CN109438272A - The synthetic method of C5a receptor antagonist W-54011 - Google Patents

The synthetic method of C5a receptor antagonist W-54011 Download PDF

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CN109438272A
CN109438272A CN201811365171.9A CN201811365171A CN109438272A CN 109438272 A CN109438272 A CN 109438272A CN 201811365171 A CN201811365171 A CN 201811365171A CN 109438272 A CN109438272 A CN 109438272A
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methoxyl group
methyl
isopropyl phenyl
amido
naphthalene
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陈新
芮雪
陈至立
赵帅
孟凯成
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CHANGZHOU NIMROD BIOLOGICA TECHNOLOGY Co Ltd
Changzhou University
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CHANGZHOU NIMROD BIOLOGICA TECHNOLOGY Co Ltd
Changzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
    • C07C2602/28—Hydrogenated naphthalenes

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  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention discloses the synthetic methods of C5a receptor antagonist W-54011.The present invention by Wittig reaction, demethylation, tautomerism, oxidation and etc. obtain 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- carboxylic acid；Then 4- (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline is obtained by reductive amination process using 4- isopropyl aniline and 4- (dimethyl amido) benzaldehyde as raw material；Finally, by 7- methoxyl group -1,2,3,4- tetrahydronaphthalene -1- carboxylic acids are converted to acyl chlorides, then with 4- (((4- isopropyl phenyl) amido) methyl)-N, accelerine reacts to obtain N- (4- (dimethylamino) benzyl)-N- (4- isopropyl phenyl) -7- methoxyl group -1,2, and 3,4- tetrahydronaphthalene -1- formamide to get arrive C5a receptor antagonist W-54011.The present invention is using 7- methoxyl group -1- tetralone cheap and easy to get as starting material, by six-step process, has smoothly synthesized C5a receptor antagonist W-54011, and this method is easy to operate, and reaction condition is mild, and cost is relatively low, raw material is cheap and easy to get, is suitble to large-scale production.

Description

The synthetic method of C5a receptor antagonist W-54011
Technical field
The present invention relates to the synthetic methods of C5a receptor antagonist W-54011 a kind of, belong to pharmaceutical synthesis field.
Background technique
C5a is the polypeptide of 74 amino acid, effective chemotactic factor (CF) of neutrophil leucocyte and other leucocytes, and is weight The inflammatory mediator wanted.C5a is in mast cell degranulation, smooth muscle contraction, monocyte emigration, blood vessel dilatation, inflammation part blood Pipe permeability increases and immunocyte is raised aspect and played a significant role.The bioactivity of C5a is related to a variety of diseases, such as rheumatoid Property arthritis, systemic loupus erythematosus, reperfusion injury, Alzheimer disease and septicemia etc..
W-54011 is that one kind for reporting for the first time is effective and the non-peptides C5a receptor antagonist with Orally active, can be with C5a receptor is bound directly, and is inhibited C5a activity, is facilitated the inflammation treatment of C5a adjusting.2002, Sumichika et al. passed through High flux screening finds that C5a receptor antagonist W-54011 has very high bioactivity.Its C5a that can inhibit 125I label In conjunction with granulocyte in people, Ki value is 2.2nM, also can inhibit grain in the interior stream of metabolic defect in cellular calcium ion, chemotactic factor (CF) and the people of C5a induction The generation of cellular responsibility superoxidase, half-inhibitory concentration (IC50) it is respectively 3.1,2.7 and 1.6nM.Then, It is more active than peptide mimics PMX53 in binding assay that Sumichika et al. reports the compound, and even than anti- C5a receptor monoclonal antibody is more active.In the assay, the IC of compound W-540115090nM is reached.Therefore, it finds simple The method for quickly preparing C5a receptor antagonist W-54011 has great importance.
2011, middle village's light, which is controlled et al., disclosed the amide derivatives with C5a receptor antagonistic activity, elaborated W- 54011 detailed preparation method.It is hydroxyl by carbonyl reduction, then with thionyl chloride using 7- methoxyl group -1- tetralone as raw material Halogen displacement reaction is carried out as halogenating agent, displacement then occurs with cyano and reacts, becomes acid using hydrolysis, finally turns acid It turns to acyl chlorides and obtains final product W-54011 with corresponding amine progress amidation process again；Its synthetic route is as shown in Figure 1, lack Point uses the Cymag of severe toxicity during being, be not suitable for large-scale production.
