CN104211696B

CN104211696B - A kind of preparation method of TMC-435 important intermediate

Info

Publication number: CN104211696B
Application number: CN201410411979.1A
Authority: CN
Inventors: 尚振华; 安辰红
Original assignee: Hebei University of Science and Technology
Current assignee: Hebei University of Science and Technology
Filing date: 2014-08-20
Publication date: 2017-01-04
Anticipated expiration: 2034-08-20

Abstract

The invention discloses the preparation method of a kind of TMC 435 important intermediate, the steps include: 1, compound B obtains compound C with dimethyl sulfate through methylation reaction in the basic conditions；2, compound C obtains compound D through F-K reaction；3, compound D through iron powder reducing be amino-compound intermediate I；4, compound E obtains compound F through carbonyl α position bromination reaction；5, compound F and thiourea cyclization obtain compound G；6, compound G obtains compound H through diazo-reaction, nucleophilic substitution；7, compound H and Cupricin. react to obtain compound I and compound J under the high temperature conditions；8, compound I and compound J hydrolyzes to obtain intermediate II in the basic conditions；9, intermediate II and acyl chlorides reagent reacting obtain compound K, compound K and intermediate I warpNAcylation reaction obtains compound L；10, compound L cyclization in the basic conditions obtains target compound A.This method production cost, equipment requirements are low, and technology stability is high.

Description

A kind of preparation method of TMC-435 important intermediate

Technical field

The invention belongs to medicinal chemistry art, the preparation method of a kind of TMC-435 important intermediate.

Background technology

TMC-435 important intermediate, chemical name: 4-hydroxyl-2-(4-isopropyl thiazol-2-yl)-7-methoxyl group-8-methyl Quinoline, U.S. chemical abstract accession number CAS:923289-21-8, there is formula A structural formula:

Simeprevir (TMC-435) is a kind of novel protease inhibitor, Yang Sen and Medivir develop jointly, Treatment for gene-1 type patients with chronic hepatitis C compensatory hepatic disease.Simeprevir is received through blocking-up to be made HCV survives and the protease that replicates and generation effect in host cell.

In JIUYUE, 2013, Simeprevir (trade name Sovriad) obtains the approval of work hygiene Department of Welfare of Japan, with poly-second two Alcoholization interferon and ribavirin combination medication, for the treatment of genotype-1 chronic hepatitis C viral (HCV) the infected, this It it is the whole world first supervision approval that Simeprevir obtains.

At present, disclosed in international literature, the preparation method of TMC-435 intermediate is as follows:

1, the preparation of intermediate I:

Preparation method about intermediate I has following documents to report: 1.1, WO2007014919, WO2007014927； 1.2、CN101921269；1.3、CN102531932.

1.1, world patent WO2007014919, WO2007014927 disclosed in 2007 provides an intermediate I (2- Methyl-3-amino-4-acetylbenzene methyl ether) synthetic method: as shown in Scheme 1:

This route is with 2-methyl-3-methoxybenzoic acid as initiation material, in the basic conditions with diphenyl phosphate azide (DPPA) reacting to obtain acyl azide, reset to obtain compound (1) through Curtius, compound (1) hydrolyzes in acid condition Compound (2), compound (2) obtains intermediate I through Hoesch acylation reaction.This route has been used expensive DPPA and three Boron chloride, severe reaction conditions, operation complexity, limit the application of this route.

1.2, the Chinese patent application of publication number CN101921269A provides the synthetic method of an intermediate I, as Shown in Scheme 2:

This route, with 2-methyl-3-nitro aniline as initiation material, obtains diazol through diazo-reaction, and diazo is by hydroxyl Replace to obtain compound B, compound B to obtain compound C, compound C through methylation reaction and obtain amino-compound (2) through reduction reaction, Compound (2) obtains intermediate I through Hoesch acylation reaction.This route total recovery is 21.5%, and cost of material is more expensive, uses equally Expensive boron chloride, limits the application of this route.

1.3, the Chinese patent application of publication number CN102531932A provides the synthetic method of an intermediate I, as Shown in Scheme 3:

This route, with 2-methyl-3-hydroxy benzoic acid as initiation material, obtains compound (3), compound through methylation reaction (3) reacting to obtain chloride compounds with thionyl chloride, chloride compounds obtains amide compound (4), compound (4) through N-acylation reaction Degrading to obtain amino-compound (2) through Hoffman, compound (2) obtains intermediate I through Hoesch acylation reaction.This route total recovery 49.7%, cost of material is more expensive, and reactions steps is loaded down with trivial details, has used expensive boron chloride equally, has limited this route Application.

2, the preparation of intermediate II:

Have about the preparation method of intermediate II and report with following documents: 2.1, WO2012054874, WO20090269305, WO2009098448,2011017389 etc.；2.2、WO2012093809、WO2006002981、 WO2008100423, CN101921269 etc..

2.1, the international application for patent of publication number WO2012054874 provides the synthetic method of an intermediate II, as Shown in Scheme 4:

This route with 3-methyl-2-butanone as initiation material, through carbonyl alpha-position bromo-reaction obtain compound F, compound F with Ethyl thiooxamate cyclization obtains compound (5), and compound (5) hydrolyzes to obtain intermediate II in the basic conditions.This synthetic route Shorter, but used expensive ethyl thiooxamate, limit the application of this route.

2.2, the synthetic method of another intermediate II, as shown in Scheme 5:

This route with 3-methyl-2-butanone as initiation material, through carbonyl alpha-position bromo-reaction obtain compound F, compound F with Thiourea cyclization obtains compound G, compound G and obtains diazol through diazo-reaction, then nucleo philic substitution reaction obtains compound H, chemical combination Thing H first obtains Grignard reagent intermediate through Grignard reagent exchange reaction, then obtains intermediate II through hydrolysis.Although this route is kept away Exempt from the use of ethyl thiooxamate, but rear two step operations are more complicated, easily generate impurity 4-isopropyl in final step Thiazole, therefore also limit the application of this route.

3, the synthesis of intermediate A:

Publication No. WO2009099596, WO2010118078, WO2011017389WO2011038293, The international application published of the WO2012109398 synthetic method of intermediate A, as shown in the Scheme 6:

Compound (6) and oxalyl chloride react to obtain chloride compounds K, and compound K and intermediate I obtain amide through N-acylation reaction Compound L；Compound K obtains amide compound (7) with (2) through N-acylation reaction, and compound (7) obtains chemical combination through paying a gram acylation reaction Thing L；Compound L cyclization obtains intermediate A.

, there is following defect during intermediate A preparing in summary said synthesis route: (1) when preparing intermediate I, Expensive DPPA, boron chloride are used；When preparing intermediate II, use expensive sulfur equally for oxamidic acid. Ethyl ester；(2) when preparing intermediate II, the post processing by compound G synthesis compound H is more complicated, finally with substantial amounts of Organic solvent extracts；During compound H to intermediate II, operation complexity, reaction condition requires harsh, and course of reaction In easily generate impurity 4-isopropyl thiazole, these defects all limit the industrialized production of intermediate A.

Summary of the invention

The technical problem to be solved in the present invention is to provide that a kind of technique is simple, the TMC-435 important intermediate of low cost Preparation method.

For solving above-mentioned technical problem, the preparation method of TMC-435 important intermediate shown in formula A,

Its technique is: (1) compound B obtains compound C with dimethyl sulfate through methylation reaction in the basic conditions:

(2) compound C obtains compound D through F-K reaction:

(3) compound D through iron powder reducing be corresponding amino-compound-intermediate I:

(4) compound E obtains compound F through carbonyl alpha-position bromination reaction:

(5) compound F and thiourea cyclization obtain compound G:

(6) compound G obtains compound H through diazo-reaction, nucleophilic substitution:

(7) compound H and Cupricin. react to obtain compound I and compound J under the high temperature conditions:

(8) compound I and compound J hydrolyzes to obtain intermediate II in the basic conditions:

(9) intermediate II and acyl chlorides reagent reacting obtain compound K, and compound K and intermediate I obtain chemical combination through N-acylation reaction Thing L:

(10) compound L cyclization in the basic conditions obtains target compound A:

Further, method step of the present invention is: it is molten that compound B and phase transfer catalyst are joined alkali by (1) In liquid, dripping dimethyl sulfate under stirring, normal-temperature reaction, to terminating, obtains solid, shaped compound C after separation；

(2) compound C is dissolved in anhydrous organic solvent, adds Lewis acid catalyst under condition of ice bath, stir Rear dropping chloroacetic chloride, drips complete temperature control and reacts to terminating；Through extraction, separate, obtain solid, shaped compound D；

