CN111646985A - Synthetic method of pyrimidine heterocyclic antitumor drug molecule AZD6738 - Google Patents
Synthetic method of pyrimidine heterocyclic antitumor drug molecule AZD6738 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
- B01J31/223—At least two oxygen atoms present in one at least bidentate or bridging ligand
- B01J31/2234—Beta-dicarbonyl ligands, e.g. acetylacetonates
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- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
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- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
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- B01J2531/50—Complexes comprising metals of Group V (VA or VB) as the central metal
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Abstract
The invention belongs to the technical field of heterocyclic chemistry, particularly relates to a heterocyclic anti-tumor chemical drug, and more particularly relates to a synthesis method of a pyrimidine-containing heterocyclic anti-tumor drug molecule AZD 6738. The chiral sulfoxide is prepared by using a chiral ligand induced asymmetric oxidation method and oxidizing methyl sulfide by using the combination of the chiral ligand and a cheap oxidant (such as hydrogen peroxide) to efficiently realize the conversion, so that the chiral sulfoxide compound 7 for AZD6738 is prepared, and the final product AZD6738 is prepared by batch reaction. In addition, the AZD6738 is prepared by a fluid chemistry method, the total synthesis yield is obviously improved compared with that of an intermittent reaction, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of heterocyclic chemistry, particularly relates to a heterocyclic anti-tumor chemical drug, and more particularly relates to a synthetic method of a pyrimidine-containing heterocyclic anti-tumor drug molecule AZD 6738.
Background
AZD6738, also known as (S) -Ceralaertib, a drug developed by Aslicon, UK for the treatment of solid tumors and hematological cancers in phase I/II clinical trials, is a potent selective sulfoximine morpholinopyrimidine ATR kinase inhibitor with excellent preclinical physicochemical and Pharmacokinetic (PK) characteristics, with an IC50 of 2.578 nM.
AZD6738 has the following english name: (S) -imino (methyl) (1- (6- ((R) -3-methylmopholino) -2- (1H-pyrolo [2,3-b ] pyridin-4-yl) pyrimidin-4-yl) cyclopropyl) -l6-sulfanone, and the structural general formula is shown as formula I:
i formula
Patents WO2011154737a1 and US2011/306613 report methods for the synthesis and pharmaceutical activity of AZD 6738. However, the synthesis methods reported in the patents so far are all characterized by batch reaction, are not environment-friendly and have poor economy.
The parent nucleus of the AZD6738 substrate is a pyrimidine ring containing two chiral centres. Wherein chiral center can be introduced from chiral raw material methylmorpholine, and the introduction of sulfoxide imine as another chiral center is the key of the whole molecular synthesis.
Chiral sulfoxides have become an important target in organic synthesis in recent years, and their chemical properties have been reviewed in recent years (org. chem. Highlights 2004, December 24). The use of these compounds is becoming more and more widespread, from chiral auxiliaries to pharmaceuticals. Whereas, sulfide enantioselective sulfur oxidation is the most direct method for synthesizing sulfides, with peroxidation being the major problem. The processes available for enantioselective sulfur oxidation are very extensive (Tetrahedron 2005, 61, 1933.DOI 10.1016/j.tet.2005.05.044; Tetrahedron 2005, 61, 8315. DOI 10.1016/j.tet.2004.11.041). The synthesis of AZD6738 recently reported by org. Process Res. Dev. (2019, 23, 7, 1333-1342) uses an enzyme catalysis reaction technology to synthesize an intermediate of chiral sulfoxide, and is relatively innovative, but the used raw materials and reactors are expensive, and the Process production investment is large.
Disclosure of Invention
The invention aims to provide a preparation method of an AZD6738 chiral sulfoxide intermediate, which takes a chiral organic ligand and a vanadium salt as a catalyst to catalyze asymmetric oxidation of a thioether compound in the presence of an oxidant to generate the AZD6738 chiral sulfoxide intermediate.
The invention realizes the aim through the following technical scheme, a preparation method of chiral sulfoxide for AZD6738, the reaction equation is as follows:
under the participation of an oxidant, a vanadium salt and a chiral organic ligand thereof in an organic solvent system, catalyzing the asymmetric oxidation of a chiral thioether compound 6 to generate a chiral sulfoxide compound 7; the chiral organic ligand is a compound 13 and a compound 14 which react in situ to serve as a ligand or a compound 12 which is generated by condensation reaction of equimolar compound 13 and compound 14 and serves as a chiral organic ligand;
preferably, the oxidant is hydrogen peroxide or sodium hypochlorite, and further preferably hydrogen peroxide;
preferably, the vanadium salt is vanadyl acetylacetonate (VO (acac)2) The molar ratio of the vanadium salt to the chiral thioether compound 6 is 0.001-0.010:1, more preferably 0.004-0.006:1, such as 0.005:1, 0.006:1 or 0.007: 1;
preferably, the molar ratio of the chiral organic ligand to the chiral thioether compound 6 is 0.001-0.010:1, more preferably 0.004-0.006:1, such as 0.005:1, 0.006:1 or 0.007: 1.
The amount of the oxidant and the kind of the solvent used in the asymmetric oxidation can be routinely screened by those skilled in the art, and the screening is performed by using the conversion rate and the chiral purity as indexes, for example, the molar ratio of the oxidant to the substrate chiral thioether compound 6 when the solvent system is dichloromethane or the oxidant is hydrogen peroxide can be 1.5-1.0:1, such as 1.1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5: 1.
The chiral ligand is used for inducing an asymmetric oxidation method, and the chiral ligand is combined with a cheap oxidant (such as hydrogen peroxide) to oxidize the methyl sulfide to prepare the chiral sulfoxide, so that the conversion is efficiently realized; no biological enzyme catalysis is used, the reaction cost is greatly reduced, the yield is basically equivalent to the yield of the original process, the purification is convenient, and the preparation of chromatographic separation is not needed.
