CN1694860A - The preparation method of spirofluorenol - Google Patents

Abstract

A spirofluorenol such as 3 ', 9' -dimethoxy-5 '-hydroxyspiro [ (1H-cyclopenta [ d, e, f ] phenanthrene) -1, 7' -benzo [ c ] fluorene ] or the like is produced by protecting a hydroxyl group bound to a specific fluorenone compound such as 3, 9-dimethoxy-5-hydroxybenzo [ c ] fluoren-7-one with a "substituted silyl group having 5 to 12 total carbon atoms of substituents bound to a silicon atom" such as t-butyldimethylsilyl group, reacting the protected hydroxyl group with a specific organometallic compound such as 1-lithiophene to cyclize the resulting product, and deprotecting the product. By the method, the spirofluorenol which can be used as a photochromic compound raw material can be efficiently prepared.

Description

The preparation method of spirofluorenol

Field of invention

The invention relates to a preparation method of spirofluorenol which can be used as a photochromic compound raw material.

current technology

In recent years, chromene derivatives, especially spiroindenonaphthopyranes, have attracted attention as photochromic compounds because of their rapid color development and fading properties, ease of color tone control, and high durability. Spiroindenonaphthopyrans are known to include spiroketal-type compounds (see Patent Document 1), biphenyl-type spiro compounds and phenanthrene-type spiro compounds (refer to Patent Documents 2 and 3), and the latter two compounds in particular The color sensitivity is high, the fading speed is fast, and it has excellent durability.

It is known that the above compound can be obtained by preparing an indenonaphthopyran-one represented by the following formula (5) having a desired substituent as an intermediate and further modifying the intermediate (see Patent Documents 2 and 3).

However, when this method is used, since the above-mentioned indenonaphthopyran-one itself as an intermediate has photochromism, there is a problem that by-product impurities generated during the reaction usually also have photochromism. That is, when such impurities are mixed in the spiro compound which is the target substance, the color tone at the time of color development becomes different from the original color tone of the target substance. Therefore, a high degree of purification is required in order to obtain the target substance of desired color tone.

On the other hand, a method for producing a target substance, a chromene derivative, from spirofluorenol is known as a production method that is less likely to generate photochromic impurities (see Patent Document 3).

Patent Document 1: Japanese PCT Publication No. H10-508031

Patent Document 2: Japanese Patent Laid-Open No. 2000-34418

Patent Document 3: Japanese Patent Laid-Open No. 2001-192378

However, the above-mentioned method is to react hydroxyfluorenone having a phenolic hydroxyl group with a Grignard reagent, etc., and to obtain spirofluorenol by performing spirocyclization under acidic conditions, so in order to terminate the reaction, an excessive amount of Grignard reagent, etc. must be used, As a result, there was a problem that the yield was low.

Contents of the invention

Therefore, the object of the present invention is to provide a method for efficiently preparing spirofluorenol, which can be used as a raw material for photochromic compounds.

The inventors of the present invention considered reducing the amount of organometallic reagents such as Grignard reagents by protecting the hydroxyl group of hydroxyfluorenone when preparing spirofluorenol, and therefore studied the effects of various protecting groups. As a result, it was found that when a specific protecting group was used to protect the hydroxyl group, compared with the case of using a commonly used protecting group, the selectivity and conversion rate were high when the protecting group was introduced, and the protecting group was not easy to fall off in the reaction of the subsequent step, and In deprotection (removal of the protecting group), the reaction can proceed in good yield, and the present invention has been accomplished.

The present invention relates to the preparation method of spirofluorenol compound, and this method is following formula (1)

The preparation method of the shown spirofluorenol compound is characterized in that: the hydroxyl group combined on the fluorenone compound shown in the following formula (2) is protected with a protecting group formed by a substituted silyl group, and the substituted silyl group is connected with The number of carbon atoms of the substituent bonded to the silicon atom is 5-12 in total, and then the fluorenone compound is reacted with an organometallic compound represented by the following formula (3) to obtain a hydroxy-aryl fluorenol whose hydroxyl group is protected by the above-mentioned protecting group, The resulting hydroxy-arylfluorenol is spirocyclized and deprotected,

In the formula, M is Li, MgCl, MgBr, MgI or CuLi;

In the above formula (1) to formula (3),

X is a single bond or any divalent group selected from the following group A,

Y is a group that forms an aromatic hydrocarbon ring group or an unsaturated heterocyclic group together with two carbon atoms of the benzo ring,

When X is a single bond, R ¹ and R ² are respectively a hydrogen atom, any univalent group selected from the following group B, or are combined to form any divalent group selected from the following group A (wherein -Z - and -CR ⁵ R ⁶ - except) groups,

When X is a group selected from group A, ^R1 and ^R2 are each a hydrogen atom or any monovalent group selected from the following group B,

R ³ and R ⁴ are hydrogen atoms or any monovalent group selected from the following group B,

p and q are each independently an integer of 0-3;

Group A:

-Z-, -(CR ⁵ R ⁶ ) _n -, -(CR ⁵ R ⁶ ) _m -Z-, -Z-(CR ⁵ R ⁶ ) _l -Z-, -(CR ⁵ R ⁶ ) _a -Z -(CR ⁵ R ⁶ ) _b -, -(CR ⁵ =CR ⁶ ) _k - and -CR ⁵ =N- (wherein -Z- is -O-, -S- or -NR ⁵ , R ⁵ and R ⁶ are each independently a hydrogen atom or any monovalent group selected from the following group B. When there are multiple -Z-, R ⁵ or R ⁶ in one group, the multiple -Z-, R ⁵ or R ⁶ Can be different from each other, a, b, k and l are each independently an integer of 1-4, m and n are each independently an integer of 1-6);

Group B:

Alkyl, aralkyl, substituted or unsubstituted aryl, hydroxyl, alkoxy, aralkoxy, amino, monosubstituted amino, disubstituted amino, cyano, nitro, halogen atom, trifluoromethyl, A substituted or unsubstituted heterocyclic group with a bond (bonding hand) on a carbon atom or a nitrogen atom, or a bonded substitution on a carbon atom or a nitrogen atom composed of a fused heterocyclic ring formed by condensing an aromatic hydrocarbon ring or a heterocycle or an unsubstituted fused heterocyclic group.

