Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to a process for the industrial synthesis of strontium ranelate of formula (I):
• Strontium ranelate has very interesting pharmacological and therapeutic properties, in particular remarkable anti-osteoporotic properties, which make this compound useful in the treatment of bone diseases.
• Strontium ranelate its preparation and its use in therapy have been described in European patent EP 0415 850.
• the Applicant has developed a process for the synthesis of strontium ranelate of formula (I) in which these conditions have been met by the use of a set of particularly advantageous techniques and processes.
• Patent EP 0415 850 describes access to strontium ranelate from the tetraester ethyl of formula (Ha)
• This process has the advantage of using easily accessible raw materials, and of being simple to implement, but, transposed to the scale of a few hundred kg, it does not make it possible to obtain the compound of formula ( Illa) with a yield greater than 70%.
• R represents a linear or branched (C Ce) alkyl group
• the amount of methanol is between 1 and 3 ml per gram of compound of formula (IN).
• the reaction temperature between the compounds of formulas (IN) and (N) is preferably less than 50 ° C.
• the reaction time at reflux after addition of the sulfur is preferably between 1 h 30 and 3 h.
• the second step of the process for the industrial synthesis of strontium ranelate of formula (I) developed by the Applicant consists in transforming the compound of formula (III) into a compound of formula (II):
• R is as defined above, and R 'represents a linear or branched alkyl group (-C ⁇ ).
• R represents a linear or branched alkyl group (-C ⁇ ).
• the Applicant to synthesize strontium ranelate of formula (I) industrially, has developed a simple industrial synthesis process, making it possible to obtain the compound of formula (II) with a very good yield, a considerably longer reaction time. short and of excellent purity, and in which the saline aqueous discharges are completely suppressed.
• R represents a linear or branched (Ci-C 6 ) alkyl group
• R ' represents a linear or branched (CrC 6 ) alkyl group
• R ' represents a linear or branched (CrC 6 ) alkyl group
• a catalytic amount of a quaternary ammonium of Cs-o type, and of potassium carbonate at reflux of an organic solvent, than l
• the reaction mixture is then filtered, then the medium is concentrated by distillation, a cosolvent is then added, the reaction mixture is cooled and filtered, to lead, after drying of the powder thus obtained, to the compound of formula (II).
• quaternary ammonium of type C 8 -C 10 is meant a compound of formula (A) or a mixture of compounds of formula (A):
• Ri represents an alkyl group (-C ⁇ )
• R 2 , R 3 and R4 identical or different, each represents an alkyl group (C 8 -C 10 )
• X represents a halogen atom
• Quaternary ammonium type C 8 -C 10 preferred are catalysts Adogen 464 and Aliquat 336 ®.
• the isolation allows, thanks to the particular conditions which have been developed, to obtain the compound of formula (II), not only with a very good yield (89%), but also with an excellent purity (greater than 98%), and by removing the environmental charge represented by saline aqueous discharges.
• the amount of potassium carbonate is preferably between 2 and 3 moles per mole of compound of formula (III).
• the amount of compound of formula (VU) is preferably between 2 and 3 moles per mole of compound of formula (III).
• the initial volume of organic solvent is preferably between 6 and 12 ml per gram of compound of formula (III).
• the preferred organic solvents for the reaction are acetone and acetonitrile.
• the preferred co-solvent for isolation is methanol.
• the third and last step of the industrial synthesis process for strontium ranelate of formula (I) developed by the Applicant consists in transforming the tetraester of formula (II) into the distrontic salt of the corresponding tetracid.
• Patent EP 0415 850 describes three methods for this transformation.
• the third of the methods described which consists in heating the compound of formula (Ha), special case of the compounds of formula (II), in an alcoholic medium, with strontium hydroxide, then in distilling ethanol and in isolating the compound of formula (I) by precipitation, has the advantage of being extremely simple to implement.
• strontium ranelate being insoluble in most solvents, its subsequent purification is extremely laborious. Such a method was therefore incompatible with the use of strontium ranelate as a pharmaceutical active ingredient, which requires a purity greater than or equal to 98%.
• the Applicant has developed an industrial synthesis process which makes it possible to obtain strontium ranelate, not only with excellent chemical purity, requiring no reprocessing before its use as a pharmaceutical active principle, but also with an excellent yield.
• R and R ′ which are identical or different, each represent a linear or branched (C 1 -C 6 ) alkyl group, R preferably representing the methyl group, and R ′ preferably representing a methyl or ethyl group,
• the amount of water in the reaction mixture is preferably greater than or equal to 8 ml per gram of compound of formula (II).
• the amount of strontium hydroxide is preferably between 2 and 2.5 moles per mole of compound of formula (II).
• the examples below illustrate the invention, but do not limit it in any way.
• Examples 1A and IB illustrate the first step in the process of industrial synthesis of strontium ranelate by the Applicant; Examples 2A, 2B, 2C and 2D, the second step of this process; finally, example 3 illustrates the third and last step of this process.
• EXAMPLE 1 A: 5-Amino-4-cyano-3- (2-methoxy-2-oxoethyl) -2-methyl thiophenecarboxylate.
• the mixture is then brought to reflux.
• Methyl 5- [bis (2-methoxy-2-oxoethyl) amino] -4-cyano-3- (2-methoxy-2-oxoethyl) -2-thiophene-carboxylate is thus obtained with a yield greater than 85% and a chemical purity greater than 98%.
• EXAMPLE 2B 5- [Bis (2-methoxy-2-oxoethyl) amino] -4-cyano-3- (2-methoxy-2-oxoethyl) -2-methyl thiophenecarboxylate.
• EXAMPLE 2D 5- [Bis (2-ethoxy-2 ⁇ ox Q ethyl) ammoH-cyano-3- (2-methoxy-2-oxoethyl) -2-methyl thiophenecarboxylate.
• the distrontic salt octahydrate of 5- [bis (carboxymethyl) amino] -3- carboxymethyl-4-cyano-2-thiophenecarboxylic acid is thus obtained with a yield of 96% and a chemical purity of 98%.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Physical Education & Sports Medicine (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Rheumatology (AREA)
• Pharmacology & Pharmacy (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Cardiology (AREA)
• Vascular Medicine (AREA)
• Urology & Nephrology (AREA)
• Heart & Thoracic Surgery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Heterocyclic Compounds Containing Sulfur Atoms (AREA)
• Plural Heterocyclic Compounds (AREA)
• Inorganic Insulating Materials (AREA)
• Crystals, And After-Treatments Of Crystals (AREA)

