CN109824587A - The preparation method of tyrosine kinase inhibitor XJF007 and its intermediate - Google Patents
The preparation method of tyrosine kinase inhibitor XJF007 and its intermediate Download PDFInfo
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Abstract
The invention discloses the preparation methods of a kind of tyrosine kinase inhibitor XJF007 with the following general formula (I) structural formula and its intermediate.Preparation method of the invention, using first building core pharmacophore, the collective-type synthetic strategy for reconnecting both sides side chain connects alkaline 3 grades of amine in the end stage or final stage of synthesis, significantly reduces by the basic group bring low-yield and post-reaction treatment and the difficulty isolated and purified.The method of the present invention route is short, and convergence is strong, easy to operate, and yield is high, significantly reduces cost, is suitable for amplification and industrialized production.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of tyrosine kinase inhibitor XJF007 and its intermediate
Preparation method.
Background technique
Protein kinase is a kind of phosphotransferase, shifts the gamma phosphoric acid ester group of adenosine triphosphate atp to specific amino
Sour residue, to realize the phosphorylation of albumen, to realize its physiology and biochemical function.
Protein kinase has critical function on Information Conduction.Unusual protein kinase not can be carried out normal signal and pass
It passs, may lead lesion such as tumor cell proliferation, cell death, inflammation, cardiovascular disease etc..Protein kinase is broadly divided into two
Class: protein tyrosine kinase PTKs and receptor tyrosine kinase RTKs.ROS1/C-MET in MET race protein kinase is RTKs
One important subbreed, also referred to as hHGFR and RON;ROS1/C-MET can growth to initial tumor cell and metabolism play weight
It acts on, is the target of a variety of clinical drug researchs.
Therefore, the junket of ROS1/C-MET kinase inhibitor, especially small molecule compound is badly in need of in bio-medical technology field
Histidine kinase inhibitor.French Exelixis has the research of leading property to the field, and wherein Cabozantinib is successfully listed;And
Think active preferably N- p-fluorophenyl-N-3- fluoro- 4-[6- methoxyl group -7- (3- morpholine -1-) propoxyl group quinoline -4-] oxygroup benzene
Basic ring propyl- 1,1- diformamide (Foretinib) have entered the clinic II/III phase to breast cancer, kidney, gastric cancer etc., have had very
Broad application prospect, structural formula are as follows:
Be five segments (seeing below structural formula) of A/B/C/D/E Foretinib point, at present for preparation method just like
Lower 5 kinds: 1) CN102227164A, CN105218445A and WO10036831A1 use the method for DE+ABC;2)
WO13059788A1 and CN102282134A obtains the method for reconnection AB after CDE using DE+C;3) WO2005030140A is used
D+ABC obtains the method for reconnection E after ABCD;4) add the method for AB after WO10056960A1 uses DE+C to obtain CDE again;5)
The method that CN103965104A obtains reconnection A after BCDE using BC+DE.Wherein D segment is typically employed in other segments
Shi Guanhuan building, the method lead to inefficiency.
Summary of the invention
The invention solves the method inefficiency of Foretinib is prepared at present, a kind of N- is provided to fluorine
The fluoro- 4-[6- methoxyl group -7- of phenyl-N-3- (3- morpholine -1-) propoxyl group quinoline -4-] phenyl cyclopropyl -1,1- diformamide
(foretinib) preparation method of analog (the tyrosine kinase inhibitor XJF007 of abbreviation i.e. of the present invention), this method route
Short, convergence is strong, easy to operate, and yield is high, significantly reduces cost, is suitable for amplification and industrialized production.
