CN104610075A - Synthetic method of 4-animo-1-butanol - Google Patents
Synthetic method of 4-animo-1-butanol Download PDFInfo
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- CN104610075A CN104610075A CN201510073822.7A CN201510073822A CN104610075A CN 104610075 A CN104610075 A CN 104610075A CN 201510073822 A CN201510073822 A CN 201510073822A CN 104610075 A CN104610075 A CN 104610075A
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Abstract
The invention discloses a synthetic method of 4-animo-1-butanol. The synthetic method is characterized by comprising the following steps: reacting a raw material A in an acid solution to obtain an intermediate product B, carrying out contact reaction on the intermediate product B and a raw material C in the presence of alkaline substances to obtain an intermediate product D, and transforming the intermediate product D into the target product, namely 4-animo-1-butanol, in the presence of a reducing agent. The synthetic method is suitable for large-scale synthesis, synthesis steps are short, and the operation is convenient.
Description
Technical field
The present invention relates to the synthetic method of a kind of 4-amino-n-butyl alcohol.
Background technology
4-amino-n-butyl alcohol (4-amino-1-butanol), molecular formula C
4h
11nO, molecular weight 89.0841, its structural formula is such as formula shown in I:
4-amino-n-butyl alcohol is in organic chemistry, especially conventional in pharmaceutical chemistry synthetic intermediate (Chen Guiqin, Liu Hongbin, the study on the synthesis [J] of king's blunt .7-A-methoxy compound 7-MAC. Heilungkiang medicine, 2006,19 (2): 90-92.), in organic synthesis, synthesis nitrogenous compound is widely used in.The Measures compare of the preparation 4-amino-n-butyl alcohol reported in document is many, mostly from different nitrogen-containing materials, such as 4-hydroxyl nitrine reduction, the reduction of 4-halo butyronitrile and 4-Aminobutanoicacid reduction etc., also have plenty of the method using nitrogenous reagent to introduce nitrogenous source to synthesize, as drop cloth riel amine synthesis method etc., but these methods all can not meet the processing requirement of a large amount of preparation, some existence synthesis dangerous (such as trinitride can explode), some reductive agents costly, some experiment conditions are very harsh, some experimental implementation are very loaded down with trivial details etc., all can not meet the technology synthesis of 4-amino-n-butyl alcohol.
Summary of the invention
The present invention aims to provide a large amount of synthetic methods of a kind of 4-amino-n-butyl alcohol.
The present invention take raw material A as starting raw material, prepares 4-amino-n-butyl alcohol successively through addition, open loop and reduction reaction.
The structural formula of target product 4-amino-n-butyl alcohol of the present invention is such as formula shown in I:
The preparation method of target product of the present invention carries out as follows:
(1) raw material A is first made to be obtained by reacting intermediate product B in an acidic solution; The structural formula of described raw material A is such as formula shown in II, and the structural formula of described intermediate product B is such as formula shown in III;
(2) make intermediate product B and raw material C in the presence of a basic contact reacts obtain intermediate product D; The structural formula of described raw material C is such as formula shown in IV, and the structural formula of described intermediate product D is such as formula shown in V;
(3) intermediate product D is made to be transformed into target product 4-amino-n-butyl alcohol in the presence of a reducing agent;
Wherein: R
1, R
2and R
3be selected from hydrogen, C1-C4 alkyl, aryl, benzyl, C1-C4 acyl group independently of one another, by any one in the benzyl of hydroxyl, C1-C4 alkoxyl group, nitro or halogen substiuted on methoxyl methyl, ethoxymethyl, isopropylidene, hexamethylene ketone group or phenyl ring;
Raw material C shown in formula IV is that free state or salt form exist, example hydrochloric acid salt, vitriol or tosilate.
Described phenyl ring can be 1-5 by the substituting group quantity of the benzyl of hydroxyl, C1-C4 alkoxyl group, nitro, halogen substiuted, be preferably 1-2.
Described C1-C4 alkyl can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl.
Described C1-C4 alkoxyl group can be methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy or tert.-butoxy.
Described C1-C4 acyl group can be formyl radical, ethanoyl, positive propionyl, iso-propionyl, positive butyryl radicals, isobutyryl or tertiary butyryl radicals.
