CN108658845A - The preparation method of deuterated intermediate - Google Patents
The preparation method of deuterated intermediate Download PDFInfo
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- CN108658845A CN108658845A CN201810219700.8A CN201810219700A CN108658845A CN 108658845 A CN108658845 A CN 108658845A CN 201810219700 A CN201810219700 A CN 201810219700A CN 108658845 A CN108658845 A CN 108658845A
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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
- C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
- C07D211/84—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 two 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 directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The present invention provides a kind of preparation methods of deuterated intermediate.Deuterated intermediate has structure shown in Formulas I：The preparation method includes the following steps：Amino in raw material A is carried out aldimine condensation with the organic matter containing aldehyde radical to react, obtains aldimine condensation product, raw material A has structure shown in Formula II：By aldimine condensation product and D2O carries out deuterated reaction, obtains deuterated product；And deuterated product is subjected to the first deprotection reaction, obtain deuterated intermediate.Compared to existing synthetic route, which is significantly shortened, and product yield is effectively promoted with the shortening of synthetic route.And deuterated rate can be controlled by deuterated number; simultaneously in the preparation method; D-atom only needs progress amino deprotection reaction to can be obtained required deuterated intermediate after introducing; thus being also helped using preparation method provided by the present application reduces the occurrence probability of side reaction, and then improves the purity of deuterated intermediate.Formula I；Formula II.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, in particular to a kind of preparation method of deuterated intermediate.
Background technology
Hydrocarbon structure (C:H) it is one of structure most basic in pharmaceutical chemistry structure, the carbon-hydrogen link of formation is most basic
Chemical bond.Hydrogen bond is with X-H ..., and Y is indicated, and distance between X-Y is set to the bond distance of hydrogen bond.Hydrogen bond has bond energy, the structure of hydrogen bond
Parameter (such as bond distance, bond angle, directionality) can be changed quite interior on a large scale, and influence bond energy, and bond distance is shorter, and hydrogen bond is got over
By force.Although the bond energy of hydrogen bond is little, the influence to physical property is very big, and reason has two：On the one hand, it is former that most hydrogen bonds are formed
It manages, is intended to generate hydrogen bond as much as possible to reduce the energy of system inside substance；On the other hand, because hydrogen bond energy is small,
Activation energy is also small needed for its formation and destruction, between substance interior molecules under the conditions of motion change continuous with intramolecular, hydrogen bond
It is constantly broken and is formed, and keep a certain number of Hydrogenbonds in substance.Various physics of the formation of hydrogen bond to substance
Chemical property can all have deep effect, also serve in the physiology of the mankind and animals and plants, biochemical process highly important.Cause
This, changes chemical bond and hydrogen bond energy in medical compounds molecular structure, you can changes chemistry, the pharmaceutical of medical compounds
Matter.But the technological approaches and means for changing chemical bond and hydrogen bond energy in medical compounds molecular structure are extremely limited.
There are three types of isotopes for hydrogen atom：Atomic weight be 1 hydrogen (Hydrogen, symbol of element H, be generally called hydrogen, be stable
Isotope)；Atomic weight be 2 deuterium (Deuterium, the symbol of element be D or2H, also known as heavy hydrogen are stable isotopes) and it is former
The tritium (symbol of element T, a kind of radioactive isotope) that son amount is 3.A kind of stable form isotope of the deuterium as hydrogen, its atom
Core is made of a proton and a neutron.A neutron (D-atom amount is 2, microcrith 1) more than hydrogen nuclei, so
C-D chemical bonds stablize (fast 6 times of c h bond breakdown rate ratio C~D keys compared with c h bond；Important feature that there are one deuteriums is it in drug
Shape and volume in molecule is substantially the same with hydrogen, that is to say, that if hydrogen the replacing with by selectivity in drug molecule
Deuterium, deuterated drug generally can also retain original bioactivity and selectivity, but it is deuterated after may improve metabolic stability and
Curative effect, risk of toxicity are all extremely low.Deuterated drug can be used for pharmacokinetic, also has and chemoprophylaxis or treatment is remarkably reinforced
The function of disease, additionally it is possible to reduce poisonous side effect of medicine.
