EP4688794A1 - Synthesis of 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3)-ol - Google Patents

Synthesis of 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3)-ol

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Publication number
EP4688794A1
EP4688794A1 EP24720412.6A EP24720412A EP4688794A1 EP 4688794 A1 EP4688794 A1 EP 4688794A1 EP 24720412 A EP24720412 A EP 24720412A EP 4688794 A1 EP4688794 A1 EP 4688794A1
Authority
EP
European Patent Office
Prior art keywords
hydroxyethoxy
bromo
chloro
phenyl
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24720412.6A
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German (de)
French (fr)
Inventor
Aasa Elisabeth Gladwin
David Darryl Pascoe
Philip John Rushworth
Michael Robert WEBB
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GlaxoSmithKline Intellectual Property No 2 Ltd
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GlaxoSmithKline Intellectual Property No 2 Ltd
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Application filed by GlaxoSmithKline Intellectual Property No 2 Ltd filed Critical GlaxoSmithKline Intellectual Property No 2 Ltd
Publication of EP4688794A1 publication Critical patent/EP4688794A1/en
Pending legal-status Critical Current

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Classifications

    • 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
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/14—Preparation of nitro compounds by formation of nitro groups together with reactions not involving the formation of nitro groups
    • 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
    • C07C213/02—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 involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups

Definitions

  • the present invention relates to improved synthetic methods for 3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1 ,2]oxaborol-1(3/-/)-ol, which is a compound that is useful as an anti- mycobaterial, for example in the treatment of tuberculosis.
  • Mycobacterium is a genus in the class of bacteria called Actinobacteria with its own distinct family known as Mycobacteriacae.
  • Mycobacterium contains various obligate and opportunistic pathogens of animals, which may also be transmitted to humans and cause disease in humans, thus exhibiting a considerable zoonotic potential.
  • members of the Mycobacterium avium- intracellulare complex (MAIO) emerged as pathogens of human diseases, including lymphadenitis in children, pulmonary tuberculosis-like disease, and disseminated infections (occurring predominantly in immunocompromised persons, particularly AIDS patients).
  • MAIC includes M. intracellulars and 4 subspecies of M. avium, namely, M. avium subsp. avium, M. avium subsp. hominissuis, M. avium subsp. silvaticum, and M. avium subsp. paratuberculosis.
  • M. avium subsp. avium M. avium subsp. hominissuis
  • M. avium subsp. silvaticum M. avium subsp. paratuberculosis.
  • members of the M. tuberculosis complex are transmitted by direct host contact, MAIC species are acquired predominantly from environmental sources, including soil, water, dust, and feed.
  • Mycobacterium tuberculosis is a small aerobic non-motile high-GC bacillus with an "outermembrane” that is unusually thick, "waxy,” hydrophobic, rich in mycolic acids, and extremely impermeable, making mycobacterium infections difficult to treat.
  • MTB Mycobacterium tuberculosis
  • One third of the world's population is thought to be infected (including latent MTB), but this number increases to upwards of 80% of the population in many Asian and African countries. If untreated, the death rate from active MTB infections is more than 50%.
  • the combination of HIV and MTB is deadly and increasing numbers of MTB strains are becoming resistant to standard of care drugs; approximately 300,000 new cases of multidrug resistant (MDR) M.
  • MDR multidrug resistant
  • MDR Multidrug resistant
  • XDR extensive drug resistant M. tuberculosis
  • tuberculosis therapy and prevention are well known.
  • the current available vaccine, BCG was introduced in 1921 and fails to protect most people past childhood.
  • TBCTA T uberculosis Coalition for Technical Assistance
  • TBCTA T uberculosis Coalition for Technical Assistance
  • partners include Centers for Disease Control, American Thoracic Society, Tuberculosis Foundation, KNCV, the World Health Organization and the International Union against Tuberculosis and Lung Disease - patients who do become infected with active disease currently endure two months of combination therapy with medicines introduced between 50 and 60 years ago - isoniazid (1952), rifampin (1963), pyrazinamide (1954) and ethambutol (1961 ) - followed by another 4 months of isoniazid and rifampin (also known as rifampicin).
  • the continuation phase could include Isoniazid and ethambutol for six months when adherence cannot be assessed, but according to this report, a longer continuation phase is associated with a higher rate of failure and relapse, especially in patients with HIV infection.
  • the doses of antituberculosis drugs used should conform to international recommendation and fixed-dose combinations of two (isoniazid and rifampicin), three (isoniazid, rifampicin, and pyrazinamide), and four (isoniazid, rifampicin, pyrazinamide, and ethambutol) drugs are highly recommended, especially when it is not possible to monitor the patient to ensure the treatment is ingested.
  • MDR-TB multi-drug resistant strains
  • WO2015021396A2 discloses benzoxaborole compounds that show unexpected selectivity for inhibiting replication of Mycobacterium tuberculosis (M. tuberculosis) versus inhibition (toxicity) of human cells compared to other benzoxaborole compounds, and exhibit sub-micromolar MIC values against mycobacterium species, particularly Mycobacterium tuberculosis and Mycobacterium tuberculosis complex (MTC), Mycobacterium avium and Mycobacterium avium complex (MAC) and Mycobacterium avium intracellulare complex (MAIC).
  • MTC Mycobacterium tuberculosis and Mycobacterium tuberculosis complex
  • MAC Mycobacterium avium and Mycobacterium avium complex
  • MAIC Mycobacterium avium intracellulare complex
  • WO2015021396A2 discloses (S)-3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1 ,2]oxaborol-1(3/-/)-ol (in a close-ring tricyclic configuration):
  • Disclosed herein is a method for preparing 3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol: salt thereof; the method comprising preparing tert-butyl ((3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a- borabenzo[cd]azulen-2-yl)methyl)carbamate: followed by conversion of tert-butyl ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2- yl)methyl)carbamate to 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1 ,2]oxaborol-1(3H)-ol or salt thereof.