(3) in water and organic solvent miscible with water, it is sequentially added into reduced iron powder, ammonium chloride and compound D, rises Temperature back flow reaction is to terminating；Separate, extract, after sloughing extractant, obtain powder intermediate I；

(4) being dissolved in organic solvent by compound E, drip bromine under condition of ice bath, temperature control reacts to terminating；Through extracting, Liquefied compound F is obtained after sloughing extractant；

(5) joining in organic solvent by thiourea, compound F successively, temperature rising reflux reacts to terminating；Remove organic molten Agent, adds aqueous slkali and adjusts pH for alkalescence, obtain liquefied compound G after extracting, sloughing extractant；

(6) bromide is dissolved in organic solvent, under condition of ice bath, drips nitrite tert-butyl, compound G successively, control Temperature reaction is to terminating；Liquefied compound H is obtained after extracting, sloughing extractant；

(7) being dissolved in organic solvent by compound H, add Cupricin. under stirring, pyroreaction is to terminating；Through extracting, Separate, slough after extractant to obtain the mixed liquor of compound I and J；

(8) being joined by aqueous slkali in the mixed liquor of compound I and J, pyroreaction is to terminating；Organic solvent extracts, divides Liquid；The water layer obtained adjusts pH for acidity, obtains liquefied compound-intermediate II after extracting, separate, sloughing extractant；

(9) intermediate II is dissolved in organic solvent, drips acyl chlorides reagent under cryogenic conditions, when reaction to bubble-free produces Temperature reaction, to terminating, obtains compound K after removing organic solvent；Compound K is dissolved in organic solvent, adds intermediate I, control Temperature reaction is to terminating；Solid, shaped compound L is obtained after extracting, separate, sloughing extractant；

(10) being dissolved in organic solvent by compound L, add highly basic after stirring and dissolving, temperature reaction is to terminating；Tune pH is Acidity, obtains solid, shaped compound A after extracting, separate, sloughing extractant.

Preferably, in described step (1): described alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate；Institute The mass fraction stating aqueous slkali is 5～30%；Described phase transfer catalyst is tetrabutyl ammonium bromide；Described compound B, sulphuric acid two Methyl ester, alkali are 1.0:(1.0～5.0 with the mol ratio of phase transfer catalyst): (1.0～5.0): (0.01～0.3)；

In described step (2): described acylation reaction temperature is 0～40 DEG C, the response time is 4.0～10.0 hours；Institute State anhydrous organic solvent selected from dichloromethane, 1,2-dichloroethanes, nitromethane；Described Lewis acid catalyst is selected from tri-chlorination Aluminum, ferric chloride, anhydrous stannic chloride；Described compound C, chloroacetic chloride are 1.0:(1.0～5.0 with the mol ratio of catalyst): (1.0～5.0)；

In described step (3): described reduction reaction is carried out at a reflux temperature, the response time is 0.5～3.0 hour；Institute Stating compound D, reduced iron powder is 1.0:(2.3～4.0 with the mol ratio of ammonium chloride): (2.0～5.0).

It is furthermore preferred that in described step (1): described alkali is sodium hydroxide and/or potassium hydroxide；The matter of described aqueous slkali Amount mark is 10～25%；The mol ratio of described compound B, dimethyl sulfate, alkali and phase transfer catalyst be 1.0:(2.0～ 4.0): (2.0～4.0): (0.1～0.2)；

In described step (2): described acylation reaction temperature is 0～30 DEG C, the response time is 5.0～8.0 hours；Described Anhydrous organic solvent is dichloromethane and/or 1,2-dichloroethanes；Catalyst is aluminum chloride and/or ferric chloride；Describedization Compound C, chloroacetic chloride are 1.0:(1.0～4.0 with the mol ratio of catalyst): (1.0～4.0)；

In described step (3): described can be little molecular fat alcohol or oxolane with the organic solvent of water mixing；Describedization Compound D, reduced iron powder are 1.0:(2.5～3.5 with the mol ratio of ammonium chloride): (2.5～3.5).

Preferably, in described step (4): described organic solvent is selected from methanol, ethanol, dichloromethane, ethyl acetate；Reaction Temperature is 0～20 DEG C；Response time is 1.0～4.0 hours；Compound E is 1.0:(1.0～3.0 with the mol ratio of bromine)；

In described step (5): described ring-closure reaction is carried out at a reflux temperature, organic solvent is selected from methanol, ethanol, dichloro Methane, ethyl acetate；Response time is 0.5～3.0 hour；Compound F is 1.0:(1.0～3.0 with the mol ratio of thiourea)；

In described step (6): described organic solvent is selected from acetonitrile, dichloromethane, 1,2-dichloroethanes；Reaction temperature is 0 ～30 DEG C；Bromide is selected from copper bromide, cuprous bromide；Compound G, bromide, the mol ratio of nitrite tert-butyl are 1.0: (1.0～2.0): (1.0～2.5).

It is furthermore preferred that in described step (4): organic solvent is methanol and/or ethanol；Reaction temperature is 5～15 DEG C；Reaction Time is 1.0～3.0 hours；Compound E is 1.0:(1.0～2.0 with the mol ratio of bromine)；

In described step (5): described ring-closure reaction is carried out at a reflux temperature, organic solvent is methanol and/or ethanol；Instead It is 0.5～2.0 hour between Ying Shi；Compound F is 1.0:(1.0～2.0 with the mol ratio of thiourea)；

In described step (6): organic solvent is acetonitrile and/or dichloromethane；Bromide is copper bromide；Reaction temperature is 0 ～25 DEG C；Compound G, bromide, the mol ratio of nitrite tert-butyl are 1.0:(1.0～1.5): (1.0～2.0).

Preferably, in described step (7): described reaction is carried out at a reflux temperature, organic solvent is selected from N, N-dimethyl Methanamide, DMAC N,N' dimethyl acetamide, oxolane；Response time is 2.0～6.0 hours；Compound H rubs with Cupricin. That ratio is 1.0:(1.0～4.0)；

In described step (8): alkali used is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, Feldalat NM；During reaction Between be 2.0～6.0 hours；Compound I is 1.0:(8.0～15.0 with the mol ratio of alkali).

It is furthermore preferred that in described step (7): described reaction organic solvent is DMF and/or N, N-bis- Methylacetamide；Response time is 3.0～5.0 hours；Compound H is 1.0:(1.0～3.0 with the mol ratio of Cupricin .)；

In described step (8): alkali used is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate；Response time is 3.0 ～5.0 hours；Compound I is 1.0:(9.0～13.0 with the mol ratio of alkali).

Preferably, in described step (9): the described acyl chloride reaction stage, organic solvent selected from toluene, dichloromethane, 1, 2-dichloroethanes；Acyl chlorides reagent is selected from oxalyl chloride, phosphorus oxychloride, thionyl chloride；Response time is 1.0～5.0 hours；Intermediate II is 1.0:(1.0～4.0 with the mol ratio of acyl chlorides reagent)；

In the amidation process stage, reaction temperature is 30～120 DEG C；Response time is 0.5～2.0 hour；Intermediate II with The mol ratio of intermediate I is 1.0:(0.5～3.0)；

In described step (10): described reaction is carried out at a reflux temperature, organic solvent selected from the tert-butyl alcohol, oxolane, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide；Described highly basic is selected from potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, hydrogen-oxygen Change potassium；Compound L is 1.0:(1.0～3.0 with the mol ratio of highly basic).

It is furthermore preferred that in described step (9): the organic solvent in described acyl chloride reaction stage is toluene and/or dichloromethane Alkane；Response time is 1.5～4.0 hours；Intermediate II is 1.0:(1.5～3.0 with the mol ratio of acyl chlorides reagent)；

The reaction temperature in described amidation process stage is 30～100 DEG C；Response time is 0.5～2.0 hour；Intermediate II is 1.0:(0.8～1.5 with the mol ratio of intermediate I)；

In described step (10): described organic solvent is the tert-butyl alcohol and/or oxolane；Described highly basic is potassium tert-butoxide And/or sodium tert-butoxide；Compound L is 1.0:(1.5～2.0 with the mol ratio of highly basic).

Use and have the beneficial effects that produced by technique scheme: during (1) synthetic intermediate I, have employed price relative Cheap 2-methyl-3-nitro phenol, and be first acylated and reduce afterwards, it is to avoid the expensive boron chloride of use, thus have Imitate reduces production cost, improves the yield of product.(2), during synthetic intermediate II, compound G and nitrous acid are selected The tert-butyl ester reacts a step and obtains compound H, simplifies course of reaction, and post processing is simple；Use compound H and Cupricin. React to obtain cyano compound I and amide compound J, hydrolyzed under basic conditions obtains intermediate II, it is to avoid use carbon dioxide Gas, simplifies course of reaction, improves product yield.

