CN109232607A - Laura replaces the synthetic method of Buddhist nun - Google Patents
Laura replaces the synthetic method of Buddhist nun Download PDFInfo
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- CN109232607A CN109232607A CN201811099565.4A CN201811099565A CN109232607A CN 109232607 A CN109232607 A CN 109232607A CN 201811099565 A CN201811099565 A CN 201811099565A CN 109232607 A CN109232607 A CN 109232607A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
The invention belongs to pharmaceutical technology fields, it is related to the synthetic method that Laura replaces Buddhist nun (PF-06463922), that is fluoro--1 (3H) -one of 3- methyl isobenzofuran of 5- and 1- methyl-3-((methylamino) methyl)-1H- pyrazoles-5- nitrile pass through ammonolysis, replace, coupling, the reaction steps such as chiral resolution synthesize Laura finally for Buddhist nun (PF-06463922), or fluoro--1 (3H) -one of 3- methyl isobenzofuran of (S)-5- and 1- methyl-3-((methylamino) methyl)-1H- pyrazoles-5- nitrile pass through ammonolysis, replace, the reaction steps such as coupling are collectively referred to as into Laura finally for Buddhist nun (PF-06463922), new method is provided for anti-tumor drug Laura for the synthesis of Buddhist nun (PF-06463922).
Description
Technical field
The present invention relates to technical field of pharmaceuticals, are related to the synthetic method that drug Laura replaces Buddhist nun (PF-06463922).Specifically relate to
And fluoro--1 (3H) -one of 3- methyl isobenzofuran of 5- and 1- methyl-3-((methylamino) methyl)-1H- pyrazoles-5- nitrile pass through ammonia
The reaction steps such as solution, substitution, coupling, chiral resolution synthesize Laura finally for Buddhist nun, or the different benzo furan of the fluoro- 3- methyl of (S) -5-
- 1 (3H) -one of muttering and 1- methyl-3-((methylamino) methyl)-1H- pyrazoles-5- nitrile are by reaction steps such as ammonolysis, substitution, couplings
The method that final synthesis Laura replaces Buddhist nun.
Background technique
Laura is Pfizer (Pfizer) company by replacing Buddhist nun (Crizotinib) to gram azoles for Buddhist nun (PF-06463922)
The ALK inhibitor of transformation enters clinical test in the drug 2014, for the treatment of lung cancer, inhibits mainly for first generation ALK
Agent gram azoles is drug resistant for Buddhist nun (Alectinib) for Buddhist nun's drug resistance and second generation ALK inhibitor Ceritinib (Ceritinib) and Ai Le
Patients with Non-small-cell Lung.In the patent WO 2013132376 that it is delivered, US 8680111, JP 2015510879, EP
In 2822953, CN 104169286, US 2016115178, WO 2014207606, the four of the drug and its intermediate are described
Synthetic route, the related Laura synthetic method final for Buddhist nun, gives a kind of synthetic method, but its synthetic route is long, at
This height, time-consuming, and yield is low.Therefore, it is necessary to a kind of new preparation method be developed, with raw material is easy to get, step is short, cost
Advantage low, post-processing operation is easy is easy to industrialize.
Summary of the invention
Technical problem to be solved by the invention is to provide the synthetic methods that a kind of Laura replaces Buddhist nun.
The present invention realizes by the following method:
Fluoro--1 (3H) -one of 3- methyl isobenzofuran of 5- and 1- methyl-3-((methylamino) methyl)-1H- pyrazoles-5- nitrile
Synthesize Laura finally by reaction steps such as ammonolysis, substitution, coupling, chiral resolutions for Buddhist nun；
Or fluoro--1 (3H) -one of 3- methyl isobenzofuran of (S)-5- and 1- methyl-3-((methylamino) methyl)-1H- pyrrole
Azoles -5- nitrile synthesizes Laura finally by reaction steps such as ammonolysis, substitution, couplings for Buddhist nun.
