CN104513147A - Preparation method of fluorene ethyl ketone derivative - Google Patents
Preparation method of fluorene ethyl ketone derivative Download PDFInfo
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- CN104513147A CN104513147A CN201410668438.7A CN201410668438A CN104513147A CN 104513147 A CN104513147 A CN 104513147A CN 201410668438 A CN201410668438 A CN 201410668438A CN 104513147 A CN104513147 A CN 104513147A
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- 0 CC(c(cc1C2(F)F)ccc1-c1c2cc(*)cc1)=O Chemical compound CC(c(cc1C2(F)F)ccc1-c1c2cc(*)cc1)=O 0.000 description 5
- SRUVBJCAQMMEGF-IWBZHGLYSA-N C/C=C(/C=C(C1(F)F)/C=C\C=C)\C1=C/CC(C)=O Chemical compound C/C=C(/C=C(C1(F)F)/C=C\C=C)\C1=C/CC(C)=O SRUVBJCAQMMEGF-IWBZHGLYSA-N 0.000 description 1
- FZBKISCVWOMXEF-UHFFFAOYSA-N CC(c(cc1)cc(C2(F)F)c1-c(cc1)c2cc1Br)=O Chemical compound CC(c(cc1)cc(C2(F)F)c1-c(cc1)c2cc1Br)=O FZBKISCVWOMXEF-UHFFFAOYSA-N 0.000 description 1
- OMUAUDWUNONHLH-UHFFFAOYSA-N CC(c1c2)(c3cc(Br)ccc3-c1ccc2C(C)=O)F Chemical compound CC(c1c2)(c3cc(Br)ccc3-c1ccc2C(C)=O)F OMUAUDWUNONHLH-UHFFFAOYSA-N 0.000 description 1
- KCZXXMXMFNEMBY-UHFFFAOYSA-N FN(c(cc(cc1)Br)c1C1=CC2)C1=CC2Br Chemical compound FN(c(cc(cc1)Br)c1C1=CC2)C1=CC2Br KCZXXMXMFNEMBY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
- C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Abstract
The present invention provides a preparation method of a fluorene ethyl ketone derivative, and particularly provides a preparation method of compounds of formula 1, definition of each group is as described in the specification. The compounds can be used as intermediates for preparation of ledipasvir, and used for the preparation of ledipasvir synthesis key intermediates and further preparation of ledipasvir. The method is low in cost, mild in reaction conditions, and suitable for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical intermediate preparation field, particularly, the invention provides a kind of preparation method of Lei Dipawei synthetic intermediate.
Background technology
Lei Dipawei (Ledipasvir, LDV) be the third liver medicine that Gilead develops, FDA has authorized LDV/SOF (Sofosbuvir) fixed dosage medicinal composition breakthrough therapy identification, this combination treatment was expected to cure genotype 1 HCV patient in the time being as short as 8 weeks, simultaneously without the need to injection of interferon or associating ribavirin (Ribavirin).
At present, in Lei Dipawei preparation method known in the art, mostly need pass through as shown in the formula the key intermediate shown in 7
(wherein X, X
1be halogen).Therefore, in order to suitability for industrialized production Lei Dipawei, this area need a kind of can the method for synthesis type 7 compound expeditiously.
US20100310512 reports a kind of formula 7 compounds process for production thereof as follows:
With the method preparation formula 7 compound, in fluorination reaction process, BAST is heated and easily decomposes, and has larger potential safety hazard; Lack selectivity in ethanoyl introducing process, use expensive Pd reagent, and the method also needs to use the organotin of severe toxicity to react, and therefore limits the use of this method largely.
US2013324740 reports following preparation method:
It is safer that aforesaid method carries out fluoridation, and acetylizad selectivity is better, but Weinreb acid amides (i.e. the chloro-N-methoxy-. N-methyl-ethanamide of 2-) costly, is not suitable for suitability for industrialized production.
In sum, this area is in the urgent need to developing the method for new preparation formula 7 compound.
Summary of the invention
The invention provides a kind of method of new preparation formula 7 compound.
