SPECIFICATION
Title of the Invontion: Optically Active Dibenzylamine Derivative), and Method for Preparing Thereof
Technical Field [0001]
The proflonfc Invention relates to an optically active dibonzylumino derivative useful as an aotlve ingredient of medicament or the like, and a motliod for preparing the same. Background Art [0002]
In recont yours, patients suffering from dyslipidomla (liyporlipidemia) and arteriosclerotic diseases induced thereby have been rapidly incrouNod due to changes in dietary habits to take high calorie and high cholesterol-typo foods with improvement of a living standard, obesity, lack of exercise, aging, and the like. It luis been revealed from many etiological researches including the Framingham study that a low-density lipoprotein (LDIJ) cholesterol level positively correlates to an onset rate of heart diseases. Therofore, in drug therapies for dyslipidemia and arteriouolerosis, reduction of a LDL cholesterol value has been importantly focused (Non-patent document l). [0003]
For hyper-LDL cholesterolemia, which is one of potent risk factors of cardiovascular diseases, therapeutic methods have been markedly progressed by the launch of HMG-CoA reductase inhibitors (statins). However, although statins potently reduce LDL cholesterol, decrease in cardiac accidents and mortality of cardiovascular diseases remains as high as about 30%. It is considered that a lower death risk of cardiovascular diseases can be achieved by further reducing LDL cholesterol. However, a high dose administration of statins cannot be applied due to enhanced increased risk of rhabdomyolysis.
Therefore, a medicament has been desired which has a potent reducing action on blood LDL cholesterol and is based on different mode of action from that of statins. [0004]
Proprotein convertases (PCs) are members of the mammalian serine protease

family, of which homology to suhtilisin in bacteria and koxiu in yoiiHli has been observed. One of PCs, PONICI) (proprotoln oouvertase subtilisin/kexln 0), k mainly expressed in the liver and secreted extracellularly, and then bound with LDL receptor on the membrane surfaces of hepatocytos to promote migration of the LDL roceptor into the cells. The LDL roooptor migrated into the cells are decomposed by coll organelles. Since the LDL roue]) tor hus a function of transporting lipoproteins containing LDL cholesterol to the liver from circulating blood, production of the P08K9 protein inhibits uptake of blood LDL cholestorol into the liver, which results in nn Increase of blood LDL cholesterol level. In fact, it is known that LDL blood cholontorol level is high in humans with a function acquisition-type mutation in the P0SK9 gono, which relates to autosomal dominant hypercholesterolemia (Non-patont document 2). Whilst, a low level of blood LDL cholesterol is maintained in humans with a function deletion type mutation in tho POSJCO gono (Non-patent document 8). Further, It has boen demonstrated in nn iinlmal that LDL cholesterol level is low in iiilno deficient in the PCSK9 gene of the liver (Non -patent document 4). [0005]
It is considered from the reasons set forth above that reduotion of the amount of the PCSK9 protoln by suppression of the production thereof or Inhibition against the function of the P0SK9 protein leads to increase in tho amount of tho LDL receptor, and thus provides a potent LDL cholesterol-reducing action. [0006]
Under the circumstances, active researches have recently boon conducted on functional inhibition of the PCSK9 protein or suppression of the production thereof. For example, as those using an antibody or antisense oligonucleotide, functional inhibition of the PCSK9 protein using a monoclonal antibody directed to PCSK9, suppression of the PCSK9 protein production based on RNA interference, and the like have been reported (Non-patent documents 5 to 7). Further, as those using a low molecular weight compound, it has been reported that berberine reduces mRNA and protein level of PCSK9 in HepG2 cells (Non-patent document 8), and 5-azacytidine, which is an annexin A2 activator, promotes binding of the PCSK9 protein with annexin A2 and suppresses decomposition of LDL receptor (Patent document l). However, almost no compounds with a low molecular weigh as inhibitors against PCSK9 protein function or suppressors against PCSK9 protein production have been reported except

for those mentioned ubove. [0007]
Patent document 2 discloses pyrimidine compounds having a dibonzylamine structure, which havo potent Inhibitory activity against oholoBteryl water transfer protein (CETP), and also havo n potent blood HDL oholentoroHiuiroimlng action. The document discloses tho uompouiid of the following formula (!) an n moemate in Example 45: [Formula l]
(trans-{4-[({2-[({l-[3,5-bls(trilliioromethyDpheny]]ethyl}{5-[2-(methylsulfonyl)otboxylpyr I mid in-2-y0amino)methylJ-4"
(trifluoromethyl)pheny]}(ethyl)ninino)methyl]cyclohexyl}aoetio acid, henceforth also referred to as "racemato compound (I)" in the specification). However, any relationship between the racomate compound (I) and the PCSKO protein has not been described or suggested. [0008]
Since PCs have influences on proliferation, motility, adluiaion, and invasion of cancer cells, they have been focused as a target of cancer treatment (Non*patent document 9). There are also known relationship of PCs with obeaity, diabetes, and Alzheimer disease, and involvements of PCs in diseases such as viral infectious diseases including acquired immunodeficiency syndrome (AIDS) and severe acute respiratory syndrome (SARS) (Non-patent documents 10 and ll).
Therefore, use of a compound having a reducing action on amount of PCSK9 protein or an inhibitory action against PCSK9 protein function as an active ingredient of a medicament for the aforementioned diseases is also expected. Prior art references

Patent documents
[0009]
Patent document l: International Patent Publication WO2009/14fl(IHn
Patent document 2: International Patent Publication WO2008/129051.
Non-patent documents
[0010]
Non-patent document l: Nippon Rinsho, Vol. 59, Extra isBiio 3, Hyperllpidemia (vol. 2),
381-386 (2001)
Non-patent document 2! Nat. Genet., 34, 154-156 (2008)
Non-patent document U: N. Engl. J. Med., 354, 1264-1272 (200(1)
Non-patent documont 4: Proa. Nntl. Acad. Sci. USA, 102, flfl74-5JI70 (2005)
Non-patent document «! Proo. Nntl. Acad. Sci. USA, 106, 9820-OHMft (2000)
Non-patent document 0: J. Lipid Itos., 48, 763-767 (2007)
Non-patent document T- Proc. Natl. Acad. Sci. USA, 105, 11915-11920 (2008)
Non-patent documont 8: Atherosclerosis, 201 (2), 266-73 (2008)
Non-patent documont»: Mol. Gurolnogen., 44(3), 151-161 (2005)
Non-patent documont 10: J. Mol. Mod., 83, 842-843 (2005)
Non-patent document 11: J. Mol. Mod., 83, 844-855 (2005)
Summary of tho Invention
Object to be Achieved by the Invention
[0011]
An object of tho prosont invention is to provide a low molooiilnr weight compound having antiona of reducing amount of the PCSK9 protein mid increasing amount of LDL rouuptoi', and a medicament comprising said low molecular weight compound as an notlvo ingredient. Means for Achieving the Object [0012]
The inventors of the present invention conducted varlouB rtiHoarahes to achieve the aforementioned object. As a result, they found that the racenmie compound (!) and one of enantiomers thereof, (R)-trans-{4-[({2-[({l-[3,5-bi8(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfony])ethoxy]pyrimidin-2-y])amino)methyl]-4-(trifluoromothyl)pheny]}(ethyl)amino)methyl]oyolohoxyl}aceticacid represented by the following formula (II) (henceforth also referred to as "(RHsomer

compound (ED" in the specification):
[0013]
[Formula 2]
(ID
had almost no actions of reducing amount of the PCSK9 protein awl increasing amount of LDL receptor, whilst they also found that levorotatory (S)-trans-{4'[({2-[({l-[3,5-bis(trifiuoromethy])phoiiy]]ol;hyl}{5-[2-(methylsulfonyDethoxylpyi'itnltlin-2-y]}amino)methyn'4'(trllluoroinothy])pheny]}(ethy])amin())mol.hy]|(iy()l(iliBxyl}aceticacid represented by the following formula (ffl) (henceforth also roferrml <ound (II) in a substantially optically pure form as described below.
Specifically, as a general point of view, it is known that a substantially optically pure compound may be prepared by synthesizing racemnto, and then subjecting the ruoemato to optical resolution using a chiral column,
However, in the optical resolution using a chiral oolumn, it may sometimes be very difficult to sot conditions of the resolution for a certain type of oompound, and the process is unsuitable for industrial scale production. Practically, it waa found that the set of the conditions of the optical resolution using a chiral oolumn for preparing substantially optically pure (SHsomer compound (ill) or (KMsomor compound (ID was extremely difficult. More specifically, it was attempted to fractionate each enantiomer from the racemate compound (I) prepared in accordance with the method described in Patent document 2, Example 45 while variously changing the conditions such as types of a chiral column (for example, CHIRALCEL ODH, CHIRALCEL OJ-H, and the like), types of a solvent used as a mobile phase (for example, MeOH/TFA mixture, EtOH/TFA mixture, and the like), and flow rate of the mobile phase. However, the resolution was not successful under almost all conditions applied. Under the circumstances, it was found that each enantiomer was successfully separated under the conditions described in Example 1-1 which will be mentioned later. However, it was also found that a decomposition product (ethyl ester compound) was produced under the aforementioned conditions. [0025]
Patent document 2 also discloses that the racemate compound (I) can be prepared by a method comprising the steps of coupling an intermediate compound (a) and a racemate benzyl bromide compound (b) in the presence of a bane, hydrolyzing the ester group of the resulting compound (c) to prepare a compound (d), find finally

oxidizing tho sulfur atom of tho compound (d) according to Hohomo I shown below. [0026] Scheme 1 [Formula 4]
[0027]
With reference to Scheme 1, the inventors of the present invention attempted to obtain substantially optically pure (S)-isomer compound (III) or the QiMsomer compound (II) by using optically active l-[3,5-bis(trifluoromethyl)phenyl]-l-methanesulfonyloxyethane instead of the racemate benzyl bromide compound (b). However, the elimination reaction of l-[3,5-bis(trifluoromethy])phenyll-l-methanesulfonyloxyethane preferentially occurred, and the objective compound was

not successfully obtained.
Furthor, the preparation was further attempted by using nil optically active benzylating agent having a leaving group such as toluenosulfonyl group, chloromethanoHiilfonyl group, or 2,4,6-triisopropylbenzenoHuH'ojiyl group instead of methanesulfonyl group. Howovor, substantially optically pure (B)-inomer compound (Til) or the (ItHsomor compound (II) was not successfully obtalnud tin In the case of using l-[3,6-bis(trifluoromethyl)phenyl]-l-methanesulfonyloxyethano. [0028]
When tho bonzyl bromide compound (b) was used, introduolJon of [8,5-bis(trifluoromethyl)phonyl]-l-othyl group into the nitrogen atom of the intermediate compound (a) was alreudy successfully achieved. Accordingly, it cun be contemplated to obtain substantially optically pure (S)-isomer compound Gil) or (HHHomer compound (II) by using an optically active benzyl bromido oompound Instead of racemate benzyl bromide compound (b).
However, it is generally known that, in a nucleophilic substitution reaction in which bromide ion is eliminated, the bromide ion produced by tho roaotion reacts with benzyl bromide in the roaotion system, and racemization advances. Further, it is also generally known thut, in a nuoleophilic substitution reaction at boir/yl position, an SN1 type substitution reaction also competitively occurs due to stabilisation of the benzyl cation, and therefore racemization partially occurs.
As for tho compound having a moderate optical purity obtained as a result of decrease in optical purity duo to partial racemization (in tho speoliloatlon, "compound having a moderato optical purity" means a compound having an optical purity not lower than about 10%ee and lower than about 90%ee, preferably about 20 to 80%ee, and most preferably about 40 to 70%ee, and the compound having the moderate optical purity may also be henceforth referred to as "semi-chiral compound". Further, as for the semi-chiral compound, when a compound, in which the asymmetric earbon atom indicated with * in the partial structure shown below is in the S'configuration, is present in a larger amount as compared with a compound in the It-configuration, the compound is specifically referred to as "(S)-isomerdominant semi-chiral compound". Whilst, as for the semi-chiral compound, when the compound in which the asymmetric carbon atom indicated with * is in the R-configuration is present in a larger amount as compared with the compound in the S-configuration, the compound is specifically

referred to as "(R)-isomerdominant semi-chiral compound".), [Formula 5]
it is known that optical purity thereof can be increased by preferentially crystallizing one of the enantiomeric
However, uncording to tho study of the inventors of the pninMint invention, crystallization did not udvanoo in the case of the racemato compound 0) or an ethyl ester derivative thereof, and optical purity thereof was not HtiocoHHfiilly increased by the preferential crystallization. [0029]
Under tho cirouinstanoos as described above, tho inventory of tho present invention converted the carboxylic acid of the racemate compound (!) into benzyl ester, and found that the rosulting benzyl oster compound was successfully isolated as a crystal comprising tho racemato us a main component.
Then, by propuring a somi-chiral compound (IV) of an arylulkyl or heteroarylalkyl oster compound, and then crystallizing crystals of u. low optical purity dominantly containing the racomuto as a component (henceforth ulwo referred to as "racemate-dominunt crystals") and removing the crystals to obtain nil urylalkyl or heteroarylalkyl ostor compound (V) or (V1) with a high optical purity, and then by using the compound (V) or (V1) as a sturting material as shown in Scheme 2 mentioned below, the inventors successfully preparod a desired enantiomer of the racomate compound (I) ((S)-isomer compound (III) or (RHsomer compound (II)) in a substantially optically pure form. [0030] Scheme 2 [Formula 6]

