CN107383000A - The preparation method of thrombocythemia agent - Google Patents
The preparation method of thrombocythemia agent Download PDFInfo
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- CN107383000A CN107383000A CN201710664827.6A CN201710664827A CN107383000A CN 107383000 A CN107383000 A CN 107383000A CN 201710664827 A CN201710664827 A CN 201710664827A CN 107383000 A CN107383000 A CN 107383000A
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- thrombocythemia
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- 0 *NNc1nc(-c2cc(Cl)c[s]2)c[s]1 Chemical compound *NNc1nc(-c2cc(Cl)c[s]2)c[s]1 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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Abstract
The present invention relates to a kind of preparation method of thrombocythemia agent, preparation process are as follows：Intermediate 1 and intermediate 2 carry out amidation process in non-protonic solvent under catalyst action；Alkali progress basic hydrolysis is added in the solvent of intermediate A and obtains target compound.The first synthetic intermediate 2 of the present invention, then reacted with intermediate 1；The synthetic route of the present invention is reacted for convergent type, and yield improves, and is easy to quality control.In addition, the feasibility that we react amplification is studied, the operation such as column chromatography is avoided, the technique for being more suitable for industrialization production, reduces the discharge of waste liquid.Route products obtained therefrom purity of the present invention is high, high income, and pollution is small, is adapted to industrialized production.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of preparation method of thrombocythemia agent.
Technical background
Blood platelet is the cytode played an important roll in physiological hemostasis and pathologic thrombus forming process, by live body
Polymerization cell persistently produce.As other haemocytes, blood platelet is derived from polymerization cell, promegakaryocyte and megacaryocyte.
During megakaryocytic maturation, precocious megacaryocyte is not only related to cell division to become the DNA of polyploid synthesis.
Thereafter, cytoplasm starts ripe to form blood platelet seperation film, and passes through the broken release blood platelet of cytoplasm.
Thrombopenia is the disease being clinically commonly encountered, and is common in tumor radiotherapy, chemotherapy and Patients Following Bone Marrowtransplantation,
See ITP (ITP), myelodysplastic syndrome (MDS) and chronic liver disease etc..
Avatrombopag is second oral non-peptide analoglike thing, can be swashed and what is searched by library screening
The micromolecular compound of thrombopoietin (TPO) acceptor living.Avatrombopag absorbs good, linear pharmacokinetics
Feature, half-life period 16h.In vitro can stimulating human CD34 cells and megacaryocyte propagation, and can stimulating human fetal livers
Human blood platelets generation after dirty CD34 cell transplantations in Mice Body.In vitro test shows that Avatrombopag can promote TPO to rely on
Cell line growth, increases the ability of CD34+ Hemapoiesis megacaryocytes, and can stimulate in transplanting people's tire liver CD34+ Mice Bodies
Human blood platelets generates.Clinicalⅰstage research shows that healthy volunteer has good tolerance to Avatrombopag, without serious
Side reaction occur.After healthy volunteer takes single or multiple dosage Avatrombopag, dosage is presented in hematoblastic produce
With concentration correlation effect.
Avatrombopag's and its like derivatives synthesis, has been retouched in its original chemical patent CN1639157
State, but only refer to reaction expression, specific reaction scheme is not described, also the amplification feasibility of reaction is not ground
Study carefully, and be unfavorable for the technique of amplification using column chromatography etc., product quality is not also reported.
In general, the regular course for synthesizing Avatrombopag is straight chain type reaction, and same reaction can make starting material
Consume larger, total recovery is low；One link is problematic to directly affect whole piece production line.
Straight chain type reacts (contrast)：
The content of the invention
It is an object of the invention to provide a kind of preparation method of thrombocythemia agent, method is controllable, is easy to amplification production, fits
Industrialized production is closed, obtains product purity height, yield is good, pollutes small, the correlative study for pharmaceutical raw material medicine.
A kind of preparation method of thrombocythemia agent, preparation process are as follows：
(1) intermediate 1 and intermediate 2 carry out amidation process in non-protonic solvent under catalyst action；
(2) alkali progress basic hydrolysis is added in the solvent of intermediate A and obtains target compound.
The preparation method of described thrombocythemia agent, in step (1), intermediate 1 and intermediate 2 react acylated examination used
Agent is POCl3, thionyl chloride or oxalyl chloride.
Non-protonic solvent used in step (1) is acetone, acetonitrile, tetrahydrofuran or dichloromethane.
Catalyst used in step (1) is pyridine, DMAP or DMA.
Alkali used is potassium hydroxide, sodium hydroxide or lithium hydroxide in step (2).
Solvent is tetrahydrofuran, methanol, ethanol or isopropanol in step (2).
Using 4- (the chloro- 2- thienyls of 4-)-abadol as raw material in the preparation process of intermediate 1.
Using one kettle way or in two steps, reaction obtains in the synthesis of intermediate 1.
The preparation method of intermediate 1 is that 4- (the chloro- 2- thienyls of 4-)-abadol is obtained by halo and aminating reaction, is made
Standby equation is as follows:
One kettle way is used in the synthesis of intermediate 1, is comprised the following steps that：
4- (the chloro- 2- thienyls of 4-)-abadol is dissolved in reaction dissolvent, bromo, Ran Houyu are carried out by adding NBS
Cyclohexylpiperazin is reacted, and obtains intermediate 1, and acid binding agent potassium carbonate is added in reaction.
NBS (N-bromosuccinimide) described in above-mentioned stepwise reaction or one kettle way preparation is bromating agent.
Reaction dissolvent described in above-mentioned stepwise reaction or one kettle way preparation is tetrahydrofuran, methyl tertiary butyl ether(MTBE), N-
Methyl pyrrolidone or DMF；
The preparation method of intermediate 2 is that 5,6- dichloro-nicotinic acids and 4- piperidine ethyl formates react to obtain, and it is as follows to prepare equation:
In the synthesis of intermediate 2, tetrahydrofuran, methyl tertiary butyl ether(MTBE) or DMF are used as solvent；Add
Enter sodium hydroxide, sodium acid carbonate or sodium carbonate；Add Malaysia acid for adjusting pH ＜ 2；Extracted with dichloromethane and/or ethyl acetate etc.,
Washing, is concentrated to give product.
A kind of convergent type preparation method of Avatrombopag intermediate As, by the way that intermediate 1 is prepared one step ahead respectively
With intermediate 2, then it polymerize to obtain key intermediate A.By way of convergent type reaction, reach shortening route, technique more may be used
Control.
Compared with prior art, the invention has the advantages that：
The first synthetic intermediate 2 of the present invention, then reacted with intermediate 1；The synthetic route of the present invention is reacted for convergent type, yield
Improve, be easy to quality control.In addition, the feasibility that we react amplification is studied, the operation such as column chromatography is avoided, is more suitable for
The technique of industrialization production, reduces the discharge of waste liquid.Route products obtained therefrom purity of the present invention is high, high income, and pollution is small, is adapted to
Industrialized production.
Embodiment
With reference to embodiment, the present invention will be further described.
Embodiment 1
1st, the preparation method of intermediate 1
4- (the chloro- 2- thienyls of 4-)-abadol (200g) is dissolved in 1-METHYLPYRROLIDONE 3L, adds N- bromo ambers
Amber acid imide (NBS) (166g), 30min is stirred under ice bath.HPLC monitoring reaction completely after, add cyclohexylpiperazin (280g) and
Potassium carbonate (234g), stirred in 60 DEG C of oil baths.HPLC is tracked, and reaction in 5 hours is finished.After cooling, water 3L is added, yellowish-brown is separated out and consolidates
Body.Yield 81%.HPLC purity 95.04%.
2nd, prepared by intermediate 2
5,6- dichloro-nicotinic acids (250g) and 4- piperidine ethyl formates (210g) are dissolved in THF (1.25L), back flow reaction,
3h is stirred, HPLC tracking reactions are complete, add sodium acid carbonate, are stirred at room temperature 0.5 hour.Malaysia sour water is added dropwise into reaction solution again
Solution adjusts ph to 1, is extracted with dichloromethane (1L × 2), washes liquid separation.Concentration, add n-hexane 2L and separate out solid.Among obtaining
Body 2, white solid, yield 88%.HPLC purity 99.89%.
3rd, prepared by intermediate A
Intermediate 2 (327g) is dissolved in dichloromethane 1L, adds DMA, -20 DEG C of coolings are lower to be added dropwise chlorine
Change sulfoxide (130g), stir 1h, reaction solution is added dropwise in the dichloromethane 3L solution of intermediate 1 (400g), it is small to be stirred at room temperature 1
When, HPLC tracking reactions are complete.Saturation sodium hydrate aqueous solution, liquid separation are added dropwise in reaction solution.Concentration, add n-hexane and separate out admittedly
Body.Obtain intermediate A, slightly yellow solid 585g, yield 83%.HPLC purity 98.61%.
4th, prepared by Avatrombopag
Intermediate A (200g) is dissolved into methanol 4L, is hydrogenated with sodium oxide molybdena 37g, 60 DEG C of stirring 2h, HPLC monitorings at room temperature
Reaction is complete.Room temperature is down to, adds 1M aqueous hydrochloric acid solution (910mL), separates out solid, is filtered, washing.
Avatrombopag, yield 92%.Product continues to recrystallize with tetrahydrofuran 800mL, is refining to obtain highly finished product.HPLC purity
99.82%.
Embodiment 2
1st, the preparation method of intermediate 1
1) preparation of 4- (the chloro- 2- thienyls of 4-) bromo- abadols of -5-：
4- (the chloro- 2- thienyls of 4-)-abadol (700g) is dissolved in DMF (3.5L), is placed in cooling down in ice-water bath,
NBS (605g) is added, 0.5h is stirred under ice-water bath.HPLC is tracked, and reaction is complete.At room temperature, reaction solution is added dropwise in water 10L
In, there are a large amount of solids to produce.Filter, filter cake is washed with water, and dries, obtains pale solid, 4- (the chloro- 2- thienyls of 4-) bromo- 2- of -5-
Thiazole amine, yield 91%, HPLC purity 98.97%.
2) preparation method of intermediate 1
4- (the chloro- 2- thienyls of 4-) bromo- abadols of -5- (650g) are dissolved in DMF (4.9L), add cyclohexylpiperazin
(550g), potassium carbonate (300g), 4h is stirred in 70 DEG C of oil baths.HPLC is tracked, and reaction is complete.Add water (10L) in reaction solution,
EtOAc (3L × 3) is extracted.Merge organic phase, distillation washing (4L × 2), saturated common salt washing (5L), anhydrous sodium sulfate drying.
Solid precipitation has been concentrated into, has added n-hexane to separate out solid complete.Filter, Tan solid 720g, yield 85%, HPLC purity
98.13%.
2nd, the preparation method of intermediate 2
5,6- dichloro-nicotinic acids (500g) and 4- piperidine ethyl formates (409g) are dissolved in methyl tertiary butyl ether(MTBE) (2.5L), returned
Stream reaction, stirs 3h.HPLC tracking reactions are complete.Sodium hydroxide is added, is stirred at room temperature 0.5 hour.It is added dropwise again into reaction solution
Malaysia sour water regulation ph to 1, dichloromethane (2L) extraction, washes liquid separation.Concentration, add n-hexane and separate out solid.Obtain intermediate
2, white solid, yield 86%.HPLC purity 99.32%.
3rd, intermediate A preparation method
Intermediate 1 (300g) and intermediate 2 (245g) are dissolved in pyridine, under -20 DEG C of coolings, POCl3 is added dropwise
(132g), drop finishes to be transferred to stirs 1h at room temperature.HPLC tracking reactions are complete.Lithium hydroxide aqueous solution is added dropwise in reaction solution, analyses
Go out solid.After filtering, washing.Obtain intermediate A, slightly yellow solid, 410g, yield 78%.HPLC purity 97.95%.
4th, Avatrombopag preparation methods
Intermediate A (120g) is dissolved into tetrahydrofuran (240mL), is hydrogenated with potassium oxide (29g), 60 DEG C of stirrings at room temperature
2h, HPLC monitoring reaction are complete.Room temperature is down to, adds water 720mL, 1M aqueous hydrochloric acid solution 545mL is added dropwise, separates out solid, mistake
Filter, washing.Obtain Avatrombopag, yield 94%.HPLC purity 97.45%.
Embodiment 3
1st, the preparation method of intermediate 1
1) preparation of 4- (the chloro- 2- thienyls of 4-) bromo- abadols of -5-：
4- (the chloro- 2- thienyls of 4-)-abadol (64g) is dissolved in methyl tertiary butyl ether(MTBE) (350mL), is placed in frozen water
Cooled down in bath, add NBS (55g), stir 1.5h.HPLC is tracked, and reaction is complete.At room temperature, reaction is added dropwise in water 300mL
In liquid, liquid separation；Salt solution 300mL is added to stir, liquid separation.N-hexane 250mL is added, separates out solid, is filtered, is dried, is obtained canescence and consolidate
Body, 4- (the chloro- 2- thienyls of 4-) bromo- abadols of -5-, yield 94%, HPLC purity 97.44%.
2) prepared by intermediate 1
4- (the chloro- 2- thienyls of 4-) bromo- abadols of -5- (65g) are dissolved in tetrahydrofuran (400mL), add hexamethylene
Base piperazine (55g), potassium carbonate (30g), 70 DEG C of return stirring 6h.HPLC is tracked, and reaction is complete.Add water (2.4L) in reaction solution,
Solid separates out.Filter, Tan solid 61g, yield 74%, HPLC purity 95.87%.
2nd, the preparation method of intermediate 2
5,6- dichloro-nicotinic acids (80g) and 4- piperidine ethyl formates (65g) are dissolved in DMF (400mL)
In, back flow reaction, 3h is stirred, HPLC tracking reactions are complete, add sodium carbonate, are stirred at room temperature 0.5 hour.Dripped again into reaction solution
Add aqueous maleic acid to adjust ph to 1, extracted with dichloromethane 350mL, wash liquid separation.Concentration, add n-hexane and separate out solid.
Obtain intermediate 2, yield 89%.HPLC purity 98.86%.
3rd, intermediate A preparation method
Intermediate 1 (15g) and intermediate 2 (12.5g) are dissolved in acetone (60mL), add DMAP, it is cold
But under, POCl3 (6.1g) is added dropwise, drop finishes to be transferred to stirs 1.5h at room temperature.It is complete that HPLC tracks to reaction.In reaction solution
Potassium hydroxide aqueous solution is added dropwise, is extracted with ethyl acetate (60mL × 3), anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure, with second
Acetoacetic ester/n-hexane (1:1) it is beaten, after filtering.Obtain intermediate A, slightly yellow solid, yield 80%.HPLC purity 98.43%.
4th, Avatrombopag preparation methods
Intermediate A (30g) is dissolved into isopropanol (60mL), is hydrogenated with potassium oxide (7.4g) at room temperature, 60 DEG C are stirred 2h,
HPLC monitoring reactions are complete.Room temperature is down to, 1M aqueous hydrochloric acid solution 135mL is added dropwise, separates out solid, is filtered, washing.
Avatrombopag, yield 95%.HPLC purity 97.01%.
Claims (8)
1. a kind of preparation method of thrombocythemia agent, it is characterised in that preparation process is as follows：
(1) intermediate 1 and intermediate 2 carry out amidation process in non-protonic solvent under catalyst action；
(2) alkali progress basic hydrolysis is added in the solvent of intermediate A and obtains target compound.
2. the preparation method of thrombocythemia agent according to claim 1, it is characterised in that in step (1), intermediate 1
It is POCl3, thionyl chloride or oxalyl chloride to react acylating reagent used with intermediate 2.
3. the preparation method of thrombocythemia agent according to claim 1, it is characterised in that the non-matter used in step (1)
Sub- property solvent is acetone, acetonitrile, tetrahydrofuran or dichloromethane.
4. the preparation method of thrombocythemia agent according to claim 1, it is characterised in that the catalysis used in step (1)
Agent is pyridine, DMAP or N, accelerine.
5. the preparation method of thrombocythemia agent according to claim 1, it is characterised in that alkali used in step (2)
For potassium hydroxide, sodium hydroxide or lithium hydroxide.
6. the preparation method of thrombocythemia agent according to claim 1, it is characterised in that solvent is four in step (2)
Hydrogen furans, methanol, ethanol or isopropanol.
7. the preparation method of thrombocythemia agent according to claim 1, it is characterised in that in the preparation process of intermediate 1
Using 4- (the chloro- 2- thienyls of 4-)-abadol as raw material.
8. the preparation method of thrombocythemia agent according to claim 1, it is characterised in that the wherein preparation method of mesosome 2
To react to obtain by 5,6- dichloro-nicotinic acids and 4- piperidine ethyl formates, it is as follows to prepare equation:
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| CN201710664827.6A CN107383000A (en) | 2017-08-07 | 2017-08-07 | The preparation method of thrombocythemia agent |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2709496C1 (en) * | 2019-08-01 | 2019-12-18 | Марат Феликсович Фазылов | Method of producing avatrombopag |
| CN111620863A (en) * | 2020-06-23 | 2020-09-04 | 苏州明锐医药科技有限公司 | Preparation method of atrabopag |
| CN115477644A (en) * | 2022-09-28 | 2022-12-16 | 湖南先施制药有限公司 | Alvatripopa maleate impurity single crystal and preparation method and application thereof |
| CN115477645A (en) * | 2022-09-28 | 2022-12-16 | 湖南先施制药有限公司 | Alvatripopa maleate series impurities and preparation method and application thereof |
| CN115504975A (en) * | 2022-10-18 | 2022-12-23 | 河北常山凯库得生物技术有限公司 | Preparation method of Alvatripopa maleate intermediate |
| CN115925680A (en) * | 2022-12-02 | 2023-04-07 | 浙江工业大学 | Trifluoromethyl-containing pyridine compound and preparation method and application thereof |
| CN116396271A (en) * | 2022-10-26 | 2023-07-07 | 湖南先施制药有限公司 | Series of maleic acid atorvastatin impurities as well as preparation method and application thereof |
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| WO2004029049A1 (en) * | 2002-09-30 | 2004-04-08 | Yamanouchi Pharmaceutical Co., Ltd. | Novel salt of 2-acylaminothiazole derivative |
| US20040077697A1 (en) * | 2001-02-02 | 2004-04-22 | Hiroyuki Koshio | 2-Acylaminothiazole derivative or its salt |
| CN1639157A (en) * | 2002-01-18 | 2005-07-13 | 山之内制药株式会社 | 2-acylaminothiazole derivative or salt thereof |
| WO2007036769A1 (en) * | 2005-07-05 | 2007-04-05 | Pfizer Products Inc. | Aminothiazole derivatives as agonists of the thrombopoietin receptor |
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2017
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Patent Citations (4)
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| US20040077697A1 (en) * | 2001-02-02 | 2004-04-22 | Hiroyuki Koshio | 2-Acylaminothiazole derivative or its salt |
| CN1639157A (en) * | 2002-01-18 | 2005-07-13 | 山之内制药株式会社 | 2-acylaminothiazole derivative or salt thereof |
| WO2004029049A1 (en) * | 2002-09-30 | 2004-04-08 | Yamanouchi Pharmaceutical Co., Ltd. | Novel salt of 2-acylaminothiazole derivative |
| WO2007036769A1 (en) * | 2005-07-05 | 2007-04-05 | Pfizer Products Inc. | Aminothiazole derivatives as agonists of the thrombopoietin receptor |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2709496C1 (en) * | 2019-08-01 | 2019-12-18 | Марат Феликсович Фазылов | Method of producing avatrombopag |
| WO2021021000A1 (en) * | 2019-08-01 | 2021-02-04 | Марат Феликсович ФАЗЫЛОВ | Method for producing avatrombopag |
| CN111620863A (en) * | 2020-06-23 | 2020-09-04 | 苏州明锐医药科技有限公司 | Preparation method of atrabopag |
| CN115477644A (en) * | 2022-09-28 | 2022-12-16 | 湖南先施制药有限公司 | Alvatripopa maleate impurity single crystal and preparation method and application thereof |
| CN115477645A (en) * | 2022-09-28 | 2022-12-16 | 湖南先施制药有限公司 | Alvatripopa maleate series impurities and preparation method and application thereof |
| CN115504975A (en) * | 2022-10-18 | 2022-12-23 | 河北常山凯库得生物技术有限公司 | Preparation method of Alvatripopa maleate intermediate |
| CN116396271A (en) * | 2022-10-26 | 2023-07-07 | 湖南先施制药有限公司 | Series of maleic acid atorvastatin impurities as well as preparation method and application thereof |
| CN115925680A (en) * | 2022-12-02 | 2023-04-07 | 浙江工业大学 | Trifluoromethyl-containing pyridine compound and preparation method and application thereof |
| CN115925680B (en) * | 2022-12-02 | 2024-01-23 | 浙江工业大学 | Trifluoromethyl-containing pyridine compound and preparation method and application thereof |
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