CN106478425A - A kind of 2 methyl 1,2 propane diamine and its preparation method of salt - Google Patents
A kind of 2 methyl 1,2 propane diamine and its preparation method of salt Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
- C07C209/34—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/42—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitrogen-to-nitrogen bonds
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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Abstract
The present invention discloses the preparation method of a kind of 2 methyl 1,2 propane diamine and its salt, belongs to fine chemistry industry and pharmaceutical technology field.Prepare 2 nitro 2 methylpropane sulfonyl ester with 2 methyl 2 nitro-propanol first, prepare 2 nitro, 2 methyl 2 nitrine propane with 2 nitro 2 methylpropane sulfonyl ester again, 2 nitro, 2 methyl 2 nitrine propane is reduced into 2 methyl 1 through 2 nitro 2 methyl propylamine, 2 propane diamine, or 2 methyl 1,2 propane diamine is directly reduced to by 2 nitro, 2 methyl 2 nitrine propane.The invention is characterized in that：Raw material sources are stable, low cost, reaction condition are gentle, reaction yield is high, and the product purity obtaining is high, and in course of reaction, solvent is easily recycled, and is suitable for industrialized great production.
Description
Technical field
The present invention relates to a kind of 2- methyl isophthalic acid, the preparation method of 2- propane diamine and its salt, belong to fine chemistry industry and medical skill
Art field.
Background technology
2- methyl isophthalic acid, 2- propane diamine is my Ge Lieting (Anagliptin) and anti-malaria medicaments QZ277
(Arterolane) key intermediate, my Ge Lieting (Anagliptin) developed by Wu Tian company in June, 2010 one
Plant DPP-IV inhibitor, be the choice drug for the treatment of diabetes.OZ277 (Arferolane) medicine mainly overcomes protozoon to biography
The Drug resistance of system anti-malaria medicaments, have oral effectively, toxicity low, beneficial to absorbing, duration of efficacy length and market prospect
More wide.2- methyl isophthalic acid simultaneously, 2- propane diamine is also the ideal material preparing battery, metal-chelator and polyamide etc..
2- methyl isophthalic acid, 2- propane diamine have many uses general, but current synthetic method exist many deficiencies, the deficiency of such as raw material,
Toxicity is big, stability is poor, the response time is long, high cost, yield are low, side reaction is many etc. leads to be difficult to purify it is difficult to industrialization
Produce.
Chemistry world (2011,52 (12), 728-730) and patent CN102976951, US2587043,
It is raw material that JP08027072, WO2005113512 report with 2- amino-2-methyl propionitrile, through acetylation, reduction cyclization, hydrolysis
Obtain 2- methyl isophthalic acid, 2- propane diamine.Need in course of reaction to use under tens atmospheric pressure, react under higher temperature, there is peace
Full hidden danger.Document J.Am.Chem.Soc. (70:Report 184-186,1948) and in patent CN103951589, US2408171
In ammonia and metallic catalyst such as Raney's nickel, palladium, palladium carbon, palladium, palladium dydroxide, PtO2Deng metal catalyst reduction hydrogenation directly
Reductase 12-amino-2-methyl propionitrile generates 2- methyl isophthalic acid, 2- propane diamine, or with Lithium Aluminium Hydride reductase 12-amino-2-methyl third
Nitrile generates 2- methyl isophthalic acid, 2- propane diamine.Need reaction under comparative high temperature and high pressure, have larger danger.Document
J.Am.Chem.Soc.(70:184-186,1948) reporting 2,2- dimethyl aziridine in is raw material, in ammonia or
Be hydrogenated with the presence of ammonium chloride, the condition of reaction be pressure be 130atm, 100 DEG C of reaction generation 2- methyl isophthalic acids of temperature, 2- propane diamine,
Yield yield is 87.3%.But this synthetic method reactant is difficult to obtain, severe reaction conditions.Document
J.Am.Chem.Soc.(107:2931-2934,1985) report with 2- ethyoxyl -5,5- dimethyl-imidazol at Ba (OH)2Deposit
Under, reaction be obtained 2- methyl isophthalic acid, 2- propane diamine, but 2- ethyoxyl -5, the more difficult acquisition of 5- dimethyl-imidazol, reaction receive
Rate is relatively low.Patent US 24 08171 reports and is passed through ammonia synthesis 2- at 75atm, -35 DEG C with 2- nitro -2- methylpropanol
Methyl -2- nitro-propylamine；Again n-propylamine and Raney Ni be catalyst, pressure 40atm, at 52 DEG C reaction generate 2- methyl-
1,2- propane diamine, purity is 79.5%.Patent US4902831 report 2- nitro reacts generation schiff bases with corresponding benzylamine, then
In the presence of the metallic catalyst such as Raney's nickel or palladium carbon, Hydrogen Vapor Pressure is 344.8KPa (50Psi), reaction temperature 80～100
DEG C about under, occurred reduction reaction to obtain 2- methyl isophthalic acid in 2～24 hours, 2- propane diamine, yield is about 60%～80%.
