CN100528832C - Technique of synthesizing levorotatory betaxolol hydrochloride - Google Patents
Technique of synthesizing levorotatory betaxolol hydrochloride Download PDFInfo
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- CN100528832C CN100528832C CNB2007100539680A CN200710053968A CN100528832C CN 100528832 C CN100528832 C CN 100528832C CN B2007100539680 A CNB2007100539680 A CN B2007100539680A CN 200710053968 A CN200710053968 A CN 200710053968A CN 100528832 C CN100528832 C CN 100528832C
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Abstract
The invention discloses a synthesizing technique of left-handed hydrochloric betamicin, which comprises the following steps: adopting p-hydroxyphenethylol and R-epoxy halogen propane as original raw material; alkylating; aminating; protecting; alkylating; removing protection; obtaining pure high-antimer left-handed betamicin and hydrochlorate.
Description
Technical field
The present invention relates to the synthetic of organic compound, relate in particular to the synthesis technique of l-betaxolol hydrochloride.
Background technology
L-betaxolol hydrochloride went on the market in the U.S. in February, 2000, and commodity are called " Betaxon ".This medicine is mainly used in the chronic open angle glaucoma of treatment or high intraocular pressure patient reduces intraocular pressure.Glaucoma is that glaucoma is a kind of very serious ophthalmic diseases because the increase of intraocular part pressure causes optic nerve to damage gradually.Such disease can cause visual deterioration, and morbidity rapidly, hazardness causes losing one's sight greatly, at any time, is a kind of common difficult illness in eye.Sickness rate rises to some extent in recent years, add up according to the World Health Organization, present global glaucoma patient is about 6,700 ten thousand, and about 4,500,000 people lose eyesight because of glaucoma, in China, age is greater than among 40 years old the crowd, the sickness rate 1%～2% of primary glaucoma, in the whole nation 1,300,000,000 populations, primary glaucoma patient surpasses 7,000,000, glaucoma has become the second largest ophthalmology common disease of China, accounts for 14.36% of ophthalmic diseases.Statistic data shows that glaucoma has become second largest blinding factor.Present glaucomatous clinical treatment is based on operation and pharmacological agent.The just temporary transient intraocular pressure that reduces of operation can only relief of symptoms for the glaucoma of some type, finally still comes to an end with blind.The treatment glaucoma medicine comprises that mainly parasympathomimetic agent, adrenomimetic drug, adrenergic block medicine, carbonic anhydrase inhibitor, height ooze dewatering agent etc.Wherein choice drug adrenergic block medicine such as timolol, betaxolol (raceme) etc. have bronchospasm, bradyrhythmia, increase cardiac block, eye and systemic side effects such as bring high blood pressure down, this also is external no longer with its major cause as choice drug.It is little that left-handed betaxolol is treated glaucomatous side effect, and the curative effect height is expected to one of main medicine that becomes the chronic open angle glaucoma of treatment.
Left-handed betaxolol is the levo form of betaxolol, and the affinity of β-1 acceptor is higher than its raceme far away, and this highly selective makes its side effect considerably less, and does not have film stable (toponarcosis) effect and the effect of endogenous sympathomimetic amine.Levobetaxolol also has higher avidity to β-2 acceptor of eye ciliated epithelium, can reduce the generation of aqueous humor and reduces intraocular pressure, also can avoid multiple injury by retardance L-voltage-dependent calcium channel protection optic nerve.
The building-up process of left-handed betaxolol relates to the protection of phenol hydroxyl, like this can be so that phenolic hydroxyl group is unaffected during the alkylation of contraposition hydroxyethyl.Therefore protection and deprotection process determined complete synthesis process step how much and the length of time.
(the U.S.Pat.No.4 of Manoury group, 252,984) reported with the p-hydroxyphenylaceticacid to be raw material, at first pass through the benzyl protection of phenolic hydroxyl group, and then be that hydroxyl obtains 2-(4-benzyloxy phenyl) ethanol with carboxyl reduction, obtain encircling third methyl-2-(4-benzyloxy phenyl) ether with the ring third methyl halide reaction subsequently; Then with behind the ether debenzylation that obtains with epichlorohydrin reaction, product is used the Isopropylamine open loop again, finally obtains betaxolol.