2012, Richmond et al. reported synthesis 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- carboxylic acid another kind Method, for synthetic route as shown in Fig. 2, disadvantage uses CO gas during being, it is raw to be not suitable for scale for trivial operations It produces.
Summary of the invention
The present invention in order to overcome the shortcomings in the prior art, proposes a kind of C5a receptor antagonist W-54011's of improvement New synthetic method, easy to operate, reaction condition is mild, and cost is relatively low, raw material is cheap and easy to get, is suitble to large-scale production.
To achieve the above object, The technical solution adopted by the invention is as follows:
The synthetic method of C5a receptor antagonist W-54011, comprising the following steps:
(1) 7- methoxyl group -1- (methoxymethylene) -1,2,3,4-tetralin preparation
Under the action of low temperature, nitrogen protection and alkali, by (methoxy) triphenylphosphinebromide and 7- methoxyl group -1- naphthalene Full ketone carries out Wittig reaction in tetrahydrofuran solution, after reaction overnight after being quenched, being concentrated, extract, wash drying After managing step, 7- methoxyl group -1- (methoxymethylene) -1,2,3,4-tetrahydro-naphthalene is obtained；
(2) 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- formaldehyde preparation
Under the action of an acid, 7- methoxyl group -1- (methoxymethylene) -1,2,3,4-tetrahydro-naphthalene is dissolved in organic solvent Middle progress demethylation reaction and tautomerism, heated overnight at reflux, then by extraction, washing, dry, concentration post-processing step To get arriving 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- formaldehyde after rapid；
(3) 7- methoxyl group -1,2,3,4-tetralin -1- carboxylic acid preparation
Under the action of low temperature, oxidant, 7- methoxyl group -1,2,3,4-tetralin -1- formaldehyde is dissolved in organic solvent In be converted into carboxylic acid compound, after fully reacting by extraction, drying, concentration, recrystallization post-processing step after, obtain 7- methoxy Base -1,2,3,4-tetralin -1- carboxylic acid；
(4) preparation of 4- (((4- isopropyl phenyl) imido grpup) methyl)-n,N-Dimethylaniline
Under nitrogen protection, 4- isopropyl aniline and 4- (dimethyl amido) benzaldehyde are dissolved in organic solvent and are carried out instead It answers, after reaction overnight by concentration, recrystallization, filtering, dry post-processing step, obtains 4- (((4- isopropyl phenyl) imines Base) methyl)-n,N-Dimethylaniline；
(5) preparation of 4- (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline
4- (((4- isopropyl phenyl) imido grpup) methyl)-n,N-Dimethylaniline is dissolved in organic solvent, is being restored It is reacted under conditions of agent, after fully reacting after being quenched, extracting, be concentrated, dry post-processing step and column chromatographic purifying, Obtain 4- (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline；
(6) N- ((4- dimethylaminophenyl) methyl)-N- (4- isopropyl phenyl) -7- methoxyl group -1,2,3,4- tetrahydros Change the preparation of naphthalene -1- formamide W-54011
Under the conditions of nitrogen protection, 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- carboxylic acid is dissolved in excessive thionyl chloride In, heating reflux reaction 1~3 hour, chloride compounds are translated into, excessive solvent are then evaporated, equally in nitrogen protection With the two of triethylamine and 4- (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline is slowly added under conditions of low temperature Chloromethanes solution carries out amidation process, reacts 8~16 hours at room temperature, then by concentration, column chromatographic purifying, obtains N- ((4- dimethylaminophenyl) methyl)-N- (4- isopropyl phenyl) -7- methoxyl group -1,2,3,4-tetralin -1- formamide.
Further, low temperature described in step (1) is -78~0 DEG C；The alkali is n-BuLi, potassium tert-butoxide, carbon Sour potassium, lithium hexamethyldisilazide or double trimethyl silicon substrate amido potassium, preferably n-BuLi or potassium tert-butoxide；Described The molar ratio of (methoxy) triphenylphosphinebromide and 7- methoxyl group -1- tetralone is 1~3:1, preferably 1.2:1.
Further, acid described in step (2) is 2N HCl, sulfuric acid or 48%HBr, preferably 2N HCl；Described Solvent is methanol.
Further, low temperature described in step (3) is -40~10 DEG C, preferably -10~10 DEG C；The oxidant For Jones reagent, acid potassium permanganate or acid potassium bichromate, preferably Jones reagent；The solvent is acetone or dichloromethane Alkane, preferably acetone；The reaction time is 1~3 hour.