Patent CN103626664 is reported with 2- methyl -2- aminopropanol as raw material, with Ni or Co metallic catalyst, temperature 160～
220 DEG C, pressure be 2.0～3.0atm under the conditions of, react with the liquefied ammonia of 6～15 equivalents and obtain 2- methyl isophthalic acid, 2- propane diamine, yield
It is about 50～60%, selectivity of product is about 80% about.Patent JP 2005298495 in the presence of ammonia, acetone with
CH3NO2 generates 2- methyl-2-amino -1- nitropropane, more acid hydrogenation obtains 2- methyl isophthalic acid, 2- third under RaneyNi catalysis
Diamidogen.Low temperature and high pressure (about 75atm) is needed, yield is 52% in course of reaction.Document J.Chem.Soc. (1948,52-60)
Report 2- methyl isophthalic acid, 2- dinitro-propane is dissolved in acetic acid, obtain target using Pt metal for catalyst hydrogenation reduction
Product, total recovery is 59%, and the method raw material sources are difficult, and yield is medium.
Content of the invention
It is an object of the invention to provide a kind of 2- methyl isophthalic acid, the preparation method of 2- propane diamine and its salt.Solve existing skill
2- methyl isophthalic acid is prepared, the method condition of 2- propane diamine and its associated salts is harsh, needs elevated pressures and temperature, there is safety in art
The problem of hidden danger, prepared 2- methyl isophthalic acid, 2- propane diamine and its associated salts high income, purity is high.Preparation method key step is such as
Under：
(1) preparation of 2- methyl -2- nitro-propanol sulphonic acid ester
Add the methylamine hydrochloride with dichloromethane dissolving of 2- methyl -2- nitro-propanol, catalytic amount molten in reaction bulb
Liquid, stirring forms solution, cooling, adds paratoluensulfonyl chloride or mesyl chloride, then is slowly added dropwise triethylamine and dichloromethane
Mixed solution, after 2-5 hour is stirred at room temperature, filter, adjust pH, extraction, be dried, evaporation solvent, recrystallizing methanol, obtain product 2-
Methyl -2- nitropropane sulphonic acid ester；
(2) preparation of 2- nitro -2- methyl isophthalic acid-nitrine propane
2- methyl -2- nitropropane the sulphonic acid ester that (1) is obtained adds azide, adds polar non-solute anti-
Should, dilute, extraction, dry product 2- nitro -2- methyl isophthalic acid-nitrine propane are rushed in reaction with water after terminating；
(3) 2- methyl isophthalic acid, the preparation process of 2- propane diamine and its salt is shown in following A or step B
A：2- nitro -2- methyl isophthalic acid-nitrine propane prepared by step (2) is taken to be dissolved in organic solvent, slow at -5-20 DEG C
Trialkyl phosphite solution under slow addition, 2-5 hour of used time, after completion of dropwise addition, 3-8 hour is stirred at room temperature, adds
The highly basic reaction 3-5 hour of the 1-5 times of equivalent of molal quantity of former reactant 2- nitro -2- methyl isophthalic acid-nitrine propane, discards organic
Layer, distills eliminating water, obtains product 2- nitro -2- methyl propylamine；Or rubbing with former reactant 2- nitro -2- methyl isophthalic acid-nitrine propane
The acid of 1-5 times of equivalent of your number replaces above-mentioned highly basic to react 3-5 hour, discards organic layer, distills eliminating water, collects solid, obtains product
Thing 2- nitro -2- methyl-prop amine salt；
Prepare 2- methyl isophthalic acid, 2- propane diamine and its salt with 2- nitro -2- methyl propylamine or associated salts
Take 2- nitro -2- methyl propylamine or its salt to be dissolved in organic solvent, add 2- nitro -2- methyl propylamine or its salt matter
The catalyst of 2-10% of amount and appropriate reducing agent, are reacted 3-5 hour in the range of temperature 10-100 DEG C, are followed the tracks of with TLC, instead
After should terminating, Filtration of catalyst, solvent is evaporated off, obtains corresponding product.If initial reactant is 2- nitro -2- methyl propylamine
Salt then obtains 2- methyl isophthalic acid, 2- propane diamine salt.If initial reactant 2- nitro -2- methyl propylamine, obtain 2- methyl isophthalic acid, 2- third
Diamidogen；Or add acid in the reaction beginning with 2- nitro -2- methyl propylamine as initial reactant or course of reaction, then obtain
2- methyl isophthalic acid, 2- propane diamine salt；
B：With 2- nitro -2- methyl isophthalic acid-nitrine propane preparation 2- methyl isophthalic acid, 2- propane diamine and its salt
Take 2- nitro -2- methyl isophthalic acid-nitrine propane prepared by step (2) to be dissolved in 500mL organic solvent, add 2- nitre
The catalyst of 2-10% of base -2- methyl isophthalic acid-nitrine propane quality and appropriate reducing agent, in the range of temperature is for 10-100 DEG C
Reaction 3-5 hour, is followed the tracks of with TLC method, after reaction terminates, Filtration of catalyst, and solvent is evaporated off, obtains 2- methyl isophthalic acid, 2- third
Diamidogen.If 2- methyl isophthalic acid is being prepared with 2- nitro -2- methyl isophthalic acid-nitrine propane, in the course of reaction of 2- propane diamine or anti-
Add acid when should start, then obtain 2- methyl isophthalic acid, 2- propane diamine salt.
