CN106588591A - Salmeterol intermediate ionic liquid catalytic bromination technology - Google Patents
Salmeterol intermediate ionic liquid catalytic bromination technology Download PDFInfo
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- CN106588591A CN106588591A CN201611056602.4A CN201611056602A CN106588591A CN 106588591 A CN106588591 A CN 106588591A CN 201611056602 A CN201611056602 A CN 201611056602A CN 106588591 A CN106588591 A CN 106588591A
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- ionic liquid
- salmaterol
- bromide
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- C07—ORGANIC CHEMISTRY
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- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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Abstract
The invention discloses a salmeterol intermediate ionic liquid catalytic bromination technology. The salmeterol intermediate is (4-(6-bromohexaoxy)butylbenzene and is prepared from 6-(4-phenylbutyl-oxo)hexyl methanesulfonate and potassium bromide as raw materials under the conditions of ionic liquid [bmim]BF4 and acetonitrile. The technology has the advantages of short bromination reaction time, mild conditions and high total yield. The bromination reagent used by the technology is cheap and easily available and has low toxicity. The ionic liquid [bmim]BF4 is a medium having high halogenation activity, can realize strong nucleophilicity of halogen ions and can be widely used in many halogenation reactions.
Description
Technical field
The present invention relates to a kind of ionic liquid-catalyzed bromination technique of salmaterol intermediate, category medicine synthesis technique neck
Domain.
Background technology
Salmaterol (Salmeterol), chemical name：2- (methylol) -4- [1- hydroxyl -2- [6- (4- phenyl fourth oxygen) oneself
Base amino] ethyl]-phenol Xinafoate salt.It is new selective Long-effect β_2 reactant excitomotor agent, dose its bronchiectasis are made
With sustainable 12 hours.With powerful suppression pulmonary mastocyte release anaphylaxiss medium effect, suction antigen can be suppressed to lure
The early stage sent out and late phase reaction, reduce airway hyperreactivity, for asthma (including Nocturnal and exercise-induced asthma), pant
Property bronchitis and Reversible airway obstruction.
Salmaterol intermediate bromide it is chemical entitled (4- (6- bromohexane epoxides) butyl benzene, No. CAS be 94749-
73-3, chemical structural formula is shown below：
Synthesized by the intermediate obtain salmaterol synthetic route it is as follows：
(4- (6- bromohexane epoxides) butyl benzenes have at present substantial amounts of patent as the important intermediate of synthesis salmaterol
With the synthesis that the intermediate is reported on periodical, wherein what it is beautiful et al.《Chemistry world》The change is reported in 1998,12,644～646
The synthesis of compound, with benzene and succinic anhydride as raw material, Jing is acylated, Clemensen reduction and lithium aluminium hydride reduction are obtained 4- phenyl fourths
After alcohol then prepared with NaH, the reaction of 1,6- dibromo-hexanes (4- (6- bromohexane epoxides) butyl benzene, but 1,6- dibromo-hexane is one
The volatile carcinogen of class, total recovery is low, and wherein final step yield only has 50%, is unfavorable for industrialized production.In document
Tetrahedron:Asymmetry, also reports the (system of 4- (6- bromohexane epoxides) butyl benzene in 2008,19,1824～1828
It is standby, and obtain 81% yield, but still with 1,6- dibromo-hexanes and 4- phenylbutanols for raw material.
The content of the invention
It is an object of the invention to provide a kind of ionic liquid-catalyzed bromination technique of salmaterol intermediate, overcomes document report
The factor that yield is low in the synthetic method in road and raw material is dangerous, there is provided the simple and direct preparation of a suitable large-scale industrial production
Method.
The technological means that adopt of the present invention for：
(4- (6- bromohexane epoxides) butyl benzene, structural formula is shown below salmaterol intermediate：
With 6- (4- phenyl butyl oxygen) hexanol methanesulfonate ester (compound A) and potassium bromide as raw material, in ionic liquid
Bromination obtains salmaterol intermediate (4- (6- bromohexane epoxides) butyl benzene, synthetic route under conditions of [bmim] BF4 and acetonitrile
It is shown below：
Wherein potassium bromide could alternatively be the bromides such as sodium bromide, ammonium bromide, lithium bromide.
