WO2016078505A1

WO2016078505A1 - Preparation method of fluorene ethyl ketone derivative

Info

Publication number: WO2016078505A1
Application number: PCT/CN2015/093114
Authority: WO
Inventors: 张锡璇; 傅绍军; 魏哲文; 李巍; 黄成军
Original assignee: 上海众强药业有限公司
Priority date: 2014-11-20
Filing date: 2015-10-28
Publication date: 2016-05-26
Also published as: CN104513223B; CN104513223A

Abstract

Provided is a preparation method of a fluorene ethyl ketone derivative, particularly a preparation method of a compound of formula I, each group being as defined in the specification. The compound can be used as an intermediate in the preparation of ledipasvir (LDV) for preparing a key intermediate in LDV synthesis to prepare the LDV. The method has a low cost and mild reaction conditions, and is suitable for industrial production.

Description

Preparation method of anthraquinone derivative

Technical field

The invention relates to the field of preparation of pharmaceutical intermediates, in particular, the invention provides a preparation method of a synthetic intermediate of Radipavir.

Background technique

Ledipasvir (LDV) is a hepatitis C treatment developed by Gilead. The FDA has awarded LDV/SOF (Sofosbuvir) a fixed-dose combination drug breakthrough therapy, which is expected to cure genotypes in as little as 8 weeks. 1 HCV patients, without the need to inject interferon or combined with ribavirin.

At present, most of the preparation methods of the Radipavir known in the art are subjected to the key intermediates shown in the following formula I.

(wherein Z ₁ and Z ₂ are both halogen). Therefore, in order to industrially produce radiavir, there is a need in the art for a method for efficiently synthesizing a compound of formula 5.

US20100310512 reports the synthesis of Formula I as follows:

During the fluorination reaction, BAST is easily decomposed by heat, which has great safety hazards; the lack of selectivity in the introduction of acetyl groups, the use of expensive Pd reagents, and the use of highly toxic organotins, the above factors limit the method. use.

US2013324740 reports the following preparation methods:

The above method is safe to carry out the fluorination reaction, and the selectivity of acetylation is good, but the Weinreb amide (i.e., 2-chloro-N-methoxy-N-methyl-acetamide) is relatively expensive and is not suitable for industrial production.

In summary, there is an urgent need in the art to develop new methods for preparing compounds of formula I.

Summary of the invention

The present invention provides a novel process for the preparation of compounds of formula I.

In a first aspect of the invention, there is provided a process for the preparation of a compound of formula I,

The method includes the steps of:

(i) reacting a compound of formula II with a compound of formula III in an inert solvent under the action of a catalyst to produce a compound of formula IV;

(ii) reacting a compound of formula IV with a compound of formula V in an inert solvent to produce a compound of formula VI;

(iii) reacting a compound of formula VI with a fluorinating agent and a base in an inert solvent to produce a compound of formula VII;

(iv) a deprotection reaction with a compound of formula VII in an inert solvent to produce a compound of formula I;

In the above formulas:

Z ₁ , Z ₂ are each independently selected from the group consisting of H, Cl, Br or I;

Z ₃ is halogen or OCOR ₁ ; wherein R _{1 is} selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl;

R ₂ and R ₃ are each independently H or a C1-C2 alkyl group;

R ₄ and R ₅ are each independently none, H or methyl;

n is 0 or 1;

An additional condition is that when n is 0, R ₄ and R ₅ are none.

In another preferred embodiment, the deprotection reaction is a hydrolysis reaction.

In another preferred embodiment, said Z ₁ and Z ₂ are the same.

In another preferred embodiment, said Z ₁ and Z ₂ are different.

In another preferred embodiment, in the step (i), the reaction temperature is usually from (-40) ° C to 40 ° C.

In another preferred embodiment, in the step (i), the reaction time is usually from 1 to 12 hours, preferably from 1 to 4 hours.

In another preferred embodiment, in the step (i), the inert solvent is selected from the group consisting of dichloromethane, dichloroethane, chlorobenzene, dichlorobenzene, carbon tetrachloride, carbon disulfide, or a combination thereof.

In another preferred embodiment, in the step (ii), the reaction temperature is usually -20 ° C to 150 ° C.

In another preferred embodiment, in the step (ii), the reaction time is usually from 1 to 12 hours, preferably from 1 to 5 hours.

In another preferred embodiment, in step (ii), the inert solvent is selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, dioxane, acetonitrile, dichloromethane, dichloroethane, benzene, toluene, and Toluene, or a combination thereof.

In another preferred embodiment, in the step (iii), the reaction temperature is usually -100 ° C to 30 ° C.

In another preferred embodiment, in the step (iii), the reaction time is usually from 5 minutes to 24 hours, preferably from 1 to 2 hours.

In another preferred embodiment, in the step (iii), the inert solvent is selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, or a combination thereof. .

In another preferred embodiment, in the step (iv), the reaction temperature is usually from 0 ° C to 100 ° C.

In another preferred embodiment, in the step (iv), the reaction time is usually from 0 to 24 hours, preferably from 1 to 4 hours.

