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WO2013119625A1 - Methods for the preparation of hiv attachment inhibitor piperazine prodrug compound - Google Patents

Methods for the preparation of hiv attachment inhibitor piperazine prodrug compound Download PDF

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Publication number
WO2013119625A1
WO2013119625A1 PCT/US2013/024880 US2013024880W WO2013119625A1 WO 2013119625 A1 WO2013119625 A1 WO 2013119625A1 US 2013024880 W US2013024880 W US 2013024880W WO 2013119625 A1 WO2013119625 A1 WO 2013119625A1
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Prior art keywords
compound
aryl
yield
reacting
produce
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PCT/US2013/024880
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French (fr)
Inventor
Martin D. Eastgate
Michael S. BULTMAN
Ke Chen
Dayne Dustan FANFAIR
Richard J. Fox
Thomas E. LA CRUZ
Boguslaw M. Mudryk
Christina Ann RISATTI
James H. Simpson
Maxime C. SOUMEILLANT
Jonathan Clive TRIPP
Yi Xiao
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Priority to JP2014556625A priority Critical patent/JP6114314B2/en
Priority to ES13705076.1T priority patent/ES2644747T3/en
Priority to CN201380007908.9A priority patent/CN104080785B/en
Priority to BR112014019289A priority patent/BR112014019289A8/en
Priority to EP13705076.1A priority patent/EP2812332B1/en
Priority to EA201491446A priority patent/EA024872B1/en
Priority to MX2014009279A priority patent/MX352320B/en
Priority to CA2864087A priority patent/CA2864087A1/en
Publication of WO2013119625A1 publication Critical patent/WO2013119625A1/en
Anticipated expiration legal-status Critical
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/02—Lithium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/098—Esters of polyphosphoric acids or anhydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the invention relates to methods of making HIV attachment inhibitor compounds useful as antivirals, and in particular, to methods of making the piperazine prodrug compound identified as l-benzoyl-4-[2-[4-methoxy-7-(3-methyl-li7-l,2,4-triazol-l-yl)-l- [(phosphonooxy)methy 1] - l//-pyrrolo [2 ,3 -c]pyridin-3 -yl] - 1 ,2 -dioxoethyl] -piperazine .
  • the invention also relates to the compounds, including intermediates, obtained by the processes herein set forth.
  • HIV-1 human immunodeficiency virus -1 infection
  • AIDS immunodeficiency syndrome
  • drugs for the treatment of HIV include nucleoside reverse transcriptase (RT) inhibitors or approved single pill combinations:
  • zidovudine (or AZT or Retrovir ® ), didanosine (or Videx ® ), stavudine (or Zerit ® ), lamivudine (or 3TC or Epivir ® ), zalcitabine (or DDC or Hivid ® ), abacavir succinate (or Ziagen ® ), Tenofovir disoproxil fumarate salt (or Viread ® ), emtricitabine (or FTC or Emtriva ® ), Combivir ® (contains -3TC plus AZT), Trizivir ® (contains abacavir, lamivudine, and zidovudine), Epzicom ® (contains abacavir and lamivudine), Truvada ® (contains Viread ® and Emtriva ® ); non-nucleoside reverse transcriptase inhibitors: nevirapine (or Viramune ® ), delavir
  • HIV attachment inhibitors are a novel subclass of antiviral compounds that bind to the HIV surface glycoprotein gpl20, and interfere with the interaction between the surface protein gpl20 and the host cell receptor CD4. Thus, they prevent HIV from attaching to the human CD4 T-cell, and block HIV replication in the first stage of the HIV life cycle.
  • the properties of HIV attachment inhibitors have been improved in an effort to obtain compounds with maximized utility and efficacy as antiviral agents.
  • HIV attachment inhibitor compound in particular, has now shown considerable prowess against HIV.
  • This compound is identified as l-(4-benzoyl-piperazin-l-yl)-2-[4- methoxy-7-(3-methyl-[l,2,4] triazol-l-yl)-lH-pyrralo [2,3-c] pyridine-3-yl]-ethane-l,2- dione, and is set forth and described in U.S. 7,354,924, which is incorporated herein in its entirety:
  • the above compound is the parent compound of the prodrug known as 1 -benzoyl-4- [2-[4-methoxy-7-(3-methyl-li7-l,2,4-triazol-l-yl)-l-[(phosphonooxy)methyl]-li7- pyrrolo[2,3-c]pyridin-3-yl]-l,2-dioxoethyl]-piperazine. It is set forth and described in U.S. Patent No. 7,745,625, which is incorporated by reference herein it its entirety. The compound is represented by the formula below:
  • R 2 each independently -H, -C0 2 R, -S0 2 Aryl, -CHO;
  • X 2 -CI, -Br, -I, -N(R 2 ) 2 , -OS0 2 R;
  • R 1 is -SC ⁇ Aryl.
  • Aryl herein is preferably phenyl.
  • X 1 is -H.
  • X 3 is -H.
  • the dihydroxy compound is ethylene glycol.
