KR20160082062A - Method for preparing thioxo furopyrimidinone derivatives, and intermediates used therein - Google Patents

Abstract

The present invention relates to a method for manufacturing a compound of chemical formula 1 through a process of a fourth step from a compound of chemical formula 2, and relates to an intermediate used therefor. The compound of chemical formula 1 can be efficiently used as the intermediate for manufacturing drugs such as an anticancer agent or the like.

Description

METHOD FOR PREPARING THIOXO FUROPYRIMIDINONE DERIVATIVES AND INTERMEDIATES USED THEREIN BACKGROUND OF THE INVENTION 1. Field of the Invention [0001]

TECHNICAL FIELD The present invention relates to a process for producing a thioxo puropyrimidine derivative and intermediates used therefor.

Korean Patent Publication No. 2011-0139653, International Publication Nos. WO2008 / 073785 and WO2008 / 152394 disclose furo [3,2-d] pyrimidine-2,4-dicyclohexylcarbamate (1H, 3H) -dione.

(A)

However, the compound of formula (A) disclosed in the above document has the following problems in the manufacturing process.

First, the compound of formula A is prepared by reacting tert - butylfuran -3-ylcarbamate with butyllithium at -30 ° C at low temperature to give methyl 3-aminofuran-2-carboxylate which is reacted with urea or chlorosulfonyl (ClSO ₂ NCO). However, since the production yield of the process is low and flammable high-risk reagents are used, cryogenic reaction conditions are required, so that the process cost is high and mass production is not easy.

Second, the compound of formula (A) has limited and low selectivity in the substitution reaction, and its utilization is low.

Accordingly, the present inventors have completed the present invention by developing a production method for mass production of a target compound at a high yield under a more safe and mild condition.

Korean Patent Publication No. 2011-0139653 International Publication No. WO 2008/073785 International Publication No. WO 2008/152394

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 accomplish the above object, the present invention provides a process for preparing a compound of formula (I), comprising the steps of: 1) reacting a compound of formula (2) 2) reacting the compound of formula 4 with hydrochloric acid or trifluoroacetic acid (TFA) to obtain a compound of formula 5 by Boc-deprotection; 3) reacting the compound of formula 5 with benzoylisothiocyanate to obtain a compound of formula 6; And 4) cyclizing the compound of formula (6) in the presence of a base to provide a 2-thioxopyrimidin-4-one compound of formula (1)

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

[Chemical Formula 1]

Wherein R < ¹ > is halogen.

In order to achieve the above object, the present invention provides a compound of the formula (4), a compound of the formula (5) and a compound of the formula (6) as an intermediate for preparing the compound of the formula (1).

Furthermore, the present invention provides a compound of formula (I) which is the final product of the above-described preparation process.

The present invention provides a series of processes for efficiently preparing a compound of formula (I) from a compound of formula (II) using a reagent which is easy to handle, safe and relatively inexpensive, and the process of the present invention is useful for the treatment of cancer and rheumatoid arthritis Can be used to prepare the furopyrimidinedione derivatives represented by the formula (A) and various other furopyrimidine derivatives which are key intermediates for producing an effective selective tyrosine kinase activity inhibitor.

The process for the preparation of the 2-thioxo puropyrimidin-4-one compound of formula (I) according to the present invention comprises the steps of: 1) reacting a compound of formula (2) with a compound of formula step; 2) reacting the compound of formula 4 with hydrochloric acid or trifluoroacetic acid (TFA) to obtain a compound of formula 5 by Boc-deprotection; 3) reacting the compound of formula 5 with benzoylisothiocyanate to obtain a compound of formula 6; And 4) cyclizing the compound of Formula 6 in the presence of a base.

As used herein, the term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

In a preferred example of the compounds of formulas (3) to (6) used in the preparation method of the present invention, R ¹ is chlorine.

Hereinafter, the production method of the present invention will be described in detail for each step.

First, in step 1), a compound of the formula (2) is reacted with a compound of the formula (3) in a solvent, as shown in the following reaction scheme 1, to obtain a compound of the formula (4).

[Reaction Scheme 1]

Wherein R < ¹ > is halogen.

