Argatroban

ArgatrobanMolecular Formula: C23H36N6O5S
Formula Weight: 508.63
CAS No.: 74863-84-6 

(2R,4R)-1-[(2S)-5-(diaminomethylideneamino)-2-
[[(3R)-3-methyl-1,2,3,4-tetrahydroquinolin-8-yl]
sulfonylamino]pentanoyl]-4-methyl-piperidine-2-
carboxylic acid

PATENT

US 7,589,106, 7,687,516, EP 0008746; US 4258192, US 4201863

Argatroban is an anticoagulant that is a small molecule direct thrombin inhibitor.[1] In 2000, argatroban was licensed by the Food and Drug Administration (FDA) for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). In 2002, it was approved for use during percutaneous coronary interventions in patients who have HIT or are at risk for developing it. In 2012, it was approved by the MHRA in the UK for anticoagulation in patients with Heparin-Induced Thrombocytopenia Type II (HIT) who require parenteral antithrombotic therapy.[2]

Argatroban is given intravenously and drug plasma concentrations reach steady state in 1-3 hours.[3] Argatroban is metabolized in the liver and has a half-life of about 50 minutes. It is monitored by PTT. Because of its hepatic metabolism, it may be used in patients with renal dysfunction. (This is in contrast to lepirudin, a direct thrombin inhibitor that is primarily renally cleared).

Argatroban is used as an anticoagulant in individuals with thrombosis and heparin induced thrombocytopenia. Often these individuals require long term anticoagulation. If warfarin is chosen as the long term anticoagulant, this poses particular challenges due to the falsely elevated prothrombin time and INR caused by argatroban. The combination of argatroban and warfarin may raise the INR to greater than 5.0 without a significant increased risk of bleeding complications.[4] One solution to this problem is to measure the chromogenic factor X level. A level < 40-45% typically indicates that the INR will be therapeutic (2-3) when the argatroban is discontinued.

 ……………………………………………………….

Argatroban monohydrate

Argatroban is a synthetic direct thrombin inhibitor and the chemical name is 1-[5-[(aminoiminomethyl) amino]-1-oxo2[[(1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2- piperidinecarboxylic acid, monohydrate. Argatroban has 4 asymmetric carbons. One of the asymmetric carbons has an R configuration (stereoisomer Type I) and an S configuration (stereoisomer Type II). Argatroban consists of a mixture of R and S stereoisomers at a ratio of approximately 65:35.

The molecular formula of argatroban is C23H36N6O5S•H2O. Its molecular weight is 526.66 g/mol. cas 141396-28-3

Argipidine, Argatroban monohydrate, GN1600, DK-7419, MDI-805 Acova, Slonnon, Novastan

Mitsubishi Chemical (Originator), Encysive Pharmaceuticals (Licensee), Mitsubishi Pharma (Distributor), Daiichi Pharmaceutical (Codevelopment), GlaxoSmithKline (Codevelopment), Mitsubishi Pharma (Codevelopment), Sanofi-SynthLabo (Codevelopment)

Antithrombocytopenic, CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, HEMATOLOGIC DRUGS, Hematopoiesis Disorders Therapy, Ischemic Stroke, Treatment of, NEUROLOGIC DRUGS, Peripheral Vascular Disease, Treatment of, Stroke, Treatment of, Treatment of Peripheral Obstructive Vascular Disease, Thrombin Inhibitors

Synthesis of argatroban on the method reported in the literature there are two synthetic routes, patent EP8746, US4258192, US4201863, JP8115267 relates to a route is: with 4 – methyl-piperidine as a starting material was prepared first intermediate body (2R, 4R) -4 – methyl-2 – ethyl-piperidine, and the first and a t-BOC protected amino nitro-L-arginine condensation, and then the 3 – methyl – 8 – quinoline sulfonyl chloride condensation after hydrolysis, hydrogenation, hydration be argatroban. This entry route synthesis process complicated procedure to be carried out under the protection of nitrogen, the raw material is highly toxic gas phosgene, the operation more difficult.

US4117127, JP02-212473, EP823430, EP8746, JC S Perk Transl 1981 (5), JP02-212473 relates to an alternative route is: nitro L-arginine prior to the 3 – methyl-8 – subsequent condensation quinoline sulfonyl chloride Intermediate (2R, 4R) -4 – methyl-2 – piperidinecarboxylate condensation, and then after hydrolysis, hydrogenation, hydration be argatroban. This synthetic route despite the relatively simple process method, to obtain raw materials, but this method using reagents such as phosphorus oxychloride, phosphorus trichloride has a pungent odor, easy to absorb moisture in humid air, intense smoke, environmental pollution, greater stimulation of the body’s respiratory tract, can cause eye and skin irritation and burning, and the use of this method, complex operation, low yield, high cost.

Patent CN100586946C Argatroban discloses a method for separating optically active isomeric compounds, the feedstock argatroban mixed solvent of alcohol and water was heated to reflux 5-10 hours, cooled and allowed to stand, and filtered to give White crystalline product, dried, repeated 2-6 times. [0008] Patent CN101033223A discloses a Argatroban is the main by-product (2R, 4R)-l_ [N2-(3_ methyl-8 – quinolinesulfonyl)-L-arginyl] -4 – methyl-2 – carboxylic acid, argatroban, and the byproducts are difficult to isolate, argatroban two diastereomeric isomer 21 (S) and 21 (R) separation of work attracted a lot of research persons. Because both physical and chemical properties are very similar, so separation is very difficult. 1993 Rawson, Thomas E.; VanGorp, Kimmie A.; Yang, Janet so first by high pressure liquid chromatography and column chromatography separation to obtain a single 21 (S) and 21 (R) argatroban [ Journal of Pharmaceutical Sciences vol. 82, No. 6,672]; Thibaudeau Karen et al. reported Protein A chromatographic separation [US6440417]. However, due to the separation of these methods a small amount of low efficiency, so there is no practical value industrialization. 2006 China Tianjin Weijie Technology Co., Ltd. Song Honghai et al. Reported using recrystallization Separation 21 (S) and 21 (R) argatroban way [0 With 951,936 it], so that the mass 21 (5) Aga music classes as possible, but the law of low yield, complicated operation, high cost, and a large amount of a small amount of 21 (S) of 21 (R)-product argatroban, from the viewpoint of industrial production, is still a ideal method. [0009] These methods can be effectively prepared argatroban, but the purity of the desired product is not high, poor color, content is low, affecting the quality of the results of its preparation.

U.S. Pat. No. 4,201,863 (6 May 1980) and EP 8746 (filed on 22 Aug. 1979 with priority based on the application for the cited US patent) describe a class of N2-arylsulphonyl-L-argininamide drugs, with anti-thrombotic activity, and the processes for obtaining them. Of these, the compound 4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulphonyl)-L-arginyl]-2-piperidine carboxylic acid (argatroban, isomers mixture) is described. The described process comprises the synthesis of an intermediate NG-substituted-N2-quinolinesulphonyl-L-argininamide from which the desired compound is obtained by catalyzed hydrogenolysis or acidolysis and catalyzed hydrogenation. The general conditions provided for the hydrogenolysis and hydrogenation reaction are: i) inert solvents (methanol, ethanol, tetrahydrofuran or dioxane); ii) presence of a catalyst (Raney nickel, palladium, platinum, ruthenium, rhodium); iii) hydrogen atmosphere at a pressure between 1 and 100 kg/cm2 and preferably between 5 and 50 kg/cm2; iv) temperature between 0° C. and 200° C. and preferably between 50° C. and 150° C.; v) reaction temperature from 2 hours to 120 hours. The crude product obtained is then purified by trituration or by re-crystallization from diethyl ether-tetrahydrofuran, diethyl ether-methanol or from water-methanol or by chromatography. No example is given of this purification step. In particular, both U.S. Pat. No. 4,210,863 and EP 8746 in example 1(E) describe the preparation of argatroban, isomers mixture. This compound is obtained in amorphous form by hydrogenation of [NG-nitro-N2-(3-methyl-8-quinolinesulphonyl)-L-arginyl]-4-methyl-2-piperidine carboxylic acid in ethanol in the presence of Pd/C with hydrogen pressure of 10 kg/cm2 at 100° C. for 8 hours. The catalyst is removed by filtration of the ethanol solution which is then evaporated without further purification and/or re-crystallization steps. In the US patent at issue as indeed in patent application EP 8746, no mention is made of polymorphic forms of the compounds and, for the obtained compound, the following characteristics are reported: Amorphous solid, I.R. (KBr) (cm−1) 3400; 1620; 1460; 1380; Molecular composition (%): theoretical C 54.31; H 7.13; N 16.52; found (%) C 54.01; H 6.98; N 16.61.

