CN108658845B - Preparation method of deuterated intermediate - Google Patents
Preparation method of deuterated intermediate Download PDFInfo
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- CN108658845B CN108658845B CN201810219700.8A CN201810219700A CN108658845B CN 108658845 B CN108658845 B CN 108658845B CN 201810219700 A CN201810219700 A CN 201810219700A CN 108658845 B CN108658845 B CN 108658845B
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- 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
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Abstract
The invention provides a preparation method of a deuterated intermediate. DeuteriumThe substituted intermediate has a structure shown in formula I: the preparation method comprises the following steps: carrying out an aldehyde-amine condensation reaction on amino in a raw material A and an organic matter containing aldehyde groups to obtain an aldehyde-amine condensation product, wherein the raw material A has a structure shown in a formula II: reaction of the aldol condensation product with D2Carrying out a deuteration reaction on O to obtain a deuteration product; and carrying out first deprotection reaction on the deuterated product to obtain a deuterated intermediate. Compared with the existing synthetic route, the synthetic route of the preparation method is greatly shortened, and the product yield is effectively improved along with the shortening of the synthetic route. Moreover, the deuteration rate can be controlled through the deuteration frequency, and in the preparation method, the required deuteration intermediate can be obtained only by carrying out amino deprotection reaction after the introduction of deuterium atoms, so that the preparation method provided by the application is favorable for reducing the occurrence probability of side reaction, and further the purity of the deuteration intermediate is improved.
Formula I;
formula II.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of a deuterated intermediate.
Background
The carbon-hydrogen structure (C: H) is one of the most basic structures in the chemical structure of a drug, and the formed carbon-hydrogen bond is the most basic chemical bond. The hydrogen bonds are denoted by X-H … Y, and the distance between X-Y is defined as the bond length of the hydrogen bond. Hydrogen bonds have a bonding energy, and the structural parameters of hydrogen bonds (e.g., bond length, bond angle, directionality) can vary over a relatively large range and affect the bonding energy, with shorter bond lengths and stronger hydrogen bonds. The bond energy of the hydrogen bond is not large, but the influence on the material property is large, and the two reasons are that: on the one hand, the most hydrogen bond principle is formed, and the internal part of the substance tends to generate hydrogen bonds as much as possible to reduce the energy of the system; on the other hand, since the hydrogen bond energy is small, the activation energy required for its formation and destruction is also small, and under the conditions of constant intermolecular and intramolecular movement changes within a substance, the hydrogen bond is constantly broken and formed, and a certain number of hydrogen bond bonds are maintained within the substance. The formation of hydrogen bonds has a profound influence on various physicochemical properties of substances, and plays an important role in physiological and biochemical processes of human beings, animals and plants. Therefore, the chemical bond and the hydrogen bond energy in the molecular structure of the drug compound are changed, namely the chemical and pharmaceutical properties of the drug compound are changed. However, there are limited technical approaches and means for changing the chemical and hydrogen bonding energies in the molecular structure of pharmaceutical compounds.
The hydrogen atom has three isotopes: hydrogen with an atomic weight of 1 (Hydrogen, element symbol H, commonly known as Hydrogen, is a stable isotope); deuterium with atomic weight 2 (Deuterium, symbol of element D or2H, also known as deuterium, is a stable isotope) and tritium (symbol T, a radioactive isotope) with an atomic weight of 3. Deuterium is a stable isotope of hydrogen whose nucleus consists of one proton and one neutron. The deuterium-substituted drug can be used for pharmacokinetic research, has the function of obviously enhancing the drug to prevent or treat diseases and can reduce the toxic and side effects of the drug.
The existing new drug development modes and processes are increasingly difficult to find new drugs, and almost all known chemical molecules and biological targets are developed by the pharmaceutical industry. Although the cost of new drug development has increased year by year, new drugs that are successfully marketed have continued to decrease. In this environment, deuteration shows its advantages. For example, Glaxo SmithKHn and Concert pharmaceutical companies are working together to develop deuterated products, including Bristol-Myers Squibb's HIV protease inhibitor Ruikai (Reyataz).
