CN109761932A - Phenothiazine compound and its application - Google Patents
Phenothiazine compound and its application Download PDFInfo
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- CN109761932A CN109761932A CN201910087336.9A CN201910087336A CN109761932A CN 109761932 A CN109761932 A CN 109761932A CN 201910087336 A CN201910087336 A CN 201910087336A CN 109761932 A CN109761932 A CN 109761932A
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Abstract
The present invention provides phenothiazine compound and its applications in the drug of preparation breast cancer and melanoma.Phenothiazine compound is higher than triperazine and thioridazine to the inhibitory activity of breast cancer cell MDA-MB-231, SUM159, MCF-7, SKBR-3 and melanoma cells A375, B16BL6, can be applied to treatment breast cancer and melanoma.Wherein, the general formula of phenothiazine compound are as follows:Wherein, R1ForR2For Wherein, n=1,2,3 or 4；X is O or N.
Description
Technical field
The present invention relates to phenothiazine compound and its applications.
Background technique
Phenothiazines are dopamine-receptor antagonists, are generally used for the mental disorders such as treatment schizophrenia.It grinds
Study carefully discovery, dopamine and dopamine receptor the Emergence and Development of cancer and in terms of have very close connection, with more
The mental patient of bar amine receptor antagonist pharmaceuticals suffers from the probability of the carcinoma of the rectum, colon cancer, prostate cancer significantly lower than normal population,
This shows that the generation of certain cancers has dopamine dependant, in addition studies have found that suffering from the Parkinson's disease of dopamine deficiency disease
Human cancer disease incidence is lower, confirms this viewpoint further.
But the anti-tumor activity of current phenothiazines does not protrude, this also restricts phenothiazine compound anti-
The further development of tumor area.Therefore the phenothiazine compound for synthesizing series is desirably to obtain anti-tumor activity preferably first
Compound is led, is highly desirable.
Summary of the invention
The present invention provides phenothiazine compound and its applications in the drug of preparation breast cancer and melanoma.
The present invention provides a kind of phenothiazine compound, the general formula of the phenothiazine compound are as follows:
Wherein, R1ForR2For
Wherein, n=1,2,3 or 4；X is O or N.
The present invention also provides application of the phenothiazine compound in the drug of preparation breast cancer and melanoma.
The present invention also provides the drug of a kind of anti-breast cancer and melanoma, including above-mentioned phenothiazine compound and its
Pharmaceutically acceptable salt and auxiliary material.
In above-mentioned anti-breast cancer and the drug of melanoma, wherein the pharmaceutically acceptable salt be organic salt or
Inorganic salts, organic salt are mesylate, formates, benzene sulfonate, toluenesulfonate, naphthalene sulfonate, lactate, acetate
Or benzoate, inorganic salts are hydrochloride, hydrobromate, sulfate or phosphate.
In above-mentioned anti-breast cancer and the drug of melanoma, wherein the anti-breast cancer and the drug of melanoma
Dosage form be selected from tablet, capsule, pill, suppository, aerosol, oral liquid, granule, powder, injection, syrup or
Their combination.
In above-mentioned anti-breast cancer and the drug of melanoma, wherein anti-breast cancer and the drug of melanoma are given
Prescription formula include take orally, inject, being implanted into, external application, spraying, sucking or their combination.
The phenothiazine compound of synthesis is to breast cancer cell MDA-MB-231, SUM159, MCF-7, SKBR-3 and black
Plain oncocyte A375, B16BL6 have inhibitory activity, and inhibitory activity is higher than triperazine and thioridazine, can be applied to
Treat breast cancer and melanoma.
Detailed description of the invention
Fig. 1 shows compound 5a's1H NMR。
Fig. 2 shows compound 5a's13CNMR。
Fig. 3 shows compound 5b's1HNMR。
Fig. 4 shows compound 5b's13C NMR。
Fig. 5 shows compound 5c's1H NMR。
Fig. 6 shows compound 5c's13C NMR。
Fig. 7 shows compound 6a's1H NMR。
Fig. 8 shows compound 6a's13C NMR。
Fig. 9 shows compound 6b's1H NMR。
Figure 10 shows compound 6b's13C NMR。
Figure 11 shows compound 6c's1H NMR。
Figure 12 shows compound 6c's13C NMR。
Figure 13 shows compound 11a's1H NMR。
Figure 14 shows compound 11a's13C NMR。
Figure 15 shows compound 11b's1H NMR。
Figure 16 shows compound 11b's13C NMR。
Figure 17 shows compound 11c's1H NMR。
Figure 18 shows compound 11c's13C NMR。
Figure 19 shows compound 12a's1H NMR。
Figure 20 shows compound 12a's13C NMR。
Figure 21 shows compound 12b's1H NMR。
Figure 22 shows compound 12b's13C NMR。
Figure 23 shows compound 12c's1H NMR。
Figure 24 shows compound 12c's13C NMR。
Figure 25 shows compound 20a's1H NMR。
Figure 26 shows compound 20a's13C NMR。
Figure 27 shows compound 20b's1H NMR。
Figure 28 shows compound 20b's13C NMR。
Figure 29 shows compound 20c's1H NMR。
Figure 30 shows compound 20c's13C NMR。
Figure 31 shows compound 21a's1H NMR。
Figure 32 shows compound 21a's13C NMR。
Figure 33 shows compound 21b's1H NMR。
Figure 34 shows compound 21b's13C NMR。
Figure 35 shows compound 21c's1H NMR。
Figure 36 shows compound 21c's13C NMR。
Figure 37 shows compound 22a's1H NMR。
Figure 38 shows compound 22a's13C NMR。
Figure 39 shows compound 22b's1H NMR。
Figure 40 shows compound 22b's13C NMR。
Figure 41 shows compound 22c's1H NMR。
Figure 42 shows compound 22c's13C NMR。
Figure 43 shows compound 23a's1H NMR。
Figure 44 shows compound 23a's13C NMR。
Figure 45 shows compound 23b's1H NMR。
Figure 46 shows compound 23b's13C NMR。
Figure 47 shows compound 23c's1H NMR。
Figure 48 shows compound 23c's13C NMR。
Figure 49 shows compound 29a's1H NMR。
Figure 50 shows compound 29a's13C NMR。
Figure 51 shows compound 29b's1H NMR。
Figure 52 shows compound 29b's13C NMR。
Figure 53 shows compound 29c's1H NMR。
Figure 54 shows compound 29c's13C NMR。
Figure 55 shows inhibition of the compound 5b-c to SUM159 cell.