In order to solve the above-mentioned technical problem, the present invention is achieved through the following technical solutions:
In one aspect of the invention, a kind of preparation method of logical formula (I) compound is provided, comprising the following steps:
Compound D and substituted 4- nitrophenol heat reaction under base catalysis effect, obtain compound CD, the chemical combination
Object CD deprotection base PG under reducing agent effect, forms compound CD1, wherein the reagent for playing base catalysis has N, N- bis-
Wopropyl ethyl amine (DIPEA) etc.;
Compound CD1 is reacted with the compound containing R6 group, generates compound CDE, and compound CDE makees in reducing agent
With lower reduction nitro, compound CDE1 is formed;
Compound CDE1 and compound AB reaction, obtains compound shown in logical formula (I);
Wherein, R1, R2, R3, R5 are respectively hydrogen, halogen, lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl
One of alkyl, Lower cycloalkyl alkyl, hydroxyl, lower alkoxy, lower cycloalkyloxy, light alkene base, Lower alkyne base
Or it is a variety of;
R4 is hydrogen, lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl, one in Lower cycloalkyl alkyl
Kind;
R6 isLower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl,
One of Lower cycloalkyl alkyl, K are selected from lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl, Lower cycloalkyl
One of alkyl;
A, c respectively indicates number 0,1,2 or 3, and e is number 1 or 2 or 3;
PG is hydroxyl protection base, including benzyl, to methoxy-benzyl, dimethoxy-benzyl, trimethoxy benzyl, triphenyl
Methyl, methoxyl methyl, trimethyl silicon substrate ethyl, dihydrofuran protecting group, dihydropyran protecting group, triethyl group silicon substrate, dimethyl
Tert-butyl silicon substrate, diphenyl tert-butyl silicon substrate;PG is preferably to methoxy-benzyl;
R7 is one of OH, Cl, active aliphatic radical, acid anhydrides, mixed acid anhydride, the active aliphatic radical, acid anhydrides, mixed acid anhydride packet
It includes
R9, R10, R11, R12, R13, R14, R15 are respectively hydrogen, halogen, lower halogenated alkyl, lower halogenated cycloalkane
Base, lower alkyl alkyl, Lower cycloalkyl alkyl, hydroxyl, lower alkoxy, lower cycloalkyloxy, light alkene base, Lower alkyne base
One of or it is a variety of;
X1, X2, X3, X4, X5, X6, X7 are respectively selected from hydrogen, halogen, NO2, CN, lower halogenated alkyl, lower halogenated ring
One of alkyl, lower alkyl alkyl, Lower cycloalkyl alkyl, X1~X7 can also form heterocycle, bridged ring or spiral shell between each other
Ring.
In another aspect of this invention, the preparation method of another logical formula (I) compound, including following step are additionally provided
It is rapid:
Compound D and substituted 4- nitrophenol heat reaction under base catalysis effect, obtain compound CD, the chemical combination
Object CD forms compound CD2 under reducing agent effect, wherein playing the reagent of base catalysis has n,N-diisopropylethylamine
(DIPEA) etc.;
Compound CD2 is reacted with compound AB, generates compound ABCD, and compound ABCD is removed under reducing agent effect
Protecting group PG forms compound ABCD1;
Compound ABCD1 is reacted with the compound containing R6 group, obtains compound shown in logical formula (I);
Wherein, R1, R2, R3, R5 are respectively hydrogen, halogen, lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl
One of alkyl, Lower cycloalkyl alkyl, hydroxyl, lower alkoxy, lower cycloalkyloxy, light alkene base, Lower alkyne base
Or it is a variety of;
R4 is hydrogen, lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl, one in Lower cycloalkyl alkyl
Kind;
R6 isLower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl,
One of Lower cycloalkyl alkyl, K are selected from lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl, Lower cycloalkyl
One of alkyl;
A, c respectively indicates number 0,1,2 or 3, and e is number 1 or 2 or 3;
PG is hydroxyl protection base, including benzyl, to methoxy-benzyl, dimethoxy-benzyl, trimethoxy benzyl, triphenyl
Methyl, methoxyl methyl, trimethyl silicon substrate ethyl, dihydrofuran protecting group, dihydropyran protecting group, triethyl group silicon substrate, dimethyl
Tert-butyl silicon substrate, diphenyl tert-butyl silicon substrate;PG is preferably to methoxy-benzyl;
R7 is one of OH, Cl, active aliphatic radical, acid anhydrides, mixed acid anhydride, the active aliphatic radical, acid anhydrides, mixed acid anhydride packet
It includes
R9, R10, R11, R12, R13, R14, R15 are respectively hydrogen, halogen, lower halogenated alkyl, lower halogenated cycloalkane
Base, lower alkyl alkyl, Lower cycloalkyl alkyl, hydroxyl, lower alkoxy, lower cycloalkyloxy, light alkene base, Lower alkyne base
One of or it is a variety of;
X1, X2, X3, X4, X5, X6, X7 are respectively selected from hydrogen, halogen, NO2, CN, lower halogenated alkyl, lower halogenated ring
One of alkyl, lower alkyl alkyl, Lower cycloalkyl alkyl, X1~X7 can also form heterocycle, bridged ring or spiral shell between each other
Ring.
