DE1620711A1 - Process for the preparation of 11-basic substituted 5H-dibenzo [b, e] [1,4] diazepines - Google Patents

Description

JV ff? . / 2. Z

Dr. Α. Wander AG I '1 Bern (Switzerland)

Process for the production of ll-hasiech substituted ₉ eJ / T _t 47diaz © pine

Sas main patent Nv * .. » „ » _o . _β . (Gresuch V / '-5C IS-) relates to a process for the production! »Basically substituted 5H-Dibenso / b" _t e7 / l, 47diaz8pin © of the formula I:

as well as acid addition salts and quaternary ammonium derivatives thereof. In formula I, H means hydrogen or an alkyl or alkenyl group with 1 to 5 O atoms. " R ^ and B- are identical or different and mean hydrogen _p aryl" - or aralkyl groups which can have substituents of the same type as R- , Alkenyl or alkyl radicals with 1 to 5 carbon atoms, the

009823/1888 bad original

optionally also form a ring which can contain all other heteroatoms 0, 9 or N, the N in turn carrying hydrogen or an alkyl, hydroxyalkyl or alkoxyalkyl group, or finally amino or aminoalkyl groups, which can be alkylated.R and R ₅ are identical or different and denote hydrogen, halogen atoms, hydroxyl groups, alkyl, alkoxy or alkyl mercapto groups containing 1 to 3 carbon atoms or trifluoromethyl groups.

For the manufacture of these products, among other things, a connection of formula II:

(II),

in which R ,, R. and R ₁ - have the abovementioned meaning and in which A represents a halogen atom or an alkoxy or alkylthio group having at most 3 carbon atoms, with ammonia or an appropriately substituted primary or secondary amine of the formula HNR ₂ Rx implemented, optionally with subsequent introduction of an alkyl or alkenyl group in the 5-position, the reaction products being obtained as free bases or as additives with suitable acids or subsequently converted into mono- or biquaternary ammonium derivatives.

009823/1888

It has now been shown that! Products of the formula I are also obtained * if you use an acid amide or thioamide of the formula ZII:

"(HI).

where R represents an oxygen or sulfur atom, R ₁ , R 2, R-, R. and Rc have the abovementioned meaning and R. can also be a removable group, for example an acyl group, for example quaternary ammonium derivatives of such compounds by intramolecular Brings condensation to the ring closure.

Bine purely thermal condensation is possible in the acid amides, the In turn sum example, are obtainable by reduction of corresponding nitro compounds, not likely, however, does not as a rule at the thioamides, which can, for example, by treating the pillars reaaidemit Fhoephorpentasulfid obtained and prior to the subsequent condensation to give It is advisable to work in the presence of condensing agents such as phosphorus pentachloride, phosphorus oxychloride, phosgene, polyphosphoric acid and the like, particularly with acid amides. It can be assumed that the ring closure is partly via intermediate stages, such as

& Ä & ORlGJNAk

009823/1888

Imide chlorides, amide chlorides, imidophosphates, amldophosphates or sals-like derivatives thereof, which are usually undetectable, runs. The condensation of the thioamides can through Presence of mercury salts or favored by intermediate formation of possibly activated imldothioäthem will. It is advisable to use heat and, if necessary, an inert diluent, when working with phosphorus oxychloride, phosphorus pentachloride is used.

The present patent thus relates to a process for the production of 11-Basically substituted 5H-dibenzo ^ p " _t e7Z £» 47diazepines according to formula I as well as acid addition salts and quaternary ammonium derivatives thereof, which is characterized in that one an acid amide or thioamide of the formula III condensed intramolecularly "

If compounds according to formula I are obtained in this way in which the radicals Rp and / or R- are hydrogen, radicals Rp and / or R which are not hydrogen can be introduced subsequently by reacting the amines obtained with reactive esters of alcohols of the formula R ₂ -OH or Rv-OH, preferably those of the hydrohalic acids, sulfuric acid or de? Toluenesulfonic acid, if desired with prior or simultaneous action of a basic catalyst or metallizing agent such as sodium amide, lithium amide, sodium hydride, butyllithium, phenyl sodium, sodium ethylate or aluminum t-butylate.

