CN106831538A - The preparation method of tropsch imatinib intermediate - Google Patents
The preparation method of tropsch imatinib intermediate Download PDFInfo
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- CN106831538A CN106831538A CN201710046205.7A CN201710046205A CN106831538A CN 106831538 A CN106831538 A CN 106831538A CN 201710046205 A CN201710046205 A CN 201710046205A CN 106831538 A CN106831538 A CN 106831538A
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- LCUPRUHAQNWPPG-CCEZHUSRSA-N CC(CCN(Cc1ccccc1)C1)/C1=N/C Chemical compound CC(CCN(Cc1ccccc1)C1)/C1=N/C LCUPRUHAQNWPPG-CCEZHUSRSA-N 0.000 description 1
- BSBVJNUGGBQEPO-UHFFFAOYSA-N CC(CCN(Cc1ccccc1)C1)C1=O Chemical compound CC(CCN(Cc1ccccc1)C1)C1=O BSBVJNUGGBQEPO-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D211/56—Nitrogen atoms
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Abstract
The present invention relates to a kind of new preparation method of tropsch imatinib intermediate, specifically related to tropsch imatinib intermediate (3R, 4R) 1 benzyl N, the preparation method of the amine dihydrochloride of 4 lupetidine 3, with the methyl 1 of 1 benzyl 4, 2, 3, 6 tetrahydropyridines are used as initiation material, by one-step method by olefin oxidation into ketone II, after forming imines III with amine afterwards, amine is formed with asymmetric reduction imines, cis-structure IV is obtained by recrystallizing removal transisomer, finally end-product (3R is obtained with chiral resolution, 4R) 1 benzyl N, the amine dihydrochloride I of 4 lupetidine 3.The process innovation of this preparation method, shortens processing step, greatly improves asymmetric compound synthesis yield, is that industrialized production is taken a firm foundation.
Description
Technical field
The present invention relates to a kind of preparation method of tropsch imatinib intermediate, and in particular to (3R, 4R) -1- benzyls-N, 4- bis-
The preparation method of methyl piperidine -3- amine dihydrochlorides.
Background technology
JAK/STAT is the important cytokine signaling conduction path of a class, with disease in the blood system, tumour, rheumatoid
Many diseases such as arthritis and psoriasis are related.The JAK inhibitor tropsch imatinibs of Pfizer (Pfizer) company research and development
(Tofacitinib, structure sees below formula) energy Selective depression JAK3 kinases, on November 6th, 2012 by U.S.'s food and medicine
Management board (FDA) is by assessment of risks and mitigates tactful (REMS) and ratifies, for treating activities of adults phase and anti-to methotrexate (MTX)
Should it is not good in severe rheumatoid arthritis (rheumatoid arthritis, RA) patient.
As tropsch imatinib important intermediate (3R, 4R) -1- benzyls-N, 4- lupetidine -3- amine dihydrochloride (I),
The development of its synthesis technique is worth chemist research, and condition survey is reported currently for such material, consults the change
In compound synthetic method, its Patent WO2010123919A2 reports：
The patent is used as initiation material by 3- amino-4-methylpyridines, by amine ester exchange reaction, pyrrole is formed with benzyl bromine
Pyridine salt, the salt first uses sodium borohydride reduction, is then reduced into piperidine ring with platinum oxide, then obtain most by tetrahydrochysene lithium aluminium reduction
Product.The method not using only costly metallic reducing agent platinum oxide, while the use of tetrahydrochysene lithium aluminium, undoubtedly increased big industry
Security risk in production.And the method does not refer to chiral synthesis, final product and there are four kinds of isomers, reduce optical voidness
Degree, also reduces ultimate yield.
And refer to that route is as follows in document J.Med.Chem.2008,51,8012-8018：
The route has equally used the rhodium C catalyst of expensive go back original reagent 5%, while being hydrogenated with hydrogen, increases
Operation difficulty.And final step reduction has equally used tetrahydrochysene lithium aluminium.
