CN102942570A - 1-trifluoromethyl-2,8-diazospiro[4.5]decane derivative and preparation method thereof - Google Patents
1-trifluoromethyl-2,8-diazospiro[4.5]decane derivative and preparation method thereof Download PDFInfo
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- CN102942570A CN102942570A CN2012105147272A CN201210514727A CN102942570A CN 102942570 A CN102942570 A CN 102942570A CN 2012105147272 A CN2012105147272 A CN 2012105147272A CN 201210514727 A CN201210514727 A CN 201210514727A CN 102942570 A CN102942570 A CN 102942570A
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- 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
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Abstract
The invention relates to a novel 1-trifluoromethyl-2,8-diazospiro[4.5]decane derivative and a preparation method thereof, and mainly solves the problems of few types of substituent groups on the spiro ring system of a 2,8-diazospiro[4.5]decane compound, limited space structure and the like. The chemical structural formula is shown in the specification, wherein R1 is a substituent functional group or amino protective group and is one of H and C1-10 straight-chain or substituent-side-chain-containing benzyl, acyl, sulfonyl, urea or thiourea; and R2 is hydrogen or alkoxycarbonyl.
Description
Technical field
The present invention relates to a kind of 1-trifluoromethyl-2, the preparation method of 8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester.
Background technology
2,8-diaza-spiro [4.5] decane compounds is the more special molecule of a class formation, the pharmacophore unit of key effectively can be connected and be incorporated in its rigid structure, formation has the molecule of special space configuration/conformation, thereby the space structure that can mate different biomacromolecules in the organism, produce different biological activity or effectiveness, have wide using value, particularly in the drug research process as template compound.The present invention reaches the purpose of improving its quasi-medicated property matter in the hope of electronic effect and the steric effect that changes molecular structure, and the synthetic method of this class novel cpd is provided at 1 introducing trifluoromethyl of 2,8-diaza-spiro [4.5] decane.Below be partial monopoly with document in disclosed and relevant with patent of the present invention some examples
It is a series of 2 that patent WO2005040167 reports, the compound of 8-diaza-spiro [4.5] decane class fragment is such as compound
1The CCR8 acceptor is shown good activity, and CCR8 is the target of class treatment asthma.
Patent WO2007140383 report contains the compound of 2,8-diaza-spiro [4.5] decane class fragment
2, this compound has all shown well in vivo with in the external experiment to the activity of bradykinin acceptor, can be used for treating because the inflammation that the bradykinin regulation causes the symptoms such as pain.
Patent WO2005023809 has reported compound
3Have anti-human immunodeficiency virus (HIV) effect as a kind of CCR5 antagonist, simultaneously, this compound also has resisting rheumatoid arthritis, analgesia, the effects such as diabetes.
Patent WO01/94346 has reported the compound of a series of spirane structures
4This compounds is neurokinin 1(NK-1, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2) antagonist.Neurokinin 1 is distributed in the mammiferous neural system widely, especially the nervous center of brain and spinal cord.This compounds shows good activity, is expected to be applied to treat the relative diseases such as migraine, rheumatosis, sacroiliitis, asthma
Biological organic and pharmaceutical chemistry wall bulletin (the Bioorganic ﹠amp of document; Medicinal Chemistry Letters 20,2010,608 – 611) once report is pointed out, if use saturated 2,8-diaza-spiro [4.5] thus the compound that decane replaces original phenyl ring to obtain
6Maintenance is to the active selectivity that has greatly improved simultaneously Cannabined receptor CB2 of Cannabined receptor CB1.
It is a series of 2 that patent W2005097794 has reported, 8-diaza-spiro [4.5] decane class fragment, wherein compound
4This compound equally also shows the good activity of neurokinin, and is especially active to the inhibition of NK-1.Be expected to be applied to treatment and prevention schizophasia, faint from fear the relative diseases such as asthma.
