CN104650004B - A kind of preparation method of hydrobromic acid Vortioxetine - Google Patents
A kind of preparation method of hydrobromic acid Vortioxetine Download PDFInfo
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- CN104650004B CN104650004B CN201510100629.8A CN201510100629A CN104650004B CN 104650004 B CN104650004 B CN 104650004B CN 201510100629 A CN201510100629 A CN 201510100629A CN 104650004 B CN104650004 B CN 104650004B
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- hydrobromic acid
- vortioxetine
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- 0 Cc1ccc(*)*(C)c1 Chemical compound Cc1ccc(*)*(C)c1 0.000 description 3
- XHLDTXBBXATFFB-UHFFFAOYSA-N C1CN=CCNC1 Chemical compound C1CN=CCNC1 XHLDTXBBXATFFB-UHFFFAOYSA-N 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N C1NCCNC1 Chemical compound C1NCCNC1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- CFNHVUGPXZUTRR-UHFFFAOYSA-N CCCNCCN Chemical compound CCCNCCN CFNHVUGPXZUTRR-UHFFFAOYSA-N 0.000 description 1
- AMNLXDDJGGTIPL-UHFFFAOYSA-N Cc(cc1)cc(C)c1S Chemical compound Cc(cc1)cc(C)c1S AMNLXDDJGGTIPL-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to a kind of preparation method of hydrobromic acid Vortioxetine, comprise the following steps：2; 4- dimethyl iodobenzene, bromothiophenol and 1-Boc- piperazines are reacted under appropriate palladium catalyst, part, alkali and Catalyzed By Phase-transfer Catalyst at 25~40 DEG C, prepare compound II; compound II obtains hydrobromic acid Vortioxetine shown in formula I through hydrobromic acid solution deprotection；Or：2; 4- thiophenol dimethyl benzenes, adjacent iodine tribromophenyl and 1-Boc- piperazines are reacted, prepare compound II under appropriate palladium catalyst, alkali and Catalyzed By Phase-transfer Catalyst at 25~40 DEG C; compound II obtains hydrobromic acid Vortioxetine shown in formula I through hydrobromic acid solution deprotection.Present invention process is succinct, reaction selectivity is high, impurity is few, purifying pressure is small and high income.
Description
Technical field
The invention belongs to organic synthesis field, the preparation method of Vortioxetine bulk drug and intermediate is specifically related to.
Background technology
Vortioxetine is by Lundbeck drugmaker of Denmark (Lundbeck) and the military field drug company (Takeda of Japan
Pharmaceutical) a medicine for major depressive disorder (MDD) treatment of cooperative research and development.The medicine is 5-HT3、5‐HT7With
5‐HT1DReceptor antagonist, 5-HT1AReceptor stimulating agent, 5-HT1BAcceptor portion agonist, 5-HT transporter inhibitors.The medicine energy
Enough improve the level of brain privileged site serotonin neurotransmitter, norepinephrine, dopamine, acetylcholine and histamine.
Clinical test shows that the medicine is safely and effectively to major depressive disorder.FDA ratifies medicine listing in September, 2013.Chinese
Translated name is usually " Vortioxetine ", and structural formula is as follows：
The synthetic method of Vortioxetine, be mainly seen in Lundbeck drugmaker international monopoly (WO2003029232,
WO2007144005, WO2010094285), using following substrate, progressively synthesize.
Substrate：
Route 1：
Route 2：
Above-mentioned two lines, the selectivity of compound structure is realized by the reactivity of halogen.But, because from
Piperazine directly participates in reaction, and the reactivity of two secondary amino groups is identical on piperazine, and the selectivity of reaction is reduced on the contrary, generates
A series of impurity.This problem, international monopoly WO2010094285 has further elucidated above in WO2013102573.
On the basis of preceding 2 routes, international monopoly WO2007144005, WO2013102573 further discloses " one
Pot is boiled " method synthesize Vortioxetine.
Route 3：
Route 4：
Above-mentioned route is succinct, but is further degrading the selectivity of halogen and the selectivity of piperazine, causes impurity more.
