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AN 2898
AN2898
(5-(3,4-dicyanophenoxy)-1-hydroxy -1,3-dihydro-2,1-benzoxaborole)
1,2-Benzenedicarbonitrile, 4-((1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy)-,
AN-2898
cas: 906673-33-4
UNII: 6O60L94RMB,
MW 276.0581, MF C15 H9 B N2 O3
A PDE4 inhibitor potentially for the treatment of fungal infection.
AN-2898, a novel topical anti-inflammatory compound that inhibits phosphodiesterase 4 and 7 enzyme activit
PHASE 2 FUNGAL INFECTION, Anacor Pharmaceuticals for the treatment of atopic dermatitis
Anacor Pharmaceuticals Inc. | |
Description | Boron-containing small molecule phosphodiesterase-4 (PDE-4) inhibitor that reduces the production of tumor necrosis factor (TNF) alpha, IL-12 and IL-23 |
Molecular Target | Phosphodiesterase-4 (PDE-4) |
Mechanism of Action | Phosphodiesterase-4 (PDE-4) inhibitor |
Therapeutic Modality | Small molecule |
AN2898 (5-(3,4-dicyanophenoxy)-1-hydroxy -1,3-dihydro-2,1-benzoxaborole) is a broad spectrum anti-inflammatory compound currently in development for the topical treatment of plaque and atopic psoriasis.
AN2898 inhibited phosphodiesterase 4 (PDE4) enzyme activity (IC50 0.060 μM) and the release of multiple cytokines including TNF-α (IC50 0.16 μM) from peripheral blood mononuclear cells (hPBMCs) stimulated by lipopolysaccharide (LPS) or phytohemag- glutinin.
Further, AN2898 was also found to inhibit IL-23 release (IC50 1.0 μM) from THP-1 cells stimulated by LPS and IFN-γ. Investigation of the structure-activity relation-ship around this compound was reported to identify a more potent dual TNF-α/IL-23 inhibitor
( ref………. Akama T, Antunes J, Freund Y, Kimura R, Dong C, Sanders V, et al. Structure-activity studies of novel oxaborole dual inhibitors of PDE4 and IL-23 release. 69th Annu Meet Soc Invest Dermatol (May 6-9, Montreal) 2009 Abst 282. ).
PATENT
WO 2007095638
https://www.google.co.in/patents/WO2007095638A2?cl=en
PATENT
WO 2006089067
http://www.google.co.in/patents/WO2006089067A2?cl=en
US 7582621
http://www.google.co.in/patents/US7582621
WO 2009111676
http://www.google.im/patents/WO2009111676A2?cl=en
WO 2007078340
http://www.google.im/patents/WO2007078340A2?cl=en
US 20070286822
http://www.google.com/patents/US20070286822
REFERENCES
1 Structure-activity studies led to the discovery of AN2898 in development for topical treatment of psoriasis and atopic dermatitis, J Am Acad Dermatol 2009, 60(3, Suppl. 1): Abst P1317
2 FEBS Letters (2012), 586(19), 3410-3414
See all Bboroles at………http://apisynthesisint.blogspot.in/p/borole-compds.html
/////////AN2898, AN 2898, ANACOR, BOROLE
B1(c2ccc(cc2CO1)Oc3ccc(c(c3)C#N)C#N)O
крисаборол , كريسابورول , Crisaborole, AN 2728
Crisaborole
Treatment for Inflammatory Skin Diseases, including Atopic Dermatitis and Psoriasis
C14H10BNO3, Average mass251.045 Da
4-[(1-Hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile ,
4-((1-Hydroxy-1,3-dihydrobenzo(c)(1,2)oxaborol-6-yl)oxy)benzonitrile
CAS 906673-24-3, AN-2728
Benzonitrile, 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]-
1,3-Dihydro-1-hydroxy-5-(4-cyanophenoxy)-2,1-benzoxaborole
5-(4-Cyanophenoxy)-l, 3-dihydro-l-hydroxy-2, 1-benzoxaborole
crisaborol, crisaborole, Crisaborole, crisaborolum
UNII-Q2R47HGR7P
крисаборол
كريسابورول
In phase 3 for treatment of mild to moderate atopic dermatitis……Anacor Pharmaceuticals, Inc.
