Title of Invention

A PROCESS FOR PREPARING PYRAZOLOPYRIMIDINONE DERIVATIVES FOR THE TREATMENT OF IMPOTENCE

Abstract The present invention relates to the method for preparing pyrazolopyrimidinone derivatives and their pharmaceuti-cally acceptable salts having efficacy on the treatment of impotence, one of male sexual dysfunctions. The method according to the present invention comprises the steps of chlorosufonation the pyrazokmide, followed by amination with amine and intramolecular cyclization. The method provides the pyrazolopyrimidinone derivatives and their pharmaceuticaliy acceptable salts with high yield and in an economic manner.
Full Text A PROCESS FOR PREPARING PYRAZOLOPYRIMIDINONE DERIVATIVES FOR THE TREATMENT OF IMPOTENCE
TECHNICAL FIELD
The present invention relates to a process for preparing pyrazolopyrimidinone derivatives of formula 1 and pharmaceutically acceptable salts thereof which have an efficacy on impotence, comprising the steps of chlorosulfonation of pyrazolamide compounds of formula 2, followed by amination with a primary amine and intramolecular cyclization.
Formula 1
(Formula Removed)
Formula 2
(Formula Removed)
The compounds of formula 1 may exist in tautomeric equilibrium as shown below.

The compounds of formula 1 may asymmetric centers and thus they can exist as enantiomers. The present invention includes both racemic mixture and separate individual enantiomers.
BACKGROUND ART OF THE INVENTION
Male erectile dysfunction is one of the most common sexual dysfunctions in man. Although erectile dysfunction can be primarily psychogenic in origin, it often accompanies chronic illnesses, such as diabetes mellitus, heart disease and a variety of neurological diseases. It is estimated that about 2 ~ 7% of the male population are impotent. Its prevalence is strongly related to age. For example, 18 ~ 75% of the age group of 55 to 80 years is believed to be impotent.
Various treatment options for erectile dysfunction are available, such as counseling, hormone replacement therapy, self-injection or transurethral application of vasodilator agents, vacuum devices, and vascular surgery. However, these therapeutic options have several limitations

such as side effects, high cost and low efficacy.
Recently, Sildenafil has been developed as a therapeutic agent for male erectile dysfuction by oral administration. Sildenafil is the first in a new class of
i
drugs known as inhibiting phosphodiesterase-5 enzyme distributed specifically in corpus cavernosal tissues and induces relaxation of the corpus cavernosal smooth muscle cells, so that blood flow to the penis is enhanced, leading to an erection. Sildenafil has shown a response rate of around 80% in men with erectile dysfunction of organic cause.
Since sildenafil has been developed, various compound$ for inhibiting phosphodiesterase-5 have been
reported Among them, pyrazolopyrimidinone compounds of
formula ,1 (KR Pat. No. 99-49384) IN/PCT/2001/00271/ were reported having
better potency than that of sildenafil, based on the mechanism of inhibiting phosphodiesterase-5 and having better selectivity over phosphodiesterase-6 distributed in retina and phosphodiesterase-3 distributed in heart to reduce the side effects. Further, the pyrazolopyrimidinone compounds of formula 1 were said to be improved the solubility and the metabolism in the liver, which are very important factor affecting the rate of the absorption when administered orally.
The KR patent No. 99-49384 also disclosed a process for preparing the pyrazolopyrimidinone compounds of formula

1, comprising the steps of: ' .
a) reacting chlorosulfonated alkoxy bonzoie acid with a
primary amine to obtain sulfonamide-substituted
benzoic acid;
b) reacting the obtained sulfonamide-substituted
benzoic acid with pyrazolamine in the presence of
activating reagent of carboxylic group or coupling
agent of carboxylic group with amine group to obtain
corresponding amide compound? and,
c) performing an intramolecular cyclization of the
obtained amide compound to obtain the
pyrazolopyrimidinone compound of formula 1.
This reaction is represented in scheme 1. Scheme 1
(Scheme Removed)
However, the said process has several disadvantages. First, the reaction of the sulfonamide-substituted benzoic

