JPH0160019B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel piperidine derivatives, in particular the following general formula () (In the formula, A represents an oxygen atom or a sulfur atom,
R is a halogen atom, an alkyl group, an alkenyl group,
Aralkyl group, alkoxy group, alkanoyl group,
It has 1 to 3 substituents selected from an alkanoylamino group, a nitro group, a cyano group, a formyl group, an aminosulfonyl group, a trihalogenomethyl group, an alkoxycarbonyl group, a benzyloxycarbonyl group, a carboxyl group, and an aryl group. represents a phenyl group, a pyridyl group, a naphthyl group, an indanyl group, or a tetrahydronaphthyl group, which may be However, when A is an oxygen atom, the case where R is a phenyl group which may have one substituent selected from an alkyl group, an alkoxy group, a halogen atom, and a benzyloxycarbonyl group is excluded. and n represents an integer of 0 or 2) The present invention relates to a novel amidinopiperidine derivative represented by the following formula, an acid addition salt thereof, and a method for producing the same. The present inventors have been synthesizing piperidine-based compounds over a long period of time and studying their pharmacological effects.
The present invention has been completed based on the discovery that a novel amidinopiperidine derivative represented by the above general formula () and its acid addition salt have excellent anti-complement effects, allergic inflammation suppressing effects, proteolytic enzyme inhibiting effects, etc. Therefore, an object of the present invention is to provide a novel compound represented by the general formula () and an acid addition salt thereof having excellent pharmacological action. Another object is to provide a method for producing a novel compound represented by the general formula (). Groups that can be substituted with the phenyl group, pyridyl group, naphthyl group, indanyl group, or tetrahydronaphthyl group represented by R in the novel amidinopiperidine derivative represented by the general formula () include halogen atoms such as chlorine, bromine, and fluorine; Alkyl groups such as methyl, ethyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, alkenyl groups such as allyl group, benzylphenethyl,
Aralkyl groups such as α,α-dimethylbenzyl and phenylpropyl, alkoxy groups such as methoxy, ethoxy, propoxy and butyloxy groups, alkanoyl groups such as acetyl and propanoyl groups, trihalogenomethyl groups such as trifluoromethyl, and alkanoyl groups , nitro group, cyano group, formyl group, aminosulfonyl group, alkoxycarbonyl group, benzyloxycarbonyl group, carboxyl group, and aryl group. and,
Not only one of these substituents may be used, but up to three may be substituted in various combinations. In addition, acid addition salts of the compound of general formula () include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid,
Examples include acid addition salts such as methanesulfonic acid and p-toluenesulfonic acid. The novel amidinopiperidine derivatives of general formula () and acid addition salts thereof of the present invention are produced as follows. (In the formula, R′ is a halogen atom, an alkyl group, an alkenyl group, an aralkyl group, an alkoxy group, an alkanoyl group, an alkanoylamino group, a nitro group,
Cyano group, formyl group, aminosulfonyl group, trihalogenomethyl group, alkoxycarbonyl group,
It represents a phenyl group, a pyridyl group, a naphthyl group, an indanyl group, or a tetrahydronaphthyl group which may have one to three substituents selected from a benzyloxycarbonyl group and an aryl group. however,
When A is an oxygen atom, R' is not a phenyl group which may have one substituent selected from an alkyl group, an alkoxy group, a halogen atom, and a benzyloxycarbonyl group. and A, R and n are the same as above) In other words, the novel amidinopiperidine derivative of the general formula () is a compound of the general formula (), a salt thereof or a reactive derivative thereof, a compound represented by the general formula () or its reactive derivative. When a sulfite derivative is reacted to optionally obtain a compound having a carboxyl group as a substituent in the group represented by R as the target product, the compound having a benzyloxycarbonyl group may be subjected to a hydrogenation reaction. Manufactured by. Examples of reactive derivatives of the compound of general formula () include acid halides such as acid chloride and acid bromide, mixed acid anhydrides and active esters such as ethyl chlorocarbonate and butyl chlorocarbonate. The sulfite derivative of the compound of general formula () can be easily obtained by reacting the compound of general formula () with thionyl chloride in the presence of a tertiary amine. Reaction combinations include reactions between reactive derivatives of compounds of general formula () and compounds of general formula ();
Examples include a reaction between a compound represented by the general formula () or a salt thereof and a compound represented by the general formula (), and a reaction between a compound represented by the general formula () or a salt thereof and a sulfite derivative of the compound represented by the general formula (). The reaction between the reactive derivative of the compound of the general formula () and the compound of the general formula () is 0.5 to 5% at -10°C to room temperature.
This is done by stirring for a period of time. Examples of the reaction solvent include dimethylformamide, dichloromethane, dichloroethane, chloroform, and acetonitrile, and the reaction is preferably carried out in the presence of a tertiary amine such as triethylamine and dimethylaniline. The reaction between the compound of general formula () or a salt thereof and the compound of general formula () is preferably carried out using a carbodiimide such as dicyclohexylcarbodiimide as a condensing agent and stirring at room temperature for 5 hours to 5 days. Preferred solvents include dimethylformamide, dimethylacetamide, pyridine, toluene, xylene, dimethyl sulfoxide, and mixtures thereof. In addition, the reaction between the compound of general formula () or its salt and the sulfite derivative of the compound of general formula () is carried out by stirring in a solvent such as dimethylformamide, dimethylacetamide, pyridine, or a mixture thereof at 0°C to room temperature for 1 to 10 hours. This is done by In addition, when a compound having a benzyloxycarbonyl group in the R group is obtained among the compounds of the general formula () by the above condensation reaction, it can be obtained by subjecting it to a hydrogenation reaction if desired. It can be converted into a carboxyl group. The hydrogenation method is easily carried out by adding hydrogen in the presence of palladium or the like. When obtaining the acid addition salt of the novel amidinopiperidine derivative of the general formula (), it is preferable to use the acid addition salt of the compound of the general formula () as a raw material to obtain the desired product in the form of its salt. The compound of general formula (), which is a raw material, can be easily obtained by reacting 4-piperidinecarboxylic acid or 4-piperidinepropionic acid with o-methylisourea or S-methylisothiourea at room temperature for 5 to 20 hours. The compound of the present invention having the general formula () obtained as described above has an anti-complement effect, an inhibitory effect on allergic inflammation such as inhibition of the Arthus reaction, and suppression of delayed-type hypersensitivity, as well as a protease inhibitory effect. , useful as a medicine. Regarding the effect on complement, human and guinea pig fresh serum was used to examine how the compounds of the present invention inhibit hemolytic reactions via the classical pathway and the alternative pathway. That is, the classical route was tested by adding gelatin veronal buffer, sheep red blood cells, and anti-sheep red blood cell antibodies to fresh human or guinea pig serum to cause a hemolytic reaction. The second route was tested by adding rabbit red blood cells to fresh human or guinea pig serum to cause a hemolytic reaction. 50 for the classical path obtained in this way
% inhibitory concentration (CH ₅₀ ) and 50 for the alternative pathway
The % inhibitory concentration (ACH ₅₀ ) is shown in Table 1.

【table】

[Table] The effect on allergic inflammation was investigated by testing how the compounds of the present invention suppress Arthus reaction and delayed-type hypersensitivity. The Arthus reaction was tested in reverse passive mode using guinea pigs. That is, ovalbumin was administered as an antigen into the forelimb vein, and 15 minutes later, rabbit antiserum collected in advance was injected intradermally into the back. It was observed in The test compound was orally administered 1 hour before antigen administration. Observations were made by measuring the long axis x short axis of redness and edema, and expressed as inhibition rate (%) relative to control. The results are shown in Table 2.

【table】

[Table] BCG in ICR mice for delayed-type hypersensitivity
Sensitization was performed by intradermally administering live bacteria to the back, and 6 days later, BCG live bacteria was again administered intradermally to the footpads for induction.
The thickness of the paw swelling was measured at 24 hours by intradermal administration of live BCG bacteria. The test compound was orally administered continuously for 6 days from the day after sensitization. The results are shown in Table 3, expressed as the inhibition rate (%) determined from the difference in foot thickness from the control.

