CN103724211A - Preparation method for m-aminophenylacetylene - Google Patents
Preparation method for m-aminophenylacetylene Download PDFInfo
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Abstract
The invention discloses a preparation method of m-aminophenylacetylene. The preparation method comprises the following steps: allowing dimethyl acetylmethylphosphonate to react with 4-methylbenzenesulfonylazide under a strong-alkali condition to obtain (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester; allowing the (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester to react with m-nitrobenzaldehyde under a catalytic condition to obtain 3-nitrophenylacetylene; finally, reducing the 3-nitrophenylacetylene to obtain the m-aminophenylacetylene. The preparation method has the advantages as follows: the starting raw materials are convenient and easy to obtain; the process route is simple and reasonable; the cost is low; three-waste pollution is small; large scale production is achieved; the product quality is good; the yield is high.
Description
Technical field
The present invention relates to a kind of preparation method of m-aminophenyl acetylene, belong to organic chemistry and pharmaceutical chemistry field.
Background technology
M-aminophenyl acetylene, has another name called 3-acetylene aniline, has amino and alkynyl Liang Ge functional group, can derive a series of important intermediate.Structural formula is:
M-aminophenyl acetylene itself has good mechanical property and very high physical strength, can bear the quite high shear force of turning round, and resistance to elevated temperatures wear resisting property is very good, the polyimide compounds that it and maleic anhydride reaction generate is very important, with the resin that this polymkeric substance is made, there is very high thermostability and very high physical strength, be a kind of high-grade resin for the synthesis of fields such as Aeronautics and Astronautics, military affairs, can be applicable to the empennage of aircraft and the housing of guided missile; M-aminophenyl acetylene and quinazoline compound reaction generate the compound with anti-tumor activity, as Conmana, erlotinib etc.New type anticancer medicine is erlotinib (popular name: key intermediate Erlotinib).Erlotinib hydrochloride is researched and developed by Roche Holding Ag, it is a kind of small molecules epidermal growth factor recipient tyrosine kinase reversible inhibitor, the 2005 Nian U.S. go on the market, and are mainly used in clinically the treatment of local late period or Metastatic Nsclc two wires or the treatment of three lines and carcinoma of the pancreas.By U.S. FDA approval, can be combined as advanced pancreatic cancer first-line treatment with gemcitabine recently.
At present, known formula I compounds process for production thereof mainly contains:
Method one: introduce in US Patent No. 20060224016, European patent EP 2433931 that to take a halo aniline and 2-methyl-3-butyne-2-alcohol be starting raw material, by there is Sonogashira linked reaction under triphenylphosphine, acid chloride and cuprous iodide catalysis, generate 1-(3-aminophenyl)-3-methyl-3-hydroxyl-ethyl acetylene, then heating generation elimination reaction obtains target product under highly basic condition.The method is used expensive palladium catalyst, and eliminates reaction and need heating carry out, and can produce a large amount of polyreaction by products, and yield lower (bibliographical information 66%, revision test is far below reported values), therefore be not suitable for suitability for industrialized production.Document (Org.Bio.Chem., 2003,1:4441-4450 in addition; Beilstein J.Org.Chem., 2011, reported respectively that similarly take a bromine or a halo aniline, an iodo oil of mirbane etc. is starting raw material with the dihydroxypropyl alkynes of band protection, also exists above-mentioned unfavorable factor in 7:426-431).
Method two: U.S. US4125563, US6127583 be take m-nitroacetophenone as starting raw material, phosphorus oxychloride is mixed with into vilsmiere reagent with dry DMF, m-nitroacetophenone is added in batches, make β-chloro m-nitro propionic aldehyde, through highly basic, eliminate and make m-nitrobenzene acetylene again, the nitro that finally reduces makes m-aminophenyl acetylene.The method the first step exothermic heat of reaction is violent, is difficult to control, and eliminates reaction side reaction more, and final product separation needs rectifying, and yield is lower, therefore be not suitable for suitability for industrialized production.
