CN107382780A - The preparation method of amides compound - Google Patents
The preparation method of amides compound Download PDFInfo
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- CN107382780A CN107382780A CN201710682214.5A CN201710682214A CN107382780A CN 107382780 A CN107382780 A CN 107382780A CN 201710682214 A CN201710682214 A CN 201710682214A CN 107382780 A CN107382780 A CN 107382780A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- -1 amides compound Chemical class 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims abstract description 27
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 9
- 125000001424 substituent group Chemical group 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract 3
- 238000006243 chemical reaction Methods 0.000 claims description 103
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 66
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 60
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 31
- 239000000047 product Substances 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- 239000006227 byproduct Substances 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 239000000243 solution Substances 0.000 description 101
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 20
- 239000010410 layer Substances 0.000 description 17
- 230000035484 reaction time Effects 0.000 description 16
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 12
- 239000002994 raw material Substances 0.000 description 12
- 238000013517 stratification Methods 0.000 description 11
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 238000009835 boiling Methods 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000010792 warming Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- AESUECJLDNUSMZ-UHFFFAOYSA-N [Li]CCCC.C1CCCCC1 Chemical compound [Li]CCCC.C1CCCCC1 AESUECJLDNUSMZ-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000010924 continuous production Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920001774 Perfluoroether Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000006182 dimethyl benzyl group Chemical group 0.000 description 1
- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 description 1
- 229960001826 dimethylphthalate Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 229940058401 polytetrafluoroethylene Drugs 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a kind of preparation method of amides compound.Preparation method is as follows：The solution A of the I containing compound and the solution B containing n-BuLi, after being reacted at 80~10 DEG C, then the solution C with the II containing compound, reacted at 80~10 DEG C, you can；Compound I concentration is 5wt%~40wt% in solution A, and compound II concentration is 5wt%~50wt% in solution C, and the flow velocity of solution A and solution C is respectively 0.1~25L/s, 0.1~1.5L/s, and n is 0~5 integer, and R1It is each independently C1~C6Alkyl, C1~C6Alkoxy or " substituted or unsubstituted C6~C10Aryl "；R2For hydrogen, C1~C6Alkyl or " substituted or unsubstituted phenyl ", the substituent of substituted phenyl is C1~C6Alkyl or C1~C6Alkoxy；R3For C1~C6Alkyl or " methyl of one or more phenyl substitutions ".
Description
Technical field
The present invention relates to a kind of preparation method of amides compound.
Background technology
In organic synthesis, acid amides be the very extensive compound of a kind of application (J.Biotechol.2016,235,32；
Curr.Pharma.Des.2016,22,5029；Org.Biomol.Chem.2016,14,10134；
Eur.J.Med.Chem.2015,91,15)。
In the synthesis of amides compound, the acylation of aminated compounds is a kind of most directly can effectively to obtain such
Method (the Org.ProcessRes.Dev.2016,20,140 of compound；Photochem.Rev.2016,15,729；
Mol.Bio.Syst.2015,11,338；Sci.Synth.Biocatal.Org.Synth.2015,1,329).
In the acylation reaction of aminated compounds, n-BuLi as addition alkali reaction have the short time, efficiency high,
The good remarkable advantage of yield (Chem.Rev.2016,116,12029)；But because n-BuLi reactivity is high, it is participated in
Reaction, system can quick release go out substantial amounts of heat, cause to react uncontrollable, therefore, such reaction generally in very low temperature
Carried out under degree (- 80~-50 DEG C), reaction condition is harsh；In addition, during n-BuLi is added dropwise, if leaking, easily draw
Play the security incidents such as fire；All it is at low ambient temperatures, n-BuLi to be slowly added dropwise, but this causes in general industry production
Reaction time extends, and the industrialized production cycle is elongated, and production efficiency is low.Therefore, a kind of n-BuLi is developed to participate in, react bar
Part is gentle, security is good, production efficiency is high, easily operated amine is acylated the problem of production technology is this area urgent need to resolve.
The content of the invention
The technical problems to be solved by the invention are pacified to overcome in amides compound preparation process in the prior art
The defects of full property is poor, severe reaction conditions, reaction time length, low production efficiency, and provide that a kind of security is good, reaction condition temperature
With the preparation method of high, the easily operated amides compound of, production efficiency.The preparation method is entered by the kinetic energy of fluid in itself
Row mass-and heat-transfer, without mechanical agitation, without reaction channel outside continuation course of reaction, you can acquisition is higher than traditional reactor
Yield.Compared with traditional technique, the preparation method, it can accurately control reaction condition, cause reaction raw materials extremely short
Complete to convert in time and reduce the formation of accessory substance, the fluctuation of temperature and concentration can be avoided and then cause course of reaction peace
Entirely, continuous production can be realized.