In another preferred embodiment, in the step (iv), the reaction is carried out in a solvent selected from the group consisting of acetone, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetonitrile, methanol, ethanol, water. , or a combination thereof.

In a second aspect of the invention, there is provided a compound of formula A:

Wherein M and Q are each independently F or H; the remaining groups are as defined in the first aspect of the invention. Preferably, the M and Q are both F, or the M and Q are both H.

According to a third aspect of the invention, there is provided a process for the preparation of a compound of formula A according to the second aspect of the invention, the method comprising the steps of:

(iia) reacting a compound of formula A1 with a compound of formula V in an inert solvent to produce a compound of formula A;

And optional step (iiia): reacting a compound of formula A with a fluorinating agent and a base;

Wherein each group is as defined in the second aspect of the invention.

In another preferred embodiment, when the optional step (iiia) is carried out, in the compound of the formula A1, M and Q are not simultaneously F.

In another preferred embodiment, the method further includes the steps of:

Wherein each group is as defined in the first aspect of the invention.

According to a fourth aspect of the invention, there is provided a process for the preparation of a compound of formula I, the process comprising the steps of:

(iv) Deprotection with a compound of formula VII in an inert solvent to provide a compound of formula I; wherein each group is as defined in the first aspect of the invention.

In another preferred embodiment, the catalyst in the step (i) is selected from the group consisting of AlY ₃ , BY ₃ , a complex of BY ₃ and Et ₂ O, FeY ₃ , ZnY ₂ , TiY ₄ , H ₂ SO ₄ , HF, polyphosphoric acid, sulfonic acid type ion exchange resin,

Or a combination thereof;

Wherein R ₆ is H or a C1-C4 alkyl group;

Y is selected from the group consisting of chlorine, bromine or iodine.

In another preferred embodiment, the catalyst is AlY ₃ .

In another preferred embodiment, in the step (iii) or the step (iiia), the fluorinating agent is selected from the group consisting of:

Wherein, Ra is selected from the group consisting of CF ₃ , C ₂ F ₅ , C ₈ F ₁₇ , C ₆ F ₅ , 4-FC ₆ H ₄ , 4-CF ₃ C ₆ H ₄ , Ph, 4-MeC ₆ H ₄ , n-Bu, t-Bu; Rb is selected from the group consisting of C1-C10 alkyl, 4-(2,3,5,6-tetrafluoropyridyl), 4-(2,5,6-trifluoropyridine Base), cC ₆ H ₁₁ , CH ₂ Bu-t, endo-2-norbornyl, exo-2-norbornyl;

Wherein R is selected from the group consisting of F, OH, CH ₂ Cl, CH ₃ , C ₂ H ₅ , nC ₈ H ₁₇ , CH ₂ CF ₃ , CH ₂ Cl; and X is selected from the group consisting of F, BF ₄ , OTf , PF ₆ , FSO ₃ , HSO ₄ , H ₂ F ₃ , SbF ₆ .

In another preferred embodiment, the fluorinating agent is selected from the group consisting of NFSI, NFOBS, and Selectfluor.

In another preferred embodiment, in the step (iii) or the step (iiia), the base is selected from the group consisting of MMHDS, MH, MNH ₂ , R ₇ OM, PhM, (Ph) ₃ CM, R ₇ M, LDA,

DBU, DBN

Wherein M is Li, Na or K, and R ₇ is a C1-C4 alkyl group.

Preferred are LiHMDS, NaHMDS, LDA or DBU.

In another preferred embodiment, the deprotection in the step (iv) is carried out under acid catalysis;

Preferably, the acid is selected from the group consisting of H ₂ SO ₄ , HX, H ₃ PO ₄ , polyphosphoric acid, HNO ₃ , CH ₃ SO ₃ H, CF ₃ SO ₃ H, HOAc, CF ₃ COOH,

a sulfonic acid type ion exchange resin, HXO ₄ , or a combination thereof; wherein R ₆ is H or a C1-C4 alkyl group; and X is selected from the group consisting of Cl, Br, and I.

According to a fifth aspect of the invention, there is provided a method for preparing radipavir, the method comprising the steps of:

(iv) deprotecting a compound of formula VII to give a compound of formula I;

(v) using a compound of formula I as an intermediate to produce Ledipasvir (LDV);

Preferably, the method further comprises the steps of:

In another preferred embodiment, when Z2 is H in the compound of formula I, the process further comprises the step of: (1) reacting a compound of formula I with a halogenating agent in an inert solvent.

In another preferred embodiment, in the step (1), the halogenating agent is selected from the group consisting of bromine, chlorine, SO ₂ Cl ₂ or I ₂ .

In another preferred embodiment, in the step (1), the reaction temperature is usually -50 ° C to 50 ° C.

In another preferred embodiment, in the step (1), the reaction time is usually from 5 minutes to 24 hours, preferably from 0.5 to 6 hours.

In another preferred embodiment, the inert solvent is selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, or a combination thereof.

