Allisartan isoproxil

Allisartan isoproxil

CAS: 947331-05-7

553.01, C27 H29 Cl N6 O5

Shanghai Allist Pharmaceutical, Inc.

Allist Shanghai Pharmaceutical Co., Ltd.

2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-methyl]-imidazole-5-carboxylic acid, 1-[(isopropoxy)-carbonyloxy] methyl ester,

2-Butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylic acid isopropoxycarbonyloxymethyl ester

2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester

Allisartan is an orally-available angiotensin AT1 antagonist in phase II clinical trials at Shanghai Allist Pharmaceutical for the treatment of mild to moderate essential hypertension.

Shanghai Allist Pharmaceutical PHASE 2 for Hypertension

The prior art discloses Arleigh medoxomil illiquid, low bulk density, electrostatic phenomena evident. Chinese patent discloses a CN200710094131.0 Alicante medoxomil polymorph and method of preparation. Allie medoxomil based crystal prepared by the method has high stability characteristics, but relatively small bulk density of the crystal clear after the electrostatic phenomenon and poor liquidity dried, crushed and used for easy dispensing generate dust, operating the site clean and labor protection inconvenience, on the other hand also for accurate weighing and packaging products inconvenience.

CN200710094021.4 and CN201110289695.6 disclose the preparation of Alicante medoxomil, the inventor repeated, the proceeds of crystal and Chinese patent CN200710094131.0 consistent disclosed.

Allisartan isoproxil

Angiotensin II AT-1 receptor antagonist

Essential hypertension

Amorphous form of allisartan isoproxil is claimed in WO 2015062498. Useful for treating hypertension. Shenzhen Salubris Pharmaceuticals, in collaboration with Allist, has developed and launched allisartan isoproxil. In October 2012, Shenzhen Salubris signed a strategic cooperation framework agreement with Allist Pharmaceutical for the production and marketing of allisartan isoproxil. Family members of the product case of allisartanWO2007095789, expire in the EU and in the US in 2026. For a prior filing see WO2009049495 (assigned to Allist Pharmaceuticals), claiming the crystalline form of allisartan and its method of preparation.

The compound of formula (I) is an Ang II receptor antagonist. Its chemical name is 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-methyl]-imidazole-5-carb-oxylic acid, 1-[(isopropoxy)-carbonyloxy] methyl ester. Chinese Patent CN101024643A describes the structure, and its use as antihypertensive drugs.

As regards to the solid physical properties of the compound of formula (I), the patent document of CN101024643A discloses that it is a white solid, and its melting point is 134.5-136° C. However, CN101024643A dose not disclose the crystalline structure of the compound of formula (I).

CHINA

NEW PATENT

WO-2015062498

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015062498

2-butyl-4-chloro -1- [2 ‘- (1H- tetrazol-5-yl) -1,1′-biphenyl- – methyl] – imidazole-5-carboxylic acid, 1 – [(isopropoxy) – oxy] -, methyl ester, is a novel angiotensin Ⅱ receptor antagonist. China Patent CN200680000397.8 disclosed structural formula Alicante medoxomil compound. Allie medoxomil toxicity, blood pressure better than the same type of products (such as losartan), which by generating active metabolite (EXP3174) in vivo metabolism, and thus play its antihypertensive effect.

The prior art discloses Arleigh medoxomil illiquid, low bulk density, electrostatic phenomena evident. Chinese patent discloses a CN200710094131.0 Alicante medoxomil polymorph and method of preparation. Allie medoxomil based crystal prepared by the method has high stability characteristics, but relatively small bulk density of the crystal clear after the electrostatic phenomenon and poor liquidity dried, crushed and used for easy dispensing generate dust, operating the site clean and labor protection inconvenience, on the other hand also for accurate weighing and packaging products inconvenience.

CN200710094021.4 and CN201110289695.6 disclose the preparation of Alicante medoxomil, the inventor repeated, the proceeds of crystal and Chinese patent CN200710094131.0 consistent disclosed.

