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Revaprazan hydrochloride
Molecular formula: C22H23FN4 =362.5.
Reversible H+/K+-ATPase Inhibitors
CAS: 199463-33-7FREE BASE . CAS 178307-42-1
UNII code: 5P184180P5.
SB-641257A
YH-1885
N-(4-Fluorophenyl)-4,5-dimethyl-6-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidin-2-amine hydrochloride
N-[4,5-Dimethyl-6-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidin-2-yl]-N-(4-fluorophenyl)amine hydrochloride
5,6-dimethyl-2-(4-fluorophenyl¬ amino)-4-(1-methyl-l,2,3,4-tetrahvdroisoquinolin-2-yl)- pyrimidine hydrochloride
INTRO
Revaprazan hydrochloride, a reversible proton pump inhibitor with long-lasting acid-suppressive effects, was first launched in Korea in 2005 by Yuhan for the treatment of duodenal ulcer, gastric ulcer and gastritis. The compound is also undergoing phase II clinical studies for the treatment of of Non-erosive Reflux Disease (NERD).
Discovered by Yuhan, revaprazan hydrochloride was licensed to GlaxoSmithKline (GSK) in 2000 for worldwide development and commercialization except in South and North Korea.
Revaprazan, whose chemical name is 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine, is represented by the following Formula 1. Revaprazan can be used in a form of an acid addition salt, including e.g., HCl salt (see International Publication No. WO1996/05177, WO1997/042186, and WO1998/018784).
Formula 1
Revaprazan or its salt is reversibly bound to a H+/K+ exchange site of a proton pump (H+/K+ ATPase) existing in a gastric parietal cell so that secretion of H+ into the gastric lumen is competitively inhibited. Revaprazan or its salt is also bound to a specific site of H+/K+ ATPase, thereby inhibiting transport of H+ and suppressing an acid secretion to the gastric lumen, which results in increasing the intragastric pH. Unlike irreversible proton pump inhibitors, e.g., omeprazole, revaprazan or its salt is not dependent upon acid activation of a drug in a stomach or secretion status of a proton pump. Therefore, based on the mechanism different from irreversible proton pump inhibitors, such as omeprazole, revaprazan or its salt is classified into an acid pump antagonist (APA).
Revaprazan has very low water-solubility, i.e. less than 0.2 mg/mL, and even lower solubility in a buffer solution having pH 1 to 12. And also, revaprazan has very low intrinsic dissolution rate, i.e., about 0.0086 mg/min/cm2. Due to such a low solubility and intrinsic dissolution rate, its dissolution in the gastrointestinal tract is also very low. Therefore, when revaprazan is orally administered, its absorption rate is relatively low. Revaprazan also has strong adhesion and agglutination properties, and thus, when revaprazan is formulated into a capsule or a tablet, it may be stuck to a punch or a die, thereby showing low formulation processability. In order to address these problems, WO 2008/078922 has disclosed a pharmaceutical composition for oral administration comprising a solid dispersion in which revaprazan particles are surface-modified with a water-soluble polymer, a water-soluble saccharide, a surfactant, or a mixture thereof.
WO-2014060908 patent………. Improved process for preparation of revaprazan hydrochloride comprising reacting 1-methyl-1,2,3,4-tetrahydroisoquinoline with 4-halide-2-(4-flurophenylamino)-5,6-dimethylpyrimidine in the presence of a transfer catalyst (eg tetra butyl ammonium bromide), solvent (eg methyl isobutyl ketone) and treated with HCl. Also claims purification and crystallization of the API. Appears to be the first filing from the Lupin on this API. Family members of the product case, WO9605177 (assigned to Yuhan Corp, Yuhan Corporation ), expire in August 2015
Chlorination of 5,6-dimethyl-2,4-dihydroxypyrimidine (VIII) using phosphorus oxychloride in the presence of N,N-dimethylaniline provided dichloropyrimidine (IX). The 4-chloro group of (IX) was then selectively displaced with tetrahydroisoquinoline (IV) to afford adduct (X). The title compound was then obtained by condensation of the 2-chloropyrimidine (X) with 4-fluoroaniline (XI), followed by conversion to the corresponding hydrochloride salt
In a different method, amine (I) was alkylated with 2-bromoethanol (V) to give the N-(hydroxyethyl) amine (VI), which was further converted to bromo amine (VII) by treatment with concentrated HBr. Friedel-Crafts cyclization of (VII) upon heating in the presence of AlCl3 furnished tetrahydroisoquinoline (IV).
………….
The intermediate tetrahydroisoquinoline (IV) has been prepared by two synthetic strategies. Condensation of alpha-methyl benzylamine (I) with alpha-chloro-alpha-(methylsulfanyl)acetyl chloride (II) in the presence of SnCl2 furnished the tetrahydroisoquinolinone (III). Reductive cleavage of the methylsulfanyl group of (III) employing Raney-Ni, followed by lactam reduction, provided intermediate (IV).
In a different method, cetylation of phenethylamine (XVI) with acetyl chloride (XVII) by means of Et3N in dichloromethane provides N-(2-phenylethyl)acetamide (XVIII), which is cyclized with hot polyphosphoric acid to afford 1-methyl-3,4-dihydroisoquinoline (XIX). Finally, compound (XIX) is reduced with sodium borohydride in EtOH.