  • tert-butyl ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate; 2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof;
  • Also disclosed herein is a method for preparing 3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1 ,2]oxaborol-1(3H)-ol or salt thereof comprising: a) converting 2-bromo-3-(2-hydroxyethoxy)benzaldehyde to 1-(2-bromo-3-(2- hydroxyethoxy)phenyl)-2-nitroethan-1-ol; b) converting 1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol to 2-amino-1-(2- bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof; c) converting 2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof to 2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)e
  • a method for preparing 3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol comprising preparing a compound selected from: followed by conversion said selected compound to 3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1 ,2]oxaborol-1(3H)-ol or salt thereof.
  • the method comprises: and/or thereof; and/or (iv)
  • 2-bromo-3-(2-hydroxyethoxy)benzaldehyde may be synthesised from 2-bromo-3- hydroxybenzaldehyde, which may in turn some examples be synthesised from 3-hydroxybenzaldehyde.
  • the method may comprise mixing a solution of ((3-chloro-7,8-dihydro-2H-1 ,6,9- trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate in solvent (e.g. isopropyl alcohol) with sulfuric acid, at a temperature below 25°C. It may further comprise heating (e.g. to 45-55°C). It may further comprise subsequent cooling (e.g. to 20-30°C), filtering, and the cake with solvent (e.g. isopropyl alcohol). It some cases it may comprise one or more further cycles of heating, cooling, filtering and washing. In some cases, the wet cake may be dried under vacuum.
  • solvent e.g. isopropyl alcohol
  • the solid may be dissolved in a solvent (e.g. methanol) and recrystallised to improve purity.
  • a solvent e.g. methanol
  • Preparation of ((3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate from 2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof may in some cases involve a Pd-catalysed borylation.
  • the reaction may comprise a Miyaura borylation.
  • the borylation may be preceded by a Boc-protection reaction.
  • the method comprises:
  • base e.g. potassium pivalate
  • Pd catalyst e.g. palladium(ll) acetate
  • phosphine ligand e.g. tri-t-butylphosphine tetrafluoroborate
  • a borylating agent e.g. B2pin2, HBpin and B2(OH)4
  • Preparation of 2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof from 2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof may in some cases involve chlorination by aromatic electrophilic substitution.
  • the chlorinating agent may comprise N-chlorosuccinimide.
  • a crystalline salt of the chlorination product may be formed, such as a mesylate salt, to enable isolation of the reaction product.
  • Preparation of 2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof from 1-(2- bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol may comprise a nitro-reduction reaction.
  • this may be metal catalysed, e.g. Raney nickel catalysed hydrogenation to reduce the nitro group.
  • the reduction may be catalysed by Pt, Pd, Rh, Ru or Ir based catalysts.
  • a crystalline salt of the reaction product may be formed, such as a tartrate salt, to enable isolation of the reaction product.
  • Preparation of 1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol from 2-bromo-3-(2- hydroxyethoxy)benzaldehyde may in some cases involve an asymmetric nitroaldol reaction (e.g. an asymmetric Henry reaction).
  • This may include use of a copper catalyst, such as a copper(ll) catalyst, such as CU(OAC)2, Cu(OTf)2, CUCI2 and the like.
  • a ligands used in the reaction may be a diamine ligand such as a diaminocyclohexane, a chiral oxazoline, a Schiff base ligand, or a chiral salen based ligand.
  • the ligand comprises (1 R,2R,4R)-1 ,7,7-trimethyl-N-(pyridin-2- ylmethyl)bicyclo[2.2.1 ]heptan-2-amine dihydrochloride.
  • the asymmetric nitroaldol reaction comprises:
  • the method may relate to one stereoisomer of the listed compound.
  • the method may relate to synthesis of (S)-3-(aminomethyl)-4- chloro-7-(2-hydroxyethoxy)benzo[c][1 ,2]oxaborol-1(3/-/)-ol: or a salt thereof.
  • tert-butyl ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2- yl)methyl)carbamate may be (S)-((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2- yl)methyl)carbamate:
  • 2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or a salt thereof may be (S)-2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol:
  • 2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or a salt thereof may be (S)-2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol: or a salt thereof.
  • (S)-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol may be (S)-1-(2- bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol:
  • B2piri2 bis(pinacolato)diboron also known 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2- dioxaborolane
  • reaction mixture was cooled to -18 °C and a solution of nitromethane (175 kg) in 2-MeTHF (351 L) added slowly. The reaction mixture was stirred until HPLC showed the reaction was complete. The reaction was quenched by addition of aqueous HCI solution (1 M, 142 kg) and warmed to 25 °C. Aqueous Na2SO4 solution (15%w/w, 213 kg) followed by water (444 L) were then added and the layers separated. To the organic phase was added aqueous HCI solution (1 M, 142 kg) and aqueous EDTA.2Na.2H2O solution (5%w/w, 214 kg).
  • the organic phase was washed with a mixture of aqueous N-Ac-Cys (5%w/w, 231 kg) and aq. KHCO3 (5%w/w, 226 kg) (three times) mixed solution.
  • the organic phase was then stirred with silica thiol (15 kg), filtered and the cake was washed with EtOAc 32 L).
  • the filtrate was concentrated and switched with IPA to a solution volume of -110 L.
  • the residue was diluted with IPA (160 L), cooled to 0°C and GSK3177484A seed (0.25 kg) was added and the mixture was stirred and then filtered.
  • the wet cake was washed with IPA (33 L) and then dried at 40 °C in vacuo to get GSK3177484A as a white solid (36.5 kg, 66% over 2 steps).
  • GSK3036656E (27.4 kg, 1.0 wt.), purified water (19 L, 0.7 vol.) and MeOH (372 L, 13.6 vol.) was charged into a reactor ( R 1 ). The mixture was heated to 64 °C and stirred at 60-68 °C for 0.2 h to give a clear solution. The solution in R1 was transferred via a 0.22 pm in-line filter into another reactor (R2), which was preheated to 62-68 °C. Purified water (22 L, 0.8 vol.) was added into R1 and the water wash transferred into R2 via the in-line filter. The mixture in R2 was adjusted to 50-60 °C and stirred for 0.5 h to give a clear solution.
