Vincadifformine synthesis process

The preparation of vincadifformine and some derivatives thereof for use as a starting material for synthesis of the corresponding vincamine derivatives or for synthesis of bisindole alkaloids having clinically important antitumor properties.

BACKGROUND OF THE INVENTION: 
(1) Field of the Invention 
The present invention relates to a process for the synthesis of 
vincadifformine and related derivatives. 
(2) Description of the Prior Art 
The compounds prepared by the process of the invention are of the general 
formula: 
##STR1## 
wherein: 
R.sub.1 and R.sub.2 are the same or different and are selected from the 
group consisting of hydrogen, hydroxy, acyloxy, carbamate, halo, lower 
alkyl or alkoxy radical; 
R.sub.3 is hydrogen or a lower alkyl; 
R.sub.4 is a lower alkyl or a substituted alkyl such as an alkoxyethyl or a 
hydroxy substituted alkyl. 
R.sub.5 is a lower alkyl radical. 
The term "lower alkyl", as used in this application, means saturated 
hydrocarbon radicals, branched or not, containing from one to seven carbon 
atoms. 
The numbering of vincadifformine and its derivatives is in accordance with 
the teachings of Le Men and Taylor, Experientia 1965, 21, 508. 
Vincadifformine of the formula Ia (R.sub.1 =R.sub.2 =R.sub.3 =H, R.sub.4 
=ethyl, R.sub.5 =methyl) is an alkaloid which is the raw material used in 
the preparation of the vincamine group alkaloids as described in Belgian 
Pat. No. 772,005 and Belgian Pat. No. 848,475. 
Vincamine and some vincamine derivatives are well-known alkaloids used in 
human therapeutics as psychotropic drugs having high efficiency and having 
a relatively low order of toxicity. Furthermore, it has been shown that 
the rearrangement of vincadifformine resulting in vincamine may be applied 
to a large number of vincadifformine derivatives to provide vincamine 
related compounds (see French Patent Application No. 76 22336, French 
Patent Application No. 76 22275 and Belgian Pat. No. 816,692). 
Vincadifformine derivatives may also be used as a starting material for the 
synthesis of therapeutically useful bisindole alkaloids. Vincadifformine 
of the formula I.sub.b (R.sub.1 =11 methoxy, R.sub.2 =R.sub.3 =H, R.sub.4 
=ethyl and R.sub.5 =methyl) may be easily N(a)-methylated to provide a 
compound which may be used as the starting material for synthesis of the 
vindoline moiety of the anti-tumor agent vinblastine (J. P. Kutney et al., 
J. Amer. Chem. Soc. 100, 4220, 1978). 
Two vincadifformine synthesis methods are disclosed in the literature: 
Kutney et al., J. Amer. Chem. Soc. 90, 3891, 1968 and J. V. Laronze et 
al., Tetrahedron Letters 491, 1974. A further method of total synthesis of 
vincadifformine is disclosed in applicant's U.S. Patent application Ser. 
No. 865,657 filed on Dec. 29, 1977 now U.S. Pat. No. 4,154,943. 
11-methoxy vincadifformine (ervinceine) of the formula Ib is an alkaloid 
occurring in Vinca Erecta and described by D. A. Rakhimov, V. M. Malikov, 
M. R. Yagudaev and S. N. Yunusov (Khim. prir. Soedin. 226, 1970). 
It is one object of the present invention to provide a method of 
synthesizing vincadifformine and related polycyclic compounds, the method 
producing high yields, the method having a reduced number of intermediate 
steps, and the method using inexpensive reagents. 
SUMMARY OF THE INVENTION 
In accordance with the synthesis process of the present invention, an 
.alpha.-carboalkoxy-.alpha.-methyl-tetrahydro-.beta.-carboline compound 
and an aldehyde are condensed in one step to provide the corresponding 
vincadifformine. The synthesis process has a high yield, has a reduced 
number of steps and uses inexpensive reagents. 
