CN105801553B - A kind of preparation method of Benzochromene derivatives - Google Patents
A kind of preparation method of Benzochromene derivatives Download PDFInfo
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- CN105801553B CN105801553B CN201610225503.8A CN201610225503A CN105801553B CN 105801553 B CN105801553 B CN 105801553B CN 201610225503 A CN201610225503 A CN 201610225503A CN 105801553 B CN105801553 B CN 105801553B
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- 0 *c1ccccc1F Chemical compound *c1ccccc1F 0.000 description 7
- CFAIUTMGXFVOQE-UHFFFAOYSA-N Clc1ccc2-c3ccccc3OCc2c1 Chemical compound Clc1ccc2-c3ccccc3OCc2c1 CFAIUTMGXFVOQE-UHFFFAOYSA-N 0.000 description 1
- BBBRYVDJZUVJPB-UHFFFAOYSA-N O=C(CCC1)c2c1cc(-c(cc1)c(CO3)cc1Cl)c3c2 Chemical compound O=C(CCC1)c2c1cc(-c(cc1)c(CO3)cc1Cl)c3c2 BBBRYVDJZUVJPB-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/32—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions without formation of -OH groups
- C07C29/34—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions without formation of -OH groups by condensation involving hydroxy groups or the mineral ester groups derived therefrom, e.g. Guerbet reaction
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/40—Halogenated unsaturated alcohols
- C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
Abstract
The invention discloses the method for Benzochromene derivatives shown in a kind of formula (I), which can be as the synthetic intermediate of the synthetic intermediate of drug, such as Velpatasvir.The method of the present invention provides a completely new synthetic route for preparing Benzochromene derivatives, entire reaction route total recovery is high, is suitable for large-scale industrial production using cheap and easily-available adjacent fluorine halogeno-benzene as initial feed.
Description
Technical field
The present invention relates to a kind of preparation method of Benzochromene derivatives more particularly to the systems of Velpatasvir intermediates
Preparation Method.
Background technology
Many Benzochromene derivatives all have extensive pharmacological activity and physiological activity, and there are also Benzochromene derivatives
Object can be as the compound of the intermediate for preparing of drug, especially following formula (I a) structure：
It is the important intermediate for preparing hepatitis new drug Velpatasvir.
Patent WO2013075029 discloses a kind of synthetic method of Velpatasvir, is directed to Benzochromene spread out
The preparation method of biology, key step are as follows：
But -1 (2 hydrogen) -one of starting material 7- hydroxyl -3,4- dihydronaphthalene of this method first step, which is usually all multistep, closes
Into, it is with high costs, also, the catalyst Pd (OPiv) of its second step2With ligand P (4-F-Ph)3Price it is also very expensive.
As it can be seen that being prepared for Benzochromene derivatives, existing method production cost is higher, it is difficult to adapt to large-scale industry
The needs of metaplasia production.Therefore, there is an urgent need for explore the industrialized production road of the relatively low Benzochromene derivatives of a production cost at present
Line.
Invention content
To solve the above problems, the method that the present invention provides Benzochromene derivatives shown in a kind of formula (I), including it
Racemic mixture or chipal compounds：
Wherein, R1、R2、R3、R4、R5And R6Separately it is selected from hydrogen or C1~C4 alkyl；C1~C4 alkyl includes
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl and sec-butyl.
The method includes following step：
(1)
Formula (D) compound is obtained by raw material of formula (A) compound；Wherein, X represents Cl, Br or I；
(2)
In the presence of base, formula (E) compound is obtained by raw material of formula (D) compound；
(3)
Under acid condition, formula (E) compound and formula (F) compound are subjected to friedel-crafts acylation reaction, obtain formula (G) change
Close object；
(4)
The carbonyl of reduction-type (G) compound obtains formula (H) compound；
(5)
The carboxyl that chloride formula (H) compound is obtains formula (J) compound；
(6)
Under acid condition, formula (J) compound is subjected to intramolecular friedel-crafts acylation reaction, obtains formula (I) compound.
Further, the R1、R2、R3、R4、R5And R6It is hydrogen, specifically, i.e. the following institute of structure of formula (I) compound
Show,
Carry out as steps described below：
(1a)
Formula (Da) compound is obtained by raw material of formula (A) compound；Wherein, X represents Cl, Br or I；
(2a)
In the presence of base, formula (Ea) compound is obtained by raw material of formula (Da) compound；
(3a)
Under acid condition, formula (Ea) compound and formula (Fa) compound are subjected to friedel-crafts acylation reaction, obtain formula (Ga)
Compound；
(4a)
The carbonyl of reduction-type (Ga) compound obtains formula (Ha) compound；
(5a)
The carboxyl of chloride formula (Ha) compound obtains formula (Ja) compound；
(6a)
Under acid condition, formula (Ja) compound is subjected to intramolecular friedel-crafts acylation reaction, obtains formula (I a) compound.
