CN120835890A - Synthesis of 3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol - Google Patents
Synthesis of 3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-olInfo
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- CN120835890A CN120835890A CN202480020331.3A CN202480020331A CN120835890A CN 120835890 A CN120835890 A CN 120835890A CN 202480020331 A CN202480020331 A CN 202480020331A CN 120835890 A CN120835890 A CN 120835890A
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- 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
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- C07—ORGANIC CHEMISTRY
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- 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
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- 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
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- 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
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- 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
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Abstract
本发明提供了制备3‑(氨基甲基)‑4‑氯‑7‑(2‑羟基乙氧基)苯并[c][1,2]氧杂硼杂环戊‑1(3H)‑醇的方法；该方法包括制备((3‑氯‑7,8‑二氢‑2H‑1,6,9‑三氧杂‑9a‑硼杂苯并[cd]薁‑2‑基)甲基)氨基甲酸叔丁酯；并将该化合物转化为3‑(氨基甲基)‑4‑氯‑7‑(2‑羟基乙氧基)苯并[c][1,2]氧杂硼杂环戊‑1(3H)‑醇或其盐。The present invention provides a method for preparing 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol. The method comprises preparing tert-butyl ((3-chloro-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulene-2-yl)methyl)carbamate; and converting the compound into 3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol or a salt thereof.
Description
Technical Field
The present invention relates to an improved synthesis of 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborole-1 (3H) -ol, which is useful as an antimycobacterial compound, for example for the treatment of tuberculosis.
Background
Mycobacteria are a genus of the class of bacteria known as actinomycetes, and their own unique family is known as Mycobacteriaceae. Mycobacteria contain a variety of animal obligate and opportunistic pathogens that may also be transmitted to humans and cause human disease, thus exhibiting considerable zoonotic potential. In the last few decades, members of the mycobacterium avium-intracellular complex (MAIC) have become causative agents of human diseases, including childhood lymphadenitis, tuberculosis-like diseases, and disseminated infections (mainly occurring in immunocompromised populations, especially aids patients). Also important animal diseases are caused by infections of the group members in animals, such as avian tuberculosis and ruminant paratuberculosis. MAIC comprises M.intracellulare (M. intracellulars) and 4 Mycobacterium avium subspecies, namely Mycobacterium avium subspecies (M.avium subsp. Avium), mycobacterium avium hominissuis subspecies (M.avium subsp. Hominissuis), mycobacterium avium subsp. Silvaticum) and Mycobacterium avium subsp. Paratuberculosis (M.avium subsp. Paratuberculosis). Although members of the Mycobacterium tuberculosis complex are transmitted by direct contact with the host, MAIC species are mainly obtained from environmental sources (including soil, water, dust, and feed).
Mycobacterium Tuberculosis (MTB) is a small aerobic, non-motile, high-GC Bacillus whose "outer membrane" is exceptionally thick, "waxy," hydrophobic, mycolic acid-rich and extremely impermeable, which makes mycobacterial infections difficult to treat. One third of the world's population is considered to be infected with mycobacterium tuberculosis (including latent mycobacterium tuberculosis), but in many asian and african countries this number rises to over 80% of the population. If untreated, the mortality rate of active MTB infection exceeds 50%. In addition, the combination of HIV and MTB is fatal, and more Mycobacterium tuberculosis strains develop resistance to standard therapeutic drugs, with about 300,000 new cases of multi-drug resistant (MDR) Mycobacterium tuberculosis reported annually. Multi-drug resistant (MDR) mycobacterium tuberculosis is resistant to isoniazid and rifampicin, while extensively drug resistant (XDR) mycobacterium tuberculosis is also resistant to at least one quinolone and one aminoglycoside.
Synthetic drugs for the treatment of Tuberculosis (TB) have been known for over half a century, but the incidence of this disease continues to rise worldwide. Currently, more than 20 million people are infected with mycobacterium tuberculosis, most of which are latent cases, and new cases produced worldwide are estimated to be more than 900 tens of thousands per year, resulting in 170 to nearly 200 tens of thousands of deaths per year. Only in 2004, about 24,500 new infections and nearly 5,500 deaths were recorded per day. See Zignol, the combined infection of M et 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) with HIV is driving an increased incidence (Williams, B.G.; dye, C.science, 2003, 301, 1535), and the cause of death in 31% of AIDS patients in Africa may be attributed to tuberculosis. See Corbett, E.L et al, arch, intl, med, 2003, 163, 1009, septkowitz, A et al, clin. Microbiol. Rev. 1995, 8, 180).
