JPH0410452B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a decarboxylation reaction of a compound having a carboxyl group. More specifically, in the decarboxylation reaction, vinyl ketones are used as a catalyst.

Conventionally, compounds that are easily decarboxylated have been decarboxylated by direct heating. However, if the decarboxylation reaction does not go well in the direct heating method because the compound itself decomposes, the decarboxylation reaction is often carried out in the presence of a solvent. However, this reaction also has various drawbacks. For example, in the reaction of decarboxylating amino acid compounds using peroxide as a catalyst in the presence of tetralin or cyclohexanol (Pharmaceutical Journal, Vol. 85, p. 531, 1965), a dangerous peroxide is used as a catalyst. It has drawbacks such as high yield and low yield. In addition, in the reaction in which tryptophan is brought into contact with the microorganism Micrococcus persitreus to decarboxylate it (French Patent No. 2239459), the culture of the microorganism,
It has drawbacks such as requiring complicated operations for collecting the product. In addition, 9-phenanthrylacetic acid
In the reaction in which decarboxylation is carried out by reacting at 240°C for 24 hours (Can.J.Chem., Vol. 56, No. 5, p. 628, 1978), the reaction is carried out at a high temperature, the reaction time is long, etc. It has the following disadvantages. In addition, in the reaction of decarboxylating dodecylic acid at 320°C in the presence of equivalent moles of copper bromide (US Pat. No. 4,262,157), the reaction is carried out at a high temperature, a large amount of copper bromide is used, etc. It has the following disadvantages. Furthermore, the reaction in which tyrosine is decarboxylated at 260 to 265° C. in the presence of diphenylmethane (Synthesis, p. 475, 1972) has drawbacks such as the reaction being carried out at a high temperature and the yield being low.

The present invention has advantages such as using a small amount of cheap and safe vinyl ketones as a catalyst, allowing the reaction to proceed at a relatively low temperature, and achieving a high yield of 80% or more. Since the present invention can be applied to a wide range of compounds, it can be said to be an extremely excellent and groundbreaking invention.

In carrying out the present invention, compounds having a carboxyl group can be mentioned as compounds to be decarboxylated without particular limitation. For example, alicyclic aminocarboxylic acids such as azetidine-2-carboxylic acid, pyrrolidine-2-carboxylic acid, piperidine-2-carboxylic acid, hexamethyleneimine-2-carboxylic acid, piprazine-2-carboxylic acid; pyrrole-2-carboxylic acid; acid, imidazole-5-carboxylic acid, 4-pyridone-2,6-dicarboxylic acid,
Indole-2-carboxylic acid, 2,3-dihydroindole-2-carboxylic acid, 1,2,3,4-
Tetrahydroquinoline-2-carboxylic acid, thiazole-2-carboxylic acid, benzothiazole-2-
Heterocyclic aminocarboxylic acids such as carboxylic acid and benzothiazoline-2-carboxylic acid; glycine,
Monoamino monocarboxylic acids like alanine, valine, leucine, isoleucine, sarcosine, asparagine, glutamine, serine, threonine,
Aliphatic amino acids such as oxyamino acids such as homoserine, sulfur-containing amino acids such as methionine and cystine, basic amino acids such as arginine, lysine and ornithine, and acidic amino acids such as aspartic acid, glutamic acid and N-carboxymethylleucine. Aliphatic amino acids having an aromatic ring such as phenylalanine, tyrosine, 3-nitrotyrosine, N-carboxymethylphenylalanine, N-carboxymethyltyramine;
These include aliphatic amino acids having a heterocycle such as tryptophan, histidine, 2-thienylglycine, and 3-thienylglycine; aromatic amino acids such as anthranilic acid, m-aminobenzoic acid, and p-aminobenzoic acid; and the like. Preferably, a carboxylic acid compound having an amino group at the α, β, or γ position is suitable. These compounds may also have a group that does not participate in the reaction as a substituent. Examples of such substituents include alkyl such as methyl, ethyl, and propyl, alkoxy such as methoxy, ethoxy, and propoxy, halogen such as chloro and bromo, and hydroxy. Note that even if these compounds are stereoisomers, for example optical isomers, they are not affected by the reaction.