Further, the X is selected from Br.
Further, in step (2) or step (2a), the alkali is selected from potassium tert-butoxide or potassium carbonate, and the solvent of reaction selects
From DMF, the tert-butyl alcohol or Isosorbide-5-Nitrae-dioxane.
Further, the alkali is selected from potassium tert-butoxide, and the solvent of reaction is selected from DMF.
Further, the temperature of reaction can be in 60 DEG C~90 DEG C, such as 60 DEG C.
Further, in step (3) or step (6), the friedel-crafts acylation reaction be in the presence of a lewis acid into
Capable；Preferably, the lewis acid is selected from alchlor.
Further, in step (4), the method for the reducing carbonyl is Wolff-Kishner- huang-Minlon reductions.I.e.
By carbonyls in high boiling solvent such as diglycol (such as diethylene glycol (DEG)), in the presence of sodium hydroxide or potassium hydroxide
Under, with hydrazine reaction.
Further, in step (5), the chloride reagent of the chloride is thionyl chloride.
In the step of formula (D) compound is obtained using formula (A) compound as raw material (1), those skilled in the art can be used
Known method can also be carried out by following routes：
(1-1)
Formula (B) compound is obtained by raw material of formula (A) compound；Wherein, Y represents hydroxyl, alkyl or alkoxy；
(1-2)
Suzuki cross-coupling reactions are carried out with formula (B) compound and formula (C) compound, obtain formula (D) compound.
Further, the Y represents hydroxyl.
Further, in step (1-1), when Y represents hydroxyl, formula (A) compound is reacted with organometallic reagent
It is reacted with borate, formula (B) compound is obtained after acidification；
The organometallic reagent is Grignard Reagent, preferably isopropylmagnesium chloride or n-BuLi；The borate is preferred
Trimethylborate or triisopropyl borate ester etc..
Further, in step (1-2), the catalyst of the Suzuki cross-coupling reactions is selected from four (triphenyl phosphorus)
The bis- Diphenyl phosphino ferrocene palladium chlorides of palladium, 1,1'- or palladium, preferably four (triphenyl phosphorus) palladiums.
Further, in step (1-2), the catalyst alkali of the Suzuki cross-coupling reactions is selected from potassium carbonate or phosphoric acid
Potassium is molten；Solvent is selected from THF, Isosorbide-5-Nitrae-dioxane or toluene；Reaction temperature is 60 DEG C~120 DEG C.
As it is a kind of more specifically, obtain the embodiment of Velpatasvir intermediates shown in formula (I a), it is specific
Synthetic route is as follows：
(1) boration reacts
The synthesis of adjacent fluorobenzoic boric acid：O-fluorobenzyl bromide is dissolved in solvent, organometallic reagent is added dropwise under low temperature, then boron is added dropwise
Acid esters is risen again overnight naturally.Reaction finishes, and pours into dilute hydrochloric acid, and extraction is concentrated to give adjacent fluorobenzoic boric acid.Solvent for use is
THF, ether etc., temperature are 0 DEG C Dao -70 DEG C, and organometallic reagent is Grignard Reagent, such as isopropylmagnesium chloride or positive fourth
Base lithium.Borate is trimethylborate, triisopropyl borate ester etc..
(2) Suzuki cross-coupling reactions
The synthesis of (the chloro- 2'- fluorine biphenyl -2- bases of 4-) methanol：By adjacent fluorobenzoic boric acid, (the bromo- 5- chlordiphenyls of 2-) methanol, alkali,
Palladium catalyst, solvent add in reactor, heating stirring reaction certain time, and TLC tracking determines reaction end.Reaction finishes,
Enter in ice water, extract, be concentrated to give (the chloro- 2'- fluorine biphenyl -2- bases of 4-) methanol.Alkali used is potassium carbonate, potassium phosphate etc., and solvent is
THF, Isosorbide-5-Nitrae-dioxane, toluene etc., catalyst be four triphenyl phosphorus palladiums, 1,1'- bis- Diphenyl phosphino ferrocene palladium chlorides, vinegar
Sour palladium etc., temperature is from 60 DEG C to 120 DEG C.