DETAILED DESCRIPTION OF THE INVENTION 
The starting raw material used is an 
.alpha.-carbomethoxy-.alpha.-methyl-tetrahydro-.beta.-carboline of the 
following general formula: 
##STR2## 
wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.5 have the meaning previously 
described. These compounds can be advantageously obtained by condensing 
the corresponding tryptamine with an alkyl pyruvate. The following is an 
example of such a reaction: 
##STR3## 
According to the present invention, compound (II) is condensed with an 
appropriate functionalized aldehyde to yield vincadifformine or a 
vincadifformine derivative. The aldehyde is of the following general 
formula: 
##STR4## 
The aldehyde is preferably a 2-alkyl substituted 5-halo, arylsulfoxy, alkyl 
or fluoroalkylsulfoxy-pentanal for which a corresponding tertiary enamine 
may be N-alkylated intramolecularly. Examples of such aldehydes are 
5-chloro-2-ethylpentanal, 5-bromo-2-ethylpentanal, 
5-sulfomethoxy-2-ethylpentanal. 
As shown in the schedule which follows, the preferred aldehyde is 
5-chloro-2-ethylpentanal (VIa) and is preferably prepared by condensing a 
primary amine such as cyclohexylamine (III) with butyraldehyde (IV) to 
form 1-butylidine cyclohexylamine (V). 1-butylidine cyclohexylamine (V) on 
reaction with a strong base such as lithium diisopropylamine and 
alkylation with 1-bromo-3-chloropropane gives the 5-chloro-pentanal (VIa). 
##STR5## 
The condensation occurs by heating compound II and one to two molar 
equivalents of aldehyde VI in a suitable solvent and in presence of a 
small amount of acid catalyst for 10 to 160 hours. It is preferable to use 
an aromatic solvent such as dry benzene or toluene, but, other inert 
solvents may be used. It has been found that p-toluene sulfonic acid is a 
suitable acid catalyst. Water formed during the initial enamine formation 
is preferably eliminated from the reaction mixture by using a Dean-Stark 
water separator or molecular sieves. The temperature of the reaction 
medium may vary from about 30.degree. C. to the boiling point of the 
reaction mixture, but, the temperature of the reaction medium is 
advantageously about 100.degree. C. 
In some cases, that is, for vincadifformine synthesis, after an initial 
period of heating in presence of the acid catalyst, an organic base such 
as diazabicycloundecene (DBU) may be advantageously added. 
The condensation products are isolated from the reaction mixture in 
accordance with the standard procedures of the art.

The following examples describe the synthesis method of the invention. 
EXAMPLE 1: PREATION OF 1-BUTYLIDENE CYCLOHEXYLAMINE (FORMULA V) 
At 0.degree. C., 16.3 g (20 mL, 0.23 mol) of butyraldehyde (Formula IV) was 
added dropwise to 21.7 g (25 mL, 0.22 mol) of cyclohexylamine (Formula 
III). After 1 h, 6 g of anhydrous sodium sulfate was added and the mixture 
stirred for 5 h. The product was decanted from the salt water slurry, 
dried by addition of further 10 g of anhydrous sodium sulfate, filtered 
and distilled. Characteristics of the product: bp 88.degree. C. (20 mm); 
yield 86%; NMR (CDCl.sub.3, .delta.): 1.0 (3H, t) 1.1-2.1 (12H), 2.3 (2H, 
g), 3.0 (1H, m), 7.8 (1H, t). 
EXAMPLE 2: PREATION OF 5-CHLORO-2-ETHYL PENTANAL (FORMULA VIa) 
A solution of 15.3 g (18.2 ml, 0.10 mol) of 1-butylidene cyclohexylamine 
(Formula V) in 30 mL of tetrahydrofuran was added at -78.degree. C. to a 
solution of lithium diisopropylamide (0.105 mol), prepared from 45.6 ml of 
2.3 molar n-butyllithium and 16 ml of diisopropylamine in 20 ml of 
tetrahydrofuran under nitrogen. After 30 min 11 ml (0.11 mol) of 
1-bromo-3-chloropropane was added dropwise at -78.degree. C. over 30 min. 
The reaction mixture was allowed to warm to 20.degree. C. and stirred for 
48 h. Addition of 200 ml of water and extraction with two 150 ml portions 
of dichloromethane, washing of the extracts with 200 ml of brine, and 
concentration gave a yellow oil which was combined with 40 g of oxalic 
acid in 350 ml of water. Steam distillation and subsequent redistillation 
provided 5.5 g (37% yield) of the chloroaldehyde having the following 
characteristics: bp 43.degree.-53.degree. C. (50-120.mu.); NMR 
(CDCl.sub.3, .delta.): 9.6 (1H, d), 3.5 (2H, t), 2.2 (1H, m), 1.8 (6H, m), 
0.95 (3H, t). 
