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GDC 0575

GDC-0575
CAS:  1196541-47-5

C16 H20 Br N5 O, 378.27

(R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-indol-3-yl)cyclopropanecarboxamide

N-[4-[(3R)-3-Amino-1-piperidinyl]-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]cyclopropanecarboxamide

Cyclopropanecarboxamide, N-[4-[(3R)-3-amino-1-piperidinyl]-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-

ARRY-575; GDC-0575; RG 7741; RO 6845979,
  • AK 687476
  • ARRY 575
  • GDC 0575
  • RG 7741

Image result for gdc 0575

GDC-0575, also known as ARRY-575 and RG7741, is a potent and selective CHK1 inhibitor.

GDC-0575 is a highly selective small-molecule Chk-1 inhibitor invented by Array and licensed to Genentech.  Genentech is responsible for all clinical development and commercialization activities. Array received an upfront payment of $28 million and is eligible to receive clinical and commercial milestone payments up to $380 million and up to double-digit royalties on sales.

Chk-1 is a protein kinase that regulates the tumor cell’s response to DNA damage often caused by treatment with chemotherapy. In response to DNA damage, Chk-1 blocks cell cycle progression in order to allow for repair of damaged DNA, thereby limiting the efficacy of chemotherapeutic agents. Inhibiting Chk-1 in combination with chemotherapy can enhance tumor cell death by preventing these cells from recovering from DNA damage. GDC‑0575 is designed to enhance the efficacy of some chemotherapeutic agents.  GDC-0575 is currently advancing in a Phase 1 trial in patients with lymphoma or solid tumors.

  • Originator Array BioPharma
  • Developer Genentech
  • Class Antineoplastics; Small molecules
  • Mechanism of Action Checkpoint kinase 1 inhibitors

Highest Development Phases

  • Phase I Lymphoma; Solid tumours

Most Recent Events

  • 11 Jan 2018 Genentech completes a phase I trial in Lymphoma (Late-stage disease, Metastatic disease, Second-line therapy or greater, Combination therapy, Monotherapy) in France and USA (PO) (NCT01564251)
  • 05 Dec 2017 GDC 0575 is still in phase I trials for Solid tumours and lymphoma in USA and France (Genentech pipeline, December 2017) (NCT01564251)
  • 04 Nov 2017 No recent reports of development identified for phase-I development in Lymphoma in France (PO)

 Array BioPharma

PATENTS

U.S. Patent, 8,841,304

U.S. Patent 8,178,131,

PAPER

Org. Process Res. Dev. 201721664– 668 

Highly Regioselective and Practical Synthesis of 5-Bromo-4-chloro-3-nitro-7-azaindole

 Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
 Department of Pharma Technical Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, CH-4070 Basel, Switzerland
Org. Process Res. Dev.201721 (4), pp 664–668
DOI: 10.1021/acs.oprd.7b00060
Abstract Image

We report an efficient and highly regiocontrolled route to prepare a functionalized 7-azaindole derivative—5-bromo-4-chloro-3-nitro-7-azaindole—from readily available parent 7-azaindole featuring a highly regioselective bromination of the 4-chloro-3-nitro-7-azaindole intermediate. In addition to the high efficiency and excellent control of regioisomeric impurities, the process is operationally simple by isolating each product via direct crystallization from the reaction mixture with no liquid–liquid extractions or distillation steps needed. We demonstrated the route on >50 kg scale and 46% overall yield to provide the target product in 97% purity by HPLC, which can serve as a useful building block for the preparation of a series of 3,4,5-substituted-7-azaindole derivatives.

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.7b00060/suppl_file/op7b00060_si_001.pdf

-Bromo-4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (1)(10)

Into ………….. afford 5-bromo-4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine 1 as a tan solid (66.4 kg, 96.2 wt %, 90% yield, 96.9 A % HPLC; unreacted starting material 5: 0.99 A% HPLC; impurity 8: 0.95 A% HPLC): mp 269 °C dec; 1H NMR (300 MHz, DMSO-d6) δ 13.68 (s, 1H), 8.93 (s, 1H), 8.66 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 146.9, 146.4, 133.9, 133.2, 12