6- (4- phenyl butyl oxygen) the hexanol methanesulfonate ester, the molar ratio of potassium bromide are 1：(3～8), preferably
1：(4～6)；
The bromination reaction temperature is 85～115 DEG C, and the response time is 20～90min, and further preferred reaction temperature is
95～105 DEG C, the response time is 20～50min.
Ionic liquid [bmim] BF4, the volume ratio of acetonitrile are 1：(0.9～1.1), preferred ion liquid [bmim]
BF4, the volume ratio of acetonitrile are 1: 1.
6- (4- phenyl butyl oxygen) the hexanol methanesulfonate esters are 1g with the consumption of ionic liquid [bmim] BF4：(1.5
～3) ml.
Beneficial effect：The bromide reagent that this process route gained is used is conventional potassium bromide, cheap and easily-available and nontoxic,
The bromination reaction time is short, mild condition, and total recovery is high, and response speed is fast and almost equivalent is converted, and separation yield is high.
Specific embodiment
Ionic liquid [bmim] BF4 list of references Organic Syntheses, Coll.Vol.10 used herein,
p.184(2004)；Vol.79, p.236 (2002). method synthesis, comprise the following steps that：N- methyl miaows are added in reactor
The mixing of azoles (152g, 1.85mol), 1-chlorobutane (220g, 2.4mol) and 100ml acetonitriles, by mixed liquor 75～80 DEG C are heated to
48 hours are maintained the reflux for, vacuum distillation removes volatile solvent, wiring solution-forming in 250ml acetonitriles is then added at room temperature, will
Acetonitrile solution is slowly added in 1000ml ethyl acetate, and is cooled to -30 DEG C of crystallizations, and resulting product is at 30 DEG C after filtration
Lower vacuum drying 6 hours, obtains 289g intermediate 1- butyl -3- methylimidazolium chlorides.Take 1- butyl -3- Methylimidazole .s therein
It is little that chloride (91.6g, 0.52mol) and potassium tetrafluoroborate (66.3g, 0.52mol) stir 2 in 25 DEG C of 200ml distilled water
When, then vacuum distillation removes water at 80 DEG C, in being re-dissolved in 100ml dichloromethane, and is dried with 35g magnesium sulfate, crosses and filters
After removing magnesium sulfate desiccant, vacuum distillation removes volatile matter solvent, obtains 107g ionic liquids [bmim] BF4.
Raw material 6- (4- phenyl butyl oxygen) hexanol methanesulfonate ester is adopted synthesis with the following method and is obtained：
Load 25g 1,6- hexanediol and 10g sodium hydroxide in 1L chuck kettles, be warmed up to 60 DEG C of insulation 2h, add
31g 4- phenylbutanols and 200g toluene, are warming up to 110 DEG C, and flow back 4h, and HPLC monitoring 4- phenylbutanol reactions are complete, are cooled to
40 DEG C, add 150g water to stir to solidss and all dissolve, organic faciess add water washing to neutrality, are concentrated to give the faint yellow oil of 60g
Shape liquid.Load above-mentioned 60g pale yellow oily liquids and 200g toluene in other 1L chucks kettle, add 28g triethylamines, drop
Temperature is slowly added dropwise 25g methylsufonyl chlorides to 10 DEG C, below 25 DEG C of temperature of control, reacts 5h, and HPLC monitoring raw material reactions are complete,
Dilute hydrochloric acid is added, plus water washing is to neutrality, organic faciess are concentrated to give 90g6- (4- phenyl butyl oxygen) hexanol methanesulfonate ester.
Embodiment 1
By 6- (4- phenyl butyl oxygen) hexanol methanesulfonate esters (10g, 30.4mmol) and potassium bromide (18g, 152.2mmol)
Be heated in the ionic liquid [bmim] [BF4] of 30ml and the acetonitrile (moisture 5%) of 30ml 100 DEG C react 30 minutes, then
50ml ethyl acetate and the extraction of 50ml water are added, organic faciess are separated, (4- (6- bromohexane epoxides) butyl benzene 9.2g (yields are obtained
96%).