  • the invention is directed to a process for preparing the compound of Formula I
  • R 2 each independently -H, -C0 2 R, -S0 2 Aryl, -CHO;
  • R 3 -H, -C0 2 R, -CH 2 SR, -CH 2 OR, -CH(OR) 2 , -CH(OR)(NR 2 ), -CH(NR 2 ) 2 ;
  • R each independently -H, -Ci-C 6 alkyl, -aryl, -CH 2 Aryl;
  • X 3 each independently -H, -OR, -NR 2 , CI, -Br, -I, -SR, -S0 2 R, -S0 3 R, -SR 2 + ;
  • X 4 -CI, -Br, -I, -OTs, +NR 3 , -pyridium, and ⁇ 0 _s- R .
  • R 1 is -S0 2 Aryl.
  • Aryl herein is preferably phenyl.
  • X 1 is -H.
  • X 3 is -H. It is preferred that the dihydroxy compound is ethylene glycol.
  • R 1 -H, -Boc, -Piv, -S0 2 Aryl, -CH 2 SAryl, -CH 2 OP(0)(OR) 2 , -CH 2 OR, - CH 2 Aryl;
  • R 2 each independently -H, -C0 2 R, -S0 2 Aryl, -CHO;
  • R 3 -H, -C0 2 R, -CH 2 SR, -CH 2 OR, -CH(OR) 2 , -CH(OR)(NR 2 ), -CH(NR 2 ) 2 ;
  • R each independently -H, -Ci-C 6 alkyl, -aryl, -CH 2 Aryl;
  • X 2 -CI, -Br, -I, -N(R 2 ) 2 , -OS0 2 R;
  • X 3 and X 5 each independently -H, -OR, -NR 2 , -CI, -Br, -I, -SR, -S0 2 R, -S0 3 R, -SR 2 + ;
  • R 1 is -S0
  • R 5 -H, -OR, -NR 2 , -CI, -Br, -I, -SR;
  • R 6 -H, -Boc, -Piv, -S0 2 Aryl, -CH 2 SAryl, CH 2 OP(0)(OR) 2 , -CH 2 OR, - CH 2 Aryl, -Li, -Na, -K, -Ca, -Mg, TMG (Tetramethyl guanidine);
  • R each independently -H, -Ci-C 6 alkyl, -aryl, -CH 2 Aryl ;
  • X 5 -H, -OR, -NR 2 , -CI, -Br, -I, -SR
  • R -H, -Ci-C 6 alkyl, aryl, -CH 2 Aryl; and further wherein PyBrop is the peptide coupling reagent Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate.
  • Aryl herein is preferably phenyl.
  • the invention is also directed to a compound, including pharmaceutically acceptable salts and mixtures thereof, which is selected from the group of:
  • the first solvent is selected from the group of carboxylic acid, NMP (N-methyl-2-pyrrolidone), DMSO, MeCN, MeOH, and acetone.
  • the acid is selected from the group of H 2 S0 4 , HNO 3 , HCl, phosphoric and carboxylic acids.
  • the second solvent is selected from the group of water, alkyl ketone, heptane, toluene, ethyl acetate, DMSO, MeCN, MeOH and acetone. Even more preferably, the acid is acetic acid, and the second solvent is acetone.
  • the present invention is directed to these, as well as other important ends, hereinafter described.
  • alkyl group refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups.
  • the alkyl group has 1 to 20 carbon atoms (whenever a numerical range; e.g., "1-20", is stated herein, it means that the group, in this case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms.
  • the alkyl group may be substituted or unsubstituted.
  • C 1 6 alkyl as used herein and in the claims means straight or branched chain alkyl groups with up to and including 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and the like.
  • aryl refers to an all carbon monocyclic or fused-ring polycyclic(i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, napthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.
  • the synthesis of the piperazine prodrug compound can be set forth in the following flow diagram:
  • the synthesis of the piperazine prodrug compound begins from the N-sulfonylated pyrrole la. Friedel-Crafts acylation with 2-chloro acetyl chloride, in the presence of aluminum trichloride, provides the 3-acryl pyrrole derivative 2a. Displacement of the 2-choro ketone by the sodium salt of the 7V-formyl sulfonamide, in the presence of a tetraalkylammonium halide, preferably bromide, preferably tetrabutylammonium bromide, provides the amino-ketone 3 a.
  • a tetraalkylammonium halide preferably bromide, preferably tetrabutylammonium bromide
  • TMOF trimethyl orthoformate
  • Oxidation of the pyridine nitrogen provides the -oxide 7a which is then treated with PyBrop in the presence of base, which brominates the C7-position, yielding the bromo-azaindole 8a after hydrolysis of the sulfonyl protecting group.
  • a second Friedel-Crafts acylation onto C3 of the indole provides the oxalate 9a, which is coupled with the ⁇ -benzoyl piperazine to give the amide 10a.
  • Addition of the triazole is catalyzed by copper, in the presence of an appropriate ligand and base, to give the indole 11c which is isolated as its lithium salt (or optionally as a co-salt with KBr).
  • Alkylation of the indole nitrogen with the chloro-phosphate 14a gives the phosphate ester 12a, and subsequent solvolysis of the tert-butyl groups provides the final compound 13a.

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  • Chemical Kinetics & Catalysis (AREA)
  • Materials Engineering (AREA)
  • Engineering & Computer Science (AREA)
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  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Description

METHODS FOR THE PREPARATION OF HIV ATTACHMENT INHIBITOR PIPERAZINE PRODRUG COMPOUND
CROSS REFERENCE TO RELATED APPLICATION This non-provisional application claims the benefit of U.S. Provisional Application
Serial Number 61/596,362 filed February 8, 2012.
