TW418186B - Retinoid-like compounds - Google Patents

Abstract

The present invention relates to a compound of formula I or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, in which X is -O-CO-, -NH-CO-, -CS-NH-, -CO-O-, -CO-NH-, -COS-, -SCO-, -SCH2-, -CH2-CH2-, -C 3BOND C-, -CH2-NH-, -COCH2-, -NHCS-, -CH2S-, -CH2O-, -OCH2-, -NHCH2- or -CR5=CR6-; Rm and Rk are independently hydrogen, halogen, C1-6alkyl, hydroxy, C1-6alkyloxy or nitro; n is zero or one; R4 is -(CH2)t-Y, C1-6alkyl, or C3-6cycloalkyl; R1 is -CO2Z, C1-6alkyl, CH2OH, -CONHRy, or CHO; R2 and R3 are independently hydrogen or C1-6alkyl; Ra and Rb are independently hydrogen or C1-6alkyl; but when n is one, Ra and Rb together can form a radical of the formula, Y is naphthyl or phenyl, both radicals can be optionally substituted with one to three same or different C1-6alkyl or halogen; Z is hydrogen or C1-6alkyl; R5, R6 and Ry are independently hydrogen or C1-6alkyl; and t is zero to six. Also provided by this invention are methods for preventing and/or treating tumors, arthritis and non-malignant skin disorders comprising administering a compound of formula I to a mammal. Further provided is a pharmaceutical formulation (composition) comprising a compound of formula I in admixture with (a) pharmaceutically acceptable excipient(s).

Description

418186 A7 B7_ V. Description of the invention () f The present invention provides compounds having retinoid-like activity • More specifically • The compounds of the present invention can be used to prevent and / or treat various skin diseases,% (but not limited to) acne (Acne), psoriasis, and injury from radiation. In addition, the compounds of the present invention have antitumor and anti-arthritis activities. Retinoic acid and its natural and synthetic analogs (retinoids) exhibit a wide range of biological effects.

They can affect cell growth and differentiation, and may become therapeutic drugs for several types of cancers * Please refer to R 〇 b e r t s, A. B. an n d S ρ 〇 r n, M. B. i η I *

The Retinoids, ^ Sporn, MB ,, Roberts, AB, and Goodman, DS, eds, 1 9 84, 2. »pp.209-286, Academic Press, New York; Lippman, SH, Kess1er, JF, and Meyskens, FL, Cancer Treat. Rep., 1 987, 2_L, p. 3 91; ibid., P. 493; Hong, VK et a 1., N. Engl. J. Med., 1 9 0, 323. p 795; Huang, U. et a 1., Blood, 1988, 1Z, p. 567. Retinoids have also been shown to be useful in the treatment of rheumatic diseases. For details, see JW Coffey et al., Retinoids as Potential An ti rheumat ic Agents, Chemistry and Biology of Synthetic Retinoids, pp520-537, CRC Press Inc., Μ. I. Dawson and WH Okamura Ed, (1990) * This paper size applies the Chinese national standard (CNS M4 Grid (2I0X297 mm) ) (Please read the precautions before filling in this page) Order f Printed by the Central Consumers' Bureau of the Ministry of Economic Affairs for Consumer Cooperative Printing * -4-

^^ COOH

BOTRETTNOW

A7 B7 V. Description of the invention (2) ^ There are several types of retinoids that have entered the stage of clinical use in the treatment of dermatosis (such as acne and psoriasis) • For example, isotretinoin is clinically used The above is an oral treatment for severe acne. And etretinate is particularly useful for the treatment of psoriasis. For more details, please refer to 0 rfa η 〇s, CE, E h 1 ert, R., and G ο 1 I nick, H., Drugs, 1987, 3X, pp.459-503

Other examples of COOH III * retinoid compounds include arotinoid of formula CII) and .retinobenzoic acid of formula (III) where Q is -NHC0 ...- C0NH -'- C0CH = CH- '-CH = CHC0-, stomach C0CH2-, etc. * For related materials, please refer to Loeliger, P +, Bollag, W., and Mayer, H., Eur. J. Med. Chem. 1980, L5l, pp .9-15; Kagechika, H. eta 1., J. Med. Chem., 1 988, 3JL, No. 11, pp. 2 1 82-2 1 92 · The present invention is related to a formula (i) Compounds, or their non-toxic pharmaceutically acceptable salts • Physiologically hydrolyzable esters or their solvates, this paper is used in Λ scale, a Ming Cen Han-Jun (CNS) A4 Washer (210X297) Li) --------- ya— (锖 Please read the note on the back before filling in this 萸)-Order the seal of the Ministry of Economic Affairs and the Central Procurement Bureau for Off-line Consumer Cooperatives »

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Printed by A7 B7 of the Central Co-opper Bayer Consumer Cooperative of the Ministry of Common Carriages 5. Description of the Invention (q) 〇R4 Rm where X is -0-C0- '-NH-CO ~' -CS-NH-, -C0-0 -, -CO-NH-, -COS-, -SCO- '-SCH2-, -CHd-, -C = C-' -CHss-NH- '-C0CH2-' -NHCS-, -CHaS- '-CH2 〇-, -〇CH2-, -NHCHz-'W, -CR5 = CRe-; R " and Iϊ11 are each independently argon, halogen, (^ -βalkyl, hydroxy, Ge alkoxy, or nitro; η is 0 or 1: R4 is-(CH2) i: -Y, Le alkyl, or C3-e cycloalkyl: R1 is -C〇2Z, (^ -β alkyl, CH2OH, -C0NHRy, or CH0: R2 and R3 are each independently hydrogen or he alkyl; "and!? · 9 are each independently fluorene or Ci-e alkyl: but when η is 1," and ^ can form a group of the formula C =

In the selection of the scale of the sheet, the «B Scaling Rate (CNS) Regulation 8 (2 丨 0: < 297 public envy J (Please read the precautions on the back before continuing to write this page)

f 418 186 A7 B7 printed by Shellfish Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs; --it- V. Description of the invention (4) f Y is a certain group or phenyl group, and this two groups can be selected from one to three identical or Substituted by different he alkyl or halogen; * Z is gas or Ci-e;

Re, 1-6, and 1 ^ are each independently hydrogen or Ci-e alkyl: and t is 0 to 6. The present invention also provides a method for preventing and / or treating tumors, arthritis, and non-malignant dermatosis, including: Administration of a compound of formula (I) in a mammal • In addition, the present invention also provides a pharmaceutical formula (composition) containing a compound of formula (I) and a medically acceptable excipient. Figure 1, Figure 2IB and Figure 3 is a cytotoxic dose response curve for lung cell line L2987 (lung line L2987). Figure 4 is a dose response curve for collagen-induced arthr itis. * The present invention relates to a formula (I ) Compounds, or their non-toxic pharmaceutically acceptable salts, their physiologically hydrolyzable esters, or their solvates,

Of which, this paper size is applicable to China's national standard (CNS > A4 size (210X297 mm) (Please read the precautions on the back before filling this page)

i 7 418186 V. Description of the invention (5) X is -0-C0-, -NH-CO-, -CS-NH- '-C0-0-, -CO-NH-' -COS-, -SCO-, -SCHa-, -CH2-CH2-, _Ctri-C-, -CHp-NH-, -COCH2- '-NHCS-' -CH2S- '-CH2〇-, -0CH2-, -NHCHz-' or -CR5 = CR0-: R " ^ Rk are each independently hydrogen, halogen, alkyl, hydroxyl, Ci-βalkoxy or nitro: π is 0 or 1; R4 is-(CH2) tY, Ci-e alkyl or C3 -e cycloalkyl; R1 is -CO2Z, Ci-ealkyl, CHzOH'-CONHRy, or CHO: R2 and R3 are each independently hydrogen or Ci-ealkyl;

Ra and Rb are each independently hydrogen or Ci-β alkyl; but when η is 1, 1 ^ and 1? 11 can form the following formula (please read the precautions on the back before filling this page)

The Department of Economics, Central Bureau of Quarantine and Bureau of Japan ’s Shellfish Consumer Cooperation Du Yin ^ Υ is fluorenyl or phenyl, and this diradical may be optionally substituted by one to three identical or different Ci-e alkyl or halogen; Z is gas or Ci-efluorenyl groups; R5 'Re & Ry are each independently hydrogen or Cbe alkyl; and t is 0 to 6 · The subscript numbers after the symbol "C" herein refer to the number of carbon atoms that a particular group can contain • For example, Cid alkyl refers to straight paper waves with one to six carbon atoms. Applicable to China National Standards (CNS) Λ4 specifications (Ή〇 × 297 mm) 8 Central Bureau of Standards of the Ministry of Economic Affairs ^ Printed by Consumer Cooperatives 5. Description of the invention ( 6) f-chain or branched alkyl, such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, third butyl, n-pentyl, n-hexyl, 3-methylpentane , Or similar alkyl groups; C3-e cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl: and halogen refers to fluorine, chlorine, bromine, or iodine. After the definition, it will maintain the same meaning until it is redefined. Some compounds of formula (I) can also form pharmaceutically acceptable metal salts and amines. And the cations do not have a significant effect on the toxicity or biological activity of the salts. These salts are also part of the present invention. • Suitable gold salts include sodium, potassium, calcium, and barium salts. , Zinc sulfonium, and aluminum salts, with sodium and potassium salts being preferred. • Amines capable of forming stable salts include trialkylamines, such as triethylamine, procaine, dibenzylamine, N- Narrow-fluorene-phenethylamine, 1-ephenamine, Ν, Ν · -diweidyl ethylenediamine 'dehy droabietjrlamine, N-ethylhexahydropyridine, Fluorenylamine, dicyclohexylamine, or similar pharmaceutically acceptable amines * If the compound of formula (I) contains a carboxyl group, physiologically hydrolyzable esters can be formed. This ester is used as a prodrugs » Hydrolyzed in the body to produce compounds of formula (I). Daoesters should be administered orally. • The reason is that in many cases the hydrolysis occurs mainly under the influence of digestive enzymes. • If the ester itself is active or the ester When hydrolysis occurs in the blood, 薬 can be given parenterally * Related formula (I) Examples of physiologically hydrolyzable esters of the compounds include Ci-e alkyl esters; fluorene esters: 4-methoxybenzyl esters: dihydroep (indanyl) esters; phthalic esters; methoxymethyl esters; he alkylfluorenyloxy Ci -β Alkyl esters such as ethoxymethyl, trimethyl ethoxymethyl or propyloxymethyl This paper is sized for China National Standards (CNS) A4 (2IOX297 mm) (Please read the back first (Notes for filling in this page)

-9-Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards and Quarantine of the Ministry of Economic Affairs «.!,.. A7-^-i— V. Description of the invention (7) f Ester: Alkoxycarbonyloxy alkyl ester * such as methoxycarbonyloxy Methyl or ethoxycarbonyloxy methyl esters; glycine methyl oxomethyl; phenyl glycamine methyl oxomethyl; (5-methyl-2-fluorene-1,3 --pentanyl dioxolen-4_yl ) -Methyl vinegar [(5-111611171 '· 2-oxo-l, 3- di〇Jtolen-4-yl) -aiethyl]; and other uses such as penicilli η and cephalosporin Known physiologically hydrolyzable esters of other technologies • Such esters are prepared according to conventional techniques known in the ifc technology field. The structural formulas drawn herein are believed to best represent the structure of the compounds of the invention, but * Some of the compounds belonging to the plaque of the present invention may be in other tautomeric forms, in which the hydrogen atom is shifted to other parts of the molecule * and the chemical bonds between the atoms in the molecule are thus rearranged Where tautomeric forms may exist, the formula represents all tautomeric forms. Compounds of formula (I) can be synthesized in various ways using conventional starting materials and Process to complete. The following synthetic description and beta examples are provided for illustrative purposes only. They are not intended to limit the present invention. Compounds of formula (I) can use the methods shown in Figures I to XX II or vice versa. Easy to see the changes to make, all steps in Figure 1 to ffl XXII are any standard methods that can be implemented by those skilled in the art *, and the hip example provided after synthesis is used to explain the implementation The specific conditions available for specific step thinking in the picture. But it must not be interpreted as being limited to these conditions. R7 in the circle is a general carboxy protecting group. It is preferably an alkyl group or a phenyl group. It is more preferable to use a tributyl group or a third butyl group. • If RT is a third butyl group, it can be removed with trifluoroacetic acid. -1 {Please read the notes on the back before copying this page) Order 4 18 186 a? ___B7 V. Description of the invention (8) J 一 (please read the notes on the back before filling this page) The compound of formula (XVIII) in step (a) is reacted with at least two R5Li units, wherein R5 is as previously defined, A first-stage Ci-e alkyl group is preferred. (Assuming that the compound of formula (XIX) is R5 being hydrogen, a reducing agent that converts the carboxylic acid residue of the compound of formula (XVIII) into an aldehyde is suitable.) • Many such reducing agents are well known in this technical field). Then, the anion of p-[(diethoxyphosphonium) methyl] benzene derivative of formula (XX) can be made with formula (XIX ) Compounds are reacted according to the Horner-Wadsworth-Emmons reaction (see: Org. React., 25, 73-253 (1 977); Stec, Acc., Chem., Res ·, 4U-417C1983)) to provide the formula ( Is) compound * and subsequent hydrolysis will produce compounds of formula (Ie) • Compounds of formula (Iβ) Fan Yuan can also be prepared according to the method shown in plaque IVa • in Figure V Fluorenyl groups such as tert-butyldimethylsilyl groups can be removed with tetrabutylammonium cyanide (TBAF). Figure III, IV, VI 'VII, XI, XII, XIII general formula (XV m) fe The starting compounds can be prepared by various methods using conventional starting materials and processes. The synthesis of some compounds belonging to the formula (XVIII) is shown in Figure XI} to Figure ΧΧΠ · Interest Order of the Ministry of Economic Affairs, Ministry of Economic Affairs, the Ministry of Economic Affairs, the Ministry of Economic Affairs Consumers' cooperative seal ¾

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Printed by the Ministry of Economic Affairs of the Ministry of Economic Affairs * R Feng Feng * Consumer Cooperative R K * C〇3

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The scale of this paper is in accordance with China's national standards (CNS > A4 * n grid (210X297 mm) -30 V. Description of the invention (28)

Step (a) A7 B7

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Printed by the Central Ministry of Economic Affairs of the Jung Kung Consumer Cooperative «. This paper uses the standard of fl fl (CNS > A4« t grid (210 X 297 mm) -34-t 418186 Cooperative production of A7 --- *-V. Description of the invention (32) f Description of specific implementation system The following specific examples are intended to illustrate the synthetic process of the representative combination of the present invention, but it is not intended to limit the scope of the present invention These methods can be varied to produce compounds that are within the scope of the present invention but are not specifically and slightly disclosed. In addition, the methods can be changed in more or less different ways to produce the same compound It is also obvious and easy to understand. If the curse degree in the examples is not specified, it means Celsius temperature. Nuclear magnetic resonance (NMR) spectral characteristics refer to the reference quasi-tetramethylsilane (TMS) in ppm (each Chemical displacements expressed in parts per million (< 5) · The relative area provided by the proton NMR spectrum data for each different displacement is equivalent to the number of specific functional hydrogen atoms in the moleculeThe properties of multiplicity are broad singlet (bs), wide doublet (bd), wide triplet (bt), wide quadruple (bq), singlet (s), multiple Peak (m), doublet (d), quadruple (Q), triplet (t), double doublet (dd), double triplet (dt), and double quadruple (dq) * As for the solvent used to test the spectrum of NM 则, D MSO-de (perdeuterodinethylsulfoxid e), DzO (^ «* i 水水 * deuterated water), 〇) (Μ3 (^ ι · ί Deuterochloroforu), and other commonly used neonizing solvents. The description of infrared (IR) spectrum includes only the absorption wave number (cm-1) with the identification value of the functional group. * Ce 1 ite is Johns-Manvi11e Products Corporation Registered trademark for diatomaceous earth * This paper size applies Chinese National Standard (CNS) A4 pit (210 X297 mm) (Please read the precautions on the back before filling this page)

t _ 35-Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Bei Gong Xiao F, A7 Β7 --- Ⅴ-Description of Invention (33) f The abbreviations used in the text are commonly used abbreviations in this technical field. * Some of the meanings are as follows: ^ MS Mass Spectrometry HRMS High Resolution Mass Spectrometry

Ar: aryl DCI desorption (or direct) chemical ionization method

Hex: hexane (class) tBu: third butyl h: hours min minutes

Ph: phenyl Y: yield THF tetrahydrofuran

Tf20 Trifluoromethanesulfonic anhydride SEMC1 2- (trimethylsilyl) ethane gas methyl Example 1 5,5-dimethyl-dihydrofuran-2-one (IV) will contain 4-pentanoic acid A solution of ethyl acetate (50.0 g, 0.345 mole), anhydrous ether (200 mL) and anhydrous benzene (200 mL) was treated with magnesium methyl bromide (3.0 M 121.0 bL, 0.365 mole in ether) at 0 ° C. Dropwise treatment for more than 30 minutes at C. At this time, diethyl ether was removed by slow distillation. The resulting benzene solution was heated under reflux for 2 hours. Then, an ice-cold solution of 20% phosphoric acid (500 mL) was added at 0eC. ) And Ethyl Acetate Paper Standards General Chinese National Standards (CNS > A4 Specification (2 丨 0 X 297 mm) (谙 Please read the notes on the back before filling this page) -5 i -36-V. Description of the Invention (34) A7 B7 ester (500 m L) * Then the organic phase was separated and washed with brine (1 x 300 m L) > then dried over m water, magnesium sulfate, filtered, and vacuum titrated and utilized. The obtained crude oil was purified by distillation (b.P., 4 30C '0.35 mm Hg) to give 26.0 g of the title compound (Y 66%): 1 Η — N MR (CDC 1 3): δ 2. 6 2 (t »J = 8 • 5 Hz» 2 Η) V 2. 0 5 (tt J = 8 .5 Hz > 2 Η) »1. 4 2 (s» 6 Η) # {Please read the precautions on the back before filling out this page) Printed Example 2 of the Central Governmental Standards and Quarantine Bureau Zhengong Consumer Cooperative Co., Ltd. 4,4-dimethyl- Bu tetrahydroone (V) Add 5,5-dimethyl-dihydrofuran-2-one (0.149 mole, 17.0 g) to anhydrous 1R aluminum chloride (0.446 nmol, 59_36 g) over 45 minutes In an anhydrous benzene (94.0 mL) solution (5eC). Then the reaction mixture was slowly warmed to 90-10OeC. After 3 hours, the reaction mixture was stopped with ice water, 1N HC1 and ethyl acetate at 0eC. The reaction was followed by separation of the organic phase and titration in vacuum. The residue was decanted on silica gel (dissolved with 3% ethyl acetate in hexane) to give 18.70 g (Y: 72%) of 4, 4-Dimethyl-butrahydroone * Η-NM MR (CD c 1 3): < 5 8 .0 1 (m «1 H), 7.50 (mf 1 H) * 7. 4 1 (m • 1 H) • 7. 2 8 (m »1 H)» 2. 7 2 (t VJ = 7.0 Hz »2 H) t 2 .0 2 (t 1 J = 7 .0 Hz «2 H) t This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) Order -37-418186 Staff Consumer Cooperatives' Seal of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (35) 1.3 9 (s * 6 Η): MS (DCI) m / e: 174 (MH +). Elemental analysis values for C12 and 14001: Calculated value C: 81.77; Thallium: 9.14 Actual donation value C: 81.70: Thallium: 9.12 Example 3 4,4-Dimethyl-7-nitro-but tetrahydrogen The ketone (VI) was prepared according to the procedure disclosed by Heck and Winstein in J. Org. Chem., Vol. 37, No. 6, 1 9 72, p. 825. 1 Η — N MR (CDC 1 a): 1 5 8 8 4 (d * J = 2 5 H z 1 1 H) »8 3 6 (dd 1 J = 7 • 0 H z, 2 • 5 H z '1 H)' 7 6 2 (dt J = 7 • 0 H z > 2 H) 2 8 0 (tt J = 7 0 H z V 3 H) 1 2 • 0 8 (t 1 J = 7 0 H z »3 H) 1 4 5 (s» 6 H) 1 MS (DCI) m / e 1 2 2 0 (MH +) Example 4 4, 4-Dimethyl-7-amino-p-tetrahydrogen Ketone (VII) The title compound 9'H was prepared according to the procedure disclosed in H eck and \ nstei η in J 0 r g. C he m., V ο 1. 37, N 0.6, 1972, p. 825 -NMR (CDC13): δ This paper is suitable for China's standard (CNSTA4 specification (210X297mm) (Please read the precautions below and then fill out this page)

-38 — 418 186 A7 B7 V. Description of the invention (ie) 7 · 2 8 (dtj 8 5 H zt 1 H) * 7 2 1 (d 9 j = 2 5 H zt 1 H),. 6 _ 8 6 ( dd • J = 8 • 5 9 2 • 5 H z, 1 H) 3 7 3 (bs * 2 H) V 2 7 0 (ttj = 7-0 H zt 2 H) · 1. 9 7 (t »j = 7-0 H zt 2 H), 1. 3 7 (st 6 H) 1 MS (DCI) m / e: 190 (MH +). Example 5 4-[[(5,6,7,8-tetrahydro-5,5-dimethyl-8-one-2-fruit) amino] carbonyl] methyl benzoate (IXa)

(Read the precautions on the back before filling this page)

The Ministry of Economic Affairs, Central Bureau of Standards, Shellfish Consumer Cooperative, printed the solution of monomethyl terephthalate (VIIIa) (2.86 g, 15.89 mmoles) in sulfur trioxide (50 mL) and two drops of N, N-dimethylformamide Stir at room temperature. • The mixture is homogeneous within 30 minutes and then concentrated under vacuum. * The residue is dissolved in 30 mL of anhydrous pyridine 'and then 4, 4-dimethyl-7-amino group. -Treated with tetrahydropyranone (3.0 g, 15.9 mmoles). After 16 hours at room temperature, IN HC1 was added to the mixture and extracted with ethyl acetate. Washed with IN HC 1 (4 X 200 mL), and then washed with saturated sodium bicarbonate (2 X 2QQ oiL). The organic phase was separated, and then the size of the sulfur paper was applied to the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) -39-A7 B7 V. Description of the invention (37) The magnesium acid was dried and concentrated in vacuo to obtain 5.07 g (Y: 91%) of the title compound. Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 1 Η--N MR (CD c 1 3: δ 8. 2 7 (dd »J = 8 7 1 2 5 Hz 8. 1 9 (bst 1 H) & gt 8. 1 4 (d 3 = 8 4 H zt 2 H), 7.9 5 (d J 8 4 H z »2 H), 7.9 1 (d J — 2 • 5 H z 9 1 H) , 7. 4 6 (d J = 8 * 7 H z 1 1 H), 3. 9 4 (s 3 H) t 2. 7 0 (t J 7-0 H z 3 H), 2. 0 0 ( t J = 7-0 H z 3 H), 1. 3 8 (s 6 H) MS (DCI) m / e 3 5 2 (MH +) o Example 6 «-[2- (trimethylsilyl) ethyl Oxymethyl] -4-[[(5,6,7,8-tetrahydro-5,5-dimethyl-8-one-2-a) amino] carbonyl] benzoic acid methyl ester (Xa)

Add 4-[[(5, 6, 7, 8-tetrahydro-5, 5-dimethyl-8-one-2-a) amino] carbonyl] benzoic acid methyl ester (5.07 g, 14.4 mmol) Anhydrous Ν, Ν-dimethyl (please read the precautions before filling this page)-° This paper size applies the Chinese National Standard (CNS) A4 specification (2Ι0 × 2ί »7mm) -40-Central Ministry of Economic Affairs A 7 B7 printed by the quasi bureau S industrial consumer fr Cooperatives 5. Description of the invention (38) A solution of methylformamide (75 mL) (0 ° C) was treated with 80% sodium hydride (477 mg, 15.9 mmols) * When the release of hydrogen stopped, slowly add 2- (trimethylsilyl) ethoxymethyl gas (3.61 g, 21.7 mmol), and after 16 hours at room temperature, use 10% sodium bicarbonate solution (100 raL) The mixture was diluted and extracted with ether * followed by concentration of the organic phase in vacuo, and the residue was chromatographed on silica gel (dissolved with 20% ethyl acetate in hexane) to give 4. 24 g (Y : 61%) of the title compound MS (DCI) m / e 482 (ΜΗ +) ^ -NMR (CDC 13): δ 7.9 (d * J = 7.5 Hz, 2H), 7.8 2 (s, 1 H), 7. 4 5 (d · J = 7. 5 H z · 2 H), 7. 2 5 (m · 2 H) · 5.22 (bs, 2H), 3.93 (s · 3H), 3.67 (t, J = 8.0 Hz, 2H), 2.6.9 (t-J = 7.0 Hz-2 H), 1. 9 8 (t > J = 7. 0 H z-2 H), 1.3 3 (s, 6 H), 0.96 (t * J = 8. 0Ηζ · 2Η), 0 0 0 (s * 9 H) · Example 7 N- [2- (trimethylsilyl) ethoxymethyl] -4-[[(5,6,7,8-tetrahydro-5,5-di Methyl-8-ethyl-8-hydroxy-2-fruit) amino] carbonyl] benzoic acid methyl vinegar (This paper size applies to China National Standards (CNS) grid (2I0X297 mm) (Please read the note on the back first) ^^ Refill this page} -41-418186 A7 B7 V. Description of the invention (39 XIa)

Printed by the Central Working Group of the Ministry of Economic Affairs, the Consumers Cooperatives. Ethylmagnesium bromide (3.0 M ether solution, 1.05 mL 3. 15 mmol) was added to compound (Xa) (1.t 17 g, 2.22 mmo) in anhydrous tetrahydrofuran (15 mL) solution (--78 * C) after t 俟 for 10 minutes, the reaction mixture was allowed to warm to room temperature. After 3 hours at room temperature, it was diluted with ethyl acetate (100 ml). The reaction mixture was washed with water (100 mL). The organic phase was evaporated, and the residue was chromatographed on silica gel (dissolved with 20% ethyl acetate in hexane) to obtain 103 mg (Υ: 9 %) Of the title compound • 1 Η -N MR (CD C 1 3): δ 7 .8 7 (m, 2 Η) > 7 4 0 C m »2 Η) 7. 2 0 (m • 1 )) 1 7 • 1 0 (m -2 Η) 5 .4 0 (m, 1 Η) 5 • 2 0 (m * 1 Η) 3 .9 0 (s * 3 Η) »3 * 7 5 (m '2 Η) * 2 .0 0 (m • 1 Η) V 1 .7 8 -1 .4 2 (m 1 5 Η) »1.2. 7 (S, 3 Η) > 1 * 2 5 (s * 3 Η) » 1 .0 5 (t, J = δ • 0 Η ζ 3 H) * 0 .9 5 (m, 2 Η) »0 0 0 (s 9 Η) t Μ S (DCI) m / e; 4 9 4 (Μ Η + — Η ζ 0) ο Private paper size applies to China National Standard (CNS > A4 size (210X297 mm) {Please read the precautions on the back before filling this page)

42 4 1¾ ΓΒ 6

A7 B7 ~ V. Description of the invention (40) Example 8 ^ 4-[[(5,6-digas-5,5-dimethyl-8-ethyl_2 ~ · series) amine-based] mineral] Methyl benzoate (1)

Sr ^ ο Add p-toluenesulfonic acid (pTsOH) monohydrate (some crystals) to a solution of compound (XIa) (169 mg, 0_33 mmol) in toluene (10 mL) * After heating at 75 ° C for 5 minutes * let The reaction mixture was concentrated under vacuum * and the residue was chromatographed on silica gel (eluted with 15% ethyl acetate in hexane) to give 34 mg (Y: 28%) of the title compound. (Please read the precautions before filling out this page) The Central Bureau of Standards, Ministry of Economic Affairs, Consumer Co-operation. Printed by the agency-ΝΜR (CDC 1 3) δ 8. 2 0 C d J = 8 .5 Hz • 2 H), 7. 9 5 C d J = 8.5 Hz, 2 H) 1 7. 5 0 (m 2 H) > 7. 3 5 (d J = 7.0 Hz, 1 H), 5. 8 0 (t J = 4.4 Hz, 1 H), 3. 9 5 (s 3 H) 1 2. 5 0 (q J τ = 7.0 Hz, 2 H) · 2. 2 0 ( d > J = 4.4 Hz • 2 H), 1. 2 5 (s 6 H) t This paper size is based on the standard of Chinese garden (CNS) Λ4 specification (210X297 mm) -43-A7 — __ V. Description of the invention (41) 1 10 (t-J = 7. 0 Η z * 3 Η) · Example 9 4 ~ [[(5, 6-dihydro-5,5-dimethyl-8- Ethyl-2-a) amino] carbonyl] benzoic acid (I 2a)

To the stirred solution of compound (1 ^) (34 rag, 0.094 mmol) in ethanol and tetrahydrofuran (5 niL, 1: 1) was added 10N NaOH (1 · Ommoj? * 〇1 ml) at room temperature. After 72 hours, 'Add 1 N HC1 (20 mL) to the above. * Collect the precipitate in vacuum depletion mode, and then wash with 1N HC1 and water. Iodized to give 21 mg (Y: 64%) of the title. Compounds · (Please read the notes on the back before filling out this page)

θ d 1 ο s Μ D fx R M N i H δ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy s / V 5 0 8 H 1 s / tv 2 3 0 1 \ ly Η 4 7 7 2

2 J J J J 6 md t Q d s -c κίν fv χί \ / V 7 7 8 1 3 8 CO CO VI 4 * 1 ± rH

H

HZ—N vlx. \ Ly Η Η Η H 112 2 ft 9 tzzzz Η Η Η H 0 4 0 4 9 4 7 4 This paper size applies to China National Wax Standard (CNS) A4 specification (2 丨 0X297 mm) -44 -Staff and capital cooperation of the Central Standards Bureau of the Ministry of Economic Affairs Du Yinzhuang Λ7 B7 V. Description of invention (42) 1. 1 2 (t-J = 7.0 Hz, 3H): 13C-NMR (DMS0-de): ^ 1 6 6. 7 9-1 6 4. 6 3-1 6 4. 55, 1 4 0. 3 0-1 3 8. 6 4-1 3 6. 99 '1 3 6. 75, 133.5 5 0 * 1 3 3. 26- 129. 2 6-1 2 7. 8 4-1 2 3. 94, 122. 48, 119. 13, 115. 43, 3 8. 0 6-3 2. 86, 28. 23, 25. 13, 1 3. 2 2: MS (DCI) m / e: 350 (MH +); IR (KB r): 2962, 1700, 1652, 1 5 3 2 · C 22H 23〇3N j · 0 7 4Η2 Elemental analysis value of 〇: Calculated value C: 7 2.80; Η: 6.80; Ν: 3.86 found C: 72.49; Η: 6.56; Ν: 3. 74 Example 1 〇 H- [2- (trimethylsilyl) Ethoxymethyl] -4-[[(5,6, 7, 8-tetrahydro-5, 5, 8-trimethyl-8-hydroxy-2-some) amino] carbonyl] benzoic acid methyl ester ( Xlb) (Please read the precautions before filling out this page}

This paper size applies Chinese National Standard (CNS) Λ4 grid (210X297) -45-Printed by the Consumers' Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs 4 18 18 6 a7 B7 JL, Description of Invention (43) MgBr (3.0 M ether solution · 0.43 mL, 1. 30 raraol) was added to a solution of compound (Xa) (438 mg, 0.91 mmol) in anhydrous tetrahydrofuran (10 mL) (-78 ° C) After 10 minutes at -78 ° C, the reaction mixture was allowed to warm to room temperature. After 3 hours at room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (10 OmL), and the organic phase was evaporated. The residue was chromatographed on silica gel (20% Ethyl acetate solution in hexane) to give 90 n] g (Y: 20%) of the title compound * ^ -NMR (CDC 13): < 5 7.90 (m, 2H), 7 '40 ( m, 2H), 7. 2 5 (tn · 2 Η) * 7. 10 (m · 1 Η), 5. 2 5 (m * 2 Η), 3. 9 Ο (s · 3 Η), 3. 7 0 (m, 2 Η) · 1. 9 0 (t · J = 7. Ο Η ζ * 2 Η), 1.75 (t, J = 7-〇Hz, 2H) · 1. 30 (s, 3H) , 1 · 2 9 (s · 3 Η), 1. 2 7 (s · 3 Η) · 1. 0 〇 (t * J = 8. 0Ηζ, 3Η) · Ο. Ο (s, 9 Η): MS (DC I) m / e: 480 (ΜΗ + -Η20) · Example 1 1 4-[[((5, 6-dihydro-5, 5,8-trimethyl-2-fluorene) -amino group ] Carbonyl] Phenyl benzoate (Pb) This paper uses Chinese national standard (CNS > Λ4 size (210X297 mm) (Please read the precautions on the back before filling in this page)

-46-B7 V. Description of the Invention (44)

Printed by the Central Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, p-toluenesulfonic acid monohydrate (70 rag, 0.37 mmol) was added to the compound α (XI b) < [218 a Ig '0.44 mmol) The toluene (10 niL) solution was heated at 75 ° C for 15 minutes, and the reaction mixture was concentrated under vacuum. The residue was then chromatographed on silica gel (solved with 20% ethyl acetate in hexane Analysis) to give 280 g (Y 18%) of the title compound «1 Η — N MR (CDC 1 3): δ 8 2 0 (d 1 J = 9 0 Hz t 2 Η)» 7 * 9 5 ( d 9 J = 9 ten 0 Hz 9 2)) f 7 9 0 (bs «1 Η) * 7. 5 0 (m $ 2 Η) 7 * 3 5 (d • J = 8 5 Hz t 1 Η) 1 5 • 8 0 (mt 1 H) 3 .9 5 (s »3 Η) > 2 • 2 5 (m, 2 H)» 2 1 0 (df J = 1-4 Hz • 3 Η) »1 3 0 (st 6 H) Ca M S (DCI) m / e: 3 5 0 (M Η +) • Example 1 24-[[(5, 6-dihydro-5,5, 8-trimethyl- 2-a) Amine] carbonyl] Benzoic acid (I2b) This paper size is applicable to the National Standard for Difficulties (CNS) A4 (2 丨 0X297mm) (Please read the precautions on the back before filling in this page} Order -47-4 78 1 86 at

~~ ___ E V. Description of the Invention (45)

At room temperature, 10 N NaOH (1.0 mraol, 0.1 raL) was added to a stirred solution of the compound (ID (〇097 omol, 34 mg) in ethanol and tetrahydrofuran (pyramid, 1: 1, 5 mL)). After 72 hours, add excess IN HC1 (20 mL). Collect the precipitate in a vacuum and wash with IN HC1 and water. After drying, 14 mg (Y: 43%) of the title compound is obtained * 'H-NMRCDMSO-de) 1 0. 32 (s, lH) * 8. 4.0 (s · 4 Η), 7. 6 6 (dd · J = 8. 3 * 2. 1Ηζ, 1Η), 7. 6 2 (d · J = 2.1 H z * 1 H), 7. 2 7 (d · J = 8.3 Hz, lH) · Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs --- ---- ^-(Please read the two notes before filling in this page) 5. 8 0 (m · 1 H), 2. 14 (m * 2 H) · 2. 0 1 (d- J = 1.4 Hz · 3 H), 1.1 8 (s, 6 H): 13C-NMR (DMS0-de) δ 1 6 6. 79, 164.6 6 4-1 3 9. 95, 1 3 6. 96 * 134. 1 5 ► 1 3 0 > 8 4 * 129. 27 * 127. 85, 124. 41, this paper size is commonly used in China National Standard (CNS) A4 specification (21 OX 297 mm) -48-4 ^ 1ββ A7 B7 V. Description of the invention (46) 123. 84 * 119. 30-115. 72- 38. 25, 32. 96, 28. 4 2 * 1 9. 1 8 ·; MS (DCI) m / β · 336 (ΜΗ) > IR (KBr): 3422, 2962 · 1700 Elemental analysis value of 1652 · 1532 * 5Η20. Calculated value C: 69.60; Η: 6.68; Ν: 3.86 Measured value C. 69.53: Η: 6.97; Ν: 3,76 Implementation Example 1 3 Ν- [2- (trimethylsilyl) ethoxymethyl] -4 _ [[(5,6,7,8-tetrahydro-5,5, -dimethyl-8-phenyl-8- Hydroxy-2- 棻) amino] carbonyl] methyl benzoate (XIc) --------- ^-(Please read the precautions on the back before filling this page)

, 1T Printed by the Consumer Standards Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

Add benzylmagnesium bromide (3.0 M ether solution, 0.59 mL, 1.76 mraol) to an anhydrous tetrahydrofuran solution (-78 ° C) of compound (Xa) (595 mg '1.24 mraol) at -78 ° C After 10 minutes, the reaction mixture was diluted with ethyl acetate (100 mL) * and washed with water (100 niL). The organic phase was evaporated and the residue was chromatographed on silica gel (20% ethyl acetate Hexane solution) to obtain 449nig (Y paper size universal Chinese storehouse standard (CNS) Λ4 size (210X297 mm) —49 _ ^ cTl 8 6 Λ7 * B7 V. Description of the invention (47) 67%) Title compound O-NM R (c DC 1 3); δ 7. 8 5 (d > 2 H) »7. 2 0 — 6 8 0 (m» 1 0 H) * 5. 2 0 (τη 1 2 H) * 3 9 5 (s, 3 H), 3. 6 5 (mt 2 H) 1 2. 2 0 — 2 * 0 0 (m > 2 H) »1. 8 5 (m 1 1 H) »1 5 0 (m, 1 H) * 1. 1.4 0 (s» 3 H) 1 3 0 (s, 3 H), 0.9 5 (m I 2 H) 9 0-0 0 (s, 9 H); S (DCI) m / e: 5 4 2 (MH + -H 2 0) · Real Example 1 44-[[(5, 6-Dihydro-5, 5-dimethyl-8-phenyl-2-some) amino] carbonyl] benzoic acid methyl ester (Tc) ------- -^-(Please read the notes on the back before filling out this page) Printed by the Central Standards of the Ministry of Economy 扃 Employee Consumer Cooperatives

5 小时。 P-toluenesulfonic acid (190 mg, 1.0 mnol) was added to a solution of compound (XIc) (as a monohydrate, 449 mg, 0.83 mnol) in toluene (10 niL), heated at 75 ° C for 0.5 hours After that, the reaction mixture was diluted with ethyl acetate (100 raL), and then a saturated sodium bicarbonate solution (100 paper size was applicable to the Chinese National Standard (CNS) Λ4 standard (210X297 cm) -50-4 18 186 A7 B7 V. Description of the invention (48) raL) Wash it. The organic phase was then concentrated under vacuum, and the residue was chromatographed on silica gel (15% ethyl acetate in hexane) to give 162 mg (Y: 48%) of the title compound. Η-ΝΜR cc DC 1 3) δ 8 .1 5 (d J = 8 5 H z > 2 H) »7 • 9 0 (d J — 8 5 H z > 2 H) * 7.9 0 (m 1 H) 9 7 6 5 (m 1 H) * 7. 4 0 (m 5 H) 6 9 0 (m 1 H) * 6. 0 5 (t J = 4 6 H z • 1 H) »3 .9 5 (s 3 H) 2 • 4 0 (d J — 4 6 H z» 2 H) «1. 4 0 (s 6 H)» S (DCI) m / e 4 1 2 (MH + ) »Example 1 Printed by the Male Workers Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5 4-[[((5, 6-Dihydro-5,5-dimethyl-8-phenyl-2-some) amino] carbonyl ] Benzoic acid (I2c)