Limitations in the treatment and prevention of tuberculosis are well known. Currently available vaccine BCG was introduced in 1921, but it was not able to protect most post childhood individuals. According to the report of 2006- "tuberculosis care international standard", which is a file-infection active disease patient formulated by the tuberculosis technical aid consortium (TBCTA) (its partners include centers for disease control, the american society of thoracic, tuberculosis foundation, KNCV, world health organization and international union for anti-tuberculosis and pulmonary disease), currently needs to receive a combination therapy of two months, wherein the drugs are isoniazid (1952), rifampin (1963), pyrazinamide (1954) and ethambutol (1961), which are released 50 to 60 years ago, and then received isoniazid and rifampin (rifampin) (also called rifampin (rifampicin)) for another 4 months. Or when compliance cannot be assessed, the duration may include six months of use of isoniazid and ethambutol, but according to this report, longer durations are associated with higher failure and recurrence rates, particularly for HIV-infected patients. Furthermore, as detailed in the present report, the dosage of antitubercular drugs used should be in accordance with international recommendations and it is strongly recommended to use fixed dose combinations of two (isoniazid and rifampin), three (isoniazid, rifampin and pyrazinamide) and four (isoniazid, rifampin, pyrazinamide and ethambutol) drugs, especially when the patient cannot be monitored to ensure treatment.
During these treatment phases, daily dosing is required and poor compliance drives the emergence and spread of multi-drug resistant strains, which presents a treatment challenge. There is an urgent need for more active agents that can be taken less frequently and present a high barrier to the emergence of resistance, i.e. agents that are effective against multi-drug resistant strains of TB (MDR-TB). Report (http://www.aidsmap.com/Once-weekly-continuation-phase -TB-treatment-equals-standard-of-care/page/2589498/) of month 3 of 2013 shows that dual drug combination of rifapentine (a long-acting derivative of rifampin) with moxifloxacin (a fluoroquinolone antibiotic not previously used for tuberculosis treatment) allows Tuberculosis (TB) treatment to be performed once per week during a four month extended period and to meet the same standard of care as conventional extended treatments with isoniazid and rifampin treatment per day. Such a treatment phase would allow for treatment supervision to be extended throughout the extended phase, thereby improving compliance. However, moxifloxacin has not been approved for the treatment of tuberculosis and once a week treatment regimen has not been approved or approved as an alternative standard of care treatment—international and national guidelines require review of published evidence to determine whether such alternative continued treatment regimen should be recommended and employed. Furthermore, rifapentine is expensive and in non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors, the interaction between rifapentine and antiretroviral drugs may prevent its use in TB patients who are also HIV positive and are taking antiretroviral drugs. Thus, at present, the cost/benefit analysis of weekly rifapentine versus daily sustained treatment of rifampin has not been fully evaluated.
WO2015021396A2 discloses benzoxaborole (benzoxaborole) compounds which exhibit unexpected selectivity for inhibiting mycobacterium tuberculosis (m. Tuberculosis) replication compared to other benzoxaborole compounds (relative to inhibition of human cells (toxicity)), and which exhibit submicron MIC values for mycobacterium species, particularly mycobacterium tuberculosis and Mycobacterium Tuberculosis Complex (MTC), mycobacterium avium and Mycobacterium Avium Complex (MAC), and mycobacterium avium complex (MAIC).
Specifically, WO2015021396A2 discloses (S) -3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborol-1 (3H) -ol (closed-loop tricyclic configuration):
Description of the synthetic route the synthesis of this sulphate salt is described in example 4-II.
Summary of The Invention
The present invention discloses a process for preparing 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborol-1 (3H) -ol or a salt thereof:
;
The process comprises preparing tert-butyl ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate:
;
Tert-butyl ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate is then converted to 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborolan-1 (3H) -ol or a salt thereof.
Also disclosed herein are the following compounds:
tert-butyl ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate;
2-amino-1- (2-bromo-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof;
2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a 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 process for preparing 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborol-1 (3H) -ol or a salt thereof comprising:
a) Converting 2-bromo-3- (2-hydroxyethoxy) benzaldehyde into 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 a salt thereof;
c) Converting 2-amino-1- (2-bromo-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof to 2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof;
d) Converting 2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof into ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate, and
E) The ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate was converted to 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborolan-1 (3H) -ol or a salt thereof.
