DE1695841A1 - Process for the preparation of new benzodiazepines - Google Patents

Description

", · ■ '.''-·' · - '■ VT ₁ Kr

L ..μ.- .j. -. · .... _r r · ■■■ 1

1- ■ ι '"■■■ -'->. ■■. _W. ^ Ί. ^; Πι

1 R Q ^ P Λ

SCHERICO LTD., Töpferstrasse 5, Lucerne (Switzerland)

Process for the production of new benzodiazapines

The invention relates to a method of manufacture of new substituted benzodiazapines. According to the invention, these new compounds are the 1,4-benzodiazapines of the formula

CH ₂ CF ₃

are, where X and Y are hydrogen, halogen, trifluoromethyl, nitro, alkyl or alkoxy, R ₁ and R _{p are} hydrogen, alkyl or free or esterified hydroxy, preferably alkanoyloxy, but in cases where one of the radicals R, and R _{p is} a free or esterified hydroxyl group, the other radical is hydrogen, and the 4-oxides of these compounds

Documents (Art? £ l Para. 2 l; r. \ Sau 3 of the amendment · »« · v. 4.

109886/1728

fertilize, being 3- _; and R _{P are} independently hydrogen or alkyl / produced by a process = which is characterized in that known processes are used

T} ie possibly present alkyl _; Alkorcy- and Alkanoylcxysubstituenteii are preferably lower alkyl, lower alkoxy and lower alkanecylory. The term "lower alkyl" preferably means lower aliphatic, in particular saturated hydrocarbon radicals with up to 6 carbon atoms including the straight-chain and branched isomers. In the same

Ψ The lower alkoxy radical has a similar range of preferably up to 6 carbon atoms- v / whether ei in particular saturated, straight-chain and branched iscmers are included = lower alkoxy? / Io: xy preferably means hydrocarbyl carbonic acid radicals, .. in particular those _; which are derived from saturated acids, with up to 6 carbon atoms. These include ethyl, methyl, propylene, isopropyl, butyl. Pentyl, He: * yl _:. Methoxj ¹ "" Ethoxy, acetyl; Propion: / !, Iscautyryl und Caprcylc The expression: "Halogen" includes all four halogens. Of particular value, however, are compounds in which X is chlorine or bromine and Y is fluorine or

\ - chlorine stands.

The compounds prepared according to the invention act on the central nervous system and as such are v. ^r erful I.; us]: elerelaxants, sedatives and valuable remedies against convulsions and anxiety.

The K-trifluoroethylated 1; 4-3enzodiazapines and their 4-oxides can be prepared in any suitable manner Averden, for example, by processes which can be used to prepare the corresponding Yei hindrances without the 1-'j} rifluoroethyl substituent _; preferably the corresponding 1-unsubstituted or ί methyl-substituted. Connections are suitable, they can be very beneficial

109806/1728

can be produced with the aid of intermediate products which already contain the desired trifluoroethyryl residue. They can also be prepared by: -tri'luorethylation of the corresponding, "i-unsubstituted compounds or their derivatives which contain a portion in the 2-position which can be converted into O instead of an oxy group Compounds are to be prepared from any corresponding "unsubstituted compounds", various erifluoroethyiating methods can be used, e.g. methods in which compounds of the formula CP ^ CH ₂ -P-? In which P is a reactive group, e.g., a reactive group organic or inorganic ester group is used ™

It is also possible to first introduce "for example a group C (HaIK-CHg-? In which EaI is a halogen, besides fluorine. Then Hai is replaced by fluorine, for example by reaction with silver fluoride" alkylation with a sulfonate of general formula voru trifluoroethanol -CPtCH ₂ OSO ₂ Zj wherein Z Alkyl.- aryl "aralkyl barren polyhaloalkyl is subjected _s Suitable sulfonates are, for example, 2 _r 2 _s 2 * rrifluor - ätliylinethylsulfonat, 2 _S 2.2-trifluoroethyl! -phenylsulfcnat, 2.2,2-Trif luoräthylbenzylsulf onate and 2, 2 _f 2-tri ~ ·-fluoroethyl trichlormethylsulfonate "in-the lurchführung this alkylation reaction are" the reaction part-.nehmer usually together in 'an anhydrous solvent system in the presence of an inorganic Bases such as potassium carbonate / heated under reflux ,, Suitable solvents for this reaction are, for example, riphenyl ether, digiime and tetral In, in a further expedient embodiment, dis-used; correspondingly X- and Y-substituted bencodiazapines with a 2,2,2-trifluorethyl bromide, · chloride or preferably -godid alkylated. The tri-.fluoroethylene reaction with these halides is 109886/1728

169584 t ⁴ "

"-preferably in non-reactive organic lösungsmitteln5 as Biraet _{iylferraamid:,} © aromatic Kohlenwasserstoffens as Ben.z © ly Tolmol or _xylene-5 in the presence of a basic condensation ionsmittels by conventional methods you rehgeführt as basic Kondensationsniittel look suitable, beiapiels- ■. travel Katriuinnetho: xyd> Eatritisfrydriä _s Kali, Egg and Eatriumanidf. The reaction becomes, usual.

Temperatures in the range of about ^{20- "10 0} Qy preferably = about 65 ⁰ G, carried out for an acidity of Ί-24 hours * τογ-preferably ctv / a 7 hours, before then further trifluoride halide was added * and the reaction is continued for a further period of about 6 hours. The trifluoroethylated benEodiazapines formed as products can be isolated by filtering off the insoluble salts, evaporating the piltrate; - "by - selective solvent extraction; i further isolated and purified by chromatography, for example by elution from an aluminum chloride adsorption column

I) he benzodiazapiiie used as starting compounds and their precursors; for example, 2 - aminobenzophenones, i3en according to the invention-for the preparation of the compounds over the Crlfluoräthylierung the corresponding w 'i-unsubBtituierten Connections are made könneji by methods which are analcg the _process: in the literature, "for example, in J Organic Ohen 27th 562 ff. And 5J.85 ffV, fcescviriecen-are :.

