Molecular formula: C22H23FN4 =362.5.

Yuhan Corporation

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) .

,,,,,,,,,,,,,,,,,,,,,,,,

 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- l_r2.3.4-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