DE2934342A1 - METHOD FOR PRODUCING + VINCADIFFORMIN AND RELATED DERIVATIVES AND INTERMEDIATE COMPOUNDS - Google Patents

Description

The invention relates to a synthetic process for the production of + _ vincadifformin and related polycyclic derivatives, which are suitable as starting material for the synthesis of, inter alia, alkaloid vincamine and similar compounds with interesting psychopharmacological properties, as well as new 1, 2,3,4,5,6 -hexahydroazepino- \ _A , 5bJ-indole derivatives, which are suitable as intermediate compounds.

The compounds prepared by means of the process according to the invention are of the general formula I.

Ia R ₁ = R ₂ = R ₅ = HR ₃ = CH ₂ -CH ₃ A = -

R ₄ = CH ₃

Ib R ₁ = H-OCH ₃ R ₂ = HR ₃ = CH ₂ -CH ₃ R ₄ = CH ₃ R ₅ = H

A = Ic R ₁ = R ₂ = R ₅ = HR ₃ = CH ₂ -CH ₃ ^R 4 ^{= CH} 3

Id R ₁ = R ₂ = R ₅ = HR ₃ = CH ₂ -CH ₃

A = -CH ₂ -CH (OH) -CH ₂ -NA- = N-CH (CH ₂ OH) -

₁ = R ₂ = R ₅ = HR ₃ = HR ₄ = CH ₃ A = -CH ₂ CH (CH ₂ -CH ₃ ) -CH ₂ -

Ie R ₁ = R ₂ = R ₅ = HR ₃ = HR ₄₃

If R ₁ = R ₂ = R ₅ = HR ₄ = CH ₃ A = -CH ₂ -COH (CH ₂ -CH ₃ ) -CH ₂ - Ig R ₁ = IO-Cl R ₂ = R ₅ = HR ₃ = CH ₂ -CH ₃ R ₄ = CH ₃

A = - (CH ₂ ) ₃ -Ih R ₁ = IO-Br R ₂ = R ₅ = HR ₃ = CH ₂ -CH ₃ R ₄ = CH ₃

030011/07 * 1

Ii R ₁ = IO-OCH ₃ R ₂ = R ₅ = HR ₃ = CH ₂ -CH ₃ ^R 4 ^{= CH} 3

In the above general formula, R ₁ and R _{3 are the} same or different and are selected from the group consisting of hydrogen, hydroxy, acyloxy, carbamate, halogen, lower alkoxy or alkyl, and R ₃ , R and R ₅ are lower alkyl or Hydrogen or a combination of such radicals. A represents a saturated or unsaturated alkyl chain which contains from 1 to 7 carbon atoms and can be substituted by one or more alkyl, hydroxy or hydroxyalkyl radicals.

As used herein, the term "lower alkyl" includes branched ones or straight chain saturated hydrocarbon radicals containing from 1 to 7 carbon atoms.

Examples of according to the method according to the invention Compounds prepared are given in the above formulas Ia to Ii.

Vincadifformin and its derivatives are numbered according to Le Men and Taylor, Experientia, 1965, 21 , 508.

Vincadifformin of the formula Ia is an alkaloid which forms the starting material for the preparation of the vincamine group alkaloids, which is described in Belgian patents 772 005 and 848 475.

Vincamine and some of its derivatives are high and low potency in human therapy as psychotropic drugs Toxicity order known alkaloids.

030011/0745

It was also shown that the rearrangement of vincadifformin to vincamine to a large number of other, similar derivatives can be applied to the vincamine related compounds (see FR patent applications No. 76 22335, 76 22275, BE-PS 816 692 and Ü.S. patent application S.N. 968 147, filing date December 11, 1978, Applicant J. Hannart).

For example, 1O-bromo-vincamin and 1O-bromo-vincamon Compounds superior to vincamine in the experiment of hypoxic anoxia in mice. These connections can be easily made the corresponding 1O-bromo-vincadifformin obtained.

Two total synthetic methods for vinca difformin are already in place has been described in the literature by J. Kutney et al., J. Amer. Chem. Soc., j ^ 0_, 3891, 1968 and J.V. Laronze et al., Tetrahedron Letters, 491, 1974.

11-methoxyvincadifformin (Ervincein) of Formula Ib is a Alkaloid occurring in Vinca Erecta and has been described by D.A.Rakhimov, V.M. Malikov, M.R. Yagudaev and S.N. Yunusov (Khim, prir. Soedin, 226, 1970).

Alkylation of ervincein yields the corresponding N (CX) -methyl derivative. An enantiomer of this compound, which is obtained by the degradation of vindoline, has recently been converted back to vindoline, the indoline semisheet of the "dimeric" oncolytic alkaloid vincaleukoblastin (JPKutney et al., J.Amer.Chem.Soc, 100 , 4220 (1978).

Pseudo-vincadifformin of formula Ie is an alkaloid occurring in various Apocynacea, which is produced by semi-synthesis (J.P. Kutnex, E. Piers and R.T. Brown, J. Amer. Chem. Soc., 92, 1700, 1970).

Pandolin of the formula If can be obtained from certain plants of the genus Pandaca (M.Zeches, M.M.Debray, G.Ledouble,

030011/07 * 5

L. Lemen-Olivier and J. Le Men, Phytochemistry, J_4, 1122, 1975) No overall synthesis of this rare alkaloid has been reported to date.

Various 1, 2,3,4,5,6-hexahydroazepino- [_A, 5bJ -indoles have been reported in the literature (Dutch patent application 65 15701, FR-PS 1 524 830 by JBHester et al. (J. Med. Chem. 11, 101, 1968)).

Some of these derivatives have interesting pharmacological properties, particularly on the central nervous system.

The object of the invention is to provide a process for the production of vincamine and related polycyclic compounds in high To create a yield in which the number of intermediate steps is reduced and inexpensive reagents are used can.

The invention differs in particular by the fact that in a first process step a tetrahydro- / 3-carboline (II) when processing with benzoyl chloride a 2-benzoyl-1, 2,3 ^ -tetrahydro-gH-pyrido- £ 3,4bJ -indole (III) supplies.

Γ 1 B J,

II a b

III a b

IV a b

R - t \ * y - R - H

R ₁ = H-OCH ₃

R ₁ = R ₂ = R = HR ₁ = 11-OCH ₃ R- ⁼ i \ * j ⁼ R ⁼ ii

R ₁ = H-OCH ₃

R ₂ = R = H

R = C

R = CO ^

R ₂ = H

R = CH ₂ I

R ₂ = HR =

030011/0745

In these formulas, R ₁ and R have the meaning given above and <| represents a phenyl radical.

In a second process step, the reduction of the compound III by means of a reducing agent such as e.g. Lithium aluminum hydride (LAH) in tetrahydrofuran (THF) the corresponding 2-benzyl-1,2,3,4-tetrahydro-9H-pyrido- [3,4b1 indole (IV).

Other protecting groups such as a p-halobenzyl or benzhydryl group can be used to protect the nβ> of the β- carboline (II).

In a third process step, the derivative IV is through Exposure to tertiobutyl hypochlorite or a similar chlorinating agent converted to a chlorine indolenine (V), that immediately with a dialkylthallium or sodium malonate or an analogous compound, preferably t-butylmethylthallium malonate, is treated.

NCH ₇ §

(V)

A 3-benzyl-1,2,3,4,5,6-hexahydroazepino- £ 4,5b7 indole-5,5-diialkylcarboxylate) derivative of the formula VI.

CO ₂ R ₄

CO ₂ R ₄ '

030011/07 * 5

(VI)

R ₁ = R ₂ = H;

R ₁ = R ₂ = HR ₁ = H; R ₁ = H; R ₁ = H;

R ₅ = H

Via - VIf

being in these formulas

R ₄ = CH ₃ ; R ₂ = H;

R ₄ ¹ = t-butyl, R ₄ = R ₄ ^{I = CH} 3

. = R. '= CH, 4 4 j

R ₂ = 9-OCH ₃ ; R ₄ = R ₄ ^{I = CH} 3

R ₂ = 9-Cl; R ₂ = 9-Br;

R ^ = R. '= CH ^ 4 4 3

R. = R. ^I = CH, 4 4 3

c = Hf and R ₁ , R ₂ and R, which have the meanings given above. R ^ ¹ is a lower alkyl group, typically methyl, ethyl or t-butyl.

Any solvent which is inert under the reaction conditions can be used for this condensation. Benzene and toluene are particularly useful and suitable for this purpose. The compound VI can also be obtained starting from the corresponding / "- carboline V ¹ , as is described in US patent application SN 936 454, filing date August 24, 1978.

The compound V is chlorinated with the dialkyl sodium thallium or analogous malonate and condensed, the same Process steps as based on the compound V are applied.

NO

(V)

The starting material V can, for example, advantageously from N-benzylpiperidone, an inexpensive compound of

030011/0745

formula

be prepared by through this an N-Benzylpiperidonphenylhydrazone the general formula

^R 1

NH - N = i
^R 2

Λ-J

is passed through.

(Rs-H)

Optionally, the compound VI can be prepared using known alkylation processes for indole derivatives N are alkylated (J.Med.Chemistry, 11/101, 1968) to obtain compound VI, in which Rc is lower alkyl.

In a fourth process step the derivative VI becomes partial to an alkyl-3-benzyl-1,2,3,4,5,6-hexahydroazepino-L4,5bJ -indole-5-carboxylate (VII) decarboxylated.

For example, in the case of a t-butyl methyl dicarboxylate this conversion is best achieved by means of trifluoroacetic anhydride or trifluoroacetic acid. In the case of the corresponding dimethyl derivative takes place monodecarbomethoxylation by lithium chloride in dimethylformamide.

