CN115466254A - Inhibitor and preparation method thereof - Google Patents
Inhibitor and preparation method thereof Download PDFInfo
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- CN115466254A CN115466254A CN202210954667.XA CN202210954667A CN115466254A CN 115466254 A CN115466254 A CN 115466254A CN 202210954667 A CN202210954667 A CN 202210954667A CN 115466254 A CN115466254 A CN 115466254A
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 10
- LEWSYNYKTYXRHP-UHFFFAOYSA-N (6-methylpyridin-2-yl)thiourea Chemical compound CC1=CC=CC(NC(N)=S)=N1 LEWSYNYKTYXRHP-UHFFFAOYSA-N 0.000 claims abstract description 6
- GUABFMPMKJGSBQ-UHFFFAOYSA-N 5-methyl-1,3-thiazol-2-amine Chemical compound CC1=CN=C(N)S1 GUABFMPMKJGSBQ-UHFFFAOYSA-N 0.000 claims abstract description 5
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 239000007821 HATU Substances 0.000 claims description 2
- PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 10
- 239000000047 product Substances 0.000 abstract description 7
- 238000000746 purification Methods 0.000 abstract description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052794 bromium Inorganic materials 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 5
- 238000004440 column chromatography Methods 0.000 abstract description 4
- 238000004537 pulping Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 abstract description 2
- 239000012043 crude product Substances 0.000 abstract description 2
- 238000001035 drying Methods 0.000 abstract description 2
- 239000013067 intermediate product Substances 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract 1
- 230000006837 decompression Effects 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- 230000006872 improvement Effects 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102100036876 Cyclin-K Human genes 0.000 description 1
- 101000713127 Homo sapiens Cyclin-K Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of an inhibitor, which comprises the following steps: step 1: adding N- (6-methyl-2-pyridyl) thiourea and 4-chloroacetoacetic acid ethyl ester into a solvent for cyclization reaction, and removing the solvent by decompression concentration to obtain an intermediate F crude product which is directly used for the next reaction; and 2, step: hydrolyzing the intermediate F, pulping with water and MTBE, and drying to obtain a product intermediate G; and 3, step 3: and carrying out condensation reaction on the intermediate G and 5-methyl-2-aminothiazole to obtain HQ461. The crude intermediate product in the first step of the synthesis method is directly used for the next step of reaction, the first two steps of reaction are combined and purified, the purification steps are reduced, the synthesis efficiency is improved, the use of bromine which is easy to prepare in the original synthesis process is avoided, the process is simple and efficient to operate, all the intermediates and products are not separated by column chromatography, pure products can be directly obtained by pulping, and the operation simplicity is improved.
Description
Technical Field
The invention relates to the technical field of inhibitor processing, in particular to an inhibitor and a preparation method thereof.
Background
HQ461 (CAS: 1226443-41-9) is a molecular glue that promotes CDK12-DDB1 interaction to trigger cyclin K degradation, the synthesis of which is disclosed in WO2021249517A1 (page 26):
firstly, aminolysis of a raw material B by 5-methyl-2-aminothiazole (A) to obtain a compound C, bromination of bromine on the compound C to obtain a compound D, and ring closure of the compound D and the compound E to obtain HQ461.
Bromine is used in the second step in the route to participate in the reaction, and the bromine is required to be dropwise added at the temperature of 60 ℃ to participate in the reaction, so that the reaction equipment and the operation requirement are high, in addition, a plurality of byproducts are generated in the reaction process, and column chromatography is used for purification, so that the purification is tedious, and the mass production cannot be easily amplified.
Disclosure of Invention
OBJECT OF THE INVENTION
Aiming at the technical problems, the invention provides an inhibitor and a preparation method thereof, which are used for solving the technical problems that in the prior art, a large number of byproducts are produced in the synthesis reaction process of HQ461, column chromatography is used for purification, the purification is complicated, and the mass production cannot be easily amplified.
Technical scheme
In order to achieve the purpose, the technical scheme provided by the invention is as follows: a method for preparing an inhibitor, comprising the steps of:
step 1: adding N- (6-methyl-2-pyridyl) thiourea E and 4-chloroacetoacetic acid ethyl ester into a solvent for reflux reaction for 2 hours to generate an intermediate F;
step 2: hydrolyzing the intermediate F to generate an intermediate G;
and 3, step 3: and condensing the intermediate G with 5-methyl-2-aminothiazole (A) to obtain HQ461.
