SK694A3 - Process for the preparation of diphenyl derivatives - Google Patents

Abstract

The invention relates to a method for the preparation of a compound of the general formula (I) <IMAGE> in which X represents an optionally protected formyl group and R denotes a group which is itself inert to the reaction conditions of the synthesis, for example -CN, characterised in that a compound of the general formula (II) <IMAGE> where X is as defined above, is reacted with a substituted phenyl halogen compound of the formula (III) <IMAGE> where Hal denotes e.g. bromine. The compounds are useful intermediates for pharmaceutical synthesis.

Description

Process for preparing diphenyl derivatives

Technical field

The invention relates to special diphenyl derivatives and to a process for their preparation.

BACKGROUND OF THE INVENTION

In the manufacture of active substances, such as blood circulation drugs, it has been shown that diphenyl derivatives are important among the product in the manufacturing process. For example, EP-A 503 162 discloses the preparation of blood pressure lowering medicaments comprising as active ingredient compounds of the angiotensin II receptor antagonist type characterized by a specially substituted diphenyl system.

To date, various processes for the production of substituted diphenyl derivatives have been described; it is possible, for example, to combine phenylboronic acid derivatives with aryl and halogenated catalysts using transition metal catalysts, e.g. Appropriate reactions have been described, for example, by R. B. Miller et al. in Organometallics, 1984, 3, 1261 or A.Zuzuki et al., Synthetic Commun. 11 (7), 513 (1981).

SUMMARY OF THE INVENTION

The invention relates to a process for the preparation of diphenyl derivatives of the general formula I

in which X where appropriate, formyl or -CH / OR ^Ί / OR ² is protected, group, especially -CHO R ^1, R ² independently of one another denotes an alkyl group with carbon atoms or R ^{@ 1} and R @ ² together represent a cylene chain - (CH3) n -, wherein n is 3, 4, or 5, and with 1 to 6 atoms and 1 - 1 é number 2, R denotes a moiety which is itself the reaction conditions in the synthesis. inert against themselves At the method of the invention is is based from friends,

optionally protected forms of phenyl halides, for example bromides or iodides, and boronic acid derivatives are obtained by Grignard reaction (see, for example, H. Feulner et al., Chemische Berichte 123, 1990, 1841-1843) of formula II

X

I / 11 /,

Y

Ktorom O 0Ξ wherein the substituent X represents a -CHO group or an appropriately protected formyl group, for example acetal. The compounds of formula II are then coupled with substituted phenyl halides of formula III

which can be obtained by known methods, are converted to the diphenyl compounds of the formula (I), in particular bromides or iodides, preferably in particular the bromides; and R is as defined above.

Instead of the boronic acid derivatives of the formula II, the corresponding boronic esters can also be used in the process according to the invention, which can be synthesized from the bromomethyl phenyl boronic acid derivatives which serve as starting materials.

The coupling of the two phenyl derivatives of formulas II and III to the corresponding corresponding diphenyl compound can be carried out using a catalyst, preferably a palladium catalyst. The reaction conditions may be varied according to the reactivity of the starting materials, with a temperature range of from 20 to 150 ° C and a pressure of from 1 to 1 bar. Suitable solvents are, for example, mixtures of benzene or toluene with alcohols, in particular ethanol.

Suitable substituents R in the compounds of the formula I are all those moieties which do not change even under the reaction conditions used to join the two benzene nuclei. The following groups are particularly suitable as substituents R: R represents a fluorine atom, a chlorine atom, a nitro group, an

- / ChSA -COOR ^3, - / CHCl / m C0NHR ^3, - / CHCl / m -CN, -SO 2 NH-COOR ^3, -SO 2 NH-CO-NHR ^3, -SO -NH-SO 2 R ^3, -NHSO 2 R ³ ,

NN / N O ^O - trityl, -POaR ^3, -NH-SO ₃ or -CF = -SOeNR '''' N wherein R ³ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, cycloalkyl having 3 1oa1ky1ovú or (C 3-C cyk) cycloalkyl group substituted with (C až-C alky) alkyl; and

R ⁴ is = O-Ν (0-3) =, m is an integer of 0, 1, 2, 3 or 4.