(In the scheme, 11 roprosents a Co-io aryl group which may have a HiiliNtltuent, or a 5- to 10-membered hotorooryl group which may have a substituent, and n rwpresents an integer of 1 to 6.) [0031]
The proHont invention UIUH provides a method for preparing Hiibstuntially optically pure (SMsomor compound (III) or substantially optically puro (RMeomer compound (II), or a Bait thereof, or a solvate thereof, which comprises the step of removing racemate-dominant crystals from a semi-chiral compound of a compound represented by tho following general formula (TV)-' [Formula 7]

(in the formula, R represents a Ca-io aryl group which may have a Bubatituent, or a 6-to 10-membered heteroaryl group which may have a substituent, and n represents an integer of 1 to 6) by preferential crystallization in a solvent to obtain ft substantially optically pure compound represented by the following general formula (V) or (V'): [Formula 8]
(V) (V)
(in the formuluM, It and n huvo tho same meanings as those dofinod ftir the general formula (IV)). [0032]
By the aforementioned method, when the compound roprtiHunted by the general formula (IV) is an (SMBomordominant semi-chiral compound, the (S)-isomer compound (III) can be prepared, and when the compound represented by the general formula (IV) is an (R)'lsomordominant semi-chiral compound, the OlHaomer compound (II) can bo prepared. [0033]
The present invention further provides the aforementioned method, which further comprisos tho step of removing the group represented as '(OHiiXrR from the compound represented by the gonerul formula (V) or (V1). [0034]

The present invention farther provides '■ (A) the aforementioned method, which further comprises the step of reacting a semi-chiral compound of a compound represented by the following general formula (VI): [Formula 9]
(in the formula, E and n have the same meanings as those defined for the general
formula (TV)) with an oxidizing agent in a solvent to prepare a semWihlral compound of
a compound represented by the general formula GV)>'
[0035]
(B) the aforementioned method (A), which further comprises the stop of reacting a
semi-chiral compound of a compound represented by the following formula (VII):
[Formula 10]
with a compound represented by the following general formula (VIII) [Formula 11]
R-(CHa)„-OH (VIII) (in the formula, It und n have the same meanings as those defined for the general formula 0V)) in a solvont in tho presence of a catalyst to propare iho uomi-ohiral compound of a compound represented by the general formula (VI)!

[0036]
(C) the aforementioned method (B), which further comprises the stop of hydrolyzing a
semi-chiral compound of a compound represented by the following general formula
OX):
[Formula 12]
(in the formula, R1 represents a Ci-e alkyl group) in a solvent in the presence of a base
to prepare the semi-chiral compound of a compound represented by the formula (VII);
and
[0037]
(D) the aforementioned method (C), which further comprises the step of reacting a
compound represented by the following general formula 00 or (X')i
[Formula 13]
(in the formula, X reproHonts a halogen atom), and a compound repvotiented by the following general formula (XI): [Formula 14]

an the formula, II1 has the same meaning as that defined for tho nemo ml formula (IX)) in a solvent in the presence of a base to prepare the semi-ohiral compound of a compound represented by the general formula (IX). [0038]
The present invention also provides the aforementioned method (D), which further comprises the step of halogenating optically active l-[3,5-bis(trifluoromethyl)phenyl]ethanol in the presence of a halogenating agent to prepare the compound represented by the general formula 00 or (X'X [0039]
As another aspect, the present invention provides a compound represented by the aforementioned general formula (TV), or a salt thereof, or a solvate thereof. The compound wherein R is phenyl, and n is 1, a salt thereof, or a solvate thereof is a preferred embodiment of this invention. [0040]
The present invention further provides a substantially optically pure compound represented by the aforementioned general formula (V) or (V1), or a salt thereof, or a solvate thereof. A compound wherein R is phenyl, and rt is 1, or a salt thereof, or a solvate thereof is a preferred embodiment of this invention, Effect of the Invention [0041]
The (S)-isomer compound (III) has superior PCSK9 protoin amount-reducing action and LDL receptor amount-increasing action, and haB superior Mood LDL cholesterol-reduoliiK nation. Therefore, the compound is useful as, for example, an active ingredient of u modicumont for reducing blood LDL oholestorol, nnd the like.
Further, tho (B)-inomor compound Gil) is also UBBUII na un noMvo ingredient of

a medicament for prophylactic and/or therapeutic treatmont of a (IIHCIIIHO in which PCs are involved, more specifically, cancer, obesity, diabetes, Akhelmor disease, or viral infectious diseases.
Further, uooording to the preparation method of tho present invention, a desired enantlomor of the raoeniate compound G) ((SMsomer compound (III) or (R)-isomer compound (IT)) can bo conveniently prepared in a substantially optically pure form. For example, tho method can be preferably used as a method for preparing substantially optically pure (SMsomer compound (III), which is useful as an active ingredient of a medicament, or the like. Modes for Carrying out the Invention [0042]
In the specification, the term "substantially optically pure" moans that optical purity of a compound 1B 90%ee or higher, preferably 95 to 100%ee, most preferably 97 to 100%ee.
Therefore, for example, "substantially optically pure (S)-tranB-{4-[({2"[({l-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin"2-y0amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid", "substantially optically pure levorotatory enantiomer of trans-{4-[({2-[({l-[3,5-bis(trifluoromethyl)phenyl]ethy]}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-y0ammo)methyl]-4-(trifluoromethy])phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid" and "substantially optically pure (S)-isomer compound Oil)" mean the (S)-isomer compound (III) having an optical purity of 90%ee or higher, preferably 95 to 100%ee, most preferably 97 to 100%ee.
In the present invention, optical purity of the (S)-isomer compound (III) is preferably 98%ee or higher, most preferably 99%ee or higher, as determined under the chiral HPLC analytic conditions described in Example 1-1 mentioned later, from a viewpoint of obtaining favorable PCSK9 protein amount-reducing action and/or LDL receptor amount-increasing action. If the aforementioned optical purity is achieved, the (S)-isomer compound (III) becomes to not substantially contaiu tho other enantiomer ((R)-isomer oompound (II)). [0043]
In the specification, the term "Ci-e alkyl group" means a linear or branched alkyl group having 1 to fl carbon atoms, and examples include, for example, methyl

group, ethyl group, n-propyl group, isopropyl group, nrbutyl group, isobutyl group, sec-butyl group, tort-butyl group, n-pentyl group, isopentyl group, nnopontyl group, n-hexyl group, isohexyl group, und the like. [0044]
In tho upooifiontion, tho "Ooio aryl" moiety of the "OHIO uryl group which may have a substituunt" meunB an aromatic hydrocarbon group having (J to 10 carbon atoms, and examples includo, for example, phenyl group, naphthyl group, uKiilenyl group, and the like. [0045]
In the Npoolfluution, tho "B" to 10-membered hetorouryl" mnluty of the "5- to 10-membered heterouryl group which may have a substituent" meaiiH a B- to 10-membered monocyclic, polyoyclic or condensed ring type aromatic hotorooycllo group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms. Examples include, for example, furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, laolihlazolyl group, imidazolyl group, pyruzolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, benzofurunyl group, isobonzofuranyl group, benzothienyl group, indolyl group, isoindolyl group, indazolyl group, benzimidazolyl group, benzoxazolyl group, benzisoxazolyl group, bonzothiazolyl group, benzisothiazolyl group, honzoxadiazolyl group, benzothiadiazolyl group, benzotriazolyl group, quinolyl group, isoquinolyl group, cinnolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, naphthyridinyl group, purinyl group, pteridinyl group, furopyridyl group, thienopyridyl group, pyrrolopyridyl group, oxazolopyridyl group, thiazolopyridyl group, imidazopyridyl group, and the like. [0046]
In the specification, examples of the substituent of the "Coio aryl group which may have substituent", and "5- to 10-membered heteroaryl group which may have a substituent" include, for example, a halogen atom, carboxyl group, carbamoyl group, sulfonyl group, sulfamoyl group, nitro group, and the like. Number of the substituent is from 1 to the maximum substitutable number, and the groups may generally have 1 to 5 substituents. As the halogen atom, any of fluorine atom, chlorine atom, bromine atom, and iodine atom may be used.

[0047]
In tho general formulas, the C6-10 aryl group which may huvo a substituent as R is preferably phony] group.
In tho general formulas, the integer as n is preferably 1.
In tho goneral formulas, the C1-6 alkyl group aB It1 is preferably a Ci-4 alkyl group, more proforahly ethyl group.
In the general formulas, tho halogen atom as X is proforahly (ihlorine atom or bromine atom, more preferably bromine atom. [0048]
In the present invontion, examples of salt of each compound (for example, the (S)-isomer compound (III), a compound represented by the goneral formula (TV), a compound reproHontod by tho genoral formula (V), a compound roprosontod by the general formula (V1), and tho like) include, for example, acid addition salts, base addition salts, and tho like, and the salt is not particularly limited so long as a pharmaceutically acceptable* salt is used. Specifically, examploH of the acid addition salts include acid addition salts with an inorganic acid such as hydrochloride, hydrobromide, hydrolodide, sulfate, nitrate, and phosphate! and add addition salt with an organic acid suoh as benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, and acetate. Examples of the baso addition salts include base addition salts with n metal such as sodium salt, potassium salt, lithium salt, calcium salt and magnesium salt! salts with an amine such as ammonia, trimethylamine, triethylamine, pyridine, oollidine, and lutidine.' base addition salts with an organic base such as lysine and arginine, and the like. [0049]
In the present invention, examples of the solvent forming a solvate of each compound (for example, the (S)-isomer compound (III), a compound represented by the general formula (TV), a compound represented by the general formula (V), a compound represented by the general formula (V*), and the like) or a salt thereof include water and physiologically acceptable organic solvents, for example, ethanol, hexane, ethyl acetate, and the like, but are not limited to these examples. Examples of the active ingredient of the medicament of the present invention include, for example, hydrates and the like, but are not limited to these examples.