In sum, the present invention has that production cost is low, equipment requirements is low, technology stability high, it is simple to industry Metaplasia is produced.

Detailed description of the invention

Below in conjunction with specific embodiment, the present invention is further detailed explanation.

Embodiment 1: the preparation method of this anti-hepatitis C medicine TMC-435 important intermediate uses following concrete technology step Suddenly.

(1) synthesis of compound C:

The sodium hydroxide solution (sodium hydroxide 32.70g, 0.0817mol) of preparation 10wt% joins in reaction bulb, successively Add compound B (5.00g, 0.0327mol) and tetrabutyl ammonium bromide (0.53g, 0.0016mol), slowly drip after stirring 0.5h Adding dimethyl sulfate (10.30g, 0.0817mol), after normal-temperature reaction 1.0h, TLC determines that reaction is completely.Stopped reaction, adds hydrogen Sodium hydroxide solution, after stirring 0.5h, sucking filtration, filter cake washing (2 × 50mL), it is dried, activated carbon decolorizing obtains 5.1g yellow solid；Receive Rate 93.5%,¹H-NMR(500MHz,CDCl₃) δ (ppm): 2.36 (3H, s), 3.89 (3H, s), 7.04 (1H, d), 7.26 (1H, T), 7.39 (1H, d).

(2) synthesis of compound D:

By anhydrous for 80mL 1,2-dichloroethanes joins in reaction bulb, stirring lower addition compound C (10.00g, 0.0600mol), ice bath stirring is cooled to 0 DEG C, is dividedly in some parts aluminum chloride (16.00g, 0.1200mol), drips second after 0.5h Acyl chlorides (9.42g, 0.1200mol), controls temperature TLC after 0 DEG C of reaction 5h and determines that reaction is completely.Stopped reaction, to reactant liquor Middle addition 30mL water, washes with water (3 × 100mL) after separating organic layer, and anhydrous magnesium sulfate is dried, sucking filtration, and filtrate decompression rotation is evaporated off Going organic solvent 1,2-dichloroethanes to obtain red solid, add sucking filtration after petroleum ether (50mL) stirring 2h, filter cake petroleum ether is washed (3 × 20mL), is dried to obtain 9.39g yellow solid；Yield 75.0%,¹H-NMR(500MHz,CDCl₃)δ(ppm):2.13(3H, S), 2.55 (3H, s), 3.95 (3H, s), 6.94 (1H, d), 7.74 (1H, d).

(3) synthesis of intermediate I:

50mL water and 50mL ethanol are joined in reaction bulb, be sequentially added under stirring reduced iron powder (4.02g, 0.0718mol), ammonium chloride (3.84g, 0.0718mol) and compound D (5.00g, 0.0239mol), heating reflux reaction 0.5h Rear TLC determines that reaction is completely.Stopped reaction, while hot sucking filtration, add 50mL dichloromethane, extraction, separate organic rear layer in filtrate Washing (2 × 100mL) with water, anhydrous sodium sulfate is dried, sucking filtration, and filtrate decompression rotation is evaporated off organic solvent dichloromethane and obtains red Solid, activated carbon decolorizing obtains 3.85g light yellow solid；Yield 90.0%,¹H-NMR(500MHz,CDCl₃)δ(ppm):2.00 (3H, s), 2.54 (3H, s), 3.86 (3H, s), 6.30 (1H, d), 6.45 (2H, d), 7.64 (1H, d).

(4) synthesis of compound F:

Joining in reaction bulb by 30mL methanol, stirring is lower adds compound E (5.00g, 0.0581mol), and ice bath stirs It is cooled to 0 DEG C, dropping bromine (10.05g, 0.0628mol are dissolved in 30mL methanol), control temperature gas after 0 DEG C of reaction 2h Detection reaction is completely mutually.Stopped reaction, adds dichloromethane (100mL), water (50mL), wash with water after separating organic layer (2 × 50mL), anhydrous magnesium sulfate is dried, sucking filtration, and filtrate decompression rotation is evaporated off organic solvent dichloromethane and obtains 8.80g colourless liquid；Receive Rate 91.7%,

¹H-NMR(500MHz,CDCl₃) δ (ppm): 1.15 (6H, d), 2.96 (1H, m), 3.96 (2H, s).

(5) synthesis of compound G:

30mL dehydrated alcohol is joined in reaction bulb, is sequentially added into thiourea (3.63g, 0.0478mol) and compound F (7.88g, 0.0478mol), after heating reflux reaction 1h, vapor detection reaction is completely.Stopped reaction, vacuum rotary steam removes organic Etoh solvent, remaining liq adds sodium hydroxide solution and adjusts pH ＞ 12, and methyl tertiary butyl ether(MTBE) (100mL) extracts, and separates organic layer After wash (2 × 50mL) with water, anhydrous magnesium sulfate is dried, sucking filtration, filtrate decompression rotation organic solvent methyl tertiary butyl ether(MTBE) is evaporated off Obtain 5.65g yellow liquid；Yield 83.3%,¹H-NMR(500MHz,CDCl₃) δ (ppm): 1.21 (6H, d), 2.83 (1H, m), 5.32 (2H, d), 6.04 (1H, s).

(6) synthesis of compound H:

Joining in reaction bulb by 30mL acetonitrile, add copper bromide (7.85g, 0.0352mol) under stirring, ice bath is cooled to 0 DEG C, it is sequentially added into nitrite tert-butyl (5.45g, 0.0528mol) and compound G (5.00g, 0.0352mol), controls temperature After 0 DEG C of reaction 0.5h, TLC determines that reaction is completely.Stopped reaction, vacuum rotary steam removes organic solvent acetonitrile, then adds methylene chloride (100mL), water (100mL), sucking filtration, filtrate washes with water (5 × 100mL) after separating organic layer, and anhydrous magnesium sulfate is dried, and takes out Filter, filtrate decompression rotation is evaporated off organic solvent dichloromethane, and activated carbon decolorizing obtains 5.66g yellow liquid；Yield 78.0%,¹H- NMR(500MHz,CDCl₃) δ (ppm): 1.28 (6H, d), 3.06 (1H, m), 6.81 (1H, d).

(7) synthesis of compound I and J:

The DMF of 20mL is joined in reaction bulb, be sequentially added under stirring compound H (3.20g, 0.0155mol) with Cupricin. (1.67g, 0.0186mol), after being warming up to back flow reaction 3.5h, TLC determines that reaction is completely.Stop Only reaction, adds dichloromethane (100mL), water (100mL), repeatedly sucking filtration after being cooled to room temperature, filtrate is used after separating organic layer Water washing (5 × 100mL), anhydrous magnesium sulfate is dried, sucking filtration, and vacuum rotary steam removes organic solvent dichloromethane, activated carbon decolorizing Obtain 1.81g yellow liquid；Yield 76.5%.Compound I:¹H-NMR(500MHz,CDCl₃) δ (ppm): 1.33 (6H, d), 2.18 (1H, q), 7.25 (1H, d))；Compound J:¹H-NMR(500MHz,CDCl₃) δ (ppm): 1.25 (6H, d), 2.48 (1H, m), 7.55 (1H, s), 7.76 (1H, s), 7.95 (1H, s).

(8) synthesis of intermediate II:

The mixture of compound I (12.30g) and compound J (3.08g) is joined in reaction bulb, the lower dropping of stirring Sodium hydroxide (40.46g, the 1.0115mol) solution of 30%, after the 100 DEG C of reaction 3.5h that heat up, TLC determines that reaction is completely.Stop Reaction, is cooled to room temperature, and add methylene chloride in reactant liquor (3 × 50mL) extraction, and separate water layer adding dilute hydrochloric acid tune pH is 2～3, Dichloromethane (2 × 100mL) extracts, and anhydrous magnesium sulfate is dried, sucking filtration, and vacuum rotary steam removes organic solvent dichloromethane and obtains 10.3g brown liquid；Yield 72.5%,¹H-NMR(500MHz,CDCl₃) δ (ppm): 1.29 (6H, d), 3.12 (1H, m), 7.36 (1H,d)。

(9) synthesis of compound L:

Joining in reaction bulb by 40mL toluene, add intermediate II (5.00g, 0.0292mol) under stirring, ice bath is lowered the temperature To 0 DEG C, dropping oxalyl chloride (7.43g, 0.0585mol), continue stirring and produce to bubble-free, heat up 100 DEG C of reaction 3h, decompression rotation Organic solvent toluene is evaporated off, and residual reaction liquid adds Isosorbide-5-Nitrae-dioxane (30mL) and dissolves, and adds intermediate I under stirring (4.19g, 0.0234mol), temperature control TLC after 30 DEG C of reaction 0.5h determines that reaction is completely.Stopped reaction, vacuum rotary steam removes to be had Machine solvent Isosorbide-5-Nitrae-dioxane, remaining liq adds methylene chloride (100mL), and water (100mL) washes (2 with water after separating organic layer × 100mL), anhydrous magnesium sulfate is dried, sucking filtration, and vacuum rotary steam removes organic solvent dichloromethane, and it is solid that activated carbon decolorizing obtains brown Body, recrystallization obtains 6.07g pale yellow powder shape solid；Yield 62.5%,¹H-NMR(500MHz,CDCl₃)δ(ppm):1.40 (6H, d), 2.16 (3H, s), 2.57 (3H, s), 3.22 (1H, m), 3.92 (1H, s), 6.78 (1H, d), 7.16 (1H, s), 7.74 (1H, d), 11.27 (1H, s).