……………………..

PATENT

http://www.google.com/patents/CN103965171A?cl=en

Hypertension is a major disease threat to human health, looking for efficiency, low toxicity anti-hypertensive drugs can help relieve social pressures and family responsibilities, with good social and economic benefits.

 Angiotensin II (Ang II) is the renin – angiotensin – aldosterone system (RAAS) main vasoconstrictor hormone, which plays an important role in the pathobiology of many chronic diseases, particularly its the role of blood pressure regulation is particularly prominent, and therefore Ang II receptor is believed to be a good target for the development of anti-hypertensive drugs.

EP0253310 discloses a series of imidazole derivatives, DuPont declared and obtained by the study of losartan potassium-listed in 1994, was the first non-peptide Ang II receptor antagonist anti-hypertensive drugs. Thereafter, he listed a series of losartan antihypertensive drugs: candesartan cilexetil, valsartan, irbesartan, telmisartan and olmesartan medoxomil, etc. (EP0253310, W02005049587, GB2419592, EP1719766, US5196444) .

The losartan potassium in the body, the active metabolite EXP3174 has a stronger antihypertensive effect than losartan potassium, but EXP3174 polar molecular structure, is difficult to form passive absorption by diffusion through the cell membrane. US5298915 discloses five carboxyl ester group transformation EXP3174 is a series of derivatives, focusing on the compound HN-65021, and discloses hypotensive test results HN-65021 administered by the oral route, its hypotensive activity with chlorine Similar losartan potassium (BritishJouurnal ofClinical Pharmacology, 40,1995,591).

CN200680000397.8 _5_ discloses a class of imidazole carboxylic acid derivatives, namely Alicante medoxomil compound 8 has a good blood pressure lowering effect, the structure of formula I, the preparation method disclosed in this patent document follows the route A, losartan potassium by oxidation, the protecting group into an ester, deprotected to give a compound of formula I, the route step oxidation process of hydroxyl to carboxyl groups, will be reduced to very fine granular potassium permanganate, manganese dioxide, filtration This manganese mud time-consuming, inefficient, polluting; the second step conversion was about 70%, and post-processing cumbersome; byproducts and produced the first two steps more. This makes the high cost of the entire route, not suitable for the production of amplification.

CN200710094021.4 discloses another method for preparing the compounds of formula I, the following route B, the starting material by nucleophilic substitution, oxidation, an ester, a tetrazole ring to obtain a compound of formula I, the first step of the method nucleophilic substitution easy to generate an imidazole ring -3 para isomer impurities difficult to remove; the last step into the ring to use sodium azide, operating dangerous.

CN201210020174.5 disclosed a series of anti-hypertensive compound and preparation method, the following line C, the temperature control in the first step of its preparation O ~ 5 ° C, a mixed solution of acetone and water, with a 5% aqueous solution of sodium hypochlorite oxidation, yield 70%, the second step use of potassium permanganate, manganese dioxide will produce the same, and a yield of only 40%, the first two steps total yield of 28%, is very low, and the post-treatment methods are by column separation, the first two steps are used are organic and inorganic mixed solvent is not conducive to recovery, not suitable for scale-up.

Example 8 2-Butyl-4-chloro _1- [2 ‘- (1-tetrazol-5-yl biphenyl – methyl] imidazole

5-carboxylic acid, 1 – [(isopropoxy) carbonyl] -L-methoxy ester (Alicante medoxomil crude)

To a 20L reactor 9800ml of methanol, stirring was started, the rotational speed is added at 200r / min 1225.3g solid compound of formula II, and heated to reflux. The reaction 8-10h evacuation HPLC detection, the formula II compound residue <1.0% seen as a response endpoint. After reaching the end of the reaction the heating was stopped, continued stirring speed of 180r / min. About 3_4h fell 20_25 ° C, colorless transparent crystalline solid precipitated. The reaction mixture was cooled to continue to 15-20 ° C, to maintain 15-20 ° C with stirring 3h, the reaction mixture was filtered to give a pale yellow clear filtrate. The filtrate was concentrated under reduced pressure to move 20L flask, vacuum degree of 0.075MPa, 40_45 ° C methanol distilled off under until no distillate. 800ml of absolute ethanol was added, a vacuum degree of 0.075MPa, 40-45 ° C under distillation until no distillate.

