CN110526870A - A kind of preparation method of eltrombopag olamine - Google Patents
A kind of preparation method of eltrombopag olamine Download PDFInfo
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- CN110526870A CN110526870A CN201910929363.6A CN201910929363A CN110526870A CN 110526870 A CN110526870 A CN 110526870A CN 201910929363 A CN201910929363 A CN 201910929363A CN 110526870 A CN110526870 A CN 110526870A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
- C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
Abstract
The present invention relates to medical manufacturing technology fields, and disclose a kind of preparation method of eltrombopag olamine, comprising the following steps: 1. successively by starting material I, glacial acetic acid, hydrobromic acid sustained response to finishing to obtain intermediate I.2. intermediate I obtains intermediate II through hydrazine hydrate reduction under palladium chtalyst effect.3. intermediate II obtains eltrombopag olamine through diazotising addition.This method avoids being reduced directly nitro with hydrogen under the premise of ensuring drug quality, and production that can be safe is amplified, and increases the market competitiveness of the kind.
Description
Technical field
The present invention relates to medical manufacturing technology field, specially a kind of preparation method of eltrombopag olamine.
Background technique
Eltrombopag olamine (entitled 3'- [(2Z)-[1- (3,4- 3,5-dimethylphenyl) -1,5- dihydro -3- methyl -5- oxo-of chemistry
4H- pyridine -4- subunit] diazanyl -2'- carboxyl-[1,1'- xenyl] -3- carboxylic acid, molecular formula C25H22N4O4):
It is the oral platelet generation factor type drug of Britain's GlaxoSmithKline PLC company exploitation, is small molecule thrombopoietin
Receptor stimulating agent, it can interact with the thrombopoietin receptor of human body transmembrane region, generate signal cascade amplification, from
And the proliferation and differentiation of inducing bone marrow megacaryocyte, the medicine obtain Food and Drug Adminstration of the US (FDA) batch in November, 2008
Standard lists in the U.S., and for treating through glucocorticoid medicine, immunoglobulin therapy is invalid or the chronic spy of Postsplenectomy
The decrease of platelet of hair property thrombocytopenic purpura (ITP) patient, eltrombopag olamine are that the first treatment Adult chronic ITP that is approved suffers from
Person's takes orally non-peptides thrombopoietin receptor agonist, and approval treatment ITP patient is an important milestone, currently, should
Medicine is also ground in the clinic for carrying out treatment Hepatitis C Virus, chronic liver disease and caused thrombopenia relevant with tumour
Study carefully.
Such as one kind disclosed in Chinese patent CN201710766607.4 is for treating idiopathic thrombocytopenic purple
The preparation method of the drug eltrombopag olamine of purplish or white patches on the skin, the preparation process reduce the toxic components of drug, are beneficial to the subsequent system of drug
The quality for making and guaranteeing product can promote the economic technology development of eltrombopag olamine bulk pharmaceutical chemicals, but according to the preparation stream of the invention
From the point of view of journey, for the preparation of drug eltrombopag olamine, chemical reaction process therein is complicated, and raw material is more difficult to get, and increases production
Cost is unsuitable for producing in enormous quantities, and need to utilize hydrogen reducing nitro, is unfavorable for realizing industrialization, so propose a kind of Chinese mugwort
The preparation method of bent wave pa is set forth above to solve the problems, such as.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of preparation method of eltrombopag olamine, there is efficiently preparation work
The advantages that skill is safer solves the problems, such as to be difficult to industrialize in its reaction process and preparation flow is longer.
