LV11178B - Synthesis of 3-£4-(2-aminoethoxy) benzoyl|-2-aryl-6-hydroxybenzo £b| thiophenes - Google Patents

Synthesis of 3-£4-(2-aminoethoxy) benzoyl|-2-aryl-6-hydroxybenzo £b| thiophenes Download PDF

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LV11178B
LV11178B LVP-95-285A LV950285A LV11178B LV 11178 B LV11178 B LV 11178B LV 950285 A LV950285 A LV 950285A LV 11178 B LV11178 B LV 11178B
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hydroxy
formula
crystalline
benzoyl
benzo
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LVP-95-285A
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LV11178A (lv
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Elizabeth S Labell
Wayne D Luke
John Mc Mcgill
Randal S Miller
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Lilly Co Eli
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Priority claimed from US08/308,325 external-priority patent/US5629425A/en
Application filed by Lilly Co Eli filed Critical Lilly Co Eli
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Publication of LV11178B publication Critical patent/LV11178B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Gynecology & Obstetrics (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Claims (10)

  1. LV 11178 Izgudrojuma formula 1. Paņēmiens kristāliska solvāta iegūšanai savienojumam ar formulu (I)
    i kurā: R1 ir ūdeņraža atoms vai hidroksilgrupa; R2 un R3, neatkarīgi viens no otra, ir Ci^alkilgrupa, vai arī, R2 un R3 abi kopā ar slāpekļa atomu veido heterociklisku grupu no rindas: pirolidinilgrupa, heksmetilēniminogrupa un morfolinilgrupa; HX ir HCI vai HBr, kas atšķiras ar to, ka ietver šādus posmus: (a) benzotiofēna atvasinājuma ar formulu (II)
    1 II kurā: R4 ir ūdeņraža atoms vai Ci_4alkoksigrupa un R5 ir Ci-*alkilgrupa, acilēšanu ar acilējošu reaģentu (III)
    kur: R6 ir hlora atoms, broma atoms vai hidroksilgrupa un ΗΧ, R2 un R1 nozīmes ir jau minētās, BX’3 klātienē, kur X’ ir hlora atoms vai broma atoms; (b) dealkilē vienu vai vairākas fenola hidroksilgrupas posmā (a) iegūtajā acilētajā produktā, to apstrādājot ar papildus daudzumu BX’3, kur X’nozīmes ir jau minētās; (c) izolē kristālisko solvātu.
  2. 2. Paņēmiens pēc 1. punkta, kurā R1 ir hidroksilgrupa, R2 un R1 abi kopā ar slāpekļa atomu veido piperidinilgrupu, R4 ir metoksigrupa, R5 ir metilgrupa, R6 ir hlora atoms, HX ir HCI un X’ ir hlora atoms.
    kurā: R1 ir ūdeņraža atoms vai hidroksilgrupa; R2 un R1, neatkarīgi viens no otra, ir Ci^alkilgrupa, vai arī, R2 un R1 abi kopā ar slāpekļa atomu veido heterociklisku grupu no rindas: pirolidinilgrupa, heksmetilēniminogrupa un morfolinilgrupa; HX ir HCI vai HBr, kas atšķiras ar to, ka ietver šādus posmus: 2 1 Paņēmiens kristāliskā solvāta iegūšanai savienojumam ar formulu (I) LV 11178 (a) benzotiofēna atvasinājumu ar formulu (IV)
    kurā: R4 ir ūdeņraža atoms vai Ci^alkoksigrupa; R5 ir Ci-4alkilgrupa un HX, R2 un RrnozTmes ir jau minētās, dealkilē, apstrādājot ar BX’3l kur X’ir hlora atoms vai broma atoms, un (b) izolē kristālisko solvātu.
