ChemicalBook CAS DataBase List LeterMovir

LeterMovir synthesis

10synthesis methods

Product Name:LeterMovir
CAS Number:917389-32-3
Molecular formula:C29H28F4N4O4
Molecular Weight:572.55

Letermovir, also known as MK-8828 and AIC-246, is an antiviral drug that is being developed for the treatment of cytomegalovirus (CVM) infections. Letermovir has been tested in CMV infected patients with allogeneic stem cell transplants and may also be useful for other patients with a compromised immune system such as those with organ transplants or HIV infections. Synthetic Description Reference: Humphrey, Guy & M. Dalby, Stephen & Andreani, Teresa & Xiang, Bangping & R. Luzung, Michael & Jake Song, Zhiguo & Shevlin, Michael & Christensen, Melodie & Belyk, Kevin & M. Tschaen, David. (2016). Asymmetric Synthesis of Letermovir Using a Novel Phase-Transfer-Catalyzed Aza-Michael Reaction. Organic Process Research & Development. 20. 10.1021/acs.oprd.6b00076. Synthetic Description Reference: P.-S. Wang, M.-L. Shen, T.-C. Wang, H.-C. Lin, L.-Z. Gong, Angew. Chem. Int. Ed. 2017, 56, 16032. Synthetic Description Reference: Goossen, Kaethe; Kuhn, Oliver; Berwe, Mathias; Krueger, Joachim; Militzer, Hans-Christian. Process for preparation of dihydroquinazolineacetic acids via hydrolysis of the corresponding alkyl esters. WO 2006133822. (Assignee Bayer Healthcare A.-G., Germany) Synthetic Description Reference: Paulus, Kerstin; Schwab, Wilfried; Grunder, Dominique; Van Hoogevest, Peter. Pharmaceutical preparation containing an antivirally effective dihydroquinazoline derivative. WO 2013127970. (Assignee AiCuris GmbH & Co. KG, Germany) Synthetic Description Reference: Grunenberg, Alfons; Berwe, Mathias; Keil, Birgit; Aret, Edwin; Paulus, Kerstin; Schwab, Wilfried. Preparation of sodium and calcium salts of dihydroquinazoline derivatives useful in the prevention and/or treatment of viral infections. WO 2013127971. (Assignee AiCuris GmbH & Co. KG, Germany) Synthetic Description Reference: Luzung, Michael; Humphrey, Guy; Xiang, Bangping; Belyk, Kevin M.; Dalby, Stephen Mark; Schwab, Wilfried; Klenke, Burkhard; Moody, Tom; Brown, Gareth. Process for the preparation of substituted quinazoline compounds. WO 2015088931. (Assignee Merck Sharp & Dohme Corp., USA; AiCuris GmbH & Co. KG) Synthetic Description Reference: Zhang, Chengzhi; Chakma, Justin. Preparation of deuterated dihydroquinazoline inhibitors of viral terminase. WO 2016109360. (Assignee Auspex Pharmaceuticals, Inc., USA) Synthetic Description Reference: Chung, Cheol K.; Humphrey, Guy R.; Liu, Zhijian; McLaughlin, Mark; Xu, Yingju; Yu, Younong. Novel processes for making substituted quinazoline compounds using hydrogen bonding catalysts. WO 2017091453. (Assignee Merck Sharp & Dohme Corp., USA)

Synthetic Routes

ROUTE 1

ROUTE 2

ROUTE 3

ROUTE 4

ROUTE 5

ROUTE 6

ROUTE 7

ROUTE 8

Reference: Humphrey, Guy & M. Dalby, Stephen & Andreani, Teresa & Xiang, Bangping & R. Luzung, Michael & Jake Song, Zhiguo & Shevlin, Michael & Christensen, Melodie & Belyk, Kevin & M. Tschaen, David. (2016). Asymmetric Synthesis of Letermovir Using a Novel Phase-Transfer-Catalyzed Aza-Michael Reaction. Organic Process Research & Development. 20. 10.1021/acs.oprd.6b00076.

917389-30-1 Synthesis

Butanedioic acid, 2,3-bis[(4-methylbenzoyl)oxy]-, (2S,3S)-, compd. with methyl (4S)-8-fluoro-3,4-dihydro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4-quinazolineacetate (1:1)

917389-30-1
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917389-32-3
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Yield:917389-32-3 96.4%

Reaction Conditions:

with water;sodium hydrogencarbonate;sodium hydroxide in tert-butyl methyl ether;Reflux;Large scale;

Steps:

3b

A mixture of (2S 3^-2,3-bis [(4-methylbenzoyl)oxy]succininc acid -{(45 8-fluoro-2-[4-(3- methoxyphenyl)piperazin- 1 -yl] -3 -[2-methoxy-5-(trifluoromethyl)phenyl] -3 ,4-dihydro- quinazolin-4-yl} acetic acid methyl ester (l :l-salt) (30,8 kg), sodium hydrogen carbonate (16.4 kg) and water (315 L) is stirred with MTBE (160 L). The phases obtained are separated and the organic phase is treated with 35 L of a 7% sodium hydrogen carbonate solution. The phases obtained are separated again and the organic phase is treated with 125 L of a 4% sodium hydroxide solution. The mixture is heated under reflux conditions. The solvent is distilled to run dry. The residual content of the reactor is stirred for further 5 h at 55 - 60°C. To the mixture MTBE (160 L) and water (65 L) is added under stirring at 22°C. The phases obtained are separated again and the organic phase is extracted with the aid of a 6% aqueous sodium chloride solution (30 L). The aqueous phases are reunited and stirred with water (25 L) and MTBE (160 L). The pH is adjusted to 6.5 with the aid of IN muriatic acid. The organic phase is separated, the solvent is gently distilled to run dry and the residue is dissolved in acetone (approximately 75 L). A change of the solvent is conducted towards acetone by means of 6 distillation steps of 130 L each. The product is subsequently precipitated by adding the residual solvent (approximately 60 L) under stirring conditions (61 rpm) in an excess of water (492 L) at room temperature. Followed by centrifugation, the isolated product is dried in a vacuum dryer equipped with a spiral crumbling roller at 40 to 80°C. By this procedure a yield of 16,5 kg of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin- l-yl]-3-(2-memoxy-5-trifluormethylphenyl)-3,4-dihydroquina2olin-4-yl}acetic acid is obtained as amorphous compound corresponding to 96.4% in theory.1H NMR (300 MHz, d₆-DMSO): δ = 7,53 (d,²J - 8,4, 1H), 7,41 (brs, 1H), 7,22 (d,²J = 8,5, 1H), 7,09-7,01 (m, 2H), 6,86 (m, 2H)₅6,45 (dd,²J = 8,2,³J = 1,8, 1H), 6,39-6,34 (m, 2H), 4,87 (t,²J= 7,3, 1H), 3,79 (brs, 3H), 3,68 (s, 3H), 3,50-3,38 (m, 4H), 2,96-2,75 (m, 5H), 2,45- 2,40 (m, 1H) ppm; MS (API-ES-neg.): m/z = 571 [(M-H), 100 %];

References:

WO2014/202737,2014,A1 Location in patent:Page/Page column 53