900ml of absolute ethanol was added, heated to reflux. N-heptane was added slowly 1100ml, reflux 15min, to -10 ° c / h speed cooled to 15 ± 2 ° C, keep stirring 3h. Filtered under reduced pressure, ethanol / n-heptane = 1 mixture of filter cake was washed / 3, the back pressure dry vacuum filtration lh, was Allie medoxomil crude (800.lg, yield 93.8%).Purification was used directly in the next step without drying.

 Example 9 2-butyl-4-chloro-_1- [2 ‘- (1-tetrazol-5-yl biphenyl – methyl] imidazole-5-carboxylic acid, 1 – [(isopropylamino oxy) carbonyl] -L-methoxy ester (Alicante medoxomil)

850ml of absolute ethanol was added to the 3L reaction vessel was charged with crude Alicante medoxomil (800.lg, 1.45mol), heated to reflux. After completely dissolved clear, slow addition of n-heptane 1300ml, reflux 15min, to -10 ° C / h speed cooled to 10 ± 2 ° C, keep stirring 3h. Filtered under reduced pressure, ethanol / n-heptane = 1 mixture of filter cake was washed / 3, the back pressure dry vacuum filtration, the purified Alicante medoxomil (780.9g, 97.6% yield).

Example 10 2-butyl-4-chloro _1- [2 ‘- (1-tetrazol-5-yl biphenyl – methyl] imidazole

5-carboxylic acid, 1 – [(isopropoxy) carbonyl] -L-methoxy ester (Alicante medoxomil)

950ml of absolute ethanol was added to the 5L reaction vessel was charged with crude Alicante medoxomil (549.9g, 1.72mol), heated to reflux. After completely dissolved clear, slow addition of n-heptane 1200ml, reflux 15min, to -10 ° C / h speed cooled to 10 ± 2 ° C, keep stirring 3h. Filtered under reduced pressure, ethanol / n-heptane = cake was washed with a mixture of 1/3, and dried under reduced pressure after filtration to obtain a purified Alicante medoxomil (540.0g, 98.2% yield).

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PATENT

http://www.google.com/patents/US20090036505

Example 122-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester (compound 8)

To a 100 ml of one-necked flask, 0.523 g of material, 0.124 g of potassium carbonate, 5 ml of N,N-dimethylacetamide were added in turn. The solution was stirred at room temperature for 20 minutes. Then 0.562 g of 1-chloromethyl isopropyl carbonate was added and the mixture was reacted at 45-50° C. for 16 hours. After the reaction was completed, the mixture solution was filtered, and 30 ml of water was added into the filtrate. The resulting mixture was extracted with 30 ml of ethyl acetate twice. The organic phase was dried and concentrated to give 1.724 g of oil, which was directly used in the next reaction without purification.

10 ml of dioxane and 5 ml of 4 mol/L HCl were added, and the resulting mixture was reacted at room temperature for 16 hours. The reaction was stopped and the solution was adjusted to pH 6-7 using aqueous sodium bicarbonate solution. The solution went turbid, and was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, concentrated to give 0.436 g of 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester.

In addition, the following reaction condition can be used to deprotect the protecting group. To 1.7 g of oily product, 5 ml absolute methanol was added and the mixture was heated slowly to reflux and stirred for 8 hours. When the insoluble solid disappeared totally, the mixture was discontinued to heating and cooled to 5° C. The white solid precipitated, and was separated by filtration, and the filter cake was washed with a small quantity of methanol. The combined filtrate was concentrated to dryness to give 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester with the yield of 70%.