  • GSK3036656E seed (71 g, 0.26% wt.) was then added into R2 rinsing in with MeOH/purified water (9:1 v/v). The mixture was stirred at 50-60 °C for 3 h, then cooled to 5 °C over 5.5 h and stirred at 0-10 °C for 5 h. The slurry was then wet milled for a total of 3.5 h. The mixture was aged at 0-10 °C for 15 h then warmed to 50- 60 °C over 3 h and stirred at this temperature for 1 h.
  • the mixture was cooled to 0-10 °C over 5 h and stirred at this temperature for 2 h, then warmed to 50-60 °C over 2.5 h and stirred in this range for 1 h.
  • the mixture was then cooled to 0-10 °C over 5 h and stirred at this temperature for 8 h before warming to 50-60 °C over 3 h and holding in this range for 1.5 h.
  • the mixture was cooled to 0-10 °C over 6 h and aged at this temperature for 19 h.
  • the mixture was filtered and the cake washed with MeOH/purified water (9:1 v/v, 44 kg, 1.6 wt.).
  • the wet cake was dried under vacuum at 35-45 °C for 5 h and then at 45-55 °C for a further 26 h to give GSK3036656E (20.3 kg, 76%) as a white solid.

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  • Organic Chemistry (AREA)
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Abstract

The invention provides a method for preparing 3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol; the method comprising preparing tert-butyl ((3-chloro- 7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate; and converting that compound to 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol or salt thereof.

Description

Synthesis of 3-(aminomethyl)-4-chloro-7-(2-hvdroxyethoxy)benzo[c1[1 ,21oxaborol-1(3/-/)-ol
FIELD OF THE INVENTION
The present invention relates to improved synthetic methods for 3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1 ,2]oxaborol-1(3/-/)-ol, which is a compound that is useful as an anti- mycobaterial, for example in the treatment of tuberculosis.
BACKGROUND OF THE INVENTION
Mycobacterium is a genus in the class of bacteria called Actinobacteria with its own distinct family known as Mycobacteriacae. Mycobacterium contains various obligate and opportunistic pathogens of animals, which may also be transmitted to humans and cause disease in humans, thus exhibiting a considerable zoonotic potential. During the past few decades, members of the Mycobacterium avium- intracellulare complex (MAIO) emerged as pathogens of human diseases, including lymphadenitis in children, pulmonary tuberculosis-like disease, and disseminated infections (occurring predominantly in immunocompromised persons, particularly AIDS patients). Similarly, important animal diseases result from infections in an animal by members of this group, e.g., avian tuberculosis and paratuberculosis in ruminants. MAIC includes M. intracellulars and 4 subspecies of M. avium, namely, M. avium subsp. avium, M. avium subsp. hominissuis, M. avium subsp. silvaticum, and M. avium subsp. paratuberculosis. Whereas members of the M. tuberculosis complex are transmitted by direct host contact, MAIC species are acquired predominantly from environmental sources, including soil, water, dust, and feed.
Mycobacterium tuberculosis (MTB) is a small aerobic non-motile high-GC bacillus with an "outermembrane" that is unusually thick, "waxy," hydrophobic, rich in mycolic acids, and extremely impermeable, making mycobacterium infections difficult to treat. One third of the world's population is thought to be infected (including latent MTB), but this number increases to upwards of 80% of the population in many Asian and African countries. If untreated, the death rate from active MTB infections is more than 50%. In addition, the combination of HIV and MTB is deadly and increasing numbers of MTB strains are becoming resistant to standard of care drugs; approximately 300,000 new cases of multidrug resistant (MDR) M. tuberculosis are reported each year. Multidrug resistant (MDR) M. tuberculosis are resistant to isoniazid and rifampicin, and extensive drug resistant (XDR) M. tuberculosis are also resistant to at least one quinolone and one aminoglycoside.
Synthetic drugs for treating tuberculosis (TB) have been available for over half a century, but incidences of the disease continue to rise world-wide. More than 2 billion people are currently infected with M. tuberculosis, most being latent cases, and it is estimated that over 9 million new cases occur each year, worldwide, resulting in from 1 .7 to nearly 2 million deaths per year. In 2004 alone approximately 24,500 new infections and close to 5,500 deaths were recorded, each day. See Zignol, Met al., M. Surveillance of anti- tuberculosis drug resistance in the world: an updated analysis, 2007-2010. Bull. World Health Organ 2012, 90 (2), 1 1 1 -1 19D) Co-infection with HIV is driving the increase in incidence (Williams, B. G.; Dye, C. Science, 2003, 301 , 1535) and the cause of death in 31 % of AIDS patients in Africa can be attributed to TB. See Corbett, E. Let al.,. Arch. Inti. Med., 2003, 163, 1009, Septkowitz, Aet al., Clin. Microbiol. Rev. 1995, 8, 180).
The limitations of tuberculosis therapy and prevention are well known. The current available vaccine, BCG was introduced in 1921 and fails to protect most people past childhood. According to a 2006 report - "International Standards for T uberculosis Care", a document developed by the T uberculosis Coalition for Technical Assistance (TBCTA) which partners include Centers for Disease Control, American Thoracic Society, Tuberculosis Foundation, KNCV, the World Health Organization and the International Union Against Tuberculosis and Lung Disease - patients who do become infected with active disease currently endure two months of combination therapy with medicines introduced between 50 and 60 years ago - isoniazid (1952), rifampin (1963), pyrazinamide (1954) and ethambutol (1961 ) - followed by another 4 months of isoniazid and rifampin (also known as rifampicin). Alternatively the continuation phase could include Isoniazid and ethambutol for six months when adherence cannot be assessed, but according to this report, a longer continuation phase is associated with a higher rate of failure and relapse, especially in patients with HIV infection. Moreover, as detailed in this report, the doses of antituberculosis drugs used should conform to international recommendation and fixed-dose combinations of two (isoniazid and rifampicin), three (isoniazid, rifampicin, and pyrazinamide), and four (isoniazid, rifampicin, pyrazinamide, and ethambutol) drugs are highly recommended, especially when it is not possible to monitor the patient to ensure the treatment is ingested.
