CN-122010817-A - Preparation method of 4-chloro-5- (2-chloroethyl) indol-2-one

CN122010817ACN 122010817 ACN122010817 ACN 122010817ACN-122010817-A

Abstract

The invention relates to the technical field of organic synthesis, and particularly discloses a preparation method of 4-chloro-5- (2-chloroethyl) indol-2-one. The preparation method of the 4-chloro-5- (2-chloroethyl) indole-2-ketone comprises the following steps of carrying out reduction reaction on 6-chloro-5- (2-chloroacetyl) -indolone and polymethyl hydrosiloxane under the condition of a solvent to obtain the 4-chloro-5- (2-chloroethyl) indole-2-ketone. In the preparation method provided by the invention, the yield of the 4-chloro-5- (2-chloroethyl) indol-2-one is stabilized at 92% -96%, and the purity is more than or equal to 99.5%. Meanwhile, the high risk and high pollution of the traditional reducing agent are avoided, the environmental-friendly treatment cost is reduced, and the method has remarkable industrial application value.

Inventors

WU HAIXIA
WANG YUEKE
CAO YIBO
YANG XIAOTIAN
SONG JIAQIAN
LI BINGRUI

Assignees

河北科技大学

Dates

Publication Date: 20260512
Application Date: 20260202

Claims (10)

1. The preparation method of the 4-chloro-5- (2-chloroethyl) indol-2-one is characterized by comprising the following steps: Under the condition of solvent, 6-chloro-5- (2-chloracetyl) -indolone and polymethyl hydrosiloxane undergo a reduction reaction to obtain 4-chloro-5- (2-chloroethyl) indol-2-one.
2. The preparation method of 4-chloro-5- (2-chloroethyl) indol-2-one according to claim 1, wherein the preparation method of 4-chloro-5- (2-chloroethyl) indol-2-one specifically comprises the following steps: s1, continuously conveying a 6-chloro-5- (2-chloroacetyl) -indolone reaction solution and a polymethylhydrosiloxane solution into a microchannel reactor at 15-20 ℃ and 3-8 bar for continuous flow reduction reaction, and performing water quenching to obtain a 4-chloro-5- (2-chloroethyl) indol-2-one reaction solution; S2, under the conditions of 40-45 ℃ and 0.08-0.09 MPa, sending the 4-chloro-5- (2-chloroethyl) indol-2-one reaction liquid into a thin film evaporator for evaporation, enabling the evaporation residue to flow into a continuous mixer for uniform mixing with a first solvent, then flowing into a continuous liquid separation tower for phase separation, mixing an organic phase with an alcohol solvent, then flowing into a continuous crystallizer for recrystallization, continuously filtering a crystallization liquid, and continuously drying to obtain 4-chloro-5- (2-chloroethyl) indol-2-one.
3. The method for preparing 4-chloro-5- (2-chloroethyl) indol-2-one according to claim 2, wherein the purity of 6-chloro-5- (2-chloroacetyl) -indolone in the 6-chloro-5- (2-chloroacetyl) -indolone reaction solution is not less than 98%, and the purity of byproducts is not more than 1.5%; in S1, the inner diameter of the micro-channel reactor is 0.5-1 mm, and the effective reaction volume is 50-100 mL.
4. The method for preparing 4-chloro-5- (2-chloroethyl) indol-2-one according to claim 2, wherein in S1, the polymethylhydrosiloxane solution is a methylene dichloride solution of polymethylhydrosiloxane, and the concentration is 0.6-0.7 g/mL.
5. The method for preparing 4-chloro-5- (2-chloroethyl) indol-2-one according to claim 2, wherein in S1, 6-chloro-5- (2-chloroacetyl) -indolone reaction liquid is diluted with dichloromethane and then sent into a thin film evaporator for evaporation, and the volume ratio of the 6-chloro-5- (2-chloroacetyl) -indolone reaction liquid to the dichloromethane is 1 (1-1.2).
6. The method for preparing 4-chloro-5- (2-chloroethyl) indol-2-one according to claim 2, wherein the continuous flow reduction reaction time in S1 is 1 to 3min.
7. The method for producing 4-chloro-5- (2-chloroethyl) indol-2-one according to claim 2, wherein in S1, the ratio of the feed flow rates of the 6-chloro-5- (2-chloroacetyl) -indolone reaction solution and the polymethylhydrosiloxane solution is 1 (1-1.5), and the total feed flow rate is 260-320 mL/min.
8. The process for the preparation of 4-chloro-5- (2-chloroethyl) indol-2-one according to claim 2, wherein in S2, the first solvent is 2-methyltetrahydrofuran; S2, the volume ratio of the steam residue to the first solvent is (9-10) 1; in S2, the volume ratio of the alcohol solvent to the first solvent is 1 (9-10); S2, the recrystallized solvent comprises 2-methyltetrahydrofuran aqueous solution, wherein the volume ratio of the 2-methyltetrahydrofuran to water is (9-10) 1; in S2, the volume mass ratio of the recrystallized solvent to the 6-chlorooxindole is (9-10) mL, namely 1g.
9. The method for preparing 4-chloro-5- (2-chloroethyl) indol-2-one according to claim 2, wherein in S2, the recrystallization is performed by heating to 60-65 ℃ for a first heat preservation, and then cooling to 0-5 ℃ for a second heat preservation.
10. The method for preparing 4-chloro-5- (2-chloroethyl) indol-2-one according to claim 9, wherein the temperature is reduced to 0-5 ℃ at a rate of 5-10 ℃ per hour.

