CN112110897B - Preparation method of deuterated crizotinib and derivative thereof - Google Patents
Preparation method of deuterated crizotinib and derivative thereof Download PDFInfo
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Abstract
The invention relates to a preparation method of deuterated crizotinib and derivatives thereof, belonging to the technical field of synthesis of medicinal compounds. The invention synthesizes 4 deuterated crizotinib with different configurations, and inspects the influence of the deuterated position and different chirality of the crizotinib on the biological activity and the drug metabolism property of the crizotinib, and the result shows that the deuterated crizotinib and the crizotinib have similar anticancer activity, have certain physicochemical property advantages compared with deuterated crizotinib raceme and the crizotinib, have good anticancer application prospect, and provide a new compound for synthesizing novel antitumor drugs. The resolution of the racemic phenethyl alcohol derivative is a key step in the synthesis of deuterated crizotinib, the ee value of the racemic phenethyl alcohol derivative directly influences the ee value of a final product, and the resolution method has the characteristics of easiness in operation, low cost and the like.
Description
This application is a divisional application of the invention patent application having application number "201410383868.4". The original application is named as deuterated crizotinib and derivatives thereof, a preparation method and application, and the application date is 2014, 08 and 06.
Technical Field
The invention relates to a preparation method of deuterated crizotinib and derivatives thereof, belonging to the technical field of synthesis of medicinal compounds.
Background
Deuterated drugs refer to replacement of a portion of the hydrogen atoms in a drug molecule with deuterium. Since deuterium is essentially the same shape and volume as hydrogen in a drug molecule, deuterated drugs generally retain the biological activity and selectivity of the original drug. Meanwhile, the carbon-deuterium bond vibrates at a lower frequency and is stronger than the carbon-hydrogen bond, and the absorption, distribution, metabolism, excretion properties and the like of the medicament can be directly influenced, so that the medicament brings good news for improving the curative effect, safety and tolerance of the medicament. The deuterated drugs have the advantages of short research time, low cost, high safety and success rate, few tested persons and the like, and have received wide attention.
The crizotinib is an oral tyrosine kinase receptor inhibitor developed by a pfeizu pharmaceutical, can effectively reduce malignant tumors of patients with advanced gene mutation type non-small cell lung cancer (NSCLC) through clinical verification, has obvious treatment effect on the patients with advanced non-small cell lung cancer, and is the most effective medicament for the lung cancer at present.
Chinese patent (application number: 201110002814.5) discloses deuterated achiral crizotinib and derivatives thereof, wherein the structural formula of the deuterated crizotinib is shown in formulas XI and XII, and R is shown in the specification3Is hydrogen or tert-butyloxycarbonyl:
however, the chiral compound with single configuration has better biological activity and drug metabolism property compared with racemate. Therefore, the synthesized deuterated crizotinib with different configurations plays a key role in improving the biological activity and the physicochemical property of deuterated crizotinib series compounds.
Disclosure of Invention
The invention aims to provide a preparation method of deuterated crizotinib and derivatives thereof.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
deuterated crizotinib and derivatives thereof have structural formulas shown as formulas I, II, III or IV:
in the formulas I, II, III or IV, R is respectively selected from H or tert-butyloxycarbonyl.
The preparation method of deuterated crizotinib and the derivative thereof comprises the following steps: dissolving a deuterated compound of the formula V and a non-deuterated compound of the formula VI with different chiralities or dissolving the non-deuterated compound of the formula V and the non-deuterated compound of the formula VI with different chiralities in N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), dioxane or triethylamine, adding sodium carbonate, potassium acetate or triethylamine, sequentially adding palladium acetate and triphenylphosphine under the protection of nitrogen, heating to 60-150 ℃, reacting for 2-24 hours, and separating to obtain a deuterated crizotinib derivative; and taking the separated deuterated crizotinib derivative, removing the protective group, and recrystallizing to obtain deuterated crizotinib.
In the formula V, R1Selected from H or D, R in formula VI2Selected from H or D.
The preparation of the deuterated or non-deuterated compounds of formula V is described in the published patent (application No.: 201110002814.5).
The preparation method of the different chiral non-deuterated or deuterated compound of the formula VI comprises the following steps:
(1) preparation of racemic phenethyl alcohol derivatives
Reacting 2, 6-dichloro-3-fluoro acetophenone with deuterated or non-deuterated reductant at room temperature to obtain the compound shown in the formula 2.
The deuterated reducing agent is deuterated lithium aluminum hydride (LiAlD)4) Deuterated sodium borohydride (NaBD)4) Deuterated sodium borohydride acetate (NaB (OAc)3D) Or deuterated sodium cyanoborohydride (NaBCND)3)。
The solvent adopted in the reaction is benzene, dichloromethane, acetonitrile, tetrahydrofuran, toluene, methanol, ethanol, dioxane or trichloromethane; ethanol is preferred.
The amount ratio of the reducing agent to the 2, 6-dichloro-3-fluoro acetophenone is (1-4) to 1; preferably 1.2: 1.
