JPS5879971A - Preparation of 1-phenylthio-2-aminopropane derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formulaI(R<1> is halogen; R<2> is H or halogen; R<3> is methyl, ethyl or hydroxyethyl). EXAMPLE:(S)-2-Benzyloxycarbonylamino-1-(4-chlorophenylthio)propane. USE:A preventing agent and remedy for obesity and diabetes, exhibiting hypophagic, glucose tolerance enhancing, hyperinsulinisum inhibitory action and biosynthetic inhibitory action of fatty acids from carbohydrates. PROCESS:A compound expressed by formula II (R<4> is acyl) is deacylated to give the compound expressed by formulaI. The deacylation reaction can be carried out by the hydrolysis with an acid, e.g. hydrochloric acid, or an alkali, e.g. NaOH, or by the protecting group removing reaction in the peptide chemistry in case R<4> is -COOR<4>,, (R<4>,, is aralkyl or tert-butyl).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel 1-phenylthio-2-aminopropane derivative having excellent anti-obesity and anti-diabetic effects.

More specifically, the present invention provides a compound represented by the formula [wherein R1 represents halogen, R2 represents hydrogen or halogen, R3 represents methyl, ethyl/l' or hydroxyethyl, and R4 represents acyl]. This is a method for producing a 1-phenylthio-2-aminopropane derivative represented by the formula [the symbols in the formula have the same meanings as -F], which is characterized by subjecting it to an acyl reaction.

In the above formulas (1) and (1), the halogens represented by R1 and R2 include fluorine, chlorine, or bromine, and when R2 is a halogen, the halogen may be the same as or different from the halogen represented by R1. You can leave it there.

The reaction formula of the method of the present invention, together with the method for producing the raw material compound, is as follows.

[In the formula, Hl, R2, R3 and R4 have the same meanings as above, and X represents a leaving group] In the above formulas (1), (fil) and (V), the acyl represented by R4 is represented by the formula % formula % [wherein R4' is a group represented by lower argyl, aryl, aralkyl or 10Re (R4" is lower alkyl, aryl or aralkyl]] is preferred. As R4', R4// Examples of lower alkyl are methyl, ethyl, and propyl.

Those having 1 to 4 carbon atoms such as isopropyl, n-Y':Irv, 5ee-butyl, and tert-methyl are preferred.

Aryl as R4' and R4'' is preferably phenyl, and aralkyl is preferably phenyl-lower (C1-2)-alkyl having 7-8 carbon atoms, such as benzyl, phenethyl, and α-methylbenzyl. 4/ Alternatively, when R4'' contains a benzene ring, it may have a substituent such as methyl, ethyl, methoxy, chlorine, bromine, 2)p, etc. at any position on the benzene ring.

[In step A), 2-amino-1-phenylthiopro, pan derivative (IV), R4,! Compound (I) is obtained by acylation with an acid halide or acid anhydride corresponding to the acyl represented by =. This acylation generally proceeds advantageously in the presence of a base in a solvent. Examples of such bases are hydrogen carbonate, potassium hydrogen carbonate,
Sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.

Examples of solvents include triethylamine, pyridine, etc., respectively. The reaction usually proceeds advantageously at -20°C to 30°C, but may be heated as appropriate to accelerate the reaction.

Compound (1) in which R4 is a group represented by -COORe (R'" has the same meaning as above) is a thiophenol derivative (V
It is also produced by reacting 1) with compound (V) [Step B]. Preferred examples of the leaving group
Examples include sulfonyloxy groups. compound (vl)
The reaction between (Y) and (Y) is generally preferably carried out in an appropriate solvent in the presence of a base, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, etc. be able to. Any solvent may be used as long as it does not inhibit the reaction, such as methanol, ethanol, tetrahydrofuran, dimethoxyethane, dioxane, dimethylformamide, or water-containing solvents thereof. The reaction proceeds even at 0°-30°C, but in order to accelerate the reaction, it may be heated to around the boiling point of the solvent. The amounts of (Vl) and (V) used in this reaction may be 1:1 in molar ratio, and either one may be used in a small excess as appropriate.