In an alternative procedure, 4-fluoroaniline (XI) was condensed with cyanamide under acidic conditions to afford the fluorophenyl guanidine (XII). Cyclization of guanidine (XII) with ethyl 2-methylacetoacetate (XIII) in hot DMF produced pyrimidine (XIV). After chlorination of (XIV) with POCl3, the resultant chloropyrimidine (XV) was condensed with tetrahydroisoquinoline (IV) in the presence of either KOAc or Et3N to furnish the title diaminopyrimidine.
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WO1996005177
http://www.google.com/patents/WO1996005177A1?cl=en
Example 15: Synthesis of 5,6-dimethyl-2-(4-fluorophenyl¬ amino)-4-(1-methyl-l,2,3,4-tetrahvdroisoquinolin-2-yl)- pyrimidine hydrochloride
After 4-fluoroaniline(l.0ml, lOmmol) waε added to a mixture εolution of 5,6-dimethyl-4-(1-methyl-l,2,3,4- tetrahydroiεoquinolin-2-yl )-2-chloropyrimidine( 1.4g, 4.8mmol) and dimethylformamide(10ml) , 1.32g of the title compound waε obtained in accordance with the εame procedure as in Step 2 of Example 1. Yield: 69% M.P.: 205-208°C 1H-NMR(DMSO-d6) : δ 1.58(d, 3H), 2.17(s, 3H), 2.36(s, 3H), 2.89(bd, IH), 3.08(m, IH), 3.59(m, IH), 4.19(bd, IH), 5.38(q, IH), 7.34(m, 6H), 7.60(m, 2H), 10.40(s, IH). Example 16: Synthesis of (R)-5,6-dimethyl-2-(4-fluorophenyl¬ amino)-4-(1-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)- pyrimidine hydrochloride
After 4-fluoroaniline(lml, lOmmol) was added to a mixture solution of (R)-5,6-dimethyl-4-(1-methyl-l,2,3,4- tetrahydroiεoquinolin-2-yl )-2-chloropyrimidine(1.4g, 4.8mmol) and dimethylformamide(10ml) , 1.20g of the titled compound waε obtained in accordance with the εame procedure as in Step 2 of Example 1. Yield: 62.7% M.P.: 205-207°C
1H-NMR(DMSO-d6) : δ 1.58(d, 3H), 2.17(s, 3H), 2.36(s, 3H), 2.89(bd, IH), 3.08(m, IH), 3.59(m, IH), 4.19(bd, IH), 5.38(q, IH), 7.34(m, 6H), 7.60(m, 2H), 10.40(s, IH) .
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http://www.google.com/patents/EP0900214A1?cl=en
5,6-Dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetra- hydroisoquinolin-2-yl)pyrimidine of the above formula (I) inhibits gastric acid secretion by means of a reversible proton-pump inhibiting effect and, therefore, can be used as an anti -ulcer agent. This compound was developed by the inventors of the present invention, who then applied for patents for the compound and/or its method of preparation in Korea and other countries (see International Publication No. WO 96/05177).
According to the method disclosed in the above patent application, 5,6-dimethyl-2-(4-f luoropheny lamino) -4- ( 1 -methyl- 1, 2,3,4 -tetrahydroisoq uinolin-2-yl)pyrimidine is prepared according to the following reaction scheme A:
Reaction scheme A
Since the starting material of the above reaction scheme has two reactive sites (i.e., the two CI atoms), the first reaction inevitably produces a side product, which reduces the yield of the desired compound.
The present inventors have long labored to develop a novel method for preparing 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine of formula (I) without producing side products. As a result, we have discovered that the desired compound of formula (I) can be efficiently prepared without side products by reacting the pyrimidine derivative represented by formula (LI-A) with l-methyl-l,2,3,4-tetrahydroisoquinoline represented by formula (III) and, thus, have completed the present invention.
DISCLOSURE OF THE INVENTION
The present invention relates to a novel process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroiso- quinolin-2-yl)pyrimidine represented by formula (I) and its acid addition salts.
More specifically, the present invention relates to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4- tetrahydroisoquinolin-2-yl)pyrimidine represented by formula (I),
and its acid addition salts wherein a pyrimidine derivative represented by the following formula (II-A),
in which Hal represents a halogen, is reacted with 1 -methyl- 1,2,3,4 – tetrahydroisoquinoline represented by formula (HI),
In addition, the present invention relates to a process for preparation of the pyrimidine derivative of formula (II-A) and the compound of formula (HI). Further, the present invention relates to a novel intermediate compound represented by the following formula (LI), which includes the pyrimidine derivative represented by formula (II-A),
in which R represents hydroxy or a halogen.
BEST MODE FOR CARRYING OUT THE INVENTION
According to the present invention, the compound of formula (I) can be prepared by reacting the compound of formula (LI-A) with 1 -methyl -1,2,3,4-tetrahydroisoquinoline of formula (IT), as depicted in the following reaction scheme 1:
Reaction scheme 1
ω
Since the starting compound of the reaction scheme 1 (i.e., the compound of formula (II-A)) contains a single reactive site (i.e., Hal), this reaction scheme does not produce any side product and, thus, optimizes the yield of the compound of formula (I), the desired product.
