HK1191057B - Process for the enzymatic synthesis of an intermediate of ivabradine, and application in the synthesis of ivabradine and salts thereof - Google Patents

Description

Process for the enzymatic synthesis of an intermediate of ivabradine and use in the synthesis of ivabradine and salts thereof

Technical Field

The invention relates to a method for the enzymatic synthesis of a compound of formula (I), namely (7S) -1- (3, 4-dimethoxybicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) N-methylmethanamine:

(I)

and relates to their use in the synthesis of ivabradine of formula (II):

(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, more particularly its hydrochloride, have very valuable pharmacological and therapeutic properties, in particular heart rate slowing (bradycardic) properties, which make these compounds useful for the treatment or prevention of various clinical manifestations of myocardial ischemia, such as angina pectoris, myocardial infarction and related rhythm disorders, and also for various diseases involving rhythm disorders, in particular supraventricular arrhythmias, and for heart failure.

The preparation and therapeutic use of ivabradine and addition salts thereof with a pharmaceutically acceptable acid, more particularly the hydrochloride salt thereof, have been described in european patent specification EP 0534859.

The patent specification describes the synthesis of ivabradine hydrochloride from the compound of formula (I).

The compounds of formula (I) are key intermediates in the synthesis of ivabradine and pharmaceutically acceptable salts thereof.

The prior art discloses several methods for obtaining compounds of formula (I).

Patent specification EP0534859 describes the synthesis of compounds of formula (I) as follows: by BH₃Reducing racemic nitrile of formula (III) in tetrahydrofuran:

(III)

subsequent addition of hydrochloric acid affords the racemic hydrochloride of the amine of formula (IV):

(IV)

reacting it with ethyl chloroformate to obtain a carbamate of formula (V):

(V)，

by LiAlH₄Reducing it to give the racemic methylated amine of formula (VI):

(VI)，

it is resolved with camphorsulfonic acid to give the compound of formula (I).

The disadvantage of this process is that starting from racemic nitriles of the formula (III), the compounds of the formula (I) are obtained only in very low yields of 2 to 3%.

This very low yield is caused by the low yield (4-5%) of the resolution step of the secondary amine of formula (VI).

Patent specification EP1598333 describes the following obtaining of the compound of formula (I):

converting racemic primary amine of formula (IV) to its salt using N-acetyl-L-glutamic acid, followed by recrystallization and then reversion to base, to give optically active primary amine of formula (VII):

(VII)，

methylation is then carried out using the same reaction sequence described above (conversion to carbamate followed by reduction).

The process gives methylamine of the formula (I) in about 30% yield over 4 steps starting from a racemic primary amine of the formula (IV).

Disclosure of Invention

The technical problem of the present invention is to obtain the compounds of formula (I) starting from racemic primary amines of formula (IV) with a reduced number of steps while maintaining a good overall yield.

More particularly, the present invention relates to a process for the synthesis of carbamates of formula (IX) as follows:

，

wherein R is₁Represents a straight or branched chain C₁-C₆An alkyl group, an allyl group or a benzyl group,

in an organic solvent or an aqueous solvent, an organic solvent mixture, or a mixture of an organic solvent and an aqueous solvent,

at a concentration of from 5 to 500g/L of compound of formula (IV) per litre of solvent or solvent mixture,

at an E/S ratio of 10/1 to 1/100, preferably 1/1 to 1/10,

at a temperature of 25 ℃ to 40 ℃,

using a lipase (EC 3.1.1.3 in the international classification of enzymes) and an amount of 1 to 15 molar equivalents of R wherein R is relative to the amine of formula (IV)₁Formula R as defined above₁O-(CO)-OR₁Enantioselective enzymatic acylation of racemic amines of the formula (IV).

The carbamates of formula (IX) obtained by the process of the present invention preferably have an enantiomeric purity of more than 85%, in other words an enantiomeric excess of more than 70%.

Among the lipases which can be used in the enzymatic esterification process of the present invention, mention may be made, without being limited thereto, of Pseudomonas fluorescens (lipases), Pseudomonas cepacia (lipases), porcine pancreatic lipase and the lipase PS 'Amano' SD (Burkholderia cepacia) and IM (immobilized on diatomaceous earth).

