Preparation method of ilastrant intermediate

Abstract

The invention provides a preparation method of an ilastrant intermediate compound F. The preparation method comprises the following steps: in the presence of a catalyst, removing benzyl from a compound E, and reducing nitryl into amido to prepare the key intermediate compound F of the ilastrant. The preparation method provided by the invention has the advantages of easily available raw materials, mild reaction conditions, shorter synthetic route compared with the prior art, high synthetic efficiency, no use of hazardous chemical substances and expensive reagents, less catalyst dosage, simple operation, safety and low cost, and is suitable for large-scale production of # imgabs0 #, and is suitable for large-scale production of # imgabs0 #.

Description

Technical Field

[0001] The present invention relates to the field of chemical synthesis, and in particular to a method for preparing an elastostrat intermediate. Background Art

[0002] Elacestrant hydrochloride (English name: Elacestrant dihydrochloride) is an oral selective estrogen receptor degrader (SERD) developed by Radius, CAS: 1349723-93-8, molecular weight 531.56, pure product is a white powder solid, easily soluble in organic solvents such as methanol. On October 20, 2021, Menarini / Radius jointly announced that Elacestrant had achieved positive results for patients with ER+ / HER2- advanced or metastatic breast cancer. On January 27, 2023, the FDA approved it for the treatment of postmenopausal women or adult men with advanced or metastatic breast cancer with ER+\HER2-\ERS1 mutations. Its structural formula is as follows:

[0003]

[0004] 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydro-2-naphthol is an important intermediate in the synthesis of elastomeric. Its CAS number is 722520-36-7 and its molecular formula is C 17 H 19 NO 2 , molecular weight is 269.34, structural formula is as follows:

[0005]

[0006] At present, the synthesis of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydro-2-naphthol is disclosed in patent WO2004058682A1, and the route is as follows:

[0007]

[0008] The technical problems of this route are: the starting material needs to be synthesized through five steps of reaction, including α-carbonyl bromination, carbonyl reduction, dehydration, palladium / ketone-catalyzed Ullmann coupling and nitro reduction deprotection. The synthetic route is long and the synthetic efficiency is low. In particular, the use of hazardous liquid bromine during the reaction increases the difficulty of operation and poses a safety hazard to production. In addition, the key synthetic step, the Ullmann reaction, requires the simultaneous use of palladium and copper catalysis, a large amount of metal is used, and the reaction conditions are severe (requiring a high temperature of 120°C for reaction). This greatly limits the large-scale production of this intermediate.

[0009] Another route for synthesizing 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydro-2-naphthol disclosed in patent CN 113348163 A is as follows:

[0010]

[0011] The technical problem of this route is that it also needs to go through three steps of α-carbonyl bromination, carbonyl reduction, and dehydration to convert into the important synthetic intermediate 7-(benzyloxy)-3-bromo-1,2-dihydronaphthalene, and the synthetic route is relatively long. 2 (PPh 3 ) 2 After coupling with diboron pinacol ester to form alkenyl borate ester under the catalysis of, Suzuki coupling reaction with N-(2-bromo-5-methoxyphenyl) acetamide is carried out, followed by hydrogenation and hydrolysis to obtain 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydro-2-naphthol. This coupling requires the use of diboron pinacol ester which is relatively expensive, and the synthetic route is long, which increases the cost. Summary of the invention

[0012] In view of the technical problems existing in the prior art, the purpose of the present invention is to provide an improved preparation method of elastostrat intermediates. The preparation method of the present invention has readily available raw materials, mild reaction conditions, a shorter synthesis route than the prior art, high synthesis efficiency, no use of hazardous chemicals and expensive reagents, a small amount of catalyst, simple and safe operation, low cost, and is suitable for large-scale production.

[0013] The purpose of the present invention is achieved through the following technical solutions:

[0014] A method for preparing an elastomeric intermediate compound D comprises the following steps:

[0015]

[0016] In the presence of a metal catalyst, a ligand and a phenol additive, compound B and compound C react to obtain compound D.

[0017] Wherein, the substituent L on the compound C is a leaving group.

[0018] According to the method for preparing the elastomeric intermediate compound D of the present invention, L is selected from F, Cl, Br, I, OTf, ONf or OTs.

[0019] According to the method for preparing the elastomeric intermediate compound D of the present invention, in this step, the metal catalyst is used to catalyze the arylation reaction of the α-position of the ketone, the ligand is used to stabilize the metal catalyst and accelerate the reaction rate, and the phenol additive is used to promote the reaction process;

[0020] The metal catalyst is selected from Pd 2 (dba) 3 ·CHCl 3 , Pd 2 (dba) 3 、Pd(dba) 2 , PdCl 2 、Pd(OAc) 2 、Pd(TFA) 2 , or Pd(PCy 3 ) 2 , preferably Pd 2 (dba) 3 ·CHCl 3 ;

[0021] The ligand is selected from 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (Davephos), 2-(dicyclohexylphosphino)biphenyl, 2,2'-bis(dicyclohexylphosphino)-1,1'-biphenyl, or 2-di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenyl, preferably 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl;

[0022] The phenol additive is selected from 2,6-dimethylphenol, phenol, 2-methylphenol, 2,6-diisopropylphenol, mesitylenetrimethoxyphenol, mesitylenetrimethylphenol, or 2-trifluoromethylphenol, preferably 2,6-dimethylphenol.

[0023] According to the method for preparing the elastomeric intermediate compound D of the present invention, in this step, the reaction solvent used is selected from one or more of benzene, toluene, xylene, DMF, 1,4-dioxane and THF.

[0024] According to the method for preparing the elastomeric intermediate compound D of the present invention, in this step, the molar ratio of the metal catalyst to the ligand is 1:1 to 1:6, preferably 1:1 to 1:4, for example, 1:1, 1:2, 1:3, or 1:4.

[0025] According to the method for preparing the elastomeric intermediate compound D of the present invention, in this step, the amount of the ligand relative to compound C is 1 mol% to 6 mol%, preferably 2 mol% to 5 mol%, for example, 2 mol%, 4 mol%, or 5 mol%.

