CN100368374C - Carboxylic compound and medicine comprising the same - Google Patents

Abstract

A compound represented by the following general formula (1): [wherein m is an integer of 0 to 4; n is an integer of 5 to 9; and W represents -CH(OR)- (R represents hydrogen or a hydroxy-protecting group) or -C(=O)-], a salt of the compound, or an ester of the compound. The compound, salt, or ester is effective in blood sugar depression, plasma insulin reduction, and triglyceride reduction and is useful for the prevention of and/or treatments for diabetes, complications of diabetes, hyperlipemia, etc.

Description

Carboxylic acid cpd and contain the medicine of this compound

Technical field

The present invention relates to a kind of demonstrate strong blood sugar reduction effect, plasma insulin reduction effect and glyceryl ester reduction effect, and be not attended by weight increase and carboxylic acid cpd fat, that can prevent and/or treat diseases such as diabetes, diabetic complication, high fat of blood, arteriosclerosis, and the medicine that contains this carboxylic acid cpd.

Background technology

Diabetes are the metabolic diseases that produced by multiple reason, are divided into 1 type of hypoinsulinism or follow 2 types of the insulin sensitivity reduction of tip tissue.Diabetes B is a background with environmental factorss such as fat and overfeedings, sharply increases in recent years, it is said that world's onset diabetes rate is 5%.

Regular Insulin and the sulfonylureas of using in the medication of Diabetes Mellifus more, but hypoglycemia and sulfonylurea caused because liver fatigue and secondary is invalid as its side effect meeting.Biguanides has been improved insulin sensitivity, has corrected hyperglycemia reluctantly, but the situation of bringing out lactic acidosis is arranged.Kai Fa thiazole methane series Remedies for diabetes it is said and has the effect (expert opinion of drug research of improving the tip insulin resistance in recent years, 9, pp1347-1361,2000), and can not cause hypoglycemia, controlling blood sugar still claims that as the side effect report liver is had severe impairment etc. well.Therefore, expect to have the medicine that improves insulin resistance of non-thiazole methane series.

On the other hand, as the compound of non-thiazole methane series, 2,2-dichloro alkanoic acid compound exhibits goes out to reduce the blood glucose value of diabetes type animal, reduces plasma insulin and reduce the effect of plasma glycerol ester simultaneously, these be known (European drug chemistry periodical, 33, pp775-787,1998).Insulism shows as insulin resistance, and high fat of blood conduct and diabetes complicated metabolism of fat have arteriosclerotic danger unusually.Thereby overcoming these problems is the keys that prevent and/or treat diabetes and diabetic complication.

For example, following compd A is to show antidiabetic effect to various animal-types (European drug chemistry periodical, 33, pp.775-787, the compound 3e of record in 1998; Metabolism, 48, pp34-40,1999), it is renderd a service surpasses the thiazolidine based compound.And, because do not show the mechanism of action PPAR γ activation (toxicology archives, 73, pp440-450,1999) of thiazolidine based compound, obviously showing the effect different with the thiazolidine based compound, expectation is about alleviating the compound of side effect.

Compd A

Summary of the invention

In order effectively to treat diabetes and diabetic complication, except alleviating, avoid purposes such as side effect, want easy controlling blood sugar value, avoid the drug interaction used together with other reagent, expect more highly active compound or have under the low consumption equal or equal more than active compound.

According to this viewpoint, lack and have equal or equal above active compound than the higher compound of compd A activity or amount ratio compd A and expect that it is useful to preventing and/or treating diabetes and diabetic complication and high fat of blood and arteriosclerosis.

Thus, the inventor studies in order to find more highly active compound, the carboxylic acid cpd that found that following general formula (1) expression has strong blood sugar reduction effect, can not follow weight increase and obesity, the useful conduct of energy prevents and/or treats the medicine of diabetes, diabetic complication, high fat of blood, arteriosclerosis etc.The present invention is based on above-mentioned discovery finishes.

That is, the invention provides following general formula (1):

[in the formula, m is 0～4 integer, and n represents 5～9 integer, W represents-CH (OR)-(R represents the blocking group of hydrogen atom or hydroxyl) or-C (=O)-] compound of expression, its salt or ester.

And; the invention provides to contain and be selected from above-mentioned general formula (1) [in the formula; m is 0～4 integer; n represents 5～9 integer, W represents-CH (OR)-(R represents the blocking group of hydrogen atom or hydroxyl) or-C (=O)-] material of the ester of permitting on the salt of permitting on the compound of expression, physiology and the physiology is as the medicine of effective constituent.

Above-mentioned medicine can be as the medicine that prevents and/or treats the disease that is selected from high fat of blood, arteriosclerosis, diabetes, diabetic complication, inflammation and cardiac failure.The preferred medical composition as the carrier that contains the material of above-mentioned effective constituent and pharmaceutically permit of these medicine provides.

For other viewpoints; the present invention also is provided for above-mentioned medicine manufacturing; be selected from above-mentioned general formula (1) [in the formula; m is 0～4 integer; n represents 5～9 integer; W represents-CH (OR)-(R represents the blocking group of hydrogen atom or hydroxyl) or-C (=O)-] compound of expression; the use of the material of the ester of permitting on salt of permitting on the physiology and the physiology; and prevent and/or treat and be selected from high fat of blood; arteriosclerosis; diabetes; diabetic complication; the method of the disease of inflammation and cardiac failure; and in the dosing step that comprises human mammal; comprise and be selected from above-mentioned general formula (1) [in the formula; m is 0～4 integer; n represents 5～9 integer, W represents-CH (OR)-(R represents the blocking group of hydrogen atom or hydroxyl) or-C (=O)-] compound of expression; the method that prevents and/or treats significant quantity of the material of the ester of permitting on salt of permitting on the physiology and the physiology.

The optimal morphology that carries out an invention

Compound as general formula (1) expression can have been enumerated an alkali metal salts such as sodium salt, sylvite; Alkaline earth salt such as calcium salt, magnesium salts; Organic alkali salts such as ammonium salt, trialkyl amine salt; Inorganic acid salt such as hydrochloride, vitriol; Organic acid salts such as acetate etc.The salt of permitting on this wherein preferred physiology.

The ester of permitting on its physiology of compound of general formula (1) expression is the ester that the carboxyl by the compound of general formula (1) expression forms, absorbs the ester of the easy hydrolysis in back in rear intestinal specific absorption height preferably for oral administration and the organism.(this alkyl can be that arriving of straight chain shape, chain, ring-type or its combination can be a kind of for example to enumerate alkyl ester, for example carbonatoms is about 1～20, can contain heteroatoms and/or unsaturated link(age)s such as 1 above Sauerstoffatom or nitrogen-atoms in the alkyl chain, can have more than 1 or 2 substituting group arbitrarily on this chain) and the aryl acid esters etc.More specifically be ethyl ester, phenyl ester, carboxyl ester, dimethylamino methyl esters, new pentane acyloxy methyl esters, oxyethyl group carbon acyloxy ethyl ester, phthalidyl ester, (5-methyl-2-oxygen-1,3-dioxolane-4-yl) methyl esters, cyclohexyl oxidation phosphinylidyne ethyl ester etc., but be not limited thereto.And, can also use the acid amides of permitting on the physiology of compound of general formula (1) expression, for example methyl nitrosourea.

In the general formula (1), W represents-CH (OR)-(R represents hydrogen atom or hydroxy-protective group) or-C (=O)-.(such blocking group can reference example such as プ ロ テ Network テ イ Block グ Le-プ ス イ Application オ-ガ ニ Star Network シ Application セ シ ス except synthetic the useful blocking group for the hydroxy-protective group of representing as R; P.G.M. Block Star Star, T.Green compile; the 3rd edition; 1999; John ウ イ リ-and サ Application ズ publication etc.); the protecting group that can also use can offer R and be the such characteristic of the compound of hydrogen atom; it can improve the specific absorption of compound in enteron aisle of being protected, and easy in vivo deprotection.Compound with the such blocking group of the latter can be usefully as prodrug according to various purposes.For example can enumerate ethanoyl, hexadecanoyl, propyl alcohol base, valeryl, succinyl, fumaroyl base, alanyl or dimethylaminomethyl carbonyl etc., but be not limited thereto as blocking group.

In the general formula (1), m represents 0～4 integer, and n represents 5～9 integer, but preferred m+n is the integer of 8～10 scopes, preferred especially 9.M is preferably 1～3 integer, is preferably 1 or 2 especially.N is preferably 6～9 integer, and preferred especially 7 or 8.

Compound, its salt or its ester of general formula (1) expression have situation about existing as the solvate that with the hydrate is representative, but solvate is also contained in the scope of the present invention arbitrarily.And, the compound of general formula (1) expression has 1 asymmetric carbon during for hydrogen atom at R, according to the kind of R or the kind of ester, compound of the present invention (situation of following title " compound of the present invention " comprises the compound and the ester thereof of general formula (1) expression) can further have the asymmetric carbon more than 1.Based on steric isomers such as the optical isomer of the pure form of the asymmetric carbon more than 1 or diastereomer isomer, or any mixture of the steric isomer of raceme etc. is also contained in the scope of the present invention.