Instead of linking both phenyl derivative systems via a boronic acid derivative, it is also possible to prepare diphenyl derivatives of formula I using zinc or tin halophenyl or methyl phenyl derivatives or Grignard compounds.

The preparation of protected formyl moieties and Grignard compounds can be accomplished by conventional methods. .

The invention also relates to compounds of formula I as such, with preference given to those compounds in which R is SO ² NHCOOR ³ , SO ² NHCONHR ³ , SO = NHSO = R ^3, or SOcNR ", where SO ² NHCONHR ³ and SO ² NR ⁴ are particularly preferred; furthermore, it relates to compounds of formula III as such, with those compounds in which R is SO 2 NH-COOR ³ , SO 2 NH-CO-NHR ³ or SO 2 NH-SO ² R ³ , with SO ² NHCONHR ³ being particularly preferred.

The following Examples illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Process for preparing 4-formyl-2'-N, N-dimethylaminoformyl-diphenylsulfonamide of the formula

CHO

1a / 4-Bromobenzaldehyde diethyl acetal

To a solution of 2.7 g (1.1 mol) ammonium nitrate in 65 ml anhydrous ethanol was added 100 g (0.54 mol) molten 4-bromobenzaldehyde and 90 ml (0.54 mol) triethyl orthoformate. After 18 hours at room temperature, the reaction mixture was filtered and made basic with piperidine (about pH 10). The title compound is obtained by distillation in vacuo.

Yield 90% of theory;

boiling point (at 6.6 Pa) = 110-115 ° C.

1b / 4-Form 1 phenyl boronic acid

Under an argon atmosphere, 3.65 g of magnesium shavings were overlaid with ml of anhydrous tetrahydrofuran and 0.5 ml of 1,2-dibromoethane was added. After a slight heating, a violent reaction occurs. After removal of the solvent, the solvent is removed by pipette, 40 ml of anhydrous tetrahydrofuran and 1/3 of the solution of the product of Example 1a / in 30 ml of anhydrous tetrahydrofuran are added. The reaction is started by the addition of Red-Al (see explanatory notes after the examples) and heating. The remainder of the product of Example 1a) is now added dropwise over 35 min. After completion of the dropwise addition, the mixture is refluxed for 1 hour. The Grignard reagent was then added dropwise to a solution of 33.5 mL of tributyl borate in 50 mL of tetrahydrofuran cooled to -68 ° C under argon. After 30 min, the cooling was removed. The mixture was stirred at room temperature for 1 h, then evaporated, the honey-colored oil was taken up in 100 mL of ether and 80 mL (1 M) of ice-cold sulfuric acid was added. The ether layer was separated, the residue was extracted twice more with 500 ml of ether each time; Evaporate and add 30% (6 N) potassium hydroxide solution until alkaline (pH 14). 70 ml of water are added and azeotropic butanol is removed under high vacuum at 35-40 ° C. This procedure is repeated once more with 50 ml of water. The residue is acidified with 1 M sulfuric acid (pH 1) and boiled for 30 min. Filtration gave the title compound as a pale yellow solid.

Melting point - 255-260 ° C.

1c / 4-Formyl-2'-N, N-dimethylaminoformyl-diphenylsulfonamide

To a solution of 7 g (0.024 mol) of 2-bromo-N, N-dimethylaminoformylbenzenesulfonamide and 0.7 g of triphenylphosphine (0.1 equivalent) in 100 ml of toluene is added a solution of 5.7 g of sodium carbonate (2 equivalents) while warm. in 30 ml of water. It is purged well with argon and 0.3 g of palladium (II) acetate (0.05 equivalents) is added at 60 ° C in an argon stream. After 10 ke, which in the meantime stained the compounds of Example 1b / 1.1 again under argon. Thereafter, a solution of 4 g equivalent / in 70 ml of ethanol was added to the reaction mites, brown, heated to reflux and refluxed for 3.5 hours. After cooling, the solvent was removed in vacuo. The residue is taken up in 150 methyl acetate and washed 5 times with saturated sodium carbonate solution. The organic phase is dried over magnesium sulphate and filtered through a pad of diatomaceous earth. Evaporation of the solvent in vacuo gave 8 g. of the title compound as a brown, partially crystalline crude substance. It can be purified by boiling with about 30 ml of ethyl acetate.

Yield: 83%.

