TW389760B - Synthesis of 3-[4-(2-aminoethoxy)-benzoyl]-2-aryl-6-hydroxybenzo [b] thiophenes - Google Patents

Description

No. 84105614 Patent Application Chinese Manual Revised Page (February 86) A7 B7

m ± reading member Ming spear

: τ- 'Hostage, printed by Shelley Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs. 5. Description of the Invention (i) The present invention relates to the preparation of 2-aryl-6-hydroxy_3- [4- (2-amine A new chemical method for ethoxy) fluorenyl] benzo [b] fluorene. The synthesis of aromatic ketones is reproduced by Gore in 〇aj ^ Friedel-Crafts and Related Reactions, Volume 3 ,. Part 1, Chapter XXXI (1964). Generally, the fluorenyl component reacts with an aromatic matrix in the presence of a Lewis acid catalyst to produce an aromatic ketone. Suitable Lewis acid catalysts for this type of reaction include metal halides such as aluminum chloride, bromine, aluminum oxide, iron gaseous iron, iron bromide, and boron trifluoride. See Olah, Friedel-Crapts and Related Reactions, Volume 1, Chapters 11, 111 and I V (1 9 6 3). Such compounds prepared by the method of the present invention are first described in U.S. Patent 4,133,814. The patent describes a number of methods for the preparation of such compounds, including the appropriately protected 2-arylphenylhydrazones and the tritiated effects of thiophenes. This patent teaches the use of a phenolic hydroxy group, a benzoyl group, and an alkyl protecting group for the phenolic hydroxyl group. The alkyl protecting group was removed by treatment with a phenol ether with pyridine hydrochloride. The patent also suggests that phenol methyl ether can be cracked by reaction with boron tribromide, which will not affect the 3 · aryl alcohol alkoxy ·, but the yield of the 3 -aryl alcohol alkoxy substituted compound is low. The method described in U.S. Patent No. 4,3 5 8,5 93 uses a particularly advantageous protecting group to prepare 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-aminoethoxy Group) benzylfluorenyl] phenylfluorenyl [b], stilbene. The favorable protecting groups are ethynyl, substituted ethylfluorenyl, benzylfluorenyl, alkylsulfonyl and arylsulfonyl. This patent teaches the use of traditional Friedel-Crafts catalysts in the protection of 2- (4-hydroxyphenyl) -6-hydroxybenzene hydrazone [b], the thiolation of thiophenes, including metal halides, such as aluminum vaporized aluminum , Aluminum bromide, zinc gaseous, boron trifluoride, tribromide shed, four gas (please read the precautions on the back before filling this page) -pack. CNS) A4 Specification (210X2.97 mm) No. 84105614 Patent Application Chinese Specification Revision Sheet (February 86) A7 B7

m ± reading member Ming spear

: τ- 'Hostage, printed by Shelley Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs. 5. Description of the Invention (i) The present invention relates to the preparation of 2-aryl-6-hydroxy_3- [4- (2-amine A new chemical method for ethoxy) fluorenyl] benzo [b] fluorene. The synthesis of aromatic ketones is reproduced by Gore in 〇aj ^ Friedel-Crafts and Related Reactions, Volume 3 ,. Part 1, Chapter XXXI (1964). Generally, the fluorenyl component reacts with an aromatic matrix in the presence of a Lewis acid catalyst to produce an aromatic ketone. Suitable Lewis acid catalysts for this type of reaction include metal halides such as aluminum chloride, bromine, aluminum oxide, iron gaseous iron, iron bromide, and boron trifluoride. See Olah, Friedel-Crapts and Related Reactions, Volume 1, Chapters 11, 111 and I V (1 9 6 3). Such compounds prepared by the method of the present invention are first described in U.S. Patent 4,133,814. The patent describes a number of methods for the preparation of such compounds, including the appropriately protected 2-arylphenylhydrazones and the tritiated effects of thiophenes. This patent teaches the use of a phenolic hydroxy group, a benzoyl group, and an alkyl protecting group for the phenolic hydroxyl group. The alkyl protecting group was removed by treatment with a phenol ether with pyridine hydrochloride. The patent also suggests that phenol methyl ether can be cracked by reaction with boron tribromide, which will not affect the 3 · aryl alcohol alkoxy ·, but the yield of the 3 -aryl alcohol alkoxy substituted compound is low. The method described in U.S. Patent No. 4,3 5 8,5 93 uses a particularly advantageous protecting group to prepare 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-aminoethoxy Group) benzylfluorenyl] phenylfluorenyl [b], stilbene. The favorable protecting groups are ethynyl, substituted ethylfluorenyl, benzylfluorenyl, alkylsulfonyl and arylsulfonyl. This patent teaches the use of traditional Friedel-Crafts catalysts in the protection of 2- (4-hydroxyphenyl) -6-hydroxybenzene hydrazone [b], the thiolation of thiophenes, including metal halides, such as aluminum vaporized aluminum , Aluminum bromide, zinc gaseous, boron trifluoride, tribromide shed, four gas (please read the precautions on the back before filling this page) -pack. CNS) A4 size (210X2.97 mm) Patent Application No. 84105614 printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs

Revised page of Chinese manual (February 86) A-;-B7 V. Description of the invention (2) ϋ ~~~ 充 充 本 // year > Moon 〆 β titanium oxide, titanium tetrabromide, gasification tin, Tin bromide, bismuth trigas and iron gas. After tritiation, the protecting group is generally removed under alkaline conditions. A particularly useful compound in 2-aryl-3- [4- (2 · aminoethoxy) benzylfluorenyl] benzo [b] fluorene is 6 · hydroxy-2- (4-hydroxyphenyl)- 3. · [4- (2, -hexahydroeridinylethoxy) fluorenyl] benzo [b] · »sphene" This compound and its preparation method are first described in US Patent 4,418,068. This compound is a non-steroidal anti-estrogen and can be used for estrogen-dependent pathological symptoms in endocrine target organs. An improved method for synthesizing 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-aminoethoxy) dodecyl] benzo [b] is described in US Patent No. 4,380,635 in. These compounds are prepared by Friedel-Crafts dehydration of di-o-o-fluorenyl-protected benzo [b] pyrene using aluminum chloride as a catalyst. The intermediate tritiated product is demethylated. The tritiated reaction mixture is treated with sulfur compounds such as methanethiol, ethanethiol, diethylsulfide, and methionine. Unfortunately, the reaction product contains many undesired Impurities, which are difficult to remove from phenylhydrazone and thiophene, include (but are not limited to) aluminum salts and various thioester by-products. Moreover, the product has a poor residual thiol or sulfide odor. Boron halides, such as boron trioxide and boron tribromide, can be used to cleave arylmethyl chains. See Bahtt and Kulkami, Synthesis, 249-282 (1 83). Boron tribromide has previously been used to cleave arylmethylphosphonium in phenylpyridine compounds. See German patent DE 4117512 A1. According to the present invention, the applicant has discovered a novel method for preparing 2-aryl-6-hydroxy-3 · [4- (2 · aminoethoxy) pyridyl] benzo [b], a thiophene. The inventive method has several advantages over the prior art methods described in the literature. Book--5 · ____ _ This paper size is in accordance with China National Standard (CNS) A4 (210X297 mm) -------- f --Package ------ Order ----- K-line (Xu Xian «Please read the notes on the back before filling out this page) Patent Application No. 84105614 printed by the Consumer Cooperatives of the Central Bureau of the Ministry of Economic Affairs

Revised page of Chinese manual (February 86) A-;-B7 V. Description of the invention (2) ϋ ~~~ 充 充 本 // year > Moon 〆 β titanium oxide, titanium tetrabromide, gasification tin, Tin bromide, bismuth trigas and iron gas. After tritiation, the protecting group is generally removed under alkaline conditions. A particularly useful compound in 2-aryl-3- [4- (2 · aminoethoxy) benzylfluorenyl] benzo [b] fluorene is 6 · hydroxy-2- (4-hydroxyphenyl)- 3. · [4- (2, -hexahydroeridinylethoxy) fluorenyl] benzo [b] · »sphene" This compound and its preparation method are first described in US Patent 4,418,068. This compound is a non-steroidal anti-estrogen and can be used for estrogen-dependent pathological symptoms in endocrine target organs. An improved method for synthesizing 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-aminoethoxy) dodecyl] benzo [b] is described in US Patent No. 4,380,635 in. These compounds are prepared by Friedel-Crafts dehydration of di-o-o-fluorenyl-protected benzo [b] pyrene using aluminum chloride as a catalyst. The intermediate tritiated product is demethylated. The tritiated reaction mixture is treated with sulfur compounds such as methanethiol, ethanethiol, diethylsulfide, and methionine. Unfortunately, the reaction product contains many undesired Impurities, which are difficult to remove from phenylhydrazone and thiophene, include (but are not limited to) aluminum salts and various thioester by-products. Moreover, the product has a poor residual thiol or sulfide odor. Boron halides, such as boron trioxide and boron tribromide, can be used to cleave arylmethyl chains. See Bahtt and Kulkami, Synthesis, 249-282 (1 83). Boron tribromide has previously been used to cleave arylmethylphosphonium in phenylpyridine compounds. See German patent DE 4117512 A1. According to the present invention, the applicant has discovered a novel method for preparing 2-aryl-6-hydroxy-3 · [4- (2 · aminoethoxy) pyridyl] benzo [b], a thiophene. The inventive method has several advantages over the prior art methods described in the literature. Book--5 · ____ _ This paper size is in accordance with China National Standard (CNS) A4 (210X297 mm) -------- f --Package ------ Order ----- K-line (Xu Xian «Read the notes on the back side and fill in this page) Chinese Explanation of Patent Application No. 84105614 ♦ Amendment 1F (86 cars February) A7 B7 丨 Supplement Peach 5. Description of Invention (11) xr 0R- R4 + tv

Br RS0

α;

α-Kί1 phenyl mercaptan is prepared by reacting with phenylfluorenyl or 4, · alkoxybenzyl bromide in the presence of a strong base. Suitable conversion reactions include, but are not limited to, argon oxide and sodium hydroxide. The reaction is generally performed in ethanol or a mixture of water and ethanol at a temperature of about 0 * C to about 50 * C. The next step is the cyclization of the arylphenylfluorenyl sulfide. The cyclization is conveniently carried out by heating the arylphenylfluorenyl sulfide in polyphosphoric acid. The cyclization is generally performed at a temperature of about 80 ° to about i 2 0, preferably between 85 eC and 90 ° C. Benzophene of formula II is generally purified by recrystallization. For example, when R4 is a methoxy group and R5 is a methyl group, the compound of the formula? Can be recrystallized from ethyl acetate. The halogenating agent of the method of the present invention is a compound of formula III, which can be prepared as shown in 囷 π, wherein R2, R3, R6 and Ηχ are as defined above, and the ruler is ^ · ~ 蜾. Figure Π .--'---- install ------ order ------- line (please read the "Notes on the back" and fill in this page first) ί Staff of the Central Ministry of Economic Affairs Consumer cooperatives