According to a second aspect of the present invention there is provided a process for the preparation of AZD6738 by a batch reaction, the reaction equation being as follows:
the preparation method of the AZD6738 comprises the following steps:
(1) taking the compound 1 as a raw material, and carrying out N-alkylation with the compound 2 under the conditions of alkali and a solvent to generate a compound 3;
the base is organic base, the organic base is triethylamine, pyridine, 4-Dimethylaminopyridine (DMAP), triethylenediamine (DABCO), Diazabicyclo (DBU) and the like, and the organic base is preferably triethylamine;
the molar ratio of the compound 1 to the compound 2 is 0.979; the molar amount of the organic base is 1.875 times of that of the compound 1;
(2) in a solvent system, reducing the compound 3 to obtain a compound 4;
preferably, the reducing agent in the reduction is lithium borohydride, sodium borohydride and the like, and the amount of the sodium borohydride used is preferably 5 equivalents;
(3) reacting the compound 4 with methylsulfonyl chloride (MsCl) under the conditions of organic base and a solvent, quenching, and extracting with the solvent to obtain a solution of a compound 5 or desolventizing the solvent to obtain the compound 5;
preferably, the organic base is triethylamine, pyridine, 4-Dimethylaminopyridine (DMAP), triethylenediamine (DABCO), Diazabicyclo (DBU), or the like;
preferably, the molar ratio of the compound 4 to the methylsulfonyl chloride is 1: 1.2;
(4) reacting the compound 5 or the solution of the compound 5 with sodium methyl mercaptide to obtain a thioether compound 6 after the thionation;
preferably, the molar ratio of the compound 5 to the sodium methyl mercaptide is 1: 1;
(5) catalyzing asymmetric oxidation of a chiral thioether compound 6 to generate a chiral sulfoxide compound 7 in an organic solvent system in the presence of an oxidant, a vanadium salt and a chiral organic ligand of the vanadium salt;
(6) reacting the compound 7 with trifluoroacetamide under the catalysis of iodobenzene diacetate, magnesium oxide and dimeric rhodium acetate to generate a sulfoximine compound 8;
preferably, the molar amount of the trifluoroacetamide is 1-1.5 times that of the compound 7;
preferably, the molar amount of the iodobenzene diacetate is 1.5-2 times of that of the compound 7;
preferably, the molar amount of the magnesium oxide is 4.5-5 times of that of the compound 7;
preferably, the molar amount of the dimeric rhodium acetate is 0.0006-0.0007 times of that of the compound 7;
(7) reacting the compound 8 with 1, 2-dihaloethane under the condition of inorganic base to generate an intermediate compound 9 containing a three-membered ring;
preferably, the 1, 2-dihaloethane is 1, 2-dibromoethane;
preferably, the inorganic base is an aqueous solution of inorganic strong base such as NaOH and KOH, preferably an aqueous NaOH solution;
(8) the compound 9 and the compound 10 are subjected to Suzuki coupling reaction to generate a target product AZD 6738; wherein the compound 10 can be replaced by borate corresponding to the compound 10;
the catalyst in the Suzuki coupling is a 0-valent or + 2-valent palladium catalyst, such as Pd (PPh)3)4，Pd(dppf)2Cl2(ii) a The dosage of the palladium catalyst is 1 to 5 weight percent of the compound 9, and the preferred dosage is 5 weight percent.
According to a third aspect of the present invention there is provided a process for the preparation of AZD6738 using fluid chemistry, using conventional batch reaction means in addition to the fifth step (compound 6 to compound 7) and the sixth step (compound 7 to compound 8), the remaining steps in the synthesis of AZD6738 using continuous flow synthesis (flow chemistry fluid chemistry). Specifically, the synthesis method of AZD6738 and derivatives thereof comprises the following steps:
(a) dissolving compound 1 in organic solvent solution, dissolving compound 2 and alkali with organic solvent, pumping the solutions of compounds 1 and 2 into a mixer at set flow rate, and introducing into a coil reactor with set temperature of 40-100 deg.CoC, preferably 50oC, keeping the material in the reactor for 30-60 min, preferably 45 min; the organic solvent is dichloromethane, and the alkali is triethylamine;
pumping water through another pump to quench the reaction liquid from the coil reactor, then feeding the reaction liquid into a membrane separator (Zaiput brand) to realize liquid-liquid separation, and continuously feeding the water phase into a next-stage liquid-liquid separator to extract by using an organic solvent; organic phases are combined and concentrated to obtain a crude product of the compound 3, and the crude product is directly used in the next step; the organic solvent is dichloromethane;
(b) dissolving the compound 3 in an organic solvent, pumping the solution and 2M organic solvent solution of lithium borohydride into a mixer at a set flow rate by a pump, and introducing the mixture into a coil reactor with a set temperature of 50-100 deg.CoC. The coil reactor is provided with a back pressure regulating valve for regulating the internal pressure of the reactor; controlling the retention time of the material in the pipe to be 30-60 min, preferably 40 min; the organic solvent is 2-methyltetrahydrofuran;
then pumping into water quenching reaction by a pump, pumping into ethyl acetate for extraction, and entering into a membrane separator for liquid-liquid separation and extraction. Combining and concentrating the organic phases to obtain a crude product, and recrystallizing to obtain a compound 4; the recrystallization is carried out by using a mixed solvent with the volume ratio of n-hexane/ethyl acetate = 3/1;
(c) dissolving the compound 4 and organic base in an organic solvent, pumping the solution and the organic solution of MsCl into a mixer by using a pump according to a calculated flow rate, and then entering a coil reactor with a set temperature, wherein the temperature of the coil reactor is 20-40 ℃, the preferred temperature is 30 ℃, and the retention time of materials in the reactor is 10-20min, and the preferred time is 15 min; the organic base is triethylamine, and the organic solvent is 2-methyltetrahydrofuran;
pumping water through another pump to quench the reaction liquid from the coil reactor, then feeding the reaction liquid into a membrane separator to realize liquid-liquid separation, continuously feeding the water phase into the next-stage liquid-liquid separator, and extracting once with an organic solvent. The organic phases are combined to obtain an organic solution of the compound 5, which is directly used in the next step; the organic solvent is 2-methyltetrahydrofuran;
(d) simultaneously pumping the organic solution of the compound 5 and the organic solution of the sodium methyl mercaptide into a mixer by a pump, and then feeding the mixture into a coil reactor with a set temperature, wherein the temperature of the coil reactor is 40-100 DEG CoC, preferably 60oC. The coil reactor is provided with a back pressure regulating valve for regulating the internal pressure of the reactor; controlling the retention time of the material in the pipe to be 30-60 min, preferably 50 min;