Embodiment 2
6- (4- phenyl butyl oxygen) hexanol methanesulfonate esters (20g, 60.8mmol) and potassium bromide (31g, 260mmol) are existed
95 DEG C are heated in the ionic liquid [bmim] [BF4] of 40ml and the acetonitrile (moisture 2%) of 44ml to react 40 minutes, are subsequently adding
60ml ethyl acetate and 70ml water are extracted, and separate organic faciess, obtain (4- (6- bromohexane epoxides) butyl benzene 18.5g (yields
95%).
Embodiment 3
6- (4- phenyl butyl oxygen) hexanol methanesulfonate esters (20g, 60.8mmol) and potassium bromide (28g, 243mmol) are existed
95 DEG C are heated in the ionic liquid [bmim] [BF4] of 40ml and the acetonitrile (moisture 2%) of 40ml to react 30 minutes, are subsequently adding
60ml ethyl acetate and 70ml water are extracted, and separate organic faciess, obtain (4- (6- bromohexane epoxides) butyl benzene 18.6g (yields
96%).
Embodiment 4
6- (4- phenyl butyl oxygen) hexanol methanesulfonate esters (20g, 60.8mmol) and potassium bromide (43g, 360mmol) are existed
95 DEG C are heated in the ionic liquid [bmim] [BF4] of 40ml and the acetonitrile (moisture 2%) of 35ml to react 40 minutes, are subsequently adding
60ml ethyl acetate and 70ml water are extracted, and separate organic faciess, obtain (4- (6- bromohexane epoxides) butyl benzene 18.5g (yields
94%), nuclear-magnetism characterization result is as follows：
1H NMR(CDCl3):7.27–7.22(m,2H),7.18–7.16(m,3H),3.42–3.36(m,6H),2.64–
2.60(m,2H),1.86–1.79(m,2H),1.68–1.52(m,6H),1.48–1.33(m,4H)；
13C NMR(CDCl3):142.4,128.3,128.1,125.6,70.6,70.6,35.6,32.7,32.4,29.5,
29.3,27.9,27.2,25.3。
Embodiment 5
6- (4- phenyl butyl oxygen) hexanol methanesulfonate esters (20g, 60.8mmol) and sodium bromide (37g, 360mmol) are existed
97 DEG C are heated in the ionic liquid [bmim] [BF4] of 30ml and the acetonitrile (moisture 3%) of 35ml to react 35 minutes, are subsequently adding
65ml ethyl acetate and 70ml water are extracted, and separate organic faciess, obtain (4- (6- bromohexane epoxides) butyl benzene 18.5g (yields
94%), nuclear-magnetism characterization result is as follows：
1H NMR(CDCl3):7.27–7.22(m,2H),7.18–7.16(m,3H),3.42–3.36(m,6H),2.64–
2.60(m,2H),1.86–1.79(m,2H),1.68–1.52(m,6H),1.48–1.33(m,4H)；
13C NMR(CDCl3):142.4,128.3,128.1,125.6,70.6,70.6,35.6,32.7,32.4,29.5,
29.3,27.9,27.2,25.3。
Embodiment 6
6- (4- phenyl butyl oxygen) hexanol methanesulfonate esters (20g, 60.8mmol) and lithium bromide (30g, 345mmol) are existed
It is heated to 97 DEG C in the ionic liquid [bmim] [BF4] of 38ml and the acetonitrile (moisture 3.6%) of 35ml to react 35 minutes, Ran Houjia
Enter 65ml ethyl acetate and the extraction of 70ml water, separate organic faciess, obtain (4- (6- bromohexane epoxides) butyl benzene 18.3g (yields
93%), nuclear-magnetism characterization result is as follows：
1H NMR(CDCl3):7.27–7.22(m,2H),7.18–7.16(m,3H),3.42–3.36(m,6H),2.64–
2.60(m,2H),1.86–1.79(m,2H),1.68–1.52(m,6H),1.48–1.33(m,4H)；
13C NMR(CDCl3):142.4,128.3,128.1,125.6,70.6,70.6,35.6,32.7,32.4,29.5,
29.3,27.9,27.2,25.3。
Embodiment 7
6- (4- phenyl butyl oxygen) hexanol methanesulfonate esters (20g, 60.8mmol) and ammonia bromide (34g, 350mmol) are existed
It is heated to 95 DEG C in the ionic liquid [bmim] [BF4] of 40ml and the acetonitrile (moisture 3.6%) of 35ml to react 30 minutes, Ran Houjia
Enter 65ml ethyl acetate and the extraction of 70ml water, separate organic faciess, obtain (4- (6- bromohexane epoxides) butyl benzene 18.6g (yields
95%), nuclear-magnetism characterization result is as follows：
1H NMR(CDCl3):7.27–7.22(m,2H),7.18–7.16(m,3H),3.42–3.36(m,6H),2.64–
2.60(m,2H),1.86–1.79(m,2H),1.68–1.52(m,6H),1.48–1.33(m,4H)；
13C NMR(CDCl3):142.4,128.3,128.1,125.6,70.6,70.6,35.6,32.7,32.4,29.5,
29.3,27.9,27.2,25.3。
Claims (10)
1. the ionic liquid-catalyzed bromination technique of a kind of salmaterol intermediate, it is characterised in that with 6-（4- phenyl butyl oxygen）
Hexanol methanesulfonate ester and Bromide are raw material, and bromination obtains Sha Meite under conditions of ionic liquid [bmim] BF4 and acetonitrile
Sieve intermediate (4- (6- bromohexane epoxides) butyl benzene.
