JPS634821B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides N-[4-
(3-aminopropyl)aminobutyl]-2-
[(S)-7-guanidino-3-hydroxyheptaneamide] Novel compound (S)-7-guanidino-3-hydroxyheptane useful as a synthetic intermediate for -2-hydroxyethanamide or its 3-0-acyl derivative This invention relates to amides and methods for producing the same. The first invention is a novel compound of the following formula () The hydrochloride is a crystalline white powder with a decomposition point of 101-103°C, [α] ²² _D
-2° (C2, water) is shown. The elemental analysis value is
Theoretical value of C ₈ H ₁₈ N ₄ O ₂・HCl (C40.25%, H7.60
%, N23.47%, Cl29.71%), and the FD mass spectrum showed m/e203 (MH ⁺ ). Proton NMR measured in heavy water shows δ1.8−2.3(4−,5
-, 6-CH ₂ ), 2.95 (2-CH ₂ , J=2 and 6
Hz), 3.69 (7-CH ₂ , t, J = 7Hz), 4.5 (3-CH 2 , t, J = 7Hz),
CH) showed a characteristic signal. (S)-7-guanidino-3-hydroxyheptanamide according to the present invention is usually preferably obtained as an acid addition salt in view of its stability. The acid to be added is
Inorganic salts such as hydrochloric acid, sulfuric acid, phosphoric acid, and boric acid, and organic acids such as acetic acid, citric acid, tartaric acid, and glutaric acid are used. The second invention starts from L-lysine.
Arndt-Eistert reaction (Journal of Organic Chemistry, vol. 17, p. 347, 1952)
to produce (S)-3,7-diaminoheptanoic acid, followed by deamination of the β-amino group with nitrite, converting the carboxyl group to an amide group and the amino group to a guanidine group. It is a manufacturing method for synthesizing (S)-7-guanidino-3-hydroxyheptanamide. Next, this manufacturing method will be specifically described. That is, the following formula () Two amino groups of L-lysine represented by are protected with an amino protecting group to form the following formula (-1) [In the formula, A is a hydrogen atom, B is a monovalent amino protecting group, or A and B jointly represent a divalent amino protecting group]. As the amino protecting group, amino protecting groups conventionally used in peptide synthesis can be used, but in the method of the present invention, it is preferable to use a phthaloyl group as the divalent amino protecting group.
Introducing phthaloyl groups into the two amino groups of L-lysine is carried out by reacting excess N-ethoxycarbonylphthalimide in an aqueous solution in a conventional manner. Next, the carboxyl group of the above amino-protected product is expressed by the following general formula (-2). The acid chloride represented by (when R is -COCl) was used. Acid chlorides can be obtained by conventional methods using thionyl chloride or oxalyl chloride. Subsequently, a diazomethyl group is introduced by treatment with diazomethane in ether [when R is -COCHN ₂ in formula (-2)], and carbon is transferred by Arndt-Eistert reaction in methanol with silver benzoate as a catalyst at room temperature. Ester of carboxylic acid with one chain extended [(-
2) where R is -CH ₂ COOCH ₃ ].
Next, the amino protecting group and the carboxyl protecting group are removed by a conventional method, and the following formula () is obtained. (S)-3,7-diaminoheptanoic acid represented by was synthesized. Next, 7 of (S)-3,7-diaminoheptanoic acid
Only the amino group at position is protected with an amino protecting group, and the following general formula (-1) is obtained. (In the formula, A is a hydrogen atom, and B is a monovalent amino protecting group, or A and B jointly represent a divalent amino protecting group). As the amino protecting group, protecting groups commonly used in peptide synthesis can be used as described above, but
In this case, a benzyloxycarbonyl group, a tert-butoxycarbonyl group, etc., whose protecting group can be easily removed, are used. The primary amino group at the 7-position is more reactive than the secondary amino group at the 3-position, so by limiting the amount of acylating agent used to protect the amino group to 1 equivalent, the amino-protected form at the 7-position is usually protected. Generate with priority. Known acid amides as acylating agents,
Preferably, active esters and the like are used. Next, the amino group at position 3 is deaminated to give the following general formula (-2) (In the formula, A and B are the same as above, and R represents OH)
A 3-hydroxy compound represented by was synthesized. The deamination reaction was carried out using nitrite in an aqueous acetic acid solution in a conventional manner to obtain the 3-hydroxy form with the same stereochemistry. This 3-hydroxy form is treated with diazomethane in ether to form a methyl ester [when R is OCH ₃ in formula (-2)], and reacted with ammonia in methanol by a conventional method to form an amide [(-2)].
