HK1140188B - New process for the synthesis of 7,8-dimethoxy-1,3-dihydro-2h-3-benzazepin-2-one, and application thereof - Google Patents

Description

Method for synthesizing 7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepin-2-ketone and application thereof

Technical Field

The invention relates to the synthesis of 7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepine of formula (I)Process for the synthesis of ivabradine, addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof

The compound of formula (I) obtained according to the process of the invention can be used for the synthesis of ivabradine of formula (II),or 3- {3- [ { [ (7S) -3, 4-dimethoxybicyclo [4.2.0]]Oct-1, 3, 5-trien-7-yl]Methyl } (methyl) amino]-propyl } -7, 8-dimethoxy-1, 3, 4, 5-tetrahydro-2H-3-benzazepine-2-ketones, their addition salts with pharmaceutically acceptable acids and their hydrates.

Background

Ivabradine and its addition salts with a pharmaceutically acceptable acid, in particular its hydrochloride, have very valuable pharmacological and therapeutic properties, in particular heart rate slowing properties, which make these compounds useful for the treatment or prevention of various clinical conditions of myocardial ischemia, such as angina pectoris, myocardial infarction and related arrhythmias, and also for various diseases involving arrhythmias, in particular supraventricular arrhythmias, and heart failure.

The preparation and therapeutic use of ivabradine and its addition salts with a pharmaceutically acceptable acid, in particular its hydrochloride, are described in european patent specification EP 0534859.

The specification of this patent describes the synthesis of ivabradine starting from a compound of formula (III):

and the compound was prepared with reference to document J.Med.chem 1990, Vol.33(5), 1496-1504.

The synthetic route described in this document for the preparation of compounds of formula (III) employs alkylation of compounds of formula (I):

the preparation of compounds of formula (I) by using the intermediate N- (2, 2-dimethoxyethyl) -2- (3, 4-dimethoxyphenyl) acetamide prepared from (3, 4-dimethoxyphenyl) acetic acid is described in the above-mentioned document. The phenylacetamide obtained was cyclized in acetic acid in the presence of hydrochloric acid to obtain a compound of the formula (I) in an overall yield of 58% based on (3, 4-dimethoxyphenyl) acetic acid.

In view of the industrial value of ivabradine and its salts, it is highly desirable to find an effective 7, 8-dimethoxy-1, 3-dihydro-2 of formula (I) which is able to be obtained in excellent yieldsH-3-benzazepine-2-ketone.

Disclosure of Invention

The applicant has now surprisingly found that by using specific operating conditions, it is possible to obtain on an industrial scale a compound of formula (I) with a chemical purity greater than 99.5% in a yield higher than 92%.

More particularly, the present invention relates to a process for synthesizing a compound of formula (I):

characterized in that (3, 4-dimethoxyphenyl) acetic acid of formula (IV):

conversion to a compound of formula (V):

wherein the radical R₁And R₂May be the same or different and represents a linear or branched (C)₁-C₆) Alkoxy, or together with the carbon atom bearing them, form a 1, 3-dioxane, 1, 3-dioxolane or 1, 3-dioxepane ring,

carrying out cyclization reaction in an acidic medium, and separating to obtain the compound of the formula (I).

In a preferred embodiment of the invention, the conversion of the compound of formula (IV) into the compound of formula (V) is carried out by: the compound of formula (IV) is first converted in an organic solvent to a compound of formula (VI):

wherein X represents a halogen atom or OCOR₃Group, wherein R₃Is straight-chain or branched (C)₁-C₆) Alkyl, phenyl, benzyl or imidazolyl,

then carrying out condensation reaction on the compound of the formula (VI) and the compound of the formula (VII) in an organic solvent in the presence of a base:

wherein the radical R₁And R₂May be the same or different and represents a linear or branched (C)₁-C₆) Alkoxy, or together with the carbon atom bearing them, form a 1, 3-dioxane, 1, 3-dioxolane or 1, 3-dioxepane ring,

to produce a compound of formula (V):

in another preferred embodiment of the invention, the compound of formula (IV) is converted to the compound of formula (V) by reaction with a compound of formula (VII):

wherein the radical R₁And R₂May be the same or different and represents a linear or branched (C)₁-C₆) Alkoxy, or together with the carbon atom bearing them, form a 1, 3-dioxane, 1, 3-dioxolane or 1, 3-dioxepane ring,

in the presence of a coupling agent in an organic solvent,

to produce a compound of formula (V):

coupling agents useful in the condensation reaction of a compound of formula (VII) with a compound of formula (IV) include, but are not limited to, the following reagents or reagent pairs: EDCI, EDCI/HOBT, EDCI/HOAT, EDCI/NHS, DCC/HOBT, DCC/HOAT, DCC/NHS, HATU, HBTU, TBTU, BOP, PyBOP, CDI, T3P.

