CN111646972A - Preparation method of selective estrogen receptor degradation agent and intermediate thereof - Google Patents
Preparation method of selective estrogen receptor degradation agent and intermediate thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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Abstract
The invention relates to a method for preparing a benzothiophene-based selective estrogen receptor degradation agent (LSZ-102) and an intermediate thereof. The preparation method of LSZ-102 comprises the following steps: a. carrying out substitution reaction on the compound 1 and the compound 2 to obtain a compound 3; b. carrying out reduction reaction on the compound 3 and a reducing agent to obtain a compound 4; c. performing iodination reaction on the compound 4 and an iodinating agent to obtain a compound 5; d. the compound 5 and the compound 6 are subjected to Heck reaction to obtain an LSZ-102 intermediate compound A; e. carrying out bromination reaction on the compound A and a brominating agent to obtain a compound 7; f. carrying out dealkylation on the compound 7 to obtain a compound 8; and g, carrying out Suzuki coupling reaction on the compound 8 and the compound 9 to obtain a compound LSZ-102. The method has the advantages of low price of the starting material, short reaction route, mild reaction conditions in each step, simple and convenient operation and high yield, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of organic compound synthesis, in particular to a benzothiophene-based selective estrogen receptor degradation agent (LSZ-102) and a preparation method of an intermediate thereof.
Background
LSZ-102 is a potent, orally bioavailable Selective Estrogen Receptor Degrader (SERD), CAS: 2135600-76-7, chemical name (E) -3- (4- ((2- (2- (1, 1-difluoroethyl) -4-fluorophenyl) -6-hydroxybenzo [ b ] thiophen-3-yl) oxy) phenyl) acrylic acid. A series of benzothiophene-containing compounds, LSZ-102, and the like, exhibit oral bioavailability and clinical effects for the treatment of estrogen receptor alpha (era) positive breast cancer. The structure of LSZ-102 is shown below:
LSZ-102 compounds and methods for their preparation are disclosed in WO2014130310A1, and the synthesis of LSZ-102 is as follows:
intermediate A shown above1The catalyst is obtained by six steps of reactions including oxidation, bromination, substitution, debromination, carbonyl reduction and Heck reaction, the route is long, and the synthetic route is low in chemical atom economy through oxidation, reducition, bromination and debromination; in addition, when the carbonyl reduction reaction is carried out, a large amount of anhydrous tetrahydrofuran and a dangerous reagent DIBAL-H are used in the amplification reaction, and the chemical reaction operation is not facilitated; and the last step of Heck reaction is carried out in a microwave reactor, so that the industrial production is difficult to realize. Synthesis of intermediate compound A by using 6-methoxy benzothiophene as starting material1The yield of (D) was 32.8%.
In addition, from intermediate A1The LSZ-102 is obtained through four steps of bromination, demethylation, Suzuki and hydrolysis, partial ester hydrolysis byproducts exist in the demethylation step, the post-treatment is complex, and the atom utilization rate is low. The several reactions gave a yield of 41% of LSZ-102.
Therefore, it is urgently needed to develop a new process which has high yield, simple operation, high atom utilization rate, safe reaction and suitability for industrial production.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The object of the present invention is to provide a process for the preparation of benzothiophene based selective estrogen receptor degraders (LSZ-102) of the formula and a process for the preparation of the key intermediate compound a thereof.
The preparation method comprises the following steps:
a. carrying out substitution reaction on the compound 1 and the compound 2 to obtain a compound 3;
b. carrying out reduction reaction on the compound 3 and a reducing agent to obtain a compound 4;
c. performing iodination reaction on the compound 4 and an iodinating agent to obtain a compound 5;
d. carrying out Heck reaction on the compound 5 and the compound 6 to obtain an LSZ-102 intermediate compound A;
e. carrying out bromination reaction on the compound A and a brominating agent to obtain a compound 7;
f. carrying out dealkylation on the compound 7 to obtain a compound 8; and
g. and carrying out Suzuki coupling reaction on the compound 8 and the compound 9 to obtain a compound LSZ-102.
Wherein R is C1-C4 alkyl, and is preferably tert-butyl.
The preparation method of the invention uses 6-methoxy-benzothiophene-3-alcohol as an initiator to obtain an intermediate compound A of LSZ-102 through substitution reaction, reduction reaction, iodination and Heck reaction.
The reactions in the steps are all conventional reaction types, the reaction conditions are relatively mild, the operation is simple and convenient, the raw materials are easy to obtain, and high yield can be obtained.
In particular, in the step d, the reaction is heated by adopting an atmospheric oil bath, so that the microwave reaction in the prior art is avoided. In the method, the compound 5 is an iodide, so that the reaction activity is greatly improved compared with that of a bromide, the Heck reaction is avoided by using microwaves, the operation is simple and convenient, the safety is greatly improved, and the method is favorable for large-scale production.
Moreover, the above process allows to obtain very high yields, for example when R is tert-butyl, starting from 6-methoxy-benzothiophen-3-ol, the reaction of steps a-d above gives the intermediateBody compound A1The total yield of the product can reach 51.4 percent.
