CN110526919A - The synthetic method of compound - Google Patents
The synthetic method of compound Download PDFInfo
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- CN110526919A CN110526919A CN201910647850.3A CN201910647850A CN110526919A CN 110526919 A CN110526919 A CN 110526919A CN 201910647850 A CN201910647850 A CN 201910647850A CN 110526919 A CN110526919 A CN 110526919A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
A kind of synthetic method of the structural formula such as compound of (V), comprising: the 1) hydrogenation of compounds of structural formula such as (I) takes off the compound that benzyl obtains structural formula such as (II)；2) compound of the compound with structural formula such as (II) of structural formula such as (III) contacts, to obtain the compound of structural formula such as (IV)；3) compound of structural formula such as (IV) contacts removing tertbutyloxycarbonyl protection with acid solution, to obtain the compound of structural formula such as (V).Its synthetic thread of synthetic method of the present invention is short out, simple process, raw material are easy to get, post-process simple, high-quality, high income, is suitble to industrialized production support method for cloth and its intermediate.
Description
Technical field
The present invention relates to a kind of synthetic methods of pharmaceutical intermediate, more particularly to the weight of drug Tasocitinib a kind of
Want the synthetic method of intermediate.
Background technique
N- methyl-N- ((3R, 4R) -4- methyl piperidine -3- base) -7H- pyrrolo- [2,3-D] pyrimidine -4- amine is Pfizer's medicine
The important intermediate of object Tasocitinib.Tasocitinib is U.S. Food and Drug Administration's on November 6th, 2012
(FDA) approval treatment moderate has reacted not methotrexate (MTX) [methotrexate (MTX)] to severe activity rheumatoid arthritis (RA)
It is good, or be not resistant to grow up；It is a kind of new oral JAK inhibitor.
N- methyl-N- ((3R, 4R) -4- methyl piperidine -3- base) -7H- pyrrolo- [2,3-D] pyrimidine -4- amine is a kind of white
Color has following chemical name to pale powder:
N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]
pyrimidin-4-amine
Structural formula is
Molecular formula: C13H19N5；Molecular weight: 245.32；CAS accession number: 477600-74-1.The intermediate has some texts
Report synthetic method is offered, but these methods have apparent defect:
(1) original route of Pfizer:
This route needs to complete the hydrogenation of two steps, and also in need to use tetrahydrochysene lithium aluminium, it is high-risk reaction that this, which writes step all,.Its
In a step hydrogenate final step again, cause synthesis cost very high, product difficulty purifying is not easy to operate and industrialize.
(2) synthetic route of Jiang, J.-k:
The too long a total of 16 step reaction of this route, centre also relate to tetrahydrochysene lithium aluminium, hydrogenation, grubbs reagent
Using separating the contour danger of important intermediate (3R, 4R) -4- methyl -3- (methylamino) -1- piperidines benzyl with column chromatographic purifying
And step at high cost.
Summary of the invention
In view of the foregoing deficiencies of prior art, the purpose of the present invention is to provide the changes of structural formula of compound such as (V)
Close the conjunction of the hydrochloride of object N- methyl-N- ((3R, 4R) -4- methyl piperidine -3- base) -7H- pyrrolo- [2,3-D] pyrimidine -4- amine
At method, synthetic thread is short out, simple process, raw material are easy to get, post-process simple, high-quality, high income, is suitble to industrialized production
Support method replaces cloth and its intermediate.
Term " contact " used in herein shall be understood in a broad sense, and can be and any enables at least two
The mode that reactant chemically reacts, such as can be and mix two kinds of reactants under suitable condition.According to need
It wants, can under stiring mix the reactant contacted, the type stirred as a result, is not particularly restricted,
Such as can be mechanical stirring, i.e., it is stirred under the action of mechanical force.
Herein, term " first ", " second " are used for description purposes only, and are not understood to indicate or imply relatively heavy
The property wanted or the quantity for implying indicated technical characteristic.Define " first " as a result, the feature of " second " can be expressed or
Implicitly include one or more of the features.
In order to achieve the above objects and other related objects, the present invention is by including that technical solution below obtains.
