JP2008239546A - Aminoalcohol derivative and immunosuppressive agent containing the same as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an aminoalcohol derivative having excellent immunosuppressive activity and exhibiting fewer side effects. <P>SOLUTION: The aminoalcohol derivative having a mechanism of action different from those of an antimetabolite and a calcineurin inhibitor, and being represented by general formula (1) (wherein, R<SP>1</SP>is a chlorine atom, a 1-3C linear alkyl group or a trifluoromethyl group; R<SP>2</SP>is a fluorine atom or a chlorine atom; R<SP>3</SP>is a 1-3C linear alkyl group; X is SO or SO<SB>2</SB>; and n is 2 or 3), or a pharmacologically acceptable salt or a hydrate thereof is provided. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to amino alcohol derivatives, salts and hydrates useful as immunosuppressants.

Immunosuppressants are widely used as therapeutic agents for rheumatoid arthritis, nephritis, knee osteoarthritis, autoimmune diseases such as systemic lupus erythematosus, chronic inflammatory diseases such as inflammatory bowel disease, and allergic diseases such as asthma and dermatitis. Has been. In particular, with the advancement of medical technology, many transplantation operations for tissues and organs have been carried out in recent medical practice, and how transplant rejection can be controlled well. Immunosuppressants play a very important role in this area as well.

  In organ transplantation, antimetabolites typified by azathioprine and mycophenolate mofetil, calcineurin inhibitors typified by cyclosporin A and tacrolimus, and corticosteroids typified by prednisolone are used. However, some of these drugs are insufficiently effective, and some drugs require blood concentration monitoring in order to avoid serious side effects such as kidney damage. It is not always satisfactory.

  Furthermore, in order to reduce the side effects of immunosuppressive drugs and obtain sufficient immunosuppressive action, multi-drug combination therapy using multiple drugs with different mechanism of action is common, and action different from the immunosuppressive drugs described above Development of new types of drugs with mechanisms is also desired.

In recent years, various aminoalcohol derivatives such as 2-amino-1,3-propanediol derivatives and 2-aminoethanol derivatives have been reported as novel immunosuppressants and attracted attention. Is not holding. The phosphoric acid ester that is metabolized and produced in vivo after administration of these drugs is the true physiologically active substance, and the produced phosphoric acid ester is against various sphingosine-1-phosphate (S1P) receptors. Shows agonistic and antagonistic effects. In particular, it was first reported in 2002 that an agonistic action on the S1P ₁ receptor regulates leukocyte migration and exerts an immunosuppressive action (Non-patent Documents 1 and 2). In addition to the effectiveness against various organ transplants and GVHD, a series of derivatives introduced in these non-patent documents include rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, Hashimoto's disease, multiple sclerosis, myasthenia gravis, I and Autoimmune diseases such as type II diabetes and Crohn's disease, allergic diseases such as atopic dermatitis, allergic rhinitis, allergic conjunctivitis, allergic contact dermatitis, inflammatory diseases such as inflammatory bowel disease or ulcerative colitis It is disclosed in (Patent Document 1 and Patent Document 2) that it is effective for the above. Since these reports, not only amino alcohol derivatives, various compounds such as amino phosphoric acid ester derivative or amino acid derivatives are disclosed as S1P ₁ ～S1P ₅ receptor modulators around the immunosuppressive agent or S1P ₁ receptor (Patent Documents 3 to 66).

Furthermore, the S1P ₄ receptor is extremely distributed in immune cells such as leukocytes and organs that are greatly involved in the immune system, suggesting a deep involvement in the immune system. In fact, autoimmunity such as SLE and rheumatism is suggested. disease and asthma, a compound having a SlP ₄ agonistic activity for the purpose of allergic diseases and inflammatory diseases by such as atopic dermatitis is disclosed in (Patent Document 34,39,50).

There is a lot of interest in S1P receptor agonists with such a wide range of medical uses, but not all S1P receptor agonists necessarily provide the desired effects for the body. is not.

For example, S1P receptor agonists that have been shown to be useful in suppressing organ transplant rejection in clinical trials have bradycardia as a side effect after administration, and this effect is due to agonistic effects on S1P ₃ receptors. There is also a report that it may be (Non-Patent Document 3, Non-Patent Document 4). In addition, agonists for the S1P ₃ receptor may cause effects such as myocardial blood flow inhibition (Non-Patent Document 5), cerebral artery spasm (Non-Patent Document 6), and pulmonary edema (Non-Patent Document 7) in animal experimental models. It has been reported.
WO0218395 pamphlet WO02076995 pamphlet WO9408943 pamphlet JP-A-9-2579602 WO0206268 pamphlet JP 2002-53572 A JP 2002-167382 A WO02076995 pamphlet JP 2003-137894 A WO03040097 brochure WO02064616 pamphlet WO02062389 pamphlet JP 2002-316985 A JP 2003-267936 A 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 WO05020882 pamphlet WO04002531 pamphlet WO05032465 pamphlet WO05041899 pamphlet WO05058848 pamphlet WO05070886 pamphlet WO05082089 pamphlet WO05082841 pamphlet WO05021503 pamphlet WO0505040091 pamphlet WO05085179 pamphlet WO05118523 pamphlet WO05001425 pamphlet WO06020951 pamphlet WO06001463 pamphlet WO03029184 pamphlet WO03029205 pamphlet WO04026817 pamphlet WO04074297 pamphlet WO05021503 pamphlet JP 2004-307439 A JP 2004-307440 A JP 2004-307441 A JP 2004-307442 A WO06041015 pamphlet JP 2004-137208 A Japanese Patent Laid-Open No. 2005-41867 JP 2005-47899 A WO0505040091 pamphlet WO05063671 pamphlet WO05079788 pamphlet S. Mandala et al., Science, 296,346 (2002). V. Brinkmannet al., J. Biol. Chem., 277, 21453 (2002). MGSannaet al., J. Biol. Chem., 279, 13839 (2004). M. Forrestet al., J. Pharmacol. Exp. Ther., 309, 758 (2004). B. Levkauet al., Circulation, 110, 3358 (2004). S. Salomone et al., Eur. J. Pharmacol. 469, 125 (2003). Y. Gon et al., PNAS 102, 9270 (2005).

  The problem to be solved by the present invention is to provide an aminoalcohol derivative having an excellent immunosuppressive action and few side effects.

  As a result of intensive research on immunosuppressive agents that have different mechanisms of action from antimetabolites and calcineurin inhibitors, the present inventors have found that a novel amino alcohol derivative has high safety and excellent immunosuppression. It discovered that it had an effect | action, and completed this invention.

That is, the present invention
1)
General formula (1)

[Wherein R ¹ represents a linear alkyl group having 1 to 3 carbon atoms which may be substituted with a chlorine atom or a halogen atom, R ² represents a fluorine atom or a chlorine atom, and R ³ represents a carbon atom having 1 to ³ carbon atoms. A linear alkyl group, X represents SO or SO ₂ , and n represents 2 or 3]
An amino alcohol derivative represented by the formula, a pharmacologically acceptable salt thereof or a hydrate thereof,

2)
The compound represented by the general formula (1) is represented by the general formula (1a).

[Wherein R ³ , X and n are the same as defined above]
1) the amino alcohol derivative according to 1), a pharmacologically acceptable salt thereof or a hydrate thereof,

3) The amino alcohol derivative according to 1) or 2), wherein R ³ is a methyl group in the general formula (1) or (1a), a pharmacologically acceptable salt thereof or a hydrate thereof,

4) The compound represented by the general formula (1) is
(R) -2-amino-5- [2-chloro-4- (3-trifluoromethylphenylsulfinyl) phenyl] -2-methylpentan-1-ol,
Or (R) -2-amino-5- [2-chloro-4- (3-trifluoromethylphenylsulfonyl) phenyl] -2-methylpentan-1-ol, the amino alcohol derivative according to 1), pharmacology Pharmaceutically acceptable salts or hydrates thereof,

5) General formula (2)

[Wherein, R ¹ represents a linear alkyl group having 1 to 3 carbon atoms which may be substituted with a chlorine atom or a halogen atom, R ² represents a fluorine atom or a chlorine atom, A represents a halogen atom, and X represents SO Or SO ₂ , n represents 2 or 3]
And a compound represented by the general formula (10)

[Wherein R ³ represents a linear alkyl group having 1 to ³ carbon atoms, and R ⁴ represents an alkyl group having 1 to 6 carbon atoms]
A step in which a compound represented by the formula is allowed to act in the presence of a base, and after acid-decomposing the product in the above step, the nitrogen atom is further protected with a t-butoxycarbonyl group and reduced to deprotect the nitrogen atom. 1) the amino alcohol derivative according to 1), a pharmacologically acceptable salt thereof or a hydrate thereof,

6) A pharmaceutical comprising as an active ingredient the amino alcohol derivative according to any one of 1) to 5), a pharmacologically acceptable salt thereof or a hydrate thereof,

7) The medicament according to 6), which is an immunosuppressant,

8) The medicament according to 6), which is a preventive or therapeutic agent for rejection in organ transplantation or bone marrow transplantation,

9) A phosphate ester of the amino alcohol derivative according to any one of 1) to 5), a pharmacologically acceptable salt thereof or a hydrate thereof,
It is about.

According to the present invention, it is possible to provide an amino alcohol derivative excellent in immunosuppressive action and safety. The compound of the present invention is used for preventing or treating rejection in organ transplantation and bone marrow transplantation, inflammatory bowel disease, systemic lupus erythematosus, Crohn's disease, nephrotic syndrome, glomerulosclerosis, glomerulonephritis, multiple sclerosis, severe muscle Preventive or therapeutic agent for autoimmune diseases such as asthenia, preventive or therapeutic agent for rheumatoid arthritis, psoriasis, allergic contact dermatitis, preventive or therapeutic agent for atopic dermatitis, hepatitis, fatty liver, toxic liver disorder, cirrhosis It is also useful as a prophylactic or therapeutic agent for diabetes-derived liver disease, a prophylactic or therapeutic agent for allergic rhinitis, allergic conjunctivitis, etc., and a prophylactic or therapeutic agent for pulmonary fibrosis, idiopathic interstitial pneumonia and bronchial asthma.

In the present invention, the linear alkyl group having 1 to ³ carbon atoms of R ¹ and R ³ is a methyl group, an ethyl group, or an n-propyl group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The straight-chain alkyl group having 1 to 3 carbon atoms substituted with a halogen atom is an alkyl group in which one or more hydrogen atoms of the straight-chain alkyl group are substituted with a halogen atom. For example, monofluoromethyl Group, difluoromethyl group, trifluoromethyl group, perfluoroethyl group and the like.