Shown in the reaction equation of said method such as following formula (1)：
In one embodiment of the invention, the 2- methyl -2- nitro-propanol in step (1) by 2- nitropropane and is consolidated
Body paraformaldehyde occurs condensation reaction to generate.
In one embodiment of the invention, catalyst described in step (1) is trimethylamine hydrochloride, and consumption is 2- first
The 2-20% of base -2- nitro-propanol quality, temperature used by reaction is -5-20 DEG C, 2- methyl -2- nitro-propanol：Sulfonic acid chloride：Three second
The mol ratio of amine is 1.0:(1.1-2.0):(1.5-3.0), described regulation pH is to adjust pH to 1 with the hydrochloric acid of 1N；Described extraction
Taking is to be extracted 3 times with dichloromethane, and drying is to use anhydrous sodium sulfate drying.
In one embodiment of the invention, in step (1), the consumption of catalyst trimethylamine hydrochloride is 5-10%, instead
Temperature is answered to be 5-10 DEG C, 2- methyl -2- nitro-propanol：Sulfonic acid chloride：The mol ratio of triethylamine is 1.0:(1.1-1.5):(1.5-
2.0).
In one embodiment of the invention, the polar non-solute described in step (2) is dimethyl sulfoxide
(DMSO), N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N, N- diethyl acetamide, N-
Methyl pyrrolidone or acetonitrile, solvent for use is one of above-mentioned, or above-mentioned in two or more mixtures, or
One or more of above-mentioned solvent and water ratio are 100：1-1：5 mixture, reaction temperature is 90～140 DEG C, during reaction
Between 5-32h, described extraction is to be extracted with ethyl acetate.Described azide is Hydrazoic acid,sodium salt, potassium azide, Azide
TBuA or organic azide such as tetramethylsilane azido compound etc..
In one embodiment of the invention, in step (2), organic compound and the mixture of water are dimethyl sulfoxides
Or N,N-dimethylformamide and water by volume 3 (DMSO):1-1:1 ratio mixing, reaction temperature is 110～130 DEG C, instead
It is 16-18h between seasonable.
In one embodiment of the invention, 2- nitro -2- methyl isophthalic acid described in step (3) A-nitrine propane is dissolved in and having
In machine solvent, organic solvent is toluene and various substituted benzene, n-hexane, a kind of or wherein two or more in thiacyclohexane etc.
Mixture；Described trialkyl phosphite is NSC 6513, NSC 5284, tripropyl phosphite, phosphorous acid
Three benzyl esters one or more mixtures therein；2- nitro -2- methyl isophthalic acid-nitrine propane：Trialkyl phosphite：Alkali or
The mol ratio of acid is 1.0:1.1-2.0:1.5-3.0, described 2- nitro -2- methyl isophthalic acid-nitrine propane is dissolved in organic solvent
Refer to take 100g 2- nitro -2- methyl isophthalic acid-nitrine propane to be dissolved in 250ml organic solvent.Described highly basic be sodium hydroxide or
Person's potassium hydroxide；Acid used is hydrochloric acid, sulphuric acid or phosphoric acid.
In one embodiment of the invention, 2- nitro -2- methyl isophthalic acid-nitrine propane in step (3) A：Phosphorous acid three
Arrcostab：The mol ratio of alkali or acid is 1.0:(1.1-1.5):(1.5-2.0).
In one embodiment of the invention, 2- nitro -2- methyl propylamine described in step (3) A or its salt are dissolved in and having
In machine solvent, organic solvent is alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, the tert-butyl alcohol, ether, tetrahydrochysene furan
Mutter, methyltetrahydrofuran, in some cases can be without solvent；Catalyst can be Pd, Pd/C, PtO2、Raney Ni；Institute
The reducing agent used can be hydrogen, cyclohexene, ammonium formate；Described 2- nitro -2- methyl propylamine or its salt are dissolved in organic solvent
In refer to take 0.5mol 2- nitro -2- methyl propylamine or its salt to be dissolved in 500mL organic solvent.During to be prepared into salt, used
Acid can be hydrochloric acid, sulphuric acid, acetic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid etc..
