HU184576B - Process for preparing 14,15-dihydro-d-nor-eburnamenine derivatives - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to a novel 14,15 dihydro-D-norburbamenine derivative of the formula Ia and / or Ic, wherein R2 is (C1-C4 alkoxy) carbonyl or a cyano group such that i) a - optionally an acid addition salt of formula IIb, wherein X "is an anion-free anion-liberated l-ethylindolo (3,2-g) indolizine derivative, an acrylic acid derivative of formula III wherein Y is halogen, R2 is the reaction product is hydrogenated by chemical reduction and, if desired, the resulting mixture is separated; for the preparation of a (C 1 -C 4) alkoxy) carbomyl group, optionally 11b from an acid addition salt of the general formula wherein X 'is the in situ release of the 1-ethylindolo [3,2-g] indolizine derivative with an acrylic acid derivative of formula IIP wherein R 1 is (C 1 -C 4 alkoxy) carbonyl; And Y is as defined below, by reacting the resulting 14,15-dihydro-H '-1-

Description

(57) EXTRAS

The present invention relates to novel 14,15 dihydro-D-nor-eburbamenine derivatives of the formula Ia and / or Ic

R 2 is for the preparation of a (C 1 -C 4 alkoxy) carbonyl group or a cyano group such that ti) from an acid addition salt of formula (11b) optionally wherein X is an acid anion of l-ethyl indole liberated in situ. Reacting a 2-g] indolizine derivative with an acrylic acid derivative of the Formula III wherein Y is halogen and R ₂ is as defined above, then hydrogenating the reaction product and, if desired, separating the resulting mixture;

b) a 14,15-dihydro-D-nor-cburnamenine derivative of the Formula Ia which is a narrower group of compounds of Formula Ia, wherein R ₂ is a compound of formula (C 1 -C 4 alkoxy) carbonyl; in the case 1-ethylindolo [3,2-g] indolizine derivative from the acid addition salt of formula 11b, wherein X 'is the above-described in situ liberated derivative, with an acrylic acid derivative of formula IIP, wherein R ₂ is (1-4 alkenoxy) and Y is as defined below, to give the 14,15-dihydro-

H '

The -1-3,4-dehydro-D-nor-eburnamenine derivative wherein R a and X are as defined above is hydrogenated by catalytic hydrogenation or chemical reduction.

The compounds of formula Ia, lb, le according to the invention are novel and have significant biological activity and a significant vasodilator effect.

The present invention relates to novel 14,15-dihydro-D-nor-ebumannanine derivatives of the general formulas Ia, 1b and Ic, wherein

R ₂ is (C 1 -C 4 alkoxy) carbonyl or cyano,

In the compounds of the formulas Ia, lb and Ic prepared according to the process of the invention, R _{2 is a} linear or branched alkoxy group such as methoxy, ethoxy, n-propoxy, as a (C 1 -C 4) alkoxy carbonyl group. η-butoxy, i-butoxy, tert-butoxycarbonyl.

According to the present invention, the novel 14,15-dihydro-D-nor-eburnamenine derivatives of the formulas Ia, Ib and Ic, wherein R ₂ is as defined above, are prepared by:

a) from an acid addition salt of formula IIb optionally wherein X is a new 1-ethylindolo [2,3-guinololizine derivative of formula IIa which is liberated in situ from an acid anion by an acrylic acid derivative of formula III wherein Y is halogen, R ₂ is and reacting the resulting reaction product with chemical reduction and separating the resulting compounds, if desired.

b) For the preparation of the 14,15-dihydro-D-nor-eburnamenine derivatives of the general formula la, wherein R ₂ is (C 1 -C 4) alkoxy) carbonyl, a compound of formula Ia a new l-ethyl indolo (3,2-g) indolizine derivative of the formula (IIb), optionally liberated in situ by acid addition of formula (IIb), wherein X 'is as defined above for an acrylic acid derivative of formula (III') in which Y is and R ₂ is (C 1 -C 4 alkoxycarbonyl) to give the resulting Id

The 14,15-dihydro-3,4-dehydro-D-nor-eburnamenine derivative wherein R ₂ and X are as defined above is saturated by catalytic hydrogenation or chemical reduction.

All of the compounds of the present invention are novel and have significant biological activity: studies in anesthetized dogs have shown that the novel compounds of the present invention have significant vasodilatory activity.