Logical formula (I) compound of the invention, referred to as tyrosine kinase inhibitor XJF007.
The preparation method of above two logical formula (I) compound requires first to synthesize intermediate shown in formula (II).
The active aliphatic radical, acid anhydrides, mixed acid anhydride are selected from:
The compound AB is preferred are as follows:
The Lower cycloalkyl alkyl that the K is selected from includes cycloalkyl groupThe K is selected from
Lower halogenated alkyl include alkyl halide alkylWherein b, d are number 0,1,2,3 or 4, and E, F are hydrogen, halogen
One of element, hydroxyl, alkoxy, ketone, sulfydryl, alkyl thiol.
The preparation method of tyrosine kinase inhibitor XJF007 of the present invention reconnects two using core pharmacophore is first constructed
The collective-type synthetic strategy of avris chain connects alkaline 3 grades of amine in the end stage or final stage of synthesis, significantly reduce by
The basic group bring low-yield and post-reaction treatment and the difficulty isolated and purified, the method for the present invention route is short, and convergence is strong,
Easy to operate, yield is high, significantly reduces cost, is suitable for amplification and industrialized production.
Specific embodiment
Since Foretinib is the representation compound of the logical formula (I) compound of the present invention, below to prepare Foretinib's
Method is that embodiment is described in further detail the preparation method of the logical formula (I) compound of the present invention.
Embodiment 1
The synthesis step of 1- (the fluoro- 4- nitrobenzophenone of 2-) -6- benzyl -7- methoxy-auinolin
The chloro- 6- benzyl -7- methoxy-auinolin (10g, 30mmol) of 1- is dissolved in chlorobenzene (100mL), and the fluoro- 4- nitre of 2- is added
Base phenol (5g, 30mmol) and DIPEA (3g, 30mmol), heating stirring is overnight.After reaction solution is diluted with water, methylene chloride extraction
It takes, saturated common salt washing, after anhydrous sodium sulfate is dry, concentration is evaporated.Silica gel column chromatography purifying, obtain yellow solid (9g,
63%).
The synthesis step of 1- (the fluoro- 4- nitrobenzophenone of 2-) -6- hydroxyl -7- methoxy-auinolin
1- (the fluoro- 4- nitrobenzophenone of 2-) -6- benzyl -7- methoxy-auinolin (2g, 5mmol) is suspended in acetic acid (20mL),
It is added hydrobromic acid acetic acid solution (10mL), is stirred overnight at room temperature.A large amount of solids are precipitated, filter, and washed with massive laundering, it is dry,
Obtain brown solid (1g, 64%).
The synthesis step of 1- (the fluoro- 4- nitrobenzophenone of 2-) -6- morpholine propoxyl group -7- methoxy-auinolin
1- (the fluoro- 4- nitrobenzophenone of 2-) -6- hydroxyl -7- methoxy-auinolin (1g, 3mmol) and chloropropyl morpholine (0.5g,
It 3mmol) is dissolved in acetonitrile (50mL), is added cesium carbonate (2g, 5mmol), return stirring is overnight.After reaction solution concentration is evaporated, add
Enter water, ethyl acetate extraction.The washing of organic phase saturated common salt, after anhydrous sodium sulfate is dry, concentration is evaporated.Cross column (EA/PE=2:
1) yellow solid (1g, 72%) is obtained.
The synthesis step of 1- (the fluoro- 4- aminophenyl of 2-) -6- morpholine propoxyl group -7- methoxy-auinolin
1- (the fluoro- 4- nitrobenzophenone of 2-) -6- morpholine propoxyl group -7- methoxy-auinolin (1g, 1mmol) is dissolved in methanol
It in (100mL), is added palladium carbon (0.1g), under hydrogen atmosphere, is stirred overnight at room temperature.After reaction solution filters, concentration is evaporated.Silicagel column
Chromatographic purifying obtains yellow solid (0.9g, 96%).