The 2- _j \ minobenzophenone precursors can be prepared by known processes. "The choice of method depends on the position and the nature of the desired substituents on the aromatic rings from-'Sines the most common method in which a substituted anthranilic acid (II) is used, in g ^ 31- 3'ö '. described, Here an anthranilic acid \ II ;. with acetic anhydride to an Eenzoza-

Ί09886 / 172Θ ^^

: zinoii (ill) "lametzt, from which by implementing with • data of the corresponding Phe.nyl ~ Grignard reagent and subsequent Hydrolysis of the desired 2-AmInOl) enzophenone (IV) is obtained .-- This succession of Reactions can be represented as follows: Reaction scheme A:

COOH

Acetic acid- y- anhydride "^

TTT

H-f

= 0

v / a further suitable process for the production of 2 · -ΛΕΐίηοΐ3οη2ορ1ιοηοηβη reads therein _; . that an X-substituted aniline (V) is condensed with benzoyl chloride (VI), preferably under Friedel-Crafts reaction conditions, and the primary reaction product is vigorously hydrolyzed, the desired 2-amino] ocnzophenone (IV) being obtained,
Reaction scheme B:

KH ₂ ■

Cl I
CO

VI

109086/1720

c - 0

f. 6 -

Here, X and Y have the meaning already mentioned

It is evident that the p-position to the amino group corresponds to the 7-position in the end product. A substituent in the m-position to the amine group appears in the 6- or 8-position of the end product, while an o-substituent appears in the 9-position of the end product appears., By the appropriate number of reactants, 2-amiobenzophenon.e .. which contain the substituents X and Y of the meaning already mentioned, are obtained and used for the synthesis of valuable embodiments - which also contain X and Y substituents "

The cyclization of the 2-amine benzophenones to a 2-Ccrc-D-phenyl -'- -3 "dihydro-2H- 'ij / I-benzodiazai ^ in can be carried out by a number of known processes. For example, a 2-j \ minobenzophenone IY can be condensed with a glycine ethyl ester hydrochloride or an α-alkylated derivative thereof, preferably in the presence of pyridine as a solvent, with heating; the cyclized starting material YIII is obtained - This sequence of reactions can be represented as follows:
Reaction topic G:

+ C (RR ₂ ) -COOC ₂ H ₅

c KCl

109886/1728

BATH

YIII

XY, R ₁ and Ep have the meaning already mentioned *

As an alternative, a glycylamidobenzophenone (X) can first be prepared and then cyclized by heating in a non-reactive solvent such as pyridiii / The glycylamidobenzophenones can be obtained by acylating the correspondingly substituted 2-aminobenzophenone with a glycyl chloride hydrochloride or a haloacetyl halide the 2-aninobenzophenone with a Halogenaeetylhalogenid ^f .z B-. Bromacc-tylbroriid} acy- ^

is lated, the intermediate product obtained therefrom is ^

treated with aononiak. that as in Case of the product that is made by reacting a GlycylohlorldüyuroChlorids with the aminobenzophenone is obtained in situ under the reaction conditions cyclized, forming the glycylamidobenzophenone will. Optionally, the acylating reagents contain protective groups which are split off by hydrolysis to form the glycylanidobenZOphenone - These alternative processes for the preparation of EeiiE-odlazapine (YIIl) can be illustrated as "fclgt are, although the special protective Carbobenzoxy- 'and Ihthalamidgruppen represented { , but of course other groups that act in the same way can also be used *

Reaction chart a D:

, ^ _nn _ ■ "- ■ ^ / HHCGGR ^ R ₅ Br + ErCR ₁ R ₂ COBr j r ^^ V

NiI

3._4

109886/1728

1895841

-t-

χ
• ι
VIII O
It
Il
"ο
»- H
^ h il
^ y—> - ^ v ^ ... ί HCl
UcCH ϋ
2.2.5. IV + eic σ "--0R-B _n
3 = 0 X '
oe ^ ^ν π-- · ο

C = J

O ■ '. Τ; 3: IV + CIC-CR-R ₀ KHo-HCI 7 X

OO
D_4j. IV + CiCCR, R ₀ KHCOCH ₀ "..

■ -> VIII

109886/1728

1635841

908 Germany March 15, 1970 IK-Je

NHC-CR R NHC

C = 0

Ο -> X

VIII

XII

When the 2-trifluoro-thylertians 2-0xo-5-phenyl-1,3-dihydro-2H-1,4-benzodiazapine to be prepared according to the invention from intermediate products which already contain the trifluoroethyl radical contain. Several synthetic methods are applicable. Usually used in the various synthetic methods last used an N-trifluoroethyl-substituted aminobenzophenone, which has the general partial formula

CH ₂ CP ₃

C = 0

has, where X and Y have the meaning already mentioned, the by condensation reactions, e.g., of the type represented by Reaction Schemes C and D, into the desired 1,4-benzodiazapine can be converted, optionally into one of the 4-oxides already mentioned can be converted.- For example, an aminobenzophenone the general formula

1 0 9 8 8 β / 1 7 2 NC

(undy

wherein XVx have the meaning already mentioned: preferably in the presence of a solvent; such as pyridine _r and under heating with a compound of the formula

■ H.
C.

_v HHH "'■ ..". ■■

where B * and H _{2 have} the meanings already mentioned _: Q _{2 stands} for 0 or a group which can be converted into it, v / ie (H-Hv-.

Imino _{r is} dihalogeno, ketals and cyclic ketals, and E 'and E "are alkyl or hydrogen; or are condensed with an addition ^{salt of this compound, -E;} is preferably lower alkyl, especially ethyl, while R" is very conveniently hydrogen - Of the accumulation salts. which can be used- "if the chloride is preferred-

■■■ '■■ "■... -." Ν. "■

In a further very advantageous embodiment of the method according to the invention v / ith a W 'triiluoräthyl substituted aminobenzophenone of the general iOrmel

fkk.

10 9830/172

Germany March 16, 197c IK-Je

y ^

OR ₁ B ₂

NHR

1 1

where X, Y, Q, R- ,, R _p and R ¹ 'have the meaning already mentioned, preferably subjected to intramolecular condensation by heating in a non-reactive solvent.

Instead of the above-mentioned N-trifluoroethyl-substituted Aminobenzophenones can also be used in the corresponding compound in which the NHR '' group is replaced by chlorine, iodine or preferably bromine. The desired can also be achieved by amination of this compound 1,4-benzodiazapine can be obtained.