Figure 56 shows the inhibition of compound 6a-c, 11b-c to SUM159 cell.
Figure 57 shows inhibition of the compound 20a-c to SUM159 cell.
Figure 58 shows inhibition of the compound 21a-c to SUM159 cell.
Figure 59 shows inhibition of the compound 22a-c to SUM159 cell.
Figure 60 shows inhibition of the compound 23a-c to SUM159 cell.
Figure 61 shows inhibition of the compound 29a-c to SUM159 cell.
Figure 62 shows inhibition of the compound 5b-c to MDA-MB-231 cell.
Figure 63 shows inhibition of the compound 6a-c to MDA-MB-231 cell.
Figure 64 shows inhibition of the compound 20a-c to MDA-MB-231 cell.
Figure 65 shows inhibition of the compound 21a-c to MDA-MB-231 cell.
Figure 66 shows inhibition of the compound 22a-c to MDA-MB-231 cell.
Figure 67 shows inhibition of the compound 23a-c to MDA-MB-231 cell.
Figure 68 shows inhibition of the compound 29a-c to MDA-MB-231 cell.
Figure 69 shows inhibition of the compound 5b-c to MCF-7 cell.
Figure 70 shows inhibition of the compound 6a-c to MCF-7 cell.
Figure 71 shows inhibition of the compound 20a-c to MCF-7 cell.
Figure 72 shows inhibition of the compound 21a-c to MCF-7 cell.
Figure 73 shows inhibition of the compound 22a-c to MCF-7 cell.
Figure 74 shows inhibition of the compound 23a-c to MCF-7 cell.
Figure 75 shows inhibition of the compound 29a-c to MCF-7 cell.
Figure 76 shows the inhibition of compound 5b-c, 6c to SKBR3 cell.
Figure 77 shows inhibition of the compound 20a-c to SKBR3 cell.
Figure 78 shows inhibition of the compound 21a-c to SKBR3 cell.
Figure 79 shows inhibition of the compound 22a-c to SKBR3 cell.
Figure 80 shows inhibition of the compound 23a-c to SKBR3 cell.
Figure 81 shows inhibition of the compound 29a-c to SKBR3 cell.
Figure 82 shows inhibition of the compound 5a-c to A375 cell.
Figure 83 shows inhibition of the compound 6a-c to A375 cell.
Figure 84 shows inhibition of the compound 11a-b to A375 cell.
Figure 85 shows inhibition of the compound 20a-c to A375 cell.
Figure 86 shows inhibition of the compound 21a-c to A375 cell.
Figure 87 shows inhibition of the compound 22a-c to A375 cell.
Figure 88 shows inhibition of the compound 23a-c to A375 cell.
Figure 89 shows inhibition of the compound 29a-c to A375 cell.
Figure 90 shows inhibition of the compound 5a-c to B16BL6 cell.
Figure 91 shows inhibition of the compound 6a-c to B16BL6 cell.
Figure 92 shows inhibition of the compound 11a-b to B16BL6 cell.
Figure 93 shows inhibition of the compound 20a-c to B16BL6 cell.
Figure 94 shows inhibition of the compound 21a-c to B16BL6 cell.
Figure 95 shows inhibition of the compound 22a-b to B16BL6 cell.
Figure 96 shows inhibition of the compound 23a-c to B16BL6 cell.
Figure 97 shows inhibition of the compound 29a-c to B16BL6 cell.
Specific embodiment
The following examples can make those skilled in the art that the present invention be more fully understood, but not limit in any way
The present invention.
The general formula of phenothiazine compound provided by the invention is as follows:
Wherein, R1ForR2For
Wherein, n=1,2,3 or 4；X=O or N.