The present invention solves above-mentioned technical problem by the following technical programs：
The present invention provides a kind of preparation method of amides compound, and the preparation method is carried out in tubular reactor,
The tubular reactor includes the first reaction zone and second reaction zone；
The preparation method comprises the following steps：
(1) the organic solution A and the organic solution B containing n-BuLi of the I containing compound, at -80~10 DEG C, described
One reaction zone reacts, and obtains reaction solution；
(2) the organic solution C of the reaction solution and the II containing compound, at -80~10 DEG C, enters in the second reaction zone
Row reaction, you can；
The net reaction that the compound I and the compound II react is as follows：
Wherein, the mass fraction of compound I described in the organic solution A is 5%~40%, the organic solution A's
Flow velocity is 0.1~25L/s；Compound II mass fraction described in the organic solution C is 5%~50%, described organic molten
Liquid C flow is 0.1~1.5L/s；The number of substituent on the phenyl ring of the compound I is n, n 0,1,2,3,4 or 5,
And R1It is each independently C1~C6Alkyl, C1~C6Alkoxy or " substituted or unsubstituted C6~C10Aryl "；R2For hydrogen, C1~
C6Alkyl or " substituted or unsubstituted phenyl ", the substituent of the substituted phenyl is C1~C6Alkyl or C1~C6Alkoxy；
R3For C1~C6Alkyl or " methyl of one or more phenyl substitutions ".
In the present invention, the diameter of the tubular reactor disclosure satisfy that foregoing flow velocity, such as can be 1~30mm, institute
The material for stating tubular reactor is preferably stainless steel or tetrafluoroethylene-perfluoro alkoxy vinyl ethers copolymer (English full name
Polytetrafluoro ethylene, abridge PFA).
In the present invention, it is anti-that the tubular reactor generally comprises the first pipeline, second pipe, the 3rd pipeline, the first tubular type
Device and the second tubular reactor are answered, the head end of first pipeline, the second pipe and first tubular reactor is through this
The conventional use of threeway in field is connected, the tail end of first tubular reactor, second tubular reactor head end with
3rd pipeline is connected through threeway commonly used in the art.
In the present invention, first reaction zone refers to the inner passage that the outer wall of first tubular reactor is formed,
It is used to carry out the reaction in abovementioned steps (1), and the second reaction zone refers to the outer wall shape of second tubular reactor
Into inner passage, it is used to carry out the reaction in abovementioned steps (2).
In use, the organic solution A of the I containing compound through the outflow of the first pipeline contains with what is flowed out through second pipe
Head ends of the organic solution B of n-BuLi through the first tubular reactor enters the first reaction zone, after reaction terminates, through the first tubular type
The organic solution C of the reaction solution and the II containing compound through the outflow of the 3rd pipeline of the tail end outflow of reactor, through the described second pipe
The head end of formula reactor, while enter second reaction zone, reacted.
In the present invention, the organic solvent in the organic solution A, organic solution B or organic solution C can be that this area is conventional
The organic solvent of use, such as can be ether solvent and/or alkane solvents.
Wherein, the ether solvent is preferably methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofurans and Isosorbide-5-Nitrae-two
One or more in the ring of oxygen six.
Wherein, the alkane solvents are preferably one kind in petroleum ether, pentane, n-hexane, hexamethylene and heptane
It is or a variety of.
In step (1), the temperature of the reaction is preferably -10~10 DEG C, is more preferably 0~5 DEG C.
In step (1), the pressure of the reaction is preferably 0.5~2MPa, is more preferably 0.5~1.5MPa, such as can
For 1.0MPa.
In step (1), the residence time of the reaction is preferably 10~100s, such as can be 20s, 30s, 45s.
In step (1), compound I mass fraction described in the organic solution A is preferably 11%~16%, such as
Can be 12%.
In step (1), the flow velocity of the organic solution A is preferably 2~5.5L/s, such as can be 2.12L/s, 2.54L/
s、5.31L/s。
In step (1), the flow of the organic solution A is preferably 5~100mL/min, is more preferably 10~25mL/
Min, such as can be 12mL/min.
In step (1), the mass fraction of n-BuLi is preferably 15%~25% described in the organic solution B, more
It is 20% goodly.