In a fifth process step, the derivative VII is hydrogenated in the presence of a catalyst, typically 5% Pd on charcoal, in order to precipitate the protective benzyl group, an alkyl-1,2,3,4,5,6-hexahydroazepino- f4,5bj - indole-5-carboxylate derivative of the general formula VII is obtained in which R _{5 is} hydrogen.

030011/0745

NO

VII R ₁ = R Vila R ₁ = S VIIb R ₁ = H VIIc R ₁ = H VIId R ₁ = H VIIf. R = H VIII R ₁ = R villa R ₁ = S VIIIb R ₁ = H VIIIc R ₁ = H VIIId R ₁ = H VIIIf

R ₅ = H
R ₄ = CH ₃

R ₂ = 9-OCH ₃

R ₂ = 9-C1

R ₂ = 9-Br

R ₅ = H
R ₄ = CH ₃

R ₂ = H

R ₂ = 9-OCH ₃
R ₂ = 9-C1
R ₂ = 9-Br

R ₄ = CH ₃ R ₄ = CH ₃ R ₄ = CH ₃ R ₄ = CH ₃

R ₄ = CH ₃ R ₄ = CH ₃ R ₄ = CH ₃ R ₄ = CH ₃

According to a modified procedure, the product VI can be hydrogenated in the presence of 5% Pd / C to give a dialkyl 1,2,3,4,5,6-hexahydroazepino- | _4,5bJ -indole-SjS-dicarboxylate (VI ¹⁾ .

030011/0745

Vl'a
R ₁ = R ₂ = R ₅ = H

NO.

(VI ¹ )

R ₄ ¹ OOC

This compound is then partially decarbalkoxylated to compound VIII and further processed in the manner described below or by means of the method described in the aforementioned U.S. Patent application S.N. 936 454 Process converted into the vincadifformin derivatives I.

The intermediates VT, VI ¹ , VII and VIII represent a new class of azepinoindoles. The azepinoindoles substituted by one or two carboalkoxy groups in position -5 are in fact novel intermediates which are very useful for the synthesis of new indole alkaloids.

In a sixth process step, the derivative VIII is functionalized with a Aldehyde IX condenses, vincadifformin or related derivatives of the formula (I) being obtained.

Functionalized aldehyde is understood to mean an aldehyde for which a corresponding tertiary enamine derivative to an enammonium salt intramolecularly May be N-alkylated.

Typically such compounds are hydrogen, aryl or alkylsulfoxy or epoxy aldehydes having 3 to 14 carbon atoms.

Examples of such aldehydes are the compounds IXa, IXb, IXc, IXd and IXe.

Aldehydes which are further substituted by a hydroxyl group can be used in the equivalent semi-acetalized form can be used for IXf.

IXa

IXb

030011/0745

IXc

MesO

MesO = mesyloxy

IXe

IXd

IXf

In the case of the reaction of a haloaldehyde with the azepinoindole VIII the cyclic enammonium intermediate compound of the general formula X is obtained.

CO ₂ R ₄

In some cases, a catalytic amount of an organic base such as triethylamine can advantageously be added to the reaction mixture.

In the condensation (VIII + aldehyde through compound X) has proven to be advantageous, a solvent such as

030011/0745

use dry methanol. However, other solvents which are inert under the reaction conditions can also be used such as use dry benzene.

The reaction temperature can be from -20 ^° C. to the boiling point of the reaction medium. Preferred working temperatures are from 20 ^° C. up to 80 ^° C.

5-Bromo-2-ethylpentanal (IXa), which in the last process step the vincadifformin synthesis can be used, can by means of the novel, practical and very expedient procedure described below.

Methyl or ethyl 4-formyl hexanoate becomes methyl 4-dimethoxymethyl hexanoate or ethyl 4-diethoxymethyl hexanoate is acetalized by means of lithium aluminum hydride to each 4-dimethoxymethyl-1-hexanol or 4-diethoxy-methyl-1-hexanol is reduced.

The alcohol obtained in this way is dehydroxybrominated, where in each case 1-bromo-4-dimethoxymethyl-hexane and 1-bromo-4-diethoxymethyl-hexane is obtained which hydrolyzes to the desired 1-bromo-4-formylhexane or 5-bromo-2-ethylpentanal will.

Another method for the preparation of 5-bromo-2-ethylpentanal is described by W.Oppolzer, H.Hauth, P.PfäffIi, R. Wenger, HeIv., J> £, 1861 (1977).

In the case of the Pandolin and epi-Pandolin synthesis, this becomes adequate functionalized aldehyde IXd was obtained by means of the reaction sequence of Scheme I below, as detailed is described in the examples.

030011/07 * 5

.A

_{oc / J}

OH ₀

^0CH

3 y OSO ₂ CH ₃

(XII ')

CXIII) OCII ₃

I ο

Se

OCH ₃

(XIV) (XV)

CHO

(IXd)

030011/07 * 5

Scheme I.

Procedures for preparing the other functionalized aldehydes are described in the examples.

In the examples below are the features of the invention Method explained in more detail, it should be noted that the method does not the examples described here are limited.

example 1

2-Benzoyl-1, 2, 3 ^ -tetrahydro-gH-pyrido-p, 4bJ-indole (HIa)

Tetrahydro- β- carboline (Ha) (3 g, 17.44 mmol) was suspended in dry benzene (50 ml) and pyridine (20 ml). Benzoyl chloride (3 ml, 25.8 mmol) was added dropwise with stirring at room temperature. After the addition was complete, the mixture was ^{heated to 70 °} C. for one and a half hours.

The hot mixture was then poured into 200 ml of water, separating layers. The water layer was washed with benzene (2 × 50 ml), and the combined organic phases were washed with water (2 × 25 ml), 1 η HCl (2 × 20 ml), water (20 ml) and (saturated) sodium bicarbonate (2 χ 20 ml) .

The solvent was evaporated and the residual brown oil dissolved in 10 ml of benzene. Under cockroaches to induce

Crystallization was slowly added to hexane (60 ml). It

pure benzoylated amine (4.57g, 95%) was obtained. By

Recrystallization from aqueous ethanol gave white needles

obtain.

FP 156 to 157 ⁰ C

IR (CHCl ₃ ): 3470, 3060, 3020, 2925, 2860, 1625, 1620, 1575, 1490,

1460, 1435, 1305, 1205, 1150, 1045, 1025, 980 cm " ¹ NMR (CDCl ₃ ) S 2.80 (bs, 2H); 3.65 (bs, 2H); 4.80 (bs, 2H) ;

7.0-7.30 (m, 9H); 8.75 (bs, 1H)

Mass spectrum: (80 eV) m / e (relative intensity) 276 (M ⁺ , 8),

262 (16), 168 (15), 143 (100), 105 (15), 91 (21), 77 (16), 44 (44), 40 (71)

030011/0745

C. 78 , 24; H 5 .84; N 10 , 14 C. 78 , 24; H 5 .92; N 10 , 18

Analysis calculated for

found

Example 2

2-Benzyl-1,2,3 ^ -tetrahydro-gH-pyrido-f3,4bJ -indole (IVa)

A solution of lithium aluminum hydride (1 g, 26.3 nmol) in 100 ml of dry tetrahydrofuran was added at room temperature a solution of N-Benzoyltetrahydro - ^ - carboline (purple) (4.5 g, 16.3 mmol) in 100 ml of dry THF was added over a period of minutes.

The stirred solution was refluxed for 10 hours and then cooled to room temperature.

Water (1 ml) was added dropwise, followed by a 15% aqueous NaOH (1 ml) and water (3 ml) with vigorous stirring of the solution for 30 minutes.

The granular precipitate was filtered off and washed several times with ether. The filtrate and the washout were dried over sodium sulfate.

Filtration and evaporation of the solvent gave a white solid (4.26 g, 99.5%). FP: 140 - 141 ⁰ C (Lit .: FP 142 ⁰ C, see

a) M.Onda and M.Samamoto, Pharm.Bull (Tokyo), 5, 305 (1957)

b) M. Protiva, ZJVedjdelek, JOJilek and K.Macek, Coll. Czech. Chem. Comm., 2-4, 3978 (1959).

NMR. (CDCl ₃ ) S 2.80 (bs, 4H); 3.45 (s, 2H); 3.65 (s, 2H);

6.92-7.40 (m, 9H); 7.48 (br.s, 1H). Mass spectrum (80 eV) m / e (rel.intensity) 262 (M ⁺ , 19)

261 (5), 144 (24), 143 (100), 142 (4), 91 (19),

40 (21).

030011/07 * 5

Example 3

t-Butylmethyl-3-benzyl-i, 2,3,4,5,6-hexahydroazepino-L4, 5bJ-indole-5,5-carboxylate (VIa)

The chloroindolenine (Va) was prepared in the manner that the N-benzyl amine (IVa) (3.522 g, 13.44 itiMol) dissolved in 100 ml of dry benzene and the whole was cooled to 5 ⁰ C.

The cold, stirred solution was dry triethylamine (1.16 g, 10 mmol, 1.6 ml), and then t-butyl hypochlorite dropwise (1.458 g, 13.44 mmol, 1.6 ml) added.

The reaction mixture was kept in an ice bath for one and a half hours and then poured into water (20 ml) ^{at 0 ° C.}

The benzene layer was separated and dried over sodium sulfate. The solution was filtered and its volume reduced to half by evaporation in vacuo. It got dry Benzene added up to a total volume of approx. 100 ml. Thallium t-butylmethylmalonate (5.28g, 14mmol) was then added and refluxing the stirred solution for 36 hours. The reaction mixture was then cooled to room temperature and filtered through fiberglass paper. The solvent was separated off and the residue was adsorbed onto silica gel (20 g, Woelm Act III for dry column chromatography). The adsorbed Material was attached to the top of the column (15.2 χ 3.8 cm) of the dry column silica gel and washed out with dichloromethane.