acid with pyrazolamine in the step b) requires the expensive coupling reagent or activation reagent such as trichloro benzoyl chloride and EEDQ (N-ethoxycarbonyl-2-ethoxy-1,3-dihydroquinoline) . Second, the yield of the step a) in which the chlorosulfonated alkoxy bonzoic acid reacts with a primary amine to produce sulfonamide-substututed benzoic acid is somewhat low, and thus, reduces the total yield of the process.
Leading to the present invention, the intensive and thorough research for efficiently preparing the pyrazolopyrimidinone compound useful for the treatment of impotence, carried out by the present inventors aiming to avoid the problems encountered in the prior arts, resulted in the finding that the pyrazolopyrimidinone compound can be prepared under mild condition in high yield, with high purity and in a economic manner by chlorosulfonation, amination with a primary amine and intramolecular cyclization of a pyrazolamide compound obtained by the reaction of alkoxy benzoic acid with pyrazolamine.
Therefore, it is an object of the present invention to provide a process for preparing pyrazolopyrimidinone derivatives of formula I and pharmaceutically acceptable salts thereof.

DISCLOSURE OF THE INVENTION
A method for preparing pyrazolopyrimidinone derivatives of formula 1, comprising the following steps of:
a) chlorosulfonating a pyrazolamide compound of formula 2 to obtain a chlorosulfonated
compound of formula 3;
b) reacting the chlorosulfonated compound of formula 3 with a primary amine in the
presence of a solvent as herein described to obtain a sulfonamide compound of
formula 4 at a temperature between 20 deg. C. or lower and,
c) performing an intramolecular cyclization of the sulfonamide compound of formula 4 in
the presence of a solvent as herein described and optionally in the presence of a base
to produce the compound of formula 1.
(Formula Removed)
d)
Wherein,
R1 represents hydrogen, C1-C6 alkyl, C1-C3 alkyl fluoride or C3-C6 cycloalkyl;
R2 represents hydrogen, substituted or unsubstituted C2-C6 alkyl, C1-C3 alkyl fluoride or C3-C6 cycloalkyl;
R3 represents substituted or unsubstituted C1-C6 alkyl, C1-C6 alkyl fluoride, C3-C6 cycloalkyl, C3-C6 alkenyl or C3-C6 alkynyl; and,
R4 represents substituted or'.. unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C9 alkenyl,
•substituted-or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted ber.zene, or substituted or • unsubstituted
heterocycle selected from the group consisting of

pyridine, isoxazole-, thiazole, pyrimidine, indan,
ben.zthiazole, pyrazole, . thiadi-azol, oxazole, piperidine,
morphorine, imidazole, pyrrolidine, thienyl, triazole, pyrrole and furyl.
As a substituent of R2, R3 and R4, C1-C10 alkyl, C3-C6 cycloalkyl, halogen, C1-C6 alkyl fluoride, C1-C10 alkyloxy, substituted or unsubstituted bezene, or substituted or unsubstituted heterocycle selected from the group consisting of pyridine, isoxazole, thiazole, pyrimidine, indan, benzthiazole, pyrazole, thiadiazole, oxazole, piperidine, morphorine, imidazole, pyrrolidine, thiehyl, triazole, pyrrole, and furyl can be mentioned.
Preferably, R1 represents C1-C3 alkyl; R2 represents substituted or unsubstituted C2-C6 alkyl; R3 represents substituted or unsubstituted C2-C6 alkyl; R4 represents substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted bezene, substituted or unsubstituted pyridine, or substituted or unsubstituted pyrrole, wherein the substituent of R2, R3 and R4 is halogen, substituted 'or unsubstituted benzene, substituted or unsubstituted heterocycle selected from the group consisting of pyridine, pyrrolidine, piperidine, pyrrole, and substituted or unsubstituted C3-C6 cycloalkyl.
More preferably,- R4 represents substituted C1-C6
alkyl, wherein the substituent is pyrrolidine.
Particularly preferred are as follows:
(1) 5-[2-propoxy-5-(l-methyl-2-pyrrolidinylethyl
amidosulfonyl)phenyl]-l-methyl-3-propyl-l, 6-dihydro-7H-
pyrazolo(4,3-d)pyrimidin-7-one;
(2) 5-[2-propoxy-5-(l-methyl-3-pyrrolidinylmethyl
amidosulf onyl) phenyl] -l-methyl-3-propyl-l, 6-dihydro-7H-
pyrazolo(4,3-d)pyrimidin-7-one; and
(3) 5-[2-propoxy-5-(2-pyridylmethyl amidosulfonyl)
phenyl]-l-methyl-3-propyl-l,6-dihydro-7H-pyrazolo(4,3-
d)pyrimidin-7-one.
Hereinafter, a detailed description will be given of the method of the present invention according to each step.
I. Chlorosulfonation Step (step a)
4-(2-alkoxy benzamido)-l-alkyl-3-alkyl-5-carbamoyl pyrazole of formula 2 is directly reacted with chlorosulfonic acid or reacted with a mixture of chlorosulfonic acid and suitable amounts of thionyl chloride at an appropriate temperature, 20 °C or lower, to prepare the chlorosulfonated compound of formula 3.
II. Sulfonamidization Step (step b)
The obtained chlorosulfonated compound is reacted

