CN105017026B - The synthetic method of 2,4 difluoro benzene methanamines - Google Patents

The synthetic method of 2,4 difluoro benzene methanamines Download PDF

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CN105017026B
CN105017026B CN201510382776.9A CN201510382776A CN105017026B CN 105017026 B CN105017026 B CN 105017026B CN 201510382776 A CN201510382776 A CN 201510382776A CN 105017026 B CN105017026 B CN 105017026B
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difluoro
synthetic method
ammonium salt
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CN105017026A (en
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吴晓东
刘郝敏
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Nanjing Jieyun Pharmaceutical Co Ltd
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Abstract

The present invention relates to one kind synthesis as medicine and field of agrochemicals, specifically intermediate 2, the synthetic method of 4 difluoro benzene methanamines.The synthetic method of 2,4 difluoro benzene methanamines includes three below step：Step one：M-difluorobenzene, halogenating agent and paraformaldehyde react in the presence of catalyst, and 2,4 difluoro halogenation benzyls are made；Step 2：Quarternary ammonium salt compound IV is made with methenamine reaction in obtained 2,4 difluoro halogenation benzyls；Step 3：Obtained quarternary ammonium salt compound is obtained into 2,4 difluoro benzene methanamines with concentrated hydrochloric acid hydrolysis.The invention enables the cost reduction for preparing 2,4 difluoro benzene methanamines, operation more facilitates, and safety coefficient is high, is especially suitable for industrialized production.

