CN107987082B - 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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Abstract
The present invention relates to field of medicinal chemistry, and in particular to a kind of Preparation Method And Their Intermediate of Larotrectinib, with chloro- 3 nitropyrazole of 5-, simultaneously [1,5-a] pyrimidine obtains 5 compound of formula through three-step reaction for raw material to this method6 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 technique
Larotrectinib is researched and developed by Loxo Oncology company, as a broad-spectrum tumor medicine, is used 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 fusion is distributed widely in many cancers, and influences institute's has age, while and tumorgenesis
It is unrelated.The drug authorizes breakthrough drug qualification by FDA on July 13rd, 2016, for the mutation of TRK fusion it is positive at
Can not perform the operation excision or the metastatic solid tumors of people and children, Larotrectinib have been demonstrated in extensive age and tumour
In the Trk fusion cancer of type, there is lasting anti-tumor activity effect and good tolerance.Larotrectinib will
The therapeutic agent developed and ratified simultaneously in adult and children as first, and be 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-
Simultaneously [1,5-a] pyrimidine is raw material to chloro- 3 nitropyrazole, and substitution reaction occurs with Formula II and obtains formula III compound, formula III compound
It is restored to obtain formula IV compound with zinc powder/hydrochloric acid, formula IV compound and the anti-raw condensation reaction of phenyl chloroformate obtain Formula V chemical combination
Object, Formula V compound and (S) -3- pyrrolidinol react to obtain Larotrectinib:
In the synthetic method, have the following problems: 1) preparation cost of Formula II compound is higher, reacts with compound of formula I
Also need three-step reaction that can obtain Larotrectinib afterwards, therefore, the availability of Formula II compound is lower, and production cost is opposite
It is higher；2) reaction temperature of Formula V compound and (S) -3- pyrrolidinol is 50 DEG C, and the reaction time is up to 19 hours, by-product
Object is more, and purification process is complicated, industrializes at high cost.
Summary of the invention
The present invention is in view of the shortcomings of the prior art, creatively devise the new Larotrectinib's of one kind through overtesting
Preparation Method And Their Intermediate.This method replaces phenyl chloroformate in the prior art with p-nitrophenyl chloroformate ester, effectively drops
The reaction temperature and reaction time of low (S) -3- pyrrolidinol and 3 compound of formula, and highest 6 compound of formula of cost is placed on
Final step reaction, effectively reduces the loss of 6 compound of formula, reduces production cost, and medical industry metaplasia is suitble to produce.
Specific technical solution 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, making solvent with methanol (or ethyl alcohol), and 5% palladium/carbon catalysis is added
Agent is reacted 12 hours under 1atm hydrogen.
Iron powder-ammonium chloride system: solvent is done with first alcohol and water, is reacted 4-8 hours under the conditions of flowing back under 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 under alkaline condition, and the alkali used is selected from sodium carbonate, sodium bicarbonate, 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 piperidine, morpholine or N- first
One or more of base morpholine, preferably diisopropyl ethyl amine.
The reaction dissolvent of above-mentioned reaction is selected from water, methanol, ethyl alcohol, chloroform, methylene chloride, tetrahydrofuran, dioxane, second
One of ether, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile, toluene, dichloroethanes, N-Methyl pyrrolidone or
It is several, preferred methylene chloride.
Preferable reaction temperature is 0-10 DEG C, and the reaction time is 1-2 hours.
(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 5-80 DEG C reaction 2-8 hours, more preferably 25 DEG C reaction 2-8 hours.
(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 under alkaline condition, and the alkali is selected from sodium carbonate, sodium bicarbonate, 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 piperidine, morpholine or N-methylmorpholine
One or more of, preferred diisopropyl ethyl amine.
The reaction dissolvent that above-mentioned reaction uses be selected from methanol, ethyl alcohol, isopropanol, propyl alcohol, n-butanol, chloroform, methylene chloride,
Tetrahydrofuran, dioxane, ether, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile, toluene, dichloroethanes, N- first
One or more of one or more of base pyrrolidones, preferably methanol, ethyl alcohol, isopropanol, propyl alcohol or n-butanol.
0-40 DEG C of preferable reaction temperature, 20-30 DEG C of more preferable reaction temperature is reacted 5-8 hours.