(10) synthesis of target compound A:

The 30mL tert-butyl alcohol is joined in reaction bulb, under stirring, is sequentially added into compound L (3.20g, 0.0096mol) and uncle Butanol potassium (2.28g, 0.0202mol), after temperature rising reflux reaction 4h, TLC determines that reaction is completely.Stopped reaction, reactant liquor is cooled to Room temperature, vacuum rotary steam removes the organic solvent tert-butyl alcohol, and residual reaction liquid adds dichloromethane (150mL), and dilute hydrochloric acid solution adjusts pH Being 2～3, wash with water (3 × 100mL) after separating organic layer, anhydrous magnesium sulfate is dried, sucking filtration, and vacuum rotary steam removes organic molten Agent dichloromethane obtains yellow solid, and recrystallization obtains TMC-435 important intermediate shown in 2.65g faint yellow solid shape formula A；Yield 87.5%,¹H-NMR(500MHz,CDCl₃) δ (ppm): 1.38 (6H, d), 2.42 (3H, s), 3.19 (1H, m), 3.97 (1H, s), 6.71 (1H, d), 6.99 (1H, d), 7.08 (1H, s), 8.24 (1H, and d) 9.52 (1H, s).

The preparation method of embodiment 2: this TMC-435 important intermediate uses following concrete technology step.

(1) synthesis of compound C:

The potassium hydroxide solution (36.62g, 0.0981mol) of preparation 15% joins in reaction bulb, is sequentially added into compound B (5.00g, 0.0327mol) and tetrabutyl ammonium bromide (1.06g, 0.0033mol), be slowly added dropwise dimethyl sulfate after stirring 0.5h Ester (12.36g, 0.0981mol), control temperature is at about 30 DEG C, and after room temperature reaction 1h, TLC determines that reaction is completely.Stopped reaction, Add potassium hydroxide solution, after stirring 0.5h, sucking filtration, filter cake washing (2 × 50mL), it is dried, activated carbon decolorizing obtains 4.97g yellow Solid；Yield 91.0%.

(2) synthesis of compound D:

Joining in reaction bulb by 80mL anhydrous methylene chloride, stirring is lower adds compound C (10.00g, 0.0600mol), Ice bath stirring cool to 0 DEG C, be dividedly in some parts ferric chloride (48.60g, 0.1800mol), after 0.5h drip chloroacetic chloride (14.13g, 0.1800mol), control temperature TLC after 10 DEG C of reaction 6h and determine that reaction is completely.Stopped reaction, adds 30mL in reactant liquor Water, washes with water (3 × 100mL) after separating organic layer, and anhydrous magnesium sulfate is dried, sucking filtration, and filtrate decompression rotation is evaporated off organic molten Agent dichloromethane obtains red solid, adds sucking filtration after petroleum ether (50mL) stirring 2h, and filter cake petroleum ether washes (3 × 20mL), dry Dry 8.76g yellow solid；Yield 70.0%.

(3) synthesis of intermediate I:

50mL water and 50mL normal propyl alcohol are joined in reaction bulb, be sequentially added under stirring reduced iron powder (4.69g, 0.0837mol), ammonium chloride (4.48g, 0.0837mol) and compound D (5.00g, 0.0239mol), heating reflux reaction 1.5h Rear TLC determines that reaction is completely.Stopped reaction, while hot sucking filtration, filtrate extracts, washes with water (2 × 100mL) after separating organic layer, Anhydrous sodium sulfate is dried.Sucking filtration, filtrate decompression rotation is evaporated off organic solvent ethyl acetate and obtains red solid, and activated carbon decolorizing obtains 3.64g light yellow solid；Yield 85.0%.

(4) synthesis of compound F:

Joining in reaction bulb by 30mL ethanol, stirring is lower adds compound E (5.00g, 0.0581mol), and ice bath stirs Being cooled to 0 DEG C, dropping bromine (13.95g, 0.0872mol are dissolved in 30mL ethanol), temperature control is gas after 10 DEG C of reaction 2.5h Detection reaction is completely mutually.Stopped reaction, adds dichloromethane (100mL), water (50mL), wash with water after separating organic layer (2 × 50mL), anhydrous magnesium sulfate is dried, sucking filtration, and filtrate decompression rotation is evaporated off organic solvent dichloromethane and obtains 7.67g colourless liquid；Receive Rate 80.0%.

(5) synthesis of compound G:

30mL methanol is joined in reaction bulb, is sequentially added into thiourea (5.45g, 0.0717mol) and compound F (7.88g, 0.0478mol), after heating reflux reaction 1h, vapor detection reaction is completely.Stopped reaction, vacuum rotary steam removes organic Solvent methanol, remaining liq adds sodium hydroxide solution and adjusts pH ＞ 12, and methyl tertiary butyl ether(MTBE) (100mL) extracts, and separates organic layer After wash (2 × 50mL) with water, anhydrous magnesium sulfate is dried, sucking filtration, filtrate decompression rotation organic solvent methyl tertiary butyl ether(MTBE) is evaporated off Obtain 5.09g yellow liquid；Yield 75.0%.

(6) synthesis of compound H:

30mL dichloromethane is joined in reaction bulb, under stirring, adds cuprous bromide (7.60g, 0.0528mol), ice bath It is cooled to 0 DEG C, is sequentially added into nitrite tert-butyl (7.25g, 0.0704mol) and compound G (5.00g, 0.0352mol), control Temperature processed TLC after 10 DEG C of reactions 1.5 determines that reaction is completely.Stopped reaction, add methylene chloride (100mL), water (100mL), take out Filter, filtrate washes with water (5 × 100mL) after separating organic layer, and anhydrous magnesium sulfate is dried, sucking filtration, and filtrate decompression rotation has been evaporated off Machine methylene chloride, activated carbon decolorizing obtains 5.08g yellow liquid；Yield 70.0%.

(7) synthesis of compound I and J:

20mL N,N-dimethylacetamide is joined in reaction bulb, be sequentially added under stirring compound H (3.20g, 0.0155mol) with Cupricin. (2.09g, 0.0233mol), after being warming up to back flow reaction 4.0h, TLC determines that reaction is completely.Stop Only reaction, adds dichloromethane (100mL), water (100mL), repeatedly sucking filtration after being cooled to room temperature, filtrate is used after separating organic layer Water washing (5 × 100mL), anhydrous magnesium sulfate is dried, sucking filtration, and vacuum rotary steam removes organic solvent dichloromethane, activated carbon decolorizing Obtain 1.70g yellow liquid；Yield 72.0%.

(8) synthesis of intermediate II:

The mixture of compound I (12.30g) and compound J (3.08g) is joined in reaction bulb, the lower dropping of stirring KOH (67.97g, the 1.2138mol) solution of 30%, after the 100 DEG C of reaction 5.0h that heat up, TLC determines that reaction is completely.Stopped reaction, Be cooled to room temperature, reactant liquor add methylene chloride (3 × 50mL) extraction, separate water layer add dilute hydrochloric acid adjust pH be 2～3, dichloromethane (2 × 100mL) extracts, and anhydrous magnesium sulfate is dried, sucking filtration, and vacuum rotary steam removes organic solvent dichloromethane and obtains 9.69g brown liquid Body；Yield 70.0%.