EXAMPLE 3: PREATION OF 
A-CARBOMETHOXY-A-METHYLTETRAHYDRO-.beta.-CARBOLINE (FORMULA II) 
A solution of 4.0 g (20 m mol) of tryptamine hydrochloride and 20.0 ml (22 
m mol) of methyl pyruvate in 80 ml of dry methanol was refluxed for 21 h, 
cooled and concentrated under vacuum. The residual solid was dissolved in 
40 ml of hot water, filtered and 3 ml of conc. ammonium hydroxide solution 
added. The precipitated crystalline product was recrystallized from 
ethanol and water (3:5), giving 3.5 g (72% yield) and had the following 
characteristics: mp 136.degree.-138.degree. C. (reported mp 138.degree. 
C.*); NMR (CDCl.sub.3, .delta.): 8.6 (1H, s), 7.3-7.9 (4H, m), 3.9 (3H, 
s), 3.3 (2H, t), 2.8 (2H, sp.t). 
FNT * G. Hahn, D. Scheles, L. Buerwald and H. Werner, Just. Lieb. Ann., 520, 
107 (1935). 
EXAMPLE 4: PREATION OF VINCADIFFORMINE (FORMULA I) 
A solution of 300 mg (1.23 m mol) of 
a-Carbomethoxy-a-methyltetrahydro-.beta.-carboline (Formula II) and 0.22 
ml (1.5 m mol) of 5-chloro-2-ethyl-pentanal and 1 mg of p-toluenesulfonic 
acid in 25 ml of toluene was refluxed 100 h under nitrogen with a Dean 
Stark water separator. To the hot solution 0.38 ml (3.0 m mol) of 
diazabicycloundecene (DBU) was added and heating continued for 18 h. The 
reaction mixture was cooled, concentrated under vacuum and the residue 
dissolved in dichloromethane. Filtration through a column of Baker silica 
(25 g, 40 cm length) and washing with 3% methanol in dichloromethane gave 
360 mg (84%) of crude vincadifformine after concentration under vacuum of 
the second 100 ml of eluate. The NMR spectrum of this product matched that 
of an authentic sample of dl-vincadifformine and TLC comparison indicated 
only minor impurities. Recrystallization from acetonitrile gave a sample, 
mp and mixture mp 124.degree.-125.degree. C. (reported 
124.degree.-125.degree. C.*). MS (80 eV) m/e (rel. intens. %): 124 (100), 
214 (4), 328 (85) M.sup.+. 
FNT * C. Djerassi, H. Budzikiewicz, J. M. Wilson, J. Gosset, M. M. Janot, Tet. 
Lett. 235 (1962); J. Gosset, J. LeMen, M. M. Janot, Ann. Pharm. France, 
20, 448 (1962). 
EXAMPLE 5: PREATION OF 
1-CARBOMETHOXY-7-METHOXY-1-METHYL-1,2,3,4-TETRAHYDRO-9H-PYRIDO[3,4-B]INDOL 
E (IIB) 
A solution of 113 mg of 6-methoxytryptamine.sup.1 and 80 .mu.L of methyl 
pyruvate in 5 mL of methanol was refluxed under nitrogen for 18 h. The 
cooled reaction mixture was partitioned between 10 mL of saturated aqueous 
sodium carbonate and 15 ml of dichloromethane and the aqueous phase 
extracted with two 15 ml portions of dichloromethane. The combined organic 
extracts were washed with brine, filtered through phase separating paper 
and concentrated. Trituration with 2 mL of ether gave 110 mg (80% yield) 
of product with mp 182.degree.-184.degree. C. An analytical sample was 
recrystallized from ethyl acetate to mp 184.degree.-185.degree. C. NMR 
(CDCl.sub.3).delta. 8.25 (br s, 1H), 7.44 (d, 1H), 6.85 (m, 2H), 3.84 (s, 
3H), 3.80 (s, 3H), 3.21 (t, 2H), 2.72 (t, 2H), 2.28 (br s, 1H), 1.70 (s, 
3H). Anal. Calcd. for C.sub.15 H.sub.18 N.sub.2 O.sub.3 : C, 65.67; H, 
6.61; N, 10.21. Found: 65.68; H, 6.76; N, 9.92. 
