WO2020232625A1 - 重氮甲烷的制备工艺 - Google Patents

重氮甲烷的制备工艺 Download PDF

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WO2020232625A1
WO2020232625A1 PCT/CN2019/087761 CN2019087761W WO2020232625A1 WO 2020232625 A1 WO2020232625 A1 WO 2020232625A1 CN 2019087761 W CN2019087761 W CN 2019087761W WO 2020232625 A1 WO2020232625 A1 WO 2020232625A1
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solution
diazomethane
acid
preparation process
continuous
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PCT/CN2019/087761
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English (en)
French (fr)
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洪浩
卢江平
张恩选
申慰
闫红磊
张震
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凯莱英医药集团（天津）股份有限公司
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Priority to EP19930141.7A priority Critical patent/EP3974411B1/en
Priority to PCT/CN2019/087761 priority patent/WO2020232625A1/zh
Priority to KR1020217028083A priority patent/KR20210124350A/ko
Priority to US17/611,712 priority patent/US20220242818A1/en
Publication of WO2020232625A1 publication Critical patent/WO2020232625A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/12—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom
    • C07C245/14—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom having diazo groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C245/16—Diazomethane

Definitions

  • the invention relates to the field of diazomethane preparation, in particular to a preparation process of diazomethane.
  • Diazomethane is a yellow gas with a strong pungent odor. It is soluble in ethanol and ether. It will explode when exposed to heat, fire, friction and impact. It is very active in nature and can occur many types of reactions. It is an important reagent in organic synthesis. It is mainly used in the methylation reaction of carboxyl groups, phenolic hydroxyl groups, enols, etc., and used in the preparation of diazoketones for the homologous series of ketones and carboxylic acids. Chemical reaction, 1,3 dipolar cycloaddition reaction, etc. Moreover, because of its low molecular weight, the reaction of diazomethane has better atomic efficiency and nitrogen is the only by-product after the reaction.
  • Diazald MNU and MNNU
  • MNNU MNNU
  • Diazald and MNU are usually used for the preparation of diazomethane.
  • Diazomethane prepared in batches needs to be diluted with nitrogen or diluted in ether to form a solution before use in order to prevent explosion due to excessive concentration.
  • Aerojet-General Corporation (now AMPAC Fine Chemicals) is the first company to carry out large-scale production and application of diazomethane. It has patents for continuous production of diazomethane (US5854405B2) and batch production of diazomethane (EP0916649). Its continuous route uses non-toxic N-methylurea as starting material and continuous reaction with sodium nitrite/hydrochloric acid system to prepare diazomethane precursor MNU ether solution, and then reacts with alkali aqueous solution to generate diazomethane. Dissolved in organic solvents. Although the preparation of MNU is a continuous reaction, the preparation of diazomethane is actually a preparation using three reactors (3000L), which is essentially a batch reaction. The diazomethane prepared in this way may introduce a small amount of water during the liquid separation process, which makes it unusable for subsequent reactions that are sensitive to water.
  • Rossi E. et al. reported that a special heart-shaped coil was used to prepare diazomethane solution with NMU as a raw material, and the aqueous phase was directly passed into the reaction system for methyl esterification of carboxylic acid without separating the alkaline aqueous phase.
  • this method is only suitable for reaction systems that are not sensitive to water (Organic Process Research & Development, 2017, 16(5): 1146-1149.).
  • Carlson E. et al. reported the use of a reactor to prepare diazomethane gas with Diazald as a raw material, and directly pass the olefin substrate solution to carry out the cycloaddition reaction.
  • Maurya RA et al. reported the use of a dual-channel coil reactor with a polydimethylsiloxane (PMDS) semipermeable membrane to prepare and separate diazomethane gas for the reaction (Synthetic Communications, 2016, 46 ( 1):55-62.).
  • PMDS polydimethyls
  • Mastronardi F et al. reported the use of AF-2400 material as a semi-permeable membrane tube in tube (tube in tube) using Diazald as a raw material for continuous production and reaction of diazomethane (Organic Letters, 2013, 15(21): 5590 -5593.). Dallinger D. et al. also used AF-2400 material as a semi-permeable membrane tube in flask for continuous preparation and reaction of diazomethane with Diazald as a raw material (Journal of Organic Chemistry, 2016, 81(14): 5814-5823.). Lehmann H. et al.
  • the main purpose of the present invention is to provide a process for preparing diazomethane to solve the problem of high cost of equipment for preparing diazomethane in a continuous process in the prior art.
  • a process for preparing diazomethane includes: step S1, using N-methylurea as a raw material in a continuous reactor to continuously prepare N-methane The first product system of N-N-nitrosourea; step S2, continuous extraction and back extraction are performed on the first product system to obtain an N-methyl-N-nitrosourea solution; step S3, make N-methyl The N-nitrosourea solution and the alkali solution are continuously reacted in a continuous reactor to obtain a second product system containing diazomethane; and step S4, the second product system is continuously separated and frozen to remove water, Obtain diazomethane.
  • step S1 includes: continuously feeding acid, solvent, sodium nitrite and N-methylurea into a continuous reactor for reaction to prepare the first product system.
  • the above-mentioned acid is any one selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, p-toluenesulfonic acid and methanesulfonic acid
  • the solvent includes water and an organic solvent
  • the organic solvent is selected from chloroform and dichloromethane. Any one or more of ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, toluene and xylene.
  • reaction temperature in the above step S1 is 0 to 120°C, preferably 10 to 30°C, preferably the molar ratio of N-methylurea, sodium nitrite and acid is 1:1.5 to 2.5:1 to 2, preferably a solvent
  • the volume ratio of reclaimed water and organic solvent is 1:3 to 5; preferably, the retention time of step S1 is 5 to 30 minutes.
  • the above-mentioned continuous reactor is a continuous coil reactor.
  • step S2 includes: continuously sending the first product system to the first extraction column and using the extractant for extraction to obtain the extract; continuously sending the extract to the second extraction column and using the alkaline back extraction solution for back extraction, N-methyl-N-nitrosourea solution is obtained, wherein the extractant is selected from any one of chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, toluene and xylene or A variety of basic back extraction solutions are selected from triethylamine, diisopropylethylamine, tert-butylammonium, 1,4-diazabicyclo, 1,8-diazabicycloundec-7 -An aqueous solution of any one of alkene, KOH, NaOH, K 2 CO 3 , Na 2 CO 3 , NaHCO 3 , Cs 2 CO 3 , KHCO 3 , sodium acetate and
  • the lye in the above step S3 is potassium hydroxide solution, sodium hydroxide solution, lithium hydroxide solution, potassium carbonate solution, sodium carbonate solution, potassium bicarbonate solution or sodium bicarbonate solution.