Daily dosing is required in these treatment phases and poor compliance drives the emergence and spread of multi-drug-resistant strains, which are challenging to treat. Shorter courses of more active agents which can be taken less frequently and which present a high barrier to the emergence of resistance, i.e. agents which are effective against multi-drug resistant strains of TB (MDR-TB), are urgently required. A March 2013 report (http://www.aidsmap.com/Once-weekly-continuation-phase-TB- treatment-equals-standard- of-care/page/2589498/) suggests that a two-drug combination of rifapentine (a long-acting derivative of rifampicin) with moxifloxacin (a fluoroquinolone antibiotic that has not been used previously in TB treatment) can allow tuberculosis (TB) treatment to be taken once- weekly during the four-month continuation phase and achieves the same standard of care as the traditional continuation treatment of daily treatment with isoniazid and rifampin. Such a treatment phase would allow treatment supervision to extend throughout the continuation phase, increasing adherence. However, moxifloxacin is not yet approved for treatment of TB, and the once-weekly treatment protocol is not yet endorsed or approved as an alternative standard of care treatment - guideline panels at international and national levels will need to review the published evidence to determine if this alternative continuation treatment protocol should be recommended and adopted. In addition, rifapentine is expensive, and interactions between rifapentine and antiretroviral drugs in the nonnucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor classes may prevent its use in TB patients who are also HIV positive and taking antiretroviral medicines. Thus, at present, the costs/benefits analysis of a continuation treatment with weekly rifapentine versus daily rifampicin is yet to be fully assessed.
WO2015021396A2 discloses benzoxaborole compounds that show unexpected selectivity for inhibiting replication of Mycobacterium tuberculosis (M. tuberculosis) versus inhibition (toxicity) of human cells compared to other benzoxaborole compounds, and exhibit sub-micromolar MIC values against mycobacterium species, particularly Mycobacterium tuberculosis and Mycobacterium tuberculosis complex (MTC), Mycobacterium avium and Mycobacterium avium complex (MAC) and Mycobacterium avium intracellulare complex (MAIC).
In particular, WO2015021396A2 discloses (S)-3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1 ,2]oxaborol-1(3/-/)-ol (in a close-ring tricyclic configuration):
H2O
A synthetic route is described Synthesis of the sulfate salt is described in Example 4-II
SUMMARY OF THE INVENTION
Disclosed herein is a method for preparing 3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol: salt thereof; the method comprising preparing tert-butyl ((3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a- borabenzo[cd]azulen-2-yl)methyl)carbamate: followed by conversion of tert-butyl ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2- yl)methyl)carbamate to 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1 ,2]oxaborol-1(3H)-ol or salt thereof.
Also disclosed herein at the compounds: tert-butyl ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate; 2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof;
2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof;
1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol; and
2-bromo-3-(2-hydroxyethoxy)benzaldehyde.
Also disclosed herein is a method for preparing 3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1 ,2]oxaborol-1(3H)-ol or salt thereof comprising: a) converting 2-bromo-3-(2-hydroxyethoxy)benzaldehyde to 1-(2-bromo-3-(2- hydroxyethoxy)phenyl)-2-nitroethan-1-ol; b) converting 1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol to 2-amino-1-(2- bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof; c) converting 2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof to 2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof; d) converting 2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof to ((3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate; and e) converting ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2- yl)methyl)carbamate to 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1 ,2]oxaborol-1(3H)-ol or salt thereof.
DETAILED DESCRIPTION
The synthetic route described herein may offer any of the following advantages over that disclosed in WO’396:
• Improvement in overall yield. • Reduction in cost; cheaper reagents can be used.
• Improved reliability - does not use cryogenic lithiation chemistry (in contrast to WO’396 route);
• Present route has a greater number of isolatable intermediates (for control of purity) - WO’396 route has several oils which needed to be telescoped through the synthesis.
In some examples, there is provided a method for preparing 3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol: the method comprising preparing a compound selected from: followed by conversion said selected compound to 3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1 ,2]oxaborol-1(3H)-ol or salt thereof. In some examples, the method comprises: and/or thereof; and/or (iv)
(v) preparing
In some examples, 2-bromo-3-(2-hydroxyethoxy)benzaldehyde may be synthesised from 2-bromo-3- hydroxybenzaldehyde, which may in turn some examples be synthesised from 3-hydroxybenzaldehyde.
Preparation of 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1 ,2]oxaborol-1(3/-/)-ol or salt thereof from ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate may comprise Boc-deprotection using sulfuric acid, and the reaction product is the sulfate salt of 3- (aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol.
In some such examples, the method may comprise mixing a solution of ((3-chloro-7,8-dihydro-2H-1 ,6,9- trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate in solvent (e.g. isopropyl alcohol) with sulfuric acid, at a temperature below 25°C. It may further comprise heating (e.g. to 45-55°C). It may further comprise subsequent cooling (e.g. to 20-30°C), filtering, and the cake with solvent (e.g. isopropyl alcohol). It some cases it may comprise one or more further cycles of heating, cooling, filtering and washing. In some cases, the wet cake may be dried under vacuum. In some cases, the solid may be dissolved in a solvent (e.g. methanol) and recrystallised to improve purity. Preparation of ((3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate from 2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof may in some cases involve a Pd-catalysed borylation. In some cases, the reaction may comprise a Miyaura borylation. In some cases, the borylation may be preceded by a Boc-protection reaction.
In some such examples, the method comprises:
(i) mixing 2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol with BOC2O, base (e.g. KHCO3) and solvent (e.g. MTBE(aq));
(ii) adding base (e.g. potassium pivalate), Pd catalyst (e.g. palladium(ll) acetate) and a phosphine ligand (e.g. tri-t-butylphosphine tetrafluoroborate);
(iii) adding a borylating agent (e.g. B2pin2, HBpin and B2(OH)4);
(iv) washing; and
(v) crystallising the ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2- yl)methyl)carbamate.
Preparation of 2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof from 2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof may in some cases involve chlorination by aromatic electrophilic substitution. In some cases, the chlorinating agent may comprise N-chlorosuccinimide. In some cases, a crystalline salt of the chlorination product may be formed, such as a mesylate salt, to enable isolation of the reaction product.
Preparation of 2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof from 1-(2- bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol may comprise a nitro-reduction reaction. In some cases, this may be metal catalysed, e.g. Raney nickel catalysed hydrogenation to reduce the nitro group. (In other such examples, the reduction may be catalysed by Pt, Pd, Rh, Ru or Ir based catalysts.) In some cases, a crystalline salt of the reaction product may be formed, such as a tartrate salt, to enable isolation of the reaction product.