r2I N

Rr Ν I a 0

R6 0 III -14- This paper size is applicable to China National Standards (CNS) Congxie (publication of 21 × χ297) A7 B7 Printed by the Central Government Standards Bureau of the Ministry of Economic Affairs # Cooperative cooperatives V. Description of invention (3) Method of invention The system uses boron tribromide or boron trioxide as a tritiation catalyst, which replaces aluminum gasification. Vaporized aluminum is difficult to handle, especially on a commercial scale. In addition, a large amount of aluminum gas is required, usually six equivalents, to carry out the dehalation and dealkylation. Aluminum chloride produces a large amount of aluminum by-products, is insoluble in the processing solvent, and is difficult to be converted from one of the medically active 2-aryl-6-yl- 3- [4 · (2 · aminoethoxy) fluorenyl groups ] Benzene [b] methylphenene was removed. The reactions catalyzed by aluminum gasification are generally heterogeneous mixtures. The method of the present invention is uniform, and the boron by-product is dissolved in the processing solvent. In addition, the dealkylation catalyzed by aluminum chloride requires the addition of a thiol or a sulfide, which cracks the tiger-based aryl ether, produces a dipityl sulfide, and has an unpleasant odor. These mercaptans or sulfides can be removed by recrystallization, but they can make the recrystallization solvent odorous impurities. The method of the present invention is free of the use of aluminum and odorous mercaptans and sulfides. Prior art methods produced large amounts of related substances and large amounts of residual aluminum salts in the final product. Representatives of related substances include 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-hexahydropyridylethoxy) pyrene] benzene, [b] phene, 2- (4-hydroxyphenyl) -6-methoxy · 3- [4- (2-hexahydropyridylethoxy) benzyl] benzo [b] pyrene, 6-hydroxy-3- (4 -Hydroxyfluorenyl) -2- (4-hydroxyphenyl) phenylhydrazone [b] pyrimidine, 4- (2-hexahydropyridylethoxy) thiobenzoic acid propyl ester, 4- (2-hexadecyl Hydroxypyridylethoxy) benzoic acid methyl ester, 6-hydroxy-2- (4-hydroxyphenyl) -3- (4- (2 · hexahexadinylethoxy) benzylfluorenyl] -5- [4- (2-Hexahydropyridylethoxy) pyrene] phenylpyrene [b] «Sphene, and 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2- Hexahydropyridylethoxy) benzylfluorenyl] -7- [4- (2-hexaargyridinylethoxy) benzylfluorenyl] phenylfluorene [b] pyrimidine. Boron by-products can be easily changed from the final product Removal. The method of the present invention can also avoid the treatment of aluminum waste. When reacted in 1,2-digas ethane | ____: _ ^ 6 -_______ ^ The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 public ^ " (Please read the precautions on the back before filling this page) Γ. Install _, βτ Central Office of the Ministry of Economic Affairs Fei Cooperative Co., Ltd. Printed the Revised Page of the Chinese Specification for Patent Application No. 84105614 (2, 1992, Fifth, Description of the Invention (33) —-—--Supplementary Preparation on the Revision Date 1 ----- 6 -methoxy-2- A solution of (4-methoxyphenyl) benzo [b], thiophene 3.methoxyphenylthiol (! 00 g) and potassium hydroxide (39.1 g) in water (300 ml) was added with denatured ethanol ( 750 ml), the resulting mixture was cooled to about 0.0. The cold mixture was treated with 4, -methoxyphenylphosphonium bromide (164 g) in small portions. After the addition was complete, the mixture was cooled for 10 minutes and then heated to Room temperature. After 3 hours, the mixture was concentrated in the air and the residue was treated with water (200 ml). The resulting mixture was treated with ethyl acetate and the phases were separated. The organic phase was treated with water (2X), sodium bicarbonate solution (2X ) And sodium vaporized solution (2X). Then, the organic phase was dried over magnesium sulfate, filtered, and evaporated to dryness in the air to obtain 202 g of α- (3-methoxyphenylthio) -4-methoxyphenethyl. The ketone >> crude product was crystallized from methanol, washed with hexane to obtain 158 g, melting point 5 3 * C »polyphosphoric acid (930 g) was heated to 85 * C, and The above intermediate product (124. g) was divided into several small portions and treated for 30 minutes. After the addition was complete, the resulting mixture was stirred at 90 eC. After 45 minutes, the reaction mixture was cooled to room temperature. The mixture was treated with crushed ice while the mixture was treated with Cool in an ice bath. The resulting mixture was treated with water (100 ml) to give a pale pink precipitate. 9 The precipitate was separated by filtration ', washed with water and methanol at 40. (: Dried in the air to obtain 119 g of a crude product of 6-fluorenyloxy 2- (4-methoxyphenyl) phenylhydrazone [b] pyrimidine β in hot methanol, filtered, and washed with cold methanol. The resulting solid matter was recrystallized from ethyl acetate (4 liters), filtered, washed with hexane, and dried in the air to obtain 68 g of the title compound. Melting point 8 7 · 1 9 0.5 * C. Preparation 2 (CNS ) A4 ^ m (210X297 ^ t) -------------------- install -------- order -------- line / fex /. 7K (Please read the note on the back before filling in this page)

Φ A7 B7 V. Description of the invention (4) When the reaction proceeds, the reaction is uniform, a higher concentration can be used, and a solvate crystal that can be easily separated is produced. The present invention relates to an improved method for synthesizing 2-aryl-6-hydroxy-3- 3- [4- (2-aminoethoxy) fluorenyl] benzo [b], a phenanthine, which includes brewing pyrene When the protected starting compound and the protected phenol group are dealkylated, the desired product is produced. According to a comparative aspect of the present invention, the dehydration and dealkylation steps are performed continuously in a single reactor. More specifically, the present invention relates to a solvate crystal for preparing a compound of the formula: ^ -〇CH2CH2N (R2.HX R1 R1 is hydrogen or leptin; R2 and R3 are each Cl_C4 alkyl, or R2 &amp; R3 is connected to The nitrogen atom forms a heterocyclic ring selected from pyrrolidinyl, hexahydropyridyl, cyclohexaneimine, and morphol <* limyl; and HX is HC1 or HBr; including the following step (a) Benzopyrophene (Please read the notes on the back before filling out this page) • 11 Packing · Ordering Printed by the Central Bureau of Standards of the Ministry of Economic Affairs

No. 84105614¾ Chinese specification of patent application amended 1786 car 7th, A7 ~~-B7 V. Description of invention (34) Duty production cooperation of Central Samples Bureau of Ministry of Economic Affairs Du printed 4_ (2-hexahydropyridylethoxy) ) Ethyl formate 4-Ethyl benzoate (831 g), ι_ (2-Gasethyl) hexapyridine monohydrochloride (10.13 g), potassium carbonate (16.59 g) and methyl ethyl ketone (60 ml) of the mixture was heated to 80 X :. After 1 hour, the mixture was cooled to about 55 C 'and treated with 1 · (2-gasethyl) hexahydropyridine monohydrochloride (092 g). The resulting mixture was heated to 80 °. (: The reaction was detected by thin layer chromatography (TLC) using a silicone film and ethyl acetate / acetonitrile / triethylamine (10: 6: 1, volume / ¾ volume). Add several 1- (2-Gasyl) Base) hexahydropyridine hydrochloride until the initial 4-consumed by benzoate. After the reaction is complete, the reaction mixture is treated with water (60 ml) and cooled to room temperature. The aqueous layer is discarded and the organic layer is discarded. Concentrate at 4 ° C and 40 mmHg in the air. The resulting oil was used in the next step without further purification. Preparation of 3 4 · (2 · Hexahydropyridylethoxy) benzoate salt such as A solution of the compound prepared in the above Preparation 2 (approximately 13.87 g) in methanol (30 ml) was treated with 5N sodium hydroxide (15 ml) and heated to 40 eC »After 4 1/2 hours, 'water ( 40 ml). The resulting mixture was cooled to 5-10 C. Conc. Hydrochloric acid (18 ml) was slowly added. The title compound crystallized during tomb formation. The crystalline product was collected by filtration and dried at 40-50. (3 was dried in the air. 'The title compound was obtained in 83% yield "edge 2 70-2 7 1 * C. Preparation of 4 4- (2-hexahydropyridylethoxy) benzylfluorenyl gas salt A solution of the salt such as the compound prepared in Preparation 3 (30.01 g) and dimethylformamide (2 ml) in methane dichloride (500 ml) with chloramphenicol (105 ml (please read the back first) (Please note this page before filling in this page) • Installation. Threading • —Γ 人 S *. 通 Ｍ S Ν C Junzhu Tzugu * 7 7 2 V. Description of the invention (5) R4 is Ci.4 alkoxy R5 is a Ci.4 alkyl group, and a halogenating agent of the formula R6

III A7 B7 r3 och2ch2n (ηχ R2 In the printed format of the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, R &lt; s is gas, bromine or hydroxyl, and HX, R2 and R3 are as defined above; in the presence of Β ×, 3, where X , Is gas or bromine; (b) —Dealkylation of one or more phenolic groups, by reaction with another 6} (, 3, where X, as defined above;... (C) separation of solvate crystals Other aspects of the present invention are 6-hydroxy-2- (4-hydroxyphenyl) _3- [4- (2-hexafluoroton-leanylethoxy) fluorenyl] benzene, [b] fluorenyl methanoate Solvate crystals, which are novel products of the method of the present invention. The present invention also relates to a 6_hydroxy_2_ (4-leanyl) _3_ [4_ (2_hexahydropyridylethoxy) A new method of benzamyl] benzyl [b] phenphene hydrochloride, including the following steps: (a) Fermentation of phenoxaphene of the formula

R4 This paper uses the national standard of the T country (CNS) A4 specification (21 ο X 297) (Please read the precautions on the back before filling this page)-Packing. Order the Chinese manual for patent application No. 84105614 Front page (February, 86) A7 ____ B7 Printed by the Bayong Consumer Cooperative of the Central Rubbing Bureau of the Ministry of Economic Affairs 5. Description of Invention (35)) Processing for 30-35 minutes. The analysis was complete with stirring for 8 h at η p l C. If starting carboxylic acid is present, grass gas can be added to the reaction. After completion, the reaction solution was evaporated to dryness in the air. The residue was dissolved in dichloromethane (200 ml) and the resulting solution was evaporated to dryness. The dissolution / evaporation procedure was repeated to obtain the title compound as a solid. The title compound can be stored as a solid or as a 0.2M solution in digas methane (500 ml). Example 1 6-methoxy-2- (4-methoxyphenyl) -3- (4- (2-hexahydropyridylethoxy) benzylfluorenyl] benzenefluorene [b] fluorene hydrochloride such as The mixture of the compound prepared in Preparation 1 (8.46 g) and the base gas (10.0 g) prepared in Preparation 4 in digas methane (350 ml) was cooled to about 20.5 ° C. The cooled mixture was treated with boron trioxide (2.6 ml), and the resulting mixture was stirred mechanically. The reaction was detected by "PLC using the above analysis method" after 85 minutes according to 6-methoxybenzene-2- (4- Methoxyphenyl) _3_ [4_ (2-Hexahydropyridylethoxy) fluorenyl] phenyl [[B]] phene The standard HPLC yield was 88%. Example 2 6-hydroxyl. Hydroxyphenylpyrene mono-^-ortho-hexapyridylethoxy ethenyl] phenyl] [b] pyrene hydrochloride 1,2-digasethane solvate (Form I) 6 · methoxy 2- (4- (methoxymethoxyphenyl) -3- [4- (2-hexaargonium) than fluorenylethoxy) fluorenyl] phenylfluorene [b], thiophene hydrochloride (2.0 g) The solution in 1,2-digas ethane (20 ml) was treated with boron trigas (2.0 ml). The resulting mixture was stirred at 35 ° C for about 18 hours. The mixture of ethanol and formazan (10 ml, 95: 5, 3A) was treated with the above reaction mixture to bring the alcohol mixture back to -38- P. Eil I -------- r / ^ — .-C · (Please read the back first Please fill in this page if you want to pay $.> Binding paper size Chinese standard (CNS) A4 specification (210X297 mm) A7 B7 Five 'invention description (6) In the formula · R4 is 〇1.4 蜣 oxy , R5 is C! · 4 gauge group, the following formulating agent

Printed by the Central Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, J ^ 3 〇ch2ch〆 · ηχ… V where R6 is gas, bromine or hydroxyl, Ηχ is HC1 or HBr, argon formed by R and R and the nitrogen atom connected to it Pyridyl; in the presence of BX'3, where χ is gas or bromine; (b) dealkylation of the phenol group of the tritiated product of step (a), by reacting with another BX'3, where X, as defined above; (c) isolating a solvate crystal of a compound of the formula yR3 〇CH2CH2W (. Η × Η. ~ Ί ... where I R1 is a hydroxyl group, HX, R2 and R3 are as defined above; (d) the solvate crystal React with about one equivalent of base in methanol or a mixture of methanol and water, (e) selectively extract the solution obtained from step (d) with an aliphatic hydrocarbon solvent,--9-

This paper is compliant with the Chinese National Standard (€ milk) 8-4 specifications (210 '乂 297 mm) (Please read the precautions on the back before filling this page)-Packing ·

Tt. Explanation of the invention ((1) 1 equivalent of hydrochloric acid is added to the methanol solution obtained from the step or (g) to separate non-solvated crystalline compounds. In a preferred aspect of the present invention, the variable symbol in the above method is defined as follows: Methoxy 'R5 is methyl, R6 is gas, HX is HC1, BX, 4 BCh, the aliphatic hydrocarbon solvent is hexane or heptane, and the base is sodium hydroxide. The invention also relates to the second preparation! 6_Hydroxy ---------------------- ^ 2_ (4 · residue) _3_ [4_ (2hexahydropyridylethoxy) ) Benzyl] benzidine [b] Thifene hydrochloride method, including the following steps: (a) Brewing benzene hydrazone, thiophene (Please read the precautions on the back before filling in this page j

Order II Central Ministry of Economic Affairs

OGH2CH2N ^ · HX R2 where R is a &lt; 31-4 alkoxy group, R is a C1 4 alkyl group, an amylating agent of the formula

, RJ where R6 is gas, bromine or mesogen, HX is HC1 or HBr, and the size 2 and 1 ^ are the hydropyridyl group formed by the connected nitrogen atom-10- This paper standard is applicable to Chinese National Standard (CNS) Bagu ^ (210X297 mm) V. Description of the invention (8 A7 B7 in the presence of BX'3, where χ is gas or bromine; (b) dealkylation of the phenolic group of the halogenated product of step (a) Effect, by the reaction of another BX'3, wherein X, as defined above; (c) separation of the compound solvate crystal of the following formula