Method three: patent WO2007067506, document (Tetrahedron, 2008,64(44): 10195-10200), introduce that to take a nitro iodobenzene and trimethyl silicane ethyl-acetylene be raw material, under two (triphenylphosphine) palladium chlorides and cuprous iodide or cuprous chloride catalysis, coupling obtains (3-nitrophenyl)-(trimethyl silicon based)-acetylene, again under microwave radiation through hexacarbonylmolybdenum/1,8-diazacyclo [5.4.0] 11-7 alkene (DBU) reduction obtains target compound.This method is raw materials used expensive, complex operation, total recovery 67% left and right.
A kind of method four: introduced preparation method in the Chinese patent CN102775315A of Shanghai Institute Of Technology's application, take m-nitrobenzaldehyde as starting raw material, first in alcohol solvent, by basic catalyst catalysis, carry out condensation with propanedioic acid, then decarboxylation obtains m-nitro-cinnamic acid, and then again in acetum bromination obtain α, beta-2-dibrom-3-(3 '-nitrophenyl) propionic acid, afterwards by weak base decarboxylation and selective debromination, make (Z)-1-(2-bromine second rare)-3-oil of mirbane, through the complete debrominate of highly basic, make an alkynyl oil of mirbane again, finally by iron powder reducing further rectifying purifying, obtain m-aminophenyl acetylene.Totally five step reactions, selective debromination process reaction condition is difficult to control, and can produce a large amount of byproducts of reaction, finally needs in addition high vacuum rectification, and high to equipment requirements, yield is lower by 58%, thereby causes product cost higher, therefore be not suitable for suitability for industrialized production.In Chinese patent CN1313274, introduce in addition that to take an alkynyl oil of mirbane be starting raw material, direct-reduction obtains m-aminophenyl acetylene, exists raw material to be difficult to obtain.
Method five: document (Huaxue Shijie, 2011,52:423-426; Chem.Lett., 2005,34:28-29; Tetrahedron Lett., 2011, has introduced in 52:2394-2396) etc. and take alpha, beta-2-dibrom-3-(3 '-nitrophenyl) propionic acid is raw material, by eliminating and react to obtain m-nitrobenzene acetylene under alkaline condition, and by reducing to obtain m-aminophenyl acetylene.This route simple economy, but exist and eliminate the more difficult control of side reaction according to the current method of bibliographical information, by product many and need to utilize microwave promote the effects limit such as the dehalogenation reaction industrialization of this route use.
Method six: the Zhang Jun of Institutes Of Technology Of Zhejiang etc. are at document (Chinese Journal of Pharmaceuticals.2012,43(10), 812-814), introduce and take m-nitrobenzaldehyde as starting raw material, first by Perkin, react and generate m-nitro-cinnamic acid, through bromine addition, make 2 again, the bromo-3-(3-nitrophenyl of 3-bis-) propionic acid, then simultaneously dehydrobromination and carboxyl obtain the bromo-2-(3-oil of mirbane of (Z)-1-) second is rare, sodium hydride dehydrobromination obtains m-nitrobenzene acetylene again, finally by iron powder reducing, obtains m-aminophenyl acetylene.The method raw material is easy to get, totally five step reactions, but selective debromination process reaction condition is difficult to control, and can produce a large amount of byproducts of reaction, and yield is lower by 45%, thereby causes product cost higher, therefore be not suitable for suitability for industrialized production.
Summary of the invention
Technical problem to be solved by this invention is to provide that a kind of starting raw material is conveniently easy to get, easy rationally cost is low, three-waste pollution is little for operational path, can be in scale operation, and good product quality, the preparation method of the m-aminophenyl acetylene that yield is high
Technical scheme of the present invention is as follows: a kind of preparation method of m-aminophenyl acetylene, reacts under strong alkaline condition by acetonyl dimethyl phosphonate with to Methyl benzenesulfonyl nitrine and obtains (1-diazo-2-oxopropyl) dimethyl phosphonate; Then (1-diazo-2-oxopropyl) dimethyl phosphonate and m-nitrobenzaldehyde are reacted and obtain m-nitrobenzene acetylene under basic catalyst condition; Finally m-nitrobenzene acetylene is obtained to m-aminophenyl acetylene through reduction.