Preferred lipases of the invention are those of Pseudomonas cepacia (Pseudomonas cepacia) and PS 'Amano' IM.

Preferred carbonates R₁O-(CO)-OR₁Is wherein R is₁Those representing an allyl, ethyl or benzyl group.

Among the organic solvents that can be used in the enzymatic acylation reaction of the present invention, mention may be made, but not limited to, ethyl acetate, TBME, THF, 2-MeTHF, toluene, 1, 4-dioxane, tert-amyl alcohol, CPME and acetonitrile.

Preferred solvents are TBME, THF, 2-MeTHF and 1, 4-dioxane, either as such or mixed with a buffer pH = 7.

The enzymatic acylation scheme of the present invention is shown below:

the carbamate of formula (IX) is then isolated from the reaction mixture, followed by the use of an aluminum hydride, such as lithium aluminum hydride (LiAlH)₄) Or sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) to reduce the aluminum hydroxide,

to give the methylated amines of the formula (I).

The methylated amine of formula (I) is then coupled with a compound of formula (X):

(X)，

wherein X represents a halogen atom, preferably an iodine atom, or, in the presence of a reducing agent, with a compound of formula (XI):

(XI)，

wherein R is₂Expressed in CHO and CHR₃R₄Wherein R is₃And R₄Each represents a straight chain or branched chain (C)₁-C₆) Alkoxy groups, or together with the carbon atom bearing them, form a 1, 3-dioxane, 1, 3-dioxolane or 1, 3-dioxepane ring,

ivabradine is obtained which is then converted into an addition salt with a pharmaceutically acceptable acid.

The compounds of formula (I) can also be used in reductive amination reactions in the form of their addition salts with pharmaceutically acceptable acids, preferably their hydrochloride salts. In this case ivabradine is obtained directly in the form of the hydrochloride.

Definition of

Racemic compounds are understood to be compounds in the form of a mixture of two enantiomers in a ratio of from 55:45 to 45: 55.

Enantioselective acylation of an amine in the form of a mixture of two enantiomers is understood to preferentially acylate one of the enantiomers in the mixture.

Among the pharmaceutically acceptable acids, mention may be made, without being limited thereto, 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.

Among the reducing agents which can be used in the reductive amination reaction between the compound of formula (I) and the compound of formula (XI), mention may be made, without limitation, of hydride donor compounds such as sodium triacetoxyborohydride or sodium cyanoborohydride, andh in the presence of a catalyst₂Such as palladium, platinum, nickel, ruthenium, rhodium or compounds thereof, in particular on a support or in the form of oxides.

A preferred reducing agent for the reductive amination reaction between a compound of formula (I) and a compound of formula (XI) is palladium on carbon catalyzed H₂。

The examples which follow illustrate the invention.

Abbreviations

CPME Cyclopentylmethyl Ether

DEA diethylamine

E enantioselectivity coefficient

Enzyme/substrate ratio of E/S in g/g

ee enantiomeric excess

eq molar equivalent

HPLC high performance liquid chromatography

Red-Al sodium bis (2-methoxyethoxy) aluminum hydride

NMR Nuclear magnetic resonance (Spectroscopy)

TBME Tert-butyl methyl Ether

THF tetrahydrofuran

2-Me HF 2-methyltetrahydrofuran

rpm revolutions per minute

Detailed Description

Example 1{ [ (7S) -3, 4-Dimethoxybicyclo [4.2.0]]Oct-1, 3, 5-trien-7-yl]Methyl ethyl carbamate

5mg of 1- (3, 4-dimethoxybicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) methylamine and 12.6mg (10eq) of diethyl carbonate were dissolved in 2-MeTHF.

5mg of Lipase II (PS-CII Amano) from Pseudomonas cepacia (Pseudomonas cepacia) were then added to the mixture (E/S ratio 1/1). The reaction mixture was maintained at 30 ℃ with rotational stirring at 250rpm for 24 to 96 hours.

