JP2007001921A - Aminosulfonic acid derivative and its addition salt and s1p receptor regulator - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an aminosulfonic acid derivative having excellent sphingosine-1-phosphate(S1P) receptor-regulating activity. <P>SOLUTION: As a result of zealously conducting studies repeatedly for the purpose of creating highly safe compounds having S1P receptor-regulating activity, it has been found that the aminosulfonic acid derivative of the general formula(1) differing in structure from known S1P receptor regulators has powerful S1P receptor-regulating activity. An example of this derivative is 3-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-hydroxymethylpentane-1-sulfonic acid. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to an aminosulfonic acid derivative useful as an S1P (sphingosine-1-phosphate) receptor modulator, an addition salt thereof, and a hydrate thereof.

Sphingosine-1-phosphate (hereinafter abbreviated as S1P) was considered to be only an intermediate metabolite in sphingosine metabolism, but has been reported to have a cell growth promoting action and a cell motility function controlling action. In addition, it has been clarified that they are new lipid mediators that exhibit various physiological functions such as apoptosis, cell shape regulation, and vasoconstriction (Non-patent Documents 1 and 2). This lipid has both an action as an intracellular second messenger and two actions as an intercellular mediator. In particular, research on the action as an intercellular mediator has been actively conducted, and a plurality of G proteins present on the surface of a cell membrane. It has been reported that information is transmitted through a conjugated receptor (Endothelial Differentiation Gene, EDG) (Non-patent Documents 1 and 3). Currently, five subtypes of Edg-1, Edg-3, Edg-5, Edg-6 and Edg-8 are known for the S1P receptor, and S1P ₁ , S1P ₃ , S1P ₂ , S1P ₄ , S1P Also called ₅ .

From various studies on these S1P receptors, reports have been made that so-called S1P receptor modulators exhibiting agonist activity or antagonist activity on this receptor exert effectiveness against various diseases. For example, it is disclosed in Patent Document 1 that a compound that acts on Edg-5 is effective for arteriosclerosis, renal fibrosis, pulmonary fibrosis, and liver fibrosis. In addition, compounds acting on Edg-1, Edg-3 or Edg-5 may be chronic bronchial asthma, diffuse hamartoma pulmonary angiomyomatosis, adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) (Patent Document 2) discloses that it is effective as a therapeutic and preventive agent for respiratory diseases such as interstitial pneumonia, idiopathic interstitial pneumonia, lung cancer, and hypersensitivity pneumonitis. In addition, compounds with Edg-1 agonist activity are obstructive arteriosclerosis, obstructive thromboangiitis, Buerger's disease, peripheral arterial disease of diabetic neuropathy, sepsis, vasculitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edema Varicoses, arteriosclerosis, hemorrhoids, anal fissures, fistulas, dissecting aortic aneurysms, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure, misalignment, burns, ulcerative colitis, Crohn's disease It is effective as a therapeutic and preventive agent for heart transplantation, kidney transplantation, skin transplantation, liver transplantation, bone marrow transplantation, osteoporosis, chronic hepatitis, cirrhosis, chronic renal failure, glomerulosclerosis (Patent Document 3). It is disclosed. Furthermore, it has been reported that a compound having S1P receptor agonist activity regulates leukocyte migration (Non-patent Documents 4 and 5), and a series of derivatives introduced in the above-mentioned non-patent documents are various organs. Rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, Hashimoto's disease, multiple sclerosis, myasthenia gravis, autoimmune diseases such as type I and II diabetes, Crohn's disease, atopic dermatitis, It is disclosed in Patent Document 4 and Patent Document 5 that it is effective for allergic diseases such as allergic rhinitis, allergic conjunctivitis, allergic contact dermatitis, inflammatory bowel disease, and ulcerative colitis. Has been. Moreover, the phosphoric acid derivative similar to the said (patent document 4) and (patent document 5) is also disclosed by (patent document 6) as a S1P receptor antagonist. Recently, S1P receptor modulators are also disclosed in patent documents such as various compounds such as amino alcohol derivatives and carboxylic acid derivatives (Patent Documents 7 to 29).

As a result of intensive studies aimed at developing compounds having a modulating action on S1P receptors involved in various diseases, the present inventors have focused on aminosulfonic acid derivatives having a structure different from that of conventional compounds. Thus, a new type of S1P receptor modulator was searched. In addition, although a sulfonic acid derivative is disclosed as an S1P receptor agonist in (Patent Document 12) and (Patent Document 14), it is different from the compound of the present application.
WO0198301 pamphlet WO03020313 pamphlet WO02092068 pamphlet WO0218395 pamphlet WO02076995 pamphlet Japanese Patent Laid-Open No. 2003-137894 WO03040097 brochure WO02064616 pamphlet WO02062389 pamphlet WO 03051876 pamphlet WO03061567 pamphlet WO03062248 pamphlet WO03062252 pamphlet WO03073986 pamphlet WO03074008 pamphlet WO03105771 pamphlet WO04010949 pamphlet WO04024673 pamphlet WO04058149 brochure WO04071442 pamphlet WO04096752 pamphlet WO04096757 pamphlet WO04103279 pamphlet WO04103306 pamphlet WO04103309 pamphlet WO04110979 pamphlet WO04113330 pamphlet WO04074297 pamphlet WO05014603 pamphlet Y. Takuma et al., Mol. Cell. Endocrinol., 177, 3 (2001) Y. Igarashi, Ann, NY Acad. Sci., 845, 19 (1998) H. Okazaki et al., Biochem. Biophs. Res. Commun., 190, 1104 (1993) S. Mandala et al., Science, 296, 346 (2002) V. Brinkmann et al., J. Biol. Chem., 277, 21453 (2002)

  The problem to be solved by the present invention is to provide an aminosulfonic acid derivative that has an excellent regulatory action on the S1P receptor and has few side effects.

  As a result of intensive studies to create a compound having an S1P receptor modulating action and a high safety, the present inventors have different structures from the known S1P receptor modulating agents. The novel aminosulfonic acid derivative was found to have a potent S1P receptor modulating action, and the present invention was completed.

That is, the present invention relates to the general formula (1)

[Wherein, R ₁ represents an optionally substituted phenyl group, or an optionally substituted alkyl group having 1 to 10 carbon atoms,
R ₂ represents a hydrogen atom, a halogen atom, a trihalomethyl group, a lower alkyl group having 1 to 4 carbon atoms, or a lower alkoxy group having 1 to 4 carbon atoms,
R ₃ represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms which may have a substituent,
R ₄ represents a hydroxy group, a lower alkoxy group having 1 to 4 carbon atoms or an amino group,
X represents O, S, SO, SO ₂ , or CH ₂ ,
Y is CH = CH or (CH ₂₎ n (n is 1-2 integer),
m represents an integer of 2 to 4]
An aminosulfonic acid derivative, an optical isomer and a pharmacologically acceptable salt thereof, and a hydrate thereof,

The compound represented by the general formula (1) is represented by the general formula (1a).

[Wherein, X, Y, R ₂ , R ₃ and m are the same as defined above]
1) the aminosulfonic acid derivative according to 1), its optical isomers and pharmacologically acceptable salts, and hydrates thereof,

3) The aminosulfonic acid derivative according to 2), the optical isomer and pharmacologically acceptable salt thereof, and the hydrate thereof, wherein R ₂ in the general formula (1a) is a chlorine atom,
The compound represented by the general formula (1) is
3-amino-5- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethylpentane-1-sulfonic acid,
3-amino-5- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethyl-1-pentene-1-sulfonic acid,
3-amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethylhexane-1-sulfonic acid,
3-amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethyl-1-hexene-1-sulfonic acid,
3-amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-propylhexane-1-sulfonic acid,
The aminosulfonic acid derivative according to claim 1, which is 3-amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-propyl-1-hexene-1-sulfonic acid Acceptable salts and hydrates thereof,

General formula (1)

[Wherein, R ₁ represents an optionally substituted phenyl group, or an optionally substituted alkyl group having 1 to 10 carbon atoms,
R ₂ represents a hydrogen atom, a halogen atom, a trihalomethyl group, a lower alkyl group having 1 to 4 carbon atoms, or a lower alkoxy group having 1 to 4 carbon atoms,
R ₃ represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms which may have a substituent,
R ₄ represents a hydroxy group, a lower alkoxy group having 1 to 4 carbon atoms or an amino group,
X represents O, S, SO, SO ₂ , NH or CH ₂ ,
Y is CH = CH or (CH ₂₎ n (n is 1-2 integer),
m represents an integer of 2 to 4]
An S1P receptor modulator comprising, as an active ingredient, at least one of aminosulfonic acid derivatives, optical isomers and pharmacologically acceptable salts thereof, and hydrates thereof,

The compound represented by the general formula (1) is represented by the general formula (1a)

[Wherein, X, Y, R ₂ , R ₃ and m are the same as defined above]
The S1P receptor according to claim 5, wherein at least one of the aminosulfonic acid derivative represented by the following formula, its optical isomer, pharmacologically acceptable salt, and hydrate thereof is used as an active ingredient. Body regulator,

7) Contains at least one of the aminosulfonic acid derivatives, optical isomers, pharmacologically acceptable salts and hydrates thereof described in any one of 1) to 6) as active ingredients Medicines,
It is about.

As described above, the present invention has been found that a novel aminosulfonic acid derivative and an addition salt thereof have an excellent S1P receptor modulating action. Such compounds having S1P receptor modulating action are arteriosclerosis, obstructive arteriosclerosis, obstructive thromboangiitis, renal fibrosis, liver fibrosis, chronic bronchial asthma, diffuse hamartoma pulmonary vascular myoma , Adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), interstitial pneumonia, idiopathic interstitial pneumonia, lung cancer, hypersensitivity pneumonitis, Buerger's disease, diabetic neuropathy peripheral arterial disease, sepsis , Vasculitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edematous disease, varicose vein, dissecting aortic aneurysm, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure, failure, burn, ulcerative colon As therapeutic and prophylactic agents for inflammation, Crohn's disease, etc., and preventive or therapeutic agents for rejection such as heart transplantation, renal transplantation, skin transplantation, liver transplantation, bone marrow transplantation, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, Hashimoto disease Multiple sclerosis, myasthenia gravis, diabetes, atopic dermatitis, is useful as allergic rhinitis, allergic conjunctivitis, prophylactic or therapeutic agent such as allergic contact dermatitis.

  The above general formula (1) and general formula (1a) in the present invention are novel compounds.

  Examples of the pharmacologically acceptable salt of the compound represented by the general formula (1) in the present invention include hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, and citrate. And acid addition salts such as tartrate.

  In the general formula (1) of the present invention, the “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and the “trihalomethyl group” represents a trifluoromethyl group or a trichloromethyl group, The “C1-C10 alkyl group” is, for example, a straight or branched hydrocarbon having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like. Is mentioned. Examples of the “lower alkyl group” such as “a lower alkyl group having 1 to 4 carbon atoms” and “a lower alkoxy group having 1 to 4 carbon atoms” include methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. A straight chain or branched C1-C4 hydrocarbon is mentioned. “A phenyl group which may have a substituent” means a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a trifluoromethyl group, or a lower alkyl having 1 to 4 carbon atoms at any position of the benzene ring. Group, a C1-C4 lower alkoxy group, a hydroxy group, and an aralkyloxy group. The “aralkyl group” of the “aralkyloxy group” mentioned here includes a benzyl group, a diphenylmethyl group, a phenethyl group, and a phenylpropyl group. In addition, “lower alkyl group having 1 to 10 carbon atoms which may have a substituent” and “lower alkyl group having 1 to 4 carbon atoms which may have a substituent” are branched or linear carbon. Examples thereof include those having a hydroxy group, a methoxymethyloxy group or a lower alkoxy group having 1 to 4 carbon atoms on the chain.

According to the present invention, among the compounds represented by the general formula (1), a compound in which Y is CH ₂ and R ₄ is a hydroxy group, that is, the general formula (1b)

[Wherein R ₁ , R ₂ , R ₃ , X and m are as described above]
The compound represented by can be produced by the following route, for example.

<Synthesis route 1>

  In the synthesis route 1, the general formula (3)

[Wherein Boc represents a t-butoxycarbonyl group, Ms represents a methanesulfonyl group, and R ₁ , R ₂ , R ₃ , X and m are as described above]
The compound represented by general formula (2)

[Wherein R ₁ , R ₂ , R ₃ , X, Boc and m are as described above]
Can be produced by reacting with a methanesulfonyl chloride or methanesulfonyl bromide in the presence of a base (step A).

  In the reaction, 1,4-dioxane, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF), ethyl acetate, benzene, toluene, methylene chloride, chloroform, acetonitrile, etc. are used as reaction solvents. It is preferable to react with methanesulfonyl chloride or methanesulfonyl bromide at −0 ° C. to room temperature using an organic base such as triethylamine or diisopropylethylamine.

  In the synthesis route 1, the general formula (1c)

[Wherein R ₁ , R ₂ , R ₃ , X and m are as described above]
Can be produced by acid-decomposing the compound represented by the general formula (3) (step B).

  The reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or mixed with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, ethyl acetate, etc. The reaction can be performed in a solution and the reaction temperature can be from 0 ° C. to room temperature.