In the formula 2, R2Selected from H or D.
The compound of formula 2 is a racemate comprising a chiral molecule and its enantiomers.
(2) Resolution of racemic phenethyl alcohol derivatives
a. The compound shown in the formula 2 is reacted with phthalic anhydride under the action of alkali in a heating way to obtain a compound shown in the formula 3, wherein the reaction temperature is 80-120 ℃. The compound of formula 3 is also a racemate.
The alkali is organic amine, pyridine or pyridine derivatives, the organic amine is triethylamine and the like, and the pyridine derivatives are 4-Dimethylaminopyridine (DMAP) and the like; pyridine is preferred.
b. Salifying the compound of the formula 3 and single chiral phenethylamine or a derivative thereof in an organic solvent, and separating to obtain the compound of the single chiral formula 4.
The single chiral phenylethylamine is R-alpha-phenylethylamine or S-alpha-phenylethylamine; chiral phenethylamine derivatives such as R-alpha-amphetamine, S-alpha-amphetamine and the like.
Such as ethyl ether, t-butyl methyl ether, and the like. The compound of formula 3 and single chiral phenethylamine or derivatives thereof are salified in ether and separated to obtain the single chiral compound of formula 4 with certain purity. To further improve the purity of the single chiral compound of formula 4, the isolated single chiral compound of formula 4 may be purified (one or more times).
The mass ratio of the compound of the formula 3 to the single chiral phenethylamine or the derivative thereof is 1 (0.2-0.5); preferably 1: 0.45.
c. The compound of the single chiral formula 4 is hydrolyzed under the action of alkali to obtain the compound of the single chiral formula 5.
The alkali is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; potassium hydroxide is preferred. The ee value of the compound of formula 5 is > 99% by HPLC.
In the formula 3, 4, 5, R2Are respectively selected from H or D; in formula 4, R4Selected from alkyl with 1-10 carbon atoms.
(3) Etherification reaction
The compound of the single chiral formula 5 and 2-nitro-3-hydroxypyridine are subjected to Mitsunobu etherification reaction to obtain a compound of a formula 6 with an inverted configuration.
The solvent adopted in the etherification reaction is tetrahydrofuran.
The feeding proportion of the etherification reaction is as follows: the compound of formula 5 is triphenyl phosphine, DEAD, 3-hydroxy-2-nitropyridine, 1, (1-3) and (1-3) calculated by the amount of the substance; preferably 1:1.5:1.5: 1.1.
The reaction temperature of the etherification reaction is 0-25 ℃; preferably 0 deg.c.
In the formula 6, R2Selected from H or D.
(4) Reduction of nitro group
The compound of formula 6 (containing nitro group) is reduced with a reducing agent to give the compound of formula 7 (containing amino group).
The mass ratio of the compound of formula 6 to the reducing agent is 1 (2-20). The reducing agent is preferably iron powder.
The solvent adopted in the nitro reduction reaction is a mixture of ethanol and acetic acid, and the ethanol and the acetic acid are (1-3) in volume ratio; preferably 1: 1.5.
The reaction temperature of the nitro reduction reaction is 50-80 ℃; preferably 60 deg.c.
In the formula 7, R2Selected from H or D.
(5) Bromination reaction
The compound of formula 7 is reacted with N-bromosuccinimide to obtain the bromo-compound of formula 8.
The mass ratio of the compound of formula 7 to the N-bromosuccinimide is 1 (0.6-3).
The solvent adopted in the bromination reaction is acetonitrile, dichloromethane or tetrahydrofuran.
The reaction temperature of the bromination reaction is 0-25 ℃; preferably 0 deg.c.
In the formula 8, R2Selected from H or D.
An application of deuterated crizotinib, in particular to an application of deuterated crizotinib in preparing anti-cancer drugs.
The cancer is lung cancer. The deuterated crizotinib has similar biological activity with crizotinib, and the action targets are anaplastic lymphoma kinase ALK.
The invention has the beneficial effects that:
the invention synthesizes 4 deuterated crizotinib with different configurations, and inspects the influence of the deuterated position and different chirality of the crizotinib on the biological activity and the drug metabolism property of the crizotinib, and the result shows that the deuterated crizotinib and the crizotinib have similar anticancer activity, and simultaneously have certain physicochemical property advantages compared with deuterated crizotinib raceme and the crizotinib, so the invention has good anticancer application prospect and provides a new compound for synthesizing novel antitumor drugs.
The resolution of the racemic phenethyl alcohol derivative is a key step in the synthesis of deuterated crizotinib, the ee value of the racemic phenethyl alcohol derivative directly influences the ee value of a final product, and the resolution method has the characteristics of easiness in operation, low cost and the like.
Detailed Description
The following examples are intended to illustrate the invention in further detail, but are not to be construed as limiting the invention in any way.