The first 20 ml was thrown away, and that in the next 150 ml of contained product (3.69 g, 63.3%) was removed from aqueous Recrystallized methanol.

FP: 118-120 ⁰ C.

IR (CHCl ₃ ): 3460, 3440, 3080, 3050, 3020, 2995, 2975, 2940,

2820, 1730, 1610, 1445, 1365, 1250, 1150, 1025,

840, 695 cm " ¹
NMR (CDCl ₃ ) S 1.44 (s, 9H); 2.82 (br.s, 4H); 3.60 (s, 2H);

3.66 (s. 3H); 3.76 (s, 2H); 6.84-7.4 (m, 9H); 8.36 (brs, 1H).

03001 1/0745

Mass spectrum (80 eV) m / e (relative intensity) 434 (7), 334 (30), 216 (57), 156 (57), 91 (68), 59 (78), 56 (76), 44 (81), 41 (78), 40 (100).

Analysis calculated for C-cHoqN-O.

C. 71 .86; H 6th , 96; N 6th , 45 C. 71 , 97; H 7th , 03; N 6th , 16.

found

In like manner, the corresponding diethyl and Dimethylazepinoindolderivate (FP respectively 145 ⁰ C and 166-168 ⁰ C) obtained by Kondesation of diethyl or Dimethylthalliummalonats with benzylamine (V).

Example 4

Methyl 3-benzyl-1, 2,3,4,5,6-hexahydroazepino-Γ4, 5bI-indole-5-carboxylate (VIIa)

a) From t-butyl methyl diester (VIa):

The t-butyl methyl ester (VIa) (1.890 g, 4.35 mmol) was in 80 ml of 1,2-dichloroethane dissolved and the system with nitrogen flushed through. Anhydrous trifluoroacetic acid (1.6 ml) was added added by means of a lifter through a rubber heather. The solution was stirred under reflux for 3.5 hours. The hot reaction mixture was poured into 100 ml of cold (saturated), Poured out aqueous sodium carbonate. The layers were separated and the aqueous phase extracted with 50 ml dichloroethane. The combined organic phases were washed with (saturated) sodium carbonate solution and filtered through phase separation paper separated on anhydrous potassium carbonate. Filtration and evaporation of the solvent turned brown obtained oil which was triturated with ethyl acetate heptane, whereby crystallization was initiated.

The off-white solid was collected in two amounts, yielding 1.219 g (84%) of the desired decarboxylated amine of the formula VII were obtained. These compounds were recrystallized twice from aqueous ethanol for analysis.

030011/0745

FP: 135 to 135.5 ⁰ C.

IR (CHCl ₃ ): 3480, 3075, 3045, 2940, 2840, 1740, 1600, 1500, 1460, 1435, 1350, 1275, 1230, 1220, 1200, 1163, 1026 cm " ¹

NMR (CDCl ₃ ) 8 2.94 (bs, 4 H); 3.24 (m. 2H); 3.76 (s, 3H); 3.88 (s, 2H); 4.16 (m. 1H); 6.97-7.7 (m, 9H); 8.68 (br.s, 1H).
Mass spectrum (80 eV) m / e (relative intensity) 334 (M ⁺ , 37),

216 (100), 156 (61), 91 (49), 42 (32) analysis calculated for C ₃₁ H ₂₂ N ₃ O ₂

C 75.42; H 6.63; N 8.38 Found C 75.63; H 6.90; N 8.41

b) From the dimethyl diester (VIc):

Diester VIc (9.3 g, 24 mmol), lithium chloride (1.3 g, 30 mmol) and water (620 mg, 34 mmol) were dissolved in anhydrous trimethylformamide (20 ml) under nitrogen and the stirred solution was left for 1 hour used for a long time in a preheated oil bath (160 165 ⁰ C). The solution immediately became cloudy and developed CO 2. After cooling, the reaction mixture was poured into water (400 ml) with vigorous stirring. The gummy solid that formed was collected by filtering through glass wool, dissolved in methylene chloride and dried (MgSO ₄ ). After concentrating the solution, the product was purified by column chromatography on silica gel, washing out with methylene chloride. A solid was obtained which was recrystallized from hexane to give compound VIIa, which was identical to the compound shown above (6.6 g, 83%).

Example 5

Methyl-1-birfcy ^ lj ^ ij ^ 3,4,5,6-hexahydroazepino-L4,5bJ-yn5ol- 5,5- dicarboxylate (VI '; R ₁ = R = - H; R. = CH _Q ; R ₄ ¹ = t-butyl)

A solution of N-Benzylamine (VIa) (202 mg, 0.465 mmol) in dry acetic acid (7.5 mmol) was added under hydrogen and

030011/0745

under a pressure of 1 bar with 5% Pd / C catalyst (22 mg) Hydrogenated for an hour and a half.

The catalyst was filtered off and washed with hot methanol.

The solvent was removed from the filtrate by evaporation, leaving a slightly yellowish oil which was dissolved in dichloromethane (50 ml). The solution was ^{cooled to 0 °} C., then 10% strength aqueous NaOH (25 ml) was added, and the solution was stirred vigorously for 10 minutes.

The organic phase was separated and dried over anhydrous potassium carbonate. It was then filtered off and the solvent evaporated to give a slightly yellowish oil which withstood any attempt at crystallization but consisted of the desired pure debenzylated diesteramine (155 mg, 97%).
IR (CHCl ₃ ): 3445, 3435, 3035, 2975, 2915, 1730, 1615, 1455,

1430, 1365, 1250, 1140, 1020, 840, 800 cm ^-1 NMR (CDCl ₃ ) <f 1.48 (s, 9H); 2.24 (s. 1H); 2.96 (m, 2H);

3.16 (m. 2H); 3.72 (m, 2H); 3.78 (m, 3H);

7.04-7.60 (m, 4H), 8.88 (bs, 1H). Mass spectrum (80 eV) m / e (relative intensity) 344 (M ⁺ , 100%),

245 (82), 229 (56), 216 (96), 215 (87),

203 (87), 171 (67), 155 (74).

Example 6

Methyl 1,2,3,4,5,6-hexahydroazepino-L4,5bJ-indole-5-carboxylate (Villa)

The monoester benzylamine (VIIa) from Example 4 (915 mg, 274 mmol) was dissolved in 50 ml of glacial acetic acid and it became 100 mg 5% Pd / C catalyst added. The mixture was hydrogenated under a pressure of 1 bar for 18 hours and then filtered through fiberglass paper.

03001 1/074 5

The catalyst was washed with 50 ml of hot methanol and the pooled filtrates were evaporated, leaving a oily residue remained. The residue was dissolved in 75 ml of chloroform, followed by 100 ml of saturated aqueous Sodium carbonate was added. The two-phase system was washed vigorously for 15 minutes and the layers separated separated. The aqueous phase was washed with chloroform and the pooled chloroform phases were washed with brine washed, after which they were separated by phase separation paper on anhydrous potassium carbonate. The material was filtered, and the solvent evaporated leaving a thick, oily residue which was triturated with ethyl acetate heptane was solidified. The material was filtered yielding 532 mg (80%) of the debenzylated amine sought (Villa) became.

The mother liquor was chromatographed on silica gel with dichloromethane as the eluent, a further 87 mg of the substance being sought and the overall yield increasing to 93%. The substance can be recrystallized from ethyl acetate heptane.
FP: 138-139 ⁰ C
IR (CHCl ₃ ): 3465, 2950, 2925, 1735, 1630, 1460, 1435, 1220,

1160, 1015 cm " ¹

NMR (CDCl ₃ ) <f 2.20 (bs, 4H); 8.48 (br.s, 1H); Mass spectrum (80 eV) m / e (relative intensity) 244 (M ⁺ , 58),

215 (29), 202 (100), 170 (31), 156 (26),

142 (35), 43 (80), 42 (30).

Example 7

Dimethyl-3-benzyl-1,2,3,4,5,6-hexahydroazepino-r4, 5bJ-indole - 5,5b -dicarboxylate (VIc)

A solution of 0.25 g (0.96 mmol) of N-benzyl-tetrahydro - /? - carboline (IVa) and 110 μΐ of triethylamine in 7 ml of dry benzene, which was stirred under nitrogen at 5 ⁰ C, was added drop by drop

03001 1/0745

wise 110 μl tert-butyl hypochlorite (0.9 54 mmol) added. The mixture was stirred for one and a half hours at 5 ⁰ C, and then poured into a separatory funnel in 3 ml cold water. After shaking gently, the layers were allowed to separate, discarding the water layer. The benzene layer was filtered by filtering through a sodium sulfate cone in phase separation paper. The separatory funnel and filter cone were washed with dry benzene and the benzene filtrate evaporated to 3 ml in vacuo. The volume was brought to 7 ml by the addition of dry benzene, 0.335 g (1 mmol) of thallium dimethylmalonate was added and the vigorously stirred solution was refluxed under nitrogen for 23 hours. The reaction mixture was then cooled to room temperature and filtered through fiberglass paper, after which the benzene was evaporated in vacuo. The residue was taken up in dichloromethane and applied to a silica column (1.5 cm × 30 cm). Wash out with dichloromethane provided 0.205 g (55%) of a light colored product. White crystals of compound VIc were obtained by recrystallization from methanol.
FP and mF.P. 166 - 168 ⁰ C.
NMR (CDCl ₃ , S ): 2.97 (s, 4H); 3.8 (s, 2H); 3.88 (s, 6H);

3.93 (s, 2H); 7.24-7.8 (m, 9H); 8.64 (bs, 1H) IR (KBr, V ): 3510, 3010, 3000, 2950, 2940, 2920, 2880,