A:
The fluoro- 4-[6- methoxyl group -7- of N- p-fluorophenyl-N-3- (3- morpholine propyl) methoxy quinoline -4-] phenyl ring
Propyl- 1, the synthesis step of 1- diformamide
N- is dissolved in methylene chloride (20mL) fluoroanilino-cyclopropyl dioctyl phthalate (0.1g, 0.4mmol), and HATU is added
(0.24g, 0.8mmol), DIPEA (0.12g, 0.8mmol) and 1- (the fluoro- 4- aminophenyl of 2-) -6- morpholine propoxyl group -7- methoxy
Yl-quinoline (0.18g, 0.4mmol), is stirred overnight at room temperature.After reaction solution dilution, washing, saturated common salt washing, anhydrous sodium sulfate
After drying, concentration is evaporated.Silica gel column chromatography purifies (EA/PE=3:1), obtains white solid (0.14g, 53%).B:
N- is to fluoroanilino-cyclopropyl dimethyl chloride synthesis step
N- is dissolved in methylene chloride (30mL) fluoroanilino-cyclopropyl dioctyl phthalate (0.1g, 0.4mmol), and oxalyl chloride is added
(0.2g, 2mmol) and 1 drop n,N-Dimethylformamide, is stirred at room temperature 2 hours.Concentration is evaporated, obtain yellow solid (0.1g,
100%).
The fluoro- 4-[6- methoxyl group -7- of N- p-fluorophenyl-N-3- (3- morpholine propyl) methoxy quinoline -4-] phenyl ring
Propyl- 1, the synthesis step of 1- diformamide
1- (the fluoro- 4- aminophenyl of 2-) -6- morpholine propoxyl group -7- methoxy-auinolin (0.18g, 0.4mmol) is dissolved in dichloro
In methane (20mL), be added DIPEA (0.12g, 0.8mmol) and N- to fluoroanilino-cyclopropyl dimethyl chloride (0.1g,
0.4mmol) it is stirred overnight at room temperature.After reaction solution dilution, washing, saturated common salt washing, after anhydrous sodium sulfate is dry, concentration is steamed
It is dry.Silica gel column chromatography purifies (EA/PE=3:1), obtains white solid (0.09g, 51%).
C:
N- is to fluoroanilino-cyclopropyl dioctyl phthalate phenyl-pentafluoride phenolic ester synthesis step
N- is dissolved in methylene chloride (100mL) fluoroanilino-cyclopropyl dioctyl phthalate (1.3g, 5mmol), addition DCC (2g,
8mmol), DMAP (1g, 8mmol) and pentafluorophenol (0.9g, 5mmol), are stirred overnight at room temperature.It after reaction solution dilution, washes, satisfies
It is washed with salt, after anhydrous sodium sulfate is dry, concentration is evaporated.Silica gel column chromatography purifies (EA/PE=1:5), obtains white solid
(2g, 88%).
The fluoro- 4-[6- methoxyl group -7- of N- p-fluorophenyl-N-3- (3- morpholine propyl) methoxy quinoline -4-] phenyl ring
Propyl- 1, the synthesis step of 1- diformamide
1- (the fluoro- 4- aminophenyl of 2-) -6- morpholine propoxyl group -7- methoxy-auinolin (0.18g, 0.4mmol) and N- are to fluorine
Phenylamino-cyclopropyl dioctyl phthalate phenyl-pentafluoride phenolic ester (0.18g, 0.4mmol) is dissolved in acetonitrile (50mL), addition potassium carbonate (0.2g,
1mmol), return stirring is overnight.After reaction solution concentration is evaporated, water, ethyl acetate extraction is added.The washing of organic phase saturated common salt,
After anhydrous sodium sulfate is dry, concentration is evaporated.It crosses column (EA/PE=2:1) and obtains the fluoro- 4-[6- of white solid N- p-fluorophenyl-N-3-
Methoxyl group -7- (3- morpholine propyl) methoxy quinoline -4-] phenyl cyclopropyl -1,1- diformamide.
Embodiment 2
The synthesis step of 1- (the fluoro- 4- nitrobenzophenone of 2-) -6- benzyl -7- methoxy-auinolin
The chloro- 6- benzyl -7- methoxy-auinolin (10g, 30mmol) of 1- is dissolved in chlorobenzene (100mL), and the fluoro- 4- nitre of 2- is added
Base phenol (5g, 30mmol) and DIPEA (3g, 30mmol), heating stirring is overnight.After reaction solution is diluted with water, methylene chloride extraction
It takes, saturated common salt washing, after anhydrous sodium sulfate is dry, concentration is evaporated.Silica gel column chromatography purifying, obtain yellow solid (9g,
63%).
