CN114591326B - Intermediate of CCT-251921 and preparation method thereof - Google Patents
Intermediate of CCT-251921 and preparation method thereof Download PDFInfo
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- CN114591326B CN114591326B CN202210189282.9A CN202210189282A CN114591326B CN 114591326 B CN114591326 B CN 114591326B CN 202210189282 A CN202210189282 A CN 202210189282A CN 114591326 B CN114591326 B CN 114591326B
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- VPJXPDLMACOGIZ-UHFFFAOYSA-N 8-[2-amino-3-chloro-5-(1-methylindazol-5-yl)pyridin-4-yl]-2,8-diazaspiro[4.5]decan-1-one Chemical compound C=1C=C2N(C)N=CC2=CC=1C1=CN=C(N)C(Cl)=C1N(CC1)CCC21CCNC2=O VPJXPDLMACOGIZ-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 29
- -1 nitrogen-containing hetero spiro compound Chemical class 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 229940125782 compound 2 Drugs 0.000 claims description 17
- 238000005660 chlorination reaction Methods 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000006467 substitution reaction Methods 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- 229940126214 compound 3 Drugs 0.000 claims description 11
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 10
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 10
- 229940125904 compound 1 Drugs 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000012445 acidic reagent Substances 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 238000010511 deprotection reaction Methods 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000012320 chlorinating reagent Substances 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 4
- RQMWVVBHJMUJNZ-UHFFFAOYSA-N 4-chloropyridin-2-amine Chemical compound NC1=CC(Cl)=CC=N1 RQMWVVBHJMUJNZ-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000006880 cross-coupling reaction Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000013341 scale-up Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 description 2
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- XHBZKKFNCZNQFW-UHFFFAOYSA-N tert-butyl 2-ethylnonanoate Chemical compound CCCCCCCC(CC)C(=O)OC(C)(C)C XHBZKKFNCZNQFW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to an intermediate of CCT-251921 and a preparation method thereof. The intermediate of the CCT-251921 is prepared by a nitrogen-containing hetero-spiro compound, the structure of the nitrogen-containing hetero-spiro compound has the structural characteristics shown in the following formula (A), the nitrogen-containing hetero-spiro compound can be used as an intermediate for synthesizing the CCT-251921 or a key intermediate (B) thereof, the synthesis step of the CCT-251921 or the key intermediate (B) thereof is simplified, and meanwhile, the method has the advantages of higher yield, mild reaction conditions, convenient operation and convenient post-treatment, and is suitable for industrial amplified production of the CCT-251921 or the key intermediate (B) thereof.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to an intermediate of CCT-251921 and a preparation method thereof.
Background
CCT-251921 is a potent, highly selective oral CDK8 inhibitor. In the past studies, CCT-251921 showed potent cellular activity and could exert inhibitory activity against β -catenin mutant (LS 174T), APC mutant (SW 480 and Colo 205) or WNT ligand-dependent PA-1 human teratoma cells, etc. Inhibition of CDK8 function and reduction of proliferation were also demonstrated in animal models of human xenogenic colorectal cancer. Therefore, the synthesis of CCT-251921 by a chemical method has great significance.
The structure of CCT-251921 is as follows:
the traditional synthesis method of CCT-251921 mainly comprises three methods:
firstly, 2-amino-4-chloropyridine is used as a starting material, and CCT-251921 is prepared through 6 steps of reaction of bromine adding, chlorine adding, protection adding, substitution, cross coupling reaction and deprotection, and the synthetic method comprises the following steps:
the method has complicated steps, the total yield is only 3.68%, and the method is unfavorable for industrial scale-up production.
The second, regard 2-amino-4-chloropyridine as the initial raw materials, go through bromine, chlorine, protect, substitute, cross coupling reaction and deprotection 6 steps of reactions to prepare CCT-251921, its synthetic method route is as follows:
the method has complicated steps, the total yield is only 14.1%, and the method is unfavorable for industrial scale-up production.
