TW420661B - Preparation of lignan analogues - Google Patents

Abstract

This invention relates to a process for preparing the compounds of lignan series in a selective manner in terms of the positions, and to intermediates therefor. This invention provides a process for preparing compounds of the formula (I), which is characterized by that a lactone compound of the formula (II), is reacted with an unsaturated ketone represented by the formula (III), and the resulting compound is subjected to dehydration in which, R1 is alkyl, cycloalkyl, cycloalkyl (lower alkyl), or aralkyl; R2 and R3 each is lower alkyl or R2 and R3 are combined together to form an alkylenedioxy; R4 is lower alkoxy or hydrogen; R5 and R6 each is lower alkyl; and R7 is lower alkyl. The invention also provides the compounds of the formulas (II) and (III).

Description

42066 1 A7 B7 V. Description of the invention () The present invention is a new method for preparing compounds of the xylan series of cyanocyanine and its intermediate products. In more detail, it relates to a method for efficiently preparing a xylan queue compound having an alkyl copper chain, which includes the use of a Hockel addition reaction that provides a regioselective reaction. The xylan streak compounds are useful for the treatment of dysplasia *, especially fatty arteriosclerosis *, and the present inventors have disclosed various compounds (Japanese Patent Publication Kokai No. 310634/1993, International Patent Publication WO 93/08155). The present invention relates to a method for preparing a compound represented by formula (I): OH 0

^ 1 JII! ..!! N I (Please read the note on the back before filling in this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where R1 is alkyl * cycloalkyl, cycloalkyl-lower alkyl Or * and aralkyl; and 1 ^ is lower alkyl or 1 ^ and 113 are combined to form an alkylene dioxy group t R4 is lower alkoxy or hydrogen; and R1 is lower alkyl; and R7 is lower Alkyl group; its special feature is the lactone compound represented by the chemical formula (II): This paper size applies the Chinese National Standard {CNS) A4 specification (210X297 mm) 6 83.3.10,000 42066: A7 B7 V. Description of the invention (Ο

OR6 (Π) where Ra, Ra * R4, Ra & Re are as defined above, and react with a compound of formula (II): (I) (Please read the precautions on the back before filling this page) r7o2c · Central Ministry of Economic Affairs Printed by the Zhuanxi Sub-consumer Cooperative, where R1 and R7 are as defined above, the produced compounds are dehydrated in the presence of a base. In the present invention, the dwelling compound can be efficiently prepared. Therefore, the method of the present invention is suitable as a method for large-scale synthesis of xylan analogs. In other aspects, the present invention relates to the aforementioned compounds (II) and (III), which are useful in the method of the present invention. In terms of definition, the term "alkyl" of R1 means straight or branched from 0 to C ,. Alkyl, and "lower alkyl" refers to straight or branched bonds (^ to "alkyl such as methyl, ethyl * η-propyl, isopropyl, η-butyl, isobutyl, secondary butyl Groups, η-pentyl, 1-ethylpropyl, 2-ethylbutyl, etc. "Cycloalkyl" is a paper size that applies to Chinese national standards (CNS> A4 specification (210X297 mm) 83. 3.10,000 A7 B7 ^ 2066 V. Description of the invention () The word 傈 means C * to. Cycloalkyl such as cyclopentyl, cyclohexyl and cycloheptyl. The term "shenyl-lower alkyl" refers to a methyl group in which The lower alkyl group defined has a fluorenyl alkyl substituent as defined above and its examples are cyclohexylmethyl and cyclopentylethyl, etc. The term "arylfluorenyl" refers to a fluorenyl group as defined above Is substituted by a monoaryl group, and examples thereof are benzyl, dimethoxybenzyl, phenethyl, phenylpropyl, methyl, and the like. "Lower alkoxy refers to monomethyl where oxy is as defined above It is substituted by lower alkyl, and examples thereof include methoxy, vinyl dioxy and propioni dioxy.

The term w-alkylenedioxyfluorene of Rfl and? 13 refers to alkylenedioxy groups such as methyldioxy, ethylenedioxy and propylenedioxy from Cl to C3. The preparation method of the present invention includes the following two steps provided: Step 1 I., I I ---- IT—— — 装 —----- Order (please read the note on the back before filling in this page ) 0

.Λ r7〇2c OR6 base (ill) H〇 〇

Du Yinye, Consumer Co-operation of the Central Sample Bureau of the Ministry of Economic Affairs Step 2 H〇 〇

acid

OH O

(ί) The national standard (CNS) A4 specification of this paper standard (210 father 297 public 嫠 > 8 83.3.10,000 Employee Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 印 2066 1 a? _B7_______ V. Description of the invention ( ) In step 1 *, a lactone (II) and a ketone (πι) are slept back in the presence of a hydrazone to form the compound (IV). In the second step, the compound (IV) is treated with 睃) Dehydration to produce the desired compound (I). The compound (丨 1) used in the first step is not particularly limited in terms of the ratio of the compound (IIU, but U π) usually exceeds the compound (〗丨) expensive use, preferably 1: 1 to 1: 2: Examples of the base used in this step are general dialkyl metal amines such as lithium diisopropylamine, and diisohexylamine I, sodium, etc. and bis- (trialkylsilyl) metal amines such as bis- (trimethylsilyl) cyanamide, etc. It is preferable to use bis- (trimethylsilyl) Lithium amine. For the reaction solvent, it can be used alone or in combination, such as K type of tetrahydrofuran, diethyl ether and dioxane, such as Π-hexane And Π-pentane sulfohydrogen compounds; such as benzene and methylbenzyl aromatic hydrocarbons; such as digas methane halogenated sulfohydrogen compounds; and such as N, N-dimethylformamide and hexamethyl phosphate tris The best solvents are amines. The preferred solvents are tetrahydrofuran, dichloromethane, N ', N-dimethylformamide and trimethylamine hexamethyl phosphate. The reaction in this step is usually -100¾ to 100Ό (compared with Best from -801: to room temperature) and completed within a few minutes to several hours. Examples of acids used in the second step are such as g chloric acid, sulfuric acid, trifluoroacetic acid, sulfonic acid (methanesulfonic acid * P ~ Toluenesulfonic acid) organic or inorganic acid * or Lewis ether (boron trifluoride or titanium trifluoride, etc.). It is more trivalent or trifluorinated shed or methanesulfonic acid. There are no specific restrictions on the aspect of the acid. , But it is better to use 1 (please read the precautions on the back and fill in this page) '17 This paper size is applicable to China National Standards (CNS) M specifications (210X297 mm) 9 83.3. 10,000 Ministry of Economic Affairs t 夬 Standards Bureau Printed by the employee consumer cooperative ^ 2 ^ 661 A7 B7 V. Description of the invention () to 2 equal amounts .. Solvents with a hydrazone reaction, such as benzene and formazan Aromatic aromatic compounds of benzene; such as dihydric compounds of digas methane; nitriles such as acetonitrile. The reaction in this step is generally from -70 t to 1001C (preferably -20t to room temperature) in several parts to several shovel. Completed within hours. The lactone (1Π and the unsaturated hydrazone (III) of the present invention, which is also the starting material of the method * can be prepared from known compounds, for example, by the following evasion method. The present invention will The cleavage preparation and working examples are further described, but it is not intended to limit the scope of the present invention. The synthesizer Π Π synthesizes the sound potential and synthesizes 3- (3,4-dimethoxyphenylbubble 4, 5, 6-trimethoxy-1 (3 H) -isobenzofuran g Purpose: II-1 Step 1—Spot synthesis of 4,4-dimethyl-2- (3,4 * 5-trimethyl (Oxyphenyl) -2-oxazoline: 2. Under ice-cooling, a solution of 500 g (2.17 moles) of 3, 4, 5-trimethoxyphenylhydrazine (Compound 1 > in 1 liter of dry digas methane) was added dropwise over a period of 2 hours. To a solution of 386 g (4.34 mils) of 2-amino-2-methyl-propanol in 1 liter of dry dichloromethane. After the addition was complete, the mixture was stirred again for 1 hour and the reaction solution was filtered through A glass filter. Rinse the mixture with 500 Bl dichloromethane, combine the filtrate with the rinse solution, and then shrunk under vacuum. Suspend the residue in a mixture of 900al dry toluene and 100ml dry dichloromethane, and ice Under bath cooling, 206®1 (2.82 millimolar) (Please read the precautions on the back before filling this page) This paper size applies to China National Standard (CNS) A4 (210X: 297 mm) «3. 3.10,000 420661 Instruction A7 B7_7, Central Cooperative Consumers' Cooperative of the Ministry of Economic Affairs V5. Description of the invention () Thiophane gas is added dropwise. While continuing to search for 30 minutes, allow the mixture to warm to room temperature. Then * the mixture was cooled again in an ice bath, and 200 · 1 of water and an aqueous hydroxide solution (500 g NaOH in 1.8 liters of water). The mixture was then extracted with toluene. The extract was washed with water and brine, and then dried over anhydrous magnesium sulfate. After concentration in vacuo, the residue was taken from methane-η-hexane. It crystallized in alkane (200 ml-2.0 liters) to obtain 495 g of the desired oxazoline as the first crystal and 61 g as the second crystal. Total yield: 565 g (from Compound 1 to 5%). Melting point: 87-891: l-NMR: δ (CDCU) 1.39 < 6H, s) 3,88 (3H, s) 3.91 (6H, s) 4.10 (2H, s) 7.20 < 2H, s). Flute 2 quasi-synthetic compound Π-1 Under nitrogen flow * 1.66N η-butyllithium in hexane solution (800βΠ; 1.33 its ears) was added dropwise to 355 g (1.26 its ears) over a period of 1 hour and 15 minutes. The oxazoline (compound 2) obtained above was dissolved in 1.7 liters of dry THF, and its M refrigerant was cooled to -35 to -401. After the addition is complete, the mixture is stirred for an additional hour at -20 to -35C, then cooled to -78t, and 231 grams (1.39 mole * 1.10 equivalent) of 3,4-dimethoxybenzaldehyde are added dropwise at 500 ml of dry THF solution. After the addition was complete, the cooling-bath was replaced with an ice bath, and the mixture was stirred for 1 hour. Then, 400 nl of a saturated ammonium chloride aqueous solution and 400 »1 of water were added, and the mixture was extracted with ethyl acetate. The extract was washed with water and tritium water, dried over anhydrous magnesium sulfate and concentrated in a vacuum chamber. The residue was dissolved in 1.4 liters of 10% sulfuric acid, and the mixture was heated under rolling for 40 minutes. Add ice water to the reaction solution, and collect it by filtration (please read the note on the back before filling this page) The paper's dimensions apply to the Chinese national standard (CNS) Α4 size (2 丨 0 X 297 mm) 83 3.10,000 4 2 Ο 6 6 A7 B7 V. Description of the invention () Collect the precipitated crystals. Dissolve the crystals in 1.5 liters of dichloromethane, wash with water, dry dry with anhydrous magnesium acid, and then wolf in vacuum. The residue was recrystallized from dichloroformamidine to obtain 390 g (85.7¾ from compound 2) of the desired lactone Π-1. The melting point was 141-142¾. ^ H-NMR: 8 (CDCla ) 3.52 (3Η > s) 3.83 (3H > s) 3.89 (3H, s) 3'92 < 3H, s) 3.95 (3H, s > 6.32 (1H, s) 6.72UH, s) 6.86 (2H 's ) 7.21 (1H, s). The reaction M prepared in the first step is shown in the following rolling range.