/ H3 OCH2CH2l &lt;-HX Λ ^ R2 R1 is a hydroxyl group, and HX, R2 and R3 are as defined above; (d) The solvate crystal is dissolved in methanol and In a hot solution of water; (e) selectively filtering the solution obtained from step (d), (0) distilling and concentrating the solution obtained from step ((1) or (6), and (g) separating non-solvated crystalline compounds In the preferred aspect of the present invention, the variable symbols in the above method are defined as follows: R is f oxidation, R5 is methyl, R6 is gas, hmhc1, bX, 3 is BC13. In the above formula, alkyl "B The vocabulary list has a straight chain alkyl group of 4 to 4 carbon atoms. Generally Cl-C4 alkyl groups include methyl, ethyl, n-propyl, and n-butyl. The "Ci-C4 alkoxy" ethyl vocabulary list such as Methoxy, ethoxy, n-propoxy and n-butoxy. The preferred Ci_c4 alkoxy is methoxy. The term "mole equivalent" as used herein refers to the relative molar number of the boron trihalide reagent. At the beginning, the mole number of the phenanthrene compound is shown. For example, the reaction of one of three millimoles of boron gas with one millimolar of the phenylpyrimidine compound is shown in Table 3. Moore-: ---- ---; __- 11-Private paper size is applicable to Chinese National Standard (CNS) A4 (210x297). (Please read the precautions on the back before filling this page}

1, 1T Central Ministry of Economic Affairs, Central Bureau of Quasi-Government, Shellfish Consumption Cooperative # 社 印 ^ Α7 Β7 5. Description of the invention (9) Three boron gas. "The solvate J word list-: § Condensate containing one or more molecules of soluble 1 (such as a compound of formula I) and one molecule of soluble L. Representative solvates are with dichloromethane Ethyl chloride, aeroform and 1,2,3-trifluoropropane. The method of the present invention can be used to synthesize a series of compounds with anti-estrogen and anti-androgenic activity. See U.S. Patent Nos. 4,418,068 and 4,133,814. Representative compounds of the I compound 'products of the method of the present invention include the following compounds: 6-fluorenyl-2-hanyl-3- [4- (2-dimethylaminoethoxy) imido] benzene [ b] phenone, 6-acidyl 2- (4-chirophenyl) -3- [4- (2-dimethylaminoethoxy) fluorenyl] phenylhydrazine [b] pyrimidine, 6-hydroxy-2-phenyl-3 · [4- (2-diethylaminoethoxy) benzylfluorenyl] phenylfluorene [b] fluorene; 6-hydroxy-2- (4-hydroxyphenyl ) -3- [4- (2-Diethylaminoethoxy) fluorenyl] phenylhydrazine [b], thiophene, 6-carboxy-2-phenyl-3- [4- (2-di Isopropylaminoethoxy) pyridinyl] benzo [b] p-thiophene '6-quinyl-2- (4-carboxyphenyl) -3- [4- (2-diisopropylamine Ethoxy) benzylfluorenyl] phenylfluorene [b] 1 * thiophene, 6-transyl'2-benzene -3- [4- (2- (Di-n-butylaminoethoxy) benzyl] phenyl] [phenylene] [b] p thiophene, 6-hydroxyl = 2- (4-hydroxyphenyl) -3- [4 -(2 · Di-n-butylaminoethoxy) benzyl] phenylphenyl ib] p phenphen 'yongyl-2 · phenylpyridinylaminoethoxy) benzyl] phenyl] [b] 1 * Sphene; 6-Ethyl-2- (4-hydroxyphenyl) -3-14- (2-0 Biharylaminoethoxy) Benzyl] Benzene [b] 11 Sphene , 6-Cycloyl-2-phenyl-3- 3- [4- (2-hexazine ** than alkylaminoaminoethoxy) benzyl] phenylhydrazone [b] pyrimidine, 6-hydroxy · 2_ ( 4-Phenyl) -3_ [4- (2.Hexahydropyridylaminoethoxy) pyrene] phenylpyrene [bP thiophene, 6_hydroxy · 2 · phenyl- 3- [4- ( 2 -Cyclohexaneiminoaminoethoxy) fluorenyl] phenylene _ -_ -12- __ —------ This paper is compliant with China National Standards (CNS) A4 (210x297) (Please read the precautions on the back before filling out this page) • Packing · ， 11 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (10) [b] phenphene, 6 -hydroxyl-2 -(4-hydroxyphenyl) -3- [4- (2-cyclohexaneiminoaminoethoxy) fluorenyl] phenylfluorene [b] «Sphene, 6-hydroxyl -2-Phenylpyrene 4- (2-morpholinylaminoethoxy) benzylpyrene] phenylpyrene [b] · phene, 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-morpholinylaminoethoxy) fluorenyl] phenylhydrazine [b] p thiophene. A preferred product of the method of the present invention is a compound of formula I in which R1 is a hydroxyl group and R2 and R3 together with the nitrogen atom to form a pyrrolidinyl, hexahydropyridyl or cyclohexaneimine group. Representative products of this preferred group include 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-pyrrolidinylethoxy) pyreno] benzo [b] pyrimidine, 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-hexaargyridinylethoxy) benzylfluorenyl] phenylfluorene [b] phene, and 6-hydroxy-2-2- ( 4-hydroxyphenyl) -3- [4- (2-cyclohexaneiminoethoxy) fluorenyl] phenylfluorene [b] pyrimidine. The product of the present invention is more preferably a compound of formula I in which R2 and R3 form a pyrrolidinyl or hexahydropyridyl group together with a nitrogen atom attached thereto. Representative products of this preferred group include 6-hydroxy-2- (4-hydroxyphenyl) -3- [4-(; 2-pyrrolidinylethoxy) fluorenyl] phenylfluorene [b] thiophene, And 6-hydroxy_2- (4-hydroxyphenyl) -3- [4- (2-hexakis-pyridylethoxy) fluorenyl] benzene [b] fluorene. The product of the present invention is preferably a compound of formula I in which R1 is a hydroxyl group and R2 and R3 together with the nitrogen atom to form a hexaargylpyridyl group. The most preferred product is 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-hexahydrosuccinylethoxy) benzyl] phenylhydrazine [b] p thiophene. Compounds of formulae II and III are the starting materials of the present invention and can be prepared using standard organic synthetic methods. The starting compound of Formula 11 can be easily obtained by the synthetic method exemplified in the following Preparation and listed in Figure I.

Circle I ____ 13- This paper size applies to China National Standard (CNS) A4 specifications (210X 297 male sauce j one-two (please read the precautions on the back before filling this page).

A Patent application No. 84105614 Chinese description ♦ Amendment 1F (86 cars February) A7 B7 丨 supplement peach 5. Description of the invention (11) xr 0R- R4 + tv

Br RS0

α;

α-Kί1 phenyl mercaptan is prepared by reacting with phenylfluorenyl or 4, · alkoxybenzyl bromide in the presence of a strong base. Suitable conversion reactions include, but are not limited to, argon oxide and sodium hydroxide. The reaction is generally performed in ethanol or a mixture of water and ethanol at a temperature of about 0 * C to about 50 * C. The next step is the cyclization of the arylphenylfluorenyl sulfide. The cyclization is conveniently carried out by heating the arylphenylfluorenyl sulfide in polyphosphoric acid. The cyclization is generally performed at a temperature of about 80 ° to about i 2 0, preferably between 85 eC and 90 ° C. Benzophene of formula II is generally purified by recrystallization. For example, when R4 is a methoxy group and R5 is a methyl group, the compound of the formula? Can be recrystallized from ethyl acetate. The halogenating agent of the method of the present invention is a compound of formula III, which can be prepared as shown in 囷 π, wherein R2, R3, R6 and Ηχ are as defined above, and the ruler is ^ · ~ 蜾. Figure Π .--'---- install ------ order ------- line (please read the "Notes on the back" and fill in this page first) ί Staff of the Central Ministry of Economic Affairs Consumer cooperatives

r2I N

Rr Ν I a 0

R6 0 III -14- This paper size is applicable to China National Standards Standard (CNS) Congxie (publication of 21 × χ297) Employees' Central Bureau of Standards, Ministry of Economic Affairs, Consumer Consumption Du printed A7 ____B7 V. Description of Invention (丨 2) General, 4 -The hydroxy benzoic acid CrC4 alkyl ester is alkylated with chloroethylamine in the presence of an inorganic residue, and the ester group is hydrolyzed to produce a compound of formula III, in which Han 6 is hydroxyl. Examples of gas ethylamines which can be used to prepare compounds of formula I are 1- (2-gasethyl) hexahydropyridine, 4- (2-gasethyl) morpholine and 1- (2.gas ethylpyrrolidine. Inorganic bases suitable for this alkylation include potassium carbonate and sodium carbonate. Solvents suitable for this alkylation are non-reactive polar organic solvents such as methyl ethyl ketone and dimethylformamide. The esters are used Standard synthetic methods hydrolyze, such as by reacting an alkylated intermediate with an aqueous solution of an acid or base. For example, ethyl esters can be easily hydrolyzed by reaction with 5 N sodium hydroxide in a water-miscible organic solvent such as methanol. The acidification of the hydrochloric acid reaction produces the hydrochloride salt of a compound of formula II (wherein R6 is a hydroxyl group). A compound of formula III, wherein R6 is gas or bromine, can be prepared from a compound of formula hydroxy. Krypton gas, submerged gas, sulfenyl bromide, phosphorus tribromide, triphosgene, and phosgene. R6 is preferably gas. Suitable solvents for this reaction include digas methane, 1,2 digas benzene, and gas benzene. And 1,2-digas ethane. The halogenation reaction is preferably performed in the same solvent as the subsequent halogenation reaction. The amount of dimethylformamide, about 0.05 to about 0.25 equivalents, was added to the chlorination reaction. When the reaction was carried out in 1,2-digas ethane, the reaction was carried out at about 4 7 ° C over 2 Completed in 5 hours. Compound of formula 111, in which R6 is gas, can be stored as a solid or as a solution or mixture in dichloromethane, benzene, L2-diphenylbenzene or 1,2-diphenylethane. Gasification The reaction and the fermentation reaction are preferably carried out in the same reactor one after another. ---- -15- _ This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) — I. —— I 11 11 — ^ r— 11 * 一 'w- (Please read the notes on the back before filling this page)

, 1T &quot; A7 B7

cr V. Description of the invention (I3) 2-arylhydroxyl_3_ [4_ (2-aminoethoxy) pyrene] phenylpyrimidine can be dehalidated by phenol group and then dealkylated Prepared in two different steps or sequentially in the "one pot" J reaction. The step-by-step synthesis is described below. The fermented stupid thiophene intermediate (the compound with the formula) can be as shown in Figure II. Shows the preparation, wherein R2, r3, r4, r5, ruler 6 and Η X are as defined above.

囷 III R2 • R3

III nn mu n ΙΛ \ &lt; 1 ^ —m ml 1 J · / -— t (please read the precautions on the back before filling this page)

〇CH2CH2N: .R3 \ r2 According to the Ministry of Economic Affairs of the Central Standards Bureau, the consumption of male workers will be made by Du 16- In general, the phenanthrene intermediate Π is brewed with a compound of formula Iπ, using tri-gas boron or boron tribromide As a tritiation catalyst, β reaction is based on organic solvents such as gaseous benzene, digasmethane, 1,2-digasethane, 1,2-digasbenzene, bromobenzene, aerobic, 1,1,2,2 -tetrakis Gas ethane, 1,2,3-trifluoropropane or fluorobenzene. Tritiation is preferably carried out in digas methane, gas benzene, or 2-digas ethane. Tritiation is best carried out in methane. The halogenation rate of the compound of the formula π and the dealkylation rate of the phenol ether of the compounds of the formulae II and IV vary with the choice of the solvent, the reaction temperature and the choice of the boron trihalide. Because the compound of formula π has one or more unprotected phenolic groups, it is not easy under these conditions. The paper size is applicable to the Chinese National Standard (CNS) α4 specification (2 丨 0X297 mm) Central Ministry of Economic Affairs Central Labor Bureau Shellfish Consumer Cooperative. Print

A7 ______B7____ 5. Description of the invention (14), so the amount of dealkylation must be minimal. Since boron tribromide is better for the dealkylation of phenol ethers, the boron trihalide which has better catalytic tritiation is boron trioxide. For the reaction of boron trigas catalyzed in digas methane, the tritiation reaction can be carried out at room temperature, and the dealkylation of the compounds of formula II and IV is the smallest. In other solvents, the tritiation reaction is carried out at a relatively low temperature, such as -10 ° C to ίο ° C, in order to minimize the amount of dealkylation of the reaction starting materials and products. When R6 is chlorine, at least the molar equivalent of boron trihalide reagent is required for fermentation. When using benzoic acid as a brewing agent, 5 equivalents of tri-boron are generally used. Compounds of formula IV can be isolated as the hydrochloride or bromate or free base. In a stepwise process, the brewed intermediate (compound of formula IV) is dealkylated to produce a compound of formula I, as shown in Figure IV, where R1, R.2, Rs, R4, R5 and HX are as The above definition.圏 IV (Please read the notes on the back before filling this page)

