CN109651376B - Synthetic method of azepino [5,4,3-cd ] indol-6-one compound - Google Patents
Synthetic method of azepino [5,4,3-cd ] indol-6-one compound Download PDFInfo
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Abstract
The invention relates to an azepino [5,4,3-cd]The invention discloses a synthesis method of an indol-6-one compound, in particular to a preparation method of an IA compound, which comprises the following steps: compounds of formula IA are prepared by reacting compounds of formula II with compounds of formula III via a Grandberg reaction. The method has the advantages of cheap and easily-obtained raw materials, short reaction steps and high yield, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of organic chemistry, in particular to a synthesis method of a poly (ADP-ribose) polymerase inhibitor Rucapari intermediate 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-ketone and analogues thereof.
Background
Ricipramine, chemically known as 8-fluoro-2- {4- [ (methylamino) methyl ] phenyl } -1,3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one, is a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), developed by the company Peucedani, approved by the US FDA for marketing in 2016 12 months, and is clinically used for the treatment of BRCA advanced ovarian cancer. The structural formula is as follows:
the preparation methods of the Ruipairui have more reports, but the industrially feasible process routes mainly comprise:
WO2000042040 discloses the preparation of intermediate 6-fluoroindole-4-carboxylic acid methyl ester (4) by nitration, esterification, condensation, reduction and cyclization of 2-methyl-5-fluorobenzoic acid. The latter is processed by indole cycloalkenyl, reduction and ring closure to obtain tricyclic intermediate 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one (7 or I), and the intermediate is processed by bromination, Suzuki coupling, amination and reduction to obtain Ruocapride, as shown in scheme 1:
this reaction step has problems of long route and low yield, for example, the yield from intermediate 4 to intermediate 7 is only 28%.
Process res.dev.2012,16, 1897-: the intermediate 6-fluoroindole-4-carboxylic acid methyl ester (4) is alkylated, deprotected and ring-closed to obtain tricyclic intermediate 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one (7 or I), as shown in scheme 2:
although the method shortens one-step reaction, the method has the defects of more steps for synthesizing the Rucapecitabine, lower reaction yield and only 38 percent of yield from the intermediate 4 to the intermediate 7.
In the two routes, a key tricyclic intermediate 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one (a compound shown in a formula I) is used:
in both scheme 1 and scheme 2, the method for synthesizing the intermediate has the defects of long route and low yield, so that a method for efficiently synthesizing the intermediate needs to be found.
Disclosure of Invention
The invention aims to provide a method for efficiently synthesizing 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one and analogues thereof.
In a first aspect of the invention, there is provided a process for the preparation of a compound of formula IA, comprising the steps of:
(II) subjecting the compound of formula II to a Grandberg reaction with a compound of formula III to form a compound of formula IA;
in the formula (I), the compound is shown in the specification,
R1and R2Each independently selected from hydrogen, C1-C10 alkyl, halogenated C1-C10 alkyl, halogen (fluorine, chlorine, bromine, iodine), sulfonic acid (SO)3H) Nitro (NO)2) Amino (NH)2)；
R3Selected from hydrogen or C1-C10 alkyl;
R4selected from hydrogen, cyano, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted C3-C18 cycloalkyl, unsubstituted or substituted 3-18 membered heterocycloalkyl, unsubstituted or substituted C6-C18 aryl, unsubstituted or substituted 4-18 membered heteroaryl, -C (O) -R11OR OR11Or NR11R12；
R5Selected from hydrogen or C1-C10 alkyl;
R6and R7Each independently selected from hydrogen or C1-C10 alkyl, or R6And R7Together form an unsubstituted or substituted methylene group, wherein said substitution is by a group selected from the group consisting of: C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C18 cycloalkyl, 3-18 membered heterocycloalkyl, C6-C18 aryl, 4-18 membered heteroaryl, OR11Or NR11R12；
R8Selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C18 cycloalkyl, substituted or unsubstituted 3-18 membered heterocycloalkyl, substituted or unsubstituted C6-C18 aryl, or substituted or unsubstituted 4-18 membered heteroaryl;
R9selected from halogen OR-OR13Wherein R is13Selected from substituted carbonyl or sulfonyl, wherein said substitution is with a substituent selected from the group consisting of: unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C18 cycloalkyl, unsubstituted or substituted 3-18 membered heterocycloalkyl, unsubstituted or substituted C6-C18 aryl, or unsubstituted or substituted 4-18 membered heteroaryl;
R10selected from OR11Or NR11R12(ii) a Or two R10Together with the formula ═ O or ═ NR11(ii) a Or two R10Forming a bridge-Z1-(CH2)n-Z2-, wherein Z1And Z2Are each independently O or NR11N is an integer of 1 to 3;
R11and R12Is independently hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted C3-C18 cycloalkyl, unsubstituted or substituted 3-18 membered heterocycloalkyl, unsubstituted or substituted C6-C18 aryl, or unsubstituted or substituted 4-18 membered heteroaryl;
in each of the above groups, the substituted independently means substituted with a group selected from the group consisting of: halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C18 cycloalkyl, 3-18 membered heterocycloalkyl, C6-C18 aryl, 4-18 membered heteroaryl.