Thirdly, 2-amino-4-chloropyridine is used as a starting material, and CCT-251921 is prepared through 4 steps of reaction of bromine adding, chlorine adding, substitution and cross coupling, and the synthetic method comprises the following steps:
although the preparation steps are simplified, the method needs to utilize 220 ℃ microwave reaction for synthesizing the key intermediate compound B, and has severe conditions, which is not beneficial to industrial scale-up production.
Disclosure of Invention
Based on the above, the invention provides an intermediate of CCT-251921 with the advantages of simplified preparation steps, mild reaction conditions and high yield and a preparation method thereof.
In a first aspect of the present invention, there is provided a method for preparing a nitrogen-containing heterospiro compound, comprising the steps of:
performing t-butyloxycarbonyl protection reaction on the compound 1 in the presence of an acidic reagent to prepare a compound 2;
in the presence of an alkaline reagent, carrying out substitution reaction on the compound 2 and the compound 3 to prepare the nitrogen-containing hetero spiro compound;
wherein, the structures of the compound 1, the compound 2, the compound 3 and the nitrogen-containing hetero spiro compound are as follows:
nitrogen-containing heterospirocyclic compounds.
In one embodiment, the acidic reagent is selected from one or more of trifluoroacetic acid, hydrochloric acid and methanesulfonic acid.
In one embodiment, the organic solvent used in the t-butoxycarbonyl protecting reaction is selected from one or more of dichloromethane, methanol, ethanol, ethyl acetate, 1, 4-dioxane, water and tetrahydrofuran.
In one embodiment, the basic reagent is selected from one or more of triethylamine, pyridine, and N, N-diisopropylethylamine.
In one embodiment, the organic solvent used in the substitution reaction is selected from one or more of N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, chloroform and methylene chloride.
In a second aspect of the present invention, there is provided a nitrogen-containing heterospiro compound having the structural feature of formula (a):
in a third aspect of the present invention, there is provided a method for preparing an intermediate of CCT-251921, comprising the steps of:
preparing a nitrogen-containing heterospiro compound according to the preparation method of the first aspect, or obtaining the nitrogen-containing heterospiro compound of the second aspect;
performing chlorination reaction on the nitrogen-containing hetero spiro compound to prepare an intermediate of the CCT-251921;
the intermediate of the CCT-251921 has the structural characteristics shown in the following formula (B):
in one embodiment, the chlorinating reagent used in the chlorination reaction is selected from one or more of N-chlorosuccinimide, hydrogen chloride, and sulfonyl chloride.
In one embodiment, the organic solvent used for the chlorination reaction is selected from one or more of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and chloroform.
In a fourth aspect of the present invention, there is provided a method of preparing CCT-251921, comprising the steps of:
preparing an intermediate of CCT-251921 according to the preparation method of the third aspect;
carrying out Suzuki coupling reaction on the intermediate of the CCT-251921 and the compound 4 to prepare CCT-251921;
the structure of compound 4 is as follows:
in one embodiment, the SuzuKi coupling reaction is carried out in the presence of palladium tetraphenylphosphine and cesium carbonate.
The invention takes the compound 1 with low price as the initial raw material, firstly carries out deprotection reaction, and the obtained product directly carries out substitution reaction with the fluorine-containing compound 3, thus the prepared nitrogen-containing hetero spiro compound can be used as an intermediate for synthesizing CCT-251921 or a key intermediate (B) thereof, the synthesis steps of CCT-251921 or the key intermediate (B) thereof are simplified, and meanwhile, the invention has the advantages of higher yield, mild reaction conditions, convenient operation and convenient post treatment, and is suitable for industrial amplified production of CCT-251921 or the key intermediate (B) thereof.
Drawings
FIG. 1 is a LCMS monitoring spectrum of comparative example one.
Detailed Description
The intermediate of the CCT-251921 of the present invention and the preparation method thereof are described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
Herein, "one or more" refers to any one, any two, or any two or more of the listed items.