with a primary amine in an appropriate solvent at suitable temperature, to produce the sulfonamide compound of formula 4.
s
The solvent which can be used in this reaction includes alcohol, dichloromethane and chloroform, but not limited thereto. The skilled in the art would adapt an appropriate solvent in the consideration of the solubility of the starting material, reaction condition, etc.
As a primary amine used,, 2- (2-aminoethyl) -1-methylpyrrolidine, 3-aminomethyl-l-methylpyrrolidine or 2-amihomethyl-pyridine can be preferably mentioned. The amount of the primary amine used in this reaction is no less than 2 equivalents based on the chlorosulfonated compound. Alternatively, when acid scavenger such as tertiary amine, which scavenging the, acid generated during the reaction, is used, the primary amine can be used in a stoichiometric quantity.
The reaction temperature of this reaction is preferably 20 °C or lower. The sulfonamide compound of formula 4 can be worked up from the reaction mixture and proceeded, to the next reaction step c) . Or step c) can be performed in situ by just adding a suitable base to the

reaction mixture in situ without workup.
III. Intramolecular Cyclization Step (step c) Pyrazolopyrimidinone of formula 1 is prepared through intramolecular cyclization of the sulfonamide compound of formula 4. The intramolecular cyclization is carried out in the presence of a suitable base at the appropriate temperature. For example, metal salts of alcohol, metal salts of ammonia, amine, alkali or alkali earth metal hydrides, hydroxides, carbonates, bicarbonates, and bicyclic amidines such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and DBN (1,5-diazabicyclo[4.3.0]non-5-ene) can be mentioned as a suitable base.
The solvent which can be used in the intramolecular cyclization includes alcohol such as methanol, ethanol, isopropanol and t-butanol; ether including tetrahydrofuran, dimethoxyethane and ,dioxane; aromatic hydrocarbons, such as benzene, toluene, xylene, chloro benzene; acetonitrile, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidin-2-one and pyridine.
The present invention provides the sulfonamide compound of formula 4 from step a) and step b) reaction in good yield and in high purity. And as previously mentioned, the step c) can be performed in situ with the

sulfonamide compound of formula 4 produced in the step b) in a one-pot reaction, thereby reducing the overall procedure of the reaction and effectuating the efficient synthesis of pyrazolopyrimidinone compound of formula 1.
In particular, according to the preferred embodiment of the present invention, even though tertiary amine was used as a part of substituent of R4, the yield of the reaction was high.
The present invention also provides a method for preparing pharmaceutically acceptable salts of pyrazolopyrimidinone compound as represented in formula 1, wherein the pharmaceutically acceptable salts of pyrazolopyrimidinone compound can be prepared by adding a pharmaceutically acceptable free acid to the pyrazolopyrimidinone compound of formula 1. Examples of a free acid include inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and so on; and organic acids, for example, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, p-toluenesulfonic acid, galacturonic acid, glutamic acid, or aspartic acid.

