WO 2016181414, IVACAFTOR, NEW PATENT, COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

CSIR, Dr. D. Srinivasa Reddy

WO2016181414, PROCESS FOR THE SYNTHESIS OF IVACAFTOR AND RELATED COMPOUNDS

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016181414&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

REDDY, Dumbala Srinivasa; (IN).
NATARAJAN, Vasudevan; (IN).
JACHAK, Gorakhnath Rajaram; (IN)

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH [IN/IN]; Anusandhan Bhawan, Rafi Marg New Delhi 110001 (IN)

The present patent discloses a novel one pot two-step process for the synthesis of ivacaftor and related compounds of [Formula (I)], wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and Ar₁are as described above; its tautomers or pharmaceutically acceptable salts thereof starting from indole acetic acid amides

See Eur J Org Chem, Nov 2015, for an article by the inventors, describing a process for preparing ivacaftor using 4-quinolone-3-carboxylic acid amides. The inventors appear to be based at National Chemical Laboratories of CSIR.

Ivacaftor, also known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide, having the following Formula (A):

Formula (A)

[003] Ivacaftor was approved by FDA and marketed by vertex pharma for the treatment of cystic fibrosis under the brand name KALYDECO® in the form of 150 mg oral tablets. Kalydeco® is indicated for the treatment of cystic fibrosis in patients age 6 years and older who have a G55ID mutation in the CFTR (cystic fibrosis transmembrane conductance regulator)gene.

[004] U.S. 20100267768 discloses a process for preparation of ivacaftor, which involves the coupling of 4-oxo-l,4-dihydro-3- quinoline carboxylic acid with hydroxyl protected phenol intermediate in the presence of propyl phosphonic anhydride (T₃P®) followed by deprotection of hydroxyl protection group and optional crystallization with isopropyl acetate. The publication also discloses the use of highly expensive coupling reagent, propyl phosphonic anhydride; which in turn results to an increase in the manufacturing cost. The process disclosed is schematically represented as follows:

[005] Article titled "Discovery of N-(2,4-Di-te -butyl-5-hydroxyphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a Potent and Orally Bioavailable CFTR Potentiator" byHadida,S et. al in . Med. Chem., 2014, 57 (23), pp 9776-9795 reportsN-(2,4-di-teri-butyl-5-hydroxyphenyl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxamide (VX-770, 48, ivacaftor), an investigational drug candidate approved by the FDA for the treatment of CF patients 6 years of age and older carrying the G551D mutation.

[006] WO 2014125506 A2 discloses a process for the preparation of ivacaftor in high yield and purity by using novel protected quinolone carboxylic acid compounds as intermediates.

[007] Article titled "Expeditious synthesis of ivacaftor" by Jingshan Shen et. al in Heterocycles, 2014, 89 (4), pp 1035 - 1040 reports an expeditious synthesis for ivacaftor featuring modified Leimgruber-Batcho procedure. The overall yield is 39% over six steps from commercially available 2-nitrobenzoyl chloride.

[008] U.S.2011/064811 discloses a process for preparation of ivacaftor, which involves condensation of 4-oxo-l,4-dihydro-3- quinolone carboxylic acid with 5- amino-2,4-di-(tert-butyl)phenol in the presence of HBTU followed by the formation of ethanol crystalate, which is then treated with diethyl ether to yield ivacaftor as a solid.

[010] U.S. 7,495,103 discloses modulators of ATP-binding cassette transporters such as ivacaftor and a process for the preparation of modulators of ATP-binding cassette transporters such as quinolone compounds. The process includes condensation of 4-oxo-l,4-dihydro-3 -quinolone carboxylic acid with aniline in presence of 2-(lH-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoro phosphate methanaminium (HATU) as shown:

[011] U.S. 2011/230519 discloses a process for preparation of 4-oxo-l,4-dihydro-3-quinoline carboxylic acid by reaction of aniline with diethylethoxymethylenemalonate at 100-110°C followed by cyclization in phenyl ether at temperature 228-232°C and then hydrolysis, as shown below:

[012] US 7,402,674 B2 discloses 7-Phenylamino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments.

[013] US 4,981,854 discloses l-aryl-4-quinolone-3 carboxylic acids, processes for their preparation and anti-bacterial agents and feed additives containing these compounds.

Article titled "Ozonolysis Applications in Drug Synthesis" by Van Ornum,S.G. ; Champeau,R.M.; Pariza,R. in Chem. Rev., 2006, 106 (7), pp 2990-3001 reports that ozonolysis for the synthesis of numerous interesting bioactive natural products and pharmaceutical agents.

[014] Article titled "Safe Execution of a Large-Scale Ozonolysis: Preparation of the Bisulfite Adduct of 2-Hydroxyindan-2-carbox-aldehyde and Its Utility in a Reductive Animation" by RaganJ.A. et. al. in Org. Proc. Res. Dev., 2003, 7 (2), pp 155-160 reports various routes to bisulfite adduct, the most efficient of which involved vinyl Grignard addition to 2-indanone followed by ozonolysis and workup with aqueous NaHS0₃ to effect reduction and bisulfite formation in a single pot. The utility of bisulfite adduct is as an aldehyde surrogate in a reductive amination reaction.

[015] The reported methods for the synthesis of ivacaftor suffered from several drawbacks such as harsh conditions, high temperature reactions and use of large excess of polyphosphoric acid and corrosive phosphoryl chloride etc. Furthermore, synthesis of ivacaftor requires use of high performance liquid chromatography (HPLC) techniques for the separation of ivacaftor and their analogues.

[016] Therefore, development of a simple and efficient synthetic route is in urgent need. Accordingly the present inventors developed environmentally benign, cost effective and short synthetic route for the synthesis of ivacaftor and their analogues.

Example 1:

Procedur A:

To a solution of indole acetic acid (500 mg, 2.85 mmol), aniline (2.85 mmol), HOBt (3.4 mmol) in acetonitrile (10 mL), EDC.HCl (3.4 mmol) followed by DIPEA (11.4 mmol) was added, and mixture was stirred for 16 h at ambient temperature. The

reaction mixture was evaporated to dryness, diluted with EtOAc (25 mL), washed with saturated aqueous NaHC0₃ solution (5 mL), H₂0 (5 mL), brine (5 mL), and dried over Na₂S04. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate - pet ether) to afford corresponding amide as a colorless solid.

[040] Example 2:

2-(lH-indol-3-yl)-N-phenylacetamide (1) :

Yield: 570 mg; 80%; 1H NMR (200MHz, DMSO-d₆) δ = 10.95 (brs, 1 H), 10.14 (s, 1 H), 7.64 (d, J = 7.8 Hz, 3 H), 7.47 - 7.24 (m, 4 H), 7.21 - 6.92 (m, 3 H), 3.76 (s, 2H); MS: 273 (M+Na)⁺.

[041] Example 3:

5-(2-(lH-indol-3-yl)acetamido)-2,4-di-tert-butylphenyl methyl carbonate (2): Yield: 800 mg; 64%; 1H NMR (200 MHz, DMSO-d₆) δ = 11.51 (brs, 1 H), 9.41 (s, 1 H), 8.12 (d, J = 7.6 Hz, 1 H), 7.96 - 7.78 (m, 3 H), 7.71 - 7.42 (m, 3 H), 4.34 (s, 3 H), 4.30 (s, 2 H), 1.79 (s, 9 H), 1.64 (s, 9 H); MS: 459 (M+Na)⁺.

[042] Example 4:

(S)-2-(lH-indol-3-yl)-N-(l-phenylethyl)acetamide (3):

Yield: 620 mg; 78%; 1H NMR (400MHz ,DMSO-d₆)5 = 10.88 (brs, 1 H), 8.48 (d, J = 8.1 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.39 - 7.26 (m, 5 H), 7.25 - 7.16 (m, 2 H), 7.08 (t, J = 7.3 Hz, 1 H), 7.02 - 6.95 (m, 1 H), 4.96 (t, J = 7.3 Hz, 1 H), 3.59 (s, 2H), 1.38 (d, J = 7.1 Hz, 3 H).

[043] Example 5:

N-(4-Fluorophenyl)-2-(lH-indol-3-yl)acetamide (4):

1H NMR (400 MHz, DMSO-d₆) : δ 10.93 (brs, 1H), 10.17 (s, 1H), 7.68 - 7.61 (m, 3H), 7.36 (d, J= 8.1 Hz, 1H), 7.27 (d, J= 2.0 Hz, 1H), 7.15 - 7.13 (m, 3H), 7.11 - 6.99 (m, 1H), 3.73 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆) : δ 170.1, 159.5, 157.1, 136.6, 136.3, 127.7, 124.4, 121.5, 121.3, 121.2, 119.1, 118.9, 115.8, 115.6, 111.8, 108.9, 34.2; MS: 269 (M+H)⁺

[044] Example 6:

N-(4-Chlorophenyl)-2-(lH-indol-3-yl)acetamide (5):

1H NMR (200 MHz, DMSO-d₆): 510.93 (brs, 1H),10.24 (s, 1H), 7.67 - 7.59 (m, 3H), 7.36 - 7.27 (m, 4H), 7.12 - 6.98 (m, 2H), 3.74 (s, 2H); ¹³CNMR (100 MHz, DMSO-d₆): 5170.4, 138.9, 136.7, 129.1, 127.8, 127.1, 124.5, 121.6, 121.2, 119.2, 119.0, 115.7, 111.9, 108.9, 34.3; MS: 285 (M+H)⁺.