(3) intramolecular nucleophilic substitution reaction
The synthesis of chloro- 6 hydrogen of 8--benzo [c] chromene：By (the chloro- 2'- fluorine biphenyl -2- bases of 4-) methanol, alkali, the mixing of solvent
Object heating stirring is reacted, TLC tracking reactions.Reaction finishes, and pours into ice water, and extraction is concentrated to give chloro- 6 hydrogen of 8--benzo [c] color
Alkene.Alkali is potassium tert-butoxide, potassium carbonate etc., and solvent DMF, the tert-butyl alcohol, Isosorbide-5-Nitrae-dioxane, reaction temperature is 50 DEG C to 90 DEG C.
(4) intermolecular Friedel-Crafts acylation reactions
The synthesis of 4- (chloro- 6 hydrogen of 8--benzo [c] chromene -2- bases) -4- carbonyl butyric acid：By chloro- 6 hydrogen of 8--benzo [c] color
Alkene, succinic anhydride are dissolved in dichloroethanes, and alchlor is then added portionwise, in 60 DEG C of reactions.Reaction finishes, and pours into ice water
In, extraction, alkali cleaning, acidification, then extract, it is concentrated to give 4- (chloro- 6 hydrogen of 8--benzo [c] chromene -2- bases) -4- carbonyl butyric acid.
Huang Min-lon reduction
(5) Wolff-Kishner- Huang Min-lon reductions are reacted
The synthesis of 4- (chloro- 6 hydrogen of 8--benzo [c] chromene -2- bases) butyric acid：By 4- (chloro- 6 hydrogen of 8--benzo [c] chromene -2-
Base) -4- carbonyl butyric acid, hydrazine hydrate, potassium hydroxide is dissolved in diethylene glycol (DEG), divides water between being warming up to 140 DEG C to 150 DEG C, divided water
Afterwards, it is reacted between being warming up to 180 DEG C to 190 DEG C.Reaction finishes, and pours into ice water, adjusts acid, and extraction is concentrated to give 4- (8- chloro- 6
Hydrogen-benzo [c] chromene -2- bases) butyric acid.
(6) intramolecular Friedel-Crafts acylation reactions
The synthesis of compound I：By 4- (chloro- 6 hydrogen of 8--benzo [c] chromene -2- bases) butyric acid, DMF is dissolved in dichloromethane,
Thionyl chloride is added dropwise, drips off temperature rising reflux reaction.Alchlor is added portionwise in cooling, and 10 DEG C or so reactions are to the reaction was complete.
Enter in ice water, extract, be concentrated to give compound (Ia).
The present invention also provides the formula (D), formula (G) and formula (H) compounds；Further, R1、R2、R3、R4、R5With
R6It is hydrogen namely formula (Da), formula (Ga) and formula (Ha) compound.These compounds can be as the system of Benzochromene derivatives
Standby intermediate, especially formula (Da), formula (Ga) and formula (Ha) compound, can be as the Velpatasvir shown in formula (I a)
Prepare intermediate, great market application value.
The method of the present invention provides one and completely new prepares benzo color using cheap and easily-available adjacent fluorine halogeno-benzene as initial feed
The synthetic route of ene derivative, and the often step reaction of the synthetic route is screened and optimized.Entire reaction route is total
High income is suitable for large-scale industrial production.
In the present invention, the corresponding Chinese full name of english abbreviation is as shown in the table：
| Bu | Tertiary butyl |
| DCM | Dichloromethane |
| DMF | N,N-dimethylformamide |
| DMSO | Dimethyl sulfoxide (DMSO) |
| EA | Ethyl acetate |
| MTBE | Methyl tertiary butyl ether(MTBE) |
| Pd(dppf)Cl2 | The bis- Diphenyl phosphino ferrocene palladium chlorides of 1,1'- |
| THF | Tetrahydrofuran |
Obviously, the above according to the present invention according to the ordinary technical knowledge and customary means of this field, is not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The above of the specific embodiment present invention of form is described in further detail again by the following examples.
But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all real based on the above of the present invention institute
Existing technology all belongs to the scope of the present invention.