Organic solvents that may be used in the condensation reaction of the compound of formula (VII) and the compound of formula (IV) in the presence of a coupling agent include, but are not limited to, toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, 1, 2-dichloroethane, chloroform and dioxane.

In a preferred embodiment of the invention, the compound of formula (V) is not isolated.

In a preferred embodiment of the present invention, the compound of formula (VI) is not isolated.

The group X in the compounds of the formula (VI) preferably represents a chlorine atom.

Organic solvents that may be used in the reaction to convert the compound of formula (IV) to the compound of formula (VI) include, but are not limited to, toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, 1, 2-dichloroethane, chloroform and dioxane.

The preferred organic solvent used in the reaction to convert the compound of formula (IV) to the compound of formula (VI) is dichloromethane.

The temperature of the reaction for converting the compound of formula (IV) to the compound of formula (VI) is preferably from 20 to 40 ℃.

A preferred reagent for converting the compound of formula (IV) to a compound of formula (VI) wherein X represents a chlorine atom is thionyl chloride.

The amount of thionyl chloride used in the reaction to convert the compound of formula (IV) to the compound of formula (VI) is preferably 1 to 1.3 moles per mole of the compound of formula (IV).

Organic solvents that may be used in the reaction between the compound of formula (VI) and the compound of formula (VII) include, but are not limited to, toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, 1, 2-dichloroethane, chloroform and dioxane.

A preferred organic solvent for the reaction between the compound of formula (VI) and the compound of formula (VII) is dichloromethane.

The temperature at which the compound of formula (VI) is reacted with the compound of formula (VII) is preferably from 0 to 40 ℃.

The amount of the compound of the formula (VII) used in the reaction with the compound of the formula (VI) is preferably 1 to 1.2 moles per mole of the compound of the formula (VI).

The amount of base used in the reaction between the compound of formula (VI) and the compound of formula (VII) is preferably 1 to 1.3 moles per mole of the compound of formula (VI).

Bases that may be used in the reaction between the compound of formula (VI) and the compound of formula (VII) include, but are not limited to, pyridine, DMAP and tertiary amines such as triethylamine, DIEA, N-methylpiperidine, DBU, DABCO, DBN and N-methylmorpholine.

The base used in the reaction between the compound of formula (VI) and the compound of formula (VII) is preferably triethylamine.

Acids that may be used to carry out the cyclization of compound of formula (V) to form compound of formula (I) include, but are not limited to, concentrated sulfuric acid, polyphosphoric acid, aqueous concentrated hydrochloric acid, concentrated hydrochloric acid in acetic acid, concentrated hydrobromic acid in acetic acid, and methanesulfonic acid.

The amount of acid used in the reaction to cyclize the compound of formula (V) to form the compound of formula (I) is preferably from 5 to 15 moles per mole of the compound of formula (V).

The temperature at which the cyclization of the compound of the formula (V) in the acidic medium is carried out is preferably from 0 to 40 ℃.

The acid used to carry out the cyclisation of the compound of formula (V) to form the compound of formula (I) is preferably concentrated sulphuric acid.

When the reaction intermediate is not isolated during the reaction, the amount of concentrated sulfuric acid used in the cyclization reaction of the compound of formula (V) is preferably 1.5 to 3 ml per gram of (3, 4-dimethoxyphenyl) acetic acid of formula (IV).

The compounds of formula (I) obtained according to the process of the present invention are particularly useful as synthesis intermediates for the synthesis of ivabradine, addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof.