Priority Applications (10)

Applications Claiming Priority (2)

Publications (1)

Family

ID=29415189

Family Applications (1)

Country Status (37)

Cited By (5)

Families Citing this family (16)

Citations (2)

Family Cites Families (2)

• 2002
  • 2002-09-24 FR FR0211763A patent/FR2844795B1/fr not_active Expired - Fee Related
• 2003
  • 2003-09-17 MY MYPI20033542A patent/MY134921A/en unknown
  • 2003-09-22 JP JP2003330440A patent/JP4136867B2/ja not_active Expired - Fee Related
  • 2003-09-22 EP EP03292319.5A patent/EP1403266B1/fr not_active Expired - Lifetime
  • 2003-09-22 UA UAA200503858A patent/UA79156C2/uk unknown
  • 2003-09-22 AU AU2003248281A patent/AU2003248281B2/en not_active Ceased
  • 2003-09-22 HR HRP20050359AA patent/HRP20050359B1/hr not_active IP Right Cessation
  • 2003-09-22 PT PT3292319T patent/PT1403266E/pt unknown
  • 2003-09-22 RS RSP20050240 patent/RS53509B1/sr unknown
  • 2003-09-22 DK DK03292319.5T patent/DK1403266T3/da active
  • 2003-09-22 WO PCT/FR2003/002777 patent/WO2004029036A1/fr not_active Ceased
  • 2003-09-22 GE GEAP20048761A patent/GEP20074215B/en unknown
  • 2003-09-22 RS YUP-2005/0240A patent/RS20050240A/sr unknown
  • 2003-09-22 ES ES03292319.5T patent/ES2478620T3/es not_active Expired - Lifetime
  • 2003-09-22 ME MEP-2008-689A patent/ME00455B/me unknown
  • 2003-09-22 SI SI200332352T patent/SI1403266T1/sl unknown
  • 2003-09-22 OA OA1200500083A patent/OA12934A/en unknown
  • 2003-09-22 AP AP2005003256A patent/AP1910A/xx active
  • 2003-09-22 AU AU2003282179A patent/AU2003282179A1/en not_active Abandoned
  • 2003-09-23 BR BR0304213-8A patent/BR0304213A/pt not_active Application Discontinuation
  • 2003-09-23 KR KR1020030065783A patent/KR100551501B1/ko not_active Expired - Fee Related
  • 2003-09-23 MX MXPA03008643A patent/MXPA03008643A/es active IP Right Grant
  • 2003-09-23 NO NO20034235A patent/NO328638B1/no not_active IP Right Cessation
  • 2003-09-23 NZ NZ528402A patent/NZ528402A/en not_active IP Right Cessation
  • 2003-09-23 EA EA200300925A patent/EA007489B1/ru not_active IP Right Cessation
  • 2003-09-23 CA CA002442878A patent/CA2442878C/fr not_active Expired - Fee Related
  • 2003-09-23 PL PL362365A patent/PL214400B1/pl unknown
  • 2003-09-23 AR ARP030103453A patent/AR041355A1/es not_active Application Discontinuation
  • 2003-09-23 ZA ZA200307409A patent/ZA200307409B/xx unknown
  • 2003-09-24 CN CNB031348130A patent/CN1212321C/zh not_active Expired - Fee Related
  • 2003-09-24 MA MA27321A patent/MA26102A1/fr unknown
  • 2003-09-24 US US10/669,301 patent/US7214805B2/en not_active Expired - Fee Related
  • 2003-09-24 SG SG200305555A patent/SG110071A1/en unknown
• 2005
  • 2005-03-08 IL IL167316A patent/IL167316A/en not_active IP Right Cessation
  • 2005-03-18 CR CR7764A patent/CR7764A/es unknown
  • 2005-03-23 TN TNP2005000087A patent/TNSN05087A1/fr unknown
  • 2005-04-19 IS IS7807A patent/IS7807A/is unknown
  • 2005-04-22 EC EC2005005741A patent/ECSP055741A/es unknown
• 2014
  • 2014-06-05 CY CY20141100397T patent/CY1115162T1/el unknown

Patent Citations (2)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events