Detailed Description
The synthetic route described herein may have any of the following advantages over the synthetic route disclosed in WO' 396:
Improving the overall yield.
Reducing cost and using cheaper reagents.
Increased reliability-without the use of low temperature lithiation chemistry (as opposed to the WO'396 route);
This route has a greater number of separable intermediates (for purity control) -the WO'396 route has several oils that need to be telescoping throughout the synthesis (telescoped).
In some examples, methods are provided for preparing 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborol-1 (3H) -ol or a salt thereof:
;
The method comprises preparing a compound selected from the group consisting of:
; Or a salt thereof; Or a salt thereof; or 2-bromo-3- (2-hydroxyethoxy) benzaldehyde;
The selected compound is then converted to 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborol-1 (3H) -ol or a salt thereof.
In some examples, the method includes:
(i) From the following components PreparationOr a salt thereof, and/or
(Ii) From the following componentsOr salts thereofAnd/or
(Iii) From the following componentsOr salts thereofOr a salt thereof, and/or
(Iv) From the following componentsPreparationOr a salt thereof, and/or
(V) Preparation from 2-bromo-3- (2-hydroxyethoxy) benzaldehyde。
In some examples, 2-bromo-3- (2-hydroxyethoxy) benzaldehyde can be synthesized from 2-bromo-3-hydroxybenzaldehyde, and in some examples 2-bromo-3-hydroxybenzaldehyde can in turn be synthesized from 3-hydroxybenzaldehyde.
Preparation of 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborol-1 (3H) -ol or a salt thereof from ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate may comprise Boc-deprotection with sulfuric acid and the reaction product is a sulfate salt of 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborol-1 (3H) -ol.
In some such examples, the process may comprise mixing a solution of ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate in a solvent (e.g. isopropanol) with sulfuric acid at a temperature of less than 25 ℃. It may also include heating (e.g., to 45-55 ℃). It may also include subsequent cooling (e.g., to 20-30 ℃), filtration, and mixing the filter cake with a solvent (e.g., isopropanol). In some cases, it may include 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 recrystallized to improve purity.
In some cases, the preparation of ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate from 2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof may involve Pd-catalyzed boronation. In some cases, the reaction may comprise a Miyaura boride reaction. In some cases, the boration reaction may precede the Boc protection reaction.
In some such examples, the method includes:
(i) Mixing 2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol with Boc 2 O, a base (e.g., KHCO 3) and a solvent (e.g., MTBE (aqueous solution));
(ii) Adding a base (e.g., potassium pivalate), a Pd catalyst (e.g., palladium (II) acetate), and a phosphine ligand (e.g., tri-tert-butylphosphine tetrafluoroborate);
(iii) Adding a borating agent (e.g., B 2pin2, HBpin, and B 2(OH)4);
(iv) Washing and
(V) Crystalline ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate.
In some cases, preparing 2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof from 2-amino-1- (2-bromo-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof may involve chlorination by aromatic electrophilic substitution. In some cases, the chlorinating agent may comprise N-chlorosuccinimide. In some cases, a crystalline salt of the chlorinated product, such as a mesylate salt, may be formed to enable isolation of the reaction product.
Preparation of 2-amino-1- (2-bromo-3- (2-hydroxyethoxy) phenyl) ethan-1-ol from 1- (2-bromo-3- (2-hydroxyethoxy) phenyl) -2-nitroethan-1-ol or a salt thereof may comprise a nitroreduction reaction. In some cases, this may be metal-catalyzed, such as Raney nickel catalyzed hydrogenation to reduce nitro groups. (in other such examples, the reduction may be catalyzed by Pt, pd, rh, ru or Ir-based catalysts.) in some cases, crystalline salts of the reaction product, such as tartrate, may be formed to enable isolation of the reaction product.