(9) synthesis of compound L:

40mL dichloromethane is joined in reaction bulb, under stirring, adds intermediate II (5.00g, 0.0292mol), ice bath It is cooled to 0 DEG C, dropping phosphorus oxychloride (6.71g, 0.0438mol), continue stirring and produce to bubble-free, heat up 40 DEG C of reaction 4h, Then vacuum rotary steam removes organic solvent dichloromethane, and residual reaction liquid adds Isosorbide-5-Nitrae-dioxane (30mL) and dissolves, and adds under stirring Entering intermediate I (5.23g, 0.0292mol), temperature control TLC after about 50 DEG C reaction 0.5h determines that reaction is completely.Stopped reaction, Vacuum rotary steam removes organic solvent Isosorbide-5-Nitrae-dioxane, and remaining liq adds methylene chloride (100mL) and water (100mL), separated Washing with water (2 × 100mL) after machine layer, anhydrous magnesium sulfate is dried, sucking filtration, and vacuum rotary steam removes organic solvent dichloromethane, lives Property carbon decoloring obtains brown solid, and recrystallization obtains 5.44g pale yellow powder shape solid；Yield 56.0%.

(10) synthesis of target compound A:

30mL oxolane is joined in reaction bulb, be sequentially added under stirring compound L (3.20g, 0.0096mol) and Sodium tert-butoxide (1.38g, 0.0144mol), after temperature rising reflux reaction 5h, TLC determines that reaction is completely.Stopped reaction, reactant liquor cools down To room temperature, vacuum rotary steam removes oxolane, and residual reaction liquid adds dichloromethane (150mL), and dilute hydrochloric acid solution adjusts pH to be 2 ～3, washing with water (3 × 100mL) after separating organic layer, anhydrous magnesium sulfate is dried, sucking filtration, and vacuum rotary steam removes organic solvent two Chloromethanes obtains yellow solid, and recrystallization obtains 2.65g faint yellow solid shape TMC-435 important intermediate；Yield 87.5%.

The preparation method of embodiment 3: this TMC-435 important intermediate uses following concrete technology step.

(1) synthesis of compound C:

Prepare 30% sodium carbonate liquor (46.22g, 0.1308mol) and join in reaction bulb, be sequentially added into compound B (5.00g, 0.0327mol) and tetrabutyl ammonium bromide (3.16g, 0.0098mol), be slowly added dropwise dimethyl sulfate after stirring 0.5h (16.48g, 0.1308mol), after normal-temperature reaction 2h, TLC determines that reaction is completely.Stopped reaction, adds sodium carbonate liquor, stirring After 0.5h, sucking filtration, filter cake washing (2 × 50mL), it is dried, activated carbon decolorizing obtains 4.97g yellow solid；Yield 91.0%.

(2) synthesis of compound D:

Joining in reaction bulb by anhydrous for 80mL nitromethane, stirring is lower adds compound C (10.00g, 0.0600mol), Ice bath stirring cools to 0 DEG C, is dividedly in some parts anhydrous stannic chloride (70.20g, 0.2700mol), drips chloroacetic chloride after 0.5h (21.20g, 0.2700mol), controls temperature TLC after about 25 DEG C reaction 8h and determines that reaction is completely.Stopped reaction, to reaction Adding 30mL water in liquid, wash with water (3 × 100mL) after separating organic layer, anhydrous magnesium sulfate is dried, sucking filtration, and filtrate decompression rotation is steamed Remove organic solvent nitromethane and obtain red solid, add sucking filtration after 50mL petroleum ether and stirring 2h, filter cake petroleum ether wash (3 × 20mL), 8.13g yellow solid it is dried to obtain；Yield 65.0%.

(3) synthesis of intermediate I:

50mL water and 50mL oxolane are joined in reaction bulb, be sequentially added under stirring reduced iron powder (5.35g, 0.0956mol), ammonium chloride (5.11g, 0.0956mol) and compound D (5.00g, 0.0239mol), heating reflux reaction 1.0h Rear TLC determines that reaction is completely.Stopped reaction, while hot sucking filtration, add dichloromethane (50mL), extraction, separate organic layer in filtrate After wash (2 × 100mL) with water, anhydrous magnesium sulfate is dried, sucking filtration, and filtrate decompression rotation is evaporated off organic solvent dichloromethane and obtains red Color solid, activated carbon decolorizing obtains 3.51g light yellow solid；Yield 82.0%.

(4) synthesis of compound F:

Joining in reaction bulb by 30mL dichloromethane, stirring is lower adds compound E (5.00g, 0.0581mol), ice bath Stirring is cooled to 0 DEG C, dropping bromine (23.25g, 0.1453mol are dissolved in 30mL dichloromethane), controls temperature at 15 DEG C After left and right reaction 2.5h, vapor detection reaction is completely.Stopped reaction, adds water 50mL, wash with water after separating organic layer (2 × 50mL), anhydrous magnesium sulfate is dried, sucking filtration, and filtrate decompression rotation is evaporated off organic solvent dichloromethane and obtains 8.15g colourless liquid；Receive Rate 85.0%.

(5) synthesis of compound G:

30mL dichloromethane is joined in reaction bulb, is sequentially added into thiourea (9.08g, 0.1195mol) and compound F (7.88g, 0.0478mol), after heating reflux reaction 1.5h, vapor detection reaction is completely.Stopped reaction, vacuum rotary steam removes to be had Machine methylene chloride, remaining liq adds sodium hydroxide solution and adjusts pH ＞ 12, and methyl tertiary butyl ether(MTBE) (100mL) extracts, and separates Washing (2 × 50mL) after organic layer with water, anhydrous magnesium sulfate is dried, sucking filtration, and filtrate decompression rotation is evaporated off organic solvent methyl-tert Butyl ether obtains 5.65g yellow liquid；Yield 83.3%.

(6)) the synthesis of compound H, except following difference, remaining is with embodiment 1: organic solvent uses 1,2-bis-chloroethene Alkane；Temperature control is at about 20 DEG C；Response time is 1.5h；Obtain the yellow liquid compound H that yield is 72.0%.

(7) synthesis of compound I and J:

20mL oxolane is joined in reaction bulb, be sequentially added under stirring compound H (3.20g, 0.0155mol) and Cupricin. (3.47g, 0.0388mol), after being warming up to back flow reaction 3.5h, TLC determines that reaction is completely.Stopped reaction, is cooled to After room temperature add dichloromethane (100mL), water (100mL), repeatedly sucking filtration, filtrate wash with water after separating organic layer (5 × 100mL), anhydrous magnesium sulfate is dried, sucking filtration, and vacuum rotary steam removes organic solvent dichloromethane, and activated carbon decolorizing obtains 1.81g yellow Liquid；Yield 76.%.

(8) synthesis of intermediate II:

The mixture of compound I (12.30g) and compound J (3.08g) is joined in reaction bulb, the lower dropping of stirring The Na of 30%₂CO₃(68.62g, 0.6474mol) solution, after the 100 DEG C of reaction 5.5h that heat up, TLC determines that reaction is completely.Stop anti- Should, be cooled to room temperature, reactant liquor add methylene chloride (3 × 50mL) extraction, separate water layer add dilute hydrochloric acid adjust pH be 2～3, dichloromethane Alkane (2 × 100mL) extracts, and anhydrous magnesium sulfate is dried, sucking filtration, and vacuum rotary steam removes organic solvent dichloromethane and obtains 8.72g brown Liquid；Yield 63.0%.

(9) synthesis of compound L:

40mL1,2-dichloroethanes is joined in reaction bulb, under stirring, adds intermediate II (5.00g, 0.0292mol), Ice bath is cooled to 0 DEG C, dropping thionyl chloride (10.42g, 0.0876mol), continues stirring and produces to bubble-free, heats up 85 DEG C instead Answering 4h, vacuum rotary steam removes organic solvent 1,2-dichloroethanes, and residual reaction liquid adds Isosorbide-5-Nitrae-dioxane (30mL) and dissolves, stirring Lower addition intermediate I (7.84g, 0.0438mol), control temperature is at 80 DEG C, and after stirring 0.5h, TLC determines that reaction is completely.Stop Reaction, vacuum rotary steam removes organic solvent Isosorbide-5-Nitrae-dioxane, and remaining liq adds methylene chloride (100mL) and water (100mL), point Washing with water (2 × 100mL) after going out organic layer, anhydrous magnesium sulfate is dried, sucking filtration, and vacuum rotary steam removes organic solvent dichloromethane Alkane, activated carbon decolorizing obtains brown solid, and recrystallization obtains 5.54g pale yellow powder shape solid；Yield 57.0%.

