CN114456181A - Preparation method of luccotinib - Google Patents

Preparation method of luccotinib Download PDF

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Publication number
CN114456181A
CN114456181A CN202210157540.5A CN202210157540A CN114456181A CN 114456181 A CN114456181 A CN 114456181A CN 202210157540 A CN202210157540 A CN 202210157540A CN 114456181 A CN114456181 A CN 114456181A
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luccotinib
reaction
sulfonyl chloride
preparing
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陈洪斌
成碟
林义
颜剑波
郑志华
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Zhejiang Lepu Pharmaceutical Co ltd
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Zhejiang Lepu Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention discloses a preparation method of luccotinib. The preparation method takes cyclopentyl acrylonitrile as a starting material, and the rucotinib can be obtained through reaction in a plurality of steps, wherein the structural formula of the rucotinib is shown as a formula I. The invention has the advantages of simple process, low production cost, easy commercial production and the like.

Description

Preparation method of luccotinib
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of luccotinib.
Background
The lucocotinib (Ruxolitinib) is a selective JAK1/JAK2 tyrosine kinase inhibitor developed by Incyte and Novartis in a cooperative way, is approved as the first medicament for treating myelofibrosis by the US FDA in 11 months 2011, and is indicated as intermediate or high-risk myelofibrosis, including primary myelofibrosis, secondary erythrocytosis myelofibrosis and primary thrombocytosis myelofibrosis, and is commercially known as Jakafi. Lucotinib is currently marketed in more than 50 countries and regions, with a global sales of $ 32.76 billion in 2020, and the 36 th highest on-market worldwide drug.
The chemical name of the luccotinib is (R) -3- (4- (7H-pyrrolo [2,3[2,3-d ] pyrimidin-4-yl ] -1H-pyrazol-1-yl) -3-cyclopentylpropanenitrile, and the chemical structure of the luccotinib is shown as follows:
Figure BDA0003513389280000011
currently, there are several main synthetic routes for luccotinib:
patent WO2007070514a1 reports a route to the synthesis of luccotinib starting from cyclopentyl formaldehyde and diethyl cyanomethylphosphonate. The route is a patent of the Lucotinib compound, but as the key intermediate (R) -2 needs to be prepared by a chiral preparation column, the efficiency is low, the atom economy is poor, the comprehensive cost is high, and the actual application value is low. The reaction route is as follows:
Figure BDA0003513389280000021
patent WO2010083283A2 simultaneously reports a chemical resolution of D- (+) -dibenzoyltartaric acid, asymmetric hydrogenation under the action of a chiral metal catalyst and a chiral small molecule catalyzed asymmetric synthesis route of the luccotinib. Wherein, the chemical resolution and repeated recrystallization are carried out, and the yield is low; the starting materials for asymmetric hydrogenation are not easy to prepare, and the chiral catalyst is difficult to prepare; the chiral small molecular catalyst is a non-commercial product, the preparation cost is high, and the stereoselectivity of the reaction is not high.
Patent CN108699063B reports a route for synthesizing lucentitinib by taking cyclopentyl-formaldehyde as a starting material. One of the key steps of the reaction is the resolution of the racemic compound (rac) -5 into the chiral fragment (R) -5 by tartaric acid. In general, the synthesis route is long, reaction conditions of some steps are harsh, and the comprehensive cost is high. The reaction route is as follows:
Figure BDA0003513389280000031
in summary, currently, the synthesis of luckentinib is still complex and tedious, and the cost is high. Therefore, the field still needs to develop a synthetic route of the luccotinib, which is simple in route, low in cost and suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of the luccotinib, which has simple steps, simple and reliable process and easy industrial production.
The invention comprises the following steps:
1) reacting the compound II (cyclopentyl acrylonitrile) with a compound III (borafenanol ester) under the action of a chiral catalyst to obtain an intermediate IV; the intermediate IV generates a compound V under the action of an oxidant;
2) reacting the compound V with alkyl/aryl sulfonyl chloride to obtain a sulfonate intermediate VI; reacting the sulfonate intermediate VI with a compound VII under the action of alkali to obtain a compound VIII;
3) and removing the protecting group of the compound VIII under the action of a SEM removing reagent, and recrystallizing to obtain the compound I.