pumping water through another pump to quench the reaction liquid from the coil reactor, then feeding the reaction liquid into a membrane separator to realize liquid-liquid separation, continuously feeding the water phase into a next-stage liquid-liquid separator, and extracting once by using an organic solvent; organic phases are combined and concentrated to obtain a crude product of the compound 6;
(e) preparing a compound 7 from a compound 6 by adopting the preparation method of the AZD6738 batch reaction, and further synthesizing a compound 8;
(f) dissolving the compound 8, tetraoctylammonium bromide (TOAB) and 1, 2-dibromoethane in an organic solvent; weighing the amount of NaOH solid according to the proportion, and dissolving the NaOH solid with distilled water; pumping the two solutions into a mixer at the same time according to a set flow rate by a pump, and then feeding into a 3-stage CSTR system (small serially connected continuous stirring reaction kettles), wherein the material retention time of each small kettle is controlled to be 20-40min, preferably 30 min; the organic solvent is 2-methyltetrahydrofuran;
pumping into water quenching reaction by a pump, pumping into an organic solvent for extraction, and entering into a membrane separator to realize liquid-liquid separation. Combining and concentrating the organic phases to obtain a crude product, and recrystallizing to obtain a compound 9; the recrystallization is carried out by using a mixed solvent with the volume ratio of n-hexane/ethyl acetate = 3/1;
(g) the compound 9 is reacted with Na2CO3Dissolving with mixed solvent of ethanol and water, dissolving another reaction raw material 10 and Pd catalyst with mixed solvent of ethanol and water, pumping the two solutions into a coil reactor with set temperature via a T-shaped mixer at set flow rate, wherein the temperature of the coil reactor is 90-120 deg.C, preferably 110 deg.CoC; controlling the retention time of the materials in the tube to be 10-30min, preferably 20 min; the Pd catalyst is Pd (PPh)3)4，Pd(OAc)2，Pd(dppf)2Cl2Etc., preferably Pd (PPh)3)4(ii) a Ethanol/water =5/1 in the mixed solvent of ethanol and water by volume ratio;
pumping water to quench reaction, pumping organic solvent into membrane separator to separate liquid from liquid, and extracting. Combining and concentrating organic phases to obtain a crude product, and performing column chromatography separation by using a mobile phase with n-hexane/ethyl acetate =3/1 to obtain a target product AZD 6738; the organic solvent is ethyl acetate.
Preferably, the Pd catalyst can be loaded on a load column to carry out catalytic reaction; the method specifically comprises the following steps: the compound 9 and the organic base are dissolved in an organic solvent, and the other reaction material 10 is dissolved in an organic solvent. The two solutions are pumped simultaneously into a sieve type mixer at a set flow rate of 1.0-1.5mL/min (preferably 1.25 mL/min) using a plunger pump and then the mobile phase is passed into a temperature-set supported column packed with Pd catalyst (e.g. 1% Pd/C), the column retention volume is 20-40mL (preferably 30 mL), and the temperature of the coil reactor is 55-75 deg.C (preferably 65 deg.C). The outlet of the packed column is equipped with a back pressure regulating valve by which the retention time of the material in the tube is controlled to be 15-25min (preferably 20 min). And directly concentrating the mobile phase flowing out of the column to obtain a crude product, and then performing column chromatography separation by using a mobile phase with dichloromethane/methanol = 60/1-30/1 to obtain a target product AZD 6738.
Wherein the structural formulas of the compounds 1-10 and AZD6738 are shown as follows:
the innovation point of the invention is that a continuous flow reaction mode is used, and a plurality of steps of serial continuous reactions are carried out. By selecting a novel reactor, the reaction progress of certain reactions can be accelerated by increasing the temperature and pressure of the reaction conditions, which is not achieved under conventional reaction vessels and conditions. The method selects cheap reaction reagents, reduces the use of hazardous chemicals, replaces the hazardous chemicals, uses a green and environment-friendly fluid chemical synthesis process, improves the post-treatment convenience, the reaction yield and the safety, is convenient for post-treatment and purification, and does not need special preparation means. Especially the final Suzuki coupling stage, using supported catalytic fluid chemistry, using supported Pd/C (Cenakaili)®KL-YP01-Pd01) to successfully realize high-efficiency and rapid Suzuki coupling, and the post-reaction treatment is simple and convenient, and the catalyst can be recycled.
The invention has the following advantages:
1) compared with the prior art, the raw materials of the invention have lower price, the invention utilizes cheaper compounds to synthesize, the synthetic route is mature, the invention is suitable for process amplification, and the total yield of eight steps for synthesizing AZD by a batch method is about 16.6%.
2) The method removes the use of some dangerous chemical reagents such as lithium aluminum hydride and the like in the synthesis process, so that the method is safer and more environment-friendly.
3) The invention has the advantages of shortening the process steps and greatly improving the efficiency.
4) The chiral sulfoxide imine is prepared by using a chiral ligand induced asymmetric oxidation method and combining the chiral ligand with the cheap hydrogen peroxide oxidized methyl sulfide, so that the conversion is efficiently realized; no biological enzyme catalysis is used, the reaction cost is greatly reduced, the yield is basically equivalent to the yield of the original process, the purification is convenient, and the preparation of chromatographic separation is not needed.
5) The invention uses a large amount of green and environment-friendly fluid chemical synthesis process, so that the AZD6738 is simple, efficient, economic and environment-friendly in amplification production. The total yield of the total synthesis finished by combining the fluid chemistry means and the conventional batch synthesis is more than 25 percent.
Drawings
FIG. 1 is a nuclear magnetic spectrum of Compound 3.
FIG. 2 is a nuclear magnetic spectrum of Compound 4.
FIG. 3 is a nuclear magnetic spectrum of Compound 5.
FIG. 4 is a nuclear magnetic spectrum of compound 11-AZD 6738.
Figure 5 is an HPLC profile of compound 7, wherein the purity of compound 7 is given.
Figure 6 is a flow diagram of the fluid chemistry for the preparation of compound 3 from compound 1.
Figure 7 is a flow diagram of the fluid chemistry for compound 3 to compound 4.
Figure 8 is a flow diagram of the fluid chemistry for compound 4 to compound 5.