FIELD OF THE INVENTION
The invention relates to methods of making HIV attachment inhibitor compounds useful as antivirals, and in particular, to methods of making the piperazine prodrug compound identified as l-benzoyl-4-[2-[4-methoxy-7-(3-methyl-li7-l,2,4-triazol-l-yl)-l- [(phosphonooxy)methy 1] - l//-pyrrolo [2 ,3 -c]pyridin-3 -yl] - 1 ,2 -dioxoethyl] -piperazine . The invention also relates to the compounds, including intermediates, obtained by the processes herein set forth.
BACKGROUND OF THE INVENTION
HIV-1 (human immunodeficiency virus -1) infection remains a major medical problem, with tens of millions of people still infected worldwide at the end of 2011. The number of cases of HIV and AIDS (acquired immunodeficiency syndrome) has risen rapidly. In 2005, for example, approximately 5.0 million new infections were reported, and 3.1 million people died from AIDS. Currently available drugs for the treatment of HIV include nucleoside reverse transcriptase (RT) inhibitors or approved single pill combinations:
zidovudine (or AZT or Retrovir®), didanosine (or Videx®), stavudine (or Zerit®), lamivudine (or 3TC or Epivir®), zalcitabine (or DDC or Hivid®), abacavir succinate (or Ziagen®), Tenofovir disoproxil fumarate salt (or Viread®), emtricitabine (or FTC or Emtriva®), Combivir® (contains -3TC plus AZT), Trizivir® (contains abacavir, lamivudine, and zidovudine), Epzicom® (contains abacavir and lamivudine), Truvada® (contains Viread® and Emtriva®); non-nucleoside reverse transcriptase inhibitors: nevirapine (or Viramune®), delavirdine (or Rescriptor®) and efavirenz (or Sustiva®), Atripla® (Truvada® + Sustiva®), and etravirine, and peptidomimetic protease inhibitors or approved formulations: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, KaletraH(lopinavir and Ritonavir), darunavir, atazanavir (Reyataz®), and tipranavir (Aptivus®), and integrase inhibitors such as raltegravir (Isentress®), and entry inhibitors such as enfuvirtide (T-20) (Fuzeon®) and maraviroc (Selzentry®).
In addition, HIV attachment inhibitors are a novel subclass of antiviral compounds that bind to the HIV surface glycoprotein gpl20, and interfere with the interaction between the surface protein gpl20 and the host cell receptor CD4. Thus, they prevent HIV from attaching to the human CD4 T-cell, and block HIV replication in the first stage of the HIV life cycle. The properties of HIV attachment inhibitors have been improved in an effort to obtain compounds with maximized utility and efficacy as antiviral agents.
One HIV attachment inhibitor compound, in particular, has now shown considerable prowess against HIV. This compound is identified as l-(4-benzoyl-piperazin-l-yl)-2-[4- methoxy-7-(3-methyl-[l,2,4] triazol-l-yl)-lH-pyrralo [2,3-c] pyridine-3-yl]-ethane-l,2- dione, and is set forth and described in U.S. 7,354,924, which is incorporated herein in its entirety:
Figure imgf000003_0001
The above compound is the parent compound of the prodrug known as 1 -benzoyl-4- [2-[4-methoxy-7-(3-methyl-li7-l,2,4-triazol-l-yl)-l-[(phosphonooxy)methyl]-li7- pyrrolo[2,3-c]pyridin-3-yl]-l,2-dioxoethyl]-piperazine. It is set forth and described in U.S. Patent No. 7,745,625, which is incorporated by reference herein it its entirety. The compound is represented by the formula below:
Figure imgf000003_0002
Various methods for making this prodrug compound have been set forth, including those detailed in the '625 reference. In particular, the '625 reference includes various methods for acylation, alkylation and phosphorylation. Another patent reference, U.S. S.N. 13/359,708 filed January 27, 2012, entitled "METHODS OF MAKING HIV
ATTACHMENT INHIBITOR PRODRUG COMPOUND AND INTERMEDIATES", also details various procedures for making the piperazine prodrug compound. These include a
multi-step process which uses the compound
Figure imgf000004_0001
as a starting material, which is subsequently brominated, and then nitrated. Further on, a triazolyl moiety is added to the compound before further attaching the piperazine moiety separated by dual carbonyl groups.
What is now needed in the art are new methods of making the piperazine prodrug compound which is useful against HIV. These methods should provide a further comprehensive and efficient means for making the prodrug molecule, both in terms of overall yield and material throughput.
