with the mol ratio of lithium borohydride to wherein said 5-benzyloxy-8-(2,2-dihydroxyl ethanoyl)-2H-benzo [b], preferred 1:2; Wherein said reductive agent is lithium borohydride, sodium borohydride, lithium aluminium hydride, preferred lithium borohydride; [mol ratio of Isosorbide-5-Nitrae] oxazine-3 (4H)-ketone is 1:1-6 to wherein said reductive agent and 5-benzyloxy-8-(2,2-dihydroxyl ethanoyl)-2H-benzo [b], preferred 1:3; Wherein said solvent is tetrahydrofuran (THF), dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), ethanol, preferred tetrahydrofuran (THF); Wherein said temperature of reaction is-10 ° of C-50 ° of C, preferred 0 ° of C-30 ° of C.
Wherein the described catalyzer of step (7) is palladium carbon (5%-10%) (mass percent), platinum carbon (5%-10%), platinum oxide, Raney nickel, preferred palladium carbon (5%-10%); Wherein said solvent is methyl alcohol, ethanol, tetrahydrofuran (THF), dioxane, dimethyl formamide, particular methanol, ethanol.
Advantage of the present invention: the present invention through the reaction of seven steps, has synthesized benzo oxazinyl β take the 2-nitro-resorcinol as raw material
2-AR agonist BI-167107, the raw material that uses and reagent cheap and easy to get, and avoided the use toxic reagent, easy and simple to handle, go for preparing relatively large BI-167107 and the compound of similar thereof.
Embodiment:
Describe the present invention below in conjunction with embodiment, but the present invention is not limited to these embodiment.
Embodiment 1
Step 1: embodiment 1: under the nitrogen protection, in the 100mL round-bottomed flask, add respectively oil of mirbane (135mL) and AlCl
3(1.91g, 14.32mmol) stirred 10 minutes, slowly added 2-nitro-resorcinol (1) (10.00g, 64.50mmol) in mixing solutions more in batches, dripped Ac again in solution
2O(6.40mL), in 100 ℃ of lower reaction 5h.Behind the stopped heating, cool to room temperature is iced HCl (120mL) cancellation reaction with 2M.The mixed solution extracted with diethyl ether (2 * 200mL), merge organic phase.With organic phase with 2M NaOH extraction 2 times (2 * 150mL), merge water.Merge the water obtain with ether washing 4 times (4 * 200mL), be adjusted to pH=1 with 2M HCl again.With the precipitation suction filtration that generates, washing in air drying, obtains the dark yellow solid.Column chromatography purification (eluent: DCM/ sherwood oil PE=3:1), obtain glassy yellow solid 2,4-dihydroxyl-3-nitro-acetophenone 2(8.64g), productive rate 68%.
1H?NMR(300MHz,CDCl
3):δ14.85(s,1H),11.35(s,1H),7.90(d,J=9.09Hz,1H),6.63(d,J=9.09Hz,1H),2.62(s,3H).
Step 2: embodiment 1: in the 100mL there-necked flask, 2,4-dihydroxyl-3-nitro-acetophenone (8.64g, 64.5mmol) is dissolved among the DMF (85mL), at N
2The lower trimethyl carbinol lithium LiOBu that adds of protection
t(3.51g), stir 10min under the room temperature.Add benzyl bromine (5.21mL), behind the stirring 20h, water (50mL) cancellation is reacted under the room temperature.Add 1M NaOH(43mL), with ether washing 2 times (2 * 200mL).Under the ice-water bath condition, use 2M HCl(173mL) be acidified to pH=1, there is precipitation to generate, suction filtration, washing in air drying, obtains yellow solid.Column chromatography purification (eluent: DCM/PE=5:1), obtain faint yellow solid 2-hydroxyl-3-nitro-4-benzyloxy methyl phenyl ketone 3(6.72g), productive rate 53%.
1H?NMR(300MHz,CDCl
3):δ13.07(s,1H),7.76(d,J=9.06Hz,2H),7.41-7.31(m,5H),6.58(d,J=9.06Hz,1H),5.25(s,2H),2.58(s,3H)。
Step 3: embodiment 1: in the 25mL round-bottomed flask, with 3(6.72g, 23.4mmol) be dissolved in AcOH(68mL) in, slowly add Zn powder (6.72g) in batches, stir 2h under the room temperature.Suction filtration is poured frozen water (680mL) in filtrate, generate precipitation, and suction filtration in air drying, obtains yellow solid.Column chromatography purification (eluent: DCM/PE=1:1), obtain yellow solid 2-hydroxyl-3-amino-4-benzyloxy methyl phenyl ketone 4(4.90g), yield 82%.