  • reaction temperature of the above step S3 is -20-100°C, preferably 0-30°C, and the retention time of step S3 is preferably 30-150 seconds.
  • step S4 includes: continuously sending the second product system to the third extraction column for liquid separation treatment to obtain the upper overflow organic solution; freezing the upper overflow organic solution to solidify the water in it to obtain diazonium Organic solution of methane.
  • the above-mentioned freezing treatment includes: continuously feeding the upper overflow organic solution into the continuous reactor and keeping the temperature at -30 ⁇ -50°C under stirring conditions for 40 ⁇ 80min, and the organic solution of diazomethane from the continuous reactor
  • the upper layer overflows, and it is preferable that the overflow port of the continuous reactor is provided with a filter screen.
  • the continuous preparation of diazomethane in the prior art requires the use of expensive semi-permeable membranes or liquid-liquid separators to separate the diazomethane from the water phase in order to carry out subsequent reactions sensitive to moisture, resulting in The equipment investment is large and the production cost is high.
  • the present application provides a preparation process of diazomethane.
  • the preparation process of the diazomethane includes: step S1, using N-methylurea as a raw material to continuously prepare N-methyl-N-nitroso
  • the first product system of methyl urea includes: step S2, the first product system is continuously extracted and stripped to obtain N-methyl-N-nitrosourea solution; step S3, N-methyl-N-nitroso
  • the base urea solution and the alkali solution are continuously reacted in a continuous reactor to obtain a second product system containing diazomethane; and step S4, the second product system is continuously separated and frozen to remove water to obtain diazomethane.
  • the above-mentioned preparation process of this application uses safe and non-toxic N-methylurea as a raw material, uses full continuous reaction and post-treatment to obtain the 2-methyltetrahydrofuran solution of diazomethane precursor MNU, and then directly uses full continuous reaction and post-treatment.
  • the treatment obtains an anhydrous diazomethane solution, in which the freezing process is used to remove water, avoiding the use of expensive semi-permeable membranes or liquid-liquid separators. Therefore, the preparation process is more than the existing batch diazomethane preparation process. Safe and controllable; compared with the existing continuous diazomethane preparation process, the cost is lower. specifically:
  • the preparation process of the present application does not use expensive water removal membranes or equipment, and can obtain a diazomethane solution with extremely low water content at a lower cost, and can directly react with water-sensitive materials or systems;
  • the continuous preparation of MNU can be directly used for the second step of continuous diazomethane preparation without separation and purification, which reduces the exposure to the carcinogenic and allergic material MNU Compared with most reactions that use Diazald as the precursor of diazomethane, the cost is lower and the three wastes are less;
  • the reaction mechanism for preparing MNU using N-methylurea as a raw material in this application is the same as the prior art.
  • the above step S1 includes: continuously feeding acid, solvent, sodium nitrite, and N-methylurea into a continuous reactor. React to prepare the first product system.
  • the above-mentioned N-methylurea is dissolved in water and acid (added as an aqueous solution) in advance, and then the mixed solution of acid, water and N-methylurea is continuously fed in.
  • Sodium nitrite is also continuously fed in as an aqueous solution.
  • the above-mentioned solvent includes a solvent for dissolving sodium nitrite and N-methylurea.
  • the acid and solvent used in this application can be selected from the common acids and solvents in the prior art using N-methylurea as raw materials.
  • the above-mentioned acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Any one of formic acid, acetic acid, p-toluenesulfonic acid and methanesulfonic acid
  • the solvent includes water and an organic solvent selected from the group consisting of chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, Any one or more of toluene and xylene.
  • the solvent contains water and organic solvent at the same time, and the two form a layering effect, which is beneficial to the separation of the product from the reaction system.
  • the reaction temperature for preparing MNU can refer to the prior art.
  • the reaction temperature in step S1 is 0 to 120°C, more preferably 10 to 30°C, to ensure the stability of the reaction.
  • the molar ratio of N-methylurea, sodium nitrite and acid is 1:1.5 ⁇ 2.5:1 ⁇ 2, and the ratio of raw materials or pump speed of each material is adjusted.
  • the above-mentioned molar ratio is realized; preferably, the volume ratio of water and organic solvent in the solvent is 1:3 to 5 to improve the separation efficiency of the product.
  • the retention time of the above step S1 is 5-30 min.
  • the continuous reactor used in the above-mentioned preparation process can be a tubular continuous reactor or a tank-type continuous reactor commonly used in the prior art, wherein a semi-permeable membrane is not required, and the above-mentioned continuous reactor is preferably a continuous coil reactor.
  • the above step S2 includes: continuously sending the first product system to the first extraction column and using the extractant for extraction to obtain the extract; continuously sending the extract to the second extraction column and using the alkaline reaction
  • the extraction solution is subjected to back extraction to obtain an N-methyl-N-nitrosourea solution, wherein the extractant is selected from chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, toluene and xylene
  • the basic back extraction solution is selected from triethylamine, diisopropylethylamine, tert-butylammonium, 1,4-diazabicyclo (DABCO), 1,8-di Any one of azabicycloundec-7-ene (DBU), KOH, NaOH, K 2 CO 3 , Na 2 CO 3 , NaHCO 3 , Cs 2 CO 3 , KHCO
  • the lye in step S3 is potassium hydroxide solution, sodium hydroxide solution, lithium hydroxide solution, potassium carbonate solution, sodium carbonate solution, and hydrogen carbonate. Potassium solution or sodium bicarbonate solution.
  • the reaction temperature of step S3 can also refer to the prior art.
  • the reaction temperature of step S3 is -20-100°C, preferably 0-30°C.
  • the retention time of step S3 is preferably 30-150 seconds. .
  • the above step S4 includes: continuously sending the second product system to the third extraction column for liquid separation treatment to obtain the upper overflow organic solution;
  • the upper overflow organic solution is refrigerated to solidify the water in it to obtain an organic solution of diazomethane.
  • the extraction column is used for liquid separation treatment, most of the water in the second product system is frozen, and then the water and diazomethane are used for freezing treatment to freeze the water, thereby obtaining an organic solution of diazomethane.
