DE2240610A1 - PHOSPHINYLALKYLAMINOBENZOPHENONE AND METHOD FOR MANUFACTURING THEREOF - Google Patents

Description

FARBWERKE HOECHST AG formerly Master Lucius & Erünittg

Date: August 17, 1972 Dr. HG / ie

File number HÖE 71 / F 352

Phosphinylalkylaminobenzophenonen and process for their preparation

The present invention relates to ortho-substituted aminobenzophenones and a method for their production.

It is known that in the direct alkylation of amines of the aniline type with primary alkyl halides, a mixture of mono- and dialkylated products is obtained «, This applies in particular when using an excess of alkyl halides. To get a good yield of only mono.alkylated anilines, in particular Ortho-aminobenzophenones, to date, was initially obtained the amino group is protected, e.g. by tosylation, the tosylated intermediate obtained is alkylated and then the <Tosyl protective group removed by hydrolysis (J. Org. Chem., Volume 27, p. 3781 (1962). This multi-stage process is tedious and for the large-scale production of the desired Connections not suitable. Attempts have also been made to use Ortho-Arainobenzophenone directly without using a Protective group to alkylate, but the yields of monoalkylated products are low (j. Org. Chem., Volume 28, p. 2456 (1963).

The present process can be substituted orthophosphinylalkylaminobenzophenones by direct reaction of Oirtho-aminobenzophenones with substituted phosphinylalkyl halides or substituted phosphinyl alkyl sulfonyl esters easily and with excellent yields. The yields of the desired products are generally around $ 90

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according to thin-layer chromatographic analysis of the reaction mixture.

It is almost surprising that when using an excess almost no phosphorus-containing alkylating agents dialkylated product is formed. The high yields of monoalkylated product are particularly unexpected in view of this the relatively low reactivity of the phosphinyl alkyl

compounds as alkylating agents.

The compounds obtained according to the invention can be used for the preparation of pharmaceutically active phosphorus-containing benzodiazeflins insert.

The present invention therefore relates to P-substituted Grtho-Phosphinylalkylaminobenzophenone, their preparation by the following reaction equation is explained:

R *

in which X is a halogen atom, e.g. B. a chlorine; Fluorine-i bromine or Iodine atom, or a sulfonate group, e.g. B. a tosyloxy or mesyloxy group, Y represents an oxygen or sulfur atom, n_ for an integer from 1 to 6, preferably 1 to 3 »

1 2
R and R, which are identical or different, represent an alkyl group with 1 to 6, preferably 1 to U, carbon atoms, and R to R, which are identical or different, represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a trifluoromethyl group, an alkyl group with 1 to 6, preferably 1 to h carbon atoms, an alkoxy group with 1 to 6, preferential prices 1 to h carbon atoms, or an alkylthio

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group with 1 to 6, preferably 1 "to k, carbon atoms.

Compounds preferred according to the invention are P-alkyl-substituted Ortho-oxophosphinylalkylaminobenzophenones of the formula

12th
in which η for 1, 2 or 3 »R and R, which are the same or different

den are, for a methyl, ethyl, propyl or butyl group, R for a halogen atom, a nitro or trifluoromethyl group and R stands for a hydrogen or halogen atom, a trifluoromethyl, methyl ", ethyl, propyl or butyl group or a methoxy-y Ä Propoxy or Butoxygrupoe are available.

These preferred compounds are made by the implementation of Ortho Aminobenzophenones of the formula

3 h
in which R and R have the same meanings as above, with dialkyloxophosphinylalkyl halides or dialkyloxophosphinylalkyl sulfonic acid esters of the formula

-R '

in which X stands for a halogen atom, preferably a chlorine atom, or a sulfonyl ester group, preferably a tosyloxy or mesyl

1 2

oxy group, and R and R, which are the same or different j-for a methyl, ethyl ·; Prop3'-1 or butyl group, where R

2
and R preferably have the same meaning.

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The substituted ortho-aminobenzophenones used as starting compounds can be produced by known processes. Qrtho-aminobenzophenones with a substituent in the 5-position are particularly suitable. Suitable aminobenzophenones are z. B. 2-amino-5-chlorobenzophenone, 2-amino-6-chlorobenzophenone, 2-amino-5-nitrobenzophenone, 2-amino-5-trifluoromethylbenzophenone, 2-amino-2 ', 5-dichlorobenzophenone, 2-amino-5-chloro-2 · -' fluorobenzophenone, 2-amino-5-chloro-4-methylbenzophenone, 2-amino-5-chloro-4'-butylbenzophenone, 2-amino-5-chloro-4'-methoxybenzophenone and 2-amino-5-fluoro-4 * -trifluoromethylbenzophenone.

