JPH03215475A - Production of 1-amino-5-halogenouracil - Google Patents

Abstract

PURPOSE:To obtain the objective compound useful as a drug having central nerve suppressing action and antianxiety action in high yield without causing side reaction by reacting a 1-acylaminouracil with a halogenation agent and deacylating the product. CONSTITUTION:The objective compound of formula III can be produced by reacting a 1-acylaminouracil of formula I (R is acyl) with a halogenation agent (e.g. N-halogenosuccinimide) in a solvent (e.g. DMF) at a temperature between 50 deg.C and the refluxing temperature to obtain a 1-acylamino-5-halogenouracil of formula II (X is halogen) and removing the acyl group from the compound of formula II by deacylating the compound with an acid (e.g. hydrochloric acid) at a temperature between 50 deg.C and the refluxing temperature.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel method for producing 1-amino-5-halogenouracil.

1-Amino-5-halogenouracil has a central nervous system depressing effect and an anxiolytic effect, and is a compound expected to be used as a pharmaceutical.

[Prior Art] Conventionally, a method for producing 1-amino-5-fluorouracil has been reported as a method for producing a compound having an amino group at the 1-position of pyrimidine, such as a 5-monosubstituted derivative of 1-aminouracil. Specifically, in this method, 5-fluorouracil is aminated with 0-(2,4-dinitrophenyl)hydroxyamine or hydroxylamine 10-sulfonic acid, and then penzylidened to form 11penzylidene amino and 1.3- 1-Amino-5-fluorouracil was prepared by obtaining a mixture with a bisbenzylidene amino compound, separating the 1-benzylidene amino compound (1-penzylidene amino-5-fluorouracil), and then performing acidic hydrolysis (conventional method). (Sci. Pharm.
, 52. 46 (1984), Bull. Che
m. Soc. Jpn. , 62, 674 (19
89)).

[Problems to be Solved by the Invention] In the conventional method, when preparing the 1-benzylidene amino form of pyrimidine, which is an intermediate, the 1,3-bisbenzylidene amino form is always produced. This method requires separation of the 1,3-bisbenzylidene amino compound and has the drawback that the target compound can only be obtained in a low yield.

The present inventors previously demonstrated that the 2nd and 4th positions of 5-halogenouracil
We developed a method for synthesizing 1-amino-5-halogenouracil by introducing a protecting group at the <. PCT/JP 8 9/
O O 7 0 8). This method can synthesize the target product in high yield, but the aminating agent used (e.g.
O-mesitylenesulfonylhydroxyamine) is unstable, difficult to handle, and expensive, making it unsuitable for large-scale synthesis.

Although a method of directly halogenating 1-aminouracil is also considered, direct halogenation reaction of 1-aminouracil (for example, reaction with N-halogenosuccinimide in acetic acid or in the presence of a base such as sodium acetate) , a method involving treatment with a halogen) involves deamination as a side reaction, so it is impossible to obtain 1-amino-5-halogenouracil in good yield.

[Means for Solving the Problems] As a result of repeated research on a simple and efficient method for producing 1-amino-5-halogenouracil, the present inventors found that the amino group of 1-aminouracil, a known compound, was converted into acyl. The present invention was completed based on the finding that a halogen atom can be introduced into the 5-position without a deamination reaction by using a group-protected compound as a raw material.

That is, the present invention is based on the formula [I] [wherein, X represents a halogen atom]. ] A method for producing 1-amino-5-halogenouracil represented by the formula [1
1 [Wherein, R represents an acyl group. ] is reacted with a halogenating agent (halogenation reaction) to form a compound of the formula [I[[]○ [wherein X and R have the same meanings as above. ] 1-
Acylamino-5-halogenouracil was obtained, formula [II[
] A method for producing 1-amino-5-halogenouracil, which comprises subjecting the compound represented by formula [I] to a deacylation reaction to remove an acyl group to obtain a compound represented by formula [I]. It is related to.

The present invention will be explained in detail below.

(Preparation of raw material compound) 1-acylaminouracil used as a raw material compound in the present invention can be prepared by subjecting 1-aminouracil to an acylation reaction. 1-Aminouracil is W. Klotzer, M. Herberz
(Mh. Chem. 96. 1731 (196
5)) This is a known compound reported by.

Acylation of 1-aminouracil is carried out by the usual acylation reaction (
For example, if excess acid anhydride and 1-aminouracil are
℃ to reflux temperature for 1 to 30 hours, in the presence of a tertiary organic base such as pyridine, vicolin, or triethylamine, an excess amount of an acylating agent such as an acid anhydride or an acid halide and 1-aminouracil are reacted to 0. It can be carried out by a method of reacting at ~50°C for 1 to 30 hours).

The acylating agent is not particularly limited, but it is usually an acid anhydride or acid halide of a carboxylic acid having a lower acyl group, preferably having 5 or less carbon atoms (such as acyl chloride, acyl fluoride, acyl bromide, acyl iodide, etc.). ) are preferred. Specifically, acid anhydrides or acid halides such as acetic acid, probionic acid, bivaric acid (trimethylacetic acid), and butyric acid can be mentioned.

