CN106146507A - A kind of expelling pathogens by strengthening vital QI is for the new synthetic method of Buddhist nun - Google Patents
A kind of expelling pathogens by strengthening vital QI is for the new synthetic method of Buddhist nun Download PDFInfo
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- CN106146507A CN106146507A CN201510104199.7A CN201510104199A CN106146507A CN 106146507 A CN106146507 A CN 106146507A CN 201510104199 A CN201510104199 A CN 201510104199A CN 106146507 A CN106146507 A CN 106146507A
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Abstract
The present invention relates to a kind of JAK inhibitor expelling pathogens by strengthening vital QI synthetic method for Buddhist nun.The method as raw material with (4-picoline-3-base) methyl carbamate, through catalytic hydrogenation, benzyl protection, reduction, becomes salt, splits, deprotection, and amide chemical conversion salt prepares expelling pathogens by strengthening vital QI for Buddhist nun.Specifically include: (1) by (4-picoline-3-base) methyl carbamate at sulphuric acid, Pd/C catalytic hydrogen reduction；(2) cis-(4-methyl piperidine-3-base) methyl carbamate and benzyl chlorine react cis-(1-benzyl-4-methyl piperidine-3-base) methyl carbamate；(3) N-[(3R, 4R)-4-methyl piperidine-3-base]-N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine prepares expelling pathogens by strengthening vital QI for Buddhist nun's free alkali with cyanoacetic acid through HOBT catalyzing and condensing.The preparation method raw material of the present invention is easy to get, and reaction condition is gentle, and easy and simple to handle, yield is higher, is suitable to industrialized production.
Description
Technical field
The invention belongs to organic and technical field of medicine synthesis, be specifically related to a kind of JAK inhibitor expelling pathogens by strengthening vital QI for Buddhist nun (Tofacitinib)
Synthetic method.
Background technology
Expelling pathogens by strengthening vital QI replaces the chemical entitled 3-of Buddhist nun (Tofacitinib) [(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)
Amino] piperidin-1-yl]-3-oxypropionitrile, be Pfizer Inc. research and development one novel JAK inhibitor, in November, 2012 warp
FDA ratifies listing, trade name Xeljanz.Extracellular target spot is mainly acted on different from other RA medicines of Most current
It is that expelling pathogens by strengthening vital QI with Cellular Signaling Transduction Mediated path as target spot, acts on the core of cytokine for Buddhist nun, for methotrexate
Treatment response is insufficient or the moderate that do not tolerates is to the treatment of severe Active rheumatoid arthritis (RA) adult patient, is one
Plant new oral JAK inhibitor.Rheumatoid arthritis whole world number of patients nearly 30,000,000 at present, expelling pathogens by strengthening vital QI is public for Ni Shi Pfizer
Take charge of one of new drug of most market prospect.Expelling pathogens by strengthening vital QI is as follows for Buddhist nun's chemical structural formula:
At present expelling pathogens by strengthening vital QI has a following two kinds for the main preparation methods of Buddhist nun:
Method one, Pfizer, at document Organic Process Research&Development 2003, report in 7,115-120
Synthetic route as follows:
This route is with 4-methyl pyridine as initiation material, through Benzylation, and sodium borohydride reduction, borine hydroxylating, oxidation, first
The steps such as amination prepare key intermediate cis-1-benzyl-3-methylamino-4-methyl piperidine, then through splitting, coupling, amidatioon obtains
Expelling pathogens by strengthening vital QI replaces Buddhist nun.Although this route raw material is easy to get, but overall route is long, and yield is relatively low, is not suitable for industrialized production.
Method two, Pfizer carry out industry improvement on the basis of as above method, apply for a patent WO2007012953, and in 2008
Year is open in China, Publication No. CN101233138A.Concrete synthetic route is as follows:
Amido, with 3-amino-4-methylpyridine as raw material, is first protected by this route, rhodium catalysis reduction pyridine ring, generated amine benzyl
Base is protected, and Lithium Aluminium Hydride reduces, and obtains key intermediate cis-1-benzyl-3-methylamino-4-methyl piperidine, then through splitting, coupling,
Amidatioon obtains expelling pathogens by strengthening vital QI for Buddhist nun.This route cost of material is higher, but overall route is shorter, and yield is higher, and worth industry melts
Sending out, weak point is still the use of reagent costly, and complex operation, and room for improvement is bigger.
Summary of the invention:
It is an object of the invention to provide a kind of JAK inhibitor expelling pathogens by strengthening vital QI synthetic method for Buddhist nun.