In one embodiment of the invention, in step (3) A, the consumption of catalyst is 5-8%.
In one embodiment of the invention, in step (3) A, with hydrogen, for during reducing agent, with alcohol as solvent, pressure is
3-5atm, temperature is 50-100 DEG C of reaction 3-6h；
In one embodiment of the invention, in step (3) A with ammonium formate for during reducing agent with alcohol as solvent, pressure
For 3-5atm, temperature is 50-100 DEG C or 60-80 DEG C, and the response time is 3-6 hour；
In one embodiment of the invention, in step (3) A with cyclohexene for during reducing agent with alcohol as solvent or plus
Enter excessive cyclohexene, pressure is 1atm, temperature is 60-80 DEG C, the response time is 5-6 hour.
Organic solvent described in step (3) B is alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tertiary fourth
Alcohol, ether, oxolane, methyltetrahydrofuran, in some cases can be without solvent；Catalyst can be Pd, Pd/C,
PtO2, Raney Ni, used reducing agent can be hydrogen, cyclohexene, ammonium formate, tetrahydrochysene lithium aluminium；Described 2- nitro -2- first
Base -1- nitrine propane is dissolved in organic solvent referring to take 0.5mol 2- nitro -2- methyl isophthalic acid-nitrine propane being dissolved in 500mL to be had
In machine solvent.During to be prepared into salt, acid used can be hydrochloric acid, sulphuric acid, acetic acid, maleic acid, fumaric acid, oxalic acid, winestone
Acid etc..
In one embodiment of the invention, in step (3) B, the consumption of catalyst is 5-8%.
In one embodiment of the invention, in step (3) B with hydrogen for during reducing agent with alcohol as solvent, pressure be
3-5atm, temperature are 50-100 DEG C or 60-80 DEG C, and the response time is 3-6 hour.
In one embodiment of the invention, in step (3) B with ammonium formate for during reducing agent with alcohol as solvent, pressure
It is 50-100 DEG C or 60-80 DEG C for 3-5atm, temperature, the response time is 3-6 hour, 2- nitro -2- methyl isophthalic acid-nitrine propane
Mol ratio with ammonium formate is 1:1.5-2.
In one embodiment of the invention, with cyclohexene for reducing agent with alcohol as solvent or addition in step (3) B
Excessive cyclohexene, pressure is 1atm, and temperature is 60-80 DEG C, and the response time is 5-6 hour；With cyclohexene for reducing agent with alcohol
During for solvent, 2- nitro -2- methyl isophthalic acid-nitrine propane is 1 with the mol ratio of cyclohexene:1.5-3.
In one embodiment of the invention, in step (3) B with tetrahydrochysene lithium aluminium for during reducing agent with ether, tetrahydrochysene furan
Mutter or methyltetrahydrofuran is solvent, between reaction temperature is 0-10 DEG C, 2- nitro -2- methyl isophthalic acid-nitrine propane and tetrahydrochysene
The mol ratio of lithium aluminum is 1:1.5-2.
The beneficial effects of the present invention is：
The use of methylamine hydrochloride is catalyst during present invention preparation 2- methyl -2- nitro-propanol sulphonic acid ester, improves
Yield, is 70.0-95.2%；The yield preparing 2- nitro -2- methyl isophthalic acid-nitrine propane is 90.15-96.3%, during it
With polar non-solute, shorten the response time, improve reaction yield, improve the dissolubility of product；Preparation 2- nitro-
The yield of 2- methyl propylamine or its salt is 90-95%, using trialkyl phosphite, product is easily isolated during it；With
2- nitro -2- methyl propylamine or its salt preparation 2- methyl isophthalic acid, the yield of 2- propane diamine and its salt is 91.5-96.4%, uses 2- nitre
Base -2- methyl isophthalic acid-nitrine propane preparation 2- methyl isophthalic acid, the yield of 2- propane diamine and its salt is 91.5-96.4%；
The inventive method does not need very high temperature and pressure, reduces the potential safety hazard in production process, prepares
2- methyl isophthalic acid, 2- propane diamine and its purity salt are more than 97%；
The raw material sources of the present invention are stable, and low cost, reaction condition are gentle, reaction yield is high, and in course of reaction, solvent is easy
In recovery, it is suitable for industrialized great production.
Specific embodiment
The synthesis of 2- methyl -2- nitro-propanol：(with nitropropane as raw material)
2- methyl -2- nitro-propanol is according to document (Wang Naixing etc., chemical reagent:1996:18(4):250:25) method is real
Apply.
2- nitropropane injects reaction bulb, then is slowly added into solid formaldehyde, is subsequently adding a NaOH and makees catalyst, 60
It is heated to reflux about 15min, filtered while hot under the conditions of DEG C.Solvent in filtrate is evaporated off, stands overnight, have clear crystal to separate out.Dry in the air
Product is obtained after dry.Yield is：70.1%.