[0050]
An example of the method for preparing substantially optioully pure (S)-isomer compound (111) of the present invention is shown in Schemo II mentioned below, and an example of tho method for preparing substantially optically pure (R)-ieomer compound (II) of tho present invontion is shown in Scheme 4 mentioned below (in the following schemoH, 11, It1, X, and n have the same meaning** us tlniHU defined above). [0051] Scheme 3 [Formula 15]

[0053]
This Btop Is to roact an amine (XI) with an optically aotivo benzyl halide (X) or (X1) in the presence of a baso to prepare a semi-chiral compound (IX), The compound (X) or (X1) may bo used in an amount of 1.0 to 3.0 molar equivalent*, preferably 1.5 to 2.5 molar equivalents, based on tho compound (XI).
The amino (XI) is a known compound, and the preparation method thereof is described in, for example, Patent dooument 2. [0054]
This reaction can be performed in a solvent in tho prosenoo of a base. The solvent is not particularly limited. For example, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, aoetonitrile, propionitrile, and tho like can bo used alone or in combination. Prolbrred examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, and mixed solvents of these. The volume of the solvent is not particularly limited, Tho Holvent may be used in a 2- to 20-fold amount (V/W), preferably 5- to 12-fold amount (V/W), more preferably

7- to 10-fold amount (V7W), based on the compound (XI). [0055]
The base is not particularly limited. For example, alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; alkali metals such as metal lithium, metal sodium, and metal potassium; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; aljcali metal carbonates such as lithium carbonate, sodium carbonate, potassium ctarbonate, and cesium carbonate; alkali metal amides such as lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide! alkoxyalltall metals such as t-butoxysodium, and t-butoxypotassium; and organic lithium compounds such as n-butyllithium, s-butyllithium, and t"butyllithium can be used. Proibrred examples of the base include alkali metal hydrides, and a more preferred example 1B sodium hydride. The base may bo used in an amount of 1.0 to 5.0 molar oqulvalent, preferably 2.0 to 4.0 molar equivalents, based on the compound (XI). [0056]
The reaction tomperaturo is generally in the range of--80 to l00"O, preferably -30 to 50°C, more preferably -20 to 5°C. The reaction timo is gonorully 5 minutes to 48 hours, preferably 80 nunutos to 24 hours, more preferably 8 to H hours. In this reaction, it is proforablo to use substantially optically pure bonzyl halide (X) or (X'). By this reaction, racomization partially advances, and the semi-ohiral compound (IX) is obtained. This somi-ohlral compound (IX) can be used for the next *»tep without any treatment. Optical purity is substantially maintained through Steps B to D, and the semi-chiral compound (IV) having an optical purity comparable to that of the semi-chiral compound (IX) can be obtuinod. According to the study by the Inventors of the present invention, oven if the reaction with the optically aotlvo benzyl halide (X) or (X1) is performed in this step by using the amine (XI) wherein R1 is ben/.y] group, the semi-chiral compound (IX) as the objootlve compound cannot be obtnined in a satisfactory yield, but if a Ci-o alkyl group is used as R1, the desired semi-chiral compound (IX) can be obtained in a Hul'flolont yield. [0057]
This step is to hydrolyze the semi-chiral compound (IX) to prepare a semi-

chiral compound (VII). [0058]
This reaction can be performed in a solvent in the presence of a base. Although the solvent is not particularly limited, for example, alcohols such as methanol, ethanol, propanol, isopropanol, and tert-butanol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N,N"dimethylformamide, N-methylpyrrolidone, dioxane, water, and the like can be used alone or in combination. Preferred examples of the solvent include a combination of an alcohol and water, and more preferred examples of the solvent include a combination of ethanol and water. Although the volume of the solvent is not particularly limited, the solvent can be used in a 10' to 100-fold amount (WW), preferably 20- to 50-fold amount (V/W), more preferably 30" to 40-fold amount (WW), based on the compound (IX). [0059]
The base is not particularly limited. For example, alkali mntal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide! alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium oarbonate, and cesium carbonate; quaternary ammonium hydroxides such as tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonimn hydroxido, and benzyltrimethylammonium hydroxide (Triton B), and the like can bo used. Preferred examples of the base include alkali metal hydroxides, and moro proferrod examples include sodium hydroxido, The base may preferably be used in un amount of 1.0 to 5.0 molar equivalents, moro preferably 2.0 to 3.0 molar equivalents, Imsod on the compound (IX). [0060]
The roaction temperature is generally in the range of 0 to 100°C, preferably 30 to 80°C, more preferably 40 to 00°C. The reaction time is generally preferably 5 minutes to 48 hours, more preferably 30 minutes to 12 hours, maul; proforably 2 to 5 hours. [0061]
This stop is to condense tho semi-chiral compound (VII) and an alcohol (VIII) to prepare a seml-ohlral compound (VI). The alcohol (VIII) can bo uttod in an amount of 0.8 to 2.0 molnr equivalents, proforably 1.0 to 1.2 molar equivalents, based on the

compound (VII). [0062]
This reaction can be performed by using a condensing agent in a solvent in the presence or absence of a base. The reaction may be performed in the presence of a condensation accelerator. Although the solvent is not particularly limited, for example, halogenated hydrocarbons such as 1,2-dichloroethane, chloroform, and dichloromethane! acetic acid esters such as ethyl acetate, and isopropyl acetate! aromatic hydrocarbons such as toluene, and benzene," tetrahydrofuran, dioxane, acetonitrile, propionitrile, and the like can be used. Preferred examples of the solvent include halogenated hydrocarbons, and more preferred examples include dichloroethane. Although the volume of the solvent is not particularly limited, the solvent can be used in a 5- to 100-fold amount (V/W), preferably 10- to 20-fold amount (WW), based on the compound (VII). [0063]
The base is not particularly limited. For example, organic bases such as pyridine, 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8" diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3,O]non-0-oi:|e (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), triethylamine, diisopropyletbylnmine, diisopropylpentylamine, and trimethylamine! alkali metal hydridoH mioh as lithium hydride, sodium hydride, and potassium hydride! alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide." alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium oarbonate, and cesium carbonate! ulkuli metal bicarbonates such as sodium hydrogen loarbonate, and potassium hydrogonoarbonate, and the like can be used. [0064]
Although the condensation accelerator is not particularly limited, DMAP, 1-hydroxy-7-azaben/,otrlHiM)lo (I fOAt), 1-hydroxybenzotrlazolo (llOIlt), ll,4"dihydro-3-hydroxy-4-oxo-l,2,3-bon,/()triu»ilno(lIODhbt), N-hydroxy5-norbornono"2,3-dicarboxyimido (110NU), pontuttuorophenol (HOPfp), N-hydruxyphtlmllmide (HOPht), N-hydroxysuccinimide (HOSu), and the like can be used. As tho condensation accelerator, DMAP is preferred. Tho condensation accelerator may bo used in an amount of 0.001 to 1.0 molar equivalent, preferably 0.05 to 0.5 raolur equivalent, based on the compound (VII).

[0065]
Although tho condensing agent is not particularly llmituil, Dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (D1POI), NH(8-dimethylaminopropyO'N'-ethyl-carbodiimide (commonly called water soluble carbodiimide (WSCI)), WSC -HO], and the like can be used. As the condensing agent, WSC -HC1 is proferred. The condensing agent may be used in an amount of 1.0 to 3.0 molar equivalents, preferably 1.0 to 1.2 molar equivalents, based on the compound (VII). [0066]
The reaction temperature is generally 0 to 100°C, preferably 0 to 80°C, more preferably 10 to 30°C. The reaction time is generally preferably 5 minutes to 48 hours, more preferably 30 minutes to 24 hours, most preferably 8 to 16 hours. [0067]
This step is to oxidize the sulfur atom of the semi-chiral compound (VI) to prepare the semi-chiral compound (TV). [0068]
As the oxidization method, ordinary methods for converting sulfur atom into sulfonyl group can be used. As the oxidizing agent, for example, aqueous hydrogen peroxide as used in oxidization reaction using a catalytic amount of sodium tungstate, molybdenum dioxide dichloride, or tantalum pentachloride, sodium perborate, Oxone (registered trademark), sodium periodate, potassium periodate, mBfca*phloroperbenzoic acid (mCPBA), pyridinium chlorochromate (PCC), pyridinium diahromate (PDC), N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosucoiirimlde (NIS), iodine, bromine, and the.like can be used. A preferred oxidizing agent is u combination of tantalum pentachloride and aqueous hydrogen peroxide. Tantalum pentachloride can be used in an amount of 0.001 to 1.0 molar equivalent, preferably 0,0ft to 0.5 molar equivalent, based on the compound (VI). Aqueous hydrogen peroxide can be used in an amount of 1.0 to 10 molar equivalents, preferably 4.0 to 0.0 molar equivalents, based on the compound (VI). [0069]
The solvouti In not particularly limited. Examples Include, for oxample, water, alcoholB such an niollmnol, othauol, isopropanol and tort'butuno.1, aootonitrile, acetone,

tetrahydrofurun, dlohloromothuno, chloroform, 1,2-diohloroethano, ourbon tetrachloride, N,N-dimethylformuinido, acotio ucid, and the like. Preferred examples of the solvent include alcoholN, and more proforred examples include 2-propannl. Although volume of the solvent is not particularly limited, the solvent may be used in a 5- to 100-fold amount (WW), preferably 10- to 30-fold amount (V/W), based on the compound (VI). [0070]
The reaction tomperature may be generally 0 to 100°C, proferably 10 to 60°C, more preferably 10 to 30°C. The reaction time is generally preferably 5 minutes to 48 hours, more preferably 80 minutes to 24 hours, most preferably H to 16 hours. [0071]
This step is to preferentially crystallize racemate-dominant crystals of low optical purity from the semi-ohiral compound (IV) to prepare the optioal isomer (V) or (V) with high optical purity. [0072]
This step is to crystallize racemate-dominant crystals in a solvent containing the semi-chiral compound (IV), and then to remove the resulting racemate-dominant crystals to have the optical isomer (V) or (V) with high optical purity left in the mother solution.
Examples of the solvent include alcohols such as methanol, ethanol, n-propanol, and isopropanol. Alcohols having a linear or branched chain containing 1 to 6 carbon atoms are preferred, and ethanol and isopropanol are particularly preferred. Amount of the solvent is a 2- to 20-fold amount (V/W), preferably 4- to 10-fold amount (V/W), more preferably 5- to 8-fold amount (V/W), based on the compound (IV). [0073]
The crystallization may be performed by dissolving the semi-ohiral compound GV) in the solvent, and stirring the solution at 10 to 40°C, preferably tfl to 20°C, for 30 minutes to two days, preferably 15 to 24 hours. If it is desired to increase yield of the crystals, the stirring may be then performed for 30 minutes to 24 hours, preferably 2 to 5 hours, under cooling the solution to -10 to 10°C, preferably -B to H"(). The racemate-dominant crystals may be crystals absolutely consisting of racemato, or they may generally be crystals of low optical purity (about 0 to 40%ee) containing about 60 to 100% of racemate components.

