TW200817334A - New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid - Google Patents

Abstract

A method of synthesis of ivabradine of formula (I), (I) the salts thereof for addition to a pharmaceutically acceptable acid and the hydrates thereof. The crystalline form α of ivabradine hydrochloride is also described.

Description

200817334 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to an industrial synthetic formula (I) ivabradine:

(or 3-{3-[{[(73)_3,4-dimethoxybicyclo[4.2.0]octyl-1,3,5-trien-7-yl]methyl}(fluorenyl) Amino]-propyl b 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-phenylindolezin-2-one, which is added with a pharmaceutically acceptable acid Method for salt formation and its hydrates. [Prior Art] Ivabradine and its addition salts with pharmaceutically acceptable acids, and especially its hydrochloride salts, have valuable pharmacological and therapeutic properties, especially To slow down the nature of heart rate drugs, these compounds are useful in the treatment or prevention of various clinical conditions of myocardial U ischemia, such as angina pectoris, myocardial infarction and related heart rhythm disorders, as well as including cardiac rhythm disorders, especially supraventricular rhythm disorders. (supraventricular rhythm disturbance) a variety of conditions, and is suitable for the treatment of heart failure. Ivabradine and its addition salts with pharmaceutically acceptable acids, and more particularly the preparation and therapeutic use of its hydrochloride has been in Europe The patent specification is described in EP 0 534 859. This patent specification describes the synthesis of ivabradine hydrochloride by combining 115002.doc 200817334 formula (II) : ^^^ och3 [1 Shang compound (Π) CH3HN ^ V ^ ~~ formula (III) Reaction:

(m)

To produce a compound of formula (IV):

(IV), catalytic hydrogenation to produce ivabradine, followed by conversion to its hydrochloride. This process has the disadvantage of producing ivabradine hydrochloride in a very low yield of less than 17%, generally in three steps. With regard to the pharmaceutical value of ivabradine and its salts and more particularly its hydrochloride, it is important to be able to obtain ivabradine and its salts in satisfactory yields by including a very small number of steps and It is obtained in particular by an efficient industrial synthesis method for its hydrochloride. SUMMARY OF THE INVENTION The Applicant has now developed a synthetic process that allows ivabradine salts to be obtained in a single step starting from a salt of a compound of formula (II) in excellent yield. More specifically, the present invention relates to a method for synthesizing the addition salt of ivabradine, which is a pharmaceutically acceptable acid addition salt of 115002.doc 200817334, and a hydrate thereof, wherein the formula (v) is Catalytic hydrogenation of compounds: c, human- 0

They may be the same or different, each representing a straight or branched bond (Ci_C8) alkoxy' or together with the carbon atom to which they are attached form a 1,3-dioxane, a 1,3-oxolane or a 1, a 3-oxocycloheptane ring, and then in the presence of hydrogen and a catalyst, the compound of formula (VI) thus obtained is obtained:

Ch3o ch3o wherein R1 and R2 are as defined above, and react with a compound of formula (VII): _r^^〇-CH3 CH3NHx^J~ΗΧ(νπ), 〇-CH3, wherein HX represents a pharmaceutically acceptable acid, After the catalyst is filtered off and separated, the addition salt of ivabradine and acid hydrazine is directly produced, and when it is desired to obtain the free efvabride timing, the addition salt is subjected to the test as the case may be. Among the pharmaceutically acceptable pharmaceutically acceptable acids, mention may be made as non-limiting examples: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, milk 115002.doc •10-200817334 acid, acetone Acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, nitric acid, citric acid, ascorbic acid, oxalic acid, methylated acid, benzoic acid and brain acid . This process makes it possible to obtain the ivabradine addition salt (especially its hydrochloride salt) directly from the corresponding salt of the amine of formula (11) in a single step, with excellent purity and excellent yield. Among the catalysts which can be used for the hydrogenation of the compound of the formula (V), there may be mentioned (without implied any limitation) palladium, platinum, nickel, ruthenium, iridium and their compounds, in particular in the form of a support or an oxide. The catalyst for the hydrogenation reaction of the compound of the formula (V) is preferably a temperature at which the carbon (palladium-on-carbon) compound of the formula (V) is deuterated preferably at a temperature of from 2 Torr to 1 Torr, more preferably from 40 to 80 °. C, even more preferably 45 to 65 C. The hydrogen pressure during the hydrogenation of the compound of the formula (v) is preferably from i to bar' more preferably from 1 to 100 bar, even more preferably from 1 to 3 bar. The hydrogenation reaction of the compound of the formula (v) is preferably carried out in a non-acid solvent. Among the preferred non-acid solvents which can be used in the hydrogenation reaction of the compound of the formula (V), there may be mentioned (without any limitation) acetic acid vinegar, alcohol (preferably ethanol, methanol or isopropanol), tetrahydrogen bite Methane, toluene, methylene chloride and xylene. Advantageously, the intermediate compound of formula (VI) is not isolated and the crude reaction product is used as such in the reductive amination reaction. Among the catalysts which can be used for the reductive amination reaction between the compound of the formula (VI) and the compound of the formula (VII), there may be mentioned (without any limitation) palladium, 115002.doc 200817334 platinum, nickel, rhodium, ruthenium And compounds thereof, especially in the form of a carrier or an oxide. The catalyst for the reductive amination reaction between the compound of the formula (VI) and the compound of the formula (VII) is preferably carbon. The temperature of the reductive amination reaction between the compound of the formula (VI) and the compound of the formula (VII) is preferably from 30 to 120 C, more preferably from 40 to 10 ° C, even more preferably from 6 to 95 ° C.

The hydrogen pressure during the reductive amination reaction of Lj between the compound of the formula (VI) and the compound of the formula (VII) is preferably from 1 to 220 bar, more preferably from 1 to 100 bar, even more preferably from 10 to 60 bar. In the process according to the invention, the compounds of the formulae (V) and (VI) which are preferably used are the compounds of the formulae (Va) and (VIa), which are the specialties of the compounds of the formulae (7) and (5), R1 and R2 together with The carbon atoms to which they are attached form a 1,3-dioxane, a 1,3-dioxolane or an anthracene, a 3-dioxocycloheptane ring. a compound of the formula (Va) which is a special case of the compound of the formula (ν) wherein & and & together with the carbon atom to which they are attached form a mm dioxolane or a π dioxepane ring, also a formula (VI) a compound which is a novel product suitable for use as a synthetic intermediate in the chemical or pharmaceutical industry: η, particularly suitable for the synthesis of ivabradine and its addition salts with pharmaceutically acceptable acids, and thus forms the present invention main part. According to a preferred method of the present invention, a method of using a compound of the formula (VIIa) as a synthetic intermediate, which is a specific example of the compound of the formula (VI1), thereby producing a ivabradine hydrochloride of the formula (10), wherein Ηχ represents hydrochloric acid. In this case, the process according to the invention produces a crystalline form, ivabradine hydrochloride of the alpha form 115002.doc -12 - 200817334, which is well defined and highly reproducible and which is in filtration, drying, stability And easy to deploy is particularly valuable. The alpha crystalline form is novel and constitutes another aspect of the invention. The alpha crystalline form of ivabradine hydrochloride is characterized by the following measurement using a PANalytical XTert Pro diffractometer along with an XfCelerat(R) detector and by ray position (Bragg's angle 20, expressed in degrees), light Height (in counts), light area (expressed in counts of X degrees), ray width at half height ("FWHM", expressed in degrees), and interplanar spacing d (indicated by A) for powder X-ray diffraction Figure:

Τ'·:' ' 1 degree 2Θ, nil stock, τ Μ: '(诂(5) degrees) tends to liass (degrees) pain gamma 1 4.1 1341 177 0.1338 21.486 2 7.7 1266 146 0.1171 11.440 3 8.1 1325 197 0.1506 10.923 4 10.4 1630 161 0.1004 8.488 5 11.8 753 87 0.1171 7.473 6 12.1 292 29 0.1004 7.301 7 13.2 917 106 0.1171 6.709 8 13.8 875 130 0.1506 6.423 9 15.3 281 37 0.1338 5.790 10 16.2 816 108 0.1338 5.478 11 16.5 2784 459 0.1673 5.381 12 17.4 1308 129 0.1004 5.106 13 18.1 455 52 0.1171 4.885 14 19.4 223 37 0.1673 4.569 15 20.2 3282 487 0.1506 4.389 16 20.6 305 45 0.1506 4.310 17 21.3 550 91 0.1673 4.165 18 21.9 1266 230 0.184 4.050 19 22.4 416 41 0.1004 3.972 20 23.0 262 35 0.1338 3.861 21 23.3 184 27 0.1506 3.814 22 24.4 309 51 0.1673 3.651 23 25.0 362 72 0.2007 3.566 24 25.7 1076 142 0.1338 3.459 25 26.5 2925 579 0.2007 3.363 26 26.8 821 135 0.1673 3.325 115002.doc -13- 200817334