There is Chinese patent (CN201410028213) to propose another synthetic route：
Using the route, each step yield is relatively low, and process contaminants are equally more.
Above route, all has that process contaminants are more, and purifying pressure is big, and yield is relatively low.
On this basis, we attempt substituting the precursor II that piperazine " treating different things alike " synthesizes Vortioxetine with 1-Boc- piperazines：
Because 1-Boc- piperazine only one of which secondary amine participates in reaction, therefore overcomes by the miscellaneous of many reaction sites generations of piperazine
Matter.But, further analyzing the impurity time spectrum of the reaction, it has been found that Boc groups are in C-N, C-S coupling reaction temperature (100
DEG C to 120 DEG C) a small amount of decomposition is had, and the isobutene for generating may proceed to participate in reaction under the catalysis of palladium salt, generate other secondary
Product.Therefore, we continue to optimize reaction process, and the method by adding phase transfer catalyst is greatly reduced reaction temperature, enters
One step improves reaction selectivity.
The content of the invention
Many it is an object of the invention to impurity in being directed to prior art, purifying pressure is big, and the relatively low problem of yield is carried
For a kind of concise in technology, reaction selectivity hydrobromic acid Vortioxetine preparation method high.
To reach above-mentioned purpose, the present invention is achieved by the following technical solutions：
A kind of preparation method of hydrobromic acid Vortioxetine, comprises the following steps：2,4- dimethyl iodobenzene as shown in formula A,
Bromothiophenol as shown in formula B is with the 1-Boc- piperazines as shown in formula C in appropriate palladium catalyst, part, alkali and phase transfer
Under catalyst, reacted at 25~40 DEG C, prepare compound II, compound II is obtained through hydrobromic acid solution deprotection
To hydrobromic acid Vortioxetine shown in formula I；
Or：2,4- thiophenol dimethyl benzenes as shown in formula A, the adjacent iodine tribromophenyl as shown in formula B and the 1- as shown in formula C
Boc- piperazines are reacted under appropriate palladium catalyst, alkali and Catalyzed By Phase-transfer Catalyst at 25~40 DEG C, prepare chemical combination
Thing II, compound II obtain hydrobromic acid Vortioxetine shown in formula I through hydrobromic acid solution deprotection；
Described reaction process is：
Described palladium catalyst is double (bis- Ya Benzyl benzylacetones) palladium or three (dibenzalacetone) two palladium, the palladium catalyst
Molar ratio be 0.05~0.5.
The molar ratio of the palladium catalyst is 0.1~0.2.
Described part is 1,1'- dinaphthalene -2, and 2'- double diphenyl phosphine, double (2- diphenylphosphines) phenylates or triphenylphosphines are described
The molar ratio of part is 0.05~0.5.
Described part is 1,1'- dinaphthalene -2, and 2'- pairs of diphenyl phosphines, molar ratio is 0.1~0.2.
Described alkali is potassium tert-butoxide or sodium tert-butoxide.
Described phase transfer catalyst is 18- crown ethers -6 or TBAB, and described phase transfer catalyst feeds intake
Mol ratio is 1.0~5.0.
Described phase transfer catalyst is 18- crown ether -6, and molar ratio is 2.0~3.0.
Beneficial effects of the present invention are as follows：
The preparation method of hydrobromic acid Vortioxetine of the present invention, concise in technology, reaction selectivity are high, impurity is few, purifying pressure
Small and high income.
Specific embodiment
With reference to specific embodiment, the present invention is further illustrated, but protection scope of the present invention is not limited to
This.
The raw material used in the present invention can be synthesized using mode well known in the art, it would however also be possible to employ commercially available prod.
