DE1815788A1 - 4,5-substituted N-oxy- and hydroxyhydoimidazoles - Google Patents

Description

Synvar Associates, 3221 Porter Drive, PaIo Alto, Calif. IV.St.A. )

4,5-substituted N-oxy- and hydroxyhydroimidazoles

The invention relates to dihydro- and tetrahydroimidazoles. In particular, "the invention relates to those imidazoles in which
at least one ring nitrogen atom is oxidized to the hydroxide or oxide state.

In the preferred embodiment, the invention relates to a Class of new compounds with the formula

BATH ORIGINAL

where Rp- hydrogen or an organic group »R *, Rp, R ^ uild .R. Alkyl groups, alkenyl groups, alkynyl groups or aryl groups' each having about 1-12 carbon atoms or a part

form an alkylene or alkenylene group R ^ Rp or R ^ R. ",

these alkylene and alkenylene groups each having about 3-10 carbon atoms contain;

every atom pair N ^ C _n and Ν _Ί --- Β by a single or double

bond is connected, with the proviso that only if the atom pair N ^ C ^ is linked by a single bond, also a

Hydrogen atom is directly connected to Cp; and A and B are hydroxyl groups or oxygen or hydrogen atoms

according to the order of the bond between the atom pairs N ^ C ^

P and Ν-, -—B mean, with the following provisos;

1) The atomic pairs N., C _n and N-, -—B are represented by simple-

bonds connected: A and B are both hydroxyl groups;

2) the atomic pairs N-, C ₀ and N-, B are both represented by Dop-

pel bonds connected: A and B are both oxygen atoms;

3) the atomic pair N .. C ₀ is connected with a double bond and the atom pair N-, B is connected with a single bond: A is an oxygen ether and B an oxygen atom, a hydrogen atom or a hydroxyl group »

By the definition given above, the following connection types in which R ^, R ^, R ^, R. and R, - the above have given meanings:

■ 0 ·

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BATH ORIGINAL

til)

OH

■ Ν-

OH

(III)

■

0-

OH

(IV)

R,

0-

N-

(V)

0-

-R ₅

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It should be noted that the compounds of the latter Type have a positive excess charge. Therefore they are obtained together with a suitable counterion, e.g. the chloride ion, that balances the charge.

The compounds according to formula V are suitable as oxidizing agents due to their strong oxidizing properties. The other compounds of the formulas I, II, III and IV are suitable as antioxidants. In general, the compound of formula I, which has a free radical structure, suitable for measurement of weak magnetic fields in accordance with known methods. Furthermore, due to their free radical structure, the compounds of the formula I show an electron spin resonance (ESR), which is why they can be used as "spin labeling substances ^11" for attachment to biologically active molecules. If they are used for this purpose, it is usually desirable to use a to choose a suitable functional group as part of R 1, Rp, R-, R, or Rc, which serves as a "hook" for connecting or attaching the free radical molecule to the biologically active molecule.

Finally, as will be explained in more detail below, everyone can Compounds with the formulas I - IV as starting substances for the production of compounds having the other corresponding formulas can be used by essentially undergoing an oxidation or reduction reaction is carried out. Therefore, all of these compounds can be used as intermediates for the manufacture of the other Compounds according to the invention are considered.

All compounds within the scope of the invention differ from one another primarily due to the different oxidation states of the nitrogen atoms in the imidazole ring. All connections have the imidazole ring basic structure with the required tertiary carbon atoms in ring positions 4 and 5. Also located In all compounds there is at least one ring nitrogen atom in the oxidized state, i.e. in the form of an oxide or a Hydroxyds. All compounds can be called hydroimidazoles, since at least one of the normally occurring Irnida

BATH ORIGINAL

zolring double bonds is saturated. If one considers the formulas I - V, one recognizes that all compounds can be designated as 4,5-dihydroimidazoles, with the exception of the compound according to the formula II, which is a tetrahydroimidazole. In the presence of the hydroimidazole ring structure, of tertiary C, - and tertiary CfT carbon atoms in the ring and at least one ring nitrogen atom that is oxidized to the oxide or hydroxide state, the greatest possible scope of protection for the nature of the substituents R-] to R ₁ - claimed in the formulas. Details of this aspect are discussed below in connection with the various methods of making the compounds.

For the sake of simplicity, however, it is often only the simplest Be noted that the required tertiary structure Character of the C, - and C, - ring carbon atoms results. To this The purpose is to use the symbol —1 to designate the structure

A- ---

CH,
5 ·

(JH, C _K

3 5

CH,

used.

° Synthesis method

_m In general, the novel compounds according to a type of condensation ^ * sationsreaktion between a vicinal diamino-Kohlenstoffverbincn dung, that is a diamine having hydroxylamino groups at the _o Benach disclosed tertiary carbon atoms (hereinafter referred to as a bis-hy-

droxylamine), and one of the Re-A explained below action participant, based on the desired R ^ group

I Ö I O / ÖO

is selected in the final product, manufactured, the reactants adhere to the structure!

R ₅

in which the free valences of Cp are connected to one or more atoms or groups which, together with a proton from each of the hydroxylamino nitrogen atoms, can be eliminated in order to create relationships that allow C to bond "to the" If one of the valences of Gp is originally saturated with a hydrogen atom, as is the case with the aldehyde reactants discussed below, a saturated ring structure of the type of formula II is obtained Open or free valences of C _? originally saturated by a hydrogen atom, then directly unsaturated ring compounds of the formula III type and structures which can be derived therefrom are obtained.

0
(1) Aldehydes - R ₅ - C - H

The reaction between a bis-hydroxylamine and an aldehyde is the most commonly applicable manufacturing process; it allows a synthesis of practically all compounds according to Invention. The reaction path can be indicated as follows:

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QRlQtNAL INSPECTED

OH

NHOH

NHOH

+ R ₅ CHO ->

OH

0-

(D

HCl

■ R _c

'(IV)

(H) H.