The improvement of the effect of deuteration on drugs is also recognized by the U.S. patent and trademark office. Among them, patents of deuterated Rimonabant (Rimonabant), Mosapride (Mosapride) and oxybutynin, a drug for treating urinary incontinence, have been approved. More importantly, the first deuterated drug, teva, deutetrabenazine (trade name Austedo) has recently been approved by the FDA for the treatment of huntington's disease, which means that future deuterated drugs may have promising application prospects.
Compound (I)
(3-deuterohydrogen-3-amino-2, 6-piperidione) is an extremely important deutero-intermediate for preparing deutero-drugs. At present, the synthesis method of the compound has a plurality of methods, including the introduction mode of deuterium atoms, and the deuterium atoms are introduced from the second step in the conventional method, so that the synthesis cost is greatly increased, and the yield is about 10 wt%. The synthetic route is as follows:
boc represents a tert-butoxycarbonyl group.
The synthesis route is long, the atom utilization rate is low, and the overall synthesis efficiency is low.
Disclosure of Invention
The invention mainly aims to provide a preparation method of a deuterated intermediate, which aims to solve the problems of high preparation cost and long deuterated reaction route of the conventional deuterated intermediate.
In order to achieve the above object, the present invention provides a method for preparing a deuterated intermediate, wherein the deuterated intermediate has a structure represented by formula I:
the preparation method comprisesThe method comprises the following steps:
carrying out an aldehyde-amine condensation reaction on amino in a raw material A and an organic matter containing aldehyde groups to obtain an aldehyde-amine condensation product, wherein the raw material A has a structure shown in a formula II:
reaction of the aldol condensation product with D2Carrying out a deuteration reaction on O to obtain a deuteration product; and carrying out first deprotection reaction on the deuterated product to obtain a deuterated intermediate.
Further, in the aldehyde-amine condensation reaction, the molar ratio of the raw material A to the organic matter containing aldehyde groups is 1: 1-5; preferably 1:1 to 3.
Further, in the aldehyde-amine condensation reaction, the organic matter containing aldehyde group is selected from aromatic aldehyde and/or aliphatic aldehyde; preferably benzaldehyde and/or isovaleraldehyde.
Further, deuteration reactions include: condensation of the aldehyde amine with D in the presence of a basic catalyst2O and deuteration reaction, aldehyde amine condensation product, basic catalyst and D2The molar ratio of O is 1:1 to 3:8 to 15; preferably 1:1 to 2:10 to 12.
Further, the basic catalyst is selected from one or more of the group consisting of dimethylisopropylamine, butyllithium, and dimethylisopropylaminolithium.
Further, the first deprotection reaction comprises: and carrying out protonation reaction on the deuterated product and acid to obtain a deuterated intermediate.
Further, the mole ratio of the deuterated product to the acid is 1: 1-10; preferably 1:1 to 2.5.
Further, the preparation method of the raw material A comprises the following steps:
will be provided with
The amino protection reaction is carried out according to the following route to obtain
Will be provided with
The condensation reaction is carried out according to the following route to obtain
And
will be provided with
The second deprotection reaction was carried out according to the following scheme to give starting material a:
further, the amino protecting reagent is selected from one or more of the group consisting of benzyl chloroformate, bromobenzyl, chlorobenzyl and di-tert-butyl dicarbonate.
Further, the condensation reagent is one or more selected from the group consisting of N, N-carbonyldiimidazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-propylphosphoric anhydride.