  • the above-mentioned freezing treatment includes: continuously feeding the upper overflow organic solution into a continuous reactor and keeping the temperature at -30 ⁇ -50°C under stirring conditions for 40 ⁇ 80min,
  • the organic solution overflows from the upper layer of the continuous reactor, and it is preferable that the overflow port of the continuous reactor is provided with a filter screen. Freezing under stirring conditions is conducive to the full separation of water and organic matter; in addition, because the upper overflow organic solution is continuously fed, the organic solution of diazomethane can overflow from the continuous reactor after the freezing treatment.
  • a filter screen is installed at the overflow port to intercept the ice debris, thereby improving the efficiency of water removal.
  • Configure beater system A add 100g of N-methylurea to beater bottle A, add 100ml of water, slowly add 266g 37% hydrochloric acid, and stir until dissolved.
  • Configure feeding system B add 1750mL 2-Me-THF to feeding bottle B.
  • Configure beater system C add 140g of sodium nitrite to beater bottle C, add 400ml of water, and stir until dissolved.
  • Configure the feeding system D add 600mL 2-Me-THF to the feeding bottle D.
  • Configure beater system E add potassium bicarbonate to beater E, add 654ml of water, and stir until dissolved.
  • Equipment preparation add about 500ml tap water to the first extraction column to half the height of the column; add about 200ml potassium bicarbonate aqueous solution to the second extraction column to 1/4 of the column height.
  • Feeding connect feeder bottle A, feeder bottle B, and feeder bottle C to the four-way of the 200ml first PTFE coil reactor, and set feeder pump A, feeder pump B and feeder pump B on their respective connecting pipelines.
  • Feed pump C turn on feed pump A, feed pump B, and feed pump C, and control their respective flow rates to 3.57g/min; 11.42g/min; 4.11g/min.
  • the three materials join at the four-way.
  • the reaction is carried out in the first tetrafluoro coil reactor with a retention time of 10 min.
  • the first PTFE coil reactor is connected to the upper end of the first extraction column, and the feeding bottle D is connected to the lower end of the first extraction column, and a feeding pump D is set on the connecting pipeline, and the feeding pump D is started and 600mL 2 -Me-THF is pumped from the lower end of the first extraction column for continuous back extraction.
  • the flow rate of the feed pump D is: 3.95g/min.
  • the lower end of the first extraction column releases the water phase, and the upper organic phase enters the second extraction column for extraction.
  • the organic phase from the upper end of the first extraction column is pumped in from the lower end of the second extraction column, connect the feeding bottle E and the upper end of the second extraction column, set a feeding pump E on the connecting pipeline, and start the feeding pump E.
  • Receiving Accept the organic phase of the second extraction column, and determine the QNMR yield is 81% and the pH value is 6.4.
  • the measurement method is to use deuterated chloroform to dissolve the sample, add mesitylene as the internal standard, and then proceed NMR analysis.
  • Disposing the beater system F add the 2-methyltetrahydrofuran solution of the organic phase N-nitroso-N-methylurea obtained above into the beater bottle F.
  • Configuration of beater system G Dissolve potassium hydroxide in water, stir until the solid is dissolved, and prepare a 15% wt solution.
  • Equipment preparation Add tap water to the third extraction column to half the height of the column.
  • Feeding Connect the feeder bottle F and feeder G to the tee of the 200ml second PTFE coil reactor and set feeder pump F and feeder pump G on their respective connecting pipes, and turn on feeder pump F , Feeding pump G, and control the flow rate of 14.75g/min; 5.25g/min, the two materials merge at the tee, and then enter the 20ml second tetrafluoro coil reactor for reaction, the retention time is 1min.
  • the second tetrafluorocoil reactor is connected to the upper end of the third extraction column so that the second product system of the second tetrafluorocoil reactor is separated in the second extraction column, and the upper layer of yellow organic phase overflows It flows into the CSTR at -40°C and stirs for 1 hour to freeze and remove water.
  • the water freezes into ice at low temperature and is separated from the system.
  • the organic solution of the upper layer of diazomethane overflows through an overflow with a filter, which is obtained by nuclear magnetic verification.
  • the product is diazomethane, and the water content is detected by Karl Fischer (KF) moisture analyzer.
  • the HPLC external standard is determined after derivatization with excess benzoic acid. The yield is 57%.
  • the obtained diazomethane solution can directly overflow into the mixed anhydride solution to prepare diazoketone.
  • Example 1 The difference from Example 1 is that the upper yellow organic phase overflowed into the CSTR at -50°C and stirred for 40 minutes to freeze and remove water during the liquid separation and dewatering process. The water solidified into ice at low temperature and separated from the system. The organic solution of methane overflows through an overflow with a filter.
  • Example 1 The difference from Example 1 is that the upper yellow organic phase overflowed into the CSTR at -30°C and stirred for 80 min to freeze and remove water during the liquid separation and dewatering process.
  • the water freezes into ice at low temperature to separate from the system.
  • the organic solution of methane overflows through an overflow with a filter.
  • Example 1 The difference from Example 1 is that the acid in the feeding bottle A is 162 g of acetic acid, and the feeding speed of the feeding pump A is 2.77 g/min.
  • Example 1 The difference from Example 1 is that the acid in the feeding bottle A is an acid solution obtained by using 464 g of p-toluenesulfonic acid dissolved in 693 g of water, and the feeding speed of the feeding pump A is 9.63 g/min.
  • Example 2 The difference from Example 1 is that 1750 mL of dichloromethane is in the driving bottle B, and the solvent in the driving bottle D is 388 mL of dichloromethane.
  • Example 1 The difference from Example 1 is that the driving bottle B contains toluene, and the solvent in driving bottle D is toluene.
  • Example 2 The difference from Example 1 is that 1750 mL of ethyl acetate is contained in bottle B, and the solvent in bottle D is 573 ml of ethyl acetate.
  • Example 1 The difference from Example 1 is that the temperature of the first tetrafluoro coil reactor is about 50°C.
  • Example 1 The difference from Example 1 is that the temperature of the first tetrafluoro coil reactor is about 120°C.
  • Example 1 The difference from Example 1 is that the temperature of the first tetrafluoro coil reactor is about 10°C.
  • Example 2 The difference from Example 1 is that the temperature of the first tetrafluoro coil reactor is about 0°C.
  • Example 1 The difference from Example 1 is that the retention time in the first tetrafluoro coil reactor is 5 min.
  • Example 1 The difference from Example 1 is that the retention time in the first tetrafluoro coil reactor is 30 min.
  • Example 1 The difference from Example 1 is that the alkaline solution in the feed pump E is triethylamine.