Figure 9 is a flow diagram of the fluid chemistry for compound 5 to compound 6.
Fig. 10 is a flow diagram of the fluid chemistry for the preparation of compound 9 from compound 8.
Figure 11 is a flow diagram of the fluid chemistry for compound 9 to make compound AZD 6738.
Figure 12 is a flow diagram of the fluid chemistry for compound 9 to make AZD6738 catalyst supported form of compound.
Detailed Description
HPLC chemical purity detection conditions in compound 7: (3R) -4- (2-chloro-6- ((methylsulfinyl) methyl) pyrimidin-4-yl) -3-methylthiopholine was eluted on a C18 column at 254nm using acetonitrile/water system 10-80. UV wavelength of 220 nm and temperature of 25 ℃.
Abbreviations for reagents:
triethylamine-TEA, tetrahydrofuran-THF, dichloromethane-DCM, methyl tert-butyl ether-MTBE, EA-ethyl acetate, D-PTTA = Di-p-toluoyl-D-tartaric acid, acac = acetylacetanoate acetylacetonate.
The name of the equipment and the relevant information such as the specification and the model of the manufacturer are as follows:
a coil reactor: vapourtec or a self-made coil; a plunger pump: thirdly, performing; liquid-liquid membrane separator: zaiput.
Example 1 batch synthesis of AZD 6738:
(1) the first step is as follows: synthesis of Compound 3:
1H NMR (400 MHz, CDCl3) 7.17 (s, 1H), 4.39 (s, 1H), 4.41 (d,J=13.2 Hz, 1H), 4.26-4.07 (m, 1H), 3.99 (s, 3H), 3.82 (t,J= 7.5, 1H), 3.74-3.69 (m, 1H), 3.60-3.53 (m, 1H), 3.02 (s, 3H),3.35 (dd,J= 17.3, 7.2 Hz,1H), 1.37 (d,J= 6.8, 3H). MS m/z (ESI)：272.1[M+H]。
(2) The second step is that: synthesis of Compound 4:
dissolving compound 3 (920 g) in tetrahydrofuran (4600 mL), reducing the temperature to 0 under the protection of nitrogenoC, slowly adding sodium borohydride (640 g) and calcium chloride (720 g) into the reaction solution at 0oC for 16h, LC-MS shows complete reaction, addThe reaction was quenched into 4000mL of water, concentrated in vacuo to remove most of the tetrahydrofuran, and the remaining organic phases were combined by extraction with ethyl acetate (4000 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent removed by rotary evaporation in vacuo to give crude compound 4, which was then purified with n-hexane: ethyl acetate =3:1 slurried to give the product 4 (880 g) as a white solid powder, which was used directly in the next step.
(3) The third step: synthesis of Compound 5:
dissolving the compound 4 (880 g) in dichloromethane (4400 mL), adding triethylamine (480 mL) for nitrogen protection, and cooling to-10 to-5oC, slowly adding MsCl (256 mL) and keeping the temperature of the system at-10-15 DEG CoAnd C, reacting for 1h, naturally heating to room temperature, stirring for 16h, indicating complete reaction under LC-MS, adding 4000mL of water to quench the reaction, adding dichloromethane for extraction (3000 mL × 2), and combining organic phases. The organic phase was dried over anhydrous sodium sulfate, filtered and the solvent removed by rotary evaporation in vacuo to give crude 5 (880 g) as an oil which was used in the next step without purification.
(4) The fourth step: synthesis of Compound 6:
compound 5 (880 g) was dissolved in DMF (4400 mL), sodium thiomethoxide (280 g, 1eq) was added and stirred at room temperature for 16h, the reaction was complete under LC-MS, 4000mL of water was added to quench the reaction, and the combined organic phases were extracted with dichloromethane (3000 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered and the solvent removed by rotary evaporation in vacuo to give crude 6 (800 g) as an oil which was used in the next step without further purification.
(5) The fifth step: synthesis of compound 7:
compound 6 (800.0 g) was dissolved in methylene chloride (4000 ml), and vanadyl acetylacetonate (4.0 g) as a catalyst, 3-tert-butyl-2-hydroxy-5-nitrobenzaldehyde 13 (4.88 g) as a catalyst ligand and L-tert-leucinol 14 (2.56 g) were added to the solution, and 30% H was added dropwise thereto2O2(365 g, 1.1 eq). The reaction mixture was stirred at room temperature for 24 hours. LC-MS detection shows that the reaction is finished, water and dichloromethane are added for extraction, drying and concentration are carried out under ice bath, and white solid is obtained by beating with ethyl acetate (537.5 g, yield: 54.7 percent of three-step total yield), and the dr value is 10:1 (diastereoisomers can be separated by silica gel column chromatography), purity>99%, as shown in fig. 5, where the component Rt =2.276min is the target product, and Rt =2.784min is the diastereomer (i.e. the chiral forms of morpholine ring segments are the same, and the chirality of sulfoxide segments is different).
Preferably, a chiral ligand prepared in advance can be used, and the reaction process is as follows:
compound 6 (800 g) was dissolved in dichloromethane (4000 ml), and catalyst vanadyl acetylacetonate (4g, 0.5 mol%) and chiral ligand compound 12 (equivalent 0.7 mol%) were added thereto, to which 30% H was added dropwise2O2(365 g, 1.1 eq). The reaction mixture was stirred at room temperature for 24 hours. LC-MS detection shows that the reaction is finished, water is added to quench the reaction under ice bath, dichloromethane is added for extraction, drying, suction filtration and concentration are carried out, and the white solid is obtained after pulping by ethyl acetate (570 g, yield: 58 percent of three-step total yield).
The ligand is prepared as follows:
compound 13 and compound 14 were added to methanol at 1:1 equivalent (4.88 g for compound 13 and 2.56 g for compound 14) and refluxed overnight. And (3) monitoring the reaction to be complete by a dot plate, and directly performing spin-drying and column-passing purification to obtain the chiral ligand compound 12.