The present invention provides the synthetic method of the structural formula such as compound of (V), includes the following steps:
The compound of structural formula such as (I) hydrogenates the chemical combination that de- benzyl obtains structural formula such as (II) under palladium-carbon catalyst effect
Object；
The compound of the compound with structural formula such as (II) of structural formula such as (III) contacts, to obtain structural formula such as (IV)
Compound；
The compound of structural formula such as (IV) contacts removing tertbutyloxycarbonyl protection with acid solution, to obtain structural formula such as
(V) compound；
Specifically, N- methyl-N- ((3R, 4R) -4- methyl piperidine -3- base) -7H- pyrrolo- [2,3- of the present invention
D] pyrimidine -4- amine hydrochloride be using structural formula such as (I) hydrogenation of compounds take off benzyl, then again with structural formula such as (II) change
Object reaction is closed, then is obtained after removing tertbutyloxycarbonyl protection.Shown in its reaction route formula specific as follows.
Technical solution according to the present invention, the condition that the hydrogenation of compounds of structural formula such as (I) takes off benzyl are not particularly limited, as long as
The compound of structural formula such as (II) can be effectively obtained, those skilled in the art can flexible choice according to the actual situation.One
In a embodiment, in step 1), structural formula such as (I) compound in the first organic solvent and palladium-carbon catalyst effect under with
Hydrogen contact hydrogenates de- benzyl, and first organic solvent is selected from one of ethyl alcohol, methanol and isopropanol or a variety of.Preferably second
Alcohol.Feed temperature and the reaction temperature for hydrogenating debenzylation reaction are unrestricted.Preferably, reaction feed temperature is 0 DEG C~50 DEG C.
Preferably, reaction temperature control is being no more than 80 DEG C.
Technical solution according to the present invention, palladium content in palladium carbon catalyzer be 5wt%~20wt%, preferably 5wt%~
15wt%, such as can be 10wt%, 11wt%, 8wt%, 9wt%.The additive amount of palladium-carbon catalyst can be according to practical catalysis
It needs to be added.
Technical solution according to the present invention, structural formula such as (I) compound and the first organic solvent volume ratio for 1:(5~
10)。
Technical solution according to the present invention is post-processed after hydrogenation debenzylation reaction is complete.Post-processing includes to reaction solution
It is filtered, then adjusts solution and be concentrated, extraction to alkalinity, then organic phase is concentrated the compound for obtaining structural formula such as (II).
Specifically, reaction can be tracked by TLC to determine whether reaction is complete.Specifically, sodium hydroxide or hydroxide can be passed through
The aqueous solution of potassium adjusts alkalinity, and such as adjusting alkalinity to pH is greater than 8, if pH is 9 or 10.Specifically, have by concentration removal first
Solvent.Specifically, it can be extracted using methylene chloride DCM when extraction.Organic phase concentration is obtained again colorless and transparent
The compound of structural formula such as (II).Pass through above-mentioned post-processing, it is possible to reduce impurity obtains structural formula of the purity greater than 99% such as
(II) compound.
Technical solution according to the present invention, the item that the compound of the compound with structural formula such as (II) of structural formula such as (III) contacts
Part is not particularly limited, as long as the compound of structural formula such as (IV) can be obtained effectively, those skilled in the art can be according to reality
Border situation flexible choice.It is embodied situation according to the present invention, in step 2), under alkaline condition, the change of structural formula such as (III)
Object is closed to contact with the compound of structural formula such as (II)；Alkaline condition is modulated by organic base or inorganic base；The inorganic base is choosing
From at least one of potassium carbonate, sodium carbonate and sodium bicarbonate, preferably potassium carbonate；The organic base is selected from triethylamine and N, N
At least one of diisopropylethylamine.Preferably triethylamine.It is highly preferred that the additive amount of the inorganic base be structural formula such as
(II) 2~5 times of compound, such as can be 2 times, 3 times, 3.5 times.Implementation method according to the present invention, structural formula is such as
(III) molar ratio of the compound and structural formula such as chemical combination of (II) is (1~1.5): 1.In a preferred embodiment, In
Under conditions of being heated to reflux, the compound of the compound with structural formula such as (II) of structural formula such as (III) is contacted.It is preferred at one
In embodiment, the temperature that the compound of the compound with structural formula such as (II) of structural formula such as (III) contacts is 20 DEG C~150 DEG C, more
Preferably 60 DEG C~130 DEG C.Side reaction is advantageously reduced as a result, improves reaction efficiency and yield.
Technical solution according to the present invention has been reacted in the compound of the compound with structural formula such as (II) of structural formula such as (III)
Quan Hou is post-processed to obtain the compound of high-purity structural formula such as (IV).Post-processing includes cooling, filters to obtain crude product, use
Solvent recrystallization.Impurity in products can be reduced by above-mentioned post-processing step, obtains structural formula such as (IV) that purity is greater than 98%
Compound.