In the compound of the present invention, can enumerate 2 as preferred compound, 2-two chloro-12-(4-chloro-phenyl-)-10-hydroxylauric acid and 2,2-two chloro-12-(4-chloro-phenyl-)-11-hydroxylauric acid, with and physiology on the ester of permitting on the salt of permitting and the physiology.

Compound of the present invention for example can be made by the method for record in following synthetic line 1 or the synthetic line 4.And the m in the The compounds of this invention is that 0 compound can be made by the method for record in the synthetic line 2.And then the m in the The compounds of this invention is that 1 compound can be made by the method for record in the synthetic line 3.

(in the following chart, m and n be with aforementioned identical, R ¹The blocking group of expression hydroxyl, R ²Expression alkyl, aryl or allyl group, X and Y represent halogen atom.)

＜synthetic line 1 〉

Step 1:

In inert solvents such as tetrahydrofuran (THF) (THF), dioxan, ether or glycol dimethyl ether, dissolve after the aldehyde, be added in the rare gas element atmosphere solution of the inert solvent of the Grignard reagent (I) by corresponding halogenide preparation, cooling and even stir 30 minutes～several hrs under the room temperature and make compound (III)

Step 2:

Step with suitable blocking group protection compound (III) such as ethanoyl, methoxymethyl.The kind of blocking group and introducing condition can reference example such as プ ロ テ Network テ イ ズ グ Le-プ ス イ Application オ-ガ ニ Star Network シ Application セ シ ス, and P.G.M. ズ Star Star, T.Green compile, and the 3rd edition, 1999, John ウ イ リ-and サ Application ズ publication etc.

Step 3:

This step is at THF, dioxan, 1, the ester of dissolved compound (IV) and dichloroacetic acid in 2-glycol dimethyl ether, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) equal solvent, add sodium alkylate, sodium hydride, LDA alkali such as (LDA) under the rare gas element atmosphere, stirring was finished in 1 hour～24 hours under room temperature and even heating.

Step 4:

The protection hydroxyl of compound (V) is carried out the step of deprotection.The deprotection condition of hydroxyl can reference example such as プ ロ テ Network テ イ Block グ Le-プ ス イ Application オ-ガ ニ Star Network シ Application セ シ ス, and P.G.M. Block Star Star, T.Green compile, and the 3rd edition, 1999, John ウ イ リ-and サ Application ズ publication etc.In addition, can carry out deprotection simultaneously in the step 5 below, step 4 just can be omitted like this.

Step 5:

At methyl alcohol, ethanol, THF, dioxan, 1, dissolved compound (VI) in the 2-glycol dimethyl ether equal solvent, add lithium hydroxide, sodium hydroxide. alkali such as potassium hydroxide, cooling was stirred 1～24 hour down and even under the heating, acid such as adding hydrochloric acid make system be acid, can prepare target product.

＜synthetic line 2 〉

Step 1:

Prepare compound (IX) according to ordinary method esterification compound (VIII).Esterification method is not particularly limited, and can be undertaken by the suitable methods such as active esterification process, mixed anhydride method or condensation method of general use.

Step 2:

Dissolved compound (IX) in tetracol phenixin, hexanaphthene, benzene equal solvent adds halogenating agents such as N-bromosuccinic acid imide, stirs under room temperature and even heating and can obtain compound (X) in 1～24 hour.In order to promote reaction, also can add radical initiators such as dibenzoyl peroxide and Diisopropyl azodicarboxylate.

Step 3:

Dissolved compound (X) in the mixed solvent of organic solvent such as water or acetone, THF, DMF and water adds Silver Nitrate, crosses alkali such as silver salt such as silver chlorate or sodium bicarbonate, can obtain compound (XI) in 1 hour～24 hours stirring under the cooling or under the heating.

Step 4:

This step adopts the method identical with the step 5 of synthetic line 1 to realize.

＜synthetic line 3 〉

Step 1:

Dissolved compound (XIII) in not having solvent or toluene, acetone or DMSO equal solvent adds acid such as sulfuric acid, phosphoric acid, oxalic acid, tosic acid, stirs under room temperature and even heating and can obtain compound (XIV) in 1 hour～24 hours.

Step 2:

Dissolved compound (XIV) in chloroform, methylene dichloride, diethyl ether equal solvent, in the mixing solutions of this solution or above-mentioned solution and sodium bicarbonate aqueous solution etc., add peracid such as M-nitro benzoic acid, 3-chloro perbenzoic acid, trifluoro peroxyacetic acid, stir under cooling off and even under the heating and can obtain compound (XV) in 1 hour～24 hours.

Step 3:

Dissolved compound (XV) in THF, vinyl acetic monomer, alcohols, acetic acid equal solvent adds the carbonization palladium, how to draw catalyzer such as nickel, stirs 1～24 hour under cooling under normal pressure or the pressurized hydrogen atmosphere gas and even heating, makes compound (XVI).

Step 4:

This step adopts the method identical with the step 5 of synthetic line 1 to realize.

＜synthetic line 4 〉

Step 1:

This step is a dissolved compound (VI) in methylene dichloride, acetone, diethyl ether equal solvent, adds pyridinium chlorochromate (PCC), dichromic acid pyridine (PDC) etc., what stirring realized in 1 hour～24 hours under the cooling and even under the heating.

Step 2:

This step is to adopt the method identical with the 5th step of synthetic line 1 to realize.

Can carry out aftertreatment according to ordinary method after above-mentioned synthetic line 1 and even each reactions steps of 4, come as raw material by the refining back of ordinary method operation according to the difference of target product.

The optically active isomer of The compounds of this invention for example can be by optical resolution raceme of the present invention compound or the method for its intermediate, and the asymmetric reaction of The compounds of this invention or its intermediate waits and obtains.For example can enumerate by use as the method for optical resolution has the chromatography of optically active weighting agent to emanate, emanate by being derivatized to chromatography behind the asymmetric isomer compound, emanate etc. by the recrystallize that is derivatized to after the asymmetric isomer salt.Can enumerate for example use as the method for asymmetric reaction the asymmetric oxidation reaction of optically active reagent and catalyzer, asymmetric reduction reaction, the reaction of asymmetric carbon carbon bond, the reduction of using organism catalyzer such as enzyme and yeast, hydrolysis, esterification etc. are arranged.

The The compounds of this invention that obtains by above-mentioned synthetic line can use refining means commonly used such as recrystallize method, column chromatography to make with extra care as required.And also can make above-mentioned desired salt or solvate as required by ordinary method.In addition, among this specification sheets embodiment, more specifically and at length put down in writing the manufacture method of The compounds of this invention, those skilled in the art can be with reference to specific description among the general remark of above-mentioned manufacture method and the embodiment, select suitable reaction reagent, starting raw material and reaction conditions, and appropriate change and modify these methods as required, just can easily make compound of the present invention.

As described later shown in the experiment, The compounds of this invention and salt thereof can be as the effective constituents that prevents and/or treats medicine such as diabetes, diabetic complication, high fat of blood, arteriosclerosis because demonstrate strong plasma glucose reduction effect in the live body appraisement system.This medicine can be taken for the mammal that comprises the mankind, and having can be with weight increase and fat very good feature.

Medicine of the present invention contains and is selected from above-mentioned general formula (1) [in the formula; m represents 0～4 integer; n represents 5～9 integer, W represents-CH (OR)-(R represents hydrogen atom or hydroxy-protective group) or-C (=O)-] material of the ester of permitting on the salt of permitting on the compound of expression, its physiology and the physiology is as its effective constituent.As medicine of the present invention, can use original above-mentioned substance, but general preferred be mixed with contain above-mentioned substance and 1 or the preparation more than 2 kind come confession to take with the medical composition of additive.Can also be used in combination above-mentioned substance more than 2 kinds as medicine of the present invention.

The administration path of medicine of the present invention is not particularly limited, and can take by oral or non-oral any administration path.As being suitable for oral medical composition can be any of solid or liquid medical composition, can enumerate for example preparation forms such as injection, some drops, suppository, external preparation, eye drop, nasal drops, [, adhesive agent as being not suitable for oral medical composition.

Oral drugs in solid composition for example can add vehicle in above-mentioned effective constituent, and then add as required preparations such as tackiness agent, decomposition agent, lubricant, tinting material or seasonings with additive after, by ordinary method preparation as lozenge, particle reagents, powder, capsule reagent.Can use additive commonly used in this field as preparation with additive.For example vehicle such as lactose, sodium-chlor, glucose, starch, avicel cellulose, silicic acid can have been enumerated; Tackiness agent such as water, ethanol, propyl alcohol, simple syrup, gelatin, hydroxypropylcellulose, methylcellulose gum, ethyl cellulose, shellac, Polyvinylpyrolidone (PVP); Decomposition agents such as agar end, Sodium Lauryl Sulphate BP/USP, glyceryl monostearate; Lubricants such as Talc, stearate, borax, polyoxyethylene glycol; Tinting materials such as beta-carotene, yellow ferric oxide, caramel; Seasonings such as white sugar, orange peel.