The synthetic route and process of some phenothiazine compounds are described below.
Route one:
The synthesis of compound 3a-c:
The single necked round bottom flask of 50mL is taken, is added sodium hydride (400mg, 60%, 10.04mmol), compound 1a-c
(5.02mmol) is injected 12mL dimethyl amide (DMF), is stirred at room temperature 30-60 minutes under the protection of argon gas.Then will
Reaction system is placed at 0 DEG C, and the compound 2 (1.58g, 10.04mmol) for being dissolved in 3mL DMF is slowly injected into system, is continued
1h (if reaction is not exclusively, displaceable to react at room temperature) is reacted at 0 DEG C.Thin-layer chromatography (TLC) monitors after the reaction was completed, will be anti-
It answers liquid to pour into the separatory funnel for filling suitable quantity of water, is extracted with dichloromethane three times, anhydrous Na2SO4It dries, filters, decompression rotation
It is dry, it crosses column purification (PE), obtains compound 3a-c.
Compound 3a: white solid, 51%.1H NMR(400MHz,CDCl3):δ7.23-7.14(m,4H),7.01-
6.88 (m, 4H), 4.12 (t, J=6.5Hz, 2H), 3.70 (t, J=6.1Hz, 2H), 2.32-2.22 (m, 2H).
Compound 3b: white solid, 57%.1H NMR(400MHz,CDCl3):δ7.32-7.16(m,4H),7.12(s,
1H), 7.06-6.88 (m, 2H), 4.14 (t, J=6.5Hz, 2H), 3.63 (dt, J=5.85,6.1Hz, 2H), 2.45-2.20
(m,2H)。
Compound 3c: white solid, 77%.1H NMR(600MHz,CDCl3):δ7.19-7.16(m,2H),7.07(d,J
=7.8Hz, 1H), 6.95 (td, J=7.6,1.0Hz, 1H), 6.91 (d, J=8.1Hz, 1H), 6.85 (dd, J=8.0J,
1.8Hz, 1H), 6.83 (d, J=1.7Hz, 1H), 4.08 (t, J=6.5Hz, 2H), 3.67 (t, J=6.1Hz, 2H), 2.47 (s,
3H),2.26-2.22(m,2H)。
The synthesis of compound 5a-c:
Take the single necked round bottom flask of 25mL, compound 3 (1.09mmol) be dissolved in 5mL DMF at normal temperature, successively plus
Enter diethanol amine (172mg, 1.64mmol), triethylamine (331mg, 3.27mmol), potassium iodide (362mg, 2.18mmol), later
2h or so will be reacted under the conditions of 80 DEG C of the oil bath of reaction system dislocation, TLC is monitored to reaction and completed.Reaction solution is poured into and is filled in right amount
In the separatory funnel of water, it is extracted with dichloromethane three times, anhydrous Na2SO4It dries, filters, decompression is spin-dried for, and is crossed column purification, is obtained oily
Object 5a-c.
Compound 5a: colorless oil, 69%.1H NMR(400MHz,CDCl3)δ7.21-7.12(m,4H),6.96-6.88
(m, 4H), 3.99 (t, J=6.2Hz, 2H), 3.55 (t, J=5.2Hz, 4H), 2.70 (t, J=6.8Hz, 2H), 2.59 (t, J=
5.2Hz, 4H), 2.45-2.34 (m, 2H), 1.96 (p, J=6.5Hz, 2H)；13C NMR(100MHz,CDCl3)δ145.32,
127.72,127.46,125.64,122.77,115.83,59.62,55.88,51.45,44.01,24.24。
Compound 5b: colorless oil, 68%.1H NMR(600MHz,CDCl3)δ7.23-7.15(m,4H),7.06(s,
1H), 6.99-6.92 (m, 2H), 4.00 (t, J=6.3Hz, 2H), 3.56 (t, J=5.2Hz, 4H), 2.72 (t, J=6.9Hz,
2H), 2.61 (t, J=5.2Hz, 4H), 2.54 (s, 2H), 1.97 (q, J=6.6Hz, 2H)；13C NMR(150MHz,CDCl3)δ
(145.71,144.56,130.46,129.75 q, J=32.4Hz), 127.88,127.79,127.71,124.52,124.26
(d, J=270.3Hz), 123.39,119.32 (q, J=3.5Hz), 116.16,112.20 (q, J=3.6Hz), 59.64,
55.87,51.54,44.52,24.16。
Compound 5c: faint yellow oily, 72%.1H NMR(600MHz,CDCl3)δ7.19-7.13(m,2H),7.06(d,
J=7.8Hz, 1H), 6.95-6.89 (m, 2H), 6.85-6.80 (m, 2H), 3.96 (t, J=6.2Hz, 2H), 3.53 (t, J=
5.2Hz, 4H), 2.67 (t, J=6.8Hz, 2H), 2.57 (t, J=5.0Hz, 6H), 2.46 (s, 3H), 1.93 (p, J=6.5Hz,
2H)；13C NMR(150MHz,CDCl3)δ145.77,145.02,137.84,127.79,127.70,127.50,125.69,
122.92,122.57,120.95,116.03,114.83,59.61,55.90,51.50,44.20,24.23,16.52。
The synthesis of compound 6a-c:
The single necked round bottom flask for taking 10mL, by sodium hydride (52mg, 60%；1.3mmol；Dry tetrahydrofuran can be used in advance
(THF) wash twice, wash away its surface oil impurities) it is suspended in the dry THF of 1.5mL, under protection of argon gas, system is set
It is slowly injected into the compound 5 (0.44mmol) for being dissolved in 1mL THF at 0 DEG C, then reaction system is placed under room temperature and stirs 1h.