SUMMARY OF THE INVENTION
In a first embodiment, the invention provides a process for preparing the compound of Formula I
Figure imgf000004_0002
(I)
which comprises: reacting the compound 1
Figure imgf000005_0001
1 with the acid chloride compound
Figure imgf000005_0002
form the compound 2 ; and then contacting the compound 2 with a di-substituted amine (R2)2NH in base to produce
Figure imgf000005_0003
the compound 3 ; and thereafter reacting the compound 3 with the dihydroxy compound HO OH n acid solution, wherein the linker between the hydroxyl groups is Ci - Ce alkyl, to yield the
Figure imgf000005_0004
compound 4 ^ ; and
(d) reacting the compound 4 with the compound x Η 3χ χχ33 in acid to produce the
Figure imgf000005_0005
compound 5 contacting the compound 5 with Me-X4 in base or MeO-R3 in acid to produce
Figure imgf000006_0001
compound 6 ; and then performing an oxidation reaction on compound 6 using [O] to yield the
Figure imgf000006_0002
compound 7 ; and
H triazolyl group l-A V>48
adding the to compound 7, and then conducting a functional group interconversion reaction, to obtain the compound (I) above, wherein:
R1 = -H, -Boc, -Piv, -S02Aryl, -CH2SAryl, -CH2OP(0)(OR)2, -CH2OR, - CH2Aryl;
R2 = each independently -H, -C02R, -S02Aryl, -CHO;
R3 and R4 = each independently -H, -C02R, -CH2SR, -CH2OR, -CH(OR)2,■ CH(OR)(NR2), -CH(NR2)2, (Ci-C6) alkyl; = each independently -H, -Ci-C6 alkyl, -aryl, -CH2Aryl;
Figure imgf000006_0003
X2 = -CI, -Br, -I, -N(R2)2, -OS02R;
X3 = each independently -H, -OR, -NR2 -CI, -Br, -I, -SR, -S02R, -S03R, -SR2 +;
O
I I
and X = -CI, -Br, -I, OTs (tosylate group), +NR3, -pyridium, and "O-S-R
I I
O In this embodiment, it is preferred that R1 is -SC^Aryl. Aryl herein is preferably phenyl. It is also preferred that X1 is -H. Additionally, it is preferred that X3 is -H. It is also preferred that the dihydroxy compound is ethylene glycol. In a further embodiment, the invention is directed to a process for preparing the compound of Formula I
Figure imgf000007_0001
(I) which comprises:
reacting the compound 1
Figure imgf000007_0002
with the acid chloride compound
Figure imgf000007_0003
to form the compound 2 ; and then
(b) contacting the compound 2 with a di-substituted amine (R2)2NH in base to produce
O v1
R, 2
R1
3
the compound 3 ; and thereafter reacting the compound 3 with the dihydroxy compound HO OH n acid solution, wherein the linker between the hydroxyl groups is Ci - Ce alkyl, to yield the
Figure imgf000008_0001
compound 4 ; and
(d) reacting the compound 4 with the compound x V x3 in acid to produce the
Figure imgf000008_0002
compound 5 contacting the compound 5 with Me-X4 in base or MeO-R3 in acid to produce
Figure imgf000008_0003
compound 6 ^ ; and
then performing an oxidation reaction on compound 6 using [O] to yield the
Figure imgf000008_0004
compound ; and
(g) adding the triazolyl group 9
Figure imgf000008_0005
to compound 7, to obtain the compound (I) above wherein: R1 = -H, -Boc, -Piv, -S02Aryl, -CH2SAryl, -CH2OP(0)(OR)2, -CH2OR, - CH2Aryl;
R2 = each independently -H, -C02R, -S02Aryl, -CHO;
R3 = -H, -C02R, -CH2SR, -CH2OR, -CH(OR)2, -CH(OR)(NR2), -CH(NR2)2;
R = each independently -H, -Ci-C6 alkyl, -aryl, -CH2Aryl;
Figure imgf000009_0001
X2 = -CI, -Br, -I, -N(R2)2, -OS02R;
X3 = each independently -H, -OR, -NR2, CI, -Br, -I, -SR, -S02R, -S03R, -SR2 +;
cS O
and X4 = -CI, -Br, -I, -OTs, +NR3, -pyridium, and ^0_s-R .
II
O
In this further embodiment, it is preferred that R1 is -S02Aryl. Aryl herein is preferably phenyl. It is also preferred that X1 is -H. Additionally, it is preferred that X3 is -H. It is preferred that the dihydroxy compound is ethylene glycol.