It is starting raw material that the present invention adopts business-like m-nitrobenzaldehyde, with (1-diazo-2-oxopropyl) dimethyl phosphonate (Bestmann-Ohira reagent), Seyferth – Gilbert carburetting occurring reacts, (1-diazo-2-oxopropyl) dimethyl phosphonate (Bestmann-Ohira reagent) is by alkali deprotonation, Formed negative ion, and ketone carbonyl is carried out to nucleophilic addition(Adn), the alkoxyl group negative ion generating is the interior attack phosphorus atom of molecule again, cyclisation generates dislikes phospha fourth ring, then open loop, emit dimethyl phosphate, and produce vinyl diazonium compound, the latter finally emits nitrogen, obtain vinyl Cabbeen, and occur 1, 2-migration, obtain final product m-nitrobenzene acetylene, through reduction nitro, make m-aminophenyl acetylene again, whole reaction process simple and effective, reaction conditions is gentle, yield can reach more than 80%, starting material are easy to get, cost reduces greatly, efficiently, pollution simple to operate is little, suitability for industrialized is produced.
Concrete operation step of the present invention is:
(1), by acetonyl dimethyl phosphonate under reaction solvent and highly basic effect, and Methyl benzenesulfonyl azide reaction is made to (1-diazo-2-oxopropyl) dimethyl phosphonate;
(2), step (1) gained (1-diazo-2-oxopropyl) dimethyl phosphonate crude product do not need purifying, directly reacts under basic catalyst with starting raw material m-nitrobenzaldehyde, makes m-nitrobenzene acetylene;
Described basic catalyst is salt of wormwood or sodium carbonate or sodium bicarbonate or potassium tert.-butoxide or sodium methylate or sodium ethylate;
Described m-nitrobenzaldehyde: basic catalyst: the mol ratio of (1-diazo-2-oxopropyl) dimethyl phosphonate is 1:1.5～4.0:1～1.5, wherein (1-diazo-2-oxopropyl) dimethyl phosphonate is by pure rear calculation;
(3), step (2) gained m-nitrobenzene acetylene is through reduction, more purified, finally makes target product m-aminophenyl acetylene; Reaction equation is:
In technique scheme: the reaction solvent in described step (1) is benzene or toluene or tetrahydrofuran (THF); Described highly basic is potassium hydroxide or sodium hydride or hydrolith; Ratio of components is calculated as acetonyl dimethyl phosphate in molar ratio: highly basic: to Methyl benzenesulfonyl nitrine, be 1:1～1.2:1～1.2.
In technique scheme: in described step (2), reaction solvent used is methyl alcohol or ethanol or acetonitrile or tetrahydrofuran (THF) or DMF.
In technique scheme: adopt iron powder or palladium carbon or RannyNi hydrogenating reduction or Reduction with Stannous Chloride method reduction m-nitrobenzaldehyde.
In technique scheme: described m-nitrobenzaldehyde adopts iron powder reducing.Iron powder is cheap, is easy to get.
In technique scheme: described m-nitrobenzene acetylene is through iron powder, after reducing under reaction solvent and ionogen existence condition, more purified, finally make target product m-aminophenyl acetylene; Described reaction solvent is methyl alcohol or ethanol or Virahol; Described ionogen is sodium-chlor or ammonium chloride or acetic acid or dilute hydrochloric acid; The ratio of components of raw material is calculated as m-nitrobenzene acetylene in molar ratio: iron powder: ammonium chloride is 1:3.5～6:0.05～0.1, and normal press control temperature of reaction is at 50～80 ℃, reaction times 2～6h.
Beneficial effect: compared with prior art, the present invention has the following advantages:
(1), a key character of the present invention is the stock yard nitrobenzaldehyde that uses market to be easy to get, and so just avoided using expensive stock yard iodo oil of mirbane, bromo nitryl benzene or m-nitrobenzene acetylene, reduced production cost.