Liquid medical composition for oral use can add one or two or more kinds that preparations such as seasonings, stablizer or sanitas are used additive in above-mentioned effective constituent, be mixed with liquid preparation for oral administration, syrup preparation, Radix Glycyrrhizae vina etc. by ordinary method.Can use this area additive commonly used as preparation with additive.Seasoningss such as white sugar have for example been enumerated; Stablizers such as gum tragacanth; Sanitass such as p-Hydroxybenzoate.

Injection can add preparation additive such as stablizer or isotonization agent more than a kind or 2 kinds in above-mentioned effective constituent, made the injection of subcutaneous injection, intramuscular injection or used for intravenous injection by ordinary method.Can use this area additive commonly used as preparation with additive.Stablizers such as Sodium Pyrosulfite for example can have been enumerated; Isotonization agent such as sodium-chlor.

Suppository can be made with the ordinary method of additive by add preparations such as carrier and tensio-active agent in above-mentioned effective constituent.Can use this area additive commonly used as preparation with additive.For example carriers such as polyoxyethylene glycol, tristearin can have been enumerated; Tensio-active agents such as polysorbate 80.

External preparation can add preparation additives such as matrix, water-soluble polymer, solvent, tensio-active agent or sanitas more than a kind or 2 kinds in above-mentioned effective constituent, make liquid preparation, emulsion, gel preparation, ointment etc. by ordinary method.Can use this area additive commonly used as preparation with additive.Matrix such as whiteruss, white vaseline, refined wool fat for example can have been enumerated; Water-soluble polymers such as carboxyvinyl polymer; Glycerine, water equal solvent; Tensio-active agents such as polyoxyethylene fatty acid esters; Sanitass such as p-Hydroxybenzoate.

Eye drop can prepare with the ordinary method of additive by add preparations such as stablizer, isotonization agent or sanitas more than a kind or 2 kinds in above-mentioned effective constituent.Can use this area additive commonly used as preparation with additive.For example stablizers such as Sodium Pyrosulfite, EDTA can have been enumerated; Isotonization agent such as sodium-chlor; Sanitass such as butylene-chlorohydrin.

Nasal drops can prepare with the ordinary method of additive by add preparations such as stablizer, isotonization agent or sanitas more than a kind or 2 kinds in above-mentioned effective constituent.Can use this area additive commonly used as preparation with additive.For example stablizers such as Sodium Pyrosulfite, EDTA can have been enumerated; Isotonization agent such as sodium-chlor; Sanitass such as chloro benzylidene hemlock.

[can prepare with the ordinary method of additive by add preparations such as stablizer, isotonization agent or sanitas more than a kind or 2 kinds in above-mentioned effective constituent.Can use this area additive commonly used as preparation with additive.For example stablizers such as Sodium Pyrosulfite, EDTA can have been enumerated; Isotonization agent such as sodium-chlor; Sanitass such as chloro benzylidene hemlock.

Adhesive agent can add preparation additives such as tackiness agent, solvent, linking agent or tensio-active agent more than a kind or 2 kinds in above-mentioned effective constituent, make water type adhesive agent, gypsum adhesive agent etc. by ordinary method.Can use this area additive commonly used as preparation with additive.Tackiness agent such as polyacrylic acid part neutralized reaction product, sodium polyacrylate, polyacrylic acid 2-ethylhexyl, styrene isoprene styrene block copolymer (SIS) for example can have been enumerated; Glycerine, water equal solvent; Linking agents such as dihydroxyl aluminium aminoacetate, Aluminium Hydroxide; Tensio-active agents such as polyoxyethylene fatty acid esters.

The dosage of medicine of the present invention is not particularly limited, can be according to suitable selections such as patient's age, body weight and symptom, administration form, administration path and administration number of times.Usually count adult's dosage of 0.1～100mg every day with the quality of above-mentioned effective constituent.Medicine of the present invention can 1 day 1 time or is divided for several times oral or non-oral.

Embodiment

Embodiment

Be described more specifically the present invention below by embodiment, but scope of the present invention is not limited to these embodiment.

Embodiment 1

(1) 10-bromo-1-(4-chloro-phenyl-)-5-decyl alcohol is synthetic

(591mg adds the anhydrous THF of 5mL in 24.31mmol), stirs in argon atmosphere gas, under the room temperature, adds iodine (10mg), stirs almost to disappear up to dark brown in 2 hours at magnesium.In reaction solution, drip 4-(4-brombutyl) chlorobenzene (6.02g, anhydrous THF solution 24.32mmol) 10 minutes of 10mL.Continuously stirring 3 hours at room temperature after dripping is made Grignard reagent.

(4.79g 49.58mmol) is dissolved among the anhydrous THF of 10mL with 6-bromo hexanal under ice-cooled stirring.The Grignard reagent of dropping preparation in this solution 10 minutes.Make reaction solution be returned to room temperature, continue to stir 18 hours.

After reaction finished, the water-cooled reaction solution slowly added 20mL Purified Water and 20mL saturated aqueous common salt, stirs 20 minutes.Extract this mixture with diethyl ether (50mL, 100mL, 20mL * 2), then extraction liquid is cleaned 1 time with the 20mL Purified Water, clean 1 time,, obtain thick product light green oily matter 16.54g with concentrating under reduced pressure after the dried over sodium sulfate with the 30mL saturated aqueous common salt.With refining this oily matter of silica gel column chromatography (liquid effluent normal hexane/vinyl acetic monomer=10/1), obtain target compound (3.14g, productive rate 37.1%) colorless oil.

¹H-NMR(CDCl ₃)δ：1.23-1.67(12H，m)，1.87(2H，tt，J＝7,7Hz)，2.59(2H，t，J＝8Hz)，3.41(2H，t，J＝7Hz)，3.58(1H，m)，7.10(2H，d，J＝8Hz)，7.24(2H，d，J＝8Hz).

(2) 5-acetoxyl group-10-bromo-1-(4-chloro-phenyl-) decane is synthetic

In the 50mL methylene dichloride dissolving 10-bromo-1-(4-chloro-phenyl-)-5-decyl alcohol (3.14g, 9.03mmol), 4-dimethylaminopyridine (111mg, 0.903mmol) and pyridine (3.97g, 18.1mmol).Ice-cooled this solution stirred after 10 minutes, the Acetyl Chloride 98Min. of Dropwise 5 0mL in 10 minutes (851mg, dichloromethane solution 10.8mmol), restir 3 hours at room temperature after being added dropwise to complete.

After reaction was finished, the water-cooled reaction soln slowly added hydrochloric acid and the 20mL saturated aqueous common salt of 20mL2mol/L, stirs 5 minutes.After separating organic layer, use 2 water layers of 100mL chloroform extraction again.Clean 1 time with the 30mL Purified Water and also clean 1 extraction liquid,, obtain the faint yellow oily thing of thick product 4.33g with concentrating under reduced pressure after the dried over sodium sulfate with the 30mL saturated aqueous common salt.With the refining thick product that obtains of silica gel flash distillation column chromatography (liquid effluent normal hexane/vinyl acetic monomer=20/1), obtain target compound (3.50g, productive rate 99.4%) colorless oil.

¹H-NMR(CDCl ₃)δ：1.22-1.65(12H，m)，1.84(2H，tt，J＝7,7Hz)，2.02(3H，s)，2.56(2H，t，J＝8Hz)，3.39(2H，t，J＝7Hz)，4.85(1H，m)，7.08(2H，d，J＝8Hz)，7.24(2H，d，J＝8Hz).

(3) 8-acetoxyl group-2,2-two chloro-12-(4-chloro-phenyl-) Laurate methyl synthetic

In argon atmosphere gas, under the room temperature, stir, make that the 5-acetoxyl group-(3.50g 8.97mmol) is dissolved among the DMF of 50mL 10-bromo-1-(4-chloro-phenyl-) decane.(5.14g 35.9mmol), uses ice-cold cooling to add Methyl Dichloro Acetate therein.In this solution-(1.50g 35.9mmol), stirred 1 hour inferior adding sodium hydride, and then continuously stirring 36 hours at room temperature.

The water-cooled reaction solution slowly adds the saturated aqueous common salt of 20mL, stirs 5 minutes.And then behind the interpolation 80mL water, with 50mL diethyl ether extraction 3 times, then use 50mL Purified Water cleaning 1 time, clean 1 extraction liquid with the 50mL saturated aqueous common salt, with concentrating under reduced pressure after the dried over sodium sulfate, obtain the faint yellow oily thing of thick product 6.24g.With refining this thick product of silica gel flash distillation column chromatography (liquid effluent normal hexane/vinyl acetic monomer=20/1), obtain target compound (1.43g, productive rate 35.5%) colorless oil.