The compound represented by the general formula (1b) in the synthesis route 1 can be produced by reacting the compound represented by the general formula (4) with sodium sulfite (step C).
The reaction can be carried out at room temperature with sodium sulfite using water as a solvent and optionally adding ethanol, methanol and THF.

  Further, in the synthesis route 1, the general formula (5)

[Wherein Ac represents an acetyl group, and R ₁ , R ₂ , R ₃ , X, Boc and m are as described above]
Can be produced by subjecting the compound represented by the general formula (2) and thioacetic acid to the Mitsunobu reaction (step D).

  In the reaction, methylene chloride, chloroform, ethyl acetate, 1,4-dioxane, preferably THF is used as a solvent, and diethyl azodicarboxylate or diisopropyl azodicarboxylate and thioacetic acid are reacted in the presence of triphenylphosphine. The temperature can be from 0 ° C. to room temperature.

  The compound represented by the general formula (1b) in the synthesis route 1 can be produced by oxidizing the general formula (5) (step E).

  The reaction can be carried out at 0 ° C. to room temperature by adding hydrogen peroxide in acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, preferably trifluoroacetic acid.

Of the compounds represented by the general formula (1), Y is CH═CH and R ₄ is a lower alkoxy group having 1 to ₄ carbon atoms, that is, the general formula (1c)

[Wherein R ₅ represents a lower alkyl group having 1 to 4 carbon atoms, and R ₁ , R ₂ , R ₃ , X and m are as described above]
Can be produced by the following synthetic route.

<Synthesis route 2>

In the synthesis route 2, the general formula (6)

[Wherein R ₁ , R ₂ , R ₃ , Boc, X and m are as described above]
Can be produced by oxidizing the compound represented by the general formula (2) (step F).

  For the reaction, a generally used oxidation method of an alcohol to an aldehyde can be used. For example, a chromium oxide-pyridine complex such as pyridinium chlorochromate or pyridinium dichromate, or a metal oxidant such as chromium oxide, silver carbonate, or manganese dioxide. And DMSO oxidation using various DMSO activators such as oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, DCC, and sulfur trioxide-pyridine complex.

  In the synthesis route 2, the general formula (7)

[Wherein R ₁ , R ₂ , R ₃ , R ₅ , Boc, X and m are as described above]
The compound represented by general formula (6) and the compound represented by general formula (8)

[Wherein R ₆ represents a lower alkyl group having 1 to 4 carbon atoms, and R ₅ is as described above]
In the presence of a base (Step G).

  The reaction uses THF, DMSO, 1,4-dioxane as a solvent, and the compound represented by the general formula (8) is converted into sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium. A base such as methoxide, potassium ethoxide, potassium-t-butoxide and the like can be reacted at 0 ° C. to room temperature, and then reacted with the compound represented by the general formula (6).

  The compound represented by general formula (1c) in the synthetic pathway 2 can be manufactured by acid-decomposing the compound represented by the said general formula (7) (process H).

  The reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, ethyl acetate. The reaction temperature can be 0 ° C to room temperature.

Among the compounds represented by the general formula (1), a compound in which Y is CH═CH and R ₄ is a hydroxy group, that is, the general formula (1d)

[Wherein R ₁ , R ₂ , R ₃ , X and m are as described above]
Can be produced by hydrolyzing the compound represented by the general formula (1c).

  The reaction can be carried out in hydrochloric acid or hydrobromic acid with heating under reflux.

Of the compounds represented by the general formula (1), Y is (CH ₂ ) ₂ and R ₄ is a lower alkoxy group having 1 to ₄ carbon atoms, that is, the general formula (1e)

[Wherein R ₁ , R ₂ , R ₃ , R ₅ , X and m are as described above]
The compound represented by general formula (1c) can be produced by reducing the compound represented by general formula (1c) or by acid decomposition after reducing the compound represented by general formula (7).

  The reduction reaction uses ethanol, methanol, THF, DMF using 5% paradium carbon, preferably poisoned with ethylenediamine, in the presence of palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon and the like as catalytic reduction catalysts. In a solvent such as ethyl acetate, the reaction can be carried out at room temperature to 100 ° C. under normal pressure to hydrogen pressure. Moreover, it can also carry out by adding sodium borohydride in ethanol at 0 degreeC-normal temperature. Further, as described above, the acid decomposition reaction may be carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or methanol, ethanol, THF, 1,4-dioxane, ethyl acetate, etc. The reaction temperature can be 0 ° C to room temperature.

Of the compounds represented by the general formula (1), compounds in which Y is (CH ₂ ) ₂ and R ₄ is a hydroxy group, that is, the general formula (1f)

[Wherein R ₁ , R ₂ , R ₃ , X and m are as described above]
The compound represented by general formula (1e) is hydrolyzed, the compound represented by general formula (1d) is reduced, or represented by general formula (7). The compound can be produced by reducing and then hydrolyzing.

  The reduction reaction uses ethanol, methanol, THF, DMF using 5% paradium carbon, preferably poisoned with ethylenediamine, in the presence of palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon and the like as catalytic reduction catalysts. In a solvent such as ethyl acetate, the reaction can be carried out at room temperature to 100 ° C. under normal pressure to hydrogen pressure. Moreover, it can also carry out by adding sodium borohydride in ethanol at 0 degreeC-normal temperature. Furthermore, the hydrolysis reaction can be carried out under heating and refluxing in hydrochloric acid or hydrobromic acid as described above.

Among the compounds represented by the general formula (1), a compound in which R ₄ is an amino group, that is, the general formula (1g)

[Wherein R ₁ , R ₂ , R ₃ , X and m are as described above]
The compound represented by the general formula (1h)

[Wherein R ₁ , R ₂ , R ₃ , X and m are as described above]
Can be produced by reacting with ammonia.

In the reaction, methylene chloride or chloroform is used as a solvent, phosgene, phosgene dimer or triphosgene is allowed to act, and then aqueous ammonia is preferably allowed to act at −78 ° C. to room temperature.
In addition, about the synthesis | combining method of the compound represented by General formula (2), it can manufacture with the method described in each pamphlet of WO9408943, WO03029184, WO03029205, WO04026817, WO0246733, WO041107979.

Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.
As the intermediate represented by the general formula (2), synthetic compounds in pamphlets of WO9408943, WO03029184, WO03029205, WO04026817, WO0246733 and WO041107979 can be used. The intermediates newly synthesized using these references are described in the following reference examples.

<Reference Example 1>
4- (4-Benzyloxyphenylthio) -2-chlorobenzaldehyde

Parahydroxybenzenethiol (5.00 g) was dissolved in DMF (100 mL), 2-chloro-4-fluorobenzaldehyde (6.28 g) and potassium carbonate (5.56 g) were added, and the mixture was stirred at 50 ° C. for 5 hours. Under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and then saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off and silica gel column chromatography (hexane: ethyl acetate = 4: 1 and then 2
: Purification by 1) gave 4- (4-hydroxyphenylthio) -2-chlorobenzaldehyde (10.1 g) as a pale yellow oil. The obtained aldehyde (10.0 g) was dissolved in methylene chloride (100 mL) under ice cooling, ethyldiisopropylamine (7.79 mL) and benzyl chloride (6.36 g) were added, and the mixture was stirred at the same temperature for 1 hour. Under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and then saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the desired product (13.3 g) as a pale yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.12 (2H, s), 6.98-7.02 (2H, m),
7.05-7.08 (2H, m), 7.36-7.50 (7H, m), 7.74 (1H, d, J = 8.3Hz), 10.36 (1H, s).

<Reference Example 2>
4- (4-Benzyloxyphenoxy) -2-chlorobenzaldehyde

The target product was obtained as a brown powder by reacting with 2-chloro-4-fluorobenzaldehyde in the same manner as in Reference Example 1 using parabenzyloxyphenol.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.08 (2H, s), 6.88-6.92 (2H, m),
7.02 (4H, s), 7.33-7.43 (5H, m), 7.88 (1H, d, J = 8.3Hz), 10.34 (1H, s)

<Reference Example 3>
2-Chloro-4- [2- (4-methoxyphenyl) ethoxy] benzaldehyde

2-Chloro-4-fluorobenzaldehyde (5.28 g) and potassium carbonate (13.8 g) were added to a solution of 4-methoxyphenethyl alcohol (7.60 g) in DMF (60 mL), and the mixture was stirred at 95 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed in turn with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the desired product (7.86 g) as a pale yellow oil.
MS (FAB +): 291 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.06 (2H, t, J = 7.3 Hz), 3.80 (3H, s),
4.20 (2H, t, J = 7.3Hz), 6.86-6.89 (3H, m), 6.92 (1H, d, J = 1.8Hz), 7.18-7.20 (2H, m),
7.87 (1H, d, J = 8.6Hz), 10.32 (1H, s).

<Reference Example 4>
4 ′-[4- (Benzyloxy) phenoxy] -2′-ethyl chlorocinnamate

60% sodium hydride (220 mg) was added to a solution of ethyl diethylphosphonoacetate (1.19 mL) in THF (30 mL) at 0 ° C. under an argon gas stream, and the mixture was stirred for 15 min. ) In THF (5 mL) was added. After stirring for 1 hour, 5% citric acid was added, extracted with ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to obtain the desired product (1.86 g) as a pale yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H, t, J = 7.3 Hz), 4.27 (2H, q,
J = 7.3Hz), 5.07 (2H, s), 6.34 (1H, d, J = 16.1Hz), 6.85 (1H, dd, J = 2.4, 8.8Hz),
6.94 (1H, d, J = 2.4Hz), 7.33-7.46 (9H, m), 7.56 (1H, d, J = 8.8Hz), 8.03 (1H, d,
(J = 16.1Hz)

<Reference Example 5>
4 '-[4- (Benzyloxy) phenylthio] -2'-ethyl chlorocinnamate

The target product was obtained as a pale yellow powder by reacting in the same manner as in Reference Example 4 using the compound of Reference Example 1. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.33 (3H, t, J = 7.3 Hz), 4.26 (2H, q, J = 7.3 Hz), 5.11 (2H, s), 6.35 (1H,
d, J = 15.9Hz), 6.96 (1H, dd, J = 1.2, 7.8Hz), 7.01-7.07 (3H, m), 7.34-7.49 (8H, m),
8.00 (1H, d, J = 15.9Hz)

<Reference Example 6>
4 ′-(4-Bromophenylthio) -2′-ethyl chlorocinnamate

After reacting in the same manner as in Reference Example 1 using parabromothiophenol, the resulting aldehyde was reacted in the same manner as in Reference Example 4 to obtain the desired product as a colorless oil.
¹ H-NMR (400MHz, CDCl ₃ ) δ 1.34 (3H, t, J = 7.3Hz), 4.27 (2H, q, J = 7.3Hz), 6.39 (1H,
d, J = 16.1Hz), 7.08 (1H, dd, J = 2.0, 8.3Hz), 7.23 (1H, d, J = 2.0Hz), 7.32 (2H, d,
J = 8.3Hz), 7.50-7.53 (3H, m), 8.01 (1H, d, J = 16.1Hz)

<Reference Example 7>
4 ′-(4-biphenylthio) -2′-ethyl chlorocinnamate

To a solution of the compound of Reference Example 6 (1.23 g) in toluene (40 mL), tetrakistriphenylphosphine palladium (179 mg), phenylboric acid (452 mg) in ethanol (5 mL), 2 mol / L-Na ₂ CO ₃ aqueous solution (8.7 mL) And heated to reflux for 8 hours. Ethyl acetate was added, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain the desired product (1.07 g) as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H, t, J = 7.3 Hz), 4.27 (2H, q,
J = 7.3Hz), 6.39 (1H, d, J = 16.1Hz), 7.12 (1H, dd, J = 2.0, 8.3Hz), 7.36-7.41 (1H, m),
7.45-7.55 (5H, m), 7.60-7.64 (5H, m), 8.02 (1H, d, J = 16.1Hz).

<Reference Example 8>
4 ′-[4- (3,5-dichlorophenyl) phenylthio] -2′-ethyl chlorocinnamate

The target product was obtained as a pale yellow oil by reacting the compound of Reference Example 6 with 3,5-dichlorophenylboric acid in the same manner as in Reference Example 7.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H, t,
J = 7.3Hz), 4.27 (2H, q, J = 7.3Hz), 6.40 (1H, d, J = 16.1Hz), 7.15 (1H, dd, J = 2.0,
8.3Hz), 7.29 (1H, d, J = 2.0Hz), 7.37 (1H, t, J = 2.0Hz), 7.47 (2H, d, J = 1.5Hz),
7.50-7.56 (5H, m), 8.02 (1H, d, J = 16.1).

<Reference Example 9>
4 '-[4- (Benzyloxy) phenoxy] -2'-chlorodihydrocinnamyl alcohol

The compound of Reference Example 4 (1.86 g) was dissolved in ethanol (30 mL), and BiCl ₃ (719 mg) and NaBH ₄ (689 mg) were added with stirring at 0 ° C. After stirring at the same temperature for 30 minutes and at room temperature for 5 hours, water was added, insoluble matter was filtered off through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was dissolved in THF (30 mL), LiAlH ₄ (173 mg) was added at 0 ° C., and the mixture was stirred for 1 hr. An aqueous sodium hydroxide solution was added, insolubles were filtered off through celite, the residue was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (1.50 g) as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.31 (1H, br s), 1.84-1.91 (2H, m),
2,78 (2H, t, J = 7.8Hz), 3.69 (2H, d, J = 6.4Hz), 5.06 (2H, s), 6.79 (1H, dd, J = 2.4,
8.3Hz), 6.92-6.96 (5H, m), 7.15 (1H, d, J = 8.3Hz), 7.30-7.45 (5H, m).