ΪΏ3.Χ

2825, 1750, 1705, 1490, 1450, 1440, 1435,

1345, 1320, 1285, 1275, 1255, 1240, 1220 (wide),

1185, 1165, 1145, 1135, 1125, 1110, 1090,

1075, 1055, 1035, 980, 960, 935, 700, 690,

670, 635 cm " ¹

IR (CHCl ,, ^): 3440, 3000, 1725, 1455, 1425, 1210 (broad),

1045, 1025, 975 cm "

Mass spectrum (m / e) 392 (M ⁺ )

030011/0745

- 31 -

Example 8

Diethyl-1,2,3,4 / 5,6-hexahydroazepino-f4,5bJ-indole-5,5-dicarboxylate (vi'a )

To 1.6 g (4.08 mmol) of diesterbenzylamine (VIc) dissolved in 50 ml of acetic acid, 0.2 g of 5% palladium catalyst on charcoal was added. In the case of hydrogenation under atmospheric pressure with vigorous stirring, the hydrogen uptake ceased after 3 hours. The solution was filtered through fiberglass paper and the bottle and filter washed with dichloromethane. The dichloromethane was removed under vacuum from a water pump, and the acetic acid was distilled off by means of a vacuum pump with a dry ice / acetone trap. The residue was taken up in dichloromethane, washed with 10% aqueous sodium carbonate and dried over potassium carbonate, then filtered and concentrated in vacuo to a white powder (Compound VI'a, 1.231 g-100%).
NMR (CDCl ₃ , ^): 2.4 (bs, 1H); 2.9 (t, 2H); 3.1 (t, 2H);

3.66 (s, 2H); 3.72 (s, 6H); 6.9-7.5 (m, 4H);

8.66 (brs, 1H).
Mass spectrum (m / e) 302 M.

Example 9

Dimethyl-3-benzyl-9-methoxy-1,2,3,4,5,6-hexahydroazepino La, 5b] indole-5,6-dicarboxylate (VId)

According to the process transition for illustrating the Indolazepins VIc was the 9-Methoxyisomer VId, FP 128-130 ⁰ C shown in a yield of 65%.
NMR (CDCl ₃ ) S : 8.34 (br s, 1H); 7.29 (m, 6H); 6.90 (m. 2H);

3.81 (S ₇ 3H); 3.76 (s, 6H); 3.67 (s, 2H);

2.87 (s, 4H)
IR (KBr) U " _v : 3400, 2960, 2840, 1749, 1722, 1480, 1465, 1450,

1430, 1250, 1220, 1140, 1030, 835, 740, 700 era "

Analysis calculated for Co4 * ⁱ 26 ^N 2 ⁱ "^> 5 ^:

C 68.23 H 6.20 N 6.63
found C 68.20 H 6.24 N 6.50

030011/0745

Example 10

Dimethyl-3-benzyl-9-chloro-1,2,3,4,5,6-hexahydroazepino LA , 5bJ-indole-5,5-dicarboxylate (VIe)

According to the process for the production of indolazepine VIc became the 9-chloro compound VIe, F.P. 111-113 shown in 60% yield.

NMR (CDCl ₃ ) S : 8.49 (s, 1H); 7.22 (m, 8H); 3.78 (s, 2H);

3.74 (s, 6H); 3.65 (s, 2H); 2.84 (s, 4H);

IR (KBr) J ^ _ax : 3404, 2960, 2920, 2890, 2840, 1725, 1455,

1430, 1320, 1260, 1250, 1230, 1130, 1050, 880, 803, 802, 740, 735, 695 cm " ¹

UV (ethanol) λ _max 239, 295 ran.

Analysis calculated for C ₂₃ H ₂₃ N ₂ O ₄ Cl:

C 64.71 H 5.43 N 6.56 Cl 8.31 found C 64.76 H 5.53 N 6.54 Cl 8.55

Example 11

Dimethy1-3-benzy1-9-bromo-1,2,3,4,5,6-hexahydroazepine-f4, 5bJ-indole-5,5-dicarboxylate (VIf)

According to the method for producing the transition Indolazepins VIc the 9-bromo compound VIf, FP has been illustrated 116-118 ⁰ C in 55% yield.
NMR (CDCl ₃ ) S : 8.48 (br S, 1H); 7.54 (s. 1H); 7.25 (s, 5H);

7.14 (S, 2H); 3.77 (s, 2H); 3.72 (s, 6H);

3.62 (s, 2H); 2.81 (s, 4H); IR (KBr) V _max '■ 3440, 2950, 2905, 2815, 1745, 1732, 1465,

1435, 1245, 1220, 1140, 1045, 1025, 790,

740, 695 cm " ¹

UV (ethanol) X. _mav 238, 293 nm
Iu ax

Analysis calculated for C ₂₃ H ₂₃ N ₃ O ₄ Br

C 58.60 H 4.92 N 5.94 Br 16.95 .. found C 58.56 H 4.84 N 5.82 Br 17.10

03001 1/0745

Example 12

a) Methy1-4-dimethoxymethy1-hex anoate

A solution containing (70 ml) anhydrous methanol and (3 drops) concentrated sulfuric acid were added (10.2 g, 64.5 mmol) of methyl 4-formylhexanoate was added. The solution was stirred at room temperature for 24 hours and then potassium carbonate in solid form to neutralize the acid added. Most of the solvent was evaporated in vacuo, after which water (100 ml) was added and the Solution was extracted twice with hexane (50 ml) and once more with ether. The organic phases were combined and dried over anhydrous magnesium sulfate.

The solvent was evaporated in vacuo to give the dissolved acetate without aldehyde contamination (12.27 g, 93.2%).

Boiling point: 60 - 70 ⁰ C (Kugelrohr, 0.1 mm) IR (pure): 2950, 2820, 1730, 1430, 1170, 1105, 1070, 960,

885 cm " ¹
NMR (CDCl ₃ ) <?: 0.88 (t, 3 H); 1.24-1.96 (m, 5H); 2.34 (t, 2H);

3.32 (s, 6H); 3.82 (s, 3H); 4.10 (d, 1 H) mass spectrum (80 eV) m / e (relative intensity) 204 (M ⁺ , 1)

203 (6), 173 (100), 141 (99), 109 (73), 99 (90),

75 (97).

b) ethyl 4-diethoxymethyl-hexanoate

The ethyl acetal was recovered from the aldehyde in 84% yield in the same manner as the methyl acetal. The ester group changes under these conditions.

Boiling point: 90 - 100 ⁰ C (spherical tube, 0.1 mm)

NMR (CDCl ₃ ) S'- 0.95 (t, 3 H); 1.23 (t, 6H); 1.33 (t, 3H);

1.25-2.06 (m, 5H); 2.43 (t, 2H); 3.63 (q, 4H);

4.23 (q, 2H); 4.40 (d, 1H)

c) 4-dimethoxymethyl-1-hexanol

The methyl acetal ester (9.8 g, 48 mmol) as the end product of both

030011 / 07A5

game 7a was dissolved in tetrahydrofuran, and dissolved at 0 ⁰ C a solution of ether was added dropwise lithium aluminum hydride (LAH, 50 ml of a 1 M solution) was added (THF 20 ml). After the addition was complete (after about 30 minutes) the reaction mixture was allowed to warm to room temperature while slowly adding water (1 ml). Sufficient 20% aqueous KOH was added to dissolve the solid and the solution extracted five times with ether (25 ml). The ether extracts were washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvent gave the sought alcohol (7.86 g, 93%) as a clear, colorless liquid.
IR (pure): 3400, 2940, 2830, 1460, 1380, 1190, 1110, 1060,

960 cm " ¹

NMR (CDCl ₃ ) £ 0.9 (t, 3 H); 1.4 (m, 7H); 2.9 (br.s, 1H); 3.2 (s, 6H); 3.42 (t, 2H); 4.15 (d, 1H)

d) 4-diethoxymethyl-1-hexanol

A solution of the ethyl acetal ester end product (9.367 g, 38 mmol) from Example 7b in tetrahydrofuran (40 ml) was added to a lithium aluminum hydride solution in ether (40 ml in a 1 M solution) ^{at a temperature of 0 ° C.} added. The reaction mixture was refluxed for one hour and then allowed to cool to room temperature. Magnesium sulfate heptahydrate (9.86 g, 40 mmol) was added and the reaction mixture stirred vigorously for 12 hours. The solid was filtered off and washed several times with ether. The pooled filtrate and washed solids were washed with 10% aqueous KOH (10 ml) and with brine (10 ml) and dried over anhydrous sodium sulfate. After evaporation of the solvent and Kugelrohr distillation (boiling point of 90-100 ⁰ C, 0.1 mm), the hydroxy-acetal (7.0 g, 90.3%) was obtained. IR (neat): 3400, 2985, 2940, 1880, 1460, 1380, 1115, 1065, 730 cm " ¹

030011/07 * 5

NMR (CDCl ₃ ) & 0.93 (t, 3 H); 1.23 (t, 6H); 1.16-1.83 (m, 7H); 2.16 (br.s, 1H); 3.66 (m, 6H); 4.40 (d, 1H)

e) i-Bromo-4-dimethoxymethylhexane and 1-Bromo-4-formylhexane (IXa)

Carbon tetrabromide (1.824 g, 5.5 mmol) and triphenylphosphine (1.443 g, 5.5 mmol) in ether (15 ml) were refluxed for half an hour and then cooled to room temperature. The 4-dimethoxymethyl-1-hexanol in ether (6 ml) was added dropwise, rapidly decolorizing the yellow slurry and precipitating a buff solid. The mixture was then filtered through Celite and the solvent evaporated in vacuo. The residue was placed under high vacuum (ca. 10 mm Hg column) to remove the excess carbon tetrabromide and the bromoform by-product. The distillation vessel was heated to 50 - 60 ⁰ C is heated and the distillate is collected by means of a dry ice trap. The distillate was the desired bromoacetal (700 mg, 66%) which was contaminated with traces of carbon tetrabromide and bromoform. This compound was used for hydrolysis without further purification.