By applying the technical scheme of the invention, the raw material A is taken as an initial raw material, and the required deuterated intermediate can be obtained by sequentially carrying out three steps of an aldehyde-amine condensation reaction, a deuteration reaction and an amino deprotection reaction. Compared with the existing synthetic route, the synthetic route of the preparation method is greatly shortened, and the product yield is effectively improved along with the shortening of the synthetic route. Meanwhile, in the preparation method, the deuterium atom is introduced and then only an amino deprotection reaction is needed to obtain the required deuterated intermediate, so that the preparation method provided by the application is favorable for reducing the occurrence probability of side reactions and further improving the purity of the deuterated intermediate. In conclusion, by adopting the preparation method provided by the application, the deuterated intermediate is prepared from the special starting material, the method combining chemical synthesis and deuterium exchange is adopted, the cheap deuterium is used, and the target object can be obtained through two-step deuteration reaction, so that the preparation method is short in route, low in cost and good in selectivity. And products with different deuteration rates can be obtained according to requirements.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
FIG. 1 shows the preparation of deuterated intermediates from example 1 of the present invention1H-NMR test spectrum;
FIG. 2 shows the deuterated intermediate prepared in example 1 of the present invention13C-NMR test spectrum;
FIG. 3 shows the secondary deuterated intermediates of example 1 of the present invention1H-NMR test patterns;
FIG. 4 shows the preparation of the triple deuterated intermediate of example 1 of the present invention1H-NMR test pattern.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
As described in the background art, the existing preparation method of deuterated intermediate has the problem of high cost. In order to solve the technical problem, the application provides a preparation method of a deuterated intermediate, wherein the structural formula of the deuterated intermediate is shown as a formula I:
the preparation method comprises the following steps: carrying out an aldehyde-amine condensation reaction on amino in a raw material A and an organic matter containing aldehyde groups to obtain an aldehyde-amine condensation product, wherein the raw material A has a structure shown in a formula II:
reaction of the aldol condensation product with D2Carrying out a deuteration reaction on O to obtain a deuteration product; and carrying out first deprotection reaction on the deuterated product to obtain a deuterated intermediate.
In the deuteration reaction process, an amino group in the raw material A is protected through an aldehyde-amine condensation reaction to obtain an aldehyde-amine condensation product, which is beneficial to avoiding the interference of the amino group on the subsequent deuteration reaction and further beneficial to improving the purity of the product. Subsequent condensation of the aldehyde amine with D2Carrying out a deuteration reaction on O to obtain a deuteration product; and finally, removing the protecting group on the amino group in the deuterated product to obtain the deuterated reagent required by the application.
In the preparation method of the deuterated intermediate, the raw material A is taken as an initial raw material, and the required deuterated intermediate can be obtained by sequentially carrying out aldehyde-amine condensation reaction, deuterated reaction and amino deprotection reaction. Compared with the existing synthetic route, the synthetic route of the preparation method is greatly shortened, and the product yield is effectively improved along with the shortening of the synthetic route. Meanwhile, the required deuterated intermediate can be obtained only by carrying out amino deprotection reaction after the introduction of the deuterium atom in the preparation method, so that the preparation method provided by the application is favorable for reducing the occurrence probability of side reactions and further improving the purity of the deuterated intermediate. In conclusion, the preparation method provided by the application is adopted, and the special starting materials are used for preparing the deuterated intermediate, so that the preparation cost of the deuterated intermediate is reduced, and the product yield and purity are improved.
In the above method for preparing a deuterated intermediate, the molar ratio of the raw material a to the organic compound containing an aldehyde group in the aldehyde-amine condensation reaction can be in a range commonly used in the art. In a preferred embodiment, in the aldehyde amine condensation reaction, the mole ratio of the raw material A to the organic matter containing aldehyde groups is 1: 1-5; preferably 1:1 to 3.
In a preferred embodiment, the aldehyde group-containing organic material in the aldehyde-amine condensation reaction includes, but is not limited to, aromatic aldehydes and/or aliphatic aldehydes, preferably benzaldehyde and/or isovaleraldehyde. The substances have lower cost and wide sources and are easy to obtain, so that the selection of the substances as the organic matters containing aldehyde groups in the application is favorable for further reducing the process cost.