Specific embodiment
The preparation of 1 compound 2 of embodiment
1 4kg of compound (22.9mol) is sequentially added in 50L reaction kettles under nitrogen protection, THF20L is cooled to -70
℃.N-BuLi 6.8kg are added dropwise below -70 DEG C of temperature control, drip off 0.5 hour stirred below after -70 DEG C.It is dripped below -70 DEG C of temperature control
Add triisopropyl borate ester 4.75kg, rise again naturally after dripping off overnight.It pours into 20L (1N) dilute hydrochloric acid, liquid separation, water phase is used again
EA10L extractions are primary.Merge organic phase, washed once with saturated salt solution 10L, anhydrous sodium sulfate drying is filtered, and concentration must be changed
Close 2 2.4kg of object, yield 85%.
The preparation of 2 compound 4 of embodiment
Method 1：
Compound 3 500g, THF3L, 2 382g of compound, potassium carbonate are added in 10L four-hole bottles successively under nitrogen protection
626g, deionized water 3L, four (triphenyl phosphorus palladium) 6g are warming up to back flow reaction and stay overnight.The reaction was complete (about 16 hours) for TLC monitoring
After pour into 3L ice water, liquid separation, water phase EA1L extracts primary.Merge organic phase, washed once with saturated salt solution 2L, anhydrous sulphur
Sour sodium drying, filtering are concentrated to give 4 482g of compound, yield 96%.
HNMR(CDCl3,400MHz):δ7.62(s,1H),7.49-7.11(m,6H),4.69(1H,s),4.50(2H,s).
Method 2：
Compound 3 50g, THF 300mL, 2 38.2g of compound, carbon are added in 10L four-hole bottles successively under nitrogen protection
Sour potassium 62.6g, deionized water 300mL, Pd (dppf) Cl20.6g is warming up to back flow reaction 20h.TLC monitoring is after the reaction was complete
It pours into 500mL ice water, liquid separation, water phase EA 300mL extract primary.Merge organic phase, one is washed with saturated salt solution 200mL
Secondary, anhydrous sodium sulfate drying, filtering is concentrated to give 4 42.8g of compound, yield 80%, HPLC=88%.
As can be seen that when catalyst is four (triphenyl phosphorus palladium), the yield of target product is higher.
The preparation of 3 compound 5 of embodiment
Method 1：
Under nitrogen protection, compound 4 50g, DMSO 500mL, potassium tert-butoxide 35.6g are sequentially added in 1L four-hole bottles,
60 DEG C are warming up to react 1 hour.TLC monitoring raw materials disappear, and pour into 1L ice water, are extracted with MTBE 1L x 3.Merge organic
Phase is washed once with water 1L, and saturated salt solution 1L is washed once, and anhydrous sodium sulfate drying, filtering is concentrated to give compound 37.5g, receives
Rate 82%, HPLC=90%.
Method 2：
Under nitrogen protection, compound 4 50g, DMF 500mL, K are sequentially added in 1L four-hole bottles2CO343.7g heating
It is reacted 1 hour to 60 DEG C.TLC monitoring raw materials disappear, and pour into 1L ice water, are extracted with MTBE 1L x 3.Merge organic phase, use
Water 1L is washed once, and saturated salt solution 1L is washed once, and anhydrous sodium sulfate drying, filtering is concentrated to give 5 29.8g of compound, yield
65%, HPLC=85%.
Method 3：
Under nitrogen protection, compound 4 482g, DMF5L, potassium tert-butoxide 347g are sequentially added in 10L four-hole bottles, is heated up
It is reacted 0.5 hour to 60 DEG C.TLC monitoring raw materials disappear, and pour into 10L ice water, are extracted with MTBE10L x 3.Merge organic phase,
It is washed once with water 10L, saturated salt solution 10L is washed once, and anhydrous sodium sulfate drying, filtering is concentrated to give 5 419g of compound, receives
Rate 95%.
HNMR(CDCl3,400MHz):δ 7.67 (d, 1H, J=8.0Hz), 7.60 (d, 1H, J=8.4Hz), 7.33 (d,
1H, J=8.0Hz), 7.22 (m, 1H), 7.13 (s, 1H), 7.04 (m, 1H), 6.97 (d, 1H, J=8.0Hz), 5.06 (s, 2H)
As can be seen that when using potassium tert-butoxide, and solvent is DMF, the yield of target product is higher.
The preparation of 4 compound 6 of embodiment
Under nitrogen protection, compound 5 419g, dichloroethanes 3L, succinic anhydride 194g are sequentially added in 10L four-hole bottles.
