EP2282993A1

EP2282993A1 - Process for preparing 3-indolyl fatty acid amides with saturated, unsaturated or hydroxy fatty acids

Info

Publication number: EP2282993A1
Application number: EP09753830A
Authority: EP
Inventors: Christian Hinkel; Karl Speer
Original assignee: Technische Universitaet Dresden
Current assignee: Technische Universitaet Dresden
Priority date: 2008-05-26
Filing date: 2009-05-22
Publication date: 2011-02-16
Also published as: DE102008025893A1; WO2009144175A1; DE102008025893B4

Abstract

The invention relates to a process for preparing fatty acid amides by reacting a fatty acid and an amine, especially serotonin as well as tryptamine, tyramine and derivatives thereof, in the presence of a coupling reagent which is capable of activating the carboxylic acid, and of a preferably apolar, aprotic solvent. The coupling reagents are especially selected from phosphonium salts, uronium and/or guanidinium salts. Surprisingly, there is no need to protect hydroxyl groups and other reactive groups in the amine.

Description

PROCESS FOR PREPARING 3-INDOLYL FATTY ACID AMIDES WITH SATURATED, UNSATURATED OR HYDROXY FATTY ACIDS

The invention relates to a process for the preparation of fatty acid amides from saturated, unsaturated or hydroxy fatty acids with amines, in particular serotonin in addition to tryptamine, tyramine and derivatives thereof. The invention also relates to the use of fatty acid amides prepared by the process according to the invention for the preparation of standard solutions for analytics and as active pharmaceutical ingredients.

Amides of fatty acids (eg with serotonin, tryptamine or tryptamine derivatives as amine) occur as phytochemicals in numerous crops and crops. There they can have both desirable effects and undesirable side effects for humans. They play a special role in the analysis of the quality of food. For example, in German retail coffee is offered, which are considered by a special treatment with steam before roasting as gentle on the stomach and irritating as untreated coffee. The market share of such mildly treated coffee was 18% in 2006 (Deutscher Kaffeeverband e.V., Annual Report 2006). The content of carboxylic acid 5-hydroxytryptamides (C-5HT) can be used as a parameter for checking the attenuation of the green coffee, since the attenuation of the green coffee removes about 30% of these compounds from the coffee (Wurziger J. (1973), 6th International Colloquium on the Chemistry of Coffee, 332-42, ASIC, Paris, Hinkel C. and Speer K (2006), 21st International Colloquium on the Chemistry of Coffee, 133-42, ASIC, Paris).

The quantification of fatty acid tryptamides also plays a role in the quality testing of various cocoa products. Thus, the cocoa shell content in cocoa butter is an important quality parameter for chocolate production and is determined analytically by the content of the fatty acid tryptamides lignoceric acid tryptamide and behenic acid tryptamide. Also in the production of cocoa butter can be determined by the content of these two compounds, whether it is a higher quality product of shelled cocoa beans or a lower quality so-called Expellerbutter from whole, unpeeled cocoa beans. The determination is carried out by conventional methods such as HPLC or GC.

For all of these methods, standard solutions of the substances to be determined are needed for the comparison, which therefore initially requires considerable effort for quantification from the respective Raw material must be isolated or chemically synthesized.

Serotonin fatty acid amides, also referred to as 5-hydroxytryptamine, also play a pharmacological role. N-arachidonoyl serotonin has been shown to possess strong analgesic properties in vitro and in the mouse model (Maione et al., British Journal of Pharmacology (2007) 150, 766-781).

Previous synthesis approaches for the preparation of fatty acid amides are based on fatty acid chlorides and put them in the sense of an aminolysis with serotonin to acid amide. The hydroxyl group on the indole base is protected as a potential second reaction site by a benzyl group, which must be removed again after the reaction (Hubert P. et al., (1977), Z. Anal. Chem., 285, 242-50). Alternatively, the fatty acid chloride is added dropwise to an amine solution (Lang R. et al., (2005) Eur. Food Res. Technol. 220, 638-43) or reacted directly with it (Münch M et al., 1999, Z. Lebensm. Unters. Forsch. A 208, 39-46).

Due to the cleavage of the benzyl protecting group by low-pressure hydrogenation, C-5HT can not be synthesized with unsaturated fatty acids because this step will lose the double-bond character of the fatty acid. However, if the protective group is omitted, there is a risk of side reactions due to the lack of selectivity of the fatty acid chloride used. The yields of the applied methods were with 57- 75% only in a middle range.