(10) synthesis of target compound A,

By the LN of 30m, dinethylformamide joins in reaction bulb, be sequentially added under stirring compound L (3.20g, 0.0096mol) with sodium hydroxide (0.96g, 0.0240mol), after temperature rising reflux reaction 5h, TLC determines that reaction is completely.Stop anti- Should, after reactant liquor is cooled to room temperature, vacuum rotary steam removes organic solvent DMF, and residual reaction liquid adds dichloro Methane (150mL), dilute hydrochloric acid solution tune pH is 2～3, washes with water (3 × 100mL) after separating organic layer, and anhydrous magnesium sulfate is done Dry, sucking filtration, vacuum rotary steam removes organic solvent dichloromethane and obtains yellow solid, and recrystallization obtains 2.65g faint yellow solid shape TMC- 435 important intermediate；Yield 80.5%.

The preparation method of embodiment 4: this TMC-435 important intermediate uses following concrete technology step.

(1) synthesis of compound C, except following difference, remaining is with embodiment 1: aqueous slkali is the potassium carbonate of 10wt% Solution；Response time is 1.5h；Obtain the light yellow solid Compound C that yield is 92.0%.

(2) synthesis of compound D: except following difference, remaining is with embodiment 1: reaction temperature is 40 DEG C；Response time For 6h；Obtain the yellow solid compound D that yield is 70%.

(3) synthesis of intermediate I, except following difference, remaining is with embodiment 1: organic solvent uses propylene glycol；Reduction Response time is 2h；Compound D: reduced iron powder: ammonium chloride=1.0:2.5:5.0 (mole)；Obtain yield be 85.5% shallow Yellow solid compound-intermediate I.

(4) synthesis of compound F, except following difference, remaining is with embodiment 1: organic solvent uses ethyl acetate；Instead It is 2.5h between Ying Shi；Obtain the colourless liquid compound F that yield is 90%.

(5) synthesis of compound G, except following difference, remaining is with embodiment 1: organic solvent uses ethyl acetate；Change Compound F: thiourea=1.0:3.0 (mole)；Response time is 1.0h；Obtain the yellow liquid compound G that yield is 80.0%.

(6) synthesis of compound H, except following difference, remaining is with embodiment 1: organic solvent uses dichloromethane；Instead It is 1.5h between Ying Shi；Obtain the yellow liquid compound H that yield is 72.5%.

(7) synthesis of compound I and J, except following difference, remaining is with embodiment 1: organic solvent uses tetrahydrochysene furan Mutter；Back flow reaction 4.0h；Obtain yellow liquid compound I and J of 72.0%.

(8) synthesis of intermediate II, except following difference, remaining is with embodiment 1: alkali used uses the K of 30wt%₂CO₃ Solution；Response time is 6.0h；Obtain brown liquid compound-intermediate II that yield is 65.0%.

(9) synthesis of compound L, except following difference, remaining is with embodiment 1: acyl chloride reaction stage, organic solvent Use dichloromethane；Reaction temperature is 40 DEG C；Response time is 4h；In the amidation process stage, reaction temperature is reflux temperature；In Mesosome II: intermediate I=1.0:2.0 (mole)；Obtain the faint yellow solid compound L that yield is 50.0%.

(10) synthesis of compound A:

30mL, N,N-dimethylacetamide are joined in reaction bulb, be sequentially added under stirring compound L (3.20g, 0.0096mol) with potassium hydroxide (1.61g, 0.0288mol), after temperature rising reflux reaction 4.5h, TLC determines that reaction is completely.Stop Reaction, after reactant liquor is cooled to room temperature, vacuum rotary steam removes organic solvent N,N-dimethylacetamide, and residual reaction liquid adds two Chloromethanes (150mL), dilute hydrochloric acid solution is adjusted pH to be 2～3, is washed (3 × 100mL), anhydrous magnesium sulfate after separating organic layer with water Being dried, sucking filtration, vacuum rotary steam removes organic solvent dichloromethane and obtains yellow solid, and recrystallization obtains 2.65g faint yellow solid shape TMC-435 important intermediate；Yield 83.5%.

The preparation method of embodiment 5: this TMC-435 important intermediate uses following concrete technology step.

(1) synthesis of compound C, except following difference, remaining is with embodiment 1: aqueous slkali is the potassium carbonate of 15wt% Solution；Compound B: dimethyl sulfate: potassium carbonate: tetrabutyl ammonium bromide=1.0:3.0:3.0:0.1 (mole)；Obtain yield The light yellow solid Compound C of 90.0%.

(2) synthesis of compound D: except following difference, remaining is with embodiment 1: organic solvent is dichloromethane；Reaction Time is 8h；Obtain the yellow solid compound D that yield is 68.0%.

(3) synthesis of intermediate I, except following difference, remaining is with embodiment 1: organic solvent uses isopropanol；Reaction Time is 1.5h；Compound D: reduced iron powder: ammonium chloride=1.0:2.3:5.0 (mole)；Obtain yield be 80.5% pale yellow Color solid chemical compound-intermediate I.

(4) synthesis of compound F, except following difference, remaining is with embodiment 1: compound E: bromine=1.0:3.0 (mole)；Organic solvent uses ethanol；Response time is 3h；Obtain the colourless liquid compound F that yield is 80.0%.

(5) synthesis of compound G, except following difference, remaining is with embodiment 1: organic solvent uses methanol；Backflow is anti- Answer 1.5h；Obtain the yellow liquid compound G that yield is 81.0%.

(6) synthesis of compound H, except following difference, remaining is with embodiment 1: bromide is cuprous bromide；During reaction Between be 2h；Obtain the yellow liquid compound H that yield is 70.5%.

(7) synthesis of compound I and J, except following difference, remaining is with embodiment 1: organic solvent uses N, N-diformazan Yl acetamide；Response time is 3.0h；Obtain yellow liquid compound I and J of 73.0%.

(8) synthesis of intermediate II, except following difference, remaining is with embodiment 1: alkaline solution is 30wt% Feldalat NM Solution；Response time is 4.0h；Compound I: alkali=1.0:15 (mole)；Obtain the brown liquid chemical combination that yield is 60.0% Thing-intermediate II.

(9) synthesis of compound L, except following difference, remaining is with embodiment 1: acyl chloride reaction stage, organic solvent Use 1,2-dichloroethanes；Response time is 4h；The amidation process stage, intermediate II: intermediate I=1.0:1.0 (mole)； Obtain the faint yellow solid compound L that yield is 56.0%.

(10) synthesis of target compound A, except following difference, remaining is with embodiment 1: organic solvent uses tetrahydrochysene furan Mutter；Response time is 3.5h；Obtain the faint yellow solid shape shape TMC-435 important intermediate that yield is 85.0%.

The preparation method of embodiment 6: this TMC-435 important intermediate uses following concrete technology step.

(1) synthesis of compound C, except following difference, remaining is with embodiment 2: aqueous slkali is the hydroxide of 25wt% Sodium and potassium hydroxide (mol ratio 1:1) mixed solution；Compound B: dimethyl sulfate: (potassium hydroxide+sodium hydroxide): the tetrabutyl Ammonium bromide=1.0:2.0:4.0:0.2 (mole)；Obtain the light yellow solid Compound C of yield 91.5.0%.

(2) synthesis of compound D: except following difference, remaining is aluminum chloride with embodiment 2:Lewis acid catalyst With ferric chloride (mol ratio 1:1)；Compound C, chloroacetic chloride are 1.0:1.0:4.0 with the mol ratio of catalyst；Obtaining yield is The yellow solid compound D of 68.5%.

(3) synthesis of intermediate I, except following difference, remaining is with embodiment 2: the response time is 3.0h；Compound D: Reduced iron powder: ammonium chloride=1.0:2.5:3.5 (mole)；Obtain light yellow solid Compound-intermediate that yield is 82.5% Ⅰ。

(4) synthesis of compound F, except following difference, remaining is with embodiment 2: organic solvent uses ethanol and methanol (volume ratio 1:1)；Reaction temperature is 5 DEG C, and the response time is 3.0h；Compound E: bromine=1.0:2.0 (mole)；Obtain yield It is the colourless liquid compound F of 85.0%.

(5) synthesis of compound G, except following difference, remaining is with embodiment 2: organic solvent uses methanol and ethanol (volume ratio 1:1)；Back flow reaction 2.0h；Compound F: thiourea=1.0:2.0 (mole)；Obtain the yellow liquid that yield is 81.5% Body compound G.

(6) synthesis of compound H, except following difference, remaining is with embodiment 2: organic solvent is acetonitrile and dichloromethane Alkane (volume ratio 1:2), bromide is copper bromide；Reaction temperature is 25 DEG C；Compound G: bromide: nitrite tert-butyl=1.0: (1.2:1.0 mole)；Obtain the yellow liquid compound H that yield is 71.5%.

(7) synthesis of compound I and J, except following difference, remaining is with embodiment 2: organic solvent uses N, N-diformazan Base Methanamide and DMAC N,N' dimethyl acetamide (volume ratio 2:1)；Response time is 5.0h；Compound H: Cupricin .=1.0: 3.0 (moles)；Obtain yellow liquid compound I and J of 73.5%.