1H-NMR (CDCl3) δ H (ppm): 0.89 (t, 3H, J=14.6), 1.24 (d, 6H, J=6.3), 0.37 (m, 2H, J=22.1), 1.69 (m, 2H, J=30.5), 2.64 (t, 2H, J=15.5), 4.81 (m, 1H, J=12.4), 5.54 (s, 2H), 5.86 (s, 2H), 6.95-7.64 (8H), 8.08 (d, 1H, J=7.42)

ESI(+) m/z: 552.7

Mp: 134.5-136° C.

Shanghai Allist Pharmaceutical, Inc.

 

WO2005011646A2*

20 Jul 2004

10 Feb 2005

Nicoletta Almirante

Nitrooxy derivatives of losartan, valsatan, candesartan, telmisartan, eprosartan and olmesartan as angiotensin-ii receptor blockers for the treatment of cardiovascular diseases

US7943648*	Jun 5, 2009	May 17, 2011	Shanghai Allist Pharmaceutical Inc.	Salts of imidazole-5-carboxylic acid derivatives, a method for preparing same and pharmaceutical compositions comprising same
US8138214	Jul 2, 2009	Mar 20, 2012	Shanghai Allist Pharmaceutical, Inc.	Pharmaceutical composition
USRE44873	Jul 31, 2006	Apr 29, 2014	Salubris Asset Management Co., Ltd.	Imidazole-5-carboxylic acid derivatives, the preparation method therefor and the uses thereof

CITING PATENT	FILING DATE	PUBLICATION DATE	APPLICANT	TITLE
US8455526 *	6 Jun 2008	4 Jun 2013	Shanghai Allist Pharmaceuticals, Inc.	Therapeutic use of imidazole-5-carboxylic acid derivatives
US20100168193*	6 Jun 2008	1 Jul 2010	Shanghai Allist Pharmaceuticals, Inc.	Therapeutic use of imidazole-5-carboxylic acid derivatives
USRE44873	31 Jul 2006	29 Apr 2014	Salubris Asset Management Co., Ltd.	Imidazole-5-carboxylic acid derivatives, the preparation method therefor and the uses thereof

CN101024643A	20 Feb 2006	29 Aug 2007	上海艾力斯医药科技有限公司	Imidazo-5-carboxylic-acid derivatives, its preparing method and use
US5298519 *	24 Sep 1992	29 Mar 1994	Chemish Pharmazeutische Forschungsgesellschaft M.B.H.	Acylals of imidazole-5-carboxylic acid derivatives, and their use as angiotensin (II) inhibitors

……………….

Shanghai , CHINA

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RIVAROXABAN

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 (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.

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

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.
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RIVAROXABAN
IH NMR PREDICT

RIVAROXABAN

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13 C NMR PREDICT

.

http://www.google.com/patents/WO2013120465A1?cl=en

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, 2x1 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.

EXAMPLE 30 (preparation of rivaroxaban)

10.5 g of the amine prepared according to Example 26 were suspended in 200 ml of dichloromethane and then 5.4 ml of triethylamine dissolved in 50 ml of dichloromethane were added. This was followed by addition of 14.4 ml of a solution of 5-chlorothiophene-2- carboxylic acid chloride in toluene (2.46 M) and 25 ml of dichloromethane. The reaction mixture was stirred and heated at boiling for 1.5 hours and then slowly cooled below 30°C. The separated product was filtered off, washed with dichloromethane (15 ml) and ethanol (2 x 15 ml). The crude product was crystallized from a mixture of acetic acid (20 ml) and ethanol (200 ml). 10.5 g (yield 67%) of rivaroxaban was obtained in the form of an off-white powder with the melt, point of 228-230°C, HPLC 99.97%, content of the (i?)-isomer below 0.03%. The NMR and MS spectra were in accordance with Example 28.