[0026] According to the method for preparing elastomeric intermediate compound D of the present invention, in this step, the amount of the metal catalyst relative to compound C is 0.5 mol% to 2 mol%, for example, 1 mol%, 1.5 mol%, or 2 mol%.

[0027] According to the method for preparing the elastomeric intermediate compound D of the present invention, in this step, the amount of the phenol additive relative to compound C is 10 mol% to 30 mol%, for example, 10 mol%, 20 mol%, or 30 mol%.

[0028] According to the method for preparing the elastomeric intermediate compound D of the present invention, in this step, the molar ratio of compound B to compound C is 3.0:1 to 1:1, preferably 2.5:1 to 1.5:1, for example, 2.5:1, 2:1, or 1.5:1.

[0029] According to the method for preparing the elastomeric intermediate compound D of the present invention, in this step, a base is also added to the reaction, and the molar ratio of compound B to the base is 1:2 to 2:1, preferably 1:1.5 to 1.5:1, for example, 1:1, 1.2:1, or 1.4:2. Preferably, the base is selected from one or more of potassium carbonate, cesium carbonate, tripotassium phosphate, sodium hydroxide and potassium hydroxide.

[0030] According to the method for preparing the elastomeric intermediate compound D of the present invention, in this step, the molar volume ratio of compound B to the reaction solvent is: 2.5:1 to 0.5:1, preferably 2:1 to 1:1, for example, 2:1, 1.5:1, or 1:1.

[0031] According to the method for preparing the elastomeric intermediate compound D of the present invention, in this step, the reaction temperature is 50°C to 90°C, preferably 60°C to 80°C, and the reaction time is 20h to 26h, preferably 22h to 24h, for example, 22h, 23h, or 24h.

[0032] According to the method for preparing the elastomeric intermediate compound D of the present invention, compound B is prepared by the following steps:

[0033]

[0034] Compound A reacts with benzyl bromide to obtain compound B.

[0035] According to the method for preparing elastomeric intermediate compound D of the present invention, in the step of preparing compound B from compound A, the molar ratio of compound A to benzyl bromide is 1:1.5 to 1:0.8, preferably 1:1.2 to 1:1, for example, 1:1.2, 1:1.1, or 1:1.

[0036] According to the method for preparing the elastomeric intermediate compound D of the present invention, in the step of preparing compound B from compound A, the reaction solvent used is selected from one or more of acetonitrile, acetone, DMF, ethyl acetate, butanone, tetrahydrofuran and dimethyl sulfoxide.

[0037] According to the method for preparing the elastomeric intermediate compound D of the present invention, in the step of preparing compound B from compound A, the molar volume ratio (mmol / mL) of compound A to the reaction solvent is 0.30:1 to 0.12:1, preferably 0.25:1 to 0.16:1, for example, 0.25:1, 0.22:1, 0.20:1, 0.18:1, or 0.16:1.

[0038] According to the method for preparing the elastomeric intermediate compound D of the present invention, in the step of preparing compound B from compound A, the reaction temperature is 40°C to 70°C, preferably 50°C to 60°C, and the reaction time is 4h to 8h, preferably 5h to 7h, for example, 5h, 6h, or 7h.

[0039] A method for preparing an elastomeric intermediate compound E comprises the following steps:

[0040]

[0041] The compound D obtained above is subjected to a reduction reaction to obtain compound E.

[0042] According to the method for preparing the elastomeric intermediate compound E of the present invention, wherein in this step, the reducing agent used is selected from sodium borohydride / BF 3 ·Et 2 O、NaBH(OAc) 3 , Et 3 SiH / TFA, hydrazine hydrate, or sodium borohydride / AlCl 3 .

[0043] According to the method for preparing the elastomeric intermediate compound E of the present invention, in this step, the reaction solvent used is selected from one or more of tetrahydrofuran, dioxane, methanol and ethanol.

[0044] According to the method for preparing elastomeric intermediate compound E of the present invention, in this step, the molar ratio of compound D to reducing agent is 1:1 to 1:4, preferably 1:1 to 1:3, for example, 1:1, 1:2, or 1:3.

[0045] According to the method for preparing the elastomeric intermediate compound E of the present invention, in this step, the molar volume ratio of compound D to the reaction solvent is 1.5:1 to 0.5:1, for example, 1.5:1, 1:1, or 0.5:1.

[0046] According to the method for preparing the elastomeric intermediate compound E of the present invention, in this step, the reaction temperature is 40°C to 70°C, preferably 50°C to 65°C, and the reaction time is 2h to 4h, for example, 2h, 3h, or 4h.

[0047] A method for preparing an elastomeric intermediate compound F comprises the following steps:

[0048]

[0049] Compound E obtained above is subjected to reduction reaction to obtain compound F (the benzyl group of compound E is removed and the nitro group is reduced to an amine group, thereby obtaining compound F, a key intermediate of elastostat).

[0050] According to the method for preparing the elastomeric intermediate compound F of the present invention, in this step, the reduction reaction is carried out in the presence of hydrogen and a metal catalyst, wherein the metal catalyst is selected from Pd(OH) 2 / C, Pd / C, or Raney nickel; or, the reduction reaction is carried out in the presence of a metal reducing agent, wherein the metal reducing agent is selected from iron powder, lithium aluminum tetrahydride or zinc powder.

[0051] According to the method for preparing the elastomeric intermediate compound F of the present invention, in this step, the reaction solvent used is selected from one or more of ethyl acetate, isopropyl acetate, methanol, tetrahydrofuran, ethanol, and 1,4-dioxane.

[0052] According to the method for preparing the elastomeric intermediate compound F of the present invention, in this step, when the reduction reaction is carried out in the presence of hydrogen and a metal catalyst, the amount of hydrogen used is 10 to 4 times, for example, 10 times, 6 times, or 4 times, of the amount of the solvent used, by volume, and the amount of the metal catalyst used relative to compound E is 3 mol% to 10 mol%, for example, 4 mol%, 6 mol%, or 8 mol%; when the reduction reaction is carried out in the presence of a metal reducing agent, the amount of the metal reducing agent used relative to compound E is 3-5 equivalents, for example, 3 equivalents, 4 equivalents, or 5 equivalents.