The hydrolysis of the bromoacetal into the corresponding bromoaldehyde (1-bromo-4-formylhexane) was carried out in such a way that Tetrahydrofuran / 1 η HCl (10: 1) (6 ml) at room temperature 24 Was stirred in for hours (94% yield).

For comparison, the bromoacetal was prepared from the bromo-aldehyde. The bromo-aldehyde (52.4 mg, 0.27 mmol) was dissolved in dry methanol (1 ml) and a crystal of p-toluenesulfonic acid added. The solution was stirred at room temperature for 48 hours and then poured into dichloromethane (15 ml). The solution was washed with saturated aqueous sodium carbonate (5 ml) and over anhydrous sodium sulfate dried. Concentration gave the acetal (60 → 4 mg, 93.2%) as a colorless oil with the properties shown below obtain:

03001 1/0745

IR (neat): 2960, 1460, 1110, 1070 cm ^-1

NMR (CDCl ₃ ) S 0.92 (t, 3 H); 1.20-2.04 (m, 7H); 3.38 (s, 6H);

3.40 (t, 2H); 4.16 (d, 1H)

Mass spectrum (80 eV) m / e (relative intensity) 238, 240 (M ⁺ , 0.01)

207, 209 (38, 37), 75 (100).

f) (±) vincadifformin (Ia) Procedure 1:

The bromoaldehyde-1-bromo-4-formylhexane (194.5 mg, 1 mmol) was dissolved in 6 ml of dry methanol under a nitrogen atmosphere and 123 mg (0.50 mmol) of Amin Villa in 6 ml of methanol was added. The mixture was stirred for one hour at room temperature and then dry triethylamine (0.5 ml) was added and the solution was ^{heated to 40 °} C. for 12 hours. The reaction mixture was then cooled to room temperature and the solvent evaporated. The residue was taken up in CH ₂ Cl ₂ (40 ml) and extracted with (saturated) aqueous sodium carbonate (10 ml). The organic layer was dried over anhydrous potassium carbonate and filtered. The solvent was evaporated and the residue applied to a TLC preparation plate (2 mm, Merck Alumina) and developed with dichloromethane. The band at Rf 0.4-0.6 was washed out to give 71 mg of pure ^ vincadifformin as a white solid. The alkaloid was recrystallized from 95% ethanol.
FP: ^{124-125 0} C (Lit .: 124-125 ⁰ C, see J.Kutney, K.Chan, A.Failli, JMFromson, C.Gletsus and V.Nelson, J.Am.

Chem. Soc, 9j), 3891 (1968)

IR (CHCl ₃ ): 3420, 3360, 2930, 2850, 2775, 1665, 1605, 1470, 1460, 1432, 1290, 1275, 1250, 1235, 1155, 1110, 1045 cm " ¹
NMR (CDCl ₁ ) £ 1.6-3.6 (complex m, 18 H); 3.76 (s, 3H);

(), 74-7.5 (m, 4H), 8.96 (bs, 1H). UV (JTtOJl) nm (log €) 225 (4.12), 297 (3.15), 327 (4.06)

ι ι / rm 5

Mass spectrum (80 eV) m / e (relative intensity) 338 (M ⁺ , 67), 124 (100).

Procedure 2:

The amine Villa (125.8 mg, 0.515 mmol) was dissolved in dry benzene (3 ml) and 1-bromo-4-formylhexane (97.5 mg, 0.505 mmol) was added. The mixture was stirred for 51 hours at 45 ^° C. and then dissolved in ether / dichloromethane (1: 4). The solution was extracted with 1.0 η HCl and the aqueous phase was washed with benzene. The aqueous layer was adjusted to pH 11 to 12 with aqueous sodium hydroxide and extracted with chloroform. After drying and concentration, a slightly yellowish oil (90 mg) remained, which was separated by PTLC (Merck Alumina, 5% methanol / 95% dichloromethane). The band at R _f 0.5-0.7 was isolated and washed out to give + vincadifformin (45 mg, 26%) as an oil which crystallized upon inoculation.

Example 13 JiH-Methoxyvincadifformin (Ib) (Ervincein)

a) Methyl 8-methoxy-1,2,3,4,5,6-hexahydroazepino-£ 4,5bI-indole carboxylate VIIIb

A solution of dimethyl-3-benzyl-8-methoxy-1, 2, 3, 4, 5, 6-hexahydroazepino [4,5b] indole-5,5-dicarboxylate VIb (1.00 g, 2nd , 37 mmol, obtained from 6-methoxytryptamine by a similar procedure as that described for VIa), lithium chloride (0.111 g, 2.61 mmol) and 128 μΐ water in 10 ml of N, N-dimethylformamide was under nitrogen at 140 for two hours ⁰ C stirred. The mixture, which became heterogeneous during this time, was ^{cooled to 20 °} C., poured into 200 ml of water and extracted with two portions of 75 ml of benzene each time. The benzene solutions were washed with brine, _{dried over K 2} CO ₃ , filtered and concentrated in vacuo to give 0.747 g (86%) of the monoester VIIb which was purified by chromatography on silica. Wash out with 2.5% methanol

030011/07 * 5

in dichloromethane and crystallization from methanol to give FP 118 - 119 ⁰ C.

NMR (CDCl ₃ ) S 8.12 (s, 1 H); 7.2 (m, 6H); 6.6 (m, 2H);

3.66 (s, 5H); 3.54 (s, 3H); 3.5-3.2 (m, 3H);

3.1-2.6 (m, 4H)

The above-mentioned N-benzylaminomonoester (0.375 g, 1.03 mmol) and 38 mg of a 10% Pd / C catalyst were dissolved in acetic acid at 20 ⁰ C under a pressure of 1 bar of hydrogen for 17 hours. After filtering and washing the catalyst with methanol, the solvents were evaporated in vacuo and the residue dissolved in dichloromethane. Extraction with saturated aqueous K-CO ₃ solution, brine, drying over K-CO ₃ , filtration and concentration gave 0.276 g (97%) of the amino ester VIIIb, which was crystallized from methanol.

FP 166-167 ⁰ C
NMR (CDCl ₃ ) S 8.6 (s, 1 H); 7.25 (d, 1H, J = 8Hz), 6.68 (m, 2H);

3.74 (s, 3H); 3.64 (s, 3H); 3.58-2.70 (m, 7H);

2.30 (br, s, 1 ■ H).
Analysis calculated for C ₁ CH ₁₈ N ₂ O ₃

C. 65.67 H 6th , 61 N 10.21 C. 65.45 H 6th , 62 N 10.02

found

b) 2-ethyl-5-mesyloxypentanal IXe

20 ml of 1.2 HCl were added to a solution of 2.55 g (0.01 mol) of 4-dimethoxymethyl-1-methanesulfonyloxyhexane in 40 ml of diethyl ether and the mixture was stirred under reflux for 12 hours. Solid potassium carbonate (3 g) was slowly added, the organic layer separated and the aqueous layer extracted with 25 ml of ether. The combined ether solutions were washed with brine and dried over magnesium sulfate, filtered off and concentrated to 1.66 g of the aldehyde IXe.
NMR (CDCl ₃ ) ^ 9.57 (d, 1 H); 4.20 (m, 2H); 3.00 (s, 3H);

2.23 (m, 1H); 1.88-1.09 (m, 6H); 0.92 (t, 3H)

030011/0745

IR (film) I? 2955, 2930, 2870, 2700, 1715, 1450, 1340,

Iu 3. X -

1170, 970-910, 820 cm " ¹

c) 11-methoxyvincadifformin or ervincein (Ib)

A solution of the amino ester VIIIb (mg 100, 0.369 mmol), the Mesyloxyaldehyds IXe (0.0835 g, 0.401 mmol) and triethylamine (0.122 g, 1.20 mmol) was dissolved in 5 ml of anhydrous methanol for 17 hours at 65 ⁰ C. stirred under a nitrogen atmosphere. The solvent was evaporated in vacuo and the residual oil was chromatographed with PTLC (1.5 mm silica, 3% methanol in dichloromethane). The Ervincein tape was found by spraying the edge of the plate with ceric ammonium sulfate, which resulted in a characteristic blue coloration. Washing ervincein from the separate tape with 1:10 methanol in ether and concentrating provided 0.0981 g (73%) ervincein Ib. The product crystallized from methanol. FP: 90-92 ⁰ C NMR _(CDCl3) <£ 8.88 (bs, 1H); 7.04 (d. 1H); 6.36 (m, 2H);

3.74 (s, 6H); 3.27-0.69 (m, 14H); 0.55 (t, 3H) IR (KBr): 3390, 1685, 1620, 1500, 1270 cm " ¹ MS (80 eV) m / e: 368 (M ⁺ ), 124 (base)

UV (ethanol) X _m (log £): 249 (4.00), 330 (4.12). Max

Example 14

± Pandolin and epi-Pandolin

a) 4-Ethyl-5-hydroxypentanoic acid lactone (XII)

Aldehyde ester XI (15.3 g, 97 mmol) was cooled in anhydrous metha nol (125 ml) at 0 ⁰ C and sodium borohydride (1.84 g, 48 mmol) was added at such a rate that the reaction temperature below 20 ⁰ C was . After the addition was complete, the solution was stirred for half an hour and then poured into water. The watery one? Solution was extracted in Ά \ her (3 × 75 ml). The combined exi-rnM "became with saturated Snli'lau'R;<} f: Wii;. 'c]) rn, qetrof]:]: "; t