For the purpose for realizing the above-mentioned efficient safer environmental protection of preparation process, the invention provides the following technical scheme:
A kind of preparation method of eltrombopag olamine, it is characterised in that the following steps are included:
1) it successively takes starting material I, glacial acetic acid, hydrobromic acid to be reacted, filters after completion of the reaction, filter cake obtains intermediate after drying
Body I
Starting material I: glacial acetic acid: the equivalent proportion of hydrobromic acid is 1:11.7vol:5.85vol；
2) palladium catalyst and hydrazine hydrate reduction act on lower generation intermediate II to intermediate I in water；
Intermediate I: palladium catalyst: the equivalent proportion of hydrazine hydrate is 1:2%-12%w/w:5vol;
3) effect of the intermediate II through hydrochloric acid and sodium nitrite and the progress diazotising addition generation eltrombopag olamine of starting material II are thick
Product；Eltrombopag olamine is made by recrystallizing；
Intermediate II: sodium nitrite: the molar ratio of starting material II is 1:1.05:1.Wherein the hydrobromic acid is dilute by hydrobromic acid
It releases to 48% aqueous solution.The palladium catalyst is palladium carbon, palladium dydroxide or palladium chloride；Palladium charcoal refers to: the palladium of 2%-5% is negative
It is downloaded on active carbon and is made, and the content of palladium charcoal is 2%-5%.The hydrazine hydrate is the aqueous solution of 40%-98%.
It is preferred that the aqueous solution that hydrazine hydrate is 98%.The recrystallization solvent is tetrahydrofuran/n-hexane or 2- methyl tetrahydro
Furans/petroleum ether.It is preferred that it is 1:3 that recrystallization solvent, which is tetrahydrofuran/n-hexane ratio,.
More detailed description of the present invention is as follows:
A kind of preparation method of eltrombopag olamine, comprising the following steps:
1) it successively takes starting material I, glacial acetic acid, hydrobromic acid to be reacted, filters after completion of the reaction, filter cake obtains intermediate after drying
Body I；
2) palladium catalyst and hydrazine hydrate reduction act on lower generation intermediate II to intermediate I in water；
3) effect of the intermediate II through hydrochloric acid and sodium nitrite and the progress diazotising addition generation eltrombopag olamine of starting material II are thick
Product；Eltrombopag olamine is made by recrystallizing.
The hydrobromic acid is the aqueous solution that 48% is diluted to by hydrobromic acid.
The palladium catalyst includes palladium carbon, palladium dydroxide, palladium chloride.
The palladium carbon is to be loaded on active carbon to be made by the palladium of 2%-5%, and the content of palladium charcoal is 2%-5%.
The hydrazine hydrate be 40%-98% aqueous solution, preferably hydrazine hydrate be 98% aqueous solution.
Recrystallization solvent is tetrahydrofuran/n-hexane, and 2- methyltetrahydrofuran/petroleum ether, wherein recrystallization solvent is four
Ratio is 1:3 when hydrogen furans/n-hexane.
The quality control standard of eltrombopag olamine prepared by the present invention specifically includes that under conditions of normal temperature storage, finished product is in
Red or brown crystals powder is slightly soluble in water, and single largest impurity must not cross 0.1%, and total impurities must not cross 1.0%.
The preparation method of eltrombopag olamine disclosed by the invention compared with prior art, have it is following the utility model has the advantages that
(1) preparation method of the eltrombopag olamine, by starting material I after demethylation, reduction with starting material II through diazotising
Addition obtains eltrombopag olamine.Starting material is more easy to get in the process, and reaction route is relatively simple, and operability is stronger.
(2) preparation method of eltrombopag olamine, by that chemical reaction process can be made to add in step 2 hydrazine hydrate reduction nitro
Fastly, the time of preparation is reduced, while being solved hydrogen reducing nitro and being unfavorable for industrialized problem.
(3) preparation method of the eltrombopag olamine, by controlling intermediate II, starting material II, nitrous acid in step 3)
The ratio of sodium is classified as 1:1:1.05, and reaching control impurity, (single largest impurity must not cross 0.1%, and total impurities must not cross base 1.0%)
Reaction can be made more rapidly so that the time of preparation process is reduced, improve the preparation of eltrombopag olamine on plinth
Speed enhances the competitiveness of enterprise.