It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.

detailed description

After long-term and intensive research, the present inventors have unexpectedly found that a method of performing a Friedel-Craft reaction using a compound represented by Formula II and then performing fluorination in the presence of a carbonyl protecting group can be prepared simply, conveniently, and at low cost. The Radipavir intermediate shown by I. The method has good atomic economy, is easy to implement, has mild reaction conditions, and has good industrialization value. Based on the above findings, the inventors completed the present invention.

the term

As used herein, the term "C1-C4 alkyl" refers to an alkyl group having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, n-butyl, t-butyl, or the like.

The term "halogen" means fluoro, chloro, bromo, iodo. In particular, herein, unless otherwise specified, references to "halogen" are preferably chlorine, bromine or iodine.

Herein, the term "room temperature" means 10-40 ° C, preferably 20-25 ° C.

Unless otherwise specified, the term "alkyl" is preferably a C1-C10 alkyl group, more preferably a C1-C4 alkyl group.

Compound of formula A and preparation thereof

The present invention provides a compound of the following formula A:

Wherein, M and Q are each independently F or H; the remaining groups are as defined in the first aspect of the invention; preferably, both M and Q are F, or said M and Q All are H.

The compound of formula A can be prepared by the following steps:

In the above formulas:

R ₂ and R ₃ are each independently H or a C1-C2 alkyl group;

R ₄ and R ₅ are each independently H or methyl;

n is 0 or 1;

An additional condition is that when n is 0, R ₄ and R ₅ are none.

The Z ₁ and Z ₂ may be the same or different, preferably the same. In particular, when one or both of M and Q are H in the compound of formula A1 used, the reaction may optionally comprise the step (iiia): reacting a compound of formula A with a fluorinating agent and a base .

In each of the above steps, various reaction conditions are not particularly limited. Preferably, in the step (iia) or the step (iiia), the fluorinating agent is selected from the group consisting of:

RaRa	RbRb	RaRa	RbRb
CF₃ CF ₃	4-(2,3,5,6-四氟吡啶基)4-(2,3,5,6-tetrafluoropyridyl)	4-MeC₆H₄ 4-MeC ₆ H ₄	MeMe
CF₃ CF ₃	4-(2,5,6-三氟吡啶基)4-(2,5,6-trifluoropyridyl)	4-MeC₆H₄ 4-MeC ₆ H ₄	t-But-Bu
CF₃ CF ₃	MeMe	4-MeC₆H₄ 4-MeC ₆ H ₄	c-C₆H₁₁ cC ₆ H ₁₁
CF₃ CF ₃	n-Bun-Bu	4-MeC₆H₄ 4-MeC ₆ H ₄	exo-2-降冰片基Exo-2-norkel base
CF₃ CF ₃	t-But-Bu	4-MeC₆H₄ 4-MeC ₆ H ₄	endo-2-降冰片基Endo-2-norborne base
C₂F₅ C ₂ F ₅	烷基alkyl	4-MeC₆H₄ 4-MeC ₆ H ₄	CH₂Bu-tCH ₂ Bu-t

C₈F₁₇ C ₈ F ₁₇	烷基alkyl	4-MeC₆H₄ 4-MeC ₆ H ₄	n-Bun-Bu
C₆F₅ C ₆ F ₅	n-Prn-Pr	4-MeC₆H₄ 4-MeC ₆ H ₄	n-Prn-Pr
C₆F₅ C ₆ F ₅	CH₂Bu-tCH ₂ Bu-t	n-Bun-Bu	CH₂Bu-tCH ₂ Bu-t
4-FC₆H₄ 4-FC ₆ H ₄	烷基alkyl	t-But-Bu	MeMe
4-CF₃C₆H₄ 4-CF ₃ C ₆ H ₄	烷基alkyl	t-But-Bu	n-Bun-Bu
PhPh	t-But-Bu	t-But-Bu	CH₂Bu-tCH ₂ Bu-t

Among them, the most preferred fluorinating agent is selected from the group consisting of NFSI and Selectfluor.

In a preferred embodiment of the invention, in the step (iii) or the step (iiia), the base is selected from the group consisting of MHMDS, MH, MNH ₂ , R ₇ OM, PhM, (Ph) ₃ CM. , R ₇ M, LDA,

DBU, DBN; wherein M is Li, Na, K, R ₇ is a C1-C4 alkyl group; more preferably selected from the group consisting of LiHMDS, NaHMDS, LDA or DBU.

The reaction conditions of the step (iia) or the step (iiia), such as the temperature, the reaction time, the solvent and the like, are not particularly limited, and those skilled in the art can select an appropriate temperature according to actual needs, by a method commonly used in the art (eg, TLC) and the like determine the end point of the reaction, and the solvent may be selected from any inert solvent which does not react with the reactant. In another preferred embodiment, in the step (iia), the reaction temperature is usually -20 ° C to 120 ° C, the reaction time is usually 1 to 12 hours, preferably 1 to 5 hours; and the inert solvent may be selected from the group consisting of Solvent: tetrahydrofuran, methyltetrahydrofuran, dioxane, acetonitrile, dichloromethane, dichloroethane, toluene, or a combination thereof. In another preferred embodiment, in the step (iiia), the reaction temperature is usually -100 ° C to 20 ° C, the reaction time is usually 5 min to 24 hours, preferably 1 to 2 hours; the solvent can be selected from the group consisting of the following Solvent: tetrahydrofuran, methyltetrahydrofuran, dioxane, or a combination thereof.