The amount of base to be used is 1 to 1.2 mol per 1 mol of (■), but when compound (V) is in the form of an acid addition salt (e.g., hydrochloride, hydrobromide, hydroiodide), When using the solution, add the necessary amount to completely neutralize the acid. In addition, when X is relatively less reactive chlorine or has an odor, add 0.1 to 1 molar equivalent of sodium iodide or potassium iodide to compound (4) to accelerate the reaction. may be done.

In the alkylation reaction of compound (1) in step (step), first, (III) is converted into an anion using an appropriate base in an anhydrous solvent, and then a common alkylating agent is reacted with the anion. Examples of such bases include sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc., and examples of solvents include dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane, dimethoxyecune, and the like. As the alkylating agent, those used in ordinary alkylation reactions can be used, for example, R
Alkyl halides (e.g., chloride, bromide, iodite), sulfuric acid esters (e.g., dimethyl sulfate, diethyl sulfate), sulfonic acid esters (e.g., methane sulfonate, benzene sulfonate,
toluenesulfonate). The reaction is usually carried out at a temperature of 0 to 40°C, but it can be carried out at a temperature lower or higher than this in order to control the reaction rate.

The thus produced (1) can then be subjected to a deacylation reaction to lead to the υ compound ('I) (5t
ep D). This deacylation reaction involves hydrolysis with acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid), alkali (e.g., thorium hydroxide, potassium hydroxide, barium hydroxide), and R4 100OR4. When "(R4" is aralkyl or t-butyl), this can be easily carried out by using a deprotection reaction known per se in peptide chemistry. In other words, by reacting hydrogen bromide and acetic acid, when p' is an aralkyl group or a t-butyN group,
If l-IJ fluoroacetic acid, hydrogen chloride-organic solvent, or hydrogen chloride-acetic acid is used, those in which R is p-methoxybenzyl group and t-butyN group are removed, respectively. Note that these R4" are aralkyl or t-butyN
When deprotecting the group, good results may be obtained by adding anisole, mercaptoethanol, methyl ethyl sulfide, etc. to suppress side reactions.

The target compound (I) thus produced can be isolated in the form of a free base or in the form of an acid addition salt by means known per se. For example, free bases can be purified by distillation, and acid addition salts can be purified by recrystallization. Acid addition salts include organic acid salts and organic acid salts such as acetates, maleates, fumarates, acidic fumarates, succinates, tartrates, citrates, malates, and the like.

Compound (1) has an optically active form in which the feed configuration marked with * in general formula (1) is S configuration, and an isomer in which feed configuration marked with * is R configuration, but each isomer and Any of these mixtures is naturally included within the scope of the present invention, and isomers can also be produced individually if desired.

For example, by using an optically active compound (S configuration or R configuration) as the starting compound (■) or (V), (1) can be obtained as the corresponding isomer, or the product can be of two types of isomer. In the case of mixtures of d-
and e-tartaric acid, (1- and e-malic acid, d-camphorcarboxylic acid, etc.) or an optically active sulfonic acid (e.g., d-camphorunurphonic acid, etc.) to form a salt with both isomers by recrystallization. It is also possible to separate Mu into each isomer by first separating it into a salt of the isomer, and then extracting the free optically active (1) and then converting it into an appropriate acid salt.

Of the optically active (1) thus obtained, generally Sl
! ! ! The i3-position compound exhibits more favorable physiological activity than the corresponding R-configuration 1q isomer.