In step (1), the flow velocity of the organic solution B is preferably 1~3L/s, for example, can be 1.27L/s, 1.70L/s,
2.55L/s。
In step (1), the flow of the organic solution B is preferably 1~100mL/min, is more preferably 6~12mL/
Min, such as can be 8mL/min.
In step (1), the mol ratio of the compound I and the n-BuLi is preferably 1:1~1:10.
In step (1), the organic solution A and organic solution B flow-rate ratio is preferably 10:1~1:10.
In step (1), the organic solution A and organic solution B velocity ratio is preferably 10:1~1:10.
In step (2), the temperature of the reaction is preferably -10~10 DEG C, is more preferably 0~5 DEG C.
In step (2), the pressure of the reaction is preferably 0.5~2MPa, is more preferably 0.5~1.5MPa, such as can
For 1.0MPa.
In step (2), the residence time of the reaction is preferably 10~100s, such as can be 20s, 40s, 45s.
In step (2), compound II mass fraction is preferably 30%~40% described in the organic solution C, example
Such as can be 35%, 36%.
In step (2), the flow velocity of the organic solution C is preferably 0.4~0.7L/s, for example, can be 0.42L/s,
0.53L/s、0.64L/s。
In step (2), the flow of the organic solution C is preferably 0.6~5mL/min, is more preferably 2~3mL/min,
Such as can be 2.5mL/min.
In the present invention, it is preferred that the R1It is each independently one or more hydrogen, methyl, ethyl, n-propyl, isopropyl
Base, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group or phenyl.
In the present invention, the R2Preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary fourth
Base, phenyl, p-methylphenyl, o-tolyl, a tolyl, p-methoxyphenyl, guaiacyl or m-methoxyphenyl.
In the present invention, the R3Preferably methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group,
Benzyl or benzhydryl.
In the present invention, it is preferred that the R1For hydrogen, the R2For methyl, ethyl or phenyl, the R3For methyl, ethyl or
Benzyl.
In the present invention, after step (2) terminates, the post processing mode of products therefrom can be the post processing that this area routinely uses
Mode, it is preferred that after products therefrom is mixed with watery hydrochloric acid, concentration, heating, mix, be layered with toluene, obtain the first organic phase；
Again with watery hydrochloric acid, mix, layering, obtain Second Organic Phase；Cooling, crystallization, filtering, washing, drying, obtain product.
Wherein, the outlet temperature of the heating is preferably 65~80 DEG C；
Wherein, the outlet temperature of the cooling is preferably 0~5 DEG C；
Wherein, the washing preferably uses toluene.
In the present invention, since the described residence time refer to material particle entering tubular reactor, anti-to tubular type is left
Untill answering device, the residence time altogether in tubular reactor.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and it is each preferably to produce the present invention
Example.
Agents useful for same and raw material of the present invention are commercially available.
The positive effect of the present invention is：The present invention provides a kind of preparation method of amides compound, the preparation
Method, security is good, reaction condition is gentle, production efficiency is high, easily operated, and mass transfer biography is carried out by the kinetic energy of fluid in itself
Heat, without mechanical agitation, without reaction channel outside continuation course of reaction, you can obtain the yield higher than traditional reactor.
Compared with traditional process system, the process system, it can accurately control reaction condition, cause reaction raw materials in the extremely short time
It is interior to complete to convert and reduce the formation of accessory substance, the fluctuation of temperature and concentration can be avoided and then cause course of reaction safety,
Continuous production can be realized.
Brief description of the drawings
Fig. 1 is the process chart of the preparation method of amides compound of the present invention.
Fig. 2 is the HPLC chromatogram of the products obtained therefrom of embodiment 1.
Fig. 3 is the HPLC chromatogram of the products obtained therefrom of embodiment 2.
Fig. 4 is the HPLC chromatogram of the products obtained therefrom of embodiment 3.
Fig. 5 is the HPLC chromatogram of the products obtained therefrom of comparative example 1.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Apply among a scope.The experimental method of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification selects.
In following embodiments, the purity of products therefrom is HPLC purity, and testing conditions are as follows：
High performance liquid chromatograph：Agilent 1200 (LC chem workstations) or HPLC system suitable therewith；Chromatographic column：
5 μm or suitable therewith of Agilent XDB-C18,150 × 4.6mm；
Main agents and material：Acetonitrile (HPLC levels) water (Milli-Q) phosphoric acid (analysis level)
Chromatographic condition：Detection wavelength：210nm；Flow velocity：1.0mL/min；Column temperature：25℃；Sample size：5μl；Run time：
22min；Mobile phase A：0.1% phosphate aqueous solution；Mobile phase B：Acetonitrile.