For the purpose of obtaining high safety, R ¹ is preferably an ethyl group, a propyl group or a trifluoromethyl group, more preferably a trifluoromethyl group. R ³ is preferably a methyl group, and n is preferably 3.

For the purpose of obtaining a high immunosuppressive action, the configuration of R ³ is preferably a configuration manufactured as a main product by the synthesis route B (using compound (10)) described later.

Examples of the pharmaceutically acceptable salt in the present invention include acid addition salts such as hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, citrate, and tartrate. Can be mentioned.

  The compound represented by the general formula (1) according to the present invention can be produced, for example, by the synthesis route A as shown below.

<Synthesis route A>

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

[Wherein R ¹ , R ² , R ³ , R ⁴ , X and n are as described above]
The compound represented by general formula (2)

[Wherein R ¹ , R ² , A, X and n are as described above]
And a compound represented by the general formula (7)

[Wherein R ³ and R ⁴ are as described above]
In the presence of a base (Step A-1).

  In the reaction, methanol, ethanol, 1,4-dioxane, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF) or the like is used as a reaction solvent, sodium hydride, potassium hydride, sodium methoxy. Sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, potassium carbonate, etc., in the presence of an inorganic base, the reaction temperature is 0 ° C. to heating under reflux, preferably 80 ° C. to It can be performed at 100 ° C.

  In the synthesis route A, the general formula (4)

[Wherein R ¹ , R ² , R ³ , R ⁴ , X and n are as described above]
Can be manufactured by hydrolyzing the compound represented by General formula (3) (process A-2).

In the reaction, methanol, ethanol, 1,4-dioxane, DMF, DMSO, THF or the like is used as a reaction solvent in the presence of a base such as an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide or an aqueous solution of lithium hydroxide, and the reaction temperature is The reaction can be performed at 0 ° C. to heating under reflux. Preferably, a method in which potassium hydroxide is used as a base and allowed to act at 50 ° C. in an ethanol solvent is preferable.

The compound according to the present invention is preferably a specific optically active substance, but there is no particular limitation on the timing of optical resolution. At this stage, optical resolution is performed by HPLC using a chiral column, and the desired asymmetry is achieved. A compound having a center can also be obtained.

  In the synthesis route 1, the general formula (5)

[Wherein R ⁵ represents an alkyl group having 1 to 6 carbon atoms, and R ¹ , R ² , R ³ , R ⁴ , X and n are as described above]
The compound represented by General formula (4) can be manufactured by carrying out Curtius rearrangement (process A-3).

For the reaction, a general method for converting a carboxyl group into a carbamate can be used. For example, a technique composed of a combination of ethyl chlorocarbonate and NaN ₃ , oxalyl chloride and NaN ₃ or a technique performed using only diphenyl phosphate azide (DPPA) can be used. Preferably, diphenyl phosphate azide is heated to reflux in a solvent of benzene or toluene in the presence of an organic base such as triethylamine, and then the general formula (8)
R ⁵ OH (8)
[Wherein R ⁵ is as described above]
The alcohol represented by the formula (8) is used as a reaction solvent after continuing the reaction by heating and stirring or by distilling off the solvent such as benzene and toluene used in the above reaction. They can also be used for reaction under heating and reflux.

  At this stage, optical resolution can be performed by HPLC using a chiral column to obtain a compound having a desired asymmetric center.

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

[Wherein R ¹ , R ² , R ³ , R ⁵ , X and n are as described above]
Can be produced by reducing the compound represented by the general formula (5) (step A-4).

Reactions include alkylborane derivatives such as borane and 9-borabicyclo [3.3.1] nonane (9-BBN), diisobutylaluminum hydride ((iBu) ₂ AlH), sodium borohydride (NaBH ₄ ), lithium borohydride (LiBH ₄ ), metal hydride complex compounds such as lithium aluminum hydride (LiAlH ₄ ), preferably LiBH ₄ , and the reaction night solvent is THF, 1,4-dioxane, ethanol, methanol, etc. The reaction can be performed under heating and reflux, preferably at room temperature.

  Also at this stage, optical resolution can be performed by HPLC using a chiral column to obtain a desired compound having an asymmetric center.

  The compound represented by general formula (1) in the synthetic pathway A can be manufactured by acid-decomposing or hydrolyzing the compound represented by general formula (6) (step A-5).

  The reaction is carried out at room temperature to under reflux in an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, or hydrochloric acid, hydrobromic acid, methanesulfonic acid, An organic solvent such as methanol, ethanol, THF, or 1,4-dioxane may be added to an inorganic acid or organic acid such as acetic acid or trifluoroacetic acid, and the reaction may be performed at room temperature to under reflux. In addition, methanol, ethanol, THF, 1,4-dioxane, DMSO, DMF or the like is used as a reaction solvent, and the reaction solution is heated to 0 ° C. to reflux in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution. Below, it can carry out at 80 to 100 degreeC preferably.

Among the compounds represented by the general formula (5) in the synthesis route A, a compound in which R ⁵ is a t-butyl group, that is, the general formula (5a)

[Wherein Boc represents a t-butoxycarbonyl group, and R ¹ , R ² , R ³ , R ⁴ , X and n are as described above]
A compound represented by
Among the compounds represented by the general formula (6) in the synthesis route A, a compound in which R ⁵ is a t-butyl group, that is, the general formula (6a)

[Wherein R ¹ , R ² , R ³ , X, Boc and n are as described above]
Can also be produced by the synthetic route B.

<Synthetic route B>

  In the synthesis route B, the general formula (9)

[Wherein R ¹ , R ² , R ³ , R ⁴ , X and n are as described above]
The compound represented by general formula (2a)

[Wherein, Xa represents a sulfur atom, and R ¹ , R ² , A and n are as defined above] and a general formula (10)

[Wherein R ³ and R ⁴ are as described above]
In the presence of a base (step B-1).

  In the reaction, 1,4-dioxane, THF, ether or the like is used as a reaction solvent, and a base such as n-butyllithium or lithium diisopropylamide, preferably n-butyllithium is used, and the formula (10) is used at −78 ° C. Then, the compound represented by the general formula (2) is allowed to react at -78 ° C while gradually raising the temperature gradually to room temperature.

  The compound represented by the general formula (5a ′) in the synthesis route B protects a nitrogen atom with a t-butoxycarbonyl group (Boc group) after acid-decomposing the compound represented by the general formula (9). (Step B-2).

In the reaction, methanol, ethanol, THF, 1,4-dioxane, ethyl acetate in which hydrochloric acid is dissolved, preferably 1,4-dioxane containing hydrochloric acid is reacted under heating and reflux, neutralized with a base, and amino An ester body is obtained. Further, it is preferable that the amino ester is reacted with Boc ₂ O at 0 ° C. to room temperature using ethyl acetate, THF, DMF, 1,4-dioxane, methylene chloride, chloroform, methanol, ethanol, acetonitrile and the like as a solvent.

The compound represented by the general formula (6a ′) in the synthesis route B can be produced by reducing the compound represented by the general formula (5a ′) (Step B-3).

The reaction is carried out using an alkylborane derivative such as borane or 9-BBN, a metal hydride complex compound such as (iBu) ₂ AlH, NaBH ₄ , LiBH ₄ , LiAlH ₄ , preferably LiBH _4, and THF as the reaction night solvent. The reaction can be performed using 1,4-dioxane, ethanol, methanol, or the like at 0 ° C. to heating under reflux, preferably at room temperature.

The compound represented by general formula (5a) in the synthetic pathway B can be manufactured by oxidizing the compound represented by general formula (5a ') (process B-4).
The reaction is carried out using hydrogen peroxide solution, metachloroperbenzoic acid or potassium permanganate, preferably metachloroperbenzoic acid as an oxidizing agent, and DMSO, 1,4-dioxane, methylene chloride, chloroform, benzene, toluene, etc. as a solvent. The reaction can be carried out at 0 ° C. to room temperature.

  The compound represented by the general formula (6a) in the synthesis route B can be produced by oxidizing the compound represented by the general formula (6a ′) (Step B-5). The reaction is the same as in step B-4.

In addition, about the synthesis method of the compound represented by General formula (2), it can manufacture by the method described in each pamphlet of WO03029184, WO03029205, WO04026817, WO04074297, and WO050444780.

The compounds of the present invention, by a phosphoric acid ester product which is metabolized in vivo, having S1P ₁ agonist activity and SlP ₄ agonistic activity. Therefore, the compound of the present invention is a prophylactic or therapeutic agent for rejection in organ transplantation and bone marrow transplantation, inflammatory bowel disease, systemic lupus erythematosus, Crohn's disease, nephrotic syndrome, glomerulosclerosis, glomerulonephritis, multiple sclerosis , Preventive or therapeutic agent for autoimmune diseases such as myasthenia gravis, preventive or therapeutic agent for rheumatoid arthritis, preventive or therapeutic agent for psoriasis, allergic contact dermatitis, atopic dermatitis, hepatitis, fatty liver, toxic liver Useful as a prophylactic or therapeutic agent for disorders, liver cirrhosis or diabetes-derived liver disease, prophylactic or therapeutic agent for allergic rhinitis, allergic conjunctivitis, etc., pulmonary fibrosis, idiopathic interstitial pneumonia and bronchial asthma is there.

For the above uses, the required dosage will of course vary depending on the mode of administration, the particular condition being treated and the effect desired. In general, a daily dose of about 0.03 to 2.5 mg / kg body weight is preferred. The indicated daily dose in mammals, eg, humans, is in the range of about 0.5 mg to about 100 mg, preferably administered in divided doses or delayed form no more than 4 times daily. Suitable unit dosage forms for oral administration contain about 1-50 mg of active ingredient.

The compounds of the invention may be administered by any conventional route, in particular enterally, for example orally, for example in tablet or capsule form, or parenterally, for example in injectable solution or suspension form, topically. For example, it can be administered in the form of a lotion, gel, ointment or cream, or in the form of a nasal or suppository. A pharmaceutical composition comprising a free form or pharmaceutically acceptable salt form of a compound of the invention together with at least one pharmaceutically acceptable carrier or diluent is conventionally used by mixing with a pharmaceutically acceptable carrier or diluent. Can be manufactured in a conventional manner.