PATENT

WO 2010118390

https://patents.google.com/patent/WO2010118390A1/und

PATENT

WO 2015027090

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015027090

PATENT

WO 2015027092

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015027092&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 1: Preparation of (i?)-5-bromo-4-(3-amino)piperidin-l-yl)-3- (cyclopropanecarboxamido)-lH-pyrrolo[2,3-&]pyridine:

[0096] Step 1 : Preparation of (i?)-5-bromo-4-(3-(/ert-butoxycarbonylamino)piperidin-l-yl)-3-nitro-lH-pyrrolo[2,3-6]pyridine:

[0097] To an inerted 10 L jacket reactor, equipped with a mechanic stirrer, a nitrogen/vacuum manifold, a thermocouple, and a condenser, were charged 2-methyl-2-butanol (3.30 L), 5-bromo-4-chloro-3-nitro-lH-pyrrolo[2,3-6]pyridine (330 g, 1.00 equiv), (R)-tert-butyl piperidin-3-ylcarbamate (456 g, 2.00 equiv), and N-methylmorpholine (115 g, 1.00 equiv). The reaction mixture was stirred at 85 °C for 48 h and cooled to 20 °C. The mixture was then washed with 15 wt % citric acid aqueous solution (3.30 kg) and water (3.30 kg). The majority of 2-methyl-2-butanol was distilled off under vacuum at 50 °C. Acetonitrile was added to bring the mixture back to its original volume. Continuous distillation was conducted until a total of 10.3 kg of acetonitrile was added. Water (3.20 kg) was slowly charged to the suspension over approximately 1 h at 55 °C. The slurry was slowly cooled to 20 °C over 4 h. The resulting solid was collected by filtration and washed with a 1 : 1 (v/v) mixture of acetonitrile and water (1.60 L). The product was dried in a vacuum oven under nitrogen at 70 °C to provide 358 g (69% yield) of (i?)-5-bromo-4-(3-(ter/-butoxycarbonylamino)piperidin-l-yl)-3-nitro-lH-pyrrolo[2,3-6]pyridine as a yellow solid. !H NMR (600 MHz, DMSO-i/6): δ 13.12 (s, 1H), 8.60 (s, 1H), 8.39 (s, 1H), 6.80 (d, J= 6.8 Hz, 1H), 3.49 (m, 1H), 3.34 (m, 2H), 3.22 (t, J = 11.2 Hz, 1H), 3.00 (t, J = 10.2 Hz, 1H), 1.88 (dd, J = 12.3, 2.8 Hz, 1H), 1.74 (m, 2H), 1.38 (m, 1H), 1.34 (s, 9H). 13C NMR (150 MHz, DMSO-<¾): δ 154.8, 148.9, 148.2, 147.9, 130.6, 128.5, 113.8, 109.6, 77.6, 54.7, 48.9, 47.3, 30.0, 28.1 (3C), 24.2. HRMS-ESI (m/z): [M + H]+ calcd for C17H23BrN504, 440.0928; found, 440.0912.

[0098] Steps 2 and 3: Preparation of (i?)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin- 1 -yl)-3 -(cyclopropanecarboxamido)- 1 H-pyrrolo[2,3 -&]pyridine:

[0099] To an inerted 1 L pressure reactor were charged (i?)-5-bromo-4-(3-(tert-

butoxycarbonylamino)piperidin-l-yl)-3-nitro-lH-pyrrolo[2,3-6]pyridine (75.0 g, 1.00 equiv), 1% Pt + 2% V/C (11.3 g, 15 wt %), N-methylmorpholine (29.3 g, 1.70 equiv), and 2-MeTHF (750 mL). The reaction mixture was stirred at 50 °C at 5 bar of hydrogen for a minimum of 2 h. Cyclopropanecarbonyl chloride (26.7 g, 1.50 equiv) was charged into the reactor over 10 min at 15 °C. The reaction mixture was stirred at 25 °C for 1 h and filtered through Celite. The cake was washed with 2-MeTHF (150 mL). The filtrate was washed with 15 wt % aqueous ammonium chloride solution (450 mL) and water (450 mL) and then distilled in vacuo to 1/3 of it’s original volume. Toluene was added to bring the solution back to its original volume. Continuous vacuum distillation was conducted at 55 °C while adding toluene until the 2-MeTHF was below 2 wt %. The resulting solid was isolated by filtration, washed with toluene and dried in a vacuum oven at 40 °C overnight to give 69.8 g (69% corrected yield) of (i?)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-l-yl)-3-(cyclopropanecarboxamido)-lH-pyrrolo[2,3-6]pyridine (1 :1 toluene solvate) as an off-white solid. 1H NMR (600 MHz, THF-i 8, 4 °C): δ 10.76 (s, 1H), 9.72 (s, 1H), 8.15 (s, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.18-7.08 (m, 5H), 6.41 (d, J = 7.8 Hz, 1H), 3.82 (m, 1H), 3.60 (m, 1H), 3.44 (t, J = 10.6 Hz, 1H), 3.30 (dd, J= 10.6, 3.9 Hz, 1H), 3.03 (d, J = 10.9 Hz, 1H), 2.29 (s, 3H), 2.08 (m, 1H), 1.89 (m, 2H), 1.66 (m, 1H), 1.37 (s, 9H), 1.36 (m, 1H), 0.95-0.80 (m, 4H). 13C NMR (150 MHz, THF-ci8, 4 °C): δ 170.0, 155.8, 149.0, 147.8, 147.6, 138.4, 129.6 (2C), 128.9 (2C), 126.0, 116.6, 115.6, 111.9, 108.8, 78.5, 55.8, 50.2, 49.1, 31.8, 28.6 (3C), 26.3, 21.5, 15.8, 7.70, 7.56. HRMS-ESI (m/z): [M + H]+ calcd for C21H29BrN503, 478.1448; found, 478.1431.

[00100] Step 4: Preparation of (i?)-5-bromo-4-(3-amino)piperidin-l-yl)-3-(cyclopropanecarboxamido)- 1 H-pyrrolo [2,3 -6]pyridine :

[00101] To an inerted 1 L jacket reactor, equipped with a mechanic stirrer, a nitrogen/vacuum manifold, a thermocouple, and a condenser, were charged (i?)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-l-yl)-3-nitro-lH-pyrrolo[2,3-0]pyridine (1 : 1 toluene solvate) (30.0 g, 1.00 equiv), tetrahydrofuran (180 mL, 6.00 mL/g), followed by 4.5 M sulfuric acid (36.1 mL, 3.00 equiv). The reaction mixture was stirred at 50 ± 5 °C for 2 h and then cooled to 20 °C. An aqueous piperazine solution (42.4 g dissolved in 190 mL of water) was added slowly at 25 °C followed by addition of 15.0 mL of sat’d brine. The aqueous bottom layer was removed. The resulting solution was stirred at 20 °C for 5 min. Water (22.0 mL) was added. Continuous distillation was conducted at 50 °C by adjusting the feed rate of ethanol to match the distillation rate until a total of 260 mL of ethanol was added. Water (340 mL) was added at 50 °C over 1 h. The resulting solid was isolated by filtration, washed with 20% ethanol in water (2 x 60 mL) and dried in a vacuum oven at 50 °C overnight to give 16.4 g (78% corrected yield) of (i?)-5-bromo-4-(3-amino)piperidin-l-yl)-3-(cyclopropanecarboxamido)-l H-pyrrolo [2,3 -b]pyridine as a light yellow solid. (Note: The proton ( H) and carbon- 13 ( C) spectra of freebase product are very broad. Therefore, the spectra shown below are of freebase converted to a bis-HCl salt.) 1H NMR (300 MHz, DMSC ): δ 11.98 (br, 1H), 9.78 (s, 1H), 8.44 (br, 3H), 8.25 (s, 1H), 7.45 (d, J = 2.4 Hz, 1H), 3.57 (m, 1H), 3.43 (m, 1H), 3.41 (m, 1H), 3.28 (m, 1H), 3.14 (m, 1H), 2.15 (m, 1H), 1.90 (penta, J = 6.5 Hz, 1H), 1.81 (m, 1H), 1.72 (m, 1H), 1.52 (m, 1H), 0.83 (m, 4H). 13C NMR (75 MHz, DMSO- 6): 5 172.9, 149.5, 145.9, 145.1, 121.9, 114.2, 113.1, 107.8, 53.8, 51.1, 47.5, 28.6, 24.37, 14.7, 7.55, 7.45. HRMS-ESI (m/z): [M + H]+ calcd for C16H21BrN50, 378.0924; found, 378.0912.