I __ · 17 · This paper size is applicable to China National Standard (CNS) A4 specification (210 × 297 mm) V. Description of invention (l5) A7 B7 Printed by the Consumer Cooperative of the Shiyang Prototype Bureau of the Ministry of Economy The hydrochloride or bromic acid of the compound can be reacted with Sanhuan butterfly or digasified butterfly to produce β. One of the better debasing effects is boron tribromide. This dealkylation can be used in a variety of organic solvents such as -methane, benzene, 1,2-digas ethane, gas imitation, ^, dihydrazane, ethane, 1,2,3-trichloropropane, in i, 2-dichlorobenzene or fluorobenzene. The preferred solvent is 1,2-digasethane. When acid addition or salt is used as the starting material, the amount of by-products produced by the dealkylation of the amine ethyl group is minimal. When Erqijiakeng is used as a solvent and the tertiary reagent is a tri-gasification butterfly, the reaction is generally carried out at a temperature of 55 to about 75 »c, yielding a compound of formula I, and no amine ethyl group cleavage is measured. In other solvents such as chloroform, 1,2-diethane, benzene, it, or benzene, dealkylation occurs easily at ambient temperatures. For example, when 2-chloroethane is used as a solvent, the reaction is generally performed at 25 ° C to 35 ° C, and amine ethyl group is not cracked. At least four equivalents of three _ boron reagents-generally used to complete the reaction within a reasonable time. "The compound of formula I is preferably prepared by the" one "reaction of compounds of formula II and III, as shown in 圏 V, where Rl , R2, R3, R4, r5, ruler 6 and HX are as defined above.

a R4 + ’cx

III R2 (Please read the precautions on the back before filling out this page)-Install. Type ---. Ο -18-This paper size applies to China National Standard (CNS) A4 (210X297 mm) A7 B7

iv

〇cH2CH2N Phenylpyrimidine compound of formula 11 printed by Shenyang Junquan Bureau Shellfish Consumer Cooperative of Ministry of Economy is based on formula I 丨! The compounds are fermented in the presence of boron trioxide or a second-class butterfly; for the Γ-steel method, the three-burner butterfly is preferred. The reaction can be performed in a variety of organic solvents such as gas imitation, three gas methyl sintering, two gas diacetone, 1,2,3-three gas propane, 1,1,2,2-tetragas ethane, 1,2 -Carried out in two gas benzene, gas benzene or fluorobenzene. The preferred solvent for this synthesis is palladium ethane. The reaction is carried out at a temperature of about -10 eC to about 2 5 X :, preferably 0 ° C. The reaction is preferably carried out over a benzopyrimidine compound of formula II at a concentration of about 0.2 M to 1.0 M. The fermentation reaction is generally completed after about 2 hours to about 8 hours. The fermented pyridophene (compound of formula IV) conversion or compound of formula I was not isolated. This conversion is performed by adding boron trioxide and heating the reaction mixture. Preferably 2 to 5 mole equivalents of boron trioxide are added to the reaction mixture, and most preferably 3 mole equivalents. This reaction is performed at a temperature of about 2 5 t to about 40 ° C ', preferably at 35 ° C. The reaction is generally complete after about 4 to 48 hours. The halogenation / dealkylation reaction is quenched with an alcohol or a mixture of alcohols. Suitable alcohols for quenching reactions include methanol, ethanol and isopropanol. The tritiated / dealkylated reaction mixture is preferably added to a 95: 5 mixture (3A) of 6 alcohols and methanol. 3A ethanol can be heated to reflux at room temperature or preferably at reflux. When quenching is performed in this manner, the compound of formula I is conveniently crystallized from an alcohol mixture. In general, 1.25-3.75 ml of alcohol is used per millimolar acetophenone starting material. When using BCI3, the crystalline product of this "one-pot" method is separated as the solvate of the hydrochloride. These solvate crystals are obtained under various conditions. • 19- SI ttf] S) OR (έ * 1 / ~ ^ ντη \ A Λ χα II. \ Qian ί st J st 着 公 97 ^ 1 pack -------- order ------ meaning- -c 1 (Please read the notes on the back before filling this page) A7 B7 V. Description of the invention (η) Solvate of the compound of formula I (where R1 is hydroxyl group, HX is HC1, R2 and R3 are connected nitrogen atoms The hydropyridyl group formed together is prepared as described above. Jones et al., J. Med. Chem., 27, 1 057 (19 84) 〇Generally, the form of the product of the method of the present invention is by brewing / dealkylation The choice of the solvating solvent, boron trihalide, and processing conditions is particularly useful. The solvates of the compounds of formula I which are particularly useful are: 2 · digas ethane solvates. This solvate is carried out in i, 2 _ digas ethane. Prepared by the "one-pot" deuteration / dealkylation method. When Ri is a hydroxyl group, and the ruler 2 and ruler 3 are hydropyridyl HX formed with the connected nitrogen atom and are HC1, 1,2 dioxane ▲ The solvate can exist in two different forms. A crystalline form of the solvate is called Biform I, which is prepared by ethanol quenching in the brewing / dealkylation reaction catalyzed by boron trioxide. B is preferred A mixture of methanol and methanol (9 5: 5) is used in the preparation of this crystal form. This crystal form is characterized by the X-ray diffraction circle shown in Table i. Table 1 X-ray diffraction pattern d-line interval i / of Form I i〇 (Angel) (xlOO) 16.1265 3.80 10.3744 8.63 8.3746 5.29 7.9883 36.71 7.2701 5.06 6.5567 70.77 6.2531 6.79 5.5616 24.05 5.3879 100.00 5.0471 89.64 4.7391 85.96 -20- This paper size applies to China National Standards (CNS) A4 specification (210X297 mm) ) ----------- 1 Pack-(Please read the precautions on the back before filling this page) Order 0 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (18) Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China A7 B7-Line interval 1/1 Angstrom (xlOO) 4.6777 39.36 4.6332 .62.60 4.5191 77.56 4.2867 36.82 4.2365 41.66 4.1816 49.60 4.0900 11.28 3.9496 11.85 3.7869 36.25 3.7577 56.16 3.6509 40.62 3.5751 15.65 3.5181 21.52 3.4964 18.53 3.4361 33.60 3.3610 6.21 3.3115 4.95 3.2564 7.36 3.2002 3.80 3.1199 15.77 3.0347 14.84 2.8744 9.67 2.8174 10.82 2.7363 11.51 (Please read the back first Please pay attention to this page and fill in this page again)-binding · binding-21- This paper size is applicable to China National Standard (CNS) A4 size (210X297 mm) Printed by the Bayer Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A 7 ___B7_ _. Description of the Invention (I9) 6-Hydroxy-2_ (4-Hydroxyphenyl) -3- [4- (2-Hexahydropyridylethoxy) tanthenyl] phenyl} [b] n The amount of stipene hydrochloride was about 87.1%, and it was measured using high performance liquid chromatography (η PLC) described below. The amount of 1,2-digasethane present in this crystal was about 0.55 mole equivalents, and was measured by proton nuclear magnetic resonance light. Large, pure, single crystals of Form 1,1,2-digasethane solvate were prepared for single crystal X-ray analysis. This single crystal system consists of 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-hexahydropyridylethoxy) benzylfluorenyl] phenylfluorene [b] &gt; A saturated methanolic solution of the acid salt was prepared by placing it in a saturated atmosphere of 1,2-dichloroethane (see Example 8). A total of 8419 reflections were obtained, 20 being less than 116 ° to determine the structure. The X-ray structure clearly shows that the crystal is a 1,2-digasethane solvate, and the ratio of the solvent to the solute molecules is 丨: 2. In theory, the X-ray powder diffraction pattern and the calculation of the electric single crystal X-ray data are equivalent to those listed in Table 2, indicating that the two solvates are the same. The second solvate crystal form is called Form 11, which is similar to Form j. The second form is prepared by quenching / dealkylating the tri-gasification reaction in 1,2-digas ethane with methanol quenching. Alternatively, the tritiation / dealkylation reaction catalyzed by boron trioxide uses 1,2,3-trifluoropropane as a solvent to produce a crystalline form of 1,2,3-trichloropropane solvate. This crystal form is characterized by the X-ray diffraction pattern shown in Table 2. _______-__- 22- This paper size applies to China National Standards (CNS) A4 specifications (210X297 mm) ί Please read the notes on the back before filling this page) Binding --- ^ V. Description of the invention (2〇) A7 B7 Table 2 X-ray diffraction pattern d-line interval of Form 11 "ι / ι〇 (Angstrom..1 (x100) 10.4311 22.64 8.9173 10.73 8.4765 5.31 8.0095 50.39 7.3068 4.23 6.6094 79.23 5.6196 22.34 5.4223 89.86 5.1959 11.81 5.0746 74.90 4.8017 100.00 4.7262 57.97 4.6569 53.35 4.5378 96.75 4.4376 10.83 4.3397 56.89 4.2782 48.23 4.2129 40.94 4.1037 12.80 — I-.---- 1----I 11 I -I-1--\-1 I-H, -C (Please (Read the notes on the back before filling out this page)

'1T Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs-23- This paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) V. Description of the invention (2)) A7 B7-Line spacer / 10. Egypt &gt; (xlOO) 3.9880 14.76 3.8863 8.17 3.7999 42.13 3.7662 57.09 3.6738 38.58 3.5701 18.50 3.5393 19.00 3.4622 39.57 3.3867 5.02 3.3321 4.33 3.2686 6.79 3.1535 14.86 3.0450 13.58 2.9028 12.30 2.8302 19.59 2.7544 12.30 -2.63 66 6.89 (Please read the back side first) (Fill in this page again)

、 1T Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 24- This paper size is applicable to China National Standard (CNS) A4 specifications (210'〆297 mm) A7 ----- 5L .__— V. Description of the invention (22) 6-Hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-77 hydralide ethoxy) fluorenyl] phenylpyrene [b] pyrimidine present in this crystal The responsibility of phenone hydrochloride is about 8 6 -8. / 〇. The amount of 2,2-dichloroethane present in this crystal was about 5%. It was determined by gas chromatography. The compounds of formula 1 form various solvates with aromatic solvents. One example of an aromatic solvate is gas benzene solvate, which exists in different forms and is referred to as Form 111. This crystal system is characterized by the X-ray diffraction pattern shown in Table 3. Table 3 X-ray diffraction pattern of Form III (please read the precautions on the back before filling this page) Printed line interval of the staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 1/10 Angstroms (xlOO) 14.3518 7.24 10.3335 6.17 8.8305 4.29 7.9475 38.16 6.5904 64.25 6.2848 6.52 5.6048 28.06 5.4107 100.00 5.1544 11.26 5.0493 53.26 5.0224 46.11 4.8330 76.94 4.7694 34.23 4.6461 50.22 4.5754 38.61 4.4953 72.65 4.3531 49.15 4.2940 41.64 4.2425 35.75 • This specification is applicable to the Chinese standard of China. (Mm) V. Description of the invention (23) Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7-Line interval 1/1 Angstrom (xlOO) 4.1856 21.63 4.1338 9.47 4.0793 12.69 3.9960 18.50 3.9037 9.03 3.7854 40.39 3.7521 54.16 3.6787 28.60 3.6509 17.96 3.5444 31.72 3.4679 41.55 3.3899 7.69 3.3101 '5.72 3.2561 7.42 3.1784 15.19 3.0445 11.17 3.0146 8.94 2.9160 11.89 2.8217 18.23 2.7500 12.06 2.6436 9.65 2.6156 6.97 (Please read the precautions on the back before filling this page) -Installation -26- Paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 V. Description of the invention (24) The 6-hydroxy-2- (4-hydroxyphenyl) -3- [ The amount of 4- (2. Dihydropyridylethoxy) fluorenyl] benzo [bp thiophene hydrochloride is about 7 8-6 ° / 〇. The amount of chlorobenzene present in this crystal was about 12 · 3%, which was measured by ΗPLC. The fourth solvate crystal form is called crystalline form IV. This crystal form system is prepared by a method of dehydration / dealkylation of a gasification catalyst using digas methane or gas imitation as a solvent. This crystal system is characterized by the X-ray diffraction pattern shown in Table 4. Table 4 X-ray diffraction pattern of Form IV 1-11 n--11 n HH n 1 (Please read the notes on the back before filling in this page) d-Line interval. 1 / 1〇 (Angstrom) (xlOO) 10.3696 14.40 8.9032 10,19 8.3125 7.61 Order

Printed by the UT Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs • 27 · This paper size is applicable to China's Standards (CNS) A4 (210X297 mm) V. Description of the invention (25) Consumption cooperative printing A7 B7 d-line spacer / worker 0) (xlOO) 7.9818 41.03 7.2036 7.34 6.5411 74.18 6.2367 6.39 5.5539 20.11 5.3689 100 _ 00 5.0272 95.92 4.7085 89.13 4.6406 73.37 4.6199 77.58 4.5347 69.70 4.4818 49 4.20 4.2589 47.69 47.69 44.16 4.0957 11.96 3.9347 11.28 3.7818 40.90 3.7614 53.53 3.6375 36.68 3.5773 20.11 3.5037 25.14 3.4409 32.34 3.4270 39.54 3.3088 12.64 3.2611 9.65 3.1046 12.77 3.0263 17.53 2.8536 8.29 2.8131 12.09 2.7309 8.97 --------- ^. 1 Installation-Μ- ✓cx. (Please read the notes on the back before filling this page)