The present invention includes the following steps:
(1) fluoro- 3- methyl isobenzofuran -1 (3H) -one (9) of 5- or the fluoro- 3- methyl isobenzofuran -1 of (S) -5-
(3H) -one (9S) and 1- methyl-3-((methylamino) methyl)-1H- pyrazoles-5- nitrile (IX) open loop obtain intermediate (18) or (18R)；
(2) intermediate (18) or (18R) in MTBE (methyl tertiary butyl ether(MTBE)) by substitution reaction obtain intermediate (19) or
(19R)；- 5-40 DEG C of temperature range, preferably 0-20 DEG C.
(3) intermediate (19) or (19R) pass through with compound (20) under conditions of alkalinity and replace instead using DMF as solvent
Deserved intermediate (21) or (21R)；
(4) intermediate (21) or (21R) are in cataCXium A (chlorine [(two (1- adamantyl)-N- butyl phosphines) -2- (2-
Amino-biphenvl)] palladium (II), Pd (OAc)2, KOAc, t-AmOH (tert-pentyl alcohol) condition, which is issued, obtains intermediate by coupling reaction
(22) or (22R)；
(5) intermediate (22) or (22R) carry out-Boc group in acid condition and respectively obtain intermediate (23) and labor
It draws and replaces Buddhist nun；
Further, intermediate 23 carries out chiral resolution under the conditions of Whelk-O1 (R, R), MeOH, finally obtains Laura
For Buddhist nun.
Wherein, in step (1), intermediate (18) or (18R) the preparation method is as follows: aluminum trichloride (anhydrous) is dissolved in organic
In solvent, stirring, 5-25 DEG C of temperature control, preferably 10-15 DEG C are slowly added dropwise a small amount of DCE solution, are added dropwise, 5-30 DEG C of reaction
Then (9) or (9S) are added in 30min-60min, preferably 15-20 DEG C, react 3-4h, reaction solution is quenched with ice water, diatomite
Filtering, DCM washing, filtrate are extracted with organic solvent, and anhydrous sodium sulfate is dry, are concentrated to give product, column chromatography.Anhydrous tri-chlorination
Aluminium: 9 or (9S): IX=0.8:2:1--2.2:2:1, preferably 1:2:1.The organic solvent be selected from DCE (facing dichloroethanes),
1,3- dioxane or toluene extract organic solvent used and are selected from DCM, petroleum ether, ether or ethyl acetate.
In step (2), intermediate (19) or (19R) the preparation method is as follows: intermediate (18) or (18R) are dissolved in organic
In solvent, under ice bath, alkali is added, mesyl chloride is added dropwise, finishes, is warmed to room temperature, react 30min-60min, TLC detection has been reacted
Finish, end of reaction is quenched with ice water, DCM extraction, saturated sodium-chloride water solution washing, and anhydrous sodium sulfate is dry.18 or 18R: three
Ethamine: mesyl chloride=1:2:1.5--1:2:3, preferably 1:2:1.8.The organic solvent is selected from methyl tertiary butyl ether(MTBE), alkylation
Oil, isooctane of changing products, polyisobutene, the alkali are selected from triethylamine, triethanolamine or pyridine.
In step (3), intermediate (21) or (21R) the preparation method is as follows: by alkali, compound (20) dissolution, which is scattered in, to be had
In solvent, under nitrogen protection, 10-30 DEG C, preferably 20-25 DEG C are added dropwise the DMF solution of intermediate (19) or (19R), finish,
It is warming up at 35-50 DEG C and reacts 4h or so, 40-45 DEG C of preferable temperature.Then DCM dilution is added into reaction solution, is slowly poured into
It is quenched in ice water, organic solvent extraction, saturated sodium-chloride water solution washs 5 times, and anhydrous sodium sulfate is dry.19:20=1:1.2-
1:3, preferably 1:1.5.The alkali is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, saleratus or pyridine, the organic solvent
Selected from DMF, DMSO, NMP or dioxane, extracts organic solvent used and be selected from DCM, petroleum ether or ethyl acetate.
