Apixaban preparation process WO 2012168364

Publication number	WO2012168364 A1
Publication type	Application
Application number	PCT/EP2012/060800
Publication date	Dec 13, 2012
Filing date	Jun 7, 2012
Priority date	Jun 10, 2011
Also published as	EP2718262A1, US8884016, US20140058107,US20150025242
Inventors	Chiara Vladiskovic, Emanuele Attolino,Alessandro Lombardo, Simone TAMBINI
Applicant	Dipharma Francis S.R.L.
External Links: Patentscope, Espacenet

http://www.google.com/patents/WO2012168364A1?cl=en

l-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l -yl)phenyl]-4, 5,6,7- tetrahydro- lH-pyrazolo[3,4-c]pyridine-3-carboxyamide of formula (I), also known come apixaban, is a powerful inhibitor of coagulation factor Xa disclosed in US 6,967,208. Said compound is used in the prevention and treatment of thromboembolic disorders.

(I)

US 7, 153,960 discloses a process for the preparation of apixaban wherein the key step is the formation of intermediate (A) by 1 ,3 dipolar cycloaddition reaction between the compounds of formula (B) and (C) and its subsequent conversion to the compound of formula (D) by treatment with an acid. The compound of formula (D), after simple manipulations of functional groups, is converted to apixaban

B C A D

Said patent discloses the preparation of the compounds of formula (B) and (C). While the synthesis of the hydrazone of formula (B) has been known for some time, the preparation of the key intermediate of formula (C) is complex and uses reagents which are expensive and potentially hazardous, such as phosphorus pentachloride (PC1₅), and drastic reaction conditions.

US 7, 153,960, for example, discloses as preferred the preparation of an enamine intermediate of formula (C) wherein the amine residue NR_bR_c is a morpholine. The conditions used for the success of the reaction actually involve the use of morpholine as solvent at high temperatures, such as reflux temperature (about 130- 135°C).

The complexity of the known processes for the preparation of the intermediate of formula C, the expense and danger of the reagents and the drastic reaction conditions used make said processes difficult to apply and scale up industrially, especially for the purpose of preparing the intermediates of formula A and D and apixaban.

There is consequently a need for an alternative method for the preparation of apixaban and its intermediates which does not involves the problems described above. Said method should in particular be more industrially scalable, allow the desired compounds to be obtained with high yields, and use cheaper reagents which are simpler to handle, also using mild reaction conditions.

Example 6. Synthesis of compound of formula (I): l-(4- Methoxyphenyl)-6-[4-(2-oxo-piperidinyl)phenyl]-7-oxo-4,5,6,7-tetrahydro- l//-pyrazolo[3,4-c]pyridine-3-carboxyamide: Apixaban (I)

The compound of formula II, prepared as in Example 5 (17.50 g, 35.82 mmol), is suspended in 100 ml of 33% NH₃ and 200 ml of MeOH in a 1L 4-necked flask equipped with coolant, thermometer and magnetic stirrer, in nitrogen atmosphere, and heated to 45°. MeOH (250 ml) is added until completely dissolved, and the solution is left under stirring for 2h. Another addition of 33% NH₃ (50 ml) is performed, and the progress of the reaction is monitored by TLC (AcOEt/MeOH 9: 1) and HPLC. After 18h the solvent is evaporated under low pressure, and the solid residue obtained is suspended in 200 ml of H₂O and left under stirring for 2h. The white solid is filtered through a Buchner funnel, and washed with H₂O (50 ml). The product of formula (I) is stove-dried at 50°C to a constant weight (12.60 g, yield 76%). The HPLC purity of the product exceeds 99%.

1H NMR (300 MHz, CDC1₃): 67.47 (2H, dd, J₀=8.7 Hz, Ar-H), 7.31

(2H, dd, J₀=8.7 Hz, Ar-H), 7.23 (2H, dd, J₀=8.7 Hz, Ar-H), 6.93 (2H, dd, J₀=8.7 Hz, Ar-H), 6.83 (1H, s, N-H), 5.53 (1H, s, N-H), 4.1 1 (2H, t, J=6.6 Hz, CH₂CH₂N), 3.81 (3H, s, Ar-OCH₃), 3.59 (2H, m, NCH₂CH₂CH₂CH₂CO) 3.37 (2H, t, J=6.6 Hz, CH₂CH₂N), 2.55 (2H, m, NCH₂CH₂CH₂CH₂CO), 1.93 (4H, m, NCH₂CH^CH₂CH₂CO).