It is another object of the present invention to provide the following compound (5 compound of formula 3 and formula) with formula:
Compared with prior art, the present invention replaces chloromethane with p-nitrophenyl chloroformate ester when preparing Larotrectinib
When acid phenenyl ester, reaction temperature can be significantly reduced, shorten the reaction time, reduce the type and content in relation to substance in reaction, nothing
Furthermore highest 6 compound of formula of production cost is placed on final step reaction by palpus column chromatographic purifying, effectively reduce the change of formula 6
The loss for closing object, reduces production cost, and medical industry metaplasia is suitble to produce.
Detailed description of the invention
Fig. 1 is the Larotrectinib high-efficient liquid phase chromatogram that the method for the invention is prepared.
Specific embodiment
Term as used in the present invention generally there are those of ordinary skill in the art usually to manage unless otherwise indicated
The meaning of solution.
The present invention is described in further detail combined with specific embodiments below and referring to data.It should be understood that the embodiment is
In order to demonstrate the invention, it rather than limits the scope of the invention in any way.
In the examples below, the various processes and method being not 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), ethyl alcohol (500mL), ammonium chloride (133g, 2.5mol) aqueous solution (500mL)
It is added in reaction flask, heats with iron powder (140g, 2.5mol), reacted 4-8 hours under the conditions of flowing back under nitrogen protection.It has reacted
Bi Hou is concentrated under reduced pressure, and water and methylene chloride is added, and layering, organic phase saturated common salt water washing is dry with anhydrous sodium sulfate,
It is concentrated under reduced pressure 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 two
Chloromethanes (400mL) is added in reaction flask, is down to 0-10 DEG C, and p-nitrophenyl chloroformate ester (50.2g, 249mmol) slowly is added dropwise
Dichloromethane solution, keep temperature be no more than 10 DEG C, controlled in TLC, after completion of the reaction, with saturated common salt water washing, use is anhydrous
Sodium sulphate is dry, is concentrated to get 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
At room temperature by 3 compound of formula (70g, 210mmol), 4 compound of formula (18g, 207mmol) and ethyl alcohol (300mL)
Be added reaction flask in, 25 DEG C reaction 2-8 hours, controlled in TLC, after completion of the reaction, methyl tertiary butyl ether(MTBE) be added under stiring
(800mL), there is solid precipitation, continues stirring 30 minutes at this temperature, and filtering drains to obtain 5 compound 36g of formula, and recycling is female
Liquid continues with obtaining 5 compound 18g of formula, total 54g, yield 91% after column chromatographic purifying.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。
The synthesis of embodiment 4:Larotrectinib
5 compound of formula (30g, 106mmol), 6 compound of formula (18g, 98.2mmol) and ethyl alcohol (200mL) are added and reacted
It in flask, is added dropwise n,N-diisopropylethylamine (16.5g, 128mmol), keeps reaction temperature within 30 DEG C, after being added dropwise,
The reaction was continued 5-8 hours, controls in TLC, after completion of the reaction, is added methyl tertiary butyl ether(MTBE) (300mL), there is solid precipitation, warm herein
Continue stirring 30 minutes under degree, 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 column, 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 Fig. 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 described in claim 1, it is characterised in that step (1) uses 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 described 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 bicarbonate, 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- methyl piperidine,
One or more of morpholine or N-methylmorpholine.
4. preparation method as described in claim 1, it is characterised in that the reaction dissolvent that step (2) uses is selected from water, methanol, second
Alcohol, chloroform, methylene chloride, tetrahydrofuran, dioxane, ether, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile,
One or more of toluene, dichloroethanes, N-Methyl pyrrolidone.
5. preparation method as described 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 described 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 bicarbonate, 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- methyl piperidine,
One or more of morpholine or N-methylmorpholine.
7. preparation method as described in claim 1, it is characterised in that the reaction dissolvent that step (4) uses be selected from methanol, ethyl alcohol,
Isopropanol, propyl alcohol, n-butanol, chloroform, methylene chloride, tetrahydrofuran, dioxane, ether, dimethyl sulfoxide, N, N- dimethyl methyl
Amide, acetone, acetonitrile, toluene, dichloroethanes, N-Methyl pyrrolidone.
8. the compound with formula:
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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 |
| CN109705124B (en) * | 2018-12-14 | 2021-09-24 | 上海健康医学院 | Radioactive fluorine labeled Larotrectinib compound and preparation method 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 |
| CN111333561B (en) * | 2020-04-30 | 2020-11-27 | 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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