CH648018A5 - METHOD FOR PRODUCING OMEGA-INDOL-3-YL-ALKANOL COMPOUNDS. - Google Patents

Description

The invention relates to a process for the preparation of ü) -indol-3-yl-alkanol compounds according to the preamble of claim 1, in particular an improved procedure for the preparation of such compounds in a single process step.

As is known, various co-indoï-3-yl alkanol compounds have been found in natural products and can be used as a starting material for the production of various indol derivatives, indole alkaloids and medicaments.

A number of processes for the preparation of w-in-dol-3-yl-alkanol compounds are known per se. Of these known methods, the following use Fi-Scher's indole synthesis:

A mixture of a substituted hydrochloric acid phenylhydrazine salt and dihydrofuran is heated in water containing dioxane for a long period of time.

A mixture of a substituted phenylhydrazine and 2-hydroxytetrahydrofuran is refluxed in benzene while water formed is removed from the reaction mixture by azeotropy, whereupon the condensation product obtained is decomposed by exposure to heat at elevated temperature under reduced pressure.

A mixture of a substituted phenylhydrazine and a-formyl-v-biityrolactone is heated in an aqueous alcohol solvent in the presence of hydrochloric acid for a long period of time.

The above-mentioned procedures are disadvantageous in that the implementation takes a long time to be complete. The procedures are also cumbersome or some of the starting materials for the implementations are not readily available. Therefore, these known methods are unsatisfactory from an industrial application standpoint.

The purpose of the invention is therefore to create a process for the preparation of w-indol-3-yl-alkanol compounds in a single process step over a short period of time.

Another purpose of the invention is to provide a process for producing w-indol-3-yl-alkanol compounds from readily available starting materials with a satisfactory yield.

Such a process for the preparation of a w-indol-3-yl-alkanol compound of the general formula (I):

Ri

I.

(CH) n-CH2CH2OH

in which

Ri is hydrogen, a lower alkyl, aryl or aralkyl radical,

R2 is hydrogen, a lower alkyl, aryl, aralkyl, a lower alkoxyl, aryloxyl or aralkoxyl radical or a halogen,

Rs is hydrogen or a lower alkyl radical and n is 0 or 1,

is characterized according to the invention in that a phenylhydrazine derivative of the formula (II):

R2-

■ NNH-

(Ii)

<1

io where R 1 and R 2 have the above meaning, with at least one oxacycloalkan-2-ol derivative of one of the following formulas (purple, Illb, IIIc):

R4 ° -k,

(Illa)

"? 3

25th

A (Mjh

R50- (CH2) m-0-

diib)

R:

35

(CH> rh

* 6

R-:

, (CH),

rh

- (0-CH2-CH- (CH2) k) z-0- ^ o ^ J

(IIIc)

40 R4

Rs r6

k z

45 m

(D

in which

R3 and n have the meaning given above,

a lower alkyl or acyl radical,

a lower alkyl radical,

Hydrogen or methyl radical,

0, 1 or 2,

I or 2 and 2, 3 or 4,

is reacted in a solvent with at least one alcoholic component in the presence of such an amount of a strong acid that at least one mole of phenylhydrazine derivative per mole of oxacycloalkan-2-ol derivative: .t is present in the reaction mixture as a salt of this strong acid .

According to the process of the invention, co-indol-3-ylalkanol compounds of the formula (I) are:

(CH) n-CH2CH2OH

(i)

prepared by the reaction of a phenylhydrazine de 65 rivate of the formula (II):

648018

4th

r2-

NNH2 (il)

<1

with at least one oxacycloalkan-2-ol derivative of one of the following formulas (purple, Illb, IIIc):

Ri

R4 ° -k0 ^

(purple)

* 3

r5o - (. ch2 ^ -

p r ° -k

(CH) ^

(Illb)

0 ^

(CH) ^

? 6

- (0-CH2-CH- (CH2) k) z-0

(IIIc)

in an alcoholic solvent.