In addition, in the method for preparing the compound LSZ-102 from the intermediate compound A, the compound A is subjected to bromination, dealkylation and Suzuki coupling reaction to obtain the compound LSZ-102. The reactions in the steps are all conventional reaction types, the reaction conditions are relatively mild, the operation is simple and convenient, the raw materials are easy to obtain, and high yield can be obtained.
Particularly, in the step f, the demethylation reaction is carried out and the ester hydrolysis reaction is carried out simultaneously, so that the reaction step is shortened, the step of separating the compound 8 and the ester form is omitted, the post-treatment is simple and convenient, and the atom utilization rate is high. In the step g, the Suzuki coupling reaction can be carried out at 35-45 ℃, the reaction temperature is low, the operation is simple and convenient, and the safety is greatly improved.
Moreover, the above process allows to obtain very high yields, for example 50% of the total yield of the compound LSZ-102 prepared from intermediate a in the three reactions from steps e to g, when R is tert-butyl.
The LSZ-102 and the intermediate A thereof are prepared by the reaction, the reaction time of each step can be monitored by a conventional monitoring means, such as TLC (thin layer chromatography) to monitor the reaction degree, continuous reaction or reaction ending is selected, and whether purification or next reaction is directly carried out or not is selected according to requirements after the reaction is ended.
The conditions for carrying out the above-mentioned reactions in the respective steps can be conventional ones, but the following preferred embodiments can improve the yield of the product, increase the reaction rate, and reduce the cost.
Preferably, in step a, compound 1 and compound 2 undergo a substitution reaction in the presence of a base and an organic solvent a to give compound 3.
Preferably, the base is selected from one or more of potassium carbonate, potassium phosphate, potassium hydroxide, sodium carbonate, sodium hydrogen, cesium carbonate, potassium tert-butoxide, and potassium fluoride, more preferably from one or more of sodium hydroxide, sodium hydrogen, cesium carbonate, and potassium tert-butoxide, and still more preferably from sodium hydrogen.
Preferably, the organic solvent a is selected from one or more of ethanol, N-dimethylformamide, dimethylsulfoxide, acetonitrile, nitrogen methyl pyrrolidone, tetrahydrofuran, dioxane and N, N-dimethylacetamide, more preferably from one or more of N, N-dimethylformamide, dimethylsulfoxide and N, N-dimethylacetamide, and still more preferably is N, N-dimethylacetamide.
The reaction temperature in the step a is preferably-10-50 ℃, and more preferably 20-35 ℃. The reaction time of the step a is preferably 0.5-5 h, and more preferably 1-2 h.
In step a, the molar ratio of the compound 1 to the compound 2 to the base is preferably 1: 0.9-2): (0.9 to 2), more preferably 1: 1 (0.9 to 1.3): (0.9-1.3).
The following raw material adding sequence and reaction mode can be adopted in the step a:
dissolving the compound 1 in an organic solvent A, cooling the mixture to about 0 ℃ with ice water, adding alkali in batches, removing an ice water bath after the addition is finished, reacting for 30 minutes at about 20-35 ℃, dropwise adding the compound 2, and reacting for 1-2 hours at 20-35 ℃.
After the reaction is finished, pouring the reaction liquid into a hydrochloric acid aqueous solution, extracting by ethyl acetate, combining organic phases, washing by water and a saturated sodium chloride aqueous solution in sequence, drying by anhydrous sodium sulfate, filtering, concentrating, and carrying out column chromatography to obtain a pure compound 3.
Preferably, in step B, compound 3 and a reducing agent are subjected to a reduction reaction in the presence of an acid, water and an organic solvent B to obtain compound 4.
Preferably, the reducing agent is selected from one or more of iron powder, stannous chloride, cobalt, zinc and stannic chloride, more preferably iron powder and/or zinc, and further preferably iron powder.
Preferably, the acid is selected from one or more of formic acid, ammonium chloride and hydrochloric acid, more preferably ammonium chloride.
Preferred organic solvents B are selected from one or more of ethanol, methanol, tetrahydrofuran, dichloromethane, N-dimethylformamide, acetonitrile and dioxane, more preferably ethanol and/or methanol, more preferably ethanol.
The reaction temperature in the step b is preferably 80-100 ℃, and more preferably 85-95 ℃. The reaction time of the step b is preferably 2-5 h, and more preferably 2-3 h.
In the step b, the molar ratio of the compound 3 to the reducing agent to the acid is preferably 1: 3-8: (3-8), more preferably 1: 4-6): (4-6). The volume ratio of water to the organic solvent B is preferably 1: (3-8), more preferably 1: 4 (6).
The following raw material addition sequence and reaction mode can be adopted in the step b:
and dissolving the compound 3 in a mixed solvent of water and an organic solvent B, adding a reducing agent and an acid, heating to 85-95 ℃, and reacting for 2-3 hours.
After the reaction is finished, cooling, filtering, washing a filter cake with ethyl acetate, adding water into filtrate, stirring, layering, separating liquid, extracting a water phase with ethyl acetate, combining organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, spin-drying, and carrying out column chromatography to obtain a pure compound 4.
Preferably, in step C, compound 4 is iodinated with an iodinating agent in the presence of an oxidizing agent, an acid, water, and an organic solvent C to give compound 5.