The compounds of the present invention are also useful in combination with immunosuppressive agents having different mechanisms and / or drugs having anti-inflammatory action. Examples of drugs that can be used in combination include acute or chronic rejection of allogeneic and xenografts, immunosuppressive agents used for the treatment and prevention of inflammatory diseases and autoimmune diseases, immunosuppressive agents and / or anti-inflammatory agents with immunomodulating effects, and malignant cell proliferation Anti-inflammatory agent with suppression. Specifically, cyclosporin A and FK506 as calcineurin inhibitors, rapamycin as mTOR inhibitor, 40-O- (2-hydroxymethyl) -rapamycin, CCI779, ABT578, ABT281 as ascomycins having immunosuppressive action, ASM981 and mycophenolic acid, mycophenolate mofetil, azathioprine, mizoribine, cyclophosphamide and the like. Also, antifolate antimetabolites such as methotrexate, corticosteroids with broad anti-inflammatory activity, auranofin with immunomodulating activity, actarit, mesalazine or sulfasalazine, anti-TNFα antibody infliximab, anti-IL-6 receptor antibody Some MRAs, natalizumab, an anti-integrin antibody, and the like.

EXAMPLES 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), compounds in pamphlets of WO03029184, WO03029205, WO04026817, WO04074297, and WO050444780 can be used. (5S) -3,6-diethoxy-2-methyl-5-isopropyl-2,5-dihydropyrazine, (5S) -3,6-dimethoxy-2-methyl-5-isopropyl-2,5-dihydropyrazine And (5S) -2-allyl-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine are described in Ulrich Shollkopf et.al Synthesis 969 (1981) and Chunrong Ma et.al., J. Org. Chem. , 66, 4525 (2001). In addition, intermediates newly synthesized based on the experimental procedures described in these references are described as reference examples below.

<Reference Example 1>
2-Fluoro-4- (3-trifluoromethylphenylthio) benzaldehyde

Ethyldiisopropylamine (7.0 mL), tris (dibenzylideneacetone) dipalladium (0) in a solution of 4-bromo-2-fluorobenzaldehyde (4.06 g) in 1,4-dioxane (42 mL) at room temperature under an argon atmosphere Chloroform adduct (518 mg), xantphos (578 mg) and 3-trifluoromethylthiophenol (3.56 g) were added, and the mixture was heated to reflux for 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 = 30: 1) to obtain the desired product (4.08 g) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 6.86 (1H, dd, J = 10, 1.8
Hz), 7.02 (1H, dd, J = 7.9, 1.8 Hz), 7.58 (1H, t, J = 7.9 Hz), 7.68-7.73 (2H,
m), 7.76 (1H, t, J = 7.9 Hz), 7.80 (1H, s), 10.26 (1H, s)
EIMS (+): 300 [M]
⁺ .

<Reference Example 2>
2-Chloro-4- (3-chlorophenylthio) benzaldehyde

3-chlorobenzenethiol and 2-chloro-4-fluorobenzaldehyde were reacted in the same experimental procedure as in Reference Example 1 of WO03029205 to obtain the desired product as a colorless oil.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.11 (1H, dd, J = 9.2, 1.8 Hz),
7.17 (1H, d, J = 1.8 Hz), 7.36-7.44 (3H, m), 7.52 (1H, t, J = 1.8 Hz), 7.80
(1H, d, J = 7.9 Hz), 10.37 (1H, s)
EIMS (+): 282 [M]
⁺ .

<Reference Example 3>
2-Chloro-4- (3-ethylphenylthio) benzaldehyde

3-Ethylbenzenethiol and 2-chloro-4-fluorobenzaldehyde were reacted in the same experimental procedure as in Reference Example 1 of WO03029205 to obtain the desired product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.26 (3H, t, J = 7.3 Hz),
2.68 (2H, q, J = 7.3 Hz), 7.04-7.11 (2H, m), 7.28-7.40 (4H, m), 7.76 (1H, d, J
= 8.6 Hz), 10.35 (1H, s).
EIMS (+): 276 [M]
⁺ .

<Reference Example 4>
[2-Chloro-4- (3-ethylphenylthio) phenyl] acetaldehyde

  The target product was obtained as a pale yellow oil by reacting the compound of Reference Example 3 by the same experimental procedure as in Reference Example 326 of WO04074297.

<Reference Example 5>
3- [2-Chloro-4- (3-ethylphenylthio) phenyl] ethyl acrylate

The target product was obtained as a pale yellow oil by reacting the compound of Reference Example 3 by the same experimental procedure as in Reference Example 10 of the pamphlet of WO03029205.
EIMS (+): 346 [M]
⁺ .

<Reference Example 6>
3- [2-Chloro-4- (3-ethylphenylthio) phenyl] propan-1-ol

The compound of Reference Example 5 was reacted by the same experimental procedure as Reference Example 19 of WO03029205, and then reduced by the same experimental procedure as Reference Example 35 of WO03029205 to obtain the desired product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz,): δ 1.22 (3H, t, J = 7.3
Hz), 1.84 -1.90 (2H, m), 2.62 (2H, q, J = 7.6 Hz), 2.78-2.82 (2H, m), 3.69 (2H,
t, J = 6.1 Hz), 7.10-7.18 (4H, m), 7.23-7.29 (3H, m).

<Reference Example 7>
3- [2-Fluoro-4- (3-trifluoromethylphenylthio) phenyl] propan-1-ol

The target product was obtained as a colorless oil by sequentially reacting the compound of Reference Example 1 in the same manner as in Reference Example 5 and then in Reference Example 6.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.88 (2H, tt, J = 6.7,
6.1 Hz), 2.75 (2H, t, J = 6.7 Hz), 3.69 (2H, t, J = 6.1 Hz), 7.05 (1H, dd, J = 10,
1.8 Hz), 7.10 (1H, dd, J = 7.9, 1.8 Hz), 7.20 (1H, t, J = 7.9 Hz), 7.38-7.51
(3H, m), 7.55 (1H, s).

<Reference Example 8>
3- [2-Chloro-4- (3-chlorophenylthio) phenyl] propan-1-ol

The target product was obtained as a colorless oil by sequentially reacting the compound of Reference Example 2 in the same manner as in Reference Example 5 and then in Reference Example 6.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.33 (1H, br s),
1.83-1.95 (2H, m), 2.81-2.85 (2H, m), 3.70 (2H, br s), 7.15-7.23 (5H, m),
7.24-7.29 (1H, m), 7.38 (1H, d, J = 1.8 Hz).

<Reference Example 9>
2-Chloro-4- (3-ethylphenylthio) -1- (2-iodoethyl) benzene

The target product was obtained as a colorless oil by reacting the compound of Reference Example 4 by the same experimental procedure as in Reference Example 327 of WO04074297.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.22 (3H, t, J = 7.3 Hz),
2.63 (2H, q, J = 7.3 Hz), 3.23-3.28 (2H, m), 3.32-3.35 (2H, m), 7.09-7.29 (7H,
m).
EIMS (+): 402 [M] ⁺ .

<Reference Example 10>
2-Chloro-4- (3-ethylphenylthio) -1- (3-iodopropyl) benzene

The target product was obtained as a colorless oil by reacting the compound of Reference Example 6 by the same experimental procedure as in Reference Example 164 of WO03029184 pamphlet.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.22 (3H, t, J = 7.3 Hz),
2.12 (2H, quintet, J = 7.3 Hz), 2.63 (2H, q, J = 7.3 Hz), 2.81 (2H, t, J = 7.3
Hz), 3.19 (2H, t, J = 7.3 Hz), 7.09-7.19 (4H, m), 7.24-7.28 (3H, m).
EIMS (+): 416 [M] ⁺ .

<Reference Example 11>
2-Fluoro-1- (3-iodopropyl) -4- (3-trifluoromethylphenylthio) benzene

The target product was obtained as a colorless oil by reacting the compound of Reference Example 7 in the same manner as in Reference Example 164 of WO03029184.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.13 (2H, quintet, J = 7.3
Hz), 2.76 (2H, t, J = 7.3 Hz), 3.18 (2H, t, J = 6.7 Hz),
7.03 (1H, dd, J = 10, 1.8 Hz), 7.09 (1H, dd, J = 7.9, 1.8 Hz), 7.20 (1H, t, J =
7.9 Hz), 7.39-7.52 (3H, m), 7.57 (1H, s).
EIMS (+): 404 [M] ⁺ .

<Reference Example 12>
2-Chloro-4- (3-chlorophenylthio) -1- (3-iodopropyl) benzene

The target product was obtained as a colorless oil by reacting the compound of Reference Example 8 in the same experimental procedure as in Reference Example 164 of the pamphlet of WO03029184.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.14 (2H, tt, J = 7.3, 6.7 Hz), 2.84 (2H, t, J = 7.3 Hz), 3.20 (2H, t, J
= 6.7 Hz), 7.16-7.25 (5H, m), 7.28 (1H, t, J = 1.8 Hz),
7.36 (1H, d, J = 1.8 Hz).
EIMS (+): 422 [M] ⁺ .

<Example 1>
(2R, 5S) -2- [2-Chloro-4- (3-trifluoromethylphenylthio) phenyl] propyl-3,6-diethoxy-2-methyl-5-isopropyl-2,5-dihydropyrazine

N-Butyllithium- (5S) -3,6-diethoxy-2-methyl-5-isopropyl-2,5-dihydropyrazine (460 mg) in THF (8 mL) at −78 ° C. in an argon atmosphere A hexane solution (1.58 mol / L, 1.68 mL) was added, and the mixture was stirred at −78 ° C. for 30 minutes. Further, a solution of 2-chloro-1- (3-iodopropyl) -4- (3-trifluoromethylphenylthio) benzene (1.21 g) in tetrahydrofuran (2 mL) was added to the mixture at −78 ° C. for 30 minutes, 0 ° C. For 1 hour. 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 = 60: 1) to obtain the desired product (740 mg) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 0.63 (3H, d, J = 6.7
Hz), 1.07 (3H, d, J = 6.7 Hz), 1.18-1.29 (10H, m), 1.34-1.66 (2H, m), 1.79-1.91
(1H, m), 2.25 &#8211; 2.33 (1H, m), 2.70 (2H, t, J = 7.6 Hz), 3.85 (1H, br s),
3.99-4.23 (4H, m), 7.16 (2H, d, J = 7.9 Hz), 7.20 (1H, dd, J = 7.9, 1.8 Hz),
7.36-7.42 (3H, m), 7.44-7.50 (1H, m), 7.52 (1H, br s).

<Example 2>
(2R, 5S) -2- [2-Chloro-4- (3-trifluoromethylphenylthio) phenyl] ethyl-3,6-diethoxy-2-methyl-5-isopropyl-2,5-dihydropyrazine

(5S) -3,6-diethoxy-2-methyl-5-isopropyl-2,5-dihydropyrazine and 2-chloro-1- (3-iodoethyl) -4- (3-trifluoromethylphenylthio) benzene. The reaction was carried out in the same manner as in Example 1 to obtain the desired product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 0.72 (3H, d, J = 6.7
Hz), 1.08 (3H, d, J = 6.7 Hz), 1.28 (6H, t, J = 7.3 Hz), 1.35 (3H, s),
1.68-1.90 (1H, m), 2.10-2.19 (1H, m), 2.38-2.57 (1H, m), 3.95 (1H, d, J = 3.1
Hz), 4.02-4.22 (4H, m), 7.13 (1H, d, J = 7.9 Hz), 7.18 (1H, dd, J = 7.9, 2.4
Hz), 7.35-7.42 (3H, m), 7.43-7.48 (1H, m), 7.54 (1H, br s).