Tai Kung B Day + ^ ———-J--Y with 3.057 & is about the form containing the active ingredient and - or a variety of suitable inert and non-toxic forms: Le, and mouth. Among the pharmaceutical compositions according to the present invention, there may be mentioned that they are more suitable for oral, parenteral (intravenous "subcutaneous (tetra), bismuth, lozenge or dragee, Sublingual tablets, capsules, mouths containing J-weight brakes, creams, ointments, skin gels, injectable preparations and drinkable suspensions. The effective dose can be determined by the nature and severity of the condition, the route of administration and the age of the patient. The body weight varies. In one or more administrations, the daily dose varies from 1 to 500 mg. [Embodiment] The following examples illustrate the invention. X-ray powder diffraction spectra were measured under the following experimental conditions: -PANalytical X, Pert Pro diffractometer, X'Celerator detector, - Voltage 45 kV, intensity 40 mA, - Mounting Θ-Θ, -Κβ (Ni) filter, Incident beam and diffraction beam Soller slit (Soller Slit) : 0.04 rad ' - Fixed angle of divergence slit: 1/8°, - Masking: 10 mm, - Backscattering slit: 1/4°, 115002.doc -14- 200817334 - Measurement method: 0.017. The increment is from 3 to 30. Continuous, - Measurement time per step: 19.7 s, - Total time: 4 min 32 s , - Measurement speed: 0.108Q/s, - Measurement temperature: ambient temperature Example 1: 3-{3-[{[(7S)-3,4-Dimethoxybicyclo[4.2.0] s- Trien-7-yl]fluorenyl}(methyl)amino]propyl b,7,8-dimethoxy-1,3,4,5-tetrahydro-2-indole_3_benzoquinoneoxime_2__salt The only crystalline form of the acid salt will be 5.5 kg of 3-[2-(1,3-dioxolan-2-yl)ethyl]_7,8-dimethoxy-1,3-dihydro-2H-3 -Phenylhydrazin-2-one, 27.5 liters of ethanol and 550 g of palladium on carbon were charged into the autoclave. Purified with nitrogen and then purified with hydrogen, heated to "force and then hydrogenated at this temperature at a pressure of 5 bar. Until the theoretical amount has been absorbed. Then return to the ambient temperature and release the pressure of the autoclave. Then add 4 1^(78)-354-dimethoxybicyclo[4.2.0] xin_1,3,5- Triene-7-yl]-indole-methylmethylamine hydrochloride, u liters of ethanol, 5,000 liters of water, carbon. Purified with nitrogen and then purified with hydrogen, heated at 85 and then at / Hydrogenating at a pressure of 30 bar until the theoretical amount of hydrogen has been absorbed. Then returning to the ambient temperature and purifying the high pressure}; then passing the hydrazine reaction mixture 'de solvent' and then by Ivabradine hydrochloride was isolated by crystallizing from a mixture of toluene/p-methyl-2-pyrrolidinone. Thus, ivabradine hydrochloride was obtained in a yield of 85% and chemical purity was greater than 115002.doc 200817334 99%. Powder diffraction pattern: The X-ray powder diffraction profile (diffraction angle) of the alpha crystalline form of ivabradine hydrochloride is given by the important light contrasted in the table below: , , ;! Hemp - : J degree ― 繁 (度) γ (counting '44 ·; 'fineness) U : ':::1, (m) r 1 1 crystal face:: > to "乂 (4) > (Λ) ν 1 4.1 1341 177 0.1338 21.486 2 7.7 1266 146 0.1171 11.440 3 8.1 1325 197 0.1506 10.923 4 10.4 1630 161 0.1004 8.488 5 11.8 753 87 0.1171 7.473 6 12.1 292 29 0.1004 7.301 7 13.2 917 106 0.1171 6.709 8 13.8 875 130 0.1506 6.423 9 15.3 281 37 0.1338 5.790 10 16.2 816 108 0.1338 5.478 11 16.5 2784 459 0.1673 5.381 12 17.4 1308 129 0.1004 5.106 13 18.1 455 52 0.1171 4.885 14 19.4 223 37 0.1673 4.569 15 20.2 3282 487 0.1506 4.389 16 20.6 305 45 0.1506 4.310 17 21.3 550 91 0.1673 4.165 18 21.9 1266 230 0.18 4 4.050 19 22.4 416 41 0.1004 3.972 20 23.0 262 35 0.1338 3.861 21 23.3 184 27 0.1506 3.814 22 24.4 309 51 0.1673 3.651 23 25.0 362 72 0.2007 3.566 24 25.7 1076 142 0.1338 3.459 25 26.5 2925 579 0.2007 3.363 26 26.8 821 135 0.1673 3.325 27 27.8 488 97 0.2007 3.212 28 28.4 620 123 0.2007 3.142 29 29.2 428 56 0.1338 3.057 115002.doc 16- 200817334 Example 2: Pharmaceutical composition Preparation of 1000 formulations each containing 5 mg of ivabradine base tablets: Example 1 Compounds................................................ ............5.39 g corn starch................................. ......................... 20 g Anhydrous gelatinous cerium oxide................. ...............................0.2 g mannitol......... .................................................. ..........63.91 g PVP.................................... ......................................... 10 g Stearic acid town... .................................................. ................0.5 g 115002.doc -17-