People such as Ippolito (U.S.Pat.No.4,760,182) have reported to be that raw material is translated into the form of salt and then obtains 1-(4-(2-hydroxyethyl) phenoxy group)-2,3-propylene oxide with epichlorohydrin reaction with the p-hydroxyphenylethanol in the presence of alkali.
Wang etc. (U.S.Pat.No.5,731,463) have reported to be that raw material obtains an intermediate product through the dianion selectivity alkylene of peroxide with the p-hydroxyphenylethanol, and then and epichlorohydrin reaction after make betaxolol with the Isopropylamine amination again.
Recently, people (U.S.Pat.No.6,989,465) such as Ramesh A.Joshi report is being that starting raw material has synthesized l-betaxolol hydrochloride to this ethanol of hydroxyl and R-epoxy chloropropane.At first will form 4-(2-allyloxy ethyl) phenol to this ethanol of hydroxyl selectivity allylation (yield 48%); Then with the R-epoxy chloropropane 0～5 ℃ down reaction after 50 hours with the phenolic hydroxyl group alkylation, form S-1-(4-(2-allyloxy ethyl) phenoxy group)-3-isopropylamine base propan-2-ol with the Isopropylamine amination subsequently; Do under the solvent at dry toluene with zinc ethyl and methylene iodide at last two key cyclisation are got left-handed betaxolol.
Very regrettably, in above-mentioned building-up process, except that most steps need the nitrogen protection, used reagent and catalyzer all are the comparison costlinesses such as zinc ethyl, methylene iodide in the building-up process, and zinc ethyl can spontaneous combustion in air. contacted with damp atmosphere, chlorine, oxygenant and caused danger of combustion, so this step reaction requires reaction system definitely anhydrous, very high to the requirement of production process operating skill, toxicity is big; Because second reaction times in step of reaction is oversize, make that the whole production cycle is long in addition; The first step yield is relatively lower to cause the total recovery of this technology very low, adds that agents useful for same and catalyzer cost an arm and a leg, and makes cost very high, and above drawback makes this technology be difficult to suitability for industrialized production.
Summary of the invention
The objective of the invention is to overcome the deficiency of prior art, provide a kind of technology simple, raw material is easy to get, toxicity is low, operational safety, easy, pollute little, the yield height, the technique for synthesizing levorotatory betaxolol hydrochloride that the cycle is short, thus change the situation that the present domestic glaucoma medication overwhelming majority market share is occupied by imported medicine.
The realization of the object of the invention; mainly be that employing p-hydroxyphenylethanol and R-epoxyhalopropane are starting raw material, obtain the left-handed betaxolol and the hydrochloride thereof of generated in high enantiomeric purity under certain condition through reactions such as alkylation, amination, protection, alkylation, deprotections.
Technical solution of the present invention is as follows:
R
1=R
2=H or R
1=R
2=CH
3Or R
1=C
6H
5The time, R
2Do not exist.
Particularly, l-betaxolol hydrochloride of the present invention (S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propyl alcohol) synthesis technique is realized as follows:
A) be starting raw material with p-hydroxyphenylethanol and R-epoxyhalopropane, it is dissolved in the organic solvent, with 1: 1～20 mol ratios, in the presence of basic cpd, under 10～150 ℃ of temperature, reacted 2～15 hours, the filtering basic solution, the filtrate evaporate to dryness gets viscous fluid, gained viscous fluid recrystallization in organic solvent obtains S-1-(4-(2-hydroxyethyl) phenoxy group)-2,3-propylene oxide white solid.
B) S-1-(4-(2-hydroxyethyl) phenoxy group)-2, the 3-propylene oxide in organic solvent with amination reagent with 1: 1～20 mol ratios, reacted 2～36 hours down at 0～50 ℃, then with the reaction solution evaporate to dryness, obtain viscous fluid, gained viscous fluid recrystallization in organic solvent obtains S-1-(4-(2-hydroxyethyl) phenoxy group)-3-isopropylamine base-2-propyl alcohol white solid.