<Reference Example 10>
4 ′-[4- (Benzyloxy) phenoxy] -2′-chlorodihydrocinnamyl iodide

While stirring a solution of the compound of Reference Example 9 (1.50 g) in THF (30 mL) at 0 ° C., PPh ₃ (2.14 g), imidazole (554 mg) and I ₂ (2.07 g) were added and stirred for 30 minutes. A 5% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was concentrated, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to obtain the desired product (1.79 g) as a colorless powder. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.08-2.15 (2H, m), 2.79 (2H, t, J = 7.3 Hz), 3.19 (2H, t, J = 6.8 Hz),
5.06 (2H, s), 6.79 (1H, dd, J = 2.4, 8.3Hz), 6.93 (1H, d, J = 2.4Hz), 6.97 (4H, s),
7.16 (1H, d, J = 8.3Hz), 7.32-7.46 (5H, m).

<Reference Examples 11-12>
The compounds shown in Table 1 were synthesized by reacting the compounds of Reference Examples 5, 7, and 8 in the same manner as in Reference Examples 9 and 10.

<Reference Example 14>
4- [4- (Benzyloxy) phenylthio] -2-chlorophenethylaldehyde

To a solution of (methoxymethyl) triphenylphosphonium chloride (8.28 g) in THF (280 mL) under argon and ice cooling, t-butoxypotassium (6.76 g) was added and stirred for 1 hour. The compound of Reference Example 1 (11.2 g) ) In THF (20 mL) was added and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed in turn with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and silica gel column chromatography (hexane: ethyl acetate = 6: 1, then 2
: Purified in 1) to obtain a vinyl ether form (4.63 g) as a pale yellow oil. The obtained vinyl ether (4.63 g) was dissolved in THF (66 mL), 6 mol / L aqueous hydrochloric acid solution (60 mL) was added, and the mixture was stirred at 60 ° C. for 3 hr. The mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Silica gel column chromatography (hexane: ethyl acetate = 6: 1 then 4
: Purified in 1) to obtain the desired product (3.70 g) as a colorless powder.
MS (EI +): 382 ([M] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.82 (2H, d,
J = 1.8Hz), 5.02 (2H, s), 7.16 (2H, d, J = 1.8Hz), 7.25 (1H, d, J = 8.6Hz), 7.35 (1H, d,
J = 1.2Hz), 7.50 (2H, d, J = 8.6Hz), 7.54 (2H, d, J = 8.0Hz), 7.66 (1H, t, J = 8.0Hz),
8.20 (2H, dd, J = 1.2Hz, 8.6Hz), 9.75 (1H, t, 1.8Hz).

<Reference Example 15>
2-Chloro-4- [2- (4-methoxyphenyl) ethoxy] phenethylaldehyde

The target product was obtained as a pale yellow oil by reacting in the same manner as in Example 14 using the compound of Reference Example 3.
MS (FAB +): 305 ([M] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.03 (2H, t, J = 6.7 Hz), 3.75 (2H, d,
J = 1.8Hz), 3.80 (3H, s), 4.12 (2H, t, J = 6.7Hz), 6.79 (1H, dd, J = 3.1, 8.6Hz),
6.86 (2H, d, J = 8.6Hz), 6.97 (1H, d, J = 2.5Hz), 7.10 (1H, d, J = 8.6Hz), 7.18 (2H, d,
J = 8.6Hz), 9.71 (1H, t, J = 1.8Hz).

<Reference Example 16>
4- [4- (Benzyloxy) phenylthio] -2-chlorophenethyl iodide

The alcohol obtained by reducing the compound of Reference Example 14 with NaBH ₄ under ice cooling was reacted in the same manner as in Reference Example 10 to obtain the desired product as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.23-3.30 (2H, m), 3.31-3.40 (2H, m), 5.03 (2H,
s), 7.12-7.18 (2H, m), 7.23 (2H, d, J = 8.6Hz), 7.30 (1H, d, J = 1.2Hz), 7.47 (2H, d,
J = 8.6Hz), 7.53 (2H, d, J = 8.0Hz), 7.66 (1H, t, J = 8.0Hz), 8.20 (2H, dd, J = 1.2Hz,
(8.6Hz).

<Reference Example 17>
2-Chloro-4- [2- (4-methoxyphenyl) ethoxy] phenethyl iodide

The target product was obtained as a pale yellow oil by reacting in the same manner as in Reference Example 16 using the compound of Reference Example 15.
MS (FAB +): 416 ([M] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.02 (2H, t, J = 7.3 Hz), 3.21 (2H, t,
J = 7.3Hz), 3.34 (2H, t, J = 6.7Hz), 3.79 (3H, s), 4.10 (2H, t, J = 6.7Hz), 6.75 (1H, dd,
J = 2.4, 8.6Hz), 6.85 (2H, d, J = 8.6Hz), 6.90 (1H, d, J = 2.4Hz), 7.11 (1H, d,
J = 8.6Hz), 7.18 (2H, d, J = 8.6Hz).

<Reference Example 18>
4'-Benzyloxydihydrocinnamyl iodide

  4-Benzyloxydihydrocinnamate ethyl was reduced in the same manner as in Reference Example 9 and then iodinated in the same manner as in Reference Example 10 to obtain the desired product as a yellow powder.

<Reference Example 19>
Ethyl 5-[(4-benzyloxy) phenyl] -2-t-butoxycarbonylamino-2-ethoxycarbonylpentanoate

To a solution of diethyl 2-t-butoxycarbonylaminomalonate (11.7 g) in THF (180 mL) and DMF (30 mL) was added NaOtBu (4.09 g), and the mixture was heated under reflux for 30 minutes, then the compound of Reference Example 18 (10.0 g) In THF (120 mL) was added and stirred at reflux for 8 hours. Ice water was added, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.22 (6H, t, J = 7.1 Hz), 1.42 (9H, s),
1.44-1.47 (2H, m), 2.31 (2H, br s), 2.57 (2H, t, J = 7.6Hz), 4.11-4.27 (4H, m), 5.03 (2H,
s), 5.92 (1H, br s), 7.06 (2H, d, J = 8.8Hz), 7.29-7.43 (5H, m), 8.88 (2H, d,
J = 8.8Hz).

<Reference Examples 20-24>
The compounds shown in Table 2 were synthesized by reacting in the same manner as in Reference Example 19 using Reference Examples 10 to 13 and 16.

<Reference Example 25>
5-[(4-Trifluoromethylphenoxy) phenyl] -2-t-butoxycarbonylamino-2-ethoxycarbonylpentanoic acid ethyl ester

The crude product obtained in Reference Example 19 was dissolved in ethanol (300 mL), 10% Pd / C (2.00 g) was added, and the mixture was stirred at a hydrogen pressure of 294 kPa and 50 ° C. After 2 hours, the catalyst was removed by filtration through celite, and the residue was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 then 2: 1) and purified by 5- (4-hydroxyphenyl) -2- Ethyl t-butoxycarbonylamino-2-ethoxycarbonylpentanoate (12.0 g) was obtained as a colorless oil. Copper acetate (133 mg), triethylamine (0.205 mL), and MS4A (1.00 g) were added to a methylene chloride (5 mL) solution of the obtained phenol compound (300 mg) and paratrifluoromethylphenylboric acid (279 mg) at room temperature. And stirred for 1 day. Insoluble material was removed by filtration through Celite, and the residue was purified through silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired product (235 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.24 (6H, t, J = 7.3 Hz), 1.42 (9H, s),
1.46-1.52 (2H, m), 2.34 (2H, br s), 2.64 (2H, t, J = 7.8Hz), 4.18-4.25 (4H, m),
5.94 (1H, br s), 6.95 (2H, d, J = 8.3Hz), 7.01 (2H, d, J = 8.3Hz), 7.16 (2H, d,
J = 8.3Hz), 7.55 (2H, d, J = 8.3Hz).

<Reference Examples 26 and 27>
2-t-butoxycarbonylamino-2- [4- (4-trifluoromethylphenoxy) phenyl] propyl-1,3-propanediol and 2-t-butoxycarbonylamino-5- [4- (4-trifluoro) Methylphenoxy) phenyl] pentan-1-ol

LiBH ₄ (92.6 mg) and EtOH (0.5 mL) were added to a THF (10 mL) solution of the compound of Reference Example 25 (235 mg) at 0 ° C., and the mixture was stirred for 1 day while raising the temperature to room temperature. A saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After concentrating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 and then 3: 2) to obtain a diol form (147 mg) and a monool form (24.3 mg) as colorless oils.
Diol form; ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.44 (9H, s), 1.62-1.64 (4H, m), 2.62 (2H, br s), 3.36 (2H, br s),
3.59 (2H, d, J = 11.2Hz), 3.83 (2H, d, J = 11.2Hz), 4.91 (1H, br s), 6.97 (2H, d,
J = 8.8Hz), 7.02 (2H, d, J = 8.8Hz), 7.18 (2H, d, J = 8.8Hz), 7.55 (2H, d, J = 8.8Hz).
Monool form: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.45 (9H, s), 1.53-1.77 (4H, m), 2.60-2.69 (2H, m), 3.54-3.57 (1H, m),
3.68 (2H, d, J = 8.3Hz), 4.62 (1H, br s), 6.97 (2H, d, J = 8.8Hz), 7.02 (2H, d,
J = 8.8Hz), 7.18 (2H, d, J = 8.8Hz), 7.55 (2H, d, J = 8.8Hz).

<Reference Examples 28-35>
The compounds shown in Table 3 were synthesized by reacting the compounds of Reference Examples 20 to 24 in the same manner as in Reference Examples 26 and 27.

<Reference Example 36>
2-t-Butoxycarbonylamino-2- [2-chloro-4- (4-methoxyphenylethoxy) phenyl] ethyl-1,3-propanediol

The compound of Reference Example 17 was used and reacted in the same manner as in Reference Example 19, and then reduced in the same manner as in Reference Example 26 to obtain the desired product as a colorless powder.
MS (FAB +): 480 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.45 (9H, s), 1.79-1.83 (2H, m),
2.64-2.68 (2H, m), 3.01 (2H, t, J = 7.3Hz), 3.37-3.47 (2H, br), 3.63-3.67 (2H, m),
3.80 (3H, s), 3.89-3.93 (2H, m), 4.08 (2H, t, J = 7.3Hz), 5.07 (1H, br s), 6.73 (1H,
dd, J = 2.5, 8.6Hz), 6.85-6.87 (2H, m), 6.88 (1H, d, J = 2.5Hz), 7.10 (1H, d,
J = 7.9Hz), 7.18 (1H, d, J = 8.6Hz).

<Reference Example 37>
2-Allyl-4-[(4-benzyloxyphenylthio) -2-chlorophenyl] -ethyl 2-ethoxycarbonylbutyrate

Under argon, 60% sodium hydride (661 mg) was added to a THF: DMF (7: 1) mixed solution (80 mL) of diethyl malonate (2.61 mL), and the mixture was stirred at 80 ° C. for 30 minutes. A THF: DMF (7: 1) mixed solution (20 mL) of the compound of Reference Example 16 (5.67 g) was added and stirred at 80 ° C. for 30 minutes. The reaction vessel was ice-cooled, 60% sodium hydride (2.28 g) was added to the reaction mixture, and the mixture was stirred for 30 min. Thereafter, allyl iodide (5.21 mL) was added, and the mixture was stirred for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain the desired product (3.56 g) as a pale yellow oil.
MS (EI +): 552 ([M] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.26 (6H, t,
J = 7.3Hz), 2.07-2.11 (2H, m), 2.56-2.63 (2H, m), 2.74 (2H, d, J = 7.3Hz), 4.19 (4H, q,
J = 7.3Hz), 5.08 (2H, s), 5.12-5.18 (2H, m), 5.64-5.72 (1H, m), 6.96-6.99 (3H, m),
7.04 (1H, d, J = 7.9Hz), 7.11 (1H, d, J = 1.8Hz), 7.32-7.45 (7H, m).

<Reference Example 38>
2-Allyl-4-[(4-benzyloxyphenylthio) -2-chlorophenyl] -2-ethoxycarbonylbutyric acid

To a mixed solution (90 mL) of the compound of Reference Example 37 (3.56 g) in ethanol-THF (2: 1) was added 1 mol / L-potassium hydroxide aqueous solution (20 mL), and the mixture was heated to reflux for 2.5 hours. A 10% aqueous hydrochloric acid solution was added to the reaction solution to adjust the pH to 1, followed by extraction with ethyl acetate, washing with water and saturated brine in that order, and drying over anhydrous sodium sulfate. After removing the solvent, silica gel column chromatography (hexane: ethyl acetate = 3: 1
The product was purified by 1: 1) to obtain the desired product (2.67 g) as a pale yellow oil.
MS (FAB +): 524 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.31 (3H, t,
J = 7.3Hz), 2.17-2.20 (2H, m), 2.58-2.67 (3H, m), 2.76-2.81 (1H, m), 4.22-4.28 (2H,
m), 5.08 (2H, s), 5.11-5.16 (2H, m), 5.61-5.71 (1H, m), 6.96-6.99 (3H, m), 7.03 (1H,
d, J = 7.9Hz), 7.10 (1H, d, J = 1.8Hz), 7.32-7.45 (7H, m).