Add 10 N NaOH (2.1 mmol, 0.21 mL) at room temperature to compound (Pc) (0.21 nmol, 86 mg) in ethanol and tetrahydrofuran.丨 0X 297 mm) (Please read the notes on the back before filling in this page)

-51-418186 A7 B7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

V. Description of the invention (49) In a stirred solution of 1 1 (1 1 5 m L) is added to the stirred solution after 0 7 2 hours. An excess of 1 1 1 N HC1 (20 m L) is added. * The precipitate is collected by vacuum filtration. Further 1 | After drying with 1N HC1 and water to obtain 74 mg (Υ: 89%) of the title, —, please compound 1. Read ii I 1 1 Η — NM MR (DMS 0 — d β); δ t 1¾ ί 1 1 1 0 2 9 (s 1 1 Η) 7 9 8 (m 4 Η), 1 1 7 7 6 (dd 1 J = 8 4 > 2 1 Η ZZ »1 Η), the term is 4 1 1 7 3 5 (m > 7 Η)% Page 1 5 9 7 (t J = 4 6 Η ζ 1 Η) 1 1 2 8 9 (d »J = 4 6 Η ζ 2 2) 1 I 1 2 7 (s > 6 Η); 1 1 1 3 C-N MR (DMS 0 — da): Order 1 1 6 6 7 0 t 1 6 4 5 8 1 4 0 * 4 6 f 1 1 1 4 0 3 3 > 1 3 8 * 8 1 Fan 1 3 8 6 2 9 1 1 1 3 6 7 8 t 1 3 3 • 3 9 * 1 3 3 Speech 1 0 1 k 1 2 9 1 6 > 1 2 8. 4 2 »1 2 8 '3 5 * I 1 2 7 8 9 9 1 2 7 1 8 1 1 2 6 8 3 1 1 1 1 2 4 0 4 t 1 1 9 • 8 4 t 1 1 8 0 3 t I 1 3 8 4 1 > 3 2 9 9 2 8 • 0 4 1 I Μ S (DCI) m / e; 3 9 8 (Μ Η +) € 1! IR (Κ B r) · 3 0 5 6 2 9 5 8 1 7 0 0 9 1 1 1 6 5 2 1 1 5 3 2 0 1 IC 2 6 Η Z 3 0 3N 1 Ze 1 5 4 Η 20 elemental analysis value 1 1 Calculated value C 73.45 H 5. 8 1 Ν: 3 .29 _ I The paper iS · size is applicable to China National Standards (CNS) / Μ specifications (210X297 mm) -52-Printed by the Central Laboratories of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, 4 1 8 1 δ ° Α7 _ Β7 V. Description of the invention (50) Actual value C C: 73.0 5; H: 5.53; N: 3. 22 Example 1 4.4 4.4-Dimethyl-7-diazotetrafluoroborate-butrahydrophenone (XIII) Fluoroboric acid (27.86 mL) diluted with water (27.86 mL) at 0eC ( 27.86 mmol) was added to 4,4-monomethyl-7-amino-tetramethylamidine (15.10 g, 7 9. 8 9 mmol) * Then sodium nitrate (13.75 g, 199 mmol) and water ( 27.86 inL) of cold solution was added slowly while maintaining the temperature at about 10 ° C. * The reaction mixture was then cooled to C, then filtered, washed with 5% fluoboric acid (200 bL), and dried under vacuum to obtain 20.5 g (Y: 89%) of the title compound * 'H-NMR (DMSO-de): < 5 9. 1 5 (d-J = 2.5 Η z > 1 Η), 8. 75 (dd, J = 8.5, 2. 5 Η z-1 Η), 8. 2 0 (d * J = 8. 5 H z · 1 H), 2. 8 7 (t »J = 7.0 Hz, 2H), 2. 0 7 (t * J = 7. 0 H z-2 H), 1. 4 3 (s, 6 H); MS (DCI) m / e: 193 (MH + -N2BF4). Example 1 7 4.4-Dimethyl-7-hydroxy-tetrahydroone (XIV) Compound (XI II) (1.19 g, 4.13 mmol) was added to sulfuric acid (3.0 raL) and water (30 mL ) Boiling solution, after 1 hour of reflow, the paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm > (Please read the precautions on the back before filling this page)

-53-4 1 8 1 δ ο a? _____ B7 V. Description of the invention (51) The reaction mixture is cooled and extracted with ethyl acetate (2 X 50 mL) ° The combined organic phases are concentrated under vacuum, and then concentrated. The residue was chromatographed on silica (dissolved in 20% ethyl acetate in hexane) to obtain 690 mg (Y · 88%) of the title compound < »1 Η — N MR (C DC 1 3): δ 7 4 8 (d * J = 2.5 Η ζ, 1 Η) »7 • 3 3 (d, J = 8. 5 Η ζ, 1 Η) 1 7 • 0 5 (dd, J = 8 .5 · 2. 5 Η ζ, 1 Η) 2 7 5 (t, J = 7. 0 Η ζ • 2 Η) »2 0 0 (t, J = 7. 0 Η ζ, 2 Η)» 1 • 3 8 (s, 6 Η) · Example 1 8 4, 4-Dimethyl-7-trifluoromethanesulfonate-1-tetrahydrofluorenone (XV) Trifluoromethanesulfonic anhydride at 0eC (4.42 mmol '0.74 mL) to compound (XIV) (690 fflg' 3.63 mmol) in: anhydrous pyridine (m L) solution * then allow the reaction mixture to rise to room temperature * 16 hours --- --- ^-(Please read the notes on the back first Please fill in this page again.) Order the Central Laboratories of the Ministry of Economic Affairs, Shellfish Consumer Cooperation, Du printed and add 1 Ν HC1 (25 inL), and then extract the reaction mixture with ethyl acetate (2 x 50 mL). The combined organic phases were dried over magnesium sulfate and concentrated under vacuum to give 1.17 g (Y: 100%) of the title compound. Η-NM R (CDC 1 3): δ 7.8 8 (d , J — 2 • 8 Hz, 1 H), 7. 5 2 (d, J = 8.7 Hz, 1 H) · This paper scale is applicable to China National Standards (CNS) Μ Appearance (2 丨 〇 '乂297 mm > -54-A18 1 8d A7 —----- B7__ V. Description of the invention (52) 7-4 0 (dd-J = 8.7, 2. 8 H z-1 H) 2- 76 (t, J = 7.0 Hz, 2H), 2, 04 (t, J = 7.0 Hz, 2H), 1. 40 (s, 6 H); MS (DCI) m / e '323 ( MH +) · Example 1 9 5,5-Dimethyl-8_one-5,6,7,8_tetrahydrofluorene-2_carboxylic acid methyl ester (; ^ 13) (Please read the notes on the back first Refill this page) Ο

The central sample of the Ministry of Economic Affairs printed triethylamine (1.09 0α, 7.82 mmol), palladium acetate (II valence) (24 mg, 0.11 nmol), and 1,3-bis (diphenyl) for shellfish consumer cooperatives. Phosphine) propane (44 mg, 〇-11001001) was added to contain the compound (fork 10 (1.15 it, 3.57 111010)), methanol (10.8 mL), and dimethyl subreagent I (10.8 mL) In the solution * Then the reaction mixture was saturated with carbon monoxide at room temperature, and then heated to 70 ° C for 3 hours with a carbon monoxide balloon. After cooling to room temperature, pour the reaction mixture into water. It was extracted with ethyl acetate. The organic phase was then concentrated under vacuum, and the residue was chromatographed on silica gel (15% ethyl acetate in hexane) to give 692 93% of the title product. · ^ -NMR (CDC13) · δ 8. 6 6 (d · J = 2. 0 Η z · 1)), this paper size applies to China National Standard (CNS) Λ4 specification (2I0X297 public 嫠) -55-41816 -A7 B7 V. Description of the invention (53) 8.18 (dd, J = 8, 3 * 2. 0 H z-1 Η) -7. 52 (d * J = 8. 3Ηζ-1Η)-· 3. 9 2 (s, 3 Η), 2. 76 (t, J = 7. Η Η z · 2 Η ), 2. 04 (t, J = 7. Η ζ ζ * 2 Η), 1. 4 1 (s, 6 Η); MS (DCI) m / e: 233 (ΜΗ +). Example 2 Ο 5 , 5-Dimethyl-8-hydroxy-8-phenyl-5,6,7,8-tetrahydrofluorene-2-carboxylic acid methyl ester (XVI I a) (Please read the precautions before and fill in (This page) Ο

Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, adding benzyl magnesium (3.0 M ether solution, 1. 0 mmo1 1 0.35 D iL) to compound (XVIa) (167 mg '0.72 mmol) In a tetrahydrofuran (5 mL) solution (-78 ...), after warming to room temperature (2 hours), the reaction mixture f was concentrated and the residue was chromatographed on silica gel (10% ethyl acetate in hexane solution). Analysis) to obtain 152 mg (Υ 68%) of the title product 9 1 Η-NM MR (CDC 1 3) 'δ 7.. 9 5 (dd 1 J = 8.3-2 .0 Η ζ, 1 Η) taste 7. 8 5 (dt J = 2. 0 Η ζ * 1 »)» This paper size applies to China National Standard (CNS) A4 (2I0X297 mm) -56-Staff Consumption Cooperation of the Central Bureau of Standards, Ministry of Economic Affairs Equipment Fifth, description of the invention (54) 7.50 C d > J = 8. 3 Η z »1 Η), 7. 2 5 (m, 5 Η), 3. 8 2 (s · 3 Η). 2 · 2〇 (m, 2H) '1. 8 5 (m · 1 Η) * 1.6 (m'lH), 1. 43 (s, 3H), 1. 38 (s * 3H); MS (DCI) m / e: 311 (MH +) «Example 2 1 5, 5-two Yl-5,6-dihydro-8-phenyl 'a 2-carboxylic acid (XVina)

Add several milligrams (2-4 mg) of p-toluenesulfonic acid to a solution of compound (XV 丨 la) (150 mg, 0.484 mmol) in toluene (7 niL) * After heating at 70 ° C for 5 minutes, the reaction mixture Cool and concentrate in vacuo • Dissolve the concentrated residue in ethanol (7 raL) and treat with 10 N NaOH (7.5 mmol '0.74 mL) at room temperature. After 16 hours, add excess 1 N HC1 (30 mL) * The precipitate was collected by vacuum filtration to obtain 135 mg (Y: 99%) of the title compound.Η--NM (DMS 0-d Θ): 67. 9 5 (dd «J = 2 • 0, 8, 5 H z, 1 H), 7. 7 5 (d J = 2. 0 H z '1 H), 7. 4 7 (d * J 8. 5 H z · 1 H)-This paper size is applicable to China National Standards (CMS} A4 size (2 丨 0X297mm) -1 57 _ (#Read the precautions for fatality before filling this page) Order 4 \ 8 1 86 A7 B7 _ V. Description of the invention (55) 7. 3 8 (m · 5 Η) · 6.05 (tJ = 4.6Hz, lH),. 2.4 0 (d »J = 4. 6 H z · 2 H ), 1. 40 (s »6 H); MS (DCI) m / e: 279 (MH +) · Example 2 2 4-[[(5, 6-dihydro-5, 5-dimethyl- 8-phenyl -2-A) carbonyl] amino] benzoic acid methyl ester (I3a) (Please read the notes on the back first # Fill this page)

The compound (XVIIIa) (135 mg, 0.485 mmol) was dissolved in thiosulfan gas at the Central Standards Bureau of the Ministry of Economic Affairs and the Consumer Cooperative Cooperative Neem (5 mL) solution with two drops of N, N-dimethylformamide at room temperature Stir. The mixture became homogeneous within 1 hour and was then concentrated under vacuum. The residue was dissolved in anhydrous pyridine (5 mL) * and methyl 4-aminobenzoate (from Aldrich, 0.534 mmole, 81 mg) was added. After 16 hours at room temperature, the mixture was diluted with 1 N HC1, extracted with ethyl acetate (100 mL), washed with 1 N HC1 (3 X 100 inL), and then saturated with sodium bicarbonate (2 X 100 mL) to wash * The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo to obtain 68 mg (Y: 34%) of the title compound. &Quot; H-NMR (CDC13): < 5 applicable to paper size China® Home Sample Standard (CNX) (210X297 male shame) ~ -58-4181 & 6 Α7 Β7 V. Description of the invention (8 7 7 7 56) 0 5 (d 7 5 (m 6 5 (d 5 Ο (m 6 〇8 (t 3. 9 Ο (s 2. 4 5 (d 1. 4 0 (s MS (DCI)

〇H z, 2 HJ = 7 2 H) J = 7 1 H) J = 4 3 H) J = 4 6 H): m / e-412 (MH + 〇 H z · 2 H) '7. 4 0 (m, 5H) 6Hz, 1H), 6Hz, 2H), Example 2 3 6-dihydro-5,5-dimethyl-8-phenyl-2-() carbonyl Amine] Benzoic acid (I 4a) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Add 1 ON NaOH (0 165 fflL, 1.65 mmol) to the acetic acid (5 inL) solution of compound (I3a) (Q.165 mmol, 68 rag) at room temperature. After 72 hours, add Excess IN HC1 (30 mL), the precipitate was collected by vacuum filtration, washed with IN HCI and water, and air-dried to give 45 mg (Y: 69%) of the title compound * JH-NMR (DMSO-de ): «5 This paper is suitable for Chinese National Standards (CNS) A4 ^ grid (2IOX297 mm) (Please read the precautions on the back before filling this page)

-59-4⑷86 V. Description of the invention (57 A7 B7 Printed by Zhengong Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs 1 0 4 2 (s 1 1 H) 7 8 3 (m 5 7 5 2 (d »J == 8 0 H z 1 H) 7 3 8 (τη f 6 H) * 6 0 5 (t * J = 4 6 H z 1 H) 2 3 3 (d J — 4 * 6 H z 2 H) 1 3 0 (s * 6 H) t 1 3 C — N MR (DMS 0 — d β) 1 6 6 9 1 * 1 6 6 0 0 > 1 4 8 2 6 1 4 3 2 5 »1 4 3 • 1 4 1 3 9 8 6 t 1 3 8 • 2 9 1 1 3 3 * 3 6 1 3 2-4 8 1 1 3 0 1 7 1 1 2 8 5 5 9 1 2 8 ten 3 1 > 1 2 7 4 1 1 1 2 7 • 3 1 t 1 2 6 8 4 1 2 5 4 0 > 1 2 5 0 0 1 1 2 3 9 5 1 1 1 9 speech 3 8 * 1 1 9 3 0 »3 7- 9 9 »3 3 5 2 2 7 • 7 5 Μ SCDCI) m / e 3 9 8 (MH +) f IR (Κ Β r) 2 9 5 8 1 6 8 8 9 1 5 9 1 5 2 2 〇C 2 Θ Η 2 3 Ν 1 〇3 * 0 5 H 20 Elemental analysis value If Calculated C _ · 76.83 H: 5. 95 N: 3. 45 Measured value C 76 .47 H: 6. 00: N : 3 .22 Example 2 4 5, 5-Dimethyl-8_ethyl-8_hydroxyl-5,6 7,8-tetrahydrofluorene-2- (Please read the precautions before filling this page)

This paper is suitable for China National Standard (CNS) A4 (2 丨 0 · 〆297mm) -60-418 1 8b A7 B7 5. Description of the invention (58) (XVI Ib)

Using a similar method to prepare the 8-phenyl derivative (XVIIa), 490 mg (2.11 mmol) of the compound (XV 丨 a) was prepared to give 130 mg (Y: 24%) of the title compound-Example 2 5 5,6- Dihydro-8-ethyl-5,5-dimethylfluorene-2-carboxylic acid (乂 ¥ 1111 >)

(Please read the notes on the back before filling out this page) The f 夬 Standards Bureau Consumers' Cooperatives printed the compound (XVI 130 rag ¢ 0.49 mmol) using a similar method to prepare 8-phenyl derivatives (XVIIIa). b) The title product of 113 nig (Y: 100%) was prepared. 'H-NMR (DMSO-de)' δ 7.9 8 (d-J = 2.0 H z · 1 H), 7. 9 5 (dd-J = 8.5, 2. 0 Hz, lH) '7. 4 0 (d ► J = 8. 5 Hz, 1 H), 5. 8 3 (t, J = 4. 6 Hz, 1 H), the standard of this paper is Chinese national standard (CNS > Λ4 specification (2I0X297 mm) -61-B7 V. Description of the invention (59) 2-5 5 (Q, J = 7. 5 Hz, 2H ), 2-1 5 (d, J = 4.6 H z * 2 H), 1 · 2 7 (s, 6 H) > 1. 1. 8 (t, J = 7.5 H z, 3 H ) ° Example 2 6 4 _ [[(5, 6_Digas-5,5-dimethyl-8_ethyl ~ 2_)) Pseudo] amino] methylbenzoate (I3b)

Using a similar method to prepare 8-phenyl derivative (I3a), 113 mg (0.491 nunol) of compound (XVIIIb) was used to prepare 163 mg (Y: 92%) of the title compound. • Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. ) 3 ·) * 8 · 1 8 H 2 8 || 8 4) c || 1 II II J 11 II HDJ Ϊ JJ * JJ 00 fsf * * 〇tt 9 (dbddddt s R / IV / TV Γν / ίκ / κ / V / IV M85955080 N09776489 H87777753

Xu VI / Η 2 tz H 5 t, 7U t ·) HN— / Η Η ο Η H 12 1 1 t »t 9 zz» zz Η ο ο Η H 0 5 .06 Η 1 {Please read the note on the back first $ Items to fill out this page)

This paper size applies to China National Standard (CNS) Λ4 specification (210X 297 mm) 62 4 18 186 a? B7 11 V. Description of the invention (60) 2 55 (* 3 1 J = 7. 5 Η z * 2 Η ) '2 25 (d'J = 4-6Hz'2H)' * 1 · 3 Ο (s, 6 Η) '1 l8 (t' J = 7. 5 Η z 1 3 Η); MS (DC I) m / e: 364 (MH +)-Example 2 (I4b) --------- ^-(Please read the note on the back first # Fill this page)

定 _ Impression of Zhengong Consumer Cooperative, Central Bureau of Quasi-Ministry of Economic Affairs, using a similar method for the preparation of 8-phenyl derivatives (I4a) with 128 mg (Y: 92%) Title compound * lH-NMR (DMSO-de)-δ 10. 4 6 (s · 1 Η)-7.9 1 (m * 4 Η) · 7.7 7 (m »2 H) t 7. 4 5 (d »J = 7 .9 H z, 1 H), 5. 8 4 (t» J = 4 .6 H z, 1 H) 1 2. 5 2 C q, J = 7 .4 H z, 2 H) * 2. 1 7 (d, J = 4 6 H 2, 2 H), this paper size is applicable to China National Chess Examination (CNS) A4 «L (210X297 mm) -63-Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by a consumer cooperative 4 1 8 1 Βό a? Β7 V. Description of the invention (61) 1.2. 1 (s, 6 Η), l.ll (t, J = 7.4Hz, 3H): 13C-NMR (DMSO -de): 1 6 6. 97, 166.1 1 3 3-1 4 8. 61, 1 4 3. 33, 136. 36, 133. 27 · 1 3 2. 54, 130. 19, 126. 72, 125. 52-123. 95-1 2 2. 80- 1 2 2. 1 1-1 1 9. 5 0-1 1 9. 4 1-37. 6 2-3 3. 42, 27. 94 * 2 4.65, 12.86; MS (DCI) m / e: 350 (MH +); IR (KBr): 2964, 1690, 1596, 1 5 2 4. C 22H 230 3N! · 〇. 7 5 1 ^ 〇 elemental analysis value: calculated value C: 72.81; osmium: 6.80: N: 3.86 found C: 72.84; osmium: 6.61; N: 3.86 Example 2 8 8- Hydroxy-5, 5, 8-trimethyl-5, 6, 7, 8-tetrahydromethyl-2-carboxylate (XV II c)

(Please read the notes on the back before filling this page)

This paper size is in accordance with Chinese National Standard (CNS) A4 (2 丨 0X297 mm) -64-Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 418186 A7 _ B7 V. Description of the invention (62) Preparation of 8-benzene (C XV Ila) based on 292 mg (1.26 mmol) of compound (XVIa) to give 188 rag (Y 60%) of the title compound * NMR (CDC 13): δ 8. 2 9 (d · J = 2. 0Ηζ, 1Η)-7. 8 5 (dd * J = 8. 0 H z * 2. 0Hz, lH), 7. 38 (d, J = 8. 0Hz, lH), 3 9 0 (s, 3 H), 2. 0 (t, J = 7, 0 Hz, 2H) · 1.87 (t, J = 7, 0 Hz, 2H), 1. 6 0 (d * J = 1.3 Hz , 3H), 1.3 8 (s, 6 H) · Example 2 9 5,6-Dihydro-5,5,8-trimethyl-2-carboxylic acid (also ¥ 111 «:)- ------- \ 衣-(Please read the precautions on the back before filling out this page), 1Τ

Using a similar method for the preparation of 8-phenyl derivative (XVIIIa) with 188 mg (0.76 mmol) of the compound (XV lie), 154 mg (Y: 94%) of the title compound were obtained. ^ -NMR (DMSO-de) '' · Δ 7.96 (m, 2 Η), ____ This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (2 丨 〇297297 mm > " " -65-^ 18 1 δ ^ Α7 Β7 V. Description of the invention (63) 7. 4 0 (d-J = 8. OHz'lH), 5. 8 7 (m 1 Η), 2. 27 (m, 2H), 2. 17 (d-J = 1.3 H z · 3 H) '1. 2 7 (s, 6 H) · Example 3 0 4-[[(5, 6-dihydro-5, 5, 8-trimethyl-2-a) carbonyl] Amine] methyl benzoate (I3c) (Please read the notes on the back before filling this page)

The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed a similar method for the preparation of 8 phenyl derivatives (I 3a) with 154 rag (.713 1 m in ιο) of compound (XVI 1 Ic) to obtain 90 mg (Y • 36% of the title compound ο 1 Η--NM R c CDC 1 3) 6 8. 0 5 (d, J = 8 _ 5 H z »2 H) 1 7. 9 0 (bs» 1 H) f 7 7 5 (d review J = 8 5 H z • 2 H) 1 7. 7 5 (dt J = 2 * 0 H z 1 1 H) 1 7. 6 5 (dd »J = 8 0» 2 0 H z > 1 H) · 7. 4 3 (d * J = 8 '0 H z V 1 H) »5. 8 7 (m) 1 H) 3 9 2 (s ϊ 3 H) > 2. 2 7 (m 1 2 H) »This paper size applies to China National Standard (CNS) Λ4 specification (2IOX 297 mm) -66-418186 A7 B7 V. Description of the invention (64) 2. 18 (d · J = 1. 3 Η z »3 Η), 1. 3 Ο (s * 6 Η); I MS (DC I) m / e: 350 (MH +). Example 3 1 4-[[(5, 6-Dihydro-5, 5, 8-trimethyl-2-some) carbonyl] amino] benzoic acid (I4c) (Please read the precautions before and then Fill out this S)

Using a similar method for the preparation of 8-phenyl derivative (I4a), 90 mg (Y: 81%) of the title compound was prepared from 90 ing (0.26 mmol) of compound (I3c). 1 Η —NM MR (DMS 0 — de) δ 1 2. 7 2 (bs 1 H) > 1 0 • 4 6 (S * 1 H), 7. 8 9 (mt 5 H) t 7. 7 9 (dd «J = 8 0 • 2-0 H z * 1 H), 7. 7 2 (d > J = 2 0 H 2 1 H) 1 7 .4 5 (dt J = 8 0 HZ 1 1 H), 5 .8 5 C m 1 1 H) »2 1 7 (m 1 H) 2 .0 9 (d» J = 1 3 H z 3 H) »1.2. 2 (s 6H) The size of this paper is applicable to the Chinese national sample (CNS) Λ4 grid (210X297 mm) -67-A7 d18196 B7 V. Description of the invention (65) MS (DC I) m / e: 3 3 6 (MH +) · IR ( KBr): 2958, 1674, 1656 '(Please read the notes on the back before filling this page) 14 16; 13C-NMR: 1 66. 93, 166. 13- 14 8. 21, 143.3 3 8-1 3 3. 98 · 1 3 2. 5 8 * 1 3 0. 63, 130. 22, 126. 89-125. 36-124. 90- 1 2 3. 8 3-1 2 2. 48, 119. 48 ' 119. 3 9-3 7. 8 4-3 3. 54 · 28. 14 * 19. 12 ·

Elemental analysis value of CuHnNiOa: Calculated C: 75. 20; Thallium: 6. 31; N: 4. 1 Measured value C: 74.9 0; Thallium: 6.36; N: 3.99 Example 3 2 1- (5, 6- — Nitrogen-5,5-—methyl_8 -phenylpyrene_2 -yl) -acetamidine (XlXa

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Ethyl paper with methyl lithium (as a 1.4 M ether solution, 4.19 mL, 5.88 mmol) was added to the compound (XVI I la) (816 mg, 2.94 mmol). The scale is applicable to China's family standard (0 milk > eight 4 gauge_grid ^ 2 丨 0 > < 297mm) -68-1Q6 A7 B7 V. Description of the invention (66)> ether (15,0 mL) stirring solution (-78 ° C). After 1 hour at room temperature, add IN HCL (50 mL) «After separating the organic phase, wash it with brine (50 raL) and IN NaOH (50 mL), and then dry it. 600 mg (Y: 74%) of the title compound was dried and concentrated to obtain 600 mg (Y: 74%) of the title compound. 3 (d 1 J = 1 7 H z 1 1 H) 7 4 6 (d J = 8 0 H z 1 H) »7 3 7 (m 5 H) 6 0 5 (t JZ ^: 4 ten 7 H 2 1 H) > 2 4 4 (s 3 H) f 2 3 7 (d J = 4 * 7 HZ 2 H) redundant 1 3 5 (s 6 H) M S (DCI) m / e 2 7 7 (MH +) 0 7 Η z Η (Please read the notes on the back before filling this page) -V. -Β In the Ministry of Economic Affairs Standard Bureau employee consumer cooperative printed example 3 3 4- (£, B)-[2- (5,6-dihydro-5,5-dimethyl-8-phenyl-2-some) -1- Propenyl] ethyl benzoate (I5a)

Use p-[(diethoxyphosphonium) methyl] methylbenzoate (1.02 g) This paper size applies the standard of CNS (CNS > A4 (210 × 297 mm) A7 4! 8 丨 86 B7 5 、 Explanation of the invention (67) 3.40 mmol 'prepared according to Liebigs Ann. Chen. 1985, 929) Add 1M dimsyl anion in dimethyl subcode solution (3_09 mL \ 3_09 mraol | 6 Prepared by heating at 5 ° C for 1 hour. After 30 minutes, add the mixture to a solution of compound (XIX a) (595 mg, 2.16 mmol) in dimethylaso (6.5 mL) (room At room temperature). After 3 hours at room temperature * add 2M ethanol solution (1.74 raL, 3.48 amol) of sodium ethoxide concentration. After 16 hours at room temperature * use 5% sodium bicarbonate solution (50 mL) diluted the mixture * and extracted with ether (50 mL X 3). The combined organic phases were concentrated in vacuo, and the residue was decanted on silica gel (dissolved in 5% ethyl acetate in hexane). 159 mg (Y: 18%) of the title compound were obtained. NMR results showed that the E: Z was a mixture of 4: 1 isomers. Example 3 4 4- (E)-[2- (5 , 6-dihydro-5,5-dimethyl-8-phenyl-2-some) -bupropenyl] benzoic acid (Iea)

10 N NaOH solution (0.39 raL, 3.9 mmol) was added to a stirred solution (room temperature) of the compound (I5a) (159 mg'.388 mmol) in ethanol (15.0 mL) * after 48 hours • With an excess of IN HC1 (40.0 this paper size applies to the Chinese national standard (CNS > Λ4 specification (2ΙΟ × 297 mm)) (Please read the precautions on the back before filling out this page)-Binding and ordering Printed by Shelley Consumer Cooperative -70-^ Order of the Ministry of Economic Affairs, Central Bureau of Standards, Industry and Consumer Cooperatives, Printing 5. Description of Invention (68) m L) Diluted »Then filtered o Washed with water and dried the solid from ethanol 60% (Y: 40¾) of the title compound 1 Η — NM MR (DMS 0 — de;: δ 7 9 1 (d »J = 8 3 Ζ Zn 1 2 Η)» 7 4 2 cmt 9 H) 1 7 0 6 (d ♦ J = 1 7 Η ζ »1 Η) 1 6 7 0 (s * 1 H) t 6 0 3 (t > J = 4 6 Η ζ t 1 Η) 1 2 3 4 (dt J = 4 6 Η ζ f 2 Η) »2 1 2 (st 3 H) t 1 3 1 (S * 6 Η): 1 3 C — Ν R (DMS 0 — d 1: 1 4 4 4 2 »1 4 0 • 5 8 t 1 4 0 1 4 1 3 8 9 4 i 1 3 8 7 2 9 1 3 3 * 1 2 1 2 9 2 6 1 1 2 9 0 7 t 1 2 8 4 7 1 2 8 3 5 T 1 2 7 3 2 1 2 6 7 1 1 2 5 8 9 • 1 2 5 3 2 1 2 4 • 0 7 1 2 3 0 6 * 3 8 2 5 t 3 3 * 1 6 * 2 7 9 4 1 7 3 8 Μ S (DCI) m / e 3 9 5 (M Η +) IR (Κ Β r) · 2 9 5 8 »1 6 8 0% 1 6 0 2, 1 2 9 2 ο C 2 Τ Η 2 β 0 2 Elemental analysis value: Calculated C: 84.78: H 6. 85 Measured value C 84.98; H; 6. 66 paper * Standards applicable to China »| Media vehicles (CNS > A4 wash grid (2 丨 〇 × 297 mm) A7 B7 V. Description of the invention (69) Example 3 5 4,4-dimethyl-7-[(Third Ding Dimethylsilyl) oxy] -butahydrone (XXIa)

At room temperature, add tertiary butyl dimethylsilane (1.90 g, 12.6 roraol) and imidazole (1.79 g, 26.3 mraol) to compound (XIV) (2.00 g, 1.0 mmo 1) ) In dimethylformamide (16 mL).俟 After 5 hours, add 5% NaHC03 (50 mL), and then extract the mixture with hexane (2 X 75 nL). The organic phase printed by the Central Bureau of Standardization, Shellfish Consumer Cooperative, was dried with Act Titanium Sulfate 1 and concentrated in vacuo to obtain 3.22 g (: Y = 99%) of the title compound ο 1 Η-NM R (CDC 1 3) δ 7. 4 4 (d J = 2-8 Η ζ »1 Η) 7. 2 9 (d» J = 8-7 Η ζ > 1 Η) t 7. 0 1 (dd 1 J = 8 7 t 2 • 8 Η t t 1 Η 2. 7 1 (tt J = 7-0 Η ζ t 2 Η) 1 1. 9 9 (t 1 J = 7 0 h ζ I 2 Η) 1. 3 6 (s 1 6 H) 9 0 9 8 (S »9 Η) 0. 2 0 (s» 6 H) t Μ s (DCI) m / e 3 0 5 (Μ Η +) «This paper size applies to the Chinese national standard ( CNS) A4 specification (2IO × 297 mm) -72-A7 B7 V. Description of the invention (70) Example 3 6 2-[(Third butyldimethylsilyl) oxy] -5, 6-dihydro-5 , 5-dimethyl-8-trifluoromethanesulfonium (XXIU ) (Please read the notes on the back before filling out this page)

Ordered by the Zhenggong Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs ^ Sodium bis (trimethylsilyl) phosphonium amide (a 1.0 M tetrahydrofuran solution, 9.88 mmol, 9.88 mL) and N- (2-pyridyl ) Trifluoromethane based amine [N- (2-pyridyl) triflimide)] (9.98 mmol, 3.54 g) was added to compound (XX I a) (2.73 g, 8.98 UMBO 1) in tetrahydrofuran (80.0 mL) In the solution (-78eC) • After stirring at -78 ° C for 1 hour and at room temperature for 1.5 hours • The reaction mixture was concentrated in vacuo, and the concentrated residue was chromatographed on silica gel (to 10% ethyl acetate in hexane solution) to give 2.26g <: Y: 58%) of the title product * 1 Η — N MR (CDC 1 3): δ 7 1 5 (d • J = 8 • 4 Η ζ > 1 Η), 6 • 8 5 (d 1 J = 2 • 5 Η ζ, 1 Η), 6 * 7 8 (dd »J-8-4 Η Z ′ 2 .5 Η ζ, 1 Η) »5 • 9 4 (t > J = 4 8 ζ ζ * 1 Η) · 2 3 8 (d 1 J = 4 8 Η ζ, 2 Η), 1. 2 7 (s-6 ), 0.9 8 (s · 9 Η), this paper size applies to Chinese national standard (CNS > A4 specification (210X297 mm) — 73 _ Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Industrial Cooperatives Λ7 B7 V. Description of the invention (71) 〇 2 0 (s, 6 Η): MS (DCI) m / e: 437 (MH +) ·. Example 3 7 2_ (Third-butyldimethylsilyloxy) -5,6-dihydro-5,5-dimethyl8-phenyl- (XXIIIa)

° | + Add triphenylphosphonium (300 mg, 0.980 mmol), ginseng (diamidinoacetone) dipalladium (0 valence) (147 ng, 0.16 mmol) and tributylphenyltin (4. 18 g, 11 4mmol) Add compound (XXI la) (2.26 g, 5.18 mmol) in a solution of 1-methy-2-pyrrolidinone (25.0 fflL) (room temperature) at 85 ° C After stirring for 16 hours * water (50 mL) and ethyl acetate (50 mL) were added. The organic phase was separated and stirred on a saturated aqueous solution of potassium fluoride for 30 minutes. The organic phase was re-separated and concentrated in vacuo. The concentrated residue was chromatographed on silica gel (100% hexane) to give 1.10 g (Y: 58%) of the title product. ^ -NMR (CDC 13): δ 7. 1 0 (m, 5 Η), 6. 9 7 (d * J-8. 4 Hz, lH) · This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling this page)

-74-A7 B7 418186 V. Description of the invention (72) 6 4 1 (dd, J: = 8 4 H z 2 5 H z, 1 H) 1 6 2 0 (d 'J = 2 5 H zt 1 H) 5 6 8 (t, J = 4 8 H% »1 H) f 2 0 5 (d, J = 4 8 H z 1 2 H) 1 0 2 (s, 6 H) 1 0 6 0 (s) 9 H), 0 0 0 (s * 6 H) * M S (DCI) m / e; 3 6 5 (MH +) o Example 3 8 5,6- -nitrogen_5,5--• methyl_8 -Phenyl-naphthalene-2-ol (XXVa) (Please read the precautions below and fill out this page)

Printed by the Central Laboratories Consumers Cooperative of the Ministry of Economic Affairs. Tetrabutylammonium fluoride (a tetrahydrofuran solution with a concentration of 1.QM, 3.32 inL '3. 32 mmol) was added to the compound (XXIIIa) (1.10 g' 3. 02 mmol). Tetrahydrofuran (10.0 mL) in solution (room temperature). After 5 minutes, the reaction mixture was concentrated under vacuum, and the concentrated residue was chromatographed on silica gel (eluated with 10% ethyl acetate in hexane) to obtain 575 mg (Y: 76%) of Title product * 'H-NMR (CDC 13): δ 1.3.6 (m, 5 Η) · 7. 2 3 (d · J = 8. 3Hz, lH) * This paper is based on the Chinese National Standard (CNS) ) A4 grid (2IOX25 »7 mm) ~ -75-Λ7 B7 418186 V. Description of the invention (73) 6. 7 1 (dd, J = r 8 3» 2 • 7 Hz 6. 4 9 (d, J = 2-7 H z > 1 H), 5. 9 9 (t, J — 4-6 H z 1 1 H), 2. 3 4 (d -J z = 4 < 6 H zt 2 H) , 1. 3 2 (s, 6 H) t S (DCI) m / e; 2 5 1 (MH +) «Example 3 9 Di-tert-butyl terephthalate (XXVI) (Please read the note on the back first (Fill in this page again)

Tertiary butanol (803 mg, 10.8 mmol) was added to a solution of terephthalocyanine chloride (2.00 g '9.95 mmol) in dry pyridine (25.0 inL) * at 85 ° <: after 16 hours · Add Water (75.0 mL) • The solid was then filtered off. • The solid was dissolved in diethyl ether (40 mL) and washed with saturated sodium bicarbonate (2 X 75 mL). The organic phase was then dried over anhydrous magnesium sulfate and then under vacuum. Concentrated to give 1.15 g (Y: 42%) of the title compound

Q′H-NMR (CDC 13) ; A4 specification (2 10 × 297 mm) Μ printed by the Central Consumers' Bureau of the Ministry of Economic Affairs of the Consumers Cooperatives -76-418 186 A7 B7 V. Description of the invention (74) Tertiary phthalic acid monobutyl ester (XXVII)

The Ministry of Economic Affairs, Central Bureau of Standards, Work and Consumer Cooperative, India, added a solution of compound (XXVI) (1.15 g '4.14 mmol) in tert-butanol (5.5 mL) to potassium hydroxide (255 rag, 4.55 ππηοΐ) in tert-butanol (4. (3 nL) solution (0.5 mL of water added based on solubility factor) • After 3 hours at 50 ° C • Add ether (35 mL), then filter the reaction mixture • Dissolve the solid in water (35.0 mL ), Extracted with methane (2 X 50 mL), and then acidified with IN HCL * to collect the precipitate to obtain 270 rag (Y: 30%) of the title compound * NMR (CDC 13): δ 8. 0 2 (m · 4 Η) · 1.5 6 (s »9 Η); MS (DCI) m / e: 223 (MH +) * Example 4 1 4-[[(5, 6-dihydro -5,5-dimethyl-8-phenyl-2-fluorene) oxy] carbonyl] benzoic acid tert-butyl ester (Pa)

This paper size is applicable to China National Standard for Ladder (CNS) A4 (2 丨 〇 > < 297 mm) (Please read the precautions on the back before filling this page) -Order -77-Λ 1 R ^ at _ ^ _____ Β7 V. Description of the invention (75) Yin Ju, the Consumer Work Cooperative of the Central Bureau of Standards, the Ministry of Economic Affairs, added grass gas (0. IS \ (QL) and dimethylformamide (2 drops) to the α-alpha compound (XXV II) (1 07 mg '• 0.480 mmol) in a solution of dichloromethane (5 mL) (0 ° C)' • After 2 hours at room temperature, the reaction mixture was concentrated in vacuo to obtain the corresponding chloro compound ( XXIVa) (> Compound (XXVa) (120 mg, 0.48 mmol) was added to a dry pyridine solution (5 ml) of compound (XXIVa) (0.480 mmol), and the temperature was 11 5 After 1 hour, the mixture was diluted with 1N HCL, extracted with ethyl acetate (100 mL), washed with IN HC1 (4 X 100 nL), and then washed with a saturated hydrogen carbonate solution (2 X 100 m L). ♦ The organic phase was separated, dried over sulfuric acid, and concentrated in vacuo to obtain 137 mg ( Y: 63%) of the title compound · 1 Η-N MR (CDC 1 3) δ 8.6.1 (d J = 8 4 Η Z '2 Η), 8. 0 (d * J = 8 4 Η Z '2 Η) * 7.. 3 5 (m 1 6 Η) t 7. 0 7 (dd * J = 8 • 4 Hz • 2.4 Hz, 1 Η) • 6 * 8 4 (d »J = 2 4 Hz 1 Η), 6.0 4 (t VJ ~ 4 6 Η Z 1 1 Η) 1 2. 3 8 (df J = 4-6 Η 2 * 2 Η), 1.6 1 (s »9 Η) I 1 3 6 (s -6 Η), MS (DCI) m / e 4 5 5 (Μ Η +) ο Example 4 2 4- [[(5, 6 _ mono-nitrogen ~~ 5, 5- di Methyl-8-phenyl-2- 2-a) oxy] carbonyl; | benzoic acid (lBa) This paper size applies Chinese National Standard (CNS) A4 grid (210x297 mm) (Please read the notes on the back before filling (葙 Page) -78-Λ 18 ^ S6 V. Description of the invention (76)