The assay method of purity
Using gas chromatography analysis method：
Column temperature：65 DEG C of temperature programming (3min), 6 DEG C/min, 130 DEG C (2min)；Detector temperature：200℃；Injector temperature
Degree：200℃；Carrier gas：High Purity Nitrogen, flow velocity 4.0mL/min；Hydrogen flow rate：22.5mL/min；Air：160mL/min；Tail blows：
39.0mL/min；Sample size：0.5μL.
The synthesis of 2- nitro -2- methyl 1- propanol sulphonic acid ester
Embodiment 1：The synthesis of 2- nitro -2- methyl 1- propanol p-toluenesulfonic esters
Take tri- mouthfuls of reaction bulbs of a 2L to be immersed in ice bath, sequentially add 66.5g 2- methyl -2- nitro-propanol and 500mL
Dichloromethane, stirring, it is cooled to less than 5 DEG C, add 159.7g paratoluensulfonyl chloride, add 5g trimethylamine hydrochloride, stirring
It is slowly added dropwise 140mL triethylamine and the solution of 500mL dichloromethane mixing after 10 minutes, maintain the temperature in reaction system not surpass
Cross 10 DEG C, after completion of dropwise addition, continue stirring 3 hours at room temperature, TLC follows the tracks of.After reaction terminates, filter, filtrate is with the HCl of 2N
Washing three times, with anhydrous sodium sulfate drying, filters, dichloromethane in filtrate is evaporated off, obtains solid 143.8g.After recrystallizing methanol
Obtain solid 135.7g, yield is 89.1%.
Embodiment 2：The synthesis of 2- nitro -2- methyl 1- propanol methanesulfonate
Take tri- mouthfuls of reaction bulbs of a 2L to be immersed in ice bath, sequentially add 59.5g 2- methyl -2- nitro-propanol and 500mL
Dichloromethane, stirring, it is cooled to less than 5 DEG C, adds 143.5g mesyl chloride, add 4g trimethylamine hydrochloride, stir 10 points
It is slowly added dropwise 130mL triethylamine and the solution of 500mL dichloromethane mixing after clock, maintain the temperature in reaction system to be less than 10
DEG C, after completion of dropwise addition, continue stirring 3 hours at room temperature, TLC follows the tracks of, after reaction terminates, filter, dichloro in filtrate is evaporated off
Methane, recovery.Obtain solid 97.4g.With obtaining solid 93.8g after recrystallizing methanol, yield is 95.2%
Embodiment 3：The synthesis of 2- nitro -2- methyl 1- nitrine propane
49.3g 2- methyl -2- nitro-methanesulfonates, 450mLDMF, 50mL is added successively in three mouthfuls of reaction bulbs of 1L
Water and 24.5g Hydrazoic acid,sodium salt form mixture, are heated to 125～130 DEG C, and after reacting 12 hours, cooling, with 300mL acetic acid second
Ester extracts three times, with anhydrous sodium sulfate drying, filters, solvent is evaporated off, obtains colourless liquid 33.7g, and yield is 93.4%.
Embodiment 4：The synthesis of 2- nitro -2- methyl 1- nitrine propane
Successively in three mouthfuls of reaction bulbs of 1L add 68.3g 2- methyl -2- nitro-p-toluenesulfonic esters, 450mLDMSO,
80mL water, 1.2g thmethylpropyl ammonium bromide and 24.5g Hydrazoic acid,sodium salt form mixture, are heated to 135～140 DEG C, react 25
After hour, cooling, extracted three times with 300mL ethyl acetate, with anhydrous sodium sulfate drying, filter, solvent is evaporated off and obtains colourless liquid
Body 34.4g, yield is 95.6%.
Embodiment 5：The synthesis of 2- methyl -2- nitro propylamin hydrochloride：
72g 2- methyl -2- nitro -1- nitrine propane and 250mL toluene is added successively in three mouthfuls of reaction bulbs of 1L,
After the lower Deca 141g NSC 5284 of ice bath cooling, remove ice bath, stir half an hour under room temperature, add the hydrogen of 200g 20%
Sodium hydroxide solution, is heated to reflux 3 hours, and TLC follows the tracks of reaction, and after reaction terminates, after branch vibration layer, the concentrated hydrochloric acid of addition 36% is extremely
PH value is 1, divides toluene layer with separatory funnel, moisture content is evaporated off and obtains 2- methyl -2- nitro propylamin hydrochloride.Yield 96.1%,
Purity>97%.
Embodiment 6：The synthesis of 2- methyl -2- nitro propylamin hydrochloride：
72g 2- methyl -2- nitro -1- nitrine propane and 250mL toluene is added successively in three mouthfuls of reaction bulbs of 1L,
After the lower Deca 99g NSC 6513 of ice bath cooling, remove ice bath, stir half an hour under room temperature, add 150mL concentrated hydrochloric acid, plus
Hot reflux 3 hours, TLC follows the tracks of reaction.After reaction terminates, solvent is evaporated off and obtains 2- methyl -2- nitro propylamin hydrochloride crude product.With
Re-crystallizing in ethyl acetate, obtains product, and yield is 92.5%, purity>98%.