C) S-1-(4-(2-hydroxyethyl) phenoxy group)-3-isopropylamine base-2-propyl alcohol is dissolved in the organic solvent; add protection reagent benzene formonitrile HCN and an acidic catalyst (mol ratio is 1: 1～20: 0.005～0.5); in 40～150 ℃ of heating 1～20 hour, obtain its protection product (5S)-2-(4-((3-sec.-propyl-2-Ben oxazolin)-5-methoxyl group) phenyl) ethanol.
D) with (5S)-2-(4-((3-sec.-propyl-2-Ben oxazolin)-5-methoxyl group) phenyl) dissolve with ethanol in organic solvent, with the ring third Methochloride with 1: 1～10 mol ratios, under the catalysis of alkali, in the presence of phase-transfer catalyst, in-15～95 ℃ of reactions 2～18 hours, obtain (5S)-5-(4-((2-encircles third methoxyl group) ethyl) benzene oxygen) methyl-3-sec.-propyl-2-Ben oxazolin.
E) mineral acid is joined in the aqueous solution or alcoholic solution of (5S)-5-(4-((2-encircles third methoxyl group) ethyl) benzene oxygen) methyl-3-sec.-propyl-2-Ben oxazolin, under 0～60 ℃ of condition, stirred 1～12 hour, with ethyl acetate extraction three times, organic phase drying 1～24 hour, boil off ethyl acetate, obtain left-handed betaxolol S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propyl alcohol.
F) left-handed betaxolol S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propyl alcohol is dissolved in the organic solvent, add hydrochloric acid then or feed hydrogen chloride gas, when PH=1～5, stirred 1～6 hour, the evaporate to dryness reaction solution obtains the hydrochloride of S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propyl alcohol then, and recrystallization obtains white crystals in solvent.
In the synthesis technique of l-betaxolol hydrochloride, a) the R-epoxyhalopropane described in is R-epoxy chloropropane or R-epoxy bromopropane or R-epoxy iodopropane; Employed basic cpd can be sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide one of them, or inorganic alkaline compound CaO, MgO, Na
2CO
3, NaHCO
3, KOH, NaOH, K
2CO
3, KHCO
3, KF one of them; Used organic solvent is acetonitrile, acetone, tetrahydrofuran (THF), N, N-dimethyl imide, dimethyl sulfoxide (DMSO), 1,2-ethylene dichloride, trichloroethane, methylene dichloride, chloroform and dioxane one of them; The recrystallization solvent for use is one or more in water, ethanol, methyl alcohol, Virahol, acetone, acetonitrile, chloroform, methylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, the sherwood oil.
The present invention is in the synthesis technique of l-betaxolol hydrochloride, b) amination reagent described in is an Isopropylamine, reacting used organic solvent is acetonitrile, tetrahydrofuran (THF), acetone, N, N-dimethyl imide, dimethyl sulfoxide (DMSO), 1, one or more in 2-ethylene dichloride, trichloroethane, methylene dichloride, chloroform and the dioxane; The recrystallization solvent for use is one or more in water, ethanol, methyl alcohol, Virahol, acetone, acetonitrile, chloroform, methylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, the sherwood oil.
The present invention is in the synthesis technique of l-betaxolol hydrochloride, and c) middle solvent for use is one or both in benzene, chlorobenzene, toluene, hexanaphthene, acetone, trichloroethane, trichloromethane, the tetrahydrofuran (THF); Used an acidic catalyst is one or both in rare nitric acid, dilute sulphuric acid, dilute hydrochloric acid, dilute acetic acid, Zinc Chloride Anhydrous, aluminum chloride, α-Nai sulfonic acid, phenylformic acid, the p-methyl benzenesulfonic acid.Used protection reagent is formaldehyde, Paraformaldehyde 96, acetone, cyanobenzene, phenyl aldehyde, 2, a kind of in the 2-Propanal dimethyl acetal.