Tricyanoacetic acid (0.270 mL) was added to the stirred digas methane solution of compound (17a) (137 mg, 0.30 mmol) at room temperature, and after 72 hours, IN HCI (30 aL) was added. The precipitate was collected by vacuum filtration, washed with IN HCI, and air-dried to obtain 85 mg (Y: 71%) of the title compound. ^ -NMR (CDC 13) δ (Please read the precautions on the back first (Fill in this page again.) Ministry of Economic Affairs, Ministry of Economic Affairs, Tsinghua Bureau, Consumer Work Cooperatives, India Fanfan 1 3 • 3 9 (b S 1 H) t 8-1 5 (d * j = 7 * 5 HZV 2 H), 8 middle 0 5 (d »j = 7 • 6 H z» 2 H), 7 3 8 (mt 6 H) 1 7 • 1 8 (d J = 8 * 4 H z 1 H) · 6 7 3 (s 1 H ) 1 6 * 0 6 (t J = 4 • 2 H z 1 H), 2 3 5 (d J = 4 * 2 H z 2 H)-1 3 2 (s 6 H) C-N Μ R cc DC 1 3 >: 6 6 4 8 V 1 6 3 * 9 9 »1 4 8 * 5 1 4 2 5 5. * 1 3 9 * 7 7 y 1 3 8 17 5 2 4 t 1 3 4 • 5 9 f 1 3 2 4 5 · The scale of this paper is based on the sample rate of Chinese peaks (€?> Rong 4 specifications (2 丨 〇; < 297 mm >) -79-A 1 8 1 ΘΒ A7 B7 Description of the invention (77) 131. 6 1 1 3 0. 0 1-1 2 9. 6 6 · 1 2 9. 4 8 * 1 2 8. 5 7-1 2 8. 28, 1 2 7. 6 3 -1 2 7. 41, 125. 24 · 1 2 0. 7 4 * 1 1 8. 3 6 · 6 7. 39, 3 8. 24, 38. 07, 33. 12, 28. 37 * MS (DCI ) m / e: 399 (MH +); IR (KBr): 2964, 1738, 1698, 1 2 4 6 · C 24H Ο Λ · 0.5 .5 Η20 Elemental analysis value: Calculated C: 76.84; Η: 5.69 found Value C: 76.66: Η: 5.89 Example 4 3 Tert-butyl 4-hydroxybenzoate (XXVIIIa) (Please read the notes on the back before filling in this I) S-

Concentrated sulfuric acid (0.150 bL) was added to a solution of isobutene-saturated 1,4-dioxane (10.0 niL) (-7 8 eC) containing 4-hydroxybenzoic acid (2.0 g, 14.5 mmol). In a gold bullet)) • seal the bullet • and warm to room temperature • and after 72 hours at room temperature • cool the reaction mixture to -78X, then pour into a saturated sodium bicarbonate solution (30.0 nL), then Extraction with diethyl ether (2 X 50.0 inL) • Combined organic phases were added to Australian paper size. Use the national standard (CNS > "210X297 mm) " 80 Annex la: No. 85105 is 6 Revised page of the Chinese specification of the patent application No. 4 in January of the Republic of China, 4 Uj .. V. 〖V. The description of the invention (78) was reduced, and the concentrated residue was chromatographed on silica gel (diluted with 5% methanol (Chloromethane solution) to give 290 mg (Y: 10%) of the title product. '' H-NMR (CDC 13): δ 7. 8 9 (d, 'J = 8.8 Hz, 2 H), 6.8 3 (d, _ J = 8.8 Hz, 2 H), 1 5 7 (s: '9 Η) > Example 4 4 4-[[(5, 6 -—nitrogen-5, 5 -—methyl-8-benzyl-2_articles]]]] Tertiary butyl formate (I9a)

(Please read the notes on the back before filling in this page) ^. —------ Order .------- > Consumer Consumption of Intellectual Property Bureau of the Ministry of Economic Affairs: ± 1 Chlorine (0.075 mL) and dimethylformamide (2 drops) were added to a dry dichloromethane (7 mL) solution (0 ° C) of compound (XVIIIa) (200 rag, 0.720 mmol), and After 2 hours at room temperature, the reaction mixture was concentrated in vacuo. Compound (XXVIIIa) (154 mg, 0.792 mmol) was then added to a solution of the acridine residue in anhydrous pyridine (5.00 mL). After 2 hours at room temperature, the mixture was diluted with IN HCL, extracted with ethyl acetate (50 mL), washed with IN HC1 (4 X 100 mL), and then saturated sodium bicarbonate solution (2 X 100 mL) After washing *, the organic paper size was subsequently separated and applied to the Chinese National Standard (CNS > A4) (210 X 297mm *) -81: A7 _B7_ V. Description of the invention (79) The phase was concentrated under vacuum, and then concentrated The residue was chromatographed on silica gel (dissolved with 3% ethyl acetate in hexane) to obtain 203 mg (Y: 61 Employee Consumption of Intellectual Property Bureau of the Ministry of Economic Affairs: Printed%). .....-, __ 1 Η--N Μ R (CD C 1 3) δ | ί > ι Year IV, 1 8. 0 5 (m 3 H) t —_J 7. 8 5 (d J = 1 .7 H z 1 H)-7.. 5 1 (d J = 8. 1 H z) > 7. 3 8 (m 6 H) 7. 1 8 (d J = 8.6 H z 1 H) '6. 0 7 (t J = 4 6 H z 1 H), 2. 4 0 (d J 4. 6 H z 2 H), 1. 5 9 (s 9 H) -1 3 8 (s, 6 H); MS (DCI) m / e 4 5 5 (MH +) 〇 Example 4 54-[[(5, 6-Diargon-5, 5-dimethyl-8-phenyl-2-some) Carbonyl] oxy] benzoic acid (I10a)

Trifluoroacetic acid (0.4 0 0 niL) was added to a solution of compound (I9a) (203 mg, 0.480 mmol) in dichloromethane (5.00 mL) at room temperature. This paper is scaled to the National Standard for Difficulties (CNS) A4 ( 210 * 297 mm) -82-(Please read the notes on the back before filling out this page) ^ ---- Order --------- line. Printed by the Central Standards Bureau of the Ministry of Economy A7 _____B7 V. Description of the invention (80) • And after 16 hours • Add IN HC1 (30 mL). The precipitate was collected by vacuum filtration, washed with IN HC1, and air-dried to give 133 mg (Y: 75%) of the title compound "1H-NMR (DMSO ~ de) 8. 05 — 7. 3 1 ( m '1 2 Η), 6. 10 (t · J = 4.6 Hz * 1H), 2. 39 (d, J = 4.6 Hz, 2H), 1.3 4 (s, 6 H); IR ( KBr): 2962, 1742 · 1684, 1 6 0 2; MS (DCI) m / e: 399 (MH +) · C24H22O4 · 0 8 5 〇H2〇 analysis value: calculated value C: 75.47: Η: 5.77 Found C: 75.52: Thallium: 5.43 Example 4 6 5,5-Dimethyl-8-hydroxy-8- (2-fluorobenzene) -5,6,7,8-tetrahydro-2-carboxylic acid Methyl Ester (XVI Id) (Please read the precautions before filling this page)-* Μ

Lithium 2-fluorophenyl [which is a THF solution with a concentration of 0.35 M · 1.93 ill-scale paper, using the Chinese National Standards (CNS > A4 size (210X297 mm > ~ -83) Printed by Employee Consumption Cooperative 4 18 186 at _____B7__Five 'Invention Description (si) mmol, 5.50 mL; based on -78C with a second butyl clock (which is a pentane solution with a concentration of 1. 7 M, 2.41 nmol, 4.09 mL) was prepared by treating 2-fluoro-bromobenzene (552 mg, 3.15 mmol) in tetrahydrofuran (5.0 raL)] with compound (XVIa) (297 mg, 1.28 mmol) in tetrahydrofuran (7 0 mL) solution (-78 * C) [The 2-fluorophenyllithium is prepared and transferred to the solution of compound (XVIa) via a syringe after 5 minutes at -78 ° C] • at the temperature After warming to room temperature (1 hour), the reaction mixture was concentrated * and the concentrated residue was chromatographed on silica gel (dissolved with 10% ethyl acetate in hexane) to obtain 280 ng (Y: 6 7%) of the title product "(please read the note, please note ^^, then fill in this page) 1 Η — NMR (c DC 1 3) • (dd J-8 • 4 * 1. 7 H zt 1 H) 7 7 2 (d $ J = 1. 7 H z > 1 H) t 7 * 5 0 (m »2 H), 7 * 1 8 (mt 1 H) * 6 9 6 (m 9 2 H) • 3 words 8 0 (s * 3 H), 2 * 5 0 (m 1 H) * 2 * 4 0 (d J = 2 .8 H zt 1 H) 2 • 0 5 (m ♦ 2 H), 1 * 6 0 (m 1 H) * 1 * 4 3 (s > 3 H) 1 • 3 5 (s »3 H) * MS (DCI) ΤΠ / e: 3 2 9 (MH +) • Example 4 7 5,5- — • methyl-5, 6-— • nitrogen-8- (2 -phenyl) -a certain 2-junic acid (XVIIId) This paper is applicable to the China National Standard (CNS) A4 specification ( 2 丨 〇 乂 29? Mm> -84 _ AU ^ 8〇λ7 B7 V. Description of the invention (82) The title product 1 of the compound (XVI I) using the 8-phenyl derivative 0.85 mm 〇1) was prepared. Η -N MR (DMS 0 — 7 .8 1 (ddt J = 8) * 7. 5 5 — 7-2 5 (6 .0 9 (tf J = 4-2 .3 8 (dt J = 4- 1.3. 2 (s * 6 H) MS (DCI) m / e 2 9 Printed in Example 4 of the Ministry of Economic Affairs Standard Cooperative Consumer Cooperatives 4- [[[5, 6-Dihydro-5, 5 -Dimethyl group] methyl benzoate (I3g) -i- Λ (XVI I 丨 a) 209 mg (Y: 83% d β) was prepared with 280 mg (d): < 5 .〇 Η z · 1.8 Η ζ-1 Η m, 6 Η), 5 Η ζ, 1 Η), 5 Η ζ, 2 Η), 7 (Μ Η +). 8 -8- (2-Fluorophenyl) -2-a] carbonyl] amine This paper size is applicable to China National Mou (CNS) Λ4 «1 grid (210X297 mm) --------- ^- -(Please read the notes on the back before filling out this page)

* 1T -85-4 18 186 a? _____B7___ V. Description of the invention (83) Grass grass gas (0.2 mL, 2.29 mmol) and two drops of N, N-dimethylformamidine at 0 ° C The amine was treated with the compound (XVIIIdM 200 mg, 0.676 mmol) in anhydrous dichloromethane (5.0 mL). Allow the reaction mixture to stir at room temperature, and after 2 hours • Vacuum shrink the reaction mixture β. Dissolve the concentrated residue in anhydrous pyridine (5.0 mL) and add 4-aminobenzene. Consumption cooperation Du printed (please read the precautions before filling this page) methyl formate (A 1 dr ich, 102 mg, 0.68 mmol), and diluted with IN HCL after 2 hours at room temperature 赅The mixture was extracted with ethyl acetate (100 mL), washed with 1N HC1 (3 X 100 mL), and washed with saturated sodium bicarbonate solution (2 X 100 mL). The organic phase was separated, concentrated in vacuo, and then The concentrated residue was chromatographed on silica gel (eluated with 20% ethyl acetate in hexane) to obtain 226 mg (Υ · 78%) of the title compound 1 Η — N MR (CD c 1 3): δ 8-0 2 (d > J = 8-7 Η ζ 9 1 Η), 7 • 7 1 (m »1 H) t 7-6 4 (df J = 8 7 Η ζ 1 1 Η), 7 4 8 (d > J = 8 * 0 Η ζ t 1 Η) · 7-4 0 — 7 1 0 (m 1 7 Η) »6 * 1 1 (t J = 4-5 Η ζ 1 1 Η) , 3 9 0 (s 1 3 H) »2 4 2 (dt J = 4 * 5 Η ζ f 2 Η) · 1-3 9 (s > 6 H) O MS (DCI) m / e: 4 3 0 (M Η +) * This paper size is applicable to China National Huahua (CNS) A4 specification (2I0X297 mm) -86-Ί 8 18b Α7 Β7 V. Description of the invention (84) Example 4 9 4 ^ [[[5 ， 6-—- Μ-5, 5-'' methyl-8- (2-Gaphenyl) -2 -strips] fluorene] amino] benzoic acid (I4g)

ucr used the method of preparing 8-phenyl derivative (I4a) to prepare 180 mg (Y: 82%) of the title compound from 226 mg (0.527 mraol) of the compound (I3g) * (Please read the note on the back first) Please fill in this page for further details.) Equipment. Employees' cooperation of the Central Bureau of Standards of the Ministry of Economy 7 8 9 —7 * 7 8 (mt 5 H) > 7 5 3 (d * J = 8 * 0 H zf 1 H) f 7 4 8 -7 * 1 9 (mt 5 H) f 6 1 0 ( tt J = 4 in 5 H zf 1 H) »2 3 8 (d J = 4 5 H z» 2 H) 1 3 3 (s * 6 H) r 13 C — ΝΜ R (DMS 0 — de) δ 1 6 6 8 9 ， 1 6 5 8 0 > 1 6 1 • 1 2 ， 1 4 7 • 8 5 ， 1 4 3 • 2 4 > 1 3 3 • 0 8 · 1 3 2 9 5, 1 3 2 5 7 > 1 3 1 5 4, 1 3 0 1 8, 1 2 9 9 3 * 1 2 9 4 8, this paper size applies to China National Standard (CNS) A4 (210X297 mm) -87- Printed by Zhengong Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs 51 4 ⑷ 86 ^ ** ____________-i. 7-1 2 4. 8 8 · 1 2 4. 2 9-1 2 3. 8 6-1 1 9. 42 '1 1 9. 3 3-1 1 5. 75, 115. 4 6 3 7. 89 , 33. 48, 27. 75. MS (DCI) m / e: 416 (MH +). 1 ^ (KB r): 2962, 1688 * 1594, 1 5 2 0 · C ^ eH2ZN103F1 · 〇 · 2 5 H20 Elemental analysis value: Calculated value C: 7 4 · 3 6: Η ·· 5. 4 0: N: 3. 3 4 Measured value C: 74.50: Η: 5.40: N: 3.17 Example 5 〇 5, 5- 二Methyl-8-one-5,8-dihydrofruit-2-carboxylic acid methyl ester (XXXa) Ο ^^^ COOMe A compound of formula (XVI) where R7 is methyl (Figure XXI) (2.00 g, 8.60mniol ), Trimethylsilane (TMS-C1, 1. 12 g, 1 0.3 mmol), 1,8-diazabicyclo [5, 4,0] undec-7-ene (DBU, 1.70 g, 11.2 mmol) and 10 mL of anhydrous digas methane and stirred at reflux for 1 hour * Dilute the mixture with 75 mL of ether, then wash with 2Q mL of 0,1 N HCI, 20 mL of water, then use Dry over magnesium sulfate • Evaporate the solvent and dry the residue under vacuum. 30 mL of acetonitrile This paper is in accordance with the Chinese national standard (CNS > Λ4 size (210X297 mm) (Please read the precautions before filling in this page)

-88-A7 B7 V. Description of the invention (86) and palladium acetate (2.12 g, 9.50 mmol) were added to the residue, and after stirring for 16 hours, palladium acetate (1.06 g, 4.75 mmol) was added, and then the obtained The mixture was stirred for another 16 hours. The mixture was filtered through a piece of ce lit e and then washed with acetonitrile. After the collected filtrate was evaporated, the residue was diluted with water (30 mL), and then ether (30 mL X 3 ) Extraction. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The resulting residue was subjected to flash chromatography on silica gel (solution with EtOAc: hexane 1:20 to 1: 5) to obtain 1.42 g (64% yield (please read the precautions on the back first) (This page) Ding-5 Print of the Consumers' Cooperatives in the Bureau of Loss and Standards of the Ministry of Economic Affairs

Example 5 15.5,6-Trimethyl-8-one-5.6,7,8-tetrahydrofluorene-2-carboxylic acid methyl ester (XXXI Ο

) Solid title compound • 1 Η--NM MR (c DC 1 3) 1: δ 1. 5 0 (S »6 H) 3 • 9 4 (s» 3 H). 6. 4 1 (df J = 1 0 • 2 H z 1 1 H) > 6. 9 4 (d • J = 1 0-2 H z »1 H) 7. 6 2 (d» J = 8-2 H zf 1 H) » 8. 2 2 (ddt J =; 2 0 I 8 • 2 H z -1 H) 8. 8 2 (d »J = 2-0 H zt 1 H) t Μ S (DCI) m / e: 3 2 1 (MH +) Q This paper size is applicable to China National Standards (CNS) A4 Zhuge (2 (0 > α97mm > -89-Ministry of Liji_Central Bureau of Standards, Bureau of Industrial and Commercial Cooperatives, printed A7 _____B7_____ 5 Explanation of the invention (87) Slowly add methyl lithium (1.4 M • 11.5 nL, 16.2 ramol) in cuprous cyanide (724 rag, 8.08 nmol) to anhydrous at -50 ° C Ether (40 niL) suspension. After stirring for 1 hour, the solution was cooled to -78 ° C and boron trifluoride etherate (573 mg '4.04 mmol) was added to α Λ, then slowly After adding the ketene XXXa (930 mg, 4.Q4 ramol) ether (10 bL) solution * After stirring for 45 minutes, Saturated ammonium chloride solution (30 mL) to stop the reaction • Extract the mixture with ether (30 bL X 3), dry the combined ether extract through magnesium sulfate, and then evaporate after passing through a filter • make the resulting residue in silicone Was purified by flash chromatography (solving with a solution of hexane: ethyl acetate of 20: 1 to 5: 1) to obtain 251 mg (25% yield) of a solid compound as a sample. XH-NMR (CDC Ι3) δ 1. 0 5 (d J = 6.9 Η z · 3 Η) '1.3 0 * 1. 4 4 (s · 3 H each) · 2. 15-2. 30 (m-1 Η), 2. 5 5 (dd · J = 9.3, 17. 5 H z · 1 H), 2. 8 1 (dd-J = 4. 5 * 17. 5 H z-1 H) -3. 9 3 (s · 3 H), 7. 55 (d, J = 8.3 Hz, lH) '7. 6 9 (dd «J = 1. 9, 8-3 H z» 1 H)-8. 6 6 ( d ♦ J = 1. 9 H z · 1 H): MS (DC I.) m / e: 247 (MH +) · C 1SH 1 β 0 · 3 element analysis value: This paper standard applies to f 8104: Engage rate ( CNS > A44U * · (2 丨 0X297mm) ^-(Please read the precautions on the back before filling this page) Order -90-… A7 — —_B7 ___ V. Description of the invention (88) Calculated value C: 73.15: H: 7.37 Found C: 72.78: H: 7.31 Example 5 2 5,5,6-Trimethyl-8-phenyl-5,6-dihydrofluoren-2-carboxylic acid methyl ester (XXXIIa) (Please read the precautions on the back before filling this page) -—. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs at 3 (TC will add benzyl bromide (3.0 M concentration of ether solution, 1.05 raL '3. 15 mmol) to compound (XXXla) (390 mg, 1.58 mmol) in anhydrous tetrahydrofuran (10 mL) solution. After stirring for 10 minutes, the solution was raised to 0 ° C and then stirred for 20 minutes. The reaction was stopped with 20 mL of saturated ammonium chloride solution, and then Extract with ethyl acetate (25 mL X 3) • Wash the combined extracts with water (20 mL), dry over magnesium sulfate, filter and evaporate • Then add 20 bL of anhydrous benzene and p-toluenesulfonic acid (50 mg) In the evaporated residue, the solution was stirred under reflux for 30 minutes, and then evaporated. The resulting residue was subjected to flash chromatography on silica gel (1:20 to 1:10 with EtO Ac: hexane). Solution was eluted) to obtain 380 mg (78% yield) of the title compound as a pale yellow oil * W-NMRCCDCla): δ 1. Ο 1 (d · J = 7. 1Ηζ, 3Η) ' 1.29, 1.36 (s, 3H each) -2. 3 5-2. 4 3 (m · 1 H) * ding • ve

Ph

The size of this paper is applicable to the National Standard for Medium and Difficulties (CNS) Λ 4% grid (2I0X297 mm) 91 V. Description of the invention (89) A7 B7 3 .8 2 (S, 3 H) v 5 .9 4 (d, J = 5 0 H z * 1 H), 7 .3 3 — 7 .4 2 (mt 5 H) # 7 .4 3 (d, J = 8 1 H z »1 H), 7 .6 9 (d, J — 1 * 8 H z 1 H), 7.9 0 (dd * J = 1 • 8 »8 1 Hz S (DCI) m / e: 3 0 7 (MH +) o c21h22o2 elemental analysis value: (please first Read the notes on the back and fill in this page). 丨 \ Winter. The printed value of C: 82. 32: Η: 7. 24 Measured value C: 8 2. 1 0; : 7. 3 2 Example 5 3 5,5, 6-dimethyl-8-phenyl-5,6--qi disease-2-technic acid (XVIIIe) Ph will contain the compound (XXX Ila) (224 A solution of Dig '0.73 mmol), 2N NaOH (3.7 mL, 7.4 mmol), 7 mL of tetrahydrofuran and 7 mL of methanol was stirred at 60 ° C for 1.5 hours.The mixture was concentrated under reduced pressure. 10 mL of 1N HC1 was acidified and extracted with EtOAc (20 mL X 3). The combined extracts were washed with water (10 mL), dried over magnesium sulfate, filtered and evaporated. The evaporated residue was crystallized from diethyl ether-hexane to give 200 mg of the product (full ft yield) as a solid title compound. The size of the paper is in accordance with China National Standard (CNS) A4 (2 丨 0X297 mm) ) -92-Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 4 18 ^ Α7 Β7 V. Description of the Invention (90) ^ H-NMR (CDC13) 5 1. 〇2 (dJ = 7.1 Hz'3H). 1. 31'1 · 37 (s-3H each), 2. 3 5-2. 45 (m, lH), 5. 9 5 (d »J = 5.1 Hz, 1H), 7. 3 0-7. 40 (m, 5H) 1 7. 4 6 (d. J = 8. IHz 'IH), 7. 7 3 (d-J = 1. 9Hz * 1H)' 7. 9 4 C dd · J = 1. 9 · 8 · IHz'IH); MS (DCI) m / e: 293 (MH +). C2〇H2O02 · 0. 1 2 5 H20 elemental analysis value: Calculated value C: 81.53: Η: 6.93 Measured value C: 81. 68: Η: 6. 86 Example 5 4 4-[[(5, 6- Dihydro-5,5,6-trimethyl-8-phenyl-2- 棻) carbonyl] amino] methyl benzoate (I3d)

Add chlorchloramine (179 mg, 1.41 mL) and a drop of dimethylformamide at TC to a solution of compound (XVIlIe) (206 mg, 0.71 mmol) in dichloromethane (4 mL). 〇The solution is stirred for 2 hours under eC and the paper size is applicable to China® furniture standard (CNS) A4 specification (210X297 mm) --------- \ 衣 1 f (Please read the precautions on the back first Refill this page)-丁 _-兵 -93-4 \ 8 ^ 6 Λ7 —Β7 ____ V. Description of the invention (91) After stirring at room temperature for 1 hour * evaporate the solvent • then dry the center of the Ministry of Economy under vacuum The standard bureau ’s consumer cooperative prints the residue. Then p-aminobenzoic acid methyl ester (128 mg, 0,85, niol) and 4 mL of anhydrous Dll: pyridine are added to the residue. The mixture was stirred for 18 hours and the solvent was evaporated »After diluting the residue with 1 N HCL (20 mL), the mixture was extracted with EtO Ac (20 sL x 3 1). 9 The combined extracts were dried over magnesium sulfate and filtered> And evaporate it * and then subject the evaporated residue to flash chromatography on silica gel (to Institute; EtO / 1C solution from 10: 1 to 5: 1) was purified to give 234 mg (78% yield) of the title compound as a foam • 1 Η--N Μ R ( CDC 1 3) < 5 1. 0 3 (d 1 J = 7-1 Η ζ > 3 Η) t 1. 3 0 »1 • 3 7 (S t 3 Η each), 2. 3 5 — 2 • 4 5 (m% 1 Η) 1 3. 9 0 (S »3 Η) t 5. 9 8 (d * J = 5-0 Η ζ 1 1 Η)» 7. 3 0-7 • 4 1 ( m »5 Η)» 7. 4 6 (d »J rr: 8 * 1 Η ζ 9 1 Η)» 7.. 5 1 (d 9 J = 1 • 8 Η ζ f 1 Η) * 7. 6 5 ( dt J — 8 ♦ 7 ζ ζ * 1 Η) »7. 7 2 (dd * J = 1 8, 8 1 Η Zn, 1 Η), 7. 9 7 and 8 0 0 (s ο V erd J == 8.7 Ζ Η ♦ 3 Η); Μ s (DC I) m / e: 4 2 6 (Μ Η +). C 2 β Η 2 Ύ Ν 0 3 · 0. 5 Η20 elemental analysis value: The paper scale is applicable to China National Standards (CNS) Α4 specifications (210X297 public envy) t — (Please read the precautions on the back before filling in this Page) -94-418186 A7 _ B7 V. Description of the invention (92) Calculated value C: 77.39: Η: 6.50: Ν: 3.22 Measured value C: 77.34; H: 6.19; N: 3.33, Example 5 5 4- [ [(5, 6-Dihydro-5, 5, 6-trimethyl-8-phenyl-2-fluorene) carbonyl] amino] benzoic acid (I4d)

A mixture containing Compound (I3d) (224 mg, 0.53 mmol), 2N NaOH (2.65 ηα, 5.30 mraol), 5 mL of tetrahydrofuran, and 5 mL of methanol was stirred at room temperature for 16 hours. The solution was acidified with HC1 in IN, and then decompressed under reduced pressure. The residue was concentrated with 20 niL of water --------- 〆-- (Please read the precautions on the back before filling this page) Consumption cooperation with employees of the Ministry of Standards and Standards of the People's Republic of China Du printed and diluted 1 and then filtered the solid collected in diethyl ether to obtain 1 2 7 mg (59% yield) of the title product as a light yellow powder -N MR (DM S 0 — d β) δ 0 .9 7 (d • J = 7 1 Η ζ • 3 Η), 1.2 6 1 .3 1 ($ »3 Η each), 2.3 7 — 2 .4 1 (m »1 Η)« 5 .9 8 (d, J = 5 0 Η ζ 1 Η), 7. 3 1-7. 4 5 (m 9 6 Η) * 7 .5 4 (d -J = 8 1 Η ζ 1 Η), this paper size is applicable to China National Standard (CNS) A4 (210X297 mm) -95-__________B7 __________B7

V. Description of the invention (93) 7. 7 9-7. 8 9 Cm · 6 Η), 10. 4 3 C s · 1 Η), 12. 7 2 (s-1 H); MS (DC I) m / e: Elemental analysis value of 41 1 (MH +)-C27H2BN 03 · 〇 '5 H2〇: Calculated value C: 77. 12; Η: 6, 23; N: 3. 33. Found C: 77.41: Η: 6.05 : N: 3.26 Example 5 6 5, 5, 7-trimethyl-8-one-5, 6, 7, 8-tetrahydromethyl-2-carboxylate (χχχν a) 0 at -78 ° c Lithium bis (trimethylsilyl) amide (LHMDS)] (concentration of 1M in hexane, 2.71 raL, 2.71 mmol) was added to a solution containing R7 as a methyl group under a nitrogen atmosphere. In a solution of a compound of the formula (XVI) (Figure IX) (0.60 g, 2.58 mmol), 10 raL of anhydrous tetrazidine, and 1 mL of hexamethylphosphoramide (HMPA). After stirring for 2 hours, Increase the solution temperature to -40 * C, then add methyl iodide (0.73 g, 5.16 mmol) *

After the reaction mixture was stirred for 2.5 hours, the reaction was stopped with a saturated ammonium gas solution (20 mL). The mixture was then extracted with EtOAc (20 mL X 3), and the combined extracts were dried over magnesium sulfate and evaporated * The residue obtained by evaporation was subjected to flash chromatography on silica gel. (According to EtOAc: Ethane, this paper is suitable for Zhonggujiao Standard (CNS > A4) (210X297 mm) --------- 〆- -(Please read the notes on the back before filling this page)

• 1T Printed by the Central Standard of the Ministry of Economic Affairs, 扃 Shellfish Consumer Cooperatives -96-V. Description of the Invention (94) Λ7 B7 is a solution of 1:30 to 1:10 0) Purified to obtain 5 16 mg (: 81% Yield) Standard product as a white solid ο 1 Η — NM MR (CDC 1 3) δ 1 2 7 (d 1 J = 6 6 Η 2 > 3 Η) V 1 4 0 1 1 4 4 5 ( s »3 Η ea C h) I 1 9 1 (d 9 J = 2 0 Η ζ 1 1 Η) * 1 9 4 (s 9 1 H) * 2 7 8 — 2 9 1 (m 1 Η) 1 3 9 3 (s 9 3 H) • 7 5 0 (dt J = 8 2 Η ζ 1 Η) t 8 1 6 (dd (J = 1 9 t 8-2 Η ZO, 1 Η), 8 6 4 (d * J = 1 9 Η ζ t 1 Η) t Μ S (DCI) m / e; 2 4 7 ο C 1 5 Η 1 β 0 3 elemental analysis value: Calculated value C: 73.1 5:; H 7 37 Measured value C: 73.1 5;: H: 7. 51 --------- \ clothing (Please read the precautions on the back before filling this page) Order the central Ministry of Economic Affairs Example 5 75,5,7-Third Top Methyl-8-phenyl-5, 6-dihydroan-2-carboxylic acid methyl ester (XXXV la

Ph

This paper size is applicable to China National Standards (CNS) A4 (2) 〇Χ2ί »7 mm) -97-4 18 1 8 〇A7 B7 V. Description of the invention (95) Bromide slowly at 0 ° C Benzyl magnesium (3.0 M solution in diethyl ether, 1.35 mL '4.06 mmol) was added to a solution of the ketone compound (xxxva) (509 mg' 2.03 mmol) in tetrahydrofuran (20 mL). After the red mixture was stirred for 1 hour, the reaction was stopped with a saturated ammonium chloride solution (20 mL). The mixture was then extracted with ethyl acetate (25 mL x 3). The combined extracts were dried over magnesium sulfate and evaporated. • Benzene (10 raL) and p-toluenesulfonic acid (0, lg) were added. The evaporated residue was stirred at reflux for 30 minutes. After the solvent was evaporated, the residue was subjected to flash chromatography on silica gel (a solution of EtOAc: hexane 1:30 to 1:10). Eluate) Purified to give 380 mg (61% yield) of the title product. (Please read the precautions on the back before filling out this page.) Central Policy Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, India 1 印--N Μ R (CD c 1 3) < 5 1. 3 5 (s * 6 H) 1 • 7 3 (s * 3 H) * 2. 3 1 (s »2 H) * 3 • 7 7 (s * 3 H ), 7. 1 7 (d • J = 6 • 8 H z 1 2 H) y 7. 2 9 — 7 • 4 5 (mt 5 H) »7. 8 0 (dd 9 J = 1 8 1 8 * 0 H z > 1 H MS (DCI) m / e: 3 0 7 • Example 5 8 5,5,7-trimethyl-8-phenyl-5,6-dihydro-2-carboxylic acid (ΧVIIIf)

Ph

This paper size applies to the national standard of difficulty (CNS > A4 size (210X297 mm) -98-Printed by the Central Labor and Legal Bureau of the Ministry of Economic Affairs and the Consumers ’Cooperative Cooperative Printing 4 18 Ί δ〇a? _ _Β7_ V. Description of the invention (96 ) A solution containing ester (XXXVIa) (180 mg, 0.62 nnnol), ΙΝ ^ Ι NaOH (1.22 mL, 2 mmol), 5 raL tetragas furan, and 2 mL MeOH was stirred at 6 (TC for 3 hours. The solution was concentrated under reduced pressure to approximately 3 mL *, and then diluted with 1N HC1 (10 raL) and extracted with Et0Ac (30 inL X 2). After drying and evaporation of magnesium, 150 ng (83% yield) of the title acid compound was obtained in a solid state. ^ -NMR (CDC 13) δ 1. 3 5 (s * 6 Η) · 1. 7 3 (s · 3 Η ), 2. 3 2 (s, 2 Η), 7. 15 (d, J = 6. 7 Η ζ · 2 Η), 7. 32 (d, J = 1.6 Η ζ-1 Η); 7 35 — 7. 4 5 (m * 4 Η), 7. 8 6 (dd-J = 1.6-8. 0Ηζ, 1Η); MS (DCI) m / e: 293 (MH +) · C 20Η 2 〇0 2-〇. 2 5 1 ^ 2〇 element analysis value: calculated value C: 80.91; Η: 6.96 found C: 81.01; Η: 6.82 Example 5 9 4-[[(5,6 -Dihydro-5,5,7-trimethyl-8-phenyl-2- 棻) carbonyl] amino] methyl benzoate (I 3e) This paper uses China® furniture (CNS) A4 Specifications (2tOX297mm) --------- 〆-- (Please read the precautions on the back before filling this page) -99-蟪 18186 A7 B7

V. Invention Description (97)

Ph 0 N 将 Add grass gas (150 mg, 1.18 mmol) and a drop of dimethylformamide to a solution of the acid compound (XVIIIf) (171 mg, 0.59 nmol) in methane (4 mL) at 0 ° C. While the solution was stirred at 0 ° C for 1 hour and at room temperature for 16 hours • the solvent was evaporated • the residue was then dried under vacuum * then methyl p-aminobenzoate (98 rag, 0.65 mmol ) And 3 nL of anhydrous pyridine were added to the residue. The mixture was stirred at room temperature for 18 hours and the solvent was evaporated. The residue was diluted with 1N HCL (20 mL), and then EtOAc (20 mL X 3) For extraction and combined extraction --------- r " — (please read the notes on the back before filling in this page) Order-Printed by the Central Standard Bureau of the Ministry of Economic Affairs Magnesium drying, 9Mm filtration and evaporation 1 and then the evaporated residue was quickly digested on silica gel (solved with hexane EtOA χ as a solution of 20: 1 to 5: 1) to obtain 149 mg (78 % Yield) of the oily title compound '1 Η--NM R (CDC 1 3) δ 1. 3 7 (S t 6 Η) t 1-7 5 (S > 3 Η) ♦ 2. 3 4 (S • 2 Η) ψ 3 * 9 0 (S * 3 Η) * 7. 0 9 ( d 1 J = 1 • 8 ζ ζ ί 1 Η) »7. 1 8 (bd 9 J 6 ♦ 8 Η Zn V 2 Η) 7. 3 3 = 7-4 6 (m ♦ 4 Η), 7.6 0 (d • J = 8 8 Η Zn V 2 Η) 7. 6 5 and 7-6 7 (d 0 V e Γ b S »J = 1. The paper standard is not suitable for use in China (CNS) A4 grid (2 丨 OX297 mm) -100-4 18 Α7 ^ Β7 ____ V. Description of the invention (98) 9 h ζ * 1 Η), 8. 00 (d * J = 8. 7ΗZ-2Η);. MS (DCI) m / e: 426 (MH +). Example 6 0 4-[[(5,6-Dihydro-5,5,7-trimethyl-8-phenyl-2_ 棻) carbonyl] amino] benzoic acid (I4e)

The Ministry of Economic Affairs of the People's Republic of China is responsible for this. Industrial and consumer cooperation Du Yinye (please read the precautions on the back before filling this page) will contain compounds (136) (97 »^, 〇_231 ^), 2 ^ 1 skull 011 (1.15 mL, 2.30 mraol), 5 nL of tetrahydrofuran and 5 mL of MeOH were stirred at room temperature for 12 hours. The resulting solution was acidified with HC1 IN and concentrated under reduced pressure, and then the concentrate was diluted with 10 bL of water. The residue was extracted with EtOAc (15 mL X 2). The combined extracts were dried over magnesium sulfate, filtered, and evaporated. The residue was milled with Et20-hexane to give 77 rag (8296 yield) of the product as a white solid. — De) δ 1. 3 3 (s «6 H) · 1 • 6 9 (S» 3 H) · 2. 3 1 (st 2 H) · 7 • 0 2 (s 1 1 H) · 7. 1 5 (d »J = 7, 9 H z • 2 H) t 7. 3 3 — 7-4 9 (m • 4 H) 1 7. 7 5 (da J = 8. 4 H zt 1 H) t Paper size applies Chinese national standard (CNS > A4 size (210X297 mm) -101-〇

418186 A7 _____ _B7_ V. Description of the invention (99) 7 · 7 9 (d > J = 8. 6 Η ζ · 2 Η), 7-87 (d * J = 8. 6Η ζ · 2Η); _ MS (DCl ) m / e: 4i2 (MH +)-C 2tH 25N 0 3. 〇 25H20 elemental analysis value: calculated value C: 77.95; Η: 6.18: N: 3.37 found C: 77.93; Η: 6.01; N: 3.27 Example 6 1 10,10-Dimethyl-9-one-5,8,8 & 9,10108-hexahydrofluorene-2-carboxylic acid methyl ester (XXXV II a) COOMe at- 78eC ordered 1,3-butadiene saturation in a solution containing enone (xxj £ a) (500 rog, 2.17 nunol), aluminum chloride (260 mg, 1.95 mmol) and 10 mL of anhydrous toluene. * After stirring at room temperature for 18 hours, the mixture was diluted with 20 mL of 1N HC1, and then extracted with EtOAc (30 mL X 3). The combined extracts were washed with water (20 niL) and saturated sodium gas. After drying over magnesium sulfate and evaporating the solvent, the residue was purified by flash chromatography on silica gel (solving with EtOAc: hexane from 1:20 to 1: 5) to obtain 638 rag (full yield). Oily title product ^ -NMR (CDC13) δ

This paper size is applicable to China National Standards (CNS) Α4 (2Ι0 × 297 mm) (Please read the precautions on the back before filling out this page). Binding Printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperative-102-Ministry of Economic Printed by the Central Procurement Bureau Shoulder Cooperative Consumer Cooperative 4 18 t 8 6 at B7 —— V. Description of the Invention (100) 2. 10-2. 30 (m · 3 Η) '2. 99-3. 〇6 (bd , J = 18Hz'lH) 3. 2 9 C bs · 1 Η) · 3.. 9 1 (s-3 Η) '5. 5 3-5. 5 8 (m · 1 Η), 5. 7 0- 5. 7 6 (m-1 Η)-7. 4 6 (dtj = 8-2 H zf 1 H), 8. 1 6 (dd * J = 1-8 »· 8 • 2Hz1, 1 H), 8 6 4 (d > j = 1 * 8 H z »1 H); MSCDCI) m / e · 2 8 5 (MH +) ·