  3. 4. Kristāliska solvāta forma 6-hidroksi-2-(4-hidroksifenil)-3-[4-(2-piperi-diniletoksi)benzoil]benzo[b]tiofēna hidrogēnhlorīdam, kas dod šādu rentgenstaru difrakcijas ainu, izmantojot rentgenlampu ar vara anodu: d-līniju attālumi (angstrēmos) l/lo(x100) 10,4311 22,64 8,9173 10,73 8,4765 5,31 8,0095 50,39 7,3068 4,23 6,6094 79,23 5,5196 22,34 5,4223 89,86 5,1959 11.81 5,0746 74,90 4,8017 100,00 4,7262 57,97 4,6569 53,35 4,5378 96,75 4,4376 10,83 4,3397 56,89 4,2782 48,23 4,2129 40,94 4,1037 12,80 3,9880 14,76 3,8863 8,17 3,7999 42,13 3,7662 57,09 3,6738 38,58 d-līniju attālumi (angstrēmos) I/I„(x100) 3,5701 18,50 3 3,5393 19,00 3,4622 39,57 3,3867 5,02 3,3321 4,33 3,2686 6,79 3,1535 14,86 3,0450 13,58 2,9028 12,30 2,8302 19,59 2,7544 12,30 2,6366 6,89
  4. 6. Kristāliskais solvāts pēc 5. punkta, kas atšķiras ar to, ka tas ir 1,2-dihloretāna vai 1,2,3-trihlorpropāna solvāts.
  5. 7. Kristāliska solvāta forma 6-hidroksi-2-(4-hidroksifenil)-3-[4-(2-piperi-diniletoksi)benzoil]benzo[b]tiofēna hidrogēnhlorīdam, kas dod šādu rentgenstaru difrakcijas ainu, izmantojot rentgenlampu ar vara anodu: d-līniju attālumi (angstrēmos) l/lo(x100) 16,1265 3,80 10,3744 8,63 8,3746 5,29 7,9883 36.71 7,2701 5,06 6,5567 70,77 6.2531 6,79 5,5616 24,05 5.3879 100,00 5,0471 89,64 4,7391 86,96 4,6777 39,36 4,6332 62,60 4,5191 77,56 4,2867 36,82 4,2365 41,66 4,1816 49,60 4,0900 11,28 3,9496 11,85 3,7869 36,25 3,7577 56,16 3,6509 40,62 3,5751 15,65 3,5181 21,52 3,4964 18,53 3,4361 33,60 3,3610 6,21 3,3115 4,95 3,2564 7,36 3,2002 3,80 3,1199 15,77 3,0347 14,84 2,8744 9,67 2,8174 10,82 2,7363 11,51
  6. 8. Kristāliskais solvāts pēc 7. punkta, kas atšķiras ar to, ka tas ir 1,2-dihloretāna solvāts. 4 LV 11178
  7. 9. Paņēmiens nesolvatēta kristāliska 6-hidroksi-2-(4-hidroksifenil)-3-[4-(2-piperidiniletoksi)benzoil]benzo[b]tiofēna hidrogēnhlorīda iegūšanai, kas dod šādu rentgenstaru difrakcijas ainu, izmantojot rentgenlampu ar vara anodu: d-līniju attālumi (angstrēmos) l/lo(x100) 13.3864 71,31 9,3598 33,16 8.4625 2,08 7,3888 7.57 6,9907 5.80 6,6346 51,04 6,1717 29.57 5,9975 5,67 5,9135 9.87 5,6467 38,47 5,4773 10,54 5,2994 4.74 4,8680 4.03 4,7910 5.98 4,6614 57.50 4,5052 5.75 4,3701 9.03 4,2516 69,99 4,2059 57,64 4,1740 65,07 4,0819 12,44 3,9673 22,53 3,9318 100.00 3,9775 9.07 3.7096 33,38 3,6561 21,65 3,5576 3,36 3,5037 7.97 3,4522 18,02 3,4138 4,65 3,2738 10,23 3,1857 8,90 3.1333 6.24 3.0831 9.43 3,0025 12,13 2,9437 4,96 2.8642 7,70 2,7904 11,95 2,7246 3,05 2,6652 3,32 2.5882 I 7,30 atšķiras ar to, ka tas ietver šādus posmus: (a) benzotiofēna atvasinājuma ar formulu (II) 5
    kurā: R4 ir ūdeņraža atoms vai C^alkoksigrupa un R5 ir Ci^alkilgrupa, acilēšanu ar acilējošo aģentu (III)
    kur: R6 ir hlora atoms, broma atoms vai hidroksilgrupa un HX ir HCI vai HBr, R2 un R3 abi kopā ar slāpekļa atomu veido piperidinilgrupu, BX'3 klātienē, kur X’ ir hlora atoms vai broma atoms; (b) dealkilē fenola hidroksilgrupas posmā (a) iegūtajā acilētajā produktā, to apstrādājot ar papildus daudzumu ΒΧ3, kur X’nozīmes ir jau minētās, un (c) izolē kristālisku solvātu savienojumam ar formulu (I) 6 LV 11178