In some cases, the preparation of 1- (2-bromo-3- (2-hydroxyethoxy) phenyl) -2-nitroethan-1-ol from 2-bromo-3- (2-hydroxyethoxy) benzaldehyde may involve an asymmetric nitroaldol reaction (e.g., an asymmetric Henry reaction). This may include the use of copper catalysts, for example copper (II) catalysts such as Cu (OAc) 2、Cu(OTf)2、CuCl2, and the like. In some examples, the ligand used in the reaction may be a diamine ligand (e.g., diaminocyclohexane), a chiral oxazoline, a schiff base ligand, or a chiral salen-based ligand. In some examples, the ligand comprises (1 r,2r,4 r) -1, 7-trimethyl-N- (pyridin-2-ylmethyl) bicyclo [2.2.1] hept-2-amine dihydrochloride.
In some examples, the asymmetric nitroaldol reaction includes:
(i) Mixing the ligand and 2-bromo-3- (2-hydroxyethoxy) benzaldehyde in the presence of a copper catalyst, optionally in the presence of a solvent (e.g., ethanol and MeTHF co-solvent) and a base (e.g., DIPEA);
(ii) Optionally adding nitromethane in the presence of a solvent;
(iii) Quenching with acid;
(iv) Washing (e.g., with Na 2SO4 (aqueous solution), EDTA.2Na.2H 2 O (aqueous solution)) to isolate 1- (2-bromo-3- (2-hydroxyethoxy) phenyl) -2-nitroethan-1-ol, and
(V) Crystalline 1- (2-bromo-3- (2-hydroxyethoxy) phenyl) -2-nitroethan-1-ol.
Throughout this specification, in certain examples, the methods may involve one stereoisomer of a listed compound. Thus, in certain instances, the method may involve the synthesis of (S) -3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborole-1 (3H) -ol or a salt thereof:
。
In some examples, tert-butyl ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate may be (S) - ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate:
。
In some examples, the 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, the 2-amino-1- (2-bromo-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or salt thereof may be (S) -2-amino-1- (2-bromo-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or 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 (abbreviations)
In describing the present invention, chemical elements are identified according to the periodic table of elements. Abbreviations and symbols used herein are consistent with the common usage of these abbreviations and symbols by those skilled in the chemical arts. The following abbreviations are used herein:
AcOH acetic acid
AIBN2-2' -azobisisobutyronitrile
BOCN-tert-Butoxycarbonyl group
B 2pin2 bis (pinacolato) diboron, also known as 4,4', 5' -octamethyl-2, 2' -bis-1, 3, 2-dioxaborolan
DCM dichloromethane
DIPEAN N-diisopropylethylamine
DMSO-d6 deuterated dimethyl sulfoxide
DMSO dimethyl sulfoxide
EtOH ethanol
EtOAc ethyl acetate
H hours
HPLC high performance liquid chromatography
IPA isopropyl alcohol
MCH methylcyclohexane
MeOH methanol
MeCN acetonitrile
MsOH methane sulfonic acid
MTBE methyl tert-butyl ether
N-Ac-CysN-acetylcysteine
NBSN-bromosuccinimide
NCSN-chlorosuccinimide
NMR Nuclear magnetic resonance Spectroscopy
THF tetrahydrofuran
2-MeTHF 2-methyltetrahydrofuran
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 those skilled in the art in practicing the methods of the invention. While embodiments of the present invention have been described, it will be understood by those skilled in the art that various changes and modifications may be made.
Proton nuclear magnetic resonance (1 H NMR) spectra were recorded and chemical shifts were reported in parts per million (δ) of the low field of the internal standard Tetramethylsilane (TMS). The abbreviations for NMR data are as follows: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, q=four-fold peak, m = multiple peak(s). All temperatures are in degrees celsius.
An example of the synthetic route is shown in scheme 1 below.
Scheme 1
Synthesis of stage A-GW415775X
To a solution of GR44399X (116 kg) in DCM (1160L) at 20-30℃was added MsOH (9.3 kg,0.1 eq.) followed by NBS (185 kg,1.1 eq.). The reaction was stirred at 20-30 ℃ and then quenched with aqueous Na 2S2O3/KHCO3 (25% w/w,70 kg). The mixture was concentrated and replaced with EtOAc (348 l,3 volumes). After dilution with EtOAc (580L, 5 volumes), the mixture was washed with aqueous Na 2SO4 (15% w/w,3X812 kg) at 30-40 ℃. The organic layer was filtered through celite and rinsed with more EtOAc (77L). The combined filtrates were washed with aqueous Na 2SO4 (15% w/w,812 kg) at 30-40 ℃ and then the organic layer was concentrated in vacuo to about 6 volumes and cooled to-5 ℃. Methylcyclohexane (MCH) (460L, 4 volumes) was then added, the mixture was filtered after stirring, and the filter cake was washed with MCH (120L, 1 volumes). The wet cake was dried in vacuo at 50 ℃ to give GW415775X (99 kg, 52%) as a solid.