Existing new drug development pattern and flow have been increasingly difficult to find new drug, nearly all known chemical molecular
It had all been developed by pharmaceuticals industry with biological targets.Although the expense of new drug development increases year by year, the new drug of success listing
Constantly reduce.In such a case, deuterated effect just shows its advantage.Such as Glaxo SmithKHn companies with
The Concert drugmakers deuterated product of cooperation joint development, including Bristol-Myers Squibb companies
The sharp Chinese mugwort appropriate (Reyataz) of hiv protease inhibitor.
The deuterated approval that United States Patent (USP) and trademark office have also been obtained for pharmaceutically-active improvement.Wherein deuterated Rimonabant
(Rimonabant), the patents such as Mosapride (Mosapride) and treatment urinary incontinence drug oxybutynin have also gone through.
Importantly, recently, FDA has had been approved by the deuterated tetrabenazine (trade name Austedo) of first deuterated drug ladder watt, uses
In treatment Huntington's chorea, it means that the following deuterated drug might have good application prospect.
Compound(3- deuterium hydrogen -3- amino -2,6- piperidine diones) is a kind of to prepare deuterated drug
Particularly important deuterated intermediate.At present there are many kinds of the synthetic methods of the compound, including D-atom incorporation way also very
More, more commonly used at present methods, D-atom begin to introduce from second step, this causes synthesis cost to be substantially improved, and yield is about
For 10wt%.Synthetic route is as follows：
Boc indicates tertbutyloxycarbonyl.
Said synthesis route is more tediously long, atom utilization is low, and whole combined coefficient is relatively low.
Invention content
The main purpose of the present invention is to provide a kind of preparation methods of deuterated intermediate, to solve existing deuterated centre
Body manufacturing cost is higher, the problem of deuterated reaction route length.
To achieve the goals above, according to the present invention provides a kind of preparation method of deuterated intermediate, deuterated intermediates
With structure shown in Formulas I：The preparation method includes：
Amino in raw material A is carried out aldimine condensation with the organic matter containing aldehyde radical to react, obtains aldimine condensation product, raw material
A has structure shown in Formula II：
By aldimine condensation product and D2O carries out deuterated reaction, obtains deuterated product；And deuterated product is subjected to the first remove-insurance
Shield reaction, obtains deuterated intermediate.
Further, in aldimine condensation reaction, raw material A is 1 with the ratio between the molal quantity of organic matter containing aldehyde radical:1~5；It is excellent
It is selected as 1:1~3.
Further, in aldimine condensation reaction, the organic matter containing aldehyde radical is selected from aromatic aldehyde and/or fatty aldehyde；Preferably benzene
Formaldehyde and/or isopentyl aldehyde.
Further, deuterated react includes：By aldimine condensation product and D under the action of basic catalyst2O carries out anti-
It answers, and in deuterated reaction, aldimine condensation product, basic catalyst and D2The ratio between molal quantity of O is 1:1~3:8~15；Preferably
1:1~2:10~12.
Further, basic catalyst is selected from the group of dimethylisopropylamine, butyl lithium and dimethyl isopropylamino lithium composition
In it is one or more.
Further, the first deprotection reaction includes：Deuterated product and acid are subjected to protonation reaction, obtain deuterated centre
Body.
Further, the ratio between deuterated product and the molal quantity of acid are 1:1~10；Preferably 1:1~2.5.
Further, the preparation method of raw material A includes：
It willAmido protecting reaction is carried out according to following route, is obtained
It willCondensation reaction is carried out according to following route, is obtained And
It willThe second deprotection reaction is carried out according to following route, obtains raw material A：
Further, amido protecting agent is selected from the group of benzyl chloroformate, bromobenzyl, benzyl chloride and di-tert-butyl dicarbonate composition
In it is one or more.
Further, condensation reagent is selected from N, N- carbonyl dimidazoles, 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides
It is one or more in the group of hydrochloride and 1- propylphosphonic anhydrides composition.