The compound (1) of the present invention and its acid addition salt have the effect of suppressing the feeding behavior of animals, especially mammals (e.g. mice, rats, guinea pigs, rabbits, cats, dogs, monkeys, humans) (feeding suppressive effect). It exhibits very specific pharmacological effects, such as enhancing glucose tolerance, suppressing insulin hypersecretion, and inhibiting fatty acid biosynthesis from carbohydrates. Obesity or diabetes associated with obesity is known to cause overeating, increased body fat, hyperimmelinemia, decreased glucose tolerance, etc. Therefore, the compounds of the present invention are effective preventive or therapeutic agents for obesity and diabetes. becomes. Furthermore, the compounds of the present invention have low toxicity and do not exhibit central nervous system stimulant effects, which is a serious side effect generally seen in anorexia, and therefore can be safely used for long-term treatment. In addition, it is well absorbed even when administered orally and has excellent stability, so when used as the above-mentioned medicine, it can be used as a powder or by mixing with appropriate pharmaceutically acceptable carriers, excipients, and diluents. It can be safely administered orally or parenterally in the form of granules, tablets, capsules, injections, and the like. The dosage varies depending on the type, condition, age and weight of the mammal, as well as the route of administration, but for example, when administered orally to adults as a prophylactic agent for obesity or diabetes, the daily dose is approximately 0.1 to 60 nW. (/ / kg especially about 0.2-2
It is preferably about 0/1 (g), and it is desirable to divide this dose and take it approximately between meals.

In addition, as a compound similar to the compound of the present invention, Belgian patent A 653101 describes benzene ring power nitrogen I (substituted 1-
Phenylthio-2-aminopropanes (hereinafter compounds (■
) is specifically described, and is described as having a blood pressure increasing effect, a blood pressure lowering effect, and an anti-epileptic effect, but there is no mention of anti-obesity and anti-diabetic effects. South African patent A 673108 describes the antidepressant effect of rel-1-(4-chlorophenylthio)-2=aminopropane as shown by the following formula (Vill), but it also has anti-obesity,
There is no mention of anti-diabetic effects. According to the research conducted by the present inventors, compound (■) does not exhibit any anti-obesity or anti-diabetic effects, and compound (■) only exhibits a weak and transient anti-feeding effect and has no practical value. do not have. However, the compound (1) of the present invention has a specific substituent called a halogen at a specific position, para-position of the benzene ring, and has a specific secondary amine type structure.
It exhibits strong and long-lasting anti-obesity and anti-diabetic effects.

The results of pharmacological tests showing the excellent usefulness of the compound (1) of the present invention are illustrated below.

A. Feeding suppressive effect on mice. N mice, 7 weeks old, were acclimated to feeding for 6 hours a day (CB-2 powder, Nippon Talea) for 7 days, and the amount of food intake became constant.
Using CR mice (6 mice per group), 50 q/kg of the test compound dissolved in a 5% gum arabic solution was orally administered 0.5 hours before feeding on the 8th day, and 5% gum arabic alone was administered. Food intake was compared between the control group and the control group. The results are shown in Table 1). The values in the table are feeding rates (percentage) when the control is set as 100.

In Table 1, the circle marked N8 in parentheses indicates that there is no statistically significant difference. All other numbers 11α are P<0
．． It was significant at 0.02-0.001.

B. Sprague-Da, 7-week-old rats exposed to 24-hour sound
Test compound 201y/k was administered to wlay rats (6 rats per group).
g was dissolved in distilled water and administered orally by force, feeding fjg (CE-2 powder) was started 0.5 hours later, and feeding softness was measured 1 and 2 hours later. compared. The results were as shown in Table 2. The values in the table are feeding rates (percentage) when the control is set as 100.

Table 2 Glucose Tolerance Enhancing Effect in C Rats 7 Weeks Old Male Sprague-Daw Fasted for 24 Hours
A test compound dissolved in distilled water was orally administered to Ley rats (5 rats per group), and 30 minutes later, glucose (3 g/kg) was administered.
was orally administered, and 30 minutes later, glucose was measured in blood taken from the tail vein. The value of the control group to which only distilled water was administered is expressed as 100, and the results are shown in Table 3.