In the above reaction, preferred examples of the compound of formula (3) include trichloroacetyl chloride (3A), and preferred examples of the compound of formula (4) include tert -butyl (2- (2,2,2- Acetyl) furan-3-yl) carbamate (hereinafter referred to as Formula 4A).

In step 1), a base may be used. Examples of the base include triethylamine, N, N-diisopropylethylamine, pyridine, and mixtures thereof. The amount of the base to be used may be 1.0 to 3.0 molar equivalents, preferably 1.2 to 1.5 molar equivalents based on 1 molar equivalent of the compound of formula (2).

The solvent used in step 1) may be selected from dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, N, N-dimethylacetamide, 1,4-dioxane, hexane, , Dichloromethane are preferred. The amount of the organic solvent used may be 5 to 30 ml based on 1 g of the compound of formula (2).

Next, in step 2), a compound of formula (5) is obtained by Boc-deprotection by reacting a compound of formula (4) with hydrochloric acid or trifluoroacetic acid (TFA)

[Reaction Scheme 2]

Wherein R < ¹ > is halogen.

In the above reaction, preferred examples of the compound of formula (4) include tert -butyl (2- (2,2,2-trichloroacetyl) furan-3- yl) carbamate Is a 1- (3-aminofuran-2-yl) -2,2,2-trichloroethane-1-one (formula 5A).

In step 2), hydrochloric acid or trifluoroacetic acid (TFA) is used to deprotect the Boc group (t-butyloxycarbonyl) of the compound of formula 4, and the hydrochloric acid is reacted with 1 mole of the compound of formula Preferably in an amount of 6 molar equivalents based on 1 g of the compound of formula (IV), and TFA may be used in an amount of 2 to 10 mL, preferably 4.2 mL, based on 1 g of the compound of formula (IV).

Next, in step 3), the compound of formula (5) is reacted with benzoyl isothiocyanate as shown in the following reaction scheme 3 to obtain the compound of formula (6).

[Reaction Scheme 3]

Wherein R < ¹ > is halogen.

In the above reaction, a preferable example of the compound of the formula (5) is 1- (3-aminofuran-2-yl) -2,2,2-trichloroethane- A preferred example of the compound is N - ((2- (2,2,2-trichloroacetyl) furan-3-yl) carbamothioyl) benzamide (formula 6A).

The benzoyl isothiocyanate (PhCONCS) used in the above reaction may be used in an amount of 1.0 to 2.0 molar equivalents, preferably 1.2 to 1.5 molar equivalents relative to 1 molar equivalent of the compound of formula (5). The benzoylisothiocyanate can be obtained by reacting benzoyl chloride with potassium thiocyanate in an organic solvent. For example, benzoylisothiocyanate is prepared by dissolving 200 g (1443 mmol) of benzoyl chloride in 1316 ml of acetonitrile, adding 138.3 g (1443 mmol) of potassium thiocyanate to the solution, refluxing for 3 hours , The reaction mixture was cooled to room temperature, the reaction solution was filtered, and the residue obtained by distillation under reduced pressure was dried under reduced pressure to obtain the compound (228.5 g, yield: 98%).

The organic solvent used in the reaction 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, ethyl acetate Or a mixture thereof. The amount of the organic solvent used is preferably 3 to 15 ml per g of the compound of the formula (5). The reaction may be carried out at 10 to 60 캜, and the compound of formula (6) is preferably obtained by cooling the reaction solution to 0 to 10 캜 after completion of the reaction and filtering.

Next, in step 4), the compound of formula (6) is cyclized in the presence of a base to give a compound of formula (1) as shown in the following reaction formula (4).

[Reaction Scheme 4]

Wherein R < ¹ > is halogen.

In this reaction, a preferred example of the compound of formula (6) is N - ((2- (2,2,2-trichloroacetyl) furan-3-yl) carbamoyl) benzamide .

The base used in the reaction may be an alkaline base, preferably sodium hydroxide, calcium hydroxide or a mixture thereof.

The cyclization reaction of step 4) may be carried out at a pH of 10 to 14. [

The base may be used in an amount of 2.0 to 4.0 molar equivalents, preferably 2.5 to 3.0 molar equivalents relative to 1 molar equivalent of the compound of formula (VI).