Described aryl can be phenyl, 4-chloro-phenyl-, 3-chloro-phenyl-, 2-chloro-phenyl-, 4-bromophenyl, 4-fluorophenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-tert-butyl-phenyl, 4-trifluoromethyl, 4-nitrophenyl, 4-xenyl; 4-Fonnylphenyl, 4-acetylphenyl, 3-methyl-4-fluorophenyl, 3; the chloro-4-fluorophenyl of 5-dichlorophenyl, 3-, 3; the two benzofuryl of 4,5-trimethoxyphenyl, 2-furyl, 2-thienyl, the mono-benzofuryl of 2-, 4-or 2-naphthyl.
Preferably, each R
1, R
2and R
3be any one in hydrogen and C1-C4 alkyl independently.
R
1, R
2and R
3can be identical or different, preferred R
1and R
3identical and R
2difference, more preferred R
1, R
2and R
3all identical.
According to method of the present invention, step (1) is dissolved in the first solvent by acidic substance, then adds raw material A, is 1-3h, obtains intermediate product B 0-25 DEG C of reaction;
The mol ratio of described raw material A and described first acidic substance is 1:0.1-0.5.
Described acidic substance are selected from least one in hydrochloric acid, acetic acid, sulfuric acid and trifluoroacetic acid, are preferably hydrochloric acid;
Described first solvent is at least one in water, methyl alcohol, ethanol and tetrahydrofuran (THF), is preferably water;
According to method of the present invention, step (2) is dissolved in by alkaline matter in the second solvent, then adds intermediate product B and raw material C, 60-100 DEG C of reaction for 0.5-2h obtains intermediate product D;
The mol ratio of described intermediate product B and described raw material C can be 1:1-2, is preferably 1:1-1.2.；
Described alkaline matter is at least one in pyridine and triethylamine, is preferably pyridine;
Described second solvent is at least one in methyl alcohol, ethanol, chloroform and toluene, is preferably ethanol.
According to method of the present invention, step (3) adds intermediate product D and reductive agent in the 3rd solvent, then at 25-60 DEG C of reaction 0.5-2h, obtains target product 4-amino-n-butyl alcohol;
The mol ratio of described intermediate product D and reductive agent is 1:1-1.2;
Described reductive agent is metallic reducing agent, is preferably Lithium Aluminium Hydride;
Described 3rd solvent is at least one in tetrahydrofuran (THF), methyl alcohol, ether and toluene, is preferably tetrahydrofuran (THF).
According to method of the present invention, described method can also comprise from often walking reaction products therefrom the reactant isolating next step.The process of described separation can be implemented according to the method for purification of this area routine, such as, can be column chromatography, distillation method, extraction process, recrystallization method etc.
Compared with the prior art, beneficial effect of the present invention is embodied in:
The total recovery of product of the present invention is up to 73%, and method is simple, and step is short, easy to operate, is suitable for synthesizing on a large scale.
Embodiment
Below will be described the present invention by embodiment.
In the present invention, NMR spectrogram is measured by your AV400 type NMR spectrometer with superconducting magnet of Brooker, and wherein, deuterated reagent is deuterochloroform (CDCl
3) or deuterated methanol (MeOD), hydrogen spectrum is interior mark with tetramethylsilane, and carbon is composed with CDCl3 (δ=77.0) as interior mark; Mass spectrum is measured by LTQ/FT type mass spectrograph; PH value is measured by pH test paper; Specific rotation is measured by MC024-WXG-4 circle polarimeter.
The 200-300 order silicagel column of column chromatography is purchased from Yantai Chemical Industry Research Inst.; 0.2 millimeter of thin-layer chromatography silica-gel plate of TLC is purchased from Yantai Chemical Industry Research Inst..
When not making any Special Statement, agents useful for same of the present invention and solvent all use after standard method (with reference to " reagent purification handbook ") purifying.
Embodiment 1
100mL flask is placed in 0 DEG C of ice bath, add 2M HCl (20mL), get raw material A (8.3g again, 100mmol) be slowly added drop-wise in above-mentioned flask under agitation by constant voltage low liquid funnel, dropwise rear continuation and stir 30min, then flask is taken out, at room temperature stirring reaction 1 hour; After end, reactant methylene dichloride (20mL × 2) extracting twice is merged organic layer, by saturated sodium bicarbonate (20mL), organic layer is washed once again, then anhydrous magnesium sulfate drying, suction filtration is used, finally choose organic phase and obtain weak yellow liquid, be intermediate product B.The structural formula of raw material A is such as formula shown in II, and the structural formula of described intermediate product B is such as formula shown in III;
The reaction formula of this step is such as formula shown in (1).