The vinyl ketones of the catalyst used in the present invention have the formula (In the formula, R ¹ and R ² represent an organic group. And,
R ¹ and R ² may be joined together to form a ring. ). As such compounds, the following compounds can be enumerated. That is, methyl, ethyl,
Alkyl such as propyl, alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, halogen such as chlor, bromo, alkenyl such as vinyl, 1-propenyl, isopropenyl, phenyl, hydroxy, amino, etc. Δ ² -cycloalkenones which may be present; for example Δ ² -cyclopropenones such as 2,3-diphenylcyclopropenone, 2,3-dihydro-4-oxo-Δ ² -cyclobutenone, 2,3 ,4,4-tetrachloro-
Δ ² -cyclobutenones such as Δ ² -cyclobutenone, Δ ² -cyclopentenone, 3-methyl-Δ ²
-Δ ² -cyclopentenones such as cyclopentenone, Δ ² -cyclohexenone, 2-methyl-
Δ ² -cyclohexenone, 3-methyl-Δ ² -cyclohexenone, 6-methyl-Δ ² -cyclohexenone, 3-amino-Δ ² -cyclohexenone, 2
-ethyl-4-ethoxycarbonyl-3-methyl-Δ ² -cyclohexenone, 4-ethoxycarbonyl-3-methyl-Δ ² cyclohexenone, 2,
6-dimethyl-Δ ² -cyclohexenone, 5-isopropenyl-2-methyl-Δ ² -cyclohexenone, 2-chloro-Δ ² -cyclohexenone, 3
−chloro−Δ ² − Δ ² − like cyclohexenone
Cyclohexenones, Δ ² -cyclododecenone,
Δ ^{2 such as 4-methyl-Δ 2 -cyclododecenone}
- Cyclododecenones, etc.: Cycloalkanones that may have alkylidene such as methylene, ethylidene, isopropylidene, cycloalkylidene such as cyclopentylidene, cyclohexylidene, cycloheptylidene, etc. as a substituent; 2-methylenecyclopentanone, 2-
methylenecyclopentane-1,3-dione, 2-
Cyclopentanones such as cyclopentylidenecyclopentanone, 2-methylenecyclohexanone, 2-isopropylidenecyclohexanone, 2
- Cyclohexanones such as cyclohexylidene cyclohexanone: methyl as a substituent,
1-acylcyclohexenes which may contain alkyl such as ethyl, propyl, halogen such as chlor, bromo, alkenyl such as vinyl, 1-propenyl, isopropenyl, phenyl, etc.; for example, 1-formylcyclohexene, 1
- Acetylcyclohexene, 4-isopropenyl-1-formylcyclohexene, etc.: Naphthoquinones, such as potassium 1,2-naphthoquinone-4-sulfonate, etc.: Aliphatic vinyl ketones, such as 1-octen-3-one, 4-methyl- 3-penten-2-one, 5-methyl-3-hexene-
Examples include 2-one, 6-methyl-5-hepten-4-one, and the like. The amount of catalyst used is 1 to 10% V/W, preferably 3% V/W based on the raw material compound.
~5% V/W.

The reaction is carried out in the presence or absence of a solvent. It is preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction, such as cyclohexanol,
Cycloalkanols such as cycloheptanol; tetralin, Δ ^9,10 -octarine, 1,2-
Examples include naphthalenes such as dihydronaphthalene and 1,4-dihydronaphthalene; cycloalkenones such as cyclohexanone and cycloheptanone; and quinolines such as quinoline, quinaldine, and lepidine. The reaction temperature is usually
The temperature is about 120 to 250°C, preferably about 140 to 160°C.

In the reaction, after suspending or dissolving the raw material compound in a solvent, a catalyst is added, and the mixture is heated and stirred, preferably under a nitrogen stream. After the reaction has ended, the product obtained is isolated from the reaction mixture, for example by precipitation as a hydrohalide salt or by distillation. The product thus obtained is purified by recrystallization, column chromatography, etc., if necessary.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 3-Hydroxypyrrolidine 90 g of 4-hydroxy-L-proline was suspended in 450 ml of cyclohexanol, and then 4.5 ml of Δ ² -cyclohexenone was added and the mixture was heated and stirred under a nitrogen stream. The reaction mixture was stirred at 154±2° C. for 2 hours, resulting in a homogeneous solution. After the reaction was completed, the reaction mixture was cooled to 10°C, and then 850ml of ethyl acetate was added to it.
was added and cooled to 0-5°C. Then, 27.5 g of hydrogen chloride and 80 ml of isopropanol were added to the reaction mixture.
The mixture was added while keeping the internal temperature below 5°C. The reaction mixture was then stirred for 1 hour, and the precipitate was collected by filtration. The precipitate was washed with 90 ml of isopropanol and then with 90 ml of ethyl acetate, and then dried to obtain 76 g (90%) of the hydrochloride of the target compound.