MeO MeO) pfC〇C, 〇Tci2

OH

MeO 1 2) SOCI2 PhMe CH2CI2

----- J ----- y --- install ------ Order (Please read the precautions on the back before filling this page)

1) n-BuLi / THF MeOCHO MeO 2) 10% H2S04 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

OMe mp.mm Synthesis of 3- (3,4-dimethoxyphenyl) 5, 6-methyldioxy-1 (3H) -isobenzofuran ester 1-2. Step-by-step synthesis of 2- (3,4-dimethoxy-α-hydroxybenzyl) 4,5-methyl This paper is sized to the Chinese National Standard (CNS) A4 (2 丨 0X297 mm) 12 83. 3. 10,000 42066 丨 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention () Dioxybenzaldehyde ethylenedioxyacetal: 4. (U To a solution of 28.0 g (122¾ mole) of 2-bromo-4,5-methoxybenzaldehyde (compound 3) and 250 ml of benzene was added ethylene glycol (14 · 1) and 465 mg of P -Toluenesulfonic acid, and the mixture was heated under rollback for 3 hours. Using a Dean-Stark soda valve, dehydration was effected. After cooling in an ice bath, a saturated weight was added to the reaction solution. Aqueous sodium acetate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sulfuric acid, and concentrated in vacuo to obtain 33.2 g of a crude acetal product as a crystal. This product was not subjected to Further purification was used for the next reaction. (Ii) A solution of 1.64N η-butyllithium in η-hexane (80nl) (131 mils) was added dropwise to 78 ¾ under a tritium roll. 33.2 g of the crude acetal obtained above was dissolved in 300 ml of dry TH solution. After 30 minutes of mixing at the same temperature, 20.3 g (122 mmol) of 3,4-dimethoxybenzaldehyde was added in 85 μπι of a solution in dry THF, and the mixture was stirred for another 30 minutes. A saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was subjected to a medium pressure silica gel column chromatography (600 g SiOe; ethyl acetate: η-hexane). Hexane = 1: 2 to 1: 1) purification to obtain 35.6 g of the desired compound 4 (80.9% from compound 3) as an oil. • H-NMR: δ (CD30D) 3.77 (3H.s) 3.80 (3H , s) 3.90-4.17 (4H, B) 5.91 (lH.d, J = 1.2Hz) 5'93 (lH, d, J = 1.2 Hz) 5.97 (lH, s > 6.13 (lH, s > 6 ' 85 (lH, s) 6.87 (lH, s) 6-8δ (1Η, s) 6.98 (1H, s) 7.02 (1H, s). (Please read the precautions on the back before filling out this page) The paper size applies China National Standard (CNS) A4 specification (210X297 mm) 13 81110,000 420661 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7_V. Description of the invention () Must be 2 shots to synthesize 2- (3, 4- Dimethoxy ~ α-ethoxyfluorenyl) -4,5-methoxybenzoaldehyde: 5. (i) Under a thallium stream, the acetic anhydride (12. l »i; 128 mils) to 35.6 g (98.3 mils) of the compound 4, 360 g of N, N-dimethylamino lift (R) and 2U1 triethyl In 170ml of dry THF was at the same time of 50 minutes and the mixture was stirred slovenly, allowed to warm to room temperature. Methanol was added (4.4 ml), and the mixture was stirred for 20 minutes and concentrated in vacuo ed. Water was added to the residue and it was extracted with ethyl acetate. The extract was washed with water and strong water, dried over anhydrous magnesium acetate, and concentrated in vacuo to obtain 39.6 g of the crude product of the desired acetate as an oil. This was used in the next reaction without further purification. (ii) To a solution of 39.6 g of the crude acetate product in 350.11 propionol, 35b1 N hydrogen acid was added under cooling in an ice bath. While being stirred for 1 hour, allow the mixture to warm to room temperature. The reaction mixture was neutralized by adding a saturated aqueous sodium bicarbonate solution, and concentrated in vacuo. Water was added to the residue and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate and dried in a vacuum to obtain 39.0 g of an oily crude product of the desired aldehyde 5. This was used without further purification for next dip. ^ -NMR: δ (CDC13) 2. 16 (3Η. S) 3.85 (6Η, s) 6.09 (2H, s) 6.80_6.89 (3H, ιη> 7 · 09 (1Η, s> 7.32 (lH, s ) 7.58 (1H, s) 〇 {Please read the notes on the back before filling in this page) This paper size applies to China National Standard (CNS) A4 (210X297mm) 83. 3.10,000 42066 1 A7 B7 V. Explanation of the invention () Step 3-The crude product of the aldehyde 5 (39.0 g) obtained from the compound Π-2 was dissolved in 500 nl of methanol and 250 1 of dioxane, and then 130b1 2-methyl-2 butene was added Then, an aqueous solution of 57 g (365 mmol) of sodium dihydrogenate (44 g < 486 mmol) of 250b1 sodium phosgene was added, and the mixture was stirred at room temperature for 20 minutes. After adding a 5N sodium hydroxide aqueous solution (160 «il > to the reaction solution, stir the mixture for 25 minutes, then add 160 μβ1 6N hydrochloric acid, and then stir for 20 minutes. Add ice water to the reaction solution, and use two The mixture was extracted with gaseous methane. The extract was washed with water> saturated aqueous sodium disulfonate solution and brine, and dried over anhydrous magnesium sulfate. After concentration in vacuo, the crystalline crude residue was washed with ether. It was then recrystallized from methanol 27 g (86.2% from compound 4) of the desired lactone 11-2 in the form of crystals were obtained. Melting point: Π6-178T: δ (CDC1,) 3.83 (3Η »s) 3.89 (3Η, s) 6. 12 (2Η, AB type * J = 1.2Hz) 6.20 (lH, s> 6.66 (2H, d, J = 1.2Hz) 6.86 (1H, s) 6.87 (1H, s) 7.25 (1H, s). 2nd split The following procedures are prepared to indicate the above-mentioned anti-failure, which means: ----------- 1; ------ Order (please read the precautions on the back before filling out this page) Standards Bureau employee consumer cooperation, Du printed car

1) HO (CH2) 2〇H TsOH (cat.) PhH

2) n-Βυϋ / THF MeO- ^ ~ ^ -CHO MeO 0 ·

This paper size applies Chinese national standard (CNS > A4 specification (210X297 mm) 83. 3.10,000? Π00 1 Α7 87 V. Description of the invention () t) AC2〇, Et3N OMAP / THF 2) 1NHCIi acetone