Embodiment 2:
By the intermediate product B (7.0g in embodiment 1,100mmol) join in the 100mL flask containing 30mL ethanol, add oxammonium hydrochloride (7.6g under agitation, 110mmol) with pyridine (88.7mL, 110mmol), reaction solution is stirred down again be heated to 90 DEG C of back flow reaction 45min; Reaction terminates directly to revolve desolventizing ethanol afterwards, then adds methylene dichloride, has a large amount of solid (pyridine hydrochloride) to produce, and suction filtration goes out solid, revolves organic layer and obtains yellow liquid, obtain sterling intermediate product D (8.1g) through column chromatography.The reaction formula of this step is such as formula shown in (2):
The nuclear magnetic resonance result of product is:
1h NMR (400MHz, MeOD) δ 7.35 (t, J=6.0Hz, 1H), 6.66 (t, J=5.5Hz, 1H), 3.54 (td, J=6.5,1.4Hz, 4H), 2.43 – 2.31 (m, 2H), 2.25 – 2.12 (m, 2H), 1.75 – 1.56 (m, 4H).
Embodiment 3:
By the intermediate product D (5.15g in embodiment 2,50mmol) join in the 100mL flask containing 50mL dry tetrahydrofuran, take tetra lithium aluminium hydride (2.28g, 60mmol) more slowly to join in flask, and then back flow reaction 1h under agitation condition; Reaction terminates the rear ethyl acetate that first adds to remove excessive tetra lithium aluminium hydride, at dropping 10%NaOH solution, stop when there being faint yellow solid to occur dripping, last suction filtration falls solid and obtains organic layer, revolve desolventizing, obtain yellow oily product liquid (3.3g) through rectification under vacuum, be target product, its structural formula as shown in Equation 1.
The reaction formula of this step is such as formula shown in (3):
The nuclear magnetic resonance result of target product is:
1h NMR (400MHz, CDCl
3) δ 3.58 (t, J=5.7Hz, 2H), 2.95 – 2.77 (m, 2H), 2.75 (t, J=6.2Hz, 2H), 1.69 – 1.60 (m, 2H), 1.60 – 1.51 (m, 2H).
Can be proved by above-mentioned analytical results, gained yellow oily liquid is the amino-n-butyl alcohol of 4-shown in formula I.Learn by calculating, the molar yield of 4-amino-n-butyl alcohol is 74%.
More than describe the preferred embodiment of the present invention in detail; but the present invention is not limited to the detail in above-mentioned embodiment, within the scope of technical conceive of the present invention; can carry out multiple simple variant to technical scheme of the present invention, these simple variant all belong to protection scope of the present invention.
It should be noted that in addition, each the concrete technical characteristic described in above-mentioned embodiment, in reconcilable situation, can be combined by any suitable mode.In order to avoid unnecessary repetition, the present invention illustrates no longer separately to various possible array mode.
In addition, also can carry out arbitrary combination between various different embodiment of the present invention, as long as it is without prejudice to thought of the present invention, it should be considered as content disclosed in this invention equally.
