KR20160038622A - Novel process for preparing novel thioxo furopyrimidinone derivatives and intermediates used therein - Google Patents

Abstract

The present invention relates to a preparation method of 2-thioxo furopyrimidin-4-one represented by chemical formula 1 and an intermediate product used thereto. More particularly, the preparation method of the present invention obtains a thiourea carboxylate derivative represented by chemical formula 2 by having a reaction of a compound represented by chemical formula a with benzoyl isothiocyanate, and obtains the 2-thioxo furopyrimidin-4-one represented by chemical formula 1 by having a cyclization reaction of the compound represented by chemical formula 2 in presence of a base. The compound represented by chemical formula 1 can be useful as an intermediate product in preparing a medicine such as an anticancer drug, or the like.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel process for preparing a novel thioxapyrimidone derivative, and to intermediates used therefor. BACKGROUND OF THE INVENTION [0002]

The present invention relates to a novel thioxopuripyrimidine derivative, a process for producing the same, and a novel thiourea carboxylate derivative used in such a process.

Korean Patent Laid-Open Publication No. 2011-0139653, International Publication Nos. WO 2011/162515 and WO 2011/079230 disclose furo [3, 2-d] pyrimidine compound, which is a key intermediate of selective tyrosine kinase activity inhibitor, Pyrimidine-2,4 (1H, 3H) -diones and the manufacture of pharmaceuticals having a furopyrimidine structure associated therewith.

(A)

There is a problem in the production of the compound of formula (A) described in Korean Patent Publication No. 2011-0139653 and International Publication No. WO 2011/162515.

First, the methyl 3-aminofuran-2-carboxylate is reacted with urea or chlorosulfonyl isocyanate (ClSO ₂ NCO) to give the furopyrimidinedione compound (formula A) It is not easy to use and expensive reagent must be used.

Second, the puropyrimidinedione compound (Formula A) has limited selectivity in the substitution reaction, low selectivity, and low utilization thereof.

The present inventors have conducted intensive studies on a method for preparing a novel compound which is easy to produce and can increase the selective reactivity due to the nature of the structure. As a result, the present inventors have found that a novel compound can be produced easily and efficiently, And found the present invention to be completed.

(Patent Document 1) Korean Published Patent Application No. 2011-0139653

(Patent Document 2) International Publication No. WO 2011/162515

(Patent Document 3) International Publication No. WO 2011/079230

Accordingly, it is an object of the present invention to provide a method for easily and efficiently producing a novel thioxopuripyrimidinone derivative at a high yield, and an intermediate to be used therefor.

In order to achieve the above object,

1) reacting a compound of formula a with benzoylisothiocyanate to obtain a thiourea carboxylate derivative of formula 2

2) cyclizing the compound of formula 2 in the presence of a base to provide a 2-thioxopyrimidin-4-one compound of formula 1:

[Chemical Formula 1]

(A)

(2)

In the above formula (a) and 2, R is C _{1 ~ 10} alkyl.

The present invention also provides a compound of the above formula (1).

The present invention also provides a compound of formula (2) used in the synthesis of the compound of formula (1).

According to the process of the present invention, a novel thioxopuripyrimidine derivative represented by the general formula (I) and a novel intermediate thereof can be prepared from an easily obtainable compound of the general formula (a) by a novel synthetic route through an efficient production process. In addition, when such a novel substance is used, it is possible to efficiently produce a furopyrimidinedione derivative represented by the above formula (A) and various other furopyrimidine derivatives, which are key intermediates for selective tyrosine kinase activity inhibitors effective for the treatment of cancer and rheumatoid arthritis can do.

The process according to the present invention comprises the steps of reacting an amino furan carboxylate derivative of formula (a) with benzoyl isothiocyanate in an organic solvent to obtain a thiourea carboxylate derivative of formula

A step of cyclizing the compound of formula (2) in the presence of a base to obtain a 2-thioxopuripyrimidin-4-one compound of formula (1).

The 2-thioxo puropyrimidin-4-one compound of formula (I) of the present invention can be prepared by performing the reaction shown in the following reaction scheme 1:

[Reaction Scheme 1]

Wherein, R is a C _{1 ~ 10} alkyl, preferably a C _{1 ~ 4} alkyl.