, LT

U -28- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) A7 B7 V. Description of the invention (26) 6-hydroxy-2- (4-hydroxyphenyl) present in this crystal- 3- [4- (2- (Hexahydroethynyl) fluorenyl] phenyl] benzene [b], the amount of thiophene hydrochloride is about 804. / 〇 'was measured using Η P L C. The amount of gas imitation present in this crystal was about 0.42 mole equivalents, which was measured by proton nuclear magnetic resonance spectroscopy. • Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs --------- 1 Pack-m- ^ fv (Please read the precautions on the back before filling this page)

U 6 -Light-based 2- (4-hydroxyphenyl) -3- [4- (2-hexahydropyridylethoxy) pyrene] phenylpyrene [b] Preferred crystalline form of thiophene hydrochloride It is a non-solvated crystalline form. This crystalline form is preferred for pharmaceutical formulations because it does not contain solvents that may affect the patient. This crystalline form is prepared by recrystallization of a solvated hydrochloride prepared by boron trioxide-catalyzed tritiation / deionization. In a preferred recrystallization method, the solvated hydrochloride is added to a solution of sodium hydroxide in methanol or a mixture of methanol and water. At least one equivalent of base is used to dissolve the hydrochloride into a free base. Activated carbon is selectively added to the resulting solution to facilitate removal of impurities. The mixture is selectively filtered to remove activated carbon and any insoluble impurities, if any. The filtrate is optionally extracted with an aliphatic hydrocarbon solvent, such as hexane or heptane, to remove some residual solvents used in the alkylation reaction of the tritiated process. When the halogenation / dealkylation reaction is performed in an aromatic solvent such as benzene, fluorobenzene, bromobenzene, and o-diphenylbenzene, an extraction step is required. f The alcohol solution is acidified with hydrochloric acid (such as a gas or aqueous hydrochloric acid solution) to make 6-hydroxy (4-hydroxyphenyl) -3- [4- (2-hexaaziridinylethoxy) fluorenyl] benzene [b ] Pyrophene crystals or unsolvated hydrochloride. The resulting crystalline slurry is preferably stirred at ambient temperature for about 1 to about 2 hours to complete the crystallization. The unsolvated crystalline form was separated by filtration and then dried in the air. This crystal system is characterized by the X-ray diffraction pattern shown in Table 5. --Γ ----- Two buttons · This paper size applies to Chinese National Standard (CNS) A4 specifications (210X29 ^^ V. Description of the invention (27) A7 B7 Table 5. X-ray diffraction pattern of unsolvated crystalline form Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs d-Line interval 1/1 10 (Angel) (xlOO) 13.3864 71.31 9.359.8 33.16 8.4625 2.08 7.3888 7.57 6.9907 5.80 6.6346 51.04 6.1717 29.57 5.9975 5.67 5.9135 9.87 5.6467 38.47 5.4773 10.54 5.2994 4.74 4.8680 4.03 4.7910 5.98 4.6614 57.50 4.5052 5.75 4.3701 9.03 4.2516 69.99 4.2059 57.64 4.1740 65.07 4.0819 12.44 3.9673 22.53 3.9318 100.00 3.8775 9.07 3.709.6 33.38 3.6561 21.65 3.5576 3.36 3.5037 7.97 (Please read the notes on the back before filling this page) • Installation. 、? Τ ύ -30- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) V. Description of the invention (28) A7 B7 d-Line spacer / work Angstrom. (XlOO) 3.4522 18.02 3.4138 4.65 3.2738 10.23 3.1857 8.90 3.1333 6.24 3.0831 9.43 3.0025 12.13 2.9437 4.96 2.8642 Ί ΊΌ 2.7904 11.9 5 2.7246 3.05 2.6652 3.32 2.5882 7.30 ^^^ 1 I m ^ ln 1 ^ 1 ^ 1 HI n n. (Please read the precautions on the back before filling out this page) Order c_ Printed by the Central Bureau of Standards, Ministry of Economic Affairs and Consumer Cooperatives -31-This paper size is in accordance with Chinese National Standard (CNS) A4 (2IOX297mm) A7B7 Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives. 5. Description of the invention (29) 6-Jingji The amount of -2-(4-lightphenyl) _3- [4- (2-hexahydrodiphenylethoxy) benzyl] phenylhydrazine [b] »thiophene hydrochloride is at least 95%. The second method for preparing non-solvated crystalline materials is 6-Cyclo-2- (4-Cyclophenyl) -3- [4- (2-Hexahydrop-pyridylethoxy) in certain solvated forms ) Benzylfluorenyl] Benzylhydrazine [b] thiophene hydrochloride crystal. Generally, the solvated acid salt is dissolved in a hot solution from about 50 ° C to about reflux temperature. It contains methanol and water, and water accounts for about 3 to about 10% by volume. The resulting solution can be filtered to remove insoluble impurities. This solution or filtrate is concentrated by distilling the solvent to produce an unsolvated crystal. This unsolvated crystal is separated using standard techniques such as filtration and drying. This hot methanol / water crystallization method can be used to prepare non-solvated crystals from certain solvate crystals, where the sea point of the solvent in the solvate is less than about 850 ° C. This non-solvated crystalline material is more than described in the above patent The substance produced by the method is pure. The substance of the present invention does not contain aluminum impurities, vaporized aliphatic hydrocarbon solvents, and aromatic solvents. This unsolvated crystalline form is particularly useful for the manufacture of pharmaceutical compositions. The following examples further illustrate the invention. These examples are not intended to limit the scope of the invention to any aspect and should not be interpreted as such. All experiments were performed in the presence of dry nitrogen. All solvents and reagents were obtained by using. Percentages are generally calculated by weight (weight / weight); however, HPLC solvents are calculated by volume (volume / volume). Proton nuclear magnetic resonance (H NMR) spectra were obtained on a Bruker AC-300 FTNMR spectrometer at 300.135 MHz. Melting points were measured by differential scanning calorimetry (D S C) in a T A instrument D S C 2 9 2 0 using a closed cell and a heating rate of 2 ° C / min. X-ray powder diffraction spectrum is at __- -32- ---------- γ pack-Lurl '. + (Please read the precautions on the back before filling this page) Order 0 papers Λ Applicable to Chinese National Standards (CNS) A4 ^ grid (210X297) and A7 B7 ~ --------------------- · ~ · --- 5. Invention Explanation (3〇)

The Siemens D5000 X-ray powder diffractometer was obtained using copper radiation and Si (Li 彡 detector). The reaction is generally detected by high-performance liquid chromatography (ΗPLC). The radon gas is generated (R6 in Equation Π) For the reaction of gas compounds), the reaction was performed using a 2 ^^ 1 1-€ 8 column (25 cm 4.6 mm inner diameter, 5 micron particles) with 60 mM acid salt (K2P04) and 10 mM A mixture of alkanoic acid salt (pH 2.0) / acetonitrile (60:40) was dissolved and detected. The compound of formula I was derivatized with methanol and analyzed using a methyl ester reference standard. The reaction consisted of about 0-3 ml The hydrazone solution was added to 1 ml of Η PLC grade methanol and detected. The resulting mixture was shaken vigorously to derivatize it. After 30 minutes, acetonitrile (6 ml) was added, and then diluted to 100 ml with the above eluent. The trialkylation, dealkylation 'or trialkylation 7 dealkylation reaction was also detected by the PLC. The reaction mixture was mixed. The sample of the life was using a Z 〇rba XRX-C 8 column (25 cm X 4.6 Millimeter inner diameter (5 micron particles) was analyzed by dissolution at the concentration gradient shown below. Cooperative printed concentration gradient solvent system (minutes) A (%) B (%) 0 60 40 5 60 40 10 45 5 5 20 38 62 25 45 5 5 32 45 55 37 60 40 -------- --33- This paper size applies Chinese National Standard (CNS) A4 (210x297). A7 B7 Printed by the Consumers' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the invention (31) 42 60 40 A: 0.05 M HC104 ( pH = 2.〇) B: acetonitrile reaction mixture is diluted from 0.1 to 0.2 ml of sample to 50 ml for 60:40 mixture of A / B for analysis. Recrystallized mother liquor is similarly sampled in a similar manner. Crystals The amount (percentage) of 6-hydroxy- 2- (4- Yongphenyl) -3 · [4 · (2-hexahydropyridylethoxy) fluorenyl] benzene [b] thiophene hydrochloride is below (Method). A sample (5 mg) of crystalline solid was added to a 100 ml volumetric flask and dissolved in a 75/30 (v / v) mixture of 75 mM potassium phosphate buffer (pH 2.0) and acetonitrile. One aliquot of this solution (10 microliters) was analyzed by high performance liquid chromatography using a Zorbax RX-C8 column (25 cm x 4.6 mm ID, 5 micron particles) and UV detection (2 80 nm). Use the following concentration gradient solvent system: Concentration gradient solvent system --------- install-j I (谙 Read the notes on the back before filling this page) Order ν Time (minutes) A (° / 〇 ) B (%) 0 70 30 1 2 70 30 14 2 5 75 16 70 30 25 70 30 A: 75 mM KH 2P04 buffer (pH 2.0) B: 6-acyl group 1 in acetonitrile sample -2- ( 4-Hydroxyphenyl) · 3-[4- (2 34-) This paper size applies to Chinese National Standard (CNS) A4 (210X297). Employees' cooperation with the Central Bureau of Standards of the Ministry of Economic Affairs, Social Printing A7 B7 V. Invention Note: The percentage of (32 oxy) benzylfluorenyl] phenylfluorene [b] p phenphene hydrochloride is calculated using the calibration curve's peak area, slope (m), and intercept (b) with the following fractions: Peak area -b Sample volume (ml) Efficiency 〇 / 〇 =-X -—- m Sample weight (mg) The amount (percentage) of the solvent in the crystal such as methanol, ethanol or 1,2-digas is in the gas phase layer ANALYTICAL DETERMINATION. A sample (50 mg) of crystalline solid was added to a 10 ml volumetric flask and dissolved in a solution of ethyl-butanol (0.025 mg / ml) in dimethyl sulfoxide. A sample of this solution was analyzed by gas chromatography using a DB Was column (30 meters x 0.53 mm inner diameter, 1 micron particle) with 10 ml / min column flow and flame ionization detection. The column temperature was heated from 35 ° C to 230 in 12 minutes. (: The amount of solvent is determined by comparison with an internal standard (2-butanol), using the following formula:

C E G

Solvent% =-XX — XIDF Η where C = the proportion of solvent in the sample D = the average ratio of the specific solvent standard E = the average weight of the standard F = the weight of the sample (mg) G = the volume of the sample (10 ml) H = Standard volume (10,000 ml) 1 = standard purity (〇 / 0) ΐ paper; ^ applicable standard (cns) a is called ⑺. (Name: Li)------------- install-* I / V. (Please read the precautions on the back before filling in this page) Order ^. Central Ministry of Economic Affairs, Central Bureau of Work, Consumer Cooperatives Revised page of Chinese Specification for Patent Application No. 84105614 (2 Rib Fifth, 86, Description of Invention (33) —-—--Supplementary Preparation on Amendment Day 1 ----- 6 -Methoxy-2- (4 -A solution of methoxyphenyl) benzo [b], thiophene 3.methoxybenzothiol (! 00 g) and potassium hydroxide (39.1 g) in water (300 ml) was added denatured ethanol (750 ml ), The resulting mixture was cooled to about 0.0. The cold mixture was treated with 4, -methoxyphenylphosphonium bromide (164 g) in small portions. After the addition was complete, the mixture was cooled for 10 minutes and then warmed to room temperature. After 3 hours, the mixture was concentrated in the air and the residue was treated with water (200 ml). The resulting mixture was treated with ethyl acetate to separate the phases. The organic phase was treated with water (2X), sodium bicarbonate solution (2X) and Wash with gasified sodium solution (2X). Then, the organic phase was dried over magnesium sulfate, filtered, and evaporated to dryness in the air to obtain 202 g of α- (3-methoxyphenylthio) -4-methoxyacetophenone. The crude product was crystallized from methanol, washed with hexane to obtain 158 g, melting point 5 3 * C »polyphosphoric acid (930 g) was heated to 85 * C, and the above intermediate product (124. g) was divided into several small portions for processing. 30 minutes. After the addition was complete, the resulting mixture was stirred at 90 eC. After 45 minutes, the reaction mixture was cooled to room temperature. The mixture was treated with crushed ice while the mixture was cooled in an ice bath. The resulting mixture was water (100 ml) ) Treatment to produce a pale pink precipitate 9 precipitates to be separated by filtration 'washed with methanol and washed with water at 40. (: dried in the air to obtain 119 g of 6-fluorenyloxy 2- (4-methoxyphenyl) benzene The crude product of 嘧 [b] pyrimidine β was heated in hot methanol, filtered, and washed with cold methanol. The solid matter produced was recrystallized from ethyl acetate (4 liters), filtered, washed with hexane, and in the air Dried to 68 grams of the title compound. Melting point 8 7 · 1 9 0.5 * C. Preparation 2 (CNS) A4 ^ m (210X297 ^ t) ------------------- --Installation ------ Order -------- line / fex /.7K (Please read the note on the back and fill in this page first) Article 84105614¾ Chinese Application for Amendment 1786 Car 7th, A7 ~~-B7 V. Description of the invention (34) Du-printing of 4_ (2-hexahydropyridylethoxy), ethyl ethyl formate, 4-ethyl benzoate ( 831 g), ι (2-gasethyl) hexagonopyridine monohydrochloride (10.13 g), potassium carbonate (16.59 g) and methyl ethyl ketone (60 ml) were heated to 80 × :. After 1 hour, the mixture was cooled to about 55 C 'and treated with 1 · (2-gasethyl) hexahydropyridine monohydrochloride (092 g). The resulting mixture was heated to 80 °. (: The reaction was detected by thin layer chromatography (TLC) using a silicone film and ethyl acetate / acetonitrile / triethylamine (10: 6: 1, volume / ¾ volume). Add several 1- (2-Gasyl) Base) hexahydropyridine hydrochloride until the initial 4-consumed by benzoate. After the reaction is complete, the reaction mixture is treated with water (60 ml) and cooled to room temperature. The aqueous layer is discarded and the organic layer is discarded. Concentrate at 4 ° C and 40 mmHg in the air. The resulting oil was used in the next step without further purification. Preparation of 3 4 · (2 · Hexahydropyridylethoxy) benzoate salt such as A solution of the compound prepared in the above Preparation 2 (approximately 13.87 g) in methanol (30 ml) was treated with 5N sodium hydroxide (15 ml) and heated to 40 eC »After 4 1/2 hours, 'water ( 40 ml). The resulting mixture was cooled to 5-10 C. Conc. Hydrochloric acid (18 ml) was slowly added. The title compound crystallized during tomb formation. The crystalline product was collected by filtration and dried at 40-50. (3 was dried in the air. 'The title compound was obtained in 83% yield "edge 2 70-2 7 1 * C. Preparation of 4 4- (2-hexahydropyridylethoxy) benzylfluorenyl gas salt A solution of the salt such as the compound prepared in Preparation 3 (30.01 g) and dimethylformamide (2 ml) in methane dichloride (500 ml) with chloramphenicol (105 ml (please read the back first) Note: Please fill in this page again.) • Binding. Threading • —Γ 人 S *. 通 Ｍ S Ν C Junzhu Tazhuanggu * Gong 7 9 2 No. 84105614 Patent Application Chinese Specification Sheet Front Page (86 (February) A7 ____ B7 Printed by the Central Government Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, Fifth, the description of the invention (35)) Processing for 30-35 minutes. The completeness is analyzed by stirring at ι8 μηι C. If there is a starting carboxylic acid When present, grass gas can be added to the reaction. After completion, the reaction solution is evaporated to dryness in the air. The residue is dissolved in dichloromethane (200 ml) and the resulting solution is evaporated to dryness. Repeat the dissolution / evaporation procedure The title compound was obtained as a solid. The title compound can be stored as a solid or in a 0.2 M solution in digas methane (500 ml). Example 1 6-methoxy-2- (4-methoxyphenyl) -3 -(4- (2-Hexahydropyridylethoxy) benzylfluorenyl] benzenefluorene [b] fluorene hydrochloride The compound prepared as described in Preparation 1 (8.46 g) and a mixture of ammonium base gas (10.0 g) prepared in digas methane (350 ml) as described in Preparation 4 were cooled to about 20.5 ° C. The mixture was cooled to boron trioxide. (2 · 6 ml) treatment, the resulting mixture was mechanically stirred. The reaction was detected by "PLC using the above analysis method" after 85 minutes' based on 6-methoxybenzene-2- (4-methoxyphenyl) _3_ The yield of [4- (2-hexahydropyridylethoxy) fluorenyl] phenylfluorene [b] fluorene was 88% by HPLC. Example 2 6-hydroxyl. -(Hydroxyphenylsulfonyl-^-ortho-hexapyridinylethoxy 丨 fluorenyl] phenylhydrazine [b] fluorene hydrochloride 1,2-digasethane solvate (Form I) 6 · Methoxy-2- (4- (methoxyphenyl) -3- [4- (2-hexaargon u than fluorenylethoxy) fluorenyl] phenylfluorene [b], thiophene hydrochloride ( 2.0 g), the solution in 1,2-digas ethane (20 ml) was treated with boron trioxide (2.0 ml). The resulting mixture was stirred at 35 ° C for about 18 hours. A mixture of ethanol and formazan ( 10 ml, 95: 5, 3A) treated with the above reaction mixture to bring the alcohol mixture back to -38- P. Eil I -------- r / ^ — .-C · (Please read the note on the back first $ Item to fill in this page &gt; Binding book paper size Chinese National Standard (CNS) A4 size (210X297 mm) Printed by Shellfish Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs Α7 Β7 V. Description of invention (35) ) Treatment for 30-35 minutes. After stirring for 18 hours, the reaction is analyzed by hPlc for element integrity. If the initial super acid is present, the grass gas can be added to the reaction. After completion, the reaction solution is evaporated in the air Dried. The residue is dissolved in Diqijiahu (200ml) to form The liquid was evaporated to dryness and the dissolution / evaporation procedure was repeated to obtain the title compound as a solid. The title compound could be stored as a solid or as a 0.2M solution in digas methane (500 ml). Example 1 6 -Methoxy-2- (4 • methoxyphenyl) -3- (4- (2-hexahydropyridylethoxy) benzylfluorenyl] benzenefluorene [b] fluorene hydrochloride The compound prepared as described in Preparation 1 (8.46 G) and the mixture of the brewed base gas (10.0 g) prepared in one gas in one gas (350 ml) as described in Preparation 4 was cooled to about 20-2 5 ° C. The mixture was cooled with boron trioxide (2 6 Ml) treatment, and the resulting mixture was mechanically stirred. The reaction was detected by H PLC using the above analysis method. After 85 minutes, according to 6-methoxybenzene-2- (4-oxophenyl) -3- [4- The standard HPLC yield of (2-77 氲 specific ethyl ethyl lactate) erythroyl] phenyl hydrazine [{]] thiophene is 88%. Example 2 6 -Chino-2 · (4-Chinophenyl)- 3- [4- (2-Hexahydroethenylethoxy) benzyl] phenylhydrazone [b] &lt; * Sephine hydrochloride 1,2-dichloroethane solvate (Form I) 6- Methoxy-2- (4- (methoxyphenyl) -3- [4- (2-hexahydroetoethoxy) pyrene] benzene [ b] Pyrophene hydrochloride (2.0 g), the solution in 1,2-digas ethane (20 ml) was treated with boron trioxide (2.0 ml). The resulting mixture was stirred at 3 5 ° C for about 1 8 hours. A mixture of ethanol and methanol (100 ml, 95: 5, 3A) was treated with the above reaction mixture to return the alcohol mixture to -38.-This paper size applies the Chinese National Standard (CNS) A4 ^ 4M 210X297 mm)- -------- Install-知 I ^ {\ (Please read the precautions on the back before filling this page) Order

U Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (36) Stream. After the addition was completed, the resulting crystalline slurry was stirred at 25 ° C for 1 hour. After that, the crystalline product was filtered, washed with cold ethanol (10 ml), and dried in the air at 40 ° c to obtain 1.78 g of the title compound ^ X The light powder diffraction pattern is the same as that reported in Table 1. Melting point is 255 ° C. Efficiency: 8 0.2% 1,2-digas: 7 · 5. / 〇 (gas chromatography), 3 6-hydroxy-2- (4-hydroxyphenyl) -3 · [4- (2-hexahydropyridylethoxy) fluorenyl] benzene [b] 〇Sephine hydrochloride digas methane solvate (Form IV) The compound prepared as described in Preparation 1 (7.54 g) in digas methane (10 ml) and the tritium base gas prepared as described in Preparation 4 ( 140 ml of a mixture of 0.21 M solution in digas methane) was placed in a sealed reactor ---- Hastalloy Parr. The solution was cooled to 0 ° C and treated with triple gasification # (7.2 mL). The resulting reaction mixture was stirred at room temperature. After 3 hours, the reaction mixture was cooled in an ice bath for 10 minutes. A second chlorine ^ boron (4.8 ml) was added to the reaction mixture, and after heating the mixture to 7 5 2 · 5 hours, the reaction mixture was cooled to about 15 eC. The cooled mixture was treated with tetrahydrofuran (15 ml) and methanol (45 ml). The mixture was stirred at 18 ° (for about 1 hour to produce a crystalline solid. The crystalline solid was removed by filtration, rinsed with cold methanol (45 ml), and dried at 40 ° C for 18 hours in the air, yielding 12.5 g of the title compound X-ray powder diffraction pattern is the same as reported in Table 4. Melting point 207 ° C. Efficiency: 8 1.8% Digas: 0.4 Molar equivalent &quot; Η N MR)-_- 39-, this paper size applies China National Standard (CNS) A4 (210X297 mm) f Please read the notes on the back before filling out this page}-Binding and ordering Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs _. '_B7__ DESCRIPTION OF THE INVENTION (37) Example 4 6-Ritual · 2 · (4-Cancerylphenyl) -3- [4- (2-Hexathiopyridine-ylethoxy) 醯 醯] benzene 幷 [b], Sephene hydrochloride 1,2-digasethane solvate (compound obtained as described in Preparation 3 (15 g) and dimethylpyridine (0.2 ml) in dioxane (250 ml) The mixture was cooled to 0 ° C. Phosgene (8.25 ml) was condensed in a cold jacketed addition funnel (-10. (;), And added to the cold mixture over a period of 2 minutes. The mixture is heated to about 4 7 ° C. After about 2.5 hours, the reaction is analyzed by PLC for completeness. Phosgene can be added to make the reaction complete. Excess phosgene is at 30-32 * C and 105-110. mmHg was removed by vacuum distillation. After about 3 to 4 hours, the reaction solution was treated with the compound (13.52 g) prepared in Preparation 1. The resulting solution was cooled to 0 ° C. Boron trioxide (12.8 ml) Condensed in a graduated cylinder and added to the cold-reaction mixture. After 8 hours, the reaction solution was treated with boron trioxide (1 2.8 ml). The pre-formed solution was heated to 30 ° C. After 15 hours The reaction was tested for completeness by η PLC. The mixture of ethanol and methanol (125 ml, 95: 5, 3A) was heated to reflux and treated with the above reaction solution for 60 minutes. After the addition was complete, the acidification / demethylation reaction flask Rinse with 3A ethanol (30 ml). The resulting slurry is allowed to cool to room temperature and stirred. After one hour at room temperature, the crystalline product is filtered, washed with 3A ethanol (75 ml), and dried at 40 ° C in the air. To obtain 25.9 g of the title compound. X-ray powder diffraction is reported in the table! Melting point 261 ° C 〇 Efficiency: 8 7.1% ____ -40- This paper size applies to China National Standard (CNS specification (210X297 mm)-(Please read the precautions on the back before filling this page) Binding A7 B7 Economy Printed by the Ministry of Standards and Technology ’s Consumer Cooperatives. V. Description of the invention (38) l2-Digas II pit: 0.55 Molar equivalent (iH NMR) Example 5 6-Hydroxy-2- (4-hydroxyphenyl) _3_ [4 · (2-Hexahydropyridylethoxy) benzylfluorenyl] phenylhydrazine [b] fluorene hydrochloride gas benzene solvate (crystal form 1η) The compound (2.92 g) prepared as described in Preparation 1, A solution of the acid-based gas (3.45 g) prepared in benzene (52 ml) as described in Preparation 4 was cooled to about 0 t. The cold solution was treated with a two-gasification butterfly (28 ml). The resulting solution was mechanically stirred at about 0 ° C. After 3 hours, boron trichloride (2.8 ml) was added and the reaction mixture was warmed to room temperature. After about 16-20 hours, the reaction mixture was cooled to 0 ° C. The cold reaction was quenched by slowly adding ethanol (26 ml) over 30 minutes. During the addition of the alcohol ', a crystalline solid form. After the alcohol was completely added, the resulting mixture was stirred at room temperature for 1 hour. The crystalline solid was removed by filtration, washed with cold ethanol (25 ml), and dried at 4 ° C. in the air to obtain 5.94 g of the title compound. The β-ray powder diffraction pattern as a yellow solid was the same as reported in Table 3. Melting point 247 ° C. Efficiency: 7 8.6% Gas benzene: 12.3% (HPLC) Example 6 6-Hydroxy_2- (4-hydroxyphenyl) -3- [4- (2-hexapyridylethoxy) benzyl Group] Benzamidine [b] pyrimidine hydrochloride 1,2-digasethane solvate (Form I) Compound prepared as described in Preparation 1 (2.92 g), compound prepared as described in Preparation 4 ( 3.45 g) and 1,2-digas ethane (52 ml) were cooled to 0. T: boron tri-gas boron was condensed in a cold cylinder (2.8 ml) and added to the above cold mixture. At 0 ° C After 8 hours, the reaction mixture ί · ^^ 1 HI 1Λ ΐ—--I— »* f '(Please read the notes on the back before filling this page) Order