The novel starting materials of the formulas 11a and 11b, wherein R 1 is as defined above and X 'is an anion of any suitable organic or inorganic acid, preferably perhalogenates such as perchlorate, perbromate, etc., as the acid anion. starting from the corresponding 2-alkyl-4-butanol, it can be prepared by reacting the corresponding 2-alkyl-4-butanol with tryptine and then forming the 2-alkyl-4-hydroxy butanoyl tryptamide is subjected to double cyclization. Appropriate

The alkyl-4-butanol can be prepared as described in Sintezy Dushistykh Veshchestr, Sbornik State, 167-77 (1939).

The acrylic acid derivatives of the formulas III and III ¹ , wherein Y is fluoro, bromo or iodo as the halogen atom, may be prepared as described in JACS 61, 3156 (1939).

The process of the present invention may be based on the 1-ethylindolo [3,2-g] indolizine derivatives of formula 11a and the acid addition salt derivatives of 1-ethylindolo-13,2-g] indolizine IIb. Preferred examples of the acid addition salts of Formula IIb, where X is as defined above, include perhalogenates such as perchlorate, perbromate, and the like.

The starting material in the form of the acid addition salt of formula IIb is treated with a base in an inert organic solvent prior to the reaction, the solution is dried and a solution of the compound IIa thus liberated from the acid addition salt in an inert organic solvent can be used directly wherein Y is as defined above.

The base is preferably a dilute aqueous solution of an inorganic base. Preferred bases used are, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like. The inert organic solvent used is a water immiscible solvent. Such solvents include, for example, halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, trichloroethyl, and the like, with dichloromethane being the preferred solvent. The release of general needle 11a derivative occurs at room temperature in a short period of time.

To a solution of the corresponding compounds of formula IIa liberated from compounds of formula IIb in an inorganic organic solvent solution prepared as described above is added the compounds of formula III. The reaction time and temperature for the reaction of the compounds of formulas Ia and III are not critical to the reaction, preferably at room temperature.

In the variant of process a), the reaction mixture obtained is evaporated and the residue is then saturated chemically, preferably with zinc + acetic acid or with sodium borohydride. The reaction products were separated by column chromatography using cis-14,15-dihydro-D-nor-eburnamenine of formula Ia, epis-14,15-dihydro-D-nor-eburnamenine of formula 1b and epi-trans of formula Ic -14,15-dihydro-D-nor-eburnamenine derivatives are obtained.

Alternatively, the reaction mixture obtained by reacting the compounds of formula IIa and III 'as described above is evaporated, the residue is dissolved in water and acidified with a perhalic acid, preferably perchloric acid, to give the 14,15-dihydro-3,4 The dehydro-D-nor-eburnamenine perchlorate derivative is isolated and then catalytically saturated, preferably using a palladium catalyst or chemically, preferably sodium borohydride. The reduction is stereoscopic, thus obtaining the cis-14,15-dihydro-D-nor-eburramenine derivatives of formula la '.

In both process variants, the final product obtained is crystallized from a suitable solvent. Suitable solvents include, for example, aliphatic alcohols such as methanol, ethanol, n-propanol, i-propanol, n-butan-21

184,576 no., I-butanol, etc., ketones, such as on steel, aliphatic esters, especially alkane carboxylic acid esters, such as ethyl acetate; and acetonitrile and the like. After crystallization, Ia, Ib and Ic are compounds of formula - wherein R formulas, and R ₂ are the same as defined above - is obtained in well defined form having the elemental analysis of which showed good agreement with the expected, and characteristic groups measured by IR spectroscopy bands of , magnetic resonance spectroscopy and mass spectroscopy clearly demonstrate the structure of the compounds of formulas Ia, Ib and Ic in the accompanying drawings.

The invention is illustrated in more detail by the following non-limiting examples.

Example 1

2-ethyl-4-butanol

Sodium (9.2 g, 0.4 mol) was dissolved in 138 g (175 ml) of ethanol. 92 g (0.489 mol) of ethyl malonic acid diethyl ester are added and the reaction mixture is refluxed for 3 hours. The solution is then cooled to -10 ° C and a solution of 44 g (1.0 mol) of ethylene oxide in 55 g of toluene is added. The mixture was then refluxed for 4 hours. After adding a solution of 220 g of potassium carbonate in 300 ml of water, refluxing is continued for another 22 hours. The alcohol was distilled off and the residue acidified to pH 5 with 50% sulfuric acid. Concentrated sulfuric acid (40 ml) was added and refluxed for 8 hours. Water (250 mL) was added to the reaction mixture and the mixture was extracted with benzene (3 x 300 mL). The combined organic layers were washed with water (500 mL), 5% sodium bicarbonate solution (500 mL), water (500 mL), and then dried over anhydrous magnesium sulfate. The benzene is distilled off and the oily product is purified by fractional distillation in vacuo. The product

32.4 g (71.0%).