Of course, the reactions described above may be followed by the conversion of Q, ^ to O, if desired. It is further pointed out that although Q ^ has only been shown in a small number of reaction equations, of course in all similar cases the oxo group can be replaced by a (reactive) component which can be converted into it. For example, in

In the case of reaction scheme D, the aminobenzophenone used be replaced by a derivative that has a reactive component convertible to 0 in place of the contains represented oxo group. As already mentioned, the desired compounds can also be obtained by 1-trifluoroethylation the corresponding 1-unsubstituted compound, which in the 2-position is a component that can be converted into 0 contains instead of a 2-oxo group,

109866/1728

- 11 -

_ 12 -

getting produced. Furthermore, a 2 ^ ~ {2 _J: 2 _; 2 ~ TriflUoräthva); - a-bromoacetanid £ 7-benzophenone heated with ammonia v / ground _r . where the corresponding 2- / ji- (2,2j2 ~ trifluoroethyl) -aaEiinoacetamloT-benzophenone is obtained, an intramolecular condensation is simultaneously experienced under the amination conditions.

The 2- (2.2.2-! Br if Ittoräthylamino) -benzophenon-ZViischenverbiii & uiigeii can easily be prepared by different Triflueräthylierungsvorfahren., ITeTb-en. The trifluoroethylation of 2-iunino-benzophenones according to the irlfluoro-ethylation processes described above can first be introduced into the 2-aminobenzophenone compound in addition to additional groups and, if necessary, subsequently removed. For example, the 2-aminobenzophenone can be tosylated first, and then tosylated subjected to the above-described trifluoroethylation and the product obtained _{can be hydrolyzed to the desired 2- (2;} 2j2 -.! erifluoroethyl-amino) -benzophenone ₀

Of course, other variations are also possible around the. desired 2- (trifluoroethylamino} -benzophenone intermediate compounds, for example variations, which are to be regarded as equivalent to the processes described above. are bensophenone including derivatives _s contain a reactive moiety which at · 'Stolle an oxo group is converted into 0, converted - which, once they have been trifluoräthyliert, in the GeV / ünschten 2- (2 ~ ₅ 2.2 2rifluoräthylamino) The conversion into the desired benzophenones which are suitable for the preparation of the benzodiazapines according to the invention can be represented as follows

109886/1728

Reaction scheme E:

VIII

ZlY

It is also possible. To produce the desired 2- (2,2 ₇ 2-trifluoroethylamino ^x , -benzopheiion., By adding the corresponding X-substituted 2J ~ (2,2 _? 2-trifluoroethyl) aniline? appropriate X-substituted aniline can be produced by a dei 'described above Trifluoräthyligrungsmethoden. a Friedel-Crafts reaction unterv / orfen v / IRDO Alternatively, the M ~ 2 ₅ 2.2 ~ T.rifluoräthy can! aniline Zv / ischenverbindungen with Bromacetylbronid are reacted _s whereby the corresponding X-substituted il (a ~ Brorcaeetanido) -li- (2, 2, 2-trifluoroethylaniline) is obtained, which when reacted with an X-substituted benzoyl halide under Friedel-Oraits reaction conditions, the above-described X- and Y-substituted 2 / _ L ^r - ' _v 2,2,2-trifluoroethyl) -a-broiTiacetamid £ 7benzophenone forms = These reactions can be represented as follows:

BATH ORIGINAL

109886/1728

Beaktions_scherca_ Pj.

ErCRiR ₀ COEr X

■ ^

³ CR-S ₉

I -

Br

XTI

XVII

Y-eenzoyl chloride AlCl-,

N /

CH ₀ CP

Benzodiazapine according to the invention

If you have the trifluoroethylated products in which E and R _{2 are} hydrogen or alkyl _:. Subjected to a csyde.tive treatment, the desired 4--0x.yae IT-oxidation of an intermediate VIII in which R ₁ and R _{2 are} hydrogen or alkyl are obtained _; . with subsequent trifluoroethylation in the old Taeschrieüene way is a further method for the preparation of these 4-oxides. The oxidative treatment can expediently with the help of a peroxyacid; such as peracetic acid _; be performed. The benzodiazapines in which R-, or Bp is a free or esterified hydroxyl group ₇ can also through. Heating the corresponding 1 "trifluoroethyl or 1-unsutituted 4-oxide with an anhydride, vrle acetic anhydride, and, if necessary, subsequent hydrolysis of the esterified hydroxyl group to the free hydroxyl group and introduction of a trifluoroethyl substituent in the 1 position.,

109886/1728

- Λ5 -

An example of this conversion is shown below:

I> U Λ I L ₁ -

"3 ο" 3 .ν--. * _n ^ y ° ^C0GH 3

^ IT-C- ^ / ZssigsMure- · * N ^ _TT anhvdrid.

Titration with alkaliJ

CK ₂ GP ₃

XII

The hydroxyl group introduced in this way can be converted into other esters in the usual way. for example with acid chlorides or anhydrides of propionic acid, butyric acid and valeric acid _D

The compounds prepared according to the invention exert an influence on the central nervous system. * Determined by standard pharmacological methods _; and as such wetvolle Beruhigungsnlttel bz \ r _c means of getting rid of anxiety * In addition, the hay compounds valuable remedy for spasms and have muscle relaxants properties _ö The pharmacological investigation significant differences were zv / isohen a sedative dose and a I'osis that a neurological authorization causes ₅ - fixed

109886/1728 -

represents * The therapeutic ratio (the ratio of effective dose * is the erforderlieh to ,,,. neurological impairment to verursaehenj znr effective. dose, which is required to achieve a sedative effect vrn) is significantly higher in accordance with the invention compounds as that. at 'ZcZt. known analogous compounds observed ratio, in particular has T-chlorine-I. 3-dihy dro-5-phe ny 1-1- (. 2., 2 \ 2-trifluoroethyl) -2H-1.4-benzodiazapin-2 ~ one a therapeutic ratio of about 13- This means that the dose * which causes neurological impairment, is about diOizehnnal greater is required as the dose which W in accordance with accepted pkarmakologischen Untersuchungsnethoden. to bring about an adjustment effect = as a further. It has been found that test animals do not develop any tolerance to the compounds prepared according to the invention after repeated treatment for the evaluation of the effect as an anti-convulsive agent. _C