1H NMR(400MHz;DMSO-d6):10.8(1H,s),10.3(1H,s),7.28(3H,m)。
Synthesis of stage B-GSK4026152A
To a solution of GW415775X (68 kg) in 1, 4-dioxane (476L) was added a solution of LiOH.H 2 O (20 kg) in water (408L) at 20℃followed by GI148705X (52.7 kg). The reaction mixture was pumped into an HC tube reactor and heated to 130 ° C with a residence time of 30 minutes. The effluent of the flow reactor was cooled and collected. The mixture was concentrated in vacuo, then the solution was warmed and seeded with GSK4026152a (0.01 wt.). Water (680L) was slowly added and the resulting slurry was cooled, aged and filtered. The filter cake was washed with water (68L) and then dried in vacuo at 50℃to give GSK4026152A (72.6 kg, 86%) as a white solid.
1H NMR(400MHz;CDCl3)：7.57(1H,dd),7.38(1H,t),7.16(1H,dd),4.21(2H,m),4.06(2H,m),2.27(1H,t).
Stage 1-Synthesis of GSK4364445A
To a solution of (1 r,2r,4 r) -1, 7-trimethyl-N- (pyridin-2-ylmethyl) bicyclo [2.2.1] hept-2-amine dihydrochloride (GSK 2412905A) (3.65 kg) in ethanol (286L) was added DIPEA (3.75 kg) followed by 2-MeTHF-L (83L). The mixture was stirred and Cu (OAc) 2.H2 O (2.90 kg) was added. After stirring, 2-bromo-3- (2-hydroxyethoxy) benzaldehyde (GSK 4026152a,72.3 kg) was added followed by DIPEA (3.75 kg) and rinsed with 2-MeTHF f (11L). The reaction mixture was cooled to-18 ℃ and a solution of nitromethane (175 kg) in 2-MeTHF (351L) was slowly added. The reaction mixture was stirred until HPLC showed the reaction was complete. The reaction was quenched by addition of aqueous HCl (1 m,142 kg) and warmed to 25 ℃. Aqueous Na 2SO4 (15% w/w,213 kg) was added followed by water (444L) and the layers were separated. To the organic phase was added aqueous HCl (1M, 142 kg) and aqueous EDTA.2Na.2H 2 O (5% w/w,214 kg). After stirring, the layers were separated and aqueous HCl (1M, 142 kg) and aqueous EDTA.2Na.2H 2 O (5% w/w,213 kg) were added to the organic layer. The layers were separated and the organic phase was filtered. To the organic phase were further added aqueous HCl (1M, 141 kg) and aqueous EDTA.2Na.2H 2 O (5% w/w,207 kg). The mixture was filtered, washed with 2-MeTHF (29 kg), and the layers were separated. The organic phase was concentrated in vacuo to 220L volume and the solvent was converted to IPA (3 x124L IPA) by feed and draw distillation at below 40 ℃. The solution was concentrated in vacuo to a final volume of 150L, cooled to 25 ℃, then water (721L) was slowly added. The resulting slurry was cooled to 0 ℃, aged, and the product was collected by filtration, and the filter cake was washed with water (34L). The wet cake was dried under vacuum at 50 ℃ to give GSK4364445A (71.7 kg, 76%) as a white solid.
1H NMR(400MHz;DMSO-d6)：7.40(1H,t),7.22(1H,d),7.09(1H,d),6.31(1H,d),5.60(1H,m),4.88(1H,t),4.78(1H,dd),4.40(1H,dd),4.07(2H,m),3.75(2H,m).
