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RIVAROXABAN 利伐沙班 ريفاروكسابان Ривароксабан SPECTRAL VISIT

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RIVAROXABAN

5-Chloro-N-{[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinophenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide

5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide

Molecular formula: C₁₉H₁₈ClN₃O₅S, MW435.9

CAS 366789-02-8

BAY 59-7939, XARELTO

Patent Expiration Date:

Feb 8, 2021(US7157456),

Dec 11, 2020(US7585860 and US7592339)
Originator and Manufacturer:Bayer
Marketer in the US: Johnson & Johnson
Sales: $1.3 billion (2013)

Rivaroxaban (BAY 59-7939) is an oral anticoagulant invented and manufactured by Bayer;^[3]^[4] in a number of countries it is marketed as Xarelto.^[1] In the United States, it is marketed by Janssen Pharmaceutica.^[5] It is the first available orally active direct factor Xa inhibitor. Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs four hours after a dose. The effects last approximately 8–12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible.

In September 2008, Health Canada granted marketing authorization for rivaroxaban for the prevention of venous thromboembolism(VTE) in people who have undergone elective total hip replacement or total knee replacement surgery.^[8]

In September 2008, the European Commission granted marketing authorization of rivaroxaban for the prevention of venous thromboembolism in adults undergoing elective hip and knee replacement surgery.^[9]

On July 1, 2011, the U.S. Food and Drug Administration (FDA) approved rivaroxaban for prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in adults undergoing hip and knee replacement surgery.^[5]

On November 4, 2011, the U.S. FDA approved rivaroxaban for stroke prophylaxis in patients with non-valvular atrial fibrillation.

The drug compound having the adopted name “Rivaroxaban” has chemical name, 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5- yljmethyl)-2-thiophenecarboxamide; and has the structural formula I,

Formula I
The commercial pharmaceutical product XARELTO® tablets, contains rivaroxaban as active ingredient. Rivaroxaban is a factor Xa inhibitor useful as oral anticoagulant. Rivaroxaban can be used for the prevention and treatment of various thromboembolic diseases, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract, angina pectoris and restenoses after angioplasty or aortocoronary bypass, cerebral stroke,

transitory ischemic attacks, and peripheral arterial occlusive diseases.

U.S. Patent No. 7, 157,456 describes Rivaroxaban and process for the preparation thereof. The process of US ‘456 for rivaroxaban involves reaction of 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)-dione with 4-(4-aminophenyl)-3-morpholinone to provide 2-((2R)-2-hydroxy-3- { [4-(3-oxo-4-morpholiny)phenyl]amino Jpropyl)- lH-isoindole- 1 ,3(2H)-dione, which on cyclization using Ν,Ν-carbonyl diimidazole to afford 2-({5S)-2-Oxo-3-[4-(3-oxo-4-morpholiny)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione, which on reacted with methylamine followed by reaction with 5-chlorothiophene-2-carbonyl chloride to provide Rivaroxaban.

Various processes for the preparation of rivaroxaban, its intermediates, and related compounds are disclosed in U.S. Patent Nos. 7,585,860; 7,351,823, 7,816,355, and 8,101,609; patent application Nos. WO 2011/012321, WO 2012/156983, WO 2012/153155, WO 2013/053739, WO 2013/098833, WO 2013/156936, WO 2013/152168, WO 2013/120464, WO 2013/164833, US 2012/0283434 and US 2013/184457; and J. Med. Chem. 2005, 48, 5900-5908.

PAPER CONTAING SPECTRAL DATA

JOURNAL OF CHEMICAL RESEARCH v 35, issue 7, pg 400-4-1, 2011

An approach to the anticoagulant agent rivaroxaban via an isocyanate-oxirane cycloaddition promoted by MgI2.etherate

Chao Lia, Yingshuai Liua, Yongjun Zhangb and Xingxian Zhanga*
a College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310032, P. R. China
b Zhejiang Apeloa Medical Technology Co., Ltd, Dongyang 322118, P. R. China

A convergent and efficient synthesis of anticoagulant rivaroxaban was developed using the cycloaddition of commercially
available (R)-epichlorohydrin with 4-(morpholin-3-one)phenyl isocyanate catalysed by MgI2 etherate as the
key step, in 22% overall yield.
Keywords: (R)-epichlorohydrin, isocyanate, MgI2.etherate, rivaroxaban

* Correspondent. E-mail: mhmosslemin@yahoo.com

(Rivaroxaban) (1):1

rivaroxaban 1 (689 mg) in 88% yield, Rf = 0.30 (ethyl acetate), as a white solid,

m.p. 229.3–230.7 °C(lit.1, 230 °C).

[α]D20 = −37° (c = 0.5, DMSO) [lit.1, [α]D21 = –38°(c = 0.2985, DMSO)].

IR (KBr) (νmax /cm−1): 3343, 1724 (C=O), 1649(C=O), 1523, 1430, 808, 756

δH 3.60–3.62 (m, 2H), 3.71–3.73 (m,2H), 3.84–3.87 (dd, J = 6.5, 9.5 Hz, 1H), 3.96–3.98 (m, 2H), 4.20 (s,2H), 4.18–4.21 (m, 1H), 4.83–4.86 (m, 1H), 7.20 (d, J = 4.0 Hz, 1H),7.41 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 4.0 Hz,1H), 8.99 (t, J = 5.5 Hz, 1H).

δC 42.19, 47.43, 49.00, 63.46, 67.71,71.30, 118.35, 125.92, 128.11, 128.43, 133.24, 136.48, 137.08,138.43, 154.08, 160.79, 165.95.

LIT REF 1=S. Roehrig, A. Straub, J. Pohlmann, T. Lampe, J. Pernerstorfer, K.Schlemmer, P. Reinemer and E. Perzborn, J. Med. Chem., 2005, 48, 5900.

STRUCTURE

SIMILARITY

Chemical structures of linezolid (top) and rivaroxaban (bottom). The shared structure is shown in blue.

Rivaroxaban bears a striking structural similarity to the antibiotic linezolid: both drugs share the same oxazolidinone-derived core structure. Accordingly, rivaroxaban was studied for any possible antimicrobial effects and for the possibility of mitochondrial toxicity, which is a known complication of long-term linezolid use. Studies found that neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria. As for mitochondrial toxicity, in vitro studies found the risk to be low

IH NMR PREDICT

13 C NMR PREDICT

COSY NMR.

13 C NMR…..http://www.nmrdb.org/13c/index.shtml?v=v2.14.1

CLICK TO PREDICT..ALLOW SOME TIME TO LOAD ON NMRDB SITE…..CHECK JAVA AND FLASH SETTINGS

ABOVE PICTURES ARE THE ONES YOU WILL GET

· 1H NMR prediction……http://www.nmrdb.org/new_predictor/index.shtml?v=v2.12.1

· 13C NMR prediction

· COSY prediction

· HSQC/HMBC prediction

· All predictions

New patent WO-2015104605

Process for preparing rivaroxaban – comprising the reaction of a thioester compound and its salts with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one.

Wockhardt Ltd

The synthesis of (II) via intermediate (I) is described (example 7, page 15)

4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one (formula III) is (I) and rivaroxaban is (II) (claim 1, page 16).

The present invention relates to a process for the preparation of Rivaroxaban and its novel intermediates, or pharmaceutically acceptable salts thereof. The present invention provides novel intermediates, which may be useful for the preparation of Rivaroxaban or its pharmaceutically acceptable salts thereof. The process of preparation by using novel intermediate is very simple cost effective and may be employed at commercial scale. The product obtained by using novel intermediate yield the Rivaroxaban of purity 99% or more, when measured by HPLC. The present invention especially relates to a process for the preparation of Rivaroxaban from thioester of formula II, or a pharmaceutically acceptable salt thereof, wherein R is leaving group.

process includes the step of , reacting thioester of formula IIA or pharmaceutically acceptable salt thereof

Formula IIA

with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one of formula III,

Formula III

Formula I

EXAMPLE 7: One pot process for Rivaroxaban

The triphenylphosphine (11.5g) and mercaptobenzothiazole disulphide (15.31g) were taken in methylene chloride and reaction mixture was stirred at 28°C -30°C for 1 hr. The 5-chlorothiophene-2-carboxylic acid (7.2g) and triethylamine (3.8 g) were added to the above reaction mixture. The reaction mixture is stirred at 0°C -25 °C for 1 hr. after 1 hr 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one (lOg) and triethylamine (3.8g) were added. The resulting reaction mixture further stirred for 2 hrs. After completion of the reaction, water was added and stirred for 10 min. aqueous layer was separated and washed with methylene chloride. The organic layer was acidified to pH 6-7 with 2N hydrochloric acid and finally the organic layer was concentrated to get desired product. The product was purified and dried to yield Rivaroxaban.

Yield: 10.0 gm

Purity: 99.3 %

EXAMPLE 8: One pot process for Rivaroxaban

Exemplified procedure in example 7 with the replacement of solvent ethyl acetate and base potassium hydroxide were used to get the rivaroxaban.

EXAMPLE 9: One pot process for Rivaroxaban

Exemplified procedure in example 7 with the replacement of solvent acetonitile and base potassium carbonate were used, methylene chloride was added in the reaction mixture to extract the Rivaroxaban.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015104605&recNum=7&maxRec=57790&office=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22C07D%22&sortOption=Pub+Date+Desc&queryString=&tab=PCTDescription

…………..

WO 01/47919 discloses ー species from 4_ (4_ aminophenyl) -3_ morpholinone (I) Preparation of rivaroxaban approach:

…………..

US 07/149522 discloses ー kind to 5_ chlorothiophenes _2_ carbonyl chloride (IV) is a method for preparing raw rivaroxaban in:

………….

http://www.google.com/patents/CN102786516A?cl=en

Preparation 6 rivaroxaban implementation

The 12.5 g (76.9 mmol) 5- chloro-thiophene-2-carboxylic acid was suspended in 35 g of toluene was heated to 80 で, at this temperature, a solution of 11.0 g (92.5 mmol) of thionyl chloride, reaction was continued for 30 min; then warmed to the boiling point of toluene was 120 ° C, and stirring was continued under reflux until cessation of gas; cooled to room temperature, the reaction mixture was concentrated under reduced pressure to remove excess thionyl chloride and toluene to give 5-chloro-thiophene-2-carbonyl chloride;

The 11.6 g (37.0 mmol) 4- {4 – [(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3 -one hydrochloride was added 40ml of water, was added 4. 64 g (43 8 mmol.) Na2CO3 stirred and dissolved; then added 50 ml of toluene, was added dropwise at 10 ° C under the mixture, the mixture is 8. 0 g ( 44. 4 mmol) 5- chloro-thiophene-2-carbonyl chloride was dissolved in 15 ml of toluene, 20 min the addition was complete, then stirring was continued at room temperature, TLC monitoring progress of the reaction, 2 h after completion of the reaction; and the filter cake washed with water and washed with acetone to give a pale yellow solid 19. 6 g, used directly ko acid recrystallization, as a white solid 15. 2 g,

mp 227. 2 – 228. 1 ° C, [a] D21 = -38 2 ° (. c = 0. 30, DMS0), rivaroxaban yield of 94%, the total yield of 87.5% 0

1H-NMR (DMSO) 8: 3. 61 (. 2 H, t, / = 5 4 Hz), 3. 71 (2 H, t, / = 5 4 Hz.), 3.85 (IH, m ), 3.97 (2 H, t, J = 4. 5 Hz), 4. 19 (3 H, t, / = 7. 5 Hz), 4.84 (IH, m), 7. 19 (IH, d, / = 4. 2Hz), 7.40 (2 H, d, /=9.0 Hz), 7. 57 (2 H, t, /=9.0 Hz), 7. 69 (IH, d, J = 4. 19 Hz), 8. 96 (IH, t, / = 5. 7 Hz).

…………………

WO2013120465

EXAMPLE 28 (preparation of rivaroxaban)

10 g of the salt prepared according to Example 18 were suspended in 75 ml of N- methylpyrolidone, the suspension was heated at 50°C, then 14 ml of triethylamine was added and the mixture was heated at 60°C. This was followed by addition of 15.7 ml of a solution of 5-chlorothiophene-2-carboxylic acid chloride in toluene (2.46 M) and the reaction mixture was stirred and heated at 55°C for 15 minutes, then slowly cooled below 30°C, 75 ml were added and the turbid solution was filtered. The clear filtrate was stirred at 50°C, which was followed by addition of 15 ml of water and 75 ml of ethanol and stirring for 1 hour under slow cooling. The separated product was filtered off, washed with water (15 ml, 60°C), ethanol (2 x 25 ml) and dried in vacuo. 9.1 g (yield 81%) of rivaroxaban in the form of an off-white powder with the melt, point of 229.5-231°C was obtained, HPLC 99.95%, content of the ( )-isomer below 0.03%.

1H NMR (250 MHz, DMSO-D₆), δ (ppm): 3.61 (t, 2H, CH₂); 3.71 (m, 2H, CH₂); 3.85 and 4.19 (m, 2×1 H, CH₂); 3.97 (m, 2H, CH₂); 4.19 (s, 2H, CH₂); 4.84 (pent, 1H, CH); 7.18 (d, 1H); 7.40 (m, 2H); 7.56 (m, 2H); 7.68 (d, 1H); 8.95 (bt, 1H, NH).

¹³C NMR (250 MHz, DMSO-D₆), δ (ppm): 42.2; 47.4; 49.0; 63.4; 67.7; 71.3; 1 18.3; 125.9; 128.1 ; 128.4; 133.2; 136.4; 137.0; 138.4; 154.0; 160.8; 165.9.

MS (m/z): 436.0729 (M+H)⁺. ation)

The optical isomer of rivaroxaban with the (R)- configuration was obtained by a process analogous to Example 28 starting from the salt prepared according to Example 19. The yield was 76%, HPLC 99.90%, content of the (5)-isomer below 0.03%. The NMR and MS spectra were in accordance with Example 28.

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5- chloro-thiophene-2-chloride by condensation, bromide, with 4- (4-amino-phenyl) -3-morpholinone cyclization reaction rivaroxaban, the following reaction scheme 😦 References : W02005068456, US20070149522, DE10300111)

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5- chloro-thiophene-2-chloride by condensation, oxidation, and 4- (4-amino-phenyl) -3-morpholinone cyclization reaction racemic rivaroxaban, since the epoxidation step is not give any stereoselectivity, the final chiral separation need to get rivaroxaban, the reaction scheme is as follows 😦 References: W0-0147919)

…………

4- (4- amino-phenyl) -3-morpholinone by condensation, cyclization, and potassium phthalimide after reaction with methyl chloroformate to give (S) -2 – hydroxy -3- (I, 3- dioxo – isoindoline-2-yl) propyl-4- (3-oxo –morpholino) phenyl carbamate, by condensation, methylamine and Ethanol action under profit rivaroxaban, the following reaction scheme (Ref: US20110034465):

……….

4- (4- amino-phenyl) -3-morpholinone (R) and – epichlorohydrin, in the DMF solvent phthalimide potassium salt was reacted with ammonia solution and then prepared to succeed amino compound, and 5-chloro-thiophene-2-chloride in pyridine catalyzed system benefit rivaroxaban, the following reaction scheme (Ref: W02009023233):

………….

4- (4- amino-phenyl) -3-morpholinone after condensation with (R) – epichlorohydrin, then the 5-chloro-thiophene-2-amide lithium chloride and tert-butyl the reaction of an alcohol potassium enrichment rivaroxaban, the following reaction scheme (Ref: US7816355):

……………….

3-chloro-1,2-propanediol by cyclization, the reaction with phthalimide, then with 4- (4-aminophenyl) -3-morpholinone reaction, CDI and hydrazine to give 4- {4- [(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3-one under the influence, in pyridine and under the action of tetrahydrofuran and 5-chloro-thiophene-2-chloride benefit rivaroxaban, the following reaction scheme (Reference: Gutcait, A. et al Tetrahedron:.. Asymmetry 1996, 7 (6), 1641-1648 Roehrig, .. S. et al J. Med Chem 2005,48 (19), 5900-5908)..:

…………..

http://www.google.com/patents/CN102702186A?cl=zh

Compound rivaroxaban Synthesis Example 7 formula (X), [0071] Example

[0072] Method One:

[0074] The compound of formula (VIII) of (180mg, 0. 618mmol), Ni chloride (5mL) and tris ko amine (187mg,

I. 85mmol) added to the reaction flask, stirred at room temperature for 10 minutes, cooled to 0 ° C, a solution of 5-chloro-2-thiophene chloride (224mg, 1.24mm0l), stirred at room temperature overnight; after the completion of the reaction, spin dry, rinse with anhydrous alcohol ko, filtered, washed ko anhydrous alcohol three times to obtain a white solid product rivaroxaban (215mg, embodiments of the total yield of 7,8 80%).

[0075] 1H-Mffi (DMSC) JOOMHz, δ d m):…. 3 61 (t, 2H, J = 5 6Hz), 3. 71 (t, 2H, J = 5 2Hz), 3 89 ( m, 1H), 3. 97 (t, 2H, J = 4. 4Hz), 4. 20 (m, 3H), 4. 85 (m, 1H), 7. 18 (d, 1H, J = 4. 0Hz), 7. 40 (d, 2H, J = 8. 8Hz), 7. 56 (d, 2H, J = 8. 8Hz), 7. 73 (d, 1H, J = 4. 0Hz).