Although we can see 2 from top example, 8-diaza-spiro [4.5] decane structure is found in a large amount of active compounds, but 2 of present bibliographical information, 8-diaza-spiro [4.5] ten alkyl compounds are synthetic substantially all to be the preparation of substitution compound on the relative configuration of volution and the nitrogen, it mostly depends on nitrogen-atoms and removes to modify or connect other group on space structure extends, modifiable side chain is fewer, thereby the space extension is restricted.For the synthetic report that the substituting group compound is arranged on the volution then seldom, there is not yet bibliographical information for the structural modification that replaces with trifluoromethyl on the volution, can't satisfy the various enzymes of organism, acceptor diversity structurally.Therefore, we need to expand its structural modification and further improve its quasi-medicated property matter.
Efavirenz (English: Efavirenz) be a kind of specific medicament of resisting HIV (human immunodeficiency virus).The trade name of efavirenz is Sustiva or Stocrin, it is a kind of medicine that belongs to non-nucleoside reverse transcriptase inhibition (NNRTI--non-nucleoside reverse transcriptase inhibitor) classification, can use degeneration-resistant the turning in the virus therapy of high reactivity, cure Class A human immunity venereal disease poison (HIV type 1).This is the medicine that contains trifluoromethyl that has typically gone on the market.
Summary of the invention
The objective of the invention is to be to provide a kind of novel 1-trifluoromethyl-2, the preparation method of 8-diaza-spiro [4.5] decane derivative.Mainly solve 2, the substituting group kind is few on 8-diaza-spiro [4.5] the decane compounds volution, the problems such as space structure is limited, the present invention is 2, introduce trifluoromethyl for 1 of 8-diaza-spiro [4.5] decane, reach the purpose of improving its quasi-medicated property matter in the hope of electronic effect and the steric effect that changes molecular structure, and the synthetic method of this class novel cpd is provided.1-trifluoromethyl-2,8-diaza-spiro [4.5] decane derivative is the spirocyclic compound of a class formation novelty, at present without its structure of any bibliographical information and synthetic method.
Technical scheme of the present invention: 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane derivative, general structure is seen following formula:
Formula 1
R wherein
1Be to replace functional group or amino protecting group, be selected from H, C1 ~ C10 straight chain or contain a kind of in the benzyl, acyl group, alkylsulfonyl, urea, thiocarbamide of substituting group side chain; R
2Be hydrogen or amino protecting group.
According to the present invention, 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane derivative, preferred compound is: R
2During for tertbutyloxycarbonyl, for
Shown 1-trifluoromethyl-2 replaces-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester derivative:
I
R wherein
1Be to replace functional group or amino protecting group, be selected from H, C1 ~ C10 straight chain or contain a kind of in the benzyl, acyl group, alkylsulfonyl, urea, thiocarbamide of substituting group side chain.
On this basis, the further preferred compound of the present invention includes but not limited to:
I-a:2-benzyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester;
I-b:2-benzoyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester;
I-c:2-(4-Methyl benzenesulfonyl base)-and 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester;
I-d:2-ethylamino formyl radical-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester;
I-e:2-(4-fluorophenyl thiocarbamoyl)-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester.
According to the present invention, 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane derivative, preferred compound is: work as R
2During for hydrogen, for the 1-trifluoromethyl shown in the formula II-2-replaces-2,8-diaza-spiro [4.5] decane derivative:
R wherein
1Be to replace functional group or amino protecting group, be selected from H, C1 ~ C10 straight chain or contain a kind of in the benzyl, acyl group, alkylsulfonyl, urea, thiocarbamide of substituting group side chain.