  • Example 1 The difference from Example 1 is that the alkaline solution in the feed pump E is DBU.
  • Example 1 The difference from Example 1 is that the alkaline solution in the feed pump E is potassium hydroxide.
  • Example 1 The difference from Example 1 is that the alkaline solution in the feed pump E is potassium carbonate.
  • Example 1 The difference from Example 1 is that the temperature of the second tetrafluoro coil reactor is about -20°C, and the retention time is 150 seconds.
  • Example 1 The difference from Example 1 is that the temperature of the second tetrafluoro coil reactor is about 30°C.
  • Example 1 The difference from Example 1 is that the temperature of the second tetrafluoro coil reactor is about 100° C., and the retention time is 30 seconds.
  • Example 1 The difference from Example 1 is that the temperature of the second tetrafluoro coil reactor is about -10°C, and the retention time is 180 seconds.
  • Example 1 The difference from Example 1 is that 200g 37% hydrochloric acid is added to the feed bottle A.
  • Example 2 The difference from Example 1 is that 333g 37% hydrochloric acid is added to the feed bottle A.
  • Example 1 The difference from Example 1 is that 380g 37% hydrochloric acid is added to the feed bottle A.
  • Example 1 The difference from Example 1 is that the amount of sodium nitrite in the feeding bottle C is 93.1 g, the amount of water is still 400 g, and the feeding speed of the feeding pump C is 3.82 g/min.
  • Example 1 The difference from Example 1 is that the amount of sodium nitrite in the feeding bottle C is 186.3 g, the amount of water is still 400 g, and the feeding speed of the feeding pump C is 4.38 g/min.
  • Example 1 The difference from Example 1 is that the beating system B is 1500mL 2-MeTHF, and the flow rates of the beating pump A, the beating pump B and the beating pump C are respectively 3.88g/min; 10.73g/min; 4.49g/ min.
  • Example 1 The difference from Example 1 is that the beating system B is 2500mL 2-MeTHF, and the flow rates of the beating pump A, the beating pump B and the beating pump C are respectively 2.82g/min; 13.01g/min; 3.27g/ min.
  • Example 1 The method of Example 1 was used to determine the yield of MNU, the yield of diazomethane, and the moisture content in the foregoing examples. The measurement results are shown in Table 1.
  • the above-mentioned preparation process of this application uses safe and non-toxic N-methylurea as a raw material, uses full continuous reaction and post-treatment to obtain the 2-methyltetrahydrofuran solution of diazomethane precursor MNU, and then directly uses full continuous reaction and post-treatment.
  • the treatment obtains an anhydrous diazomethane solution, in which the freezing process is used to remove water, avoiding the use of expensive semi-permeable membranes or liquid-liquid separators. Therefore, the preparation process is more than the existing batch diazomethane preparation process. Safe and controllable; compared with the existing continuous diazomethane preparation process, the cost is lower.