【table】

[Table] Regarding the protease inhibitory effect, the effect of the compounds of the present invention on the water-degrading ability of synthetic substrates such as trypsin, chymotrypsin, plasmin, kallikrein, thrombin, and urokinase was investigated. As a result, the compound of the present invention showed particularly strong inhibition against trypsin, chymotrypsin, and urokinase. From the above results, the compounds of the present invention are useful as prophylactic or therapeutic agents for allergic inflammation and shock. Next, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto in any way. Example 1 1-amidino-4-piperidine propionic acid phenyl ester hydrochloride: 707 mg of 1-amidino-4-piperidine propionic acid hydrochloride and 1.1 g of diphenyl sulfite were dissolved in 8 ml of anhydrous dimethylformamide and 3 ml of anhydrous pyridine at room temperature. Stirred overnight. The solvent was distilled off under reduced pressure, the residue was washed twice with 20 ml of ether, and the resulting crystals were collected and washed with acetone. This was dissolved in 4 ml of methanol, added to a solution of 20 ml of ether and 30 ml of acetone, and crystallized. The precipitated crystals were collected and washed twice with 30 ml of hot ethyl acetate to obtain 643 mg (69% yield) of 1-amidino-4-piperidine propionic acid phenyl ester hydrochloride as colorless crystals with a melting point of 167-170.5°C. Ta. IR ν ^KBr _nax cm ^-1 : 1735 (C=O) NMR (CD ₃ OD) δ: 1.00-4.00 (13H, m, piperidine hydrogen and C H ₂ C H ₂ CO) 6.90-7.40 (5H, m, aromatic Example 2 1-amidino-4-piperidine propionic acid o
-Benzyloxycarbonyl phenyl ester hydrochloride: 707 mg of 1-amidino-4-piperidine propionic acid hydrochloride and 2.3 g of bis-(o-benzyloxycarbonylphenyl) sulfite in 8 ml of anhydrous dimethylformamide and 3 ml of anhydrous pyridine.
The mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was washed three times with 20 ml of ether. Next, washing with 20 ml of ethyl acetate precipitated crystals, which were recrystallized from isopropanol to give colorless crystals with a melting point of 148-150°C, 710 mg of 1-amidino-4-piperidine propionic acid o-benzyloxycarbonyl phenyl ester hydrochloride. (yield 51%). IR ν ^KBr _nax cm ^-1 : 1750, 1705 (C=O) NMR (CD ₃ OD) δ: 1.00-4.00 (13H, m, piperidine hydrogen _{and CH 2} C H ₂ CO) 5.20 (2H, s, C H2 _- Ph) 6.96-8.96 (9H, m, aromatic hydrogen) Example 3 1-amidino-4-piperidinepropionic acid o
-Hydroxycarbonyl phenyl ester hydrochloride: 1-amidino-4-piperidine propionic acid o
-Add 5.5g of benzyloxycarbonyl phenyl ester hydrochloride to 60ml of t-butyl alcohol and water.
10% palladium-carbon 225 dissolved in 60ml mixture
mg was added thereto, and the mixture was shaken at room temperature for 1 hour in the presence of hydrogen at an initial pressure of 2.4 Kg/cm ² . The catalyst was separated and the solvent was distilled off. Wash the residue with t-butyl alcohol,
3.5 g of 1-amidino-4-piperidine propionic acid o-hydroxycarbonylphenyl ester hydrochloride as colorless needles with a melting point of 192-194°C (yield
79.7%). IR ν ^KBr _nax cm ^-1 : 1745, 1725 (C=O) NMR (DMSO-d ₆ ) δ: 0.8 to 2.0 (7H, m, 3
- and 5-H ₂ , 4-H, β-H ₂ ) 2.65 (2H, distorted t, α-H ₂ ) 2.8-4.2 (4H, m, 2- and 6-H ₂ ) 7.2-8.3 (4H, m, aromatic hydrogen) Example 4 1-amidino-4-piperidine propionic acid
2',4'-Dichlorophenyl ester hydrochloride: 1.7 g of 1-amidino-4-piperidine propionic hydrochloride and 4.0 g of bis-(2,4-dichlorophenyl)sulfite in 10 ml of anhydrous dimethylformamide and 3 ml of anhydrous pyridine. 45 at room temperature
Stir for a minute. The solvent was distilled off under reduced pressure, and 30 ml of ethyl acetate was added to the residue to stimulate crystals to precipitate. The crystals were collected and washed successively with ethyl acetate and ether to give 2.0 g of 1-amidino-4-piperidinepropionic acid 2',4'-dichlorophenyl ester hydrochloride as a colorless powder with a melting point of 152-156°C (yield: 73 %)
I got it. IR ν ^KBr _nax cm ^-1 : 1760 (C=O) NMR (CD ₃ OD) δ: 1.10-4.00 (13H, m, piperidine hydrogen and C H ₂ C H ₂ CO) 7.20-7.70 (3H, m, aromatic Example 5 1-amidino-4-piperidine propionic acid p
-Chlorphenyl ester hydrochloride: 1.5 g of 1-amidino-4-piperidine propionic hydrochloride and bis-(p-chlorphenyl)
7.7g of sulfite in anhydrous dimethylformamide
in a mixture of 12 ml and anhydrous pyridine at room temperature.
Stir for 30 minutes. The solvent was distilled off under reduced pressure, ether was added to the residue, the precipitated crystals were collected, washed twice with ether and then with ethyl acetate, and then dissolved in methanol.
1.75 g of 1-amidino-4-piperidine propionic acid p-chlorophenyl ester hydrochloride as colorless crystals with a melting point of 173-176°C after recrystallization from ether.
(yield 79.5%). IR ν ^KBr _nax cm ^-1 : 1735 (C=O) NMR (CD ₃ OD) δ: 1.08-4.05 (13H, m, pipeperidine hydrogen and CH ₂ C H 2 CO) 7.15-7.67 (4H, m, _aromatic Example 6 1-amidino-4-piperidine propionic acid p
-Methyl phenyl ester hydrochloride: 1.5 g of 1-amidino-4-piperidine propionic hydrochloride and bis-(p-methylphenyl)
6.7g of sulfite in anhydrous dimethylformamide
The mixture was stirred at room temperature for 2 hours in a mixture of 12 ml and 6 ml of anhydrous pyridine. The solvent was distilled off under reduced pressure, ether was added to the residue, the precipitated crystals were collected, washed twice with ether and further with ethyl acetate, and recrystallized from isopropyl alcohol-isopropyl ether to give colorless crystals with a melting point of 182-184℃. As a result, 1.87 g (yield 90%) of 1-amidino-4-piperidine propionic acid p-methylphenyl ester hydrochloride was obtained. IR ν ^KBr _{nax cm} ^-1 : 1743 (C=O) NMR (CD ₃ OD) δ: 1.00-4.00 (13H, m, pipeperidine hydrogen and CH ₂ C H 2 CO) 2.29 (3H, s, -C H ₃ ) 6.61-7.20 (4H, m, aromatic hydrogen) Example 7 1-amidino-4-piperidine propionic acid p
-Methoxyphenyl ester hydrochloride: 1.5 g of 1-amidino-4-piperidine propionic hydrochloride and bis-(p-methoxyphenyl)
6.8g of sulfite in anhydrous dimethylformamide
in a mixture of 14 ml and anhydrous pyridine at room temperature.
Stirred for 35 hours. The solvent was distilled off under reduced pressure, ether was added to the residue, the precipitated crystals were collected, washed twice with ether and further with ethyl acetate, and recrystallized from isopropyl alcohol-isopropyl ether to give a colorless substance with a melting point of 148-151°C. 1.25 g (yield 57%) of 1-amidino-4-piperidinepropionic acid p-methoxyphenyl ester hydrochloride was obtained as crystals. IR ν ^KBr _nax cm ^-1 : 1754 (C=O) NMR (CD ₃ OD) δ: 1.00-4.00 (13H, m, pipeperidine hydrogen and CH 2 C H _{2 CO} ) 3.75 (3H, s, OC H ₃ ) 6.63-7.04 (4H, m, aromatic hydrogen) Example 8 1-amidino-4-piperidine propionic acid p
-t-Butyl phenyl ester hydrochloride: 5.0 g of 1-amidino-4-piperidine propionic acid hydrochloride and 9.2 g of bis-(pt-butylphenyl) sulfite in a mixture of 40 ml of anhydrous dimethylformamide and 20 ml of anhydrous pyridine at room temperature. The mixture was stirred for 3 hours. The solvent was distilled off under reduced pressure, ether was added to the residue, and the precipitated crystals were collected and washed with ether and acetone in that order. The obtained crystals were dissolved in a small amount of methanol, and after separating the insoluble matter, ether was added to collect the precipitated crystals, and the melting point was 159.