It applies the technical scheme of the present invention, using raw material A as starting material, passes through aldimine condensation reaction, deuterated reaction successively
Required deuterated intermediate is can be obtained with three steps of amino deprotection reaction.Compared to existing synthetic route, the preparation side
Method synthetic route is significantly shortened, and product yield is effectively promoted with the shortening of synthetic route.Simultaneously in the preparation method, deuterium is former
Son only needs progress amino deprotection reaction to can be obtained required deuterated intermediate after introducing, thus uses system provided by the present application
Preparation Method also helps the occurrence probability for reducing side reaction, and then improves the purity of deuterated intermediate.In conclusion using this Shen
The preparation method that please be provided prepares deuterated intermediate with distinctive starting material, is combined using chemical synthesis and heavy water exchange
Method, using cheap heavy water, by the deuterated reaction of two steps, you can obtain object, route is short, at low cost, selectivity it is good.
And can be as needed, obtain the product of different deuterated rates.
Description of the drawings
The accompanying drawings which form a part of this application are used to provide further understanding of the present invention, and of the invention shows
Meaning property embodiment and its explanation are not constituted improper limitations of the present invention for explaining the present invention.In the accompanying drawings：
Fig. 1 shows deuterated intermediate made from the embodiment of the present invention 11H-NMR tests spectrogram；
Fig. 2 shows deuterated intermediates made from the embodiment of the present invention 113C-NMR tests spectrogram；
Fig. 3 shows secondary deuterated intermediate in the embodiment of the present invention 11H-NMR test maps；
Fig. 4 shows in the embodiment of the present invention 1 deuterated intermediate three times1H-NMR test maps.
Specific implementation mode
It should be noted that in the absence of conflict, the features in the embodiments and the embodiments of the present application can phase
Mutually combination.Below in conjunction with embodiment, the present invention will be described in detail.
As described in background technology, the higher problem of preparation method cost of existing deuterated intermediate.To understand
Certainly above-mentioned technical problem, this application provides a kind of preparation method of deuterated intermediate, the structural formula such as Formulas I institutes of deuterated intermediate
Show：
The preparation method includes：Amino in raw material A is carried out aldimine condensation with the organic matter containing aldehyde radical to react, obtains aldehyde
Amine condensation product, raw material A have structure shown in Formula II：
By aldimine condensation product and D2O carries out deuterated reaction, obtains deuterated product；And deuterated product is subjected to the first remove-insurance
Shield reaction, obtains deuterated intermediate.
In above-mentioned deuterated reaction process, is reacted by aldimine condensation and protect the amino group in raw material A, obtain aldehyde
Amine condensation product, this is conducive to generate interference to subsequent deuterated reaction to avoid amino, and then is conducive to improve the pure of product
Degree.Subsequent aldimine condensation product and D2O carries out deuterated reaction, obtains deuterated product；It will finally be carried out on amino in deuterated product
Blocking group removing, to obtain the deuterated reagent needed for the application.
In the preparation method of deuterated intermediate provided by the present application, using raw material A as starting material, pass through aldimine condensation successively
Reaction, deuterated reaction and three steps of amino deprotection reaction can be obtained required deuterated intermediate.Compared to existing conjunction
At route, which is significantly shortened, and product yield is effectively promoted with the shortening of synthetic route.Simultaneously should
It only needs progress amino deprotection reaction to can be obtained required deuterated intermediate after the introducing of D-atom in preparation method, thus adopts
Being also helped with preparation method provided by the present application reduces the occurrence probability of side reaction, and then improves the purity of deuterated intermediate.
In conclusion using preparation method provided by the present application, deuterated intermediate is prepared with distinctive starting material and not only contributes to drop
The manufacturing cost of low deuterated intermediate, also advantageously improves product yield and purity.
In the preparation method of above-mentioned deuterated intermediate, mole of raw material A and the organic matter containing aldehyde radical in aldimine condensation reaction
Than proportional region commonly used in the art may be used.In a preferred embodiment, aldimine condensation reaction in, raw material A with
The ratio between molal quantity of organic matter containing aldehyde radical is 1:1~5；Preferably 1:1~3.
In a preferred embodiment, in aldimine condensation reaction, the organic matter containing aldehyde radical includes but not limited to fragrance
Aldehyde and/or fatty aldehyde, preferably benzaldehyde and/or isopentyl aldehyde.Above-mentioned several substances have lower cost, and source is extensively easy to
Obtain, thus select above-mentioned several substances as the organic matter containing aldehyde radical in the application be conducive to further decrease technique at
This.