The best way to practice the invention

(preparation of the target substance)

The spirofluorenol compound represented by the above formula (1) prepared by the preparation method of the present invention can be used as a synthetic raw material for photochromic compounds containing chromene derivatives.

In the above formula (1), X is a single bond or any divalent group selected from the above group A.

The groups listed in Group B above can be used not only as R ⁵ and R ⁶ of the groups shown in Group A, but also as R ¹ , R ² , R ³ or R ⁴ in the above formula (1). Preferred groups in the groups shown in Group B specifically include methyl, ethyl, isopropyl, tert-butyl, cyclohexyl and other alkyl groups with 1-6 carbon atoms; benzyl, phenethyl, triphenyl Aralkyl groups with 7-20 carbon atoms such as methyl; substituted or unsubstituted aryl groups such as phenyl, naphthyl, and alkoxyphenyl; hydroxyl groups; methoxy, tert-butoxy, etc. with 1 carbon atom -6 alkoxy; benzyloxy, trityloxy and other aralkyloxy groups with 7-20 carbon atoms; amino group; methylamino, cyclohexylamino and other monosubstituted carbon atoms with 1-6 Amino; disubstituted amino groups with 1-20 carbon atoms such as dimethylamino and dicyclohexylamino; cyano; nitro; halogen atoms such as chlorine atom and bromine atom; trifluoromethyl; 2-oxazolyl, 4-morpholino, 2,2,6,6-tetramethyl-1-piperidino and other substituted or unsubstituted heterocyclic groups; and 2-benzoxazolyl, 1-benzotriazolyl , 9-carbazolyl, 8-quinolyl and other substituted or unsubstituted condensed heterocyclic groups, etc.

In the above formula (1), when X is a single bond, ^R1 and ^R2 are respectively a hydrogen atom, a group selected from the above group B, or a group that combines with each other to form the group shown in the above group A. That is, when X is a single bond, the compound of the above formula (1) has a 9,9'-spirobifluorene skeleton. For example, when R ¹ and R ² combine with each other to form -CR ⁵ =CR ⁶ -, it has a spiro[fluorene-9,1'-(1H-cyclopentadiene[d,e,f]phenanthrene)] skeleton. However, due to the requirement of three-dimensional space, there will be no situation where R ¹ and R ² combine with each other to form -Z- (ie -O-, -S- or -NR ⁵ -) or -CR ⁵ R ⁶ -.

When X is a divalent group selected from the above group A, R ¹ and R ² are each a hydrogen atom or a group selected from the above group B. In this case, the compound represented by the above formula (1) has a spiro[fluorene-9,9'-xanthene] skeleton (when X is -O-), spiro[fluorene-9,9'-(9,10 -Acridine)] skeleton (when X is -NH-), spiro[fluorene-9,9'-(9,10-dihydroanthracene)] skeleton (when X is -CH ₂ -) and other skeletons , there is no special stereo restriction on R ¹ and R ² .

In the above formula (1), Y is a group that forms an aromatic hydrocarbon group or an unsaturated heterocyclic group together with two carbon atoms of the benzo ring. When Y forms an aromatic hydrocarbon group, the compound of formula (1) has, for example, a benzofluorenol skeleton or a naphthofluorenol skeleton; when Y forms an unsaturated heterocyclic group, the compound of formula (1) has, for example, a furofluorenol (furofluorenol) or indolofluorenol skeleton. In this case, the position or direction of ring fusion is completely arbitrary.

In the above formula (1), R ³ and R ⁴ are any monovalent groups shown in the above group B respectively, and p and q representing the numbers of R ³ and R ⁴ are integers of 0-3 respectively. When p or q is 2 or 3, that is, when there are multiple R ³ or R ⁴ , multiple R ³ or R ⁴ may be different from each other.

(Preparation of spirofluorenol compound)

Starting materials:

In order to prepare the spirofluorenol compound of the above formula (1), the present invention first uses a protecting group formed by a substituted silyl group to protect the hydroxyl group bound to the fluorenone compound represented by the formula (2).

In the formula, Y, R ³ , R ⁴ , p and q are as described in the formula (1). In this case, when the compound of the formula (2) contains an amino group or a substituted amino group, the amino group or a substituted amino group is also Hydroxyl groups are protected together by substituted silyl groups. The protected hydroxyl group is not limited to the hydroxyl group bonded to the 2-position of the fluorenone ring, but also includes the hydroxyl group bonded to other positions. For example, when ^R3 or ^R4 is hydroxyl, amino or a substituted amino group, these groups are also protected by a substituted silyl group together with the hydroxyl group bound to the 2-position of the fluorenone ring. Hereinafter, these groups to be protected are referred to as protective functional groups.