The further improvement is that: in the step 1, the mol ratio of the N- (6-methyl-2-pyridyl) thiourea to the 4-chloroacetoacetic acid ethyl ester is 1: (1-3), preferably 1:1.2.
the further improvement lies in that: in step 1, the solvent is at least one selected from the group consisting of absolute methanol, absolute ethanol and tetrahydrofuran, and preferably absolute ethanol.
The further improvement lies in that: the reaction temperature in step 1 is 25 to 80 ℃ and preferably 70 to 80 ℃.
The further improvement lies in that: in step 2, the hydrolysis reagent is at least one selected from sodium hydroxide, potassium hydroxide and lithium hydroxide.
The further improvement lies in that: in step 2, the hydrolysis reagent is sodium hydroxide, and the molar ratio of the sodium hydroxide is 1: (1-10), preferably 1:3.
the further improvement lies in that: in step 2, the solvent is at least one selected from anhydrous methanol, anhydrous ethanol and tetrahydrofuran, and is preferably anhydrous methanol.
The further improvement is that: the reaction temperature in step 2 is 25-80 deg.C, preferably 60 deg.C.
The further improvement lies in that: in step 3, the condensing agent is at least one selected from HATU, EDCI, T3P.
The further improvement lies in that: in step 3, the condensing agent is selected from T3P, the molar ratio of T3P is 1: (1-3), preferably 1:1.2.
the further improvement is that: in step 3, the solvent is at least one selected from dichloromethane, acetonitrile, tetrahydrofuran and DMF, preferably DMF.
The further improvement is that: the reaction temperature in step 3 is 0 to 80 ℃ and preferably 10 to 30 ℃.
The invention also discloses an inhibitor which is prepared by adopting the preparation method.
Advantageous effects
Compared with the prior art, the technical scheme provided by the invention has the following beneficial effects:
according to the synthetic method, the crude intermediate product in the first step is directly used for the next step of reaction, and the first two steps of reaction are combined and purified, so that the purification steps are reduced, the synthetic efficiency is improved, and the use of the bromine which is easy to prepare in the original synthetic process is avoided.
The process is simple and efficient to operate, all intermediates and products are not separated by column chromatography, pure products can be directly obtained by pulping, and the operation simplicity is improved.
Detailed Description
The technical solution of the present invention will be further described with reference to the following specific examples, but the present invention is not limited to these examples.
Examples
The 1H NMR spectrum was measured by a Bruker instrument (400 MHz), and the chemical shift was expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1H NMR representation method: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If a coupling constant is provided, it is in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The synthesis method of HQ461 is as follows:
the first step is as follows:
n- (6-methyl-2-pyridyl) thiourea (10g, 59.80mmol, 1eq) and ethyl 4-chloroacetoacetate (11.8g, 71.76mmol, 1.2eq) were added to absolute ethanol (100 mL) and reacted for 2 hours under reflux. Cooling the reaction liquid, concentrating under reduced pressure to remove ethanol, and directly using the concentrated residue in the next step.
The second step is that:
adding methanol (100 mL), H2O (100 mL) and NaOH (7.2g, 179.39mmol and 3eq) into the crude product obtained in the previous step, reacting at 60 ℃ for 1 hour, cooling and concentrating the reaction solution to remove the methanol, adjusting the pH of the residue to 4-5 by using 2N HCl under an ice bath, separating out a solid, performing suction filtration, pulping the solid by using water and MTBE, and drying to obtain 10g of a product (off-white solid).
Wherein, the two steps combined yield 67.11%.
1 H NMR(400MHz ，DMSO-d6)δ12.30(br ，1H)，11.23(br ，1H)，7.54-7.58(t ，1H) ，6.79-6.81(d ，1H)， 6.75-6.76(d ，1H)，6.72(s ，1H)， 3.55(s ，2H)， 2.44(s ，3H)
The third step:
a reaction flask was charged with the product (10g, 40.11mmol, 1eq) obtained in the above step, 5-methyl-2-aminothiazole (4.6g, 40.11mmol, 1eq), T3P (30.6g, 48.13mmol, 1.2eq), DIPEA (10.34 g,80.22mmol, 2eq) in DMF, and reacted at room temperature for 2 hours. Water is added into the reaction liquid, EA is extracted, an EA phase is combined and washed by saturated NaCl, the EA phase is dried by anhydrous sodium sulfate, the filtration is carried out, the filtrate is concentrated, and the residue is pulped by acetonitrile to obtain 6.3g of HQ461 (the yield Y is 45.48%).