U.S. Pat. No. 4,258,192 (24 Mar. 1981) (continuation-in-part of the aforesaid patent application U.S. Pat. No. 4,201,863) and the same patent application EP 8746 describe the stereoisomers and the preparation thereof, including argatroban used as an active principle in medicaments, i.e. the stereoisomer (2R,4R)-4methyl-[4N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulphonyl)-L-arginyl]-2-piperidine carboxylic acid, with the following characteristics: melting point (m.p.). 188-191° C.; I.R. (KBr) (cm−1) 3400, 1620, 1460, 1380; Molecular composition (%): theoretical C 54.31; H 7.13; N 16.52; found (%) C 54.05; H 6.94; N 16.65. The compound is prepared according to the description given in examples 1(E) in U.S. Pat. No. 4,258,192 and 2(E) and 3 in EP 8746 respectively by hydrogenation of (2R,4R) 1-[NG-nitro-N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulphonyl)-L-arginyl]-2-piperidine carboxylic acid in ethanol in presence of acetic acid catalyzed by Pd/C. After filtering the mass to remove the catalyst, the solvent is evaporated and the residue suspended in chloroform, the solution treated with a saturated sodium bicarbonate solution or 1N sodium hydroxide solution and after washing, the solvent is evaporated. The compound is then re-crystallized from ethanol. Again in this case, no reference is made to the obtainment of monohydrate polymorphic forms.

Said polymorphic forms are described instead in the publication Biochem. Biophys. Res. Comm. 1981, 101, 440-446 in the context of stereoisomer preparation. The monohydrate polymorph of the (2R,4R) stereoisomer is prepared by re-crystallization from ethanol/water and the reported characteristics are: m.p. 176-180° C.; [α]D 27 +76.1° (c 1, 0.2N HCl).

U.S. Pat. No. 5,925,760 (20 Jul. 1999) and EP 0823430 (filed 4 Aug. 1997) subsequently describe a new method for preparing argatroban by means of a new intermediate N2-(3-methyl-8-quinolinesulphonyl)-NG-nitro-L-arginine. In particular the patent makes reference to the preparation of a crystalline monohydrate form of argatroban, referring back to examples (D) and (E) of Japanese patent publication No. (Hei)-2-31055/1990 and generically to an I.R. spectrum identical to that of the commercially available argatroban compound. The relevant example in the cited patent publication is example (E), while example (D) concerns the preparation of (2R,4R)-1-[NG-nitro-N2-(3-methyl-8-quinolinesulphonyl)-L-arginyl]-4-methyl-2-piperidine carboxylic acid. This compound represents the starting compound for argatroban preparation by catalytic reduction in the presence of Pd/C. The crude argatroban obtained is then purified by extraction with chloroform, treatment with a saturated sodium bicarbonate solution and, after solvent evaporation, re-crystallization from ethanol or from 15% alcohol in water. It should be noted however that the Japanese patent makes no mention of the monohydrate form of argatroban being obtained and that for the compound the following characteristics are reported: m.p. 188-191° C.; molecular composition (theoretical/found) (%): C 54.31/54.01; H 7.13/6.98; N 16.52/16.61; I.R. (KBr) (cm−1) 3400; 1620; 1460; 1380. These analytical data, with the exception of the unreported melting point, are the same as those indicated in the cited patent documents describing a mixture of (2R,4R)-4methyl-[4N2-(3S-methyl-1,2,3,4-tetrahydro-8-quinolinesulphonyl)-L-arginyl]-2-piperidine carboxylic acid and (2R,4R)-4methyl-1-[N2-(3R-methyl-1,2,3,4-tetrahydro-8-quinolinesulphonyl)-L-arginyl]-2-piperidine carboxylic acid isomers of argatroban, but do not correspond to the melting point given in the publication, being the only document that identifies the monohydrate form of argatroban.

More recently, patent application CN 1,951,937 (filing date 10 Nov. 2006) described a method for preparing hydrated argatroban by treating argatroban with large quantities of water (more than 60 and up to 80 volumes of distilled water per gram of argatroban) at a temperature of 80-100° C. for a time of 0.5-1 hour and crystallization by cooling. The water content reported is comprised between 3.3 and 3.8% and the ratio of dextroisomer R to levoisomer S is R:S=63-67: 37-33.

Argatroban is a compound of wide therapeutic use, for which reason the need still exists to provide a compound of pharmaceutically acceptable quality obtained by easily industrialized and economically convenient methods. With regard to the monohydrate, this form is preferable for the applicative purpose since the anhydrous form is unstable and tends to become hydrated and/or wet. Moreover it crystallizes only with difficulty at the correct ratio between the diastereoisomers.

…..

the protection of 4-methylpiperidine (I) with (Boc)2O gives the carbamate (II), which is condensed with benzyl chloroformate by means of sec-butyl lithium and TMEDA in ethyl ether to yield (?-trans-1-(tert-butoxycarbonyl)-4-methylpiperidine-2-carboxylic acid benzyl ester (III). Deprotection of the NH group of (III) with HCl in ethyl acetate affords (?-trans-4-methylpiperidine-2-carboxylic acid benzyl ester (IV), which is condensed with the protected arginine derivative (V) by means of isobutyl chloroformate and TEA to provide the corresponding amide as a diastereomeric mixture. Resolution of this mixture by flash chromatography furnishes the desired diastereomer (VI), which is treated with HCl in ethyl acetate in order to remove the Boc-protecting group to yield compound (VII). Condensation of compound (VII) with 3-methylquinoline-8-sulfonyl chloride (VIII) by means of TEA in dichloromethane affords the expected sulfonamide (IX). Finally, this compound is submitted to hydrogenation with H2 over Pd/C in AcOH/ethanol in order to produce debenzylation, cleavage of the NO2 group and hydrogenation of the pyridine ring to yield argatroban.

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Argatroban, i.e., (2R,4R)-1-((2S)-5-((Aminoiminomethyl)amino)-1-oxo-2-((1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl)amino) pentyl)-4-methyl-2-piperidine carboxylic acid, has two diastereoisomers: 21(R) and 21(S). Usually the ratio of 21(R) to 21(S) is 64-65: 36-35 (U.S. Pat. No. 6,440,417, Cossy. J., et al, Bioorganic & Medicine Chemistry Letters, 11 (2001), 1989-1992, Journal of pharmaceutical Sciences, Vol. 82, No. 6, 672 (1993)).

The structure formula of Argatroban is reported below:

• • 21(S) Argatroban, X=CH3, Y═H;
  • 21(R) Argatroban, X=H, Y=CH3;
  • Argatroban, 21(S): 21 (R)=35:65.

