A method for synthesizing a pyrimidinone derivative and a pyrimidinone derivative

Abstract

The application discloses a synthesis method of a pyrimidinone derivative and the pyrimidinone derivative, and belongs to the field of organic synthesis. The method adopts p-toluenesulfonic acid as a reaction reagent, does not need to use an additional reaction solvent, realizes high-yield synthesis of compound 3 from compounds 1 and 2, and further selectively adds a Boc group on N of piperazine in compound 3 to obtain compound 4, so that the overall yield of the target compound 4 is greatly improved.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more specifically to a method for synthesizing pyrimidinone derivatives and pyrimidinone derivatives. Background Technology

[0002] Patent WO2022249060 A1 discloses a drug that can be used to treat diseases such as rectal cancer, gastric cancer, or endometrial cancer. The patent also discloses that compound 4 is an important intermediate in the synthesis of this drug.

[0003]

[0004] Patent WO2022249060A1 also reports the synthesis of compound 4 by constructing a pyrimidinone ring under mild reaction conditions in an ethanol solution of phosphoric acid. The reason for choosing such mild conditions is to prevent the loss of the Boc group from the starting material. Once the Boc is lost, an unprotected NH group can form, which can then undergo a series of side reactions with the carbonyl group in the starting material (see *Pharmaceutical Synthesis Chemistry*, 3rd edition, edited by Wen Ren, Beijing: Chemical Industry Press, January 2011, p. 78).

[0005] However, while mild reaction conditions can prevent Boc from detaching during the reaction, they also severely affect the reaction yield.

[0006] Furthermore, if a compound with the Boc group removed, as shown in Formula 3, is obtained, there is no effective method in the prior art to selectively attach a Boc group to the N atom of the piperazine ring and the N atom of the pyrimidinone.

[0007] Summary of the Invention

[0008] The present invention was made to solve the above-mentioned problems, and aims to provide a method for synthesizing pyrimidinone compounds in high yield even when Boc is detached during the reaction, as well as a pyrimidinone derivative intermediate used in the synthesis method.

[0009] This invention provides a method for synthesizing pyrimidinone derivatives, characterized by the following reaction formula:

[0010]

[0011] In the above formula, X is H, Cl, Br, or I, and R... 1 It is a C1-C5 alkyl group, R 2Selected from C1-C4 alkyl groups, C1-C4 alkyl groups substituted with one, two, or three halogens (F, Cl, Br, or I) or hydroxyl groups, C3-6 cycloalkyl groups, C1-4 alkoxy groups, amino-NR groups a R b -SR c R a R b It is a C1-4 alkyl group, R c It is a C1-4 alkyl group.

[0012] Includes the following steps:

[0013] Compound 1, Compound 2, and p-toluenesulfonic acid were mixed and heated to react, and no additional solvent was added to the reaction system before or during the reaction.

[0014] In one embodiment of the present invention, the C3-6 cycloalkyl group is specifically selected from cyclopropyl; the C1-4 alkoxy group is specifically selected from methoxy; the amino group is specifically selected from N,N-dimethylamino; -SR c Specifically, methyl mercaptoyl can be selected.

[0015] In one embodiment of the present invention, the molar ratio of compound 1 to compound 2 is (0.8-2):1. More specifically, it is (0.8-1.2):1.

[0016] In one embodiment of the present invention, the molar ratio of p-toluenesulfonic acid to compound 2 is (0.8-2):1. More specifically, it is (0.8-1.2):1.

[0017] In one embodiment of the present invention, the heating reaction temperature is 60-90°C; more preferably 75°C-82.5°C, and specifically 80°C. The reaction time can be specifically 16 hours.

[0018] This invention provides a method for synthesizing pyrimidinone derivatives, characterized by the following reaction formula:

[0019]

[0020] In the above formula, X is H, Cl, Br, or I; R1 is a C1-C5 alkyl group; and R2 is selected from C1-C4 alkyl groups, C1-C4 alkyl groups substituted with one, two, or three halogens (F, Cl, Br, or I) or hydroxyl groups, C3-6 cycloalkyl groups, C1-4 alkoxy groups, and amino-NR groups. a R b -SR c R a R b It is a C1-4 alkyl group, R c It is a C1-4 alkyl group.