(2), the present invention is simple to operate, do not need high-tension apparatus, do not need rectification under vacuum, equipment requirements is simple, cost-saving, environmental pollution is little, is applicable to suitability for industrialized production.
Embodiment
Below in conjunction with embodiment, the invention will be further described:
embodiment 1
The preparation of (1-diazo-2-oxopropyl) dimethyl phosphonate (Bestmann-Ohira reagent).In 1000ml reaction flask, add successively acetonyl dimethyl phosphate 33.2g(0.2mol) and 300ml toluene, add in batches NaH5.1g(0.21mol), treat that gas all discharges, will be to Methyl benzenesulfonyl nitrine 41.4g(0.21mol) and 500ml tetrahydrofuran (THF) mixed solution join in reaction solution, under room temperature, react 16h.After having reacted, add sherwood oil dilution, filter, filter cake is washed with ether, removes solvent under reduced pressure, obtains yellow liquid 33.1g, yield 86.5%.
embodiment 2
The preparation of (1-diazo-2-oxopropyl) dimethyl phosphonate (Bestmann-Ohira reagent).In 1000ml reaction flask, add successively acetonyl dimethyl phosphate 33.2g(0.2mol) and 300ml tetrahydrofuran (THF), add in batches sodium hydride 8g(0.2mol), treat that gas all discharges, will be to Methyl benzenesulfonyl nitrine 47.3g(0.24mol) and 500ml tetrahydrofuran (THF) mixed solution join in reaction solution, under room temperature, react 12h.After having reacted, add sherwood oil dilution, filter, filter cake is washed with ether, removes solvent under reduced pressure, obtains yellow liquid 33.7g, yield 88%.
embodiment 3
The preparation of m-nitrobenzene acetylene.In the 1000ml of dried and clean reaction flask, add successively m-nitrobenzaldehyde 15.1g(0.1mol), self-control (1-diazo-2-oxopropyl) dimethyl phosphonate (Bestmann-Ohira reagent) 18.3g(0.11mol) (after pure) and 750ml methyl alcohol, be cooled to 0～5 ℃, slowly add Anhydrous potassium carbonate 20.7g(0.15mol), when reinforced, controlling temperature is 0-5 ℃, finish insulated and stirred 2h.Then temperature of reaction is risen to room temperature, continue stirring reaction 8h.Stopped reaction, adds saturated aqueous ammonium chloride, and the extraction of methylene dichloride 150ml * 3, merges organic phase, anhydrous sodium sulfate drying 2h.Filter, appropriate washed with dichloromethane filter cake, merges organic phase, and concentrating under reduced pressure reclaims solvent, the freezing faint yellow solid 13.1g that solidifies to obtain, and yield is 89.2%.
embodiment 4
The preparation of m-nitrobenzene acetylene.In the 1000ml of dried and clean reaction flask, add successively m-nitrobenzaldehyde 15.1g(0.1mol), self-control (1-diazo-2-oxopropyl) dimethyl phosphonate (Bestmann-Ohira reagent) 24.9g(0.15mol) and 750ml acetonitrile, be cooled to 0～5 ℃, slowly add anhydrous sodium carbonate 42.4g(0.4mol), when reinforced, controlling temperature is 0-5 ℃, finish insulated and stirred 2h.Then temperature of reaction is risen to room temperature, continue stirring reaction 8h.Stopped reaction, adds saturated aqueous ammonium chloride, and the extraction of methylene dichloride 150ml * 3, merges organic phase, anhydrous sodium sulfate drying 2h.Filter, appropriate washed with dichloromethane filter cake, merges organic phase, and concentrating under reduced pressure reclaims solvent, the freezing faint yellow solid 13.4g that solidifies to obtain, and yield is 91.3%.