Rc 0-

■ R _E

OH

Q-

-N '

-N

(in)

(V)

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In the reaction scheme given above, the Roman numerals in the formulas relate to those given above Formulas so that a process for the preparation of each type of molecule can be derived according to the invention.

In the reaction scheme given above, R, - can represent hydrogen or any organic radical desired in the final product, provided that when R ^ - is an organic radical, its structure is such that c * aß a carbon-carbon bond between the Cp- Ring carbon atom and the radical R ^ is present. For example, R ₁ - can be any alkyl, aryl or heterocyclic

fc see group with or without substituents and containing up to 50 carbon atoms. As used herein, the terms "alkyl" or "aryl" include simple alkyl and aryl groups as well as groups containing various substituents, including those falling into the other category, for example, the term "alkyl" is intended to include aryl-substituted alkyl groups. In all cases, R ₁ -, regardless of whether it is an alkyl or aryl group, can contain functional substituents of the hydrocarbon or non-hydrocarbon type; they can be saturated or aliphatically unsaturated, the only requirement being that the selected reactant be an aldehyde having a carbon atom in <? C -position to the aldehyde function. Typical substituents that do not belong to the type of hydrocarbons include halogens, oxygen, nitrogen, hydroxyl groups, alkoxyl groups, aryloxy groups, amino groups, alkyl or arylamino groups, mercapto groups, alkyl or ary! Mercapto groups, trialkylsilyl groups, perfluoroalkyl groups, nitroxyl carboxyl groups, Nitrile groups etc. Thus, R ₁ - can represent a nitrile group or an ester or iminoester group and contain further substituents.

Typical aldehydes for reaction with a bis-hydroxylamine for generating a compound of formula II according to the reaction scheme given above include, for example, the compounds given below. In any case, this includes

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End product is an R ^ group which is one of those given above Formulas minus the aldehyde group or groups corresponds to:

glucose

Glucosamine

Citral

OHC (CHOH) ₄ CH ₂ OH OHC CHNh ₂ (CHOH) ₃ CH ₂ OH OHC C (CH ₃ ) = OHC CH

C (CH ₃ ^

OHC CH ₂ CH (OO ₂ H ₅ ) ₂ OHC CH ₂ CH (NH ₂ ) COOH OHC CHBrC ₆ H ₅ OHC COO (C ₂ H ₅ ) OHC C ₆ H ₄ CN OHC C ₆ H ₄ NiCH ₃ ) ₂ OHC CH = CHC ₆ H ₄ NO ₂ OHC CH

OHC CF ₃

OHC CH (CHj ₂

OHC CH ₂ CH ₂ CHO

OHC

CHO results in 1: 1 or 1: 2 adducts, depending on the ratio of the reaction participants

CHO

CHO

Ferrocene carboxaldehyde

, CHO

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CH ₂ O OHCCBr ₃ OHCCgH.COOH OHCCH ₀ CH (Oh) CH-OHCCOOC ₃ H ₇ OHCCONC.Hp-

D O

OHCCH

CH-

CH-, I.

CH-

, CHO

C ₁ H ^ OOC

CHO

OHC

OHCCH ₂ CH ₂ SH OHCCH ₂ Br OHCCH ₂ Cl OHCCH ₂ J «ε CCHO

OHC (CH ₂ ) ₁₂ CH ₃

^{0H (} K>

N "H

CHO

.-CHO

CHO

CH ₃ CO O

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N-CH-

Equally useful in this context are the broad classes of compounds with aldehyde groups, such as sugar, and certain Steroids, alkaloids, terpenes, amino acids, and the like.

Need in the above reaction scheme for the synthesis the intermediate compounds do not have to be isolated, and the reaction can be carried out sequentially in situ until the desired connection is formed. For example, after the formation of the compound of the formula II, it is easy to carry out the oxidation reaction directly to the corresponding compound of the formula I to continue without first isolating the intermediate with the formula III.

In the preparation of compounds with the formulas II, III and I. is the reaction in a suitable solvent in the presence of one or more suitable oxidizing agents, such as

PbO ₂ , J ₂ , Br ₂ , Gl ₂ , di-tert-butyl nitroxide, ON (SO,) ^ 2 Na ⁺ , MnO ₂ , O ₂ and the like
carried out.

Below is the preparation of typical compounds with the formulas II, III and I:

2-Benzyl-1,3-dihydroxy-4,4,5,5-tetramethyltetrahydi) imidazole

The bis-hydroxylamine (100 mg; 0.7 mmol) is dissolved in boiling benzene (25 ml) and treated with phenylacetaldehyde (0.08 ml; 0.7 mmol). The solution becomes an hour with an additional funnel between the flask and the condenser, which contains sodium sulfate for drying the returning benzene, under reflux.

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heated. The evaporation residue is in a mixture of $ 10 '' Ether and petroleum ether dissolved and chromatographed on silica, using the same mixture of solvents to elute. The product crystallizes from chloroform-hexane in the form of colorless Needles off; P. = 106-108 ° (60 mg). . ■

2-Benzyl-1,3-dioxy-4,4 5,5-tetramethyl-4,5- ^i- dihydroimidazole

PbO

2-benzyl-1,3-dihydroxy-4,4,5 »5-tetramethyltetrahydroimidazole (lg; 4.2 mmol) in benzene (50 ml) is treated with lead dioxide for 30 minutes (40 g; Öj17 mol) stirred. The mixture is filtered and that Piltrate is evaporated under reduced pressure, leaving the radical as deep purple viscous oil is obtained; Almost quantitative yield.

2-benzyl-1,3-dioxy-4,4,5,5-tetramethyl-4,5-dihydroimidazole

0-

CH 0

OH

2-Benzyl-3-hydroxy «1-oxy-4,4,5,5-tetramethyl-4,5-dihydroimidazole (30 mg; 0.12 mmol) in benzene (25 ml) is treated with lead dioxide for 20 minutes

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(1 g] 4.2 mmol). DasPiltrat is evaporated under vacuum and the 'oil in the residue is chromatographed on silica, eluting with 10 fi ether-petroleum ether. The chromatographically pure radical is obtained as a deep purple-red viscous oil ; Yield ^ almost quantitative.

