CN110713434A - Intermediate of compound with anticancer activity, preparation method and application thereof - Google Patents

Intermediate of compound with anticancer activity, preparation method and application thereof Download PDF

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CN110713434A
CN110713434A CN201911046680.XA CN201911046680A CN110713434A CN 110713434 A CN110713434 A CN 110713434A CN 201911046680 A CN201911046680 A CN 201911046680A CN 110713434 A CN110713434 A CN 110713434A
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anticancer activity
compound
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CN110713434B (en
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韩东阳
武润石
杨琦
黄庐山
胡仁铭
赖易欢
谭芷钰
杜正宇
冯予
吴可欣
黄劼
徐大振
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Nankai University
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    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
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    • C07—ORGANIC CHEMISTRY
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    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
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    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/20—Diazonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation

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Abstract

The invention relates to the technical field of organic compound synthesis, in particular to an intermediate of a compound with anticancer activity, a preparation method and application thereof. An intermediate of a compound having anticancer activity, the structural formula of which is as follows:wherein R is1Is selected from H and
Figure DDA0002254309690000012
R2selected from hydroxyl and diazonium salt groups; n is selected from 1, 2 and 3. The invention provides an intermediate of a compound with anticancer activity, a central framework can be constructed through one-step series reaction, raw materials are cheap and easy to obtain, the catalyst cost is low, and the preparation method has good selectivity, high effective conversion rate and mild reaction conditions. The intermediate can be used for preparing a compound with anticancer activity, and the total yield of the whole synthetic route is 55.3%, which is improved by more than two times compared with the yield of the existing synthetic route.

Description

Intermediate of compound with anticancer activity, preparation method and application thereof
Technical Field
The invention relates to the technical field of organic compound synthesis, in particular to an intermediate of a compound with anticancer activity, a preparation method and application thereof.
Background
Compounds containing a polyaryl central structure and modified with tertiary amine substituents are reported to possess certain biological activities. Wherein, phenanthrene is taken as a compound of one of the polyaryl groups, has anticancer activity, such as anti-proliferation effect on breast cancer cells. Among them, the compound A, the structural formula of which is shown below, has excellent anticancer activity (A new series of anti-cancer agents, biological & Medicinal Chemistry 14(2006) 1497-one 1505).
Figure BDA0002254309680000011
In the prior art, a triaryl center is constructed through multi-step reactions, and the specific synthetic route is as follows:
Figure BDA0002254309680000021
in the above synthetic route, grignard reagent is used in the first step, which is highly dangerous and has strict requirements for solvent and equipment. The second step has poor reaction selectivity, so that the effective conversion rate is reduced, and raw materials are greatly wasted. The hydroxyl group is protected by a functional group protection strategy in the synthetic route, so that steps are added, and the conversion rate is further reduced. Meanwhile, high-cost and dangerous palladium carbon is used as a reducing agent in the reaction route, and methyl iodide is used as a methylation reagent, so that the production cost is increased, and the production process is not easy to control. The compound A is prepared by the synthetic route, the total yield is only 22.05 percent, the cost is overhigh, the atom economy in the reaction process is low, and the environmental pollution is large.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The first object of the present invention is to provide an intermediate of a compound having anticancer activity, which can be used for preparing a compound having anticancer activity.
The second objective of the present invention is to provide a preparation method of the intermediate of the compound with anticancer activity, which has the advantages of good selectivity, high effective conversion rate and mild reaction conditions.
The third purpose of the invention is to provide the application of the intermediate with anticancer active compounds in the preparation of the anticancer active compounds, and the intermediate is adopted to prepare the anticancer active compounds, so that the cost is low, the steps are simplified, the pollutant emission is less, and the green chemical requirements are met.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
an intermediate I of a compound with anticancer activity, which has the following structural formula:
Figure BDA0002254309680000031
wherein R is1Is selected from H and
Figure BDA0002254309680000032
R2selected from hydroxyl and diazonium salt groups; n is selected from 1, 2 and 3.
Wherein denotes the position of attachment of the group to the rest of the intermediate I.
In one embodiment of the present invention, the intermediate I of the compound having anticancer activity is selected from the following structures:
Figure BDA0002254309680000033
in one embodiment of the invention, n is 2.
Wherein the intermediate is selected from the following structures:
Figure BDA0002254309680000034
Figure BDA0002254309680000041
wherein, the intermediate I3The anionic structure is not limited as long as the diazonium group is present.