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Abstract

本发明提供了一种重氮甲烷的制备工艺。该制备工艺包括：步骤S1，使N-甲基脲为原料在连续反应器中连续制备含N-甲基-N-亚硝基脲的第一产物体系；步骤S2，对第一产物体系进行连续萃取、反萃，得到N-甲基-N-亚硝基脲溶液；步骤S3，使N-甲基-N-亚硝基脲溶液和碱溶液在连续反应器中进行连续反应，得到含有重氮甲烷的第二产物体系；以及步骤S4，对第二产物体系进行连续分液、冷冻除水，得到重氮甲烷。采用N-甲基脲为原料，使用全连续反应及后处理得到MNU的2-甲基四氢呋喃溶液，然后直接再使用全连续反应及后处理得到无水重氮甲烷溶液，采用冷冻工艺除水，避免了采用价格昂贵的半透膜或液液分离器，因此成本更加低廉。

Description

重氮甲烷的制备工艺 技术领域
本发明涉及重氮甲烷制备领域，具体而言，涉及一种重氮甲烷的制备工艺。
背景技术
重氮甲烷是一种有强刺激性气味黄色气体，溶于乙醇和乙醚，受热、遇火、摩擦、撞击会导致爆炸。其性质非常活泼，能够发生多种类型的反应，是有机合成中重要试剂，主要用于羧基、酚羟基、烯醇等的甲基化反应、制备重氮酮中用于酮和羧酸的同系化反应、1,3偶极环加成反应等。并且，因为其分子量较低，重氮甲烷参与的反应具有较好的原子效率并且氮气是反应后的唯一副产物。
但是由于其致癌性和毒性较强，并且极易爆炸，导致重氮甲烷的制备和控制在工业生产中非常困难。大多数重氮甲烷应用的规模都处在实验室水平。
重氮甲烷的合成路线主要有以下三条：
Figure PCTCN2019087761-appb-000001
这三条路线均是由N-甲基-N-亚硝基类前体化合物和强碱反应生成重氮甲烷。考虑到此类化合物的可获得性和保存期限，一般使用Diazald，MNU和MNNU这三个化合物作为前体来进行重氮甲烷的制备。但由于MNNU的毒性、刺激性、易致癌和至突变性为三个前体化合物中最强，目前通常采用Diazald和MNU进行重氮甲烷的制备。批次制备的重氮甲烷为防止浓度过高发生爆炸，需要经过氮气稀释或通入乙醚中稀释成溶液再使用。
Aerojet-General Corporation(现AMPAC Fine Chemicals)是最早开展重氮甲烷大规模生产应用的公司，其拥有连续化制备重氮甲烷(US5854405B2)和批次制备重氮甲烷(EP0916649)的专利。其连续化路线使用无毒的N-甲基脲做起始原料和亚硝酸钠/盐酸体系进行连续反应制备出重氮甲烷前体MNU的乙醚溶液，然后和碱的水溶液反应生成重氮甲烷并溶解在有机溶剂中。虽然其MNU的制备为连续反应，但其重氮甲烷的制备实际上是使用三个反应釜(3000L)进行的制备，实质上还是批次反应。此种方式制备出的重氮甲烷可能在分液过程中会引入少量的水份，导致无法用于对水份敏感的后续反应。
为得到干燥的重氮甲烷气体，Phoenix Chemicals Ltd.研发了一种中试规模制备使用Diazald作为前体的制备重氮甲烷气体的工艺(Org.Process Res.Dev.2002,6,884.)。该装置可年产60吨的重氮甲烷。
我公司也曾研发了使用Diazald作为前体化合物连续制备重氮甲烷气体的工艺并应用于公斤级生产中(CN101844063B)。
以上三个实例是目前重氮甲烷进行工业化应用的实例，由于重氮甲烷批次大规模制备的危险性，其连续化合成技术的研发也受到了广泛的关注。
Rossi E.等人报道了使用特殊的心形盘管以NMU为原料制备重氮甲烷溶液，不经分离碱水相直接通入反应体系进行羧酸的甲酯化。但该方法仅适用于对水不敏感的反应体系(Organic Process Research&Development,2017,16(5):1146–1149.)。Carlson E.等人报道了使用反应釜以Diazald为原料制备重氮甲烷气体，直接通入烯烃底物溶液进行环加成反应。Maurya R.A.等人报道了使用具有聚二甲基硅氧烷(PMDS)半透膜的双通道盘管反应器以Diazald为原料来制备并分离重氮甲烷气体进行反应(Synthetic Communications,2016,46(1):55-62.)。
Mastronardi F等人报道了使用AF-2400材质作为半透膜的管中管(tube in tube)以Diazald为原料进行重氮甲烷连续制备和反应的工艺(Organic Letters,2013,15(21):5590-5593.)。Dallinger D.等人同样也使用AF-2400材质作为半透膜的瓶中管(tube in flask)以Diazald为原料进行重氮甲烷连续制备和反应(Journal of Organic Chemistry,2016,81(14):5814-5823.)。Lehmann H.等人使用PFA盘管和具有半透膜结构的液液分离器以N-甲基脲为原料，实现了重氮甲烷前体MNU和重氮甲烷的两步全连续反应(Green Chemistry,2016,19(6),1449.)。
由此可见，现有技术中制备重氮甲烷的工艺主要存在以下问题：
(1)批次制备放大生产时由于重氮甲烷自身的毒性和易爆性，安全风险非常大，目前几乎无批次制备重氮甲烷应用于工业生产中。
(2)连续制备需要使用昂贵的半透膜或者液液分离器进行重氮甲烷和水相的分离以便进行对水份敏感的后续反应，导致设备投资大，生产成本较高。
发明内容
本发明的主要目的在于提供一种重氮甲烷的制备工艺，以解决现有技术中的连续工艺制备重氮甲烷设备成本高的问题。
为了实现上述目的，根据本发明的一个方面，提供了一种重氮甲烷的制备工艺，该制备工艺包括：步骤S1，使N-甲基脲为原料在连续反应器中连续制备含N-甲基-N-亚硝基脲的第一产物体系；步骤S2，对第一产物体系进行连续萃取、反萃，得到N-甲基-N-亚硝基脲溶液；步骤S3，使N-甲基-N-亚硝基脲溶液和碱溶液在连续反应器中进行连续反应，得到含有重氮甲烷的第二产物体系；以及步骤S4，对第二产物体系进行连续分液、冷冻除水，得到重氮甲烷。
进一步地，上述步骤S1包括：将酸、溶剂、亚硝酸钠和N-甲基脲连续送入连续反应器中进行反应以制备第一产物体系。
进一步地，上述酸为选自盐酸、硫酸、硝酸、磷酸、甲酸、醋酸、对甲苯磺酸和甲磺酸中的任意一种，溶剂包括水和有机溶剂，有机溶剂选自氯仿、二氯甲烷、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、苯、甲苯和二甲苯中的任意一种或多种。