Less than 40 DEG C are added portionwise alchlor 388g, after adding, are warming up to 60 DEG C and react 1 hour.TLC monitoring raw materials disappear, and pour into
In 6L ice water, liquid separation, water phase is extracted with DCM3L x 2.Merge organic phase, wash organic phase with 1N sodium hydrate aqueous solutions, give up
Organic phase.Water phase 6N hydrochloric acid tune pH=1, are extracted with EA/THF (1/3) 2L x 3.Merge organic phase, with saturated salt solution 2L
It washes once, anhydrous sodium sulfate drying, filtering is concentrated to give 6 313g of compound, yield 86%.
HNMR(CDCl3,400MHz):δ 8.36 (s, 1H), 7.87 (d, 1H, d=8.0Hz), 7.71 (d, 1H, J=
8.0Hz), 7.39 (d, 1H, J=8.4Hz), 7.16 (s, 1H), 7.02 (d, 1H, J=8.4Hz), 5.15 (s, 2H), 3.32 (t,
2H, J=6.4Hz), 2.83 (t, 2H, J=6.4Hz)
The preparation of 5 compound 7 of embodiment
Wolff-Kishner- huang-Minlon reductions：
Under nitrogen protection, compound 6 313g, diethylene glycol (DEG) 2.5L, hydrazine hydrate 187g, hydrogen are sequentially added in 10L four-hole bottles
Potassium oxide 224g.Finish, water divided between being warming up to 140 DEG C to 150 DEG C 3 hours, after having divided water, be warming up to 180 DEG C to 190 DEG C it
Between react 2 hours.The reaction was complete for TLC monitoring.Cooling, pours into ice water 10L, with 6N hydrochloric acid tune pH=1, is extracted with EA 3L x 3
It takes.Merge organic phase, washed once with saturated salt solution 3L, anhydrous sodium sulfate drying, filtering is dense, dense to obtain 7 240g of compound, receives
Rate 91%.
Control methods：
Under nitrogen protection, compound 6 10g, THF 200mL, trifluoroacetic acid 6g are sequentially added in 10L four-hole bottles, is added dropwise
After 20 DEG C of temperature control is hereinafter, drip off, 8h is stirred at room temperature in triethylsilane 8g.The reaction was complete for TLC monitoring.It pours into ice water 200mL,
It is extracted with EA 200mL x 3.Merge organic phase, washed once with saturated salt solution 200mL, anhydrous sodium sulfate drying is filtered, dense
Contract to obtain 7 2g of compound, yield 20%, HPLC=88%.
As can be seen that during the carbonyl of this step selection Wolff-Kishner- huang-Minlon reductions reducing compound 6, yield is bright
It is aobvious more excellent.
The preparation of embodiment 6Velpatasvir intermediates (Ia)
Under nitrogen protection, 7 185g of compound, dichloromethane 4L, DMF1mL are sequentially added in 10L four-hole bottles.Temperature control 20
DEG C hereinafter, be added dropwise thionyl chloride 109g, back flow reaction is warming up to after dripping off 1 hour.Cool down, three are added portionwise below 10 DEG C of temperature control
Aluminium chloride 122g adds recession except ice bath, and 10 DEG C or so are reacted 0.5 hour.TLC monitoring raw materials disappear.It pours into ice water 3L, point
Liquid, water phase are extracted with DCM 1.5L x 2.Merge organic phase, washed once with 1N sodium hydrate aqueous solutions 2L, saturated salt solution 2L
It washes once, anhydrous sodium sulfate drying, filtering is concentrated to give Velpatasvir intermediates (Ia) 155g, yield 95%, purity 94%
(HPLC)。
HNMR(CDCl3,400MHz):δ 7.60 (d, 1H, J=8.0Hz), 7.58 (s, 1H), 7.50 (s, 1H), 7.30 (d,
1H, J=8.0Hz), 7.13 (d, 1H), 5.02 (s, 2H), 2.92 (t, 2H, J=6.0Hz), 2.61 (t, 2H, J=6.8Hz),
2.12(m,2H).
In conclusion the method for the present invention using cheap and easily-available adjacent fluorine halogeno-benzene as initial feed, provide one it is completely new
The synthetic route of Benzochromene derivatives is prepared, entire reaction route total recovery is high, is suitable for large-scale industrial production.
Claims (17)
1. a kind of method of formula (I) compound, including its racemic mixture or chipal compounds：
Wherein, R1、R2、R3、R4、R5And R6Separately it is selected from hydrogen or C1~C4 alkyl；
The method includes following step：
(1)
Formula (D) compound is obtained by raw material of formula (A) compound；Wherein, X represents Cl, Br or I；
(2)
In the presence of base, formula (E) compound is obtained by raw material of formula (D) compound；
(3)
Under acid condition, formula (E) compound and formula (F) compound are subjected to friedel-crafts acylation reaction, obtain formula (G) compound；
(4)
The carbonyl of reduction-type (G) compound obtains formula (H) compound；
(5)
The carboxyl of chloride formula (H) compound obtains formula (J) compound；
(6)
Under acid condition, formula (J) compound is subjected to intramolecular friedel-crafts acylation reaction, obtains formula (I) compound.