The object underlying the invention is therefore to provide a simple, rapid and inexpensive process for the preparation of fatty acid amides from amines, in particular serotonin, tyramine, tryptamine or derivatives derived therefrom, and any free fatty acid, including both saturated and unsaturated or hydroxy fatty acids.

According to the invention the object is achieved by a process for the preparation of fatty acid amides by reacting a fatty acid and an amine in the presence of a coupling reagent which is capable of activating the carboxylic acid. Preferred fatty acids and coupling reagents are mentioned below. The latter are in particular selected from phosphonium salts, uronium and / or guanidinium salts.

The amine is preferably a primary or secondary acyclic or cyclic amine. Preferably, bioactive amines are selected from primary and secondary amines containing an aromatic radical, preferably a phenyl or indole radical. Particularly preferred bioactive amines are selected from amphetamine, capsaicin, tyramine, Tryptamine and its derivatives. Amphetamine derivatives are especially metamphetamine and pervertin. Tyramine derivatives are especially dopamine and dopa. Tryptamine derivatives are especially serotonin, methylserotonin, methyltryptamine and methoxytryptamine. The amines preferably contain no carboxyl groups except Dopa.

The process according to the invention is particularly preferably suitable for the preparation of tryptamine derivatives of the general formula:

For this purpose, in the process according to the invention an amine of the general formula

with n = 0 to 5, preferably n = 1 or 2, and R ¹ , R ² , R ³ , R ⁴ R ⁵ independently selected from H ( ¹ H or ² H), halogen, OH, substituted or unsubstituted alkyl , Alkenyl, alkynyl and alkoxy,

with a fatty acid of the general formula,

O

^ (Hi)

OH with R ⁶ selected from substituted or unsubstituted alkyl, alkenyl and alkynyl reacted in the presence of the coupling reagent.

At least one of the radicals R ¹ , R ² , R ³ , R ⁴ R ⁵ , more preferably R ² , is preferably a halogen (preferably Br, Cl or F), NH ₂ , or OH. Surprisingly, due to the process according to the invention, these reactive groups do not have to be protected be provided. The halogens, OH and NH ₂ are preferably present as free, unprotected groups.

Preferred compounds of the general formula I are tryptamine or one of its derivatives, preferably selected from serotonin, methylserotonin, methyltryptamine or methoxytryptamine.

Alkyl in the present invention description denotes an unsubstituted or substituted, straight-chain or branched, preferably non-aromatic hydrocarbon radical. Alkenyl is an unsaturated alkyl radical as defined above. Alkoxy represents an oxygen-linked alkyl radical as defined above. Halogen is preferably selected from F, Cl, Br and I.

The hydrocarbon radicals in R ¹ , R ² , R ³ , R ⁴ and R ⁵ preferably have 1 to 10 carbon atoms. The hydrocarbon radical in R ⁶ preferably has from 4 to 40, preferably 10 to 32, particularly preferably 12 to 24 carbon atoms.

Fatty acids in the context of the invention are aliphatic, saturated or unsaturated monocarboxylic acids, preferably having 4 to 40 carbon atoms, preferably more than 10, particularly preferably having 12 to 24 carbon atoms. The fatty acids have an almost exclusively unbranched carbon chain (maximum of up to 3 branches), preferably they are completely unbranched. However, the term fatty acids includes methyl branched fatty acids, hydroxy acids, methoxy- and / or acetoxy-substituted fatty acids, cyclopropanecarboxylic acids, acetylenic carboxylic acids, furan fatty acids, and urofuran fatty acids. The fatty acids thus optionally carry substituents, such as. B. up to three hydroxyl groups. The fatty acids may have straight (naturally occurring fatty acids) or odd (synthetic fatty acids) carbon numbers. The fatty acids preferably contain no amino groups.

Fatty acids within the meaning of the invention are also the eicosanoids which derive from the arachidonic acid and, as lipid hormones, have very different tasks in the animal and human body. They include, among others, prostaglandins, the leukotrienes, and hydroxy and hydroperoxy fatty acids.