Then reaction system is placed at 0 DEG C again and is slowly injected into dimethyl suflfate (127mg, 1.0mmol；It can be by sulfuric acid when reacting a large amount of
Dimethyl ester is injected or is added dropwise after being diluted with THF), normal-temperature reaction is overnight, and TLC monitoring reaction is completed.It removes THF solvent under reduced pressure, adds
Enter suitable quantity of water, water phase is extracted with dichloromethane three times, anhydrous Na2SO4It dries, filters, decompression is spin-dried for, and is crossed column purification and is obtained grease
6a-c。
Compound 6a: light yellow oil, 88%.1H NMR(600MHz,CDCl3)δ7.18-7.11(m,4H),6.93-
6.88 (m, 4H) J, 3.93 (t, J=6.6Hz, 2H), 3.39 (t, J=6.0Hz, 4H), 3.26 (s, 6H), 2.70 (t, J=
6.1Hz, 6H), 1.95 (p, J=6.8Hz, 2H)；13C NMR(150MHz,CDCl3)δ145.29,127.44,127.25,
125.22,122.44,115.65,70.80,58.80,54.10,52.12,44.72,24.35。
Compound 6b: colorless oil, 60%.1H NMR(600MHz,CDCl3)δ7.22-7.10(m,4H),7.06(d,
J=1.6Hz, 1H), 6.97-6.90 (m, 2H), 3.96 (t, J=6.6Hz, 2H), 3.38 (t, J=6.0Hz, 4H), 3.26 (s,
6H), 2.68 (t, J=6.2Hz, 6H), 1.93 (p, J=6.5Hz, 2H)；13C NMR(100MHz,CDCl3)δ145.96,
(144.50,130.17,129.73 q, J=32.1Hz), 127.78,127.66,127.56,124.31 (d, J=270.6Hz),
(124.28,123.21,119.13 q, J=3.8Hz), 116.17,112.11 (q, J=3.7Hz), 71.01,58.88,54.20,
52.09,44.91,24.48。
Compound 6c: light yellow oil, 69%.1H NMR (600MHz, CDCl3) δ 7.14 (dd, J=15.2,
7.5Hz, 2H), 7.04 (d, J=7.9Hz, 1H), 6.93-6.88 (m, 2H), 6.84-6.79 (m, 2H), 3.93 (t, J=
6.5Hz, 2H), 3.43 (t, J=5.9Hz, 4H), 3.25 (s, 6H), 2.77 (s, 6H), 2.46 (s, 3H), 2.05-1.93 (m,
2H)；13C NMR(151MHz,CDCl3)δ145.85,144.94,137.78,127.66,127.57,127.41,125.56,
122.79,122.47,121.01,116.05,114.84,70.28,58.90,54.07,52.15,44.80,29.80,16.56。
Route two:
The synthesis of compound 8a-c:
The single necked round bottom flask of 25mL is taken, compound 3a-c (1.07mmol) is dissolved in 5mL DMF at normal temperature, successively
It is added piperazine (184mg, 2.14mmol), triethylamine (325mg, 3.21mmol), potassium iodide (355mg, 2.14mmol), later will
2h or so, TLC monitoring reaction to completion are reacted under the conditions of 80 DEG C of reaction system dislocation oil bath.Reaction solution is poured into and fills suitable quantity of water
Separatory funnel in, be extracted with dichloromethane three times, anhydrous Na2SO4It dries, filters, decompression is spin-dried for, and is crossed column purification, is obtained chemical combination
Object 8a-c.
Compound 8a: white solid, 71%.1H NMR(400MHz,CDCl3):δ7.18-7.07(m,4H),6.95-
6.83 (m, 4H), 3.91 (t, J=6.9Hz, 2H), 2.83 (t, J=4.8Hz, 4H), 2.49-2.28 (m, 6H), 2.06 (s,
1H),1.98-1.88(m,2H)。
Compound 8b: light yellow oil, 74%.1H NMR(400MHz,CDCl3):δ7.22-7.07(m,4H),7.03
(s, 1H), 6.98-6.84 (m, 2H), 3.96 (t, J=6.7Hz, 2H), 2.97-2.84 (m, 4H), 2.48 (m, 6H), 1.97-
1.85(m,2H)。
Compound 8c: light yellow oil, 72%.1H NMR(600MHz,CDCl3)δ7.15-7.08(m,2H),7.04-
7.00 (m, 1H), 6.92-6.86 (m, 2H), 6.80 (dd, J=7.4,1.4Hz, 2H), 3.90 (t, J=6.7Hz, 2H), 2.86-
2.80 (t, 4H), 2.48-2.29 (m, 9H), 1.93 (p, J=7.0Hz, 2H), 1.66 (s, 1H)
The synthesis of compound 11a-c:
The single necked round bottom flask of 50mL is taken, at normal temperature successively by compound 9 (500mg, 1.84mmol), paraformaldehyde
(82.7mg, 2.75mmol) and compound 8a-c (716mg, 2.20mmol) are dissolved in 10mL ethyl alcohol, later move reaction system
It sets and carries out reaction 6h or so at 45 DEG C of oil bath, TLC is monitored to reaction and completed.Then by ethyl acetate (60mL) and dilute HCl
(60mL, pH=3), which is added in reaction system, to be sufficiently mixed, after water phase pH is adjusted to 7 three times with EA extraction, anhydrous Na2SO4
It dries, filters, decompression is spin-dried for, and is crossed column purification, is obtained compound 11a-c.