[0074]
This stop may bo performed in the presence of separately prepared seed crystals of the ruoomnte. The seed crystals of the raoemnto usoil in this process are crystals of the racomuto of the compound represented by the general formula (TV). Examples inoludo, for example, crystals of racemate of trans-{4-I({2-|({l-[8,5" bis(trifluoromolhy])phoiiyl|etl)yl}{5-[2-(methylsulfonyl)ethoxy]pyi'JniltUn-2-y]}amino)methyl] -4- (trlfluorometliyl)phenyl}(ethyl)amino)methyl]oyololiexyl}acetic acid benzyl ester.
Further, the ruoemato'dominant crystals obtained in this «tep E may be used as the seed crystulB of racomato without any treatment. Crystal separately obtained by preparation of racemate of the compound represented by the general formula (IV) and successive crystallization may also be used as the seed crystals of the racemate. Such racemate of the compound represented by the general formula (IV) can be prepared by, for example, the method described below. [0075] [Formula 17]
[0076]
In this reaction, the racemate compound (I) and an alcohol (VIII) are condensed to prepare the racemate (TV). The alcohol (VIII) may be used in an amount of 0.8 to 2.0 molar equivalents, preferably 1.0 to 1.2 molar equivalents, based on the racemate compound (I). [0077]
This reaction can be performed in a solvent by using a condensing agent in the presence or absence of a base. The reaction may be performed in the presence of a condensation accelerator. The solvent is not particularly limited. For example, halogenated hydrocarbons such as 1,2-dichloroethane, chloroform, and

dichloromethano! uooUo acid enters such as ethyl acetate, and isopropyl acetate! aromatic hydrocarbons HUUII UH toluene, and benzene! totrohydrnlVimn, dioxane, acetonitrile, propionitrile, and the like can be used. Preferred oxamples of the solvent include halogenated hydrocarbons, and more preferred examples include dichloromethano. Although the volume of the solvent is not partlnularly limited, the solvent can be used in a 5- to 10()-fold amount (V/W), preforably 10- to 20-fbld amount (VAV), based on the racomate compound OD. [0078]
The baso is not particularly limited. For example, organic bases such as pyridine, 4-dimethylamlnopyridlne (DMAP), colidine, lutidino, 1,H-diazabicyclo[5.4,0]undoo-7-ono (DBU), l,5"diazabicyclo[4.3.0]non-ft"oiio (DBN), 1,4-diazabicyclo[2.2.2|ootune (DADOO), triethylamine, diisopropylethylainlne, diisopropylpentylutnino, and trlmethylamine; alkali metal hydriduH mioh as lithium hydride, sodium hydride, and potassium hydride! alkali metal hydroxides such as lithium hydroxido, sodium hydroxide, and potassium hydroxide! alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium oarbonate, and cesium carbonate! alkali metal bicarbonates such as sodium hydrogencarbonate, and potassium hydrogencarbonate, and the like can be used. [0079]
Although the condensation accelerator is not particularly limited, DMAP, 1-hydroxy-7-azabonzotriazole (HOAt), 1-hydroxybenzotriazole (HOllt), 3,4-dihydro-3-hydroxy-4-oxo- 1,2,3-bonzotriazino (HODhbt), N-hydroxy-5-norborneno-2,3-dicarboxyimide (IIONB), pentafluorophenol (HOPfp), N'hydroxyphthalimide (HOPht), N-hydroxysuccinimide (HOSu), and the like can be used. As the condensation accelerator, DMAP is preferred. The condensation accelerator may be used in an amount of 0.001 to 1.0 molar equivalent, preferably 0.05 to 0.5 molar equivalent, based on the racemate compound (I). [0080]
Although the condensing agent is not particularly limited, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPCI), N"(3-dimethylaminopropyl)-N'-ethyl-carbodiimide (commonly called water soluble carbodiimide (WS0D), WSC -HC1, and the like can be used. As the condensing agent, WSC -HC1 is preferred. The condensing agent may be used in an amount of 1.0 to 3.0

molar equivalents, preferably 1.0 to 1.2 molar equivalents, based on the racemate
compound 0).
[0081]
The reaction tomporature is generally 0 to 100°0, prefernbly 0 to 80°C, more preferably 10 to H0°O, Tho rouctlon time is generally preferably ft minutes to 48 hours, more preferably HO minutes to 24 hours, most preferably 8 to 16 hours. [0082]
The crystallization of raoomate of the compound represented by the general formula (IV) (preparation of the seed crystals of the racemuto) can bo performed under conditions similar to thoso applied to the preferential crystullkuilon of the racemate-dominant crystuls from the soml-chiral compound (IV).
More specifically, the racomate compound (TV) can be dissolved in a solvent, and the solution can bo stirred at 10 to 40°C, preferably 15 to 20°O, for 80 minutes to two days, preferably 15 to 24 hours. If it is desired to increase yJold of the crystals, the stirring may be further performed for 30 minutes to 24 hours, preferably 2 to 5 hours, under cooling tho solution to -10 to 10°C, preferably -5 to B"(J, Examples of the solvent include alcohols such as methanol, ethanol, n-propanol, and isopropanol. Alcohols having a linonr or branched chain containing 1 to 0 carbon atoms are preferred, and ethanol and isopropanol are particularly proforred. Amount of the solvent is a 2- to 20-fold amount (VAV), preferably 4- to 10-fold amount (V7W), more preferably 5- to 8-fold amount (V/W), based on the racemate compound (TV).
This stop is to perform deprotection of the compound (V) or (V) of high optical purity to prepare substantially optically pure (SHsomer compound (III) or (R)-isomer compound (II). [0083]
This reaction can be performed by catalytic reduction using a metal catalyst and a hydrogen source in a solvent, or a hydrolysis reaction using a baee in a solvent. When the deprotection is performed by the catalytic reduction, alcohols Buch as methanol, ethanol, isopropanol and tert-butanol; ethers such as diethyl ether, tetrahydrofuran and dioxane.' acetic acid esters such as ethyl acetate, and isopropyl acetate! acetic acid; water, and the like can be used as a solvent. As the solvent, alcohols are preferred, and ethanol is more preferred. The solvent may be used in a 5-

to 30-fold amount (WW), preferably 5- to 15-fold amount (V/W), buBort on the compound
(V)or(V').
[0084]
As the hydrogen source, for example, hydrogen, cyclohexadiuno, formic acid, ammonium formate, and the like can be used. As the hydrogen source, hydrogen is preferred. As the metal catalyst, palladium/carbon, palladium black, Raney nickel, platinum dioxide, platinum black, and the like can be used. As the motal catalyst, palladium/carbon is preferred. Palladium/carbon may be used in a 0,001" to 0.5-fold amount (WAV), proforubly 0.05- to 0.2-fold amount (WAV), btiBed on the compound (V) or (V') in terms of the amount of 10% Pd-C (wet). [0085]
The cattilyMu roduoUon nun generally be performed In tliu range of 0 to 100°C, preferably 10 to 60°C, more preferably 10 to 30°C. The reaction time is generally preferably 5 mimites to 24 hours, more preferably 30 minutes to 16 hours, most preferably 1 to fl hours. [0086]
When the doprotection is performed by the hydrolysis reaction, for example, alcohols such as methunol, ethanol, propanol, 2-propanol, and HntUmol, acetonitrile, propionitrile, tetrahydrofuran, dimethyl sulfoxide, N,N"dimothy]l'»niiamide, N-methylpyrrolidono, dioxano, water, and the like can be used ulono or In combination, although the solvent is not particularly limited. As the base, for example, alkali metal hydroxides such ns lithium hydroxide, sodium hydroxide, and potassium hydroxide,' alkali metal carbonatos such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium ourbonoto; quaternary ammonium hydroxides such as tetramethylamntoniuin hydroxldo, totraethylammonium hydroxido, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide, and benzyltrimethylammonium hydroxide (Triton B), and the like can be used, although the base is not particularly limited. [0087]
The optioally active benzyl halide 00 or (X') can be synthesized by, for example, the method described below. [Formula 18]

[0088]
This reaction consists of the step of halogenating optically uctive l-[3,5" bis(trifluoromethyl)phonyl]ethunol (XII) or (XH') in the presence of a halogenating agent to highly ufflaJuntly prepare optically active l-halo"l-[B,R-bis(trifluoromethyQphonyl]othanu (X) or (X1) without substantially reducing the optical purity. [0089]
Examples of tho halogenating agent used for this reaction include chlorinating agents such as thionyl ohlorido, phosphorus trichloride, phouphontH pontachloride and phosphorus oxychlnrido! brominating agents such as phosphorus tribromide, phosphorus tribromido and hydrogen bromide (30% solution in aootlo acid), phosphorus tribromide and j)yri(line, N-bromosuccinimide and methyl sulfide, N'bromosuccinimide and triphenylphosphlno, l,2-dibromo-l,l,2,2-tetrachloroethano and trlphenylphosphine, bromodimethylsiilfonium bromide, pyridinium bromide perbromlde and hexamethyldisiluno, bromine and triphenylphosphino, bromine and tributylphosphine, bromine and methyl sulfide, zinc bromide and triphenylphosphino and dimethyl azodicarboxylato, lithium bromido and chlorotrimethylsilano, lithium bromide and trifluoroacetic anhydride, bromotrimethylsilane, carbon tetrabromldo und triphenylphosphino, and thionyl bromide,' and iodinating agents suoh as hydrogen iodide, and potassium iodide and phosphoric acid. When the halogenating agent is a brominating agent, phosphorus tribromide and hydrogen bromide (30% solution in acetic acid), l,2"dlbroTno-l,l,2,2-l;etrachloroethane and triphenylphosplilne, and N-

bromosuccinimide and methyl sulfide are preferred.
The reaction using phosphorus tribromide and hydrogen bromide as the halogenating agent, and the reaction using l,2-dibromo-l,l,2,2-tetrachloroethane and triphenylphosphine as the halogenating agent will be, in particular, specifically explained below. [0090]

When phosphorus tribromide and hydrogen bromide (30% solution in acetic acid) are used as the halogenating agent, phosphorus tribromide is used in an amount of 0.3 to 2.0 molar equivalents, preferably 0.4 to 0.6 molar equivalent, based on the phenylethanol (XII) or (XII'). Hydrogen bromide is used in an amount of 0.7 to 3.0 molar equivalents, preferably 0.8 to 1.2 molar equivalents, based on the phenylethanol (XII) or (XID. [0091]
This reaction can be performed in the presence or absence of a solvent. When the reaction is performed in the presence of a solvent, the solvent to bo used is not particularly limited so long as the solvent does not participate in fcho reaction. Examples include, for oxample, aromatic hydrocarbons such as lioir/inno, toluene, xylene, mesitylono, uhlorobenzono, 1,2-dichlorobenzene, and nitrobutlKunel aliphatic hydrocarbons such HH lrpentuno, n-kexane, cyclohexane, irhuptumi, iroctane, and n-decanel halogonalod hydrocarbons such as methyleno chloride, l,!4*diuhLoroethane, chloroform, and carbon tetrachloride, and the like. Among thein, bonzone, toluene, xylene, mothylene chloride, 1,2'dichloroethane, n-pentano, irhexune, and n-heptane are preferred, und especially, toluene, methylene chloride, and n'hoptane are more preferred. Thoso solvents can bo used alone or in combination, and the amount of the solvent to be usod is not particularly limited. [0092]
The reaction temperature may be generally in tho range of - 50 to 150°C, more preferably -20 to H0°C, most preferably 0 to 15°C. Generally, the reaction time is preferably 5 minutes to 48 houra, more preferably 30 minutes to HO hours, most preferably 12 to 24 hours. [0093]

