CN117986189A - Preparation method of spiro compound - Google Patents
Preparation method of spiro compound Download PDFInfo
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- CN117986189A CN117986189A CN202410109981.7A CN202410109981A CN117986189A CN 117986189 A CN117986189 A CN 117986189A CN 202410109981 A CN202410109981 A CN 202410109981A CN 117986189 A CN117986189 A CN 117986189A
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- spiro
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- 150000003413 spiro compounds Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 238000006722 reduction reaction Methods 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- KYUSUAYEKINLQX-UHFFFAOYSA-N 2-ethyldecanal Chemical compound CCCCCCCCC(CC)C=O KYUSUAYEKINLQX-UHFFFAOYSA-N 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 150000007530 organic bases Chemical class 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- -1 triethylamine Chemical class 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 229940126214 compound 3 Drugs 0.000 abstract description 5
- 239000001301 oxygen Substances 0.000 abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000004071 biological effect Effects 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- 125000003003 spiro group Chemical group 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 4
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 108091007914 CDKs Proteins 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 1
- 238000005094 computer simulation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis and preparation method of a spiro compound. According to the invention, 3-carboxylic acid tert-butyl ester-3-azaspiro [5.5] undecane-9-formaldehyde is used as a reaction raw material, and a brand new spiro compound 3 '-oxygen subunit-2, 3,5, 6-tetrahydro-1H-spiro [ pyridine-4, 9' -spiro [5.5] undecane-1-alkene ] -1-formic acid-2-methylpropan-2-yl ester is prepared through single bond cyclization reaction and reduction reaction. The invention has simple process, safety and environmental protection, is convenient for realizing industrial production, and has very wide application prospect in the future in view of the unique chemical structure and good biological activity of the spiro compound.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis and preparation method of a spiro compound.
Background
The spiro compound plays an important role in the field of medicine research due to its unique chemical space three-dimensional structure. The spiro scaffold can provide higher Fsp 3 value and stronger three-dimensional configuration for pharmaceutical chemistry, on one hand, because the spiro system limits intermolecular conformation, and locks ideal conformation between ligand and target point, and plays a role in improving activity and selectivity. On the other hand, the spiro scaffold increases the rigidity of the molecule, so that the pharmacokinetics and physicochemical properties are greatly improved. From 2008, development of drugs based on spiro compounds is rapidly proceeding. In 2022, steven v.ley taught that nobel's chemical prize was obtained by synthesizing complex spiro compounds under mild conditions using Vapourtec UV-150 photochemical reactors. In recent years, spiro-type drugs have been introduced. It can be said that the drug discovery based on the spiro compound has entered an unprecedented age of rapid development, and brings new opportunities for drug research and development. With the development of synthetic chemistry and computational models, it is believed that more and more spiro compounds are being developed as targeted drugs in the future.
Prior art patent CN116947840 discloses a spiro compound IV with a double spiro structure having the function of constructing a CDK inhibitor skeleton, and the structural general formula is as follows:
compared with other non-spiro compounds, the compound and the composition thereof with the spiro skeleton are obviously shown to promote the degradation of target proteins and inhibit related pharmacological activities, and effectively treat, inhibit or prevent diseases or symptoms related to CDKs.
The spiro compound 3 '-oxygen subunit-2, 3,5, 6-tetrahydro-1H-spiro [ pyridine-4, 9' -spiro [5.5] undec-1-ene ] -1-formic acid-2-methylpropan-2-yl ester can provide a novel spiro skeleton in an inhibitor for treating CDK related diseases or symptoms, the spiro skeleton enables the CDK inhibitor to have higher activity and selectivity, and meanwhile, the rigidity of molecules is enhanced, so that the metabolic stability of the CDK inhibitor can be increased, the balance of solubility and fat solubility is facilitated, and the efficacy of the CDK inhibitor can be improved to a certain extent.
In view of the great use of spiro compounds, it is necessary to develop a process route which is simple in process, high in yield, high in atomic economy and suitable for industrial production.
