CN107987082A - A kind of Preparation Method And Their Intermediate of Larotrectinib - Google Patents
A kind of Preparation Method And Their Intermediate of Larotrectinib Download PDFInfo
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- CN107987082A CN107987082A CN201711121329.3A CN201711121329A CN107987082A CN 107987082 A CN107987082 A CN 107987082A CN 201711121329 A CN201711121329 A CN 201711121329A CN 107987082 A CN107987082 A CN 107987082A
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- NIJQUMQRKQSUCF-UHFFFAOYSA-N Nc(cn[n]1cc2)c1nc2Cl Chemical compound Nc(cn[n]1cc2)c1nc2Cl NIJQUMQRKQSUCF-UHFFFAOYSA-N 0.000 description 1
- IIEPKVVRBLTLFY-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1OC(Nc(cn[n]1cc2)c1nc2Cl)=O)=O Chemical compound [O-][N+](c(cc1)ccc1OC(Nc(cn[n]1cc2)c1nc2Cl)=O)=O IIEPKVVRBLTLFY-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
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- 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
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Abstract
The present invention relates to medicinal chemistry art, and in particular to a kind of Preparation Method And Their Intermediate of Larotrectinib, with 5 chlorine, 3 nitropyrazole, simultaneously for raw material, 5 compound of formula is obtained through three-step reaction to this method for [1,5 a] pyrimidine6 compound of 5 compound of formula and formula
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of Preparation Method And Their Intermediate of Larotrectinib.
Background technology
Larotrectinib is researched and developed by Loxo Oncology companies, as a broad-spectrum tumor medicine, for all tables
Up to the tumor patient for having tropomyosin receptor kinase (tropomyosin receptor kinase, TRK), rather than it is directed to
The tumour of some anatomical position.TRK fusions are distributed widely in many cancers, and influence institute's has age, while and tumorgenesis
It is unrelated.The medicine authorizes breakthrough medicine qualification on July 13rd, 2016 by FDA, it is positive for the mutation of TRK fusions into
People and children can not surgery excision or metastatic solid tumors, Larotrectinib had been demonstrated in extensive age and tumour
In the Trk fusion cancers of type, there is lasting antitumor activity effect and good tolerance.Larotrectinib will
As first in the medicine for being grown up with developing and ratify at the same time in children, and it is that the first crosses over all traditional definitions
Tumor type, the neoplasm targeted therapy in molecule meaning.The structure of Larotrectinib is as follows：
The preparation method of Larotrectinib is disclosed in the prior art, and wherein WO2016077841A1 is disclosed with 5- chloro- 3
Simultaneously [1,5-a] pyrimidine is raw material to nitropyrazole, and substitution reaction, which occurs, with Formula II obtains formula III compound, formula III compound zinc
Powder/hydrochloric acid reduces to obtain formula IV compound, and formula IV compound obtains Formula V compound, Formula V with the anti-raw condensation reaction of phenyl chloroformate
Compound reacts to obtain Larotrectinib with (S) -3- pyrrolidinols：
In the synthetic method, there are problems with：1) manufacturing cost of Formula II compound is higher, after being reacted with compound of formula I also
Three-step reaction is needed to obtain Larotrectinib, therefore, the availability of Formula II compound is relatively low, and production cost is of a relatively high；
2) reaction temperature of Formula V compound and (S) -3- pyrrolidinols is 50 DEG C, and the reaction time when 19 is small, accessory substance compared with
More, purification process is complicated, and industrialization is of high cost.
The content of the invention
The present invention is in view of the shortcomings of the prior art, creatively devise a kind of new Larotrectinib's through overtesting
Preparation Method And Their Intermediate.This method replaces phenyl chloroformate of the prior art with p-nitrophenyl chloroformate ester, effectively drop
Reaction temperature and reaction time of low (the S) -3- pyrrolidinols with 3 compound of formula, and highest 6 compound of formula of cost is placed on
Final step is reacted, and is effectively reduced the loss of 6 compound of formula, is reduced production cost, is adapted to the production of medical industry metaplasia.