2. according to the method described in claim 1, it is characterized in that：The R1、R2、R3、R4、R5And R6It is hydrogen.
3. method according to claim 1 or 2, it is characterised in that：The X is selected from Br.
4. according to the method described in claim 3, it is characterized in that：In step (2), the alkali is selected from potassium tert-butoxide or carbonic acid
Potassium, the solvent of reaction are selected from DMF, the tert-butyl alcohol or Isosorbide-5-Nitrae-dioxane.
5. according to the method described in claim 4, it is characterized in that：The alkali is selected from potassium tert-butoxide, and the solvent of reaction is selected from
DMF。
6. according to the method described in claim 3, it is characterized in that：In step (3) or step (6), the friedel-craft is acylated anti-
It should carry out in the presence of a lewis acid.
7. according to the method described in claim 6, it is characterized in that：The lewis acid is selected from alchlor.
8. according to the method described in claim 3, it is characterized in that：In step (4), the method for the reducing carbonyl is Wolff-
Kishner- huang-Minlon reductions.
9. according to the method described in claim 3, it is characterized in that：In step (5), the chloride reagent of the chloride is chlorine
Change sulfoxide.
10. according to claim 1-2,4-7 any one of them method, it is characterised in that：The step (1) includes following steps
Suddenly：
(1-1)
Formula (B) compound is obtained by raw material of formula (A) compound；Wherein, Y represents hydroxyl, alkyl or alkoxy；
(1-2)
Suzuki cross-coupling reactions are carried out with formula (B) compound and formula (C) compound, obtain formula (D) compound.
11. according to the method described in claim 10, it is characterized in that：The Y represents hydroxyl.
12. according to the method for claim 11, it is characterised in that：In step (1-1), by formula (A) compound and organic gold
Belong to reagent reaction and borate reaction, formula (B) compound is obtained after acidification；
The organometallic reagent is Grignard Reagent.
13. according to the method for claim 12, it is characterised in that：The organometallic reagent be selected from isopropylmagnesium chloride or
N-BuLi；The borate is selected from trimethylborate or triisopropyl borate ester.
14. according to the method for claim 11, it is characterised in that：In step (1-2), the Suzuki cross-coupling reactions
Catalyst be selected from four (triphenyl phosphorus) palladiums, the bis- Diphenyl phosphino ferrocene palladium chlorides of 1,1'- or palladium.
15. according to the method for claim 14, it is characterised in that：The catalyst is selected from four (triphenyl phosphorus) palladiums.
16. according to 11,14,15 any one of them method of claim, it is characterised in that：In step (1-2), the Suzuki
The catalyst alkali of cross-coupling reaction is selected from potassium carbonate or potassium phosphate；Solvent is selected from THF, Isosorbide-5-Nitrae-dioxane or toluene；Reaction
Temperature is 60 DEG C~120 DEG C.
17. formula (G) described in claim 1 and formula (H) compound, it is characterised in that：The R1、R2、R3、R4、R5And R6It is
Hydrogen.
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| CN107311852A (en) * | 2017-06-27 | 2017-11-03 | 上海同昌生物医药科技有限公司 | A kind of synthetic method of Wei Patawei intermediate As |
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| CN101932325A (en) * | 2007-11-30 | 2010-12-29 | 新联基因公司 | Ido inhibitors |
| EP2907816A1 (en) * | 2011-11-16 | 2015-08-19 | Gilead Pharmasset LLC | Condensed imidazolylimidazoles as antiviral compounds |
| CN105294713A (en) * | 2015-10-09 | 2016-02-03 | 重庆康施恩化工有限公司 | Velpatasvir intermediate and preparation method thereof |
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| CN101932325A (en) * | 2007-11-30 | 2010-12-29 | 新联基因公司 | Ido inhibitors |
| EP2907816A1 (en) * | 2011-11-16 | 2015-08-19 | Gilead Pharmasset LLC | Condensed imidazolylimidazoles as antiviral compounds |
| CN105294713A (en) * | 2015-10-09 | 2016-02-03 | 重庆康施恩化工有限公司 | Velpatasvir intermediate and preparation method thereof |
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