[00102] Example 2:

[00103] Alternatively, the compound (i?)-5-bromo-4-(3-(fer/-butoxycarbonylamino)piperidin- 1 -yl)-3 -(cyclopropanecarboxamido)- 1 H-pyrrolo [2,3 -£]pyridine can be prepared from 5-bromo-4-chloro-3-nitro-lH-pyrrolo[2,3-b]pyridine and (^)-tert-butyl piperidin-3-ylcarbamate via a through process without isolating (i?)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-l-yl)-3-nitro-lH-pyrrolo[2,3-6]pyridine. The changes to existing procedure are shown as below: The solution of (i?)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin- 1 -yl)-3 -nitro- 1 H-pyrrolo [2,3 -6]pyridine was hydrogenated directly in 2-methyl-2-butanol after aqueous washes with 15 wt % citric acid aqueous solution (10.0 g/g) and water (10.0 g/g). The solution concentration in 2-methyl-2-butanol was determined by HPLC weight assay.

PATENT

WO 2016138458

CHK1 is a serine/threonine kinase that regulates cell-cycle progression and is a main factor in DNA-damage response within a cell. CHK1 inhibitors have been shown to sensitize tumor cells to a variety of genotoxic agents, such as chemotherapy and radiation. U.S. Pat. No. 8,178,131 discusses a number of inhibitors of CHK1, including the compound (i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (Compound 1), which is being investigated in clinical trials for the treatment of various cancers.

Compound 1

PATENT

U.S. Patent Application, 20160200723

Example 1 Preparation of (R)-5-bromo-4-(3-amino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine

Step 1: Preparation of (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine

To an inserted 10 L jacket reactor, equipped with a mechanic stirrer, a nitrogen/vacuum manifold, a thermocouple, and a condenser, were charged 2-methyl-2-butanol (3.30 L), 5-bromo-4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (330 g, 1.00 equiv), (R)-tert-butyl piperidin-3-ylcarbamate (456 g, 2.00 equiv), and N-methylmorpholine (115 g, 1.00 equiv). The reaction mixture was stirred at 85° C. for 48 h and cooled to 20° C. The mixture was then washed with 15 wt % citric acid aqueous solution (3.30 kg) and water (3.30 kg). The majority of 2-methyl-2-butanol was distilled off under vacuum at 50° C. Acetonitrile was added to bring the mixture back to its original volume. Continuous distillation was conducted until a total of 10.3 kg of acetonitrile was added. Water (3.20 kg) was slowly charged to the suspension over approximately 1 h at 55° C. The slurry was slowly cooled to 20° C. over 4 h. The resulting solid was collected by filtration and washed with a 1:1 (v/v) mixture of acetonitrile and water (1.60 L). The product was dried in a vacuum oven under nitrogen at 70° C. to provide 358 g (69% yield) of (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine as a yellow solid. 1H NMR (600 MHz, DMSO-d6): δ 13.12 (s, 1H), 8.60 (s, 1H), 8.39 (s, 1H), 6.80 (d, J=6.8 Hz, 1H), 3.49 (m, 1H), 3.34 (m, 2H), 3.22 (t, J=11.2 Hz, 1H), 3.00 (t, J=10.2 Hz, 1H), 1.88 (dd, J=12.3, 2.8 Hz, 1H), 1.74 (m, 2H), 1.38 (m, 1H), 1.34 (s, 9H). 13C NMR (150 MHz, DMSO-d6): δ 154.8, 148.9, 148.2, 147.9, 130.6, 128.5, 113.8, 109.6, 77.6, 54.7, 48.9, 47.3, 30.0, 28.1 (3C), 24.2. HRMS-ESI (m/z): [M+H]+ calcd for C17H23BrN5O4, 440.0928. found, 440.091

Steps 2 and 3: Preparation of (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine

To an inserted 1 L pressure reactor were charged (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine (75.0 g, 1.00 equiv), 1% Pt+2% V/C (11.3 g, 15 wt %), N-methylmorpholine (29.3 g, 1.70 equiv), and 2-MeTHF (750 mL). The reaction mixture was stirred at 50° C. at 5 bar of hydrogen for a minimum of 2 h. Cyclopropanecarbonyl chloride (26.7 g, 1.50 equiv) was charged into the reactor over 10 min at 15° C. The reaction mixture was stirred at 25° C. for 1 h and filtered through Celite. The cake was washed with 2-MeTHF (150 mL). The filtrate was washed with 15 wt % aqueous ammonium chloride solution (450 mL) and water (450 mL) and then distilled in vacuo to ⅓ of it’s original volume. Toluene was added to bring the solution back to its original volume. Continuous vacuum distillation was conducted at 55° C. while adding toluene until the 2-MeTHF was below 2 wt %. The resulting solid was isolated by filtration, washed with toluene and dried in a vacuum oven at 40° C. overnight to give 69.8 g (69% corrected yield) of (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine (1:1 toluene solvate) as an off-white solid. 1H NMR (600 MHz, THF-d8, 4° C.): δ 10.76 (s, 1H), 9.72 (s, 1H), 8.15 (s, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.18-7.08 (m, 5H), 6.41 (d, J=7.8 Hz, 1H), 3.82 (m, 1H), 3.60 (m, 1H), 3.44 (t, J=10.6 Hz, 1H), 3.30 (dd, J=10.6, 3.9 Hz, 1H), 3.03 (d, J=10.9 Hz, 1H), 2.29 (s, 3H), 2.08 (m, 1H), 1.89 (m, 2H), 1.66 (m, 1H), 1.37 (s, 9H), 1.36 (m, 1H), 0.95-0.80 (m, 4H). 13C NMR (150 MHz, THF-d8, 4° C.): δ 170.0, 155.8, 149.0, 147.8, 147.6, 138.4, 129.6 (2C), 128.9 (2C), 126.0, 116.6, 115.6, 111.9, 108.8, 78.5, 55.8, 50.2, 49.1, 31.8, 28.6 (3C), 26.3, 21.5, 15.8, 7.70, 7.56. HRMS-ESI (m/z): [M+H]+ calcd for C21H29BrN5O3, 478.1448. found, 478.1431.

Step 4: Preparation of (R)-5-bromo-4-(3-amino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine

To an inserted 1 L jacket reactor, equipped with a mechanic stirrer, a nitrogen/vacuum manifold, a thermocouple, and a condenser, were charged (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine (1:1 toluene solvate) (30.0 g, 1.00 equiv), tetrahydrofuran (180 mL, 6.00 mL/g), followed by 4.5 M sulfuric acid (36.1 mL, 3.00 equiv). The reaction mixture was stirred at 50±5° C. for 2 h and then cooled to 20° C. An aqueous piperazine solution (42.4 g dissolved in 190 mL of water) was added slowly at 25° C. followed by addition of 15.0 mL of sat′d brine. The aqueous bottom layer was removed. The resulting solution was stirred at 20° C. for 5 min. Water (22.0 mL) was added. Continuous distillation was conducted at 50° C. by adjusting the feed rate of ethanol to match the distillation rate until a total of 260 mL of ethanol was added. Water (340 mL) was added at 50° C. over 1 h. The resulting solid was isolated by filtration, washed with 20% ethanol in water (2×60 mL) and dried in a vacuum oven at 50° C. overnight to give 16.4 g (78% corrected yield) of (R)-5-bromo-4-(3-amino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine as a light yellow solid. (Note: The proton (1H) and carbon-13 (13C) spectra of freebase product are very broad. Therefore, the spectra shown below are of freebase converted to a bis-HCl salt.)1H NMR (300 MHz, DMSO-d6): δ 11.98 (br, 1H), 9.78 (s, 1H), 8.44 (br, 3H), 8.25 (s, 1H), 7.45 (d, J=2.4 Hz, 1H), 3.57 (m, 1H), 3.43 (m, 1H), 3.41 (m, 1H), 3.28 (m, 1H), 3.14 (m, 1H), 2.15 (m, 1H), 1.90 (penta, J=6.5 Hz, 1H), 1.81 (m, 1H), 1.72 (m, 1H), 1.52 (m, 1H), 0.83 (m, 4H). 13C NMR (75 MHz, DMSO-d6): δ 172.9, 149.5, 145.9, 145.1, 121.9, 114.2, 113.1, 107.8, 53.8, 51.1, 47.5, 28.6, 24.37, 14.7, 7.55, 7.45. HRMS-ESI (m/z): [M+H]+ calcd for C16H21BrN5O, 378.0924. found, 378.0912.