Psoriasis is a chronic skin disorder caused by inflammatory cell infiltration into the dermis and epidermis, and is accompanied by keratinocyte hyperproliferation. Once triggered, a strong T-cell response is mounted, and a cascade of cytokine and chemokine production is induced.
Down-regulation of certain cytokines and chemokines is considered to be a good approach to treatment, and indeed, the biologics targeting TNF-α demonstrate the effectiveness of this approach.However, biologics have intrinsic challenges, such as limited administration route, side effects, quality control and production cost.
Small molecule approaches to treat psoriasis include systemic or topical steroids, cyclosporine, psoralen plus UVA (PUVA), retinoids, methotrexete, and vitamin D3 analogs.Atopic dermatitis is an allergic skin disorder, which is typically treated with topical steroids, antihistamines, and calcineurin inhibitors.
However, there is still a need for new treatment with improved safety profile. Recently phosphodiesterase 4 (PDE4) inhibitors have been in development for such skin diseases. CC-10004 is in development as an oral treatment for psoriasis and atopic dermatitis. AWD-12-281 was, until recently, in development for the topical treatment of atopic dermatitis. In addition, roflumilast is under Phase 1 development for both diseases.
Figure 1.
PDE4 inhibitors aiming at skin inflammatory diseases.
Anacor’s lead product candidate is crisaborole, an investigational non-steroidal topical PDE-4 inhibitor in development for the potential treatment of mild-to-moderate atopic dermatitis and psoriasis
crisaborole is an investigational topical antiinflammatory drug in phase III clinical development by Anacor Pharmaceuticals for the treatment of mild to moderate atopic dermatitis and in phase II clinical trials in mild to moderate psoriasis
A novel boron-containing small molecule, Crisaborole inhibits the release of pro-inflammatory cytokines including TNF-alpha, IL-12, and IL-23, known mediators of the inflammation associated with psoriasis.
Synthesis
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PAPER
Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis
Bioorg Med Chem Lett 2009, 19(8): 2129
http://www.sciencedirect.com/science/article/pii/S0960894X09002996
- Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA
A series of phenoxy benzoxaboroles were synthesized and screened for their inhibitory activity against PDE4 and cytokine release. 5-(4-Cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2728) showed potent activity both in vitro and in vivo. This compound is now in clinical development for the topical treatment of psoriasis and being pursued for the topical treatment of atopic dermatitis
Scheme 1.
Reagents and conditions: (a) ethylene glycol, p-TsOH, toluene, reflux, 6 h (quant.); (b) K2CO3, DMF, 100 °C, overnight (82–96%); (c) 3 M HCl, THF, reflux, 2 h (80–100%); (d) NaBH4, MeOH, rt, 1 h (quant.); (e) 3,4-dihydro-2H-pyran, camphorsulfonic acid, CH2Cl2, rt, 2 h (quant.); (f) (i-PrO)3B, n-BuLi, THF, −78 °C to rt, 3 h; (g) 6 M HCl, THF, rt, 3 h (37–44%); (h) 6 M NaOH, MeOH, 1,4-dioxane, reflux, 6 days (79%); (i) diethylamine (for 5f) or morpholine (for 5g), EDCI, HOBt, DMAP, DMF, rt, overnight (41–70%).
PATENT
http://www.google.co.in/patents/WO2006089067A2?cl=en
4.2. q 5-(4-Cyanophenoxy)-l, 3-dihydro-l-hydroxy-2, 1-benzoxaborole (C17) [0264] 1H-NMR (300 MHz,
δ ppm 4.95 (s, 2H), 7.08 (dd, J= 7.9, 2.1 Hz, IH), 7.14 (d, J= 8.8 Hz, IH), 7.15 (d, J= 2.1 Hz, IH), 7.78 (d, J= 7.9 Hz, IH), 7.85 (d, J= 9.1 Hz, 2H), 9.22 (s, IH).