Compound of formula I and preparation thereof

The invention also provides a process for the preparation of a compound of formula I, the process comprising the steps of:

(iv) Deprotection with a compound of formula VII in an inert solvent to provide a compound of formula I; wherein each group is as defined above.

Said deprotection is preferably carried out by a hydrolysis reaction; preferably, the deprotection in said step (iv) is carried out under acid catalysis;

The acid is not particularly limited, and is preferably an acid selected from the group consisting of H ₂ SO ₄ , HX, H ₃ PO ₄ , polyphosphoric acid, HNO ₃ , CH ₃ SO ₄ , CF ₃ SO ₄ , HOAc, CF. ₃ COOH,

In the above reaction, the starting compound of the formula VII can be obtained by the method of the present invention or by other methods known in the art. After the structure of the compound of the formula VII is disclosed, such preparation is carried out. It should be considered to be within the abilities of those skilled in the art. In a comparison of the present invention In a preferred embodiment, the preparation of the compound of formula I is prepared by the following starting materials and routes:

(iv) subjecting a compound of formula VII to a deprotection reaction to produce a compound of formula I;

In the above formulas:

R ₂ and R ₃ are each independently H or a C1-C2 alkyl group;

R ₄ and R ₅ are each independently H or methyl;

n is 0 or 1;

An additional condition is that when n is 0, R ₄ and R ₅ are none.

In the formulas, Z ₁ and Z ₂ are the same or different.

In each step, the reaction conditions are not particularly limited. In a preferred embodiment of the present invention, the catalyst in the step (i) is selected from the group consisting of AlY ₃ , BY ₃ , BY ₃ and Et ₂ O. Compound, FeY ₃ , ZnY ₂ , TiY ₄ , H ₂ SO ₄ , HF, polyphosphoric acid, sulfonic acid type ion exchange resin,

Or a combination thereof; wherein R ₆ is H or a C1-C4 alkyl group; Y is selected from the group consisting of chlorine, bromine or iodine. Most preferably, the catalyst described in this step is AlY ₃ .

The reaction conditions of the step (i), such as the temperature, the reaction time, the solvent and the like, are not particularly limited, and those skilled in the art can select a suitable temperature according to actual needs, and determine the reaction by a method commonly used in the art (such as TLC). At the end point, the solvent can be selected from any inert solvent that does not react with the reactants. In another preferred embodiment, the reaction temperature in the step (i) is usually from (-40) ° C to 40 ° C, the reaction time is usually from 1 to 12 hours, preferably from 1 to 4 hours; and the inert solvent is selected from the group consisting of Group of solvents: dichloromethane, dichloroethane, chlorobenzene, dichlorobenzene, carbon tetrachloride, carbon disulfide, or a combination thereof.

The reaction conditions in the step (ii) and the step (iii) are preferably in accordance with the above steps (iia) and (iiia), and those skilled in the art can select suitable reaction conditions depending on the reactants actually used.

Preparation of redipavir

The compound of formula I can be used as an intermediate to prepare radipavir. A preferred method of preparing the Radipavir of the present invention comprises the steps of:

(iv) deprotecting a compound of formula VII to give a compound of formula I:

(v) using a compound of the formula I as an intermediate to produce edipasvir (LDV); wherein said step (v) can be carried out by methods known in the art, as described in document US2013324740. The method is carried out.

Preferably, the method may further comprise the steps of:

The main advantages of the present invention over the prior art include:

(1) The preparation process of the compound of the formula I of the present invention does not require the use of iodination reaction, avoids the use of more expensive iodine, and reduces the waste of three raw materials while reducing the cost of raw materials;

(2) Preparation method of the present invention In the acetylation process, the acetyl group or the α-haloacetyl group is directly introduced by the one-step reaction of the Friedel-Craft reaction, thereby avoiding the preparation of the Grignard reagent, reducing the reaction step, and improving the operating conditions. The acetylation step replaces the expensive Weinreb amide with inexpensive and readily available reagents, thereby significantly reducing raw material costs;

(3) The steps of the carbonyl protection, fluorination, hydrolysis and the like of the method of the invention can all achieve higher yields;

(4) The invention has simple process and good safety, and the reaction is easy to realize and enlarge, and has good industrial application value;

(5) A new intermediate of the formula VI and the compound of the formula VII was prepared.

The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

Synthesis of Compound 4-1 of Example 1

16.2 g (123 mmol, 1.5 eq) of aluminum trichloride and 150 ml of dichloromethane were added to a 250 ml four-necked flask, stirring was started, and 20 g of compound 2 (82 mmol, 1.0 eq) was slowly added dropwise, and stirred for 30 minutes until most Aluminum trichloride is dissolved.

The reaction mixture was cooled to 0 ° C, and 11 g (98.4 mmol, 1.2 eq) of chloroacetyl chloride was slowly added dropwise. After the completion of the dropwise addition, the mixture was kept at 0 ° C for 1 hour, and then naturally warmed to room temperature, and stirring was continued for 2 hours. The TLC tracks until the material disappears.

