HRP20201800T1 - Postupak za pripravu (4s)-4-(4-cijano-2-metoksifenil)-5-etoksi-2,8-dimetil-1,4-dihidro-1-6-naftiridin-3-karboksamida i njegovo pročišćavanje za upotrebu kao aktivni farmaceutski sastojak - Google Patents

Postupak za pripravu (4s)-4-(4-cijano-2-metoksifenil)-5-etoksi-2,8-dimetil-1,4-dihidro-1-6-naftiridin-3-karboksamida i njegovo pročišćavanje za upotrebu kao aktivni farmaceutski sastojak Download PDF

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HRP20201800T1
HRP20201800T1 HRP20201800TT HRP20201800T HRP20201800T1 HR P20201800 T1 HRP20201800 T1 HR P20201800T1 HR P20201800T T HRP20201800T T HR P20201800TT HR P20201800 T HRP20201800 T HR P20201800T HR P20201800 T1 HRP20201800 T1 HR P20201800T1
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formula
image
compound
give
xvia
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HRP20201800TT
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Johannes Platzek
Gunnar Garke
Alfons Grunenberg
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Bayer Pharma Aktiengesellschaft
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Publication of HRP20201800T1 publication Critical patent/HRP20201800T1/hr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
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    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
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    • 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
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • 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
    • A61P9/12—Antihypertensives
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
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  • Child & Adolescent Psychology (AREA)
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  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Claims (7)

1. Postupak za pripravu spoja (I) [image] naznačen time što spoj s formulom (XIV) ili formulom (XIVa) [image] reagiraju uz dodavanje dimetil sulfata da se dobije spoj s formulom (XV) ili (XVa) [image] i neizolirani metil esteri s formulom (XV) ili (XVa) su reducirani sa 1,21 ekv. REDAL (natrij bis(2-metoksietoksi)aluminij dihidrida i 1,28 ekv. N-metilpiperazina da se dobije aldehid s formulom (XVI) ili (XVIa) [image] i aldehid (XVI) ili (XVIa) reagira dalje bez izolacije da se dobije nitril s formulom (VI) [image]
2. Postupak prema patentnom zahtjevu 1, naznačen time što spoj s formulom (XIV) ili formulom (XIVa) [image] reagiraju uz dodavanje dimetil sulfata da se dobije spoj s formulom (XV) ili (XVa) [image] i neizolirani metil esteri s formulom (XV) ili (XVa) su reducirani sa 1,21 ekv. REDAL (natrij bis(2-metoksietoksi)aluminij dihidrida i 1,28 ekv. N-metilpiperazina da se dobije aldehid s formulom (XVI) ili (XVIa) [image] i aldehid (XVI) ili (XVIa) reagira dalje bez izolacije da se dobije nitril s formulom (VI) [image] i spoj s formulom (VI) [image] otopljen u izopropanolu (3-7 struko), 5-10 mol% piperidina i 5-10 mol% ledene octene kiseline na 30°C reagira sa spojem s formulom (VII) [image] da se dobiju spojevi (VIIIa+b) [image] (VIIIa+b).
3. Postupak prema patentnim zahtjevima 1 i 2, naznačen time što spoj s formulom (XIV) ili formulom (XIVa) [image] reagiraju uz dodavanje dimetil sulfata da se dobije spoj s formulom (XV) ili (XVa) [image] i neizolirani metil esteri s formulom (XV) ili (XVa) su reducirani sa 1,21 ekv. REDAL (natrij bis(2-metoksietoksi)aluminij dihidrida i 1,28 ekv. N-metilpiperazina da se dobije aldehid s formulom (XVI) ili (XVIa) [image] i aldehid (XVI) ili (XVIa) reagira dalje bez izolacije da se dobije nitril s formulom (VI) [image] i spoj s formulom (VI) [image] otopljen u izopropanolu (3-7 struko), 5-10 mol% piperidina i 5-10 mol% ledene octene kiseline na 30°C reagira sa spojem s formulom (VII) [image] da se dobiju spojevi (VIIIa+b) [image] i što spoj s formulom (X) [image] reagira uz miješanje s 2,5-5 ekv. trietil ortoacetata u dimetilacetamidu na 100 do 120°C tijekom 1,5 do 3 sata da se dobije spoj s formulom (XI) [image]
4. Postupak prema patentnim zahtjevima 1, 2 i 3, naznačen time što spoj s formulom (XIV) ili formulom (XIVa) [image] reagiraju uz dodavanje dimetil sulfata da se dobije spoj s formulom (XV) ili (XVa) [image] i neizolirani metil esteri s formulom (XV) ili (XVa) su reducirani sa 1,21 ekv. REDAL (natrij bis(2-metoksietoksi)aluminij dihidrida i 1,28 ekv. N-metilpiperazina da se dobije aldehid s formulom (XVI) ili (XVIa) [image] i aldehid (XVI) ili (XVIa) reagira dalje bez izolacije da se dobije nitril s formulom (VI) [image] i spoj s formulom (VI) [image] otopljen u izopropanolu (3-7 struko), 5-10 mol% piperidina i 5-10 mol% ledene octene kiseline na 30°C reagira sa spojem s formulom (VII) [image] da se dobiju spojevi (VIIIa+b) [image] i što spoj s formulom (X) [image] reagira uz miješanje s 2,5-5 ekv. trietil ortoacetata u dimetilacetamidu na 100 do 120°C tijekom 1,5 do 3 sata da se dobije spoj s formulom (XI) [image] i što se spoj s formulom (XI) [image] saponificira u smjesi THF/voda (2:1, 9-struko) s vodenom otopinom natrijevog hidroksida da se dobije spoj s formulom (XII) [image]
5. Postupak prema patentnim zahtjevima 1, 2, 3 i 4, naznačen time što spoj s formulom (XIV) ili formulom (XIVa) [image] reagiraju uz dodavanje dimetil sulfata da se dobije spoj s formulom (XV) ili (XVa) [image] i neizolirani metil esteri s formulom (XV) ili (XVa) su reducirani sa 1,21 ekv. REDAL (natrij bis(2-metoksietoksi)aluminij dihidrida i 1,28 ekv. N-metilpiperazina da se dobije aldehid s formulom (XVI) ili (XVIa) [image] i aldehid (XVI) ili (XVIa) reagira dalje bez izolacije da se dobije nitril s formulom (VI) [image] i spoj s formulom (VI) [image] otopljen u izopropanolu (3-7 struko), 5-10 mol% piperidina i 5-10 mol% ledene octene kiseline na 30°C reagira sa spojem s formulom (VII) [image] da se dobiju spojevi (VIIIa+b) [image] i što spoj s formulom (X) [image] reagira uz miješanje s 2,5-5 ekv. trietil ortoacetata u dimetilacetamidu na 100 do 120°C tijekom 1,5 do 3 sata da se dobije spoj s formulom (XI) [image] i što se spoj s formulom (XI) [image] saponificira u smjesi THF/voda (2:1, 9-struko) s vodenom otopinom natrijevog hidroksida da se dobije spoj s formulom (XII) [image] i što spoj s formulom (XII) [image] reagira u reakciji u jednoj posudi u THF-u prvo s karbodiimidazolom i katalitičkim količinama 4-(dimetilamino)piridina, u drugom se koraku zagrijava pod refluksom zajedno s heksametildisilazanom tijekom 16 do 24 sata i u trećem koraku hidrolizira s THF i/ili vodom da se dobije spoj s formulom (XIII) [image]
6. Postupak za pripravu spoja s formulom (I) u kristalnom obliku polimorfa I, naznačen time što se spoj s formulom (I) pripravlja postupkom prema bilo kojem od patentnih zahtjeva 1 do 5 u jednom ili više polimorfa ili kao solvat i miješa se u inertnom otapalu na temperaturi od 20°C - 120°C i spoj s formulom (I) je izoliran u kristalnom polimorfu I, koji je naznačen time što ima rendgenski difraktogram izmjeren korištenjem izvora Cu K-alfa 1 zračenja i pokazuje maksimum vrha kuta 2 theta pri 8,5, 14,1, 17,2, 19,0, 20,5, 25,6, 26,5.
7. Postupak za pripravu lijeka naznačen time što obuhvaća korake iz patentnog zahtjeva 6.
HRP20201800TT 2014-08-01 2020-11-11 Postupak za pripravu (4s)-4-(4-cijano-2-metoksifenil)-5-etoksi-2,8-dimetil-1,4-dihidro-1-6-naftiridin-3-karboksamida i njegovo pročišćavanje za upotrebu kao aktivni farmaceutski sastojak HRP20201800T1 (hr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP14179544 2014-08-01
PCT/EP2015/067340 WO2016016287A1 (de) 2014-08-01 2015-07-29 Verfahren zur herstellung von (4s)- 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carbox-amid und dessen aufreinigung für die verwendung als pharmazeutischer wirkstoff
EP15742306.2A EP3174875B1 (de) 2014-08-01 2015-07-29 Verfahren zur herstellung von (4s)- 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carbox-amid und dessen aufreinigung für die verwendung als pharmazeutischer wirkstoff