NaCI02 · NaH2P〇4 · Aqueous solution MeOH-dioxane

ΟΜ · OMe _ water squeezing solution NaOH; 6N HC1 M compound (III) can be prepared by any of the three methods provided below. Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives, Cabinet (1 丨 1): > The first method, flute 3, to prepare synthetic methyl (E) -4-cyclohexyl ~ 4-oxo-2 -Butenyl ester: Diazepam synthesizes 3-Hexyl-5- (methoxycarbonyl) -2-isoxazoline: 8a. U) Under ice-cooling, a solution of 224 g (2.00 ears) of cyclohexanecarboxyaldehyde (compound 6a> in 133 ml of 99% ethanol) was added dropwise to 800 154 of 154 g (2.2 moles) of argon hydroxyl group Amine and 166 g of U. 20 acetic acid) potassium sulfonate in water. After the addition was completed, the mixture was allowed to warm to room temperature while stirring for 1 hour, and then extracted with 900 ml of ethyl acetate. The extract was washed with water and tritium water to obtain a solution of the desired oxime in ethyl acetate. (ii) Under ice-cooling, the oxime solution in ethyl acetate obtained above contained 200nl (2.40 ul) of methyl propylene methyl ester, and the solution was added dropwise to 3 liters of about 10% sodium hypooxygenate (about 4 bleach ) A mixture of an aqueous solution and 28 ι »1 (200 mils) of triethylamine, and violently! S mix for 2 hours. After the addition is complete, allow the mixture to warm to room temperature while searching for 1 hour, and then use ethyl acetate II ----- I-:-install ^ ------ order (please first W Read the notes on the back and fill in this page again.) This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 83.3. 10,000 A7 B7 42〇66 1 ----- 5. Description of the invention () Ester extraction. The extract was washed with water and dried * with anhydrous magnesium thiosulfate * and concentrated in vacuo to obtain 369 g of a crude product of isoporphyrin (compound 8) (88% from compound 6a). * H-NMR: δ (CDCU) 1. 10-1. 45 (5Η-m) 1. 48-1. 90 (5H, m) 2_35-2.50 (lH, m) 3.19UH, d, J = 8.2Hz 3.20 (1H, d, J = 9.4Hz) 3.79 (3H, s) 4.96 (lH, dd, J = 8.2Hz, 94Hz). Flute 2 Synthetic Compound I II-a. (i> The crude product of the isoxazoline (compound 8a) (369 g) obtained above was dissolved in a mixture of 1.5 liters of methanol * 316 ml of water and 474 ml of acetic acid in the presence of 11.1 g of 10% rake-carbon and The mixture was stirred at room temperature under hydrogen for 6 hours. The palladium-carbon was removed by filtration, and the filtrate was concentrated in vacuo. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was saturated with water * The sodium carbonate aqueous solution and brine were rinsed, dried over anhydrous magnesium sulfate, and dried in a vacuum to obtain 280 g of a crude product of the desired hydroxy ketone as an oil. (Ii > Under ice-cooling, 163 ml (2. 10 (Ear) Methanesulfonium M is added dropwise over a period of 1 hour to a solution of 280 g of the crude hydroxy ring and 8 19 mi (5.89 ears) of triethylamine in 1.4 liters of dry ethyl acetate. Stir for 1 hour At the same time, the mixture was allowed to warm to room temperature. After the addition of ice water *, concentrated hydrochloric acid acidified the hydrazone mixture * and extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bisulfate solution and brine. , M dried over anhydrous magnesium acetate, and shrunk in vacuum. Remaining I. I ϋ r— I In I— * n. Nnnn In, 1T (please read the notes on the back before filling out this page) Printed on paper by the Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperative _National standard (€ yang) 6 4 grids (: 210/297 mm) 83.3.10,000 42066 1 Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, India and India A7 B7 _5. Description of the invention (), and 158 grams Crystals of fluorene esters that do not run (62% from compound 8a). Melt: 53-56 * 0. * H-NMR: δ (CDCU) 1.10-1.50 (5H.m) 1.60-2.00 < 5H, b) 2.50-2,63 (1H, n) 3.81 (3H, s) 6.69 (lH, d, J = 15.6Hz) 7.17 < 1H, d, J = 15.6Hz) Section 4. Synthesis of methyl groups U) -6-Ethyl-4-oxy-2-octenyl ester ...- II-b. In the first step, 3- (2-ethylbutyl) -5- (methoxycarboxy) -2-iso-II-oxaline was synthesized: 8b. (i) Under a gas flow, a solution of 399 g of < 2.42 its ears) bromo-2-ethylbutane (compound 7b) in 650 ml of dry THF was added dropwise to 61.7 g (2.54 its Ear) The suspension of magnesium in 1 liter of dry THF was maintained under gentle reflux. After the addition was complete * while stirring for 1.5 hours, the mixture was allowed to warm to room temperature. The mixture was cooled in an ice bath. Then a solution of 269 | 111 (2.42 moles) bupropion in 4501 «1 dry solution was added dropwise to the mixture. After stirring for 1 hour, 300 ml of an aqueous solution of 202 g (2.9 mils) of hydroxylamine hydrochloride was added, and the mixture was allowed to warm to room temperature while stirring for 1 hour and 20 minutes. The reaction mixture was decanted and the residue was washed with ether. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain 362 g of an oily crude product. This was further purified and used in the next reaction. (ii) Under cooling in an ice bath, a solution of 362 g of the crude oxime prepared in 8 50 ml of toluene was added dropwise to 2.55 liters of hypochloroaline 10 aqueous solution-- ----- T —Package · ------ Order (please read the notes on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 83.3.10,000 at B7 Printed by the Central Standard of the Ministry of Economic Affairs and printed by the Consumers' Cooperative. V. Description of the invention () (approximately 3_8 its ears) and 306 * 1 (3.39 moles) propylene methyl ester and 51mU363 millimoles) triethylamine in 850ml toluene In a mixture of solutions and stir vigorously *. After the addition is complete * while mixing for 2 hours, allow the mixture to warm to room temperature. Ice water was added to the reaction mixture, and extraction was performed with ethyl acetate. The extract was washed with water, an aqueous solution of sodium thiosodium and brine, dried over anhydrous magnesium acetate, and concentrated in vacuo. The residue was distilled in vacuo to obtain 255 g of the desired isoxazoline (compound 8) as an oil (49.5% from compound 7b). Boiling point: 130-13510 (5πππ Hg) 〇 ^ -NHR: δ (CDC13) 0.88 (3H-t- J = 7.2Hz) 0.89 (3H > t »J = 7.2Hz) 1.27-1.61 (5H, i) 2.32 (2H * d > J = 7.0Hz) 3.2K2H * d * J = 9.0 Hz) 3. 79 (3H ^ s) 4.99 (2H- J = 9.0 Hz) 0 Synthesis of compound 11 I-b in the second step. The reaction M is carried out similarly to the method in the third step and the second step. The oxazoline (compound 8) is opened to obtain the desired unsaturated feed ester Ib. Boiling point: 85-90C (0.5mmHg). δ (CDC13) 0.86 (6H > t * J = 7.2Hz) 1. 19-1.50 (4H > i) 1.79-1.96 (1H, id) 2.54 (2H > d > J = 6.6Hz) 3.82 (3H- s) 6.67 (lH> d- J = 1 5. 8 Hz) 7. 09 (1 H. d- J = 15.8 Hz) 〇5. Synthesis of methyl (E) -5-ethyl-4-oxy 2-pentenyl ester: III-c. (Please read the notes on the back before filling this page)

The paper scale of T-book is applicable to the Chinese National Standard (CNS) A4 specification UI0X297 mm) 83.3 * 10,000 Printed by the Bayer Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics 42 066 1 A7 — B7 V. Description of the invention () Good 1 step -Synthesis of 3- (buethylpropyl) -5- (methoxycarbonyl> -2-isoxoroline: 8c. This reaction is carried out in a similar manner to the first step of the third preparation from (2-ethyl) Butylaldehyde (compound 6c) was started to obtain the desired isoxazoline (compound 8c>). Boiling point: 100-110: (2amHg) »^ -NMR: 6 (CDC13) 0.88 (3H, t. J = 7. 4Hz) 0.89 (3H > t > J = 7.4Hz) 1.33-1.71 (4H, b) 2.36-2.53 (1H. N) 3.13 (1H > d > J = 9.6Hz) 3.14 (1H »d» J = 7.8 Hz) 3.79 (3H > s) 4.99 (1H, dd »J = 9.6Hz, 7.8Hz). The second step is to synthesize 彳 h complex ΙΠ-co The reaction K is performed similarly to the method of the third step and the second step From the isoxazoline (compound 8c) prepared above, unsaturated ketone g | I Π-c is obtained. Boiling point: 68-72C (0.8 mmHg). 4H-NMR: < 5 (CDCl3) 0.86 (6H, t, J = 7.4Hz) 1.42-1.80 (4Η, ·) 2.51-2.70 (1Η-m) 3.82 (3H. S) 6.72 (lH- d. J = 15.8Hz) 7. 19 (1H »D. J = 15. BHz) 〇 Di Rho prepared synthetic methyl (E > -5-methyl-4-oxy-hexenyl ester: III-d Step 1 皤 Synthesis of 5_ (methoxycarbonyl) -3- (1-methylethyl) -2-isooxazoline: 8d. This reaction M is performed similarly to the method of the first step of the third preparation, starting from isobutylaldehyde (compound 6d) to obtain the desired iso Oxazoline (compound 8d). This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) -20-83.3.1 〇〇〇 (Please read Note 11 ^ on the back before filling this page) Order 42066 1 A7 B7 V. Description of the invention (Boiling point: 84-88t (1 amHg). LH-NHR: δ (CDC13) 1.19 (6H, d, J = 7.0Ηζ) 2.65-2.82 (lH, m > 3_23 (2H , D, J = 9.4Hz > 3.80 (3H, s > 4.99 (lH, t type, J = 9.4Hz).隹 Step 2 Synthesis of compound II I-d This reaction is carried out in a similar manner to Step 3 of Preparation 2 * from the isooxazoline prepared above (compound 8d, and the unsaturated keto ester 11 1- < 3. Boiling point: 76-80P (6nmHg). ^ -NMR: 8 (CDC13) 1. 16 (6H, d, J = 7.0Hz) 2.76-2.94 (lH, m) 3.82 (3H »s) 6.74 ( lH > d. J = 15. 8Hz) 7.20 (1H · d, J = 15.8Hz >. The above reactions prepared from 3 to 6 are described in the following reaction scheme e Method 1) Mg / THF; N — CHO; ^ — ^ 1 · ^^^ 1 1 ^ 1 nn] ^ i —xc · i 'M-^. ^ 1 < Please read the notes on the back before filling this page) R1 -Br 7bi R1 = — CHjCHEtj Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