009823/1888

In the same way, a non-hydrogen radical R _{1 can} be subsequently introduced into reaction products in which R ^ is hydrogen by reacting the reaction product with a reactive ester of an alcohol of the formula R ₁ -OH, optionally after preceding or with the simultaneous action of a basic one Catalyst or

Conversely, formula I, in which R * means hydrogen, if necessary, in the off » cleavable group contained in common material R ^ after the " Ring closure can be subsequently removed in a known manner, indea, for example, the 5-acetyl or 5-benzoyl derivative of selective hydrolysis or the 5-carbobenzoxy derivative subjected to hydrogenolysis «

The bases obtained in the manner described are yellow, in many cases crystallizable, otherwise they can be distilled without decomposition in a high vacuum, and due to the amidine grouping, apart from any other basic nitrogen atoms, have sufficient base strength to remove old inorganic and organic acids, for example hydrochloric acid and hydrogen bromide acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, toluenesulfonic acid and the like to form addition salts which are stable in water, in which form the products are also used nevead icifanen *

TM obtain the quaternary Aaaoniumderivate of the compounds according Forjwl X su, one can either use starting materials which already have quaternary nitrogen atoms, or one may the nitrogen atoms available to the quaternization after i * nflmig of the bases (I) subsequently quaternisiereu in manner known per se, for example by treating with a alkyl sulfate »alkyl halide or sulfonic acid alkyl ester» -

009823/1888 \ - ■ '.

BATH ORIGINAL

The bases, salts and quaternary ammonium derivatives obtained in the manner described are new compounds which are used as active ingredients in medicaments or as intermediates for the preparation of such compounds · in particular the products come into consideration as analgesics, chemotherapeutics, antihietaainics, antiallergics, sedatives, adrenolytics and neuroplegics. Some of them are suitable for treatment psychotic states

example 1

6.2 g of N-methyl-aminodiphenylamine-carbonsaurepiperidid are refluxed with 6.0 g of phosphorus pentasulfide in 60 ml of pyridine for 4 hours. Han concentrates the reaction mixture to dryness in a vacuum, the residue is treated with 150 ml of 2N aqueous sodium carbonate solution and the yellow crystals which have precipitated out after a while are taken up in benzene. The basic components are removed from the benzene solution by exhaustive extraction with 2N hydrochloric acid. After clarifying with charcoal, the base is precipitated from the acidic extracts with concentrated aqueous ammonia solution and taken up in ether. The ethereal solution is washed with water and dried with sodium sulfate. The binding vapor residue of the ether solution gives, after recrystallization from ether / petroleum ether, 3.4 g of 5-methyl-H-piperidino-5H-dibenzoZb _f e7Zr, 47diazepine in the form of kitron yellow grains with a melting point of 162-163 ° C, corresponding to a yield of 57% Theory · ι

6.2 g of H-ethyl ^ -aninodiphenylamine ^ '- carbonsätire ^ -dimethylamino) äthylamid are mixed with 6 g of phosphorus pentaeulfide in 60 ml Pyridine heated under reflux for 4 hours The processing of the Beaktionegeaisehee is carried out in the same way as in Example 1, with each

0 0 9 8 2 3/1888 *. ' g ^ original

1820711

but stun acid

2is @! I

vinegar

_S § S

) ufefi sit Bis

® i®r la © !, ® £ t

© al SId wei ^ 2.0 g

become 1.4 el H * I-Maoh

cooked for hours under Rttekfltass. " Narrowing the Bes & tioas ^ siischee

swigohen Benzol 'iaaS Äna @ Biak / Eie « Tefft © ilte Di © Abtreamsag rasd ÄuiTarbeit ^ mg of the basic

Beiepi®! 2 _O Mas © rhMlt 2 _B S g (41 ^ the

in the form of (yellow vem

282-184 ⁰ G

au «

009823/1888

Example 5

A solution of 2.1 g of 5-methyl-ll ° C 4 ^r 'methyl) piperazino-5H-dibenzo / b, e7 / r, 47diazepin _(prepared according to the subsequent Example 20 in IO ml of benzene, treated with a solution of 0 , 87 g
(equimolar amount) of neutral dimethyl sulfate in 30 ml of benzene, a quaternary salt immediately precipitating in crystalline form when heated. After leaving it to stand overnight, it is sucked off and washed with ether. The yield is
almost quantitative, it is therefore the monoquaternary salt o It is hygroscopic and cannot be recrystallized <The fact that the UV absorption spectrum is identical to that of the starting material suggests that the basic nitrogen atom of N-methylpiperazine, which already carries a methyl group -Reets has been quaternized »