[0053] According to the method for preparing the elastomeric intermediate compound F of the present invention, in this step, the molar volume ratio of compound E to the reaction solvent is 1:1 to 0.2:1, preferably 0.5:1 to 0.25:1, for example, 0.5:1, 0.4:1, 0.3:1, or 0.25:1.

[0054] According to the method for preparing the elastomeric intermediate compound F of the present invention, in this step, the reaction temperature is 15°C to 35°C, for example, 15°C, 20°C, 25°C, 30°C, or 35°C, the pressure is 1 atmosphere to 20 atmospheres, and the reaction time is 10h to 14h, for example, 10h, 11h, 12h, 13h, or 14h.

[0055] In one embodiment, the present invention provides a method for preparing an elastomeric intermediate compound F, comprising the following steps:

[0056]

[0057] Step 1: In the presence of a metal catalyst, a ligand and a phenol additive, compound B and compound C react to obtain compound D, wherein the substituent L on compound C is a leaving group;

[0058] Step 2: Compound D obtained above is subjected to reduction reaction to obtain compound E;

[0059] Step 3: Compound F is obtained by reducing the compound E obtained above.

[0060] According to the method for preparing the elastomeric intermediate compound F of the present invention, in step 1,

[0061] L is selected from F, Cl, Br, I, OTf, ONf or OTs;

[0062] The metal catalyst is used to catalyze the arylation reaction of the α-position of the ketone, the ligand is used to stabilize the metal catalyst and accelerate the reaction rate, and the phenol additive is used to promote the reaction process; the metal catalyst is selected from Pd 2 (dba) 3 ·CHCl 3 , Pd 2 (dba) 3 、Pd(dba) 2 , PdCl 2 、Pd(OAc) 2 、Pd(TFA) 2 , or Pd(PCy 3 ) 2 , preferably Pd 2 (dba) 3 ·CHCl 3 ;

[0063] The ligand is selected from 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (Davephos), 2-(dicyclohexylphosphino)biphenyl, 2,2'-bis(dicyclohexylphosphino)-1,1'-biphenyl, or 2-di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenyl, preferably 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl;

[0064] The phenol additive is selected from 2,6-dimethylphenol, phenol, 2-methylphenol, 2,6-diisopropylphenol, mesitylenetrimethoxyphenol, mesitylenetrimethylphenol, or 2-trifluoromethylphenol, preferably 2,6-dimethylphenol;

[0065] The reaction solvent used is selected from one or more of benzene, toluene, xylene, DMF, 1,4-dioxane, and THF;

[0066] The molar ratio of the metal catalyst to the ligand is 1:1 to 1:6, preferably 1:1 to 1:4, for example, 1:1, 1:2, 1:3, or 1:4;

[0067] The amount of the ligand relative to compound C is 1 mol% to 6 mol%, preferably 2 mol% to 5 mol%, for example, 2 mol%, 4 mol%, or 5 mol%;

[0068] The amount of the metal catalyst relative to compound C is 0.5 mol% to 2 mol%, for example, 1 mol%, 1.5 mol%, or 2 mol%;

[0069] The amount of the phenol additive relative to compound C is 10 mol% to 30 mol%, for example, 10 mol%, 20 mol%, or 30 mol%;

[0070] The molar ratio of compound B to compound C is 3.0:1 to 1:1, preferably 2.5:1 to 1.5:1, for example, 2.5:1, 2:1, or 1.5:1;

[0071] A base is also added during the reaction, and the molar ratio of compound B to the base is 1:2 to 2:1, preferably 1:1.5 to 1.5:1, for example, 1:1, 1.2:1, or 1.4:2; preferably, the base is selected from one or more of potassium carbonate, cesium carbonate, tripotassium phosphate, sodium hydroxide and potassium hydroxide;

[0072] The molar volume ratio of compound B to the reaction solvent is: 2.5:1 to 0.5:1, preferably 2:1 to 1:1, for example, 2:1, 1.5:1, or 1:1;

[0073] The reaction temperature is 50°C to 90°C, preferably 60°C to 80°C, and the reaction time is 20h to 26h, preferably 22h to 24h, for example, 22h, 23h, or 24h.

[0074] According to the method for preparing the elastomeric intermediate compound F of the present invention, in step 2,

[0075] The reducing agent used is selected from sodium borohydride / BF 3 ·Et 2 O、NaBH(OAc) 3 , Et 3 SiH / TFA, hydrazine hydrate, or sodium borohydride / AlCl 3 ;

[0076] The reaction solvent used is selected from one or more of tetrahydrofuran, dioxane, methanol, and ethanol;

[0077] The molar ratio of compound D to the reducing agent is 1:1 to 1:4, preferably 1:1 to 1:3, for example, 1:1, 1:2, or 1:3;

[0078] The molar volume ratio of compound D to the reaction solvent is 1.5:1 to 0.5:1, for example, 1.5:1, 1:1, or 0.5:1;

[0079] The reaction temperature is 40°C to 70°C, preferably 50°C to 65°C, and the reaction time is 2h to 4h, for example, 2h, 3h, or 4h.

[0080] According to the method for preparing the elastomeric intermediate compound F of the present invention, in step 3,

[0081] The reduction reaction is carried out in the presence of hydrogen and a metal catalyst, wherein the metal catalyst is selected from Pd(OH) 2 / C, Pd / C, or Raney nickel; or, the reduction reaction is carried out in the presence of a metal reducing agent, wherein the metal reducing agent is selected from iron powder, lithium aluminum tetrahydride or zinc powder;

[0082] The reaction solvent used is selected from one or more of ethyl acetate, isopropyl acetate, methanol, tetrahydrofuran, ethanol, and 1,4-dioxane;

[0083] When the reduction reaction is carried out in the presence of hydrogen and a metal catalyst, the amount of hydrogen used is 10 to 4 times, for example, 10 times, 6 times, or 4 times, the amount of the solvent used, by volume, and the amount of the metal catalyst used relative to compound E is 3 mol% to 10 mol%, for example, 4 mol%, 6 mol%, or 8 mol%; when the reduction reaction is carried out in the presence of a metal reducing agent, the amount of the metal reducing agent used relative to compound E is 3-5 equivalents, for example, 3 equivalents, 4 equivalents, or 5 equivalents;

[0084] The molar volume ratio of compound E to the reaction solvent is 1:1 to 0.2:1, preferably 0.5:1 to 0.25:1, for example, 0.5:1, 0.4:1, 0.3:1, or 0.25:1;

[0085] The reaction temperature is 15°C to 35°C, for example, 15°C, 20°C, 25°C, 30°C, or 35°C, the pressure is 1 atmosphere to 20 atmospheres, and the reaction time is 10h to 14h, for example, 10h, 11h, 12h, 13h, or 14h.