Gradient elution program：
| Time/min | Mobile phase A/% | Mobile phase B/% |
| 0 | 90 | 10 |
| 12.0 | 20 | 80 |
| 17.0 | 20 | 80 |
| 17.1 | 90 | 10 |
| 22.0 | 90 | 10 |
Embodiment 1
Reaction equation is as follows：
Raw material is prepared：10.7g compound I-1 are weighed, the I-1 of compound containing 12wt% tetrahydrofuran solution is made into, is put in
In head tank 1；20% n-BuLi cyclohexane solution 34mL is weighed, is put in head tank 2；Dimethyl carbonate 13.4g is weighed, is matched somebody with somebody
Into the II-1 of compound containing 50wt% tetrahydrofuran solution, it is put in head tank 3.
Using the process chart described in Fig. 1, the wherein caliber of tubular reactor is 10mm, reaction pressure 1.0MPa,
As steps described below：The tetrahydrofuran solution of the I-1 containing compound in head tank 1 is entered into the first reaction zone by measuring pump 1, it is former
N-BuLi cyclohexane solution in batch can 2 enters the first reaction zone by measuring pump 2；Each measuring pump 1 and measuring pump 2 is set to control
Produced compounds I-1 tetrahydrofuran solution and n-BuLi cyclohexane solution flow is respectively 25mL/min and 12mL/min, right
The flow velocity answered is respectively 5.31L/s and 2.55L/s, sets heat exchange temperature as 0 DEG C, reaction time 20s；By head tank
The tetrahydrofuran solution containing dimethyl carbonate in 3 enters second reaction zone by measuring pump 3；Setting measuring pump 3 controls carbon containing
The tetrahydrofuran solution flow of dimethyl phthalate is 3.0mL/min, and corresponding flow velocity is 0.64L/s；Heat exchange temperature is set as 0
DEG C, with being reacted by the mixture in the first reaction zone, reaction time 20s；Reacted by second reaction zone
Afterwards, product continuous discharge enters in collecting tank 4.Watery hydrochloric acid is added, normal pressure concentration steams low boiling point solvent；65~80 are warming up to again
DEG C, toluene is added, stratification collects upper organic layer, and lower aqueous layer is given up；Dilute hydrochloric acid solution is added, stratification, is received
Collect upper organic layer, lower aqueous layer is given up；Crystallization cool to 0~5 DEG C, filtering, toluene washing, dries, obtains product.
After reaction product III-1 spectrogram compares with bibliography (J.Org.Chem.2008,73,1559) spectrogram, as a result
Unanimously, it is defined as N- methyl-N- methoxycarbonyl group aniline, yield 85.7%, through efficient liquid phase chromatographic analysis, purity 90.5%.
Embodiment 2
Reaction equation is：
Raw material is prepared：16.9g compound I-2 are weighed, are made into the I-2 of compound containing 11wt% Isosorbide-5-Nitrae-dioxane solution,
It is put in head tank 1；20% n-BuLi cyclohexane solution 40mL is weighed, is put in head tank 2；Weigh diethyl carbonate
18.0g, the II-2 of compound containing 35wt% Isosorbide-5-Nitrae-dioxane solution is made into, is put in head tank 3.
Using the process chart described in Fig. 1, the wherein caliber of tubular reactor is 10mm, reaction pressure 1.0MPa,
As steps described below：The 1,4- dioxane solutions of the I-2 containing compound in head tank 1 are entered into the first reaction by measuring pump 1
Area, the n-BuLi cyclohexane solution in head tank 2 pass through measuring pump 2 and enter the first reaction zone；Set each measuring pump 1 and metering
Pump 2 control compound I-2 1,4- dioxane solutions and n-BuLi cyclohexane solution flow be respectively 10mL/min and
6mL/min, corresponding flow velocity are respectively 2.12L/s and 1.27L/s, set heat exchange temperature as 5 DEG C, reaction time is
30s；1,4- dioxane solutions containing dimethyl carbonate are entered into second reaction zone by measuring pump 3；Setting measuring pump 3 controls
Isosorbide-5-Nitrae containing dimethyl carbonate-dioxane solution flow is 2.0mL/min, and corresponding flow velocity is 0.42L/s；Set heat exchanger
Temperature is 0 DEG C, with being reacted by the mixture in the first reaction zone, reaction time 40s；By the second reaction
After area's reaction, product continuous discharge enters in collecting tank 4.Watery hydrochloric acid is added, normal pressure concentration steams low boiling point solvent；It is warming up to again
65~80 DEG C, toluene is added, stratification collects upper organic layer, and lower aqueous layer is given up；Dilute hydrochloric acid solution is added, is stood
Layering, collects upper organic layer, and lower aqueous layer is given up；Crystallization cool to 0~5 DEG C, filtering, toluene washing, dries, is produced
Product.