¹H-NMR(CDCl ₃)δ：1.22-1.42(6H，m)，1.46-1.66(8H，m)，2.03(3H，s)，2.40(2H，m)，2.57(2H，t，J＝8Hz)，3.89(3H，s)，4.85(1H，m)，7.09(2H，d，J＝9Hz)，7.23(2H，d，J＝9Hz).

Synthesizing of (4) 2,2-two chloro-12-(4-chloro-phenyl-)-8-hydroxylauric acid

With 8-acetoxyl group-2, (1.43g 3.17mmol) is dissolved in the 40mL methyl alcohol 2-two chloro-12-(4-chloro-phenyl-) Laurate methyl under ice-cooled stirring.(15.9mL 31.7mmol), stirred 15 minutes the lithium hydroxide aqueous solution of adding 2mol/L, and at room temperature restir is 20 hours in this solution.

After reaction finishes, the water-cooled reaction solution, dripping 20mL saturated aqueous common salt and 20mL2mol/L hydrochloric acid makes it to acid, with 100mL chloroform extraction 3 times, then use 50mL Purified Water cleaning 1 time, clean 1 extraction liquid with the 50mL saturated aqueous common salt, with concentrating under reduced pressure after the dried over sodium sulfate, obtain the faint yellow oily thing of thick product 1.68g.With the refining thick product that obtains of silica gel column chromatography (liquid effluent chloroform/methanol=20/1～2/1), obtain the faint yellow oily thing of target compound (749mg, productive rate 59.7%).

¹H-NMR(CDCl ₃)δ：1.24-1.77(14H，m)，2.43(2H，m)，2.58(2H，t，J＝8Hz)，3.67(1H，br)，7.09(2H，d，J＝8Hz)，7.23(2H，d，J＝8Hz).

Embodiment 2

(1) 10-bromo-1-(4-chloro-phenyl-)-3-decyl alcohol is synthetic

(1.07g adds the anhydrous THF of 20mL in 44.0mmol), stirs in argon atmosphere gas, under the room temperature, adds iodine (10mg), stirs almost to disappear up to dark brown in 2 hours at magnesium.(9.62g, anhydrous THF solution 43.8mmol) continue to stir 3 hours, made Grignard reagent slowly to add 4-(2-bromoethyl) chlorobenzene of 20mL in this reaction solution.

(10.27g 49.6mmol) is dissolved among the anhydrous THF of 30mL with 8-bromo-1-octanal in argon atmosphere gas, under the ice-cooled stirring.The Grignard reagent of dropping preparation in this solution 15 minutes.Make reaction solution be returned to room temperature, continue to stir 16 hours.

After reaction finished, the water-cooled reaction solution slowly added 20mL Purified Water and 20mL saturated aqueous common salt, stirs 20 minutes.With 2 these mixtures of 100mL diethyl ether extraction, then extraction liquid is cleaned 1 time with the 30mL Purified Water, clean 1 time with the 30mL saturated aqueous common salt, with concentrating under reduced pressure after the dried over sodium sulfate, obtain the absinthe-green oily matter 16.54g of thick product.With refining this oily matter of silica gel column chromatography (liquid effluent normal hexane/vinyl acetic monomer=8/1～4/1), obtain target compound (5.85g, productive rate 38.3%) colorless oil.

¹H-NMR(CDCl ₃)δ：1.23-1.76(12H，m)，1.80-1.88(2H，m)，2.56-2.69(1H，m)，2.70-2.81(1H，m)，3.40(2H，t，J＝7Hz)，3.51-3.66(1H，m)，7.12(2H，d，J＝9Hz)，7.24(2H，d，J＝9Hz).

(2) 3-acetoxyl group-10-bromo-1-(4-chloro-phenyl-) decane is synthetic

Dissolving 10-bromo-1-(4-chloro-phenyl-)-3-decyl alcohol in the 50mL methylene dichloride (5.85g, 16.8mmol).Ice-cooled this solution, add 4-dimethylaminopyridine (205mg, 1.68mmol) and pyridine (7.38g 33.62mmol), stirred 10 minutes.In 5 minutes in this solution Dropwise 5 0mL Acetyl Chloride 98Min. (1.58g, dichloromethane solution 20.13mmol) stir 20 minutes same as before, and then at room temperature stir 30 minutes.

After reaction was finished, the water-cooled reaction soln slowly added hydrochloric acid and the 20mL saturated aqueous common salt of 20mL2mol/L, stirs 5 minutes., then use 30mL Purified Water cleaning 1 time, clean 1 extraction liquid its extraction 2 times with the 200mL vinyl acetic monomer,, obtain the faint yellow oily thing of thick product 7.02g with concentrating under reduced pressure after the dried over sodium sulfate with the 30mL saturated aqueous common salt.With the refining thick product that obtains of silica gel column chromatography (liquid effluent normal hexane/vinyl acetic monomer=20/1), obtain target compound (5.17g, productive rate 78.8%) colorless oil.

¹H-NMR(CDCl ₃)δ：1.24-1.60(10H，m)，1.76-1.89(4H，m)，2.04(3H，s)，2.51-2.68(2H，m)，3.40(2H，t，J＝7Hz)，4.86-4.94(1H，m)，7.10(2H，d，J＝8Hz)，7.24(2H，d，J＝8Hz).

(3) 10-acetoxyl group-2,2-two chloro-12-(4-chloro-phenyl-) Laurate methyl synthetic

In argon atmosphere gas, under the room temperature, stir, make that the 3-acetoxyl group-(5.17g 13.26mmol) is dissolved among the DMF of 50mL 10-bromo-1-(4-chloro-phenyl-) decane.(5.69g 39.80mmol), stirred 10 minutes, and then stirred 10 minutes down at-10 ℃ to add Methyl Dichloro Acetate in this solution.(1.74g 39.79mmol), stirred 1 hour, and then at room temperature continued to stir 15 hours to add sodium hydride in this reaction soln rapidly.

After reaction finished, the water-cooled reaction solution slowly added the saturated aqueous common salt of 20mL, stirs 5 minutes.With 2 these mixtures of 200mL diethyl ether extraction, then use 30mL Purified Water cleaning 1 time, clean 1 extraction liquid with the 30mL saturated aqueous common salt, with concentrating under reduced pressure after the dried over sodium sulfate, obtain the faint yellow oily thing of thick product 6.39g.With refining this thick product of silica gel column chromatography (liquid effluent n-hexane/acetone=20/1), obtain the faint yellow oily thing of target compound (1.68g, productive rate 28.0%).

¹H-NMR(CDCl ₃)δ：1.22-1.65(12H，m)，1.76-1.92(2H，m)，2.04(3H，s)，2.37-2.46(2H，m)，2.50-2.66(2H，m)，3.89(3H，s)，4.86-4.96(1H，m)，7.10(2H，d，J＝9Hz)，7.24(2H，d，J＝9Hz).

Synthesizing of (4) 2,2-two chloro-12-(4-chloro-phenyl-)-10-hydroxylauric acid

With 10-acetoxyl group-2, (1.68g 3.72mmol) is dissolved in the 40mL methyl alcohol 2-two chloro-12-(4-chloro-phenyl-) Laurate methyl under ice-cooled stirring.(18.6mL 37.2mmol), stirred 10 minutes, and at room temperature restir is 16 hours to add the lithium hydroxide aqueous solution of 2mol/L therein.

After reaction finishes, the water-cooled reaction solution, dripping 20mL saturated aqueous common salt and 20mL2mol/L hydrochloric acid makes it to acid, with 150mL chloroform extraction 3 times, then use 30mL Purified Water cleaning 1 time, clean 1 extraction liquid with the 30mL saturated aqueous common salt, with concentrating under reduced pressure after the dried over sodium sulfate, obtain the faint yellow oily thing of thick product 1.68g.

With refining this oily matter of silica gel column chromatography (liquid effluent chloroform/methanol=10/1～2/1).Concentrating under reduced pressure is dissolved in the 300mL chloroform after containing the cut of target product, cleans with the mixing solutions of 30mL saturated aqueous common salt and 30mL 2mol/L hydrochloric acid, then cleans 1 time with the 50mL Purified Water, cleans 1 time with the 50mL saturated aqueous common salt.With concentrating under reduced pressure behind this solution of dried over sodium sulfate, obtain thick product colorless oil 1.32g.In this oily matter, add normal hexane, make its crystallization, obtain the 1.30g white crystalline powder.With vinyl acetic monomer-this coarse crystallization of normal hexane mixed solvent recrystallize, obtain target compound (1.00g, productive rate 67.9%) white crystalline powder.

¹H-NMR(CDCl ₃)6：1.26-1.52(10H，m)，1.54-1.63(2H，m)，1.71-1.79(2H，m)，2.41-2.47(2H，m)，2.60-2.69(1H，m)，2.72-2.81(1H，m)，3.67(1H，br)，7.12(2H，d，J＝8Hz)，7.25(2H，d，J＝8Hz).