When l,2-dibromo-l,l,2,2-tetrachloroethane and triphenylphosphine are used as the halogenating agent, l,2-dibromo-l,l,2,2-tetrachloroethane is used in an amount of 1.0 to 3.0 molar equivalents, preferably 1.0 to 1.2 molar equivalents, based on the phenylethanol (XII) or (XlD. Triphenylphosphine is used in an amount of 1.0 to 3.0 molar equivalents, preferably 1.0 to 1.2 molar equivalents, based on the phenylethanol (XII) or (Xir). [0094]
This reaction can be performed in the presence of a solvent. The solvent to be used is not particularly limited so long as the solvent that does not participate in the reaction. Examples include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, chlorobenzene, 1,2-dichlorobenzene, and nitrobenzene; aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane, n-heptane, n-octane, and n-decane; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, and carbon tetrachloride, and the like, .Preferred examples of the solvent include aromatic hydrocarbons or halogenated hydrocarbons, more preferred examples include benzene, toluene, xylene, methyjuria chloride, and 1,2-dichloroethane, and particularly preferred examples include tolueno, methylene chloride, and 1,2-diohloroethane. These solvents can be used alone or In combination. Although the volume of the Bolvent is not particularly limited, the solvent can be used in a 1- to 10-fold amount (VAV), preferably 2- to 4-fold amount (V/W), based on the phenylethanol (XII) or (XlD. [0095]
The roucitiou tomporatura maybe generally in the rango of 50 to 150CC, more preferably -20 to 80°0, moat proforably 0 to 30°C. Genornlly, thn i-onofclon time is preferably 5 minutes to 48 hours, more preferably 30 minutoH to flfl hours, most preferably 1 to 2 hours. [0096]
The (S)-isomor compound (III), or a salt thereof, or a solvate thereof has suppressing action against PCSKO mRNA expression as specifically demonstrated in the examples described below. The substance also has reducing notion on PCSK9 protein amount and increasing action on LDL receptor amount, and has an action of

reducing blood LDL cholesterol in vivo.
Although the present Invention is not bound by the following estimation, it is estimated that the (SMsomer compound (III), or a salt thereof, or a solvate thereof suppresses production of the PCSK9 protein, thereby suppresses decomposition of LDL receptor and increases amount of LDL receptor, and as a rosult, the substance promotes incorporation of blood LDLs into the LDL receptor. It Is further estimated that such, promotion of the incorporation of blood LDLs into the LDL receptor constitutes one of the factors for exhibiting the reducing action on blood LDL cholesterol value.
Therefore, a medicament and a pharmaceutical composition containing the (S)-isomer compound (III), or a salt thereof, or a solvate thereof as an active ingredient can be used as a medicament for prophylactic and/or therapeutic treatment of hyper-LDL cholesterolemia as well as such diseases as dyslipidemia (hyperlipidemia), arteriosclerosis, atherosclerosis, peripheral vascular diseases, hypercholesterolemia, familial hypercholesterolemia, cardiovascular functional disorders, angina pectoris, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion disorders, angioplastic restenosis, and hypertension. [0097]
Further, since it is known that proprotein convertaqes (PCs) including PCSK9 are enzymes involved in onset, progress, aggravation and the like of cancer, obesity, diabetes, Alzheimer disease, and viral infectious diseases, use of a Medicament and a pharmaceutical composition comprising the (S)-isomer compound Oil), or a salt thereof, or a solvate thereof as an active ingredient can be expected as a tiuitlliminent for prophylactic and/or therapeutic treatment of the aforementioned diseases in which PCs are involved. [0098]
The racemate oompound (I) and the compound described In Patent document 2, Example 44 (trans-{4-[({2-[({l-[3,5-bis(trifluoromethyDphenyl]ethyl){B-[2-(methylthio)ethoxy] py timid i n-2 -yl) amino)methyl] -4-
(trifluoromethyl)phonyl)(othy1)nmino)methyl]cyclohexyl}acotio aoltl) IIHH suppressing action against HM'G'OoA ruduotiiHo mENAexpression, as spooifioHlly demonstrated in the examples demii-ibml holow. Therefore, use of the racemate compound (I), the compound described in Patent document 2, Example 44, or an enuntiomer thereof, or a

salt thereof, or n Bolvuto thereof can also be expected as a medicament for prophylactic and/or therapeutic troatmont of u disease resulting from HMG-OoA reductase mRNA expression (for oxamplo, diseases accompanying production of isopronoids (farnesylpyrophosphoric acid, geranylgeranylpyrophoephorio acid, and the like) that perform post-translational modification of various proteins such as Has, Rho and Rac with lipids, specifically, inflammation, cancer, Alzheimer disease, osteoporosis, prostatic hypertrophy, glomerular diseases, vermination, virus infection, psoriasis, macular degeneration, and the like). [0099]
As the medicament of the present invention, the aforemontloned active ingredient, per so, may be administered. Preferably, the active ingredient can be administered as a pharmaceutical composition for oral or parenteral administration producible by methods well known to those skilled in the art. Examples of pharmaceutical composition suitable for oral administration include, for example, tablets, capsules, powders, subtilized granules, granules, solutions, syrups, and the like, and examples of pharmaceutical composition suitable for parenteral administration include, for example, injections such as intravenous injections and intramuscular injections, drip infusions, suppositories, inhalants, eye drops, nasal drops, transdermal preparations, transmucosal preparations and the like, however, the pharmaceutical composition is not limited to these examples. [0100]
The aforementioned pharmaceutical composition can be prepared by adding pharmacologically and pharmaceutically acceptable additives. Examples of the pharmacologically and pharmaceutically acceptable additives include, for example, excipients, binders, fillers, disintegrating agents, surfactants, lubricants, dispersing agents, buffering agents, preservatives, corrigents, perfumes, coating agents, diluents, and the like, but are not limited to these examples. [0101]
The dose of the medicament of the present invention is not particularly limited, and the dose can bo suitably chosen depending on a type of a disease, purpose of administration, i.e., prophylactic use or therapeutic use, a type of the active ingredient, and the like, and the dose can also be suitably increased or decreased depending on various factors that should genorally be taken into consideration, BUOII as weight and

age of a patient, symptoms, and administration route. For example, for oral
administration, the medicament can be used in an amount in the range of about 0.1 to
500 mg in terms of weight of the active ingredient as a daily doso for an adult. The
dose can be suitably ohoson by those skilled in the art, and is not Hmitod within the
aforementioned ran go,
Examples
[0102]
The proBont invention will be further explained with reference to examples. However, the present Invention is not limited to these examples. The abbreviations used in the following examples have the following meanings. a- Singlet d: Doublet t: Triplet q: Quartet m: Multiplet br: Broad
J: Coupling constant Hz: Hertz
CDCla: Deuterated chloroform ^-NMR: Proton nuclear magnetic resonance IR: Infrared absorption spectrum [0103]
Example l: Establishment of method for preparing substantially optically pure (S)-isomer compound (III) Example l-i: Optical resolution using chiral column
It has been revealed that, when the following conditions were applied, each enantiomer can be separated from the racemate compound (I) prepared according to the method described in Patent document 2 (International Patent Publication WO2008/129951), Example 45, and that the conditions were usable for measurement of the optical purities of the (SMsomer compound (III) and the (RHsojnof compound (II) by chiral HPLC analysis. The present invention thus provides a method for measuring optical purity of the racemate compound CD, the (S) -isomer compound (III), or the (R)-isomer compound (II), or a salt thereof, or a solvate thereof Using the

following chirul Hl'LCJ analysis oonditions (especially the combination of the column
and mobile phase mentioned below).
[0104]
Column: CHIRALCICL OD-H
Mobile phase: hexane/ethanol/TEA = 90/10/0.1
Flow rate: 1.0 mL/min
Column temperuturo: 40°C
Detection wavelength: 242 nm
Retention time! first peak: 21.8 minutes ((R)-isomer), second peak: 211.7 minutes ((S)-
isomer)
[0105]
However, it waa also found that, because the solvent of tho mobile phase included in the aforomontionud conditions contained EtOH and TEA, they reacted with carboxylic acid of the racemate compound 0) and/or each enantiomer to generate a decomposition product (ethyl ester compound).
Therefore, although the optical resolution using the chiral column under the aforementioned oonditions was usable for measurement of optical purity (chiral HPLC analysis), it was unsuitable for preparation of each of substantially optically pure enantiomers, especially for preparation in a large scale. [0106]
Example 1-2: Method for preparing substantially optically pure (SHsomer compound (III) by preferential crystallization
The outline of the method for preparing substantially optically pure (S)-isomer compound (III) by preferential crystallization performed by the inventors of the present invention is shown below as Scheme 5.
The absolute configuration of each compound was determined from the absolute configuration of (R)-l-bromo-l-[3,5-bis(trifluoromethyDpheny]]ethane confirmed in Step 1.
Further, optical purity of (S)-isomer compound (III) ((S)-trans-{4-[({2-[({l-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfony])ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)pheny]}(ethyl)amino)methyl]cyolohexyl}aceticacid) obtained in Step 6 was determined by chiral HPLC analysis under the conditions described in the abpve section 1-1.

Furthermore, optical purities of l-bromo-l-[8,5-biB(trlfliu)romothyl)phenyl] ethane obtained in Stop 1, and trunB-{4-[({2-[({l-[3,5-bis(trifluorometliyl)phojiyl]otliy]}{5-[2-(methylsulfony0ethoxy]pyrlitil(llii-2-y]}amino)methyl|-4-(trllluoromothyl)pheny]}(ethyl)amino)niothyl|(i.vol<)lioxyl}acetic acid benzyl ester obtnlnod hi Stops 4 nnd 5 were determined by ohJral! IPIJO analysis under the following conditions. Tho present invention thuB also provides u inothod for measuring optical purity of each compound, or a salt thereof, or a solvate thereof, which uses the following chiral HPLC analysis conditions (espeolully the combination of the following column and tho following mobile phase). [0107]
Chiral HPLC analysis conditions for l-bromo-l-[3,5-bis(trifluoronitithy])phenyl]ethane Column: CHIRALPAK AS-ltll Mobile phase: otlmnol/water = 00/40 Flow rate: 0.5 mL/minute Column temperature: 25°C Detection wavelongth: 220 nm
Retention time: first poak: 21.8 minute ((R)-isomer), second peak: 20.0 minute (Ol-igomer) [0108]
Chiral HPLC analysis conditions for trans-{4-[({2-[({l-[3,5-bis(trifluoromethyl)phonyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyjimldln-2-y]}amino)methyl]-4-(trlfluoromothyl)phenyl}(ethy0amino)methyl|oyolohexyl}aceticacid benzyl ester
Column: CHIRALCEL OD-H Mobile phase: hexane/ethanol = 80/20 Flow rate: l.o mL/min Column temperature: 40°C Detection wavelength: 242 nm
Retention time: first peak: 11.3 minutes ((RKsomer), second peak: 13.0 minutes ((S)-isomer) [0109] Scheme 5 [Formula 19]

(In the scheme, Et repreaentB ethyl group, and Bn represents bonzyl group.)
[0110]
Step l: Preparation of (R)-l-bromo-l-[3,5-bis(trifluoromethyl)p1iony]]ethane
(R)-l-Bron>o-l-[3,5-biH(trifluoromethyl)phenyl]ethane was prepared by the method described in l-(a) mentioned below, and the absolute configuration thereof was

confirmed as follows. Specifically, the confirmation was carried out by converting the resulting (R)-l-bromo-H3,5-bis(trifluoromethyl)phenyl]ethane into (S)-l-[3,5-bis(trifluoromethyDphenyl]ethylamine, and comparing the Bign of actually measured specific rotation thereof with that of a commercially available standard product of (S)-l-[3,5-bis(trifluoromethyl)phenyl]ethylamine of known absolute oonfi (juration.
Further, (R)-].-bromo-l*[3,5-bis(trifluoromethyl)phenyl]Bthaiio was also prepared by the method described in l-(b) mentioned below. [0111] l-(a): Preparation of (R)-l-bromo-l-[3,5-bis(trifluoromethyl)phenyllothane (1)
Under an argon atmosphere, l,2-dibromo-l,l,2,2-tetrachloroethane (7.57 g, 23.2 mmol) was dissolved in toluene (12.5 mlt), the solution was addwl with triphenylphosphino (0.1 g, 23.2 mmol) at 0°C, and the mixturo was stirred for 30 minutes. This roaotion mixture was added dropwise with n solution of (S)'l-[8,5-bis(trifluoromotliyl)i)lionyl]othanol (l) (5.0 g, 19.4 mmol, >l)l).fl%oo) in toluene (12.5 mL) at 0°C over 10 minutes or more, and then the mixturo was wnrmod to room temperature, mid nilrrod for 1 hour at the same temperature), Tito reaction mixture was added with n-hexane (25 mO, and the mixture was filtered through Celite. The filtrate was successively washed with water, saturated aqueous sodium hydrogencarbonuto, and saturated brine, dried over sodium sulfa to, and then evaporated under reduced pressure. The resulting residuo was distilled under reduced pressure (56"C, 0.7 mmllg) to obtain 5.52 g of (R)"l"bromo*l"[fl,5" bis(trifluorometliy])phenyl]othano (2) as colorless oil (yiold: 88.6%). [0112]
Chiral HPLG analysis: optical purify >99.5%ee (main peak: first poalc), conversion rate ^99%
[OJD2B +59.1 (c = 1.03, GHCla)
iH-NMR (CDClii) Bs 2.08 (8H, d, J=7.1Hz), 5.21 (1H, q, J=7.1H/-), 7.RI (1H, s), 7.87 (2H, a)
[0113]
Confirmation of absolute configuration of (R)-l-bromo-l-[3,5-bis(trifluoromethyl)phonyl]ethane
A solution of (R)-l-bromo-l-[3,5-bis(trifluoromethyl)pheny]|ol.hane (2) (106 mg, 0.336 mmol, 99%oe) obtained in l-(a) mentioned above in N.N-dimathylfbrmamide (1