Boiling point 101-104 ^° C (18 mm Hg).

Refractive index: no = 1.1371

Analysis for C ₆ H O _{1 O 2} (MW 114.14) based Calc'd:

C,% H,%

Calculated: 63.13 8.83

Found 62.97 8.70

IR (film): 1745 cm @ ^-1 (> C = 0).

1 H NMR (CDCl 3): 1.00 (3H, t, J = 7.2 Hz, C ₃ -CH ₂ CH ₃ ) ppm.

¹³ C NMR (CDCl ₃ ): 11.56 (C ₃ -CH 2 -CH ₃ ), 23.46 (C ₃ -CH ₇ -CH ₃ ), 28.11 (C ₄ ), 40.63 (C ₃ ), 66.58 (C 5), 179.46 (C 2) ppm.

Example 2

2-ethyl-4-hydroxy-butanoyl triptamid

Thripamine (16.0 g, 100 mmol) and 2-ethyl-4-butanol (13.0 g, 113.9 mmol) were suspended in xylene (100 mL) and refluxed with stirring for 6 hours. The xylene was discarded from the solid which was separated from the cooled reaction mixture, and the resulting crude product was crystallized from ethyl acetate.

Yield 2! , 8 g (79.5%).

Melting point: 117-118 ° C.

Analysis results based on the formula Ci _S H ₂₂ N ₂ O ₂ (MW 274.36):

C,% H,% N,% calculated 70.04 8.08 10.21 Found 69.99 7.90 10.40

IR spectrum (Kbr): 3230 cm ^-1 (indoINH),

1660-1622 cm ^-1 (> C = O).

Ή NMR (CDCl ₃ + DMSO-d _6), 3: 1:

0.86 (3H, t, J = 7.2 Hz, C 6 -CH 2 -CH 2),

2.22 (1H, m, C5'-H),

2.95 (2H, t, J = 7.0 Hz, Cl 1 -H ₂ ),

3:53 (2H, t, J = 6.2Hz, C7'-H _2),

3:59 (2H, t, C2'-H _2),

6.7 (1H, br, s, -CO-NH),

6.9-7.7 (5H, m, aromatic H),

9.7 (1H, br, s, -NH) ppm.

¹³ C NMR (CDCl 3, + DMSO-d ₆ , 3: 1):

II. 84 (C5 '_CH2-CH3);

* 25.51 (C1 ');

* 25.55 (C5 '_-CH-CH3);

35.50 (C6 '),

39.57 (C2 '),

44.60 (C5 '),

59.34 (C7),

III. 36 (C7),

112.13 (C3),

118.31 (C4, C6),

120.98 (C2),

122.37 (C5),

127.36 (C3a),

136.51 (C7a),

175.29 (C4) ppm.

Example 3

1-Ethyl-1,2,3,5,6,1-hexahydroindolo [3,2-g] indolizin-4-ium perchlorate

2-Ethyl-4-hydroxybutanoyl-tryptamide (2.0 g, 7.3 mmol) was dissolved in phosphoryl chloride (20 mL) and heated to reflux for 3 hours. The phosphoryl chloride was evaporated in vacuo and the residue was dissolved in dichloromethane (50 mL). After addition of 50 ml of water, the mixture was made alkaline with 40% sodium hydroxide to pH 8 with ice-cooling. After separation, the aqueous layer was extracted twice more with dichloromethane (30 mL each). The combined organic layers were dried over magnesium sulfate. The solution filtered from the desiccant was concentrated in vacuo and the residue was dissolved in methanol. Crystallization begins by adding 2 ml of 70% aqueous perchloric acid. The crystals were collected by filtration to give 64 g (66.7%) of a yellowish yellow solid, m.p. 171-172 ^° C.