The present invention is in the synthesis technique of l-betaxolol hydrochloride, d) used organic solvent is toluene, acetonitrile, tetrahydrofuran (THF), N in, N-dimethyl imide, dimethyl sulfoxide (DMSO), ethyl acetate, 1, one or more in 2-ethylene dichloride, trichloroethane, methylene dichloride, chloroform and the dioxane; Used alkali is one or more in potassium alcoholate class, sodium alkoxide class, sodium amide, potassium amide, sodium hydride, potassium hydride KH, hydrolith, potassium hydroxide, calcium hydroxide, the sodium hydroxide etc.; The used ring third methyl halogenide is for encircling third Methochloride or encircling third MB or encircle the third methyl iodide in the reaction process; Used phase-transfer catalyst is benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, 4-butyl ammonium hydrogen sulfate, palmityl trimethyl ammonium chloride, cetyl trimethylammonium bromide, Ethyltriphenylphosphonium brimide in the reaction process.
The present invention is in the synthesis technique of l-betaxolol hydrochloride, and e) middle solvent for use is one or more in water, methyl alcohol, ethanol, Virahol, the trimethyl carbinol; Used mineral acid is that mass concentration is a kind of in the dilute hydrochloric acid of 1%～30% dilute sulphuric acid or 1%～30%; The recrystallization solvent for use is water, ethanol, methyl alcohol, acetone, acetonitrile, chloroform, methylene dichloride, 1, one or more in 2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, sherwood oil, the dioxane.
The present invention in the synthesis technique of l-betaxolol hydrochloride, f) in used organic solvent be in methyl alcohol, ethanol, water, ethyl acetate, acetone, the tetrahydrofuran (THF) one or more; The recrystallization solvent for use is water, ethanol, methyl alcohol, acetone, acetonitrile, chloroform, methylene dichloride, 1, one or more in 2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, sherwood oil, the dioxane.To become the hydrochloride agents useful for same be mass concentration greater than the alcoholic solution of 1% hydrochloric acid, hydrochloric acid or hydrogen chloride gas wherein it
The invention has the advantages that: this processing method is simple, and is easy and simple to handle, and intermediate and final product are easy to separate, purify, the high and optical purity height of the chemical purity of product, and the yield height, the cycle is short; Having only salt of wormwood in the production process is solid residue, and through carrying out washing treatment, only staying inorganic salt can recycle after the filtration; Reaction and extract used organic solvent can recycle and reuse, waste water wherein can be through entering enterprise's three wastes treatment system after the neutralization, the whole process of production three wastes can reach emission standard.This product using dosage is little, and industrial scale is little, and three wastes discharge amount is little, can not pollute environment after treatment, is a kind of synthesis technique of environmental type.
Embodiment
For the present invention is better illustrated, as follows for embodiment:
The preparation of embodiment l-betaxolol hydrochloride (compound 6)
(1) preparation compound 1 (S-1-(4-(2-hydroxyethyl) phenoxy group)-2,3-propylene oxide)
With p-hydroxyphenylethanol (27.60g, 0.2mol), (18.50g 0.4mol) is dissolved in the organic solvent R-epoxy chloropropane, adds sodium hydroxide (16.00g, 0.4mol) back mechanical stirring, 60 ℃ of down heating 8 hours then.Reaction after finishing removes by filter yellow soda ash, and the adding re-crystallizing in ethyl acetate got S-1-(4-(2-hydroxyethyl) phenoxy group)-2 after filtrate concentrated evaporate to dryness, 3-propylene oxide 36.10g, and yield 93%, experimental data is as follows:
C
11H
14O
3，Mp?39℃，[α]
D 20＝+12.0°(c?1.00，CH
3OH)；υ＝3349，2945，2929，2873，1613，1513，1245，1047，1027，906，848，823cm
-1；
1HNMR(400MHz，D
2O)：δ7.12(d，2H，J＝8.4Hz)，6.86(d，2H，J＝8.4Hz)，4.17-4.21(dd，1H，J＝3.0Hz)，3.89-3.94(dd，1H，J＝5.8Hz)，3.76-3.80(dd，2H，J＝5.9Hz)，3.33-3.35(m，1H)，2.89(t，1H，J＝4.4Hz)，2.78(t，1H，J＝6.6Hz)，2.73-2.75(dd，1H，J＝2.8Hz)1.88(s，1H)；
13CNMR(100.6MHz，D
2O)：δ157.12，131.17，130.04，114.74，68.79，63.75，50.24，44.73，38.26。
(2) preparation compound 2 (S-1-(4-(2-hydroxyethyl) phenoxy group)-3-isopropylamine base-2-propyl alcohol)
With solid chemical compound 1 (19.40g, 0.1mol) be dissolved in the acetone, add (11.80g then, 0.2mol) Isopropylamine, 20 ℃ were stirred 10 hours, and after reaction finishes reaction solution being concentrated evaporate to dryness is thick liquid, adds acetone recrystallization, filtration obtains the white crystals 21.76g of compound 2, yield 86%.The experimental data of compound 2 is as follows:
C
14H
23NO
3, 85 ℃ of Mp, [α]
D 20=-0.9 ° (c 1.00, CH
3OH); υ=3448,3279,2964,2923,2866,1609,1512,1239,1110,1046,1023,898,866,815cm
-1 1HNMR (400MHz, D
2O): δ 7.12 (d, 2H, J=8.5Hz), 6.86 (d, 2H, J=8.5Hz), 3.93-3.96 (m, 2H), 3.82-3.85 (dd, 1H, J=7.1Hz), 3.65 (t, 2H, J=6.6Hz), 2.64-2.73 (m, 4H), 2.55-2.64 (dd, 1H, J=8.3Hz), 0.91-0.93 (m, 6H);
13CNMR (100.6MHz, D
2O): δ 156.57,131.82, and 130.08,114.75,70.45,68.47,62.54,48.14,48.01,36.76,20.97,20.87; Ee＞99% (HPLC testing conditions: chiral column OD-H; Moving phase normal hexane/Virahol/diethylamine=6/4/0.1; Flow velocity 0.5ml/min; Detect wavelength 254nm).
(3) preparation compound 3 (S-2-(4-((3-sec.-propyl-2,2-Er Jia oxazolin)-5-methoxyl group) phenyl) ethanol)
(25.3g 0.1mol) is dissolved in the 100ml hexanaphthene, adds cyanobenzene (21.0g with compound 2,0.2mol) add the α-Nai sulfonic acid of catalytic amount at last, reflux 6 hours, reaction boils off solvent after finishing, get thickness oily liquids (compound 3) 30.4g, yield 89%.
(4) preparation compound 4 (S-5-((2-(encircling third methoxyl group) ethyl) benzene oxygen) methyl)-3-sec.-propyl-2,2-Er Jia oxazolin)
Compound 3 is without purification, directly be dissolved in the dimethyl sulfoxide (DMSO), add sodium tert-butoxide (19.4g, 0.2mol), phase-transfer catalyst Tetrabutyl amonium bromide (322mg, 0.001mol), add ring third methochloride (0.12mol) down at 65 ℃ then, stirred 8 hours under this temperature, reaction is poured reaction solution in the water into after finishing, with three times (100ml * 3) of toluene extraction, merge organic phase and wash (50ml * 2), pressure reducing and steaming toluene more then with saturated nacl aqueous solution, obtain thick liquid 34.1g, yield 97%.
(5) preparation compound 5 left-handed betaxolols
The sulfuric acid of 40ml 10% is added in the ethanolic soln of compound 4 viscous fluid 34.1g, stirred 3 hours down in 30 ℃, use ethyl acetate extraction then 3 times (100ml * 3), water is transferred pH value to 12 with sodium hydroxide, use ethyl acetate extraction again 3 times (100ml * 3), merge organic phase, organic phase is washed 3 times (50ml * 3) with saturated nacl aqueous solution, organic phase is used anhydrous sodium sulfate drying 6 hours then, filter, the pressure reducing and steaming solvent obtains dope, the dope acetone recrystallization gets white crystals 20.7g.Yield 78.5%.The experimental data of left-handed betaxolol (compound 5) is as follows:
C
18H
29O
3，
1HNMR(400MHz，D