The method of writing is:

[0078] The compound 5_ gas – oh -I- thiophene carboxylic acid (500mg, 3. 08mmol), MsCl (702mg, 6. 1 Bmmol) and sodium bicarbonate (. 517mg, 6 16mmol) was suspended in THF (20ml) in , heated to 60 ° C with stirring 45min, a large white suspension washed out; the reaction mixture was cooled to room temperature, the compound of formula VIII was added portionwise (800mg, 2 75mmol.), stirred for 5 hours, after completion of the reaction distilled THF, was added after the residue was cooled to room temperature, water (IOOml), at room temperature embrace Cheung 30min, filtered, and the filter cake washed with cold water, dried and added to a ko-ol (5ml) was heated at reflux for I hour. After cooling, stirred for 5 hours at room temperature After filtration to give the product of formula (X) of the compound rivaroxaban (719mg, 60%)

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WO2011098501A1	Feb 10, 2011	Aug 18, 2011	Sandoz Ag	Method for the preparation of rivaroxaban
WO2011102640A2	Feb 16, 2011	Aug 25, 2011	Hanmi Holdings Co., Ltd.	Method for preparing sitagliptin and amine salt intermediates used therein
WO2012159992A1 *	May 18, 2012	Nov 29, 2012	Interquim, S.A.	Process for obtaining rivaroxaban and intermediate thereof
CN102786516A *	Aug 21, 2012	Nov 21, 2012	湖南师范大学	Method for synthesizing rivaroxaban
US7157456	Dec 11, 2000	Jan 2, 2007	Bayer Healthcare Ag	Substituted oxazolidinones and their use in the field of blood coagulation
US7816355 *	Apr 28, 2009	Oct 19, 2010	Apotex Pharmachem Inc	Processes for the preparation of rivaroxaban and intermediates thereof
US20110034465		Feb 10, 2011	Apotex Pharmachem Inc.	Processes for the preparation of rivaroxaban and intermediates thereof

CN101560209A *	Apr 15, 2008	Oct 21, 2009	Shenyang, one hundred million Leo Pharmaceutical Co., Ltd.	Pyrimidine oxazolidinone compound and preparation method comprising
CN101619061A *	Aug 11, 2009	Jan 6, 2010	Shenyang Pharmaceutical University	Cyanopyridyl substituted oxazolidinone compounds
CN101821260A *	Aug 14, 2008	Sep 1, 2010	Consett Pharmaceuticals Ltd.	Substituted oxazolidinone derivatives
CN102250076A *	May 27, 2011	Nov 23, 2011	Hengdian Group homes Chemical Co., Ltd.	One kind of rivaroxaban Rivaroxaban intermediates and preparation methods
CN102250077A *	Jun 15, 2011	Nov 23, 2011	Zhejiang University	A method for intermediate and rivaroxaban Rivaroxaban for the synthesis of
CN102311400A *	Jun 29, 2010	Jan 11, 2012	Xiang really Biotechnology Co., Ltd.	Aminomethyl-3-aryl-2-oxazolidinone class method – Preparation of L-5-
CN102320988A *	Jun 3, 2011	Jan 18, 2012	Shanghai Institute of Organic Chemistry	4- (4-aminophenyl) -3-morpholinone intermediate amide, the synthesis method and uses
EP2354128A1 *	Feb 10, 2010	Aug 10, 2011	Sandoz Ag	Method for the preparation of rivaroxaban
WO2010124385A1 *	Apr 28, 2010	Nov 4, 2010	Apotex Pharmachem Inc.	Processes for the preparation of rivaroxaban and intermediates thereof

FROM THE NET

RIVAROXABAN 5-Chloro-N-{[(5S) 2-oxo-3 [4-(3-oxo-4 …

https://plus.google.com/…/posts/EeEveU8xvUd

ANTHONY MELVIN CRASTO

32 mins ago – RIVAROXABAN 5-Chloro-N-{[(5S) 2-oxo-3 [4-(3-oxo-4-morpholinophenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide (Rivaroxaban) (1):1 rivaroxaban 1 …

WO 2015104605.new patent on Rivaroxaban, Wockhardt …

https://plus.google.com/…/posts/g4TXSPBA4YV

ANTHONY MELVIN CRASTO

1 hour ago – WO 2015104605.new patent on Rivaroxaban, Wockhardt Ltd Process for preparing rivaroxaban – comprising the reaction of a thioester compound and its salts …

Rivaroxaban
Systematic (IUPAC) name


(S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
Clinical data
Trade names	Xarelto
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Licence data	EMA:Link, US FDA:link
Pregnancy category	AU:C US:C (Risk not ruled out)
Legal status	AU:Prescription Only (S4) CA: ℞-only UK:Prescription-only (POM) US:℞-only
Routes of administration	oral
Pharmacokinetic data
Bioavailability	80% to 100%; Cmax = 2 – 4 hours (10 mg oral)^[1]
Metabolism	CYP3A4 , CYP2J2 and CYP-independent mechanisms^[1]
Biological half-life	5 – 9 hours in healthy subjects aged 20 to 45^[1]^[2]
Excretion	2/3 metabolized in liver and 1/3 eliminated unchanged^[1]
Identifiers
CAS Registry Number	366789-02-8
ATC code	B01AX06
PubChem	CID: 6433119
IUPHAR/BPS	6388
DrugBank	DB06228
ChemSpider	8051086
UNII	9NDF7JZ4M3
ChEMBL	CHEMBL198362
Synonyms	Xarelto, BAY 59-7939
Chemical data
Formula	C₁₉H₁₈Cl N₃O₅S
Molecular mass	435.882 g/mol

Rivaroxaban, a FXa inhibitor, is the active ingredient in XARELTO Tablets with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C₁₉H₁₈ClN₃O₅S and the molecular weight is 435.89. The structural formula is:

XARELTO (rivaroxaban) Structural Formula Illustration

Rivaroxaban is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder. Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.

Each XARELTO tablet contains 10 mg, 15 mg, or 20 mg of rivaroxaban. The inactive ingredients of XARELTO are: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. Additionally, the proprietary film coating mixture used for XARELTO 10 mg tablets is Opadry® Pink and for XARELTO 15 mg tablets is Opadry® Red, both containing ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 20 mg tablets is Opadry® II Dark Red, containing ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.

SEE ABAN SERIES AT…………http://organicsynthesisinternational.blogspot.in/p/aban-series.html

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////////SEE ABAN SERIES AT…………http://organicsynthesisinternational.blogspot.in/p/aban-series.html

VORICONAZOLE SPECTRAL VISIT

July 26, 2015 1:13 pm / Leave a comment

VORICONAZOLE

CAS 137234-62-9

(aR,bS)-a-(2,4-Difluorophenyl)-5-fluoro-b-methyl-a-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimideethanol

2R,3S-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Manufacturers’ Codes: UK-109496

Trademarks: Vfend (Pfizer)

MF: C16H14F3N5O

MW: 349.31

Percent Composition: C 55.01%, H 4.04%, F 16.32%, N 20.05%, O 4.58%

Properties: mp 127°. [a]D25 -62° (c = 1 in methanol).

Melting point: mp 127°

Optical Rotation: [a]D25 -62° (c = 1 in methanol)

Therap-Cat: Antifungal (systemic)

1H NMR……… http://file.selleckchem.com/downloads/nmr/S144202-Voriconazole-HNMR-Selleck.pdf

1H NMR DMSO-d6, peak at 3.3 is HOD

NMR PIC FROM THE NET

m.p=134

¹H-NMR (300 MHz, DMSO-d₆) δ
(ppm): 9.04 (1H), 8.84 (1H), 8.23 (1H), 7.61 (1H), 7.28 (1H), 7.17 (1H), 6.91 (1H),

5.97 (1H),

4.80 (1H),

4.34 (1H),

3.93 (1H),

1.1 (3H)………….US8263769

13 C NMR

DMSO-d6

NMR PIC FROM THE NET

1H NMR PREDICT

13C NMR PREDICT

COSY PREDICT

HMBC PREDICT

HPLC

………………….

PAPER

J. Org. Chem., 2013, 78 (22), pp 11396–11403

DOI: 10.1021/jo4019528

http://pubs.acs.org/doi/full/10.1021/jo4019528

……………………..

Org. Proc. Res. Dev., 2001, 5 (1), pp 28–36

DOI: 10.1021/op0000879

http://pubs.acs.org/doi/full/10.1021/op0000879

(2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1). ……………to provide the title compound as a white solid (7.6 g, 40% mass yield or 80% of available enantiomer), mp 134 °C

¹H NMR (DMSO-d₆) δ 1.1 (d, 3H), 3.93 (q, 1H), 4.34 (d, 1H), 4.80 (d, 1H), 5.97 (bs, 1H), 6.91 (ddd, 1H), 7.17 (ddd, 1H), 7.28 (ddd, 1H), 7.61 (s, 1H), 8.23 (s, 1H), 8.84 (s, 1H), 9.04 (s, 1H) ppm.

Cited Patent	Filing date	Publication date	Applicant	Title
US6586594	26 Jul 1996	1 Jul 2003	Pfizer, Inc.	Preparation of triazoles by organometallic addition to ketones and intermediates therefor
CN1488630A	8 Oct 2002	14 Apr 2004	张文更	Method for preparing triazole antifungal agent
CN1814597A	9 Dec 2005	9 Aug 2006	北京丰德医药科技有限公司	New method for preparing voriconazole
EP0440372A1	24 Jan 1991	7 Aug 1991	Pfizer Limited	Triazole antifungal agents
GB2452049A	Title not available
WO1993007139A1	1 Oct 1992	15 Apr 1993	Pfizer Ltd	Triazole antifungal agents
WO1997006160A1	26 Jul 1996	20 Feb 1997	Michael Butters	Preparation of triazoles by organometallic addition to ketones and intermediates therefor
WO2006065726A2	13 Dec 2005	22 Jun 2006	Reddys Lab Ltd Dr	Process for preparing voriconazole
WO2007013096A1	26 Jun 2006	1 Feb 2007	Msn Lab Ltd	Improved process for the preparation of 2r, 3s-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl) butan-2-ol (voriconazole)
WO2007132354A2	29 Jan 2007	22 Nov 2007	Medichem Sa	Process for preparing voriconazole, new polymorphic form of intermediate thereof, and uses thereof
WO2009024214A1 *	10 Jul 2008	26 Feb 2009	Axellia Pharmaceuticals Aps	Process for the production of voriconazole
WO2009084029A2	2 Dec 2008	9 Jul 2009	Venkatesh Bhingolikar	Improved process for the preparation of (2r,3s)-2-(2,4- difluqrophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl) butan-2-ol

US8575344 *	1 Feb 2011	5 Nov 2013	Dongkook Pharmaceutical Co., Ltd.	Process for preparing voriconazole by using new intermediates
US20130005973 *	1 Feb 2011	3 Jan 2013	Dongkook Pharmaceutical Co., Ltd.	Process for preparing voriconazole by using new intermediates

WO2011096697A2 *	1 Feb 2011	11 Aug 2011	Dongkook Pharmaceutical Co., Ltd.	Process for preparing voriconazole by using new intermediates
US8263769 *	4 Aug 2008	11 Sep 2012	Hanmi Science	Process for preparing voriconazole
US8575344	1 Feb 2011	5 Nov 2013	Dongkook Pharmaceutical Co., Ltd.	Process for preparing voriconazole by using new intermediates
US20100190983 *	4 Aug 2008	29 Jul 2010	Hanmi Pharm, Co., Ltd.	Process for preparing voriconazole

WO1997006160A1 *	26 Jul 1996	20 Feb 1997	Michael Butters	Preparation of triazoles by organometallic addition to ketones and intermediates therefor
WO2006065726A2 *	13 Dec 2005	22 Jun 2006	Reddys Lab Ltd Dr	Process for preparing voriconazole
EP0440372A1 *	24 Jan 1991	7 Aug 1991	Pfizer Limited	Triazole antifungal agents

Reference

Butters et al., “Process Development of Voriconazole: A Novel Broad-Spectrum Triazole Antifungal Agent,” Organic Process Research & Development, 2001, vol. 5, pp. 28-36.

References:

Ergosterol biosynthesis inhibitor. Prepn: S. J. Ray, K. Richardson, EP 440372; eidem, US 5278175 (1991, 1994 both to Pfizer); R. P. Dickinson et al., Bioorg. Med. Chem. Lett. 6, 2031 (1996).

Mechanism of action: H. Sanati et al.,Antimicrob. Agents Chemother. 41, 2492 (1997). In vitro antifungal spectrum: F. Marco et al., ibid. 42, 161 (1998).

HPLC determn in plasma: R. Gage, D. A. Stopher, J. Pharm. Biomed. Anal. 17, 1449 (1998).

Review of pharmacology and clinical development: P. E. Verweij et al., Curr. Opin. Anti-Infect. Invest. Drugs 1, 361-372 (1999); J. A. Sabo, S. M. Abdel-Rahman, Ann. Pharmacother. 34, 1032-1043 (2000).

Clinical pharmacokinetics: L. Purkins et al., Antimicrob. Agents Chemother. 46, 2546 (2002).

Clinical comparison with amphotericin B: T. J. Walsh et al., N. Engl. J. Med. 346, 225 (2002).

MOLFILE

COPY ONLY BLUE SECTION

START

64684.mol

ChemDraw07261512442D

26 28 0 0 0 0 0 0 0 0999 V2000

0.5118 1.1267 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

-0.2030 0.7149 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

-0.9179 0.3031 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0

-0.6206 1.4298 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

-0.2030 2.1447 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0

-0.6206 2.8595 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

-1.4441 2.8595 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0

-1.8559 2.1447 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

-1.4441 1.4298 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

-1.8559 0.7149 0.0000 F 0 0 0 0 0 0 0 0 0 0 0 0

0.2088 0.0000 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

-0.5062 -0.4117 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0

0.9236 0.4118 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

0.9236 1.2411 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0

1.5928 1.7215 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

1.3354 2.5107 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0

0.5118 2.5107 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

0.2545 1.7215 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0

0.6205 -0.7149 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

0.2088 -1.4297 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

0.6205 -2.1446 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

1.4440 -2.1446 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

1.8559 -2.8595 0.0000 F 0 0 0 0 0 0 0 0 0 0 0 0

1.8559 -1.4297 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

1.4440 -0.7149 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

1.8559 0.0000 0.0000 F 0 0 0 0 0 0 0 0 0 0 0 0

1 2 1 0

2 3 1 1

2 4 1 0

2 11 1 0

4 5 1 0

4 9 2 0

5 6 2 0

6 7 1 0

7 8 2 0

8 9 1 0

9 10 1 0

11 12 1 1

11 13 1 0

11 19 1 0

13 14 1 0

14 15 1 0

14 18 1 0

15 16 2 0

16 17 1 0

17 18 2 0

19 20 1 0

19 25 2 0

20 21 2 0

21 22 1 0

22 23 1 0

22 24 2 0

24 25 1 0

25 26 1 0

M END

END

/////////

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।
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सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।

POSACONAZOLE

July 25, 2015 1:34 pm / Leave a comment

……

Posaconazole 泊沙康唑 , بوساكونازول , Позаконазол
Sch–56592
4-[4-[4-[4-[[(5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one

Noxafil
SCH 56592

U.S. Patents 5,661,151; 5,703,079; and 6,958,337.

Therap-Cat: Antifungal.

CAS 171228-49-2

Molecular Formula: C37H42F2N8O4

Molecular Weight: 700.78

CAS Name: 2,5-Anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1-yl)-D-threo-pentitol

Additional Names: (3R–cis)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin-1-yl]phenyl]-2-[1(S)-ethyl-2(S)-hydroxypropyl]-3,4-dihydro-2H-1,2,4-triazol-3-one

Syn……….Dominic De Souza, “PREPARATION OF POSACONAZOLE INTERMEDIATES.” U.S. Patent US20130203994, issued August 08, 2013.

Percent Composition: C 63.41%, H 6.04%, F 5.42%, N 15.99%, O 9.13%

Melting Point

170-172 deg C

O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1365
Solubility

In water, 0.027 mg/L at 25 deg C (est)

US EPA; Estimation Program Interface (EPI) Suite. Ver.3.12. Nov 30, 2004. Available from, as of Dec 19, 2005:http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

US5661151 EXP Jul 19, 2019 PRODUCT PATENT

US 5703079 EXP Aug 26, 2014

US8410077 EXPMar 13, 2029

US9023790 EXPJul 4, 2031

US 6958337 EXP Oct 5, 2018

US 8263600 EXPApr 1, 2022

1H NMR PREDICT

13C NMR PREDICT

COSY PREDICT

CN101824009A *	May 27, 2010	Sep 8, 2010	北京德众万全药物技术开发有限公司	Simple preparation method for posaconazole and piperazine intermediate thereof

Citing Patent	Filing date	Publication date	Applicant	Title
WO2015011224A1 *	Jul 24, 2014	Jan 29, 2015	Sandoz Ag	Improved process for the preparation of crystalline form iv of posaconazole

/////
सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।
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TOFACITINIB 的合成, トファシチニブ, Тофацитиниб, توفاسيتين يب SPECTRAL VISIT

July 24, 2015 4:36 am / Leave a comment

Tofacitinib Citrate, 的合成

托法替布, トファシチニブクエン酸塩, Тофацитиниба Цитрат

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate salt

CAS : 540737-29-9

ROTATION +

Tofacitinib; Tasocitinib;

477600-75-2 base ; CP-690550;

3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile;

3-{(3R,4R)-4-methyl-3-rmethyl-(7H-pyrrolor2,3-dlpyrimidin-4-yl)-amino1- piperidin-1-yl}-3-oxo-propionitrile mono citrate salt

CP 690550 Tofacitinib; CP-690550; CP-690550-10; Xeljanz; Jakvinus; Tofacitinib citrate

Trademarks: Xeljanz; Jakvinus

MF: C16H20N6O

CAS : 477600-75-2 BASE ; 540737-29-9(citrate) 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile

Molecular Weight: 312.369

SMILES: C[C@@H]1CCN(C[C@@H]1N(C)C2=NC=NC3=C2C=CN3)C(=O)CC#N

Activity: Treatment of Rheumatoid Arthritis; RA Treatment, JAK Inhibitor; Protein Kinase Inhibitor; JAK3 Inhibitor; Janus Kinase 3 Inhibitor; JAK-STAT Signaling Pathway; JAK1 Kinase Inhibitor; Selective Immunosuppressants

Status: Launched 2012

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

Originator: Pfizer

Pfizer Inc’s oral JAK inhibitor tofacitinib was approved on November 6, 2012 by US FDA for the treatment of rheumatoid arthritis.

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Tofacitinib (trade names Xeljanz and Jakvinus, formerly tasocitinib,^[1] CP-690550^[2]) is a drug of the janus kinase (JAK) inhibitor class, discovered and developed by Pfizer. It is currently approved for the treatment of rheumatoid arthritis (RA) in the United States,Russia, Japan and many other countries, is being studied for treatment of psoriasis, inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection.

An Improved and Efficient Process for the Preparation of Tofacitinib Citrate

Yogesh S. Patil, Nilesh L. Bonde, Ankush S. Kekan, Dhananjay G. Sathe*1, and Arijit Das

Publication Date (Web): November 17, 2014 (Article)

DOI: 10.1021/op500274j

http://pubs.acs.org/doi/full/10.1021/op500274j

MS m/z 313 (M⁺ + 1);

mp 201–202 °C;

¹H NMR (CDCl₃) δ 8.34 (s, 1H), δ 7.38 (d, 1H, J = 2.4 Hz), δ 6.93 (d, 1H, J = 2.4 Hz), δ 4.97 (m, 1H), δ 3.93–4.03 (m, 4H), δ 3.66 (m, 1H), δ 3.50 (m, 4H), δ 2.91 (d, 2H, J = 15.6 Hz), δ 2.80 (t, 2H, J = 12.8 Hz), δ 2.55 (m, 1H), δ 1.99 (m, 1H), δ 1.77 (m, 1H), δ 1.13–1.18 (m, 3H).

TEAMWORK

Part of the Pfizer group responsible for Xeljanz: Front row, from left: Sally Gut Ruggeri, Chakrapani Subramanyam, Eileen Elliott Mueller, and Frank Busch. Second row, from left: Matthew Brown, Mark Flanagan, and Robert Dugger. Back row, from left: Elizabeth Kudlacz and Douglas Ball.