Preparation of intermediates 

Example 1. Synthesis of a compound of formula (III): l-(4-Iodophenyl)-3-trimeth lsilyloxy-5,6-dihydro-l -pyridin-2-one (Ilia)

v in

The compound of formula V (2.00 g, 6.35 mmol) is suspended in 15 ml of toluene in a 50 ml 3-necked flask equipped with coolant, thermometer and magnetic stirrer, in nitrogen atmosphere. Triethylamine (1.15 ml, 8.26 mmol) is added, and the mixture is cooled to 0°C. Chlorotrimethylsilane (0.97 ml, 7.64 mmol) is added drop by drop at a temperature of under 5°C. After the addition, the temperature is increased to 50°C, and after 5h the reaction mixture is cooled to room temperature, diluted with toluene (30 ml) and washed with H₂O (1x10 ml) and a saturated solution of NaCl (1x10 ml). The organic phase is anhydrified on (Na₂SO₄), filtered and evaporated under low pressure. Compound (III) is obtained as a brown solid (2.23 g, yield 90%), which is used for the next stage without further purification.

1H NMR (300 MHz, CDC1₃): 6 7.67 (2H, dd, J=8.1 Hz, Ar-H), 7.06 (2H, dd, J=8.1 Hz, Ar-H), 5.81 (1H, t, J=4.8 Hz, CHCOSiMe₃), 3.77 (2H, t, J=6.9 Hz, N-CH₂), 2.48 (2H, m, ΟΗ₂¾ϋΗ), 0.23 (9H, s, CHCOSi(CH₃ ).
 
 Dipharma Francis S.r.l.. Via Bissone, 5 20021 Baranzate (Milano) Italy Telephone +39 02 38 228.370. Fax +39 02 38228246. E-mail exclusives@dipharma.it

Example 2. Synthesis of a compound of formula (III): l-(4-

V III

The compound of formula V (370 mg, 1.17 mmol) is suspended in 2.5 ml of toluene in a 25 ml 3-necked flask equipped with coolant, thermometer and magnetic stirrer, in nitrogen atmosphere. Triethylamine (0.250 ml, 1.80 mmol), dimethylaminopyridine (16 mg, 0.132 mmol) and tosyl chloride (240 mg 1.26 mmol) are then added in sequence. The reaction proceeds at room temperature; after 16h the reaction mixture is diluted with 25 ml of AcOEt and washed with H₂O (2x10 ml) and a saturated solution of NaCl (1x10 ml). The organic phase is anhydrified with Na₂SO₄, filtered and evaporated under low pressure. The compound of formula (III) is obtained as a brown solid (470 mg, yield 87%), which is used for the next stage without further purification.

1H NMR (300 MHz, CDC1₃): 67.92 (2H, dd, J₀=8.4 Hz, Ar-H), 7.66 (2H, dd, J_o=9.0 Hz, Ar-H), 7.31 (2H, dd, J₀=8.4 Hz, Ar-H), 6.96 (2H, dd, J_o=9.0 Hz, Ar-H), 6.66 (1H, t, J=4.5 Hz, CHCOTs), 3.82 (2H, t, J=6.9 Hz, N-CH₂), 2.65 (2H, dt, J₁₌6.9 Hz, J₂=4.5 Hz CH^HaCHOTs), 2.42 (3H, s, Ar-CH₃).
 

Example 3. Synthesis of a compound of formula (IV): Chloro[(4- methoxyphenyl)hydrazono] acetic acid ethyl ester (IV)

IV p-anisidine (31.02 g, 0.252 mol) in 100 ml of H₂O is suspended in a 250 ml 4-necked flask equipped with coolant, thermometer, dropping funnel and magnetic stirrer, and cooled to 0°C in an ice bath. 60 ml of 37% HC1 is added, followed by a solution of NaNO₂ (20.95 g, 0.307 mol) in 50 ml of H₂O, through a dropping funnel, maintaining the temperature below 5°C. After the addition the mixture is left under stirring at between 0 and 5°C for lh, and the solution obtained is added at 0°C to a solution containing ethyl-2- chloroacetoacetate (41.65 g, 0.254 mol), AcONa (47.84 g, 0.583 mol), AcOEt (200 ml) and H₂O (100 ml). The biphasic system is stirred at between 0 and 5°C for lh, and then at about 25 °C for 16h. The phases are then separated and the organic phase is washed with a saturated solution of NaHCO₃ (4x80 ml), anhydrified on Na₂SO₄, filtered and evaporated under low pressure. The compound of formula (IV) is obtained as a solid (about 57 g), which is used for the next stage without further purification.

