FR2529552A1 - New process for the preparation of intermediates for the synthesis of vindoline and synthesis intermediates. - Google Patents

Abstract

New process for the preparation of indoloquinolizidines which can be employed in the synthesis of vindoline and of vindorosine.

Description

 The present invention relates to a new process for the preparation of synthetic intermediates in the preparation of vindoline and related compounds.

Vindoline (I) which constitutes the dihydroindolic part of the anti-tumor alkaloids of vinblastine type (II) is extracted from the Madagascan periwinkle (Catharanthus roseus). The vindoline content of this plant is around 200 g per tonne of dried aerial parts.

R = OMe (vindoline)
R = H (vindorosine)

 The first total synthesis of vindoline has been described by G. Büchi et al., Journal of the American Chemical Society, 6880, 97 (1975). There is also known a more complex synthesis of vindoline described by J.P. Kutney et al., J.A.-C.S., 4220, 100 (1978).

 In the total synthesis of G. Büchi, the overall yield of vindoline is 2.4%.

 The present invention provides a new process for preparing synthesis intermediates which, in three stages, make it possible to prepare vindoline or its derivatives with improved yields.

 These synthesis intermediates have already been described, as well as the three synthesis stages making it possible to prepare vindoline in the publication of Büchi mentioned previously, the stages of synthesis of vindorosine being described in the publication of G. Büchi, KE Matsumoto, H. Nishimura, J. Amer.

Chem. Soc., 3299, 93 (1971).

To do this, the present invention provides a process for the preparation of compounds of general formula (1)

avec un diène de formule générale (3) dans laquelle

In which
R1 represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C4 alkyl group, a C2-C5 acyloxy group or a C1-C4 alkoxy group
R2 represents a hydrogen atom, a group
C1-C4 alkyl, unsubstituted or substituted by a hydroxy radical or C1-C4 alkoxy
R 3 represents a hydrogen atom or a C1-C4 alkyl group
R4 represents a hydrogen atom, a group
C1-C4 alkyl, a hydroxyl group
R5 represents a hydrogen atom or a hydroxyl group; or
R4 and R5 together represent an epoxy radical;
R6 represents a hydrogen atom, a C1-C4 alkylthio group or an arylthio group
R7 represents a hydrogen atom or a group
(Cl-C4 alkoxy) carbonyl
the dotted line represents a possible double bond characterized in that
a) condensing dihydro-B-carboline of general formula (2)

with a diene of general formula (3) in which

R11 is a cyano, formyl, acetyl, (Cl-C4 alkoxy) carbonyl or nitro group, to obtain a compound of general formula (4)

b) to obtain a compound in which R2 is an C1-C4 alkyl radical, the compound of formula (4) is alkylated by the corresponding alkyl halide in the presence of a base to obtain the compound of general formula (5)

dans laquelle Rg est un groupe Cl-C4 alkyl ou aryl et R10 est un atome d'hydrogène, un groupe Cl-C4 alkyle ou (C1-C4 alcoxy) carbonyle, et on hydrogène éventuellement la double liaison 14,15
d) on traite le composé de formule (6) par un acide, un chlorure ou un anhydride d'acide pour obtenir un produit réarrangé de formule (7) dans laquelle la ligne pointillée représente une double liaison lorsque
R10 est l'hydrogène ou bien R12 est un radical Cl-C4 alkyle ou (C1-C4 alcoxy)carbonyle correspondant a R10 différent de l'hydrogène

c) the compound of general formula (5) or of general formula (4) in which R11 is an alkoxycarbonyl group is alkylated by an anion of a dialkylsulfoxide or of an arylalkylsulfoxide to obtain a compound of general formula (6)

in which Rg is a C1-C4 alkyl or aryl group and R10 is a hydrogen atom, a C1-C4 alkyl or (C1-C4 alkoxy) carbonyl group, and the double bond is optionally hydrogenated 14,15
d) the compound of formula (6) is treated with an acid, a chloride or an acid anhydride to obtain a rearranged product of formula (7) in which the dotted line represents a double bond when
R10 is hydrogen or R12 is a C1-C4 alkyl or (C1-C4 alkoxy) carbonyl radical corresponding to R10 different from hydrogen

e) the compound of formula (7) is reduced when it has
a double bond A20, 15 by an alkali metal borohydride or
alkaline earth to obtain a compound of formula (1) in which
R6 is an alkythio, arylthio, or
f) the compound obtained above is hydrogenolysed, preferably with Raney nickel or sodium in liquid ammonia to obtain a compound of formula (1) in which R6 is hydrogen.