(MgSO .) And concentrated in vacuo. The oil was taken up in benzene (200 ml) and p-toluenesulfonic acid (1 g) was added. The solution was refluxed for 15 hours using a Dean-Stark trap filled with anhydrous calcium chloride. After cooling, the reaction mixture was washed with saturated sodium bicarbonate, dried (MgSO.), And the solvent was evaporated. Distillation of the raw material provided lactone XII (7.2 g, 58%). Boiling point: 70-75 ^° C. (0.25 mm).
IR (neat): 2968, 1730, 1180, 1056 cm " ¹

NMR (CDCl ₃ ) cf 0.98 (3H, t); 1.2-2.2 (5H, m); 2.58 (2H, m); 4.0 (1H, d of d), 4.3 5 (1H, m).

b) methyl 4- (phenylseleny! methyl) hexanoate XIII

Diphenyl diselenide (3.65 g, 11.7 mmol) was dissolved in freshly distilled dimethylformamide (15 ml) and sodium borohydride (0.89 g, 23 mmol) dissolved in dimethylformamide (10 ml) was carefully added in the absence of oxygen (violent evolution of H. -). The lactone XII (3g, 23 mmol) was then added and the solution heated to 120 ⁰ C for 8 hours. After cooling, the solution was acidified with 3% HCl and extracted with ether (4 × 50 ml). The ether solution was washed with water, dried (MgSO.) And concentrated. The crude carboxylic acid was esterified by stirring under reflux for 15 hours in anhydrous methanol (20 ml) with triraethyl orthoformate (2.5 g, 23 mmol) and p-toluenesulfonic acid (100 mg). The methanol was removed in vacuo and the residue was chromatographed on silica gel in a column and washed with hexane until the yellow diselenide band had disappeared and then with ether gave the pure selenide (3.8 g, 55%). In other experiments the yield varied from 25% to 55%. See Example 14b ¹ for the spectral information.

a ') Methyl 4- (methanesulfonyloxymethyl) hexanoate (XII') aldehyde XI (6 g, 38 mmol) was dissolved in methanol (60 ml)

03Π01 1/07 * 5

and cooled to ^{0 ° C.} Sodium borohydride (0.75 g, 20 mmol) was added langesam, in order to keep the reaction temperature below 10 ⁰ C. The solution was stirred for an additional 15 minutes and then taken up in methylene chloride and washed with water and saturated brine, and then with MgSO 4. dried. After solvent deposition under vacuum at 3 0 ⁰ C is the inferred from the aldehyde XI crude alcohol was obtained which (60 ml) (g 5.2, 51 mmol) in methylene chloride with triethylamine and dissolved 0 ⁰ C was cooled. Methanesulfonyl chloride (5.5 g, 48 mmol) was added dropwise followed by stirring for 30 minutes. Another 40 ml of methylene chloride was added and the solution washed with 3% HCl, saturated aqueous sodium carbonate and then dried (MgSO.). After elimination of the solvent and subsequent distillation, the desired pure mesylate XII '(7.6 g, 81%) was obtained.
Boiling point 145 - 150 ⁰ C (0.3 mm).
IR (neat): 2965, 1734, 1350, 1175 cm " ¹

NMR (CDCl ₃ ) cf 1.0 (3H, t); 1.3-1.9 (5H, m); 2.45 (2H, t); 3.1 (3H, s); 3.8 (3H, s); 4.3 (2H, d).

b ¹ methyl 4- (phenylseleny! methyl) hexanoate (XIII)

Diphenyl diselenide (2.8 g, 8.9 mmol) was dissolved in anhydrous dimethylformamide. Sodium borohydride (690 mg, 18 mmol) was carefully added (vigorous development of HL ·), the solution changing from orange to almost colorless at the end of the reaction. The solution was flushed with nitrogen and the mesylate XII ¹ (2.1 g, 8.5 mmol) was added. The reaction mixture was stirred for 24 hours at room temperature, then for 3 hours at 45 ^° C. and then poured into water (150 ml). The product was obtained by extracting the aqueous solution with pentane (4 × 75 ml). The pentane extract was washed with water, dried (MgSO,) and concentrated to a yellow oil. By chromatography on a column on silica gel, washing out with hexane until the yellow di-

030011/0745

selenide tape came off and subsequent washing with ether gave the pure selenide XIII (2.2 g, 90%). IR (neat): 3060, 2960, 1735, 1578 cm " ¹ NMR (CDCl ₃ ) 6 0.85 (3H, t); 1.2-1.9 (5H, m); 2.3 (2H, t );

2.9 (2H, d); 3.6 (3H, s); 7.15 (3H, m),

7.44 (2H, m).

c) methyl 4-ethyl-4-pentanoate (XIV)

(G 1.8, 6.0 mmol) to a solution of selenide XIII wherein in methylene chloride (15 ml) - 78 ⁰ C (85%, 6.3 mmol, 1.28 g,) was added m-chloroperbenzoic acid. The solution was allowed to warm to room temperature over 30 minutes and then washed with water, saturated sodium carbonate and dried (MgSO ₄ ). The methylene chloride was removed in vacuo and the selenium oxide taken up in carbon tetrachloride (15 ml). Triethylamine (640 mg, 6.3 mmol) was added and the solution refluxed for 2 hours. The reaction mixture was taken up in methylene chloride (25 ml), washed with saturated aqueous sodium carbonate, dried (MgSCK) and concentrated on a rotary evaporator. The Roholefingemisch XIV was distilled, bp 70-75 ⁰ C (25 mm) to give a colorless oil (630 mg, 74%) was obtained. IR (neat): 3070, 2960, 1740, 1654, 1160 cm " ¹ NMR (CDCl ₃ ) <f 1.0 (3H, t); 2.03 (2H, q); 2.2-2.6 ( 4H, m), 3.64 (3H, s), 4.7 (2H, d).

d) methyl 4-ethyl-4-oxyranylpentanoate (XV)

At 0 ⁰ C was added m-chloroperbenzoic acid (1.25 g, 85%, 6.1 mmol) of a-stirred solution of olefin XIV (800 mg, 5.6 mmol) in methylene chloride (8 ml). The solution was allowed to warm to room temperature and stirred for an additional 3 hours. The solution was then diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate, dried (MgSO-) and concentrated in vacuo. The raw

030011/07 * 5

product was purified by distillation, boiling point 43 ^° C. (0.3 mm) (730 mg, 82%).
IR (neat): 2965, 1735, 1165 cm " ¹

NMR (CDCl ₃ ) S 0.95 (3H, t); 1.6 (2H, m); 1.98 (2H, t); 2.4 (2H, t); 2.65 (2H, s); 3.8 (3H, s).

e) 4-ethyl-4-oxyranylpentanal (IXd)

This compound was obtained from compound XV by reduction in dichloromethane with a 1 M DIBAL solution (Diisobutylaminaluminiumhydrid) in hexane at - 75 ⁰ C. The process is identical to the gear (Example 10b) as described for the synthesis of compound IXc.

f) Pandolin If and epi-20-Pandolin If ¹

Amin Villa (670 mg, 2.8 mmol) and epoxyaldehyde IXd (470 mg, 3.7 mmol) were refluxed under nitrogen in methanol (10 ml) for one and a half hours. Thin-layer chromatography on silica gel (CH-Cl- - MeOH, 99: 1) showed two main products (visible as blue spots after spraying with 10% ceric ammonium sulfate in 85% phosphoric acid). The methanol was removed in vacuo and the residue was chromatographed on silica gel in the column, washing with methylene chloride-methanol (99: 1). Two main ingredients were obtained. The first component, Pandolin (If) was ^{recrystallized from acetonitrile (FP 150 - 151 0} C, 290 mg, 3 0%), and the second, epi-20-Pandolin (If) / was made from acetonitrile water (9: 1 ) (FP 114 - 116 ⁰ C, 205 mg, 21%) recrystallized. Both main components are identical in all respects, with the exception of the optical rotation in natural samples.
For Pandolin (If):

IR (KBr): 3500, 3400, 2965, 2800, 1678, 1620 cm " ¹ NMR (CDCl ₃ ) ί 0.96 (3H, t); 1.3-1.7 (4H, m); 1.7 -2.3 (4H, m);

2.5-2.8 (3H, m); 2.8-3.1 (4H, m); 3.79 (3H, s);

6.8-7.05 (2H, m); 7.15-7.4 (2H, m); 9.05 (1H, broad)

030011/0745

UV (MeOH) nm 228, 298, 326; MS (m / e) 354 (M ⁺ ). Analysis calculated for C ₃₁ H ₂₆ N ₂ O ₃

C. 71 , 16 H 7th , 39 N 7th , 90 C. 70 , 90 H 7th , 35 N 7th , 78

found

For epi-20-Pandolin (If):

IR (KBr): 3450 (broad), 3400, 2960, 2805, 1682, 1620 cm " ¹

NMR (CDCl ₃ ) £ 0.96 (3H, t); 1.2-2.2 (8H, m); 2.45 (2H, m);

2.5-2.95 (3H, m); 3.05 (1H, s); 3.1 (1H, d);

3.78 (3H, s); 6.7-7.0 (2H, m); 7.05 - 7.3 (2H, m);

8.9 (1H, broad)
UV (MeOH) nm 228, 298, 326; MS (m / e) 354 (M ⁺ ).