The invention also provides a preparation method of the intermediate I of the compound with anticancer activity, which comprises the following steps:
intermediate I1The preparation method comprises the following steps: a) under the action of organic alkali, 2, 4-dihydroxy benzaldehyde, 9-phenanthrene boric acid and anisole react in an organic solvent under the catalysis of trivalent ferric salt to obtain an intermediate I1；
Intermediate I2The preparation method comprises the following steps: b) under the action of inorganic base, the intermediate I1And
Figure BDA0002254309680000042
reflux reaction in organic solvent to obtain intermediate I2；
Intermediate I3The preparation method comprises the following steps: c) under the action of N, N-diisopropylethylamine, the intermediate I2Reacting with diazotization reagent in organic solvent to obtain intermediate I3。
In one embodiment of the present invention, the step a) comprises: under the action of organic alkali, 2, 4-dihydroxybenzaldehyde and 9-phenanthreneboronic acid react in an organic solvent for 20-60 min, and then trivalent iron salt and anisole are added to react for 1-3 h to obtain an intermediate I1。
The reflux reaction refers to the conventional reflux reaction operation in the field, and the reflux reaction temperature is adjusted according to the actual reaction condition.
In a specific embodiment of the invention, in the step a), the molar ratio of the 2, 4-dihydroxybenzaldehyde, the 9-phenanthreneboronic acid, the anisole, the organic base and the trivalent iron salt is 1: 1 (1: 1.5) to 1.5 (1: 2) to 0.5: 1, preferably 1: 1 (1: 1.2) to 1.2 (1.5: 2) to 0.5: 1, and more preferably 1: 1.2: 1.5.
By adopting the dosage proportion in the range, the raw material 2, 4-dihydroxy benzaldehyde can be ensured to react completely, the conversion rate can be reduced when the dosage of the other two raw materials is reduced, and the column chromatography separation efficiency can be reduced when the dosage of the other two raw materials is increased.
When the amount of the trivalent iron salt is decreased, the reaction efficiency is decreased and the reaction time is required to be increased, but the increase of the reaction time causes an increase in side reactions. Thus, by optimizing the reaction conditions, the reaction yield is improved.
In one embodiment of the present invention, the reaction temperature in step a) is 80 to 100 ℃, preferably 90 to 100 ℃, and more preferably 100 ℃.
In a specific embodiment of the present invention, in the step a), the organic base is selected from any one or two of piperidine and ethylenediamine, and is preferably piperidine.
In a specific embodiment of the present invention, in the step a), the ferric salt is ferric chloride, and more preferably anhydrous ferric chloride.
In a specific embodiment of the present invention, the organic solvent in step a) is selected from one or two of chlorobenzene and toluene, preferably chlorobenzene.
Chlorobenzene has relatively low toxicity, high boiling point, low consumption at reaction temperature and high economy.
In a particular embodiment of the invention, in said step b), the intermediate I is1、
Figure BDA0002254309680000051
The molar ratio of the inorganic base to the inorganic base is 1: 1.2: 1: 2, preferably 1: 1.2: 2.
In one embodiment of the present invention, the first and second substrates are,is 2-chloroethyldimethylamine.
In a specific embodiment of the present invention, the inorganic base is selected from any one or more of sodium bicarbonate, sodium carbonate and potassium carbonate, preferably sodium bicarbonate.
The regioselectivity of the reaction can be further improved by using sodium bicarbonate. If the basicity is too strong, the regioselectivity of the reaction is reduced. Meanwhile, the reaction speed is proper by regulating the using amount of the sodium bicarbonate within the range, and the regioselectivity and the yield are further ensured.
In a specific embodiment of the present invention, the organic solvent in step b) is acetone.
In a specific embodiment of the present invention, in the step c), the diazotizing agent is diphenyl phosphorazidate.
In a particular embodiment of the invention, in said step c), the intermediate I2The molar ratio of the diazotization reagent to the N, N-diisopropylethylamine is 1: 1 (1-1.5) to (1-1.2), preferably 1: 1 (1-1.2) to (1-1.1), and more preferably 1: 1.2 to 1.1.
In a specific embodiment of the present invention, the organic solvent in step c) is DMF.
In a specific embodiment of the present invention, in the step c), the reaction temperature is 20 to 25 ℃. Such as room temperature reaction.
The progress of the reaction can be monitored according to TLC, and the corresponding reaction time can be adjusted.