Description

Preparation method of 4-chloro-5- (2-chloroethyl) indol-2-one Technical Field The invention relates to the technical field of organic synthesis, in particular to a preparation method of 4-chloro-5- (2-chloroethyl) indol-2-one. Background Ziprasidone hydrochloride is used as a second generation atypical antipsychotic, and takes an irreplaceable position in the treatment of diseases such as schizophrenia, bipolar disorder and the like by virtue of double antagonism of a dopamine D2 receptor and a 5-hydroxytryptamine 2A receptor, so that the ziprasidone hydrochloride has remarkable clinical application value and continuously climbs market demands. The 4-chloro-5- (2-chloroethyl) indol-2-one is a core intermediate for synthesizing ziprasidone hydrochloride, and a stable amide bond and a high-activity alkyl chloride group in the molecular structure can be accurately butted with a piperazine ring through an SN2 substitution reaction, so that the preparation method is a key link for constructing a ziprasidone hydrochloride molecular skeleton. The synthesis routes of the intermediate are reported at present, 6-chlorooxindole is taken as a starting material, and an acylation-reduction two-step process is adopted, but the technical details and process performances of different routes are obviously different, and a standardized scheme is not formed yet. The existing synthesis process has various common bottlenecks that the enrichment of byproducts is caused by low reaction selectivity, the product purity is difficult to meet the severe requirements of the high-end medicine field, the severe exothermic reaction is accompanied by insufficient heat transfer efficiency, potential safety hazards exist, high energy consumption is caused, the production efficiency is limited by lengthy reaction period, the market expansion requirement is difficult to match, and the equipment investment or the catalyst cost is high, so that the process economy is greatly weakened. In summary, aiming at 4-chloro-5- (2-chloroethyl) indol-2-one, a preparation method with high selectivity, high efficiency, high safety and low cost is developed, the pain point of the existing process is broken, the key of promoting the industrialization upgrade of ziprasidone hydrochloride and meeting the clinical medication requirement is also the technical problem to be broken through in the field. Disclosure of Invention In view of this, the present invention provides a process for the preparation of 4-chloro-5- (2-chloroethyl) indol-2-one. The invention solves the technical problems of poor selectivity, long reaction period, low safety and high cost in the existing 4-chloro-5- (2-chloroethyl) indole-2-ketone synthesis process, provides a preparation method with continuous whole flow, accurate and controllable parameters and high product yield and purity, realizes the product yield of more than or equal to 92 percent and the HPLC purity of more than or equal to 99.5 percent, shortens the total reaction period to less than 1/10 of the traditional process, controls the reaction temperature to 15-20 ℃ without low-temperature bath, avoids high-pressure and high-corrosivity reagents, and reduces equipment investment and environmental protection cost. In order to solve the technical problems, the technical scheme provided by the invention is as follows: The invention provides a preparation method of 4-chloro-5- (2-chloroethyl) indol-2-one, which comprises the following steps: Under the condition of solvent, 6-chloro-5- (2-chloracetyl) -indolone and polymethyl hydrosiloxane undergo a reduction reaction to obtain 4-chloro-5- (2-chloroethyl) indol-2-one. Compared with the prior art, the method selects the polymethylhydrosiloxane as the reducing agent, wherein a specific reducing agent breaks Si-H bond in a reaction system to release active hydrogen atoms, the active hydrogen atoms and aliphatic acyl ketone carbonyl groups in 6-chloro-5- (2-chloroacetyl) -indolone molecules undergo nucleophilic addition reaction to generate a hemiacetal intermediate, then the intermediate undergoes intramolecular hydrogen transfer reaction, and the selective reduction of the ketone carbonyl groups to methylene is finally realized along with the removal of one molecule of water to obtain a target product. Preferably, the preparation method of the 4-chloro-5- (2-chloroethyl) indol-2-one specifically comprises the following steps: s1, continuously conveying a 6-chloro-5- (2-chloroacetyl) -indolone reaction solution and a polymethylhydrosiloxane solution into a microchannel reactor at 15-20 ℃ and 3-8 bar for continuous flow reduction reaction, and performing water quenching to obtain a 4-chloro-5- (2-chloroethyl) indol-2-one reaction solution; S2, under the conditions of 40-45 ℃ and 0.08-0.09 MPa, sending the 4-chloro-5- (2-chloroethyl) indol-2-one reaction liquid into a thin film evaporator for evaporation, enabling the evaporation residue to flow into a continuous mixer for uniform mixing