embodiment 5
The preparation of m-nitrobenzene acetylene.In the 1000ml of dried and clean reaction flask, add successively m-nitrobenzaldehyde 15.1g(0.1mol), self-control (1-diazo-2-oxopropyl) dimethyl phosphonate (Bestmann-Ohira reagent) 24.9g(0.13mol) and 750ml ethanol, be cooled to 0～5 ℃, slowly add sodium methylate 10.8g(0.2mol), when reinforced, controlling temperature is 0-5 ℃, finish insulated and stirred 2h.Then temperature of reaction is risen to room temperature, continue stirring reaction 8h.Stopped reaction, adds saturated aqueous ammonium chloride, and the extraction of methylene dichloride 150ml * 3, merges organic phase, anhydrous sodium sulfate drying 2h.Filter, appropriate washed with dichloromethane filter cake, merges organic phase, and concentrating under reduced pressure reclaims solvent, the freezing faint yellow solid 12.7g that solidifies to obtain, and yield is 86.7%.
Above-mentioned gained m-nitrobenzene acetylene TLC detects, infrared and nuclear magnetic data is as follows:
R
f=0.6(petroleum?ether:EtOAc=3:1);IR(KBr)ν
max:3288,2116,1528,736,668cm
-1;
1H?NMR(400MHz,CDCl
3):δ3.23(s,1H),7.54(d,1H,J=8.0Hz),7.80(d,1H,J=8.0Hz),8.22(d,1H，J=8.0Hz),8.34（s，1H）ppm。
embodiment 6
The preparation of m-aminophenyl acetylene.In the 1000ml of dried and clean reaction flask, add successively m-nitrobenzene acetylene 14.7g(0.1mol), reduced iron powder 23.5g(0.42mol), ammonium chloride 0.3g(0.006mol) and 90% ethanol 200ml, stirring heating back flow reaction 4h.Stopped reaction, filtered while hot, appropriate hot ethanol washing leaching cake, merging filtrate, concentrating under reduced pressure reclaims solvent, obtains weak yellow liquid 9.9g, and yield is 92.7%.
embodiment 7
The preparation of m-aminophenyl acetylene.In the 1000ml of dried and clean reaction flask, add successively m-nitrobenzene acetylene 14.7g(0.1mol), reduced iron powder 33.6g(0.6mol), sodium-chlor 0.58g(0.01mol) and 90% ethanol 200ml, stirring heating back flow reaction 4h.Stopped reaction, filtered while hot, appropriate hot ethanol washing leaching cake, merging filtrate, concentrating under reduced pressure reclaims solvent, obtains weak yellow liquid 10g, and yield is 93.2%.
embodiment 8
The preparation of m-aminophenyl acetylene.In the 500ml of dried and clean reaction flask, add successively m-nitrobenzene acetylene 14.7g(0.1mol), 5%Pd/C and the Virahol 200ml of 3g water content 50%, sealing, nitrogen replacement, normal temperature and pressure leads to H2 stirring reaction 5h.Stopped reaction, filters, appropriate hot washed with isopropyl alcohol filter cake, and merging filtrate, concentrating under reduced pressure reclaims solvent, obtains weak yellow liquid 10g, and yield is 93.2%.
Above-mentioned gained m-aminophenyl acetylene TLC detects, infrared and nuclear magnetic data is as follows:
R
f=0.6(petroleum?ether:EtOAc=1:1);IR(KBr)ν
max:3448,3287,2101,1623,1579，784，620cm
-1;
1H?NMR(400MHz,CDCl
3):δ3.02(s,1H),3.66（s，2H），6.67(dd,1H,J
1=8.0Hz，J
2=4.0Hz),6.81（s，1H），6.90(d,1H,J=8.0Hz),7.1(t,1H，J=8.0Hz)ppm。
The present invention is not limited to embodiment, so long as any distortion on basis of the present invention all falls within the scope of protection of the present invention.
Claims (7)
1. a preparation method for m-aminophenyl acetylene, reacts under strong alkaline condition by acetonyl dimethyl phosphonate with to Methyl benzenesulfonyl nitrine and obtains (1-diazo-2-oxopropyl) dimethyl phosphonate; Then (1-diazo-2-oxopropyl) dimethyl phosphonate and m-nitrobenzaldehyde are reacted and obtain m-nitrobenzene acetylene under basic catalyst condition; Finally m-nitrobenzene acetylene is obtained to m-aminophenyl acetylene through reduction.