In formulas (I), (II), (purple), (Illb) and (IIIc) mean

Rj is hydrogen, lower alkyl, aryl and aralkyl radicals, Ra is hydrogen, lower alkyl, aryl, aralkyl, lower alkoxyl, aryloxyl or aralkoxyl radicals or halogen atoms,

R3 is hydrogen or a lower alkyl radical,

R4 lower alkyl or acyl radicals,

R5 is a lower alkyl radical,

R6 is hydrogen or methyl radical,

k 0, 1 or 2,

z 1 or 2,

m 2, 3 or 4 and n 0 or 1.

The lower alkyl radical Rj preferably has 1 to 4 carbon atoms and can be a methyl, an ethyl, a propyl or a butyl radical.

The aryl radical of Rj can be a phenyl or a tolyl radical and the aralkyl radical of Rj can be a benzyl or a phenylethyl radical.

The lower alkyl radical of R2 can preferably have 1 to 4 carbon atoms and can be a methyl, ethyl, propyl or butyl radical. The aryl radical of R2 can be a phenyl or tolyl radical. The aralkyl radical of R2 can be a benzyl or phenylethyl radical. The alkoxyl radical of R2 can be a methoxy, ethoxy or propoxy radical. The aryloxy radical of R2 can be a phenoxy or tolyloxy radical. The aralkoxyl radical of R2 can be a benzyloxy or phenylethyloxy radical.

The lower alkyl radical of R3 preferably has 1 to 3 carbon atoms and can be a methyl, ethyl or propyl radical.

The lower alkyl radical of R4 preferably has 5 1 to 6 carbon atoms and can be a methyl, ethyl, propyl, butyl, pentyl or hexyl radical and the acyl radical of R4 can be an acetyl or propionyl -Ra-dical.

The lower alkyl radical of R5 preferably has 10 1 to 3 carbon atoms and can be a methyl, ethyl or propyl radical.

Phenylhydrazine derivatives of the formula (II), as can be used for the process according to the invention, are phenylhydrazine, tolylhydrazine, p-benzylphenylhydrazine, methoxyphenylhydrazine, benzyloxyphenylhydrazine, chlorophenylhydrazine, 1,1-diphenylhydrazine, 1-benzyl-1- phenylhydrazine and 1-methyl-l-phenylhydrazine.

Oxacycloalkan-2-ol derivatives of the formula (purple) for the process according to the invention can be 2-alkoxy- or 20 2-acyloxytetrahydrofuran, -tetrahydropyran and -4-methyl-tetrahydropyran.

Derivatives of the formula (IIIb) can be 2- (alkoxyalkyleneoxy) tetrahydrofuran, 2- (alkoxyalkyleneoxy) tetrahydropyran or 2- (alkoxyalkyleneoxy) -4-methyltetrahydropyran. 25 The derivatives according to formula (IIIc) can be 2,2 '- (alkylenedioxy) -ditetrahydrofuran, 2,2' - (alkylenedioxy) -ditetrahy-dropyran and 2,2 '- (alkylenedioxy) -di (4- methyltetrahydro-pyran).

In such an oxacycloalkan-2-ol compound, the oxacycloalkane ring accordingly consists of tetrahydrofuran or tetrahydropyran. The alkoxy radical according to R40 can be a methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy radical and the acyloxy radical can be an acetoxy or a propioxy radical. 35 The alkoxyalkyleneoxy radical according to R50- (CH2) m-0-can be a methoxyethyleneoxy, ethoxyethyleneoxy, propoxyethyleneoxy, methoxypropyleneoxy, ethoxypropylene lenoxy, propoxypropyleneoxy, methoxybutyleneoxy, ethoxybutyleneoxy or propoxybutylene. 40 The alkylenedioxy radical according to - [0-CH2-CH (R6) - (CH2) k] z-0-, where z = 1, can be an ethylenedioxy, propylenedioxy or butylenedioxy radical.

The oxydialkylenedioxy radical according to - [0-CH2-CH (R6) - (CH2) k] z-0-, where z = 2, can be an oxydiaethylene-45 dioxy or an oxydipropylenedioxy radical.