Fusing point: 100.0～101.7.℃ (recrystallize solvent: vinyl acetic monomer-normal hexane)

Embodiment 3

Synthesizing of (1) 2,2-two chloro-12-(4-chloro-phenyl-) Laurate methyl

Dissolve 2 in 1000mL methyl alcohol, (47.3g, 124.5mmol), (6.10g 62.19mmol), heat and made its stirring that refluxes in 24 hours 2-two chloro-12-(4-chloro-phenyl-) lauric acid to add sulfuric acid.

Behind the cooling reaction solution, concentrating under reduced pressure adds 500mL chloroform, 500mL water, separates organic layer.After using chloroform extraction (100m * 3) water layer again, merge organic layer, washing (200mL), behind anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the faint yellow oily thing of thick target compound (47.35g, productive rate 96.6%).

¹H-NMR(CDCl ₃)δ：1.22-1.40(12H，m)，1.51-1.62(4H，m)，2.41(2H，m)，2.56(2H，t，J＝8Hz)，3.89(3H，s)，7.10(2H，d，J＝8Hz)，7.23(2H，d，J＝8Hz).

(2) the 12-bromo-2,2-two chloro-12-(4-chloro-phenyl-) Laurate methyl synthetic

Dissolving thick 2 in the 500mL tetracol phenixin, 2-two chloro-12-(4-chloro-phenyl-) Laurate methyl (47.25g, 120.0mmol), add 22.42gN-bromosuccinic acid imide (126.0mmol), 39.4mg2,2 '-azo isobutyronitrile (0.24mmol), heating is 1 hour under argon atmosphere gas, it is refluxed stir.Behind the cooling reaction solution, concentrating under reduced pressure is dissolved in the 800mL vinyl acetic monomer, and washing (200mL * 3) after the saturated common salt washing (200mL), is used anhydrous sodium sulfate drying.Make this solution decompression, heat up in a steamer and desolvate, obtain the faint yellow oily thing of thick target compound (57.35, quantitative).

¹H-NMR(CDCl ₃)δ：1.22-1.62(14H，m)，2.10(1H，m)，2.24(1H，m)，2.41(2H，m)，3.89(3H，s)，4.90(1H，t，J＝7Hz)，7.30(2H，d，J＝9Hz)，7.33(2H，d，J＝9Hz).

Synthesizing of (3) 2,2-two chloro-12-(4-chloro-phenyl-)-12-hydroxylauric acid methyl esters

The thick 12-bromo-2 of dissolving in the mixed solvent of 1000mL acetone-200mL water, and 2-two chloro-12-(4-chloro-phenyl-) Laurate methyl (57.35g, 120.0mmol).At room temperature drip 40% and cross silver chlorate aqueous solution 68.4mL (132mmol) 10 minutes, at room temperature stirred after being added dropwise to complete 90 minutes to this solution.In reaction solution, add the 200mL saturated aqueous common salt, stir elimination insolubles after 30 minutes.After decompression is heated up in a steamer acetone from filtrate down, merge, separate organic layer with the washing lotion of cleaning insolubles with the 500mL vinyl acetic monomer.After using ethyl acetate extraction (200mL * 2) water layer again, water (200mL) and saturated aqueous common salt (200mL) clean organic layer.After obtaining organic layer with anhydrous sodium sulfate drying, heat up in a steamer under the decompression and desolvate.With the refining residue of silica gel column chromatography (liquid effluent n-hexane/acetone=8/1～2/1), obtain the faint yellow oily thing of target compound (28.97g, productive rate 58.9%).

¹H-NMR(CDCl ₃)δ：1.22-1.44(12H，m)，1.51-1.83(4H，m)，2.40(2H，m)，3.89(3H，s)，4.65(1H，br)，7.27(2H，d，J＝6Hz)，7.32(2H，d，J＝6Hz).

Synthesizing of (4) 2,2-two chloro-12-(4-chloro-phenyl-)-12-hydroxylauric acid

Dissolve 2 in 300mL methyl alcohol, (28.88g, 70.48mmol), (70.5mL 141mmol), at room temperature stirred 1 hour 2-two chloro-12-(4-chloro-phenyl-)-12-hydroxylauric acid methyl esters to add the 2mol/L lithium hydroxide aqueous solution.Decompression adds 200mL water after heating up in a steamer methyl alcohol from reaction solution down, and the ice-cooled 2mol/L hydrochloric acid that drips down makes it be acid.

In this mixture, add 10: 1 mixed solution of 800mL chloroform-methanol, separate organic layer, use 10: 1 mixed solution of chloroform-methanol extraction (200mL * 3) water layer again.Water (100mL) and saturated aqueous common salt (100mL) are used anhydrous sodium sulfate drying after cleaning organic layer, under reduced pressure heat up in a steamer and desolvate, and obtain colorless oil.In this oily matter, inoculate crystal seed, and then drying under reduced pressure under agitation, thick target product white crystalline powder 27.80g obtained.With this crystal powder of mixed solution recrystallize of diethyl ether-normal hexane, obtain target compound (16.00g, productive rate 57.4%) white crystalline powder.

¹H-NMR(CDCl ₃)δ：1.22-1.45(12H，m)，1.57(2H，m)，1.68(1H，m)，1.78(1H，m)，2.45(2H，m)，4.03-5.01(1H，br)，4.70(1H，dd，J＝8，6Hz)，7.27(2H.d，J＝9Hz)，7.32(2H，d，J＝9Hz).

Fusing point: 62.2～63.5 ℃ of (recrystallize solvents: diethyl ether-normal hexane)

Embodiment 4

Methyl 2,2-two chloro-12-(4-chloro-phenyl-)-11-laurylene acid esters synthetic

Dissolve 2 in 300mL toluene, (8.89g, 21.91mmol), (1.67g 8.78mmol), stirred 4 hours down at 80 ℃ 2-two chloro-12-(4-chloro-phenyl-)-12-hydroxylauric acid methyl esters to add p-toluenesulphonic acids-hydrate.In reaction solution, add 200mL water, the saturated sodium bicarbonate water of 10mL, clean, use 100mL ethyl acetate extraction water layer again.Merge organic layer, clean, behind anhydrous sodium sulfate drying, with the refining extraction liquid of silica gel column chromatography (liquid effluent vinyl acetic monomer/normal hexane=1/1) with saturated aqueous common salt.Decompression is heated up in a steamer and is desolvated, and obtains target compound (8.38g, productive rate 97.6%) yellow oil.

¹H-NMR(CDCl ₃)δ：1.24-1.41(8H，m)，1.42-1.51(2H，m)，1.52-1.63(2H，m)，2.14-2.25(2H，m)，2.37-2.48(2H，m)，3.89(3H，s)，6.20(1H，dt，J＝16，7Hz)，6.32(1H，d，J＝16Hz)，7.22-7.30(4H，m).

(2) 2,2-two chloro-12-(4-chloro-phenyl-)-11,12-epoxy group(ing) Laurate methyl synthetic

Dissolving methyl 2 in the 200mL chloroform, (8.38g, 21.39mmol), (7.38g 42.77mmol), at room temperature stirred 2 hours 2-two chloro-12-(4-chloro-phenyl-)-11-laurylene acid esters to add 3-chloro perbenzoic acid.Use hypo solution, the 200mL saturated aqueous common salt cleaning reaction liquid of 200mL5% successively, behind anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains faint yellow crystalline residue 12.24g.Refining with silica gel column chromatography (liquid effluent normal hexane/chloroform=1/9), obtain target compound (8.30g, productive rate 95.2%) colorless oil.

¹H-NMR(CDCl ₃)δ：1.23-1.41(8H，m)，1.42-1.62(4H，m)，1.62-1.72(2H，m)，2.36-2.46(2H，m)，2.89(1H，td，J＝6,2Hz)，3.58(1H，d，J＝2Hz)，3.89(3H，s)，7.16-7.22(2H，d，J＝9Hz)，7.28-7.33(2H，d，J＝9Hz).

Synthesizing of (3) 2,2-two chloro-12-(4-chloro-phenyl-)-11-hydroxylauric acid methyl esters

In the 200mL vinyl acetic monomer, dissolve 2,2-two chloro-12-(4-chloro-phenyl-)-11, and 12-epoxy group(ing) Laurate methyl (6.87g, 16.85mmol),-12 ℃ add down 10% carry palladium-carbon catalysts (1.37g), under uniform temp, in the atmosphere of hydrogen gas, stirred 1 hour.Filter and carry palladium carbon, with 60mL vinyl acetic monomer cleaning and filtering thing.Filtrate is heated up in a steamer in decompression, obtains the residue 6.89g of colorless oil.Refining with silica gel column chromatography (liquid effluent normal hexane/vinyl acetic monomer=8/1～4/1), obtain target compound (6.27g, productive rate 90.8%) colorless oil.