The present invention is described in more detail below. Although the 4-halogeno-2-(4-fluorophenylamino)-5,6-dimethyl- pyrimidine represented by formula (II-A) can be reacted according to the present invention with an equivalent amount of 1 -methyl- 1,2,3,4-tetra- hydroisoquinoline represented by formula (HI), it is preferable to conduct the reaction using an excess, rather than an equivalent amount, of the latter. Since the latter is a liquid under reaction conditions, the unreacted l-methyl-l,2,3,4-tetrahydroisoquinoline can be readily removed after the reaction has gone to completion.
Preparation of 5.6-dimethyl-2-(4-fluorophenylaminn)-4-(l-methyl- lr2.3.4-tetrahvdroisoαuinolin-2-yl)pyrimidine and its hydrochloride
In Examples 14 to 20, inclusive, l-methyl-l,2,3,4-tetrahydroiso- quinoline prepared according to the method disclosed in International 0 Publication No. WO 94/14795 was used as the reactant.
Example 14
2.65g(27 mmole) of potassium acetate and 4.0g(26.9 mmole) of 5 1-methyl -1,2,3,4-tetrahydroisoquinoline were added to 85ml of n-hexanol and then warmed to 80 °C. 6.17g(24.5 mmole) of 4-chloro-2-(4-fluoro- pheny lamino) -5,6 -dimethy Ipyrimidine was added thereto and then reacted at 140 °C for 28 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluo- rophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. 0
The reaction solution was cooled to room temperature, diluted with 20ml of acetone and then added dropwise to 120ml of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 30ml of water, dissolved in 150ml of dichloromethane 5 and then washed successively with 20ml of 4N-HC1, 20ml of water and then 20ml of 4N-sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with 100ml of ethanol. To this reaction solution was added 30g of cone, hydrochloric acid, and the 0 mixture thereby obtained was stirred for 5 hours. The resulting solid product was filtered, washed with 20ml of ethanol and then dried to obtain 6.1g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l- methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)ρyrimidine hydrochloride.
S5 Yield : 62.4% m.p. : 255*0
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 211), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
Examnle 15
8.12g(11.2ml, 80.3 mmole) of triethylamine, 30ml of n-butanol and 6.58g(44.1 mmole) of 1-methyl- 1,2,3,4-tetrahydroisoquinoline were added to 40ml of ethylene glycol. 10.1g(40.1 mmole) of 4-chloro-2-(4-fluoro- phenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 130 °C for 30 hours under refluxing to prepare 5,6-dimethyl-2-(4- f luorophenylamino )- 4 -( 1 – methyl – 1 ,2,3,4 – tetrahydroisoquinolin- 2 – yl ) -pyri – midine. This product was treated according to the procedure detailed in Example 14 to obtain 14.7g of purified 5,6-dimethyl-2-(4-f luorophenyl – amino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydro¬ chloride.
Yield : 91% m.p. : 256*0
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
III), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
F/xatnple 1β
45ml of triethylamine, 50ml of n-butanol and 32g(217 mmole) of l-methyl-l,2,3,4-tetrahydroisoquinoline were added to 150ml of ethylene glycol. 51.3g(203.8 mmole) of 4-chloro-2-(4-f luorophenylamino) -5,6- dimethy Ipyrimidine was added thereto and then reacted at 135 °C for 28 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)- 4- (1-methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 66g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2, 3,4-tetrahydroiso-quinolin-2-yl)pyrimidine hydrochloride.
Yield : 81.1% > m.p. : 256*0
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 311), 2.84(m,
III), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, IH), 13.43(bs, IH) 0
75ml of triethylamine and 65g(442 mmole) of 1-methyl- 1,2,3,4- tetrahydroisoquinoline were added to 100ml of 1,2 -propylene glycol. 5 100.9g(0.40 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dime- thy Ipyrimidine was added thereto and then reacted at 120 °C for 64 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l- methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 91g 0 of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4- tetrahy droi soquinolin – 2 – y 1 )py rimidine hydrochloride.
Yield : 57.1% m.ρ. : 258°C 5 NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
0 Fvample 18
720ml of triethylamine and 695g(4.72 mmole) of l-methyl-1,2,3,4- tetrahydroisoquinoline were added to 2100ml of 1,2-propylene glycol.
1179g(4.68 mmole) of 4-chloro-2-(4-f luorophenylamino) -5,6-dimethyl-
35 pyrimidine was added thereto and the mixture thereby obtained was reacted at 130°C for 58 hours to prepare 5,6-dimethyl-2-(4-fluorophenyl- amino ) – 4 – ( 1 – methyl – 1 ,2,3,4 – tetrahydroisoquinolin – 2 – y 1 )pyrimidine . Thi s product was treated according to the procedure detailed in Example 14 to obtain 1250g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l- methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 66.9% m.p. : 258*0
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH),
5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
Example 19
110ml of n-butanol, 240ml of triethylamine and 236g(1.60 mmole) of 1-methyl- 1,2,3,4-tetrahydroisoquinoline were added to 600ml of ethylene glycol. 400g(1.59 mmole) of 4-chloro-2-(4-fluorophenyl- amino)-5,6-dimethylpyrimidine was added thereto and then reacted at 140 °C for 48 hours to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4- ( 1 -methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 485g of purified 5,6-dimethyl-2- (4-f luorophenylamino) -4- (1 -methyl – l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 76.5% m.p. : 257 °C
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33
(s, IH), 13.43(bs, IH)
Example 20
240ml of triethylamine and 9.7g(65.8 mmole) of 1-methyl- 1,2,3,4- tetrahydroisoquinoline were added to 25ml of 1,2-propylene glycol. Then, 15g(51 mmole) of 4-bromo-2-(4-fluorophenylamino)-5,6- dimethyl- pyrimidine was added thereto and the mixture thereby obtained was reacted at 110°C for 28 hours. The resulting product was treated according to the procedure detailed in Example 14 to obtain 15.86g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetra- hydroisoquinolin-yDpyrimidine hydrochloride.