(1) Melting point 107.8℃ (hydrochloride) (2) Nuclear magnetic resonance spectrum (d ⁶ -DMSO) δ:
ppm Measured at 60MHz using TMS as an internal standard (the same applies to the following examples).

1.75~2.10 (2H, m) 3.05~3.35 (4H, overlap of d and t, J=2Hz,
J=6Hz) 4.42 (1H, m) (3) Infrared absorption spectrum ν ^Nujol _nax cm ^-1 : 3300, 2460, 1600, 1340, 1210 Example 2 Pyrrolidine Same as Example 1 using 90g of L-proline. When carried out, 77.4 g (92%) of the hydrochloride salt of the target compound was obtained.

(1) Melting point 87-88℃ (hydrochloride) (2) Nuclear magnetic resonance spectrum (d ⁶ -DMSO) δ:
ppm 1.6-1.78 (4H, m) 2.7-2.9 (4H, m) (3) Infrared absorption spectrum ν _nax cm ^-1 : 3250, 1350, 1070 Example 3 20 g of 1,5-diaminopentane L-lysine hydrochloride cyclohexanol
The suspension was suspended in 100 ml, and then 21.2 ml of 28% sodium methoxide was added, followed by 1 ml of 3-methyl-Δ ² -cyclohexenone. The reaction mixture was incubated at 155°C for 3
The mixture was heated and stirred for hours. After the reaction was completed, 20 ml of an isopropanol solution containing 4 g of hydrogen chloride was added to the reaction mixture. Then, the precipitate precipitated from the reaction mixture was collected by filtration. When the precipitate was dried, 16.3 g (85%) of the dihydrochloride of the target compound was obtained.

(1) Melting point 255-257℃ (dihydrochloride) (2) Nuclear magnetic resonance spectrum (d ⁶ -DMSO) δ:
ppm 1.45-1.95 (6H, m) 2.65-3.30 (4H, m) 8.20 (4H, s) (3) Infrared absorption spectrum ν ^Nujol _nax cm ^-1 : 3350, 1600 Example 4 (-)-1-amino- 2-propanol L-threonine 35.7g, cyclohexanol
The same procedure as in Example 1 was carried out using 180 ml and 1.8 ml of Δ ² -cyclohexenone, and treatment with oxalic acid yielded 39.6 g (80%) of the oxalate of the target compound.

(1) Melting point 140-142℃ (bioxalate) 97℃ (hydrochloride) (2) Boiling point 160℃ (educt) (3) Specific rotation Hydrochloride [α] ²⁰ _D = -32.00° (C = 2.925,
H ₂ O) Bioxalate [α] ²⁰ _D = -22.65° (C =
2.052, H ₂ O) (4) Nuclear magnetic resonance spectrum (d ⁶ −DMSO) δ:
ppm 1.25 (3H, d, = 6Hz) 2.38-2.50 (2H, m) 3.6-3.8 (1H, m) (5) Infrared absorption spectrum ν _nax cm ^-1 : 3350, 1600, 1460, 1140, 1050 Example 5 β-phenethylamine 10 g of 1-(-)-phenylalanine, 50 ml of cyclohexanol and 0.5 ml of ³ -methyl-Δ2cyclohexenone were carried out in the same manner as in Example 1. 8.6 g of the hydrochloride of the target compound (90% )was gotten.

(1) Melting point 217℃ (hydrochloride) (2) Boiling point 197-200℃ (educt) (3) Nuclear magnetic resonance spectrum (d ⁶ -DMSO) δ:
ppm 2.55-2.85 (4H, m) 7.22 (5H, s) Example 6 Isobutylamine If carried out in the same manner as in Example 1 using 20 g of valine, 100 ml of cyclohexanol and 1 ml of 3-methyl-Δ ² -cyclopentenone. Hydrochloride of target compound
16.8g (90%) was obtained.