Further, the molar ratio of 4- isopropyl aniline described in step (4) and 4- (dimethyl amido) benzaldehyde is 1:1~2, preferably 1:1；The solvent is dehydrated alcohol or anhydrous methanol.
Further, organic solvent described in step (5) is methanol, ethyl alcohol or tetrahydrofuran, preferably methanol；It is described Reducing agent is sodium borohydride, sodium cyanoborohydride, tetrahydrochysene lithium aluminium or hydrogen, preferably sodium borohydride or sodium cyanoborohydride；Institute Stating the reaction time is 2~4.
Further, 4- described in step (6) (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline, 7- methoxyl group -1,2,3,4-tetralin -1- carboxylic acid, thionyl chloride and triethylamine molar ratio is 1:1.2:2.5:1.5；It is described Low temperature be -20~10 DEG C.
Beneficial effects of the present invention:
The present invention by Wittig reaction, demethylation, tautomerism, oxidation and etc. obtain methoxyl group -1,2,3 7-, 4- tetrahydronaphthalene -1- carboxylic acid；Then pass through reduction amination using 4- isopropyl aniline and 4- (dimethyl amido) benzaldehyde as raw material Reaction obtains 4- (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline；Finally, by 7- methoxyl group -1,2,3,4- Tetrahydronaphthalene -1- carboxylic acid is converted to acyl chlorides, then anti-with 4- (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline It should obtain N- (4- (dimethylamino) benzyl)-N- (4- isopropyl phenyl) -7- methoxyl group -1,2,3,4-tetralin -1- first Amide obtains C5a receptor antagonist W-54011；The present invention is using 7- methoxyl group -1- tetralone cheap and easy to get as reaction Starting material has smoothly synthesized C5a receptor antagonist W-54011, this method is easy to operate, reaction condition by six-step process Mildly, cost is relatively low, raw material is cheap and easy to get, is suitble to large-scale production.
Detailed description of the invention
The village Tu1Wei Zhong light control et al. disclosed in W-54011 synthetic route chart；
Fig. 2 is 7- methoxyl group -1,2,3,4-tetralin -1- carboxylic acid synthetic route chart disclosed in Richmond et al.；
Fig. 3 is W-54011 synthetic route chart of the invention, wherein 1 is 7- methoxyl group -1- tetralone, and 2 be 7- methoxyl group - 1- (methoxymethylene) -1,2,3,4-tetrahydro-naphthalene, 3 be 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- formaldehyde, and 4 be 7- first Oxy-1,2,3,4- tetrahydronaphthalene -1- carboxylic acids, 5 be 4- isopropyl aniline, and 6 be 4- (dimethyl amido) benzaldehyde, and 7 be 4- (((4- isopropyl phenyl) imido grpup) methyl)-n,N-Dimethylaniline, 8 be 4- (((4- isopropyl phenyl) amido) methyl)- N,N-Dimethylaniline, 9 be W-54011.
Specific embodiment
The present invention will be described in detail with reference to embodiments, but the present invention is not limited to these embodiments.
The preparation of step 1:7- methoxyl group -1- (methoxymethylene) -1,2,3,4-tetralin
Embodiment 1: under nitrogen protection, (methoxy) triphenylphosphinebromide (21.1g, 54.5mmol) is dissolved in nothing In the tetrahydrofuran (150mL) of water, be placed in -78 DEG C of stirring 10min, in 20min be added dropwise n-BuLi (27mL, 61.1mmol, 2.5mol/L in n-hexane) after, it moves to and half an hour is stirred at room temperature, 7- first is then added dropwise under the conditions of -78 DEG C The tetrahydrofuran solution of Oxy-1-tetralone (8.0g, 45.4mmol) is moved back to room temperature, and reaction is overnight.After complete reaction, It is quenched, is concentrated under reduced pressure with the ammonium chloride solution of saturation, ethyl acetate and water is added and is extracted, collect organic phase, then with being saturated Brine It, anhydrous sodium sulfate is dry, is concentrated to get 7- methoxyl group -1- (methoxymethylene) -1,2,3,4- tetrahydros Naphthalene is colorless oil.This product is not purified to be directly used in the next step.1H NMR(400MHz,CDCl3):δ1.72-1.78 (m, 2H), 2.46-2.50 (m, 2H), 2.66 (t, J=6.1Hz, 2H), 3.72 (s, 3H), 3.78 (s, 3H), 6.60 (s, 1H), 6.64 (dd, J1=8.3Hz, J2=2.6Hz, 1H), 6.89 (d, J=2.6Hz, 1H), 6.97 (d, J=8.3Hz, 1H)；13C NMR(100MHz,CDCl3): δ 22.85,23.43,29.83,55.40,60.17,106.87,111.53,114.95,129.24, 129.38,135.20,143.13,157.92.