In a preferred embodiment, the deuteration reaction comprises the condensation of an aldehyde amine with D in the presence of a basic catalyst2O, and in the deuteration reaction, aldehyde amine condensation product, basic catalyst and D2The molar ratio of O is 1:1 to 3:8 to 15; preferably 1:1 to 2:10 to 12. Aldehyde amine condensation product, basic catalyst and D2The mole ratio of O includes, but is not limited to, the above range, and limiting it to the above range is advantageous to further improve the conversion rate of the deuterated product and the yield of the product.
To further increase the deuteration rate of the deuteration reaction, the aldehyde amine condensation product is preferably subjected to deuteration reaction multiple times. Wherein in the first deuteration reaction, the aldehyde-amine condensation product, the basic catalyst and D2The mole ratio of O is in the above ratio relationship, and in the second deuteration reaction and the subsequent deuteration reaction, the product of the last deuteration reaction, the basic catalyst and D2The molar ratio of O needs to be adjusted according to the actual situation of the last deuteration reaction. The deuteration rate is improved by the deuteration number, and the deuteration rate of the deuteration intermediate prepared by the method is more than 80%, preferably more than 90%, and more preferably more than 95%.
Preferably, the above basic catalyst includes, but is not limited to, one or more of the group consisting of dimethylisopropylamine, butyllithium, and dimethylisopropylaminolithium. In the deuteration reaction process, an alkaline catalyst removes active hydrogen atoms on an aldehyde-amine condensation product to form carbanions; then let D2The deuterium hydrogen of O is combined with the above carbanion to give the desired deuterated product.
Preferably, in the above preparation method, after the deuteration reaction, the first deprotection reaction includes: and carrying out protonation reaction on the deuterated product and acid to obtain a deuterated intermediate. Preferably, the acids include, but are not limited to, sulfuric acid and/or hydrochloric acid. More preferably, the mole ratio of the deuterated product to the acid is 1: 1-10; preferably 1:1 to 2.5. The mole ratio of deuterated product to acid includes, but is not limited to, the above range, and limiting it to the above range is advantageous to increase the efficiency of deprotection of the amino group and thus the yield of deuterated intermediates.
In the above production method, the raw material a may be a commercially available product or may be prepared by itself.
In a preferred embodiment, the process for preparing starting material a comprises:
will be provided with
The amino protection reaction is carried out according to the following route to obtain
Will be provided with
The condensation reaction is carried out according to the following route to obtain
And
will be provided with
The second deprotection reaction was carried out according to the following scheme to give starting material a:
The structural formula of the L-glutamine is shown as
In the above production method, in order to prevent the reaction of the amino group at the position close to the carboxyl group, the amino group on the side chain in L-glutamine is subjected to an amino group protecting reaction with an amino group protecting agent to obtain a first intermediate product. Under the action of a condensation reagent, the amino group and the carboxyl group in the first product undergo intramolecular dehydration condensation reaction to obtain a condensation product. And finally, Pd/C is used as a catalyst, and the protecting groups on the amino groups in the condensation product are removed under the reduction action of hydrogen to obtain the required raw material A.
Preferably, the amino protecting reagent includes, but is not limited to, one or more of the group consisting of benzyl chloroformate, bromobenzyl, chlorobenzyl, and di-tert-butyl dicarbonate.
Preferably, the condensation reagent includes, but is not limited to, one or more of the group consisting of N, N-carbonyldiimidazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-propylphosphoric anhydride.
The present application is described in further detail below with reference to specific examples, which should not be construed as limiting the scope of the invention as claimed.
Example 1
1. Synthesis of the first intermediate
Into a 5L three-necked flask were added L-glutamine (100g, 0.685mol, 1eq) and 3.33 wt% NaHCO in that order3Uniformly stirring the solution (1.8L) to obtain a mixed solution, and cooling the mixed solution to 0-5 ℃ by adopting an ice water bath to obtain a white emulsion of the system.