2. the preparation method of m-aminophenyl acetylene according to claim 1, is characterized in that: concrete operation step is:
(1), by acetonyl dimethyl phosphonate under reaction solvent and highly basic effect, and Methyl benzenesulfonyl azide reaction is made to (1-diazo-2-oxopropyl) dimethyl phosphonate;
(2), step (1) gained (1-diazo-2-oxopropyl) dimethyl phosphonate crude product do not need purifying, directly reacts under basic catalyst with starting raw material m-nitrobenzaldehyde, makes m-nitrobenzene acetylene;
Described basic catalyst is salt of wormwood or sodium carbonate or sodium bicarbonate or potassium tert.-butoxide or sodium methylate or sodium ethylate;
Described m-nitrobenzaldehyde: basic catalyst: the mol ratio of (1-diazo-2-oxopropyl) dimethyl phosphonate is 1:1.5～4.0:1～1.5, wherein (1-diazo-2-oxopropyl) dimethyl phosphonate is by pure rear calculation;
(3), step (2) gained m-nitrobenzene acetylene is through reduction, more purified, finally makes target product m-aminophenyl acetylene.
3. the preparation method of m-aminophenyl acetylene according to claim 2, is characterized in that: the reaction solvent in described step (1) is benzene or toluene or tetrahydrofuran (THF); Described highly basic is potassium hydroxide or sodium hydride or hydrolith; Ratio of components is calculated as acetonyl dimethyl phosphate in molar ratio: highly basic: to Methyl benzenesulfonyl nitrine, be 1:1～1.2:1～1.2.
4. where basis requires the preparation method of m-aminophenyl acetylene described in 2, it is characterized in that: in described step (2), reaction solvent used is methyl alcohol or ethanol or acetonitrile or tetrahydrofuran (THF) or DMF.
5. the preparation method of m-aminophenyl acetylene according to claim 2, is characterized in that: in described step (3): adopt iron powder or palladium carbon or RannyNi hydrogenating reduction or Reduction with Stannous Chloride method reduction m-nitrobenzaldehyde.
6. the preparation method of m-aminophenyl acetylene according to claim 5, is characterized in that: described m-nitrobenzaldehyde adopts iron powder reducing.
7. the preparation method of m-aminophenyl acetylene according to claim 6, is characterized in that: described m-nitrobenzene acetylene is through iron powder, after reducing under reaction solvent and ionogen existence condition, more purified, finally make target product m-aminophenyl acetylene; Described reaction solvent is methyl alcohol or ethanol or Virahol; Described ionogen is sodium-chlor or ammonium chloride or acetic acid or dilute hydrochloric acid; The ratio of components of raw material is calculated as m-nitrobenzene acetylene in molar ratio: iron powder: ammonium chloride is 1:3.5～6:0.05～0.1, and normal press control temperature of reaction is at 50～80 ℃, reaction times 2～6h.
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| CN107175134A (en) * | 2017-05-31 | 2017-09-19 | 成都西岭源药业有限公司 | It is a kind of to be used to prepare 3-aminophenylacetylene or the composition of its salt and application thereof |
| CN115611760A (en) * | 2022-10-13 | 2023-01-17 | 天津药明康德新药开发有限公司 | Chemical synthesis method suitable for large-scale production of (S) -2-amino-5-alkynyl caproic acid |
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| CN107175134A (en) * | 2017-05-31 | 2017-09-19 | 成都西岭源药业有限公司 | It is a kind of to be used to prepare 3-aminophenylacetylene or the composition of its salt and application thereof |
| CN107175134B (en) * | 2017-05-31 | 2018-03-23 | 成都西岭源药业有限公司 | It is a kind of to be used to prepare 3-aminophenylacetylene or the composition of its salt and application thereof |
| CN115611760A (en) * | 2022-10-13 | 2023-01-17 | 天津药明康德新药开发有限公司 | Chemical synthesis method suitable for large-scale production of (S) -2-amino-5-alkynyl caproic acid |
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Application publication date: 20140416 |