Disclosure of Invention
The invention provides a novel spiro framework and a synthesis and preparation scheme thereof. In particular, the invention provides a novel spiro compound 3 '-oxy subunit-2, 3,5, 6-tetrahydro-1H-spiro [ pyridine-4, 9' -spiro [5.5] undec-1-ene ] -1-formic acid-2-methylpropan-2-yl ester and a synthesis preparation scheme thereof.
In order to achieve the technical purpose of the invention, the technical scheme of the invention is as follows:
firstly, the invention provides a brand new compound 3 '-oxygen subunit-2, 3,5, 6-tetrahydro-1H-spiro [ pyridine-4, 9' -spiro [5.5] undec-1-alkene ] -1-formic acid-2-methylpropan-2-yl ester with the following structural formula:
The spiro compound of the formula I takes a three-spiro structure as a skeleton center, the original double-spiro structure is further expanded and extended, and the corresponding structural information and synthetic preparation routes are not reported in related patent documents at present.
The invention provides an intermediate compound shown in a formula II, which has the following structural formula:
The invention further provides a preparation method of the compound of the formula I, which is prepared by the reduction reaction of the compound of the formula II,
The solvent for the reduction reaction may be any of tetrahydrofuran, methanol, ethanol, acetonitrile, and the like.
The catalyst for the reduction reaction can be any metal catalyst such as palladium carbon, raney nickel and the like.
The reaction temperature of the reduction reaction is-10-65 ℃.
The invention further provides a preparation method of the compound of the formula II, which is prepared by the single bond cyclization reaction of the compound of the formula III and butenone,
The solvent for the single bond cyclization reaction may be any of ethanol, tetrahydrofuran, methanol, acetonitrile, and the like.
The alkali for the single bond cyclization reaction can be inorganic alkali such as potassium hydroxide, potassium carbonate, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, or organic alkali such as triethylamine, N-diisopropylethylamine, etc.
The reaction temperature of the single bond cyclization reaction is-10-65 ℃.
In the single bond cyclization reaction, 3-carboxylic acid tert-butyl ester-3-azaspiro [5.5] undecane-9-formaldehyde: butenone: ethanol: the molar ratio of potassium hydroxide is 1: (1-10): (1-10): (0.1-3).
The invention provides a novel synthetic preparation scheme of spiro compound 3 '-oxygen subunit-2, 3,5, 6-tetrahydro-1H-spiro [ pyridine-4, 9' -spiro [5.5] undeca-1-ene ] -1-formic acid-2-methylpropan-2-yl ester, which has simple process, safety and environmental protection, is convenient for realizing industrial production, and has very broad application prospect in the future in view of unique chemical structure and good biological activity of spiro compound.
Drawings
Fig. 1: the hydrogen nuclear magnetic spectrum of the structural formula I prepared in the example 2.
Fig. 2: the carbon nuclear magnetic spectrum of the structural formula I prepared in the example 2.
Detailed Description
For a further understanding of the present invention, the following detailed description of the invention is provided in connection with the examples. It should be understood that these examples are presented merely to further illustrate the features of the present invention and are not intended to limit the scope of the invention or the scope of the claims.
Example 1:
synthesis of 2-methylpropan-2-yl 3 '-oxy-subunit-2, 3,5, 6-tetrahydro-1H-spiro [ pyridin-4, 9' -spiro [5.5] undec-1-ene ] -1-carboxylate (structural formula II):
Anhydrous ethanol (11.6 g,0.252mol,2.36 eq) and potassium hydroxide (2.3 g,0.041mol,0.38 eq) are added into a four-necked flask filled with nitrogen, and stirred at 40 ℃ until the solution is clear, and the potassium hydroxide/ethanol solution after the solution is clear is ready for use. Into a four-necked flask filled with nitrogen gas, tert-butyl 3-carboxylate-3-azaspiro [5.5] undecane-9-formaldehyde (structural formula III) (30.0 g,0.107 mol), tetrahydrofuran (270.0 g), butenone (10.0 g,0.143mol,1.34 eq) were added, stirring was performed until the solution was clear, cooling at 0 ℃, dropwise adding a prepared potassium hydroxide/ethanol solution at an internal temperature of-5 ℃ was controlled, after the dropwise addition was completed, heating at 25 ℃, and stirring at a temperature of heat preservation until the reaction was completed. After completion of the reaction, n-heptane (60.0 g), saturated brine (72.0 g), was added to the reaction mixture, stirred uniformly, and then the mixture was allowed to stand still for separation to give an organic phase, which was washed once with saturated brine (72.0 g) and purified by column chromatography to give 3 '-oxy-2, 3,5, 6-tetrahydro-1H-spiro [ pyridine-4, 9' -spiro [5.5] undec-1-ene ] -1-carboxylic acid-2-methylpropan-2-yl ester (structural formula II) as a brown oil (31 g, yield: 87.2%).