R1 -CHO aqueous solution HflN0H * HC1 2) Water soluble NaCIO Et3N / PhMe ^^ 002Mθ

1) η2νοη.ηο K2C〇3 / aqueous solution EtOH 2) Aqueous solution NaClO / EtOAc Et3N ^ 'COWe N-OΛΛ COgM White paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 83.3.1〇.〇 〇〇2066 1 A7 B7 V. Description of the invention (6a; R1 = -〇c; R1 =-CHEt2 d; R1 =-CHMe2 8a; R1 = -ob; R1 = -CH2CHEt2 c; R1 = -CHEt2 d; R1 = -CHMe2

1) H2 / Pd-C MeOH-, 7f < ^ AcOH

2) MsCl I EtOAc Et3N

Me〇2〇 IH- a; Ft1

(3rd preparation) b; R1 = -CH2CHEt2 (4th preparation) c; R1 =-CHEt2 d; R1 = -CHMe2 (5th preparation) (6th preparation) 2 method (please read the notes on the back before filling this page) Order the synthetic methyl (E) -4-cyclohexyl-4-oxy-2-butenyl ester printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs: Πϊ-a. Step L: Synthesis of (±) -3-vinyloxy-3- (methoxymethoxy) propionic acid: 10 «201 g (1.50 moles) of DL-hydroxysuccinic acid (Compound 9 >) and 750 ml The mixture of acetochloro chloride was stirred at room temperature for 68 hours, and stirred for another 2 hours. The reaction solution was concentrated in vacuo, and 300 nl of methylbenzyl was added to the resulting residue. The mixture was again in vacuum Concentrate, and then add the residue again for a curling operation. The acid anhydride produced is from China Paper Standard (CNS) A4 (210X297 mm) 83.3.10,000

42066 I Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 _V. Description of the invention () 100 · 1 Jiaben crystallized. To a crystalline residue obtained by evaporating toluene in a vacuum, 1.5 liters of methanol was added under cooling in an ice bath. The mixture was stirred at room temperature for 1 hour, and then left to stand for 15 hours. After being condensed in vacuum, 300 ml of toluene was added to the residue, and the mixture was concentrated again in vacuo. The residue was crystallized from 150 · 1 of toluene, and the crystals were washed with petroleum ether to obtain 279 g (98%) of the desired osmic acid (compound 10) as crystals. Melting point: ~ 63Τ :. ^ -NMR: δ (CDC1,) 2. 16 (BH, s) 2.96 (2H, d ^ J = 6.0 Hz) 3.78 (3H * s) 5.49 UH, t, J = 6.0 Hz). Synthesis of compound III-a. (i) A mixture of the carboxylic acid (compound 10) prepared on 196 grams (1.10 ears) and 196 ml (1.65 mole) of thionine was stirred at 30C for 30 minutes * and at 50C for another 1 hour. The reaction solution was concentrated in vacuo > and 250 ml of toluene was added to the resulting residue. The mixture was concentrated again in vacuo, and the residue was subjected to an addition and concentration operation again to produce the desired acid chloride. This was used in the next reaction without further purificationa (ii) Under a nitrogen stream * 1.17 liters (1.19 morin) of a solution of 1.02 M cyclohexylmagnesium bromide in THF was added dropwise over a period of 25 ¾ 2.5 hours A suspension of the crude acid gaseous product obtained above and 9.52 g (5.00 mmol) of cuprous iodide in 1 liter of dry THF. After the addition was complete, the mixture was stirred for another 30 minutes, and the reaction was quenched by adding 1 liter of 1.3 N hydrogen acid and ice. The reaction solution was extracted with ethyl acetate, and the extract was shaken with brine. (Please read the precautions on the back before filling out this page.) This paper size applies to China National Standards (CNS) A4 (210 ×: 97mm) 83.3. 10,000 42066 1 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention () Saturated dinitrate sodium hydroxide solution, sodium hydroxide solution and brine washing and drying with anhydrous magnesium acetate. Under vacuum Shrink the solution at medium temperature to obtain the crude product of the desired ketones. This was used in the next-fluorene reaction without further purification. (Iii) To the solution of the crude fluorene prepared in 550 ml of dry acetonitrile, 230b1 (1.65 Mol) triethylamine, the mixture was heated under reflux for 1 hour. Under ice-cooling, 1 liter of 1.3 N hydrogen acid was added to the anti-sleep solution, and the mixture was extracted with ethyl acetate. The The extract was washed with brine and dried over anhydrous magnesium sulfate. After being condensed under vacuum, the residue was crystallized by adding 1 liter of petroleum ether. The crystal was recrystallized from an 85% methanol aqueous solution to obtain 76.8 g. Desaturated diaphragm Crystallization of 11 I -a. Furthermore, the mother liquor of crystallization and recrystallization was combined with distillation in vacuum, and then the distillation solution was recrystallized from an 85% methanol aqueous solution to obtain another 32.5 g of the desired compound. Total yield: 109 g (51% from compound 10). 瑢 酤: 56-57 Ό. The 1H-NMR spectrum of this compound is the same as that obtained in the third preparation. Fut ft cut to synthesize methyl < E) -6-ethyl- 4-oxy ~ 2-octenyl ester: IU-b. This reaction is carried out in a similar manner to the second step of the seventh preparation. The compound 10 (the first step of the seventh preparation) and the (2-ethyl) butylmagnesium bromide are opened to obtain the desired unsaturated ketone S. II bb. The physical properties of the compound produced were completely consistent with those obtained in the fourth preparation. Section 3. Preparation. Preparation. Synthesis of methyl (E > -5_ethyl-4-amino-2-pentenate: ΙΠ-c. The reaction is performed in a manner similar to Step 2 of Step 7 Self-combination {Please read the precautions on the back before filling this page) This paper size is applicable to Chinese National Standard (CNS) A4 (210 > < 297 mm) 83. 3 * 10,000 42066 A7 B7 V. Description of the invention '(Compound 10 (Step 7 in the first step of the preparation) and (2-ethyl) butylmagnesium bromide are opened to give the desired unsaturated ester 111-1). The physical properties of the compound produced were completely consistent with those obtained in the fourth preparation.隹 9 Trimming Synthesis of methyl (E) -5-ethyl-4-oxy-2-pentenyl ester: III-c. This reaction is carried out in a similar manner to the second step of the seventh preparation, starting from compound 10 (the first step of the seventh cracking preparation) and magnesium bromide Π-ethyl) propyl * to obtain the desired unsaturated ketone g | in -c. The physical properties of the produced compound were identical to those of the compound prepared in the fifth step. Sheng 10 prepared a methyl (4-oxo-2-hexenyl ester: Π Ie. This reaction was performed in a similar manner to the second step of the seventh preparation, from compound 10 (the first step of the seventh preparation). ) And ethyl magnesium bromide to obtain the desired unsaturated fluorene ester Πί-e. Boiling point: 87-90TC (8 nmHg>). ^ -NMR: δ (CDC13) 1. 14 (3Η, t-J = 7.2 Hz) 2.67 {2H, q- J = 7.2Hz) 3.81 (3H. S) 6.69 (lH »d > J = 16.0Hz) 7.09 (1H. D. J = 16.0Hz) 〇 (Please read the note on the back first Please fill in this page for further details.) The reactions prepared by the Consumer Cooperatives of the 4-Central Standards Bureau of the Ministry of Economic Affairs printed the above 7 to 10 are described in the following reaction flow. Method 2 HO ho2c ¥, co2h

) AcCI

AcO

2) MeOH

Me〇2〇

, C02H This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 83.3.10,000 ^ 2066] A7 B7 V. Description of the invention ()

1) soci2 ----- 2) R1 ~ Mg r / THF Cul (cat.) 3) Et3N / MeCN

III- a; b; R — ^ ^ (Preparation 7) R1 = -CH2CHB2 (Preparation 8) C; R1 = -CHEt2 (Preparation 9) e; R1 =-Et (Preparation 10) i 谙 前 间Read the notes on the back and fill out this page] Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