Technical solution according to the present invention, the compound of structural formula such as (IV) contact removing tertbutyloxycarbonyl protection with acid solution
Condition be not particularly limited, as long as can effectively obtain structural formula such as (V) compound, those skilled in the art can root
According to actual conditions flexible choice.It is embodied situation according to the present invention, in step 3), the acid used when removing tertbutyloxycarbonyl is molten
Liquid is the mixed solution of aqueous hydrochloric acid solution and ethyl alcohol.The volume ratio of aqueous hydrochloric acid solution and ethyl alcohol is 1:(3~9).Aqueous hydrochloric acid solution
Concentration be 4mol/L~6mol/L.The temperature of deprotection is unrestricted, it is preferable that the temperature of deprotection be no more than 80 DEG C,
It for example 0~80 DEG C, is just able to carry out at room temperature.Be conducive to as a result, simplify operation, reduce side reaction, improve reaction efficiency and
Yield.
Technical solution according to the present invention has been contacted in the compound of structural formula such as (IV) with the mixed solution of hydrochloric acid and ethyl alcohol
Quan Hou, such as room temperature reaction 3 hours or more, have white solid precipitation, can be post-processed, to obtain high-purity structural formula such as (V)
Compound.The post-processing is washed including filtering, filtering the filter cake obtained using organic solvents such as ethyl alcohol.By above-mentioned
Post-processing step can reduce impurity in products, obtain the compound of structural formula of the purity greater than 99% such as (V), solid for white
Body powder or crystallization.The compound of the higher structural formula of purity such as (V) is obtained by above-mentioned processing.
In technical solution of the present invention, structural formula such as (I) compound be the prior art, can use domestic applications number for
The technical solution recorded in 201410026502.1 patent obtains the compound of structural formula such as (I).Also reference can be made to above-mentioned synthesis
Route.
In technical solution of the present invention, the compound of structural formula such as (V) is N- methyl-N- ((3R, 4R) -4- methyl piperidine -
3- yl) -7H- pyrrolo- [2,3-D] pyrimidine -4- amine hydrochloride, can be that raw material preparation support method replaces cloth using it, it is specific
Preparation route is as shown above.
The scheme that cloth is replaced for the compound preparation support method using structural formula such as (V), specifically can be with the following method.
By mass volume ratio, (1~1.5) ︰ (6~12) is respectively completely dissolved the compound of structural formula such as (V) with n-butanol, then
It is added in cyan-acetic ester and organic base (such as triethylamine, DIPEA, DBU) reaction solution, 45 DEG C~50 DEG C of reaction temperature；Add
Thermal response 3 hours~4 hours, add water, filter, filter cake is washed 1 time with n-butanol, and liquid separation concentration is tied again with alcohols (such as ethyl alcohol)
Crystalline substance obtains qualified support method for cloth, can get white solid powder or the crystallization of chemical purity > 99.5%, EE > 99.5%.Knot
The compound of structure formula such as (V) can be directly used for the synthesis that support method replaces cloth, and synthesis yield is high, and the support method of formation replaces the change of cloth
Learn purity is high.
The technique purified using the synthetic method of the above-mentioned offer of the present invention using critical process step, so that the intermediate of synthesis
Control of Impurities to minimum, obtain N- methyl-N- ((3R, 4R) -4- methyl piperidine -3- of white solid powder shape or crystallization
Base) -7H- pyrrolo- [2,3-D] pyrimidine -4- amine hydrochloride, purity HPLC content reaches > 99%, EE > 99%, guarantee at
The curative effect of medicine.And according to synthetic route provided herein, N- methyl-N- ((3R, 4R) -4- methyl piperidine -3- base) -
The total recovery of the hydrochloride of 7H- pyrrolo- [2,3-D] pyrimidine -4- amine is more than 80%, improves at least 5 times than traditional handicraft, together
When, energy consumption is reduced, intermediate N methyl-N- ((3R, 4R) -4- methyl piperidine -3- base) -7H- pyrrolo- [2,3- is utilized
D] hydrochloride of pyrimidine -4- amine is highly susceptible to purifying for cloth as synthesis material synthesis support method, obtain very good product.