<Example 3>
(2R, 5S) -2- [2-Chloro-4- (3-ethylphenylthio) phenyl] ethyl-3,6-diethoxy-2-methyl-5-isopropyl-2,5-dihydropyrazine

(5S) -3,6-diethoxy-2-methyl-5-isopropyl-2,5-dihydropyrazine and the compound of Reference Example 9 were reacted in the same manner as in Example 1 to obtain the desired product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 0.72 (3H, d, J = 6.7
Hz), 1.07 (3H, d, J = 6.7 Hz), 1.21 (3H, t, J = 7.3 Hz), 1.28 (3H, t, J = 7.3
Hz), 1.29 (3H, t, J = 7.3 Hz), 1.34 (3H, s), 1.70-1.79 (1H, m), 2.09-2.16 (1H,
m), 2.24-2.32 (1H, m), 2.35-2.52 (2H, m), 2.61 (2H, q, J = 7.3 Hz), 3.95 (1H, d,
J = 3.1 Hz), 4.03-4.20 (4H, m), 7.04-7.15 (4H, m), 7.21-7.26 (3H, m).
ESIMS (+): 501 [M + H] ⁺ .

<Example 4>
(2R, 5S) -2- [2-Chloro-4- (3-ethylphenylthio) phenyl] propyl-3,6-diethoxy-2-methyl-5-isopropyl-2,5-dihydropyrazine

(5S) -3,6-diethoxy-2-methyl-5-isopropyl-2,5-dihydropyrazine and the compound of Reference Example 10 were reacted in the same manner as in Example 1 to obtain the desired product as a colorless oil.
¹ H-NMR (CDCl ₃ ,
400 MHz): δ 0.68 (3H, d, J = 6.7 Hz), 1.04 (3H, d, J =
6.7 Hz), 1.20-1.26 (9H, m), 1.31 (3H, s), 1.36-1.43 (1H, m), 1.50-1.57 (1H, m),
1.85-1.92 (1H, m), 2.21-2.28 (1H, m), 2.60-2.65 (4H, m), 3.88 (1H, d, J = 3.7
Hz), 4.00-4.16 (4H, m), 7.06-7.16 (4H, m), 7.22-7.27 (3H, m).
ESIMS (+): 515 [M + H] ⁺ .

<Example 5>
(2R, 5S) -2- [2-Chloro-4- (3-chlorophenylthio) phenyl] propyl-3,6-diethoxy-2-methyl-5-isopropyl-2,5-dihydropyrazine

(5S) -3,6-diethoxy-2-methyl-5-isopropyl-2,5-dihydropyrazine and the compound of Reference Example 12 were reacted in the same manner as in Example 1 to obtain the desired product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 0.69 (3H, d, J = 6.7
Hz), 1.08 (3H, d, J = 6.7 Hz), 1.18-1.29 (7H, m), 1.31 (3H, s), 1.34-1.47 (1H,
m), 1.50-1.63 (1H, m), 1.85-1.95 (1H, m), 2.20 &#8211; 2.30 (1H, m), 2.65 (2H, t, J =
7.6 Hz), 3.89 (1H, d, J = 3.1 Hz), 3.99-4.23 (4H, m), 7.11-7.23 (6H, m), 7.35
(1H, d, J = 1.8 Hz).
ESIMS (+): 521
[M + H] ⁺ .

<Example 6>
(2R, 5S) -2- [2-Fluoro-4- (3-trifluoromethylphenylthio) phenyl] propyl-3,6-diethoxy-2-methyl-5-isopropyl-2,5-dihydropyrazine

(5S) -3,6-diethoxy-2-methyl-5-isopropyl-2,5-dihydropyrazine and the compound of Reference Example 11 were reacted in the same manner as in Example 1 to obtain the desired product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 0.67 (3H, d, J = 6.7
Hz), 1.06 (3H, d, J = 6.7 Hz), 1.18-1.29 (7H, m), 1.33 (3H, s), 1.36-1.66 (2H,
m), 1.85-1.95 (1H, m), 2.23 &#8211; 2.33 (1H, m), 2.67 (2H, t, J = 7.6 Hz), 3.89 (1H,
d, J = 3.1 Hz), 3.99-4.23 (4H, m), 7.02 (1H, dd, J = 9.8 Hz, 1.8 Hz), 7.08 (1H,
dd, J = 7.9 Hz, 2.4 Hz), 7.13 (1H, t, J = 7.9 Hz), 7.38-7.50 (3H, m), 7.55 (1H,
s).

<Example 7>
(2S, 5S) -2-Allyl-2- [2-chloro-4- (3-trifluoromethylphenylthio) phenyl] propyl-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine

(5S) -2-Allyl-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine and 2-chloro-1- (3-iodopropyl) -4- (3-trifluoromethylphenylthio) benzene Was reacted in the same manner as in Example 1 to obtain the desired product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 0.67 (3H, d, J = 6.7
Hz), 1.05 (3H, d, J = 6.7 Hz), 1.23 (3H, t, J = 6.4 Hz), 1.25 (3H, t, J = 6.4
Hz), 1.30-1.64 (3H, m), 1.80-1.90 (1H, m), 2.23-2.39 (2H, m), 2.53 (1H, dd, J =
12.4, 7.3 Hz), 2.65 (2H, t, J = 7.6 Hz), 3.83 (1H, d, J = 3.1 Hz), 4.03-4.18
(4H, m), 4.92-5.04 (2H, m), 5.60-5.73 (1H, m), 7.13 (2H, d, J = 7.9 Hz), 7.18
(1H, dd, J = 7.9 Hz, 1.8 Hz), 7.36 (1H, d, J = 1.8 Hz), 7.38-7.42 (2H, m), 7.44-7.49
(1H, m), 7.55 (1H, br s).

<Example 8>
(R) -2-T-butoxycarbonylamino-5- [2-fluoro-4- (3-trifluoromethylphenylthio) phenyl] -2-methylpentanoic acid ethyl

A 0.5 mol / L aqueous hydrochloric acid solution (15 mL) was added to a solution of compound 1 (740 mg) in dioxane (30 mL), and the mixture was stirred at room temperature for 1 hour and then allowed to stand overnight at room temperature. After concentration, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration of the extract, the residue was dissolved in acetonitrile (30 mL), and di-tert-butoxy dicarbonate (727 mg) was added. The mixture was stirred at room temperature for 1 hour and left at room temperature 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, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the desired product (498 mg) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.26 (3H, t, J = 7.3
Hz), 1.42 (9H, s), 1.51 (3H, s), 1.45-1.68 (2H, m), 1.77-1.86 (1H, m),
2.09-2.20 (1H, m), 2.69 (2H, t, J = 7.6 Hz), 4.13-4.23 (2H, m), 5.29 (1H, br
s), 7.02 (1H, dd, J = 9.8 Hz, 1.8 Hz), 7.08 (1H, dd, J = 7.9 Hz, 2.4 Hz), 7.13
(1H, t, J = 7.9 Hz), 7.38-7.50 (3H, m), 7.55 (1H, s).

<Example 9>
(S) -2-Allyl-2-t-butoxycarbonylamino-5- [2-chloro-4- (3-trifluoromethylphenylthio) phenyl] ethyl pentanoate

The compound of Example 7 was reacted in the same manner as in Example 8 to obtain the target product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz) δ 1.24 (3H, t, J = 7.3 Hz),
1.29-1.39 (1H, m), 1.43 (9H, s), 1.60-1.70 (1H, m), 1.78-1.86 (1H, m),
2.32-2.50 (2H, m), 2.66-2.73 (2H, m), 2.99-3.10 (1H, m), 4.19 (2H, q), 5.03 (1H,
d, J = 3.1 Hz), 5.09 (1H, s), 5.49 (1H, br s), 5.54-5.68 (1H, m), 7.16 (1H, d,
J = 7.9 Hz), 7.19 (1H, dd, J = 7.9, 1.8 Hz), 7.35 (1H, d, J = 1.8 Hz), 7.39-7.44
(2H, m), 7.45-7.50 (1H, m), 7.54 (1H, br s).

<Example 10>
(R) -2-t-Butoxycarbonylamino-5- [2-chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-propylpentanoic acid ethyl ester

To a solution of the compound of Example 9 (400 mg) in ethyl acetate (20 mL) was added palladium-activated carbon / ethylenediamine complex (100 mg), and the mixture was stirred at room temperature for 24 hours while purging with hydrogen. The reaction mixture was filtered through celite, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to obtain the desired product (293 mg) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 0.91 (3H, t, J = 7.3
Hz), 1.42 (9H, s), 1.15-1.77 (8H, m), 2.72 (2H, t, J = 7.3 Hz), 3.63 (1H, d, J
= 12 Hz), 3.67 (1H, d, J = 12 Hz), 4.52 (1H, br s), 7.19-7.22 (2H, m), 7.39 (1H,
s), 7.40-7.50 (3H, m), 7.54 (1H, br s).
FABMS (+): 532 [M + H] ⁺ .

<Example 11>
(R) -2-t-Butoxycarbonylamino-5- [2-chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-methylpentan-1-ol

Compound of Example 8 (498
mg) in tetrahydrofuran (10 mL) was added lithium borohydride (99 mg) under ice-cooling, ethanol (1 mL) was added dropwise, and the mixture was stirred under ice-cooling for 2 hr. To the reaction solution was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate, 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 = 2: 1) to obtain the desired product (452 mg) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.14 (3H, s), 1.42 (9H,
s), 1.48-1.76 (4H, m), 1.81-1.90 (1H, m), 2.74 (2H, t, J = 6.7 Hz), 3.61 (1H,
d, J = 12 Hz), 3.65 (1H, d, J = 12 Hz), 4.56 (1H, br s), 4.58 (1H, br s), 7.20
(2H, d, J = 1.2 Hz), 7.37-7.50 (4H, m), 7.54 (1H, br s).
Optical rotation: [α] _D ²⁷ +14.31 (c 0.63, CHCl ₃ ).