Other asymmetric oxidation systems:
the previous system we screened included the use of D-PTTA (1.0 eq)/H2O230% (4.0 eq) system. Compound 6 (1.0 eq), D-PTTA (1.0 eq) and H2O230% (4.0 eq) of waterSolution (5V) was stirred at room temperature for 2 weeks, dr value 5:1, the purity of the target product after column chromatography separation is 95 percent. After stirring for 3 weeks at room temperature, the reaction was worked up until the dr value reached 6: 1. therefore, the reaction rate is too low and the reaction time is too long under such conditions, which is not suitable for scale-up production.
Later, we tried compound 6 (1.0 equiv.)/ligand 15 (1.5-3 mol%)/VO (acac)2/ （1-2 mol%）/ H2O235% (1.1 equiv.) oxidation catalyst system, a series of chiral ligands are screened, and under the condition, the reaction yield is slightly improved, the three-step yield is between 54% and 65%, but the selectivity of chiral sulfoxide is poor (dr value is 2: 1-3: 1). This oxidative catalytic system is not suitable for the present substrate, since the selectivity is not high, although slightly higher in yield than our final selection method.
Summarizing the above, ligand 12 (0.5-3 mol%)/VO (acac)2（0.5-5 mol%）/ H2O2A35% (0.8-1.1 equiv.) oxidation catalyst system is most suitable for the substrate.
(6) And a sixth step: synthesis of compound 8:
compound 7 (400 g) and 2,2, 2-trifluoroacetamide (210.4 g) were dissolved in anisole (4000 mL), and iodobenzene diacetate (710.8 g), magnesium oxide (276 g), and rhodium diacetate (400 mg) were added. The reaction mixture was stirred at room temperature for 24 hours. The reaction was followed by LC-MS and after completion of the reaction, concentrated hydrochloric acid (800ml) was added thereto under ice bath and stirred for 20 minutes. Water was added for extraction, and the aqueous phase was retained. Sodium carbonate was added, and extracted with 2-methyltetrahydrofuran (2.0L), and the resulting solution was used directly in the next reaction.
(7) The seventh step: synthesis of compound 9:
a solution of compound 8 in 2-methyltetrahydrofuran, 1, 2-dibromoethane (1160 g) and tetraoctylammonium bromide (40g) were dissolved in 2-methyltetrahydrofuran (10L), and sodium hydroxide (400 g, prepared as a 50% aqueous solution) was added. The reaction solution was stirred at room temperature for 24 hours and LC-MS detection indicated completion of the reaction. Water (8L) was added, the aqueous phase was separated, ethyl acetate (8L) and water (8L) were added to the organic phase, extraction was performed 3 times, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation in vacuo to give the crude product. The crude product was purified by silica gel chromatography on dichloromethane/methanol (0% to 5% methanol) as the mobile phase and rotary evaporated in vacuo to give compound 9 (248 g, light brown oil, yield: two step yield 63%).
1H-NMR (400 MHz, DMSO-d 6) 6.96 (d,J= 2.5 Hz, 1H), 4.39 (s, 1H),3.93 (dd,J= 11.5, 3.4 Hz, 1H), 3.85 (s, 1H), 3.72 (d,J= 11.5 Hz, 1H),3.58 (dd,J= 11.6, 3.1 Hz, 1H), 3.43 (t,J= 11.2 Hz, 1H), 3.17 (d,J= 7.4Hz, 1H), 3.02 (s, 3H), 1.66 (dd,J= 11.1, 4.0 Hz, 1H), 1.56 (s, 1H), 1.42(ddd,J= 9.8, 6.5, 4.1 Hz, 2H), 1.28 (d,J= 5.6 Hz, 3H). MS m/z (ESI)：331.0[M+H]。
(8) Eighth step: synthesis of AZD 6738:
compound 9 (104 g) and compound 10 (76 g) were dissolved in a mixed solution of ethanol (400mL) and water (80 mL), and sodium carbonate (130.4 g) and bis (triphenylphosphine) palladium dichloride (5.2 g) were added. And replacing nitrogen for three times, heating the reaction liquid to 100 ℃ and carrying out stirring reaction for 6 hours. LC-MS detection shows that the reaction is completed, the reaction solution is cooled to room temperature, the solvent is removed by vacuum rotary evaporation, and then the compound 11 (80 g, white-like solid, yield: 64.9%) is obtained by separation and purification through a silica gel chromatographic column, namely AZD 6738.
1H NMR(400MHz,DMSO-d6)11.81(s,1H),8.34(d,J＝5.0Hz, 1H),7.95(d,J＝5.0Hz,1H),7.61–7.58(m,1H),7.22(dd,J＝3.3,2.0 Hz,1H),7.00(s,1H),4.60(s,1H),4.18(s,1H),4.04–3.99(m,1H), 3.84(s,1H),3.81(d,J＝11.4Hz,1H),3.67(dd,J＝11.4,2.9Hz,1H), 3.52(dd,J＝11.8,9.1Hz,1H),3.28–3.24(m,1H),3.12(s,3H),1.79– 1.73(m,1H),1.52(dd,J＝12.4,5.6Hz,2H),1.45(d,J＝9.2Hz,1H), 1.28(d,J＝6.7Hz,3H).MS m/z(ESI)：413.1[M+H]
Example two: fluid chemical synthesis method of AZD 6738:
(1) in the first step, compound 1((R) -2-methylmorpholine, 48g) and triethylamine (90g) are dissolved in dichloromethane solution to prepare 250mL of solution A, compound 2 (100g) is also dissolved in dichloromethane to prepare 250mL of solution B, two dichloromethane solutions A and B are respectively pumped into a T-shaped mixer by a pump according to a set flow rate of 2.77mL/min, and then the mixture enters a coil reactor with a set temperature, wherein the retention volume of the coil reactor is 250mL, the temperature is 36 ℃, and the retention time of materials in the reactor is set to be 45 min. The reaction solution from the coil reactor was quenched by pumping water (300mL) at a rate of 5mL/min by another pump, and then passed to a membrane separator (Zaiput brand) for liquid-liquid separation, and the aqueous phase was further passed to the next stage liquid-liquid separator, and extracted once with dichloromethane (300mL) at a rate of 5 mL/min. The organic phases are combined and concentrated to obtain crude compound 3, which is directly used in the next step, and the flow chart is shown in figure 6;
(2) and secondly, dissolving the compound 3 in 2-methyltetrahydrofuran to prepare 420mL of solution, pumping the solution and 2M 2-methyltetrahydrofuran solution (420mL) of lithium borohydride into a T-shaped mixer through pumps according to a set flow rate (each pump is 3.12mL/min), and then feeding the mixture into a coil reactor with a set temperature, wherein the temperature of the coil reactor is 50 ℃, and the coil retention volume is 250 mL. The coil reactor is provided with a back pressure regulating valve for regulating the internal absolute pressure of the reactor to be less than 1.5 atm. The retention time of the material in the tube was controlled to 40 min. The reaction was then quenched by pumping water (500mL) at 3.72mL/min followed by ethyl acetate at 3.72mL/min into a membrane separator for liquid-liquid separation and extraction was repeated twice. The organic phases were combined and concentrated to give crude product, which was recrystallized from a mixed solvent of n-hexane/ethyl acetate 3/1 to give compound 4(90g, 78.5% overall yield in two steps) as shown in fig. 7;