And (3) dropwise adding benzyl chloroformate (250g, 1.466mol and 2.1eq) into the emulsion to ensure that the temperature of the reaction system is not obviously increased, controlling the temperature of the reaction system between 0 and 5 ℃, and finishing dropping for 30 min. Adding NaHCO into the reaction system3The reaction system was allowed to react at low temperature (0-5 ℃) for 1 hour for a solid (200g, 2.38mol, 3.5eq) and then at room temperature (20 ℃) for 2 hours to obtain a reaction solution, which showed no remaining raw material by LC-MS.
The reaction solution was washed with ethanol (500mL × 4), adjusted to pH 1 with 38% hydrochloric acid (200mL), stirred in an ice-water bath for 10min, and then a large amount of solid precipitated from the reaction solution, and filtered to obtain a first-order cake. The filter cake was then rinsed with water (2L) and drained to give a second filter cake. And mixing the secondary filter cake with ethanol (500mL), and pulping for 1h to obtain slurry. Then adding petroleum ether (1500mL) into the slurry, stirring and filtering to obtain a third-level filter cake. The above-mentioned three-stage filter cake was evaporated to dryness at 50 ℃ by a rotary evaporator to obtain 113.7g of an off-white solid (first intermediate). The synthetic route is as follows:
2. Synthesis of condensation products
A10L four-necked flask was charged with the first intermediate (500g, 1.79mol, 1.0eq), 1, 4-dioxane (5L), CDI (579g, 3.57mol, 2eq), DMAP (10.24g, 0.084mol, 0.047eq) and stirred well, with part undissolved, N2And (4) after three times of replacement, communicating a bubbling device, heating to 100 ℃, carrying out reflux reaction for 15 hours, and displaying that the raw materials basically disappear by TLC (thin layer chromatography) to obtain a reaction solution.
The reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure to give a residue. The residue was dissolved in ethanol (8L) to obtain an organic phase. The organic phase is washed with water (5 L.times.4) and then successively with saturated NaHCO3The organic phase was washed with 5L of solution and 3L of saturated brine, and finally concentrated to dryness to give 374g of off-white solid (condensation product).
3. Synthesis of reduction reaction products and aldehyde amine condensation products
The condensation product (370g, 1.41mol), THF (3.7L), 10% Pd/C (111g) were added to a 10L three-necked flask and stirred uniformly to obtain a mixed solution. With N2The gas in the three-mouth bottle is replaced three times and then H is used2The gas in the three-necked flask was replaced three times, and the mixture was reacted at room temperature (15 ℃ C.) and normal pressure for 12 hours, followed by TLC to obtain a reaction solution without starting material. The reaction mixture was directly filtered (celite pad) to obtain a cake. The above cake was rinsed with THF (500mL) and dried to give the crude product of the reduction.
The crude product of the reduction product, benzaldehyde (150g, 1.41mol, 1.0eq) and toluene (3L) were put into a reaction flask (5L), and stirred uniformly to obtain a mixed solution. With N2The reaction mixture was reacted for 1.5 hours with three gas replacements in a three-necked flask, and monitored by TLC (DCM: MeOH ═ 10:1, bromocresol green, UV, Rfsm ═ 0.2, and Rfp ═ 0.8) with substantially no starting material remaining, to obtain a reaction solution. The reaction mixture was cooled to room temperature and filtered (through celite) to obtain a cake. The filter cake was rinsed with DCM (3L) to give a filtrate and a residue. Concentrating the filtrate to dryness, mixing the residue with ethanol (500mL), and pulping for 2h to obtain a slurry. And filtering the slurry to obtain a filter cake. The filter cake was rinsed with ethanol (300mL) and dried by suction to give 136.5g of a greenish solid (the aldol condensation product).