20 g of 2-({(5S -2-oxo-3-[4-(3-oxomo holin-4-yl) henyl]-l ,3-oxazolidin-5-yl}methyl)-lH- isoindole-l,3(2H)-dione was suspended in 450 ml of ethanol, which was followed by addition of 6 ml of hydrazinehydrate in 50 ml of ethanol and the mixture was stirred and refluxed for 3 hours. Then, the suspension was cooled down to 65°C and filtered and the cake was washed with 2x50 ml of nearly boiling ethanol. After drying 7.2 g of an off-white powder were obtained, which slowly melted at a temperature over 260°C (this fraction contained 99.9% of 2,3-dihydrophtalazine-l,4-dione according to HPLC). After cooling of the hot filtrate another solid fraction separated. After its isolation by filtration and drying, 12.5 g of white lumpy powder with the melt, point of 141-144°C was obtained (this fraction contained 86.7% of the desired product, 12.7% of 2,3-dihydrophtalazine-l,4-dione, and the rest to 100 % were other unidentifiable impurities according to HPLC). The yield of the isolated amine calculated to the pure substance was 73%.

(S)-isomer 99,79 % (R)-isomer 0,21 % (S)-isomer 99,81 % / (R)-isomer 0,19 %

Crude rivaroxaban with the chemical purity of 99.5%, containing 0.21% of the (i?)-enantiomer and 0.50% of unidentified impurities, was crystallized from a mixture of acetic acid and ethanol.

Crystallization 1: 22 g of crude rivaroxaban were dissolved in 180 ml of acetic acid at boiling and the obtained solution was still hot filtered. The filtrate was brought to boil again and 400 ml of ethanol was gradually added to the boiling solution. The mixture was stirred under slow cooling for ca. 1 hour (resulting temperature of the suspension ca. 28°C). Subsequently, filtration was performed, the cake was washed with 2x30 ml of ethanol and vacuum-dried. 20.3 g of the product was obtained, melt, point 227.5-228.5°C. The yield of the crystallization was 92%, HPLC 99.8%, content of the ( ?)-enantiomer 0.21%, contents of unidentified impurities 0.15%.

Crystallization 2: 20 g of once crystallized rivaroxaban were dissolved in 150 ml of acetic acid at boiling and the obtained solution was still hot filtered (the filter was washed with 20 ml of boiling acetic acid to the filtrate). The filtrate was brought to boil again and 340 ml of ethanol was gradually added to the boiling solution. The mixture was stirred under slow cooling for ca. 1.5 hours (resulting temperature of the suspension ca. 26°C). Subsequently, filtration was performed, the cake was washed with 2x50 ml of ethanol and vacuum-dried. 19.1 g of the product was obtained, melt, point 230-231 °C. Crystallization yield 96%, HPLC 99.96%, content of the (fl)-enantiomer 0.19%, the contents of unidentified impurities was 0.04%.

After two crystallizations the final chemical purity of rivaroxaban achieved was 99.96%, the contents of unidentified impurities was reduced from 0.50% to 0.04%. After two crystallizations the achieved content of the (/?)-isomer was 0.19%, which is an excessive value (limit 0.15%) and is comparable to the initial level of 0.21%. The yield of rivaroxaban after the two crystallizations was 88% (calculated to the starting crude rivaroxaban).

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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

SYNTHESIS
SYN 1


BAYER HEALTHCARE AG Patent: WO2004/60887 A1, 2004 ; Location in patent: Page/Page column 8; 10-11 ;

SYN 2



MEDICHEM S.A.; MANGION, Bernardino; DURAN LOPEZ, Ernesto Patent: WO2012/35057 A2, 2012 ; Location in patent: Page/Page column 34 ;


SYN 3


EGIS GYOGYSZERGYAR NYILVANOSAN MUeKOeDOe RESZVENY-TARSASAG; SIPOS, Eva; KOVANYINE LAX, Gyoergyi; HAVASI, Balazs; VOLK, Balazs; KRASZNAI, Gyoergy; RUZSICS, Gyoergy; BARKOCZY, Jozsef; TOTHNE LAURITZ, Maria; LUKACS, Gyula; BOZA, Andras; HEGEDUeS, Laszlo Jozsef; TABORINE TOTH, Maria Julia; PECSI, Eva Patent: WO2012/153155 A1, 2012 ; Location in patent: Page/Page column 49 ;