In another embodiment, there is provided a process for the preparation of the
compound of Formula , which comprises:
Figure imgf000009_0002
(I)
reacting the compound 1
Figure imgf000010_0001
1 with the acid chloride compound
Figure imgf000010_0002
form the compound 2 ; and then
(b) contacting the compound 2 with a di-substituted amine (R2)2NH in base to produce
Figure imgf000010_0003
3
the compound 3 ; and thereafter
reacting the compound 3 with the dihydroxy compound HO OH in acid solution, wherein the linker between the hydroxyl groups is Ci - C6 alkyl, to yield the
Figure imgf000010_0004
compound 4 ^ ; and
(d) reacting the compound 4 with the compound x x in acid to produce the
Figure imgf000010_0005
compound 5 contacting the compound 5 with Me-X4 in base or MeO-R3 in acid to produce
Figure imgf000011_0001
compound 6 6 ; and then performing an oxidation reaction on compound 6 using [O] to yield the compound 7
Figure imgf000011_0002
; and
Figure imgf000011_0003
performing an activation reaction to yield the resultant compound 10 10 and then
(h) adding the triazolyl group 9
Figure imgf000011_0004
to compound 10 in the presence of Cu ion and a ligand to yield the compound of Formula (I) above wherein:
R1 = -H, -Boc, -Piv, -S02Aryl, -CH2SAryl, -CH2OP(0)(OR)2, -CH2OR, - CH2Aryl;
R2 = each independently -H, -C02R, -S02Aryl, -CHO;
R3 = -H, -C02R, -CH2SR, -CH2OR, -CH(OR)2, -CH(OR)(NR2), -CH(NR2)2;
R = each independently -H, -Ci-C6 alkyl, -aryl, -CH2Aryl;
Figure imgf000012_0001
X2 = -CI, -Br, -I, -N(R2)2, -OS02R;
X3 and X5 = each independently -H, -OR, -NR2, -CI, -Br, -I, -SR, -S02R, -S03R, -SR2 +;
O
and X4 = -CI, -Br, -I, -OTs, +NR3, pyridium, and ^J ^Q-S-R · The ligand is
II
O
selected from the group of 1,2-diaminocyclohexane, trans-1,2- diaminocy clohexane, cis-/trans-diaminocyclohexane, cis-N,N'-dimethyl- 1 ,2- diaminocyclohexane, trans-N,N'-dim ethyl- 1 ,2-diaminocy clohexane, cis-/trans- Ν,Ν'-dimethyl- 1,2-diaminocyclohexane, 1,2-diaminoethane, N,N'-dimethyl-l,2- diaminoethane, 1,10-phenanthroline, 4,7-diphenyl-l,10-phenantroline, 5-methyl- 1,10-phenanthroline, 5-chloro-l,10-phenantroline, and 5 -nitro- 1,10- phenanthroline. In this further embodiment, it is preferred that R1 is -S02Aryl. Aryl herein is preferably phenyl. It is also preferred that X1 is -H. Additionally, it is preferred that X3 is -H.
Also provided herein is a method of making the compound of Formula II
Figure imgf000013_0001
which comprises:
Figure imgf000013_0002
(a) acylating the compound 10 10 using x O to yield the compound 11
Figure imgf000013_0003
11 ; and then
Ph
13
reacting compound 11 with compound 13 HN m an activation reaction to
produce compound 14
Figure imgf000014_0001
v I]
Me
adding the triazolyl compound 9 9 in the presence of Cu ion and a ligand to
obtain compound 15
Figure imgf000014_0002
; and
O
II
X7 O I o
R
with compound 15 to produce compound 18
Figure imgf000015_0001
; and conducting a functional group interconversion reaction to yield the compound of Formula II above; wherein:
R5= -H, -OR, -NR2, -CI, -Br, -I, -SR;
R6 = -H, -Boc, -Piv, -S02Aryl, -CH2SAryl, CH2OP(0)(OR)2, -CH2OR, - CH2Aryl, -Li, -Na, -K, -Ca, -Mg, TMG (Tetramethyl guanidine);
R = each independently -H, -Ci-C6 alkyl, -aryl, -CH2Aryl ;
Figure imgf000015_0002
X5 = -H, -OR, -NR2, -CI, -Br, -I, -SR
X6 = -H, -OR, -NR2, -CI, -Br, -I,-SR, -S02R, -SR2 +, -OS02R, -OS03R; and X7 = -CI, -Br, -I, -OS02R.
In this embodiment, the ligand may be selected as previously set forth. It is also preferred that R = teri-butyl, R6 and X1 are -H, and R5 is -OMe. Aryl herein is preferably phenyl. For a further embodiment of the invention, there is set forth process for making the
compound of Formula III , which comprises:
(1) reacting compound
Figure imgf000016_0001
with phthalic anhydride, H2O2 and
dichloromethane to yield compound
Figure imgf000016_0002
; and conducting a PyBrop bromination reaction by reacting compound ii with PyBrop to prepare compound III,
OMe
— PyBrop
Figure imgf000016_0003
(III) wherein R7 = -H, alkyl, aryl, -S02R, -C(0)OR, and -C(0)NR2; and
wherein R = -H, -Ci-C6 alkyl, aryl, -CH2Aryl; and further wherein PyBrop is the peptide coupling reagent Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate. Aryl herein is preferably phenyl. In addition, the invention is also directed to a compound, including pharmaceutically acceptable salts and mixtures thereof, which is selected from the group of:
Figure imgf000017_0001
-16- (1) removal of the t-butyl groups from the compound a
solvent in the presence of water to obtain the comp
Figure imgf000018_0001
ound ; and
(2) reacting the compound
Figure imgf000018_0002
with TRIS
(tris(hydroxymethyl)aminomethane) and optionally a second solvent to obtain the
compound
Figure imgf000019_0001
According to this process, the first solvent is selected from the group of carboxylic acid, NMP (N-methyl-2-pyrrolidone), DMSO, MeCN, MeOH, and acetone. The acid is selected from the group of H2S04, HNO3, HCl, phosphoric and carboxylic acids. The second solvent is selected from the group of water, alkyl ketone, heptane, toluene, ethyl acetate, DMSO, MeCN, MeOH and acetone. Even more preferably, the acid is acetic acid, and the second solvent is acetone.
The present invention is directed to these, as well as other important ends, hereinafter described.
DETAILED DESCRIPTION OF THE EMBODIMENTS
Unless otherwise specifically set forth, many reagents have been identified herein by their commonly accepted letter abbreviations in the art for ease of reference.