In step (4), the preparation method of intermediate (22) or (22R), intermediate (21) or (21R) are in cataCXium A
(chlorine [(two (1- adamantyl)-N- butyl phosphines) -2- (2- Amino-biphenvl)] palladium (II)), Pd (OAc)2, KOAc, t-AmOH (uncle
Amylalcohol) in, 2-3h is reacted under conditions of 130-150 DEG C, 140-145 DEG C of preferable temperature, finally obtains intermediate (22) or centre
Body (22R).
In step (5), Laura in the preparation method of Buddhist nun, intermediate (22) or (22R) carry out in acid condition-
Boc group obtains intermediate (23) and Laura for Buddhist nun, and further, intermediate (23) is in Whelk-O1 (R, R) 30%MeOH
Chiral resolution is carried out under the conditions of 120bar, 4mL/min, finally obtains Laura for Buddhist nun.
The method of the present invention compared with the existing technology has synthesis step short, and easy to operate, yield is significantly improved excellent
Gesture.
Specific embodiment
Embodiment 1
(1) N- ((5- cyano -1- methyl-1 H- pyrazole-3-yl) methyl) the fluoro- 2- of -4- (1- ethoxy)-N- methylbenzene first
The synthesis of amide
Or
(R)-N- ((5- cyano -1- methyl-1 H- pyrazole-3-yl) methyl) the fluoro- 2- of -4- (1- ethoxy)-N- methylbenzene first
The synthesis of amide
50mL three-necked bottle, equipped with thermometer, stirrer, dropping funel is molten by aluminum trichloride (anhydrous) 0.11g (0.79mmol)
In 8mL DCE, under stirring, 10-15 DEG C of temperature control, the DCE solution 4mL of 0.23g (1.51mmol) IX is slowly added dropwise, is added dropwise,
Then 0.1g (0.61mmol) intermediate (9) or (9S) are added in 20 DEG C of reaction 30min, react 3h, reaction solution is quenched with ice water
It goes out, diatomite filtering, DCM is washed, and filtrate is extracted with DCM, and anhydrous sodium sulfate is dry, is concentrated to give 0.15g, yield 78.9%.Column
Chromatograph to obtain 0.12g.ESI-MS (m/z): 317.1 [M+H]+, 339.1 [M+Na]+.
(2) 1- (2- (((5- cyano -1- methyl-1 H- pyrazole-3-yl) methyl) (methyl) carbamoyl) -5- fluorobenzene
Base) ethyl ester synthesis
(R) -1- (2- (((5- cyano -1- methyl-1 H- pyrazole-3-yl) methyl) (methyl) carbamoyl) -5- fluorobenzene
Base) ethyl ester synthesis
0.95g (3.01mmol) intermediate (18) or (18R) is dissolved in methyl tertiary butyl ether(MTBE) 15mL, under ice bath, is added
Triethylamine 0.83mL (6.02mmol) is added dropwise 0.4mL (5.19mmol) mesyl chloride, finishes, be warmed to room temperature, and reacts 10min,
TLC detects end of reaction, and end of reaction is quenched with ice water, DCM extraction, saturated sodium-chloride water solution washing, and anhydrous sodium sulfate is dry
It is dry.Obtain 0.73g, yield 65.7%.ESI-MS (m/z): 395.1 [M+H]+, 811.2 [2M+Na]+.
(3) bromo- 3- (1- (2- (((5- cyano -1- methyl-1 H- pyrazole-3-yl) methyl) (methyl) carbamoyl) -5-
Fluorophenyl) ethyoxyl) pyridine pyridine -2- base) and t-butyl carbamate synthesis
(the bromo- 3- of 5- (R)-(1- (2- (((5- cyano -1- methyl-1 H- pyrazole-3-yl) methyl) (methyl) carbamyl
Base) -5- fluorophenyl) ethyoxyl) pyridine pyridine -2- base) t-butyl carbamate synthesis
By 0.55g (4mmol) potassium carbonate, 0.43g (1.5mmol) compound (20) dissolution is scattered in 20mL DMF, nitrogen
Under gas shielded, 20 DEG C, the DMF solution of 0.395g (1.0mmol) intermediate (19) or (19R) is added dropwise, finishes, is warming up at 40 DEG C
React 4h or so.Then DCM dilution is added into reaction solution, is slowly poured into ice water and is quenched, DCM extraction, saturated sodium chloride water
Solution washs 5 times, and anhydrous sodium sulfate is dry, and yield is lower between 15-30%.ESI-MS (m/z): 587.1 [M+H]+,
609.1[M+Na]+。
(4) (Z)-(the fluoro- 11,4,7- trimethyl -6- oxo -11H-12-4,3- oxa- -12- base -4,7- of 15- cyano -55-
Diaza -2 (3,5)-pyridine -1 (4,2)-pyrazoles -5 (1,2)-t-butyl carbamate synthesis
(R, Z)-(fluoro- 11,4,7- trimethyl -6- oxo -11H-12-4,3- oxa- -12- base -4,7- of 15- cyano -55-
Diaza -2 (3,5)-pyridine -1 (4,2)-pyrazoles -5 (1,2)-t-butyl carbamate synthesis
By 1g intermediate (21) or (21R) in 20mol%cataCXium A, 20mol%Pd (OAc)2, 5 equivalents
2h is reacted under conditions of KOAc, t-AmOH, 140 DEG C, finally obtains intermediate 22.Obtain 0.78g, yield 58.2%.ESI-
MS (m/z): 508.2 [M+H]+.
(5) synthesis of intermediate 23
Laura replaces the synthesis of Buddhist nun
1g intermediate (22) is sufficiently mixed with (22R) and HCl, blocking group-Boc is sloughed, finally obtains intermediate 23
It replaces Buddhist nun with Laura, obtains 0.83g product, yield 95.3% (mass spectrometric data is identical for Buddhist nun's synthesis with next step Laura).ESI-MS
(m/z): 408.1 [M+H]+, 430.1 [M+Na]+.
Laura replaces the synthesis of Buddhist nun (PF-06463922)
Intermediate 23 carries out chiral resolution under the conditions of Whelk-O1 (R, R) 30%MeOH 120bar, 4mL/min, finally
Laura is obtained for Buddhist nun.ESI-MS (m/z): 408.1 [M+H]+.
Claims (10)
1. the synthetic method that Laura replaces Buddhist nun, which is characterized in that fluoro--1 (3H) -one of 3- methyl isobenzofuran of 5- and 1- methyl-3-
((methylamino) methyl) -1H- pyrazoles -5- nitrile replaces Buddhist nun by ammonolysis, substitution, coupling, chiral resolution reaction synthesis Laura；
Or fluoro--1 (3H) -one of 3- methyl isobenzofuran of (S)-5- and 1- methyl-3-((methylamino) methyl)-1H- pyrazoles-
5- nitrile replaces Buddhist nun by ammonolysis, substitution, coupling reaction synthesis Laura.