Credit: Pfizer

Mark Flanagan, who was on the team at Pfizer that discovered Xeljanz, (tofacitinib citrate), an oral treatment for rheumatoid arthritis, remembers testing the drug in a rat model and seeing the drug decrease the level of inflammation in the rats’ footpads. “What we look for is physical measurements of the size of the joint. In the control animals, there was quite a bit of inflammation in the joints, whereas animals treated with different doses of the drug showed a dose-dependent decrease in the size of the joint. “Tofacitinib showed robust efficacy in the first such study run. I can remember the excitement that this data generated on the team,” he says.

Tofacitinib, chemically known as (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3- d]pyrimidin-4-ylamino)-B-oxo-l -piperidinepi panenitrile, is represented Formula I. Tofacitinib citrate, a janus kinase inhibitor, is approved as XELJANZ® tablets for treatment .of rheumatoid arthritis.

Various intermediates and processes for preparation of tofacitinib are disclosed in patents like US7301 023 and US8232394.

Formula I or isomers or a mixture of isomers thereof by following any method provided in the prior art, for example, by following Example 14 of U.S. Patent No. RE41,783 or by following Example 6 of U.S. Patent No. 7,301,023. Tofacitinib of Formula I or isomers of tofacitinib or a mixture of isomers thereof may be converted into a salt by following any method provided in the prior art, for example, by following Example 1 of U.S. Patent No. 6,965,027 or by following Example 1 or Example 8 of PCT Publication No. WO 2012/135338. The potential significance of JAK3 inhibition was first discovered in the laboratory of John O’Shea, an immunologist at the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH).^[5] In 1994, Pfizer was approached by the NIH to form a public-private partnership in order to evaluate and bring to market experimental compounds based on this research.^[5] Pfizer initially declined the partnership but agreed in 1996, after the elimination of an NIH policy dictating that the market price of a product resulting from such a partnership would need to be commensurate with the investment of public taxpayer revenue and the “health and safety needs of the public.”^[5] The drug discovery, preclinical development, and clinical development of tofacitinib took place exclusively at Pfizer.^[6] In November 2012, the U.S. Food and Drug Administration (FDA) approved tofacitinib for treatment of rheumatoid arthritis. Once on the market, rheumatologists complained that the $2,055 a month wholesale price was too expensive, though the price is 7% less than related treatments.^[6] A 2014 study showed that tofacitinib treatment was able to convert white fat tissues into more metabolically active brown fat, suggesting it may have potential applications in the treatment of obesity.^[7] It is an inhibitor of the enzyme janus kinase 1 (JAK1) and janus kinase 3 (JAK 3) , which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription.^[3] Recently it has been shown in a murine model of established arthritis that tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. This efficacy in this disease model correlated with the inhibition of both JAK1 and 3 signaling pathways, suggesting that tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3.^[4]

Preparation of 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate salt (Tofacitinib citrate, Xeljanz, CP-690550-10)

To a round-bottomed flask fitted with a temperature probe, condenser, nitrogen source, and heating mantle, methyl-[(3R,4R)-4-methyl-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (5.0 g, 20.4 mmol) was added followed by 1-butanol (15 mL), ethyl cyanoacetate (4.6 g, 40.8 mmol), and DBU (1.6 g, 10.2 mmol). The resulting amber solution was stirred at 40 °C for 20 h. Upon reaction completion, citric acid monohydrate (8.57 g, 40.8 mmol) was added followed by water (7.5 mL) and 1-butanol (39.5 mL). The mixture was heated to 81 °C and held at that temperature for 30 min. The mixture was then cooled slowly to 22 ºC and stirred for 2 h. The slurry was filtered and washed with 1-butanol (20 mL). The filter cake was dried in a vacuum oven at 80 °C to afford 9.6 g (93%) of tofacitinib citrate as an off-white solid.

1H NMR (500 MHz, d6-DMSO): δ 8.14 (s, 1H), 7.11 (d, J=3.6 Hz, 1H), 6.57 (d, J=3.6 Hz, 1H), 4.96 (q, J=6.0 Hz, 1H), 4.00-3.90 (m, 2H), 3.80 (m, 2H), 3.51 (m, 1H), 3.32 (s, 3H), 2.80 (Abq, J=15.6 Hz, 2H), 2.71 (Abq, J=15.6 Hz, 2H), 2.52-2.50 (m, 1H), 2.45-2.41 (m, 1H), 1.81 (m, 1H), 1.69-1.65 (m, 1H), 1.04 (d, J=6.9 Hz, 3H).

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

PAPER

3-((3R,4R)-4-Methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (1) Monocitrate

http://pubs.acs.org/doi/full/10.1021/jm1004286

J. Med. Chem., 2010, 53 (24), pp 8468–8484

DOI: 10.1021/jm1004286

1monocitrate as a white crystalline solid (mp = 201 dec).

LRMS: m/z 313.2 (MH⁺).

¹H NMR (400 MHz) (D₂O) δ HOD: 0.92 (2 H, d, J = 7.2 Hz), 0.96 (1 H, d, J = 7.6 Hz), 1.66 (1 H, m), 1.80 (1 H, m), 2.37 (1 H, m), 2.58 (2 H, 1/2 ABq, J = 15.4 Hz), 2.70 (2 H, 1/2 ABq, J = 15.4 Hz), 3.23 (2 H, s), 3.25 (1 H, s), 3.33 (1 H, m), 3.46 (1 H, m), 3.81 (4 H, m), 4.55 (1 H, m), 6.65 (1 H, d, J = 3.2 Hz), 7.20 (1 H, t, J = 3.2 Hz), 8.09 (1 H, m).

Anal. Calcd for C₂₂H₂₈N₆O₈: C, 52.38; H, 5.59; N, 16.66. Found: C, 52.32; H, 5.83; N, 16.30. For additional characterization of the monocitrate salt of 1 see WO 03/048162.

NMR PREDICT

References:

Weiling Cai, James L. Colony,Heather Frost, James P. Hudspeth, Peter M. Kendall, Ashwin M. Krishnan,Teresa Makowski, Duane J. Mazur, James Phillips, David H. Brown Ripin, Sally Gut Ruggeri, Jay F. Stearns, and Timothy D. White; Investigation of Practical Routes for the Kilogram-Scale Production of cis-3-Methylamino-4-methylpiperidines; Organic Process Research & Development 2005, 9, 51−56

Ripin, D. H.B.; 3-amino-piperidine derivatives and methods of manufacture, US patent application publication, US 2004/0102627 A1

Ruggeri, Sally, Gut;Hawkins, Joel, Michael; Makowski, Teresa, Margaret; Rutherford, Jennifer, Lea; Urban,Frank,John;Pyrrolo[2,3-d]pyrimidine derivatives: their intermediates and synthesis, PCT pub. No. WO 2007/012953 A 2, US20120259115 A1, United States Patent US8232393. Patent Issue Date: July 31, 2012

Kristin E. Price, Claude Larrive´e-Aboussafy, Brett M. Lillie, Robert W. McLaughlin, Jason Mustakis, Kevin W. Hettenbach, Joel M. Hawkins, and Rajappa Vaidyanathan; Mild and Efﬁcient DBU-Catalyzed Amidation of Cyanoacetates, Organic Letters, 2009, vol.11, No.9, 2003-2006

MORE NMR PREDICT

Tofacitinib

13C NMR PREDICT

SEE…….https://newdrugapprovals.org/2015/07/24/tofacitinib-%E7%9A%84%E5%90%88%E6%88%90-spectral-visit/

COSY PREDICT सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

NMR PICTURE FROM THE NET

PAPER

Tetrahedron Letters

Volume 54, Issue 37, 11 September 2013, Pages 5096–5098

Asymmetric total synthesis of Tofacitinib

^a Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, P.O. Box 747, Talca, Chile
^b Laboratory of Natural Products, Department of Chemistry, University of Antofagasta, P.O. Box 170, Antofagasta, Chile

http://dx.doi.org/10.1016/j.tetlet.2013.07.042

Abstract

A novel stereoselective synthesis of Tofacitinib (CP-690,550), a Janus tyrosine kinase (JAK3) specific inhibitor, has been achieved starting from (5S)-5-hydroxypiperidin-2-one in 10 steps from 2 with a 9.5% overall yield. The potentiality of this synthetic route is the obtention of tert-butyl-(3S,4R)-3-hydroxy-4-methylpiperidine-1-carboxylate (6b) as a new chiral precursor involved in the synthesis of CP690,550, in a three-step reaction, without epimerizations, rather than the 5 or more steps used in described reactions to achieve this compound from analogues of 6b.

Graphical abstract

…………………. Tofacitinib synthesis: US2001053782A1

Tofacitinib synthesis: WO2002096909A1

Tofacitinib synthesis: Org Process Res Dev 2014, 18(12), 1714-1720 (also from a chinese publication, same procedure just slight changes in reagents/conditions)

References:

1. Blumenkopf, T. A.; et. al. Pyrrolo[2,3-d]pyrimidine compounds. US2001053782A1

2. Flanagan, M. E.; et. al. Optical resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors. WO2002096909A1

3. Das, A.; et. al. An Improved and Efficient Process for the Preparation of Tofacitinib Citrate. Org Process Res Dev2014, 18(12), 1714-1720.

Synthesis of Tofacitinib Citrate

Author(s): ZHAO Fanglu, ,CHEN Guohua, ,YAO Shilun, ,ZHANG Zhenxia Journal: Chinese Journal of Pharmaceuticals, Year 2014 , Issue 3 , Page 201-204,253 Keyword: tofacitinib citrate%; anti-rheumatoid arthritis drug%; synthesis%;

http://caod.oriprobe.com/articles/41372497/Synthesis_of_Tofacitinib_Citrate.htm

PATENT https://www.google.co.in/patents/WO2003048162A1?cl=en The crystalline form of the compound of this invention 3-{4-methyl-3-[methyl- (7H-pyrrolot2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile mono citrate salt is prepared as described below. Scheme 1

Scheme 2

Example 1 3-{(3R,4R)-4-methyl-3-rmethyl-(7H-pyrrolor2,3-dlpyrimidin-4-yl)-amino1- piperidin-1-yl}-3-oxo-propionitrile mono citrate salt Ethanol (13 liters), (3R, 4R)-methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-amine (1.3 kg), cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (1.5 kg), and triethylamine (1.5 liters) were combined and stirred at ambient temperature. Upon reaction completion (determined by High Pressure Liquid Chromotography (HPLC) analysis, approximately 30 minutes), the solution was filtered, concentrated and azeotroped with 15 liters of methylene chloride. The reaction mixture was washed sequentially with 12 liters of 0.5 N sodium hydroxide solution, 12 liters of brine and 12 liters of water. The organic layer was concentrated and azeotroped with 3 liters of acetone (final pot temperature was 42°C). The resulting solution was cooled to 20°C to 25°C followed by addition of 10 liters of acetone. This solution was filtered and then aqueous citric acid (0.8 kg in 4 liters of water) added via in-line filter. The reaction mixture was allowed to granulate. The slurry was cooled before collecting the solids by filtration. The solids were dried to yield 1.9 kg (71 %) (3R, 4R)- 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- propionitrile mono citrate. This material was then combined with 15 liters of a 1:1 ratio of ethanol/water and the slurry was agitated overnight. The solids were filtered and dried to afford 1.7 kg (63% from (3R, 4R)-methyl-(4-methyl-piperidin-3-yl)-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amine) of the title compound as a white crystalline solid. ¹H NMR (400 MH2)(D₂0) δ HOD: 0.92 (2H, d, J = 7.2 Hz), 0.96 (1H, d, J = 7.6 Hz), 1.66 (1H, m), 1.80 (1H, m), 2.37 (1H, m), 2.58 (2H, ¹/₂ ABq, J = 15.4 Hz), 2.70 (2H, 3 ABq, J = 154 Hz), 3.23 (2H, s), 3.25 (1H, s), 3.33 (1H, m), 3.46 (1H, m), 3.81 (4H, m), 4.55 (1 H, m), 6.65 (1 H, d, J = 3.2 Hz), 7.20 (1 H, t, J = 3.2 Hz), 8.09 (1 H, m).

Patent

http://www.google.co.in/patents/EP1913000A2?cl=en Example 10 Preparation of methyl-[(3R, 4R)-4-methyl-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine:

KEY INTERMEDIATE

To a clean, dry, nitrogen-purged 2 L hydrogenation reactor were charged 20 wt% Pd(OH)₂/C (24.0 g, 50% water wet), water (160 ml), isopropanol (640 ml), (1-benzyl-4-methyl-piperidin-3-yI)-methyi- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (160.0 g, 0.48 mol), and acetic acid (28.65 g, 0.48 mol). The reactor was purged with three times at 50 psi with nitrogen and three times at 50 psi with hydrogen. Once purging was complete, the reactor was heated to 45-55°C and pressurized to 50 psi with hydrogen through a continuous feed. The hydrogen uptake was monitored until no hydrogen was consumed for 1 hour. The reactor was cooled to 20-30⁰C and purged three times at 50 psi with nitrogen. The reaction mixture was filtered through wet Celite and the filtrate was sent to a clean, dry, nitrogen-purged vessel. A solution of sodium hydroxide (39.33 g) in water (290 ml) was charged and the mixture was stirred for a minimum of 1 hour then heated to 75-90⁰C. The isopropanol was removed by distillation. The reaction mixture was cooled to 20-30°C and 2-methyltetrahydrofuran (1.6 L) was added. The aqueous layer was drained off and the 2-methyltetrahydrofuran was displaced with toluene (1.6 L). The distillation was continued until the final volume was 800 ml. The slurry was cooled to 20-30°C and held for a minimum of 7 hours. The resulting solids were isolated by filtration and washed with toluene (480 ml). After drying under vacuum between 40-50^DC for a minimum of 24 hours with a slight nitrogen bleed 102.3 g (87.3%) of the title compound were isolated. Mp 158.6-159.8°C. ¹H NMR (400 MHz, CDCI₃): δ 11.38 (bs, 1H), 8.30 (s, 1H), 7.05 (d, J=3.5 Hz, 1H), 6.54 (d, J=3.5 Hz, 1H), 4.89-4.87 (m, 1H), 3.39 (s, 3H), 3.27 (dd, J=12.0, 9.3 Hz, 1 H), 3.04 (dd, J=12.0, 3.9 Hz, 1H), 2.94 (td, J=12.6, 3.1 Hz, 1H0, 2.84 (dt, J=12.6, 4.3 Hz, 1H), 2.51-2.48 (m, 1H), 2.12 (bs, 2H), 1.89 (ddt, J=13.7, 10.6, 4 Hz, 1 H), 1.62 (dq, J=13.7, 4Hz, 1 H), 1.07 (d, J=7.3 Hz, 3H). ¹³C NMR (400 MHz, CDCI₃): δ 157.9, 152.0, 151.0, 120.0, 103.0, 102.5, 56.3, 46.2, 42.4, 34.7, 33.4, 32.4, 14.3. KEY INT

Example 11 Preparation of 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3- oxo-propionitrile….TOFACITINIB BASE

To a clean, dry, nitrogen-purged 1.0 L reactor were charged methyl-(4-methyl-piperidin-3-yI)-(7H- pyrroIo[2,3-d]pyrimidin-4-yl)-amine (32.0 g, 0.130 mol), toluene (160 ml), ethyl cyanoacetate (88.53 g, 0.783 mol) and triethyl amine (26.4 g, 0.261 mol). The reaction was heated to 100⁰C and held for 24 hours. The reaction was washed with water (160 ml). The organic layer concentrated to a volume of 10 ml and water (20 ml) was added. The residual toluene was removed by distillation and the mixture was cooled to room temperature. Acetone (224 ml) was added followed by citric acid (27.57 g, 0.144 mol) in water (76 ml). The resulting slurry was stirred for 7 hours. The solids were isolate by filtration, washed with acetone (96 ml), and dried under vacuum to afford 42.85 g (65.3%) of the title compound. Example 13 Preparation of 3-{(3R, 4R)~4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- propionitrile citrate salt:…………..TOFACITINIB CITRATE To a clean, dry, nitrogen-purged 500 ml reactor were charged methyl-(4-methyl-piperidin-3-yl)-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amine (25.0 g, 0.102 mol) and methylene chloride (250 ml). The mixture was stirred at room temperature for a minimum of 2.5 hours. To a clean, dry, nitrogen-purged 1 L reactor were charged cyanoacetic acid (18.2 g, 0.214 mol), methylene chloride (375 ml), and triethyl amine (30.1 ml, 0.214 mol). The mixture was cooled to -15.0— 5.0⁰C over one hour and trimethylacetyl chloride (25.6 ml, 0.204 mol) was added at a rate to maintain the temperature below O⁰C. The reaction was held for a minimum of 2.5 hours, then the solution of the amine was added at a rate that maintained the temperature below O⁰C. After stirring for 1 hour, the mixture was warmed to room temperature and 1 M sodium hydroxide (125 ml) was added. The organic layer was washed with water (125 ml) The methylene chloride solution.was displaced with acetone until a volume of 500 ml and a temperature of 55-65⁰C had been achieved. Water (75 ml) was charged to the mixture while maintaining the temperature at 55-65°C. A solution of citric acid (20.76 g, 0.107 mol) in water (25.0) was charged and the mixture was cooled to room temperature. The reactor was stirred for a minimum of 5 hours and then the resulting solids were isolated by filtration and washed with acetone (2×75 ml), which was sent to the filter. The salt was charged into a clean, dry, nitrogen-purged 1L reactor with 2B ethanol (190 ml) and water (190 ml). The slurry was heated to 75-85⁰C for a minimum of 4 hours. The mixture was cooled to 20-30⁰C and stirred for an additional 4 hours. The solids were isolated by filtration and washed with 2B ethanol (190 ml). After drying in a vacuum oven at 50⁰C with a slight nitrogen bleed, 34.6 g (67.3%) of the title compound were isolated. ¹H NMR (500 MHz, CZ₆-DMSO): δ 8.14 (s, 1 H), 7.11 (d, J=3.6 Hz, 1 H), 6.57 (d, J=3.6 Hz, 1 H), 4.96 (q, J=6.0 Hz, 1 H), 4.00-3.90 (m, 2H), 3.80 (m, 2H), 3.51 (m, 1 H), 3.32 (s, 3H), 2.80 (Ab_q, J=15.6 Hz, 2H), 2.71 (Ab_q, J=15.6 Hz, 2H), 2.52-2.50 (m, 1 H), 2.45-2.41 (m, 1 H), 1.81 (m, 1 H), 1.69-1.65 (m, 1 H), 1.04 (d, J=6.9 Hz, 3H)