In another preferred embodiment, R1、R2、R3、R4、R5Each independently selected from H, C1-C10 alkyl, halogen.
In another preferred embodiment, the compound of formula II is prepared by the following steps:
a) diazotizing a compound of formula IV with a nitrite or nitrite ester to form a compound of formula V;
b) reacting the compound of formula V with a reducing agent, thereby forming a compound of formula II;
wherein X is selected from halogen, sulfate radical, bisulfate radical, C1-C10 alkyl sulfonate radical, C6-C18 aryl sulfonate radical; r is1、R2、R8The definition of (1) is as above; r3、R6、R7Selected from hydrogen.
In another preferred embodiment, step b) is: after the reaction of step a) is finished, adding a reducing agent directly into the reaction mixture obtained in step a), and directly carrying out the reaction of step b), thereby forming the compound of formula II.
In another preferred embodiment, the compound of formula II is prepared by the following process: reacting a compound of formula VI with a compound of formula VII to form a compound of formula II;
wherein Y is halogen OR-OR13；R1、R2、R3、R6、R7、R8、R13The definition of (A) is as above.
In another preferred embodiment, in step a), the nitrite is selected from alkali metal nitrite, alkaline earth metal nitrite or ammonium nitrite;
in step a), the nitrite is selected from alkyl or aryl nitrite;
in step b), the reducing agent is selected from bisulfite, sulfite or stannous chloride.
In another preferred embodiment, the compound of formula II is methyl 3-hydrazino-5-fluorobenzoate of formula IIa and is prepared by the following steps:
i) reacting the compound methyl 3-amino-5-fluorobenzoate of formula IVa with sodium nitrite to form the compound 3-methoxycarbonyl-5-fluorophenyl diazonium salt of formula Va;
ii) reducing the compound of formula Va 3-methoxycarbonyl-5-fluorophenyl diazonium salt with stannous chloride to form the compound of formula IIa 3-hydrazino-5-fluorobenzoic acid methyl ester;
in another preferred embodiment, the steps i) and ii) are a one-pot frying process.
In another preferred embodiment, the compound of formula II is methyl 3-hydrazino-5-fluorobenzoate of formula IIa and is prepared by the following steps:
reacting the compound VIa, methyl 3, 5-difluorobenzoate, with a compound of formula VIIa, hydrazine hydrate, to form a compound of formula IIa;
in another preferred embodiment, the compound of formula II is the compound of formula IIb, methyl 3- [2- (diphenylmethylene) hydrazino ] -5-fluorobenzoate, and is prepared by the following steps:
coupling a VIb compound methyl 3-bromo-5-fluorobenzoate with a compound benzophenone hydrazone of formula VIIb in the presence of a metal catalyst to form a compound of formula IIb;
in another preferred embodiment, the metal catalyst is a palladium metal catalyst or a copper metal catalyst.