<Example 12>
(R) -2-t-Butoxycarbonylamino-4- [2-chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-methylbutan-1-ol

The compound of Example 2 was reacted in the same manner as in Example 8 to obtain an ester, and then this ester was reacted in the same manner as in Example 11 to obtain the desired product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.25 (3H, s), 1.44 (9H,
s), 1.79-1.89 (1H, m), 2.05-2.13 (1H, m), 2.66-2.83 (2H, m), 3.68 (1H, d, J =
12 Hz), 3.71 (1H, d, J = 12 Hz), 4.69 (1H, br s), 7.20-7.23 (2H, m), 7.37-7.42
(3H, m), 7.45-7.50 (2H, m), 7.55 (1H, br s).

<Example 13>
(R) -2-t-butoxycarbonylamino-4- [2-chloro-4- (3-ethylphenylthio) phenyl] -2-methylbutan-1-ol

The compound of Example 3 was reacted in the same manner as in Example 8 to obtain an ester, and then this ester was reacted in the same manner as in Example 11 to obtain the desired product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.22 (3H, t, J = 7.3 Hz),
1.24 (3H, s), 1.44 (9H, s), 1.77-1.85 (1H, m), 2.02-2.09 (1H, m), 2.62 (2H, q, J
= 7.3 Hz), 2.63-2.78 (2H, m), 3.64-3.73 (2H, m), 4.08 (1H, br), 4.68 (1H, br s),
7.10-7.17 (4H, m), 7.22-7.28 (3H, m).
ESIMS (+): 450 [M + H] ⁺ .

<Example 14>
(R) -2-t-Butoxycarbonylamino-5- [2-chloro-4- (3-ethylphenylthio) phenyl] -2-methylpentan-1-ol

The compound of Example 4 was reacted in the same manner as in Example 8 to obtain an ester, and then this ester was reacted in the same manner as in Example 11 to obtain the desired product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.14 (3H, s), 1.22 (3H,
t, J = 7.3 Hz), 1.43 (9H, s), 1.54-1.70 (3H, m), 1.79-1.89 (1H, m), 2.62 (2H, q,
J = 7.3 Hz), 2.70 (2H, t, J = 7.0 Hz), 3.57-3.66 (2H, m), 4.05 (1H, br), 4.55
(1H, br s), 7.10-7.17 (4H, m), 7.17-7.28 (3H, m).
ESIMS (+): 464 [M + H] ⁺ .

<Example 15>
(R) -2-t-Butoxycarbonylamino-5- [2-chloro-4- (3-chlorophenylthio) phenyl] -2-methylpentan-1-ol

The compound of Example 5 was reacted in the same manner as in Example 8 to obtain an ester, and then this ester was reacted in the same manner as in Example 11 to obtain the desired product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.14 (3H, s), 1.43 (9H,
s), 1.58-1.74 (3H, m), 1.79-1.92 (1H, m), 2.73 (2H, t, J = 6.7 Hz), 3.61 (1H,
d, J = 12 Hz), 3.64 (1H, d, J = 12 Hz), 4.08 (1H, br s), 4.57 (1H, br s),
7.17-7.27 (6H, m), 7.37 (1H, s).
ESIMS (+): 470 [M + H] ⁺ .

<Example 16>
(R) -2-t-Butoxycarbonylamino-5- [2-fluoro-4- (3-trifluoromethylphenylthio) phenyl] -2-methylpentan-1-ol

The compound of Example 6 was reacted in the same manner as in Example 8 to obtain an ester, and then this ester was reacted in the same manner as in Example 11 to obtain the desired product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.14 (3H, s), 1.42 (9H,
s), 1.55-1.74 (3H, m), 1.75-1.85 (1H, m), 2.65 (2H, t, J = 6.7 Hz), 3.58-3.64
(2H, m), 4.03 (1H, br s), 4.55 (1H, br s), 7.04 (1H, dd, J = 9.8 Hz, 1.8 Hz),
7.10 (1H, dd, J = 7.9 Hz, 1.8 Hz), 7.17 (1H, t, J = 7.9 Hz), 7.38-7.50 (3H, m),
7.54 (1H, br s).

<Example 17>
(R) -2-t-butoxycarbonylamino-5- [2-chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-propylpentan-1-ol

The compound of Example 10 was reacted in the same manner as in Example 11 to obtain the target product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 0.92 (3H, t, J = 7.3
Hz), 1.42 (9H, s), 1.14-1.80 (8H, m), 2.72 (2H, t, J = 7.3 Hz), 3.62 (1H, d, J
= 12 Hz), 3.66 (1H, d, J = 12 Hz), 4.54 (1H, br s), 7.16-7.22 (2H, m), 7.39
(1H, s), 7.40-7.48 (3H, m), 7.55 (1H, br s).
FABMS (+): 532 [M + H] ⁺ .

<Example 18>
(R) -2-Amino-5- [2-chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-methylpentan-1-ol hydrochloride

A 10 w / w% hydrochloric acid methanol solution (40 mL) was added to the compound of Example 11 (4.07 g), stirred at room temperature for 1 hour, and then allowed to stand at room temperature overnight. Concentration gave the target product (3.51 g) as a white powder.
¹ H-NMR
(DMSO-d ₆ , 400 MHz): δ1.09 (3H, s), 1.49-1.63
(4H, m), 2.65-2.71 (2H, br s), 3.34 (1H, d, J = 12 Hz), 3.38 (1H, d, J = 12
Hz), 7.34 (1H, dd, J = 7.9 Hz, 2.4 Hz), 7.41 (1H, d, J = 7.9 Hz), 7.49 (1H, d,
J = 2.4 Hz), 7.55 (1H, d, J = 7.9 Hz), 7.61 (1H, d, J = 2.4 Hz), 7.67 (1H, d, J
= 7.9 Hz), 7.53-7.74 (3H, br s).
ESIMS (+): 404 [M + H] ⁺ .
Elemental analysis: found C 51.65%, H 4.86%, N 2.86%, C ₁₉ H ₂ ClF ₃ NOS.
Calculated as HCl C 51.82%, H 5.04%, N 3.18%.
Optical rotation: [α] _D ²³ −3.45 (c 1.00,
CHCl ₃ ).

<Example 19>
(R) -2-Amino-4- [2-chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-methylbutan-1-ol hydrochloride

The compound of Example 12 was reacted in the same manner as in Example 18 to obtain the target product as a white powder.
¹ H-NMR
(DMSO-d ₆ , 400 MHz): δ1.22 (3H, s), 1.66-1.83
(2H, m), 2.72 (2H, t, J = 8.6 Hz), 3.42 (1H, dd, J = 11.0, 7.9 Hz), 3.49 (1H,
dd, J = 11.0, 7.9 Hz), 5.54 (1H, t, J = 4.9 Hz), 7.36 (1H, dd, J = 7.9, 1.8
Hz), 7.42 (1H, d, J = 7.9 Hz), 7.50 (1H, d, J = 1.8 Hz), 7.53-7.64 (3H, m),
7.67 (1H, d, J = 7.9 Hz), 7.82 (3H, br s).
FABMS (+): 390 [M + H] ⁺ .
Elemental analysis: measured value C 50.47%,
H 4.65%, N 3.36%, C ₁₈ H ₁₉ ClF ₃ NOS.Calculated as HCl C 50.71%, H 4.73%, N 3.29%.
Optical rotation: [α] _D ²⁷ +5.78 (c 0.33, CHCl ₃ ).

<Example 20>
(R) -2-Amino-4- [2-chloro-4- (3-ethylphenylthio) phenyl] -2-methylbutan-1-ol hydrochloride

The compound of Example 13 was reacted in the same manner as in Example 18 to obtain the target product as a white powder.
¹ H-NMR
(DMSO-d ₆ , 400 MHz): δ1.14 (3H, t, J = 7.3
Hz), 1.22 (3H, s), 1.67-1.81 (2H, m), 2.59 (2H, q, J = 7.3 Hz), 2.69 (2H, t, J =
8.6 Hz), 3.42 (1H, dd, J = 11.6, 5.5 Hz), 3.48 (1H, dd, J = 11.6, 5.5 Hz), 5.52
(1H, t, J = 4.9 Hz), 7.16-7.22 (2H, m), 7.26-7.27 (2H, m), 7.30-7.35 (2H, m),
7.93 (3H, br s).
ESIMS (+): 350 [M + H] ⁺ .
Elemental analysis: measured value C 58.90%,
Calculated as H 6.42%, N 3.59%, C ₁₉ H ₂₄ ClNOS.HCl C 59.06%, H 6.52%, N 3.63%.

<Example 21>
(R) -2-Amino-5- [2-chloro-4- (3-ethylphenylthio) phenyl] -2-methylpentan-1-ol hydrochloride

The compound of Example 14 was reacted in the same manner as in Example 18 to obtain the target product as a colorless oil.
¹ H-NMR
(DMSO-d ₆ , 400 MHz): δ1.10 (3H, s), 1.15 (3H,
t, J = 7.3 Hz), 1.52-1.58 (4H, m), 2.59 (2H, q, J = 7.3Hz), 2.62-2.66 (2H, m),
3.32-3.39 (2H, m), 5.43 (1H, br), 7.15-7.22 (3H, m), 7.26 (2H, d, J = 1.8Hz),
7.32 (2H, dd, J = 7.3, 1.8Hz), 7.81 (3H, br s).
HRESIMS (+): 364.15051 (calculated as C ₂₀ H ₂₇ ClNOS
364.15019).

<Example 22>
(R) -2-Amino-5- [2-chloro-4- (3-chlorophenylthio) phenyl] -2-methylpentan-1-ol hydrochloride

The compound of Example 15 was reacted in the same manner as in Example 18 to obtain the target product as a colorless amorphous.
¹ H-NMR
(DMSO-d ₆ , 400 MHz): δ1.10 (3H, s), 1.49-1.64
(4H, m), 2.68 (2H, br s), 3.33 (1H, dd, J = 12, 4.9 Hz), 3.38 (1H, dd, J = 12,
4.9 Hz), 5.45 (1H, t, J = 4.9 Hz), 7.26 (1H, dt, J = 7.3, 1.8 Hz), 7.30-7.43
(5H, m), 7.45 (1H, d, J = 1.8 Hz), 7.77 (3H, br s).
HREIMS
(+): 370.0 799 (calculated as C ₁₈ H ₂₁ Cl ₂ NOS 370.0799).
Optical rotation: [α] _D ²⁷ &#8211; 3.81 (c 0.50, CHCl ₃ ).