Detailed description of the invention
Fig. 1 is shown as the HPLC spectrogram of the structural formula such as compound of (V) of the preparation of embodiment 3
Fig. 2 is shown as the EE spectrogram of the structural formula such as compound of (V) of the preparation of embodiment 3
Fig. 3 is shown as the HPLC spectrogram of the structural formula such as compound of (V) of the preparation of embodiment 4
Fig. 4 is shown as the EE spectrogram of the structural formula such as compound of (V) of the preparation of embodiment 4
Fig. 5 is shown as the HPLC spectrogram of the structural formula such as compound of (V) of the preparation of embodiment 5
Fig. 6 is shown as the EE spectrogram of the structural formula such as compound of (V) of the preparation of embodiment 5
Specific embodiment
Embodiments of the present invention are illustrated by particular specific embodiment below, those skilled in the art can be by this explanation
Content disclosed by book is understood other advantages and efficacy of the present invention easily.
Before further describing the specific embodiments of the present invention, it should be appreciated that protection scope of the present invention is not limited to down
State specific specific embodiment；It is also understood that term used in the embodiment of the present invention is specific specific in order to describe
Embodiment, rather than limiting the scope of protection of the present invention.The test method of actual conditions is not specified in the following example,
Usually according to normal condition, or according to condition proposed by each manufacturer.
When embodiment provides numberical range, it should be appreciated that except non-present invention is otherwise noted, two ends of each numberical range
Any one numerical value can be selected between point and two endpoints.Unless otherwise defined, the present invention used in all technologies and
Scientific term is identical as the normally understood meaning of those skilled in the art of the present technique.Except specific method, equipment used in embodiment,
Outside material, grasp and record of the invention according to those skilled in the art to the prior art can also be used and this
Any method, equipment and the material of the similar or equivalent prior art of method described in inventive embodiments, equipment, material come real
The existing present invention.
Overall synthetic route is as follows in the present embodiment.
1) hydrogenation of compounds of structural formula such as (I) takes off the compound that benzyl obtains structural formula such as (II)；
2) compound of the compound with structural formula such as (II) of structural formula such as (III) contacts, to obtain structural formula such as (IV)
Compound；
3) compound of structural formula such as (IV) is contacted with the mixed solution of aqueous hydrochloric acid solution and ethyl alcohol, to obtain structural formula
Such as the compound of (V)；
Embodiment 1
By compound (3R, 4R)-1- tertbutyloxycarbonyl-3- [(S)-N- methyl-1-benzene of the structural formula of 4.83Kg such as (I)
Base ethylamino] -4- methyl-sends pyridine-L-TARTARIC ACID salt, and it is dissolved in the ethyl alcohol of 10 times of quality, is then added in hydriding reactor, then by knot
Palladium-carbon catalyst (containing 10wt%Pd) is added in the 10% of the structure formula such as compound quality of (I), under nitrogen protection, is passed through hydrogen,
TLC shows that fully reacting, reaction solution filtering adjust pH value of solution to 10 with 3mol/L sodium hydroxide solution, and concentration removes ethyl alcohol, uses
DC M extraction, concentration send pyridine except DCM (3R, the 4R) -1- tertbutyloxycarbonyl -3- methylamino -4- methyl-for obtaining colorless and transparent degree
The compound of 2.1Kg, as structural formula such as (II), yield are 92.3% purity > 99%, EE > 99%.
1H NMR(CDCl3, 300MHz): 3.82~3.93 (m, 2H), 2.98~2.85 (d, 2H), 2.37 (s, 4H), 1.75
(s, 1H), 1.38 (s, 11H), 0.90-0.88 (d, J=6.9Hz, 3H)；MS:m/z=229 (M+H)+。
Embodiment 2
By compound (3R, 4R) -1- tertbutyloxycarbonyl -3- methylamino -4- methyl-group of the structural formula of 2.28Kg such as (II)
Compound 4-chloro -7- tertbutyloxycarbonyl -7H- pyrroles [2,3-D] pyrimidine of the structural formula of pyridine and 2.5 Kg such as (III), which is added to, to be contained
In the aqueous solution of 2mol/L potassium carbonate, heating (120 DEG C) back flow reaction 8 hours detects fully reacting, and reaction cooling is filtered, obtained
Crude product, recrystallization is primary, obtains crude product purity > 98%, is LC-MS:m/z=446 (M+H) through testing result+, it is structure
The compound of formula such as (IV), yield 89%.