-318 * 576

Analysis revealed for C ₆ H _i9 CLN ₂ O ₄ (MW 338.79) Calc'd:

C,% H,% N,% calculated 56.72 5.65 8.27 Found 56.81 5.48 8.41

IR (KBr): 3200 cm- ¹ (indole NH) 1622 cm- ¹ (> C = N-) ¹ H NMR (CDCl ₃ + DMSO-d ₆ , 4: 1):

I 04 (3H, t, J = 7.2 Hz, Cl-CH CIf), 3:40 (2H, t, 06-H _2),

3.9-4.4 (4H, m, C5-H2, C3-H _2),

7.1-7.8 (4H, m, aromatic H),

12.0 (1H, br, s, -NH) ppm.

¹³ C NMR _(DMSO-d6 + CDC1 _3, 3: 1):

II. 08 _{(CHn-Cl-CH3);}

19.26 (C6),

24.47 * (C2),

24.96 * (cl-CHz-CHsT,

46.02 (Cl),

46.85 (C5),

56.77 (C3),

113.35 (CIO),

121.45 (C7, C8),

122.81 (C6a),

123.12 (C6b),

124.1 (Cila),

128.36 (09),

141.21 (CIOa),

170.67 (Cl lb) ppm.

Example 4

14,15-Dihydro-14a-methoxycarbonyl-D-nor-eburnamenine (3a, 14 / 3,16a), 14,15-dihydro-14/3-methoxycarbonyl-D-nor-eburnamenine (3a, 14a, 16a) and a mixture of 4,15-dihydro-14-methoxycarbonyl-D-nor-eburnamenine (3 / 3,14α, 16a).

1-Ethyl-1,2,3,5,6,11-hexahydroindolo [3,2-g] indolizin-4-ium perchlorate (29.5 mmol) is suspended in 100 ml of dichloromethane and stirred under constant stirring. add 100 ml of water and 20 ml of normal sodium hydroxide solution. The mixture was stirred for 10 minutes, the separated organic layer was separated and dried over magnesium sulfate. The desiccant was filtered off, and methyl (2-bromoacrylate) (8 mL, 70.3 mmol) was added to the solution and the reaction was allowed to stand at room temperature for 30 minutes. The solvent was evaporated in vacuo and the residue was dissolved in methanol (500 mL). The mixture was cooled to ^r 0 in small portions sodium borohydride (10.0 g, 264.3 mmol) was added under constant mixing tube. After addition, stirring was continued at 0 ° C for 1 hour. The solution was then acidified with 5N hydrochloric acid and concentrated in vacuo to 50 ml. Water (100 mL) and dichloromethane (100 mL) were added to the residue and the mixture was basified to pH 10 with 2N sodium hydroxide solution. After separation, the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were dried over magnesium sulfate. The solution filtered off with the desiccant was evaporated and chromatographed to give a triplet of material.

The mixture was separated on a silica gel column eluting with benzene / methanol (3: 1). Fractions of 10 ml were collected and the fractions were checked by TLC. The products come down from the column in the following order:

1a: 3.47 g (36.3%) m.p. 86-88 ^° C (methanol) 1b: 2.41 g (25.2%) m.p. 98-100 ° C (methanol)

Ic: 1.08 g (11.3%), m.p. 119-121 ^° C

(Methanol) analysis Results a C ₂₀ H ₂₄ N ₂ O ₂ (MW 324.4) by nail pattern: C,% H,% N,% calculated 74.04 7.46 8.64 Found la 73.89 7.41 8.64 lb 74.11 7.38 8.50 ic 73,92 7.38 8.64

IR spectrum (KBr): 1α: 1742 cm ^-1 (> C = O) 1b: 1742 cm ^-1 (> C = O)

Ic: 1748 cm⁻¹ (> C = O) Ia: Ή NMR (CDC1 _3):

0.99 (3H, t, J = 7.2 Hz, Clo-CH3-CHa),

1.27 (1H, ddd, J _m = 12.5 Hz, J _vic = 7.5 + 3.0 Hz, Cl 7 -H),

1.65 (1H, dd, J _m = 14.5 Hz, J _v j _c = 5-9 Hz, C15-H),

1.7 (2H, _06-CH-CH3);

1.85 (1H, dd, J = 8.1 Hz _v ic Cl, 7-H);

2:55 1H, dd, J _v i _c = 04.08 Hz, C15-H);

3.4 (2H, m, C 5 -H _2);

3.82 (3H, s, -COOCH ₃ ),

3.99 (1H, t, J = 4.5Hz, C3-H),

4.78 (1H, dd, C 14 H),

7.0-7.6 (4H, m, aromatic H) ppm.