The invention also provides the application of the intermediate I of the compound with anticancer activity in the preparation of the compound A with anticancer activity;
the structural formula of compound a is as follows:
Figure BDA0002254309680000061
in one embodiment of the present invention, the preparation method of compound a comprises:
a) under the action of organic alkali, 2, 4-dihydroxy benzaldehyde, 9-phenanthrene boric acid and anisole react in an organic solvent under the catalysis of trivalent ferric salt to obtain an intermediate I1；
b) Under the action of inorganic base, the intermediate I1Andreflux reaction in organic solvent to obtain intermediate I2；
c) Under the action of N, N-diisopropylethylamine, the intermediate I2Reacting with a diazotizing agent in an organic solvent;
d) and c), acidifying the system in the step c) for finishing the reaction at 0-5 ℃ until the pH value is 5-6 to obtain the compound A.
In a specific embodiment of the present invention, in step d), an acid solution is used for acidification. Optionally, the acid solution is hypophosphorous acid.
In one embodiment of the invention, the acidification is performed under ice bath conditions.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides an intermediate of a compound with anticancer activity, a central framework can be constructed through one-step series reaction, raw materials are cheap and easy to obtain, the catalyst cost is low, and the preparation method has good selectivity, high effective conversion rate and mild reaction conditions;
(2) the intermediate can be used for preparing a compound with anticancer activity, and the total yield of the whole synthetic route is 55.3%, which is more than twice higher than that of the existing synthetic route;
(3) in the preparation method, the requirement on a reaction solvent is low, and the production cost can be reduced to a great extent; meanwhile, a functional group protection strategy is not involved, the atom economy in the reaction process is high in cost and low in cost, the steps are simplified, the pollutant emission is less, and the requirement of green chemistry is met.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following detailed description, but those skilled in the art will understand that the following described examples are some, not all, of the examples of the present invention, and are only used for illustrating the present invention, and should not be construed as limiting the scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
Intermediate I of compound with anticancer activity1Preparation method of (1)
Figure BDA0002254309680000081
Intermediate I of this example1The preparation method comprises the following steps:
(1) 690mg (5mmol) of 2, 4-dihydroxybenzaldehyde and 1332mg (6mmol) of phenanthreneboronic acid are taken, 637.5mg (7.5mmol) of piperidine is added, the mixture is dissolved in 5mL of chlorobenzene, the temperature is increased to 100 ℃, the reaction is reacted for 40min, and the reaction is completely finished through TLC detection.
(2) 405mg (2.5mmol) of anhydrous ferric chloride and 648mg (6mmol) of anisole are directly added into the system of the step (a) and reacted at 100 ℃ for 2 h. TLC monitored the reaction was complete. Separating by column chromatography to obtain intermediate I11725.5mg, 85% yield. Intermediate I1It is a pale yellow solid with a melting point of 94-96 ℃.
The intermediate I obtained in the step (2)1The pure product is characterized, and the structural characterization data is as follows:
1H NMR(500MHz,CDCl3):δ8.78(d,J＝8.4Hz,1H),8.70(d,J＝8.4Hz,1H),8.07(d,J＝8.4Hz,1H),7.82(d,J＝7.8Hz,1H),7.66–7.60(m,2H),7.54–7.46(m,1H),7.21(s,1H),7.08(d,J＝8.6Hz,2H),7.04(d,J＝8.5Hz,2H),6.88(d,J＝8.8Hz,2H),6.75(d,J＝8.4Hz,2H),6.14(s,1H),4.65(s,1H),4.43(s,1H),3.77(s,3H)。
wherein, in the preparation process, the organic solvent chlorobenzene in the step (1) can be replaced by toluene.
Example 2
This example refers to the preparation of example 1, with the only difference that: the dosage of the 2, 4-dihydroxy benzaldehyde, the phenanthrene boric acid and the anisole is 5mmol, 5mmol and 5mmol respectively. The yield was 70%.
Example 3
This example refers to the preparation of example 1, with the only difference that: the amount of anhydrous ferric chloride is 1 mmol. The yield was 50%.
Example 4
Intermediate I of compound with anticancer activity2Preparation method of (1)
Figure BDA0002254309680000091
Intermediate I of this example2The preparation method comprises the following steps:
(3) 1624mg (4mmol) of intermediate I are taken1And 513.8mg (4.8mmol) of 2-chloroethyldimethylThe amine was dissolved in 8mL of acetone, and 672.1mg (8mmol) of sodium hydrogencarbonate was added to the solution, followed by refluxing for 10 hours. TLC monitoring reaction is finished, and the intermediate I is obtained by column chromatography separation21335mg, yield 70%. Intermediate I2Is a brown yellow solid with a melting point of 85-86 ℃.