2-Benzyl-3-hydroxy-1-oxy-4, 4, 5,5-tetramethyl-4,5-dihydroimidazole

PbO,

2-benzyl-1,3-dihydroxy-4,4,5 »5-tetramethyl-4,5-tetrahydroimidazole (1 gj 4.2 mmol) in benzene (25 ml) was treated with lead dioxide for 3 hours (3.5 g> 14.6 mmol) was stirred. The mixture is filtered and that pink piltrate is evaporated under reduced pressure. The residue is made up of chloroform-hexane under a nitrogen atmosphere recrystallized to give 600 mg of product. P. = 110-111 °. ~.

Synthesis of 1,3-dihydroxy-2-phenyl-4,4, 5,5-tetramethyl-tetra-

hydroimidazole

NHOH NHOH

+ OHC

OH

N ■ N

OH

b.

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A solution of N, N'-dihydroxy-2,3-diamino-2,3-dimethyrbutane (4.44 g; 0.3 mol) in 150 ml of methanol, to which 3.5 g (0.33 mol) of benzaldehyde were added The mixture is stirred for 24 hours at room temperature. The white precipitate formed is filtered, with 2.67 g of the compound b ^ being obtained. When the mother liquor is evaporated, a further fraction of b_ / an falls: total yield 74.3 ° . the melting point of the recrystallized from benzene / ether material is 168-169 ° the mass spectrum and the NMR spectrum consistent with the structure b_j_ match..

Analysis: calculated for

found:

66.08; 66.17;

H
H

8.535 8.72;

N N

11.85; 12.02.

0 13.55

Synthesis of 1-hydroxy-2-phenyl-3-oxy-4,4,5,5-tetramethyl-4,5-dihydroimidazole

PbO,

a.

b.

c.

CO O (O OO CO CO

The oxidation of only one N-hydroxyl group of the compound a ^ to the corresponding nitrone b ^ takes place by subjecting the compound a ± to a brief treatment with PbO_.

The 1,3-dihydroxy-2-phenyl-4,4, 5,5-tetramethyltetrahydroimidazole (50 mg; 0.21 mol) is dissolved in 25 ml of benzene and treated with PbO_ for 15 minutes at room temperature. The reaction is followed by thin-layer chromatography. At this stage the chromatographic plate has only one spot which turns blue on treatment with Jm. The reaction mixture is filtered immediately, and that

The solvent is evaporated in vacuo. A white solid is isolated in a yield of about 30 mg (60 #), which is identified by analysis and spectroscopy as compound b ^ * When standing in air, the solid ΐκ_ quickly turns blue, and when the white material with PbOp in benzene gives a blue solution immediately. The blue product can be isolated almost quantitatively by filtering and evaporating the solvent. It is identical to the compound c_ ^

The product (b ^) was also obtained by treating 1,3-dioxy-2- phenyl- 4,4,5 »5-tetramethyl-4,5-dihydroimidazole (c_ ^), which was dissolved in glycol methyl ether, with excess sodium metal dispersion obtain. After the blue color had disappeared, the reaction mixture was immediately poured into methanol containing enough HCl to keep the mixture acidic. The solvents were evaporated in vacuo and the residue was treated with powdered anhydrous sodium carbonate. The residue was triturated with methanol previously purged with nitrogen and the methanol solution was then chromatographed on silica gel. (All of the above-mentioned working steps were carried out under nitrogen.) The compound b ^ was isolated as a white crystalline solid substance and was identical to the product of the controlled PbO ₂ oxidation.

Synthesis of 1,3-dioxy-2-phenyl-4,4,5,5-tetramethyl-4,5-dihydroimidazole

ΟΙ

ί
0-

a. c.

1.45 g (0.00615 moles) 1,3-dihydroxy-2-phenyl-4,4,5,5-tetramethyltetrahydroimidazole (a ^) are dissolved in 250 ml of benzene and at Treated room temperature for 45 minutes with 20 g of PbOp. The reaction

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mixture is made by MgSO. filtered, and the deep blue benzene solution is evaporated in vacuo. It becomes a crystalline dark. blue solid isolated: yield 1.43 g (100 #). The product c_j_ is soluble in all organic solvents as well as in water, it is recrystallized from Xther, and its melting point is 85 °. The mass spectrum shows a molecular ion with a molecular weight of 233, which corresponds to the molecular weight of the compound C _-1 . *

Analysis; Calculated for

C. 66 , 93; H 7th , 345 N 12, 00; found: C. 67 , 03; H 7th , 41; N 12, 04.

0 13.71

The ESR spectrum shows a typical pattern of 5 lines (a _N 7.5 G in benzene).

2-bromomethyl-1,3-dihydroxy-4,4,5,5-tetramethylimidazolidine

+ CH ₂ Br-CHO

CH ₂ Br

O CO OO CO OO

2 ml (16 mmol) of bromoacetaldehyde (prepared by the method of Fischer and Landsteiner, "Chem. Ber." £ 5, 2549 (ΐ892)) are mixed with bis-hydroxylamine (500 mg; 3 , 4 mmol) and anhydrous calcium sulfate (Drierite ^) (1 g), first being cooled in ice. The mixture is filtered and the organic fraction of the residue is dissolved in ether. This solution is filtered off and evaporated to give a crude product which is further purified by chromatography on silica with ether. Yield: 630 mg ($ 70); F. = 123 - 124 ° (decomp.).