The reaction was monitored by chiral phase HPLC under conditions enabling determination of the enantiomeric excess of the carbamate and amine:

chiral phase conditions:IC250 x 4.6 column

50% Anhydrous ethanol +0.1% DEA +50% heptane +0.1% DEA

1ml/min,25°C,288nm

Example 2{ [ (7S) -3, 4-Dimethoxybicyclo [4.2.0]]Oct-1, 3, 5-trien-7-yl]Methyl ethyl carbamate

0.5g of 1- (3, 4-dimethoxybicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) methylamine was dissolved in 50mL of 2-MeTHF, and diethyl carbonate (1.5mL,12eq) was added. 0.5g (E/S ratio 1/1) of Lipase II from Pseudomonas cepacia (PS-CII Amano) was added to the mixture, which was maintained under stirring at 220rpm at 30 ℃ for 48 hours.

After 48 hours, the reaction mixture was filtered to remove the enzyme and then evaporated. After separation on a SiO2 column eluting with cyclohexane/ethyl acetate 95/5 then 80/20 and finally 50/50 (to recover the more polar amine) the carbamate of configuration S was obtained.

The ethyl carbamate of configuration S (224mg) was then obtained in a yield of 32.5% with respect to the starting amine (65% with respect to the expected amount of carbamate), an enantiomeric purity of 90%.

The reaction was monitored by chiral phase HPLC under conditions enabling determination of the enantiomeric excess of the carbamate and amine:

chiral phase conditions:IC250 x 4.6 column

50% Anhydrous ethanol +0.1% DEA +50% heptane +0.1% DEA

1ml/min,25°C,288nm

Example 3{ [ (7S) -3, 4-Dimethoxybicyclo [4.2.0]]Oct-1, 3, 5-trien-7-yl]Methyl allyl carbamate

0.87g of 1- (3, 4-dimethoxybicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) methylamine was dissolved in 100mL of 2-MeTHF, followed by addition of diallyl carbonate (1.5mL, 2 eq). 0.5g (E/S ratio 1/1) of Lipase II from Pseudomonas cepacia (PS-CII Amano) was added to the mixture, which was maintained under stirring at 220rpm at 30 ℃ for 42 hours.

The reaction mixture was filtered to remove the enzyme and then evaporated. In SiO₂Allyl carbamate was obtained after separation on a column, eluting with cyclohexane/ethyl acetate 95/5 then 80/20 and finally 50/50 (to recover the more polar amine).

Allyl carbamates of the configuration S (440mg) are then obtained in a yield of 35% relative to the starting amine (70% relative to the expected amount of carbamate), in an enantiomeric purity of 88%.

The reaction mixture was analyzed by reverse phase HPLC according to the method described below, and the enantioselectivity (ee) of the carbamate and the amine was monitored by chiral phase HPLC:

and (3) reverse phase conditions:LUNA HST50 x 3 column C18(2)2.5 μm

0-100% B0.8ml/min40 ℃ over 8min

A (1000 Water +25ACN +1TFA)

B (1000ACN +25 Water +1TFA)

Chiral phase conditions:IC250 x 4.6 column

50% isopropanol +0.1% EA +50% heptane +0.1% EA

1ml/min,30°C,288nm

Example 4{ [ (7S) -3, 4-Dimethoxybicyclo [4.2.0]]Oct-1, 3, 5-trien-7-yl]Methyl } carbamic acid benzyl ester

0.5g of 1- (3, 4-dimethoxybicyclo [4.2.0] oct-1, 3, 5-trien-7-yl) methylamine was dissolved in 50mL of 2-MeTHF, and dibenzyl carbonate (4.5g,7eq) was added. 0.5g (E/S ratio 1/1) of Lipase II from Pseudomonas cepacia (PS-C II Amano) was added to the mixture, which was maintained at 30 ℃ with stirring at 220 rpm.

After 24 hours, the reaction mixture was filtered to remove the enzyme and then evaporated. In SiO₂On the column, the carbamate of configuration S is obtained after separation with cyclohexane/ethyl acetate 95/5 then 80/20 and finally with 50/50 (to recover the more polar amine).

Benzyl carbamate of configuration S (0.26g) is then obtained in a yield of 30% with respect to the starting amine (60% with respect to the expected amount of carbamate), in an enantiomeric purity of 95%.

