CN105622441A - Synthesis technology of L-betaxolol hydrochloride - Google Patents
Synthesis technology of L-betaxolol hydrochloride Download PDFInfo
- Publication number
- CN105622441A CN105622441A CN201410588103.4A CN201410588103A CN105622441A CN 105622441 A CN105622441 A CN 105622441A CN 201410588103 A CN201410588103 A CN 201410588103A CN 105622441 A CN105622441 A CN 105622441A
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- China
- Prior art keywords
- phenoxy group
- propanol
- organic solvent
- phenyl
- ethoxy
- Prior art date
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- 229960004347 betaxolol hydrochloride Drugs 0.000 title claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 title abstract description 4
- 238000005516 engineering process Methods 0.000 title abstract description 4
- 238000003786 synthesis reaction Methods 0.000 title abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229960004324 betaxolol Drugs 0.000 claims abstract description 7
- 238000005576 amination reaction Methods 0.000 claims abstract description 5
- YCCILVSKPBXVIP-UHFFFAOYSA-N 2-(4-hydroxyphenyl)ethanol Chemical compound OCCC1=CC=C(O)C=C1 YCCILVSKPBXVIP-UHFFFAOYSA-N 0.000 claims abstract description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 18
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- -1 methyl halide Chemical class 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 9
- LYVGEQNLCUDJLI-UHFFFAOYSA-N 2-phenyl-3-propan-2-yl-1h-pyrrole Chemical class C1=CNC(C=2C=CC=CC=2)=C1C(C)C LYVGEQNLCUDJLI-UHFFFAOYSA-N 0.000 claims description 6
- YAVVGPBYBUYPSR-UHFFFAOYSA-N benzene;oxygen Chemical compound [O].C1=CC=CC=C1 YAVVGPBYBUYPSR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000001294 propane Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000005815 base catalysis Methods 0.000 claims description 3
- QICQRRAHXUYAHB-UHFFFAOYSA-N benzene;formonitrile Chemical compound N#C.C1=CC=CC=C1 QICQRRAHXUYAHB-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 239000003444 phase transfer catalyst Substances 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 230000029936 alkylation Effects 0.000 abstract description 3
- 238000005804 alkylation reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a synthesis technology of L-betaxolol hydrochloride. High-enantiomeric purity L-betaxolol and hydrochloride thereof are prepared from p-hydroxyphenylethanol and R-epoxyhalopropane through alkylation, amination, protection, alkylation and deprotection reactions. Compared with the prior art, the technology disclosed in the invention has the advantages of simplicity, easily available raw materials, low toxicity, safe operation, small pollution, high yield and short period.
Description
Technical field
The invention belongs to chemical process field, be specifically related to a kind of technique for synthesizing levorotatory betaxolol hydrochloride synthesis technique.
Background technology
Technique for synthesizing levorotatory betaxolol hydrochloride at least includes the basic processes such as alkylation, amination, protection. In current technique for synthesizing levorotatory betaxolol hydrochloride synthesis technique, technological process is not easy to implement, and separation efficiency is low, it is impossible to achieve the recycling of raw material, and manufacturing process is complicated, and production efficiency is low.
Summary of the invention
For the above-mentioned technical problem overcoming prior art to exist, it is an object of the invention to, it is provided that a kind of technique for synthesizing levorotatory betaxolol hydrochloride, the present invention not only manufacturing process is simple, improve work efficiency, and achieves the guarantee of product quality.