Analysis: Calculated for CnH ₁₇ N _? 0 _p Br:

found:

C C

37.98; 37.84;

6.77;
6.89;

N N

11.07; 11.10;

Br Br

31.59 31.36,

2-chloromethyl-1,3-dioxy-4,4 »5,5-ΐetramethyl-4,5-dihydroimidazole

+ OH ₂ Cl-CHO

PToO,

Dry chloroacetaldehyde (7.5 ml; 6OmMoI), which is prepared similarly to the bromoacetaldehyde, is stirred in benzene (7.5 ml) over anhydrous calcium sulfate (Drierite ^) and during the addition of the bis-hydroxylamine (0.5 g; 3.4 mmol) cooled. The mixture is stirred for a further hour at room temperature. The mixture is then filtered and the filtrate is stirred with lead dioxide (7 g) for 2 minutes. Subject to filtering and diluting with chloroform, the solution is washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica and eluted with Either. The purple-colored product (250 mg, 35 % fo) crystallizes out in the form of needles on evaporation of the hexane solution at room temperature in vacuo. F. = 73-75

Analysis; Calculated for C

found

C. 46 , 71? H 6th .86; N 1 3 .62; Cl 17th , 24 C. 46 .86; H 6th .59; N 1 3 .58; · Cl 17th , 17th

Although the iodomethyl radical can be prepared in a manner similar to that given above, the example below shows an alternative method :

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1,3-DiOXy ^ -iodomethyl-4,4,5,5-tetramethyl-4,5-dihydroimidazole

KJ

2-Chloromethyl-1,3-dioxy-4,4,5-tetramethyl-4,5-dihydroimidazole (100 mg) is dissolved in a saturated solution (20 ml) of potassium iodide in acetone. After five minutes at room temperature, the solution is evaporated in vacuo and the residue is extracted with Xther. Chromatography in the dark on silica with the same solvent gives 30 mg ($ 20) of a dark blue product .. = 58 -60 °.

The next example illustrates a typical process for making compounds in which R ₁ - contains one hydroimidazole ring such that the entire molecule contains two or more hydroimidazole rings of the type of interest. To make compounds with multiple hydroimidazole rings, one uses a polyaldehyde and enough bis-hydroxylamine to react with each aldehyde group in the polyaldehyde molecule.

1,2-bis- (i, 3-dihydroxy-4,4, 5,5-tetramethyl-tetrahydroimidazol-2-yl) « A * than

NHOH NHOH

+ OHCCH ₂ CH ₂ CHO

OH I

-N f OH

OH I

N-

OH

N, N'-dihydroxy-2,3-diamino-2,3-dimethyrbutane (3.0g! 0.02 mol) are suspended in benzene (250 ml). An essential solution (30 ml) of succinaldehyde (made by hydrolysis of 5.8 g

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Sueeinaldehydoxime and evaporation of the ethereal succinaldehyde solution to 50 ml) is added to the suspension, and the solution is refluxed for 30 minutes. The solvent is then evaporated and the solid residue is poured onto silica gel (80 g)

Chromatographed using Xther as eluant. The desired product begins to flow out of the column after. 125 ml of eluent have been collected, ie it is present in the next 350 ml of eluent. The solvent is removed, with 2.7 g (77 90 of the above compound being obtained. P. = 212-216 ° (from ethyl acetate / benzene).

Analysis; Found! C 62.155 H 9.27; N 13.4-8; Theoretical for C ₁₆ H ₃₄ N ₄ O ₄ -C ₆ H ₅ : C 62.23; H 9.50; N 13.20.

A molecule containing two imidazole rings can also be formed by some type of condensation reaction between a 2- halohydroimidazole and a metal such as copper and the like . A typical example is given below:

- (1,3-dioxy-4,4, 5,5-tetramethyl-4,5-dihydroimidazol-2-yl)

Cu

1,3 ~ Dioxy-2-iodo-4,4, 5,5-tetramethyl-4,5-dihydroimidazole (100 mg) and copper powder (300 mg) are stirred vigorously in dimethylformamide (2 ml), the temperature being slowly increased increased to 65 ⁰ C. Near this temperature, the color of the solution changes from purple to red. The solution is then poured into water (10 ml) and filtered. The filtrate is extracted with chloroform (.2 x 10 ml) and the chloroform extract is dried over sodium sulfate and filtered, whereupon the chloroform is removed in vacuo. The solid residue is washed twice with water and dried in vacuo, 35 mg (65 ° C.) of the above

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"Compound. M.p. = 220-222 ° (from benzene).

Analysis; Calculated for Cj ^ H ^ NO,

C 53.835 H 7.74.5. N 17.94 # Found: C 53.94? H 7.555 N 17.87 5 Molecular weight (mass spectrometry) '=. 312

In discussing the general reaction scheme for the preparation of the compounds of the various formulas, it is mentioned that a compound of the formula I is prepared from a corresponding compound of the formula II by oxidizing the compound of the formula II with the aid of an oxidizing agent such as FbO ₂ can be. Some typical examples are given below:

2-bromomethyl-1,3-dioxy-4,4,5,5-tetramethyl-4,5-dihydroimidazole

PbO,

GH ₂ Br

CH ₂ Br

2-bromomethyl-1,3-dihydroxy-4,4,5,5-tetramethylimidazolidine (0.2 g »8 mm oil) in Xther (15 ml) is stirred with lead dioxide (2 g) for 15 minutes. After filtering off, the filtrate is evaporated and chromatographed on silica, eluting with ether. The main product (140 mg; 55 i °) crystallizes out in the form of needles on evaporation of a hexane solution in vacuo. F. = 93-94 °.

Analysis: Calculated for

Found:

, N "0" Br

38.43?
38.39;

5.64? 5.67;

N N

11.20; 11.225

Br Br

31.95 31.76.