(3) thirdly, dissolving the compound 4(88g, 361mmol) and an organic base such as triethylamine (48mL) in 2-methyltetrahydrofuran to prepare a 250mL solution, adding the 250mL solution and 250mL of 2-methyltetrahydrofuran solution of MsCl (25.6mL) respectively into a T-shaped mixer by using a plunger pump according to a calculated flow rate (8.3mL/min), then feeding the mixture into a coil reactor with a set temperature, wherein the temperature of the coil reactor is 30 ℃, the retention volume of the coil is 250mL, and the retention time of the materials in the reactor is controlled to be 15 min. Water (500mL) was pumped in at a rate of 16.7mL/min by another plunger pump to quench the reaction solution from the coil reactor, and then the reaction solution was fed to a membrane separator to effect liquid-liquid separation, and the aqueous phase was further fed to the next-stage liquid-liquid separator and extracted once with 2-methyltetrahydrofuran (250mL) by the plunger pump at a rate of 8.3 mL/min. The organic phases were combined to give a solution of compound 5 in 2-methyltetrahydrofuran which was used directly in the next step, as shown in the scheme in FIG. 8;
(4) in the fourth step, a solution of compound 5 in 2-methyltetrahydrofuran (700mL) and a solution of sodium thiomethoxide (28g) in DMF (350mL) were pumped simultaneously into a mixer by plunger pumps at flow rates of pump A: 3.33 mL/min; and a pump B: 1.67 mL/min; then the mixture enters a coil reactor with a set temperature, the volume of the coil is 250mL, and the temperature of the coil reactor is 60 ℃. The coil reactor is provided with a back pressure regulating valve for regulating the internal pressure of the reactor and regulating the flow rate by regulating the pressure. The retention time of the material in the tube was controlled to 50 min. Water (500mL) is pumped in at the speed of 3mL/min by another plunger pump to quench the reaction liquid from the coil reactor, then the reaction liquid enters a membrane separator to realize liquid-liquid separation, the water phase continues to enter the next-stage liquid-liquid separator, 2-methyltetrahydrofuran (350mL) is pumped in at the pump speed of 2.5mL/min for extraction once, and the organic phase is combined and concentrated to obtain the crude compound 6 (82g, the yield of the two steps is 83%), and the flow chart is shown in FIG. 9. The subsequent fifth step and the sixth step continue to use the batch synthesis process to obtain a 2-methyltetrahydrofuran solution of the compound 8;
(5) in the seventh step, the 2-methyltetrahydrofuran solution of the above compound 8, TOAB (4g) and 1, 2-dibromoethane (116g) were dissolved in 2-methyltetrahydrofuran to prepare 600mL of a solution. NaOH (40g) was weighed out as a solid in proportion and dissolved in distilled water (400 mL). The two solutions are respectively pumped into a micro-channel membrane mixer by a pump according to set flow rate (9.96mL/min,6.64mL/min), and then enter a 3-stage CSTR system (continuous stirring reaction small kettles connected in series, each small kettle has a volume of 500mL), and the retention time of materials in each kettle is controlled to be 30min by the pump speed. The reaction was quenched by pumping water (800mL) at a pump rate of 16.6mL/min using a plunger pump, while ethyl acetate (400mL) was pumped at a pump rate of 16.6mL/min using a plunger pump, into a membrane separator to effect liquid-liquid separation, and three extractions were performed using a total of 1200mL of ethyl acetate. The organic phases were combined and concentrated to give crude product, which was recrystallized from a mixed solvent of n-hexane/ethyl acetate 3/1 to give compound 9 (50g, 52%) according to the scheme shown in fig. 10;
(18) eighth step, compound 9(10g, 1.0eq) was mixed with Na2CO3(13g, 4.0eq) was dissolved in a mixed solvent of ethanol/water (50mL/10mL), and the other reaction material 10(5.6g, 1.1eq) and Pd (dppf)2Cl2(the amount was 5% by weight of Compound 9) was also dissolved in a mixed solvent of ethanol/water (50mL/10 mL). The two solutions are respectively pumped into a T-shaped mixer by a pump according to a set flow rate of 1.25mL/min and enter a coil reactor with a set temperature, the retention volume of the coil is 50mL, and the temperature of the coil reactor is 110 ℃. The retention time of the material in the tube was controlled to be 20 min. Pumping water (100mL) by a plunger pump at the pump speed of 2.5mL/min, simultaneously pumping ethyl acetate (100mL) by the plunger pump at the pump speed of 2.5mL/min, entering a membrane separator to realize liquid-liquid separation, and repeating the process to extract with ethyl acetate once again. The organic phases were combined and concentrated to give a crude product which was isolated by column chromatography using a mobile phase of n-hexane/ethyl acetate 3/1 to give the desired product AZD6738(9g, 72.7%) according to the scheme shown in figure 11.
In the eighth step, we also adopt the fluid chemical means of catalyst supported catalysis, and the specific flow chart and operation are as shown in the following figure 12:
(19) compound 9(10g, 31mmol) was reacted with Et3N (12.4g) was dissolved in ethanol (50mL), and the other starting material 10(5.6g, 1.1eq) was also dissolved in ethanol (50 mL). The two solutions are respectively pumped into a sieve-plate mixer by a plunger pump according to a set flow rate of 1.25mL/min and then the mobile phase enters a load column with a set temperature, and 1 percent Pd/C (is filled in the column body)
KL-YP01-Pd01)30g, a column retention volume of 30mL, and a temperature of the coil reactor of 65 ℃. The outlet of the packed column was equipped with a back pressure regulating valve by which the retention time of the material in the tube was controlled to 20 min. The mobile phase flowing out of the column is directly concentrated to obtain a crude product, and then the crude product is subjected to column chromatography separation by using a mobile phase containing dichloromethane/methanol (60/1-30/1) to obtain the target product AZD6738(9.1g, 73.5%).