In a preferred embodiment, deuterated reaction is included in aldimine condensation product under the action of basic catalyst
And D2O is reacted, and in the deuterated reaction, aldimine condensation product, basic catalyst and D2The ratio between molal quantity of O 1:1~3:
8~15；Preferably 1:1~2:10~12.Aldimine condensation product, basic catalyst and D2The ratio between molal quantity of O includes but unlimited
In above range, and limited the receipts of the conversion rate and product that are conducive to further increase deuterated product within the above range
Rate.
In order to further increase the deuterated rate of deuterated reaction, aldimine condensation product is preferably subjected to repeatedly deuterated reaction.
Aldimine condensation product, basic catalyst and D wherein in first time deuterated reaction2The ratio between molal quantity of O relationship according to the above ratio, and
In second of deuterated reaction and subsequent deuterated reaction, product, basic catalyst and the D of last deuterated reaction2The molal quantity of O
The ratio between need the actual conditions according to last deuterated reaction to be adjusted.Deuterated rate is improved by deuterated number, use is above-mentioned
The deuterated rate of deuterated intermediate made from method is 80% or more, preferably 90% or more, more preferably 95% or more.
Preferably, above-mentioned basic catalyst includes but not limited to dimethylisopropylamine, butyl lithium and dimethyl isopropylamino
It is one or more in the group of lithium composition.In deuterated reaction process, basic catalyst is former by the active hydrogen on aldimine condensation product
Son removing, forms carbanion；Then make D2The deuterium hydrogen of O is combined with above-mentioned carbanion, obtains required deuterated product.
Preferably, in above-mentioned preparation method, after deuterated reaction, the first deprotection reaction includes：By deuterated product with
Acid carries out protonation reaction, obtains deuterated intermediate.Preferably, above-mentioned acid includes but not limited to sulfuric acid and/or hydrochloric acid.More preferably
Ground, the ratio between deuterated product and the molal quantity of acid are 1:1~10；Preferably 1:1~2.5.The ratio between deuterated product and the molal quantity of acid
Including but not limited to above range, and the efficiency for being conducive to improve amino deprotection within the above range is limited, Jin Erti
The yield of high deuterated intermediate.
Commercially available commodity may be used in raw material A in above-mentioned preparation method, can also voluntarily prepare.
In a preferred embodiment, the preparation method of raw material A includes：
It willAmido protecting reaction is carried out according to following route, is obtained
It willCondensation reaction is carried out according to following route, is obtained And
It willThe second deprotection reaction is carried out according to following route, obtains raw material A：
T is in amido protecting reaction, in amido protecting agent
The group combined with amino.
The structural formula of L-Glutamine is
It in above-mentioned preparation method, reacts in order to prevent close to the amino of carboxyl site, by branch in L-Glutamine
On amino and amino protecting agent carry out amido protecting and react, obtain the first intermediate product.Under the action of condensation reagent, first
The dehydration condensation of intramolecular occurs with carboxyl for the amino in product, obtains condensation product.Finally using Pd/C as catalyst,
The blocking group on the amino in condensation product is removed under the reduction of hydrogen, obtains required raw material A.
Preferably, amido protecting agent includes but not limited to benzyl chloroformate, bromobenzyl, benzyl chloride and di-tert-butyl dicarbonate group
At group in it is one or more.
Preferably, condensation reagent includes but not limited to N, N- carbonyl dimidazoles, 1- (3- dimethylamino-propyls) -3- ethyl carbon
It is one or more in the group of diimmonium salt hydrochlorate and 1- propylphosphonic anhydrides composition.
The application is described in further detail below in conjunction with specific embodiment, these embodiments should not be understood as limitation originally
Apply for range claimed.
Embodiment 1
1, the synthesis of the first intermediate product
L-Glutamine (100g, 0.685mol, 1eq), 3.33wt%NaHCO are sequentially added into 5L there-necked flasks3Solution
(1.8L) is stirred evenly, and obtains mixed liquor, and between above-mentioned mixed liquor is cooled to (0~5 DEG C) using ice-water bath, the system of obtaining is in
White emulsion.
