CN106831538B - The preparation method of tropsch imatinib intermediate - Google Patents
The preparation method of tropsch imatinib intermediate Download PDFInfo
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- CN106831538B CN106831538B CN201710046205.7A CN201710046205A CN106831538B CN 106831538 B CN106831538 B CN 106831538B CN 201710046205 A CN201710046205 A CN 201710046205A CN 106831538 B CN106831538 B CN 106831538B
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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
Abstract
The present invention relates to a kind of preparation methods that tropsch imatinib intermediate is new, more particularly to tropsch imatinib intermediate (3R, 4R) -1- benzyl-N, the preparation method of 4- lupetidine -3- amine dihydrochloride, with 1- benzyl -4- methyl-1, 2, 3, 6- tetrahydropyridine is as starting material, by one-step method by olefin oxidation at ketone II, after forming imines III with amine later, amine is formed with asymmetric reduction imines, cis-structure IV is obtained by recrystallization removal transisomer, finally final product (3R is obtained with chiral resolution, 4R) -1- benzyl-N, 4- lupetidine -3- amine dihydrochloride I.The process innovation of this preparation method, shortens processing step, greatly improves asymmetric compound synthesis yield, takes a firm foundation for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods of tropsch imatinib intermediate, and in particular to (3R, 4R) -1- benzyl-N, 4- bis-
The preparation method of methyl piperidine -3- amine dihydrochloride.
Background technique
JAK/STAT is a kind of important cytokine signaling conduction path, with disease in the blood system, tumour, rheumatoid
Many diseases such as arthritis and psoriasis are related.The JAK inhibitor tropsch imatinib of Pfizer (Pfizer) company research and development
(Tofacitinib, structure see below formula) energy selective depression JAK3 kinases, on November 6th, 2012 by U.S.'s food and drug
Management board (FDA) is by assessment of risks and mitigates tactful (REMS) approval, for treat the activities of adults phase and to methotrexate (MTX) it is anti-
It answers in bad to severe rheumatoid arthritis (rheumatoid arthritis, RA) patient.
As tropsch imatinib important intermediate (3R, 4R) -1- benzyl-N, 4- lupetidine -3- amine dihydrochloride (I),
The development of its synthesis technology is worth chemist research, reports condition survey for the substance at present, consults the change
It closes in object synthetic method, wherein patent WO2010123919A2 is reported:
The patent, as starting material, by amine ester exchange reaction, forms pyrrole with benzyl bromine by 3- amino-4-methylpyridine
Pyridine salt, the salt first use sodium borohydride reduction, are then reduced into piperidine ring with platinum oxide, then restore to obtain most by tetrahydrochysene lithium aluminium
Product.Costly metallic reducing agent platinum oxide, while the use of tetrahydrochysene lithium aluminium are not used only for this method, undoubtedly increase big industry
Security risk in production.And this method does not refer to chiral synthesis, final product and there are four types of isomers, reduces 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 expensive 5% rhodium C catalyst of go back original reagent, while adding hydrogen with hydrogen, increases
Operation difficulty.And final step reduction has equally used tetrahydrochysene lithium aluminium.
Summary of the invention
Purpose: in order to overcome the deficiencies in the prior art, the present invention provides a kind of preparation of tropsch imatinib intermediate
Method, with 1- benzyl -4- methyl-1,2,3,6- tetrahydropyridines are as starting material, by one-step method by olefin oxidation at ketone
(II), after forming imines (III) with amine later, amine is formed with asymmetric reduction imines, trans-isomerism is removed by recrystallization
Body obtains cis-structure (IV), finally obtains final product (3R, 4R) -1- benzyl-N, 4- lupetidine -3- with chiral resolution
Amine dihydrochloride (I).The process innovation of this method, shortens processing step, avoids the use of these hazardous agents of tetrahydrochysene lithium aluminium,
Asymmetric compound synthesis yield is greatly improved with asymmetric reduction simultaneously, is taken a firm foundation for industrialized production.
Technical solution: in order to solve the above technical problems, the technical solution adopted by the present invention are as follows:
A kind of preparation method of the pharmaceutical intermediate of tropsch imatinib, the tropsch imatinib intermediate are (3R, 4R) -1- benzyl
Base-N, 4- lupetidine -3- amine dihydrochloride, molecular structural formula are as follows:
Synthetic route is as follows:
Specifically includes the following steps:
Step 1) compound II passes through trimethyl silicon substrate trifluoro sulfonic acid by 1- benzyl -4- methyl-1,2,3,6- tetrahydropyridine
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 form group with imine moiety III；
Step 3) group with imine moiety III is obtained cis- by asymmetric reduction after being restored by 3-sec-butyl lithium borohydride: anti-
Formula is configured as 90:10, forms cis-isomer IV by hydrochloric acid salt refining；
Step 4) cis-isomer IV under alkalinity effect by chiral selectors fractionation, by salt intermediate V, one
Pot method forms final tropsch imatinib intermediate (3R, 4R) -1- benzyl-N, 4- lupetidine -3- amine dihydrochloride (I).