Preparation of 1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol from 2-bromo-3-(2- hydroxyethoxy)benzaldehyde may in some cases involve an asymmetric nitroaldol reaction (e.g. an asymmetric Henry reaction). This may include use of a copper catalyst, such as a copper(ll) catalyst, such as CU(OAC)2, Cu(OTf)2, CUCI2 and the like. In some examples, a ligands used in the reaction may be a diamine ligand such as a diaminocyclohexane, a chiral oxazoline, a Schiff base ligand, or a chiral salen based ligand. In some examples, the ligand comprises (1 R,2R,4R)-1 ,7,7-trimethyl-N-(pyridin-2- ylmethyl)bicyclo[2.2.1 ]heptan-2-amine dihydrochloride.
In some examples, the asymmetric nitroaldol reaction comprises:
(i) mixing a ligand and 2-bromo-3-(2-hydroxyethoxy)benzaldehyde in the presence of a copper catalyst, optionally in the presence a solvent (e.g. ethanol and MeTHF cosolvent) and a base (e.g. DIPEA); (ii) adding nitromethane, optionally in the presence of a solvent;
(Hi) quenching with acid;
(iv) washing (e.g. with Na2SC>4(aq), EDTA.2Na.2H2O(aq))) to isolate 1-(2-bromo-3-(2- hydroxyethoxy)phenyl)-2-nitroethan-1-ol; and
(v) crystallising the 1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol.
Throughout this specification, in some examples the method may relate to one stereoisomer of the listed compound. Thus, in some cases, the method may relate to synthesis of (S)-3-(aminomethyl)-4- chloro-7-(2-hydroxyethoxy)benzo[c][1 ,2]oxaborol-1(3/-/)-ol: or a salt thereof.
In some examples, tert-butyl ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2- yl)methyl)carbamate may be (S)-((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2- yl)methyl)carbamate:
In some examples, 2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or a salt thereof may be (S)-2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol:
or a salt thereof.
In some examples, 2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or a salt thereof may be (S)-2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol: or a salt thereof.
In some examples, (S)-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol may be (S)-1-(2- bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol:
Abbreviations In describing the invention, chemical elements are identified in accordance with the Periodic Table of the Elements. Abbreviations and symbols utilized herein are in accordance with the common usage of such abbreviations and symbols by those skilled in the chemical arts. The following abbreviations are used herein:
AcOH Acetic acid
AIBN 2-2'-Azoisobutyronitrile
BOC N-tert-butoxycarbonyl
B2piri2 bis(pinacolato)diboron, also known 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2- dioxaborolane
DCM dichloromethane
DIPEA N, /V-Diisopropy lethylamine
DMSO-d6 deuterated dimethylsulfoxide
DMSO dimethylsulfoxide
EtOH ethanol
EtOAc ethyl acetate h hours
HPLC high performance liquid chromatography
IPA isopropyl alcohol
MCH Methylcyclohexane
MeOH methanol
MeCN methyl cyanide
MsOH methanesulfonic acid
MTBE Methyl tertiary-buty I ether
N-Ac-Cys N-acetyl cysteine
NBS N-bromosuccinimide
NCS N-chlorosuccinimide
NMR Nuclear Magnetic Resonance spectroscopy
THF tetrahydrofuran
2-MeTHF 2-methyl tetrahydrofuran
Examples
The following examples illustrate the invention. These Examples are not intended to limit the scope of the invention, but rather to provide guidance to the skilled artisan as to implementation of methods of the invention. While embodiments of the invention are described, the skilled artisan will appreciate that various changes and modifications can be made.
Proton nuclear magnetic resonance (1 H NMR) spectra were recorded, and chemical shifts are reported in parts per million (5) downfield from the internal standard tetramethylsilane (TMS). Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. All temperatures are reported in degrees Celsius.
An example synthetic route is shown below in Scheme 1.
Stage A - Synthesis of GW415775X
To a solution of GR44399X (116 kg) in DCM (1160 L) was added MsOH (9.3 kg, 0.1 eq.) followed by NBS (185 kg, 1.1 eq.) at 20-30 °C. The reaction was stirred at 20-30 °C, then the reaction mixture was quenched with aqueous Na2S20s /KHCO3 (25%w/w, 70 kg). The mixture was concentrated and switched with EtOAc (348 L, 3 vol.). After dilution with EtOAc (580 L, 5 vol.), the mixture was washed with aqueous Na2SC>4 solution (15%w/w, 3 x 812 kg) at 30-40°C. The organic layer was filtered through diatomite, rinsing with more EtOAc (77 L). The combined filtrates were washed with aqueous Na2SO4 solution (15%w/w, 812 kg) at 30-40°C, then the organic layer was concentrated in vacuo to ~6 vol. and cooled to -5 °C. Methylcyclohexane (MCH), (460 L, 4 vol.) was then added and after stirring, the mixture was filtered and the cake washed with MCH (120 L, 1 vol.). The wet cake was dried in vacuo at 50 °C to yield GW415775X (99 kg, 52%) as a solid.
1H NMR (400MHz; DMSO-d6): 10.8 (1 H, s), 10.3 (1 H, s), 7.28 (3H, m).
Stage B - Synthesis of GSK4026152A
To a solution of GW415775X (68 kg) in 1 ,4-dioxane (476 L) at 20 °C was added a solution of UOH.H2O (20 kg) in water (408 L) followed by GI148705X (52.7 kg). The reaction mixture was pumped through a HC tubular reactor, heating to 130 °C for a residence time of 30 mins. The output of the flow reactor was cooled and collected. The mixture was concentrated in vacuo then the solution warmed and GSK4026152A seed (0.01 wt.) added. Water (680 L) was added slowly and the resulting slurry cooled, aged, then filtered. The cake was washed with water (68 L), then dried in vacuo at 50 °C to give GSK4026152A (72.6 kg, 86%) as a white solid.