Table 3 ※※P<0.001, *P<0.05D Insulin hypersecretion suppressive effect in rats Dissolved in distilled water in 7-week-old male Sprague-Dawley rats (5 rats per group) fed 24 hours a day. (S)-1-(4nichlorophenylthio)-2-methylaminopropane fumar ml
kl,s.

10 and 20 wl/kg were orally administered, 30 minutes later glucose (3 g/kg) was orally administered, and 30 minutes later, plasma was separated from the blood collected from the tail vein and insulin was measured. The value of the control group administered only with distilled water was 10.
Expressed as 0.

Table 4 E Inhibitory effect on fatty acid synthesis 8 7-week-old male pragues acclimated to 6 hours a day of feeding ((Jnee 2 powder, Nippon Talea) for 10 days
- Dawley rats (5 rats per group) were orally administered 204'/kg of 1-(4-chlorophenylthio)-2-methylaminopropane fumarate dissolved in distilled water;
After 0 minutes, glucose-U-C (85μC1/3g/kg
) was orally administered, and 60 minutes later, the cells were killed, and the incorporation of radioactivity into fatty acids in the liver and epidermal adipose tissue was measured. The inhibition rate compared to the control group in which distilled water was administered instead of the test compound was 46.6% in the liver and 58.6% in the epidermal adipose tissue.
It was 8%.

F Acute toxicity (LD5o) (S)-1-(4
-chlorophenylthio)-2-methylaminopropane
Oral administration of fumarate as an aqueous solution (500,75
0,1000,1250 and 15009/kg). The animals were reared and observed for 5 days, and the LDbo value was calculated by the probit method.

LD5o=1070! Iv/kg The present invention will be explained in more detail below with reference to Reference Examples and Examples, but the scope of the present invention is not limited thereto.

Reference Example/ (1) In a mixture of sodium borohydride (1.36 g) and dry dioxane (20 ml), N-carbobenzyloxy-L-alanine (4,
A solution of 46 g) in dry dioxane (101 ml) was added dropwise. Then, to this, boron trifluoride ethyl ether (6,
A solution of 2g/) in dry dioxane (10gl) was added dropwise,
The mixture was stirred for 1 hour while cooling with water. After making it acidic by adding water and acetic acid, the solvent was distilled off, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water, sodium chloride water, and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and crystallized from ice-cooled isopropyl ether to give (S)-2-benzyloxycarbonylaminopropanol (2670 g). 4
Ta. Recrystallization from isopropyl ether gave colorless needles. Melting point 77-78℃ [α] Sweet 4.7° (0 = 2.
0. Methanol) Elemental analysis value C□, H, NO3 calculation (11i C63,14,H7,23,N 6.
69 Experiment fil e 63.08. H7,09,N
6.54(2)(S)-2-Benzyloxycarbonylaminopropano-/L/(2,09g), dichloromethane (20a+l), ) ethylamine (1,68m/
) was added dropwise to a mixed solution of mesyl chloride (0.92 m/) while cooling with ice-salt. After stirring under cooling for 40 minutes, the mixture was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The remaining crystals were collected by filtration and washed with isopropyl ether to obtain 5)-N-benzyloxycarbonyl-(2-mesyloxy-1-methyl)ethylamine (2.4 g). Recrystallization from methanol gave colorless prism crystals.

Melting point 1()4-105℃ [α] tube-19,3°(Q-
2,1, Methanol/I/) Elemental analysis value C, H17NO5S Calculated value C50,16, H5,96, N 4.87 Experimental value C50,04, H5,71, N 4.59 Reference example λ (1 ) N-ethoxycarbonyl-L-abnine ethyl ester (18.9 g) in ethanol (100 ml)
) Sodium borohydride (4.56 g) was added to the solution and stirred at room temperature for 4 hours. After adding acetone dropwise to decompose the excess reagent, water was added until the washed material was dissolved, and then acetic acid was added until the mixture became acidic. The solvent was distilled off, the residue was dissolved in water, and then sodium chloride was added until saturation, followed by extraction with dichloromethane.