The synthetic route of the invention is as follows:
Figure BDA0003513389280000041
the central metal of the chiral catalyst in the step 1) is selected from one of cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate and cuprous trifluoromethanesulfonate toluene complex; the chiral ligand of the chiral catalyst is one of (S) - (-) -1- [ (R) -2-diphenylphosphino ] ferrocenyl ethyldicyclohexyl phosphine and (S) -1- [ (S) -2- (di-tert-butylphosphino) ferrocenyl ] ethyl di (2-methylphenyl) phosphine.
Further, in the step 1), the molar ratio of the chiral catalyst to the compound II is 1: 100-1: 1000, and the reaction temperature is 0-50 ℃.
Further, the intermediate IV generated by the reaction in step 1) may be reacted with an oxidizing agent without purification, or may be first purified and then reacted with an oxidizing agent. Preferably directly with the oxidizing agent without purification.
Further, in the step 1), the oxidant is one of sodium perborate and Oxone, the molar ratio of the oxidant to the intermediate IV is 1: 1-10: 1, and the temperature of the oxidation reaction is 0-80 ℃.
The alkyl/aryl sulfonyl chloride in the step 2) is selected from one of methyl sulfonyl chloride, ethyl sulfonyl chloride, p-toluene sulfonyl chloride and p-nitrobenzene sulfonyl chloride;
further, in the step 2), the molar ratio of the sulfonyl chloride to the compound V is 1: 1-2.0: 1, and the reaction temperature is 0-80 ℃.
Further, the sulfonate intermediate VI generated in step 2) may be directly reacted with the compound VII without purification; or purified first and then reacted with compound VII. Preferably directly with compound VII without purification.
Further, in the step 2), the base is selected from one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydrogen, potassium carbonate and cesium carbonate.
Further, in the step 2), the molar ratio of the alkali to the intermediate VI is 1: 1-10: 1, and the reaction temperature is 0-80 ℃.
In the step 3), the SEM removing reagent is one of boron trifluoride diethyl etherate, lithium fluoroborate, ammonium bifluoride and the like;
further, in the step 3), the molar ratio of the SEM removing reagent to the compound VIII is 1: 1-10: 1, and the reaction temperature is 0-80 ℃.
Further, the solvent for recrystallization in the step 3) is one or more of ethyl acetate, isopropyl acetate, methyl tertiary ether, n-hexane and n-heptane.
Compared with the prior art, the invention has the following remarkable advantages:
1) the invention adopts an asymmetric catalysis mode to realize the high stereoselectivity synthesis of the compound V, and avoids the defect that the original grinding process needs chiral chromatographic column resolution or chiral resolution reagent for chemical resolution. The purity of the compound I reaches more than 99 percent, and the requirement of API production is completely met;
2) the method has mild reaction conditions, does not have dangerous process and special equipment requirements, and is suitable for commercial production;
3) compared with the prior art, the invention has low comprehensive cost and high market competitiveness.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be noted that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention, and it should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention. Although efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), some errors and deviations should be accounted for. Unless otherwise specified, temperature is in units of ° c or at ambient temperature, and pressure is at or near atmospheric pressure. The following examples are merely exemplary, and the temperature, catalyst, concentration, reactant composition, and other process conditions may be selected and adjusted within the limits of the present invention, and the following examples therefore provide one of ordinary skill in the art with a complete understanding of how to make and evaluate the present invention.
Example 1
Preparation of Compound V
0.19g of cuprous iodide, 0.60g of (S) - (-) -1- [ (R) -2-diphenylphosphine under nitrogen]Ferrocene ethyldicyclohexyl phosphonium and 0.17g potassium tert-butoxide were added to a 2L three-necked round bottom flask, followed by 800mL of methanol. After stirring for 30 minutes at room temperature, 137.5g of borano pinacol ester and 121g of cyclopentylacrylonitrile were added. Stirring at room temperature until the reaction is complete, and concentrating under reduced pressure. The intermediate IV thus obtained was dissolved in a mixed solvent of 2L of tetrahydrofuran and 2L of water, 462g of sodium perborate were added in portions, stirred at room temperature until the reaction was completed, the insoluble matter was removed by suction filtration, the filtrate was freed from tetrahydrofuran under reduced pressure, and the aqueous phase was extracted 2 times with 2L of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 122.5g of intermediate compound V in 88% yield, 98.5% purity and 98.2% ee.1HNMR(CDCl3,600MHz)δ3.77-3.64(m,1H),3.32(d,J＝5.6Hz,1H),2.62(dd,J＝16.8,4.1Hz,1H),2.50(dd,J＝16.8,6.8Hz,1H),2.02(h,J＝8.2Hz,1H)1.90-1.79(m,1H),1.77-1.51(m,5H),1.46-1.34(m,1H),1.25-1.11(m,1H)；
13CNMR(CDCl3,101MHz)δ118.35,71.56,45.53,29.09,28.68,25.61,25.43,25.28；HRMS(ESI):m/z calcd for C8H13NO[M+H]+140.1070,found:140.1067.