_Rf = 0.4 / E / H 2/1 /; MS (M + 1) = 317;

mp = 161 ° C.

Analogously, using the appropriate starting materials, the compounds of Examples 2 to 6 can be prepared. Their structure and physical data are shown in Table 1.

This gave the title compound.

R f = 0.5 (E / H 2/1 / MS (M + 1) = 321).

Example 8

Process for the preparation of 2-iodophenyl-n-propylsulphonyl urea

8a / 2-Iodobenzenesulfonamide

A mixture of 2-aminobenzenesulfonamide (3.5 g) and sulfuric acid (25 ml) of horse (98%) was heated to 60 ° C until a clear solution was formed and cooled to 0 ° C by the addition of 20 g of ice. A solution of 1.45 g of sodium nitrite in 4 ml of water is then carefully added dropwise such that the temperature does not exceed 5-6 ° C and the reaction mixture is further stirred at 5-6 ° C for 3 hours. After the dropwise addition of a solution of 3.75 g of potassium iodide in 25 ml of water, the resulting red mixture was again stirred for 18 hours. After addition of 50 ml of water, the precipitate formed is filtered off and washed several times with water. The solid obtained was dissolved in ethyl acetate, washed once with 0.2 N sodium thiosulfate solution and twice with water, and the solvent was evaporated. 4 g of slightly yellowish substance are obtained.

Yield 62% of theory;

IR (nujol): 3360, 3255, 1562 cm @ ^-1 ; MS (M +): 283;

mp = 197-198 ° C.

8b) 2-Iodophenyl-n-propylsulfonylurea

To a solution of 4 g of 2-iodobenzenesulfonamide in 40 ml of acetone, 3.92 g of solid potassium carbonate are added in one portion with stirring, and the mixture is further refluxed under nitrogen. The n-propyl isocyanate is added dropwise to the hot reaction mixture, then refluxed for 2 hours, cooled to room temperature and evaporated to dryness. After addition of 200 ml of water, the cooled reaction mixture is acidified to pH 4 with 2N hydrochloric acid and filtered. The precipitate was recrystallized from acetone / isopropyl ether to give the title compound, yield 4.1 g.

IR (nujol): 3406, 3368, 1715, 1565, 1539 cm @ ^-1 ;

MS (M +): 368;

mp = 211-212 ° C.

Data on the title compounds of the embodiment no. 1, 2, 3, 5, 8a (and 8b) obtained at ¹ HN MR are summarized in Table 2.

Table 2

1: / DMSO-d / d = 2.68 (s, 3H); D = 2.72 (S, 3H); d = 7.2 (s, 1H); d = 7.25 to 7.35 / m, 1 H /; d = 7.45 to 7.75 (M, 4 H); d = 7.95 / d, J = 8Hz 1 H; d = 8.05 and from 8.15 (M, 2H); D = 10.1 (S, 1H), Λ. ú · / CDCls / d = 1.0 / t, J = 7Hz, 3 H /; d = 4.1 / q J = 7Hz,

H /; d = 7.3-7.6 (m, 5H); d = 7.85 to 8.0 (m, 3H); d = 10.1 (S, 1H).

3: (CDCl 3) d = 7.2-7.8 (m, 6H); 7.95 to 8.05 (m, 2H); d = 10.1 (S, 1H). 5: (DMSO-d 6) d = 1.0 (t, J = 7 Hz, 3 H); d = 1.3 / dq, J = = 7 Hz, 2H; d = 2.85 (dd, J = 7 Hz, J = 9.5 Hz, 2H); d = 6.1 (t, J = 7 Hz, 1H); d = 7.1 to 7.4 (m, 1H); d = = 7.4 to 7.8 (m, 4H); d = 7.9-8.1 (m, 3H); d = 9.9 (s, 1H); d = 10.1 (s, 1H). 8 /: (CDCl 3) 5.17 (s, I, NH ₌ ); 7.23 to 7.52 (td aromatics 2H); 8.08 to 8.20 (dd, aromatics 2H). 8b /: (CDCl 3) 0.82 (t, J = 7.5 CH 3, 3 H); 1.45 / m, CH = 2H; 3.14 (m, CH3, 2H); 6.39 (t, CONH, 1H); 7.29 (dt, J = 1.5 aromatics); 7.54 (td, J = 8.15 aromatics); 8.13 (m, aromatics); 7.59 (s, SOsNH, 1H).