mL) was added with sodium azide (64.4 mg, 0.990 mmol), and the mixture was stirred
at • 18 to • 15°C for 4 hours. The reaction solution was extracted with ethyl acetate/n-
hexane (Ll) and water, the organic layer was washed with saturated brine, dried over
anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain
111.5 mg of l-[3,5-bis(trifluoromethyl)phenyl]ethyl azide (crude product: 111.5 mg).
[0114]
iH-NMR (CDCla) 8:1.61 (3H, d, J=6.8Hz), 4.79 (1H, q, J=6.8Hz), 7.78 (2H, s), 7.84 (1H,
s)
[0115]
The resulting l-[3,6-bis(trifluoromethy])phenyl]ethyl azido (tirade product: 111.5 mg) was dissolved in methanol (6 mL) and the solution was added with palladium-fibroin (18 mg) for hydrogen substitution, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroformlmethanol« 50:1 to 5:1) to obtain 77.6 mg of H3,R"bis(trifluoromethyl)phenyl]ethylamlne as colorless oil (yield: 91%, for 2 steps). [0116]
iH-NMR (CDOln) fl: 1.42 (all, d, ,l«G.8Hz), 1.58 (2H, bre), 4.H0 (111, <], J-0.8Hs), 7.75 (1H, s), 7.85 (2H, s) [0117]
Specific rotation of the resulting l-[3,5-bis(trifluoromothyl)phenyl]ethylamine was as follows. [ab2« -15.9 (c= 1.31, CHCln) [0118]
Specific rotation of a commercially available standard product ((S)-l-[3,5-bis(trifluorometbyl)plionyl]ethylumine (Central GlasB Co., Ltd., Lot. 0102000, optical purify: 99%ee)) wus as follws. [O]D2B-15.9 (c =1.15, GIICIB) [0119]
The sign of the actually moasured specific rotation was found to be conform with that of the commercially available standard product, and aoooriHngly, it was confirmed that the resulting l-[3,5-bis(trifiuoromethy])phonyl]ethylamlne was the (S)-

isomer. Further, because this amine was obtained from l-bromo- l-[8,5"
bi8(trifluoromethyl)phenyl]ethane through a nucleophilic substitution reaction of azide
ion, it was confirmed that l-bromo- l-[3,5-bis(trifluoromethyl)phenyl]ethane obtained in
l-(a) mentioned above was the (R)-isomer.
[0120]
l-(b): Preparation of (R)-l-bromo-l-[3,5-bis(trifluoromethyl)phenyl]ethane (2)
Under argon atmosphere, (S)-l-[3,5-bis(trifluoromethyl)phenyl]ethanol (l) (300 g, 1.16 mol, 96%ee) was added dropwise with phosphorous tribromide (157.3 g, 0.58 mol) at a temperature lower than 20°C on a water bath, and the mixture was stirred at 19 to 22°C for 30 minutes. The reaction mixture was cooled, and added dropwise with hydrogen bromide (30% solution in acetic acid, 228 mL, 1.16 mol) at a temperature lower than 0°C, and the mixture was stirred at 13 to 15°C for 16 hours. The reaction mixture was poured into ice water, and the mixture was extracted with n-hexane (3 L x 2). The organic layers were combined, successively washed with saturated aqueous sodium hydrogencarbonate (3 L), and saturated brine (3 D, dried over anhydrous magnosium sulfate, and then concentrated under reduced pressure (90 to 100 mmHg) to obtain 389.2 g of a crude product. The resulting crude product was purified by column chromatography (silica gel: 900 g, developing solvent: n-hexane) to obtain 349.8 g of (R)-l-bromo-l-[8,5-bis(trhluoromethyl)phenyl]ethane (2) as colorless oil (yield: 93.8%).
The first puuk was obsorved as the main peak in the chiral IIPLC analysis as described below, and accordingly, it was confirmed that l-bromo- 1.-[}),B" bis(trifluoromeUiyl)phonyl]ethano prepared in l-(b) was also the (lO'Uomer, like that obtained in l*(a), [0121]
Chiral HPLO aiiulysls! optical purify: >93.9%ee (main poak: first poult), conversion rate: 97.8%
iH-NMR (CDCla) fi: 2.08 (3H, d, J=7.1Hz), 5.21 (1H, q, J=7.1IIz), 7.81 (1H, s), 7.87 (2H, s)
[0122]
Step 2: Preparation of (S)-isomordominant semi-chiral compound of trans-{4-[({2-[({l-[3,5-bis(trifluor()mothy])phortyl]othyl}{5-[2-(methylthio)etlu)xy]pyi'linldin-2-yl}amino)methyl] -4- (trifluoromothyl)phenyl}(ethyDamino)mo thy I loyolohoxyOacetic acid

Under urgon atmosphere, a Bolution of ethyl trana-[4"([(oth,yl){2-[({5-[2-(methylthio)ethoxy]pyrlraidin-2-yl}amino)methyl]-4-
(trifluoromethyl)phenyl}amino]methyl)cyclohexy]]acetate (8) (565.4 g, 0.99 mol) synthesized by the method described in Patent document 2 (International Patent Publication WO2008/129951) in anhydrous tetrahydrofuran (THF, 2.26 U) was added with NaH (60% in oil, 119 g, 2.98 mol) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to -80°C, and added dropwise with a solution of (R)-l-bromo-l-[3,5-bis(trifluoromethyl)phenyl]ethane (2) (682 g, 1.99 mol, 93.9%ee) obtained in Step 1 in anhydrous N,N-dimethylformamide (4.53 L) so that temperature of the inside of the reaction system was maintained to be -15°C or lower, and the mixture was stirred at -15 to -1°C for 5 hourB. The reaction mixture was poured into a mixed solution of ice water (35 L) and toluene (30 H), the mixture was added with citric acid up to pH being 6.9, and the organic layer was separated. [0123]
The aqueous layer was extracted twice with toluene (20 V}, the organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in ethanol (8 D, the solution was added with 2 M aqueous NaOH (1,24 L, 2.48 mol) under ice cooling, and the mixture was stirred at 50°C for 3.5 hours. The reaction mixture was added with 1M aqueous HC1 under ice cooling up to pH of the mixture being 5.4, the mixture was poured into water (251), and the mixture was extracted twice with ethyl acetate (22 L). The organic layer was washed with saturated brine (12 L), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel: 21 g, developing solvent: hoptano/ucotone = 7/1 -* 3/1) to obtain a semi-ohiral compound (4) of trans-{4- [({2- [({l • [3,&-l>is(triuuoromethy])pheny]]ethyl} {B-12-(methylthio)ethoxy]i)yi'lmidin'2-yl}amino)methyl]-4-
(trifluoromethyl)i)honylKethyl)amino)methyl]cyclohexy]}atiotlon(ilfl (yellow oil, 744.1 g, yield: 96%). [0124]
(R)-l-Bromo-l-[3,5-bis(trifluoromethyl)phenyl]othane (2) of which absolute configuration was confirmed as described in Step 1 mentioned above was used as the

starting material, and tho nucleophllic substitution reaction witli tho amine (3)
advanced. Accordingly, the resulting semi-chiral compound (4) was an (S)-isomer
dominant compound.
[0125]
iH-NMR (CDOla) 8: 0.85-0.90 (711, m), 1.35-1.45 (4H, m), 1.(10-1.78 (BIT, m), 2.18-2.21
(5H, m), 2.69 (lH, in), 2.81-2.91 (5H, m), 4.16 (2H, q, J=6.8Hz), 4.(31 (HI, d, J=17.1Hz),
4.85 (1H, d, J=17.1Hz), 6.22 (lH, q, J=6.8Hz), 7.11 (1H, d, J=8.6Hz), 7.23 (lH, s), 7.37
(1H, d, J=8.3Hz), 7.70 (lH, s), 7.73 (2H, s), 8.14 (2H, s)
[0126]
Step 3: Preparation of (SHsomordominant semi-chiral compound of trans-{4-[({2-[({l-
[3,5-bis(trifluoromethy])phenyl]othyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-
yl}amino)methyl]-4-(trifluoromethy0phenyl}(ethyl)amino)methy]]cyclohexyl}aceticacid
benzyl ester
Under argon atmosphere, a solution of the (S)-isomer-dominant semi-chiral compound (4) of trans-{4-[({2-[({l-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-y]}amino)methyl]-4-
(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid (744.1 g, 0.95 mol) obtained in Step 2 in anhydrous dichloroethane (11.6 L) was added with benzyl alcohol (113.1 g, 1.05 mol), WSC -HC1 (200.5 g, 1.05 mol) and DMAP (11.9 g, 98 mmol) under ice cooUng, and the mixture was stirred overnight at room temperature, The reaction mixture was added with water (10 L), and the mixture was extracted with chloroform (19 L, 14 L). The organic layer was washed with saturated brine (12 D, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel: 28 g, developing solvent: heptane/ethyl acetate "= 6/1) to obtain a semi-chiral compound (5) of trans-{4-[({2-[({l-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]'4-(trlfluoromethyl)phenyl}(ethy])amino)ni0thylloyolohexyl}aceticacid benzyl ester (yellow oil, 745.8 g, yield: 90%). [0127]
The resulting semi-chiral compound (5) was an (SHsomerdominant compound in the same manner UH the semi-chiral compound (4). [0128] iH-NMR (CDClii) B: 0.87-0.95 (711, m), 1.37 (lH.m), 1.43 (311, d, J-7.11U), 1.65-1.77 (5H,

m), 2.20 (2H, d, J^O.HHz), 2.22 (Jffl, B), 2.66-2.71 (2H, m), 2.82-2.1)1 (411, m), 4.15 (2H, t,
J=6.6Hz), 4.62 (III, d, J=17.1Hz), 4.85 (1H, d, J=17.1Hz), 5.10 (2IJ, «), 0.21 (1H, q,
J=7.1Hz), 7.10 (lit, d, J=8.3Hz), 7.22 (1H, s), 7.28-7.38 (611, m), 7.70 (IH, a), 7.73 (2H,
s), 8.14 (2H, B)
[0129]
Step 4: Preparation of (H)-iaomordominant semi-chiral compound of trans-{4-[({2-[({l-
[3,5-bis(trifluoromotliy0phonyl]ethyl}{5-[2-(methylsulfony])ethoxy]pyrimidin-2-
yl}amino)methyU-4-(trifluoromothyl)phenyl}(ethy0amino)methy]]cyclohexyl}aceticacid
benzyl ester
Under argon atmosphere, a solution of the (SHsomerdominant semi-chiral compound (5) of trans-{4-[({2-[({l-[3,5-bis(trifluoromethyl)phenyl]oi;hyl){5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-
(trifluoromethyl)phenyl}(ethyl)umino)methy]]cyclohexyl}acetic aold benzyl ester (745.8 g, 0.87 mol) obtained in Step 3 in 2-propanol (15.2 D was added with tantalum pentachloride (31.8 g, 87.3 mmol) and 30% aqueous hydrogen peroxide (496 mL, 4.38 mol), and the mixture was stirred at room temperature for 5 hours, The reaction mixture was quenched with saturated aqueous sodium hydrogenaulfite (3.1 L), and added with water (15 L), and the mixture was extracted with chloroform (14 L, 12 L). The organic layer was washed with saturated brine (20 L), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel: 26 kg, developing solvent: heptane/ethyl acetate = 3/1 —> 2/1) to obtain a semi-chiral compound (6) of trans-{4-[({2-[({l-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}aceticacid benzyl ester (yellow amorphous, 619.5 g, yield: 79%). [0130]
The resulting semi-chiral compound (6) was an (SHsomerdominant compound in the same manner as the semi-chiral compound (4) and the semi-chiral compound (5). [0131]
Chiral HPLC analysis: optical purify: 67.7%ee (main peak: second peak) »H-NMR (CDCIB) 6= 0.87-0.96 (7H, m), 1.38 (IH, m), 1.45 (311, d, J=»7.1Hls), 1.65-1.80 (5H, m), 2.21 (2H, d, J*=6.6Hz), 2.69 (IH, m), 2.81-2.91 (3H, m), 3.08 (OH, s), 3.44 (2H, t, J=5.4Hz), 4.44 (2H, t, J=5.4Hz), 4.64 (IH, d, J=17.lHz), 4.86 (IH, d, J=17.3Hz), 5.10