1H?NMR(300MHz,CDCl
3):δ12.49(s,1H),7.45-7.34(m,5H),7.16(d,J=8.91Hz,1H),6.50(d,J=8.94Hz,1H),5.17(s,2H),2.55(s,3H)。
Step 4: embodiment 1: in 50mL single port flask, add respectively 4(4.90g, 19.0mmol), NaHCO
3(3.54g) and DMF (30mL).Then, in mixed solution, drip chloroacetyl chloride (1.70mL),
Step 5: embodiment 1: in the 50mL flask, adding 5-benzyloxy-8-ethanoyl-2H-benzo [Isosorbide-5-Nitrae] oxazine-3 (4H) ketone 5 (1.08g, 3.6mmol), DMSO (10mL) and 48% HBr(1.56mL), be heated to 55 ℃, reaction 20h.TLC analyzes demonstration, the raw material completely dissolve.After being cooled to room temperature; with frozen water (50mL) cancellation reaction, with ethyl acetate (3 * 100mL) extractions, the combining extraction liquid water (2 * 100mL) and saturated aqueous common salt (2 * 100mL) wash respectively; anhydrous sodium sulfate drying; filter, underpressure distillation obtains yellow solid 5-benzyloxy-8-(2; 2-dihydroxyl ethanoyl)-2H-benzo [b] [1; 4] oxazine-3 (4H)-ketone 6 is not purified, directly drops into next step reaction.
Step 6: embodiment 1: in the 50mL flask; 5-benzyloxy-8-(2 that the upper step was obtained; 2-dihydroxyl ethanoyl)-2H-benzo [b] [1; 4] oxazine-3 (4H)-ketone 6 are dissolved in THF(22mL) in; add 2-methyl isophthalic acid-(o-tolyl) propyl group-2-amine (0.63g; 3.87mmol), react 14h under the room temperature.After reaction mixture is cooled to 0 ° of C, add LiBH
4(0.23g, 10.6mmol), and at 0 ℃ of lower reaction 3h.With frozen water (55mL) cancellation reaction, with methylene dichloride (3 * 150mL) extractions, the combining extraction liquid water (2 * 150mL) and saturated aqueous common salt (2 * 150mL) wash anhydrous sodium sulfate drying respectively.Crude product is through column chromatography purification (eluent: DCM/MeOH=50:1; DCM/MeOH=20:1), obtain yellow solid 5-benzyloxy-8-(1-hydroxyl-2-((2-methyl isophthalic acid-(o-tolyl) third-2-yl) amino) ethyl)-2H-benzo [b] [1,4] oxazines-3 (4H)-ketone 7 (0.95g), productive rate 57%.
1H?NMR(400MHz,CDCl
3):δ7.73(s,1H),7.42-7.37(m,5H),7.20-7.16(m,5H),6.64(d,J=8.00Hz,1H),5.52(d,J＝12.00Hz,1H),5.07(s,2H),4.57(d,J＝16.00Hz,1H),4.34(d,J＝16.00Hz,1H),3.35(d,J＝12.00Hz,1H),3.22(m,J＝4.00Hz,1H),3.02(t,J＝12.00Hz,1H),2.37(s,3H),1.38(s,6H);ESI-MS(positive):m/z?461[M+H]。
Step 7: embodiment 1: in the 50mL round-bottomed flask, 7 (0.95g, 2.06mmol) are dissolved in MeOH(20mL) in, adds 10%Pd/C (200mg), at normal temperatures and pressures catalytic hydrogenation 4h.Behind the diatomite filtration catalizer, crude product is through column chromatography purification (eluent: DCM/MeOH=30:1), obtain BI-167107, be faint yellow solid (0.74g) that productive rate is 97%.