Embodiment 2: under nitrogen protection, (methoxy) triphenylphosphinebromide (10.6g, 27.3mmol) is dissolved in nothing It in the tetrahydrofuran (75mL) of water, is placed in after potassium tert-butoxide (3.5g, 30.1mmol) is added dropwise under ice bath, moves to and be stirred at room temperature half Hour, the tetrahydrofuran solution of 7- methoxyl group -1- tetralone (4.0g, 22.7mmol) is then added dropwise under condition of ice bath, moves back To room temperature, reaction is overnight.After complete reaction, it is quenched, is concentrated under reduced pressure with the ammonium chloride solution of saturation, ethyl acetate and water is added Extracted, collect organic phase, then with saturation brine It, anhydrous sodium sulfate dry, be concentrated to get 7- methoxyl group -1- (methoxymethylene) -1,2,3,4-tetrahydro-naphthalene is colorless oil.This product is not purified to be directly used in the next step. Product1H NMR and13C NMR and embodiment 1 are completely the same.
Embodiment 3: under nitrogen protection, (methoxy) triphenylphosphinebromide (7g, 18.2mmol) is dissolved in anhydrous Tetrahydrofuran (50mL) in, under the conditions of being placed in -78 DEG C be added dropwise lithium hexamethyldisilazide (20.3mL, 20.4mmol, 1mol/L in THF) after, it moves to and half an hour is stirred at room temperature, 7- methoxyl group -1- tetralone is then added dropwise under the conditions of -78 DEG C The tetrahydrofuran solution of (2.7g, 15.2mmol) is moved back to room temperature, and reaction is overnight.After complete reaction, with the ammonium chloride of saturation Solution is quenched, and is concentrated under reduced pressure, and ethyl acetate and water is added and is extracted, and collects organic phase, then with the brine It being saturated, nothing Aqueous sodium persulfate is dry, is concentrated to get 7- methoxyl group -1- (methoxymethylene) -1,2,3,4-tetrahydro-naphthalene, is colorless oil. This product is not purified to be directly used in the next step.Product1H NMR and13C NMR and embodiment 1 are completely the same.
The preparation of step 2:7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- formaldehyde
Embodiment 4: by previous step crude product 7- methoxyl group -1- (methoxymethylene) -1,2,3,4-tetralin (9.5g) is dissolved in methanol (60mL), then adds dilute hydrochloric acid (300mL, 2N), is heated to reflux and is stayed overnight.To fully reacting Afterwards, it is extracted with ethyl acetate, collects organic phase, then use saturated common salt water washing, anhydrous sodium sulfate is dry, is concentrated, obtains 7- first Oxy-1,2,3,4- tetrahydronaphthalene -1- formaldehyde, are colourless oil liquid.Product is not purified to be directly used in the next step.1H NMR(400MHz,CDCl3): δ 1.76-1.84 (m, 2H), 1.89-1.96 (m, 1H), 2.18-2.25 (m, 1H), 2.74 (t, J= 6.3Hz, 1H), 3.59 (t, J=5.0Hz, 1H), 3.81 (s, 3H), 6.71 (d, J=2.5Hz, 1H), 6.81 (dd, J=8.4, 2.6Hz, 1H), 7.09 (d, J=8.4Hz, 1H), 9.69 (d, J=2.2Hz, 1H)
Embodiment 5: by previous step crude product 7- methoxyl group -1- (methoxymethylene) -1,2,3,4-tetrahydro-naphthalene (4.8g) is dissolved in methanol (30mL), then adds the concentrated sulfuric acid (20mL), is heated to reflux and is stayed overnight.After complete reaction, it quenches It goes out, ethyl acetate extraction collects organic phase, then uses saturated common salt water washing, and anhydrous sodium sulfate is dry, is concentrated, obtains 7- methoxy Base -1,2,3,4-tetrahydro-naphthalene -1- formaldehyde, is colourless oil liquid.Product is not purified to be directly used in the next step.Product 's1H NMR and13C NMR and embodiment 4 are completely the same.