U This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm). Printed by the Masonry Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. A7 B7 5. Invention Description (39) ~ Treated with boron trioxide (2.8 ml). The resulting solution was heated to 35x :. After 16 hours, the reaction was complete. Methanol (30 ml) was treated with the above reaction mixture for 20 minutes, and the methanol was refluxed. The resulting slurry is at 25. 〇 Stir. After 1 hour, the crystalline product was filtered ', washed with cold methanol (8 ml), and dried in the air at 40 ° C to obtain 5.14 g of the title compound. The calender powder diffraction pattern is reported in Table 2. Melting point 22 5 ° C 〇 Efficiency: 8 6.8 〇 Digas ethane: 6.5% (gas chromatography) Example 7 6-Cycloyl 2- (4-hydroxyphenyl) -3- [4- (2 -Hexahydropyridinylethoxy) fluorenyl] phenylphosphonium [b] phenophenone hydrochloride The compound (4.0 g) prepared as described in Example 4 was slurried in methanol (30 ml) at room temperature. . The resulting mixture was treated with a solution of sodium hydroxide (0313 g) in methanol (10 ml). After complete dissolution, activated carbon (0.4 g, Darco G-60, Aldrich Chem. Co., Inc., Milwaukee, WI) was added to the solution. After 30 minutes, the slurry was filtered through Whatman # 1 filter paper (Hyflo Supper Cel®, Aldrich Chem. Co.) precoated with diatomaceous earth. The filter cake was rinsed with methanol (10 ml). The combined filtrates were treated (dropwise) with 2N hydrochloric acid (4 mL). The resulting slurry was stirred at room temperature for 60 minutes and simmered. The mash was rinsed with cold methanol (14 ml, 0 ° C), and dried in the air at 60 ° C for about 18 hours to obtain 3.00 g of an off-white free-flowing powder. Melting point 262 eC. Efficiency: 9 9.1% ~-42-This paper size adopts China National Standard (CNS) A4 specification (210X297 cm) I--I -I— II---II— HA.. &Gt;:! : * »,. / Ν. (Please read the note on the back before filling this page) Order

U Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (4〇) Relevant substances: 0.8 5% Example 8 6-Echil-2- (4-Epiphenyl) _3_ [4_ (2_ Hexaargylpyridylethoxy) benzyl] phenylbenzene [b] pyrimidine hydrochloride 12_digasethane solvate (crystalline form) 6-Weiyi-2- (4-Weiphenyl) _3_ [ A saturated solution of 4_ (2_hexahydropyridylethoxy) fluorenyl] benzene [b] fluorenic acid salt was prepared by stirring a slurry of the compound prepared in Example 7 in methanol at room temperature overnight, and Manufacturing. The mixture was filtered (Whatman # 1 through paper). A portion of the filtrate (205-2 ml) was placed in a 50 ml Erlenmeyer flask. Β This flask was placed in a glass jar (3.5 inches x 4 inches) containing U2-digas ethane (about 10 ml). The cylinder was sealed and placed at room temperature. After 24 hours, the single-crystals crystallized from the methanol solution. The crystals were filtered and dried in the air. Fusion Stick 273 τ. The crystal structure was measured with a Siemens R 3 m / v automatic quadrupole diffractor using monochromatic copper radiation (again = 1.5 4 1 7 8 Angstroms). The crystal structure is determined using the direct method, the general TREF of the SHELXTL PLUS library. The full matrix is the squared correction system f. The anisotropic temperature factor of all atoms (except hydrogen) enters ~, which includes the isotropic temperature factor in the calculation position. Final + 8.0 2%. The crystallization data are shown below. Crystallization data

Spacer C2 / C anisotropic unit a = 20.720 (7) angstroms b = 9.492 (2) angstroms c = 28.711 (4) angstroms--43-ΪPaper size is applicable to Chinese National Standard (CNS) A4 specifications (210X297mm H ~ ^ ~ ^ --- (Please read the precautions on the back before filling out this page) Installation, 1T V. Description of the invention () A7 B7 Printed by the Staff Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs / 5 = 96.50 (2) ° 5610 (2) Angstrom 3 1.409 mg / m3 3.951 mm'1 X-ray structure clearly shows that the crystalline substance is a solvate of 1,2-digas, and a molecule pair of 1,2-digas. -(4-Epiphenyl) -3- [4- (2-hexahydropyridylethoxy) benzylfluorenyl] benzenefluorene [b] &quot; Sephen hydrochloride has a 1: 2 ratio. Example 9 6-Hydroxy-2 · (4-hydroxyphenyl) · 3- [4- (2-Hexahydropyridylethoxy) benzylfluorenyl] benzenefluorene [b] 〇thiophene hydrochloride1,2,3 -Trichloropropane solvate (crystal form II) Compound (2.70 g) prepared as described in Preparation 1, compound (3.60 g) prepared as described in Preparation 4 and 1,2,3-trifluoropropane (50 ml) The mixture was treated with boron trioxide (2.6 ml). After 3 hours at 20-2 5 ° C, the reaction mixture was treated with boron trioxide (2 · 6 ml). After about 18 hours, the reaction mixture was treated with tetrahydrofuran (15 ml), and then methanol (15 ml) was slowly added. After these additions were complete, the resulting mixture was stirred at room temperature. In 1 hour Then, the crystalline solid was collected by tritium, washed with cold methanol (10 ml), and dried in tritium at 50 ° C to obtain 4.13 g of the title compound. The X-ray powder diffraction pattern was equal to that reported in Table 2 Ό. Efficiency: 7 8.9 〇 / 〇1,2,3-trigas propane: 0.5 Molar equivalent (丨 {1 NMR) Example 1 0 ------ &quot; -44- Bulk density (calculated) Absorption coefficient --------- r 1 pack— -m χ-ίν (Please read the precautions on the back before filling in this page), ιτ

'Ί IV This paper Α degree is applicable to national standard (CNS) Α4 size of τ country (210X297 mm). A7 printed by Huanggong Consumer Cooperative of Central Bureau of Standards of the Ministry of Economic Affairs; __B7____ 5. Description of the invention (42) 6 -hydroxyl- 2- (4-hydroxyphenyl) -3- [4- (2-hexahydropyridylethoxy) benzylfluorenyl] phenylhydrazine [b] pyrimidine hydrochloride aeroform solvate (Form IV) The title compound (4.22 g) was prepared using the procedure described in Example 9, but the reaction solvent was aerobic (50 ml). X-ray powder diffraction is equivalent to the reporter in Table 4. Melting point is 258 ° C. Efficiency: 8 0.4 Aeroform: 0.42 Molar equivalent NMR) Example 1 1 6-Hydroxy-2- (4-hydroxyphenyl) -3_ [4- (2-hexahydropyridylethoxy) fluorenyl] benzene幷 [b] «• Sephine hydrochloride sodium hydroxide (0.313 g) in methanol (10 ml) was diluted with methanol (50 ml). This solution was treated with a compound (40 g) prepared as described in Example 6. After 45 minutes at room temperature, the solution was filtered (What man # 1 遽 paper), the paper was rinsed with methanol (3 ml), and the liquid was treated with 2N man · acid (4 ml) to produce a crystal solution. After 1 1/2 hours, the crystallized product was washed with methanol, washed with methanol (5 ml), and dried in the air at 45-50X) to obtain 2.103 g of the title compound. The X-ray powder diffraction pattern is the same as reported in Table 5. Melting point 2 6 1 ° C. Efficiency: 9 6.5. Example 1 2 6-Ethyl-2- (4 · Ethyl) -3- [4- (2-hexahydro? Pyridylethoxy) benzyl] benzo [b] pyrene salt A solution of the sodium hydroxide (0.313 g) in methanol (10 ml) was diluted with methanol (40 ml) and water (10 ml). This solution was prepared as described in Example ____- · 45 _ This paper size applies to Chinese National Standard (CNS) Α4 size (210X297 mm) ---- f Please read the precautions on the back before filling this page } -Packing · 1T &quot; B7 ______ V. Description of the Invention (43) &quot;-t compound (4.0 g) treatment. The resulting solution was extracted with hexane (2 x 50 ml) to remove benzene. The methanol phase was treated with 2N hydrochloric acid (4 ml) to produce a crystalline slurry. After 1 hour, the crystalline product was filtered, washed with methanol (5 ml), and dried in the air at 60C to obtain 223 g of the title compound. The light powder diffraction pattern was the same as reported in Table 5. Melting point 272. (:. Efficiency: 9 7.5% Residual benzene: <3% (HPLC) Related substances: 0.9 4% Example 1 3 6-Hydroxy-2- (4-hydroxyphenyl) -3_ [4_ (2 · hexahydro Pyridylethoxy) benzylfluorenyl] phenylhydrazine [b] »» Sephine hydrochloride The Central Sample Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, printed the compound prepared as described in Example 4 (50 g) in methanol ( The mixture in 1125 ml) and water (60 ml) was heated to reflux until completely dissolved. The hot stock solution was washed over (Whatman # 1 paper), and the residue was washed with methanol (200 ml). The combined filtrate Concentrate by distillation and remove 207 ml of the discharged material. Crystallization occurred during copper evaporation. The resulting liquid was cooled to room temperature and filtered. The crystals were washed with cold (0 ° C) methanol (170 ml). This The material was dried in the air at 60 ° C for about 18 hours and washed with a small amount of nitrogen to obtain 38.79 g of a yellow-brown free-flowing solid. Melting point 275.6 aC. Efficiency 9 9.4 0 / 〇 Residual methanol: <0.6 ° / 〇 (GC ) Related substances: 0.5 1% (Η PLC): _______ · 46-This paper size applies the Chinese National Standard (CNS) Α4 specification (210χ: 297 mm) ''- ---

Claims (1)