The compounds prepared according to the invention are preferably administered orally and, for this purpose, are made into pharmaceutical preparations such as tablets. Capsules: elixirs and solutions; processed, .- During the production of the preparations, a unit dose of the ■■ commonly used auxiliary substances ·; included as starch, vegetable gums and alcohol bases ,, These compounds may also together with other therapeutically active agents are incorporated ^ The "in a unit dose. lös is dependent on the patient and the severity of the treated! everything from _t Kormalerweise suffice in three or "given four parts ^{; =} - total dose of about p _r 1-1.0 mg / kg body weight per day in order to achieve a therapeutic effect _n

The preparation of compounds according to the invention is described in the following examples,

■■■■■■ ,. 109886/1728 '' ^BA0

T-ChI οτ-1,3-dihydro-5-phenyl - 1 - [2nd Z. 2- tr ifluo räthyl) -

A solution of Ifatriummethylat is prepared by dissolving 3 g _T 9 Eatriuiriinetall in 500 al of methanol, 39.0 g 7-0hlor- "i .3-dihydro-5-phenyl-1 ~ 2K _r To solve 4-benzodiazapine-2 optionally --on "the Reaktionsgenisch is evaporated to a residue which is dissolved in 170 ml of dimethylformamide r / ii-do supplied while adding 30 g of 2, _2? 2-Srifluoräthyl.3odid is stirred for 30 minutes at Eaumtemoeratur and then another. 7 hours heated to 60-7O ⁰ O .. JSaeli addition of "9 g 2.2 _? 2-5rifluorätbyljodid v / urther t6 hours with stirring to 60-70 ° C erhitct _o The solids are filtered off and the PiItrat is evaporated in vacuo to a residue The residue is triturated with water and with ethyl ether · extracted "The ether extract washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated off. The residue is. extracted with ethyl ether and filtered. "The ■ ether extract is concentrated to a residue. The residue is dissolved in benzene and chromatographed on 300 g of aluminum oxide contained in a glass column 38 mm in diameter". The crude product is obtained Column is eluted with benzene * The product is recrystallized from Acoton petroleum ether.

whereby the desired product is obtained "»

As an alternative, the compound of this example is prepared as follows: 38 ₅ 6 g of 2 «- benzyl-5 ^; -chlor "P-toluenesulfonamide and 5 _; 4 g of sodium methoxide in 250 ml of benzene are refluxed for 1 hour. After addition of 42 g of 2j2,2-irifluoroethyl; iodide, the reaction mixture is refluxed for 12 hours while stirring, Lan is cooled, filtered those Peststoffe from, the solvent is evaporated Ebb, the residue is dissolved in 100 ml of concentrated Sohurofölsäure and the solution was heated 25 minutes on

109880/1728

the steam bath- One cools the solution -.- pours in power with irr, n: oniak basic and extracted with Ohioreform-Kau, washes the Ohioreform extracts with V.'acser, dries over anhydrous sodium sulfate and evaporates the chloroform from ₇ - "whereby 2 ( 2,2,2-2riflucräthyl; -sminc-5-chlorobenzophenone is obtained.- which is used in the next stage.

29.5 g of 2- (2,2,2 ~ trifluoroethyl) amino-5-ch benzophenoii are dissolved; which was obtained in the manner described above5 and 21.½ g Glycinäthylesterhyörochlcr.Lö in 200 ml pyridine Man ern.it nt the solution to the reflux temperature and maintain the reflux for 15 hours with stirring. During the first hour about 50 ml of solvent are removed ; · Which is replaced by dry lyridine .v / ird *. Ivlan concentrates the solution under reduced pressure to a residue * triturates the residue in water and extracts with ether - filters off any remaining solids and separates the solvent layers, Kan sets the / Cw-Y / er of the aqueous solution to 8 , 0-8.5 and extracted again with ethereal extracts, combined the ethereal extracts, washes them with water and dries them over anhydrous sodium sulphate. Chromatograph in the manner described above.

T-Ohlor-1. 3 ~ dihydro-5-phenyl · '! - (2.2. ₅ 2 - trif luoroethyl ) -

5O.0 g of 7-Ohlor-i are dissolved _; 3-dihydro-5-phenyl-2II ~ _1;: 4-benzodiazapine-2-cn in '.Z5O ral acetic _β Kan the solution is cooled slightly and peracetic acid are added with stirring 50 ml -IO ^. This solution is kept for 24 hours at room temperature and precipitated by adding 10 l ascer while stirring. The suspension is neutralized with sodium carbonate and filtered. The precipitate is washed with water and 7-chloro-crystallized. _r 3 ~ aihyärc-5 ~ phenyl ~ 2H- '. _s 4-benzodiazapin-2-one-4-csiyd from alcohol for

109888/1728

Use in the next stage *

A solution - / on Katriuiamethyiat is prepared by dissolving 3 .. 9 g Katriuinmetall in 530 ml methanol, 39.8 g 7-Chlor- ^ 3-dihydro ~ 5-phenyi-2H-1,4- ■ beneodiazapin-2 are given -cn-4-oxide with stirring to _r The methanol is evaporated and the residue is dissolved in ITO ml of dimethylformamide compartment Addition of 30 g of 2 _; 2 _: .2 »Trifluoroethyl iodide is stirred for 30 minutes at room temperature - the mixture is heated for Y hours with stirring, to 60 ° -70 ° C. Kan is added, 9 g of 2.2 _r 2-trifluoroethyl iodide are added and a further" .6 Hours of stirring at 60-70 ° C. The insoluble substances are filtered off and the filtrate is evaporated to a residue under reduced pressure. The residue is triturated with water, extracted with ether, the ether solution is washed with water, the solution is dried over anhydrous sodium sulfate and evaporated on a residue, the residue is triturated with ether and filtered, the ether is evaporated off. "Dissolve the residue in benzene and chromatograph on 300 g of aluminum which is contained in a glass column of 38 mm diameter,! Can elutes with Eenzene and thereby receives the product *. This product is recrystallized from Aeoton petroleum ether, the purified product being obtained =

3-Acotoxy-7-chloro-1., 3-d-iliyäro-5-plienyl-1- (2, 2, 2-tri-

Suspending 0 g of T-chloro- ₅ 3-dihydro-5-phenyl- "i ~; 2 j 2.2-trifluoro-ethyl) -2K- ':. 4-benzodiazapin-2-one-4-O: -; yd in lOOml Essigsäureanhydridr the mixture is heated 30 minutes under stirring to your steam bath, cooled and the product filtered off through _D Umkristailisation from acetone-petroleum ether, the desired product is obtained

109886/1728

7-ChloT-i.3-cUhydro ~ 3-hydrcxy ~ 5-: phenyl-1 ~ (2 _; 2.2-tri- ^ Ii ¹ PjIiJ ¹ XlJr2JtJjiriP / ^ il ^ J ^ APAiV ^ rAi ¹ .. ^., » . ^ >> ^ _ »... ■■ *.

