JPS5821914B2 - Imidazole Yudou Taino Seihou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an imidazole derivative, and more particularly to a method for producing an imidazole derivative represented by the following formula: [wherein k represents a hydrogen atom or a benzyl group].

The target compound (I) is a sulfolene compound represented by the formula (■): Formula: X, NHCOORl or X2. NC00R1(
X is a halogen atom, R1 is a lower alkyl group) is reacted with a halogenourethane compound represented by the formula (■)
: A compound represented by the formula (■) is obtained by reacting it with a dehalogenating agent, which is then hydrolyzed and decarboxylated to form the formula (
V): A compound represented by: or an acid addition salt thereof is obtained, and this is converted into the formula:
It can be obtained by reacting with isocyanic acid represented by NCO (R represents H, NH, an alkali metal atom, or a benzyl group) or a derivative thereof.

Here, the sulfolene compound represented by formula (II) can be used without solvent, benzene, ether, T, HoFl,
In solvents such as dioxane and carbon disulfide, under inert gas,
The reaction is carried out with a halogenourethane compound at a temperature ranging from room temperature to reflux temperature.

Examples of the halogenourethane compound to be used include dichlorourethane, cyfuromourethane, and monochlorourethane. In addition, known methods using halogen and cyanamide can also be carried out.

The thus obtained compound represented by formula (III) is treated with a dehalogenating agent such as NaHCO3, NaOH1Na2
It is reacted with C03 or a tertiary amine or a metal catalyst such as zinc or magnesium in an appropriate solvent.

The compound represented by formula (IV) thus obtained is reacted with hydroiodic acid, hydrobromic acid, hydrochloric acid, or an alkali to obtain a compound represented by formula (V) or an acid addition salt thereof.

The compound represented by formula (V) is. An acid addition salt type is preferred in terms of stability.

The thus obtained compound represented by formula (V) or an acid addition salt thereof is treated with incyanic acid or its derivative RNCO (
R represents H, NH4, an alkali metal atom or a benzyl group) in the absence of a solvent or in an organic solvent or water, followed by ring closure to obtain the object compound (I) of the present invention.

The isocyanic acid derivatives used here are:
KNCO, NaNC01NH4NCO, C6H3CH2
NCO, etc. The method of the present invention includes formula (III),
Via the new compounds represented by (IV) and (V),
It is characterized in that the compound represented by formula (I) can be obtained in high yield and as a cis-type compound.

The target compound of the present invention is a compound useful as an intermediate for biotin production, but the method of the present invention is generally applicable to industrial
This method is useful as a method for producing compounds with a cis-type bone core.

Next, the method of the present invention will be explained with reference to Examples.

Example 1 Preparation of 3-chloro-4-ethoxycarbonylaminothiophane-1,1-dioxide: Nisulfolene 15 (1) was suspended in 1501 rL of dry benzene and the reaction temperature was raised to 20-25 ml while stirring in a nitrogen stream.
200 g of N--N dichlorourethane was gradually added dropwise while maintaining the temperature at °C.

After the addition was complete, the reaction mixture was kept at reflux for 1 hour at room temperature.
Stir for 5 hours and then cool to room temperature.

Next, the internal temperature is cooled to 0 to 5°C, and 400 rrL of a 20% aqueous sodium bisulfite solution is gradually added dropwise with stirring at 5 to 10°C over 1 hour or more, and further stirred for 1 hour.

One precipitate, which is the target product, is taken and washed with benzene and water.

Wash the benzene layer with water and dry with Glauber's salt.

The solvent is removed and the resulting oily residue is allowed to stand overnight to obtain white crystals.

Yield 114.51 (yield 37.4%), melting point 190-1
Ha 1.5℃.

ujol IRν m': 3320 (-NH-), aX 1685.1540 (-NHCOOC2H5), 133
0.1130 (-8O□-).

NMR (10ONIHz, d6 DMSO) δppm
:120 (3H1 triple line, J=7-OHz, 0-C-
CF2), 2.99-3-40 (2H1 multiplet), 3.
44-3.90 (2H, multiplet), 4.06 (2H1
quartet, J = 7.0Hz, 0~CH2-C), 4.
20-4.90 (2H1 multiplet), 7.56-7.8
8 (In2 broad, -NH-C.

(Exchanged with D20).

Elemental analysis value (%): Actual value: C, 34,76; H14,8]; N, 5.7
8S, l 3.03; C1, 14,678 theoretical value (C7H, 204 NSCI): C134,79; H2
S, 00; N, 5.80; S, 13.27; C
1,14,67゜Example 2 Production of 2,3-dehydro-4-ethoxycarbonylaminothiophane-1,1-dioxide: Compound 101 obtained in Example 1 was mixed with 30 ml of ethyl alcohol and 5 g of anhydrous sodium carbonate. and stirred at 95-100°C for 2 hours.