Yield : 78% m.p. : 257 °C
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 311), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 211), 10.33 (s, IH), 13.43(bs, IH)
Example 21
8.12g(11.2ml, 80.3 mmole) of triethylamine, 30ml of n-butanol and 6.58g(44.1 mmole) of 1-methyl- 1,2,3,4-tetrahydroisoquinoline as prepared in Example 5 were added to 40ml of ethylene glycol. 10.1g(40.1 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 130 °C for 30 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-( 1-methyl- 1, 2,3,4 -tetra- hydroisoquinolin-2-yl)pyrimidine.
The reaction solution was cooled to room temperature, diluted with 30ml of acetone and then added dropwise to 200ml of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60ml of water, dissolved in 250ml of dichloromethane and washed successively first with 35ml of 4N-HC1, 35ml of water and then with 40ml of 4N- sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with 200ml of ethanol. To this reaction solution was added 45g of concentrated hydrochloric acid, and the mixture was stirred for 5 hours. The resulting solid product was filtered, washed with 30ml of ethanol and then dried to obtain 9.82g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetra- hydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 66.53% m.p. : 255 °C
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
Example 22
75ml of triethylamine and 65g(442 mmole) of l-methyl-1,2,3,4- tetrahydroisoquinoline as prepared in Example 7 were added to 100ml of 1,2-propylene glycol. 100.9g(0.40 mmole) of 4-chloro-2-(4-fluoro- phenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 120*0 for 64 hours to prepare 5,6-dimethyl-2-(4-fluorophenylamino)- 4- (1-methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 21 to obtain 95.1g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 59.67% m.p. : 258 °C
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21 (s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
Example 23
14ml of triethylamine and 9.7g(65.8 mmole) of 1-methyl- 1,2,3,4- tetrahydroisoquinoline as prepared in Example 7 were added to 25ml of 1,2-propylene glycol. 15g(51 mmole) of 4-bromo-2-(4-fluorophenyl- amino) -5,6 -dimethy Ipyrimidine was added thereto and then reacted at 120 °C for 28 hours to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l- methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 21 to obtain 14.9g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4- tetr ahy droisoquinolin – 2 – y 1 ) pyrimidine hydrochloride.
Yield : 73.28% m.p. : 257*0 NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
Example 24
8.12g(11.2ml, 80.3 mmole) of triethylamine, 30ml of n-butanol and 6.58g(44.1 mmole) of (R)-(+)-l-methyl-l,2,3,4-tetxahydroisoquinoline as prepared in Example 9 were added to 40ml of ethylene glycol. 10. Ig (40.1 mmole) of 4-chloro-2-(4-f luorophenylamino) -5,6-dimetlιylpyrimidine was added thereto and then reacted at 130 °C for 30 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4- tetrahy droisoquinolin- 2 – y 1 ) pyrimidine.
The reaction solution was cooled to room temperature, diluted with
30ml of acetone and then added dropwise to 200ml of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60ml of water, dissolved in 250ml of dichloromethane arid then washed successively with 35ml of 4N-HC1, 35ml of water and then 40ml of 4N-sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with 200ml of ethanol. To this reaction solution was added 45g of cone, hydrochloric acid, and the resulting mixture was stirred for 5 hours. The resulting solid product was filtered, washed with 30ml of ethanol and then dried to obtain 9.21g of purified (R)-(+)-5,6-dimethyl-2-(4-fluorophenylamino)-4-(l- methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 62.4% m.p. : 255 °C
[ a h20 : +250° (c=l, in CHC13)
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
Example 25
23ml of triethylamine and 16g(108.5 mmole) of (R)-(+)-l-methyl- 1,2,3,4-tetrahydroisoquinoline as prepared in Example 10 were added to 75ml of ethylene glycol. 25.7g(101.8 mmole) of 4-chloro-2-(4-fluoro- phenylamino)-5,6-dimethylpyrimidine was added thereto and the mixture thereby obtained was reacted at 135 °C for 28 hours under refluxing to prepare (R)-(+)-5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl- 1,2,3, 4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 24 to obtain 33g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-( 1-methyl- 1,2,3,4-tetra- hydroisoquinolin-2-yl)-pyrimidine hydrochloride.
Yield : 81.1% m.p. : 257 °C
I a h20 ■ +250° (c=l, in CHCI3)
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33
(s, IH), 13.43(bs, IH)
Example 2β
14ml of triethylamine and 9.7g(65.8 mmole) of (R)-(+)-l-methyl- 1,2,3,4-tetrahydroisoquinoline as prepared in Example 10 were added to 25ml of 1,2-propylene glycol. 15g(51 mmole) of 4-bromo-2-(4-fluoro- phenylamino)-5,6-dimethylpyrimidine was added thereto and the mixture thereby obtained was reacted at 120 °C for 28 hours. The reaction product was thentreated according to the procedure detailed in Example 24 to obtain 16.2g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4- ( 1 – methyl – 1 ,2,3,4 – tetrahy droisoquinolin – 2 – y 1 )py rimidine hydrochloride.