On this basis, the further preferred compound of the present invention includes but not limited to:
-c:2-(4-Methyl benzenesulfonyl base)-and 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane;
-d:2-ethylamino formyl radical-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane;
The above-mentioned structural formula of compound of mentioning is as follows:
A kind of 1-trifluoromethyl-2 for preparing, the method for 8-diaza-spiro [4.5] decane derivative, preparation process is as follows: adopt compound 1-carbonyl-2,8-diaza-spiro [4.5] decane
1Be raw material, protect to get 1-carbonyl-2 through carbobenzoxy-(Cbz), 8-diaza-spiro [4.5] decane-2-carboxylic acid-2-benzyl ester
2, compound
2Obtain 1-hydroxyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-2-carboxylic acid-2-benzyl ester through trifluoromethylation
3, compound
3Obtain 1-trifluoromethyl-2 through the hydrogenation deprotection, 8-diaza-spiro [4.5] decane
4Reaction formula is as follows:
Suc as formula
IShown in described 1-trifluoromethyl-2, the preparation method of 8-diaza-spiro [4.5] decane derivative is characterized in that: R among the formula I
2During for hydrogen, 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane derivative are that 1-trifluoromethyl-2 replaces-2,8-diaza-spiro [4.5] decane, preparation process: adopt compound 1-carbonyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
1Be raw material, protect to get 1-carbonyl-2 through carbobenzoxy-(Cbz) (Cbz), 8-diaza-spiro [4.5] decane-2,8-dicarboxylic acid-2-benzyl ester-8-tert-butyl ester
2, compound
2Obtain 1-hydroxyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-2,8-dicarboxylic acid-2-benzyl ester-8-tert-butyl ester through trifluoromethylation
3, compound
3Obtain 1-trifluoromethyl-2 through the hydrogenation deprotection, 8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
4, compound
4Obtain 1-trifluoromethyl-2 with benzyl bromine, Benzoyl chloride, Tosyl chloride, ethyl isocyanate, the reaction of 4-fluorophenyl lsothiocyanates respectively and replace-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester derivative
I-a ~ e, compound
I-a ~ E withThe hydrochloric ethyl acetate reaction is sloughed tertbutyloxycarbonyl and is got 1-trifluoromethyl-2 replacement-2,8-diaza-spiro [4.5] decane derivative
-a ~ e, reaction formula is as follows:
R wherein
1For a kind of in benzyl, benzoyl, p-toluenesulfonyl, ethylamino formyl radical, the 4-fluorophenyl thiocarbamoyl.
Beneficial effect of the present invention
:We further improve its quasi-medicated property matter at 1 introducing trifluoromethyl of 2,8-diaza-spiro [4.5] decane with the electronic effect and the steric effect that change molecular structure.We provide the method for preparing such novel cpd.The compounds of this invention has faint restraining effect to the growth of human lung cancer cell A549's cell, and further research and development are had directive significance.
Embodiment
Enumerate embodiment so that the present invention is described in detail, but the present invention is not limited to these embodiment.
Embodiment 1: 1-carbonyl-2,8-diaza-spiro [4.5] decane-2,8-dicarboxylic acid-2-benzyl ester-8-tert-butyl ester
2Preparation
Operation steps:
Under the nitrogen protection, in the three-necked bottle of a drying, add compound 1-carbonyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
1(5.0 grams, 19.7 mmoles) and tetrahydrofuran (THF) (25 milliliters) slowly add n-Butyl Lithium (7.9 milliliters, 19.8 mmoles, 2.5 moles of every liter of hexane solutions) under dry ice acetone bath.Reaction solution stirred 30 minutes at-78 degrees centigrade, then slowly added tetrahydrofuran (THF) (10 milliliters) solution of chloroformic acid benzyl ester (2.89 milliliters, 20.0 mmoles).Slowly rise to stirred overnight at room temperature, with (100 milliliters) saturated aqueous ammonium chloride cancellation reaction, reaction solution (100 milliliters) ethyl acetate extraction three times, the concentrated product 1-carbonyl-2 that to get of organic phase drying, 8-diaza-spiro [4.5] decane-2,8-dicarboxylic acid-2-benzyl ester-8-tert-butyl ester
2, 6.8 grams, yield 89%.Be directly used in next step reaction.