Preferably, the iodinating agent is selected from one or more of potassium iodide, sodium iodide, N-iodosuccinimide (NIS), and diiodomethane, more preferably potassium iodide.
Preferably, the oxidizing agent is selected from one or more of sodium nitrite, nitrous oxide and potassium nitrite, more preferably sodium nitrite.
Preferably, the acid is selected from one or more of hydrochloric acid, p-toluenesulfonic acid, sulfuric acid and acetic acid, more preferably p-toluenesulfonic acid.
Preferably, the organic solvent C is selected from one or more of N, N-dimethylformamide, acetonitrile, dichloromethane, tetrahydrofuran and dioxane, more preferably acetonitrile.
The reaction temperature in the step c is preferably 10-40 ℃, and more preferably 20-30 ℃. The reaction time of the step c is preferably 16-20 h, and more preferably 16-18 h.
In step c, the molar ratio of compound 4, iodinating agent, oxidizing agent and acid is preferably 1: 1 (1 to 3): (1-5): (1-5), more preferably 1: 1.5-2.5): (2-3): (2-4). The volume ratio of water to the organic solvent C is preferably 1: (0.5 to 1), more preferably 1: 0.5 to 0.7.
The following raw material addition sequence and reaction mode can be adopted in the step c:
adding the compound 4 and acid into the organic solvent C and water, stirring at room temperature, cooling to 0-5 ℃, dropwise adding a mixed solution of an iodinating agent, an oxidizing agent and water, and reacting for 16-18 h at 20-30 ℃.
After the reaction is finished, adding water and ethyl acetate, stirring uniformly, separating liquid, extracting a water phase by using ethyl acetate, combining organic phases, washing by using saturated salt solution, drying by using anhydrous sodium sulfate, filtering, spin-drying and carrying out column chromatography to obtain a pure compound 5.
Preferably, in the step D, the compound 4 and the compound 5 are subjected to Heck reaction in the presence of a catalyst, a base and an organic solvent D to obtain an intermediate compound A of LSZ-102.
Preferably, the catalyst is selected from palladium catalysts including one or more of palladium acetate, palladium chloride, bis (cyanophenyl) palladium (II) dichloride, tetratriphenylphosphine palladium and bis (triphenylphosphine) palladium chloride, more preferably bis (triphenylphosphine) palladium chloride.
Preferably, the base is selected from one or more of potassium carbonate, tri-tert-butyl amine, triethylamine, potassium phosphate, sodium bicarbonate and potassium hydroxide, more preferably triethylamine.
Preferably, the organic solvent D is selected from one or more of N, N-dimethylformamide, dioxane, nitrogen methyl pyrrolidone and dichloromethane, more preferably N, N-dimethylformamide.
The compound 6 is selected from one of methyl acrylate, ethyl acrylate, propyl acrylate, isopropyl acrylate, butyl acrylate, sec-butyl acrylate and tert-butyl acrylate, and is more preferably tert-butyl acrylate.
The reaction temperature in the step d is preferably 70-100 ℃, and more preferably 80-90 ℃. The reaction time of the step d is preferably 3-6 h, and more preferably 4-5 h.
The reaction mode of the step d is selected from an atmospheric oil bath and/or a microwave reactor, and is preferably an atmospheric oil bath.
In the step d, the molar ratio of the compound 5 to the compound 6 to the catalyst to the base is preferably 1: 5 to 10: (0.05-0.2): (3-10), more preferably 1: 5-7): (0.05-0.1): (4-6).
The following raw material addition sequence and reaction mode can be adopted in the step d:
dissolving the compound 5 in an organic solvent D, adding the compound 6, a catalyst and alkali, protecting with inert gas, and reacting at 80-90 ℃ for 4-5 h.
And after the reaction is finished, filtering to remove inorganic salt and catalyst, adding water into the mother liquor for dilution, extracting by ethyl acetate, combining organic phases, washing by water and saturated sodium chloride, drying by anhydrous sodium sulfate, filtering, concentrating, and carrying out column chromatography separation to obtain the pure intermediate compound A of the LSZ-102.
The total yield of the selective estrogen receptor degradation agent (LSZ-102) obtained by the intermediate compound A through the steps e-g (bromine adding reaction, dealkylation reaction and Suzuki coupling reaction) can reach 50%.
Preferably, in step E, compound a and brominating agent undergo bromination reaction in the presence of organic solvent E to obtain compound 7.
Preferably, the brominating agent is selected from one or more of liquid bromine, hydrogen bromide, phosphorus tribromide, aluminum tribromide, and N-bromosuccinimide, preferably N-bromosuccinimide.
Preferably, the organic solvent E is selected from one or more of N, N-dimethylformamide, dioxane, carbon tetrachloride, tetrahydrofuran and dichloromethane, and more preferably tetrahydrofuran.
The reaction temperature in the step e is preferably 15-40 ℃, and more preferably 25-35 ℃. The reaction time of the step d is preferably 1-6 h, and more preferably 2-3 h.
In step e, the molar ratio of compound A to the brominating agent is preferably 1: 1 (1-1.5), and more preferably 1: 1 (1-1.1).