Benzyl chloroformate (250g, 1.466mol, 2.1eq) is added dropwise into above-mentioned emulsion, reaction system is made to be risen without apparent
Temperature, and by the control of the temperature of reaction system between 0~5 DEG C, 30min is dripped off.NaHCO is added into above-mentioned reaction system3Gu
Body (200g, 2.38mol, 3.5eq) makes above-mentioned reaction system react 1h under low temperature (0~5 DEG C), then at room temperature (20 DEG C)
Lower reaction 2h, LC-MS show no starting material left, obtain reaction solution.
Above-mentioned reaction solution is washed with ethyl alcohol (500mL × 4), then with 38% hydrochloric acid (200mL) by above-mentioned reaction solution tune
To pH=1, and it is stirred to 10min in ice-water bath, then there are a large amount of solids to be precipitated in reaction solution, after filtering, obtain level-one
Filter cake.Then above-mentioned filter cake water (2L) is eluted and is drained, obtain two level filter cake.By above-mentioned two level filter cake and ethyl alcohol
After (500mL) mixing, it is beaten, time 1h obtains slurries.It states then up and petroleum ether (1500mL) is added in slurries,
Stirring, filtering, obtain three-level filter cake.Above-mentioned three-level filter cake is evaporated with rotary evaporator at 50 DEG C, off-white powder is obtained
113.7g (the first intermediate product).Synthetic route is as follows：
Cbz-Cl is chloro-carbonic acid benzyl
Ester.
2, the synthesis of condensation product
Above-mentioned first intermediate product (500g, 1.79mol, 1.0eq), Isosorbide-5-Nitrae-dioxane are put into 10L four-hole bottles
(5L), CDI (579g, 3.57mol, 2eq), DMAP (10.24g, 0.084mol, 0.047eq) are stirred evenly, not molten, the N in part2
Displacement is connected to bubbling device afterwards three times, is warming up to 100 DEG C of back flow reaction 15h, TLC display raw materials and disappears substantially, obtains reaction solution.
Above-mentioned reaction solution is down to room temperature, and is concentrated to dryness, residue is obtained.Above-mentioned residue is molten with ethyl alcohol (8L)
Solution, obtains organic phase.Above-mentioned organic phase is washed with water (5L × 4), then successively with saturation NaHCO3Solution (5L), saturated common salt
Water (3L) washs organic phase, is finally concentrated to dryness organic phase, obtains off-white powder 374g (condensation product).
3, the synthesis of reduction reaction product and aldimine condensation product
Condensation product (370g, 1.41mol), THF (3.7L), 10%Pd/C (111g) stirrings are added into 10L there-necked flasks
Uniformly, mixed liquor is obtained.Use N2Three times to the gas displacement in there-necked flask, then H is used2Three times to the gas displacement in there-necked flask, will
Above-mentioned mixed liquor reacts 12h under room temperature (15 DEG C), normal pressure, and TLC is monitored without starting material left, obtains reaction solution.By above-mentioned reaction
After liquid directly filters (pad diatomite), filter cake is obtained.Above-mentioned filter cake is eluted with THF (500mL), and it is thick to be dried to obtain reduzate
Product.
Above-mentioned reduzate crude product, benzaldehyde (150g, 1.41mol, 1.0eq), toluene (3L) are put into reaction bulb bottle
It in (5L), stirs evenly, obtains mixed liquor.Use N2Three times to the gas displacement in there-necked flask, above-mentioned mixed liquor is reacted into 1.5h,
TLC monitors (DCM：MeOH=10:1, bromocresol green, UV, Rfsm=0.2, Rfp=0.8) substantially without starting material left, it is reacted
Liquid.Above-mentioned reaction solution is down to room temperature after filtering (pad diatomite) and obtains filter cake.Above-mentioned filter cake is eluted with DCM (3L), is obtained
To filtrate and residue.Above-mentioned filtrate is concentrated to dryness, above-mentioned residue is beaten after being mixed with ethyl alcohol (500mL), time 2h,
Obtain slurries.Above-mentioned slurries are filtered, filter cake is obtained.After above-mentioned filter cake is eluted with ethyl alcohol (300mL), drain light green color is solid
Body 136.5g (aldimine condensation product).
