DE2417917A1 - PROCESS FOR MANUFACTURING INDOLDER DERIVATIVES WITH A CONDENSED RING SYSTEM - Google Patents

Description

DR. BERG DIP ^ -ING. STaPF DIPL.-ING. SCHWaBE DR. DP .. SANDMAIR

8 MUNICH 86, POST BOX 86 02 45

Dr. Berg Dlpl.-Ing. Stapf and Partner, 8 Munich 86, P. O. Box 86 02 45

Your sign Your ref.

Our sign

Ourref. 24 971

8 MONKS 80

Wall Decree 4511 April 1 1974

Lawyer file no .: 24 971

John Wyeth & Brother Limited T a ρ 1 ο w / Great Britain

"Process for the production of indole derivatives with a fused ring system ¹¹

Addition to DBP (P 22 00 534.1)

The present invention relates to indole derivatives having a fused ring system, and in particular it relates to a process for the preparation of certain pyrimido [l, 2-a] indoles and indoles diazepino [l _s 2-a] and the process products.

40 * 9842/1136

X / dr

The German Offenlegungsschrift 2 200 584 describes certain imidazo [1 ₃ 2-a] indoles, pyrimido [1,2-a] indoles and diazepino [1,2-a] indoles and various processes for their preparation. It has now been found that some of these compounds can be made by a new alternative process.

The present invention therefore provides a process for the preparation of an indole derivative of the general formula I. ,1

(D

12 or an acid addition salt thereof, worm R, R, R ^

H
and R each is hydrogen, a hydroxyl group, a lower alkyl, lower alkoxy, halogen-lower-alkyl

CT f.

Radical or halogen, R and R are each hydrogen or is lower alkyl and m and η are 0, 1, 2 or 3 and the sum of m + η has the value 2 or 3 ·, in which one is an indole derivative of the general formula II

409S42 / 1136

-1 2 "5 4

where R, R, R and R have the same meaning as above, with a dihaloalkane of the general formula III

R-

HaI. (CH ₂ ) _m .C

(HD

wherein R, R, m and η have the same meaning as above and the substituents Hai and Hai 'each separately chlorine and bromine or iodine, condensed, and optionally an acid addition salt obtained into the free base, or a free base converted into an acid addition salt.

The indole derivative of the general formula II. Can. In the alternative tautomeric form of the general formula Ha

(XIa)

are present. 409842/1138

Therefore, if in this description a formula or a name is used ₃ which refers to a compound having the structure of the general formula II, this should be understood to mean that this compound name or this structural formula also includes the tautomeric compound of the general formula Ha ₃ or a Includes mixture of the two tautomeric forms.

The expression "lower * ¹ or" lower ¹¹ used in the description is intended to mean radicals which contain up to 6 carbon atoms, preferably up to 4 carbon atoms.

12 3 The following radicals are examples of the groups R ₃ R ₅ R ₅

R: hydrogen: hydroxyl: lower alkyl ₃ such as methyl, ethyl, propyl and butyl: lower alkoxy ₃ such as methoxy, ethoxy, propoxy and butoxy, halo-lower alkyl ₃ e.g. B. trifluoromethyl and halogen, no example

12 3 wise chlorine and bromine. Preferably each group is R ₃ R ₃ R

and R is hydrogen or at least one of the groups is halogen and the remaining groups are hydrogen.

The groups R and R are hydrogen or lower alkyl, ζ. B. methyl, ethyl, propyl and butyl. Both groups R " ⁵ and R are preferably hydrogen.

409842/1136 " ^5th

The compounds of general formula I in which the sum of m + η is 2 are pyrirnido [1,2-a] indoles and the compounds ^ in which the sum of m + η is 3 are l ₃ 3 "diazepino [ Preferably the indices m and η have the value 1 or 2, ie both have the value 1, or one has the value 1 and the other has the value 2.