Concrete technical scheme of the present invention is as follows：
A kind of preparation method of Larotrectinib, includes the following steps：
(1) 1 compound of formula obtains 2 compound of formula through reduction reaction,
Zinc powder-hydrochloric acid system, iron powder-ammonium chloride system or palladium carbon/H can be used21 compound of reduction system formula obtains formula 2
Compound.
Palladium carbon/H2System reaction condition：Under room temperature, make solvent with methanol (or ethanol), add 5% palladium/carbon catalysis
Agent, when reaction 12 is small under 1atm hydrogen.
Iron powder-ammonium chloride system：Solvent is done with first alcohol and water, when reaction 4-8 is small under the conditions of the lower reflux of nitrogen protection.
(2) 2 compound of formula and p-nitrophenyl chloro-formate react to obtain 3 compound of formula,
Above-mentioned reaction needs to react in alkaline conditions, and the alkali used is selected from sodium carbonate, sodium acid carbonate, potassium carbonate, carbonic acid
Hydrogen potassium, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, tertiary fourth
Sodium alkoxide, potassium tert-butoxide, triethylamine, diisopropyl ethyl amine, pyridine, N, N- lutidines, N- methyl piperidines, morpholine or N- first
One or more in base morpholine, preferably diisopropyl ethyl amine.
The reaction dissolvent of above-mentioned reaction is selected from water, methanol, ethanol, chloroform, dichloromethane, tetrahydrofuran, dioxane, second
One kind in ether, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile, toluene, dichloroethanes, 1-methyl-2-pyrrolidinone or
It is several, preferred dichloromethane.
Preferable reaction temperature is 0-10 DEG C, when the reaction time is 1-2 small.
(3) 3 compound of formula and 4 compound of formula react to obtain 5 compound of formula,
A preferred embodiment of the present invention, 3 compound of formula and 4 compound of formula react the formula that obtains 5 in alcohols solvent
Compound, preferred alcohol.It is preferred that when 5-80 DEG C of reaction 2-8 is small, more preferably when 25 DEG C of reaction 2-8 are small.
(4) 5 compound of formula and the generation substitution reaction of 6 compound of formula obtain Larotrectinib and its derivative,
Above-mentioned reaction is reacted in alkaline conditions, and the alkali is selected from sodium carbonate, sodium acid carbonate, potassium carbonate, saleratus, hydrogen
Lithia, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, uncle
Butanol potassium, triethylamine, diisopropyl ethyl amine, pyridine, N, N- lutidines, N- methyl piperidines, morpholine or N-methylmorpholine
In one or more, preferred diisopropyl ethyl amine.
The reaction dissolvent that above-mentioned reaction uses be selected from methanol, ethanol, isopropanol, propyl alcohol, n-butanol, chloroform, dichloromethane,
Tetrahydrofuran, dioxane, ether, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile, toluene, dichloroethanes, N- first
One or more in one or more in base pyrrolidones, preferably methanol, ethanol, isopropanol, propyl alcohol or n-butanol.
0-40 DEG C of preferable reaction temperature, more preferably 20-30 DEG C of reaction temperature, when reaction 5-8 is small.
It is another object of the present invention to provide following compounds (5 compound of formula 3 and formula) with formula：
Compared with prior art, the present invention replaces chloromethane when preparing Larotrectinib with p-nitrophenyl chloroformate ester
During acid phenenyl ester, reaction temperature can be significantly reduced, shortens the reaction time, reduces species and content in relation to material in reaction, nothing
Palpus column chromatography purifying, is placed on final step reaction by highest 6 compound of formula of production cost in addition, effectively reduces formula 6 and change
The loss of compound, reduces production cost, is adapted to the production of medical industry metaplasia.
Brief description of the drawings
Fig. 1 is the Larotrectinib high-efficient liquid phase chromatograms that the method for the invention is prepared.
Embodiment
Used term in the present invention, unless otherwise indicated, generally there are those of ordinary skill in the art usually to manage
The implication of solution.