Reaction product III-2 spectrogram compares with bibliography (Bull.Chem.Soc.Jpn.1988,61,2913) spectrogram
Afterwards, as a result unanimously, it is defined as N- phenyl-N- carbethoxyl group aniline, yield 84.7%, through efficient liquid phase chromatographic analysis, purity is
88.6%.
Embodiment 3
Reaction equation is：
Raw material is prepared：12.1g compound I-3 are weighed, are made into the I-3 of compound containing 16wt% t-butyl methyl ether solution,
It is put in head tank 1；20% n-BuLi cyclohexane solution 35mL is weighed, is put in head tank 2；Weigh dimethyl benzyl
26.4g, the II-3 of compound containing 36wt% t-butyl methyl ether solution is made into, be put in head tank 3.
Using the process chart described in Fig. 1, the wherein caliber of tubular reactor is 10mm, reaction pressure 1.0MPa,
As steps described below：The t-butyl methyl ether solution of the I-3 containing compound in head tank 1 is entered into the first reaction by measuring pump 1
Area, the n-BuLi cyclohexane solution in head tank 2 pass through measuring pump 2 and enter the first reaction zone；Set each measuring pump 1 and metering
Pump 2 control the t-butyl methyl ether solution of the I-3 containing compound and n-BuLi cyclohexane solution flow be respectively 12mL/min and
8mL/min, corresponding flow velocity are respectively 2.55L/s and 1.70L/s, set heat exchange temperature as 5 DEG C, reaction time is
45s；T-butyl methyl ether solution containing dimethyl carbonate is entered into second reaction zone by measuring pump 3；Setting measuring pump 3 controls
T-butyl methyl ether solution flow containing dimethyl carbonate is 2.5mL/min, and corresponding flow velocity is 0.53L/s；Set heat exchanger
Temperature is 0 DEG C, with being reacted by the mixture in the first reaction zone, reaction time 45s；By the second reaction
After area's reaction, product continuous discharge enters in collecting tank 4.Watery hydrochloric acid is added, normal pressure concentration steams low boiling point solvent；It is warming up to again
65~80 DEG C, toluene is added, stratification collects upper organic layer, and lower aqueous layer is given up；Dilute hydrochloric acid solution is added, is stood
Layering, collects upper organic layer, and lower aqueous layer is given up；Crystallization cool to 0~5 DEG C, filtering, toluene washing, dries, is produced
Product.
After reaction product III-3 spectrogram compares with bibliography (J.Org.Chem.1960,25,1874) spectrogram, as a result
Unanimously, it is defined as N- ethyl-N- benzyloxycarbonyl group aniline, yield 86.3%, through efficient liquid phase chromatographic analysis, purity 91.2%.
Embodiment 4
Reaction equation is as follows：
Raw material is prepared：The I-1 of compound containing 5wt% tetrahydrofuran solution is prepared, is put in head tank 1；Prepare 15% just
Butyl lithium cyclohexane solution, it is put in head tank 2；The II-1 of compound containing 5wt% tetrahydrofuran solution is prepared, is put in head tank
In 3.
Using the process chart described in Fig. 1, the wherein caliber of tubular reactor is 30mm, reaction pressure 0.5MPa,
As steps described below：The tetrahydrofuran solution of the I-1 containing compound in head tank 1 is entered into the first reaction zone by measuring pump 1, it is former
N-BuLi cyclohexane solution in batch can 2 enters the first reaction zone by measuring pump 2；Each measuring pump 1 and measuring pump 2 is set to control
Produced compounds I-1 tetrahydrofuran solution and n-BuLi cyclohexane solution flow velocity is respectively 0.1L/s and 0.4L/s, and setting is changed
Hot device temperature is -80 DEG C, reaction time 10s；The tetrahydrofuran solution containing dimethyl carbonate in head tank 3 is passed through
Measuring pump 3 enters second reaction zone；Set measuring pump 3 and control the flow velocity of the tetrahydrofuran solution containing dimethyl carbonate as 0.1L/
s；Heat exchange temperature is set as -80 DEG C, with being reacted by the mixture in the first reaction zone, reaction time 10s；
After being reacted by second reaction zone, product continuous discharge enters in collecting tank 4.Watery hydrochloric acid is added, normal pressure concentration steams low boiling
Point solvent；65~80 DEG C are warming up to again, adds toluene, and stratification collects upper organic layer, and lower aqueous layer is given up；Add
Dilute hydrochloric acid solution, stratification collect upper organic layer, and lower aqueous layer is given up；Crystallization cool to 0~5 DEG C, filtering, toluene is washed
Wash, dry, obtain product.