Claims (1)

(I) 200817334 X. Patent application scope: ivabradine of type (1) Or 3-{3-[{[(7S)_3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-triene-7- Methyl}(methyl)aminopropylpropyl}_7,8-dimethoxy 4,3,4,^tetrahydro-2H-3-phenylindole azol-2-one, which is pharmaceutically acceptable A method for synthesizing an acid addition salt and a hydrate thereof, which is characterized in that a compound of the formula (V) is subjected to a catalytic hydrogenation reaction: Ο Its center and chemistry 2 may be the same or different, each representing a straight or branched (Ci_ a) alkoxy group, or together with the carbon atoms to which they are attached, to form ruthenium, 3_two-ring, burn, 1,3 a monooxolane or an ι,3-dioxoheptane ring, and then the compound of the formula (VI) thus obtained is obtained in the presence of hydrogen and a catalyst: Wherein 1 and 112 are as defined above, reacting with a compound of formula (VII): 115002.doc 200817334 ch3nh o-ch3 o-ch3 HX (VII) wherein HX represents a pharmaceutically acceptable acid to filter out the catalyst After separation, the addition salt of ivabradine and the acid HX is directly produced, and when it is desired to obtain the free efvabride timing, the addition salt is subjected to the action of a base as the case may be. 2. The synthesis method of claim 1, wherein the catalyst for the hydrogenation reaction of the compound of the formula (V) is a palladium-on-cabron. 3. The synthesis method according to claim 1 or 2, wherein the hydrogen pressure during the hydrogenation reaction of the compound of the formula (V) is from 1 to 220 bar. 4. The synthesis method according to claim 1 or 2, wherein the temperature during the hydrogenation reaction of the compound of the formula (V) is from 20 to 100 °C. 5. The synthesis method of claim 4, wherein the temperature of the hydrogenation of the compound of the formula (V) is from 40 to 80 °C. 6. The method of synthesis of claim 1 or 2, wherein the intermediate compound of formula (VI) is not isolated. 7. The synthesis method according to claim 1 or 2, wherein the catalyst for the reaction between the compound of the formula (VI) and the compound of the formula (VII) is palladium carbon. 8. The synthesis method according to claim 1 or 2, wherein the hydrogen pressure during the reaction between the compound of the formula (VI) and the compound of the formula (VII) is from 1 to 220 bar. 9. The synthesis method according to claim 1 or 2, wherein the temperature of the reaction between the compound of the formula (VI) and the compound of the formula (VII) is from 30 to 120 °C. 10. The synthesis method of claim 9, wherein the temperature of the reaction between the compound of the formula (VI) and the compound of the formula (VII) is from 40 to 100 °C. 115002.doc 200817334 11. The synthesis method of claim 1 or 2, which uses compounds of the formulae (Va) and (VIa), which are special cases of the compounds of the formulae (V) and (VI), Together with the carbon atoms to which they are attached, they form a hydrazine, a 3-dioxane, an anthracene, a dioxolane or a dioxepane ring. 12. A method of synthesizing the item i or 2, which uses a formula (vna) intermediate which is a special case of the compound of the formula (VII) wherein hydrazine represents hydrochloric acid, thereby producing ivabradine hydrochloride. 