1H NMR (300 MHz, CDC1₃): 68.24 (1H, s, N-H), 7.16 (2H, dd, J_o=9.0

Hz, Ar-H),6.88 (2H, dd, J_o=9.0 Hz, Ar-H), 4.37 (2H, q, J=7.2 Hz, COOCH₂CH₃), 3.79 (3H, s, Ar-OCH₃), 1.39 (3H, t, J=7.2 Hz, COOCH₂CH₃).

Example 4. Synthesis of a compound of formula (II): l-(4- methoxyphenyl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-l//- pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester

III IV II

Compound (IV) (0.82 g, 3.19 mmol) is dissolved in 5 ml of AcOEt in a ml 3-necked flask equipped with coolant, thermometer and magnetic stirrer, in nitrogen atmosphere, and cooled to 0° with an ice bath. Compound (III) (1.02 g, 2.63 mmol) and triethylamine (0.89 ml, 6.40 mmol) are added. When the additions have been completed, the reaction is heated to reflux temperature for 3h, after which another portion of compound (IV) (350 mg) and triethylamine (0.25 ml) are added. When compound (III) has completely disappeared, the end-of-reaction mixture is cooled to 0°C, treated with a solution of HC1 (1.80 g of 37% HC1 in 3.20 g of H₂O) and maintained under stirring at room temperature overnight. A solid precipitates, which is filtered through a Buchner funnel and washed with 5 ml of a 1 : 1 solution of AcOEt and isopropanol. The compound of formula (II) is obtained as a solid (0.85 g, yield 63%).

1H NMR (300 MHz, CDC1₃): 67.67 (2H, dd, J₀=8.7 Hz, Ar-H), 7.46 (2H, dd, J_o=9.0 Hz, Ar-H), 7.06 (2H, dd, J_o=9.0 Hz, Ar-H), 6.90 (2H, dd, J_o=9.0 Hz, Ar-H), 4.45 (2H, q, J=7.2 Hz,

4.09 (2H, t, J=6.6 Hz, CH₂(¾N), 3.81 (3H, s, Ar-OCH₃), 3.32 (2H, t, J=6.6 Hz, (¾CH₂N), 1.43 (3H, t, J=7.3 Hz, COOCH₂CH₃).
 

Example 5. Synthesis of a compound of formula (II): l-(4- methoxyphenyl)-6-[4-(2-oxo-piperidinyl)phenyl]-7-oxo-4,5,6,7-tetrahydro- l//-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester

II II

Compound II, prepared as in Example 4 (35.90 g, 69.40 mmol) is suspended in 250 ml of toluene in a 1L 4-necked flask equipped with coolant, thermometer and magnetic stirrer, in nitrogen atmosphere, δ-valerolactam (13.74 g, 138.60 mmol), K₃PO₄ (30.25 g, 142.50 mmol) and Cul (2.54 g, 13.34 mmol) are then added in sequence. The suspension obtained is degassed 3 times at room temperature; N,N'-dimethylethylenediamine (1.65 ml, 26.78 mmol) is then added and the mixture is heated to reflux temperature. After 48 h the end-of-reaction mixture is filtered through a Buchner funnel, and the filter is washed with 200 ml of toluene. The toluene phase is washed with a solution of Na₂S₂O₃ (50 g in 160 ml of H₂O, 2x80 ml), 15% NH₃ (2x80 ml) and a saturated solution of NaCl (1x80 ml). The organic phase is anhydrified on (Na₂SO₄), filtered and evaporated under low pressure. A solid product is obtained (37 g), which is crystallised by AcOEt. After crystallisation the product is obtained as a pure white solid (22.7 g, yield 67%).