[045] Example 7:

2-(lH-Indol-3-yl)-N-(p-tolyl)acetamide (6) :

1H NMR (400 MHz, DMSO-d₆): 510.91 (brs, 1H), 10.01 (s, 1H), 7.62 (d, J= 7.8 Hz, 1H), 7.50 (d, J= 8.6 Hz, 2H), 7.37 (d, J= 8.1 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.10 - 7.07 (m, 3H), 7.01 - 6.99 (m, 1H), 3.71 (s, 2H), 2.23 (s, 3H); ¹³C NMR (100 MHz, DMSO-de): 5170.0, 137.4, 136.6, 132.4, 129.5, 127.7, 124.3, 121.4, 119.6, 119.2, 118.8, 111.8, 109.1, 34.2, 20.9; MS: 265 (M+H)⁺.

[046] Example 8:

N-(4-Ethylphenyl)-2-(lH-indol-3-yl)acetamide (7):

^XH NMR (400 MHz, DMSO-d₆): 510.91 (brs, 1H), 10.01 (s, 1H), 7.61 (s, 1H), 7.52 (d, J= 8.3 Hz, 2H), 7.36 (d, J= 8.1 Hz, 1H), 7.26 (s, 1H), 7.15 - 7.04 (m, 3H), 6.99 (s, 1H), 2.55 (t, J= 7.5 Hz, 2H), 1.15 (t, J= 7.5 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): 5169.9, 138.9, 137.6, 136.6, 128.3, 127.7, 124.3, 121.4, 119.6, 119.2, 118.8, 111.8, 109.1, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.4, 34.2, 28.0, 16.2; MS: 279 (M+H)⁺.

[047] Example 9:

2-(lH-Indol-3-yl)-N-(4-propylphenyl)acetamide (8):

1H NMR (400 MHz, DMSO-d₆): 58.48 (brs, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.50 - 7.42 (m, 2H), 7.33 - 7.15 (m, 6H), 7.07 (d, J= 8.3 Hz, 2H), 3.92 (s, 2H), 2.52 (t, J= 7.6 Hz, 2H), 1.65 - 1.53 (m, 2H), 0.91 (t, J= 7.3 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): 5169.7, 138.9, 136.5, 135.2, 128.8, 126.9, 124.0, 122.8, 120.4, 120.1, 118.7, 111.6, 108.7, 37.4, 34.5, 24.6, 13.7; MS: 315 (M+Na)⁺.

[048] Example 10:

2-(lH-Indol-3-yl)-N-(4-isopropylphenyl)acetamide (9) :

yield 79% ; 1H NMR (400 MHz, DMSO-d₆): δ 10.91 (brs, 1H), 10.01 (s, 1H), 7.62 (d, = 7.8 Hz, 1H), 7.55 - 7.49 (m, = 8.6 Hz, 2H), 7.37 (d, = 8.1 Hz, 1H), 7.26 (d, = 2.0 Hz, 1H), 7.18 - 7.11 (m, = 8.6 Hz, 2H), 7.11 - 7.05 (m, 1H), 7.02 - 6.95 (m, 1H), 2.95 - 2.71 (m, 1H), 1.17 (d, = 6.8 Hz, 6H); ¹³C NMR (100 MHz, DMSO-d₆): δ 169.9, 143.5, 137.6, 136.6, 127.7, 126.8, 124.3, 121.4, 119.7, 119.2, 118.8, 111.8, 109.2, 24.4; MS: 315 (M+Na)⁺.

[049] Example 11:

2-(lH-indol-3-yl)-N-(4-(trifluoromethoxy)phenyl)acetamide (10):

Yield 85% ; 1H NMR (400 MHz, CDC1₃): δ 8.35 (brs., 1 H), 7.44 - 7.38 (m, 2 H), 7.27 - 7.21 (m, 3 H), 7.12 - 7.05 (m, 1H), 7.03 - 6.95 (m, 2H), 6.93 (d, = 8.6 Hz, 2H), 3.75 (s, 2H); ¹³C NMR (100 MHz, CDC1₃): δ 170.0, 145.3, 136.5, 136.2, 126.8, 124.1, 123.0, 121.6, 121.2, 120.5, 118.5, 111.7, 108.2, 34.4; MS: 335 (M+Na)⁺.

[050] Example 12:

N-(2-chloro-5-methoxyphenyl)-2-(lH-indol-3-yl)acetamide (11):

Yield 75% ; ^XH NMR (200 MHz, DMSO-d₆): δ 10.98 (brs, 1H), 9.27 (s, 1H), 7.59 (d, = 7.8 Hz, 1H), 7.53 (d, = 2.9 Hz, 1H), 7.39 - 7.32 (m, 3H), 7.09 - 6.99 (m, 2H), 6.74 (dd, = 3.0, 8.8 Hz, 1H), 3.85 (s, 2H), 3.71 (s, 3H); ¹³C NMR (400 MHz, DMSO-d₆): δ 170.4, 160.1, 141.1, 136.7, 130.0, 127.8, 124.4, 121.6, 119.2, 119.0, 111.9, 109.1, 105.4, 55.4, 34.4; MS: 315 (M+Na)⁺.

[051]Example 13:

N-(2-ethylphenyl)-2-(lH-indol-3-yl)acetamide (12):

Yield 78% ; 1H NMR (400 MHz, CDC1₃): δ 8.68 (brs, 1H), 7.95 (d, = 8.1 Hz, 1H), 7.67 (d, = 7.8 Hz, 1H), 7.48 - 7.44 (m, 2H), 7.29 - 7.23 (m, 1H), 7.22 - 7.20 (m, 3H), 7.05 (d, = 4.4 Hz, 2H), 2.00 (q, = 7.4 Hz, 2H), 0.67 (t, = 7.6 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃): δ 169.9, 136.6, 135.0, 134.3, 128.7, 126.7, 125.1, 124.1, 123.0, 122.5, 120.4, 118.7, 111.6, 108.6, 34.4, 24.2, 13.6.

[052] Example 14:

N-(2-bromophenyl)-2-(lH-indol-3-yl)acetamide(13):

Yield 76%; 1H NMR (200 MHz, DMSO-d₆): δ 11.00 (brs, 1H), 9.30 (s, 1H), 7.81 -7.77 (m, 1H), 7.63 - 7.56 (m, 2H), 7.41 - 7.35 (m, 3H), 7.11 - 7.05 (m, 3H), 3.85 (s, 2H);¹³C NMR (100 MHz, DMSO-d₆): δ 169.9, 136.2, 132.5, 128.0, 127.2, 126.4, 125.5, 124.4, 121.2, 118.7, 118.5, 116.4, 111.4, 108.0, 33.2.

[053] Example 15:

N-benzyl-2-(lH-indol-3-yl)acetamide (14):

Yield 85%; 1H NMR (400 MHz, DMSO-d₆): δ 10.89 (brs., 1H), 8.40 (t, = 5.7 Hz, 1H), 7.57 (d, = 7.8 Hz, 1H), 7.36 (d, = 8.1 Hz, 1H), 7.32 - 7.18 (m, 6H), 7.08 (t, = 7.5Hz, 1H), 7.03 - 6.90 (m, 1H), 4.28 (d, = 5.9Hz, 2H), 3.60 (s, 2H); ¹³C NMR (100 MHz, DMSO-de): δ 171.2, 140.1, 136.6, 128.7, 127.7, 127.2, 124.3, 121.4, 119.2, 118.7, 111.8, 109.3, 42.7, 33.2.

[054] Example 16:

2-(lH-indol-3-yl)-N-(4-methoxybenzyl)acetamide(15):

Yield 85% ; 1H NMR (400 MHz, DMSO-d₆): δ 10.87 (brs, 1 H), 8.32 (t, = 5.6 Hz, 1 H), 7.55 (d, = 7.8 Hz, 1H), 7.35 (d, = 8.1 Hz, 1H), 7.22 - 7.13 (m, 3H), 7.11 - 7.05 (m, 1 H), 7.00 - 6.94 (m, 1H), 6.84 (d, = 8.6 Hz, 2H), 4.20 (d, = 6.1 Hz, 2H), 3.72 (s, 3H), 3.56 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 171.1, 158.6, 136.6, 132.0, 129.0, 127.7, 124.2, 121.4, 119.2, 118.7, 114.1, 111.8, 109.4, 55.5, 42.1, 33.2.