进一步地，上述步骤S1的反应温度为0～120℃，优选为10～30℃，优选N-甲基脲、亚硝酸钠和酸的摩尔比为1：1.5～2.5：1～2，优选溶剂中水和有机溶剂的体积比为1:3～5；优选步骤S1的保留时间为5～30min。
进一步地，上述连续反应器为连续盘管反应器。
进一步地，上述步骤S2包括：将第一产物体系连续送入第一萃取柱利用萃取剂进行萃取，得到萃取液；将萃取液连续送入第二萃取柱利用碱性反萃溶液进行反萃，得到N-甲基-N-亚硝基脲溶液，其中，萃取剂选自氯仿、二氯甲烷、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、苯、甲苯和二甲苯中的任意一种或多种，碱性反萃溶液选自三乙胺、二异丙基乙基胺、叔丁铵、1,4-二氮杂二环、1,8-二氮杂二环十一碳-7-烯、KOH、NaOH、K 2CO 3、Na 2CO 3、NaHCO 3、Cs 2CO 3、KHCO 3、乙酸钠和乙酸钾中的任意一种的水溶液，优选反萃过程中萃取体系的pH值为5～7。
进一步地，上述步骤S3的碱液为氢氧化钾溶液、氢氧化钠溶液、氢氧化锂溶液、碳酸钾溶液、碳酸钠溶液、碳酸氢钾溶液或碳酸氢钠溶液。
进一步地，上述步骤S3的反应温度为-20～100℃，优选为0～30℃，优选步骤S3的保留时间为30～150秒。
进一步地，上述步骤S4包括：将第二产物体系连续送入第三萃取柱进行分液处理，得到上层溢流有机溶液；对上层溢流有机溶液进行冷冻处理使其中的水凝固，得到重氮甲烷的有机溶液。
进一步地，上述冷冻处理包括：将上层溢流有机溶液连续送入连续反应釜中并在搅拌条件下降温至-30～-50℃下保持40～80min，重氮甲烷的有机溶液从连续反应釜的上层溢流而出，优选连续反应釜的溢流口设置有滤网。
应用本发明的技术方案，采用安全无毒的N-甲基脲为原料，使用全连续反应及后处理得到重氮甲烷前体MNU的2-甲基四氢呋喃溶液，然后直接再使用全连续反应及后处理得到无水重氮甲烷溶液，其中采用冷冻工艺除水，避免了采用价格昂贵的半透膜或液液分离器，因此该制备工艺与现有的批次重氮甲烷制备工艺相比，更加安全可控；与现有的连续重氮甲烷制备工艺相比，成本更加低廉。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。
如本申请背景技术所分析的，现有技术中连续制备重氮甲烷需要使用昂贵的半透膜或者液液分离器进行重氮甲烷和水相的分离以便进行对水份敏感的后续反应，导致设备投资大，生产成本较高，为了解决该问题，本申请提供了一种重氮甲烷的制备工艺。在本申请一种典型的实施方式中，该一种重氮甲烷的制备工艺包括：步骤S1，使N-甲基脲为原料在连续反应器中连续制备含N-甲基-N-亚硝基脲的第一产物体系；步骤S2，对第一产物体系进行连续萃取、反萃，得到N-甲基-N-亚硝基脲溶液；步骤S3，使N-甲基-N-亚硝基脲溶液和碱溶液在连续反应器中进行连续反应，得到含有重氮甲烷的第二产物体系；以及步骤S4，对第二产物体系进行连续分液、冷冻除水，得到重氮甲烷。
本申请的上述制备工艺采用安全无毒的N-甲基脲为原料，使用全连续反应及后处理得到重氮甲烷前体MNU的2-甲基四氢呋喃溶液，然后直接再使用全连续反应及后处理得到无水重氮甲烷溶液，其中采用冷冻工艺除水，避免了采用价格昂贵的半透膜或液液分离器，因此该制备工艺与现有的批次重氮甲烷制备工艺相比，更加安全可控；与现有的连续重氮甲烷制备工艺相比，成本更加低廉。具体地：
本申请的制备工艺不使用昂贵的除水膜或设备，能够以较低的成本得到含水量极低的重氮甲烷溶液，可直接与对水敏感的物料或体系反应；
使用价格低廉，无毒性的N-甲基脲做起始物料，连续制备得到的MNU无须分离纯化即可直接进行第二步骤的连续重氮甲烷的制备，降低了接触易致癌、易过敏物料MNU的风险，并且相对于大多数反应使用Diazald作为重氮甲烷前体的反应来说，成本更低，三废更少；
连续化设备特有的属性(反应体系小，热交换速度远高于批次设备)使反应条件即便更加剧烈，但安全性也是高于批次反应；
连续化工艺特有属性，生产上几乎没有放大效应，适合工业化重现小试收率。
本申请的利用N-甲基脲为原料制备MNU的反应机理与现有技术相同，优选上述步骤S1包括：将酸、溶剂、亚硝酸钠和N-甲基脲连续送入连续反应器中进行反应以制备第一产物体系。上述的N-甲基脲事先溶于水和酸(以水溶液的方式添加)中然后将酸、水和N-甲基脲的 混合溶液连续送入，亚硝酸钠也是以水溶液的状态连续送入，上述溶剂包含了用于溶解亚硝酸钠和N-甲基脲的溶剂。
用于本申请的酸、溶剂可以选用现有技术中以N-甲基脲为原料的常用酸和溶剂，为了更好地适应连续反应，优选上述酸为选自盐酸、硫酸、硝酸、磷酸、甲酸、醋酸、对甲苯磺酸和甲磺酸中的任意一种，溶剂包括水和有机溶剂，该有机溶剂选自氯仿、二氯甲烷、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、苯、甲苯和二甲苯中的任意一种或多种。溶剂中同时包含水和有机溶剂，二者形成分层效果，有利于产物从反应体系中分离出来。
上述制备MNU的反应温度可以参考现有技术，优选上述步骤S1的反应温度为0～120℃，进一步优选为10～30℃，以保证反应的稳定性。另外，为了提高转化率和进一步保证安全性，优选N-甲基脲、亚硝酸钠和酸的摩尔比为1：1.5～2.5：1～2，通过调节各物料的原料配比或泵速来实现上述摩尔比；优选溶剂中水和有机溶剂的体积比为1:3～5，以提高产物分离效率。另外，在提高反应效率的同时为了提高物料的转化率，优选上述步骤S1的保留时间为5～30min。
上述制备工艺中所采用的连续反应器可以采用现有技术中常用的管式连续反应器或釜式连续反应器，其中不需要配置半透膜，优选上述连续反应器为连续盘管反应器。
在本申请一种实施例中，上述步骤S2包括：将第一产物体系连续送入第一萃取柱利用萃取剂进行萃取，得到萃取液；将萃取液连续送入第二萃取柱利用碱性反萃溶液进行反萃，得到N-甲基-N-亚硝基脲溶液，其中，萃取剂选自氯仿、二氯甲烷、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、苯、甲苯和二甲苯中的任意一种或多种，碱性反萃溶液选自三乙胺、二异丙基乙基胺、叔丁铵、1,4-二氮杂二环(DABCO)、1,8-二氮杂二环十一碳-7-烯(DBU)、KOH、NaOH、K 2CO 3、Na 2CO 3、NaHCO 3、Cs 2CO 3、KHCO 3、乙酸钠和乙酸钾中的任意一种的水溶液，优选反萃过程中萃取体系的pH值为5～7。通过第一萃取柱对第一产物体系实现连续萃取分离，利用其连续性实现了工业化生产，不需要使用价格昂贵的液液分离器。在萃取分离之后，利用碱液进行反萃取，实现了对MNU的高效回收。
本申请由MNU制备重氮甲烷的原理也是和现有技术相同，优选上述步骤S3的碱液为氢氧化钾溶液、氢氧化钠溶液、氢氧化锂溶液、碳酸钾溶液、碳酸钠溶液、碳酸氢钾溶液或碳酸氢钠溶液。