1H NMR (300 MHz, DMSO-dtf): 67.47 (2H, dd, J₀=8.7 Hz, Ar-H), 7.32 (2H, dd, J_o=9.0 Hz, Ar-H), 7.28 (2H, dd, J₀=8.7 Hz, Ar-H), 6.90 (2H, dd, J_o=9.0 Hz, Ar-H), 4.32 (2H, q, J=6.9 Hz, COOCEbCH^, 4.06 (2H, t, J=6.6 Hz, CH₂CH₂N), 3.79 (3H, s, Ar-OCH₃), 3.57 (2H, m, N(¾CH₂CH₂CH₂CO) 3.19 (2H, t, J=6.6 Hz, ¾CH₂N), 2.36 (2H, m, NCH₂CH₂CH₂CH₂CO), 1.83 (4H, m, NCH₂CH₂CH₂CH₂CO), 1.31 (3H, t, J=6.9 Hz, COOCH₂CH₃).

CN 103342704 A.........Preparation method of Apixaban as anti-thrombotic drug

http://www.google.com/patents/CN103342704A?cl=en

Publication number	CN103342704 A
Publication type	Application
Application number	CN 201310315775
Publication date	Oct 9, 2013
Filing date	Jul 25, 2013
Priority date	Jul 25, 2013
Inventors	薛吉军, 李毅, 王仕祥, 郑保富, 高强, 徐少军
Applicant	甘肃皓天化学科技有限公司
Export Citation	BiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet

......

cut paste

apixaban as shown in formula I, chemical name: 1- (4-methoxyphenyl) -7_ oxo-6- [4- (2_-oxo-piperidin-1-yl ) phenyl] -1H- _4,5,6,7- tetrahydro-pyrazolo [3,4-c] pyridine-3-carboxamide.

[0003] apixaban, compound Apixaban by Bristol-Myers Squibb and Pfizer jointly developed a new oral direct factor Xa inhibitor, in March 2011 approved the listing in the EU, the trade name Eliquis, clinically used Prevention of adult patients undergoing elective hip or knee replacement surgery venous thromboembolism occurs (VTE). Clinical study results show that, compared with the 40 mg once daily injections of enoxaparin (enoxaparin), twice daily oral administration of a better effect on the prevention of VTE after total hip and total knee arthroplasty appears, and does not increase the risk of bleeding . This product is a no cross-resistance and the advantages of fewer adverse reactions, etc., is expected to become the first-line oral antithrombotic drugs.

[0004] Currently, the preparation of the international literature Apixaban disclosed in the literature are as follows: (1) J.Med.Chem, 2007,50 (22), 5339 - 5356; (2) W02010 / 30983; (3. ) W02003 / 049681; (4) CN101967145

Literature (J.Med.Chem, 2007, 50 (22), 5339 -. 5356) for apixaban discovery process was discussed in detail and gives a pharmaceutical chemical synthesis route, see Formula 2,

Route to iodine aniline and 5-bromo-pentyl chloride as raw materials by amidation - one-pot preparation of the compound 5,5 ring in chloroform and then with phosphorus pentachloride dichloride, condensation in the presence of excess morpholine - elimination reaction give intermediate 6. Then anisidine as starting material after diazotization of 2-chloro acetyl ethyl Japp-Klingmann hydrazone synthesis occurs continuously prepared pyrazole compound 3,3 and intermediate 6 via [3 + 2] cycloaddition co - elimination strategy generating compound 7,7 and δ - valerolactam Ullmann condensation reaction under similar conditions compound 8,8 glycol solution of ammonia in the ammonia solution to obtain the objective product Apixaban. Obviously 7 valerolactam condensation reaction of a low yield of 21% so that the actual application of these route very low value.

[0005] W02010 / 030983, in the same route to prepare the Apixaban, although the 7 δ - valerolactam condensation reaction yield was improved to 29%, but the total yield of only 1.3%.

[0006] World Patent Bristol-Myers Squibb company disclosed in 2003 W02003 / 049681 discloses two Apixaban of synthetic routes. Wherein a route as shown in formula 3:

In line 3 in the formula δ- valerolactam as a raw material under the action of phosphorus pentachloride α- active hydrogen dichloride obtained under the action of the lithium carbonate compound 9,9 elimination of hydrogen chloride to a part 10 and 10 with morpholine to give the compound to a condensation reaction in the presence of triethylamine to form compounds 11 and 11 obtained by reacting compound 3 with compound 5 at 12, 12 and the effect of potassium iodide as a catalyst to give the compound 13, 13 via a coupling reaction with isobutyl chloroformate butyl mixed anhydride formed with excess ammonia ammonia solution and then get Apixaban. The route is only 5.2% total yield, reaction steps tedious, limiting the application of the route.