As long as the hydroxyfluorenone used as the starting material is the compound shown in the above formula (2), there is no special limitation to it, but, from the performance considerations of the target photochromic compound, it is preferred that Y is a compound of benzo-fused ring ( That is, a compound having a hydroxybenzofluorenone skeleton). In addition, considering the performance of the target photochromic compound, preferably R ³ and R ⁴ are alkyl groups with 1-6 carbon atoms such as methyl, ethyl, isopropyl, tert-butyl, and cyclohexyl; benzyl, benzene Aralkyl groups with 7-20 carbon atoms such as ethyl and trityl; substituted or unsubstituted aryl groups such as phenyl, naphthyl and alkoxyphenyl; hydroxyl; methoxy, tert-butoxy, etc. Alkoxy with 1-6 carbon atoms; aralkyloxy with 7-20 carbon atoms such as benzyloxy and trityloxy, and p and q are 0 or 1.

Specific examples of hydroxyfluorenone represented by formula (2) that can be preferably used in the present invention include: 3-methoxy-5-hydroxybenzo[c]fluoren-7-one, 9-methoxy-5-hydroxy Benzo[c]fluoren-7-one, 3,9-dimethoxy-5-hydroxybenzo[c]fluoren-7-one, etc.

Import of protective base

In the present invention, a substituted silyl group can be used as a protecting group for protecting the above-mentioned protective functional group. The biggest feature of the substituted silyl group is that the total number of carbon atoms of the three substituents bonded to the silicon atom is 5-12. That is, by using a substituted silyl group with a large steric hindrance as a protecting group, the selectivity and conversion rate when introducing the protecting group can be improved at the same time, and the protecting group will not fall off in the subsequent reaction steps, and the yield of deprotection can be obtained. As a result, the target substance spirofluorenol can be efficiently prepared.

Usually, in addition to methyl and benzyl, there are acetal types such as methoxymethyl or tetrahydropyranyl, ester types such as acetyl or benzoyl, and carbonates such as benzyloxycarbonyl or tert-butoxycarbonyl. Various protecting groups such as trimethylsilyl type, silyl ether type such as trimethylsilyl group are proposed as hydroxyl protecting group. However, in the case of using a methyl group as a protecting group, when ^R3 or ^R4 of hydroxyfluorenone has an alkoxy group such as a methoxy group, the alkoxy group will be destroyed in the step of removing the protecting group, so it cannot as a general preparation method. In addition, when a benzyl group is used as a protecting group, when the protecting group is introduced, not only the protecting group enters the target hydroxyl group, but also the molecular skeleton is also introduced into the benzyl group. In the step of removing the protecting group (deprotection), there are often Side reactions such as the destruction of the alkoxy group or the reduction of the molecular skeleton occur, and the efficiency is low. For the acetal type of protecting group, there is also a problem in the selectivity when introducing the protecting group, while the ester type and carbonate type cannot withstand the reaction of the subsequent steps. Also, for the silyl ether type, it cannot be used because a simple steric structure such as a trimethylsilyl group cannot withstand the reaction of the subsequent step.

The substituted silyl group used as a protecting group in the present invention is not particularly limited as long as the total number of carbon atoms of the three substituents is 5-12. Silylation agents are readily available and effective, so tert-butyldimethylsilyl, triisopropylsilyl and 2-methyl-3,3-dimethyl-2-butyl are particularly preferred Dimethylsilyl.

The above-mentioned silylation agent for introducing a protecting group is a compound in which the above-mentioned substituted silyl group is bonded to a leaving group, such as a compound represented by the following formula (6).

E-SiR ⁷ R ⁸ R ⁹ (6)

In the formula, E is a leaving group, R ⁷ , R ⁸ and R ⁹ are alkyl groups respectively, and the total number of carbon atoms of these alkyl groups is 5-12.

Examples of the above-mentioned leaving group include a halogen atom, an azido group, an alkoxy group, an arylsulfonyloxy group, and a trialkylsilylamino group having 5 or more carbon atoms in total. Among the silylating agents represented by the above formula (6), it is preferred to use tert-butyldimethylchlorosilane, triisopropylchlorosilane, 2-methyl-3,3-dimethyl- Chlorinated silicon compounds such as 2-butyldimethylchlorosilane.

That is, by reacting the above-mentioned silylation agent with the hydroxyfluorenone of the formula (2), a protecting group composed of a substituted silyl group can be introduced to protect a protective functional group represented by a hydroxyl group.

The reaction conditions at the time of protection are not particularly limited, but generally, by using a solvent, adding a tertiary amine compound to a mixed solution of hydroxyfluorenone and a silylating agent, and reacting while trapping the acid generated during the reaction, the This imports the protecting base. In addition, the hydroxyl group of hydroxyfluorenone can be reacted with sodium hydroxide, potassium tert-butoxide, sodium hydroxide or potassium hydroxide in advance to form an alkali metal salt and then reacted with a silylation agent to introduce a protecting group. Of course, it is also possible to react by combining the two methods.

The solvent used here is not particularly limited as long as it does not react with the above-mentioned silylating agent, and aromatic hydrocarbons such as toluene and xylene; chlorinated hydrocarbons such as methylene chloride and chloroform; acyclic or Cyclic ethers; nitriles such as acetonitrile and butyronitrile; acyclic or cyclic amides such as dimethylformamide and N-methylpyrrolidone; acyclic or cyclic sulfoxides such as dimethyl sulfoxide and sulfolane; sulfone; or a mixed solvent of these solvents, etc.