PAPER

Org. Lett., 2009, 11 (9), pp 2003–2006

DOI: 10.1021/ol900435t

http://pubs.acs.org/doi/full/10.1021/ol900435t

PATENT

http://www.omicsonline.org/open-access/advances-in-the-inhibitors-of-janus-kinase-2161-0444.1000540.php?aid=29799 …………….. सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Clinical trials

Rheumatoid arthritis

Phase II clinical trials tested the drug in rheumatoid arthritis patients that had not responded to DMARD therapy. In a tofacitinib monotherapy study, the ACR score improved by at least 20% (ACR-20) in 67% of patients versus 25% who received placebo; and a study that combined the drug with methotrexate achieved ACR-20 in 59% of patients versus 35% who received methotrexate alone. In a psoriasis study, the PASI score improved by at least 75% in between 25 and 67% of patients, depending on the dose, versus 2% in the placebo group.^[8] The most important side effects in Phase II studies were increased blood cholesterol levels (12 to 25 mg/dl LDL and 8 to 10 mg/dl HDL at medium dosage levels) andneutropenia.^[8] Phase III trials testing the drug in rheumatoid arthritis started in 2007 and are scheduled to run until January 2015.^[9] In April 2011, four patients died after beginning clinical trials with tofacitinib. According to Pfizer, only one of the four deaths was related to tofacitinib.^[10] By April 2011, three phase III trials for RA had reported positive results.^[11] In November 2012, the U.S. FDA approved tofacitinib “to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate.”^[12]

Psoriasis

As of April 2011 a phase III trial for psoriasis is under way.^[11]

Alopecia

In June 2014, scientists at Yale successfully treated a male patient afflicted with alopecia universalis. The patient was able to grow a full head of hair, eyebrows, eyelashes, facial, armpit, genitalia and other hair. No side effects were reported in the study.^[13]

Ulcerative colitis

The OCTAVE study of Tofacitinib in Ulcerative Colitis started in 2012. It is currently enrolling patients, though the NIH trials page states that they expect the trial to close in June 2015.^[14]

Vitiligo

In a June 2015 study, a 53-year-old woman with vitiligo showed noticeable improvement after taking tofacitinib for five months.^[15]

Development of Safe, Robust, Environmentally Responsible Processes for New Chemical Entities

– Dr. V. Rajappa, Director & Head-Process R&D, Bristol-Myers Squibb, India

A PRESENTATION

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Herper, Matthew (2 March 2011). “Why Pfizer’s Biggest Experimental Drug Got A Name Change”. Forbes. Retrieved 3 March 2011.
Kremer, J. M.; Bloom, B. J.; Breedveld, F. C.; Coombs, J. H.; Fletcher, M. P.; Gruben, D.; Krishnaswami, S.; Burgos-Vargas, R. N.; Wilkinson, B.; Zerbini, C. A. F.; Zwillich, S. H. (2009). “The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo”. Arthritis & Rheumatism 60 (7): 1895–1905. doi:10.1002/art.24567. PMID 19565475. edit
“Tasocitinib”. Drugs in R&D 10 (4): 271–284. 2010. doi:10.2165/11588080-000000000-00000. PMC 3585773. PMID 21171673. edit
Ghoreschi, K.; Jesson, M. I.; Li, X.; Lee, J. L.; Ghosh, S.; Alsup, J. W.; Warner, J. D.; Tanaka, M.; Steward-Tharp, S. M.; Gadina, M.; Thomas, C. J.; Minnerly, J. C.; Storer, C. E.; Labranche, T. P.; Radi, Z. A.; Dowty, M. E.; Head, R. D.; Meyer, D. M.; Kishore, N.; O’Shea, J. J. (2011). “Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550)”. J Immunol. 186 (7): 4234–4243. doi:10.4049/jimmunol.1003668. PMC 3108067. PMID 21383241. edit
^ Jump up to:^a ^b ^c “Seeking Profit for Taxpayers in Potential of New Drug”, Jonathan Weisman, New York Times, March 18, 2013
Ken Garber (9 January 2013). “Pfizer’s first-in-class JAK inhibitor pricey for rheumatoid arthritis market”. Nature Biotechnology 31 (1): 3–4. doi:10.1038/nbt0113-3. PMID 23302910.
Jump up^ Moisan A, et al. White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nature Cell Biology, 8 December 2014. DOI 10.1038/ncb3075
“EULAR: JAK Inhibitor Effective in RA But Safety Worries Remain”. MedPage Today. June 2009. Retrieved 9 February 2011.
Clinical trial number NCT00413699 for “Long-Term Effectiveness And Safety Of CP-690,550 For The Treatment Of Rheumatoid Arthritis” at ClinicalTrials.gov
Matthew Herper. “Pfizer’s Key Drug Walks A Tightrope”. Forbes.
“Two Phase III Studies Confirm Benefits of Pfizer’s Tofacitinib Against Active RA”. 28 Apr 2011.
“FDA approves Xeljanz for rheumatoid arthritis”. 6 Nov 2012.
“Hairless man grows full head of hair in yale arthritis drug trial”. 19 Jun 2014.
https://clinicaltrials.gov/ct2/show/NCT01465763?term=A3921094&rank=1
“This Drug Brought Pigment Back for Woman with Vitiligo”. TIME. June 27, 2015. Retrieved June 29, 2015.
Nordqvist, Christian (27 April 2013). “Pfizer’s Arthritis Drug Xeljanz (tofacitinib) Receives A Negative Opinion In Europe”. Medical News Today. Retrieved 2 August 2013.
“”XALEJANZ PRESCRIBING INFORMATION @ Labeling.Pfizer.com””.

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

Tofacitinib
Systematic (IUPAC) name

3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile
Clinical data
Trade names	Xeljanz, Jakvinus
AHFS/Drugs.com	entry
Licence data	US FDA:link
Pregnancy category	US: C (Risk not ruled out)
Legal status	US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	74%
Protein binding	40%
Metabolism	Hepatic (via CYP3A4 andCYP2C19)
Biological half-life	3 hours
Excretion	Urine
Identifiers
CAS Registry Number	477600-75-2
ATC code	L04AA29
PubChem	CID: 9926791
IUPHAR/BPS	5677
DrugBank	DB08183
ChemSpider	8102425
UNII	87LA6FU830
ChEBI	CHEBI:71200
ChEMBL	CHEMBL221959
Synonyms	CP-690550
Chemical data
Formula	C₁₆H₂₀N₆O
Molecular mass	312.369 g/mol

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How flow chemistry can make processes greener…………Supercritical fluids

July 23, 2015 10:49 am / 1 Comment on How flow chemistry can make processes greener…………Supercritical fluids

Safe, small scale access to supercritical fluids

The ability to safely access high temperatures and pressures in flow reactors has implications not only on the rate of chemical reactions, but also on the types of solvents one can use. Many greensolvents such as methanol and acetone have boiling points too low for certain batch applications, whereas performing reactions at high pressure in a flow reactor may allow for their safe use at elevated temperatures.

Supercritical fluids are particularly interesting, since these solvents are entirely inaccessible without high pressure conditions. The use of supercritical fluids in a flow system offers numerous advantages over batch reactors.

Reactions may be performed on a small scale, improving safety and reducing the amount of material required. Depending on the type of reactor, it may be possible to visualize the reaction to evaluate the phase behaviour. Moreover, the reaction can be analyzed and the temperature and pressure subsequently changed without stopping the reaction and cleaning the vessel, as is necessary in a simple autoclave.

Continuous methods for utilizing supercritical fluids for extraction,¹ chromatography,² and as a reaction medium³ have all been commercialized, particularly for supercritical carbon dioxide (scCO₂).⁴ Academic examples using scMeOH, scH₂O, and scCO₂ for continuous reactions such as hydrogenations, esterifications, oxidations, and Friedel–Crafts reactions have been reported.⁵

A recent example that illustrates many of the green advantages of performing supercritical fluid chemistry in flow is in the ring opening of phthalic anhydride with methanol by Verboom and co-workers (Scheme 1).⁶ They designed a microreactor with a volume of just 0.32 μL that can withstand very high pressures.

The exceptionally small channel causes a large build-up of pressure, and supercritical conditions with pressures of up to 110 bar and temperatures up to 100 °C can occur inside the reactor, giving an ‘on-chip’ phase transition. The channel size increases near the outlet, allowing the fluid to expand to atmospheric conditions.

Thus, the total volume of scCO₂ under high pressure is exceptionally small, alleviating the major hazards of operating under supercritical conditions. The reaction was thoroughly studied on this small scale, allowing the authors to determine rate constants at several different temperatures and pressures.


	Scheme 1 Small scale continuous use of supercritical fluids.

Near- and supercritical water (scH₂O) can be an interesting green solvent only obtainable at very high temperature (T_c = 374 °C) and pressure (P_c = 221 bar). It is commonly used for completeoxidation of organic waste materials to CO₂; however, it has also been shown to be an effective solvent for selective oxidations.⁷ Given the harshness of the reaction conditions, it is not surprising that side product formation is common and highly dependent on the reaction time. For fast reactions in a batch reactor, precise control of reaction time is challenging, as the vessel takes time to heat and cool. In contrast, rapid heating, cooling, and quenching can be accomplished in a continuous process, allowing for well defined reaction times.

Fine tuning of the temperature, pressure, and time is also easier in a continuous process, as these variables can be changed without stopping and starting the reaction between samples. Thus, more data points can be obtained with less material and fewer heating and cooling cycles.

The Poliakoff group used these advantageous to perform a detailed study on the oxidation of p-xylene to terephthalic acid in scH₂O, a reaction carried out on industrial scale in acetic acid (Scheme 2).⁸ By using a flow reactor, reaction times as low as 9 seconds could be used. The equivalents of oxygen could also be finely varied on a small scale through the controlled thermal decomposition of H₂O₂.

Studying this aerobic oxidation with such precision in a batch process would prove highly challenging. Under optimal conditions, excellent selectivity for the desired product could be obtained. Further research by the same group identified improved conditions for this transformation.⁹


	Scheme 2 Selective oxidation in supercritical water.

Schematic Diagram of sample Supercritical CO2 system

Table 1. Critical properties of various solvents (Reid et al., 1987)
Solvent	Molecular weight	Critical temperature	Critical pressure	Critical density
Solvent	g/mol	K	MPa (atm)	g/cm³
Carbon dioxide (CO₂)	44.01	304.1	7.38 (72.8)	0.469
Water (H₂O) (acc. IAPWS)	18.015	647.096	22.064 (217.755)	0.322
Methane (CH₄)	16.04	190.4	4.60 (45.4)	0.162
Ethane (C₂H₆)	30.07	305.3	4.87 (48.1)	0.203
Propane (C₃H₈)	44.09	369.8	4.25 (41.9)	0.217
Ethylene (C₂H₄)	28.05	282.4	5.04 (49.7)	0.215
Propylene (C₃H₆)	42.08	364.9	4.60 (45.4)	0.232
Methanol (CH₃OH)	32.04	512.6	8.09 (79.8)	0.272
Ethanol (C₂H₅OH)	46.07	513.9	6.14 (60.6)	0.276
Acetone (C₃H₆O)	58.08	508.1	4.70 (46.4)	0.278
Nitrous oxide (N₂O)	44.013	306.57	7.35 (72.5)	0.452

Table 2 shows density, diffusivity and viscosity for typical liquids, gases and supercritical fluids.

Comparison of Gases, Supercritical Fluids and Liquids
	Density (kg/m³)	Viscosity (µPa∙s)	Diffusivity (mm²/s)
Gases	1	10	1–10
Supercritical Fluids	100–1000	50–100	0.01–0.1
Liquids	1000	500–1000	0.001

F. Sahena, I. S. M. Zaidul, S. Jinap, A. A. Karim, K. A. Abbas, N. A. N. Norulaini and A. K. M. Omar, J. Food Eng., 2009, 95, 240–253
D. J. Dixon and K. P. Jhonston, in Encyclopedia of Separation Technology, ed. D. M. Ruthven, John Wiley, 1997, 1544–1569
P. Licence, J. Ke, M. Sokolova, S. K. Ross and M. Poliakoff, Green Chem., 2003, 5, 99–104
X. Han and M. Poliakoff, Chem. Soc. Rev., 2012, 41, 1428–1436
S. Marre, Y. Roig and C. Aymonier, J. Supercrit. Fluids, 2012, 66, 251–264
F. Benito-Lopez, R. M. Tiggelaar, K. Salbut, J. Huskens, R. J. M. Egberink, D. N. Reinhoudt, H. J. G. E. Gardeniers and W. Verboom, Lab Chip, 2007, 7, 1345–1351
R. Holliday, B. Y. M. Jong and J. W. Kolis, J. Supercrit. Fluids, 1998, 12, 255–260
P. A. Hamley, T. Ilkenhans, J. M. Webster, E. García-Verdugo, E. Vernardou, M. J. Clarke, R. Auerbach, W. B. Thomas, K. Whiston and M. Poliakoff, Green Chem., 2002, 4, 235–238
E. Pérez, J. Fraga-Dubreuil, E. García-Verdugo, P. A. Hamley, M. L. Thomas, C. Yan, W. B. Thomas, D. Housley, W. Partenheimer and M. Poliakoff, Green Chem., 2011, 13, 2397–2407

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।

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Odalasvir

July 23, 2015 8:14 am / Leave a comment

ACH-3102 , Odalasvir

Odalasvir
ACH-0143102; ACH-3102
CAS : 1415119-52-6
Dimethyl N, N ‘- (tricyclo [8.2.2.24,7] hexadeca-1 (12), 4,6, 10,13,15-hexaene-5,11-diylbis {1H-benzimidazole-5,2-diyl [(2S, 3aS, 7aS) -octahydro-1H-indole-2,1-diyl] [(1S) -1 – (1-methylethyl) -2-oxoethylene]}) biscarbamate

Carbamic acid, N,N’-(tricyclo(8.2.2.24,7)hexadeca-4,6,10,12,13,15-hexaene-5,11-diylbis(1H-benzimidazole-6,2-diyl((2S,3aS,7aS)-octahydro-1H-indole-2,1-diyl)((1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl)))bis-, C,C’-dimethyl ester

Dimethyl N,N’-(1,4(1,4)-dibenzenacyclohexaphane-12,42-diylbis(1hbenzimidazole-5,2-diyl((2S,3aS,7aS)-octahydro-1H-indole-2,1-diyl)((2S)-3-methyl-1-oxobutan-1,2-diyl)))biscarbamate

2D chemical structure of 1415119-52-6
Mechanism of Action: HCV NS5A Protein inhibitor
Indication: Hepatitis C
Developer: Achillion Pharmaceuticals, Inc.

Achillion Pharmaceuticals, Inc

C60-H72-N8-O6

1001.2788

Odalasvir^[1] is an investigational new drug in development for the treatment hepatitis C.

Achillion Pharmaceuticals Inc’s Odalasvir (ACH-3102) is an investigational new drug in development for the treatment hepatitis C. Achillion’s ongoing study tests its NS5A inhibitor, ACH-3102, with Sovaldi in previously untreated genotype 1 hepatitis C patients over six and eight weeks of therapy. The main goal is to achieve a cure, or sustained virological response, 12 weeks after the completion of therapy.

Odalasvir is a hepatitis C virus (HCV NS5A) inhibitor in phase II clinical studies at Achillion for the treatment of hepatitis C.

In 2012, fast track designation was assigned to the compound in the U.S. for the treatment of chronic hepatitis C.

WILL BE UPDATED………….

WO 2012166716

http://www.google.com/patents/US20120302538

Figure US20120302538A1-20121129-C00189

General Considerations

All nonaqueous reactions were performed under an atmosphere of dry argon gas using oven-dried glassware and anhydrous solvents. The progress of reactions and the purity of target compounds were determined using one of the following two HPLC methods: (1) Waters AQUITY HPLC BEH C18 1.7 μm 2.1×50 mm column with an isocratic elution of 0.24 min at 90:10 water:acetonitrile containing 0.05% formic acid followed by a 4.26-min linear gradient elution from 90:10 to 10:90 at a flow rate of 1.0 mL/min with UV (PDA), ELS, and MS (SQ in APCI mode) detection (method 1); and (2) Waters AQUITY HPLC BEH C18 1.7 μm 2.1×50 mm column with an isocratic elution of 0.31 min at 95:5 water:acetonitrile containing 0.05% formic acid followed by a 17.47-min linear gradient elution from 95:5 to 5:95 at a flow rate of 0.4 mL/min with UV (PDA), ELS, and MS (SQ in APCI mode) detection (method 2).

Target compounds were purified via preparative reverse-phase HPLC using a YMC Pack Pro C18 5 μm 150×20 mm column with an isocratic elution of 0.35 min at 95:5 water:acetonitrile containing 0.1% trifluoroacetic acid followed by a 23.3-min linear gradient elution from 95:5 to 5:95 at a flow rate of 18.9 mL/min with UV and mass-based fraction collection.

Example 1

Synthesis of Compound 10

Compound 10 was prepared via bromination of [2.2]paracyclophane as outlined previously (Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3527-3533; Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3534-3543). Compounds 1, 2, 6, 8, and 10 can be obtained from commercial sources. Compounds 3-7 and 9 were prepared using general synthetic methods known in the art.

Example 2Synthesis of Compound 11

A deoxygenated (argon) mixture of 9 (284.2 mg), 10 (52.3 mg), K₃PO₄(248.1 mg), and PdCl₂dppf.CH₂Cl₂(7.4 mg) in dioxane/water (5.5 mL/0.55 mL) was irradiated in a microwave for 2 h at 80° C. The resulting mixture was evaporated under reduced pressure and the remaining solid was extracted with DCM. This crude material was purified by PTLC (20 cm×20 cm×2000 μm glass plates; eluted with 45:50:5 v/v/v DCM:EtOAc:MeOH, R_f0.28) to give 75.3 mg of 11. The purity of 11 was determined via analytical reverse-phase HPLC using a 3.5-min gradient elution of increasing concentrations of ACN in water (10-90%) containing 0.05% formic acid with a flow rate of 1.0 mL/min on a Waters AQUITY HPLC BEH C18 1.7 μm 2.1×50 mm column with UV (PDA), ELS, and MS (SQ in APCI mode) detection. HPLC: t_R1.57 min (98% purity). MS m/z calculated for C₅₆H₆₄N₈O₆([M]+), 945. found, 946 ([M+1]+).