The substituted as alkylating agents used according to the invention Phosphinylalkyl compounds can also be prepared by known methods. Chloroalkylphosphinyl compounds are preferred because they are easier and cheaper to manufacture, although their fluorine, bromine and iodine analogs are also used like sulfonyl ester groups - i like tosyloxy and mesyloxy groups - containing compounds can also be used. The bromine and iodine analogs can be obtained independently or in situ from the Preparing chloroalkylphosphinyl compounds by halogen exchange by reacting the reaction mixture with a bromide or Iodide salt, e.g. B. Potassium bromide or iodide added · For halogen exchange a catalytic amount or a full molar equivalent of the halide salt is employed. Suitable phosphinylalkyl compounds are z. B. Chlorinethyl-dimethylphosphine oxide, Chloromethyl-dimethylphosphine sulfide, chlorine thyl-di-n-buty iphosphine oxide, 2-chloroethyl-dimethylphosphine oxide, 3-chloropropyldimethylphosphine oxide, Bromine thyl-dimethyl -:> phosphine oxide, iodomethyl-dimethylphosphine oxide, Tosyloxymethyl dimethylphosphine oxide and mesyloxymethyl dimethylphosphine oxide.

The reaction is generally preferred in the presence of an organic or inorganic base in amounts between 1 and 51 1 to 2 equivalents, based on the amino

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benzophenone, carried out. Tertiary bases are used as organic bases aliphatic amines, e.g. triethylamine, tri-n-butylamine, aromatic .Amine, e.g. B. Pyridines, Collidines and Quinolines Used Suitable inorganic bases are alkali or alkaline earth oxides, hydroxides, carbonates and hydrogenocarbonates, e.g. B. Magnesium oxide, potassium hydroxide, potassium carbonate, calcium carbonate and potassium hydrogen carbonate.

The reaction can be carried out in an inert organic solvent or carry out in mixtures of organic solvents, preferably aromatic hydrocarbons or halogenated aliphatic ^ hydrocarbons. Suitable solvents are z. B. benzene, xylene, pseudocumene (1, 2, 4-trimethylbenzene), Phrenitol (1,2,3,4-tetramethylbenzene), tetrachloroethane, Dimethylacetamide, dimethylformamide and dimethyl sulfoxide. However, the use of a solvent or a base is for the desired implementation is not necessary.

The reaction is carried out very advantageously at temperatures between room temperature and 250.degree. To carry out the Implementation, higher temperatures are preferred, i.e. temperatures between 80 and 200 ° C.

One molar equivalent of the phosphinylalkyl compound is generally sufficient to carry out the reaction, but using an excess is advantageous in some cases. in the in general, the phosphinylalkyl compounds are used in amounts from 1 to 5 »preferably 1 to 3 molar equivalents are used.

The reaction is usually carried out under normal pressure. Depending on the boiling point of the solvent used however, one works at pressures between 1 to 50, preferably 1 to 10 atü.

As examples of ortho-phosphinylalkylaminobenzonhenones according to the invention the following are mentioned:

.3 09810/1169

2- (N-dimethyloxophosphinylraethyl) amino-5-chlorobenzophenone, 2- (N-di-n-butyloxophosphinylmethyl) -amino-5-chlorobenzophenone, 2- (N-dimethyloxophosphinylpropyl) -amino-5-chlorobenzophenone, 2- (N-dimethyloxophosphinylmethyl) -amino-5-nitrobenzophenone, 2- (N-dimethyloxophosphinylmethyl) -amino-6-chlorobenzophenone, 2- (N-dimethyloxophosphinylmethyl) -amino-2 *, 5-dichlorobenzophenone, 2- (N-dimethyloxophost> hinylmethyl) -amino-5-chloro-2 '■ -fluorobenzohenone and 2- (N-dimethyloxophosphinylmethyl) -amino-5-chloro-2'-fluorobenzqphenone and 2- (N-dimethyloxophosphinyl methyl) -amino-5-chloro - ^ '- methoxybenzophenone.

The compounds prepared by the process of the invention are valuable intermediates for the synthesis of heterocyclic ones Links. In particular, they are intermediates for the preparation of phosphinylalkyl-1,4-benzodiazepines, the as sedatives, muscle relaxants and anti-seizure drugs are suitable.

These phosphinylalkyl-1, '! -Benzodiazepines are by reaction the ortho-hiosphinylalkylaminobenzophenones with aminoacetic acid derivatives, e.g. esters, iminoesters and orthoesters, or with haloacetyl halides, and subsequent reaction with Ammonia produced according to the following reaction scheme:

1!