[0086] The present invention also provides an elastomeric intermediate compound D, whose structural formula is:

[0087]

[0088] The present invention also provides an elastomeric intermediate compound E, whose structural formula is:

[0089]

[0090] The reagents and substituents used in the present invention are explained as follows:

[0091] Tf: trifluoromethanesulfonyl

[0092] Nf:Perfluorobutylsulfonyl

[0093] Ts: p-Toluenesulfonyl

[0094] Pd 2 (dba) 3 ·CHCl 3 :Tris(dibenzylideneacetone)dipalladium-chloroform adduct Pd 2 (dba) 3 :Tris(dibenzylideneacetone)dipalladium

[0095] Pd(dba) 2 :Bis(dibenzylideneacetone)palladium

[0096] Pd(TFA) 2 :Palladium trifluoroacetate

[0097] Pd(PCy3 ) 2 :Bis(tricyclohexylphosphine)palladium

[0098] Davephos: 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl

[0099] DMF: N,N-dimethylformamide

[0100] THF: Tetrahydrofuran

[0101] E 3 SiH / TFA: triethylsilane / trifluoroacetic acid

[0102] Beneficial Effects

[0103] The preparation method of the present invention has readily available raw materials and mild reaction conditions. Compared with the prior art, the synthesis route is shorter and more efficient, no hazardous chemicals and expensive reagents are used, the amount of catalyst used is small, the operation is simple, safe and low-cost, and it is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0104] Figure 1 This is the H NMR spectrum of compound B prepared in Example 1 of the present invention.

[0105] Figure 2 This is the carbon NMR spectrum of compound B prepared in Example 1 of the present invention.

[0106] Figure 3 This is the LCMS spectrum of compound B prepared in Example 1 of the present invention.

[0107] Figure 4 This is the H NMR spectrum of compound D prepared in Example 5 of the present invention.

[0108] Figure 5 This is the carbon NMR spectrum of compound D prepared in Example 5 of the present invention.

[0109] Figure 6 This is the LCMS spectrum of compound D prepared in Example 5 of the present invention.

[0110] Figure 7 This is the H NMR spectrum of compound E prepared in Example 14 of the present invention.

[0111] Figure 8 This is the carbon NMR spectrum of compound E prepared in Example 14 of the present invention.

[0112] Fig. 9 This is the LCMS spectrum of compound E prepared in Example 14 of the present invention.

[0113] Fig.10This is the H NMR spectrum of compound F prepared in Example 18 of the present invention.

[0114] Fig.11 This is the LCMS spectrum of compound F prepared in Example 18 of the present invention. DETAILED DESCRIPTION

[0115] In the following examples, reagents and raw materials not specifically described are all commercially available.

[0116] LCMS test instrument and test conditions:

[0117] Waters liquid chromatography-mass spectrometer (model: Quattro micro API). Test conditions: direct injection of H 2 O:MeOH=10:90.

[0118] NMR test equipment and test conditions:

[0119] Nuclear magnetic resonance spectrometer, hydrogen spectrum: AVANCE III HD 400, automatic sampling.

[0120] NMR spectrometer, carbon spectrum: AVANCE III HD 400, automatic injection.

[0121] In Examples 5 to 13, "mol %" refers to the molar percentage relative to Compound C.

[0122] In Examples 14 to 17, "mol %" refers to the molar percentage relative to Compound D.

[0123] In Examples 18 to 22, "mol %" refers to the molar percentage relative to Compound E.

[0124] Example 1 Synthesis of Compound B

[0125] At room temperature, compound A16.2 g (100 mmol, 1 eq) was dissolved in CH 3 CN (600 mL), followed by K 2 CO 3 20.7 g (150 mmol, 1.5 eq), BnBr 17.1 g (100 mmol, 1 eq). After stirring evenly, the above solution was moved to a 60°C oil bath and heated for 6 hours. After the reaction was completed, the upper CH 3 CN, then add 500mL water and 300mL EA, extract and separate the layers, extract twice more with EA (2*200mL), combine the organic layers and spin dry, slurry in a mixed solvent of PE / EA (100 / 1), filter, and obtain 24.7g of compound B with a yield of 98%. The H NMR spectrum of compound B prepared in Example 1 is as follows Figure 1 As shown, the NMR carbon spectrum is as follows Figure 2 As shown, the LCMS spectrum is as Figure 3 shown.

[0126] The NMR data of compound B prepared in Example 1 are as follows:

[0127] 1 H NMR (400 MHz, CDCl 3 )δ8.02(d,J=8.7Hz,1H),7.56–7.30(m,5H),6.90(dd,J=8.7,2.5Hz,1H),6.79(d,J=2. 4Hz,1H),5.11(s,2H),2.91(t,J=6.1Hz,3H),2.74–2.56(m,3H),2.11(p,J=6.4Hz,3H).

[0128] 13 C NMR (101 MHz, CDCl 3 )δ197.3,162.8,147.1,136.3,129.7,128.8,128.3,127.6,126.6,113.8,113.7,70.1,39.0,30.2,23.4.

[0129] Example 2 Synthesis of Compound B

[0130] At room temperature, 16.2 g (100 mmol, 1 eq) of compound A was dissolved in acetone (400 mL), and K 2 CO 3 20.7g (150mmol, 1.5eq), BnBr 20.5g (120mmol, 1.2eq). After stirring evenly, the above solution was moved to a 50°C oil bath and heated for 5 hours. After the reaction was completed by TLC monitoring, the upper layer of acetone was dried by spin drying, and then 500mL of water and 300mL of EA were added. After extraction and stratification, EA (2*200mL) was used for extraction twice. The organic layers were combined and then dried by spin drying, slurried in a mixed solvent of PE / EA (100 / 1), and filtered to obtain 23.9g of compound B with a yield of 95%.