The synthesis step of 1- (the fluoro- 4- aminocarbonyl phenyl of 2-) -6- benzyl -7- methoxy-auinolin
1- (the fluoro- 4- nitrobenzophenone of 2-) -6- benzyl -7- methoxy-auinolin (2g, 5mmol) is dissolved in methanol (100mL),
Iron powder (0.2g) and 1N hydrochloric acid (5mL) is added, is stirred at room temperature 2 hours.Reaction solution is neutralized with sodium bicarbonate solution, is filtered.Silica gel
Column chromatographic purifying obtains yellow solid (1.8g, 97%).
A:
The fluoro- 4- of N- p-fluorophenyl-N-3- (6- methoxyl group -7- benzyl methoxy quinoline -4-) phenyl cyclopropyl -1,1- bis-
The synthesis step of formamide
N- is dissolved in methylene chloride (100mL) fluoroanilino-cyclopropyl dioctyl phthalate (0.6g, 2.5mmol), and HATU is added
(1.2g, 4mmol), DIPEA (0.6g, 4mmol) and 1- (the fluoro- 4- aminocarbonyl phenyl of 2-) -6- benzyl -7- methoxy-auinolin
(0.9g, 2.5mmol), is stirred overnight at room temperature.After reaction solution dilution, washing, saturated common salt washing, after anhydrous sodium sulfate is dry,
Concentration is evaporated.Silica gel column chromatography purifies (EA/PE=3:1), obtains yellow solid (1g, 73%).
The fluoro- 4- of N- p-fluorophenyl-N-3- (6- methoxyl group -7- hydroxymethoxy quinoline -4-) phenyl cyclopropyl -1,1- bis-
The synthesis step of formamide
The fluoro- 4- of N- p-fluorophenyl-N-3- (6- methoxyl group -7- benzyl methoxy quinoline -4-) phenyl cyclopropyl -1,1- bis-
Formamide (1g, 2.5mmol) is dissolved in methanol (100mL), is added palladium carbon (0.1g), under hydrogen atmosphere, is stirred overnight at room temperature.Instead
After answering liquid to filter, concentration is evaporated.Silica gel column chromatography purifying, obtains yellow solid (0.8g, 94%).
The fluoro- 4-[6- methoxyl group -7- of N- p-fluorophenyl-N-3- (3- morpholine propyl) methoxy quinoline -4-] phenyl ring
Propyl- 1, the synthesis step of 1- diformamide
The fluoro- 4- of N- p-fluorophenyl-N-3- (6- methoxyl group -7- hydroxymethoxy quinoline -4-) phenyl cyclopropyl -1,1- bis-
Formamide (0.5g, 1mmol) chloropropyl morpholine (0.15g, 1mmol) is dissolved in acetonitrile (50mL), addition potassium carbonate (0.2g,
1.5mmol), return stirring is overnight.After reaction solution concentration is evaporated, water, ethyl acetate extraction is added.Organic phase saturated salt solution
It washes, after anhydrous sodium sulfate is dry, concentration is evaporated.It crosses column (EA/PE=2:1) and obtains white solid (0.3g, 48%).
B:
The fluoro- 4- of N- p-fluorophenyl-N-3- (6- methoxyl group -7- benzyl methoxy quinoline -4-) phenyl cyclopropyl -1,1- bis-
The synthesis step of formamide
1- (the fluoro- 4- aminocarbonyl phenyl of 2-) -6- benzyl -7- methoxy-auinolin (1g, 2.5mmol) and N- are to fluoroanilino-ring
Third dimethyl chloride (0.62g, 2.5mmol) is dissolved in acetonitrile (50mL), and DIPEA is added, and return stirring is overnight.Reaction solution concentration is steamed
After dry, water, ethyl acetate extraction is added.The washing of organic phase saturated common salt, after anhydrous sodium sulfate is dry, concentration is evaporated.Cross column
(EA/PE=2:1) white solid (1g, 87%) is obtained.