(2H, s), 6.19 (1H, q, J=6.9Hz), 7.12 (1H, d, J=8.3Hz), 7.19 (HI, s), 7.30-7.39 (6H, m),
7.71 (1H, a), 7.72 (211, H), 8.10 (2H, s)
[0132]
Step 5: Preparation of (substantially optically pure (S)-tran8-{4-[({2,l({l'[3,6-
bis(trifluoromothyl)phonyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrlmi(lin-2"
yOamino)methyl]M-(trifluoromethyl)phenyl}(ethyOamino)inethyI.|cy(ilohexyl}aceticacid
benzyl ester
The (S)-lHomordominunt semichiral compound (fl) of tnuiH'{4-K{2-[({l-[3,6-bis(trifluoromethyl)phonyl]ethyl}{5"[2-(methylsulfonyl)ethoxy]pyrlmlilln-2-yl}amino)metliyll-4-(trlfluoromothyl)pb.enyl}(ethyl)amino)niothy]]oyolohexyl}aceticacid benzyl ester (111.7 g, 123.7 mmol, 67.7%ee) obtained in Step 4 WUH disoolved in ethanol (825 mL), and added with separately prepared seed crystals (the raoemate crystals prepared in Step 7 described below, 2.0 mg) at a temperature of 15 to 20CC, and the mixture was stirred at the same temperature for 21 hours, and at 0°0 for 3 hours. The precipitates were separated by filtration, and washed with ooolod othanol (165 mL), and then the mother solution was concentrated under reduced proHHuro to obtain substantially optically pure trans-{4-[({2-[({l-[3,5-bis(trifluoromethyl)phonyt|ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-
(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexy]}acetic acid benzyl ester (7) (yellow amorphous, 66.38 g, yield: 59%).
The resulting trans-{4-[({2-[({l-[3,5-bis(trifluoromethyl)phonyllethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-
(trifiuoromethyl)pheny0(ethyl)amino)methy]jcyclohexyl}acetic acid benzyl ester (7) was obtained by separating racemate-dominant crystals from the (SMsomer-dominant semi-chiral compound (6) by filtration, and therefore, the result was the (SMsomer. [0133]
Chiral HPLC analysis: optical purify >99%ee (main peak: second peak) [CJD20 -42.36 (c = 1.0 w/v%, CHCla) [0134]
Optical purify of the racemate-dominant crystals separated by filtration was 22%ee as determined by chiral HPLC analysis (43.39 g, yield: 39%). [0135] Step 6: Preparation of substantially optically pure (S)-trans-{4-[({2-|({l"[8,5-

bis(trifluoromethyDi)lioi»yl]ethyl){5-[2-(methylsulfonyl)ethoxy]pyrli)il(lln-2-y0amino)methytl-4-(ti'inuoroniotiliy])pheny]}(ethyl)amino)tn()thyl|(!y(!l()hoxyJ)aceticacid
Under nitrogen atmosphere, a solution of (S)-tranH-{4-[({2-[(ll -[3,5-bis^rifluoromoiliyDplionynoiliylHrt-te-dnethylsiiKonyDetlioxylpyr'Imlilln^-yl}amino)methyl]-4-(trlfluoromothyl)phenyl}(ethy])amino)methyl]cyolohexyl}aceticacid benzyl ester (7) (34.2 g, 37.88 mmol, >99%ee) obtained in Stop 5 in othanol (340 mL) was added with 10% Pd-C (wot, 3.4 g) for hydrogen substitution, and then the mixture was stirred at room tomperaturo for 2 hours. The reaction suspension was filtered through Celite, and washed with othanol (50 mD, and the washing solution was concentrated undor reduced proseure to obtain substantially optically pure trans-{4-[({2-[({l43,5-bis(trifluoromothy0imenyl]ethy0{5-[2-(methylHulibi)yl)ol.h()xy]pyrimidin-2-yl}amino)methyl]-4-(trlfluorometliyl)phenyl}(ethyl)amino)methyl|nyoU)hexyl}aceticacid (III) (white amorphous, 31.78 g, yield: 100%).
The resulting compound was a levorotatory compound as shown by the specific rotation mentioned below. Further, because the resulting compound was obtained by deprotection of tho ester moiety of the (S)-isomer benzyl estor (7), the result was also the (S)-isomer. [0136]
Chiral HPLC analysis.' optical purify: >99%ee (main peak: second peak) [O]D20 -46.68 (c = 1.0, CHCla) IR (ATR) cm-': 2921, 1706,1479, 1279,1134
iH-NMR (CDCls) 6! 0.80-0.96 (711, m), 1.38 (lH.m), 1.47 (3H, d, J=7.1H/.), 1.65-1.77 (5H, m), 2.19 (2H, d, J=6.8Hz), 2.72 (1H, m), 2.81-2.91 (3H, m), 3.08 (3H, s), 3.45 (2H, t, J=5.2Hz), 4.44 (2H, q, J=5.4Hz), 4.62 (1H, d, J=17.1Hz), 4.86 (1H, A, J=17.4Hz), 6.21 (1H, q, J=7.1Hz), 7.13 (lH, d, J=8.3Hz), 7.19 (1H, s), 7.38 (1H, d, «T=0.6Hz), 7.71 (1H, s), 7.73 (2H, s), 8.15 (2H, s) [0137]
Step 7: Preparation of racemate seed crystals of trans-{4-[({2-[({l-[3,5" bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfony])ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyDpheny]}(ethyl)amino)methyl]cyclohexyl}aceticacid
benzyl ester
Asolutionoftrans-{4-[({2-[({l-[3,5-bis(trifluoromethyl)pheny]]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-

(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acoticaoid (moemate compound CO, 20 g, 24.61 mmol) synthesized by the method described in Patent document 2 (International Patent Publication WO2008/120051), Kxample 45 in anhydrous dichloromethane (200 mL) was added with benzyl alcohol (2,03 g, 27.07 mmol), DMAP (300 mg, 2.46 mmol) and WSC -HC1(5.19 g, 27.07 mmol) under ice cooling, and the mixture) was warmed to room temperature, and Hfclrrod for 16 hours. The reaction mixture was added with water (100 mL), and the mlxUira was extracted with chloroform (BOO mL). The organic layer was washeil with 2 M aqueous hydrochloric add (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfato, and then concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel: 350 g, developing solvent: N-hexane/ethyl acotate = 3/1 -♦ 1/1) to obtain trans-{4-[({2-f({l-fll,B-bis(trifluoromethyl)phonyl]othyl}{5-[2-(methyl8ulfbnyl)ethoxy]pyrlmidin-2-yl}amino)methyl] -4- (trifluoromothyl)pheny]}(ethyl)amino)motliyl]oyclohexyl}acetic acid benzyl ester (21,15 g, yield: 95.2%) as white amorphous. [0138]
The resulting trans-{4-[({2-[({l-[3,5-bis(trifluoromothyl)phonyllethyl}{5-[2-(methylthio)ethoxy]pyriinidin-2"yl}amino)methyl]-4-
(trifluoromethyl)plienyl}(ethyl)amino)methyl]cyclohexyl}acotlc acid benzyl ester as white amorphous (7.9 g) was dissolved in ethanol (40 mL), the mixture was stirred at room temperature for 15 hourB, and the resulting precipitates woro collected by filtration, washod with cooled ethunol (20 mL), and dried at 00°O for 4 hours under reduced pressure to obtain racomate crystals of trans-{4-[({2-[({l"[3,5-bis(trifluoromethyl)phenyUethyl}{5-[2-(methylsulfony])ethoxy]pyrimidin-2-yl}amino)methyl|-4'(trlfluoromotliyl)phenyl}(ethyl)amino)mothynoyolohexyl}aceticacid benzyl ester (white crystalline powder, 6.98 g, recovery yield: 88.4%). [0139]
Example 2- Study of influence of (S)-isomer compound (HI) on amount of PCSK9 protein and amount of LDL receptor
Influence of a test compound on amount of PCSK9 protein ond amount of LDL receptor was studied by adding the test compound to human hepatoma cell strain, HepG2 cells, and measuring amount of PCSK9 protein and amount of LDL receptor (LDLR) by Western blotting after culture for 48 hours.

Specifically, the HepG2 cells were inoculated on a 6"well plate at a density of 5 x 10B cells/well and cultured overnight, and a test compound dissolved in dimethyl sulfoxide (DMSO), or only DMSO was added to the culture medium in a 1/1000-fold amount. The cells wore cultured at 37°C for 48 hours in a CO2 inoubutor, the culture was added with 100 fit, of the RIPA buffer (50 mM Tris-HCl, pH 7.H, 150 mM NaCl, 1% NP-40, 0.5% sodium dooxycholate, 0.1% SDS, proteinase inhibitor) to disrupt the cells, and proteins wore extracted. The extracted proteins were centrifuged at 10000 x g, the supernatant was collected, and added with an SDS sample buffer (60 mM Tris-HCl, pH 6.8, 2% SDS, 10% glycerol, 3% mercaptoethanol), and the mixture was subjected to separation by SDS-PAGE (SDS-polyacrylamide gel electrophoresis) vising 8% acrylamide gel. Aftor completion of the separation, the protein* wore fixed on a nitrocellulose momlmmo by using ililot Gel Transfer System (liivRmgun), und blocked by using Block Aco (DS Phurma Biomedical, Catalog No. UK-B HO),
Detection ofl.be POSKI) protein, LDLR, and D-actln protein, and measurement of the amounts thereof were performed by labeling the proteins on the membrane using Anti-PCSK9 (Cayman, Catalog No. 1000718), Anti-LDLR (BioVislon, Catalog No. 3839-100), and Anti-B-Aetin (Sigma, Catalog No. A5316), respectively, us tho primary antibody, and Anti-Rabbit IgCHLRP (Sigma, Catalog No. A0545) or Anti-Mouse IgG-HRP (Sigma, Catalog No. A4416) as the secondary antibody, reaotlng a chemiluminesconoe reagent (substrate of HRP) with the secondary antibody on the membrane, and tlion measuring signal intensity using Lumlno Image Analyzer LAS-3000 (Fuji Photo Film). Tho resulting signal intensity waa numerically evaluated by using image analysis software, Science Lab 2002 Multi Gauge (Fuji Photo Film). [0140]
The resulting measured values of the PCSK9 protein amount and the LDL receptor amount woro corrected between those obtained for the Hiimplo added with a test compound and the control Bample (sample added with only DMSO) using the B-actin protein amounts as index. The corrected PCSK9 protein amount and LDL receptor amount of tho test compound addition sample were represented by relative values based on the PCSK9 protein amount and LDL receptor amount of the control sample, respectively, which were taken as 1.
The results are shown in Table 1. [0141]