The chemical names of the two diastereoisomers mentioned above are:

• 21(S) Argatroban: (2R,4R)-1-((2S)-5-((Aminoiminomethyl)amino)-1-oxo-2-((((3S)-1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl)amino)pentyl)-4-methyl-2-piperidine carboxylic acid (121785-72-6); and
• 21(R) Argatroban: (2R,4R)-1-((2S)-5-((Aminoiminomethyl)amino)-1-oxo-2-((((3R)-1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl)amino)pentyl)-4-methyl-2-piperidine carboxylic acid (121785-71-5).

In 1978, S. Akamoto et al from Japanese Mitsubishi Chemical Corporation first disclosed the anti-thrombin activity of Argatroban monohydrate (U.S. Pat. No. 4,101,653). In the next 20 years, numerous researchers had in-depth studies on Argatroban about its biological activity and medicine values. In 1981, S. Akamoto compared Argatroban with heparin in vivo (Okamoto, S. et al., Biochem. Biophys. Res. Commun. 101, 440 (1981)); T. Kumoto disclosed its three-dimensional selective activity (Kumada, T. et al., Thromb. Res. 24, 285 (1981)). In 1984, R. Kumato made a clinical evaluation of hemodialysis of Argatroban (Kikumoto, R. et al., Biochemistry 23, 85 (1984)), and in 1986, he further disclosed that Argatroban can inhibit the thrombin activity of mammals, and can be used as active ingredient to treat and prevent thrombosis and as an inhibitor of platelet aggregation. Argatroban monohydrate can be used as a selective anti-thrombosis agent for treatment of chronic arterial blockage and cerebral thrombosis, etc (JP 61-48829). In 1992 and 1993, Taparelli and Jakubowski separately disclosed the reversibility of Argatroban in anti-thrombin (Taparelli, C., Trends Pharmacol. Sci., 1993, 14, 366, Jakubowski, J. A. et al, Rep. Med. Chem., 1992, 27, 99). In 1990s, many researchers such as L. R. Buch reported other related research (Buch, L. R., Cadiosvasc. Drug Rev., 1991, 9, 247, Strupcnewski, J. D. et al., Academic: San Diego, 1991; Vol. 26, p 299, Brundish, D. et al., J. Med. Chem. 1999; 42, 4584, Shebuski, R. J., Academic: San Diego, 1999; Vol. 26, p 98). In 1992, Argatroban monohydrate was first approved as an anti-thrombin medicine in Japan (Hijikata-Okunomiya, A., et al, Thromb. Hemostasis, 1992, 18, 135).

Updated in sept 2015, reader there may be duplication

	Argatroban

AC1L99H9; AC-15185; TL8005144; C04931;
MOLECULAR FORMULA:	C23H36N6O5S
MOLECULAR WEIGHT:	508.63414 g/mol

(2R,4R)-1-[5-(diaminomethylideneamino)-2-[(3-methyl-1,2,3,4-tetrahydroquinolin-8-yl)sulfonylamino]pentanoyl]-4-methylpiperidine-2-carboxylic acid, cas 74863-84-6

PATENT	SUBMITTED	GRANTED
Prodrugs of (2R)-2-Propyloctanoic Acid For the Treatment of Stroke [US7495029]	2008-06-05	2009-02-24

Tomiya Mano, Jin Shiomura, “Argatroban preparations for ophthalmic use.” U.S. Patent US5506241, issued October, 1986.

US5506241

Argatroban is an anticoagulant that is a small molecule direct thrombin inhibitor.[1] In 2000, argatroban was licensed by the Food and Drug Administration (FDA) for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). In 2002, it was approved for use during percutaneous coronary interventions in patients who have HIT or are at risk for developing it. In 2012, it was approved by the MHRA in the UK for anticoagulation in patients with Heparin-Induced Thrombocytopenia Type II (HIT) who require parenteral antithrombotic therapy.[2]

Argatroban is given intravenously and drug plasma concentrations reach steady state in 1-3 hours.[3] Argatroban is metabolized in theliver and has a half-life of about 50 minutes. It is monitored by PTT. Because of its hepatic metabolism, it may be used in patients with renal dysfunction. (This is in contrast to lepirudin, a direct thrombin inhibitor that is primarily renally cleared).

Argatroban is a direct, selective thrombin inhibitor. The American College of Cardiologists (ACC) recommend using bivalirudin or argatroban in patients who have had, or at risk for, heparin induced thrombocytopenia (HIT) and are undergoing percutaneous coronary intervention. Argatroban is a non-heparin anticoagulant shown to both normalize platelet count in patients with HIT and prevent the formation of thrombi. Parental anticoagulants must be stopped and a baseline activated partial thromboplastin time must be obtained prior to administering argatroban.

Transitioning to warfarin in individuals with heparin induced thrombocytopenia

Argatroban is used as an anticoagulant in individuals with thrombosis and heparin induced thrombocytopenia. Often these individuals require long term anticoagulation. If warfarin is chosen as the long term anticoagulant, this poses particular challenges due to the falsely elevated prothrombin time and INR caused by argatroban. The combination of argatroban and warfarin may raise the INR to greater than 5.0 without a significant increased risk of bleeding complications.[4] One solution to this problem is to measure the chromogenic factor X level. A level < 40-45% typically indicates that the INR will be therapeutic (2-3) when the argatroban is discontinued.

http://www.google.com/patents/WO2009124906A2?cl=en

………….

NMR paper

Complete 1H and 13C assignments of (21R) and (21S) diastereomers of argatroban

1. Diego Colombo1,*,
2. Patrizia Ferraboschi1,
3. Paride Grisenti2 and
4. Laura Legnani3

Article first published online: 20 DEC 2007

DOI: 10.1002/mrc.2122, http://onlinelibrary.wiley.com/doi/10.1002/mrc.2122/abstract

click on image for clear view

1H NMR PREDICT

13C NMR PREDICT

References

1 Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med 2005;353:1028-40. PMID 16148288

2http://www.pharmatimes.com/Article/12-07-03/UK_launch_for_Mitsubishi_s_blood_thinner_Exembol.aspx

3Dhillon S. Argatroban: A Review of its Use in the Management of Heparin-Induced Thrombocytopenia. Am J Cardiovasc Drugs 2009; 9 (4): 261-82. Link text

4. Hursting MJ, Lewis BE, Macfarlane DE. (2005). “Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia.”. Clin Appl Thromb Hemost 11 (3): 279–87. doi:10.1177/107602960501100306. PMID 16015413.

External links

• GlaxoSmithKline’s website on argatroban

EP0823430A1 *	Aug 4, 1997	Feb 11, 1998	Mitsubishi Chemical Corporation	Method for preparing n2-arylsulfonyl-l-argininamides
US4201863 *	Aug 31, 1978	May 6, 1980	Mitsubishi Chemical Industries, Limited	N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
REFERENCE
1		None
2	*	OKAMOTO S ET AL: “Potent inhibition of thrombin by the newly synthesized arginine derivative No. 805. The importance of stereo-structure of its hydrophobic carboxamide portion” BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol. 101, no. 2, 30 July 1981 (1981-07-30), pages 440-446, XP024844713 ISSN: 0006-291X [retrieved on 1981-07-30] cited in the application
3	*	SONG H: “Method for preparing argatroban monohydrate in pure water” CASREACT,, 25 April 2007 (2007-04-25), XP002493272 & CN 1 951 937 A (TIANJIN WEIJIE TECHNOLOGY CO L [CN]) 25 April 2007 (2007-04-25)
CITING PATENT	FILING DATE	PUBLICATION DATE	APPLICANT	TITLE
WO2012136504A1	Mar 26, 2012	Oct 11, 2012	Lundbeck Pharmaceuticals Italy S.P.A.	Method for the preparation of process intermediates for the synthesis of argatroban monohydrate
CN102408468A *	Sep 20, 2011	Apr 11, 2012	海南灵康制药有限公司	Argatroban compound and preparation method thereof
EP2752412A1	Mar 26, 2012	Jul 9, 2014	Lundbeck Pharmaceuticals Italy S.p.A.	Intermediates for the synthesis of Argatroban monohydrate

Argatroban is a synthetic direct thrombin inhibitor and the chemical name is 1-[5[(aminoiminomethyl)amino]1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl]amino]pentyl]-4methyl-2-piperidinecarboxylic acid, monohydrate. Argatroban has 4 asymmetric carbons. One of the asymmetric carbons has an R configuration (stereoisomer Type I) and an S configuration (stereoisomer Type II). Argatroban consists of a mixture of R and S stereoisomers at a ratio of approximately 65:35.

