WO2023249414A1 - Procédé de production d'un dérivé de benzoamine - Google Patents

Procédé de production d'un dérivé de benzoamine Download PDF

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WO2023249414A1
WO2023249414A1 PCT/KR2023/008635 KR2023008635W WO2023249414A1 WO 2023249414 A1 WO2023249414 A1 WO 2023249414A1 KR 2023008635 W KR2023008635 W KR 2023008635W WO 2023249414 A1 WO2023249414 A1 WO 2023249414A1
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formula
compound
benzoamine
producing
derivative
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PCT/KR2023/008635
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English (en)
Korean (ko)
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이현명
어진용
이경호
박대현
홍중연
김영민
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대웅바이오(주)
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Publication of WO2023249414A1 publication Critical patent/WO2023249414A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring

Definitions

  • the present invention relates to a method for producing benzoamine derivatives, and more specifically, to improve the safety of the reaction and the ease of operation, 1,1'-carbonyldiimidazole, a coupling catalyst, is used to produce benzoamine in high yield and purity. It relates to a method for producing amine derivatives.
  • Niclosamide (5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide, CAS NO. 50-65-7) treats tapeworm, tapeworm, tapeworm, and dwarf tapeworm infections. It is a benzoamine derivative used as an effective anthelmintic. Niclosamide is also being studied as an anticancer drug and an antiviral agent in addition to being an antihelminthic drug (Cellular Signalling, Volume 41, 89 ⁇ 96, 2018, ACS Infect. Dis. 2020, 6, 5, 909-915).
  • anhydride in the case of anhydride, it has a low-energy crystal structure, has the highest density, and has a small amount of voids, making it easy to store.
  • it when stored for a long period of time, it can maintain a stable hydrate form without interaction with moisture (Talanta, Volume 199, 1 July 2019, Pages 679-688).
  • Anhydrous type 1 crystals are a crystal structure that can be obtained at temperatures below 100°C, and anhydrous type 2 crystals are dehydrated at high temperatures above 140°C and have a structurally rearranged crystal structure (AAPS PharmSciTech, volume 5, 2004, Article number: 101).
  • a benzoamine derivative is prepared using PCl 3 in a xylene solvent at high temperature using a compound of Formula 1 and a compound of Formula 2.
  • the present inventors completed the present invention by identifying a manufacturing method suitable for mass production that is not only economical but also can produce the final compound with improved yield using reagents that are inexpensive and have low toxicity and risk.
  • Patent Document 0001 China Registered Patent No. 105566147
  • Patent Document 0002 China Registered Patent No. 106957298
  • Patent Document 0003 China Registered Patent No. 106431949
  • the purpose of the present invention is to provide a manufacturing method of benzoamine derivatives that is safe and easy to operate, is easy to apply to mass production, and has no problems in equipment use, in order to solve the problems of the prior art as described above. Do it as
  • the present invention provides a method for producing benzoamine derivatives that is not only safe and easy to operate, but also has high yield.
  • the final target compound a benzoamine derivative, is the same as the compound of formula 1 below.
  • X is halogen (eg F, Cl, Br or I);
  • R 1 is independently hydrogen or hydroxy
  • R 2 is independently hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, or nitro.
  • the compound of Formula 1 may be a compound of Formula 1a below.
  • the present invention provides a method for preparing the compound of Formula 1, comprising the following.
  • X is halogen (eg F, Cl, Br or I);
  • R 1 is independently hydrogen or hydroxy
  • R 2 is independently hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, or nitro.
  • the compound of Formula 2 may be a compound of Formula 2a below.
  • the compound of Formula 3 may be a compound of Formula 3a below.
  • the production method of the present invention uses carbonyldiimidazole (compound of formula 4) and a base, so no hydrochloric acid gas is generated during the reaction, so the safety of the work is high and there is no risk of equipment corrosion. . Under these safe conditions, not only is reactivity further increased, but mass production is also possible, and economic feasibility can also be greatly improved as production is possible with high yield.
  • the method for producing a compound of Formula 1 according to the present invention includes the step of coupling a compound of Formula 2 and a compound of Formula 3 under basic conditions using a compound of Formula 4 as a catalyst to obtain a compound of Formula 1 ( It can be prepared including step 1).
  • the solvent used in step 1 is one selected from the group consisting of toluene, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, methylene chloride, water, methanol, ethanol, isopropyl alcohol, ethyl acetate, and acetone. It may be more than this, and it is preferable to use methylene chloride, acetonitrile, tetrahydrofuran, or toluene, considering the reaction temperature and the ease of later concentration and removal of the solvent.
  • the solvent is used in an amount of 5 to 25w/v, for example, 5 to 8w/v, 8 to 10w/v, 10 to 12.5w/v, 12.5 to 15w/v, 15 to 18w/v, relative to the starting material.
  • v may range from 18 to 20 w/v, 20 to 23 w/v, and 23 to 25 w/v.
  • using it in the range of 8w/v to 18w/v may be advantageous when considering reactivity.
  • the base may be one or more selected from the group consisting of N,N-diisopropylethylamine, triethylamine, diethylamine, diisopropylamine, and pyridine, and is preferably N,N-diisopropylethylamine.
  • amines, or triethylamine may be advantageous when considering reactivity.
  • the amount of the base used is 0.5 to 2.0 equivalents, for example, 0.5 to 0.7 equivalents, 0.7 to 0.9 equivalents, 0.9 to 1.1 equivalents, 1.1 to 1.3 equivalents, 1.3 to 1.5 equivalents, based on the compound of Formula 2. , 1.5 to 1.7 equivalents, 1.7 to 2.0 equivalents. Preferably, it may be advantageous to use it in the range of 0.9 to 1.5 equivalents when considering reactivity.