Embodiment 7：The synthesis of 2- methyl -2- nitro propylamine：
72g 2- methyl -2- nitro -1- nitrine propane and 250mL toluene is added successively in three mouthfuls of reaction bulbs of 1L,
After the lower Deca 141g NSC 5284 of ice bath cooling, remove ice bath, stir half an hour under room temperature, add the hydrogen of 200g 20%
Sodium hydroxide solution, is heated to reflux 3 hours, and TLC follows the tracks of reaction, after reaction terminates, solvent is evaporated off, obtains 2- first after branch vibration layer
Base -2- nitro propylamine.Yield 91.5%, purity>97%.
Embodiment 8：2- methyl isophthalic acid, 2- propane diamine are synthesized by 2- methyl -2- nitro propylamine
23.6g 2- methyl -2- nitro-propane, 2g Raney's nickel, 50mL ethanol is added successively in tri- mouthfuls of reaction bulbs of 250mL
With 10mL cyclohexene, it is heated to reflux 2 hours, TLC follows the tracks of reaction, after reaction terminates, filters, evaporation, obtain 2- methyl isophthalic acid, 2- the third two
Amine.Yield 93.7%, purity>98%.
Embodiment 9:2- methyl isophthalic acid, 2- propane diamine are synthesized by 2- methyl -2- nitro propylamine
23.6g 2- methyl -2- nitro-propane, 1g Pd/C, 50mL ethanol is added successively in tri- mouthfuls of reaction bulbs of 250mL
With 10mL cyclohexene, it is heated to reflux 3 hours, TLC follows the tracks of reaction, after reaction terminates, filter, evaporate, obtain 2- methyl isophthalic acid, 2- third
Diamidogen, yield 91.5%, purity>97%.
Embodiment 10：2- methyl isophthalic acid, 2- propane diamine are synthesized by 2- methyl -2- nitro propylamine
11.8g 2- methyl -2- nitro-propane, 1g Pd/C, 50mL ethanol is added successively in tri- mouthfuls of reaction bulbs of 250mL
With 5mL concentrated hydrochloric acid, hydrogenating reduction 3 hours under 3atm and at 50 DEG C, TLC follows the tracks of reaction, after reaction terminates, filtration, evaporation, and obtain
2- methyl isophthalic acid, 2- propane diamine.Yield 92.4%, purity>97%.
Embodiment 11:By 2- methyl -2 nitros-nitrine propane synthesis 2- methyl isophthalic acid, 2- propane diamine hydrochlorate
14.4g 2- methyl -2- nitro-nitrine propane, 1g Pd/C, 50mL is added successively in tri- mouthfuls of reaction bulbs of 250mL
Ethanol and 5mL concentrated hydrochloric acid, hydrogenating reduction 3 hours under 3atm and at 50 DEG C, TLC follows the tracks of reaction.After reaction terminates, filter, steam
Send out, obtain 2- methyl isophthalic acid, 2- propane diamine hydrochlorate.Yield 92.6%, purity>97%.
Embodiment 12：2- methyl isophthalic acid, 2- propane diamine are synthesized by 2- methyl -2- nitroazide propane
28.8g 2- methyl -2- nitro-nitrine propane, 2g Raney's nickel, 50mL is added successively in tri- mouthfuls of reaction bulbs of 250mL
Ethanol and 10mL cyclohexene, are heated to reflux 2 hours, and TLC follows the tracks of reaction, after reaction terminates, filter, evaporate, obtain 2- methyl isophthalic acid, 2-
Propane diamine.Yield 94.6%, purity>98%.
Embodiment 13：2- methyl isophthalic acid, 2- propane diamine are synthesized by 2- methyl -2- nitroazide propane
28.8g 2- methyl -2- nitro-nitrine propane, 1g Pd/C, 50mL is added successively in tri- mouthfuls of reaction bulbs of 250mL
Ethanol and 10mL cyclohexene, are heated to reflux 3 hours, and TLC follows the tracks of reaction, after reaction terminates, filter, evaporate, obtain 2- methyl isophthalic acid, 2-
Propane diamine.Yield 93.5%, purity>97%.
Embodiment 14:2- methyl isophthalic acid, 2- propane diamine are synthesized by 2- methyl -2- nitroazide propane
14.4g 2- methyl -2- nitroazide propane and the anhydrous tetrahydrochysene of 150mL is added successively in tri- mouthfuls of reaction bulbs of 250mL
Furan, is slowly added into 4.5g Lithium Aluminium Hydride under ice bath cooling, charging is stirred at room temperature 2 hours after finishing, and TLC follows the tracks of reaction,
After reaction terminates, add the ammonium chloride solution of saturation, be extracted with ethyl acetate three times (200mL × 3), done with anhydrous sodium sulfate
Dry, filter, solvent is evaporated off after obtain 2- methyl isophthalic acid, 2- propane diamine.Yield 81.3%, purity>96%.