1H NMR (400MHz; CDCI3): 7.57 (1 H, dd), 7.38 (1H, t), 7.16 (1 H, dd), 4.21 (2H, m), 4.06 (2H, m), 2.27 (1H, t).
Stage 1 - Synthesis of GSK4364445A
To a solution of (1R,2R,4R)-1 ,7,7-trimethyl-N-(pyridin-2-ylmethyl)bicyclo[2.2.1]heptan-2-amine dihydrochloride (GSK2412905A) (3.65 kg) in EtOH (286 L) was added DIPEA (3.75 kg) followed by 2- MeTHF (83 L). The mixture was stirred and Cu(OAc)2.H2O (2.90 kg) was added. After stirring, 2-bromo- 3-(2-hydroxyethoxy)benzaldehyde (GSK4026152A, 72.3 kg) followed by DIPEA (3.75 kg) were added, rinsing in with 2-MeTHF (11 L). The reaction mixture was cooled to -18 °C and a solution of nitromethane (175 kg) in 2-MeTHF (351 L) added slowly. The reaction mixture was stirred until HPLC showed the reaction was complete. The reaction was quenched by addition of aqueous HCI solution (1 M, 142 kg) and warmed to 25 °C. Aqueous Na2SO4 solution (15%w/w, 213 kg) followed by water (444 L) were then added and the layers separated. To the organic phase was added aqueous HCI solution (1 M, 142 kg) and aqueous EDTA.2Na.2H2O solution (5%w/w, 214 kg). After stirring the layers were separated and to the organic layer was added further aqueous HCI solution (1 M, 142 kg) and aqueous EDTA.2Na.2H2O solution (5%w/w, 213 kg). The layers were separated and the organic phase filtered. To the organic phase was added further aqueous HCI solution (1 M, 141 kg) and aqueous EDTA.2Na.2H2O solution (5%w/w, 207 kg). The mixture was filtered rinsing with 2-MeTHF (29 kg) and the layers separated. The organic phase was concentrated in vacuo to 220 L volume and the solvent switched into IPA below 40 °C with a put and take distillation (3 x 124 L of IPA). The solution was concentrated in vacuo to a final volume of 150 L, cooled to 25 °C and water (721 L) was added slowly. The resulting slurry was cooled to 0 °C, aged, then the product was collected by filtration washing the cake with water (34 L). The wet cake was dried in vacuo at 50 °C to give GSK4364445A as a white solid (71.7 kg, 76%).
1H NMR (400MHz; DMSO-d6): 7.40 (1H, t), 7.22 (1 H, d), 7.09 (1 H, d), 6.31 (1 H, d), 5.60 (1 H, m), 4.88 (1H, t), 4.78 (1H, dd), 4.40 (1 H, dd), 4.07 (2H, m), 3.75 (2H, m).
Stage 2 - Synthesis of GSK4023557B
To the reactor was charged Raney Ni (15.0 kg) followed by EtOH (598 L), GSK4364445A (71.7 kg) and acetic acid (67.6 kg), rinsing in with EtOH (13L). The reaction mixture was then stirred under a H2 atmosphere at 25 °C until HPLC showed the reaction was complete. The mixture was then filtered through a pad of diatomite, washing the cake with EtOH (248 L). The filtrate solution was warmed to 50 °C and L-tartaric acid (34.0 kg) added. The resulting slurry was stirred then cooled to 20 °C and aged. The product was collected by filtration washing the cake with EtOH (87 L). The wet cake was dried in vacuo at 50 °C to give GSK4023557B as a white solid (88.1 kg, 90%).
1H NMR (400MHz; D2O): 7.46 (1H, t), 7.26 (1 H, d), 7.12 (1 H, d), 5.42 (1 H, dd), 4.50 (2H, s), 4.22 (2H, m), 3.97 (2H, m), 3.30 (1 H, dd), 3.16 (1H, dd).
Stage 3 - Synthesis of GSK4023558B
To a suspension of GSK4023557B (63.8 kg) in MeCN (325 L) and MeOH (93 L) was added MsOH (43.8 kg). A solution of NOS (22.0 kg) in MeCN (249 L) was then added rinsing in with further MeCN (17 L). The mixture was stirred at 20 °C until HPLC showed the reaction was complete. GSK4023557B seed (0.40 kg) was added, the mixture stirred and then MeCN (762 L) was added slowly. The mixture was cooled to -18 °C, stirred and the slurry filtered. The cake was washed with MeCN (48 L) and then dried in vacuo at 40 °C to give GSK4023558B as a white solid (50.9 kg, 82%).
1H NMR (400MHz; MeOD): 7.40 (1 H, d), 7.06 (1 H, d), 5.79 (1 H, dd), 4.14 (2H, m), 3.92 (2H, m), 3.69 (1H, t), 3.08 (1 H, dd), 2.70 (3H, s).
Stage 4 - Preparation of GSK3177484A
To a solution of GSK4023558B (50.9 kg) in MTBE (147 L) and water (153 L) was added and KHCO3 (14.0 kg) followed by BOC2O (28.9 kg), rinsing in with MTBE (7 L). The mixture was stirred at 20 °C until HPLC showed the reaction was complete. The reaction mixture was allowed to stand and separated, then the organic phase washed with H2O (2 x 100 L). The organic layer was concentrated and switched into MeCN to get a solution of C14111825-GA in MeCN (-290 L).
To the solution of C14111825-GA in MeCN was added further MeCN (319 L), and potassium pivalate (25.9 kg), in water (50 L) and MeCN solution was added palladium (II) acetate (1.93 kg) and tri-t- butylphosphine tetrafluoroborate (5.0 kg), followed by adding a solution of B2pin2(63.0 kg) in MeCN (99 L) and the reactor purged with N2. The reaction mixture was warmed to 40 °C and stirred until HPLC showed the reaction was complete. The reaction mixture was filtered, and the cake was washed with MeCN (94 L). The filtrate was concentrated to -100L and then diluted with EtOAc (445 L) and the layers separated. The organic phase was washed with a mixture of aqueous N-Ac-Cys (5%w/w, 231 kg) and aq. KHCO3 (5%w/w, 226 kg) (three times) mixed solution. The organic phase was then stirred with silica thiol (15 kg), filtered and the cake was washed with EtOAc 32 L). The filtrate was concentrated and switched with IPA to a solution volume of -110 L. The residue was diluted with IPA (160 L), cooled to 0°C and GSK3177484A seed (0.25 kg) was added and the mixture was stirred and then filtered. The wet cake was washed with IPA (33 L) and then dried at 40 °C in vacuo to get GSK3177484A as a white solid (36.5 kg, 66% over 2 steps).