9 0 9 8 3 8/1500

1,2-Ms-d, 3-Dioxy-4,4 »5,5-tetramethyl-4,5-dihydroimidazol-2-yl) · ethane

PbO ₀

Ι, 2-MS-2 ', 2 · - (1', 3 '-dihydroxy-4', 4 ', 5', 5 '-tetramethyltetrahydroimidazolyl) -ethane (104 mg) are suspended in benzene (40 ml) and mixed with lead dioxide (1.0 g). The mixture is warmed and shaken for five minutes. Thereafter, only the above-mentioned compound can be detected by thin layer chromatography. The solution is filtered and the solvent is removed under reduced pressure. The semi-crystalline residue is recrystallized at 30 to 60 ° from benzene / petroleum ether, 4 ^ 5 mg of the above compound being obtained. F. = 160-161 °. (Found: C 56.38; H 8.13; N .16.62; theoretical for C ₁₆ H ₂₈ N ₄ O ₄ : C 56.45; H 8:29; N 16.46.)

In the above reaction scheme for the preparation of the compounds with the various formulas it was also indicated that a compound of the formula IV is obtained from a corresponding compound with the formula I by reducing the compound with the formula I, for example with the aid of a hydrochloric acid-ethyl alcohol solution can be obtained. The following example illustrates such a reduction process:

Synthesis of 3-0xy-2-phenyl-4,4,5-5-tetramethyl-4,5-dihydroimidazole

HCl

C ₀ H ₁ -OH ^{2 5}

i
0-

c_t. cU.

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The free radical c _; _ (200 mg; 0.86 mmol), dissolved in 20 ml of 95 GpH ₅ OH, which contains 1.5 ml of concentrated HCl, is refluxed for about 10 minutes; During this time the color of the reaction mixture changes from "deep blue to colorless. The reaction mixture is cooled to room temperature and evaporated to dryness under vacuum. The solid material obtained is dissolved in methanol, the solution is treated with NaHCO-, Ms it is weakly basic, and then evaporated to dryness. The residue is extracted with chloroform; the extracts are dried over MgSO 4 and filtered. The filtrate is evaporated in vacuo to an oily film which solidifies on trituration with petroleum ether. The white material ( cUj »which is obtained in an amount of 150 mg (yield 80 %) is recrystallized from chloroform / petroleum ether, p. = 189-190 ° (decomp.). The mass spectrum and the NMR spectrum agreed with the structure d_ ^.

Analysis; Calculated for C | JH. | GNpO:

C 71.51; H 8.31; N 12.835 0 7.33 Found: C 71.37; H 8.25; N 12.70.

The above reaction is reversible and the amino nitrogen of Formula IV can be oxidized to give the stable free radical of Formula I. A typical process using hydrogen peroxide and phosphotungsten

H 0 <

I I

HpOp j N

Phosphotungstic acid

I '. I.

0- 0-

d.

The 3-0xy-2-phenyl-4,4,5,5-tetramethyl-4,5-dihydroimidazole (5 mg) is dissolved in 4 ml of water containing 1 ml of 30% HpO ₂ and 0.5 mg of phosphotungstic acid, suspended, and the suspension is 2 days

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stirred at tree temperature. During this time it evolves slowly turning a purple color. The reaction mixture is extracted with benzene and the extracts are dried over MgSO. dried. That blue benzene filtrate shows the typical ESR signal of 1,3-dioxy-2-phenyl-4 »4t5r5-tetramethyl-4,5-dihydroimidazole (c ^). The aqueous layer, which has become colorless after this extraction, is developed on standing for several days at room temperature again a violet color, which indicates that this oxidation is particularly slow is.

According to the general reaction scheme given above a compound with the formula V is obtained from the corresponding compound with the formula I by oxidation, for example with chlorine or with a compound that releases chlorine, such as SOpCIp, or by the action of a strong Lewis acid, such as trifluoroacetic acid, manufactured. A typical example of this reaction is given below:

Ci ₂

The free radical eu_ used as the starting material is converted into a inert solvent, such as benzene or carbon tetrachloride, brought, whereupon excess chlorine is added. In this example gives a solution of the reaction mixture in carbon tetrachloride after evaporation of the solvent as indicated above Reaction product b ^ in the form of an orange solid substance.

In a strongly acidic solution of the starting material a ^ this becomes same end product b_ ^ in an equilibrium mixture of relatives Get connections. Products like Td ^ are exceptional powerful oxidizing agents. They do not only oxidize aqueous ones

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181578a

Iodide or bromide solutions easily release free halogen, but also attack many organic compounds and most solvents. The product bj_ is already reduced by water, and it has been found that it oxidizes aqueous alkaline solutions to hydrogen peroxide. The starting material & ± can be recovered from acidic solutions to obtain b ^, the acidic solution of b ^ being neutralized or the aqueous solutions of the orange solid are treated with alkali.

(2). Aldehyde derivatives

Instead of an aldehyde, as indicated above, the compounds referred to here as aldehyde derivatives can be used with a suitable bis-hydroxylamine according to the one given below.

Implement the equation:

0-

4 NHOH

+ RCHXX '

-NHOH

I I

O·

ROHXX '

The aldehyde derivative / includes those compounds in which X and X ^{1 are} halogen, OR ', NR' or SR ¹ . R and R · can be hydrogen, or alkyl or aryl groups, which can contain any desired functional substituents. R and R 'and X and X' can be the same or different from one another, provided, however, that only one X or X ¹ can be fluoro.

A general reaction mode using an aldehyde derivative to prepare the compounds according to the equation given above is given below: A suspension of the bis-hydroxylamine (1 equivalent) in benzene is reacted with at least one equivalent of RCHXX '. If X or X ^{1 is} halogen, a base such as solid sodium carbonate or pyridine must be added to the solution

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can be added. If neither of the substituents X or X ^{1 is} halogen, a little more than 1 equivalent of acid is added. The solution is then heated on a steam bath for a few minutes to a few hours. The resulting solution is washed with water and then shaken with excess FbOp or another oxidizing agent. Alternatively, the intermediate product can be isolated by evaporation of the solvent before the oxidation is carried out The oxidized solution is evaporated to dryness and the radical can be isolated from the residue by chromatography or by crystallization.