4, the synthesis of deuterated product：
Deuterated reaction for the first time
Above-mentioned aldimine condensation product (30g, 0.139mol, 1.0eq) is dissolved in THF (690mL), and in nitrogen protection
Under, at -70 DEG C, be slowly dropped into above-mentioned reaction system prepare LDA [butyl lithium (55.5mL, 0.146mol,
1.05eq), diisopropylamine (16.3g, 0.161mol, 1.16eq), THF (690mL)], reaction system has apparent heat release, control anti-
The temperature of system is answered to be less than -70 DEG C, 1h drops finish, and reaction system color is peony at this time.By above-mentioned reaction system at -70 DEG C
Under, 30min is reacted, reaction system is warmed naturally into 0 DEG C (about 2h), D then is added dropwise into above-mentioned reaction system at 0 DEG C2O
(28g, 1.39mol, 10eq), reaction system are dripped off without apparent heating, 1min.By above-mentioned reaction system at 0 DEG C first time deuterium
Generation reaction, reaction time 5min, with buffer solution (600mL, KH2PO4:The molar ratio of NaOH is 2:1 saturated solution) in nitrogen
Above-mentioned deuterated reaction is quenched under gas shielded, obtains reaction solution.The THF in above-mentioned reaction solution is removed by depressurizing method, then
It is extracted with DCM (600mL × 4), obtains organic phase.Above-mentioned organic phase is dried with anhydrous sodium sulfate (20g), and is subtracted
Pressure, which is concentrated into, to be just precipitated without solid, and enriched product is obtained.Petroleum ether (50mL) is added dropwise into above-mentioned enriched product, in enriched product
A large amount of solids are precipitated, after filtering, obtain filter cake.Above-mentioned filter cake is eluted with ethyl alcohol (30mL), drains to obtain light-blue solid 19.2g
(the first deuterated product), deuterated rate 81wt%.
Second of deuterated reaction
Under the protection of nitrogen, temperature be -70 DEG C when, to prepare LDA [butyl lithium (8.4mL, 0.02mol,
0.25eq), diisopropylamine (2.47g, 0.02mol, 0.275eq), THF (442mL)] in be slowly dropped into the first deuterated product
THF (442mL) solution of T1380-5-1 (19.2g, 0.089mol, 1.0eq) controls the temperature of reaction system without apparent heat release
Less than -70 DEG C, 1h drops finish.Above-mentioned reaction system is reacted into 30min at -70 DEG C, reaction system is warmed naturally to 0 DEG C (about
2h), D is added dropwise into above-mentioned reaction system for 0 DEG C2O (17.8g, 0.89mol, 10eq), the reaction system is without apparent heating, 1min
Drop finishes.Above-mentioned reaction system is carried out to second of deuterated, reaction time 5min at 0 DEG C, with buffer solution (384mL) in nitrogen
Above-mentioned deuterated reaction is quenched under protection, obtains reaction solution.The THF in above-mentioned reaction solution is removed by depressurizing method, is then used
DCM (384mL × 4) is extracted, and organic phase is obtained.Above-mentioned organic phase is dried with anhydrous sodium sulfate (12g), and is depressurized
It is concentrated into and is just precipitated without solid, obtain enriched product.It states then up and petroleum ether (32mL), enriched product is added dropwise in enriched product
It is middle that a large amount of solids are precipitated, after filtering, obtain filter cake.Above-mentioned filter cake is eluted with ethyl alcohol (30mL), drains to obtain light-blue solid
The second deuterated products of 13.6g.This product is subjected to MS measurement, it is 88.9wt% to measure deuterated rate into analysis,.To above-mentioned second deuterium
It is carried out for product1H-NMR is tested, and test map is shown in Fig. 3.