Yield : 79.97% m.p. : 257 °C
[ a h20 : +250° (c=l, in CHC13)
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33(s, IH), 13.43(bs, IH)……….SDEE PATENT
………………………………..
http://www.google.com/patents/CN102863423A?cl=en
the formula I 5,6 _ ni-2 – (4 – fluorophenyl amino) -4 – (1 – methyl-1, 2,3,4 tetrahydro-isoquinolin-2 _ – yl) pyrimidine and its hydrochloride salt is a kind of reversible proton pump inhibitors ー having novel and unique mechanism of action of potassium competitive acid pump inhibitor to acid inhibition stronger, faster onset smaller side, the Short-term treatment of gastritis, duodenal ulcer, gastric ulcer and gastroesophageal reflux has certain advantages.
[0003]
[0004] CN95194599. 8 for the first time disclosed the compound and its preparation method, CN97194367. 2 discloses the compound to another ー preparation methods.
[0005] CN95194599. 8 discloses prepared as follows:
[0006]
[0007]
[0008] 2,4 – chloro-5 ,6 ni – ni methylpyrimidine with two chlorine in the preparation, to be equivalent to twice the substrate in the reaction of phosphorus oxychloride; the two chlorine atoms, or two a reactive centers, and I-methyl-1, 2,3,4 – tetrahydroisoquinoline reaction inch, will inevitably produce structurally similar by-products affecting the yield of the reaction, while the reaction Refined product difficult.
[0009] The CN97194367. 2 Public Preparation: [0010]
[0011] 1_ methyl-1, 3,4 – four oxyiso Thrill Lynn is by I-methyl -3,4-_ ■ oxyiso obtained by the reduction of noise Lynn, there is not sufficient to restore the problem, raw materials and products of similar structure, easy separation and purification. Prepared by this method to obtain an I-methyl-1, 2,3,4 – tetrahydroisoquinoline is often close to tan a brown liquid, and I-methyl-1, 2,3,4 – tetrahydro- isoquinoline is ー secondary amines, placed in contact with air at room temperature, long time ー easy oxidative deterioration, become darker in color, is not conducive to storage.
More particularly, the present invention relates to formula I is 5,6 _ ni-2 – (4 – fluorophenyl amino) -4 – (1 – methyl-1 ,2,3,4 – Four Hydrogen isoquinolin-2 – yl) pyrimidine and its hydrochloride salt thereof. In the method, represented by formula III 5,6 – ni methyl -2 – (4 – fluorophenyl amino) pyrimidine represented by formula II and I-methyl-3 ,4 – ni isoquinoline hydrogen, to give a quaternary ammonium salt represented by formula IV.
[0014]
Then borohydride reduction obtained with high purity 5,6 – ni methyl -2 – (4 – fluorophenyl-amino) -4 – α-methyl-1, 2,3,4 – tetrahydro- isoquinolin-2 – yl) pyrimidine and its hydrochloride.
reaction scheme is as follows:
Example I
I-methyl-3 ,4 – ni hydrogen isoquinoline 20g, 5,6 – ni methyl -2 – (4 – fluorophenyl-amino) pyrimidine 28.8g, in 200mL of dry toluene, loading a stirrer, a thermometer, a reflux condenser, drying tube reaction flask under nitrogen, heated to reflux, began to produce turbidity, the reaction 30h. Filtration, washed with anhydrous ether ko. Solid rapidly dissolved with anhydrous ko alcohol 200mL, graded by adding NaBH44. 8g, plus complete, continue stirring at room temperature lh. The solvent was distilled off under reduced pressure, the residue was added water, 200mL, concentrated aqueous ammonia was adjusted to pH> 10, ni chloride extract was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and then dissolved in acetone, which leads to dry HCl gas, a solid precipitated. Filtered and the solid was dissolved with anhydrous alcohol ko, active carbon, filtered, frozen crystallization to give a white powder 29. 2g, yield 63.9%.
Example 2
I-methyl-3 ,4 – ni hydrogen isoquinoline 15g, 5,6 – ni methyl -2 – (4 – fluorophenyl amino) Li Jie secret 21. 6g, in 150mL of dry toluene , flask equipped with stirrer, thermometer, reflux condenser, drying tube reaction flask under nitrogen, heated to reflux, began to produce turbidity, the reaction 24h. Filtration, washed with anhydrous ether ko. Solid rapidly dissolved with anhydrous ko alcohol 150mL, graded by adding NaBH43. 6g, plus complete, continue stirring at room temperature lh. The solvent was distilled off under reduced pressure, the residue was added water, 150mL, concentrated aqueous ammonia was adjusted to pH> 10, ni chloride extract was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and then dissolved in acetone, which leads to dry HCl gas, a solid precipitated. Filtered and the solid was dissolved with anhydrous alcohol ko, active carbon, filtered, frozen crystallization to give a white powder 21. 9g, yield 64. I%.