7.2 g (yield: 92%) of 1-amidino-4-piperidinepropionic acid pt-butylphenyl ester hydrochloride was obtained as colorless crystals at ~163°C. IR ν ^KBr _{nax cm} ^-1 : 1748 (C=O) NMR (CD ₃ OD) δ: 0.84-3.84 (13H, m, pipeperidine hydrogen and CH ₂ C H 2 CO) 1.29 (9H, s, C (C H3 ) ₃ ) 6.48-7.14 (4H, m, aromatic hydrogen) Example 9 ₁ -amidino-4-piperidinepropionic acid p
- Acetaminophenyl ester hydrochloride: 2.0 g of 1-amidino-4-piperidine propionic hydrochloride and p-acetaminophenol
1.29 g was dissolved in 20 ml of anhydrous pyridine, 1.75 g of dicyclohexylcarbodiimide was added while stirring under ice cooling, and the mixture was stirred overnight at room temperature. The precipitated crystals were collected, washed with ethyl acetate and ether in that order, and air-dried. The obtained crystals were refluxed in 600 ml of dichloromethane, the insoluble matter was removed, washed with dichloromethane, and further recrystallized from methanol-ethyl acetate to give 1-amidino-4-piperidine propion as colorless crystals with a melting point of 258-261°C. 1.5 g (yield 48.4%) of acid p-acetaminophenyl ester hydrochloride was obtained. IR ν ^KBr _nax cm ^-1 : 1761 (C=O) _NMR (CD ₃ OD) δ: 0.89-4.05 (13H, m, pipeperidine hydrogen CH 2 C H ₂ CO) 2.10 (3H, s, COC H ₃ ) 7.01-7.70 (4H, m, aromatic hydrogen) Example 10 1-amidino-4-piperidine propionic acid o
-Allyl phenyl ester hydrochloride: 3.7 g of bis-(o-allylphenyl) sulfite prepared from o-allylphenol and thionyl chloride was dissolved in a mixture of 16 ml of anhydrous dimethylformamide and 8 ml of anhydrous pyridine, and 1-
Amidino-4-piperidine propionic hydrochloride
2.0 g was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and diluted with acetone.
This was poured into ether with stirring, and the precipitated crystals were washed with ether, acetone, and ether in this order.
After drying, 2.3 g (yield 77.2%) of 1-amidino-4-piperidinepropionic acid o-allylphenyl ester hydrochloride was obtained as colorless crystals with a melting point of 116-119°C. When this substance is further purified, it has a melting point of 122-124
It became a colorless crystal at ℃. IR ν ^KBr _nax cm ^-1 : 1762 (C=O) NMR (CDCl ₃ ) δ: 1.01 to 4.42 (13H, m, pipeperidine hydrogen and C H ₂ C H ₂ CO) 3.36 (2H, d, C H ₂ - Ph) 5.03 to 5.34 (2H, m, =C H ₂ ) 5.82 to 6.23 (1H, m, -C H =) 6.98 to 7.77 (4H, m, aromatic hydrogen) Example 11 1-amidino-4-piperidine propionic acid p
-Acetyl phenyl ester hydrochloride: 2.00 g of 1-amidino-4-piperidine propionic hydrochloride and 1.15 g of p-acetylphenol
was suspended in 20 ml of anhydrous pyridine, 1.74 g of dicyclohexylcarbodiimide was added under ice cooling, and the mixture was stirred at room temperature for 2 nights. The precipitated crystals were collected and the solvent was distilled off under reduced pressure. Add ethyl acetate to the residue, collect the precipitated crystals, and recrystallize from ethanol-ethyl acetate to obtain colorless crystals with a melting point of 104-106°C.1-amidino-4-piperidinepropionic acid p-acetylphenyl ester hydrochloride 2.2 g (yield 73.3%). IR ν ^KBr _nax cm ^-1 : 1768 (C=O) NMR (CD ₃ OD) δ: 0.83-4.20 (13H, m, pipeperidine hydrogen and CH 2 C H ₂ CO) 2.69 (3H _, s, COC H ₃ ) 7.30-8.49 (4H, m, aromatic hydrogen) Example 12 1-amidino-4-piperidine propionic acid
2'-Chloro-4'-t-butyl phenyl ester hydrochloride: Bis-(2-chloro-4-t) prepared from 2-chloro-4-t-butylphenol and thionyl chloride.
-butylphenyl) sulfite (5.3 g) in 16 ml of anhydrous dimethylformamide and 8 ml of anhydrous pyridine.
2.0 g of 1-amidino-4-piperidine propionic hydrochloride was added to the mixture under stirring, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, ether was added to the residue, and the mixture was stirred to collect precipitated crystals. After air drying, it was recrystallized from methanol-ethyl acetate to give 1-amidino-4-piperidinepropionic acid 2'-chloro-4'- as a colorless powder with a melting point of 186-189°C.
2.2 g of t-butyl phenyl ester hydrochloride (yield
64.7%). IR ν ^KBr _{nax cm} ^-1 : 1769 (C=O) NMR (CD ₃ OD) δ: 0.94-3.99 (13H, m, piperidine hydrogen and CH ₂ C H 2 CO) 1.34 (9H, s, C (C H3 ) ₃ ) 7.00-7.49 (3H, m, aromatic hydrogen) Example 13 ₁ -amidino-4-piperidine propionic acid p
- Isopropylphenyl ester hydrochloride: 2 g of 1-amidino-4-piperidine propionic hydrochloride, 4.05 g of bis-(p-isopropylphenyl) sulfite prepared from p-isopropylphenol and thionyl chloride, 10 ml of anhydrous dimethylformamide and anhydrous After stirring a mixture of 5 ml of pyridine at room temperature for 1 hour, the solvent was distilled off. Add ether to the residue, collect the precipitated crystals, wash with ether and ethyl acetate in that order, and recrystallize from isopropyl alcohol-ethyl acetate-ether to obtain 1-amidino as colorless needle crystals with a melting point of 119-121°C. 2.9 g (yield 97%) of -4-piperidine propionic acid p-isopropylphenyl ester hydrochloride was obtained. IR ν ^KBr _nax cm ^-1 : 1755 (C=O) NMR (CD ₃ OD) δ: 1.24 (6H, d, J = 7.2Hz,
C H ₃ × 2) 1.0 to 2.0 (7H, m, β-H ₂ , 3- and 5
-H ₂ , 4-H) 2.7 to 4.0 (5H, m, 2- and 6-H ₂ , C
H) 6.99~7.26 (each 2H, each d, J=84
Hz, aromatic hydrogen) Example 14 1-amidino-4-piperidine propionic acid
2'-Naphthyl ester hydrochloride: Bis-(2-naphthyl) sulfite made from 2 g of 1-amidino-4-piperidine propionic hydrochloride, β-naphthol and thionyl chloride.
After stirring a mixture of 4.3 g, anhydrous dimethylformamide 10 ml and anhydrous pyridine 5 ml at room temperature for 3 hours,
The solvent was distilled off. The residue was powdered with ether and then recrystallized from methanol-ether to determine the melting point.
1-amidino-4 as colorless needle crystals at 185-187℃
2.4 g (yield 78%) of -piperidinepropionic acid 2'-naphthyl ester hydrochloride was obtained. IR ν ^KBr _nax cm ^-1 : 1745 (C=O) NMR (CD ₃ OD) δ: 1.0 to 2.0 (7H, m, β-
H ₂ , 3- and 5-H ₂ , 4-H) 2.68 (2H, t, J=7.8Hz, α-H ₂ ) 2.9-4.0 (4H, m, 2- and 6-H ₂ ) 7.1-8.0 (7H, m, aromatic hydrogen) Example 15 1-amidino-4-piperidine propionic acid
1'-Naphthyl ester hydrochloride: 2 g of 1-amidino-4-piperidine propionic hydrochloride, 4.25 g of bis(1-naphthyl) sulfite made from α-naphthol and thionyl chloride.
