WO2008014249A2 - Préparation améliorée de composés d'azaindole - Google Patents

Préparation améliorée de composés d'azaindole Download PDF

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Publication number
WO2008014249A2
WO2008014249A2 PCT/US2007/074202 US2007074202W WO2008014249A2 WO 2008014249 A2 WO2008014249 A2 WO 2008014249A2 US 2007074202 W US2007074202 W US 2007074202W WO 2008014249 A2 WO2008014249 A2 WO 2008014249A2
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WO
WIPO (PCT)
Prior art keywords
compound
formula
reaction
substituted
pyrrolo
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PCT/US2007/074202
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English (en)
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WO2008014249A3 (fr
Inventor
Danette Astolfi
Timothy Allen Ayers
Sithamalli V. Chandramouli
Andrea Hillegass
Gregory G. Kubiak
George Everett Lee
David J. Lythgoe
Matthew R. Powers
Witold Subotkowski
Benoit Vanasse
Franz J. Weiberth
Yong Yu
Boris Gordonov
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Sanofi-Aventis
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Publication of WO2008014249A2 publication Critical patent/WO2008014249A2/fr
Publication of WO2008014249A3 publication Critical patent/WO2008014249A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention is directed to improved methods for preparing azaindole compounds and intermediates that are useful in the synthesis of the azaindole compounds.
  • 6-(5-Methoxy-l -methyl- 1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine was synthesized according to the following reactions.
  • the present invention is directed to an improved process for preparing a compound of Formula I or that is an intermediate useful in preparing a compound of Formula I.
  • the improved process comprises:
  • Sonogashira chemistry is well established in the literature to have application towards the preparation of bisarylethynes, which, when appropriately substituted, are important intermediates in the preparation of indoles.
  • a recent paper describes the use of a one-pot, double Sonogashira protocol to prepare unsymmetrical alkynes.
  • Performing the coupling sequences in one pot is advantageous because it avoids the need to isolate intermediate 6 indicated in the scheme above, which has been shown to be thermally unstable.
  • This technology represents a novel and facile way to prepare (generally) 2- substituted-4,7-diazaindoles with specific application to the preparation of the compound of Formula I and its metabolites.
  • Intramolecular Chichibabin-type reactions are employed to prepare heterocycles such as pyrrolopyridine and pyrrolopyrazine, but generally proceed in low yield, especially for the synthesis of pyrrolopyrazines from 2-methylpyrazine (Wakefield, B. J., et al. Tetrahedron 1992, 48, 939; Meijer, L., et al, J. Med. Chem. 2003, 46, 222; see also: Leffier, M. Org. React., 1942, 1, 91; Kelly, T. R., et al. J. Org. Chem. 1997, 62, 2774).
  • the low yields were the result of several factors, including: 1) low reactivity of 2-methylpyrazine anion towards 5-methoxy-1- methyl-1H-indol-3-carbonitrile, 2) unfavorable Chichibabin cyclization of the imine anion, 3) competing deprotonation of 5 -methoxy-1 -methyl- 1H-indol-3-carbonitrile at 2-position (leading to polymerize indol-nitrile).
  • volume Improvement The volumes for the reaction (initially -60/1, THF/nitrile) and the work-up (>30/l, acetone, MeOH/nitrile) were improved to -20/1 and 2/1 (HOAc/nitrile), respectively, primarily by using 10 M n-BuLi rather than 2.5 M n-BuLi for both the LVO and pyrazine anion formation and by optimizing the work up.
  • reaction could be conducted in high yield at room temperature (20 degrees C) (61%) than at higher or lower temperature (at 40 0C, 47%; at 0 0 C, 51%).
  • This technology represents a novel, facile and reproducible way to prepare the compound of Formula I on large scales in high yields.
  • the Chichibabin reaction could be performed in one pot, which is advantageous for large-scale synthesis of the compound of Formula I.
  • this methodology can be used to prepare various related heterocycles, including, substituted 2-indolyl-1H-pyrrolo[2,3-b]pyrazine, substituted 2- indolyl-1H-pyrrolo[2,3-b]quinoxaline, substituted 2-indolyl-1H-pyrrolo[2,3-b]pyridine, substituted 2-indolyl-1H-pyrrolo[2,3-b]quinoline, substituted 2-indolyl-1H-pyrrolo[2,3- b]pyrimidine, and substituted 2-Ar-1H-pyrrolo[2,3-b]pyrazine, substituted 2 -Ar-1H- pyrrolo[2,3-b]quinoxaline, substituted 2-Ar-1H-pyrrolo[2,3-b]pyridine, substituted 2-Ar-1H- pyrrolo[2,3-b]quinoline, substituted 2-Ar-1H-pyrrolo[2,3-b]pyrimidine, where Ar represents
  • Solvent effect Furthermore, it was found that using 1,4-dioxane or 1,3-dioxolane as solvents improved the yield by as much as 15 % in the lab. The observed solvent effect was quite unique to these two solvents among about 15 other solvents that were screened in this reaction.