CleH2 (> Element of 03; Analytical value: Calculated C: 76.03; Η: 7.09 Measured value C: 75. 73: Η: 7. 25 Example 6 2 10,10-dimethyl-9-phenyl -5, 8, 10, 10a-tetrahydro M-2-carboxylic acid methyl ester (XXXVI I la)

Ph

Slowly add benzylmagnesium bromide (its concentration in the ether is 3.0 M, 1.76 mL, 5.28 mmol) at -3 ° C to compound (XXXVIIa) (600 mg '2.11 mmol) in anhydrous tetrahydrofuran (5 inL) solution, after stirring for 15 minutes • The temperature of the mixture was slowly raised to 0 ° C within 20 minutes. Then stop the reaction with a saturated ammonium chloride solution (30 mL), and then use the Chinese paper size (CNS > A4 size (210X297 mm)) (Please read the precautions before filling this page)政--103-A7 B7 4 丨 8 彳 86 V. Description of the invention (101) The central sample of the Ministry of Economic Affairs printed E t 0 A c (30 m LX 3 :) for employees' cooperatives for extraction and extraction at 9 fG The solution was dried over magnesium sulfate and filtered, and then evaporated. • The evaporated residue was subjected to flash chromatography on silica μ (elute with EtOA C: hexane solution of 1:20 to 1: 5) and partially purified. 520 mg of crude alcohol was then added Jrrt. Benzene (10 mL) and p-toluenesulfonic acid (50 mg) to methanol, and stirred at reflux for 3 hours. After evaporation of the solvent > the residue was placed in silicone Purification by flash chromatography (solution elution with Et OA c: hexane from 1:20 to 1: 5) to obtain 265 mg (36% yield) of the title compound as an oil · 1 Η-N MR (CDC 1 3) < 5 1. 3 4 * 1. 4 4 (S »3 Η each) • 1. 9 2 -2. 0 5 (m 1 1 Η)» 2. 2 5 —2. 4 5 (mf 2 Η) 1 2. 6 5 1 2 8 0 (m »2 Η) t 3. 7 8 (s, 3 Η) t 5. 5 5 —5. 7 8 (m * 2 Η) 1 7. 1 6 (d * J = 6-8 Η ζ» 2 Η) t 7. 3 1 (d »J = 1 7 Η ζ, 1 Η) 1 7. 3 0-7. 5 0 (m 6 Η)» 7. 8 2 (dd * J = 1 • 7, 8 * OH Zn, 1)) Example 6 3 10, 10-Dimethyl-9-phenyl-5, 8, 10, 10a-tetrahydrothin-2-carboxylic acid (XVI IIg) (please (Read the precautions before filling in this page)

This paper size applies to China National Standard (CNS) Λ4 gauge pile (210X297 mm > -104 _ Α7 Β7 4 18 8 ο 5. Description of the invention (102)

Ph η

A solution containing the compound (XXXVII la) (260 mg, 0.75 nmol), 3 N NaOH (2.5 mL, 7.5 mmol), and 100 mM methanol was stirred at 80 ° C for 3 hours. * After the solvent was evaporated, the evaporated residue was acidified with HC1 with an IN concentration of 1 and extracted with EtOAc (30 mL X 3). The combined extracts were washed with water (20 丨 L) 1, dried over magnesium sulfate, and filtered. After evaporation, 235 ag (95% yield) of the chemical compound is obtained. 1 Η--NM MR (c DC 1 3 ') δ 1.3. 1. 9 3-2 0 5 (m, 1 Η) • 2. 2 5 — 2 3 7 (m, 1 Η) * 2. 4 1 (dd • J = 5 .0 * 1 1-9 Η ζ • 1 Η) 1 2. 6 5 — 2 * 8 0 (m, 2 Η) • 5.. 6 0-5 * 7 0 (m, 2 Η) f 7. 1 4 (d • I = 6 * 7 ζ ζ * 2 Η) * 7. 3 2 (d 1 J = 1 * 8 Η ζ »1 Η)» 7. 3 6 — 7 • 4 6 C m, 4 Η) t 7. 8 5 (dd »J 1. 8 »8 0 Η Z * 1 Η): Μ S 丨 〔DCI) m / e: 3 3 1 (Μ Η +) ♦ C 22 Analytical value of 2 yuan: Calculated value C: 83. 61: Η: 6. 71 Measured value C: 83. 25: Η: 6. 86 «Country Marriage« rate (CNS > A4) Specifications (2 丨 OX M7 mm) n ^ p — i.---- 1— I-I TJ ys, ** (Please read the notes on the back before filling in this card) Central Ministry of Economic Affairs Bureau of Labor and Consumer Affairs Cooperative Association ¾ Λ7

418186 B7____ V. Description of the invention (103) Example 6 4. 4- [[(5, 8, 10, 10a -tetrahydro_10,10-dimethyl-9-phenyl- 2-M group) ] Amino] methyl benzoate (Ι3ί)

Ph 〇 ^^ / COOMe Chlorine chloride (172 rag, 1.36 mmol) and a drop of dimethylformamide were added to the acid (XVIIIg) (225 ng, 0.68 mnol) in methylene chloride (4 niL) at 0 ° C. Solution, and after stirring the solution at 0eC for 2 hours and at room temperature for 1 hour * the solvent was evaporated * then the residue was dried under vacuum. Then methyl p-aminobenzoate (122 mg, 0.81 mmol) (Please read the note ^^ on the back before filling out this page) T Pack 'Printed by the Central Consumers' Bureau of the Ministry of Economic Affairs and Consumer Cooperatives and 2 mL of anhydrous pyridine added to the residue 0 at room temperature The mixture was stirred for 16 hours and the solvent was evaporated. 1 The residue was diluted with 1N HCL (20 mL) and extracted with EtOAc (30 mL X 3). The combined extracts were dried over magnesium sulfate, filtered and evaporated, then The evaporated residue was purified by flash chromatography on silica gel (solved with hexane: EtOA c as a solution of 20: 1 to 5: 1) to obtain 21.0 mg (67% yield) of the title compound. 0 1 Η -N Μ R (CDC 1 3) δ 1 .3 6 * 1 • 4 5 (S, 3 Η ea C h) 1 1 .9 5 —2 * 0 5 (m * 1 Η) * 2 .3 3 (dt * J = 4 .6 t 1 6 1 Ζ ZE * 1)) This paper size is applicable to the National Standard for Medium and Difficulties (CNS) Λ4 specification (2 丨 OX 297 mm) -10R-86 A7 B7 V. Description of the invention (104), 2.4 4 C dd > J = 5 • 1 * 1 2 0 H, 2. 6 5 — 2 8 2 (m 2 H) t 3. 8 9 C s * 3 H) »5. 6 0 — 5 7 3 C m 9 2 H) * 7 • 0 9 (d * J — 1 • 9 H z 1 H), 7. 1 8 (bd • J = 6 • 7 HZ * 2 H) 7. 3 3 — 7 * 4 7 (m • 4 H) 1 7 .5 9 — 7 6 5 (mt 3 H) t 7 .7 0 (bst 1 H) 8 -0 0 (d »J = 8, 8 H z ♦ 2 H): MSCDCI) m / e: 4 6 4 (MH +) • Η (Please read the precautions on the back before filling out this page) Packing-Printed by Dingzheng Consumers Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs, Paper Size Applicable to China National Standards (CNS) A4 specification (210X297 mm) Example 6 5 4-[[((5,8,10,1〇3-tetrahydro-10,1〇-dimethyl-9-phenyl-2-cidyl) carbonyl ] Amino] benzoic acid (IM)

The solution containing the ester (I3f) (2I0 ng, 0.45 mmol), dibutyltin oxide (228 mg, 0.92 mmol) and 5 niL of anhydrous toluene was stirred under reflux for 2 days, then 1N HC1 (20 mL) was added, and then Extract with EtOAc (20 mL X 3) * The combined extracts were washed with water and concentrated to approximately 20 mL remaining. Then let the gadolinium solution and 10 "concentration -107-A7 B7 418186. V. Description of the invention (I (} 5) (please read the precautions on the back before filling this page)) Stir for 20% potassium fluoride solution for 30 minutes * The mixture was extracted with EtOAc (20 mL X 2), then the combined extracts were sulphuric acid, dried, filtered and evaporated. • The evaporated residue was subjected to flash chromatography on silica gel (MeOH: CHzCU as Solution resolution from 1: 100 to 1: 5) and purification to give 72 mg (3596 yield) of the title product 'yellow solid cross * Central Ministry of Economic Affairs, Zhunzhou Sub-consumer Cooperative Consumer Cooperative, India: Η Ν Μ R ( DMS 0-d β) δ 1. 3 0 »1 * 4 1 (s * 3 H each) · 1. 8 5 (bt J ssz 1 2 • 1 H z * 1 H), 2. 2 8 — 2- 3 5 (m »1 H) 2 4 1 (dd J = 5 0 1 1 5 H z * 1 H) J 2. 5 5 (bd J = 1 9 1 HZ? 1 H), 2 7 5 (bd J = 1 9 • 1 HZ 1 H) 5 6 0-5-8 0 (m 2 H) 7, 0 2 (d * J 1 • 9 H zt 1 H) 1 7 1 2 (d »J = 6 9 H z 2 H) «7 3 5-7 • 4 8 (m« 4 H) »7 7 3 (d d $ J = 1-9 * 8 * 2 H z 1 H) 7 7 7 (df J = 8 8 H z 2 H) 7 8 6 (df J = 8 8 H z * 2 H) 1 1 0 3 5 (s * 1 H) «Μ S (DCI) m / e ·· 4 5 0 (MH +) • C 3 0 Η 2 7 Ν 0 3 · 0-7 £ H 2 0 element analysis value; it · Calculated value C; 7 7, 81: K: 6. 20: N: 3. 02 Measured value C ·· 78 .09: H: 5. 99: N: 3.14 V paper scale -Rate (CNS) Α4 «Μβ · (210 X 297 male *) -108 •% A7 J ι 3] 3 3 B7 _________ V. Description of the invention (i〇6) Example 6 6.4, 4-dimethyl -7-Iodo-tetrahydroone (XXXIX) Add 4,4-dimethyl-7-amino-tetrahydropyrone (XII) (1,82 g, 10_0 mmol) to ice water (3.13 idL) ) In concentrated hydrochloric acid (4.69 raL). The reaction mixture was cooled to 0 ° C using an ice-salt bath, and then was added dropwise with sodium nitrite (0.76 g, 11.0 mmol) and water (3 13 mL) solution to diazotize the reaction mixture. After stirring for 15 minutes, add the reaction mixture to a solution containing potassium iodide (3.63 g, 21.9 mmol) and water (18,8 mL) and let stand for 30 minutes. After that, the dark gum was extracted with ethyl acetate (1 X 100 mL). Then the organic phase was concentrated under vacuum, and the concentrated residue was chromatographed on a silicon knee (5% ethyl acetate). Hexane of esters (please read the note on the back #Fill this page first) -Load · -s Dissolution of the printing solution of the Central Laboratories of the Ministry of Economic Affairs of the Consumers Cooperative Printing Co., Ltd. to obtain 1. 56 g (54% yield) of Title product · 1 Η-N MR (CDC 1 s): 6 8. 3 3 (df J = 2.0 H zf 1 Η) · 7.8 2 (ddt J = 8. 3 1 2-0 Η z · 1 Η) 7. 1 7 (d > J = 8 • 4 H z 1 1 H)-2. 7 2 C t 1 J rr 6 • 8 H z »2 Η), 2. 0 1 (t» J = 6 .8 H zt 2 Η), 1. 3 7 (s 1 6 H) t MS (DCI) m / e: 3 0 1 (MH +) · Example 6 7 This paper size applies to Chinese National Standards (CMS > A4 size (210X297 mm) ιη «-A7 Staff Consumption of Central Bureau of Standards, Ministry of Economic Affairs Printed by the cooperative V. Description of the invention (107) methyl 4-vinylbenzoate COzCHj-1,8-diazabicyclo [5, 4,0] undec-7-ene at 0 ° C Aldrich · 2.46 g, 16.2 ramol) and A-Research Institute (Aldrich, 3.13 g, 22.1 mmol) was added to a solution of 4 -ethanoylbenzoic acid (Aldrich, 2.18 g, 14.7 mmol) in anhydrous acetonitrile (14.0 mL). The temperature of the reaction mixture was raised to room temperature and stirred for 3 hours. • Ethyl acetate (10 OnL) was added to the mixture, and the solution was washed with brine (50 mL). The organic phase was then separated and concentrated in vacuo. * The concentrated residue was chromatographed on silica gel (dissolved in 5% ethyl acetate in hexane) to give 1.05 g (44% yield) of the title product. ^ -NMR (CDC 13): δ

8. 0 0 (d, j = 8-4 H z 2 H) »7. 4 7 (d, j = 8 • 4 HZ 1 2 H) t 6. 7 6 (m * 1 H) 9 5. 8 7 (d, J = 1 7 * 6 Hz r 1 H), 5. 3 8 (d, J = 1 1-0 H zt 1 H), 3. 9 1 (s * 3 H); MS (DCI) m / e: 163 (ΜΗ +) * Example 6 8 4-[[(£)-(5,6,7,8-tetrahydro-5,5-dimethyl-8-one) -2- 棻Base] Vinyl paper music is again applicable to China ’s poor family ladder (CNS > Λ4 size (210 × 297 mm) (Please read the precautions on the back before filling this page)

-110-4 18 186 ΑΊ Α7 B7 V. Description of the invention (108) yl] methylbenzoate (XLa)

Add palladium acetate (II valence) (Aldrich, 58 mg, 0.259 mmol), tetrabutylammonium chloride hydrate (Aldrich · 1.49 g, 5.17 nmol), and sodium bicarbonate (Mallinckrodt, 1.09 g, 12.9 mmol) to 4 , 4-Dimethyl-7-iodo-tetrahydroone (XXXIX) (1.55 g, 5. Π mmol), methyl 4-vinylbenzoate (1.67 g, 10.34 mmo1) and two In a solution of methylformamide (16.0 bL) • Heat the reaction mixture to 7 (TC for 4 hours, then stir at room temperature for 16 hours). Then add ethyl acetate (50 mL) to the mixture, and then The solution was washed with ® water (50 mL). The organic phase was shrunk under vacuum, and the concentrated residue was decanted on silica gel (dissolved with 10% ethyl acetate in hexane) to obtain 1.29 g (75 % Yield) of the title compound * (please read the notes on the back before filling this page) δ 8. 1 9 (d »J == 1. 7 H z 1 1 H) 8. 0 4 (dt J = 8 • 2 H zf 2 H)» 6. 6 9 (dd 1 J ss 8. 1 1 1 • 7 H z, 1 H 7. 5 7 (d • J — 8 .2 H z 2 H) ♦ 7. 4 5 (d > J = 8 .XH z • 1 H) »7.. 2 1 (s» 2 H), 3 9 3 (s 1 3 H ), 2. 7 6 (t • J — 6.8 H zf 2 H) 1 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -111-(ς I ρ A7 B7 V. Description of the invention (109) 2. 0 5 (t · J = 6.8 Η z-2 Η) '1. 4 1 C s > 6 Η);, MS (DC I) m / e: 335 (MH +). Implementation Example 6 9 4-[[(£)-(5,6,7,8-tetrahydro-5,5-dimethyl-8-phenyl-8-hydroxy) -2-some] vinyl] benzene Methyl formate (XLla)

Using the method for preparing an 8-phenyl derivative (XVIU), 1.39 g (Y: 87¾) of the title compound was prepared from 1.29 g (3.86 mmol) of the compound (XLa). ^ -NMR (CDC 13): δ (Please read the precautions before filling out this page)-Binding-Order Printed by the Employees' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs 7. 7. 7. 9 8 (d 4 8 (m 0 3 (m 2 2 (m 6 0 (m 3 5 (s J = 8. 1 H z > 2 H) * 5 H) · 7. 3 1 (s-5 H), 2 H) ^ 3.9 1 (s · 3 H), 2 H) · 1. 8 5 Cm · 1 H), 1 H), 1. 40 (s, 3 H), 3 H). Example 7 0 This paper size is applicable to China National Standards (CNS) A4 Washing (210X 297 mm) -112-… A 7 B7 V. Description of the Invention (no) 4-[[(E) _ (5, 6_ — Μ 5 _ 5, 5 — —methyl_8_benzyl) _2 -baryl] ethanoyl] benzoic acid (I1)

P-Toluenesulfonic acid (p-TsOH, 20 mg) was added to a solution of compound (XLIa) ¢ 1.38 g, 3.35 mmol) in toluene (20 mL) * After heating at 70 eC for 0.5 hour, the reaction mixture was cooled and Concentrate in vacuo. Dissolve the concentrated residue in a 1: 1 ethanol and tetrahydrofuran solution (20.0 mL). Treat with 10 N NaOH (33.7 mmol, 3.37 raL) at room temperature. • After 16 hours • Add 1 N HC1 (75 mL). * Collect the precipitate by vacuum filtration to obtain 1.23 g (Y: 97%) of the title compound. (Please read the precautions on the back before (Fill in this page) Binding and ordering 1 Η -N Μ R (DMS 0 1 de) * δ 1 2. 8 7 (st 1 H) * 7. 8 5 (d * J = 8-4 H z »2 H) , 7 .6 3 (dy J — 8 4 H zt 2 H) · 7 .5 8 (dd J = 8 1 • 1-7 Hz 7. 4 7 — 7 2 4 (mt 7 H) 7 .0 7 ( m * 2 H) * 6. 0 0 (t • J = 4-5 H z »1 H) · 2. 3 0 (d J 4 5 H z 2 H) · Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs This paper size applies to China National Standard (CNS) A4 (210 X 2M mm) -1 13-A7 B7 418186 Revision: V. Description of the invention (111) 1. 2 8 (s-6 Η); 13C-NMR (DMSO-de) 16 7. 02 14 0. 16 12 9 12 7 12 6 5 2 2 3 3 1 4 5 14 5 13 8 13 0 12 8 12 6 12 5 0 9 5 9 9 6 5 2 8 7 3 0 14 1 13 4 12 9 12 8 12 6 3 5 2 2 6 6 3 3 6 5 12 4. 69 3 8. 2 3-3 3. 29 12 4. 46 2 7. 8 9; MS (DCI) m / e: 381 (MH +); IR (KBr): 2922, 2818, 1684 C Η 24 O 2 · 0.6 5 H2〇 elemental analysis value: Calculated value C: 82.69; Η: 6.50 Measured value C 83.00: H: 6.41 (Please read the precautions on the back before filling this page)-line. Member of the Economic, Intellectual Property Bureau, Consumer Consumption, and Printing and Printing Example 7 1 4-[[[[((5, 6 -—Ga-5,5 -—Methyl-8-benzyl) -2 -Nylyl] Parent Group ] Thio] benzoic acid (i〃a)

This paper size applies to the standard of the poor households (CNS > A4 size (210 X 297 mm) -114-A7 B7 Printed by the Bayer Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (112) 1 1 Grasshopper chlorine (0.13 m L »1. 5 mmol) and two drops of N, N-1 I dimethylformamide added compound (XV I 1 1 a) (11 9 mg '0. 430raraol ί I ) In a solution of anhydrous dichloromethane (5.0 mL) «Stir the reaction at room temperature for 1 1 ί. After 2 hours of the mixture, concentrate the reaction mixture in vacuo 'and then dissolve the residue obtained by first reading the concentration 1 1 1 in Anhydrous spinach (5.0 mL) was added with 1-I formic acid (A p ΐ η 66 mg '0.43 mmol) 9 4-sodium benzene, and after 3 hours at room temperature i Dilute the mixture with IN HC1 and extract it with ethyl acetate (50 ml). Fill in the items 1 and wash with IN HC1 (3 X 50 ml). Then use a saturated sodium bicarbonate solution (2 Write this page 1 X 1 00 ID L) Washing · Subsequent separation of the organic phase • After vacuum concentration, 1 IV »M * concentrated residue The product was chromatographed on silica gel (dissolved with 5¾ methanol in dichloromethane J | liquid lysis) to obtain 40 mg (23% yield) of the title product. 1 1 Order 1 Η 1 N MR (D MO S 0 ) δ 1 7 * 9 δ (d, J = 8 3 Η ζ * 2 Η), 1 1 7 * 9 1 (dd, J = 8 1 * 2 • 0 Η ζ, 1 Η), 1 1 7 6 2 (d, J = 8 • 2 Η ζ 9 1 Η), 1 line, 7 * 5 6 (d · J = 8 * 2 Η ζ 2 Η), 1 I 7-4 8-7. 2 7 (m 9 6 Η) 1 1 I 6 1 1 (t, J = 4 5 Η ζ 1 Η) * 1 1 2 '3 8 (d · J = 4 • 5 Η ζ »2 Η) · 1 1 1 3 3 (s »6 H) 1 1 Μ S (DCI) m / e 4 1 5 (Μ Η +) 1 1 l IR (K Β r): 3 4 4 0 2 9 6 2 1 6 8 4, i I 1 5 9 4 cm —1 · 1 1 | C 2 6 Η 2 2 0 3 S ΐ * 1.. 2 Η 20 elemental analysis value: 1 1 This paper size applies to China National Standard (CNS) A4 (210X297 mm)- 115-A7 A7 revised supplement ¥ η 'β

B7 V. Explanation of the invention (m) Calculated value C: 71.60; H; 5.64 Measured value C: 7 1. 6 5; Η: 5. 4 4 Example 7 2 4-[[[((5, 6, 7, 8 -Tetrahydro-5,5-dimethyl-8-one) -2-fluorenyl] thio] carbonyl] benzoic acid tert-butyl ester (XLIVa); grass gas (0.17 mL · at 0 ° C) 1.95 mmol) and two drops of N, N-dimethylformamide were added to a solution of mono-tert-butyl phthalate (122 mg '0.550 mmol) in anhydrous dichloromethane (5.0 mL) * and stirred at room temperature After 2 hours, the mixture was concentrated in vacuo, then the concentrated residue was dissolved in anhydrous pyridine (5.0 mL) and 4, 4-dimethyl-7-fluorenyl-butrahydrohydrone (XLI II) was added ( 1 13 mg, 0.550 mmol). After 2 hours at room temperature, the mixture was diluted with IN HC1, extracted with ethyl acetate (50 raL), washed with IN HC1 (3 X 50 mL), and then washed with saturated sodium bicarbonate solution (2x 50 mL). The organic phase was subsequently separated. After concentration in vacuo, the concentrated residue was chromatographed on silica gel (eluated with ethyl acetate in hexane) to give 80 mg (35% yield) of the title product. -NMR (CDC 13): 3 paper size is applicable to China Standard for Household Standards (CNS) A4 (210 x 297 mm) _ Πβ-(Please read the precautions on the back before filling this page) • ^ Order:- -Line · Member of the Intellectual Property Bureau of the Ministry of Economic Affairs, L. Save money, spit out A7, B7 Invention description (114) Amendment 8.16 (d, J — 1 8 H z 1 H), Supplement 8. 1 1-8. 0 3 (m 4 H) 7 .6 7 (dd J = 8 3 2 1 Hz 1 7 .5 4 (d, J = 8 5 H z 1 H)-2 .7 7 (t, J = 6 8 H z 2 H), 2.0 0 (t * J = 6-8 H z 2 H), 1.6 3 (sf 9 H) 1 4 4 (s, 6 Η) S (DCI) m / e 3 5 5 (M a c 4H 9 + Η in 丨 (Please read the precautions on the back before filling in this ) Example 7 3 4-[[[((5, 6, 7, 8 -tetraaza_5, 5_ —methyl-8-phenyl-8_ mesyl) -2 -baryl] thio] carbonyl] benzene Tertiary butyl formate (XLV a)

-Consumption of Economic Perch Wisdom Player 1 ^ " ^ By using the method of preparing 8-phenyl derivative (XVIIa) with 80 mg (0.19 mmol) of compound (XLI Va), 46 mg (Y: 50%) of the title product. XH-NMR (CDC 13): δ 8. 0 3 (m > 4 Η)-7. 5 2 (d-J = 8. 2 Hz, lH), 7. 4 3 (dd-J = 8. 2 * 2. 1Hz, 1H), this paper size is applicable to China Standard for Households (CNS) A4 (210 X 297 mm) -117-

4 18 186 a7 _ B7 V. Description of the invention (115) 7. 2 0 (m, 6 Η), 2. 3 0-2. 1 0 (η 1. 9 0 (m, 1 Η)), 1. 4 5 (s · 3 Η) · 1. 3 7 (s »3 Η): MS (DC I) m / e: 471 (MH +)» Example 7 4 4-[[[((5, 6-Dihydro-5 , 5-dimethyl-8-phenyl) -2-anyl] thio] carbonyl] benzoic acid (i13a) (Please read the precautions on the back before filling this page)

Μ6. Add several mg (about 3 mg) of p-toluenesulfonic acid to a solution of compound (XLVa) (46 mg, 0.094 mmol) in toluene (5_0 mL) " heated at 70 ° C for 0.5 hour, put The reaction mixture was cooled and concentrated in vacuo. The condensed residue was dissolved in methane (2.0 mL) at room temperature and trifluoroacetic acid (0.08 inL) was added. After 16 hours, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with 1N HC1 (20 mL). The organic phase was subsequently separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 34 mg (87% yield) of the title product. ^ -NMR (DMS〇-de): δ 8. 0 3 (m · 4 Η) ·; Line _ Economy Zou Zhizhi Property Manager 1- | Consumption ^ The size of printed paper is applicable to national standards < CNS) A4 specification (210 * 297 mm) -118-4 · 1 ό 1 3 θ Λ7 Β7 V. Description of the invention (116) 7. 5 3 (dtj = 8-1 H z »1 H), 7.4 3 — 7 3 0 (m 6 H) Try 6. 9 6 (d 1 J = 1 9 H z > 1 H), 6. 0 7 (t »J — 4 • 5 H z 1 1 H), 2 . 3 6 (d * J = 4-5 H z > 2 H) > 1. 1 8 (s * 6 H) * S (DCI) m / e: 4 1 5 (Μ H +) R (KB Γ) 3 4 3 2 »2 9 6 2 * 16 1 2 0 2 · C zeH 22 0 3 S! · 〇. 3 5 1 ^ 20 element analysis value: calculated value C: 74.21: Η: 5.44 measured value C: 74.18; Η: 5.22 寊 Example 7 5 4-[[((5, 6-Dihydro-5,5-dimethyl-8-phenyl) -2-yl] ethyl] benzoate ethyl ester (Please read the notes on the back before filling in this page K), printed by the Consumer Standards Cooperative of the Central Standardization Bureau of the Ministry of Economic Affairs

Lead-poisoned 5% Pd / calcium carbonate (Aldrich, Lindlar catalyst, 15 mg) was added to a stirred solution of compound (I15a) (118 mg '0.290 mmol) in toluene (7.0 mL) at 45 psi H2. . 16 The paper scale is applicable to China National Standards (CNS) A4 (210X297 mm) ~ -119-Λ7 B7 418186 V. Description of the invention (117) hours later, the reaction mixture is filtered through a piece of Celite and then vacuumed The filtrate was concentrated in a state to obtain 60 mg (Y: 50%) of the title compound, Compound 1 Η 7 7 7 7 NMR (CDC 1 3) · δ 4 2 2 .9 3 (d 3 0 (m .1 8 ( d .0 5 (dd .8 1 (d .9 7 (t .3 8 (q 8 4 (m .3 4 (d .4 2 (t .3 3 (s J = 8 6 H) J = 8

4 H

6 H 4 4 7 1 H z, 2 H), 1 H z, 2 H), 9, 1.8 H z 8 H z, 1 H), 5 H z. 1 H), 1 H z, 2 H ), 5 H z * 2 H), 1 H z, 3 H), 1 H), (Please read the precautions on the back & fill in this page first)

1. MS (DCI) m / e: 411 (MH +) printed by Shelley Consumer Cooperative of Central Standards Bureau of Ministry of Economic Affairs. Example 7 6 4-[[(5,6 -Digas-5, 5-methyl-8-phenyl) -2-baryl] ethyl] benzoic acid (I17a)

This paper is applicable to the standard of the middle and poor countries (CNS) A4 specification (2IOX297 mm) -120-A7 I b I 6 c B7 V. Description of the invention (118) 10 N Na0H (2.0 mmol '0.20 mL) is added to the compound 4-[[(5,6-dihydro-5, 5-dimethyl-8-phenyl) -2-yl] ethyl] benzene. Ethyl acetate (60 mg, 0.146 mmol) in ethanol (5.0 mL) solution. After 1 hour at 7 ° C, excess IN HC1 (20 mL) was added • and the precipitate was collected by vacuum filtration to give 59 mg (Y: 99%) of the title product ): ≪ 5 7. 7 9 (d-J = 8. 2Hz, 2H), 7. 3 8-7. 29 (m, 3H) · 7. 2 5 (d · J = 8. 2Hz, 2H) , 7. 21-7. 1 0 (m · 4 H) > 6. 62 (d, J = l. 7 H z * 1 H), 5. 9 3 (t-J = 4.5 Hz-lH) , 2. 7 8 (m · 4 H), 2. 25 (d, J = 4.5 H z · 2 H), 1. 2 4 (s * 6 H). MS (DCI) m / e: 383 (MH +); IR (KBr): 2956, 1688, 1610 * 1 4 2 2 cm-1 · C 2 τ Η 2 e 0 2 Elemental analysis value: Calculated value C: 84.78: Η: 6.85 Actual 孭! I value C: 84.53; Η: 6.81 Example 7 7 This paper size is applicable to the sample rate of Chinese families (CNS > Λ4 size (210 × 297 cm)) (Please read the precautions on the back before filling this page). Printed by the staff of the Bureau of Cooperatives -121-418186 Λ7 B7 V. Description of the invention (119) Methyl] thiocarbonyl] amino] benzoic acid methyl ester.

Diphosphorus pentasulfide (Aldrich, 0.05 rag, 0.461 mmol) was added to a solution of compound I3a (285 mg, 0.693 mmol) in tetrahydrofuran (6.0 mL), and the mixture was concentrated after 0.75 hours under reflux, and dichloride Dilute with methane (50 mL) and wash with 5% sodium carbonate (2 X 50 raL). • Concentrate the organic phase in vacuum. Then chromatograph the concentrated residue on silica gel (solve with 10% ethyl acetate in hexane). Analysis) and got 88 mg (Y: 30%) of the product of the question. (Please read the precautions on the back #Fill this page first)-installed, 1T printed by the Employees ’Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs — Ν MR (CDC 1 3): δ 8. 9 2 (st 1 H) t 8. 0 5 (d * J 8. 6 H z, 2 H), 7. 7 4 (dd * J = 8. 2 > 1 • 8 Hz 7. 4 3 (dt J 8 .1 H z * 1 H)-7. 3 3 (m »8 H) t 6. 0 7 (t ♦ J = 4.5 H zt 1 H) , 3. 9 2 (st 3 H) 1 2. 3 8 (dt J = 4.5 H z »2 H)-1. 3 6 (s, 6 H) > This paper size applies to Chinese national standards ( CNS > Α4 size (210X297 mm) Η -122-418186 A7 B7 V. Description of the invention (120) MS (DCI) m / e: 428 (MH +) 〇 Example 7 84-[[[((5,6 -—Ga-5,5--methyl-8-phenyl) -2 -Stripyl] thiocapsyl] amino] benzoic acid (丨 18a)

Using the method of preparing the 8-phenyl derivative (I4a), 80 mg (0.186 mmol) of the compound 4-[[[((5, 6-dihydro-5,5-dimethyl-8-phenyl) -2-Methenyl] thiocarbonyl] amino] benzoic acid was prepared to give 69 mg (Y: 90%) of the title product. (Please read the precautions before filling out this page} Central Bureau of Standards Printed decoration of Zhengong Consumer Cooperative— NM MR (DMS 0-de) δ 1 2 * 8 8 (sf 1 H) »1 1 * 8 9 (s» 1 H) y 7 8 7 (m * 1 H ), 7 • 6 0 (dd 1 J = 8 • 0 1 * 7 Hz, 1 H), 7 4 7 (d * J = 8 * 1 H z * 1 H), 7 * 3 5 (mt 6 H) 9 6 0 7 (t J = 4 '5 H z 1 1 H) · 2 3 5 (d * J = 4 * 5 H z 1 2 H)-1-3 2 (s 6 H) »S (DCI) m / e; 4 1 4 (MH +) 1; This paper size is applicable to 81 Chinese standards (CNS) A4 Zhuge (2I0X297) 嫠 -123-418186 A7 B7 V. Description of the invention (121) IR (KBr) : 2922, 1688, 1606, 1 5 1 4 cm ~ 1 · C2eH 83 02N1S1 · 〇 5H20 elemental analysis value: Calculated value C: 73.91; H: 5.73: N: 3.31 Measured value C: 73.60: Η: 5.76; N: 3.21 Example 7 9 5, 6-Dihydro-5, 5-dimethyl-2- [1- (trimethylsilyl) oxy] vinyl-8-phenyl (LVU ) (Jing first read the back notice before filling out this page)

Yinju, a co-operative consumer cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, will include 1,8-diazabicyclo [5,4,0] undec-7-ene (Aldrich, 1.80 g, 11.87 mmol) and gas trimethyl sand (1.18 g, 10.9 mmol) was added to the solution of the compound (XIXa) (2.73 g, 9.89 mmol) in Example 32 in anhydrous dichloromethane (10.0 mL). Then the reaction mixture was gently refluxed for 2 hours, and then in the room. Stir for 16 hours at warm temperature. • Add pentane (100 mL) to the mixture. • Wash the solution with 0.1N HC1 (50 mL) and dilute sodium bicarbonate (50 mL), then dry the organic phase over anhydrous magnesium sulfate. * After concentrating it in vacuo, 3.17 g (Y: 92%) of the title product was obtained. ^ -NMR (CDC 13): δ 7. 45 (dd, J = 8. 0, 2. 0Ηζ, 1Η), this paper Applicable to China National Standard (CNS) A4 (210X29? Mm) '~ —' -124-4 (8186 A7 B7 V. Description of the invention (122) 7. 3 9 — 7 .2 4 (m »7 H) 5. 9 9 (t, J = 4.5 Hz, 1 H) · 4. 7 4 (d, J 1. 6 H z * 1 H), 4. 3 0 (d, J = 1. 6 H z, 1 H), 2. 3 5 (d, J = 4.5 H z »2 H) · 1. 3 4 (s, 6 H) · 0.1 4 (s * 9 H) * Example 8 0 4-[[[((5, 6-1M-5, 5-~ methyl-8_phenyl) _2_yl] excitryl] methyl] benzoic acid Methyl ester (I22a)

(Please read the precautions before filling in this page.) * 17 Cooperating with the Central Bureau of Procurement, Ministry of Economic Affairs, Du printed the tributyltin (Aldrich * 806 mg '2.61 mmol) and PdCl2 ( P (o-CH3CeIU) 3) 2 [(59 og, 0.074 mmol), consisting of bis (eye) palladium chloride (II-valent) (Aldrich · 0.074 mmol, 19. 3 mg) and tri-pair -Tolylphosphine (Aldrich, 0.149 mmol, 45.3 mg)] Add the compound (LVIa) (864 mg, 2.48 nmol), 4-bromobenzoic acid methyl acetate (Aldrich * 355 ug, 1.65 mmol) and anhydrous benzene (10. 0 mL) solution. After refluxing for 4 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1N NaOH (50 mL). The organic phase is chromatographed on silica gel (approximately 5% ethyl acetate in hexane. This paper is compliant with the Chinese National Standard (CNS > A4 size (210X297 mm) -125-Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Preparation ___ B7 V. Explanation of the invention (123) Solution dissolution) to obtain 26 5iog (Y: 39%) of the title product "1H-NMR (CDC13) δ ^ 7.92 (d, J = 8. 5Ηζ, 2Η), 7. 8 7 (dd · J = 8. 2 * 2. OHz, lH), 7. 6 3 (d > J = 2. 〇Hz, lH), 7. 4 4 (d * J = 8. 2 H z · 1 H) · 7, 4 1 (m * 3 H)-7. 2 9 (m · 2 H), 7. 1 7 (d · J = 8. 0 H z-2 H) · 6. 0 3 (t »J = 4.5 H z · 1 H) · 4. 1 2 (s * 2 H), 3. 9 0 (s · 3 H), 2. 3 7 (d * J = 4.5 Hz, 2H) · 1. 3 5 (s, 6 H); MS (DCI) m / e: 411 (MH +). Example 8 1 4-[[[((5, 6--nitrogen-5) , 5-'' methyl-8-phenyl) -2-fluorenyl] mine] methyl] benzoic acid (Isaa)

Dibutyltin oxide (Aldrich * 364 mg, 1.46 mmol) was added to the anhydrous toluene solution of compound (I22a) (200 mg, 0.488 πβοΙ). • After 16 hours of reflux, the reaction mixture was vacuum-contracted. Then the paper was scaled to China.蔺 家 橾 隼 (CNS) A4 specification (2IOX297mm) — ~~~ (Please read the precautions on the back before filling in this page) I Binding · Ordering M -126-4A7 B7 V. Description of the invention (丨 24) The concentrated residue was chromatographed on silica gel (dissolved in 5% methanol in dichloromethane) to obtain 70 fflg of impure product (containing tin by-products). • Second purification by preparative thin layer chromatography And 10 mg (Y: 5%) of the title product was obtained. ) 7 8 2 (d * J — δ .0 Η z I 2 Η) »7 1 5 4 (d * J — 8 .0 Η zt 1 Η) 9 7 • 4 9 (s 1 1 H) • 7 4 2 (m * 3 H) · 6 A 0 5 (t * J = 4.5 Η z I 1 Η) »4 3 0 (sf 1 H), 4 2 8 (s »1 H) 2 • 3 4 (d» J = 4.5 .5 Η z * 2 Η) »1 • 3 1 (s 6 H) 1 Μ S (DCI) m / e 3 9 7 (Μ Η +) 镠 髙 Analyzed US calculated value 397.1804: Measured value: 3 9 7, 1816 * 3. 0 ppM deviation 0 (please read the precautions on the back before filling this page) Printed by Local Shellfish Consumer Cooperative, Example 8 2 5, 6 ~ Mono · nitro-5, 5 -monomethyl_2 -transmethyl-8-phenylphosphonium (LVIIa)

This paper is scaled to the Chinese National Standard (CNS) Λ4 specification (2 丨 OX 29 * 7 mm) -127-A7 A7 Printed by the Central Government Standards Bureau of the Ministry of Economic Affairs and printed by the Shellfish Consumer Cooperative B. V. Description of Invention (125) Order A solution of 95% lithium aluminum hydride powder (LAH 40 mg '1.0 mmo1) in anhydrous ether (5.0 ml) was refluxed until most of the hydride was dissolved. * Then slowly add compound XV I [la (485 mg '1 • 66 mmo1) solution in anhydrous ether (5.0 m L) After 0.5 hours, ethyl acetate (20 ml) and 1 N hydrochloric acid (20 mL) were added and the organic phase was separated. After drying over anhydrous magnesium sulfate and concentrating in vacuo, 368 mg (Y: 84%) of the title compound was obtained ο 1 Η — N Μ RCCDC 1 3): δ 7 3 6 (m% 6 Η) > 7. 2 6 (m * 1 Η), 7 0 2 (d VJ = 1 8 Η z · 1 Η) 5-9 9 (tt J 4 5 Η z · 1 Η) hit 4 • 5 5 (sf 2 Η) 2-0 5 (d * J = 4 • 5 Η Z ♦ 2 Η) 1 1 • 3 4 (s V 6 Η) > Μ S (DCI) m / e: 2 4 7 (Μ + _ -0 Η] Example 8 3 5, 6-Dihydro-5,5-dimethyl-2-bromomethyl-8-phenyl (LV Ilia)