A mixture of 10 ml of anhydrous dimethylformamide and 4 ml of anhydrous pyridine was stirred at room temperature for 1 hour. After evaporating the solvent, the residue was treated with ethyl acetate to precipitate crystals. This product was washed with ethyl acetate to obtain 2.9 g (yield 94%) of 1-amidino-4-piperidinepropionic acid 1'-naphthyl ester hydrochloride as pale brown needle crystals with a melting point of 187-190°C. . IR ν ^KBr _nax cm ^-1 : 1755 (C=O) NMR (CD ₃ OD) δ: 1.0 to 2.0 (7H, m, β-
H ₂ , 3- and 5-H ₂ , 4-H) 2.78 (2H, t, J=7.2Hz, α-H ₂ ) 3.0 to 4.0 (4H, m, 2- and 6-H ₂ ) 7.1 to 8.0 (7H, m, aromatic hydrogen) Example 16 1-amidino-4-piperidine propionic acid
2',4'-Dimethylphenyl ester hydrochloride: 4.0 g of 1-amidino-4-piperidine propionic acid hydrochloride and 6.9 g of bis-(2,4-dimethylphenyl)sulfite (2,4-dimethylphenol and chloride) (prepared from thionyl) was added to a mixture of 34 ml of anhydrous dimethylformamide and 17 ml of anhydrous pyridine and left at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue to precipitate crystals. The obtained crystals were recrystallized from methanol-ether to give 4.5 g of 1-amidino-4-piperidinepropionic acid 2',4'-dimethylphenyl ester hydrochloride as colorless needle crystals with a melting point of 191-193°C.
(yield 78%). IR ν ^KBr _{nax cm} ^-1 : 1745 (C=O) NMR (CD ₃ OD) δ: 0.96-3.96 (13H, m, pipeperidine hydrogen and CH ₂ C H 2 CO) 2.08 (3H, s, 4'- C H ₃ ) 2.26 (3H, s, 2'-C H ₃ ) 6.66-7.04 (3H, m, aromatic hydrogen) Example 17 1-amidino-4-piperidine propionic acid p
-Fluorophenyl ester hydrochloride: 2.00 g of 1-amidino-4-piperidine propionic hydrochloride and 0.95 g of p-fluorophenol
was suspended in 20 ml of anhydrous pyridine, 1.74 g of dicyclohexylcarbodiimide was added to the suspension under stirring under ice cooling, and the mixture was allowed to stand at room temperature for 4 days. The precipitated dicyclohexylurea was separated, and the liquid was concentrated under reduced pressure. Add ethyl acetate to the residue, collect the precipitated crystals,
Recrystallized from methanol-ether, melting point 131~
1.4 g (yield 50.0%) of 1-amidino-4-piperidine propionic acid p-fluorophenyl ester hydrochloride was obtained as colorless crystals at 133°C. IR ν ^KBr _nax cm ^-1 : 1750 (C=O) NMR (CD ₃ OD) δ: 0.88-3.96 (13H, m, pipeperidine hydrogen and CH 2 C H _{2 CO} ) 6.80-7.15 (4H, m, aromatic Example 18 1-amidino-4-piperidine propionic acid p
-Cyclohexyl phenyl ester hydrochloride: 8 g of bis-(p-cyclohexyl phenyl) sulfite made from p-cyclohexylphenol and thionyl chloride and 1-amidino-4-
4 g of piperidine propionic hydrochloride was dissolved in 20 ml of anhydrous dimethylformamide and 8 ml of anhydrous pyridine and stirred at room temperature for 2.5 hours. Distill the solvent,
The residue was treated with ethyl acetate to precipitate crystals. This was recrystallized from isopropanol-ether to give 5.6 g of 1-amidino-4-piperidine propionic acid p-cyclohexyl phenyl ester hydrochloride (yield 83.6) as colorless crystals with a melting point of 115-116°C.
%) was obtained. IR ν ^KBr _nax cm ^-1 : 1760 (C=O) NMR (CD ₃ OD) δ: 1.00-4.00 (24H, m, piperidine hydrogen cyclohexane hydrogen and C H ₂ C H ₂ CO) 6.8-7.20 (4 H, m , aromatic hydrogen) Example 19 1-amidino-4-piperidine propionic acid p
-(α,α-dimethylbenzyl)phenyl ester hydrochloride: Bis-[p-] prepared from p-(α,α-dimethylbenzyl)phenol and thionyl chloride.
9.6 g of (α,α-dimethylbenzyl)phenyl]sulfite and 4 g of 1-amidino-4-piperidine propionic hydrochloride were added to a mixture of 20 ml of anhydrous dimethylformamide and 8 ml of anhydrous pyridine, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off, ethyl acetate was added to the residue, and the mixture was stirred for crystallization. After washing with ethyl acetate and ether, recrystallization from isopropanol-ether gives a melting point of 155~
5.5 g of 1-amidino-4-piperidinepropionic acid p-(α,α-dimethylbenzyl) phenyl ester hydrochloride as colorless crystals at 156°C (yield 75.3
%) was obtained. After repeated recrystallization, this product became colorless crystals with a melting point of 195-196°C. IR ν ^KBr _nax cm ^-1 : 1765 (C=O) NMR (CD ₃ OD) δ: 1.0-4.0 (13H, m, pipeperidine hydrogen and C H ₂ C H ₂ CO) 1.64 (6 H, s, C (C H3 ) ₂ ) 6.80-7.30 (4H, m, aromatic hydrogen) Example 20 ₁ -amidino-4-piperidinepropionic acid
4'-Formyl-2'-methoxyphenyl ester hydrochloride: 1-amidino-4-piperidine propionic acid hydrochloride 4.7 g, vanillin 3 g, dicyclohexylcarbodiimide 4.1 g, anhydrous dimethylformamide
A mixture of 20 ml and 10 ml of anhydrous pyridine at room temperature
Stir for hours. After separating the precipitated dicyclohexylurea, the solvent was distilled off. The residue was treated with ethyl acetate to give a white powder. After sequentially washing with ethyl acetate and ether, recrystallization from isopropanol-ether gave colorless crystals with a melting point of 98-105°C. 1-amidino-4-piperidinepropionic acid 4'-
Formyl-2′-methoxyphenyl ester hydrochloride
5.8g (yield 79.5%) was obtained. IR ν ^KBr _nax cm ^-1 : 1700, 1750, 1770 (C=O) NMR (CD ₃ OD) δ: 1.04-4.20 (13H, m, pipeperidine hydrogen _{and CH 2} C H ₂ CO) 3.95 (3H, s , OC H ₃ ) 7.50-8.0 (3H, m, aromatic hydrogen) 10.4 (1H, s, CHO ) Example 21 1-amidino-4-piperidine propionic acid p
-Aminosulfonyl phenyl ester hydrochloride: 1-amidino-4-piperidine propionic hydrochloride 4.7 g, p-hydroxybenzenesulfonamide 3.5 g, dicyclohexylcarbodiimide 4.1
A mixture of 10 ml of anhydrous dimethylformamide and 20 ml of anhydrous pyridine was stirred at room temperature for 24 hours. After separating the precipitated dicyclohexylurea, the solvent was distilled off. The residue was treated with ethyl acetate followed by ether to obtain crystals. Dissolve this in methanol, separate the insoluble matter, add ether and collect the precipitated crystals as yellow crystals with a melting point of 206-209°C. 1-amidino-4-piperidinepropionic acid p-
Aminosulfonylphenyl ester hydrochloride 4.5g
(yield 57.7%). IR ν ^KBr _nax cm ^-1 : 1760 (C=O) NMR (CD ₃ OD) δ: 1.04-4.20 (13H, m, pipeperidine hydrogen and C H ₂ C H ₂ CO) 7.44-8.28 (4H, m, aromatic Example 22 1-amidino-4-piperidine propionic acid m
-Trifluoromethylphenyl ester hydrochloride: 4.0 g of 1-amidino-4-piperidine propionic acid hydrochloride and 2.75 g of m-trifluoromethylphenol were suspended in 27 ml of anhydrous pyridine, 3.5 g of dicyclohexylcarbodiimide was added, and the mixture was heated to room temperature. The mixture was stirred for 6 hours. The precipitated dicyclohexylurea was separated, the solvent was distilled off, and the residue was washed with ether, dissolved in chloroform, and stirred.
After removing insoluble materials, the mixture was washed twice with saturated brine and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, 1-amidino-
4-piperidinepropionic acid m-trifluoromethylphenyl ester hydrochloride 4.0g (yield 62.0%)
I got it. IR ν ^KBr _nax cm ^-1 : 1760 (C=O) NMR (CDCl ₃ ) δ: 0.92-4.52 (13H, m, piperidine hydrogen and C H ₂ C H ₂ CO) 7.20-7.92 (4H, m, aromatic Hydrogen) Example 23 1-amidino-4-piperidine propionic acid p
Formyl phenyl ester hydrochloride: 4.0 g of 1-amidino-4-piperidine propionic hydrochloride and 2.1 g of p-hydroxybenzaldehyde were suspended in 20 ml of anhydrous pyridine, 3.5 g of dicyclohexylcarbodiimide was added under stirring, and the mixture was stirred at room temperature. Stir overnight. The precipitated dicyclohexylurea was separated, and the liquid was concentrated under reduced pressure. Ethyl acetate was added to the residue and stirred to precipitate crystals. The obtained crystals were recrystallized from methanol-ether to give 2.1 g (yield 36.4%) of 1-amidino-4-piperidine propionic acid p-formyl phenyl ester hydrochloride as colorless crystals with a melting point of 144-147°C.