<Example 23>
(R) -2-Amino-5- [2-fluoro-4- (3-trifluoromethylphenylthio) phenyl] -2-methylpentan-1-ol hydrochloride

The compound of Example 16 was reacted in the same manner as in Example 18 to obtain the target product as a colorless amorphous.
¹ H-NMR
(DMSO-d ₆ , 400 MHz): δ1.09 (3H, s), 1.48-1.61
(4H, m), 2.57-2.64 (2H, br s), 3.32 (1H, dd, J = 11, 4.9 Hz), 3.37 (1H, dd, J =
11, 4.9 Hz), 5.44 (1H, t, J = 4.9 Hz), 7.20 (1H, dd, J = 7.9, 1.8 Hz), 7.26
(1H, dd, J = 9.8, 1.8 Hz), 7.37 (1H, t, J = 7.9 Hz), 7.54-7.68 (4H, m), 7.74
(3H, br s).
HRESIMS
(+): 388.1345 (Calculated value as C ₁₉ H ₂₂ F ₄ NOS 388.1358).
Optical rotation: [α] _D ²⁴ -3.23 (c 0.69, CHCl ₃ ).

<Example 24>
(R) -2-Amino-5- [2-chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-propylpentan-1-ol hydrochloride

The compound of Example 17 was reacted in the same manner as in Example 18 to obtain the target product as a white powder.
¹ H-NMR
(DMSO-d ₆ , 400 MHz): δ0.84 (3H, t, J = 7.3
Hz), 1.20 (2H, q, J = 7.3 Hz), 1.36-1.63 (6H, m), 2.68 (2H, t, J = 7.3 Hz),
3.36 (2H, d, J = 4.9 Hz), 5.40 (1H, d, J = 4.9 Hz), 7.35 (1H, dd, J = 7.9 Hz,
1.8 Hz), 7.42 (1H, d, J = 7.9 Hz), 7.50 (1H, d, J = 1.8 Hz), 7.55 (1H, d, J =
7.9 Hz), 7.58-7.63 (2H, m), 7.67 (1H, d, J = 7.9 Hz), 7.69 (3H, br s).
FABMS (+): 432 [M + H] ⁺ .
Elemental analysis: measured value C 53.46%,
H 5.62%, N 2.98%, C ₂₁ H ₂₅ ClF ₃ NOS.Calculated as HCl C 53.85%, H 5.59%, N 2.99%.
Optical rotation: [α] _D ²³ +3.85 (c 0.63, CHCl ₃ ).

<Example 25>
(R) -2-Amino-5- [2-chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-methylpentan-1-ol

Example 18 (9.3 g) of ethyl acetate (450 g)
To the solution, a saturated aqueous sodium hydrogen carbonate solution (450 mL) was added and stirred at room temperature for 10 minutes. The organic layer was washed with water and saturated brine in that order and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by NH-silica gel column chromatography (ethyl acetate: methanol = 4: 1) to obtain the desired product (8.9 g) as a white powder.
¹ H-NMR
(DMSO-d ₆ , 400 MHz): δ0.85 (3H, s), 1.21 (2H,
br s), 1.28 (2H, t, J = 8.6 Hz), 1.46-1.67 (2H, m), 2.65 (2H, t, J = 8.6 Hz),
3.06 (2H, br s), 4.49 (1H, br s), 7.32 (1H, dd, J = 7.9, 1.8 Hz), 7.40 (1H, d,
J = 9.8 Hz), 7.47 (1H, d, J = 1.8 Hz), 7.54 (1H, dd, J = 6.7, 1.8 Hz),
7.56-7.62 (2H, m), 7.65 (1H, dd, J = 6.7, 1.8 Hz).
ESIMS
(+): 404 [M + H] ⁺ .
Elemental analysis: measured value C 56.26%,
Calculated as H 5.14%, N 3.40%, C ₁₉ H ₂₁ ClF ₃ NOS C 56.50%, H 5.24%, N 3.47%.

<Example 26>
2- {3- [2-Chloro-4- (3-trifluoromethylphenylthio) phenyl] propyl} -2-methylmalonate diethyl

2-chloro-1- (3-iodopropyl) -4- (3-trifluoromethylphenylthio) benzene and diethyl 2-methylmalonate are reacted in the same manner as in Example 152 of WO04026817 to give the desired product. Obtained as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.25 (6H, t, J = 7.4 Hz),
1.40 (3H, s), 1.51-1.63 (2H, m), 1.90-1.97 (2H, m), 2.73 (2H, t, J = 7.9 Hz),
4.17 (4H, q, J = 7.4 Hz), 7.17-7.23 (2H, m), 7.38 (1H, d, J = 2.2 Hz),
7.39-7.44 (2H, m), 7.45-7.50 (1H, m), 7.55 (1H, s).
EIMS (+): 502 [M] ⁺ .

<Example 27>
(±) -5- [2-Chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-ethoxycarbonyl-2-methylpentanoic acid

To a solution of the compound of Example 26 (16.8 g) in ethanol (167 mL) was added potassium hydroxide (2.40 g), and the mixture was stirred at 50 ° C. for 24 hours. Water was added to the reaction solution, neutralized with 2 mol / L hydrochloric acid aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order 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 the desired product (11.2 g) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.26 (3H, t, J = 7.4 Hz),
1.47 (3H, s), 1.55-1.66 (2H, m), 1.87-2.06 (2H, m), 2.73 (2H, t, J = 7.9 Hz),
4.22 (2H, q, J = 7.4 Hz), 7.18 (1H, d, J = 7.9 Hz), 7.20 (1H, dd, J = 7.9, 1.8
Hz), 7.38 (1H, d, J = 1.8 Hz), 7.39-7.44 (2H, m), 7.45-7.50 (1H, m), 7.54 (1H,
s).
ESIMS (+): 475 [M + H] ⁺ .

<Example 28>
(±) -5- [2-Chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-methoxycarbonylamino-2-methylpentanoic acid ethyl ester

Compound of Example 27 (15.8 g) of benzene (166
Diphenylphosphoryl azide (7.86 mL) and triethylamine (6.01 mL) were added to the solution, and the mixture was heated to reflux for 1.5 hours. The reaction solution was returned to room temperature, methanol (20 mL) was added dropwise over 20 minutes, and the mixture was heated under reflux for 30 minutes. To the reaction solution was added saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order 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 (15.6 g) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.25 (3H, t, J = 7.3 Hz),
1.32-1.47 (1H, m), 1.52-1.67 (1H, m), 1.57 (3H, s), 1.80-1.90 (1H, m),
2.20-2.37 (1H, m), 2.62-2.76 (2H, m), 3.64 (3H, s), 4.15-4.25 (2H, m), 5.62
(1H, br s), 7.16 (1H, d, J = 7.9 Hz), 7.20 (1H, dd, J = 7.9, 1.8 Hz), 7.38 (1H,
d, J = 1.8 Hz), 7.40-7.44 (2H, m), 7.45-7.50 (1H, m), 7.55 (1H, s).
ESIMS (+): 504 [M + H] ⁺ .

<Example 29>
(±) -5- [2-Chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-methoxycarbonylamino-2-methylpentan-1-ol

To a solution of the compound of Example 28 (15.6 g) in THF (249 mL) was added lithium borohydride (3.75 g) under ice cooling, then ethanol (16.6 mL) was added dropwise, and the mixture was cooled under ice cooling for 1 hour. Stir. To the reaction solution was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate, washed with water and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product (12.9 g) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.18 (3H, s), 1.54-1.74
(3H, m), 1.78-1.89 (1H, m), 2.73 (2H, t, J = 7.9 Hz), 3.63 (3H, s), 3.56-3.70
(2H, m), 4.23 (1H, br s), 7.17-7.22 (2H, m), 7.38-7.50 (4H, m), 7.54 (1H, s).
ESIMS (+): 462 [M + H] ⁺ .

<Example 30>
(±) -2-t-Butoxycarbonylamino-5- [2-chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-methylpentan-1-ol

Example 29 (12.9 g) of THF (60
mL) and methanol (120 mL)
A mol / L potassium hydroxide aqueous solution (60 mL) was added, and the mixture was heated to reflux for 86 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. After concentration of the extract, the residue was dissolved in 1,4-dioxane (279 mL), and di-tert-butoxydicarbonate (9.13 g) was added. The mixture was stirred at room temperature for 2 hours and left at room temperature 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, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (13.0 g) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.14 (3H, s), 1.42 (9H,
s), 1.53-1.74 (3H, m), 1.79-1.92 (1H, m), 2.74 (2H, t, J = 7.9 Hz), 3.58-3.69
(2H, m), 4.05 (1H, br s), 4.57 (1H, br s), 7.20-7.22 (2H, m), 7.38-7.50 (4H,
m), 7.54 (1H, s).
ESIMS (+): 504 [M + H] ⁺ .

<Examples 31 and 32>
(+)-2-t-butoxycarbonylamino-5- [2-chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-methylpentan-1-ol and (-)-2-t- Butoxycarbonylamino-5- [2-chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-methylpentan-1-ol The compound of Example 30 was subjected to high performance liquid chromatography (CHIRALCEL OJ-H, hexane : Isopropanol: diethylamine = 98: 2: 0.1 (v / v), measurement wavelength: UV 278 nm, flow rate: 1.0 mL / min), and [α] _D ²⁵ +15.08 (c 0.63,
Colorless oil CHCl ₃₎ (Example 31), from the rear eluting portion ^{_{[α] D 26 -13.91 (c}} 0.63, give a colorless oil CHCl ₃₎ (Example 32).

<Example 33>
(−)-2-Amino-5- [2-chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-methylpentan-1-ol hydrochloride The compound of Example 31 is the same as Example 18. The desired product was obtained as a white powder.
ESIMS (+): 404 [M + H] ⁺ .
Optical rotation: [α] _D ²⁵ −4.48 (c 1.00, CHCl ₃ ).

<Example 34>
(±) -5- [2-Chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-ethoxycarbonylamino-2-methylpentanoic acid ethyl ester

In the experiment of Example 28, ethanol was used in place of methanol to obtain the target product as a colorless oil.
¹ H-NMR
(DMSO-d ₆ , 400 MHz): δ1.12 (6H, t, J = 6.8Hz),
1.30 (3H, s), 1.47-1.55 (2H, m), 1.65-1.72 (1H, m), 1.78-1.86 1H, m), 2.66 (2H,
t, J = 7.3Hz), 3.94 (2H, q, J = 6.8Hz), 4.03 (2H, q, J = 6.8Hz), 7.33-7.68 (8H,
m).

<Example 35>
(+)-5- [2-Chloro-4- (3-trifluoromethylphenylthio) phenyl] -2-ethoxycarbonylamino-2-methylpentanoic acid ethyl ester

The compound of Example 34 was optically resolved by high performance liquid chromatography (CHIRALCEL OD, hexane: isopropanol = 90: 10 (v / v)), and [α] _D ²⁵
A colorless oil of +4.1 (c 1, MeCN) was obtained.