[0131] The NMR data and mass spectrometry data of compound B prepared in Example 2 are consistent with those in Example 1.

[0132] Example 3 Synthesis of Compound B

[0133] At room temperature, compound A16.2 g (100 mmol, 1 eq) was dissolved in DMF (800 mL), and then K 2 CO 320.7g (150mmol, 1.5eq), BnBr 25.6g (150mmol, 1.5eq). After stirring evenly, the above solution was moved to a 40°C oil bath and heated for 4 hours. After the reaction was completed by TLC monitoring, the upper layer of DMF was dried by spin drying, and then 500mL of water and 300mL of EA were added. After extraction and stratification, EA (2*200mL) was used for extraction twice. The organic layers were combined and then dried by spin drying, slurried in a mixed solvent of PE / EA (100 / 1), and filtered to obtain 24.4g of compound B with a yield of 97%.

[0134] The NMR data and mass spectrometry data of compound B prepared in Example 3 are consistent with those in Example 1.

[0135] Example 4 Synthesis of Compound B

[0136] At room temperature, 16.2 g (100 mmol, 1 eq) of compound A was dissolved in tetrahydrofuran (300 mL), and K 2 CO 3 20.7g (150mmol, 1.5eq), BnBr 13.7g (80mmol, 0.8eq). After stirring evenly, the above solution was moved to a 70°C oil bath and heated for 8 hours. After the reaction was completed by TLC monitoring, the upper layer of tetrahydrofuran was dried by spin drying, and then 500mL of water and 300mL of EA were added. After extraction and stratification, EA (2*200mL) was used for extraction twice. The organic layers were combined and then spin dried, slurried in a mixed solvent of PE / EA (100 / 1), and filtered to obtain 23.4g of compound B with a yield of 93%.

[0137] The NMR data and mass spectrometry data of compound B prepared in Example 4 are consistent with those in Example 1.

[0138] Example 5 Synthesis of Compound D

[0139] At room temperature, 5.0 g (20 mmol, 2 eq) of compound B, 2.3 g (10 mmol, 1 eq) of 4-bromo-3-nitroanisole, and Pd 2 (dba) 3 .CHCl 3 102mg (1mol%), Davephos 157mg (4mol%), 2,6-dimethylphenol 244mg (20mol%), K 2 CO 32.8g (20mmol, 2eq) and 10mL of xylene were mixed evenly and then ultrasonicated for 30 seconds, heated to 80°C and reacted for 24h. After the reaction, 5mL of water was added, extracted with EA (3*15mL), and the organic phases were combined and dried by column separation to obtain 3.4g of compound D with a yield of 85%. The H NMR spectrum of compound D prepared in Example 5 is shown in Figure 4 As shown, the NMR carbon spectrum is as follows Figure 5 As shown, the LCMS spectrum is as Figure 6 shown.

[0140] The NMR data of compound D obtained in Example 5 are as follows:

[0141] 1 H NMR (400 MHz, CDCl 3 )δ8.04(d,J=8.8Hz,1H),7.51(d,J=2.7Hz,1H),7.46–7.33(m,5H),7.23(d,J= 8.7Hz,1H),7.12(dd,J=8.6,2.7Hz,1H),6.92(dd,J=8.7,2.4Hz,1H),6.83(d, J=2.1Hz,1H),5.13(s,2H),4.39(dd,J=12.6,4.7Hz,1H),3.86(s,3H),3.20(d dd,J=16.8,12.3,4.8Hz,1H),3.03(dt,J=16.6,3.5Hz,1H),2.60–2.33(m,2H).

[0142] 13 C NMR (101 MHz, CDCl 3 )δ195.0,163.0,158.8,150.4,146.3,136.3,131.6,130.5,128.8,128.4,12 7.6,126.9,126.4,119.8,114.1,113.7,109.7,70.2,55.9,50.7,30.8,30.2.

[0143] Example 6 Synthesis of Compound D

[0144] At room temperature, 5.0 g (20 mmol, 2 eq) of compound B, 3.2 g (10 mmol, 1 eq) of 4-p-toluenesulfonate-3-nitroanisole (L=OTs), and Pd 2 (dba) 3 .CHCl 3102mg (1mol%), Davephos 157mg (4mol%), 2,6-dimethylphenol 244mg (20mol%), K 2 CO 3 5.5 g (40 mmol, 4 eq) and 10 mL of xylene were mixed evenly and then ultrasonicated for 30 seconds, heated to 80 ° C and reacted for 24 hours. After the reaction, 5 mL of water was added and extracted with EA (3*15 mL). The organic phases were combined and dried by column separation to obtain 2.7 g of compound D with a yield of 67%.

[0145] The NMR data and mass spectrum data of compound D prepared in Example 6 are consistent with those in Example 5.

[0146] Example 7 Synthesis of Compound D

[0147] At room temperature, 5.0 g (20 mmol, 2 eq) of compound B, 4.5 g (10 mmol, 1 eq) of 4-perfluorobutanesulfonate-3-nitroanisole (L=ONf), Pd 2 (dba) 3 .CHCl 3 102mg (1mol%), Davephos 157mg (4mol%), 2,6-dimethylphenol 244mg (20mol%), K 2 CO 3 1.4 g (10 mmol, 1 eq) and 10 mL of xylene were mixed evenly and then ultrasonicated for 30 seconds, heated to 80 ° C and reacted for 24 hours. After the reaction, 5 mL of water was added and extracted with EA (3*15 mL). The organic phases were combined and dried by column separation to obtain 2.6 g of compound D with a yield of 65%.

[0148] The NMR data and mass spectrum data of compound D prepared in Example 7 are consistent with those in Example 5.