The reaction between the phenylhydrazine component and the oxacycloalkan-2-ol component takes place in a solvent which contains at least one alcoholic compound. This alcoholic compound can be a monohydric aliphatic alcohol, for example methyl, ethyl, propyl or butyl alcohol, a dihydric aliphatic alcohol, for example ethylene glycol or propylene glycol, an aliphatic ether alcohol, for example ethylene glycol methyl ether or ethylene glycol mono-55 ethyl ether, and also mixtures with at least one of these compounds mentioned above with water.

The type of solvent is selected according to the property of the w-indol-3-yl-alkanol compound to be produced. The solvent can consist of a single alcoholic compound, a mixture of two or more alcoholic compounds, or a mixture of at least one alcoholic compound with water. The weight ratio of the alcoholic compound to water is preferably 1:10 or more. 65 According to the process of the invention, the phenylhydrazine component is preferably used in an amount of 1 mol or more, preferably from 1.1 mol to 3 mol, per mol of oxacycloalkan-2-ol component. It is

5

648018

it is important that the reaction of the phenylhydrazine component with the oxacycloalkan-2-ol component is carried out in the presence of a strong acid, in such an amount of a strong acid that at least the proportion of phenylhydrazine component used which corresponds to at least one mole of the phenylhydrazine component per mole of the oxacycloalkan-2-ol component, is converted into a salt of this strong acid.

The strong acid can be, for example, hydrochloric acid, sulfuric acid or p-toluenesulfonic acid, which are suitable for forming salts with the phenylhydrazine compounds of the formula (II).

If the phenylhydrazine component is used in an amount of more than one mole per mole of oxacycloalkan-2-ol component, it is advantageous if the molar ratio of the phenylhydrazine component in the form of the hydrochloric acid salt to the remaining amount of the phenylhydrazine component Component which is not in the form of a hydrochloric acid salt is 2 or more. The phenylhydrazine component, which is not in the form of the strongly acidic salt, can be in the form of the free base or in the form of a salt with a weak acid, for example with acetic acid.

The presence of the strong acid keeps the reaction mixture under acidic conditions, as is essential for carrying out the reaction between the phenylhydrazine component and the oxacycloalkan-2-ol component.

However, it is advantageous if the amount of strong acid which is added to the reaction mixture is not in excess in excess of the amount necessary to convert the entire proportion of the phenylhydrazine component in the reaction mixture into its strongly acidic salt.

The reason why the reaction between the phenylhydrazine component and the oxacycloalkan-2-ol component is promoted in the presence of a certain amount of a strong acid has not yet been fully clarified. However, it has been found that when the strong acid contained in the reaction mixture is in excess of the amount necessary to convert the entire amount of phenylhydrazine component in the reaction mixture to its salt of the strong acid, the oxacycloalkan-2-ol component , which is a kind of intramolecular acetal, is decomposed and the decomposition product polymerizes or condenses, so that the yield of the desired product, ie of the co-indol-3-yl alkanol compound (the tryptophol compound) decreases. When the reaction mixture is kept under basic conditions, there is no reaction between the phenylhydrazine component and the oxacycloalkan-2-ol component. Only in the case when the strong acid in the certain amount to convert at least one mole of the phenylhydrazine component per mole of the oxacycloalkan-2-ol component in the reaction mixture in its salt, but no excess over the amount to convert the entire portion is present on the phenylhydrazine component, the phenylhydrazine component can condense directly with the oxacycloalkan-2-ol component with the formation of an indole ring, while preventing undesirable side reactions.

The reaction between the phenylhydrazine component and the oxacycloalkan-2-ol component is preferably carried out at a temperature between 70 ° C and 170 ° C for a sufficient period of time to complete the reaction, usually 30 minutes or longer, for example from 30 minutes to several Hours. If the reaction at a temperature less than 70 ° C

the reaction speed is very low. This reaction rate reaches its highest value at a temperature of about 170 ° C. A reaction temperature above 170 ° C, however, has no further effect on the promotion of the reaction rate.

If a phenylhydrazine component with an ether-like substituent, for example a methoxy or benzyloxy radical on the benzene ring, is used with an increased reactivity, it is advantageous that the reaction temperature is kept lower than for other phenylhydrazine components, for example in a range from 70 ° C to 90 ° C.