<Examples 36 and 37>
Ethyl 5- [2-chloro-4- (3-trifluoromethylphenylsulfinyl) phenyl] -2-ethoxycarbonylamino-2-methylpentanoate and

  Ethyl 5- [2-chloro-4- (3-trifluoromethylphenylsulfonyl) phenyl] -2-ethoxycarbonylamino-2-methylpentanoate

Under ice-cooling, the compound of Example 35 (4.00
g) in methylene chloride (60 mL) was added to m-chloroperbenzoic acid (65% equivalent,
A solution of 3.07 g) in methylene chloride (17 mL) was added and stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract layer was washed three times with a saturated aqueous sodium hydrogen carbonate solution, then washed with water and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain sulfinyl compound Example 36 (1.87 g) and sulfonyl compound Example 37 (2.69 g), respectively. Obtained.

Example 36
Colorless oil
¹ H NMR
(CDCl ₃ , 400 MHz): δ 1.29 (6H, t, J = 7.3
Hz), 1.38 (1H, br s), 1.53 (3H, s), 1.54-1.66 (1H, m), 1.83 (1H, td, J = 12.8,
4.3 Hz), 2.28 (1H, br s), 2.65-2.78 (2H, m), 4.06 (2H, q, J = 7.3 Hz), 4.17
(2H, q, J = 7.3 Hz), 5.56 (1H, br s), 7.31 (1H, d, J = 7.9 Hz), 7.45 (1H, dd, J
= 7.9, 1.8 Hz), 7.63 (1H, t, J = 7.9 Hz), 7.64 (1H, d, J = 1.8 Hz), 7.73 (1H,
d, J = 7.9 Hz), 7.81 (1H, d, J = 7.9 Hz), 7.95 (1H, s).
ESIMS (+): 534 [M + H] ⁺ .

Example 37
Colorless oil
¹ H NMR
(CDCl ₃ , 400 MHz): δ 1.29 (6H, t, J = 7.3
Hz), 1.30-1.44 (1H, m), 1.54 (3H, s), 1.55-1.66 (1H, m), 1.85 (1H, ddd, J =
13.4, 12.2, 4.3 Hz), 2.30 (1H, br s), 2.68-2.82 (2H, m), 4.06 (2H, q, J = 7.3
Hz), 4.18 (2H, q, J = 7.3 Hz), 5.56 (1H, br s), 7.36 (1H, d, J = 7.9 Hz), 7.67
(1H, t, J = 7.9 Hz), 7.76 (1H, dd, J = 7.9, 1.8 Hz), 7.85 (1H, d, J = 7.9 Hz), 7.92
(1H, d, J = 1.8 Hz), 8.12 (1H, d, J = 7.9 Hz), 8.20 (1H, s).
ESIMS (+): 550 [M + H] ⁺ .

<Example 38>
5- [2-Chloro-4- (3-trifluoromethylphenylsulfinyl) phenyl] -2-ethoxycarbonylamino-2-methylpentan-1-ol

The target product was obtained as a colorless oil by reacting in the same manner as in Example 29 using the compound of Example 36.
¹ H NMR
(CDCl ₃ , 400 MHz): δ1.15 (3H, s), 1.22 (3H,
t, J = 7.3 Hz), 1.53-1.73 (3H, m), 1.76-1.89 (1H, m), 2.75 (2H, t, J = 7.3 Hz),
3.63 (2H, t, J = 12.2 Hz), 4.06 (2H, q, J = 7.3 Hz), 4.69 (1H, br s), 7.35 (1H,
d, J = 7.9 Hz), 7.46 (1H, dd, J = 7.9, 1.8 Hz), 7.63 (1H, t, J = 7.9 Hz), 7.65
(1H, d, J = 1.8 Hz), 7.73 (1H, d, J = 7.9 Hz), 7.81 (1H, d, J = 7.9 Hz), 7.94
(1H, s).
ESIMS (+): 492 [M + H] ⁺ .

<Example 39>
5- [2-Chloro-4- (3-trifluoromethylphenylsulfonyl) phenyl] -2-ethoxycarbonylamino-2-methylpentan-1-ol

The target product was obtained as a colorless oil by reacting in the same manner as in Example 29 using the compound of Example 37.
¹ H NMR
(CDCl ₃ , 400 MHz): δ 1.15 (3H, s), 1.22 (3H,
t, J = 7.3 Hz), 1.55-1.72 (3H, m), 1.80-1.87 (1H, m), 2.78 (2H, t, J = 7.6 Hz),
3.64 (2H, s), 4.05 (2H, q, J = 7.3 Hz), 4.69 (1H, br s), 7.40 (1H, d, J = 7.9
Hz), 7.69 (1H, t, J = 7.9 Hz), 7.76 (1H, dd, J = 7.9, 1.8 Hz), 7.85 (1H, d, J =
7.9 Hz), 7.93 (1H, d, J = 1.8 Hz), 8.13 (1H, d, J = 7.9 Hz), 8.21 (1H, s).
ESIMS (+): 508 [M + H] ⁺ .

<Example 40>
2-Amino-5- [2-chloro-4- (3-trifluoromethylphenylsulfinyl) phenyl] -2-methylpentan-1-ol

Compound of Example 38
(1.71 g) in a tetrahydrofuran (7 mL) / methanol (14 mL) mixed solution
A mol / L aqueous potassium hydroxide solution (7 mL) was added, and the mixture was heated to reflux for 25 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by NH type silica gel column chromatography (ethyl acetate alone followed by ethyl acetate: methanol = 1: 9) to obtain the desired product.
(1.08 g) was obtained as a colorless oil. .
¹ H NMR
(CDCl ₃ , 400 MHz): δ1.03 (3H, s), 1.36-1.67
(4H, m), 2.74 (2H, t, J = 7.9 Hz), 3.25 (1H, d, J = 10.4 Hz), 3.31 (1H, d, J =
10.4 Hz), 7.35 (1H, d, J = 7.9 Hz), 7.46 (1H, dd, J = 7.9, 1.8 Hz), 7.63 (1H,
t, J = 7.9 Hz), 7.65 (1H, d, J = 1.8 Hz), 7.73 (1H, d, J = 7.9 Hz), 7.82 (1H,
d, J = 7.9 Hz), 7.94 (1H, s).
ESIMS (+): 420 [M + H] ⁺ .

<Example 41>
2-Amino-5- [2-chloro-4- (3-trifluoromethylphenylsulfonyl) phenyl] -2-methylpentan-1-ol

The compound of Example 39 was reacted in the same manner as in Example 40 to obtain the target product as a white amorphous.
¹ H NMR
(CDCl ₃ , 400 MHz): δ 1.03 (3H, s), 1.35-1.54
(2H, m), 1.57-1.70 (2H, m), 2.77 (2H, t, J = 7.9 Hz), 3.26 (1H, d, J = 10.4
Hz), 3.31 (1H, d, J = 10.4 Hz), 7.40 (1H, d, J = 7.9 Hz), 7.69 (1H, t, J = 7.9
Hz), 7.77 (1H, dd, J = 7.9, 1.8 Hz), 7.85 (1H, d, J = 7.9 Hz), 7.93 (1H, d, J =
1.8 Hz), 8.13 (1H, d, J = 7.9 Hz), 8.21 (1H, s).
ESIMS (+): 436 [M + H] ⁺ .

<Example 42>
(+)-2-Amino-5- [2-chloro-4- (3-trifluoromethylphenylsulfinyl) phenyl] -2-methylpentan-1-ol hydrochloride

The compound of Example 40 (550 mg) was dissolved in a 10% hydrochloric acid methanol solution (13 mL) and stirred at room temperature for 30 minutes. The reaction solution was evaporated under reduced pressure, diisopropyl ether was added and the crystals were collected by filtration. The obtained powder was dried under reduced pressure to obtain the desired product (322 mg) as a white powder.
Optical rotation: [α] _D ²⁶ +2.40 (c
0.50, CH ₃ OH).
¹ H NMR
(DMSO-d ₆ , 400 MHz): δ1.09 (3H, s), 1.49-1.63
(4H, m), 267 (2H, br s), 3.32 (1H, d, J = 11.0 Hz), 3.36 (1H, d, J = 11.0 Hz),
7.54 (1H, d, J = 7.9 Hz), 7.72 (1H, dd, J = 7.9, 1.8 Hz), 7.79 (1H, t, J = 7.9
Hz), 7.82 (3H, br s), 7.87 (1H, d, J = 1.8 Hz), 7.90 (1H, d, J = 7.9 Hz), 8.08
(1H, d, J = 7.9 Hz), 8.15 (1H, s).
HRESIMS (+) 420.10304 (Calculated as C ₁₉ H ₂₁ ClF ₃ NO ₂ S
420.10119).
Elemental analysis: measured C 49.82%, H 5.16%, N 2.94%, calculated as C ₁₉ H ₂₁ ClF ₃ NO ₂ S.HCl C 50.01%, H 4.86%, N 3.07%.

<Example 43>
(+)-2-Amino-5- [2-chloro-4- (3-trifluoromethylphenylsulfonyl) phenyl] -2-methylpentan-1-ol hydrochloride

The target product was obtained as a white powder by reacting in the same manner as in Example 42 using the compound of Example 41.
Optical rotation: [α] _D ²⁶ +3.75 (c
1.00, CH ₃ OH).
¹ H NMR
(CDCl ₃ , 400 MHz): δ 1.08 (3H, s), 1.45-1.64
(4H, m), 2.73 (2H, t, J = 7.3 Hz), 3.34 (1H, d, J = 4.9 Hz), 3.37 (1H, d, J =
4.9 Hz), 5.43 (1H, t, J = 4.9 Hz), 7.63 (1H, d, J = 7.9 Hz), 7.89 (3H, br s),
7.89 (1H, t, J = 7.9 Hz), 7.99 (1H, dd, J = 7.9, 1.8 Hz), 8.12 (1H, d, J = 7.9
Hz), 8.14 (1H, d, J = 1.8 Hz), 8.35 (1H, d, J = 7.9 Hz), 8.36 (1H, s).
HRESIMS (+) 436.09753 (calculated as C ₁₉ H ₂₁ ClF ₃ NO ₃ S
436.09610).
Elemental analysis: actual measurement C 47.49%, H 4.93%, N 2.93%, C ₁₉ H ₂₁ ClF ₃ NO ₃ S.
HCl. Calculated as 1 / 2H ₂ O C 47.41%, H 4.82%, N
2.91%.