I got it. IR ν ^KBr _nax cm ^-1 : 1700, 1760 (C=O) NMR (CD ₃ OD) δ: 0.92-4.16 (13H, m, pipeperidine hydrogen and CH 2 C H ₂ CO ₎ 7.40-8.20 (4H, m , aromatic hydrogen) 10.16 (1H, s, C H O) Example 24 1-amidino-4-piperidine propionic acid p
-Cyanophenyl ester hydrochloride: 4 g of 1-amidino-4-piperidine propionic hydrochloride, 2.0 g of p-cyanophenol and 3.5 g of dicyclohexylcarbodiimide were stirred overnight in 20 ml of anhydrous pyridine. The reaction was filtered and washed with pyridine. Furthermore, the crystals on the filter were dissolved in a mixed solvent of 20 ml of water and 20 ml of t-butanol for about 20 min.
The mixture was stirred for a minute and extracted. The above liquid, washing liquid, and extract were combined, and the solvent was distilled off under reduced pressure. The residue was recrystallized from water to give 1-amidino-4-piperidinepropionic acid p as colorless crystals with a melting point of 164.5-169°C.
-Cyanophenyl ester hydrochloride 3.4g (yield 59
%) was obtained. IR ν ^KBr _nax cm ^-1 : 2240 (CN), 1765 (C=O) NMR (CD ₃ OD) δ: 1.00 to 4.10 (13H, m, piperidine hydrogen _{and CH 2} C H ₂ CO) 7.40 to 8.10 ( 4H, m, aromatic hydrogen) Example 25 1-amidino-4-piperidine propionic acid o
-Cyanophenyl ester hydrochloride: 4.0 g of 1-amidino-4-piperidine propionic hydrochloride, 2.0 g of o-cyanophenol and 3.5 g of dicyclohexylcarbodiimide were stirred in 20 ml of anhydrous pyridine for 24 hours. The precipitated dicyclohexyl urea was filtered and washed with anhydrous pyridine. The solution and washing solution were combined, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue for crystallization.
The obtained crystals are recrystallized from water to a melting point of 159.5~
2.1 g (yield: 37%) of 1-amidino-4-piperidine propionic acid o-cyanophenyl ester hydrochloride was obtained as colorless crystals at 162.5°C. IR ν ^KBr _nax cm ^-1 : 2240 (CN), 1775 (C=O) NMR (CD ₃ OD) δ: 1.00 to 4.10 (13H, m, pipeperidine hydrogen _{and CH 2} C H ₂ CO) 7.40 to 8.00 ( 4H, m, aromatic hydrogen) Example 26 1-amidino-4-piperidine propionic acid o
-Methyl phenyl ester hydrochloride: Bis-(o-methylphenyl) sulfite made from o-methylphenol and thionyl chloride
6.7 g and 4 g of 1-amidino-4-piperidine propionic hydrochloride were dissolved in anhydrous dimethylformamide.
The mixture was stirred for 24 hours in a mixed solvent of 20 ml and 6 ml of anhydrous pyridine. The solvent was distilled off under reduced pressure, and 50 ml of ethyl acetate and 20 ml of ether were added to the residue for crystallization. The crystals were collected and recrystallized from isopropanol-ether and then from methanol-ether. Further, it is recrystallized from water and has a melting point.
1-amidino-4 as colorless crystals at 184-185.5℃
2.1 g (yield: 38%) of -piperidine propionate o-methylphenyl ester hydrochloride was obtained. IR ν ^KBr _nax cm ^-1 : 1750 (C=O) NMR (CD ₃ OD) δ: 1.00-4.05 (13H, m, pipeperidine hydrogen and CH 2 C H ₂ CO) 2.14 (3H _, s, C H ₃ ) 6.90-7.30 (4H, m, aromatic hydrogen) Example 27 1-amidino-4-piperidine propionic acid o
-Methyl phenyl ester hydrochloride: A mixture of 4 g of 1-amidino-4-piperidine propionic hydrochloride, 1.9 g of o-methylphenol, 3.5 g of dicyclohexylcarbodiimide, and 20 ml of anhydrous pyridine was stirred at room temperature overnight. The precipitated crystals were filtered and washed with pyridine. The solution and washing solution were combined, and the solvent was distilled off under reduced pressure. Ethyl acetate and ether were added to the residue to precipitate crystals. The crystals were collected and washed successively with ethyl acetate and ether. After air drying, recrystallize from water to a melting point of 184 ~
1-amidino- as a colorless prismatic crystal at 185.5℃
3 g (yield 54%) of 4-piperidinepropionic acid o-methylphenyl ester hydrochloride was obtained. IR and NMR were consistent with the compound obtained in Example 26. Example 28 1-amidino-4-piperidinepropionic acid
3'-Pyridyl ester hydrochloride: A mixture of 4.71 g of 1-amidino-4-piperidine propionic hydrochloride, 1.95 g of 3-hydroxypyridine, 4.13 g of dicyclohexylcarbodiimide, 40 ml of anhydrous dimethylformamide, and 20 ml of anhydrous pyridine was heated at room temperature for 19 hours. Stirred. After separating the precipitated dicyclohexylurea, the solvent was distilled off. The residue was washed with ethyl acetate and then dissolved in methanol. Insoluble materials were separated and ethyl acetate was added. The precipitated crystals were washed with ethyl acetate and then with ether to obtain 6.2 g of 1-amidino-4-piperidine propionic acid 3'-pyridyl ester hydrochloride as colorless needle crystals with a melting point of 177-179°C (yield 99%). I got it. IR ν ^KBr _nax cm ^-1 : 1765 (C=O) NMR (CD ₃ OD) δ: 1.0 to 2.1 (7H, m, 3- and 5-H ₂ , 4-H and β-H ₂ ) 2.84 (2H , t, J=7.6Hz, α-H ₂ ) 3.0-4.2 (4H, m, 2- and 6-H ₂ ) 7.7-8.9 (4H, m, pyridine hydrogen) Example 29 1-amidino-4-piperidine propionic acid o
- Phenyl phenyl ester hydrochloride: 4 g of 1-amidino-4-piperidine propionic hydrochloride, 9.3 g of bis-(o-phenyl phenyl) sulfite (made from o-phenyl phenol and thionyl chloride), 40 ml of anhydrous dimethylformamide After stirring a mixture of 20 ml of anhydrous pyridine at room temperature for 4 hours, the solvent was distilled off under reduced pressure. The residue was recrystallized from water and washed with ethyl acetate and then with ether to give 1-
Amidino-4-piperidinepropionic acid o-phenyl phenyl ester hydrochloride 3.45g (yield 52%)
I got it. IR ν ^KBr _nax cm ^-1 : 1755 (C=O) NMR (CD ₃ OD) δ: 0.8 to 1.9 (7H, m, 3- and 5-H ₂ , 4-H and β-H ₂ ) 2.52 (2H , t, J=7.0Hz, α-H ₂ ) 2.8-4.1 (4H, m, 2- and 6-H ₂ ) 7.3-7.9 (9H, m, aromatic hydrogen) Example 30 1-amidino-4- piperidine propionate p
- Phenyl phenyl ester hydrochloride: 4 g of 1-amidino-4-piperidine propionic hydrochloride, 9.3 g of bis-(p-phenylphenyl) sulfite (made from p-phenylphenol and thionyl chloride), 40 ml of anhydrous dimethylformamide After stirring a mixture of 8 ml of anhydrous pyridine at room temperature for 3 hours, the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to determine the melting point.