In another preferred embodiment, the palladium metal catalyst is preferably selected from Pd (OAc)2、Pd2(dba)3、PdCl2(dppf)。
In another preferred embodiment, the copper metal catalyst is preferably selected from the group consisting of CuI and Cu2O。
In another preferred embodiment, the compound of formula IA is the compound of formula IA 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one, and is prepared by the following steps:
reacting the compound of formula IIa, methyl 3-hydrazino-5-fluorobenzoate, with the compound of formula IIIa, 4-chlorobutyraldehyde, to form the compound of formula Ia;
in another preferred embodiment, the compound of formula IA is the compound of formula IA 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one, and is prepared by the following steps:
reacting the compound of IIb, methyl 3- [2- (diphenylmethylene) hydrazino ] -5-fluorobenzoate, with the compound of formula IIIa, 4-chlorobutyraldehyde, to form the compound of formula Ia;
in another preferred embodiment, the reaction is carried out in the presence of p-toluenesulfonic acid.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventors of the present invention have made extensive and intensive studies and have unexpectedly found a method for efficiently synthesizing 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one and analogues thereof. On this basis, the inventors have completed the present invention.
The reactions of the present application are all carried out in an inert solvent. The inert solvent is selected from the group consisting of: alcohols (e.g., ethanol), water, dimethyl sulfoxide, toluene, or combinations thereof. The reactions herein are all carried out at a suitable temperature (e.g., -10 ℃ to solvent reflux temperature).
Definitions and terms
As used herein, the term "alkyl" refers to a branched or straight chain (linear) alkane group (saturated aliphatic group) having from 1 to 10 carbon atoms in the chain (represented as C1-C10, the same applies hereinafter), which can generally be represented by the formula CkH2k+1Wherein k is an integer of 1 to 10. Alkyl groups of 1 to 6 carbon atoms are preferred.
The term "alkenyl" refers to a branched or straight chain alkene group (an unsaturated aliphatic group having one or more double bonds) containing from 2 to 10 carbon atoms in the chain. Alkenyl of 2 to 6 carbon atoms is preferred.
The term "alkynyl" refers to a branched or straight chain hydrocarbon group having one or more carbon-carbon triple bonds, with 2 to 10 carbon atoms in the chain. Alkynyl of 2 to 6 carbon atoms is preferred.
The term "carbocycle" refers to a saturated, partially saturated, unsaturated, or aromatic monocyclic or fused or non-fused polycyclic ring structure having only carbon ring atoms (no heteroatoms, i.e., non-carbon ring atoms).
The term "heterocycle" refers to a saturated, unsaturated, or aromatic monocyclic or fused or non-fused polycyclic ring structure having one or more heteroatoms selected from nitrogen, oxygen, and sulfur.
The term "cycloalkyl" refers to a non-aromatic, monovalent, monocyclic or fused polycyclic ring structure having a total of 3 to 18 carbon ring atoms (no heteroatoms) in the ring structure. Cycloalkyl of 3 to 8 carbon atoms is preferred.
The term "heterocycloalkyl" refers to a non-aromatic, monovalent monocyclic or fused polycyclic ring structure having a total of 3 to 18 ring atoms, including 1 to 5 (e.g., 1,2, 3,4, or 5) heteroatoms selected from nitrogen, oxygen, and sulfur. Preference is given to heterocycloalkyl having from 3 to 10 ring atoms.
The term "aryl" refers to an aromatic monocyclic or fused polycyclic structure having a total of 4 to 18, preferably 6 to 18, ring carbon atoms (no heteroatoms). More preferably from 6 to 10 ring carbon atoms.
The term "heteroaryl" refers to an aromatic, monovalent monocyclic or fused polycyclic ring structure having 4 to 18, preferably 5 to 18 ring atoms, including 1 to 5 (e.g., 1,2, 3,4 or 5) heteroatoms selected from nitrogen, oxygen and sulfur. More preferably 5 to 10 ring atoms.
The term "substituent" or "suitable substituent" refers to a substituent group recognized by a group or readily selected by a skilled artisan, such as by routine experimentation, that is pharmaceutically suitable. Illustrative examples of suitable substituents include hydroxy, halogen, oxygen, alkyl, acyl, sulfonyl, mercapto, nitro, alkylthio, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy, amino (primary, secondary or tertiary), carbamoyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, and the like (e.g., as illustrated by the exemplary compounds described herein).
Preferred optional substituents for alkyl and aryl groups in the compounds of the invention include halogen and aryl. Substituted alkyl is particularly preferably perfluoro substituted alkyl. Particularly preferred optional substituents for the aryl moiety include halogen, lower alkyl, hydroxy, nitro, cyano, carboxy, lower alkoxy, aryl, aryloxy, lower alkoxycarbonyl, amido, amino, trifluoromethyl and the like. The aryl moiety may also be optionally substituted with two substituents to formBridge, example-O- (CH)2)n-O-, wherein n is an integer of 1,2 or 3.