The molecular formula of argatroban is C23H36N6O5S•H2O. Its molecular weight is 526.66 g/mol. The structural formula is:

Argatroban Injection is a sterile, non-pyrogenic, clear, colorless to pale yellow isotonic solution. It is supplied in a single use polyolefin bag containing 250 mg of argatroban in 250 mL sodium chloride solution (1 mg/mL). Each mL contains 1 mg argatroban, 9 mg sodium chloride, USP, and 3 mg sorbitol, NF in water for injection, USP. The pH of the solution is between 3.2 to 7.5.

ARGATROBAN

SYSTEMATIC (IUPAC) NAME
(2R,4R)-1-[(2S)-5-(diaminomethylideneamino)-2- [[(3R)-3-methyl-1,2,3,4-tetrahydroquinolin-8-yl] sulfonylamino]pentanoyl]-4-methyl-piperidine-2- carboxylic acid
CLINICAL DATA
TRADE NAMES	Argatroban
AHFS/DRUGS.COM	monograph
ROUTES OF ADMINISTRATION	intravenous
PHARMACOKINETIC DATA
BIOAVAILABILITY	100% (intravenous)
PROTEIN BINDING	54%
METABOLISM	hepatic
BIOLOGICAL HALF-LIFE	39 and 51 minutes
IDENTIFIERS
CAS REGISTRY NUMBER	74863-84-6
ATC CODE	B01AE03
PUBCHEM	CID: 440542
DRUGBANK	DB00278
CHEMSPIDER	389444
UNII	OCY3U280Y3
KEGG	C04931
CHEMBL	CHEMBL1166
CHEMICAL DATA
FORMULA	C23H36N6O5S
MOLECULAR MASS	508.635 g/mol

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Lemborexant

Lemborexant
E2006
CAS Number: 1369764-02-2
MF C₂₂ H₂₀ F₂ N₄ O₂
MW 410.42
Chemical Name: (1R, 2S) -2 – {[(2,4-dimethylpyrimidin-5-yl) oxy] methyl} -2- (3-fluorophenyl ) N (5-fluoropyridin-2-yl) cyclopropanecarboxamide
Cyclopropanecarboxam​ide, 2-​[[(2,​4-​dimethyl-​5-​pyrimidinyl)​oxy]​methyl]​-​2-​(3-​fluorophenyl)​-​N-​(5-​fluoro-​2-​pyridinyl)​-​, (1R,​2S)​-
(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide
Indication: Insomnia
Company: Eisai
Eisai R&D Management Co., Ltd

Lemborexant (INN) (code name E-2006) is a dual antagonist of the orexinOX₁ and OX₂receptors which is under development byEisai for the treatment of insomnia.^[1][2][3] As of December 2014, it is in phase IIclinical trials.^[4]

Orexin receptors are G-protein coupled receptors found predominately in the brain. Their endogenous ligands, orexin-A and orexin-B, are expressed by neurons localized in the hypothalamus. Orexin-A is a 33 amino acid peptide; orexin-B consists of 28 amino acids. (Sakurai T. et al., Cell, 1998, 92, 573-585). There are two subtypes of orexin receptors, OXi and OX₂; OX) binds orexin-A preferentially, while OX₂ binds both orexin-A and -B. Orexins stimulate food consumption in rats, and it has been suggested that orexin signaling could play a role in a central feedback mechanism for regulating feeding behavior (Sakurai et al., supra). It has also been observed that orexins control wake-sleep conditions (Chemelli R.M. et al., Cell, 1999, 98, 437-451). Orexins may also play roles in brain changes associated with opioid and nicotine dependence (S.L. Borgland et al, Neuron, 2006, 49, 598-601; C.J. Winrow et al., Neuropharmacology, 2010, 58, 185-194), and ethanol dependence (J.R. Shoblock et al, Psychopharmacology, 2011, 215, 191-203). Orexins have additionally been suggested to play a role in some stress reactions (T. Ida et al, Biochem. Biophys. Res. Commun., 2000, 270, 318- 323).
Compounds such as (lR,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3- fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (Compound A, below) have been found to be potent orexin receptor antagonists, and may be useful in the treatment of sleep disorders such as insomnia, as well as for other therapeutic uses.

 ……………….

paper

Journal of Medicinal Chemistry (2015), 58(11), 4648-4664.

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b00217

http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b00217/suppl_file/jm5b00217_si_001.pdf

The orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of orexin-1 (OX₁) and orexin-2 (OX₂) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these receptors constitutes a promising target for novel treatments of disorders associated with the control of sleep and wakefulness, such as insomnia, the development of orexin receptor antagonists has emerged as an important focus in drug discovery research. Here, we report the design, synthesis, characterization, and structure–activity relationships (SARs) of novel orexin receptor antagonists. Various modifications made to the core structure of a previously developed compound (–)-5, the lead molecule, resulted in compounds with improved chemical and pharmacological profiles. The investigation afforded a potential therapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006), an orally active, potent orexin antagonist. The efficacy was demonstrated in mice in an in vivo study by using sleep parameter measurements.

(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide

(1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (34)

The title compound was synthesized as a white solid (3.66 g, 56.4% yield) from (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropanecarboxylic acid 18c by adapting the procedure described for compound 23.

¹H NMR (400 MHz, DMSO-d) δ (ppm): 1.46–1.50 (m, 1H), 1.68 (t, J = 6.0 Hz, 1H), 2.01 (s, 3H), 2.36 (s, 3H), 2.59–2.63 (m, 1H), 4.27 (d, J = 10.4 Hz, 1H), 4.66 (d, J = 10.4 Hz, 1H), 7.06–7.11 (m, 1H), 7.37–7.44 (m, 3H), 7.60–7.65 (m, 1H), 7.85–7.89 (m, 1H), 8.11 (s, 1H), 8.30 (d, J = 3.2 Hz, 1H), 11.20 (br s, 1H).

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 18.7, 18.7, 25.0, 29.0, 34.9, 70.7, 114.5, 114.7, 115.9, 124.2, 125.4, 130.2, 135.5, 138.9, 144.1, 147.3, 149.1, 156.4, 157.0, 159.8, 162.8, 167.9.

HRMS (ESI(+)) calcd for C₂₂H₂₁F₂N₄O₂ [M + H]⁺, 411.1627; found, 411.1622. Purity: >95%.

………………………….