(TTT): > ^ 3 Method Policy Preparation Synthesis of methyl (E) -6-ethyl-4-oxy-2-octenyl ester: l I-b. The first hit was to synthesize (E) -3_ (methoxycarbonyl) acrolein gas: 12 < i) To a suspension of 300 g (3.06 moles) of cis-butenedioic anhydride in 900 ml of dry toluene was added 136 ml (3.37 (Ear) methane and 3.0 ml of thorium gas, the mixture was heated under reflux for 2 hours to cool the reaction solution in an ice bath, and the precipitated crystals were collected to obtain crude crystals of the desired compound. This crystal was recrystallized from THF (500sil) -isopropyl ether (1 liter) to obtain 210 g (52,7%) of the desired single methyl vinegar. Melting point: 145-146 ^. (U) In a mash float of methyl ester obtained in 97.5 g (750 millimoles) in 250 ml of dry benzene, 82.2sil (1.13 of its ears) thionyl chloride and l. CllBlDMF, the mixture was stirred at 70 ° C for 2.5 hours. The reaction mixture was concentrated and distilled in vacuo to obtain 95.3 g (85.3%) of the desired hydrazone gaseous compound (Compound 12). Boiling point: 72-731 (15aiHg >. HMR: S (CDC13) 3.86 < 3H, s) 6.99 (1H, AB type, J This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 83, 3.! 〇, 〇〇〇〇e〇e6 丨 A7 B7 _ V. Description of the invention () = 15_4Hz> 7.00 (1H, AB type, J = 15.4Hz). The second step synthesizes compound III-b. Next, a solution of 728.1 (837 milli-kilars) 1.15M zinc vaporized in TP was added dropwise to 0,97M bromide (2-ethyl) butyl bromide under ice-cooling for a period of 55 minutes. A solution of magnesium (860 ml; 837 mmol) in THF. After the addition was complete, the mixture was stirred for 50 minutes, and 14 S g < 12.8 mmol) of tetrakis (triphenylphosphine) -palladium was added. Then, a solution of 95.3 g (639 mmol) of the acid gaseous compound (Compound 12) prepared in 25.0 nl of dry THF was added dropwise over a period of 1.5 hours. After the addition was completed, the mixture was stirred for 30 minutes, 600 »1 3N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. After concentration in vacuo, the residue was dissolved in 200 ml of a mixture of diethyl ether and η-hexane (1: 4), and filtered through a silicone pad (300 g). Ml of the same mixed solvent on top was rinsed. The filtrate and rinse were combined * and the mixture was concentrated in vacuo. The residue was evaporated in vacuo to give 67.6 g (53.4¾) of the desired unsaturated ester 111-b in the form of an oil. Central Bureau of Standards, Ministry of Economic Affairs The physical properties of the compounds produced by the industrial and commercial cooperative impressions are exactly the same as those obtained in the fourth preparation. The reaction of the above eleven preparation is described in the following reaction scheme. 83.3. 10,000 (Please read the precautions on the back before filling this page) This paper size applies the Chinese National Standard (CNS) A4 specification (2 丨 OX "7mm) 420661 A7 B7 V. Description of the invention ()) MeOH / PhMe S〇aa {cat)» 2 > SOCVPhH Μβ〇2〇3 method

12 11

R1 -MgBr / THF ZnC! 2 [Ph3P] 4Pd (cat.) Me〇aC

lll-b; R1 = -CH2CHEt2 Printed by the Male Workers Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs An example of the preparation of compound (I) is provided below. Example 1 Synthesis of 3 (-Cyclohexanecarbonyl) -Bu (3,4-dimethoxyphenyl) -4-hydroxyS-2- (methoxycarbonyl) -6,7,8-trimethoxy Naphthalene: I-la. Step _1 ... Synthesis of 3- (Cyclohexanecarbonylb (3,4-dimethoxyphenyl) > 1,2-dihydro-1,4-dihydroxy-2- (methoxy Carbonyl) -6,7 > 8-trimethoxynaphthalene: IV-la. 1.64Mn-butylpyrene in η-hexane (700ml; 1.1 5 acetic acid) under thallium gas flow under cooling in an ice bath. The solution was added dropwise to a solution of 256 m (1.15 mmol) (TMS) eNH in 1.15 liters of dry THF. 207 g (575 mils) of lactone Π-1 (preparation 1) in 1.15 liters of dry DMF The mash solution in M was added dropwise to the reaction solution cooled by M with ice and acetone over a period of 1 hour. After the mixture was continuously stirred for 45 minutes, 134 g (684 mil) of unsaturated forage ester ΙΠ-a (Preparation 3) was added dropwise over a period of 5 minutes in a solution of 456al of dry THF solution M4. After the addition was completed, * the mixture was stirred for 15 minutes and allowed to warm to 0 ° C. And stirred at the same temperature 3 hours. Add 1.8 liters of 2N hydrochloric acid to the anti-sleep solution and extract the mixture with ethyl acetate. Extract ^^^ 1- — ^ n in it n (, please read the precautions on the back before filling in this Page) The size of the paper used in the edition is subject to the Chinese National Standard (CNS) A 4 Specifications (210X297 mm) 83.110,000 420661 A7 B7 Printed by the Ministry of Economic Affairs, Central Standards Bureau, Employee Consumer Cooperatives. V. Description of the invention () Material water and 0 [Water cleaning, anhydrous magnesium sulfate drying, and in vacuum Shrinking. Crystallizing the residue from 1 liter of methanol to obtain 180 g of crude crystals of the desired compound IV-la. Then, the mother liquor of recrystallization was concentrated * and the residue was recrystallized twice to obtain another 7.0 g Compound IV-la. Yield: 155 g (49% from compound II-1). Melting point: 154-155C. ^ -NMR: δ (CDC1 3) 0.90-1.83 (10H, m) 2.40-2.58 (1Η , N) 3.45 (3H, s) 3.67 (3H, s > 3.82 (3H, s) 3.85 (3H, s) 3.93 (1H, s) 3.94 (3H, s> 3.99 (3H, s > 5.57 < lH, s &6.4; (1H, dd, J = 8.4Hz, 2.4Hz) 6.64 (lH, d > J = 8,4Hz > 7.14 < 1H, d, J = 2.4Hz> 7.51 (lH, s). Step 2 A synthetic compound IU was added. Under an air current, 44.8 ml (364 mmol) of BF3 · 0EU in 90 nl of dry dichloromethane was added to 155 g (279 mmol) in an ice bath for 30 minutes. ; The obtained compound was obtained. Compound IV-la in 750 ml of dry dichloromethane Solution, stirring was continued visiting at the same temperature for 50 minutes. To the reaction solution was added 58.4 ml (420 milliliters) of triethylamine, and the mixture was stirred at room temperature for 30 minutes. After concentration in vacuo * water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid * water and brine, and dried over anhydrous magnesium sulfate. After concentration in vacuo, the residue was crystallized from 500B1 methanol, and the crystals were recrystallized twice from methane-methanol to give 140 g (93%) of the desired compound I-la. Melting point: 150-151Ϊ :. (Please read the notes on the back before filling this page) This paper size is applicable to China National Standards (CNS) A4 ^ (210X297 mm) 83. 3.10,000 420661 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention () ^ -NMR: δ (CDC13) 1.15-1.90 (lOH, m) 2.70-2.90 (1Η -m) 3.24 (3H > s) 3.44 (3H »s) 3.86 (3H > s) 3.89 (3H · s) 3.93C3H. S) 4.03 (3H ^ s) 6.8 1-6.87 (3H »m) 7.71 (lH > s) 13.99 (1H, s). 1R; υ {Nujol) 1714 > 1606- 1580 »1516 * 1489» 1410 * 1240, 1197, 1142, 1107, 1063, 1027, 1004 cm-1. Analysis of C3nH34〇3 calculated: C66.90%, H6.36%, found: C66.92%, H6.39%. 2nd synthesis of (3,4-dimethoxyphenyl) -3- (3-ethyl-boxypentyl) _ 4-hydroxy-2- (methoxycarbonyl) _6,7,8- Trimethoxy_: I-lb? The first step is to synthesize (3,4-dimethoxyphenyl) -3- (3-ethyl-oxopentyl) -1,2-dihydro-1 , 4-Dihydroxy_2- (methoxymethoxy) -6,7,8-trimethoxynaphthalene: IV-lb. Under a thoron roll, a solution of 180 g (0.05 ul) of lactone 11-1 (first preparation) in 500 ml of dry dichloromethane was added dropwise to 1 liter of 1.0 M LiN at -781 over a period of 1 hour. TMS) 2-THF solution (1.0 mole * 2.0 equivalents). After the mixture was stirred for 40 minutes, a solution of 109 g (0.55 mol, i. 1 equivalent) of unsaturated ethyl ester III-b (Production 4) in 300 ml of dry THF was dripped over 40 minutes. Join. After the addition was complete, the mixture was allowed to warm to 0 ° F. * and stirred for 3 hours under cooling in an ice bath. To the reaction solution was added 1 liter of 2N hydrogen acid and ice, and the mixture was extracted with ethyl acetate. The extract was washed with water and hair * Dried with anhydrous magnesium sulfate, and in a vacuum (please read the precautions on the back before filling this page) The paper size is in accordance with the Chinese National Standard (CNS) Α4 specification (210X297 mm) 83.3 .10,000 420661 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () Condensed. The residue was crystallized from 700 al of methanol to obtain crystals. This crystal was further recrystallized twice from 600 ml of methanol to obtain 194 g (70%) of the desired compound IV-lb. Melting point: 132-133 ^. * H-NMR: δ (CDC1a) 0.65 (ΒΗ-t > J = 7.2Hz) 0.69 (3Η »t. J = 7.2Hz) 0.80-1. 29 (5H. M) 2.〇3 (lH > dd» J = 14.0 Hz, 7.0 Hz) 2.31 (lH, dd, J = 14.0Hz, 6.4Hz) 3.40 (3H, s) 3.67 (3H * s) 3.81 (3H. S) 3.86 (3H. S) 3.88 ( lH > s) 3.94 (3H »s) 3.99 (3H * s) 5.73 (lH» s) 6.43 (lH. dd. J = 8.4Hz -2.2Hz) 6.64 (lH ^ d ^ J = 8.4Hz) 7. 14 (1H »d · J = 2.2Hz) 7.54 (1H, s). m P. Synthetic compound BU 1 b. This reaction M is carried out in a similar manner to the second step of the first example, and the desired compound I-lb is obtained starting from the compound IV-lb prepared above. Melting point: 128 · 5-129.5C (methane to methanol). LR: d (CDC13) 0.83 (6H, t, J = 7 Hz) 1.20-1.42 (4H »m) 1. 96-2. 12 (1H-m) 2.73 (2H * dJ = 6 Hz) 3.25 ( 3H, s) 3.44 (3H, s) 3.86 (3H.s) 3.89 (3H, s) 3.93 (3H.s) 4.04 (3H, s) 6.78-6.90 (3H, ra) 7.73 (lH, s) 14.38 ( lH, s). 1R; υ (CHC13) 2968, 1729, 1606, 1576, 1514, 1489, 1464, 1412, 1139, 1064, 1028 cm -1 ° C3〇H3S〇9 calculation points: C66.65%, H6.71% ; Found: C66.72%, H6. 69%. ί · ί—-If ----------- Dings ^ -5 (Please read the notes on the back before filling in this page) This paper size applies to China National Standard (CNS) A4 specification (210X297 Mm) 83.3.10,000 42066 1 A7 ____B7_ V. Description of the invention () The third example