The above-mentioned tertiary amine compounds are not particularly limited, but acyclic or cyclic aliphatic tertiary amines such as triethylamine and N-methylmorpholine; aromatic tertiary amines such as dimethylaniline and methyldianiline; pyridine , 4-dimethylaminopyridine and other heterocyclic tertiary amines, etc. Wherein, more preferably use 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,7-diazabicyclo[4.3.0]non-6-ene etc. have following formula (4 ) The tertiary amine compound of structure shown in, because it can further improve selectivity and transformation rate. Furthermore, a catalytic amount of a tertiary amine compound represented by the formula (4) may be used in combination with other tertiary amine compounds.

In the formula, i is an integer of 2-4, and j is an integer of 3-6.

In this way, the hydroxyfluorenone with protected functional groups such as hydroxyl groups can be obtained. The compound can be isolated and purified according to conventional methods, and can also be directly used in subsequent reactions. Reactions with organometallic compounds:

In the preparation method of the present invention, the hydroxyfluorenone protected by a substituted silyl group obtained above is reacted with an organometallic compound represented by formula (3) to prepare a hydroxyarylfluorenone.

In the formula, M is Li, MgCl, MgBr, MgI or CuLi, and X, R ¹ and R ² are the same as those described in formula (1).

When carrying out this reaction, since the protective functional groups such as the hydroxyl group bound to the 2-position of the fluorenone ring are protected by the substituted silyl group, they do not participate in the reaction with the above-mentioned organometallic compound, and only the carbonyl (C=O) reacts with the organometallic compound . Accordingly, the obtained hydroxy-aryl fluorenone is, for example, represented by the following formula (7), in which the hydroxyl group and the like are protected by a substituted silyl group.

In addition, in the above formula (7), when R ³ or R ⁴ is a hydroxyl group, an amino group or a substituted amino group, these groups are also protected by a protecting group (substituted silyl group, -SiR ⁷ R ⁸ R ⁹ ).

The organometallic compound used in the above reaction can be obtained by making the halide with the molecular structure corresponding to the molecular skeleton shown in formula (3) and organolithium compounds such as butyllithium, lithium metal, magnesium metal or alkylcopper lithium compound, etc. produced by the reaction. In addition, it can also be prepared by reacting an organolithium compound having a molecular structure corresponding to the molecular skeleton represented by formula (3) and a copper compound.

The reaction of the hydroxyfluorenone having a protected hydroxyl group and the above organometallic compound can be carried out by directly reacting the organometallic compound obtained above with the hydroxyfluorenone having a protected hydroxyl group without isolation. The solvent used during the reaction is not particularly limited as long as it is a solvent that does not react with the organometallic compound, and acyclic or cyclic aliphatic hydrocarbons such as hexane and cyclohexane can be used; aromatic hydrocarbons such as toluene and xylene; Acyclic or cyclic ethers such as diethyl ether and tetrahydrofuran, etc., and mixed solvents of these solvents can also be used. The reaction temperature and reaction time are not particularly limited, and the appropriate temperature and time can be determined while confirming the progress of the reaction within the temperature range from -10°C to about the boiling point of the solvent and within the reaction time range of about 0.5 hours to 10 hours. . After the reaction is completed, it is quenched with water to obtain a hydroxy-arylfluorenol in which the hydroxy group and the like have been protected. The thus obtained hydroxy-arylfluorenol in which the hydroxy group and the like are protected can be isolated and purified according to conventional methods, and can also be used as it is in the subsequent reaction.

Spirocyclization and deprotection:

In the present invention, the above-prepared "hydroxy-aryl fluorenol with protected hydroxyl groups" is spirocyclized under acidic conditions to obtain spirofluorenols in which protective functional groups such as hydroxyl groups are protected by substituted silyl groups.

Acids are used to create acidic conditions. The acid used is not particularly limited, and inorganic acids such as sulfuric acid and phosphoric acid; organic acids such as p-toluenesulfonic acid and trifluoroacetic acid; aluminum chloride, titanium tetrachloride, silicon tetrachloride, tin chloride, ferric chloride, etc. can be used. Inorganic Lewis acids; solid acids such as acidic aluminas, acidic ion exchange resins; etc. known acids. Dehydrating agents that react with water to form acids such as phosphorus pentoxide, phosphorus pentachloride, thionyl chloride, and sulfuryl chloride can also be used. The amount of the acid used varies depending on the type, and is not particularly limited, but is generally 0.01 to 1000 parts by weight, more preferably 1 to 50 parts by weight, per 100 parts by weight of hydroxy-arylfluorenol.

Spirocyclization reactions under acidic conditions are usually carried out in solvents. The solvent used here is not particularly limited as long as it is a solvent that does not react with the acid used, and is preferably acyclic or cyclic aliphatic hydrocarbons such as hexane and cyclohexane; aromatic hydrocarbons such as toluene and xylene; Chlorinated hydrocarbons such as dichloromethane and chloroform; Cyclic ethers such as tetrahydrofuran; Esters such as ethyl acetate and butyl acetate; Nitriles such as acetonitrile. The reaction temperature and reaction time are not particularly limited, and the appropriate temperature and time can be determined while checking the progress of the reaction within a temperature range from room temperature to about the boiling point of the solvent and a reaction time range of about 0.5 hours to 10 hours. At this time, depending on the conditions, removal of the protecting group (substituted silyl group) may occur, but this has no influence on the subsequent steps. The spirofluorenol obtained by protecting the hydroxyl group and the like thus obtained can be isolated and purified according to conventional methods, and can also be directly used in subsequent reactions.

In the preparation method of the present invention, deprotection (removal of the substituted silyl group) is finally carried out on the spirofluorenol which has been protected such as the hydroxyl group prepared above. The method of deprotection is not particularly limited, and it can be easily performed by reacting with a deprotecting agent containing fluoride anion in a solvent.