[055] Example 17:

N,N-dibenzyl-2-(lH-indol-3-yl)acetamide (16):

Yield 70% ; 1H NMR (400 MHz, DMSO-d₆): δ 10.91 (brs, 1H), 7.50 (d, = 7.8 Hz, 1H), 7.37 - 7.34 (m, 3H), 7.30 (d, = 6.6 Hz, 1H), 7.25 - 7.19 (m, 3H), 7.17 (t, = 6.6 Hz, 5H), 7.16 (d, = 7.8 Hz, 1H), 7.00 - 6.97 (m, 1H), 4.59 (s, 2H), 4.50 (s, 2H), 3.86 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 171.7, 138.2, 136.6, 129.2, 128.8, 128.1, 127.8, 127.7, 127.5, 127.1, 124.2, 121.5, 119.2, 118.8, 111.8, 108.5, 50.7, 48.4, 31.2.

[056] Example 18:

2-(lH-indol-3-yl)-N-propylacetamide (17):

Yield 75% ; ^XH NMR (200 MHz, DMSO-d₆): δ 10.86 (brs, 1H), 7.88 - 7.80 (m, 1H), 7.56 (d, = 7.6 Hz, 1H), 7.31 (d, = 7.8 Hz, 1H), 7.17 (d, = 2.3 Hz, 1H), 7.06 - 6.92 (m, 2H), 3.48 (s, 2H), 3.00 (q, J = 6.8 Hz, 2H), 1.39 (sxt, / = 7.2 Hz, 2H), 0.88 - 0.75 (t, = 7.2 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 171.0, 136.6, 127.8, 124.2,

121.4, 119.2, 118.7, 111.8, 109.6, 39.4, 33.3, 22.9, 11.9.

[057] Example 19:

N-hexyl-2-(lH-indol-3-yl)acetamide (18) :

Yield 87% ; 1H NMR (400 MHz, DMSO-d₆): δ 10.84 (brs, 1H), 7.83 (brs, 1H), 7.54 (d, = 7.8 Hz, 1H), 7.33 (d, = 8.1 Hz, 1H), 7.21 - 7.13 (m, 1H), 7.06 (t, = 7.6 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 3.47 (s, 2H), 3.03 (q, / = 6.8 Hz, 2H), 1.37 (t, = 6.5 Hz, 2H), 1.30 - 1.15 (m, 6H), 0.84 (t, = 6.7 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 170.9, 136.6, 127.7, 124.2, 121.3, 119.1, 118.7, 111.7, 109.5, 39.06, 33.2, 31.5, 29.6, 26.5, 22.5, 14.4.

[058] Example 20:

Methyl (2-(lH-indol-3-yl)acetyl)-L-alaninate (19):

Yield 79% ; 1H NMR (400 MHz, CDC1₃): δ 8.53 (brs, 1H), 7.60 (d, = 7.8 Hz, 1H), 7.41 (d, = 8.1 Hz, 1H), 7.25 - 7.23 (m, 1H), 7.19 - 7.14 (m, 2H), 6.27 (d, = 7.3 Hz, 1H), 4.63 (t, = 7.3 Hz, 1H), 3.78 (s, 2H), 3.68 (s, 3H), 1.31 (d, = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃): δ 173.4, 171.2, 136.4, 127.0, 123.8, 122.5, 119.9, 118.7,

111.5, 108.5, 52.4, 48.0, 33.3, 18.2.

[059] Example 21:

-(6-chloro-lH-indol-3-yl)-N-phenylacetamide(20):

To a solution of 6-Chloro indole 20a (300 mg, 1.98 mmol )in anhydrous THF, Oxalyl chloride (186 μΤ, 276 mg, 2.18 mmol) was added and the mixture stirred at room temperature. After 2 h, N,N-Diisopropylethylamine (758 μΤ, 562 mg, 4.35 mmol) was

introduced to the mixture, followed by the aniline (221.0 mg, 2.37 mmol). The temperature was raised to 45 °C, and heating continued for 18 h. The solvent was evaporated, and then mixture was diluted with EtOAC (15 mL), washed with brine and dried over anhydrous Na₂S0₄. The crude material obtained after removal of solvent was purified by column chromatography (10 - 20% EtOAc : Petroleum ether) to afford 20b (295 mg, 51% yield) as a yellow coloured solid. IR O_max(film): 3346, 3307,2853, 1724, 1678 cm^"1; 1H NMR (400 MHz, DMSO-d₆): δ 12.40 (br. s., 1H), 10.68 (s, 1H), 8.79 (d, = 3.2 Hz, 1H), 8.25 (d, = 8.6 Hz, 1H), 7.85 (d, = 7.8 Hz, 2H), 7.62 (d, = 1.7 Hz, 1H), 7.41 - 7.30 (m, 3H), 7.19 - 7.13 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 182.5, 162.5, 140.0, 138.4, 137.4, 129.2, 128.5, 125.4, 124.8, 123.4, 122.9, 120.8, 113.0, 112.3; HRMS (ESI) Calculated for Ci₆HnN₂OCl[M+H]⁺: 299.0582, found 299.0580;

A solution of 20b (300 mg, 0.99 mmol) dissolved in MeOH (40 mL) was added to NaBH₄ (45 mg, 1.23 mmol). The reaction was stirred for 4h and then added to saturated solution of Na₂S0₄. The reaction mixture was further stirred for lh and then filtered through Celite.The filtrate obtained was concentrated in vacuo, and then mixture was diluted with EtOAc (15 mL), washed with brine and dried over anhydrous Na₂S0₄. The crude material obtained after removal of solvent was forwarded for next step without further purification.In an N₂ atmosphere, TMSC1 (1.272 mL, 9.9 mmol) in CH₃CN (40 mL) was added to sodium iodide (1.488 mg, 9.9 mmol) and stirred for 2h. The reaction mixture was cooled to 0 °C and a solution of above crude alcohol (0.99 mmol) in CH₃CN (10 mL) was then added drop wise over 30 min, followed by stirring for 3h. The reaction mixture was poured into NaOH (7g in 40 mL of water) and then extracted with ethyl acetate (15x2). The organic layer was washed with aq.Na₂S₂0₃, dried over Na₂S0₄ and concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc:Pet ether) to afford 20 as a off white solid (two steps 38 % ); IR Umax(film): 3273, 3084,2953, 2857, 1629, 1562 cm^"1; 1H NMR (400 MHz, DMSO-d₆): δ 11.06 (br. s., 1H), 10.13 (br. s., 1H), 7.62 - 7.57 (m, 3H), 7.40 (s, 1H), 7.30 - 7.25 (m, 3H), 7.04 - 6.99 (m, 2H), 3.71 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 170.1,

139.7, 136.9, 129.2, 126.5, 126.3, 125.5, 123.7, 120.6, 119.6, 119.3, 111.5, 109.4, 34.0; HRMS (ESI):Calculated for Ci₆Hi₄N₂OCl[M+H]⁺: 285.0789, found 285.0786.

[060] Example 22:

2-(5-chloro-lH-indol-3-yl)-N-phenylacetamide(21):