The solvent used for the reaction is preferably an apolar aprotic solvent, preferably halogenated hydrocarbons, such as. For example, dichloromethane, chloroform, carbon tetrachloride, hexafluorobenzene, alkanes (such as pentane, hexane, heptane, cyclopentane, cyclohexane), alkenes, alkynes, aromatics without substituents or with exclusively aliphatic and aromatic substituents (eg benzene, toluene), silanes or boranes with exclusively aliphatic and aromatic substituents (such as tetramethylsilane), carbon disulfide and at high pressures also carbon dioxide. The solvent or solvent mixture used is preferably anhydrous, ie it preferably contains less than 1%, more preferably less than 0.1% of water. The solvent does not contain amide groups. An aprotic solvent has no functional groups from which hydrogen atoms in the molecule can be split off as protons by means of alkalis such as NaOH or KOH. The dielectric constant of the solvent at 25 ⁰ C is preferably below 12, preferably below 10. The dipole moment of the solvent is preferably below 6 ^■ 10 ^"30 cm, preferably below 5.5 ^■ ^{10" 30} cm.

Advantageously, the method according to the invention can also be applied to unsaturated fatty acids. These contain preferably 1 to 10, preferably 1 to 6 double bonds and optionally also up to three triple bonds.

Preferred fatty acids of the invention are selected from the following Tables 1 to 5:

Table 1: Saturated fatty acids

Table 2: Monounsaturated fatty acids

The chemical names of the unsaturated fatty acids (unless explicitly stated) include all (Z) - (E) isomers.

Table 3 Polyunsaturated fatty acids:

The chemical names of polyunsaturated fatty acids (unless explicitly stated) include all (Z) - (E) isomers. Table 4: Hydroxyfatty acids

The chemical names of the hydroxy fatty acids listed above include all enantiomers and (Z) - (E) isomers.

Surprisingly, the hydroxy groups of the hydroxy fatty acids do not have to be provided with protective groups due to the process according to the invention. Table 5: unusual fatty acids

Further fatty acids which can be converted into amides by the process according to the invention are prostaglandins, preferably prostaglandin G ₂ , prostaglandin D ₂ , prostaglandin E ₂ , prostaglandin F _2α , thromboxane A ₂ and prostacyclin I ₂ , and leukotrienes, preferably leukotriene A ₄ . Leukotriene B ₄ , leukotriene C ₄ , leukotriene D ₄ , and leukotriene E ₄ . The prostaglandins and leukotrienes may also contain amine groups. For the reaction, the amine - preferably according to the general formula (I) - preferably first dissolved in an organic solvent. The solvent is preferably an apolar aprotic solvent (preferably as mentioned above) or a mixture of an apolar aprotic solvent (such as dichloromethane) and a polar protic solvent (such as ethanol). The solvent or solvent mixture used is preferably anhydrous, ie it preferably contains less than 1%, more preferably less than 0.1% of water. The solvent preferably contains no amide groups.

Parallel or subsequently, the addition of a coupling reagent which is capable of activating the carboxylic acid takes place. Such coupling reagents are known from peptide synthesis and belong to different classes, such as. B .:

Phosphonium salts (eg BOP),

Uronium and / or guanidinium salts (eg HBTU, HATU),

• Immonium reagents,

Carbodiimide reagents (eg DCC),

• imidazolium reagents,

• organophosphorous reagents,

Acidic halogenating reagents,

• chloroformates.

Phosphonium salts, uronium and / or guanidinium salts are preferably used as coupling reagents.

The coupling reagents preferably have the following general structure:

(AW) ⁺ Y ^" (IV)

A stands for two or three amine radicals which are bonded to a central atom selected from P and C. The amine radicals are preferably completely substituted by aliphatic and / or cyclic alkyl radicals. If the central atom is a carbon, preferably 2 amino nitrogens are bound thereto. If the central atom is a phosphorus, 3 Am are preferentially bound in nitrogen. The aliphatic alkyl radicals preferably contain 1 to 4 C atoms. The cyclic alkyl radicals preferably contain 4 to 6 C atoms. The nitrogen of the amine is preferably part of the ring system. W is a halogen, azide (N ₃ ) or a substituted or unsubstituted alkyl or alkylene radical which is bonded directly or via an oxygen or a sulfur to the P or C atom of the radical A. Preference is given to a substituted or unsubstituted cyclic alkyl radical which contains an aromatic, heteroaromatic or nonaromatic ring system having preferably 1 to 3 rings and preferably 5 to 12 C atoms and up to 6 N atoms.