Deuterated reaction for the third time
Under nitrogen protection, temperature be -70 DEG C when, to prepare LDA [butyl lithium (2.9mL, 0.007mol,
0.12eq), diisopropylamine (0.84g, 0.008mol, 0.132eq), THF (19mL)] in be slowly dropped into the second deuterated product
THF (312mL) solution of T1380-5-2 (13.6g, 0.06mol, 1.0eq) controls the temperature of reaction system without apparent heat release
Less than -70 DEG C, 10min drops finish.Above-mentioned reaction system is reacted into 30min at -70 DEG C, system is warmed naturally to 0 DEG C (about
2h), D2O (12g, 0.6mol, 10eq) is added dropwise into above-mentioned reaction system for 0 DEG C, the reaction system is without apparent heating, 1min drops
Finish.Above-mentioned reaction system is carried out to the deuterated reaction of third time, reaction time 5min, with buffer solution (272mL) in nitrogen at 0 DEG C
Above-mentioned deuterated reaction is quenched under gas shielded, obtains reaction solution.The THF in above-mentioned reaction solution is removed by depressurizing method, then
It is extracted with DCM (272mL × 4), obtains organic phase.Above-mentioned organic phase is dried with anhydrous sodium sulfate (7g), and is subtracted
Pressure, which is concentrated into, to be just precipitated without solid, and enriched product is obtained.It states then up and n-hexane (7mL) is added dropwise in enriched product, concentration production
A large amount of solids are precipitated in object, after filtering, obtain filter cake.Above-mentioned filter cake is eluted with ethyl alcohol (10mL), drains to obtain light-blue solid
This product is carried out MS measurement by the deuterated product of 8.6g thirds, and it is 93.8wt% to measure deuterated rate into analysis.It is deuterated to above-mentioned third
Product carries out1H-NMR is tested, and test map is shown in Fig. 4.
The synthesis of deuterated intermediate：
Deuterated product (20g, 0.092mol, 1.0eq), THF (200mL) are put into 500mL there-necked flasks, it is above-mentioned after stirring
Reaction raw materials all dissolve, and obtain mixed liquor.6M hydrochloric acid (18mL) is added dropwise into above-mentioned mixed liquor, reaction system has puts on a small quantity
Heat, the temperature that reaction system is controlled using ice-water bath are less than 20 DEG C, and 15min drops finish, and reacting liquid pH value is 3~4 at this time.It will be above-mentioned
Reaction system monitors (DCM in room temperature 15 DEG C of heat preservations 1h, TLC：MeOH=20:1, UV, Rfsm=0.4) without starting material left, it obtains
Reaction solution.Then filter cake is obtained by filtration in trade company's reaction solution.Above-mentioned filter cake is eluted with ethyl alcohol (50mL) finally, is drained
Pure white solid 13.4g (deuterated intermediate).The yield of deuterated intermediate is 87.6wt%, and nuclear-magnetism is pure.
Above-mentioned product is carried out1H-NMR is tested, and spectrogram is shown in Fig. 1, the structure of product can be determined for the application institute through analysis
The deuterated intermediate 3- deuteriums hydrogen -3- amino -2,6- piperidine diones needed.
Above-mentioned product is carried out13C-NMR is tested, and spectrogram is shown in Fig. 2, the structure of product can be determined for the application institute through analysis
The deuterated intermediate 3- deuteriums hydrogen -3- amino -2,6- piperidine diones needed.
Embodiment 2
Difference with embodiment 1 is：The ratio between molal quantity of condensation product and benzaldehyde is 1:3.The yield of deuterated intermediate
For 38.8wt%.
Embodiment 3
Difference with embodiment 1 is：The ratio between molal quantity of condensation product and benzaldehyde is 1:0.5.The receipts of deuterated intermediate
Rate is 28.3wt%.
Embodiment 4
Difference with embodiment 1 is：For the first time in deuterated reaction, aldimine condensation product, basic catalyst and D2Mole of O
The ratio between number is 1:1.1:10.The yield of deuterated intermediate is 75.7wt%.
Embodiment 5
Difference with embodiment 1 is：For the first time in deuterated reaction, aldimine condensation product, basic catalyst and D2Mole of O
The ratio between number is 1:2.5:10.The yield of deuterated intermediate is 66.3wt%.
Embodiment 6
Difference with embodiment 1 is：For the first time in deuterated reaction, aldimine condensation product, basic catalyst and D2Mole of O
The ratio between number is 1:0.5:8.The yield of deuterated intermediate is 53.8wt%.
Embodiment 7
Difference with embodiment 1 is：The ratio between molal quantity of deuterated product and hydrochloric acid is 1:4, the yield of deuterated intermediate is
45.7wt%.
It can be seen from the above description that the above embodiments of the present invention realize following technique effect：
Comparing embodiment 1 to 7 and existing synthetic route using preparation method provided by the present application it is found that be conducive to substantially
Improve the yield and purity of deuterated intermediate.