<Example 44>
2-t-Butoxycarbonylamino-5- [2-chloro-4- (3-trifluoromethylphenylsulfonyl) phenyl] -2-methylpentan-1-ol

Compound of Example 41
Di-tert-butyl dicarbonate (500 mg) was added to a solution of (666 mg) in 1,4-dioxane (60 mL), stirred at room temperature for 2 hours, and allowed to stand overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (765 mg) as a colorless oil.
¹ H NMR
(CDCl ₃ , 400 MHz): δ 1.11 (3H, s), 1.41 (9H,
s), 1.57-1.73 (3H, m), 1.81-1.92 (1H, m), 2.79 (2H, t, J = 7.9 Hz), 3.60 (2H,
d, J = 6.1 Hz), 3.98 (1H, br s), 4.55 (1H, s), 7.40 (1H, d, J = 7.9 Hz), 7.69
(1H, t, J = 7.9 Hz), 7.76 (1H, dd, J = 7.9, 1.8 Hz), 7.85 (1H, d, J = 7.9 Hz),
7.93 (1H, d, J = 1.8 Hz), 8.13 (1H, d, J = 7.9 Hz), 8.21 (1H, s).
ESIMS (+): 536 [M + H] ⁺ .

<Example 45>
2-t-Butoxycarbonylamino-5- [2-chloro-4- (3-trifluoromethylphenylsulfinyl) phenyl] -2-methylpentan-1-ol

The target product was obtained as a colorless oil by reacting in the same manner as in Example 44 using the compound of Example 40.
¹ H NMR
(CDCl ₃ , 400 MHz): δ1.13 (3H, s), 1.42 (4.5
H, s, diastereomer), 1.43 (4.5 H, s, diastereomer), 1.59-1.73 (3H, m),
1.82-1.92 (1H, m), 2.77 (2H, t, J = 7.3 Hz), 3.62 (2H, d, J = 6.1 Hz), 4.04
(1H, br s), 4.57 (1H, s), 7.36 (1H, d, J = 7.9 Hz), 7.47 (1H, dd, J = 7.9, 1.8
Hz), 7.64 (1H, t, J = 7.9 Hz), 7.66 (1H, d, J = 1.8 Hz), 7.74 (1H, d, J = 7.9
Hz), 7.82 (1H, d, J = 7.9 Hz), 7.96 (1H, s).
ESIMS (+): 520 [M + H] ⁺ .

<Example 46>
2-tert-Butoxycarbonylamino-5- [2-chloro-4- (3-trifluoromethylphenylsulfonyl) phenyl] -1-dimethoxyphosphoryloxy-2-methylpentane

Carbon tetrabromide (948 mg) and trimethyl phosphite (0.337 mL) were added to a solution of the compound of Example 44 (765 mg) in pyridine (3.2 mL) under ice cooling, and the mixture was stirred for 1 hour under ice cooling. did. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain the desired product (720 mg) as a colorless oil.
¹ H NMR
(CDCl ₃ , 400 MHz): δ 1.23 (3H, s), 1.40 (9H,
s), 1.58-1.67 (3H, m), 1.84-1.99 (1H, m), 2.77 (2H, t, J = 7.3 Hz), 3.76 (3H,
d, J = 11.0 Hz), 3.77 (3H, d, J = 11.0 Hz), 3.95 (1H, dd, J = 9.8, 5.5 Hz),
4.13 (1H, dd, J = 9.8, 5.5 Hz), 4.51 (1H, s), 7.39 (1H, d, J = 7.9 Hz), 7.69
(1H, t, J = 7.9 Hz), 7.76 (1H, dd, J = 7.9, 1.8 Hz), 7.85 (1H, d, J = 7.9 Hz),
7.93 (1H, d, J = 1.8 Hz), 8.13 (1H, d, J = 7.9 Hz), 8.21 (1H, s).
ESIMS (+): 644 [M + H] ⁺ .

<Example 47>
2-Amino-5- [2-chloro-4- (3-trifluoromethylphenylsulfonyl) phenyl] -2-methylpentylphosphonic acid monoester

Trimethylsilane iodide (0.61 mL) was added dropwise to a solution of the compound of Example 46 (720 mg) in acetonitrile (11 mL) under an argon atmosphere under ice cooling, and the mixture was stirred under ice cooling for 1 hour. Water (100 mL) was added, and the mixture was further stirred for 30 minutes under ice cooling, and then the reaction mixture was concentrated. The residue was subjected to reverse phase silica gel column chromatography (water
: Acetonitrile = 9: 1 → 6: 1: 1 → 3: 1 → 1: 1) to obtain the desired product (220 mg) as a white powder.
Optical rotation: [α] _D ²¹ +5.24 (c
0.50, DMSO-1% TFA).
¹ H NMR
(DMSO-d ₆ -dTFA, 400 MHz): δ 1.14 (3H, s),
1.52-1.70 (4H, m), 2.74 (2H, t, J = 6.7 Hz), 3.75 (1H, dd, J = 11.0, 5.5 Hz),
3.81 (1H, dd, J = 11.0, 5.5 Hz), 7.61 (1H, d, J = 7.9 Hz), 7.87 (1H, t, J = 7.9
Hz), 7.98 (1H, dd, J = 7.9, 1.8 Hz), 8.09 (1H, d, J = 7.9 Hz), 8.13 (1H, d, J =
1.8 Hz), 8.32 (1H, s), 8.33 (1H, d, J = 7.9 Hz).
HRESIMS (-) 514.04669 (Calculated as C ₁₉ H ₂₁ ClF ₃ NO ₆ PS
514.04678).
Elemental analysis: actual measurement C 44.24%, H 4.30%, N 2.72%, C ₁₉ H ₂₂ ClF ₃ NO ₆ PS.
Calculated as 5 / 4H ₂ O C 42.39%, H 4.59%, N 2.60%.

<Example 48>
2-Amino-5- [2-chloro-4- (3-trifluoromethylphenylsulfinyl) phenyl] -2-methylpentylphosphonic acid monoester

To a solution of the compound of Example 45 (411 mg) and di-tert-butylphosphonate (3.07 g) in carbon tetrachloride (8 mL) under an argon atmosphere, tetraethylammonium iodide (509 mg) and 50% aqueous sodium hydroxide solution ( 4 mL) was added and stirred at room temperature for 27 hours. The reaction mixture was diluted with methylene chloride, washed with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give a pale yellow oil. This was dissolved in 10% hydrochloric acid-methanol (30 mL), allowed to stand at room temperature for 3 days, and then the solvent was distilled off under reduced pressure. Water was added to the residue, and the precipitated crystals (A) were collected by filtration and separated from the filtrate (A ′). Crystal A was suspended in ethyl acetate and washed well, followed by filtration to obtain a white solid (B) and a filtrate (B ′). Further, the filtrates A ′ and B ′ were combined and concentrated under reduced pressure, water was added to the resulting residue, and the precipitated crystals were collected by filtration to obtain a white solid (C). C and B were combined and purified by reverse layer TLC (RP-18, acetonitrile: water = 1: 1) to give a white solid. Dissolve this in methanol, remove the insoluble material with a disk filter for HPLC pretreatment (0.45 μm), concentrate under reduced pressure, and finally crystallize with a small amount of methanol and ethyl acetate. Product (130 mg) was obtained as a white solid.
Optical rotation: [α] _D ²² +10.7 (c
0.533, DMSO-1% TFA).
¹ H NMR
(DMSO-d ₆ -dTFA, 400 MHz): δ 1.14 (3H, s),
1.53-1.68 (4H, m), 2.68 (2H, t, J = 6.9 Hz), 3.74-3.83 (2H, m), 7.53 (2H, d, J
= 8.3 Hz), 7.72 (1H, dd, J = 8.3, 1.8 Hz), 7.78 (1H, t, J = 7.9 Hz), 7.87-7.90
(2H, m), 8.07 (1H, d, J = 7.9 Hz), 8.14 (1H, s).
HRESIMS (+) 500.06706 (Calculated as C ₁₉ H ₂₃ ClF ₃ NO ₅ PS
500.06752).
Elemental analysis: actual measurement C 44.38%, H 4.64%, N 2.72%, C ₁₉ H ₂₂ ClF ₃ NO ₅ PS.
Calculated as H ₂ O C 44.06%, H 4.67%, N 2.70%.

Claims (9)

General formula (1)

[Wherein R ¹ represents a linear alkyl group having 1 to 3 carbon atoms which may be substituted with a chlorine atom or a halogen atom, R ² represents a fluorine atom or a chlorine atom, and R ³ represents a carbon atom having 1 to ³ carbon atoms. A linear alkyl group, X represents SO or SO ₂ , and n represents 2 or 3]
Or a pharmacologically acceptable salt or hydrate thereof. The compound represented by the general formula (1) is represented by the general formula (1a).

[Wherein R ³ , X and n are the same as defined above]
The aminoalcohol derivative according to claim 1, which is represented by the formula: a pharmacologically acceptable salt thereof or a hydrate thereof. The amino alcohol derivative according to claim 1 or 2, a pharmacologically acceptable salt thereof or a hydrate thereof, wherein R ³ in the general formula (1) or (1a) is a methyl group. The compound represented by the general formula (1) is
1) (R) -2-amino-5- [2-chloro-4- (3-trifluoromethylphenylsulfinyl) phenyl] -2-methylpentan-1-ol,
2) The amino alcohol derivative according to claim 1, which is (R) -2-amino-5- [2-chloro-4- (3-trifluoromethylphenylsulfonyl) phenyl] -2-methylpentan-1-ol, A pharmacologically acceptable salt or hydrate thereof. General formula (2)

[Wherein, R ¹ represents a linear alkyl group having 1 to 3 carbon atoms which may be substituted with a chlorine atom or a halogen atom, R ² represents a fluorine atom or a chlorine atom, A represents a halogen atom, and X represents SO Or SO ₂ , n represents 2 or 3]
And a compound represented by the general formula (10)

[Wherein R ³ represents a linear alkyl group having 1 to ³ carbon atoms, and R ⁴ represents an alkyl group having 1 to 6 carbon atoms]
A step of reacting a compound represented by formula (I) in the presence of a base, and acid-decomposing the product in the step, and further protecting and reducing the nitrogen atom with a t-butoxycarbonyl group to deprotect the nitrogen atom. The amino alcohol derivative according to claim 1, which is produced by a process, a pharmacologically acceptable salt thereof or a hydrate thereof. The pharmaceutical which contains the amino alcohol derivative in any one of Claims 1-5, its pharmacologically acceptable salt, or its hydrate as an active ingredient. The medicament according to claim 6, which is an immunosuppressant. The medicament according to claim 6, which is a preventive or therapeutic agent for rejection in organ transplantation or bone marrow transplantation. The phosphate ester of the amino alcohol derivative in any one of Claims 1-5, its pharmacologically acceptable salt, or its hydrate.