21a 21b 21

To a solution of 5-Chloro indole 21a (300 mg, 1.98 mmol )in anhydrous THF(20 mL), Oxalyl chloride (186 ^L, 276 mg, 2.18 mmol) was added and the mixture stirred at room temperature. After 2 h, N,N-diisopropylethylamine (758 μΕ, 562 mg, 4.35 mmol) was introduced to the mixture, followed by the aniline (221.0 mg, 2.37 mmol). The tempera ture was raised to 45 °C, and heating continued for 18 h. The solvent was evaporated, and then mixture was diluted with EtOAC (15 mL), washed with brine and dried over anhydrous Na₂S04. The crude material obtained after removal of solvent was purified by column chromatography (10 - 20% EtOAc : Petroleum ether) to afford (21b) (305 mg, 53% yield) as a yellow coloured solid. IR rj_max(film): 3346, 3307,2853, 1724, 1678 cm^"1; 1H NMR (400 MHz, DMSO-d₆): δ 12.40 (br. s., 1H), 10.68 (s, 1H), 8.79 (d, = 3.2 Hz, 1H), 8.25 (d, = 8.6 Hz, 1H), 7.85 (d, = 7.8 Hz, 2H), 7.62 (d, = 1.7 Hz, 1H), 7.42 - 7.30 (m, 3H), 7.20 - 7.14 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 182.4, 162.4, 140.3, 138.4, 135.4, 129.2, 127.9, 124.8, 124.1, 120.8, 114.8, 112.0; HRMS (ESI) Calculated for Ci₆HnN₂OCl[M+H]⁺: 299.0582, found 299.0580; A solution of 21b (200 mg, 0.66 mmol) dissolved in MeOH (30 mL) was added to NaBH₄ (30 mg, 0.82 mmol). The reaction was stirred for 4h and then added to saturated solution of Na₂S0₄. The reaction mixture was further stirred for lh and then filtered through Celite. The filtrate obtained was concentrated in vacuo, and then mixture was diluted with EtOAc (15 mL), washed with brine and dried over anhydrous Na₂S0₄. The crude material obtained after removal of solvent was forwarded for next step without further purification. In an N₂ atmosphere, TMSC1 (848 mL, 6.6 mmol) in CH₃CN (25 mL) was added to sodium iodide (992 mg, 6.6 mmol) and stirred for 2h. The reaction mixture was cooled to 0 °C and a solution of above crude alcohol(0.66 mmol) in CH₃CN (5 mL) was then added dropwise over 30 min, followed by stirring for 3h. The reaction mixture was poured into NaOH (5g in 30 mL of water) and then extracted with ethyl acetate(15x2). The organic layer was washed with aq.Na₂S₂0₃, dried over Na₂S0₄ and concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc:Pet ether) to afford 22 as a off white solid (two steps 42 % ); IR Umax(film): 3273, 3084,2955, 2857, 1629, 1562 cm^"1; 1H NMR (400 MHz, DMSO-d₆): δ 11.13 (br. s., 1H), 10.11 (s, 1H), 7.67 (s, 1H), 7.60 (d, = 7.8 Hz, 2H), 7.39 - 7.27 (m, 4H), 7.13 - 7.02 (m, 2H), 3.16 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 169.9, 139.8, 135.0, 129.2, 128.9, 126.2, 123.6, 121.4, 119.6, 118.6, 113.4, 109.0, 34.0; HRMS (ESI) Calculated for Ci₆H₁₄N₂OCl[M+H]⁺: 285.0789, found 285.0786.

[061] Example 23:

2-(l-benzyl-lH-indol-3-yl)-N-phenylacetamide (22):

Yield 79% ; 1H NMR (400 MHz, DMSO-d₆): δ 7.67 (d, = 7.8 Hz, 1H), 7.54 (brs, 1H), 7.43 - 7.31 (m, 6H), 7.31 - 7.25 (m, 3H), 7.23 - 7.15 (m, 4H), 7.12 - 7.06 (m, 1H), 5.36 (s, 2H), 3.91 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 169.7, 137.7, 137.2, 137.0, 128.9, 128.9, 127.9, 127.6, 126.9, 124.3, 122.7, 120.2, 119.9, 119.0, 110.2, 107.9, 77.4, 77.1, 76.8, 50.1, 34.5.

[062] Example 24:

Procedure B:

2-(lH-indol-3-yl)-N-phenylacetamidel(100 mg; 0.4 mmol) was dissolved in DCM:MeOH(50 mL; 5: 1), then a stream of 0₃ was passed through the solution until a blue color developed (10 min). The 0₃ stream was continued for 4 min. Then surplus O3 was removed by passing a stream of 0₂ through the solution for 10 min or until the blue colorcompletely vanished. Afterwards pyridine (0.1 mL;1.2mmol) was added to the cold (- 78 °C) mixture. The mixture was allowed to warm to room temperature (1 h) and then Et₃N (0.35 mL; 2.4 mmol) were added. After stirring at room temperature overnight the reaction mass was concentrated under reduced pressure to dryness, diluted with EtOAc (30 mL), washed with H₂0 (5 mL), brine (5 mL), and dried over Na₂S0₄. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 230-400 mesh, MeOH - DCM) to give desired quinolone carboxamide as colorless solid.

[063] Example 25:

4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide (23):

Yield: 65 mg; 62%; ^XH NMR (200MHz ,DMSO-d₆) δ = 12.97 (brs, 1 H), 12.49 (s, 1 H), 8.89 (s, 1 H), 8.33 (d, J = 8.2 Hz, 1 H), 7.91 - 7.69 (m, 4 H), 7.62 - 7.50 (m, 1 H), 7.37 (t, J = 7.8 Hz, 2 H), 7.18 - 7.01 (m, 1 H); MS: 287 (M+Na)⁺.

[064] Example 26:

2,4-di-tert-butyl-5-(4-oxo-l,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate (24):

Yield: 35 mg; 34%; 1H NMR (400MHz ,DMSO-d₆) δ = 12.96 (brs, 1 H), 12.08 (s, 1 H), 8.94 - 8.82 (m, 1 H), 8.44 - 8.28 (m, 1 H), 7.86 - 7.79 (m, 1 H), 7.78 - 7.73 (m, 1 H), 7.59 (s, 1 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.39 (s, 1 H), 3.86 (s, 3 H), 1.46 (s, 9 H), 1.32 (s, 9 H).

[065] Example 27:

(S)-4-oxo-N-(l-phenylethyl)-l,4-dihydroquinoline-3-carboxamide (25):

Yield: 56 mg; 53%; 1H NMR (500MHz ,DMSO-d₆) δ = 12.75 (brs, 1H), 10.54 (d, J = 7.6 Hz, 1H), 8.73 (brs, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.73 -7.68 (m, 1 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.42 - 7.34 (m, 4 H), 7.29 - 7.23 (m, 1 H), 5.18 (t, J = 7.2 Hz, 1 H), 1.50 (d, J = 6.7 Hz, 3 H).

[066] Example 28:

Synthesis of ivacaftor (26):

To a solution of 2,4-di-tert-butyl-5-(4-oxo-l,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate 5 (30 mg, 0.06mmol) in MeOH (2 mL) was added NaOH (5.3 mg, 0.13mmol) dissolved in H₂0 (2 mL), and the reaction mixture was stirred at room temperature for 5h. Reaction mass was evaporated to one third of its volume (temperature not exceeding 40°C) and acidified with aq.2N HC1 to pH 2-3. The resulting precipitate was collected by suction filtration give desired compound 7 (19 mg, 76%) as off white solid H NMR (400MHz ,DMSO-d₆) δ = 12.88 (d, J = 6.6 Hz, 1 H), 11.81 (s, 1 H), 9.20 (s, 1 H), 8.86 (d, J = 6.6 Hz, 1 H), 8.32 (d, J = 7.8 Hz, 1 H), 7.88 - 7.65 (m, 2 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.16 (s, 1 H), 7.10 (s, 1 H), 1.38 (s,9H), 1.36 (s, 9H).

[067] Example 29:

N-(4-fluorophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (27):

Yield 56% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.96 (br. s., 1H), 12.50 (s, 1H), 8.88 (s, 1H), 8.33 (d, = 7.3 Hz, 1H), 7.86 - 7.72 (m, 4H), 7.54 (t, = 7.3 Hz, 1H), 7.20 (t, = 8.8 Hz, 2H); ¹³C NMR (400 MHz, DMSO-d₆): δ 176.8, 163.2, 159.7, 157.3, 144.6, 139.6, 135.7, 133.5, 126.4, 125.9, 125.8, 121.8, 119.7, 116.1, 115.9, 110.9.

[068] Example 30:

N-(4-chlorophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (28):

Yield 51% ; 1H NMR (400 MHz, DMSO-d₆): δ 13.00 (brs., 1H), 12.59 (br. s., 1H), 8.89 (s, 1H), 8.34 (d, = 7.6 Hz, 1H), 7.83 - 7.76 (m, 4H), 7.56 (s, 1H), 7.42 (d, = 7.9 Hz, 2H); ¹³C NMR (400 MHz, DMSO-d₆): δ 176.8, 163.4, 144.7, 139.6, 138.2, 133.5, 129.4, 127.4, 126.4, 125.9, 125.8, 121.6, 119.7, 110.8.

[069] Example 31:

4-oxo-N-(p-tolyl)-l,4-dihydroquinoline-3-carboxamide (29):

Yield 57% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.94 (brs., 1H), 12.40 (s, 1H), 8.88 (s, 1H), 8.33 (d, = 7.8Hz, 1H), 7.82 - 7.80 (m, 1H), 7.76 - 7.7 (m, 1H), 7.63 (d, = 8.3 Hz, 2H), 7.53 (t, = 7.3 Hz, 1H), 7.17 (d, = 8.1 Hz, 2H), 2.29 (s, 3H); ¹³C NMR (100 MHz, DMSO-de): δ 176.8, 163.1, 144.5, 139.6, 136.8, 133.4, 132.8, 129.9, 126.4, 125.9, 125.7, 120.0, 119.6, 111.1, 20.9; HRMS (ESI):Calculated for Ci₇H₁₅0₂N₂[M+H]⁺: 279.1128, found 279.1127.