(8) synthesis of intermediate II, except following difference, remaining is with embodiment 2: alkaline solution is 30wt% hydroxide Potassium and sodium carbonate (mol ratio 2:1) mixed solution；Response time is 3.0h；Compound I: alkali=1.0:9.0 (mole)；Received Rate is the brown liquid compound-intermediate II of 65.5%.

(9) synthesis of compound L, except following difference, remaining is with embodiment 2: acyl chloride reaction stage, organic solvent Use toluene and dichloromethane (volume ratio 1:2)；Response time is 1.5h；Intermediate II: acyl chlorides reagent=1.0:1.5 (rubs You)；In the amidation process stage, reaction temperature is 100 DEG C, and the response time is 1.5 hours, intermediate II: intermediate I=1.0: 1.5 (moles)；Obtain the faint yellow solid compound L that yield is 57.0%.

(10) synthesis of target compound A, except following difference, remaining is with embodiment 2: organic solvent uses the tert-butyl alcohol With oxolane (volume ratio 3:1)；Highly basic is potassium tert-butoxide and sodium tert-butoxide (mol ratio 1:1)；Compound L: highly basic=1.0: 2.0 (moles)；Obtain the faint yellow solid shape shape TMC-435 important intermediate that yield is 84.5.0%.

The preparation method of embodiment 7: this TMC-435 important intermediate uses following concrete technology step.

(1) synthesis of compound C, except following difference, remaining is with embodiment 1: aqueous slkali is the potassium hydroxide of 5wt% Solution；Compound B: dimethyl sulfate: (potassium hydroxide+sodium hydroxide): tetrabutyl ammonium bromide=1.0:5.0:2.0:0.1 (rubs You)；Obtain the light yellow solid Compound C of yield 92.5%.

(2) synthesis of compound D: except following difference, remaining is with embodiment 1: anhydrous organic solvent is dichloromethane With 1,2-dichloroethanes (volume ratio 5:1)；Acylation reaction temperature is 30 DEG C, and the response time is 4.0h；Compound C, chloroacetic chloride It is 1.0:4.0:1.0 with the mol ratio of catalyst；Obtain the yellow solid compound D that yield is 71.5%.

(3) synthesis of intermediate I, except following difference, remaining is with embodiment 1: the response time is 2.0h；Compound D: Reduced iron powder: ammonium chloride=1.0:2.8:2.0 (mole)；Obtain light yellow solid Compound-intermediate that yield is 84.5% Ⅰ。

(4) synthesis of compound F, except following difference, remaining is with embodiment 1: reaction temperature is 20 DEG C, the response time For 1.0h；Compound E: bromine=1.0:1.0 (mole)；Obtain the colourless liquid compound F that yield is 82.0%.

(5) synthesis of compound G, except following difference, remaining is with embodiment 1: back flow reaction 0.5h；Obtaining yield is The yellow liquid compound G of 82.5%.

(6) synthesis of compound H, except following difference, remaining is with embodiment 1: bromide is copper bromide and protobromide Copper (mol ratio 2:1)；Reaction temperature is 30 DEG C；Compound G: bromide: nitrite tert-butyl=1.0:2.0:1.5 (mole)； Obtain the yellow liquid compound H that yield is 73.5%.

(7) synthesis of compound I and J, except following difference, remaining is with embodiment 1: the response time is 2.0h；Chemical combination Thing H: Cupricin .=1.0:1.0 (mole)；Obtain yellow liquid compound I and J of 72.5%.

(8) synthesis of intermediate II, except following difference, remaining is with embodiment 1: the response time is 5.0h；Compound I: alkali=1.0:13.0 (mole)；Obtain brown liquid compound-intermediate II that yield is 62.5%.

(9) synthesis of compound L, except following difference, remaining is with embodiment 1: the acyl chloride reaction stage, acyl chlorides reagent For oxalyl chloride and phosphorus oxychloride (volume ratio 1:2)；Response time is 5.0h；Intermediate II: acyl chlorides reagent=1.0:4.0 (rubs You)；In the amidation process stage, reaction temperature is 120 DEG C, and the response time is 2.0 hours, intermediate II: intermediate I=1.0: 0.5 (mole)；Obtain the faint yellow solid compound L that yield is 56.5%.

(10) synthesis of target compound A, except following difference, remaining is with embodiment 1: compound L: highly basic=1.0: 1.8 (moles)；Obtain the faint yellow solid shape shape TMC-435 important intermediate that yield is 83.5%.

The preparation method of embodiment 8: this TMC-435 important intermediate uses following concrete technology step.

(1) synthesis of compound C, except following difference, remaining is with embodiment 3: aqueous slkali is the hydroxide of 20wt% Sodium solution；Compound B: dimethyl sulfate: (potassium hydroxide+sodium hydroxide): tetrabutyl ammonium bromide=1.0:1.0:5.0:0.01 (mole)；Obtain the light yellow solid Compound C of yield 91.5%.

(2) synthesis of compound D: except following difference, remaining is with embodiment 3: acylation reaction temperature is 5 DEG C, instead It is 10.0h between Ying Shi；Compound C, chloroacetic chloride are 1.0:5.0:5.0 with the mol ratio of catalyst；Obtaining yield is 70.0% Yellow solid compound D.

(3) synthesis of intermediate I is with embodiment 3, obtains light yellow solid Compound-intermediate I that yield is 82.5%.

(4) synthesis of compound F, except following difference, remaining is with embodiment 3: reaction temperature is 5 DEG C, the response time For 4.0h；Compound E: bromine=1.0:3.0 (mole)；Obtain the colourless liquid compound F that yield is 81.0%.

(5) synthesis of compound G, except following difference, remaining is with embodiment 3: back flow reaction 3.0h；Obtaining yield is The yellow liquid compound G of 82.0%.

(6) synthesis of compound H, except following difference, remaining is with embodiment 3: compound G: bromide: nitrous acid uncle Butyl ester=1.0:1.5:2.5 (mole)；Obtain the yellow liquid compound H that yield is 71.5%.

(7) synthesis of compound I and J, except following difference, remaining is with embodiment 3: the response time is 6.0h；Chemical combination Thing H: Cupricin .=1.0:4.0 (mole)；Obtain yellow liquid compound I and J of 70.0%.

(8) synthesis of intermediate II, except following difference, remaining is with embodiment 3: the response time is 2.0h；Compound I: alkali=1.0:8.0 (mole)；Obtain brown liquid compound-intermediate II that yield is 63.0%.

(9) synthesis of compound L, except following difference, remaining is with embodiment 3: the response time is 1.0h；Intermediate II: acyl chlorides reagent=1.0:1.0 (mole)；The amidation process stage, intermediate II: intermediate I=1.0:3.0 (mole)；? To the faint yellow solid compound L that yield is 58.0%.

(10) synthesis of target compound A, except following difference, remaining is with embodiment 3: compound L: highly basic=1.0: 1.0 (moles)；Obtain the faint yellow solid shape shape TMC-435 important intermediate that yield is 83.0%.

Claims

1. a preparation method of TMC-435 important intermediate shown in formula A,

It is characterized in that: (1) compound B obtains compound C with dimethyl sulfate through methylation reaction in the basic conditions: by chemical combination Thing B and phase transfer catalyst join in aqueous slkali, drip dimethyl sulfate under stirring, and normal-temperature reaction, to terminating, obtains after separation To solid, shaped compound C；

(2) compound C obtains compound D through F-K reaction: be dissolved in anhydrous organic solvent by compound C, ice bath bar Add Lewis acid catalyst under part, after stirring, drip chloroacetic chloride, drip complete temperature control and react to terminating；Through extraction, separate, To solid, shaped compound D；

(3) compound D through iron powder reducing be corresponding amino-compound-intermediate I: at water and miscible with water organic Being sequentially added into reduced iron powder, ammonium chloride and compound D in solvent, temperature rising reflux reacts to terminating；Separate, extract, slough extraction Powder intermediate I is obtained after solvent；

(4) compound E obtains compound F through carbonyl alpha-position bromination reaction: be dissolved in organic solvent by compound E, under condition of ice bath Dropping bromine, temperature control reacts to terminating；Liquefied compound F is obtained after extracting, sloughing extractant；

(5) compound F and thiourea cyclization obtain compound G: join in organic solvent by thiourea, compound F successively, temperature rising reflux Reaction is to terminating；Remove organic solvent, add aqueous slkali and adjust pH for alkalescence, after extracting, sloughing extractant, obtain liquefied compound G；