2O)：δ7.10(d，2H，J＝7.2Hz)，6.80(d，2H，J＝7.1Hz)，3.93-3.97(t，2H，J＝9.3Hz)，3.85(d，1H)，3.56-3.59(t，2H，J＝6.9Hz)，2.66-2.87(m，5H)，2.04(s，1H)，0.83-0.97(m，6H)0.33(d，1H，J＝7.2Hz)，0.00(d，2H，J＝3.7Hz)。
(6) preparation of l-betaxolol hydrochloride (compound 6)
In the reaction flask of 500ml, the left-handed betaxolol of 20.7g (compound 5) is dissolved in the 200ml methyl alcohol, add concentrated hydrochloric acid 10ml, when PH=1～4, stirring at room 2 hours was put into refrigerator-freezer to system freezing 8 hours then, separated out crystallization, filter, reclaim acetone, filter cake is used acetone recrystallization again, obtains white solid 21.9g, yield 95%, the experimental data of l-betaxolol hydrochloride (compound 6) is as follows:
C
18H
30ClNO
3, 92 ℃ of Mp
1HNMR (400MHz, D
2O): δ 7.06 (d, 2H, J=7.7Hz), 6.79 (d, 2H, J=8.0Hz), 4.10-4.14 (dd, 1H, J=3.5Hz), 3.90-3.92 (m, 2H), 3.55 (d, 2H, J=5.1Hz), 3.28-3.33 (m, 1H), 3.02-3.15 (m, 4H), 2.64 (t, 2H, J=6.4Hz), 1.20-1.23 (m, 6H), 0.82-0.86 (m, 1H), 0.33 (d, 2H, J=7.6Hz) ,-0.01 (d, 2H, J=3.7Hz);
13CNMR (100.6MHz, D
2O): δ 156.37,131.87, and 130.12,129.98,114.67,75.45,70.91,69.46,65.54,50.95,46.61,34.00,18.20,17.77,9.52,2.36; Ee＞99% (HPLC testing conditions: chiral column OD-H; Moving phase normal hexane/Virahol/diethylamine=6/4/0.1; Flow velocity 0.5ml/min; Detect wavelength 254nm).
Claims (9)
1, the synthesis technique of a kind of l-betaxolol hydrochloride (S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propyl alcohol) is characterized in that, and is synthetic according to following steps:
A) in the presence of basic cpd, p-hydroxyphenylethanol and R-epoxyhalopropane are dissolved in the organic solvent with 1: 1～20 mol ratios, be to react 2～15 hours under 10～150 ℃ of conditions, recrystallization gets S-1-(4-(2-hydroxyethyl) phenoxy group)-2,3-propylene oxide white solid;
B) S-1-(4-(2-hydroxyethyl) phenoxy group)-2, the 3-propylene oxide reacted 2～36 hours down at 0～50 ℃ with mol ratio 1: 1～20 with amination reagent in organic solvent, and recrystallization obtains S-1-(4-(2-hydroxyethyl) phenoxy group)-3-isopropylamine base-2-propyl alcohol white solid;
C) S-1-(4-(2-hydroxyethyl) phenoxy group)-3-isopropylamine base-2-propyl alcohol is dissolved in the organic solvent, add protection reagent benzene formonitrile HCN and an acidic catalyst, three's mol ratio is 1: 1～20: 0.005～0.5, in 40～150 ℃ of reacting by heating 1～20 hour, obtain its protection product (5S)-2-(4-((3-sec.-propyl-2-Ben oxazolin)-5-methoxyl group) phenyl) ethanol;
D) with (5S)-2-(4-((3-sec.-propyl-2-Ben oxazolin)-5-methoxyl group) phenyl) dissolve with ethanol in organic solvent, with the ring the third methyl halogenide with 1: 1～10 mol ratios, under base catalysis, in the presence of phase-transfer catalyst, in-15～95 ℃ of reactions 2～18 hours, obtain (5S)-5-(4-((2-encircles third methoxyl group) ethyl) benzene oxygen) methyl-3-sec.-propyl-2-Ben oxazolin;
E) mineral acid is joined in the aqueous solution or alcoholic solution of (5S)-5-(4-((2-encircles third methoxyl group) ethyl) benzene oxygen) methyl-3-sec.-propyl-2-Ben oxazolin, stirred 1～12 hour under 0～60 ℃ of temperature, through extraction, drying, obtain left-handed betaxolol S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propyl alcohol;
F) left-handed betaxolol S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propyl alcohol is dissolved in the organic solvent, add hydrochloric acid then or feed hydrogen chloride gas, when PH=1～5, stirred 1～6 hour, recrystallization obtains the hydrochloride of white crystals S-1-(4-(2-cyclo propyl methoxy ethyl) phenoxy group)-3-isopropylamine base-2-propyl alcohol.