As the deprotecting agent containing fluorine anion, quaternary ammonium fluorides such as tetrabutylammonium fluoride and benzyltrimethylammonium fluoride; alkali metal fluorides such as sodium fluoride and potassium fluoride can be used. When alkali metal fluoride is used as the deprotecting agent, it is preferable to use tetrabutylammonium bromide, benzyltrimethylammonium chloride and other quaternary ammonium salts in combination. The solvent used here is not particularly limited as long as it is a solvent that does not hinder the reaction, and acyclic or cyclic aliphatic hydrocarbons such as hexane and cyclohexane; aromatic hydrocarbons such as toluene and xylene; dichloromethane, Chlorinated hydrocarbons such as chloroform; acyclic or cyclic ethers such as diethyl ether and tetrahydrofuran; nitriles such as acetonitrile and butyronitrile; alcohols such as methanol and ethanol; acyclic or cyclic ethers such as dimethylformamide and N-methylpyrrolidone Cyclic amides; acyclic or cyclic sulfoxides such as dimethyl sulfoxide and sulfolane; sulfone; mixed solvents of these solvents. Additionally, these solvents may be aqueous solvents.

Furthermore, as a deprotection method, a method of reacting the compound represented by the above formula (4) together with alcohols or water with a protected spirofluorene alcohol such as a hydroxyl group is also simple. As the solvent at this time, the above-mentioned solvents can be used, but alcohols are preferably used as the reaction reagent and solvent.

Deprotection can also be performed with a Lewis acid such as boron trifluoride. The solvent at this time is not particularly limited as long as it is not decomposed by an acid, but a chlorinated hydrocarbon or the like is preferably used.

The spirofluorenol obtained through the deprotection can be separated and purified by conventional methods, and can also be directly used in the reaction of synthesizing photochromic compounds.

In addition, in the production method of the present invention, the spirocyclization reaction and the deprotection reaction can be carried out in one step using an acid, and such a method is particularly preferable in terms of efficiency. At this time, as the acid, among examples of acids usable in the above-mentioned spirocyclization reaction and deprotection reaction, organic sulfonic acids, organic acids, or Lewis acids, particularly p-toluenesulfonic acid, trifluoroacetic acid, trifluoroacetic acid, boron (usually used in ether complex form), magnesium bromide or aluminum chloride. In addition, as a solvent, there is no particular limitation on the solvent usable in the above-mentioned spirocyclization reaction or deprotection reaction, but acetonitrile is most preferably used in view of the selectivity of the reaction. After completion of the reaction, for example, after making the acid inert, washing is added with water or brine, and the solvent is further removed from the organic layer to obtain the target substance.

Through the preparation method of the invention, the spirofluorenol which can be used as the raw material of the photochromic compound can be efficiently prepared.

Example

Hereinafter, examples are given to describe the present invention in detail, but the present invention is not limited to these examples.

Example 1

Suspend 2g (6.5mmol) of 3,9-dimethoxy-5-hydroxybenzo[c]fluoren-7-one in 10ml of tetrahydrofuran (THF), add 0.31g (7.8mmol) of sodium hydroxide in methanol ( 40ml) solution was stirred at room temperature for 1 hour. After adding 80 ml of toluene, all the solvent was distilled off under reduced pressure to obtain a sodium salt. This was dissolved in 50ml of THF, and a THF (20ml) solution of 1.2g (7.8mmol) tert-butyldimethylchlorosilane was added dropwise, and allowed to react at room temperature for 2 hours. The conversion rate at this time was 99%.

Then THF was distilled off under reduced pressure, and crystallized in 30ml of methanol to obtain 2.4g (purity 97%, yield 87%) 3,9-dimethoxy-5-tert-butyldimethylsilyloxybenzo[ c] Fluoren-7-one (abbreviated as DBBF).

Dissolve 2.1g (8.3mmol) of 1-bromophenanthrene in 43ml of heptane, add 5.3ml (1.6mol/l, 8.5mmol) of butyl lithium at room temperature to form 1-lithium phenanthrene, and cool to -5 ℃, add 2.2g (5.2mmol) of the above DBBF, stir for 1 hour, then add THF below 0℃, and stir at this temperature for 2 hours. The conversion rate at this time was 99%.

After the reaction, it was washed with 8.5 ml of 1N hydrochloric acid and 10 ml of water, and the solvent was distilled off under reduced pressure. Crystallization in 20ml of methanol gave 2.5g (purity 97%, yield 82%) of 3,9-dimethoxy-5-tert-butyldimethylsilyloxy-7-hydroxyl-7-phenanthrene- 1-ylbenzo[c]fluorene (abbreviated as DBHPBF).

Suspend 1.0 g (1.7 mmol) of the resulting 2.5 g DBHPBF in 10 g of acetic acid and heat to 60°C. A solution containing 3.5 g of acetic acid, 0.7 g of concentrated sulfuric acid, and 2.1 g of water was added thereto, and stirred at 60° C. for 3 hours. The conversion rate at this time was 99%.

After cooling, add 46ml of 5N aqueous sodium hydroxide solution and 50ml of THF to wash, then wash with 20ml of water, repeat washing twice, and distill off the solvent under reduced pressure. Crystallization in 30ml of methanol gave 0.87g (purity 96%, yield 90%) of 3',9'-dimethoxy-5'-tert-butyldimethylsilyloxyspiro[(1H-cyclo Penta[d,e,f]phenanthrene)-1,7'-benzo[c]fluorene] (abbreviated as DBCPBF).