<Reference Example 39>
2-Allyl-4-[(4-benzyloxyphenylthio) -2-chlorophenyl] -2-methoxycarbonylaminobutyric acid ethyl ester

To a solution of the compound of Reference Example 38 (1.22 g) in benzene (15.0 mL) were added triethylamine (0.42 mL) and diphenylphosphoric acid azide (550 μL), and the mixture was heated to reflux for 40 minutes. It returned to normal temperature, the methanol (15 mL) solution and sodium methoxide (251 mg) were added, and it heated and refluxed for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired product (1.21 g) as a pale yellow oil.
MS (FAB +): 553 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.28 (3H, t, J = 7.3 Hz), 2.06-2.12 (1H, m),
2.44-2.51 (2H, m), 2.60-2.65 (2H, m), 3.05-3.15 (1H, m), 3.63 (3H, s),
4.14-4.22 (2H, m), 5.05-5.07 (2H, m), 5.58-5.64 (1H, m), 5.80 (1H, br s),
6.93-6.99 (3H, m), 7.02 (1H, d, J = 7.9Hz), 7.10 (1H, d, J = 1.8Hz), 7.32-7.45 (7H, m).

<Reference Example 40>
2-Allyl-4-[(4-benzyloxyphenylthio) -2-chlorophenyl] -2-methoxycarbonylaminobutanol

Under ice-cooling, lithium borohydride (281 mg, 12.90 mmol) was added to a THF (15 mL) solution of the compound of Reference Example 39 (1.43 g), ethanol (0.75 mL) was added dropwise, and the mixture was stirred for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain the desired product (1.10 g) as a colorless oil. MS (FAB +): 512 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.82-1.94 (2H,
m), 2.31-2.36 (1H, m), 2.45-2.50 (1H, m), 2.64-2.71 (2H, m), 3.64 (3H, s),
3.71-3.81 (3H, m), 4.90 (1H, br s), 5.08 (2H, s), 5.17-5.21 (2H, m), 5.80-5.89 (1H, m), 6.96-7.00 (3H, m) , 7.08-7.12 (2H, m), 7.32-7.45 (7H, m).

<Reference Example 41>
2-Allyl-2-amino-4-[(4-benzyloxyphenylthio) -2-chlorophenyl] -butanol

To a solution of the compound of Reference Example 40 (1.10 g) in DMSO (14 mL), add 5 mol / L-potassium hydroxide aqueous solution (14 mL) and 1 mol / L-lithium hydroxide aqueous solution (7 mL), and heat at 100 ° C. for 17 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (aminated silica, ethyl acetate alone, then ethyl acetate: ethanol = 10: 1) to obtain the desired product (1.16 g) as colorless crystals.
MS (FAB +): 454 ([M + H] ⁺ )
¹ H-NMR (400 MHz, DMSO) δ 1.29 (2H, br s), 1.38-1.42 (2H, m),
2.08 (2H, d, J = 7.9Hz), 2.57-2.70 (2H, m), 3.13-3.17 (2H, m), 4.56 (1H, t, J = 4.9Hz),
5.00-5.07 (2H, m), 5.13 (2H, s), 5.80-5.90 (1H, m), 7.03-7.10 (4H, m), 7.22 (1H, d,
J = 7.9Hz), 7.31-7.46 (7H, m).

<Reference Example 42>
2-t-Butoxycarbonylamino-2-methoxymethyloxymethyl-4- (4-octylphenyl) butan-1-ol

FTY-720 (2.02 g) (compound described in WO9408943 pamphlet) was added to a 1,4-dioxane (60 mL) solution, and a 1 mol / L potassium hydroxide aqueous solution (5.96 mL) was further added and dissolved. Di-t-butyl dicarbonate (1.66 g) was added and stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed in turn with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain an N-Boc form (2.46 g) as a colorless powder. The obtained crystals were added to a methylene chloride (20 mL) solution, and N-ethyldiisopropylamine (1.33 mL) and chloromethyl methyl ether (579 μL) were added under ice-cooling and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed in turn with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (1.33 g) as a colorless oil.
MS (FAB +): 452 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.88 (3H, t, J = 7.3 Hz), 1.24-1.29 (12H,
m), 1.45 (9H, s), 1.85-1.90 (1H, m), 2.02-2.10 (1H, m), 2.50-2.57 (1H, m), 2.55 (2H,
t, J = 7.3Hz), 2.61-2.69 (1H, m), 3.39 (3H, s), 3.55 (1H, d, J = 11.6Hz), 3.76 (1H, d,
J = 11.6Hz), 3.74-3.80 (2H, m), 4.64 (2H, s), 5.15 (1H, br s), 7.09 (4H, s).

<Example 1>
1-acetylthio-2-t-butoxycarbonylamino-2-methoxymethyloxymethyl-4- (4-octylphenyl) -butane

To a THF (20 mL) solution of the compound of Reference Example 42 (1.59 g), diisopropyl azodicarboxylate (1.36 mL), triphenylphosphine (1.85 g), and thioacetic acid (276 μL) were sequentially added under ice cooling overnight. Stir. The solvent was distilled off, hexane was added, and the precipitated crystals were filtered off. The filtrate was evaporated and purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired product (771 mg). Was obtained as a brown oil.
MS (FAB +): 510 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.88 (3H, t, J = 6.8 Hz), 1.26-1.29 (10H,
m), 1.45 (9H, s), 1.53-1.61 (2H, m), 2.03-2.17 (2H, m), 2.36 (3H, s), 2.52-2.63 (4H,
m), 3.38 (3H, s), 3.39 (1H, d, J = 14.1Hz), 3.49 (1H, d, J = 14.1Hz), 3.64 (2H, br s),
4.62 (2H, s), 4.91 (1H, br s), 7.08 (4H, s).

<Example 2>
2-Amino-2-hydroxymethyl-4- (4-octylphenyl) butane-1-sulfonic acid

To a solution of the compound of Example 1 (500 mg) in trifluoroacetic acid (1.0 mL) was added 30% aqueous hydrogen peroxide (0.15 mL) under ice cooling, and the mixture was stirred overnight. The precipitated crystals were separated by filtration, washed with water and diisopropyl ether, and then dried under reduced pressure to obtain the desired product (53 mg) as a light brown powder.
MS (FAB +): 372 ([M + H] ⁺ )
^{1 H-NMR (400MHz, DMSO} ) δ 0.84 (3H, t, J = 7.3Hz), 1.15-1.30 (10H, m),
1.46-1.55 (2H, m), 1.87 (1H, td, J = 12.8, 4.9Hz), 2.03 (1H, td, J = 12.8, 4.9Hz),
2.43-2.61 (3H, m), 2.63 (1H, td, J = 12.8, 4.9Hz), 2.84 (1H, d, 14.8Hz), 2.91 (1H, d,
14.8Hz), 3.52-3.56 (1H, m), 3.60-3.64 (1H, m), 5.39 (1H, t, J = 5.5Hz), 7.06 (2H, d,
J = 8.6Hz), 7.10 (2H, d, J = 8.6Hz), 7.81 (2H, br).

<Example 3>
5- [4- (3-Benzyloxyphenylthio) -2-chlorophenyl] -2-t-butoxycarbonylamino-1-methanesulfonyloxy-2-methoxymethyloxymethylpentane

To a solution of 5- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -2-t-butoxycarbonylamino-2-methoxymethyloxymethylpentan-1-ol (500 mg) in acetonitrile (8.0 mL), Triethylamine (231 μL) and methanesulfonyl chloride (83.5 μL) were added little by little under ice-cooling, and the mixture was stirred for 40 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the desired product as a pale yellow oil.
MS (FAB +): 679 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.41 (9H, s), 1.63-1.73 (4H, m), 2.70 (2H,
t, J = 7.3Hz), 3.00 (3H, s), 3.35 (3H, s), 3.55 (1H, d, J = 9.8Hz), 3.61 (1H, d,
J = 9.8Hz), 4.38 (1H, d, J = 9.2Hz), 4.48 (1H, J = 9.2Hz), 4.60 (2H, s), 5.02 (2H, s),
6.86-6.88 (1H, m), 6.92-6.96 (2H, m), 7.11 (1H, d, J = 7.9Hz), 7.15 (1H, dd, J = 1.8,
7.9Hz), 7.23 (1H, t, J = 7.9Hz), 7.31-7.39 (6H, m).

<Example 4>
2-Amino-5- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -2-methanesulfonyloxypentan-1-ol hydrochloride

The compound of Example 3 (1.30 g) was dissolved in a 10% hydrochloric acid-methanol (8.0 mL) solution and allowed to stand overnight. The solvent was distilled off to obtain the desired product (415 mg) as a colorless amorphous.
MS (EI +): 536 ([M + H] ⁺ )
¹ H-NMR (400MHz, DMSO) δ 1.49-1.68 (4H, m), 2.66 (2H, t, J = 7.3Hz), 3.25 (3H,
s), 3.52 (2H, s), 4.27 (2H, s), 5.09 (2H, s), 6.90 (1H, d, J = 7.9Hz), 6.96-7.01 (2H,
m), 7.23 (1H, dd, J = 1.8, 18.5Hz), 7.29-7.41 (8H, m), 8.26-8.31 (3H, m).

<Example 5>
2-Amino-5- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -2-hydroxymethylpentane-1-sulfonic acid

The compound of Example 4 (415 mg) was dissolved in water (1.5 mL), sodium sulfite (147 mg) was added, and the mixture was stirred overnight. Remove the aqueous layer, dissolve the organic layer in a small amount of ethanol and DMF, and silica gel column chromatography (reverse phase silica, water: acetonitrile = 9:
After purification by 1 → 6: 1 → 3: 1 → 1: 1, only acetonitrile), the desired product (46 mg) was obtained as a colorless powder.
MS (FAB +): 522 ([M + H] ⁺ )
¹ H-NMR (400 MHz, DMSO) δ 1.69-1.82 (4H, m), 2.62-2.66 (2H, m), 3.42-3.44 (2H,
m), 3.55-3.57 (2H, m), 5.08 (2H, s), 5.28-5.30 (1H, m), 6.88-6.90 (1H, m),
6.95-6.99 (2H, m), 7.20-7.23 (1H, m), 7.29-7.41 (9H, m), 7.76 (2H, br s).

<Example 6>
2-t-Butoxycarbonylamino-2-methoxymethyloxymethyl-4- (4-octylphenyl) butanal

To a solution of oxalyl chloride (135 μL) in methylene chloride (10 mL) at −78 ° C., a mixture of DMSO (148 μL) in methylene chloride (1 mL) was added and stirred for 30 minutes. 3 mL) solution was added dropwise. After stirring for 1 hour, triethylamine (789 μL) was added at −60 ° C. and stirred for 10 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution at 0 ° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and then saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired product (286 mg) as a pale yellow oil.
MS (FAB +): 450 ([M + H] ⁺ )

<Example 7>
4- [4- (4-Benzyloxyphenylthio) -2-chlorophenyl] -2-t-butoxycarbonylamino-2-methoxymethyloxymethylbutanal

Methoxymethylation was carried out in the same manner as in Reference Example 42 using the compound of Reference Example 30, and then reacted in the same manner as in Example 6 to obtain the desired product as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.46 (9H, s), 1.99-2.06 (1H, m),
2.25-2.35 (1H, m), 2.47 (1H, dt, J = 13.8, 4.9Hz), 2.61 (1H, dt, J = 13.8, 4.9Hz),
3.32 (3H, s), 3.80 (1H, d, J = 9.7Hz), 4.02 (1H, d, J = 9.7Hz), 4.58 (2H, s), 5.08 (2H,
s), 5.49 (1H, br s), 6.95-7.00 (4H, m), 7.09-7.12 (1H, m), 7.33-7.45 (7H, m),
9.46 (1H, s).

<Example 8>
5- [4- (4-Benzyloxyphenylthio) -2-chlorophenyl] -2-t-butoxycarbonylamino-2-methoxymethyloxymethylpentanal

The target product was obtained as a pale yellow oil by reacting in the same manner as in Example 7 using the compound of Reference Example 31.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.43 (9H, s), 1.53-1.64 (2H, m),
1.77-1.85 (1H, m), 2.04-2.17 (1H, m), 2.68 (2H, t, J = 7.3Hz), 3.30 (3H, s), 3.78 (1H,
d, J = 10.4Hz), 3.95 (1H, d, J = 10.4Hz), 4.56 (2H, s), 5.02 (2H, s), 5.39 (1H, br s),
6.86-6.96 (3H, m), 7.07-7.14 (2H, m), 7.22 (1H, t, J = 7.9Hz), 7.30-7.41 (6H, m),
9.40 (1H, s).