Compound (LVIIa) (900 mg, 3.41 mmol) was added to a compound containing tetrabromide (Aldrich, 1.36 g, 4.09 mmol) 'triphenylphosphine (j wood paper scale applicable to 11 Chinese standards (CNS) A4 specifications ( 210X297 mm) (Please read the notes on the back before filling this page)

-128-Printed by the Consumer Procurement Cooperative of the Central Procurement Bureau of the Ministry of Economic Affairs ... J A7 —__ B7 V. Description of the Invention

Aldrich, 1.07 g, 4.09 mmol) and anhydrous ether (20 mL) • After 16 hours at room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The concentrated residue was then chromatographed on silica gel (eluted with 3% ethyl acetate in hexane) to obtain 7900 mg (Y: 71%) of the title product. ^ -NMR (CDC 13): δ 7.39 ( m, 6H), 7. 2 7 (dd * J = 8. 1-1. 8 H z · 1 H), 7. 0 4 (d · J = 1.8 Hz, 1H) > 6. 0 1 ( t * J = 4. 5 H z * 1 H) '4. 3 9 (S, 2 H), 2. 3 5 (d * J = 4. 5 H z · 2 H), 1, 3 4 (s , 6 H): MS (DCI) m / e: 327 (MH +) · Example 8 4 4-[[[((5, 6-dihydro-5, 5-dimethyl-8-phenyl) -2 -A certain group] methyl] oxy] ethyl benzoate (I25a)

At room temperature, 60% sodium hydride (1.05 mmol, 43 mg) force αλ4- This paper size applies to China National Standards (CNS) Λ4 specifications (210X297 mm) -129 τ (Please read the precautions on the back before filling (This page) • Packing _ A7 A7 Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China Ben_____ B7 V. Description of the invention (127) Ethyl benzoate (Aldrich, 152 mg, 0.917 mmol) ethylene glycol dimethyl ether (6. 0 mL) solution, after 0. 15 hours, Coga compound (LVIIIa) (330 mg, 1.01 mmol) * After 16 hours, the reaction mixture was diluted with ethyl acetate (50 mL), and then 1N Washed with hydrochloric acid (2 X 50 mL) • The organic phase was concentrated under vacuum, and the concentrated residue was chromatographed on silica gel (dissolved with 10% ethyl acetate in hexane) to obtain 64 mg (Y: 1 7%) of the title product * 1 Η -N MR (CDC 1 3) δ 7 .9 7 (dt J = 8-8 H zf 2 H) »7 • 3 6 (mr 7 H) 7 0 6 (s * 1 6 .9 2 (d * J = 8 8 H z ♦ 2 H) try 6. 0 1 (t * J = 4-5 H z «1 H) > 4 .9 6 (s »2 H) * 4 • 3 4 (Q t J = 7- 2 H z • 2 H) »2 .3 6 (dt J = 4-5 H z ♦ 2 H) t 1 .4 0 (t» J = 7-2 H z 3 H) »1.3. 5 (s 6 H) MS (DCI) m / e: 4 1 3 (MH +) «» Example 8 5 4- [[[((5, 6-dihydro-5, 5-dimethyl-8-phenyl) -2-A certain group] methyl] oxy] benzoic acid (I2ea) This paper size is applicable to China National Standard (CNS) Λ4 specification (2! 0 × 297 mm) ---------- packing-( (Please read the notes on the back and fill in this page first) Order " -130-418186 A7 B7 V. Description of the invention (128)

Using the method for preparing an 8-phenyl derivative (I4a), 64 mg (0.155 nmol) of the compound I25a was prepared to obtain the title product of 50 rag (Y: 84%). ^ -NMR (DMSO-de): δ Central Ministry of Economic Affairs Printed by Lou Zhunzhen Zhengong Consumer Cooperatives 1 2 5 9 (S 1 H) * 7 8 3 (d, j =; 8 • 8 HZ »2 H), 7 3 3 (m * 7 H) > 6 9 7 (d, J s 8 9 H zt 2 H) · 6 9 6 (s * 1 H) $ 5 9 9 (t, J 4 5 H z 1 H), 5 0 4 (s, 2 H) 2 3 0 (d, J = 4 5 H z 2 H) * X 2 7 (S f 6 H) M SCDCI) m / e; 3 8 5 (MH +) P 1 R (Κ Β Γ): 2 0 5 8 * 1 6 8 2 t 16 1 2 5 2 C m -i * C 2 Ο Η 2 4. 0 3 " 0, 2 5 H z 0 Elemental analysis value: Calculated value C; 80.28; H; 6. 35 Measured value C: 8Q.41: H: 6. 23 ---------- ^ ------ 1T ------ y (Please read the precautions on the back before filling in 5r (This page) In this case, the scale of the book is made by the Chinese government. (Guide (CNS) (210X297 mm) -131-^ 8 186 A7 B7 _ V. Description of the invention (29)) Example 8 6 4 ~ [[[ (5, 6 ~ —gluco-5,5 ** dimethyl_8_phenyl) _2_yl] oxy] methyl] benzoic acid (I27a)

60% sodium hydride (36 rag, 0.888 mmol) was added to a solution of the compound (XXVa) (193 rag, 0.772 mraol) in ethylene glycol dimethyl ether (5.0 mL) at room temperature, after 15 minutes • Add 4- (bromomethyl) benzoic acid methyl vinegar (Aldrich * 195 mg, 0.848 mmol). After 16 hours at room temperature, add 60X sodium hydride (36mg, 0.888ramol). After refluxing for 24 hours, add acetic acid. Dilute the reaction mixture with ethyl acetate (50 mL) and wash with 1N azanitrate (2 X 50 mL). • Shrink the organic phase under vacuum. • Chromatograph the concentrated residue on silica gel (5% 170 mg of impure substance was obtained by dissolving methanol in digas methane solution. • The crude substance was dissolved in ethanol (3 mL), and 1N hydrogen acid (20 mL) was added. The precipitate was collected by vacuum filtration. 50nig (Y: 16%) of the title product ^ -NMRCDMSO-de) 'δ 1 2. 9 5 (S 9 1 Η) »7.8 9 (d · J " 8 3 Η z ， 2))-7 .4 2 (d, J = 8.3 Η ζ, 2 Η), this paper size is applicable to the Chinese family ladder (CNS) Λ4 specification (210 × 297 mm) (please read the note on the back first) Please fill in this page again.) Order the consumption cooperation of the Central Economic and Technical Bureau of the Ministry of Economic Affairs of the People's Republic of China -132-A7 4 18 189 B7 V. Description of the invention (130) 7 • 3 9 — 7.. 2 1 (m 9 6 Η) t 6 8 8 (dd »J = 8 5 2 7 Hz, 1 Η) 6 4 4 (d · J = 2 * 7 Η ζ 1 Η), 5 9 7 (t, J = 4 5 Η ζ» 1 Η ), 5 0 4 (s * 2 H) »2 2 7 (d, J 4 5 Η ζ» 2 Η), 1 2 4 (s' 6 H) * MS (DCI) m / e; 3 8 5 (Μ Η +) IR (Κ Β r): 3 4 4 2 »1 6 8 2 * 12 8 2 C m -1 β C 2 6 Η 2 4 0 3 · 0. 5 1 H z 0 : Calculated value C 80 .59; H: 6. 50 Measured value C: 80.31;; H: 6. 26 Example 8 7 (Please read the precautions on the back first & fill in this page) -Installation_

r1T Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5,5--methyl-8-Jingji_8_ (2,4--tolyl) -5,6, 7,8 -Tetragas-Article-2- Methyl carboxylate (XV II e)

The title product was prepared from 311 mg (1.34 mmol) of compound (XVIa) using the method of preparing 8- (2-fluorophenyl) derivative (XVIId). The paper size is common in China Standard (CNS > A4 specification (210X297 mm) -133-Λ7 V. Description of the invention (131) Η--N Μ R (c DC 1 3) δ 7. 9 1 C dd J-8 • 3 t 1 8 H z 1 H 7. 6 6 (s 1 H) 7. 4 9 (d J = 8 3 H z 2 H) 7. 0 2 cd J = 8 * 0 H z 1 H) * 6 9 9 ( s 1 H) t 3 8 0 (s 3 H), 2. 7 6 cm 1 H) * 2 3 4 (m 1 H) 2. 3 2 cs 3 H) 2 0 8 (m 1 H)-1. 6 3 (m 1 H) 1 5 5 (s 3 H) > 1. 1.4 2 (s 3 H) 1 3 5 (s 3 H); S (DCI) m / e 3 3 9 (MH +) o (Please read the precautions on the back before filling out this page) Example 8 8 5,5-Dimethyl-5, 6-dihydro-8- (2, 4-xylyl)-2-carboxylic acid (XVIIIh)

Using the method for preparing an 8-phenyl derivative (XVIIIe), 285 mg (Y: 63%) of the title product was prepared from 311 mg (1.34 mmol) of the compound (XVIIa). ^ -NMR (CDC 13): δ 7. 7 8 (dd · J = 8. 0 · 1. 7 Η z · 1 Η), the size of this paper applies to the ten national standards (CNS) A4 specification (210X297 mm) ) -134-A7 B7 V. Description of the invention (132 7 .4 8 (d 7 .1 8 (d 7 .0 6 (m 5 .8 6 (t 2 .3 5 (m 1 .9 9 (S 1. 2 8 (s S (DCI) J = 8. 〇 Η ζ · 1 Η) J = 1.6 Η ζ 1 Η) 3 Η) · J = 4 2 Η) 3 Η) 3 Η); m / e: 307 (ΜΗ + 5 Η ζ-1 Η), 2. 3 3 (s, 3 Η) X. 3 9 (s · 3 Η) (Please read the precautions on the back before filling this page) Installation Example 8 9

Ja 4-[[[[[5, 6-— nitrogen_5, 5-—methyl-8_ (2,4_ — • tolyl)]-2 -naphthyl] carbonyl] amino] methylbenzoate (I3h )

67% (Y: 21%) of 221 mg (0.722 mmol) of compound (XVIIIh) was prepared by the method of preparing 8- (2-fluorophenyl) derivative (I3g) using the method of preparing 8- (2-fluorophenyl) derivative (I3g). ) Product of the title * ^ -NMR CCDCla): δ 8. 0 0 (d-J = 8. 7 Η ζ-2 Η) · 7. 7 7 (s * 1 Η), 7. 6 8 (dd- J = 8. 2-1. 7 ζ ζ > 1 Η), 7. 6 3 (d > J = 8. 7Η ζ, 2 Η), the standard of Chinese standard (CMS) Α4 (210X297) (Mm) -135-Λ7 B7 V. Description of the invention (133) 7. 4 7 (d, J 8.0.0 HZ 1 H) -7.1. 5 (d, J = 1. 7 H z 1 H), 7 .0 6 (m, 3 H) »5. 9 3 (t, J = 4.5 H z 1 H), 3. 9 0 (s, 3 H), 2 4 3 (m, 2 H), 2 .3 6 (s, 3 H), 2 • 0 8 (s, 3 H)-1. 4 5 (s, 3 H) t MS (DCI) m / e 4 4 0 (MH +) 9 (Please first Read the precautions on the back and fill out this page). Equipment. Example 9 0

, 1T 4-[[[[[5 * 6--nitrogen _5, 5--methyl-8_ (2,4_ -tolyl)]-2 -baryl] carbonyl] amino] benzoic acid (J4h)

Yinju, a central government bureau of the Ministry of Economic Affairs, used the method of preparing 8-phenyl derivatives (I4a) to prepare 67 mg (0.153 mmol) of the compound (Iah) to obtain 61 mg (Y: 94%) of the title product. 'H-NMR (DMSO-de): δ 12. 7 2 (s * 1 Η) -10. 40 (s, 1H), 7. 8 7 (d · J = 8.8 Hz, 2H), 7.8 0 (m, 3 H)-7. 5 2 (d · J = 8. 0 H z · 1 H), this paper size is applicable to China National Standards (CNS > A4 format (210X297 mm) — -136 -4 18 186 A7 B7 V. Description of the invention (134) 7 〇4 (m · 4 Η), 5 8 8 (t * J — 4.5 Η z * 1 Η), 2 3 8 (m · 2 Η) , 2. 3 1 (s * 3 Η), 1 9 9 (s * 3 Η) ♦ 1. 4 1 (s · 3 Η), 1. 2 9 (s, 3 Η); MS (DCI) m / e: 426 (MH +); I r (KB r): 2960 · 1 688 * 1594, 1518cm-1 · 0.5H20 Elemental analysis value: Calculated C: 77. 39; Η: 6. 50; N: 3 22 Found C: 77.57; Η: 6.50; N: 3.22 寊 Example 9 1 5,5-dimethyl-8-hydroxy- (4-tolyl) -5,6,7, 8-tetrahydro- Some methyl-2-carboxylate (XVI If)

Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). The method for preparing 8- (2-fluorophenyl) derivatives (XV lid) is 260 rag (1. 12 mmol) of compound (XVIa) was prepared to give 189 rag (Y: 52%) of the title product. ^ -NMR (CDCla) ·· δ 7. 9 2 (dd · J = 8. 4 · 1. 7Hz, lH), the paper fiT scale applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -137-B7 V. Description of the invention (135) 7. 8 4 (d · J = 1. 7 Η z > 1 Η), 7.47 (d, J = 8.4 Hz, lH),. 7. 1 〇 (s-4 Η) -3.82 (s, 3H), 2. 3 4 (s-3 Η) · 2. 18 (m, 2H), 1. 8 0 (m > 1 H) -1. 6 0 (m · 1 H), 1. 3 9 (s 3 H), 1. 3 4 (s · 3 H); MS (DCI) m / e: 325 (MH +). Example 9 2 5,5- —Methyl-5,6 — — · Nitrogen-8- (4-Tolyl) -Article-2-Unsaturated Acid (XVIIIi (Please read the precautions on the back before filling this page). Loading ·

、 -Α The Central Bureau of Standards, Ministry of Economic Affairs, Work and Consumption Cooperation, Du Yinhua This paper size applies the Chinese National Standard (CNS) A4 (2IOX2S »7 mm) The method for preparing 8-phenyl derivative (XVIIIa) is (0.583 mmol) of the compound (XVIIf) was prepared to give 155 mg (Y: 91%) of the title product. 7 Hz-1 H) 7. 5 1 (d J = 1. 7 Hz -1 H)-7. 4 9 (d J = 8. 0 Hz > 1 H) * 7. 2 3 (m * 4 H) > 6.0 0 (t • J 4.5 Hz, 1 H), -138 _ Λ7 B7 V. Description of the invention (136) 2. 3 5 (s, 3 Η), 2. 33Cd * J = 4. 5Ηζ * 1Η)-, 1 · 3 Ο (s, 6 Η); MS (DCI) m / e: 293 (ΜΗ +). Example 9 3 Methyl 4-[[[[[5 I3i) --------- k— < Please read the notes on the back before filling in this page)

， 1T printed by Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs, using the method of preparing 8- (2-fluorophenyl) derivatives (I3g) to prepare 143 mg (155 mg (0-531 mmol) of compound (XVIIIi) Y: 63%) of the title product · 'H-NMRCCDCla): δ 8. 02 (d, J = 8. 8 Η z * 2 Η), 7. 7 4 (s · 1 Η), 7. 7 2 (dd * J = 8. 0 * 1. 8Hz, 1H), 7. 6 6 (d J = 8. 8Hz, 2H), 7. 5 3 (d · J = 1.8 H z · 1 H), 7. 4 9 (d · J = 8. 0 H z * 1 H), 7. 2 3 (m, 4 H), 6. 0 6 (t-J = 4.5 H z · 1 H), this Paper size applies to Chinese national chess rate (CNS > Λ4 specification (210X297mm) 139-'4 1 8 1 8 6 A7 B7 V. Description of invention (137) 3. 9 0 (s-3 Η)-2.4 0 (s · 3 Η), 2.39 (d, J = 4.5Hz, 2H),. 1. 5 4 (s 3 Η) · 1. 3 7 C s-3 Η); MS (DC I) m / e : 426 (MH +) <-Example 9 4 4 ~ [[[[[5, 6-— · Mi * 5, 5-—methyl-8- (4-tolyl)]-2-baryl] [Amino] amino] benzoic acid (I4i) (Please read the precautions on the back before filling this page)

123 mg (Y: 89%) of the title product was prepared from 143 mg (0.336 mraol) of compound (I3i) by the method of preparing 8-phenyl derivative (I4a). Printed by Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs. 1 Η-NM MR (DMD 0-d β) • δ 1 2. 7 2 (s V 1 H) »1 0 .4 2 (s · 1 H)-7 .8 5 (m 5 H)-7 .5 2 (d J — 8. 0 HZ -1 H) * 7. 4 4 (d J = 1.8 H z • 1 H) · 7. 2 1 (s 4 H)-6 .0 2 (t J = 4.5 H z -1 H), 2.3 3 (s 3 H), 2.3 3 (d 1 J = 4.5 H z • 2 H), the standard of this paper is applicable to Chinese national standards ( CNS) A4 grid (2IOX297 mm) -140-4 1 8 6. A7 B7 V. Description of the invention (138) 1 3 1 (s 1 6 H) 13 C NM MR (DMS 0 — de) 1 6 6 9 0 y 1 6 6 • 0 6 1 1 4 8. 7 7 1 4 3 * 2 8 1 3 8 1 6 »1 3 6. 9 3 1 3 6 * 6 0 1 3 3 • 4 9 • 1 3 2 4 8 1 3 0 • 1 9 1 2 9 • 1 2 »1 2 8. 2 1 1 2 6-7 5 1 2 5 3 5 1 2 5. 0 3 1 2 3-9 2» 1 1 9 * 3 8 1 1 9. 2 9 3 7-9 8 • 3 3-5 2 2 7 • 7 5 2 0-7 9 Μ S (DCI) m / e 4 1 2 (MH +) IR (Κ B r); 2 9 6 0 ♦ 1 6 8 8 1 5 9 4 · (Please read the note on the back first (Fill in this page again) r.

、 1T Printed C 27H 25N printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives! 0 3 · ο. 2 5 1 ^ 0 Yuan cable analysis value: Calculated value C: 77.96: Η: 6.18; N: 3.37 Measured value C: 77.73: Rhenium: 6.09; N: 3.29 Example 9 5 4,4-Dimethyl-7-bromo-tetrahydrofluorenone (fork 1 ^ 111) A solution of methyl-7-amino-tetrahydrofluorenone (XII) (5.0 g, 26.46 mmol) in glacial acetic acid (89 mL) was added to a solution containing sodium nitrate (2.18 g, 13.92 mmol) and concentrated sulfuric acid (28,4 » α) and glacial acetic acid (26.27 mL) in a cooled (1 (TC) stirred solution [sodium nitrate is added to cooled (ioc) concentrated sulfuric acid, heated to dissolve, cooled, and then added with glacial acetic acid Prepared] li · This paper size applies to China's national kneading rate (CNS > A4 Zhuge (210X297 mm) -141-Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 _ V. Description of the invention (139) Add the resulting solution slowly (more than 10 minutes) to a heated (§0 " C) solution containing copper bromide (I-valence) (16.66g) and concentrated hydrobromic acid (159 «nL) * let the mixture Warm up to 90 ° C for 1 After 0 minutes • After cooling, diluting with water (250 mL), and extracting with ethyl acetate (2 X 200 mL) * After combining the organic phases and concentrating in vacuo, the concentrated residue was chromatographed on silica gel (3% Ethyl acetate solution in hexane) to give 1.95 g (Y: 29%) of the title product * ^ -NMR (CDC 13) ·· δ 8. 1 3 C d · J = 2.3 Η z- 1 Η)-7. 6 2 C dd · J = 8.5, 2. 3 H z · 1 H), 7.31 Cd «J = 8.5Hz * lH) · 2. 7 3 (t * J = 7. 〇 H z · 2 H), 2. 01 (t, J = 7. 〇 H z-2 H), 1. 3 8 (s, 6 H): MS (DCI) m / e: 253 (MH +) · Implementation Example 9 6 4,4-Dimethyl-7-trimethylsilylethynyltetrahydrogen M (IL) Add (trimethylsilyl) acetylene (Aldrich * 3.0 mL, 21.23 nnnol) to a compound containing ( XLVI】 丨) (1.53 g, 6.04 mmol), palladium acetate (II valence) (Aldrich, 15.4 mg, 0.975 mmol) 'triphenylphosphine (31 mg' 0.118 mmol) and anhydrous triethylamine (30 mL) of the degassed solution • and heated to 100 eC over 0.5 hours. After 4 hours at 1QQ ° C, cool the reaction mixture to room temperature. The paper size is in accordance with Chinese standards (〇 阳) 厶 4 size (210/297 mm) ~~~ -142-(Please read the (Please fill in this page again for attention).

, 1T 4 19, 1 μ μ__B7 V. Description of the invention (140) C 1 6 hours) »Next, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The concentrated residue was chromatographed on silica gel (using 3% ethyl acetate). Hexane solution of hydrazine) to give 1.24 g of CY: 7 6 96) the title product "» 1---NM MR (CDC 1 3) 1: δ 8.. 1 1 (d * J = 1 • 8 Hz, 1 Η) »7. 5 8 (ddf J = 8 • 2 · 1. 8 Η z» 1 Η) · 7. 3 6 (d 9 J = 8 • 2 Hz, 1 Η) t 2. 7 2 (tt J = 7 • 0 Hz, 2 Η) »2. 0 1 (t» J 7 > 0 Hz 2 Η) f 1, 3 7 (s 6 H) $ 0. 2 4 (s 9 H ); MS (DC I) m / e271 (MH +) · (Please read the precautions before filling in this page) Inner Example 9, 4,4-Dimethyl, Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs -7-Ethynyl-tetrahydropyrone (L) Anhydrous potassium carbonate (170 mg, 1.21 mmol) was added to the absolute ethanol of the compound (IL) (1.24 g, 4.59 ramol) (8 OmL) solution. After 2 hours, the reaction mixture was concentrated under vacuum, diluted with saturated sodium bicarbonate (25 mL), and then extracted with methane (2 X 25 nL). The organic phases were combined and concentrated in vacuo, and the concentrated residue was Chromatography on silica gel (eluting with 5% ethyl acetate in hexane) gave 694 mg (Y: 76%) of the title product. ^ -NMR (CDC 13): δ 8. 1 5 (d · J = 1. 9Hz * 1 Η), 7. 6 2 (dd. J = 8. 2 1. 9 H z · 1 H), ^ Paper size applies to China B-house standard (CNS) Λ4 specification (210 X 297 male Centa-143-B7 V. Description of the invention (141) 7.3 9 (d, J 8.2.2 H z 1 H), 3.07 (S, 1 H) -2.7.3 (t 'J = 7 0 H z, 2 H), 2.0 0 (t, J = 7. 0 H z 2 H), 1.3 (9, s, 6 H): S (DCI) m / e: 19 9 (M H +). Example 9 8 4-[[(5, 6, 7, 8_ tetrazol-5,5-—methyl-8-fluorenyl) -2-¾¾yl] ethoxy] ethyl benzoate ( LU) (Please read the notes on the back before filling this page)

Printed by the Shellfish Anti-Poverty Cooperative of the China Standards Bureau of the Ministry of Economic Affairs will contain the compound (L) (153 mg, 0.773 mmol), ethyl 4-benzoate (Lancaster, 160 mg, 0.58 mmol), chlorinated at room temperature Bis (triphenylphosphine) palladium (II-valent) (Aldrich, 923 mg, 0.013 mmol) 'Bowl 4 cuprous copper (I-valent) (Aldrich, 4.5 mg' 0.02 mmol) and anhydrous triethylamine (3. 0 mL) was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with water (1 X 25 mL). After concentrating the organic phase in vacuo, the residue was chromatographed on silica gel (solved with 10% ethyl acetate in hexane) to obtain 183 mg (Y: 91%) of the title product. 1H-NMR (CDC13): δ 8. 2 0 (d > J = 1.8Ηζ, 1Η), this paper size applies Chinese National Standard (CNS) Λ4 specification (2I0X297 mm) -144-4 18 186 at B7_ V. Description of the invention (142) 8 〇4 (d * J = 8. 3 Η ζ · 2 Η), γ 67 (dd * J = 8. 2 * 1. 8Ηζ * 1Η) * 7 5 8 (d-J = 8. 3 Η ζ * 2 Η), 7 4 4 (d-J = 8. 2 Η ζ-1 Η), 4. 3 9 (q * J = 7. 1 Η ζ-2 Η) · 2 76 (t, J = 6. 8 Η ζ * 2 Η), 2 〇4 (t »J = 6.8 ζ ζ · 2 Η), 1 4 1 (t * J = 7. 1 Η ζ-3 Η) , 1. 4 1 (s, 6 Η); MS (DCI) m / e: 347 (MH +) · Example 9 9 4-[[((5, 6, 7, 8-四 气 -5, 5 -— Methyl_8-phenyl_8_Cycloyl) -2-yl group] ethynyl] ethyl benzoate (LIU)

M · Ministry of Economics, Central Bureau of Standards, Consumer Cooperatives Co., Ltd. 11 (Please read the precautions on the back before filling out this page) Using the method of preparing 8-phenyl derivative (XVIIa), 183 rag (0.529 mmol) of compound (Lla) 177 mg (Y: 79%) of the title product was prepared * 1 Η-NM R c CD C 1 3): 5 7 .9 8 (d • J = 8.3 Hz, 2 H) * 7 • 5 0 (d • J = 8 .3 Hz • 2 H) · This paper is also suitable for China Store Standard (CNS) Λ4 specification (210X297 mm) 145-A7

4 18 i Μ B B7 V. Description of the invention (143) 7. 4 7 — 7. 2 6 (m 1 8 H) »4. 3 7 (q, J — 7 * 0 H z» 2 H) * 2. 2 0 (m, 2 H) > 1 8 9 (m * 1 H), 1.6 .0 (m • 1 H) 1 1 • 4 1 (s * 6 H), 1.3. 9 (t, J = 7-0 H z * 3 H) S (DCI) m / e: 4 2 5 (MH +) o Example 1 0 0 4-[[(5, 6-dihydro-5,5-dimethylformate -8-phenyl) -2-anyl] ethynyl] benzoic acid (I 10a) (Please read the notes on the back before filling this page)

The Ministry of Economic Affairs, Central Bureau of Standards, Labor and Consumer Cooperation, Du Duan, added a few milligrams (~ 10-20 mg) of p-toluene sulfuric acid to a solution of compound (LIIa) (177 mg, 0.42 mmol) • heated at 70eC 0 After 5 hours • The reaction mixture was cooled and concentrated in vacuo to give 4-[[(5, 6-dihydro-5, 5-dimethyl-8-phenyl) -2-fluorenyl] ethynyl] benzene Ethyl formate (Ilsa), the concentrated residue was dissolved in ethanol (5.0 inL), and then treated with 10 N NaOH (6.5 mmol, 0.65 aL) at 70 ° C. After 0.5 hour • Added 1 N HC1 (20 mL) was placed, and the precipitate was collected by vacuum filtration to obtain 142 mg (Y: 90%) of the title product. ^ -NMR (DMSO-de): < 5 This paper scale is applicable to China National Standards & CNS) A4 specifications (210X297 mm) 1-146 _Central Bureau of the Ministry of Economic Affairs, Monthly Consumer Cooperatives, India A7 B7 5 Description of the invention (144) 13. 1 3 (s 1 Η) · 7. 9 0 (d · J = 8. 4 Η z-2 Η) 7. 5 8 (d · J = 8. 4 H z-2 H), 7. 3 9 (m, 6 H) · 7. 3 0 (dj J = 6.6 Hz, 1H), 6. 9 9 (s, 1 H) * 6. 0 3 (t * J = 4 5 H z-1 H), 2. 3 3 (d-J = 4. 5 H z-2 H) 2 9 (s, 6 H) 1 3 C -N MR (D Μ S 0 — de; 1 6 6 6 4 * 1 4 6 1 4 1 1 3 9 .7 9, 1 3 7 9 6 t 1 3 3 7 5 f 1 3 1 .5 0, 1 3 0 9 8 1 1 3 0 3 7 t 1 2 9 .4 8 ， 1 2 8 6 3 1 2 8 3 8 1 2 7 .8 8 ， 1 2 7 6 0 1 2 7 4 9 1 2 6 .5 4 ， 1 2 4 6 9 1 1 9 2 3 9 1 • 9 6 > 8 8 1 1 3 7 • 9 8 3 3 4 0, 2 7.7.5 M SCDCI) m / e: 3 7 9 (MH +) IRC Κ Β Γ); 2 9 5 8 * 1 6 8 4, 1 6 0 4, 1 4 2 0 cm-1 · C 27H 22 0 2 · 〇. 15H2〇 Analytical value: Calculated C: 85.08; Η: 5.90 Measured value C: 85.06; Η: 5.97 This paper ft size is not used in China Gujia Standard (CNS) Α4 size (2 丨 〇 X 297 mm) (Please read the precautions on the back before filling this page)

-147-41818t A7 _____B7____ 5. Description of the invention (145) Example 1 Ο 1 4,4-dimethyl-7-[(dimethylamino) thiocarbonyloxy] -bu tetrahydroone (.XL Π ) A solution containing N, N-dimethylthiamine formamidine (2. 67 g · 21. 6 mmol) and tetrahydrofuran (4.30 mL) was added to a solution containing 4,4-dimethyl-7-hydroxy- Bu tetrahydroone (XIV) (3.07 g, 16.16 mmol), water (10.77 mL) and potassium hydroxide (904 rag) and cooled to below 10 ° C • Keep the reaction mixture below 12 After 10 minutes at a temperature of ° C • Add 10% K0H aqueous solution (5.39 mL) to mix the reaction (please read the precautions on the back before filling this page). The product was extracted with ethyl acetate (2 X 50 ml) at basicity * After the organic phase was concentrated in vacuo * the concentrated residue was chromatographed on silica gel (eluated with 10% ethyl acetate in hexane) to obtain 3.74 g (Υ: 84%) of the title product • 1 Η--NM R (CD c 1 3) ·· δ 7.6 8 (d 1 J = 2 6 Hz »1 Η)» 7. 4 5 (d J = 8 5 Hz f 1 Η) * 7.. 2 7 (dd * J 8 5, 2 • 6 Η ζ, 1 Η). 3. 4 6 (s 1 3 H) * 3. 3 4 (s * 3 Η), 2. 7 3 (t »J = 6 • 8 Hz 2 Η) 1 2. 0 4 (t * J = 6-8 Hz * 2 Η) f 1. 4 1 (st 6 H ) 1 Μ S '(DCI) m / e: 2 7 8 (M Η +) ·-丁-^-0 Example 1 0 2 This paper size applies to China National Standards (CNS > Λ4 specifications (2IOX297 public « > -148-A7 repair supplement 418186 B7 V. Description of the invention (146) 4,4-dimethyl-7-sulfo-1-tetrahydrofluorene _ (\ 1 ^ 111) — ~ — In a salt bath ( Is a 1: 1 molar mixture of potassium nitrate and sodium nitrate). The compound (XLI I) (3.74 g, .13.50 mraol) under nitrogen and with a gas outlet is heated at a temperature of 270-275 ° C. 0.75 hours.俟 After cooling, add a solution containing potassium hydroxide (1. 13 g), water (1. 35 mL) and ethylene glycol (10. G mL) to the reaction mixture and reflux for 1 hour * Then cool the reaction The mixture was poured onto ice (30 g). The mixture was washed with dichloromethane (2 X 50 mL), made acidic with 1N HC1, and extracted with dichloromethane (2 X 50 mL). After the organic phase was concentrated in vacuo, the concentrated residue was chromatographed on silica gel (eluted with 5% ethyl acetate in hexane) to obtain 1.22 g (Y: 44%) of the title product. (Please read the notes on the back before filling this page) Η _ Ν Μ R (CDC 1 3) 1,: δ 7 .9 1 cd > J 2 2 H z 1 1 H), 7. 4 1 (dd »J = 8-2 > 2 2 Hz 7 .3 0 (d 9 J 2 8 2 H z 9 1 H), 3 .4 8 (si 1 H) 1 2 .7 1 (t 9 J = 6 8 H z 1 2 H), 2.0 0 (t IJ = 6 * 8 H zt 2 H), 1.3 7 (sf 6 H) »S (DCI) m / e; 2 0 7 (MH +)« Η Example 1 0 3 4-[[[((5, 6, 7,8-tetrahydro-5,5-dimethyl-8-one) -2-yl] thio] methyl] benzoate Ester (XLVU) Table paper size is applicable to the Chinese standard β standard (CNS> A4 size (210 * 297mm) _ 149 _ 4 13 18c A7 B7 V. Description of the invention (147)

Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs will contain 4,4-dimethyl-7-fluorenyl-1-tetrahydroone (XLI 1 1) (262 mg, 1. 27 nmol) at room temperature , 4- (bromomethyl) benzoic acid methyl ester (Aldrich, 291 mg, 1 * 27 mmol) ', diisopropylethylamine (Aldrich * 179 mg, 1.38 mmol) and anhydrous dichloromethane were stirred * After 1.5 hours, the reaction mixture was vacuum-condensed, and the concentrated residue was chromatographed on silica gel (dissolved with 5% ethyl acetate in hexane) to give 402 mg (Y: 89%) of the title. product. 'H-NMR (CDC 13) ·· δ 7. 9 8 (d > J = 2. ΙΗζ'ΙΗ), 7. 9 5 (d · J = 8. 5Hz, 2H), 7. 3 8 (dd * J-8. 3 2. 1Hz, 1H) '7. 38 (d, J = 8.5 Hz, 2H), 7. 2 9 (d * J = 8. 3Hz, 1H), 4. 17 (s, 2H), 3. 9 0 (s ♦ 3 H), 2.71 (t, J = 6.8Hz, 2H), 1, 9 9 (t * J = 6.8 H z * 2 H) · 1. 3 6 ( s ♦ 6 H); MS (DCI) m / e: 355 (MH +) · Example 1 0 4 This paper size is applicable to the Chinese national kneading rate (CNS) Λ4 specification (210 X 2S »7 mm) (please first W (Read the back, & notes before filling out this page)

-150-4 16 ί 8 S —-—--------- Α7 Xiu King μ% --- j # ;, charge twenty-one L -_— V. Description of the invention (148) ^ 4-[[ [(5,6,7,8-Tetrahydro-5,5-dimethyl-8-phenyl-8-mercapto) -2-fluorenyl] thio] methyl] benzoic acid methyl ester (XLVIIa)

Using the method of preparing 8-phenyl derivative (XVila) to prepare 415 mg (Y: 85%) of the title compound with 400 mg (1.13 raraol) of the compound (XLVla) " (Please read the precautions on the back first Refill this page) 1 Η-N Μ R (c D c 1 3): 5 7. 8 7 (d, J — 8 .2 Hz * 2 7. 3 0 1Ί · 1 8 C m > 9 H ) t 7. 0 2 (d * J 2.0 .0 Hz, 1 iJ · 3. 9 7 (s * 2 Η) > 3. 9 1 C s-3 Η), 2. 2 2-2. 0 8 (m > 3 Η), 1. 8 5 Cm- 1 Η), 1. 3 6 (s · 3 Η), 1. 2 8 C s * 3 Η); MS (DCI) m / e: 433 ( MΗ +). Example 1 0 5 4-[[[[(5, 6-Dihydro-5, 5-dimethyl-8-phenyl) -2-fluorenyl] thio] methyl] benzoic acid (I 14a); Line · Consumption of Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Wang Jian The paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 151 4 彳 8 彳 86 A7 ___ _B7 V. Description of Invention (149)

According to the method for preparing the compound 4-[(E)-(5, 6-digas-5,5-dimethyl-8-phenyl-2-some) vinyl] benzoic acid (I1), 415 mg (0.96 mmol) of the compound (XLV1U) to obtain the title compound of 365 rag (Y: 95%) · (Please read the precautions on the back before filling this page)

-V Printed by Zhengong Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs 1 1 — NMR (DMS 0 1 de): δ 1 2 • 8 7 (s 1 H) 7 7 8 (d J 8 * 2 H z »2 H) t 7 • 3 7 (m • 3 H) * 7 ♦ 2 9 (s 1 H) 7-2 5 (d »J = 8 * 2 H z 2 H) 1 7 * 2 5 (d» J = 8 * 1 H zt 1 H) 7 * 1 3 (mt 2 H) 6-6 7 (d 1 J = 1 9 H z 1 H) 5 9 5 (tt J = 4-5 H z 1 H) 4. 0 9 (s 9 2 H) t 2-2 7 (dt J ss 4-5 H 2 2 H) > 1-2 4 C s I 6 H) Μ s CDCI) m / e: 4 0 1 (MH + ) IR (KB r) ·· 2 9 5 6 1 6 8 4 f 1 6 1 0 1 4 2 2 1 2 8 6 cm -1 • C 2eH 24〇2 S! · 0. 5Η20 Elemental analysis value: L This paper is applicable to the standard of the Chinese family storehouse according to the standard (CNS > A4 grid (210x297 mm)> -152-418186 A7 B7 V. Description of the invention (150) Calculated value C: 7 6. 2 5: Η: 6. 15 Found C: 76.20: H: 6,15. Example 1 0 6 5,5_dimethyl_5,6--nitrogen-8_phenyl-series-2 -residual acid 'N, 0 -— • Amides group by group (Lilia)

Printed under oeC (0.39 nL, 4.49 nmol) and two drops of N, N printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the precautions on the back before filling this page)-dimethylformamide Amidine was added to a solution of compound (XVIIIa) (1.04 g, 3.74 mmol) in anhydrous dichloromethane (15.0 mL), and the reaction mixture was stirred at room temperature. After 2 hours, add N, 0-dimethylhydroxylamine gaseous radical (Aldrich * 401 mg, 4.11 mmol) and anhydrous B-pyridine (650 mg, 0.665 mL) at 0 ° C. 2 at room temperature After hours, the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL), washed with brine (2 X 50 inL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 1.13 g (Y: 94%) of Title product »» Η — NMR (CDC13): δ 7. 5 5 (dd * J = 8. 0-1. 9 Hz, lH), 7. 3 9 (d * J = 8. 0 H z-1 H) , 7. 3 7 (m, 5 H), 7. 3 2 (d · J = 1.8 Hz, lH), this paper size applies to Chinese national sample (CNS > Λ4 specification (210X297)) -153- A7 B7 V. Description of the invention (151) 6. 0 1 (t • j = 4.5 H 2 • 1 H), 3. 4 9 (S, 3 H), 3 2 7 (s * 3 H), 2 3 7 (d, J = 4.5 H z, 2 H), 1.3 5 (s, 6 H) MS (DCI) m / e: 322 (MH +) · Example 1 〇 7 5, 5 Dimethyl-5, 6-dihydro-2-methylfluorenyl-8-phenyl (LI Va) (Please read the precautions on the back before filling this page)