A better understanding of the present invention may be obtained in light of the following examples which are set forth to illustrate, but are not to be construed to limit the present invention.
EXAMPLE
Molecular structures of the present compounds were confirmed by infrared spectrometry, ultraviolet spectrometry, nuclear magnetic resonance spectrometry, mass spectrometry, and elemental analysis of representative compounds by comparing calculated values with observed values.
The pyrazolamide compound of formula 2, which is a starting material of the present invention, can be obtained in high yield by reacting alkoxy benzoic acid with pyrazolamine as illustrated in the scheme 2.
Preparation of 4-[2-propoxy benzamido]-1-methyi-3-propyl-5-carbamoyl pyrazole
To a solution of 25 g of 2-propoxy benzoic acid dissolved in dichloromethane, 66 g of thionyl chloride was added and stirred for 3 hours under reflux. After reaction was completed, the solvent and excessive thionyl chloride were distilled off under reduced pressure. To the residue was added 200 ml of dichloromethane (reaction solution 1) . In another container, to 24 g of l-methyl-3-

propyl-4'-amino-5-carbamoyl pyrazole in dichloromethane was added 13.4 g of triethylamine and 100 mg of dimethylaminopyridine and then cooled to 0°C, to which said reaction solution 1 was slowly added while maintaining the temperature of the solution at 0°C, and then stirred for 1 hour. The reaction mixture was successively washed with water, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product and then triturated with hexane to give 39 g of the title compound.
1H NMR{CDC13) : 0.91(t,3H), 1.05(t,3H), 1.62(m, 2H) , 1.89(m,2H), 2.52(t,2H), 4.06(s,3H), 4.18(t,2H), 5.57(br s,lH), 7.09(m,2H), 7.52(m,lH), 7.73(br s,1H), 8.26(dd,lH), 9.45(br s,lH)
Preparation of 5-[2-propoxy-5-(l-methyl-2-pyrolidinylethyl amidosulf onyl) phenyl] -1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo (4,3-d)pyrimidin-7-one
(Step a) preparation of 4- [2-propoxy-5-
(chlorosulfonyl)benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole
To 23 ml of chlorosulfonic acid cooled to 0°C, 10 g of 4-[2-propoxy benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole was added and then stirred at room temperature

for 2 hours. Reaction mixture was added to ice water of 0 °C and then stirred for 1 hour to obtain white solid, which Was filtered and washed with water. The obtained white solid was dissolved in ethyl acetate. The solution was successively washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product and triturated with hexane to give 9.14 g of the title compound.
1H NMR(CDC13) : 0.92(t,3H), 1.08(t,3H), 1.62(m,2H), 1.97(m, 2H), 2.50(t, 2H) , 4.04(s,3H), -4 .32 (t, 2H)> 5.63(br s,lH), 7.24(d,1H), 7.54(br s, 1H) , 8.15(dd,1H), 8.93(d,lH), 9.17(br S,1H)
(Step 2) preparation of 4-[2-propoxy-5-(l-methyl-2-
pyrolidinylethyl amidosulf onyl) benzamido] -l-methyl-3-
propyl-5-carbamoyl pyrazole
To 9.14 g of 4-[2-propoxy-5-(chlorosulfonyl) benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole in dichloromethane, 5 ml of 2-(2-aminoethyl)-1-methyl pyrrolidine was added at 0°C and stirred for 1 hour at room temperature. After completion of reaction, the reaction solution was diluted with dichloromethane. The solution was- successively washed with saturated sodium bicarbonate solution, water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The

filtrate was concentrated under reduced pressure to produce a crude product and triturated with a mixture of hexane: ethyl acetate (10:1) to give 9.69 g of the pure title compound.
Hi NMR(CDC13) : 0.90(t,3H), 1.06{t,3H), 1.59(m,2H), 1.70(m,6H), 1.93(m, 2H) , 2.15(m,lH), 2.29(s,3H), 2.39(m.lH), 2.49(t,2H), 3.04(m,3H), 4.02(s,3H), 4.24(t,2H), 5.82(br s,lH), 7.13(d,lH). 7.58(br s,1H), 7.96(dd,lH), '8.67(d,lH), 9.26(br s,lH)