The following raw material addition sequence and reaction mode can be adopted in the step e:
dissolving the compound A in an organic solvent E, adding a brominating agent, and reacting for 2-3 h at 25-35 ℃.
After the reaction is finished, concentrating, and carrying out column chromatography separation to obtain a compound 7.
Preferably, in step F, compound 7 undergoes dealkylation in the presence of boron tribromide and organic solvent F to give compound 8.
Preferably, the boron tribromide is a solution of boron tribromide in an organic solvent G, preferably the organic solvent G is selected from one or more of heptane, hexane, and dichloromethane, more preferably dichloromethane.
Preferably, the organic solvent F is selected from one or more of heptane, hexane, and dichloromethane, more preferably dichloromethane. The organic solvent F and the organic solvent G may be the same or different.
The reaction temperature of the step f is preferably 15-40 ℃, and more preferably 25-35 ℃. The reaction time of the step f is preferably 16-24 hours, and more preferably 18-20 hours. In the step f, the mixing temperature of the compound 7 and boron tribromide is preferably-10 ℃, and more preferably-5 ℃.
In step f, the molar ratio of the compound 7 to the boron tribromide is preferably 1: 1 to 5, and more preferably 1: 2 to 3.
The following raw material adding sequence and reaction mode can be adopted in the step f:
and dissolving the compound 7 in an organic solvent F, cooling to-5 ℃ under the protection of argon, slowly dropwise adding a solution of an organic solvent G of boron tribromide, and reacting for 18-20 hours at the temperature of 25-35 ℃.
After the reaction is finished, slowly pouring the reaction liquid into saturated sodium bicarbonate water solution, extracting with methyl tertiary ether, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating, and carrying out column chromatography separation to obtain the compound 8.
Preferably, in step g, compound 8 and compound 9 undergo a Suzuki coupling reaction in the presence of a catalyst, a base, lithium bromide, a surfactant and an organic solvent H to obtain compound LSZ-102.
Preferably, the catalyst is preferably a palladium catalyst, such as one or more of tetrakis (triphenylphosphine) palladium, bis (tri-tert-butylphosphino) palladium, bis (triphenylphosphine) palladium dichloride, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, dichloro [1,1 '-bis (di-tert-butylphosphino) ferrocenepalladium (II) ], more preferably dichloro [1,1' -bis (di-tert-butylphosphino) ferrocenepalladium (II) ].
Preferably, the base is selected from one or more of potassium carbonate, sodium carbonate, potassium phosphate, cesium fluoride, and cesium carbonate, more preferably potassium phosphate.
Preferably, the surfactant is DL-alpha-tocopheryl methoxy polyethylene glycol succinic acid solution.
Preferably, the organic solvent H is selected from one or more of toluene, dioxane, dimethoxyethane, and acetone, more preferably acetone.
Preferably, the reaction temperature in the step g is preferably 30-50 ℃, and more preferably 35-45 ℃. The reaction time of the step g is preferably 2-5 h, and more preferably 3-4 h.
In step g, the molar ratio of compound 8 to compound 9 is preferably 1: 1 (1-2), more preferably 1: 1 (1-1.5). In step g, the mass ratio of the compound 8, the catalyst, the lithium bromide and the base is preferably 1: (0.02-0.15): (0.3-0.6): (1-5), more preferably 1: (0.05-0.1): (0.4-0.5): (2-3). In step g, the volume ratio of the organic solvent H to the surfactant is preferably 1: (3-10), more preferably 1: (4-6).
The step g can adopt the following raw material adding sequence and reaction mode:
under the protection of argon, dissolving the compound 9 in a surfactant and an organic solvent H, adding lithium bromide, a catalyst, alkali and a compound 8, and reacting for 3-4 hours at 35-45 ℃.
And after the reaction is finished, adding a hydrochloric acid water solution into the reaction liquid, adjusting the pH value to 2-4, extracting with 2-methyltetrahydrofuran, drying with anhydrous sodium sulfate, filtering, concentrating, and carrying out column chromatography to obtain a pure LSZ-102 product.
Compared with the prior art, the invention has the beneficial effects that:
(1) the reaction starting materials are cheap;
(2) the synthetic route is simple, the reaction conditions in each step are mild, and the operation is simple and convenient;
(3) the atom utilization rate is high, the yield is high, the total yield can reach 25.8 percent, the purification is convenient, and the efficiency is high;
(4) safe reaction and industrial production.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following detailed description, but those skilled in the art will understand that the following described examples are some, not all, of the examples of the present invention, and are only used for illustrating the present invention, and should not be construed as limiting the scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Some of the reagents and the like used in the embodiments of the present invention may be as follows:
| reagent | Raw materials supplier |
| Sodium hydrogen | Shandong Guobang pharmaceutical Co Ltd |
| Iron powder | SINOPHARM CHEMICAL REAGENT Co.,Ltd. |
| P-toluenesulfonic acid | Suzhou hong cheng science and technology limited |
| Sodium nitrite | Wentong potassium salt group Co Ltd |
| Potassium iodide | Nantong Lin chemical industry Co., Ltd |
| Bis (triphenylphosphine) palladium chloride | Xiamen research Biotechnology Co., Ltd |
Example 1
(E) -3- (4- ((6-methoxybenzo [ b ]]Thien-3-yl) oxy) phenyl) acrylic acid tert-butyl ester (intermediate A)1) Preparation of
Intermediate A of this example1The preparation method comprises the following steps:
a. 60g of compound 1 is dissolved in 1L N, N-dimethylacetamide, ice water is cooled to about 0 ℃, 14.6g of sodium hydride is slowly added in batches, after the addition is finished, an ice water bath is removed, reaction is carried out for 30min at about 30 ℃, 51.7g of compound 2 is added dropwise, and reaction is carried out for 2h at 30 ℃. The reaction solution was poured into 400mL of 1M aqueous hydrochloric acid solution, extracted 3 times with ethyl acetate, the organic phases were combined, washed 3 times with water, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to give pure compound 3(83g, 83%).