Embodiment 6: by previous step crude product 7- methoxyl group -1- (methoxymethylene) -1,2,3,4-tetralin (3.2g) is dissolved in methanol (20mL), then adds 48%HBr (30mL), is heated to reflux and is stayed overnight.After complete reaction, it quenches It goes out, ethyl acetate extraction collects organic phase, then uses saturated common salt water washing, and anhydrous sodium sulfate is dry, is concentrated, obtains 7- methoxy Base -1,2,3,4-tetrahydro-naphthalene -1- formaldehyde, is colourless oil liquid.Product is not purified to be directly used in the next step.Product 's1H NMR and13C NMR and embodiment 4 are completely the same.
The preparation of step 3:7- methoxyl group -1,2,3,4-tetralin -1- carboxylic acid
Embodiment 7: under condition of ice bath, to 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- formaldehyde (7.5g, Acetone (70mL) is added in 39.4mmol), Jones reagent (10.5mL) is slowly added dropwise, after complete reaction, ethyl acetate is added Extraction, organic phase is dry with anhydrous sodium sulfate, and concentration is recrystallized with ethyl acetate and petroleum ether, obtains 7- methoxyl group -1,2, and 3, 4- tetrahydronaphthalene -1- carboxylic acid, is faint yellow solid.1H NMR(400MHz,CDCl3):δ1.72-1.77(m,1H),1.92- 2.02 (m, 2H), 2.14-2.20 (m, 1H), 2.65-2.78 (m, 2H), 3.76 (s, 3H), 3.80 (t, J=5.6Hz, 1H), 6.75 (t, J=4.9Hz, 2H), 7.02 (d, J=8.6Hz, 1H)；13C NMR(100MHz,CDCl3):δ20.69,26.54, 28.37,44.79,55.41,113.66,114.32,129.53,130.43,133.43,157.59,181.50.HRMS (ESI) m/z:calcd.For C12H14NaO3+:229.0835,Found:229.0840[M+Na]+.
Embodiment 8: under condition of ice bath, to 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- formaldehyde (3.8g, Acetone (35mL) is added in 19.7mmol), acid potassium permanganate aqueous solution (5mL) is slowly added dropwise, after complete reaction, second is added Acetoacetic ester extraction, organic phase is dry with anhydrous sodium sulfate, and concentration is recrystallized with ethyl acetate and petroleum ether, obtains 7- methoxyl group- 1,2,3,4-tetrahydro-naphthalene -1- carboxylic acid, is faint yellow solid.Product1H NMR and13C NMR and embodiment 7 are completely the same.
Embodiment 9: under condition of ice bath, to 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- formaldehyde (2.5g, Acetone (20mL) is added in 13.2mmol), acid potassium dichromate aqueous solution (4mL) is slowly added dropwise, after complete reaction, second is added Acetoacetic ester extraction, organic phase is dry with anhydrous sodium sulfate, and concentration is recrystallized with ethyl acetate and petroleum ether, obtains 7- methoxyl group- 1,2,3,4-tetrahydro-naphthalene -1- carboxylic acid, is faint yellow solid.Product1H NMR and13C NMR and embodiment 7 are completely the same.
The preparation of step 4:4- (((4- isopropyl phenyl) imido grpup) methyl)-n,N-Dimethylaniline
Embodiment 10: by 4- isopropyl aniline (2.03mL, 14.8mmol) and 4- (dimethyl amido) benzaldehyde (2.21g, It 11.8mmol) is added in dehydrated alcohol (100mL), is stirred overnight at room temperature.After complete reaction, reaction solution is true Sky concentration, is recrystallized with ethyl alcohol and petroleum ether, is filtered, and with petroleum ether, filtration cakes torrefaction obtains 4- (((4- cumene Base) imido grpup) methyl)-n,N-Dimethylaniline is yellow-green crystal shape solid.1H NMR(400MHz,CDCl3):δ1.26 (d, J=6.8Hz, 6H), 2.86-2.96 (m, 1H), 3.00 (s, 6H), 6.71 (d, J=8.8Hz, 2H), 7.17 (d, J= 8.4Hz, 2H), 7.21 (d, J=8.0Hz, 2H), 7.75 (d, J=8.8Hz, 2H), 8.33 (s, 1H)；13C NMR(100MHz, CDCl3): δ 24.2,33.7,40.3,111.7,120.9,124.7,127.1,130.4,145.8,150.7,152.5,159.7.