When R is NH ₂ in the formula], remove the amino protecting group and convert to the following formula () (S)-7-amino-3-hydroxyheptanoic acid amide represented by was synthesized. Next, convert the amino group at position 7 to a guanidine group to form the following formula () (S)-7-guanidino-3-hydroxyheptanamide represented by was synthesized. In order to convert the amino group at the 7-position into a guanidine group, a guanidine group can be obtained by reacting 1 equivalent of 2-methyl-1-nitroisourea, S-methylthiourea, etc. in an alkaline aqueous solution. For example, when the former is used, the nitro group, which is a protective group for the guanidine group, can be easily removed by conventional hydrolysis using palladium, platinum oxide, or the like as a catalyst. N-[4-(3-aminopropyl)aminobutyl]-2-[(S)-7-guanidino-3-hydroxyheptanamide]-2-hydroxy useful as an anticancer substance using the compound of the present invention To synthesize ethanamide (hereinafter abbreviated as GHA-GS), the compound of the above formula () of the present invention and the following formula It can be obtained by heating and condensing N-[4-3-aminopropyl)aminobutyl]-2,2-dihydroxyethanamide represented by in the presence of an inorganic or organic acid. GHA-GS is a murine leukemia as shown below.
It shows anticancer effects against L1210 and is useful as an anticancer agent. Anticancer effect on mouse leukemia L1210 group 5
L1210 cells in male BDF ₁ mice (6 weeks old)
Immediately after, a sample dissolved in physiological saline was intraperitoneally administered once a day for 6 consecutive days, and the survival rate (T ^/ C = average survival days of treated group/no The average survival days of the treated group was determined. The results are shown in the table below.

[Table] Examples are shown next. Example (a) Synthesis of (S)-3,7-diaminoheptanoic acid Dissolve 15 g (82.15 mmol) of L-lysine hydrochloride in 500 ml of water and add 8.7 g of sodium carbonate.
(82.15 mmol) and 43.2 g (200 mmol) of N-ethoxycarbonylphthalimide were added, and the mixture was stirred at room temperature for 20 hours. After washing the reaction solution with 50 ml of ethyl acetate, the aqueous layer was adjusted to pH 3.0 with 6N hydrochloric acid and extracted three times with 100 ml of toluene. extract liquid
After washing twice with 100ml of water adjusted to PH2.0,
Dehydrated with anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain a white powder of di-N-phthaloyl-L-lysine.
Obtained 27.95g. Yield 84%, decomposition point 71-72℃,
[α] ²² _D −32° (C1, methanol). Di-N-phthaloyl-L-lysine 27.0g
(66.4 mmol) and added 40 ml of oxalyl chloride.
After heating in a 90°C oil bath, 40 ml of 1,2-dimethoxyethane was added and heated under reflux for 2 hours. After the reaction solution was concentrated to dryness, it was again dissolved in 20 ml of 1,2-dimethoxyethane, added dropwise to 500 ml of an ether solution of diazomethane (330 mmol) under ice cooling, and then stirred for 1 hour. The reaction solution was concentrated to dryness, dissolved in 250 ml of anhydrous methanol, and 3.4 g (14.8 mmol) of silver benzoate was added to triethylamine.
A solution dissolved in 50 ml was added and stirred at room temperature for 15 hours. The precipitate was collected, dissolved in 100 ml of chloroform to remove insoluble materials, and concentrated to dryness.
15.3 g of (S)-3,7-diphthaloylaminoheptanoic acid methyl ester was obtained. Yield 53%, decomposition point 118-119°C, [α] ²² _D −3° (C2, chloroform). (S)-3,7-diphthaloylaminoheptanoic acid methyl ester 15.0g (34.5 mmol)
100 ml of 1M ethanolic hydrazine hydrate and 100 ml of 95% ethanol were added and heated under reflux for 1 hour (oil bath temperature: 90°C). The reaction solution was concentrated to dryness and added with 5% hydrochloric acid.