The intermediate I obtained in the step (3)2The pure product is characterized, and the structural characterization data is as follows:
1H NMR(500MHz,CDCl3):δ8.74(d,J＝8.4Hz,1H),8.67(d,J＝8.4Hz,1H),8.13(d,J＝8.4Hz,1H),7.74(d,J＝7.8Hz,1H),7.63–7.58(m,2H),7.54–7.45(m,1H),7.15(s,1H),7.06(d,J＝8.8Hz,2H),7.02(d,J＝8.5Hz,2H),6.83(d,J＝8.7Hz,2H),6.75(d,J＝8.6Hz,2H),6.14(s,1H),4.47(s,1H),4.15(t,2H,J＝7.8Hz),3.77(s,3H),2.91(t,2H,J＝7.8Hz),2.84(s,6H)。
wherein, in the preparation process, the sodium bicarbonate in the step (3) can be replaced by sodium carbonate.
Raw material intermediate I in step (3)1Reference is made to the preparation process in example 1.
Example 5
This example refers to the preparation of example 3, with the only difference that: the amount of 2-chloroethyldimethylamine used was 4.4 mmol. The yield of step (3) was 63%.
Example 6
This example refers to the preparation of example 3, with the only difference that: the amount of sodium bicarbonate used was 4 mmol. The yield of step (3) was 50%.
Example 7
Preparation method of compound A with anticancer activity
Figure BDA0002254309680000101
The preparation route of the compound with anticancer activity of the embodiment is shown as above, and the preparation method comprises the following steps:
(4) 1431mg (3mmol) of intermediate I are taken2426.3mg (3.3mmol) of N, N-diisopropylethylamine and 990mg (3.6mmol) of diphenyl phosphate azide, and then9mL of DMF is added and reacted at room temperature to obtain an intermediate I3And after the reaction is monitored by TLC, adding hypophosphorous acid into the reaction system under the ice bath condition, and acidifying until the pH value of the system is 5-6. After column chromatography separation, the compound A1286.9mg with anticancer activity is obtained, and the yield is 93%. The compound A with anticancer activity is white solid, and has a melting point of 89-91 deg.C.
And (3) characterizing the pure compound with the anticancer activity obtained in the step (4), wherein the structural characterization data is as follows:
1H NMR(400MHz,CDCl3):δ8.72(d,J＝8.1Hz,1H),8.65(d,J＝8.2Hz,1H),8.04(d,J＝8.2Hz,1H),7.67(d,J＝7.8Hz,1H),7.60(t,J＝7.1Hz,2H),7.58–7.48(m,2H),7.15(s,1H),7.07–7.04(m,4H),6.83(t,J＝8.2Hz,4H),6.14(s,1H),4.04(t,J＝5.8Hz,2H),3.78(s,3H),2.71(t,J＝5.8Hz,2H),2.32(s,6H)。
example 8
Preparation method of compound A with anticancer activity
Figure BDA0002254309680000111
The preparation route of the compound with anticancer activity of the embodiment is shown as above, and the preparation method comprises the following steps:
(1) 690mg (5mmol) of 2, 4-dihydroxybenzaldehyde and 1332mg (6mmol) of phenanthreneboronic acid are taken, 637.5mg (7.5mmol) of piperidine is added, the mixture is dissolved in 5mL of chlorobenzene, the temperature is increased to 100 ℃, the reaction is reacted for 40min, and the reaction is completely finished through TLC detection.
(2) 405mg (2.5mmol) of anhydrous ferric chloride and 648mg (6mmol) of anisole are directly added into the system of the step (a) and reacted at 100 ℃ for 2 h. TLC monitored the reaction was complete. Separating by column chromatography to obtain intermediate I11725.5mg, 85% yield.
(3) 1624mg (4mmol) of intermediate I are taken1And 513.8mg (4.8mmol) of 2-chloroethyldimethylamine dissolved in 8mL of acetone, 672.1mg (8mmol) of sodium hydrogencarbonate was added, and the reaction was refluxed for 10 hours. TLC monitoring reaction is finished, and the intermediate I is obtained by column chromatography separation21335mg, yield 70%.
(4) Get1431mg (3mmol) of intermediate I2426.3mg (3.3mmol) of N, N-diisopropylethylamine and 990mg (3.6mmol) of diphenyl phosphate azide were added to 9mL of DMF and the mixture was reacted at room temperature to give intermediate I3And after the reaction is monitored by TLC, adding hypophosphorous acid into the reaction system under the ice bath condition, and acidifying until the pH value of the system is 5-6. After column chromatography separation, the compound A1286.9mg with anticancer activity is obtained, and the yield is 93%.
The total yield of the compound having anticancer activity obtained by reacting the initial raw material 2, 4-dihydroxybenzaldehyde was 55.3%.