The reaction solution was poured into 100 ml of a 10% ice water-hydrochloric acid mixture, stirred for 30 minutes, and the organic layer was separated. The organic layer was washed with water, washed with aq. NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

Synthesis of Compound 4-2 of Example 2

The reaction mixture was cooled to 0 ° C, and 7.7 g (98.4 mmol, 1.2 eq) of acetyl chloride was slowly added dropwise. After the completion of the dropwise addition, the mixture was kept at 0 ° C for 1 hour, and then naturally warmed to room temperature, and stirring was continued for 2 hours. The TLC tracks until the material disappears.

The reaction solution was poured into 100 ml of a 10% ice water-hydrochloric acid mixture, stirred for 30 minutes, and the organic layer was separated. The organic layer was washed with water, washed with 10% sodium hydrogen carbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to afford 22.0 g of compound 4-2 (yield: 93.8%).

Synthesis of Compound 6-1 of Example 3

Into a 100 ml four-necked flask was added 5 g (15.6 mmol, 1.0 eq) of compound 4-1, 6.0 g (57.7 mmol, 3.7 eq) of neopentyl glycol, 3.6 g (24.2 mmol, 1.55 eq) of triethyl orthoformate and 50 ml of dichloromethane was stirred at room temperature for 20 minutes, then 0.16 g (1.1 mmol, 0.07 eq) of boron trifluoride diethyl ether was added.

The reaction mixture was heated to reflux for 2 h. The TLC was traced until the starting material disappeared, and triethylamine was added to adjust the pH of the reaction mixture to 8-9. The solvent was concentrated under reduced pressure to give a syrup. 50 ml of water was added to beat at 50 ° C to remove excess neopentyl glycol. The pale yellow solid was filtered and dried at 50 ° C to yield 5.8 g of Compound 6-1 (yield 92.4%).

1H NMR (400MHz, CDCl3): δ 7.80 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.52 ( Dd, J = 10.8, 4.2 Hz, 2H), 3.68 - 3.49 (m, 6H), 1.36 (s, 3H), 0.62 (s, 3H).

Synthesis of Compound 6-2 of Example 4

In a 100 ml four-necked flask were added 5 g (17.5 mmol, 1.0 eq) of compound 4-2, 6.73 g (64.7 mmol, 3.7 eq) of neopentyl glycol, 4.0 g (27.1 mmol, 1.55 eq) of triethyl orthoformate and 50 ml of dichloromethane was stirred at room temperature for 20 minutes, then 0.17 g (1.1 mmol, 0.07 eq) of boron trifluoride diethyl ether was added.

The reaction mixture was heated to reflux for 2 h. The TLC was traced until the starting material disappeared, and triethylamine was added to adjust the pH of the reaction mixture to 8-9. The solvent was concentrated under reduced pressure to give a syrup. 50 ml of water was added to beat at 50 ° C to remove excess neopentyl glycol. The pale yellow solid was filtered and dried at 50 ° C to give 5.95 g of Compound 6-2 (yield: 91.5%).

1H NMR (400MHz, CDCl3) δ 7.76 (d, J = 7.9 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H), 7.53 - 7.43 (m, 2H), 3.93 (d, J = 18.0 Hz, 2H), 3.45 (dd, J = 29.4, 10.9 Hz, 4H), 2.66 (s, 1H), 1.58 (s, 3H), 1.29 (s, 3H), 0.59 (s, 3H).

Synthesis of compound 6-3 of Example 5:

1.6 g (5.24 mmol, 1.0 eq) of compound 4-1, 1.2 g (19.4 mmol, 3.7 eq) of ethylene glycol 5-2, 1.2 g (8.13 mmol, 1.55 eq) of orthoformic acid were added to a 100 ml four-necked flask. Ethyl acetate and 25 ml of dichloromethane were stirred at room temperature for 20 min then 0.05 g (0.35 mmol, 0.07 eq.

The reaction mixture was heated to reflux for 2 h. The TLC was traced until the starting material disappeared, and triethylamine was added to adjust the pH of the reaction mixture to 8-9. The solvent was concentrated under reduced pressure to give a syrup. 20 ml of water was added to beat at 50 ° C to remove excess ethylene glycol. The pale yellow solid was filtered and dried at 50 ° C to yield 1.59 g of Compound 6-4 (yield: 91.9%).

1H NMR (400MHz,) δ 7.74 (d, J = 7.9 Hz), 7.69 (s), 7.64 (d, J = 8.1 Hz), 7.55 (d, J = 8.0 Hz), 7.50 (d, J = 8.2) Hz), 4.21(s), 4.00–3.93(m), 3.90(s), 3.80(s).

Synthesis of Compound 6-4 of Example 6

1.5 g (5 mmol, 1.0 eq) of compound 4-2, 1.15 g (18.5 mmol, 3.7 eq) of ethylene glycol 5-2, 1.5 g (7.75 mmol, 1.55 eq) of triethyl orthoformate were added to a 100 ml four-necked flask. The ester and 25 ml of dichloromethane were stirred at room temperature for 20 min then 0.05 g (0.35 mmol, 0.07 eq.