Consumption cooperation with employees of the Central Bureau of Prototype, Ministry of Economic Affairs, Du Duan added diisobutyl aluminum hydride (DIBAL, 1.0M hexane solution, 5, 28 mmol, 5. 28 mL) to compound (Lilia) (1. 13 g, 3. 5 2 raraol) in tetrahydrofuran (32 mL) solution (-78 ° C) * After 1 hour * dilute with 5% HC1 in ethanol (10 mL) solution and brine (10 nL), and then use This mixture was extracted with ethyl acetate (2 X 40 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, and then concentrated in vacuo to give 720 rag (Y: 78%) of the title product. ^ -NMR (CDC 13) : δ 9. 8 6 (s, 1 Η) · 7. 7 6 (dd · J = 8. 0 * 1. 7 H z · 1 H), 7. 5 4-7. 5 2 (m · 2 H ), The standard of this paper is Chinese national standard (CNS > A4 grid (2IOX297mm) -154-A7 B7 V. Description of the invention (152) 7. 5 2 — 7. .2 6 (m, 5 H) »6 0 7 (t, J = 4.5 Hz, 1 H), 2. 4 0 (d, J = 4.5 H z * 2 H), 1. 3 8 (s, 6 H); MS ( DCI) m / e: 263 (MH +)-Example 1 0 8 4-[[[[((5,6-Dihydro-5, 5-dimethyl-8-phenyl) -2-fluorenyl] methyl ] Amino] methyl benzoate (I2 a) (Please read the Notes on the back and κ reloading the page)

.1T Add the compound (LlVa) (720 mg, 2.75 ramol) and 1% glacial acetic acid in methanol (6.0 mL) to a solution containing methyl 4-aminobenzoate (505 mg, 3.35 mmol) and 1% ice To a solution of methanolic acetate solution (6.0 mL) * and then add sodium cyanoborohydride (174 Central Bureau of Standards of the Ministry of Economic Affairs β: printed by Industrial and Commercial Cooperatives, mg 2.75 mnio 1) over 1 hour (add The method is 6 X 29 mg, once every 10 minutes) 0 After 16 hours at room temperature, the reaction mixture is concentrated in vacuo, and the concentrated residue is chromatographed on silica gel (10% ethyl acetate in hexane Solution elution) to give 856 mg (Υ: 78%) of the title product < »1 Η — NM MR (CDC 1 3): δ 7 8 3 (df J — 8 9 Η ζ-2 Η) * 7 3 4 (m 1 6 Η) 1 This paper size applies to the Chinese national standard (CNS > A4 size (2 丨 0X297 mm) -155-4] 0 丨 ο ο Α7 Β7 V. Description of the invention (153) 7. 21 (dd, J = 7. 8 · 2. OHz'lH) 6 .9 9 (d -J 2-0 H z 1 H), 6 .5 2 (d, J = 8 9 H z 2 H) ' 5 .9 9 ( t, J = 4 5 H zt 1 H), 4 • 3 7 (m, 1 H) 4. 2 3 (d J — 5 5 H z 2 H) * 3. 8 4 (s, 3 H) 2. 3 5 (t, J = 4 ten 5 H z 2 H) * 1 • 3 4 (s, 6 H) S (DCI) m / e: 3 9 8 (MH ") e (Please read the note on the back first Please fill in this page again) Example 1 0 9 4-[[(5, 6-dihydro-5,5-dimethyl-8-phenyl) -2-some] methyl] amino] benzoic acid , Hydrochloride (I21a)

10 N NaOH (22.0 mmol, 2.2 mL) was added to a solution of the compound (I20a) (197 mg, 0.496 mmol) in ethanol (5_0 mL). After 4 hours at reflux • Add excess 1 N HC1 (40 mL) and collect the precipitate by vacuum filtration to obtain 175 mg (Y: 92%) of the title product * ^ NMR (DMS〇-de): < 5 This paper is suitable for medium- and poor countries (CNS > A4 size (210X297 mm)

、 1T Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives -156-.8? 8 6 V. Invention Description (154) 7. 6 0 (d A7 B7 8 7 6 6 5 4 2 3 2 (m 9 Ο ( d 4 9 (d 9 6 (t 1 6 (s 2 7 (d 2 4 (s

4 HJ = 8 J = 4 2 H) J = 4 6 H) 8 H z · 2 H), 7. 2 0 (m, 3 H) 6 H z, 1 H)-8 H z, 2 H), 5 H z, 1 H),

Hz * 2 H) MS (DCI) m / e: 384 (MH +): IR (KBr): 3418 * 2960-1672 1602, 1176cm-1. C 2ΘΗ 2B0 ZN! * 1, OHC 1 elemental analysis value: Calculated value: C: 74.3 6; Η: 6.24; N: 3.34 Measured value: C: 74.39: Η: 6.19; N: 3.29 Item 洱 4 Write this page) J'a M Printed Example 1 by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 1 1 〇 4-[[[((5, 6 -—Nitrogen_5, 5-methyl-8-benzene ) -2 -naphthyl] amino] thiothroyl] methyl benzoate

Using the method for preparing the compound 4-[[[[(5,6-dihydro-5,5 ~ dimethyl-8-phenyl) -2-some) thiocarbonyl] amino] benzoic acid methyl ester The paper size is in accordance with China National Standards (CNS > A4 size (210X297 mm) M 157-4 ι8 186 A7 B7 V. Description of the invention (155) 0. 462 mm ο 1) of compound (I) was prepared to obtain 1 04 mg (Υ: 52%) of the title compound «* 1 Η-N MR (CDC 1 a) δ 8. 8 4 (S t 1 H) 8. 0 5 (d J = 8. 2 Η ζ» 2 Η) , 7.9 1 (dd J — 8 • 8, 2 4 Η ζ, 1 Η), 7.8 1 (d »J 8 _ 2 Η ζ 2 Η), 7. 4 4 (d J = 8 8 Η ζ 1 Η), 7. 3 5 (m 5 H) 7.1 3 (d J = 2 • 4 Η ζ 1 Η), 6. 0 4 (t J = 4 5 Η ζ 1 Η), 3.9 4 (s > 3 H) t 2. 3 8 (d * J = 4 5 Η ζ 2 Η) · 1. 3 5 (s 6 H) Μ S (DCI) m / e: 4 2 8 (Μ Η +) (Please read the precautions before you fill in this page #) -φ Μ Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Example 1 1 1 4-[[[((5, 6-dihydro-5,5-dimethyl-8-phenyl) -2-some] amino] thiocarbonyl] benzoic acid (I iea)

Using the method of preparing 8-phenyl derivative (I4a) at 104 mg (0.240 paper size) applicable to China National Standard (CNS) A4 specification (210X297 mm) -158-4 18 18b at B7 V. Description of the invention (156) mmol) of the compound 4-[[[((5,6-dihydro-5,5-dimethyl-8-phenyl) -2 a certain group] amino] thiocarbonyl] methyl benzoate to obtain 80 rag (title compound for 1 o 1 Η-NM R (DMS 0-de): δ 1 1 8 0 (s »1 H)» 7. 9 3 (d J = 8 4 H z, 2 Η), 7 7 7 (d J = 8 4 H z, 2 Η) * 7. 7 5 (s 1 H) t 7. 4 3 (d J = 8-4 H z, 1 Η)-7. 3 4 (m 6 H) T 6. 0 2 (t J = 4 5 H z, 1 Η) · 2. 3 3 (d J — 4 5 H z, 2 Η), 1. 3 0 (s 6 H) 1 (Please Read the precautions and fill in this page first) I11 Printed MS (DCI) m / e: 414 (MH +); IR (KBr): 2958, 1694, 1490, 1410cm -1 · C2eHz3〇2N1S1 * 0.5 H20 elemental analysis value: Calculated C: 73.91; Η: 5.73; N: 3. 31 Measured value C: 73.78; Η: 5.55; N: 3.22 Example 112 Methyl 4-fluorenylbenzoate HS 乂 ^ This paper size applies to Chinese National Standards (CNS > Λ4 size (210X297 mm) 1 I I mi -159-A7

4 18 ι 8 δ B7 V. Description of the invention (157) Concentrated sulfuric acid (0.43 mL) was added to a solution of 4-mercaptobenzyl (ΑρΤϊΓ ^ 1.72 g, 11.17 mmol) in anhydrous methanol (20.0 niL), and then the reaction mixture was allowed to warm up. To reflux for 16 hours. After concentration in vacuo, dilution with ethyl acetate (100 mL) and washing with saturated sodium bicarbonate (2 X 100 mL), the organic phase was separated, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain 712 mg (Y : 38%) of the title compound. 1 Η-NM R c CDC 1 3): 6 7 .8 9 cd, J = 8.7 Hz, 2 H), 7 2 9 cd * J = 8.7 Hz, 2 H), 3. 9 0 (s, 3 H), 3.6 .0 (s, 1 H). Example 113 4-[[[[[5, 6-Dihydro-5, 5-dimethyl-8-phenyl) -2-fluorenyl] methyl] thio] methyl benzoate (PS) (Please (Read the notes on the back before filling in this page)

A member of the Consumer Affairs Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs and Economics, at the room temperature, 60% sodium hydride (0.607 raaioi, 24 mg) was added to methyl 4-dimethylbenzoate (89 mg, 0.528 mmol) in ethylene glycol. In methyl ether (3.0 mL) solution, after Q. 15 hours • Add compound (LVI I la) (190 mg '0.581 mmol) * After 2 hours, dilute the reaction mixture with ethyl acetate (50 mL), Wash with 1N hydrochloric acid (2 X 50 mL). Concentrate the organic phase under vacuum, and then make the concentrated residue applicable to the Chinese National Standard (CNS) A4 specification (210χ 297 public ¾) _16D_ 41818ο Α7 Β7.

A

V. Description of the invention (158) Chromatography on a silica gel (elution with 10% ethyl acetate in hexane) gave 30 mg (Y: 13%) of the title product. " H-NMR (CDC 13): S 7. 8 8 (d 7. 2 8 (m 6. 9 8 (d 5. 9 8 (t 4. 0 7 (s 2. 3 3 (d 1. 3 2 (s MS (DCI)

Hz

2 H m J = 8. 9 H) J = 1.4 H z · 1 H) J = 4.5 H z-1 H) 2 H), 3. 9 0 (s, J = 4.5 H z , 2 H) 6 H): / e: 4 1 5 (Μ H +)

3 H (Please read the precautions on the back before filling this page) Order: Example 114. Line. 4-[[[((5,6 -— 气 _5,5 -—methylbenzyl) _2-strip base] Methyl] thio] benzoic acid (I34a)

Using the method for preparing an 8-phenyl derivative (I4a), 30 mg (0.07 mmol) of the compound (I24a) was prepared to obtain 21 mg (Y: 72%) of the title product. ^ -NMR (DMSO-de): δ 12, 8 7 (s > 1 Η), 161 This paper size is applicable to China Standard for Household Standards (CNS) A4 (210 X 297 mm). Printed by the consumer cooperative Λ 7 Β7 V. Description of the invention (159) 7. 7 7 (d-J = 8.5 Hz, 2H), 7. 3 5 (m-7 Η) >, 7. 2 8 (d- J = 1. 8 H z-1 H), 7. 1 9 (dd · J = 7.9, 1. 8 Hz, lH), 6. 9 0 (d · J = 1.5 H z-1 H) , 5. 9 5 (t · J = 4.5 Hz, lH), 4. 1 9 (s · 2 H) · 2. 2 7 (d-J = 4.5 H z * 2 H), 1.2 4 (s, 6 H): MS (DCI) m / e: 401 (MH +); IR (KBr): 3346-2960-1688, 1592cm-1-C 2eH 2 < t0 2S! · H20 elemental analysis value: Calculated C: 76.93; Η: 6.11 Measured C: 7 6. 9 1; Η: 6. 0 3 Example 1 1 5 1,2-dihydro-1, budimethyl-6-nitro-8 -(Trifluoromethanesulfonyloxy) C LX I) (Please read the precautions before filling this page), -β Μ

Lithium bis (trimethylsilyl) fluoride (series 1.0M hexane solution) The paper scale is applicable to China Store Standard (CNS) A4 (210 X 297 mm) " ~~ ~~ -162 -4l8i8b A7 B7 V. Description of the invention (160), 12.05 111111〇1, 12.05 11 ^) Add 4,4-dimethyl-7-nitro-bu tetrahydropanone (VI) (2.4 g, 10.96 nmol) Tetrahydrofuran (10_mL) solution (-78 ° C), and then N- (2-pyridyl) triflimide (12.05 mmol, 4.30 g) β at -78 ° C, after 0.5 hours at -78 ° C, The reaction mixture was diluted with water and extracted with ethyl acetate (2 jc 50 mL). After the organic phases were combined and concentrated in vacuo, the concentrated residue was chromatographed on silica gel (5% ethyl acetate in hexane Solution dissolution) to obtain 2.68 g (Y: 70%) of the title product * (Please read the precautions on the back before reading this page) Example 1 printed by Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs 6 1, 2 _ —Ammonia_1,1_ — " Methyl-6-nitro_4_phenyl strip (LXIIa)

Contains triphenylhydrazone (442 fflg, 1.44 mmol), ginseng (diamidinoacetone) dipalladium (0 valence) (217 mg, 0.237 mmol), tributylphenyltin hydrazone —NM MR (CDC 1 a): δ 8 .2 0 (m »2 H) * 7 .4 9 C d TJ = 8 .2 H z, 1 H), 6 .1 5 (ti J 4 • 5 H z, 1 H), 2.5 .0 (dt J = 4.5 H z, 2 H), 1.3. 7 (sy 6 H) PS (DCI) m / e: 3 5 2 (MH +) Applicable to the Chinese Standard Circle (CNS) A4 specification (210X297 mm) -163-418 186 A7 B7 Printed by the Central Government Bureau of the Ministry of Economic Affairs, Bei Gong Xiao F Cooperative, V. Invention Description (161) (6 · 17 g, 16.78 mmol) and anhydrous 1-methyl-2-pyrrolidone (5.0 mL) was added to compound (LX 1) (2.68 g, 7.64 mmol.) In anhydrous 1-methyl-2-〇71 ^ 〇11 ( !; 111 (^ 6 (30.01111)) solution * After 60 hours (: 16 hours, the reaction mixture was diluted with water and extracted with ethyl acetate (2 X 100 mL). The organic phases were combined It was stirred on a saturated potassium fluoride aqueous solution for 0.5 hours. After separation and vacuum concentration, the concentrated residue was put on a silicon knee Chromatography (analysis with 20% ethyl acetate in hexane) gave 1.93 g (Y: 9096) of the title product. * H-NMR (CDC 13): δ 8.07 (dd * J-8. 5 * 2. 5Hz, lH), 7. 8 7 (d · J = 2.5Ηζ, 1Η) *, 7.50 (d, J = 8.5 H 2 * 1 H), 7. 3 6 (m , 5 H), 6. .12 (t · J = 4.5 H z * 1 H) 1 2. 4 1 (d 1 J = 4.5 Hz, 2 H), 1. 3 9 (s-6 H); MS (DCI) m / e: 280 (MH +) · Example 117 5,5-Dimethyl-8-phenyl-5, 6-dihydro-some-2-base (LX Ilia)

This paper size applies to Chinese national standards (CNS > A4 size (2 丨 0X297mm) {Please read the precautions on the back before filling this page)

* 1T Μ -164-418 186 A7 ____ B7 V. Description of the invention (162) Ferric chloride (33%, 2.94 mL) and water (11.9 mL) were added to the compound (LX II a) (1.75 g • 6. 27 mmol) of benzene (15 m L ·), solution ο The reaction mixture was heated to reflux and iron (3, 50 g) was added in four equal portions over a period of 1.5 hours. • The resulting mixture was then returned to 1 6 hours • After cooling to room temperature, filter the reaction mixture through a piece of 1 te »After separating the organic phase and drying over anhydrous magnesium sulfate · Concentrate under vacuum to obtain 1. 56 g (Y: 99% ) Of the title Η -N Μ R (CDC 1 3):: «5 7 .3 5 (m • 5 Η)» 7. .1 5 (dt J-8 .1 Η Z · 1 Η), 6.5 7 (ddt J = 8. 1, 2 • 5 Η ζ, 1 Η), 6.. 3 7 (dt J = 2.5. 5 Η z »1 Η), 5. 9 5 (t» J = 4.5 .5 Η Z »1 Η), 3.4 .5 (bs * 2 Η) · 2. 3 1 (d» J = 4.5 .5 Η Z »2 Η), (Please read the precautions before filling in this page ) Consumption by the Chenli Bureau of the Ministry of Economic Affairs Printed by the cooperative 1.30 (s, 6 Η): MS (DCI) m / e: 250 (MH +) · Example 118 Gas diester toluene toluene) a Benzene I 8 Methyldimethylmethyl TJ amine TJ Basic Paper Standards Applicable in China® National Standards (CNS > 6 4 Zhuge (2 丨 0X297 mm) -165-4 18 1 8ό Α7 Β7 V. Description of the Invention (163)

Using the preparation of 4-[[[[(5,6-dihydro-5,5-dimethyl-8-phenyl) -2-] ] Methyl benzoate (I2Qa) method uses 1.35 g (5.38 mm ο 1) of the compound (LXI II a) and 4-methylmethyl benzoate (Aldri ch, 723 mg, 4.41 mmol) ) Prepared 1.38 g (Y: 79%) of the title product ο 1 Η--N MR (c DC 1 3): δ 7.9 5 (d 1 J 8 * 5 Η ζ f 2 Η) 1 7 2 9 (m * 7 H) 1 7. 1 6 C d 1 J = 8 3 Η ζ 1 Η) t 6. 4 7 (dd * J = 8 3 t 2 6 Η Z 1 1 Η), 6. 2 9 (d, J = 2 6 Η ζ * 1 Η) 1 5. 9 4 (tt J = 4 • 5 * 1 Η) ϊ 4. 5 3 (s > 2 H) t 3 9 1 (s » 3 H), 2. 3 0 (d J = 4 5 Η ζ * 2 Η) »1. 2 9 (s > 6 H) M S (DCI) m / e: 3 9 8 (Μ Η +) ο Example 1 1 9 4- [[[((5, 6-dihydro-5 |, 5 --methyl-8-phenyl) ~ 2-fluorenyl] amino] methyl] benzoic acid (20a) --------- f (Please read first Note the surface to fill out this page) This paper applies China National Qiu scale rate (CNS) A4 size (210X2 »7 mm >? &Quot; 166-

Δ ^ 8 1 dC A7 __ B7 V. Description of the invention (164)

10 N NaOH (35.0 mmol, 3.5 mL) was added to a solution of compound (I28a) (1.38 g, 3.48 mmol) in ethanol / tetrahydrofuran (1: 1 mixture, 15.0 mL) at room temperature. After 16 hours , Add excess 1 N HC 1 (100 mL), and collect the precipitate by vacuum filtration to obtain 1.28 g (Y: 96%) of the title product as a hydrochloride. (Please read the precautions on the back before (Fill in this page) Η-NM MR (DM D 0-de): < 5 7. 8 4 (d • J 8. 2 H z • 2 H) · 7. 3 6 (d, J = 8. 2 H z, 1 H), 7. 3 1 (m, 5 H), 7 1 5 (m -4

， 1T 6. 9 9 (bs-1 Η) · 6. 3 6 (bs-1 Η), printed by the Beige Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5 • 9 0 (t, J = 4 * 5 H z , 1 H) 1 4 3 2 (s · 2 H) 2 2 1 (d, J = 5 H zr 2 H) 1 1 1 9 (s, 6 H) MS (DCI) m / e 3 8 4 (Μ H +) * IR (Κ Β Γ) ** 3 4 2 0 2 9 5 8, 1 6 9 1 6 0 6 C m -i 9 c 2 0 Η 2 5 Ν 1 C 2 * 1 0 HC 1 yuan Cable analysis value: Calculated value C 72 .80; H · + B. 34 N '3 .27 Measured value C · 72 .98; H ·· 6. 09 N • 3 .14 This paper size applies the Chinese solid standard ( CNS) A4 specifications (2 丨 0X297 mm)-167 _ 4 18 Ido A7 ___B7 V. Description of the invention (165) Example 1 2 0 3, 3 -Dimethyl-6-nitro-dihydrofluorene-butanone 〇

Slowly add 4.18 mL of a 70% nitric acid in sulfuric acid (20 mL) solution at 0-5 ° C to 3,3-dimethyldihydrofluorene-butanone (LXIV) (16.3 g, 5 0.9 mraο 1 ) (Harms, W. M., and E. i. Bra., E.J. • Prep. Proc. Int. 1 972, 4, 67-72) in 56 mL sulfuric acid solution. After stirring for 1 hour, pour the reaction mixture into 600 g of ice * Filter the precipitate and wash with water • Dissolve the collected solid in 600 mL of ethyl acetate and wash with NaHC03 (80 mLx2), and then After sulfur (please read the precautions on the back before filling this page), the staff of the Central Bureau of Standards of the Ministry of Economic Affairs, Co-operative Society printed the magnesium acid, dried it, evaporated it, and the residue was coded with methanol to obtain 22.2 g of a yellow solid. The title compound · 1 Η -N MR (CDC 1 3) · · δ 1 • 4 9 (S 1 6 Η) • 2. 7 1 (s 1 2 H) ♦ 7. 6 8 C d, J ss 8 .4 Hz, 1 H) »8 .4 8 (dd» J = 2.0, 8. 4 H z I 1 Η), 8 • 5 3 (d, J = 2.0 Hz, 1 H) • Μ S m / e 2 0 6 C Μ Η +) · i C 11 Η 11 N 0 3 elemental analysis value = calculated value C: 64.38: Η 5. 40: N: 6.83 This paper size applies to China橾 Umbrella (CNS) Λ4 specification (2 丨 0 X 297 mm) -168-4 J8 186 A7 B7 V. Description of the invention (166) Measured value C: 6 4.33: Η: 5.33; Ν: 6.86 Example 1 2 16-Amino-3,3-dimethyl-dihydrofluoran-1-one (LXV) Ο

It will contain 3,3-dimethyl-6-nitro-dihydrofluorenone-butanone (22.2 g, 5 4.1 mmol), oxidation pin (0.44 g, 1.94 mmol), 3 0 raL B (please read the first Note for refilling this page) Consumption cooperation between employees of the Central Government Bureau of the Ministry of Economic Affairs, Du Yin ^ A mixture of ethyl acetate and 60 m L of methanol was vaporized on Parr Sh ak: er for 40 minutes »Then a piece of ce 1 ite: The mixture was filtered. The residue obtained after evaporation of the filtrate was milled with hexane to give 18-4 g (97% yield) of the title product O 1 Η--NM R (CDC 1 3) as a yellow solid. • δ 1. 3 8 CS 1 6 H) »2.5. 6 (s 1 2 Η)» 6. 9 8 (d * J = 2-3 Hz, 1 H) t 7. 0 2 (dd $ J = 2 3-8 • 2 H zt 1 Η) * 7.. 3 0 (d 9 J = 8 ten 2 Hz, 1 H) > Μ S m / e 1 7 6 (M Η +) < »

Elemental analysis value of CnHuNOa: calculated value C: 75.40;;: 7.48; Ν: 7.99 found C: 75.0 7; Η: 7.45: Ν: 7. 94 This paper method is applicable to China National Standard (CNS) Α4 specification (210 X 297) -169-Printed by Λ1 β ^ of Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs: Α7 _Β7 ___ V. Description of the Invention (167) Example 1 2 2 6-Hydroxy-3, 3-dimethyl- Dihydrofluorene-butanone (LXVI). At 0-5 ° C, slowly add a solution containing sodium nitrite (14.8 g, 214 mmol) and 30 mL of water to a solution containing 6-amino-3,3-di Methyl-dihydro 15-butanone (14.0 g, 85-8 amol), 30raL of 48% tetrafluoroboric acid and 30 mL of water • After stirring for 30 minutes, the mixture was filtered, and then cooled with cold 5% The solid was washed with fluoroboric acid and then dried under vacuum. "The solid was then added to a boiling solution containing 50 mL of sulfuric acid and D. 5 liters of water in several portions. After 1 hour of refluxing, the solution was cooled to room temperature. Ethyl acetate (100 mL X 3) extraction • The combined extracts were dried over sulfuric acid, and then evaporated. The obtained residue was subjected to flash chromatography (EtOAc: hexane = 1: 10 to 1: 2) Purified to obtain 7.60 g (50% yield) of the title compound as a solid. ^ -NMR (CDC 13) δ 1. 4 0 (s * 6 Η), 2. 6 4 (s · 2 Η). 7. 1 3 (s, 1 Η), 7. 1 8 (d · J = 8. 2 H z · 1 H), 7. 39 (d, J = 8. 2 Hz, 1 H); MSm / el77 (MH +) · Analytical value of element cable: Calculated value C: 74. 98: Η: 6. 86 Measured value C: 7 4 · 8 1; Η: 6. 7 6 Example 1 2 3 (Please read Jing (Note the following items and then fill out this page).

'IT Μ This paper size applies to Chinese National Standard (CNS) A4 specifications (210 × 2ί > 7 mm) -170-Printed by Duty Consumption Cooperation, Central Standards Bureau, Ministry of Economic Affairs 4 ⑷ SG A7 B7 V. Description of the invention (168) 3 1,1-dimethyl-3-one-dihydrofluoren-5-yl ester of fluoromethanesulfonic acid

Slowly add trifluoromethanesulfonic anhydride (9. 65 g, 34.2 mmol) at -78 ° C to a solution containing 6-hydroxy-3, 3-dimethyl-dihydro 15-butanone (4.01 g, 24.4 mmol), 4-dimethylaminopyridine (DMAP, 5.97 g, 48.9 mmol) and 30 mL: Digas methane solution • After stirring at room temperature for 1 hour, dilute with digas methane (60 mL) The mixture * was washed with 1 N HC 1 (10 mL X 2) and water (10 mL), dried over magnesium sulfate and evaporated. The obtained residue was purified by flash chromatography (EtOAc: hexane = 1: 10 to 1: 5) to obtain 5.58 g (74% yield) of the title compound. Η -N MR (CDC 1 3) δ 1.. 4 6 (sr 6 H), 2. 7 (s 1 2 H), 7. 5 1 (dd 1 J = 2. 3 t 8 • 4 H z , 1 H), 7 .5 7 (d J = 2 .3 H zf 1 H) t 7 .6 0 (d 1 J = 8 .4 H zt 1 H) »S m / e 3 0 9 (MH + ) · Elemental analysis value of C12HiiF3〇4S: Calculated value C: 46.75; H: 3.60 Measured value C: 4 6.83: Η: 3.58 Example 1 2 4 This paper size applies the Chinese National Standard (CNS) Α4 specification (210X297 mm) ) (Please read the notes on the back before filling out this page) Order M-171-Printed by the Central Standard Ministry of Economic Affairs and Consumer Cooperatives 4 18 186 Αν B7 ——— ~-° 1 V. Description of Invention (169) 1 , 1-monomethyl-3 -Er --- εε-5_ Junic acid methyl vinegar (LXVII)

Let Yiyi contain trifluoromethanesulfonic acid 1, budimethyl-3-one-dihydro | $ -5-yl vinegar (3.08 g, 10.0 mmol), triethylamine (2.02 g, 20.0 mmol), and palladium acetate ( 0,11 g, 0.50 mmol), 1,3-bis (diphenylphosphino) cranium (dppp, 0 2 1 g, 0.5 0 mm ο 1), 30 m L of anhydrous dimethyl iodide and 20 The mL of methanol solution was saturated with carbon monoxide for 10 minutes, and then stirred at 65-70eC for 2 hours with a carbon monoxide balloon. Evaporate the methanol, dilute the resulting solution with 50 mL of water, and extract with ether (40 mL) 9 Combined extracts > dried over magnesium sulfate and evaporated> Purified the residue by flash chromatography (EtOAc: hexane = 1: 20 to 1: 5) to 1.98 g (91% yield) B: The title compound as a light yellow solid ZengΗ — N MR (CDC 1 3 >) δ 1 < 4 5 (s 1 6 Η) »2 • 6 5 (St 2 Η), 3 9 4 (s * 3 Η) f 7 5 8 (dd 1 J = 8-1 Η ζ 9 1 Η) f 8 • 3 0 (dd > J === 1 * 6 »8 • 1 Η ζ» 1)) • 8 3 6 cd > J 1 6 Η ζ * 1)) »S m / e 2 1 9 (Μ Η +) 1 ο C 13H 14〇3 element analysis value: Calculated value C: 71,54: H: e_U Measured value C: 71. 71: Η: 46 Example 1 2 5 1, 1-dimethyl-3_ (trifluoromethanesulfonyloxy) -ιη-fluorene-5-carboxylic acid methyl ester Redness of this paper 14 SSJ household materials (CNS) Congwei (2 | QX297 Public Love) (Please read the precautions on the back before filling this page)

172 _ B7 V. Description of the invention (170)

(Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs) Added a methyl ester containing 1,3-dimethyl-3-one-dihydrofluorene-5-carboxylic acid (0.90 g, 4.12 mmol), 2, 6-2 Tertiary butyl 4-methyl Dtt (1.10 mg, 5.36 mmol) and 10 mL of digas methane. After stirring at room temperature for 16 hours, the mixture was diluted with 70 mL of ether, washed with 1N HC1 (20 mL), and dried over magnesium sulfate. The resulting residue was evaporated by flash chromatography (EtOAc: hexane). Alkane = 1:20 to 1: 5) and purified to obtain 1.23 g (85% yield) of the title compound. ^ -NMR (CDC 13) < 5 1. 4 1 (s · 6 H), 3. 9 5 (s · 3 Η), 6. 3 0 (s, 1 Η), 7. 4 4 (d · J = 7.8 Η z »1 Η), 7.9 9 (s, 1 Η), 8. 0 6 (d > J = 7.8 Hz, 1H); MSm / e351 (MH +) · Example 1 2 6 1, Dimethyl-3-phenyl-1H-fluorene-5-carboxylic acid methyl ester Ester (LXVlIIa) (Please read the precautions before filling this page).

、 1T Μ This paper size is suitable for Chinese storehouses (CNS > Λ4 size (210X297mm) -173-4 18 18ο Α7 Β7 V. Description of the invention (171)

Ph

Contains 1,1-dimethyl-3- (trifluoromethanesulfonyloxy) -1H-fluorene-5-carboxylic acid methyl ester (580 mg, 1.86 mmol), ginseng (dioxine) at 55 ° C Acetone) dipalladium (0 valence) (Pd2dba3, 17 mg, 0_02 nmol), triphenylbenzene (46 mg, 0.15 mmol), hydrazine (240 mg, 5.59 mmol), phenyltributyltin (680 mg , 1.86 mmol) and 5 nL of 2-methylpyrrolidone were stirred for 1.5 days • The mixture was diluted with water (30 mL), and then extracted with ether (30 mL X 3). (Please read the notes on the back before filling this page)-Installed by the Central Ministry of Economic Affairs, the Standards and Consumers' Cooperatives Cooperative ^ dried with magnesium sulfate 1 and evaporated • The obtained residue was subjected to flash chromatography (EtOAc = hexane = 1:20 to 1: 5) was purified to give 0.43 g (83% yield) of the title compound as a white solid. 1 Η — NM MR (C DC 1 3) < 5 1 * 4 1 (SP 6 Η ) »3. 9 1 (s, 3 Η), 6 4 8 (S t 1 Η)« 7 3 9-7 6 2 (m • 6 Η) »7 9 9 (d 1 J = 6 8 Η Z» 1 Η), 8 1 4 (S t 1 Η ) ♦ Μ S m / e 2 7 9 (Μ Η +) ♦ C 19 Η 1 8 Ο 2 »(). 2 5 Η a 〇 Elemental analysis value: Calculated value C: 80.68: Η: 6.49 Measured value C: 80.7 6 ： Η: 6. 41 The paper size of the paper is suitable for Chinese National Standards (CNS) A4 specifications (210X297 mm) -174-A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ) Example 1 2 7, 4-[(1, Dimethyl-3-phenyl-1 苯基 -Ιί-5-carbonyl) amino] benzoic acid methyl ester

Η Connect 1,1-dimethyl-3-phenyl-1Η-^-5-carboxylic acid methyl ester (315 mg, 1.13 mmol) with 10 N NaOH (1.1 mL, 11.0 mmol), 5 mL methanol and A 10 mL solution of tetrahydrofuran was stirred at 60 ° C for 1.5 hours. Β The solution was concentrated under reduced pressure *, then acidified with 1N HC1 (15 mL), and then extracted with ethyl acetate (15 mL X 3). The combined water was washed with water (10 mL) • dried over magnesium sulfate and evaporated • the residue was dried under vacuum • then dissolved in 2.5 mL of dichloromethane • grass gas (348 mg * 2.74) at 0 ° C mmol) and two drops of dimethylformamide were added to the solution, and stirred at 0 ° C for 30 minutes, and then stirred at room temperature for 30 minutes. Then the mixture was evaporated and dried in vacuo. The resulting residue was Stir together with a solution containing methyl 4-aminobenzoate (181 mg, 1.32 mmol) and 2 raL of anhydrous pyridine for 18 hours. Evaporate the pyridine, dilute the residue with 20 mL of 2N HC1, and diethyl ether (30 mL). x4) Extraction • The combined extracts were washed with water (10 mL), dried over magnesium sulfate, and evaporated. The obtained residue was purified by flash chromatography (EtOAc: hexane = 1: 20 to 1: 5) to obtain 372 mg (85% yield) of the title compound as a glass block. (CNS) Λ4 is now (2ΙΟχ297) 漦 --------- ^-< Please read the precautions before filling this page), 1T- -175-418186 A7 B7 V. Invention Explanation (173) Η — N MR (c DC 1 a) δ 1 4 3 (s »6 H) 3. 9 1 (s 9 3 H) '6 * 5 2 (s * 1 H) * 7 4 0 — 7 5 0 (m -4 H) »7 5 9 — 7 6 1 (m 2 H)» 7 7 2 _ 7 7 5 (m, 3 H) • 7 9 6 (s > 1 H) t 8 0 0 (bs * 1 H) 8 0 5 (d »J = 8 • 7 H z 2 H) · S m / e 3 9 8 (MH +) 2 6 Η 2 3 Ν 0 3. 0 1 1; Elemental analysis value of 2 5 H 2 0; Calculated value C: 78.1 2; H: 5.93: N: 3.50 (please read this precaution before filling out this page). Installation and measured value C : 77.9 7; hydrazone: 5.50: N: 3. 24 Example 1 2 8 4-[(1, Dimethyl-3-phenyl-1H-IS-5-carbonyl) amino] benzoic acid Τ 3 0 ",

C〇2H

5 nL 2 N The methyl 4-[(1, budimethyl-3-phenyl-lΗ- 喆 -5-carbonyl) amino] benzoate (35 9 mg, 0 90 nmol) NaOH, 5 mL of methanol, and 5 mL of tetrahydrofuran were stirred together for 10 hours. The solution was acidified with 1N HC1 and concentrated under reduced pressure. 15 mL of wood paper was added according to the Chinese national standard (CNS > A4 Zhuge (2 丨 OX ”7mm) Printed by the Consumer Standards Cooperative of the Central Standards Bureau of Ministry of Economic Affairs

-176-A7 B7 V. Description of the invention (174) After water, the mixture was extracted with ethyl acetate (15 mL X 3). The extracts were combined and washed with water (10 niL), dried over magnesium sulfate, and evaporated. The residue was triturated in ether-hexane to give 326rag (9496 yield) of the title compound as a solid, 1 Η-NM R (DMS 0-d 0) δ 1. 3 9 (s > 6 H) 9 6. 6 8 (s »1 H) 9 7. 3 9 — 7 5 3 (m • 3 H), 7. 6 4 — 7 6 8 (m 3 H) · 7. 8 5-7 9 7 ( m * 6 H) · 10 5 4 (s > 1 H) • (Please read the notes on the back before filling this page) · 1 Η); MSm / e 3 84 (MH +) · C25H21N 〇 3 * 0 2 5 Element analysis value of Ηζ〇: Calculated value C: 77.39: Η: 5.46; Ν: 3.6 1 Measured value C: 77. 26 ; Η: 5.51; Ν: 3. 52 Example 1 2 9 1, dimethyl-5-nitro-3- (trifluoromethanesulfonyloxy) -ι η- 品 〇

Trifluoromethanesulfonic anhydride (1.57 g, 5.58 mmol) is applied at -7 & ° C. This paper size applies to China National Standards (CNS > A4il grid (210X297 mm). Cooperative Indopoly A7 B7 V. Description of the invention (175)) Add one containing 3,3-dimethyl-6-nitro-dihydrofluoran-1-one (LX IX) (1.00 g, 4,65 mmol), In a solution of 2,6-di-tert-butyl-4-methylpyridine (1.19 g, 5.80 ffljnol) and 10 mL of digas methane. After stirring at room temperature for 16 hours, use 1N HC1 (20 mL) The mixture was diluted and extracted with ether (30 mL X 3). The combined extracts were washed with water (20 mL), dried over magnesium sulfate and evaporated. The obtained residue was subjected to flash chromatography (EtOAc: hexane = 1:20 to 1:10) and purified to obtain 1.37 g (87% yield) of an oily title compound. ^ -NMR (CDC 13) S 1. 4 5 (s > 6 Η) · 6. 43 (s, lH), 7. 5 3 (d * J = 8. 3 Η z * 1 Η), 8. 1 5 (d · J = 2.0 Hz, lH), 8. 2 4 (dd * J = 2. 0 * 8. 3Hz, lH); MSm / e 338 (MH +) · C12H, 〇F3N05S elemental analysis value: Calculated C: 42.73; Η: 2.99; N: 4 .15 Measured value C: 42. 70; Η: 2.80; N: 4. 10 寊 Example 1 3 01, dimethyl-5-nitro-3-phenyl-1H-S5 (LXXa) ( (Please read the precautions before filling this page)

Ph

This paper size is applicable to China National Standards (CNS) A4 (2 丨 OX 297 mm) -178-418186 A7 B7 Printed by the staff of the Central Bureau of Standards, Ministry of Economic Affairs, and printed by the cooperative. V. Description of the invention (176) at 60 ° C The following will contain 1,2-dimethyl-5-nitro-3- (trifluoromethanesulfonylamino group (1.32 g, 2.89 ramol), ginseng (diamidinoacetone) secondary sales (0 valence) (21 rag , 0.02 mmol), triphenylhydrazone (70 rag, 0.2 3 mm ο 1) 'lithium chloride (0.37 g, 8 -6 7 ram ο 1) and phenyltributyltin (1.06 g, 2.89 mmol The mixture was stirred for 48 hours. The mixture was diluted with water (30 mL), and extracted with ether (30 mL X 3). After the combined extracts were dried over magnesium sulfate and evaporated. The obtained residue was subjected to flash chromatography It was purified by the method (EtOAc: hexane = 1: 25 to 1: 5) to obtain a solid, which was recrystallized from hexane to give 575 mg (75% yield) of the title compound as pale yellow crystals * 'H-NMR (CDC13) δ 1. 4 4 (s-6 Η), 6. 5 8 (s-1 Η), 7. 4 0-7. 6 0 (m · 6 Η), 8. 18 (d, J = 2. 0-8. 2 Η ζ · 1 Η), 8. 3 2 (d * J = 2. 〇Ηζ, 1Η); MSm / e 266 (ΜΗ +) * ChHmNOz element analysis value: calculated value C: 76.96: Η: 5.70; Ν: 5.28 found C: 76.71; Η: 5.69; Ν: 5.22 Example 1 3 1 5-Amino-1, budimethyl-3-phenyl-1H-I5 (UXIa) --------- Private Clothing-(Please read the back notice first # Fill this page) * ^ τ This paper size applies to China National Standards (CNS Zhuge (2 丨 0X297) 嫠 -179-A 1 3 8 〇a? B7 V. Description of the invention (177)