[0149] Example 8 Synthesis of Compound D

[0150] At room temperature, 3.8 g (15 mmol, 1.5 eq) of compound B, 3.0 g (10 mmol, 1 eq) of 4-methoxy-2-nitrophenyl trifluoromethanesulfonate (L=OTf), and Pd 2 (dba) 3 137 mg (1.5 mol%), 2-(dicyclohexylphosphino)biphenyl 210 mg (6 mol%), 2,6-dimethylphenol 244 mg (20 mol%), K 2 CO 31.4 g (10 mmol, 1 eq) and 10 mL of DMF were mixed evenly and ultrasonicated for 30 seconds, heated to 80°C and reacted for 24 hours. After the reaction, 5 mL of water was added and extracted with EA (3*15 mL). The organic phases were combined and dried by column separation to obtain 2.7 g of compound D with a yield of 68%.

[0151] The NMR data and mass spectrum data of compound D prepared in Example 8 are consistent with those in Example 5.

[0152] Example 9 Synthesis of Compound D

[0153] At room temperature, compound B 7.5 g (30 mmol, 3 eq), 4-bromo-3-nitroanisole 2.3 g (10 mmol, 1 eq), PdCl 2 35 mg (2 mol%), 2,2'-bis(dicyclohexylphosphino)-1,1'-biphenyl 327 mg (6 mol%), 2,6-dimethylphenol 244 mg (20 mol%), K 2 CO 3 3.5 g (25 mmol, 2.5 eq) and 30 mL of xylene were mixed evenly and then ultrasonicated for 30 seconds, heated to 50 ° C and reacted for 26 hours. After the reaction, 5 mL of water was added, extracted with EA (3*15 mL), and the organic phases were combined and dried by column separation to obtain 2.1 g of compound D with a yield of 51%.

[0154] The NMR data and mass spectrum data of compound D prepared in Example 9 are consistent with those in Example 5.

[0155] Example 10 Synthesis of Compound D

[0156] At room temperature, 2.5 g (10 mmol, 1 eq) of compound B, 2.3 g (10 mmol, 1 eq) of 4-bromo-3-nitroanisole, and Pd 2 (dba) 3 .CHCl 3 51mg (0.5mol%), Davephos 78.5mg (2mol%), 2,6-diisopropylphenol 534mg (30mol%), K 2 CO 3 2.1 g (15 mmol, 1.5 eq) and 20 mL of xylene were mixed evenly and then ultrasonicated for 30 seconds, heated to 60°C and reacted for 20 h. After the reaction, 5 mL of water was added and extracted with EA (3*15 mL). The organic phases were combined and dried by column separation to obtain 2.7 g of compound D with a yield of 67%.

[0157] The NMR data and mass spectrum data of compound D prepared in Example 10 are consistent with those in Example 5.

[0158] Example 11 Synthesis of Compound D

[0159] At room temperature, compound B 6.3 g (25 mmol, 2.5 eq), 4-bromo-3-nitroanisole 2.3 g (10 mmol, 1 eq), Pd(TFA) were added into a dried Stark tube in sequence. 2 33mg (1mol%), Davephos 39.3mg (1mol%), mesitylene phenol 272mg (20mol%), K 2 CO 3 2.8 g (20 mmol, 2 eq) and 10 mL of xylene were mixed evenly and then ultrasonicated for 30 seconds, heated to 80 ° C and reacted for 24 hours. After the reaction, 5 mL of water was added and extracted with EA (3*15 mL). The organic phases were combined and dried by column separation to obtain 3.1 g of compound D with a yield of 77%.

[0160] The NMR data and mass spectrum data of compound D prepared in Example 11 are consistent with those in Example 5.

[0161] Example 12 Synthesis of Compound D

[0162] At room temperature, 5.0 g (20 mmol, 2 eq) of compound B, 2.3 g (10 mmol, 1 eq) of 4-bromo-3-nitroanisole, and Pd 2 (dba) 3 .CHCl 3 102 mg (1 mol%), Davephos 196.3 mg (5 mol%), 2,6-dimethylphenol 244 mg (20 mol%), K 2 CO 3 3.9 g (28.5 mmol, 2.85 eq) and 10 mL of benzene were mixed evenly and then ultrasonicated for 30 seconds, heated to 80°C and reacted for 22 h. After the reaction, 5 mL of water was added and extracted with EA (3*15 mL). The organic phases were combined and dried by column separation to obtain 2.8 g of compound D with a yield of 70%.

[0163] The NMR data and mass spectrum data of compound D prepared in Example 12 are consistent with those in Example 5.

[0164] Example 13 Synthesis of Compound D

[0165] At room temperature, 5.0 g (20 mmol, 2 eq) of compound B, 2.3 g (10 mmol, 1 eq) of 4-bromo-3-nitroanisole, and Pd 2 (dba) 3 .CHCl 3 102mg (1mol%), Davephos 157mg (4mol%), 2,6-dimethylphenol 244mg (30mol%), K 2 CO 3 2.8 g (20 mmol, 2 eq) and 10 mL of THF were mixed evenly and then ultrasonicated for 30 seconds, heated to 90°C and reacted for 24 hours. After the reaction, 5 mL of water was added and extracted with EA (3*15 mL). The organic phases were combined and dried by column separation to obtain 2.3 g of compound D with a yield of 58%.

[0166] The NMR data and mass spectrum data of compound D prepared in Example 13 are consistent with those in Example 5.

[0167] Example 14 Synthesis of Compound E

[0168] At 0°C, THF (10 mL) and NaBH were added to the dry reaction bottle in sequence. 4 0.7 g (20 mmol, 2 eq), the reaction bottle was heated to 55 ° C, and then compound D4.0 g (10 mmol, 1 eq) and BF were added dropwise to the above solution. 3 ·Et 2 O 2.8g (20mmol, 2eq) mixed solution. Then the reaction liquid temperature was raised to 65°C, and the reaction was continued for 3h. After the reaction was monitored, the reaction was quenched with water, extracted with EA, and separated by column chromatography to obtain 3.6g of compound E with a yield of 93%. The H NMR spectrum of compound E prepared in Example 14 is shown as follows Figure 7 As shown, the NMR carbon spectrum is as follows Figure 8 As shown, the LCMS spectrum is as Fig. 9 shown.