The reaction mixture was heated to reflux for 2 h. The TLC was traced until the starting material disappeared, and triethylamine was added to adjust the pH of the reaction mixture to 8-9. The solvent was concentrated under reduced pressure to give a syrup. 20 ml of water was added to beat at 50 ° C to remove excess ethylene glycol. The pale yellow solid was filtered and dried at 50 ° C to give 1.62 g of Compound 6-1 (yield: 89%).

1H NMR (400MHz,) δ 7.72 (d, J = 7.9 Hz), 7.67 (s), 7.65 (s), 7.63 (d, J = 8.1 Hz), 7.50 (t, J = 8.5 Hz), 4.10– 4.04(m), 3.87(d, J=7.4Hz), 3.85–3.79(m), 1.70(s).

Synthesis of Compound 7-1 of Example 7

5 g (12.3 mmol, 1.0 eq) of compound 6-1, 11.44 g (36.3 mmol, 2.95 eq) of NFSI and 100 ml of anhydrous THF were added to a 250 ml four-necked flask, and the reaction mixture was degassed three times, and the mixture was evaporated under vacuum.

The reaction mixture was cooled to -65 ° C, and 37 mL (36.9 mmol, 3.0 eq) of LiHMDS/THF solution was added dropwise. The TLC tracks until the material disappears. The reaction was quenched by the addition of 5 ml of a 7N ammonia/methanol solution.

The reaction solution was concentrated to remove low-boiling substances, dissolved in 25 ml (5 vol) of THF, and then 50 ml of isopropanol was slowly added thereto, and crystals were precipitated. The suspension was concentrated to 50 ml (10 vol), 50 ml of isopropanol was again added, and the mixture was again concentrated to 50 ml (5 vol). The mixture was cooled to 20-25 ° C and stirred for 30 minutes. The solid was filtered and washed with 10 ml of isopropyl alcohol. Drying in vacuo to give compound 7-1: 5.0 g (yield: 91.9%)

1H NMR (400MHz, CDCl ₃ ) δ 7.78 (d, J = 1.2 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J = 8.4 Hz, 3H), 7.47 (d, J = 8.0 Hz, 1H), 3.60 (d, J = 5.7 Hz, 2H), 3.54 (d, J = 11.1 Hz, 2H), 3.45 (d, J = 10.9 Hz, 2H), 1.33 (d, J = 7.7 Hz, 3H) , 0.64 (s, 3H).

Synthesis of Compound 7-2 of Example 8

5 g (13.44 mmol, 1.0 eq) of compound 6-2, 12.5 g (39.65 mmol, 2.95 eq) of NFSI and 100 ml of anhydrous THF were added to a 250 ml four-necked flask, and the reaction mixture was degassed three times and nitrogen was evaporated.

The reaction mixture was cooled to -65 ° C, and 40.3 mL (40.3 mmol, 3.0 eq) of LiHMDS/THF solution was added dropwise. The TLC tracks until the material disappears. The reaction was quenched by the addition of 5 ml of a 7N ammonia/methanol solution.

The reaction solution was concentrated to remove low-boiling substances, dissolved in 25 ml (5 vol) of THF, and then 50 ml of isopropanol was slowly added thereto, and crystals were precipitated. The suspension was concentrated to 50 ml (10 vol), 50 ml of isopropanol was again added, and the mixture was again concentrated to 50 ml (5 vol). The mixture was cooled to 20-25 ° C and stirred for 30 minutes. The solid was filtered and washed with 10 ml of isopropyl alcohol. Drying in vacuo gave compound 7-2: 5.0 g (yield: 90.0%)

1H NMR (400MHz, CDCl3) δ 7.78 (d, J = 1.2 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J = 8.4 Hz, 3H), 7.47 (d, J = 8.0 Hz, 1H) ), 3.54 (d, J = 11.1 Hz, 2H), 3.45 (d, J = 10.9 Hz, 2H), 1.58 (s, 3H), 1.33 (d, J = 7.7 Hz, 3H), 0.64 (s, 3H) ).

Synthesis of Compound 7-3 of Example 9

5 g (13.75 mmol, 1.0 eq) of compound 6-1, 13 g (40.56 mmol, 2.95 eq) of NFSI and 100 ml of anhydrous THF were added to a 250 ml four-necked flask.

The reaction mixture was cooled to -65 ° C and 42 mL (41.25 mmol, 3.0 eq). The TLC tracks until the material disappears. The reaction was quenched by the addition of 5 ml of a 7N ammonia/methanol solution.

The reaction solution was concentrated to remove low-boiling substances, dissolved in 25 ml (5 vol) of THF, and then 50 ml of isopropanol was slowly added thereto, and crystals were precipitated. The suspension was concentrated to 50 ml (10 vol), 50 ml of isopropanol was again added, and the mixture was again concentrated to 50 ml (5 vol). The mixture was cooled to 20-25 ° C and stirred for 30 minutes. The solid was filtered and washed with 10 ml of isopropyl alcohol. Drying in vacuo gave compound 7-3: 4.4 g (yield: 80.0%)

1H NMR (400MHz) δ 7.79 (s), 7.76 (d, J = 1.4 Hz), 7.65 (d, J = 7.9 Hz), 7.61 (d, J = 8.1 Hz), 7.55 (d, J = 7.9 Hz), 7.45 (d, J = 8.1 Hz), 4.21 (td, J = 6.2, 4.0 Hz), 3.98 - 3.92 (m), 3.76 (s).