A specific example of the above procedure is as follows:

2- (2 ', 2'-D: methoxyethyl) -1,3-dioxy-4,4,5,5-tetramethyl-4,5-dihydroimidazole

• NHOH

~ - ^ THOH

GH ₃ O) ₂ 0HCH ₂ 0H (

Supreme Court

0 ·

Supreme Court

0-

c.

N, F'-dihydroxy-2,3-diamino-2,3-dimethylbutane (100 mg) and malonaldehyde tetramethyl ketal (500 mg) in methanol (50 ml) are mixed with 50 volumes of sulfuric acid (2.5 ml), and the mixture is stirred for 66 hours. Then enough ammonium hydroxide is added until the solution is just alkaline. The solution is filtered,

909838/1500

dried over sodium sulfate and filtered again. A small part of the solution is oxidized with lead dioxide, and the ESR spectrum of the radical found shows that 2- (2 ', 2'-dimethoxyethyl) -1 , 3-dioxy-4,4,5,5-tetramethyl-4,5-dihydroimidazole.

Similarly, the reaction given below is carried out :

NHOH NHOH

+ ClCH ₂ OCH ₃

Here, a radical is obtained in the product.

is a hydrogen atom, as

So there are 10 mg of N, N'-dihydroxy-2,3-diamino-2,3-dimethylbutane heated under reflux for 5 minutes in 10 ml of benzene with 100 mg of chloromethyl ether. The resulting mixture is then solidified with stirring Sodium carbonate is heated, filtered off and then washed with water. After drying over sodium sulfate, the obtained is The solution was stirred with excess PbOp and filtered off. When the solvent evaporates, a bright red residue appears of 1,3-dioxy-4,4,5,5-tetramethyl-4,5-dihydroimidazole.

(3). Preparation of compounds in which R ^

is a strong electron withdrawing group

If one wishes to obtain a compound according to the invention in which Hr is a strong electron withdrawing group, then a reaction carried out according to the following scheme:

NHOH NHOH

0 || + R ₅ CX

909838/1500

In this reaction, X means the group -OCR ₅ a halogen or another easily exchangeable group (where R is an alkyl or aryl group with or without functional substituents), and R is a strong electron-withdrawing group, such as -CX '· ,, -CX ¹ JR ¹ or Λ »«. Where-X' halogen- R 'is hydrogen or »an alkyl or aryl group with or without functional substituents and R" represents the groups OR', MR ¹ , NR ' ₂ or SI «mean«

Mn general knowledge of how to carry out an implementation with eitler strong elektr®neadeivenden group proceeds as follows: One equivalent of bis-hydroxylamine in benzene with an excess suspended in pyridine (2-10 equivalents) or another base is treated with at least one equivalent of the compound RCOX "Which is added to the stirred solution at room temperature, The solution is left to de-mach.der reactivity of the compound RCOX "Stand at room temperature or heat them on a steam ibaä. (1 minute to 10 hours). The solution generally develops intense color and is made by washing with water and evaporating the solvent worked up. The product can be criated out or be isolated by means of Ehromatography.

A typical implementation according to this scheme is as follows:

_J- ^ NHOH 9 L N +

T (CPO) 0 * J ^

+ (CP ₃ O) ₂ 0 - * J

4 NHOH "T -— N

4th

(4.) Orthoesters and their derivatives

Another process for the preparation of the compounds according to the invention relates to the use of orthoesters and their derivatives according to the reaction scheme given below:

909838/1500

O-

ι, NHOH

~ Τ ~ "—NHOH

+ R ^ C Χ »

• R

Here "X, X ¹ and X", which can be the same or different from one another, denote the groups OR ', NR'p, SR ¹ , halogen or other easily exchangeable groups (provided that not more than two groups represent fluorine) and R ^{1 is} any alkyl or aryl group with or without functional substituents, and R ^ can be hydrogen or any alkyl or aryl group with or without functional substituents.

A typical procedure for carrying out the reaction is as follows: A solution of the bis-hydroxylamine (one equivalent) in tetrahydrofuran or benzene is ^{treated with at least one equivalent of the compound RCXX 1} X ", whereupon more than one equivalent of a strong acid such as CF. ^ COOH or benzenesulfonic acid is added. After heating on a steam bath for a period of one minute to 10 hours, the acid is extracted with sodium carbonate. The resulting solution changes color as a result of oxidation with air. The colored radical can be removed by evaporation and chromatography or by Crystallize to be isolated.

A specific example using this procedure is as follows?

0-

NHOH H

+ HC (

NHOH

⁺ J -Nt

τ—— R

909838/1500

(5.) Process for the preparation of compounds in which R ^ is hydrogen

In addition to the general processes given above, which are used for the preparation of compounds in which R ^ is hydrogen or a Any * organic group means can be used, some special reactive routes have been used to make compounds found with a hydrogen atom in the R ^ position. The first Process relates to the decarboxylation of a corresponding ester. The ester can first be prepared according to one of the above general procedures. The ester is prepared according to the equation and procedure given below treated, obtaining the desired compound:

0-

N 0

a. ■ b. c-.

2 ml of a solution of the ester a ± (about 2 mg) are shaken with aqueous potassium carbonate. A red color appears in the aqueous layer, which can be attributed to the compound Td ^ by ESR spectroscopy. By acidifying the solution, the ESR spectrum of the compound c_ ^ is obtained. This compound can be obtained by evaporating the aqueous solution in vacuo and extracting the residue with benzene. The obtained benzene solution of the radical ο. can be evaporated to give the radical C _-1 . · '■

Another specific reaction relates to the oxidation of a tetrahydroimidazole, which can conveniently be prepared from a bis-hydroxylamine and hydroxyacetaldehyde. The preparation of the desired compound, in which R _{1 is} hydrogen, proceeds as follows:

909838/1500

CH ₂ OH

PbO,

ΟΙ

-N

N 0-

PbO,

CH ₂ OH

b.