After reaction product III-3 spectrogram compares with bibliography (J.Org.Chem.1960,25,1874) spectrogram, as a result
Unanimously, it is defined as N- methyl-N- methoxycarbonyl group aniline, yield 82.1%, through efficient liquid phase chromatographic analysis, purity 90.2%.
Embodiment 5
Reaction equation is as follows：
Raw material is prepared：The I-1 of compound containing 40wt% tetrahydrofuran solution is prepared, is put in head tank 1；Prepare 25% just
Butyl lithium cyclohexane solution, it is put in head tank 2；The II-1 of compound containing 40wt% tetrahydrofuran solution is prepared, is put in raw material
In tank 3.
Using the process chart described in Fig. 1, the wherein caliber of tubular reactor is 1mm, reaction pressure 2.0MPa, is pressed
According to following step：The tetrahydrofuran solution of the I-1 containing compound in head tank 1 is entered into the first reaction zone, raw material by measuring pump 1
N-BuLi cyclohexane solution in tank 2 enters the first reaction zone by measuring pump 2；Each measuring pump 1 and measuring pump 2 is set to control
Compound I-1 tetrahydrofuran solution and n-BuLi cyclohexane solution flow velocity is respectively 25L/s and 0.7L/s, sets heat exchanger
Temperature is 10 DEG C, reaction time 100s；The tetrahydrofuran solution containing dimethyl carbonate in head tank 3 is passed through into metering
Pump 3 enters second reaction zone；Set measuring pump 3 and control the flow velocity of the tetrahydrofuran solution containing dimethyl carbonate as 1.5L/s；If
Heat exchange temperature is determined for 10 DEG C, with being reacted by the mixture in the first reaction zone, reaction time 100s；Passing through
After crossing second reaction zone reaction, product continuous discharge enters in collecting tank 4.Watery hydrochloric acid is added, it is molten that normal pressure concentration steams low boiling
Agent；65~80 DEG C are warming up to again, adds toluene, and stratification collects upper organic layer, and lower aqueous layer is given up；Add dilute salt
Acid solution, stratification collect upper organic layer, and lower aqueous layer is given up；Crystallization cool to 0~5 DEG C, filtering, toluene washing, does
It is dry, obtain product.
After reaction product III-3 spectrogram compares with bibliography (J.Org.Chem.1960,25,1874) spectrogram, as a result
Unanimously, it is defined as N- methyl-N- methoxycarbonyl group aniline, yield 81.5%, through efficient liquid phase chromatographic analysis, purity 89.6%.
Comparative example 1
10.7g compound I-1 will be weighed, are made into the I-1 of compound containing 12wt% tetrahydrofuran solution, after stirring and dissolving,
Less than -50 DEG C are cooled to, 20% n-BuLi cyclohexane solution 34mL about 2h are added dropwise, then dimethyl carbonate 13.4g is added dropwise, is continued
2-3h is reacted, adds watery hydrochloric acid, normal pressure concentration steams low boiling point solvent.65~80 DEG C are warming up to again, adds toluene, collect upper strata
Organic layer, lower aqueous layer are given up；Dilute hydrochloric acid solution is added, stratification collects upper organic layer, and lower aqueous layer gives up cooling
Crystallization is to 0~5 DEG C, filtering, toluene washing, dries, obtains product.Yield is 82%, purity 85.7%.
Comparative example 2
Raw material is prepared：10.7g compound I-1 are weighed, the I-1 of compound containing 12wt% tetrahydrofuran solution is made into, is put in
In head tank 1；20% n-BuLi cyclohexane solution 34mL is weighed, is put in head tank 2；Dimethyl carbonate 13.4g is weighed, is matched somebody with somebody
Into the II-1 of compound containing 50wt% tetrahydrofuran solution, it is put in head tank 3.