Example 2

Alternatively, the compound (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine can be prepared from 5-bromo-4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine and (R)-tert-butyl piperidin-3-ylcarbamate via a through process without isolating (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine. The changes to existing procedure are shown as below: The solution of (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine was hydrogenated directly in 2-methyl-2-butanol after aqueous washes with 15 wt % citric acid aqueous solution (10.0 g/g) and water (10.0 g/g). The solution concentration in 2-methyl-2-butanol was determined by HPLC weight assay.

PAPER

An Efficient Through-Process for Chk1 Kinase Inhibitor GDC-0575

 Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
 Department of Pharma Technical Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, CH-4070 Basel, Switzerland
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00388

Abstract

Abstract Image

We report an efficient route to prepare Chk1 kinase inhibitor GDC-0575 from 5-bromo-4-chloro-3-nitro-7-azaindole featuring a sequence of nucleophilic aromatic substitution, hydrogenative nitro-reduction, and a robust, high-yielding end-game involving deprotection–crystallization steps. The developed route was demonstrated on 10 kg scale in 30% overall yield to provide the target API in >99.8 A % HPLC purity.

(R)-5-Bromo-4-(3-amino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine (GDC-0575)

To ………….. to give (R)-5-bromo-4-(3-amino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine as a light yellow solid (5.1 kg, 76% yield, 99.9 A % by HPLC analysis).
Both 1H and 13C spectra of GDC-0575 freebase are very broad.
Therefore, the spectra shown below are of freebase converted to a bis-HCl salt: mp = 267 °C;
1H NMR (300 MHz, DMSO-d6): δ 11.98 (br, 1H), 9.78 (s, 1H), 8.44 (br, 3H), 8.25 (s, 1H), 7.45 (d, J = 2.4 Hz, 1H), 3.57 (m, 1H), 3.43 (m, 1H), 3.41 (m, 1H), 3.28 (m, 1H), 3.14 (m, 1H), 2.15 (m, 1H), 1.90 (penta, J = 6.5 Hz, 1H), 1.81 (m, 1H), 1.72 (m, 1H), 1.52 (m, 1H), 0.83 (m, 4H);
13C NMR (75 MHz, DMSO-d6): δ 172.9, 149.5, 145.9, 145.1, 121.9, 114.2, 113.1, 107.8, 53.8, 51.1, 47.5, 28.6, 24.37, 14.7, 7.55, 7.45;
HRMS–ESI (m/z): [M + H]+ calcd for C16H21BrN5O, 378.0924; found, 378.0912.

REFERENCES

1: Duan W, Gao L, Aguila B, Kalvala A, Otterson GA, Villalona-Calero MA. Fanconi
anemia repair pathway dysfunction, a potential therapeutic target in lung cancer.
Front Oncol. 2014 Dec 19;4:368. doi: 10.3389/fonc.2014.00368. eCollection 2014.
PubMed PMID: 25566506; PubMed Central PMCID: PMC4271581.

Publications

GDC-0575 / Cancer

07/01/2011

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics

Single-Agent Inhibition of Chk1 Is Antiproliferative in Human Cancer Cell Lines In Vitro and Inhibits Tumor Xenograft Growth In Vivo

K. D. Davies, et al.

GDC-0575 / Cancer

04/05/2011

American Association for Cancer Research Annual Meeting

Chk1 inhibition and Wee1 inhibition combine synergistically to inhibit cellular proliferation

K. D. Davies, et al.

GDC-0575 / Cancer

03/11/2011

International Symposium on Targeted Anticancer Therapies

Preclinical characterization of ARRY-575: A potent, selective, and orally bio-available small molecule inhibitor of Chk1

M. J. Humphries, et al.

///////// GDC0575,  GDC 0575, ARRY-575, GDC-0575, RG 7741, RO 6845979, AK 687476, ARRY 575, GDC 0575, RG 7741, PHASE 1

O=C(Nc1cnc2ncc(Br)c(c12)N3CCC[C@@H](N)C3)C4CC4

AVOID CONFUSING

GLXC-11762   WRONG  COMPD 2097938-64-0

N ATOM MISSING IN RING

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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