(Please read the note ^ on the back before filling in this page. W Synthesis of 1- (3,4-dimethoxyphenyl) -3- (2-ethyl-1-oxybutyl) -4-hydroxy-2 -(Methoxy (yl) -6,7,8-trimethoxynaphthalene: I-lc. Step 1_Synthesis of 1_ (3,4-dimethoxyphenyl > -3- (2- Ethyl-oxobutyl) -1,2-dihydro-1,4-dihydroxy-2- (methoxycarbonyl) 6,7,8-trimethoxynaphthalene: iV-lc. The same reaction starts with The method is similar to the first step of the first example, and the desired compound IV-lc is obtained from the lactone 11-1 (the first preparation) and the unsaturated fluorene ester II Ic (the fifth preparation). Melting point: 154.5-1 56t: (Dichloromethane-methanol) ^ -NMR: δ (CDC13) 0.19 (3Η. J = 7.4Hz) 0.75 (3Η > t, J = 7.4Hz) 1. 13-1.72 (4H * m) 2.35- 2.51 (1H ^ m) 3.42 (3H, s) 3.65 (3H > s) 3.79 (3H > s) 3.86 (3H > s) 3.94 (3H- s) 3.96 (1H »s) B.99 (3H > s) 5.76 (lH > s) 6.42 (lH * άά > J = 8.4Hz »2.2Hz) 6.64 (1H > d * J = 8.4Hz) 7. 14 (1H» d »J = 2.2Hz) 7 · 56 (1H, s). Step 2 Think about the synthesis of compounds 丨 c. Du Yince, the consumer cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs, this reaction is similar to the method in the first step and the second step. The process proceeds from the compound IV-lc prepared above to obtain the desired compound lc. Melting point: 113-115 ^ (acetone-η-hexane).

lH-NMR: δ (CDC13) 0.82 (3H. t > J = 8 Hz) 0.83 (3H > J = 8 Hz) 1.42-1.6〇 {2H > n) 1.64-1.81 (2H »m) 2.78 ~ 2 · 90 (1Η, ι〇3 · 24 (3Η, s > 3.42 (3H, s) 3.86 (3H, s) 3.89 (3H 83.3.10,000 This paper size applies to China National Standard (CNS) A4 specification (2 丨 0X297) (B) 42Π661 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7__V. Description of the invention (), s) 3.93 (3H, s) 4.03 (3H, s) 6.8b 6.87 (3Η, β) 7.72 ( 1Η, s > 14.18 (1Η, s >.1R; υ (CHCU) 1730, 1606, 1575, 1523, 1490, 1463, 1412, 1137, 1062, 1029 cm-1. Ca9H34〇3 plan analysis: C66. 14%, H6.51%; found: C66.09% * H6.64%. 4 cases of flute synthesis of 1- (3, 4-dimethoxyphenyl) _4-hydroxy-2- (methoxycarbonyl) -3- (2-methyl-1-oxopropyl) _6, 7, 8-tripropoxy sacrifice: Id. 隹 1 think about synthesis of 1- (3,4-dimethoxyphenyl) 1,2,2-dihydro-1,4-dihydroxy-2- (methoxycarbonyl 3- (2-methyl-1-oxopropyl) -6,7,8-trimethoxynaphthalene: IV -ld. This reaction is performed in a similar manner to the first step of the first example, from lactone 11-1 (first preparation) And unsaturated ketoester III-d (preparation 6) to obtain the desired compound I V-ld. Melting point: 15 5-15613 (digas methane_methanol). ^ -NMR: δ (CDC13) 0.67 (3Η. d * J = 7.0Hz) 1.04 (3Η, d, J = 6.8Hz) 2. 73-2.88 (1Η. b) 3.43 (3H ^ s) 3-67 (3H, s) 3.81 (3H, s) 3.86UH , S> 3.91 (1H, s) 3.94 (3H, s) 3.99 (3H, s) 5.74 (lH, s > 6,44 (lH, dd, J = 8.4Hz, 2.0Hz) 6.65 (1H > d- J = 8.4Hz) 7.14 (1H > d »J = 2.0Hz) 7.52 (1H > s) 〇 (Please read the precautions on the back before filling this page) This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83. 3. 10,000 42〇 β0ι Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Α7 Β7_V. Description of the invention () _2 _ ^ & _ Synthesis of compound I-Id This reaction is carried out in a similar manner to the first step 2 of step 圏 [, starting from the compound IV-ld prepared above, and The desired compound I-ld is obtained. Melt: 108-110 (90% methanol in water). ^ -NMR: δ (CDC13) 1. 15 (3Η »d * J = 7 Hz) 1.16 (3H * d» J = 7 Hz) 3.09-3.20 (lH * m) 3.24 (3H »s) 3.43 (3H, s) 3.86 (3H, s) 3.89 (3H, s) 3.93 (3H, s) 4.03 (3H, s) 6.79 -6.90OH. ·) 7.71 (1Η. s) 13.76 (lH · s) 〇1R; υ ( nujol) 1724, 1604, 1579, 1510, 1410, 1195, 1133 * 1104, 1024, 988, 959, 843 cm-1. CS7H3nos calculation analysis: C65.05%, H6.07%; found: C65. 16%, H6.08%. Part B: Synthesis of (3, 4-dimethoxyphenyl, 4-hydroxy-2- (methoxycarbonyl) -3-U_oxopropyl) -6 * 7,8-trimethoxynaphthalene : I-le. Step 1 I want to synthesize < 3,4-dimethoxybenzyl) -1,2-dihydro-1,4-dihydroxy-2- (methoxycarbonyl) -3-U-oxopropane Group> -6, 7, 8-trimethoxynaphthalene: IV-le. This reaction K is performed similarly to the method of step 1 in the second example. "The lactone Π-1 (step 1) and unsaturated ketoester 丨 Π-e (preparation 10) are opened to obtain the desired compound IV-le . Melting point: 143-145¾ (methanol). ^ -NMR: δ (CDC13) 0.89 (BH ^ t * J = 7.4Hz) 2. 3 1 (2H —-K—1L ----- *-install, ------ order ( Please read the notes on the back before filling out this page.) The scale of this paper applies to the Chinese family standard (CNS) A4 specification (210X297 mm) 83.3.10,000 420661 A7 B7 V. Description of the invention () (Please read the note on the back first Please fill in this page again), q. J = 7.4Hz) 3.41 (3H. S) 3.68 (3H »s) 3.82 (3H, s) 3.86 (3H, s) 3.87 (1H, s > 3,94 (3H, s) 3.99 (3H, s >, 5.73 (1H * s) 6-44 (lH »dd» J = 8.4Hz * 2.2Hz) 6.65 (1H »d > J — 8.4Hz) 7. 12 < 1H, d, J = 2.2Hz > 7.51 (1H, s >. The second step is to synthesize compound I-le. This reaction is similar to the method of the first step and second step, starting from the compound IV-le obtained above. Compound I-le is obtained. Melting point: 145-1461C (ethyl acetate-diisopropyl ether). ^ -NHR: δ (CDC1 3) 1. 18 (3Η-t * J = 7.2Hz) 2.81- 2.91 (2Η > i) 3.25 (3H > s) 3.45 (3H. S) 3.86 (3H »s) 3-89 (3H, s) 3.93 (3H > s) 4.03 (3H» s) 6.80-6.85 (3H »M) 7.74 (1H, s) 14.60 (1H, s). 1R; υ (nujol) 1730, 1604, 1577, 1202, 1117 * 1023 cm) °