Example 15

14-Hydroxyvincadifformin Ic and 14-Hydroxymethyl-e-norvincadifformin Id

a) methyl 2-ethyl-4-oxyranylpentanoate

To methyl 2-ethyl-4,5-dehydropentanoat (3.85 g, 27 mmol) in methylene chloride (25 ml) at 0 ⁰ C (85%, 32 mmol 6.5 g,) was added m-chloroperbenzoic acid was added. The solution was brought to room temperature and stirred for 12 hours. The solid that formed was filtered off, washed with methylene chloride, and the pooled solutions were then washed with saturated aqueous sodium carbonate, dried (MgSO-) and concentrated. Distillation (100 ^° C., 25 mm) of the crude oil yielded the epoxy (3.5 g, 81%). IR (neat): 2960, 1733, 1192, 1172 cm " ¹

NMR (CDCl ₃ ) S 0.90 (3H, t); 1.4-2.0 (4H, m); 2.38-2.68 (2H, m); 2.75 (1H, t); 2.95 (1H, m); 3.74 (3H, s).

b) 2-ethyl-4-oxyranylpentanal IXc

The epoxy ester (2.08 g, 13.1 mmol) was placed in methylene chloride (20 ml) under nitrogen and at - 78 ⁰ C cooled. With vigorous stirring, diisobutyl aluminum hydride (1.2

030011/07 * 5

equiv., 20% in hexane) added dropwise over 10 minutes. The reaction mixture was stirred for a further 20 minutes and then quenched ^{at -78 ° C. with methanol (2 ml).} The solution was poured into water and extracted with methylene chloride. The aluminum salts formed were separated by gravity filtration through glass wool and washed with methylene chloride. The pooled extracts were dried (MgSO.) And concentrated in vacuo. Distillation (60-65 ⁰ C, 25 mm) afforded 2-ethyl-4-oxyranylpentanal IXc (925 mg, 55%).

IR (neat): 3055, 2023, 2910, 1720, 1450, 1260 cm " ¹ NMR (CDCl ₃ ) <f 1.0 (3H, t); 1.1-2.1 (4H, m); 2, 3-2.6 (2H, m); 2.85 (1H, t); 3.05 (1H, m); 9.85 (1H, d).

c) 14-Hydroxyvincadifformin Ic and isomer Id

Amin Villa (500 mg, 2.1 mmol) and epoxyaldehyde IXc (0.5 g, 3.9 mmol) were refluxed in methanol (10 ml) under nitrogen for 2 hours. The methanol was removed under vacuum. The compound Id crystallized out after settling overnight. It was (503 mg, 68%) from acetonitrile, FP 153-154 ⁰ C recrystallized. The remaining residue was purified by preparative TLC (silica gel, 3% methanol in methylene chloride, r _f 0.6 for Ic and 0.15 for Id), with a second component (Ic) as an amorphous solid (105 mg, 14%) was obtained.

For Id:

-1

IR (KBr): 3260, 2950, 1682, 1605 cm

UV (MeO)

For Ic:

IR (Fill

UV (MeOH) nm 228, 298, 328; MS (m / e) 354 (M ⁺ ).

UV (MeOH) nm 226, 298, 328; MS (m / e) 354 (M ⁺ )

IR (film): 3360 (wide), 2950, 2790, 1640, 1600 cm " ¹

030011 / ΓΙ745

Example 16

+ Pseudo-vincadifformin Ie and epi-14-pseudovincadifformin Ie '

a) 4-ethyl-5-hydroxypentanoic acid lactone

Methyl-4-formylhexanoat (15.3 g, 97 mmol) was dissolved in anhydrous methanol (125 ml) cooled to 0 ⁰ C, and sodium borohydride (1.84 g, 48 mmol) was added at such a rate that the reaction temperature below 20 ⁰ C remained. After the addition was completed, the solution was stirred for 30 minutes and then poured into water. The aqueous solution was extracted with ether (3 × 75 ml). The pooled extracts were washed with saturated brine, dried (MgSO 4) and concentrated in vacuo. The oil was taken up in benzene (200 ml) and then p-toluenesulfonic acid (1 g) was added. The solution was refluxed for 15 hours using a Dean-Stark trap filled with anhydrous calcium chloride. After cooling, the reaction mixture was washed with saturated sodium bicarbonate, dried (MgSO.) And the solvent evaporated. Distillation of the raw material gave 4-ethyl-5-hydroxypentanoic acid lactone. Boiling point 70 - 75 ⁰ C (0.25 mm) (7.2 g, 58%) IR (pure): 2968, 1730, 1180, 1056 cm " ¹

NMR (CDCl ₃ ) (f 0.98 (3H, t); 1.2-2.2 (5H, m); 2.58 (2H, m); 4.0 (1H, d of d); 4 , 3 5 (1H, m).

b) methyl 4- (bromomethyl) hexanoate

Anhydrous HBr gas was (3 g, 23 mmol) by the 4-ethyl-5-hydroxypentanoic acid lactone at 60 ⁰ C for 30 minutes passed. The solution was allowed to cool and then methanol (15 ml) with trimethyl orthoformate (2.5 g, 23 mmol) was added. The solution was then stirred for 8 hours, concentrated and distilled, boiling point 70-75 ⁰ C CQ * 1 mm), the searched Bromoester (4.3 g, 83%) was obtained. IR (neat): 2955, 1733, 1170 cm " ¹

NMR (CDCl ₃ ) S 0.98 (3H, t); 1.3-2.0 (5H, m); 2.45 (2H, t); 3.6 (2H, d); 3.82 (3H, s).

030011/0745

c) 4- (bromomethyl) hexanal IXb

The aforementioned Bromester (1.9 g, 8.5 mmol) was dissolved in anhydrous methylene chloride (20 ml) and under vigorous stirring at - 78 ⁰ C cooled. Diisobutylaluminum hydride (10.2 ml, 1 mol in hexane) was added dropwise over 10 minutes. The solution was further 20 minutes at - 78 stirred ⁰ C and then quenched by addition of methanol (2 ml). The solution was then poured into 3% HCl, extracted with methylene chloride (3 × 30 ml) and dried (MgSO.). Removal of the solvent gave a pale oil which was purified by distillation. Boiling point 78 ⁰ C (0.4 mm) (1.38 g, 84%).

d) Pseudo-vincadifformin Ie (14-ethyl-18,19-dinorvincadifformin) and epi-14-pseudovincadifformin Ie '

Azepinoindole Villa (1.00 g, 4.1 mmol) was dissolved in methanol (30 ml) at room temperature and bromaldehyde IXb (1.0 g, 5.3 mmol) was added. The solution was stirred for four hours, with triethylamine (1 ml, in excess) being added and the solution then being heated ^{to 40 ° C. for 16 hours with stirring.}

The methanol was removed in vacuo and the residue taken up in methylene chloride (75 ml), washed with saturated aqueous sodium carbonate, dried (MgSO.) And concentrated. HPLC (using a commercially available 25.4 cm Mikroporacil column with a throughput of 0.9 ml / min) washing out with chloroform yielded two components Ie (retention time: 10.3 min) and Ie ¹ (retention time: 8.5 min ) in a ratio of 4: 1, which corresponds to the two components (ratio 4: 1) in a sample of natural pseudovincadifformin. The main isomer could be isolated as a homogeneous material (by HPLC) by trituration in methanol and water by means of column chromatography under medium pressure (1.2 m × 3.2 cm), silica gel, washing out with chloroform. It was recrystallized from methanol-water (95: 5) recrystallized FP 118-119 ⁰ C.

030011/0745

(170 mg, 12%). Enrichment of the remaining epimer mixture (460 mg, 34%) by selective crystallization provided a Mixture in a ratio not better than 1: 1 For Ie:

IR (KBr): 3365, 2955, 2773, 1666, 1605, 740 cm " ¹ NMR (CDCl ₃ ) £ 0.95 (3H, t); 1.1-1.6 (4H, m); 1.6 -2.15 (4H, m);

2.15-2.65 (3H, m); 2.65-2.95 (4H, m);

3.68 (3H, s); 6.5-6.7 (2H, m); 6.8-7.2 (2H, m);

8.7 (1H, broad)
UV (methanol) nm 228, 298, 328.

For a mixture of Ie and Ie ¹ (about 1: 1) the NMR spectrum showed a shift in the absorption bands, which led to more protons in the range O 1.6-2.5 and fewer protons in the range 0 1.1-1 , 6 indicates.

Example 17

+ _ 15-chloro-, 15-bromo- and 1 5-methoxyvincadifformin

Starting from the hydrogenated azepinoindoles VIIIc, VIIId and VIIIf, which were obtained in each case from the compounds VIIc, VIId and VIIf by a similar procedure as that for the preparation of the compound Villa, these compounds were prepared by the procedure given for vincadifformin Ia. The chlorine and bromine products were purified by preparative TLC on silica Merck and developed with 2% methanol in dichloromethane. The bromovincadifformin Ih Rf 0.60 could easily be separated from the smaller vincadifformin Ia component Rf 0.48, which was due to the contaminating indolazepine Villa. The chlorine compound Ig (yield 70%) crystallized from methanol, FP 131-132 ⁰ C.
NMR (CCl ₄ ) 8.98 (br s, 1 H); 7.02 (m, 2H); 6.71 (d, J = 8Hz,

1 H); 3.72 (s, 3H); 3.20-0.80 (br m, ~ 15H);

0.64 (+, 3H)
IR (CHCl,) V 3370, 2930, 2770, 1665, 1600, 1465, 1290,

j ITl el X μ

1260, 1150 cm

030011/0745

UV (MeOH) X _mav (log £) 225

(s, 4.11), 311 (4.20), 338 (4.17); MS (80 eV) m / e (relative intensity in%) 372 (45, 125 (15, 124 (100).

The bromine compound Ih (yield 45%) resisted crystallization.

r
NMR (CCl ₄ J ₈₉₄

^ _{1 H)} . _{7fl0 (m} ^ _{2 H} j. ₆ ^ _{58 (d} ^ j _ _10HZf

1 H); 3.64 (s, 3H); 3.20-0.76 (br m, 15H);

0.60 (t, 3H);
IR (CHCl ₃ ) 3360, 2930, 2775, 1665, 1600, 1460, 1290, 1260,

1150 cm " ¹
UV (MeOH) λ (log £) 225 (sh, 4.11); 310 (4.19), 331 (4.17),

MS (80 eV) m / e (relative intensity in%) 418 (12),

416 (12), 125 (39), 124 (100).