13·—a compound of the formula (va), CH3O ch3o wherein R! and R2 together with the carbon atoms to which they are attached form a U bismuth, 1,3-dioxolane or dioxepane ring. 14. A compound of formula (VI), U (VI) wherein they may be the same or different, each represents a direct bond or a bond (Ci_c8) alkoxy, or together with the carbon atom to which they are attached, form a dioxane, a 1,3-dioxolane or U3_dioxepane ring. 15. The crystalline form of ivabradine hydrochloride of formula (Ia), 115002.doc 200817334 , HC1 It is characterized by the following measurement using a PANalytical X'Pert Pro diffractometer together with an X'CeleratoiM detector and by ray position (Braggfs angle 20, expressed in degrees), ray height (in counts), light The area of the material (indicated by the X degree), the ray width at half height (•'FWHM'', expressed in degrees), and the interplanar spacing d (indicated by A) represent the powder X-ray diffraction pattern: .毅餐编杂鸡杂面毅1 Angle 2Θ~ (degrees) λ (tm); Area, (count X degrees) ^WHM 丨, :::, (degree 1 ' 'parallax spacing' ::(for 1 4.1 1341 177 0.1338 21.486 2 7.7 1266 146 0.1171 11.440 3 8.1 1325 197 0.1506 10.923 4 10.4 1630 161 0.1004 8.488 5 11.8 753 87 0.1171 7.473 6 12.1 292 29 0.1004 7.301 7 13.2 917 106 0.1171 6.709 8 13.8 875 130 0.1506 6.423 9 15.3 281 37 0.1338 5.790 10 16.2 816 108 0.1338 5.478 11 16.5 2784 459 0.1673 5.381 12 17.4 1308 129 0.1004 5.106 13 18.1 455 52 0.1171 4.885 14 19.4 223 37 0.1673 4.569 15 20.2 3282 487 0.1506 4.389 16 20.6 305 45 0.1506 4.310 17 21.3 550 91 0.1673 4.165 18 21.9 1266 230 0.184 4.050 19 22.4 416 41 0.1004 3.972 20 23.0 262 35 0.1338 3.861 21 23.3 184 27 0.1506 3.814 22 24.4 309 51 0.1673 3.651 23 25.0 362 72 0.2007 3.566 24 25.7 1076 142 0.1338 3.459 25 26.5 2925 579 0.2007 3.363 26 26.8 821 135 0.1673 3.325 115002.doc -4- 200817334 16. A pharmaceutical composition comprising as an inert, non-toxic carrier of the crystalline form of 17. evabutazone hydrochloride, as defined in claim 15. Or a therapeutic use of a clear crystal form of ivabradine hydrochloride as claimed in claim 15 for use in the manufacture of a medicament for use as a slowing heart rate agent. 15 Use of an alpha crystalline form of efvabradine hydrochloride for the manufacture of a variety of clinical conditions for the treatment or prevention of myocardial ischemia, such as angina pectoris, myocardial infarction and related cardiac rhythm disorders, and also including cardiac rhythm Disorders, especially multiple conditions of supreme rhythm disorder, and drugs used to treat heart failure. 115002.doc 200817334 VII. Designation of Representative Representatives (1) The representative representative of the case is: (none) (2) A brief description of the symbol of the representative figure: (8) If there is a chemical formula in this case, please reveal the best display invention. Characteristic chemical formula: 115002.doc