(Step 3) preparation of 5-[2-propoxy-5-(l-methyl-2-
pyrolidinylethyl amidosulfonyl)phenyl] -l-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4, 3-d)pyrimidin-7-one
To a solution of 9.59 of 4-[2-propoxy-5-(l-methyl-2-pyrolidinylethyl amidosulfonyl)benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole dissolved in 192 ml of t-butanol, 4.02 g of potassium t-butoxide was added and then stirred for 8 hours under reflux. After completion of reaction, the reaction solution was cooled to room temperature and diluted with ethyl acetate. The solution was successively washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum-distilled to remove the solvent. Column chromatography of the residue on' silica gel gave 7 g of the pure title compound.
1H NMR(CDC13) : 0.99(t,3H), 1.15(t,3H), 1.56(m,4H),

1.79(m,4H), 2.02(m,3H), 2.28(s,3H), 2.36(m,lH), 2.89(t,2H), 3.07(m,3H), 4.23(t,2H), 4.24(sf3H), 7.11(d,lH), 7.92(dd,lH), 8.88 (d,1H)
Preparation of 5-[2-propoxy-5- (l-met.hyl-2-pyrolidinylethyl amidosulfonyl)phenyl] -l-methyl-3-propyl-1, 6-dihydro-7H-pyrazolo (4,3-d)pyrimidin-7-one
(Step 1) preparation of 4~ [2-propoxy-5-
(chlorosulfonyl)benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole
To 32.8 ml of chlorosulfonic acid cooled to 0 °C, 8.48 ml of thionyl chloride and 20 g of 4-[2-propoxy benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole were successively added dropwise and portionwise, and then stirred for 2 hours at room temperature. Reaction mixture was added to ice water of 0 °C. After 1 hour, the reaction mixture was extracted with ethyl acetate. The organic solution was successively washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure • to obtain a crude product and triturated with a mixture of- hexane:ethyl acetate (10:1) to give 23 g of the title compound.
1H NMR(CDC13) : 0.92(t,3H), 1.08{tr3H), 1.62(m,2H), 1.97(m,2H), 2.50(t, .2H) , 4.04(s,3H), 4.32(t,2H), 5.63 (br s,lH), 7.24(d,lH), 7.%54(br s, 1H) , 8.15 (dd, 1H),
t
8.93(d,lH},r 9.17(br s,lHJ.

(Steps 2 and 3) preparation of 5-[2-propoxy-5-(1-methyl-2-pyrolidinylethyl amidosulfonyl)pheny1]-1-methyl-3-propyl-l, 6-dihydro-7H-pyra2olo (4, 3-d)pyrimidin-7-one
To 20.8 g of 4-[2-propoxy-5-(chlorosulfonyl} benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole in sthanol, 11.3 ml of 2-(2-aminoethyl)-1-methyl pyrrolidine was added at 0 °C and stirred for 1 hour at room temperature. To this solution, 12 g of sodium ethoxide was added and stirred for 5 hours under reflux. After completion of reaction, the reaction solution was cooled to room temperature and adjusted to pH 9 by concentrated hydrochloric acid. The reaction solution was diluted with dichloromethane. The solution was successively washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, which was then recrystallized with ethanol to give 18.4 g of the pure title compound.
1H NMR('CDC13) : 0.99(t/3H), 1.15(t,3H), 1.56 (m, 4H) , 1.79(m,4H), ,2.02(m,3H), 2.28(s,3H), 2.36 (m, 1H) , 2.89{t,'2H), 3.07(m,3H), 4.23{t,2H), 4.24(s,3H), 7.11{d,lH), 7.92(dd,lH), 8.88 (d,1H).
Preparation of 5-[2-propoxy-5-{l-methyl-3-pyrolidinylmethyl amidosulfonyl)phenyl]-1-methyl-3-

propyl-1, 6-dihydro-7H-pyrazolo (4,3-d)pyrimidin-7-one
(Step Ij preparation of 4- [2-propoxy-5-
(chlorosulfonyl) benzamido] -l-rnethyl-3-propyl-5-carbamoyl
pyrazole .
The title compound was produced in the same manner as in the step 1 of the above example IB.
(Step 2) preparation of 4-[2-propoxy-5-(l-methyl-3-
pyrrolidinylmethyl amidosulfonyl)benzamido]-l-methyl-3-
propyl-5-carbamoyl pyrazole
To 1.0 g of 4-[2-propoxy-5-(chlorosulfonyl) benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole in dichloromethane, 516 mg of 3-aminomethyl-l-methyl pyrrolidine was added at 0 °C and stirred for 1 hour at room temperature. After completion of reaction, the reaction solution was diluted with dichloromethane. The solution was successively washed with saturated sodium bicarbonate solution, water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a crude product and triturated with hexane to give 825 mg of the pure title compound.
1H NMR(CDC13) : 0. 91 (t, 3H) , 1.06(t,3H), 1.60{m,3H), 1.99(m,3H), 2.34(s, 3H) , 2.40(m, 6H), 2.85(m,lH), 2.94(d.2H), 4.03(s,3H), 4.24(t,2H), 5.82(br s,lH), 7.13(d,lH). 7.58(br s,lH), 7.99(dd,1H), 8.88(d,lH),