2. the ionic liquid-catalyzed bromination technique of a kind of salmaterol intermediate according to claim 1, it is characterised in that
The 6-（4- phenyl butyl oxygen）Hexanol methanesulfonate ester is 1 with the molar ratio of Bromide：（3~8）.
3. the ionic liquid-catalyzed bromination technique of a kind of salmaterol intermediate according to claim 1, it is characterised in that
The Bromide is at least one in potassium bromide, sodium bromide, ammonium bromide or lithium bromide.
4. the ionic liquid-catalyzed bromination technique of a kind of salmaterol intermediate according to claim 1, it is characterised in that
Ionic liquid [bmim] BF4, the volume ratio of acetonitrile are 1：（0.9~1.1）.
5. the ionic liquid-catalyzed bromination technique of a kind of salmaterol intermediate according to claim 1, it is characterised in that
Bromination reaction temperature is 85 ~ 115 DEG C, and the response time is 20 ~ 90min.
6. the ionic liquid-catalyzed bromination technique of a kind of salmaterol intermediate according to claim 1, it is characterised in that
The 6-（4- phenyl butyl oxygen）Hexanol methanesulfonate ester is 1g with the consumption of ionic liquid [bmim] BF4：（1.5~3）ml.
7. the ionic liquid-catalyzed bromination technique of a kind of salmaterol intermediate according to claim 2, it is characterised in that
The 6-（4- phenyl butyl oxygen）Hexanol methanesulfonate ester is 1 with the molar ratio of Bromide：（4~6）.
8. the ionic liquid-catalyzed bromination technique of a kind of salmaterol intermediate according to claim 4, it is characterised in that
Ionic liquid [bmim] BF4, the volume ratio of acetonitrile are 1：1.
9. the ionic liquid-catalyzed bromination technique of a kind of salmaterol intermediate according to claim 5, it is characterised in that：
Bromination reaction temperature is 95 ~ 105 DEG C, and the response time is 30 ~ 50min.
10. a kind of ionic liquid-catalyzed bromination technique of salmaterol intermediate according to claim 5, its feature exists
In：The water content of the acetonitrile is less than 5%.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102319550A (en) * | 2011-07-08 | 2012-01-18 | 中国林业科学研究院林产化学工业研究所 | Low-concentration viscoelastic surfactant solution and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102319550A (en) * | 2011-07-08 | 2012-01-18 | 中国林业科学研究院林产化学工业研究所 | Low-concentration viscoelastic surfactant solution and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| DONG WOOK KIM ET AL: "New method of fluorination using potassium fluoride in ionic liquid:significantly enhanced reactivity of fluoride and improved selectivity", 《J.AM.CHEM.SOC.》 * |
| DONG WOOK KIM ET AL: "Significantly enhanced reactivities of the nucleophilic substitution reactions in ionic liquid", 《J.ORG.CHEM.》 * |
| 钟平: "室温离子液体的合成及其在有机合成中的应用", 《温州师范学院学报(自然科学版)》 * |
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Application publication date: 20170426 |