WO 2013123240

https://www.google.co.in/patents/WO2013123240A1?cl=en

E. Preparation of Compounds of Formula V

((lR,2S)-2-(((2,4-dimethylpyrimidin-5-yI)oxy)methyl)-2-(3-fluorophenyl)-cyclopropyl) methanol (11). ((lR,2S)-2-(3-fluorophenyl)-2-((tosyloxy)methyl)cyclopropyl)metliyl acetate (8, 11.05 g, 0.028 mol, 1.0 equiv.), 2,4-dimethylpyrimidin-5-ol (3.74 g, 0.030 mol, 1.07 equiv.), and cesium carbonate (22.94 g, 1.8 equiv.) were dissolved in ACN (110.5 mL), under nitrogen. The solution was stirred vigorously and heated to 65-70 °C for 2-3 hours. The reaction was monitored by HPLC and TLC (EtO Ac/Heptane = 1/1). Once complete, aqueous 1 N NaOH solution (71.82 mL) was added to the reaction mixture. The reaction mixture was stirred at 20-25 °C for 10-16 h, and was monitored by HPLC and TLC (EtO Ac/Heptane = 1/1). Once the hydrolysis reaction was complete, the reaction mixture was diluted with MTBE (110.50 mL) and stirred for at least 15 min. The aqueous layer was back extracted once with MTBE (55.25 mL). The organic layers were combined and washed once with saturated aqueous NaCl solution (33.15 mL). The solvent was removed under reduced pressure to afford the title compound; ((lR,2S)-2-(((2,4- dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopi pyl)methanol: (11, 8.51 g).
((lR,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)- cyclopropyl)methanol: 1H NMR (500 MHz, DMSO-d₆) δ 8.21 (s, 1H), 7.33 (td, J = 8.0, 6.5 Hz, 1H), 7.20 (d, J= 7.9 Hz, 1H), 7.19 – 7.14 (m, 1H), 7.01 (ddd, J= 8.3, 2.6, 1.2 Hz, 1H), 4.63 (t, J = 5.4 Hz, 1H), 4.36 (dd, J= 22.5, 10.5 Hz, 2H), 3.72 – 3.61 (m, 2H), 2.45 (s, 3H), 2.22 (s, 3H), 1.51 – 1.43 (m, 1H), 1.23 (dd, J= 8.9, 5.0 Hz, 1H), 1.01 (dd, J= 6.0, 5.3 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d_fi) δ 162.48 (d, J_CF = 243.0 Hz), 158.91, 156.26, 149.51, 147.47 (d, J_CF = 7.5 Hz), 139.85, 130.35 (d, J_CF = 8.5 Hz), 124.72 (d, J_CF = 2.5 Hz), 115.54 (d, J_CF = 21.3 Hz), 113.43 (d, JCF = 20.9 Hz), 72.73, 60.70, 29.23, 28.64, 24.94, 18.77, 17.06.
HRMS Calculated for C₁₇H₂₀FN₂O₂ [M+H]⁺ 303.1590; found 303.1517.

F. Preparation of Compounds of Formula VII

(lR,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropane- carboxylic acid (13). ((lR,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3- fluorophenyl)cyclopropyl)methanol (11, 87.5 g, 290 mmol, 1.0 equiv.) was dissolved in toluene (390 mL). To the mixture was added pH 7 buffer (107 g, prepared from 4.46 g of sodium phosphate dibasic and 7.79 g of sodium phosphate monobasic in 94.4 mL of water) and 2,2,6,6- tetramethylpiperidine 1-oxyl (TEMPO) (0.93 g, 5.9 mmol, 0.02 equiv.). The mixture was cooled to 0 °C and sodium hypochlorite solution (5% active chlorine, 383 mL, 304 mmol, 1.05 equiv.) was added dropwise, maintaining the internal temperature below 9 °C. The mixture was allowed to warm to room temperature and stirred for 2 h. To the mixture was added aqueous hydrochloric acid (2.0 M, 8.73 mL, 0.05 equiv.) followed by a solution of sodium chlorite (36.0 g, 318 mmol, 1.1 equiv.) in water (87 mL), maintaining the internal temperature below 26 °C. The mixture was stirred at room temperature for 4 h, and then cooled to 10 °C. A solution of sodium thiosulfate (92 g, 579 mmol, 2.0 equiv.) in water (177 mL) was added, maintaining the internal temperature below 20 °C. The mixture was stirred for 20 min, and then aqueous sodium hydroxide solution (4 N, 87 mL, 348 mmol, 1.2 equiv.) was added to achieve ca. pH = 13. The mixture was heated to 80 °C for 4 hours, then cooled to room temperature. Stirring was halted and the phases allowed to split. The lower aqueous phase was collected and the upper organic phase was washed once with 4 N sodium hydroxide solution (17 mL). The combined aqueous phases were acidified with aqueous hydrochloric acid solution (4 N, 17 mL) to pH = 4 and extracted with ethyl acetate (2 x 470 mL). The combined organic phases were washed with ca. 20% aqueous NaCl solution (175 mL). The organic phases were concentrated by rotary evaporation to yield 96.84 g of crude oil. A portion (74 g) of this crude oil was dissolved in acetonitrile (400 mL) and concentrated to dryness by rotary evaporation. Another portion of acetonitrile (400 mL) was added and the mixture was again concentrated to dryness. To the residue was added acetonitrile (370 mL). The mixture was heated to 65 °C resulting in a clear solution. The mixture was cooled to room temperature, then to 0 °C and held at this temperature for 6 h. The mixture was filtered and the wet cake was washed with acetonitrile (2 x 74 mL). The cake was dried under vacuum with a nitrogen sweep, then in a vacuum oven at 20 torr and 40 °C to afford (lR,2S)-2-(((2,4- dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropanecarboxylic acid (13, 56.9 g, 80% yield) as an off-white crystalline solid.
(lR,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluoi phenyl)- cyclopropanecarboxylic acid: 1H NMR (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.17 (s, 1H), 7.39 (td, J= 8.0, 6.4 Hz, 1H), 7.29 (d, J= 7.9 Hz, 1H), 7.27 – 7.22 (m, 1H), 7.10 (td, J – 8.3, 2.1 Hz, 1H), 4.63 (d, J= 10.2 Hz, 1H), 4.30 (d, J= 10.2 Hz, 1H), 2.46 (s, 3H), 2.26 (s, 3H), 2.13 (dd, J= 7.7, 6.6 Hz, 1H), 1.63 – 1.54 (m, 2H); ¹³C NMR (126 MHz, DMSO-d₆) δ 172.65, 162.48 (d, J_CF = 243.6 Hz), 159.08, 156.24, 149.45, 145.15 (d, J_CF = 7.5 Hz), 139.60, 130.71 (d, J_CF = 8.5 Hz), 124.79 (d, JCF = 2.6 Hz), 115.60 (d, J_CF = 21.8 Hz), 114.32 (d, J_CF = 20.8 Hz), 71.15, 33.92 (d, J_CF = 2.0 Hz), 26.46, 24.96, 19.72, 18.70.
HRMS Calculated for Ci₇Hi₈FN₂0₃ [M+H]⁺ 317.1301; found 317.1298.
G. Preparation of Compounds of Formula IX