H ₂ N-CH ₂ COOR

(The symbols Y, n, R to R have the meanings given above) .

The ring closure is at elevated temperature according to known methods, preferably carried out in boiling pyridine.

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example 1

A stirred mixture of 46.3 grams of 2-amino-5- ° l ¹ lorbenzophenone, 75 »9 grams of chloromethyl-dimethylphosphine oxide and 26.7 grams of symmetrical collidine (2, h, 6-trimethylpyridine) in 225 milliliters of pseudocumene (1, 2 , 4-trimethylbenzene) as a solvent is refluxed under nitrogen overnight (about 15 hours). According to analysis by thin-layer chromatography, the reaction product is formed in a yield of at least 90 ° fo . The reaction mixture is then cooled to room temperature and dissolved in one liter of chloroform. The organic solution is then extracted four times with water, dried (Na ₂ SO ^), treated with activated charcoal and filtered. The chloroform is removed in a water jet vacuum, the product beginning to crystallize from the remaining pseudocumene. The mixture obtained is diluted with 225 milliliters of diisopropyl ether and left to stand at .0 C overnight. After filtration, pure 2- (N-dimethyloxophosphinylmethyl) -amino-5-chlorobenzophenone with a melting point of 136.5-138.0 ° C. is obtained. The NMR and IR spectrum corresponds to the structure assignment.

The same product is obtained if one uses oilinolin or potassium carbonate instead of collidine.

Example 2

A stirred mixture of 9t26 grams of 2-amino-5-chlorobenzophenone, 8.43 grams of chloromethyl di-n-butylphosphine oxide and 5 »34 Grams of collidine in 100 milliliters of dimethyl acetamide is used with 6.64 grams of potassium iodide were added as a catalyst. After heating at 80 ° C. under nitrogen, a solution is obtained; after a short time Reflux shows the incipient precipitation of potassium chloride indicates that the desired halogen exchange for iodomethyldi-n-butylphosphine oxide takes place. After refluxing overnight, the reaction mixture is cooled to room temperature and the inorganic salt filtered off. The solvent will then

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- ο -

removed in vacuo and the remaining oil purified by chromatography on a silica gel column, whereupon 2- (N-di-n-butyloxophosphinylmethyl) -amino-5-chlorobenzophenone is retained as a yellow oil, N _n ^J = 1.5078. The NMR and IR spectrum corresponds to the structure assignment.

Example 3

A stirred mixture of 9 »26 grams of 2-amino-6-chlorobenzophenone, 8.20 grams of Mss jfckxymethyl-dimethylphosphine oxide and 5-3 grams Collidine in 50 milliliters of benzene is kept under nitrogen for as long refluxed until analysis of a sample by thin layer chromatography shows that the reaction has essentially ended. The mixture is then cooled to room temperature and dissolved in 200 milliliters of chloroform. This organic solution is extracted four times with water, dried (Na SO,), with Treated activated carbon and filtered. The solvent is then removed under reduced pressure and the remaining Oil is crystallized with the addition of a small amount of acetonitrile. Recrystallization from acetonitrile gives 2- (N-dimethyloxophosphinylmethyl) -amino-6-chlorobenzophenone as yellow crystals with a melting point of 155 - 157 ° C. The NMR and IR spectrum corresponds to the structure assignment.

example H

The mixture of 4.29 grams of 2-amino-5-chlorobenzophenone, 5172 grams of 3-chloropropyl-dimethylphosphine oxide and 2.42 grams of collidine in 22 milliliters of xylene is stirred and refluxed overnight. The reaction mixture is then cooled to room temperature and dissolved in 100 milliliters of methylene chloride. The organic solution is extracted four times with water, dried (Na ₃ SO.) And concentrated in vacuo to an oil which crystallizes after standing overnight. It is triturated with di-isopropyl ether and then from benzene / hexane (4/1 parts by volume)

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recrystallized, whereupon 2- (N-dimethyloxophosphinylpropyl) -amino-

o 5-chlorobenzophenone with a melting point of 117-119 ° C is obtained. The NMR and IR spectrum corresponds to the structure assignment.

Example 5

If you work according to example! But instead of 2-amino-5-chlorobenzophenone, 2-amino-5-chloro-4 ^l -methoxybenzophenone is used, you get 2- (N-dimethyloxophosphinylmethyl) -amino-5-chloro-^ ^1- methoxybenzophenone in the form of yellow crystals with a melting point of 125 - 126 ° C. The NMR and IR spectrum corresponds to the structure assignment.