Compound 11a: white solid, 33%.1H NMR(400MHz,CDCl3)δ12.44(s,1H),9.86(s,2H),
7.27 (s, 1H), 7.25 (s, 1H), 7.12 (td, J=7.7,6.6,1.7Hz, 4H), 6.93-6.79 (m, 6H), 5.94 (s,
1H), 5.27 (dd, J=12.8,3.0Hz, 1H), 3.91 (t, J=6.6Hz, 2H), 3.77 (s, 2H), 3.10-2.11 (m,
12H), 1.95 (p, J=6.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ195.82,169.53,162.59,161.42,
156.90,145.19,130.02,128.05,127.61,127.34,125.35,122.65,115.85,115.66,101.77,
99.76,96.39,78.87,55.16,53.02,52.50,51.96,44.98,43.02,24.06。
Compound 11b: white solid, 38%.1H NMR(400MHz,CDCl3)δ12.42(s,1H),10.27(s,2H),
7.26 (s, 1H), 7.24 (s, 1H), 7.19-7.08 (m, 4H), 7.03 (d, J=1.6Hz, 1H), 6.96-6.79 (m, 4H),
5.94 (s, 1H), 5.27 (dd, J=12.8,2.9Hz, 1H), 3.95 (t, J=6.6Hz, 2H), 3.78 (s, 2H), 3.12-2.09
(m, 12H), 1.94 (p, J=6.6Hz, 2H)；13C NMR(100MHz,CDCl3)δ195.78,169.76,162.62,161.43,
(156.95,145.65,144.21,130.18,129.84,129.56 q, J=32.2Hz), 128.02,127.73,127.67,
(127.60,124.24,124.20 d, J=270.6Hz), 123.28,119.19 (d, J=3.6Hz), 116.02,115.81,
111.98 (q, J=3.6Hz), 101.64,99.61,96.43,78.84,54.90,52.99,52.43,51.91,45.04,
42.92,23.82。
Compound 11c: white solid, 43%.1H NMR(600MHz,CDCl3)δ12.44(s,1H),7.53(s,2H),
7.27 (s, 1H), 7.26 (s, 1H), 7.12 (t, J=7.6Hz, 2H), 7.03 (d, J=8.0Hz, 1H), 6.90 (td, J=7.5,
1.1Hz, 1H), 6.87-6.76 (m, 5H), 5.93 (s, 1H), 5.31-5.24 (m, 1H), 3.91 (t, J=6.6Hz, 2H), 3.77
(s, 2H), 3.10-2.08 (m, 15H), 1.94 (p, J=6.8Hz, 2H)；13C NMR(150MHz,CDCl3)δ195.82,
169.36,162.59,161.46,156.72,145.73,144.90,137.70,130.28,128.05,127.74,127.64,
127.39,125.48,122.83,122.42,120.90,115.93,115.84,114.84,101.85,99.89,96.37,
78.88,55.14,53.00,52.58,52.06,45.06,43.09,24.10,16.56。
The synthesis of compound 12a-c:
The single necked round bottom flask of 50mL is taken, at normal temperature successively by compound 10 (500mg, 1.84mmol), paraformaldehyde
(82.7mg, 2.75mmol) and compound 8a-c (716mg, 2.20mmol) are dissolved in 10mL ethyl alcohol, later move reaction system
It sets and carries out reaction 6h or so at 45 DEG C of oil bath, TLC is monitored to reaction and completed.Then by ethyl acetate (60mL) and dilute HCl
(60mL, pH=3), which is added in reaction system, to be sufficiently mixed, after water phase pH is adjusted to 7 three times with EA extraction, anhydrous Na2SO4
It dries, filters, decompression is spin-dried for, and is crossed column purification, is obtained compound 12a-c.