FNT (1) R. B. Woodward, F. E. Bader, H. Bickel, A. J. Frey and R. W. Kierstead, 
Tetrahedron 2, 1 (1958). 
EXAMPLE 6: PREATION OF .+-.ERVINCEINE (16-METHOXYVINCADIFFORMINE) 
To 130 mg (0.47 mM) of the methoxytetrahydrocarboline ester IIb and a 
crystal of p-toluene sulfonic acid in 3 ml of toluene was added 100 .mu.l 
(0.75 mM) of 5-chloro-2-ethylpentanal in 1 ml of toluene. Under a 
Dean-Stark water trap containing 3 A Davison Molecular Sieves and a 
nitrogen atmosphere, the mixture was refluxed for 72 h. Concentration and 
partitioning of the residue between 10 ml of 10% HCl and 5 ml of hexane, 
addition of excess KOH to the aqueous solution followed by four 
extractions with 15 ml of dichloromethane and concentration gave a basic 
residue. This was purified by solution in 50 ml of ethyl acetate and rapid 
filtration of the solution through 3 g of Baker silica gel. The 
concentrated eluate gave 160 mg (92%) of ervinceine as an amber oil which 
was homogeneous by TLC (Merck Silica gel, Rf 0.7, ethyl acetate). The 
product formed a picrate, mp and mmp 183.degree.-184.degree. C., and had 
spectroscopic data matching those of an authentic sample. NMR 
(CDCl.sub.3).delta. 8.90 (br s, 1H), 7.00-7.28 (m, 1H), 6.30-6.50 (m, 2H), 
3.76 (s, 6H), 3.40-0.80 (m, 15H), 0.58 (t, 3H); MS (80eV) m/e (rel intens. 
%): 124 (100), 184 (12), 244(12), 309(12), 368 (90) M.sup.+. 
EXAMPLE 7: PREATION OF N(A)-METHYLTRYPTAMINE 
A solution of 3.20 g (20.0 m mol) of tryptamine and 3.10 g (20.0 m mol) of 
phthalic anhydride in 40 ml of toluene was refluxed under a Dean-Stark 
water separator for 12 h. Cooling, filtration and concentration of the 
filtrate gave a crude phthalimide which was recrystallized from ethanol to 
produce 4.85 g (84%), of phthalimide, mp 164.degree.-165.degree. C.; 
reported 164.degree.-165.degree. C..sup.3 
A solution of 0.58 g (2.0 m mol) of the phthalimide in 1.5 mL of 
dimethylformamide (DMF) was added over 2 min to (0.22 m mol) of 50% sodium 
hydride in mineral oil suspended in 1 mL of DMF. After stirring at 
20.degree. C. under N.sub.2 for 30 min, 0.25 ml (4.0 m mol) of 
methyliodide was added. The dark brown solution turned pale yellow. After 
15 min the mixture was poured into 40 ml of half saturated brine and the 
resultant precipitate was filtered after 20 min and washed with water. 
Recrystallization of the N-methyl derivative from ethanol gave 0.40 g 
(65%) mp 174.degree.-175.degree. C., reported 175.degree.-176.degree. or 
177.degree.-178.degree. C..sup.4.5 
A mixture of 824 mg (2.7 m mol) of the N-methyl tryptamine phthalimide and 
0.7 ml (14 m mol) of hydrazine hydrate (85% solution, Fischer) in 80 ml of 
ethanol was refluxed for 24 h; then 20 ml of 10% aqueous HCl was added and 
the solution refluxed an additional 30 min. After cooling, concentration 
and partitioning of the residue beween 60 mL of saturated aqueous sodium 
carbonate and 60 ml of dichloromethane, the aqueous portion was extracted 
with 60 ml of dichloromethane and the combined organic extracts were 
washed with brine. Concentration and Kugelrohr distillation gave 0.45 g 
(96%); bp 95.degree.-105.degree. C. (0.06 mm). The oil was dissolved in 
ethyl acetate and HCl gas bubbled into the solution. The resultant amine 
hydrochloride was filtered and washed with ethyl acetate containing HCl 
and then with ether. The N(a)-methyl tryptamine hydrochloride had a mp 
201.degree.-202.degree. C.; reported 198.degree.-199.degree. C..sup.6.7 
FNT (3) R. H. F. Manske, J. Am. Chem. Soc., 51, 1202 (1929). 