Description

The synthetic method of 2,4 difluorobenzene methylamine
Technical field
The present invention relates to one kind synthesis as medicine and field of agrochemicals, specifically intermediate 2,4- difluoro benzene methanamines Synthetic method.
Background technology
2,4- difluoro benzene methanamines are a kind of important medicine intermediates, and one of purposes is synthesizing anti-AIDS new drug Dolutegravir.In August, 2013, FDA approvals Dolutegravir combines with other antiretroviral agents for previously Treated or just controlled HIV-1 adults and 12 years old and at least 40 kilograms childhood infection persons of above body weight.Analyst, it is expected that Dolutegravir is expected to turn into the heavy pound medicine that annual sales amount reaches multi-million dollar.
Existing 2,4- difluorobenzenes synthetic methylamine route is substantially to be obtained by reduction reaction, specific as follows：
1. at present it has been reported that 2,4 difluorobenzene methylamine synthetic method (US5068371 and Chemistry- AEuropeanJournal, 2013, vol.19, #14p.4437-4440), pressurizeed by 2,4- difluorobenzonitriles in ammonia atmosphere Hydrogenation is made, and the route raw material is expensive, and yield is only 67%, and needs to use inflammable and explosive Raney nickel, hydrogen at high temperature Gas and ammonia, operating condition are harsher.
2. another have been reported that the method that benzonitrile is reduced with Borane-THF complex (JournaloftheChemicalSociety, PerkinTransactions1 (2002), (2), 197-206), is equally existed Reducing agent is expensive, wherein the market price 500-650 members of 2,4- difluorobenzonitriles/kilogram, and toxicity is very big, and operation is not Just the problem of.
3. for analog fluorobenzene formaldehyde (J.Med.Chem.2006,49,6197-6208), handled and obtained with azanol Oxime, then with the method for PtO2 hydro-reductions, its raw material and catalyst are expensive, hydroprocessing inconvenience.
4.WO2009100169 reports the preparation of analog 5- bromine 6- fluorobenzene methylamines, and this method is with corresponding benzamide For raw material, using BH3-Me2S as reducing agent, 50 DEG C of reactions are heated in THF, it is expensive there is also reducing agent, and toxicity It is very big, unhandy problem.
5.WO2012076673 then reports that using LiAlH4 as reducing agent the reducing agent is also expensive, and reagent is not Safety, is not suitable for industrialized production.
From the point of view of above-mentioned 2,4- difluorobenzenes synthetic methylamine method, although most reaction only needs step reduction, It is that yield is relatively low, and cost of material used is higher, such as United States Patent (USP) US5068731 reports are only yield 66%, still It is about 805 yuan/kilogram to calculate cost price.
The content of the invention
It is easy to operate it is an object of the invention to overcome deficiency of the prior art there is provided a kind of reduction of cost, safety system The synthetic method of the 2,4 difluorobenzene methylamine of the high suitable industrialized production of number.
To achieve the above object, the present invention provides following technical scheme：
The synthetic method of 2,4- difluoro benzene methanamines, including three below step：
Step one：M-difluorobenzene, halogenating agent and paraformaldehyde react in the presence of catalyst, and 2,4- difluoro halogen is made Change benzyl；
Step 2：Quarternary ammonium salt compound is made in obtained 2,4- difluoros halogenation benzyl and methenamine reaction；
Step 3：Obtained quarternary ammonium salt compound is obtained into 2,4 difluorobenzene methylamine with concentrated hydrochloric acid hydrolysis.
In further technical scheme, step one, solvent orange 2 A, paraformaldehyde, a difluoro are sequentially added in four-hole boiling flask Benzene, is slowly added to halogenating agent while stirring, adds catalyst, and by mixture heating reflux reaction 4-10 hours, treats After HPLC detection reactions completely, concentration of reaction solution is made in removed under reduced pressure solvent orange 2 A, then is extracted with dichloromethane, and what extraction was obtained has Machine layer desolvation A obtains colourless transparent liquid, then obtains with -5 DEG C -0 DEG C of refrigerant vacuum distillation 2,4- difluoro halogenation benzyls.
Solvent orange 2 A in further technical scheme, step one is ethyl acetate, THF, dioxane, acetonitrile or acetone.
Halogenating agent in further technical scheme, step one is concentrated hydrochloric acid, hydrobromic acid or hydrogen chloride gas；
Paraformaldehyde refers to metaformaldehyde, five polyformaldehyde or eight polyformaldehyde；
Catalyst is zinc chloride, iron chloride, copper chloride or the concentrated sulfuric acid.
The mol ratios of m-difluorobenzene, halogenating agent, paraformaldehyde and catalyst in further technical scheme, step one For 1：(5-10)：(1-5)：(0.1-0.6).
In further technical scheme, step 2,2,4- difluoro halogenation benzyls and solvent B are mixed, methenamine is added, It is heated to reflux 2-5 hours, is cooled to room temperature, obtains the mixture containing white solid, then after depressurizing suction filtration and being washed with toluene Obtain white solid i.e. quarternary ammonium salt compound.