The compound formed a picrate, the crystallized from 95% ethanol, FP 203-204 ⁰ C.

The methoxy compound Ii (yield 60%) was amorphous.

NMR (CDCl ₃ ) S 8.75 (br s, 1 H); 6.77 (br s, 1H); 6.62 (m, 2H);

3.73 (s, 3H); 3.71 (s, 3H); 3.38-0.80

(m, 15H); 0.58 (t, 3H); IR (CHCIo) ^ 3380, 2925, 2760, 1660, 1600, 1210, 1140 cm " ¹

j ITIaX

(logE) 228 (sh, 4.10), 313 (4.23), 331 (4.14).

MS (80 eV) m / e: 368 (M +), 124 (base), a picrate was recrystallized from 95% ethanol, FP 152 - 153 ⁰ C.

030011/0745

ORIGINAL INSPECTED

Claims (29)

DIPL.-ING. J. RICHTER DIPL.- ING. F. WERDERMANN PATE NTANWALTE REINS. REPRESENTATIVES AT THE EPO · PROFESSIONAL REPRESENTATIVES BEFORE EPO ■ MANDATAIRES AGREES PRtS J-1OEB • APPLICANT: Martin E. Kuehne Burlington, Vermont / USA TITLE: Process for the production of - Vincadifformin and related derivatives. And intermediate compounds ADDITIONAL to P 27 58 896. I D -2OOO HAMBURG 36 NEW WALL IO 3p (O 4 O) 34 00 45/34 00 56 TELESRAMME: INVENTIUS HAMBURG YOUR CHARACTERISTICS / YOUR FILE OUR CHARACTERISTICS / OUR FI1_e2 8 8 6 ~ IZ ~ 7 9 3 8 ^ DATE / DATE 2J> . AUgUSt 1979 patent claims: 1.) Process for the preparation of + vincadifformin and related Derivatives of the general formula I CO ₂ R ₄ (D in which R and R _{2 are} hydrogen, hydroxy, acyloxy, carbamate, alkoxy, alkyl or halogen or a combination of such substituents, Rj, R and R ^ are the same or different and hydrogen or alkyl with 1 to 7 carbons P 3 η O 1 1 / * · :: " I. are material atoms, A is a saturated or unsaturated alkyl chain with 1 to 7 carbon atoms, which can be substituted by one or more alkyl, hydroxy or hydroxyalkyl radicals with 1 to 7 carbon atoms, characterized in that a) a tetrahydro- β- carboline the formula (ID with benzoyl chloride to give a compound of the formula (III), in which (Jj represents a phenyl radical, reacted, b) the compound of formula III by means of a reducing agent to a compound of formula (IV) reduced, 030011/0745 c) the compound of formula IV with t-butyl hypochlorite in Presence of triethylamine to form a compound of the formula N-CHn- (V) chlorinated, d) the compound of formula V with dialkyl malonate salt reacted under reflux to a compound of the formula VI in which R ₅ = H (VI), 0OR, R ₄ OOC which can optionally be N «-alkylated to a compound of the formula VI in which R _{5 is} an alkyl group with 1 to 7 carbon atoms, e) the compound of formula VI partially to a compound of the formula N-CH -, - - (VII) j COOR ₄ 030011/0745 is decarbalkoxylated, in which R, - is hydrogen or a C - C ₇ ~ alkyl group, f) the compound of formula VII into a compound of formula (VIII) COOR, hydrogenated and g) the compound of formula VIII with a functionalized aldehyde capable of being an enammonium intermediate with a secondary amine, typically a halogen or epoxy aldehyde, in the presence of To form triethylamine, to the desired vincadifformin or vincadifformin analogous to formula I is implemented. 2. The method according to claim 1, characterized in that in process steps e) the compound of formula VI to form a compound R ₄ OOC (VI '), in which R _{5 is} a hydrogen atom on a C.-C_-alkyl 030011/07 * 5 group is, hydrogenated, f) the compound of formula VI ¹ partially to a compound of the formula (VIII) COOR, decarbalkoxylated and g) the compound of formula VIII with a functionalized aldehyde, typically a halogen or epoxy aldehyde, in the presence of triethylamine to form the desired vincadifformin or vincadifformin analogous to formula I is implemented. 3. The method according to claim 1, characterized in that in process step b) lithium aluminum hydride as the reducing agent is used. 4. The method according to claim 1, characterized in that the hydrogenation in process step f) in the presence of a Pd catalyst is carried out. 5. The method according to claim 1, characterized in that the dialkyl malonate salt in process step d) is thallium t-butylmethylmalonate is used. 6. The method according to claim 5, characterized in that the decarbalkoxylation in process step e) by processing is done with a reagent selected from 030011/0745 anhydrous trifluoroacetic acid, anhydrous trifluoroacetic anhydride and mixtures of these substances. 7. The method according to claim 1, characterized in that tallium dimethyl malonate as the dialkyl malonate salt in process step d) is used. 8. The method according to claim 1, characterized in that the decarbalkoxylation in process step e) by means Lithium chloride is run in dimethylformamide. 9. The method according to claim 1, characterized in that the functionalized aldehyde is selected from the group consisting of 1-bromo-4-formylhexane, 4-ethyl-4-oxyranylpentanal, 2-ethyl-4-oxyranylpentanal, 4-bromomethylhexanal and 2-ethyl-5-mesyloxypentanal. 10. The method according to claim 2, characterized in that the reducing agent in process step b) is lithium aluminum hydride is used. 11. The method according to claim 2, characterized in that the hydrogenation in process step c) in the presence of a Pd catalyst is carried out. 12. The method according to claim 2, characterized in that the dialkyl malonate salt in process step d) is thallium t-butylmethylmalonate is used. 13. The method according to claim 2, characterized in that the Decarbalkoxylation is carried out in process step f) by processing with a reagent which is selected from anhydrous trifluoroacetic acid, anhydrous trifluoroacetic anhydride and mixtures of these substances. 030011/07 * 5 14. The method according to claim 2, characterized in that as Dialkyl malonate salt in process step d) thallium dimethyl malonate is used. 15. The method according to claim 2, characterized in that the Decarbalkoxylation is carried out in process step f) by means of lithium chloride in dimethylformamide. 16. The method according to claim 2, characterized in that the functionalized aldehyde is selected from the group consisting of 1-bromo-4-formyl-hexane, 4-ethyl-4-oxyranylpentanal 2-ethyl-4-oxyranylpentanal, 4-bromomethylhexanal and 2-ethyl-5-mesyloxypentanal. 17. Process for the preparation of a dialkyl-3-benzyl-1,2,3,4,5, 6-hexahydroazepino- | _4,5bJ -indole-5,5-dicarboxylate der formula (VI), R ₄ OOC characterized in that 2-benzyl-1,2,3,4-tetrahydro-9H-pyrido ~ L3,4bJ -indole of the formula (IV) with t-eutylliypochlorite with cooling in the presence of '030011/0745 dry triethylamine to a chlorine indolenine of the formula (V) chlorinated and this chlorine indolenine (V) is immediately reacted with a dialkyl malonate salt. 18. Process for the preparation of + vincadifformin and related derivatives of the general formula 5 COOR, characterized in that methyl 1,2,3,4,5,6-hexahydroazepino-L4,5bj -indole-5-carboxylate of the formula (VIII) COOR, with a functionalized aldehyde, typically one 030011/0745 Halogenaldehyde or epoxyaldehyde, in a solvent which is inert under the reaction conditions, to give the desired compound (I) is implemented. 19. The method according to claim 18, characterized in that as Solvent dry methanol is used. 20. The method according to claim 18, characterized in that the solvent is a catalytic amount of dry triethylamine is added. 21. The method according to claim 18, characterized in that dry benzene is used as the solvent. 22. Intermediate connection which can be produced by the method according to any one of claims 1 to 21, characterized in that them the formula NO corresponds, in which R ₁ and R _{2 are} hydroxy, acyloxy, carbamate, alkoxy, alkyl or halogen or a combination of these substituents and R ₁ or R "can also be hydrogen, R ₅ hydrogen or an alkyl group with 1 to 7 carbon atoms, R Hydrogen or benzyl, R ₇ or R _{ß are} hydrogen or carbalkoxy or R- and R _ß both represent carbalkoxy, and the alkoxy group has 1 to 4 carbon atoms and can be different from one another. 030011/0745 23. Intermediate compound according to claim 22, characterized in that it consists of dimethyl-3-benzyl-1,2,3,4,5,6-hexahydro-azepino- [_ 4,5bj -indole-5,5-dicarboxylate. 24. Intermediate compound according to claim 22, characterized in that it consists of dimethyl 1,2,3,4,5,5-hexahydroazepino £ 4,5bjindole-5,5-dicarboxylate consists. 25. Intermediate compound according to claim 22, characterized in that it consists of dimethyl-8-methoxy-1,2,3,4,5,6-hexahydroazepino - (4,5bJ-indole-5,5-dicarboxylate consists. 26. Intermediate compound according to claim 22, characterized in that it consists of methyl 8-methoxy-1,2,3,4,5,6-hexahydroazepino [A , öbj-indole-S-carboxylate. 27. Intermediate compound according to claim 22, characterized in that it consists of methyl-9-methoxy-1,2,3,4,5,6-hexahydroazepino- [4 , 5bJ-indole-5-carboxylate. 28. Intermediate compound according to claim 22, characterized in that it consists of methyl-9-chloro-i, 2,3,4,5,6-hexahydroazepino- [4 , 5bj-indole-5-carboxylate. 29. Intermediate compound according to claim 22, characterized in that it consists of methyl 9-bromo-1,2,3,4,5,6-hexahydroazepino [4,5bI-indole-5-carboxylate consists. 030011/0745