Embodiment 2: 1-hydroxyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-2,8-dicarboxylic acid-2-benzyl ester-8-tert-butyl ester
3Preparation
Operation steps:
Under nitrogen protection, 1-carbonyl-2,8-diaza-spiro [4.5] decane-2,8-dicarboxylic acid-2-benzyl ester-8-tert-butyl ester
2(6.8 grams, 17.5 mmoles) are dissolved in the anhydrous tetrahydro furan (50 milliliters), add fast cesium fluoride (1.32 grams, 8.8 mmoles) and trifluoromethyl trimethyl silicane (7.5 grams, 52.8 mmoles).This reaction solution added tetrabutyl fluoride amine (9.0 grams, 34.5 mmoles) after stirring at room 2-3 hour, this reaction solution was stirring at room 10 minutes.Concentrating under reduced pressure, crude product is through silica gel column chromatography (petrol ether/ethyl acetate=20:1) obtain 1-hydroxyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-2,8-dicarboxylic acid-2-benzyl ester-8-tert-butyl ester
3, 3.6 grams, yield 45%.
1 (400MHz, CDCl
3) δ: 7.29 (t,
J=8.8Hz, 5H), 6.84 (s, 1H), 5.10 (s, 2H), 3.91 (d,
J=4.4Hz, 2H), 3.45-3.55 (m, 2H), 2.78-2.94 (m, 1H), 1.94-2.04 (m, 4H), 1.71-1.83 (m, 1H), 1.38 (s, 9H), 1.12-1.18 (m, 1H). Anal. Calcd. for C22H29F3N2O5 (MS [M+Na]
+: 481.1921), Measured Mass: 481.1907. error: -2.77 ppm。
Embodiment 3: 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
4Preparation
Operation steps:
1-hydroxyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-2,8-dicarboxylic acid-2-benzyl ester-8-tert-butyl ester
3(3.6 grams, 7.9 mmoles) are dissolved in the methyl alcohol (150 milliliters), add wet palladium carbon (0.45 gram, palladium content is ten Percent), and stirring reaction spends the night under 1 atmospheric hydrogen pressure.Reaction soln removes by filter palladium carbon, and mother liquor is concentrated, and silica gel column chromatography obtains 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
4, 0.44 gram, yield 18%.
1 (400MHz, CDCl
3): 3.77 (s, 2H), 2.89-3.19 (m, 5H), 1.70-1.81 (m, 5H), 1.57-1.62 (m, 2H), 1.39 (s, 9H). Anal. Calcd. for C14H23F3N2O2 (MS [M+H]
+: 309.1784), Measured Mass: 309.1784. error: -0.2 ppm。
Embodiment 4: 2-benzyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
I-aPreparation
In one 50 milliliters single port flask, add 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
4(50 milligrams, 0.16 mmole), (44 milligrams in salt of wormwood, 0.32 mmole) and the DMF(5 milliliter), then this reaction solution at room temperature stirs and spends the night, and reaction solution dilutes with ethyl acetate, washes with water two to three times, merge organic phase with anhydrous sodium sulfate drying after, filter, the concentrated thick product of yellow oily that to get.Thick product obtains 2-benzyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester through the silica-gel plate separation
I-a, 48 milligrams, yield 75%.
1 (400MHz, CDCl
3) δ: 7.23-7.33 (m, 5H), 4.15-4.19 (m, 1H), 3.63-3.74 (m, 3H), 2.97-3.11 (m, 4H), 2.51-2.58 (m, 2H), 1.72-1.89 (m, 3H), 1.56-1.59 (m, 1H), 1.35-1.43 (m, 11H). Anal. Calcd. for C21H30F3N2O2 (MS [M+H]
+: 399.2254), Measured Mass: 399.2259. error: 1.26 ppm。
Embodiment 5: 2-benzyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane
-aPreparation
In one 50 milliliters single port flask, add 2-benzyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
I-a(48 milligrams, 0.12 mmole) and hydrochloric ethyl acetate (5 milliliters), then this reaction solution at room temperature reacted 2 hours, and reaction solution concentrates to get 2-benzyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester hydrochloride
-a, 36 milligrams, yield 91%.