Example 2
Preparation of Compound V
0.13g of cuprous acetate, 0.60g of (S) - (-) -1- [ (R) -2-diphenylphosphino ] ferrocene ethyldicyclohexylphosphorus and 0.17g of potassium tert-butoxide are added under nitrogen to a 2-L three-necked round-bottomed flask, and 800mL of methanol are added. After stirring for 30 minutes at room temperature, 137.5g of borano pinacol ester and 121g of cyclopentylacrylonitrile were added. Stirring at room temperature until the reaction is complete, and concentrating under reduced pressure. The intermediate IV thus obtained was dissolved in a mixed solvent of 2L of tetrahydrofuran and 2L of water, 462g of sodium perborate were added in portions, stirred at room temperature until the reaction was completed, the insoluble matter was removed by suction filtration, the filtrate was freed from tetrahydrofuran under reduced pressure, and the aqueous phase was extracted 2 times with 2L of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 120g of intermediate compound V in 86% yield, 97% purity and 94.3% ee.
Example 3
Preparation of Compound V
0.52g of cuprous triflate toluene complex, 0.60g of (S) - (-) -1- [ (R) -2-diphenylphosphino ] ferrocene ethyldicyclohexylphosphorus and 0.17g of potassium tert-butoxide were added under nitrogen to a 2L three-neck round-bottom flask, followed by 800mL of methanol. After stirring for 30 minutes at room temperature, 137.5g of borano pinacol ester and 121g of cyclopentylacrylonitrile were added. Stirring at room temperature until the reaction is complete, and concentrating under reduced pressure. The intermediate IV thus obtained was dissolved in a mixed solvent of 2L of tetrahydrofuran and 2L of water, 462g of sodium perborate were added in portions, stirred at room temperature until the reaction was completed, the insoluble matter was removed by suction filtration, the filtrate was freed from tetrahydrofuran under reduced pressure, and the aqueous phase was extracted 2 times with 2L of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 127g of intermediate compound V in 91% yield, 97.5% purity and 97.1% ee.
Example 4
Preparation of Compound V
0.19g of cuprous acetate, 0.57g of (S) -1- [ (S) -2- (di-tert-butylphosphino) ferrocenyl ] ethylbis (2-methylphenyl) phosphine and 0.17g of potassium tert-butoxide were charged under nitrogen to a 2L three-necked round bottom flask, and 800mL of methanol were added. After stirring for 30 minutes at room temperature, 137.5g of borano ester and 121g of cyclopentylacrylonitrile were added. Stirring at room temperature until the reaction is complete, and concentrating under reduced pressure. The intermediate IV thus obtained was dissolved in a mixed solvent of 2L of tetrahydrofuran and 2L of water, 462g of sodium perborate were added in portions, stirred at room temperature until the reaction was completed, the insoluble matter was removed by suction filtration, the filtrate was freed from tetrahydrofuran under reduced pressure, and the aqueous phase was extracted 2 times with 2L of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 125g of intermediate compound V in 90% yield, 98.8% purity and 98.8% ee.