The reaction mixture was analyzed by reverse phase HPLC according to the method described below, and the enantioselectivity (ee) of the carbamate and the amine was monitored by chiral phase HPLC:

and (3) reverse phase conditions:LUNA HST50 x 3 column C18(2)2.5 μm

0-100% B0.8ml/min40 ℃ over 8min

A (1000 Water +25ACN +1TFA)

B (1000ACN +25 Water +1TFA)

Chiral phase conditions:IC250 x 4.6 column

50% isopropanol +0.1% DEA +50% heptane +0.1% DEA

1ml/min,25°C,288nm

Example 5(7S) -3, 4-dimethoxybicyclo [4.2.0]Oct-1, 3, 5-trien-7-yl]N-methyl methylamine

Lithium aluminium hydride (1.41kg) and tetrahydrofuran (32.5l) were loaded into the reactor under nitrogen and a solution of ethyl { [ (7S) -3, 4-dimethoxybicyclo [4.2.0] oct-1, 3, 5-trien-7-yl ] methyl } carbamate (5kg) in tetrahydrofuran (50l) was poured at 20 ℃. Heated to reflux for 1 hour, then cooled to a temperature below 15 ℃ and the reaction mixture was hydrolyzed with water (1l), 5N aqueous sodium hydroxide solution (1l), then water (1 l). The resulting solid was filtered off. The organic phase was dried. The title product was recovered as an oil in 93% yield.

¹H NMR(DMSO-d6,ppm/TMS)=2.60(m;3H);2.85(m;1H);3.15(m;1H);3.25(dd;1H);3.30(m;1H);3.62(m;1H);3.70(s;6H);6.82(s;1H);6.89(s;1H);8.48(sl;1H).

Example 6(7S) -3, 4-dimethoxybicyclo [4.2.0]Oct-1, 3, 5-trien-7-yl]N-methyl methylamine hydrochloride

(7S) -3, 4-Dimethoxybicyclo [4.2.0] oct-1, 3, 5-trien-7-yl ] N-methylmethanamine (5kg), ethyl acetate (40l) and ethanol (10l) were loaded into the reactor. After stirring for 30 minutes at 20 ℃, hydrogen chloride gas (1.012kg) was added through the reactor bottom valve or immersion tube. The resulting suspension is stirred at 15-20 ℃ for 1 hour and then filtered or drained off under suction. The precipitate was washed with an 4/1 mixture of ethyl acetate/ethanol (2 × 5l) and then dried to give the title product in 92% yield.

Example 7Ivabradine hydrochloride

5.5kg of 3- [2- (1, 3-dioxolan-2-yl) ethyl ] -7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepin-2-one, 27.5l of ethanol and 550g of palladium on carbon were loaded into the autoclave.

Flushed with nitrogen and then with hydrogen, heated to 55 ℃ and then hydrogenated at this temperature under a pressure of 5 bar until the theoretical amount of hydrogen was absorbed.

Then returned to ambient temperature and the autoclave was depressurized.

4kg of (7S) -3, 4-dimethoxybicyclo [4.2.0] oct-1, 3, 5-trien-7-yl ] N-methylmethanemethanemethanol hydrochloride, 11l of ethanol, 5.5l of water and 1kg of palladium on carbon are then added.

Flushed with nitrogen and then with hydrogen, heated to 85 ℃ and then hydrogenated at this temperature under a pressure of 30 bar until the theoretical amount of hydrogen was absorbed.

Then returning to ambient temperature, flushing the autoclave and then filtering the reaction mixture; the solvent is distilled off and the ivabradine hydrochloride is then isolated by crystallization from a toluene/1-methyl-2-pyrrolidone mixture.

Thus, ivabradine hydrochloride was obtained in 85% yield and with a chemical purity of more than 99%.

Example 8For the enzymatic acylation of 1- (3, 4-dimethoxybicyclo [4.2.0]]Screening of Lipase of octa-1, 3, 5-trien-7-yl) methylamine

Racemic 1- (3, 4-dimethoxybicyclo [4.2.0]]Octa-1, 3, 5-trien-7-yl) methylamine (5mg; c =10g/L) and formula R₁O-(CO)-OR₁Was dissolved in 0.5mL of TBME (10 eq).

5mg (c =10g/L) of the lipase under investigation were then added to the medium (E/S ratio = 1/1). The reaction mixture was maintained under rotational stirring at 30 ℃ at 250rpm for 24 hours.