After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off.
An oily substance (S)-2-ethoxycarbonylaminopropanol (13.4 g) was obtained.

(2) Dissolve the oil (x3.4g) obtained in (1) in 150+t of dichloromethane, and dissolve triethylamine (14g).
After adding d), the mixture was cooled with ice-salt, and mesyl chloride (7.8 g/) was added dropwise while stirring. After stirring for 40 minutes, the mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was crystallized from isopropyl ether (
S)-N-ethoxycarbonyl-(2-mesyloxy-
Crystals of 1-methy/L/)ethylamine were obtained. Yield 18
．． A portion of 3 g of this product was recrystallized from ituburobanol to obtain colorless needle crystals.

Melting point 63-64℃, CQ':J2r)' -36,7
°(c=2.methanol/I/) Elemental analysis value C7H15N05S Calculated value C37,32,H6,71,N 6.22Experimental value C37,47,f(6,82,N 6.31Reference example 3 1) L-alaninow/L/ (16 g) was dissolved in 48% hydrobromic acid (80 ml), and the reaction solution was heated on an oil bath while gradually distilling. 45 gt was distilled in 4 hours.

Add 40d of 48% hydrobromic acid and add 40d of 48% hydrobromic acid for 6 hours.
0ml was distilled. Finally, the reaction solution was concentrated to dryness under reduced pressure.
Acetone (50+l) and pen were obtained as a hygroscopic semi-solid material. Yield M, 35g.

The ice crystals were used in the next reaction without further purification.

(2) p-chlorothiophenol (14.5 g).

Add (S)-2-aminopropylbromide/hydrobromide obtained in (2) above into a mixture of methanol-zL/(80m/) and 28% sodium methoxide/methanol solution (45ml) with stirring. A solution of the salt (28.4 g) in methanol (60 ml) was added dropwise. After stirring for another 2 hours in a room, the solvent was distilled off and diluted with water (50 (1+/). Hydrochloric acid was added to make it acidic. After washing with ethyl ether to remove soluble components, the aqueous layer was removed. Make it strong alkaline with an aqueous sodium hydroxide solution.

The precipitated oil was extracted with ethyl ether, and the ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 5)-2-amino-1-(4-chlorophenylthio)propane as an oil. Purification by vacuum distillation gave an oil with a boiling point of 135-137°C (0.5+nmHg). Yield 14゜6 g, Ca3%" +32
．． 3° (c=2.)II/-/l/) Elemental analysis value
C9H, ClN5 calculated value C53,59,H6,0 sail N6.94 experimental value
C53,59, H6,03, N 7.06 Example/ (1) p-chlorothiophenol (0.72 g).

(S)-N-benzyloxycarbonyl-(2-mesyloxy-1-methyl)ethylamine (1°448)l Sodium iodide (0.2g), methano-# (15m/)
and 28% sodium methoxide/methanol (1,
The mixture of 0 g) was stirred at room temperature for 4 hours and then under reflux for 2 hours, and then methanol was distilled off. Water was added and extracted with ethyl ether, and the ethyl ether layer was washed with sodium hydroxide solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and hegisan was added to obtain crystals (1.30 g) of (S)-2-benzyloxycarbonylamino-1-(4-chlorophenylthio)propane. Recrystallization from isopropyl ether gave colorless prism crystals. Melting point 66-6'1 [α] All +53.7° (C-2, Ol methanol) Elemental analysis value C17H 8 CINO2S calculated value C60, 80, H5, 40, N 4.17 experimental value
C60, 81, H5, 24, N 4.09 (2) (S)
To a solution of -2-benzyloxycarbonylamino-1-(4-chlorophenylthio)propane (1.0 g) in N,N-dimethylformamide (6111) was added sodium hydride (60% oil, o, i2 g) with stirring. and stirred for 40 minutes. Next, this was cooled on ice, and methyl iodide (0°2 g+/) was added dropwise, and the mixture was stirred for 15 minutes while cooling with water and for 30 minutes at room temperature. Water was added and extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. When the solvent was distilled off, an oily product (0.90 g) of (S)-2-(N-benzyloxycarbonyl)methylamino-1-(4-chlorophenylthio)propane was obtained.