Example 5
Preparation of Compound V
0.19g of cuprous iodide, 0.57g of (S) -1- [ (S) -2- (di-tert-butylphosphino) ferrocenyl ] ethylbis (2-methylphenyl) phosphine and 0.17g of potassium tert-butoxide are charged under nitrogen to a 2L three-necked round-bottomed flask, and 800mL of methanol are added. After stirring for 30 minutes at room temperature, 137.5g of borano pinacol ester and 121g of cyclopentylacrylonitrile were added. Stirring at room temperature until the reaction is complete, and concentrating under reduced pressure. The intermediate IV thus obtained was dissolved in a mixed solvent of 4L tetrahydrofuran and 4L water, 1850g of oxone was added in portions, stirred at room temperature until the reaction was complete, the insoluble matter was removed by suction filtration, the filtrate was freed from tetrahydrofuran under reduced pressure, and the aqueous phase was extracted 2 times with 2L ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 116g of intermediate compound V in 83% yield, 98.2% purity and 98.7% ee.
Example 6
Preparation of Compound VIII
139.2 g of compound V and 122g of triethylamine are dissolved in 1L of dichloromethane, stirred in an ice bath for 20 minutes and 126 g of methanesulfonyl chloride are added dropwise. After the reaction, 200mL of water was added, the layers were separated by extraction, and the aqueous layer was extracted once more with 200mL of dichloromethane. The combined organic phase is dried by anhydrous magnesium sulfate, and concentrated and dried under reduced pressure to obtain the mesylate intermediate compound VI.
60g of 60% sodium hydride are dissolved in 1.5L of anhydrous tetrahydrofuran and 315g of compound VII are added in portions on an ice bath. After stirring for 30 minutes at room temperature, mesylate intermediate VI (dissolved in 500mL tetrahydrofuran) was added. Stirring at room temperature until the reaction is finished, slowly adding 200mL of saturated ammonium chloride for quenching, and extracting and separating liquid. The aqueous phase was extracted twice more with 1000mL ethyl acetate and the combined organic phases were dried over anhydrous magnesium sulfateAfter drying, the mixture was concentrated to dryness under reduced pressure to give 406 g of compound VIII (oil, which was subjected to the subsequent reaction without purification) in 93% yield and 98.1% HPLC purity.1HNMR(CDCl3,400MHz)δ8.83(s,1H),8.32(s,1H),8.30(s,1H),7.38(d,J＝2.4Hz,1H),6.78(d,J＝2.8Hz,1H),5.66(s,2H),4.25(td,J＝9.4,4.0Hz,1H),3.52(t,J＝8.1Hz,2H),3.12(dd,J＝11.2,5.6Hz,1H),2.95(dd,J＝11.6,2.8Hz,1H),2.65-2.55(m,1H),1.96-1.80(m,1H),1.71-1.53(m,6H),1.31-1.21(m,2H),0.90(t,J＝5.6Hz,2H),-0.07(s,9H)；
13CNMR(CDCl3,101MHz)δ152.29,151.94,150.96,140.15,130.09,128.49,121.66,116.89,114.32,100.98,72.88,66.63,64.38,44.51,30.27,30.12,25.53,24.89,23.71,17.83,-1.35；
HRMS(ESI):m/z calcd for C23H33N6OSi[M+H]+437.2480,found:437.2483.
Example 7
Preparation of Compound VIII
139.2 g of compound V and 122g of triethylamine are dissolved in 1L of dichloromethane, stirred in an ice bath for 20 minutes and 141 g of ethylsulfonyl chloride are added dropwise. After the reaction, 200mL of water was added, the layers were separated by extraction, and the aqueous layer was extracted once more with 200mL of dichloromethane. The combined organic phase is dried by anhydrous magnesium sulfate, and concentrated and dried under reduced pressure to obtain the ethanesulfonate intermediate compound VI.
84g of potassium tert-butoxide are dissolved in 1.5L of anhydrous tetrahydrofuran and 315g of compound VII are added in portions in ice bath. After stirring for 30 minutes at room temperature, the ethanesulfonate intermediate VI (dissolved in 500mL tetrahydrofuran) was added. Stirring at room temperature until the reaction is finished, slowly adding 200mL of saturated ammonium chloride for quenching, and extracting and separating liquid. The aqueous phase was extracted twice more with 1000mL ethyl acetate and the combined organic phases were dried over anhydrous magnesium sulphate and concentrated to dryness under reduced pressure to give 384 g of compound VIII (oil, which was subjected to subsequent reaction without purification) in 88% yield and 97.2% purity by HPLC.