<Example 9>
5- [4- (3-Benzyloxyphenylthio) -2-chlorophenyl] -2-t-butoxycarbonylamino-2-propylpentanal

To a solution of 2-amino-5- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -2-propylpentan-1-ol (2.17 g) in 1,4-dioxane (20 mL) was added dicarbonate. -t-Butyl (1.21 g) was added and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain N-Boc compound (2.78 g) as a pale yellow oil. The obtained N-Boc form was reacted in the same manner as in Example 6 to obtain the desired product as a colorless oil.
MS (FAB +): 568 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.88 (3H, t, J = 7.3 Hz), 0.98-1.10 (1H, m),
1.20-1.37 (2H, m), 1.42 (9H, s), 1.42-1.64 (2H, m), 1.70-1.77 (1H, m), 2.07-2.29 (2H,
m), 2.65-2.70 (2H, m), 5.02 (2H, s), 5.24-5.30 (1H, br), 6.87 (1H, dd, J = 1.8,
7.9Hz), 6.92-6.94 (2H, m), 7.07 (1H, d, J = 7.9Hz), 7.13 (1H, dd, J = 1.8, 7.9Hz),
7.23 (1H, t, J = 7.9Hz), 7.26-7.41 (6H, m), 9.23 (1H, s).

<Example 10>
2-t-Butoxycarbonylamino-2- (t-butyldimethylsilyloxymethyl) -4- [2-chloro-4- (4-methoxyphenylethoxy) phenyl] butan-1-ol

Under ice-cooling, triethylamine (284 μL) was added to a DMF (4 mL) solution of the compound of Reference Example 36 (391 mg), and a DMF (1 mL) solution of t-butyldimethylsilyl chloride (122 g) was added over 10 minutes. The mixture was stirred overnight while returning. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the solvent, silica gel column chromatography (hexane: ethyl acetate = 9: 1
The product was purified in 4: 1) to obtain the desired product (293 mg) as a colorless oil.
MS (FAB +): 594 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.08 (6H, s), 0.91 (9H, s), 1.45 (9H, s),
1.64-1.73 (1H, m), 1.89-1.96 (1H, m), 2.58-2.70 (2H, m), 3.01 (2H, t, J = 7.3Hz),
3.57 (1H, d, J = 9.8Hz), 3.73-3.75 (2H, m), 3.80 (3H, s), 3.90 (1H, d, J = 9.8Hz),
4.08 (2H, t, J = 7.3Hz), 5.15-5.20 (1H, br), 6.72 (1H, dd, J = 2.5, 8.6Hz),
6.85-6.87 (3H, m), 7.09 (1H, d, J = 8.6Hz), 7.18 (2H, d, J = 8.6Hz).

<Example 11>
2-t-Butoxycarbonylamino-2- (t-butyldimethylsilyloxymethyl) -4- [2-chloro-4- (4-methoxyphenylethoxy) phenyl] butanal

The target product was obtained as a pale yellow oil by reacting in the same manner as in Example 6 using the compound of Example 10.
MS (FAB +): 592 ([M + H] ⁺ )
¹ H-NMR (400MHz, CDCl ₃ ) δ 0.02 (6H, s), 0.86 (9H, s), 1.46 (9H, s),
1.94-2.02 (1H, m), 2.24-2.28 (1H, m), 2.40-2.48 (1H, m), 2.55-2.63 (1H, m),
3.01 (2H, t, J = 7.3Hz), 3.80 (3H, s), 3.87 (1H, d, J = 10.4Hz), 4.06-4.09 (3H, m),
5.42 (1H, br s), 6.70 (1H, dd, J = 2.4, 8.6Hz), 6.84-6.87 (3H, m), 7.02 (1H, d,
J = 8.6Hz), 7.18 (2H, d, J = 8.6Hz), 9.41 (1H, s).

<Example 12>
3-t-Butoxycarbonylamino-3-methoxymethyloxymethyl-5- (4-octylphenyl) -1-pentaten-1-sulfonic acid ethyl ester

1.58 mol / Ln-butyllithium (500 μL) was slowly added dropwise to a THF (3.0 mL) solution of diethoxyphosphorylmethanesulfonic acid ethyl ester (190 mg) at −78 ° C. and stirred for 60 minutes. A solution of the compound of Example 6 (286 mg) in THF (1.0 mL) was added dropwise and stirred overnight while warming to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired product (342 mg) as a pale yellow oil.
MS (FAB +): 556 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.88 (3H, t, J = 6.8 Hz), 1.25-1.30 (10H,
m), 1.37 (3H, t, J = 7.3Hz), 1.45 (9H, s), 1.49-1.60 (2H, m), 1.98-2.05 (1H, m),
2.25-2.33 (1H, m), 2.54-2.63 (4H, m), 3.38 (3H, s), 3.68 (1H, d, J = 9.8Hz), 3.74 (1H,
d, J = 9.8Hz), 4.18 (2H, q, J = 7.3Hz), 4.63 (2H, s), 5.04 (1H, br s), 6.50 (1H, d,
J = 15.3Hz), 6.93 (1H, d, J = 15.3Hz), 7.06 (2H, d, J = 7.9Hz), 7.10 (2H, d, J = 7.9Hz).

<Example 13>
5- [4- (4-Benzyloxyphenylthio) -2-chlorophenyl] -3-t-butoxycarbonylamino-3-methoxymethyloxymethyl-1-pentene-1-sulfonic acid ethyl ester

The target product was obtained as a colorless oil by reacting in the same manner as in Example 12 using the compound of Example 7.
MS (FAB +): 691 ([M] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.37 (3H, t, J = 7.3 Hz), 1.44 (9H, s),
1.90-2.05 (1H, m), 2.17-2.30 (1H, m), 2.64-2.71 (2H, m), 3.37 (3H, s), 3.67 (1H, d,
J = 9.7Hz), 3.75 (1H, d, J = 9.7Hz), 4.18 (2H, q, J = 7.3Hz), 4.63 (2H, s), 5.08 (2H, s),
6.30 (1H, d, J = 15.3Hz), 6.93 (1H, d, J = 15.3Hz), 6.96-7.00 (3H, m), 7.05 (1H, d,
J = 7.9Hz), 7.11 (1H, d, J = 1.8Hz), 7.33-7.45 (7H, m).

<Example 14>
5- [4- (3-Benzyloxyphenylthio) -2-chlorophenyl] -3-t-butoxycarbonylamino-3-methoxymethyloxymethyl-1-pentene-1-sulfonic acid ethyl ester

After oxidation with 4- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -2-t-butoxycarbonylamino-2-methoxymethyloxymethylbutan-1-ol as in Example 6, The obtained compound was reacted in the same manner as in Example 12 to obtain the target product as a pale yellow oil.
MS (FAB +): 691 ([M] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.37 (3H, t, J = 7.3 Hz), 1.45 (9H, s),
1.98-2.05 (1H, m), 2.20-2.28 (1H, m), 2.66-2.77 (2H, m), 3.38 (3H, s), 3.68 (1H, d,
J = 9.8Hz), 3.76 (1H, d, J = 9.8Hz), 4.18 (2H, q J = 7.3Hz), 4.64 (2H, s), 5.03 (2H, s),
5.10 (1H, br s), 6.32 (1H, d, J = 15.3Hz), 6.88-6.96 (4H, m), 7.10-7.15 (2H, m),
7.24 (1H, t, J = 8.0Hz), 7.30-7.41 (6H, m).

<Example 15>
6- [4- (3-Benzyloxyphenylthio) -2-chlorophenyl] -3-t-butoxycarbonylamino-3-methoxymethyloxymethyl-1-hexene-1-sulfonic acid ethyl ester

The target product was obtained as a pale yellow oil by reacting in the same manner as in Example 12 using the compound of Example 8.
MS (FAB +): 705 ([M] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.36 (3H, t, J = 7.3 Hz), 1.42 (9H, s),
1.55-1.66 (3H, m), 1.76-1.85 (1H, m), 2.70 (2H, t, J = 7.3Hz), 3.34 (3H, s), 3.60 (1H,
d, J = 9.8Hz), 3.65 (1H, d, J = 9.8Hz), 4.17 (2H, q, J = 7.3Hz), 4.59 (2H, s), 5.03 (2H,
s), 6.25 (1H, d, J = 15.5Hz), 6.87 (1H, d, J = 15.5Hz), 6.87-6.97 (3H, m),
7.11-7.16 (2H, m), 7.23 (1H, t, J = 7.9Hz), 7.31-7.41 (6H, m).

<Example 16>
6- [4- (3-Benzyloxyphenylthio) -2-chlorophenyl] -3-t-butoxycarbonylamino-3-propyl-1-hexene-1-sulfonic acid ethyl ester

The target product was obtained as a colorless oil by reacting in the same manner as in Example 12 using the compound of Example 9.
MS (FAB +): 673 ( [M] +)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 7.3 Hz), 1.18-1.24 (2H, m),
1.36 (3H, t, J = 7.3Hz), 1.40 (9H, s), 1.54-1.61 (4H, m), 1.66-1.75 (2H, m),
2.66-2.74 (2H, m), 4.17 (2H, q, J = 7.3Hz), 4.48-4.55 (1H, br), 5.02 (2H, s),
6.16 (1H, d, J = 15.3Hz), 6.78 (1H, d, J = 15.3Hz), 6.88 (1H, dd, J = 2.4, 7.3Hz),
6.93-6.96 (2H, m), 7.09 (1H, d, J = 7.9Hz), 7.15 (1H, dd, J = 1.8, 7.9Hz), 7.23 (1H, t,
J = 7.9Hz), 7.31-7.43 (6H, m).

<Example 17>
3-Allyl-5- [4- (4-benzyloxyphenylthio) -2-chlorophenyl] -3-t-butoxycarbonylamino-1-pentene-1-sulfonic acid ethyl ester

The compound of Reference Example 41 was converted to Boc, oxidized in the same manner as in Example 6, and then reacted in the same manner as in Example 12 to obtain the target product as a pale yellow oil.
MS (FAB +): 657 ([M] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.37 (3H, t, J = 7.3 Hz), 1.43 (9H, s),
1.88-1.94 (1H, m), 2.09-2.15 (1H, m), 2.47-2.52 (1H, m), 2.52-2.70 (3H, m),
4.18 (2H, q, J = 7.3Hz), 4.66 (1H, br s), 5.08 (2H, s), 5.19-5.25 (2H, m),
5.66-5.74 (1H, m), 6.21 (1H, d, J = 15.5Hz), 6.85 (1H, d, J = 15.5Hz), 6.96-7.04 (4H,
m), 7.10-7.11 (1H, m), 7.33-7.45 (7H, m).

<Example 18>
6- [4- (4-Benzyloxyphenylthio) -2-chlorophenyl] -3-t-butoxycarbonylamino-3-methoxymethyloxymethyl-1-hexene-1-sulfonic acid ethyl ester

The target product was obtained as a colorless oil by reacting in the same manner as in Example 12 using the compound of Example 8.
MS (FAB +): 705 ([M] ⁺ )
^{1 H-NMR (400MHz, CDCl} 3) δ 1.36 (3H, t, J = 7.3Hz), 1.41 (9H, s),
1.54-1.60 (3H, m), 1.75-1.84 (1H, m), 2.66 (2H, t, J = 7.3Hz), 3.33 (3H, s),
3.60-3.66 (2H, m), 4.16 (2H, q, J = 7.3Hz), 4.59 (2H, s), 4.93 (1H, br s), 5.08 (2H,
s), 6.24 (1H, d, J = 15.5Hz), 6.86 (1H, d, J = 15.5Hz), 6.96-7.00 (3H, m), 7.03 (1H, d,
J = 7.9Hz), 7.11 (1H, d, J = 1.8Hz), 7.34-7.45 (7H, m).

<Example 19>
3-t-Butoxycarbonylamino-3-t-butyldimethylsiloxymethyl-5- [2-chloro-4- (4-methoxyphenylethoxy) phenyl] -1-pentene-1-sulfonic acid ethyl ester

The target product was obtained as a pale yellow oil by reacting in the same manner as in Example 12 using the compound of Example 11.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.08 (6H, s), 0.91 (9H, s), 1.36 (3H, t,
J = 7.3Hz), 1.44 (9H, s), 1.91-1.99 (1H, m), 2.08-2.16 (1H, m), 2.58-2.71 (2H, m),
3.01 (2H, t, J = 7.3Hz), 3.65-3.79 (2H, m), 3.80 (3H, s), 4.09 (2H, t, J = 7.3Hz),
4.18 (2H, q, J = 7.3Hz), 4.92-4.95 (1H, br), 6.27 (1H, J = 15.3Hz), 6.73 (1H, dd,
J = 2.5, 8.6Hz), 6.85-6.93 (4H, m), 7.05 (1H, d, J = 8.6Hz), 7.18 (2H, d, J = 8.6Hz).

<Example 20>
3-t-Butoxycarbonylamino-3-methoxymethyloxymethyl-5- (4-octylphenyl) pentane-1-sulfonic acid ethyl ester

To a solution of the compound of Example 12 (262 mg) in ethanol (4 mL) was added sodium borohydride (21.4 mg) under ice cooling, and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed in turn with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (169 mg) as a pale yellow oil.
MS (FAB +): 558 ([M + H] ⁺ )
¹ H-NMR (400MHz, CDCl ₃ ) δ 0.88 (3H, t, J = 7.9Hz), 1.24-1.30 (10H,
m), 1.41 (3H, t, J = 7.3Hz), 1.45 (9H, s), 1.50-1.60 (2H, m), 1.85-1.89 (1H, m),
2.13-2.26 (2H, m), 2.42 (1H, td, J = 14.0, 4.9Hz), 2.53-2.58 (4H, m), 3.18-3.28 (2H,
m), 3.40 (3H, s), 3.59 (2H, s), 4.28 (2H, q, J = 7.3Hz), 4.63 (2H, s), 4.78 (1H, br
s), 7.08 (4H, s).