The present invention relates to a kind of JAK inhibitor expelling pathogens by strengthening vital QI synthetic method for Buddhist nun.The method is with (4-picoline-3-base) amino first
Acid methyl ester is raw material, through catalytic hydrogenation, benzyl protection, reduction, becomes salt, splits, deprotection, and amide chemical conversion salt prepares
Expelling pathogens by strengthening vital QI replaces Buddhist nun.Specifically include: (1) by (4-picoline-3-base) methyl carbamate at sulphuric acid, Pd/C catalytic hydrogen reduction；
(2) cis-(4-methyl piperidine-3-base) methyl carbamate and benzyl chlorine react cis-(1-benzyl-4-methyl piperidine-3-base) carbamic acid
Methyl ester；(3) N-[(3R, 4R)-4-methyl piperidine-3-base]-N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine and cyanoacetic acid warp
HOBT catalyzing and condensing prepares expelling pathogens by strengthening vital QI for Buddhist nun's free alkali.The preparation method raw material of the present invention is easy to get, and reaction condition is gentle, behaviour
Making simplicity, yield is higher, is suitable to industrialized production.
Its synthetic route is as follows:
The method have the characteristics that and provide the simple synthesis preparing expelling pathogens by strengthening vital QI for Buddhist nun, be embodied in:
A () (4-picoline-3-base) methyl carbamate A, under the conditions of Pd/C, sulphuric acid catalysis, hydro-reduction is prepared suitable
-(4-methyl piperidine-3-base) methyl carbamate B.
(b) cis-(4-methyl piperidine-3-base) methyl carbamate B and benzyl chlorine at diisopropyl ethyl amine as reaction alkali condition
Lower coupling prepares cis-(1-benzyl-4-methyl piperidine-3-base) methyl carbamate C.
C () N-[(3R, 4R)-4-methyl piperidine-3-base]-N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine D and cyanoacetic acid are through 1-
The lower condensation of hydroxybenzotriazole catalysis prepares expelling pathogens by strengthening vital QI for Buddhist nun free alkali E.
For step (a), catalytic hydrogenation can use 5% or 10%Pd/C, and Bronsted acid can use cheap and easily-available concentrated sulphuric acid,
Hydrogenation pressure is 3～10MPa, hydrogenates under preferably 5MPa Hydrogen Vapor Pressure, and wherein Pd/C consumption is 10～30% mass fraction raw material,
Concentrated sulphuric acid consumption is 5%～15% molar fraction raw material, and the response time is 12～48 hours, preferably 24 hours.
For step (b), this coupling reaction can select multiple inorganic base or organic base to carry out, but in order to avoid excessive alkyl
Changing and improve reaction yield, reaction can be at triethylamine, diisopropyl ethyl amine, DMAP, N-methylmorpholine condition
Lower coupling, preferably diisopropyl ethyl amine.
For step (c), this type of is amide condensed, and multiple known method can be used to carry out, and the most universal has two kinds of methods,
One is now carboxylic acid to be prepared as acyl chlorides, then reacts with amine；Another kind is first carboxylic acid to be prepared as active ester with condensing agent, then
It is condensed with amine.This programme uses second method, and condensing agent can use I-hydroxybenzotriazole or 1-hydroxyl-7-azo benzo
Triazole etc., preferably I-hydroxybenzotriazole.
Another feature of the present invention is that reaction temperature is gentle, and reaction temperature is all at 10～40 degree.
The invention has the advantages that, all raw materials of use and reagent are easy to get inexpensively, environmental protection.Concise in technology, easy and simple to handle, reaction
Mild condition, yield is higher, and generated intermediate purity is higher, and impurity is few.Therefore this case invention is suitable for industrialized production.
Detailed description of the invention:
Further illustrate this invention below by embodiment, but present disclosure can not be limited.
