CN101343249A - Preparation of 3-(3-chlorine propyl)-7, 8-di methoxy-1, 3-dihydrogen-2H-3-benzo aza -ketone - Google Patents

Preparation of 3-(3-chlorine propyl)-7, 8-di methoxy-1, 3-dihydrogen-2H-3-benzo aza -ketone Download PDF

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CN101343249A
CN101343249A CNA2008100387432A CN200810038743A CN101343249A CN 101343249 A CN101343249 A CN 101343249A CN A2008100387432 A CNA2008100387432 A CN A2008100387432A CN 200810038743 A CN200810038743 A CN 200810038743A CN 101343249 A CN101343249 A CN 101343249A
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ketone
preparation
aza
benzo
dimethoxy
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岑均达
郭珩
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Shanghai Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
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Abstract

The invention relates to the technique field of a preparation method of an intermediate compound of Ivabradine. The preparation method of 3-(3-chloropropyl)-7, 8-dimethoxy-1, 3-dihydro-2H-3-benazepine-2-ketone comprises: making 7, 8-dimethoxy-1, 3-dihydro-2H-3-benazepine-2-ketone and 1, 3-chlorobromide have the alkylation reaction. The preparation method unexpectedly selects an alkaline reagent used commonly, and has advantages of mild reaction conditions, safety and reliability, and rather high yield, and the method fully overcomes the defects of strong water absorption, easy deterioration, or easy explosion under rather low temperature of the alkylation reagent used in the prior art, and is extremely applied to the industrialized big-production.