Synthesis of Compound 7-4 of Example 10

5.0 g (15.15 mmol, 1.0 eq) of compound 6-2, 14.1 g (44.70 mmol, 2.95 eq) of NFSI and 100 ml of anhydrous THF were added to a 250 ml four-necked flask, and the reaction mixture was degassed three times and nitrogen was evaporated.

The reaction mixture was cooled to -65 ° C, and 45.5 ml (45.45 mmol, 3.0 eq) of LiHMDS/THF solution was added dropwise. The TLC tracks until the material disappears. The reaction was quenched by the addition of 5 ml of a 7N ammonia/methanol solution.

The reaction solution was concentrated to remove low-boiling substances, dissolved in 25 ml (5 vol) of THF, and then 50 ml of isopropanol was slowly added thereto, and crystals were precipitated. The suspension was concentrated to 50 ml (10 vol), 50 ml of isopropanol was again added, and the mixture was again concentrated to 50 ml (5 vol). The mixture was cooled to 20-25 ° C and stirred for 30 minutes. The solid was filtered and washed with 10 ml of isopropyl alcohol. Drying in vacuo gave compound 7-4: 5.0 g (yield: 90.0%)

1H NMR (400MHz) δ 7.75(s), 7.60 (t, J = 6.8 Hz), 7.52 (d, J = 7.9 Hz), 7.43 (d, J = 8.1 Hz), 4.10 - 4.04 (m), 3.85 –3.78(m), 1.68(s).

Synthesis of Compound 1-3 of Example 11

5.0 g (15.5 mmol, 1.0 eq) of compound 7-1 was added to a 100 ml four-necked flask, 45 ml of a 70% aqueous acetic acid solution was added, and the reaction mixture was heated to 70 ° C, and kept under stirring for 12 hours, and the TLC was traced until the starting material disappeared. The reaction solution was poured into 450 ml of water, and a pale yellow solid was filtered, and dried in vacuo to give 4.4 g (yield: 88%)

1H NMR (400MHz, CDCl3) δ 8.20 (d, J = 1.1 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.70 - 7.63 (m) , 2H), 7.52 (d, J = 8.1 Hz, 1H), 2.66 (d, J = 5.8 Hz, 3H).

Synthesis of Compound 1-2 of Example 12

6.9 g (21.4 mmol, 1.0 eq) of compound 1-3, 200 ml of isopropyl acetate and 20 ml of isopropanol were added to a 500 ml three-necked flask, the reaction mixture was cooled to 0-10 ° C, and 0.57 g (10 mol%) of tribromide was added. Phosphorus was added, followed by dropwise addition of 3.3 g (20.6 mmol, 0.96 eq) of bromine in isopropyl acetate for about 30 minutes.

The reaction mixture was added to 50 ml of a saturated sodium hydrogensulfite solution and the excess of bromine was added, and the organic phase was separated. The aqueous phase was extracted twice with 20 ml of ethyl acetate. Concentrated to a crude product of 8.5 g (containing starting material, monobromo and dibromo). The crude product was purified by beating with 42.5 ml (5 vol) of isopropanol to give the title compound 1-2 (yield: 70%).

1H NMR (400MHz, CDCl3) δ 8.21 (d, J = 1.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 1.4 Hz, 1H), 7.65 (t, J) = 10.3 Hz, 2H), 7.51 (d, J = 8.1 Hz, 1H), 4.52 - 4.39 (m, 2H), 1.59 (s, 1H).

Synthesis of Compound 1-1 of Example 13

In a 500 ml three-necked flask, 6.9 g (21.4 mmol, 1.0 eq) of compound 1-3, 69 ml of acetonitrile, 1 ml of acetic acid, warmed to 30-35 ° C, and added 3.1 g (1.1 eq) of sulfonyl chloride (predissolved in 10 ml of acetonitrile) Medium), after the completion of the dropwise addition, it was kept at 30-35 ° C for 3 hours, and TLC was traced until the starting material disappeared. The reaction solution was poured into 100 ml of water and filtered to give a pale yellow solid.

The crude product was purified by beating with 42.5 ml (5 vol) of isopropanol to give the title compound 1-2 (yield: 81.7%).

Synthesis of Compound 1-1 of Example 14

4.5 g (11.3 mmol, 1.0 eq) of compound 7-1 was added to a 100 ml four-necked flask, 45 ml of a 70% aqueous acetic acid solution was added, and the reaction mixture was heated to 70 ° C, and the mixture was stirred for 12 hours, and the TLC was traced until the starting material disappeared. The reaction mixture was poured into 450 ml of water, and filtered to give a pale yellow solid.