The reaction may be carried out in a solvent. The solvent used may be selected from the group consisting of methanol, ethanol, isopropanol and water, and a mixed solvent of water and methanol is preferably used. The weight ratio thereof is 1: 9 to 9: 1 is preferable. The amount of the solvent to be used is preferably 5 to 20 ml per 1 g of the compound of the formula (6). The reaction may be carried out at a temperature of 15 to 90 ° C, preferably at room temperature, and the reaction time may be 1 to 5 hours, preferably 4 hours.

After the reaction is completed, the pH of the reaction solution is neutralized to 7.5 to 8.0 with hydrochloric acid, and then the reaction solution is cooled to 0 to 10 ° C and filtered to obtain the desired 2-thioxopuripyrimidin- .

The present invention also provides a novel compound of formula (IV).

[Chemical Formula 4]

Wherein R < ¹ > is halogen.

A preferable example of the compound of formula (4) may be a compound represented by the following formula (4A).

[Chemical Formula 4A]

The present invention also provides a novel compound of formula (5).

 [Chemical Formula 5]

Wherein R < ¹ > is halogen.

A preferable example of the compound of formula (5) may be a compound represented by the following formula (5A).

[Chemical Formula 5A]

The present invention also provides a novel compound of formula (6).

 [Chemical Formula 6]

Wherein R < ¹ > is halogen.

A preferable example of the compound of the formula (6) may be a compound represented by the following formula (6A).

[Chemical Formula 6A]

The above-mentioned compounds of the formulas (4), (5) and (6) can be usefully used as an intermediate for preparing the compound of the formula (1).

In addition, the compound of formula (1) described above is useful as a key intermediate for the production of selective tyrosine kinase activity inhibitors effective for the treatment of cancer and rheumatoid arthritis. The furopyrimidinedione derivative represented by the formula (A) and various other furopyrimidine derivatives ≪ / RTI > For example, the compound of formula (I) may be reacted with chloroacetic acid to form a compound of formula (A).

EXAMPLES Hereinafter, the present invention will be described in detail with reference to Examples. However, the following Examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example  1: 2- Thioxo -2,3- Dihydro-furo [3,2-d] pyrimidine -4 (1H) -one < / RTI >

<1-1> tert -Butyl (2- (2,2,2- Trichloroacetyl ) Furan -3 days) Carbamate (Formula 4A )

40 g (218 mmol) of tert -butylfuran-3-ylcarbamate (formula 2A ; see WO2008073785A2) was diluted with 400 mL of dichloromethane (MC), followed by the addition of 26.5 g 262 mmol). After the reaction was cooled to 0 ° C, a solution of 29.2 ml (262 mmol) of trichloroacetyl chloride (Formula 3A ) in 200 ml of dichloromethane was added slowly and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was cooled to 0 占 폚, adjusted to pH 7 with a saturated aqueous sodium bicarbonate solution, and washed sequentially with distilled water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain a solid, which was dried under reduced pressure to obtain 73 g of the title compound (yield: 100%).

¹ H-NMR (300 MHz, DMSO-d ₆ )? 8.93 (s, IH), 8.16 (d, IH), 7.26 (d, IH), 1.49 (s, 9H).

&Lt; 1-2 > 1- (3- Aminofuran Yl) -2,2,2- Trichloroethane One (formula 5A )

73 g (222 mmol) of the compound ( 4A ) prepared in Example <1-1> was diluted with 365 ml of ethyl acetate, cooled to 0 ° C, and 58.8 ml (1332 mmol) of 12N hydrochloric acid was slowly added thereto. Lt; / RTI &gt; The reaction mixture was cooled to 0 &lt; 0 &gt; C and adjusted to pH 7 with a saturated aqueous sodium bicarbonate solution. Then, the reaction mixture was filtered under reduced pressure using a Celite-packed filter and washed with ethyl acetate. After filtration under reduced pressure, the obtained filtrate was separated, and the obtained aqueous layer was washed with ethyl acetate (X2). After filtration under reduced pressure, the separated organic layer was further extracted with an aqueous layer and the organic layer was dried over anhydrous sodium sulfate. The filtrate was subjected to vacuum filtration and distillation under reduced pressure to dry the residue under reduced pressure to obtain 46.2 g (yield: 91%) of the title compound.