In addition, if an excess of acyl group is introduced into the amino group at the 1-position and the 3-position of the uracil skeleton, the reaction solution after the acylation reaction can be treated with the usual method applied to partial hydrolysis. 1-Aminouracil can be obtained. For example, the reaction solution is mixed with 1 to 2 equivalents of potassium carbonate in an alcohol such as methanol or ethanol at 0°C to room temperature.
1-acylaminouracil can be obtained by treating for ~30 hours, or by adjusting the reaction solution to pH 10-12 with aqueous ammonia and treating it at 10-60°C.

The 1-acylaminouracil thus obtained can be isolated and purified by appropriately combining conventional isolation and purification means applied to nucleic acid bases (for example, chromatography methods such as adsorption, recrystallization methods, etc.).

(Halogenation reaction) Halogenation of 1-acylaminouracil can be carried out using a normal halogenating agent containing a halogen atom such as chlorine, fluorine, bromine, or iodine, according to a normal halogenation reaction method and conditions. can.

As the halogenating agent, for example, N-halogenosuccinimide, molecular (single substance) halokenna, etc. can be used.

When N-halogenosuccinimide is used as the halogenating agent, the reaction can be carried out, for example, by mixing 1-acylaminouracil with 1 to 1
, 50°C using 5 equivalents of N-halogenosuccinimide.
This can be carried out by treatment at ~reflux temperature for 1 to 5 hours.

The l-acylamino-5-halogenouracil thus obtained can be isolated and purified by an appropriate combination of conventional isolation and purification methods applied to nucleic acid bases (for example, chromatography methods such as adsorption, recrystallization methods, etc.). can.

(Deacylation Reaction) The acyl group of the amino group at the 1-position can be removed by treatment using a conventional method and conditions depending on the acyl group to be removed. For example, acid treatment (for example, in an aqueous mineral acid solution such as hydrochloric acid, perchloric acid, or sulfuric acid at 50°C to reflux temperature)
It can be removed by a method of processing for ~30 hours).

The 1-amino-5-halogenouracil thus obtained can be purified by conventional isolation and purification means applied to nucleic acid bases (for example,
Isolation and purification can be carried out by appropriately combining chromatography methods such as adsorption, recrystallization methods, etc.).

[Example] Below, reference examples and examples are shown, I will explain in detail.

(Reference Example) 1-Acetylaminouracil The present invention was prepared using 1-aminouracil (80 g, 629 mmol).
) was refluxed in acetic anhydride (420 ml) for 1 hour. After cooling the reaction solution, it was concentrated to dryness under reduced pressure. The resulting residue was suspended in water (400 ml), dissolved while adjusting the pH to 11 with aqueous ammonia, and allowed to stand for 15 minutes. Next, the crude product obtained by concentration was mixed with water (500 ml
) to obtain 69 g (yield 65%) of l-acetylaminouracil crystals. .

Melting point 241-242℃ Silent spectrum (δ, ppm, DMSO-ds)
1.97 (3H, s) 5.55 (IH, dd, J=7.8, 2.4Hz
, singlet with the addition of D20) 7.56 (LH, s) 11.86 (IH, s, disappears with the addition of D20) (Example 1) 1-acetylaminouracil (40 g, 236 m
N-chlorosuccinimide (34.7 mol) was dissolved in acetic acid (377 ml) by heating to 90°C.
g, 260 mmol) and stirred for 2 hours. After cooling the reaction solution, it was concentrated to dryness under reduced pressure. Water (
After stirring for 30 minutes, the mixture was cooled overnight.

The resulting crystals were collected by filtration and dried to give 1-acetylamino-5-
39.9 g (yield: 83%) of chlorouracil was obtained.

Melting point: 282-284℃ (decomposed) Spectrum: 1.97 (3H, 8.35 (LH, 11.03 (LH, LH, 12.10 (IH, Torr (δ, ppm, DMSO-da)S) S) s, D Disappeared upon addition of 20) s, D Disappeared upon addition of 20) 1-acetylamino-5-chlorouracil (39.9
g, 196 mmol) in 1.2N sulfuric acid (980 m
l) and heated at 90°C for 3 hours. The precipitate formed by cooling the reaction solution was collected by filtration, suspended in water (300 ml), and dissolved while adjusting the pH to 11 with aqueous ammonia.

Next, the crude crystals obtained by concentration were collected by filtration, and water (500
ml) to obtain 28 g (yield: 88%) of 1-amino-5-chlorouracil as colorless crystals.