The indole derivative II can be reacted with the dihaloalkane III in an inert., Organic solvent, ie a solvent., V / e.1 before the reactants dissolve but does not interact with them, examples of such an inert organic solvent Dimethylformamide and alcohols such as ethanol and isopropanol ₃ are. The reaction mixture can be heated, e.g. B. to reflux temperature. A base such as potassium carbonate or diisopropylamine can be added to the reaction mixture, but this is not critical. The product can be separated from the reaction medium using conventional methods. Isolation sometimes gives the indole derivative I in the form of its hydrohalic acid addition salt. The free base can be obtained in a conventional manner by making a solution of the acid addition salt alkaline. The free base can be converted into acid addition salts, in particular into pharmaceutically acceptable acid addition salts, by

409842 / 113b - 6 -

the free base is dissolved in a suitable organic solvent and the solution is treated with a solution of the selected acid in accordance with conventional procedures for the preparation of acid addition salts from basic compounds. Examples of acids ₃ that can be used are hydrochloric acid ^ hydrobromic acid ~ tartaric acid j phosphoric acid ₃ lialic acid. Citric acid ₃ methanesulfonic acid or p-toluenesulfonic acids.

In the dihaloalkane of the general formula III, the groups Hai and Hai ^{1 can be} identical or different. If the groups are different ₃ , the indole derivative I is obtained as a mixture of hydrohalic acid addition salts, from which the free base "can be obtained by the process described above. Preferably the groups Hai and Hai ^{1 are the} same. For example, they can both especially The dihaloalkanes of the general formula III are known compounds or they can be prepared by processes already described in the literature.

The indole derivative of the general formula II can be prepared by the process described in US Pat 3,576,001 and by S. Ci Bell et al in J. Heterocyclic Chern., 1969j 6, 599 to 6oU. In this procedure

409842/1136 - 7 -

For example, the indole derivative is made by a "'process involving' the cyclization of a 2-benzoylacylanilide with an ionic cyanide such as potassium cyanide. The 2-benzoylacylanilides can be prepared by the acylation of a 2-aminobenzophenone. The 2-aminobenzophenones are known compounds or they can be prepared by processes already described in the literature, for example in J. Am. Chem. Soc, 19 ^ 3, §5_, 363 or J. Heterocyclic Chem., 1971 * j3 _a 903 to 910.

The compounds of the general formula I have at least one asymmetric carbon atom and they are therefore optical enantiomorphs possible and the compounds can, as pure enantiomorphic compounds or as mixtures of such enantiomorphic compounds, such as, for example as racemates. The pure enantiomorphs Compounds can be obtained according to the process of the present invention by using optically active starting materials begins. Optionally, a racemic mixture of the compound of general formula I by a Procedure to be separated in the German Offenlegungsschrift 2,200,584.

As stated in the last description,

409842/1136 - 8 -

- 8 - 241791?

show the compounds of general formula I a pharmacological activity, e.g. B. antidepressant ₅ anti-inflammatory ₃ antihistamine ₃ cardiovascular, diuretic or hypoglycemic activity. Examples of specific compounds with a good antidepressant activity based on testing with standardized pharmacological tests are 2,3,4,10-tetrahydro-10-phenyl-pyrimido [1,2-a] indole-10-oil, 10- (m -Chlorophenyl) -2 ₃ 3 ₅ 4 ₅ 10-tetrahydropyrimido [l ₃ 2-a] indole-10 -ol and 2 ₃ 4,5:, 11-tetrahydro-11-phenyl-3H-l ₅ 3-diazepino [lj2-a] indole-II-ol. The latter compound also has good hypoglycemic activity.

The following examples illustrate the invention.

example 1

2,3, 4,10-tetrahydro-10-phenylpyr imido [1,2-a] indole-10-ol (a) of dichloroacetyl chloride (88 ml) in dichloromethane (200 ml) was added dropwise to a stirred solution of 2-aminobenzophenone (157;, 6 g) in dichloromethane (400 ml) and triethylamine (116 ml) were added, the temperature being kept between 20 to 30 ° C. by external cooling in ice. After the addition was complete, the reaction mixture was stirred at room temperature for an additional 1-5 hours. The reaction mixture was successively washed through with distilled water

- Q -

2417947

diluted hydrochloric acid and finally washed with distilled water. After drying over anhydrous magnesium sulfate, the solvent under reduced pressure was removed gave a solid residue which after recrystallization from absolute ethanol 222 g of 2 '· -3enzoyl-2 3 2-dichloroacetanilide _J having a melting point 112-114 ⁰ C gave one .and received .
Analysis for C ₁₅ H ₁₁ Cl ₂ NO ₂ :
Calculated: C 58.5 %, H 3 ₅ 6 %, N 4.5 %. Found: C 58.5%, H 3 , 1% » N 4.5 Si.