  • reaction was then held 51 °C for 1 hour and sampled for HPLC (IPM- 1 : 21.3 A% enamine, 57.2 A % compound of Formula I, 0.7A% nitrile) At this point the reaction was cooled to 20 °C and a solution of 103.4 g of ammonium chloride in IL of water was added over 75 min. between 20 and 52 °C. The mixture was stirred at 50 °C for 15 min. then cooled to 15 °C. Agitation was turned down to 50 rpm and the aqueous layer was allowed to separate over 30 min. This aqueous layer was removed and the organic layer containing the solids was filtered.
  • HPLC IPM- 1 : 21.3 A% enamine, 57.2 A % compound of Formula I, 0.7A% nitrile
  • the filter cake was washed with 2 x 250 ml of 84/16 ethano I/water at 20 °C. The filter cake was then placed in the oven over night at 50 °C and 50 mbar vacuum to yield 75 g of the compound of Formula I as a yellow solid (99.5A%, 90.9wt% pure, 50% yield).
  • 1,3-dioxolane was chosen for scaleup in the plant. Results from the plant run are shown in the table below.
  • the initial lots of the compound of Formula I were prepared using a intramolecular Chichibabin type reaction using LDA (generated in situ from BuLi/diisopropyl amine) as base.
  • LDA generated in situ from BuLi/diisopropyl amine
  • For scaling up the synthesis of this compound it became necessary to use 10 M BuLi solution to carry out the reaction at a reasonable concentration.
  • Some of the features of the reaction are still not well understood posing a scale-up risk.
  • scale -up in the pilot plant using 10 M BuLi posed serious handling issues as well.
  • Use of the Sodiumhexamethyldisilazide was shown to have the desired features for scale up. Subsequently the reaction was scaled up to about an 11 kg scale.
  • this methodology can be used to prepare various related heterocycles, including, substituted 2-indolyl-1H-pyrrolo[2,3-b]pyrazine, substituted 2- indolyl-1H-pyrrolo[2,3-b]quinoxaline, substituted 2-indolyl-1H-pyrrolo[2,3-b]pyridine, substituted 2-indolyl-1H-pyrrolo[2,3-b]quinoline, substituted 2-indolyl-1H-pyrrolo[2,3- b]pyrimidine, and substituted 2-Ar-1H-pyrrolo[2,3-b]pyrazine, substituted 2 -Ar-1H- pyrrolo[2,3-b]quinoxaline, substituted 2-Ar-1H-pyrrolo[2,3-b]pyridine, substituted 2-Ar-1H- pyrrolo[2,3-b]quinoline, substituted 2-Ar-1H-pyrrolo[2,3-b]pyrimidine, where Ar represents
  • the invention involves adding lithium phenoxides (simple and substituted) in the reaction of nitrile A003204699 with methylpiperazine (A000486825) to enhance the performance of the reaction by providing higher yields of the compound of Formula I.
  • Side product (A003377523) of this reaction is generated in higher levels without these additives.
  • LiOPh as the additive
  • LiHMDS LiHMDS
  • Method A used commercially available LiOPh as a solution in the reaction
  • Method B used n- BuLi and PhOH to generate the LiOPh
  • Method C generated LiOPh using LiOMe (only done in scouting experiments).
  • Typical experimentals are provided below. Note that the ratio of desired product and enamine are up to 80:20 under these conditions whereas the ratio is typically 7:93 without the phenoxide additive. Tables with explanations are provided to summarize the different conditions including different bases and additives.
  • Method A Experimental for the compound of Formula I preparation using commercial grade 1M Lithium phenoxide.
  • a 500 mL round-bottom flask was charged with 150 mL (150 mmol, 5.6 eq.) of 1M Lithium phenoxide in THF and concentrated on the rotary evaporator.
  • the resultant light brown residue was taken up in 90 mL (90 mmol, 3.3 eq.) of 1M LHMDS in THF at room temperature with a nitrogen cover.
  • the contents were transferred to a 500 mL 3 -neck round-bottom flask equipped with mechanical stirrer, condenser, temperature probe, and nitrogen inlet.
  • the flask was charged with 3.4 g (36 mmol, 1.3 eq.) of Methylpyrazine in one portion.
  • the dark red mixture was stirred at room temperature under nitrogen for 15 min.
  • the dark solution was warmed to 40 °C. After 5 hours at 40 °C the hplc showed 25 A% enamine, 59 A% the compound of Formula I, and 16 A% nitrile with a Formula I: enamine ratio of 68:32.
  • the reaction was stirred at room temperature over the weekend to provide 30 A% enamine, 64 A% compound of Formula I, and 6 A% nitrile with 68:32 Formula I: enamine ratio.
  • the reaction was treated with 7.1 g (118 mmol, 4.4 eq.) of glacial acetic acid keeping the reaction temperature less than 25 °C. Added 90 mL of water and stirred at room temperature for 2.5 hours. Filtered solids then washed cake twice with 25 mL of 1 : 1 THF/water followed by 25 mL of water. The cake was dried in a vacuum oven at 60 °C and 20 in Hg overnight to afford 3.23 g of a yellow solid of 91.6 A% purity and 92.9 w/w %, 40% yield corrected for assay.
  • Method B Experimental for compound of Formula I preparation where Lithium phenoxide was generated using 10M n-BuLi.
  • the chiller set at -20 °C and the batch temperature of-17 °C, 32 mL (322 mmol, 6 eq.) of 10 M n-Butyllithium at a rate to keep the reaction temperature less than 5 °C.
  • the total addition time was 40 min.
  • the resultant yellow solution was warmed to 0 °C and held for 15 min.
  • the solids were filtered while cold over buchner funnel with 7 cm Whatman paper.
  • the cake was washed twice with 50 mL of 3 : 1 ethanol: water followed by 50 mL of water to give 23.35 g of a wet yellow solid.