A first aspect of the present invention, provides a kind of preparation method of formula 1 compound,
Wherein X
1for Cl, Br or I;
Each X
2be selected from as F or H respectively;
The method comprises:
A formula 2 compound, by step (a1), (a2), (a3) or (a4), is obtained formula 3, formula 4, formula 5 or formula 6 compound as raw material by (),
(a1) by formula 2 compound and alkali reaction, obtained formula 3 compound;
Wherein X
1, X
2the same, X
3for Br, I or H, M is Li, and alkali is the lithium alkylide of C1-C4;
(a2) by formula 2 compound and alkali reaction, obtained formula 4 compound;
Wherein X
1, X
2the same; X
4for Br or I;
M' is Mg;
Alkali is alkyl Grignard reagent, ethynyl magnesium halide, proyl magnesium halide, the butynyl magnesium halide of C1-C4, or its combination;
(a3) by formula 2 compound and alkali reaction, obtained formula 3 compound; Then formula 3 compound and Lewis acid are reacted, obtained formula 5 compound:
Wherein X
1, X
2, X
3and M is as defined above, alkali is the lithium alkylide of C1-C4, and Lewis acid is MgY
2, ZnY
2, CuY, CuY
2, FeY
2, FeY
3, CeY
3or its arbitrary combination, Y is Cl, Br or iodine, M, and " be selected from lower group: Mg, Zn, Cu, Fe, Ce or its combination, m is 1 or 2;
(a4) by formula 2 compound and alkali reaction, obtained formula 4 compound; Then formula 4 compound and Lewis acid are reacted, obtained formula 6 compound:
Wherein X
1, X
2, X
4, M' and m be as defined above, alkali is selected from lower group: C1-C4 Grignard reagent, ethynyl magnesium halide, proyl magnesium halide, butynyl magnesium halide, or its combination; Lewis acid is selected from lower group: ZnY
2, CuY, CuY
2, FeY
2, FeY
3, CeY
3, or its combination, Y is Cl, Br or iodine, M " ' be selected from lower group: Zn, Cu, Fe, Ce, or its combination;
B any one or the multiple compounds that are selected from formula 3, formula 4, formula 5, formula 6 and acetylation reagent react by (), obtained formula 1 compound.
In another preference, each X
2identical.
In another preference, each X
2all F.
In another preference, in step (a1), temperature of reaction is generally-80 DEG C to-30 DEG C.
In another preference, in step (a1), usual 5 minutes ~ 24 hours of reaction times was preferably 0.5-6 hour.
In another preference, in step (a2), temperature of reaction is-40 DEG C to 40 DEG C.
In another preference, in step (a2), usual 5 minutes ~ 24 hours of reaction times was preferably 0.5-6 hour.
In another preference, in the second step reaction of step (a3), temperature of reaction is-80 to 40 DEG C.
In another preference, in the second step reaction of step (a3), usual 5 minutes ~ 24 hours of reaction times was preferably 0.5-6 hour.
In another preference, in the second step reaction of step (a4), temperature of reaction is-40 to 40 DEG C.
In another preference, in the second step reaction of step (a4), usual 5 minutes ~ 24 hours of reaction times was preferably 0.5-6 hour.
In another preference, m is 1.
In another preference, M " being Mg, Zn, Ce or its combination, M " ' is Zn, Ce or its combination.
In another preference, the Fe that M ", M " ' is divalence.
In another preference, described reaction (a1), (a2), (a3), (a4), (b) carry out in inert solvent.
In another preference, the inert solvent in described reaction (a1), (a2), (a3), (a4), (b) is identical or substantially identical.
In another preference, described inert solvent is selected from lower group: THF, methyltetrahydrofuran, methyl tertiary butyl ether, ether, methylene diethyl ether, or its combination.
In another preference, described acetylation reagent is selected from lower group:
H
3cCOOCOR
1, wherein R
1for the alkyl of H or C1-C4;
H
3cCOOR
2, wherein R
2for COOR
3, R
3for the alkyl of C1-C4;
H
3cCOY, wherein Y is Cl, Br or I;
H
3cCOOR
3, wherein R
3definition as above;
H
3cCONMe (OMe), H
3cCONR
1r
3, R
1and R
3the same;
wherein n is 0,1 or 2;
Or the arbitrary combination of above-mentioned acetylation reagent.
In another preference, described acetylation reagent is selected from lower group: H
3cCOOCOR
1, H
3cCOY, H
3cCONMe (OMe), H
3cCONR
1r
3, or its combination; Wherein, the definition of each group as above.
In another preference, described Grignard reagent is C3 Grignard reagent.
In another preference, described acetylation reagent is selected from lower group: aceticanhydride, Acetyl Chloride 98Min., H
3cCONMe (OMe), or its combination.
A second aspect of the present invention, provides a kind of as shown in the formula the compound shown in 1a:
In formula, X
1for halogen (Cl, Br, I).
In another preference, X
1for Br.
A third aspect of the present invention, provides a kind of preparation method as shown in the formula 7 compounds, and described method comprises step:
(1) in inert solvent, formula 1a compound and halogenating agent are reacted, thus obtained formula 7 compound
In formula, X
1for halogen (Cl, Br, I); X is halogen (Cl, Br or I).
In another preference, in step (1), temperature of reaction is generally-50 DEG C to 50 DEG C.
In another preference, in step (1), usual 5 minutes ~ 24 hours of reaction times was preferably 0.5-6 hour.
In another preference, described inert solvent is selected from lower group: methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene, or its combination.