(b) 2'-Benzoyl-2,2-dichloroacetanilide (50 g) was suspended in 91 # ethanol (750 ml) and treated with a solution of potassium cyanide (30 g) in water (50 ml). The reaction mixture was stirred at room temperature for 40 hours. The crystalline precipitate was filtered off and the mother liquors diluted with water, whereby further fractions of 2-amino-3-phenyl-3H-indole-3 "oil were obtained. The total yield was 37 g. The product could be obtained from acetonitrile or from aqueous dimethylformamide be recrystallized and had a melting point of 204 to 206 ⁰ C (decomp.).
Analysis for C ^ H ^ NgO:

Calculated: C 74.9 % ₉ H 5.6 S ₃ N 12 ₃ 4 % _-3 Found: 'C 75.0 %, Ii 5 ₃ 4 %, N 12.5 £.

42/1136

- 10 -

(c) 2-Amino-3-phenyl-3H-indol-3-ol (2.24 g) was refluxed with isopropanol (20 ml) and 1,3-dibromopropane (2.0 g) for 20 hours . The reaction mixture was concentrated to a volume of about 10 ml and diluted with a little ether. It was the title compound in the form of its hydrobromide salt in an amount of 0.73 g erhaltenj melting point 260-262 ⁰ C (dec.). The compound could be recrystallized from methanol, ethanol or isopropanol with or without the addition of ethyl acetate or ether. Analysis for C ₁₇ H ₁₆ N ₂ O-HBr:
Calculated: C 59.15 %, H 4.8 %, _s N 8.1 %; Found: C 58.7 %, H 5.1 % » N 7.8 %.

Example 2

2,4 3 5> II-Tetrahydro -II-phenyl-3H-1,3-diazepino [1,2-a] indole II ^ ol

2-Amino-3-phenyl-3H-indol-3-ol (8.96 g) was refluxed with 1,4-dibromobutane (8.64 g) in absolute ethanol (65 ml) for 30 hours. The reaction mixture was evaporated to a small volume and set aside for crystallization. The product was obtained (4.67 g) ₃ melting point of 27O to 272 ⁰ C (dec.) In the form of its hydrobromide salt and was recrystallized from ethanol, the melting point was 262 to 277 ° C (dec.). Analysis for C ₁₃ H ₁₈ N ₂ O.HBr:

409842/1136

- 11 -

Calculated: C 60.3 ^ ₃ H 5.3 ί, Ν 7.8%; Found: C 60.6% H _3. 5 ₃ 5 # ₃ N 7.8 %.

B e i s ρ i el 3

8-chloro-2 j 3,4 _a 10-tetrahyd r6-10-phenylpyrimido [ 1,2-a] indole

The reaction of 2-amino-5 "chloro-3-phenyl-3H-indol-3 ~ ol (2 j 58 g) with I., 3-dichloropropane (I ₃ I g) according to the method of Example 1 Step (c) provided the title compound in the form of its hydrochloride salt, melting point 279 to 282 C (dec.).

Example 4

2 j 3,4, 10-T etrahydro-2 (un d4) -m ethyl-10-phenyl-pyrimido [l, 2-a] indole-10-ol

2-Amino-3-phenyl-3H-indol-3-ol (2.24 g) was refluxed with 1,3-dibromobutane (2 ₅ 16 g) in absolute ethanol (10 ml) for 16 hours. On cooling, colorless needles were obtained., It is believed by those that it (197-199 ⁰ C 500 mg melting point) were 2 ~ ethoxy-3 "phenyl-3H-indol-3-ol. These were discarded. The mother liquors were concentrated under reduced pressure to a foam which was redissolved in hot isopropanol. 697 mg of a mixture of the hydrobromides of the title compounds were obtained on cooling.

409842/1138 - 12 -

installation from ethanol / ether.
Analysis for C ₁₈ E ₁₈ N ₂ O.HBr:
Calculated: C 60.3 %, ₃ H 5.3 %, N 7.8 #; Found: C 6O ₅ I % ₃ H 5 ₃ ¹ Y %> N 7.7 3.