Melting point 224-225℃ Elemental analysis Calculated value as C4H4N302Cl (%)
C, 29.74; H, 2.50; N, 26.
01 Actual value (%) C, 29.83; H, 2.55
; N, 25.93 excitation spectrum 5.54(2H, 8.09(LH, 11.86(LH, L(δ, ppm, DMSO-de)S, NH
2, D Disappears with the addition of 20) s, 6-H) S, NH, Disappears with the addition of D 20) MS spectrum (EI) C4H4N302 Cl, m/z 161 (M)
．． tis, 90 (Example 2) 1-amino-5-promouracil 1-acetylaminouracil (40 g, 236 dishes o
1) was added to acetic acid (37'7 ml), heated to 90°C to dissolve, and N-promosuccinimide (34.
7 g, 260 mmol) and stirred for 2 hours. After cooling the reaction solution, it was concentrated to dryness under reduced pressure. Water (180 ml) was added to the resulting residue, stirred for 30 minutes, and then cooled overnight. The resulting crystals were collected by filtration and dried to yield 39.9 g of 1-acetylamino-5-promouracil (yield: 83%).
Obtained.

Melting point 236-238℃ (decomposed) 1.97 (3H, 8.24 (LH, 11.02 (IH, 12.06) S) s, , D Disappeared by addition of 20) s, D Disappeared by addition of 20) 1-acetylamino-5-promouracil (39.7
g, 160 mmol) in 1.2N sulfuric acid (800 m
1) and heated at 85°C for 5 hours. The reaction solution was cooled overnight, and the resulting precipitate was collected by filtration, suspended in water (300 ml), and dissolved while adjusting the pH to 11 with aqueous ammonia. Next, the crude crystals obtained by concentration were collected by filtration, and water (6
00 ml) to obtain 29.3 g (yield 89%) of l-amino-5-promouracil as pale yellow crystals.
)Obtained.

Melting point 213-214°C Elemental analysis Calculated value as C4H4N302Br-H20 (%) C, 21.62; H, 2.69; N
, 18.75 Actual value (%) C, 21.76; H
, 2.66; N, 18.71 NMR spectrum (δ
, ppm, DMSO-da) 5.54 (2H,
Disappeared by adding S, NH2, D20) 8.14 (L
H, s, 6-H) 11.84 (LH, S, NH, D Disappeared by addition of 20) MS spectrum (EI) C4H4N302 Br, m/z 205, 207
(M ”), 164, 162, 136, 134
(Example 3) 1-Amino-5-iodouracil 1-acetylaminouracil (1.69 g, 10 m
mol) was added to acetic acid (20 ml), heated to 80°C to dissolve, and to this was added N-iodosuccinimide (3.3
7 g, 15 mmol) and stirred for 2 hours. After cooling the reaction solution, it was concentrated to dryness under reduced pressure. Water (20 ml) was added to the resulting residue, and after stirring for 30 minutes, the resulting crystals were collected by filtration and dried to obtain 1.32 g (yield: 45%) of 1-acetylamino-5-iodouracil. Ta.

Melting point 247-249℃ (decomposition) Traction spectrum (δ, ppm, DMSO-da)
1. 96 (3H, s) 8.16 (LH, s) 10.97 (LH, S, D disappears with addition of 20) 11
．． 91 (disappeared upon addition of IH, s, D 20) 1-acetylamino-5-iodouracil (472 mg, 1.
Add 6 mmol) to 1.2N sulfuric acid (8 ml),
Heated at 5°C for 5 hours. The reaction solution was cooled and the resulting precipitate was collected by filtration, suspended in water (30 ml), and purified with aqueous ammonia.
The solution was dissolved while adjusting H to 11. Next, the crude crystals obtained by concentrating with a ν ball were collected by filtration, and then recrystallized from water to obtain 12 omg of l-amino-5-iodouracil (yield 30%).
Obtained Melting point 195-196℃ Elemental analysis C4H4N302 Calculated value (%)
C, 18.99; H, 1.59; N, 16.61
Actual value (%) C, 19.05; H, 1.57
; N, 16.51 NMR spectrum (δ, ppm
, DMSO-da) 5.51 (2H, S, N
Disappeared by adding H2, D20) 8.08 (LH, s
, 6-H) 11.69 (LH, s, NH, D
MS spectrum (EI) C4H4N302 I, m/z 253 (M ),
210, 182, 153 [Effects of the Invention] The method of the present invention halogenates the 5-position of 1-acylaminouracil using an extremely simple method compared to conventional methods, thereby achieving high yields without causing side reactions. 1-Amino-5-halogenouracil can be prepared. Furthermore, the reagents used can be selected to be inexpensive and easy to handle.

Patent applicant (677) Yamasa Soy Sauce Co., Ltd. Continued Supplementary Positive book (spontaneous) 2. name of invention Method for producing 1-amino-5-halogenouracil 3. person who makes corrections Relationship with the incident

Claims (1)

[Claims] 1) Formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, X represents a halogen atom. ] A method for producing 1-amino-5-halogenouracil represented by the formula [I
I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R represents an acyl group. 1-acylaminouracil represented by ] is reacted with a halogenating agent to form the formula [III] ▲There are numerical formulas, chemical formulas, tables, etc.▼ [In the formula, X and R have the same meanings as above. ] 1-
Acylamino-5-halogenouracil was obtained, formula [III]
A method for producing 1-amino-5-halogenouracil, which comprises subjecting the compound represented by the above formula to a deacylation reaction to remove an acyl group to obtain a compound represented by the formula [I].