Example 6

If you work according to the procedure given in Example 1, but instead of 2-amino-5-chlorobenzophenone, 2-araino-2 ^f , 5-dichlorobenzophenone is used, 2- (N-dimethylphosphinylmethyl) -amino-2 *, 5-dichlorobenzophenone as yellow crystals with a melting point of 135 - 137 ° <3. The NMR and IR spectrum corresponds to the structure assignment.

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Claims (1)

Patent claims: in the Y for an oxygen or sulfur atom, η for a 1 2
Number from 1 to 6, R and R, which are the same or different, 1 6 for an alkyl group with 1 to 6 carbon atoms and R to R, which are identical or different, for a hydrogen atom or halogen atom, a hydroxy; Cyano; Nitro-; Tri fluorine thy 1 group , an alkyl group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms or an alkyl mercapto group with 1 to 6 carbon atoms. 2) compounds of the formula 0 _R l NH- (CH ₉ ) - p ₉ 2 η \ _R 2 in the η for 1, 2 or 3, R and R, which are the same or different are, for a methyl, ethyl, propyl or butyl 3
group, R for a halogen atom, a nitro or trifluoro k
methyl group xii.l R for a hydrogen or halogen atom, a tri fluorine thy 1-, methyl, ethyl, propyl or butyl group or a methoxy; Ethoxy> propoxy-odor butoxy group standing « 309810/1159 3) compounds according to claim 2, characterized in that 3
the halogen atom for R is a chlorine atom. k) 2- (N-dimethyloxophosphinylmethyl) -amino-5 = chlorobenzophenone » 5) 2- (N-di-n-butyloxopho sphinylmethyl) -aminO "5-chlorobenzophenone _c 6) 2- (N-dimethyloxophosphinylpropyl) -amino-5-chlorobenzophenone 7) 2- (N-dimethyloxophosphinylmethyl) -amino-5-nitrobenzophenone. » 8) 2- (N-dimethyloxophosphinylmethyl) -amino-6-chlorobenzophenone ^ 9) 2- (N-dimethyloxophosphinylmethyl) -amino-2 ·, 5-d.ichlorobenzophenone. 1O) 2- (N-Dimethyloxopho sphinylmethyl) -amino-5-chloro-2 ^s -fluorobenzophenone. 'S) Process for the preparation of Phosphinylalkylaminobenzophenonen, characterized in that compounds of the formula in which R to R, which are the same or different, represent a Hydrogen or halogen atom, a hydroxy-j Cyano *? · Nitro * y Trifluoromethyl group, an alkyl group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms, or an alkyl mercapto group with 1 to 6 carbon atoms, with phosphorus-containing compounds of the formula Il J *
^X - < ^CH 2> n- < _R 2 3 0 9 8 10/1159 in which X stands for a halogen atom or a sulfonyl ester group, Y for a hydrogen or sulfur atom, η for a whole 1 2
Number from 1 to 6 and R and R ^, which are identical or different, represent an alkyl group with 1 to 6 carbon atoms, converts 12) Process for the preparation of Oxophosphinylalkylaminobenzophenonen, characterized in that compounds of the formula NH " 3
in which R stands for a halogen atom, a nitro group or a Trlfluormethylgruppe and R for a hydrogen or halogen atom, a trifluoromethyl, methyl ·, ethyl, propyl or Butyl group, or a methoxy-> ethoxy-y propoxy or butoxy group » stand, with phosphorus-containing compounds of the formula ⁰ , R ¹ ^ R ² in which X stands for a halogen atom or a sulfonyl ester group, 1 2
. n_ represents 1, 2 or 3 and R and R, which are identical or different, represent a methyl · ^ ethyl "·, propyl or butyl group. 13) Method according to claim 12, characterized in that chloromethyl-dimethyl-phosphine oxide as a phosphorus-containing compound is used. ~ \ h) Process according to claim 11, characterized in that the reaction is carried out in the presence of an organic or inorganic base. 3098 10/1159 ^ 15) Method according to claim 11, characterized in that: the reaction is carried out in the presence of an inert organic solvent. . . 16) Process according to claim 11, characterized in that the phosphorus-containing compounds are used in amounts of 1 to k molar equivalents. . . _; · - _:. . 17) Method according to claim 11, characterized in that "gelcerihzeicnnet" * that the Implementation at temperatures from room temperature to 25 ° C is carried out. 18) Method according to claim 11, characterized in that the reaction carried out at a pressure of 1 to 50 atmospheres will. 19) Method according to claim 11, characterized in that ■ that the Implementation carried out under an inert gas atmosphere will. .--. * ■ -..- 309810/1 159