Comparing embodiment 1 to 3 by raw material A and the ratio between the molal quantity of organic matter containing aldehyde radical it is found that be limited to this Shen
It please be conducive to further increase the yield and purity of deuterated intermediate within preferred protection domain.
Comparing embodiment 1,4 to 6 is it is found that by aldimine condensation product, basic catalyst and D2The ratio between molal quantity of O is limited to
Be conducive to further increase the yield and purity of deuterated intermediate within the preferred protection domain of the application.
The ratio between deuterated product and the molal quantity of acid are limited to by comparing embodiment 1 and 7 it is found that in amino deprotection reaction
Be conducive to further increase the yield and purity of deuterated intermediate within the preferred protection domain of the application.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, any made by repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of deuterated intermediate, which is characterized in that the deuterated intermediate has structure shown in Formulas I：
The preparation method includes：
Amino in raw material A is carried out aldimine condensation with the organic matter containing aldehyde radical to react, obtains aldimine condensation product, the raw material
A has structure shown in Formula II：
By the aldimine condensation product and D2O carries out deuterated reaction, obtains deuterated product；And
The deuterated product is subjected to the first deprotection reaction, obtains the deuterated intermediate.
2. preparation method according to claim 1, which is characterized in that in the aldimine condensation reaction, the raw material A and institute
It is 1 to state the ratio between molal quantity of organic matter containing aldehyde radical:1~5；Preferably 1:1~3.
3. preparation method according to claim 1 or 2, which is characterized in that described to contain aldehyde radical in the aldimine condensation reaction
Organic matter be selected from aromatic aldehyde and/or fatty aldehyde；Preferably benzaldehyde and/or isopentyl aldehyde.
4. preparation method according to any one of claim 1 to 3, which is characterized in that the deuterated reaction is urged in alkalinity
It is carried out under the action of agent, and in the deuterated reaction, the aldimine condensation product, the basic catalyst and D2Mole of O
The ratio between number is 1:1~3:8~15；Preferably 1:1~2:10~12.
5. preparation method according to claim 4, which is characterized in that the basic catalyst be selected from dimethylisopropylamine,
It is one or more in the group of butyl lithium and dimethyl isopropylamino lithium composition.
6. preparation method according to claim 1, which is characterized in that first deprotection reaction includes：By the deuterium
Protonation reaction is carried out for product and acid, obtains the deuterated intermediate.
7. preparation method according to claim 6, which is characterized in that the ratio between the molal quantity of the deuterated product and the acid
It is 1:1~10；Preferably 1:1~2.5.
8. preparation method according to claim 1, which is characterized in that the preparation method of the raw material A includes：
It willAmido protecting reaction is carried out according to following route, is obtained
It will be describedCondensation reaction is carried out according to following route, is obtained
It will be describedThe second deprotection reaction is carried out according to following route, obtains the raw material A：
9. preparation method according to claim 8, which is characterized in that the amido protecting agent be selected from benzyl chloroformate,
It is one or more in the group of bromobenzyl, benzyl chloride and di-tert-butyl dicarbonate composition.
10. preparation method according to claim 8, which is characterized in that the condensation reagent be selected from N, N- carbonyl dimidazoles,
It is one or more in the group of 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides and 1- propylphosphonic anhydrides composition.
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Citations (3)
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| WO2012015986A2 (en) * | 2010-07-27 | 2012-02-02 | Concert Pharmaceuticals Inc. | Substituted dioxopiperidinyl phtalimide derivatives |
| WO2012068512A1 (en) * | 2010-11-18 | 2012-05-24 | Deuteria Pharmaceuticals Llc | 3-deutero-pomalidomide |
| CN105566190A (en) * | 2016-01-19 | 2016-05-11 | 扬州大学 | Method for synthesizing diselenides |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012015986A2 (en) * | 2010-07-27 | 2012-02-02 | Concert Pharmaceuticals Inc. | Substituted dioxopiperidinyl phtalimide derivatives |
| WO2012068512A1 (en) * | 2010-11-18 | 2012-05-24 | Deuteria Pharmaceuticals Llc | 3-deutero-pomalidomide |
| CN105566190A (en) * | 2016-01-19 | 2016-05-11 | 扬州大学 | Method for synthesizing diselenides |
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