Compound 12a: yellow solid, 71%.1H NMR(400MHz,CDCl3)δ12.72(s,1H),9.59(s,1H),
7.82-7.80(m,2H),7.58-7.51(m,3H),7.16-7.11(m,4H),6.91-6.87(m,4H),6.62(s,1H),
6.28 (s, 1H), 396-3.92 (m, 4H), 2.52 (t, J=7.0Hz, 10H), 1.95 (p, J=6.9Hz, 2H)；13C NMR
(100MHz,CDCl3)δ182.44,165.77,163.14,161.67,154.79,145.27,131.88,131.62,
129.27,127.57,127.28,126.16,125.30,122.56,115.62,105.89,104.78,100.31,98.46,
55.21,53.77,52.89,52.64,45.06,24.34。
Compound 12b: yellow solid, 60%.1H NMR(600MHz,CDCl3)δ12.72(s,1H),9.04(s,1H),
7.86-7.77(m,2H),7.59-7.50(m,3H),7.20-7.08(m,4H),7.07-7.04(m,1H),6.96-6.88(m,
2H), 6.63 (s, 1H), 6.27 (s, 1H), 3.99 (t, J=6.6Hz, 2H), 3.95 (s, 2H), 2.54 (t, J=6.7Hz,
10H), 1.94 (p, J=6.7Hz, 2H)；13C NMR(100MHz,CDCl3)δ182.48,165.79,163.19,161.70,
(154.81,145.93,144.17,131.91,131.61,130.87,129.60 q, J=32.2Hz), 129.28,127.74,
(127.71,127.54,126.17,124.34 d, J=270.5Hz), 124.20,123.28,119.06 (q, J=3.8Hz),
(116.04,112.12 q, J=3.7Hz), 105.87,104.81,100.32,98.48,54.64,53.78,52.84,52.65,
44.97,24.05。
Compound 12c: yellow solid, 64%.1H NMR(400MHz,CDCl3)δ12.72(s,1H),9.48(s,1H),
7.85-7.78 (m, 2H), 7.58-7.49 (m, 3H), 7.17-7.08 (m, 2H), 7.02 (d, J=8.4Hz, 1H), 6.92-6.85
(m, 2H), 6.79 (td, J=4.1,1.7J Hz, 2H), 6.62 (s, 1H), 6.27 (s, 1H), 3.96 (s, 2H), 3.93 (t, J=
6.6Hz, 2H), 2.47 (d, J=31.0Hz, 13H), 1.93 (p, J=6.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ
182.43,165.77,163.14,161.66,154.78,145.72,144.88,137.58,131.87,131.60,129.26,
127.65,127.56,127.30,126.16,125.36,122.70,122.29,120.80,115.85,114.80,105.86,
104.77,100.30,98.46,55.08,53.76,52.87,52.60,45.04,24.27,16.53。
Route three:
The synthesis of compound 15:
250mL single necked round bottom flask is taken, compound 13 (12.0g, 71.30mmol) is dissolved in 48mL glacial acetic acid, 30%
Hydrogenperoxide steam generator (18mL) is added into reaction system, and stirring at normal temperature 2.5h, TLC monitoring reaction obtains compound to completion
14 solution.Above-mentioned solution is placed at 0 DEG C, fuming nitric aicd (30mL, 95%) is added dropwise and in 0 DEG C of stirring 5min, then
Reaction is placed at 110~110 DEG C of oil bath the 2h that flows back.Then reaction system is cooled to room temperature, pours into 0 DEG C or so of distilled water
In, there are a large amount of white-yellowish solids to be precipitated, filtering is obtained white solid with a large amount of distillations water washing solid (until cleaning solution pH=7)
Body compound 15 (7.30g, 56%).1H NMR(600MHz,DMSO-d6)δ8.13-8.10(m,2H),7.97-7.89(m,
4H),7.81-7.77(m,2H),7.76-7.73(m,2H)。
The synthesis of compound 17a-d:
50mL single necked round bottom flask is taken, compound 15 (500mg, 1.37mmol) is dissolved in about 14mL tetrahydrofuran, room
It sequentially adds compound 16 (2.74mmol), 50%NaOH (110mg, 2.74mmol), feeds into reaction system under the conditions of temperature
After the reaction was continued about 2 hours, TLC monitoring reaction to complete.It directly removes THF under reduced pressure after completion of the reaction, appropriate steam is added
Distilled water and methylene chloride, liquid separation continue to be extracted with dichloromethane water phase twice, merge organic phase, anhydrous Na 2SO4 is dry, mistake
Filter is concentrated under reduced pressure.Crude product obtains compound 17 by column chromatographic isolation and purification.