Synthesis of stage 2-GSK4023557B
Raney nickel (15.0 kg) was added to the reactor, followed by ethanol (598L), GSK4364445A (71.7 kg) and acetic acid (67.6 kg), which were washed with ethanol (13L). The reaction mixture was then stirred under a hydrogen atmosphere at 25 ℃ until HPLC showed the reaction to be complete. The mixture was then filtered through a pad of celite and the filter cake was washed with ethanol (248L). The filtrate was warmed to 50 ℃ and L-tartaric acid (34.0 kg) was added. The resulting slurry was stirred, then cooled to 20 ℃ and aged. The product was collected by filtration and the filter cake was washed with ethanol (87L). The wet cake was dried under vacuum at 50 ℃ to give GSK4023557B (88.1 kg, 90%) as a white solid.
1H NMR(400MHz;D2O)：7.46(1H,t),7.26(1H,d),7.12(1H,d),5.42(1H,dd),4.50(2H,s),4.22(2H,m),3.97(2H,m),3.30(1H,dd),3.16(1H,dd).
Synthesis of stage 3-GSK4023558B
To a suspension of GSK4023557B (63.8 kg) in MeCN (325L) and MeOH (93L) was added MsOH (43.8 kg). Then a solution of NCS (22.0 kg) in MeCN (249L) was added and washed with additional MeCN (17L). The mixture was stirred at 20 ℃ until HPLC showed the reaction to be complete. GSK4023557B seed (0.40 kg) was added, the mixture stirred, and MeCN (762L) was then added slowly. The mixture was cooled to-18 ℃, stirred and the slurry filtered. The filter cake was washed with MeCN (48L) and then dried in vacuo at 40 ℃ to give GSK4023558B (50.9 kg, 82%) as a white solid.
1H NMR(400MHz;MeOD)：7.40(1H,d),7.06(1H,d),5.79(1H,dd),4.14(2H,m),3.92(2H,m),3.69(1H,t),3.08(1H,dd),2.70(3H,s).
Preparation of stage 4-GSK3177484A
To a solution of GSK4023558B (50.9 kg) in MTBE (147L) and water (153L) was added KHCO 3 (14.0 kg), followed by Boc 2 O (28.9 kg) and washing with MTBE (7L). The mixture was stirred at 20 ℃ until HPLC showed the reaction to be complete. The reaction mixture was allowed to stand and separate, then the organic phase was washed with H 2 O (2X 100L). The organic layer was concentrated and transferred to MeCN to give a MeCN solution of C14111825-GA (about 290L).
To the MeCN solution of C14111825-GA, meCN (319L) and potassium pivalate (25.9 kg) were further added, palladium (II) acetate (1.93 kg) and tri-tert-butylphosphine tetrafluoroborate (5.0 kg) were added to the water (50L) and MeCN solution, then the MeCN (99L) solution of B 2pin2 (63.0 kg) was added, and the reactor was purged with N 2. The reaction mixture was warmed to 40 ℃ and stirred until HPLC showed the reaction to be complete. The reaction mixture was filtered and the filter cake was washed with MeCN (94L). The filtrate was concentrated to about 100L, then diluted with EtOAc (445L) and the layers separated. The organic phase was washed (three times) with a mixture of aqueous N-Ac-Cys (5% w/w,231 kg) and aqueous KHCO 3 (5% w/w,226 kg) mixed solution. The organic phase was then stirred with silathiol (15 kg), filtered, and the filter cake was washed with EtOAc (32L). The filtrate was concentrated and displaced with IPA to a solution volume of about 110L. The residue was diluted with IPA (160L), cooled to 0 o C, then seeded with GSK3177484A (0.25 kg) and the mixture was stirred and then filtered. The wet cake was washed with isopropanol (33L) and then dried in vacuo at 40 ℃ to give GSK3177484a as a white solid (36.5 kg, 66% yield in two steps).
1H NMR(400MHz;DMSO-d6)：7.42(1H,d),6.96(0.8H,s),6.89(1H,d),6.62(0.2H,s),5.32(1H,m),4.34-4.19(4H,m),3.74(1H,m),3.21(1H,m),1.33(9H,s).