IJAN suspended 5.0 g of the product obtained according to Example 3 in 100 nil alcohol, one equivalent of a 5 $ sodium hydroxide solution with stirring to the reaction mixture diluted with water, the product Ms is completely precipitated * the product was filtered and washed with ob.- Water "dries in the air and crystallizes from hexane, giving the desired compound".

3 ~ propionyloxy-7 ~ -chlor-1 ,. 3-dihydro-5-phenyl ~ 1 '~ (2p 2 _? 2-

Kan suspended 3 _; 7 g 7-0hlor-1o3-dihydro-3-hydroxy-5-phenyl-1- (2 _r 2J2-trifluoroethyl) -2H-1 ₅ 4-benzodiazapine-2-one in 25 ml of benzene and 1 ml of propionyl chloride ZUC Man heats the Semisch to the reflux temperature and maintains the reflux for 2 hours _o Kan cools the reaction mixture and dilutes it with hexane until crystallization begins. Cool and filter to obtain the desired product,

T-Ohlor-1.3-dihydro-3-raethyl-5 ~ pher! Yl-1 - (2.2.2-tri-

Dissolve 23.2 g of 2-ümino-5-chlorobenzophenone in 200 ml of pyridine,? In are 22 _r 9 g Alaninäthylesterhydrochlorid and brings the mixture to the Rückflußteniperaturo Tom reaction mixture about 40 ml of solvent is distilled off slowly _t. The mixture is refluxed for a total of about 15 hours; Then cools slightly and the mixture is concentrated under reduced pressure to a residue. Water is added to the residue and extracted with ether. If insoluble substances are present,

109886/1728

the mixture is filtered and separates die'Lösungsmittel-, ABV layers Adjust the pg-JTert the aqueous layer to 8 _r ö-8 ₅ 5; sin and extracted with itherV Combine the ether layers, wMscht; -with water and dried 'The mixture is filtered and: concentrated & Xe layers on a crystalline slurry, a _o In this case, one obtains 7-chloro-1 y 3-dihydro-3T-me thyl- ^ ^ henyl-Sli-1 ■ _Ä 4-benzodiazapΐη-δ-οη ^ that used in the next stage

A solution of sodium methylate is prepared by dissolving 1.0 g of sodium metal in 125 ml of methanol. 9 _and 8 g of 7-chlorine are added 1.S-dihydro-S-methyl-S-phenyl-2H-1 _? 4-benzodiazapin-2-one and evaporated the Iqsung to a residue. The residue is dissolved in 45 ml of dimethylformamide, 8 g of 2,2j2-2rifiuoräthyljodid are added, stirred for 30 minutes at room temperature, and. are .erhitzt further 7 hours at ⁰ C 60-7Q Ean 5 g _"2.2? 2-Trifluoräthyljodid added and stirred v / urther .16 hours at 60-7O ⁰ Cc is filtered off Eückstand and works in the manner described in Example 1 V / eise auf ^ v / obei maftv receives the desired connection,

Beijsp1 e I ^ χ ' ^: · ''■; .

1, S-mhydro-S-phenyl-i - '^^^ - trifluQratshyli-aH -'! ^ - iJI ¹ ^ οd ^ a_zapjtn _r _2-pi \ ^ _. i '^ ^ ^' _{β h} _

Prepare a solution of Uatriummethylat by dissolving 2; 4 g STatriummetall in 400 ml of methanol forth _u 'you are 23 ₅ 6 1 ₅ 3 g-Dihydrc-5-phenyl-2H - _1? 4 - benzodiazapine-2-one and the reaction mixture evaporated to a residue and the residue in 150 ml of dimethylformamide is dissolved _0, 25 g 2 _{5 2?} 2 ~ Sr'ifluoräthyljodid to the mixture, stirred for 30 minutes at room temperature and a further 7 hours at erhitst 6c-70 ° C _o Add 15 g 2,2.2-trifluoroethyl,] to iodide and stirring is continued for -16 hours · boi 60-7O ⁰ Co Kan filters the solids off and evaporates the piltrate under reduced pressure. On a residue a ₀ Kan triturates the residue with Waster and extracts with ethyl ether, washes the ether extract,

109808/1728

with water, dry over anhydrous sodium sulfate and evaporates-the solvent from * One extracts the Residue with ethyl ether and filter the solids ab * The ether extract is concentrated to a residue. dissolves the residue in benzene and chromatographed on 300 g of aluminum oxide on the above. Examples described üoise ·, taking the desired Connection received = _. . - "

Example_8

1 .3-mhydro-5-phenyl- '~ (2. 2, 2-trifluoroethyl) -2H-1,4 · .-

-2-on - '! - o;: yd

Dissolve 5.0 g of the product obtained in Example 7 geiräß 125 ml "acetic acid - = - The solution is cooled slightly and are _5;? OMI 4Q $ peracetic acid to _o Kan holds this solution 24 stood at room temperature, the product precipitated by the addition , of 1 _r 0 1 of cold water and subsequent neutralization with sodium carbonate solution.from? filtered and washed-the precipitate with Yiassor and crystallized, from alcohol _? whereby the unseeded .N-Oxide

-0hlor-1- (2.2,2-trifluoroethyl) -5-phenyl ~ 1 ₇ 3-dihyaro-2R-

^^ i ^ rFPIL _ V ~ -.