<Example 21>
5- [4- (4-Benzyloxyphenylthio) -2-chlorophenyl] -3-t-butoxycarbonylamino-3-methoxymethyloxymethylpentane-1-sulfonic acid ethyl ester

The target product was obtained as a pale yellow oil by reacting in the same manner as in Example 20 using the compound of Example 13.
MS (FAB +): 693 ([M] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 1.44 (9H, s),
1.80-1.86 (1H, m), 2.05-2.10 (1H, m), 2.18-2.25 (1H, m), 2.43 (1H, td, J = 14.1,
4.9Hz), 2.63-2.68 (2H, m), 3.18-3.26 (2H, m), 3.40 (3H, s), 3.58 (1H, d, J = 9.8Hz),
3.61 (1H, d, J = 9.8Hz), 4.27 (2H, q, J = 7.3Hz), 4.64 (2H, s), 4.80 (1H, br
s), 5.08 (2H, s), 6.97-7.00 (3H, m), 7.05 (1H, d, J = 7.9Hz), 7.10 (1H, d, J = 1.8Hz),
7.34-7.45 (7H, m).

<Example 22>
5- [4- (3-Benzyloxyphenylthio) -2-chlorophenyl] -3-t-butoxycarbonylamino-3-methoxymethyloxymethylpentane-1-sulfonic acid ethyl ester

The target product was obtained as a colorless oil by reacting in the same manner as in Example 20 using the compound of Example 14.
MS (FAB +): 694 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.37 (3H, t, J = 7.3 Hz), 1.45 (9H, s),
1.80-1.90 (1H, m), 2.04-2.27 (2H, m), 2.41-2.49 (1H, m), 2.62-2.80 (1H, m),
3.18-3.31 (2H, m), 3.38 (3H, s), 3.68 (1H, d, J = 9.8Hz), 3.76 (1H, d, J = 9.8Hz),
4.18 (2H, q, J = 7.3Hz), 4.64 (2H, s), 5.03 (2H, s), 5.10 (1H, br s), 6.88-6.96 (3H,
m), 7.10-7.15 (2H, m), 7.24 (1H, t, J = 8.0Hz), 7.30-7.41 (6H, m).

<Example 23>
6- [4- (3-Benzyloxyphenylthio) -2-chlorophenyl] -3-t-butoxycarbonylamino-3-methoxymethyloxymethylhexane-1-sulfonic acid ethyl ester

The target product was obtained as a colorless oil by reacting in the same manner as in Example 20 using the compound of Example 15.
MS (FAB +): 707 ([M] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.3 Hz), 1.42 (9H, s),
1.53-1.62 (3H, m), 1.88-1.92 (1H, m), 2.12-2.21 (1H, m), 2.32-2.40 (1H, m), 2.69 (2H,
t, J = 7.3Hz), 3.10-3.25 (2H, m), 3.35 (3H, s), 3.48 (1H, d, J = 9.8Hz), 3.51 (1H, d,
J = 9.8Hz), 4.27 (2H, q, J = 7.3Hz), 4.58 (2H, s), 4.71 (1H, br s), 5.02 (2H, s),
6.86-6.96 (3H, m), 7.10-7.16 (2H, m), 7.23 (1H, t, J = 7.9Hz), 7.31-7.41 (6H, m).

<Example 24>
6- [4- (3-Benzyloxyphenylthio) -2-chlorophenyl] -3-t-butoxycarbonylamino-3-propylhexane-1-sulfonic acid ethyl ester

The target product was obtained as a colorless oil by reacting in the same manner as in Example 20 using the compound of Example 16.
MS (FAB +): 695 ( [M] +)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 7.3 Hz), 1.16-1.28 (2H, m),
1.30-1.40 (4H, m), 1.41 (9H, s), 1.47-1.59 (3H, m), 1.76-1.84 (1H, m),
2.12-2.19 (1H, m), 2.25-2.32 (1H, m), 2.69 (2H, t, J = 7.9Hz), 3.03 (2H, t, J = 7.9Hz),
4.14-4.20 (1H, br), 4.26 (2H, q, J = 7.3Hz), 5.03 (2H, s), 6.86-6.90 (1H, m),
6.92-6.97 (2H, m), 7.11 (1H, d, J = 7.9Hz), 7.15 (1H, dd, J = 1.8, 7.9Hz), 7.23 (1H, t,
J = 7.9Hz), 7.30-7.41 (6H, m).

<Example 25>
3-Allyl-5- [4- (4-benzyloxyphenylthio) -2-chlorophenyl] -3-t-butoxycarbonylaminopentane-1-sulfonic acid ethyl ester

The target product was obtained as a colorless oil by reacting in the same manner as in Example 20 using the compound of Example 17.
MS (FAB +): 659 ([M] ⁺ )
^{1 H-NMR (400MHz, CDCl} 3) δ 1.40 (3H, t, J = 7.3Hz), 1.43 (9H, s),
1.70-1.78 (1H, m), 1.80-2.00 (1H, m), 2.23-2.38 (3H, m), 2.44-2.49 (1H, m),
2.59-2.69 (2H, m), 3.14 (2H, t, J = 7.9Hz), 4.28 (2H, q, J = 7.3Hz), 4.34 (1H, br s),
5.08 (2H, s), 5.19-5.23 (2H, m), 5.75-5.85 (1H, m), 6.94-7.00 (3H, m), 7.04 (1H, d,
J = 7.9Hz), 7.11 (1H, d, J = 1.8Hz), 7.33-7.45 (7H, m).

<Example 26>
6- [4- (4-Benzyloxyphenylthio) -2-chlorophenyl] -3-t-butoxycarbonylamino-3-methoxymethyloxymethylhexane-1-sulfonic acid ethyl ester

The target product was obtained as a colorless oil by reacting in the same manner as in Example 20 using the compound of Example 18.
MS (FAB +): 707 ([M] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 1.42 (9H, s),
1.55-1.65 (3H, m), 1.65-1.70 (2H, m), 1.87-1.90 (1H, m), 2.10-2.20 (1H, m), 2.30-2.67 (1H,
m), 2.65 (2H, t, J = 7.3Hz), 3.34 (3H, s), 3.46 (1H, d, J = 10.3Hz), 3.50 (1H, d,
J = 10.3Hz), 4.26 (2H, q, J = 7.3Hz), 4.58 (2H, s), 4.68 (1H, br s), 5.08 (2H, s),
6.96-7.00 (3H, m), 7.04 (1H, d, J = 7.9Hz), 7.11 (1H, d, J = 1.8Hz), 7.34-7.45 (7H, m).

<Example 27>
3-tert-Butoxycarbonylamino-3-tert-butyldimethylsiloxymethyl-5- [2-chloro-4- (4-methoxyphenylethoxy) phenyl] pentane-1-sulfonic acid ethyl ester

The target product was obtained as a colorless oil by reacting in the same manner as in Example 20 using the compound of Example 19.
MS (FAB +): 700 ([M + H]
¹ H-NMR (400MHz, CDCl ₃ ) δ 0.09 (3H, s), 0.10 (3H, s), 0.91 (9H, s),
1.40 (3H, t, J = 7.3Hz), 1.44 (9H, s), 1,73-1.81 (1H, m), 1.91-2.00 (1H,
m), 2.21-2.32 (2H, m), 2.57-2.67 (2H, m), 3.01 (2H, t, J = 7.3Hz), 3.20 (2H, t,
J = 7.3Hz), 3.61-3.67 (2H, m), 3.78 (3H, s), 4.08 (2H, t, J = 7.3Hz), 4.27 (2H, q,
J = 7.3Hz), 4.60-4.63 (1H, br), 6.72 (1H, dd, J = 2.5, 8.6Hz), 6.84-6.89 (3H, m),
7.06 (1H, d, J = 8.6Hz), 7.18 (2H, d, J = 8.6Hz).

<Example 28>
3-Amino-3-hydroxymethyl-5- (4-octylphenyl) pentane-1-sulfonic acid

A 10% aqueous hydrochloric acid solution (5.0 mL) was added to the compound of Example 20 (169 mg), and the mixture was heated to reflux for 4 hours. The precipitated crystals were collected by filtration, washed with water and diisopropyl ether, and then dried under reduced pressure to obtain the desired product (90.2 mg) as a colorless powder.
MS (FAB +): 386 ([M + H] ⁺ )
¹ H-NMR (400MHz, DMSO) δ 0.84 (3H, t, J = 7.4Hz), 1.20-1.28 (10H, m),
1.49-1.54 (2H, m), 1.68-1.83 (2H, m), 1.89-1.99 (2H, m), 2.45-2.54 (4H, m),
2.59 (2H, t, J = 7.4), 3.41-3.48 (2H, m), 5.49 (1H, t, J = 4.9Hz), 7.09 (4H, s),
7.87 (3H, br).

<Example 29>
3-Amino-3-hydroxymethyl-5- (4-octylphenyl) -1-pentene-1-sulfonic acid

The target product was obtained as a colorless powder by reacting in the same manner as in Example 28 using the compound of Example 12.
MS (FAB +): 384 ([M + H] ⁺ )
¹ H-NMR (400MHz, DMSO) δ 0.84 (3H, t, J = 6.7Hz), 1.22-1.26 (10H, m),
1.50-1.54 (2H, m), 1.85-1.90 (2H, m), 2.45-2.53 (4H, m), 3.49 (1H, d, J = 11.6Hz),
3.53 (1H, d, J = 11.6Hz), 5.60-5.70 (1H, m), 6.13 (1H, d, J = 15.9Hz), 6.44 (1H, d,
J = 15.9Hz), 7.06 (2H, d, J = 7.9Hz), 7.10 (2H, d, J = 7.9Hz), 8.10-8.15 (3H, m).

<Example 30>
3-Amino-5- [4- (4-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethylpentane-1-sulfonic acid

The target product was obtained as a colorless powder by reacting in the same manner as in Example 28 using the compound of Example 21.
HRMS (FAB +): 522 ([M + H] ⁺ ) (mmu -0.5)
¹ H-NMR (400 MHz, DMSO) δ 1.67-1.74 (2H, m), 1.90-2.00 (2H, m), 2.53-2.66 (4H,
m), 3.44-3.48 (2H, m), 5.13 (2H, s), 7.07-7.12 (4H, m), 7.26-7.28 (1H, m),
7.31-7.47 (7H, m), 7.89 (3H, br).

<Example 31>
3-Amino-5- [4- (4-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethyl-1-pentene-1-sulfonic acid

The target product was obtained as a colorless powder by reacting in the same manner as in Example 28 using the compound of Example 13.
HRMS (FAB +): 520 ([M + H] ⁺ ) (mmu +1.8)
¹ H-NMR (400 MHz, DMSO) δ 1.80-1.86 (2H, m), 2.58 (2H, t, J = 8.6 Hz), 3.50 (1H, d,
J = 11.0Hz), 3.57 (1H, d, J = 11.0Hz), 5.13 (2H, s), 5.60-5.71 (1H, br), 6.13 (1H, d,
J = 15.9Hz), 6.47 (1H, d, J = 15.9Hz), 7.05-7.12 (4H, m), 7.22 (1H, d, J = 8.0Hz),
7.31-7.46 (7H, m), 8.12 (3H, br s).

<Example 32>
3-Amino-5- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethylpentane-1-sulfonic acid

The target product was obtained as a colorless powder by reacting in the same manner as in Example 28 using the compound of Example 22.
HRMS (FAB +): 522 ([M + H] ⁺ ) (mmu -1.1)
¹ H-NMR (400 MHz, DMSO) δ 1.70-1.80 (2H, m), 1.94-2.02 (2H, m), 2.60-2.67 (4H,
m), 3.46 (1H, d, J = 11.0Hz), 3.51 (1H, d, J = 11.0Hz), 5.09 (2H, s), 5.51 (1H, br s),
6.90 (1H, d, J = 6.7), 6.96-7.00 (2H, m), 7.24 (1H, dd, J = 1.8, 7.9Hz), 7.29-7.41 (8H,
m), 7.90 (3H, br).

<Example 33>
3-Amino-5- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethyl-1-pentene-1-sulfonic acid

The target product was obtained as a brown powder by reacting in the same manner as in Example 28 using the compound of Example 14.
HRMS (FAB +): 520 ([M + H] ⁺ ) (mmu +1.8)
¹ H-NMR (400 MHz, DMSO) δ 1.82-1.92 (2H, m), 2.63 (2H, t, J = 8.6 Hz), 3.52 (1H, d,
J = 11.0Hz), 3.59 (1H, d, J = 11.0Hz), 5.09 (2H, s), 6.14 (1H, d, J = 15.3Hz), 6.48 (1H,
d, J = 15.3Hz), 6.90 (1H, d, J = 7.3Hz), 6.96-7.00 (2H, m), 7.22-7.40 (9H, m),
8.14 (3H, br s).