1H?NMR(400MHz,DMSO-d
6):δ9.92(s,1H),7.15-7.06(m,J=4.71Hz,4H),6.90(d,J＝8.64Hz,1H),6.52(d,J＝8.43Hz,1H),4.85(dd,J＝5.58Hz,1H),4.48(d,J＝1.83Hz,2H),2.72(d,J＝1.83Hz,1H),2.63(t,J＝9.00Hz,1H),2.29(s,3H),1.86(s,2H),1.00(s,6H);
13CNMR(100MHz,DMSO-d
6):δ164.43,144.23,141.20,136.87,136.42,131.29,130.20,126.08,125.19,122.03,115.15,108.99,66.94,65.82,55.12,48.36,41.77,25.81,25.50,20.19;ESI-MS(positive):m/z?371[M+H]。
Embodiment 2: step 1: add respectively methylene dichloride (135mL) and AlCl in the 100mL round-bottomed flask
3(1.91g, 14.32mmol) stirred 10 minutes, slowly added 2-nitro-resorcinol (10.00g, 64.50mmol) in mixing solutions more in batches, dripped Ac again in solution
2O(6.40mL), in 40 ℃ of lower reaction 10h.Aftertreatment and purification process be with embodiment 1, the productive rate 52% of products obtained therefrom.
Step 2: embodiment 2: other conditions are changed into salt of wormwood with used alkali trimethyl carbinol lithium, the productive rate 20% of products obtained therefrom with embodiment 1.
Step 3: embodiment 2: other conditions are changed into iron powder with embodiment 1 with used Zn powder, the productive rate 75% of products obtained therefrom.
Step 4: embodiment 2: other conditions are changed into salt of wormwood with embodiment 1 with used cesium carbonate, the productive rate 38% of products obtained therefrom.
5-benzyloxy-8-(2,2-dihydroxyl ethanoyl)-2H-benzo [the b] [preparation method of Isosorbide-5-Nitrae] oxazine-3 (4H)-ketone (6)
Step 5: embodiment 2: other conditions are changed into tin anhydride and dioxane with embodiment 1 with used 48%HBr and DMSO, and TLC analyzes demonstration, and the transformation efficiency of raw material is less than 40%.
Step 5: embodiment 3: other conditions are changed into 20-30 ℃ with embodiment 1 with temperature of reaction, and TLC analyzes demonstration, and the transformation efficiency of raw material is less than 20%.
Step 6: embodiment 2: other conditions are changed into sodium borohydride with embodiment 1 with used borane reducing agent lithium hydride, the productive rate 42% of products obtained therefrom.
5-hydroxyl-8-(1-hydroxyl-2-((2-methyl isophthalic acid-(o-tolyl) third-2-yl) amino) ethyl)-2H-benzo [the b] [preparation method of Isosorbide-5-Nitrae] oxazine-3 (4H)-ketone (BI-167107)
Step 7: embodiment 2: other conditions are changed into 5% platinum carbon with catalyst system therefor 10% palladium carbon, the productive rate 86% of products therefrom with embodiment 1.
Claims (3)
1. benzo oxazinyl β
2The preparation method of-AR agonist is characterized in that carrying out according to following step: (1) 2-nitro-resorcinol and diacetyl oxide react under the aluminum chloride effect, with about 5 hours of heating in oil of mirbane, generate 2,4-dihydroxyl-3-nitro-acetophenone;
(2) during room temperature, 2,4-dihydroxyl-3-nitro-acetophenone carries out alkylation with the benzyl bromine in dimethyl formamide DMF under the alkali effect, generates 2-hydroxyl-3-nitro-4-benzyloxy methyl phenyl ketone;
(3) 2-hydroxyl-3-nitro-4-benzyloxy methyl phenyl ketone is reduced the agent reduction in acetic acid, generates 2-hydroxyl-3-amino-4-benzyloxy methyl phenyl ketone;
(4) 2-hydroxyl-3-amino-4-benzyloxy methyl phenyl ketone and chloroacetyl chloride react under the alkali effect, generate 5-benzyloxy-8-ethanoyl-2H-benzo [Isosorbide-5-Nitrae] oxazine-3 (4H) ketone;
(5) [Isosorbide-5-Nitrae] oxazine-3 (4H) ketone reacts with oxidizer system in dimethyl sulfoxide (DMSO) 5-benzyloxy-8-ethanoyl-2H-benzo, generates 5-benzyloxy-8-(2,2-dihydroxyl ethanoyl)-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-3 (4H)-ketone;
(6) under the room temperature, 5-benzyloxy-8-(2,2-dihydroxyl ethanoyl)-2H-benzo [b] [1,4] oxazine-3 (4H)-ketone and 2-methyl isophthalic acid-(o-tolyl) propyl group-2-amine reaction, then, through the reductive agent reduction, generate 5-benzyloxy-8-(1-hydroxyl-2-((2-methyl isophthalic acid-(o-tolyl) third-2-yl) amino) ethyl)-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-3 (4H)-ketone;
(7) 5-benzyloxy-8-(1-hydroxyl-2-((2-methyl isophthalic acid-(o-tolyl) third-2-yl) amino) ethyl)-2H-benzo [b] [1,4] oxazine-3 (4H)-ketone are dissolved in the methyl alcohol, in the presence of catalyzer, through catalytic hydrogenation, generate 5-hydroxyl-8-(1-hydroxyl-2-((2-methyl isophthalic acid-(o-tolyl) third-2-yl) amino) ethyl)-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-3 (4H)-ketone.