Using the process chart described in Fig. 1, the wherein caliber of tubular reactor is 10mm, reaction pressure 1.0MPa,
As steps described below：The tetrahydrofuran solution of the I-1 containing compound in head tank 1 is entered into the first reaction zone by measuring pump 1, it is former
N-BuLi cyclohexane solution in batch can 2 enters the first reaction zone by measuring pump 2；Each measuring pump 1 and measuring pump 2 is set to control
Produced compounds I-1 tetrahydrofuran solution and n-BuLi cyclohexane solution flow is respectively 100mL/min and 48mL/min, right
The flow velocity answered is respectively 21.2L/s and 10.2L/s, sets heat exchange temperature as 0 DEG C, reaction time 5s；By head tank 3
In the tetrahydrofuran solution containing dimethyl carbonate second reaction zone is entered by measuring pump 3；The setting control of measuring pump 3 contains carbonic acid
The tetrahydrofuran solution flow of dimethyl ester is 12.0mL/min, and corresponding flow velocity is 2.55L/s；Heat exchange temperature is set as 0 DEG C,
With being reacted by the mixture in the first reaction zone, reaction time 5s；By second reaction zone hybrid reaction
Afterwards, product continuous discharge enters in collecting tank 4.Watery hydrochloric acid is added, normal pressure concentration steams low boiling point solvent；65~80 are warming up to again
DEG C, toluene is added, collects upper organic layer, lower aqueous layer is given up；Dilute hydrochloric acid solution is added, stratification, collecting upper strata has
Machine layer, lower aqueous layer are given up；Crystallization cool to 0~5 DEG C, filtering, toluene washing, dries, obtains product.Yield is 65.2%,
Purity is 77.1%.
Comparative example 3
Raw material is prepared：10.7g compound I-1 are weighed, the I-1 of compound containing 12wt% tetrahydrofuran solution is made into, is put in
In head tank 1；20% n-BuLi cyclohexane solution 34mL is weighed, is put in head tank 2；Dimethyl carbonate 13.4g is weighed, is matched somebody with somebody
Into the II-1 of compound containing 50wt% tetrahydrofuran solution, it is put in head tank 3.
Using the process chart described in Fig. 1, the wherein caliber of tubular reactor is 10mm, reaction pressure 1.0MPa,
As steps described below：The tetrahydrofuran solution of the I-1 containing compound in head tank 1 is entered into the first reaction zone by measuring pump 1, it is former
N-BuLi cyclohexane solution in batch can 2 enters the first reaction zone by measuring pump 2；Each measuring pump 1 and measuring pump 2 is set to control
The tetrahydrofuran solution and n-BuLi cyclohexane solution flow velocity for making the I-1 containing compound are respectively 5mL/min and 2.4mL/min,
Corresponding flow velocity is respectively 1.06L/s and 0.51L/s, sets heat exchange temperature as 0 DEG C, reaction time 110s；By original
The tetrahydrofuran solution containing dimethyl carbonate in batch can 3 enters second reaction zone by measuring pump 3；Setting measuring pump 3 controls
Tetrahydrofuran solution flow containing dimethyl carbonate is 0.6mL/min, and corresponding flow velocity is 0.13L/s；Set heat exchange temperature
For 0 DEG C, with being reacted by the mixture in the first reaction zone, reaction time 110s；By second reaction zone
After hybrid reaction, product continuous discharge enters in collecting tank 4.Watery hydrochloric acid is added, normal pressure concentration steams low boiling point solvent；Heat up again
To 65~80 DEG C, toluene is added, collects upper organic layer, lower aqueous layer is given up；Dilute hydrochloric acid solution is added, stratification, is received
Collect upper organic layer, lower aqueous layer is given up；Crystallization cool to 0~5 DEG C, filtering, toluene washing, dries, obtains product.Yield is
62.2%, purity 73.1%.