In another preference, described halogenating agent is selected from lower group: bromine, chlorine, SO
2cl
2or I
2.
A fourth aspect of the present invention, provides the preparation method of a kind of Lei Dipawei, and described method comprises step:
(1) formula 1a compound and halogenating agent are reacted, thus obtained formula 7 compound:
In formula, X
1for halogen (Cl, Br, I); X is halogen (Cl, Br or I).
In another preference, in step (1), temperature of reaction is generally-50 DEG C to 50 DEG C.
In another preference, in step (1), usual 5 minutes ~ 24 hours of reaction times was preferably 0.5-6 hour.
In another preference, described inert solvent is selected from lower group: methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene or its arbitrary combination.
Halogenating agent is: bromine, chlorine, SO
2cl
2or I
2.
(2) using formula 7 compound as intermediate, thus obtained Lei Dipawei (Ledipasvir, LDV).
In another preference, described method also comprises step: with method preparation formula 1a compound as described in the first aspect of the invention.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Embodiment
The present inventor is through long-term and deep research; be surprised to find that; compound as shown in Equation 2 and alkali is adopted to react; then acetylizad method is carried out; can prepare Lei Dipawei intermediate as shown in Equation 1 simple and convenient, at low cost, and then the Lei Dipawei shown in preparation formula 7 synthesizes key intermediate.Described method Atom economy is good, and easily realizes, and reaction conditions is gentle, has good industrial value.Based on above-mentioned discovery, contriver completes the present invention.
Term
As used herein, term " C1-C4 alkyl " refers to the alkyl with 1-4 carbon atom, as methyl, ethyl, propyl group, normal-butyl, the tertiary butyl, or similar group.
Term " C1-C4 lithium alkylide " refers to the alkyl lithium reagents with 1-4 carbon atom, as lithium methide, tert-butyl lithium, or similar reagents.
Term " C1-C4 Grignard reagent " refers to the Grignard reagent with 1-4 carbon atom, as propyl group magnesium chloride, butylmagnesium chloride, or similar reagents.
Term " halogen " refers to fluorine, chlorine, bromine, iodine.Especially, in this article, unless otherwise noted, mention that " halogen " part is all preferably chlorine, bromine or iodine.
Formula 1 compound and preparation thereof
The present invention relates to compound and preparation method thereof shown in formula 1,
Wherein X
1for halogen (Cl, Br, I), X
2for F or H.
This formula 1 compound is the intermediate of compound shown in formula 7, and formula 7 is key intermediates of synthesis Lei Dipawei (Ledipasvir), can by formula 1 through the convenient preparation of the reactions such as chloro, bromo, iodo.
Particularly, the preparation method of formula 1 compound provided by the invention comprises the following steps (a) and step (b):
A () is by (a1), (a2), (a3) or (a4), formula 2 compound is obtained formula 3, formula 4, formula 5 or formula 6 compound as raw material, in this step, by selecting different alkali, can be made into different metal reagents.For carrying out next step linked reaction.Wherein the actual conditions of each step is as follows:
(a1) by formula 2 compound and alkali reaction, obtained formula 3 compound;
Wherein X
1, X
2the same, X
3for Br, I or H, M is Li, in step (a1), and the lithium alkylide of the alkali that can select comprises (but being not limited to): C1-C4;
The reaction conditions of described step (a1), as temperature, reaction times, solvent etc. have no particular limits, those skilled in the art can be according to actual needs, select suitable temperature, the method (as TLC) etc. conventional by this area determines reaction end, solvent can select arbitrarily not with the inert solvent of reactant reaction.In another preference, in step (a1), temperature of reaction is generally-80 DEG C to-30 DEG C; Usual 5 minutes ~ 24 hours of reaction times was preferably 0.5-6 hour.
(a2) by formula 2 compound and alkali reaction, obtained formula 4 compound;
Wherein X
1, X
2the same; X
4for Br or I; M' is Mg; In step (a2), alkyl Grignard reagent, ethynyl magnesium halide, proyl magnesium halide, the butynyl magnesium halide of the alkali that can select comprises (but being not limited to): C1-C4, or its combination;
The reaction conditions of described step (a2), as temperature, in the reaction times, solvent etc. have no particular limits, and those skilled in the art can select according to actual needs.In another preference, in step (a2), temperature of reaction is-40 DEG C to 40 DEG C; Usual 5 minutes ~ 24 hours of reaction times was preferably 0.5-6 hour.
(a3) by formula 2 compound and alkali reaction, obtained formula 3 compound; Then formula 3 compound and Lewis acid are reacted, obtained formula 5 compound:
Wherein X
1, X
2, X
3and M is as defined above, in step (a3), the lithium alkylide of the alkali that can select comprises (but being not limited to): C1-C4.