¹³ C NMR (CDC1 _3):

8:53 (C16 CIVCH _3).

16.43 (C6),

32.85 (Cl0-CH2-CIE),

05.05 (05),

37.39 (07),

43.22 (06),

44.30 (C5),

46.82 (06),

52.44 (~ COOCH ₃ ),

54.14 (04),

62.30 (C3),

106.38 (C7),

109.27 (02),

118.55 (C9),

119.87 (CIO),

121.23 (Cll),

128.69 (C8),

134.25 (C2).

184,576

137.97 (C13),

172.37 (-COOCH ₃ ) ppm.

Ib: Ή NMR (CDCl ₃ ):

1.00 (3H, t, J = 7.2 Hz, Cl6 -CH2 -CH3),

2.09 (1H, dd, J _gem = 14.6 Hz, J _v i _c = 5.2 Hz,

C15-H);

2.40 (1H, dd, J _vic = 6.2 Hz, C15-H),

3.4 (2H, m, C 5 -H _2);

3.64 (3H, s, -COOCH ₃ ),

3.81 (1H, t, J = 4Hz, C3-H),

4.95 (1H, dd, C14-H),

6.95-7.55 (4H, m, aromatic H) ppm.

¹³ C NMR (CDCl ₃ ):

8.68 (Cl 10 -CH ₂ -CH ₃ ),

16.59 (C6),

32.90 * _{(C16-CH2-CH3);}

33.41 * (C17),

34.60 (Cl5),

42.07 (C16),

44.41 (C5),

47.12 (C18),

52.07 (-COOOCH3),

54.71 (C14),

61.92 (C3),

107.12 (C7),

110.24 (C12),

11:45 (09),

119.76 (CIO),

121.16 (Cl 1),

129.24 (C8),

133.76 (C2),

138.14 (C12),

171.63 (-COOCH3) ppm.

IC: Ή NMR (CDCl3):

0.5 (4H, dqd, J _gem = 13.5 Hz, J = 2.1 _A2 Hz, C _H -CH _3),

0.78 (3H, Cl6-CH2-CHa),

0.95 (1H, dqd, J = 1.6 Hz _{B I2,} C16-CH _A H _B -CH _3);

1.70 (1H, dddd, J _gem = 12.0 Hz, J _v i _c = 9.6 + + 8.6 Hz, C17-H),

1.92 (1H, ddd, J _gem = 13.2 Hz, J _v ic = ¹⁰ · ² Hz, C15-H),

2.06 (1H, ddd, J _vic = 6.5 + 1.5 Hz, C17-H), 2.77 (1H, dd, J _vic = 7.3 Hz, C15-H),

3.52 (1H, ddd, J _gem = 10.2 Hz, C18-H),

3.82 (3H, s, -COOCH ₃ ),

3.86 (1H, br, s, C3-H),

4.71 (1H, dd, C14-H),

7.0-7.6 (4H, m, aromatic H) ppm.

¹³ C NMR (CDCl 3):

8:54 _{(C16-CH-CH3);}

21.52 (Cl 10 -CH 2 -Cl h),

22.45 (C6),

34.64 (C15),

35.13 (Cl 7),

45.85 (Cl6),

51.19 (C5),

52.64 (-COOCH3),

54.32 (Cl8),

55.75 (C14),

64.84 (C3),

105.54 (C7),

110.02 (C12),

118.48 (09),

120.15 (CIO),

120.76 (Cll).

128.46 (C8),

137.27 (C2),

138.29 (C13),

172.32 (-COOCH ₃ ) ppm.

MS (m / e):

la: 325, 324, 323, 295, 269, 268, 266, 265, 252, 238, 237, 208, 194, 132, 36.

lb: 325, 324, 323, 295, 268, 266, 265, 252, 238, 237, 208, 194, 132.

Ic: 325, 324, 323, 309, 265, 239, 238, 237, 235, 234, 132.

Example 5

14,15-Dihydro-14a-cyano-D-nor-eburnamycin (3α, 14 / 3,16a), 14,15-dihydro-14/3-cyano-D-nor-eburnamycin (3n, 14a, 16a) ) and a mixture of 14,15-dihydro-14 H -cyano-D-norcburnamycin (3/1, 14a, 16 (t)).

Each was prepared as in Example 4, except that 8 ml (99.4 mmol) of 2-chloroacrylonitrile was used as reagent.