Further technical scheme, described solvent B is toluene, dimethylbenzene, acetonitrile, THF, chloroform, methanol, ethanol or two The ring of oxygen six.
The mol ratios of 2,4- difluoro halogenation benzyls and methenamine in further technical scheme, step 2 are 1：(1-2).
In further technical scheme, step 3, quarternary ammonium salt compound and solvent C are mixed, concentrated hydrochloric acid is added, and will Mixture heating reflux reaction 3-10 hours, removed under reduced pressure solvent C, and it is cooled to 0 DEG C, residue adds water dissolving, then uses ammonia Water regulation PH is extracted to 7-8, then with dichloromethane, and vacuum distillation can obtain 2,4- difluoro benzene methanamines；The matter of quarternary ammonium salt compound Amount and the volume ratio of concentrated hydrochloric acid are 1：1-1：5 (units：g/ml).
Further technical scheme, solvent C is isopropanol, toluene, dimethylbenzene, acetonitrile, THF, chloroform, methanol, ethanol or Dioxane.
Beneficial effect
Compared with prior art, the present invention has following remarkable advantage：
1st, need to determine reaction end with HPLC in step one of the invention, control reaction time 4-10 hour, if because Overlong time (more than 10h) can cause dichloromethyl product to increase；, it is necessary to use -5 DEG C -0 DEG C of refrigerant during vacuum distillation product Distillate is cooled down, portioned product loss is otherwise had；In step 2, reaction time 2-5 hour is controlled, if because reaction time mistake Length will cause yield to be less than 82% (more than 5h)；In step 3, control reaction time 3-10 hour, if because the reaction time not (3h is less than when sufficient), and yield will be caused to be less than 73%.
2nd, this patent introduces halomethyl using Blanc reactions on phenyl ring, compared to other generation 2,4- difluoro halogenation benzyls Method, Blanc reactions have larger advantage, and such as 2,4- difluoro toluenes generate 2,4-2,4- difluoro halogenations with chlorine reaction Benzyl, chlorine toxicity is higher, and operation inconvenience, condition is harsh；And use NBS generate 2,4- difluoro cylites, reagent it is expensive and Yield is relatively low, poor selectivity；Also 2,4- difluoro-benzyl alcohols are used to generate 2,4- difluoro cylites, same examination with tribromide phosphine reaction Agent is expensive, produces more spent acid；From cost, safety, the three wastes angularly from the point of view of, Blanc reaction be all optimal method.
3rd, the present invention is the synthetic method that chloromethyl is introduced on phenyl ring, and the use of cheap m-difluorobenzene is original Material, using halogenating agent, paraformaldehyde and catalyst as chloromethylation reagents, obtains 2,4- difluoro halogenation benzyls.Then with Wu Luotuo Product are processed into quaternary ammonium salt, then hydrolyze and obtain 2,4- difluoro benzene methanamines, and product purity is more than 99%, and total recovery is more than 77% and whole In individual synthetic route, operating method is easy, and raw material and reagent are cheap, are adapted to industrial-scale production.
Brief description of the drawings
Fig. 1 is the mass spectrogram of the product 2,4 difluorobenzene methylamine prepared in embodiment 1；
Fig. 2 is the nmr spectrum of the product 2,4 difluorobenzene methylamine prepared in embodiment 1.
Embodiment
With reference to embodiment, the present invention is further detailed explanation.
Embodiment 1
The synthetic method of 2,4- difluoro benzene methanamines, including three below step：
The synthesis of compound (III)
Added in 500ml four-hole boiling flasks two between 250ml acetonitriles, the polyformaldehyde of 35g (1.17mol) eight and 45g (0.39mol) Fluorobenzene, slowly pours into 33% concentrated hydrochloric acid 200ml (2.4mol) under stirring, add 21g (0.16mol) zinc chloride, and will be mixed Compound is slowly heated to reflux, and solid gradually react 8 hours by dissolved clarification, after HPLC detection reactions completely, is cooled to room temperature, 45 DEG C of decompressions Acetonitrile is removed, two-phase mixture is obtained, 150ml dichloromethane is added and extracts twice, and merges organic layer, anhydrous sodium sulfate is used Dry, then suction filtration, and filtrate decompression be concentrated to give transparency liquid, then with -5 DEG C -0 DEG C of refrigerant vacuum distillation, collect 60 DEG C/ 10mmHg cut, obtains colourless transparent liquid, yield 86.3%, 2, the 4- difluoro halogenation benzyls of purity 96.9%.
The synthesis of compound (IV)
1000ml toluene, 252g (1.56mol) 2,4- difluoro halogenation benzyls and 298.8g are added in 2L four-hole boiling flasks (2.13mol) methenamine, is heated to reflux 2 hours, is cooled to room temperature, obtains the mixture containing white solid, then depressurizes suction filtration, White solid i.e. quarternary ammonium salt compound 421.9g, yield 99.9%, purity 99.1% are obtained after being washed with 100mL toluene.
The synthesis of compound (I)