In the process according to the invention, the reaction is carried out in such a way that the phenylhydrazine component and the oxacycloalkan-2-ol component are dissolved separately in a certain amount of an alcoholic solvent and then one of the solutions obtained is added dropwise to the other solution, while maintaining the temperature of the reaction mixture at the desired level.

In another procedure, the phenylhydrazine component and the oxacycloalkan-2-ol component are dissolved together in the solvent and the solution obtained is heated to the desired temperature.

The product obtained, the o) -indol-3-yl-alkanol compound, can be eliminated from the reaction mixture by means of customary separation processes. For example, the reaction mixture can be mixed with water and then shaken with a water-insoluble organic solvent, for example chloroform, in order to extract the reaction product using the organic solvent. The extract obtained is then distilled to remove the organic solvent. The distillation residue is subjected to further distillation under reduced pressure or made to crystallize to obtain the purified reaction product.

The type of co-indol-3-yl-alkanol compound produced according to the invention naturally depends on the type of the phenylhydrazine component and the oxacycloalkan-2-ol component, which react together. The co-indol-3-yl-alkanol compound produced according to the invention can thus be 2- (indol-3-yl) ethanol, which is usually referred to as tryptophol, furthermore 4-methyltryptophol, 5-methyltryptophol, 6-methyltryptophol, 7-methyl-tryptophol, 5-chlortryptophol, 7-chlortryptophol, 5-bromo-tryptopol, N-methyltryptophol, N-phentyltryptophol, N-ben-cyltryptophol, 5-methoxytryptophol, 5-benzyloxytryptophol, 3- (indol-3-yl ) propanol or 3- (indol-3-yl) butanol.

The process according to the invention is explained in more detail by the following examples, which, however, do not restrict the invention to this. In these examples, the% yield of the end product is the ratio in% of the actual yield of the product to the theoretical yield, calculated on the amount of oxycycloalkan-2-ol used.

example 1

A solution of 2.17 g (15 mmol) of hydrochloric acid phenylhydrazine in 50 ml of ethylene glycol monomethyl ether is heated with stirring. When the temperature of the phenylhydrazine salt solution has reached 123 ° C, a solution of 1.02 g (10 mmol) of 2-methoxytetrahydrofuran in 20 ml of ethyleneglycol monoethyl ether is added dropwise to the pynhelhydrazine salt solution over a period of Dropped 30 minutes. The reaction mixture is stirred for a further hour, the temperature of the reaction mixture being kept at a level of 122 ° C. to 124 ° C.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

648 018

6

After the reaction is complete, the reaction mixture is cooled to room temperature. The cooled reaction mixture is mixed with 100 ml of water and then extracted twice, each time with 100 ml of chloroform. The two chloroform extracts are combined and washed with water until the aqueous phase has become neutral. The washed extract is distilled under reduced pressure to remove the chloroform. The brown oily distillation residue obtained is subjected to distillation under reduced pressure. Tryptophol was obtained as a fraction at a distillation temperature of 167 ° C to

173 ° C at a pressure of 2 mmHg in a yield of 1.32 g, which corresponds to a% yield of 82%. The tryptophole obtained had a melting point of 76 ° C.

5

Examples 2 to 8 In each of Examples 2 to 8, the same procedure was used as described in Example 1, except that the strong acid used in Table 1 was used. A derivative according to Table 1 and an alcoholic solvent component according to Table 1 were also used as the oxacycloalkan-2-ol component. The% yield of the tryptophol obtained is also shown in Table 1.

Alcoholic% yield

Solvent tryptophol n-hexanol 82

n-propanol 52

Ethylene glycol 64

monomethyl ether

Ethylene glycol 50

monomethyl ether n-propanol 39

Ethylene glycol- 56

monomethyl ether

Mixture of n-Pro 60

panol and water

(7: 3)

Example 9

The same procedures as in Example 1 were carried out, with the exception that a solution of 2.89 g (20 mmol) of phenylhydrazine hydrochloride in 50 ml of n-propanol and a solution of 1.02 g (10 mmol) of 2-meth- oxytetrahydrofuran in 20 ml of n-propanol were subjected to the reaction. The resulting tryptophol was obtained as a fraction at a distillation temperature of 160 to 165 ° C at a pressure of 0.5 mmHg. The tryptophol obtained was 0.84 g, which corresponds to a% yield of 52%, and thus had a melting point of 57 ° C.