[0021] Includes the following steps:

[0022] Step 1: Mix compound 1, compound 2 and p-toluenesulfonic acid and heat to react, without adding any additional solvent to the reaction system before or during the reaction.

[0023] Step 2: Compound 3 reacts with Boc2O in the presence of a base and a solvent to give compound 4.

[0024] In one embodiment of the present invention, the C3-6 cycloalkyl group is specifically selected from cyclopropyl; the C1-4 alkoxy group is specifically selected from methoxy; the amino group is specifically selected from N,N-dimethylamino; -SR c Specifically, methyl mercaptoyl can be selected.

[0025] In one embodiment of the present invention, the molar ratio of compound 3 to Boc2O is 1:(0.8-1.2).

[0026] In one embodiment of the present invention, the relative solvent concentration of compound 3 is 0.05-0.1 g / mL.

[0027] In one embodiment of the present invention, the solvent is tetrahydrofuran, a mixture of tetrahydrofuran and water, or a mixture of tetrahydrofuran and DMF.

[0028] In one embodiment of the present invention, the solvent is a mixture of tetrahydrofuran and water, with a volume ratio of (1-2):(1-2), preferably 1:1.

[0029] In one embodiment of the present invention, the solvent is a mixture of tetrahydrofuran and DMF, with a volume ratio of (1-2):(1-2), preferably 1:1.

[0030] In one embodiment of the present invention, the molar ratio of compound 3 to the base is 1:(1-5); specifically, 1:2 may be selected.

[0031] In one embodiment of the present invention, the alkali is selected from any one or more of the following: sodium hydroxide, potassium hydroxide, triethylamine, and diisopropylethylamine.

[0032] This invention provides a pyrimidinone derivative having the following characteristics and structural formula:

[0033]

[0034] In the above formula, X is H, Cl, Br, or I, and R2 is selected from C1-C4 alkyl groups, C1-C4 alkyl groups substituted with one, two, or three halogens (F, Cl, Br, or I) or hydroxyl groups, C3-6 cycloalkyl groups, C1-4 alkoxy groups, amino groups, and NR groups. a R b-SR c R a R b It is a C1-4 alkyl group, R c It is a C1-4 alkyl group.

[0035] In one embodiment of the present invention, the C3-6 cycloalkyl group is specifically selected from cyclopropyl; the C1-4 alkoxy group is specifically selected from methoxy; the amino group is specifically selected from N,N-dimethylamino; -SR c Specifically, methyl mercaptoyl can be selected.

[0036] In one embodiment of the present invention, the pyrimidinone derivative can be used as an intermediate in the synthesis of an active compound.

[0037] The role and effect of invention

[0038] According to the method for synthesizing pyrimidinone derivatives of the present invention, since p-toluenesulfonic acid is used as the reaction reagent and no additional reaction solvent is required, although the method causes Boc to be released, it has been unexpectedly found that no theoretically possible side reactions occur, thereby obtaining the target product in high yield.

[0039] Furthermore, the present invention also provides a method for selectively attaching a Boc group to the N of a piperazine, thereby greatly improving the overall yield of the target compound. Detailed Implementation

[0040] To make the technical means, creative features, objectives and effects of this invention easy to understand, the invention will be specifically described below in conjunction with embodiments.

[0041] In the following embodiments, unless otherwise stated, all raw materials are commercially available products or synthesized in accordance with published literature.

[0042] <Example 1>

[0043] Preparation of compound 3a

[0044] This embodiment provides a method for preparing compound 3a, and the reaction formula is as follows:

[0045]

[0046] Includes the following steps:

[0047] 78 g of compound 1a (0.478 mol, 1.57 eq), 100 g of compound 2a (0.304 mol, 1.0 eq), and 75 g of p-toluenesulfonic acid (0.436 mol, 1.43 eq) were mixed without adding any additional solvent. The mixture was heated to 80 °C, and the reaction system was converted into a liquid state. The mixture was stirred for 16 h. After the reaction was completed, column chromatography was performed to obtain 98.5 g of compound 3a as a yellow solid, with a yield of 99.0%.

[0048] LCMS:m / z(ESI),[M+H] + =327

[0049] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 3.87–3.76 (m, 2H), 3.24 (d, J = 12.0 Hz, 2H), 3.04–2.90 (m, 3H), 2.74–2.63 (m, 4H), 1.11 (t, J = 7.5 Hz, 3H). (Note: One nitrogen and hydrogen peak was not observed.)