[0169] The NMR data of compound E obtained in Example 14 are as follows:

[0170] 1 H NMR (400 MHz, CDCl 3)δ7.44(d,J=7.3Hz,2H),7.41–7.30(m,4H),7.27(s,1H),7.11(dd,J=8.7,2.8Hz,1H),7.00(d,J=8.2Hz,1H),6.83–6.72(m,2H),5.05 (s,2H),3.85(s,3H),3.47–3.33(m,1H),3.04(dd,J=16.1,4.9Hz,1H),2.99–2.73(m,3H),2.07(d,J=12.9Hz,1H),1.98–1.83(m,1H).

[0171] 13 C NMR (101 MHz, CDCl 3 )δ158.0,157.1,150.4,137.4,137.2,132.5,130.0,129.0,128.7,128.6,12 8.0,127.6,119.6,114.7,113.1,108.7,70.2,55.9,36.5,35.1,30.3,30.1.

[0172] Example 15 Synthesis of Compound E

[0173] At 0°C, ethanol (20 mL) was added to the dry reaction bottle in sequence, and the reaction bottle was heated to 50°C, and then a mixed solution of 4.0 g (10 mmol, 1 eq) of compound D and 1.5 g (30 mmol, 3 eq) of hydrazine hydrate was added dropwise to the above solution. The temperature of the reaction solution was then raised to 60°C, and the reaction was continued for 4 h. After the reaction was monitored, the reaction was quenched with water, extracted with EA, and separated by column chromatography to obtain 3.5 g of compound E with a yield of 91%.

[0174] The NMR data and mass spectrometry data of compound E prepared in Example 15 are consistent with those in Example 14.

[0175] Example 16 Synthesis of Compound E

[0176] At 0°C, dioxane (10 mL) was added to a dry reaction bottle in sequence, and the reaction bottle was heated to 55°C. Compound D4.0 g (10 mmol, 1 eq) and NaBH(OAc) were then added dropwise to the above solution. 3 2.1 g (10 mmol, 1 eq) of mixed solution was prepared. The reaction liquid temperature was then raised to 70°C and the reaction was continued for 2 h. After the reaction was monitored to be complete, the reaction was quenched with water, extracted with EA, and separated by column chromatography to obtain 3.4 g of compound E with a yield of 88%.

[0177] The NMR data and mass spectrometry data of compound E prepared in Example 16 are consistent with those in Example 14.

[0178] Example 17 Synthesis of Compound E

[0179] At 0°C, tetrahydrofuran (6.7 mL) and NaBH were added to the dry reaction bottle in sequence. 4 1.4 g (40 mmol, 4 eq), the reaction flask was heated to 40 ° C, and then compound D4.0 g (10 mmol, 1 eq) and AlCl were added dropwise to the above solution. 3 6.0g (40mmol, 4eq) of mixed solution. Then the reaction liquid temperature was raised to 50°C and the reaction was continued for 2h.

[0180] After the reaction was monitored, the reaction was quenched with water, extracted with EA, and separated by column chromatography to obtain 3.3 g of compound E with a yield of 86%.

[0181] The NMR data and mass spectrometry data of compound E prepared in Example 17 are consistent with those in Example 14.

[0182] Example 18 Synthesis of Compound F

[0183] Compound E 3.9 g (10 mmol, 1 eq) was dissolved in EA (40 ml) solvent, and Pd(OH) was added. 2 / C70.2mg (5mol%), then H 2 (160cm 3 , 1 atmosphere), react at room temperature for 12 hours, filter the reaction solution with diatomaceous earth, spin dry, and recrystallize with EA to obtain 2.6 g of product F with a yield of 98%. The H NMR spectrum of compound F obtained in Example 18 is as follows Fig.10 As shown, the LCMS spectrum is as Fig.11 shown.

[0184] The NMR data of compound F obtained in Example 18 are as follows:

[0185] 1 H NMR (400MHz, DMSO) δ9.01(s,1H),6.87(t,J=7.9Hz,2H),6.51(d,J=8.0Hz,2H),6.24(d,J=2.5Hz,1H),6.12(dd,J= 8.4,2.5Hz,1H),4.91(s,2H),3.63(s,3H),2.94–2.68(m,4H),2.59–2.53(m,1H),1.94–1.83(m,1H),1.70(m,1H).

[0186] Example 19 Synthesis of Compound F

[0187] Compound E 3.9 g (10 mmol, 1 eq) was dissolved in tetrahydrofuran (20 ml) solvent, Pd / C12 1.5 mg (10 mol%) was added, and then H 2 (200cm 3 , 1 atmosphere), react at room temperature for 12 h, filter the reaction solution with diatomaceous earth, spin dry, and recrystallize with EA to obtain 2.5 g of product F with a yield of 94%.

[0188] The NMR data and mass spectrometry data of compound F prepared in Example 19 are consistent with those in Example 18.

[0189] Example 20 Synthesis of Compound F

[0190] 3.9 g (10 mmol, 1 eq) of compound E was dissolved in 1,4-dioxane (50 ml) solvent, and 2.8 g (5 equivalents, relative to the molar amount of compound E) of iron powder was added. After reacting at 35° C. for 12 h, the reaction solution was filtered with diatomaceous earth, spin-dried, and recrystallized with EA to obtain 2.2 g of compound F with a yield of 83%.

[0191] The NMR data and mass spectrometry data of compound F prepared in Example 20 are consistent with those in Example 18.

[0192] Example 21 Synthesis of Compound F

[0193] 3.9 g (10 mmol, 1 eq) of compound E was dissolved in EA (10 ml) solvent, 1.9 g (3 equivalents, relative to the molar amount of compound E) of zinc powder was added, and then reacted at 15° C. for 12 h. The reaction solution was filtered through diatomaceous earth, spin-dried, and recrystallized from EA to obtain 2.1 g of compound F with a yield of 79%.

[0194] The NMR data and mass spectrum data of compound F prepared in Example 21 are consistent with those in Example 18.

[0195] Example 22 Synthesis of Compound F

[0196] Compound E 3.9 g (10 mmol, 1 eq) was dissolved in methanol (40 ml) solvent, Raney nickel 25.7 mg (3 mol%) was added, and then H 2 (160cm 3 , 20 atmospheres), react at room temperature for 12 h, filter the reaction solution with diatomaceous earth, spin dry, and recrystallize with EA to obtain 2.5 g of compound F with a yield of 96%.