b. 65g of Compound 3 was dissolved in 240mL of a mixed solvent of water and 1.2L of ethanol, 60g of iron powder and 58.3g of ammonium chloride were added, and the mixture was heated to 90 ℃ to react for 3 hours. Cooling the reaction solution to about 30 ℃, filtering, washing a filter cake with 2L of ethyl acetate, adding 1L of water into mother liquor, stirring and layering, adding ethyl acetate into a water phase, extracting for 2 times, adding 1.2L of solvent each time, combining organic phases, washing with 1.5L of saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, draining, and carrying out column chromatography separation to obtain a pure compound 4(52.7g, 90%).
c. After suspending 10g of Compound 4 in 120mL of acetonitrile, 19g of p-toluenesulfonic acid, and 100mL of water, stirring at room temperature for 5min, cooling with ice water, dropwise adding a mixed solution of 19.2g of sodium nitrite and 5.1g of potassium iodide in 100mL of water, controlling the internal temperature to be lower than 5 ℃, after the addition, stirring at 25 ℃ for 18 h. Adding 500mL of water and 150mL of ethyl acetate into the reaction solution, stirring uniformly, then carrying out layering, adding ethyl acetate into the water phase, extracting for 2 times, combining the organic phases, washing with 200mL of saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, concentrating, and carrying out column chromatography purification to obtain a pure compound 5(12g, 85%).
d. Dissolving 65g of compound 5 in 1L N, dissolving in N-dimethylformamide, adding 121g of compound 6-1, 79.5g of triethylamine, 11g of bis (triphenylphosphine) palladium chloride under the protection of argon, heating to 80 ℃, stirring for 4h, filtering to remove inorganic salt and palladium catalyst, adding 1.5L of water into mother liquor for dilution, extracting with ethyl acetate for 3 times, 1500mL each time, combining organic phases, washing with water for three times, 2L of water each time, washing with 2.5L of saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, concentrating, and separating by column chromatography to obtain the pure LSZ-102 intermediate compound A1(53g,81％)。
Reacting the compound 1 to obtain a compound A1The total yield of (a) was 51.4%.
Conventionally separating and purifying the compound obtained in each step, and characterizing the pure product, wherein the structural characterization data are respectively as follows:
compound 3:1H NMR(CDCl3):8.20(d,J＝9.1Hz,2H),7.40 (d,J＝8.8Hz,1H),7.31(d,J＝2.0Hz,1H),7.10(d,J＝9.1 Hz,2H),6.97(dd,J＝8.8,2.0Hz,1H),6.85(s,1H),3.89(s, 3H)；ESI-MS:m/z C15H11NO4S[M+H]+calculated value is 302.0; found 302.0;
compound 5:1H NMR(CDCl3):7.64-7.58(m,2H),7.52(d,J ＝8.8Hz,1H),7.27(s,1H),6.97(dd,J＝8.8,2.2Hz,1H),6.88 -6.83(m,2H),6.55(s,1H),3.88(s,3H)；ESI-MS:m/z C15H11IO2S [M+H]+calculated value 382.9; found 382.9;
intermediate A1：1H NMR(CDCl3):7.59-7.44(m,4H),7.27-7.28(m, 1H),7.06(d,J＝8.6Hz,2H),6.97(dd,J＝8.8,2.0Hz,1H),6.64 (s,1H),6.28(d,J＝16.0Hz,1H),3.88(s,3H),1.53(s,9H)； ESI-MS:m/z C22H22O4S[M+H]+Calculated value 383.1; found 383.1.
Example 2
(E) Preparation method of (LSZ-102) -3- (4- ((2- (2- (1, 1-difluoroethyl) -4-fluorophenyl) -6-hydroxybenzo [ b ] thiophene-3-yl) oxy) phenyl) acrylic acid
The route of preparation of LSZ-102(SER degrader) of this example is shown above, and the preparation method comprises the following steps:
e. 28g of Compound A1Adding into 500mL tetrahydrofuran, adding 13.6g N-bromosuccinimide, reacting at room temperature for 3h, concentrating to remove tetrahydrofuran, and separating by column chromatography to obtain pure compound 7-1(31g, 94%).
f. Dissolving 32.9g of compound 7-1 in 350mL of dichloromethane under the protection of argon, cooling to 0 ℃, slowly and dropwise adding 156.5mL of 1M dichloromethane solution of boron tribromide, stirring at room temperature for 18h, slowly pouring the reaction solution into 1L of saturated sodium bicarbonate aqueous solution, uniformly stirring, extracting methyl tert-ether for three times, combining organic phases, washing with 1L of saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating, and carrying out column chromatography separation to obtain a pure compound 8(22.8g, 82%).