B e i s ρ i el 5

ll- (m-chloropheny _i l) -2 _iJi 4 ₃ 5 _? ll "tetrahydro-3H-1,3-diazepinO" [l _a 2-a] indol-ll-ol

(a) 2-Amino "3 ^T ~ chlorobenzophenone (6.12 g) were dissolved in acetone (25 mi) was added dropwise under stirring and cooling with dichloroacetyl chloride (4.86 g) was added. After additional 20 ilin. stirring at room temperature was The reaction mixture was poured into water, the acetone was removed under reduced pressure and the oil obtained was taken up in chloroform, after drying over magnesium sulfate, the chloroform was removed under reduced pressure and the product was recrystallized from ethanol _(a 88 g 6) received 2 ₃ 2-dichloroacetanilide in the form of yellow needles having a melting point of 73 ° to 75 ° C after recrystallization from ethanol ·.

Analysis for C ₁₅ H ₁₀ Cl ₃ NO ₂ :

Calculated: C 52.6 %, H 2.9 %, N 4.1 %:

Found: C 52.8 %, H 2.9 %, N 4.1 %.

(b) The dichloroacetanilide obtained above was dissolved in ethanol

409842/1136 - 13 -

(150 ml) and treated with a solution of potassium cyanide (6 g) in water (50 ml). After stirring at room temperature overnight, the mixture was treated with animal charcoal _s filtered off and the ethanol removed under reduced pressure. The oil obtained was taken up in chloroform, dried over magnesium sulfate and evaporated to an oil which, on treatment with isopropanol and hydrogen chloride in dry ether, contained 4.6 g of 2-amino-3 "(m-chlorophenyl) -3H-indole-3 ~ ol in the form of its hydrochloride with a melting point of 247 to 250 ° C (decomp.).

Analysis for C ₁₄ II ₁₁₂

Calculated: C 56.9 %, H 4.1 %, ₃ N 9.4 % » found; C 57.1 Ji ₃ H 4.1 %, N 9.1 %.

(c) 2-Amino-3 "(m-chlorophenyl) -3H-indole-3-ol hydrochloride (8.66 g) were converted into the oily base and then refluxed with 1,4-dibromobutane (6, -35 g heated) in ethanol (20 ml) for 4 hrs.. on cooling the title compound is obtained in the form of its hydrobromide salt (2.4L g) of melting point 270-275 ⁰ C (dec.) after recrystallization from methanol / ethyl acetate.
Analysis for C ₁₃ H ₁₇ ClN ₂ CHBr:
Calculated: C 54.9 %> H 4.35 % » N 7.1 % i Found: C 54.85 JS, H 4.6 %, N 7.1 %.

409842/1136

Example 6

10- (M-- Chlorphe nyl) -2,3 ₃ 4 ₃ 10 - te trahydropyrimido [1, 2-a] indol-10 _ _-ol

2-Amino-3 ~ (m-chlorophenyl) -3H-indol-3-ol. Hydrochloride (2.3 g) was converted into its oily base and then heated under reflux in ethanol (10 ml) with 1,3-dibromopropane (I ₃ 55 g) for 20 hours. After cooling, the title compound was obtained in the form of its hydrobromide, with a melting point of 270 to 273 ° C. (decomp.)

E.g.iel 7

9-chloro-ll- (o-chlorophenyl) -2 _{J 4, J} 5 ll-tetrahydro-3H-3-l _J diazepino [1,2-a] indole-ll-ol

(a) Dichloroacetyl chloride (17 ml) in dichloromethane (50 ml) was added dropwise to a stirred solution of 2-amino-2 ^f -, 5-dichlorobenzophenone (40.8 g) and triethylamine (24 ml) in dichloromethane (100 ml) admitted. The mixture was stirred at room temperature for 15 hours and washed with water. After drying over magnesium sulfate, the solvent was removed under reduced pressure and the oil obtained was recrystallized from ethanol. After recrystallization from ethanol, 48.14 g of colorless crystals were obtained

a melting point of 130 to 133 C.