Another route [0007] has been disclosed as shown in Equation 4:

6 using the intermediate of formula 4 in the cesium carbonate and Cu (PPh3) 3Br and exists δ - valerolactam and 3 by the reaction of 14 and 14 [3 + 2] cyclization - 8,8 elimination reaction to give an excess of sodium methoxide in the presence of Under the action with formamide get Apixaban. Similarly, the total yield of this route is low, the reaction process using a larger amount of auxiliary reagents, limiting the application of the route. [0008] Chinese patent discloses a synthetic route Apixaban CN101967145, as shown in Equation 5:

Formula 5 routes to p-nitroaniline as starting material under alkaline conditions and the 5-chloro-valeryl chloride after amidation - two-step one-pot cyclization reaction to give the compound 16, 16 dichloride, phosphorus pentachloride, and then with an excess of it morpholine condensation - an elimination reaction to give the compound 18, 18 5-chloro-valeryl chloride and amide compounds 17 and 17 is sodium sulfide - a two-step one-pot cyclization reaction after 14, 14 and 3 [3 + 2] cyclization - Elimination of reaction 8, the last aminolysis get Apixaban.

 formula 6:

 

The preparation of compound Apixaban

Compound 24 (0.3 g) was dissolved in 4.5mL of anhydrous tetrahydrofuran was added dropwise 5-bromo-Shu chloride (0.24g) was added triethylamine (0.16g), ice-water cooling. Naturally to room temperature, the reaction was stirred for half an hour, the reaction was quenched with 5mL of water and ethyl acetate (IOmLX 2), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product.

[0041] The crude product was dissolved in a mixed solvent of 2mL of ethanol and 2mL of tetrahydrofuran was added anhydrous magnesium hydroxide (0.47g), the reaction was heated at reflux for 12 hours, concentrated under reduced pressure, to the residue was added 5mL / K, dichloromethane (IOmLX 2), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated to recover the solvent pressure to give the crude product crystallized from ethyl acetate with petroleum ether to give an off-white solid 270mg, 75% yield.

US 8735390...Glaxosmithkline Intellectual Property Development Limited

 6-Chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole

 US8735390
 http://www.google.com/patents/US8735390
Glaxosmithkline Intellectual Property Development Limited

Intermediate 6
6-Chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole

Method A 4-[5-(Bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazole (0.580 g, 1.28 mmol) was dissolved in dichloromethane (5 ml) and (2R,6S)-2,6-dimethylmorpholine (0.317 ml, 2.56 mmol) added. The reaction mixture was stirred at RT for 3 h then the solvent removed under a stream of nitrogen. The resultant yellow solid was dissolved in dichloromethane (5 ml) and washed with water (2×2.5 ml). The layers were separated (hydrophobic frit) and the organic evaporated in vacuo to give the title compound as a pale yellow solid (0.60 g).
LCMS (Method A): Rt 0.86 mins, MH⁺ 487.
¹H NMR (400 MHz, Chloroform-d) δ (ppm) 8.93 (d, J=1.0 Hz, 1 H), 8.33 (dd, J=1.0, 1.5 Hz, 1H), 8.04-8.00 (m, 2 H), 7.98 (d, J=1.5 Hz, 1 H), 7.62 (tt, J=1.5, 7.5 Hz, 1 H), 7.51 (t, J=7.5 Hz, 2 H), 7.15 (s, 1 H), 3.67 (s, 2 H), 3.75-3.66 (m, 2 H), 2.79-2.72 (m, 2 H), 1.86 (dd, J=10.5, 11.0 Hz, 2 H), 1.16 (d, J=6.5 Hz, 6 H).


Method B
(2R,6S)-2,6-dimethylmorpholine (160 ml) and then triethylamine (180 ml) were added to a suspension of 4-[5-(Bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazole (478.1 g) in acetone (3.8 L) stirred under nitrogen at less than 25° C. The reaction mixture was stirred at 20-25° C. for 2.5 hours and then water (3.8 L) was added. The resultant suspension was stirred at than 25° C. for 35 min and was then filtered, washed with a mixture of 2:1 v/v water:acetone (2×1.0 L) and the solid dried under vacuum at 45±5° C. to give the title compound as an off-white solid (500.5 g). LCMS (Method B): Rt 3.43 min, MH⁺ 487.