The products come down from the column in the following order:

la: 3.41 g (39.7%) m.p. 121-122 ^° C (methanol) lb: 2.58 g (30.0%) m.p. 133-134 ° C (methanol)

Ic: 1.01 g (11.8%), m.p. 181-183 ^° C (ethanol)

Analysis results based on the formula: C19H21N3 (MW 291.38) C,% H,% N,% calculated 78.31 7.27 14.42 Found la 78.28 7.21 14.22 lb 78.42 7.11 14.50 1c 78,40 7.20 14.51

IR spectrum (KBr):

la: 2310 cm ^-1 (-CN) 1b: 2260 cm ^-1 (-CN)

1c: 2240 cm⁻¹ (-CN) la: Ή NMR _(CDCl3):?

1.05 (3H, t, J = 7.3 Hz, Cl 10 -CH 2 -CH 2).

1.24 (1H, ddd, C17-H),

1.74 (1H, dd, J _gctn = 14.5 Hz, J _vic = 5.4 Hz, C15-H),

-518

2:50 (IH, dd, J = 5.8 Hz _v ic, CI5 - H);

4.04 (1H, t, J = 4.7 Hz, C3-H),

4.87 (1H, dd, C 14 H) ppm.

¹³ C NMR (CDCl 3):

8:55 (CÍ6-CH ₂ -CH _3);

16.35 (C6),

32.47 (C16 ~ _CH2-CH3), .86 (C17),

36.05 (C15),

42.19 (04),

43.04 (C16),

44.0S (C5),

46.62 (C18),

61.83 (C3),

108.43 (Cl7),

109.91 (C12),

118.85 (~ CN),

118.83 (C9),

120.94 (CIO),

122.11 (CIO,

129.22 (C8),

133.74 (C2),

138.31 (C13) ppm.

Ib: 1 H NMR (CDCl ₃ ):

1.00 (3H, t, J = 7.4Hz, C 1-6 -CH ₇ -CH ₃ ).

2.14 (1H, dd, J _gem = 14.8 Hz, J _vjc = 4.2 Hz, C15-H),

2:46 (IH, dd, J = 5.8 Hz _v i _c, C15 / H),

3.75 (1H, t, J = 4.4 Hz, C3-H),

5.16 (1H, dd, C14-H) ppm.

¹³ C NMR (CDCl ₃ ):

8.56 (Cl 6 -CH a -CH ₃ ),

16.62 (C6),

31.59 * (07),

32.39 * (C16-CH2-CHo),

33.83 (05),

42.34 (Cl6),

42.45 (C14),

43.98 (C5),

46.44 (Cl8),

61.55 (C3),

130.11 (C7),

111.45 (C32),

117.32 (-CN),

118.73 (C9),

121.36 (CIO),

122.35 (Cll),

130.26 (C8),

133.81 (C'2),

138.38 (C13) ppm.

1c: 1 H NMR (CDCl ₃ ):

0:06 (lH, dqd, J _gem = 13.5 Hz, J = 2.1 Hz _A2, C16-CH _{3 CH-Hb),}

0.77 (3H, C16-CH ₃ -CH);

0.95 (IH, dqd, Jr., _I2 = 5.1 Hz, C16-CH ₃ -CH ~ _Hb),

1.7 (IH, dddd, _Jgem: 12.0 Hz, J = 10.0 + _v j _c 8 6 Hz, C17),

2:06 (IH, ddd, J _v i _c = 6.6 + 1.4 Hz, 017-H), 2.23 (IH, ddd, J _gem = 13.5 ^Hz - ¹⁰ · ^J vic = ^5Hz> C15-H);

2.80 (1H, dd, Jvic = 6.7 Hz, C15-H),

3.5O (1H, ddd, 1H _gem = 10.6 Hz, C18-H),

3.83 (1H, br, s, Cl3-H),

4.82 (1H, dd, 04-H) ppm.

¹³ C NMR (CDCl ₃ ):

8:47 _{(CI6-CH2-CH3);}

21.24 (C10-CH2-CH5),

22.38 (C6),

34.86 (C17),

35.69 (05),

43.38 (Cl4),

45.38 (Cl 6),

50.81 (C5),

54.05 (Cl8),

64.43 (C3),

106.99 (C7),

110.28 (02),

117.93 (-CN),

18.85 (C9),

121.12 (CIO),

121.59 (Cll),

128.78 (C17),

135.45 (C2),

138.45 (Cl 2) ppm.