In step (a3), the Lewis acid that can select comprises (but being not limited to): MgY
2, ZnY
2, CuY, CuY
2, FeY
2, FeY
3, CeY
3, or its combination; Wherein, Y is Cl, Br or iodine, M, and " be selected from lower group: Mg, Zn, Cu, Fe, Ce or its combination, m is 1 or 2; Preferably, described Lewis acid " is corresponding with described M.
The reaction conditions of described step (a3), as temperature, in the reaction times, solvent etc. have no particular limits, and those skilled in the art can select according to actual needs.In another preference, the actual conditions of the first step reaction of step (a3) can with reference to step (a1); In the second step reaction of step (a3), temperature of reaction is-80 to 20 DEG C; Usual 5 minutes ~ 24 hours of reaction times was preferably 0.5-6 hour.
(a4) by formula 2 compound and alkali reaction, obtained formula 4 compound; Then formula 4 compound and Lewis acid are reacted, obtained formula 6 compound:
Wherein X
1, X
2, X
4, M' and m be as defined above, in step (a4), the alkali that can select comprises (but being not limited to): C1-C4 Grignard reagent, ethynyl magnesium halide, proyl magnesium halide, butynyl magnesium halide, or its combination.
In step (a4), the Lewis acid that can select comprises (but being not limited to): ZnY
2, CuY, CuY
2, FeY
2, FeY
3, CeY
3, or its combination, Y is Cl, Br or iodine, M " ' be selected from lower group: Zn, Cu, Fe, Ce, or its combination.
The reaction conditions of described step (a4), as temperature, in the reaction times, solvent etc. have no particular limits, and those skilled in the art can select according to actual needs.In another preference, the actual conditions of the first step reaction of step (a4) can with reference to step (a2); In the second step reaction of step (a4), temperature of reaction is-40 to 40 DEG C; Usual 5 minutes ~ 24 hours of reaction times was preferably 0.5-6 hour.
B any one or the multiple compounds that are selected from formula 3, formula 4, formula 5, formula 6 and acetylation reagent react by (), obtained formula 1 compound.
In another preference, above-mentioned various in, each X
2identical; Preferably, each X
2all F.
In another preference, above-mentioned various in, m is 1.
In another preference, above-mentioned various in, M " be Mg, Zn, Ce or its combination, M " ' be Zn, Ce or its combination; In another preference, the Fe that M ", M " ' is divalence.
In another preference, described reaction (a1), (a2), (a3), (a4), (b) carry out in inert solvent.
In another preference, the inert solvent in described reaction (a1), (a2), (a3), (a4), (b) is identical or substantially identical; Preferably be selected from the inert solvent of lower group: THF, methyltetrahydrofuran, methyl tertiary butyl ether, ether, methylene diethyl ether, or its combination.
In described step (b), can select suitable acetylation reagent known in the art, the preferred described acetylation reagent of a class is selected from lower group:
H
3cCOOCOR
1, wherein R
1for the alkyl of H or C1-C4;
H
3cCOOR
2, wherein R
2for COOR
3, R
3for the alkyl of C1-C4;
H
3cCOY, wherein Y is Cl, Br or I;
H
3cCOOR
3, wherein R
3definition as above;
H
3cCONMe (OMe), H
3cCONR
1r
3, R
1and R
3the same;
wherein n is 0,1 or 2;
Or the arbitrary combination of above-mentioned acetylation reagent.
In another preference, described acetylation reagent is selected from lower group: H
3cCOOCOR
1, H
3cCOY, H
3cCONMe (OMe), H
3cCONR
1r
3, or its combination; Wherein, the definition of each group as above.More preferably, described acetylation reagent is selected from lower group: aceticanhydride, Acetyl Chloride 98Min., H
3cCONMe (OMe), or its combination.
Preferably, above-mentioned step (a) uses Grignard reagent as alkali, and preferred described Grignard reagent is C3 Grignard reagent.
In the present invention, additionally provide a class new formula 1 compound, the structure of described new compound is as shown in the formula shown in 1a:
In formula, X
1for halogen (Cl, Br, I).
In another preference, X
1for Br.
The preparation of formula 7 compound
In the present invention, additionally provide the preparation method of a class as shown in the formula 7 compounds, described method comprises step:
I formula 1a compound and halogenating agent, in inert solvent, react by (), thus obtained formula 7 compound:
In formula, X
1for halogen (Cl, Br, I); X is halogen (Cl, Br or I).
The reaction conditions of described step (i), as temperature, reaction times, solvent etc. have no particular limits, those skilled in the art can be according to actual needs, select suitable temperature, the method (as TLC) etc. conventional by this area determines reaction end, solvent can select arbitrarily not with the inert solvent of reactant reaction.In another preference, in step (i), temperature of reaction is generally-50 DEG C to 50 DEG C; Usual 5 minutes ~ 24 hours of reaction times was preferably 0.5-6 hour.