In addition, unless otherwise specifically set forth elsewhere in the application, the following terms may be used herein, and shall have the following meanings:
An "alkyl" group refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms (whenever a numerical range; e.g., "1-20", is stated herein, it means that the group, in this case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. The term "C1 6 alkyl" as used herein and in the claims means straight or branched chain alkyl groups with up to and including 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and the like.
An "aryl" "Aryl" or "Ar" group refers to an all carbon monocyclic or fused-ring polycyclic(i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, napthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.
In a preferred embodiment of the invention, the synthesis of the piperazine prodrug compound can be set forth in the following flow diagram:
Figure imgf000020_0001
Even more preferably, as further set forth below, the synthesis of the piperazine prodrug compound begins from the N-sulfonylated pyrrole la. Friedel-Crafts acylation with 2-chloro acetyl chloride, in the presence of aluminum trichloride, provides the 3-acryl pyrrole derivative 2a. Displacement of the 2-choro ketone by the sodium salt of the 7V-formyl sulfonamide, in the presence of a tetraalkylammonium halide, preferably bromide, preferably tetrabutylammonium bromide, provides the amino-ketone 3 a. Ketal protection of the ketone, in the presence of glycol and acid, results in the cleavage of the 7V-formyl protecting group and formation of the desired dioxalane 4a. A Pictet-Spengler cyclization with a formaldehyde equivalent, catalyzed by acid, provides the ketone 5a, which is treated with trimethyl orthoformate (TMOF) and acid in the presence of a radical initiator such as A1BN or cumene hydroperoxide to give the 6-azaindole 6a. Oxidation of the pyridine nitrogen provides the -oxide 7a which is then treated with PyBrop in the presence of base, which brominates the C7-position, yielding the bromo-azaindole 8a after hydrolysis of the sulfonyl protecting group. A second Friedel-Crafts acylation onto C3 of the indole provides the oxalate 9a, which is coupled with the Λ^-benzoyl piperazine to give the amide 10a. Addition of the triazole is catalyzed by copper, in the presence of an appropriate ligand and base, to give the indole 11c which is isolated as its lithium salt (or optionally as a co-salt with KBr). Alkylation of the indole nitrogen with the chloro-phosphate 14a gives the phosphate ester 12a, and subsequent solvolysis of the tert-butyl groups provides the final compound 13a.
Thus, the production of the piperazine prodrug compound may be shown more precisely as follows:
Figure imgf000021_0001
Figure imgf000021_0002
The foregoing description is merely illustrative and should not be understood to limit the scope or underlying principles of the invention in any way. Indeed, various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description and examples. Such modifications are also intended to fall within the scope of the appended claims.

Claims

What is claimed is:
1. A process for preparing the compound
Figure imgf000022_0001
(I)
which comprises:
reacting the compoun
Figure imgf000022_0002
form the compound 2 ; and then
(b) contacting the compound 2 with a di-substituted amine (R )2NH in base to
Figure imgf000022_0003
3
produce the compound 3 ; and thereafter reacting the compound 3 with the dihydroxy compound HO OH m acid solution, wherein the linker between the hydroxyl groups is d - C6 alkyl, to yield
Figure imgf000023_0001
the compound 4 ; and
reacting the compound 4 with the compound x V x3 in acid to produce
Figure imgf000023_0002
compound 5
(e) contacting the compound 5 with Me-X4 in base or MeO-R3 in acid to produce the
Figure imgf000023_0003
compound 6 ^ ; and then performing an oxidation reaction on compound 6 using [O] to yield
Figure imgf000023_0004
compound 7
H
N- II
(g) adding the triazolyl group to compound 7, and then conducting a functional group interconversion reaction, to obtain the compound (I) above wherein: R1 = -H, -Boc, -Piv, -S02Aryl, -CH2SAryl, -CH2OP(0)(OR)2, -CH2OR, - CH2Aryl;
R2 = each independently -H, -C02R, -S02Aryl, -CHO;
R3 and R4 = each independently -H, -C02R, -CH2SR, -CH2OR, -
CH(OR)2, -CH(OR)(NR2), -CH(NR2)2, (C C6) alkyl;
= each independently -H, -Ci-C6 alkyl, -aryl, -CH2Aryl;
Figure imgf000024_0001
X2 = -CI, -Br, -I, -N(R2)2, -OS02R
X3 = each independently -H, -OR, -NR2, -CI, -Br, -I, -SR, -S02R, -S03R, -SR2 +;