(4) reaction yield, purity are higher, and safety is stronger, meet the requirement of industrialized production.
Specific embodiment
To keep the purposes, technical schemes and advantages of the application clearer, below in conjunction with the application specific embodiment pair
Technical scheme is clearly and completely described.Obviously, described embodiment is only some embodiments of the present application,
Instead of all the embodiments.Based on the embodiment in the application, those of ordinary skill in the art are not making creative labor
Every other embodiment obtained under the premise of dynamic, shall fall in the protection scope of this application.
Wherein starting material I (2'- methoxyl group-3'- nitrobiphenyl-3- carboxylic acid), (the 3- methyl-1-(3,4- of starting material II
3,5-dimethylphenyl) -2- pyrazolin-5-one) it purchases from hundred friendship Biotechnology Co., Ltd of Shanghai.
Embodiment 1:
The preparation method of eltrombopag olamine:
1) 34.10g starting material I, 400ml glacial acetic acid and 200ml hydrobromic acid (48%) are weighed in 1L there-necked flask, opens stirring,
120 DEG C are warming up to, is reacted 3 hours, reaction is stopped.25 DEG C are cooled to, is filtered, filter cake is beaten with about 400ml water and is filtered, at 55 DEG C
It is 6 hours dry, obtain 30.7g greenish yellow solid intermediate I, yield 94.9%, purity: 96.5%.1HNMR(400MHz,d6DMSO)δ
13.90(s, 1H), 10.66 (s, 1H), 8.12 (t, J=1.7Hz, 1H),
8.07(dd,J=8.4,1.7Hz,1H),7.98(dt,7.8,1.5Hz,1H),7.74(dd,J=7.5,1.7Hz,1H),
7.17(dd,J=8.4,7.5Hz,1H)。
2) 30g intermediate I, 1.2gPd/C, 150ml water are weighed in 500ml there-necked flask, 150ml water is added dropwise into system
It closes hydrazine (98%), during which heat release is deflated acutely, and 25 DEG C of temperature control.85 DEG C are warming up to after being added dropwise, reaction was down to room temperature after two hours
It filtering, filtrate cools down 5 DEG C, and pH to 7-8 is adjusted with concentrated hydrochloric acid, is filtered, filter cake 50ml water washing, forced air drying at 55 DEG C.
To 19.05g light tan solid intermediate II, yield 71.8%, purity: 97.6%.1HNMR(400MHz,d6DMSO)11.3-8.7
(brs,4H),8.08(s,1H),7.95(d,J=7.8Hz,1H),7.74(d,J=7.8Hz,1H),7.61(t,J=7.8Hz,1H),
7.34(dd,J=7.8,1.4Hz,1H),7.24(dd,J=7.8,1.3Hz,1H),7.04(t,J=7.8Hz,1H)。
3) 19.05g intermediate II, 285ml hydrochloric acid (2M) are weighed in 1L there-necked flask, 0 DEG C of temperature control is added into system
The 96ml aqueous solution of 6.12g sodium nitrite is added after starting material II stirs 0.5 hour at 0 DEG C and 379ml ethyl alcohol, carbon is added
Sour hydrogen sodium adjusts pH to 7-8.It is filtered after stirring 24 hours at room temperature, filter cake is beaten 0.5h with 421ml water, filters, and filter cake is used again
421ml concentrated hydrochloric acid acidification mashing 0.5h, filters, and filter cake 126ml tetrahydrofuran and 379ml n-hexane are heated to reflux dissolved clarification
Afterwards, it is cooled to after persistently stirring 2 hours at 0 DEG C and filters, worry, which is finished, is put into forced air drying 12h at 55 DEG C for solid, obtains 12.47g depth
Red solid, yield 33.9%, purity: 99.5%.1HNMR(400MHz,d6DMSO) 13.76(s,1H),13.12(s,1H),
9.70(s,1H),8.14(s,1H),7.81(dd,J=7.7Hz,1H),7.74-7.60(m,5H),7.22-7.13(m,3H),
2.34(s,3H),2.27(s,3H),2.23(s,3H)。
According to eltrombopag olamine obtained by above-mentioned formula and technique, miscellaneous list is 0.08%, and total impurities 0.47% are suitable for
Most of insufficient patient of blood platelet, which treats, to be used, and the competitiveness of enterprise is improved.
Embodiment 2:
The preparation method of eltrombopag olamine:
1) 341g starting material I, 4L glacial acetic acid and 2L hydrobromic acid (48%) are weighed in 1L there-necked flask, stirring is opened, is warming up to
After 120 DEG C, reaction 3 hours, stop reaction.25 DEG C are cooled to, is filtered, filter cake is beaten with about 4L water and is filtered, and dry 6 is small at 55 DEG C
When 310g greenish yellow solid intermediate I, yield 95.8%, purity: 96.7%.
1HNMR(400MHz, d6DMSO) δ 13.90(s, 1H), 10.66 (s, 1H), 8.12 (t, J=1.7Hz, 1H), 8.07
(dd,J=8.4,1.7Hz,1H),7.98(dt,7.8,1.5Hz,1H),7.74(d d,J=7.5,1.7Hz,1H),7.17
(dd,J=8.4,7.5Hz,1H)。
2) 300g intermediate I, 6gPd/C, 1.5L water are weighed in 5L there-necked flask, 1.5L hydrazine hydrate is added dropwise into system
(98%), during which heat release is deflated acutely, and 25 DEG C of temperature control.85 DEG C are warming up to after being added dropwise, room temperature pumping is down in reaction after two hours
Filter, filtrate cool down 5 DEG C, adjust pH to 7-8 with concentrated hydrochloric acid, filter, and filter cake 500ml water washing, forced air drying at 55 DEG C obtain
193.14g light tan solid intermediate II, yield 72.8%, purity: 97.3%.1HNMR(400MHz,d6DMSO)1.3-8.7
(brs,4H),8.08(s,1H) ,7.95(d,J=7.8Hz,1H),7.74(d,J=7.8Hz,1H),7.61(t,J=7.8Hz,
1H),7.34(dd,J=7.8,1.4Hz,1H),7.24(dd,J=7.8,1.3Hz,1H),7.04(t,J=7.8Hz,1H)。
3) 190g intermediate II, 2.86L hydrochloric acid (2M) are weighed in 10L four-hole bottle, 0 DEG C of temperature control is added into system
The 0.96L aqueous solution of 61.04g sodium nitrite is added after starting material II stirs 0.5 hour at 0 DEG C and 3.78L ethyl alcohol is added,
Sodium bicarbonate adjusts pH to 7-8.It is filtered after stirring 24 hours at room temperature, filter cake is beaten 0.5h with 4.2L water, filters, and filter cake is used again
After 4.2L concentrated hydrochloric acid acidification mashing 0.5h, suction filtration, filter cake 1.26L tetrahydrofuran and 3.78L n-hexane are heated to reflux dissolved clarification,
It is cooled to after persistently stirring 2 hours at 0 DEG C and filters, worry, which is finished, is put into forced air drying 12h at 55 DEG C for solid, and it is dark red to obtain 128.72g
Color solid, yield 35.1%, purity: 99.1%.1HNMR(400MHz,d6DMSO)13.76(s,1H),13.12(s,1H),9.70
(s,1H),8.14(s,1H),7.81(dd,J=7.7Hz,1H),7.74-7.60(m,5H),7.22-7.13(m,3H),2.34(s,
3H),2.27(s,3H),2.23(s,3H)。
According to eltrombopag olamine obtained by above-mentioned formula and technique, miscellaneous list is 0.09%, total impurities 0.87%, and due to
Palladium carbon amount used is 2% mass ratio in intermediate I, and cost of manufacture is lower, is suitble to promote production preparation.
Embodiment 3:
The preparation method of eltrombopag olamine:
1) 3.41g starting material I, 40ml glacial acetic acid and 48% hydrobromic acid of 20ml (48%) are weighed in 100ml there-necked flask, is opened
Stirring stops reaction after being warming up to 120 DEG C, reaction 3 hours.25 DEG C are cooled to, is filtered, filter cake is beaten with about 40ml water and is filtered,
Dry 6 hours 3.10g greenish yellow solid intermediate Is at 55 DEG C, yield: 92.7%, purity: 96.1%.1HNMR(400MHz,
d6DMSO) δ 13.9(s, 1H), 10.66 (s, 1H), 8.12 (t, J=1.7Hz, 1H),
8.07(dd,J=8.4,1.7Hz,1H), 7.98(dt,7.8,1.5Hz,1H),7.74(dd,J=7.5,1.7Hz,1H)
,7.17(dd,J=8.4,7.5Hz,1H)。
2) 3g intermediate I, 0.15gPd/C, 15ml water are weighed in 100ml there-necked flask, 15ml 98% is added dropwise into system
Hydrazine hydrate, during which heat release deflate acutely, 25 DEG C of temperature control.85 DEG C are warming up to after being added dropwise, reaction was down to room temperature after two hours
It filters, filtrate cools down 5 DEG C, adjusts pH to 7-8 with concentrated hydrochloric acid, filters, and filter cake 5ml water washing, forced air drying at 55 DEG C obtain
1.86g light tan solid intermediate II, yield 69.6%, purity: 98.0%.
1HNMR(400MHz,d6DMSO)1.3-8.7(brs,4H),8.08(s,1H) ,7.95(d,J=7.8Hz,1H),
7.74(d,J=7.8Hz,1H),7.61(t,J=7.8Hz,1H),7.34(dd,J=7.8,1.4Hz,1H),7.24(dd,J=7.8,
1.3Hz,1H),7.04(t,J=7.8Hz,1H)。
3) 1.86g intermediate II, 28ml 2M hydrochloric acid are weighed in 100ml there-necked flask, 0 DEG C of temperature control is added into system
The 10ml aqueous solution of 0.60g sodium nitrite is added after starting material II stirs 0.5 hour at 0 DEG C and 37ml ethyl alcohol, carbonic acid is added
Hydrogen sodium adjusts pH to 7-8.It is filtered after stirring 24 hours at room temperature, filter cake is beaten 0.5h with 41ml water, filters, and filter cake uses 41ml again
After concentrated hydrochloric acid acidification mashing 0.5h, suction filtration, filter cake 12ml tetrahydrofuran and 37ml n-hexane are heated to reflux dissolved clarification, it is cooled to
It is filtered after persistently stirring 2 hours at 0 DEG C, worry, which is finished, is put into forced air drying 12h at 55 DEG C for solid, obtains 0.14g dark red solid, receives
Rate 31.9%, purity: 99.5%.1HNMR(400MHz,d6DMSO) 13.76(s,1H),13.12(s,1H),9.70(s,1H),
8.14(s,1H),7.81(dd,J=7.7Hz,1H),7.74-7.60(m,5H),7.22-7.13(m,3H),2.34(s,3H),
2.27(s,3H),2.23(s,3H)。
According to eltrombopag olamine obtained by above-mentioned formula and technique, reaction scale is small, and manufacturing speed is fast, improves the product
Preparation efficiency, can be as the use of general drug.
The beneficial effects of the invention are as follows obtained through demethylation, reduction, with starting material II through diazotising addition by starting material I
Eltrombopag olamine.Starting material is more easy to get in the process, and reaction route is relatively simple, and operability is stronger.By in step
Rapid 2 use hydrazine hydrate reduction nitro, chemical reaction process can be made to accelerate, the time of preparation is reduced, while solving hydrogen also
Former nitro is unfavorable for industrialized problem.By control in step 3 intermediate II, starting material II, sodium nitrite ratio column
For 1:1:1.05, reaching can make reaction that more rapidly the time of preparation process can further can be made to obtain on the basis of controlling impurity
To shorten, the preparation speed of eltrombopag olamine is improved, the competitiveness of enterprise is enhanced.