2. the synthetic method that Laura as described in claim 1 replaces Buddhist nun, which comprises the steps of:
(1) fluoro- 3- methyl isobenzofuran -1 (3H) -one (9) of 5- or fluoro- 3- methyl isobenzofuran -1 (3H) -one of (S) -5-
(9S) and 1- methyl-3-((methylamino) methyl)-1H- pyrazoles-5- nitrile (IX) open loop obtain intermediate (18) or (18R)；
(2) intermediate (18) or (18R) obtain intermediate (19) or (19R) by substitution reaction in methyl tertiary butyl ether(MTBE)；
(3) intermediate (19) or (19R) are obtained with compound (20) by substitution reaction under conditions of alkalinity using DMF as solvent
Intermediate (21) or (21R)；
(4) intermediate (21) or (21R) are in chlorine [(two (1- adamantyl)-N- butyl phosphines) -2- (2- Amino-biphenvl)] palladium
(II), Pd (OAc) 2, KOAc, tert-pentyl alcohol condition, which is issued, obtains intermediate (22) or (22R) by coupling reaction；
(5) intermediate (22) or (22R) carry out that-Boc group respectively obtains intermediate (23) and Laura replaces in acid condition
Buddhist nun；Further, intermediate 23 carries out chiral resolution, finally obtains Laura for Buddhist nun；
3. the synthetic method that Laura as claimed in claim 2 replaces Buddhist nun, which is characterized in that
In step (1), intermediate (18) or (18R) the preparation method is as follows: aluminum trichloride (anhydrous) is dissolved in organic solvent, stir
It mixes, 5-25 DEG C of temperature control, a small amount of DCE solution is slowly added dropwise, is added dropwise, react, (9) or (9S) then are added, reaction is quenched,
Filtering is washed, and is extracted, dry, concentration, column chromatography；Aluminum trichloride (anhydrous): 9 or (9S): IX=0.8:2:1-2.2:2:1；It is described
Organic solvent be selected from and face dichloroethanes, 1,3- dioxane or toluene, extraction is used to be selected from DCM, stone dissolved with solvent
Oily ether, ether or ethyl acetate.
4. the synthetic method that Laura as claimed in claim 2 replaces Buddhist nun, which is characterized in that
In step (2), intermediate (19) or (19R) the preparation method is as follows: intermediate (18) or (18R) are dissolved in organic solvent
In, under ice bath, alkali is added, mesyl chloride is added dropwise, finishes, heats up, reaction, TLC detects end of reaction, and end of reaction is quenched,
DCM extraction, is washed, dry；18 or 18R: triethylamine: mesyl chloride=1:2:1.5--1:2:3, the organic solvent are selected from first
Base tertbutyl ether, alkylate oil, isooctane of changing products, polyisobutene, the alkali are selected from triethylamine, triethanolamine or pyridine.
5. the synthetic method that Laura as claimed in claim 2 replaces Buddhist nun, which is characterized in that
In step (3), intermediate (21) or (21R) the preparation method is as follows: by alkali, compound (20) dissolution is scattered in organic molten
In agent, under nitrogen protection, the DMF solution of intermediate (19) or (19R) is added dropwise, finishes, is warming up at 35-50 DEG C and reacts, DCM is dilute
It releases, is quenched, organic solvent extraction is washed, dry；Intermediate 19: intermediate 20=1:1.2-1:3, the alkali are selected from carbonic acid
Potassium, sodium carbonate, sodium bicarbonate, saleratus or pyridine, the organic solvent are selected from DMF, DMSO, NMP or dioxane, extraction
Organic solvent used is taken to be selected from DCM, petroleum ether or ethyl acetate.
6. the synthetic method that Laura as claimed in claim 2 replaces Buddhist nun, which is characterized in that
In step (4), the preparation method of intermediate (22) or (22R), intermediate (21) or (21R) are in chlorine [(two (1- adamantane
Base)-N- butyl phosphine) -2- (2- Amino-biphenvl)] palladium (II), Pd (OAc) 2, KOAc, in tert-pentyl alcohol, under conditions of 130-150 DEG C
Reaction, obtains intermediate (22) or intermediate (22R).
7. the synthetic method that Laura as claimed in claim 2 replaces Buddhist nun, which is characterized in that
In step (5), intermediate (22) or (22R) carry out-Boc group in acid condition and obtain intermediate (23) and Laura
For Buddhist nun.
8. the synthetic method that the Laura as described in claim 2 or 7 replaces Buddhist nun, which is characterized in that intermediate (23) is in Whelk-O1
Chiral resolution is carried out under the conditions of (R, R), MeOH, obtains Laura for Buddhist nun.