SYN4



EGIS GYOGYSZERGYAR NYILVANOSAN MUeKOeDOe RESZVENY-TARSASAG; SIPOS, Eva; KOVANYINE LAX, Gyoergyi; HAVASI, Balazs; VOLK, Balazs; KRASZNAI, Gyoergy; RUZSICS, Gyoergy; BARKOCZY, Jozsef; TOTHNE LAURITZ, Maria; LUKACS, Gyula; BOZA, Andras; HEGEDUeS, Laszlo Jozsef; TABORINE TOTH, Maria Julia; PECSI, Eva Patent: WO2012/153155 A1, 2012 ; Location in patent: Page/Page column 68 ;

SYN 5


INTERQUIM, S.A.; Berzosa Rodríguez, Xavier; Marquillas Olondriz, Francisco; Llebaria Soldevilla, Amadeo; Serra Comas, Carme Patent: US2014/128601 A1, 2014 ; Location in patent: Paragraph 0068 ;



SYN 6


MEGAFINE PHARMA (P) LTD; MATHAD Vijayavitthal Thippannachar; PATIL NILESH SUDHIR, Nilesh; NIPHADE NAVNATH CHINTAMAN, Navnath; MALI ANIL CHATURLAL, Anil; BODAKE MAHENDRA BHAGIRATH, Mahendra; IPPAR SHARAD SUBHASH, Sharad; TALLA RAJESH, Rajesh Patent: WO2013/121436 A2, 2013 ; Location in patent: Page/Page column 31 ;

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PATENT

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.

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

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http://www.google.com/patents/WO2013120465A1?cl=en

Rivaroxaban, chemically (S)-5-chloro-N-({2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3- oxazolidin-5-yl}methyl)thiophene-2-carboxamide, described by formula (1), was developed by the company Bayer Healthcare (WO 01/47919, 2001). Rivaroxaban is applied in the clinical practice as the active ingredient of an orally available anticoagulant that is commercially marketed as Xarelto and is used in the prevention and treatment of arterial or venous thromboembolic disorders. In its effect, rivaroxaban is characterized by direct selective inhibition of the FXa coagulation enzyme (Drugs of the Future 2006, 31(6): 484-493).

H₂

For the preparation of rivaroxaban several key structures, referred to as building blocks, can be used as advanced intermediates. Virtually all the so far described syntheses are using two such building blocks. The first one are derivatives of 4-(4-aminophenyl)morpholin-3-one, where it may be the case of an unsubstituted amine (2, G means hydrogen), or a derivative alkylated on nitrogen, or a carbamate derived from this compound (2, G means an alkyl or COOalkyl group). The other general and commonly used building block for the rivaroxaban molecule are derivatives of 5-chlorothiophene-2-carboxylic acid (3, X means -OH), or its functional derivatives such as the chloride and amide (3, X means -CI or -NH₂). Various synthetic approaches used for synthesis of rivaroxaban differ from each other mainly as regards the chiral building block, which is the source for the construction of the central heterocycle, i.e., 2-oxo-l,3-oxazolidine, wherein the chirality centre is also located. For pharmaceutical purposes one optical isomer derived from rivaroxaban is only used, in particular the target molecule with the absolute configuration (5)-. The selection of a suitable chiral building block must be subjected to this fact.

(4) (5) (6) (7) (8)

Chiral building blocks that have been successfully used for synthesis of rivaroxaban include (5)-glycidyl phthalimide (4), (S)-3-aminopropane-l,2-diol (5), ( ?)-epichlorohydrin (6) and (i?)-glycidyl butyrate (7). (S)-glycidol (8) was used as a starting material for the preparation of (5)-glycidyl phthalimide (4) (Tetrahedron: Asymmetry, Vol. 7, No. 6, pp. 1641-1648, 1996).