(lR,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(S- fluoropyridin-2-yl)cyclopropanecarboxamide (14). (lR,2S)-2-(((2,4-dimethylpyrimidin- 5-yl)oxy)methyl)-2-(3-fluorophenyl)-cyclopropanecarboxylic acid (13, 12.80 g, 0.040 mol, 1.0 equiv.), and 2-amino-5-fluoiOpyridine (4.76 g, 0.0425 mol, 1.05 equiv.) were dissolved in ethyl acetate (102.4 mL), under nitrogen. The solution was cooled to 0-5 °C, and N,N- diisopropylethylamine (14.10 mL, 0.081 mol, 2.0 equiv.) was added to the reaction mixture while maintaining the internal temperature at 0-15 °C. The reaction mixture was stirred at 0-10 °C for 20-30 minutes. n-Propylphosphonic anhydride (T3P; 50% w/w solution in ethyl acetate, 36.1 g, 1.4 equiv.) was added to the reaction mixture while maintaining the internal temperature at 0-15 °C. The reaction was stirred at 20-25 °C for at least 20-24 hour and monitored by HPLC and TLC (EtO Ac/Heptane = 1/1). Upon completion of the reaction, the reaction mixture was cooled to 0-5 °C and then was quenched with water (64.0 mL) while maintaining the internal temperature below 10-15 °C. The aqueous layer was back extracted once with MTBE (76.8 mL). The organic layers were combined and washed once with saturated aqueous NaHC0₃ solution (38.4 mL) and once with water (38.4 mL). The organic layer was polish filtered and the filter rinsed with MTBE (12,8 mL). The organic layer was then concentrated under reduced pressure to a minimum stirrable volume. Ethyl acetate (60.8 mL) was added to the reaction mixture and the mixture was heated to no more than 50 °C to achieve a clear solution. n-Heptane (86.3 mL) was added slowly with agitation. The reaction mixture was cooled to 20-25 °C, and the suspension was stirred for at least 1 h at 20-25 °C and then stirred at least for 1 h at 0-5 °C. The suspension was filtered and the cake was washed two times with 5 : 1 heptane/ethyl acetate (2 x
12.8 mL). The cake was dried under nitrogen and/or vacuum to provide the title compound, (lR,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluoiOphenyl)-N-(5-fiuoropyridin^ yl)cyclopropanecarboxamide, (14, 12.54 g, >99% ee) as a white to off white solid.
(lR,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluoiOphenyl)-N-(5- fluoropyridin-2-yl)cyclopropanecarboxamide:
1H NMR (500 MHz, DMSO-d₆) δ 11.19 (s, 1H), 8.31 (d, J = 3.0 Hz, 1H), 8.12 (s, 1H), 7.94 – 7.85 (m, 1H), 7.62 (tt, J = 8.7, 3.1 Hz, 1H), 7.44 (dd, J = 10.6, 1.5 Hz, 1H), 7.41 – 7.40 (m, 1H), 7.39 (s, 1H), 7.14 – 7.06 (m, 1H), 4.67 (d, J = 10.2 Hz, 1H), 4.29 (t, J= 9.9 Hz, 1H), 2.63 (t, J= 7.0 Hz, 1H), 2.38 (s, 3H), 2.03 (s, 3H), 1.76 – 1.64 (m, 1H), 1.49 (dd, J = 8.0, 4.8 Hz, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ 168.68, 161.98 (d, JcF = 242.3 Hz), 158.46, 155.15, 155.38 (d, J_CF = 247.9 Hz), 148.90, 148.51, 145.00 (d, J_CF = 7.7 Hz), 139.37, 135.15 (d, J_CF = 24.9 Hz), 130.06 (d, J_CF = 8.4 Hz), 125.05 (d, J_CF = 19.5 Hz), 124.70 (d, J_CF = 2.6 Hz), 115.71 (d, J_CF = 21.7 Hz), 114.20 (d, J_CF = 4.1 Hz), 113.70 (d, J_CF =
20.9 Hz), 70.80, 34.09 (d, J_CF = 1.9 Hz), 26.90, 24.38, 18.37, 17.78.
HRMS Calculated for C₂₂H₂₁F₂N₄0₂ [M+H]⁺ 411.1627; found 411.1632.

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WO 2012039371

http://www.google.com.ar/patents/WO2012039371A1?cl=en

Production Example 14
(1R, 2S) -2 – Synthesis of {[(2,4-dimethyl-pyrimidin-5-yl) oxy] methyl} -2- (3-fluorophenyl) cyclopropanecarboxylic acid (Prep14-6)