For example, a compound of formula (I) is alkylated with a compound of formula (VIII):

wherein R is₄And R₅May be the same or different and each represents a linear or branched (C)₁-C₆) Alkoxy, or together with the carbon atom bearing them, forms 1, 3-dioxane or 1, 3-dioxolane, and Y represents a halogen atom, preferably a bromine atom, or a tosylate, mesylate or triflate group,

to produce a compound of formula (IX)

Which is catalytically hydrogenated to form the corresponding hydrogenated compound of formula (X):

wherein R is₄And R₅As defined in the compound of formula (VIII),

deprotection of the diacetal moiety to give an aldehyde of the formula (XI):

reacting it with (7S) -3, 4-dimethoxybicyclo [4.2.0] oct-1, 3, 5-trien-7-yl ] -N-methyl-methylamine under reductive amination conditions to form ivabradine, which can optionally be converted into an addition salt with a pharmaceutically acceptable acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid and camphoric acid and converted into a hydrate.

Detailed description of the preferred embodiments

Abbreviations used:

BOP: benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphates

CDI: carbonyl diimidazoles

DABCO: 1, 4-diazabicyclo [2.2.2] octane

DBN: 1, 5-diazabicyclo [4.3.0] non-5-ene

DBU: 1, 8-diazabicyclo [5.4.0] undec-7-ene

DCC: dicyclohexylcarbodiimide

DIEA: n, N-diisopropylethylamine

DMAP: 4-dimethylaminopyridine

EDCI: 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride

HATU: o- (7-azabenzotriazol-1-yl) -1, 1,3, 3-tetramethyluronium hexafluorophosphate

HBTU: o- (benzotriazol-1-yl) -1, 1,3, 3-tetramethyluronium hexafluorophosphate

HOAT: 1-hydroxy-7-azabenzotriazoles

HOBT: 1-hydroxybenzotriazoles

NHS: n-hydroxysuccinimide

NMP: n-methyl pyrrolidone

PyBOP: o- (benzotriazol-1-yl) -oxytis (pyrrolidin-1-yl) phosphonium hexafluorophosphate

TBTU: o- (benzotriazol-1-yl) -1, 1,3, 3-tetramethyluronium tetrafluoroborate

T3P: n-propanephosphonic acid anhydride

The following examples illustrate the invention.

7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepinePreparation of (E) -2-ketones

Step A: (3, 4-Dimethoxyphenyl) acetyl chloride

135g of (3, 4-dimethoxyphenyl) acetic acid and 270ml of dichloromethane are added to the reactor, and then the temperature of the reaction mixture is raised to reflux and 90g of thionyl chloride is added dropwise. The mixture was stirred at reflux for 3 hours. The resulting solution was used directly in the subsequent step.

And B: n- (2, 2-Dimethoxyethyl) -2- (3, 4-Dimethoxyphenyl) acetamide

225ml of dichloromethane, 44.15g of 2, 2-dimethoxyethylamine and 44.35g of triethylamine were added to the reactor, and then the mixture was cooled to 10 ℃ and 237.4g of the solution obtained in the preceding step (corresponding to 75g of (3, 4-dimethoxyphenyl) acetic acid) were added dropwise, maintaining the temperature of the reaction mass at 10 ℃. The mixture was stirred at 15 ℃ for 2 hours. The resulting solution was used directly in the subsequent step.

And C: 7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepine-2-ketones

150ml of 36N sulfuric acid are added to the reactor containing the solution obtained in the previous step and cooled to 10 ℃ while maintaining the temperature below 20 ℃. The mixture was stirred at 15-20 ℃ for 10 hours, then the reaction mixture was allowed to separate and the product-containing sulfuric acid phase was collected.

The product was obtained by precipitation with a water/NMP mixture (4/1), filtration and drying in 92.9% yield based on (3, 4-dimethoxyphenyl) acetic acid and with a chemical purity of greater than 99.5%.

Claims (20)

1. A method of synthesizing a compound of formula (I):

characterized in that (3, 4-dimethoxyphenyl) acetic acid of formula (IV):

conversion to a compound of formula (V):

wherein the radical R₁And R₂May be the same or different and represents a linear or branched (C)₁-C₆) Alkoxy, or together with the carbon atom bearing them, form a 1, 3-dioxane, 1, 3-dioxolane or 1, 3-dioxepane ring,

the compound is directly subjected to cyclization reaction in an acid medium without separation to obtain the compound shown in the formula (I) after separation.

