WO2012051737A1 - Procédé de préparation de cinacalcet et de sels pharmaceutiques de celui-ci - Google Patents

Procédé de préparation de cinacalcet et de sels pharmaceutiques de celui-ci Download PDF

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Publication number
WO2012051737A1
WO2012051737A1 PCT/CN2010/001638 CN2010001638W WO2012051737A1 WO 2012051737 A1 WO2012051737 A1 WO 2012051737A1 CN 2010001638 W CN2010001638 W CN 2010001638W WO 2012051737 A1 WO2012051737 A1 WO 2012051737A1
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WO
WIPO (PCT)
Prior art keywords
compound
group
reaction
cinacalcet
palladium
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PCT/CN2010/001638
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English (en)
Chinese (zh)
Inventor
胡长春
陈艳辉
Original Assignee
上海永颐生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by 上海永颐生物科技有限公司 filed Critical 上海永颐生物科技有限公司
Priority to PCT/CN2010/001638 priority Critical patent/WO2012051737A1/fr
Priority to CN2010800696906A priority patent/CN103201252A/zh
Publication of WO2012051737A1 publication Critical patent/WO2012051737A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C07C209/70—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by reduction of unsaturated amines

Definitions

  • the invention relates to a method for synthesizing cinacalcet and a pharmaceutically acceptable salt thereof, and belongs to the field of organic synthesis. Background technique
  • Cinacalcet hydrochloride is the first oral calcimimetic drug approved by the FDA for the treatment of secondary hyperparathyroidism in patients with dialysis chronic kidney disease. It can also be used to treat parathyroid glands. Hypercalcemia in cancer patients. Cinacalcet chemical name is N-[I-(R: -)-I-naphthyl:)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-propanamine, the structural formula is:
  • a calcimimetic is a class of orally active small molecules that reduce the secretion of parathyroid hormone by activating calcium receptors.
  • Calcium-calcium agents are used to treat hyperparathyroidism, a condition characterized by calcium receptors on the parathyroid glands that lose normal response to calcium in the blood and cause excessive secretion of parathyroid hormone.
  • High levels of parathyroid hormone are hallmarks of secondary hyperparathyroidism, with altered calcium and phosphorus metabolism, which may lead to bone pain, fractures, and increased risk of cardiovascular death.
  • cinacalcet hydrochloride has been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease undergoing dialysis.
  • Cinacalcet and its pharmaceutically acceptable acid addition salts are generally described in U.S. Patent 6,016,068, but do not provide any examples of preparation.
  • U.S. Patent No. 6,211, 244 describes cinacalcet and its pharmaceutically acceptable acid chloride addition salts, but does not provide any examples of the preparation of cinacalcet and cinacalcet hydrochloride.
  • Drugs of future 2002, 27(9), 831-836 disclose synthetic schemes for the preparation of cinacalcet hydrochloride. As shown in Scheme 1, this synthetic route uses m-trifluoromethylpropialdehyde, which is difficult to prepare.
  • U.S. Patent No. 7,250,533 discloses another synthetic route of cinacalcet which converts the hydroxyl group of 3-[3-(trifluoromethyl)phenyl]propanol into a group which is easily removed, and then in an organic solvent. Cinacalcet is obtained by condensation with (R)-l-naphthylethylamine in the presence of a base. Among them, 3-[3-(trifluoromethyl)phenyl]propanol was obtained by coupling 3-bromotrifluoromethylbenzene with ethyl acrylate Heck, followed by reduction. As shown in scenario 2:
  • PCT Patent WO 2007127445 discloses a route for the synthesis of cinacalcet by a reductive amide process, as shown in Scheme 3, wherein the acid chloride of 3-[3-(trifluoromethyl)phenyl]propanoic acid and (R)-l- Condensation of naphthylamine gives N-[l-(R)-(-)-l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-propanamide, after reduction Can get Cinacalc.
  • a similar method is also reported in PCT Patent WO 2008035381, WO 2008058235, Indian Patent 555/MUM/2007 and Tetrahedron Letters 2008, 49(1), 13-15.
  • PCT Patent WO 2007127449 discloses a process for preparing cinacalcet by a coupling reaction, in which 3-bromobenzotrifluoride and N-allyl-(R)-l-naphthylethylamine are unsaturated under the action of a catalyst and a base. The intermediate of the cascading, palladium carbon reduced to obtain cinacalcet.
  • the existing synthetic route has the following disadvantages, such as some routes using expensive reagents such as Titanium isopropoxide and diisobutylaluminum hydride are not conducive to large-scale industrial production; some routes use ethyl acrylate, which is carcinogenic, flammable and unstable; some routes require separation of products by column chromatography and chiral chromatography, Conducive to industrial production.
  • the object of the present invention is to provide a novel and effective synthesis method for preparing cinacalcet I and a pharmaceutically acceptable salt thereof, which has simple raw materials, mild reaction conditions, can be easily applied to industrial large-scale production, and provides high-purity West.
  • the present invention provides a novel process for the synthesis of cinacalcet and its pharmaceutically acceptable salts which are advantageous for industrial production, in particular to provide a process for the synthesis of cinacalcet and its hydrochloride in high yield and high purity.
  • X is a leaving group
  • Y is a halogen
  • Z is an amino protecting group
  • X is a leaving group selected from the group consisting of halogen, a C1-C6 alkyl sulfonate group, a substituted or unsubstituted C6-C10 aryl sulfonate group, and the like, wherein the substitution
  • the substituent in the C6-C10 aryl sulfonate group is selected from the group consisting of halogen, C1-C6 alkyl, and preferably X is a bromine, mesylate or p-toluenesulfonate group.
  • Compound III is (R)-l-naphthylethylamine, which is commercially available.
  • the bases used in this step include organic bases and inorganic bases.
  • the organic base may be triethylamine or a quaternary ammonium salt;