Dissolve 0.58g (1.0mmol) of the resulting 0.87g DBCPBF in 30ml THF, add 1.3g (4mmol) tetrabutylammonium bromide and 0.23g (4mmol) potassium fluoride, and heat to reflux for 10 hours. The conversion rate at this time was 98%. After cooling, it was washed with 10 ml of water, and the washing was repeated three times, and the solvent was distilled off under reduced pressure. 0.47 g (yield 100%) of 3',9'-dimethoxy-5'-hydroxyspiro[(1H-cyclopenta[d,e,f]phenanthrene)-1,7 with a purity of 95% was obtained '-Benzo[c]fluorene]. The overall yield was calculated to be 64%.

Comparative example 1

Dissolve 0.28g (7mmol) of sodium hydroxide in 20ml of methanol, add 2g (6.6mmol) of 3,9-dimethoxy-5-hydroxybenzo[c]fluoren-7-one and 0.82g (6.5mmol) Benzyl chloride, add 20ml THF, reflux for 20 hours. The conversion rate at this time was 90%. A by-product that is believed to be formed by the reaction of two benzyl groups was formed in the reaction. The solvent was distilled off under reduced pressure, and crystallized in 32 ml of acetone to obtain 1.4 g of 3,9-dimethoxy-5-benzyloxybenzo[c]fluoren-7-one (purity 97%, yield 52%).

Carry out phenanthrene addition and dehydration reaction according to Example 1 to obtain 3', 9'-dimethoxy-5'-benzyloxyspiro[(1H-cyclopenta[d,e,f]phenanthrene)-1, 7'-benzo[c]fluorene] (abbreviated as spirobenzofluorene). The purity and yield were 85%, 90%, respectively.

0.67g (1.2mmol) of the obtained spirobenzofluorene was dissolved in 30ml of THF and 50ml of methanol, 0.27g of 5% palladium on carbon, 15.1g (240mmol) of ammonium formate were added, and allowed to react at room temperature for 2 hours. The conversion rate at this time was 99%. After the reaction, the palladium carbon was filtered off, washed with 20 ml of water, and the solvent was distilled off under reduced pressure. 0.55 g (yield 99%) of 3',9'-dimethoxy-5'-hydroxyspiro[(1H-cyclopenta[d,e,f]phenanthrene)-1,7 with a purity of 98% was obtained '-Benzo[c]fluorene]. The overall yield was calculated to be 39%.

Comparative example 2

10g (32.6mmol) 3,9-dimethoxy-5-hydroxybenzo[c]fluoren-7-one was dissolved in 500ml THF, 10.7g (49mmol) di-tert-butyl dicarbonate and 0.04g 4 - Dimethylaminopyridine (0.3 mmol), stirred at room temperature for 3 hours. THF was concentrated until crystals were precipitated, and 400ml of heptane was added for crystallization to obtain 12.8g (purity 96%, yield 97%) of 3,9-dimethoxy-5-tert-butoxycarbonyloxybenzo[c ] Fluoren-7-one (abbreviated as benzofluorenone).

The above-mentioned benzofluorenone was reacted with 1-lithium phenanthrene in the same manner as in Example 1, whereby the tert-butoxycarbonyl group was reacted, and the purity decreased to 61%. As in Example 1, the dehydration reaction was carried out directly, and it was found that a deprotection reaction had also taken place at the same time, and only 3', 9'-dimethoxy-5'-hydroxyl spiro[(1H-cyclopentacene) with a purity of 44% was obtained. [d,e,f]phenanthrene)-1,7'-benzo[c]fluorene]. It could not be purified. And even if the purification was carried out without loss, the total yield was calculated to be only 43%.

Example 2

10 g (36.2 mmol) of 3-methoxy-5-hydroxybenzo[c]fluoren-7-one were suspended in 150 ml of THF, and 4.4 g (43.5 mmol) of triethylamine were added. Then, a solution obtained by dissolving 6.55 g (43.5 mmol) of tert-butyldimethylchlorosilane in 50 ml of THF was added dropwise at room temperature, and stirred at 45° C. for 6 hours. The conversion rate at this time was 98%. THF was distilled off under reduced pressure, and crystallized in 230ml of methanol to obtain 12g (purity 98%, yield 85%) of 3-methoxy-5-tert-butyldimethylsilyloxybenzo[c]fluorene- 7-keto (abbreviated as MBBF).

Dissolve 10.9 g (38.9 mmol) of 2-iodobiphenyl in 150 ml of heptane, and cool to -5°C. 26.5 mL (1.6 mol/l, 42.4 mmol) of butyllithium was added thereto, and stirred at -5°C for 1 hour. 10.5 g (27 mmol) of the above-prepared MBBF was added thereto, and THF was added below 0° C., and stirred at this temperature for 2 hours. The conversion rate at this time was 99%. After the reaction, add 42ml 1N hydrochloric acid, 200ml THF to wash, then wash twice with water, each with 50ml water. The solvent was distilled off under reduced pressure. Obtain 14g of 3-methoxy-5-tert-butyldimethylsilyloxy-7-hydroxyl-7-(2-phenylphenyl)benzo[c]fluorene (abbreviated as MBHPBF) (purity 95 %, yield 95%).

Suspend 10.9 g (20 mmol) of the obtained 14 g MBHPBF in 115 g of acetic acid and heat to 60°C. A solution containing 55 g of acetic acid, 10.9 g of concentrated sulfuric acid, and 32.6 g of water was added thereto, and stirred at 60° C. for 3 hours. The conversion rate at this time was 99%. Afterwards, cool to 30 ℃, add 740ml 5N sodium hydroxide aqueous solution and 400ml ethyl acetate to wash, then wash with 200ml 10% brine. The solvent was distilled off to obtain 10g of 3'-methoxy-5'-tert-butyldimethylsilyloxy spiro[fluorene-9,7'-benzo[c]fluorene] (abbreviated as MBSFBF) (purity 95%, yield 95%).