  • Step 1 is not limited thereto, but may be performed at 20 to 120°C, for example, 20 to 30°C, 30 to 50°C, 50 to 70°C, 70 to 90°C, 90 to 100°C, 100 to 100°C. It may be 120°C. Preferably it may be 30°C to 100°C.
  • the reflux temperature of the solvent can be set.
  • Step 1 may be prepared including the following steps 1-1 to 1-2.
  • Step 1-1 is not limited thereto, but the amount of 1,1'-carbonyldiimidazole (compound of Formula 4) used is 0.5 to 2.0 equivalents, for example, 0.5 to 0.7 equivalents, 0.7 equivalents, based on the compound of Formula 2. to 0.9 equivalents, 0.9 to 1.1 equivalents, 1.1 to 1.3 equivalents, 1.3 to 1.5 equivalents, 1.5 to 1.7 equivalents, 1.7 to 2.0 equivalents. Preferably, it may be advantageous to use it in the range of 0.9 to 1.5 equivalents when considering reactivity.
  • Step 1-1 is not limited thereto, but can be performed for a reaction time of 1 to 6 hours, for example, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, or 5 to 6 hours. there is. Preferably it may be 1 to 3 hours. If the time range is outside the above time range, the reaction may not occur sufficiently or an addition reaction may occur, resulting in a decrease in yield.
  • the steps 1-2 are not limited thereto, but the reaction time is 1 to 12 hours, for example, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, 5 to 6 hours, or 6 to 6 hours. It can be performed for 7 hours, 7 to 8 hours, 8 to 9 hours, 9 to 10 hours, 10 to 11 hours, and 11 to 12 hours. If the time range is outside the above time range, there is a problem that the reaction is not sufficiently carried out or an addition reaction occurs, resulting in a decrease in yield.
  • step 1 step 1-2 can be performed without performing a separate post-treatment or purification process after step 1-1 is completed.
  • the step of reacting a compound of Formula 2 with a compound of Formula 4 below and then coupling the compound of Formula 2 with a compound of Formula 3 to obtain a compound of Formula 1 is performed in toluene, and the reaction temperature is Can be carried out at 30°C to 100°C.
  • the carboxyl group of the compound of Formula 2 is converted to ester using 1,1'-carbonyldiimidazole (compound of Formula 4), and then the amidated compound of Formula 2' is obtained, and N,N-diisopropylethylamine
  • 1,1'-carbonyldiimidazole compound of Formula 4
  • N,N-diisopropylethylamine N,N-diisopropylethylamine
  • the amount of solvent used in step 2 can be within the range of 15 to 50w/v based on the benzoamine derivative, for example, 15 to 18w/v, 18 to 20w/v, 20 to 23w/v, 23 to 25w. /v, 25 to 30w/v, 30 to 33w/v, 33 to 35w/v, 35 to 40w/v, 40 to 43w/v, 43 to 45w/v, 45 to 50w/v.
  • using it within the range of 15 v/w to 30 v/w may be advantageous in increasing purification yield.
  • Step 2 is not limited thereto, but may be performed at pH less than 6.0. In one embodiment according to the present invention, it was carried out in the pH range of 0.3 to 5.0.
  • Figure 1 shows XRD data of niclosamide prepared by the method of Example 1 according to the present invention.
  • Figure 2 is DSC data of niclosamide prepared by the method of Example 1 according to the present invention.
  • the washed niclosamide crystals were added to 150.0 mL of methanol and the pH was adjusted to 1.0 by adding concentrated hydrochloric acid. The pH-adjusted mixture was refluxed for 1 hour, cooled, and the crystals were filtered to obtain 14.1 g (74%, purity 99.9%) of niclosamide.
  • Figure 1 is XRD data of niclosamide prepared by the method of Example 1 according to the present invention
  • Figure 2 is DSC data of niclosamide prepared by the method of Example 1 according to the present invention.
  • the washed crystals were added to 150.0 mL of methanol and the pH was adjusted to 1.0 by adding concentrated hydrochloric acid.
  • the pH-adjusted mixture was refluxed for 1 hour, cooled, and the crystals were filtered to obtain 14.7 g (77%) of niclosamide.
  • the washed crystals were added to 150.0 mL of methanol and adjusted to pH 1.0 by adding concentrated hydrochloric acid. The pH-adjusted mixture was refluxed for 1 hour, cooled, and the crystals were filtered to obtain 14.4 g (76%) of niclosamide.
  • the washed crystals were added to 150.0 mL of methanol and adjusted to pH 1.0 by adding concentrated hydrochloric acid.
  • the pH-adjusted mixture was refluxed for 1 hour, cooled, and the crystals were filtered to obtain 13.8 g (73%) of niclosamide.
  • the washed crystals were added to 150.0 mL of methanol, and the pH was adjusted to 0.3 by adding concentrated hydrochloric acid. The pH-adjusted mixture was refluxed for 1 hour, cooled, and the crystals were filtered to obtain 14.4 g (76%) of niclosamide.
  • the washed crystals were added to 150.0 mL of ethanol and adjusted to pH 5.0 by adding concentrated hydrochloric acid.
  • the pH-adjusted mixture was refluxed for 1 hour, cooled, and the crystals were filtered to obtain 14.4 g (76%) of niclosamide.
  • Examples 1 to 6 according to the present invention used carbonyldiimidazole (compound of formula 4) and a base, so no hydrochloric acid gas was generated during the reaction, so the safety of work was high and there was no risk of equipment corrosion. Under these safe conditions, niclosamide, a benzoamine derivative, could be produced in high yield within a short period of time.
  • the method for producing benzoamine derivatives according to the present invention uses 1,1'-carbonyldiimidazole, a coupling catalyst, to not only improve the safety of the reaction and ease of operation, but also to produce benzoamine derivatives in high yield and purity. You can.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de production d'un dérivé de benzoamine, et plus particulièrement, un procédé de production d'un dérivé de benzoamine avec un rendement élevé et une grande pureté à l'aide de 1,1'-carbonyldiimidazole en tant que catalyseur de couplage afin d'améliorer la sécurité de la réaction et la facilité de fonctionnement. Le procédé de production selon la présente invention utilise des réactifs économiques et sûrs, offrant ainsi un degré élevé de sécurité de fonctionnement et étant bien adapté à une production à l'échelle commerciale sans risque de corrosion de l'équipement, et améliore le rendement et la pureté de la réaction, augmentant ainsi au maximum l'efficacité de production et étant utile pour la production en masse.
PCT/KR2023/008635 2022-06-22 2023-06-21 Procédé de production d'un dérivé de benzoamine WO2023249414A1 (fr)