Odalasvir

Systematic (IUPAC) name
Dimethyl N,N′-(1,4(1,4)-Dibenzenacyclohexaphane-12,42-diylbis(1hbenzimidazole-5,2-diyl((2S,3aS,7aS)-octahydro-1H-indole-2,1-diyl)((2S)-3-methyl-1-oxobutan-1,2-diyl)))biscarbamate
Clinical data
Legal status	Investigational
Identifiers
CAS Registry Number	1415119-52-6
ATC code	None
Chemical data
Formula	C₆₀H₇₂N₈O₆
Molecular mass	1001.28 g/mol

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//////////

Verubecestat (MK-8931)

July 22, 2015 6:20 am / Leave a comment

Verubecestat (MK-8931)

Merck Alzheimer’s drugs Verubecestat (MK-8931) is an oral β- amyloid precursor protein cleaving enzyme (BACE1 or β-secretase enzyme) inhibitor, is currently in Phase III clinical trials

Verubecestat
MK 8931, MK-8931, SCH 900931
2-Pyridinecarboxamide, N- (3 – ((5R) -3-amino-5,6-dihydro-2,5-dimethyl-1 , 1-dioxido-2H-1,2,4-thiadiazin-5-yl) -4-fluorophenyl) -5-fluoro-

N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide

CAS : 1286770-55-5

C₁₇ H₁₇ F₂ N₅ O₃ S, 409.41
Mechanism: Oral β- amyloid precursor protein cleavage enzyme (BACE) inhibitors
Indications: Alzheimer’s disease
Development progress: phase III clinical
Companies: Merck

Verubecestat (MK-8931) is a small-molecule inhibitor of beta-secretase cleaving enzyme (BACE) 1 and BACE2 in development by Merck for the treatment of Alzheimer’s Disease.

MK-8931 is a beta-secretase 1 (BACE1) inhibitor in phase III development for the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer’s disease at Merck & Co. The company is also conducting phase II/III trials for the treatment of Alzheimer’s type dementia.

Alzheimer’s disease (AD) is a devastating, progressive neurodegenerative disease that is associated with up to 80% of the estimated 47 million cases of dementia worldwide and is a leading cause of death in the United States.(1, 2) As the elderly population increases, the worldwide incidence of dementia is expected to nearly triple to approximately 132 million by 2050, creating an unsustainable socioeconomic burden.(1) Currently available therapies, which include acetylcholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist memantine, produce modest and transient improvement in cognitive function but do not alter the progression of AD.(3) Treatments that delay or halt disease progression by targeting the underlying causes of AD would have lasting impacts on patient function and quality of life and would address an urgent unmet medical need.

Two histopathological hallmarks are invariably observed in the brains of AD patients, namely, extracellular amyloid plaques composed primarily of β-amyloid (Aβ) peptides and intraneuronal neurofibrillary tangles composed primarily of aggregates of abnormally phosphorylated tau protein. Aβ peptides are formed by two sequential cleavages of the amyloid precursor protein (APP), first by β-site amyloid precursor protein cleaving enzyme 1 (BACE1) followed by cleavage of the resulting C-terminal fragment C99 by γ-secretase. This cleavage sequence results in production of a family of Aβ peptides, of which Aβ40 is the most abundant isoform and Aβ42 is more highly prone to aggregate into neurotoxic, oligomeric species.(4) According to the amyloid hypothesis, aberrant production and/or accumulation of Aβ peptides, principally Aβ42, over a period of decades is causative of the underlying disease pathogenesis that ultimately leads to neuronal cell death.(4, 5) In addition to the invariant presence of amyloid plaques in the brains of AD patients, the amyloid hypothesis is underpinned by several other lines of evidence. First, many distinct neurodegenerative diseases are associated with the invariant presence of abnormal protein aggregates analogous to amyloid plaques. Second, low levels of Aβ42 in the CSF are a reasonably good diagnostic/prognostic biomarker for AD. Finally, and most significantly, early onset autosomal dominant familial AD is associated with mutations in APP and the presenilin proteins (which are components of the γ-secretase enzyme), and all of these mutations share the common phenotype of increasing total Aβ levels or the relative proportion of Aβ42.(6) Given this multifaceted evidence supporting the role of Aβ peptides in AD progression, substantial efforts have been invested in the development of amyloid-lowering therapies as a disease-modifying approach to AD treatment.(7) Prominent among these has been inhibition of BACE1 to reduce or prevent production of the Aβ peptides. This approach has been further supported by the recent finding that a rare mutation (A673T) near the BACE1 cleavage site in APP reduces Aβ peptide production and is associated with reduced risk of developing AD and improved cognitive function in the elderly.(8)

BACE1 is a membrane-bound aspartyl protease expressed primarily in the central nervous system (CNS), is the sole enzymatic activity responsible for the initial β-site APP cleavage, and is required for Aβ peptide production in vivo.(9) In the brain, BACE1 is expressed mainly in neurons and cleaves APP predominantly in the endosomal compartments where the acidic pH is near the optimum for its enzymatic activity (pH 5).(10) Since the characterization of BACE1 more than 15 years ago,(11) there have been intensive efforts to overcome the challenges of identifying small molecule inhibitors that can penetrate the CNS and inhibit the formation of centrally derived Aβ peptides.(12) These efforts have been driven by evidence that BACE1 inhibition, in comparison with γ-secretase inhibition and antiamyloid immunotherapy, may be an inherently safer amyloid-lowering approach,(7) a notion that has been informed by an evolving understanding of BACE1 biology. In this regard, Bace1 knockout mice have been reported to have a number of subtle phenotypes, including reduction of central and peripheral nerve myelination, and several putative BACE1 substrates other than APP have recently been proposed.(10, 13, 14) However, many of these phenotypes and substrates remain to be independently confirmed, have little if any functional consequence, are not recapitulated by pharmacological inhibition of BACE, or may be mitigated through partial BACE1 inhibition.(8, 10, 13-15)

Smiles: C [C @] 1 (CS (= O) (= O) N (C (= N1) N) C) c2cc (ccc2F) NC (= O) c3ccc (cn3) F

COSY PREDICT

PATENT

https://www.google.co.in/patents/CN102639135A?cl=en

Scheme 3a:

https://www.google.co.in/patents/CN102639135A?cl=en

Scheme 3b:

The amine A (Scheme 3a, step 4) (13.7 g) in n-butanol (150 mL) was added a slurry solution of cyanogen bromide (5M, in MeCN). The resulting mixture was heated to reflux for 4 hours. The mixture was concentrated to 1/3 of original volume. To this mixture was added Et20 (200 mL). The resulting solid was removed by filtration, and the solid was washed with Et20 (2x). The solid was partitioned between EtOAc and saturated Na2CO3 (aq). The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 10.6 g

Scheme 10:

The nitro compound (Scheme 3b) (2. 50 g, 6. 0 mmol) of Et0H (150 mL) was degassed (To this solution was bubbled with nitrogen time 3 min). To this solution was added Pd / C (10% w / w, 50% water, 698 mg). The mixture was placed in a nitrogen atmosphere. Exhaust, and backfilled with H2 (3x). The obtained mixture at room temperature, followed by stirring under H2 balloon for 2 hours. Bubbling nitrogen gas, and the mixture was purged, filtered through Celite, and concentrated.Small plug filtered through a silica gel column, eluting with EtOAc, and the product was purified to give the aniline (2. 2g, 97%).

SEE

PATENT

http://www.google.co.in/patents/WO2011044181A1?cl=en

SNAPSHOT

SYNTHESIS CONSTUCTION

AND

ON RXN WITH WITH BuLi GIVES

THIS GIVES

THIS ON TREATMENT WITH BrCN

ON BOC2O TREATMENT GIVES

GIVES ON HYDGN

REACTION WITH

GIVES

FINAL COMPD Verubecestat

1H NMR PREDICT

13C NMR PREDICT

Updated…….WATCH OUT FOR MORE

https://www.google.co.in/patents/US8729071?cl=en

Steps 1-4:

These steps were performed using similar procedures to those described in steps 1-4 of Scheme 1a.

Step 5:

To a solution of the amine from step 4 (10.5 g, 36 mmol) in CH₂Cl₂(200 mL) was added benzoylisothiocyanate (4.3 mL, 1.1 eq.). The resulting solution was stirred at RT for 2.5 days. Additional benzoylisothiocyanate (0.86 mL, 0.2 eq.) was added and the solution was stirred at RT for an additional 2 hours. The solution was then concentrated in vacuo.

A portion of this material (6.5 g, ˜14 mmol) was dissolved in MeOH (200 mL). To this solution was added Na₂CO_{3 (s)}(1.52 g, 14 mmol). The resultant mixture was stirred at RT for 45 min. After that time, a slight excess of HOAc was added to the solution. The mixture was then concentrated. The residue was partitioned between CH₂Cl₂and ½ sat. NaHCO_{3 (aq.)}. The aqueous layer was extracted with CH₂Cl₂(3×). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The thiourea (˜4.9 g) was carried onto the next reaction without further purification.

Step 6:

Example 15 was prepared using a method similar to that described in Scheme 1a step 6.

To a shiny of amine A (Scheme 3a step 4) (13.7 grams) in n-butanol (150 mL) was added a solution of cyanogen bromide (5M in MeCN). The resultant mixture was heated to reflux for 4 hours. The mixture was concentrated to ⅓ of the original volume. To the mixture was added Et₂O (200 mL). The resultant solid was removed via filtration and the solid was washed with Et₂O (2×). The solid was partitioned between EtOAc and sat. Na₂CO₃(aq.). The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to afford 10.6 grams of Ex. 15. This material was converted to the t-butyl carbamate using a procedure similar to that described in Scheme 3.

Step 7:

A mixture of the bromide (3.00 g, 6.92 mmol), benzophenone imine (1.39 mL, 8.30 mmol), Pd₂(dba)₃(0.634 g, 0.692 mmol), John-Phos (0.413 g, 1.38 mmol), sodium tert-butoxide (2.13 g, 22.1 mmol), and toluene (51 mL) was degassed (vacuum/N₂). The mixture was then stirred at 65° C. under nitrogen for 3 h. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of Celite and rinsed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The residue was then dissolved in methanol (76 mL) and the resulting solution was charged with hydroxyl amine hydrochloride (2.16 g, 31.1 mmol) and sodium acetate (2.55 g, 31.1 mmol). The reaction mixture was stirred at room temperature for 40 min. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (100 mL), water (100 mL), and brine (100 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0-100% ethyl acetate/heptane) to afford the amino pyridine (0.880 g, 34%).

To a flame-dried flask was added a pyridyl bromide (Table IIb, Entry 15, 1.5 g, 3.3 mmol), Pd₂(dba)₃(305 mg, 0.3 mmol), (2-biphenyl)di-tert-butylphosphine (200 mg, 0.7 mmol), sodium tert-butoxide (1.02 g, 0.011 mmol), benzophenone imine (670 ul, 4 mmol), and toluene (21 mL). The mixture was evacuated under vacuum and back-filled with N₂(3×). The mixture was stirred at 60° C. for 1 h. After filtration through celite, the filtrate was concentrated. The crude residue was dissolved in 36 mL of methanol, and hydroxyl amine hydrochloride (458 mg, 6.6 mmol) and sodium acetate (541 mg, 6.6 mmol) were added. The reaction was stirred for 35 min and then quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the combined organic portions were dried over magnesium sulfate and concentrated. The crude residue was purified by a flash silica column (50% ethyl acetate/hexane) to get an aminopyridine product (730 mg, 68%).

A solution of the nitro compound (Scheme 3b) (2.50 g, 6.0 mmol) in EtOH (150 mL) was degassed by bubbling N₂through the solution for 3 min. To this solution was added Pd/C (10% w/w, 50% H₂O, 698 mg.). The mixture was placed under an atmosphere of N₂. The atmosphere was evacuated and back-filled with H₂(3×). The resulting mixture was stirred at RT under a H₂balloon for 2 h. The mixture was purged by bubbling N₂through it, filtered through Celite and concentrated. The product was purified by filtering through a small plug of silica gel column eluting with EtOAc to afford the aniline (2.2 g, 97%).

ENTRY 25

MH⁺: 410.0, HPLC1.79 min, LCMSMETHOD D

Method D:

Column: Agilent Zorbax SB-C18 (3.0×50 mm) 1.8 uM

Mobile phase: A: 0.05% Trifluoroacetic acid in water

- B: 0.05% Trifluoroacetic acid in acetonitrile

Gradient: 90:10 (A:B) for 0.3 min, 90:10 to 5:95 (A:B) over 1.2 min, 5:95 (A:B) for 1.2 min.

Flow rate: 1.0 mL/min

UV detection: 254 and 220 nm

Mass spectrometer: Agilent 6140 quadrupole

update…………..

Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)–A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer’s Disease

Departments of ^†Discovery Chemistry, ^‡Neuroscience, ^§Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ^ΔTranslational Medicine, ^#Structural Chemistry, ^⊥Molecular and Materials Characterization, ^∥Pharmaceutical Sciences and Clinical Supply, and ^¶Toxicological Sciences, MRL, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States

^∇ Albany Molecular Research Inc., 26 Corporate Circle, Albany, New York 12203, United States

J. Med. Chem., Article ASAP

DOI: 10.1021/acs.jmedchem.6b00307

Publication Date (Web): November 18, 2016

*Phone: 908-740-4729. E-mail: jack.scott@merck.com., *Phone: 973-868-2088. E-mail: andy.stamford1@gmail.com.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Abstract

Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer’s disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.

N-[3-[(5R)-3-Amino-5,6-dihydro-2,5-dimethyl-1,1-dioxido-2H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoro-2-pyridinecarboxamide (3)

3 (2.70 g, 89% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (s, 1H), 8.73 (d, J = 2.8 Hz, 1H), 8.22 (dd, J = 8.8, 4.8 Hz, 1H), 8.03–7.95 (m, 2H), 7.79 (m, 1H), 7.14 (dd, J = 11.6, 8.8 Hz, 1H), 6.03 (br s, 2H), 3.78 (s, 1H), 3.34 (s, 1H), 3.05 (s, 3H), 1.61 (s, 3H). ESI MS m/z 410.2 [M + H]⁺. [α]_D²⁰ 37.2° (c 0.367, CH₃OH).

To generate its hydrochloride salt, 3prepared above was added to CH₂Cl₂ (50 mL) followed by a solution of HCl (2 N in Et₂O, 3.6 mL, 7.2 mmol), and the mixture was concentrated in vacuo. The product was slurried in distilled water (50 mL) and lyophilized to afford the HCl monohydrate salt of 3 (2.58 g, 79% yield, 3 steps) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.59 (d, J = 2.8 Hz, 1H), 8.26 (dd, J = 8.8, 4.8 Hz, 1H), 8.02 (dd, J = 7.6, 2.8 Hz, 1H), 7.82–7.75 (m, 2H), 7.22 (dd, J = 12.0, 8.8 Hz, 1H), 4.49 (dd, J = 14.4, 0.8 Hz, 1H), 4.30 (d, J = 14.4 Hz, 1H), 3.30 (s, 3H), 1.96 (s, 3H). ESI MS m/z410.2 [M + H]⁺. Anal. Calcd (C₁₇H₂₀ClF₂N₅O₄S): C, 44.02; H, 4.35; N, 15.10; Cl, 7.64; S, 6.91. Found: C, 43.77; H, 4.32; N, 14.81; Cl, 7.84; S, 7.04.

References

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(a) Wortmann, M.Dementia: a global health priority – highlights from an ADI and World Health Organization report Alzheimer’s Res. Ther. 2012, 4, 40– 43, DOI: 10.1186/alzrt143

(b) Alzheimer’s Disease International. World Alzheimer Report 2015. http://www.alz.co.uk/research/WorldAlzheimerReport2015.pdf.
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Haass, C.; Selkoe, D. J.Soluble protein oligomers in neurodegeneration: Lesson from the Alzheimer’s amyloid β-peptide Nat. Rev. Mol. Cell Biol. 2007, 8, 101– 112, DOI: 10.1038/nrm2101
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(a) Hardy, J.; Selkoe, D. J.The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics Science 2002, 297, 353– 356, DOI: 10.1126/science.1072994

(b) Karran, E.; Mercken, M.; De Strooper, B.The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics Nat. Rev. Drug Discovery 2011, 10, 698– 712, DOI: 10.1038/nrd3505

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Jonsson, T.; Atwal, J. K.; Steinberg, S.; Snaedal, J.; Jonsson, P. V.; Bjornsson, S.; Stefansson, H.; Sulem,P.; Gudbjartsson, D.; Maloney, J.; Hoyte, K.; Gustafson, A.; Liu, Y.; Lu, Y.; Bhangale, T.; Graham, R. R.; Huttenlocher, J.; Bjornsdottir, G.; Andreassen, O. A.; Jönsson, E. G.; Palotie, A.; Behrens, T. W.; Magnusson, O. T.; Kong, A.; Thorsteinsdottir, U.; Watts, R. J.; Stefansson, K.A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline Nature 2012, 488, 96– 99, DOI: 10.1038/nature11283
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Roberds, S. L.; Anderson, J.; Basi, G.; Bienkowski, M. J.; Branstetter, D. G.; Chen, K. S.; Freedman, S. B.; Frigon, N. L.; Games, D.; Hu, K.; Johnson-Wood, K.; Kappenman, K. E.; Kawabe, T. T.; Kola, I.; Kuehn,R.; Lee, M.; Liu, W.; Motter, R.; Nichols, N. F.; Power, M.; Robertson, D. W.; Schenk, D.; Schoor, M.; Shopp, G. M.; Shuck, M. E.; Sinha, S.; Svensson, K. A.; Tatsuno, G.; Tintrup, H.; Wijsman, J.; Wright, S.; McConlogue, L.BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics Hum. Mol. Genet. 2001, 10, 1317– 1324
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Vassar, R.; Kuhn, P.-H.; Haass, C.; Kennedy, M. E.; Rajendran, L.; Wong, P. C.; Lichtenthaler, S. F.Function, therapeutic potential and cell biology of BACE proteases: current status and future prospectsJ. Neurochem. 2014, 130, 4– 28, DOI: 10.1111/jnc.12715

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(a) Vassar, R.; Bennett, B. D.; Babu-Khan, S.; Kahn, S.; Mendiaz, E. A.; Denis, P.; Teplow, D. B.; Ross, S.; Amarante, P.; Loeloff, R.; Luo, Y.; Fisher, S.; Fuller, J.; Edenson, S.; Lile, J.; Jarosinski, M. A.; Biere, A. L.; Curran, E.; Burgess, T.; Louis, J.-C.; Collins, F.; Treanor, J.; Rogers, G.; Citron, M.β-Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE Science 1999,286, 735– 741

(b) Sinha, S.; Anderson, J. P.; Barbour, R.; Basi, G. S.; Caccavello, R.; Davis, D.; Doan, M.; Dovey, H. F.; Frigon, N.; Hong, J.; Jacobson-Croak, K.; Jewett, N.; Keim, P.; Knops, J.; Lieberburg, I.; Power, M.; Tan, H.; Tatsuno, G.; Tung, J.; Schenk, D.; Seubert, P.; Suomensaari, S. M.; Wang, S.; Walker, D.; Zhao, J.; McConlogue, L.; John, V.Purification and cloning of amyloid precursor protein β-secretase from human brain Nature 1999, 402, 537– 540, DOI: 10.1038/990114