1 (400MHz, Methanol-d4) δ: 7.49-7.59 (m, 5H), 4.67-4.70 (m, 1H), 4.46-4.49 (m, 2H), 3.57-3.60 (m, 1H), 3.37-3.47 (m, 3H), 3.12-3.20 (m, 2H), 2.34-2.37 (m, 1H), 2.08-2.18 (m, 5H). Anal. Calcd. for C16H22F3N2 (MS [M+H]
+: 299.1730), Measured Mass: 299.1726. error: -1.07 ppm。
Embodiment 6: 2-benzoyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
I-bPreparation
In one 50 milliliters single port flask, add 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
4(50 milligrams, 0.16 mmole), Benzoyl chloride (34 milligrams, 0.24 mmole) and pyridine (3 milliliters), then this reaction solution at room temperature stirred 4 hours, and reaction solution concentrates to get oily crude product.Thick product obtains 2-benzoyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester through the silica-gel plate separation
I-b, 40 milligrams, yield 61%.
1 (400MHz, Methanol-d4) δ: 7.44-7.55 (m, 5H), 4.91-4.95 (m, 1H), 3.79-3.84 (m, 1H), 3.61-3.67 (m, 2H), 3.20-3.39 (m, 3H), 2.11-2.17 (m, 1H), 1.96-2.04 (m, 1H), 1.84-1.91 (m, 1H), 1.68-1.75 (m, 2H), 1.48-1.51 (m, 10H). Anal. Calcd. for C21H27F3N2NaO3 (MS [M+Na]
+: 435.1866), Measured Mass: 435.1847. error: -4.25 ppm。
Embodiment 7: 2-benzoyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane
-bPreparation
In one 50 milliliters single port flask, add 2-benzoyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
I-b(40 milligrams, 0.10 mmole) and hydrochloric ethyl acetate (5 milliliters), then this reaction solution at room temperature reacted 2 hours, and reaction solution concentrates to get 2-benzoyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane hydrochloride
-b, 29 milligrams, yield 87%.
1 (400MHz, Methanol-d4) δ: 7.46-7.57 (m, 5H), 5.02-5.04 (m, 1H), 3.85-3.90 (m, 1H), 3.41-3.43 (m, 1H), 3.12-3.30 (m, 3H), 2.09-2.19 (m, 3H), 1.71-2.00 (m, 3H). Anal. Calcd. for C16H20F3N2O (MS [M+H]
+: 313.1522), Measured Mass: 313.1522. error: -0.05ppm。
Embodiment 8: 2-(4-Methyl benzenesulfonyl base)-and 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
I-cPreparation
In one 50 milliliters single port flask, add 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
4(50 milligrams, 0.16 mmole), triethylamine (48 milligrams, 0.48 mmole) and methylene dichloride (5 milliliters), 0 ℃ of lower (36 milligrams of Tosyl chloride that add, 0.19 mmole), this reaction solution at room temperature stirred 4 hours, and concentration of reaction solution is dissolved in water (10 milliliters), ethyl acetate (3 * 5 milliliters) extraction, dry the concentrating of organic phase to get slightly product.Thick product obtains 2-(4-Methyl benzenesulfonyl base through the silica-gel plate separation)-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
I-c, 43 milligrams, yield 57%.
1 (400MHz, Methanol-d4) δ: 7.76 (d,
J=8.4Hz, 2H), 7.41 (d,
J=8.0Hz, 2H), 4.18-4.24 (m, 1H), 3.49-3.54 (m, 1H), 3.32-3.38 (m, 3H), 3.09-3.16 (m, 2H), 2.45 (s, 3H), 1.87-2.02 (m, 2H), 1.72-1.77 (m, 1H), 1.56-1.59 (m, 1H), 1.41 (s, 9H), 0.82-0.96 (m, 2H). Anal. Calcd. for C21H29F3N2O4 (MS [M+H]
+: 463.1873), Measured Mass: 463.1852. error: -4.45 ppm。
Embodiment 9: 2-(4-Methyl benzenesulfonyl base)-and 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane
-cPreparation
In one 50 milliliters single port flask, add 2-(4-Methyl benzenesulfonyl base)-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
I-c(43 milligrams, 0.09 mmole) and hydrochloric ethyl acetate (5 milliliters), then this reaction solution at room temperature reacted 2 hours, reaction solution concentrates to get 2-(4-Methyl benzenesulfonyl base)-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane hydrochloride
-c, 32 milligrams, yield 86%.