The present invention is described in further detail with reference to specific embodiment and with reference to data.It is to be understood that the embodiment is
In order to demonstrate the invention, rather than limit the scope of the invention in any way.
In the examples below, the various processes and method not being described in detail are conventional methods as known in the art.Under
Material used in example, reagent, device, instrument, equipment etc. are stated, unless otherwise specified, is commercially obtained.
Embodiment 1：The synthesis of 2 compound of formula
By 1 compound of formula (50g, 250mmol), ethanol (500mL), ammonium chloride (133g, 2.5mol) aqueous solution (500mL) and iron
Powder (140g, 2.5mol) is added in reaction bulb, heating, when reaction 4-8 is small under the conditions of the lower reflux of nitrogen protection.Reaction finishes
Afterwards, it is concentrated under reduced pressure, adds water and dichloromethane, layering, organic phase saturated common salt water washing, is dried with anhydrous sodium sulfate, subtracted
Pressure is concentrated to give 2 compound 40g of formula, yield 95.2%.δ=9.29 (d, J=7.2Hz, 1H), 8.71 (s, 1H), 8.16 (d,
J=7.2Hz, 1H), 5.92 (s, 2H)；MS(m/z)[M+H]+calcd for C6H6ClN4 169.0,found 169.8。
Embodiment 2：The synthesis of 3 compound of formula
At room temperature by 2 compound of formula (40g, 237mmol), n,N-diisopropylethylamine (36.8g, 284mmol) and dichloromethane
Alkane (400mL) is added in reaction bulb, is down to 0-10 DEG C, is slowly added dropwise the two of p-nitrophenyl chloroformate ester (50.2g, 249mmol)
Chloromethanes solution, keeps temperature to be no more than 10 DEG C, is controlled in TLC, after completion of the reaction, with saturated common salt water washing, use anhydrous slufuric acid
Sodium is dried, and is concentrated to give 3 compound 74g of formula, yield 93.5% at reduced pressure conditions.1H NMR(300MHz,d6DMSO) δ=
10.2 (s, 1H), 9.32 (d, J=7.2Hz 1H), 8.81 (s, 1H), 7.4-8.6 (m, 5H)；MS(m/z)[M+H]+calcd
for C13H9ClN5O4 334.0,found 333.8。
Embodiment 3：The synthesis of 5 compound of formula
3 compound of formula (70g, 210mmol), 4 compound of formula (18g, 207mmol) and ethanol (300mL) are added at room temperature
In reaction bulb, when 25 DEG C of reaction 2-8 are small, controlled in TLC, after completion of the reaction, add methyl tertiary butyl ether(MTBE) under agitation
(800mL), there is solid precipitation, continues stirring 30 minutes at this temperature, filtering, drains to obtain 5 compound 36g of formula, recycling is female
Liquid continues to be obtained formula 5 compound 18g, common 54g, yield 91% after purification with column chromatography.1H NMR(300MHz,d6DMSO)δ
=9.26 (d, J=7.2Hz 1H), 8.73 (s, 1H), 8.78 (s, 1H), 8.07 (d, J=7.2Hz, 1H), 4.02 (m, 1H),
3.62(m,2H),3.48(m,2H),2.36(m,2H)；MS(m/z)[M+H]+calcd for C11H13ClN5O2 282.1,
found 281.9。
Embodiment 4：The synthesis of Larotrectinib
5 compound of formula (30g, 106mmol), 6 compound of formula (18g, 98.2mmol) and ethanol (200mL) are added into reaction flask
In, n,N-diisopropylethylamine (16.5g, 128mmol) is added dropwise, keeps reaction temperature within 30 DEG C, after being added dropwise, continues
When reaction 5-8 is small, controlled in TLC, after completion of the reaction, add methyl tertiary butyl ether(MTBE) (300mL), have solid precipitation, at this temperature
Continue stirring 30 minutes, filtering, drains to obtain Larotrectinib38.6g, yield 85%.
1H NMR(300MHz,d6DMSO) δ=9.12 (d, J=7.2Hz 1H), 8.73 (s, 1H), 8.78 (s, 1H),
8.07 (d, J=7.2Hz, 1H), 6.8-7.3 (m, 3H), 4.17 (m, 1H), 4.02 (m, 1H), 3.62 (m, 2H), 3.48 (m,
2H),1.75-2.86(m,8H)；LCMS(apci,m/z,429.1,M+H).
Measure the Larotrectinib purity being prepared.Efficient liquid phase condition：C18 chromatographic columns, mobile phase A：Water, stream
Dynamic phase B：Acetonitrile.With 1 gradient elution of table.
Table 1
| Time (min) | A (%) | B (%) |
| 0 | 60 | 40 |
| 8 | 30 | 70 |
| 12 | 20 | 80 |
| 15 | 10 | 90 |
| 19 | 10 | 90 |
| 19.01 | 60 | 40 |
| 22 | 60 | 40 |
As a result as shown in Table 2 and Figure 1.
Table 2
| Retention time (min) | Peak area (mAU*s) | Peak area (%) | |
| 1 | 2.444 | 1.11157 | 0.0787 |
| 2 | 9.707 | 1408.33545 | 99.6516 |
| 3 | 11.492 | 1.77062 | 0.1253 |
| 4 | 11.967 | 2.04147 | 0.1445 |
Claims (8)
1. a kind of preparation method of Larotrectinib, it is characterised in that include the following steps：
(1) 1 compound of formula obtains 2 compound of formula through reduction reaction,
(2) 2 compound of formula and p-nitrophenyl chloro-formate react to obtain 3 compound of formula,
(3) 3 compound of formula and 4 compound of formula react to obtain 5 compound of formula,
(4) 5 compound of formula and the generation substitution reaction of 6 compound of formula obtain Larotrectinib,
2. preparation method as claimed in claim 1, it is characterised in that step (1) is using zinc powder-hydrochloric acid system, iron powder-chlorination
Ammonium system or palladium carbon/H21 compound of reduction system formula obtains 2 compound of formula.
3. preparation method as claimed in claim 1, it is characterised in that step (2) is reacted in the presence of a base, and the alkali is selected from carbon
Sour sodium, sodium acid carbonate, potassium carbonate, saleratus, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, hydrogen
Barium monoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropyl ethyl amine, pyridine, N, N- dimethyl
One or more in pyridine, N- methyl piperidines, morpholine or N-methylmorpholine.
4. preparation method as claimed in claim 1, it is characterised in that the reaction dissolvent that step (2) uses is selected from water, methanol, second
Alcohol, chloroform, dichloromethane, tetrahydrofuran, dioxane, ether, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile,
One or more in toluene, dichloroethanes, 1-methyl-2-pyrrolidinone.
5. preparation method as claimed in claim 1, it is characterised in that in step (3), 3 compound of formula and 4 compound of formula are in alcohol
Reaction obtains 5 compound of formula in class solvent.
6. preparation method as claimed in claim 1, it is characterised in that step (4) is reacted in the presence of a base, and the alkali is selected from carbon
Sour sodium, sodium acid carbonate, potassium carbonate, saleratus, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, hydrogen
Barium monoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropyl ethyl amine, pyridine, N, N- dimethyl
One or more in pyridine, N- methyl piperidines, morpholine or N-methylmorpholine.
7. preparation method as claimed in claim 1, it is characterised in that the reaction dissolvent that step (4) uses be selected from methanol, ethanol,
Isopropanol, propyl alcohol, n-butanol, chloroform, dichloromethane, tetrahydrofuran, dioxane, ether, dimethyl sulfoxide, N, N- dimethyl methyls
Acid amides, acetone, acetonitrile, toluene, dichloroethanes, 1-methyl-2-pyrrolidinone.