The preparation of step 5:4- (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline
Embodiment 11: by 4- (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline (2.5g, 9.6mmol), Sodium borohydride (398.7mg, 10.5mmol) is added in the methanol of 35mL, and 2h is stirred at room temperature.After complete reaction, with full It is quenched, is concentrated in vacuo with ammonium chloride solution, extracted with ethyl acetate and water, collect organic phase, it is dry with anhydrous sodium sulfate.Then It is recrystallized, is filtered with petroleum ether, with petroleum ether, filtration cakes torrefaction obtains 4- (((4- isopropyl phenyl) amido) methyl)- N,N-Dimethylaniline is transparent flakey solid.1H NMR (400MHz, CDCl3): δ 1.20 (d, J=7.2Hz, 6H), 2.75-2.85 (m, 1H), 2.92 (s, 6H), 4.16 (s, 2H), 6.58 (d, J=8.8Hz, 2H), 6.71 (d, J=8.4Hz, 2H), 7.03 (d, J=8.4Hz, 2H), 7.23 (d, J=8.4Hz, 2H)；13C NMR(100MHz,CDCl3):δ24.4,33.3, 40.8,48.4,112.9,112.9,127.2,127.5,128.9,137.9,146.6,150.1.
Embodiment 12: by 4- (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline (1.3g, 4.8mmol), Sodium cyanoborohydride (330mg, 5.3mmol) is added in the methanol of 18mL, and 3h is stirred at room temperature.After complete reaction, it uses Saturated ammonium chloride solution is quenched, and vacuum concentration is extracted with ethyl acetate and water, collects organic phase, dry with anhydrous sodium sulfate.It connects Recrystallized with petroleum ether, filter, with petroleum ether, filtration cakes torrefaction obtains 4- (((4- isopropyl phenyl) amido) first Base)-n,N-Dimethylaniline is transparent flakey solid.Product1H NMR and13C NMR and embodiment 11 are completely the same.
Embodiment 13: by 4- (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline (0.8g, 3.2mmol), Lithium Aluminium Hydride (132.9mg, 3.5mmol) is added in the methanol of 10mL, and 2h is stirred at room temperature.After complete reaction, with full It is quenched, is concentrated in vacuo with ammonium chloride solution, extracted with ethyl acetate and water, collect organic phase, it is dry with anhydrous sodium sulfate.Then It is recrystallized, is filtered with petroleum ether, with petroleum ether, filtration cakes torrefaction obtains 4- (((4- isopropyl phenyl) amido) methyl)- N,N-Dimethylaniline is transparent flakey solid.Product1H NMR and13C NMR and embodiment 11 are completely the same.
Embodiment 14: by 4- (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline (2.54g, 9.6mmol) It is dissolved in the ethyl alcohol of 35mL, is constantly passed through hydrogen, stir 3h, there is white solid precipitation.After complete reaction, saturated ammonium chloride is used Solution is quenched, and vacuum concentration is extracted with ethyl acetate and water, collects organic phase, concentration dry with anhydrous sodium sulfate.Then it uses Petroleum ether recrystallization, filters, and with petroleum ether, filtration cakes torrefaction obtains 4- (((4- isopropyl phenyl) amido) methyl)-N, Accelerine is transparent flakey solid.Product1H NMR and13C NMR and embodiment 11 are completely the same.
Step 6:N- ((4- dimethylaminophenyl) methyl)-N- (4- isopropyl phenyl) -7- methoxyl group -1,2,3,4- four The preparation of hydrogenated naphthalene -1- formamide W-54011
Embodiment 15: by 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- carboxylic acid (200mg, 0.97mmol), 2- (7- azo Benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (479.5mg, 1.27mmol) and N, N- diisopropylethylamine In the n,N-Dimethylformamide of (164.2 μ L, 1.27mmol) molten 10mL, after 30min, it is subsequently added into 4- (((4- cumene Base) amido) methyl)-n,N-Dimethylaniline (260.3mg, 0.97mmol), N, N- bis- are added under condition of ice bath after 30min Wopropyl ethyl amine (481 μ L, 2.91mmol), is then stirred at room temperature 12h.Vacuum concentration the, through (elution of column chromatographic purifying Agent is petroleum ether: ethyl acetate=10:1), final product is not obtained.
Embodiment 16: by 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- carboxylic acid (200mg, 0.97mmol), 1- hydroxy benzenes And triazole (144.2mg, 1.07mmol) and 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (204.7mg, 1.07mmol) in the n,N-Dimethylformamide of molten 10mL, after stirring 10min, it is subsequently added into 4- (((4- isopropyl phenyl) amine Base) methyl)-N, N, N- diisopropyl is added after 30min in accelerine (312.4mg, 1.17mmol) under condition of ice bath Ethamine (481 μ L, 2.91mmol), is then stirred at room temperature 13h.Vacuum concentration, through column chromatographic purifying, (eluant, eluent is stone Oily ether: ethyl acetate=10:1), final product is not obtained.