[070] Example 32:

N-(4-ethylphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (30):

Yield 51% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.95 (br. s., 1H), 12.40 (d, = 7.8 Hz, 1H), 8.87 (d, = 6.1 Hz, 1H), 8.33 (d, = 8.1 Hz, 1H), 7.81 - 7.76 (m, 2H), 7.66 - 7.62 (m, = 8.3 Hz, 2H), 7.53 (t, 7 = 7.5 Hz, 1H), 7.22 - 7.17 (m, = 8.3 Hz, 2H), 2.58 (q, = 7.6 Hz, 2H), 1.18 (t, = 7.6 Hz, 3H); ¹³C NMR (400 MHz, DMSO-d₆): δ 181.5, 167.8, 149.3, 144.3, 144.0, 141.7, 138.2, 133.4, 131.1, 130.7, 130.5, 124.8, 124.4, 115.9, 32.8, 20.9.

[071] Example 33:

4-Oxo-N-(4-propylphenyl)-l,4-dihydroquinoline-3-carboxamide (31):

Yield 51%; 1H NMR (500 MHz, DMSO-d6): δ12.93 (brs, 1H), 12.40 (s, 1H), 8.87 (s, 1H), 8.36 - 8.29 (m, 1H), 7.86 - 7.78 (m, 1H), 7.75 (d, J= 7.9 Hz, 1H), 7.68 - 7.61 (m, J= 8.2 Hz, 2H), 7.54 (t, J= 7.6 Hz, 1H), 7.22 - 7.14 (m, J= 8.2 Hz, 2H), 2.55 - 2.51 (m, 2H), 1.64 - 1.53 (m, 2H), 0.90 (t, J= 7.3 Hz, 3H); ¹³C NMR (500 MHz, DMSO-d6): 176.8, 163.1, 144.5, 139.6, 137.6, 137.0, 133.5, 129.3, 126.4, 125.9, 125.7, 120.0, 119.7, 111.1, 37.2, 24.6, 14.1.

[072] Example 34:

N-(4-isopropylphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (32):

Yield 46% ; 1H NMR (500 MHz, DMSO-d₆): δ 12.93 (br. s., 1H), 12.40 (br. s., 1H), 8.89 - 8.86 (m, 1H), 8.33(d, = 7.6 Hz, 1H), 7.81 - 7.50 (m, 5H), 7.25 - 7.21 (m, 2H), 2.90-2.83 (m, 1H), 1.22-1. l l(m, 6H); ¹³C NMR (100 MHz, DMSO-d₆): δ 176.8, 163.1, 144.5, 143.9, 139.6, 137.1, 133.4, 127.2, 126.4, 125.9, 125.7, 120.1, 119.6, 111.1, 33.4, 24.4.

[073] Example 35:

4-oxo-N-(4-(trifluoromethoxy)phenyl)-l,4-dihydroquinoline-3-carboxamide(33):

Yield 57% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.98 (br. s., 1H), 12.63 (s, 1H), 8.88 (d, = 4.9 Hz, 1H), 8.32 (d, = 7.8 Hz, 1H), 7.89 - 7.83 (m, = 8.8 Hz, 2H), 7.79 (d, = 7.6 Hz, 1H), 7.77 - 7.73 (m, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.40 - 7.34 (m, = 8.6 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 176.8, 163.5, 144.7, 144.0, 139.5, 138.5, 133.5, 126.3, 125.9, 125.8, 122.3, 121.4, 119.7, 110.7.

[074] Example 36:

N-(2-chloro-5-methoxyphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(34):

Yield 54% ; ^XH NMR (400 MHz, DMSO-d₆): δ 12.98 (br. s., 1H), 12.49 (s, 1H), 8.88 (s, 1H), 8.33 (d, = 7.8 Hz, 1H), 7.83 - 7.75 (m, 1H), 7.56-7.48 (m, 3H), 7.27 - 7.21 (m, 1H), 6.67 (d, = 7.8 Hz, 1H), 3.77 (s, 3H); ¹³C NMR (400 MHz, DMSO-d₆): δ 176.8, 163.4, 160.2, 144.7, 140.4, 139.6, 133.5, 130.3, 126.4, 125.9, 125.8, 119.7, 112.3, 111.0, 109.5, 105.7, 55.5.

[075] Example 37:

N-(2-ethylphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(35):

Yield 58% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.94 (br. s., 1H), 12.37 (s, 1H), 8.90 (s, 1H), 8.36 (dd, = 8.1, 1.4 Hz, 2H), 8.32 (dd, = 8.1, 1.4 Hz, 2H), 7.82 - 7.74 (m, 1H), 7.53- 7.19 (m, 3H), 7.15 - 7.06(m, 1H), 2.79 (q, = 7.3 Hz, 2H), 1.26 (t, = 7.5 Hz, 3H); 293 (M+H)⁺.

[076] Example 38:

N-(2-bromophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(36):

Yield 47% ; 1H NMR (200 MHz, DMSO-d₆): δ 12.98 (br. s., 1H), 12.69 (s, 1H), 8.90 (d, = 5.9 Hz, 1H), 8.54 (dd, 7 = 1.4, 8.3 Hz, 1H), 8.34 (d, = 7.6 Hz, 1H), 7.86 - 7.67 (m, 3H), 7.57 - 7.49 (m, 1H), 7.40 (t, = 7.2 Hz, 1H), 7.10 - 7.05 (m, 1H); ¹³C NMR (100 MHz, DMSO-de): δ 176.7, 163.7, 145.0, 139.5, 137.7, 133.5, 133.1, 128.6, 126.4, 126.0, 125.8, 125.3, 122.9, 119.7, 113.4, 110.8.

[077] Example 39:

N-benzyl-4-oxo-l,4-dihydroquinoline-3-carboxamide(37):

Yield 58% ; 1H NMR (400 MHz, CD₃OD-d₆): δ 8.82 (s, 1 H), 8.35 (d, = 8.1 Hz, 1 H), 7.79 - 7.77 (m, 1 H), 7.65 (d, = 8.3 Hz, 1 H), 7.52 (t, = 7.6 Hz, 1 H), 7.42 - 7.34 (m, 4 H), 7.31 - 7.26 (m, 1 H), 4.67 (s, 2 H); ¹³C NMR (400 MHz, DMSO-d₆): δ 176.6, 165.0, 144.2, 140.0, 139.5, 133.2, 128.9, 128.7, 127.8, 127.3, 126.6, 125.9, 125.4, 119.5, 111.2, 42.6.

[078] ] Example 40:

N-(4-methoxybenzyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(38):

Yield 56% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.73 (br. s., 1H), 10.35 (t, = 5.3 Hz, 1H), 8.78 (d, = 6.1 Hz, 1H), 8.24 (d, = 8.1 Hz, 1H), 7.76 (d, = 7.1 Hz, 1H), 7.73 -7.68 (m, 1H), 7.48 (t, = 7.5 Hz, 1H), 7.28 (d, = 8.3 Hz, 2H), 6.91 (d, = 8.1 Hz, 2H), 4.49 (d, = 5.6 Hz, 2H), 3.74 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 176.6, 164.8, 158.8, 144.1, 139.5, 133.1, 131.9, 129.2, 126.6, 125.8, 125.4, 119.5, 114.3, 111.3, 55.5, 42.0.

[079] Example 41:

N,N-dibenzyl-4-oxo-l,4-dihydroquinoline-3-carboxamide(39):

Yield 43% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.21 (br. s., 1H), 8.27 (d, = 4.9 Hz, 1H), 8.21 (d, = 7.6 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.41 - 7.35 (m, 3H), 7.33 - 7.20 (m, 5H), 7.20 - 7.11 (m, 7 = 7.1 Hz, 2H), 4.59 (br. s., 2H), 4.42 (s, 2H).

[080] Example 42:

4-oxo-N-propyl-l,4-dihydroquinoline-3-carboxamide(40):

Yield 47% ;1H NMR (400 MHz, DMSO-d₆): δ 12.7 (br.s., 1H)10.05 (t, = 5.5 Hz, 1H), 8.74 (s, 1H), 8.26 (d, = 8.1 Hz, 1H), 7.83 - 7.66 (m, 2H), 7.52 - 7.44 (m, 1H), 3.33 - 3.22 (m, 2H), 1.61 - 1.49 (m, 2H), 0.93 (t, = 7.5 Hz, 3H); ¹³C NMR (100 MHz, DMSO-de): δ 176.6, 164.8, 143.9, 139.5, 133.1, 126.6, 125.9, 125.3, 119.4, 111.4, 39.3, 23.1, 12.0

[081] Example 43:

N-hexyl-4-oxo-l,4-dihydroquinoline-3-carboxamide(41):

Yield 51% ;1H NMR (400 MHz, DMSO-d₆): δ 12.68 (m, 1H), 10.02 (t, = 5.5 Hz, 1H), 8.73 (d, = 6.1 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.77 - 7.67 (m, 2H), 7.47 (t, = 7.5 Hz, 1H), 3.33 - 3.29 (m, 2H), 1.56 - 1.45 (m, 2H), 1.34 - 1.25 (m, 6H), 0.88 - 0.82 (m, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 176.6, 164.8, 143.9, 139.5, 133.1, 126.6, 125.9, 125.3, 119.4, 111.4, 38.7, 31.5, 29.8, 26.7, 22.5, 14.4.