After stirring to 250ml and heating at 80℃ for 1 hour,
The pH was adjusted to 7.1 with 17% ammonia water and poured into a column (inner diameter 27 mm) filled with 300 ml of Amberlite CG-50 (70% NH ₄ type), followed by 900 ml of water each.
Wash with 0.2M ammonia water, elute with 0.5M ammonia water, collect ninhydrin-positive fractions and concentrate to dryness to obtain colorless candy-like (S)-3,7-diaminoheptanoic acid (C ₇ H ₁₆ N ₂ O ₂・1/4H ₂ CO ₃ )
3.15g was obtained. Yield 57%, [α] ²¹ _D +29° (C1,
water). (b) Synthesis of (S)-7-guanidino-3-hydroxyheptanamide 3.1 g (19.3 mmol) of (S)-3,7-diaminoheptanoic acid obtained in the previous section (a) was added to pyridine-water-triethylamine ( 4.81 g (19.3 mmol) of N-benzyloxycarbonyloxysuccinimide was gradually added to the mixture, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated to dryness, dissolved in 30 ml of water, adjusted to pH 6.4 with 6N hydrochloric acid, and mixed with Amberlite CG-50 (80%
_NH4 type) into a 100ml column (inner diameter 16mm),
Developed with ml of water. The effluent was collected and added to a Dowex 50W-X4 (H type) 100ml tower (inner diameter 16mm).
mm), washed with 300 ml of water and 0.2 M ammonia water, and eluted with 0.5 M ammonia water (10 ml fractions). Fractions 16 to 33 were combined and concentrated to dryness. 2.73 _{g of} white powder _of -amino-7- _{benzyloxycarbonylaminoheptanoic} acid ( _{C15H22N2O4.H2O} ) was obtained. Yield 48%, decomposition point 143-147℃, [α] ²² _D +
14° (C1, methanol). In addition, amber light
The CG-50 column was eluted with 0.5 ammonia water to recover 746 mg of (S)-3,7-diaminoheptanoic acid. Recovery rate: 24%. 2.7 g (9.17 mmol) of (S)-3-amino-7-benzyloxycarbonylaminoheptanoic acid was dissolved in 33% acetic acid water, and sodium nitrite was added.
A solution of 1.9 g (27.51 mmol) dissolved in 10 ml of water was added over 1 hour under ice cooling, stirred for an additional 1 hour, and then left at 5°C for 24 hours. water in reaction solution
50 ml of the solution was added and extracted twice with 50 ml of ethyl acetate, and the solvent layer was dehydrated with anhydrous sodium sulfate and concentrated to dryness to obtain 2.16 g of crude powder. This was developed by column chromatography (inner diameter 28 mm) using 200 g of silica gel (Wako Gel C-200) with a mixture of chloroform, methanol, and concentrated aqueous ammonia (30:10:1 volume) (20 ml fractions), and fractionated. 51-60 were combined and concentrated to dryness to obtain 460 mg of white powder of (S)-7-benzyloxycarbonylamino-3-hydroxyheptanoic acid. Yield 17%, decomposition point 115
−117°C, [α] ²³ _D +3° (C2, methanol). 450 mg (1.52 mmol) of (S)-7-benzyloxycarbonylamino-3-hydroxyheptanoic acid was dissolved in 1,2-dimethoxyethane, and 7 ml (4.56 mmol) of an ether solution of diazomethane was added dropwise under ice cooling for 30 minutes. Stirred. The reaction solution was concentrated to dryness to obtain 461 mg of (S)-7-benzyloxycarbonylamino-3-hydroxyheptanoic acid methyl ester. Yield 98%, [α]
²¹ _D 1°. (S)-7-Benzyloxycarbonylamino-3-hydroxyheptanoic acid methyl ester
450 mg (1.45 mmol) in 50 ml of absolute methanol
The mixture was stirred, cooled to -10°C, saturated with ammonia gas, and then left in a sealed tube at room temperature for 3 days. After concentrating the reaction solution to dryness, a 50 g column of silica gel (Wako Gel C-200) (inner diameter 20
mm), chloroform-methanol (100:1
Perform chromatography to develop the
The mixture was fractionated into 10 ml portions, and fractions 82-106 were combined and concentrated to dryness to obtain 371 mg of white powder of (S)-7-benzyloxycarbonylamino-3-hydroxyheptanamide. Yield 87%, decomposition point 126-127℃,
[α] ²² _D −3° (C5, methanol). (S)-7-benzyloxycarbonylamino-3-hydroxyheptanamide 350 mg
(1.19 mmol) was dissolved in a mixture of 10 ml of 90% methanol water and 0.01 ml of acetic acid, 50 mg of 5% palladium-carbon was added, and the catalyst was stirred at room temperature in a hydrogen stream for 3 hours. The liquid was concentrated to dryness, and a small amount was again added. Dowex 50W-X4 (H type) 30ml dissolved in water.