Ph

Add 33% vaporized iron (1 mL) and 4 mL of water to a solution of 1,2-dimethyl-5-nitro-3-phenyl, 1H-e5 (0.56 g, 2.11 mmol) in benzene (5 mL) • Stir the mixture under reflux and add iron powder (1.00 g, 5.28 mmol) in four portions over a period of 2 hours. Then stir the resulting mixture for an additional 18 hours under reflux. Then use 20 mL of water and 20 Dilute the radon mixture with mL of ethyl acetate • Filter it through a piece of celite * The filtrate is extracted with ethyl acetate (20 mL X 3). The combined extracts are dried over magnesium sulfate to give 0.49 g (Y: 98%) of crude The title compound, which was used in the next reaction without further purification. ^ -NMR (CDC 13) δ 1.3. 7 (s > 6 Η), (Please read the note below ^ ¢-before filling in this Page). Ordering. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy

0 1 3 9 6 c 4 7 9 1 3 / * m 6 6 6 7 7 s M s d d d / V (XIN (3

, 2 · m +) __ 2 7 (Η HJ II II 8 Μ 1 t JJ 5 / IX Λ— / Η 1 ζ I >))) 9 Η Η ♦ 1 1 · I 7 t ·) 丨 zz Η ο Η Η 5 Example 1-Shiji Shiben 1 Toluene formate I-carbonyl carbonyl U amine) The basic paper size is applicable to China National Rubbing (CNS) Λ4 Zhuge (210 X 297 mm) -180-418186 Λ7 B7

Let 5-amino-1,1-dimethyl-3-phenyl-1Η-? Ϊ́5 (0.49 g, 2.06 raraol) and monomethyl terephthalate chloride (0.49 g, 2.47 ramol) in 5 mL of pyridine Stir for 18 hours, then evaporate the solvent | dilute the residue with IN HC1 (20 mL) • After extracting with ethyl acetate (20 mL X 3), wash the combined extracts with a saturated NaCl solution and pass through magnesium sulfate Evaporate after drying. The resulting crude product was purified by flash chromatography (EtOAc: hexane = 1: 10 to 1: 5) to give 772 mg (94% yield) of the title compound 'and 720 mg was crystallized from EtOAc-hexane Crystal · (Please read the precautions before filling this page) -Installation- • -β Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ^ 1 Η-Ν Μ R (CDC 1 3) δ 1. 4 1 ( S t 6 H) ♦ 3 9 6 (s 3 H) * 6. 4 7 (S redundant 1 H) »7. 3 7 — 7 '6 0 (m 9 7 H), 7. 6 8 (S f 1 H) «7 • 8 4 (st 1 H)-7. 9 4 (d« J = 8 • 3 H z, 2 H), 8. 1 6 (d »J = 8 * 3 H z, 2 H) »MS m / e 3 9 8 (MH +) • Elemental analysis value of C ζβΗ 2 3 Ν 0 3: Calculated value C: 78.57: H: 5.83 • N: 3.52 Measured value C: 78.45: H: 5. 76 t N: 3.41 This paper size applies the Chinese National Standard (CNS) A4 (2 丨 0X297 mm) -181-Central Bureau of Standards of the Ministry of Economic Affairs, Shellfish Consumer Cooperation Du printed 418 an A7 B7 5 Description of the invention (179) Example 1 3 3. 4-[[(1,1-dimethyl-3-phenyl-1H- 5-yl) amino] carbonyl] benzoic acid (I31a)

4-[[(1, Dimethyl-3-phenyl-lΗ-fluoren-5-yl) amino] carbonyl] benzoic acid methyl ester (325 rag, 0.82 mmol), 4.1 mL 2 N NaOH, 10 mL of tetrahydrofuran and 10 mL of methyl alcohol for 2 hours. • The mixture was concentrated and acidified with 1N HC1 (20 nL) * and then extracted with ethyl acetate (35 mL X 3). Then the combined extracts were combined with water (10 mL). ) To wash, dried over magnesium sulfate, and evaporated. • The residue was milled in ether-hexane to give 24 6 mg (78% yield) of the title compound as a white solid. (Please read the notes on the back before filling This page) Binding and ordering Μ 1 Η 一 Ν Μ R (D Μ s 0 -d β) < δ 1 * 3 5 (S »6 H)» 6. 5 8 (S »1 H), 7 3 8 — 7 • 7 0 (mt 7 H) 9 7-7 3 (d »J = 7-9 Hz» 1 Η) t 7-9 0 (S • 1 H) t 8 .0 4 (s »4 H) * 1 0 3 8 (b S t 1 H) »1 3 • 2 5 (bs 1 1 H) • Μ s τη / e 3 8 4 (MH +) • C 2 G Η 2 1 Ν 0 3 _ • 1 o. 2! 5 H 2 0 element analysis value; this paper size is suitable for those who are in trouble (CNS) Λ4 pit grid (2 丨 0X297 %> _ 182-4 18 186 at B7 _ — ~ 1 side _ ~ r _ _r V. Description of the invention (180) Calculated value C: 77.4 0: Η: 5.59: Ν: 3.61 Found C: 77.24: H: 5.33: N: 3.41. Example 1 3 4 4- (1, Budimethyl-3-one-dihydrow-5-yloxymethyl) -methyl benzoate (LXXIla)

Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page)-3,3-dimethyl-dihydro 15-ketone (0.72 g, 4.37 mmol) In methylformamide (5 inL) solution, after stirring for 3D minutes, methyl 4-bromomethylbenzoate (1.00 g, 4.37 mraol) was added. * The mixture was stirred at 0 ° C for 1 hour. Stir at temperature for 2 hours. The mixture was then cooled to 0 ° C and then acidified with 1 N HC1. The solvent was then evaporated and the residue was acidified with 20 raL of 1 N HC1 and extracted with ether (30 mL X 3). The extract was dried over magnesium sulfate and evaporated. The obtained residue was purified by flash chromatography (EtOAc: hexane = 1: 20 to 1: 4) to obtain 0.68 g (48% yield) of carcass. Title compound * iH-NMR (CDCl3) < 5 1. 4 1 (s · 6 Η) · 2. 6 1 (s · 2 Η), 3. 9 3 (s · 1 Η) * 5. 1 5 C s 2 Η), 7. 1 8 (d * J = 2.5 Hz, lH), the paper size is applicable to China National Standard (CNS > A4 specification (210X297 mm) -183-A7 B7 4 18 V. Invention Explanation (181) 7. 3 0 (d · 3 = 2.5, 8. 4 Η z * 1 Η), 7.42 (d, J = 8.4 Hz, lH), 7.51 (d, J = 8.3 Hz, 2H) , 8. 0 7 (d * J = 8. 3Hz, 2H); MSm / e 325 (MH +). C 20H 2. 0 4 elemental analysis value: Calculated value C: 74.06: H: 6.21 Measured value C: 73.99 : Hydrazone: 6.24 Example 1 3 5 4- [1, Dimethyl-3- (trifluoromethanesulfonyloxy) -1 H-fluoren-5-yloxymethyl] benzoic acid methyl ester (please first Read the back Notes # Fill this page) -install- 、-= * 〇

Printed by Zhengong Consumer Cooperative of the Central Standards Bureau of the Ministry of Online Economics Add trifluoromethanesulfonic anhydride (705 mg, 2.50 nmol) to a mixture containing 4- (1,1-dimethyl-3-one-di Hydrazone-5-yloxymethyl) -benzoic acid methyl ester (675 mg, 2.08 mmol), 2,6-di-tert-butyl-4-methyl-0 than B (534 mg, 2.60 mmol) and 5 mL of digas formamidine solution. After stirring at room temperature for 16 hours, the mixture was diluted with 1 N HC1 (20 mL), and extracted with ether (20 mL X 3). The combined extracts were dried over magnesium sulfate and evaporated. The resulting residue was quickly layered. Analytical method (Chinese paper standard (CNS) A4 size (210X297 mm) for wood and paper scales) -184-Α7 Β7 V. Description of the invention (182)

EtOAc: hexane = 1: 2C to 1:10) was purified to give 84.9 mg (! Yield) of the title compound as a solid o 1 1-N MR (CD c 1 a) δ 1. 3 7 cs * 6 H) 9 3. 9 3 (s, 1 Η), 5. 1 5 (s 1 2 H) t 6. 2 4 (s, 1 Η), 6.9 0 — 6 9 4 (m, 2 )) • 7. 2 5 (d 0 V er C Η C 1 3 '-J = 1 8. 8 Η z · 1 Η) f 7. 5 3 (dt J = 8 7 Η ζ 2 Η), 8. 0 8 (dt J 8 7 Η ζ 2 Η); M S m / e 4 5 7 (MH +) β C 21 H 1 Θ F 3 〇β S elemental analysis value: (Please read the precautions on the back before (Fill in this page). Install 'Dong Yinzhong's calculated value of employee's consumer cooperation of the Central Standards Bureau of the Ministry of Economics C: 55.26; H: 4.20 Measured value C: 55.39; H: 4.08 Example 1 3 6 4- (1, dimethyl -3-phenyl-1H-I5-5-yloxymethyl] methyl benzoate

Contains methyl 4- [1, budimethyl-3- (trifluoromethanesulfonyloxy) -1Η-fluoren-5-yloxymethyl] benzoate (838 mg '1.84 mmol at 60 ° C ), Ginseng (diarylene acetone) dipalladium (0 valence) (17 mg, 0.02 mmol) This paper size is applicable to China National Standard (CNS) 8 4 specifications (2 10 × 297 mm) -185- Industrial and consumer cooperation Du Yin 4 ί8 1 β6 Λ7 Β7 V. Description of the invention (183), triphenylhydrazone (64 mg, 0.20 nmol), lithium chloride (2 3 4 mg, 5.5 1 mraol), and phenyltributyltin ( 676 mg, 1,84 mmol) was stirred for 18 hours. The mixture was diluted with water (30 mL) and extracted with ether (30 mL X 3). The combined extracts were dried over magnesium sulfate and evaporated. The resulting residue was subjected to flash chromatography (E tO Ac 'hexane (= 1: 25 to 1:10) and purified to give a product 'recrystallized from EtOAc-hexane (1:20 to 1:10) to give 454 mg (64% yield) of the title compound as crystals · JH- NMR (CDC 13) S 1. 3 8 (s · 6 H), 3. 93 (s, 1H) 5. 13 (s-2 Η) 6. 4 4 (s-1 Η), 6. 8 6 ( dd * J = 2.2, 8. 1 H z > 1 H), 7. 11 (d, J = 2.2 Hz, 1H), 7. 2 7-7. 55 (m, 8H). 8. 0 6 (d * J = 8. 1 H z 2 H); MSm / e385 (MH +) * C 2Θ Η 24 O a · 0 · 1 2 5 H20 elemental analysis value: Calculated C: 80.75; Η: 6.32 Measured value C: 80.76; Η: 6.19 Example 1 3 7 4-[(1, Budimethyl-3-phenyl-lΗ-ru-5-yloxymethyl] benzoic acid (I32a) This paper is applicable to the standard China National Standard (CNS > A4 Zhuge (210X297)) (Please read the precautions on the back before filling this page) T, -0

M -186-A7 B7 Printed by the Consumer Co-operation of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Description (184)

At room temperature, methyl 4- (1,4-dimethyl-3-phenyl- 1Η-fluoren-5-yloxymethyl) benzoate (300 mg, 0.78 mmol), 3,9 mL of 2 N NaOH , 5 mL of tetrahydrofuran and 5 bL of methanol were stirred for 16 hours. • The mixture was concentrated and acidified with 1N HC1 (10 mL), and then extracted with ethyl acetate (20 mL X 3). Then the extracts were combined and water (10 mL) was used. ) To wash (please read the precautions on the back before filling this page)

'' Evaporate after drying over magnesium sulfate. Crystallize the residue from ether-hexane to 247 mg (85% yield) of the title compound as a white crystal. 0 1 Η — N MR (D MS 0-d β) δ 1 • 3 1 (S »6 H) t 5 * 2 0 (S t 2 Η) · 6 5 7 (S» 1 H) f 6 • 8 9 (dd, J = 1 • 1 I 8-2 Η ζ · 1 Η) 7 * 0 2 (d »J = 1 1 Η ζ * 1 Η) 1 7-3 6 — 7. 5 7 cm 1 8 Η)» 7 * 9 5 (dt J = 8 3 ζ ζ »2 Η)« 1 2-9 4 (b S '1 H) t Μ S m / e 3 7 1 (MH +) (• CZS Η 2 2 0 3 * 0 I. 2 5 H 2 0 Value: Calculated value C: 80 .08;: H: 6. 05 Measured value C: 80 .17;: H: 5. 86 This paper size applies to Chinese national standard (CNS > A4 specification (210X297 mm) -187 -A7 B7 V. Description of the invention (185) Example 1 3 8 6-Bromo-3,3-dimethyl-dihydrofluorene-butanone (LXXIV) 〇

Add 3,3-methyl-1-azapine-1-hydrazone (2.00 g, 12, 5 mmol) to aluminum chloride (4. 16 g, 31 2 mmol) * After stirring for 15 minutes * bromine (2.39 g, 15.0 mmol) was slowly added, then the mixture was stirred at 100 ° C for 1 hour, and then the reaction was stopped with ice-water (200 g). Then use Ethyl acetate (40 mL X 3) (please read the precautions on the back before filling out this page) -pack. Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Zhengong Cooperative Cooperative Extraction β Extracts are combined and dried over magnesium sulfate 1 The residue obtained by further evaporation was subjected to flash chromatography C EtOA c: hexane = 1: 20 to 1: 15) and purified to obtain ~ · crude product t was recrystallized from Me OH-EtOAc to obtain 1 · 23 g (41% yield) of the title compound as JnC m colored crystals 〇1 Η — N MR (CDC 1 3) δ 1 4 2 (S »6 Η) t 2. 6 1 (s 2 Η) 1 7 3 9 (d • J = 8 * 2 Η z, 1 Η) 1 7 7 2 (dd 1 J = 2. 0 8. 2 Η Z * 1 Η) 9 7 8 2 (d 1 J =: 2 • OH z ， 1 Η) * Μ S m / e 2 3 9 (Μ Η +) 0 C! α Η X α B r 03 Elemental analysis value: Calculated C: 55.26; H: 4.64 Found C: 55.19: H : 4.61 Binding paper applies Chinese national standard (CNS > Λ4 specification (210X297mm) -188-4) 8 186 A? B7 ~ ^ ^ --- V. Description of the invention (186) Example 1 3 9 methyl 4- [2- (1, budimethyl-3-one-dihydrofluoren-5-yl) vinyl] benzoate (LXXVa)

At 80-100 eC, 6-bromo-3,3-dimethyl-dihydrofluoran-1-one (1.20 g, 5.02 mmol), 4-ethylethylbenzoate methyl ester (1.63 g, 10.0 mmol) , Acetic acid (56 mg, 0.25 mmol), vaporized tetrabutylammonium hydrate (1.53 g, 5.52 nmol) and sodium bicarbonate (1.05 g, 12.6 mmol) in 10 mL of anhydrous Ν, Ν-dimethyl Stir in formamidine for 8 hours. Then dilute the mixture with water (100 nL) and extract with dichloromethane (50 raL X 3). * The combined extracts are dried over magnesium sulfate and evaporated. The obtained residue was purified by flash chromatography (CH2C12: hexane = 1:] to 1: 0, then CH2CU: EtOAc * 10: 1) and purified (please read the precautions on the back before filling this page)- Binding and binding. Printed by the Consumer Cooperatives of the Central Bureau of Standards and Commerce of the Ministry of Economic Affairs ^ 12 8 (70% yield) The title compound as a yellow solid · Η-NM MR (CDC 1 3: δ 1. 4 5 (s »6 H) »2 * 6 4 (st 2 Η 5. .3 0 (s * 3 H) f 7 .1 8 (d J-1 6 • 5 Η ζ 1 Η), 7. 2 6 (d J 1 6 * 5 Η ζ 1 Η), 7. 5 2 (d J nr 8-1 Η ζ y 1 Η) t 7 .5 8 (d * J = 8 5 Η ζ * 2 Η) f This paper size is applicable to Chinese countries 榡Standard (CNS) Λ4 specification (2IOX297 mm > 189 A7 A7 Printed by the Industrial and Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs _____ B7 V. Description of the invention (187) 7. 7 8 (d * J = 1. 7 »8 1 H z, 1 H) 7 .8 6 (d · J = .7 H z '1 H),. 8 .0 5 (d, J = 8 .5 HZ', 2 H); MS m / e 3 2 1 (MH +) • C 21H 2. Elemental analysis value of 〇3: Calculated C: 78. 18; H: Μ Measured C: 78, 22: Η : 6. 26 Example 1 4 0 [2- [1,1-Dimethyl-3- (tricyanomethanesulfonyloxy-5-yl] ethenyl] benzoate methyl ester 0

Trifluoromethanesulfonic anhydride (434 mg, 1.54 mmol) was added to a solution containing 4- [2- (1, budimethyl-3-one-dihydrofluoren-5-yl) ethylene at -78 ° C. Methyl] benzoate (450 mg, 1.40 ΠΜΠΟ 1), 2, 6-di-tert-butyl-4 -methyl Hit steep (345 mg, 1.68 mmol) and 5 mL dichloromethane solution . After stirring at room temperature for 16 hours, the mixture was diluted with 1 N HC1 (20 mL) • Re-extracted with ether (20 mL X 3) • The combined extracts were dried over magnesium sulfate and evaporated • The resulting residue was layered quickly Analysis & (CH2CU: hexane ~ 1: 2 to 1: 1) and purified to obtain 606 mg (95% of this paper size, using China National Standards (CNS) A4 size (210X297 mm) (read the first (Notes for filling out this page)

-190-Consumption Cooperation with Employees of the Central Bureau of Standards, Ministry of Economic Affairs, Du Yin 4 18 186 at B7 V. Description of the Invention (188) Yield) of the solid title compound O 1 Η — NM R (CD C 1 3) 6 1. 4 1 (S, 6 H) »3. 9 4 (s 3 H 6. 2 7 (S, 1 H) t 7. 1 5 (d * J 1 6 .3 H z 1 H), 7. 2 7 (d, J = 16. 3 H z 1 H), 7. 3 7 (d, J = 8 2 H z * 1 H) f 7.49 and 7.50 ((1 over s · J = 8. 2 Η z, 2 Η), 7. 59 (d, J = 8. 4 Η z-2 Η), 8. 05 (d, J = 8. 4 Η z · 2 Η); MSm / e453 (MH +)-C 22H i0F3ObS Elemental analysis value: Calculated value C: 58.40: Η: 4.23 Measured value C: 58.38; Η: 4.00 Example 141 4_ [2 ~ (l, I -monomethyl-3_phenyl-1Η_εϊ5_5 -yl) -B Burnt-based] methyl benzoate binding line (please read the precautions on the back before filling this page)

At 95 ° C, this paper will contain [2- [1, budimethyl- 3- (trifluoromethanesulfonyl sulfonium oxide). This paper is suitable for the size of the paper_Chinese National Standard (CNS) A4 specification (210X297 mm) ~ -191-Economy Du Yinzheng

A7 B7 V. Description of the invention (189) yl) -1Η- 芘 -5-yl] vinyl] methyl benzoate (590 mg, 1.30 mmol), ginseng (dibenzylideneacetone) dipalladium (0 valence) ( Mixture of 48 mg, 00§ mmol), triphenylhydrazone (64 mg, 0.20 mmol), lithium gasification (166 rag, 3.91 mmol) and phenyltributyltin (525 mg, 1.43 mraol), stir 16 Hours • Dilute the mixture with water (75 mL) and extract with ethyl acetate (20 mL X 2) and ether (20 mL X 2). The combined extracts are dried over magnesium sulfate and evaporated. The obtained residue was purified by flash chromatography (EtOAc: hexane = 1: 25 to 1:10) to give a product, which was recrystallized from EtOAc-hexane to give 311 mg (63% yield) as yellow Title compound as a solid · ^ l-NMR (CDC 13) δ 1. 4 2 (s · 6 H), 3. 93 (s, 3H), 6. 4 5 (s, 1 Η), 7. 1 1 ( d-J = 16 .4 Hz, lH), 7. 2 9 (d · J = 16. 3 H z · 1 H), 7. 4 1-7. 65 (m, 10H), 8. 0 2 (d * J = 8. 4 H z · 2 H) · Example 1 4 2 4- [2-Clt Budimethyl-3-phenyl-1H-fluoren-5-yl) -vinyl] benzoic acid (I33a) COaH

This paper size applies to China® Home Sample Rate (CNS) A4 size (210X297 mm) (Please read the precautions on the back before filling in this page) Packing · Ding,-'° Spicy -192-Central Bureau of Standards, Ministry of Economic Affairs Zhengong Consumption Cooperation Du Yin 4 18 186 A7 B7 _____ ------------------------------------- 5. Description of the invention (〖9〇) will contain 4- [2- ( 1, dimethyl-3-phenyl-1H-I5-5-yl) -vinyl] methylbenzoate 294 mg '0.77 nmol), 0.77 mL 10 ¢ 1 NaOH, 7 mL tetrahydrofuran and 5 mL The methanol solution was stirred for 1 hour under reflux. After the mixture was concentrated, it was acidified with 1N HC1 (10 mL). Then: extracted with ethyl acetate (30 niL * 2). The combined extracts were washed with water (10 aL), dried over magnesium sulfate, and evaporated. The residue was milled in hot methanol to obtain 276 mg (90% yield) of the title compound containing — 'molecular methanol «1 Η — NM MR (D Μ S 0 — d β) 6 1 3 4 (s * 6 H) > 3 • 1 4. (St 3 Η) * 6 5 8 (s * 1 H) »7 2 5 (d * J = 1 6 4 Η ζ I 1 Η) > 7 • 3 7 — 7.7 1 (m »1 1 Η) 1 7 9 0 (d, J = 8 3 Η ζ» 2 Η) τ Μ S (DCI) m / e 3 6 7 (Μ Η +) i > C 2 β Η 2 β 0 3 'C: elemental cable analysis value of H 3 0 H; calculated value C: 81.38; H: 6. 58 found value C: 81.18; H: 6. 78 Example 1 4 3N -(2-Pyridyl) trifluoromethanesulfonamide The paper scale is applicable to Chinese national standards (CNS > A4 Zhuge (210X297 cm)) (Please read the precautions on the back before filling this page) r Pack-Order -Line- -193-4 18 186 A7 B7 V. Description of the invention (m)

cf3 This title compound was prepared according to the procedure described by Comins & Dehghani in Tetrahedron Lett., Vol. 33, No. 42, 1 992, p. 6299 * ^ -NMR (CDC 13): δ 8. 6 6 (m 1 H) * 7. 9 5 (m * 1 H), 7. 5 6 (m * 1 H)-7. 48 (d, lH). MS (DCI) m / e: 359 (MH +). Example 1 4 4 4-[[[[((5, 6-Dihydro-5,5-dimethyl-8-phenyl) -2-some] carbonyl] amino] -2-hydroxybenzoic acid benzene Ester (I3 j) with i cable (please read the notes on the back before filling this page) Page of the Central Bureau of Standards of the Ministry of Economic Affairs

Using the method for preparing 8- (2-fluorophenyl) derivative (I3g), 230 mg (0.83 mmol) of compound (XVlIIa) and 4-aminosalicylic acid phenyl ester (Aldrich, 190 mg, 0.83 mmol) ) 193 ug (Y: 48%) of the title product was prepared. This paper size is applicable to China National Standard (CNS) / M specifications (2IOX297 mm) -194-4 18 idb Λ7 B7 V. Description of the invention (192) ^- NMRCCDCla) δ 8.03 (d, J = 9.3Hz, lH), · 7. 7 5-7. 71 (m, 2H), 7. 5 1-7. 19 (m-1 3 H), 6. 0 9 (t-J = 4.5 Hz, lH), 2. 4 0 (d · J = 4.5 Hz, 2H) '1. 3. 8 (s · 6 H): MS (DCI) m / e: 490 (MH + ) Example 1 4 5 4-[[[[(5,6-dihydro-5,5-dimethyl-8-phenyl) -2-fruityl] carbonyl] amino] -2-hydroxybenzoic acid （L4 j） (Please read the precautions before filling in this page)-installed ', va

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs ^ Using the method for the preparation of 8-phenyl derivatives (14a) with 193 mg (0.39 mmol) of the compound (I3 j) to obtain the title of 135 rag (Y: 83%) product. 1 Η 1 NM R (DM S 0-de): δ 1 1 • 3 3 (bst 1 H) * 1 0. 3 8 (s, 1 H), 7 8 3 (dd-J = 8 0 * 1 7 Hz-1 H), 7. 7 1 (d τ J = 8 7 H z * 1 H) > This paper wave scale is applicable to China National Standard (CNS) Λ4 specification (210X2? 7mm) -195- A7 B7 418186 V. Description of the invention (193) 7 5 4 (d 'J = 8. 〇Ηζ, 1Η) > 7 45-7. 2 9 (m · 7 Η), {Please read the precautions on the back before Fill out this page) 7 24 (dd-J = 8. 7 '1. 8 Η z · 1 Η)' 6. 〇6 (t, J = 4.5 5 Η z · 1 Η), 2 3 5 (d ' J = 4.5 Η z · 2 Η) '1.3. 2 (s · 6 Η): MS (DCI) m / e: 400 (ΜΗ +); IR (KB r): 2960 · 1668 · 1600 · 1 5 0 8 · C 2βΗ 23N i〇4 * 0 · 5H2O The calculated value of the cable analysis value C: 73. 92: Η 5.73; N: 3.32 Measured value C: 73. 91: Η: 5. 73: N: 2 99 Examples 1 4 6 2 -Ga-4-nitrobenzoic acid

The Ministry of Economic Affairs and the Central Government Bureau of Shellfish Consumer Cooperatives printed the solution containing 2-Λ-4 -nitrotoluene (3.95 g, 25.5 mmol * Janssen) and water (200 11L) in batches at 80 " C. Knead acid (24.6 g, 0.15 mmol) treatment · After 2 hours, filter the mixture while hot, acidify with 5N nitric acid and extract with ethyl acetate (2 X 100 nL). • The extract was dried over anhydrous sodium sulfate. It was then concentrated in vacuo to obtain 1.15 g. (This paper is widely used in the standard, and B household standard (CNS > A < Specification (2 丨 0 > &297; 297) *) ^ ': 3 I e-' A7 _______ B7____

Five 'invention description (1 (J 194 γ: 24%) the title compound ·' H-nmR CDMSO-de): δ 8. 2 1 (d · J = 1 0.5 Η ζ, 1 Η), 8. 16-8. Ο 8 (m-2 Η): MS (DCI) m / e: 186 (MH ”《Example 1 4 7 2 ~~ cyano-4 mononitrobenzoate (please read the“ Precautions on the back ” Fill out this page >

V

Ordered by the Ministry of Economic Affairs to order the Central Bureau of Quasi-Bureau Consumer Cooperative to print the absolute ethanol of p-toluenesulfonic acid monohydrate (100rag) with 2-fluoro-4-nitrobenzoic acid (1.15 g, 6.22 mmol) (20 mL) solution. After 16 hours under reflux, the reaction mixture was concentrated in vacuo. The concentrated residue was chromatographed on silica gel (dissolved with 5% ethyl acetate in hexane) to obtain 770 mg ( Y: 58%) ^ -NMR (CDC 13): δ 8. 16-8. 00 Cm · 3 Η) 4. 4 5 (q · J = 7. 1 H z * 2 H), 1.43 (t, J = 7.1Hz, 3H) · MS (DCI) m / e: 214 (MH ". Example 1 4 8 Paper & Standards Application" 国 著 輮 准 （〇 飑 > 厶 4 # 1 cell (2 丨 0 formula 297 mm) -197-A7 B7 V. Description of the invention (195) 2-fluoro-4-aminobenzoic acid ethyl ester

A solution of ethyl 2-fluoro-4-nitrobenzoate (770 mg, 3.6 2 raraol) in methanol (15 mL) was treated with platinum oxide (V value) under H2 at 40 psi. After 0.5 hours, the reaction mixture was filtered with celite and concentrated in vacuo to obtain the title product of 700 mg (Y: 99%) · (Please read the precautions on the back before filling this page) Pack-1 Η — Ν Μ R (CD c 1 3) 1: 5 7. 7 6 (t TJ = 8 3 HZ '1 H)-6. 4 2 (d * J = 8 6 HZ' 1 H)-6. 3 5 (dt J 1 2 9 Hz * 1 H) 4. 3 3 (qf J 7 • 1 H 2 * 2 H), 4.. 2 0 (bs 1 2 H) t 1. 3 6 (t (J = 7 1 HZ, 3 H); MS (DCI) m / e: 184 (MH +)-Consumer Co-operative Society of Indonesia, Central Procurement Bureau, Ministry of Online Economy, Example 1 4 9 4-[[[[(5, 6-Dihydro-5,5 -Dimethyl-8-phenyl) -2-a] carbonyl] amino] -2-fluorobenzoic acid ethyl ester (I3k) This paper size is applicable to China National Sample (CNS) M specifications (2 丨 〇 X297 mm) -198-A7 B7 4 18 186 V. Description of the invention (196)

250 mg (0.90 mmol) of compound (XVIIIa) and ethyl 2-fluoro-4-aminobenzoate (181 rag, 0.99 by the method of preparing 8- (2-fluorophenyl) derivative (I3g) mmol) prepared 240 mg (Y: 60%) of the title product * ^ -NMRCCDCla): δ 7. 9 1 (t >; = 8. 5 Η z · 1 Η), 7. 7 2 (d- J = 1 〇. 1 H z · 1 H), 7. 6 6 (d-J = 1.8 H z · 1 H), 7. 5 1-7. 48 (m * 1 H), 7.4 4- 7. 3 5 (m-6 H), 7. 2 0 (d-J = 8.6 Hz, lH), 6. 0 8 (t-J = 4.5 Hz, lH), 4. 3 7 (q · J = 7. 1 H z-2 H) · 2. 4 0 (d · J = 4.5 H Z > 2 H), 1. 3 8 (t-J = 7. 1 H z 3 H), 1. 3 7 (s, 6 H); MS (DCI) m / e: 444 (MH +) · Example 1 5 0 This paper applies China's 81% rate (€ yang) 戍 4 size (2 丨 0 parent) 297 mm) (Please read the notes on the back before filling this page)

IV Ordered by the Ministry of Economic Affairs and the Central Government Bureau Zhengong Consumer Cooperative Cooperative Association »-199-d 丨 'π A7 B7 V. Description of the Invention (197) 4-[[[[(5, 6-Dihydro-5, 5- 二Methyl-8-phenyl) -2-fluorenyl] carbonyl] amino] -2-fluorobenzoic acid (I4k).

Using the method for preparing an 8-phenyl derivative (I4a), 240 rag (0.54 mmol) of the compound (I3k) was prepared to obtain 175 mg (Y: 78%) of the title compound. (Please read the precautions on the back before filling out this page). Equipment. 1 Η — NM MR (DMD 0 — de): < 5 1 2 .9 8 (bst 1 H) * 1 0 .5 8 (s »1 H) 9 7. 8 9-7. 7 7 (m 2 Η), 7. 7 3 (d, j = 1.5 H z -1 H), 7. 5 4 (d * j = 8. 1 H z, 1 H), 4 4-7. 3 0 (m * 7 Η), printed by the consumer cooperation of the Central Bureau of Standards of the Ministry of Line Economy 6 0 6 (tf J = 4-5 H z 1 1 H) * 2 3 4 (d 1 J = 4 • 5 H zt 2 H) t 1 3 1 cs 9 6 H) 0 S (DCI) m / e * 4 1 6 (MH +) 1 »R (KB r) 2 9 6 0 * 1 6 9 2 * 1 5 9 6 5 2 6 e 2 Θ H 2 2 N 1 0 1 3 F 1 ， -0. 2 5 H 2 0 Elemental analysis value This paper standard applies Chinese national standard ( CNS > Α4 specification (2Ι0 × 297mm) -200-Zhong Jibu Central Government, Zhunji employees, cooperative cooperative seal »4 18 18 6 a? _B7_ V. Description of the invention (1QR) 1 ϊί 0 Calculated value C: 74.3 6: Η: 5.40: Ν: 3.34 found C 7 4. 1 6; H: 5. 74: Ν: 3. i 3 Example 1 5 1 N- (4-methyl-3-nitro-phenyl) ethyl Amidine

A solution of 4-methyl-3-nitroaniline (3.60 g, 23.7 mmol) in acetic anhydride (28 inL) was stirred at room temperature. After 16 hours, the reaction mixture was concentrated in vacuo. • Diluted with ethyl acetate (25 mL). * Washed with saturated sodium bicarbonate (2 X 50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 4.20 g (Y: 99%) of the title compound * ^ -NMR (CDC 13): δ 8.10 ( d, J = l. 7 Η z · 1 Η), 7. T 5 (dd-J = 8. 5 * 1. 7 H z 1 H), 7. 3 8 (bs · 1 H)-7. 2 9 C d * J = 8.5 Hz, lH), 2. 5 6 (s 3 H) · 2. 2 1 (s-3 H); MS (DCI) m / e: 195 (MH +) · Example 1 5 '2 4-Ethylamido-2-nitrobenzoic acid Standard for domestic paper #CNS 戍 4 gauge < Grid (210X297 mm) ~ -201------- ---- <-(Please read the notes on the back before filling out this page)-Order 418186 A7 87 V. Description of Invention (199

At the temperature of 80eC, Neem, the Shellfish Consumer Cooperative of the Central Bureau of Quasi-Ministry of Economic Affairs, will contain N- (4-methyl-3-nitro-phenyl) acetamide (4.20 g '23.6 ramol) and water (200 nL). The solution was treated with potassium permanganate (22.77 g, 0.144 nmol) in batches. After 2 hours, the mixture was heated while hot, acidified with 5N hydrochloric acid, and extracted with ethyl acetate (2 X 100 bL). After drying with anhydrous sodium sulfate, vacuum shrinkage was performed to obtain 1.80 g (Y: 34%) of the title compound. ^ -NMRCCDCla) δ 10. 6 3 (s · 1 Η) * 8. 19 (d »J = 1. 7Ηζ · 1Η) · 7.85 (d, J = 8.5 5 Η ζ * 1 Η), 7. 7 8 (dd, J = 8.5, 1.7Hz, 1H) · 2.1〇 (s, 3H): MS (DCI ) m / e: 225 (MH +) · Example 1 5 3 Ethyl 4-amino-2-nitrobenzoate

This paper is for paper and scales. The middle and top samples (CNS > A4 * t grid (ZI0X297)) I 1 I!-I-—I In n ^----^^ 1 I--. ^ ϋ t ^ i (Please read the notes on the back before filling in the next page) 202-

f. A. 0? Ci ο A7 B7 V. Description of the invention (200) It will contain 4-ethylamidoamino-2-nitrobenzoic acid (1.80 g, 8. 0 mmol) 12 N hydrochloric acid (14 m L) and absolute ethanol (10 m L.) solution was heated to 90 -1 0 0 ec for 5 hours * then concentrated under vacuum to remove only ethanol V adjust the pH to 4 with sodium hydroxide IN The precipitate was filtered off to give 140 mg (Y: 8%) of the title compound 0 1 Η -NM (CD C 1 3): δ 7 * 6 1 (d • .J = 8. 5 Η ζ, 1 Η ) · 6 8 2 (d • J = 2. 1 Η ζ »1 Η) · 6 * 7 4 (dd, J = 8 • 5, 2 • 1 Hz _] L Η), 6 • 5 2 (bs · 2 Η) > 4 • 1 7 (a • J = 7. 1 Η ζ, 2 Η) * 1 2 1 (t • J = 7. 1 Η ζ »3 Η); M S (DCI) m / e : 2 1 1 (Μ Η + '> · Example 1 5 4 4- [[[((5, 6-Dihydro-5,5 -dimethyl-8-phenyl)-2-fluorenyl] carbonyl ] Amino] -Ethyl 2-nitrobenzoate (131) (Please read the precautions before completing this page) r. Order

Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Bei Gong Xiao F Cooperative, using the method for preparing 8- (2-fluorophenyl) derivatives (I3g) with 199 M (0.Ή mraol) of compound (XVIIIa) and 140 mg (0.78 mmol) ) This paper size applies to China's national standard (CNS > Λ4 specification (210 × 2ίΠmm) -203-Duty and consumer cooperation of Central Standards Bureau of the Ministry of Economic Affairs Du Yinsu Λ7 B7 V. Description of the invention (201) 4-amino-2-nitrate Preparation of ethyl benzoate to give 155 ing (Y: 46%) of the title product. ^ H-NMR (CDC 13) ·· δ 8. 1 5 (s-1 Η) · 7.84 (s, 1H) , 7. 7 9 (s-1 Η) · 7. 7 3 (dd · J = 8. 1-1.. 9 H z-1 H), 7. 52-7. 49 (m * 2H), 7. 4 1-7. 2 6 (m · 5 H), 6. 09 (t, J = 4.5 Hz > 1 H), 4. 3 6 (q · J = 7. 2Hz, 2H), 2 4 0 (d * J = 4.5 Hz · 2 H), 1. 3 7 (s, 6 H), 1. 3 4 (t-J = 7.2 Hz, 3H); MS (DCI) m / e: 471 (MH +) * Example 1 5 5 4 _ [[[((5, 6--Ga-5, 5--methyl-8-phenyl) -2 -stripyl] trisyl] amine] ] -2-Nitrobenzoic acid ()

Use the method of preparing 8-phenyl derivative (l4a) to apply 155 mg (0.33 paper) to the standard of the middle and poor countries (CNS) (210 X 297 cm) (Please read the precautions on the back before filling (This page)

'1T -204-4 18 ί 8 d A7 B7 V. Compound (131) of the description of the invention (202) mmol) to prepare 105 mg (Y: 72%) of the title compound ".. — NM R (DMS 0 — de): δ 1 3 6 5 (bs «1 H)» 1 0 7 6 (s 1 1 H) T 8 3 1 (dt J = 1 7 HZ > 1 H) * 7 9 9 (dd 1 J 8 • 3 ♦ · 1 Ten 7 HZ 7 9 0 — 7 Middle 8 4 (m * 2 H) t 7 5 5 (d * J = 8 3 H z 1 H) «7 4 7 (d 1 J = 1 • 7 H z »1 H) f 7 4 4 — 7 3 0 (m 1 5 H)» 6 0 7 (t »J = 4 * 5 H z» 1 H) »2 3 3 (d» J = 4 -5 H z 2 H) f 1 3 1 (s 6 H) »S (DCI) m / e: 4 4 3 (MH +) R (κ B r): 2 9 6 0 1 7 0 2« 1 5 (Please read the notes on the back before filling this page).