上述步骤S3的反应温度也可以参考现有技术，比如上述步骤S3的反应温度为-20～100℃，优选为0～30℃，为了提高反应效率，优选步骤S3的保留时间为30～150秒。
在完成上述反应后，需要分离出其中的水分以适用于水分敏感的反应，优选上述步骤S4包括：将第二产物体系连续送入第三萃取柱进行分液处理，得到上层溢流有机溶液；对上层溢流有机溶液进行冷冻处理使其中的水凝固，得到重氮甲烷的有机溶液。在利用萃取柱进行分液处理后，将第二产物体系中大部分水分，然后利用水和重氮甲烷的凝固点不同进行冷冻处理使其中的水凝固，进而得到重氮甲烷的有机溶液。
在本申请一种实施例中，上述冷冻处理包括：将上层溢流有机溶液连续送入连续反应釜中并在搅拌条件下降温至-30～-50℃下保持40～80min，重氮甲烷的有机溶液从连续反应釜的上层溢流而出，优选连续反应釜的溢流口设置有滤网。在搅拌条件下进行冷冻，有利于水分和有机物的充分分离；另外由于上层溢流有机溶液的连续送入，因此冷冻处理后重氮甲烷的有机溶液可以自行由连续反应釜中溢流而出。为了避免溢流中夹带冰屑，在溢流口设置滤网以对冰屑进行拦截，进而提高除水效率。
以下将结合实施例和对比例，进一步说明本申请的有益效果。
Figure PCTCN2019087761-appb-000002
实施例1
配置打料体系A：将100g N-甲基脲加入到打料瓶A中，加入100ml水，缓慢加入266g 37％盐酸，搅拌至溶解。
配置打料体系B：将1750mL 2-Me-THF加入到打料瓶B中。
配置打料体系C：将140g亚硝酸钠加入到打料瓶C中，加入400ml水，搅拌至溶解。
配置打料体系D：将600mL 2-Me-THF加入到打料瓶D中。
配置打料体系E：将碳酸氢钾加入到打料瓶E中，加入654ml水，搅拌至溶解。
设备准备：向第一萃取柱中加入约500ml自来水，至柱高一半处；向第二萃取柱中加入约200ml碳酸氢钾水溶液，至柱高的1/4处。
将200ml第一四氟盘管反应器中打满自来水至23～27℃(目标温度25℃)，温度稳定10min后，可进行打料。
打料：将打料瓶A、打料瓶B和打料瓶C与200ml的第一四氟盘管反应器的四通相连且各自的连接管路上设置打料泵A、打料泵B和打料泵C，开启打料泵A、打料泵B和打料泵C，并控制各自流速分别为3.57g/min；11.42g/min；4.11g/min，三股物料在四通处汇合进入第一四氟盘管反应器进行反应，保留时间10min。
萃取：第一四氟盘管反应器与第一萃取柱上端相连，将打料瓶D和第一萃取柱下端相连，并且在连接管路上设置打料泵D，启动打料泵D将600mL 2-Me-THF由第一萃取柱下端泵入进行连续反萃，打料泵D流速为：3.95g/min，第一萃取柱的下端放出水相，上端的有机相进入第二萃取柱，萃取过程中控制第一萃取柱的有效持液量～400ml，理论RT＝30min。
反萃：第一萃取柱上端出来的有机相由第二萃取柱的下端泵入，将打料瓶E和第二萃取柱的上端相连并在连接管路上设置打料泵E，启动打料泵E将碳酸氢钾溶液(163g碳酸氢钾 +654mL水)连续泵入第二萃取柱进行连续调pH至5～7之间，打料泵E的流速为：4.0ml/min，下端放出水相。反萃过程中控制第二萃取柱的持液量～400ml，理论RT＝20min。
收料：接受第二萃取柱的有机相，并测定QNMR的收率为81％和pH值为6.4，其中测定方法为取样使用氘代氯仿溶解后，加入均三甲苯做内标物，然后进行核磁分析。
配置打料体系F：将上述得到的有机相N-亚硝基-N-甲基脲的2-甲基四氢呋喃溶液加入到打料瓶F中。
配置打料体系G：将氢氧化钾溶于水中，搅拌至固体溶解，配制成15％wt的溶液。
设备准备：向第三萃取柱中加入自来水，至柱高的一半。
向20mL第二四氟盘管反应器中打入部分氢氧化钾溶液，直至两股料汇聚处充满氢氧化钾溶液，将第二四氟盘管反应器置于冰水浴中，控温0～5℃。
打料：将打料瓶F、打料瓶G与200ml的第二四氟盘管反应器的三通相连且各自的连接管路上设置打料泵F、打料泵G，开启打料泵F、打料泵G，且控制自流速分别为14.75g/min；5.25g/min，两股物料在三通处汇合，然后进入20ml第二四氟盘管反应器进行反应，保留时间1min。
分液与除水：第二四氟盘管反应器与第三萃取柱上端相连使第二四氟盘管反应器的第二产物体系进行第二萃取柱中分液，其中上层黄色有机相溢流进入-40℃的CSTR中搅拌1h冷冻除水，水在低温下凝固成冰从而与体系分离，上层重氮甲烷的有机溶液经带有滤网的溢流口溢流，其中采用核磁验证所得产物为重氮甲烷，采用卡尔费休(KF)水份测定仪检测水份，使用过量苯甲酸衍生后测定HPLC外标，收率57％。所得到的重氮甲烷溶液可直接溢流入混酐溶液进行重氮酮的制备。
实施例2
与实施例1不同之处在于，分液与除水过程中上层黄色有机相溢流进入-50℃的CSTR中搅拌40min冷冻除水，水在低温下凝固成冰从而与体系分离，上层重氮甲烷的有机溶液经带有滤网的溢流口溢流。
实施例3
与实施例1不同之处在于，分液与除水过程中上层黄色有机相溢流进入-30℃的CSTR中搅拌80min冷冻除水，水在低温下凝固成冰从而与体系分离，上层重氮甲烷的有机溶液经带有滤网的溢流口溢流。
实施例4
与实施例1不同之处在于，打料瓶A中的酸为162g醋酸，打料泵A打料速度2.77g/min。
实施例5
与实施例1不同之处在于，打料瓶A中的酸为采用693g水溶解的464g对甲苯磺酸得到的酸溶液，打料泵A打料速度9.63g/min。
实施例6
与实施例1不同之处在于，打料瓶B中为1750mL的二氯甲烷，打料瓶D中的溶剂为388mL二氯甲烷。
实施例7
与实施例1不同之处在于，打料瓶B中为甲苯，打料瓶D中的溶剂为甲苯。
实施例8
与实施例1不同之处在于，打料瓶B中为1750mL的乙酸乙酯，打料瓶D中的溶剂为573ml的乙酸乙酯。
实施例9
与实施例1不同之处在于，第一四氟盘管反应器的温度为50℃左右。
实施例10
与实施例1不同之处在于，第一四氟盘管反应器的温度为120℃左右。
实施例11
与实施例1不同之处在于，第一四氟盘管反应器的温度为10℃左右。
实施例12
与实施例1不同之处在于，第一四氟盘管反应器的温度为0℃左右。
实施例13
与实施例1不同之处在于，在第一四氟盘管反应器保留时间为5min。
实施例14
与实施例1不同之处在于，在第一四氟盘管反应器保留时间为30min。
实施例15
与实施例1不同之处在于，打料泵E中的碱性溶液为三乙胺。
实施例16
与实施例1不同之处在于，打料泵E中的碱性溶液为DBU。
实施例17
与实施例1不同之处在于，打料泵E中的碱性溶液为氢氧化钾。
实施例18
与实施例1不同之处在于，打料泵E中的碱性溶液为碳酸钾。
实施例19
与实施例1不同之处在于，第二四氟盘管反应器的温度为-20℃左右，保留时间为150秒。
实施例20
与实施例1不同之处在于，第二四氟盘管反应器的温度为30℃左右。
