CN109485597A - The preparation method of 4- halo-isoindoline hydrochloride - Google Patents

The preparation method of 4- halo-isoindoline hydrochloride Download PDF

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Publication number
CN109485597A
CN109485597A CN201710816259.7A CN201710816259A CN109485597A CN 109485597 A CN109485597 A CN 109485597A CN 201710816259 A CN201710816259 A CN 201710816259A CN 109485597 A CN109485597 A CN 109485597A
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reaction
follows
compound
preparation
amide
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沈杞容
孙海
高红军
李原强
车大庆
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Ruibo Hangzhou Pharmaceutical Technology Co Ltd
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Zhejiang Jiuzhou Pharmaceutical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles

Abstract

The present invention provides a kind of preparation methods of 4- halo-isoindoline hydrochloride, are raw material by 2,3- dihalomethyl -3- halogeno-benzene, type I compound are prepared through cyclization reaction, reaction equation is as follows:N is 1 or 2；Wherein, X1For halogen, R is alkoxy, carbamyl, phenoxy group, benzyloxy, carbonyl, hydroxyl, amide or alkyl-substituted amide.The cyclization reaction reagent is alcoxyl amine, urea, Atenolol, benzyloxy amine, azanol or hydrazides etc..4- halo-isoindoline hydrochloride is prepared by reduction or hydrolysis.