Reaction process of the invention is as follows：
Embodiment 1
100mL four-hole bottles equip magnetic stirrer, condenser pipe and thermometer.Input 2,4- dimethyl iodobenzene (2.32g,
10mmol, 1.0eq), bromothiophenol (1.90g, 10mmol, 1.0eq) and tetrahydrofuran 25mL, nitrogen displacement 3 times.Input Pd
(dba)2(0.58g, 1mmol, 0.1eq), BINAP (0.93g, 1.5mmol, 0.15eq) and 1-Boc- piperazines (1.86g,
10mmol, 1.0eq), nitrogen displacement 3 times.Finally input 18-C-6 (7.40g, 28mmol, 2.8eq) and sodium tert-butoxide (2.69g,
28mmol, 2.8eq), 30 DEG C of insulated and stirreds 24 hours, HPLC display selectivity is 98.6%.
Input activated carbon 0.1g, stirs 2 hours.Filtrate precipitation puts into toluene 40mL to dry, stirs 0.5 hour.Filtering,
To 48% hydrobromic acid (2.53g, 15mmol, 1.5eq) is added dropwise in filtrate, stir 0.5 hour.Filtering, filter cake toluene 10mL×2
Drip washing.Obtain hydrobromic acid Vortioxetine.50 DEG C are vacuum dried 12 hours, obtain yellowish coloured particles 2.9g.
Embodiment 2
100mL four-hole bottles equip magnetic stirrer, condenser pipe and thermometer.2,4- of input thiophenol dimethyl benzenes (1.38g,
10mmol, 1.0eq), bromothiophenol (2.83g, 10mmol, 1.0eq) and tetrahydrofuran 25mL, nitrogen displacement 3 times.Input
Pd2(dba)3(0.46g, 0.5mmol, 0.05eq), DPEphos (0.27g, 0.5mmol, 0.05eq) and 1-Boc- piperazines
(1.86g, 10mmol, 1.0eq), nitrogen displacement 3 times.Finally put into 18-C-6 (7.40g, 28mmol, 2.8eq) and potassium tert-butoxide
(3.37g, 30mmol, 3.0eq), 40 DEG C of insulated and stirreds 36 hours, HPLC display selectivity is 98.2%.
Input activated carbon 0.1g, stirs 2 hours.Filtrate precipitation puts into toluene 40mL to dry, stirs 0.5 hour.Filtering,
To 48% hydrobromic acid (2.53g, 15mmol, 1.5eq) is added dropwise in filtrate, stir 0.5 hour.Filtering, filter cake toluene 10mL×2
Drip washing.Obtain hydrobromic acid Vortioxetine.50 DEG C are vacuum dried 12 hours, obtain yellowish coloured particles 2.8g.
Embodiment 3
100mL four-hole bottles equip magnetic stirrer, condenser pipe and thermometer.Input 2,4- dimethyl iodobenzene (2.32g,
10mmol, 1.0eq), bromothiophenol (1.90g, 10mmol, 1.0eq) and tetrahydrofuran 35mL, nitrogen displacement 3 times.Input Pd
(dba)2(2.9g, 5mmol, 0.5eq), BINAP (3.11g, 5mmol, 0.5eq) and 1-Boc- piperazines (1.86g, 10mmol,
1.0eq), nitrogen displacement 3 times.Finally input 18-C-6 (11.90g, 45mmol, 4.5eq) and sodium tert-butoxide (2.69g,
28mmol, 2.8eq), 25 DEG C of insulated and stirreds 20 hours, HPLC display selectivity is 98.8%.
Input activated carbon 0.1g, stirs 2 hours.Filtrate precipitation puts into toluene 50mL to dry, stirs 0.5 hour.Filtering,
To 48% hydrobromic acid (2.53g, 15mmol, 1.5eq) is added dropwise in filtrate, stir 0.5 hour.Filtering, filter cake toluene 10mL×2
Drip washing.Obtain hydrobromic acid Vortioxetine.50 DEG C are vacuum dried 12 hours, obtain yellowish coloured particles 2.7g.
Embodiment 4
100mL four-hole bottles equip magnetic stirrer, condenser pipe and thermometer.Input 2,4- dimethyl iodobenzene (2.32g,
10mmol, 1.0eq), bromothiophenol (1.90g, 10mmol, 1.0eq) and tetrahydrofuran 50mL, nitrogen displacement 3 times.Input Pd
(dba)2(1.15g, 2mmol, 0.2eq), DPEphos (1.62g, 3mmol, 0.3eq) and 1-Boc- piperazines (1.86g,
10mmol, 1.0eq), nitrogen displacement 3 times.Finally put into tetrabutylammonium iodide (16.63g, 45mmol, 4.5eq) and potassium tert-butoxide
(2.24g, 20mmol, 2.0eq), 40 DEG C of insulated and stirreds 66 hours, HPLC display selectivity is 95.3%.
Input activated carbon 0.1g, stirs 2 hours.Filtrate precipitation puts into toluene 40mL to dry, stirs 0.5 hour.Filtering,
To 48% hydrobromic acid (2.53g, 15mmol, 1.5eq) is added dropwise in filtrate, stir 0.5 hour.Filtering, filter cake toluene 10mL×2
Drip washing.Obtain hydrobromic acid Vortioxetine.50 DEG C are vacuum dried 12 hours, obtain yellowish coloured particles 2.0g.
The preparation method of hydrobromic acid Vortioxetine of the present invention, concise in technology, reaction selectivity are high, impurity is few, purifying pressure
Small and high income.
Above-described embodiment is only used for illustrating inventive concept of the invention, rather than the restriction to rights protection of the present invention,
All changes for carrying out unsubstantiality to the present invention using this design, all should fall into protection scope of the present invention.
Claims (1)
1. a kind of preparation method of hydrobromic acid Vortioxetine, it is characterised in that comprise the following steps：
100mL four-hole bottles equipment magnetic stirrer, condenser pipe and thermometer, then put into 2,4- thiophenol dimethyl benzenes 1.38g, neighbour
Iodine tribromophenyl 2.83g and tetrahydrofuran 25mL, nitrogen displacement 3 times；Three (dibenzalacetone) two palladium 0.46g of input, double (2- hexichol
Base phosphine) phenylate 0.27g and 1-Boc- piperazine 1.86g, nitrogen displacement 3 times；Finally put into the 7.40g of 18- crown ethers -6 and potassium tert-butoxide
3.37g, 40 DEG C of insulated and stirreds 36 hours, HPLC display selectivity is 98.2%；
Input activated carbon 0.1g, stirs 2 hours；Filtrate precipitation puts into toluene 40mL to dry, stirs 0.5 hour；Filtering, to filter
48% hydrobromic acid 2.53g is added dropwise in liquid, stirs 0.5 hour；Filtering, filter cake toluene drip washing 2 times uses toluene 10mL, so every time
50 DEG C are vacuum dried 12 hours afterwards, obtain faint yellow granular hydrobromic acid Vortioxetine.
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| CN106556663B (en) * | 2015-09-30 | 2018-05-29 | 成都弘达药业有限公司 | A kind of detection method of 1- [2- (2,4- dimethylphenylsulfanyls) phenyl] piperazines or its salt |
| CN105348220B (en) * | 2015-11-10 | 2017-08-25 | 山东川成医药股份有限公司 | A kind of synthetic method of hydrobromic acid Vortioxetine |
| CN105367516A (en) * | 2015-11-11 | 2016-03-02 | 北京万全德众医药生物技术有限公司 | Novel preparation method of vortioxetine |
| CN108314662A (en) * | 2017-01-17 | 2018-07-24 | 北京蓝贝望生物医药科技股份有限公司 | A kind of preparation method of Vortioxetine impurity |
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| SMT201900248T1 (en) * | 2012-01-03 | 2019-07-11 | H Lundbeck As | Process for the manufacture of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine |
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Address after: 528451 Guangdong province Zhongshan Nanlang town of Southern China modern Chinese Medicine City Branch Chong Park No. 2 Applicant after: Zhongshan Wan Han Pharmaceutical Co., Ltd. Address before: Guangdong city of Zhongshan province Southern China Nanlang 528400 modern Chinese Medicine City Branch Chong Park No. 2 Applicant before: Zhong Shanwanhan Pharmaceutical Technology Co., Ltd |
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