¹H-NMR(CDCl ₃)δ：1.23-1.64(14H，m)，2.36-2.46(2H，m)，2.63(1H，dd，J＝14,8Hz)，2.79(1H，dd，J＝14,4Hz)，3.79(1H，m)，3.89(3H，s)，7.15(2H，d，J＝8Hz)，7.28(2H，d，J＝8Hz).

Synthesizing of (4) 2,2-two chloro-12-(4-chloro-phenyl-)-11-hydroxylauric acid

In 25mL methyl alcohol, dissolve 2, (4.62g 11.27mmol), drips 2mol/L lithium hydroxide solution (11.3mL to 2-two chloro-12-(4-chloro-phenyl-)-11-hydroxylauric acid methyl esters under the frozen water cooling, 22.60mmol) about 5 minutes, under uniform temp, stirred 30 minutes.In reaction solution, add the 75mL saturated aqueous common salt, under the frozen water cooling, drip 15mL 2mol/L hydrochloric acid and make it be acid, with chloroform extraction (50mL, 20mL * 2).Merge organic layer, behind 100mL saturated aqueous common salt cleaning organic layer, use anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated.In this residue, add the 100mL normal hexane, under the frozen water cooling, stir and make its crystallization, filter and obtain crystallization, clean with normal hexane, air-dry, obtain 4.41g clear crystal powder.This crystallization obtains the colourless small needle-like crystal of target compound (4.01g, productive rate 89.9%) with the mixed solution recrystallize of 5mL vinyl acetic monomer-40mL normal hexane.

¹H-NMR(CDCl ₃)δ：1.24-1.42(10H，m)，1.42-1.65(4H，m)，2.38-2.48(2H，m)，2.67(1H，dd，J＝14,8Hz)，2.81(1H，dd，J＝14,4Hz)，3.86(1H，m)，7.15(2H，d，J＝8Hz)，7.27(2H，d，J＝8Hz).

Fusing point: 84.1～85.8 ℃ of (recrystallize solvents: vinyl acetic monomer-normal hexane)

Embodiment 5

(1) 3-benzoyloxy-10-bromo-1-(4-chloro-phenyl-) decane is synthetic

Adopt the method identical with embodiment 2 (2) by 10-bromo-1-(4-chloro-phenyl-)-3-decyl alcohol (196mg, 0.564mmol) and Benzoyl chloride (95mg 0.676mmol) obtains target compound (211mg, productive rate 82.8%) colorless oil.

¹H-NMR(CDCl ₃)δ：1.24-1.80(12H，m)，1.80-2.09(2H，m)，2.57-2.76(2H，m)，3.34(2H，t，J＝7Hz)，5.11-5.22(1H，m)，7.09(2H，d，J＝9Hz)，7.21(2H，d，J＝9Hz)，7.44(2H，t，J＝7Hz)，7.56(1H，t，J＝7Hz)，8.02(2H，d，J＝7Hz).

(2) 10-benzoyloxy-2,2-two chloro-12-(4-chloro-phenyl-) Laurate methyl synthetic

(116mg 0.257mmol) obtains target compound (31.3mg, productive rate 23.7%) colorless oil by 3-benzoyloxy-10-bromo-1-(4-chloro-phenyl-) decane with embodiment 2 (3) identical methods in employing.

¹H-NMR(CDCl ₃)δ：1.15-1.82(12H，m)，1.82-2.11(2H，m)，2.33-2.44(2H，m)，2.58-2.76(2H，m)，3.88(3H，s)，5.11-5.22(1H，m)，7.10(2H，d，J＝9Hz)，7.22(2H，d，J＝9Hz)，7.45(2H，t，J＝7Hz)，7.57(1H，t，J＝7Hz)，8.02(2H.d，J＝7Hz).

Matter

(3) 10-benzoyloxy-2, the optical resolution of 2-two chloro-12-(4-chloro-phenyl-) Laurate methyl

By the high-speed liquid chromatography method (post: the Chiralcel0J that ダ イ セ Le chemical industry is made that uses optically active column, mobile phase normal hexane: optical resolution 10-benzoyloxy-2 2-propyl alcohol 19/1), the raceme 1.28g of 2-two chloro-12-(4-chloro-phenyl-) Laurate methyl.

(a) merge the cut that goes out the peak composition that only contains the retention time weak point, behind the concentrating under reduced pressure, use flash distillation column chromatography (liquid effluent normal hexane/vinyl acetic monomer=20/1～10/1) refining once more, obtain (+)-10-benzoyloxy-2, the colorless oil of 2-two chloro-12-(4-chloro-phenyl-) Laurate methyl (optically active column Chiralcel 0J retention time short go out peak composition) (449mg, productive rate 35.1%).

Optical purity according to HPLC area ratio:＞99%ee (Chiralcel 0J, mobile phase normal hexane: 2-propyl alcohol 19/1)

Specific rotatory power: [α] _D ²⁷=+8.23 (c1.15, CHCl ₃)

(b) merge the cut that goes out the peak composition that only contains retention time length, behind the concentrating under reduced pressure, use flash distillation column chromatography (liquid effluent normal hexane/vinyl acetic monomer=20/1～10/1) refining once more, obtain (-)-10-benzoyloxy-2, the colorless oil of 2-two chloro-12-(4-chloro-phenyl-) Laurate methyl (optically active column Chiralcel 0J retention time long go out peak composition) (432mg, productive rate 33.8%).

Optical purity according to HPLC area ratio:＞99%ee (Chiralcel 0J, mobile phase normal hexane: 2-propyl alcohol 19/1)

Specific rotatory power: [α] _D ²⁷=-8.06 (c 1.10, CHCl ₃)

(4) (+)-2,2-two chloro-12-(4-chloro-phenyl-)-10-hydroxylauric acid synthetic

Adopt the method identical by (+)-10-benzoyloxy-2 with embodiment 2 (4), 2-two chloro-12-(4-chloro-phenyl-) Laurate methyl (the preceding composition of optically active column Chiralcel 0J,＞99%ee) (44.2g, 86.0mmol) obtain the white crystalline powder of target compound (19.58g, productive rate 57.5%).

Fusing point: 103.1～103.6 ℃ of (recrystallize solvents: vinyl acetic monomer-normal hexane)

¹H-NMR(CDCl ₃)δ：1.26-1.63(12H，m)，1.71-1.79(2H，m)，2.38-2.47(2H，m)，2.58-2.69(1H，m)，2.70-2.80(1H，m)，3.68(1H，br)，7.12(2H，d，J＝8Hz)，7.24(2H.d.J＝8Hz).

Optical purity according to HPLC area ratio:＞99%ee (Chiralpak AD-RH, mobile phase ethyl urea: 5mM H3PO4 damping fluid 70: 30)

Specific rotatory power: [α] _D ²³=+8.06 (c 5.00, CHCl ₃)

(5) (-)-2,2-two chloro-12-(4-chloro-phenyl-)-10-hydroxylauric acid synthetic

Adopt the method identical by (-)-10-benzoyloxy-2 with above-mentioned (4), 2-two chloro-12-(4-chloro-phenyl-) Laurate methyl (the back composition of optically active column Chiralcel 0J,＞99%ee) (44.3g, 86.2mmol) obtain the white crystalline powder of target compound (20.59g, productive rate 60.4%).

Fusing point: 103.0～103.7 ℃ of (recrystallize solvents: vinyl acetic monomer-normal hexane)

¹H-NMR(CDCl ₃)δ：1.19-1.63(12H，m)，1.68-1.85(2H，m)，2.38-2.47(2H，m)，2.58-2.68(1H，m)，2.70-2.81(1H，m)，3.68(1H，br)，7.12(2H，d，J＝9Hz)，7.24(2H，d，J＝9Hz).

Optical purity according to HPLC area ratio:＞99%ee (Chiralpak AD-RH, mobile phase ethyl urea: 5mM H ₃PO ₄Damping fluid 70: 30)

Specific rotatory power: [α] _D ²³=-8.02 (c 5.00, CHCl ₃)

Embodiment 6

(1) 10-bromo-1-(4-chloro-phenyl-)-5-methoxymethoxy decane is synthetic

Under ice-cooled stirring, embodiment 1 (1) obtained 10-bromo-1-(4-chloro-phenyl-)-5-decyl alcohol (14.51g, 41.7mmol) and diisopropylethylamine (10.78g 83.4mmol) is dissolved in the 200mL chloroform.Drip therein the chloro dimethyl cellosolve (5.04g, 62.6mmol) after, ice-cooledly stirred 1 hour down, at room temperature continue again to stir 30 hours.

Under frozen water cooling reaction solution, slowly add 100mL 2mol/L hydrochloric acid, after the stirring, separate organic layer.After using chloroform extraction (50mL * 2) water layer again, merge organic layer, clean 1 time, then clean 1 time, use dried over sodium sulfate, concentrating under reduced pressure with the 50mL saturated aqueous common salt with the 50mL Purified Water.With refining this residue of silica gel flash distillation column chromatography (liquid effluent normal hexane/vinyl acetic monomer=20/1), obtain target compound (13.30g, productive rate 81.4%) colorless oil.