Example 10

The same procedure as in Example 9 was used except that phenylhydrazine hydro-55 chloride was used in an amount of 12.5 mmol.

The% yield of the tryptophol obtained was 40%.

Example 11

A solution of 8.5 g (58.8 mmol) of phenylhydrazine-60 hydrochloride in 175 ml of ethylene glycol monomethyl ether was heated with stirring. When the temperature of the phenylhydrazine salt solution reached 120 ° C, a solution of 5.02 g (39.2 mmol) of 2-methoxy-4-methyltetra-hydropyran in 25 ml of ethylene glycol monomethyl ether was added dropwise to the phenylhydrazine salt solution added dropwise over a period of 30 minutes. The reaction mixture was then boiled with stirring for one hour.

TABLE 1

Example Strong acid oxacycloalkan-2-ol compound

No.

2 hydrochloric acid 2-methoxytetrahydrofuran

3 hydrochloric acid 2-methoxytetrahydrofuran

4 hydrochloric acid 2-propoxytetrahydrofuran

5 sulfuric acid 2-methoxytetrahydrofuran

6 p-Toluene-sulfo-2-propoxytetrahydrofuran acid

7 hydrochloric acid 2-acetoxytetrahydrofuran

8 hydrochloric acid 2-methoxytetrahydrofuran

7

648018

When the reaction had ended, half of the amount of solvent was removed by distillation. The residue was cooled to room temperature, 50 ml of water was added and then extracted twice, each time with 100 ml of chloroform. The two chloroform extracts were combined and washed with water until the aqueous phase became neutral.

The washed extract was distilled under reduced pressure to remove the chloroform. The oily brown distillation residue obtained was distilled under reduced pressure. The resulting 3-indo-3-yl-butanol was obtained as a fraction at a distillation temperature of 182 ° C to 185 ° C under a reduced pressure of 0.5 mmHg in an amount of 5.19 g (= 70%) . This compound was liquid at room temperature.

Example 12

The same procedure as in Example 11 was repeated with the exception that 4.55 g (39.2 mmol) of 2-methoxytetrahydropyran was used instead of 2-metho :: y-4-methyltetrahydropyran.

The 3- (indol-3-yl) propanol formed was obtained as a fraction at a distillation temperature of 162 ° C to 166 ° C under a pressure of 0.5 mmHg in an amount of 6.04 g (= 88%). This compound was liquid at room temperature.

Examples 13 to 17 In each of Examples 13 to 17, the same procedure was used as in Example 11, with the exception that the reactions were carried out as follows: A solution of the type and amount of a ring-substituted phenylhydrazine hydrochloride according to Table 2 in 300 ml of ethylene glycol monomethyl ether was heated to boiling temperature with stirring. A solution 15 of 5.1 g (50 mmol) of 2-methoxytetrahydrofuran in 20 ml of ethylene glycol monomethyl ether was added dropwise to this solution over a period of 30 minutes while the reaction mixture was kept at the boil. The reaction was continued for an additional hour while the reaction mixture continued to boil 20. The reaction product shown in Table 2 was obtained as a fraction at a distillation temperature as shown in Table 2, at a pressure of 0.5 mmHg and in a% yield and with a melting point, as also indicated in Table 2 ben is.

TABLE 2

Example hydrochloric acid salt of subst. Reaction product boiling temperature% yield melting point

No. Phenylhydrazine component temperature (° C)

Quantity used (at 0.5 mmHg)

Ra = g mmol

13

p-methyl

11.9

75

5 -Methy ltryptoph ol

154-158

84

53

14

o-methyl

11.9

75

7-methyltryptophol

155-160

51

82-83.5

15

p-chlorine

13.43

75

5-chlortryptophol

172-180

58

74-76

16

o-chlorine

13.43

75

7-chlortryptophol

172-177

72

34-35

17th

m-chlorine

13.43

75

Mix of

6-chlortryptophol and

4-chlorotryp tophol

160-165 (1 mmHg)

85

Examples 18, 19 and 20 In each of Examples 18, 19 and 20, a solution of the type and amount as given in Table 3 of an N-substituted phenylhydrazine hydrochloride in 470 ml of ethylene glycol monomethyl ether was heated with stirring. As soon as the temperature of this solution reached 123 ° C., a solution of 8.16 g (80 mmol) of 2-methoxytetrahydrofuran in 30 ml of ethylene glycol monomethyl 55 ether was added dropwise to the solution described first over a period of 30 minutes. The reaction mixture was then kept under stirring at boiling temperature for one hour.