The reaction mixture was concentrated to dryness under reduced pressure, and the residue was dissolved in water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate.

Then ml of solvent was removed to obtain 8.01 oil,
When this is treated with ether, crystals are precipitated, and after 1 suction, 7.8 P (yield 93%, melting point 100-103°C) is obtained.
Obtain the crystals.

When recrystallized from a mixture of ether and ethyl acetate, the melting point is 106 ~
A purified product with a temperature of 107.5°C is obtained.

Br IRv cra': 3320.3060.
1690, aX]530.1300,1285.1255.1100.
1050°NMR (6OMHz, d6-DMSO) δppm;
1.12 (3H1 triplet, J=7, OHz, 0-C-C
H5), 2.97 (IH, double track, JAX=48Hz
, JAB=13.2H2), 3.62 (IH1 double double double line BX = 7.2 Hz, JAB = 13
．． 2Hz), 3.98 (2H1 quartet, J=7.0Hz
, 0-CH2-C), 4.55-5.10 (IH1 multiplet), 6.72 (IH, double line multiplet, J ANX/ =
2.4Hz, JAB'=6.6 H7), 7
．． 0 (IH, double track, JR'X' = 2.4 H7,
JA'By = 6.6 Hz), 7.50-7.95
(IH, broad, -NH-C.

(Replaced with D20) Elemental analysis value (%) 2 Actual values: C, 40, 9]; H5, 36; H16, 56
S, 15.47° Theoretical value (C7H,,04NS): C140,97
; H5,40; N, 6.82'; S, l 5
．． 62゜Example 3 Production of 2,3-dehydro-4-aminothiophane-11-dioxide hydrobromide: Compound 5f obtained in Example 2 was added to a 47% aqueous solution of hydrobromic acid 501nj! and reflux for 2.5 hours.

The solution portion was separated, concentrated to dryness, and the residue was treated with methanol, and then 1 portion was taken to obtain crude crystals.5. OS' (yield 96%, melting point 258° C.) is obtained.

When recrystallized from a mixture of methanol and water, the melting point is 260-26.
Obtain a purified product at 2°C (decomposition).

Br IRI/CIIL': 31.75.2800
-2500゜aX 1580.1485.1290.1130.760゜NIVIR (l OOMHz, D20) δppm
: 3.54 (IH1 double double double line double line AX=4.5H
z, JAB = 15, 0Hz), 3-96 (IH, double track, JBX 8.OH7, JAB = 15, OHz
), 4.88-5.10 (IH, multiplet), 7.07
(IH1 double double double line double line A'zl = 1.8 Hz,
tlA'B"" 6.0 Hz), 7.27 (IH1
Double double double line double line Blx/2- I Hz 1JA'B'
-6-oHz).

Elemental analysis value (%): Actual value: C122,45; H, 3,77; N, 6.7
0; S, l 4.76; Br, 37.27° Theoretical value (C4H,0□N5Br): C,22,4
4;H.

3.77; N, 6.54: S, 14.97
;Br.

37.32゜Example 4 Hexahydro-2-oxo-1H-cheno-[3°4-
d]-Manufacture of imidazole-5,5-dioxide: 2.0y of the compound obtained in Example 3 and 1.57y of potassium isocyanate were mixed in 12ml of water and refluxed for 3 hours.

Next, when left at 10°C or lower, crystals precipitate, which are dried in a vacuum desiccator to yield 7671nfi! (Yield 47%
) to obtain crystals.

Recrystallize with water to obtain a purified product with a melting point of 318-320°C (decomposed).

Br IRv Confucian-1:3200.3060.1710,a
x 1480.1325.1170.1145°NMR(1
00MH2, CF3CO0H) δppm: 3.60 (
4H1 multiplet), 5.00 (5H1 multiplet), 6.2~
8.5 (2H1 wide).

Claims (1)

[Scope of Claims] 1. A compound represented by the formula: or an acid addition salt thereof, and an isocyanic acid represented by the formula 2NCO [wherein R represents an alkali metal atom such as H, NH, or a benzyl group] or a derivative thereof. A method for producing an imidazole derivative represented by the formula: [In the formula, R' represents H or a benzyl group]. 2 The sulfolene compound represented by the formula: X, NCOOR' or X2. NCOOR' [in the formula, R1 is a lower alkyl group,
A compound represented by the formula: This is hydrolyzed and decarboxylated to obtain a compound represented by the formula: This compound or an acid addition salt thereof is then converted into a compound represented by the formula: [wherein R represents f(, NH,, an alkali metal atom or a benzyl group] ] A method for producing an imidazole derivative represented by the formula: [wherein k represents H or a benzyl group], which is characterized by reacting with incyanic acid or a derivative thereof represented by the following.