Compound 17a: white solid, 72%.1H NMR (600MHz, CDCl3) δ 8.06 (dd, J=8.5,1.3Hz,
2H), 7.78-7.74 (m, 1H), 7.62 (dd, J=8.4,7.4Hz, 2H), 4.48 (t, J=6.3Hz, 2H), 3.76 (t, J=
6.2Hz,2H),2.03-1.97(m,2H),1.79-1.73(m,2H),1.61(s,1H)。
Compound 17b: white solid, 87%.1H NMR(600MHz,CDCl3)δ8.08-8.06(m,2H),7.79-
7.75 (m, 1H), 7.63 (dd, J=8.5,7.4Hz, 2H), 4.57-4.53 (m, 2H), 4.06-4.03 (m, 2H), 2.10 (s,
1H)。
Compound 17c: white solid, 87%.1H NMR(600MHz,CDCl3)δ8.10-8.05(m,2H),7.80-
(7.74 m, 1H), 7.66-7.60 (m, 2H), 5.11 (t, J=1.8Hz, 2H), 4.35 (t, J=1.8Hz, 2H), 1.72 (s,
1H)；13C NMR(100MHz,CDCl3)δ158.1,137.9,135.9,129.8,128.8,110.7,88.3,77.7,59.0,
51.1。
Compound 17d: white solid, 78%.1H NMR(600MHz,CDCl3)δ8.08-8.05(m,2H),7.7-7.74
(m, 1H), 7.62 (dd, J=8.5,7.4Hz, 2H), 4.60-4.56 (m, 2H), 3.95-3.93 (m, 2H), 3.79 (dd, J=
5.3,3.7Hz,2H),3.72-3.69(m,2H),1.98(s,1H)。
The synthesis of compound 19a-d:
10mL single necked round bottom flask is taken, compound 17a-d (0.91mmol) is dissolved in 5mL dry methylene chloride, room temperature
Under the conditions of sequentially added into reaction system 4-dimethylaminopyridine (DMAP) (56mg, 0.46mmol), succinic anhydride (109mg,
1.09mmol), charging, which finishes, is placed on the lower 40 DEG C of heating 5h of oil bath, TLC monitoring reaction to completion.Reaction solution is poured into water
Water phase is extracted with dichloromethane three times in (50mL), and anhydrous Na 2SO4 is dried, filtered, and is concentrated under reduced pressure, obtains crude Compound 19a-d,
It is directly entered in next step.
Route four:
The synthesis of compound 20a-c:
Under protection of argon gas, compound 19a (22.5mg, 0.07mmol) and 8a-c (0.07mmol) are dissolved in 2mL drying
Methylene chloride in, sequentially add DMAP (8.4mg, 0.07mmol), carbodiimides to reaction system under room temperature
(EDCI) (26.5mg, 0.134mmol), charging, which finishes to be placed on, to be stirred overnight at room temperature, TLC monitoring reaction to completion.It is added and steams
Distilled water (10mL) quenching reaction, is extracted with dichloromethane water phase three times, anhydrous Na2SO4It dries, filters, is concentrated under reduced pressure.Crude product is logical
Column chromatographic isolation and purification is crossed, compound 20a-c is obtained.
Compound 20a: light yellow oil, 80%.1H NMR(400MHz,CDCl3)δ8.06-8.04(m,2H),
7.77-7.73 (m, 1H), 7.64-7.60 (m, 2H), 7.14 (t, J=7.6Hz, 4H), 6.92-6.87 (m, 4H), 4.44 (t, J
=6.3Hz, 2H), 4.17 (t, J=6.3Hz, 2H), 3.95 (t, J=6.6Hz, 2H), 3.55 (s, 2H), 3.41 (s, 2H),
2.67-2.58 (m, 4H), 2.50 (t, J=6.9Hz, 2H), 2.39 (d, J=15.8Hz, 4H), 1.96 (dq, J=8.9,
6.5Hz,4H),1.86-1.78(m,2H).13C NMR(150MHz,CDCl3)δ173.24,169.59,159.04,145.29,
138.20,135.74,129.80,128.66,127.61,127.35,125.38,122.64,115.73,110.58,71.13,
63.82,55.33,53.32,52.81,45.18,44.97,41.73,29.34,27.93,25.35,25.10,24.17。
Compound 20b: light yellow oil, 73%.1H NMR(600MHz,CDCl3)δ8.07-8.01(m,2H),
7.77-7.71 (m, 1H), 7.64-7.58 (m, 2H), 7.21-7.07 (m, 4H), 7.03 (d, J=1.6Hz, 1H), 6.96-6.88
(m, 2H), 4.44 (t, J=6.3Hz, 2H), 4.17 (t, J=6.4Hz, 2H), 3.98 (t, J=6.7Hz, 2H), 3.53 (s,
2H), 3.40 (t, J=5.2Hz, 2H), 2.67-2.58 (m, 4H), 2.49 (t, J=6.8Hz, 2H), 2.38 (d, J=24.4Hz,
4H), 1.99-1.90 (m, 4H), 1.81 (dq, J=9.6,6.4Hz, 2H)13C NMR(150MHz,CDCl3)δ173.22,
169.55,159.02,145.75,144.37,138.17,135.72,130.16,129.78 129.67 (q, J=32.1Hz),