Technique for synthesizing levorotatory betaxolol hydrochloride provided by the invention, comprises the following steps:
(1) under the existence of alkali compounds, p-hydroxyphenylethanol and R-epoxyhalopropane are dissolved in organic solvent with 1: 1��11 mol ratios, it is in that under 100��150 DEG C of conditions and reacts 2��8 hours, recrystallization obtains S-1-(4-(2-ethoxy) phenoxy group)-2,3-expoxy propane white solids;
(2) S-1-(4-(2-ethoxy) phenoxy group)-2,3-expoxy propane reacts 2��30 hours with mol ratio 1: 1��20 with amination reagent in organic solvent at 0��50 DEG C, and recrystallization obtains S-1-(4-(2-ethoxy) phenoxy group)-3-isopropylamine base-2-propanol white solid;
(3) S-1-(4-(2-ethoxy) phenoxy group)-3-isopropylamine base-2-propanol is dissolved in organic solvent, add protection reagent benzene formonitrile HCN and acidic catalyst, three's mol ratio is 1: 1��20: 0.005��0.5, in 40��150 DEG C of reacting by heating 1��20 hour, obtain its protection product (5S)-2-(4-((3-isopropyl-2-phenyl azoles quinoline)-5-methoxyl group) phenyl) ethanol;
(4) (5S)-2-(4-((3-isopropyl-2-phenyl azoles quinoline)-5-methoxyl group) phenyl) ethanol is dissolved in organic solvent, with ring the third methyl halide with 1: 1��10 mol ratios, under base catalysis, in the presence of a phase transfer catalyst, react 2��18 hours in-15��95 DEG C, obtain (5S)-5-(4-((2-ring the third methoxyl group) ethyl) benzene oxygen) methyl-3-isopropyl-2-phenyl azoles quinoline;
(5) mineral acid is joined in aqueous solution or the alcoholic solution of (5S)-5-(4-((2-ring the third methoxyl group) ethyl) benzene oxygen) methyl-3-isopropyl-2-phenyl azoles quinoline, stir 1��12 hour at 0��60 DEG C of temperature, through extracting, drying, obtain left-handed betaxolol S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propanol;
(6) left-handed betaxolol S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propanol is dissolved in organic solvent, it is subsequently adding hydrochloric acid or passes into hydrogen chloride gas, when PH=1��5, stirring 1��6 hour, recrystallization obtains the hydrochlorate of white crystals S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propanol.
Technique for synthesizing levorotatory betaxolol hydrochloride provided by the invention, it has the beneficial effects that, overcoming prior art, to prepare operation in l-betaxolol hydrochloride process more, and the problem that workload is big improves work efficiency; Improve the utilization rate of reactant and the yield of product.
Detailed description of the invention
Below in conjunction with an embodiment, technique for synthesizing levorotatory betaxolol hydrochloride provided by the invention is described in detail.
Embodiment
The technique for synthesizing levorotatory betaxolol hydrochloride of the present embodiment, comprises the following steps:
(1) under the existence of alkali compounds, p-hydroxyphenylethanol and R-epoxyhalopropane are dissolved in organic solvent with 1: 1 mol ratio, being in that under 150 DEG C of conditions and react 2 hours, recrystallization obtains S-1-(4-(2-ethoxy) phenoxy group)-2,3-expoxy propane white solids;
(2) S-1-(4-(2-ethoxy) phenoxy group)-2,3-expoxy propane reacts 30 hours with mol ratio 1: 1 with amination reagent in organic solvent at 50 DEG C, and recrystallization obtains S-1-(4-(2-ethoxy) phenoxy group)-3-isopropylamine base-2-propanol white solid;
(3) S-1-(4-(2-ethoxy) phenoxy group)-3-isopropylamine base-2-propanol is dissolved in organic solvent, add protection reagent benzene formonitrile HCN and acidic catalyst, three's mol ratio is 1: 1: 0.005, in 150 DEG C of reacting by heating 20 hours, obtain its protection product (5S)-2-(4-((3-isopropyl-2-phenyl azoles quinoline)-5-methoxyl group) phenyl) ethanol;
(4) (5S)-2-(4-((3-isopropyl-2-phenyl azoles quinoline)-5-methoxyl group) phenyl) ethanol is dissolved in organic solvent, with ring the third methyl halide with 1: 1 mol ratio, under base catalysis, in the presence of a phase transfer catalyst, react 18 hours in 95 DEG C, obtain (5S)-5-(4-((2-ring the third methoxyl group) ethyl) benzene oxygen) methyl-3-isopropyl-2-phenyl azoles quinoline;
(5) mineral acid is joined in aqueous solution or the alcoholic solution of (5S)-5-(4-((2-ring the third methoxyl group) ethyl) benzene oxygen) methyl-3-isopropyl-2-phenyl azoles quinoline, stir 12 hours at 60 DEG C of temperature, through extracting, drying, obtain left-handed betaxolol S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propanol;
(6) left-handed betaxolol S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propanol is dissolved in organic solvent, it is subsequently adding hydrochloric acid or passes into hydrogen chloride gas, as PH=5, stirring 6 hours, recrystallization obtains the hydrochlorate of white crystals S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propanol.