¹H-NMR(CDCl ₃)δ：1.22-1.66(12H，m)，1.86(2H，quint.，J＝7Hz)，2.58(2H，t，J＝8Hz)，3.36(3H，s)，3.41(2H，t，J＝7Hz)，3.52(1H，quint.，J＝7Hz)，4.63(2H，s)，7.09(2H，d，J＝8Hz)，7.23(2H，d，J＝8Hz).

Synthesizing of (2) 2,2-two chloro-12-(4-chloro-phenyl-)-8-methoxymethoxy Laurate methyl

Adopt the method identical by 10-bromo-1-(4-chloro-phenyl-)-5-methoxymethoxy decane (13.30g with embodiment 1 (3), 33.95mmol) and Ethyl dichloroacetate (19.42g, 135.8mmol) obtain target compound (4.02g, productive rate 26.1%) colorless oil.

¹H-NMR(CDCl ₃)δ：1.25-1.64(14H，m)，2.38-2.44(2H，m)，2.58(2H，t，J＝8Hz)，3.36(3H，s)，3.51(1H，quint.，J＝6Hz)，3.89(3H，s)，4.63(2H，s)，7.09(2H，d，J＝9Hz)，7.23(2H，d，J＝9Hz).

Synthesizing of (3) 2,2-two chloro-12-(4-chloro-phenyl-)-8-hydroxylauric acid methyl esters

With 2, (4.02g 8.86mmol) is dissolved in the 150mL methyl alcohol 2-two chloro-12-(4-chloro-phenyl-)-8-methoxymethoxy Laurate methyl under ice-cooled stirring.Add 0.2mL hydrochloric acid therein, ice-cooled stirring down 15 minutes was at room temperature stirred 20 hours again.

The concentrating under reduced pressure reaction solution adds 100mL chloroform and 100mL Purified Water in the residue that obtains, separate organic layer.After using chloroform extraction (20mL * 3) water layer again, merge organic layer, clean 1 time, then clean 1 time, use dried over sodium sulfate, concentrating under reduced pressure with the 50mL saturated aqueous common salt with the 50mL Purified Water.With refining this residue of silica gel flash distillation column chromatography (liquid effluent normal hexane/vinyl acetic monomer=10/1～5/1), obtain target compound (2.93g, productive rate 80.7%) colorless oil.

¹H-NMR(CDCl ₃)δ：1.22-1.51(10H，m)，1.54-1.67(4H，m)，2.39-2.45(2H，m)，2.59(2H，t，J＝8Hz)，3.58(1H，m)，3.89(3H，s)，7.10(2H，d，J＝9Hz)，7.24(2H，d，J＝9Hz).

Synthesizing of (4) 2,2-two chloro-12-(4-chloro-phenyl-)-8-oxo Laurate methyl

With 2, (1.50g 3.66mmol) is dissolved in the 50mL methylene dichloride 2-two chloro-12-(4-chloro-phenyl-)-8-hydroxylauric acid methyl esters under ice-cooled stirring.Slowly add therein pyridinium chlorochromate (PCC) (1.58g, purity 98%, 7.33mmol) after, ice-cooledly stirred 30 minutes down, again continuously stirring 3 hours at room temperature.

Under the water-cooled reaction solution, slowly add the 100mL diethyl ether, stirred 10 minutes.After using silica gel column chromatography (liquid effluent chloroform) to remove polar component same as before to this solution, heat up in a steamer under the decompression and desolvate.Recycle silicon glue flash distillation column chromatography (liquid effluent normal hexane/vinyl acetic monomer=20/1～10/1) is made with extra care this residue, obtains the faint yellow oily thing of target compound (1.35g, productive rate 90.4%).

¹H-NMR(CDCl ₃)δ：1.35(2H，quint.，J＝8Hz)，1.53-1.65(8H，m)，2.36-2.44(6H，m)，2.58(2H，t，J＝7Hz)，3.89(3H，s)，7.09(2H，d，J＝8Hz)，7.23(2H，d，J＝8Hz).

(5) 2,2-two chloro-12-(4-chloro-phenyl-)-8-oxo is lauric synthetic

Adopt the method identical with embodiment 1 (4) by 2, (1.35g 3.31mmol) makes the white crystalline powder of target compound (1.15g, productive rate 88.2%) to 2-two chloro-12-(4-chloro-phenyl-)-8-oxo Laurate methyl.

Fusing point: 48.8～49.7 ℃ of (recrystallize solvents: diethyl ether-normal hexane)

¹H-NMR(CDCl ₃)δ：1.37(2H，quint.，J＝8Hz)，1.53-1.68(8H，m)，2.38-2.46(6H，m)，2.58(2H，t，J＝7Hz)，7.09(2H，d，J＝9Hz)，7.23(2H，d，J＝9Hz).

Embodiment 7

(1) 10-bromo-1-(4-chloro-phenyl-)-3-methoxymethoxy decane is synthetic

Adopt the method identical with embodiment 6 (1), 10-bromo-1-(4-the chloro-phenyl-)-3-decyl alcohol (5.80g that obtains by embodiment 2 (1), 16.7mmol) and chloromethyl methyl ether (4.04g 40.1mmol) makes the colorless oil of target compound (5.73g, productive rate 87.7%).

¹H-NMR(CDCl ₃)δ：1.25-1.60(10H，m)，1.72-1.89(4H，m)，2.61(1H，m)，2.70(1H，m)，3.40(3H，s)，3.50-3.59(3H，m)，4.65(1H，d，J＝7Hz)，4.68(1H，d，J＝7Hz)，7.12(2H，d，J＝8Hz)，7.24(2H，d，J＝8Hz).

Synthesizing of (2) 2,2-two chloro-12-(4-chloro-phenyl-)-10-methoxymethoxy Laurate methyl

Adopt the method identical by 10-bromo-1-(4-chloro-phenyl-)-3-methoxymethoxy decane (5.70g with embodiment 1 (3), 14.6mmol) and Methyl Dichloro Acetate (6.23g, 43.6mmol) make the faint yellow oily thing of target compound (645mg, productive rate 9.8%).

¹H-NMR(CDCl ₃)δ：1.23-1.79(14H，m)，2.41(2H，m)，2.61(1H，m)，2.70(1H，m)，3.40(3H，s)，3.56(1H，m)，3.89(3H，s)，4.65(1H，d，J＝7Hz)，4.68(1H，d，J＝7Hz)，7.12(2H，d，J＝8Hz)，7.24(2H，d，J＝8Hz).

Synthesizing of (3) 2,2-two chloro-12-(4-chloro-phenyl-)-10-hydroxylauric acid methyl esters

Adopt the method identical with embodiment 6 (3), by 2, (1.09g 2.40mmol) makes the colorless oil of target compound (842mg, productive rate 85.6%) to 2-two chloro-12-(4-chloro-phenyl-)-10-methoxymethoxy Laurate methyl.

¹H-NMR(CDCl ₃)δ：1.23-1.63(12H，m)，1.64-1.82(2H，m)，2.41(2H，m)，2.64(1H，m)，2.77(1H，m)，3.60(1H，m)，3.89(3H，s)，7.13(2H，d，J＝8Hz)，7.24(2H，d，J＝8Hz).

Synthesizing of (4) 2,2-two chloro-12-(4-chloro-phenyl-)-10-oxo Laurate methyl

Adopt the method identical with embodiment 6 (4), by 2, (840mg 2.05mmol) makes the colorless oil of target compound (749mg, productive rate 89.6%) to 2-two chloro-12-(4-chloro-phenyl-)-10-hydroxylauric acid methyl esters.

¹H-NMR(CDCl ₃)δ：1.19-1.42(6H，m)，1.49-1.61(4H，m)，2.37(2H，t，J＝8Hz)，2.40(2H，m)，2.70(2H，t，J＝8Hz)，2.86(2H，t，J＝8Hz)，3.89(3H，s)，7.12(2H，d，J＝8Hz)，7.23(2H，d，J＝8Hz).

(5) 2,2-two chloro-12-(4-chloro-phenyl-)-10-oxo is lauric synthetic

Adopt the method identical with embodiment 1 (4), by 2, (735mg 1.80mmol) makes the faint yellow oily thing of target compound (567mg, productive rate 79.9%) to 2-two chloro-12-(4-chloro-phenyl-)-10-oxo Laurate methyl.

¹H-NMR(CDCl ₃)δ：1.19-1.42(6H，m)，1.47-1.65(4H，m)，2.39(2H，m)，2.43(2H，m)，2.71(2H，t，J＝8Hz)，2.86(2H，t，J＝8Hz)，7.11(2H，d，J＝8Hz)，7.24(2H，d，J＝8Hz).