9.29(br s,lH).
(Step 3) preparation of 5-[2-propoxy-5-(l-methyl-3-
pyrrolidinylmethyl amidosulfonyl)phenyl]-l-methyl-3-
propyl-1, 6-dihydro-7ff-pyrazolo (4, 3-d) pyrimidin-7-one
To a solution of 825 mg of 4-[2-propoxy-5-(1-methyl-3-pyrrolidinylmethyl amidosulfonyl) benzamido]-1-methyl-3-propyl-5-carbarnoyl pyrazole dissolved in 10 ml of t-butanol, 213 mg of potassium t-butoxide was added and then stirred for 8 hours under reflux. After completion of reaction, the reaction solution was cooled to room temperature and diluted with dichloromethane. The solution was successively washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. Column chromatography of the crude product on silica gel gave 719 mg of the pure title compound.
XH NMR(CDC13) : 1.00(t,3H), 1.16(t,3H), 1.60(m,lH), 1.82(m,2H), 2.02(m,3H), 2.38(s/3H), 2.50(m,4H), 2.90(t,2H), 3.01(d,2H), 4.23(t,2H), 4.25(s,3H), 7.12(d,lH), 7.94(dd,lH), 8.88 (d
Preparation of 5-[2-propoxy-5-(2-
pyridylmethyl amidosulfonyl)phenyl]-l-methyl-3-propyl-
1, 6-dihydro-7H-pyrazolo (4 ,3~d) pyrimidin-7-one

(Step 1) preparation of 4- [2-p'ropoxy-5-
(chlorosulfpnyl)benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole
The title compound was prepared in the same manner as in the step 1 of the above example IB.
(Step 2) preparation of 4- [2-propoxy-5- (2-
pyridylmethyl amidosulfonyl) benzamido] -l-me-thy.l-3-prppyl-5~carbamoyl pyrazole
To 1.0 g of 4-[2-propoxy-5-(chlorosulfonyl) benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole in dichloromethane, 0.47 ml of 2-aminomethyl-pyridine was added at 0 °C and stirred for 1 hour at room temperature. After completion of reaction, the reaction solution was diluted with dichloromethane. The solution was successively washed with saturated sodium bicarbonate solution, water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to furnish a crude product and triturated with hexane to give 955 mg of the pure title compound.
1H NMR(CDC13) : 0.90(t,3H), 1.05 (t, 3H) , 1.59.(m,2H) , 1.90(m,2H), 2.49(t, 2H) , 2.65(br s,lH), 4.02(s,3H), 4.25(t,2H), 4.28(d,2H), 5.79(br s,lH), 6.28(t,lH), 7.09(d,lH). 7.26(d,lH), 7.16(m,lH), 7.61(m,lH), 7.99(dd,lH), 8;42(d,lH), 8.69(d,lH), 9.22(br s,1H).