Mix 120 g "irichlormethylsulfonylchlorid and 50 g of 2,2 ^ _Jr ^-2rifluo.i> ethanol in 150 ml \ 7ascer that Genisch heated to 50 ⁰ C., and 44 g · 5G> $ owned Katriumhydroxydlösung to =. The mixture is stirred the reaction mixture for 2 hours at: '- ~ 4Q 45- ⁰ O _r separates the layers UKD washing the organic layer with dilute ammonium dlösung'ii3'örcx5 * and then washed with üasner- Kaη gewacchene dries the organic layer over anhydrous sodium sulfate wacrer and distilled, giving 2 ₇ 2.2 irifluoroethyl trichloroethyl sulfonate with a boiling point of ε * to 86 ° σ / 20 mm Eg "refractive index Ii ^ = 1 _S 42T5"

109886/1728

• - BAD OFttQlNAL

- ? -jt iL * 3-7 JJJÄRPJJlii ¹ JA ⁹ X ¹ A ¹ I ⁰ J ~

One Eiiseht stirring "OO g of 2 - / ;: nino-5 ~ chlorbenzcphenon and β", g ~ 2.2.2-Trifluoräthyi trichiormethylsulfoiiat, the mixture was heated .to 16O ⁰ C and holding for 5 hours under stirring "in this Temperature lan! cool the reaction mixture to Raumtemperatur.und are 2.0 1 of ethyl ether to. filtered to remove the insoluble Peststoffs and evaporate the greater part of the ether al)! .lan are 5CO ml of benzene and the suspension is filtered again. the filtrate is concentrated to 83 g an oily residue and dissolve the residue in the smallest possible volume of a 2: "! mixture of hexane and benzene

0C0 g of silica gel in a 2: 1 mixture of hexane and benzene and the solution is from above onto the column _c Kan elutes the column with a 2: 1 mixture of hexane and benzene and collects 750 ml portions The column is monitored by subjecting an aliquot of each fraction to infrared analysis, thin-layer chromatography and melting point measurements. The appropriate eluates are combined. concentrated by evaporation to a residue and the residue is crystallized uirij wherein one 40.2 g of 2- (2.2,2-! Erifluoräthylaraino) -5-chlorobenzophenone of melting point 99-C receive '0O ⁰

Co; 2- _i / ~ li- (2 _r 2, "2-sifluoroethyl) -a-br

40.0 g of the product obtained according to Example 9B are dissolved in 750 ml of benzene and 31 g of bromoacetylbronide are added. Man. the mixture is heated to reflux temperature and refluxed for 3 hours. “The benzene solution is cooled and washed three times with a total of about 450 ml of water. 1 g 2 ~ / ~ l {- {2 ₅ 2 _? 2-trifluoroethyl) -2-bromolcetamide £ 7-5-chloi-benzophenone with a melting point of 15 ° -17 ° C.

109836/1728

■■■■■■ - 24> -: ■■■■■■. ■■ '■■■. · .:: ■■ * ■■ -.

7 ^ 0hlar-l- (2 _i 2 _f 2 ~ trifluöräthyi) -5-phejiy.i - 1- _? '3r-Gli-

52 g of the product obtained according to Example 90 are dissolved in 1-0 l of chloroform and amir.oiiia gas is allowed to pass through at room temperature for 18 hours, the solution bubbling ₅ it is extracted with ether and Can trock net washes the jitherlösung with water _0! the solution over anhydrous sodium sulfate and the solution evaporated to a residue _c Recrystallize the residue from-a acetone-3? etroläther ~ mixture, .man the at 164 ~ * S6 ° C melting desired compound is obtained. ■

7-chloro - * .- (2,2, 2-trifluoroethyl) -5-phenyl-1 _? 3-dihydro-

Is added dropwise with stirring 266 g of 2,2-SRII _y 2 "luoräthyltrichlormethylsitlfonat in a heated refluxing solution of 319 g p-Öhloranilin in 800 ml Toluol Heat the reaction mixture for 10 hours under reflux" cooled and filtered, the solid material is extracted from ₀ the piltrate with dilute hydrochloric acid, the toluene evaporates and the residue is distilled. under a prevented truck, where one p-Cblor * -IT -> (2 _? 2 _? 2-; .triiluoroethyl) ~ at a boiling point of 116-119 ° Ct / 16 mm Hg

stir 5 g of the product obtained according to Example 10A with 15.5 g of anhydrous aluminum chloride and 8.2 g of 3enzoyl chloride for 3 hours at room temperature in 40 ml of carbon disulfide. The mixture is heated to the reflux temperature and refluxed for 3 hours. An ice-cold solution is setat of diluted hydrochloric acid to ₀ The solvents are separated

^109886/1728

169584t

layers, and removing the carbon disulfide by distillation * AEEN residue is dissolved in aqueous alcoholic hydrochloric acid solution and heated the posting 1 hour am'Rückfluß "Uan the solution is cooled and removed the desired product by extraction mit.lthylathes ** llan washing the ether extract with Vfösser 2 To remove the excess acid and concentrate the Estferakt on a chopping stand. The residue is dissolved in the minimum volume of one

2? I genes of hexane and benzene ujid work on the method described in Example 9B "on ₅ where & ei the, Ik? I iOÖ ^e O melting desired product is obtained"

Qo 2-jjTM 2, 2o 2-I

In Example 90 "test described v; irö 2 (E, 2. S-SrifluarHthylawine ^ -S-cnloriienzophenon repeated wöfcei da3 with HA" - 7 ⁰ O schnsizende obtain desired product '

2K-I, <i-benzodia2attin ~ 2-en * "'

ras obtained according to Example 100 '# rodufe ^' τ / ird on Example 9B described \ 7ise treated «

Example 11
2 "2-tri

Ά, K-Ca-Bromacetraidoj-p-chloro-H-fS ^, 2 - tri £ luoroethyl) -auiline 'j

A solution of 20 g of p-chloro (2.2 "2" tx "ifluoroethyl) aniline prepared according to Example 10A ₅ is refluxed with 19 g of brorcacotyl bromide in 400 ml of benzene for 3 hours." The benzene solution is washed with water and dried over anhydrous sodium sulfate. The benzene is evaporated and the residue is recrystallized; whereby W-Ca-Brcroacetsmido) -

is obtained.