1-amidino-4 as colorless needle crystals at 200-203℃
-4 g (yield: 61%) of p-phenyl phenyl ester hydrochloride of piperidine propionate was obtained. IR ν ^KBr _nax cm ^-1 : 1755 (C=O) NMR (CD ₃ OD) δ: 1.0 to 2.0 (7H, m, 3- and 5-H ₂ , 4-H and β-H ₂ ) 2.61 (2H , t, J=6.8Hz, α-H ₂ ) 2.8-4.0 (4H, m, 2- and 6-H ₂ ) 7.0-7.6 (9H, m, aromatic hydrogen) Example 31 1-amidino-4- piperidine propionic acid
2',4',6'-trimethylphenyl ester hydrochloride: 1-amidino-4-piperidinepropionate hydrochloride 4g, 2,4,6-trimethylphenol
2.3g and dicyclohexylcarbodiimide 3.5
g was stirred in anhydrous pyridine at room temperature overnight. The precipitated crystals were filtered and washed with a small amount of anhydrous pyridine. Furthermore, it was thoroughly washed with a mixed solvent of 25 ml of t-butanol and 25 ml of water. The liquid and washing liquid were combined and concentrated under reduced pressure. 50 ml of ethyl acetate was added to this, and the mixture was thoroughly stirred to cause crystallization. The crystals were collected and recrystallized from water to give 1-amidino-4-piperidinepropionic acid 2',4', as colorless crystals with a melting point of 220-223°C.
6′-Trimethylphenyl ester hydrochloride 3.3g
(yield 55%). IR ν ^KBr _nax cm ^-1 : 1750 NMR (CD ₃ OD) δ: 1.00-4.16 (13H, m, piperidine hydrogen and C H ₂ C H ₂ CO) 2.12 (6H, s, 2,6-C H ₃ ) 2.26 (3H, s, 4- CH ₃ ) 6.92 (2H, 7, aromatic hydrogen) Example 32 1-amidino-4-piperidine propionic acid
2',6'-dimethylphenyl ester hydrochloride: 7.4 g of bis-(2,6-dimethylphenyl) sulfite made from 2,6-dimethylphenol and thionyl chloride was mixed with 36 g of anhydrous dimethylformamide.
ml and anhydrous pyridine, 4.0 g of 1-amidino-4-piperidine propionic hydrochloride was added thereto under stirring, and the mixture was left at room temperature for 4 days.
The solvent was distilled off under reduced pressure, ether was added to the residue, and the precipitated crystals were collected and washed with ether and ethyl acetate in that order. Recrystallization from water gave 3.3 g (yield 57%) of 1-amidino-4-piperidinepropionic acid 2',6'-dimethylphenyl ester hydrochloride as pale yellow crystals with a melting point of 191-194°C. IR ν ^KBr _nax cm ^-1 : 1740 (C=O) _NMR (CD ₃ OD) δ: 0.96-4.32 (13H, m, pipeperidine hydrogen and CH 2 C H ₂ CO) 2.24 (6H, s, 2,6 -C H ₃ ) 7.24-7.60 (3H, m, aromatic hydrogen) Example 33 1-amidino-4-piperidinepropionic acid
5'-indanyl ester hydrochloride: 7.0 g of bis-(5-indanyl) sulfite made from 5-indanol and thionyl chloride.
was dissolved in a mixture of 25 ml of anhydrous dimethylformamide and 12 ml of anhydrous pyridine, and 3.0 g of 1-amidino-4-piperidine propionic acid hydrochloride was added while stirring, followed by standing for 4 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue to precipitate crystals. The obtained crystals were washed with ethyl acetate and ether in that order, and recrystallized from methanol-ether to give a melting point of 184-188°C.
1-amidino-4-piperidinepropionic acid 5'-indanyl ester hydrochloride as colorless crystals 3.6
g (yield 80%) was obtained. IR ν ^KBr _nax cm ^-1 : 1760 (C=O) NMR (CD ₃ OD) δ: 0.84-4.32 (19H, m, piperidine hydrogen C H ₂ C H ₂ CO and C H ₂ C
H ₂ C H ₂ ) 7.00-7.64 (3H, m, aromatic hydrogen) Example 34 1-amidino-4-piperidine propionic acid p
-Methoxycarbonyl phenyl ester hydrochloride: 1-amidino-4-piperidine propionic hydrochloride 5 g, methyl p-hydroxybenzoate 3.23
After stirring a mixture of g, dicyclohexylcarbodiimide 4.38 g, anhydrous dimethylformamide 100 ml and anhydrous pyridine 20 ml at room temperature for 24 hours, Example 9
processed in the same way. The obtained crystals were recrystallized from isopropanol-ether to a melting point of 163-164.5℃.
5.7 g (yield 72.7%) of 1-amidino-4-piperidinepropionic acid p-methoxycarbonylphenyl ester hydrochloride was obtained as colorless needle-like crystals. IR ν ^KBr _nax cm ^-1 : 1700, 1730, 1755 (C=O) Example 35 1-amidino-4-piperidine propionic acid o
- Acetaminophenyl ester hydrochloride: 4.0 g of 1-amidino-4-piperidine propionic hydrochloride and 2.6 g of o-acetaminophenol
g was dissolved in 40 ml of anhydrous pyridine, 3.5 g of dicyclohexylcarbodiimide was added while stirring under ice cooling, and the mixture was allowed to stand at room temperature for 44 hours. The precipitated dicyclohexyl urea was separated, and the solvent was distilled off under reduced pressure. After washing the residue with ethyl acetate, anhydrous ether was added to precipitate crystals, which were washed several times with ether. After washing with warm dichloromethane and ethyl acetate,
Add anhydrous ether and evaporate to dryness to give 1-amidino-4-piperidine propionic acid o-acetaminophenyl ester hydrochloride 5.8 as hygroscopic crystals.
g (yield 92.7%). IR ν ^KBr _nax cm ^-1 : 1750 (C=O) _NMR (CD ₃ OD) δ: 0.92 to 4.26 (13H, m, pipeperidine hydrogen CH 2 C H ₂ CO) 2.40 (3H, s, COC H ₃ ) 7.28-8.20 (4H, m, aromatic hydrogen) Example 36 1-amidino-4-piperidine propionic acid
5',6',7',8'-tetrahydro-2'-naphthyl ester hydrochloride: 4 g of 1-amidino-4-piperidine propionic hydrochloride, 5,6,7,8-tetrahydro-2-
A mixture of 2.5 g of naphthol, 4 g of dicyclohexylcarbodiimide and 25 ml of anhydrous pyridine was stirred at room temperature for 1 day and further stirred in an oil bath at 50° C. for 6 hours. After separating the precipitated dicyclohexylurea, the solvent was distilled off under reduced pressure. The residue was washed with ethyl acetate and ether in that order, dissolved in a small amount of isopropanol, and water was added to precipitate crystals. The obtained crystals were washed successively with ethyl acetate and ether to obtain 1-amidino-4-piperidinepropionic acid 5', 6', 7', 8'- as a colorless powder with a melting point of 113-115°C.
Tetrahydro-2′-naphthyl ester hydrochloride 3.5
g (yield 56.5%) was obtained. IR ν ^KBr _nax cm ^-1 : 1758 (C=O) NMR (CD ₃ OD) δ: 1.70 to 1.94 (8H, m-(C
H ₂ ) ₄ -) 1.04-4.20 (13H, m, piperidine hydrogen and C H ₂ C H ₂ CO) 7.00-7.44 (3H, m, aromatic hydrogen) Example 37 1-amidino-4-piperidine propionic acid p
- Nitrophenyl ester hydrochloride: 5.0 g of 1-amidino-4-piperidine propionic hydrochloride, 7.6 g of bis-(p-nitrophenyl) sulfite (made from p-nitrophenol and thionyl chloride), 20 ml of anhydrous dimethylformamide and A mixture of 6 ml of anhydrous pyridine was stirred for 22 hours at room temperature. The solvent was distilled off under reduced pressure, 70 ml of ethyl acetate and 30 ml of ether were added to the residue, and the mixture was thoroughly stirred, and the supernatant liquid was removed by decantation.
Furthermore, 50 ml of ether was added, and the mixture was similarly stirred and decanted to remove the supernatant. A small amount of water was added to the residue to stimulate crystallization. After further adding acetone and stirring, crystals were collected. The obtained crystals were washed with acetone and then with ether and dried to obtain 3.2 g of 1-amidino-4-piperidine propionic acid p-nitrophenyl ester hydrochloride as a colorless powder with a melting point of 131-136°C. IR ν ^KBr _nax cm ^-1 : 1770 (C=O) NMR (DMSO-d ₆ ) δ: 0.92 to 4.08 (13H, m,
Pipiperidine hydrogen and C H ₂ C H ₂ CO) 6.90-7.10 (6H, m, NH ₂ and aromatic hydrogen) 7.80-8.00 (2H, m, aromatic hydrogen) Example 38 1-amidino-4-piperidine propion Acid phenyl thioester hydrochloride: A mixture of 2.4 g of 1-amidino-4-piperidine propionic hydrochloride, 1.1 g of thiophenol, 2.1 g of dicyclohexylcarbodiimide and 15 ml of anhydrous dimethylformamide was stirred for 17 hours. After separating the precipitated dicyclohexylurea, the solvent was distilled off. The residue was washed with ether and t-butanol to give 1 as colorless crystals with a melting point of 168-170°C.