and X4 = -CI, -Br, -I, OTs, +NR3, -pyridium, and
Figure imgf000024_0002
2. The process of claim 1, wherein R is -S02Aryl.
3. The process of claim 2, wherein X is -H.
4. The process of claim 3, wherein X3 is -H.
5. A process for preparing the compound
Figure imgf000024_0003
(I) which comprises: reacting the compound 1
Figure imgf000025_0001
2
to form the compound 2 ; and then
contacting the compound 2 with a di-substituted amine (R2)2NH in base
Figure imgf000025_0002
produce the compound 3 ; and thereafter reacting the compound 3 with the dihydroxy compound HO OH
Figure imgf000025_0003
solution to yield the compound 4 reacting the compound 4 with the compound x V x3 in acid to produce the
Figure imgf000025_0004
compound 5 5 (e) contacting the compound 5 with Me-X4 in base or MeO-R3 in acid to produce the
compound 6
Figure imgf000026_0001
; and then performing an oxidation reaction on compound 6 using [O] to yield the
Figure imgf000026_0002
compound
adding the triazolyl group 9
Figure imgf000026_0003
to compound 7, to obtain the compound (I) above wherein:
R1 = -H, -Boc, -Piv, -S02Aryl, -CH2SAryl, -CH2OP(0)(OR)2, -CH2OR, CH2Aryl;
R2 = each independently -H, -C02R, -S02Aryl, -CHO;
R3 = -H, -C02R, -CH2SR, -CH2OR, -CH(OR)2, -CH(OR)(NR2), -
CH(NR2)2;
R = each independently -H, -Ci-C6 alkyl, -aryl, -CH Aryl;
Figure imgf000026_0004
X2 = -CI, -Br, -I, -N(R2)2;
X3 = each independently -H, -OR, -NR2 CI, -Br, -I, -SR, -S02R, -S03R, -
SR2 +; and X4 = -CI, -Br, -I, -OTs, +NR3, -pyridium, and ·
Figure imgf000026_0005
6. The process of claim 5, wherein R1 is -S02Aryl.
7. The process of claim 6, wherein X1 is -H.
8. The process of claim 7, wherein X3 is -H.
A process for the preparing the compound which comprises:
Figure imgf000027_0001
(I) x
N
o reacting the compound 1 1 with the acid chloride compound
Figure imgf000027_0002
form the compound 2 ; and then contacting the compound 2 with a di-substituted amine ^ '2 in base
Figure imgf000027_0003
3
produce the compound 3 ; and thereafter reacting the compound 3 with the dihydroxy compound HO OH j
Figure imgf000028_0001
solution to yield the compound 4
Η 3χχ3
reacting the compound 4 with the compound * X3 in acid to produce the
compound 5
Figure imgf000028_0002
contacting the compound 5 with Me-X4 in base or MeO-R3 in acid to produce the
Figure imgf000028_0003
compound 6 ; and then
performing an oxidation reaction on compound 6 using [O] to yield the
compound 7
Figure imgf000028_0004
performing an activation reaction to yield the resultant compound 10
Figure imgf000028_0005
; and then H adding the triazolyl group 9 Me to compound 10 in the presence of Cu a ligand to yield the compound of Formula (I) above wherein:
R1 = -H, -Boc, -Piv, -S02Aryl, -CH2SAryl, -CH2OP(0)(OR)2, -CH2OR, -CH2Aryl;
R2 = -H, -C02R, -S02Aryl, -CHO;
R3 = each independently -H, -C02R, -CH2SR, -CH2OR, -CH(OR)2, -CH(OR)(NR2), -CH(NR2)2;
R = each independently -H, -Ci-C6 alkyl, -aryl, -CH Aryl;
Figure imgf000029_0001
X2 = -CI, -Br, -I, -N(R2)2;
X3 and X5 = each independently -H, -OR, -NR2 -CI, -Br, -I, -SR, -S02R,
; and also
Figure imgf000029_0002
wherein said ligand is selected from the group of 1 ,2- diaminocyclohexane, trans- 1,2-diaminocyclohexane, cis-/trans- diaminocyclohexane, cis-N,N'-dimethyl-l ,2-diaminocyclohexane, trans- Ν,Ν'-dimethyl- 1 ,2-diaminocyclohexane, cis-/trans-N,N'-dimethyl- 1 ,2- diaminocyclohexane, 1 ,2-diaminoethane, N,N'-dimethyl-l,2- diaminoethane, 1,10-phenanthroline, 4,7-diphenyl-l,10-phenantroline, 5- methyl- 1,10-phenanthroline, 5-chloro-l,10-phenantroline, and 5-nitro- 1 , 10-phenanthroline.
The process of claim 9, wherein R1 is -S02Aryl. The process of claim 10, wherein X1 is -H. The process of claim 11 , wherein X3 is -H. A method of making the compound
Figure imgf000030_0001
which comprises:
Figure imgf000030_0002
Ph
13
reacting compound 11 with compound 13 N ' in an activation reaction
to produce compound 14
Figure imgf000031_0001
W ] I
N— \
Me
adding the triazolyl sence of Cu ion and a ligand
to obtain compound
Figure imgf000031_0002
; and
O
I I
X7 O I O
R
rea with compound 15 to produce compound
Figure imgf000032_0001
• and conducting a functional group interconversion reaction to yield Compound II above; wherein:
-H, -OR, -NR.2, -CI, -Br, -I, -SR;
R6 = -H, -Boc, -Piv, -S02Aryl, -CH2SAryl, -CH2OP(0)(OR)2, -CH2Aryl, -Li, Na, K, Ca, Mg, TMG ;
R = each independently -H, -Ci-C6 alkyl, -aryl, -CH2Aryl ;
Figure imgf000032_0002
X5 = -H, -OR, -NR2 -CI, -Br, -I, -SR;
X6 = -H, -OR, -NR2, -CI, -Br, -I, -SR, -S02R, -SR2 +, -OS02R, -OS03R; and X7= -CI, -Br, -I, -OS02R.