1,3-dihydroxy-2-hydroxymethyl-4,4,5,5-tetramethyl-tetrahydroimidazole (a ^) (3 mg) is suspended in benzene (1 ml). Then lead dioxide becomes (100 mg) is added and the mixture is shaken periodically. The benzene solution is examined every 15 minutes by thin layer chromatography (silica gel / ethyl acetate). First is only one Radically identical to that produced by oxidation of 1 ^ -dihydroxy ^ -hydroxymethyl ^^^^ - tetramethyl-tetrahydroimidazole (See below with manganese dioxide. It begins however, a new radical can be formed from the first radical, and this conversion is complete after three hours. This new radical was detected as 1,3-dioxy-4,4,5,5-tetramethyl-4,5-dihydroimidazole (b ^) by thin layer chromatography and electron spin resonance and is identical to the radical obtained by oxidation of 1,3-dihydroxy-4,4,5,5-tetramethyl-tetrahydroimidazole (c ^) became.

OH

OH

These examples show that all radicals with the formula I are as expected be converted by oxidation or hydrolytic reagents into the corresponding radical with Rj- = COOH, among the given conditions into the corresponding radical with Rf- = H can be converted. The COOH group can be obtained under other conditions or at a reduced temperature.

^ 9098 3 8/1500

(6.) Variations "with respect to R ₁ , Rp, R ^ and R,

■ In the above explanations, the simplest bis-hydroxylamine structure was used, which provides the required tertiary structure UBT G, - and öc-carbon atoms through the use of four methyl groups. when R ₁ , R ₂ , R, and R ^ represent any other alkyl, alkenyl, alkynyl or aryl groups (these terms should always also include substituents based on hydrocarbons or substituents that do not belong to the type of hydrocarbons) , including those cases in which R ₁ -Rp and R - ^ - R, form cyclic groups with carbon atoms Cf- and C., respectively. In the preferred embodiment, R ₁ , Rp, R ^ and R. are each alkyl, alkenyl, alkynyl, aryl or aryl-substituted alkyl groups, each having about 1-12 carbon atoms, or R ₁ -Rp and / or R ^ -R. are alkylene or alkenylene groups each having about 3-10 carbon atoms, it being possible for the alkylene or alkenylene groups to contain alkyl or aryl substituents as desired.

To connect a compound according to the invention with a specific, desired To obtain atomic configuration, one need only select the appropriate bis-hydroxylamine and one of the above carry out specified reactions to form the hydroimidazole ring. The bis-hydroxylamine is reduced by a corresponding Dinitro compound produced. The dinitro compounds and the processes for their preparation are known per se. The general Reaction route is given below and comprises the reaction of the salt of a secondary nitro compound and a halonitro compound, where the halogen atom and the nitro group are on the same carbon atom:

90 9 8 3 8/1500 BAD

C -NO,

CHNO,

R.

Br

NO,

CHNO,

NO,

σ — no,

J-NHOH

C-NHOH

4th b.

The preparation of the dinitro compounds (eu_) was described by LW Seigle and HB Haas in "Journal Organic Chemistry", Vol. 5 (1940) _f p.100. In this work the authors report the synthesis of a variety of dinitro compounds including those compounds in which R ^, Rp, R-, and R represent alkyl groups, aryl groups, and asymmetric combinations including those given below:

909838/1500

, CH, 3 3

7 \

CH

NO

NO

2 ·

If you want a product in which R ^ = R-, and R ₂ = R ,, then one preferably applies the synthesis of Sayre: JACS 77, 6689 (1955)

As a non-limiting example of the general response intended serve to produce tetramethyl-bis-hydroxylamine. The dinitro intermediate (a ^) was made as follows:

■ 2,3-dimethyl-2,3-dinitrobutane

A mixture of 6N sodium hydroxide (675 ml) and 356 g of 2-nitropropane (4 mol) is stirred and cooled, while 320 g of bromine (2 mol) are added dropwise. Ethanol is then added and the solution is carefully refluxed for 3 hours before being mixed with ice water (1.5 liters). The crystalline product is washed thoroughly with 50% ethanol. Yield: 280 g; F. = 213-215 ° (lit.215 °).

The corresponding bis-hydroxylamine is obtained by reducing the dinitro compound, manufactured according to the following process:

N, N'-dihydroxy-2,3-diamino-2,3-dimethylbutane

2,3-Dimethyl-2,3-dinitrobutane (175 gi 1 mol) is in a solution of ammonium chloride (100 g; 1.9 mol) in 50% aqueous ethanol

909838/1500

(2 liters) suspended and kept below 15 °, while zinc-- ' dust (400 g; 6.2 mol) added over a period of 3 hours will. The reaction mixture is allowed to warm to room temperature and is stirred overnight. After! Filtering, the combined Filtrates and wash water acidified to pH 2 (150 ml HCl) and under reduced pressure to a viscous mass "evaporated. Anhydrous potassium carbonate (1 kilogram) is under Stir in cooling, and the powder obtained is extracted continuously overnight with chloroform (2.5 liters). The chloroform extract is dried over anhydrous sodium carbonate and evaporated to a viscous oil. Then petroleum ether is added to to promote the crystallization of the product (40 g). P. = 162-163 ° (Lit. 157-159 °).

Although only one embodiment of the invention is shown and explained Changes and modifications can of course also be made without departing from the scope of protection of the invention is left.