In the present invention, "first aspect", "second aspect", "third aspect", "fourth aspect", etc. are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or quantity, nor as implying an importance or quantity of technical features indicated. Moreover, the terms "first," "second," "third," "fourth," and the like are used for non-exhaustive list description purposes only, and are not to be construed as limiting the number of closed forms.
In the invention, the technical characteristics described in an open mode comprise a closed technical scheme composed of the listed characteristics and also comprise an open technical scheme comprising the listed characteristics.
In the present invention, the numerical ranges are referred to as continuous, and include the minimum and maximum values of the ranges, and each value between the minimum and maximum values, unless otherwise specified. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range description features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to include any and all subranges subsumed therein.
The percentage content referred to in the present invention refers to mass percentage for both solid-liquid mixing and solid-solid mixing and volume percentage for liquid-liquid mixing unless otherwise specified.
The percentage concentrations referred to in the present invention refer to the final concentrations unless otherwise specified. The final concentration refers to the ratio of the additive component in the system after the component is added.
The temperature parameter in the present invention is not particularly limited, and may be a constant temperature treatment or a treatment within a predetermined temperature range. The constant temperature process allows the temperature to fluctuate within the accuracy of the instrument control.
The invention provides a preparation method of a nitrogen-containing hetero spiro compound, which comprises the following steps:
(a) Performing t-butyloxycarbonyl protection reaction on the compound 1 in the presence of an acidic reagent to prepare a compound 2;
(b) In the presence of an alkaline reagent, carrying out substitution reaction on the compound 2 and the compound 3 to prepare the nitrogen-containing hetero spiro compound;
wherein, the structures of the compound 1, the compound 2, the compound 3 and the nitrogen-containing hetero spiro compound are as follows:
(1-oxo-2, 8-diazaspiro [4.5 ]]Decane-8-carboxylic acid tert-butyl ester
Nitrogen-containing heterospirocyclic compounds.
Further, the reaction conditions in each step are further preferable, and the yield of synthesis, the reaction rate and the cost can be improved.
Specifically, in step (a):
in one specific example, the acidic reagent is selected from one or more of trifluoroacetic acid, hydrochloric acid, and methanesulfonic acid. Further, the acidic reagent is hydrochloric acid.
In one specific example, the organic solvent used in the t-butoxycarbonyl protecting reaction is selected from one or more of dichloromethane, methanol, ethanol, ethyl acetate, 1, 4-dioxane, water and tetrahydrofuran. Further, the organic solvent used for the t-butoxycarbonyl deprotection reaction is a mixture of 1, 4-dioxane and dichloromethane. Without limitation, the volume ratio of 1, 4-dioxane to dichloromethane is 1 (1-1.5).
In one specific example, the temperature of the t-butoxycarbonyl deprotection reaction is-10℃to 30 ℃. Further, the temperature of the protection reaction of the t-butyloxycarbonyl group is 20-30 ℃.
In one specific example, the time for the t-butoxycarbonyl deprotection reaction is 0.5 to 8 hours. Further, the time for the protection reaction of the t-butoxycarbonyl group is 1 to 3 hours.
In one specific example, the molar ratio of the compound 1 to the acidic reagent is 1 (3 to 5). Further, the molar ratio of the compound 1 to the acidic reagent is 1:4.
Specifically, in step (b):
in one specific example, the basic reagent is selected from one or more of triethylamine, pyridine, and N, N-diisopropylethylamine. Further, the basic reagent is N, N-diisopropylethylamine.
In one specific example, the organic solvent used in the substitution reaction is selected from one or more of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, chloroform, and dichloromethane. Further, the organic solvent used in the substitution reaction is dimethyl sulfoxide.
In one specific example, the temperature of the substitution reaction is 25℃to 140 ℃. Further, the substitution reaction temperature is 75-85 ℃.
In one specific example, the substitution reaction time is 2 to 24 hours. Further, the time of the substitution reaction is 14 to 18 hours.