In another preference, described inert solvent is selected from lower group: methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene, or its combination.
In described step (i), preferred described halogenating agent is selected from lower group: bromine, chlorine, SO
2cl
2or I
2.
The preparation of Lei Dipawei
Present invention also offers the preparation method of a kind of Lei Dipawei, described method comprises step:
I formula 1a compound and halogenating agent, in inert solvent, react by (), thus obtained formula 7 compound:
In formula, X
1for halogen (Cl, Br, I); X is halogen (Cl, Br or I).
The reaction conditions of described step (i), as temperature, reaction times, solvent etc. have no particular limits, those skilled in the art can be according to actual needs, select suitable temperature, the method (as TLC) etc. conventional by this area determines reaction end, solvent can select arbitrarily not with the inert solvent of reactant reaction.In another preference, in step (i), temperature of reaction is generally-50 DEG C to 50 DEG C; Usual 5 minutes ~ 24 hours of reaction times was preferably 0.5-6 hour.
In another preference, described inert solvent is selected from lower group: methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene or its arbitrary combination.
In described step (i), preferred described halogenating agent is selected from lower group: bromine, chlorine, SO
2cl
2or I
2.
(ii) using formula 7 compound as intermediate, thus obtained Lei Dipawei (Ledipasvir, LDV).Wherein, described preparation method has no particular limits; the method preparation that this area can be adopted to have reported, or by those skilled in the art in conjunction with technology designed, designed known in the art, such version should be considered to fall within protection scope of the present invention.
In another preference, described method also comprises step: with method preparation formula 1a compound as described in the first aspect of the invention.
Compared with prior art, major advantage of the present invention comprises:
(1) in preparation method of the present invention, starting materials of formulae 2 compound can adopt US2013324740 similar approach to prepare, and technique is simple, and security is good;
(2), in preparation method of the present invention, acylation reaction can be carried out, without the need to using expensive palladium metal reagent with comparatively inexpensive alkali (as alkyl lithium reagents, Grignard reagent etc.); Meanwhile, the inventive method substitutes Weinreb acid amides with acylating reagent cheap and easy to get, significantly reduces material cost;
(3) the inventive method Atom economy is good, decreases three waste discharge; The reagent that inapplicable toxicity is larger simultaneously, reaction conditions is gentle, reaction process safety, and synthesis technique very easily realizes, and has good industrial value;
(4) the inventive method additionally provides the new compound shown in formula 1, and this compound as the synthetic intermediate of Lei Dipawei, can prepare Lei Dipawei key intermediate formula 7 compound expeditiously.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number calculate by weight.
Embodiment 1
(1) 2.5g compound 2A is added in reaction flask, the anhydrous THF of 25mL, stirring and dissolving.The solution cryosel bath obtained is cooled to-5 DEG C, slow dropping 3.93mL i-PrMgCl tetrahydrofuran solution (concentration is 2mol/L), time for adding is 10 minutes, dropping process keeps temperature to be no more than 0 DEG C, drip rear system to react 1 hour at-5 ~ 0 DEG C, obtain reaction mixture.
(2) in another one there-necked flask, 2.59g diacetyl oxide is added, nitrogen replacement 3 times, cryosel bath is cooled to-5 DEG C, the grignard reagent (i.e. the reaction mixture of preparation in step (1)) prepared above is added drop-wise in aceticanhydride, time for adding 20 minutes, dropping process keeps temperature to be no more than 0 DEG C, drips rear system and reacts 1 hour at-5 ~ 0 DEG C.
(3) 20mL saturated ammonium chloride solution is added drop-wise to cancellation reaction in system, separatory; Aqueous phase is extracted with ethyl acetate once, merges organic phase, and once, system pH is 8 in saturated sodium bicarbonate solution washing, and once, anhydrous sodium sulfate drying 30 minutes, concentrates in saturated common salt water washing.
(4) the concentrated thick product 30mL normal hexane backflow making beating obtained 1 hour, is slowly as cold as room temperature, filters, filter cake with n-hexane once, after drying the yellow product of 1.4g, yield 72.44%.
Product C-0011H NMR (400MHz, CDCl
3) δ 8.199 (1H, s), 8.115 (1H, d, J=8); 7.816 (1H, s), 7.640 (2H, t, J=8), 7.506 (1H, d, J=8), 2.664 (3H, s)
Embodiment 2
(1) thermometer will be housed, addition funnel, the there-necked flask nitrogen replacement of nitrogen protection device three times, in reaction flask, add 4.07g compound 2A, the anhydrous THF of 50mL, stirring and dissolving.The solution dry ice acetone bath obtained is cooled to-70 DEG C, slow dropping 4mL n-Butyl Lithium/tetrahydrofuran solution (concentration is 2.5mol/L), time for adding is 10 minutes, dropping process keeps temperature to be no more than-65 DEG C, drip rear system to react 1 hour at-65 DEG C, obtain reaction mixture.