The double bond between and and Ru can be hydrogenated
if desired by hydrogen in the presence of a catalyst such as
Pdsur coal,
In the preceding compounds, the radicals
aryls mentioned are preferably radicals
aryls with one or two cycles which may include
from 3 to 12 atoms in the cycle (s), some of
these atoms being able to be heteroatoms other than
carbon, in particular nitrogen, oxygen or
sulfur, these aryl radicals can optionally
be substituted by C1 to C4 alkyl radicals
either by hydroxy radicals or by atoms
halogen.

Step a) is preferably carried out in a
organic solvent, preferably an aromatic solvent
such as benzene, toluene or chlorobenzene.

 Among the dienes which can be used in stage a), methyl pentadienoate, and -cyano-lbutadiene, should be mentioned by way of example.

 The compounds of formulas (2) or (3) are known or can be prepared by methods known in the art.

 This step can be carried out in the presence or not of a Lexis acid such as AlCl3 or ZnC12.

 This stage leads to a mixture of three compounds in which the double bond in 15, 14 or 20, 15 of the indoloquinolizidines are placed differently but it is useless to separate them the following reaction leading to the same product.

 The alkylation stage b), which is stereospecific and which makes it possible to obtain in C20 and in C21 relative configurations which are the same as in the alkaloids of the aspidospane type, is preferably carried out in a polar aprotic solvent or an mE - solvent mixture such as tetrahydrofuran and hexamethylene phosphorotriamide, HMPT allowing selective alkylation.

 The base used in this step is preferably an amide such as lithium diisopropylamide.

 Taking into account that, among the aspidospermane type derivatives, those which are more particularly advantageous are those in which the radical R2 is an ethyl radical, use will preferably be made, as alkylating agent, of an ethyl halide, for example ethyl iodide.

 Step c), which consists of an alkylation of the indoloquinolizine-tetracyclic of general formula (5), is preferably carried out in a solvent which may be ether or tetrahydrofuran, in the presence of an excess of the reaction, for example dimethylsulfoxide, under these conditions the anion of this step will be the anion derived from dimethylsulfoxide.

 In order to prepare the anion of step c), a base such as butyl lithium or sodium hydride can be reacted with dimethyl sulfoxide or with other sulfoxides which are variously substituted.

 Step d) is a rearrangement of the compound of formula (6) to obtain the compound of formula (7).

This rearrangement involving the indolic nucleus is carried out by treatment with an acid, for example a mineral acid such as hydrochloric acid, or an organic acid such as a sulfonic or halosulfonic acid, for example an alkyl or arylsulfonic acid, or alternatively using a carboxylic acid such as alkanecarboxylic acids or haloalkanecarboxylic acids; it is also possible to use anhydrides or acid chlorides derived from these acids, for example acetic or trifluoroacetic anhydrides.

 The solvent used in this step is preferably a haloalkane, for example dichloromethane.

 This rearrangement leads to a pentacyclic derivative of formula (7).

 In step e), sodium or potassium borohydrides and in particular sodium cyanoborohydrides are preferably used as borohydride, this reduction is preferably carried out in a hydroxylated solvent such as an alcohol, for example methanol.

 The reduction in step f) is carried out in the presence of Raney nickel or sodium in liquid ammonia, when Raney nickel is used the solvent is preferably a ketone such as acetone.

 The compounds of formula (1) thus obtained can be treated by the methods described in the above-mentioned articles by Büchi in order to obtain both vindoline and vindorosine or their derivatives.

The present invention also relates, as synthesis intermediates, to the compounds of formulas (4) and (5), in particular those in which
R1 is H or CH3 0
R3 is CH3 or H
R4 is H or C 2H5
R2 is H or C2H5
R11 is a (C1-C-alkoxy) carbonyl radical.

 R5 is H.

EXAMPLE 1
Preparation of a compound of formula (1) in which R1 = R4 = R5 = H,
R2 = C2H5
R3 = CH3
R6 = R7 = H and the dotted line represents a double bond a) Preparation of the indoloquinolizidines of formula (4)
To an imine solution of formula (2) in which
RI = H, R3 = CH3 (l, lg, 5.97 mmol) in chlorobenzene (40 ml) the diene of formula (3) is added in which
R = R5 = H, R11 = C02CH3, (1.5 g, 13.4 mmol).