[082] Example 44:

Methyl (4-oxo-l,4-dihydroquinoline-3-carbonyl)-L-alaninate(42):

Yield 38% ; 1H NMR (400 MHz, CD₃OD): δ 8.74 (s, 1H), 8.47 - 8.29 (m, 1H), 7.86 -7.76 (m, 1H), 7.64 (d, = 8.3 Hz, 1H), 7.58 - 7.44 (m, 1H), 4.69 (d, = 7.3 Hz, 1H), 3.79 (s, 3H), 1.55 (d, = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CD₃OD): δ 177.3, 173.3, 165.5, 143.6, 139.2, 132.9, 126.3, 125.4, 125.2, 118.5, 110.3, 51.5, 47.0, 17.0.

[083] Example 45:

7-chloro-4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide(43):

Yield 48% ; IR O_max(film): 2920, 2868, 1661, 1601 cm^{" 1;} 1H NMR (400 MHz, DMSO-de): δ 12.91 (br. s., 1H), 12.30 (s, 1H), 8.90 (s, 1H), 8.29 (d, = 8.8 Hz, 1H), 7.80 -7.67 (m, 3H), 7.58 - 7.51 (m, 1H), 7.36 (t, = 7.7 Hz, 2H), 7.09 (t, = 7.3 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 176.3, 162.9, 145.4, 140.3, 139.2, 138.0, 129.5, 128.2, 126.1, 125.1, 123.9, 120.1, 118.8, 111.6.

[084] Example 46:

6-chloro-4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide(44):

Yield 52% ; 1H NMR (400 MHz, DMSO-d₆): δ 13.05 (brs, 1H), 12.27 (s, 1H), 8.88 (s, 1H), 8.21 (d, = 2.2 Hz, 1H), 7.86 - 7.67 (m, 4H), 7.36 (t, = 7.8 Hz, 2H), 7.16 - 7.04 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.6, 162.9, 144.9, 139.1, 138.2, 133.5, 130.4, 129.5, 127.5, 124.9, 123.9, 122.0, 120.1, 111.4.

[085] Example 47:

l-benzyl-4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide(45)

Yield 55% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.30 (s, 1H), 9.05 (s, 1H), 8.60 (dd, = 1.7, 8.1 Hz, 1H), 7.82 (d, = 7.8 Hz, 2H), 7.69 - 7.62 (m, 1H), 7.55 - 7.45 (m, 2H), 7.43 - 7.34 (m, 5H), 7.24 - 7.18 (m, 2H), 7.17 - 7.10 (m, 1H), 5.53 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 176.9, 162.9, 148.7, 139.3, 138.7, 134.1, 133.1, 129.4, 128.9, 128.7, 128.0, 127.4, 126.2, 125.5, 123.9, 120.5, 116.9, 112.3, 57.9; HRMS (ESI): Calculated for C₂₃H₁₈0₂N₂Na [M+Na]⁺: 377.1260, found 377.1259; MS: 355 (M+H)⁺.

[086] Advantages of invention:

1. Cost-effective process for synthesis.

2. Carried out at environmentally benign conditions.

3. Short synthetic route.

4. Useful for making several related compounds of medicinal

DR SRINIVASA REDDY recieving NASI – Reliance Industries Platinum Jubilee Award (2015) for Application Oriented Innovations in Physical Sciences.

MYSELF WITH HIM

From left to right: Dr. D. Srinivasa Reddy, Shri Y. S. Chowdary, Dr. Harsh Vardhan, Dr. Girish Sahni

• Dr D. Srinivasa Reddy receiving the prestigious "SHANTI SWARUP BHATNAGAR" award at the occasion of the 75th Foundation day of CSIR.

Shanti Swarup Bhatnagar awardees with the honorable Prime Minister of India

NCL PUNE

DSR Group

//////////WO-2016181414, WO 2016181414,  IVACAFTOR, new patent, COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH,  Anusandhan Bhawan, Rafi Marg New Delhi, INDIA, CSIR, Dr. D. Srinivasa Reddy

Sacubitril, WO 2016180275, New patent, SUZHOU PENGXU PHARMATECH CO., LTD

Sacubitril, WO 2016180275, New patent, SUZHOU PENGXU PHARMATECH CO., LTD

AHU-377 INTERMEDIATES AND METHOD FOR PREPARING AHU-377 AND AHU-377 INTERMEDIATES PATENT

WO2016180275, new patent, SUZHOU PENGXU PHARMATECH CO., LTD. [CN/CN]; 3rd Floor Building 7, 2358 Chang An Road, Wujiang Suzhou, Jiangsu 215200 (CN)

WANG, Peng; (CN).

LI, Pixu; (CN).

GU, Xiangyong; (CN)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016180275&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Heart failure is a very high mortality syndrome, for patients with heart failure, so far no drug can significantly improve mortality and morbidity, and thus a new type of therapy is necessary. AHU-377 (CAS No. 149709-62-6) is an enkephalinase inhibitor, which is a prodrug ester groups can be lost through hydrolysis, converted to pharmaceutically active LBQ657, inhibit endorphin enzyme (NEP) the role of the main biological effects of NEP is to natriuretic peptides, bradykinin and other vasoactive peptide degradation failure. AHU-377 and angiotensin valsartan composition according to the molar ratio of 1 LCZ696. LCZ696 is an angiotensin receptor enkephalinase inhibitors, which can lower blood pressure, treat heart failure may become a new drug. Clinical data show, LCZ696 is more effective for the treatment of hypertension than valsartan alone.

 

Patents US 5,217,996 and US 5,354,892 reported the first synthesis of AHU-377, the synthetic route is as follows:

 

 

 

 

Reaction with unnatural D-tyrosine derivative as a substrate, more expensive, while the second step in the synthesis is necessary to use Pd-catalyzed Suzuki coupling reaction, whereby preparative route costs than the AHU-377 high.

 

 

Patent US 8,115,016 above routes also reported the departure from the pyroglutamate, through multi-step process for preparing a reaction AHU-377, which is more difficult methylation reaction, and the yield is not high. Patent US 8,580,974 also reported a carbonyl group of the a- introducing N, N- dimethyl enamine is converted to methyl, however, there are some problems in the route for constructing methyl chiral centers, are not suitable for scale-up synthesis route as follows:

 

 

 

 

About the latest AHU377 synthesis intermediates, Patent WO2014032627A1 reported using a Grignard reagent to react with epichlorohydrin, a quicker been important intermediates, synthetic route Compound AHU377 synthesized as follows:

 

However, the second step of the synthetic route use succinimide nitrogen atoms introduced by Mitsunobu reaction with hydrochloric acid hydrolysis to remove, then converted to Boc protected at the end of the synthesis process AHU377 Boc will have to take off protection, then any connection with succinic anhydride reaction product introduced into the structure of succinic acid portion, so that this method of atom economy and the economy of the steps are low.

 

Example 1

 

Synthesis of Compound 2

 

 

In inert atmosphere, a solution of three 500mL flask was added compound 1 (10g, 1eq), dissolved after 90mL THF, was added CuI (4.814g, 0.1eq), the system moves to the low temperature in the cooling bath to -20 ℃ when, biphenyl magnesium bromide dropwise addition, the internal temperature was controlled not higher than -10 ℃. Bi closed refrigeration drop, return to room temperature overnight. Completion of the reaction, the reaction solution was poured into saturated the NH ₄ of Cl (10vol, 100 mL) was stirred at room temperature for 0.5h. Suction filtered, the filter cake was rinsed with a small amount of EA, and the filtrate was transferred to a separatory funnel carved, and the aqueous phase was extracted with EA (10vol × 2,100mL × 2) and the combined organic phases with saturated NaHC [theta] ₃ , the NH ₄ of Cl, each Brine 150mL (15vol) washed once, dried over anhydrous over MgSO ₄ dried, suction filtered, and concentrated to give a white solid. Product obtained was purified by column 15.2g, yield 78%.

 

NMR data for the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.6Hz, 2H), 7.52 (D, J = 8.1Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.38-7.25 (m, 8H), 4.62-4.47 ( m, 2H), 4.09 (dd, J = 6.7,3.5Hz, 1H), 3.54 (dd, J = 9.5,3.5Hz, 1H), 3.43 (dd, J = 9.4 , 6.9Hz, 1H), 2.84 ( d, J = 6.6Hz, 2H), 2.38 (s, 1H).