Above preferred embodiment is merely to illustrate present disclosure, and in addition, the present invention also has other embodiment,
In every case those skilled in the art enlighten because of technology involved in the present invention, and adopt equivalent or equivalent deformation mode formed
Technical scheme all falls within protection scope of the present invention.
Claims (10)
1. a kind of 2- methyl isophthalic acid, the preparation method of 2- propane diamine and its salt is it is characterised in that comprise the following steps：
(1) preparation of 2- methyl -2- nitro-propanol sulphonic acid ester
2- methyl -2- nitro-propanol is taken to add dichloromethane, stirring forms solution, cooling, adds catalyst, adds to toluene sulphur
Acyl chlorides or mesyl chloride, then the mixed solution of Deca triethylamine and dichloromethane, are stirred at room temperature 2-5h after completion of dropping
Afterwards, filter, adjust pH, extraction, be dried, evaporation solvent, recrystallization, obtain 2- methyl -2- nitro-propanol sulphonic acid ester；
(2) preparation of 2- nitro -2- methyl isophthalic acid-nitrine propane
Take the 2- methyl -2- nitro-propanol sulphonic acid ester that step (1) is obtained to add azide, add polar non-solute anti-
Should, reaction terminates rear dilute with water, extraction, dry 2- nitro -2- methyl isophthalic acid-nitrine propane；
(3) 2- methyl isophthalic acid, the preparation of 2- propane diamine and its salt is as shown in A or B
A:2- nitro -2- methyl isophthalic acid-nitrine propane that step (2) is obtained is taken to be dissolved in organic solvent, Deca is sub- at -5-20 DEG C
Trialkylphosphate ester solution is reacted, and reaction adds highly basic reaction preparation 2- nitro -2- methyl propylamine after terminating, or adds
Acid reaction prepares 2- nitro -2- methyl-prop amine salt；2- nitro -2- methyl propylamine or its salt is taken to be dissolved in organic solvent, addition is urged
Agent and reducing agent reaction, TLC follows the tracks of, and after reaction terminates, removes catalysts and solvents and obtains product 2- methyl isophthalic acid, 2- propane diamine
Or its salt；Or acid during the course of the reaction or is added when reacting and starting for substrate with 2- nitro -2- methyl propylamine, obtains 2- first
Base -1,2- propane diamine salt；
B:With 2- nitro -2- methyl isophthalic acid-nitrine propane preparation 2- methyl isophthalic acid, 2- propane diamine and its salt
Take 2- nitro -2- methyl isophthalic acid-nitrine propane that step (2) is obtained to be dissolved in organic solvent, add catalyst and reducing agent
Reaction, is followed the tracks of with TLC, after reaction terminates, removes catalysts and solvents, obtains 2- methyl isophthalic acid, 2- propane diamine；Or reacting
Add acid in journey or when reaction starts, obtain 2- methyl isophthalic acid, 2- propane diamine salt.
2. 2- methyl isophthalic acid according to claim 1, the preparation method of 2- propane diamine and its salt is it is characterised in that step (1)
Described in catalyst be methylamine hydrochloride, consumption be 2- methyl -2- nitro-propanol quality 2-20%；Described cooling is cooling
It is -5-20 DEG C to temperature, reacted at this temperature；2- methyl -2- nitro-propanol：Paratoluensulfonyl chloride or methylsulfonyl
Chlorine：The mol ratio of triethylamine is 1.0:(1.1-2.0):(1.5-3.0)；Described regulation pH is to adjust pH to 1 with the hydrochloric acid of 1N；Institute
The extraction stated is to be extracted 3 times with dichloromethane, and drying is to use anhydrous sodium sulfate drying, and recrystallization is to utilize recrystallizing methanol.
3. 2- methyl isophthalic acid according to claim 1 and 2, the preparation method of 2- propane diamine and its associated salts it is characterised in that
The consumption of described catalyst is 5-10%, and temperature is cooled to 5-10 DEG C, 2- methyl -2- nitro-propanol：Paratoluensulfonyl chloride or
Mesyl chloride：The mol ratio of triethylamine is 1.0:(1.1-1.5):(1.5-2.0).
4. 2- methyl isophthalic acid according to claim 1, the preparation method of 2- propane diamine and its salt is it is characterised in that step (2)
In reaction be add polar non-solute after, at 90～140 DEG C react 5-32h；Described polar non-solute is
Dimethyl sulfoxide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N, N- diethyl acetamide,
The mixing of one or more of N-Methyl pyrrolidone or acetonitrile, or one or more of above-mentioned solvent and water volume
Than for 100：1 to 1：5 mixture；Described extraction is to be extracted with ethyl acetate；Described 2- methyl -2- nitro-propanol sulphur
Acid esters is 1 with the ratio with polar non-solute:(8-15)；The addition of described azide is 2- methyl -2- nitro third
1.5-3 times of equivalent of alcohol sulphonic acid ester.