Compared with the prior art, the invention has the main advantages that:
a) a novel process for the preparation of azepino [5,4,3-cd ] indol-6-one compounds (such as the intermediate 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one) is provided;
b) the method has the advantages of easily obtained starting raw materials and short reaction steps;
c) the method has high yield up to 67 percent and is suitable for industrial mass production.
The invention will be further illustrated with reference to the following specific examples. For illustrative purposes only, the process of the present invention is illustrated by way of example for the preparation of the compound 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one of formula Ia, it being understood that these examples are intended to be illustrative only and not to limit the scope of the invention, the experimental procedures in the following examples being carried out under conditions not specified, generally in accordance with conventional conditions or in accordance with the recommendations of the manufacturer.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
EXAMPLE 1 preparation of methyl 3-hydrazino-5-fluorobenzoate as compound of formula IIa
Methyl 3-amino-5-fluorobenzoate (3.3g,19.6mmol), water (15mL), concentrated hydrochloric acid (15mL) was added to the reaction flask and cooled to-10 ℃. An aqueous solution (10mL) of sodium nitrite (2.1g,30mmol) at-10 ℃ was added dropwise over 15 minutes, and stirring was continued for 1.5 hours while maintaining the temperature. Adding SnCl dropwise into the reaction mixed liquid2·2H2An aqueous solution (40mL) of O (19.4g,86mmol) was added dropwise over 30 minutes, and stirring was continued for 1.5 hours under constant temperature. Inverse directionAfter completion of the reaction, a 6N NaOH solution (30mL) was added dropwise to the reaction mixture, and the mixture was extracted three times with methylene chloride (20 mL). The dichloromethane layers were combined, washed successively with water (30mL) and saturated brine (30mL), dried over anhydrous sodium sulfate, and concentrated to dryness to give 3.3g of product in 91.8% yield.1H-NMR(300MHz,CDCl3)δ2.0(br,2H),3.6(br,1H),3.89(s,3H),6.88(d,1H),6.98(s,1H),7.08(d,1H)。
Example 2 preparation of the Compound of formula IIa methyl 3-hydrazino-5-fluorobenzoate
Methyl 3, 5-difluorobenzoate (3.4g,20.0mmol), 35% hydrazine hydrate (3.7g,40.5mmol), and dimethyl sulfoxide (20mL) were added to a reaction flask, heated to 60 ℃ and stirred for 24 hours with constant temperature. After cooling to room temperature, water (100mL) was added and the mixture was stirred for 1 hour. Filtration, washing of the solid with water (20mL), vacuum drying at 60 ℃ gave 3.2g, 87.4% yield.
EXAMPLE 3 preparation of the Compound of formula Ia 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one
Methyl 3-hydrazino-5-fluorobenzoate (3.7g, 20.2mmol), 4-chlorobutanal (2.5g, 23.7mmol), ethanol (40mL), water (4mL) were added to the reaction flask, heated to reflux, and refluxed for 7 hours. Cooled to room temperature and concentrated under reduced pressure to about 10 mL. The mixture was cooled in ice water and stirred for 2 hours. Filtering, washing the solid with 2mL of 0 ℃ ethanol, and vacuum drying at 50 ℃ to obtain 3.0g of product with 73.2% yield.1H-NMR(300MHz,DMSO-d6)δ2.79(m,2H),3.41(m,2H),7.03(s,1H),7.20(d,1H),7.58(d,1H),8.23(br,1H),12.12(br,1H)。
EXAMPLE 4 preparation of the Compound of formula IIb methyl 3- [2- (diphenylmethylene) hydrazino ] -5-fluorobenzoate