Abbreviations:

E = ethyl acetate

H = n-heptar>

Red-Al-sodium dihydrido-bis- (2-methoxy-ethoxy) and 1 µminate

Trityl = three bitches

Industrial usability

The compounds that can be prepared by the process of this invention are important intermediates for the production of blood pressure lowering drugs, especially angiotensin II receptor antagonists.

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Claims (9)

PATENT CLAIMS A process for producing a compound of formula I / V, wherein: X is optionally a protected formyl group and R is a group which is itself inert to the reaction conditions in the synthesis, characterized in that the compound of formula II (H) in which X is as defined above is reacted with a substituted phenyl group. and h) a compound of formula III Hal wherein Hal is halo and R is as defined above. Process according to Claim 1, characterized in that in formula I the substituents have the following meanings: R ² is -CHO or -CH / OR ¹ / OR ⁼ , independently of one another is C or R ¹ and the cylene chain - (CH 2) -, 3, 4 or S, denotes fluorine, chlorine, - (CH 3) m -COOR ³ , - (CH 3) m -CONHR ³ -SO = NH-COOR ³ , -SO 2 NH-CO-NHR ³ , an alkyl group having 1 to 3 6 R ² together skillfully form and 1 cause n is the integer 2, -nitro grouping R ^3, - / CH / m-CN, -SO = NH-SO = R ³ -NHSO2R ³ , NN / q N -trityl, -PO ₃ R ³ , -NH-SO-CF ₃ or -SO = NR ⁴ , wherein R ³ represents a hydrogen atom having 1 to 6 carbon atoms, a cyclic group having 6 carbon atoms a (C 3 -C 6) cycloalkyl group which is substituted by a (C 1 -C 6) alkyl group or a (C 3 -C 6) alkyl group And R ⁴ is = CN (CH ₂ ) ₌ , m is an integer of 0, 1, 2, 3 or 4. The process according to claim 1, wherein the reaction of the compound of formula (II) with the compound of formula (III) is carried out in the presence of a transition metal group. Third that is 4. A compound of formula (I), wherein the palladium compound is a catalyst (1) in which the substituents have the following meanings: X is -CHO or -CH / OR ² / OR ² R ¹ , R ² independently of each other denote an alkyl group having 1 to 6 carbon atoms, or R ¹ and R ² together form an alkylene chain - / CH - / n -, where n is an integer of 2,3,4 or 5 R represents a fluorine atom, a chlorine atom, a nitro group, a moiety - / CH 2 / m-COOR ³ , - (CH 2) m -CONHR ³ , - (CH 3) m-CN, -SO 2 NH-COOR ³ , -SO 2 NH-CO-NHR ³ , -SO 2 NH-SO 2 R ³ , -NHSO 2 R ³ , NN ¢ 0 ^N -trityl, -PO ³ R ³ , -NHSO 2 -Ca or -SO 2 NR ³ , N wherein R ³ represents a hydrogen atom or a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group C 3 -C 3 cycloalkyl 6 carbon atoms which is substituted by alkyl C 1 -C 6 and R ⁴ is = CN / CH ₃ / => m is an integer of 0, 1, 2, 3 or 4th 5. A compound according to claim 4 in y z n and no e n á t ý m that within of formula R indicates group -SO2- NR ⁿ or - SC2NHCONHR ³ why R ³ is hydrogen or alkyl group s 1 up to 6 a- carbon atoms and R ^d is = CN / _CH3 / second Use of a compound prepared according to any one of claims 1 to 4 as an intermediate for the synthesis of active substances. 7. Use of a compound according to any one of claims 4 or 5 as an intermediate product for the synthesis of angiotensin II receptor antagonists. A compound of formula III Hal in which the substituents have the following meaning: Ή31 denotes a bromine or iodine atom, R is -SO 2 NH-COOR moiety ^3, -SO 2 NH-CO-NHR ^3, -SO = NH-SO 0 -R ³ wherein R ³ is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl substituted with alkyl C 1 -C 6. Compound according to claim 8, characterized in that in formula III, R represents a group -SO 2 NH-CO-NHR ³ in which R ³ represents an alkyl group having 1 to 6 carbon atoms.