1H NMR (400MHz; DMSO-d6): 7.42 (1 H, d), 6.96 (0.8H, s), 6.89 (1 H, d), 6.62 (0.2H, s), 5.32 (1 H, m), 4.34-4.19 (4H, m), 3.74 (1 H, m), 3.21 (1 H, m), 1.33 (9H, s).
Stage 5 - Preparation of IG GSK3036656E
To a solution of GSK3177484A (36.5 kg, assay 75.5%wt.) in IPA (196 L, 7.3 vol.) was added aq. sulfuric acid solution (50% w/w, 25.1 kg, 0.91 wt.) maintaining the internal temperature below 25 °C. The reaction mixture was heated to 45-55 °C and stirred for 33 h after which time HPLC showed the reaction was complete. The mixture was cooled to 20-30 °C and then filtered, washing the cake with IPA (8 L, 0.3 vol.). The wet cake was transferred back into the reactor and IPA (245 L, 8.9 vol.) was added. The mixture was heated to 45-55 °C, stirred at this temperature for 3 h, then cooled to 20-30 °C. The product was collected by filtration, washing the cake with IPA (8 L, 0.3 vol.). The wet cake was dried under vacuum at 40-50 °C for 24 h to give intermediate grade GSK3036656E (27.5 kg, 93%) as a white solid.
Stage 6 - Purification of GSK3036656E
GSK3036656E (27.4 kg, 1.0 wt.), purified water (19 L, 0.7 vol.) and MeOH (372 L, 13.6 vol.) was charged into a reactor ( R 1 ). The mixture was heated to 64 °C and stirred at 60-68 °C for 0.2 h to give a clear solution. The solution in R1 was transferred via a 0.22 pm in-line filter into another reactor (R2), which was preheated to 62-68 °C. Purified water (22 L, 0.8 vol.) was added into R1 and the water wash transferred into R2 via the in-line filter. The mixture in R2 was adjusted to 50-60 °C and stirred for 0.5 h to give a clear solution. GSK3036656E seed (71 g, 0.26% wt.) was then added into R2 rinsing in with MeOH/purified water (9:1 v/v). The mixture was stirred at 50-60 °C for 3 h, then cooled to 5 °C over 5.5 h and stirred at 0-10 °C for 5 h. The slurry was then wet milled for a total of 3.5 h. The mixture was aged at 0-10 °C for 15 h then warmed to 50- 60 °C over 3 h and stirred at this temperature for 1 h. The mixture was cooled to 0-10 °C over 5 h and stirred at this temperature for 2 h, then warmed to 50-60 °C over 2.5 h and stirred in this range for 1 h. The mixture was then cooled to 0-10 °C over 5 h and stirred at this temperature for 8 h before warming to 50-60 °C over 3 h and holding in this range for 1.5 h. The mixture was cooled to 0-10 °C over 6 h and aged at this temperature for 19 h. The mixture was filtered and the cake washed with MeOH/purified water (9:1 v/v, 44 kg, 1.6 wt.). The wet cake was dried under vacuum at 35-45 °C for 5 h and then at 45-55 °C for a further 26 h to give GSK3036656E (20.3 kg, 76%) as a white solid.
1H NMR (400MHz; D2O): 7.40 (1 H, d), 6.88 (1 H, d), 5.39 (1 H, dd), 4.16 (2H, m), 4.03 (2H, m), 3.82 (1 H, dd), 3.19 (1 H, dd).
It is to be understood that the invention covers all combinations of aspects with all other suitable aspects and/or exemplary embodiments described herein. It is to be understood that the invention also covers all combinations of exemplary embodiments with all other suitable aspects and/or exemplary embodiments described herein.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1 . A method for preparing 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1 ,2]oxaborol-1 (3H)- ol: salt thereof; the method comprising preparing tert-butyl ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a- borabenzo[cd]azulen-2-yl)methyl)carbamate: followed by conversion of tert-butyl ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2- yl)methyl)carbamate to 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1 ,2]oxaborol-1 (3H)-ol or salt thereof.
RECTIFIED SHEET (RULE 91) ISA/EP The method of claim 1 , wherein tert-butyl ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a- borabenzo[cd]azulen-2-yl)methyl)carbamate is prepared from 2-amino-1 -(2-bromo-6-chloro-3-(2- hydroxyethoxy)phenyl)ethan-1-ol:
3. The method of claim 2, further comprising preparing 2-amino-1-(2-bromo-6-chloro-3-(2- hydroxyethoxy)phenyl)ethan-1 -ol or salt thereof from 2-amino-1 -(2-bromo-3-(2- hydroxyethoxy)phenyl)ethan-1-ol:
The method of claim 3, further comprising preparing 2-amino-1 -(2-bromo-3-(2- hydroxyethoxy)phenyl)ethan-1-ol or salt thereof from 1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2- nitroethan-1-ol:
2
RECTIFIED SHEET (RULE 91) ISA/EP
5. The method of claim 4, further comprising preparing 1-(2-bromo-3-(2-hydroxyethoxy)phenyl)- 2-nitroethan-1-ol from 2-bromo-3-(2-hydroxyethoxy)benzaldehyde.
6. The method of any claims 2-4, wherein the method of converting 2-amino-1-(2-bromo-6-chloro- 3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof into tert-butyl ((3-chloro-7,8-dihydro-2H-1 ,6,9- trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate includes a includes a Miyaura Borylation.
7. A compound selected from: tert-butyl ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate; 2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof;
2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof;
1 -(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1 -ol; and 2-bromo-3-(2-hydroxyethoxy)benzaldehyde.