5. 2- methyl isophthalic acid according to claim 4, the preparation method of 2- propane diamine and its salt is it is characterised in that described
Polar non-solute is that dimethyl sulfoxide, N,N-dimethylformamide and water press 3:1-1:1 volume ratio mixes, and reaction temperature is
110～130 DEG C, the response time is 16-18h.
6. a kind of 2- methyl isophthalic acid according to claim 1, the preparation method of 2- propane diamine and its salt is it is characterised in that walk
Suddenly 2- nitro -2- methyl isophthalic acid described in (3) A-nitrine propane is dissolved in organic solvent, and organic solvent is toluene and various replacement
Benzene, n-hexane, the mixture of one or more of thiacyclohexane, described trialkyl phosphite is NSC 6513, Asia
One of triethyl phosphate, tripropyl phosphite, Tribenzyl Phosphite or multiple mixture, described Deca phosphorous acid three alkane
The base ester solution used time is 2-5 hour, after completion of dropwise addition, 3-8 hour is stirred at room temperature, and described addition highly basic is that addition is former anti-
1-5 times of molal quantity answering thing 2- nitro -2- methyl isophthalic acid-nitrine propane reacts 3-5 hour, discards organic layer, removes moisture, obtains
Product 2- nitro -2- methyl propylamine；Described add acid be addition former reactant 2- nitro -2- methyl isophthalic acid-nitrine propane mole
1-5 times of number is reacted 3-5 hour, discards organic layer, removes moisture, obtains product 2- nitro -2- methyl-prop amine salt；2- nitro -2-
Methyl isophthalic acid-nitrine propane：Trialkyl phosphite：The mol ratio of alkali or acid is 1.0:(1.1-2.0):(1.5-3.0)；Described
2- nitro -2- methyl isophthalic acid-nitrine propane be dissolved in organic solvent and refer to take 100g 2- nitro -2- methyl isophthalic acid-nitrine propane molten
In 250ml organic solvent.
7. the 2- methyl isophthalic acid described in 6 is required according to profit, the preparation method of 2- propane diamine and its salt is it is characterised in that 2- nitro -2-
Methyl isophthalic acid-nitrine propane：Trialkyl phosphite：The mol ratio of alkali or acid is 1.0:(1.1-1.5):(1.5-2.0).
8. 2- methyl isophthalic acid according to claim 1, the preparation method of 2- propane diamine and its associated salts is it is characterised in that walk
Suddenly 2- nitro -2- methyl propylamine described in (3) A or its salt are dissolved in organic solvent, and organic solvent is alcohols, ether, tetrahydrochysene furan
Mutter or methyltetrahydrofuran, catalyst is Pd, Pd/C, PtO2Or Raney Ni, the consumption of catalyst be 2- nitro -2- methyl -
The 2-10% of 1- nitrine propane, reducing agent is hydrogen, cyclohexene or ammonium formate；Described 2- nitro -2- methyl propylamine or its salt are molten
Refer to take 0.5mol 2- nitro -2- methyl propylamine or its salt to be dissolved in 500mL organic solvent in organic solvent.
9. 2- methyl isophthalic acid according to claim 1, the preparation method of 2- propane diamine and its salt is it is characterised in that step (3)
- 2- methyl the propylamine of 2- nitro described in B or its salt are dissolved in organic solvent, and organic solvent is alcohols, ether, oxolane, first
Base oxolane, catalyst is Pd, Pd/C, PtO2Or Raney Ni, the consumption of catalyst is 2- nitro -2- methyl isophthalic acid-nitrine
The 2-10% of propane, used reducing agent is hydrogen, cyclohexene, ammonium formate or tetrahydrochysene lithium aluminium；Described 2- nitro -2- methyl -
1- nitrine propane be dissolved in organic solvent refer to take 0.5mol 2- nitro -2- methyl isophthalic acid-nitrine propane be dissolved in 500mL organic
In solvent.
10. 2- methyl isophthalic acid, 2- propane diamine and its salt according to the preparation of claim 1-9 arbitrary methods described.
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| GRÉGORY DURAND ET AL.: "Amphiphilic Amide Nitrones：A New Class of Protective Agents Acting as Modifiers of Mitochondrial Metabolism", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| MORRIS FREIFELDER ET AL.: "Synthesis of Primary 1,2-Diamines by Hydrogenation of α-Aminonitriles", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| 卞林芝 等: "2-硝基-2-甲基丙胺的合成工艺研究", 《中国化学会第30届学术年会摘要集-第九分会：有机化学》 * |
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