(c) Hussain, I.; Powell, D.; Howlett, D. R.; Tew, D. G.; Meek,T. D.; Chapman, C.; Gloger, I. S.; Murphy, K. E.; Southan, C. D.; Ryan, D. M.; Smith, T. S.; Simmons, D. L.; Walsh, F. S.; Dingwall, C.; Christie, G.Identification of a novel aspartic protease (Asp 2) as β-SecretaseMol. Cell. Neurosci. 1999, 14, 419– 427, DOI: 10.1006/mcne.1999.0811

(d) Yan, R.; Bienkowski, M. J.; Shuck, M. E.; Miao, H.; Tory, M. C.; Pauley, A. M.; Brashler, J. R.; Stratman, N. C.; Mathews, W. R.; Buhl, A. E.; Carter, D. B.; Tomasselli, A. G.; Parodi, L. A.; Heinrikson, R. L.; Gurney,M. E.Membrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity Nature 1999,402, 533– 537, DOI: 10.1038/990107

(e) Lin, X.; Koelsch, G.; Wu, S.; Downs,D.; Dashti, A.; Tang, J.Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 1456– 1460, DOI: 10.1073/pnas.97.4.1456
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(a) Oehlrich, D.; Prokopcova, H.; Gijsen, H. J. M.The evolution of amidine-based brain penetrant BACE1 inhibitors Bioorg. Med. Chem. Lett. 2014, 24, 2033– 2045, DOI: 10.1016/j.bmcl.2014.03.025

(b) Yuan, J.; Venkatraman, S.; Zheng, Y.; McKeever, B. M.; Dillard, L. W.; Singh, S. B.Structure-based design of β-site APP cleaving enzyme 1 (BACE) inhibitors for the treatment of Alzheimer’s disease. disease J. Med. Chem. 2013, 56, 4156– 4180, DOI: 10.1021/jm301659n

(c) Probst, G.; Xu, Y. z.Small-molecule BACE1 inhibitors: a patent literature review (2006 – 2011) Expert Opin. Ther. Pat. 2012, 22, 511– 540, DOI: 10.1517/13543776.2012.681302
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(a) Willem, M.; Garratt, A. N.; Novak, B.; Citron, M.; Kaufmann, S.; Rittger, A.; DeStrooper, B.; Saftig, P.; Birchmeier, C.; Haass, C.Control of peripheral nerve myelination by the β-Secretase BACE1 Science2006, 314, 664– 666, DOI: 10.1126/science.1132341

(b) Hu, X.; Hicks, C. W.; He, W.; Wong, P.; Macklin, W. B.; Trapp, B. D.; Yan, R.Bace1 modulates myelination in the central and peripheral nervous system Nat. Neurosci. 2006, 9, 1520– 1525, DOI: 10.1038/nn1797
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Cheret, C.; Willem, M.; Fricker, F. R.; Wende, H.; Wulf-Goldenberg, A.; Tahirovic, S.; Nave, K.-A.; Saftig,P.; Haass, C.; Garratt, A. N.; Bennett, D. L.; Birchmeier, C.Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles EMBO J. 2013, 32, 2015– 2028, DOI: 10.1038/emboj.2013.146
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McConlogue, L.; Buttini, M.; Anderson, J. P.; Brigham, E. F.; Chen, K. S.; Freedman, S. B.; Games, D.; Johnson-Wood, K.; Lee, M.; Zeller, M.; Liu, W.; Motter, R.; Sinha, S.Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice J. Biol. Chem. 2007,282, 26326– 26334, DOI: 10.1074/jbc.M611687200

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Wang, Y.-S.; Strickland, C.; Voigt, J. H.; Kennedy, M. E.; Beyer, B. M.; Senior, M. M.; Smith, E. M.; Nechuta, T. L.; Madison, V. S.; Czarniecki, M.; McKittrick, B. A.; Stamford, A. W.; Parker, E. M.; Hunter, J. C.; Greenlee, W. J.; Wyss, D. F.Application of fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design to identify novel μM leads for the development of nM BACE-1 (β-site APP cleaving enzyme 1) inhibitors J. Med. Chem. 2010, 53, 942– 950, DOI: 10.1021/jm901472u
17.

The CAS name represents the 3-aminothiadiazine tautomer, and the structures depicted in the manuscript represent the 3-iminothiadiazinane tautomer.

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Toremifene

July 16, 2015 3:22 am / Leave a comment

Toremifene

2-[4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenoxy]-N,N-dimethylethanamine

(Z)-2-[4-(4-Chloro-1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine

(Z)-4-Chloro-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]-1-butene

(Z)-Toremifene

2-({4-[(1Z)-4-chloro-1,2-diphenylbut-1-en-1-yl]phenyl}oxy)-N,N-dimethylethanamine

4-chloro-1,2-diphenyl-1-[4-[2-(N ,N-dimethylamino)ethoxy]phenyl]-1-butene

Toremifene; Acapodene; Farestone; Z-Toremifene; Toremifeno; Toremifenum

Molecular Formula:	C₂₆H₂₈ClNO
Molecular Weight:	405.95962 g/mol

cas 89778-26-7

Launched – 1988.Orion (FI), greast cancer

Citrate, Toremifene, GTx-006
NK-622
- 89778-27-8
Fareston
FC 1157a
FC-1157a
FC1157a
Toremifene
Toremifene Citrate
Toremifene Citrate (1:1)
Toremifene, (E)-Isomer
- C₂₆H₂₈ClNO · C₆H₈O₇
- Molecular Weight 598.08Toremifene Citrate

Toremifene is a first generation selective estrogen receptor modulator (SERM). Like TAMOXIFEN, it is an estrogen agonist for bone tissue and cholesterol metabolism but is antagonistic on mammary and uterine tissue.

The company GTx is conducting phase III clinical trials for the prevention of prostate cancer in men who have been diagnosed with high grade prostatic intraepithelial neoplasia (PIN).

Toremifene citrate is an oral selective estrogen receptor modulator (SERM) which helps oppose the actions of estrogen in the body. Licensed in the United States under the brand name Fareston, toremifene citrate is FDA-approved for use in advanced (metastatic)breast cancer. It is also being evaluated for prevention of prostate cancer under the brand name Acapodene.^[1]

ChemSpider 2D Image | Toremifene | C26H28ClNO

In 2007 the pharmaceutical company GTx, Inc was conducting two different phase 3 clinical trials; First, a pivotal Phase clinical trial for the treatment of serious side effects of androgen deprivation therapy (ADT) (especially vertebral/spine fractures and hot flashes, lipid profile, and gynecomastia) for advanced prostate cancer, and second, a pivotal Phase III clinical trial for the prevention of prostate cancer in high risk men with high grade prostatic intraepithelial neoplasia, or PIN. Results of these trials are expected by first quarter of 2008^[2]

An NDA for the first application (relief of prostate cancer ADT side effects) was submitted in Feb 2009,^[3] and in Oct 2009 the FDA said they would need more clinical data, e.g. another phase III trial.^[4]

Originally developed at Orion, toremifene was subsequently licensed to Nippon Kayaku in Japan and to Asta Medica (now, part of Meda) in Germany.

Synthesis

……….

PATENT

http://www.google.com/patents/CN104230723A?cl=en

Toremifene (Toremifene), chemical name (Z) -4- chloro-1,2-diphenyl–1- [4- (2- (N, N- dimethylamino) ethoxy yl) phenyl] -1-butene, having the structure I.Toremifene to tamoxifen (Tamoxifen) analogues with anti-estrogenic activity, can be used in the treatment of hormone-dependent breast cancer, and its E-isomer has the presence of estrogenic activity, E isomers toremifene may counteract anti-estrogenic activity, and therefore isomeric purity is essential toremifene.Toremifene was developed in 1983 by the Finnish Famos company, listed in 1996 by the Orion company in the EU, the trade name Fareston, 2002 to enter the country, the trade name of toremifene.

RJ Toivola et al., European Patent EP95875, disclosed in U.S. Patent US4696949A synthetic route toremifene, that following a synthetic route, the synthetic route to phenol as a raw material, by acylation, rearrangement, alkyl group and an addition reaction to give 1,2-diphenyl -1- [4- [2- (N, N- dimethylamino) ethoxyphenyl]] – 1,4-diol (Compound 5) as the key intermediate, further HCl in ethanol or hydrochloric acid elimination reaction occurs, then get toremifene thionyl chloride reaction. The main problem with this approach is that the elimination reaction of the compound 5 in ethanol occurs when hydrochloric acid or concentrated hydrochloric acid, the resulting triaryl alcohol butyrate (Compound 6) having a Z / E configuration, both the ratio of 1: 2 ~ 2: 1, stereo selectivity is not high, and there are 5% of the cyclization by-product; on the Z / E configuration Miyoshi butyric fractional crystallization of alcohol, you can get pure Z-type Miyoshi butyric alcohol , but the yield is only 41%; then, Z-type Miyoshi butyric alcohol chlorination reaction occurs in the action of thionyl chloride, the purified product toremifene.

U.S. Patent US5491173A also reported another synthetic route toremifene namely the following two synthetic routes. The route to the aryl ketone (Compound 7) with a phenyl Grignard reagent addition reaction of ketone carbonyl groups to give triaryl-butanediol (compound 5), which is the elimination of toremifene and chlorinated reaction products happen again.

Chinese Patent Publication No. CN1125716A application reported an efficient synthesis of Z-type Miyoshi butyric alcohol (compound 6) method, US4696949A compared with the US patent, the method mild conditions, reduce the acid concentration and reaction temperature, reaction time, triarylphosphine butanediol (Compound 5) in concentrated hydrochloric acid or concentrated hydrochloric isopropanol or ethanol effect of concentrated hydrochloric acid, can be 60-78% selectivity and 95% yield of type 2 Miyoshi butyric alcohol But after Publication No. 0 02,126,969 attached eight patent applications after the inventor repeated experiments show that the technique disclosed in the patent application programs can not achieve their claimed technical effect.

Publication No. CN102126969A of Chinese patent applications through the intermediate Miyoshi butyric alcohol occurs at a catalytic converter configuration of concentrated hydrochloric acid, while taking advantage of differences in solubility, so E- type Miyoshi butyric alcohol continuously into Z-type Miyoshi butyric alcohol (compound 6) precipitates, thereby undermining the balance, so that one of the E-type Miyoshi butyric alcohol continuously into Z-type Miyoshi butyric alcohol (compound 6) to give the Z-Miyoshi butyric alcohol ( Compound 6) and then get toremifene thionyl chloride after chlorination. Although to some extent, improve the yield, but increased operating procedure, is not conducive to industrial production.

Currently, the key intermediate is patent protected, and z-type Miyoshi butyric alcohol (compound 6) stereoselective low yield and isolated intermediates, to solve this problem, to overcome technical barriers to foreign pharmaceutical companies, urgent need to find a simple process, low cost, easy to separate and viable for large-scale production of synthetic routes.

To achieve the above object, according to one aspect of the present invention, there is provided a method of synthesizing toremifene, synthetic method comprising: a step S1, so that a compound having the structural formula II with a compound B having the structural formula III C occurs Mike Murray to give compound D having the structural formula IV; step S2, the Compound D and Compound E or Compound E of the hydrochloride salt of the formula V having a phenolic hydroxyl group on the occurrence of a selective alkylation reaction, to give a compound having the structural formula VI F; step S3, the compound F is reacted with thionyl chloride to give toremifene, wherein,

Formula II is:

Structural formula III as follows:

Formula IV is

Of formula V is C1CH2CH2N (CH 3) 2; formula VI is

FIG. 1 illustrates the present invention obtained in Example 1 H NMR spectrum of compound D of implementation;

FIG. 2 shows the 1 H NMR spectrum of the present invention, the compound obtained in Example F;

FIG. 3 shows the present invention is a proton nuclear magnetic resonance spectrum of toremifene obtained in Example.

Figure 1, which shows a spectrum of results for Che bandit? (400 cm take, 01 ^ 0) 3 = 9.20 (! 8,1 1), 7.37 (^ = 7.4 to take, 2 1!), 7.30- 7. 23 (m, 3H), 1.22- 7. 15 (m, 2H), 7. 15 – 7. 06 ( m, 3H), 6. 61 (dd, J = 9. 0, 2. 2Hz, 2H), 6. 49 -. 6. 32 (m, 2H), 4 48 (s, 1H), 3 30 (. m, 2H), 2 55 (t, J = 7. 5Hz, 2H);. F proton nuclear magnetic resonance spectrum of the compound attached to the

Figure 2, showing spectrum results Che NMR (400MHz, DMSO) δ = 7. 36 (d, J = 7. 3Hz, 2H), 7. 31 – 7. 25 (m, 3H), 7. 21 – 7. 10 (m, 5H), 6. 75 – 6. 69 (m , 2H), 6. 59 (d, J = 8. 8Hz, 2H), 4. 49 (s, 1H), 3. 88 (t, J = 5. 8Hz, 2H), 3. 31 (d, J = 4. 3Hz, 2H), 2. 57 (t, J = 7.5Hz, 2H), 2.52 (t, J = 4.6Hz, 2H), 2 15 (s, 6H);.

Tommy remifentanil NMR hydrogen spectrum in Figure 3 attached, showing spectrum results Che NMR (400MHz, CDC13) δ = 7. 41 -. 7. 33 (m, 2H), 7 29 (dt, J = 7. 1, 2. 9Hz, 3H), 7. 20 (dd, J = 10. 0, 4. 3Hz, 2H), 7. 13 (dd, J = 7. 1, 4. 3Hz, 3H), 6.87- 6. 72 (m, 2H), 6. 57 (dd, J = 6. 8, 4. 8Hz, 2H), 3. 92 (t, J = 5. 8Hz, 2H), 3. 41 (t, J = 7. 5Hz, 2H), 2. 92 (t, J = 7. 5Hz, 2H), 2. 63 (t, J = 5. 8Hz, 2H), 2. 28 (s, 6H).

The synthetic routes above synthetic method are as follows:

Synthesis of toremifene:

To a 2L reaction flask 1. 1L of toluene, 110g (0. 28mol) obtained in the above step Z configuration compound F, mixed to obtain a sixth system, the cooling system to the sixth mixed 0~5 ° C , was slowly added dropwise 99. 93g (0. 84mol) thionyl chloride addition was complete the formation of the seventh mixed system, the mixed system was slowly warmed to a seventh ll〇 ° C, for 1 hour to obtain a third product system, stop The third product heating and cooling system to 15~25 ° C, the third product system slowly poured into 1L of water, adding NaOH solution to a pH 9~10 and get the second system, the second in and a system for liquid separation, and the resulting aqueous phase to obtain a second solution was extracted with 1L toluene extraction, the organic phase of the second extraction solution and liquid separation were combined and concentrated to give crude toremifene, the crude product was mass ratio of 1 : mixed solvent of ethyl acetate and acetone 1 crystals to give 103. 7g toremifene products.

Synthesis of toremifene:

[0062] To a 5L reaction flask 3. 3L of toluene, 110g (0. 28mol) obtained in the above step Z configuration compound F, mixed to obtain a sixth system, the cooling system to the sixth mixed 0~5 ° C , was slowly added dropwise 33. 31g (0. 28mol) thionyl chloride addition was complete the formation of the seventh mixed system, the mixed system was slowly warmed to a seventh ll〇 ° C, after the reaction for 6 hours to obtain a third product system, stop The third product heating and cooling system to 15~25 ° C, the third product system slowly poured into 1L of water, potassium carbonate solution to a pH 9~10 and get the second system, the second and system for liquid separation, and the resulting aqueous phase to obtain a second solution was extracted with 1L ethyl acetate, the organic phase after the second extraction solution and liquid separation were combined and concentrated to give crude toremifene, the crude product was quality ratio was crystallized from acetone to give 92. 2g toremifene products.

Purity of toremifene following method:

[0107] to take the product, add the mobile phase dissolved and diluted into 1ml of 1. Omg solution containing, according to HPLC octadecylsilane bonded silica as a filler to square 1% trifluoroacetic acetic acid aqueous solution (A) and acetonitrile (B) as the mobile phase gradient elution (T = Omin 10% B; T = lOmin 95% B; T = 12min 100% B; T = 15min 10% B), detection wavelength 210nm; area normalization method to calculate the Z configuration purity compound F, where F Z configuration compound retention time of 6. 76min. The purity of the above calculation or Z configuration detection obtained compound D, compound D Z configuration and E configuration of the weight ratio, toremifene yield and purity are reported in Table 1 below.

……………..

PATENT

http://www.google.com/patents/US5491173

c) 4-chloro-1,2-diphenyl-1-[4-[2-(N ,N-dimethylamino)ethoxy]phenyl]-1-butene (Z and E)

(Z)-isomer: The reaction is performed under dry conditions. 42.4 g of (Z)-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino )ethoxy]phenyl]-1-buten-4-ol are dissolved in 250 ml of chloroform. Then 23.8 g of thionyl chloride areadded dropwise. The mixture is refluxed 3 h. The solvent is evaporated, after which the product is recrystallized from ethyl acetate. The yield ofthe hydrochloride salt is 36.7 g (83%), m.p. 194°-6° C. The base can be liberated from the Salt with 1M sodium carbonate solution, after which the base is extracted in toluene. The toluene solution is dried and the solvent is evaporated. The free base has m.p. 108°-10° C. (from acetone).

¹ H-NMR-spectrum (CDCl₃): δ 2.27 (6H, s), 2.63 (2H, t), 2.91 (2H, t), 3.41 (2H, t), 3.92 (2H, t), 6.54 (2H, d), 6.79 (2H. d), 7.15(5H, s), 7.31 (5H, s). MS: m/z 405/407 (M⁺, 7/3), 72 (20), 58 (100).

The citric acid salt can be prepared as follows: 40.6 g of the (Z)-isomer as a free base are dissolved in 175 ml of warm acetone and 24.3 g of citric acid are dissolved in 100 ml of warm acetone. The solutions are combined and the mixture is allowed to cool. The citrate, m.p. 160°-162° C., is collected by filtration.

(E)-isomer: The compound is prepared from (E)-1,2-diphenyl-1-[4-[2-(N ,N-dimethylamino)ethoxy]phenyl]-1-buten-4-ol in the same manner as the corresponding (Z)-isomer. The hydrochloride salt is crystallized from toluene. The yield is 35.8 g (81%) of a product having m.p. 183°-5° C. The base can be liberated from the salt in the same manner as the corresponding (Z)-isomer. It has m.p. 69°-71° C. (from hexane).

¹ H-NMR-spectrum (CDCl₃): b 2.34 (6H, s), 2.74 (2H, t), 2.97 (2H,t), 3.43 (2H, t), 4.08 (2H, t), 6.80-7.30 (14H, m).

