CN118255694A - Method for preparing DCC (DCC) by continuous oxidation through micro-channel method - Google Patents
Method for preparing DCC (DCC) by continuous oxidation through micro-channel method Download PDFInfo
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- CN118255694A CN118255694A CN202410498875.2A CN202410498875A CN118255694A CN 118255694 A CN118255694 A CN 118255694A CN 202410498875 A CN202410498875 A CN 202410498875A CN 118255694 A CN118255694 A CN 118255694A
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- 238000000034 method Methods 0.000 title claims abstract description 41
- 238000007254 oxidation reaction Methods 0.000 title claims abstract description 27
- 230000003647 oxidation Effects 0.000 title claims abstract description 16
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims abstract description 39
- AZERQDZCGIDXHT-UHFFFAOYSA-N 1,1-dicyclohexylthiourea Chemical compound C1CCCCC1N(C(=S)N)C1CCCCC1 AZERQDZCGIDXHT-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000000047 product Substances 0.000 claims abstract description 17
- 239000007864 aqueous solution Substances 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 239000005708 Sodium hypochlorite Substances 0.000 claims abstract description 14
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 239000012043 crude product Substances 0.000 claims abstract description 8
- 239000007788 liquid Substances 0.000 claims abstract description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000004537 pulping Methods 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 238000010924 continuous production Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 6
- 238000005086 pumping Methods 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Abstract
The invention relates to the field of chemical industry, and discloses a method for preparing DCC (direct-coupled catalyst) by continuous oxidation by a micro-channel method, which comprises the following operation steps: mixing N, N-dicyclohexylthiourea and an organic solvent, pulping and proportioning; simultaneously feeding the prepared feed liquid and sodium hypochlorite aqueous solution into a tubular reactor according to the molar ratio; the temperature of the reaction liquid is controlled by using circulating water to carry out oxidation reaction, and crude N, N-dicyclohexylcarbodiimide product, namely crude DCC product is prepared; and (3) obtaining qualified DCC from the DCC crude product through desolventizing and rectifying processes. The invention adopts the micro-channel reactor to carry out oxidation reaction, realizes continuous production, successfully solves the safety risks of large heat release and the like of the traditional kettle type intermittent reaction for preparing DCC, and realizes intrinsic safety in the process; the operation method is simple, the reaction efficiency is high, and the product quality is good.
Description
Technical Field
The invention relates to the field of chemical industry, in particular to a method for preparing DCC by continuous oxidation by a micro-channel method.
Background
DCC, N-dicyclohexylcarbodiimide, is mainly used for the condensation of amino acids in the artificial synthesis of polypeptides. As in Fmoc-solid phase synthesis, the carboxyl group of an amino acid forms an amide bond with the amino group of another amino acid. In order to make the carboxyl group more susceptible to attack by nucleophile, the negatively charged oxygen atom must be first activated by Chemicalbook to form a better leaving group, which DCC exerts. The oxygen atom of the carboxyl on the amino acid is taken as a nucleophilic reagent to attack the carbon atom in the middle of the DCC molecule to combine the DCC and the carboxyl to form an ester structure, so that the nucleophilic attack of the amino is easy to carry out. The method is used for synthesizing and dehydrating amikacin and amino acid, is a good low-temperature biochemical dehydrating agent, and is also used for synthesizing acid, anhydride, aldehyde, ketone and the like. In japan, the dehydrating agent for glutathione accounts for 90% of the total consumption. When the product is used as a dehydration condensing agent, the product can be obtained through short-time reaction at normal temperature, and the product after the reaction is dicyclohexylurea. The solubility of the product in organic solvent is Chemicalbook small, so the reaction product is easy to separate; meanwhile, since the product is hardly soluble in water, the reaction can proceed even in an aqueous solution. The product can be used for synthesizing peptide and nucleic acid, and can be used for synthesizing peptide from compound with free carboxyl and compound with free amino at room temperature with high yield. Is used for producing the antihypertensive agent and the cyclic adenosine monophosphate.