Embodiment 17: by 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- carboxylic acid (200mg, 0.97mmol), hexafluorophosphoric acid Benzotriazole -1- base-oxygroup tripyrrole alkyl (608.9mg, 1.17mmol) is dissolved in the n,N-Dimethylformamide of 10mL, is stirred After mixing 30min, n,N-diisopropylethylamine (481 μ L, 2.91mmol) is added under condition of ice bath, 4- is added after 1h, and (((4- is different Propyl phenyl) amido) methyl)-N, accelerine (312.4mg, 1.17mmol) is stirred at room temperature 12h.Vacuum Concentration, through column chromatographic purifying (eluant, eluent is petroleum ether: ethyl acetate=10:1), does not obtain final product.
Embodiment 18: by 7- methoxyl group -1,2,3,4-tetralin -1- carboxylic acid (490mg, 2.38mmol) and thionyl chloride (359 μ L, 4.95mmol) is in N2It is heated to reflux under protection 2 hours, extra thionyl chloride is evaporated, then in N2Protection and 0 DEG C of item Under part, it is slowly added to the anhydrous methylene chloride solution of triethylamine (412.9 μ L, 2.97mmol), is subsequently added into 4- (((4- isopropyl Phenyl) amido) methyl) and-n,N-Dimethylaniline (528.7mg, 1.98mmol) anhydrous methylene chloride solution, by it in room temperature Lower stirring 12 hours.After its fully reacting, vacuum concentration, through column chromatographic purifying (eluant, eluent is petroleum ether: ethyl acetate= 10:1) obtain product N- ((4- dimethylaminophenyl) methyl)-N- (4- isopropyl phenyl) -7- methoxyl group -1,2,3,4- four Hydrogenated naphthalene -1- formamide W-54011 is faint yellow viscous liquid.1H-NMR(400MHz,CDCl3): δ 1.24 (d, J= 6.8Hz, 6H), 1.41-1.50 (m, 1H), 1.85-1.90 (m, 1H), 1.97-2.04 (m, 2H), 2.54-2.61 (m, 1H), 2.73-2.81 (m, 1H), 2.85-2.91 (m, 1H), 2.93 (s, 6H), 3.68 (s, 3H), 3.73 (t, J=4.8Hz, 1H), 4.58 (d, J=13.6Hz, 1H), 5.06 (d, J=18Hz, 1H), 6.52 (s, 1H), 6.52 (s, 1H), 6.63-6.68 (m, 3H), 6.93-6.99 (m, 3H), 7.13-7.18 (m, 4H)；13C NMR(100MHz,CDCl3):δ21.8,24.0,24.1, 27.6,28.6,33.8,40.8,43.0,52.8,55.3,112.6,112.8,126.2,127.7,128.2,129.8,130.2, 130.3,137.0,140.6,148.7,150.0,157.7,175.4.HRMS (ESI) m/z:calcd.For C30H36N2NaO2 +:479.2669,Found:479.2666[M+Na]+.。

Claims (7)

  1. The synthetic method of 1.C5a receptor antagonist W-54011, which comprises the following steps:
    (1) 7- methoxyl group -1- (methoxymethylene) -1,2,3,4-tetralin preparation
    Under the action of low temperature, nitrogen protection and alkali, by (methoxy) triphenylphosphinebromide and 7- methoxyl group -1- tetralone Wittig reaction is carried out in tetrahydrofuran solution, after reaction overnight by being quenched, being concentrated, extracting, washing dry post-processing step After rapid, 7- methoxyl group -1- (methoxymethylene) -1,2,3,4-tetrahydro-naphthalene is obtained；
    (2) 7- methoxyl group -1,2,3,4-tetralin -1- formaldehyde preparation
    Under the action of an acid, by 7- methoxyl group -1- (methoxymethylene) -1,2,3,4-tetrahydro-naphthalene be dissolved in organic solvent into Row demethylation reaction and tautomerism, heated overnight at reflux, then by extraction, washing, dry, concentration post-processing step Afterwards to get arrive 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- formaldehyde；
    (3) 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- carboxylic acid preparation
    Under the action of low temperature, oxidant, 7- methoxyl group -1,2,3,4-tetralin -1- formaldehyde is dissolved in organic solvent transfer Carboxylic acid compound is turned to, after fully reacting after extraction, drying, concentration, recrystallization post-processing step, obtains 7- methoxyl group- 1,2,3,4-tetralin -1- carboxylic acid；
    (4) preparation of 4- (((4- isopropyl phenyl) imido grpup) methyl)-n,N-Dimethylaniline