(1) (1S, 5R) -1- (3- fluorophenyl) -3-hexane-2-one to oxabicyclo [3.1.0] (Prep14-1)
3-fluorophenyl acetonitrile (70g) was dissolved in THF (500ml), ice – salt bath under cooling, was added dropwise NaHMDS (1000ml, 1.06M). After allowed to stir 1 hour, R – (-) – it was added dropwise epichlorohydrin (40.6ml) (approximately 10 minutes, the internal temperature <10 ℃). After it was allowed to stirred for 2 hours (maintained before and after the internal temperature 0 ℃), and stirred at room temperature for 14 hours. The reaction was I was dropping a small amount of water cooled with ice. The reaction solution was concentrated under reduced pressure, the residue in ethanol (700ml), 1N potassium hydroxide aqueous solution (1000ml) was added and heated to reflux for 5 hours. After returning to room temperature, it was added 5N hydrochloric acid (400ml), and stirred for 1 hour at 60 ℃. The reaction mixture was concentrated under reduced pressure, it was added thereto to carry out a liquid separation with ethyl acetate and water. The organic layer saturated aqueous sodium hydrogen carbonate solution, it was washed successively with saturated sodium chloride aqueous solution. Dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a purified by (n- heptane-ethyl acetate) The title compound (84.9g).
¹ H-NMR (400MHz, CDCl ₃₎ ^δ (ppm): 1.41 (t, J = 5.2Hz, 1H), 1.64 (dd, J = 8.0,5.2Hz, 1H), 2 .56-2.63 (m, 1H), 4.30 (d, J = 9.2Hz, 1H), 4.47 (dd, J = 9.2,4.8Hz, 1H), 6.96- 7.02 (m, 1H), 7.16-7.21 (m, 2H), 7.28-7.35 (m, 1H).
(2) (1S, 2R) -1- (3- fluorophenyl) cyclopropane-1,2-dimethanol (Prep14-2)
THF- methanol compound Prep14-1 (72.7g) (440ml-220ml) sodium borohydride solution (25g) was added at 0 ℃, and the mixture was stirred for 65 hours at room temperature. Under ice-cooling, water and 5N hydrochloric acid were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and then dried with magnesium sulfate. The solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography to obtain a purified by (n- heptane-ethyl acetate) The title compound (72.7g).
¹ H-NMR (400MHz, CDCl ₃₎ ^δ (ppm): 0.80 (t, J = 5.0Hz, 1H), 1.10 (dd, J = 8.6,5.0Hz, 1H), ¹ .62-1.71 (m, 1H), 3.41 (t, J = 11.4Hz, 1H), 3.58 (d, J = 12.0Hz, 1H), 4.12-4.25 ( m, 2H), 6.90-6.96 (m, 1H), 7.08-7.14 (m, 1H), 7.16-7.21 (m, 1H) 7.24-7.32 (m, 1H).
(3) {(1S, 2R) – [2- (tert- butyldiphenylsilyloxy) -1- (3-fluorophenyl) cyclopropyl]} methanol (Prep14-3)
Compound Prep14-2 a (42.4g) was dissolved triethylamine (33.0ml) in dichloromethane (216ml), was cooled to -20 ℃, was added dropwise tert- butyldiphenylsilyl chloride (56.3ml) (about 30 minute, almost at the same time insoluble matter is deposited with the completion of the dropping). After stirring for 1 hour, further stirred at room temperature for 20 hours.Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. Washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a purified by (n- heptane ethyl acetate) The title compound (67.8g).
¹ H-NMR (400MHz, CDCl ₃₎ ^δ (ppm): 0.73 (t, J = 5.2Hz, 1H), 1.04 (dd, J = 8.4,5.2Hz, 1H), ¹ .09 (s, 9H), 1.48-1.53 ​​(m, 1H), 3.52 (t, J = 12.0Hz, 1H), 3.56 (dd, J = 9.6,1. 6Hz, 1H), 3.70 (dd, J = 9.6,1.6Hz, 1H), 4.18 (t, J = 12.0Hz, 1H), 4.20 (dd, J = 12.0 , 5.2Hz, 1H), 6.93 (tdd, J = 8.0,2.4,1.2Hz, 1H), 7.11 (dt, J = 9.6,2.4Hz, 1H), 7.20 (dt, J = 8.0,1.2Hz, 1H), 7.28 (td, J = 8.0,6.0Hz, 1H), 7.37-7.49 (m, 6H) , 7.69-7.74 (m, 4H).
(4) {(1R, 2S) -2 – {[(-5- 2,4- dimethyl-pyrimidin-yl) oxy] methyl} -2- (3-fluorophenyl) cyclopropyl} methanol (Prep14-4)
Compound Prep14-3 (581mg), triphenylphosphine (1.3g) and Preparation Example 4 to give 2,4-dimethyl – THF (10ml) solution of diisopropyl azodicarboxylate pyrimidin-5-ol (183mg) ( The 0.316ml) was added dropwise at 0 ℃, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography (n- heptane: ethyl acetate = 19: 1 → 7: 3) was purified by. The resulting (1S, 2R) -2- (tert- butyldiphenylsilyloxy-methyl) -1 – {[(2,4-dimethyl-pyrimidin-5-yl) oxy] methyl} -1- (3-fluorophenyl) cyclopropane was dissolved in THF (15ml), tetrabutylammonium fluoride (1M-THF solution: 1.61ml) was added dropwise at room temperature and stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, silica gel column chromatography (n- heptane: ethyl acetate = 10: 1 → 0: 1) to obtain purified by the title compound (238mg).
¹ H-NMR (400MHz, CDCl ₃₎ ^δ (ppm): 1.00 (t, J = 5.6Hz, 1H), 1.25-1.33 (m, 1H), 1.78-1.88 (m, 1H), 2.39 (s, 3H), 2.61 (s, 3H), 3.58 (dd, J = 12.0,9.6Hz, 1H), 4.02-4.11 (m, 1H), 4.12 (d, J = 10.4Hz, 1H), 4.43 (d, J = 9.6Hz, 1H), 6.92-6.98 (m, 1H), 7 .10-7.16 (m, 1H), 7.18-7.23 (m, 1H), 7.29 (td, J = 8.0,6.0Hz, 1H), 8.00 (s, 1H).
(4 alternative method)
((1R, 2S) -2 – {[(2,4- dimethyl-pyrimidin-5-yl) oxy]} methyl] -2- (3-fluorophenyl) cyclopropyl} methanol (Prep14-4) (alternative method)
Triethylamine (14.5ml) was added in dichloromethane (200ml) solution of compound Prep14-3 (41.3g), cooled to 0 ℃. It was added dropwise methanesulfonyl chloride (7.34ml), and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. Dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue in acetonitrile (200ml) solution obtained in Production Example 4- (2) 2,4-dimethyl – pyrimidin-5-ol (14.1g) and cesium carbonate (61.8g) was added, 70 ℃ It was heated to. After 4 hours of stirring at 70 ℃, the reaction solution was cooled to 0 ℃, tetrabutylammonium fluoride (1M-THF solution: 190ml) was added dropwise, and the mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH- silica gel column chromatography (n- heptane: ethyl acetate = 9: 1 to 1: 1) to give the title compound (20.7g) was purified by.
(5) (1R, 2S) -2 – {[(2,4- dimethyl-pyrimidin-5-yl) oxy] methyl} -2- of (3-fluorophenyl) cyclopropane carbaldehyde (Prep14-5)
Oxalyl dichloromethane solution of chloride (137μl) a (7ml) was cooled to -78 ℃, there was added dropwise dimethyl sulfoxide (226μl) (internal temperature below -60 ℃). After stirring for 10 minutes at the same temperature, dichloromethane (3ml) solution of the compound to the reaction mixture Prep14-4 (238mg) was dropped at -78 ℃, and the mixture was stirred at the same temperature for 30 minutes. After stirring for 15 minutes triethylamine (671μl) was added to the reaction mixture, and the temperature was raised to room temperature. Saturated sodium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude title compound (236mg).
¹ H-NMR (400MHz, CDCl ₃₎ ^δ (ppm): 1.67 (dd, J = 8.0,4.8Hz, 1H), 1.96-2.00 (m, 1H), 2.36 (s, 3H), 2.49-2.55 (m, 1H), 2.59 (s, 3H), 4.19 (d, J = 9.6Hz, 1H), 4.44 (d, J = 10.0Hz, 1H), 6.97-7.04 (m, 1H), 7.14-7.20 (m, 1H), 7.21-7.25 (m, 1H), 7.30 -7.37 (m, 1H), 7.95 (s, 1H), 9.87 (d, J = 3.2Hz, 1H).
(6) (1R, 2S) -2 – {[(2,4- dimethyl-pyrimidin-5-yl) oxy] methyl} -2- (3-fluorophenyl) cyclopropanecarboxylic acid (Prep14-6)Compound Prep14- 5 (18.9g) and 2-methyl-2-butene (26.1ml), sodium dihydrogen phosphate the (9.07g) was dissolved in acetone-water mixed solvent (200ml · 40ml), sodium chlorite ( 6.26g) and I were added little by little. After stirring for 2 hours at room temperature, the reaction solution was concentrated under reduced pressure. The precipitated solid was filtered off, washed with dichloromethane, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n- heptane: After 1, ethyl acetate: ethyl acetate = 1: 1-0 methanol = 10: 1) to give the title compound (16.2g) was purified by.
¹ H-NMR (400MHz, CDCl ₃₎ ^δ (ppm): 1.55 (dd, J = 8.4,5.6Hz, 1H), 1.76 (t, J = 5.6Hz, 1H), 2 .25 (dd, J = 8.4,6.4Hz, 1H), 2.33 (s, 3H), 2.55 (s, 3H), 4.47 (t, J = 9.6Hz, 1H) , 4.50 (d, J = 9.6Hz, 1H), 6.99 (tdd, J = 8.0,2.4,1.2Hz, 1H), 7.21 (dt, J = 9.6 , 2.4Hz, 1H), 7.26 (td, J = 8.0,1.2Hz, 1H), 7.32 (td, J = 8.0,6.0Hz, 1H), 8.21 ( s, 1H).
Compound Prep14-6 can be prepared directly by the following method from the compound Prep14-4.
Compound Prep14-4 (300mg) and TEMPO (5mol%, 7.74mg) was dissolved in phosphate buffer solution of acetonitrile · pH6.4 (5ml · 5ml), 2N- hydrochloric acid (150μl), sodium chlorite (180mg ) and it was added. After heating to 40 °, 5w% of the hypochlorite solution (2mol%, 26.5μl) were added and stirred for 2 hours. Cooled to room temperature, the reaction mixture was stirred for 5 minutes was added an excess of 2-methyl-2-butene in. The reaction solution was extracted with dichloromethane, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n- heptane: ethyl acetate = 1: 1 to 0: After 1, ethyl acetate: methanol = 9: 1) in was purified to give the title compound (215mg).
Example 95
(1R, 2S) -2 – {[(2,4- dimethyl-pyrimidin-5-yl) oxy] methyl} -2- (3-fluorophenyl) -N- (5- fluoro-2-yl) cyclopropane The synthesis of carboxamide (95)

Acid Prep14-6 a (226mg) was dissolved in dichloromethane (10ml), oxalyl chloride (122μl), and stirred for 1 hour at room temperature was added DMF (a few drops). The reaction mixture was concentrated under reduced pressure to give the crude acid chloride. N in THF (10ml) solution of 2-amino-5-fluoro pyridine (96.1mg), N- diisopropylethylamine (283μl) was added mixture was heated to 60 ℃, the temperature of intact dropwise a THF solution of the crude acid chloride in it was allowed to stir for 1 hour. The reaction mixture was allowed to cool to room temperature and allowed to stir for 1 hour, after which the reaction mixture was concentrated under reduced pressure, partitioned between ethyl acetate and water, the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by NH- silica gel column chromatography (n- heptane: ethyl acetate = 2: 1) to give diethyl ether to the obtained target compound was added. The precipitated solid was filtered dried to give the title compound (130mg).
¹ H-NMR (400MHz, d-DMSO) ^δ (ppm): 1.46-1.50 (m, 1H), 1.68 (t, J = 6.0Hz, 1H), 2.01 (s, 3H), 2.36 (s, 3H), 2.59-2.63 (m, 1H), 4.27 (d, J = 10.4Hz, 1H), 4.66 (d, J = 10. 4Hz, 1H), 7.06-7.11 (m, 1H), 7.37-7.44 (m, 3H), 7.60-7.65 (m, 1H), 7.85-7. 89 (m, 1H), 8.11 (s, 1H), 8.30 (d, J = 3.2Hz, 1H), 11.20 (brs, 1H)
MS ^{[M +} H] ⁺ = 411