    kurā: R1 ir hidroksilgrupa un ΗΧ, R2 un R^nozTmes ir jau minētās; (d) apstrādā minēto kristālisko solvātu metanolā vai metanola un ūdens maisījumā ar apmēram vienu ekvivalentu bāzes; (e) neobligāti ekstraģē posmā (d) iegūto šķīdumu ar alifātisku ogļūdeņradi; (f) pievieno apmēram vienu ekvivalentu hlorūdeņražskābes metanolu saturošajam šķīdumam, kas iegūts posmā (d) vai (e), un (g) izolē nesolvatēto kristālisko savienojumu.
  8. 10. Paņēmiens pēc 9. punkta, kurā R4 ir metoksigrupa, R5 ir metilgrupa, R6 ir hlora atoms, HX ir HCI, ΒΧ3 ir BCI3, alifātiskais ogļūdeņradis ir heksāns vai heptāns un bāze ir nātrija hidroksīds.
  9. 11. Paņēmiens nesolvatēta kristāliska 6-hidroksi-2-(4-hidroksifenil)-3-[4-(2-piperidiniletoksi)benzoil]benzo[b]tiofēna hidrogēnhlorīda iegūšanai, kas dod šādu rentgenstaru difrakcijas ainu, izmantojot rentgenlampu ar vara anodu: d-līniju attālumi (angstrēmos) Ι/Ιο(χ100) 13,3864 71,31 9.3598 33,16 8,4625 2.08 7,3888 7,57 6,9907 5,80 6,6346 51,04 d-līniju attālumi (angstrēmos) I/Io(x100) 6,1717 29,57 5,9975 5,67 5,9135 9,87 5,6467 38,47 5,4773 10,54 5,2994 4,74 4,8680 4,03 4,7910 5,98 4,6614 57,50 7 4,5052 5,75 4,3701 9,03 4,2516 69,99 4,2059 57,64 4,1740 65,07 4,0819 12,44 3,9673 22,53 3,9318 100,00 3,9775 9,07 3,7096 33,38 3,6561 21,65 3,5576 3,36 3,5037 7,97 3,4522 18,02 3,4138 4,65 3,2738 10,23 3,1857 8,90 3,1333 6,24 3,0831 9,43 3,0025 12,13 2,9437 4,96 2,8642 7,70 2,7904 11,95 2,7246 3,05 2,6652 3,32 2,5882 7,30 atšķiras ar to, ka tas ietver šādus posmus: (a) benzotiofēna atvasinājuma ar formulu (II)
    kurā: R4 ir Ci^alkoksigrupa un R5 ir Ci^alkilgrupa, acilēšanu ar acilējošo aģentu (III) LV 11178
    kur. R6 ir hlora atoms, broma atoms vai hidroksilgrupa un HX ir HCI vai HBr, R2 un R3 abi kopā ar slāpekļa atomu veido piperidinilgrupu, BX’3 klātienē, kur X’ ir hlora atoms vai broma atoms; (b) dealkilē fenola hidroksilgrupas posmā (a) iegūtajā acilētajā produktā, to apstrādājot ar papildus daudzumu BX’3, kur X’nozīmes ir jau minētās, un (c) izolē kristālisku solvātu savienojumam ar formulu (I)
    kurā: R1 ir hidroksilgrupa un HX, R2 un R^nozīmes ir jau minētās; (d) šķīdina minēto kristālisko solvātu karstā metanola un ūdens maisījumā; (e) neobligāti filtrē posmā (d) iegūto šķīdumu; (f) ietvaicē posmā (d) vai (e) iegūto šķīdumu un (g) izolē nesolvatēto kristālisko savienojumu. 9
  10. 12. Paņēmiens pēc 11. punkta, kurā R4 ir metoksigrupa, R5 ir metilgrupa, R* ir hlora atoms, HX ir HCI un ΒΧ3 ir BCI3. 10
LVP-95-285A 1994-09-19 1995-09-18 Synthesis of 3-£4-(2-aminoethoxy) benzoyl|-2-aryl-6-hydroxybenzo £b| thiophenes LV11178B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/308,325 US5629425A (en) 1994-09-19 1994-09-19 Haloalkyl hemisolvates of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-piperidinoethoxy)-benzoyl]benzo[b]thiophene
US42791495A 1995-04-26 1995-04-26

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LV11178A LV11178A (lv) 1996-04-20
LV11178B true LV11178B (en) 1996-08-20

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LVP-95-284A LV11177B (en) 1994-09-19 1995-09-18 Novel pharmaceutical product
LVP-95-285A LV11178B (en) 1994-09-19 1995-09-18 Synthesis of 3-£4-(2-aminoethoxy) benzoyl|-2-aryl-6-hydroxybenzo £b| thiophenes

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