5 ^

Maw dissolves 11 g of the rawduct obtained according to Example MA in sulfur colil oil, and adds 13 g of anhydrous Altmiftipir and 7 g of benzotrichloride. stirs for 18 hours at room- _{; f}

c. In an ice-cold Xosung of vcr ^ It is ■■ hydrochloric acid and rtihrt the Genisch '0-Ϊ5 minutes * "^ that I" ösungsjnittelschiolT: th and works viie "±' n

90 on y v / o if you want that. at 115-117 ^ 0 Γ melting, product, obtained. ; . . ". ·: '

ft dissolves the product obtained according to Example 1 "B in-Ghloroiorin: and works the solution in the way in Example SjD bepeh $% & bejie in>ννιοΐ> βί ^: the desired product V which melts at 164-166 ° G _Oi ; - ;. .. \ -

- ^:: v ^v Example 12

1- (2 _? 2 ₅ 2-trifluoroethylene;

2v - / "2- (N-Acetoxyaeetanido) -If- (S; S ^^

3Tp4 "^; -g / £

phonon and 19 ₅ 4, g K-Aeetc ^ - ^ acet ^ lglycyl chloride in? ; 5½ ml of benzene, refluxed in the solution for 3 hours and removed the benzene under reduced pressure. recrystallizes the residue from an Ac Genisch, whereby the desired product is obtained B _? 7 »Ghlor-1- (2.S ^ t ^

27 g of the product obtained according to Example 2 / are dissolved in lOÖ ml of ethyl alcohol? gives 10 ml of I5 ^ ige Ghlorv / asserstcffsäuye and heated for 15 minutes at reflux * Man diluted with water and cool quickly. The pests are filtered out from j it washes with the mother liquor and with water and

/ romt / m-i -wo

- 2.H -

ti ^T oeknet bei ^ Q ⁰ C llan recrystallizes the pesticides in the alcohol, whereby you get "the desired product _r .

In addition to .p-chloroaniline, other appropriately substituted anilines can also be trifluoroethylated as described in Example IQA. Examples of such suitably substituted anilines are: c-chloroaniline "- BL-ITitroaniline _f p-2rifluoromethy . £ aniline _?. P-A'tho: -; yar; ilin «.rc-isobuty! Aniline., O-tlethylaniline ... p-brcnaniline, c-iritrcaniline, - m-isopropoyyaniline., E - iodaniliflu p -Pluoroaniline _r o-Peiitylejiilin «ei · -tort, -Butoxyaniline P-ethylaniline, ni- Pluoranilin« - p-liitroaniline- The above-mentioned substituted anilines give the corresponding "E- ^ when treated in the manner described in Example IJA ₅ 2 _P 2-TrifluorUthyl) * · aniline _o ■ These ring-substituted H- (2 _? 2-2-irifluoroethyl ') - anilines. Provide the substituents. which occupy the 6-S position in the finished products and are limited to the groups indicated above for the substituent X.

As described in Example 10B and Example 11B used beiicycyl chloride can carry ring substituents .. V. if they are present are, these substituents are limited to the groups identified above for T., To these substituted Benzoyl chlorides include the following compounds j c-Iiethylbenzoylchloridj p-Bat-ombenzoylchlorid » m-ITitrobenzoyl chloride, p-IIethoicybenzoylochloride, o-butyl ■ bonsoylcliloriilf ii-Crifluorraethylbenzoylchlorid; m-JodbonzoylChloridy p-Isopropoxybenzoylchloridy o-Flucrbenzcylohloridj m-pentylbenzoyl chloride .. p-chlorobenzoyl chloride, g p-17itrobenzoylchloride

It is thus obvious that the reaction of the ring-substituted K- (2 " 2 _?. 2-Trifluoroethyl) -anilines and the ring-substituted benzoyl chlorides under Friedel-Crafts conditions actually a synthetic route to the 2 - ν2 5 2j 2 -Trifluoräthylariino) -benzophenonen represents _r , the substituents on both benzene rings, on one of the benzene

10ΛΜ / .17Μ ·· ^

rings do not wear your rings on any of the benzene rings, and that these 2 ~ i, 2j a ^ -TrifluorätJiylainino ^ -ljenzopIienonej when they go through the remaining steps of the process according to the invention
performed v; ₅ ground lead to the desired present invention VeI- Oindungen ¹ ", which carry the Ringsubstituente.n above-described in-the positions designated"

10988S / 1728

Claims (17)