The fluoro- 4- of N- p-fluorophenyl-N-3- (6- methoxyl group -7- hydroxymethoxy quinoline -4-) phenyl cyclopropyl -1,1- bis-
The synthesis step of formamide
The fluoro- 4- of N- p-fluorophenyl-N-3- (6- methoxyl group -7- benzyl methoxy quinoline -4-) phenyl cyclopropyl -1,1- bis-
Formamide (1g, 2.5mmol) is dissolved in methanol (100mL), is added palladium carbon (0.1g), under hydrogen atmosphere, is stirred overnight at room temperature.Instead
After answering liquid to filter, concentration is evaporated.Silica gel column chromatography purifying, obtains yellow solid (0.8g, 94%).
The fluoro- 4-[6- methoxyl group -7- of N- p-fluorophenyl-N-3- (3- morpholine propyl) methoxy quinoline -4-] phenyl ring
Propyl- 1, the synthesis step of 1- diformamide
The fluoro- 4- of N- p-fluorophenyl-N-3- (6- methoxyl group -7- hydroxymethoxy quinoline -4-) phenyl cyclopropyl -1,1- bis-
Formamide (0.5g, 1mmol) chloropropyl morpholine (0.15g, 1mmol) is dissolved in acetonitrile (50mL), addition potassium carbonate (0.2g,
1.5mmol), return stirring is overnight.After reaction solution concentration is evaporated, water, ethyl acetate extraction is added.Organic phase saturated salt solution
It washes, after anhydrous sodium sulfate is dry, concentration is evaporated.It crosses column (EA/PE=2:1) and obtains white solid (0.3g, 48%).
Embodiments of the present invention above described embodiment only expresses, the description thereof is more specific and detailed, but can not
Therefore limitations on the scope of the patent of the present invention are interpreted as.It should be pointed out that for those of ordinary skill in the art,
Without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection model of the invention
It encloses.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (7)
1. the preparation method of logical formula (I) compound, comprising the following steps:
Compound D and substituted 4- nitrophenol heat reaction under base catalysis effect, obtain compound CD, compound CD
The deprotection base PG under reducing agent effect, forms compound CD1;
Compound CD1 is reacted with the compound containing R6 group, generates compound CDE, compound CDE is under reducing agent effect
Nitro is restored, compound CDE1 is formed;
Compound CDE1 and compound AB reaction, obtains compound shown in logical formula (I);
Wherein, R1, R2, R3, R5 be respectively hydrogen, halogen, lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl,
One of Lower cycloalkyl alkyl, hydroxyl, lower alkoxy, lower cycloalkyloxy, light alkene base, Lower alkyne base are more
Kind;
R4 is one of hydrogen, lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl, Lower cycloalkyl alkyl;
R6 isIt is lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl, rudimentary
One of cycloalkyl group, K are selected from lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl, Lower cycloalkyl alkyl
One of;
A, c respectively indicates number 0,1,2 or 3, and e is number 1 or 2 or 3;
PG is hydroxyl protection base, including benzyl, to methoxy-benzyl, dimethoxy-benzyl, trimethoxy benzyl, triphenyl first
Base, methoxyl methyl, trimethyl silicon substrate ethyl, dihydrofuran protecting group, dihydropyran protecting group, triethyl group silicon substrate, dimethyl uncle
Butyl silicon substrate, diphenyl tert-butyl silicon substrate;
R7 is one of OH, Cl, active aliphatic radical, acid anhydrides, mixed acid anhydride, and the active aliphatic radical, acid anhydrides, mixed acid anhydride include
R9, R10, R11, R12, R13, R14, R15 be respectively hydrogen, halogen, lower halogenated alkyl, lower halogenated cycloalkyl group,
Lower alkyl alkyl, Lower cycloalkyl alkyl, hydroxyl, lower alkoxy, lower cycloalkyloxy, light alkene base, in Lower alkyne base
It is one or more;
X1, X2, X3, X4, X5, X6, X7 are respectively selected from hydrogen, halogen, NO2, CN, lower halogenated alkyl, lower halogenated cycloalkane
One of base, lower alkyl alkyl, Lower cycloalkyl alkyl, X1~X7 can also form heterocycle, bridged ring or loop coil between each other.