<Example 34>
3-Amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethyl-1-hexene-1-sulfonic acid

The compound of Example 15 was reacted in the same manner as in Example 28 to obtain the target product as a light brown powder.
HRMS (FAB +): 534 ([M + H] ⁺ ) (mmu +1.3)
¹ H-NMR (400 MHz, DMSO) δ 1.48-1.61 (2H, m), 1.67-1.75 (2H, m), 2.60-2.70 (2H,
m), 3.56-3.62 (2H, m), 5.09 (2H, s), 6.03 (1H, d, J = 15.9Hz), 6.36 (1H, d,
J = 15.9Hz), 6.89-7.00 (3H, m), 7.20-7.21 (1H, m), 7.22-7.41 (8H, m), 7.79 (1H, br
s), 8.10 (3H, br s).

<Example 35>
3-Amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethylhexane-1-sulfonic acid

The target product was obtained as a pale green amorphous product by reacting in the same manner as in Example 28 using the compound of Example 23.
HRMS (FAB +): 536 ([M + H] ⁺ ) (mmu -0.9)
¹ H-NMR (400 MHz, DMSO) δ 1.48-1.63 (4H, m), 1.79-1.89 (2H, m), 2.50-2.53 (2H,
m), 2.62-2.70 (2H, m), 3.37-3.42 (2H, m), 5.09 (2H, s), 5.41 (1H, br s),
6.89-6.99 (3H, m), 7.22 (1H, dd, J = 1.8Hz, 7.9Hz), 7.29-7.41 (8H, m), 7.70 (3H, br
s).

<Example 36>
3-Amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-propyl-1-hexene-1-sulfonic acid

The target product was obtained as a colorless powder by reacting in the same manner as in Example 28 using the compound of Example 16.
HRMS (FAB +): 546 ([M + H] ⁺ ) (mmu -2.3)
¹ H-NMR (400MHz, DMSO) δ 0.85 (3H, t, J = 7.3Hz), 1.14-1.24 (2H, m),
1.46-1.70 (6H, m), 2.68 (2H, t, J = 7.3Hz), 5.09 (2H, s), 6.05 (1H, d, J = 15.6Hz),
6.29 (1H, d, J = 15.6Hz), 6.88-6.92 (1H, m), 6.95-7.01 (2H, m), 7.22 (1H, dd, J = 1.8,
7.9Hz), 7.29-7.42 (8H, m), 8.00-8.04 (3H, br).

<Example 37>
3-Amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-propylhexane-1-sulfonic acid

The target product was obtained as a yellow amorphous substance by reacting in the same manner as in Example 28 using the compound of Example 24.
HRMS (FAB +): 548 ([M + H] ⁺ ) (mmu +0.9)
¹ H-NMR (400MHz, DMSO) δ 0.84 (3H, t, J = 7.3Hz), 1.12-1.25 (2H, m),
1.43-1.47 (2H, m), 1.49-1.59 (4H, m), 1.85 (2H, t, J = 7.3Hz), 2.50-2.55 (2H, m),
2.63-2.70 (2H, m), 5.08 (2H, s), 6.88 (1H, d, J = 7.9Hz), 6.95-7.00 (2H, m), 7.23 (1H,
dd, J = 1.8, 7.9Hz), 7.29-7.41 (8H, m), 7.78-7.89 (3H, br).

<Example 38>
3-Allyl-3-amino-5- [4- (4-benzyloxyphenylthio) -2-chlorophenyl] -1-pentene-1-sulfonic acid

The target product was obtained as a colorless powder by reacting in the same manner as in Example 28 using the compound of Example 17.
HRMS (FAB +): 530 ([M + H] ⁺ ) (mmu +1.4)
¹ H-NMR (400 MHz, DMSO) δ 1.76-1.84 (2H, m), 2.44-2.50 (2H, m), 2.61 (2H, t,
J = 8.5Hz), 5.22-5.26 (2H, m), 5.70-5.77 (1H, m), 6.17 (1H, d, J = 15.8Hz), 6.43 (1H,
d, J = 15.8Hz), 7.04-7.11 (4H, m), 7.22 (1H, d, J = 7.9Hz), 7.32-7.46 (7H, m),
8.18 (3H, br s).

<Example 39>
3-Allyl-3-amino-5- [4- (4-benzyloxyphenylthio) -2-chlorophenyl] pentane-1-sulfonic acid

The target product was obtained as a colorless powder by reacting in the same manner as in Example 28 using the compound of Example 25.
MS (FAB +): 532 ([M + H] ⁺ )
¹ H-NMR (400 MHz, DMSO) δ 1.68-1.72 (2H, m), 1.97 (2H, t, J = 7.3 Hz), 2.41 (2H, d,
J = 7.3Hz), 2.62-2.66 (4H, m), 5.13 (2H, s), 5.22-5.28 (2H, m), 5.78-5.85 (1H, m),
7.06-7.13 (4H, m), 7.25 (1H, d, J = 7.9Hz), 7.32-7.46 (7H, m), 8.03 (3H, br).
Elemental analysis (%): As C ₂₇ H ₃₀ ClNO ₄ S ₂

C H N
Calculated value: 60.94 5.68 2.63
Actual value: 60.89 5.61 2.33

<Example 40>
3-Amino-6- [4- (4-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethyl-1-hexene-1-sulfonic acid

The target product was obtained as a light brown powder by reacting in the same manner as in Example 28 using the compound of Example 18.
MS (FAB +): 534 ( [M + H] +)
¹ H-NMR (400 MHz, DMSO) δ 1.47-1.52 (2H, m), 1.63-1.66 (2H, m), 2.62 (2H, t,
J = 7.9Hz), 3.42-3.50 (2H, m), 5.13 (2H, s), 5.58 (1H, br s), 6.01 (1H, d, J = 15.9Hz),
6.34 (1H, d, J = 15.9Hz), 7.04-7.09 (4H, m), 7.11 (1H, d, J = 2.4Hz), 7.24-7.47 (7H,
m), 7.96 (3H, br s).
Elemental analysis value (%): As C ₂₆ H ₂₈ ClNO ₅ S ₂

C H N
Calculated value: 58.47 5.28 2.62
Actual value: 58.18 5.20 2.35

<Example 41>
3-Amino-6- [4- (4-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethylhexane-1-sulfonic acid

The target product was obtained as a light brown powder by reacting in the same manner as in Example 28 using the compound of Example 26.
HRMS (FAB +): 536 ([M + H] ⁺ ) (mmu +0.3)
¹ H-NMR (400 MHz, DMSO) δ 1.46-1.57 (4H, m), 1.75-1.90 (2H, m), 2.45-2.52 (2H,
m), 2.58-2.66 (2H, m), 5.13 (2H, s), 5.40 (1H, t, J = 4.9Hz), 7.04-7.11 (4H, m),
7.26 (1H, d, J = 8.6Hz), 7.31-7.46 (7H, m), 7.75 (3H, br s).
Elemental analysis (%): As C ₂₆ H ₃₀ ClNO ₅ S ₂
C H N
Calculated value: 58.25 5.64 2.61
Actual value: 58.27 5.56 2.33

<Example 42>
3-Amino-5- [2-chloro-4- (4-methoxyphenylethoxy) phenyl] -3-hydroxymethyl-1-pentene-1-sulfonic acid

The target product was obtained as a colorless powder by reacting in the same manner as in Example 28 using the compound of Example 19.
HRMS (FAB +): 456 ([M + H] ⁺ ) (mmu -3.1)
¹ H-NMR (400 MHz, DMSO) δ 1.79-1.87 (2H, m), 2.53-2.58 (2H, m), 2.93 (2H, t,
J = 7.3Hz), 3.50 (1H, dd, J = 4.9, 11.0Hz), 3.57 (1H, d, J = 4.9, 11.0), 3.71 (3H, s),
4.12 (2H, t, J = 7.3Hz), 5.65 (1H, t, J = 4.9Hz), 6.13 (1H, d, J = 15.9Hz), 6.47 (1H, d,
J = 15.9Hz), 6.83-6.88 (3H, m), 6.99 (1H, d, J = 2.5Hz), 7.16-7.23 (3H, m),
8.05-8.18 (3H, br).
Elemental analysis (%): C ₂₁ H ₂₆ ClNO ₆ S / 3 / 4H ₂ O
C H N
Calculated value: 53.78 5.90 2.98
Actual value: 53.70 5.59 2.94

<Example 43>
3-Amino-5- [2-chloro-4- (4-methoxyphenylethoxy) phenyl] -3-hydroxymethylpentane-1-sulfonic acid

The target product was obtained as a colorless powder by reacting in the same manner as in Example 28 using the compound of Example 27.
HRMS (FAB +): 458 ([M + H] ⁺ ) (mmu +0.2)
¹ H-NMR (400 MHz, DMSO) δ 1.66-1.77 (2H, m), 1.88-2.02 (2H, m), 2.55-2.66 (4H,
m), 2.93 (2H, t, J = 7.3Hz), 3.42-3.51 (2H, m), 3.71 (3H, s), 4.12 (2H, t, J = 7.3Hz),
5.48 (1H, t, J = 4.3Hz), 6.84-6.89 (3H, m), 6.98 (1H, d, J = 2.4Hz), 7.20-7.22 (3H, m),
7.77-7.87 (3H, br).
Elemental analysis (%): C ₂₁ H ₂₈ ClNO ₆ S / 3 / 4H ₂ O
C H N
Calculated value: 53.50 6.31 2.97
Actual value: 53.36 6.01 2.98

<Example 44>
3-Amino-6- [4- (3-hydroxyphenylthio) -2-chlorophenyl] -3-hydroxymethylhexane-1-sulfonic acid

Under ice cooling, 1 mol / L-BBr ₃ -methylene chloride solution (280 μL) was added to a solution of the compound of Example 35 (50 mg) in methylene chloride (3 mL), and the mixture was stirred for 4 hours. The solution was concentrated, 6 mol / L aqueous hydrochloric acid solution was added, and the precipitated crystals were collected by filtration, washed with water and diisopropyl ether, and then dried under reduced pressure to obtain the desired product (2.63 mg) as a light brown powder.
HRMS (FAB +): 446 ([M + H] ⁺ ) (mmu +2.6)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.50-1.59 (4H, m), 1.80-1.87 (2H, m),
2.45-2.49 (2H, m), 2.63-2.68 (2H, m), 3.36-3.43 (2H, m), 5.40-5.42 (1H, m), 6.71-6.78 (3H,
m), 7.17-7.24 (2H, m), 7.30-7.36 (2H, m), 7.74-7.81 (2H, m), 9.69 (1H, s).

<Example 45>
3-Amino-6- [4- (3-hydroxyphenylthio) -2-chlorophenyl] -3-hydroxymethyl-1-hexene-1-sulfonic acid

The target product was obtained as a light brown powder by reacting in the same manner as in Example 44 using the compound of Example 34.
HRMS (FAB +): 444 ([M + H] ⁺ ) (mmu -0.7)
¹ H-NMR (400 MHz, DMSO) δ 1.46-1.52 (2H, m), 1.62-1.65 (2H, m), 2.59-2.62 (2H,
m), 3.40-3.49 (2H, m), 5.57 (1H, br s), 6.01 (1H, d, J = 15.8Hz), 6.33 (1H, d,
J = 15.8Hz), 6.83-6.86 (2H, m), 6.98-7.00 (2H, m), 7.22 (1H, d, J = 2.4Hz),
7.33-7.36 (2H, m), 7.96 (3H, br s), 9.93 (1H, s).
Elemental analysis (%): C ₂₆ H ₃₀ ClNO ₅ S ₂ + 1 / 2H ₂ O
C H N
Calculated value: 50.38 5.11 3.09
Actual value: 50.43 4.89 2.68

<Example 46>
3-Amino-6- [4- (4-hydroxyphenylthio) -2-chlorophenyl] -3-hydroxymethylhexane-1-sulfonic acid

The target product was obtained as a light brown powder by reacting in the same manner as in Example 44 using the compound of Example 41.
HRMS (FAB +): 446 ([M + H] ⁺ ) (mmu -3.3)
¹ H-NMR (400 MHz, DMSO) δ 1.48-1.54 (4H, m), 1.75-1.90 (2H, m), 2.45-2.50 (2H,
m), 2.57-2.66 (2H, m), 3.36-3.42 (2H, m), 5.40 (1H, br s), 6.83-6.86 (2H, m),
6.98-7.00 (2H, m), 7.24 (1H, d, J = 9.1Hz), 7.33-7.35 (2H, m), 7.75 (3H, br s), 9.93 (1H,
s).

<Example 47>
3-Amino-6- [4- (4-hydroxyphenylthio) -2-chlorophenyl] -3-hydroxymethyl-1-pentene-1-sulfonic acid

The target product was obtained as a colorless powder by reacting in the same manner as in Example 44 using the compound of Example 31.
HRMS (FAB +): 430 ([M] ⁺ ) (mmu +0.2)
¹ H-NMR (400 MHz, DMSO) δ 1.47-1.60 (2H, m), 2.42-2.50 (1H, m), 2.58-2.66 (1H,
m), 3.20 (2H, br s), 4.72 (1H, br s), 6.10 (1H, d, J = 15.5Hz), 6.23 (1H, d,
J = 15.5Hz), 6.80-6.85 (2H, m), 6.96-6.99 (2H, m), 7.18 (1H, d, J = 7.3Hz),
7.31-7.34 (2H, m).