  • the inorganic base is selected from the group consisting of alkali metal and alkaline earth metal hydroxides, carbonates, hydrogencarbonates, and the like, and combinations thereof, and is preferably potassium carbonate or sodium hydroxide. Potassium hydroxide, sodium carbonate or a combination thereof.
  • the solvent used in this step is acetonitrile, tetrahydrofuran, dioxane, hydrazine, hydrazine-dimethylformamide, and the solvent is used in an amount of 5 to 15 times the weight of the compound II.
  • the reaction temperature of this reaction is 20-100 °C.
  • the operation is easy, the reaction after the reaction is simple, and the product can be put into the sputum reaction without purification, which is advantageous for industrial production.
  • Z is an amino protecting group selected from the group consisting of -S0 2 R, -COR, -COOR and -CONRR', wherein R, R' may be a C1-C8 alkyl group, a C2-C8 alkenyl group, C2-C8 alkynyl or C6-C10 aryl, and preferably Z is tert-butyloxycarbonyl (Boc) or acetyl.
  • the base used in the reaction is triethylamine, pyridine, potassium carbonate, sodium hydroxide or potassium hydroxide.
  • the reaction solvent is dichloromethane, chloroform, 1,2-dichloroethane or tetrahydrofuran, and the solvent is used in an amount of 5 to 15 times the weight of the compound IV.
  • the reaction temperature is 0-40 °C.
  • the reaction after the reaction is simple, the yield is high, the product purity is good, column chromatography is not required, and industrial production is easy.
  • Y is a halogen, and is preferably bromine or iodine.
  • reaction systems can be used in this step, including: (i) cuprous iodide, diisopropylamine and tetrakistriphenylphosphine palladium systems; (ii) cuprous iodide, potassium acetate and tetrakistriphenylphosphine palladium system (iii) cuprous iodide, triethylamine and tetrakistriphenylphosphine palladium system; (iv) cuprous iodide, diisopropylamine, triphenylphosphine and palladium chloride systems; (V) iodide Cuprous, diisopropylamine, triphenylphosphine and palladium carbon systems and (vi) palladium acetate, triethylenediamine, potassium carbonate systems, and the like.
  • the reaction solvent used is (i) hydrazine, hydrazine-dimethylformamide (DMF); (ii) 3 ⁇ 40 or (iii) acetonitrile (CH 3 CN) and the like.
  • the temperature of the reaction is 20-100 °C.
  • the obtained target compound VII can be purified without column chromatography, which simplifies the entire operation and is advantageous for industrial production.
  • the reduction systems employed in this step include: (i) palladium on carbon/hydrogen; (ii) Raney nickel/hydrogen and (iii) platinum dioxide/hydrogen.
  • the solvent to be used is a conventional solvent such as ethanol, methanol, ethyl acetate or the like.
  • the reaction temperature is 25-55 °C.
  • the reaction system is operated at a pressure of 1-6 atmospheres (atm), and in consideration of cost and reaction efficiency, it is preferred to use a pressure of 3 atm.
  • the post-treatment of the reaction system is simple and the obtained target compound has good purity, which is advantageous for industrial production.
  • the amino protecting group can be removed using the following methods, including: (i) dilute hydrochloric acid (1N-5N); (ii) dilute sulfuric acid (10-35% by weight); (iii) hydrobromic acid and (iv) Dilute hydrochloric acid and acetic acid, etc. It is preferred to use dilute hydrochloric acid (1N-5N).
  • the propargyl alcohol (11.2 g) was dissolved in dichloromethane (150 ml), and potassium hydroxide (40 g) and p-toluenesulfonyl chloride (42.0 g) were successively added thereto at room temperature, and reacted for 2-3 hours, and then added. After water quenching, the mixture was separated and the aqueous layer was extracted twice with dichloromethane.
  • Example 2 The compound ⁇ -a (45.7 g) prepared in Example 1 was mixed with compound III (61.3 g) in DMF (320 ml), and 37 g of potassium carbonate was added thereto. After reacting at room temperature overnight, it was poured into ice water with ethyl acetate. The organic phase was combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude product (IV).
  • Example 4 Preparation of N-(R)-(1-naphthyl-1-ethyl)-N-2-propynyl-acetamide (V)
  • Crude product IV prepared in Example 3 (56.0 g) and triethylamine (56.2 ml) were dissolved in dry dichloromethane (300 ml), and 100 ml of a solution of acetyl chloride (23 ml) in dichloromethane was added dropwise in an ice bath. After the dropwise addition, the reaction was carried out at room temperature.
  • the compound VII (10.Og) prepared in the fifth embodiment was dissolved in 80 ml of methanol, and 0.8 g was added.
  • Cinacalcet and its hydrochloride can be prepared by using the propargyl p-toluenesulfonate ( ⁇ -b) prepared in Example 2 in the same manner as above.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention porte sur un procédé de préparation de cinacalcet I et de sels pharmaceutiques de celui-ci, lequel comprend les étapes suivantes : a) la réaction du composé II avec le composé III en présence d'un alcali par une réaction de SN2 pour obtenir le composé IV; b) la protection du groupe amino présent dans le composé IV pour obtenir le composé V; c) la réaction du composé V avec le composé VI en présence d'un catalyseur par une réaction de Sonogashira pour obtenir le composé VII; d) le fait de soumettre le composé VII à une hydrogénation réductrice pour obtenir le composé VIII; et e) la conversion du composé VIII en cinacalcet et en sels pharmaceutiques de celui-ci, les composés II-VIII étant tels que décrits dans la description.
PCT/CN2010/001638 2010-10-18 2010-10-18 Procédé de préparation de cinacalcet et de sels pharmaceutiques de celui-ci WO2012051737A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2010/001638 WO2012051737A1 (fr) 2010-10-18 2010-10-18 Procédé de préparation de cinacalcet et de sels pharmaceutiques de celui-ci
CN2010800696906A CN103201252A (zh) 2010-10-18 2010-10-18 西那卡塞及其药用盐的制备方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109456235A (zh) * 2018-12-17 2019-03-12 苏州华道生物药业股份有限公司 一种苯磺酸炔丙酯的绿色合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080319229A1 (en) * 2007-06-22 2008-12-25 Dipharma Francis S.R.L. process for the preparation of cinacalcet
WO2009002427A2 (fr) * 2007-06-21 2008-12-31 Amgen Inc. Procédés de synthèse du cinacalcet et de ses sels
CN101516360A (zh) * 2006-08-18 2009-08-26 利奥制药有限公司 用于治疗疾病的取代的炔属化合物