8. the compound with formula：
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109608464A (en) * | 2018-12-12 | 2019-04-12 | 上海健康医学院 | A kind of radioiodination Larotrectinib compound and its preparation method and application |
| CN109705124A (en) * | 2018-12-14 | 2019-05-03 | 上海健康医学院 | A kind of labeled with radioactive fluorine Larotrectinib compound and preparation method thereof |
| CN111333561A (en) * | 2020-04-30 | 2020-06-26 | 安徽德信佳生物医药有限公司 | Synthetic method of ralotinib intermediate (2R) -2- (2, 5-difluorophenyl) pyrrolidine |
| CN111848626A (en) * | 2019-04-30 | 2020-10-30 | 江苏柯菲平医药股份有限公司 | TRK kinase inhibitor and application thereof |
| CN113307812A (en) * | 2021-07-01 | 2021-08-27 | 郑州大学第一附属医院 | Preparation method of broad-spectrum tumor drug erlotinib |
| WO2021187878A1 (en) * | 2020-03-17 | 2021-09-23 | 제이투에이치바이오텍 주식회사 | Compound for inhibiting mutagenic trk fusion protein, and pharmaceutical use and manufacturing method thereof |
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| WO2016077841A1 (en) * | 2014-11-16 | 2016-05-19 | Array Biopharma, Inc. | Crystalline form of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate |
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2017
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| CN102264736A (en) * | 2008-10-22 | 2011-11-30 | 阵列生物制药公司 | Substituted pyrazolo[1,5-a]pyrimidine compounds as trk kinase inhibitors |
| WO2016077841A1 (en) * | 2014-11-16 | 2016-05-19 | Array Biopharma, Inc. | Crystalline form of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate |
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| CN109608464B (en) * | 2018-12-12 | 2021-09-24 | 上海健康医学院 | Radioiodine-labeled Larotrectinib compound and preparation method and application thereof |
| US20220072164A1 (en) * | 2018-12-12 | 2022-03-10 | Shanghai University Of Medicine&Health Sciences | Radioactive i-labeled larotrectinib compound and preparation method and application thereof |
| WO2020119206A1 (en) * | 2018-12-12 | 2020-06-18 | 上海健康医学院 | Radioactive iodine-labelled larotrectinib compound, preparation method therefor and use thereof |
| CN109608464A (en) * | 2018-12-12 | 2019-04-12 | 上海健康医学院 | A kind of radioiodination Larotrectinib compound and its preparation method and application |
| WO2020119205A1 (en) * | 2018-12-14 | 2020-06-18 | 上海健康医学院 | Radioactive fluorine-labeled larotrectinib compound and preparation method therefor |
| CN109705124A (en) * | 2018-12-14 | 2019-05-03 | 上海健康医学院 | A kind of labeled with radioactive fluorine Larotrectinib compound and preparation method thereof |
| AU2019400110B2 (en) * | 2018-12-14 | 2022-12-08 | Shanghai University Of Medicine&Health Sciences | Radioactive fluorine-labeled Larotrectinib compound and preparation method therefor |
| CN109705124B (en) * | 2018-12-14 | 2021-09-24 | 上海健康医学院 | Radioactive fluorine labeled Larotrectinib compound and preparation method thereof |
| CN111848626A (en) * | 2019-04-30 | 2020-10-30 | 江苏柯菲平医药股份有限公司 | TRK kinase inhibitor and application thereof |
| CN111848626B (en) * | 2019-04-30 | 2021-11-30 | 江苏柯菲平医药股份有限公司 | TRK kinase inhibitor and application thereof |
| WO2021187878A1 (en) * | 2020-03-17 | 2021-09-23 | 제이투에이치바이오텍 주식회사 | Compound for inhibiting mutagenic trk fusion protein, and pharmaceutical use and manufacturing method thereof |
| CN111333561A (en) * | 2020-04-30 | 2020-06-26 | 安徽德信佳生物医药有限公司 | Synthetic method of ralotinib intermediate (2R) -2- (2, 5-difluorophenyl) pyrrolidine |
| CN113307812B (en) * | 2021-07-01 | 2022-07-22 | 郑州大学第一附属医院 | Preparation method of broad-spectrum tumor drug erlotinib |
| CN113307812A (en) * | 2021-07-01 | 2021-08-27 | 郑州大学第一附属医院 | Preparation method of broad-spectrum tumor drug erlotinib |
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