The mixture is heated under argon at 1200C for 4 hours with stirring. The solvent is then evaporated under reduced pressure and the residue is chromatographed quickly on a silica column (Kieselgel Merck, 70-230 mesh). Elution with a mixture of methylenepentane chloride, 1-1, then with methylene chloride provides 1.25 g of the mixture of three compounds of formula (4); yield 718.

b) This mixture (0.27 g, 0.91 mmol) is directly
subject to alkylation:
To 1.2 mmol of n-butyllithium, cooled under argon to -70 ° C., 0.19 ml (1.3 mmol) of diisopropylamine and 1 ml of anhydrous THF are added, with stirring. After 5 minutes of stirring at -700C, the mixture is brought to room temperature for 10 minutes (200C) then cooled to -700C before adding 0.3 ml of HMPT. After 30 minutes of stirring at -700C, the mixture is added to a solution of the three compounds of formula (4) (0.27 g, 0.91 mmol) in anhydrous THF (1 ml) maintained under argon at -70UC.

The reaction medium is stirred for 10 minutes at this temperature and then brought to OOC, before the addition of 150 l of ethyl iodide. After 10 minutes of stirring with OOC, a saturated aqueous solution of sodium chloride is added. After dilution with distilled water, the product is extracted with methylene chloride. After usual treatments, the residue is purified by chromatography on a thick layer of neutral silica (eluent CH2Cl2-CH30H, 99.5-0.5 or AcOEt-pentane, 1-1 - tank saturated with NH3 vapor). ml (quantitative yield) of the compound of formula (5) in which R2 = C2H5
IR (CHCl3 film): 2950, 1720 cm-1
1H NMR (400 MHz CDCl3, 6 = Oppm, TMS, JHz) 7.42 (d, 1H, J = 8) and 7.25 (d, 1H, J = 8): C9-H and C12-H 7 , 10 (dd, 1H, JX 8) and 7.04 (dd, 1H, JX 8): C10-H and C11-H 5.98 (2H, C14-H and C15-H); 4.06 (s, 1H, C21-H) 3.68 (s, 3H, Na-CH3); 3.17 (s, 3H, C02CH3); 2.18 (m, 1H,
C19-Ha); 1.78 (m, 1H, C19-Hb); 0.96 (t, 3H, J = 7, C18-H).

MS peaks at m / z: 324 (M), 184 (100%).

c) Preparation of the compound of formula (6)
in which Rg = CH3
10
To a solution of 0.58 ml of DMSO in 25 ml of anhydrous THF, maintained under argon at -20 C., 5 ml of 1.6 M solution of n-butyllithium (in hexane) is added dropwise and let the temperature rise to -100C for 10 minutes. The medium is cooled to -200C before the addition of 6 ml of DMSO; a solution of the compound of formula (5) (820 mg, 2.53 mmol) in anhydrous THF (10 ml) is then added dropwise. After 1 hour of stirring at room temperature, a saturated aqueous solution of ammonium chloride is added dropwise before extraction with methylene chloride. The. residue obtained after usual treatments is purified by chromatography on a silica column (eluent CH2Cl2-CH3OH, 92-8). The compound of formula (6) is isolated in the form of a mixture of diastereoisomers (700 mg, yield 75%):
IR (CHCl3 film): 2950, 1690 cm 1
SM peaks at m: z: 370 (M ++), 307, 184, 183.

d) Preparation of the compound of formula (1)
in which
R = CH3
the dotted line is a double bond d 14, 15
To a solution of compound of formula (6) (130 mg, 0.35 mmol) in THF (10 ml), maintained under argon, 280 mg of tosylic acid and 10 drops of water are added with ordinary stirring distilled. The mixture is brought to reflux until disappearance of the starting product in TLC. After evaporation of the solvent under reduced pressure, the residue is dissolved in methylene chloride. The solution is washed twice with a 10% aqueous Na2CO3 solution and once with distilled water.