Description

The preparation method of 4- halo-isoindoline hydrochloride
Technical field
The invention belongs to medical synthesis fields, and in particular to the preparation method more particularly to 4- of pharmaceutical intermediate are halogenated different The preparation method of indoline hydrochloride.
Background technique
4- halo-isoindoline hydrochloride is the pharmaceutical intermediate for preparing anti-hepatitis C (HCV), structural formula such as following formula I:
A kind of preparation method of 4- halo-isoindoline hydrochloride is disclosed in European patent EP 343560 earliest, mainly Use para toluene sulfonamide as cyclization reagent, 4- halo-isoindoline hydrochloric acid is prepared through further hydrolysis after cyclization Salt.The disadvantages such as there are severe reaction conditions for this method, expensive, and yield is low.
The a variety of different preparation methods of many other document reports afterwards.Such as Bioorganic&Medicinal 18 Issue of Chemistry Letters Volume, 14 Pages 4159-4162 Year2008 is ring using Boc acid anhydrides Reagent is closed, 4- halo-isoindoline hydrochloride is prepared through further hydrolysis after cyclization.WO2009068463 is prepared two After the product that benzyl replaces, is further restored de- dibenzyl and 4- halo-isoindoline mesylate is prepared.
Chinese patent application CN101560180A uses benzylamine for cyclization reagent, and the halogenated different Yin of 2- benzyl -4- is prepared After diindyl quinoline, 4- halo-isoindoline hydrochloride further is prepared through restoring debenzylation.Reaction equation is as follows:
Since the de- benzyl of benzylamine needs stronger hydroconversion condition, so that such preparation method and being unsuitable for industrialization life It produces.
For the present inventor during continuous experiment, it is a kind of suitable to obtain, low cost, being capable of industrialized production preparation The preparation method of the halogenated iso-indoles hydrochloride of 4-.
Summary of the invention
The present invention provides a kind of preparation method of 4- halo-isoindoline hydrochloride, reduction reaction conditions of the invention are non- Room temperature and, and be not limited to only use the technique of reduction reaction, other as hydrolysis also can high yield be prepared product. The midbody compound that preparation method of the invention is related to is new compound, thus, fail to be appointed from the prior art What technical inspiration.
The present invention provides a kind of new midbody compound, structural formula is as follows:
N is 1 or 2；
It can individually be indicated with following reaction formula:
Wherein R is alkoxy, carbamyl, phenoxy group, benzyloxy, carbonyl, amide or alkyl-substituted amide or hydroxyl. It preferably, is alkoxy, carbonyl or alkyl-substituted amide；It is highly preferred that being methoxyl group.More preferably structural formula of compound It is as follows:
R1For alkyl.
The present invention provides the preparation methods of above-mentioned type I compound, are raw material, warp by 2,3- dihalomethyl -3- halogeno-benzene Type I compound is prepared in cyclization reaction, and reaction equation is as follows:
N is 1 or 2；
When n is 1, reaction equation is as follows:
When n is 2, reaction equation is as follows:
Wherein, X1For halogen, R is alkoxy, carbamyl, phenoxy group, benzyloxy, carbonyl, amide or alkyl-substituted Amide or hydroxyl.
The cyclization reaction reagent is alcoxyl amine, urea, Atenolol, benzyloxy amine, azanol or hydrazides etc..
The cyclization reaction carries out in the presence of alkali, and the alkali can be organic base or inorganic base.The inorganic base is Potassium carbonate, calcium hydroxide etc..
Specifically, when cyclization reagent is urea, reaction equation is as follows:
Specifically, when cyclization reaction reagent is hydrazides, reaction equation is as follows:
R1For alkyl.
4- halo-isoindoline salt can be prepared through reduction reaction or hydrolysis in above-mentioned new midbody compound Hydrochlorate, reaction equation are as follows:
When the value of n is 1, reaction equation is as follows:
When the value of n is 2, reaction equation is as follows:
Wherein, the definition of R is same as described above.