In step 1), ketone catalytic reagent be cyclohexanone, acetone, one or more of 4- heptanone mixed keton, preferably
Cyclohexanone, reaction dissolvent are methylene chloride, chloroform, one of acetonitrile or two or more mixed solvents, preferably methylene chloride,
Reaction temperature is -30--10 DEG C.
In step 2), reaction dissolvent is tetrahydrofuran, toluene, ethyl alcohol, one of isopropanol or two or more mixing
Solvent, preferably tetrahydrofuran, reaction temperature are 10-30 DEG C.
In step 3), reaction dissolvent is tetrahydrofuran, and dioxane, one of acetonitrile or two or more mixing are molten
Agent, preferably tetrahydrofuran, reaction temperature are -10-70 DEG C.
In step 4), reaction dissolvent includes methanol, ethyl alcohol, one of isopropanol or two or more mixed solvents, excellent
Select methanol；
Chiral selectors are L- bis- to one of toluyl tartaric acid, L- dibenzoyl tartaric acid, tartaric acid
Or two or more mix reagents, preferential L- bis- is to toluyl tartaric acid；
Alkali used includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide mixed base, reaction temperature
5-25℃。
The utility model has the advantages that the preparation method of tropsch imatinib intermediate provided by the invention, with 1- benzyl -4- methyl-1,2,3,
6- tetrahydropyridine is as starting material, by one-step method by olefin oxidation at ketone (II), after forming imines (III) with amine later,
Amine is formed with asymmetric reduction imines, cis-structure (IV) is obtained by recrystallization removal transisomer, finally uses hand
Property splits to obtain final product (3R, 4R) -1- benzyl-N, 4- lupetidine -3- amine dihydrochloride (I).The technique of this method is created
Newly, processing step is shortened, avoids the use of these hazardous agents of tetrahydrochysene lithium aluminium, while greatly improving not with asymmetric reduction
Symmetrical compound synthesis yield, takes a firm foundation for industrialized production.
Specific embodiment
The present invention will be further explained combined with specific embodiments below.
A kind of preparation method of the pharmaceutical intermediate I of tropsch imatinib, chemical structural formula are as follows:
The preparation method is as follows: with 1- benzyl -4- methyl-1,2,3,6- tetrahydropyridines pass through one-step method as starting material
Olefin oxidation is obtained into ketone compounds II at ketone, after forming group with imine moiety III with amine later, with asymmetric reduction imines
Formed amine, by recrystallization removal transisomer obtain cis-structure IV, finally with chiral resolution obtain final product (3R,
4R) -1- benzyl-N, 4- lupetidine -3- amine dihydrochloride I to get；
Synthetic route is as follows:
Embodiment one: by raw material 1- benzyl -4- methyl-1,2,3,6- tetrahydropyridine (187mg) is dissolved in methylene chloride
(10mL), the dichloromethane solution of trimethyl silicon substrate trifluoro sulphonic acid ester (1.1g) is added at -20 DEG C of nitrogen protection, and catalysis is added
The cyclohexanone of amount, is stirred to react and middle control reaction is to fully reacting, and column chromatographs to obtain compound II.(yield 89%).
Embodiment two: compound II (17.6g) and 50ml tetrahydrofuran, nitrogen protection, cooling are sequentially added to there-necked flask
It to 15 DEG C, is added dropwise methylamine hydrochloride (7g), controls 15-20 DEG C of temperature reaction, middle control to fully reacting.It direct plunges into next step.