After the reaction was completed, the reaction mixture was distilled off to reduce the amount of the reaction mixture to a quarter of the original amount by removing a part of the solvent. The distilled reaction mixture was mixed with 100 ml of water and then extracted twice with 150 ml of chloro-65 form. The extracts obtained were combined and washed with water until the aqueous phase became neutral. The washed extract was distilled under reduced pressure to remove the chloroform. The

648018

8th

Distillation residue was subjected to a further distillation in order to obtain the reaction product according to Table 3, namely as a fraction with a boiling point under reduced pressure according to Table 3. The respective end product was obtained in a% yield according to Table 3.

TABLE 3

Example Substituted phenyl reaction product Boiling point Pressure% yield

No. hydrazine component temperature (mmHg)

Quantity used (° C)

Ri =

g mmol v

18th

Phenyl

26.23

119

N-phenyltryptophol

187-195

0.5

67

19th

Benzyl

28.17

120

N-benzyltryptophol

187-196

2nd

58

20th

methyl

19.04

120

N-methyltry ptophol

145-150

1

62

Example 21

A solution of 2.26 g (9 mmol) of p-benzoyloxyphenyl-hy irazine hydrochloride in 40 ml of ethyl alcohol was heated with stirring. When the temperature of the solution reached 76 ° C, a solution of 0.61 g (6 mmol) of 2-methoxytetrahydrofuran in 20 ml of ethyl alcohol was added dropwise to the former solution over a period of 30 minutes. The reaction mixture was maintained at a temperature of 76 ° C to 78 ° C for one hour with stirring. After the reaction was completed, 50 ml of water was added to the reaction mixture, and the resulting mixture was extracted twice with 100 ml of chloroform each. The two extracts were combined and washed with water until the aqueous phase became neutral. The washed extract was distilled under reduced pressure to remove the chloroform. The oily brown distillation residue obtained was subjected to column chromatography. This gave 5-benzyloxytryptophol with a melting point of 93 ° C to 93.5 ° C in an amount of 0.71 g, which corresponds to a% yield of 44%.

Example 22

A solution of 21.6 g (0.15 mol) of phenylhydrazine hydrochloride and 3.24 g (0.03 mol) of phenylhydrazine in a solvent of 90 ml of water and 90 ml of n-propanol with stirring to a temperature of 90 ° C heated. At this temperature of 90 ° C, a solution of 12.3 g (0.12 mol) of 2-methoxytetrahydrofuran in a solvent of 20 ml of water and 20 ml of n-propanol was added dropwise to the first solution over a period of 2 hours. The reaction mixture was stirred at boiling temperature for 3 hours.

When the reaction was complete, about half of the original amount of solvent was separated from the reaction mixture by distillation. The remaining reaction mixture was extracted twice with 70 ml of chloroform each time. The extracts were combined and then washed with water. The washed extract was distilled under reduced pressure to remove the chloroform from the extract. The oily brown distillation residue obtained was also distilled. The resulting tryptophol was obtained as a fraction at a temperature of 175 ° C to 178 ° C under a pressure of 2 mmHg in an amount of 14.5 g (= 74%) with a melting point of 56 ° C.