In the reduction reaction, it is preferably zinc/hydrochloric acid that go back original reagent, which can be metallic reducing agent/acid, zinc/acetic acid； The reduction reaction can also be restored by the way of catalytic hydrogenation, such as use palladium carbon hydrogen.Boron class can also be used Reducing agent or aluminium class reducing agent.Preferably, it is restored using metallic reducing agent/acid.In the hydrolysis, hydrolysing agent can be with For acid or alkali.
In the reduction reaction, the molar ratio of reducing agent and type I compound is 1:1-1:10.
The present invention compares preferred embodiment:
It is raw material by 2,3-, bis- bromomethyl -3- halogeno-benzene, type I compound is prepared through cyclization reaction, reaction equation is as follows:
Wherein, R is alcoxyl amine.Above-mentioned preferred cyclization reaction reagent is alcoxyl amine, and more preferably cyclization reaction reagent is Methoxamine.
Above-mentioned type I compound further prepares 4- halo-isoindoline hydrochloride through reduction reaction, and the reducing agent is more excellent Selection of land is zinc/hydrochloric acid or zinc/acetic acid.
Very particularly preferred embodiment of the invention is:
It is raw material by 2,3-, bis- bromomethyl -3- fluorobenzene, type I compound is prepared through cyclization reaction with methoxamine, reacts Formula is as follows:
Type I compound is reacted preparation 4- fluorine isoindoline hydrochloride with zinc/hydrochloric acid,
The preparation method of 4- halo-isoindoline hydrochloride provided by the invention, compared with the prior art in method have Following advantage: first, a kind of new intermediate type I compound, and cyclization reaction high income, by-product are obtained in cyclization reaction It is few；Second, reduction reaction conditions are mild；Third, reaction yield is high, at low cost, is suitable for industrialized production；4th, reduction is anti- Reducing agent used in answering is zinc/acid, and the acid in product 4- halo-isoindoline hydrochloride derives from this.
Specific embodiment
For a further understanding of the present invention, below with reference to embodiment to 4- halo-isoindoline hydrochloride provided by the invention It is described in detail.It is to be appreciated that the description of these embodiments is only the feature that present invention be described in more detail, without It is the limitation to the scope of the invention or scope of the invention as claimed.
Embodiment 1:
By bis- bromomethyl -3- fluorobenzene 10g (1eq) of 2,3-, methoxamine hydrochloride 3g (1eq), potassium carbonate 20g, DMF100ml Reaction flask is put into, in room temperature reaction 16h, 700ml water is poured into later, is extracted using ethyl acetate 200ml, ethyl acetate layer is taken to steam It is dry, obtain 5.5g, yield 95%.1H-NMR 400MHz(CDCl3): δ 7.23 (1H, m), 7.07 (1H, d, J=7.5), 6.93 (1H, T, J=8.4), 4.40 (2H, s), 4.34 (2H, s), 3.62 (3H, s)；13C-NMR 400MHz(CDCl3): δ 159.80, 157.35,142.94,142.89,129.42,129.36,125.32,125.14,118.47,118.43,114.12,113.92, 62.67,60.32,59.21.
HRMS(ESI)calcd for C9H11FNO+:168.1819,found 168.0811
Embodiment 2:
The fluoro- 2- methoxyl group isoindoline 10g (1eq) of 4- is added in reaction flask, is put into Zn powder 7.8g (2eq), second is added Alcohol 100ml, hydrochloric acid 10ml react 4h, filter after reaction, be evaporated filtrate, pour into 100ml water, the use of NaOH tune pH are 10, It is extracted using isopropyl acetate 100ml, taking isopropyl acetate layer that acidic alcohol is added to pH is 2, a large amount of solids are precipitated cross and be filtered dry 4- fluorine isoindoline hydrochloride 9.9g, yield 96% are obtained after dry.1H-NMR 400MHz (DMSO): δ 7.40-7.47 (1H, m), 7.18-7.30 (3H, m), 4.57 (2H, s), 4.55 (2H, s).
Embodiment 3:
By bis- bromomethyl -3- fluorobenzene 10g (1eq) of 2,3-, Atenolol hydrochloride 5.2g (1eq), potassium carbonate 20g, acetonitrile 100ml puts into reaction flask, in room temperature reaction 20h, is evaporated under filtering reacting liquid filtrate decompression later, obtains 7.4g, yield 90%.1H-NMR 400MHz(CDCl3): δ 7.64 (1H, m), 7.35 (1H, d, J=8.0), 7.16-7.25 (3H, m), 4.45 (2H, s), 4.39 (2H, s),13C-NMR 400MHz(CDCl3): δ 160.80,158.60,148.35,144.35,143.89,132.5, 130.56,130.44,127.22,127.04,121.35,117.24,117.20,115.90,112.52,112.32,63.97, 62.56 59.21.HRMS(ESI)calcd for C14H13FNO+:230.0976,found 230.0955