The content of the invention
Purpose：In order to overcome the deficiencies in the prior art, the present invention to provide a kind of preparation of tropsch imatinib intermediate
Method, with 1- benzyl -4- methyl isophthalic acids, 2,3,6- tetrahydropyridines as initiation material, by one-step method by olefin oxidation into ketone
(II) after, forming imines (III) with amine afterwards, amine is formed with asymmetric reduction imines, by recrystallizing removal trans-isomerism
Body obtains cis-structure (IV), finally obtains end-product (3R, 4R) -1- benzyls-N, 4- lupetidine -3- with chiral resolution
Amine dihydrochloride (I).The process innovation of this method, shortens processing step, it is to avoid the use of tetrahydrochysene lithium aluminium these hazardous agents,
Asymmetric compound synthesis yield is greatly improved with asymmetric reduction simultaneously, is that industrialized production is taken a firm foundation.
Technical scheme：In order to solve the above technical problems, the technical solution adopted by the present invention is：
A kind of preparation method of the pharmaceutical intermediate of tropsch imatinib, the tropsch imatinib intermediate is (3R, 4R) -1- benzyls
Base-N, 4- lupetidine -3- amine dihydrochlorides, its molecular structural formula is as follows：
Synthetic route is as follows：
Specifically include following steps：
Step 1) by 1- benzyl -4- methyl isophthalic acids, 2,3,6- tetrahydropyridines pass through trimethyl silicon substrate trifluoro sulfonic acid to compound II
Under ester effect, under the catalysis of ketone catalytic reagent, one-step method is direct oxidation into ketone compounds II；
Step 2) compound II and methylamine formation group with imine moiety III；
Step 3) group with imine moiety III by asymmetric reduction, obtains cis after being reduced by 3-sec-butyl lithium borohydride：Instead
Formula is configured as 90:10, cis-isomer IV is formed by hydrochloric acid salt refining；
Step 4) cis-isomer IV split under alkalescence effect by chiral selectors, by into salt intermediate V, one
Pot method forms final tropsch imatinib intermediate (3R, 4R) -1- benzyls-N, 4- lupetidine -3- amine dihydrochloride (I).
Step 1) in, ketone catalytic reagent be cyclohexanone, acetone, one or more mixed ketons in 4- heptanone, preferably
Cyclohexanone, reaction dissolvent is dichloromethane, chloroform, the one or two kinds of solvent mixed above in acetonitrile, preferably dichloromethane,
Reaction temperature is -30--10 DEG C.
Step 2) in, reaction dissolvent is tetrahydrofuran, and toluene, ethanol, the one or two kinds of in isopropanol is mixed above
Solvent, preferably tetrahydrofuran, reaction temperature are 10-30 DEG C.
Step 3) in, reaction dissolvent is tetrahydrofuran, and dioxane, the one or two kinds of in acetonitrile is mixed above molten
Agent, preferably tetrahydrofuran, reaction temperature are -10-70 DEG C.
Step 4) in, reaction dissolvent includes methyl alcohol, and ethanol, the one or two kinds of solvent mixed above in isopropanol is excellent
Select methyl alcohol；
Chiral selectors are L- bis- to the one kind in toluyl tartaric acid, L- dibenzoyl tartaric acids, tartaric acid
Or two or more mix reagents, preferential L- bis- is to toluyl tartaric acid；
Alkali used includes one or more mixed bases in NaOH, potassium hydroxide, lithium hydroxide, reaction temperature
5-25℃。
Beneficial effect：The preparation method of the tropsch imatinib intermediate that the present invention is provided, with 1- benzyl -4- methyl isophthalic acids, 2,3,
6- tetrahydropyridines as initiation material, by one-step method by olefin oxidation into ketone (II), after forming imines (III) with amine afterwards,
Amine is formed with asymmetric reduction imines, cis-structure (IV) is obtained by recrystallizing removal transisomer, finally with hand
Property split obtain end-product (3R, 4R) -1- benzyl-N, 4- lupetidines -3- amine dihydrochloride (I).The technique wound of this method
Newly, processing step is shortened, it is to avoid the use of tetrahydrochysene lithium aluminium these hazardous agents, while being greatly improved not with asymmetric reduction
Symmetrical compound synthesis yield, is that industrialized production is taken a firm foundation.
Specific embodiment
The present invention is further described with reference to specific embodiment.
A kind of preparation method of the pharmaceutical intermediate I of tropsch imatinib, chemical structural formula is as follows：
Preparation method is as follows：With 1- benzyl -4- methyl isophthalic acids, 2,3,6- tetrahydropyridines as initiation material, by one-step method
Olefin oxidation is obtained into ketone compounds II into ketone, after forming group with imine moiety III with amine afterwards, with asymmetric reduction imines
Formed amine, by recrystallize removal transisomer obtain cis-structure IV, finally with chiral resolution obtain end-product (3R,
4R) -1- benzyls-N, 4- lupetidine -3- amine dihydrochloride I, obtain final product；
Synthetic route is as follows：
Embodiment one：Raw material 1- benzyl -4- methyl isophthalic acids, 2,3,6- tetrahydropyridines (187mg) are dissolved in dichloromethane
(10mL), nitrogen protects the dichloromethane solution that trimethyl silicon substrate trifluoro sulphonic acid ester (1.1g) is added at -20 DEG C, and adds catalysis
, to reacting completely, column chromatography obtains compound II for the cyclohexanone of amount, stirring reaction and middle control reaction.(yield 89%).
Embodiment two：Compound II (17.6g) and 50ml tetrahydrofurans, nitrogen protection, cooling are sequentially added to there-necked flask
To 15 DEG C, methylamine hydrochloride (7g) is added dropwise, 15-20 DEG C of reaction of control temperature, middle control extremely reacts complete.Direct plunge into next step.
Embodiment three：3-sec-butyl lithium borohydride (19.8g) is added after above-mentioned solution is cooled into 0 DEG C, stirring is a little while
After be warming up to back flow reaction completely, pour into ice saturated ammonium chloride solution, with dichloromethane extract, merge organic phase, dry rotation
It is dry to obtain crude product, crude product is dissolved in ethyl acetate, the ethyl acetate solution stirring of HCl is added, separate out solid, filtering, solid
Washed with ethyl acetate and obtain cis-compound IV.(two step yields 68%)
Example IV：Compound IV (34g) is dissolved in 150g water, PH=11 is adjusted with 30%NaOH solution, use acetic acid
Ethyl ester is extracted, and organic phase dries and is spin-dried for being dissolved in methyl alcohol after obtaining unhindered amina, after being cooled to 5 DEG C, adds L- bis- to methylbenzene first
Acyl tartaric acid (15.78g), stirring and crystallizing is filtrated to get salt.The salt is dissolved in 150g water, PH is adjusted with 30%NaOH solution
=11, it is extracted with ethyl acetate, organic phase dries and is spin-dried for obtaining unhindered amina, and ice-water bath controls temperature at 5-20 DEG C, HCl is added dropwise
Ethyl acetate solution, stirring and crystallizing is filtrated to get crude product, and crude product absolute ethyl alcohol is refining to obtain fine work I.(yield 45%)
The above is only the preferred embodiment of the present invention, it should be pointed out that：For the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of preparation method of compound, it is characterised in that the chemical structural formula of the compound is as follows：
Preparation method is as follows：With 1- benzyl -4- methyl isophthalic acids, 2,3,6- tetrahydropyridines as initiation material, by one-step method by alkene
Hydrocarbon is oxidized to ketone and obtains ketone compounds II, after forming group with imine moiety III with amine afterwards, is formed with asymmetric reduction imines
Amine, by recrystallize removal transisomer obtain cis-structure IV, finally with chiral resolution obtain end-product (3R, 4R)-
1- benzyls-N, 4- lupetidine -3- amine dihydrochloride I, obtain final product；
Synthetic route is as follows：
2. the preparation method of compound according to claim 1, it is characterised in that specifically include following steps：
Step 1) with 1- benzyl -4- methyl isophthalic acids, 2,3,6- tetrahydropyridines are raw material, are urged in trimethyl silicon substrate trifluoro sulphonic acid ester and ketone
Change in the presence of reagent, oxidation reaction obtains ketone compounds II；
Step 2) compound II and methylamine formation group with imine moiety III；
Step 3) group with imine moiety III by asymmetric reduction, obtains cis after being reduced by 3-sec-butyl lithium borohydride：Trans structure
Type is 90:10, cis-isomer IV is formed by hydrochloric acid salt refining；
Step 4) cis-isomer IV split under alkali effect by chiral selectors, by into salt intermediate V, one kettle way shape
Into (3R, 4R) -1- benzyls-N, 4- lupetidine -3- amine dihydrochloride I, obtain final product.
3. the preparation method of compound according to claim 2, it is characterised in that：Step 1) in, ketone catalytic reagent is hexamethylene
One or more in ketone, acetone, 4- heptanone.
4. the preparation method of compound according to claim 2, it is characterised in that：Step 1) in, reaction dissolvent is dichloromethane
One or two kinds of solvent mixed above in alkane, chloroform, acetonitrile, reaction temperature is -30--10 DEG C.
5. the preparation method of compound according to claim 2, it is characterised in that：Step 2) in, reaction dissolvent is tetrahydrochysene furan
Mutter, toluene, the one or two kinds of solvent mixed above in ethanol, isopropanol, reaction temperature be 10-30 DEG C.
6. the preparation method of compound according to claim 2, it is characterised in that：Step 3) in, reaction dissolvent is tetrahydrochysene furan
Mutter, the one or two kinds of solvent mixed above in dioxane, acetonitrile, reaction temperature is -10-70 DEG C.
7. the preparation method of compound according to claim 2, it is characterised in that：Step 4) in, reaction dissolvent is methyl alcohol, second
One or more mixed solvents in alcohol, isopropanol；5-25 DEG C of reaction temperature.
8. the preparation method of compound according to claim 2, it is characterised in that：Step 4) in, chiral selectors are L-
One or more in two pairs of toluyl tartaric acid, L- dibenzoyl tartaric acids, tartaric acid.
9. the preparation method of compound according to claim 2, it is characterised in that：Chiral selectors are L- bis- to methylbenzene
Formyl tartaric acid.
10. the preparation method of compound according to claim 2, it is characterised in that：Alkali used is NaOH, hydroxide
One or more in potassium, lithium hydroxide.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108948022A (en) * | 2018-08-16 | 2018-12-07 | 山东罗欣药业集团恒欣药业有限公司 | A kind of support method replaces the synthetic method of cloth |
| CN108976164A (en) * | 2018-06-20 | 2018-12-11 | 南通常佑药业科技有限公司 | The preparation method of chiral piperidine amine compounds and the recovery method of chiral resolving agent |
| CN109734653A (en) * | 2019-02-21 | 2019-05-10 | 北京悦康科创医药科技股份有限公司 | A kind of method for splitting of argatroban starting material isomer impurities |
| CN109761884A (en) * | 2019-01-30 | 2019-05-17 | 湖北扬信医药科技有限公司 | A kind of preparation method and applications of Chiral Amine B |
| CN112424187A (en) * | 2018-07-18 | 2021-02-26 | 阿斯利康(瑞典)有限公司 | Xinafoate salts of JAK-inhibiting compounds |
| CN112552184A (en) * | 2020-12-18 | 2021-03-26 | 诚达药业股份有限公司 | Synthetic method of cyclopropyl-containing chiral amine hydrochloride |
| CN114807071A (en) * | 2022-05-11 | 2022-07-29 | 中国科学院天津工业生物技术研究所 | Enzymatic preparation method of tofacitinib key intermediate |
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Cited By (9)
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| CN108976164A (en) * | 2018-06-20 | 2018-12-11 | 南通常佑药业科技有限公司 | The preparation method of chiral piperidine amine compounds and the recovery method of chiral resolving agent |
| CN112424187A (en) * | 2018-07-18 | 2021-02-26 | 阿斯利康(瑞典)有限公司 | Xinafoate salts of JAK-inhibiting compounds |
| CN108948022A (en) * | 2018-08-16 | 2018-12-07 | 山东罗欣药业集团恒欣药业有限公司 | A kind of support method replaces the synthetic method of cloth |
| CN109761884A (en) * | 2019-01-30 | 2019-05-17 | 湖北扬信医药科技有限公司 | A kind of preparation method and applications of Chiral Amine B |
| CN109734653A (en) * | 2019-02-21 | 2019-05-10 | 北京悦康科创医药科技股份有限公司 | A kind of method for splitting of argatroban starting material isomer impurities |
| CN112552184A (en) * | 2020-12-18 | 2021-03-26 | 诚达药业股份有限公司 | Synthetic method of cyclopropyl-containing chiral amine hydrochloride |
| CN112552184B (en) * | 2020-12-18 | 2022-05-10 | 诚达药业股份有限公司 | Synthetic method of cyclopropyl-containing chiral amine hydrochloride |
| CN114807071A (en) * | 2022-05-11 | 2022-07-29 | 中国科学院天津工业生物技术研究所 | Enzymatic preparation method of tofacitinib key intermediate |
| CN114807071B (en) * | 2022-05-11 | 2023-10-20 | 中国科学院天津工业生物技术研究所 | Enzymatic preparation method of tofacitinib key intermediate |
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