.(Step 3) preparation of 5-[2-propoxy-5-(2-
pyridylmethyl amidosulf onyl) phenyl] -l-methyl-3-propyl-
1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one
To a solution of 955 mg of 4-[2-propoxy-5-(2-pyridylmethyl amidosulfonyl)benzaraido]-l-methyl-3-propyl-5-carbamoyl pyrazole dissolved in 12 ml of t-butanol, 244 mg of potassium t-butoxide was added and then stirred for 8 hours under reflux. After completion of reaction, the reaction solution was cooled to room temperature and diluted with ethyl acetate. The solution was successively washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The reidue was- column chromatographed on silica gel to give 821 mg of the pure title compound.
*H NMR(CDC13) : 1.02(t,3H), 1.15{t,3H), 1.85(m,2H), 2.04(m,2H), 2.93(t,2H), 4.21(t,2H), . 4.26 (s,-3H) , 4.41(d,2H), 6.30(t,lH), 7.09(d,lH), 7.30(m,lH), 7.39(d,lH), 7.77(m,lH), 7 . 96(dd,lH), 8.45(d,lH), 8.86(d,lH),. 10.82(br s,lH).
According to the present invention, pyrazolopyrimidinone derivatives of formula 1 can be prepared in high yield with high purity. In addition, the inexpensive reagents can be used such that they can be

prepared in an economic manner.
The present invention has been described in" an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation. Many modifications and variations of the present invention are possible in light of the above teachings. Therefore, it is to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.







We Claim:
1. A method for preparing pyrazolopyrimidinone derivatives of formula 1
(Formula Removed)
wherein
R1 represents hydrogen; C1-C6 alkyl; C1-C3 alkyl fluoride; or C3-C6 cycloalkyl,
R2 represents hydrogen; substituted or unsubstituted C2-C6, alkyl; C1-C3 alkyl fluoride; or C3-C6 cycloalkyl,
R3 represents substituted or unsubstituted C1-C6 , alkyl; C1-C6 , alkyl fluoride; C3-C6 cycloalkyl; C3-C6 alkenyl; or C3-C6alkynyl, and
R4 represents substituted or unsubstituted C1-C1o alkyl; substituted or unsubstituted C1-C9 alkenyl; substituted or unsubstituted C3-C6 cycloalkyl; substituted or unsubstituted bezene; or substituted or unsubstituted heterocycle selected from the group consisting of pyridine, isoxazole, thiazole, pyrimidine, indan, benzthiazole, pyrazole, thiadiazol, oxazole, piperidine, morphorine, imidazole, pyrrolidine, thienyl, triazole, pyrrole and furyl,
in which, substituents usable for R2, R3 and R4 comprises C1-C10 alkyl; C3-C6 cycloalkyl; halogen; C1-C6 alkyl fluoride; C1-C10 alkyloxy; substituted or unsubstituted bezene; or substituted or unsubstituted heterocycle selected from the group consisting of pyridine, isoxazole, thiazole, pyrimidine, indan, benzthiazole.

pyrazole, thiadiazole. oxazole, piperidine, morphorine. imidazole, pyrrolidine, thienyl, triazole, pyrrole, and furyl.
comprising the following steps of:
b) chlorosulfonating a pyrazolamide compound of formula 2 to obtain a chlorosulfonated compound of formula 3;
b) reacting the chlorosulfonated compound of formula 3 with a primary
amine in the presence of a solvent as herein described to obtain a
sulfonamide compound of formula 4 at a temperature between 20 deg. C.
or lower and.
c) performing an intramolecular cyclization of the sulfonamide
compound of formula 4 in the presence of a solvent as herein described
and optionally in the presence of a base to produce the compound of
formula 1.

(Formula Removed)
2. The method as claimed in claim 1, wherein R1 represents C1-C3 alkyl, R2 represents substituted or unsubstituted C2-C6, alkyl,
R3represents substituted or unsubstituted C2-C6 alkyl, and
R4 represents substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted bezene, substituted or unsubstituted pyridine, or substituted or unsubstituted pyrrole,in which, substituents usable for R2, R3 and R4 comprises halogen, substituted or unsubstituted benzene, substituted or unsubstituted heterocycle selected from the group consisting of pyridine, pyrrolidine, piperidine, pyrrole, and substituted or unsubstituted C3-C6 cycloalkyl.
3. The method as claimed in claim 1, wherein said derivative of formula
1 are 5-[2-propoxy-5-(l-methyl-2-pyrrolidinylethyl
amidosulfonyl )phenyl]-l-methyl-3-propyl-l,6-dihydro-7H-
pyrazolo(4,3-d)pyrimidin-7-one, 5-[2-propoxy-5-( 1 -methyl-3-
pyrrolidinylmethyl amidosulfonyl) phenylj-l-methyl-3-propyl-l .6-
dihydro-7H-pyrazolo(4,3-d) pyrimidin-7-one, and 5-[2-propoxy-5-(2-
pyndylmethyl amidosulfonyl) phenyl]-1 -methyl-3-propyl-l ,6-
dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one.
4. The method as claimed in claim 1, wherein said step a) is carried out
at 20 °C or lower.
5. The method as claimed in claim 1, wherein in step (b) the solvent is
selected from the group consisting of alcohol, dichloromethane and
chloroform.
6. The method as claimed in claim 1, wherein in step (c) the solvent is
selected from the group consisting of alcohols, ethers, aromatic