After conventional treatments and purification by filtration on a silica column (eluent CH3CO2C2H5-CH3OH, 95-5), 90 mg (73% yield) of the compound of formula (7) are isolated.
IR (CH2Cl2 film): 3100, 2800, 2600, 1705, 1640 cm 1
UV (CH3OH, #max nm (#): 224 (15500), 249 (18300), 300 (9000), 372 (20500),
(CH30H acidic medium): 222 (13800), 248 (18000), 296 (9000), 378 (18500),
SM (high resolution) m / zi 352 (C21 H24N20S) 305 (C20H21N2O, 100%), 265 (C18H21N2), 198 (C13H12NO), 134 (C9H12N), 122 (C8H12N), 107 (C7H9N),
1H NMR (400 MHz, CDCl3): 7.24, 6.98 (dd, 1H) and 6.87 (d, 1H): aromatic protons; 6.00 (d, 1H, J14.15 = 10.5, C15-H), 5.85 (dd, 1H, J14.15 = 10.5 and J3.14 X 4.5,
C14-H), 3.80 (s, 3H, Na-CH3), 3.39 (dd, 1H, J3a, 3b = 16.5 and J3a, 14 = 4.5, C2-Ha), 3.08 (d, 1H, J3a, 3b = 16.5 C -H), 2.97 (dd, 1H, C5-Ha), 2.81 (s, 1H, C21-H), 2.60 (m, 1H , C5-Hb or C6-Ha), 2.12 (s, 3H, S-CH3), 2.02 (m, 1H, C6Ha or C5-Hb), 1.77 (dd, 1H, J6a, 6b = 12 and J5.6 = 4.5, C6-Hb), 1.07 (q, 2H, J = 7, C19-H), 0.6 (t, 3H, J = 7, C18-H).

e) Preparation of the compound of formula (7)
in which
the dotted line represents a simplification.

0.2 ml of trifluoroacetic acid and 23 mg of cyanoborohydride are added to a solution of the compound of formula (7) (39 mg, 0.11 mmol) in methanol (2.5 ml), maintained under argon. sodium. After 5 minutes, the reaction medium is basified and extracted with methylene chloride. The purification of the crude product by CEC of silica (eluent: CH2Cl2) provides 35 mg (yield 89%) of compound of formula (1)
IR: 1705 cm 1, 1600 UV (CH30H): 252, 305; (CH30H acid medium): 248, 302
SM: m / z: 354 (M), 266 (100%), 158, 135, 122, 121, 107
NMR (400 MHz, CDCl3): 7.11 (1H) and 6.75 (dd, 1H, J = 8)
C10-H and C11-H), 7.10 (1H) and 6.45 (d, 1H, J = 8): Cg-H and
C12-H, 5.82 (ddd, 1H, J14.15 = 10, J3a, 14 = 5 and
J3b, 14 = 1.5, C14-H), 5.39 (d, 1H, J14.15 = 10, C15-H), 5.26 (d, 1H, J @ 2 Hz), 3.62 ( d, 1H, C2-H), 2.89 (s, 3H,
Na-CH3), 2.32 (s, 1H, assigned to C21-H), 2.15 (s, 3H, SCH3), 1.55 and 1.28 (m, C19-H), 0.36 ( t, 3H, J18.19 7, C18-H).

f) Preparation of the compound of formula (1)
in which R1 = R6 = R7 = R4 = R5 = H
R3 = CH3
R2 = C2H5
the dotted line is a double
bond
To a solution of 10 mg (0.028 mmol) of the compound of formula (1) obtained in c) in 1 ml of acetone, an excess of Raney nickel suspended in ethanol is added.

The mixture is brought to reflux for 20 minutes. After filtration, 8 mg (92% yield) of the compound of formula (I) identical to the intermediate described by
Büchi.

 This product leads, thanks to the end of the Büchi synthesis, to vindorosin with a yield of the order of 20 z (yield of the Büchi synthesis 0.7%).

From this intermediate, vindorosine can be prepared, as described by Büchi, in three stages
1) by action of (CO2Me) 2 in the presence of a base,
2) Then treatment with H202, and
3) reduction / acetylation.

 The precise conditions for these reactions can be found in the articles mentioned above.

EXAMPLE 2 Preparation of indoloquinolizidine of formula (1) in which R4 = R5 = R7 = H
R3 = CH3
R2 = C 5
R1 = OCH3
r6 = -SCH3 a) Preparation of indoloquinolizidines of formula t4)
To a solution of imine of formula (2) in which R1 = OCH3, R3 = CH3 (0.45 g, 2.1 mmol) in chlorobenzene (20 ml), the diene of formula (3) in which is added R4 = R5 = H, R11 2 C02CH3 (0.65 g 5.8 mmol). The mixture is heated under argon at 120 ° C. for 8 hours with stirring. The solvent is then evaporated under reduced pressure and the residue is chromatographed quickly on a silica column (Kieselgel Merck, 70-230 mesh). Elution with a methylene chloride-pentane mixture, 1-1, then with chloride
methylene provides 0.445 g of the mixture of three compounds of formula (4), yield 65%.