实施例21
与实施例1不同之处在于，第二四氟盘管反应器的温度为100℃左右，保留时间为30秒。
实施例22
与实施例1不同之处在于，第二四氟盘管反应器的温度为-10℃左右，保留时间为180秒。
实施例23
与实施例1不同之处在于，打料瓶A中加入了200g 37％的盐酸。
实施例24
与实施例1不同之处在于，打料瓶A中加入了333g 37％的盐酸。
实施例25
与实施例1不同之处在于，打料瓶A中加入了380g 37％的盐酸。
实施例26
与实施例1不同之处在于，打料瓶C中的亚硝酸钠用量93.1g，水用量仍为400g，打料泵C的打料速度为3.82g/min。
实施例27
与实施例1不同之处在于，打料瓶C中的亚硝酸钠用量186.3g，水用量仍为400g，打料泵C的打料速度为4.38g/min。
实施例28
与实施例1不同之处在于，打料体系B为1500mL 2-MeTHF，打料泵A、打料泵B和打料泵C各自流速分别为3.88g/min；10.73g/min；4.49g/min。
实施例29
与实施例1不同之处在于，打料体系B为2500mL 2-MeTHF，打料泵A、打料泵B和打料泵C各自流速分别为2.82g/min；13.01g/min；3.27g/min。
采用实施例1的方法，对上述各实施例中的MNU的收率、重氮甲烷的收率以及其中的含水率进行测定，测定结果见表1。
表1
  MNU收率(％) 重氮甲烷收率(％) 含水率(ppm)
实施例1 81 57 453
实施例2 81 57 501
实施例3 81 57 700
实施例4 65 54 429
实施例5 42 55 490
实施例6 75 58 460
实施例7 55 30 431
实施例8 72 45 476
实施例9 60 55 402
实施例10 37 49 458
实施例11 79 56 442
实施例12 77 55 435
实施例13 62 58 481
实施例14 80 54 488
实施例15 80 21 416
实施例16 81 44 493
实施例17 79 56 443
实施例18 81 41 402
实施例19 76 36 451
实施例20 80 25 480
实施例21 81 14 403
实施例22 79 39 437
实施例23 76 55 454
实施例24 80 56 453
实施例25 79 50 456
实施例26 60 50 452
实施例27 80 55 452
实施例28 62 57 434
实施例29 80 56 410
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：
本申请的上述制备工艺采用安全无毒的N-甲基脲为原料，使用全连续反应及后处理得到重氮甲烷前体MNU的2-甲基四氢呋喃溶液，然后直接再使用全连续反应及后处理得到无水重氮甲烷溶液，其中采用冷冻工艺除水，避免了采用价格昂贵的半透膜或液液分离器，因此该 制备工艺与现有的批次重氮甲烷制备工艺相比，更加安全可控；与现有的连续重氮甲烷制备工艺相比，成本更加低廉。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种重氮甲烷的制备工艺，其特征在于，所述制备工艺包括：
    步骤S1，使N-甲基脲为原料在连续反应器中连续制备含N-甲基-N-亚硝基脲的第一产物体系；
    步骤S2，对所述第一产物体系进行连续萃取、反萃，得到N-甲基-N-亚硝基脲溶液；
    步骤S3，使所述N-甲基-N-亚硝基脲溶液和碱溶液在连续反应器中进行连续反应，得到含有重氮甲烷的第二产物体系；以及
    步骤S4，对所述第二产物体系进行连续分液、冷冻除水，得到所述重氮甲烷。
  2. 根据权利要求1所述的制备工艺，其特征在于，所述步骤S1包括：
    将酸、溶剂、亚硝酸钠和所述N-甲基脲连续送入所述连续反应器中进行反应以制备所述第一产物体系。
  3. 根据权利要求2所述的制备工艺，其特征在于，所述酸为选自盐酸、硫酸、硝酸、磷酸、甲酸、醋酸、对甲苯磺酸和甲磺酸中的任意一种，所述溶剂包括水和有机溶剂，所述有机溶剂选自氯仿、二氯甲烷、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、苯、甲苯和二甲苯中的任意一种或多种。
  4. 根据权利要求3所述的制备工艺，其特征在于，所述步骤S1的反应温度为0～120℃，优选为10～30℃，优选所述N-甲基脲、所述亚硝酸钠和所述酸的摩尔比为1：1.5～2.5：1～2，优选所述溶剂中所述水和所述有机溶剂的体积比为1:3～5；优选所述步骤S1的保留时间为5～30min。
  5. 根据权利要求1所述的制备工艺，其特征在于，所述连续反应器为连续盘管反应器。
  6. 根据权利要求1所述的制备工艺，其特征在于，所述步骤S2包括：
    将所述第一产物体系连续送入第一萃取柱利用萃取剂进行萃取，得到萃取液；
    将所述萃取液连续送入第二萃取柱利用碱性反萃溶液进行反萃，得到所述N-甲基-N-亚硝基脲溶液，
    其中，所述萃取剂选自氯仿、二氯甲烷、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、苯、甲苯和二甲苯中的任意一种或多种，所述碱性反萃溶液选自三乙胺、二异丙基乙基胺、叔丁铵、1,4-二氮杂二环、1,8-二氮杂二环十一碳-7-烯、KOH、NaOH、K 2CO 3、Na 2CO 3、NaHCO 3、Cs 2CO 3、KHCO 3、乙酸钠和乙酸钾中的任意一种的水溶液，优选所述反萃过程中萃取体系的pH值为5～7。
  7. 根据权利要求1所述的制备工艺，其特征在于，所述步骤S3的碱液为氢氧化钾溶液、氢氧化钠溶液、氢氧化锂溶液、碳酸钾溶液、碳酸钠溶液、碳酸氢钾溶液或碳酸氢钠溶液。
  8. 根据权利要求1所述的制备工艺，其特征在于，所述步骤S3的反应温度为-20～100℃，优选为0～30℃，优选所述步骤S3的保留时间为30～150秒。
  9. 根据权利要求1所述的制备工艺，其特征在于，所述步骤S4包括：
    将所述第二产物体系连续送入第三萃取柱进行分液处理，得到上层溢流有机溶液；
    对所述上层溢流有机溶液进行冷冻处理使其中的水凝固，得到所述重氮甲烷的有机溶液。
  10. 根据权利要求9所述的制备工艺，其特征在于，所述冷冻处理包括：
    将所述上层溢流有机溶液连续送入连续反应釜中并在搅拌条件下降温至-30～-50℃下保持40～80min，所述重氮甲烷的有机溶液从所述连续反应釜的上层溢流而出，优选所述连续反应釜的溢流口设置有滤网。
PCT/CN2019/087761 2019-05-21 2019-05-21 重氮甲烷的制备工艺 WO2020232625A1 (zh)

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