1 (400MHz, Methanol-d4) δ: 7.78 (d,
J=8.0Hz, 2H), 7.43 (d,
J=8.4Hz, 2H), 4.35-4.41 (m, 1H), 3.37-3.47 (m, 2H), 3.08-3.20 (m, 4H), 2.46 (s, 3H), 2.00-2.06 (m, 3H), 1.85-1.88 (m, 1H), 1.27-1.35 (m, 2H). Anal. Calcd. for C16H21F3N2O2 (MS [M+H]
+: 363.1349), Measured Mass: 363.1349. error: -0.00 ppm。
Embodiment 10: 2-ethylamino formyl radical-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
I-dPreparation
In one 50 milliliters single port flask, add 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
4(50 milligrams, 0.16 mmole), ethyl isocyanate (34 milligrams, 0.48 mmole) and tetrahydrofuran (THF) (5 milliliters), this reaction solution at room temperature stirs and spends the night, and concentration of reaction solution gets thick product.Thick product obtains 2-ethylamino formyl radical-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester through the silica-gel plate separation
I-d, 29 milligrams, yield 48%.
1 (400MHz, CDCl
3) δ: 4.31-4.38 (m, 1H), 4.24 (t,
J=4.8Hz, 1H), 3.44-3.51 (m, 2H), 3.30-3.38 (m, 3H), 3.18-3.28 (m, 3H), 1.95-2.00 (m, 2H), 1.76-1.81 (m, 1H), 1.18-1.51 (m, 12H), 1.08 (t,
J=7.2Hz, 3H). Anal. Calcd. for C17H28F3N3O3 (MS [M+H]
+: 380.2156), Measured Mass: 380.2147. error: -2.30 ppm。
Embodiment 11: 2-ethylamino formyl radical-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane
-dPreparation
In one 50 milliliters single port flask, add 2-ethylamino formyl radical-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
I-d(29 milligrams, 0.08 mmole) and hydrochloric ethyl acetate (5 milliliters), then this reaction solution at room temperature reacted 2 hours, and reaction solution concentrates to get 2-ethylamino formyl radical-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane hydrochloride
-d, 21 milligrams, yield 88%.
1 (400MHz, Methanol-d4) δ: 4.42-4.48 (m, 1H), 3.31-3.46 (m, 2H), 3.08-3.19 (m, 6H), 2.10-2.15 (m, 1H), 1.82-2.01 (m, 3H), 1.59-1.63 (m, 2H), 1.03 (t,
J=7.2Hz, 3H). Anal. Calcd. for C12H20F3N3O (MS [M+H]
+: 280.1631), Measured Mass: 280.1633. error: -0.61ppm。
Embodiment 12: 2-(4-fluorophenyl thiocarbamoyl)-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
I-ePreparation
In one 50 milliliters single port flask, add 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
4(50 milligrams, 0.16 mmole), to fluorophenyl lsothiocyanates (73 milligrams, 0.48 mmole) and tetrahydrofuran (THF) (5 milliliters), this reaction solution at room temperature stirs and spends the night, and concentration of reaction solution gets thick product.Thick product obtains 2-(4-fluorophenyl thiocarbamoyl)-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester through the silica-gel plate separation
I-e, 39 milligrams, yield 53%.