Embodiment three: being added 3-sec-butyl lithium borohydride (19.8g) after above-mentioned solution is cooled to 0 DEG C, and stirring is a little while
After to be warming up to back flow reaction complete, pour into ice saturated ammonium chloride solution, be extracted with dichloromethane, 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, solid, filtering, solid is precipitated
It is washed to obtain cis-compound IV with ethyl acetate.(two step yields 68%)
Example IV: compound IV (34g) is dissolved in 150g water, is adjusted PH=11 with 30%NaOH solution, is used acetic acid
Ethyl ester extraction, organic phase drying is spin-dried for being dissolved in methanol after obtaining unhindered amina, and after being cooled to 5 DEG C, L- bis- is added to methylbenzene first
Salt is obtained by filtration in acyl tartaric acid (15.78g), stirring and crystallizing.The salt is dissolved in 150g water, adjusts PH with 30%NaOH solution
=11, it is extracted with ethyl acetate, organic phase is dry to be spin-dried for obtaining unhindered amina, and ice-water bath controls temperature at 5-20 DEG C, HCl is added dropwise
Ethyl acetate solution, crude product is obtained by filtration in stirring and crystallizing, and crude product is refining to obtain fine work I with dehydrated alcohol.(yield 45%)
The above is only a preferred embodiment of the present invention, it should be pointed out that: for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (9)
1. a kind of preparation method of compound, which is characterized in that the chemical structural formula of the compound is as follows:
The preparation method is as follows: with 1- benzyl -4- methyl-1,2,3,6- tetrahydropyridines are as starting 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 later, is formed with asymmetric reduction imines
Amine obtains cis-structure IV by recrystallization removal transisomer, finally obtains final product (3R, 4R)-with chiral resolution
1- benzyl-N, 4- lupetidine -3- amine dihydrochloride I to get；
Synthetic route is as follows:
Specifically includes the following steps:
Step 1) is with 1- benzyl -4- methyl-1, and 2,3,6- tetrahydropyridines are raw material, in Me3SiSO3CF3With the work of ketone catalytic reagent
Under, oxidation reaction obtains ketone compounds II；
Step 2) compound II and methylamine form group with imine moiety III；
Step 3) group with imine moiety III is obtained cis-: trans- structure by asymmetric reduction after being restored by 3-sec-butyl lithium borohydride
Type is 90:10, forms cis-isomer IV by hydrochloric acid salt refining；
Step 4) cis-isomer IV is split under alkali effect by chiral selectors, by salt intermediate V, one kettle way shape
At (3R, 4R) -1- benzyl-N, 4- lupetidine -3- amine dihydrochloride I to get.
2. the preparation method of compound according to claim 1, it is characterised in that: in step 1), ketone catalytic reagent is hexamethylene
One or more of ketone, acetone, 4- heptanone.
3. the preparation method of compound according to claim 1, it is characterised in that: in step 1), reaction dissolvent is dichloromethane
One of alkane, chloroform, acetonitrile or two or more mixed solvents, reaction temperature are -30 to -10 DEG C.
4. the preparation method of compound according to claim 1, it is characterised in that: in step 2), reaction dissolvent is tetrahydro furan
It mutters, toluene, one of ethyl alcohol, isopropanol or two or more mixed solvents, reaction temperature are 10-30 DEG C.
5. the preparation method of compound according to claim 1, it is characterised in that: in step 3), reaction dissolvent is tetrahydro furan
It mutters, one of dioxane, acetonitrile or two or more mixed solvents, reaction temperature are -10-70 DEG C.
6. the preparation method of compound according to claim 1, it is characterised in that: in step 4), reaction dissolvent is methanol, second
One or more of alcohol, isopropanol mixed solvent；5-25 DEG C of reaction temperature.
7. the preparation method of compound according to claim 2, it is characterised in that: in step 4), chiral selectors L-
One or more of two pairs of toluyl tartaric acid, L- dibenzoyl tartaric acid, tartaric acid.
8. the preparation method of compound according to claim 2, it is characterised in that: chiral selectors are L- bis- to methylbenzene
Formyl tartaric acid.
9. the preparation method of compound according to claim 2, it is characterised in that: alkali used be sodium hydroxide, potassium hydroxide,
One or more of lithium hydroxide.
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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 |
| MX2021000611A (en) * | 2018-07-18 | 2021-04-13 | Astrazeneca Ab | A xinafoate salt of a jak inhibiting compound. |
| CN108948022B (en) * | 2018-08-16 | 2020-02-18 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis method of tofacitinib |
| CN109761884B (en) * | 2019-01-30 | 2020-03-31 | 湖北扬信医药科技有限公司 | Preparation method and application of chiral amine B |
| CN109734653B (en) * | 2019-02-21 | 2020-07-14 | 北京悦康科创医药科技股份有限公司 | Resolution method of argatroban starting material isomer impurities |
| 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 |
| 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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| CN1439010A (en) * | 2000-06-26 | 2003-08-27 | 辉瑞产品公司 | Pyrrolo [2,3-d] pyrimidine compounds as immunosuppressive agents |
| CN1729192A (en) * | 2001-05-31 | 2006-02-01 | 辉瑞产品公司 | Optical resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors |
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| CN1439010A (en) * | 2000-06-26 | 2003-08-27 | 辉瑞产品公司 | Pyrrolo [2,3-d] pyrimidine compounds as immunosuppressive agents |
| CN1729192A (en) * | 2001-05-31 | 2006-02-01 | 辉瑞产品公司 | Optical resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors |
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