Embodiment 4:
The fluoro- 2- phenoxy group isoindoline 10g (1eq) of 4- is added in reaction flask, is put into Zn powder 15g (5eq), acetic acid is added 100ml reacts 4h, filters after reaction, be evaporated filtrate, pour into 100ml water, the use of NaOH tune pH is 10, different using acetic acid Propyl ester 100ml extraction, taking isopropyl acetate layer that acidic alcohol is added to pH is 2, obtains 4- after a large amount of solid filtration dryings are precipitated Fluorine isoindoline hydrochloride 7.2g, yield 95%.
1H-NMR 400MHz (DMSO): δ 7.40-7.47 (1H, m), 7.18-7.30 (3H, m), 4.57 (2H, s), 4.55 (2H, s).
Embodiment 5:
By bis- bromomethyl -3- fluorobenzene 10g (1eq) of 2,3-, Phenylmethoxyamine hydrochloride 5.7g (1eq), potassium carbonate 20g, acetonitrile 100ml puts into reaction flask, in room temperature reaction 20h, is evaporated under filtering reacting liquid filtrate decompression later, obtains 8.0g, yield 92%.1H-NMR 400MHz(CDCl3): δ 7.35-7.5 (5H, m), δ 7.31 (1H, m), 7.12 (1H, d, J=7.3), 7.02 (1H, t, J =7.9), 4.82 (2H, s) 4.50 (2H, s), 4.42 (2H, s),；13C-NMR400MHz(CDCl3): δ 158.29,156.15, 141.84,141.72,136.56,129.64,128.36,127.55,127.22,126.82,126.56,123.42,123.24, 119.57,119.43,112.22,112.02,75.65,63.56,59.86,58.51.HRMS(ESI)calcd for C15H15FNO+:244.1132,found 244.1169
Embodiment 6:
The fluoro- 2- benzyloxy isoindoline 10g (1eq) of 4- is added in reaction flask, is put into Zn powder 14g (5eq),
Acetic acid 100ml is added, reacts 4h, filters after reaction, be evaporated filtrate, pour into 100ml water, use NaOH tune pH It is 10, is extracted using isopropyl acetate 100ml, taking isopropyl acetate layer that acidic alcohol is added to pH is 2, and a large amount of solid mistakes are precipitated Be filtered dry it is dry after obtain 4- fluorine isoindoline hydrochloride 6.6g, yield 93%.
1H-NMR 400MHz (DMSO): δ 7.40-7.47 (1H, m), 7.18-7.30 (3H, m), 4.57 (2H, s), 4.55 (2H, s).
Embodiment 7:
By bis- bromomethyl -3- fluorobenzene 10g (1eq) of 2,3-, acethydrazide 2.6g (1eq), potassium carbonate 20g, acetonitrile 100ml investment Reaction flask, in room temperature reaction 20h, filtering reacting liquid, filtrate decompression are evaporated later, obtain 6.7g object, yield 96%.1H-NMR 400MHz(CDCl3): δ 7.35 (1H, m), 7.12 (1H, d, J=7.3), 7.02 (1H, t, J=8.1), 4.52 (2H, s), 4.39 (2H, s), 2.16 (3H, s)；13C-NMR 400MHz(CDCl3): δ 170.55,156.50,154.35,139.88,139.83, 128.12,128.02,124.62,124.44,116.87,116.83,110.32,110.22,61.48,58.32,28.49. HRMS(ESI)calcd for C10H12FN2O+:159.0928,found 159.0922
Embodiment 8:
The fluoro- 2- acetamido isoindoline 10g (1eq) of 4- is added in reaction flask, is put into Zn powder 17.9g (5eq), is added Acetic acid 100ml reacts 4h, filters after reaction, be evaporated filtrate, pour into 100ml water, the use of NaOH tune pH is 10, uses vinegar Isopropyl propionate 100ml extraction, taking isopropyl acetate layer that acidic alcohol is added to pH is 2, is obtained after a large amount of solid filtration dryings are precipitated To 4- fluorine isoindoline hydrochloride 8.5g, yield 95%.
1H-NMR 400MHz (DMSO): δ 7.40-7.47 (1H, m), 7.18-7.30 (3H, m), 4.57 (2H, s), 4.55 (2H, s).
Embodiment 9:
By bis- bromomethyl -3- fluorobenzene 10g (1eq) of 2,3-, urea 2.14g (1eq), potassium carbonate 20g, acetonitrile 100ml investment Reaction flask, in room temperature reaction 20h, filtering reacting liquid, filtrate decompression are evaporated later, obtain 5.9g object, yield 92%.1H-NMR 400MHz(CDCl3): δ 7.41 (1H, m), 7.12-7.24 (3H, m), 4.40 (2H, s), 4.69 (2H, s), 4.33 (3H, s)；13C-NMR 400MHz(CDCl3): δ 165.56,162.55,160.14,146.86,146.75,131.68,131.62, 124.67,124.42,119.28,119.22,116.51,116.32,65.51,62.15.HRMS(ESI)calcd for C9H10FN2O+:181.0772,found 181.0783
Embodiment 10:
The fluoro- 2- amine formyl isoindoline 10g (1eq) of 4- is added in reaction flask, 2M NaOH100ml is put into, heats back 20h is flowed, cools down, is extracted using isopropyl acetate 100ml after reaction, takes isopropyl acetate layer that acidic alcohol is added to pH to be 2,4- fluorine isoindoline hydrochloride, 8.9g, yield 92% are obtained after a large amount of solid filtration dryings are precipitated.1H-NMR 400MHz (DMSO): δ 7.40-7.47 (1H, m), 7.18-7.30 (3H, m), 4.57 (2H, s), 4.55 (2H, s).