, 1T Printed by the Central Procurement Bureau of the Ministry of Economic Affairs, Consumer Cooperatives, 15 18 · C 2βΗ 22N 2 0 5 * 〇 5H2〇 Elemental analysis value: Calculated value C: 69.17: Η: 5.14: Ν: 6, 20 Measured value C: 69.55: hydrazone: 4.93: Ν: 5.94 Example 1 5 6 4-[[[[(5, 6-Dihydro-5, 5-dimethyl-8-phenyl) -2-fruityl] carbonyl ] Aminyl methyl 2-methoxybenzoate (I3m) This paper size applies to Chinese National Standards (CNS) Λ4 present grid (2Ι0 × 297 mm) -205-Central Laboratories Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives, India Α7 Β7 5. Description of the invention (2Q3)

Using the method for preparing 8- (2-fluorophenyl) derivative (I3g), 415 mg (1.49 mmol) of compound (XVI I la) and 297 mg (1.64 mmol) of 4-amino-2- Methyl methoxybenzoate (Apin) was prepared to give 570 mg (Y: 90%) of the title product. ^ -NMR (CDC 13): δ 7. 8 2 (d * j = 8. 5 H z -1 H), 7. 7 7 (d * j 1. 7 H z, 1 H), 7. 7 3 (s, 1 H), 7. 7 0 (d, J = 1. 9 H z, 1 H), 7. 5 1 (m · 1 Η), Ί. 4 8 (s-1 Η), 7, 4 1-7. 3 3 (m · 4 Η) * 6. 8 0 (dd * J = 8.5, 1. 9 H z * 1 H)-6. 0 8 (t · J = 4.5 H z · 1 H)-3. 9 2 (s · 3 H)-3. 8 7 (s 3 H)-2. 3 9 C d-J = 4.5 H z-2 H), 1. 3 8 (s-6 H): MS (DCI) m / e: 442 (MH +) · Example 1 5 7 This paper uses China National Standard (0? > 戍 4 gauge >) (2 丨 0 > < 297 mm > --------- y ------ it ------ T (Please read the notes on the back before filling this page) -205-A7 4 16 186 B7 _ 5. Description of the invention (204) 4-[[[((5, 6-dihydro-5, 5-dimethyl-8-phenyl) -2-fluorenyl] carbonyl] amino]]-2 -Methoxybenzoic acid (Ι4ιπ).

Using the method of preparing 8-phenyl derivative (1Aa) to prepare 135 mg (0.31 mmol) of the compound (I3m) to obtain 100 mg (Y: 77%) of the title compound * (Please read the precautions on the back before filling in this Page) 'Installation' H-NMR (DMSO-de): δ 12. 3 2 (bs * 1 Η) · 10, 3 6 (s-1 Η)-7. 8 5 (dd * J = 8. 1 -1. 7 H z-1 H), 7. 7 9 (s * 1 H), 7. 6 4 (d-J = 1. 7 H z-1 H), 7. 5 3 (d-J = 8. LHz-lH), 7. 4 4-7. 3 0 (m-7 H) · 6. 0 6 (t · J = 4.5 H z-1 H), 3. 7 6 (s, 3 H), 2. 3 4 (d-J = 4.5 Hz, 2H), 1. 3 1 (s * 6 H); MS (DCI) m / e: 428 (MH +); IR (KBr): 2960 * 1718, 1592, This paper size is applicable to China National Standards (CNS) Λ4 specifications (210X297 gong) Ordered by the Central Standards Bureau of the Ministry of Economic Affairs, printed by Fong Cooperative -207-/]. ≫ R 1 〇 · Λ7 Β7 5 Description of the invention (205) 1 5 2 4 Elemental analysis value of C27H25Ni〇4 * 0.25H2◦: Calculated value: C: 75.0 7; H: 5.95; N: 3. 24 Actual value! I value: C: 7 5. 0 4; Η: 5.86; Ν: 3 04 Example 1 5 8 4-[[[[(5,6_— gas_5,5 · —methyl-8_ (2-bar)]-2 -naphthyl] yiyl] amino] benzoic acid (Ι4η ) (Please read the precautions before filling this page) -Pack. &Quot; 5 Start with compound (XVIa) * The title was prepared by a similar method to the preparation of 8- (2-fluorophenyl) derivative (I4g) Compound * Industrial Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, India — NM R (DMS 0 — d Θ) δ 1 2. 6 9 (s * 1 H) 1 0.4 .1 (s * 1 H), 7. 9 5 — 7 * 8 8 (m 1 5 H)-7 • 8 5 (d »J = 8-7 H z -2 H), 7 .7 7 (d > J = 8 7 H z, 2 H ), 7 .5 7 — 7 4 0 (m »5 H)-6 .2 0 (t > J = 4 * 5 H z, 1 H) 2. 4 0 (d * J = 4 • 5 H z , 2 H), 1.3 5 (s, 6 H);

The size of this paper is applicable to the Chinese National Standards (CNS) A4 (210 X 297 mm) -208-18 ί 6〇Α7 Β7 V. Description of the invention (206) MS (DC I) m / e 448 (MH +) : IR (KBr): 2960-1686-1596-. 15 18. Elemental analysis value for C3 () H25O3Ni-0. 9 0H2◦: Calculated C: 77.7 0: Η: 5.83; Ν: 3. 02 Measured value C: 78.10; Η: 5.55: Ν: 3. 13 Example 1 5 94-[[(5, 6-dihydro-8-phenyl-2-some) carbonyl] amino] benzoic acid (Ι4ο (Please read the precautions on the back before filling this page)

-Φ Yinju, an employee consumer cooperative of the Bureau of Intermediate Standards Bureau of the Ministry of Economic Affairs, started with 6-methylaminohydroxanthone * The title compound was prepared in a similar manner to the preparation of 8- (2-fluorophenyl) derivatives (I 4g). 1 Η — N Μ R c DMS 0-de) δ 12 7 3 cs 1 1 H) »1 0 in 4 2 (S, 1 Η), 7.9 1 — 7 8 1 (m * 5 Η) * 7 5 5 — 7 * 2 5 (m * 7 Η)% 6. 1 8 (t J = 4 5 H ζ I 1 Η) »2. 8 6 (t» J = 7 6 H ζ 1 2 Η) try 2. 4 1 — 2 3 4 (m »2 Η)» MS (DCI) m / e; 3 7 0 (Μ Η +) I) IR (K Β r): 2 9 5 0 1 6 8 0 ♦ 1 6 4 8 ， This paper size is applicable to the standard of China Jiajia Ladder (CNS) Λ4 (210 × 297 mm) -209-A7 _____B7_ V. Description of the invention (207) 1 5 1 8 * C ieN: 0a elemental analysis value: v Calculated value C: 78.03; Η: 5. 18; N: 3.79 Measured value C: 77.61; Η: 5. 1 4; Ν: 3. 81 Example 1 6 0 4- [[(5 , 6-Dihydro-5, 5-dimethyl-8-phenyl-2-some) carbonyl] amino] -3-fluorobenzoic acid methyl ester (Ι3ρ)

320 mg was prepared from compound (XVI I la) (300 mg) and methyl 3-fluoro-4-aminobenzoate (245 mg) by the method of preparing 8- (2-fluorophenyl) derivative (I3g). (Y: 69%) The title compound as a glass block. --------- Equipment ------ ΐτ ------. ^ (Please read the precautions on the back before filling in this page) Η—N MR (CDC] 3): δ 1. 3. 8 CS ψ 6 H) »2. 4 0 (d * J ss 4.7 HZ '2 H), 3. 9 0 (s» 3 H ) > 6. 0 8 (t »J = 4. 7 HZ f 1 H), 7. 3 2 — 7 * 4 2 (m ♦ 5 H) f 7. 4 9 (d 1 J = 8. 0 HZ 1 1 H), 7. 5 6 (d J = 1. 9 H z * 1 H), this paper size uses China National Standards (CNS) A4 grid (210 X deduction 7 mm) -210-4 18 186 A7 B7 V. Description of the invention (208) 7. 7 3 (d, J = 1 9 8 0 H zy 1 H) 1 7.7.7 4 (d, J = 1 8 try 1 1 5 H z, 1 H ) · 7 4 (dd, J = 1 8 »8 5 H z, 1 H), 8. 1 1 (bd 'J = 3 8 H z 1 1 H), 8. 5 5 (t, J = 8 5 H z 1 1 H) 0 Example 1 6 14 _ [[(5, 6 ~-· M-5, 5--methyl-8-phenyl-2-baryl) -type group] amino]- 3_fluorobenzoic acid (ΙΑρ)

Yin Ce, the Central Working Group of the Ministry of Economic Affairs, Zhenggong Consumer Cooperative, used the same method to prepare 8-phenyl derivative (I4a) with 310 mg of compound (〗 3p) to obtain 170 mg (54% yield) of the title compound 9 ^ -NMR (CDC 13) < 5 1. 2 3 (s, 6 Η), 2. 3 9 (d-J = 4. 7 Η z · 2 Η), 6. 〇 7 (t-J = 4. 7 Η z * 1 Η), 7. 3 0-7. 4 2 (m · 5 Η)-7. 4 9 (d · J = = 8. 1 H z, 1 H), 7. 5 2 (d , J = = 2. 0 H z * 1 H), 7. 7 2 (d »J = = 2. 0» 8. 1 H z, 1 H) This paper size is applicable to China National Standard (CNS) A4 (21 OX 2SI7mm) Please read the gutter t first and then fill out this page) -211-^ ^ 3 j β 6 Α7 __Β7 V. Description of the invention (209) 7. 7 9 (d »J = 1 .8 »1 1 • 4 H z · 1 H) 7 .9 0 (d 1 J = 8 .5 H z V 1 H) 8 .0 6 (bd VJ = 2. 4 H z 1 1 H)- 8 .5 9 (t »J = 8.6 H zt 1 H) S m / e 4 1 6 (MH +) '9 C2eH22F Ν 03 Elemental analysis value: Calculated C: 75.17; H: 5.34: N: 3.37 Measured value C: 74.9 6; Η: 5.53: Ν: 3.33 Example 1 6 2 4 -[[(5, 6-Dihydro-5,5-dimethyl-8-phenyl-2-fluorenyl) carbonyl] amino] methyl 3-methylbenzoate (I3q) (please first M (Read the notes on the back and fill out this page).

, 1T

The Central Standards Bureau of the Ministry of Economic Affairs of the People ’s Republic of China ’s Consumer Cooperatives uses the method of preparing 8- (2-fluorophenyl) derivatives (I3g) with compounds (XV III a) (300 mg) and 3-methyl-4-amino groups. Preparation of methyl benzoate (319 mg) yielded 305 mg (69% yield) of the title compound as a glass block. O'H-NMR (CDC 13) δ 1. 3 9 (s · 6 Η), 2.2 〇 (s-3 Η), this paper is fully applicable to the Chinese National Standard (CNS > grid (2t〇x297 mm) -212-4 18 186 A7 B7 V. Description of the invention (21〇) 2. 41 (d , J = 4. 7 Η z-2 Η), 3. 8 9 (s > 3 Η) *, 6. 0 9 (t-J = 4. 7 H z · 1 H)-7. 30 — 7 45 (m, 5H) * 7. 4 8 (d-J = 2. OHz'lH), 7. 5 1 (d-J = 8. 0 H z-1 H), 7. 6 8 (s · 1 H) * 7. 7 9 (d-J = 2. 0 * 8. 0 H z > 1 H), 7. 8 5 (s · 1 H), 7. 9 1 (dd · J = 2. 0 > 8. 5 H z · 1 H), 8. 3 1 (d · J = 8. 5 H z-1 H); MSm / e426 (MH +) * C28H27N03.〇. 12 5HaO elemental analysis value: Calculated value C: 78. 6 1; Η: 6. 42; N: 3. 27. Measured value C: 78.51; Η: 6.46; N: 3.26. Example 1 6 3 --------- 1 ------ IT ------. ^ (Please read the precautions on the back before filling out this page) Employees of the Central Procurement Bureau of the Ministry of Economic Affairs Cooperative printed 4-[[(5, 6 -—nitrogen-5, 5-—methyl-8 -phenyl-2-baryl) mineral] amino] -3-methylbenzoic acid (I4q)

This paper size is applicable to China Gujia Ladder Standard (CNS) A4 (2 丨 0X297mm) -213-A7

4 UU B7 V. Description of the invention (211) Using the same method to prepare 8-phenyl derivative (14a), 280 mg of compound (I3Q) was used to obtain 223 mg (82% yield) of the titled Ministry of Economy and Sound Ministry of Economy. Printed by the Consumer Standards Cooperative of the Central Bureau of Standards-NM (CDC 1 3): δ 1. 3 7 (sf 6 H) ♦ 2 2 0 (s, 3 H) • 2. 3 9 (d J = 4 * 7 H z 1 2 H), 6. 0 7 (t 1 J r = 4 * 7 H z T 1 H), 7. 3 0 — 7 * 4 2 (m 5 H) V 7. 4 5 (d % J = 2 • 0 H z 1 1 H), 7. 5 1 C di J = 8 * 1 H z »1 H), 7. 6 8 (s V 1 H) 7. 7 8 (d TJ = 2 • 0 t 8 • 1 H z, 1 H), 7. 8 0 (s • 1 H) »7. 9 6 (dd • J = 1 • 9 * 8 • 6 Hz * 1 H) 8. 3 6 ( d »J = 8 • 6 H zf 1 H): S m / e 4 1 2 (MH +) < C27H25N 03 elemental analysis value: (Please read the precautions on the back before filling this page) Calculated value C: 78.81: H: 6.12: N: 3.40 Measured value C: 78.6 8: Η: 6.12: Ν: 3. 40 The rhino mouse studied the compound of formula (I) Several compounds are represented in the test, and their effects on the shrinkage of money and prostate sacs are tested 'and compared directly with all-trans retinoic acid. ”_ This paper size applies to China ’s B standards (CNS > A4 specifications (2 丨 0 > < 297 mm > -214-4 18 186 A7 B7__ V. Description of the invention (212) Analysis of reduction of prostate gall bladder in gold iridium (please read the precautions on the back before filling this page) Selling (Bristol-Myers Squibb) breeding area! (Colony) 6- to 9-week-old female hairless money rats (hr rh / hr) were raised. • Test retinoids (in ethanol vehicle (5 0 u 芡) li) applied to the d'orsal area (about 1.5 x 3 cm ζ) of the money rat • applied once a day for five days (from Monday to Friday) • for various For retinoids • A dose response was obtained at a concentration from 0.0033 mM to 16.5 mM • The money rat was killed by inhaling C0 2 on the next Monday • By the central dorsal side of each money rat A full thickness thrashing sample (fu 11 thicknesspunch) of 7/8 ^ * in 0.5% acetic acid After overnight incubation at 4 eC, the Ministry of Economic Affairs, Ning Yang, led the rate of the shellfish consumer cooperatives. • The epidermis inspected by the living body was removed from the dermis * and the separated epidermis was fixed in formalin. • Acetate is dehydrated * and cleared in xylene * In order to determine the diameter of the prostate gall, various epidermis are placed on glass slides in xylene · For each specimen • With the image analysis system (I Β Μ PC, I nage M easure program and a 0 1 y η pus microscope with a camera to measure the diameter of 40 prostate sacs • The percentage reduction of prostate gland (% utriculi reduction) is calculated as follows: -;-) X 100¾ The diameter of the prostate capsule in the acetic acid control group. Fit paper i4 with f 3 sleep & (CNS > A4 * t grid (2 丨 0X297 male)) * '~~~ -215 -Printed by the Chinese Ministry of Economic Affairs, the Zhuhai Pui Gong Consumer Cooperative S-^ ___ 136 A7 _____B7________ V. Description of the Invention (213) Since the maximum effect of this analysis is about 60% of the prostate ^ Shrinkage rate 1 is therefore shown in Table 1 as E D30 value lists the activity of each test compound D3. It refers to the degree of dysplasia (half of the maximum value) of 30% of the prostate capsule. Table 1 Compound 1 ED3〇CfllM) "a 1.25 I4d 0.931 I4e 0.123 I4f 0.038 I3 ° a 2.35 I33a 0. 86 I 4k 3.12- ------) inside ------ order ------ W {Please read the notes on the back before filling this page) —216-1 The following compounds are not active in this money mouse model (Not active): The scale of the cover sheet is applicable to the ten "National Engagement Rate (Renyang)" 4 rules > grid (2 丨 0 father 297 male 1) A7

4 i 8 ^ c G ___B7 V. Description of the invention (214) I 2 c, I 1 ° a, I 11 a, I 16 a, I 31 a, I 32 a 'I 4 P and I 4 0 I i — ^ ^ 1 I ^^ 1 ^^ 1 H ― n In ^^ 1-----(Please read the notes on the back before filling out this page) The following biological tests show that the compounds of the present invention are generally related to retinoids Cytotoxic activity • Therefore, one aspect of the present invention also provides a method for treating various tumors. The results of cytotoxicity analysis are based on the National Cancer Institute (DA S cudierc et al. * E va 1 uati ο η ofa S ο 1 ub 1 e

Tetrazo1ium / Formazan Assay for Cell Growth and

Drug Sensitivity in Culture Using Human and Other

Tumor Cell Linesr, Cancer Research, 48, 4827- 4 8 3 3, S p t e m b e r 1, 1 9 8 8; M · C. A 1 1 e y, et al. *

Feasibility of Drug Screening with Panels of

Human Tumor Cell Lines Using a Microculture

Tetrazo 1 i um Assay * ", Cancer Research, 4 8, 5 8 9-6 0 1,

February 1, 1 988), but a new survival stain alamarBLUETM & was used to measure the viability of the printed cells of the Consumer Cooperative of the China Standards Bureau of the Ministry of Fine Economy. In short, this analysis Involving plating of 1,000 cells in a volume of 120 L for each well in a 96-well flat corning on the first day. After 24 hours, the formula ( I) 30 # L of a suitable dilution of the compound was added (final volume 150 / iL). Seal with a plate of cells (

(Dynatech Labs) sealed the cell layer to prevent evaporation • Removed on day 5_11 ^ 131: membrane • Add 15 liters of sterile alamarBlue to each well (2 丨 Ο X 297 公 漦) -217-_87_ _87_ A7 4 18 1 86 V. Description of the invention (215) and let the cells stand for 2 hours at 37 ° C, 5% C02. The plate reader measures the optical density of each well and deducts ODS70 from ODeoo. 100% signals are measured on cells grown in complete medium containing only 0.5% DMS 0, and each well is measured three times before The average value is shown in Figure 1, Figure 2 and Figure 3 圊 The IC 50 values measured for the second experiment are listed in Table 2. -------------- ΐτ-- ---- ^ (Please read the precautions on the back before filling in this page). ¾ Printed by the Pei Gong Consumer Cooperative of the Central Samples Bureau of the Ministry of Economic Affairs «. Sheets and paper sizes are used in the middle country 5N * quasi (CNS) A4« Ufr (210X297 mm) -218-M Ministry of Economic Affairs, China Standards Bureau, Shellfish Consumer Cooperatives, A7 B7 V. Description of Invention (216) Table 2 L2987 1C 5 of the second experiment. Value compound IC 5〇 (/ £ M) Gold trans Retic acid 6 8 I 4 a 5 1 I 1 ° a 4 7 I 4g 3 8 I 4 d 2 8 I 30 a 6 0 I 2β a 4 8 I i 2 a > 10 0 I 8 a 2 8 --- ------- One long ------ π ------ y (Please read the notes on the back before filling out this page) This paper scales claws Chinese sleepy vector sound rate (CNS > A4 is now (210X297 mm) -219-Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs ^ A7 _____B7 _V. Description of the invention (217) Anti-arthritis test Classical animal model for compound I # a for rheumatic joints The assessment of inflammation, that is, the collagen induced arthritis (CIA) model described by Trentham et al. In Collagen arthritis as a relevant model of rheumatoid arthritis. For positive and negative evidence, please refer to Arthritis Rheum 25: 911-916 ( 1982); Antoimmuity to type E collagen: an experimental model of arthritis · J. Exp. Med 146: 857-868 (1977) Type E collagen (in Freund intact adjuvant) three days ago. A second collagen injection was administered on the 7th day. • About the 30th day, the animals will begin to show symptoms of arthritis, such as joint swelling. * The volume will be administered intraperitoneally (i. P.) lOm per day ^ / kg concentration of 10mg / kg and 30mg / kg of the compound I # a 'Three cases (swelling, joint deformation and joint adhesion) were visually scored daily to determine the onset of symptoms (see Figure 4) • Animals were killed at the end of the experimental period (day 70) to assess joint changes in group cuts * These changes were graded, 1 for synovial hypertrophy * 2 for arthral erosion to cartilage * 3 for arthral erosion To the bone, 4 represents the loss of joint integrity. As shown in Figure 4 * The average clinical score of each animal remained normal by about 30 days. A linear increase to approximately 2.5 (up to 4.0), showing that arthritis is well established in these animals. By comparison * Animals treated with compound I # a had average clinical scores during the same period of the segment There is a significant ft scale on the bottom of the paper, which is used in the difficult countries 1st ladder standard (CNS) A4 gauge nose (210 X297 )--I ·---— n ^ p. ^ 1 ^ 1 n ^ — man —, eaJ (Please read the note on the back before filling this page) -220-4 18) 86 A7 Ministry of Economy Printed by the Central Bureau of Standardization, Bei Gong Xiao F Cooperative — B7 V. Description of the invention (218) The average score was 0.6 on day 65, and a few animals showed joint swelling (level 1). Clinical Symptoms. And most of Ling's limbs are normal in appearance. * The preliminary data of this model (30 mg / kg) show that there is no disease at the appearance and omics level. Compounds of formula (I) can be local or systemic. Use as an anticancer agent and treatment | Improve or prevent retinopathy with retinoid and other retinoids · In this regard, it can be used in animals (including humans) to treat pre-malignant epithelial damage | Prevent tumor expansion of epithelial cells (Promotion) and treatment of skin diseases such as ichthyosis, hair follicle disease, benign epithelial disease, and other proliferative skin diseases (non-malignant skin lesions characterized by epidermal cell proliferation or incomplete cell differentiation) such as acne, psoriasis, wetness Rash, atopic dermatitis, Non-specific dermatitis and similar diseases • Compounds of formula (I) can also be used to reverse and prevent the effects of radiation damage on skin patients • Compounds of formula (I) can also be used to treat rheumatic diseases, including (but not limited to) rheumatism Arthritis • Psoriasis arthropathy, Reiter's disease and cutaneous erythema erythematosus. Compounds of formula (I) also have uses in the treatment of chronic multiple degenerative arthropathy (〇ste 〇arthritis) * If used for the above-mentioned therapeutic uses • they can generally be formulated with pharmaceutically acceptable liquid * semi-sleepy or solid carriers, pharmaceutical An acceptable carrier is a substance that is non-toxic and usually inert without adversely affecting the function of the active ingredient. Such substances are well known • Including substances known as diluents or carriers (excipients) in the field of medical preparation technology • Carriers of organic or inorganic nature can be formulated with the compounds of formula (I) Examples of acceptable carriers (Please read the precautions on the back before filling in this page)

This paper is scaled for use in China's national car (CNS > A4 size (210X297 mm). Printed by A7 B7, Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs. V. Description of the invention (219): water, gelatin, lactose, starch • Emu Oil, Cocoa Butter, Glucose, Sucrose, Glucitol • Mannitol, Gum acacia, Alginate • Cellulose, Talc • Magnesium Stearate, Polyoxyethylene Sorbate Monolaurate and Other Commonly Used Pharmaceutical Carriers • In addition to the compound of formula (I) and the carrier, this formula (composition) can also contain smaller amounts of additives such as flavoring agents, colorants * thickeners or gelling agents, emulsifiers, wetting agents · Buffering agents * stabilizers, and preservatives (such as antioxidants) * As for the formula of the compound of formula (I) and the rules of administration are based on the dosage form, method of administration, details of the condition to be treated and the condition of the patient, Therefore, the optimal therapeutic concentration is best determined through routine experiments and timeliness. * In the treatment of dermatosis, it is generally better to give it topically (although in some cases such as treatment « Cystic acne can also be administered orally.) If the compounds of the present invention are used topically, it can happen that these compounds have excellent activity even when diluted in a considerable range. Especially this (etc. ） The effective compound Ao is in the range of 0.005% reset% to 2% by weight. • Of course, higher concentrations can be used when necessary for special applications. However, the preferred concentration of active ingredients is 0.002 reset%. Reset to 1? 6 · For topical application, compounds of formula (I) can be used as unguents, gels, creams, ointments, powders, dyeing compositions, solutions, suspensions Liquid, emulsion, lotions for external use: sprays, adhesive hardening, and impregnated gaskets, etc. • The compound of the present invention can be stable and non-toxic, and is generally liquid or pasty. it-like (CNS) A4 * t grid (2 丨 0X297 mm) ^^ 1 1--· < ^ 1- ^^ 1 ί ^^ 1 «n«. ^^ 1 ^^ 1 1 ^ 1 .T (Please read the precautions on the back before filling out this page) -222-Central Sample Junma Consumer Cooperative, Ministry of Economic Affairs Packing A7 B7 V. Description of the invention (22 ()), a matrix mixture suitable for topical treatment ca1 scienee (17th edition, Mack Publishing, Inc. Easton, Pa.) * Other ingredients can also be added to this topical formulation for secondary purposes such as treating skin dryness • Provide protection during sun exposure: others for treatment Dermatosis, prevent infection, reduce irritation * Inflammation, etc. The compound of the present invention can also be used enterally Omg, the required dose can be taken once or several times. • Examples of suitable dosage forms for oral administration are tablets * pills, dragees, syrups, suspensions, emulsions, solutions * powders and granules. The method of administration is to use pills containing from 0.1 mg to about 1 mg of an effective substance.

USP 4,876i381, issued by Lang et al. (Issued October 24, 1989) proposes formulas for retinoid compounds that make up gels, broths, powders, creams, etc. This patent can be used as a formula References when using compounds of formula (I) And generalized membrane cling type, and its use is described in Physician's Desk Reference, 4th edition, 1 9 9 3 · Published by Medical Economics Data • Compounds of formula (I) can also be used to treat severe recalcitrant cystic acne or severe Paper uses China National Standard #CNS (CNS) A4 * t (210X297 mm)

In:---II ^^ 1--....... I. (Please read the notes on the back before filling out this page) -223-418186 A7 B7 V. Recalc i trant of the description of the invention (221) Psoriasis. According to this therapeutic use, the compounds of the present invention can be used in a similar manner to isotretinoin and acetinide *. Therefore, this Physicia η's D esk R eference regarding isotretinoin and acetin The Nate part can be used as a convenient guide to eliminate the need for excessive experiments. The compounds of the present invention can also be administered parenterally in the form of a solution or suspension for intravenous, intraperitoneal or intramuscular perfusion or Injection • At this time, the compound of the present invention can usually be administered at a daily weight of about 2 μg to 10 Omg per kilogram body weight. • The preferred method of administration is to use about 0. Oling: to 1mg of effective substance per m β Solutions or suspensions Several types of retinoids have been found to have antitumor properties * see Roberts, AB and Sporn, Μ.B. in 'The Retinoids, ^, Sporn, Μ.B., Roberts, Λ.B. , and Goodman, DS, eds, 1 984, Z. pp. 2 09-286, Academic Press, New York, Lippman, SM, Kessler, JF, and Heyskens, FL, Cancer Treat. Rep., 1987, 2_L, p .391; ibid., P.493 * "antitumor j — word includes chemopreventive (preventive or Tumor expansion) and therapeutic (B therapy) uses • For example, all-trans retinoic acid can be used to treat pre-myeloid leukemia, see Huang, et al ·, Blood, 1988, 12 ., P576 · Isotritinine has been proven to prevent the second primary tumor of squamous cell carcinoma of the head and neck. See also Huang, W.IL et aL ·, Ν. Engl. J. Med. , 1990 323. p795 · Compounds of formula (I) can be treated similarly to retinoids (chemical t (CNS) A4J0Ui · (210X297 ^ *) (please read the note on the back before filling this page)) ·

-Industrial Cooperative Consumption Du Yin, Central Sample Rate of Ministry of Economic Affairs «. -224-

V Α7 Β7 V. Description of the invention (222) Preventive and therapeutic) Use of various tumors • For the compound of the present invention | Antitumor dose to be administered (whether single dose, multiple doses or daily dosage) Of course, it will depend on the type of specific compound used (due to the poteney of the compound), the chosen route of administration, the size of the recipient, the type of tumor, and the nature of the patient's bark condition. Changed * There is no certain limit on the amount of life to be administered *, but it is usually effective: or in terms of Morse viscosity with a free form of physiological activity A considerable amount of physiological effects. Tumor patients who are familiar with the field of cancer treatment technology can detect the effective administration of the compounds of the present invention without undue experimentation by referring to previous research reports on visual pigments such as antitumor properties Appropriate rules for example • For example, when a compound of formula (I) is used to prevent secondary primary sores in squamous cell carcinoma of the head and neck | Oncologists can refer to Hong, WK Studies by N. Engl. J. Med., 1 990, 323, p79 5: For the treatment of acute premyelocytic leukemia, refer to Huang, M. et al. In Blood, 1 988, 72, p567 Research report * --------- Υ ------ tri ----- W (please read the note on the back before filling out this page) Central Government Bureau of the Ministry of Economic Affairs Cooperative printed flUOt 遑 for printing «Home Kneading (CNS > Α4« Λ · (2 丨 0X297 mm) -225-

Claims (1)

6 8 .1ί 8 XI 1.- 4 8 0088 ASSCD, scope of patent application Annex 2a: Bulletin No. 85105756 Patent Chinese Patent Application Amendment Application ^ Amended in January, 1989 1 · —A compound such as formula (I) · or a non-toxic pharmaceutically acceptable salt thereof, R4 Rm I (Please read the notes on the back before filling this page) Order. • Line · Where X is -0-C0-, -N Η -C 0-'-C S-N Η-' -CO-0_,- C 0 -Ν Η-, -COS-, -SCO-, -SCH2_, -CHz'CHz- '-C = C-, -CHz-NH-' -COCHa- '-NHCS-' -CHzS- '-CH2O -'-0CH2-, -NHCH2-, or -CR5 = CRe-: R m and R k are each independently hydrogen, halogen, C i -e alkyl, hydroxyl, (i-alkoxy or nitro; η Is 0 or 1; R4 is y or Ci alkyl: R1 is -C0Z; R2 and R3 are each independently hydrogen or alkyl; "and ^ are each independently hydrogen or L-β alkyl: but when η is 1 At this time, R * and this paper size apply the Chinese national standard < CNS) A4 specification < 210 x 297 public «) c Mi, the scope of patent application Rb can form the base C as follows; Y is a certain group or phenyl group, Phenyl can be optionally substituted with one or two identical Ca-e alkyl or halogen; 2 is hydrogen, Ci-e alkyl or phenyl; and R5 and Re are each independently hydrogen or alkyl. 2. If applied The compound of item 1 in the scope of profit, wherein R1 is a C02H; η is 1; each of R2 and R3 is independently methyl or hydrogen: and each of Re and Rb is independently hydrogen or Ci-e alkyl. 3. If applied The compound in the second item of the patent, which is 4-[[(5, 6-dihydro-5, 5-dimethyl-8-ethyl-2-some) amino] carbonyl] benzoic acid. 4. For example, the compound No. 2 of the scope of patent application * is 4-[[(5,6-dihydro-5,5,8-trimethyl-2-some) amino] carbonyl] benzoic acid. The compound in the scope of patent application No. 2 is 4-[[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-fluorenyl) amino] carbonyl] benzoic acid β 6 For example, the compound in the scope of patent application No. 2 is 4-[[(5, 6-dihydro-5,5-dimethyl-8-ethyl-2-fluorenyl) carbonyl] amino] benzoic acid 7. For example, the compound in the second item of the patent application scope is 4-[[(5,6-dihydro-5,5,8-trimethyl-2-some) carbonyl] amino] benzoic acid. 8. The compound according to item 2 of the scope of patent application, which is 4- (Ε)-[2-(5,6-dihydro-5, 5-dimethyl-8-phenyl-2-fructyl)- 1-Acryl] benzoic acid. This paper size is in accordance with China Standard for Household Standards (CNS) A4 (210 X 297 mm) < Please read the back of the page; I will fill in this page) -Packing) Order:- Line-8 05899 A ^ CD 418186 6. Scope of patent application 9. Scope of patent application Of compound 2, which is 4 - [[(5,6 - dihydro-5, 5-dimethyl-8-phenyl-2-one-yl) oxy] carbonyl] benzoic acid. (Please read the notes on the back before filling this page) 1 〇. If the compound in the scope of patent application No. 2 is 4-[[(5,6-— 气 -5,5--methyl-8- Phenyl-2_Qinyl) anyl] amino] benzoic acid 〇1 1. As the compound in the scope of patent application No. 2 which is 4-[[[5, 6-dihydro-5, 5-dimethyl 8-phenyl-2-fluorenyl) carbonyl] oxy] benzoic acid. 1 2. If the compound in the scope of the patent application No. 2 is 4-[[[[5,6-mono-nitrogen-5, 5--methyl-8- (2-gasbenzyl) -2-¾: Group) coagulo] amino] benzoic acid. 1 3. The compound according to item 2 of the scope of patent application, which is 4-[[((5,6-dihydro-5, 5, 6-trimethyl-8-phenyl-2-fluorenyl) carbonyl] amine Phenyl] benzoic acid. 14. The compound according to item 2 of the scope of patent application, which is 4-[[(5,6--nitrogen-5,5,7-dimethyl-8-phenyl-2-fluorenyl) phile] Amine] benzoic acid. 1 5. The compound according to item 2 of the scope of patent application, which is 4-[[(E)-(5, 6-— fi-5, 5--methyl-8-phenyl) -2-¾¾) Ethylacetate] benzoic acid β 1 6. As the compound in the scope of patent application No. 2, it is 4-[[[((5,6-dihydro-5, 5-dimethyl-8-phenyl) -2 -Fluorenyl] carbonyl] thio] benzoic acid. 17. The compound according to item 2 of the scope of patent application, which is 4-[[[[(5,6-diargon-5,5-dimethyl-8-phenyl) -2-some] thio] Carbonyl] Benzene This paper size is applicable to the national standard (CNS) A4 specification (210 X 297 mm). 6. The scope of the patent application is acid. (Please read the precautions on the back before filling out this page) 1 8 If the compound in the scope of patent application No. 2 is 4 _ [[(5,6-dihydro-5,5-dimethyl-8-phenyl ) -2-fluorenyl) ethyl] benzoic acid "1 9. As the compound in the scope of patent application No. 2 which is 4 _ [[[(5.6- dihydro-5, 5-dimethyl-8-phenyl ) -2-fluorenyl] thiocarbonyl] amino] benzoic acid. 20. The compound according to item 2 of the scope of patent application, which is 4-[[[(5, 6-dihydro-5,5-dimethyl-8-phenyl) -2_fluorenyl] carbonyl] methyl ]benzoic acid. 2 1 · The compound according to item 2 of the scope of patent application, which is 5, 6-dihydro-5, 5-dimethyl-8-phenyl) -2-fluorenyl] methyl] oxy] benzoic acid 2 2 For example, the compound in the scope of patent application No. 2 is 4-[[[((5.6-dihydro-5,5-dimethyl-8-phenyl) -2-a certain group] oxy] methyl] benzoic acid 〇 2 3. If the compound of the scope of application for the second item of the compound, which is 5, 6-dihydro-5, 5-dimethyl-8- (2, 4-dimethylphenyl)]-2- ] Carbonyl] amino] benzoic acid. 2 4. The compound according to item 2 of the scope of patent application • which is 4-[[[[5, 6-dihydro-5, 5-dimethyl-8- (4-methylphenyl)]-2_ A group] carbonyl] amino] benzoic acid. 2 5. The compound according to item 2 of the scope of patent application, which is 4-[[((5,6-dihydro-5, 5-dimethyl-8-phenylb 2-a certain group] ethynyl] benzoic acid 》 2 6. If the compound of item 2 of the scope of patent application is “Compound”, it is 4-[[[(The national standard of B in this paper is applicable to B < CNS > A4 specification (210x 297 mm) _ 4-Is) Range 5, 6-dihydro-5, 5-dimethyl-8-phenyl) -2-A group] thio] methyl] benzoic acid. (Please read the meanings on the back before filling this page) 2 7. The compound according to item 2 of the scope of patent application, which is 4-[[((5,6-dihydro-5, 5-dimethyl-8-phenyl) -2-fluorenyl] methyl] amine Phenyl] benzoic acid 02. The compound according to item 2 of the patent application, which is 4-[[[(5, 6-dihydro-5, 5-dimethyl-8-phenyl) -2- [Amino] amino] thiocarbonyl] benzoic acid. 2 9. The compound according to item 2 of the patent application, which is 4-[[[(5, 6-dihydro-5,5-dimethyl-8-benzene Group) -2-fluorenyl] methyl] thio] benzoic acid. 30. The compound according to item 2 of the patent application, which is 4-[[[(5, 6-dihydro-5,5-di Methyl-8-phenyl) -2-fluorenyl] amino] methyl] benzoic acid. Line · 3 1 . As the compound in the scope of patent application No. 2, it is 4-[[[[(5.6- —nitro-5,5-—methyl-8_phenyl) _2 -baryl] peptidyl] amine] -2 -Branylbenzoic acid. 3 2. The compound according to item 2 of the scope of patent application, which is 4-[[[(5.6- —chloro-5,5-— • methyl-8-benzyl) -2_ Strip-based] mine-based] amino] -2-gas benzoic acid. 3 3 .As the compound of the scope of patent application No. 2 | It is 4-[[[((5,6-dihydro-5, 5-dimethyl) 8-phenyl) -2-fluorenyl] carbonyl] amino] -2-nitrobenzoic acid. 3 4. As the compound in the scope of patent application No. 2, it is 4-[[[(size of this paper Applicable to China S furniture standard (CNS) A4 (210 X 297 mm) -5-A8B8C8D8, patent application scope 5, 6 -dihydro-5, 5 -dimethyl-8-phenyl) -2-棻[]] Carbonyl] amino] -2 -methoxybenzoic acid. 3 5. As the compound in the scope of patent application No. 2, it is 4 ~ [[(5, 6-dihydro-5, 5-dimethyl -8- (2-some)]-2-fruityl] carbonyl] amino] benzoic acid. 3 6 .As the compound in the scope of patent application No. 2 • It is 4-[[(5,6-dihydro -8-phenyl-2-fluorenyl) carbonyl] amino] benzoic acid. 3 7. The compound according to item 2 of the scope of patent application, which is 4-[[((5,6-—nitro-5, 5--methyl-8-phenyl_2 -stryl) phile] amine group ] -3 -Gas benzoic acid. 38. The compound according to item 2 of the scope of patent application, which is 4-[[(5, 6 ~ -nitrogen-5, 5--methyl-8 -phenyl-2 -yl) peptidyl] amino ] -Methylbenzoic acid "3 9. The compound according to item 1 of the scope of patent application, wherein R1 is -C02H; X is a CONH-; R2 and R3 are methyl groups: and Ra and Rb together form a group of the following formula . C 4 ◦. For the compound in the scope of patent application No. 39, it is 4-[[(5, 8, 10, 10a-tetrahydro-10, 10-dimethyl-9-phenyl- 2-M group ) Carbonyl] amino] benzoic acid. 41. The compound according to item 1 of the scope of patent application, wherein R1 is -C02H; η is 0: and R2 and R3 are methyl. -6 I (Please read the notes on the back before filling out this page)-The size of the paper is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) A8 418! §§ D8, patent application scope 4 2 The compound according to item 41 of the scope of patent application, which is 4-[[(1, 1,2-dimethyl-3-phenyl-1H-fluoren-5-yl) amino] carbonyl] benzoic acid. (Please read the notes on the back before filling in this page) 4 3. If the compound in the scope of patent application No. 41, it is 4-[(1,1- —methyl-3 -phenyl-lH-ε 卩_5 -yloxymethyl) Benzoic acid. 4 4. The compound according to item 41 of the scope of patent application, which is 4- [2- (1, budimethyl-3-phenyl-l-fluoren-5-yl) vinyl] benzoic acid. 4 5. The compound according to item 41 of the scope of patent application, which is 4-[(1, 1,2-dimethyl-3-phenyl-1Η-Η-5-carbonyl) amino] benzoic acid. 4 6. — A pharmaceutical composition having retinoid-like activity, which contains the compound as described in the first patent application. This paper size applies to Chinese Standard (CNS) A4 (210 X 297 male «> -7-