Example 1
The preparation of the compound of formula V in this example is described in the patent (application No.: 201110002814.5), and the synthetic route is as follows:
formula 1 a: r1H, formula 1 b: r1＝D。
Example 2
In this example, the synthetic route of the resolution method of the intermediate chiral benzyl alcohol derivative is as follows:
compound 2 a: dissolving 10g of 2, 6-dichloro-3-fluoro acetophenone in 100ml of absolute ethanol, cooling to 0 ℃, adding 3.68g of sodium borohydride in batches, heating to 30 ℃ for reaction for 3 hours, adding 10ml of water for quenching reaction, adding 50ml of water after the system is concentrated, extracting with ethyl acetate, combining organic phases, washing the organic phases with saturated salt water, filtering and concentrating the organic phases to obtain 10g of a colorless oily compound 2 a.1H NMR(400MHz,CDCl3)：δ7.26(dd,J＝4.0Hz,8.0Hz,1H),7.03(dd,J＝8.0Hz,8.8Hz,1H),5.66-5.48(m,1H),2.91(d,J＝8.0Hz,1H),1.65(d,J＝8.0Hz,3H)。
Compound 2 b: the preparation method is characterized in that 2, 6-dichloro-3-fluoro acetophenone and sodium deuteroborohydride are used as raw materials, the operation is the same as that of the compound 2a, and the raw materials are used as the compound 2 a.1H NMR(400MHz,CDCl3)：δ7.26(dd,J＝4.0Hz,8.0Hz,1H),7.03(dd,J＝8.0Hz,8.8Hz,1H),2.92(s,1H),1.64(S,3H)。
Compound 3 a: adding 10g of the compound 2a, 7.45g of phthalic anhydride and 3.8g of pyridine into a reaction bottle, heating the system to 100 ℃, reacting for 1 hour, cooling to room temperature, then putting the system into an ice water bath, dropwise adding 2M hydrochloric acid solution, adjusting the pH to 2.5 (2-3),the system is extracted by ether, organic phases are combined and extracted and washed by saturated sodium chloride solution, the organic phases are dried and concentrated to obtain oily substances, 40ml of petroleum ether is added, stirring is carried out for 1h, and filtering is carried out to obtain 3a 14g of white solid compounds.1H NMR(400MHz,CDCl3)：δ7.95-7.89(m,1H),7.82-7.75(m,1H),7.66-7.53(m,1H),7.28(dd,J＝4.8,8.8Hz,1H),7.06-7.00(dd,J＝8.0Hz,8.8Hz,1H),6.73(q,J＝6.8Hz,1H),1.78(d,J＝7.2Hz,3H)。
Compound 3 b: compound 2b was used as a raw material, compound 3a was used as a starting material, and compound 3a was used in an amount for each raw material.
Compound 4a- (R): adding 5g of the compound 3a into 15ml of anhydrous ether, dropwise adding 0.76g R-alpha-phenylethylamine at 0 ℃, dissolving the system firstly, then precipitating a solid, heating to room temperature, stirring for 24h, filtering, washing with anhydrous ether to obtain 2.8g of a white solid (the purity is 90%), dissolving the solid into ether (15ml), slowly adding 2M hydrochloric acid (10ml), stirring for reaction for 1h, standing for liquid separation, washing with water the ether layer, drying, filtering, concentrating to obtain 2.1g of an oily substance, dissolving the oily substance into 15ml of anhydrous ether, adding 0.6g of R-alpha-phenylethylamine under stirring, stirring for 24h at room temperature, and filtering to obtain 2.3g of the compound 4a- (R).1H NMR(400MHz,DMSO-d6)：δ7.7(dd,J＝4.8Hz,8.8Hz,1H),7.55(dd,J＝4.8Hz,8.8Hz,1H),7.55-7.25(m,9H),6.40(q,J＝6.6Hz,1H),4.30(q,J＝6.6Hz,1H),1.64(d,J＝6.6Hz,3H),1.46(d,6.6Hz,3H)。
Compound 4b- (R): the compound 3b and the R-alpha-phenylethylamine are used as raw materials, and the operation and the dosage of each raw material are the same as the compound 4a- (R).
Compound 4a- (S): the compound 3a and S-alpha-phenylethylamine are used as raw materials, and the operation and the dosage of each raw material are the same as that of the compound 4a- (R).
Compound 4b- (S): the compound 3b and S-alpha-phenylethylamine are used as raw materials, and the operation and the dosage of each raw material are the same as the compound 4a- (R).