  • the hplc of the cake showed phenol content so the cake was taken up in 100 mL of 1 : 1 2.5 N NaOH: water.
  • the suspension was warmed to 40 °C, held for 20 min. then cooled to room temperature and filtered over buchner with 5.5 cm Whatman paper.
  • Phenoxide was Prepared from Phenol and Lithium Methoxide.
  • a 50 mL round-bottom flask with stir bar and nitrogen blanket was charged with 5.7 g (15.1 mmol, 5.6 eq.) of 10% Lithium methoxide in methanol.
  • the solution was treated with 1.9 g (20.5 mmol, 7.6 eq.) of Phenol and stirred for 1 hour.
  • the solution was concentrated on the rotary evaporator, then the white residue was taken up in 10 mL of anhydrous THF and concentrated again to further dry the sample.
  • the resultant white solid was treated at room temperature with 7.1 mL (9.2 mmol, 3.4 eq.) of 1.3 M LHMDS in one portion followed by 0.36 g (3.8 mmol, 1.4 eq.) of methylpyrazine, also added in one portion.
  • the red solution was stirred at room temperature for 15 min., and then 0.5 g (2.7 mmol, 1.0 eq.) of the nitrile was added as a solid in one portion.
  • the reaction was warmed to 40 °C and held for 3 hours to give 23 A% compound of Formula I, 16 A% enamine, and 61 A% nitrile with Formula I: enamine ratio of 60:40.
  • the reaction was held at room temperature overnight to give 24 A% compound of Formula I, 9 A% enamine, and 67 A% nitrile with Formula I: enamine ratio of
  • Table 9 shows the effect of increasing the amount of LiOPh to the reatio of enamine and 0950, starting with no LiOPh (9:91) and increasing the amounts (Entries 3-6) from 1 to 5 eq. An effect is observed at 1 eq, but it seems to reach a maximum after 5 eq. Further studies were conducted with 3, 6 and 12 eq: 3 eq. LiOPh (56-73:44-27); 6 eq. LiOPh (32-33:68-67); 12 eq LiOPh (27-30:70-73). Thus, it appears that the amount of LiOPh needs to be preferably greater than 3 eq (equivalents), but not as much as 12 eq. The use of lithium vinyl oxide (Entry 2) and its impact to increase the ratio is also noteworthy.
  • Table 9 shows that LiOMe can be used to generate the LiOPh with excess PhOH providing the highest ratio of (27:73).
  • Table 10 shows that different substituted phenols can be used in this process, but do not add much of an advantage. Note that generating the LiOPh using excess LHMDS was less favorable.
  • Table 11 shows that different bases can also be used, although the impact is not as great. Note that Lithium vinyl oxide also works with Li(bzl)TMS amide.
  • Table 12 shows the impact of phenoxide when LDA was the base. Note that in this case, the conversion is more important than yield as mostly impurities and remaining starting material are observerd without LiOPh. Other phenoxides (used by generating in situ with excess LDA) were also demonstrated to be viable additives.
  • the compound of Formula I may be crystallized favorably by the procedure disclosed here.
  • the compound of Formula I (130 g, 0.467mole) was suspended in acetic acid (715 mL) in a jacketed reactor. The batch was stirred and heated to 85 °C until the solids had dissolved. The batch was then filtered while hot. The batch was returned to a jacketed reactor and reheated to 85 °C. A solution of 1 : 1 isopropanol (IPA):Water (1560 mL) was prepared and ca 22 wt% (328 mL) of this solution was added over 20-30 minutes. The batch was held at 85 °C, and was seeded with 0.3-wt% (0.4 g) of crystals of the compound of Formula I.
  • IPA isopropanol
  • This process has been used to recrystallize kilogram quantities of this compound. To date, the largest scale the process has been performed is 9.6 kg. The process has repeatedly produced material of high chemical purity and consistent physical quality.
  • This invention describes the process by which the compound of Formula I is recrystallized from an acetic acid, isopropyl alcohol and water mixture to afford crystalline compound.
  • These solvents are ICH class 3 solvents (i.e. have no toxicological concerns and are preferred for the final active pharmaceutical ingredient).
  • NMP N-methylpyrrolidinone
  • the crystalline form of the material produced consists of plates and rods. Previously, the existing process produced long needles. The material produced by the new process has better filtration characteristics, better flow characteristics and is more suitable for subsequent micronization.
  • the identification of acetic acid was not obvious.
  • the subject compound has very limited solubility in most other organic solvents but was found to have surprisingly good solubility in warm acetic acid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé amélioré pour fabriquer des azaindoles et des composés apparentés.
PCT/US2007/074202 2006-07-24 2007-07-24 Préparation améliorée de composés d'azaindole WO2008014249A2 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US82016206P 2006-07-24 2006-07-24
US82014806P 2006-07-24 2006-07-24
US82013806P 2006-07-24 2006-07-24
US82016006P 2006-07-24 2006-07-24
US82014906P 2006-07-24 2006-07-24
US60/820,162 2006-07-24
US60/820,160 2006-07-24
US60/820,138 2006-07-24
US60/820,148 2006-07-24
US60/820,149 2006-07-24

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WO2008014249A2 true WO2008014249A2 (fr) 2008-01-31
WO2008014249A3 WO2008014249A3 (fr) 2008-12-11

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102008052943A1 (de) 2008-10-23 2010-04-29 Merck Patent Gmbh Azaindolderivate
US9802814B2 (en) 2012-09-12 2017-10-31 Fairchild Semiconductor Corporation Through silicon via including multi-material fill

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6770643B2 (en) * 1999-12-24 2004-08-03 Aventis Pharma Limited Azaindoles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6770643B2 (en) * 1999-12-24 2004-08-03 Aventis Pharma Limited Azaindoles

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHRISTOPHER KORADIN ET AL: "Synthesis of polyfunctional indoles and related heterocycles mediated by cesium and potassium bases" TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 59, no. 9, 24 February 2003 (2003-02-24), pages 1571-1587, XP004409958 ISSN: 0040-4020 *
COREY R. HOPKINS AND NICOLA COLLAR: "6-Substituted-5H-pyrrolo[2,3-b]pyrazines via palladium-catalyzed heteroannulation from N-(3-chloropyrazin-2-yl)methane- sulfonamide and alkynes" TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, vol. 45, no. 43, 18 October 2004 (2004-10-18), pages 8087-8090, XP004584133 ISSN: 0040-4039 *
MATTHEW J. MIO ET AL: "One-pot synthesis of symmetrical and unsymmetrical bisarylethynes by a modification of the Sonogashira coupling reaction" ORGANIC LETTERS, vol. 4, no. 19, 2002, pages 3199-3202, XP002482923 cited in the application *
MICHAEL L. DAVIS ET AL: "Reactions of beta-(lithiomethyl)azines with nitriles as a route to pyrrolo-pyridines, -quinolines, -pyrazines, -quinoxalines and -pyrimidines" TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 48, no. 5, 1 January 1992 (1992-01-01), pages 939-952, XP001118259 ISSN: 0040-4020 cited in the application *
YVETTE METTEY ET AL: "Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects" JOURNAL OF MEDICINAL CHEMISTRY, US AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 46, no. 2, 18 December 2002 (2002-12-18), pages 222-236, XP002285187 ISSN: 0022-2623 cited in the application *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102008052943A1 (de) 2008-10-23 2010-04-29 Merck Patent Gmbh Azaindolderivate
US9802814B2 (en) 2012-09-12 2017-10-31 Fairchild Semiconductor Corporation Through silicon via including multi-material fill

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