Quarternary ammonium salt compound is transferred in 5L four-hole boiling flasks, 1385ml isopropanols and 800ml concentrated hydrochloric acids is added, heats back Stream reaction 5 hours, removed under reduced pressure isopropanol is simultaneously cooled to 0 DEG C, and residue adds water dissolving, then adjusts pH to 7 with ammoniacal liquor, then uses 700ml dichloromethane is extracted three times, then extract solution is dried, and solvent is recovered under reduced pressure, colourless transparent liquid, then vacuum distillation is obtained, Collect 80-83 DEG C/20mmHg cut, yield 92.6%, 2, the 4- difluoro benzene methanamines of purity 99.4%.
LCMS-ESI+m/z:[M+H-NH3]+calc’dforC7H5F2:127.04；Found:127.1.(accompanying drawing one)
1H-NMR:300MHz,(CDCl3)δ:7.270
(m,1H),6.852-6.742(m,2H),3.849(s,2H),1.490(s,2H).(accompanying drawing two)
Embodiment 2
The synthetic method of 2,4- difluoro benzene methanamines, including three below step：
The synthesis of compound (III)
Added in 500ml four-hole boiling flasks two between 250mL THF, 35g (1.17mol) five polyformaldehyde and 45g (0.39mol) Fluorobenzene, slowly pours into 33% concentrated hydrochloric acid 200mL (2.4mol) under stirring, add 25g (0.19mol) zinc chloride, and will be mixed Compound is slowly heated to reflux, and solid gradually react 6 hours by dissolved clarification, after HPLC detection reactions completely, is cooled to room temperature, 45 DEG C of decompressions THF is removed, two-phase mixture is obtained, 150ml dichloromethane is added and extracts twice and merge organic layer, it is dry using anhydrous sodium sulfate It is dry, then suction filtration, and filtrate decompression is concentrated to give transparency liquid, then with -5 DEG C -0 DEG C of refrigerant vacuum distillation, collect 60 DEG C/ 10mmHg cut, obtains colourless transparent liquid, yield (88.1%), 2, the 4- difluoro halogenation benzyls of purity (97.6%).
The synthesis of compound (IV)
1000mL dimethylbenzene, 252g (1.56mol) 2,4- difluoro halogenation benzyls and 358.6g are added in 2L four-hole boiling flasks (2.56mol) methenamine, is heated to reflux 2 hours, is cooled to room temperature, obtains the mixture containing white solid, then depressurizes suction filtration, White solid i.e. quarternary ammonium salt compound 410.5g, yield 97.2%, purity 99.3% are obtained after being washed with 100mL toluene.
The synthesis of compound (I)
Quarternary ammonium salt compound is transferred in 5L four-hole boiling flasks, 1385mL ethanol and 1200mL concentrated hydrochloric acids is added, heats back Stream reaction 4 hours, removed under reduced pressure isopropanol is simultaneously cooled to 0 DEG C, and residue adds water dissolving, then adjusts pH to 8 with ammoniacal liquor, then uses 700ml dichloromethane is extracted three times, then extract solution is dried, and solvent is recovered under reduced pressure, colourless transparent liquid, then vacuum distillation is obtained, Collect 80-83 DEG C/20mmHg cut, yield 93.5%, 2, the 4- difluoro benzene methanamines of purity 99.1%.
Embodiment 3
The synthetic method of 2,4- difluoro benzene methanamines, including three below step：
The synthesis of compound (III)
250mL dioxane, 45.5g (1.52mol) metaformaldehydes and 45g are added in 500ml four-hole boiling flasks (0.39mol) m-difluorobenzene, slowly pours into 47% hydrobromic acid 300mL (2.63mol), adds 32g's (0.20mol) under stirring Iron chloride, and mixture is slowly heated to reflux, solid gradually react 7 hours by dissolved clarification, after HPLC detection reactions completely, is cooled to Room temperature, 45 DEG C of removed under reduced pressure dioxane, obtains two-phase mixture, adds 150ml dichloromethane and extracts twice and merge organic Layer, transparency liquid is concentrated to give using anhydrous sodium sulfate drying, then suction filtration, and by filtrate decompression, then the refrigerant of -0 DEG C of use -5 DEG C subtracts Pressure distillation, collects 60 DEG C/10mmHg cut, obtains colourless transparent liquid, yield 85.2%, 2, the 4- difluoros of purity 97.8% Cylite.
The synthesis of compound (IV)
750mL dioxane, 321g (1.56mol) 2,4- difluoros cylite and 298.8g are added in 2L four-hole boiling flasks (2.13mol) methenamine, is heated to reflux 4 hours, is cooled to room temperature, obtains the mixture containing white solid, then depressurizes suction filtration, White solid i.e. quarternary ammonium salt compound 462g, yield 85.6%, purity 99.7% are obtained after being washed with 100mL dioxane.
The synthesis of compound (I)
Quarternary ammonium salt compound is transferred in 5L four-hole boiling flasks, 1000mL methanol and 800mL concentrated hydrochloric acids is added, is heated to reflux Reaction 6 hours, removed under reduced pressure isopropanol is simultaneously cooled to 0 DEG C, and residue adds water dissolving, then adjusts pH to 8 with ammoniacal liquor, then uses 700ml dichloromethane is extracted three times, then extract solution is dried, and solvent is recovered under reduced pressure, colourless transparent liquid, then vacuum distillation is obtained, Collect 80-83 DEG C/20mmHg cut, yield 90.8%, 2, the 4- difluoro benzene methanamines of purity 99.5%.