Y ^" is a suitable anion, preferably selected from monovalent inorganic anions, Y ^" is preferably selected from halogen, such as Cl ^" , F ^" and Br ^" , as well as BF ₄ ^" , PF ₆ ^" , and CIO ₄ ^" .

Preferably, the coupling reagent is a phosphonium salt having the general formula

FL

/ ⁷

N

^R * HI

- P ⁺ - wr (V)

^R 10 N

N

R ₁₂ used, wherein R ₇ to R _{12 are} preferably independently selected from aliphatic and / or cyclic alkyl radicals or alkoxy radicals, which are each substituted or unsubstituted. The aliphatic alkyl radicals or alkoxy radicals preferably contain 1 to 4 C atoms, particularly preferably methyl. The cyclic alkyl radicals preferably contain 4 to 6 C atoms. The nitrogen of the amine is preferably part of the ring system, which means that two or more of the radicals R ₇ to R ₁₂ together represent a divalent alkyl radical which forms a ring together with the N.

Preferred compounds of formula IV are (IV ^ N) ₃ P ⁺ -WY ^" and compounds having a cyclic amine, especially of the general formula:

or corresponding compounds with other heterocyclic hydrocarbons containing at least one N-atom in the ring. These heterocyclic hydrocarbons include in particular substituted pyrrolidine and / or substituted or unsubstituted azine radicals, such as pyridazines, pyrimidines and pyrazines. W in the formula IV is preferably selected from halogen (preferably Br, Cl), N ₃ and

T and T are independently selected from H, NO ₂ and CF ₃ .

Preferred W according to formula VII are in particular

OBt: with T ¹ = H, 1 ^"2 = H,

NO ₂ -OBt: with T ¹ = N0 ₂ , T ² = H

CF ₃ -OBt: with T ¹ = CF ₃ , T ² = H

CF ₃ -NO ₂ -OBt: with T ¹ = CF ₃ , T ² = NO ₂

Further preferred W are:

OAt:

ODhbt: (IX)

SPy: (X)

S N

as well as OPfp:

Y ^" in the formula IV, V and VI is particularly preferably selected from PF ₆ ^" , BF ₄ ^" , Cl ^" , F ^" , Br ^" , CIO ₄ ^" . Alternatively, the coupling reagent used is a guanidinium salt and / or uronium salt of the following general formula:

M3

/ (XII)

^R 14 \

C ⁺ -W r

/

R N

15 \

R 16

R- _I 3, R ₁₄ , R- _I5 and Ri6 are selected as described for R ⁷ to R ¹² .

Preferred compounds of formula VIII are selected from the general formulas:

wherein R ₁₃ and Ri _{4 are} as selected above, but more preferably selected from aliphatic radicals such as methyl.

W is preferably selected from halogen, in particular F, Cl, Br, and the following formulas a) to I):

Y ^" here is particularly preferably selected from PF ₆ ^" , BF ₄ ^" , Cl ^" , F ^" , Br ^" , CIO ₄ ^" .

Particularly preferred coupling reagents are:

1. HBTU (2- (1H-Benzotriazole-1-yl) -1, 1, 3,3-tetramethylaminium hexafluorophosphate):

2. HATU (CAS No. 148893-10-1):

3. HCTU (2- (6-chloro-1H-benzotriazole-1-yl) -1,3,3-tetramethylaminium hexafluorophosphate):

4. TBTU (1H-benzotriazol-1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate):

5. BOP (Benzotriazole-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate):

6. PyBOP® (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate):

7. NOP (6-nitrobenzotriazole-1-ylxytris (dimethylamino) phosphonium hexafluoro-phosphate): The mixture of amine component and coupling reagent is preferably mixed with a fatty acid of general formula (III) dissolved in the same organic solvent. The fatty acid is preferably used in a molar ratio in the range from 1: 0.5 to 1: 2, more preferably from 1: 0.8 to 1: 1, 2 to the amine used. The starting materials are preferably used in a concentration range of 5 to 500 mmol / l, especially in concentrations between 20 to 100 mmol / l.