Preparation of stage 5-IG GSK3036656E
To a solution of GSK3177484A (36.5 kg, 75.5% wt.) in isopropanol (196L, 7.3 vol.) was added aqueous sulfuric acid (50% w/w,25.1kg,0.91 wt.), maintaining the internal temperature below 25 ℃. The reaction mixture was heated to 45-55 ℃ and stirred for 33 hours after which time HPLC showed the reaction to be complete. The mixture was cooled to 20-30 ℃ and then filtered, and the filter cake was washed with isopropanol (8 l,0.3 vol.). The wet cake was transferred back to the reactor and isopropanol (245 l,8.9 vol.) was added. The mixture was heated to 45-55 ℃, stirred at this temperature for 3 hours, and then cooled to 20-30 ℃. The product was collected by filtration and the filter cake was washed with isopropanol (8 l,0.3 vol.). The wet cake was dried under vacuum at 40-50 ℃ for 24 hours 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 (19L, 0.7 vol.) and methanol (372L, 13.6 vol.) were added to the reactor (R1). The mixture was heated to 64 ℃ and stirred at 60-68 ℃ for 0.2 hours to give a clear solution. The solution in R1 was transferred through a 0.22 μm in-line filter to another reactor (R2) preheated to 62-68 ℃. Purified water (22L, 0.8 vol.) was added to R1 and the water wash was transferred to R2 through an in-line filter.
The mixture in R2 was adjusted to 50-60 o C and stirred for 0.5 hours to give a clear solution. GSK3036656E seed (71 g,0.26% wt.) was then added to R2 and washed with methanol/purified water (9:1 v/v). The mixture was stirred at 50-60 ℃ for 3 hours, then cooled to 5 o C over 5.5 hours, and stirred at 0-10 o C for 5 hours. The slurry was then wet milled for a total of 3.5 hours. The mixture was aged at 0-10 o C for 15 hours, then warmed to 50-60 o C over 3 hours and stirred at this temperature for 1 hour. The mixture was cooled to 0-10 o C over 5 hours and stirred at this temperature for 2 hours, then warmed to 50-60 o C over 2.5 hours and stirred for 1 hour over this temperature range. The mixture was cooled to 0-10 o C over 5 hours and stirred at this temperature for 8 hours and warmed to 50-60 o C over 3 hours and held at this temperature range for 1.5 hours. The mixture was cooled to 0-10 o C over 6 hours and aged at this temperature for 19 hours. The mixture was filtered and the filter cake was washed with MeOH/purified water (9:1 v/v,44kg,1.6 wt.). The wet cake was dried under vacuum at 35-45 o C for 5 hours, then at 45-55 o C for an additional 26 hours to give GSK3036656E (20.3 kg, 76%) as a white solid.
1H NMR(400MHz;D2O)：7.40(1H,d),6.88(1H,d),5.39(1H,dd),4.16(2H,m),4.03(2H,m),3.82(1H,dd),3.19(1H,dd).
It is to be understood that the present invention encompasses all combinations of the aspects described herein with all other suitable aspects and/or exemplary embodiments. It should be understood that the present invention also encompasses all combinations of the 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 incorporated by reference in their entirety for all purposes.
Claims (25)
1. A process for preparing 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborol-1 (3H) -ol or a salt thereof:
;
the process comprises preparing tert-butyl ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate:
;
Tert-butyl ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate is then converted to 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborolan-1 (3H) -ol or a salt thereof.
2. A process according to claim 1, wherein ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamic acid tert-butyl ester is prepared from 2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof:
。
3. the method according to claim 2, further comprising reacting the 2-amino-1- (2-bromo-3- (2-hydroxyethoxy) phenyl) ethan-1-ol of the formula or a salt thereof
Preparation of 2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof.
4. A process according to claim 3, further comprising reacting the 1- (2-bromo-3- (2-hydroxyethoxy) phenyl) -2-nitroethan-1-ol of the formula
Preparation of 2-amino-1- (2-bromo-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof.
5. The process according to claim 4, further comprising preparing 1- (2-bromo-3- (2-hydroxyethoxy) phenyl) -2-nitroethan-1-ol from 2-bromo-3- (2-hydroxyethoxy) benzaldehyde.
6. A process according to any one of claims 2 to 4 wherein the process of converting 2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof to tert-butyl ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate comprises a Miyaura boronation reaction.
7. A compound selected from:
Tert-butyl ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate;
2-amino-1- (2-bromo-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof;
2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof;
1- (2-bromo-3- (2-hydroxyethoxy) phenyl) -2-nitroethan-1-ol, and
2-Bromo-3- (2-hydroxyethoxy) benzaldehyde.
8. A process for preparing 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborol-1 (3H) -ol or a salt thereof comprising:
a) Converting 2-bromo-3- (2-hydroxyethoxy) benzaldehyde into 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 a salt thereof;
c) Converting 2-amino-1- (2-bromo-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof to 2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof;
d) Converting 2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof into ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate, and
E) The ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate was converted to 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborolan-1 (3H) -ol or a salt thereof.