Example 23

A solution of 24.5 g (0.17 mol) of phenylhydrazine hydrochloride and 1.09 g (0.01 mol) of phenylhydrin in a solvent of 40 ml of water and 120 ml of ethylene glycol was heated with stirring. As soon as the temperature of the solution had reached 108 ° C., a solution of 2.3 g (0.12 mol) of 2-methoxytetrahydrofuran in 25 ml of ethylene glycol was added dropwise to this solution over a period of 30 1.5 hours. The reaction mixture was stirred under boiling for 3 hours. After the reaction had ended, the reaction mixture was cooled to room temperature and 300 ml of water were added. The mixture was then extracted three times with 200 ml of chloroform 35 each. The extract obtained was washed with water and then distilled under reduced pressure to remove the chloroform from the extract. The resulting oily brown distillation residue was then distilled under reduced pressure. The resulting trypto-40 phol was obtained as a fraction at a temperature of 173 ° C to 178 ° C and a pressure of 1.5 to 2.5 mmHg in an amount of 11.2 g, corresponding to a% yield of 58% .

45 Comparative example

The same procedure as in Example 22 was used, with the exception that phenylhydrazine hydrochloride and phenylhydrazine were used in amounts of 10.1 g (0.07 mol) and 12 g (0.11 mol). The amount of 50 ge of phenylhydrazine hydrochloride used is less than one mole per mole of 2-methoxytetrahydrofuran.

No tryptophol was found in the reaction mixture obtained. It was confirmed by thin layer chromatography that the reaction mixture obtained contained a compound which could be hydrazone.

Example 24

A solution of 6.51 g (45 mmol) of phenylhydrazine hydrochloride in 150 ml of ethylene glycol monomethyl ether was heated with stirring. Once the temperature of the phenyl hydrazine solution reached 123 ° C, a solution of 3.45 g (15 mmol) of 2,2 '- (butylenedioxy) ditetrahydrofuran in 30 ml of ethylene glycol monomethyl ether was added dropwise to the phenyl hydrazine salt solution over a period of time of 30 65 minutes added. The reaction mixture was stirred for one hour while maintaining the temperature of the reaction mixture at 122 ° C to 124 ° C. When the reaction was complete, the reaction mixture was transferred to room

9

648018

temperature cooled. The cooled reaction mixture was mixed with 200 ml of water and then extracted twice with 200 ml of chloroform. The two chloroform extracts were combined and washed with water until the aqueous phase became neutral. The washed extract was distilled under reduced pressure to remove the chloroform therefrom. The brown oily distillation residue obtained was subjected to distillation under reduced pressure.

Tryptophol was obtained as a distillation fraction at a distillation temperature of 168 ° C to 173 ° C at a pressure of 2 mmHg in a yield of 4.4 g, which corresponds to a% yield of 91%. The tryptophole obtained had a melting point of 55 ° C.

Example 25

A solution of 6.51 g (45 mmol) of phenylhydrazine hydrochloride in 150 ml of ethylene glycol monomethyl ether was heated with stirring. Once the temperature of the phenylhydrazine salt solution reached 123 ° C, a solution of 3.45 g (15 mmol) of 2,2 '- (ethylenedioxy) -ditetrahydropyran in 30 ml of ethylene glycol monomethyl ether was added dropwise to the phenylhydrazine salt solution over a period of time added by an hour. The reaction mixture was stirred for 2 hours while the temperature of the reaction mixture was kept at a level of 122 ° C to 124 ° C. After the reaction was complete, the reaction mixture was cooled to room temperature. This cooled reaction mixture was then mixed with 200 ml of water and then extracted twice with 200 ml of chloroform. The two chloroform extracts were combined and washed with water until the aqueous phase became neutral. The washed extract was distilled under reduced pressure to remove the chloroform therefrom. The brown oily residue obtained was then subjected to distillation under reduced pressure. 3- (Indol-3-yl) -propan-l-ol was obtained as a distillation fraction at a distillation temperature of 181 ° C to 185 ° C at a pressure of 1 mmHg with a yield of 4.9 g, which is a % Yield corresponds to 93%.

Example 26

The same procedure as in Example 1 was carried out with the exception that 1.46 g (10 mmol) of 2-meth-20 oxyethyleneoxytetrahydrofuran was used instead of 2-methoxytetrahydrofuran. The tryptophol formed was obtained as a distillation fraction at a distillation temperature of 192 ° C. to 197 ° C. at 5 mmHg in a yield of 6.04 g (= 77%) and with a melting point of 56 ° C.

