CN108658859A - A kind of pleasure cuts down the synthetic method for Buddhist nun - Google Patents
A kind of pleasure cuts down the synthetic method for Buddhist nun Download PDFInfo
- Publication number
- CN108658859A CN108658859A CN201710199573.5A CN201710199573A CN108658859A CN 108658859 A CN108658859 A CN 108658859A CN 201710199573 A CN201710199573 A CN 201710199573A CN 108658859 A CN108658859 A CN 108658859A
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- China
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- solvent
- synthetic method
- chloro
- buddhist nun
- acid
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- ZBTVNIDMGKZSGC-UHFFFAOYSA-N COc1cc2nccc(Cl)c2cc1C(N)=O Chemical compound COc1cc2nccc(Cl)c2cc1C(N)=O ZBTVNIDMGKZSGC-UHFFFAOYSA-N 0.000 description 1
- GKACWNQKWMLZOV-UHFFFAOYSA-N COc1cc2nccc(Oc(cc3Cl)ccc3[N+]([O-])=O)c2cc1C(N)=O Chemical compound COc1cc2nccc(Oc(cc3Cl)ccc3[N+]([O-])=O)c2cc1C(N)=O GKACWNQKWMLZOV-UHFFFAOYSA-N 0.000 description 1
- DKTRZBWXGOPYIX-UHFFFAOYSA-N [O-][N+](c(c(Cl)c1)ccc1O)=O Chemical compound [O-][N+](c(c(Cl)c1)ccc1O)=O DKTRZBWXGOPYIX-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention is that a kind of pleasure cuts down the synthetic method for Buddhist nun, it is to obtain target product pleasure using m-Chlorophenol as raw material by four-step reaction and cut down for Buddhist nun.The step of synthetic method provided by the invention reduces original synthetic route simultaneously maintains higher yield, reduces cost of material, improves Atom economy.
Description
Technical field
The present invention relates to a kind of thyroid cancer drug pleasures for the treatment of to cut down synthetic route for Buddhist nun, belongs to medical synthetic technology neck
Domain.
Background technology
It is happy to cut down for the entitled 4- [3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen]-of Buddhist nun (Lenvatinib, 1) chemistry
7- methoxyl group -6- quinoline formyl amine is a kind of oral polyceptor tyrosine kinase that Japan defends the exploitation of material (Eisai) company
(RTK) inhibitor inhibits the kinase activity of vascular endothelial growth factor (VEGF) receptor VEGFR1, VEGFR2 and VEGFR3,
It is mainly used for treating differentiated thyroid carcinoma (DTC).The medicine obtained U.S. FDA approval listing, trade name on 2 13rd, 2015
Lenvima, in July, 2015, FDA further authorize the happy breakthrough medicine for cutting down and treating late period and/or metastatic renal cell cancer for Buddhist nun
Goods and materials lattice.Its structure is as follows：
It is by the chloro- 7- methoxies of intermediate 4- that the pleasure of existing literature [1,2,3,4] report, which is cut down for the principal synthetic routes of Buddhist nun,
Base quinoline -6- amides (A) are heated under alkali effect with intermediate 1- (2- chloro-4-hydroxyls phenyl) -3- cyclopropyl ureas (9) and are made
Pleasure is cut down for Buddhist nun 1.The method needs to introduce amino by diazol as shown in formula, needs lower temperature, and the bad control of reaction process
System, when amplification, be easy to cause the danger of slug.When intermediate (8) 2- chloro-4-hydroxyl aniline forms intermediate (9), hydroxyl and ammonia
Base will produce competitive reaction.Increase the difficulty isolated and purified.
In addition, also there is document [5] report di-tert-butyl dicarbonate by first and A after the amido protecting of intermediate 8 in alkali
Under the action of be made intermediate 10, then will 10 deprotection after with cyclopropylamine through obtained under the action of condensing agent CDI pleasure cut down for Buddhist nun 1.
The main deficiency of the method is：1) starting material (8) needs multistep synthesis to get, and total synthesis step is up to 7 steps.2) in alkane
When base, in order to avoid competitive reaction, need to protect the amino of intermediate (8) using di-tert-butyl dicarbonate, atom
Economy is poor.3) two dimethyl dicarbonate butyl protection group stability are poor, are easy to fall off the complication for causing intermediate (11).
4) when forming final product, CDI activity is relatively low, and yield is medium.