Benzophenone hydrazone (2.2g,11.2mmol), palladium acetate (0.11g,0.5mmol), 2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (0.3g,0.5mmol), and toluene (15mL) were added to a reaction flask under an argon atmosphere, heated to 100 ℃ and stirred for 3 minutes. After cooling to room temperature, methyl 3-bromo-5-fluorobenzoate (2.3g,9.9mmol), cesium carbonate (4.5g,13.8mmol), and toluene (5mL) were added to the reaction flask, which was then heated to 100 ℃ again and stirred for 6 hours under constant temperature. Cool to room temperature, filter through celite, and wash the filter cake with dichloromethane (10 mL). The filtrates were combined and concentrated to dryness under reduced pressure to give 2.9g of product in 84.4% yield.1H-NMR(300MHz,CDCl3)δ3.89(s,3H),6.78(d,1H),6.88(s,1H),6.99(d,1H),7.10(br,1H),7.55～7.65(m,10H)。
EXAMPLE 5 preparation of the Compound of formula Ia 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one
To the reaction flask was added methyl 3- [2- (diphenylmethylene) hydrazino ] -5-fluorobenzoate (7.0g, 20.2mmol), 4-chlorobutanal (2.6g, 24.6mmol), p-toluenesulfonic acid (0.4g,2.1mmol), ethanol (40mL), water (4mL), heated to reflux, and refluxed for 10 hours. Cooled to room temperature and concentrated under reduced pressure to about 10 mL. The mixture was cooled in ice water and stirred for 2 hours. Filtering, washing the solid with 2mL of 0 ℃ ethanol, and vacuum drying at 50 ℃ to obtain 2.7g of a product with the yield of 65.8%.
EXAMPLE 6 preparation of the Compound of formula Ib 2,7, 9-trimethyl-8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one
Adding 4, 6-dimethyl 3- [2- (diphenylmethylene) hydrazino into a reaction bottle]-methyl 5-fluorobenzoate (7.5g, 19.9mmol), 4, 4-dimethoxy-1-pentylmethanesulfonate (5.4g, 23.9mmol), p-toluenesulfonic acid (0.4g,2.1mmol), ethanol (60mL), water (6mL), heated toRefluxing for 10 hours. Cooled to room temperature and concentrated under reduced pressure to about 10 mL. The mixture was cooled in ice water and stirred for 2 hours. Filtering, washing the solid with 3mL of 0 ℃ ethanol, and vacuum drying at 50 ℃ to obtain 3.7g of a product with the yield of 75.4%.1H-NMR(300MHz,DMSO-d6)δ2.28(s,3H),2.35(s,6H),2.73(m,2H),3.45(m,2H),8.20(br,1H),12.10(br,1H)。
EXAMPLE 7 preparation of the Compound 1,3, 5-trimethyl-8-fluoro-9-chloro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one of formula Ic
To the reaction flask was added methyl 3- (1, 2-dimethyl) hydrazino-5-fluoro-4-chlorobenzoate (4.9g, 19.9mmol), 5-chloro-2-pentanone (2.9g, 24.1mmol), ethanol (40mL), water (4mL), heated to reflux, and refluxed for 8 hours. Cooled to room temperature and concentrated under reduced pressure to about 10 mL. The mixture was cooled in ice water and stirred for 2 hours. Filtering, washing the solid with 2mL of 0 ℃ ethanol, and vacuum drying at 50 ℃ to obtain 4.1g of the product with the yield of 73.5%.1H-NMR(300MHz,DMSO-d6)δ2.28(s,3H),2.73(t,2H),3.25(s,3H),3.47(t,2H),3.69(s,3H),7.77(s,1H)。
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (17)
1. A process for the preparation of a compound of formula IA,
the method is characterized by comprising the following steps: (II) allowing the compound of formula II to undergo a Grandberg reaction with the compound of formula III to form a compound of formula IA;
in the formula (I), the compound is shown in the specification,
R1and R2Each independently selected from hydrogen, C1-C10 alkyl, halogenated C1-C10 alkyl, halogen and sulfonic SO3H. Nitro NO2Amino NH2；
R3Is hydrogen or C1-C10 alkyl;
R4is hydrogen or C1-C10 alkyl;
R5is hydrogen or C1-C10 alkyl;
R6and R7Each independently hydrogen or C1-C10 alkyl, or R6And R7Together form a phenyl-substituted methylene group;
R8is C1-C10 alkyl;
R9is halogen OR-OR13Wherein R is13Is C1-C10 alkyl substituted sulfonyl;
R10is OR11(ii) a Or two R10Together form ═ O;
R11is C1-C10 alkyl.