Synthesis of Compound 1-1 of Example 15

4.5 g (11.3 mmol, 1.0 eq) of compound 7-1 was added to a 100 ml four-necked flask, 45 ml of ethanol, 45 ml of 36% hydrochloric acid were added, and the reaction mixture was heated to 75-80 ° C, and kept under stirring for 12 hours, and the TLC was traced until the starting material disappeared. . The reaction solution was concentrated to remove ethanol, and then toluene was added to 450 ml of water, and the pale yellow solid was filtered, and dried in vacuo to give the title compound 1-1 (yield: 91%).

All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims

a method for preparing a compound of formula I,

It is characterized in that it comprises the steps of:

(i) reacting a compound of formula II with a compound of formula III in an inert solvent under the action of a catalyst to produce a compound of formula IV;

(ii) reacting a compound of formula IV with a compound of formula V in an inert solvent to produce a compound of formula VI;

(iii) reacting a compound of formula VI with a fluorinating agent and a base in an inert solvent to produce a compound of formula VII;

(iv) a deprotection reaction with a compound of formula VII in an inert solvent to produce a compound of formula I;

In the above formulas:

Z 1 , Z 2 are each independently selected from the group consisting of H, Cl, Br or I;

Z 3 is halogen or OCOR 1 ; wherein R 1 is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl;

R 2 and R 3 are each independently H or a C1-C2 alkyl group;

R 4 and R 5 are each independently none, H or methyl;

n is 0 or 1;

An additional condition is that when n is 0, R 4 and R 5 are none.
A compound of the formula A below:

Wherein, M and Q are each independently F or H; the remaining groups are as defined in claim 1; preferably, both M and Q are F, or both M and Q are H.
A method of preparing a compound of formula A according to claim 2, comprising the steps of:

(iia) reacting a compound of formula A1 with a compound of formula V in an inert solvent to produce a compound of formula A;

And optional step (iiia): reacting a compound of formula A with a fluorinating agent and a base;

Wherein each group is as defined in claim 2.
The preparation method according to claim 3, wherein the method further comprises the steps of:

(i) reacting a compound of formula II with a compound of formula III in an inert solvent under the action of a catalyst to produce a compound of formula IV;

Wherein each group is as defined in claim 1.
A method for preparing a compound of formula I, characterized by comprising the steps of:

(iv) Deprotection with a compound of formula VII in an inert solvent to provide a compound of formula I; wherein each group is as defined in claim 1.
The method according to claim 1, wherein the catalyst in the step (i) is selected from the group consisting of AlY 3 , BY 3 , a complex of BY 3 and Et 2 O, FeY 3 , ZnY 2 , TiY 4 , H 2 SO 4 , HF, polyphosphoric acid, sulfonic acid type ion exchange resin,
Or a combination thereof;

Wherein R 6 is H or a C1-C4 alkyl group;

Y is selected from the group consisting of chlorine, bromine or iodine.
The method according to claim 1 or 3, wherein in the step (iii) or the step (iiia), the fluorinating agent is selected from the group consisting of:

Wherein, Ra is selected from the group consisting of CF 3 , C 2 F 5 , C 8 F 17 , C 6 F 5 , 4-FC 6 H 4 , 4-CF 3 C 6 H 4 , Ph, 4-MeC 6 H 4 , n-Bu, t-Bu; Rb is selected from the group consisting of C1-C10 alkyl, 4-(2,3,5,6-tetrafluoropyridyl), 4-(2,5,6-trifluoropyridine Base), cC 6 H 11 , CH 2 Bu-t, endo-2-norbornyl, exo-2-norbornyl;

Wherein R is selected from the group consisting of F, OH, CH 2 Cl, CH 3 , C 2 H 5 , nC 8 H 17 , CH 2 CF 3 , CH 2 Cl; and X is selected from the group consisting of F, BF 4 , OTf , PF 6 , FSO 3 , HSO 4 , H 2 F 3 , SbF 6 .
The method according to claim 1 or 3, wherein in the step (iii) or the step (iiia), the base is selected from the group consisting of MHMDS, MH, MNH 2 , R 7 OM, PhM. , (Ph) 3 CM, R 7 M, LDA,
DBU, DBN

Wherein M is Li, Na or K, and R 7 is a C1-C4 alkyl group;

Preferred bases are LiHMDS, NaHMDS, LDA, DBU, or a combination thereof.
The method according to claim 1 or 5, wherein the deprotection in the step (iv) is carried out under acid catalysis;

Preferably, the acid is selected from the group consisting of H 2 SO 4 , HX, H 3 PO 4 , polyphosphoric acid, HNO 3 , CH 3 SO 3 H, CF 3 SO 3 H, HOAc, CF 3 COOH,
a sulfonic acid type ion exchange resin, HXO 4 , or a combination thereof; wherein R 6 is H or a C1-C4 alkyl group; and X is selected from the group consisting of Cl, Br, and I.
A method for preparing radipavir, characterized in that the method comprises the steps of:

(iv) deprotecting a compound of formula VII to give a compound of formula I;

(v) using a compound of formula I as an intermediate to produce Ledipasvir (LDV);

Preferably, the method further comprises the steps of:

(iii) reacting a compound of formula VI with a fluorinating agent and a base in an inert solvent to produce a compound of formula VII;