4. Synthesis of deuterated products:
first deuteration reaction
The aldehyde amine condensation product (30g, 0.139mol, 1.0eq) was dissolved in THF (690mL) and the prepared LDA [ butyl lithium (55.5mL, 0.146mol, 1.05eq), diisopropylamine (16.3g, 0.161mol, 1.16eq), THF (690mL) were slowly added dropwise to the reaction system at-70 ℃ under nitrogen protection]The reaction system has obvious heat release, the temperature of the reaction system is controlled to be lower than-70 ℃, and the color of the reaction system is dark red after 1 hour of dripping. Reacting the reaction system at-70 deg.C for 30min, naturally heating the reaction system to 0 deg.C (about 2h), and adding dropwise D into the reaction system at 0 deg.C2O (28g, 1.39mol, 10eq), no obvious temperature rise of the reaction system, and dripping after 1 min. Subjecting the above reaction system to a first deuteration reaction at 0 deg.C for 5min, and adding buffer solution (600mL, KH)2PO4Saturated solution with NaOH in a molar ratio of 2: 1) under the protection of nitrogen, quenching the deuteration reaction to obtain reaction liquid. THF in the above reaction solution was removed by reduced pressure extraction, followed by DCM (600 mL. times.4) to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate (20g) and concentrated under reduced pressure until no solid precipitated to give a concentrated product. Adding petroleum ether (50mL) dropwise into the concentrated product, precipitating a large amount of solid from the concentrated product, filtering, and collecting filtrateAnd obtaining a filter cake. The above filter cake was rinsed with ethanol (30mL) and dried by suction to give a pale blue solid 19.2g (first deuterated product) with a deuteration of 81 wt%.
Second deuteration reaction
Under the protection of nitrogen, prepared LDA [ butyl lithium (8.4mL, 0.02mol, 0.25eq), diisopropylamine (2.47g, 0.02mol, 0.275eq), THF (442mL) was added at-70 deg.C]Slowly dripping a solution of a first deutero product T1380-5-1(19.2g, 0.089mol, 1.0eq) in THF (442mL), wherein no obvious heat release exists, the temperature of a reaction system is controlled to be lower than-70 ℃, and dripping is finished for 1 h. Reacting the reaction system at-70 deg.C for 30min, naturally heating the reaction system to 0 deg.C (about 2h), and adding dropwise D into the reaction system at 0 deg.C2O (17.8g, 0.89mol, 10eq), and the reaction system has no obvious temperature rise and the dripping is finished within 1 min. Carrying out deuteration on the reaction system for the second time at 0 ℃ for 5min, and quenching the deuteration reaction by using a buffer solution (384mL) under the protection of nitrogen to obtain a reaction solution. THF in the above reaction solution was removed by reduced pressure extraction with DCM (384 mL. times.4) to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate (12g) and concentrated under reduced pressure until no solid precipitated to give a concentrated product. Then, petroleum ether (32mL) was added dropwise to the concentrated product to precipitate a large amount of solid in the concentrated product, and the filtrate was filtered to obtain a filter cake. The filter cake was rinsed with ethanol (30mL) and drained to give 13.6g of the second deuterated product as a pale blue solid. This product was subjected to MS measurement and analyzed to determine the deuteration rate to be 88.9 wt%. Subjecting the second deuterated product to1H-NMR measurement, the test pattern is shown in figure 3.