 

Example 2

 

Synthesis of Compound 3

 

 

In an inert gas, at room temperature was added to the flask 500mL three Ph3P (18.54g, 2eq), 240mL DCM dissolution, butyryl diimide (of 6.44 g), compound 2 (15g), an ice-water bath cooling to 0 ℃ or so, was added dropwise DIAD (14mL) was complete, the reaction go to room temperature.Starting material the reaction was complete, the system was added to water (100 mL) quenched the reaction was stirred for 10min; liquid separation, the aqueous phase was extracted with DCM (100mL × 2), the combined organic phases with saturated Brine 100mL × 2), dried over anhydrous over MgSO ₄ dried , filtration, spin dry to give a white solid; product was purified by column 15.4g, yield 82%.

 

NMR data for the product are as follows:

 

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.56 (D, J = 7.4Hz, 2H), 7.49 (D, J = 8.0Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.37-7.30 (m, 3H), 7.27 ( d, J = 6.7Hz, 3H), 7.22 (d, J = 8.0Hz, 2H), 4.75 (s, 1H), 4.56 (d, J = 12.0Hz, 1H), 4.45 (d, J = 12.0Hz, 1H ), 4.06 (t, J = 9.6Hz, 1H), 3.70 (dd, J = 10.0,5.2Hz, 1H), 3.23 (dd, J = 13.8,10.3Hz, 1H) , 3.14-3.00 (m, 1H), 2.48 (d, J = 4.0Hz.4H).

 

Example 3

 

Synthesis of Compound 4

 

 

Protection of inert gas, at room temperature was added to the flask 1L three compound 3 (18.81g), 470mL EtOH was dissolved, was added Pd / C, replaced the H ₂ three times, move heated on an oil bath at 60 ℃ reaction. Raw reaction was complete, the system was removed from the oil bath, the reaction solution was suction filtered through Celite and concentrated to give the crude product. It was purified by column pure 11.8g, a yield of 81.2%.

 

NMR data for the product are as follows:

 

₁ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.8Hz, 2H), 7.51 (D, J = 7.8Hz, 2H), 7.42 (T, J = 7.5Hz, 2H), 7.33 (T , J = 7.2Hz, 1H), 7.26 (d, J = 7.2Hz, 2H), 4.55 (d, J = 5.2Hz, 1H), 4.06-3.97 (m, 1H), 3.86 (dd, J = 12.0, 3.1Hz, 1H), 3.16 (dd , J = 8.1,2.9Hz, 2H), 2.58 (t, J = 7.0Hz, 4H), 1.26 (s, 2H).

Example 4

 

Synthesis of Compound 7

 

Protection of inert gas, at room temperature to a 25mL flask was added three Dess-Martin oxidant (767.7mg), 10mL DCM was dissolved, the system was cooled down to -10 deg.] C, was added 4 (500mg). Starting material the reaction was complete, to the system was added saturated NaHCO3 and Na2S2O3 each 5mL, quench the reaction stirred for 10min; aqueous phase was extracted with DCM (10mL × 3) and the combined organic phases with saturated NaHCO3, Brine 30mL each wash, dried over anhydrous MgSO4, filtration, spin dried to give the crude product used directly in the next reaction cast.

Example 5

 

Synthesis of Compound 8

Inert gas, at room temperature for three to 500mL flask 7 (497.5mg), 10mL DCM to dissolve an ice water bath to cool, added phosphorus ylide reagent (880.6mg), the system was removed from the ice water bath at room temperature. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. Liquid separation, the aqueous phase was extracted with DCM (10mL × 2), organic phases were combined, washed with saturated Brine 20mL × 2, dried over anhydrous MgSO4, filtration, spin crude done. Product obtained was purified by column 563mg, 90% yield.

 

NMR data for the product are as follows:

 

¹ the H NMR (400MHz, CDCl ₃ ) δ7.60-7.53 (m, 2H), 7.51 (D, J = 8.1Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.33 (D, J = 7.3Hz, 1H), 7.23 (d , J = 8.1Hz, 2H), 7.13 (dd, J = 9.2,1.5Hz, 1H), 5.26 (td, J = 9.5,6.9Hz, 1H), 4.25-4.05 ( m, 2H), 3.40 (dd , J = 13.7,9.7Hz, 1H), 3.13 (dd, J = 13.8,6.7Hz, 1H), 2.53 (d, J = 2.2Hz, 4H), 1.85 (d, J = 1.4Hz, 3H), 1.30 ( t, J = 7.1Hz, 3H).

Example 6

 

Synthesis of Compound 9

 

Protection of inert gas, at room temperature to a 50mL flask was added three 8 (365mg, 1eq), 9mL of ethanol and stirred to dissolve, the system was replaced with hydrogen three times, was added Pd / C (25% w / w) at room temperature. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. The reaction mixture was suction filtered through Celite and concentrated to give the crude product. Product was purified by column, yield 80.2%, purity 97.2%.

Example 7

 

Synthesis of Compound 10

Equipped with Compound 9 (100mg) acetic acid A reaction flask (9mL), hydrochloric acid (1mL). The reaction was heated oil bath at 80 deg.] C. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. After saturated NaHCO3 and extracted with EA and concentrated to give crude product. Product obtained was purified by column 90mg, yield 84%.

 

NMR data for the product are as follows:

 

¹ the H NMR (400MHz, CDCl ₃ ) δ7.61-7.54 (m, 2H), 7.53-7.48 (m, 2H), 7.41 (dd, J = 10.5,4.9Hz, 2H), 7.31 (dd, J = 8.3 , 6.4Hz, 1H), 7.22 ( d, J = 8.2Hz, 2H), 5.93 (t, J = 9.7Hz, 1H), 4.34-4.00 (m, 3H), 2.91-2.71 (m, 2H), 2.68 -2.57 (m, 2H), 2.55 (ddd, J = 9.4,7.0,4.3Hz, 1H), 2.42 (dt, J = 13.3,6.8Hz, 2H), 1.97-1.74 (m, 1H), 1.64-1.46 (m, 1H), 1.23 ( td, J = 7.1,3.3Hz, 3H), 1.14 (dd, J = 7.1,3.9Hz, 3H)

Example 8

Synthesis of Compound 5

 

 

Example 8-1: The reaction flask was added compound 4 (1eq) was added water (2VOL), concentrated hydrochloric acid (2VOL), 110 ℃ reaction was heated in an oil bath overnight, complete conversion of starting material, the HPLC peak area 97%. 10% NaOH solution was added to adjust the pH to about 10, filtration products. Yield 85%.

 

Example 8-2: The reaction flask was added compound 4 (1eq) was added ethanol (5 vol), water (5 vol), potassium hydroxide (8 eq), was heated in an oil bath overnight at 110 ℃ reaction, complete conversion of the starting material, the HPLC peak area 99%. Water was added (5Vol), filtered to obtain the product. Yield 95%. Product was dissolved in toluene, was added ethanolic hydrochloric acid, the precipitated hydrochloride Compound 5.

NMR data for the product are as follows:

 

¹ the H NMR (400MHz, of DMSO) [delta] 8.31 (S, 3H), 7.70-7.61 (m, 4H), 7.47 (T, J = 7.6Hz, 2H), 7.42-7.31 (m, 3H), 4.09 (the dq- , J = 42.6,7.1Hz, 1H), 3.62-3.51 (m, 1H), 3.50-3.41 (m, 1H), 3.11-3.00 (m, 1H), 2.95-2.84 (m, 1H), 1.30-1.10 (m, 1H).

 

EXAMPLE 9

Synthesis of Compound 6

 

To the reactor was added compound 5, was added absolute ethanol (3vol). Temperature of the outer set 30 ℃ heating, stirring was continued after the temperature reached 25 ℃ 20min. Was added 30% NaOH aqueous solution (1.1eq). External temperature 65 ℃ heating provided, after the internal temperature reached 60 deg.] C was slowly added (of Boc) ₂ O (1.1 eq). Stirring 0.5h, reaction monitoring. After completion of the reaction, water was added slowly dropwise (8vol), turn off the heating and natural cooling. The system temperature was lowered to 25 deg.] C and continue stirring for 2h. Filter cake at 50 ℃ blast oven drying to obtain the product.

 

NMR data of the product are as follows:

 

¹ the H NMR (400MHz, CDCl ₃ ) δ7.61-7.50 (m, 4H), 7.61-7.50 (m, 4H), 7.46-7.39 (m, 2H), 7.48-7.38 (m, 2H), 7.38-7.23 (m, 3H), 7.37-7.26 ( m, 3H), 4.82 (d, J = 7.9Hz, 1H), 4.82 (d, J = 7.9Hz, 1H), 3.91 (s, 1H), 3.70 (d, J = 11.0Hz, 1H), 3.77-3.54 (m, 2H), 3.65-3.47 (m, 1H), 2.88 (d, J = 7.0Hz, 2H), 2.88 (d, J = 7.0Hz, 2H), 2.51 (s, 1H), 2.51 (s, 1H), 1.42 (s, 9H), 1.42 (s, 9H).