Claims (5)

  1. The synthetic method of 1.2,4- difluoro benzene methanamines, it is characterised in that：Including three below step：
    Step one：M-difluorobenzene, halogenating agent and paraformaldehyde react in the presence of catalyst, and 2,4- difluoro halogenations are made Benzyl：
    Solvent orange 2 A, paraformaldehyde, m-difluorobenzene are sequentially added in four-hole boiling flask, halogenating agent is slowly added to while stirring, then add Enter catalyst, and by mixture heating reflux reaction 4-10 hours, after after HPLC detection reactions completely, removed under reduced pressure solvent orange 2 A system Concentration of reaction solution, then extracted with dichloromethane, extract obtained organic layer desolvation A and obtain colourless transparent liquid, then with- 5 DEG C -0 DEG C of refrigerant vacuum distillation obtains 2,4- difluoro halogenation benzyls；
    Described solvent orange 2 A is ethyl acetate, THF, dioxane, acetonitrile or acetone；
    Step 2：Quarternary ammonium salt compound IV is made in obtained 2,4- difluoros halogenation benzyl and methenamine reaction：
    2,4- difluoro halogenation benzyls and solvent B are mixed, methenamine is added, is heated to reflux 2-5 hours, is cooled to room temperature, obtains To the mixture containing white solid, then depressurize suction filtration and white solid i.e. quarternary ammonium salt compound is obtained after being washed with toluene；
    Step 3：Obtained quarternary ammonium salt compound is obtained into 2,4 difluorobenzene methylamine with concentrated hydrochloric acid hydrolysis：
    Quarternary ammonium salt compound and solvent C are mixed, concentrated hydrochloric acid is added, and by mixture heating reflux reaction 3-10 hours, subtracted Pressure-off removes solvent C, and is cooled to 0 DEG C, and residue adds water dissolving, then is carried with ammoniacal liquor regulation PH to 7-8, then with dichloromethane Take, vacuum distillation can obtain 2,4- difluoro benzene methanamines；Wherein, the quality of quarternary ammonium salt compound and the volume ratio of concentrated hydrochloric acid are 1：1- 1：5, the unit of quality and volume ratio is g/ml；
    Halogenating agent in step one is concentrated hydrochloric acid, hydrobromic acid or hydrogen chloride gas；
    Paraformaldehyde refers to metaformaldehyde, five polyformaldehyde or eight polyformaldehyde；
    Catalyst is zinc chloride, iron chloride, copper chloride or the concentrated sulfuric acid.
  2. 2. the synthetic method of 2,4- difluoros benzene methanamine as claimed in claim 1, it is characterised in that：Difluoro between in step one Benzene, halogenating agent, the mol ratios of paraformaldehyde and catalyst are 1：(5-10)：(1-5)：(0.1-0.6).
  3. 3. the synthetic method of 2,4- difluoros benzene methanamine as claimed in claim 1, it is characterised in that：Described solvent B is toluene, Dimethylbenzene, acetonitrile, THF, chloroform, methanol, ethanol or dioxane.
  4. 4. the synthetic method of 2,4- difluoros benzene methanamine as claimed in claim 1, it is characterised in that：2,4- difluoros in step 2 The mol ratios of halogenation benzyl and methenamine are 1：(1-2).
  5. 5. the synthetic method of 2,4- difluoros benzene methanamine as claimed in claim 1, it is characterised in that solvent C is isopropanol, first Benzene, dimethylbenzene, acetonitrile, THF, chloroform, methanol, ethanol or dioxane.
CN201510382776.9A 2015-07-02 2015-07-02 The synthetic method of 2,4 difluoro benzene methanamines Expired - Fee Related CN105017026B (en)

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CN108752218B (en) * 2018-07-18 2021-03-19 浙江沙星科技有限公司 Route for preparing dolutegravir key intermediate 2, 4-difluorobenzylamine
CN108752217B (en) * 2018-07-18 2021-08-06 浙江沙星科技有限公司 Synthesis method of dolutegravir key intermediate 2, 4-difluorobenzylamine
CN112409196A (en) * 2020-11-26 2021-02-26 白云山东泰商丘药业有限公司 Preparation process of aminomethylbenzoic acid based on Delbin reaction
CN116496148A (en) * 2023-04-26 2023-07-28 湖北源洹实业投资有限公司 Process for removing o (p) chlorobenzyl alcohol impurity in o (p) chlorobenzaldehyde product

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CN100516014C (en) * 2007-04-04 2009-07-22 浙江永太科技股份有限公司 Method for preparing 2,4,5 trifluorobenzene acetic acid
CN101323578A (en) * 2008-07-17 2008-12-17 苏州敬业医药化工有限公司 Synthetic method of p-amino
CN102311351B (en) * 2011-07-11 2014-01-01 上海应用技术学院 Synthesis method of 2, 4-dimethoxybenzylamine
CN104610068B (en) * 2014-12-31 2016-03-09 浙江永太科技股份有限公司 A kind of preparation method of 2,4,6-trifluoro benzylamine compound

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