At present, in the preparation process of N, N-Dicyclohexylcarbodiimide (DCC), sodium hypochlorite aqueous solution is used as an oxidant, the reaction belongs to oxidation reaction, the heat release amount is large, most production processes are kettle type intermittent reaction, and the safety risk is high.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a method for preparing DCC by continuous oxidation by a micro-channel method, which has the following technical scheme:
A method for preparing DCC by continuous oxidation using a microchannel process, comprising the following steps:
(1) Mixing N, N-dicyclohexylthiourea and an organic solvent, pulping and proportioning;
(2) Simultaneously feeding the prepared feed liquid and sodium hypochlorite aqueous solution into a tubular reactor according to the molar ratio;
(3) The temperature of the reaction liquid is controlled by using circulating water to carry out oxidation reaction, and crude N, N-dicyclohexylcarbodiimide product, namely crude DCC product is prepared;
(4) And (3) obtaining qualified DCC from the DCC crude product through desolventizing and rectifying processes.
Further, the mixing ratio of the weight of the N, N-dicyclohexylthiourea to the volume of the organic solvent in the step (1) is 1 kg:1L-1 kg:3L.
Further, the batching ratio of the weight of the N, N-dicyclohexylthiourea to the volume of the organic solvent in the step (1) is 1 kg/1L.
Further, the organic solvent in the step (1) comprises cyclohexane, toluene, benzene and n-hexane.
Furthermore, the organic solvent in the step (1) is cyclohexane.
Further, the molar ratio of the N, N-dicyclohexylthiourea to the sodium hypochlorite aqueous solution in the step (2) is 1:1-1:1.2.
Further, the molar ratio of the N, N-dicyclohexylthiourea to the sodium hypochlorite aqueous solution in the step (2) is 1:01.
Further, the temperature of the reaction liquid in the step (3) is controlled to be 35-50 ℃.
Further, the temperature of the reaction solution in the step (3) is controlled at 45 ℃.
Further, the residence time of the step (3) is 1-3 min for oxidation reaction.
Compared with the prior art, the invention has the following beneficial technical effects:
1. The invention adopts the micro-channel reactor to carry out oxidation reaction, realizes continuous production, successfully solves the safety risks of large heat release and the like of the traditional kettle type intermittent reaction for preparing DCC, and realizes intrinsic safety in the process.
2. The method has the advantages of simple operation, high reaction efficiency and good product quality. The product yield is above 95.5% and the product purity is above 99.2% by measurement.
Detailed Description
The present invention will be described in detail with reference to specific embodiments, but it should be understood that the scope of the invention is not limited by the specific embodiments.
Example 1
(1) And (3) batching: 2000kg of N, N-dicyclohexylthiourea and 2000L of cyclohexane are added into a 5m batching kettle, stirring is started, stirring is carried out for 1h, stirring is stopped, and then the batch is transferred to a temporary storage kettle with a thickness of 10 m.
(2) Starting a 100L tubular reactor for feeding, controlling the temperature of the material in the tubular reactor to be 45 ℃, firstly pumping sodium hypochlorite aqueous solution, after the flow is stable, pumping the material liquid prepared by a 10m temporary storage kettle, controlling the molar ratio of N, N-dicyclohexylthiourea to the sodium hypochlorite aqueous solution to be 1:1.01, and carrying out oxidation reaction for 1min to prepare an N, N-dicyclohexylcarbodiimide crude product, namely a DCC crude product.
(3) And (3) carrying out central control on 0.13% of N, N-dicyclohexylthiourea, and after the reaction is finished, carrying out desolventizing and rectifying procedures to obtain qualified DCC with the purity of 99.5% and the average yield of 96.6%.
Example 2
(1) And (3) batching: 1000kg of N, N-dicyclohexylthiourea and 2000L of toluene are added into a 5 m-solution batching kettle, stirring is started, stirring is carried out for 1h, stirring is stopped, and then the batch is transferred to a temporary storage kettle with the thickness of 10 m.