In one specific example, the molar ratio of the compound 2 to the compound 3 is 1 (0.3 to 0.7). Further, the molar ratio of the compound 2 to the compound 3 is 1:0.5.
In one specific example, the molar ratio of the compound 2 to the alkaline agent is 1 (4-5). Further, the molar ratio of the compound 2 to the alkaline agent is 1:4.5.
The invention also provides a nitrogen-containing hetero spiro compound with the structural characteristics shown in the following formula (A):
the invention also provides a preparation method of the intermediate of CCT-251921, which comprises the following steps:
preparing a nitrogen-containing hetero-spiro compound according to the preparation method, or obtaining the nitrogen-containing hetero-spiro compound;
performing chlorination reaction on the nitrogen-containing hetero spiro compound to prepare an intermediate of the CCT-251921;
the intermediate of the CCT-251921 has the structural characteristics shown in the following formula (B):
in one specific example, the chlorinating reagent used in the chlorination reaction is selected from one or more of N-chlorosuccinimide, hydrogen chloride, and sulfonyl chloride. Further, the chlorinating reagent used in the chlorination reaction is N-chlorosuccinimide.
In one specific example, the organic solvent used for the chlorination reaction is selected from one or more of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and chloroform. The organic solvent adopted in the chlorination reaction is N, N-dimethylformamide.
In one specific example, the temperature of the chlorination reaction is 0 ℃ to 40 ℃. Further, the temperature of the chlorination reaction is 20-30 ℃.
In one specific example, the time of the chlorination reaction is 2 to 24 hours. Further, the time of the chlorination reaction is 8-12 hours.
In one specific example, the molar ratio of the nitrogen-containing heterospiro compound to the chloro reagent is 1 (1.2-2). The mol ratio of the nitrogen-containing hetero spiro compound to the chloro reagent is 1:1.5.
The invention also provides a preparation method of the CCT-251921, which comprises the following steps:
preparing an intermediate of CCT-251921 according to the preparation method;
carrying out Suzuki coupling reaction on the intermediate of the CCT-251921 and the compound 4 to prepare CCT-251921;
the structure of compound 4 is as follows:
in one specific example, the SuzuKi coupling reaction is carried out in the presence of palladium tetraphenylphosphine and cesium carbonate.
In one specific example, the molar ratio of the intermediate of CCT-251921 to compound 4 is 1 (1.2-2). Further, the molar ratio of the intermediate to compound 4 of CCT-251921 is 1:1.5.
In one specific example, the molar ratio of the intermediate of CCT-251921 to the tetraphenylphosphine palladium is 1 (0.01-0.05). Further, the molar ratio of the intermediate of CCT-251921 to the tetraphenylphosphine palladium is 1:0.03.
In one specific example, the molar ratio of the intermediate of CCT-251921 to cesium carbonate is 1 (1.2-2). Further, the molar ratio of the intermediate of CCT-251921 to cesium carbonate is 1:1.5.
In one specific example, the solvent used in the Suzuki coupling reaction is one or more of water, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and chloroform. The organic solvent used in the chlorination reaction is a mixture of N, N-dimethylformamide and water. The volume ratio of N, N-dimethylformamide to water is 1 (0.3 to 0.7).
In one specific example, the temperature of the Suzuki coupling reaction is 25℃to 140 ℃. Further, the temperature of the Suzuki coupling reaction is 95-105 ℃.
In one specific example, the time for the Suzuki coupling reaction is 1h to 10h. Further, the time of the SuzuKi coupling reaction is 2-4 hours.
The following examples are given by way of example, and unless otherwise indicated, all materials used are commercially available products.
EXAMPLE Synthesis of Compound 2
To a solution of compound 1 (4.00 g,1.00 eq.) in dichloromethane (20 mL) was added hydrochloric acid/1, 4-dioxane (4 m,15.73mL,4.0 eq.) and the mixture was stirred at 25 ℃ for 2h. After completion of the reaction, which was monitored by thin layer chromatography (dichloromethane: methanol=10:1, uv=254 nm, rf=0.06), the reaction mixture was concentrated to give compound 2 (2.81 g,14.74mmol,93.7% yield) as a white solid.