After washing with 90ml of water,
Elution was performed with 0.5M aqueous ammonia (3 ml fraction). Fractions 28-34 were combined and concentrated to dryness to obtain 201 mg of (S)-7-amino-3-hydroxyheptanamide. Yield 96%, [α] ²² _D −2° (C2, water). Dissolve 190 mg (1.08 mmol) of (S)-7-amino-3-hydroxyheptanamide in 3 ml of water, add 0.54 ml of 2N caustic soda, and add 2-
1 ml of a methanol solution containing 129 mg (1.08 mmol) of methyl-1-nitrosourea was added dropwise under ice cooling for 30 minutes, and the mixture was further stirred for 5 hours. reaction solution
The pH was adjusted to 6.0 with 6N hydrochloric acid, and the mixture was concentrated to dryness. This was purified by chromatography using a 30 g column (inner diameter 15 mm) of silica gel (Wako Gel C-200) developed with a mixture of chloroform, methanol, and concentrated aqueous ammonia (60:10:1 volume) (6 ml fractions). . Fractions 67-90 were combined and concentrated to dryness.
187 mg of white powder of (S)-7-nitroguanidino-3-hydroxyheptanamide was obtained. yield
70%, decomposition point 148-149°C, [α] ²² _D −2° (C2, methanol). Dissolve 170 mg (0.69 mmol) of (S)-7-nitroguanidino-3-hydroxyheptanamide in a mixture of 15 ml of water, 15 ml of methanol, and 7.5 ml of acetic acid, add 50 mg of 5% palladium-carbon, and hold for 1 hour at room temperature in a hydrogen stream. Stirred. The catalyst was removed and the liquid was concentrated to dryness to obtain 165 mg of crude powder.
Dissolve this in 10ml of water and fill it with 20ml of CM-Sephadex C-25 (Na type) in a tower (inner diameter 12mm).
and eluted with 0.5 M NaCl (2 ml fractions). Fractions 18-25 were combined and concentrated to dryness. This was extracted three times with 10 ml of methanol, and the methanol solutions were combined and applied to a column (inner diameter 20 mm) packed with 100 ml of Sephadex LH-20, and developed with methanol (1 ml fraction). Fractions 28-46 were combined and concentrated to dryness to obtain 149 mg _of white powder _of (S)-7-guanidino-3- _{hydroxyheptanamide} hydrochloride ( _{C8H18N4O2.HCl} ). Yield 91%, [α] ²² _D −2° (C2, water). Reference example Synthesis of GHA-GS (S)-7-guanidino-3-hydroxyheptane hydrochloride 51 mg (0.214 mmol), N-[4-(3
-aminopropyl)aminobutyl]-2,2-dihydroxyethanamide dihydrochloride 112 mg (0.385 mmol), glutaric acid 70 mg (0.53 mmol) and water
0.07 ml (3.9 mmol) was mixed and stirred at 60°C for 43 hours. Add 20ml of 0.4M NaCl to the reaction solution, adjust the pH to 6.1 with 10% aqueous ammonia, and equilibrate with 0.4M NaCl.
Pour 20 ml of CM-Sephadex C-25 into a column (inner diameter 12 mm), then add 80 ml each of 0.4M and
Gradient elution with 1.0 M NaCl was performed (2 ml fractions). Fractions 41-50 were combined, concentrated to dryness, and extracted three times with 10 ml of methanol. A tower (inner diameter
20 mm) and developed with methanol (1 ml fractions).
