Anticancer drug Rociletinib and its intermediate preparationTechnical field
The invention belongs to organic synthetic route design and its bulk pharmaceutical chemicals and intermediate preparation technical field, in particular to a kind ofAnticancer drug Rociletinib and its intermediate preparation.
Background technique
Rociletinib (CO-1686, AVL-301) is that a kind of epidermis that is novel, oral, targeting covalently (irreversible) is thinIntracellular growth factor acceptor (EGFR) inhibition from mutation agent, is able to suppress crucial activated mutant and T790 medicament-resistant mutation, makes wild typeEGFR signal is idle.NSCLC patient of the medicine exploitation for carrying initial activation EGFR mutation and key resistance mutations T790MTreatment.On May 20th, 2014, Clovis tumour company (Clovis Oncology) announce that U.S. FDA authorizes its investigational agentThe breakthrough therapeutic agent qualification of object CO-1686, it is non-for treating T790M mutation patient EGFR mutation as single medicine two wiresSmall Cell Lung Cancer (NSCLC).Rociletinib chemical name are as follows: N- [3- [[2- [[4- (4- acetyl group -1- piperazinyl) -2- methoxyBase phenyl] amino] -5- (trifluoromethyl) -4- pyrimidine radicals] amino] phenyl] -2- acrylamide, No. CAS: 1374640-70-6,Its structural formula is for example as follows:
Document [synthesis [J] Chinese Journal of Pharmaceuticals of CO-1686,2014,45 (8): 710-713] uses the fluoro- 2- of 5-Nitroanisole, which is passed through, is made 1- (3- methoxyl group -4- aminophenyl) -4- Acetylpiperazine with piperazine condensation, acetylation, reduction(4)；Separately with the chloro- 5- trifluoromethyl pyrimidine of 2,4- bis-, through N- is made with the condensation of 3- nitroaniline, reduction, amidation, [(2- is chloro- by 3-5- trifluoromethyl pyrimidine -4- amino) phenyl] acrylamide (7), it is anti-swollen that compound 4 and 7 is condensed obtained EGFR inhibitor classTumor medicine CO-1686, total recovery about 71%.
CN 104284584 discloses the preparation method of Formulas I, and route is as follows:
By N-Boc-1,3- diaminobenzene and 2, the product that the reaction of the chloro- 5- trifluoromethyl pyrimidine of 4- bis- generates takes off BOC protectionThe thick material being concentrated is dissolved in DIPEA (2.0mL) and DCM (25mL), and is then cooled to -30 DEG C by base.- 30At DEG C, be slowly added into reaction mixture acryloyl chloride (0.76g), reaction generate intermediate 1, under room temperature with 2- methoxyBase -4- (4- acetylpiperazinyl) aniline reaction obtains compound of formula I.In the preparation method, 1 stability of key intermediate compared withDifference is easy to happen polymerization in the reaction, and by-product is more, and needs to carry out under -30 DEG C of low temperature, and reaction is difficult to control.
The preparation method of compound of formula I existing in the prior art, severe reaction conditions are unfavorable for industrialized production, resistThe preparation technical field of cancer drug Rociletinib needs to develop a kind of more mature process route, reduces anticancer drugProduction cost.
Summary of the invention
The present invention provides a kind of anticancer drug Rociletinib and its new synthetic methods of intermediate.
The purpose of the present invention can be achieved through the following technical solutions:
A kind of new synthetic method of Rociletinib (Formulas I), synthetic route are as follows:
Include the following steps:
(1) in organic solvent by compound III dissolution, with compound IIC in concentrated hydrochloric acid, trifluoroacetic acid or to toluene sulphurReaction obtains compound IV under the catalytic action of acid；
(2) by compound IV in polar organic solvent, it is anti-that de- BOC protecting group is carried out under the action of acidic catalystIt answers, obtains midbody compound V；
(3) in organic solvent by compound V dissolution, and chlorpromazine chloride fully reacting, then in organic base or inorganic baseCatalytic action under obtain compound I；
Further,
Organic solvent is selected from one of glycol dimethyl ether, dioxane, tetrahydrofuran or DMF or several in step (1)Kind；
The reaction temperature of step (1) compound III and compound IIC is 0~80 DEG C；
In a kind of scheme, the molar ratio of compound III and compound IIC is 1:1, the temperature of reaction in step (1)Degree is 50 DEG C, and the solvent of reaction is dioxane.
Further,
Acidic catalyst described in step (2) is selected from the one or more of concentrated hydrochloric acid, trifluoroacetic acid or p-methyl benzenesulfonic acidMixing, the polar solvent are selected from one or more of methanol, DMF or DMSO mixing.
Further,
In step (3), compound V dissolves in organic solvent, and reacting with chlorpromazine chloride be in Fu's acid agent is, for example, three secondIt is carried out under the action of amine, ethylenediamine, ammonia, pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate or saleratus etc.；Compound V withChlorpromazine chloride fully reacting add 11 carbon -7- alkene of 1,8- diazabicylo, triethylamine, ethylenediamine, ammonia, pyridine, potassium carbonate,One or more of sodium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide, reaction obtain compound I.
It is found during technical study, in step (3) when inorganic base sodium bicarbonate or saleratus are selected in Fu's acid agent, insteadAnswer efficiency higher.Meanwhile organic bases triethylamine or 1,8- diazabicylo being added after compound V and chlorpromazine chloride fully reacting11 carbon -7- alkene, products therefrom purity is higher, and 11 carbon -7- alkene (DBU) of still more preferably 1,8- diazabicylo is used as alkaliCatalyst.
In a kind of scheme, intermediate V is dissolved in THF, sodium bicarbonate aqueous solution is added in reaction solution, is placed in 0 DEG C insteadIt answers, the THF solution of chlorpromazine chloride is added drop-wise in reaction solution.Tetrahydrofuran solvent is removed into reaction solution rotation after raw material fully reacting, is addedEnter saturated sodium bicarbonate aqueous solution washing, be extracted with ethyl acetate, 1, the 8- diazabicylo ten of catalytic amount is added into systemOne carbon -7- alkene (DBU), 20~80 DEG C of reactions obtain compound I.
The object of the invention is also to provide a kind of new intermediate compound IV and chemical combination for being used to prepare RociletinibObject V and its salt, structural formula are as follows:
In a kind of scheme, the salt is the hydrochloride of compound IV or compound V.By compound IV or compound VHydrochloride recrystallized in ethyl acetate, methanol or acetone；Recrystallization gained intermediate purity can reach 99.5% withOn.
The present invention dissolves compound III in organic solvent, with compound IIC in concentrated hydrochloric acid, trifluoroacetic acid or to firstReaction obtains compound IV under the catalytic action of benzene sulfonic acid；By compound IV in polar organic solvent, in acidic catalystDe- BOC protection group reaction is carried out under effect, obtains midbody compound V；In organic solvent by compound V dissolution, with chlorine thirdAcyl chloride reaction is complete, and compound I is then obtained under the catalytic action of organic base or inorganic base；The present invention provides one kindThe new process of Rociletinib intermediate preparation, resulting product purity is good, and quality is higher, and cost is relatively low, is suitable for industrializationProduction.
Specific embodiment
For ease of understanding, the present invention will be described in detail by specific embodiment below.It needs to particularly point out, specific embodiment is merely to explanation, it is clear that those skilled in the art can be according to illustrating, in the present invention hereinVarious amendments are made to the present invention in range.
Embodiment 1: the synthesis of intermediate compound IV
130ml dioxane is added in 14g intermediate III, 8.96g IIC is added, is placed at 50 DEG C and stirs 5min, then4.1g trifluoroacetic acid is added, the reaction was continued, and reaction solution is the slightly cloudy liquid of black at this time.12h, TLC are stirred to react under 50 degrees CelsiusDetect raw material fully reacting.It is down to room temperature, is filtered, filter cake is washed with 20ml dioxane.Filter cake is transferred in single-necked flask,With 80 DEG C of mashing 2h of 80ml dioxane, it is then down to room temperature, is filtered, filter cake is washed with 10ml dioxane, is dried in vacuo19g intermediate compound IV, yield 88%, purity 99%.
M/z=602.31 (M+H+).
1H NMR(DMSO-d6)δ:9.98(br,,1H),9.64(s,1H),9.54(s,1H),8.60(br,1H),7.63(s, 1H), 7.44 (d, J=8.8Hz, 1H), 7.32 (m, 2H) .6.84 (m, 1H), 6.41 (br, 1H), 3.81 (s, 1H), 3.66(m, 4H), 3.24~3.17 (m, 4H), 2.06 (s, 1H), 1.45 (m, 1H).
Embodiment 2: the synthesis of intermediate compound IV
Referring to the preparation method of embodiment 1, reaction dissolvent is changed to tetrahydrofuran, acid catalyst is p-methyl benzenesulfonic acid, insteadAnswering temperature is 0 DEG C, and fully reacting, post-processing obtains 15g intermediate compound IV, purity 98%.
M/z=602.31 (M+H+).
Embodiment 3: the synthesis of intermediate compound IV
Referring to the preparation method of embodiment 1, reaction dissolvent is changed to DMF, acid catalyst is concentrated hydrochloric acid, reaction temperature 80DEG C, fully reacting, post-processing obtains 16g intermediate compound IV, purity 97%.
M/z=602.31 (M+H+).
Embodiment 4: the synthesis of intermediate V
The methanol solution of 150ml hydrochloric acid is added into 17g intermediate compound IV, is stirred overnight at room temperature, reaction solution is that purple is muddyTurbid.TLC detects fully reacting.It is spin-dried for, the ethyl acetate and 200ml water of 150ml is added into reaction solution, with ammonium hydroxide tune pH value=8~9, liquid separation, then it is primary with ethyl acetate 100ml aqueous phase extracted, merge organic phase, organic phase is washed with water 200ml × 2 timeOrganic phase, liquid separation retain organic phase, and anhydrous sodium sulfate is dry, filters, is spin-dried for, and obtain the intermediate V of 12.1g off-white color, purity99.1%.1H NMR (DMSO-d6) δ: 8.24 (s, 1H), 8.19 (br, 1H), 8.12 (s, 1H), 7.54 (d, J=8.8Hz,1H), 6.95 (m, 1H) .6.72 (br, 1H), 6.64 (d, J=2Hz, 1H) .6.37 (d, J=7.6Hz, 1H) .5.00 (br, 2H),3.78 (s, 3H), 3.60~3.56 (m, 4H), 3.12~3.04 (m, 4H), 2.05 (s, 3H), m/z=502.46 (M+H+)。
Embodiment 5: the synthesis of intermediate compound I
5g intermediate V is dissolved with 150mlTHF, then the 2.3g sodium bicarbonate aqueous solvent that 75ml water dissolves is added to reactionIn liquid, it is placed in 0 DEG C of reaction, reaction solution is red clarified solution at this time, and 1.3g chlorpromazine chloride is diluted with 75mlTHF, is slowly added dropwiseInto reaction solution.Rear TLC detection raw material fully reacting is added dropwise.Most of tetrahydrofuran is removed into reaction solution rotation, 100ml is addedSaturated sodium bicarbonate aqueous solution, 3 × 100ml ethyl acetate extracts three times, merges organic phase, and anhydrous sodium sulfate is dry, filtering, rotation2/3 ethyl acetate is evaporated off.7g DBU is added into revolving object, 60 DEG C of stirrings 12h, TLC detect raw material fully reacting, are addedThe aqueous solution of 100ml × 3 washs, and retains organic phase, and anhydrous sodium sulfate is dry, filters, is spin-dried for obtaining off-white powder, adds acetic acid secondEster recrystallizes to obtain product 4.7g, HPLC detection purity 99.6%.
1H NMR(DMSO-d6)δ:10.17(s,1H),8.67(br,1H),8.28(s,1H),8.10(s,1H),7.74(br, 1H), 7.55~7.49 (m, 2H), 7.26 (m, 1H), 7.16 (br, 1H), 6.60 (d, J=2.4Hz, 1H), 6.47~6.41 (m, 1H), 6.28 (dd, J=17.2Hz, 2Hz, 1H), 5.77~5.74 (m, 1H), 3.70 (s, 3H), 3.55 (m, 4H),3.06~3.00 (m, 4H), 2.04 (s, 3H) .m/z=556.5 (M+H+)
Embodiment 6: the synthesis of intermediate compound I
5g intermediate V 150ml dioxane is dissolved, then the 2.3g saleratus aqueous solvent that 75ml water dissolves is added toIn reaction solution, it is placed in 0 DEG C or so reaction, reaction solution is red clarified solution at this time, by 1.3g chlorpromazine chloride 75ml dioxaneDilution, is slowly dropped in reaction solution.Rear TLC detection raw material fully reacting is added dropwise.Most of solvent is removed into reaction solution rotation,The saturated sodium bicarbonate aqueous solution of 100ml is added, 3 × 100ml methylene chloride extracts three times, merges organic phase, and anhydrous sodium sulfate is dryDry, filtering, revolving remove solvent.50ml tetrahydrofuran and 2.0g potassium carbonate, 30 DEG C of stirring 20h, TLC inspections are added into revolving objectRaw material fully reacting is surveyed, the aqueous solution washing of 100ml × 3 is added, retains organic phase, anhydrous sodium sulfate is dry, filters, is spin-dried forOff-white powder, adds acetone recrystallization to obtain product 4.2g, and HPLC detects purity 99.1%.M/z=556.5 (M+H+)
Embodiment 7: the synthesis of intermediate compound I
5g intermediate V 150ml methylene chloride is dissolved, then 3ml pyridine is added in reaction solution, is placed in 0 DEG C or so insteadIt answers, reaction solution is red clarified solution at this time, and 1.3g chlorpromazine chloride 75ml dichloro is diluted, is slowly dropped in reaction solution.DropTLC detects raw material fully reacting after adding.Most of solvent is removed into reaction solution rotation, the saturated sodium bicarbonate water of 100ml is addedSolution, 3 × 100ml methylene chloride extract three times, merge organic phase, and anhydrous sodium sulfate is dry, filter, revolving removes solvent.Xiang XuanIt steams and 50ml ethyl alcohol and 1.0g potassium hydroxide is added in object, 20 DEG C of stirrings 6h, TLC detect raw material fully reacting, and 100ml × 3 are addedAqueous solution washing, retain organic phase, anhydrous sodium sulfate is dry, filters, is spin-dried for obtaining off-white powder, adds recrystallizing methanol that must produceProduct 3.5g, HPLC detect purity 99.0%.M/z=556.5 (M+H+)。