hydrocarbons, acetonitrile. dimetylsulfoxide. dimethylfonnamide. N-methylpyrrolidin-2-one and pyridine.
7. The method as claimed in claim 1, wherein in step (c) said base is selected from the group consisting of metal salts of alcohols, metal salts of ammonia, amines, alkali or alkali earth metal hydrides, hydroxides, carbonates, bicarbonates, and bicyclic amidines such as DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) and DBN (1.5-diazabicyclo[4.3.0]non-5-ene).
8. A method for preparing pyrazolopyrimidinone derivatives of formula 1 substantially as herein described with reference to the foregoing example.


Documents:

IN-PCT-2002-01224-DEL-Correspondence Others-(09-06-2011).pdf

in-pct-2002-1224-del-abstract.pdf

in-pct-2002-1224-del-assignment.pdf

in-pct-2002-1224-del-claims.pdf

in-pct-2002-1224-del-complete specification (granted).pdf

in-pct-2002-1224-del-correspondence-others.pdf

in-pct-2002-1224-del-correspondence-po.pdf

in-pct-2002-1224-del-description (complete).pdf

in-pct-2002-1224-del-form-1.pdf

in-pct-2002-1224-del-form-13.pdf

in-pct-2002-1224-del-form-19.pdf

in-pct-2002-1224-del-form-2.pdf

in-pct-2002-1224-del-form-3.pdf

in-pct-2002-1224-del-form-5.pdf

in-pct-2002-1224-del-gpa.pdf

in-pct-2002-1224-del-pct-210.pdf

in-pct-2002-1224-del-pct-409.pdf

in-pct-2002-1224-del-pct-416.pdf


Patent Number 197681
Indian Patent Application Number IN/PCT/2002/01224/DEL
PG Journal Number 37/2008
Publication Date 12-Sep-2008
Grant Date 22-Dec-2006
Date of Filing 11-Dec-2002
Name of Patentee DONG A PHARM CO. LTD.
Applicant Address 252 YONGDOO-DONG, DONGDAEMOON-KU, SEOUL 130-070,REPUBLIC OF KOREA
Inventors:
# Inventor's Name Inventor's Address
1 YOO MOO-HI #5-801 WOOSUNG 3 CHA APT., 652, GAEPO 1-DONG, KANGNAM-KU, SEOUL 135-241,REPUBLIC OF KOREA
2 KIM SOON-HOE #316-702 DONGSHIN APT., CHONGMYEONGMAEUL, 956-2, YONGTONG-DONG, PALDAL-KU, SUWON-SI 442-470
3 KIM WON-BAE #A-1801 DAELIM ACROVIL, DOKOK-DONG, KANGNAM-KU, SEOUL 135-240,
4 CHANG MIN-SUN 6-1, MAKOK-RI, NAMSA-MYEON, YONGIN-SI 449-880
5 KIM DONG-SUNG #501-903 JOOKONG APT., CHAMSIL-DONG, SONGPA-KU, SEOUL 138-220,
6 BAE CHUL-JUN #307, 196-108, BONGCHUN 11-DONG, KWANAK-KU, SEOUL 151-061,
7 KIM YONG-DUCK #503-201 JOOKONG APT., SHINNAMOOSIL, YONGTONG-DONG, PALDAL-KU, SUWON-SI 442-470,
8 KIM EUN-HA 102-23, SUNGNAM-DONG, JUNGWON-KU, SUNGNAM-SI-462-130,
PCT International Classification Number C07D 487/04
PCT International Application Number PCT/KR01/00819
PCT International Filing date 2001-05-18
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2000-34966 2000-06-23 Republic of Korea