The known methods of chemical synthesis of rivaroxaban (1) are described in Schemes 1 to 7. The first one is the process according to Scheme 1 (WO 01/47919 Bayer, US 7 157 456 B2, J.MedChem. (2005), 48(19), 5900-5908), which starts from 4-(4-aminophenyl)morpholin-3- one and (5)-glycidyl phthalimide (4). The second synthetic process follows Scheme 2 (WO 2004/060887, Bayer) and starts from 5-chlorothiophene-2-carboxylic acid (3, X means -OH) and (5)-3-aminopropane-l,2-diol (5). 4-(4-aminophenyl)morpholin-3-one only engages in the synthesis in the penultimate stage in case of the process according to Scheme 2.

Scheme 1

The third synthetic process, which proceeds according to Scheme 3, was mainly used for preparation of deuterated analogs of rivaroxaban (WO 2009/023233 Al, Concert Pharm.). It also represents the first synthetic process in which (i?)-epichlorohydrin (6) was used as the chiral building block. The other key starting material for the third process was 4-(4- aminophenyl)morpholin-3-one. The fourth synthetic process, which proceeds according to Scheme 4 (WO 2010/124835 Al, Apotex), again uses (i?)-epichlorohydrin as the chiral building block, which reacts with the alkyl carbamate derived from 4-(4- aminophenyl)morpholin-3-one in the key stage. The fifth synthetic process, which proceeds according to Scheme 5 (US 20110034465 Al), also uses (i?)-epichlorohydrin as the chiral building block, which directly reacts with 4-(4-aminophenyl)morpholin-3-one in the key stage, which is the same reaction as in the third process. The differences between the third and fifth processes consist in the preparation method of the 2-oxo-l,3-oxazolidine cycle and in the carbonylation agent used. While the third process uses Ι,Γ-carbonyldiimidazol (CDI) as the carbonylation agent, the fifth process uses more available and cheaper alkyl chloroformates.

Scheme 3

Scheme 4

Scheme 5

The sixths synthetic process, which proceeds according to Scheme 6 (WO 2011/080341 Al), uses (7?)-glycidyl butyrate (7) as the chiral building block, which in the key stage reacts with the alkyl carbamate derived from 4-(4-aminophenyl)morpholin-3-one. The last, seventh synthetic process leading to rivaroxaban proceeds according to Scheme 7 (WO 201 1/098501 Al) and, like process 2, uses (S)-3-aminopropane-l,2-diol (5) as the chiral building block. The differences between the second and seventh processes consist in the preparation process of the 2-oxo-l,3-oxazolidine cycle and the carbonylation agent used. While the second process uses Ι,Γ-carbonyldiimidazol (CDI) as the carbonylation agent, the fifth process uses the cheaper, but very toxic phosgene.

Scheme 6

Scheme 7 The processes used for the synthesis of rivaroxaban differ from each other especially in the chiral building block (compounds 4 to 7) and in the carbonylation agents (CDI, alkyl chloroformates, phosgene) used. Another difference can be found in the method of performing deprotection reactions, i.e. such reactions that lead to elimination of the protecting groups, initially bound to the nitrogen atom of the advanced intermediates and which had the initial purpose of protecting these intermediates from undesired chemical transformations. No deprotection reactions were necessary in the case of the processes according to Schemes 2, 4 and 7, as the protecting groups bound to the nitrogen atom eventually became part of the final product. In the case of process 6 it was necessary to deprotect the fert-butyl group bound to the nitrogen. The reaction used was an acid catalyzed reaction of the tert-butyl group, releasing isobutylene according to Scheme 8. In normal conditions isobutylene is a gas and thus can be very easily separated from the final product.

isobutylen

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, 2x1 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.