1.2 g (yield 36.4%) of -amidino-4-piperidine propionic acid phenylthioester hydrochloride was obtained. IR ν ^KBr _nax cm ^-1 : 1710 (C=O) NMR (CD ₃ OD) δ: 1.0-4.16 (13H, m, pipeperidine hydrogen and C H ₂ C H ₂ CO) 7.56 (5H, s, aromatic hydrogen ) Example 39 1-amidino-4-piperidine propionic acid p
-t-Butylphenyl thioester hydrochloride: 1-amidino-4-piperidine propionic hydrochloride 3 g, p-(t-butyl)thiophenol
A mixture of 2.2 g of dicyclohexylcarbodiimide, 2.6 g of dicyclohexylcarbodiimide, and 18 ml of anhydrous dimethylformamide was stirred at room temperature for 10 hours. After separating the precipitated dicyclohexyl urea, the solvent was distilled off under reduced pressure and the resulting oil was washed with ether. Water was added to the oil that precipitated by dissolving it in t-butyl alcohol and adding ether, and it was left in a cool place overnight. The precipitated crystals were collected, washed with ethyl acetate and then ether, and then air-dried to give 2.3 g of 1-amidino-4-piperidine propionic acid pt-butylphenyl thioester hydrochloride ( Yield 46.9%)
I got it. IR ν ^KBr _nax cm ^-1 : 1710 (C=O) _NMR (CD ₃ OD) δ: 1.00-4.10 (13H, m, pipeperidine hydrogen and CH 2 C H ₂ CO) 1.40 (9H, s, C (C H ₃ ) ₃ ) 7.50-7.84 (4H, m, aromatic hydrogen) Example 40 1-amidino-4-piperidinecarboxylic acid phenyl ester hydrochloride: 826 mg of 1-amidino-4-piperidinecarboxylic acid hydrochloride and diphenyl 1.4 g of sulfite was stirred in 10 ml of anhydrous dimethylformamide and 4 ml of anhydrous pyridine at room temperature overnight. Remove the solvent under reduced pressure,
The residue was washed three times with 20 ml of ether. Next, add 10ml of acetone and stir to collect the precipitated crystals, wash with acetone and dry.
1-amidino-4 as powder crystals at 161.5℃
-Piperidine carboxylic acid phenyl ester hydrochloride
600 mg (yield 53%) was obtained. IR ν ^KBr _nax cm ^-1 : 1750 (C=O) NMR (CD ₃ OD) δ: 1.50 to 4.00 (9H, m, pipeperidine hydrogen) 6.90 to 7.40 (5H, m, aromatic hydrogen) Example 41 1- Amidino-4-piperidinecarboxylic acid o-
Benzyloxycarbonyl phenyl ester hydrochloride: 826 mg of 1-amidino-4-piperidinecarboxylic hydrochloride and 3.0 g of bis-1-o-benzyloxycarbonylphenyl) sulfite in 10 ml of anhydrous dimethylformamide and 4 ml of anhydrous pyridine.
The mixture was stirred overnight at room temperature. Remove the solvent under reduced pressure,
The residue was washed three times with 30 ml of ether. Next, 10 ml of acetone and 30 ml of ethyl acetate were added to give stimulation, and crystals were precipitated. The crystals were collected and washed with hot ethyl acetate to obtain 1015 mg (yield 61%) of 1-amidino-4-piperidinecarboxylic acid o-benzyloxycarbonylphenyl ester hydrochloride as a colorless powder with a melting point of 140.5-147°C. . IR ν ^KBr _nax cm ^-1 : 1740, 1710 (C=O) NMR (CD ₃ OD) δ: 1.50 to 4.00 (9H, m, pipeperidine hydrogen) 5.20 (2H, s, CH ₂ - Ph) 6.96 to 8.00 (9H, m, aromatic hydrogen) Example 42 1-amidino-4-piperidinecarboxylic acid 2',
4'-Dichlorophenyl ester hydrochloride: 2.0 g of 1-amidino-4-piperidinecarboxylic hydrochloride and 7.2 g of bis-(2,4-dichlorophenyl)sulfite were mixed in a mixture of 18 ml of anhydrous dimethylformamide and 9 ml of anhydrous pyridine at room temperature. The mixture was stirred for 4 hours. The solvent was distilled off under reduced pressure, and the resulting residue was washed three times with ether. Add acetone to the residue and stir, collect the precipitated crystals,
Washed with ethyl acetate and ether. This crystal is recrystallized from methanol-ether to give a melting point of
1-amidino-4 as colorless crystals at 215-218.5℃
1.27 g (yield 37.4%) of -piperidinecarboxylic acid 2',4'-dichlorophenyl ester hydrochloride was obtained. IR ν ^KBr _nax cm ^-1 : 1762 (C=O) NMR (CD ₃ OD) δ: 1.67-4.28 (9H, m, pipeperidine hydrogen) 7.31-7.82 (3H, m, aromatic hydrogen) Example 43 1- Amidino-4-piperidinecarboxylic acid p-
Chlorphenyl ester hydrochloride: 1.5 g of 1-amidino-4-piperidinecarboxylic hydrochloride and 8.8 g of bis-(p-chlorophenyl) sulfite in anhydrous dimethylformamide 14
ml and anhydrous pyridine (7 ml) at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was washed twice with anhydrous ether, and then acetone was added to precipitate crystals. The crystals were collected, washed with ether and ethyl acetate, and then recrystallized from methanol-ether to give 1-amidino-
1.62 g (yield 70.4%) of 4-piperidinecarboxylic acid p-chlorophenyl ester hydrochloride was obtained. IR ν ^KBr _nax cm ^-1 : 1744 (C=O) NMR (CD ₃ OD) δ: 1.65 to 4.15 (9H, m, pipeperidine hydrogen) 7.19 to 7.72 (4H, m, aromatic hydrogen) Example 44 1- Amidino-4-piperidinecarboxylic acid p-
Methyl phenyl ester hydrochloride: 1.5 g of 1-amidino-4-piperidinecarboxylic hydrochloride and 7.6 g of bis-(p-methylphenyl) sulfite were stirred in a mixture of anhydrous dimethylformamide and anhydrous pyridine 7 ml at room temperature for 1.5 hours. . The solvent was distilled off under reduced pressure, and ether was added to the residue to precipitate crystals. The precipitated crystals were washed with ether and ethyl acetate in that order, then reprecipitated from methanol-ether and recrystallized from isopropanol-isopropyl ether to give 1-amidino-4-piperidinecarboxylic acid p- as colorless crystals with a melting point of 187-189°C. Methyl phenyl ester hydrochloride 2.15
g (yield 99.6%) was obtained. IR ν ^KBr _nax cm ^-1 : 1742 (C=O) NMR (CD ₃ OD) δ: 1.50 to 4.00 (9H, m, pipeperidine hydrogen) 2.30 (3H, s, C H ₃ ) 6.61 to 7.23 (4H, m , aromatic hydrogen) Example 45 1-amidino-4-piperidinecarboxylic acid p-
Methoxyphenyl ester hydrochloride: 1.5 g of 1-amidino-4-piperidinecarboxylic hydrochloride and bis-(p-methoxyphenyl)
7.7g of sulfite in anhydrous dimethylformamide
in a mixture of 16 ml and 8 ml of anhydrous pyridine at room temperature.
Stirred for 18 hours. The solvent was distilled off under reduced pressure, and ether was added to the residue to precipitate crystals. The obtained crystals were washed twice with ether and further with ethyl acetate, and then recrystallized from methanol-ether to determine the melting point.