Example 6

1.5 g ll- (4'-methyl) pipera3ijio-5H-dibenzo ^ 7§7 ^, 47diazepine, prepared according to Example 3 2, with 10 ml of methanol and 4.0 ml (6.9 g) of methyl bromide in an elimination tube for 15 hours The reaction product, which has been taken up in further methanol, is evaporated to dryness after a small amount of insoluble precipitate has been filtered off. Recrystallization from isopropanol / ethyl acetate gives 19 g of a very strongly hygroBeckchen of yellow salt with the decomposition point 198-20C Formula:

198-200 ⁰ Cc It is a biquaternary salt of

CH

009 8 * ^ 3/1888

In an analogous orphan as in the aforementioned examples can be obtained from the corresponding starting materials, the products listed in the table below, Therein R, R _5, R ₃ ,, R. and Rc denote the corresponding radicals in formulas I and 111 = in the last column means 1 © Ästlasr, Bg Fstrolätter uad acetone «

BATH

009823/1888

Tabel

example ^R l -lOi-CH, ^R 4
to,
^R 5 Smpo Ijzwo
^f , *} Sdpo of the base a) 201-203 ⁰ C
(from Ac / Pe) 7th -GH ₅ -O 7-SGEL 171-173 ° C
(from Ac / Pe) * 205 "210 ° C /
0.01 Torrβ _b \ 8th -CH ₅ 8-Cl 164-165 ° C
(from Ae / Pe) 148-150 ° C
(from Ae / Pe) 9 H -NB ₂ H 129-131 ° C
(auo Ae / Pe) »204-208 ° C /
0 _f 0f Torr »^ c) 10 H 7-Cl 179-181 ⁰ C.
(from Ac / Pe) 11th -CH- -H (0 ₂ H ₅ ) ₂ H 167-168 ° C
(except Ac / Pe) 12th H -O H 184-185 ⁰ C.
(from Ac / Ae) 13th H -NH-CH ₂ -CH ₂ -N ( G ₂ H ₅ ) _?
1 H 14th H I.
-HH-CH ₂ -GH ₂ -OH ₂ -Ni C ¹ H ₁ ,) ₂ H 15th H -NH-GH- (GH ₅ ) - Ni GH.,) ₉ j
GH ^ ^ * j H 16 H H 17th II II

009823/188 8

18th H -0-0H ₂ -OH ₂ -OH H 182-184 ⁰ C
(from Ac / Pe) d) 155-156 ⁰ C.
(from Ae / Pe) β) 158-159 ⁰ C.
(from Ae / Pe) 19th -OH, -NH-CHg-CH ₂ -CHg-NCCH ₃ ) g H 73-75 ° C
(from Ae / Pe) e) 201-203 ⁰ C
(from Ac / H ^ O) 157-159 ° C
(from Ac / H ₉ 0) 20th -CH ₃ H 124-125 ⁰ C
(from Ae / Pe) f) 148-151 ⁰ C.
(bus Ae / Pe) 139 ° C
(from Ac / Pe) 21 H 2-0CH ₃ 156-158 ⁰ C.
(from Ae / Pe) 22nd H 2-OCK, 23
τ H -NH-CH ^ -GH ₀ -N; CH,} _ο
^. & _ S cm 8-οσΐΐ 24 -OH ₃ -NH-CH ₀ -GH ₀ -N-: GH,) _η
egg. egg ^ ** 7-C1 25th -CH ₃ *
W * Vl Π IT 7-Cl 26th H 8-c; _k 27 H
ι -NH-CHg-CHg-N CCH ₃ ) g 8-Cl 28 H -NH-GH-: CH «), - NC ₀ H.) ρ
OH ₃ ■ '· ■ - "'■; S.
^H ί
I. 29 H i 30th H -NH-CHp-GH.-N: C) T,} _o Γ 31 -OH, ι
* ""? ^ rf
6-OCH,
t

00 982 3/1888

BATH O.