[0197] The NMR data and mass spectrometry data of compound F prepared in Example 22 are consistent with those in Example 18.

Claims

1. A method for preparing an elastomeric intermediate compound D, comprising the following steps: In the presence of a metal catalyst, a ligand and a phenol additive, compound B and compound C react to obtain compound D. Wherein, the substituent L on the compound C is a leaving group.

2. The method for preparing the elastomeric intermediate compound D according to claim 1, wherein: L is selected from F, Cl, Br, I, OTf, ONf or OTs.

3. The method for preparing the elastomeric intermediate compound D according to claim 1 or 2, wherein: In this step, The metal catalyst is selected from Pd2(dba)3·CHCl3, Pd2(dba)3, Pd(dba)2, PdCl2, Pd(OAc)2, Pd(TFA)2, or Pd(PCy3)2, preferably Pd2(dba)3·CHCl3; The ligand is selected from Davephos, 2-(dicyclohexylphosphino)biphenyl, 2,2'-bis(dicyclohexylphosphino)-1,1'-biphenyl, or 2-di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenyl, preferably 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl.

4. The method for preparing the elastomeric intermediate compound D according to claim 1 or 2, wherein: In this step, the phenol additive is selected from 2,6-dimethylphenol, phenol, 2-methylphenol, 2,6-diisopropylphenol, mesitylenetrimethoxyphenol, mesitylenetrimethylphenol, or 2-trifluoromethylphenol, preferably 2,6-dimethylphenol.

5. The method for preparing the elastomeric intermediate compound D according to claim 1 or 2, wherein: In this step, the reaction solvent used is selected from one or more of benzene, toluene, xylene, DMF, 1,4-dioxane, and THF.

6. The method for preparing the elastomeric intermediate compound D according to any one of claims 1 to 5, wherein: In this step, the molar ratio of the metal catalyst to the ligand is 1:1 to 1:6, preferably 1:1 to 1:4; Preferably, the amount of the ligand relative to compound C is 1 mol% to 6 mol%, preferably 2 mol% to 5 mol%; Preferably, the amount of the metal catalyst relative to compound C is 0.5 mol% to 2 mol%; Preferably, the amount of the phenol additive relative to compound C is 10 mol% to 30 mol%; Preferably, the molar ratio of compound B to compound C is 3.0:1 to 1:1, preferably 2.5:1 to 1.5:1; Preferably, a base is also added during the reaction, and the molar ratio of compound B to the base is 1:2 to 2:1, preferably 1:1.5 to 1.5:1; Preferably, the molar volume ratio of compound B to the reaction solvent is: 2.5:1 to 0.5:1, preferably 2:1 to 1:1; Preferably, the reaction temperature is from 50°C to 90°C, preferably from 60°C to 80°C.

7. The method for preparing the elastomeric intermediate compound D according to claim 6, wherein: In this step, the base is selected from one or more of potassium carbonate, cesium carbonate, tripotassium phosphate, sodium hydroxide and potassium hydroxide.

8. The method for preparing the elastomeric intermediate compound D according to any one of claims 1 to 7, wherein: Compound B is prepared by the following steps: Compound A reacts with benzyl bromide to obtain compound B.

9. The method for preparing the elastomeric intermediate compound D according to claim 8, wherein: In the step of preparing compound B from compound A, the molar ratio of compound A to benzyl bromide is 1:1.5 to 1:0.8, preferably 1:1.2 to 1:1; Preferably, the reaction solvent used is selected from one or more of acetonitrile, acetone, DMF, ethyl acetate, butanone, tetrahydrofuran, and dimethyl sulfoxide; Preferably, the molar volume ratio of compound A to the reaction solvent is 0.30:1 to 0.12:1, preferably 0.25:1 to 0.16:1; Preferably, the reaction temperature is 40°C to 70°C, preferably 50°C to 60°C.

10. A method for preparing an elastomeric intermediate compound E, comprising the following steps: Compound E is obtained by subjecting compound D obtained by the preparation method according to any one of claims 1 to 9 to reduction reaction.

11. The method for preparing the elastomeric intermediate compound E according to claim 10, wherein: In this step, the reducing agent used is selected from sodium borohydride / BF3·Et2O, NaBH(OAc)3, Et3SiH / TFA, hydrazine hydrate, or sodium borohydride / AlCl3; Preferably, the reaction solvent used is selected from one or more of tetrahydrofuran, dioxane, methanol, and ethanol; Preferably, the molar ratio of compound D to the reducing agent is 1:1 to 1:4, preferably 1:1 to 1:3; Preferably, the molar volume ratio of compound D to the reaction solvent is 1.5:1 to 0.5:1; Preferably, the reaction temperature is from 40°C to 70°C, preferably from 50°C to 65°C.

12. A method for preparing an elastomeric intermediate compound F, comprising the following steps: Compound F is obtained by reducing compound E obtained by the preparation method according to claim 10 or 11.

13. The method for preparing the elastomeric intermediate compound F according to claim 12, wherein: In this step, the reduction reaction is carried out in the presence of hydrogen and a metal catalyst, wherein the metal catalyst is selected from Pd(OH)2 / C, Pd / C, or Raney nickel; or, the reduction reaction is carried out in the presence of a metal reducing agent, wherein the metal reducing agent is selected from iron powder, lithium aluminum tetrahydride, or zinc powder; Preferably, the reaction solvent used is selected from one or more of ethyl acetate, isopropyl acetate, methanol, tetrahydrofuran, ethanol, and 1,4-dioxane; Preferably, when the reduction reaction is carried out in the presence of hydrogen and a metal catalyst, the amount of hydrogen used is 10 to 4 times the amount of the solvent used, and the amount of the metal catalyst used relative to compound E is 3 mol% to 10 mol%; when the reduction reaction is carried out in the presence of a metal reducing agent, the amount of the metal reducing agent used relative to compound E is 3-5 equivalents; Preferably, the molar volume ratio of compound E to the reaction solvent is 1:1 to 0.2:1, preferably 0.5:1 to 0.25:1; Preferably, the reaction temperature is from 15°C to 35°C, and the pressure is from 1 atmosphere to 20 atmospheres.

Images