Example 8
Preparation of Compound VIII
139.2 g of compound V and 122g of triethylamine are dissolved in 1L of dichloromethane, stirred in an ice bath for 20 minutes and 126 g of methanesulfonyl chloride are added dropwise. After the reaction, 200mL of water was added, the layers were separated by extraction, and the aqueous layer was extracted once more with 200mL of dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The resulting oil was dissolved in 2L of acetone, 489g of cesium carbonate and 315g of compound VII were added, stirred at room temperature overnight, filtered with suction, and the filtrate was concentrated to dryness to give 406 g of compound VIII (oil, which was subjected to the subsequent reaction without purification) in 93% yield and 96.7% purity by HPLC.
Example 9
Preparation of Compound VIII
139.2 g of compound V and 122g of triethylamine are dissolved in 1L of dichloromethane, stirred in an ice bath for 20 minutes and then 233 g of p-nitrobenzenesulfonyl chloride are added dropwise. After the reaction, 200mL of water was added, the layers were separated by extraction, and the aqueous layer was extracted once more with 200mL of dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The resulting oil was dissolved in 2L of acetone, 489g of cesium carbonate and 315g of compound VII were added, stirred at room temperature overnight, filtered with suction, and the filtrate was concentrated to dryness to give 372 g of compound VIII (oil, which was subjected to the subsequent reaction without purification) in 85% yield and 92.4% HPLC purity.
Example 10
Preparation of Compound I
218 g of Compound VIII are dissolved in 1.5L of acetonitrile and 142g of boron trifluoride etherate are added dropwise in an ice bath. After completion of the dropwise addition, the reaction mixture was warmed to 50 ℃ until the compound VII disappeared (TLC), and after cooling to room temperature, 20% aqueous ammonia (100mL) was added thereto and the mixture was stirred at room temperature overnight. The acetonitrile was removed under reduced pressure, the aqueous phase was extracted twice with 1L of ethyl acetate, and the combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. 300mL of ethyl acetate is added to the oily substance, 500mL of n-heptane is added after heating and refluxing for 30 minutes, the temperature is slowly reduced to room temperature, the mixture is filtered after being kept for 1 hour, and the oily substance is dried in vacuum, wherein 135 g of the compound I has the yield of 88 percent, the ee value of 99.6 percent and the HPLC purity of 99.5 percent.
1HNMR(DMSO-d6,400MHz)δ12.12(s,1H),8.79(s,1H),8.68(s,1H),8.37(s,1H),7.59(dd,1H,J＝2.3,3.5Hz),6.98(dd,1H,J＝1.4,3.4Hz),4.53(td,1H,J＝19.5,4.6Hz),3.26(dd,1H,J＝9.8,17.2Hz),3.18(dd,1H,J＝4.3,17.3Hz),2.50-2.40(m,1H),1.81-1.79(m,1H),1.60-1.59(m,1H),1.54-1.50(m,2H),1.44-1.42(m,1H),1.33-1.27(m,2H),1.21-1.18(m,1H)；
13CNMR(DMSO-d6,101MHz)δ152.13,150.89,149.87,139.27,131.05,126.79,120.49,118.19,99.82,62.53,44.35,29.12,29.09,24.97,24.35,22.54；
HRMS(ESI):m/z calcd for C17H19N6[M+H]+307.1671,found:307.1667.
Example 11
Preparation of Compound I
380g of lithium fluoroborate was added to 218 g of compound VIII in acetonitrile (2L), and the mixture was refluxed until compound VII disappeared (TLC), cooled to room temperature, and then 20% aqueous ammonia (100mL) was added thereto and stirred at room temperature overnight. The acetonitrile was removed under reduced pressure, the aqueous phase was extracted twice with 1L of ethyl acetate, and the combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. Adding 300mL of isopropyl acetate into the oily matter, heating and refluxing for 30 minutes, then adding 500mL of n-heptane, slowly cooling to room temperature, keeping the temperature for 1 hour, then performing suction filtration, and performing vacuum drying to obtain 132 g of compound I, wherein the yield is 86%, the ee value is 99.5%, and the HPLC purity is 99.4%.