8. A method for preparing 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1 ,2]oxaborol-
1 (3H)-ol or salt thereof comprising: a) converting 2-bromo-3-(2-hydroxyethoxy)benzaldehyde to 1-(2-bromo-3-(2- hydroxyethoxy)phenyl)-2-nitroethan-1-ol; b) converting 1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol to 2-amino-1-(2- bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof; c) converting 2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof to 2-amino-1 -(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1 -ol or salt thereof; d) converting 2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof to ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate; and e) converting ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2- yl)methyl)carbamate to 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1 ,2]oxaborol-1 (3H)-ol or salt thereof.
9. The method of claim 8, wherein the method prepares (S)-3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1 ,2]oxaborol-1 (3H)-ol and comprises: a) converting 2-bromo-3-(2-hydroxyethoxy)benzaldehyde to (S)-1-(2-bromo-3-(2- hydroxyethoxy)phenyl)-2-nitroethan-1-ol:
3
RECTIFIED SHEET (RULE 91) ISA/EP
b) converting (S)-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol to (S)-2- amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol: c) converting (S)-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol or salt thereof to (S)-2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol: d) converting (S)-2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof to (S)-((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2- yl)methyl)carbamate:
RECTIFIED SHEET (RULE 91) ISA/EP e) converting (S)-((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2- yl)methyl)carbamate to (S)-3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1 ,2]oxaborol-1 (3H)- ol: r salt thereof.
10. The method of claim 5, 8 or 9, wherein the converting 2-bromo-3-(2- hydroxyethoxy)benzaldehyde to 1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol comprises an asymmetric nitroaldol reaction.
11. The method of claim 10, wherein the reaction is completed using a diamine ligand and/or a copper catalyst.
12. The method of claim 11 , wherein the diamine ligand is (1 R,2R,4R)-1 ,7,7-trimethyl-N-(pyridin-2- ylmethyl)bicyclo[2.2.1]heptan-2-amine dihydrochloride and/or the copper catalyst comprises CU(OAC)2.H2O.
13. The method of one of claims 10-12, wherein the asymmetric nitroaldol reaction comprises:
(i) mixing a ligand and 2-bromo-3-(2-hydroxyethoxy)benzaldehyde in the presence of a copper catalyst, optionally in the presence a solvent;
(ii) adding nitromethane, optionally in the presence of a solvent;
(iii) quenching with acid;
(iv) washing to isolate 1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol; and
(v) crystallising the 1-(2-bromo-3-(2-hydroxyethoxy)phenyl)-2-nitroethan-1-ol.
RECTIFIED SHEET (RULE 91) ISA/EP
14. The method of claim 4, 5, 8 or 9 wherein the converting 1-(2-bromo-3-(2- hydroxyethoxy)phenyl)-2-nitroethan-1 -ol to 2-amino-1 -(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1 -ol or salt thereof comprises a nitro-reduction reaction.
15. The method of claim 14, wherein the nitro-reduction reaction is catalysed by a metal catalyst selected from nickel, platinum, palladium, rhodium, ruthenium or iridium.
16. The method of claim 15, wherein the nitro-reduction reaction comprises hydrogenation catalysed by Raney nickel.
17. The method of any of claims 14 to 16, wherein L-tartaric acid is added to the reaction and the reaction product is the tartrate salt of 2-amino-1-(2-bromo-3-(2-hydroxyethoxy)phenyl)ethan-1-ol.
18. The method of claim 3, 4, 5, 8 or 9, wherein the converting 1-(2-bromo-3-(2- hydroxyethoxy)phenyl)-2-nitroethan-1-ol or salt thereof to 2-amino-1-(2-bromo-6-chloro-3-(2- hydroxyethoxy)phenyl)ethan-1-ol or salt thereof comprises chlorination by aromatic electrophilic substitution.
19. The method of claim 18, wherein the chlorinating agent comprises N-chlorosuccinimide.
20. The method of claim 18 or 19, wherein methylsulfonic acid is added to the reaction and the reaction product is the mesylate salt of 2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan- 1-ol.
21 The method of any of claims 2-5, 8 or 9, wherein the converting 2-amino-1 -(2-bromo-6-chloro- 3-(2-hydroxyethoxy)phenyl)ethan-1-ol or salt thereof to ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a- borabenzo[cd]azulen-2-yl)methyl)carbamate comprises a Boc-protection reaction and then a Pd- catalysed borylation.
22. The method of claim 21 , wherein the Pd-catalysed borylation is a Miyarua borylation.
23. The method of claim 21 or 22, comprising:
(i) mixing 2-amino-1-(2-bromo-6-chloro-3-(2-hydroxyethoxy)phenyl)ethan-1-ol with
B0C2O, base and solvent;
(ii) adding base, Pd catalyst and a phosphine ligand;
(iii) adding a borylating agent;
(iv) washing; and
(v) crystallising the ((3-chloro-7,8-dihydro-2H-1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2- yl)methyl)carbamate.
6
RECTIFIED SHEET (RULE 91) ISA/EP
24. The method of claim 23, wherein the catalyst comprises palladium(ll) acetate and/or the borylating agent is selected from B2pin2, HBpin and B2(OH)4 and/or the phosphine ligand comprises tri- t-butylphosphine tetrafluoroborate.
25. The method of any of claims 1 to 6, 8 or 9 wherein the converting of ((3-chloro-7,8-dihydro-2H- 1 ,6,9-trioxa-9a-borabenzo[cd]azulen-2-yl)methyl)carbamate to 3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1 ,2]oxaborol-1 (3H)-ol or salt thereof comprises Boc-deprotection using sulfuric acid, and the reaction product is the sulfate salt of 3-(aminomethyl)-4-chloro-7-(2- hydroxyethoxy)benzo[c][1 ,2]oxaborol-1 (3H)-ol.
7
RECTIFIED SHEET (RULE 91) ISA/EP
EP24720412.6A 2023-04-05 2024-04-03 Synthesis of 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3)-ol Pending EP4688794A1 (en)

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EP23166815 2023-04-05
PCT/EP2024/059071 WO2024208907A1 (en) 2023-04-05 2024-04-03 Synthesis of 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3h)-ol

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Publication number Priority date Publication date Assignee Title
US20160251380A1 (en) 2013-08-09 2016-09-01 Glaxosmithkline Intellectual Property (No.2) Limited Tricyclic benzoxaborole compounds and uses thereof

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