MS (m / e):

la: 293, 292. 291, 290, 263, 262, 238, 237, 236, 235,

234. 233, 223, 221, 220, 219, 218, 206, 194, 193. 145, 1.33, 132.

lb: 293, 292, 291, 290, 262, 238, 237, 236, 235, 234, 233, 223, 220, 219, 208, 206, 194, 193, 145.

Ic: 291, 290, 289, 261, 260, 249, 239, 238, 230, 236,

235, 223, 132.

Example 6

14,15-Dibydro-14a-methoxycarbonyl-D-nor-eburnamene (3 ', 14 / 3.16')

a) 2.0 g (4.73 mmol) of 4,15-dihydro-3,4-dehydro-14-phenyloxycarbonyl-D-nor-ebuminum (14,16) perchlorate is dissolved in 150 ml of methanol. The reaction mixture was cooled to 0 ° C and 2.0 g (32.9 mmol) of sodium borohydride was added in small portions. Stirring was continued at 0 ° C for an additional 1 hour. It's your mixture! It is acidified with 5N hydrochloric acid solution and concentrated in vacuo to 20 ml. Water (50 mL) and dichloromethane (50 mL) were added to the residue followed by 2N sodium hydroxide solution. pH = 10. After separation, the aqueous phase was extracted with dichloromethane (30 mL). The combined organic layers were dried over magnesium sulfate. The filtrate was evaporated in vacuo and the residue was recrystallized from methanol. 1.18 g (76.9%) of product are obtained, m.p. 86-88 ° C.

b) 2.0 g (4.73 mmol) of 14,15-dihydro-3,4-dehydic-4-methoxycarbonyl-D-nor-ebumaneine (14.16) perchlorate

184,576

Dissolve in 150 ml of methanol. A methanolic slurry of 10% palladium on carbon (1.0 g) was added and the reaction mixture was hydrogenated at room temperature under atmospheric pressure until saturated. The catalyst was filtered off and the filtrate was concentrated in vacuo. Water (50 mL) and dichloromethane (50 mL) were added to the residue and the mixture was basified to pH 10 with 2N sodium hydroxide solution. After separation, the aqueous portion was extracted with dichloromethane (30 mL). The combined organic layers were dried over magnesium sulfate. The solution filtered from the desiccant was concentrated in vacuo and the residue crystallized from methanol.

Yield: 0.98 g (63.7%), m.p. 87-88 ^° C, identical in physical product to that obtained in (a).

46.33 (Cl6),

47.47 (C5).

52.88 (-COOCH3),

53.07 (04).

56.10 (08),

112.65 (Cl2),

119.64 (C7),

121.57 (C8),

122.16 (C9),

122.26 (CIO),

125.34 (C13),

128.47 (Cll),

141.79 (C13),

170.28 (C3),

171.71 (—COOCH ₃ ) ppm.

Example 7

14,15-dihydro-3,4-dehydro-14a-methoxycarbonyl-D-nor-ebumamenin (14jS, 16a) perchlorate

10.0 g (29.5 mmol) of 1-ethyl-1,2,3,5,6,11-hexahydroindolo [3,2-g] indolizin-4-ium perchlorate are suspended in 100 ml of dichloromethane, water (100 ml) and 2N sodium hydroxide solution (20 ml) were added with constant stirring. The mixture was stirred for 10 minutes, the separated organic layer was separated and dried over magnesium sulfate. The desiccant was filtered off, methyl (2-bromoacrylate) (8 mL, 70.3 mmol) was added and the reaction was allowed to stand at room temperature for 30 minutes. The solvent was then evaporated in vacuo. The residue was dissolved in methanol (500 mL) and purified by charcoal. The activated carbon was filtered off and the filtrate was concentrated to 150 mL and crystallized in a refrigerator. The precipitated yellow crystals weighed 4.1 g (32.7%). Melting point: 222-223 ° C.

Analysis results for C ₂₀ H ₂₃ ClN ₂ O ₆ mole weight 422.86):

C,% Η,% N,%

Calculated: 56.80 5.48 6.63

Found 56.74 5.38 6.40

IR spectrum (KBr): 1742 cm < ¹ >(> C = O)

1670 ^cm-1 (> C = N) 'H NMR (CDC1 ₃ + DMSO-d, 2: 1):

1.08 (3H, t, J = 7.2 Hz, C16 CH2 _CH3);

2.68 (1H, dd, J _gem = -14.6, J _v i _c = 7.0 Hz, C15-H),

3.18 (1H, dd, J _vic = 1.6 Hz, C15-H),

3.57 (2H, m, C 6 -H ₂ ),

3.85 (3H, s, -COOCH3),

5.30 1H, dd, C14-H),

7.2-7.8 (4H, m, aromatic H) ppm.