 

Synthesis of Intermediate Compound 6 to Compound 10, i.e., the AHU-377, a synthetic route in the background of the present invention, the cited patent application WO2014032627A1 loaded in detail, not in this repeat.

 

Example 10

Synthesis of Compound 2

 

 

Benzyl glycidyl ether preparation (50g) in THF (200mL) was added. Under inert gas protection, the biphenyl magnesium bromide (365mmol) was added to THF (1020mL) was added the reaction flask is placed in a low temperature bath -40 ℃ cooling. Cuprous iodide (O.leq) when the internal temperature dropped to -9 ℃. Continued to decrease the temperature of -23 ℃ dropwise addition of benzyl glycidyl ether in THF was added dropwise to control the internal temperature process of not higher than -15 deg.] C, 47 min when used, the addition was completed the cooling off the reaction was stirred overnight. The cooling system to -20 ℃ quenched with 1N HCl aqueous solution, <10 ℃ Go stirred 30min at room temperature. Liquid separation, the aqueous phase was extracted with THF, the combined THF phases. Respectively saturated ammonium chloride (250mL), saturated brine (250mL) washed. Rotary evaporation to remove THF, and water (200 mL) Continue rotary evaporation 1h, cool to precipitate a solid. Suction crude. Crude n-heptane was added 2Vol beating, suction filtration to obtain the product in a yield of 90 ~ 95%, HPLC peak area 94%. In another column purification was pure, columned yield 88.6%, HPLC 99.1%.

 

Example 11

 

Synthesis of Compound 3

 

Preparation Example 9, said compound taking the embodiment 2 (5g) added to the reaction flask, the reaction flask was added toluene (80mL), phthalimide (2.55 g of) and triphenylphosphine (5.35g of), the nitrogen was replaced protection. An ice-salt bath cooling to -5 deg.] C, was added dropwise DIAD (4.12g), dropwise addition was exothermic, the temperature was raised to 5 ℃. The reaction was continued 1h sampling HPLC test material substantially complete reaction. Join 12g silica spin column done to collect the product (including DIEA derivative).

 

Example 12

Synthesis of Compound 11

 

 

Compound 3 (3g) was added to the reaction flask embodiment taken in Preparation Example 10, was added ethanol (30 mL), with stirring. Was added hydrazine hydrate (2g) was heated in an oil bath reflux 1h, when supplemented with 20mL ethanol was stirred difficulties, the reaction was continued to 2.5h, HPLC showed the starting material the reaction was complete. Add EA / H2O 100mL each liquid separation, the EA phase was washed with water (100mL) and the combined organic phases were washed with water (100mL) and saturated brine (100mL) washed. Anhydrous magnesium sulfate and filtered spin column was done product 1.88g, yield 88%, HPLC 94%.

 

NMR data of the product are as follows:

 

¹ the H NMR (400MHz, of DMSO) [delta] 7.64 (D, J = 7.2Hz, 2H), 7.57 (D, J = 8.1Hz, 2H), 7.45 (T, J = 7.6Hz, 2H), 7.39-7.32 ( m, 5H), 7.29 (d , J = 8.1Hz, 3H), 4.55-4.43 (m, 2H), 3.38-3.23 (m, 3H), 3.18-3.10 (m, 1H), 2.82-2.74 (m, 1H), 2.61-2.52 (m, 1H ).

 

Example 13

 

Synthesis of Compound 11

 

To the toluene solution of the compound 2 was added phthalimide (1.1 eq), triphenylphosphine (1.3 eq) with stirring. External bath set -10 ℃, to cool the system, the internal temperature dropped to 0 ~ 5 ℃, start dropping DIAD (1.3eq), control the internal temperature -5 ~ 5 ℃. Completion of the dropwise addition, the cooling bath was turned off outside the reaction was stirred at room temperature. The reaction was stirred for 1 to 4 hours. The reaction solution to give compound 3, administered directly in the next reaction. To the above reaction mixture was added hydrazine hydrate (6 eq), heated to 70 ~ 80 ℃, to complete the reaction, filtered hot, the filtrate. Aqueous sodium hydroxide solution (20vol 10%) was stirred for 0.5h, allowed to stand for liquid separation from toluene phase. Water was added (20vol) was stirred for 0.5h, allowed to stand for liquid separation from toluene phase. The toluene phase was added hydrochloric acid (20vol, 3N), stirred for 0.5h, to form a solid precipitate. Filtration and drying to obtain a product, i.e. compound 11, the hydrochloride salt, yield 60% in two steps.

NMR data of the product are as follows:

 

¹ the H NMR (400MHz, of DMSO) [delta] 8.46 (S, 3H), 7.63 (dd, J = 16.4,7.7Hz, 4H), 7.47 (T, J = 7.6Hz, 2H), 7.42-7.22 (m, 8H ), 4.56 (d, J = 12.1Hz, 1H), 4.48 (d, J = 12.1Hz, 1H), 3.58 (d, J = 7.9Hz, 2H), 3.47 (dd, J = 10.9,6.3Hz, 1H ), 3.11 (dd, J = 13.5,4.9Hz, 1H), 2.92 (dd, J = 13.4,9.1Hz, 1H).

Example 14

 

Synthesis of Compound 12

 

 

Weigh Compound 11 (1.38g) was added to the reaction flask. To the reaction flask plus DCM (14ml) and Et3N (462mg, 0.73ml). Weighed (of Boc) ₂O (1.23 g of) was added to DCM (5ml) was dissolved. Room temperature (8 ℃), a solution (of Boc) ₂ DCM solution O was added dropwise to the reaction, (2ml) rinsed with DCM. The reaction mixture was stirred at room temperature, detected by HPLC, the reaction ends 4h. Reaction mixture was washed (15ml) 3 times with Brine (15ml) The reaction solution was washed 1 times. Inorganic sulfate, concentrated and purified by column PE:EA = 15:1 give product 560mg, yield 30.8%, HPLC 99.92%.

NMR data of the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.6Hz, 2H), 7.49 (D, J = 7.4Hz, 2H), 7.43 (T, J = 7.3Hz, 2H), 7.39-7.28 (m, 5H), 7.24 ( d, J = 9.0Hz, 3H), 5.00-4.80 (br, 1H), 4.51 (q, J = 11.8Hz, 2H), 4.08-3.85 (br, 1H), 3.43 ( d, J = 2.9Hz, 2H) , 3.02-2.77 (m, 2H), 1.42 (s, 9H).

Example 15

Synthesis of Compound 6

 

 

Weigh Compound 12 (250mg) and methanol (9ml) was added to the reaction flask. Added Pd / C (138mg, 1 / 4w / w, water content 55%). The H ₂replaced 3 times, 50 ℃ stirred and heated. HPLC detection reaction, the reaction end 30h. Filtered off Pd / C, 40 ℃ concentrated under reduced pressure to remove methanol. PE:EA = 3:1 florisil column to give the product 196mg, 100% yield, 99.34% purity.

 

NMR data of the product are as follows:

 

¹ the H NMR (400MHz, CDCl ₃ ) δ7.61-7.50 (m, 4H), 7.61-7.50 (m, 4H), 7.46-7.39 (m, 2H), 7.48-7.38 (m, 2H), 7.38-7.23 (m, 3H), 7.37-7.26 ( m, 3H), 4.82 (d, J = 7.9Hz, 1H), 4.82 (d, J = 7.9Hz, 1H), 3.91 (s, 1H), 3.70 (d, J = 11.0Hz, 1H), 3.77-3.54 (m, 2H), 3.65-3.47 (m, 1H), 2.88 (d, J = 7.0Hz, 2H), 2.88 (d, J = 7.0Hz, 2H), 2.51 (s, 1H), 2.51 (s, 1H), 1.42 (s, 9H), 1.42 (s, 9H).

 

Method for preparing the AHU-377, characterized by comprising the steps of: (a) Compound (1) S- benzyl glycidyl ether and biphenyl Grignard reagent produced by the reaction of the compound (2) in an organic solvent; ( b) compound (2) with a succinimide or phthalimide Mitsunobu reaction occurs in an organic solvent to form a compound (3); (C) compound (3) in an organic solvent in the role of a catalyst under removal debenzylation protected form compound (4); (D) compound (4) with an oxidizing agent oxidation reaction occurs in an organic solvent to form a compound (7); (E) compound (7) with a phosphorus ylide reagent in an organic solvent to give the compound (8); (F.) compound (8) in an organic solvent in the selective catalytic hydrogenation of the compound (9); and (g) of the compound (9) in an organic solvent in the hydrolysis reaction of the amide compound occurs in the presence of an acid ( 10), i.e., AHU-377;