b) This mixture (0.40 g, 1.2 mmol) is directly subjected
to alkylation:
To a solution of 0.8 ml (5.47 mmol) of isopropylamine in 5 ml of anhydrous THF cooled under argon to -500C, 4 ml of butyllithium (1.5 M in hexane) is added, with stirring . After 5 minutes of stirring at -500C, the mixture is brought to room temperature for 10 minutes (200C) and then cooled to -500C before adding 1.3 ml of HMPT. After 30 minutes of stirring at -500C, a solution of the three compounds of formula (4) (0.40 g, 1.2 mmol) in a mixture of anhydrous THF-HMPT (10 ml) is maintained under argon at - 500C. The reaction medium is stirred for 15 minutes at this temperature and then brought to 0 ° C. before the addition of 0.3 ml of ethyl iodide. After 10 minutes of stirring with OOC, a saturated aqueous solution of chloride is added. sodium. After dilution with distilled water, the product is extracted with methylene chloride. After usual treatments, the residue is purified by chromatography on a thick layer of neutral silica (eluent: CH2Cl-CH3OH, 97-3 or AcOEt-hexane, 75-25 - tank saturated with NH3 vapor) -.

 160 mg are thus obtained (yield 37%) of the compound of formula (5) in which R2 = C2H5.

IR (CH2Cl2 film): 3320, 2910, 1720, 1660, 1620 cm-1
UV (CH3OH # max nm): 233, 278, 296
MS: 354 (M), 214 (100%).

c) Preparation of the compound of formula (6)
in which Rg = CH3
R10 = H
To a solution of 0.105 ml of DMSO in 5.25 ml of anhydrous THF, maintained under argon at −200 ° C., 0.88 ml of solution 1.6 m of n-butyllithium (in hexane) is added dropwise. the temperature is allowed to rise to -10 ° C. for 10 minutes. The medium is cooled to -200C before the addition of 1.75 ml of DMSO; a solution of the compound of formula (5) (140 mg, 0.39 mmol) in anhydrous THF (1.5 ml) is then added dropwise. After 1 hour of stirring at ordinary temperature, a saturated aqueous solution of ammonium chloride is added dropwise before extraction with methylene chloride. The residue obtained after usual treatments is purified by chromatography on a thick layer of silica (eluent: CH3CO2C2H5, tank saturated with NH3 vapor. The compound of formula (6) is isolated in the form of a mixture of diastereoisomers (136 mg) - yield 86%
IR: 3400, 2920, 1695, 1620 cm
SM m / z = 400 (M + weak) 292, 277, 214 (100%)
213, 187 d) Preparation of the compound of formula (7)
in which R = CH3
the dotted line is a double
link to 14.15
240 mg tosylic acid and 9 drops of distilled water are added to a solution of compound 6) (120 mg, 0.3 mmol) in THF (9 ml), maintained under argon, with stirring at ordinary temperature. The mixture is brought to reflux until disappearance of the starting product in TLC. After evaporation of the solvent under reduced pressure, the residue is dissolved in methylene chloride. The solution is washed twice with a 10% aqueous Na2CO3 solution and once with distilled water.

After conventional treatments and purification by filtration on a silica column (eluent: CH3C02C2H5 tank saturated with NH3), 80 mg (70% yield) of compound (7) are isolated.
IR (CH2Cl2 film): 2910, 1700, 1625 cm 1 +
SM peaks at m / z: 382 (M), 335 (100%), 228, 188, 134, 122.

e) Preparation of compound of formula (7)
in which the dotted line represents a
single bond
To a solution of compound (6) (42 mg, 0.11 mmol) in methanol (2.5 ml), maintained under argon, 0.2 ml of trifluoroacetic acid and 23 mg of sodium cyanoborohydride are added with stirring . After 5 minutes the reaction medium is basified and extracted with methylene chloride. The purification of the crude product by silica CCE (eluent CH2Cl2) provides 40 mg (yield 95%) of compound (7) in which R6 is SCH3
IR: 1705 cm-1, 1600
UV (CH30H): 252, 305 nm
(CH3OH acid medium): 248, 302
SM m / z: 354 (M +), 266 (100%) 158, 135, 122, 121, 107
NMR (400 MHz, CDCl3): 6.98 (d, 1H, J = 8.2, C9-H); 6.29 (dd, 1H, J9.10 = 8.2 and J10.12 = 2.2, C10-H), 6.02 (d, 1H, J10.12 = 2.2, C12-H), 5.82 (ddd, 1H,
J14.15 = 10, J3.14 = 5 and 1.5, Cl4-H), 5.40 (wide d, 1H, J14.15 = 10, C15-H), 5.29 (d, 1H, J = 2, assigned to C16-H), 3.77 (s, 3H, C11-OCH3), 3.64 (d, 1H, J216 = 2,
C2-H), 2.88 (s, 3H, Na-CH3), 2.14 (s, 3H, S-CH3), 1.58 and 1.27 (m, C19-H),, 0.40 (t, 3H, J18.19 J 7, C18-H).

 it is an intermediary in the synthesis of vindoline.