¹³ C NMR (DMSO-d 6 + CDCl ₃ 3: 1):

8.43 (Cló-CH ^CH CH),

30.36 (C6),

25.02 (Clo-CHr-CH3),

33.46 (Cl7),

35.51 (C15),

Example 8

14,15-Dihydro-14β-methoxycarbonyl-D-nor-cburnamenine (3 µ, 14 µ, 16a)

a) 2.0 g (4.73 mmol) of 14,15-dihydro-3,4-dehydro-14-methoxycarbonyl-D-nor-eburnamenine (14 / 16,16a) perclate was dissolved in a mixture of 14 ml of glacial acetic acid and 14 ml of water. . Add 5 g of zinc powder and reflux for 1 hour. The zinc powder is then filtered off and washed with 30 ml of water. The filtrate was basified to pH 10 with ammonium hydroxide. It is extracted three times with 30 ml of dichloromethane each time, the combined organic phases are dried over anhydrous magnesium sulfate and then evaporated to dryness. The residue was recrystallized from methanol.

Yield: 1.02 g (66.5%).

Melting point: 86-88 ° C.

b) In the same manner as in Example 6 b), except for 10% palladium on charcoal, 1.0 g of palladium catalyst precipitated on calcium carbonate was used. 0.94 g (61.1%) is obtained. Melting point: 87-88 ° C.

The product has the same physical characteristics as the product obtained in (a).

Claims (4)

Patent claims A process of the formula la and / or lb and / or 1c 14.15-Dihydro-D-nor-eburnamycnine derivatives wherein R ₂ is methoxycarbonyl or cyano; a) reacting a 1-ethylindolo [3,2-g] indolizine derivative of formula IIa with an acrylic acid derivative of formula III in which Y is chlorine or bromine and R ₂ is as defined herein, then hydrogenating the reaction product with sodium borohydride to give case, the resulting mixture! separated; b) for the preparation of the 14,15-dihydro-D-nor-ebumenamine derivatives of formula la ', wherein R ₂ is methoxycarbonyl, which is a narrower group of compounds of formula Ia, a 1-ethyl indolo of formula IIa [3,2 g] indolizine derivative of III 'acrylic acid derivative of formula - wherein Y is bromo, R ₂ is methoxycarbonyl and - reacting the resulting formula Id 14.15-Dihydro-3,4-dehydro-D-nor-eburnamenine derivative7 -7I84 576 zck, wherein R ₂ and X 'are perchlorate anions, are hydrogenated with sodium borohydride or in the presence of palladium catalyst. (Priority: July 20, 1981) 2. A process for the preparation of 4,15-dihydro-D-nor-eburnamenine derivatives of the formulas Ia and / or 1b and / or Ic wherein R ₂ is (C 1 -C 4) alkoxy-carbonyl or cyano. . that a) optionally liberated from an acid addition salt of formula IIb, where X 'is an acid residue anion, with a 1-ethylindolo [3,2-g] indolizine derivative of formula III with an acrylic acid derivative of formula III wherein Y is halogen, R ₂ the reaction product is hydrogenated by chemical reduction and if necessary the resulting mixture is separated; b) a 14,15-dihydro-D-nor-cburnamenine derivative of formula la ', wherein R ₂ is (C 1-4 alkoxy) carbonyl, which is a narrower group of compounds of formula Ia, in which one of the general formula IIb is optionally used; the acid addition salt of formula (II) wherein X is a 1-ethyl-irsdolo [3,2-g] indolysine derivative of formula 11a liberated above in situ with an acrylic acid derivative of formula IIP wherein Y is as defined above and R ₂ is (1-). C4 alkoxy) carbonyl to give Id The 14,15-dihydro-3,4-dehydro-D-nor-eburnamenine derivative wherein R 1 and X 'are as defined above is hydrogenated by catalytic hydrogenation or chemical reduction. (Priority: 7/19/1982) 3. A process according to claim 2, wherein the hydrogenation is carried out in the presence of sodium borohydride. (Priority: July 19, 1982) Process for process b) according to claim 2, characterized in that the hydrogenation is carried out in the presence of palladium catalyst or sodium borohydride.