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR061311A1 (es) * 2006-06-08 2008-08-20 Medichem Sa Procesos para preparar clorhidrato de cinacalcet y formas polimorficas del mismo
WO2010071689A2 (fr) * 2008-05-05 2010-06-24 Medichem, S.A. Procédé de contrôle de la dimension particulaire d'un dérivé de 3-[(trifluorométhyl)phényl]-1-aminopropane
US20110178326A1 (en) * 2008-08-06 2011-07-21 Actavis Group Ptc Ehf Unsaturated cinacalcet salts and processes for preparing cinacalcet hydrochloride
CA2754209A1 (fr) * 2009-03-05 2010-09-10 Cipla Limited Procede de preparation de cinacalcet et de ses sels, et intermediaires destines a etre utilises dans le procede
EP2406211B1 (fr) * 2009-03-09 2018-06-27 Megafine Pharma (P) Ltd. Nouveau procédé pour la préparation de cinacalcet et nouveaux intermédiaires de cette préparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101516360A (zh) * 2006-08-18 2009-08-26 利奥制药有限公司 用于治疗疾病的取代的炔属化合物
WO2009002427A2 (fr) * 2007-06-21 2008-12-31 Amgen Inc. Procédés de synthèse du cinacalcet et de ses sels
US20080319229A1 (en) * 2007-06-22 2008-12-25 Dipharma Francis S.R.L. process for the preparation of cinacalcet

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109456235A (zh) * 2018-12-17 2019-03-12 苏州华道生物药业股份有限公司 一种苯磺酸炔丙酯的绿色合成方法

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