[0050] <Comparative Example 1>

[0051] Preparation of compound 3a

[0052] This comparative example provides a method for preparing compound 3a, and the reaction formula is as follows:

[0053]

[0054] Includes the following steps:

[0055] 15 g of compound 1a (92.0 mmol, 1.0 eq), 45.3 g of compound 2a (138 mmol, 1.5 eq), and 2.38 g of p-toluenesulfonic acid (13.8 mmol, 0.15 eq) were added to 100 mL of toluene. The mixture was heated to 120 °C and stirred for 16 h. After cooling to room temperature, the solvent was removed by concentration under reduced pressure. The mixture was then subjected to column chromatography to obtain 5.3 g of compound 3a and 6.2 g of compound 1a, respectively.

[0056] <Comparative Example 2>

[0057] Preparation of compound 3a

[0058] This comparative example provides a method for preparing compound 3a, and the reaction formula is as follows:

[0059]

[0060] Includes the following steps:

[0061] 15 g of compound 1a (92.0 mmol, 1.5 eq) and 20.1 g of compound 2a (61.3 mmol, 1.0 eq) were added to 100 mL of acetic acid. The mixture was heated to 120 °C and stirred for 16 h. After cooling to room temperature, the mixture was diluted with 100 mL of water, and the pH was adjusted to 6 with the addition of solid sodium carbonate. The mixture was extracted with ethyl acetate, and the organic phase was collected, concentrated under reduced pressure, and subjected to column chromatography to obtain 6.7 g of compound 3a and 5.4 g of compound 1a, respectively.

[0062] <Example 2>

[0063] Preparation of compound 4a

[0064] This embodiment provides a method for preparing compound 4a, and the reaction formula is as follows:

[0065]

[0066] Includes the following steps:

[0067] 156 g of compound 3a (0.477 mol, 1.0 eq) was dissolved in a mixed solution of 780 mL water and 780 mL tetrahydrofuran. The solution was cooled to 0 °C, and 38 g of sodium hydroxide solid (0.950 mol, 2.0 eq) and 114 g of di-tert-butyl dicarbonate (0.525 mol, 1.1 eq) were added sequentially. The solution was allowed to return to room temperature naturally, and the mixture was stirred for 3 h.

[0068] Tetrahydrofuran was removed by concentration under reduced pressure. 500 mL of saturated saline and 500 mL of isopropanol were added, and the mixture was extracted. The organic phase was collected and concentrated under reduced pressure to form a solid. The solid was purified by column chromatography to give 167 g of compound 4a, a yellow solid, with a yield of 81.9%.

[0069] <Example 3>

[0070] Preparation of compound 4a

[0071] This embodiment provides a method for preparing compound 4a, and the reaction formula is as follows:

[0072]

[0073] Includes the following steps:

[0074] 30 g of compound 3a (91.7 mmol, 1.0 eq) was dissolved in a mixed solution of 300 mL DMF and 300 mL tetrahydrofuran. The solution was cooled to 0 °C, and 18.5 g of triethylamine (0.183 mol, 2.0 eq) and 22.0 g of di-tert-butyl dicarbonate (0.101 mol, 1.1 eq) were added sequentially. The solution was allowed to return to room temperature naturally, and the mixture was stirred for 3 h.

[0075] Tetrahydrofuran and DMF were removed by concentration under reduced pressure, and the resulting solid was purified by column chromatography to give 28.6 g of compound 4a, a yellow solid, with a yield of 72.9%.

[0076] <Example 4>

[0077] Preparation of compound 4a

[0078] This embodiment provides a method for preparing compound 4a, and the reaction formula is as follows:

[0079]

[0080] Includes the following steps:

[0081] 30 g of compound 3a (91.7 mmol, 1.0 eq) was added to 600 mL of tetrahydrofuran, cooled to 0 °C, and then 18.5 g of triethylamine (0.183 mol, 2.0 eq) and 22.0 g of di-tert-butyl dicarbonate (0.101 mol, 1.1 eq) were added sequentially. The mixture was allowed to return to room temperature naturally, and the mixture was stirred for 3 h.