(2) Starting a 100L tubular reactor for feeding, controlling the temperature of the material in the tubular reactor to be 35 ℃, firstly pumping sodium hypochlorite aqueous solution, after the flow is stable, pumping the material liquid prepared by a 10m temporary storage kettle, controlling the molar ratio of N, N-dicyclohexylthiourea to the sodium hypochlorite aqueous solution to be 1:1.2, and carrying out oxidation reaction for 1.5min to prepare an N, N-dicyclohexylcarbodiimide crude product, namely a DCC crude product.
(3) And (3) carrying out central control on 0.10% of N, N-dicyclohexylthiourea, and after the reaction is finished, carrying out desolventizing and rectifying procedures to obtain qualified DCC with the purity of 99.3% and the average yield of 95.5%.
Example 3
(1) And (3) batching: 1000kg of N, N-dicyclohexylthiourea and 3000L of cyclohexane are added into a 5m batching kettle, stirring is started, stirring is carried out for 1h, stirring is stopped, and then the batch is transferred to a temporary storage kettle with a thickness of 10 m.
(2) Starting a 100L tubular reactor for feeding, controlling the temperature of the material in the tubular reactor to be 50 ℃, firstly pumping sodium hypochlorite aqueous solution, after the flow is stable, pumping the material liquid prepared by a 10m temporary storage kettle, controlling the molar ratio of N, N-dicyclohexylthiourea to the sodium hypochlorite aqueous solution to be 1:1.1, and standing for 2min, and carrying out oxidation reaction to prepare N, N-dicyclohexylcarbodiimide product, namely a crude product of DCC.
(3) And (3) carrying out central control on 0.15% of N, N-dicyclohexylthiourea, and after the reaction is finished, carrying out desolventizing and rectifying procedures to obtain qualified DCC with the purity of 99.2% and the average yield of 95.6%.
Claims (10)
1. A method for preparing DCC by continuous oxidation using a microchannel process, comprising the following steps:
(1) Mixing N, N-dicyclohexylthiourea and an organic solvent, pulping and proportioning;
(2) Simultaneously feeding the prepared feed liquid and sodium hypochlorite aqueous solution into a tubular reactor according to the molar ratio;
(3) The temperature of the reaction liquid is controlled by using circulating water to carry out oxidation reaction, and crude N, N-dicyclohexylcarbodiimide product, namely crude DCC product is prepared;
(4) And (3) obtaining qualified DCC from the DCC crude product through desolventizing and rectifying processes.
2. The method for preparing DCC by continuous oxidation using a micro channel method according to claim 1, wherein the ratio of the weight of the N, N-dicyclohexylthiourea to the volume of the organic solvent in the step (1) is 1kg:1l to 1kg:3l.
3. The method for preparing DCC by continuous oxidation using a micro channel method according to claim 2, wherein the ratio of the weight of the N, N-dicyclohexylthiourea to the volume of the organic solvent in the step (1) is 1 kg/1 l.
4. The method for preparing DCC by continuous oxidation using a micro channel method according to claim 1, wherein the organic solvent of step (1) comprises cyclohexane, toluene, benzene and n-hexane.
5. The method for preparing DCC by continuous oxidation using a micro channel method according to claim 4, wherein the organic solvent in the step (1) is cyclohexane.
6. The method for preparing DCC by continuous oxidation according to claim 1, wherein the molar ratio of the N, N-dicyclohexylthiourea to the sodium hypochlorite aqueous solution in the step (2) is 1:1 to 1:1.2.
7. The method for preparing DCC by continuous oxidation according to claim 6, wherein the molar ratio of the N, N-dicyclohexylthiourea and the sodium hypochlorite aqueous solution in the step (2) is 1:01.
8. The method for preparing DCC by continuous oxidation using a micro channel method according to claim 1, wherein the temperature of the reaction solution in the step (3) is controlled to be 35-50 ℃.
9. The method for preparing DCC by continuous oxidation using a micro channel method according to claim 8, wherein the temperature of the reaction solution in the step (3) is controlled to 45 ℃.
10. The method for preparing DCC by continuous oxidation using a micro channel method according to claim 8, wherein the residence time of the step (3) is 1 to 3min for the oxidation reaction.
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| Publication Number | Publication Date |
|---|---|
| CN118255694A true CN118255694A (en) | 2024-06-28 |
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