| W. LI ET AL.: ‘Preparation and in vitro/in vivo evaluation of ravaprazan hydrochloride nanosuspension‘ INTERNATIONAL JOURNAL OF PHARMACEUTICS vol. 408, 02 February 2011, pages 157 – 162 |
| WO1996005177A1 * | Aug 10, 1995 | Feb 22, 1996 | Jeong Seok Chae | Novel pyrimidine derivatives and processes for the preparation thereof |
| WO2007064128A1 * | Nov 28, 2006 | Jun 7, 2007 | Ki-Baik Hahm | Composition for preventing or treating damages of the mucosa in the gastrointestinal tracts |
| WO2008078922A1 * | Dec 21, 2007 | Jul 3, 2008 | Yuhan Corp | Revaprazan-containing solid dispersion and process for the preparation thereof |
Vertex Pharmaceuticals: Another FDA Orphan Drug Designation For Cystic Fibrosis
| FDA Orphan Drug Designation Database Record | |
| Generic Name: | (R)-1-(2,2-difluorobenzo [d][1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl) cyclopropanecarboxamide |
| Trade Name: | n/a |
| Date Designated: | 04-24-2014 |
| Orphan Designation: | Treatment of cystic fibrosis |
| Orphan Designation Status: | Designated |
| FDA Orphan Approval Status: | Not FDA Approved for Orphan Indication |
| Sponsor: | Vertex Pharmaceuticals Inc. 50 Northern Avenue Boston, MA 02210-1862 The sponsor address listed is the last reported by the sponsor to OOPD. |
.
VX-661 is a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) corrector. VX-661 is being studied in combination with Kalydeco (Ivacaftor) for patients who have the F508del mutation. VX-661 is currently recruiting participants for a Phase II clinical trial to evaluate the safety and efficacy of VX-661 in combination with Kalydeco in subjects with CF who are homozygous (have 2 copies) for the F508del CFTR…
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Radiation therapy to treat uterine cancer linked with increased risk of bladder cancer later in life
Radiation therapy used to treat uterine cancer may increase a patient’s risk of developing bladder cancer. That is the conclusion of a recent study published in BJU International. The findings indicate the importance of monitoring patients for potential signs of bladder cancer to ensure early diagnosis and treatment.
In the United States, uterine cancer is the fourth most common cancer in women, with an estimated 49,560 women diagnosed in 2013. In addition to surgery, 38 percent ofpatients undergo pelvic radiation therapy to decrease uterine cancer recurrence. Studies have found that women treated with radiation therapy for uterine cancer, like men who received radiation therapy for prostate cancer, have an increased risk of developing bladder cancer later in life.
To investigate the issue, Guan Wu, MD, PhD, of the University of Rochester Medical Center, and his colleagues analyzed the records of 56,681 patients diagnosed with uterine cancer as their…
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ANTHONYFLOZIN………Find one if you can in this review
find here
http://medcheminternational.blogspot.in/p/flozin-series.html
1 TOFOGLIFLOZIN
2 SERGLIFLOZIN
3 DAPAGLIFLOZIN
4 IPRAGLIFLOZIN
5 EMPAGLIFLOZIN
6 LUSEOGLIFLOZIN
7 REMOGLIFLOZIN
8 ERTUGLIFLOZIN
9 SOTAGLIFLOZON
DR ANTHONY
BLOGS………
Fibroblasts could offer alternative to heart transplants
Cardiac fibroblasts
Fibroblasts, cells long thought to be boring and irrelevant, could offer an alternative to heart transplants for patients with heart disease. Researcher Dr Milena Furtado, and her team from the Australian Regenerative Medicine Institute (ARMI) at Monash University, found the heart cell fibroblast is a close relative to a cardiomyocyte, the cell responsible for a healthy beating heart.
In research published today in Circulation Research, Dr Furtado has found that cardiac fibroblasts are unique cells due to their genetic program, and will aid in the development of cell therapies for congenital heart disease and heart failure.
“Heart disease is still one of the major killers in our society and so far no effective therapeutic options are available. Our laboratory aims to understand how the various cell types present in a heart can improve the outcome of heart failure,’ Dr Furtado said.
“Fibroblasts were thought to act as…
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ALK Inhibitor CEP-28122
CAS: 1022958-60-6
Chemical Formula: C28H35ClN6O3
Molecular Weight: 539.06890
Elemental Analysis: C, 62.39; H, 6.54; Cl, 6.58; N, 15.59; O, 8.90
Various ALK inhibitors have been reported, such as indazoloisoquinolines (WO 2005/009389), thiazole amides and oxazole amides (WO 2005/097765), pyrrolopyrimidines (WO 2005080393), and pyrimidinediamines (WO 2005/016894).
WO 2008/051547 discloses fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors. The lead drug candidate disclosed in the ‘547 application is CEP-28122, a potent ALK inhibitor with oral efficacy against SUP-M2 and Karpas-299 ALK-dependent tumors in mouse xenograft models. CEP-28122 progressed to IND- enabling studies until its development was terminated due to the unexpected occurrence of severe lung toxicity in CEP-28122-treated monke s.
CEP-28122
Example 1047: (lS,2S,3R,4R)-3-[5-Chloro-2-(3-methoxy-7-moφholin-4-yl-6,7,8,9- tetrahydro-5H-benzocyclohepten-2-ylarnino)-pyrimidin-4-ylamino]- bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Single Diasteromer A) 1047a) (2-Hydroxymethyl-4-methoxy-phenyl)-methanol To a stirred suspension of Lithium tetrahydroaluminate (16.6 g, 0.436 mol) in Tetrahydrofuran (300 mL, 4 mol) at 0 °C under nitrogen was added dropwise a solution of 4-Methoxy-phthalic acid dimethyl ester (24.46 g, 0.1091 mol) in Tetrahydrofuran (100 mL, 1 mol). The reaction was stirred at 0 °C for 1 h then warmed to room temperature overnight. HPLC indicated no starting material present. Reaction was recooled at 0 °C and quenched with addition of water (125 mL) carefully dropwise, 1 N NaOH (100 mL) and water (125 mL). Evolution of gas was observed upon initial quenching with water. A white solid precipitated out of solution (aluminum salts). Following complete quenching of the reaction mixture, the aluminum salts were removed by filtration. The filtrate was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 17.80 grams (97%) of (2-Hydroxvmethyl-4-methoxy- phenyl)-methanol as a colorless oil.