The pH should be maintained throughout the reaction in a range of pH 7 to 11, preferably in a range of pH 8 to pH 10. The pH is adjusted by addition of a base, preferably a basic solvent, more preferably a tertiary amine or a cyclic amine as a base. Preferred tertiary amines are trimethylamine, triethylamine or tripropylamine, correspondingly mixed amines, such as. Methyldiethylamine, or another trialkylamine.

The reaction is preferably carried out at a temperature between 4 ° C and 42 ° C, more preferably between 16 ° C and 25 ° C. The reaction is preferably carried out until no decrease in the fatty acid concentration is observed.

The resulting amide, preferably according to the general formula

is obtained after separation of impurities preferably by washing the batch with aqueous solutions of various salts such as KHSO ₄ , NaHCC> 3 and NaCl from the reaction mixture, for example by crystallization. If necessary, purification may preferably be by column chromatography, solid phase extraction or recrystallization.

Through the advantageous use of coupling reagents such as phosphonium, uronium or guanidinium salts, such as BOP, NOP, TBTU, HBTU or HATU in a simple one-step synthesis tryptamine and tryptamine derivatives such as Serotonin, methylserotonin, methyltryptamine or methoxytryptamine reacted with free fatty acids to the corresponding fatty acid amides.

Advantageously, the mild reaction conditions of the process described allow the reaction of both saturated and unsaturated and hydroxy fatty acids for the synthesis of fatty acid amides. Advantageously, yields of over 90% result.

The invention also provides the use of the compounds prepared by the process according to the invention for the preparation of a standard solution for analytics, in food chemistry and in pharmacy.

In food chemistry, the compounds are preferably used as standards in the quality control of coffee and cocoa.

When used in pharmacy, the coupling of the amine to the fatty acids facilitates passage through epithelia or cell membranes, e.g. As the intestinal epithelium, and thus increases the intake in the intestine on oral administration. Moreover, the coupling of the amine to the fatty acids allows passage through the blood-brain barrier. Also in a transdermal, rectal, vaginal or nasal application, the coupling of the amine to the fatty acids facilitates passage through the mucosa or dermis. In addition, the coupling of the amide to the fatty acids can cause a depot effect, especially on subcutaneous administration.

EXAMPLES

The method according to the invention will be explained in more detail by the following exemplary embodiments, without being limited thereto:

Embodiment 1

A solution of the coupling reagent 0- (1H-benzotriazol-1-yl) -N, N, N 'is added with stirring to a solution of 0.4 mmol of the amine component serotonin in a mixture of 15 ml of dichloromethane and the same amount of ethanol. N'-tetramethyl-uronium hexafluorophosphate (HBTU, 0.44 mmol in 40 ml dichloromethane). Subsequently, a previously prepared solution of 0.44 mmol palmitic acid in dichloromethane is added under constant stirring and treated with 200 ul of triethylamine as the base. The pH is controlled throughout the reaction and maintained within the range of pH 8 to pH 10, if necessary adjusted by additional addition of the base. The course of the reaction can be monitored by means of TLC control of the fatty acid content. If no decrease in fatty acid concentration is recorded, the reaction is complete. The entire mixture is transferred while rinsing the reaction vessel with 40 ml of ethyl acetate in a separating funnel and shaken three times with 30 ml of a 5% potassium bisulfate solution. Subsequently, after three extractions with 30 ml of a 5% sodium bicarbonate solution, washed four times with 30 ml of a saturated saline solution each time. The organic phase is dried overnight with Na ₂ SC> ₄ , the solvent removed in vacuo and recrystallized from acetone.

The product 16-5HT was subsequently characterized by one-dimensional nuclear magnetic resonance (1 H NMR), liquid chromatography with mass spectrometry coupling (LC-MS) and high-resolution mass spectrometry (HRMS).

UV-Vis (acetonitrile / 2-propanol) λ _max : 222, 276, 298 nm; FL (acetonitrile / 2-propanol) λ _ex / λ _em : 280/330 nm;

LC / MS (APCI ⁺ ): 415.1 [M + H] ⁺ , (EPI 415): 398.2 [M-16] ⁺ , 282.4 [M-132] ⁺ , 256.3 [M-158 ] ⁺ , 177.1 / 160.1;