Claims (10)

1. a kind of midbody compound, structural formula are as follows:
X=F, Cl, Br, n are 1 or 2；
Wherein, R is alkoxy, carbamyl, phenoxy group, benzyloxy, carbonyl, hydroxyl, amide or alkyl-substituted amide.
2. the compound in claim 1, structural formula are as follows:
Wherein, R is alkoxy, carbamyl, phenoxy group, benzyloxy, hydroxyl, amide or alkyl-substituted amide.
3. the compound in claim 1, structural formula are as follows:
Wherein, R is carbonyl.
4. the compound in claim 1,2 or 3, structural formula are as follows:
R1For alkyl.
5. the preparation method of compound in claim 1, which is characterized in that by 2,3- dihalomethyl -3- halogeno-benzene be raw material, warp Cyclization reaction is prepared, and reaction equation is as follows:
X=F, Cl, Br, n are 1 or 2；
Wherein, X1For halogen, R is alkoxy, carbamyl, phenoxy group, benzyloxy, carbonyl, hydroxyl, amide or alkyl-substituted Amide.
6. a kind of preparation method of type I compound, which is characterized in that by 2,3- dihalomethyl -3- halogeno-benzene be raw material, through cyclization Reaction is prepared, and reaction equation is as follows:
Wherein, X1For halogen, R is alkoxy, carbamyl, phenoxy group, benzyloxy, hydroxyl, amide or alkyl-substituted amide.
7. preparation method according to claim 5 or 6, which is characterized in that the cyclization reaction reagent is alcoxyl amine, urine Element, Atenolol, benzyloxy amine, azanol or hydrazides.
8. preparation method according to claim 5 or 6, which is characterized in that the cyclization reaction carries out in the presence of alkali, The alkali is organic base or inorganic base.
9. the purposes of type I compound in claim 5 or 6, which is characterized in that halogenated through hydrolysis or reduction reaction preparation 4- Isoindoline hydrochloride, reaction equation are as follows:
10. preparation method according to claim 9, which is characterized in that the reduction reaction metallic reducing agent and acid Mixture reduction；It is restored with the method reduction of catalytic hydrogenation or with boron class reducing agent or aluminium class reducing agent.
CN201710816259.7A 2017-09-12 2017-09-12 The preparation method of 4- halo-isoindoline hydrochloride Pending CN109485597A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101560180A (en) * 2009-05-15 2009-10-21 上海清松制药有限公司 Method for preparing 4-halo-isoindoline hydrochloride
CN104045552A (en) * 2013-03-13 2014-09-17 上海先声药物研究有限公司 Medicinal compound as neuroprotective agent
CN104277002A (en) * 2013-07-01 2015-01-14 上海医药工业研究院 Glycinamide derivative, and intermediate, preparation method, pharmaceutical composition and application thereof
WO2016055482A1 (en) * 2014-10-08 2016-04-14 Ucb Biopharma Sprl Isoindoline derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101560180A (en) * 2009-05-15 2009-10-21 上海清松制药有限公司 Method for preparing 4-halo-isoindoline hydrochloride
CN104045552A (en) * 2013-03-13 2014-09-17 上海先声药物研究有限公司 Medicinal compound as neuroprotective agent
CN104277002A (en) * 2013-07-01 2015-01-14 上海医药工业研究院 Glycinamide derivative, and intermediate, preparation method, pharmaceutical composition and application thereof
WO2016055482A1 (en) * 2014-10-08 2016-04-14 Ucb Biopharma Sprl Isoindoline derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHARALAMPOS ANASTASIADIS等: "Functionalised dithiocarbamate complexes: Complexes based on indoline, indole and substituted piperazine backbones-X-ray crystal structure of [Ni(S2CNC3H6C6H4)2]", 《INORGANICA CHIMICA ACTA》 *
KREHER, RICHARD P.等: "Isoindoles and isoindolenines. 26. Simple preparations of 2H-isoindole", 《CHEMIKER-ZEITUNG》 *

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