PATENT
EXAMPLE 15
http://www.google.com/patents/WO2007095638A2?cl=en
4-(4-Cvanophenoxy)phenylboronic acid (C97)
(a) (4-cyanophenyl) (4-bromophenyl) ether. Under nitrogen, the mixture of 4-fluorobenzonitrile (7.35 g, 60.68 mmol), 4-bromophenol (10 g, 57.8 mmol) and potassium carbonate (12 g, 1.5 eq) in DMF (100 mL) was stirred at 1000C for 16 h and then filtered. After rotary evaporation, the residue was dissolved in ethyl acetate and washed with IN NaOH solution to remove unreacted phenol. The organic solution was dried and passed through a short silica gel column to remove the color and minor phenol impurity. Evaporation of the solution gave (4-cyanophenyl)(4- bromophenyl)ether (13.82 g, yield 87.2%) as a white solid. 1H NMR (300 MHz, DMSO-de): δ 7.83 (d, 2H), 7.63 (d, 2H), 7.13 (d, 2H) and 7.10 (d, 2H) ppm.
(b) 4-(4-cyanophenoxy)phenylboronic acid. The procedure described in Example 2d was used for the synthesis of 4-(4-cyanophenoxy)phenylboronic acid using (4-cyanophenyl)(4-bromophenyl)ether as starting material. The title compound was obtained as a white solid. M.p.l94-198°C. MS: m/z = 239 (M+), 240 (M+ 1) (ESI+) and m/z = 238 (M-I) (ESI-). HPLC: 95.3% purity at 254 nm and 92.1% at 220 nm. 1H NMR (300 MHz, DMSO-d6 + D2O): δ 7.83-7.76 (m, 4H), 7.07 (d, 2H) and 7.04 (d, 2H) ppm.
FURTHER METHOD
2-Bromo-5-(4-cvanophenoxy)benzyl Alcohol
1H-NMR (300 MHz, CDCl3) δ (ppm) 2.00 (br s, IH), 4.75 (s, 2H), 6.88 (dd, J= 8.5, 2.9 Hz, IH), 7.02 (d, J= 8.8 Hz, IH), 7.26 (d, J= 2.6 Hz, IH), 7.56 (d, J = 8.5 Hz, IH), 7.62 (d, J= 8.8 Hz, 2H).
PATENT
http://www.google.im/patents/EP1976536A2?cl=en
2.2.a 2-Bromo-5-(4-cyanophenoxy)benzyl Alcohol
1H-NMR (300 MHz, CDCl3) δ (ppm) 2.00 (br s, IH), 4.75 (s, 2H), 6.88 (dd, J= 8.5, 2.9 Hz, IH), 7.02 (d, J= 8.8 Hz, IH), 7.26 (d, J- 2.6 Hz, IH), 7.56 (d, J = 8.5 Hz, IH), 7.62 (d, J= 8.8 Hz, 2H).
2.2.b 2-Bromo-4-(4-cyanophenoxγ)benzyl Alcohol
1H NMR (300 MHz, DMSO-d6): δ 7.83 (d, 2H), 7.58 (d, IH), 7.39 (d, IH), 7.18 (dd, IH), 7.11- (d, 2H), 5.48 (t, IH) and 4.50 (d, 2H) ppm.
2.2.c 5- (4-Cyanophenoxy) -1 -Indanol
M.p.50-53°C. MS (ESI+): m/z = 252 (M+l). HPLC: 99.7% purity at 254 nm and 99.0% at 220 nm. 1H NMR (300 MHz, DMSOd6): δ 7.80 (d, 2H), 7.37 (d, IH), 7.04 (d, 2H), 6.98-6.93 (m, 2H), 5.27 (d, IH)5 5.03 (q, IH), 2.95-2.85 (m, IH), 2.75-2.64 (m, IH), 2.39-2.29 (m, IH) and 1.85-1.74 (m, IH) ppm.
2.2. d 2-Bromo-5-(tert-butyldimethylsiloxy)benzyl Alcohol [0429] 1H-NMR (300 MHz, CDCl3) δ (ppm) 0.20 (s, 6H), 0.98 (s, 9H), 4.67 (br s,lH), 6.65 (dd, J= 8.2, 2.6 Hz, IH), 6.98 (d, J= 2.9 Hz, IH), 7.36 (d, J= 8.8 Hz, IH).