g. Under the protection of argon, 45g of compound 9 is dissolved in 820mL of DL-alpha-tocopheryl methoxy polyethylene glycol succinic acid solution and 164mL of acetone, 18g of lithium bromide, 4.1g of dichloro [1,1' -bis (di-tert-butylphosphine) ferrocene palladium (II) ], 82g of potassium phosphate and 41g of compound 8 are added to react at 40 ℃ for 4 hours, 2M hydrochloric acid aqueous solution is added to the reaction solution, the pH is adjusted to be 2-4, 2-methyltetrahydrofuran is extracted for 3 times, anhydrous sodium sulfate is dried, filtered, concentrated and separated by column chromatography, and pure LSZ-102(32.3g and 65%) is obtained.
The reaction of the initial starting compound 1 to give LSZ-102 took 7 steps in total, giving a total yield of 25.8%.
Conventionally separating and purifying the compound obtained in each step, and characterizing the pure product, wherein the structural characterization data are respectively as follows:
compound 7-1:1H NMR(CDCl3):7.53(d,J＝15.9Hz,1H),7.44 (d,J＝8.7Hz,2H),7.32(d,J＝8.8Hz,1H),7.20(d,J＝2.1 Hz,1H),6.95-6.88(m,3H),6.25(d,J＝15.9Hz,1H),3.86(s, 3H),1.52(s,9H)；ESI-MS:m/z C22H21BrO4S[M+H]+calculated value is 463.0/461.0; found 463.0/461.0;
compound 8:1H NMR(DMSO):12.33(s,1H),9.97(s,1H),7.69 (d,J＝8.8Hz,2H),7.55(d,J＝16.0Hz,1H),7.33(d,J＝2.1 Hz,1H),7.21(d,J＝8.7Hz,1H),6.95(d,J＝8.8Hz,2H),6.85 (dd,J＝8.7,2.1Hz,1H),6.42(d,J＝16.0Hz,1H)；ESI-MS: m/zC17H11BrO4S[M+H]+calculated value is 392.9/390.9; found 392.9/390.9;
compound LSZ-102:1H NMR(CD3OD):7.54-7.34(m,5H),7.25-7.21 (m,2H),7.15(m,1H),6.89-6.83(m,3H),6.36(d,J＝15.9Hz,1H), 1.92(t,J＝18.6Hz,3H)；ESI-MS:m/zC25H17F3O4S[M+H]+calculated value is 471.1; found 471.1.
Example 3
(E) -3- (4- ((6-methoxybenzo [ b ]]Thien-3-yl) oxy) phenyl) acrylic acid methyl ester (intermediate A)2) Preparation of
Intermediate A of this example2The preparation method comprises the following steps:
d. dissolving 50g of compound 5 in 1L N, adding 78.8g of compound 6-2, 65g of triethylamine, 8.5g of bis (triphenylphosphine) palladium chloride under the protection of argon, heating to 80 ℃, stirring for 4h, filtering to remove inorganic salts and palladium catalyst, adding 1.5L of water into mother liquor for dilution, extracting for 3 times by ethyl acetate, combining organic phases, washing for three times, washing by saturated sodium chloride, drying by anhydrous sodium sulfate, filtering, concentrating, and separating by column chromatography to obtain a pure LSZ-102 intermediate compound A2(37.8g,85％)。
Compound A2：ESI-MS:m/z C19H16O4S[M+H]+Calculated value 341.1; found 341.1.
Example 4
Process for the preparation of Compound 8
The preparation route of compound 8 of this example is shown above, and the preparation method comprises the following steps:
e. 35g of Compound A2Adding into 600mL tetrahydrofuran, adding 19.4g N-bromosuccinimide, reacting at room temperature for 3h, concentrating to remove tetrahydrofuran, and separating by column chromatography to obtain pure compound 7-2(39.7g, 92%).
f. Dissolving 20g of compound 7-2 in 200mL of dichloromethane under the protection of argon, cooling to 0 ℃, slowly adding 110mL of 1M boron tribromide dichloromethane solution dropwise, stirring at room temperature for 18h, slowly pouring the reaction solution into 800mL of saturated sodium bicarbonate aqueous solution, uniformly stirring, extracting with methyl tert-ether for three times, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating, and carrying out column chromatography separation to obtain a pure compound 8(14.9g, 80%).
Example 5
Preparation of 6-methoxy-benzothiophen-3-ol (Compound 1)
The preparation route of compound 1 of this example is shown above, and the preparation method comprises the following steps:
dissolving 418g of 3-methoxythiophenol in 3.2L of acetone, adding 45g of potassium iodide, 443g of potassium carbonate and argon protection, dropwise adding 492g of ethyl bromoacetate, controlling the temperature to be lower than 50 ℃, completing the addition for 1h, heating to 50 ℃ to react for 18h after the addition is finished, cooling the reaction liquid to room temperature, filtering, washing a filter cake with acetone, concentrating a mother solution to obtain a crude product, dissolving the crude product in 2L of ethyl acetate, washing for 2 times, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a crude compound II (420g), and directly using the crude compound II in the next step.