Third deuteration reaction
Under the protection of nitrogen, prepared LDA [ butyl lithium (2.9mL, 0.007mol, 0.12eq), diisopropylamine (0.84g, 0.008mol, 0.132eq), THF (19mL) at-70 deg.C]Slowly dripping a second deutero-product T1380-5-2(13.6g, 0.06mol, 1.0eq) in THF (312mL), without obvious heat release, controlling the temperature of the reaction system to be lower than-70 ℃, and finishing dripping within 10 min. Reacting the reaction system at-70 deg.C for 30min, naturally heating the system to 0 deg.C (about 2h), adding D2O (12g, 0.6mol, 10eq) dropwise into the reaction system at 0 deg.C,the reaction system has no obvious temperature rise, and the dripping is finished after 1 min. Carrying out a third deuteration reaction on the reaction system at 0 ℃ for 5min, and quenching the deuteration reaction by using a buffer solution (272mL) under the protection of nitrogen to obtain a reaction solution. THF in the above reaction solution was removed by reduced pressure extraction, followed by extraction with DCM (272 mL. times.4) to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate (7g) and concentrated under reduced pressure until no solid precipitated to give a concentrated product. Then, n-hexane (7mL) was added dropwise to the concentrated product, and a large amount of solid was precipitated from the concentrated product, followed by filtration to obtain a cake. The filter cake is rinsed with ethanol (10mL) and drained to obtain light blue solid 8.6g of third deuterated product, and the third deuterated product is subjected to MS measurement and is analyzed to determine the deuteration rate to be 93.8 wt%. Subjecting the third deuterated product to1H-NMR measurement, the test pattern is shown in figure 4.
Synthesis of deuterated intermediate:
deuterogen (20g, 0.092mol, 1.0eq), THF (200mL) were put into a 500mL three-necked flask, and after stirring, all the above reaction materials were dissolved to obtain a mixed solution. And (3) dropwise adding 6M hydrochloric acid (18 mL) into the mixed solution, wherein a reaction system has a small amount of heat release, controlling the temperature of the reaction system to be less than 20 ℃ by adopting an ice-water bath, and controlling the pH value of the reaction solution to be 3-4 after 15min of dropwise adding is finished. The reaction was incubated at room temperature 15 ℃ for 1h and monitored by TLC (DCM: MeOH ═ 20:1, UV, Rfsm ═ 0.4) without starting material to give a reaction. And then filtering the merchant reaction liquid to obtain a filter cake. And finally, leaching the filter cake with ethanol (50mL), and draining to obtain 13.4g of pure white solid (deuterated intermediate). The yield of the deuterated intermediate is 87.6 wt%, and the product is nuclear-magnetic pure.
Subjecting the above product to1H-NMR test shows that the spectrogram is shown in figure 1, and the analysis can determine that the structure of the product is 3-deuterohydrogen-3-amino-2, 6-piperidyl diketone which is the deuterated intermediate required by the application.
Subjecting the above product to13C-NMR test, the spectrum is shown in figure 2, and the analysis can confirm that the structure of the product is 3-deuterohydrogen-3-amino-2, 6-piperidyl diketone which is the deuterated intermediate required by the application.
Example 2
The differences from example 1 are: the molar ratio of condensation product to benzaldehyde was 1: 3. The yield of deuterated intermediate was 38.8 wt%.
Example 3
The differences from example 1 are: the molar ratio of condensation product to benzaldehyde was 1: 0.5. The yield of deuterated intermediate was 28.3 wt%.
Example 4
The differences from example 1 are: in the first deuteration reaction, an aldehyde amine condensation product, a basic catalyst and D2The molar ratio of O is 1:1.1: 10. The yield of deuterated intermediate was 75.7 wt%.
Example 5
The differences from example 1 are: in the first deuteration reaction, an aldehyde amine condensation product, a basic catalyst and D2The molar ratio of O is 1:2.5: 10. The yield of deuterated intermediate was 66.3 wt%.
Example 6
The differences from example 1 are: in the first deuteration reaction, an aldehyde amine condensation product, a basic catalyst and D2The molar ratio of O is 1:0.5: 8. The yield of deuterated intermediate was 53.8 wt%.
Example 7
The differences from example 1 are: the mole ratio of deuterated product to hydrochloric acid was 1:4, and the yield of deuterated intermediate was 45.7 wt%.
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
as can be seen from comparison of examples 1 to 7 and the conventional synthetic route, the preparation method provided by the present application is advantageous for greatly improving the yield and purity of the deuterated intermediate.