Analysis for C ₁₁ -HqCI ^ NO ₂ : -

Calculated: C 47.8 %, H 2 ₃ 4 %, N 3.7 %; Found: C 48.2 %, H 2.5 %, N 3.9% ·

409842/1136 - 15 -

(b) The dichloroacetanilide obtained in step (a) above was dissolved in 90 % -j.gem ethanol (500 ml) and stirred for 24 hours at room temperature with potassium cyanide (20.95 g) in water (180 ml). The undissolved material was filtered off and the piltrate was diluted with water, and after recrystallization from aqueous dimethylformamide, 23.74 g of 2-amino-5-chloro-3- (o-chlorophenyl) -3H-indol-3-ol were obtained.

(c) 2-Amino-5-chloro-3- (o-chlorophenyl) -3H-indol ~ 3 ~ ol (5 ₅ 86 g) was refluxed with 1,4 ~ dibromobutane (4 ', 32 g) 18 Heated for hours. The hydrobromide of the title compound (67 g) with a melting point of 295 to 300 ° C. (decomp.) Precipitated on cooling.

Analysis for C ₁₃ H ₁₆ Cl ₂ N ₂ O-HBr:

Calculated: C 50.5 %, H 4.0 %, N 6.5 % ', Found: C '50.3 %, H 4.05 %, N 6.4%.

Example 8 9 ~ Chloro-II-phenyl-2,4,5,1-tetrahydro-3H-1,3-diazepino

(a) Potassium cyanide (18 g) in water (150 ml) became a suspension of 2 '- (p-chlorobenzoyl) -2,2 ~ dichloroacetanilide (30 g) in ethanol (400 ml) was added. The reaction was stirred overnight and after treatment with animal charcoal with Water diluted. 2-Amino-5-chloro-3-phenyl-3H-

40984 2/1136 -16-

" ¹⁶ " 241791?

indol-3 ~ ol (19 _S 57 g) in the form of white crystals, with a melting point of 205 to 208 ° C after recrystallization from acetonitrile.

(b) 2-Amino-5-chloro-3-phenyl-3H-indole-3 "oil (5/16 g) was refluxed with 1.4 dibromobutane (4.32 g) for 24 hours. After cooling, the The pesticide was filtered off and 1.88 g of the title compound were obtained in the form of its hydrobromide, with a melting point of 298 to 300 ° C. (decomposition) after recrystallization from methanol / ethyl acetate. Analysis for C ₁₈ H ₁₇ ClN ₂ CHBr:
Calculated: C 54.9 %, H 4.35 %, N 7.1 % y Found: C 54.5 %, H 4.6 %, N 7.0 g.

- 17 A09842 / 1136

Claims (8)

Patent sayings Process for the preparation of an indole derivative of the general formula I.
R ¹ (D or an acid addition salt thereof, wherein the radicals R, R ₃ R ⁵ and R each mean to be hydrogen, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a halo-lower alkyl group or halogen, R ^ and R are each hydrogen or lower alkyl and the indices m and η have a value of 0, 1, 2 or 3 and the sum of m + η is 2 or 3, characterized in that an indole derivative of the general formula II (ID A09QA2 / 1136 241791? wherein the radicals R ₉ R ₃ R ^ and R have the same meaning as above _s with a dihaloalkane of the general formula III Hal. (CH ₂ ) _m .C. (CH ₂ ) _n Hal '(III) c 5 wherein the radicals R ₅ R, and the indices m and η have the same meaning as above and ^{Hal and Hal 1} each separately chlorine j bromine or iodine are ₃ condensed, and optionally an acid addition salt obtained in the free base or a free base in transferred to an acid addition salt. 2. The method according to claim 1, characterized by DUT »ch j that Hal and Hal 'are both bromine. 3. The method according to any one of claims 1 and 2 _} as characterized in ₃ that the condensation is carried out in an inert organic solvent. 4. The method according to claim 3, characterized j that the reaction medium is heated. 409842/1136 L. 5. The method according to any one of claims 3 and 4, d a characterized in that the condensation is carried out in the presence of a base. 6. The method according to any one of claims 1 to 5 ₃ da - characterized in that each of the group 1 2 "^ 4
pen R, R, R ^ and R is hydrogen, or that at least one of the groups is halogen and the remaining groups are hydrogen. 7. The method according to any one of claims 1 to 6, d a - 5 characterized in that the radicals R and R are each hydrogen. 8. The method according to any one of claims 1 to 6, d a characterized in that the index m has the value 1 and the index η has the value 1 or 2, or the index m has the value 2 and η has the value 1. 409842/1136