14. The process of claim 13, wherein R = tert-butyl, R6 and X1 are -H.
15. The process of claim 13, wherein R5 is -OMe.
ch comprises:
dride, ¾(¾ and
Figure imgf000033_0001
dichloromethane to yield compound ; and
(2) conducting a PyBrop bromination reaction by reacting compound ii with PyBrop to prepare compound III,
Figure imgf000033_0002
wherein R7 = -H, alkyl, aryl, -S02R, -C(0)OR, and -C(0)NR2;
where R = -H, C C6 alkyl, -aryl, -CH2Aryl.
17. The compound, including pharmaceutically acceptable salts thereof, which is selected from the group of:
18. A
Figure imgf000034_0001
process for the production of the compound , which comprises
removal of the t-butyl groups from the compound
Figure imgf000035_0001
a first solvent in the presence of water to obtain the compound
Figure imgf000035_0002
Figure imgf000036_0001
19. The process of claim 18, wherein said first solvent is selected from the group of NMP, DMSO, MeCN, MeOH, acetone and a carboxylic acid.
20. The process of claim 18, wherein said second solvent is selected from the group of an alkyl ketone, heptane, toluene, and ethyl acetate.
21. The process of claim 18, wherein the first solvent is acetic acid, and said second solvent is acetone.
A process for preparing the compound 13a
Figure imgf000036_0002
, which comprises: O
CI
(1) reacting the compound la using 2-chloroacetyl chloride ( Cl ) in the
Figure imgf000037_0001
presence of aluminum trichloride (AICI3) to yield compound 2a ; and
(2) then reacting compound 2a to displace the 2-chloroketone by the sodium salt of the N-formyl sulfonamide in the presence of a tetraalkyl ammonium halide to
Figure imgf000037_0002
3a
yield the amino-ketone compound 3a ; and
.OH
reacting the compound 3a with HO in the presence of sulfuric acid to
Figure imgf000037_0003
4a
yield the compound 4a ; and
(4) performing a Pictet-Spengler cyclization with formaldehyde, catalyzed by
trifluoroacetic acid to yield the ketone compound 5a
Figure imgf000037_0004
; and
(5) treating compound 5a with trimethylortho formate (TMOF) and acid in the presence of a radical initiator to produce the 6-azaindole compound 6a
Figure imgf000037_0005
; and (6) oxidizing the pyridine nitrogen on compound 6a using hydrogen peroxide (H202)
and phthalic anhydride to yield the N-oxide compound 7a
Figure imgf000038_0001
; and
(7) treating compound 7a with PyBrop in the presence of bases K3PO4 and NaOH to
Figure imgf000038_0002
8a
yield the bromo-azaindole compound 8a ; and
then acylating onto the C3 of the indole group of compound 8a to produce
Figure imgf000038_0003
9a
oxalate compound 9a ; and
coupling compound 9a with N-benzoyl piperazine to yield the amide compound
(10) a
Figure imgf000038_0004
dding the triazole group to compound 10a using copper catalysis in the presence of ligand and base to produce the compound 11a
Figure imgf000038_0005
the optional formation of lib or 11c from compound 11a
Figure imgf000039_0001
(12) alkylating the indole nitrogen of compound 11a, lib or 11c using the chloro- phosphate me phosphate ester
compound
Figure imgf000039_0002
performing a sovolysis of the tert-butyl groups of compound 12a to yield the final compound 13a.
A process for preparing the compound 13a
Figure imgf000039_0003
, which comprises: I
reacting the compound la
Figure imgf000039_0004
) to yield
Figure imgf000039_0005
2a
compound 2a and (2) then reacting compound 2a to displace the 2-chloroketone by the sodium salt of the N-form l sulfonamide to yield the amino-ketone compound 3a
Figure imgf000040_0001
3a
; and
(3) reacting the compound 3a with HO in the presence of acid to yield the
Figure imgf000040_0002
4a
compound 4a ; and
(4) performing a Pictet-Spengler cyclization with formaldehyde, catalyzed by acid to
Figure imgf000040_0003
yield the ketone compound 5a ; and
(5) treating compound 5a with trimethylortho formate (TMOF) and acid in the presence of a radical initiator to produce the 6-azaindole compound 6a
Figure imgf000040_0004
; and
(6) oxidizing the pyridine nitrogen on compound 6 to yield the N-oxide compound
Figure imgf000040_0005
treating compound 7a with PyBrop to yield the bromo-azaindole compound 8a
Figure imgf000041_0001
(8) then acylating onto the C3 of the indole group of compound 8a to produce the
Figure imgf000041_0002
oxalate compound 9a ; and
coupling compound 9a with N-benzoyl piperazine to yield the amide compound
Figure imgf000041_0003
(10) adding the triazole group to compoun a us ng cata ys s
presence of ligand and base to produce the compound 11a
Figure imgf000041_0004
(11) the optional formation of lib or 11c from compound 11a
Figure imgf000042_0001
(12) alkylating the indole nitrogen of compound 11a, lib or 11c using the chloro- phosphate me phosphate ester
Figure imgf000042_0002
compound 12a ; an performing said solvolysis of the tert-butyl groups of compound 12a to yield the final compound 13a.
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