1 H NMR(400MHz ，DMSO-d6)δ12.05(br ，1H)，11.23(br ，1H)，
7.53-7.57(t ，1H)， 7.13(s ，1H) ，6.79 (s ，1H)， 6.76-6.77(d ，1H)，6.75(s ，1H)， 3.75(s ，2H)， 2.44(s ，3H)， 2.33(s ，3H)
LCMS：M/Z＝346(M+1)
While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
Claims (10)
1. A method for preparing an inhibitor, comprising the steps of:
step 1: adding N- (6-methyl-2-pyridyl) thiourea and 4-ethyl chloroacetoacetate into a solvent for reflux reaction for 2 hours to generate an intermediate F;
and 2, step: hydrolyzing the intermediate F to generate an intermediate G;
and step 3: and condensing the intermediate G with 5-methyl-2-aminothiazole to obtain HQ461.
2. The method of claim 1, wherein the inhibitor is prepared by: in the step 1, the mol ratio of the N- (6-methyl-2-pyridyl) thiourea to the 4-chloroacetoacetic acid ethyl ester is 1: (1-3).
3. The method of claim 1, wherein the inhibitor is prepared by: in step 1, the solvent is at least one selected from the group consisting of absolute methanol, absolute ethanol and tetrahydrofuran.
4. The method of claim 1, wherein the inhibitor is prepared by: the reaction temperature of step 1 is 25-80 ℃.
5. The method of claim 1, wherein the inhibitor is prepared by: in step 2, the hydrolysis reagent is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide and lithium hydroxide.
6. The method of claim 1, wherein the inhibitor is prepared by: in step 2, the solvent is at least one selected from the group consisting of absolute methanol, absolute ethanol and tetrahydrofuran.
7. The method of claim 1, wherein the inhibitor is prepared by: the reaction temperature of step 2 is 25-80 ℃.
8. The method of claim 1, wherein the inhibitor is prepared by: in step 3, the condensing agent is at least one selected from HATU, EDCI, and T3P.
9. The method of claim 1, wherein the inhibitor is prepared by: in step 3, the solvent is at least one selected from dichloromethane, acetonitrile, tetrahydrofuran and DMF.
10. An inhibitor, characterized by: the inhibitor is prepared by the preparation method of any one of claims 1 to 9.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210954667.XA CN115466254A (en) | 2022-08-10 | 2022-08-10 | Inhibitor and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202210954667.XA CN115466254A (en) | 2022-08-10 | 2022-08-10 | Inhibitor and preparation method thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101921268A (en) * | 2010-08-27 | 2010-12-22 | 中山大学肿瘤防治中心 | 5-thiazole amide compound and biology application thereof |
| CN102439007A (en) * | 2009-03-17 | 2012-05-02 | 第一三共株式会社 | Amide derivative |
| CN105777664A (en) * | 2016-01-29 | 2016-07-20 | 湖南大学 | 2-(2-benzal hydrazine)thiazole-5-carboxylate and preparation method and medical application thereof |
| CN111533710A (en) * | 2020-06-02 | 2020-08-14 | 江苏恒沛药物科技有限公司 | Method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid by one-pot method |
| WO2021249517A1 (en) * | 2020-06-10 | 2021-12-16 | National Institute Of Biological Sciences, Beijing | A molecular glue regulating cdk12-ddb1 interaction to trigger cyclin k degradation |
-
2022
- 2022-08-10 CN CN202210954667.XA patent/CN115466254A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102439007A (en) * | 2009-03-17 | 2012-05-02 | 第一三共株式会社 | Amide derivative |
| CN101921268A (en) * | 2010-08-27 | 2010-12-22 | 中山大学肿瘤防治中心 | 5-thiazole amide compound and biology application thereof |
| CN105777664A (en) * | 2016-01-29 | 2016-07-20 | 湖南大学 | 2-(2-benzal hydrazine)thiazole-5-carboxylate and preparation method and medical application thereof |
| CN111533710A (en) * | 2020-06-02 | 2020-08-14 | 江苏恒沛药物科技有限公司 | Method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid by one-pot method |
| WO2021249517A1 (en) * | 2020-06-10 | 2021-12-16 | National Institute Of Biological Sciences, Beijing | A molecular glue regulating cdk12-ddb1 interaction to trigger cyclin k degradation |
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