Claims (1)

CLAIMS l) Process for the preparation of compounds of general formula (l) wherein R1 represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C4 alkyl group, a C2-C5 acyloxy group or a group C1-C4 alkoxy R2 represents a hydrogen atom, a C1-C4 alkyl group, unsubstituted or substituted by hydroxy radical or C1-C4 alkoxy R3 represents a hydrogen atom or a C1-C4 alkyl group R4 represents a d atom hyaogene, a C1-C4 alkyl group, a hydroxyl group R5 represents a hydrogen atom or a hydroxyl group; or R4 and R5 together represent an epoxy radical; R6 represents a hydrogen atom, a C1-C4 aikylthio group or an arylthio group; R7 represents a hydrogen atom or a (Cl-C4 alkoxy) carbonyl group. The dotted line represents an optional double bond, characterized in that a) dihydro-B-carboline of general formula (2) is condensed with a diene of general formula (3) in which R11 is a cyano, formyl, acetyl, (Cl-C4 alkoxy) carbonyl or nitro group, to obtain a compound of general formula (4) b) to obtain a compound in which R2 is a C1 radical -C4 alkyl, the compound of formula (4) is alkylated with the corresponding alkyl halide in the presence of a base to obtain the compound of general formula (5)  c) the compound of general formula (5) or of general formula (4) in which R11 is an alkoxycarbonyl group is alkylated by an anion of a dialkylsulfoxide or of an arylalkylsulfoxide to obtain a compound of general formula (6)

 in which Rg is a C1-C4 group with lkyl or aryl and R10 is a hydrogen atom, a C1-C4 alkyl group or (C1-C4 alkoxy) carbonyl, and the double bond is optionally hydrogenated 14,15  d) treating the compound of formula (6) with an acid, a chloride or an anhydride of acid to obtain a rearranged product of formula (7) in which the dotted line represents a double bond when R10 is hydrogen or R12 is a C1-C4 alkyl or (C1-C4 alkoxy) carbonyl radical corresponding to R10 different from hydrogen

 e) the compound of formula (7) is reduced when it has a double bond t 20, 15 with an alkali metal or alkaline earth metal borohydride to obtain a compound of formula (1) in which R6 is an alkythio, arylthio, or  f) hydrogenolysis of the compound obtained previously, to obtain a compound of formula (1) in which R6 is hydrogen  2) Method according to claim 1, characterized in that step a) is carried out in an aromatic solvent.  3) Method according to one of claims 1 and 2, characterized in that step a) is carried out in the presence of a Lewis acid.  4) Method according to one of claims î to 3, characterized in that step b) is carried out in a polar aprotic solvent.  5) Method according to one of claims 1 to 4, characterized in that in step b) the base used is an amide.  6) Method according to one of claims 1 to 5, characterized in that in step b) the alkylating agent is an ethyl halide.  7) Method according to one of claims 1 to 6, characterized in that in step c) the anion is prepared by the action of dubutyl lithium or sodium hydride on a sulfoxide.  8) Method according to one of claims 1 to 7, characterized in that the acid used in step d) is chosen from hydrochloric acid, sulfonic acids, halosulfonic acids, carboxylic acids and anhydrides of these acids .  9) Method according to one of claims 1 to 8, characterized in that step d) is carried out in a haloalkane solvent.  10) Method according to one of claims 1 to 9, characterized in that in step e) using a sodium or potassium borohydride in a hydroxyl solvent.  11) Method according to one of claims 1 to 10, characterized in that the reduction of step f) is carried out by Raney nickel or sodium in liquid ammonia.  12) Method according to claim 11, characterized in that step f) is carried out in the presence of Raney nickel in a ketone.  13) As synthesis intermediates, the compounds of formula (5)

 which may possibly be saturated in 14.15.  14) As intermediate compounds according to claim 13, the compounds in which  R1 is H or CH30  R3 is CH3 or H  R4 is H or C2H5  R2 is H or C2H5  R11 is a (C1-C4 alkoxy) carbonyl radical  R5 is H.