CaBH * e〇3 calculation analysis: C64.46%, H5.83%; found: C64, 53%, H5. 80%. Printed by the Consumers' Cooperative of the Ministry of Economic Affairs and Standards Bureau of the People's Republic of China on Synthesis of 3- (Cyclohexanecarbonyl)-<3,4-dimethoxyphenyl> -4_hydroxy-2- (methoxy Carbonyl) -6, 7-methoxyloxy: I-2a. step 1! £ —synthesis of 3- (cyclohexanecarbonylb (3,4-dimethoxyphenyl) -1,2-dig-1,4-dihydroxy-2- (methoxycarbonyl) -6, 7-Methylenedioxynaphthalene: IV-2a. 83. 3. 10,000 This paper is in accordance with Chinese National Standards (CNS M4 (210X297 mm)) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ^ 066 1 at ___B7_ V. Description of the invention () The reaction M is similar to the method of the first step of the first case [* from the lactone 11-2 (the second split preparation) and the unsaturated ketone III-a (the third preparation). The desired compound IV-2a is obtained. Melt: 193-195X: (digas methane-methanol) ^ -NMR: δ (CDC13) 0.90-1.88 (10H &gt; «) 2.39-2.57 (1Η * β) 3.65 (3Η »S) 3.80 (3H» s) 3.82 (3H * s) 4.02 (1H &gt; s) 4.96 (1H, br.s) 6.07 (2H, s) 6.33 (1H, dd, J = 8.4Hz, 2.2Ηζ) 6.62 (1Η ^ ά &gt; J = 8.4Hz) 6.98 (1H. D * J = 2.2Hz) 7.20 (1H, s) 7.45 (lH, s). Step _2_Synthesis of compound I-2a. The method of the second step of one case was performed, starting from the compound IV-2a prepared above, and the desired compound BU 2a was obtained. Melting point: 177-178 * 0 (dioxymethane-methanol). 4H-NMR: 8 (CDC13) 1.06-1.92 (10Η. Ι) 2.70-2.88 (1Η »β) 3.52 (3Η» s) 3.86 (3H &gt; s) 3.96 (BH * s) 6.06 (2H &gt; s) 6.77 (1Η »s) 6.79 (lH &gt; d * J = 2.0Hz) 6.82 (1H »dd» J = 8.0Hz »2.0Hz) 6.94 (1H &gt; d · J = 8.0Hz) 7.79 (1H · s) 13.74 (1H, s) ° 1R; u (CHCU &gt; 1724, 1618, 1583, 1514 * 1450, 1241, 1169, 1039 cm * 1 ° CaeHa «〇d + calculation analysis: C68.28%, H5_73%; Discovery: C68.05%, H5_77% ° (Please fill in this page with the note “$” on the back of the flag) * 1T- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 83.110,000 Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs A7 B7 ___ V. Explanation of the invention () 钜 7 cases of synthesis (3 * 4-dimethoxyphenyl) -3- (3-ethyl-1-oxopentylbu 4_hydroxy-2_ &lt; methoxy Carbonyl) -6, 7-methyldioxyl: I-2b.隹 1 knockdown to synthesize 3- (3-7.-1-1-argonpentyl) -1- (3,4-dimethoxyphenyl) -1,2-dihydro-1,4-dihydroxy -2- (methoxyfluorenyl) -6,7-methoxydioxynaphthalene: IV-2b. This reaction M is performed similarly to the method of the first step in the second example, starting from lactone 11-2 (second split preparation) and unsaturated ketoester IU-b (the fourth preparation), and obtaining the desired compound IV- 2b. Melting point: 144.5 ~ 146.51C &lt; Methanol). ^ -NMR: δ (CDC13) 0.60-1. 41 (11Η »π) 2 .13 (1H, dd, J = 14.2Hz, 7.0Hz &gt; 2.28 (lH, dd, J = 14.2Hz, 7.0Hz) 3.66 ( 3H * s) 3.80 (3H &gt; s) 3.82 (3H &gt; s) 3-90 (lH- s) 4.88 (1H, s) 6.07 (2H, s &gt; 6.39UH, dd, J = 8.4Hz, 2.2Hz> 6.63 (1H * d &gt; J = 8. 4Hz) 6.98 (1H. D- J = 2.2Hz) 7.18 (1H, s) 7.48 (1H, s). Flute 2 enters the compound. I-2b. The reaction K is similar The method of the first step and the second step is carried out, and the desired compound I-2b is obtained from the compound IV-2b prepared above. Melting point: 126-1281C (methanol). UMR: 5 (CDCl3) 0.83 (6H, t, J = 7.3Hz &gt; 1.20-1.42 (4Η * π) 1.96-2. 16 (1H ^ m) 2.73 (2H * d, J = 6.6Hz) 3.5Π3Η »s) 3.86 (3H» s) 3-96 (3H &gt; s) 6.06 (2H- s) 6.72- 420661 (Please read the precautions on the back before filling out this page) This paper size uses the Chinese National Standard (CNS) A4 specification (210X297 mm) 83.3.10,000 V. Description of the invention () 6.98 (4Η »κ) 7.81 (1Η» s) 14.17 (lH &gt; s) 〇1R; u (CHCla) 1730, 1623, 1610, 1586, 1517 '1463, 1242, 1176, 1043 cm * 1. (: 88 (13 &lt; »0 * calculation analysis: C68.00%, H6.ll% Found: C67.88%, H6_15%. 隹 8 cases of synthesis of 1- (3,4-dimethoxyphenyl) _4-hydroxy-2- (methoxycarbonyl group 6,7-methoxydioxy -3-U-oxopropyl) -prohibited: I-2e. 1- (3,4-dimethoxyphenyl) -1,2-difluorene-1,4-dihydroxy -2- (methoxycarbonyl bu 6,7-methyldioxy-_3- (oxopropyl) M IV-2e 〇 This reaction M is similar to the method of the first step of the second example, from lactone 11 -2 (preparation 2) and unsaturated ethyl ester III-e (preparation 10) to obtain the desired compound IV-2e. Melting point: 138-1401 (methanol) Employees' cooperation cooperation with Central Standards Bureau, Ministry of Economic Affairs (Please read the “Notes on the back side before filling out this page”) ^ -NMR: δ (CDC13) 0.93 (3Η-t * J = 7.4 Hz) 2.21-2.50 {2H. A) 3.66 (BH »s) 3.82 ( 6H &gt; s) 3.94 (lH- s) 4.86 (1H * br. S) 6. 08 (2H »s) 6.42 (lH &gt; dd. J = 8.4Hz &gt; 2.2Hz) 6,65 (1H. D * J = 8.4Ηζ) 6.93 (1Η &gt; J = 2.2Hz) 7.20 (1H, s) 7.45 (1H * s). Step 2 铤 Synthesis of compound I _2e The reaction K is similar to the method in Step 2 of Example 1. The paper size prepared from the above applies to China National Standard (CNS) A4 (210X297 mm) S3. 3.10,000 420661 Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperative, A7 B7 _V. Description of the Invention () The compound IV-2e is obtained, and the desired compound I-2e is obtained. Melting point: 169-170¾ (digas methane-methanol> ^ H-NMR: δ (CDC13) 1. 19 (3Η * J = 7.2 Hz) 2.81- 2.9K2H · ») 3.52 (3H &gt; s) 3.86 (3H» s ) 3.95 (3H · s) 6.06 (2H »s) 6.72 (lH &gt; s) 6.79-6.92 (BH-m) 7.81 (lH &gt; s) 14.36 (1H, s). 1R; υ (CHCM 1724, 1619, 1582, 1459, 1175, 103S * 1025 cm -1. Calculation analysis: C65.75%, H5.06%; found; C65. 55%, Η5.14%. Ninth case 58 g (10.0) methanesulfonic acid (1.15 g) was added to 5.58 g (10.0) prepared in the first step of the second example using methanesulfonic acid as a dehydrating agent to prepare the compound lb of the second example. Millicel) Compound IV-lb in a suspension of 23 ml of dry acetonitrile, and the mixture was stirred at room temperature for 1 hour and 15 minutes. To the reaction solution was added 24b1 of water, and the mixture was searched under ice-cooling for 30 Min. K collected the forged crystals by filtration. The crystals were recrystallized twice from acetone-methanol to obtain the desired compound 1-5.04 g (93%). Melting point: 128-129T :. All other physical properties of this compound The properties are the same as those of the compound of Example 2. The compounds prepared in the above examples are listed in the following table. (Please read the precautions on the back before filling this page.) This paper size applies the Chinese National Standard (CNS) A4 specification (210X29). ? Mm) 83. 3.10,000 ^ 2 Ο 6 '6 1 Α7 Β7 V. Description of the invention () Table 1 OH 〇 MeO 六Me〇Q OMe omb (1st case) 丨 _ia; Ri = (2nd case) b; R1 = -CH2CHEt2 (3rd case) c; R1 = -CHEt2 (4th case) d; R1 = -CHMe2 ( (Example 5) e; R1 = -Et Table 2. — J --- * ― i-equipment ------- order (read the precautions on the reverse side and then fill out this page) Ministry of Economic Affairs t Printed by the Central Standards Bureau's Consumer Cooperatives OH Ο