HRMS: 414.3197 (C ₂₆ H ₄₂ N ₂ O _2); ¹ H-NMR (500 MHz, CDCl ₃ + DMSO) δ / ppm: 9.14 (s, 1 H, HC ₅ ), 7.25 (s, 1 H, HN ₁ ), 6.99 (d, 1 H, HC ₇ ), 6.80 (dd, 2H, HC ₄ , HC ₂ ), 6.57 (dd, 1H, HC ₆ ), 6.18 (t, 1H, HN ₁₀ ), 3.32 (q, 2H, HC ₉ ), 2.68 (t, 2H, HC ₈ ), 2.40 (t, 2H, HC ₁₂ ), 1, 93 (t, 2H, HC ₁₃ ), 1, 05 (m , 3OH, H-C _14-25 ), 0.68 (t, 3H, HC ₂₆ ).

Embodiment 2:

The following table illustrates the applications of the process starting from various amine and acid components.

^* Embodiment 1

The synthesis was carried out as described in Example 1.

The products were then characterized by one-dimensional nuclear magnetic resonance ( ¹ H-NMR), liquid chromatography (FL), mass spectrometry (LC-MS) or mass spectrometry and high-resolution mass spectrometry (HRMS) as follows:

a) s. Embodiment 1; b) 18: 2-5HT: UV-Vis (acetonitrile / 2-propanol) λ _max : 223, 276, 299 nm;

FL (acetonitrile / 2-propanol) λ _e χ / λ _em : 280/330 nm;

LC / MS (APCI ⁺ ): 439.1 [M + H] ⁺ , (EPI 439): 422.2 [M-16] ⁺ , 306.4 [M-132] ⁺ , 280.3 [M-158 ] ⁺ , 177.1 / 160.1;

HRMS: 438.3262 (C ₂₈ H ₄₂ N ₂ O _2);

¹ H-NMR (500 MHz, CDCl ₃ + DMSO) δ / ppm: 8.00 (s, 1 H, HN ₁ ), 7.21 (d, 1 H, H-C ₇ ), 7.02-6 , 97 (dd, 2H, HC ₄ , HC ₂ ), 6.80 (dd, 1H, HC ₆ ), 5.66 (s, 1H, HN ₁₀ ), 5.34 (m, 4H, HC _{19 -20, 22-23} ), 3.54 (q, 2H, HC ₉ ), 2.88 (t, 2H, HC ₈ ), 2.09 (t, 2H, HC ₁₂ ), 2.02 (m, 4H, HC _{18, 21, 24} ), 1, 56 (t, 2H, HC ₁₃ ), 1, 30 (m, 16H, HC _14-17, _25-27 ), 0.87 (t, 3H, HC ₂₈ );

c) 20-5HT: UV-Vis (acetonitrile / 2-propanol) λ _max : 222, 276, 298 nm;

FL (acetonitrile / 2-propanol) λ _e χ / λ _em : 275/330 nm;

LC / MS (APCI ⁺ ): 471.2 [M + H] ⁺ , (EPI 471): 454.2 [M-16] ⁺ , 338.3 [M-132] ⁺ , 312.3

[M-158] ⁺ , 177.1 / 160.1;

HRMS: 470.3885 (C ₃₀ H ₅₀ N ₂ O _2);

¹ H-NMR (500 MHz, CDCl ₃ + DMSO) δ / ppm: 9.88 (s, 1 H, OH-C ₅ ), 7.67 (s, 1 H, HN ₁ ), 7.08 (i.e. , 1H, HC ₇ ), 6.88-6.85 (dd, 2H, HC ₄ , HC ₂ ), 6.59 (dd, 1H, HC ₆ ), 3.34 (q, 2H, HC ₉ ), 2.75 (t, 2H, HC ₈ ), 2.05 (t, 2H, HC ₁₂ ), 1, 49 (t, 2H, HC ₁₃ ), 1, 17 (m, 36H, HC _14-29 ), 0.79 (t, 3H, HC ₃₀ );

d) 20: 1 -5HT: UV-Vis (acetonitrile / 2-propanol) λ _max : 225, 276, 298 nm;

FL (acetonitrile / 2-propanol) λ _ex / λ _em : 275/330 nm;

LC / MS (APCI ⁺ ): 469.3 [M + H] ⁺ , (EPI 469): 452.2 [M-16] ⁺ , 336.3 [M-132] ⁺ , 310.3 [M-158 ] ⁺ , 177.1 / 160.1;