FNT (4) S. Sugasawa and M. Murayama, Chem. Pharm. Bull., 6, 194 (1958). 
FNT (5) T. Hino, ibid, 9, 988 (1961). 
FNT (6) H. Wieland, W. Kung, and H. Mittasch, Justus Liebigs Ann. Chem., 613, 1 
(1939). 
FNT (7) A. W. Jackson and A. E. Smith, J. Chem. Soc., Suppl. 5510 (1964). 
EXAMPLE 8: PREATION OF 
1-CARBOMETHOXY-1-METHYL-1,2,3,4-TETRAHYDRO-9-METHYL-PYRIDO[3,4-B]LINDOLE 
(IIC). 
A mixture of 160 mg of N(a)-methyltryptamine hydrochloride and 0.1 ml (ca. 
50% excess) of methylpyruvate in 5 ml of methanol was refluxed under 
nitrogen for 30 h. The cooled solution was concentrated under vacuum and 
the residue partitioned between 20 ml of 10% aq. HCl and 10 ml of hexane. 
The aqueous layer was made basic with KOH and extracted with three 20 ml 
portions of dichloromethane. The extracts were washed with brine, 
concentrated to dryness and the residue, dissolved in ethyl acetate, 
passed through 4 g of Baker silica gel. Concentration and Kugelrohr 
distillation (bp 150.degree.-160.degree. C., 0.03 mm) gave 158 mg (80%) of 
the tetrahydro-.beta.-carboline. NMR (CDCl.sub.3).delta. 7.3(m, 4H), 
3.77(s, 3H), 3.70 (s, 3H), 3.18(t, 2H), 2.78(t, 2H), 2.22(br s, 1H) 1.75 
(s,3H). Anal. Calcd for C.sub.15 H.sub.18 N.sub.2 O.sub. 2 : C, 69.74; H, 
7.02; N, 10.85. Found: C, 69.50; H, 6.94; N, 10.63. A picrate 
recrystallized from ethanol had mp 190.degree.-191.degree. C. 
EXAMPLE 9: PREATION OF MINOVINE (IIIC) 
The preparation followed the procedure given for ervinceine. Starting with 
129 mg of the .beta.-carboline (Formula IIc) and using 50 mL of ether in 
place of ethyl acetate in the filtration through 2 g of silica gel gave 
140 mg of crude product which showed two components by TLC[Rf 0.2 and 0.7, 
major (minovine), ethyl acetate, silica gel]. Preparative TLC gave 65 mg 
(37%) of minovine as an oil with an NMR spectrum identical with that of 
sample obtained by methylation of .+-.vincadifformine. The synthetic 
sample crystallized slowly from 10:1 hexane-ether and had mp and mixture 
mp 119.degree.-121.degree. C. A picrate was recrystallized from 
methanol-ether, mp and mmp 194.degree.-197.degree. C. The contaminant with 
Rf 0.2 was found to arise from minovine on storage. In subsequent 
experiments minovine was obtained by the same procedure in 56% yield 
without preparative TLC. 
A solution of 34 mg (0.1 m mol) of .+-.vincadifformine in 1 ml of DMF was 
added at 20.degree. C. to a mixture of 10 mg (0.2 m mol) of 50% 
NaH-mineral oil in 1 ml of DMF. After 20 min 20 .mu.L (0.3 m mol) of 
methyl iodide was added to the brown solution. After 10 min 5 ml of water 
was added resulting in deposition of a gummy product. Decantation of the 
solvent, addition of ether, filtration of the ether solution through phase 
separating paper and concentration under vacuum gave 30 mg (85%) of 
minovine which showed no indolic NH singlet at .delta. 8.9 and the 
presence of the N-CH.sub.3 singlet at 3.24, integrating for 3 protons. A 
picrate was prepared with mp 194.degree.-197.degree. C., regeneration of 
the free base gave minovine, mp 119.degree.-121.degree. C., reported 
120.degree.-122.degree. C..sup.8 MS (80eV) m/e (vel. intensity %): 124 
(100), 168 (7), 228 (4) 267 (7), 352 (55) M.sup.+. 
FNT (8) J. Mokry, I. Kompis, L. Dubavkova and P. Sefcovic, Experientia, 19, 311 
(1963).