As can be seen from comparison of examples 1 to 3, limiting the molar ratio of the raw material a to the organic compound having an aldehyde group within the preferred protection range of the present application is advantageous to further improve the yield and purity of the deuterated intermediate.
Comparative examples 1,4 to 6 show that the aldehyde amine condensation product, the basic catalyst and D2Limiting the molar ratio of O within the preferred ranges of protection of the present application is advantageous for further enhancement of deuterated intermediatesYield and purity.
Comparing examples 1 and 7, it is found that limiting the mole ratio of the deuterated product to the acid in the deprotection reaction of the amino group within the preferred range of the present application is advantageous for further improving the yield and purity of the deuterated intermediate.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (14)
1. A preparation method of a deuterated intermediate is characterized in that the deuterated intermediate has a structure shown in a formula I:
the preparation method comprises the following steps:
carrying out an aldehyde-amine condensation reaction on amino in a raw material A and an organic matter containing aldehyde groups to obtain an aldehyde-amine condensation product, wherein the raw material A has a structure shown in a formula II:
reacting the aldehyde amine condensation product with D2Carrying out a deuteration reaction on O to obtain a deuteration product; and
and carrying out first deprotection reaction on the deuterated product to obtain the deuterated intermediate.
2. The preparation method according to claim 1, wherein in the aldehyde-amine condensation reaction, the molar ratio of the raw material A to the organic compound containing aldehyde groups is 1: 1-5.
3. The preparation method according to claim 2, wherein in the aldehyde-amine condensation reaction, the molar ratio of the raw material A to the organic compound containing aldehyde groups is 1: 1-3.
4. The method according to claim 1 or 2, wherein the aldehyde group-containing organic substance is selected from aromatic aldehydes and/or aliphatic aldehydes in the aldehyde-amine condensation reaction.
5. The method according to claim 4, wherein the aldehyde group-containing organic material is selected from benzaldehyde and/or isovaleraldehyde in the aldehyde-amine condensation reaction.
6. The method according to claim 1 or 2, wherein the deuteration reaction is carried out by the action of a basic catalyst, and in the deuteration reaction, the aldehyde-amine condensation product, the basic catalyst and D are reacted2The molar ratio of O is 1:1 to 3:8 to 15.
7. The method according to claim 6, wherein the deuteration reaction is carried out by the action of a basic catalyst, and wherein the aldehyde-amine condensation product, the basic catalyst and D are reacted in the deuteration reaction2The molar ratio of O is 1:1 to 2:10 to 12.
8. The method of claim 6, wherein the basic catalyst is selected from one or more of the group consisting of dimethylisopropylamine, butyllithium, and dimethylisopropylaminolithium.
9. The production method according to claim 1, wherein the first deprotection reaction includes: and carrying out protonation reaction on the deuterated product and acid to obtain the deuterated intermediate.
10. The method according to claim 9, wherein the molar ratio of the deuterated product to the acid is 1:1 to 10.
11. The method according to claim 10, wherein the molar ratio of the deuterated product to the acid is 1:1 to 2.5.
12. The method according to claim 1, wherein the method for preparing the raw material A comprises:
will be provided with
The amino protection reaction is carried out according to the following route to obtain
Will be described in
The condensation reaction is carried out according to the following route to obtain
Will be described in
A second deprotection reaction was carried out according to the following scheme to give the starting material a:
and T is a group combined with an amino group in an amino protecting reagent in the amino protecting reaction.
13. The method of claim 12, wherein the amino protecting reagent is selected from one or more of the group consisting of benzyl chloroformate, bromobenzyl, chlorobenzyl, and di-tert-butyl dicarbonate.
14. The method according to claim 12, wherein the condensation reagent is one or more selected from the group consisting of N, N-carbonyldiimidazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-propylphosphoric anhydride.
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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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| 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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