MS: m/z 405/407 (M⁺, 7/3) 72 (19) 58 (100)

EXAMPLE 4

4-chloro-1,2-diphenyl-1-[4-[2-(N ,N-diethylamino)ethoxy]phenyl ]-1-butene (Z and E)

43.3 g of 1,2-diphenyl-1-[4-[2-(N,N-diethylamino)ethoxy]phenyl]butane-1,4-diol (pureenantiomer pairs or their mixture: m.p. of (RR,SS)-pair is 107°-9° C.)is suspended in 250 ml of toluene, after which 25ml toluene is distilled off to dry the solution. The mixture is cooled to 0° C. with stirring. While stirring and keeping the temperature at 0° C. or a little below, 47.6 g of thionyl chloride of good qualityare added. The mixture is stirred for 1 h at 0° C. and the temperature is then allowed to rise to 22° C. The mixture is stirred at 80° C. until the reaction is completed (about 3 h). After that, water is added to decompose the excess of thionyl chloride followed by 20% sodium hydroxide solution to liberate the product from itshydrochloride salt. The aqueous layer is discarded and the toluene layer iswashed with water. Then the solvent is evaporated to leave a mixture of (Z)- and (E)isomers (Z:E 7:3) as an oil in quantitative yield.

(Z)-isomer: The (Z)-isomer is isolated from the isomer mixture above as thehydrochloride salt because of the low melting point of the free base. The m.p. of the hydrochloride salt is 178°-80° C. The (Z)-isomermay be freed from its salt by any normal method.

¹ H-NMR-spectrum (CDCl₃): δ 1.01 (6H, t), 2.57 (4H, q), 2.77 (2H, t), 2.91 t), 3.41 (2H, t), 3.90 t), 6.53 (2H, d), 6.78 (2H, d), 7.15 (5H, s), 7.31 (5H, s). (E)-isomer:

¹ H-NMR-spectrum (CDCl₃): δ 1.07 (6H, t), 2.66 (4H, q), 2.89 (2H, t), 2.97 (2H, t), 3.42 (2H, t), 4.07 (2H, t), 6.90-7.20 (10H, m).

……………….

SEE

http://www.google.co.ug/patents/EP0095875B1?cl=en

………….

http://www.intechopen.com/books/topics-on-drug-metabolism/electrochemical-methods-for-the-in-vitro-assessment-of-drug-metabolism

References

Price N, Sartor O, Hutson T, Mariani S. Role of 5a-reductase inhibitors and selective estrogen receptor modulators as potential chemopreventive agents for prostate cancer. Clin Prostate Cancer 2005;3:211-4. PMID 15882476
“GTx’s Phase III Clinical Development of ACAPODENE on Course Following Planned Safety Review” (Press release). GTx Inc. 2007-07-12. Retrieved 2006-07-14.
“GTx Announces Toremifene 80 mg NDA Accepted for Review by FDA” (Press release).
“GTx and Ipsen End Prostate Cancer Collaboration due to Costs of FDA-Requested Phase III Study”. 2 Mar 2011

Toremifene
Systematic (IUPAC) name

2-{4-[(1Z)-4-chloro-1,2-diphenyl-but-1-en-1-yl]phenoxy}-N,N-dimethylethanamine
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a608003
Pharmacokinetic data
Protein binding	more than 99.5%
Biological half-life	5 days
Identifiers
CAS Registry Number	89778-26-7
ATC code	L02BA02
PubChem	CID: 3005573
IUPHAR/BPS	4325
DrugBank	DB00539
ChemSpider	2275722
UNII	7NFE54O27T
KEGG	D08620
ChEBI	CHEBI:9635
ChEMBL	CHEMBL1655
Chemical data
Formula	C₂₆H₂₈Cl N O
Molecular mass	405.959 g/mol

Patent	Submitted	Granted
Triphenylalkene derivatives and their use as selective estrogen receptor modulators [US6576645]		2003-06-10
Combination therapy for the treatment of estrogen-sensitive disease [US2002119502]	2002-08-29
Triphenylalkene derivatives and their use as selective estrogen receptor modulators [US6875775]	2003-12-04	2005-04-05
Combination therapy for the treatment of estrogen-sensitive disease [US2005176691]	2005-08-11
Anti-IGFR1 antibody therapeutic combinations [US8017735]	2005-06-23	2011-09-13
Combination therapy for the treatment of estrogen-sensitive disease [US2005228053]	2005-10-13
Combination therapy for the treatment of estrogen-sensitive drugs [US2005232862]	2005-10-20
Toremifene crystallization method [US7368607]	2007-04-26	2008-05-06
Platinum therapeutic combinations [US2006205810]	2006-09-14
Methods and compositions for treating or preventing cancer [US2006233810]	2006-10-19

from PubChem……….https://pubchem.ncbi.nlm.nih.gov/compound/3005573#section=Depositor-Supplied-Patent-Identifiers

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What is SBM-TFC-039 an SGLT Inhibitor from Sirona Biochem !!

July 15, 2015 6:26 am / Leave a comment

A new “flozin” seems to me appearing on the horizon in form of SBM-TFC-039 an SGLT Inhibitor from Sirona Biochem, picked up a list from WO 2012160218, from TFChem…….see link , Sirona Biochem Announces SGLT2 Inhibitor and Skin Lightening Patent Granted, 29 Jun 2015, Patent entitled “Family of aryl, heteroaryl, o-aryl and o-heteroaryl carbasugars”

This led me to search, “Family of aryl, heteroaryl, o-aryl and o-heteroaryl carbasugars”
WO 2012160218 A1, IN 2013-DN10635, CN 103649033Tf化学公司

Applicant	Tfchem

Applicant

Tfchem

Figure imgf000110_0001

List above as in http://www.google.com/patents/WO2012160218A1?cl=en

FROM THE ABOVE LIST, SBM-TFC-039 MAY BE PREDICTED/OR AS SHOWN BELOW

COMPD 16 as in/WO2012160218

COMPD 16, PREDICTED/LIKELY SBM-TFC-039 has CAS 1413373-30-4, name D-myo-Inositol, 1-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1,2,3-trideoxy-2,2-difluoro-3-(hydroxymethyl)-

Just scrolling through the patent gave me more insight

MORE EVIDENCE….http://www.google.com/patents/WO2012160218A1?cl=en, this patent descibes compd 16 as follows

Compound 16 according to the invention has been compared to Dapaglifozin to underline the improvement of the duration of action, i.e. the longer duration of glucosuria, of the compound when the intracyclic oxygen atom of the glucose moiety is replaced by a CF₂ moiety.

This assay has been carried out at a dose of 3 mg/ kg.

The results obtained are presented on Figure 5. It appears thus that 16 (3 mg/kg) triggered glucosuria that lasted beyond 24 hours compared to Dapagliflozin.

• Compound 16 according to the invention has been compared to the compound 9 of WO 2009/1076550 to underline the improvement of the duration of action of the compound when a mimic of glucose bearing a CH-OH moiety instead of the intracyclic oxygen atom is replaced by a mimic of glucose bearing a CF₂ in place of the CH-OH moiet .

NOTE=COMPD 9 OF WO 2009/1076550 has CAS 1161430-16-5, D-scyllo-Inositol, 1-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1,3-dideoxy-3-(hydroxymethyl)- and is very similar to the compd under discussion

Company	Sirona Biochem Corp.
Description	Sodium-glucose cotransporter 2 (SGLT2) inhibitor
Molecular Target	Sodium-glucose cotransporter 2 (SGLT2)
Mechanism of Action	Sodium-glucose cotransporter 2 (SGLT2) inhibitor
Therapeutic Modality	Small molecule

Latest Stage of Development	Preclinical
Standard Indication	Diabetes
Indication Details	Treat Type II diabetes
Regulatory Designation
Partner	Shanghai Fosun Pharmaceutical Group Co. Ltd.

SBM-TFC-039

PATENT

WO 2012160218

http://www.google.com/patents/WO2012160218A1?cl=en

Examples within this first subclass include but are not limited to:

Synthesis of compound 8

C35H34O5 M = 534.64 g.mol^“

Mass: (ESI ): 535.00 (M + H); 552.00 (M + H₂0); 785.87; 1086.67 (2M + H₂0)

Procedure A:

To a solution of 4 (10.5g, 15.89mmol, leq) in toluene (400mL) were added 18-crown-6 (168mg, 0.64mmol, 0.04eq) and potassium carbonate (6.69g, 48.5mmol, 3.05eq.). The mixture was stirred overnight at room temperature, and then the remising insoluble material was filtered off and washed with toluene. The filtrate and the washings were combined, washed with 2N hydrochloric acid aqueous solution followed by saturated sodium hydrogencarbonate aqueous solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 98:2 to 80:20) to afford cyclohexenone 8 (4.07g; 48% yield) as yellowish oil.

Procedure B:

A solution of 7 (3.27g, 5.92mmol, leq) in pyridine (14mL) was cooled to 0°C before POCl₃ (2.75mL, 29.6mmol, 5eq) was added dropwise. The mixture was stirred at this temperature for 10 min before the cooling bath was removed. The reaction mixture was stirred overnight at room temperature before being re-cooled to 0°C. POCI3 (2.75mL, 29.6mmol, 5eq) was added once again trying to complete the reaction. The mixture was stirred for an additional 20h at room temperature before being diluted with Et₂0 (20mL) and poured onto crushed ice. 1M HC1 aqueous solution (lOOmL) was added, and the mixture was extracted with Et₂0 (200mL & l OOmL). The combined organic extracts were washed with brine (lOOmL), dried over sodium sulphate, filtered and concentrated before being purified on silica gel chromatography (cyclohexane / ethyl acetate 98:2 to 80:20) to afford compound 8 (1.46g, 46% yield) as an orange oil. Synthesis of compound 9

C₁₅H₁₂BrC10₂ M = 339.61 g.moF¹

Mass: (GC-MS): 338-340

The synthesis of this product is described in J. Med. Chem. 2008, 51, 1 145—1149.Synthesis of compound 10

C15H14B1CIO M = 325.63 g.mof¹

10 The synthesis of this product is described in J. Med. Chem. 2008, 51, 1145-1 149.

Synthesis of compound 11

C50H49CIO6 M = 781.37 g.moF¹

Mass: ESI⁺): 798.20 (M + H₂0)

Under inert atmosphere, Mg powder (265mg, 10.9mmol, 2.4eq) was charged into a three necked flask, followed by addition of a portion of 1/3 of a solution of the 4- bromo-l-chloro-2-(4-ethylbenzyl)benzene (2.95g, 9.1mmol; 2eq) in dry THF (25mL) and 1 ,2-dibromoethane (10 mol % of Mg; 85mg; 0.45mmol). The mixture was heated to reflux. After the reaction was initiated (exothermic and consuming of Mg), the remaining solution of 2-(4-ethylbenzyl)-4-bromo-l-chlorobenzene in dry TFIF was added dropwise. The mixture was then allowed to react for another one hour under gentle reflux until most of the Mg was consumed.

The above Grignard reagent was added dropwise into the solution of cyclohexenone 8 (2.42g, 4.53mmol, leq) in dry THF (25mL) under inert atmosphere at room temperature (about 25°C), then allowed to react for 3h. A saturated aqueous solution of ammonium chloride was added into the mixture to quench the reaction. The mixture was extracted with Et₂0, washed with brine, dried over sodium sulphate, filtered and concentrated. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 100:0 to 80:20) to afford the target compound 11 as a yellow oil (3.01g, 86%).

Synthesis of compound 12

C₅oH49C10₅ M = 765.37 g.mol^“1

+): 782.13 (M + H₂0)

Triethylsilane (0.210mL, 1.30mmol, 3eq) and boron-trifluoride etherate (48% BF₃, O. l lOmL, 0.866mmol, 2eq) were successively added into a solution of alcohol 1 1 (338mg, 0.433mmol, leq) in dichloromethane (5mL) under inert atmosphere at -20°C. After stirring for 2.5h, a saturated aqueous solution of sodium chloride was added to quench the reaction. The mixture was extracted with CH₂C1₂ (10mLx3) and the organic layer was washed with brine, dried over Na₂S0₄, filtrated and concentrated. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 9.8:0.2 to 8:2) to afford the target compound 12 as a white powder (278 mg, 0.363mmol, 84%).

Synthesis of compound 13

C₅oH_5tC10₆ M = 783.39g.moF¹

Mass: (ESI⁺): 800 (M + H₂0); 1581 (2M + H₂0)

Under inert atmosphere, borane-dimethyl sulfide complex (2M in THF, 16.7mL, 33mmol, 10.5eq) was added to a solution of 12 (2.41g; 3.15mmol, leq) in dry THF (lOOmL) cooled to 0°C. The reaction mixture was then refluxed for lh,cooled to 0°C and treated carefully with sodium hydroxide (3M in H₂0, 10.5mL, 31.5mmol, lOeq), followed by hydrogen peroxide (30% in H₂0, 3.2mL, 31.5mmol, l Oeq) at room temperature (above 30°C). The mixture was allowed to react overnight at room temperature (~25°C) before a saturated aqueous solution of ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na₂S0₄, filtered, and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate 97:3 to 73:27) to afford the desired compound 13 (1.05g; 43%) as a yellowish oil.

Synthesis of compound 14

C50H49CIO6 M = 781.37g.mol^“1

Mass: (ESI⁺): 798 (M + H₂0); 1471; 1579 (2M + H₂0)

13 14

Dess-Martin periodinane (81mg; 1.91mmol; 1.5eq) was added portion wise to a solution of alcohol 13 (l .Og; 1.28mmol, leq) in anhydrous dichloromethane (20mL) at 0°C. The reaction was then stirred overnight at room temperature before being quenched with IN aqueous solution of sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue was purified on silica gel chromatography (cyclohexane / ethyl acetate 98:2 to 82: 18), to afford the target ketone 14 (783mg, 79% yield) as a colorless oil. Synthesis of compound 15

C₅oH49ClF₂0₆ M = 803.37g.moF¹

¹⁹ F NMR (CDCU, 282.5MHz): -100.3 (d, J=254Hz, IF, CFF); -1 13.3 (td, Jl=254Hz, J2=29Hz, IF, CFF).

Mass: (ESI⁺): 820.00 (M+H₂0)

14 15

A solution of ketone 14 (421mg, 0.539mmol, leq) in DAST (2mL, 16.3mmol, 30eq.) was stirred under inert atmosphere at 70°C for 12h. The mixture was then cooled to room temperature and dichloromethane was added. The solution was poured on a mixture of water, ice and solid NaHC0₃. Agitation was maintained for 30min while reaching room temperature. The aqueous layer was extracted with dichloromethane and the organic phase was dried over Na₂S0₄, filtered and concentrated. The crude product was purified on silica gel chromatography (cyclohexane/ethyl acetate 98:2 to 80:20) to afford the desired compound 15 as a yellowish oil ( 182mg, 42% yield).

Synthesis of compound 16

C22H25CIF2O5 M = 442.88g.mor¹

¹⁹ F NMR (MeOD, 282.5MHz): -96.7 (d, J=254Hz, IF, CFF); 12.2 (td,

Jl=254Hz, J2=28Hz, IF, CFF).

Mass: (ESI⁺): 465.3 (M+Na)

o-Dichlorobenzene (0.320mL, 2.82mol, lOeq) followed by Pd/C 10% (0.342g, 0.32mol, l .leq) were added to a solution of 15 (228mg, 0.28mmol, leq) in a mixture of THF and MeOH (2: 1, v/v, 160mL). The reaction was placed under hydrogen atmosphere and stirred at room temperature for 2h. The reaction mixture was filtered and concentrated before being purified on silica gel chromatography (dichloromethane/methanol 100: 1 to 90: 10) to afford compound 16 (105mg, 83% yield).

…………………….

CN 103649033

http://www.google.com/patents/CN103649033A?cl=en

Sirona Biochem’s SGLT Inhibitor Performs Better Than Johnson and Johnson’s SGLT Inhibitor, According to Study

Vancouver, British Columbia – December 7, 2012 – Sirona Biochem Corp. (TSX-V: SBM), announced its sodium glucose transporter (SGLT) inhibitor for Type 2 diabetes reduced blood glucose more effectively than Johnson and Johnson’s canagliflozin, an advanced SGLT inhibitor being considered for market approval in Europe and the U.S. Studies compared Sirona Biochem’s SGLT Inhibitor, SBM-TFC-039, with canagliflozin and were conducted on Zucker Diabetic Fatty (ZDF) rats.

In the study, SBM-TFC-039 significantly and rapidly reduced blood glucose levels at a dose of 1.0 mg/kg. Six (6) hours after administration, SBM-TFC-039 reduced blood glucose by 44% compared to canagliflozin at 26%. SBM-TFC-039 also had a longer duration of effect than canagliflozin. At 36 and 48 hours after treatment, SBM-TFC-039, at a dose of 1.0 mg/kg, was still effective at reducing blood glucose, whereas canagliflozin lost its effect after 36 hours. Studies were conducted at the Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ) by Principal Investigator Dr. Denis Richard, Research Chair on Obesity and Professor, Faculty of Medicine, Department of Anatomy & Physiology at Laval University.

“SGLT Inhibitors are a ground-breaking new treatment for Type 2 diabetes and these results demonstrate that SBM-TFC-039 will be a significant competitor for other SGLT Inhibitors,” said Neil Belenkie, Chief Executive Officer of Sirona Biochem. “The first SGLT Inhibitor,Forxiga™, was approved last month by the European Commission. We believe there is tremendous market potential worldwide for SGLT Inhibitors in the treatment of diabetes.”

SBM-TFC-039 is a sodium glucose transporter (SGLT) inhibitor. SGLT inhibitors are a new class of drug candidates for the treatment of diabetes. In the kidneys, SGLT inhibitors reduce the reabsorption of glucose into the bloodstream by eliminating excess glucose into the urine.

About Sirona Biochem Corp.
Sirona Biochem is a biotechnology company developing diabetes therapeutics, skin depigmenting and anti-aging agents for cosmetic use, biological ingredients and cancer vaccine antigens. The company utilizes a proprietary chemistry technique to improve pharmaceutical properties of carbohydrate-based molecules. For more information visit www.sironabiochem.com.

Laboratory – France
TFChem
Voie de l’innovation
Pharma Parc II
Chaussée du Vexin
27100 Val de Reuil
France

Phone:+33(0)2.32.09.01.16
Fax:+33(0)2.32.25.07.64

……………………………………………………………………………….

Shanghai Fosun Pharmaceutical Group Co. Ltd.