- patent claims -

909838/1500

Claims (1)

Claims 1. Imidazoles with the formula! Wherein Rc is hydrogen or an organic group; the groups R-, R ", R ^ and R, each an alkyl group, one Alkenyl group, an alkynyl group or an aryl group "with each mean about 1-12 carbon atoms or part of one Alkylene group or alkenylene group R ^ Rp or R, R, form, each containing about 3-10 carbon atoms; each of the atomic pairs N ^ C ₀ and N _n B by a single or Double bond is connected, wherein only if the atomic pair N ^ - Q is connected by a single bond, a hydrogen is also directly connected to Cp; and A and B are hydroxyl groups, and oxygen and hydrogen atoms, respectively mean, in the following order of binding ^ *. ·. «R« * w τ. between the atomic pairs N ^ C »and N-, B ; 1) The atom pairs N ^ ---C _n and N-, B are both through Sinf ac! L bonds connected: A and B are both hydroxyl groups! 2) the atom pairs N ^ C "and N-, B are both linked by double bonds: A and B are both oxygen atoms; 3) the atomic pair H ,. Cp is linked by a double bond and the atomic pair N-, B is linked by a single bond: A is an oxygen atom and B is an oxygen or hydrogen atom or a hydroxyl group. 909838/1500 181578a 2. imidazoles according to claim 1, characterized by the formula O- R- ■ ν: R _r R, 3. imidazoles according to claim 1, characterized by the formula R- '4 ¹ A OH N ₁ . OH , H '2 ~ ^R 5 4. imidazoles according to claim 1, characterized by the formula O- R. OH 5. imidazoles according to claim 1, characterized by the formula R. '4 ^l 4 0- I ₊ N ₁ , 909838/1500 181 6. imidazoles according to claim 1 ₉ characterized by the formula ^R 1. 0- 1 day '2 p I ⁵ I O ^Ε 4 7. imidazoles according to claim 1, characterized in that Rjeine Meant alkyl or aryl group 8 »imidazoles according to claim 1, characterized in that R ^, Rp, R-, and R, represent lower alkyl groups » 9. imidazoles according to claim 8, characterized in that R ^, Rp, E, and R, represent methyl groups » _m 10. imidazoles according to claim 8 and 9, characterized in that R ₁ - is hydrogen. 11. imidazoles according to claim 8 and 9, characterized in that Rp · means a benzyl group » 12. imidazoles according to claim 8 and 9, characterized in that R ₁ - denotes a phenyl group. 13. imidazoles according to claim 8 and 9, characterized in that that R _{5 is} an Xthylcarboxylatgruppe (-COOCpHj- - group) 14. imidazoles according to claim 8 and 9, characterized in that Rp- means a hydroxymethyl group. 15. imidazoles according to claim 8 and 9, characterized in that that Rp- denotes a 1-propenyl group. 909838/1500 16. imidazoles according to claim 1, characterized in that Rc an imidazolyl ring as defined in claim 1 contains. "17. imidazoles according to claim 16, characterized in that R ₅ means an imidazolyl / 'ethylene group ". 18. imidazoles according to claim 1, characterized in that Rc is a 2,2-dimethoxyethyl group. 19. Imidazoles according to claim 1, characterized in that Rc w denotes a halomethyl group ". 20. Dihydro- and tetrahydroimidazoles with tertiary carbon atoms in positions 4 and 5 of the imidazole ring, characterized by the presence of at least one oxygen-carrying ring Nitrogen atom in the ring, being the oxygen-bearing Nitrogen is in the form of an oxide or hydroxide, 21. Compounds according to claim 20, characterized in that both imidazole ring nitrogen atoms are in an oxidized state are present. . 22. Compounds according to claim 20, characterized in that the molecules represent radical 4,5-dihydroimidazole nitroxides. 909838/1500 Process for the preparation of the imidazoles according to Claims 1 to 22, characterized in that one bis-hydroxylamine with the formal R ₂ O IHOH R ₈₃ O 5 -—- NHOH in the 3-L, Rg, R, and R. the meaning given above to have (A) with an aldehyde having the formula S ₅ OHO, in which E _{5 has} the meaning given above, or (b) with an aldehyde derivative with the formula E ₅ CHX ¹ , in which Ep- has the meaning given above and X and X ^{1 are} halogen, OE ¹ , NR ', SE ¹ (R' here denotes hydrogen, alkyl groups or aryl groups with or without functional substituents) and R ₅ and R 'and X and X' can be identical to or different from one another, provided that only one X or X ^{1 is} fluorine, or (c) with a compound of the formula _n E ₅ O - X, where E ^ is a strong electron withdrawing group, such as -OX'χ, -OX ', ^{111 or} 9 ' ( ^χι means here ^ H. Halogen, H ¹ hydrogen or an alkyl or aryl group with or without functional substituents and R ″ represents the groups OE ', NHE ¹ , NR' or 909838/1500 SR ¹ ) and X the group 0, -00 ¹ R a .Halogen odtr «ine other easily interchangeable group (R denotes an alkyl or aryl group * with or without functional ßubstituenten), or χ (d) with an orthoester with the formula R ^ -O χ « ^ X ¹ in which R is hydrogen or an alkyl or aryl group with or without functional substituents and X, X ¹ and X * ¹ , which can be the same or different from one another ^{, denote the groups OR 1} , NR £ halogen or another easily exchangeable group, provided that no more than two groups denote fluorine (R 'denotes an alkyl or aryl group with or without functional Bubetituen * 4m), to compounds with the formulas “Q ₁ (away) (II) or (o, d) R ₂ - ⁴ K R, 0. (D 909838/1500 condensed and these condensation products in one another or in compounds with the formulas R, 0, ^l 4 N- OH (III). R ₂ O ₁ R ₃ - O ₁ 0 " R ₅ (LV) ^r N- '2 ^R 5 (V) converted and the compounds (III) - (V) optionally converted into one another or into the compounds (I) and (II). 909838/1500 24. The method according to Anspruoh 23 daduroh characterized in that one for the production of the "imidazoles, in which IU hydrogen represents a) the intermediate product of the formula (I), in which Hc denotes an organic carboxylate group, is saponified and the acid obtained is decarboxylated or b) the intermediate with the formula (II.). , in which R ₁ denotes a hydroxymethyl group, oxidized with lead dioxide. 25. Use of the imidazoles according to claims 1-22 as spinite marking subsets. H / u 909838/1500