Dissolving 420g of compound II (crude product) in 1.34L of 4M sodium hydroxide aqueous solution, raising the temperature to 100 ℃ for 2 hours of reaction, cooling the reaction solution to 25 ℃, adding 2L of water to dilute the reaction solution, extracting with n-heptane for 2 times, adding ice to the water phase for cooling, slowly dropwise adding 6M hydrochloric acid aqueous solution, adjusting the pH value to 4-5, adding ethyl acetate to the water phase for extracting for 3 times, combining the organic phases, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, performing suction filtration, concentrating, spin-drying, adding 100ml of DCM and 200ml of methyl tert-ether, heating to 50 ℃, adding 1L of n-heptane, stirring for 18 hours, filtering, washing with n-heptane, and performing suction-drying to obtain a pure compound III (450g, 85%).
Adding 76g of the compound III into 200mL of thionyl chloride, heating to 75 ℃ for reaction for 1.5h, concentrating and draining to obtain a crude product of acyl chloride, adding 500mL of 1, 2-dichloroethane for dissolution, and directly carrying out the next reaction; adding 65g of aluminum trichloride into 3L of 1, 2-dichloroethane, raising the temperature to 80 ℃ under the protection of argon, dropwise adding a1, 2-dichloroethane solution of acyl chloride, and continuing the 80-degree reaction for 4 hours after 1 hour of dropwise addition. After cooling to room temperature, the reaction mixture was poured into 2L of 4M aqueous hydrochloric acid, filtered, the filter cake was washed with 1L of dichloromethane, after separation of the liquids, the aqueous phase was extracted 2 times with dichloromethane, the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain Compound 1(41g, 67%).
Conventionally separating and purifying the compound obtained in each step, and characterizing the pure product, wherein the structural characterization data are respectively as follows:
compound III:1H NMR(CDCl3):7.22(t,J＝8.0Hz,1H),6.99 -6.94(m,1H),6.78(dd,J＝8.3,2.2Hz,1H),6.09(s,1H),3.79 (s,2H),3.77(s,3H)；ESI-MS:m/z C9H10O3S[M+H]+calculated value is 199.0; found 199.0;
compound 1:1H NMR(CDCl3):7.70(d,J＝8.6Hz,1H),6.86 (d,J＝2.1Hz,1H),6.76(dd,J＝8.6,2.1Hz,1H),3.89(s, 3H),3.79(s,2H)；ESI-MS:m/z C9H8O2S[M+H]+calculated value is 181.0; measured value: 181.0.
example 6
Preparation of (1, 1-difluoroethyl) -4-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan cyclopentane (Compound 9)
The preparation route of compound 9 of this example is as shown above, and the preparation method comprises the following steps:
adding 100g of 2 '-bromo-5' -fluoroacetophenone into a dry three-neck flask, protecting with argon, adding 196g of bis (2-methoxyethyl) aminosulfur trifluoride, dropwise adding 2mL of ultra-dry methanol, ventilating, heating to 70 ℃, reacting for 18h, cooling the reaction solution to 20 ℃, slowly dropwise adding the reaction solution into an ice saturated sodium carbonate aqueous solution (1L), stirring until no bubbles are released, extracting with petroleum ether (500mL of 3), combining organic phases, washing with 1L of saturated saline solution, drying with anhydrous sodium sulfate, performing suction filtration, concentrating, spin-drying, and performing column chromatography to obtain a crude compound IV (65g, Purity: 90%), and directly using the crude compound IV in the next reaction.
Placing 50g of compound IV (crude product) into a dry reaction bottle, adding 79.6g of pinacol borate, 51.3g of potassium acetate, 14.7g of triphenylphosphine palladium chloride and 200mL of dioxane, keeping under the protection of argon, heating to 80 ℃, reacting for 18 hours, cooling to room temperature, filtering, eluting with PE (EA) ═ 400:1 (2L), concentrating mother liquor, and purifying by column chromatography to obtain a pure compound 9(40g, 75%).
And (3) characterizing the compound obtained in each step, wherein the structural characterization data are respectively as follows:
compound IV:1H NMR(CDCl3):7.56(dd,J＝8.8,5.2Hz,1H),7.32 (dd,J＝9.4,3.1Hz,1H),6.96(td,J＝8.3,3.0Hz,1H),2.02(t, J＝18.4Hz,3H)；ESI-MS:m/z C14H20O4[M+H]+calculated as 238.9/240.9; measured value: 238.9/240.9;
compound 9:1H NMR(CDCl3):7.55-7.50(m,1H),7.13(dd,J＝10.0, 2.4Hz,1H),7.00(td,J＝8.3,2.4Hz,1H),1.94(t,J＝18.3Hz, 3H),1.28(s,12H)；ESI-MS:m/z C14H18BF3O2[M+H]+calculated value 287.1; measured value: 287.1.
the intermediate has the advantages of simple synthetic route, mild reaction conditions in each step, simple and convenient operation, high yield, direct next-step reaction of the crude product obtained in part of the steps, and high production efficiency.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (15)
1. A process for preparing a compound of formula a, comprising the steps of:
a. carrying out substitution reaction on the compound 1 and the compound 2 under the action of alkali and an organic solvent to obtain a compound 3,
b. carrying out reduction reaction on the compound 3 and a reducing agent to obtain a compound 4;
c. performing iodination reaction on the compound 4 and an iodinating agent to obtain a compound 5; and
d. the compound 5 and the compound 6 are subjected to Heck reaction under the action of a catalyst, alkali and an organic solvent to obtain a compound A,
wherein R is C1-C4 alkyl.