Embodiment 8

Synthesizing of (1) 2,2-two chloro-12-(4-chloro-phenyl-)-11-oxo Laurate methyl

Adopt the method identical with embodiment 6 (4), by embodiment 4 (3) obtain 2, (5.06g 12.35mmol) makes the colorless oil of target compound (4.36g, productive rate 86.6%) to 2-two chloro-12-(4-chloro-phenyl-)-11-hydroxylauric acid methyl esters.

¹H-NMR(CDCl ₃)δ：1.17-1.38(8H，m)，1.49-1.61(4H，m)，2.36-2.42(2H，m)，2.44(2H，t，J＝7Hz)，3.65(2H，s)，3.89(3H，s)，7.13(2H，d，J＝9Hz)，7.30(2H，d，J＝9Hz).

(2) 2,2-two chloro-12-(4-chloro-phenyl-)-11-oxo is lauric synthetic

Adopt the method identical with embodiment 1 (4), by 2, (4.36g 10.69mmol) makes the white crystalline powder of target compound (3.90g, productive rate 92.6%) to 2-two chloro-12-(4-chloro-phenyl-)-11-oxo Laurate methyl.

Fusing point: 56.8～57.8 ℃ of (recrystallize solvents: diethyl ether-normal hexane)

¹H-NMR(CDCl ₃)δ：1.18-1.40(8H，m)，1.50-1.61(4H，m)，2.40-2.45(2H，m)，2.45(2H，t，J＝8Hz)，3.67(2H，s)，7.13(2H，d，J＝9Hz)，7.30(2H，d，J＝9Hz).

Embodiment 9

Synthesizing of (1) 2,2-two chloro-12-(4-chloro-phenyl-)-12-oxo Laurate methyl

Adopt the method identical with embodiment 6 (4), by embodiment 3 (3) obtain 2, (3.07g 7.49mmol) makes the white crystalline powder of target compound (2.87g, productive rate 93.9%) to 2-two chloro-12-(4-chloro-phenyl-)-12-hydroxylauric acid methyl esters.

Fusing point: 55.2～56.2 ℃ of (recrystallize solvents: chloroform-normal hexane)

¹H-NMR(CDCl ₃)δ：1.28-1.41(10H，m)，1.57(2H，m)，1.72(2H，m)，2.41(2H，m)，2.93(2H，t，J＝8Hz)，3.89(3H，s)，7.43(2H，d，J＝9Hz)，7.90(2H，d，J＝9Hz).

(2) 2,2-two chloro-12-(4-chloro-phenyl-)-12-oxo is lauric synthetic

Adopt the method identical with embodiment 1 (4), by 2, (2.75g 6.74mmol) makes the white crystalline powder of target compound (1.74g, productive rate 65.5%) to 2-two chloro-12-(4-chloro-phenyl-)-12-oxo Laurate methyl.

Fusing point: 82.4～83.0 ℃ of (recrystallize solvents: chloroform-normal hexane)

¹H-NMR(CDCl ₃)δ：1.27-1.42(10H，m)，1.60(2H，m)，1.72(2H，m)，2.45(2H，m)，2.94(2H，t，J＝8Hz)，7.44(2H，d，J＝9Hz)，7.91(2H，d，J＝9Hz).

Test example 1

Measure as the above-claimed cpd A of The compounds of this invention and comparative compound and the reduction effect (Metabolism of hydrochloric acid ピ オ グ リ ゾ Application plasma glucose, Regular Insulin, glyceryl ester in live body with following method, 48, pp34-40,1999, the drug chemistry periodical, 44, pp2601-2611,2001).

(1) measuring method

As experimental animal, use the C57BL/KsJ db/db mouse (clinical study periodical, 85, pp962-967,1990) of obesity, hyperlipidemia, insulism and the insulin resistant type of known Jackson laboratory (U.S.) exploitation.

Use heparin to handle kapillary, take blood plasma after the centrifugation, carry out the group of plasma glucose concentration, insulin concentration and glyceryl ester concentration and measure from the eye socket vein of the db/db mouse of 7 one full year of life the blood of mining massively.Begin the administration of compound next day from blood sampling, in 14 days 1 day oral for 1 time.The 14th day oral administration of compound after administration begins after 2 hours from the eye socket vein blood of mining massively.Take blood plasma, measure plasma glucose concentration, insulin concentration and glyceryl ester concentration.

And for plasma glucose concentration, for the ratio of the effectiveness of clear and definite The compounds of this invention and comparative compound, the mean value in the administration is to reduce by 25% dosage (ED at 100% o'clock respectively ₂₅), the ED of The compounds of this invention and comparative compound relatively respectively ₂₅(Arznimittel-Forschung, 40, pp156-162,1990).

(2) result

The reduction activity of plasma glucose, insulin concentration and the glyceryl ester of The compounds of this invention and comparative compound has been shown in the table 1.From the result shown in the table 1 can find compound of the present invention than compd A and hydrochloric acid * * have a reduction effect of better plasma glucose, insulin concentration, glyceryl ester.

The reduced rate of table 1 plasma glucose, insulin concentration and glyceryl ester

Real is executed example	Administration consumption (mg/kg)	The plasma glucose reduced rate	The plasma insulin reduced rate	Plasma glycerol ester reduced rate
					Example 2 (4)	3	44.4±17.0	-12.5±58.1	53.2±6.9
10	66.6±4.1	39.1±21.3	54.1±5.5
				30		75.2±3.1	64.3±10.1	55.7±6.3
Example 3 (4)	3	29.3±28.7	-2.8±46.6						23.2±24.7
				10	53.4±14.7	39.0±10.3	40.6±8.9
	30	74.5±3.0	61.7±18.5					25.8±24.7
				Example 4 (4)	3	35.0±21.2	-19.8±71.8		45.5±13.9
10	65.2±8.0	20.3±24.9	58.8±3.7
					30	67.2±6.8	51.1±20.2	54.1±6.6
Example 5 (4)	0.5	20.7±14.3	-22.0±84.1						42.0±17.3
				1.5	40.6±5.8	39.5±37.5	48.3±6.9
	5	42.4±11.4	43.8±26.3					44.6±9.7
				Example 5 (5)	0.5	-10.3±35.4	20.8±32.0		23.0±13.8
1.5	28.5±10.7	20.4±38.0	40.5±15.3
					5	49.2±9.6	68.9±13.2	37.6±11.3
Compd A	1	-5.0±19.5	0.7±77.6						23.4±15.3
				3	25.4±17.7	7.4±18.7	27.5±17.5
	10	65.3±5.0	10.7±61.6					54.6±4.1
				Salt acid ピ オ グ リ ゾ Application	3	13.4±18.3	-24.7±119.3		9.4±15.9
10	22.3±22.8	-18.7±52.5	25.4±16.9
					30	45.2±21.2	13.9±22.7	38.2±8.1

Because find compound amount of the present invention effect after a little while, the reduction effect for plasma glucose calculates ED ₂₅Value is relatively found the consumption of its effect.The ratio ED of effectiveness that has gathered the plasma glucose reduction effect of The compounds of this invention and comparative compound in the table 2 ₂₅In the compound of the present invention, the compound of embodiment 2 (4) is 0.6mg/kg, and the compound of embodiment 4 (4) is 1.1mg/kg, and the compound of embodiment 5 (4) is 0.5mg/kg, and is relative, and compd A is 2.8mg/kg.That is, compound exhibits of the present invention goes out 1/2.5～1/5.6 the equal plasma glucose reduction effect of consumption with compd A.

According to this result, contain that The compounds of this invention does that the medicine of effective constituent obviously can be expected alleviating of side effect and the avoidance of drug interaction when using with other reagent.

Table 2 plasma glucose reduction effect (ED ₂₅)

Real is executed example	ED 25(mg/kg)
		Example 2 (4)	0.6
Example 3 (4)	2.4
		Example 4 (4)	1.1
Example 5 (4)	0.5
		Example 5 (5)	1.7
Compd A	2.8
		Salt acid ピ オ グ リ ゾ Application	8.3

[industrial applicibility]

Compound, its salt and the ester thereof of above-mentioned general formula (1) expression have the reducing effect of strong blood sugar reducing effect, plasma insulin reducing effect and glyceride, can not follow body weight to increase and fat, can useful conduct prevent and/or treat the medical active ingredient of the diseases such as diabetes, diabetic complication, high fat of blood and arteriosclerosis.

Claims (3)

1. one kind is selected from 2,2-two chloro-12-(4-chloro-phenyl-)-10-hydroxylauric acid and 2, compound or its salt or its ester of 2-two chloro-12-(4-chloro-phenyl-)-11-hydroxylauric acid.

2. as the material of the ester of permitting on the salt of permitting on the compound of claim 1 record or its physiology or its physiology medicine as effective constituent.

3. as the medicine of claim 2 record, it is used to prevent and/or treat following disease: hyperlipidemia, arteriosclerosis, diabetes, diabetic complication.