2, technique for synthesizing levorotatory betaxolol hydrochloride according to claim 1 is characterized in that, a) described in the R-epoxyhalopropane be R-epoxy chloropropane or R-epoxy bromopropane or R-epoxy iodopropane.
3, technique for synthesizing levorotatory betaxolol hydrochloride according to claim 1 is characterized in that, a) basic cpd described in be sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide one of them, or CaO, MgO, Na
2CO
3, NaHCO
3, KOH, NaOH, K
2CO
3, KHCO
3, KF one of them, solvent for use is acetonitrile, acetone, tetrahydrofuran (THF), N, N-dimethyl imide, dimethyl sulfoxide (DMSO), 1,2-ethylene dichloride, trichloroethane, methylene dichloride, chloroform and dioxane one of them.
4, technique for synthesizing levorotatory betaxolol hydrochloride according to claim 1, it is characterized in that, b) used amination reagent is an Isopropylamine in, the reaction solvent for use is acetonitrile, tetrahydrofuran (THF), acetone, N, N-dimethyl imide, dimethyl sulfoxide (DMSO), 1, one or more in 2-ethylene dichloride, trichloroethane, methylene dichloride, chloroform and the dioxane.
5, technique for synthesizing levorotatory betaxolol hydrochloride according to claim 1 is characterized in that, c) middle solvent for use is one or both in benzene, chlorobenzene, toluene, hexanaphthene, acetone, trichloroethane, trichloromethane, the tetrahydrofuran (THF); Used an acidic catalyst is one or both in rare nitric acid, dilute sulphuric acid, dilute hydrochloric acid, dilute acetic acid, Zinc Chloride Anhydrous, aluminum chloride, α-Nai sulfonic acid, phenylformic acid, the p-methyl benzenesulfonic acid.
6, technique for synthesizing levorotatory betaxolol hydrochloride according to claim 1, it is characterized in that: solvent for use is toluene, acetonitrile, tetrahydrofuran (THF), N d), N-dimethyl imide, dimethyl sulfoxide (DMSO), ethyl acetate, 1, one or more in 2-ethylene dichloride, trichloroethane, methylene dichloride, chloroform and the dioxane; Used alkali is a kind of in potassium alcoholate class, sodium alkoxide class, sodium amide, potassium amide, sodium hydride, potassium hydride KH, hydrolith, potassium hydroxide, sodium hydroxide, the calcium hydroxide; The used ring third methyl halogenide is for encircling third Methochloride or encircling third MB or encircle the third methyl iodide; In the reaction process used phase-transfer catalyst be benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, 4-butyl ammonium hydrogen sulfate, palmityl trimethyl ammonium chloride, cetyl trimethylammonium bromide, Ethyltriphenylphosphonium brimide one of them.
7, technique for synthesizing levorotatory betaxolol hydrochloride according to claim 1 is characterized in that, e) middle solvent for use is one or more in water, methyl alcohol, ethanol, Virahol, the trimethyl carbinol; Used mineral acid is that mass concentration is wherein a kind of in the dilute hydrochloric acid of 1%～30% dilute sulphuric acid or 1%～30%.
8, technique for synthesizing levorotatory betaxolol hydrochloride according to claim 1 is characterized in that, f) middle solvent for use is one or more in methyl alcohol, ethanol, water, ethyl acetate, acetone, the tetrahydrofuran (THF).
9, technique for synthesizing levorotatory betaxolol hydrochloride according to claim 1, it is characterized in that, the used solvent of recrystallization is water, ethanol, methyl alcohol, acetone, acetonitrile, chloroform, methylene dichloride, 1, one or more in 2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, sherwood oil, the dioxane.
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| CNB2007100539680A CN100528832C (en) | 2007-02-08 | 2007-02-08 | Technique of synthesizing levorotatory betaxolol hydrochloride |
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| EP2745876A1 (en) | 2012-12-21 | 2014-06-25 | Prous Institute for Biomedical Research, S.A. | Hydroxy aliphatic substituted phenyl aminoalkyl ether derivatives |
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