Example 2:
Synthesis of 2-methylpropan-2-yl 3 '-oxy-subunit-2, 3,5, 6-tetrahydro-1H-spiro [ pyridin-4, 9' -spiro [5.5] undec-1-ene ] -1-carboxylate (structural formula I):
Tetrahydrofuran (300.0 g), 3 '-oxy-2, 3,5, 6-tetrahydro-1H-spiro [ pyridine-4, 9' -spiro [5.5] undec-1-ene ] -1-carboxylic acid-2-methylpropan-2-yl ester brown oil (31 g,0.093 mol) was added to the hydrogenation reactor, stirred and dissolved, 10% palladium on charcoal (2.4 g) was added, after gas displacement, the temperature was raised to 30℃and stirred under hydrogen pressure until the reaction was completed. After the reaction, the solution was filtered with suction and the palladium on charcoal was rinsed with tetrahydrofuran to give a filtrate, which was concentrated to give an oil, which was purified by column chromatography over a column (eluent ethyl acetate: n-heptane=1:8) to give 24.8g of a white solid product of 3 '-oxy-2, 3,5, 6-tetrahydro-1H-spiro [ pyridin-4, 9' -spiro [5.5] undec-1-ene ] -1-carboxylic acid-2-methylpropan-2-yl ester (structural formula I) in 80.0% yield. The liquid detection [2M+Na ] = 693.30,Exact Mass =335.2 and the nuclear magnetic hydrogen spectrum carbon spectrum is shown in figure 1 and figure 2.
Claims (10)
1. A spiro compound of formula I and its intermediate compound have the structural formula:
2. A preparation method of a spiro compound shown as a formula I is characterized in that the spiro compound is prepared by a reduction reaction of a compound shown as a formula II,
3. The method according to claim 2, wherein the solvent for the reduction reaction is any one of tetrahydrofuran, methanol, ethanol, acetonitrile, and the like.
4. The preparation method according to claim 2, wherein the catalyst for the reduction reaction is any one of metal catalysts such as palladium on carbon and raney nickel.
5. The method according to claim 2, wherein the reaction temperature of the reduction reaction is-10 to 65 ℃.
6. A preparation method of a compound of formula II is characterized in that the compound of formula III and butenone are prepared through single bond cyclization reaction,
7. The method according to claim 6, wherein the solvent for the single bond cyclization reaction is any one of ethanol, tetrahydrofuran, methanol, acetonitrile, and the like.
8. The method according to claim 6, wherein the base for the single bond cyclization reaction is an inorganic base such as potassium hydroxide, potassium carbonate, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, or an organic base such as triethylamine, N-diisopropylethylamine.
9. The process according to claim 6, wherein the single bond cyclization reaction has a reaction temperature of-10 to 65 ℃.
10. The method according to claim 6, wherein in the single bond cyclization reaction, tert-butyl 3-carboxylate-3-azaspiro [5.5] undecane-9-carbaldehyde: butenone: ethanol: the molar ratio of potassium hydroxide is 1:
(1～10)：(1～10)：(0.1～3)。
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| Application Number | Priority Date | Filing Date | Title |
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| CN202410109981.7A CN117986189A (en) | 2024-01-26 | 2024-01-26 | Preparation method of spiro compound |
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| CN202410109981.7A CN117986189A (en) | 2024-01-26 | 2024-01-26 | Preparation method of spiro compound |
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