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A preparation method of chiral sulfoxide is characterized in that: the reaction equation is shown below in the following,
the chiral sulfoxide is a compound 7;
under the participation of an oxidant, a vanadium salt and a chiral organic ligand thereof in an organic solvent system, catalyzing the asymmetric oxidation of a chiral thioether compound 6 to generate a chiral sulfoxide compound 7; the oxidant is hydrogen peroxide, and the vanadium salt is vanadyl acetylacetonate;
the chiral organic ligand is a compound 12 generated by condensation reaction of equimolar compound 13 and compound 14.
2. The method of claim 1, wherein: the organic ligand is compound 12 generated by the condensation reaction of compound 13 and compound 14 in equimolar amount, and compound 13 and compound 14 can be used for in-situ reaction instead.
3. The method of claim 1, wherein: the molar use ratio of the vanadium salt to the chiral thioether compound 6 is 0.001-0.010: 1; the molar dosage ratio of the chiral organic ligand to the chiral thioether compound 6 is 0.001-0.010: 1.
4. A preparation method of AZD6738 by batch reaction has the following reaction equation:
the method specifically comprises the following steps:
(1) taking the compound 1 as a raw material, and carrying out N-alkylation with the compound 2 under the conditions of alkali and a solvent to generate a compound 3;
(2) in a solvent system, reducing the compound 3 to obtain a compound 4;
the reducing agent in the reduction is lithium borohydride or sodium borohydride;
(3) reacting the compound 4 with methylsulfonyl chloride under the conditions of alkali and a solvent, quenching, and extracting with the solvent to obtain a solution of a compound 5 or desolventizing the solvent to obtain the compound 5;
(4) reacting the compound 5 or the solution of the compound 5 with sodium methyl mercaptide to obtain a thioether compound 6 after the thionation;
(5) preparing chiral sulfoxide compound 7 by the method of claim 1;
(6) reacting the compound 7 with trifluoroacetamide under the catalysis of iodobenzene diacetate, magnesium oxide and dimeric rhodium acetate to generate a sulfoximine compound 8;
(7) reacting the compound 8 with 1, 2-dihaloethane under the condition of inorganic base to generate an intermediate compound 9 containing a three-membered ring;
(8) the compound 9 and the compound 10 are subjected to Suzuki coupling reaction to generate a target product AZD 6738; wherein the compound 10 can be replaced by borate corresponding to the compound 10;
the catalyst in the Suzuki coupling is a 0-valent or + 2-valent palladium catalyst.
5. The method of claim 4, wherein: the alkali in the steps (1) and (3) is organic alkali, and the organic alkali is any one or combination of more of triethylamine, pyridine, 4-dimethylamino pyridine, triethylene diamine and diazabicyclo.
6. The method of claim 4, wherein: in the step (7), the 1, 2-dihaloethane is 1, 2-dibromoethane.
7. The method of claim 4, wherein: the molar dosage of the trifluoroacetamide in the step (6) is 1-1.5 times of that of the compound 7; the molar dosage of the iodobenzene diacetate is 1.5-2 times of that of the compound 7; the molar consumption of the magnesium oxide is 4.5-5 times of that of the compound 7; the molar amount of the dimeric rhodium acetate is 0.0006-0.0007 times of that of the compound 7.
8. The method of claim 4, wherein: in the step (8), the dosage of the palladium catalyst is 1-5 wt% of the compound 9.
9. A process for the preparation of AZD6738 using fluid chemistry comprising the steps of:
(a) dissolving compound 1 in organic solvent solution, dissolving compound 2 and alkali in organic solvent, pumping the solutions of compounds 1 and 2 into a mixer at set flow rate, and feeding into a coil at set temperatureThe temperature of the reactor and the coil reactor is 40-100 DEGoC, keeping the material in the reactor for 30-60 min;
pumping water through another pump to quench the reaction liquid from the coil reactor, then feeding the reaction liquid into a membrane separator to realize liquid-liquid separation, and continuously feeding the water phase into a next-stage liquid-liquid separator to extract by using an organic solvent; organic phases are combined and concentrated to obtain a crude product of the compound 3, and the crude product is directly used in the next step;
(b) dissolving the crude compound 3 in an organic solvent, pumping the solution and the organic solvent solution of lithium borohydride into a mixer at a set flow rate by a pump, and introducing the solution and the organic solvent solution of lithium borohydride into a coil reactor with a set temperature of 50-100 DEG CoC; the coil reactor is provided with a back pressure regulating valve for regulating the internal pressure of the reactor; controlling the retention time of the materials in the pipe to be 30-60 min;
pumping into water quenching reaction by a pump, pumping into an organic solvent for extraction, and entering into a membrane separator for liquid-liquid separation and extraction; combining and concentrating the organic phases to obtain a crude product, and recrystallizing to obtain a compound 4; the recrystallization is carried out by using a mixed solvent with the volume ratio of n-hexane/ethyl acetate = 3/1;
(c) dissolving the compound 4 and organic base in an organic solvent, pumping the solution and the organic solution of MsCl into a mixer by using a pump according to the calculated flow rate, and then entering a coil reactor with a set temperature, wherein the temperature of the coil reactor is 20-40 ℃, and the retention time of materials in the reactor is 10-20 min;
pumping water through another pump to quench the reaction liquid from the coil reactor, then feeding the reaction liquid into a membrane separator to realize liquid-liquid separation, and continuously feeding the water phase into a next-stage liquid-liquid separator to extract by using an organic solvent; the organic phases are combined to obtain an organic solution of the compound 5, which is directly used in the next step;