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US (4) US10059707B2 (hr)
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JP (1) JP6818674B2 (hr)
KR (2) KR20230066477A (hr)
CN (4) CN116655629A (hr)
AR (1) AR101403A1 (hr)
AU (1) AU2015295376C1 (hr)
BR (1) BR112017001678B1 (hr)
CA (2) CA2956529A1 (hr)
CL (1) CL2017000263A1 (hr)
CO (1) CO2017000886A2 (hr)
DK (1) DK3174875T3 (hr)
ES (1) ES2828704T3 (hr)
HR (1) HRP20201800T1 (hr)
HU (1) HUE051350T2 (hr)
IL (1) IL250239B (hr)
JO (1) JO3648B1 (hr)
LT (1) LT3174875T (hr)
MX (1) MX369467B (hr)
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PE (1) PE20170141A1 (hr)
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PT (1) PT3174875T (hr)
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RU (1) RU2729998C9 (hr)
SG (1) SG11201700785UA (hr)
SI (1) SI3174875T1 (hr)
TW (1) TWI684593B (hr)
UA (1) UA122773C2 (hr)
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US10059707B2 (en) * 2014-08-01 2018-08-28 Bayer Pharma AG Method for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro- 1-6-naphthyridine-3-carbox-amide and the purification thereof for use as an active pharmaceutical ingredient
PE20180554A1 (es) * 2015-08-21 2018-04-02 Bayer Pharma AG Procedimiento para la preparacion de (4s)-4-(4-ciano-2-metoxifenilo)-5-etoxi-2,8-dimetilo-1,4-dihidro-1,6-naftiridina-3-carboxamida y su purificacion para su uso como principio activo farmaceutico
EP3560922A1 (de) 2018-04-24 2019-10-30 Bayer Aktiengesellschaft Verfahren zur herstellung von (4s)- 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carbox-amid durch racemat-spaltung mittels diastereomerer weinsäureester
KR20210135509A (ko) 2019-03-05 2021-11-15 바이엘 악티엔게젤샤프트 4-아미노-5-메틸피리돈을 제조하는 방법
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