Example 12
Preparation of Compound I
57g of ammonium bifluoride was added to 218 g of an acetonitrile solution (1.5L) of compound VIII, and the mixture was refluxed until compound VII disappeared (TLC), cooled to room temperature, and then 20% aqueous ammonia (100mL) was added thereto and stirred at room temperature overnight. The acetonitrile was removed under reduced pressure, the aqueous phase was extracted twice with 1L of ethyl acetate, and the combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. And adding 300mL of ethyl acetate into the oily matter, heating and refluxing for 30 minutes, then adding 500mL of n-hexane, slowly cooling to room temperature, keeping the temperature for 1 hour, then performing suction filtration, and performing vacuum drying to obtain 138 g of the compound I, wherein the yield is 90%, the ee value is 99.7%, and the HPLC purity is 99.4%.

Claims (9)

1. The preparation method of the luccotinib (compound I) is characterized by comprising the following steps of:
1) reacting the compound II with a compound III under the action of a chiral catalyst to obtain an intermediate compound IV; and (3) generating a compound V by the compound IV under the action of an oxidizing agent:
Figure FDA0003513389270000011
2) reacting the compound V with alkyl/aryl sulfonyl chloride to obtain a sulfonate intermediate VI; reacting the sulfonate intermediate VI with a compound VII under the action of a base to obtain a compound VIII:
Figure FDA0003513389270000012
3) removing a protecting group from the compound VIII under the action of a SEM removing reagent, and recrystallizing to obtain a compound I:
Figure FDA0003513389270000013
2. the process for preparing the luccotinib (compound I) as claimed in claim 1, wherein in step 1), the central metal of the chiral catalyst is selected from one of cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, cuprous trifluoromethanesulfonate toluene complex; the chiral ligand of the chiral catalyst is one of (S) - (-) -1- [ (R) -2-diphenylphosphino ] ferrocenyl ethyldicyclohexyl phosphine and (S) -1- [ (S) -2- (di-tert-butylphosphino) ferrocenyl ] ethyl di (2-methylphenyl) phosphine.
3. The preparation method of the JAK inhibitor luccotinib (compound I) as claimed in claim 1, wherein in the step 1), the molar ratio of the chiral catalyst to the compound II is 1: 100-1: 1000, and the reaction temperature is 0-50 ℃.
4. The process for the preparation of luccotinib (compound I) as claimed in claim 1, wherein in step 1), intermediate IV produced in the reaction is reacted directly with an oxidizing agent without purification; or may be purified and then reacted with an oxidizing agent.
5. The method for preparing the luccotinib (compound I) of claim 1, wherein in the step 1), the oxidizing agent is one of sodium perborate and Oxone, the molar ratio of the oxidizing agent to the compound IV is 1: 1-10: 1, and the temperature of the oxidation reaction is 0-80 ℃.
6. The process for preparing rucotinib (compound I) of claim 1, wherein in step 2), said alkyl/aryl sulfonyl chloride is selected from one of methyl sulfonyl chloride, ethyl sulfonyl chloride, p-toluene sulfonyl chloride, p-nitrobenzene sulfonyl chloride; the molar ratio of sulfonyl chloride to the compound V is 1: 1-2.0: 1, and the reaction temperature is 0-80 ℃; the sulfonic acid ester intermediate VI generated by the reaction can directly react with the compound VII without purification, or can be purified to obtain the sulfonic acid ester intermediate VI and then react with the compound VII.
7. The process for preparing iridocotinib (compound I) according to claim 1, wherein in step 2), the base is one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, potassium carbonate and cesium carbonate; the molar ratio of the alkali to the compound VI is 1: 1-10: 1, and the reaction temperature is 0-50 ℃.
8. The method for preparing the luccotinib (compound I) as claimed in claim 1, wherein in step 3), the SEM removing reagent is one of boron trifluoride diethyl etherate, lithium fluoroborate and ammonium bifluoride; the molar ratio of the SEM removal reagent to the compound VIII is 1: 1-10: 1, and the reaction temperature is 0-80 ℃.
9. The method for preparing the luccotinib (compound I) as claimed in claim 1, wherein in step 3), the solvent for recrystallization is one or more of ethyl acetate, isopropyl acetate, methyl tert-ether, n-hexane and n-heptane.
CN202210157540.5A 2022-02-21 2022-02-21 Preparation method of luccotinib Pending CN114456181A (en)

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