复星医药

www.fosunpharma.com/

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Fispemifene for hypogonadism

July 15, 2015 4:00 am / Leave a comment

Fispemifene, HM 101

Fispemifene; UNII-3VZ2833V08;

cas 341524-89-8

Molecular Formula:	C₂₆H₂₇ClO₃
Molecular Weight:	422.94378 g/mol

2-[2-[4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenoxy]ethoxy]ethanol

Treatment of Hypogonadism

Androgen Decline in the Aging Male (Andropause) in phase 2

Fispemifene is the Z-isomer of the compound of formula (I)

WO 01/36360 describes a group of SERMs, which are tissue-specific estrogens and which can be used in women in the treatment of climacteric symptoms, osteoporosis, Alzheimer’s disease and/or cardiovascular diseases without the carcinogenic risk. Certain compounds can be given to men to protect them against osteoporosis, cardiovascular diseases and Alzheimer’s disease without estrogenic adverse events (gynecomastia, decreased libido etc.). Of the compounds described in said patent publication, the compound (Z)-2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol (also known under the generic name fispemifene) has shown a very interesting hormonal profile suggesting that it will be especially valuable for treating disorders in men. WO 2004/108645 and WO 2006/024689 suggest the use of fispemifene for treatment or prevention of age-related symptoms in men, such as lower urinary tract symptoms and diseases or disorders related to androgen deficiency in men.

Quatrx had been conducting phase II clinical development for the treatment of androgen decline in the aging male. Unlike testosterone replacement therapies that are typically topical or injection therapies, fispemifene is an oral treatment and is not a formulation of testosterone. Fispemifene utilizes the body’s normal feedback mechanism to increase testosterone levels. Originally developed at Hormos, QuatRx gained rights to the drug candidate following a merger of the companies pursuant to which Hormos became a wholly-owned subsidiary of QuatRx.

Known methods for the syntheses of compounds like ospemifene and fispemifene include rather many steps. WO 02/090305 describes a method for the preparation of fispemifene, where, in a first step, a triphenylbutane compound with a dihydroxysubstituted butane chain is obtained. This compound is in a second step converted to a triphenylbutene where the chain is 4-chlorosubstituted. Then the desired Z-isomer is crystallized. Finally, the protecting group is removed to release the ethanol-ethoxy chain of the molecule.

Fispemifene is a selective estrogen receptor modulator (SERM) studied in phase II clinical trials at Forendo Pharma for the treatment low testosterone in men. The compound is also in phase II clinical studies at Apricus for the treatment of men with secondary hypogonadism.

In 2013, Forendo Pharma acquired the drug from Hormos Medical for the treatment of male low testosterone.

In 2014, Apricus Biosciences acquired U.S. rights for development and commercialization

PATENT

https://www.google.com/patents/US7504530

EXAMPLE 2 2-{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxy}-ethanol (Compound I)

{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxy}-acetic acid ethyl ester was dissolved in tetrahydrofuran at room temperature under nitrogen atmosphere. Lithium aluminium hydride was added to the solution in small portions until the reduction reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride solution. The product was extracted into toluene, which was dried and evaporated in vacuo. The residue was purified with flash chromatography with toluene/triethyl amine (9.5:0.5) as eluent. Yield 68%.

¹H NMR (200 MHz, CDCl₃):

2.92 (t, 2H, ═CH ₂CH₂Cl),

3.42 (t, 2H, ═CH₂ CH₂ Cl),

3.59-3.64 (m, 2H, OCH₂CH₂O CH₂CH ₂OH),

3.69-3.80 (m, 4H, OCH₂ CH ₂OCH ₂CH₂OH),

3.97-4.02 (m, 2H, OCH₂CH₂OCH₂CH₂OH),

6.57 (d, 2H, aromatic proton ortho to oxygen),

6.78 (d, 2H, aromatic proton meta to oxygen),

7.1-7.43 (m, 10H, aromatic protons).

………….

PATENT

WO 2001036360

https://www.google.com/patents/WO2001036360A1?cl=en

……………

PATENT

WO 2002090305

http://www.google.co.in/patents/WO2002090305A1?cl=en

EXAMPLE

a) [2-(2-chloroethoxy)ethoxymethyl]benzene

is prepared from benzyl bromide and 2-(2-chloroethoxy)ethanol by the method described in literature (Bessodes, 1996).

b) {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl}phenylmethanone

The mixture of 4-hydroxybenzophenone (16.7 g, 84.7 mmol) and 48 % aqueous sodium hydroxide solution (170 ml) is heated to 80 °C. Tetrabutylammonium bromide (TBABr) (1.6 g, 5.1 mmol) is added and the mixture is heated to 90 °C. [2-(2-Chloroethoxy)ethoxymethyl]benzene (18. g, 84.7 mmol) is added to the mixture during 15 min and the stirring is continued for additional 3.5 h at 115-120 °C. Then the mixture is cooled to 70 °C and 170 ml of water and 170 ml of toluene are added to the reaction mixture and stirring is continued for 5 min. The layers are separated and the aqueous phase is extracted twice with 50 ml of toluene. The organic phases are combined and washed with water, dried with sodium sulphate and evaporated to dryness. Yield 31.2 g.

Another method to prepare {4-[2-(2-benzyloxyethoxy)ethoxy]phenyl}phenyl- methanone is the reaction of 2-(2-benzyloxyethoxy)ethyl mesylate with 4- hydroxybenzophenone in PTC-conditions.

Η NMR (CDCI3): 3.64-3.69 (m, 2H), 3.74-3.79 (m, 2H), 3.90 (dist.t, 2H), 4.22 (dist.t, 2H), 4.58 (s, 2H), 6.98 (d, 2H), 7.28-7.62 (m, 8H), 7.75 (td, 2H), 7.81 (d, 2H).

c) 1- {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl} – 1 ,2-diphenyl -butane- 1 ,4-diol

Figure imgf000013_0002 R = BENZYL

Lithium aluminum hydride (1.08 g, 28.6 mmol) is added into dry tetrahydrofuran (60 ml) under nitrogen atmosphere. Cinnamaldehyde (6.65 g, 50 mmol) in dry tetrahydrofuran (16 ml) is added at 24-28 °C. The reaction mixture is stirred at ambient temperature for 1 h. {4-[2-(2- Benzyloxyethoxy)ethoxy]phenyl}-phenyl-methanone (14.0 g, 37 mmol) in dry tetrahydrofuran (16 ml) is added at 50-55 °C. The reaction mixture is stirred at 60 °C for 3 h. Most of tetrahydrofuran is evaporated. Toluene (70 ml) and 2 M aqueous hydrogen chloride (50 ml) are added. The mixture is stirred for 5 min and the aqueous layer is separated and extracted with toluene (30 ml). The toluene layers are combined and washed with 2M HC1 and water, dried and evaporated. The product is crystallized from isopropanol as a mixture of stereoisomers (8.8 g, 50 %).

Η NMR (CDCI3 ): 1.75-2.10 (m, 2H), 3.20-4.16 (m, 1 OH), 4.52 and 4.55 (2s, together 2H), 6.61 and 6.88 (2d, together 2H), 6.95-7.39 (m, 15H), 7.49 and 7.57 (2d, together 2H).

d) Z- 1 – {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl} -4-chloro- 1 ,2-diphenyl-but- 1-ene

Figure imgf000013_0003 R = BENZYL

1 – {4- [2-(2-Benzyloxy-ethoxy)ethoxy]phenyl} – 1 ,2-diphenyl -butane- 1 ,4-diol (10.0 g, 19.5 mmol) is dissolved in toluene (50 ml). Triethylamine (2.17 g, 21.4 mmol) is added to the solution and the mixture is cooled to -10 °C. Thionyl chloride (6.9 g, 58.5 mmol) is added to the mixture at -10 – ±0 °C. The mixture is stirred for 1 hour at 0-5 °C, warmed up to 70 °C and stirred at this temperature for 4 hours. Solvent is evaporated, the residue is dissolved to toluene, washed three times with 1M HC1 solution and twice with water. The Z-isomer of the product is crystallized from isopropanol-ethyl acetate. Yield 3.0 g. The filtrate is purified by flash chromatography to give E-isomer.

Z-isomer: Η NMR (CDCI3): 2.91 (t, 2H), 3.41 (t, 2H), 3.55-3.85 (m, 6H), 3.99 (dist.t, 2H), 4.54 (s, 2H), 6.40 (s, 1H), 6.56 (d, 2H), 6.77 (d, 2H), 7.10- 7.50 (m, 15H)

E-isomer: 1H NMR (CDCI3): 2.97 (t, 2H), 3.43 (t, 2H), 3.65-3.82 (m, 4H), 3.88 (dist.t, 2H), 4.15 (dist.t, 2H), 4.58 (s, 2H), 6.86 -7.45 (m, 19H)

FINAL STEP

e) 2- {2-[4-(4-Chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethoxy } ethanol:

Z- 1 – {4-[2-(2-Benzyloxy-ethoxy)ethoxy]phenyl} -4-chloro- 1 ,2-diphenyl -but- 1-ene (3.8 g, 7.4 mmol) is dissolved in ethyl acetate under nitrogen atmosphere , Zn powder (0.12 g, 1.85 mmol) and acetyl chloride (1.27 g, 16.3 mmol) are added and the mixture is stirred at 50 °C for 3 h (Bhar, 1995). The reaction mixture is cooled to room temperature, water (10 ml) is added and stirring is continued for additional 10 min. The aqueous layer is separated and the organic phase is washed with 1 M aqueous hydrogen chloride solution and with water. Ethyl acetate is evaporated and the residue is dissolved in methanol (16 ml) and water (4 ml). The acetate ester of the product is hydrolysed by making the mixture alkaline with sodium hydroxide (1 g) and stirring the mixture at room temperature for 1 h. Methanol is evaporated, water is added and the residue is extracted in ethyl acetate and washed with 1 M hydrogen chloride solution and with water. Ethyl acetate is evaporated and the residue is dissolved in toluene (25 ml), silica gel (0.25 g) is added and mixture is stirred for 15 min. Toluene is filtered and evaporated to dryness. The residue is crystallised from heptane-ethyl acetate (2:1). The yield is 71 %.

Z-isomer: 1H NMR (CDCI3): 2.92 (t, 2H), 3.41 (t, 2H), 3.58-3.63 (m, 2H), 3.69-3.80 (m, 4H), 3.96-4.01 (m, 2H), 6.56 (d, 2H), 6.78 (d, 2H), 7.10-7.40 (m, 10H).

Z ISOMER IE FISPEMIFENE

E-2- {2- [4-(4-Chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethoxy} ethanol is prepared analogously starting from E-l-{4-[2-(2-benzyloxy- ethoxy)ethoxy]phenyl} -4-chloro- 1,2-diphenyl-but-l-ene. The product is purified by flash chromatography with toluene-methanol (10:0.5) as eluent.

E-isomer: 1H NMR (CDCI3): 2.97 (t, 2H), 3.43 (t, 2H), 3.65-3.79 (m, 4H), 3.85-3.90 (m, 2H), 4.13-4.17 (m, 2H), 6.85-7.25 (m, 2H).

Debenzylation of 1 – {4-[2-(2-benzyloxy-ethoxy)ethoxy]phenyl} -4-chloro- 1 ,2- diphenyl-but- 1-ene is also carried out by hydrogenation with Pd on carbon as a catalyst in ethyl acetate-ethanol solution at room temperature.

………….

PATENT

http://www.google.com/patents/US5491173

Patent	Submitted	Granted
Method for the preparation of 2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol and its isomers [US6891070]	2004-06-17	2005-05-10
Formulations of fispemifene [US2007104743]	2007-05-10
METHODS FOR THE PREPARATION OF FISPEMIFENE FROM OSPEMIFENE [US7504530]	2008-09-04	2009-03-17
METHOD FOR THE PREPARATION OF THERAPEUTICALLY VALUABLE TRIPHENYLBUTENE DERIVATIVES [US2011015448]	2011-01-20
METHOD FOR THE PREPARATION OF THERAPEUTICALLY VALUABLE TRIPHENYLBUTENE DERIVATIVES [US7812197]	2008-08-28	2010-10-12

WO2001036360A1	1 Nov 2000	25 May 2001	Pirkko Haerkoenen	Triphenylalkene derivatives and their use as selective estrogen receptor modulators
EP0095875A2	20 May 1983	7 Dec 1983	Farmos Group Ltd.	Novel tri-phenyl alkane and alkene derivatives and their preparation and use

Citing Patent	Filing date	Publication date	Applicant	Title
WO2008099059A1 *	13 Feb 2008	21 Aug 2008	Hormos Medical Ltd	Method for the preparation of therapeutically valuable triphenylbutene derivatives
WO2008099060A2 *	13 Feb 2008	21 Aug 2008	Hormos Medical Ltd	Methods for the preparation of fispemifene from ospemifene
CN101636372B	13 Feb 2008	27 Mar 2013	霍尔莫斯医疗有限公司	Method for the preparation of therapeutically valuable triphenylbutene derivatives
EP1636159A1 *	5 May 2004	22 Mar 2006	Hormos Medical Ltd.	Method for the treatment or prevention of lower urinary tract symptoms
EP2518039A1	13 Feb 2008	31 Oct 2012	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
EP2821385A2	13 Feb 2008	7 Jan 2015	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
US7504530	13 Feb 2008	17 Mar 2009	Hormos Medical Ltd.	Methods for the preparation of fispemifene from ospemifene
US7812197	13 Feb 2008	12 Oct 2010	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
US8293947	16 Sep 2010	23 Oct 2012	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
US8962693	19 Aug 2013	24 Feb 2015	Hormos Medical Ltd.	Method for the treatment or prevention of lower urinary tract symptoms

WO2002090305A1	Mar 21, 2002	Nov 14, 2002	Hormos Medical Corp	A new method for the preparation of 2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol and its isomers
WO2004108645A1	May 5, 2004	Dec 16, 2004	Hormos Medical Corp	Method for the treatment or prevention of lower urinary tract symptoms
WO2006024689A1 *	Jul 20, 2005	Mar 9, 2006	Taru Blom	Use of a selective estrogen receptor modulator for the manufacture of a pharmaceutical preparation for use in a method for the treatment or prevention of androgen deficiency
WO2007099410A2 *	Nov 9, 2006	Sep 7, 2007	Hormos Medical Ltd	Formulations of fispemifene
WO2014060640A1	Oct 17, 2013	Apr 24, 2014	Fermion Oy	A process for the preparation of ospemifene
CN100526277C	May 5, 2004	Aug 12, 2009	霍尔莫斯医疗有限公司	Method for the treatment or prevention of lower urinary tract symptoms
CN102532073A *	Dec 30, 2011	Jul 4, 2012	北京赛林泰医药技术有限公司	Ethylene derivative serving as selective estrogen receptor modulators (SERMs)
EP1786408A1 *	Jul 20, 2005	May 23, 2007	Hormos Medical Ltd.	Use of a selective estrogen receptor modulator for the manufacture of a pharmaceutical preparation for use in a method for the treatment or prevention of androgen deficiency
EP1951250A2 *	Nov 22, 2006	Aug 6, 2008	SmithKline Beecham Corporation	Chemical compounds
EP2258360A2	May 5, 2004	Dec 8, 2010	Hormos Medical Ltd.	Method for the treatment or prevention of lower urinary tract symptoms
EP2518039A1	Feb 13, 2008	Oct 31, 2012	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
EP2821385A2	Feb 13, 2008	Jan 7, 2015	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
US6891070	Mar 21, 2002	May 10, 2005	Hormos Medical Corporation	Method for the preparation of 2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol and its isomers
US7504530	Feb 13, 2008	Mar 17, 2009	Hormos Medical Ltd.	Methods for the preparation of fispemifene from ospemifene
US7560589	Jul 27, 2004	Jul 14, 2009	Smithkline Beecham Corporation	Cycloalkylidene compounds as modulators of estrogen receptor
US7569601	May 14, 2007	Aug 4, 2009	Smithkline Beecham Corporation	Cycloalkylidene compounds as modulators of estrogen receptor
US7799828	Jun 8, 2009	Sep 21, 2010	Glaxosmithkline Llc	Cycloalkylidene compounds as modulators of estrogen receptor
US7812197	Feb 13, 2008	Oct 12, 2010	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
US7825107	May 22, 2007	Nov 2, 2010	Hormos Medical Ltd.	Method of treating men suffering from chronic nonbacterial prostatitis with SERM compounds or aromatase inhibitors
US8293947	Sep 16, 2010	Oct 23, 2012	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
US8299112	Sep 15, 2011	Oct 30, 2012	Aragon Pharmaceuticals, Inc.	Estrogen receptor modulators and uses thereof
US8455534	Sep 13, 2012	Jun 4, 2013	Aragon Pharmaceuticals, Inc.	Estrogen receptor modulators and uses thereof
US8962693	Aug 19, 2013	Feb 24, 2015	Hormos Medical Ltd.	Method for the treatment or prevention of lower urinary tract symptoms

WO1996007402A1 *	Sep 6, 1995	Mar 14, 1996	Michael Degregorio	Triphenylethylenes for the prevention and treatment of osteoporosis
WO1996035417A1 *	May 10, 1996	Nov 14, 1996	Cancer Res Campaign Tech	Combinations of anti-oestrogen compounds and pkc modulators and their use in cancer therapy
WO1997032574A1 *	Mar 4, 1997	Sep 12, 1997	Degregorio Michael	Serum cholesterol lowering agent
WO1999042427A1 *	Feb 19, 1999	Aug 26, 1999	Kalapudas Arja	E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and pharmaceutical compositions thereof
WO1999063974A2 *	Jun 10, 1999	Dec 16, 1999	Endorecherche Inc	Selective estrogen receptor modulator in combination with denydroepiandrosterone (dhea) or analogues
EP0095875A2 *	May 20, 1983	Dec 7, 1983	Farmos Group Ltd.	Novel tri-phenyl alkane and alkene derivatives and their preparation and use

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।

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PAPER CONTAING SPECTRAL DATA

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IH NMR PREDICT

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New patent WO-2015104605

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Melting Point

Solubility

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Tofacitinib Citrate, 的合成

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate salt

CAS : 540737-29-9

Asymmetric total synthesis of Tofacitinib

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Clinical trials

Rheumatoid arthritis

Psoriasis

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Ulcerative colitis

Vitiligo

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Safe, small scale access to supercritical fluids

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Carbamic acid, N,N’-(tricyclo(8.2.2.24,7)hexadeca-4,6,10,12,13,15-hexaene-5,11-diylbis(1H-benzimidazole-6,2-diyl((2S,3aS,7aS)-octahydro-1H-indole-2,1-diyl)((1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl)))bis-, C,C’-dimethyl ester

Dimethyl N,N’-(1,4(1,4)-dibenzenacyclohexaphane-12,42-diylbis(1hbenzimidazole-5,2-diyl((2S,3aS,7aS)-octahydro-1H-indole-2,1-diyl)((2S)-3-methyl-1-oxobutan-1,2-diyl)))biscarbamate

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Verubecestat (MK-8931)

Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)–A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer’s Disease

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Toremifene

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Sirona Biochem’s SGLT Inhibitor Performs Better Than Johnson and Johnson’s SGLT Inhibitor, According to Study

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