[0082] Tetrahydrofuran was removed by concentration under reduced pressure, and the resulting solid was purified by column chromatography to give 18.6 g of compound 4a, a yellow solid, with a yield of 47.4%.

[0083] <Comparative Example 3>

[0084] Preparation of compound 4a

[0085] This comparative example provides a method for preparing compound 4a, and the reaction formula is as follows:

[0086]

[0087] Includes the following steps:

[0088] 15 g of compound 1a (92.0 mmol, 1.0 eq) was dissolved in 90 mL of ethanol, and 31.8 g of compound 2a (96.8 mmol, 1.05 eq) was added. 9 g of phosphoric acid (92.0 mmol, 1.0 eq) was added dropwise at room temperature. The mixture was heated to 80 °C and stirred for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was subjected to column chromatography to give 5.6 g of compound 4a and 5.5 g of compound 1a, respectively. The yield of compound 4a was 14.2%.

[0089] The role and effect of the embodiments

[0090] According to the method for synthesizing pyrimidinone derivatives of the present invention, since p-toluenesulfonic acid is used as the reaction reagent and no additional reaction solvent is required, although the method causes Boc to be released, it has been unexpectedly found that no theoretically possible side reactions occur, thereby obtaining the target product in high yield.

[0091] Furthermore, the present invention also provides a method for selectively attaching a Boc group to the N of a piperazine, thereby greatly improving the overall yield of the target compound. The yield of the two-step reaction can reach up to 81%, which is much higher than that of the one-step reaction.

[0092] The embodiments provided above are not intended to limit the scope of the invention, nor are the described steps intended to limit the order of execution. Any obvious modifications made to the invention by those skilled in the art based on existing common knowledge also fall within the scope of protection defined in the claims of this invention.

Claims

1. A method for synthesizing a pyrimidinone derivative, characterized in that, The reaction formula is as follows: In the above formula, X is H, Cl, Br, or I; R1 is a C1-C5 alkyl group; R2 is selected from C1-C4 alkyl groups, C1-C4 alkyl groups substituted with 1-3 independent halogens or hydroxyl groups, C3-6 cycloalkyl groups, and N,N-dimethylamino groups. Includes the following steps: Compound 1, Compound 2, and p-toluenesulfonic acid were mixed and heated to react, and no additional solvent was added to the reaction system before or during the reaction.

2. The method for synthesizing pyrimidinone derivatives according to claim 1, characterized in that: in, The temperature for the heating reaction is 60℃-90℃.

3. The method for synthesizing pyrimidinone derivatives according to claim 1, characterized in that: in, The molar ratio of p-toluenesulfonic acid to compound 2 is (0.8-2):

1.

4. The method for synthesizing pyrimidinone derivatives according to claim 1, characterized in that: in, The molar ratio of compound 1 to compound 2 is (0.8-2):

1.

5. A method for synthesizing a pyrimidinone derivative, characterized in that: in, The reaction formula is as follows: In the above formula, X is H, Cl, Br, or I, R1 is a C1-C5 alkyl group, and R2 is selected from C1-C4 alkyl groups, C1-C4 alkyl groups substituted with 1-3 independent halogens or hydroxyl groups, C3-6 cycloalkyl groups, and N,N-dimethylamino groups. Includes the following steps: Step 1: Mix compound 1, compound 2 and p-toluenesulfonic acid and heat to react, without adding any additional solvent to the reaction system before or during the reaction. Step 2: Compound 3 reacts with Boc2O in the presence of a base and a solvent to give compound 4.

6. The method for synthesizing pyrimidinone derivatives according to claim 5, characterized in that, in, The solvent in step 2 is tetrahydrofuran, a mixture of tetrahydrofuran and water, or a mixture of tetrahydrofuran and DMF.

7. The method for synthesizing pyrimidinone derivatives according to claim 5, characterized in that, in, The base used in step 2 is selected from any one or more of the following: sodium hydroxide, potassium hydroxide, triethylamine, and diisopropylethylamine.

8. The method for synthesizing pyrimidinone derivatives according to claim 5, characterized in that, in, In step 2, the molar ratio of compound 3 to Boc2O is 1:(0.8-1.2).

9. The method for synthesizing pyrimidinone derivatives according to claim 5, characterized in that, in, In step 2, the molar ratio of compound 3 to the base is 1:(1-5).

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