Synthesis coming…….watch out

References

1. Christopher, John A (2014). “Small-molecule antagonists of the orexin receptors”. Pharmaceutical Patent Analyst 3 (6): 625–638.doi:10.4155/ppa.14.46. ISSN 2046-8954.
2. Cristoph Boss, Catherine Ross (2015). “Recent Trends in Orexin Research – 2010 to 2015”. ScienceDirect.doi:10.1016/j.bmcl.2015.05.012.
3. Boss, Christoph (2014). “Orexin receptor antagonists – a patent review (2010 to August 2014)”. Expert Opinion on Therapeutic Patents 24 (12): 1367–1381.doi:10.1517/13543776.2014.978859. ISSN 1354-3776.
4. AdisInsight. “Lemborexant”. Springer. Retrieved 2015-05-23.

External links

• Lemborexant – AdisInsight

Lemborexant

Systematic (IUPAC) name
(1R,2S)-2-[(2,4-dimethylpyrimidin-5-yl)oxymethyl]-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide
Clinical data
Legal status	experimental drug
Identifiers
CAS Registry Number	1369764-02-2
ATC code	None
PubChem	CID: 56944144
ChemSpider	34500836
Chemical data
Formula	C22H20F2N4O2
Molecular mass	410.417 g/mol

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Ximelagatran

192939-46-1, EXANTA
N-​[(1R)-​1-​cyclohexyl-​2-​[(2S)-​2-​[[[[4-​ [(hydroxyamino)iminomethyl]phenyl]methyl]amino]carbonyl]-​1-​ azetidinyl]-​2-​oxoethyl]-​glycine,​ ethyl ester

C24H35N5O5
MW	473.6

CAS 260790-58-7 (Monohydrate)
CAS 260790-59-8 (MonoHBr)
CAS 260790-60-1 (Monomethanesulfonate)
ASTRAZENECA INNOVATOR
Ximelagatran (Exanta or Exarta, H 376/95) is an anticoagulant that has been investigated extensively as a replacement forwarfarin^[1] that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would withdraw pending applications for marketing approval after reports ofhepatotoxicity (liver damage) during trials, and discontinue its distribution in countries where the drug had been approved (Germany, Portugal, Sweden, Finland, Norway, Iceland, Austria, Denmark, France, Switzerland, Argentina and Brazil).^[2]
Ximelagatran is an ester prodrug of melagatran, a potent, direct, and reversible thrombin inhibitor (K_i = 1.2 nM). While melagatran has poor oral bioavailability, ximelagatran displays good bioavailability resulting, in part, from rapid absorption at the gastrointestinal tract, as well as rapid onset of action.Ximelagatran is converted to melagatran by reduction and hydrolysis at the liver and other tissues. It is used as an anticoagulant in a variety of situations, including thromboembolic disorders, stroke prevention in atrial fibrillation, and therapy in vein thrombosis

Method of action

Ximelagatran, a direct thrombin inhibitor,^[3] was the first member of this class that can be taken orally. It acts solely by inhibiting the actions of thrombin. It is taken orally twice daily, and rapidly absorbed by the small intestine. Ximelagatran is a prodrug, being converted in vivo to the active agent melagatran. This conversion takes place in the liver and many other tissues throughdealkylation and dehydroxylation (replacing the ethyl and hydroxyl groups with hydrogen).

Uses

Ximelagatran was expected to replace warfarin and sometimes aspirin and heparin in many therapeutic settings, including deep venous thrombosis, prevention of secondary venous thromboembolism and complications of atrial fibrillation such as stroke. The efficacy of ximelagatran for these indications had been well documented,^[4][5][6] except for non valvular atrial fibrillation.
An advantage, according to early reports by its manufacturer, was that it could be taken orally without any monitoring of its anticoagulant properties. This would have set it apart from warfarin and heparin, which require monitoring of the international normalized ratio (INR) and the partial thromboplastin time (PTT), respectively. A disadvantage recognised early was the absence of an antidote in case acute bleeding develops, while warfarin can be antagonised by vitamin K and heparin by protamine sulfate.

Side-effects

Ximelagatran was generally well tolerated in the trial populations, but a small proportion (5-6%) developed elevated liver enzymelevels, which prompted the FDA to reject an initial application for approval in 2004. The further development was discontinued in 2006 after it turned out hepatic damage could develop in the period subsequent to withdrawal of the drug. According to AstraZeneca, a chemically different but pharmacologically similar substance, AZD0837, is undergoing testing for similar indications.^[2]

Melagatran synthesis

Sobrera, L. A.; Castaner, J.; Drugs Future, 2002, 27, 201.
SYNTHESIS

SYNTHESIS

SYNTHESIS

……

WO 1997023499/http://www.google.com/patents/EP0869966A1?cl=en
…………

References

1.  Hirsh J, O’Donnell M, Eikelboom JW (July 2007). “Beyond unfractionated heparin and warfarin: current and future advances”. Circulation 116 (5): 552–560.doi:10.1161/CIRCULATIONAHA.106.685974. PMID 17664384.
2. “AstraZeneca Decides to Withdraw Exanta” (Press release). AstraZeneca. February 14, 2006. Retrieved 2012-07-16.
3.  Ho SJ, Brighton TA (2006). “Ximelagatran: direct thrombin inhibitor”. Vasc Health Risk Manag 2 (1): 49–58. doi:10.2147/vhrm.2006.2.1.49. PMC 1993972.PMID 17319469.
4.  Eriksson, H; Wahlander K; Gustafsson D; Welin LT; Frison L; Schulman S; THRIVE Investigators (January 2003). “A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I”. Journal of Thrombosis and Haemostasis 1 (1): 41–47. doi:10.1046/j.1538-7836.2003.00034.x. PMID 12871538.
5.  Francis, CW; Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, Peters GR, Roth AW, McElhattan J, Colwell CW Jr; EXULT A Study Group (October 2003). “Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement”. New England Journal of Medicine 349 (18): 1703–1712.doi:10.1056/NEJMoa035162. PMID 14585938.
6.  Schulman, S; Wåhlander K; Lundström T; Clason SB; Eriksson H; THRIVE III investigators (October 2003). “Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran”. New England Journal of Medicine 349 (18): 1713–1721. doi:10.1056/NEJMoa030104. PMID 14585939.

Ximelagatran

Systematic (IUPAC) name
ethyl 2-[[(1R)-1-cyclohexyl-2- [(2S)-2-[[4-(N’-hydroxycarbamimidoyl) phenyl]methylcarbamoyl]azetidin-1-yl]- 2-oxo-ethyl]amino]acetate
Clinical data
Pregnancy category	uncategorised
Legal status	Rx only/POM
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	20%
Metabolism	None
Biological half-life	3-5h
Excretion	Renal (80%)
Identifiers
CAS Registry Number	192939-46-1
ATC code	B01AE05
PubChem	CID: 9574101
IUPHAR/BPS	6381
DrugBank	DB04898
ChemSpider	7848559
UNII	49HFB70472
KEGG	D01981
ChEMBL	CHEMBL522038
Chemical data
Formula	C24H35N5O5
Molecular mass	473.57 g·mol−1 (429 g/mol after conversion)

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