Alkyl described herein includes linear alkyl, branched alkyl and cycloalkyl. As specific examples, linear alkyls include methyl, ethyl, propyl, butyl, hexyl, heptyl, octyl and the like; Branched alkyl is isopropyl, isobutyl, isopentyl, isooctyl, and the like; Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The production method of the present invention as shown in Reaction Scheme 1 will be described in more detail as follows.

First, as step 1), the step of preparing the compound of formula (2) from the compound of formula (a) is carried out.

The amount of benzoylisothiocyanate used may be from 1.0 molar equivalent to 2.0 molar equivalents, preferably from 1.2 molar equivalents to 1.5 molar equivalents, relative to one molar equivalent of the compound of formula (a).

The organic solvent used herein may be selected from the group consisting of acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, diethyl ether and mixtures thereof, and acetonitrile, Is preferred. The amount of the organic solvent used is preferably 3 to 15 ml per 1 g of the compound of formula (a). The reaction may be carried out at 10 to 60 ° C, and the compound of formula (2) is preferably obtained by cooling the reaction solution to 5 to 10 ° C after completion of the reaction and filtering.

Next, the step of preparing the compound of formula (1) from the compound of formula (2) is carried out as step 2).

The obtained compound of formula (2) is cyclized in the presence of a base to give a 2-thioxopuripimidine-4-one compound of formula (1). At this time, the base used may be an alkaline base, and sodium hydroxide, calcium hydroxide or a mixture thereof is preferable. The cyclization reaction can be carried out at a pH of from 10 to 14, preferably from 12 to 14, using the base. The amount of the base to be used may be 2.0 to 4.0 molar equivalents, preferably 2.5 to 3.0 molar equivalents, based on 1 molar equivalent of the thiourea carboxylate derivative of the formula (2).

At this time, at least one solvent selected from the group consisting of methanol, ethanol, isopropanol and water is preferable, and a mixed solvent of water and methanol is preferable, and the weight ratio thereof is preferably 1: 9 to 9: 1. The amount of the solvent used is preferably 5 to 20 ml per 1 g of the compound of formula (a). The reaction may be carried out at 80 to 110 ° C, preferably at the reflux condition, and the reaction time may be 2 to 5 hours, preferably 3 hours.

After the reaction is completed, the pH of the reaction solution is neutralized to 7.5 to 8.0 using 6N hydrochloric acid, and then the reaction solution is cooled to 5 to 10 ° C and filtered to obtain the target 2-thioxopuripyrimidine-4-one compound Can be obtained.

The present invention also provides a novel 2-thioxopyrimidin-4-one compound of formula (I).

[Chemical Formula 1]

The present invention also provides a novel thiourea carboxylate derivative of formula (2): < EMI ID =

(2)

Wherein, R is a C _{1 ~ 10} alkyl.

The compounds of formula (I) can be effectively used for the production of the furopyrimidinedione derivatives represented by the above formula (A) and various other furopyrimidine derivatives, which are key intermediates for selective tyrosine kinase activity inhibitors effective for the treatment of cancer and rheumatoid arthritis .

Hereinafter, the present invention will be described in more detail with reference to the following Production Examples. However, this is for the purpose of helping understanding of the present invention, and the scope of the present invention is not limited thereto.

Preparation Example 1: Preparation of methyl 3- (3-benzoylthioureido) furan-2-carboxylate

358 g (2.5 mol) of benzoyl chloride was added to 2.0 L of acetonitrile, and 248 g (2.5 mol) of potassium thiocyanate was added. After refluxing for 3 hours, the reaction solution was cooled to obtain benzoyl isothiocyanate Respectively. To the reaction solution was added 1.0 L of acetonitrile and 300 g (2.1 mol) of methyl 3-aminofuran-2-carboxylate of the formula a was added. The reaction mixture was stirred at 25 占 폚 for 12 hours, cooled to 0 to 5 占 폚 and stirred for 1 hour. The resulting solid was filtered under reduced pressure, washed with 500 mL of cooled acetonitrile, and dried under a humid atmosphere to obtain 492 g of the title compound (2) (yield: 76%).