As the test compound, the following compounds were used. i:(S)-trans-{4-[({2-[({l-[3,5-Bis(trifluoromethyl)phenyllethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl)amino)methyl]-4-(trifluoromethyOphenyl}(ethyl)amino)methyl]cyclohexy]}acetic acid ((S) -isomer compound (III))
The (SMsomer compound Gil) (optical purify: >99%ee) wna added to the culture medium at a final concentration of 10 uM. [0142]
2:(R)-trans-{4-[({2-[({l-[3,5-Bis(trifluoromethyl)pheny]Jethyl}{5-[2-(methylsulfonyl)ethoxylpyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexy]}aceticaoid ((RHsomer compound (II))
The (R)-isomor compound (II) (optical purify: ;>98%ee) was added to the culture medium at a final concentration of 10 uM. [0143]
3:trans-{4-[({2-l({l-[3,5-]Ji8(triiluoromethyl)pheny]]ethyl}{5-[2-(methylsulfonyDalJioxylpyrimldln^-yOaminoJmethyl]^-(trifluoromethy])phonyl}(othyl)uniino)methyl]cyclohexyl}ao()tica(il(l d'/ioomate compound (I))
The racemate compound (I) was added to the culture medium at a final concentration of 10 uM. [0144] [Table 1]

[0146]
As clearly understood from the results shown in Table 1, the (S)-isomer compound (III) markedly reduced the amount of PCSK9 protein and increased the amount of LDL receptor in comparison with the control, whilst the (R) "isomer compound (II) and the racemate compound (I) had almost no such actions. In particular, the amount of LDL receptor was remarkably increased only by the (S)-isomer compound (III) in comparison with the control.
From the above test results, it was revealed that the (SMsomer compound (III) had the reducing action on PCSK9 protein amount and the increasing action on LDL receptor amount.
In addition, although the present invention is not bound by the following estimation, it was estimated that, because the racemate compound (I) had almost no PCSK9 protein amount-reducing action and had absolutely no LDL receptor amount-increasing action despite the fact that it contained about 50% of the (B)'isomer compound (III), the (E)-isomer compound (II) as a constituent component of the racemate compound 0) inhibited the expression of the actions of the (S)-isomer compound (III) in the racemate compound (I). It was further estimated that it is preferable to increase optical purity of the (S)-isomer compound (III) to reduce the content of the OO-isomoi' compound (II) especially for enhancing the LDL receptor amount-increasing action. [0146]
Example 3: Study of influence of (S)-isomer compound (III) on POHKl) niRNA expression
In order to study the mechanism of the PCSK9 protein ninounl-reducing action revealed in Example 2 mentioned above, a test compound was added to the Hep62 cells, and expression amount of PCSK9 mRNA was measured by quantitative real-time PCR niothod after culture for 24 hours.
Specifioully, the HepG2 colls were inoculated on a 24-wofl plate at a density of 2 x 10B cells/well and cultured overnight, and then a test compound dissolved in dimethyl eulfoxido (DMSO), or only DMSO was added to the culture medium in a 1/1000-fold amount. The cells woro cultured at 37°C for 24 hours in u COa incubator, and then added with 500 uL of I800.EN (NIPPON GENE, Catalog No. 31-02501), and the total RNA was extractod. ol)NAwas synthesized from the extrimtod total RNA by

using High Capacity oDNA Reverse Transcription Kit (Applied Blowyeteme, Catalog No. 4368813). Expression amount of human PCSK9 mRNA was measured by quantitative real-time PCR using primers specific to human PCSK9 (Kourimato S. et al., J. Biol. Chem., Vol. 283, p9666), and Fast SYBR Green Master Mix (Applied Biosystems, Catalog No. 4385614). As the measurement apparatus, 7900HT Past Realtime PCR System was used. [0147]
The resulting measured values of the PCSK9 mRNA expression amount were corrected between those obtained for test compound addition samples (3 samples) and control samples (sample added with only DMSO, 3 samples) using the B-actin mRNA expression amounts as index. The corrected PCSK9 mRNA expression amount of the test compound addition samples was represented with a relative value (average ± standard error) based on average of the PCSK9 mRNA expression amounts of the control samples, which was taken as 1.
The results are shown in Table 2. [0148]
As the test compound, the following compound was used, i:(S)-trans-{4-[({2-[({l-[3,5-BiB(trifluoromethyl)phenyl]ethyl}{5-[a' (methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}aceticacid ((S)'isomer compound (III))
The (S)-isomer compound (III) (optical purify: >99%oe) was added to the
culture medium at a final concentration of 10 uM.
[0149]
[Table 2]
[0150]
From the roBults shown in Table 2, it was revealed that the (S)-isomer

compound (III) remarkably reduced the expression amount of PCSKO mRNA in comparison with the control.
Therefore, it was considered that at least a part of the PCSKO protein amount-reducing action of the (S)-isomer compound Oil) revealed in Example 2 was based on the PCSK9 gene expression-suppressing action, and the (SMsomer oompound (III) had a PCSK9 protein production-suppressing action. [0151] Example 4: Study of blood LDL cholesterol-reducing action of (S)-lHomor compound (III)
(S)-trans-{4-[({2-[({l-[3,5-Bis(trifluoromethyl)phenyl]ethyl}{fl-[2-(methylsulfony0ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifiuoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid ((S)-isomer compound Gil), optical purify: >99%ee) was suspended in a 0.5% methylcellulose solution, and orally administered repeatedly to normal hamsters (male Syrian hamsters) once a day over 14 days by using a metal probe. Four hours after the final administration, blood was collected, and plasma was obtained. Lipoproteins in the plasma were analyzed by automatic measurement using an HPLC system based on the post-labeling method according to the method described in J. Lipid. Res., 43, p805-814. Specifically, 15 fiL of a plasma sample was diluted 10 times with PBS containing 1 mM EDTA, and 80 uL of the diluted sample was injected into a gel filtration column (Superose 6 column (column size: 10 x 300 mm), GE Healthcare Bioscience) connected to an HPLC system (liquid feeding unit: Shimadzu LO20A System, Shimadzu). Separation was performed at a flow rate of 0.5 mL/minute and a column temperature of 40°C by using PBS containing 1 mM EDTA as a running buffer, A cholesterol-measuring reagent (Cholesterol E-Test Wako, Wako Pure Chemical Industries) was mixed with the eluato from the column at a flow rate of 0.25 mL/mlntito, and the reaction was performed at 40°C in a reaction coil (0.5 mm x 15 m) with feeding the eluate. Cholesterols In the eluate obtained from the reaction coil wore detected at a wavelength of 600 nm. Area ratio of the LDL fraction baaed on the resulting total peak area of cholesterols was calculated, and the total cholesterol amount measured beforehand by using Cholesterol E-Test Wako was multiplied by the urea ratio of the LDL fraction to calculate LDL cholesterol amount. [0152]
Six normal ImmstorH wore used for each of the control group (0.5%

methylcellulose solution administration group) and the test compound administration groups (10 mg/kg body weight and 30 mg/kg body weight of (SHaomer compound (III) administration groups). The hamsters were divided into the groups beforehand on the basis of the total plasma cholesterol value. [0153]
The amounts of LDL cholesterol in the plasma of the groups (LDL-C, mg/dl) are shown in Table 3. The symbols * and *** in Table 3 means that there were significant differences at a significance level of 5% or less (p < 0.05) and a significance level of 0.1% or loss (p < 0.001), respectively, as determined by a multi-group comparison test (Dunnett's multiple comparison test) performed between the control group and each of the test compound administration groups. Further, tho LDL cholesterol amount-roducing rate of the test compound administration group based on the control group was calculated in accordance with the following equation 1 as an LDL cholesterol-reducing rate, and indicated in terms of percentage. [0154]
LDL cholesterol-reducing rate (%) = [(Average of LDL cholesterol amount of control group - Average of LDL cholesterol amount of compound administration group)/Average of LDL cholesterol amount of control group] x 100 (Equation l) [0155] [Table 3]
[0156]
From the results shown in Table 3, it was revealed that the (B) -isomer compound (Jit) had superior blood LDL cholesterol-reducing action.
From tho test results mentioned above, it was also revealed that the (S)-isomer compound (III) is useful as an active ingredient of a medicamont having a blood LDL-reducing action, and the like.

[0157]
Example 5: Study of influence of racemate compound (I) and the liko on HMG-CoA
reductase mRNA expression
A test compound WBB added to the HepG2 cells and the OOIIH were cultured for 8 hours, and thon HMQ-CoA roductase mRNA expression amount wan measured by quantitative rouHimu PCR.
Specifically, tho HepG2 cells were inoculated on a 24-woll plate at a density of 2 x 10B cells/well and oulturod overnight, and then a test compound dissolved in dimethyl sulfoxido (DMSO), or only DMSO was added to the oulturo medium in a 1/1000-fold amount. The colls wore cultured at 37°C for 8 hours in u OO2 incubator, and then added with 500 uL of ISOGEN (NIPPON GENE, Catalog No. 31-02501), and the total RNA was extracted. cDNA was synthesized from the extracted total RNA by using High Capacity cDNA Reverse Transcription Kit (Applied BlosystomB, Catalog No. 4368813). Expression amount of human HMG-CoA reductase mRNA was measured by quantitative real-time PCR using a set of the following primers1 5'" GGTGTTCAAGGAaCATGCAAAG-3' and 5'-TGACAAGATGTCCTGCTGCCA-3' specific to human HMG-CoA reductase, and Fast SYBR Green Master Mix (Applied Biosystems, Catalog No. 4385614). As tho measurement apparatus, 7000.HT Font Realtime PCR System was used. [0158]
The resulting measured values of the HMG-CoA reductase mRNA expression amount were corrected between those obtained for test compound addition samples (3 samples for each compound) and control samples (sample added with only DMSO, 3 samples) using the B-actin mRNA expression amounts as index. The corrected HMG-CoA reductase mRNA expression amount of the test compound addition sample was represented with a relative value (average ± standard error) based on average of the HMG-CoA reductase mRNA expression amounts of the control samples, which was taken as 1.
The results are shown in Table 4. [0159]
As the test compound, the following compounds were used. i:trans-{4-[({2-[({l-[3,5-Bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-

(trifluoromethyOphonylKothyOuinino)methyl]cyclohexyl}aool.lo uold (ruoemate compound (I))
The racemato compound (l) was added to the culture medium at a final concentration of 10 uM. [0160]
2: trans-{4-[({2-1({1 ■ [a,5-Bis(trHluoromethyl)phenyl]ethyl}{5-|2-(methylthio)ethoxy]pyrimidin"2-y0amino)methyl]-4-
(trifluoromethyOpheny]}(ethyl)amino)methyl]cyclohexyI}acetio aoid (compound described in Patont dooumont 2, Example 44)
The compound described in Patent document 2, Example 44 wus added to the culturo medium at a final concentration of 10 uM. [0161] [Table 4]
[0162]
From the results shown in Table 4, it was revealed that both the racemate compound (I) and the compound described in Patent document 2, Example 44 remarkably reduced HMG-CoA reductase mRNA expression amount in comparison with the control. Industrial Applicability [0163]
The (SHsomer compound (III) has a PCSK9 protein amount-reducing action, and an LDL receptor amount-increasing action, and has superior blood LDL cholesterol-reducing action. Therefore, the compound can be utilized, for example, as

an active ingredient of a medicament for reducing blood LDL choloatorol, and the like, and thus can be utilised in the pharmaceutical industry.

What is claimed is:
[Claim 1]
Substantially optically pure (S)-trans-{4-[({2-[({l-[a,5-bifi(fcrHluoromethyl)-phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)mothyll-4-(trifluoromethyl)pheny]}(ethyl)amino)methyl]cyclohexyl}acetic acid, or a salt thereof, or a solvate thereof. [Claim 2]
A substantially optically pure levorotatory enantiomer of trnna"{4-[({2-[({l-[3,5-bis(trifluoroinotliy])phenyl]othyl}{5"[2-(methylsulfony])ethoxy]pyi'lml(1ln-2-yl}amino)methyl|-4-