(2) 3.06g aceticanhydride is slowly added drop-wise in above-mentioned reaction mixture, time for adding 10 minutes, and dropping process keeps temperature to be no more than-65 DEG C, drips rear system and reacts 1 hour at-55 DEG C.
(3) 20mL saturated ammonium chloride solution is added drop-wise to cancellation reaction in system, and cancellation process temperature is no more than 25 DEG C, stirs 20 minutes, separatory; Aqueous phase is extracted with ethyl acetate once, merges organic phase, and once, anhydrous sodium sulfate drying 30 minutes, concentrates in saturated common salt water washing.
(4) the concentrated thick product 30mL normal hexane backflow making beating obtained 1 hour, slowly be as cold as room temperature, filter, filter cake with n-hexane once, products obtained therefrom is pulled an oar 1 hour with 20mL methanol eddy again, cool to room temperature, filters, solid air blast is dried material and within 2 hours, is obtained the yellow product of 0.5g, yield 15%.
Product C-0011H NMR (400MHz, CDCl
3) δ 8.199 (1H, s), 8.115 (1H, d, J=8); 7.816 (1H, s), 7.640 (2H, t, J=8), 7.506 (1H, d, J=8), 2.664 (3H, s)
Embodiment 3
Thermometer will be housed, addition funnel, the there-necked flask nitrogen replacement of nitrogen protection device three times, in reaction flask, add 2.5g compound 2A, the anhydrous THF of 25mL, stirring and dissolving.The solution cryosel bath obtained is cooled to-5 DEG C, slow dropping 3.93mL i-PrMgCl tetrahydrofuran solution (concentration is 2mol/L), time for adding is 10 minutes, and dropping process keeps temperature to be no more than 0 DEG C, drips rear system and reacts 0.5 hour at-5 ~ 0 DEG C.System temperature drops to-20 DEG C, adds 0.25g anhydrous cerium chloride, stirs 30 minutes at this temperature.In another one there-necked flask, add 2.59g diacetyl oxide, nitrogen replacement 3 times, cryosel bath is cooled to-5 DEG C, the grignard reagent prepared above is added drop-wise in aceticanhydride, time for adding 20 minutes, dropping process keeps temperature to be no more than 0 DEG C, drips rear system and reacts 1 hour at-5 ~ 0 DEG C.
20mL saturated ammonium chloride solution is added drop-wise to cancellation reaction in system, and cancellation process temperature is no more than 25 DEG C, stirs 20 minutes, separatory; Aqueous phase is extracted with ethyl acetate once, merges organic phase, and once, system pH is 8 in saturated sodium bicarbonate solution washing, and once, anhydrous sodium sulfate drying 30 minutes, concentrates in saturated common salt water washing.
The concentrated thick product 30mL normal hexane backflow making beating obtained 1 hour, is slowly as cold as room temperature, filters, filter cake with n-hexane once, products obtained therefrom air blast is dried material and within 2 hours, is obtained the yellow product of 1.2g, yield 62.09%.
Embodiment 4
Thermometer will be housed, addition funnel, the there-necked flask nitrogen replacement of nitrogen protection device three times, in reaction flask, add 4.07g compound 2A, the anhydrous THF of 50mL, stirring and dissolving.The solution dry ice acetone bath obtained is cooled to-70 DEG C, slow dropping 4mL n-Butyl Lithium/tetrahydrofuran solution (concentration is 2.5mol/L), time for adding is 10 minutes, dropping process keeps temperature to be no more than-65 DEG C, drip rear system to react 0.5 hour at-65 DEG C, then add 0.2g Zinc Chloride Anhydrous at this temperature, react 0.5 hour.3.06g aceticanhydride is slowly added drop-wise in above-mentioned reaction, time for adding 10 minutes, and dropping process keeps temperature to be no more than-65 DEG C, drips rear system and reacts 1 hour at-55 DEG C.
20mL saturated ammonium chloride solution is added drop-wise to cancellation reaction in system, and cancellation process temperature is no more than 25 DEG C, stirs 20 minutes, separatory; Aqueous phase is extracted with ethyl acetate once, merges organic phase, and once, anhydrous sodium sulfate drying 30 minutes, concentrates in saturated common salt water washing.
The concentrated thick product 30mL normal hexane backflow making beating obtained 1 hour, is slowly as cold as room temperature, filters, filter cake with n-hexane once, products obtained therefrom is pulled an oar 1 hour with 20mL methanol eddy again, cool to room temperature, filter, solid air blast is dried material and within 2 hours, is obtained the yellow product of 1.5g, yield 45%.