(1) Melting point 158-160℃ (hydrochloride) (2) Boiling point 66-71℃ (educt) (3) Nuclear magnetic resonance spectrum (d ⁶ -DMSO) δ:
ppm 0.92 (6H, dd, J=6Hz) 1.35-1.70 (1H, m) 2.50 (2H, d, J=6Hz) (4) Infrared absorption spectrum ν ^Nujol _nax cm ^-1 : 1610, 1515, 1405 conducted Example 7 3-Methylthiopropylamine When the same procedure as in Example 1 was carried out using 10 g of methionine, 50 ml of cyclohexanol and Δ ² -cyclohexenone, the hydrochloride salt of the target compound was 8.1 g (85%).
was gotten.

(1) Melting point 143-144℃ (hydrochloride) (2) Nuclear magnetic resonance spectrum (d ⁶ -DMSO) δ:
ppm 2.06 (3H, s) 2.45-3.15 (4H, m) 3.42 (1H, s) 8.30 (2H, s) Example 8 N-methylphenethylamine 5g of N-carboxymethyl-L-phenylalanine was added to 50ml of tetralin Then, 0.5 ml of 3-methyl-Δ ² -cyclohexenone was added and the mixture was heated under reflux for 4 hours. After the reaction is complete, the reaction mixture is
When carried out in the same manner as in Example 1, the hydrochloride of the target compound 3.1
g (80%) was obtained.

(1) Melting point 162℃ (hydrochloride) (2) Nuclear magnetic resonance spectrum (d ⁶ -DMSO) δ:
ppm 2.30 (3H, s) 2.50-2.58 (4H, m) 7.20 (5H, s) Example 9 3-Hydroxypyrrolidine In Example 1, 9 g of 2-cyclohexylidenecyclohexanone was used instead of Δ ² -cyclohexenone. Then, a similar reaction was carried out to obtain 74.3 g (88%) of the hydrochloride of the target compound.

The physical constants were the same as those obtained in Example 1.

Example 10 3,4-dimethoxyaniline 2-amino-4,5-dimethoxybenzoic acid 20
In the same manner as in Example 1 using 100 ml of cyclohexanol and 1 ml of 3-methyl-Δ ² -cyclopentenone, 16.4 g (85 g) of the hydrochloride of the target compound was obtained.
%)was gotten.

(1) Melting point 149℃ (decomposition) (hydrochloride) (2) Nuclear magnetic resonance spectrum (d ⁶ -DMSO) δ:
ppm 3.82 (3H, s) 3.90 (3H, s) 4.82 (2H, s) 6.96 (3H, s) Example 11 Aniline 10 g of p-aminobenzoic acid was suspended in 50 ml of tetralin, and then 3-methyl-Δ ² - 1 ml of cyclohexenone was added and the mixture was heated under reflux for 5 hours. After the reaction was completed, the reaction mixture was treated in the same manner as in Example 1 to obtain 7.5 g (80%) of the hydrochloride of the target compound.

(1) Melting point 198℃ (hydrochloride) (2) Boiling point 184-186℃ (educt) (3) Nuclear magnetic resonance spectrum (d ⁶ -DMSO) δ:
ppm 3.35 (2H, s) 6.35-7.20 (5H, m) Example 12 Tryptamine Tryptophan 20g, cyclohexanol 100
ml and 1 ml of 1-octen-3-one,
When carried out in the same manner as in Example 1, the hydrochloride of the target compound 15.4
g (80%) was obtained.

(1) Melting point 250℃ (decomposed) (hydrochloride) 113-118℃ (educt) (2) Nuclear magnetic resonance spectrum (d ⁶ -DMSO) δ:
ppm 3.18 (4H, s) 6.90-7.70 (5H, m) 8.20 (1H, s) (3) Infrared absorption spectrum ν ^Nujol _nax cm ^-1 : 3320, 1600, 1540, 1240, 1180 Example 13 3R-hydroxypyrrolidine In Example 1, 4R-hydroxy-L-proline90 was used instead of 4-hydroxy-L-proline.
When the reaction was carried out in the same manner using g, 78.9 g (93%) of the hydrochloride of the target compound was obtained.

(1) Melting point 108℃ (hydrochloride) (2) Specific rotation hydrochloride [α] ²⁰ _D = -7.81° (C = 3.316, H ₂ O)

Claims (1)

[Claims] 1. A decarboxylation reaction of a compound having a carboxyl group, which is characterized by using vinyl ketones as a catalyst.