0.53g (1mmol) in the gained 10g MBSFBF was dissolved in 30ml THF, added 1.52g 1,8-diazabicyclo[5.4.0]undec-7-ene (10mmol), stirred at room temperature for 24 hours . The conversion rate at this time was 99%. Afterwards, wash with 10ml of 1N hydrochloric acid, and then wash with water 3 times, each time with 10ml of water. THF was distilled off. 0.41 g (purity 96%, yield 99%) of 3'-methoxy-5'-hydroxyspiro[fluorene-9,7'-benzo[c]fluorene] was obtained. The overall yield was calculated to be 76%.

Example 3

According to Example 2, 3'-methoxy-5'-tert-butyldimethylsilyloxyspiro[fluorene-9,7'-benzo[c]fluorene] (abbreviated as MBSFBF) was obtained.

0.53 g (1 mmol) of the above MBSFBF was dissolved in 30 ml of chloroform, cooled to 5° C., 3.4 g (24 mmol) of boron trifluoride diethyl ether complex was added, and reacted at 50° C. for 20 hours. The conversion rate at this time was 99%. Cool down afterwards, wash with 24ml 1N aqueous sodium hydroxide solution, 50ml water, carry out 4 times.

Chloroform was distilled off to obtain 0.40 g (purity 96%, yield 97%) of 3'-methoxy-5'-hydroxyspiro[fluorene-9,7'-benzo[c]fluorene]. The overall yield was calculated to be 74%.

Comparative example 3

Dissolve 0.4g (10mmol) of sodium hydroxide in 10ml of methanol, add 2.5g (9.1mmol) of 3-methoxy-5-hydroxybenzo[c]fluoren-7-one, 30ml of THF and 3.7g (29mmol) Benzyl chloride, stirred at 60°C for 10 hours. The conversion rate at this time was 95%.

Afterwards, it was cooled to 20° C., the precipitated crystals were filtered off, washed with 10 ml of water, and dried to obtain 2.0 g (purity 99%, yield 61%) of 3-methoxy-5-benzyloxybenzo[c ]Fluoren-7-one (purity 97%, yield 52%).

Carry out biphenyl addition and dehydration reaction according to Example 2 to obtain 2.5 g of 3'-methoxy-5'-benzyloxyspiro[fluorene-9,7'-benzo[c]fluorene] (abbreviated as MBOSFBF ). The yields were 97%, 95%, respectively.

0.5g (1mmol) of the above-mentioned MBOSFBF was dissolved in a mixed solvent of 50ml THF, 10ml acetic acid, 5ml methanol, and 1.5ml water, and 0.05g of 5% palladium carbon was added. Stir at 40°C for 24 hours with a balloon of hydrogen. The conversion rate at this time was 99%. After the reaction, cool, filter off palladium carbon, and distill off the solvent under reduced pressure to obtain 0.41 g (purity 98%, yield 98%) of 3'-methoxy-5'-hydroxyspiro[fluorene-9,7' -Benzo[c]fluorene]. The overall yield was calculated to be 55%.

Example 4

According to Example 1, 3,9-dimethoxy-5-tert-butyldimethylsilyloxy-7-hydroxyl-7-phenanthrene-1-ylbenzo[c]fluorene (abbreviated as DBHPBF) was obtained .

1.0 g (1.7 mmol) of this DBHPBF was dissolved in 70 ml of acetonitrile, 0.71 g (5 mmol) of boron trifluoride ether complex was added, and the mixture was stirred at 50° C. for 3 hours. Add 0.32g (5.5mmol) potassium fluoride to make the boron trifluoride ether complex inert, add 90ml THF, and then wash with 10% brine three times, each with 80ml. The solvent was distilled off under reduced pressure to obtain 0.46 g (98% yield) of 3',9'-dimethoxy-5'-hydroxyspiro[(1H-cyclopenta[d,e,f] with a purity of 98%. phenanthrene)-1,7'-benzo[c]fluorene]. The overall yield was calculated to be 63%.

Example 5-11

According to Example 4, under the conditions shown in Table 1, 3,9-dimethoxy-5-tert-butyldimethylsilyloxy-7-hydroxyl-7-phenanthrene-1-ylbenzo[c ] fluorene spirocyclization and deprotection reaction, the results shown in Table 1 were obtained.

Comparative example 4

Dissolve 2.1g (8.3mmol) of 1-bromophenanthrene in 43ml of heptane, add 5.3ml (1.6mol/l, 8.5mmol) of butyllithium at room temperature to form 1-lithiumphenanthrene, cool to -5°C, add 1.6 g (5.2 mmol) of 3,9-dimethoxy-5-hydroxybenzo[c]fluoren-7-one, stirred for 1 hour, then added THF below 0°C, and stirred at this temperature for 2 hours. The conversion rate at this time was 40%. Stirring was continued for another 20 hours, but the conversion was still 40%.

After the reaction, it was washed with 8.5 ml of 1N hydrochloric acid and 10 ml of water, and the solvent was distilled off under reduced pressure. Crystallization in 20 ml of methanol afforded 0.81 g (purity 92%, yield 32%) of 3,9-dimethoxy-5-hydroxy-7-hydroxy-7-phenanthrene-1-ylbenzo[c]fluorene (referred to as DHHPBF).