9. the synthetic method that Laura as claimed in claim 2 or 4 replaces Buddhist nun, which is characterized in that reaction temperature model in step (2)
Enclose -5-40 DEG C, preferably 0-20 DEG C.
10. the synthetic method that the Laura as described in claim 2 or 8 replaces Buddhist nun, which is characterized in that intermediate (23) is in Whelk-O1
Chiral resolution is carried out under the conditions of (R, R) 30%MeOH.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651418A (en) * | 2019-01-25 | 2019-04-19 | 安庆多辉生物科技有限公司 | A kind of method that Laura replaces Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate and Organometallic Palladium catalytic coupling to prepare Laura for Buddhist nun |
| CN110530998A (en) * | 2019-09-16 | 2019-12-03 | 山东省药学科学院 | A kind of Laura is for Buddhist nun and containing Laura for the detection method in relation to substance in the preparation of Buddhist nun |
| CN111943885A (en) * | 2020-07-01 | 2020-11-17 | 西华大学 | Synthetic method of Laolatinib intermediate 2-amino-5-bromo-3-hydroxypyridine |
| CN112724077A (en) * | 2020-12-29 | 2021-04-30 | 武汉利昌医药科技有限公司 | Synthetic method of Laolatinib intermediate |
| CN112824417A (en) * | 2019-11-21 | 2021-05-21 | 上海天慈国际药业有限公司 | Preparation method of Laolatinib |
| CN113278027A (en) * | 2021-06-02 | 2021-08-20 | 浙江合聚生物医药有限公司 | Preparation method of antitumor drug Laolatinib |
| CN113603661A (en) * | 2021-08-11 | 2021-11-05 | 沈阳药科大学 | Synthesis method of (S) -5-fluoro-3-methylisobenzofuran-3-one |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651418A (en) * | 2019-01-25 | 2019-04-19 | 安庆多辉生物科技有限公司 | A kind of method that Laura replaces Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate and Organometallic Palladium catalytic coupling to prepare Laura for Buddhist nun |
| CN110530998A (en) * | 2019-09-16 | 2019-12-03 | 山东省药学科学院 | A kind of Laura is for Buddhist nun and containing Laura for the detection method in relation to substance in the preparation of Buddhist nun |
| CN112824417A (en) * | 2019-11-21 | 2021-05-21 | 上海天慈国际药业有限公司 | Preparation method of Laolatinib |
| CN111943885A (en) * | 2020-07-01 | 2020-11-17 | 西华大学 | Synthetic method of Laolatinib intermediate 2-amino-5-bromo-3-hydroxypyridine |
| CN111943885B (en) * | 2020-07-01 | 2023-08-04 | 西华大学 | Synthesis method of Laratinib intermediate 2-amino-5-bromo-3-hydroxypyridine |
| CN112724077A (en) * | 2020-12-29 | 2021-04-30 | 武汉利昌医药科技有限公司 | Synthetic method of Laolatinib intermediate |
| CN112724077B (en) * | 2020-12-29 | 2023-07-11 | 武汉利昌医药科技有限公司 | Synthesis method of loratidine intermediate |
| CN113278027A (en) * | 2021-06-02 | 2021-08-20 | 浙江合聚生物医药有限公司 | Preparation method of antitumor drug Laolatinib |
| CN113278027B (en) * | 2021-06-02 | 2022-05-31 | 浙江合聚生物医药有限公司 | Preparation method of antitumor drug Laolatinib |
| CN113603661A (en) * | 2021-08-11 | 2021-11-05 | 沈阳药科大学 | Synthesis method of (S) -5-fluoro-3-methylisobenzofuran-3-one |
| CN113603661B (en) * | 2021-08-11 | 2024-04-09 | 沈阳药科大学 | Synthesis method of (S) -5-fluoro-3-methyl isobenzofuran-3-ketone |
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