Embodiment 1: the synthesis of cis-(4-methyl piperidine-3-base) methyl carbamate
By ethanol (150ml), (4-picoline-3-base) methyl carbamate (16.6g, 0.1mol), ethanol (150ml), dense sulfur
Acid (10.9g, 0.11mol) and 5%Pd/C (3.5g) add in hydriding reactor successively, and nitrogen is replaced 3 times, 5MPa hydrogen exchange
Three times, under 5MPa hydrogen pressure, react 24h.It is cooled to room temperature, sucking filtration, filtrate reduced in volume, obtains colourless oil liquid product
(16.4g, 95%).MS (m/z): 173 [M+H]+；1H NMR (300MHz, DMSO-d6): 6.80 (d, J=8.7Hz, 1H,
OCONH), 3.53 (s, 3H, CH3O), 3.47～3.49 (m, 1H, CHCH2NH), 2.70～2.81 (m, 2H, CHCH2NH),
2.50～2.58 (m, 2H, CHCH2CH2), 2.40～2.42 (m, 1H, CHCH2NH), 1.68～1.73 (m, 1H, CH3CH),
1.25～1.27 (m, 2H, CHCH2CH2), 0.78 (d, J=6.6Hz, 3H, CH3CH)。
Embodiment two: the synthesis of cis-(1-benzyl-4-methyl piperidine-3-base) methyl carbamate
By cis-(4-methyl piperidine-3-base) methyl carbamate (85g, 0.49mol), DIPEA (95g, 0.74mol) and acetonitrile
(400ml) add in reactor, keep the acetonitrile solution (200ml) of less than 10 degree droppings benzyl chlorine (60g, 0.5mol) of temperature, drip and finish
It is warmed to room temperature reaction 2h.Removing solvent under reduced pressure, add frozen water (1L) in residue, dropping 2mol/L hydrochloric acid (about 100ml) is adjusted
To pH 3～4, ethyl acetate extracts, and separatory, water layer strong aqua ammonia (about 10ml) is adjusted to pH 7～8, then extracts with dichloromethane
Three times.Merge organic layer, the dried sucking filtration of anhydrous sodium sulfate, filtrate reduced in volume, obtain pale yellow oil product (110.3g,
84%).MS (m/z): 263 [M+H]+；1H NMR (300MHz, CDCl3): 7.24～7.31 (m, 5H, Ar-H), 4.63 (br s, 1H,
NH), 3.64 (s, 3H, CH3O), 3.48～3.55 (m, 2H, Ar-CH2), 2.93～2.98 (m, 1H, CHCHaHbN), 2.66～
2.70 (m, 1H, CHCHaHbN), 1.96～2.03 (m, 1H, CHCHaHbN), 1.81～1.87 (m, 2H, CHCH2CH2),
1.68～1.74 (m, 1H, CH3CH), 1.25～1.39 (m, 2H, CHCH2CH2), 0.99 (d, J=6.3Hz, 3H, CH3CH)。
Embodiment 3, citric acid expelling pathogens by strengthening vital QI are for the synthesis of Buddhist nun
By N-[(3R, 4R)-4-methyl piperidine-3-base]-N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (30g, 0.12mol),
HOBT (23g, 0.17mol), cyanoacetic acid (13.6g, 0.16mol) and and dichloromethane (300ml) add in reactor, room temperature is anti-
Answer 12h.Reacting complete (300ml) cancellation that adds water, dichloromethane extracts, and water layer extracts with dichloromethane again, merges organic layer,
The dried sucking filtration of anhydrous sodium sulfate, filtrate reduced in volume, residue faint yellow solid adds hydration citric acid (2.3g, 11mmol)
Acetone (500ml) solution, in 40 DEG C stir 2h.It is stirred overnight under ice-water bath after cooling, sucking filtration, filter cake washing with acetone,
It is dried, obtains off-white color solid product (43g, 70%).MS (m/z): 313 [M+H]+；1H NMR (500MHz, CD3OD):
11.62 (s, 1H, NH), 8.17 (s, 1H, NCHN), 7.16 (d, J=3.5Hz, 1H, NHCHCH), 6.74 (d, J=3.5Hz, 1H,
NHCHCH), 4.79 (s, 1H, OH), 4.51～4.58 (m, 2H, CH2CN), 3.88～3.96 (m, 1H, CHCHaHbN), 3.70～
3.80 (m, 1H, CHCHaHbN), 3.43～3.57 (m, 2H, CHCH2CH2), 2.90 (d, J=15.5Hz, 2H, CH2COOH),
2.79 (d, J=15.5Hz, 2H, CH2COOH), 2.16 (s, 3H, CH3N), 1.92～1.95 (m, 1H, CHCHaHbN), 1.44～
1.46 (m, 1H, CH3CH), 1.21～1.35 (m, 2H, CHCH2CH2), 0.92 (d, J=6.5Hz, 3H, CH3CH)。
Claims (9)
1. 3-[(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino] piperidines-1-
Base] preparation method of-3-oxypropionitrile, it is characterised in that: with (4-picoline-3-base) methyl carbamate as raw material,
Under the conditions of Pd/C, sulphuric acid catalysis after hydro-reduction, and benzyl chlorine coupling reaction, then urge through I-hydroxybenzotriazole with cyanoacetic acid
Change lower condensation, i.e. can get 3-[(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino] piperidines
-1-base]-3-oxypropionitrile.