1047b) 1 ,2-Bis-bromomethyl-4-methoxy-benzene
Using the procedure outlined in J. Am. Chem. Soc. 1994, 116, 10593 – 10600, (2-
Hydroxymethyl-4-methoxy-phenyl)-methanol (17.80 g, 0.1058 mol) was dissolved in
Chloroform (200 mL, 2 mol) and the reaction was treated with Phosphorus tribromide (60.2 g, 0.222 mol) dropwise over 6 hours. After stirring overnight at room temperature, the mixture was cooled at 0 °C and was treated with 50 mL of water. The reaction mixture was poured over saturated sodium bicarbonate, and organics were extracted with dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The product, 16.0 grams (51%), was used without further purification.
1047c) 2-Methoxy-7-oxo-6,7,8,9-tetrahydro-5H-benzocycloh eptene-6,8-dicarboxylic acid diethyl ester
From an adapted procedure in Helvetic Chimica Acta, 2001, 84, 2051-2063, to a stirred solution of Tetra-n-butyl ammonium iodide (12.1 g, 0.0326 mol) in 0.6 M of Sodium bicarbonate in Water (300 mL) and Methylene chloride (130 mL, 2.1 mol) was added a solution of 1 ,2-Bis-bromomethyl-4-methoxy-benzene (16.00 g, 0.05442 mol) and 3- Oxopentanedioic acid, diethyl ester (14.31 g, 0.07075 mol) in Methylene chloride (40 mL, 0.6 mol). The solution was stirred vigorously at room temperature for -20 h. Saturated ammonium chloride solution was added to the reaction mixture. The product was extracted with ethyl acetate (3 X 100 mL). The ethyl acetate extracts were washed with water and brine, then dried over magnesium sulfate, filtered and concentrated in vacuo to a yellow oil. The oil was triturated with ether and a precipitate crashed out of solution and was removed by filtration (tetrabutyl ammonium salts). The filtrate was concentrated to an oil (20.0 grams, 100%) that was carried on to the next step without further purification. 1047d) 2-Methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one
2-Methoxy-7-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6,8-dicarboxylic acid diethyl ester (18.2 g, 0.0544 mol) was dissolved in ethanol and the solution was treated with Potassium hydroxide (24.4 g, 0.435 mol) in Water (14O g, 7.6 mol). The reaction was then refluxed until HPLC showed consumption of starting material (~5 hours). The reaction was then acidified with IN HCl and the product was extracted with dichloromethane.
Organic extracts were dried over sodium sulfate, filtered and reduced. The crude mixture was filtered through a plug of silica rinsing with dichloromethane before purification. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 6.0 grams (58%) of 2-Methoxy- 5,6,8,9-tetrahydro-benzocyclohepten-7-one.
1047e) 2-Methoxy-3-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one and 2-Methoxy-l- nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one 2-Methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one (6.00 g, 0.0315 mol) was dissolved in Acetonitrile (280 mL, 5.4 mol) and was added to a mixture of Trifiuoroacetic anhydride (13.4 mL, 0.0946 mol) in Acetonitrile at 0 °C. Potassium nitrate (3.19 g, 0.0315 mol) was then added and the reaction was allowed to warm to room temperature. When HPLC showed consumption of starting material, the mixture was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). The gradient run was 0% EA-50% EA. Combined fractions were reduced en vacuo to afford 3.62 (49%) of 2-Methoxy-3-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one and 1.80 grams (25%). 1047f) 4-(2-Methoxy-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-morpholine 2-Methoxy-3-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (4.94 g, 0.0210 mol) in Methylene chloride (100 mL, 2 mol) was treated with Morpholine (18.30 g, 0.2100 mol) and then Acetic acid (12.61 g, 0.2100 mol). Two mass equivalents of powdered 4A molecular sieves were added and the mixture was heated to reflux and was allowed to stir for 4 hours. The solution was then cooled to room temp and Sodium triacetoxyborohydride (8.90 g, 0.0420 mol) was added. The reaction was then allowed to proceed until HPLC showed consumption of starting material. The reaction mixture was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (DCM/MeOH). Combined fractions were reduced en vacuo to afford 5.41 grams (84%) of 4-(2-Methoxy-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-moφholine. 4-(2- Methoxy-l-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-morpholine was made in an analogous manner using the same conditions described above. 1047g) 3-Methoxy-7-moφholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine 4-(2-Methoxy-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-moφholine (5.40 g, 0.0176 mol) was dissolved in Ethanol (100 mL, 2 mol) and the reaction mixture was carefully added to 10% Palladium on Carbon (0.750 g) under nitrogen in a Parr vessel. The reaction was then placed on a Parr shaker until uptake of hydrogen had ceased (~5 hours). Catalyst was filtered and the filtrate was reduced en vacuo to afford 4.10 grams (84%) of 3-Methoxy-7-moφholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2- ylamine. 2-Methoxy-7-moφholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-l – ylamine was made in an analogous fashion. The following intermediates were made in an analogous fashion as above utilizing the appropriate amine precursors: N*7*-(2,2-Difluoro-ethyl)-3-methoxy-6,7,8,9-tetrahydro- 5H-benzocycloheptene-2,7-diamine, 3-Methoxy-N*7*-(2-methoxy-ethyl)-6,7,8,9- tetrahydro-5H-benzocycloheptene-2,7-diamine, N*7*-(2,2-Difluoro-ethyl)-2-methoxy- 6,7,8,9-tetrahydro-5H-benzocycloheptene-l ,7-diamine, 2-(2-Amino-3-methoxy-6,7,8,9- tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol and 3-Methoxy-7-(4-methyl- piperazin-l-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine.