A8 B8 · C8 D8 Patent application scope 1. A method for preparing a solvate crystal of a compound of the formula r3 och2ch2n ^ · ηχ R2 where: R1 is hydrogen or hydroxyl; 'R2 and R3 are each C / C4 alkyl, or R2 And R3 forms a heterocyclic ring with an attached nitrogen atom, selected from pyrrolidinyl, hexahydropyridyl, cyclohexaneimino and morpholino; and HX is HC1 or HBr; including the following steps (a): The following formula of phenylpyrimidine (please read the precautions on the back before filling this page) Printed by the Central Consumers Bureau of the Ministry of Economic Affairs α R4 where R4 is hydrogen or 0: 1.4 alkoxy group, and R5 is (^ .4 alkyl group, amylating agent of the following formula -47 Chinese paper standard (CNS) A4 specification (210X297 mm>) Application scope R6 III AS B8 C8 D8 0ch2ch2n (ηχ R2 where R6 is gas, bromine or hydroxyl, HX, R2 and R3 are as defined above; in the presence of BX'3, where X 'is gas or bromine; ( b) the dealkylation of one or more phenolic groups of the tritiated product of step (a) by reaction with another BX, 3, where X is as defined above; and (c) isolating the solvate crystals. 2 The method according to item 1 of the scope of patent application, wherein R1 is a hydroxyl group, R2 and R3 form a hexahydropyridyl group with a nitrogen atom connected thereto, R4 is a methoxy group, R5 is a methyl group, R6 is a gas, and HX is HC1, X 'is gas. 3. —A method for preparing the solvate crystals of the compound of the following formula: (Please read the precautions on the back before filling this page) R3 OCH2CH2N (· HX R2 where: R1 is argon or hydroxy-48- This paper size is based on Chinese national standard (CNS &gt; A4 size (210X297 mm) D8, the scope of patent application R2 and R3 are each Crq alkyl Or, R2 and R3 form a heterocyclic ring with a nitrogen atom connected thereto, selected from pyrrolidinyl, hexahydropyridyl, cyclohexaneimino and morpholino; and HX is HC1 or HBr; including (a) Dealkylation of one or more phenolic compounds of the formula och2ch2n (. hx R2 where R4 is hydrogen or 0 ^ 4 alkoxy, R5 is Ch4 alkyl, HX, R2 and R3 are as defined above; by reaction with BX'3, where X 'is gas or bromine; (b ) Separate the crystals of the agent. Printed by the Central Government Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative. 4. The method according to item 3 of the scope of patent application, where R1 is a hydroxyl group, and R2 and R3 together with the connected nitrogen atom form hexaargyridine R4 is methoxy, R5 is methyl, HX is HC1, and X 'is gas. 5.6-Hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-hexahydropyridylethoxy) Base) The solvate crystal of phenyl [b] pyrimidine hydrochloride, with the following X-ray diffraction pattern obtained by copper radiation: -49- This paper is applicable to China National Standard (CNS) A4 Specifications (210X297 mm) Printed by the Central Bureau of Standards, the Ministry of Economic Affairs, Shellfish Consumer Cooperative, A8, B8, C8, D8 6. Scope of patent application, d-line interval ι / ι0 (Angel) (xlOO) 10.4311 22.64 8.9173 10.73 8.4765 5.31 8.0095 50.39 7.3068 4.23 6.6094 79.23 5.6196 22.34 5.4223 89.86 5,1959 11.81 5.0746 74.90 4.8017 100.00 4.7262 57.97 4.6569 53.35 4.5378 96.75 4.4376 10. 83 4-3397 56.89 4.2782 48.23 4.2129 40.94 4.1037 12.80 3.9880 14.76 3.8863 8.17 3.7999 '42 .13 3.7662 57.09 3.6738 38.58 —— 3.5701 18.50 3.5393 19.00 3-4622 39.57 3.3867 5.02 3.3321 4.33 3.2686 6.79 3.1535 14.86 3.0450 13.58 2.9028 12.30 2.8302 19.59 2-7 23.7 2.6366 6.89 n ^ in ^ i ^ nt n ^ ilin--. (-(Please read the precautions on the back before filling out this page) Order • J- -50- This paper is a Chinese standard for quick use of paper standards (CNS) A4 specifications (210X297 Gong) ABCD VI. Patent Application Park 6. The solvate crystal according to item 5 of the scope of patent application, which is 丨, 2-diethane solvate or 1,2,3-tripropane solvate . 7. 6-Hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-hexahydropyridylethoxy) benzylfluorenyl] phenylfluorene [b] solvate crystals of pyrimidine hydrochloride , With the following X-ray diffraction pattern obtained with copper radiation: -Line spacing 1/1 10. Angstrom,) (xlOO) 16.1265 3.80 10.3744 8.63 8.3746 5.29 I n ^ i In ^^^ 1 ml nn K 'Jm— n ^ intw ΓΛ. (Please read the notes on the back before filling out this page) Order ^^ Printed by the WC Industrial Consumer Cooperative of the Central Ladder and Harvest Bureau of the Ministry of Economic Affairs *. -51- &gt; Paper Standards Free Use of China National Standards (CNS) A4iitt. (210X297i ¥ T A8 B8 C8 D8 VI. Application for Patent Scope Central Standards Bureau of the Ministry of Economic Affairs w: Industrial and Consumer Cooperative Cooperative Seals-Line Spacer / 10 Angstroms) (x100) 7.9883 36.71 7.2701 5.06 6.5567 70.77 6.2531 6.79 5.5616 24.05 5.3879 100.00 5.0471 89.64 4.7391 85.96 4.6777 39.36 4.6332 62.60 4.5191 77.56 4.2867 36.82 4.2365 41.66 4.1816 49.60 4.0900 11.28 3.9496 11.85 3.7869 36.25 3 Knife 577 56.16 3.6509 40.62 3.5751 15.65 3.5181 21.52 3.4964 18.53 3.4361 33.60 4.610 3.610 3.21 6.21 3.21 6.21 80 3.1199 15.77 3.0347 14.84 2.8744 9.67 2.8174 10.82 2.7363 11.51 52- (Please read the precautions on the back before filling out this page). Packing. The size of the paper is applicable to China National Standard (CNS) A4 specification (210X297 mm) 々, apply Scope of patent 8. The solvate crystal according to item 7 of the scope of patent application, which is 1,2-digasethane solvate. 9. Preparation of 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-hexaaziridinylethoxy) benzylhydrazone having the following X-ray diffraction pattern obtained with copper radiation [Method] Crystallization of the solvate of phenyl] [b] pyrene hydrochloride d-line spacing ". (Eng.) (XlOO) 14.3518 V.24 10.3335 6.17 8.8305 4.29 7.9475 38.16 6.5904 64.25 6.2848 6.52 5.6048 28.06 5.4107 100.00 5.1544 11.26 5.0493 53.26 5.0224 46.11 18330 76 · 94 4.7694 34.23 4.6461 50.22 Printed by the Consumer Cooperative Bureau of the Central Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page) 4.5754 38.61 4.4953 72.65 4.3531 49.15 4.2940 41.64 4.2425 35,75 4.1856 21.63 4.1338 9.47 4.0793 12.69 -53- This paper size applies to China National Standard (CNS) A4 specification (210X297) (Ii) 范围. Scope of patent application: The Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperatives, printed A8, B8, C8, D8, d-line spacers / 1. Egypt) (xlOO) 3.9960 18.50 3.9037 9.03 3.7854 40.39 3.7521 54.16 3.6787 28.60 3.6509 17.96 3.5444 31.72 3.4679 41.55 3.3899 7.69 3.3101 5.72 3.2561 7.42 3.1784 15.19 3.0445 .11.17 3.0146 8.94 2.9160 11.89 2.8217 18.23 2.7500 12.06 2.6436 9.65 2.6 --156 --- 1 ^ .-- * Aw / V. (Please read the notes on the back before filling in this page) -54- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 6. Apply for a patent The range includes the following steps: (a) Pyridoxine A8 B8 C8 D8 II where R4 is (^ .4 alkoxy group, R5 is C t. 4 alkyl group, amylating agent of the following formula r3 och2ch2n (· Η × R2 (please read the precautions on the back before filling in this page) In the printed form of the Central Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, R6 is gas, and R2 ml forms a hexahydropyridyl group with the connected nitrogen atom , HX is HC1 in the presence of BC13 in gaseous benzene; (b) the dealkylation of the hydrochloride salt of a compound of the formula, This paper uses Chinese National Standard (CNS) A4 specification (210X297 mm) A8 B8 C8 D8 6. In the patent application, R7 is Ci.4 alkyl, (c) The reaction in step (b) is quenched with methanol And by reacting with bC13; (d) separating the solvate crystals. 1 Preparation of unsolvated crystal 6-hydroxy-2-(4-hydroxyphenyl) -3-[4- (2-hexahydropyridylethoxy) fluorenyl] phenylfluorene [b] fluorene hydrochloride Salt, in essence, has the following X-ray diffraction pattern obtained by copper radiation: ^^^ 1 nn I * 'I ^^^ 1 I i · .. (. (Please read the notes on the back before filling (On this page) Printed by the Central Laboratories of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives «L • Line interval 1/10 Angstroms) (xlOO) 13.3864 71.31 9.3598 33.16 8.4625 2.08 7.3888 7.57 6.9907 5.80 6.6346 51.04 6.1717 29.57 5.9975 5.67 5.9135- 9.87 5.6467 38.47 5.4773 10.54 5.2994 4.74 4.8680 4.03 The size of the revised paper is applicable to the Chinese National Standard (CNS) A4 specification (21 ×: 297 mm) 6. Scope of patent application d-line interval A8 B8 C8 D8 Zhengong Consumption Cooperative of the Central Government Bureau of the Ministry of Economy Printed, Egypt 4.7910 4.6614 4.5052 4.3701 4.2516 4.2059 4.1740 4.0819 3.9673 3.9318 3.8775 3.7096 3.6561 3.5576 3.5037 3.4522 3.4138 3.2738 3.1§57 3.1333 3,0831 3.0025 2.9437 2.8642 2.7904 2.7246 2.6652 2.5882 1 / 1〇 (xlOO) 5.98 57.50 5.75 9.03 69. 99 57.64 65.07 12.44 22.53 100.00 9.07 33.38 21.65 3.36 7.97 18.02 4.65 10.23 8.90 6.24 9.43 12.13 4.96 7.70 11.95 3.05 3.32 7.30 -57- This paper uses China National Standard (CNS) A4 size (210X297 mm) (Please read the back first) (Please note this page before filling in this page) A8 B8 C8 D8 VI. The scope of patent application includes the following steps (a) Phenylpyrimidine of the following formula In the formula, R4 is Cb4 alkoxy group, R5 is Ci.4 alkyl group, the following formulating agents R6 och2ch2n, HX R2 Industry II In the formula of the Central Government Bureau of the Ministry of Economic Affairs, the Bureau of Shellfish Consumer Cooperatives, R6 is gas, bromine Or hydroxy, HX is HX1 or HB r, R2 and R3 form a hexahydropyridyl group with the nitrogen atom to which it is attached; in the presence of bx'3, where X 'is gas or bromine; (b) the halogenation of step (a) Dealkylation of the phenolic group of the product, by reaction with another bx'3, where X is as defined above; (c) separation of solvate crystals of the compound of formula -58 This paper is applicable to China National Standards (CNS) A4 specification (210X297mm) "Binding S '^% · / V / V (Please read the precautions on the back before filling out this page) 3897dC A8 B8 C8 D8 VI. Patent Application Scope 〇CH2CH2N (· HX R2 Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, where R1 is a hydroxyl group, HX, R2 and R3 are as defined above; (d) the solvate is crystallized in methanol or a mixture of methanol and water About one equivalent of a base reaction, (e) Selectively extract the solution obtained from step soil (d) with an aliphatic hydrocarbon solvent, (f) Add about 1 equivalent of hydrochloric acid to the methanol solution obtained from step (d) or (e) , And (g) to separate non-solvated crystalline compounds. Let the method according to item 10 of the scope of the patent application, where R4 is methoxy, R5 is methyl, R6 is gas, HX is HC1, and 8 乂 '3 is 80 : 〖3, the aliphatic hydrocarbon solvent is hexane or heptane, and the base is sodium oxynitride 〇— 一. 12. — Preparation of non-solvated crystals 6-light-based-2-(4-phenyl) -3- [4-(2-Hexahydropyridylethoxy) benzylfluorenyl] benzenefluorene [b] pyrene hydrochloride essentially has the following method of X-ray diffraction of europium obtained by copper radiation: • 59 · 本Paper size: National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page) l. Packing. Order 38976C A8 B8 C8 D8 Six Patent application scope d-line interval: Egypt 13.3864 '9.3598 8.4625 7.3888 6.9907 6.6346 6.1717 5.9975 5.9135 5.6467 5.4773 5.2994 4.8680 1 / 1〇 (xlOO) 71.31 33.16 2.08 7.57 5.80 51.04 29.57 5.67 9.87 38.47 10.54 4.74 4.03 (Please read the note on the back first Please fill in this page again) Printed by Zhengong Consumer Cooperative of the Ministry of Economic Affairs of the People's Republic of China -60- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 38376C A8 B8 C8 D8 Patent Application Scope Printed by the Central Labor Association, Zhenggong Consumer Cooperative Co., Ltd. d-line interval (E.). 4.7910 4.6614 4.5052 4.3701 4.2516 4.2059 4.1740 4.0819 3.9673 3.9318 3.8775 3.7096 3.6561 3.5576 3.5037 3.4522 3.4138 3.2738 3.1857 3.1333 3.0831 3.0025 2.9437 2.8642 2.7904 2.7246 2.6652 2.5882 I / I 〇 (x100) 5.98 57.50 5.75 9.03 69.99 57.64 65.07 12.44 22.53 100.00 9.07 33.38 21.65 3.36 7.97 18.02 4.65 10.23 8.90 6.24 9.43 12.13 4.96 7.70 11.95 3.05 3.32 7.30 -61-This paper uses the Chinese National Standard (CNS) A4 specification (210X297) Mm) (Please read the back Please fill in this page again for the matters needing attention)-Binding and ordering 389 generations. 6. The scope of patent application includes the following steps. (A) The phenoxyphene of the following formula A8 B8 C8 D8 In the 1 formula, R4 is C ^ .4 alkoxy group, R5 is Ci.4 alkyl group, and the following formula R6 OCH2CH2Nv'hx (please read the precautions on the back before filling this page) — equipment, 1T In the printed format of the Central Standards Bureau of the Ministry of Industry and Economics and the Industrial and Consumer Cooperatives, R6 is gas, bromine, or hydroxyl, HX is H-C1 or HBr, and R2 and R3 form a hexahydropyridyl group with the nitrogen atom attached; 3, where X 'is gas or bromine; (b) the dealkylation of the phenolic group of the tritiated product of step (a), by reaction with another BX'3, where X, as defined above; ( c) Isolate solvate crystal of compound of the formula -62 This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) ο 38976C Αδ Β8 C8 D8 6. Scope of patent application och2ch2n / rR; .hx I where R1 is a hydroxyl group, Η X, R2 and R3 are as defined above; (d) the solvate crystals are dissolved in a hot solution containing methanol and water; (e) the selectivity is obtained from The solution of step dish (d), (f) the solution obtained from step (d) or (e) is concentrated by distillation; and (g) the non-solvated crystalline compound is isolated. 13. The method according to item 12 of the scope of patent application, wherein R4 is methoxy, R5 is methyl, R6 is gas, HX is HC1, and EX'S is BC13. (Please read the note on the back before filling in this page) rv .l · Binding · Binding '· V Printed by the Central Government Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives, 63- This paper standard is free to use Chinese National Standards (CNS &gt; A4 size (210X297 mm)