2. a kind of benzo oxazinyl β according to claim 1
2The preparation method of-AR agonist, it is characterized in that wherein the mol ratio of the described 2-nitro-resorcinol of step (1) and diacetyl oxide is 1:1-5, the mol ratio of aluminum chloride and 2-nitro-resorcinol is 1:1-10, and described solvent is oil of mirbane, Nitromethane 99Min. or methylene dichloride
Step (2) described 2 wherein, the mol ratio of 4-dihydroxyl-3-nitro-acetophenone and benzyl bromine is 1:1-3, wherein said alkali is trimethyl carbinol lithium, sodium tert-butoxide, potassium tert.-butoxide, sodium ethylate, sodium hydride or salt of wormwood, wherein said 2, the mol ratio of 4-dihydroxyl-3-nitro-acetophenone and alkali is 1:1-3, and wherein said solvent is dimethyl formamide, dimethyl sulfoxide (DMSO) and acetone
Wherein the mol ratio of the described 2-hydroxyl of step (3)-3-nitro-4-benzyloxy methyl phenyl ketone and reductive agent is 1:1-10, and wherein said reductive agent is zinc powder, iron powder, tindichloride, wherein said solvent is acetic acid, hydrochloric acid or sulfuric acid, and wherein said temperature of reaction is 0
0C-80
0C,
Wherein the mol ratio of the described 2-hydroxyl of step (4)-3-amino-4-benzyloxy methyl phenyl ketone and chloroacetyl chloride is 1:1-5,
Wherein said alkali is sodium bicarbonate, cesium carbonate, trimethyl carbinol lithium, sodium tert-butoxide, potassium tert.-butoxide, sodium ethylate, sodium hydride or salt of wormwood, the mol ratio of wherein said alkali and 2-hydroxyl-3-amino-4-benzyloxy methyl phenyl ketone is 1:1-5, wherein said solvent is dimethyl formamide, dimethyl sulfoxide (DMSO) or acetone; Wherein said temperature of reaction is-10
0C-150
0C,
Wherein the described oxidizer system of step (5) is hydrobromic acid aqueous solution (mass content 40%-48%)/dimethyl sulfoxide (DMSO) system, tin anhydride, wherein said 5-benzyloxy-8-ethanoyl-2H-benzo [1,4] oxazine-3 (4H) ketone and 48% hydrobromic mol ratio are 1:1-20, wherein said solvent is dimethyl formamide, dimethyl sulfoxide (DMSO), second alcohol and water, preferred dimethyl sulfoxide (DMSO); Wherein said temperature of reaction is 0
0C-150
0C,
The described 5-benzyloxy-8-(2 of step (6) wherein; 2-dihydroxyl ethanoyl)-2H-benzo [b] [1; the mol ratio of 4] oxazine-3 (4H)-ketone and 2-methyl isophthalic acid-(o-tolyl) propyl group-2-amine is 1:1-3; wherein said 5-benzyloxy-8-(2; 2-dihydroxyl ethanoyl)-2H-benzo [b] [1; the mol ratio of 4] oxazine-3 (4H)-ketone and lithium borohydride is 1:2-6; wherein said reductive agent is lithium borohydride; sodium borohydride, lithium aluminium hydride, wherein said reductive agent and 5-benzyloxy-8-(2; 2-dihydroxyl ethanoyl)-2H-benzo [b] [1; the mol ratio of 4] oxazine-3 (4H)-ketone is 1:1-6, and wherein said solvent is tetrahydrofuran (THF), dioxane; dimethyl formamide; dimethyl sulfoxide (DMSO), ethanol, wherein said temperature of reaction is-10
0C-50
0C,
Wherein the described catalyzer of step (7) is mass percent 5%-10% palladium carbon, 5%-10% platinum carbon, platinum oxide, Raney nickel; Wherein said solvent is methyl alcohol, ethanol, tetrahydrofuran (THF), dioxane, dimethyl formamide.