Technique for synthesizing levorotatory betaxolol hydrochloride, can directly prepare l-betaxolol hydrochloride, it is not necessary to be processed further, and operation is simple, and measurement data is accurate, it is easy to implement.
Claims (1)
1. a technique for synthesizing levorotatory betaxolol hydrochloride, it is characterised in that: said method comprising the steps of:
(1) under the existence of alkali compounds, p-hydroxyphenylethanol and R-epoxyhalopropane are dissolved in organic solvent with 1: 1��11 mol ratios, it is in that under 100��150 DEG C of conditions and reacts 2��8 hours, recrystallization obtains S-1-(4-(2-ethoxy) phenoxy group)-2,3-expoxy propane white solids;
(2) S-1-(4-(2-ethoxy) phenoxy group)-2,3-expoxy propane reacts 2��30 hours with mol ratio 1: 1��20 with amination reagent in organic solvent at 0��50 DEG C, and recrystallization obtains S-1-(4-(2-ethoxy) phenoxy group)-3-isopropylamine base-2-propanol white solid;
(3) S-1-(4-(2-ethoxy) phenoxy group)-3-isopropylamine base-2-propanol is dissolved in organic solvent, add protection reagent benzene formonitrile HCN and acidic catalyst, three's mol ratio is 1: 1��20: 0.005��0.5, in 40��150 DEG C of reacting by heating 1��20 hour, obtain its protection product (5S)-2-(4-((3-isopropyl-2-phenyl azoles quinoline)-5-methoxyl group) phenyl) ethanol;
(4) (5S)-2-(4-((3-isopropyl-2-phenyl azoles quinoline)-5-methoxyl group) phenyl) ethanol is dissolved in organic solvent, with ring the third methyl halide with 1: 1��10 mol ratios, under base catalysis, in the presence of a phase transfer catalyst, react 2��18 hours in-15��95 DEG C, obtain (5S)-5-(4-((2-ring the third methoxyl group) ethyl) benzene oxygen) methyl-3-isopropyl-2-phenyl azoles quinoline;
(5) mineral acid is joined in aqueous solution or the alcoholic solution of (5S)-5-(4-((2-ring the third methoxyl group) ethyl) benzene oxygen) methyl-3-isopropyl-2-phenyl azoles quinoline, stir 1��12 hour at 0��60 DEG C of temperature, through extracting, drying, obtain left-handed betaxolol S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propanol;
(6) left-handed betaxolol S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propanol is dissolved in organic solvent, it is subsequently adding hydrochloric acid or passes into hydrogen chloride gas, when PH=1��5, stirring 1��6 hour, recrystallization obtains the hydrochlorate of white crystals S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410588103.4A CN105622441A (en) | 2014-10-29 | 2014-10-29 | Synthesis technology of L-betaxolol hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410588103.4A CN105622441A (en) | 2014-10-29 | 2014-10-29 | Synthesis technology of L-betaxolol hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105622441A true CN105622441A (en) | 2016-06-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410588103.4A Pending CN105622441A (en) | 2014-10-29 | 2014-10-29 | Synthesis technology of L-betaxolol hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105622441A (en) |
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2014
- 2014-10-29 CN CN201410588103.4A patent/CN105622441A/en active Pending
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Application publication date: 20160601 |