HRMS: 468.3750 (C ₃₀ H ₄₈ N ₂ O _2);

¹ H-NMR (500 MHz, CDCl ₃ + DMSO) δ / ppm: 7.98 (s, 1 H, HN ₁ ), 7.21 (d, 1 H, H-C ₇ ), 7.03-6 , 96 (dd, 2H, HC _4, HC _2), 6.79 (dd, 1 H, HC _6), 5.66 (s, 1 H, HN _10), 5.33 (m, 2H, HC _{21 , 22} ), 3.54 (q, 2H, HC ₉ ), 2.87 (t, 2H, HC ₈ ), 2.1 l (t, 2H, H-C ₁₂ ), 1.99 (m, 4H , C _{20, 23} ), 1, 56 (t, 2H, HC ₁₃ ), 1, 25 (m, 26H, HC _{14-19, 24-29} ), 0.87 (t, 3H, HC ₃₀ ); e) 16-OH-5HT: UV-Vis (acetonitrile / 2-propanol) λ _max : 223, 276, 299 nm;

FL (acetoynitrile / 2-propanol) λ _e χ / λ _em : 280/330 nm;

LC / MS (APCI ⁺ ): 431.2 [M + H] ⁺ , (EPI 431): 414.2 [M-16] ⁺ , 413.2 [M-17] ⁺ , 396.4 [M-34 ] ⁺ , 298.3 [M-132] ⁺ , 177.1 / 160.1;

HRMS: 430.3184 (C ₂₆ H ₄₂ N ₂ O _3);

¹ H-NMR (500 MHz, CDCl ₃ + DMSO) δ / ppm: 9.80 (s, 1 H, HO-C ₅ ), 7.60 (s, 1 H, HN ₁ ), 7.09 (i.e. , 1H, HC ₇ ), 6.98 (t, 1H, HO-Ci ₆ ), 6.88 (dd, 2H, HC ₄ , HC ₂ ), 6.60 (dd, 1H, HC ₆ ) , 3.36 (q, 2H, HC ₉ ), 2.75 (t, 2H, HC ₈ ), 2.50 (t, 2H, H-Ci ₂ ), 2.04 (t, 2H, HC ₁ 3 ), 1.50 (t, 2H, HC ₂₅ ), 1.40 (m, 2H, HC ₂₆ ), 1.16 (m, 24H, H-Ci _4-24 );

f) 16-TAM: LC / MS (APCI ⁺ ): 399.2 [M + H] ⁺ , (EPI 399): 382.1 [M-16] ⁺ , 282.2 [M-1 16] ⁺ , 256.2

[M-142] ⁺ , 161, 1 / 144,1;

¹ H-NMR (500 MHz, CDCl ₃ + DMSO) δ / ppm: 8.12 (s, 1 H, H-Ni), 7.61 (d, 1 H, H-C ₄ ), 7.36 ( d, 1H, HC ₇ ), 7.20 (t, 1H, HC ₆ ), 7.12 (t, 1H, HC ₅ ), 7.03 (s, 1H, H-C ₂ ), 5.52 (s, 1H, HN ₁₀ ), 3.60 (q, 2H, HC ₉ ), 2.97 (t, 2H, HC ₈ ), 2.09 (t, 2H, H-Ci ₂ ) , 1, 56 (t, 2H, HC ₁ 3), 1, 24 (m, 24H, H-Ci _4-25), 0.87 (t, 3H, HC _26);

g) 20-5MT: LC / MS (APCI ⁺ ): 485.3 [M + H] ⁺ , (EPI 485): 468.4 [M-16] ⁺ , 338.4 [M-132] ⁺ , 312 3

[M-158] ⁺ , 191, 2 / 174,1;

h) 21 -5HT: UV-Vis (acetonitrile / 2-propanol) λ _max : 223, 276, 299 nm;

LC / MS (APCI ⁺ ): 485.5 [M + H] ⁺ , (EPI 485): 468.4 [M-16] ⁺ , 352.4 [M-132] ⁺ , 326.5 [M-158 ] ⁺ , 177.2 / 160.3;

HRMS: 484.4018 (C ₃ iH ₅₂ N ₂ O ₂ ).