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
A variety of variations, modification, replacement can be carried out to these embodiments without departing from the principles and spirit of the present invention by understanding
And modification, the scope of the present invention is defined by the appended.
Claims (7)
1. a kind of preparation method of eltrombopag olamine, it is characterised in that the following steps are included:
1) it successively takes starting material I, glacial acetic acid, hydrobromic acid to be reacted, filters after completion of the reaction, filter cake obtains intermediate after drying
Body I
Starting material I: glacial acetic acid: the equivalent proportion of hydrobromic acid is 1:11-12vol:5-6vol；
Palladium catalyst and hydrazine hydrate reduction act on lower generation intermediate II to intermediate I in water；
Intermediate I: palladium catalyst: the equivalent proportion of hydrazine hydrate is 1:2%-12%w/w:5-6vol;
3) effect of the intermediate II through hydrochloric acid and sodium nitrite and the progress diazotising addition generation eltrombopag olamine of starting material II are thick
Product；Eltrombopag olamine is made by recrystallizing；
Intermediate II: sodium nitrite: the molar ratio of starting material II is 1:1-2.5:1-2.
2. preparation method described in claim 1, wherein the hydrobromic acid is the aqueous solution for being diluted to 48% by hydrobromic acid.
3. preparation method described in claim 1, wherein the palladium catalyst is palladium carbon, palladium dydroxide or palladium chloride；Palladium charcoal
Refer to: the palladium of 2%-5% is loaded on active carbon and is made, and the content of palladium charcoal is 2%-5%.
4. preparation method described in claim 1, wherein the hydrazine hydrate is the aqueous solution of 40%-98%.
5. preparation method as claimed in claim 4, wherein the aqueous solution that the hydrazine hydrate is 98%.
6. preparation method described in claim 1, wherein the recrystallization solvent is tetrahydrofuran/n-hexane or 2- methyl four
Hydrogen furans/petroleum ether.
7. preparation method described in claim 1, wherein it is 1 that the recrystallization solvent, which is tetrahydrofuran/n-hexane ratio:
3-4。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112552194A (en) * | 2020-12-21 | 2021-03-26 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of drug intermediate for treating idiopathic blood diseases |
| CN114507186A (en) * | 2021-12-02 | 2022-05-17 | 天津力生制药股份有限公司 | Preparation method of eltrombopag |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110212054A1 (en) * | 2000-05-25 | 2011-09-01 | Glaxosmithkline Llc. | Thrombopoietin mimetics |
| CN104725318A (en) * | 2013-12-20 | 2015-06-24 | 北京蓝贝望生物医药科技股份有限公司 | Synthetic method of eltrombopag olamine |
| CN105085276A (en) * | 2014-05-12 | 2015-11-25 | 上海医药工业研究院 | Eltrombopag intermediate and preparation method therefor and application thereof |
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2019
- 2019-09-29 CN CN201910929363.6A patent/CN110526870A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110212054A1 (en) * | 2000-05-25 | 2011-09-01 | Glaxosmithkline Llc. | Thrombopoietin mimetics |
| CN104725318A (en) * | 2013-12-20 | 2015-06-24 | 北京蓝贝望生物医药科技股份有限公司 | Synthetic method of eltrombopag olamine |
| CN105085276A (en) * | 2014-05-12 | 2015-11-25 | 上海医药工业研究院 | Eltrombopag intermediate and preparation method therefor and application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112552194A (en) * | 2020-12-21 | 2021-03-26 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of drug intermediate for treating idiopathic blood diseases |
| CN114507186A (en) * | 2021-12-02 | 2022-05-17 | 天津力生制药股份有限公司 | Preparation method of eltrombopag |
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Application publication date: 20191203 |