2. the preparation method of logical formula (I) compound, comprising the following steps:
Compound D and substituted 4- nitrophenol heat reaction under base catalysis effect, obtain compound CD, compound CD
Compound CD2 is formed under reducing agent effect;
Compound CD2 is reacted with compound AB, generates compound ABCD, compound ABCD deprotection under reducing agent effect
Base PG forms compound ABCD1;
Compound ABCD1 is reacted with the compound containing R6 group, obtains compound shown in logical formula (I);
Wherein, R1, R2, R3, R5 be respectively hydrogen, halogen, lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl,
One of Lower cycloalkyl alkyl, hydroxyl, lower alkoxy, lower cycloalkyloxy, light alkene base, Lower alkyne base are more
Kind;
R4 is one of hydrogen, lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl, Lower cycloalkyl alkyl;
R6 isIt is lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl, rudimentary
One of cycloalkyl group, K are selected from lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl, Lower cycloalkyl alkyl
One of;
A, c respectively indicates number 0,1,2 or 3, and e is number 1 or 2 or 3;
PG is hydroxyl protection base, including benzyl, to methoxy-benzyl, dimethoxy-benzyl, trimethoxy benzyl, triphenyl first
Base, methoxyl methyl, trimethyl silicon substrate ethyl, dihydrofuran protecting group, dihydropyran protecting group, triethyl group silicon substrate, dimethyl uncle
Butyl silicon substrate, diphenyl tert-butyl silicon substrate;
R7 is one of OH, Cl, active aliphatic radical, acid anhydrides, mixed acid anhydride, and the active aliphatic radical, acid anhydrides, mixed acid anhydride include
R9, R10, R11, R12, R13, R14, R15 be respectively hydrogen, halogen, lower halogenated alkyl, lower halogenated cycloalkyl group,
Lower alkyl alkyl, Lower cycloalkyl alkyl, hydroxyl, lower alkoxy, lower cycloalkyloxy, light alkene base, in Lower alkyne base
It is one or more;
X1, X2, X3, X4, X5, X6, X7 are respectively selected from hydrogen, halogen, NO2, CN, lower halogenated alkyl, lower halogenated cycloalkane
One of base, lower alkyl alkyl, Lower cycloalkyl alkyl, X1~X7 can also form heterocycle, bridged ring or loop coil between each other.
3. preparation method according to claim 1 or 2, which is characterized in that the active aliphatic radical, acid anhydrides, mixed acid anhydride choosing
From:
4. preparation method according to claim 1 or 2, which is characterized in that the Lower cycloalkyl alkyl that the K is selected from includes ring
AlkylThe lower halogenated alkyl that the K is selected from includes alkyl halide alkylWherein b, d are number 0,1,2,3 or 4, and E, F are hydrogen, halogen, hydroxyl, alkoxy, ketone, sulfydryl, alkyl thiol
One of.
5. preparation method according to claim 3, which is characterized in that the compound AB includes:
6. intermediate shown in a kind of formula (II),
Wherein, R2 be hydrogen, halogen, lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl, Lower cycloalkyl alkyl,
One of hydroxyl, lower alkoxy, lower cycloalkyloxy, light alkene base, Lower alkyne base are a variety of;
R4 is one of hydrogen, lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl, Lower cycloalkyl alkyl;
PG is hydroxyl protection base, including to methoxy-benzyl, dimethoxy-benzyl, trimethoxy benzyl, trityl group, methoxy
Methyl, trimethyl silicon substrate ethyl, dihydrofuran protecting group, dihydropyran protecting group, triethyl group silicon substrate, dimethyl tertiary butyl silicon
Base, diphenyl tert-butyl silicon substrate.
7. the preparation method of intermediate shown in formula (II), comprising the following steps:
Compound D and substituted 4- nitrophenol heat reaction under base catalysis effect, obtain intermediate compound shown in formula (II)
Object;
R2 be hydrogen, halogen, lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl, Lower cycloalkyl alkyl, hydroxyl,
One of lower alkoxy, lower cycloalkyloxy, light alkene base, Lower alkyne base are a variety of;
R4 is one of hydrogen, lower halogenated alkyl, lower halogenated cycloalkyl group, lower alkyl alkyl, Lower cycloalkyl alkyl;
PG is hydroxyl protection base, including to methoxy-benzyl, dimethoxy-benzyl, trimethoxy benzyl, trityl group, methoxy
Methyl, trimethyl silicon substrate ethyl, dihydrofuran protecting group, dihydropyran protecting group, triethyl group silicon substrate, dimethyl tertiary butyl silicon
Base, diphenyl tert-butyl silicon substrate.
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