Invention content
The embodiment of the invention discloses a kind of synthesis pleasures to cut down for the synthetic route of Buddhist nun 1, as shown in formula, is with m-Chlorophenol 2
Raw material, after react with nitrating agent heating, by simply purifying to obtain the chloro- 4- nitrophenols (3) of 3-, 3 and the chloro- 7- methoxyl groups of 4-
Quinoline -6- amides (A) heat reaction and generate 4- (the chloro- 4-nitrophenoxys of 3-) -7- methoxyl group -6- quinoline first in organic solvent
Amide (4), 4 heat reaction under the effect of the catalyst in a solvent generates 4- (the chloro- 4- amino-benzene oxygens of 3-) -7- methoxyl groups -
6- quinoline formyls amine (5), 5 react generation pleasure under alkali, catalyst action in certain temperature in organic solvent with cyclopropylamine cuts down
For Buddhist nun's target product 1.
The advantage of the invention is that：1) introduce nitro under more mild reaction condition, avoid low temperature difficult to control and
The use of diazol.2) it is used as the step of potential amino avoids the protection of amino needs and is deprotected, contracting by introducing nitro
Short synthetic route, reduces synthesis cost.3) nitro avoids the competitive reaction of amino and hydroxyl as potential amino, carries
The high selectivity of reaction, simplifies post-processing step.
Specific implementation mode
In order to it is clearer, explain the purpose of the present invention and technical solution in detail, below by related embodiment to this
Invention is described further.Following embodiment is only to illustrate the implementation of the present invention, does not limit the guarantor of the present invention
Protect range.
Embodiment 1
According to document (L-Y.Chen, et al, Arkivoc, 2014,64-71, DOI：10.3998/
Ark.5550190.p008.587 the chloro- 4- nitrophenols (3) of 3-) are synthesized
Embodiment 2：
Chloro- 7- methoxy quinolines -6- amides (A) 1.42g of chloro- 4- nitrophenols (3) 1.0g, 4- of 3- are dissolved in 60mL diformazans
Sulfoxide stirs 36 hours at 60 DEG C, drops to room temperature.Reaction solution pours into 400mL ice water, filtering, after filter cake is washed with water, vacuum
It is dried to obtain faint yellow solid 4 (1.14g, 52.9%)
[1HNMR (DMSO-d6) δ 8.78 (d, J=5.2Hz, 1H), 8.56 (s, 1H), 8.25 (d, J=9.0Hz, 1H),
7.88 (s, 1H), 7.83 (d, J=2.5Hz, 1H), 7.78 (s, 1H), 7.57 (s, 1H), 7.48 (dd, J=9.0,2.5Hz,
1H), 6.91 (d, J=5.2Hz, 1H), 4.04 (s, 3H)；
13CNMR (DMSO-d6) δ 165.71,159.49,158.22,157.74,153.46,151.89,144.29,
128.34,127.60,125.80,124.39,123.12,119.84,114.77,108.11,105.75,56.29]
ESI-MS m/z：374.2[m+H]+
Embodiment 3：
Chloro- 7- methoxy quinolines -6- amides (A) 1.70g of chloro- 4- nitrophenols (3) 1.0g, 4- of 3- are dissolved in 60mL chlorine
Benzene stirs 5 hours at 120 DEG C, drops to room temperature, filtering, and filter cake uses water respectively, is dried in vacuo after toluene washing and obtains pale yellow colored solid
Body 4 (1.50g, 69.6%)
Embodiment 4：
Chloro- 7- methoxy quinolines -6- amides (A) 1.70g of chloro- 4- nitrophenols (3) 1.0g, 4- of 3- are dissolved in 60mL N,
Dinethylformamide dropped to room temperature, filters, filter cake uses water, vacuum after toluene washing respectively in 190 DEG C of return stirrings 3 hours
It is dried to obtain faint yellow solid 4 (1.98g, 91.9%).
Embodiment 5：
By 4- (the chloro- 4-nitrophenoxys of 3-) -7- methoxyl groups -6- quinoline formyls amine (4) 1.0g, ammonium chloride 0.74g, iron powder
1.0 g are suspended in the in the mixed solvent of 20mL ethyl alcohol and 40ml distilled water, and return stirring 2.5 hours drops to room temperature, filtering.It will
Filtrate is washed with saturated sodium bicarbonate solution, and water phase is extracted with dichloromethane again, and organic phase is merged, decompression be spin-dried for yellow is solid
Body 5 (0.83g, 90.2%)
[1HNMR (DMSO-d6) δ 8.67 (s, 1H), 8.63 (d, J=5.2Hz, 1H), 7.86 (s, 1H), 7.75 (s, 1H),
7.49 (s, 1H), 7.24 (d, J=2.3Hz, 1H), 7.01 (dd, J=8.8,2.5Hz, 1H), 6.91 (d, J=8.8Hz, 1H),
6.45 (d, J=5.3Hz, 1H), 5.47 (s, 2H), 4.02 (s, 3H)]
ESI-MS m/z：344.2[m+H]+
Embodiment 6：
4- (the chloro- 4-nitrophenoxys of 3-) -7- methoxyl groups -6- quinoline formyls amine (4) 1.0g will be entered, iron powder 1.50g suspends
In 60mL acetic acid, is stirred 2.5 hours at 60 DEG C, drop to room temperature.Reaction system is adjusted to neutrality with sodium hydroxide solution, filtering,
After filtrate water is washed, water phase is extracted with dichloromethane again, and organic phase is merged, and decompression is spin-dried for obtaining yellow solid 5
(0.69g, 75.0%)
Embodiment 7：
By 4- (the chloro- 4-nitrophenoxys of 3-) -7- methoxyl groups -6- quinoline formyls amine (4) 1.0g, stannous chloride 3.6g, hang
The in the mixed solvent for floating on 37% hydrochloric acid 30mL and 10mL methanol stirs 5 hours at 75 DEG C, drops to room temperature, molten with sodium hydroxide
System is adjusted to neutrality by liquid, filtering.Liquid separation after filtrate water is washed, water phase are extracted with dichloromethane again, and organic phase is merged,
Decompression is spin-dried for obtaining yellow solid 5 (0.75g, 81.5%).
Embodiment 8：
4- (the chloro- 4- amino-benzene oxygens of 3-) -7- methoxyl groups -6- quinoline formyls amine (5) 1.0g, pyridine 0.86g are suspended in
It in 40mL tetrahydrofurans, is stirred at -10 DEG C, phenyl chloroformate 1.2g is added dropwise in 10 minutes introversive above-mentioned reaction solutions.It finishes
After be stirred at room temperature 2 hours.Cyclopropylamine 0.50g is added dropwise, is stirred at room temperature after being added dropwise 8 hours.Reaction solution is poured into 400mL
In water, filtering, vacuum drying white solid 1 (0.71g, 57.3%) after filter cake is washed with water
[1HNMR (DMSO-d6) δ 8.64 (d, J=5.6Hz, 2H), 8.24 (d, J=9.0Hz, 1H), 7.94 (d, J=
7.9Hz, 1H), 7.84 (s, 1H), 7.72 (s, 1H), 7.48 (s, 1H), 7.45 (d, J=2.7Hz, 1H), 7.21 (dd, J=
9.0,2.7Hz, 1H), 7.17 (d, J=2.9Hz, 1H), 6.51 (t, J=6.0Hz, 1H), 6.45 (d, J=5.3Hz, 1H),
4.00 (s, 3H), 2.63 (s, 1H), 0.38~0.64 (m, 4H)]
ESI-MS m/z：427.3[m+H]+
Embodiment 9：
4- (the chloro- 4- amino-benzene oxygens of 3-) -7- methoxyl groups -6- quinoline formyls amine (5) 1.0g, triethylamine 1.10g are dissolved in
50mL dimethyl sulfoxides stir at 0 DEG C, and ethyl chloroformate 1.0g is added in 10 minutes introversive above-mentioned reaction solutions.It is risen after adding
It is stirred 2 hours to 70 DEG C.Reaction solution is cooled to room temperature DEG C, cyclopropylamine 0.60g is added, 65 DEG C of stirrings 5 are warming up to after being added dropwise
Hour.Reaction solution is poured into 400mL water, filter, filter cake be washed with water after vacuum drying white solid 1 (0.73g,
58.9%).
Embodiment 10：
4- (the chloro- 4- amino-benzene oxygens of 3-) -7- methoxyl groups -6- quinoline formyls amine (5) 1.0g, pyridine 0.86g are dissolved in
In 40mLN, N- dimethylformamide, stir 10 minutes.Methylchloroformate 1.0g is added into above-mentioned reaction solution.It is risen after adding
High-temperature to 40 DEG C stir 3 hours.Reaction solution is cooled to room temperature, cyclopropylamine 0.60g is added, 40 DEG C are warming up to after being added dropwise
Stirring 5 hours.Reaction solution is poured into 400mL water, is filtered, filter cake is dried in vacuo white solid 1 after being washed with water
(0.94g, 75.8%).
Claims (5)
1. a kind of pleasure cuts down the synthetic method for Buddhist nun, it is characterised in that its preparation process is：M-Chlorophenol (2) is having with nitrating agent
In solvent heating reaction generate the chloro- 4- nitrophenols (3) of 3-, 3 with the chloro- 7- methoxy quinolines -6- amides (A) of 4- organic molten
Heating reaction generates 4- (the chloro- 4-nitrophenoxys of 3-) -7- methoxyl group -6- quinoline formyls amine (4) in agent, and 4 are urging in a solvent
Heating reaction generates 4- (the chloro- 4- amino-benzene oxygens of 3-) -7- methoxyl group -6- quinoline formyls amine (5) under the action of agent, and 5 and ring
Propylamine reacts generation pleasure in certain temperature under alkali, catalyst action in organic solvent and cuts down for Buddhist nun's target product 1,
2. synthetic method according to claim 1, it is characterised in that：Synthesis step (3) to (4) described organic solvent is selected from
One kind in chlorobenzene, n,N-Dimethylformamide, dimethyl sulfoxide solvent, preferably n,N-Dimethylformamide, the reaction temperature
Degree is in 60 DEG C~190 DEG C, preferably 100 DEG C.
3. synthetic method according to claim 1, it is characterised in that：Synthesis step (4) to (5) described solvent be methanol,
One kind in ethyl alcohol, isopropanol, formic acid, acetic acid solvent or in which several mixing, the mixed solvent of preferred alcohol and water.
4. synthetic method according to claim 1, it is characterised in that：Synthesis step (4) is to (5) described reduction system by gold
Belong to or metal salt is formed with acid, wherein the one kind of metal (or metal salt) in iron, zinc, tin, preferably iron powder, acid are selected from salt
One kind in acid, ammonium chloride, acetic acid, preferably hydrochloric acid, the reaction temperature is in 60 DEG C~100 DEG C, preferably 100 DEG C.
5. synthetic method according to claim 1, it is characterised in that：Synthesis step (5) to (1) described organic solvent is selected from
One kind in tetrahydrofuran, n,N-Dimethylformamide, dimethyl sulfoxide solvent, preferably n,N-Dimethylformamide, it is described
Alkali is selected from pyridine, triethylamine, one kind in DIPEA, preferably pyridine, and the catalyst is phenyl chloroformate, ethyl chloroformate,
Methylchloroformate, preferably phenyl chloroformate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201710199573.5A CN108658859A (en) | 2017-03-30 | 2017-03-30 | A kind of pleasure cuts down the synthetic method for Buddhist nun |
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|---|---|---|---|
| CN201710199573.5A CN108658859A (en) | 2017-03-30 | 2017-03-30 | A kind of pleasure cuts down the synthetic method for Buddhist nun |
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| CN201710199573.5A Pending CN108658859A (en) | 2017-03-30 | 2017-03-30 | A kind of pleasure cuts down the synthetic method for Buddhist nun |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111320580A (en) * | 2018-12-14 | 2020-06-23 | 江苏先声药业有限公司 | Preparation method of Lunvatinib intermediate |
| CN111377865A (en) * | 2018-12-29 | 2020-07-07 | 北京启慧生物医药有限公司 | Preparation method of high-purity lenvatinib |
-
2017
- 2017-03-30 CN CN201710199573.5A patent/CN108658859A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111320580A (en) * | 2018-12-14 | 2020-06-23 | 江苏先声药业有限公司 | Preparation method of Lunvatinib intermediate |
| CN111320580B (en) * | 2018-12-14 | 2022-12-20 | 江苏先声药业有限公司 | Preparation method of Lunvatinib intermediate |
| CN111377865A (en) * | 2018-12-29 | 2020-07-07 | 北京启慧生物医药有限公司 | Preparation method of high-purity lenvatinib |
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| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20181016 |
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| WD01 | Invention patent application deemed withdrawn after publication |