<Example 48>
3-Amino-6- [4- (4-hydroxyphenylthio) -2-chlorophenyl] -3-hydroxymethylpentane-1-sulfonic acid

The target product was obtained as a colorless powder by reacting in the same manner as in Example 44 using the compound of Example 30.
HRMS (FAB +): 432 ([M] ⁺ ) (mmu +0.2)
¹ H-NMR (400 MHz, DMSO) δ 1.65-1.75 (2H, m), 1.90-1.98 (2H, m), 2.53-2.66 (4H,
m), 3.40-3.50 (2H, m), 5.45-5.49 (1H, m), 6.84-6.86 (2H, m), 7.01-7.04 (2H, m),
7.24 (1H, d, J = 7.3Hz), 7.33-7.35 (2H, m), 7.88 (2H, br s), 9.94 (1H, s).

<Example 49>
3-Amino-6- [4- (3-hydroxyphenylthio) -2-chlorophenyl] -3-hydroxymethyl-1-pentene-1-sulfonic acid

The target product was obtained as a colorless powder by reacting in the same manner as in Example 44 using the compound of Example 33.
HRMS (FAB +): 430 ([M] ⁺ ) (mmu -3.4)
¹ H-NMR (400 MHz, DMSO) δ 1.80-1.90 (2H, m), 2.63 (2H, t, J = 7.9 Hz), 3.51 (1H, d,
J = 11.0Hz), 3.59 (1H, d, J = 11.0Hz), 6.14 (1H, d, J = 15.9Hz), 6.47 (1H, d, J = 15.9Hz),
6.71-6.78 (3H, m), 7.19-7.32 (4H, m), 8.14 (2H, br s).

<Example 50>
3-Amino-6- [4- (3-hydroxyphenylthio) -2-chlorophenyl] -3-hydroxymethylpentane-1-sulfonic acid

The target product was obtained as a colorless powder by reacting in the same manner as in Example 44 using the compound of Example 32.
HRMS (FAB +): 432 ([M] ⁺ ) (mmu -2.0)
¹ H-NMR (400 MHz, DMSO) δ 1.70-1.80 (2H, m), 1.80-2.06 (2H, m), 2.58-2.70 (4H,
m), 3.40-3.55 (2H, m), 5.52 (1H, br s), 6.71-6.78 (3H, m), 7.17-7.37 (4H, m),
7.97 (2H, br s), 9.71 (1H, br s).
<Example 51>
3-Amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-propyl-1-hexene-1-sulfonic acid ethyl ester

Trifluoroacetic acid (0.5 mL) was added to a solution of the compound of Example 16 (174 mg) in methylene chloride (2 mL) and stirred for 1 hour. The pH was adjusted to 7 using 1 mol / L-potassium hydroxide aqueous solution, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate only, then ethyl acetate: methanol = 10: 1) to obtain the desired product (140 mg) as a colorless oil.
HRMS (FAB +): 574 ([M + H] ⁺ ) (mmu -0.6)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.91 (3H, t, J = 7.3 Hz), 1.16-1.29 (2H, m),
1.35 (3H, t, J = 7.3Hz), 1.44-1.67 (6H, m), 2.68 (2H, t, J = 7.3Hz), 4.13 (2H, q,
J = 7.3Hz), 5.02 (2H, s), 6.37 (1H, d, J = 15.3Hz), 6.83 (1H, d, J = 15.3Hz),
6.87-6.90 (1H, m), 6.93-6.96 (2H, m), 7.09 (1H, d, J = 7.9Hz), 7.14 (1H, dd, J = 1.8,
7.9Hz), 7.23 (1H, t, J = 7.9Hz), 7.31-7.41 (6H, m).

<Example 52>
3-Amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-propylhexane-1-sulfonic acid ethyl ester

The target product was obtained as a colorless oil by reacting in the same manner as in Example 51 using the compound of Example 24.
HRMS (FAB +): 576 ([M + H] ⁺ ) (mmu -0.3)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.91 (3H, t, J = 7.3 Hz), 1.21-1.30 (2H, m),
1.30-1.45 (4H, m), 1.40 (3H, t, J = 7.3Hz), 1.52-1.64 (2H, m), 1.80-1.84 (2H, m), 2.69 (2H,
t, J = 7.3Hz), 3.12-3.17 (2H, m), 4.27 (2H, q, J = 7.3Hz), 5.02 (2H, s), 6.87-6.89 (1H,
m), 6.92-6.96 (2H, m), 7.12 (1H, d, J = 7.9Hz), 7.16 (1H, dd, J = 1.8, 7.9Hz),
7.23 (1H, t, J = 7.9Hz), 7.31-7.41 (6H, m).

<Example 53>
3-Amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-propylhexane-1-sulfonic acid amide trifluoroacetate

To a solution of the compound of Example 36 (402 mg) in 1,4-dioxane (10 mL), 1 mol / L-potassium hydroxide aqueous solution (0.8 mL) was added, and di-t-butyl dicarbonate (186 μL) was added and stirred overnight. did. Further, di-t-butyl dicarbonate (200 μL) was added, N, N-dimethylaminopyridine (9 mg, 0.074 mmol) was added, and the mixture was stirred for 3 days, and then stirred under reflux for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate, then ethyl acetate: methanol = 10: 1) to obtain N-Boc form (525 mg) as a colorless oil. Triphosgene (13.8 mg) and DMF (1 drop) were added to a solution of the obtained N-Boc form (60 mg) in methylene chloride (2 mL), and the mixture was stirred overnight. The reaction solution was cooled to -78 ° C, and a 26% aqueous ammonia solution was added to the reaction solution, followed by stirring for 6 hours while returning to room temperature. The reaction solution was extracted with ethyl acetate, washed in turn with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain a colorless oil (35.0 mg). Trifluoroacetic acid (0.5 mL) was added to a methylene chloride (2 mL) solution of the obtained oily substance, and the mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated to obtain the desired product (37.5 mg) as a pale yellow amorphous.
HRMS (FAB +): 545 ([M + H] ⁺ ) (mmu -1.1)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.80 (3H, t, J = 7.3 Hz), 1.12-1.20 (2H, m),
1.40-1.74 (6H, m), 2.60-2.66 (2H, m), 5.03 (2H, s), 6.41 (1H, d, J = 15.3Hz),
6.55 (1H, d, J = 15.3Hz), 6.83-6.85 (1H, m), 6.89-6.95 (2H, m), 7.17-7.19 (3H, m),
7.23-7.36 (8H, m), 8.17-8.26 (3H, br).

  Next, the results of supporting the usefulness of the compounds of the present invention are shown by experimental examples.

<Experimental Example 1> Induction of intracellular calcium mobilization of a test compound against human S1P (sphingosine-1-phosphate) receptor-expressing cells
Ham's with 10% fetal bovine serum and 200 μg / mL Geneticin
96-well black clear bottom culture plate of human S1P receptor-expressing CHO cells (hS1P ₁ receptor-expressing CHO cells or hS1P ₃ receptor-expressing CHO cells) subcultured in F-12 medium at 4 × 10 ⁴ cells / well (Coaster) was seeded and cultured overnight at 37 ° C. and 5% CO ₂ . Furthermore, Calcium Screening Kit reagent (Dojindo Laboratories) was added as a Ca ²⁺ -binding fluorescent indicator, and cultured at 37 ° C. under 5% CO ₂ for 60 minutes. After incubation, the fluorescence intensity at an excitation wavelength of 485 nm and a detection wavelength of 525 nm was measured using a microplate fluorescence spectrophotometer (FLEX Station, molecular device). Add S1P prepared in the medium to a concentration 10 times the final concentration or test compound (final DMSO concentration 0.1%) 18 seconds after the start of fluorescence measurement, and continuously measure the fluorescence intensity every 1.5 seconds until 100 seconds after addition. did. Calculate the value obtained by subtracting the minimum fluorescence intensity from the maximum fluorescence intensity from the measurement data (fluorescence increase), and the difference between the fluorescence increase when the solvent is added and the fluorescence increase when S1P is applied at 10 ^-6 M Was 100%, and the fluorescence increase rate (%) of the test compound was calculated. The EC ₅₀ value was determined using PRISM software (GraphPad) as the intracellular calcium mobilization inducing action of the test compound. The EC ₅₀ value ≧ 1 μmol / L is represented as −, 1 μmol / L> EC ₅₀ value ≧ 0.1 μmol / L is represented as +, and 0.1 μmol / L> EC ₅₀ value is represented as ++, and is shown in Table 4.

   From the above results, it was confirmed that the compound of the present invention acts on the human S1P receptor.

The present invention has been found that a novel aminosulfonic acid derivative and an addition salt thereof have an excellent sphingosine-1-phosphate (S1P) receptor modulating action. Such compounds having S1P receptor modulating action are arteriosclerosis, obstructive arteriosclerosis, obstructive thromboangiitis, renal fibrosis, liver fibrosis, chronic bronchial asthma, diffuse hamartoma pulmonary vascular myoma , Adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), interstitial pneumonia, idiopathic interstitial pneumonia, lung cancer, hypersensitivity pneumonitis, Buerger's disease, diabetic neuropathy peripheral arterial disease, sepsis , Vasculitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edematous disease, varicose vein, dissecting aortic aneurysm, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure, failure, burn, ulcerative colon As a therapeutic and prophylactic agent for inflammation, Crohn's disease, etc., as well as preventive or therapeutic agents for rejection such as heart transplantation, renal transplantation, skin transplantation, liver transplantation, bone marrow transplantation, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, Hashimoto disease Multiple sclerosis, myasthenia gravis, diabetes, atopic dermatitis, is useful as allergic rhinitis, allergic conjunctivitis, prophylactic or therapeutic agent such as allergic contact dermatitis.

Claims (7)

General formula (1)

[Wherein, R ₁ represents an optionally substituted phenyl group or an optionally substituted alkyl group having 1 to 10 carbon atoms,
R ₂ represents a hydrogen atom, a halogen atom, a trihalomethyl group, a lower alkyl group having 1 to 4 carbon atoms, or a lower alkoxy group having 1 to 4 carbon atoms,
R ₃ represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms which may have a substituent,
R ₄ represents a hydroxy group, a lower alkoxy group having 1 to 4 carbon atoms or an amino group,
X is O, S, SO, SO ₂ , or CH ₂ ,
Y is CH = CH or (CH ₂₎ n (n is 1-2 integer),
m represents an integer of 2 to 4]
Aminosulfonic acid derivatives, optical isomers and pharmacologically acceptable salts thereof, and hydrates thereof, The compound represented by the general formula (1) is represented by the general formula (1a).

[Wherein, X, Y, R ₂ , R ₃ and m are the same as defined above]
The aminosulfonic acid derivative according to claim 1, its optical isomer, pharmacologically acceptable salt, and hydrate thereof, wherein the compound is represented by the formula: The aminosulfonic acid derivative, optical isomers and pharmacologically acceptable salts thereof, and hydrates thereof according to claim 2, wherein R ₂ in the general formula (1a) is a chlorine atom. The compound represented by the general formula (1) is
1) 3-amino-5- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethylpentane-1-sulfonic acid,
2) 3-amino-5- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethyl-1-pentene-1-sulfonic acid,
3) 3-Amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethylhexane-1-sulfonic acid,
4) 3-amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-hydroxymethyl-1-hexene-1-sulfonic acid,
5) 3-Amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-propylhexane-1-sulfonic acid,
6) Aminosulfonic acid derivative and drug according to claim 1, which is 3-amino-6- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] -3-propyl-1-hexene-1-sulfonic acid Physiologically acceptable salts and hydrates thereof. General formula (1)

[Wherein, R ₁ represents an optionally substituted phenyl group or an optionally substituted alkyl group having 1 to 10 carbon atoms,
R ₂ represents a hydrogen atom, a halogen atom, a trihalomethyl group, a lower alkyl group having 1 to 4 carbon atoms, or a lower alkoxy group having 1 to 4 carbon atoms,
R ₃ represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms which may have a substituent,
R ₄ represents a hydroxy group, a lower alkoxy group having 1 to 4 carbon atoms or an amino group,
X represents O, S, SO, SO ₂ , NH or CH ₂ ,
Y is CH = CH or (CH ₂₎ n (n is 1-2 integer),
m represents an integer of 2 to 4]
An S1P receptor modulator comprising as an active ingredient at least one of aminosulfonic acid derivatives, optical isomers and pharmacologically acceptable salts thereof, and hydrates thereof, characterized by The compound represented by the general formula (1) is represented by the general formula (1a)

[Wherein, X, Y, R ₂ , R ₃ and m are the same as defined above]
The S1P receptor according to claim 5, wherein at least one of the aminosulfonic acid derivative represented by the following formula, its optical isomer, pharmacologically acceptable salt, and hydrate thereof is used as an active ingredient. Body regulator. The pharmaceutical which contains at least 1 or more types of the aminosulfonic acid derivative as described in any one of Claims 1-4, its optical isomer, a pharmacologically acceptable salt, and its hydrate as an active ingredient.