Embodiment 5
(1) thermometer will be housed, addition funnel, the there-necked flask nitrogen replacement of nitrogen protection device three times, in reaction flask, add 3.6g compound 2B, the anhydrous THF of 40mL, stirring and dissolving.The solution dry ice acetone bath obtained is cooled to-70 DEG C, slow dropping 4.4mL n-Butyl Lithium/tetrahydrofuran solution (concentration is 2.5mol/L), time for adding is 10 minutes, dropping process keeps temperature to be no more than-65 DEG C, drip rear system to react 1 hour at-65 DEG C, obtain reaction mixture.
(2) 4.08g aceticanhydride is slowly added drop-wise in above-mentioned reaction mixture, time for adding 10 minutes, and dropping process keeps temperature to be no more than-65 DEG C, drips rear system and reacts 1 hour at-55 DEG C.
(3) 20mL saturated ammonium chloride solution is added drop-wise to cancellation reaction in system, and cancellation process temperature is no more than 25 DEG C, stirs 20 minutes, separatory; Aqueous phase is extracted with ethyl acetate once, merges organic phase, and once, anhydrous sodium sulfate drying 30 minutes, concentrates in saturated common salt water washing.
(4) the concentrated thick product 30mL normal hexane backflow making beating obtained 1 hour, slowly be as cold as room temperature, filter, filter cake with n-hexane once, products obtained therefrom is pulled an oar 1 hour with 20mL methanol eddy again, cool to room temperature, filters, solid air blast is dried material and within 2 hours, is obtained the yellow product of 0.678g, yield 21%.
Embodiment 6
(1) thermometer will be housed, addition funnel, the there-necked flask nitrogen replacement of nitrogen protection device three times, in reaction flask, add 3.6g compound 2B, the anhydrous THF of 40mL, stirring and dissolving.The solution dry ice acetone bath obtained is cooled to-70 DEG C, slow dropping 4.4mL n-Butyl Lithium/tetrahydrofuran solution (concentration is 2.5mol/L), time for adding is 10 minutes, dropping process keeps temperature to be no more than-65 DEG C, drip rear system to react 1 hour at-65 DEG C, obtain reaction mixture.
(2) 2.75g Acetyl Chloride 98Min. is slowly added drop-wise in above-mentioned reaction mixture, time for adding 10 minutes, and dropping process keeps temperature to be no more than-65 DEG C, drips rear system and reacts 1 hour at-55 DEG C.
(3) 20mL saturated ammonium chloride solution is added drop-wise to cancellation reaction in system, and cancellation process temperature is no more than 25 DEG C, stirs 20 minutes, separatory; Aqueous phase is extracted with ethyl acetate once, merges organic phase, and once, anhydrous sodium sulfate drying 30 minutes, concentrates in saturated common salt water washing.
(4) the concentrated thick product 30mL normal hexane backflow making beating obtained 1 hour, slowly be as cold as room temperature, filter, filter cake with n-hexane once, products obtained therefrom is pulled an oar 1 hour with 15mL methanol eddy again, cool to room temperature, filters, solid air blast is dried material and within 2 hours, is obtained the yellow product of 0.45g, yield 13.9%.
Embodiment 7
6.9g (21.4mmol is added in the there-necked flask of 500ml, 1.0eq) compound 1a, 200ml Iso Butyl Acetate and 20ml Virahol, reaction mixture cools to 0-10 DEG C, add 0.57g (10mol%) phosphorus tribromide, then drip the Iso Butyl Acetate solution of 3.3g (20.6mmol, 0.96eq) bromine, within about 30 minutes, drip.
Reaction solution adds bromine in the saturated sodium sulfite solution of 50ml He excessive, separates organic phase, aqueous phase with 20ml extraction into ethyl acetate once, merge organic phase, anhydrous sodium sulfate drying.Concentrate to obtain crude product 8.5g (containing raw material, a bromo-derivative and two bromo-derivatives).Crude product 42.5ml (5vol) Virahol making beating purifying, obtains 6.0g target compound (yield: 70%).
1H NMR(400MHz,CDCl3)δ8.21(d,J＝1.0Hz,1H),8.14(d,J＝8.0Hz,1H),7.81(d,J＝1.4Hz,1H),7.65(t,J＝10.3Hz,2H),7.51(d,J＝8.1Hz,1H),4.52–4.39(m,2H),1.59(s,1H).
Embodiment 8
In the there-necked flask of 500ml, 6.9g (21.4mmol, 1.0eq) compound 1a, 69ml acetonitrile, 1ml acetic acid, is warmed up to 30-35 DEG C, drip 3.1g (1.1eq) SULPHURYL CHLORIDE (being dissolved in advance in 10ml acetonitrile), after being added dropwise to complete, keep 3 hours at 30-35 DEG C, TLC tracks to raw material and disappears.Reaction is also poured in the water of 100ml, filters out faint yellow solid.
