AHU-377 synthesis

5synthesis methods

Product Name:AHU-377
CAS Number:149709-62-6
Molecular formula:C24H29NO5
Molecular Weight:411.49

Sacubitril, also known as AHU377, is angiotensin receptor neprilysin inhibitor being studied for use in combination with valsartan for heart failure. Sacubitril is a prodrug that is activated to LBQ657 by de-ethylation via esterases. LBQ657 inhibits the enzyme neprilysin, which is responsible for the degradation of atrial and brain natriuretic peptide, two blood pressure lowering peptides that work mainly by reducing blood volume. Synthetic Description Reference: Zhang, Bo; Ding, Xiaohua; Dai, Dongcheng; Lei, Sijun; Liu, Xueming; Duan, Panpan; Chen, Yongkai; Wang, Chaodong. Preparation of crystal form and amorphous form of AHU-377 ammonium salt. WO 2018196860. (Wuhan Ll Science and Technology Development Co., Ltd., Peop. Rep. China; Wuhan Qr Pharmaceuticals Co., Ltd) Synthetic Description Reference: Thirumalai Rajan, Srinivasan; Eswaraiah, Sajja; Rajeshwar Reddy, Sagyam; Rajesham, Boge; Chakradhar, Nandigama; Srinivasa Rao, Ambati. Process for the preparation of trisodium sacubitril valsartan, its polymorphs, and solid dispersions thereof. WO 2017154017. (MSN Laboratories Private Limited, India) Synthetic Description Reference: Putapatri, Siddamal Reddy; Khairnar, Bhushan Balasaheb; Pandey, Gyanendra; Singh, Kaptan; Prasad, Mohan; Kumar, Ashok. Process for the preparation of sacubitril or salts thereof. WO 2017141193. (Sun Pharmaceutical Industries Limited, India) Synthetic Description Reference: Yan, Jie; Xu, Wenjie; Li, Song; Zheng, Yanxin; Zhi, Jianqiong. Process for preparation of angiotensin II receptor antagonist metabolite and nep inhibitor composite. WO 2017125031. (Process for preparation of angiotensin II receptor antagonist metabolite and nep inhibitor composite). Synthetic Description Reference: Halama, Ales; Zvatora, Pavel; Voslar, Michal; Stach, Jan; Zapadlo, Michal; Dammer, Ondrej; Krejcik, Lukas; Dvorakova, Lenka; Rezankova, Marketa; Vyslouzil, Rostislav. Preparation and characterization of sacubitril in crystal forms. WO 2017097275. (Zentiva, K.S., Czech Rep.) Synthetic Description Reference: Bodkhe, Arjun Rajaram; Maurya, Sadanand Hardeo; Samala, Rajamouli Srihari; Jagtap, Sunil Baburao; Joshi, Ashutosh Vijay; Luthra, Parven Kumar. Preparation of sacubitril and salt thereof and novel compounds used in the process. WO 2017033212. (Actavis Group Ptc Ehf., Iceland)

Synthetic Routes

ROUTE 1

ROUTE 2

ROUTE 3

ROUTE 4

ROUTE 5

ROUTE 6

ROUTE 7

ROUTE 8

ROUTE 9

ROUTE 10

Reference: Zhang, Bo; Ding, Xiaohua; Dai, Dongcheng; Lei, Sijun; Liu, Xueming; Duan, Panpan; Chen, Yongkai; Wang, Chaodong. Preparation of crystal form and amorphous form of AHU-377 ammonium salt. WO 2018196860. (Wuhan Ll Science and Technology Development Co., Ltd., Peop. Rep. China; Wuhan Qr Pharmaceuticals Co., Ltd)

108-30-5 Synthesis

108-30-5
643 suppliers
$5.00/25g

(2R,4S)-4-Amino-5-(biphenyl-4-yl)-2-methylpentanoic Acid Ethyl Ester Hydrochloride

149690-12-0
229 suppliers
$48.00/1g

149709-62-6
254 suppliers
$39.00/1mg

Yield:149709-62-6 98.5 %Chromat.

Reaction Conditions:

Stage #1:(2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride with triethylamine in dichloromethane at 20; for 0.166667 h;
Stage #2:succinic acid anhydride in dichloromethane at 0; for 4 h;

Steps:

1 EXAMPLE 1 (synthesis of AHU-377 acid)
100 ml of cliehioromethane and 12 ml of triethylamine was added to 10 g of the hydrochloride of amine (3). The mixture was agitated at the room temperature for approx. 10 minutes. This was followed by addition of 4.3 g of succinic aithydride and agitation of the mixture at the room temperature for 4 hours. 100 ml of IM HCI was added to the mixture, the layers were separated, the organic layer was washed with water and dried over sodium sulphate, Afterfiltration of the desiccant the solvent was evaporated in vacuo (75°C, 10 mbar) and the product was obtained in the form of transparent honey. According to HPLC analyses the product usually contained 97.5 to 98.5% of the desired substance.

References:

ZENTIVA, K.S.;HALAMA, Ales;ZVATORA, Pavel;DAMMER, Ondrej;STACH, Jan;ZAPADLO, Michal;KREJCIK, Lukas;VOSLAR, Michal WO2016/74651, 2016, A1 Location in patent:Page/Page column 20

108-30-5 Synthesis

108-30-5
643 suppliers
$5.00/25g