1 (400MHz, CDCl
3) δ: 7.21-7.27 (m, 2H), 7.02-7.07 (m, 2H), 5.47-5.50 (m, 1H), 3.62-3.77 (m, 2H), 3.44-3.54 (m, 2H), 3.32-3.39 (m, 2H), 2.45-2.56 (m, 4H), 2.09-2.16 (m, 2H), 1.85-1.87 (m, 1H), 1.55-1.70 (m, 2H), 1.44 (s, 9H). Anal. Calcd. for C21H27F4N3O2S (MS [M+Na]
+: 484.1652), Measured Mass: 462.1833. error: -3.90ppm。
Embodiment 13: 2-(4-fluorophenyl thiocarbamoyl)-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane
-ePreparation
In one 50 milliliters single port flask, add 2-(4-fluorophenyl thiocarbamoyl)-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester
I-e(39 milligrams, 0.08 mmole) and hydrochloric ethyl acetate (5 milliliters), then this reaction solution at room temperature reacted 2 hours, and reaction solution concentrates to get 2-(4-fluorophenyl thiocarbamoyl)-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane hydrochloride
-e, 31 milligrams, yield 93%.
1 (400MHz, Methanol-d4) δ: 7.32-7.36 (m, 2H), 7.04-7.08 (m, 2H), 5.78-5.82 (m, 1H), 3.80-3.91 (m, 2H), 3.18-3.27 (m, 4H), 2.11-2.35 (m, 3H), 1.73-2.00 (m, 3H). Anal. Calcd. for C16H19F4N3OS (MS [M+H]
+: 362.1309), Measured Mass: 362.1298. error: -3.03ppm。
In order to understand better essence of the present invention, the below is compound 4,
-a,
-e illustrates its new purposes in pharmacy field to the inhibiting the pharmacological results of tumor cell line A549 growth.
Embodiment 15:Compound 4,
-a,
-e is to the cytotoxic activity of human lung cancer cell A549's cell
A549(people's lung cancer) cell contains the foetal calf serum of quality percentage composition 10% with RPMI 1640 culture medium culturing in the substratum.Cell joins in 96 orifice plates with 2000 cells in every hole, contains volume percent 5%CO at 37 degrees centigrade
2Cultivated 24 hours in the incubator of damp atmosphere.
Cell is through after 24 hours hatch, with the compound of newly joining
1Dimethyl sulfoxide solution join in the hole, concentration is diluted to respectively 1.5 nmoles since 10 micromoles with three times extent of dilution, altogether 9 concentration.Contain volume percent 5%CO at 37 degrees centigrade
2Cultivate after 72 hours in the incubator of damp atmosphere and detect.
The mensuration of cell survival rate CTG method.First 96 orifice plates were taken out equilibrium at room temperature 30 minutes, every hole adds 50 microlitre CellTiter-Glo detection reagent (CellTiter-Glo luminescence method cell viability detection kits, CellTiter-Glo Luminescent Cell Viability Assay), light shaking 2 minutes, incubated at room made luminous signal stable in 10 minutes, selected the luminescence program to collect signal with noclilucence survey meter (Envision).Cell survival rate is by the ratio calculation of sample with respect to reference substance.
Compound
4Maximal percentage inhibition to the A549 cell is: 2%
Compound
-aMaximal percentage inhibition to the A549 cell is: 37.49%
Compound
-eMaximal percentage inhibition to the A549 cell is: 9.95%
Experiment conclusion: this experiment shows that this compounds has certain restraining effect to the growth of human lung cancer cell A549's cell, by further texture improvement and modification, potentially develops into the new medicine with antitumor action.
Claims (7)
1.1-trifluoromethyl-2,8-diaza-spiro [4.5] decane derivative, general structure is seen following formula:
Formula 1
R wherein
1Be to replace functional group or amino protecting group, be selected from H, C1 ~ C10 straight chain or contain a kind of in the benzyl, acyl group, alkylsulfonyl, urea, thiocarbamide of substituting group side chain; R
2Be hydrogen or carbalkoxy.