¹ H-NMR (300 MHz, DMSO-d ₆ )? 13.62 (s, IH), 11.87 (s, IH), 8.04 (d, IH), 7.96-7. ), 7.51-7.56 (m, 2H), 3.89 (s, 3H).

Production Example 2: Preparation of methyl 2- (3-benzoylthioureido) furan-2-carboxylate of formula (2)

10.0 kg (70.9 mol) of methyl 3-aminofuran-2-carboxylate of Formula a was added to 100 L of acetonitrile and 13.9 kg (85.2 mol) of benzoylisothiocyanate was added dropwise. The reaction mixture was stirred at 25 占 폚 for 12 hours, cooled to 0 to 5 占 폚 and stirred for 1 hour. The resulting solid was filtered under reduced pressure, washed with 20 L of cooled acetonitrile, and dried under a humid atmosphere to obtain 14.9 kg of the title compound (2) (yield: 69%).

¹ H-NMR (300 MHz, DMSO-d ₆ )? 13.62 (s, IH), 11.87 (s, IH), 8.04 (d, IH), 7.96-7. ), 7.51-7.56 (m, 2H), 3.89 (s, 3H).

Preparation Example 3: Preparation of 1, 2-thioxo-2,3-dihydrofuro [3,2-d] pyrimidin-4 (1H)

14.7 kg (48.3 mol) of methyl 3- (3-benzoylthioureido) furan-2-carboxylate of the formula 2 obtained in Preparation Example 2 was added to 161 L of methanol, and 18 L of sodium hydroxide 5.8 kg (145.0 mol) was added dropwise thereto, followed by stirring at 25 ° C for 4 hours. The reaction was neutralized with a 6N aqueous hydrochloric acid solution, cooled to 0-5 ° C and stirred for 1 hour. The resultant solid was filtered, washed with 29 L of a mixed solvent of methanol and water (5: 1), further washed with 14 L of acetone, and dried under a humid atmosphere to obtain 7.0 kg (yield: 86%) of the title compound .

^{1 H-NMR (300MHz, DMSO} -d 6) δ 12.52 (s, 2H), 8.13 (s, 1H), 6.58 (s, 1H).

Reference Example 1: Preparation of Formula A, furo [3,2-d] pyrimidine-2,4 (lH, 3H) -dion

6.9 kg (41.7 mol) of 2-thioxo-2, 3-dihydrofuro [3,2-d] pyrimidin-4 (1H) -one obtained in Production Example 3 was dissolved in 52 L of dioxane After adding to 52 L of water, 6.9 kg of chloroacetic acid was added and the mixture was refluxed at 110 DEG C for 12 hours. The reaction was cooled to room temperature and stirred for 1 hour. The resulting solid was separated by filtration under reduced pressure, and then washed with methanol: water (1: 1) and acetone (7 L) and dried to obtain 4.8 kg of the title compound of formula (A) (yield: 77%).

¹ H-NMR (300 MHz, DMSO- d ₆ )? 11.23 (s, IH), 11.10 (s, IH), 8.08 (s, IH), 6.54 (s, IH).

Claims (8)

1) reacting a compound of formula (a) with benzoylisothiocyanate to obtain a thiourea carboxylate derivative of formula (2)
2) A process for producing a 2-thioxo puropyrimidin-4-one compound represented by the following formula (1) comprising cyclizing the compound of the formula (2) in the presence of a base:
[Chemical Formula 1]

(A)

(2)

In the above formula (a) and 2, R is C _{1 ~ 10} alkyl.
The method according to claim 1,
Wherein the reaction of step 1) is carried out in an organic solvent selected from the group consisting of acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, diethyl ether and mixtures thereof Gt;
3. The method of claim 2,
Wherein the organic solvent is acetonitrile, ethyl acetate or a mixture thereof.
The method according to claim 1,
Wherein the base of step 2) is an alkali.
5. The method of claim 4,
Wherein the base is sodium hydroxide, potassium hydroxide or a mixture thereof.
The method according to claim 1,
Wherein the cyclization reaction is carried out at a pH of 10 to 14 using a base in step 2).
A compound of formula
[Chemical Formula 1]

.
A compound of formula (2)
(2)

Wherein, R is a C _{1 ~ 10} alkyl.