1 H NMR:(400MHz,DMSO)δ9.29(s,1H),8.97(s,1H),7.72(s,1H),3.25-3.22(m,2H),3.17-3.14(m,2H),2.93-2.90(m,2H),1.98-1.95(m,2H),1.84-1.80(m,2H),1.57-1.53(m,2H)。
LC-MS:(M+1) + :155.0。
EXAMPLE two Synthesis of Compound A
To a solution of compound 2 (2.08 g,1.00 eq.) and compound 3 (1.0 g,0.50 eq.) in dimethyl sulfoxide (25 mL) was added N, N-diisopropylethylamine (6.33 g,4.5 eq.). The reaction mixture was stirred at 80℃for 16h. After completion of the reaction monitored by thin layer chromatography (dichloromethane: methanol=10:1, uv=254 nm, rf=0.32), the reaction mixture was isolated by extraction with dichloromethane (20 mL) and water (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration to give compound a (1.3 g,3.91mmol, 74.7%) as a yellow solid.
1 H NMR:(400MHz,DMSO)δ8.09(s,1H),7.74-7.47(m,3H),6.30(s,1H),3.64-3.60(m,2H),3.20(t,J＝8.0Hz,2H),3.04-2.98(m,2H),2.02(t,J＝8.0Hz,2H),1.83-1.78(m,2H),1.52-1.49(d,J＝13.6Hz,2H)。
LC-MS:(M+1) + :324.8。
EXAMPLE three Synthesis of Compound B
To a solution of compound a (100 mg,301.04 μmol,1.0 eq.) in N, N-dimethylformamide (1 mL) was added N-chlorosuccinimide (60.30 mg,451.56 μmol,1.5 eq.) and the mixture was stirred at 25 ℃ for 10 hours. LCMS monitoring showed the formation of compound B. The reaction mixture was separated by extraction with ethyl acetate (3 mL) and water (2 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration to give a crude product. The crude product was slurried in ethyl acetate (1 mL) at 25℃for 1 hour to give compound B (48 mg,117.31umol,44.33% yield,87.90% purity) as an off-white solid.
1 H NMR:(400MHz,DMSO-d 6 )δ7.92(s,1H),7.58(s,1H),6.33(s,2H),3.28-3.14(m,6H),2.01(t,J＝6.4Hz,2H),1.87-1.81(m,2H),1.41-1.37(m,2H)。
LC-M:(M+1) + :360.9。
HPLC:87.90％purity(220nm，Rt＝2.043min)。
Example four Synthesis of CCT-251921
To a solution of compound B (50 mg,139.02 μmol,1 eq.) and compound 4 (36.70 mg,208.54 μmol,1.5 eq.) and cesium carbonate (67.95 mg,208.54 μmol,1.5 eq.) in N, N-dimethylformamide (1 mL) and water (0.5 mL) was added tetrakis triphenylphosphine palladium (4.82 mg,4.17 μmol,0.03 eq.). The reaction mixture was stirred under nitrogen at 100℃for 3h. LCMS monitoring showed CCT-251971 production. The reaction mixture was separated by extraction with ethyl acetate (3 mL) and water (3 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration to give a crude product. The crude product was purified by preparative HPLC to give red solid CCT-251921 (36 mg, 87.61. Mu. Mol,59.86% yield).
1 H NMR:(400MHz,DMSO)δ8.10(s,1H),7.73(d,1H),7.71(s,2H),7.52(s,1H),7.31(d,J＝10.0Hz,1H),4.08(s,3H),3.19-3.16(d,J＝12.0Hz,2H),3.08(d,J＝6.8Hz,2H),2.73-2.67(m,2H),1.79(d,J＝6.8Hz,2H),1.67-1.62(m,2H),1.25-1.21(m,2H)。
LC-MS:(M+1) + :411.1。
HPLC:95.1％purity(220nm，Rt＝2.342min)。
Comparative example one
The synthesis of compound a was performed in the same procedure as in example two, with the main difference: compound 3 was replaced with compound 3A.