3.2.k 2-Bromo-5-(2-cyanophenoχy)-l-(methoxymethoxymethyl)benzene [0443] 1H-NMR (300 MHz, CDCl3) δ (ppm) 3.41 (s, 3H), 4.64 (s, 2H), 4.76 (s, 2H), 6.8-6.9 (m, 2H), 7.16 (td, J= 7.6, 0.9 Hz, IH), 7.28 (d, J= 2.9 Hz, IH), 7.49 (ddd, J= 8.8, 7.6, 1.8 Hz, IH)5 7.56 (d, J= 8.5 Hz, IH), 7.67 (dd, J= 7.9, 1.8 Hz, IH).
EXAMPLE 32
Alternative Preparation of C17 -Intermediate
The procedure described in Example II I was followed for 1H NMR characterization of the current alcohol-borate intermediate. 1H NMR determination indicated there were 72.7 mol% of the desired alcohol-borate intermediate [2-bromo- 5-(4-cyanophenoxy)benzyl] diisopropyl borate, 20.7 mol% of an unknown intermediate and 6.5 mol% of unreacted alcohol. 1H NMR (CDCl3, 300 MHz) of [2- bromo-5-(4-cyanophenoxy)benzyl] diisopropyl borate: δ= 7.61 (d, J= 9.0 Hz, 2H), 7.52 (d, J= 8.4 Hz, IH), 7.15 (d, J= 3.0 Hz, IH), 7.03 (d, J= 8.7 Hz, 2H), 6.84 (dd, J= 8.7 Hz, J= 3.0 Hz, IH), 4.85 (s, 2H), 4.35 (septet, J= 6.1 Hz, 2H), 1.11 (d, J= 6.1 Hz, 12H) ppm.
PATENT
http://www.google.com/patents/US20090291917
- Example 154-(4-Cyanophenoxy)phenylboronic acid (C97)
-
(a) (4-cyanophenyl)(4-bromophenyl)ether. Under nitrogen, the mixture of 4-fluorobenzonitrile (7.35 g, 60.68 mmol), 4-bromophenol (10 g, 57.8 mmol) and potassium carbonate (12 g, 1.5 eq) in DMF (100 mL) was stirred at 100° C. for 16 h and then filtered. After rotary evaporation, the residue was dissolved in ethyl acetate and washed with 1N NaOH solution to remove unreacted phenol. The organic solution was dried and passed through a short silica gel column to remove the color and minor phenol impurity. Evaporation of the solution gave (4-cyanophenyl)(4-bromophenyl)ether (13.82 g, yield 87.2%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.83 (d, 2H), 7.63 (d, 2H), 7.13 (d, 2H) and 7.10 (d, 2H) ppm.
-
(b) 4-(4-cyanophenoxy)phenylboronic acid. The procedure described in Example 2d was used for the synthesis of 4-(4-cyanophenoxy)phenylboronic acid using (4-cyanophenyl)(4-bromophenyl)ether as starting material. The title compound was obtained as a white solid. M.p. 194-198° C. MS: m/z=239 (M+), 240 (M+1) (ESI+) and m/z=238 (M−1) (ESI−). HPLC: 95.3% purity at 254 nm and 92.1% at 220 nm. 1H NMR (300 MHz, DMSO-d6+D2O): δ 7.83-7.76 (m, 4H), 7.07 (d, 2H) and 7.04 (d, 2H) ppm.
see
http://www.google.co.in/patents/WO2006089067A2?cl=en
see
http://www.google.com/patents/US20090291917
US5688928 * | Jun 7, 1995 | Nov 18, 1997 | Prolinx, Inc. | Phenylboronic acid complexing reagents derived from aminosalicylic acid |
US5880188 * | May 26, 1995 | Mar 9, 1999 | Zeneca Limited | Oxaboroles and salts thereof, and their use as biocides |
US5962498 * | Dec 2, 1994 | Oct 5, 1999 | Procyon Pharmaceuticals, Inc. | Protein kinase C modulators. C. indolactam structural-types with anti-inflammatory activity |
US6369098 * | Oct 4, 2000 | Apr 9, 2002 | Bethesda Pharmaceuticals, Inc. | Dithiolane derivatives |
US20030032673 * | Jul 19, 2002 | Feb 13, 2003 | Isis Innovation Limited | Therapeutic strategies for prevention and treatment of alzheimer’s disease |
US20050239170 * | Jul 16, 2001 | Oct 27, 2005 | Hedley Mary L | Alpha-MSH related compounds and methods of use |
US20060009386 * | May 12, 2005 | Jan 12, 2006 | The Brigham And Women’s Hospital, Inc. | Use of gelsolin to treat infections |
Methods of treating anti-inflammatory conditions through the use of boron- containing small molecules are disclosed.