C 6th example) 丨 -23; ^ = — (7th case) b; R1 =-CH2CHEt2 (8th case) e: R1 =-This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3, 10,000 Printed by Shelley Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs, 420661 A7 ______B7_V. Description of Invention () Germination ^ Pharmacological tests were performed using the compounds obtained in the first and second cases.蕖 1a credit inhibits the oxidative modification of LDL. The test method is based on the method described in Proceedings of the National Academy of Sciences, USA, Group 84, p. 5928 (1987 & Kita et al. Method 1). The test is performed as follows. First, a 0.5% cavity-sterol-containing feed is self-fed Three weeks of New Zealand coaxed LDL * from white rabbits and dissolved in phosphate buffered saline (final LDL concentration: 0.2 mg protein / ml). To this was added an ethanol solution of each test compound, and then copper sulfate. (Final Cu2 + concentration: 0.5 wM) and the mixture was cultured at 37¾ for 24 hours. As a thiobarbituric acid-reactive substance (TBA-reactive substance), the fat content in each dietary solution was measured. The amount of oxides, and the regression line from the inhibition rate of LDL oxidation modification and the concentration of the compound were used to calculate the 50% inhibition concentration (ICee). The quantitative determination of TBA-reactive substances is the MTBA method to measure the upper liquid (from The culture solution was prepared by removing the TBA-reactive substance from the protein. The results are shown in Table 3 below. The ICa of the compound obtained according to the method of the present invention. The value does not exceed 10 μM. It is understood that the compound shows a strong antioxidant effect on LDL. Type 2 test reduces the effect of knee sterol. (Please read the precautions on the back before filling out this page)-The size of the paper is applicable to the Chinese National Standard (CNS) A4 Specifications (210X297 mm) 41 83.3.! 〇, 〇〇〇420661 A7 B7 V. Description of the invention (Tidal test and evaluation method Male ICR rats (skeleton weight: 30-40 g)) Free feeding with 1% cholesterol, 0.5% Sodium acid and feed with 0.12% test compound (control group did not add this compound) for 7 days, blood was collected from rats, and total serum volume was stabilized by the method described in Clinical Chemistry No. 20, p. 470 (1974) Allain The total amount of VLDL cholesterol and LDL sterol is calculated by eliminating HDL sterol M from total cholesterol. The amount of HDL cholesterol is described in Clinical Chemistry Issue 24, page 2180 (1978) Measured by the ASH and Hentschel methods. The effect of the test compound on reducing the sterol was evaluated from the sterol reduction rate calculated from the following formula. Waist sterol reduction rate = (Bu [(in the test compound group Entangled sterol) / ( Total testosterone in the control group} X100 (VLDL + LDL &gt; Cholesterol reduction rate = U-[(VLDL + LDL steroid in the test compound group) / (VLDL + LDL knee solid in the control group The results are shown in Table 3. Read the first note and read the note on the back. On the page, order the paper printed by the Central Bureau of Standards, Ministry of Economic Affairs, Consumer Cooperatives, and use the paper size of China National Standard (CNS) A4 (210X297 mm). 83. 3.10,000 4 ^ β6 \ Α7 Β7 V. Explanation of the invention () Example of Table 3 LDL-oxidation inhibition enamel sterol (VLDL + LDL) ICe〇 {u Μ) Decrease rate (96) Aminosterol decrease rate (%) 1 0.46 22 61 2 0.40 35 72 (Please read the notes on the back before filling out this page) The dihydrazone compounds printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economics have shown excellent reduction of (VLDL + LDL) cholesterol, but they are not shown in HDL observes the reduction of sterols. Therefore, it is understood that the compounds obtained by the present invention show strong and selective reduction of membrane sterols. This paper is applicable to China National Standard (CNS) A4C (210X297 mm). 83. 3. 10,000

Claims (1)

4 2066.7.1 3 year of amendment H, supplement A8 BS C8 D8 VI. Application for Patent No. 083 103282 Re-examination of the application for amendment of the scope of the patent This amendment date: July 89 1. · One is used to prepare one of the following Method for the compound represented by chemical formula ⑴: ΟΗ Ο (I) (Please read the notes on the back before filling in this page), 1T, where R1 is a radical, a cycloalkyl, a cyclocyclyl-lower alkyl or an aromatic alkyl; R and R3 are each a lower-order oxygen Or R2 and r3 are combined to form an alkylene dioxy group; R4 is a lower alkoxy group or hydrogen; R5 and R6 are each a lower alkyl group; and R7 is a lower alkyl group; The method is characterized by : In the presence of a base, a compound represented by the following chemical formula (II) is allowed to react with a compound represented by the following chemical formula (II): This paper is based on the ten-country solid standards (CNS &gt; Μ) Specifications (2 丨 〇X 297mm) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 420661 6. Application scope of patents A8 B8 C8 D8 r \ OR6 (II) (wherein R2, R3, R4, R5 and R6 are as defined above), o2 / R, (III) (wherein Ri and R7 are as defined above), and then the formed compound is dehydrated. 2. The method according to item 1 of the scope of patent application, wherein Han 1 is (: 1 _ (: 6 alkyl, c5-c7 cycloalkyl, or (: 5-(: 7 cycloalkyl (Ci_c6 alkyl)). 3 · If you apply for the method of item 1 or 2 of the patent scope, where R2, Y3 and Han4 are foxy 'and R5', R6 and R7 are Yinji. 4. If you apply for the method of item 2 of the patent scope, Wherein R1 is a cyclobutyl ethylbutyl, 1-ethylpropyl, propyl or ethyl.-A compound represented by the following chemical formula (Π): 5, -2. This paper ruler family Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling out this page) Order 42066 A8 B &amp; C8 D8 VI. Patent Application Scope OR6 (II) where R2 and R3 are each a c! _C6 alkoxy group, or ... are combined with ruler 3 to form a C2-C3 alkylene dioxy group; R4 is alkoxy or argon; and R5 and R6 is each CrC6 alkyl. 6. For example, the compound in the scope of patent application No. 5 wherein R2, R3 and R4 are fluorenyl 'and R5 and R6 are methyl. 7. — A compound represented by the following chemical formula (II): (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs R7〇2C Uii) its application R1 is C, C6 alkyl; and R is (^-(^ 6 alkyl). 8. The compound as claimed in item 7 of the patent application, wherein R1 is 2-ethyl, and R7 It is a methyl group. The scale of this paper is applicable to the Chinese National Kneading Rate (CNS) A4 specification (210X29 * 7 male shame). OH 〇 42066 ^ Four 'Chinese invention of tangerine (the name of the invention: the present invention is a method for the preparation of xylan strip compounds in a selective manner in terms of position' and its intermediates. The present invention provides the preparation of chemical formula (I Method of the compound of (1): (I) its lactone compound (continued on the next page) whose chemical formula is U), the English abstract (the name of the invention:) PREPARATION OF LIGNAN ANALOGUES This invention relates to a process for preparing the compounds of lignan series in a selective manner in terms of the positions, and to intermediates therefor. This invention provides a process for preparing compounds of the formula (I): (Please read the notes on the back before filling in each page on this page) -m 1 --vl ^ n ι ^ ϋ— f 1 * — ^ 11 fl ^^ i f1 ^ 4 tl ^ ii— Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs oh o 2 This paper uses the Chinese National Standard (CNS) A4 old standard (2〗 OX297 mm) 4 2066.7.1 3 Amendment year H, supplement A8 BS C8 D8 6. Application for Patent Reexamination Case No. 083 103282 Application for amendment to the scope of the patent Amendment date: July 89 1. · A method for preparing a compound represented by the following chemical formula ⑴: ΟΗ Ο (I) (Please read the notes on the back before filling in this page), 1T, where R1 is a radical, a cycloalkyl, a cyclocyclyl-lower alkyl or an aromatic alkyl; R and R3 are each a lower-order oxygen Or R2 and r3 are combined to form an alkylene dioxy group; R4 is a lower alkoxy group or hydrogen; R5 and R6 are each a lower alkyl group; and R7 is a lower alkyl group; The method is characterized by : In the presence of a base, a compound represented by the following chemical formula (II) is allowed to react with a compound represented by the following chemical formula (II): This paper is based on the ten-country solid standards (CNS &gt; Μ) Specifications (2 丨 〇X 297 mm) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs