CN117105820A - Preparation method of 4-fluorophenethyl isocyanate - Google Patents
Preparation method of 4-fluorophenethyl isocyanate Download PDFInfo
- Publication number
- CN117105820A CN117105820A CN202310850433.5A CN202310850433A CN117105820A CN 117105820 A CN117105820 A CN 117105820A CN 202310850433 A CN202310850433 A CN 202310850433A CN 117105820 A CN117105820 A CN 117105820A
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- CN
- China
- Prior art keywords
- reaction
- toluene
- triphosgene
- reaction liquid
- isocyanate
- Prior art date
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- FDCHHLBMDMJXGM-UHFFFAOYSA-N 1-fluoro-4-(2-isocyanatoethyl)benzene Chemical compound FC1=CC=C(CCN=C=O)C=C1 FDCHHLBMDMJXGM-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 63
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 16
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 15
- CKLFJWXRWIQYOC-UHFFFAOYSA-N 2-(4-fluorophenyl)ethanamine Chemical compound NCCC1=CC=C(F)C=C1 CKLFJWXRWIQYOC-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000004821 distillation Methods 0.000 claims abstract description 12
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 229910052786 argon Inorganic materials 0.000 claims abstract description 10
- 239000012043 crude product Substances 0.000 claims abstract description 6
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000000047 product Substances 0.000 abstract description 4
- 238000007086 side reaction Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000005457 ice water Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000011521 glass Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 238000005485 electric heating Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C263/00—Preparation of derivatives of isocyanic acid
- C07C263/10—Preparation of derivatives of isocyanic acid by reaction of amines with carbonyl halides, e.g. with phosgene
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C263/00—Preparation of derivatives of isocyanic acid
- C07C263/18—Separation; Purification; Stabilisation; Use of additives
- C07C263/20—Separation; Purification
Abstract
The invention relates to a preparation method of 4-fluorophenethyl isocyanate, which is characterized by comprising the following steps: step 1, under the protection of argon, toluene is taken as a solvent, and triphosgene is added for reaction to obtain a reaction liquid 1; step 2, adding 2- (4-fluorophenyl) ethylamine into toluene under the protection of argon to obtain a reaction liquid 2; step 3, cooling the reaction liquid 1, adding the reaction liquid 2, recovering to room temperature, and heating for reaction; and 4, directly distilling the crude product obtained in the step 3, and collecting 107-108 ℃/10mmHg fractions to obtain the 4-fluorophenethyl isocyanate. The synthesis process has the advantages of mild reaction conditions, simple operation, easy control, less side reaction, high conversion rate and the like; the target product can be directly obtained by reduced pressure distillation, wherein the distilled front fraction toluene can be directly used as a solvent for the next reaction, so that the reaction cost is greatly saved, and the method is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of 4-fluorophenethyl isocyanate, belonging to the technical field of organic chemistry.
Background
The 4-fluorophenethyl isocyanate is an important organic chemical raw material, is commonly used in the synthesis of some biological protease inhibitors, novel antibacterial agents and natural products, and belongs to an important organic medicine synthesis intermediate. At present, the research reports of the related synthesis method at home and abroad of the compound are relatively few, arya adopts phosgene as a raw material to synthesize the substance, but phosgene is extremely toxic gas, and is difficult to transport and store, thus bringing great trouble to experimental operation; wang et al synthesized this compound using triphosgene as the starting material, but they used this compound as an intermediate only for the next step without isolation and purification.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: the preparation method of the 4-fluorophenethyl isocyanate has the advantages of low cost, high product conversion rate, low toxicity and easy separation and purification.
The invention solves the technical problems by the following technical proposal:
the invention provides a preparation method of 4-fluorophenethyl isocyanate, which comprises the following steps:
step 1, under the protection of argon, toluene is taken as a solvent, and triphosgene is added for reaction to obtain a reaction liquid 1;
step 2, adding 2- (4-fluorophenyl) ethylamine into toluene under the protection of argon to obtain a reaction liquid 2;
step 3, cooling the reaction liquid 1, adding the reaction liquid 2, recovering to room temperature, and heating for reaction to obtain a crude product of 4-fluorophenylethyl isocyanate;
and 4, distilling the crude product obtained in the step 3, and collecting 107-108 ℃/10mmHg fractions to obtain the 4-fluorophenethyl isocyanate.
Preferably, in the step 1, the reaction temperature is 20-25 ℃; the reaction conditions are that triphosgene is added while stirring; the adding is dripping; the weight ratio of the volume of toluene to triphosgene is 4-5L/kg.
Preferably, in the step 2, the reaction temperature is 20-25 ℃; the weight ratio of the volume of the toluene to the 2- (4-fluorophenyl) ethylamine is 4-5L/kg; the adding is dripping.
Preferably, in the step 3, the reaction temperature is 0-5 ℃; the reaction conditions are that the reaction liquid 2 is added and then the temperature is kept for 1h, the heating temperature is 105-110 ℃, and the reaction time of the heating reaction is 2h; the molar ratio of triphosgene to 2- (4-fluorophenyl) ethylamine required was 1: (1-1.2); the adding is dripping.
Preferably, in the step 4, the distillation is reduced pressure distillation.
Compared with the prior art, the invention has the following beneficial effects:
1. the raw materials required by synthesis, such as triphosgene, 2- (4-fluorophenyl) ethylamine, toluene and the like, are cheap and easy-to-obtain industrial products; the synthesis process has the advantages of mild reaction conditions, simple operation, easy control, less side reaction, high conversion rate and the like; the target product can be directly obtained by reduced pressure distillation, wherein the distilled front fraction toluene can be directly used as a solvent for the next reaction, so that the reaction cost is greatly saved; the whole process is suitable for industrial production.
2. The invention synthesizes the 4-fluorophenethyl isocyanate in 1 step. Wherein, triphosgene reacts with 2- (4-fluorophenyl) ethylamine, and the dropping speed of reactants, the reaction temperature and the material dosage ratio are controlled to reduce the occurrence of side reaction and improve the conversion rate; the obtained crude product is directly distilled and purified under reduced pressure, so that the high-purity 4-fluorophenethyl isocyanate can be synthesized, the GC purity is more than 98.6%, and the total yield is more than 80%.
Detailed Description
In order to make the invention more comprehensible, preferred embodiments accompanied with the present invention are described in detail as follows:
example 1
A method for synthesizing 4-fluorophenethyl isocyanate comprises the following steps:
(1) Preparing a 1L glass reaction kettle, replacing argon for 3 times, adding 400.0mL of toluene at 20-25 ℃, stirring, adding triphosgene (100.0 g,337.0 mmol), and continuously stirring until the reaction system is dissolved;
(2) Preparing a 200mL glass reaction kettle, replacing argon for 3 times, adding 188.0mL toluene at 20-25 ℃, adding 2- (4-fluorophenyl) ethylamine (46.9 g,337.0 mmol) while stirring, and continuously stirring until the reaction liquid is clear and transparent;
(3) Cooling a toluene solution of triphosgene to 0-5 ℃ in an ice water bath under an argon atmosphere, then beginning to dropwise add a toluene solution of 2- (4-fluorophenyl) ethylamine, carrying out dropwise addition, keeping the ice water bath for 1h after the completion of dropwise addition, removing the ice water bath, recovering to room temperature, then heating and refluxing, gradually dissolving the solid generated by the reaction system along with the rising of the reaction temperature, and finally controlling the internal temperature of the reaction solution to be 105-110 ℃ for 2h for curing;
(4) After the reaction is finished, the reaction system is restored to room temperature, then the reaction system is added into a 1L distillation flask, an electric heating sleeve is adopted for heating, a thorn-shaped distillation column of 20cm is used for reduced pressure distillation, and a fraction of bp of 107-108 ℃/10mmHg is collected, so that 44.5g of colorless liquid is obtained.
Nuclear magnetic resonance treatment data, GC, appearance of the above-prepared compound were examined as follows:
1 H-NMR(CDCl 3 ，400MHz，δppm)：δ＝7.16～7.20(2H，m)，7.01～7.05(2H，m)，3.49～2.53(2H，t)，2.86～2.90(2H，t)
GC：98.6％
appearance: colorless liquid
Example 2
A method for synthesizing 4-fluorophenethyl isocyanate comprises the following steps:
(1) Preparing a 2L glass reaction kettle, replacing argon for 3 times, adding 1000.0mL of toluene at 20-25 ℃, stirring, adding triphosgene (200.0 g,674.0 mmol), and continuously stirring until the reaction system is dissolved;
(2) Preparing a 1L glass reaction kettle, replacing argon for 3 times, adding 562.8mL of toluene at 20-25 ℃, adding 2- (4-fluorophenyl) ethylamine (112.6 g,808.8 mmol) while stirring, and continuously stirring until the reaction liquid is clear and transparent;
(3) Cooling a toluene solution of triphosgene to 0-5 ℃ in an ice water bath under an argon atmosphere, then beginning to dropwise add a toluene solution of 2- (4-fluorophenyl) ethylamine, carrying out dropwise addition, keeping the ice water bath for 1h after the completion of dropwise addition, removing the ice water bath, recovering to room temperature, then heating and refluxing, gradually dissolving the solid generated by the reaction system along with the rising of the reaction temperature, and finally controlling the internal temperature of the reaction solution to be 105-110 ℃ for 2h for curing;
(4) After the reaction is finished, the reaction system is restored to room temperature, then the reaction system is added into a 2L distillation flask, an electric heating sleeve is adopted for heating, a thorn-shaped distillation column of 20cm is used for reduced pressure distillation, and a fraction of bp of 107-108 ℃/10mmHg is collected, so that 107.9g of colorless liquid is obtained.
Nuclear magnetic resonance treatment data, GC and appearance of the above-prepared compound were examined as follows:
1 H-NMR(CDCl 3 ，400MHz，δppm)：δ＝7.14～7.19(2H，m)，7.00～7.03(2H，m)，3.47～2.50(2H，t)，2.83～2.87(2H，t)
GC：98.8％
appearance: colorless liquid.
Claims (10)
1. The preparation method of the 4-fluorophenethyl isocyanate is characterized by comprising the following steps of:
step 1, under the protection of argon, toluene is taken as a solvent, and triphosgene is added for reaction to obtain a reaction liquid 1;
step 2, adding 2- (4-fluorophenyl) ethylamine into toluene under the protection of argon to obtain a reaction liquid 2;
step 3, cooling the reaction liquid 1, adding the reaction liquid 2, recovering to room temperature, and heating for reaction to obtain a crude product of 4-fluorophenylethyl isocyanate;
and 4, distilling the crude product obtained in the step 3, and collecting 107-108 ℃/10mmHg fractions to obtain the 4-fluorophenethyl isocyanate.
2. The method according to claim 1, wherein in the step 1, the reaction temperature is 20 to 25 ℃; the reaction conditions are that triphosgene is added while stirring; the adding is dripping.
3. The process according to claim 1, wherein the ratio by weight of toluene to triphosgene in step 1 is 4 to 5L/kg.
4. The process according to claim 1, wherein in step 2, the reaction temperature is 20 to 25 ℃.
5. The process according to claim 1, wherein the ratio by weight of toluene volume to 2- (4-fluorophenyl) ethylamine is 4 to 5L/kg.
6. The method of claim 1, wherein in step 2, the adding is dropwise adding.
7. The method according to claim 1, wherein in the step 3, the reaction temperature is 0 to 5 ℃; the reaction condition is that the reaction liquid 2 is added and then the temperature is kept for 1h, the heating temperature is 105-110 ℃, and the reaction time of the heating reaction is 2h.
8. The process of claim 1, wherein in step 3, the molar ratio of triphosgene to 2- (4-fluorophenyl) ethylamine is 1: (1-1.2).
9. The method of claim 1, wherein in step 3, the adding is dropwise adding.
10. The method according to claim 1, wherein in the step 4, the distillation is reduced pressure distillation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310850433.5A CN117105820A (en) | 2023-07-12 | 2023-07-12 | Preparation method of 4-fluorophenethyl isocyanate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310850433.5A CN117105820A (en) | 2023-07-12 | 2023-07-12 | Preparation method of 4-fluorophenethyl isocyanate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117105820A true CN117105820A (en) | 2023-11-24 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310850433.5A Pending CN117105820A (en) | 2023-07-12 | 2023-07-12 | Preparation method of 4-fluorophenethyl isocyanate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117105820A (en) |
-
2023
- 2023-07-12 CN CN202310850433.5A patent/CN117105820A/en active Pending
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