Claims (10)
1. a kind of preparation method of amides compound, it is characterised in that the preparation method is carried out in tubular reactor, institute
Stating tubular reactor includes the first reaction zone and second reaction zone；
The preparation method comprises the following steps：
(1) the organic solution A and the organic solution B containing n-BuLi of the I containing compound is anti-described first at -80~10 DEG C
Answer area to react, obtain reaction solution；
(2) the organic solution C of the reaction solution and the II containing compound, at -80~10 DEG C, carried out in the second reaction zone anti-
Should, you can；
The net reaction that the compound I and the compound II react is as follows：
Wherein, the mass fraction of compound I described in the organic solution A is 5%~40%, the flow velocity of the organic solution A
For 0.1~25L/s；Compound II mass fraction described in the organic solution C is 5%~50%, the organic solution C's
Flow is 0.1~1.5L/s；The number of substituent on the phenyl ring of the compound I is n, n 0,1,2,3,4 or 5, and R1Respectively
From independently being C1~C6Alkyl, C1~C6Alkoxy or " substituted or unsubstituted C6~C10Aryl "；R2For hydrogen, C1~C6Alkyl
Or " substituted or unsubstituted phenyl ", the substituent of the substituted phenyl is C1~C6Alkyl or C1~C6Alkoxy；R3For C1
~C6Alkyl or " methyl of one or more phenyl substitutions ".
2. preparation method as claimed in claim 1, it is characterised in that the organic solution A, organic solution B or organic solution C
For ether solvent and/or alkane solvents；
Wherein, the ether solvent is preferably methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofurans and Isosorbide-5-Nitrae-dioxy six
One or more in ring；
Wherein, the alkane solvents are preferably one kind or more in petroleum ether, pentane, n-hexane, hexamethylene and heptane
Kind.
3. preparation method as claimed in claim 1, it is characterised in that in step (1), the temperature of the reaction is -10~10
DEG C, preferably 0~5 DEG C；
In step (1), the pressure of the reaction is 0.5~2MPa, preferably 0.5~1.5MPa；
And/or in step (1), the residence time of the reaction is 10~100s, preferably 20~45s.
4. preparation method as claimed in claim 1, it is characterised in that in step (1), chemical combination described in the organic solution A
Thing I mass fraction is 11%~16%；
In step (1), the flow velocity of the organic solution A is 2~5.5L/s；
In step (1), the flow of the organic solution A is 5~100mL/min；
In step (1), the mass fraction of n-BuLi described in the organic solution B is 15%~25%, is 20%；
In step (1), the flow velocity of the organic solution B is 1~3L/s；
And/or in step (1), the flow of the organic solution B is 1~100mL/min, preferably 6~12mL/min.
5. preparation method as claimed in claim 1, it is characterised in that in step (1), the compound I and the normal-butyl
The mol ratio of lithium is 1:1~1:10；
In step (1), the organic solution A and organic solution B flow-rate ratio is 10:1~1:10；
And/or in step (1), the organic solution A and organic solution B velocity ratio is 10:1~1:10.
6. preparation method as claimed in claim 1, it is characterised in that in step (2), the temperature of the reaction is -10~10
DEG C, preferably 0~5 DEG C；
In step (2), the pressure of the reaction is 0.5~2MPa, preferably 0.5~1.5MPa；
And/or in step (2), the residence time of the reaction is 10~100s, preferably 20~45s.
7. preparation method as claimed in claim 1, it is characterised in that in step (2), chemical combination described in the organic solution C
Thing II mass fraction is 30%~40%；
In step (2), the flow velocity of the organic solution C is 0.4~0.7L/s；
And/or in step (2), the flow of the organic solution C is 0.6~5mL/min, preferably 2~3mL/min.
8. preparation method as claimed in claim 1, it is characterised in that the R1It is each independently one or more hydrogen, first
Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group or phenyl；
The R2For hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, phenyl, p-methylphenyl, adjacent first
Phenyl, a tolyl, p-methoxyphenyl, guaiacyl or m-methoxyphenyl；
And/or the R3For methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, benzyl or benzhydryl.
9. preparation method as claimed in claim 1, it is characterised in that the R1For hydrogen, the R2For methyl, ethyl or phenyl,
The R3For methyl, ethyl or benzyl.
10. preparation method as claimed in claim 1, it is characterised in that after step (2) terminates, by products therefrom and watery hydrochloric acid
After mixing, concentration, heating, mix, be layered with toluene, obtain the first organic phase；Again with watery hydrochloric acid, mix, layering, it is organic to obtain second
Phase；Cooling, crystallization, filtering, washing, drying, obtain product；
Wherein, the outlet temperature of the heating is preferably 65~80 DEG C；
Wherein, the outlet temperature of the cooling is preferably 0~5 DEG C；
Wherein, the washing preferably uses toluene.
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| US4395565A (en) * | 1981-01-28 | 1983-07-26 | Anic S.P.A. | Preparing aromatic urethans |
| CN104230775A (en) * | 2013-06-18 | 2014-12-24 | 中国石油化工股份有限公司 | Method for preparing dialkyl aminodithioformic acid by using one-step method |
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