    Under nitrogen protection, 4- isopropyl aniline and 4- (dimethyl amido) benzaldehyde are dissolved in organic solvent and are reacted, After reaction overnight by concentration, recrystallization, filtering, dry post-processing step, 4- (((4- isopropyl phenyl) imido grpup) first is obtained Base)-n,N-Dimethylaniline；
    (5) preparation of 4- (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline
    4- (((4- isopropyl phenyl) imido grpup) methyl)-n,N-Dimethylaniline is dissolved in organic solvent, in reducing agent Under the conditions of reacted, after fully reacting after being quenched, extracting, be concentrated, dry post-processing step and column chromatographic purifying, obtain 4- (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline；
    (6) N- ((4- dimethylaminophenyl) methyl)-N- (4- isopropyl phenyl) -7- methoxyl group -1,2,3,4-tetrahydro-naphthalene - The preparation of 1- formamide W-54011
    Under the conditions of nitrogen protection, 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene -1- carboxylic acid is dissolved in excessive thionyl chloride, Heating reflux reaction 1~3 hour, chloride compounds are translated into, then evaporate excessive solvent, equally in nitrogen protection and low The dichloromethane of triethylamine and 4- (((4- isopropyl phenyl) amido) methyl)-n,N-Dimethylaniline is slowly added under conditions of temperature Alkane solution carries out amidation process, reacts 8~16 hours at room temperature, then by concentration, column chromatographic purifying, obtains N- ((4- bis- Methylamino phenyl) methyl)-N- (4- isopropyl phenyl) -7- methoxyl group -1,2,3,4-tetralin -1- formamide.
  2. 2. the synthetic method of C5a receptor antagonist W-54011 according to claim 1, which is characterized in that in step (1) The low temperature is -78~0 DEG C；The alkali be n-BuLi, potassium tert-butoxide, potassium carbonate, lithium hexamethyldisilazide or Double trimethyl silicon substrate amido potassium, preferably n-BuLi or potassium tert-butoxide；(methoxy) triphenylphosphinebromide with The molar ratio of 7- methoxyl group -1- tetralone is 1~3:1, preferably 1.2:1.
  3. 3. the synthetic method of C5a receptor antagonist W-54011 according to claim 1, which is characterized in that in step (2) The acid is 2N HCl, sulfuric acid or 48%HBr, preferably 2N HCl；The solvent is methanol.
  4. 4. the synthetic method of C5a receptor antagonist W-54011 according to claim 1, which is characterized in that in step (3) The low temperature is -40~10 DEG C, preferably -10~10 DEG C；The oxidant be Jones reagent (Jones reagent), Acid potassium permanganate or acid potassium bichromate, preferably Jones reagent；The solvent be acetone or methylene chloride, preferably third Ketone.
  5. 5. the synthetic method of C5a receptor antagonist W-54011 according to claim 1, which is characterized in that in step (4) The molar ratio of the 4- isopropyl aniline and 4- (dimethyl amido) benzaldehyde is 1:1~2, preferably 1:1；The solvent For dehydrated alcohol or anhydrous methanol；The reaction time is 5~8 hours.
  6. 6. the synthetic method of C5a receptor antagonist W-54011 according to claim 1, which is characterized in that in step (5) The organic solvent is methanol, ethyl alcohol or tetrahydrofuran, preferably methanol；The reducing agent is sodium borohydride, cyano boron hydrogen Change sodium, tetrahydrochysene lithium aluminium or hydrogen, preferably sodium borohydride or sodium cyanoborohydride；The reaction time is 2~4.
  7. 7. the synthetic method of C5a receptor antagonist W-54011 according to claim 1, which is characterized in that in step (6) Described 4- (((4- isopropyl phenyl) amido) the methyl)-n,N-Dimethylaniline, 7- methoxyl group -1,2,3,4-tetrahydro-naphthalene - The molar ratio of 1- carboxylic acid, thionyl chloride and triethylamine is 1:1.2:2.5:1.5；The low temperature is -20~10 DEG C.
CN201811365171.9A 2018-11-16 2018-11-16 The synthetic method of C5a receptor antagonist W-54011 Pending CN109438272A (en)

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