2. The method of claim 1, wherein R is1、R2Each independently selected from H, C1-C10 alkyl, halogen.
3. The method of claim 1, wherein the compound of formula II is prepared by:
a) diazotizing the compound of formula IV with nitrite or nitrite ester to form a compound of formula V;
b) reacting the compound of formula V with a reducing agent, thereby forming a compound of formula II;
wherein X is selected from halogen, sulfate radical, bisulfate radical, C1-C10 alkyl sulfonate radical, C6-C18 aryl sulfonate radical; r1、R2、R8The definition of (1) is as above; r3、R6、R7Selected from hydrogen.
4. The method of claim 3, wherein step b) is: after the reaction of step a) is finished, adding a reducing agent directly into the reaction mixture obtained in step a), and directly carrying out the reaction of step b), thereby forming the compound of formula II.
5. The process of claim 1, wherein the compound of formula II is prepared by: reacting a compound of formula VI with a compound of formula VII to form a compound of formula II;
in which Y is halogen OR-OR13；R1、R2、R3、R6、R7、R8、R13The definition of (A) is as above.
6. The method of claim 3,
in step a), the nitrite is selected from alkali metal nitrite, alkaline earth metal nitrite or ammonium nitrite;
in step a), the nitrite is selected from alkyl or aryl nitrite;
in step b), the reducing agent is selected from bisulfite, sulfite or stannous chloride.
7. The process of claim 6, wherein the compound of formula II is methyl 3-hydrazino-5-fluorobenzoate of formula IIa and is prepared by the following steps:
i) reacting the compound methyl 3-amino-5-fluorobenzoate of formula IVa with sodium nitrite to form the compound 3-methoxycarbonyl-5-fluorophenyl diazonium salt of formula Va;
ii) reducing the compound of formula Va 3-methoxycarbonyl-5-fluorophenyl diazonium salt with stannous chloride to form the compound of formula IIa 3-hydrazino-5-fluorobenzoic acid methyl ester;
8. the method of claim 7, wherein steps i) and ii) are a one-pot stir-fry process.
9. The process of claim 5 wherein the compound of formula II is methyl 3-hydrazino-5-fluorobenzoate of formula IIa and is prepared by the following steps:
reacting the compound VIa, methyl 3, 5-difluorobenzoate, with a compound of formula VIIa, hydrazine hydrate, to form a compound of formula IIa;
10. the process of claim 5 wherein the compound of formula II is the compound of formula lib methyl 3- [2- (diphenylmethylene) hydrazino ] -5-fluorobenzoate and is prepared by the steps of:
coupling a VIb compound methyl 3-bromo-5-fluorobenzoate with a compound benzophenone hydrazone of formula VIIb in the presence of a metal catalyst to form a compound of formula IIb;
11. the method of claim 10, wherein the metal catalyst is a palladium metal catalyst or a copper metal catalyst.
12. The method of claim 11, wherein the palladium metal catalyst is preferably selected from Pd (OAc)2、Pd2(dba)3、PdCl2(dppf)。
13. The process of claim 11, wherein the copper metal catalyst is preferably selected from the group consisting of CuI, Cu2O。
14. The process of claim 1 wherein the compound of formula IA is the compound 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one of formula IA, and is prepared by the steps of:
reacting the compound of formula IIa, methyl 3-hydrazino-5-fluorobenzoate, with the compound of formula IIIa, 4-chlorobutyraldehyde, to form the compound of formula Ia;
15. the process of claim 1 wherein the compound of formula IA is the compound 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ] indol-6-one of formula IA, and is prepared by the steps of:
reacting the compound of IIb, methyl 3- [2- (diphenylmethylene) hydrazino ] -5-fluorobenzoate, with the compound of formula IIIa, 4-chlorobutyraldehyde, to form the compound of formula Ia;
16. the process of claim 15, wherein the reaction is carried out in the presence of p-toluenesulfonic acid.
17. The method of claim 1, wherein the halogen is fluorine, chlorine, bromine, or iodine.
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| Intramolecular Fischer Indole Synthesis for the Direct Synthesis of 3,4-Fused Tricyclic Indole and Application to the Total Synthesis of (−)-Aurantioclavine;Jun Park et,al.;《Organic Letters》;20160916;第18卷;5098-5101 * |
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