^{1 H-NMR (300MHz, DMSO} -d 6) δ 7.82 (d, 1H), 7.05 (s, 2H), 6.32 (d, 1H).

<1-3> N - ((2- (2,2,2- Trichloroacetyl ) Furan -3 days) Carbamate oil ) Benzamide (Formula 6A )

46.2 g (202 mmol) of the compound prepared in Example <1-3> (Formula 5A ) was dissolved in 92.4 ml of acetonitrile, and 49.5 g (303 mmol) of benzoylisothiocyanate was added dropwise thereto. The reaction mixture was stirred at ambient temperature for 16 hours, cooled to 0 &lt; 0 &gt; C and then further stirred for 1 hour. The resulting solid was filtered under reduced pressure, washed with 138 ml of cooled acetonitrile, and dried under a humid atmosphere to obtain 23.1 g of the title compound (yield: 67%).

^{1 H-NMR (300MHz, DMSO} -d 6) δ 13.97 (s, 1H), 12.06 (s, 1H), 8.29 (m, 2H), 8.00 (m, 2H), 7.71 (m, 1H), 7.56 ( m, 2H).

<1-4> 2- Thioxo -2,3- Dihydro-furo [3,2-d] pyrimidine -4 (1H) -one (formula One )

23.1 g (59 mmol) of the compound ( 6A ) prepared in Example <1-3> was dissolved in methanol 231, and then a solution of 7.08 g (177 mmol) of sodium hydroxide in 28.9 ml of water was slowly added dropwise thereto, And stirred for 4 hours. The reaction mixture was cooled to 0 ° C, neutralized with a 6N aqueous hydrochloric acid solution, and stirred at 0 ° C for 1 hour. The resulting solid was filtered and washed successively with 46 ml of a mixed solvent of methanol and water (methanol: water = 5: 1, v / v) and 23 ml of acetone and dried under a humid atmosphere to obtain the title compound (8.46 g, ).

^{1 H-NMR (300MHz, DMSO} -d 6) δ 12.90 (s, 1H), 12.47 (s, 1H), 8.13 (d, 1H), 6.58 (d, 1H).

Claims (12)

1) reacting a compound of formula (2) with a compound of formula (3) in the presence of a solvent to obtain a compound of formula (4);
2) reacting the compound of formula 4 with hydrochloric acid or trifluoroacetic acid (TFA) to obtain a compound of formula 5 by Boc-deprotection;
3) reacting the compound of formula 5 with benzoylisothiocyanate to obtain a compound of formula 6; And
4) A process for producing a 2-thioxopuripyrimidin-4-one compound represented by the following formula (1), comprising cyclizing the compound of formula (6) in the presence of a base:
(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

[Chemical Formula 1]

Wherein R &lt; ¹ &gt; is halogen.
2. The process according to claim 1, wherein R &lt; ^{1 &gt;} is Cl.
The method of claim 1, wherein the solvent of step 1) is selected from the group consisting of dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, N, N-dimethylacetamide, 1,4-dioxane, &Lt; / RTI &gt;
2. A process according to claim 1, wherein in step 1) a base selected from the group consisting of triethylamine, N, N-diisopropylethylamine, pyridine or mixtures thereof is used.
The method of claim 1, wherein the reaction of step 3) 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, &Lt; / RTI &gt;
6. The process according to claim 5, wherein the organic solvent is acetonitrile, ethyl acetate or a mixture thereof.
The process according to claim 1, wherein the base of step 4) is alkali.
The process according to claim 7, wherein the alkali is sodium hydroxide, potassium hydroxide or a mixture thereof.
The process according to claim 1, wherein the cyclization reaction of step 4) is carried out at a pH of from 10 to 14.
A compound of formula 4:
[Chemical Formula 4]

Wherein R &lt; ¹ &gt; is halogen.
Compounds of formula 5:
[Chemical Formula 5]

Wherein R &lt; ¹ &gt; is halogen.
Compounds of formula 6:
[Chemical Formula 6]

Wherein R &lt; ¹ &gt; is halogen.