Compound 5a- (R): dissolving 2.3g of compound 4a- (R) into 20ml of diethyl ether, adding 8ml of 2M hydrochloric acid, stirring at room temperature for 1h, washing the diethyl ether layer with water, drying over anhydrous magnesium sulfate, filtering, concentrating to obtain 1.78g of oily substance, adding 8ml of 25% potassium hydroxide solution, stirring at room temperature overnight, extracting the system with diethyl ether, combining organic phases, drying and concentrating the organic phase to obtain a colorless oily substance compound 5a- (R) (needle-like solid after standing) 1.0 g.1H NMR (400MHz, CDCl 3): δ 7.26(dd, J ═ 4.0Hz,8.0Hz,1H),7.03(dd, J ═ 8.0Hz,8.8Hz,1H),5.66-5.48(m,1H),2.91(d, J ═ 8.0Hz,1H),1.65(d, J ═ 8.0Hz, 3H). HPLC detection of ee>99％。
Compound 5b- (R): the compound 4b- (R) was used as a starting material, and the operation and the amount of each starting material were the same as those of the compound 5a- (R).1H NMR (400MHz, CDCl 3): δ 7.26(dd, J ═ 4.0Hz,8.0Hz,1H),7.03(dd, J ═ 8.0Hz,8.8Hz,1H),2.92(S,1H),1.64(S, 3H). HPLC detection of ee>99％。
Compound 5a- (S): the compound 4a- (S) was used as a starting material, and the operation and the amount of each starting material were the same as those of the compound 5a- (R).1H NMR (400MHz, CDCl 3): δ 7.26(dd, J ═ 4.0Hz,8.0Hz,1H),7.03(dd, J ═ 8.0Hz,8.8Hz,1H),5.66-5.48(m,1H),2.91(d, J ═ 8.0Hz,1H),1.65(d, J ═ 8.0Hz, 3H). HPLC detection of ee>99％。
Compound 5b- (S): the compound 4b- (S) was used as a starting material, and the operation and the amount of each starting material were the same as those of the compound 5a- (R).1H NMR (400MHz, CDCl 3): δ 7.26(dd, J ═ 4.0Hz,8.0Hz,1H),7.03(dd, J ═ 8.0Hz,8.8Hz,1H),2.92(S,1H),1.64(S, 3H). HPLC detection of ee>99％。
Example 3
The preparation method of deuterated crizotinib in the embodiment has the following synthetic route:
synthesis of compounds of formula i:
compound 6a- (R): 5g of the compound 5a- (S), 3.42g of 2-nitro-3-hydroxypyridine and 9g of triphenylphosphine were dissolved in 50ml of tetrahydrofuran, and 6.2g of DEAD was added dropwise at 0 ℃ and stirred at room temperature for 3 hours after completion of the addition, and the reaction was detected by TLC to be complete. The solvent was distilled off under reduced pressure, and the residue was washed twice with 100ml of water, then 75ml of ethanol was added and subjected to sonication for 1-2 minutes, followed by standing, filtration, and the filter cake was washed with 10ml of ethanol, and the solid was collected to obtain 6.3g of a pale yellow solid 6a- (R).1H-NMR(CDCl3)：8.03(1H,dd,J1＝1.2,J2＝4.56),7.37(1H,dd,J1＝4.56,J2＝8.44),7.30(1H,dd,J1＝4.84,J2＝8.92),7.20(1H,dd,J1＝1.12,J2＝8.44),7.08(1H,dd,J1＝7.92,J2＝8.84),6.10(1H,q,J＝6.68),1.85(3H,d,J＝6.64)。
Compound 7a- (R): 6g of Compound 6a- (R) are added to 50ml of ethanol: heating to 40 ℃ in a mixed solvent of acetic acid 2:3, adding 5g of iron powder in batches, reacting at 60 ℃ for 1 hour, detecting complete reaction by TLC, cooling to room temperature, filtering, washing a filter cake with ethanol, evaporating the filtrate solvent under reduced pressure, adding 100ml of ethyl acetate and 100ml of water, separating, washing an organic phase with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, drying, and evaporating the organic solvent to obtain 5.8g of a brown product 7a- (R).1H-NMR(CDCl3)：7.60(1H,dd,J1＝1.24,J2＝5.04),7.27(1H,dd,J1＝4.84,J2＝8.88),7.04(1H,dd,J1＝8,J2＝8.76),6.69(1H,dd,J1＝0.88,J2＝7.92),6.48(1H,dd,J1＝5.08,J2＝7.84),6.01(1H,q,J＝6.68),4.80(2H,br),1.81(3H,d,J＝6.68)。
Compound 8a- (R): 5.8g of Compound 7a- (R) was dissolved in 50ml of dichloromethane, 50ml of NBS acetonitrile solution (3.42 g) was added dropwise at-5 ℃ and stirring was continued for 1 hour after completion of the addition, and the reaction was detected by TLC to be complete. The reaction solution is filtered and evaporated to dryness, 100ml of ethyl acetate is added, the organic phase is washed by 1mol/L sodium hydroxide solution and saturated saline solution respectively, and after drying and evaporation of the organic solvent, column chromatography is carried out to obtain 4.8g of light brown product 8a- (R).1H-NMR(CDCl3)：7.66(1H,d,J＝1.92),7.31(1H,dd,J1＝4.8,J2＝8.92),7.08(1H,dd,J1＝7.84,J2＝8.88),6.83(1H,d,J＝1.84),6.01(1H,q,J＝6.68),4.83(2H,br),1.81(3H,d,J＝6.68)。
Compound 9a- (R) -b 2.4g of Compound 8a- (R), 2.85g of Compound 1b, 2.67g of sodium carbonate, 28mg of Pd (OAc)2140mg dppf are respectively added into a 100ml three-necked bottle, 50ml DMF and 5ml water are added under the protection of nitrogen, the mixture is heated to 87 ℃ for reaction for 16 hours, TLC detects that the reaction is complete, the reaction solution is filtered and evaporated to dryness, 100ml ethyl acetate is added, the organic phase is respectively washed by saturated ammonium chloride solution and saturated common salt solution, and the mixture is driedAfter the organic solvent is evaporated to dryness, column chromatography is carried out to obtain a brown product solid, then 30ml of toluene and 1g of silica gel (containing 15% of cysteine) are added, the mixture is heated to 60 ℃ to react for 1 day, the mixture is cooled and filtered, a filter cake is washed by ethyl acetate, an organic phase is dried in a spinning mode, 30ml of petroleum ether is added, the mixture is heated to 60 ℃ to react for 1 hour, and the mixture is cooled and filtered to obtain 1.5g of white solid 9a- (R) -b.1H-NMR(CDCl3)：7.76(1H,d,J＝1.6),7.57(1H,s),7.48(1H,s),7.30(1H,dd,J1＝4.8,J2＝8.8),7.05(1H,dd,J1＝8,J2＝8.8),6.87(1H,d,J＝1.6),6.07(1H,q,J＝6.8),4.77(2H,br),4.35-4.15(2H,m),3.95-2.82(2H,m),2.18-2.15(2H,m),1.97-1.88(2H,m),1.86(3H,d,J＝6.4),1.48(9H,s)。
A compound of formula I: adding 10ml of absolute ethyl alcohol into a 50ml three-necked bottle, cooling to 0 ℃, slowly dripping 10.5ml of acetyl chloride under the protection of nitrogen, controlling the internal temperature at 0-5 ℃, and after dripping is finished, heating to 20 ℃ to obtain an alcoholic solution of hydrogen chloride for later use. Dissolving 5.4g of compound 9a- (R) -b into a mixed solution of 5ml of absolute ethyl alcohol and 45ml of dichloromethane, cooling to 0 ℃, slowly dripping the prepared alcoholic solution of hydrogen chloride into the system under the protection of nitrogen, controlling the internal temperature to be between 0 and 5 ℃, heating to 25 ℃ after dripping, stirring for 3 hours, separating out white solid, slowly adding 25ml of water into the system under the control of the internal temperature of 30 ℃, stirring for 30 minutes, separating an organic phase and an aqueous phase, extracting the organic phase with 10ml of water, combining the aqueous phases, extracting the aqueous phase with 25ml of ethyl acetate twice, adding 50ml of tetrahydrofuran into the aqueous phase, cooling to 15 ℃, adjusting the pH value of the system to 13 by using 40 percent sodium hydroxide solution, separating out the organic phase, extracting the aqueous phase with ethyl acetate, combining the organic phases, drying, and evaporating the organic solvent to obtain a crude product. The crude product was added to 50ml acetonitrile and evaporated to dryness, repeated three times. Then adding 20ml of acetonitrile, heating to 72 ℃, adding 9ml of water, slowly cooling to 40 ℃, stirring for 1h to separate out white solid, slowly adding 70ml of water, cooling to room temperature after dropwise addition, continuously stirring for 3h, filtering, washing with cold acetonitrile to obtain white solid TRN001043.5g with the yield of 79.5%.1H-NMR(CDCl3)：7.76(1H,d,J＝1.72),7.57(1H,s),7.50(1H,s),7.30(1H,dd,J1＝4.8,J2＝8.88),7.05(1H,dd,J1＝7.96,J2＝8.8),6.87(1H,d,J＝1.64),6.07(1H,q,J＝6.68),4.76(2H,br),3.29-3.21(2H,m),2.83-2.73(2H,m),2.20-2.13(2H,m),1.97-1.88(2H,m),1.86(3H,d,J＝6.68)。
Synthesis of compounds of formula ii:
compound 6a- (S): the compound 5a- (R) was used as a starting material, and the operation and the amount of each starting material were the same as those of the compound 6a- (R).1H-NMR(CDCl3)：8.03(1H,dd,J1＝1.2,J2＝4.56),7.37(1H,dd,J1＝4.56,J2＝8.44),7.30(1H,dd,J1＝4.84,J2＝8.92),7.20(1H,dd,J1＝1.12,J2＝8.44),7.08(1H,dd,J1＝7.92,J2＝8.84),6.10(1H,q,J＝6.68),1.85(3H,d,J＝6.64)。
Compound 7a- (S): the compound 6a- (S) was used as a starting material, and the operation and the amount of each starting material were the same as those of the compound 7a- (R).1H-NMR(CDCl3)：7.60(1H,dd,J1＝1.24,J2＝5.04),7.27(1H,dd,J1＝4.84,J2＝8.88),7.04(1H,dd,J1＝8,J2＝8.76),6.69(1H,dd,J1＝0.88,J2＝7.92),6.48(1H,dd,J1＝5.08,J2＝7.84),6.01(1H,q,J＝6.68),4.80(2H,br),1.81(3H,d,J＝6.68)。
Compound 8a- (S): the compound 7a- (S) was used as a starting material, and the operation and the amount of each starting material were the same as those of the compound 8a- (R).1H-NMR(CDCl3)：7.66(1H,d,J＝1.92),7.31(1H,dd,J1＝4.8,J2＝8.92),7.08(1H,dd,J1＝7.84,J2＝8.88),6.83(1H,d,J＝1.84),6.01(1H,q,J＝6.68),4.83(2H,br),1.81(3H,d,J＝6.68)。
The compound 9a- (S) -b is prepared from the compound 8a- (S) and the compound 1b by the same procedure and the same amount of the raw materials as the compound 9a- (R) -b.1H-NMR(CDCl3)：7.76(1H,d,J＝1.6),7.57(1H,s),7.48(1H,s),7.30(1H,dd,J1＝4.8,J2＝8.8),7.05(1H,dd,J1＝8,J2＝8.8),6.87(1H,d,J＝1.6),6.07(1H,q,J＝6.8),4.77(2H,br),4.35-4.15(2H,m),3.95-2.82(2H,m),2.18-2.15(2H,m),1.97-1.88(2H,m),1.86(3H,d,J＝6.4),1.48(9H,s)。
A compound of formula II: starting from the compound 9a- (S) -b, the procedure and the respective starting materialsThe amount of the material used was the same as that of the compound TRN-00104.1H-NMR(CDCl3)：7.76(1H,d,J＝1.72),7.57(1H,s),7.50(1H,s),7.30(1H,dd,J1＝4.8,J2＝8.88),7.05(1H,dd,J1＝7.96,J2＝8.8),6.87(1H,d,J＝1.64),6.07(1H,q,J＝6.68),4.76(2H,br),3.29-3.21(2H,m),2.83-2.73(2H,m),2.20-2.13(2H,m),1.97-1.88(2H,m),1.86(3H,d,J＝6.68)。
Synthesis of a compound of formula iii:
compound 6b- (R): the compound 5b- (S) was used as a starting material, and the operation and the amount of each starting material were the same as those of the compound 6a- (R).1H-NMR(CDCl3)：8.03(1H,dd,J1＝1.24,J2＝4.56),7.37(1H,dd,J1＝4.56,J2＝8.44),7.30(1H,dd,J1＝4.76,J2＝8.92),7.21(1H,dd,J1＝1.24,J2＝8.44),7.08(1H,dd,J1＝7.84,J2＝8.84),1.85(3H,s)。
Compound 7b- (R): the compound 6b- (R) was used as a starting material, and the operation and the amount of each starting material were the same as those of the compound 7a- (R).1H-NMR(CDCl3)：7.60(1H,dd,J1＝1.24,J2＝5.04),7.27(1H,dd,J1＝4.84,J2＝8.68),7.04(1H,dd,J1＝8,J2＝8.76),6.69(1H,dd,J1＝1.16,J2＝7.84),6.48(1H,dd,J1＝5.08,J2＝7.84),4.80(2H,br),1.81(3H,s)。
Compound 8b- (R): the compound 7b- (R) was used as a starting material, and the operation and the amount of each starting material were the same as those of the compound 8a- (R).1H-NMR(CDCl3)：7.66(1H,d,J＝1.88),7.31(1H,dd,J1＝4.84,J2＝8.92),7.08(1H,dd,J1＝8.08,J2＝8.68),6.83(1H,d,J1＝1.8),4.81(2H,br),1.81(3H,s)。
The compound 9b- (R) -a is prepared from the compound 8b- (R) and the compound 1a by the same operation and the same amount of the raw materials as the compound 9a- (R) -b.1H NMR(CDCl3):7.73(d,J＝1.68Hz,1H),7.56(s,1H),7.48(s,1H),7.30(dd,J＝4.8Hz,8.8Hz,1H),7.05(dd,J＝8.0Hz,8.8Hz,1H),6.87(d,J＝1.8Hz,1H),5.02-4.82(br,2H),4.35-4.15(m,3H),3.02-2.82(m,2H),2.18-2.13(m,2H),1.92-1.86(m,2H),1.85(s,3H),1.48(s,9H)。
A compound of formula III: the compound TRN-00104 was used as a starting material for the compound 9b- (S) -a in the same amount as used for the preparation of the starting material.1H-NMR(CDCl3)：7.76(1H,d,J＝1.72),7.57(1H,s),7.50(1H,s),7.30(1H,dd,J1＝4.8,J2＝8.88),7.05(1H,dd,J1＝8,J2＝8.76),6.87(1H,d,J＝1.72),4.77(2H,br),4.25-4.16(1H,m),3.29-3.21(2H,m),2.83-2.73(2H,m),2.20-2.13(2H,m),1.97-1.88(2H,m),1.84(3H,s)。
Synthesis of compounds of formula iv:
compound 6b- (S): the compound 5b- (R) was used as a starting material, and the operation and the amount of each starting material were the same as those of the compound 6a- (R).1H-NMR(CDCl3)：8.03(1H,dd,J1＝1.24,J2＝4.56),7.37(1H,dd,J1＝4.56,J2＝8.44),7.30(1H,dd,J1＝4.76,J2＝8.92),7.21(1H,dd,J1＝1.24,J2＝8.44),7.08(1H,dd,J1＝7.84,J2＝8.84),1.85(3H,s)。
Compound 7b- (S): the compound 6b- (S) was used as a starting material, and the operation and the amount of each starting material were the same as those of the compound 7a- (R).1H-NMR(CDCl3)：7.60(1H,dd,J1＝1.24,J2＝5.04),7.27(1H,dd,J1＝4.84,J2＝8.68),7.04(1H,dd,J1＝8,J2＝8.76),6.69(1H,dd,J1＝1.16,J2＝7.84),6.48(1H,dd,J1＝5.08,J2＝7.84),4.80(2H,br),1.81(3H,s)。
Compound 8b- (S): the compound 7b- (S) was used as a starting material, and the operation and the amount of each starting material were the same as those of the compound 8a- (R).1H-NMR(CDCl3)：7.66(1H,d,J＝1.88),7.31(1H,dd,J1＝4.84,J2＝8.92),7.08(1H,dd,J1＝8.08,J2＝8.68),6.83(1H,d,J1＝1.8),4.81(2H,br),1.81(3H,s)。
The compound 9b- (S) -a is prepared from the compound 8b- (S) and the compound 1a by the same procedures and the same amount of the raw materials as the compound 9a- (R) -b.1H NMR(CDCl3):7.73(d,J＝1.68Hz,1H),7.56(s,1H),7.48(s,1H),7.30(dd,J＝4.8Hz,8.8Hz,1H),7.05(dd,J＝8.0Hz,8.8Hz,1H),6.87(d,J＝1.8Hz,1H),5.02-4.82(br,2H),4.35-4.15(m,3H),3.02-2.82(m,2H),2.18-2.13(m,2H),1.92-1.86(m,2H),1.85(s,3H),1.48(s,9H)。
A compound of formula IV: the compound TRN-00104 was used as a starting material for the compound 9b- (S) -a in the same amount as used for the preparation of the starting material.1H-NMR(CDCl3)：7.76(1H,d,J＝1.72),7.57(1H,s),7.50(1H,s),7.30(1H,dd,J1＝4.8,J2＝8.88),7.05(1H,dd,J1＝8,J2＝8.76),6.87(1H,d,J＝1.72),4.77(2H,br),4.25-4.16(1H,m),3.29-3.21(2H,m),2.83-2.73(2H,m),2.20-2.13(2H,m),1.97-1.88(2H,m),1.84(3H,s)。
Test example 1
Sample information: contains 9 compounds of deuterated crizotinib, deuterated crizotinib racemate, crizotinib and racemate thereof, and has the following structural formula:
the test method comprises the following steps: carrying out intragastric administration on rats by 9 compounds TRN 00101-TRN 001109 according to the dose of 10 mg/kg; rats were dosed intravenously at 1mg/kg (TRN00101, TRN00104) or 2.5mg/kg (7 additional compounds), and the concentration of the original compound in the plasma of the rats after dosing was determined and the relevant pharmacokinetic parameters were calculated. According to the elimination half-life of the crude drug in rats, Cmax,t1/2And the pharmacodynamic parameters such as AUC and bioavailability are used for judging the potency of the medicine. The test results are shown in table 1 below.
TABLE 1 test results
Test example 2
And (3) biological activity experiments of deuterated crizotinib, deuterated crizotinib racemate, crizotinib and racemate thereof.
Sample information: contains 9 compounds of deuterated crizotinib, deuterated crizotinib racemate, crizotinib and racemate thereof.
The purpose of the test is as follows: the activity of 9 compounds TRN00101 to TRN00109 on anaplastic lymphoma kinase was tested respectively.
The test method comprises the following steps: in vitro activity of 9 compounds on Anaplastic Lymphoma (ALK) was tested at ATP Km concentration using the Caliper Mobility Shift Assay method, and bioactivity screening of compounds was repeated at 10 concentrations using staurosporine as a control. The results of the tests are shown in Table 2 below.
TABLE 2 test results
| Compound numbering | IC50 |
| TRN00101 | 4.3nM |
| TRN00102 | 637nM |
| TRN00103 | 12.6nM |
| TRN00104 | 2.8nM |
| TRN00105 | >1uM |
| TRN00106 | 8.7nM |
| TRN00107 | 3.2nM |
| TRN00108 | >1uM |
| TRN00109 | 5.8nM |
The biological activity experiment and the pharmacokinetic experiment show that: compared with (S) -configuration and racemate bioactivity, the (R) -crizotinib and (R) -deuterated crizotinib are obviously improved, so that the (R) -crizotinib and (R) -deuterated crizotinib have better medicinal prospects; the (R) -deuterated crizotinib has similar biological activity compared with the (R) -crizotinib, and meanwhile, the pharmacokinetic experiment result of the (R) -deuterated crizotinib shows that the (R) -deuterated crizotinib has better drug-forming property compared with the (R) -crizotinib; and the bioavailability of the TRN00104 and the TRN00107 is higher than that of crizotinib. This indicates that (R) -deuterated crizotinib has potential pharmaceutical value.