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KR1020220076094A KR20230174902A (ko) 2022-06-22 2022-06-22 벤조아민 유도체의 제조방법
KR10-2022-0076094 2022-06-22

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1626506A (zh) * 2004-08-10 2005-06-15 李志良 高纯度、高收率氯硝柳胺的制备
US20180002322A1 (en) * 2014-11-26 2018-01-04 Takeda Pharmaceutical Company Limited Bicyclic compound
US20220017476A1 (en) * 2018-12-07 2022-01-20 Philip Reigan Stat3 transcription factor inhibitors and methods of using the same

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Publication number Priority date Publication date Assignee Title
JP5566147B2 (ja) 2010-03-23 2014-08-06 株式会社前川製作所 米加工廃水の処理方法及び装置
KR102119353B1 (ko) 2011-06-08 2020-06-29 유니버셜 디스플레이 코포레이션 헤테로렙틱 이리듐 카르벤 착물 및 이를 사용한 발광 디바이스
KR102509937B1 (ko) 2016-10-06 2023-03-15 스미또모 가가꾸 가부시키가이샤 착색 경화성 수지 조성물

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1626506A (zh) * 2004-08-10 2005-06-15 李志良 高纯度、高收率氯硝柳胺的制备
US20180002322A1 (en) * 2014-11-26 2018-01-04 Takeda Pharmaceutical Company Limited Bicyclic compound
US20220017476A1 (en) * 2018-12-07 2022-01-20 Philip Reigan Stat3 transcription factor inhibitors and methods of using the same

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JUANG YU-PU; CHOU YU-TING; LIN RU-XIAN; MA HSIU-HUA; CHAO TAI-LING; JAN JIA-TSRONG; CHANG SUI-YUAN; LIANG PI-HUI: "Design, synthesis and biological evaluations of niclosamide analogues against SARS-CoV-2", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 235, 19 March 2022 (2022-03-19), AMSTERDAM, NL , XP087022544, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2022.114295 *
WOODMAN EMILY K., CHAFFEY JULIAN G. K., HOPES PHILIP A., HOSE DAVID R. J., GILDAY JOHN P.: "N,N ′-Carbonyldiimidazole-Mediated Amide Coupling: Significant Rate Enhancement Achieved by Acid Catalysis with Imidazole·HCl", ORGANIC PROCESS RESEARCH & DEVELOPMENT, AMERICAN CHEMICAL SOCIETY, US, vol. 13, no. 1, 16 January 2009 (2009-01-16), US , pages 106 - 113, XP093118667, ISSN: 1083-6160, DOI: 10.1021/op800226b *

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