J
52 1
H 1
-2Qf-CH ₃ 3-CH ₃ 168-170 ⁰ C.
(& « ^Fl Ao / Pe) 33 H -1Qi-CH ₃ 8-CH ₃ 188-IfO ⁰ C
(aue Ao / Ae) 34 H -HH-CHg-CHg-NC CH ₃ ) g 8-CH ₃ 175-177 ⁰ C
(from Ao / Pe) 35 —CH ~ -NQi-CH ₃ B-GS ₃ 171-173 ⁰ C
(from Ac / Pe) 36 H -1Qi-CH ₃ 3-Cl 169-171 ⁰ C.
(from Ae / Pe) 37 H -NH-CHg-CH ₂ -NCCH ₃ ) g 3-Cl 136-137 ⁰ C
Caus Ae / Pe) 38 ■ H -NQi-CH ₃ 3-OCH ₃ 212-214 ° C
Caus Ao / Pe) 39 H -N-CHg-CHg-NCCH ₃ J ₀ H * 168-169 ° C /
O ₉ Ol Torr » 40 H -N-CHg-CHg-HCCH ₃ ) g
CH ₃ 8-Cl 103-106 ⁰ C
Caus Ae / Pe) 41 H -NQi-CH ₃ 8-CP ₃ 193-194 ⁰ C
(from Ae / Pe) 42 -CEL -1Ql-CH ₃ 4-SCH ₃ 14O ⁰ C
Caus Ao / Pe) 43 H -NQi-CH ₃ 2-Cl 2O3-2O5 ° C
(from Ao / Ae) 44 -CEL -NQi-CH ₃ 8-CF ₃ 184-185 ° C
Caus Ae / Pe)

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(from Ae / Jfc)

8-CEL

8-01

241-244 ⁰ O ("us chloroform / P")

48

49 50

3 (on Ae / Jfe)

51

Ae / B ©)

8-00H-

182-184 C j (from Ac / Be)

BATH ORIGiWAL

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Notes on the table (last column):

a) The hydrochloride decomposes at 230-240 ° C

b) A hygroscopic d-tartrate (1: 1 hol) was obtained

o) Bs became a hygroscopic d-tartrate (1: 1 hol) obtain

d) The hygroscopic Dikydrochlorid melting above 160 ⁰ C.

e) The hygroscopic dihydrochloride dihydrate (from

Ethanol / ether) melts at 210C with decomposition

t) A hygroscopic dihydrochloride was obtained

g) The Dihvdroohlorid melts with decomposition 244-246 C (from isopropanol / ether)

9823/1888

Claims (1)

- Vs Claim represent in which IU hydrogen © & @ r © ine alkyl »© dor alkeayl group with 1 to 5 carbon atoms; R ₂ and IU are identical or different and are hydrogen, aryl or alkyl groups, which can contain many of the same kind. Alkenyl * or alkyl radicals having 1 to 3 G-At © SEN _e optionally together form a Hing which 0 »S or H may contain, as further heteroatoms, wherein the N in turn hydrogen or an alkyl," hydroxyalkyl or alkoxyalkyl group carries , or finally amino or aminoalkyl groups, which may be alkylated; and in which R. and R. are identical or different and denote hydrogen, halogen atoa · » hydroxyl groups, trifluoromethyl groups or alkyl, alkoxy or alkyl mercapto groups containing 1 to 3 carbon atoms; also of acid addition salts and quaternary aomonium derivatives of these bases, characterized in that one 3AD ORIGINAL 009823/1888 an acid amide or thioamide of the formula: h ± I before R represents an oxygen or sulfur atom, R., Rp, R_, R. can and Rj. have the abovementioned meaning and R, and also a abepaltbare group may be _e or "condensing a quaternary AmmoniumderiTat thereof intraciolekular, optionally with subsequent removal of the cleavable group R, or introduction of do not represent hydrogen groups R and / or R ₂ and / or R, _e where the reaction products are obtained in the form of the free bases or suitable acid addition salts or, if desired, are subsequently converted into their mono- or quaternary ammonium derivatives «, 7/27/65
RFB-KRu / SpH 009823/1888