EXAMPLE 30 (preparation of rivaroxaban)

10.5 g of the amine prepared according to Example 26 were suspended in 200 ml of dichloromethane and then 5.4 ml of triethylamine dissolved in 50 ml of dichloromethane were added. This was followed by addition of 14.4 ml of a solution of 5-chlorothiophene-2- carboxylic acid chloride in toluene (2.46 M) and 25 ml of dichloromethane. The reaction mixture was stirred and heated at boiling for 1.5 hours and then slowly cooled below 30°C. The separated product was filtered off, washed with dichloromethane (15 ml) and ethanol (2 x 15 ml). The crude product was crystallized from a mixture of acetic acid (20 ml) and ethanol (200 ml). 10.5 g (yield 67%) of rivaroxaban was obtained in the form of an off-white powder with the melt, point of 228-230°C, HPLC 99.97%, content of the (i?)-isomer below 0.03%. The NMR and MS spectra were in accordance with Example 28.

20 g of 2-({(5S -2-oxo-3-[4-(3-oxomo holin-4-yl) henyl]-l ,3-oxazolidin-5-yl}methyl)-lH- isoindole-l,3(2H)-dione was suspended in 450 ml of ethanol, which was followed by addition of 6 ml of hydrazinehydrate in 50 ml of ethanol and the mixture was stirred and refluxed for 3 hours. Then, the suspension was cooled down to 65°C and filtered and the cake was washed with 2x50 ml of nearly boiling ethanol. After drying 7.2 g of an off-white powder were obtained, which slowly melted at a temperature over 260°C (this fraction contained 99.9% of 2,3-dihydrophtalazine-l,4-dione according to HPLC). After cooling of the hot filtrate another solid fraction separated. After its isolation by filtration and drying, 12.5 g of white lumpy powder with the melt, point of 141-144°C was obtained (this fraction contained 86.7% of the desired product, 12.7% of 2,3-dihydrophtalazine-l,4-dione, and the rest to 100 % were other unidentifiable impurities according to HPLC). The yield of the isolated amine calculated to the pure substance was 73%.

(S)-isomer 99,79 % (R)-isomer 0,21 % (S)-isomer 99,81 % / (R)-isomer 0,19 %

Crude rivaroxaban with the chemical purity of 99.5%, containing 0.21% of the (i?)-enantiomer and 0.50% of unidentified impurities, was crystallized from a mixture of acetic acid and ethanol.

Crystallization 1: 22 g of crude rivaroxaban were dissolved in 180 ml of acetic acid at boiling and the obtained solution was still hot filtered. The filtrate was brought to boil again and 400 ml of ethanol was gradually added to the boiling solution. The mixture was stirred under slow cooling for ca. 1 hour (resulting temperature of the suspension ca. 28°C). Subsequently, filtration was performed, the cake was washed with 2x30 ml of ethanol and vacuum-dried. 20.3 g of the product was obtained, melt, point 227.5-228.5°C. The yield of the crystallization was 92%, HPLC 99.8%, content of the ( ?)-enantiomer 0.21%, contents of unidentified impurities 0.15%.

Crystallization 2: 20 g of once crystallized rivaroxaban were dissolved in 150 ml of acetic acid at boiling and the obtained solution was still hot filtered (the filter was washed with 20 ml of boiling acetic acid to the filtrate). The filtrate was brought to boil again and 340 ml of ethanol was gradually added to the boiling solution. The mixture was stirred under slow cooling for ca. 1.5 hours (resulting temperature of the suspension ca. 26°C). Subsequently, filtration was performed, the cake was washed with 2x50 ml of ethanol and vacuum-dried. 19.1 g of the product was obtained, melt, point 230-231 °C. Crystallization yield 96%, HPLC 99.96%, content of the (fl)-enantiomer 0.19%, the contents of unidentified impurities was 0.04%.

After two crystallizations the final chemical purity of rivaroxaban achieved was 99.96%, the contents of unidentified impurities was reduced from 0.50% to 0.04%. After two crystallizations the achieved content of the (/?)-isomer was 0.19%, which is an excessive value (limit 0.15%) and is comparable to the initial level of 0.21%. The yield of rivaroxaban after the two crystallizations was 88% (calculated to the starting crude rivaroxaban).

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