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… Francisco, CA Mar. 6-10, 2009. 6, “AN2728 … Francisco, CA Mar. 6-10, 2009. 7 , “AN2728 … Kyoto, Japan, May 14-18, 2008. 10, “AN2728 …
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AN2728, 5-(4-cyanophenoxy)-2,3- dihydro-1-hydroxy-2,1- …. UK-500,001, AN2728, DE-103, Tofisopam, Dextofisopam, Levotofisopam (USAN).
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… Dermatology Annual Meeting, San Francisco, CA Mar. 6-10, 2009. 6, “AN2728 … 7, “AN2728 … Francisco, CA May 6-10, 2009. 10, “AN2728 …
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… from the group consisting of AN-2728, AN-2898, CBS- 3595, apremilast, ELB- 353, KF-66490, K-34, LAS-37779, IBFB-211913, AWD-12-281, …
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“AN2728” is the compound 4-(l-hydroxy-l,3-dihydro-2 … GSK256066, oglemilast, tetomilast, apremilast, AN2728, Compound A, Compound B, …
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AN2728, 5-(4-cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1- …. UK-500,001, AN2728, DE-103, Tofisopam, Dextofisopam, Levotofisopam (USAN).
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85.用于治疗疼痛的UK-500,001。 85. for the treatment of pain UK-500,001. 86.用 于治疗疼痛的AN2728。 86. for the treatment of pain AN2728.
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see full series on boroles
http://apisynthesisint.blogspot.in/p/borole-compds.html
http://apisynthesisint.blogspot.in/p/borole-compds.html
http://apisynthesisint.blogspot.in/p/borole-compds.html
do not miss out
///////////crisaborole, AN 2728, PHASE 3, Anti-inflammatory, Phosphodiesterase, Oxaborole, Psoriasis, Atopic dermatitis, borole
AN 3485
AN 3485
AN3485,
6-(4-(aminomethyl)-2-chlorophenoxyl)benzo[c][1,2]oxaborol-1(3H)-ol,
was synthesized at Anacor Pharmaceuticals as described in patent application WO 2010028005
A1
6-[4-(Aminomethyl)-2-chlorophenoxy]-2,1-benzoxaborol-1(3H)-ol hydrochloride
http://jpet.aspetjournals.org/content/early/2012/11/28/jpet.112.200030.full.pdf
Pro-inflammatory cytokines play a critical role in the development of autoimmune and
inflammatory diseases. Targeting the cytokine environment has proven efficient for averting
inflammation. In this study, we reported that 6-(4-(aminomethyl)-2-
chlorophenoxyl)benzo[c][1,2]oxaborol-1(3H)-ol (AN3485), a benzoxaborole analog, inhibited
TLR2-, TLR3-, TLR4- and TLR5-mediated TNF-α, IL-1β and IL-6 release from human PBMCs
and isolated monocytes with IC50s ranging from 18 to 580 nM, and the inhibition was mediated
at the transcriptional level. Topical administration of AN3485 significantly reduced PMAinduced contact dermatitis and oxazolone-induced delayed-type hypersensitivity in mice,
indicating its capability of penetrating skin and potential topical application in skin
inflammation. Oral administration of AN3485 showed dose-dependent suppression of LPSinduced TNF-α and IL-6 production in mice with an ED90 of 30 mg/kg. Oral AN3485, 35
mg/kg, twice a day, suppressed collagen-induced arthritis in mice over a 20-day period. The
potent anti-inflammatory activity in in vitro and in vivo disease models makes AN3485 an
attractive therapeutic lead for a variety of cutaneous and systemic inflammatory diseases
A new class of boron-containing small molecules has been developed over the past several
years as potential drugs. Different from carbon, boron contains an electrophilic empty p-orbital
which can form transient bonds with nucleophiles in an enzyme active site, which mimics a
tetrahedral transition state of peptide bond cleavage in an enzymatic reaction (Baker et al., 2011).