The reaction mixture was analyzed by chiral phase HPLC according to the following method in order to check the enantioselectivity:

IC20 μm column, 250 × 4.6 acetonitrile/propan-2-ol/DEA 90/10/0.1%, 1.3ml/min, 30 deg.C, 288nm

The results are summarized in the following table:

IXa:R₁= allyl group

IXb:R₁= benzyl group

IXc:R₁= ethyl group

^aEnantiomeric excess ee (en%) =% enantiomer E2-% enantiomer E1/% enantiomer E2+% enantiomer E1 (enantiomer E2 is the predominant enantiomer)

^bEnantioselectivity coefficient E = ln [ (1-c) (1-ee (S))]/ln[(1-c)(1+ee(S)](ii) a c = degree of conversion = ee (amine)/[ ee (carbamate) + ee (amine)]。

Claims (10)

1. A process for the synthesis of a compound of formula (IX) as follows:

wherein R is₁Represents a straight or branched chain C₁-C₆An alkyl group, an allyl group or a benzyl group,

in an organic solvent or an aqueous solvent, an organic solvent mixture, or a mixture of an organic solvent and an aqueous solvent,

at a concentration of from 5 to 500g/L of compound of formula (IV) per litre of solvent or solvent mixture,

at an E/S ratio of 10/1 to 1/100, at a temperature of 25 ℃ to 40 ℃,

using a lipase which is EC3.1.1.3 in the international classification of enzymes and an amount of 1 to 15 molar equivalents of the amine of formula (IV) wherein R₁Formula R as defined above₁O-(CO)-OR₁Enantioselective enzymatic carbamation of a racemic amine of formula (IV):

wherein the solvent is selected from TBME, THF, 2-MeTHF and 1, 4-dioxane, either as such or in admixture with a buffer at pH 7.

2. The synthesis process according to claim 1, wherein the lipase is selected from the group consisting of Pseudomonas fluorescens (Pseudomonas fluorescens) lipase, Pseudomonas cepacia (Pseudomonas cepacia) lipase, porcine pancreatic lipase and the lipases PS 'Amano' SD and PS 'Amano' IM.

3. The synthesis process according to claim 2, wherein the lipase is Pseudomonas cepacia (Pseudomonas cepacia) lipase or lipase PS 'Amano' IM.

4. The synthetic method according to any one of claims 1 to 3, wherein the E/S ratio is 1/1 to 1/10.

5. The synthetic method according to any one of claims 1 to 3, wherein R₁Is an ethyl, allyl or benzyl group.

6. A process for the synthesis of a compound of formula (I) as follows:

enzymatic carbamoylation of racemic amines of formula (IV) according to the process of any of claims 1-5 to obtain carbamates of formula (IX):

wherein R is₁Represents a straight or branched chain C₁-C₆An alkyl, allyl or benzyl group,

then using a catalyst selected from LiAlH₄And Red-Al, reducing it,

to obtain the compound of formula (I).

7. A process for the synthesis of ivabradine or a salt thereof, wherein a compound of formula (I) is synthesized according to the process of claim 6,

the compound of formula (I) is then coupled with a compound of formula (X):

wherein X represents a halogen atom, and X represents a halogen atom,

alternatively, the compound of formula (I) is subjected to a reductive amination reaction with a compound of formula (XI) in the presence of a reducing agent:

wherein R is₂Represents a compound selected from CHO and CHR₃R₄The group of (a) or (b),

wherein R is₃And R₄Each represents a straight chain or branched chain (C)₁-C₆) Alkoxy groups, or together with the carbon atom bearing them, form a 1, 3-dioxane, 1, 3-dioxolane or 1, 3-dioxepane ring,

ivabradine is obtained and is then converted into an addition salt with a pharmaceutically acceptable acid, in anhydrous or hydrated form.

8. The synthetic method of claim 7, wherein X is an iodine atom.

9. The synthesis according to claim 7, wherein the compound of formula (I) used in the reductive amination is in its hydrochloride form, giving ivabradine in its hydrochloride form.

10. The synthesis process according to claim 7 or claim 9, wherein the reductive amination reaction with a compound of formula (XI) is carried out in palladium on carbon catalyzed H₂In the presence of oxygen.