Fractions 30-42 were combined and concentrated to dryness.
aminopropyl) aminobutyl]-2-[(S)-7
-guanidino-3-hydroxyheptanamide]
38.4 mg of white powder of -2-hydroxyethanamide (GHA-GS) trihydrochloride was obtained. Yield 35%. GHA-GS trihydrochloride is a hygroscopic powder, and a clear melting point could not be determined, showing [α] ²² _D −1° ± 2° (C2, water). _The elemental analysis values matched the theoretical values _{of C17H37N7O4.3HCl (} C39.81%, H7.86%, N19.12 _% , Cl20.73%). Proton NMR measured in heavy water shows δ1.8−2.3 (CH ₂ ×5), 2.57 (6″−CH ₂ ), 2.95 (2
−
CH ₂ ), 3.5−3.8 (NCH ₂ ×5), 4.55 (3−CH),
A characteristic signal was shown at 5.98 (2'-CH). Note that N-[4-(3-aminopropyl)aminobutyl]-2,2-dihydroxyethanamide used in this reference example is produced as follows. Synthesis of N-[4-(3-aminopropyl)aminobutyl]-2,2-dihydroxyethanamide (a) Mono-N-benzyloxycarbonyl-1.
Synthesis of 4-butanediamine 1.76 g (20 mmol) of 1,4-butanediamine was dissolved in 30 ml of 50% methanol water, and benzyl S-4,6-dimethylpyrimid-2-ylthiocarbonate (Kokusan Kagaku Co., Ltd.) was dissolved in 30 ml of 50% methanol water. Add 5.48 g (20 mmol) of M. Co., Ltd.) and stir for 3 hours. After the reaction, the precipitate was removed (2.08 g, 29% of di-N-benzyloxycarbonyl compound was obtained), and the liquid was concentrated to dryness. Dissolve the residue in 250ml of chloroform,
Washed 5 times with 100 ml of water, dehydrated the chloroform layer with anhydrous sodium sulfate, concentrated to dryness, and mono-
1.0 g of a colorless candy-like substance of N-benzyloxycarbonyl-1,4-butanediamine was obtained. Yield 23%. (b) Synthesis of 0-tosyl-3-tert-butoxycarbonylamino-1-propanol 1.5 g (20 mmol) of 3-amino-1-propanol was dissolved in 30 ml of methanol, and tert-butyl S-4,6-dimethylpyrylene was dissolved in 30 ml of methanol. 4.8 g (20 mmol) of mid-2-ylthiocarbonate (manufactured by Kokusan Kagaku Co., Ltd.) was added and stirred for 6 hours. Concentrate the reaction solution to dryness, dissolve in 200 ml of chloroform, and add 200 ml of
Washed with water. The chloroform layer was concentrated and subjected to column chromatography using 300 g of silica gel (Wako Gel C-200) and developed with a mixture of toluene and ethyl acetate (1:1 volume) (15 ml fractions).
Fractions 82-151 were combined and concentrated to dryness to obtain 2.95 g of 3-tert-butoxycarbonylamino-1-propanol as a colorless oil. Yield 84%. 2.95 g (16.9 mmol) of 3-tert-butoxycarbonylamino-1-propanol was added to pyridine.
The mixture was diluted to 50 ml, and a pyridine solution containing 3.36 g (17.7 mmol) of paratoluenesulfonyl chloride was added dropwise over 40 minutes under ice-cooling in argon. After further standing at 7°C overnight, a small amount of water was added and the mixture was concentrated to dryness. Dissolve the residue in 200ml of chloroform,
After sequentially washing with 5% potassium hydrogen sulfate aqueous solution, saturated sodium hydrogen carbonate aqueous solution, and water,
It was dehydrated with anhydrous sodium sulfate and concentrated to dryness.
Add this to 120g of silica gel (Wakogel C-200)
Column chromatography using toluene
Developed with a mixture of ethyl acetate (8:1 volume) (15 ml
fractions), fractions 35-68 were combined, concentrated to dryness, and 0-
Tosyl-3-tert-butoxycarbonylamino-
3.06 g of a colorless oil of 1-propanol was obtained. Yield 55%. (c) N-tert-butoxycarbonyl-N-(tert-butoxycarbonylaminopropyl)-1,4-
Synthesis of butanediamine 800 mg of 0-tosyl-3-tert-butoxycarbonylamino-1-propanol obtained in section (b)
(2.43 mmol) in 15 ml of dimethylformamide
510 mg of lithium bromide (LiBrH ₂ O)
(4.8 mmol) was added and stirred at room temperature for 24 hours.
The monomer obtained in section (a) is added to the reaction solution of this bromine compound.