The benzoxaboroles, in which the boron atom is incorporated into a heteroaromatic ring system,
are able to inhibit a number of important enzymes, including bacterial and fungi Leucyl-tRNA
synthetase (Rock et al., 2007), human phosphodiesterase-4 (PDE4) (Akama et al., 2009) and
HCV NS3/4A protease (Li et al., 2010). Three benzoxaboroles, AN2690 (Tavaborole), AN2728
and AN3365 (GSK’052) are in clinical trials for treatment of onychomycosis, psoriasis/atopic dermatitis and Gram-negative bacterial infection, and have been proven safe in human when
applied topically or systemically
……………………………………………………….
Structure-activity relationships of 6-(aminomethylphenoxy)-benzoxaborole derivatives as anti-inflammatory agent
Bioorg Med Chem Lett 2013, 23(6): 1680
http://www.sciencedirect.com/science/article/pii/S0960894X13001054
Scheme 2.
Synthesis of compounds 9a–e. Reagents and conditions: (a) K2CO3, DMSO, 80–90 °C, overnight (33–61%); (b) LAH, THF, 0 °C to rt, 1 h, then 4 M HCl in 1,4-dioxane (43–68%); (c) aq NaOH, MeOH, 50 °C, 2 h (61%), (d) Ac2O, pyridine, rt (79%).
…………………………………………………………
Patent
https://www.google.com/patents/WO2010028005A1?cl=en
(X) IS AN 3485
Compound 2:
To a solution of 2-hydroxy-4-methoxy-benzaldehyde (30 g, 197 mmol) in DCM (anhydrous, 120 rnL) was added pyridine (79 mL, 986 mmol) at room temperature. After the mixture was cooled to -10 0C, the Tf2O (50 mL, 296 mmol) was slowly added to the reaction between -10 0C to 0 0C. The addition took about 2.5 hours. After the addition, the stirring was kept for 30 minutes. The EtOAc (200 mL) was added. The organic layer was washed with 1 M HCl (3 X 80 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified over silica gel, eluting with 5% EtOAc / hexanes to give trifluoro-methanesulfonic acid 2- formyl-5-methoxy-phenyl ester (2) 46 g in 82% yield. 1H NMR (400 MHz,
CHLOROFORM-^) δ ppm 10.13 (s, 1 H), 7.95 (d, J=8.99 Hz, 1 H), 7.03 (dd, J=8.60, 2.34 Hz, 1 H), 6.88 (d, J=2.34 Hz, 1 H), 3.93 (s, 3 H)
Compound 3:
To a solution of trifluoro-methanesulfonic acid 2-formyl-5-methoxy-phenyl ester (2) (46 g, 160 mmol) in 1,4-dioxane (anhydrous, 360 rnL) were added bis(pinacolato)diboron (82.3 g, 320 mmol), [l,l ‘-bis(diphenylphosphino)ferrocene] palladium(II)chloride (23.7 g, 32 mmol) and KOAc (47.6 g, 480 mmol). The mixture was stirred at room temperature with N2bubbling for 30 minutes. Then the reaction was heated at 100 0C for 3 hours. The solution was filtered, evaporated under vacuum. The residue was purified over silica gel, eluting with 20% EtOAc / hexanes to afford 4-methoxy-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzaldehyde (3) 37.8 g in 90% yield. 1H NMR (400 MHz, CHLOROFORM- d) δ ppm 10.34 (s, 1 H), 7.90 (d, J=8.60 Hz, 1 H), 7.26 (s, 1 H), 6.99 (d, J=8.60 Hz, 1 H), 3.86 (s, 3 H), 1.36 (s, 12 H)
Compound 4:
To a clear solution of 4-methoxy-2-(4,4,5,5-tetramethyl-
[l,3,2]dioxaborolan-2-yl)-benzaldehyde (3) (48 g, 180 mmol) in MeOH (anhydrous, 300 mL) was slowly added NaBH4 (6.96 g, 180 mmol). The reaction was stirred at room temperature for 2 hours. Then IM HCl (100 mL) was slowly added. After stirring for overnight, the MeOH was evaporated under vacuum. The solid was filtered, washed with water and air-dried to afford 6-methoxy-3H- benzo[c][l,2]oxaborol-l-ol (4) 23 g in 77% yield. 1H NMR (400 MHz, DMSO-J6) δ ppm 9.11 (s, 1 H), 7.29 (d, J=8.21 Hz, 1 H), 7.23 (d, J=2.34 Hz, 1 H), 7.03 (dd, J=8.40, 2.54 Hz, 1 H), 4.90 (s, 2 H), 3.75 (s, 3 H).