1-amidino-4- as colorless crystals at 198-203℃
1.9 g (yield: 83.7%) of piperidine carboxylic acid p-methoxyphenyl ester hydrochloride was obtained. IR ν ^KBr _nax cm ^-1 : 1739 (C=O) NMR (CD ₃ OD) δ: 1.48 to 4.01 (9H, m, pipeperidine hydrogen) 3.75 (3H, s, O-C H ₃ ) 6.73 to 7.05 (4H , m, aromatic hydrogen) Example 46 1-amidino-4-piperidinecarboxylic acid p-
t-Butylphenyl ester hydrochloride: 1.0 g of 1-amidino-4-piperidinecarboxylic hydrochloride and bis-(pt-butylphenyl)
3.3g of sulfite in anhydrous dimethylformamide
in a mixture of 10 ml and anhydrous pyridine at room temperature.
Stirred for 2.5 hours. The solvent was distilled off under reduced pressure, and anhydrous ether was added to the residue to precipitate crystals. The obtained crystals were washed with anhydrous ether and then with ethyl acetate, and then recrystallized from methanol-ether to give 1-amidino-4 as colorless crystals with a melting point of 211-213°C.
1.0 g (yield: 61.4%) of -piperidinecarboxylic acid pt-butylphenyl ester hydrochloride was obtained. When this material is further recrystallized, the melting point is 222 ~
It became a colorless crystal at 223℃. IR ν ^KBr _nax cm ^-1 : 1742 (C=O) NMR (CD ₃ OD) δ: 1.38 (9H, s, C (C H ₃ )
₃ ) 1.65-4.15 (9H, m, piperidine hydrogen) 7.04-7.74 (4H, m, aromatic hydrogen) Example 47 1-amidino-4-piperidinecarboxylic acid p-
(α,α-dimethylbenzyl)phenyl ester hydrochloride: Bis-[p-(α,α) prepared from p-(α,α-dimethylbenzyl)phenol and thionyl chloride
-dimethylbenzyl)phenyl]sulfite
A mixture of 10.9 g of 1-amidino-4-piperidinecarboxylic hydrochloride hydrochloride, 20 ml of anhydrous dimethylformamide and 8 ml of anhydrous pyridine was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure and the resulting oil was treated with ethyl acetate to give a powder. This was recrystallized from isopropanol-ether with a melting point of 166-168.
1-amidino-4-piperidinecarboxylic acid p-(α,α-dimethylbenzyl) as colorless crystals at °C
5.3 g (yield 68.8%) of phenyl ester hydrochloride was obtained. IR ν ^KBr _nax cm ^-1 : 1758 (C=O) NMR (CD ₃ OD) δ: 1.74 (6H, s, = C (C H ₃ )
₂ ) 1.50-4.18 (9H, m, piperidine hydrogen)) 7.18-7.60 (9H, m, aromatic hydrogen) Example 48 1-amidino-4-piperidinecarboxylic acid p-
Cyclohexyl phenyl ester hydrochloride: 9.2 g of bis-(p-cyclohexyl phenyl) sulfite, 4 g of 1-amidino-4-piperidinecarboxylic hydrochloride, anhydrous dimethylformamide
A mixture of 20 ml and 8 ml of anhydrous pyridine was heated to 18 ml at room temperature.
Stir for hours. The solvent was distilled off under reduced pressure, and the residue was crystallized by treatment with ethyl acetate. The precipitated crystals were recrystallized from isopropanol-ether to obtain 2.9 g (yield: 40.8%) of 1-amidino-4-piperidinecarboxylic acid p-cyclohexyl phenyl ester hydrochloride as colorless crystals with a melting point of 226-230°C. IR ν ^KBr _nax cm ^-1 : 1760 (C=O) NMR (CD ₃ OD) δ: 1.20 to 4.30 (20H, m, piperidine hydrogen and cyclohexane hydrogen) 7.16 to 7.64 (4H, m, aromatic hydrogen) Examples 49 1-amidino-4-piperidinecarboxylic acid 2',
4'-Dimethylphenyl ester hydrochloride: 8.4 g of bis-(2,4-dimethylphenyl) sulfite was dissolved in a mixture of 36 ml of anhydrous dimethylformamide and 18 ml of anhydrous pyridine, and 4.0 g of 1-amidino-4-piperidinecarboxylic hydrochloride was dissolved in a mixture of 36 ml of anhydrous dimethylformamide and 18 ml of anhydrous pyridine. g and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and ether was added to the residue to collect the precipitated crystals. 1-amidino-4-piperidinecarboxylic acid 2',4'-dimethylphenyl ester was obtained as colorless crystals with a melting point of 198-201°C. 5.8 g (yield 96.7%) of hydrochloride was obtained. When further refined, this product has a melting point of 205~
It became a colorless crystal at 207℃. IR ν ^KBr _nax cm ^-1 : 1745 (C=O) NMR (CD ₃ OD) δ: 1.60-4.36 (9H, m, pipeperidine hydrogen) 2.24 (3H, s, 4- CH ₃ ) 2.40 (3H, s ，
2-C H ₃ ) 7.02-7.56 (3H, m, aromatic hydrogen) Example 50 1-amidino-4-piperidinecarboxylic acid o-
Allyl phenyl ester hydrochloride: bis-(o-allylphenyl) sulfite
2.4 g was dissolved in a mixture of 10 ml of anhydrous dimethylformamide and 5 ml of anhydrous pyridine, 1.0 g of 1-amidino-4-piperidinecarboxylic hydrochloride was added thereto, and the mixture was allowed to stand at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and ether was added to the residue to collect precipitated crystals. The obtained crystals were recrystallized from isopropanol-ether to give 950 mg of 1-amidino-4-piperidinecarboxylic acid o-allylphenyl ester hydrochloride as colorless crystals with a melting point of 151-153°C (yield
61.3%). IR ν ^KBr _nax cm ^-1 : 1740 (C=O) NMR (CDCl ₃ ) δ: 1.60 to 4.52 (11H, m, pipeperidine hydrogen and -CH ₂ -Ph) 5.04 to 5.48 (2H, m, =C H ₂ ) 5.88-6.40 (1H, m, -CH =) 7.24-8.08 (4H, m, aromatic hydrogen)

Claims (1)

[Claims] 1. General formula (In the formula, A represents an oxygen atom or a sulfur atom,
R is a halogen atom, an alkyl group, an alkenyl group,
Aralkyl group, alkoxy group, alkanoyl group,
Alkanoylamino group has 1 to 3 substituents selected from nitro group, cyano group, formyl group, aminosulfonyl group, trihalogenomethyl group, alkoxycarbonyl group, benzyloxycarbonyl group, carboxyl group, and aryl group. represents a phenyl group, a pyridyl group, a naphthyl group, an indanyl group, or a tetrahydronaphthyl group. However, when A is an oxygen atom, R is an alkyl group,
This excludes the case of a phenyl group which may have one substituent selected from an alkoxy group, a halogen atom, and a benzyloxycarbonyl group. and n is 0
or an integer of 2) or an acid addition salt thereof. 2 General formula (wherein, n represents an integer of 0 or 2), a salt thereof, or a reactive derivative thereof has the general formula R'-A-H (wherein, A represents an oxygen atom or a sulfur atom,
R′ is a halogen atom, an alkyl group, an alkenyl group,
Aralkyl group, alkoxy group, alkanoyl group,
Alkanoylamino group may have 1 to 3 substituents selected from nitro group, cyano group, formyl group, aminosulfonyl group, trihalogenomethyl group, alkoxycarbonyl group, benzyloxycarbonyl group, and aryl group Indicates a phenyl group, pyridyl group, naphthyl group, indanyl group or tetrahydronaphthyl group. However, when A is an oxygen atom, R' is a phenyl group which may have one substituent selected from an alkyl group, an alkoxy group, a halogen atom, and a benzyloxycarbonyl group). phenol or its sulfite derivative, and optionally subjecting the product to a hydrogenation reaction. (In the formula, R is a halogen atom, an alkyl group, an alkenyl group, an aralkyl group, an alkoxy group, an alkanoyl group, an alkanoylamino group, a nitro group, a cyano group, a formyl group, an aminosulfonyl group, a trihalogenomethyl group, an alkoxycarbonyl group, a benzyl group) A phenyl group, a pyridyl group, a naphthyl group, which may have 1 to 3 substituents selected from an oxycarbonyl group, a carboxyl group, an aryl group,
Indanyl group or tetrahydronaphthyl group. However, when A is an oxygen atom, the case where R is a phenyl group which may have one substituent selected from an alkyl group, an alkoxy group, a halogen atom, and a benzyloxycarbonyl group is excluded. And A
and n is the same as above) A method for producing a novel amidinopiperidine derivative or an acid addition salt thereof.