Claims (8)
1. A preparation method of deuterated crizotinib and derivatives thereof is characterized by comprising the following steps:
the structural formula of the deuterated crizotinib and the derivative thereof is shown as formula I, II, III or IV:
in the formulas I, II, III or IV, R is respectively selected from H or tert-butyloxycarbonyl;
the preparation method of the deuterated crizotinib and the derivative thereof comprises the following steps: dissolving a deuterated compound of the formula V and a non-deuterated compound of the formula VI with different chiralities or dissolving the non-deuterated compound of the formula V and the non-deuterated compound of the formula VI with different chiralities in N, N-dimethylformamide, N-dimethylacetamide, dioxane or triethylamine, adding sodium carbonate, potassium acetate or triethylamine, sequentially adding palladium acetate and triphenylphosphine under the protection of nitrogen, heating to 60-150 ℃, reacting for 2-24 hours, and separating to obtain a deuterated crizotinib derivative; taking the separated deuterated crizotinib derivative, removing the protective group, and recrystallizing to obtain deuterated crizotinib;
in the formula V, R1Selected from H or D, R in formula VI2Selected from H or D;
a process for the preparation of a different chiral non-deuterated or deuterated compound of formula vi comprising the steps of:
(1) preparation of racemic phenethyl alcohol derivatives
Reacting 2, 6-dichloro-3-fluoro acetophenone with a deuterated or non-deuterated reducing agent at room temperature to obtain a compound shown in the formula 2; the deuterated reducing agent is deuterated lithium aluminum hydride, deuterated sodium borohydride, deuterated sodium acetate borohydride or deuterated sodium cyanoborohydride;
in the formula 2, R2Selected from H or D;
(2) resolution of racemic phenethyl alcohol derivatives
a. Heating and reacting a compound shown in the formula 2 with phthalic anhydride under the action of alkali to obtain a compound shown in the formula 3, wherein the reaction temperature is 80-120 ℃; the base is triethylamine, pyridine or 4-dimethylaminopyridine;
b. salifying the compound of the formula 3 and single chiral phenethylamine or a derivative thereof in an organic solvent, and separating to obtain a single chiral compound of a formula 4;
c. hydrolyzing the single chiral compound of formula 4 under the action of alkali to obtain a single chiral compound of formula 5; the alkali is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate;
in the formula 3, 4, 5, R2Are respectively selected from H or D; in the formula 4, R4Selected from alkyl with 1-10 carbon atoms;
(3) etherification reaction
The compound of the single chiral formula 5 and 2-nitryl-3-hydroxypyridine are subjected to etherification reaction to obtain a compound of a formula 6 with an inverted configuration;
in the formula 6, R2Selected from H or D;
(4) reduction of nitro group
Reducing the compound shown in the formula 6 by using a reducing agent to obtain a compound shown in a formula 7;
in the formula 7, R2Selected from H or D;
(5) bromination reaction
Reacting the compound of the formula 7 with N-bromosuccinimide to obtain a bromo-compound of a formula 8;
in the formula 8, R2Selected from H or D.
2. The method of preparing deuterated crizotinib and derivatives thereof as claimed in claim 1, characterized in that: the ratio of the reducing agent to the 2, 6-dichloro-3-fluoro acetophenone in the step (1) is (1-4) to 1.
3. The method of preparing deuterated crizotinib and derivatives thereof as claimed in claim 1, characterized in that: the mass ratio of the compound of formula 3 to the chiral phenethylamine or the derivative thereof in the step (2) is 1 (0.2-0.5).
4. The method of preparing deuterated crizotinib and derivatives thereof as claimed in claim 1, characterized in that: the organic solvent in the step (2) is diethyl ether.
5. The method of preparing deuterated crizotinib and derivatives thereof as claimed in claim 1, characterized in that: the feeding proportion of the etherification reaction in the step (3) is as follows: the compound of formula 5 is triphenyl phosphine, DEAD, 3-hydroxy-2-nitropyridine, 1, (1-3) and (1-3) calculated by the amount of the substance.
6. The method of preparing deuterated crizotinib and derivatives thereof as claimed in claim 1, characterized in that: the mass ratio of the compound of formula 6 to the reducing agent in the step (4) is 1 (2-20).
7. The method of preparing deuterated crizotinib and derivatives thereof as claimed in claim 1, characterized in that: the solvent adopted in the nitro reduction reaction in the step (4) is a mixture of ethanol and acetic acid, and the ratio of ethanol to acetic acid is (1-3) by volume.
8. The method of preparing deuterated crizotinib and derivatives thereof as claimed in claim 1, characterized in that: the mass ratio of the compound of formula 7 to the N-bromosuccinimide in the step (5) is 1 (0.6-3).
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