1047h) (lS,2S,3R,4R)-3-[5-Chloro-2-(3-methoxy-7-moφholin-4-yl-6,7,8,9-tetrahydro- 5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1 ]hept-5-ene-2- carboxylic acid amide (Single Diasteromer A)
3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (880.0 mg, 0.003184 mol), (l S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)- bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (952 mg, 0.00318 mol) and 4M of Hydrogen Chloride in 1 ,4-Dioxane (2 mL) were dissolved in 2-Methoxyethanol (30.0 mL, 0.380 mol) and the reaction was heated at 100 °C until HPLC showed consumption of starting material. The reaction mixture was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude residue was isolated and purified by Gilson prep HPLC as the first peak to elute to afford the desired product as a TFA salt. The TFA salt was taken up in dichloromethane and was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo to afford 439 mg (26%) of (lS,2S,3R,4R)-3-[5-Chloro-2-(3-methoxy-7-morpholin-4-yl- 6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]- bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Single Diasteromer A). LC/MS (ESI): 539.22. 1H NMR (400 MHz, DMSO, d6) δ 9.60 (m, IH), 8.12 (s, IH), 7.90 (s, IH), 7.79 (m, IH), 7.39 (s, IH), 6.98 (s, IH), 6.36 (m, IH), 6.16 (m, IH), 4.00 (m, 3H), 3.83 (s, 3H), 3.30 (m, 5H), 2.74 – 2.90 (m, 6H), 2.39 (m, 3H), 1.94 (d, IH, J = 4.80 Hz), 1.44 (m, 3H), 1.28 (m, IH), 1.04 (s, IH), 0.74 (s, IH).
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Morris, S. W.; Kirstein, M. N.; Valentine, M. B.; Dittmer, K. G.; Shapiro, D. N.; Saltman, D. L.; Look, A. T. Science 1994, 263, 1281– 1284
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Mosse, Y. P.; Wood, A.; Maris, J. M. Clin. Cancer Res. 2009, 15, 5608– 5614Gingrich, D. et al: J. Med Chem, 55, 4580 (2012);…
An easier, safer, and more accurate treatment for pancreatic cancer
(a) A single axial slice of the pancreas from the pre-treatment CT scans is overlaid with computed contours of light fluence levels around the fiber location. This was simulated using blood content information for tissue absorption from contrast CT. (b) A volume rendering of the blood vessels around the pancreas overlaid with the light dose map in the fiber location, in the same patient. Please see supplementary material at stacks.iop.org/PMB/59/1911/mmedia. Credit: NCCC
Using CT scans with contrast enhancement, Dartmouth researchers measured treatment response to pancreatic cancer photodynamic therapy (PDT) according to a paper published in Physics in Medicine and Biology.
The research team at Dartmouth set out to reduce the imaging obstacles for PDT, a minimally invasive and nontoxic treatment for cancer. “This study implies that treatment response can be reliably predicted using contrast CT. This would represent a major breakthrough in PDT for pancreas cancer that allows…
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New treatment could ‘protect against any strain of the flu’
The new biologic (green) binding to the surface of cells (blue nuclei), protecting the cells from invasion by the influenza virus.
Scots scientists have developed a novel treatment that could protect against any strain of the flu.
It is hoped that the new development, led by researchers at the University of St Andrews, has the potential to guard against current, future and even pandemic strains of the virus.
In an international effort, the scientists involved say that the preventative treatment could be used as a ‘frontline defence’ before an effective flu vaccine is developed. Leading influenza experts say the new development is ‘very exciting and potentially of great importance in this era’.
The BBSRC and MRC-funded research was led by Professor Garry Taylor and Dr Helen Connaris in the Biomedical Sciences Research Complex at St Andrews. They said “We have developed an alternative host-targeted approach to prevent influenza by synthesising…
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New method to analyse how cancer cells die
A team from The University of Manchester – part of the Manchester Cancer Research Centre – have found a new method to more efficiently manufacture a chemical used to monitor cancer cells.
The technique could lead to clearer and better quality images on PET scans.
The number of cells within tissue is controlled through apoptosis – a process where cells shrink and their components break up, also known as programmed cell death. Cancer is often characterised by a disruption to the normal process of this cell death.
Being able to study this process accurately would allow doctors to more effectively diagnose and monitor cancer and to test and develop new treatments designed to kill cancer cells.
Ideally, cell death would be measured non-invasively to avoid surgery and current methods are focused on using radioactive tracers – molecules that are taken up in regions of tissue where cells are…
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DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 