Example 9
This example refers to the preparation of example 8, with the only difference that: in step 4), intermediate I2The amounts of N, N-diisopropylethylamine and diphenyl phosphate azide were 3mmol, 3mmol and 3mmol, respectively. The yield of step (4) was 85%.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims (10)

1. An intermediate of a compound having anticancer activity, characterized in that it has the following structural formula I:
Figure FDA0002254309670000011
wherein R is1Is selected from H and
Figure FDA0002254309670000012
R2selected from hydroxyl and diazonium salt groups; n is selected from 1, 2 and 3.
2. Intermediate with anticancer active compounds according to claim 1, characterized in that it is selected from the following structures:
Figure FDA0002254309670000013
3. intermediate with anticancer active compounds according to claim 2, characterized in that said n is 2.
4. The process for preparing intermediates of compounds having anticancer activity according to claim 2 or 3,
the intermediate I1The preparation method comprises the following steps: a) under the action of organic alkali, 2, 4-dihydroxy benzaldehyde, 9-phenanthrene boric acid and anisole react in an organic solvent under the catalysis of trivalent ferric salt to obtain an intermediate I1。
5. The process for preparing intermediates of compounds having anticancer activity according to claim 4, wherein said step a) comprises: under the action of organic alkali, 2, 4-dihydroxybenzaldehyde and 9-phenanthreneboronic acid react in an organic solvent for 20-60 min, and then trivalent iron salt and anisole are added to react for 1-3 h to obtain an intermediate I1；
Preferably, in the step a), the molar ratio of the 2, 4-dihydroxybenzaldehyde to the 9-phenanthreneboronic acid to the anisole to the organic base to the trivalent iron salt is 1: 1 (1-1.5) to 2: 0.5;
preferably, the reaction temperature in the step a) is 80-100 ℃;
preferably, in step a), the organic base is selected from any one or two of piperidine and ethylenediamine;
preferably, in step a), the ferric salt is ferric chloride;
preferably, the organic solvent in step a) is selected from one or two of chlorobenzene and toluene.
6. Process for the preparation of intermediates of compounds with anticancer activity according to claim 4 or 5, characterized in that said intermediate I2The preparation method comprises the following steps: b) under the action of inorganic base, the intermediate I1And
Figure FDA0002254309670000021
reflux reaction in organic solvent to obtain intermediate I2；
Preferably, in said step b), intermediate I1、
Figure FDA0002254309670000022
The molar ratio of the inorganic base to the inorganic base is 1: 1 (1-1.2): 1-2;
preferably, in the step b),
Figure FDA0002254309670000023
is 2-chloroethyldimethylamine;
preferably, the inorganic base is selected from any one or more of sodium bicarbonate, sodium carbonate and potassium carbonate;
preferably, the organic solvent in step b) is acetone.
7. Process for the preparation of intermediates of compounds with anticancer activity according to claim 6, characterized in that said intermediate I3The preparation method comprises the following steps: c) under the action of N, N-diisopropylethylamine, the intermediate I2Reacting with diazotization reagent in organic solvent to obtain intermediate I3；
Preferably, in step c), the diazotizing agent is diphenyl phosphorazidate;
preferably, in said step c), intermediate I2The molar ratio of the diazotization reagent to the N, N-diisopropylethylamine is 1: 1 (1-1.5): 1-1.2;
preferably, the organic solvent in step c) is DMF;
preferably, in the step c), the reaction temperature is 20-25 ℃.
8. Use of an intermediate of a compound having anticancer activity according to claim 2 or 3 for the preparation of a compound having anticancer activity;
preferably, the compound having anticancer activity has the following structural formula A:
Figure FDA0002254309670000031
9. the use according to claim 8, characterized in that said compound with anticancer activity is prepared by a process comprising:
d) at the temperature of 0-5 ℃, the intermediate I3Acidizing until the pH value is 5-6 to obtain the compound with the anticancer activity;
preferably, in the step d), an acid solution is adopted for acidification;
more preferably, the acid solution is hypophosphorous acid;
preferably, in step d), the acidification treatment is carried out under ice bath conditions.
10. Use according to claim 9, characterized in that intermediate I is3The preparation method comprises the following steps:
a) under the action of organic alkali, 2, 4-dihydroxy benzaldehyde, 9-phenanthrene boric acid and anisole react in an organic solvent under the catalysis of trivalent ferric salt to obtain an intermediate I1；
b) Under the action of inorganic base, the intermediate I1Andreflux reaction in organic solvent to obtain intermediate I2；
c) Under the action of N, N-diisopropylethylamine, the intermediate I2Reacting with diazotization reagent in organic solvent to obtain intermediate I3。
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