(3) (S) -2-(N-benzyloxycarbonyl)methylamino-1-(4-chlorophenylthio)propane (0.7 g), acetic acid (1 ml), anisole (1 m?) in a mixture of water-cooled While stirring 2
5% hydrogen bromide/acetic acid (3.5 ml) was added dropwise. 2.5
The drained water that had been stirred for an hour was added, and the mixture was extracted with ethyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off.5)-1-(4-chlorophenylthio)-2
-Oil of methylaminopropane (0.4 g) was obtained.

This oil was dissolved in ethanol (5 g/), a solution of fumaric acid (0.12 g) in ethanol (3 liters) was added, and isopropyl ether was added, and the precipitated crystals were collected by filtration.
(s)-1-(4-chlorophenylthio)-2-methylaminopropane fumaric acid 4 (0°50 g) is i.

Recrystallization from isopropanol ethyl ether gave colorless crystals. Melting point 138-139℃ [α] Suga+12.4
° (Q = 2.0. Methanol) Elemental analysis value C1oH14clNS-%c4H4o4 Calculated value C52,64, H5,89, N 5.12 Assumed value C52,51, H6,01, N 5.12 Example λ ( 1) Add metallic sodium (0.46g) to ethanol (4
p-chlorothiophenol (2,89 g), (S)-N-ethoxycarbonyl-(2-mesyloxy-1-methyl)ethylamine (4,5 g) and sodium iodide (0+wt) were dissolved in this solution. , 3g) and stirred at room temperature for 2 hours.

Water was added and the precipitated crystals were collected by filtration to obtain (s)-1-(4-chlorophenylthio)-2-ethoxycarbonylaminopropane (4, Ig). Recrystallization from isopropyl ether gave colorless needles.

Melting point 69-70℃ Ca]2D'+37.1° (c=2
．． Methanol) Elemental analysis flItC12H16CINO2S calculated value C
52,64,H5,89,N 5.12 Experimental value C52
,87,H5,73,N 5.14(2)(S)-2-
Amino-1-(4-chlorophenylthio)propane (1
,01g), dichloromethane (641/), sodium carbonate (0.6g), and water (6d), ethyl chlorocarbonate (0-49gt) was added dropwise with stirring under water cooling. After further stirring for 30 minutes while cooling with water, the dichloromethane layer was separated and washed successively with diluted hydrochloric acid, water and water.

After drying over anhydrous magnesium sulfate, the solvent was distilled off and crystallized using hexane to give (S)-1-(4-chlorophenylthio).
Crystals of -2-ethoxycarbonylaminopropane were obtained. Yield 1.08g One point 703 -70.5℃ (a) D + 36.9° (Q=1.
Methanol) The ice crystals matched the compound obtained in (1) above in IR and NMR spectra.

(3) (S) -1-(4-chlorophenylthio)-2-ethoxycarbonylaminopropane (2,74
To a solution of g) in H,N-dimethylformamide (20 ml) was added (hydrogenated with stirring) IJum (60% oil, 0.44 g) little by little, and the mixture was stirred for 30 minutes. Next, this was cooled on ice, and methyl iodide (0.68 m/) was added dropwise, and the mixture was stirred for 3 hours under water cooling and for 1 hour in room n1^. The mixture was poured into ice water (150 m/s) and extracted with ethyl ether.

The extract was washed with water and dried over anhydrous magnesium chloride, and the solvent was distilled off to obtain an oily product of (S)-1-(4-chlorophenylthio)-2-(N-ethoxycarbonyl)methylaminopropane.