Method C
All weights, volumes and equivalents are relative to 5-(bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazole (corrected for assay).
To a suspension of 5-(bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazole (1 wt, 540 g) in acetone (8.7 vol, 4.7 L) is added 2,6-dimethylmorpholine (0.33 vol, 1.2 eq, 178 ml), followed by triethylamine (0.37 vol, 1.2 eq, 200 ml) at <25° C. under a nitrogen atmosphere. The resulting mixture is stirred at 20-25° C. for at least 0.5 hr, then monitored for completion by HPLC. Water (8.7 vol, 4.7 L) is then added to the mixture over ca 5 minutes. The resulting suspension is aged at <25° C. for at least 0.5 hr, then the solids are collected by vacuum filtration, washed with water/acetone (2:1 v/v, 2×2.2 vol, 2×1.2 L) and dried in vacuo with a nitrogen bleed at 45±5° C.
Recrystallisation—All weights, volumes and equivalents are relative to ((2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis-2,6-dimethylmorpholine. A stirred suspension of ((2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis-2,6-dimethylmorpholine (1 wt, 30 g) in DMSO (9 vol, 270 ml) is heated to 75-80° C. under a nitrogen atmosphere. The resulting clear solution is transferred to a crystallising vessel via a 5 μm Domnick hunter in line filter, then the line is washed with further DMSO (1.0 vol, 30 ml). The hot solution is allowed to cool to 20-25° C. over at least 2 hr, then the resulting suspension is aged at this temperature for at least 1 hr. The resulting solids are filtered, washed with DMSO (1.5 vol, 45 ml), followed by water/acetone (2:1 v/v, 2×2 vol, 2×60 ml) before being sucked dry for 0.5 hr. The batch is dried in vacuo at 45° C. to constant probe temperature to afford ((2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis-2,6-dimethylmorpholine as an off-white solid.

 

GLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT LTD

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  GLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT LIMITED

  
  

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GSK WO2011025799

http://www.google.com/patents/WO2011025799A1?cl=en


Example 72
7V-[(3S)-l-(3-cyano-4'-fluoro-4-biphenylyl)-3-pyrrolidinyl]-L-prolinami(ie
hydrochloride

A solution of 1,1-dimethylethyl (25)-2-({[(35)-l-(3-cyano-4'-fluoro-4-biphenylyl)- 3-pyrrolidinyl]amino}carbonyl)-l-pyrrolidinecarboxylate (72 mg, 0.150 mmol) in HCl (4 M solution in 1,4-dioxane, 0.50 mL, 2.00 mmol) was stirred at RT for 1 h 25 min. The reaction mixture was diluted with Et₂O (2 mL), and the resultant precipitate was filtered through a plug of cotton and washed with Et₂O (1 mL). The solid was dissolved in MeOH and concentrated under a stream of nitrogen at 50 ⁰C. Water (2 mL) was added and the mixture was lyophilized with a Genevac^® HT-4X to afford the title compound (48 mg, 77%). LC-MS m/z 379 (M+H)⁺, 0.95 min (ret time).














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WO 2011019801

http://www.google.im/patents/WO2011019801A1?cl=en
Intermediate 2
1,1-dimethylethyl [(15)-l-formyl-3-phenylpropyl] carbamate

To a solution of 1,1-dimethylethyl ((15)-l-{[methyl(methyloxy)amino]carbonyl}-3- phenylpropyl)carbamate (86.0 g, 0.266 mol) in THF (600 mL) at 0 ⁰C was added LiAlH₄ (13.17 g, 0.347 mol). The reaction mixture was stirred at 0 ⁰C for 1 h, quenched with Na₂SO₄-IO H₂O (40.0 g in 600 mL of water), and stirred for an additional 2 h. The reaction mixture was diluted with Et₂O (200 mL) and the layers were separated. The aqueous layer was extracted with Et₂O (3 x 200 mL). The combined organic layers were washed with 1 M aq. HCl (2 x 100 mL), saturated aq. NaHCO₃ (2 x 100 mL), and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound (60 g, 86%), which was carried to the next step without further purification. ¹H NMR (400 MHz, DMSO-J₆) δ ppm 9.55 (s, IH), 7.30 - 7.18 (m, 5H), 5.08 (d, 2H), 4.25 (m, IH), 2.71 (m, IH), 2.24 (m, IH), 1.84 (m, IH), 1.46 (s, 9H).