Embodiment 3
Crude product uses the ethyl alcohol of 3 times of quality to dissolve again, is then added drop-wise in the ethanol solution hydrochloride of the 6mol/L of 5 times of volumes,
It reacts 3 hours at room temperature, there is white solid precipitation, filter, filter cake twice, obtains N- methyl-N- ((3R, 4R)-with ethanol washing
4- methyl piperidine -3- base) -7H- pyrrolo- [2,3-D] pyrimidine -4- amine hydrochlorate 2.56Kg structural formula such as (V) chemical combination
Object, two step total recoverys are 90.8%, chemical purity > 99%, EE > 99%.Testing result is as follows:
1H NMR(300MHz,D2O) δ: 10.60 (br s, 1H), 8.35 (s, 1H), 7.07 (d, J=3.6Hz, 1H),
6.60 (d, J=3.6Hz, 1H), 4.88-4.98 (m, 1H), 3.45 (s, 3H), 3.25-3.37 (m, 1H), 2.80-3.10 (m,
3H), 2.45-2.58 (m, 1H), 1.82-2.00 (m, 1H), 1.60-1.80 (m, 2H), 1.11 (d, J=7.2Hz, 3H) LC-
MS:m/z=246 (M+H)+。
Embodiment 4
It repeats embodiment 1 and embodiment 2 its chemical yield is respectively 95% and 93%.
Repeat the compound of 3 preparation structure formula of embodiment such as (V).
Embodiment 5
It repeats embodiment 1 again and embodiment 2 its chemical yield is respectively 96% and 93%.
Repeat the compound of 3 preparation structure formula of embodiment such as (V).
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology all without departing from the spirit and scope of the present invention, carries out modifications and changes to above-described embodiment.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should be covered by the claims of the present invention.
Claims (9)
1. a kind of synthetic method of structural formula such as compound of (V), comprising:
1) hydrogenation of compounds of structural formula such as (I) takes off the compound that benzyl obtains structural formula such as (II)；
2) compound of the compound with structural formula such as (II) of structural formula such as (III) contacts, to obtain the change of structural formula such as (IV)
Close object；
3) compound of structural formula such as (IV) contacts removing tertbutyloxycarbonyl protection with acid solution, to obtain structural formula such as (V)
Compound；
2. synthetic method according to claim 1, which is characterized in that in step 1), the compound of structural formula such as (I) is the
Contact with hydrogen the de- benzyl of hydrogenation in one organic solvent and under palladium-carbon catalyst effect, first organic solvent selected from ethyl alcohol,
One of methanol and isopropanol are a variety of.
3. synthetic method according to claim 2, which is characterized in that palladium content in palladium carbon catalyzer be 5wt%~
20wt%.
4. synthetic method according to claim 2, which is characterized in that the structural formula such as compound of (I) and first organic molten
The volume ratio of agent is 1:(5~10).
5. synthetic method according to claim 1, which is characterized in that in step 2), under alkaline condition, structural formula is such as
(III) compound is contacted with the compound of structural formula such as (II)；Alkaline condition is modulated by organic base or inorganic base；
The inorganic base is selected from least one of potassium carbonate, sodium carbonate and sodium bicarbonate；
The organic base is selected from triethylamine and N, at least one of N diisopropylethylamine.
6. synthetic method according to claim 1, which is characterized in that the compound and structural formula of structural formula such as (III) are such as
(II) molar ratio of chemical combination is (1~1.5): 1.
7. synthetic method according to claim 1, which is characterized in that in step 2), under conditions of being heated to reflux, structure
The compound of the compound with structural formula such as (II) of formula such as (III) contacts.
8. synthetic method according to claim 1, which is characterized in that in step 3), used when removing tertbutyloxycarbonyl
Acid solution is the mixed solution of aqueous hydrochloric acid solution and ethyl alcohol.
9. synthetic method according to claim 8, which is characterized in that the volume ratio of aqueous hydrochloric acid solution and ethyl alcohol be 1:(3~
9)。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248509A (en) * | 2021-05-17 | 2021-08-13 | 上海中西三维药业有限公司 | Preparation method of tofacitinib citrate intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755624A (en) * | 2014-01-20 | 2014-04-30 | 兰州博实生化科技有限责任公司 | Synthetic method of piperidine derivative |
| 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 |
-
2019
- 2019-07-18 CN CN201910647850.3A patent/CN110526919A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755624A (en) * | 2014-01-20 | 2014-04-30 | 兰州博实生化科技有限责任公司 | Synthetic method of piperidine derivative |
| 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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248509A (en) * | 2021-05-17 | 2021-08-13 | 上海中西三维药业有限公司 | Preparation method of tofacitinib citrate intermediate |
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Application publication date: 20191203 |