Description

3-(3-chloropropyl)-7,8-dimethoxy-1, the preparation method of 3-dihydro-2H-3-benzoazepine-2-ketone
Technical field
The present invention relates to 3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
Figure A20081003874300042
The preparation method of-2-ketone.
Background technology
S 16257-2 and its pharmacologically acceptable salt, especially its hydrochloride, has very important pharmacology and therapeutics character, especially the character that has reducing heart rate, thereby can use these compounds to be used for the treatment of or prevent various myocardial ischaemia situations clinically, for example stenocardia, myocardial infarction and relevant rhythm disturbance also comprise the various pathology that relate to rhythm disturbance, especially supraventricular rhythm disturbance.
The preparation and the therepic use of S 16257-2 and pharmacologically acceptable salt thereof (especially hydrochloride) are described in the specification sheets of European patent EP 0534859.Described the synthetic of Ivabradine hydrochloride in above-mentioned patent specification, it is with formula (I) compound, i.e. 3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
Figure A20081003874300043
-2-ketone is raw material.
Figure A20081003874300044
The method of acquisition formula (I) compound is described in publication J.Med.Chem1990, and Vol33 (5) among the 1496-1504, also is documented in the specification sheets of European patent EP 0204349 simultaneously.This method is by in the presence of potassium tert.-butoxide, and with 1-bromo-3-chloropropane alkylation formula (II) compound, using highly basic such as potassium tert.-butoxide is the needed common condition of amide functional group deprotonation in methyl-sulphoxide.
Figure A20081003874300051
Yet the alkoxide as the potassium tert.-butoxide has extremely strong, the perishable shortcoming of water-absorbent, and this makes that their storages are difficult and is difficult to use on technical scale.
The another kind of reagent that is generally used for the amide functional group deprotonation is sodium hydride, and the solvent that is complementary with it is a dimethyl formamide.But for sodium hydride and dimethyl formamide, except it also had the fact of high-hydroscopicity, storage difficulty, also having a main shortcoming was blast easily under lower temperature.
Therefore,, seek a kind of can avoiding and use water-absorbent reagent in view of the pharmacy value of S 16257-2 and pharmacologically acceptable salt thereof, and have good yield, to come the compound of preparation formula (I) be necessary for the method that is suitable for industrialized production.
Summary of the invention
Purpose of the present invention is exactly the above-mentioned defective that solves prior art, provides a kind of safe and effective and be suitable for the 3-(3-chloropropyl)-7 of industrialized production, 8-dimethoxy-1,3-dihydro-2H-3-benzo-aza The preparation method of-2-ketone.
The concrete technical scheme that the present invention takes is as follows:
3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza The preparation method of-2-ketone, this method carry out alkylated reaction with formula (II) compound and formula (III) compound in the presence of sodium hydroxide, potassium hydroxide, ammonia soln, carbonate or supercarbonate, aftertreatment gets target product
Figure A20081003874300061
Wherein X represents leavings group.
Above-mentioned leavings group comprises but does not limit halogen atom, toluene sulfonic acide ester group, methylsulfonic acid ester group and trifluoromethanesulfonic acid ester group etc., preferred bromine atoms.
Method of the present invention can also use Tetrabutyl amonium bromide as phase-transfer catalyst.
Preparation method of the present invention carries out in organic solvent or water-containing organic solvent, and water-containing organic solvent is meant the mixture of water and organic solvent.
The organic solvent that can use comprises N-Methyl pyrrolidone (NMP), N, dinethylformamide (DMF) and methyl-sulphoxide (DMSO), and preferred organic solvent is N-Methyl pyrrolidone and N, dinethylformamide.Preferred water-containing organic solvent is the mixture of water and N-Methyl pyrrolidone.
Preferred carbonate or supercarbonate are the carbonate or the supercarbonate of sodium, potassium or caesium.Sodium hydroxide, potassium hydroxide, carbonate and supercarbonate can solid form or the form of the aqueous solution or organic solution use.When alkali is sodium hydroxide, preferably use aqueous solution form.
When using sodium hydroxide, every mole of formula (II) compound preferably uses the sodium hydroxide of 1-2 mole, the preferred 20-100 of temperature of reaction ℃; In the presence of yellow soda ash or salt of wormwood, temperature of reaction preferably is higher than 60 ℃.
Beneficial effect of the present invention:
The present invention does not need to change reaction raw materials, through experiment discovery repeatedly, can select for use common sodium hydroxide, potassium hydroxide, carbonate or supercarbonate as the used alkali of this reaction deprotonation, though this result is unexpected, because this is opposite with common lactan hydrogenation reaction situation, the deprotonation of lactan need use stronger alkali usually.Use sodium hydroxide, potassium hydroxide, carbonate or these reagent of supercarbonate to be easy to handle, be suitable for plant-scale application.And reaction result shows, the reaction conditions gentleness is safe and reliable, and yield is higher, and it is extremely strong, perishable to have solved the alkylating reagent water-absorbent of using in the prior art fully, or under lower temperature shortcoming such as blast easily.
Embodiment
Synthetic 3-(3-chloropropyl)-7 in the presence of sodium hydroxide, 8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
Figure A20081003874300071
-2-ketone:
Embodiment 1
With 1.5g (6.8mmol) 7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
Figure A20081003874300072
-2-ketone, 1.5g (9.5mmol) 1,3-bromo-chloropropane and 6mlDMF place flask, and the temperature of reaction mixture is elevated to 40 ℃, add 0.8g40% sodium hydroxide (8mmol) solution.Then with mixture heating up to 60 ℃ and stirred 2 hours; Adding 30ml frozen water also stirred 1 hour under the ice-water bath cooling.The filtering solid precipitation, washing is also dry.The yield of gained title compound is 85%.
Embodiment 2
With 1.5g7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
Figure A20081003874300073
-2-ketone, 1.5g1,3-bromo-chloropropane and 5ml N-Methyl pyrrolidone place flask, and the temperature of reaction mixture is elevated to 40 ℃, add the 0.8g40% sodium hydroxide solution.Then with mixture heating up to 60 ℃ and stirred 2 hours; Adding 30ml frozen water also stirred 1 hour under the ice-water bath cooling.The filtering solid precipitation, washing is also dry.The yield of gained title compound is 83%.
Synthetic 3-(3-chloropropyl)-7 in the presence of salt of wormwood, 8-dimethoxy-1,3-dihydro-2H-3-benzo-aza -2-ketone
Embodiment 3
With 1.5g (6.8mmol) 7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
Figure A20081003874300081
-2-ketone, 2.7g (19.5mmol) salt of wormwood and 8mlDMF mix, and stir 1 hour down at 80 ℃, add 1.9g (12.2mmol) 1 under the equality of temperature, and the 3-bromo-chloropropane continues to stir 2 hours.Add the 50ml frozen water, use dichloromethane extraction, concentrate the oily matter that obtains, add an amount of isopropyl ether and ethyl acetate, stirring is spent the night, and filters and obtains title compound, yield 80%.
Embodiment 4
With 1.5g7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
Figure A20081003874300082
-2-ketone, 2.7g salt of wormwood, 10mg Tetrabutyl amonium bromide and 8mlDMF mix, and stir 1 hour down at 80 ℃, add 1.9g1 under the equality of temperature, and the 3-bromo-chloropropane continues to stir 2 hours.Adding 50ml frozen water also stirred 1 hour under the frozen water cooling.Filtration obtains title compound, yield 85%.
Embodiment 5
With 1.5g7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
Figure A20081003874300083
-2-ketone, 2.7g salt of wormwood and 7mlN-methyl-2-pyrrolidone mix, and stir 1 hour down at 80 ℃, add 1.9g1 under the equality of temperature, and the 3-bromo-chloropropane continues to stir 2 hours.Add the 50ml frozen water, use dichloromethane extraction, concentrate the oily matter that obtains, add an amount of isopropyl ether and ethyl acetate, stirring is spent the night, and filters and obtains title compound, yield 81%.
Embodiment 6
With 1.5g7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
Figure A20081003874300084
-2-ketone, 2.7g salt of wormwood, 10mg Tetrabutyl amonium bromide and 7mlN-methyl-2-pyrrolidone mix, and stir 1 hour down at 80 ℃, add 2.9g tosic acid-3-chloropropyl ester under the equality of temperature, continue to stir 2 hours.Add the 50ml frozen water, use dichloromethane extraction, concentrate the oily matter that obtains, add an amount of isopropyl ether and ethyl acetate, stirring is spent the night, and filters and obtains title compound, yield 85%.