Claims (4)
1. a synthetic method for 4-amino-n-butyl alcohol, is characterized in that comprising the steps:
(1) raw material A is first made to be obtained by reacting intermediate product B in an acidic solution; The structural formula of described raw material A is such as formula shown in II, and the structural formula of described intermediate product B is such as formula shown in III;
(2) make intermediate product B and raw material C in the presence of a basic contact reacts obtain intermediate product D; The structural formula of described raw material C is such as formula shown in IV, and the structural formula of described intermediate product D is such as formula shown in V;
(3) intermediate product D is made to be transformed into target product 4-amino-n-butyl alcohol in the presence of a reducing agent; Described target product 4-amino-n-butyl alcohol structural formula is such as formula shown in I:
Wherein: R
1, R
2and R
3be selected from hydrogen, C1-C4 alkyl, aryl, benzyl, C1-C4 acyl group independently of one another, by any one in the benzyl of hydroxyl, C1-C4 alkoxyl group, nitro or halogen substiuted on methoxyl methyl, ethoxymethyl, isopropylidene, hexamethylene ketone group or phenyl ring;
Described phenyl ring is 1-5 by the substituting group quantity of the benzyl of hydroxyl, C1-C4 alkoxyl group, nitro or halogen substiuted;
Described C1-C4 alkyl is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl;
Described C1-C4 alkoxyl group is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy or tert.-butoxy;
Described C1-C4 acyl group is formyl radical, ethanoyl, positive propionyl, iso-propionyl, positive butyryl radicals, isobutyryl or tertiary butyryl radicals;
Described aryl is phenyl, 4-chloro-phenyl-, 3-chloro-phenyl-, 2-chloro-phenyl-, 4-bromophenyl, 4-fluorophenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-tert-butyl-phenyl, 4-trifluoromethyl, 4-nitrophenyl, 4-xenyl; 4-Fonnylphenyl, 4-acetylphenyl, 3-methyl-4-fluorophenyl, 3; the chloro-4-fluorophenyl of 5-dichlorophenyl, 3-, 3; the two benzofuryl of 4,5-trimethoxyphenyl, 2-furyl, 2-thienyl, the mono-benzofuryl of 2-or 4-or 2-naphthyl.
2. method according to claim 1, is characterized in that: step (1) is dissolved in the first solvent by acidic substance, then adds raw material A, is 1-3h, obtains intermediate product B 0-25 DEG C of reaction;
The mol ratio of described raw material A and described first acidic substance is 1:0.1-0.5.
Described acidic substance are selected from least one in hydrochloric acid, acetic acid, sulfuric acid and trifluoroacetic acid;
Described first solvent is at least one in water, methyl alcohol, ethanol and tetrahydrofuran (THF).
3. method according to claim 1, is characterized in that: step (2) is dissolved in by alkaline matter in the second solvent, then adds intermediate product B and raw material C, is 0.5-2h, obtains intermediate product D 60-100 DEG C of reaction;
The mol ratio of described intermediate product B and described raw material C is 1:1-1.2;
Shown raw material C is hydrochloride, vitriol or tosilate;
Described alkaline matter is at least one in pyridine and triethylamine;
Described second solvent is at least one in methyl alcohol, ethanol, chloroform and toluene.
4. method according to claim 1, is characterized in that: step (3) adds intermediate product D and reductive agent in the 3rd solvent, then at 25-60 DEG C of reaction 0.5-2h, obtains target product 4-amino-n-butyl alcohol;
The mol ratio of described intermediate product D and reductive agent is 1:1-1.2;
Described reductive agent is metallic reducing agent;
Described 3rd solvent is at least one in tetrahydrofuran (THF), methyl alcohol, ether and toluene.
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Cited By (2)
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| CN105481724A (en) * | 2015-12-11 | 2016-04-13 | 安徽省科学技术研究院 | Method for synthesizing leonurine |
| CN108947851A (en) * | 2018-08-02 | 2018-12-07 | 中国科学院兰州化学物理研究所苏州研究院 | A kind of synthetic method of 5- amino -1- amylalcohol |
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| CN101391964A (en) * | 2008-11-07 | 2009-03-25 | 天津大学 | Method for preparing 2-amido-1-alkyl alcohol and catalyst preparation method |
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2015
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| CN101605794A (en) * | 2006-08-21 | 2009-12-16 | 健泰科生物技术公司 | Aza-benzofuranyl compounds and using method |
| CN101391964A (en) * | 2008-11-07 | 2009-03-25 | 天津大学 | Method for preparing 2-amido-1-alkyl alcohol and catalyst preparation method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105481724A (en) * | 2015-12-11 | 2016-04-13 | 安徽省科学技术研究院 | Method for synthesizing leonurine |
| CN108947851A (en) * | 2018-08-02 | 2018-12-07 | 中国科学院兰州化学物理研究所苏州研究院 | A kind of synthetic method of 5- amino -1- amylalcohol |
| CN108947851B (en) * | 2018-08-02 | 2020-12-11 | 中国科学院兰州化学物理研究所苏州研究院 | Synthesis method of 5-amino-1-pentanol |
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