0.5 g (1.0 mmol) of the obtained DHHPBF was suspended in 5.9 g of acetic acid, and heated to 60°C. A solution containing 2.1 g of acetic acid, 0.4 g of concentrated sulfuric acid, and 1.2 g of water was added thereto, and stirred at 60° C. for 3 hours. The conversion rate at this time was 99%.

Afterwards, cool, add 27ml 5N sodium hydroxide, 30ml THF to wash, then wash with water 2 times, use 13ml water each time, decompress and distill off the solvent. Crystallization in 17 ml of methanol afforded 0.2 g (purity 95%, yield 40%) of 3',9'-dimethoxy-5'-hydroxyspiro[(1H-cyclopenta[d,e,f] phenanthrene)-1,7'-benzo[c]fluorene], the total yield was calculated to be 13%.

Table 1 Example number Raw material (mmol) Solvent (60ml) acid type The amount of acid (mmol) temperature(℃) time (hour) purity(%) Yield (%) 5 1.67 Acetonitrile Boron trifluoride-ether complex 16.7 25 10 97 97 6 1.67 Acetonitrile p-Toluenesulfonic acid 5.3 50 3 97 96 7 1.67 Acetonitrile magnesium bromide 54.3 50 3 98 98 8 1.67 THF Trifluoroacetate 6.5 40 1 96 95 9 1.67 Acetonitrile aluminum chloride 16.7 25 10 97 97 10 1.67 ethyl acetate Titanium tetrachloride 16.7 25 10 96 96 11 1.67 Acetonitrile Silicon tetrachloride 8.4 50 5 96 96

Claims (7)

1. The following formula (1) The preparation method of shown spirofluorenol compound is characterized in that: the following formula (2) The hydroxyl group bound on the fluorenone compound shown is protected by a protecting group formed by a substituted silyl group, and the total number of carbon atoms of the substituents bound to the silicon atom on the substituted silyl group is 5-12, and then the fluorenone The ketone compound reacts with the organometallic compound shown in the following formula (3) to obtain the hydroxy-aryl fluorenol whose hydroxyl group is protected by the above-mentioned protecting group, and the gained hydroxy-aryl fluorenol is spirocyclized and deprotected, In the formula, M is Li, MgCl, MgBr, MgI or CuLi; In the above formula (1) to formula (3), X is a single bond or any divalent group selected from the following group A, Y is a group that forms an aromatic hydrocarbon ring group or an unsaturated heterocyclic group together with two carbon atoms of the benzo ring, When X is a single bond, R ¹ and R ² are respectively a hydrogen atom, any univalent group selected from the following group B, or are combined to form any divalent group selected from the following group A (wherein -Z - and -CR ⁵ R ⁶ - except) groups, When X is a group selected from group A, ^R1 and ^R2 are each a hydrogen atom or any monovalent group selected from the following group B, R ³ and R ⁴ are hydrogen atoms or any monovalent group selected from the following group B, p and q are each independently an integer of 0-3; Group A: -Z-, -(CR ⁵ R ⁶ ) _n -, -(CR ⁵ R ⁶ ) _m -Z-, -Z-(CR ⁵ R ⁶ ) ₁ -Z-, -(CR ⁵ R ⁶ ) _a -Z-(CR ⁵ R ⁶ ) _b -, -(CR ⁵ =CR ⁶ ) _k - and -CR ⁵ =N- Wherein, -Z- is -O-, -S- or -NR ⁵ , R ⁵ and R ⁶ are independently hydrogen atoms or selected from For any monovalent group in the following group B, when there are multiple -Z-, R ⁵ or R ⁶ in one group, The multiple -Z-, R ⁵ or R ⁶ can be different from each other, a, b, k and l are each independently 1-4 Integers, m and n are independently integers of 1-6; Group B: Alkyl, aralkyl, substituted or unsubstituted aryl, hydroxyl, alkoxy, aralkoxy, amino, monosubstituted amino, disubstituted amino, cyano, nitro, halogen atom, trifluoromethyl, There are bonded substituted or unsubstituted heterocyclic groups on carbon atoms or nitrogen atoms, and bonded substituted or unsubstituted heterocyclic groups on carbon atoms or nitrogen atoms formed by condensed aromatic hydrocarbon rings or heterocyclic rings. Fused heterocyclic group. 2. The preparation method of claim 1, wherein when the fluorenone compound shown in the formula (2) has an amino group or a substituted amino group, the amino group or a substituted amino group is protected by the protecting group together with the hydroxyl group . 3. The preparation method of claim 1, wherein the protection carried out with a substituted silyl group Carried out in the presence of compounds represented by the following formula (4),

In the formula, i is an integer of 2-4, and j is an integer of 3-6. 4. The preparation method of claim 1, wherein spirofluorenol is deprotected by reacting spirofluorenol with quaternary ammonium fluoride or alkali metal fluoride, and said spirofluorenol is a hydroxyl group to be protected by said protecting group - Aryl fluorenol obtained by spirocyclization. 5. The preparation method according to claim 3, wherein spirofluorenol is deprotected by reacting spirofluorenol with alcohol or water in the presence of the compound of said formula (4), and said spirofluorenol is to be deprotected by said It is obtained by spirocyclization of hydroxy-aryl fluorenol protected by a protecting group. 6. The preparation method of claim 1, wherein the spirocyclization and deprotection of the hydroxy-arylfluorenol protected by the protecting group are carried out in one step by reacting with an acid in an acetonitrile solvent. 7. The production method according to claim 6, wherein at least one compound selected from the group consisting of boron trifluoride-ether complexes, magnesium bromide, p-toluenesulfonic acid, aluminum chloride and trifluoroacetic acid is used as the acid.