Claims

claims:

1. A process for the preparation of compounds of the general formula

with n = 0 to 5, R 1, R ₂ , R ₃ , R ₄ , R 5 selected from H, halogen, OH, NH ₂ , alkyl, alkenyl,

Alkynyl and alkoxy and R ₆ selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, characterized in that an amine of the general formula

with a fatty acid of the general formula

^R 6 \ (III)

OH with R ₆ selected from substituted or unsubstituted alkyl, alkenyl, alkynyl using a coupling reagent selected from phosphonium salts, uronium salts and / or guanidinium salts or a coupling reagent of the general structure

(AW) ⁺ Y ^" (IV) is implemented, where

A is two or three amine radicals bound to a central atom selected from P and C,

W is selected from halo, azide and substituted or unsubstituted alkyl or alkylene radicals wherein W is attached to the P or C atom of the A radical directly or through an oxygen or sulfur and Y ^"is a suitable anion.

2. The method according to claim 1, characterized in that at least one of the groups R ₁ , R ₂ , R ₃ , R ₄ , R 5 is selected from halogen, OH and NH ₂ .

3. The method according to claim 1 or 2, characterized in that the amine of the general my formula I is serotonin, methylserotonin tryptamine, methyltryptamine or methoxytryptamine.

4. The method according to any one of claims 1 to 3, characterized in that the coupling reagent is a phosphonium salt having the general formula

R ₀ R - ₇ i / ⁷

N

^R 9v I ₊

N - P ⁺ -WY ^" (V)

R I

10 N / \

R ₁₁ R ₁₂

is used, wherein R ₇ , R ₈ , Rg, Rio, Rn and Ri _{2 are} independently selected from aliphatic and / or cyclic alkyl radicals or alkoxy radicals, which are each substituted or unsubstituted, where appropriate, two or more of the radicals R ₇ to R ₁₂ in each case together represent a divalent radical which forms a ring together with the N.

5. The method according to claim 4, characterized in that the coupling reagent is a phosphonium salt of the general formula ((CH ₂ ) ₂ N) ₃ P ⁺ -WY ^" or

is used.

6. The method according to any one of claims 1 to 5, characterized in that W is selected from halogen (preferably Br, Cl), N ₃ and

with T ¹ and T ^2, preferably independently selected from H, NO ₂ and CF _3,

such as

7. The method according to any one of claims 1 to 3, characterized in that as a coupling reagent, a guanidinium salt and / or uronium salt selected from the general formula

R 13

R N

14 \

C ⁺ -W r

/ (XII)

R 15 \

16 is used, wherein Ri ₃ , Ri ₄ , Ri ₅ and Ri _{6 are} independently selected from aliphatic and / or cyclic alkyl radicals or alkoxy radicals, each of which is substituted or unsubstituted, optionally wherein two or more of R ₁₃ to Ri ₆ respectively together represent a divalent alkyl radical which forms a ring together with the N.

8. The method according to claim 7, characterized in that as a coupling reagent, a guanidinium salt and / or uronium salt selected from the following general formulas

is used.

9. The method according to any one of claims 1 to 8, in particular claim 7 or 8, characterized in that W is selected from halogen (preferably F, Cl or Br) or the following formulas a) to I),

10. The method according to any one of claims 1 to 9, characterized in that the anion Y ^"is selected from PF ₆ ^" , BF ₄ ^" , Cl ^" , F ^" , Br ^" and CIO ₄ ^" .

1 1. The method according to any one of claims 1 to 10, characterized in that the coupling reagent is selected from N - [(1 H-benzotriazol-1-yl) - (dimethylamino) - methylene] -N-methylmethanaminiumhexafluorophosphat-N-oxide ( HBTU), 1 H-benzotriazol-1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), (1H-benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP), 6 Nitrobenzotriazole-1-ylxytris (dimethylamino) phosphonium hexafluoro-phosphate (NOP) and N - [(dimethylamino) -1H-1,2,3-triazolo [4,5- b] pyridin-1-ylmethylene] -N -Methylmethan- aminium hexafluorophosphate N-oxide (HATU).

12. The method according to any one of claims 1 to 1 1, characterized in that it is carried out at a pH of pH 7 to pH 11, preferably pH 8 to pH 10.

13. The method according to any one of claims 12, characterized in that the pH is adjusted with a base, preferably a tertiary or cyclic amine.

14. Use of a compound prepared by the method according to any one of claims 1 to 13 in analytics, food chemistry in pharmacy or as a drug.