2. 1-trifluoromethyl-2 according to claim 1,8-diaza-spiro [4.5] decane derivative is characterized in that: work as R
2During for tertbutyloxycarbonyl, for the 1-trifluoromethyl-2 shown in the I replaces-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester derivative:
I
R wherein
1Be selected from a kind of in benzyl, acyl group, alkylsulfonyl, urea, the thiocarbamide.
3. 1-trifluoromethyl-2 according to claim 1,8-diaza-spiro [4.5] decane derivative is characterized in that: work as R
2During for hydrogen, for
Shown 1-trifluoromethyl-2-replaces-2,8-diaza-spiro [4.5] decane derivative:
R wherein
1Be selected from a kind of in benzyl, acyl group, alkylsulfonyl, urea, the thiocarbamide.
4. described 1-trifluoromethyl-2 according to claim 2,8-diaza-spiro [4.5] decane derivative is characterized in that: work as R
2During for tertbutyloxycarbonyl, described 1-trifluoromethyl-2 replaces-2,8-diaza-spiro [4.5], and decane-8-carboxylic acid tert-butyl ester derivative is a kind of in the following compound:
I-a:2-benzyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester;
I-b:2-benzoyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester;
I-c:2-(4-Methyl benzenesulfonyl base)-and 1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester;
I-d:2-ethylamino formyl radical-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester;
I-e:2-(4-fluorophenyl thiocarbamoyl)-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester.
5. described 1-trifluoromethyl-2 according to claim 3,8-diaza-spiro [4.5] decane derivative is characterized in that: work as R
2During for hydrogen, it is a kind of in the following compound that described 1-trifluoromethyl-2 replaces-2,8-diaza-spiro [4.5] decane derivative:
6. one kind prepares 1-trifluoromethyl-2 claimed in claim 1, the method for 8-diaza-spiro [4.5] decane derivative, and it is characterized in that: preparation process is as follows: adopt compound 1-carbonyl-2,8-diaza-spiro [4.5] decane
1Be raw material, protect to get 1-carbonyl-2 through carbobenzoxy-(Cbz), 8-diaza-spiro [4.5] decane-2-carboxylic acid-2-benzyl ester
2, compound
2Obtain 1-hydroxyl-1-trifluoromethyl-2,8-diaza-spiro [4.5] decane-2-carboxylic acid-2-benzyl ester through trifluoromethylation
3, compound
3Obtain 1-trifluoromethyl-2 through the hydrogenation deprotection, 8-diaza-spiro [4.5] decane
4Reaction formula is as follows:
。
7. preparation method according to claim 6 is characterized in that, compound
4Further obtain 1-trifluoromethyl-2 with benzyl bromine, Benzoyl chloride, Tosyl chloride, ethyl isocyanate, 4-fluorophenyl isocyanate reaction respectively and replace-2,8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester derivative
I-a ~ e, compound
I-a ~ E withThe hydrochloric ethyl acetate reaction is sloughed tertbutyloxycarbonyl and is got 1-trifluoromethyl-2 replacement-2,8-diaza-spiro [4.5] decane derivative
-a ~ e, reaction formula is as follows:
R wherein
1For a kind of in benzyl, benzoyl, p-toluenesulfonyl, ethylamino formyl radical, the 4-fluorophenyl thiocarbamoyl.
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| CN105017268A (en) * | 2014-04-16 | 2015-11-04 | 上海药明康德新药开发有限公司 | 2-tertbutyloxycarbonyl-7-carbonyl-5-O-2-azaspiro(3.4)octane synthesis method |
| CN109761979A (en) * | 2019-03-19 | 2019-05-17 | 中国医学科学院医药生物技术研究所 | A kind of diazaspiracyclic analog derivative and its preparation method and application of the substituent group of trifluoromethyl-phenyl containing 3- |
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| CN109761979B (en) * | 2019-03-19 | 2020-04-17 | 中国医学科学院医药生物技术研究所 | Diazaspiro ring derivative containing 3-trifluoromethyl-phenyl substituent and preparation method and application thereof |
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