Compound 5:
To a clear solution of 6-methoxy-3H-benzo[c][l,2]oxaborol-l-ol (4) (600 mg, 3.66 mmol) in DCM (anhydrous, 60 mL) was slowly added BBr3 (1M/DCM, 8.05 mL, 8.05 mmol) at -10 0C. The reaction was stirred for 3 hours, with monitoring by NMR. After all 4 had gone, 30 mL of cold water was added. Then 50 mL of EtOAc was added to extract all organic compounds. The organic layer was washed with cold brine, until the pH of aqueous layer changed to pH 7. The organic layer was dried over Na2SO4, filtered, evaporated under vacuum. The residue (-85% HPLC purity) was used directly for the next step reaction without further purification. 1H NMR (400 MHz, DMSO-J6) δ ppm 9.29 (s, 1 H), 9.04 (s, 1 H), 7.17 (d, J=8.21 Hz, 1 H), 7.07 (d, J=2.34 Hz, 1 H), 6.85 (dd, J=8.21, 2.34 Hz, 1 H), 4.85 (s, 2 H). ESMS (m/z): 149 (M- H)“. HPLC: 88.31% (220 nm), 85.02% (maxplot).
Compound 6:
To a solution of 3H-benzo[c][l,2]oxaborole-l,6-diol (5) (300 mg, 2 mmol) in DMSO (30 mL) were added K2CO3 (828 mg, 6 mmol) and 3-chloro-4-fiuoro- benzonitrile (933 mg, 6 mmol). The reaction was heated at 90 0C for 7 hours. After the cooling of reaction solution, EtOAc (50 mL) was added. The organic layer was washed with water (5 X 50 mL). The organic layer was evaporated under vacuum. The residue was purified by reverse phase chromatography to afford 3-chloro-4-(l- hydroxy-l,3-dihydro-benzo[c][l,2]oxaborol-6-yloxy)-benzonitrile (6) 190 mg in 33.3% yield. 1H NMR (400 MHz, DMSO-J6) δ ppm 9.24 (s, 1 H), 8.22 (s, 1 H), 7.77 (d, J=7.81 Hz, 1 H), 7.50 (d, J=8.20 Hz, 1 H), 7.34 (s, 1 H), 7.28 (d, J=8.20 Hz, 1 H), 7.01 (d, J=8.59 Hz, 1 H), 4.99 (s, 2 H). ESMS (m/z): 284 (M-H)“. HPLC: 96.41% (220 nm), 96.0% (maxplot).
(X): IS AN 3485
To a clear solution of 3-chloro-4-(l-hydroxy-l,3-dihydro- benzo[c][l,2]oxaborol-6-yloxy)-benzonitrile (6) (136 mg, 0.48 mmol) in THF
(anhydrous, 60 mL) was added lithium aluminum hydride (lM/ether, 1.19 mL, 1.19 mmol) at 0 0C. The reaction was stirred for 2 hours. Then the reaction was quenched with IM HCl (30 mL). MeOH (50 mL) was added and the solution was filtered. The filtrate was evaporated under vacuum. The residue was purified by reverse phase chromatography (biotage, gradient MeOH / H2O from 10% to 100%) to afford (X) 106 mg (white solid) in 68% yield. 1H NMR (400 MHz, DMSO-J6) δ ppm 9.19 (s, 1 H), 8.18 (br, s, 3 H), 7.75 (s, IH), 7.44-7.39 (m, 2 H), 7.19-7.10 (m, 3 H), 4.98 (s, 2 H), 4.03 (q, J=5.50 Hz, 2 H).
ESMS (m/z): 290 (M+H)+.
HPLC: 95.9% (220 nm), 96.85% (maxplot).
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