Claims (17)

648018 2nd PATENT CLAIMS Process for the preparation of a w-indol-3-yl-alkanol compound of the general formula (I): ? 3 R- (CH) n-CH2CH2OH (i) in which Rj is hydrogen, a lower alkyl, aryl or aralkyl radical, R2 is hydrogen, a lower alkyl, aryl, aralkyl, a lower alkoxyl, aryloxyl or aralkoxyl radical or a halogen, R3 is hydrogen or a lower alkyl radical and n is 0 or 1, characterized in that a phenylhydrazine derivative of the formula (II): (II) where R 1 and R 2 have the meaning given above, with at least one oxacycIoaIkan-2-ol derivative of one of the following formulas (Illa, Illb, IIIc): R / .0- . (CHk (purple) ^ 3 I. f (CH) nNl . R 5 0 (CH2) m ~ 0 0 / (Illb) ■ (CHW | 6 - (0-CH2-CH- (CH2) k) z-0-Jr (IIIc) in which R3 and n have the meaning given above, R4 is a lower alkyl or acyl radical, R5 is a lower alkyl radical, R6 is hydrogen or methyl radical, k 0, 1 or 2, z 1 or 2 and m 2, 3 or 4, in a solvent with at least one alcoholic Ingredient is reacted in the presence of such an amount of a strong acid that at least one mole of phenyl-hydrazine derivative per mole of oxacycloalkan-2-ol derivative is present in the reaction mixture as a salt of this strong acid. s 2. The method according to claim 1, characterized in that the lower alkyl radical of Rx in formula (I) has 1 to 4 carbon atoms. 3. The method according to claim 1, characterized in that the aryl radical of Rt in formula (I) is a phenyl or io tolyl radical. 4. The method according to claim 1, characterized in that the aralkyl radical of R! in formula (I) is a benzyl or phenylethyl radical. 5. The method according to claim 1, characterized in 15 that the lower alkyl radical of R2 in formula (I) 1 to 4 Has carbon atom. 6. The method according to claim 1, characterized in that the aryl radical of R2 in formula (I) is a phenyl or tolyl radical. 7. The method according to claim 1, characterized in that the aralkyl radical of R2 in formula (I) is a benzyl or phenylethyl radical. 8. The method according to claim 1, characterized in that the alkoxyl radical of R2 in formula (I) is a methoxy, 25 is ethoxy or propoxy radical. 9. The method according to claim 1, characterized in that the aryloxyl radical of R2 in formula (I) is a phenoxy or tolyloxy radical. 10. The method according to claim 1, characterized in 30 that the aralkoxyl radical of R2 in formula (I) is a benzyl is oxy- or a phenylethyloxy radical. 11. The method according to claim 1, characterized in that the lower alkyl radical of R3 in formula (I) has 1 to 3 carbon atoms. 35 12. The method according to claim 1, characterized in that the lower alkyl radical of R4 in formula (Illa) has 1 to 6 carbon atoms. 13. The method according to claim 1, characterized in that the acyl radical of R4 in formula (purple) is an acetyl 40 or propionyl radical. 14. The method according to claim 1, characterized in that the lower alkyl radical of Rs in formula (Illb) 1 to Has 3 carbon atoms. 15. The method according to claim 1, characterized in 45 that sulfuric acid or p-toluenesulfonic acid is used as the strong acid. 16. The method according to claim 1, characterized in that tetrahydrofuran or tetrahydropyran is used as the oxacycloalkane ring of the formulas (purple, Illb or IIIc). 17. The method according to claim 1, characterized in that the phenylhydrazine derivative of the formula (II) is used in amounts of 1.1 to 3 moles per mole of oxacycloalkan-2-ol. 18. The method according to claim 17, characterized in 55 net that the quantitative molar ratio of the phenylhydrazine derivative in the form of the strongly acidic salt to the remaining amount of the phenylhydrazine derivative, which is not present as a strongly acidic salt, is 2 and more. 19. The method according to claim 1, characterized in 60 that the solvent contains at least one monohydric or dihydric aliphatic alcohol or an aliphatic ether alcohol or mixtures thereof with water. 20. The method according to claim 1, characterized in that the reaction is carried out at a temperature of 70 ° C to ss 170 ° C. 3rd • 648 018