Claims (8)

  1. (1.3-3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
    Figure A2008100387430002C1
    The preparation method of-2-ketone, this method carry out alkylated reaction with formula (II) compound and formula (III) compound in the presence of sodium hydroxide, potassium hydroxide, ammonia soln, carbonate or supercarbonate, aftertreatment gets target product
    Figure A2008100387430002C2
    Wherein X represents leavings group.
  2. 2. 3-as claimed in claim 1 (3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
    Figure A2008100387430002C3
    The preparation method of-2-ketone is characterized in that: leavings group comprises halogen atom, toluene sulfonic acide ester group, methylsulfonic acid ester group and trifluoromethanesulfonic acid ester group.
  3. 3. 3-as claimed in claim 2 (3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
    Figure A2008100387430002C4
    The preparation method of-2-ketone is characterized in that: leavings group is a halogen atom.
  4. 4. 3-as claimed in claim 1 (3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
    Figure A2008100387430002C5
    The preparation method of-2-ketone is characterized in that: add Tetrabutyl amonium bromide as phase-transfer catalyst.
  5. 5. 3-as claimed in claim 1 (3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza The preparation method of-2-ketone is characterized in that: be reflected in alkali organic solvent or the water-containing organic solvent and carry out.
  6. 6. 3-as claimed in claim 5 (3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
    Figure A2008100387430002C7
    The preparation method of-2-ketone is characterized in that: organic solvent is N-Methyl pyrrolidone or N, dinethylformamide.
  7. 7. 3-as claimed in claim 1 (3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
    Figure A2008100387430003C1
    The preparation method of-2-ketone is characterized in that: said carbonate or supercarbonate are meant the carbonate or the supercarbonate of sodium, potassium or caesium.
  8. 8. 3-as claimed in claim 1 (3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
    Figure A2008100387430003C2
    The preparation method of-2-ketone is characterized in that: every mole of formula (II) compound uses the sodium hydroxide of 1-2 mole.
CNA2008100387432A 2008-06-10 2008-06-10 Preparation of 3-(3-chlorine propyl)-7, 8-di methoxy-1, 3-dihydrogen-2H-3-benzo aza -ketone Pending CN101343249A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011098582A2 (en) 2010-02-12 2011-08-18 Krka, D.D., Novo Mesto Novel forms of ivabradine hydrochloride
CN104072420A (en) * 2013-03-26 2014-10-01 瑟维尔实验室 Process for the Synthesis of 7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one Compounds, and Application in the Synthesis of Ivabradine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011098582A2 (en) 2010-02-12 2011-08-18 Krka, D.D., Novo Mesto Novel forms of ivabradine hydrochloride
EP2902384A1 (en) 2010-02-12 2015-08-05 KRKA, D.D., Novo Mesto Forms of ivabradine iydrochloride
CN104072420A (en) * 2013-03-26 2014-10-01 瑟维尔实验室 Process for the Synthesis of 7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one Compounds, and Application in the Synthesis of Ivabradine
CN104072420B (en) * 2013-03-26 2016-09-28 瑟维尔实验室 The synthetic method of 7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza *-2-ketone and application thereof

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