908 Deutsshland 16. Merz 1970 patent claims 1. Process for the production of new 1,4-benzo- diazapines of the general formula wherein X and Y are hydrogen, halogen, trifluorine methyl, nitro, alkyl or alkoxy, B ₁ and B ₂ hydrogen, alkyl or free or esterified hydroxy, preferably alkanoyloxy, but in cases where one of the best B, and B - is a free or esterified hydroxyl group, the other best is hydrogen, and its 4-oxides, where B, and B _{2 are} independently hydrogen or alkyl, characterized in that the compounds are prepared by processes necessary for the preparation of the corresponding compounds without the 1-trifluoroethyl substituent are suitable, preferably for the corresponding 1-unsubstituted or 1-methyl-substituted compounds. 2. Process for the preparation of new 1,4-benzodiazapines the general formula NOUS documents (Art. 1% \ Para. 2 Hr. I Clause 3 d «* Anderunüaoa- v. 4. 10 9 8 8 6/1728 903 Germany March 15; 1970 IK-je wherein X and Y are hydrogen, halogen, trifluoromethyl, nitro, alkyl or alkoxy, R ₁ and R _{3 are} hydrogen, alkyl or free or esterified hydroxy, preferably alkanoyloxy, but in cases in which one of the radicals R ₁ and R _{p is} a is free or esterified hydroxyl group, the other radical is hydrogen, and its 4-oxides, where R ₁ and R _{2 are} independently hydrogen or alkyl, characterized in that one is an N-trifluoroethyl-substituted aminobenzophenori of the general formula wherein X and Y are hydrogen, halogen, trifluoromethyl, Nitro, alkyl or alkoxy are converted into the desired 1,4-benzodiazapine by condensation reactions and if necessary converts this into the 4-oxide. 10988Ö / 1728 908 Germany Ιό, Mar ?. 1970 IK-je 3. The method according to claim 2 * characterized in that that one is an N-trifluoroethyl-substituted Compound of the general formula wherein X and Y have the meanings given above, with a compound of the general formula <j wherein R, and R _{p have} the meaning given above and Q is oxygen or a group which can be converted into these and R ^{1 is} alkyl or hydrogen, or condensed with an addition salt of this compound, preferably in the presence of a solvent such as pyridine, and with heating subsequent conversion of Qp into oxygen, if necessary. 109886/1728 - 51 - 908-Germany-16. March λ970 IK-Je 4. The method according to claim 3, characterized in that R ^{1 is} a lower alkyl, preferably ethyl. 5. The method according to any one of claims 3 or 4, characterized in that the addition salt is a halide, preferably a chloride. 6. The method according to claim 2, characterized in that one N-trifluoroethyl-substituted compounds the general formula - where X, Y, Q, R and R have the meaning given above, subjected to an intramolecular condensation, preferably by heating in a non-reactive solvent, and then, if necessary, converts Qp into oxygen. 7 · The method according to claim 2, characterized in that compounds of the general formula 10 9886/172 8 9C8 Germany 17. Mäf "3 j IK-je where X, Y, Q ₂ , R ^ and R _{2 have} the meaning given above and Hal is chlorine, bromine or iodine, condensed with ammonia and then, if necessary, converts Qp into oxygen. 8. The method according to claim 1, characterized in that that one compounds of the general formula in which X, Y, Q _p , R, and R _{p have} the meaning given above, or their 4-oxides, if R and R are independently hydrogen or alkyl, N-trifluoroethylated in the 1-position and then if necessary " Q converts to oxygen. 1 09886/1728 " 900 Deu-sscnxana IT. Marc I97O IK- je 9. one
Method according to claims 1 to 8, thereby marked that one compounds the general formula CH CP in the X, Y and Q _? have the meaning given above and R- and R are alkyl or hydrogen, are oxidized and then, if necessary, Q _{p is converted} into oxygen. 10. The method according to claim 9, characterized in that < draws that one with a peroxy acid, preferably Peracetic acid, oxidized. 11, a process for the preparation of new 1,4-benzodiazapines according to claim 1 to 8, wherein one of the radicals R ₁ and R is a free or esterified hydroxyl group, characterized in that compounds of general formula 10960 ^ / 1720 908 Germany March 17, 1970 IK-je wherein X, Y and Q _{13 have} the meaning given above and A is hydrogen or trifluoroethyl, heated with an anhydride, preferably acetic anhydride and then, if necessary, converts Q into oxygen, A into trifluoroethyl and optionally the esterified hydroxyl group into the free hydroxyl group. 12. Process for the preparation of N-trifluoroethyl-substituted Aminobenzophenones of the general formula · ■ NHCH ₂ CF C - 0 where X and Y are each independently hydrogen, Halogen, trifluoromethyl, nitro, alkyl or alkoxy mean, characterized in that one compounds the general formula wherein X and Y have the above meanings and Q _{2 is} an oxygen atom or a group which can be converted into it 109886/1728 jjeuv.sc-niana 17v. March 1970 IK-je or their tosyl derivatives are trifluoroethylated on the amino group and then optionally Qp is converted into an oxygen atom and / or the tosyl group is hydrolyzed. 13. A method for producing the in claim defined compounds, characterized in that N-trifluoroethyl-substituted anilines of the general formula CH ₂ CF ₃ with compounds of the general formula condensed, where in the formulas X, Y and Q _{2 have} the meaning given in claim 12 and Hal denotes a halogen, preferably a chlorine atom ^, and that optionally then Q is converted into an oxygen atom. 14. The method according to claim 13, characterized in that the condensation under the conditions a Friedel-Crafts reaction takes place. 109886/1728 90S Germany March 17, 1970 IK-Je 15. Process for the preparation of N-trifluoroethyl-substituted Anilines of the general formula • where X is a hydrogen or halogen atom or a trifluoromethyl, nitro, alkyl or alkoxy group, characterized in that anilines of the general formula where X has the above meaning on the amino group trifluoroethylated » 16. The method according to claims 8, 11, 12 or 15, characterized in that the N-trifluoroethylation with compounds of the formula CF-, CH P, wherein P a reactive organic or inorganic Is ester group. 17. The method according to claim l6, characterized in that that P is chlorine, bromine or preferably iodine. 18. The method according to claim l6, characterized in that P is the radical OSO ₀ Z, wherein Z is alkyl, aryl, aralkyl or polyhaloalkyl. 109886/1728 - ΎΙ - 908 Germany March 17, 1970 IK-Je 19. The method according to any one of claims 1 to 8 and 16 to 18, characterized in that R, and Rp Are hydrogen or alkyl. , 4-Benzodiazapine of the general formula wherein X and Y are hydrogen, halogen, trifluoromethyl, nitro, alkyl or alkoxy, R ₁ and R are hydrogen, alkyl or free or esterified hydroxy, preferably alkanoyloxy, but in cases in which one of the radicals R and Rp is a free or esterified hydroxyl group, the other is hydrogen, and their 4-oxides, where R ₁ and Rp are independently hydrogen or alkyl. 21. Compounds according to claim 20, characterized in that that any alkyl, alkoxy and alkanoyloxy substituents that may be present are each lower alkyl, Are lower alkoxy or lower alkanoyloxy substituents. 22. Compounds according to claims! 20 and 21, characterized marked that Are alkyl, hydroxy or alkanoyloxy. Hydrogen and R hydrogen, 109886/1728 '■ -38 - March 17, 1970 IK-je 25. Compounds according to claims 20 to 22, characterized in that X is halogen and Y is hydrogen. 24. Compounds according to claims 20 to 23, characterized in that X is chlorine. 25 .. Compounds according to claims 20 to 24, characterized in that X 7-halogen, Y and R, Hydrogen and R_ are hydrogen or lower alkyl. 26. As a compound according to claim 25, 7-chloro-l, j5-dihydro-5-phenyl-1- (2,2,2-trifluoroethyl) -2H-1,4-benzodiazapin-2-one. 27. N-trifluoroethyl-substituted aminobenzophenones of the general formula wherein X and Y are each independently hydrogen, halogen, trifluoromethyl, nitro, alkyl or -alkoxy mean. 28. 'N-trifluoroethyl-substituted anilines of the general formula 109886/1728 -'39 - 90S DetitseJiland ITi March 1970 IK-je wherein X is hydrogen, halogen, trifluoromethyl, nitro, Mean alkyl or alkoxy. 109886/1728