9. A process according to claim 8, wherein the process produces (S) -3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborole-1 (3H) -ol and the process comprises:
a) Conversion of 2-bromo-3- (2-hydroxyethoxy) benzaldehyde to (S) -1- (2-bromo-3- (2-hydroxyethoxy) phenyl) -2-nitroethan-1-ol:
;
b) Conversion of (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:
Or a salt thereof;
c) Converting (S) -1- (2-bromo-3- (2-hydroxyethoxy) phenyl) -2-nitroethan-1-ol or a salt thereof to (S) -2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol:
Or a salt thereof;
d) Converting (S) -2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof into (S) - ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate:
And (C) sum
E) Conversion of (S) - ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate to (S) -3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborolan-1 (3H) -ol:
Or a salt thereof.
10. The method according to claim 5,8 or 9, wherein 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 process according to claim 10, wherein the reaction is accomplished using a diamine ligand and/or a copper catalyst.
12. The method of claim 11, wherein the diamine ligand is (1 r,2r,4 r) -1, 7-trimethyl-N- (pyridin-2-ylmethyl) bicyclo [2.2.1] hept-2-amine dihydrochloride and/or the copper catalyst comprises Cu (OAc) 2·H2 O.
13. The method according to any 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 of a solvent;
(ii) Optionally adding nitromethane 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) Crystalline 1- (2-bromo-3- (2-hydroxyethoxy) phenyl) -2-nitroethan-1-ol.
14. The process according to claim 4, 5, 8 or 9, wherein 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 a salt thereof comprises a nitroreduction reaction.
15. The method according to claim 14, wherein the nitroreduction reaction is catalyzed by a metal catalyst selected from the group consisting of nickel, platinum, palladium, rhodium, ruthenium, or iridium.
16. The method according to claim 15, wherein the nitroreduction reaction comprises hydrogenation catalyzed by raney nickel.
17. The process according to any one of claims 14-16, wherein L-tartaric acid is added to the reaction and the reaction product is tartrate of 2-amino-1- (2-bromo-3- (2-hydroxyethoxy) phenyl) ethan-1-ol.
18. The method according to claim 3,4, 5, 8 or 9, wherein converting 1- (2-bromo-3- (2-hydroxyethoxy) phenyl) -2-nitroethan-1-ol or a salt thereof to 2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof comprises chlorination by aromatic electrophilic substitution.
19. The method of claim 18, wherein the chlorinating agent comprises N-chlorosuccinimide.
20. A process according to claim 18 or 19, wherein methanesulfonic 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. A process according to any one of claims 2-5, 8 or 9 wherein 2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol or a salt thereof is converted to ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate comprising a Boc-protection reaction followed by a Pd-catalyzed boriding reaction.
22. The method of claim 21, wherein the Pd-catalyzed borylation is Miyarua borylation.
23. A method according to claim 21 or 22, comprising:
(i) Mixing 2-amino-1- (2-bromo-6-chloro-3- (2-hydroxyethoxy) phenyl) ethan-1-ol with Boc 2 O, a base and a solvent;
(ii) Adding a base, a Pd catalyst and a phosphine ligand;
(iii) Adding a boration agent;
(iv) Cleaning and
(V) Crystalline ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate was carried out.
24. The process according to claim 23, wherein the catalyst comprises palladium (II) acetate and/or the boride is selected from B 2pin2, HBpin and B 2(OH)4 and/or the phosphine ligand comprises tri-tert-butylphosphine tetrafluoroborate.
25. A process according to any one of claims 1 to 6, 8 or 9 wherein the conversion of ((3-chloro-7, 8-dihydro-2H-1, 6, 9-trioxa-9 a-borabenzo [ cd ] azulen-2-yl) methyl) carbamate to 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborolan-1 (3H) -ol or a salt thereof comprises Boc-deprotection with sulfuric acid and the reaction product is the sulfate salt of 3- (aminomethyl) -4-chloro-7- (2-hydroxyethoxy) benzo [ c ] [1,2] oxaborolan-1 (3H) -ol.
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| EP23166815 | 2023-04-05 | ||
| EP23166815.3 | 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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