540 mg (2.43 mmol) of N-benzyloxycarbonyl-1,4-butanediamine and 0.34 ml of triethylamine were added, and the mixture was stirred at room temperature for 48 hours. Add tert-butyl S-4,6-dimethylpyrimid-2-ylthiocarbonate to this reaction solution.
mg (2.9 mmol) was added and stirred at room temperature for 13 hours. The reaction solution was concentrated to dryness, the residue was dissolved in 100 ml of chloroform, and washed with 50 ml of water.
It was dehydrated with anhydrous sodium sulfate and concentrated to dryness. This was developed by column chromatography using 200 g of silica gel (Wako Gel C-200) with a mixture of toluene and ethyl acetate (4:1 volume) (12 ml fractions), and fractions 134 to 165 were combined and concentrated to dryness. , N-
608 mg of a colorless candy-like substance of benzyloxycarbonyl-N'-tert-butoxycarbonyl-N'-(tert-butoxycarbonylaminopropyl)-1,4-butanediamine was obtained. Yield 52%. 144 mg (0.3 mmol) of this candy-like substance was dissolved in 5 ml of methanol, 100 mg of 5% palladium-barium carbonate was added, and the mixture was stirred at room temperature in a hydrogen stream for 5 hours. The catalyst was removed and the liquid was concentrated to dryness to give N-tert-butoxycarbonyl-N-(tert-butoxycarbonylaminopropyl)-1.4
-103 mg of butanediamine were obtained. Yield 100%. (d) Synthesis of N-[4-(3-aminopropyl)aminobutyl]-2,2-dihydroxyethanamide N-tert-butoxycarbonyl-N obtained in section (c)
-(tert-butoxycarbonylaminopropyl)-
1,4-butanediamine 100 mg (0.29 mmol)
and 148 mg (1 mmol) of 2,2-diethoxyacetic acid
Dissolve in 2 ml of ethyl acetate and add 135 mg (1 mmol) of 1-hydroxybenztriazole.
and dicyclohexylcarbodiimide 206mg
(1 mmol) was added and stirred at room temperature for 15 hours.
The precipitate was removed and washed with cold ethyl acetate, and the liquid and washing liquid were combined and washed successively with 1M aqueous ammonia and water. The ethyl acetate layer was dehydrated over anhydrous sodium sulfate and concentrated to dryness. This was subjected to column chromatography using 20 g of silica gel (Wako Gel C-200) using toluene-ethyl acetate (1:2 volume).
(3 ml fractions), and fractions 14-21 were combined and concentrated to dryness to give N-[4-(3-tert-butoxycarbonylaminopropyl)-4-tert-butoxycarbonylaminobutyl]. 109 mg of a colorless candy-like substance of -2,2-diethoxyethanamide was obtained. Yield 79%. Dissolve 44 mg (0.13 mmol) of this candy-like substance in 1 ml of dioxane, add 2.5 ml of 0.1N hydrochloric acid,
The mixture was stirred in a 100°C oil bath for 4 hours. reaction solution
It was neutralized with 0.2N NaOH (PH6) and concentrated to dryness.
Extract the residue with 1.5 ml of methanol and apply it to a Sephadex LH-20 100 ml column (inner diameter 16.5 mm).
and developed with methanol (2 ml fractions). Fractions 22-25 positive for ninhydrin reaction were combined and concentrated to dryness to yield 13 mg of a colorless candy-like substance of N-[4-(3-aminopropyl)aminobutyl]-2,2-dihydroxyethanamide dihydrochloride. I got it. Yield 46%.

Claims (1)

[Claims] Linear formula () (S)-7-guanidino-3-hydroxyheptanamide represented by and its acid addition salt. Quadratic formula () The two amino groups of L-lysine represented by removing the protecting groups and carboxyl protecting groups;
The following formula () (S)-3,7-diaminoheptanoic acid represented by (S)-3,7-diaminoheptanoic acid was prepared, only the terminal amino group was protected with an amino protecting group, the β-amino group was deaminated with nitrite, the carboxyl group was subsequently esterified, and the After treatment to amidate and remove the amino protecting group, the following formula () (S)-7-amino-3-hydroxyheptanoic acid amide represented by the following formula (), which is characterized by converting the amino group at position 7 to a guanidine group by a conventional method. A method for producing (S)-7-guanidino-3-hydroxyheptanamide represented by