2. The synthesis of claim 1, wherein the conversion of the compound of formula (IV) to the compound of formula (V) is carried out by: the compound of formula (IV) is first converted in an organic solvent to a compound of formula (VI):

wherein X represents a halogen atom or OCOR₃Group, wherein R₃Is straight-chain or branched (C)₁-C₆) Alkyl, phenyl, benzyl or imidazolyl,

then carrying out condensation reaction on the compound of the formula (VI) and the compound of the formula (VII) in an organic solvent in the presence of a base:

wherein the radical R₁And R₂May be the same or different and represents a linear or branched (C)₁-C₆) Alkoxy, or together with the carbon atom bearing them, form a 1, 3-dioxane, 1, 3-dioxolane or 1, 3-dioxepane ring，

To produce a compound of formula (V):

3. the synthesis of claim 1, wherein the compound of formula (IV) is converted to the compound of formula (V) by reaction with a compound of formula (VII):

wherein the radical R₁And R₂May be the same or different and represents a linear or branched (C)₁-C₆) Alkoxy, or together with the carbon atom bearing them, form a 1, 3-dioxane, 1, 3-dioxolane or 1, 3-dioxepane ring,

in the presence of a coupling agent in an organic solvent,

to produce a compound of formula (V):

4. the synthesis according to claim 2, characterized in that the compound of formula (VI) is not isolated.

5. The process of claim 4, wherein in the compound of formula (VI), X represents a chlorine atom.

6. A process as claimed in any one of claims 2, 4 or 5, wherein the solvent used to convert the compound of formula (IV) to the compound of formula (VI) is dichloromethane.

7. A synthesis process according to any one of claims 2, 4 or 5, characterised in that the reaction temperature for the conversion of the compound of formula (IV) to the compound of formula (VI) is from 20 to 40 ℃.

8. A process according to any one of claims 2, 4 or 5, wherein the reagent used to convert the compound of formula (IV) to the compound of formula (VI) is thionyl chloride.

9. The synthesis process according to claim 8, characterized in that the amount of thionyl chloride used in the reaction for converting the compound of formula (IV) into the compound of formula (VI) is 1 to 1.3 moles per mole of the compound of formula (IV).

10. A process according to any one of claims 2, 4 or 5, wherein the solvent used for the reaction between the compounds of formula (VI) and (VII) is dichloromethane.

11. A synthesis process according to any one of claims 2, 4 or 5, characterized in that the temperature of the reaction between the compounds of formulae (VI) and (VII) is between 0 and 40 ℃.

12. A process according to any one of claims 2, 4 or 5, characterized in that the amount of compound of formula (VII) used in the reaction with compound of formula (VI) is between 1 and 1.2 moles per mole of compound of formula (VI).

13. The synthesis process according to any one of claims 2, 4 or 5, characterized in that the amount of base used in the reaction between the compound of formula (VI) and the compound of formula (VII) is between 1 and 1.3 moles per mole of compound of formula (VI).

14. A synthesis process according to any one of claims 2, 4 or 5, characterized in that the base used for the reaction between the compound of formula (VI) and the compound of formula (VII) is pyridine, DMAP or a tertiary amine.

15. A synthesis process according to claim 14, characterized in that the base used for the reaction between the compound of formula (VI) and the compound of formula (VII) is triethylamine.

16. The synthesis process according to any one of claims 1 to 5, characterized in that the amount of acid used in the cyclization of the compound of formula (V) is from 5 to 15 moles per mole of the compound of formula (V).

17. The synthesis process according to any one of claims 1 to 5, characterized in that the temperature of the cyclization reaction of the compound of formula (V) is from 0 to 40 ℃.

18. The process of any one of claims 1 to 5, wherein the acid used for the cyclisation of the compound of formula (V) is sulphuric acid.

19. The process of claim 18, wherein the amount of concentrated sulfuric acid used in the cyclization of the compound of formula (V) is from 1.5 to 3 ml per gram of (3, 4-dimethoxyphenyl) acetic acid of formula (IV).

20. A process for the synthesis of ivabradine, wherein a compound of formula (IV) is converted into a compound of formula (I) according to the process of claim 1, and then the compound of formula (I) is converted into ivabradine, which is optionally converted into an addition salt with a pharmaceutically acceptable acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid and camphoric acid.