(d) simultaneously pumping the organic solution of the compound 5 and the organic solution of the sodium methyl mercaptide into a mixer by a pump, and then feeding the mixture into a coil reactor with a set temperature, wherein the temperature of the coil reactor is 40-100 DEG CoC; the coil reactor is provided with a back pressure regulating valve for regulating the internal pressure of the reactor; controlling the retention time of the materials in the pipe to be 30-60 min;
pumping water through another pump to quench the reaction liquid from the coil reactor, then feeding the reaction liquid into a membrane separator to realize liquid-liquid separation, continuously feeding the water phase into a next-stage liquid-liquid separator, and extracting once by using an organic solvent; organic phases are combined and concentrated to obtain a crude product of the compound 6;
(e) preparing compound 7 from compound 6 by the method of claim 4, and further synthesizing compound 8;
(f) dissolving the compound 8, tetraoctyl ammonium bromide and 1, 2-dibromoethane by using an organic solvent; weighing the amount of the inorganic base solid according to the proportion, and dissolving the inorganic base solid with distilled water; the two solutions are respectively pumped into a mixer at the same time according to a set flow rate by a pump, and then enter a 3-stage CSTR system, and the material retention time of each small kettle is controlled to be 20-40 min;
pumping into water quenching reaction by a pump, pumping into an organic solvent for extraction, and entering into a membrane separator to realize liquid-liquid separation; combining and concentrating the organic phases to obtain a crude product, and recrystallizing to obtain a compound 9; the recrystallization is carried out by using a mixed solvent with the volume ratio of n-hexane/ethyl acetate = 3/1;
(g) the compound 9 is reacted with Na2CO3Dissolving the other reaction raw material 10 and the Pd catalyst by using a mixed solvent of ethanol and water, and pumping the two solutions into a coil reactor with a set temperature through a T-shaped mixer according to a set flow rate by using a pump, wherein the temperature of the coil reactor is 90-120 ℃; controlling the retention time of the materials in the pipe to be 10-30 min;
pumping water to quench reaction by a pump, pumping organic solvent, and entering a membrane separator to realize liquid-liquid separation and extraction; organic phases are combined and concentrated to obtain a crude product, and column chromatography separation is carried out to obtain a target product AZD 6738;
the structural formulas of the compounds 1-10 and AZD6738 are shown as follows;
compound 10 may also be replaced with its corresponding boronic ester.
10. Process for the preparation of AZD6738 using fluid chemistry according to claim 9, characterized in that: replacing the step (g) with a method in which a Pd catalyst is loaded on a load column to perform a catalytic reaction; the method specifically comprises the following steps: dissolving the compound 9 and organic base with an organic solvent, and dissolving the other reaction raw material 10 with an organic solvent; respectively pumping the two solutions into a sieve-plate type mixer simultaneously according to a set flow rate of 1.0-1.5mL/min by using a plunger pump, then enabling the mobile phase to enter a load column with a set temperature, filling a Pd catalyst in the column, wherein the retention volume of the column is 20-40mL, and the temperature of a coil reactor is 55-75 ℃; the outlet of the packed column is provided with a back pressure regulating valve, and the retention time of the material in the tube is controlled to be 15-25min through the valve; and directly concentrating the mobile phase flowing out of the column to obtain a crude product, and then performing column chromatography separation by using a mobile phase with dichloromethane/methanol = 60/1-30/1 to obtain a target product AZD 6738.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114717211A (en) * | 2022-03-23 | 2022-07-08 | 江苏集萃分子工程研究院有限公司 | Imine reductase mutant M5 and application thereof in synthesis of azacyclo chiral amine |
| CN115286645A (en) * | 2022-08-16 | 2022-11-04 | 南京雷正医药科技有限公司 | Tricyclic heterocyclic derivatives, pharmaceutical compositions and uses thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101796048A (en) * | 2007-07-09 | 2010-08-04 | 阿斯利康(瑞典)有限公司 | Trisubstituted pyrimidine derivatives for the treatment of proliferative diseases |
| CN101801962A (en) * | 2007-07-09 | 2010-08-11 | 阿斯利康(瑞典)有限公司 | Trisubstituted pyrimidine derivatives for the treatment of proliferative diseases |
| CN101809002A (en) * | 2007-07-09 | 2010-08-18 | 阿斯利康(瑞典)有限公司 | morpholino pyrimidine derivatives used in diseases linked to mtor kinase and/or pi3k |
| CN103068391A (en) * | 2010-06-11 | 2013-04-24 | 阿斯利康(瑞典)有限公司 | Morpholino pyrimidines and their use in therapy |
| WO2019050889A1 (en) * | 2017-09-08 | 2019-03-14 | Bluevalley Pharmaceutical Llc | Substituted pyrrolopyridines as atr inhibitors |
-
2020
- 2020-06-01 CN CN202010482366.2A patent/CN111646985A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101796048A (en) * | 2007-07-09 | 2010-08-04 | 阿斯利康(瑞典)有限公司 | Trisubstituted pyrimidine derivatives for the treatment of proliferative diseases |
| CN101801962A (en) * | 2007-07-09 | 2010-08-11 | 阿斯利康(瑞典)有限公司 | Trisubstituted pyrimidine derivatives for the treatment of proliferative diseases |
| CN101809002A (en) * | 2007-07-09 | 2010-08-18 | 阿斯利康(瑞典)有限公司 | morpholino pyrimidine derivatives used in diseases linked to mtor kinase and/or pi3k |
| CN103068391A (en) * | 2010-06-11 | 2013-04-24 | 阿斯利康(瑞典)有限公司 | Morpholino pyrimidines and their use in therapy |
| WO2019050889A1 (en) * | 2017-09-08 | 2019-03-14 | Bluevalley Pharmaceutical Llc | Substituted pyrrolopyridines as atr inhibitors |
Non-Patent Citations (8)
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114717211A (en) * | 2022-03-23 | 2022-07-08 | 江苏集萃分子工程研究院有限公司 | Imine reductase mutant M5 and application thereof in synthesis of azacyclo chiral amine |
| CN114717211B (en) * | 2022-03-23 | 2023-06-02 | 江苏集萃分子工程研究院有限公司 | Imine reductase mutant M5 and application thereof in synthesis of nitrogen heterocycle chiral amine |
| CN115286645A (en) * | 2022-08-16 | 2022-11-04 | 南京雷正医药科技有限公司 | Tricyclic heterocyclic derivatives, pharmaceutical compositions and uses thereof |
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