2. The method of claim 1, wherein R is tert-butyl.
3. The process according to claim 1 or 2, wherein in step a, the base is selected from one or more of potassium carbonate, potassium phosphate, potassium hydroxide, sodium carbonate, sodium hydride, cesium carbonate, potassium tert-butoxide and potassium fluoride, preferably from one or more of sodium hydroxide, sodium hydride, cesium carbonate and potassium tert-butoxide, more preferably sodium hydride; the organic solvent is selected from one or more of ethanol, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, N-methylpyrrolidone, tetrahydrofuran, dioxane and N, N-dimethylacetamide, preferably selected from one or more of N, N-dimethylformamide, dimethyl sulfoxide and N, N-dimethylacetamide, and more preferably is N, N-dimethylacetamide.
4. The process according to claim 1 or 2, wherein in step b, compound 3 is subjected to a reduction reaction with a reducing agent in the presence of an acid, water and an organic solvent to give compound 4.
5. The method according to claim 4, wherein in step b, the reducing agent is selected from one or more of iron powder, stannous chloride, cobalt, zinc and stannic chloride, preferably iron powder and/or zinc, more preferably iron powder; the acid is selected from one or more of formic acid, ammonium chloride and hydrochloric acid, and is preferably ammonium chloride; the organic solvent is selected from one or more of ethanol, methanol, tetrahydrofuran, dichloromethane, N-dimethylformamide, acetonitrile and dioxane, preferably ethanol and/or methanol, and more preferably ethanol.
6. The method of claim 1 or 2, wherein in step c, compound 4 is iodinated with an iodinating agent in the presence of an oxidizing agent, an acid, water, and an organic solvent to give compound 5.
7. The method of claim 6, wherein in step c, the iodinating agent is selected from one or more of potassium iodide, sodium iodide, N-iodosuccinimide, and diiodomethane, preferably potassium iodide; the oxidant is selected from one or more of sodium nitrite, nitrous oxide and potassium nitrite, and is preferably sodium nitrite; the acid is selected from one or more of hydrochloric acid, p-toluenesulfonic acid, sulfuric acid and acetic acid, and is preferably p-toluenesulfonic acid; the organic solvent is selected from one or more of N, N-dimethylformamide, acetonitrile, dichloromethane, tetrahydrofuran and dioxane, and is preferably acetonitrile.
8. A process according to claim 1 or 2, wherein in step d, the catalyst is a palladium catalyst selected from one or more of palladium acetate, palladium chloride, bis (cyanophenyl) palladium (II) dichloride, tetratriphenylphosphine palladium and bis (triphenylphosphine) palladium chloride, more preferably bis (triphenylphosphine) palladium chloride; the base is selected from one or more of potassium carbonate, tri-tert-butyl amine, triethylamine, potassium phosphate, sodium bicarbonate and potassium hydroxide, and is more preferably triethylamine; the organic solvent is selected from one or more of N, N-dimethylformamide, dioxane, nitrogen methyl pyrrolidone and dichloromethane, and is more preferably N, N-dimethylformamide.
9. A process for the preparation of compound LSZ-102, characterized in that it comprises the synthesis of intermediate compound a according to the process of any one of claims 1 to 8, further comprising the steps of:
e. carrying out bromination reaction on the compound A and a brominating agent to obtain a compound 7;
f. carrying out dealkylation on the compound 7 to obtain a compound 8; and
g. and carrying out Suzuki coupling reaction on the compound 8 and the compound 9 to obtain a compound LSZ-102.
10. The process according to claim 9, wherein in step e, the brominating agent is selected from one or more of liquid bromine, hydrogen bromide, phosphorus tribromide, aluminum tribromide, and N-bromosuccinimide, preferably N-bromosuccinimide.
11. The method of claim 9, wherein in step f, demethylation is performed simultaneously with ester hydrolysis.
12. The method of claim 9, wherein in step g, compound 8 and compound 9 are subjected to Suzuki coupling reaction in the presence of a catalyst, a base, lithium bromide, a surfactant, and an organic solvent H to obtain compound LSZ-102.
13. A compound of the formula 5, wherein,
14. a compound of the formula 4, wherein,
15. a compound represented by the formula 3, wherein,
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| GEORGE S. TRIA ET AL.: "Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer", 《J. MED. CHEM.》 * |
| IAN G. C. COUTTS ET AL.: "Spirodienones. Part 5. The Synthesis and Reactions of N-Sulphonylcyclohexadienimines", 《J. CHEM. SOC. PERKIN TRANS. I》 * |
| 刘庆俭: "《有机化学（下册）》", 30 November 2018, 同济大学出版社 * |
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