To a solution of compound 2 (200 mg,1.30mmol,1.00 eq.) and compound 3A (134.53 mg,648.47 μmol,0.50 eq.) in dimethyl sulfoxide (2.5 mL) was added N, N-diisopropylethylamine (633 mg,4.5 eq.). The reaction mixture was stirred at 80℃for 16h. LCMS monitored the reaction, as shown in fig. 1, LCMS spectra showed 95.9% retention of starting compound 2 with no formation of compound a.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples merely represent a few embodiments of the present invention, which facilitate a specific and detailed understanding of the technical solutions of the present invention, but are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. It should be understood that, based on the technical solutions provided by the present invention, those skilled in the art may obtain technical solutions through logical analysis, reasoning or limited experiments, which are all within the scope of protection of the appended claims. The scope of the patent of the invention should therefore be determined with reference to the appended claims, which are to be construed as in accordance with the doctrines of claim interpretation.
Claims (10)
1. The preparation method of the nitrogen-containing hetero spiro compound is characterized by comprising the following steps of:
performing t-butyloxycarbonyl protection reaction on the compound 1 in the presence of an acidic reagent to prepare a compound 2;
in the presence of an alkaline reagent, carrying out substitution reaction on the compound 2 and the compound 3 to prepare the nitrogen-containing hetero spiro compound; the substitution reaction temperature is 75-85 ℃;
wherein, the structures of the compound 1, the compound 2, the compound 3 and the nitrogen-containing hetero spiro compound are as follows:
2. the method for producing a nitrogen-containing hetero-spiro compound according to claim 1, wherein the acidic reagent is one or more selected from trifluoroacetic acid, hydrochloric acid and methanesulfonic acid.
3. The method for preparing nitrogen-containing hetero-spiro compounds according to claim 1, wherein the organic solvent used in the t-butoxycarbonyl deprotection reaction is one or more selected from the group consisting of dichloromethane, methanol, ethanol, ethyl acetate, 1, 4-dioxane, water and tetrahydrofuran.
4. A process for the preparation of nitrogen-containing heterospiro compounds according to any one of claims 1-3, wherein the basic reagent is selected from one or more of triethylamine, pyridine and N, N-diisopropylethylamine.
5. The process for producing a nitrogen-containing hetero-spiro compound according to any one of claims 1 to 3, wherein the organic solvent used in the substitution reaction is one or more selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, chloroform and methylene chloride.
6. A nitrogen-containing heterospiro compound having the structural feature of formula (a):
7. a method for preparing an intermediate of CCT-251921, which is characterized by comprising the following steps:
preparing a nitrogen-containing heterospiro compound according to the preparation method of any one of claims 1 to 5, or obtaining a nitrogen-containing heterospiro compound of claim 6;
performing chlorination reaction on the nitrogen-containing hetero spiro compound to prepare an intermediate of the CCT-251921;
the intermediate of the CCT-251921 has the structural characteristics shown in the following formula (B):
8. the method of preparing an intermediate of CCT-251921 according to claim 7, wherein the chlorinating reagent used for the chlorination reaction is selected from one or more of N-chlorosuccinimide, hydrogen chloride and sulfonyl chloride.
9. The method for preparing an intermediate of CCT-251921 according to claim 7 or 8, wherein the organic solvent used for the chlorination reaction is one or more selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and chloroform.
10. A method for preparing CCT-251921, comprising the steps of:
an intermediate for the preparation of CCT-251921 according to the preparation method of any one of claims 7 to 9;
carrying out Suzuki coupling reaction on the intermediate of the CCT-251921 and the compound 4 to prepare CCT-251921;
the structure of compound 4 is as follows:
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