(6) compound G obtains compound H through diazo-reaction, nucleophilic substitution: be dissolved in organic solvent by bromide, ice bath Under the conditions of, dripping nitrite tert-butyl, compound G successively, temperature control reacts to terminating；Liquid is obtained after extracting, sloughing extractant State compound H；

(7) compound H and Cupricin. react to obtain compound I and compound J under the high temperature conditions: be dissolved in organic by compound H In solvent, adding Cupricin. under stirring, pyroreaction is to terminating；Compound I is obtained after extracting, separate, sloughing extractant Mixed liquor with J；

(8) compound I and compound J hydrolyzes to obtain intermediate II in the basic conditions: aqueous slkali joins compound I's and J In mixed liquor, pyroreaction is to terminating；Organic solvent extraction, separatory；The water layer obtained adjusts pH for acidity, through extracting, separating, takes off Liquefied compound-intermediate II is obtained after removing extractant；

(9) intermediate II and acyl chlorides reagent reacting obtain compound K, and compound K and intermediate I obtain compound L through N-acylation reaction: Intermediate II being dissolved in organic solvent, drip acyl chlorides reagent under cryogenic conditions, when reaction to bubble-free produces, temperature reaction is extremely Terminate, after removing organic solvent, obtain compound K；Compound K is dissolved in organic solvent, adds intermediate I, and temperature control reaction is to knot Bundle；Solid, shaped compound L is obtained after extracting, separate, sloughing extractant；

(10) compound L cyclization in the basic conditions obtains target compound A: be dissolved in organic solvent by compound L, stirring and dissolving Rear addition highly basic, temperature reaction is to terminating；It is acid for adjusting pH, obtains solid, shaped compound after extracting, separate, sloughing extractant A；

The preparation method of a kind of TMC-435 important intermediate the most according to claim 1, it is characterised in that described step (1) in: described alkali is one or more in sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate；The matter of described aqueous slkali Amount mark is 5～30%；Described phase transfer catalyst is tetrabutyl ammonium bromide；Described compound B, dimethyl sulfate, alkali and phase The mol ratio of transfer catalyst is 1.0:(1.0～5.0): (1.0～5.0): (0.01～0.3)；

In described step (2): described acylation reaction temperature is 0～40 DEG C, the response time is 4.0～10.0 hours；Described nothing Water organic solvent is one or more in dichloromethane, 1,2-dichloroethanes and nitromethane；Described Lewis acid catalyst is One or more in aluminum chloride, ferric chloride and anhydrous stannic chloride；Described compound C, chloroacetic chloride rub with catalyst That ratio is 1.0:(1.0～5.0): (1.0～5.0)；

In described step (3): described reduction reaction is carried out at a reflux temperature, the response time is 0.5～3.0 hour；Describedization Compound D, reduced iron powder are 1.0:(2.3～4.0 with the mol ratio of ammonium chloride): (2.0～5.0).

The preparation method of a kind of TMC-435 important intermediate the most according to claim 2, it is characterised in that described step (1) in: described alkali is sodium hydroxide and/or potassium hydroxide；The mass fraction of described aqueous slkali is 10～25%；Described chemical combination The mol ratio of thing B, dimethyl sulfate, alkali and phase transfer catalyst is 1.0:(2.0～4.0): (2.0～4.0): (0.1～ 0.2)；

In described step (2): described acylation reaction temperature is 0～30 DEG C, the response time is 5.0～8.0 hours；Described anhydrous Organic solvent is dichloromethane and/or 1,2-dichloroethanes；Catalyst is aluminum chloride and/or ferric chloride；Described compound C, chloroacetic chloride are 1.0:(1.0～4.0 with the mol ratio of catalyst): (1.0～4.0)；

In described step (3): described organic solvent miscible with water is little molecular fat alcohol or oxolane；Described compound D, reduced iron powder are 1.0:(2.5～3.5 with the mol ratio of ammonium chloride): (2.5～3.5).

The preparation method of a kind of TMC-435 important intermediate the most according to claim 1, it is characterised in that described step (4) in: described organic solvent is one or more in methanol, ethanol, dichloromethane and ethyl acetate；Reaction temperature be 0～ 20℃；Response time is 1.0～4.0 hours；Compound E is 1.0:(1.0～3.0 with the mol ratio of bromine)；

In described step (5): described ring-closure reaction is carried out at a reflux temperature, organic solvent be methanol, ethanol, dichloromethane and One or more in ethyl acetate；Response time is 0.5～3.0 hour；Compound F is 1.0:(1.0 with the mol ratio of thiourea ～3.0)；

In described step (6): described organic solvent is acetonitrile, dichloromethane and/or 1,2-dichloroethanes；Reaction temperature be 0～ 30℃；Bromide is copper bromide and/or cuprous bromide；Compound G, bromide, the mol ratio of nitrite tert-butyl are 1.0: (1.0～2.0): (1.0～2.5).

The preparation method of a kind of TMC-435 important intermediate the most according to claim 4, it is characterised in that described step (4) in: organic solvent is methanol and/or ethanol；Reaction temperature is 5～15 DEG C；Response time is 1.0～3.0 hours；Compound E is 1.0:(1.0～2.0 with the mol ratio of bromine)；

In described step (5): described ring-closure reaction is carried out at a reflux temperature, organic solvent is methanol and/or ethanol；During reaction Between be 0.5～2.0 hour；Compound F is 1.0:(1.0～2.0 with the mol ratio of thiourea)；

In described step (6): organic solvent is acetonitrile and/or dichloromethane；Bromide is copper bromide；Reaction temperature is 0～25 ℃；Compound G, bromide, the mol ratio of nitrite tert-butyl are 1.0:(1.0～1.5): (1.0～2.0).

The preparation method of a kind of TMC-435 important intermediate the most according to claim 1, it is characterised in that described step (7) in: described reaction is carried out at a reflux temperature, organic solvent be DMF, N,N-dimethylacetamide and/ Or oxolane；Response time is 2.0～6.0 hours；Compound H is 1.0:(1.0～4.0 with the mol ratio of Cupricin .)；

In described step (8): alkali used is the one in sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and Feldalat NM or several Kind；Response time is 2.0～6.0 hours；Compound I is 1.0:(8.0～15.0 with the mol ratio of alkali).

The preparation method of a kind of TMC-435 important intermediate the most according to claim 6, it is characterised in that described step (7) in: described reaction organic solvent is N,N-dimethylformamide and/or DMAC N,N' dimethyl acetamide；Response time be 3.0～ 5.0 hour；Compound H is 1.0:(1.0～3.0 with the mol ratio of Cupricin .)；

In described step (8): alkali used is one or more in sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate；Reaction Time is 3.0～5.0 hours；Compound I is 1.0:(9.0～13.0 with the mol ratio of alkali).

8., according to the preparation method of a kind of TMC-435 important intermediate described in claim 1-7 any one, its feature exists In, in described step (9): the described acyl chloride reaction stage, organic solvent is toluene, dichloromethane and/or 1,2-dichloroethanes； Acyl chlorides reagent is oxalyl chloride, phosphorus oxychloride and/or thionyl chloride；Response time is 1.0～5.0 hours；Intermediate II and acyl chlorides The mol ratio of reagent is 1.0:(1.0～4.0)；

In the described amidation process stage, reaction temperature is 30～120 DEG C；Response time is 0.5～2.0 hour；Intermediate II with The mol ratio of intermediate I is 1.0:(0.5～3.0)；

In described step (10): described reaction is carried out at a reflux temperature, organic solvent is the tert-butyl alcohol, oxolane, N, N-bis- One or more in methylformamide and DMAC N,N' dimethyl acetamide；Described highly basic is potassium tert-butoxide, sodium tert-butoxide, hydroxide One or more in sodium and potassium hydroxide；Compound L is 1.0:(1.0～3.0 with the mol ratio of highly basic).

The preparation method of a kind of TMC-435 important intermediate the most according to claim 8, it is characterised in that described step (9) in: the organic solvent in described acyl chloride reaction stage is toluene and/or dichloromethane；Response time is 1.5～4.0 hours； Intermediate II is 1.0:(1.5～3.0 with the mol ratio of acyl chlorides reagent)；

The reaction temperature in described amidation process stage is 30～100 DEG C；Response time is 0.5～2.0 hour；Intermediate II with The mol ratio of intermediate I is 1.0:(0.8～1.5)；

In described step (10): described organic solvent is the tert-butyl alcohol and/or oxolane；Described highly basic be potassium tert-butoxide and/or Sodium tert-butoxide；Compound L is 1.0:(1.5～2.0 with the mol ratio of highly basic).