3-the most according to claim 1 [(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)
Amino] piperidin-1-yl] preparation method of-3-oxypropionitrile, it is characterised in that specifically comprise the following steps that
1) (4-picoline-3-base) methyl carbamate, under the conditions of Pd/C, sulphuric acid catalysis, hydro-reduction is prepared suitable
-(4-methyl piperidine-3-base) methyl carbamate；
2) cis-(4-methyl piperidine-3-base) methyl carbamate and benzyl chlorine are under the conditions of diisopropyl ethyl amine is as reaction alkali
Coupling prepares cis-(1-benzyl-4-methyl piperidine-3-base) methyl carbamate；
3) N-[(3R, 4R)-4-methyl piperidine-3-base]-N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine and cyanoacetic acid warp
The lower condensation of I-hydroxybenzotriazole catalysis prepares expelling pathogens by strengthening vital QI for Buddhist nun's free alkali.
3. according to 3-[(3R, 4R)-4-methyl-3-[methyl-(the 7H-pyrrolo-[2,3-d] described in claim 1 or claim 2
Pyrimidine-4-yl) amino] piperidin-1-yl] preparation method of-3-oxypropionitrile, it is characterised in that described prepare cis-(4-methyl piperazine
Pyridine-3-base) during methyl carbamate hydrogenates under Hydrogen Vapor Pressure, catalytic hydrogenation uses 5% or 10%Pd/C, Bronsted acid
For concentrated sulphuric acid, hydrogenation pressure is 3～10MPa, and wherein Pd/C consumption is 10～30% mass fraction raw material, and concentrated sulphuric acid consumption is
5%～15% molar fraction raw material, the response time is 12～48 hours.
3-the most according to claim 3 [(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)
Amino] piperidin-1-yl] preparation method of-3-oxypropionitrile, it is characterised in that hydrogenation pressure is 3～10MPa, preferably 5MPa
Left and right.
3-the most according to claim 3 [(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)
Amino] piperidin-1-yl] preparation method of-3-oxypropionitrile, it is characterised in that the response time is 12～48 hours, preferably 24
About hour.
6. according to 3-[(3R, 4R)-4-methyl-3-[methyl-(the 7H-pyrrolo-[2,3-d] described in claim 1 or claim 2
Pyrimidine-4-yl) amino] piperidin-1-yl] preparation method of-3-oxypropionitrile, it is characterised in that described coupling reaction at triethylamine,
Diisopropyl ethyl amine, DMAP, coupling under the conditions of N-methylmorpholine, preferably diisopropyl ethyl amine.
7. according to 3-[(3R, 4R)-4-methyl-3-[methyl-(the 7H-pyrrolo-[2,3-d] described in claim 1 or claim 2
Pyrimidine-4-yl) amino] piperidin-1-yl] preparation method of-3-oxypropionitrile, it is characterised in that described amide condensed condensing agent
First carboxylic acid is prepared as active ester, then is condensed with amine.
3-the most according to claim 7 [(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)
Amino] piperidin-1-yl] preparation method of-3-oxypropionitrile, it is characterised in that described condensing agent I-hydroxybenzotriazole.
9. according to 3-[(3R, 4R)-4-methyl-3-[methyl-(the 7H-pyrrolo-[2,3-d] described in claim 1 or claim 2
Pyrimidine-4-yl) amino] piperidin-1-yl] preparation method of-3-oxypropionitrile, it is characterised in that reaction temperature is all at 10～40 degree.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108822112A (en) * | 2018-08-13 | 2018-11-16 | 山东罗欣药业集团恒欣药业有限公司 | A kind of preparation method of tropsch imatinib compound |
| CN108948021A (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 preparation method of cloth |
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2015
- 2015-03-10 CN CN201510104199.7A patent/CN106146507A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108822112A (en) * | 2018-08-13 | 2018-11-16 | 山东罗欣药业集团恒欣药业有限公司 | A kind of preparation method of tropsch imatinib compound |
| CN108822112B (en) * | 2018-08-13 | 2019-12-20 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of tofacitinib compound |
| CN108948021A (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 preparation method of cloth |
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Application publication date: 20161123 |