3. a kind of benzo oxazinyl β according to claim 2
2The preparation method of-AR agonist is characterized in that wherein the mol ratio of the described 2-nitro-resorcinol of step (1) and diacetyl oxide is 1:1; The mol ratio of aluminum chloride and 2-nitro-resorcinol is 1:4; Described solvent is oil of mirbane or Nitromethane 99Min.;
Wherein step (2) is described 2, and the mol ratio of 4-dihydroxyl-3-nitro-acetophenone and benzyl bromine is 1:1; Wherein said alkali trimethyl carbinol lithium or sodium hydride; Wherein said 2, the mol ratio of 4-dihydroxyl-3-nitro-acetophenone and alkali is 1:1; Wherein said solvent is dimethyl formamide;
Wherein the mol ratio of the described 2-hydroxyl of step (3)-3-nitro-4-benzyloxy methyl phenyl ketone and reductive agent is 1:3; Wherein said reductive agent is zinc powder, iron powder; Wherein said solvent is acetic acid; Wherein said temperature of reaction is 10
0C-30
0C;
Wherein the mol ratio of the described 2-hydroxyl of step (4)-3-amino-4-benzyloxy methyl phenyl ketone and chloroacetyl chloride is 1:1;
Wherein said alkali is sodium bicarbonate, cesium carbonate; The mol ratio of wherein said alkali and 2-hydroxyl-3-amino-4-benzyloxy methyl phenyl ketone is 1:2; Wherein said solvent is dimethyl formamide; Wherein said temperature of reaction is 20
0C-100
0C;
Wherein the described oxidizer system of step (5) is hydrobromic acid aqueous solution (mass content 40%-48%)/dimethyl sulfoxide (DMSO) system; [Isosorbide-5-Nitrae] oxazine-3 (4H) ketone and 48% hydrobromic mol ratio are 1:3 to wherein said 5-benzyloxy-8-ethanoyl-2H-benzo; Wherein said solvent is dimethyl sulfoxide (DMSO); Wherein said temperature of reaction is 40
0C-70
0C;
Wherein [mol ratio of Isosorbide-5-Nitrae] oxazine-3 (4H)-ketone and 2-methyl isophthalic acid-(o-tolyl) propyl group-2-amine is 1:1 to the described 5-benzyloxy-8-of step (6) (2,2-dihydroxyl ethanoyl)-2H-benzo [b]; Wherein said 5-benzyloxy-8-(2,2-dihydroxyl ethanoyl)-[mol ratio of Isosorbide-5-Nitrae] oxazine-3 (4H)-ketone and lithium borohydride is 1:2 to 2H-benzo [b]; Wherein said reductive agent is lithium borohydride, and wherein said reductive agent and 5-benzyloxy-8-(2,2-dihydroxyl ethanoyl)-[mol ratio of Isosorbide-5-Nitrae] oxazine-3 (4H)-ketone is 1:3 to 2H-benzo [b]; Wherein said solvent is tetrahydrofuran (THF); Wherein said temperature of reaction is 0
0C-30
0C;
Wherein the described catalyzer of step (7) is mass percent 5%-10% palladium carbon; Wherein said solvent is methyl alcohol, ethanol.
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| CN108499614A (en) * | 2018-04-28 | 2018-09-07 | 丛茜 | A kind of method that modified nickel catalytic material prepares central nervous system pharmaceutical intermediate |
| CN109748803A (en) * | 2017-11-01 | 2019-05-14 | 中国农业科学院农业质量标准与检测技术研究所 | A kind of synthetic method of phenolethanolamine A |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109748803A (en) * | 2017-11-01 | 2019-05-14 | 中国农业科学院农业质量标准与检测技术研究所 | A kind of synthetic method of phenolethanolamine A |
| CN108499614A (en) * | 2018-04-28 | 2018-09-07 | 丛茜 | A kind of method that modified nickel catalytic material prepares central nervous system pharmaceutical intermediate |
| CN108499614B (en) * | 2018-04-28 | 2021-06-04 | 西南医科大学附属医院 | Method for preparing drug intermediate for central nervous system from modified nickel catalytic material |
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