Crude product 42.5ml (5vol) Virahol making beating purifying, obtains 7.0g target compound (yield: 81.7%).
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. the preparation method of formula 1 compound,
Wherein X
1for Cl, Br or I;
Each X
2be selected from as F or H respectively;
It is characterized in that, the method comprises:
A formula 2 compound, by step (a1), (a2), (a3) or (a4), is obtained formula 3, formula 4, formula 5 or formula 6 compound as raw material by (),
(a1) by formula 2 compound and alkali reaction, obtained formula 3 compound;
Wherein X
1, X
2the same, X
3for Br, I or H, M is Li, and alkali is the lithium alkylide of C1-C4;
(a2) by formula 2 compound and alkali reaction, obtained formula 4 compound;
Wherein X
1, X
2the same; X
4for Br or I;
M' is Mg;
Alkali is alkyl Grignard reagent, ethynyl magnesium halide, proyl magnesium halide, the butynyl magnesium halide of C1-C4, or its combination;
(a3) by formula 2 compound and alkali reaction, obtained formula 3 compound; Then formula 3 compound and Lewis acid are reacted, obtained formula 5 compound:
Wherein X
1, X
2, X
3and M is as defined above, alkali is the lithium alkylide of C1-C4, and Lewis acid is MgY
2, ZnY
2, CuY, CuY
2, FeY
2, FeY
3, CeY
3or its arbitrary combination, Y is Cl, Br or iodine, M, and " be selected from lower group: Mg, Zn, Cu, Fe, Ce or its combination, m is 1 or 2;
(a4) by formula 2 compound and alkali reaction, obtained formula 4 compound; Then formula 4 compound and Lewis acid are reacted, obtained formula 6 compound:
Wherein X
1, X
2, X
4, M' and m be as defined above, alkali is selected from lower group: C1-C4 Grignard reagent, ethynyl magnesium halide, proyl magnesium halide, butynyl magnesium halide, or its combination; Lewis acid is selected from lower group: ZnY
2, CuY, CuY
2, FeY
2, FeY
3, CeY
3, or its combination, Y is Cl, Br or iodine, M " ' be selected from lower group: Zn, Cu, Fe, Ce, or its combination;
B any one or the multiple compounds that are selected from formula 3, formula 4, formula 5, formula 6 and acetylation reagent react by (), obtained formula 1 compound.
2. the method for claim 1, is characterized in that, described acetylation reagent is selected from lower group:
H
3cCOOCOR
1, wherein R
1for the alkyl of H or C1-C4;
H
3cCOOR
2, wherein R
2for COOR
3, R
3for the alkyl of C1-C4;
H
3cCOY, wherein Y is Cl, Br or I;
H
3cCOOR
3, wherein R
3definition as above;
H
3cCONMe (OMe), H
3cCONR
1r
3, R
1and R
3the same;
wherein n is 0,1 or 2;
Or the arbitrary combination of above-mentioned acetylation reagent.
3. the method for claim 1, is characterized in that, described acetylation reagent is selected from lower group: H
3cCOOCOR
1, H
3cCOY, H
3cCONMe (OMe), H
3cCONR
1r
3, or its combination; Wherein, the definition of each group as above.
4. the method for claim 1, is characterized in that: described Grignard reagent is C3 Grignard reagent.
5. method as claimed in claim 2, it is characterized in that, described acetylation reagent is selected from lower group: aceticanhydride, Acetyl Chloride 98Min., H
3cCONMe (OMe), or its combination.
6. one kind as shown in the formula the compound shown in 1a
In formula, X
1for halogen (Cl, Br, I).
7. as shown in the formula a preparation method for 7 compounds, it is characterized in that, described method comprises step:
(1) in inert solvent, formula 1a compound and halogenating agent are reacted, thus obtained formula 7 compound
In formula, X
1for halogen (Cl, Br, I); X is halogen (Cl, Br or I).
8. method as claimed in claim 7, it is characterized in that, described halogenating agent is selected from lower group: bromine, chlorine, SO
2cl
2or I
2.
9. the preparation method of Yi Zhong Lei Dipawei, is characterized in that, described method comprises step:
(1) formula 1a compound and halogenating agent are reacted, thus obtained formula 7 compound:
In formula, X
1for halogen (Cl, Br, I); X is halogen (Cl, Br or I);
(2) using formula 7 compound as intermediate, thus obtained Lei Dipawei (Ledipasvir, LDV).
10. method as claimed in claim 9, it is characterized in that, described method also comprises step: with the method preparation formula 1a compound as described in as arbitrary in claim 1-5.
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