(41(3)) 48% hydrobromic acid (8%
After adding sl) and heating under reflux for 1 hour, hydrobromic acid was distilled off under reduced pressure. The residue was dissolved in water, washed with ethyl ether, and the aqueous layer was made alkaline using solid heavy sodium chloride and an aqueous sodium hydroxide solution, and extracted with ether.

The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give (s)-i-(4-chlorophenylthio)-2-
An oily substance (11.71 g) of methylaminopropane was obtained. Ethanol of fumaric acid (o, 46 g) in water oil
/L/(8ml) of hot solution was added to dissolve and condensed, and isopropyl ether was added and the precipitated crystals were collected by filtration, (S)-1
-(4-chlorophenylthio)-2-methylaminopropane fumarate (2.03 g) was obtained.

Colorless crystals recrystallized from isopropanol (1.86g)
I got it. Melting point 140 142 C, (a) 2D3+12
．． 2° (Q=2.methanol) The infrared absorption spectrum and nuclear magnetic resonance spectrum of the ice crystal completely matched the compound obtained in Example/.

Example 3 (1) (S)′-2-amino-1-(4-chlorophenylthio)propane (2.0 g) in pyridine (8 sl
) Acetic anhydride (3 ml) was added dropwise to the solution while cooling with water. The mixture was then allowed to stand at room temperature for 1 hour, diluted with ice water, and extracted with ethyl ether. The ethyl ether layer was washed successively with 9-fold dilute sulfuric acid and water, and dried over anhydrous magnesium sulfate. After distilling off the solvent and adding hexane, (8)-
2-acetamyl'-1-(4-chlorophenylthio)propane was crystallized and obtained. Yield: 2.18g Recrystallized from isopropyl ether to obtain colorless prism crystals. 1
Melting point 88-89°C, [α] arrival +17.6°CC = 2. Methanol) Elemental analysis value C11H14CINO8 Calculated value C54,20,H5,79,N 5.75Experimental value C54,23,H5,74,N 5.71(2)(
8) -2-acetamido-1-(4-chlorophenylthio)propane (2,44 g) in dimethylformamide (2
60% oily sodium hydride (0, 44 g) was added portionwise to the solution with stirring and stirred at room temperature for 1 hour. Next, this was cooled on ice, and methyl iodide (0°68+w/) was added dropwise without stirring, and the mixture was further stirred for 2 hours while cooling with water. The reaction solution was poured into ice water (200g/) and extracted with ethyl ether. The ethyl ether layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off (S
A crude oil of )-2-(N-methylacetamide)-1-(4-chlorophenylthio)propane was obtained. Concentrated hydrochloric acid (15 ml) was added to this, and the mixture was heated for 28 hours with stirring. After diluting with water and washing with ethyl ether, the aqueous layer was made alkaline with sodium hydroxide and extracted with ethyl ether. The extracted surface was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. A hot ethanol (6 ml) solution of Fumar d (293~) was added to the residual oil (1.09 g) to dissolve and concentrate, then isopropyl ether was added and the precipitated crystals were collected by filtration. Yield: 1.39 g This was recrystallized from isopropanol to obtain colorless crystals of (S)-1-(4-chlorophenylthio)-2-methylaminopropane fumarate. Yield 1.27go melting point 140.5-14
2°C [α] +12.1° (c=2.methanol) The infrared absorption spectrum and nuclear magnetic resonance spectrum of the crystal completely matched the compound obtained in Example/.

Example G~/2 The following compound is produced in the same manner as in Examples/~3 above.

Claims (1)

[Claims] Formula [wherein R1 is halogen, R2 is hydrogen or halogen, R3 is methyl, ethyl or droxyethyl,
A method for producing a 1-phenylthio-2-aminopropane derivative represented by the formula [the symbols in the formula have the same meanings as above], which comprises subjecting a compound represented by R4 to acyl to a deacylation reaction.