(128.62,127.77,127.68,127.59,124.25 d, J=270.3Hz), 124.23,123.28,119.16 (q, J=
3.5Hz), 116.06,112.04 (q, J=3.5Hz), 110.55,71.11,63.79,55.10,53.33,52.87,45.20,
45.10,41.72,29.32,27.92,25.32,25.08,23.96。
Compound 20c: light yellow oil, 83%.1H NMR(600MHz,CDCl3)δ8.08-8.00(m,2H),
7.76-7.70 (m, 1H), 7.64-7.57 (m, 2H), 7.15-7.08 (m, 2H), 7.02 (d, J=7.8Hz, 1H), 6.92-6.85
(m, 2H), 6.79 (d, J=7.8Hz, 2H), 4.43 (t, J=6.3Hz, 2H), 4.16 (t, J=6.3Hz, 2H), 3.93 (t, J=
6.7Hz, 2H), 3.59-3.47 (m, 2H), 3.40 (t, J=5.1Hz, 2H), 2.67-2.57 (m, 4H), 2.46 (t, J=
7.0Hz, 2H), 2.44 (s, 3H), 2.41-2.36 (m, 2H), 2.34 (t, J=5.0Hz, 2H), 1.98-1.88 (m, 4H), 1.81
(dq, J=9.6,6.4Hz, 2H)13C NMR(150MHz,CDCl3)δ173.18,169.50,158.90,145.66,144.92,
138.12,137.62,135.69,129.74,128.57,127.62,127.51,127.31,125.29,122.69,122.23,
120.78,115.86,114.77,110.50,71.07,63.74,55.24,53.34,52.83,45.24,44.99,41.76,
29.29,27.90,25.28,25.03,24.16,16.51。
The synthesis of compound 21a-c:
Under protection of argon gas, compound 19b (22.5mg, 0.07mmol) and 8a-c (0.07mmol) are dissolved in 2mL drying
Methylene chloride in, sequentially add DMAP (8.4mg, 0.07mmol), carbodiimides to reaction system under room temperature
(EDCI) (26.5mg, 0.134mmol), charging, which finishes to be placed on, to be stirred overnight at room temperature, TLC monitoring reaction to completion.It is added and steams
Distilled water (10mL) quenching reaction, is extracted with dichloromethane water phase three times, anhydrous Na2SO4It dries, filters, is concentrated under reduced pressure.Crude product is logical
Column chromatographic isolation and purification is crossed, compound 21a-c is obtained.
Compound 21a: light yellow solid, 70%.1H NMR(600MHz,CDCl3)δ8.09-8.00(m,2H),7.76-
7.70 (m, 1H), 7.64-7.58 (m, 2H), 7.17-7.06 (m, 4H), 6.89 (qd, J=7.8,1.1Hz, 4H), 4.60 (dd, J
=5.6,3.5Hz, 2H), 4.50 (dd, J=5.5,3.6Hz, 2H), 3.94 (t, J=6.7Hz, 2H), 3.57-3.46 (m, 2H),
3.39 (t, J=5.1Hz, 2H), 2.69 (t, J=6.9Hz, 2H), 2.63 (t, J=7.0Hz, 2H), 2.47 (t, J=6.9Hz,
2H), 2.36 (dt, J=21.4,5.1Hz, 4H), 1.92 (p, J=6.8Hz, 2H)13C NMR(150MHz,CDCl3)δ
172.90,169.33,158.71,145.23,138.06,135.73,129.75,128.63,127.49,127.28,125.18,
122.52,115.63,110.44,68.97,61.22,55.22,53.27,52.77,45.22,44.92,41.75,29.23,
27.90,24.20。
Compound 21b: light yellow solid, 63%.1H NMR(600MHz,CDCl3)δ8.08-8.02(m,2H),7.77-
7.71 (m, 1H), 7.65-7.57 (m, 2H), 7.20-7.08 (m, 4H), 7.03 (d, J=1.7Hz, 1H), 6.96-6.89 (m,
2H), 4.64-4.59 (m, 2H), 4.51 (dd, J=5.5,3.6Hz, 2H), 3.98 (t, J=6.6Hz, 2H), 3.58-3.46 (m,
2H), 3.39 (t, J=5.0Hz, 2H), 2.70 (t, J=6.2Hz, 2H), 2.63 (t, J=7.0Hz, 2H), 2.48 (t, J=
6.8Hz, 2H), 2.36 (dt, J=22.9,5.1Hz, 4H), 1.92 (p, J=6.7Hz, 2H)13C NMR(150MHz,CDCl3)δ
172.95,169.37,158.76,145.75,144.39,138.12,135.76,130.13 129.76 (q, J=32.1Hz),
(129.79,128.69,127.76,127.67,127.58,124.26 d, J=272.5Hz), 124.20,123.25,119.15
(q, J=3.5Hz), 116.05,112.03 (q, J=3.5Hz), 110.49,69.01,61.26,55.09,53.34,52.88,
45.25,45.10,41.79,29.27,27.94,24.01。
Compound 21c: light yellow solid, 55%.1H NMR (600MHz, CDCl3) δ 8.05 (dq, J=8.6,1.3Hz,
2H), 7.74 (tt, J=7.4,1.4Hz, 1H), 7.65-7.58 (m, 2H), 7.15-7.08 (m, 2H), 7.03 (dd, J=7.8,
1.6Hz,1H),6.92-6.86(m,2H),6.82-6.78(m,2H),4.63-4.59(m,2H),4.53-4.48(m,2H),
3.93 (t, J=6.7Hz, 2H), 3.53 (s, 2H), 3.40 (t, J=4.9Hz, 2H), 2.69 (t, J=6.7Hz, 2H), 2.63
(t, J=6.4Hz, 2H), 2.49-2.43 (m, 5H), 2.36 (dt, J=21.1,5.0Hz, 4H), 1.91 (p, J=6.8Hz,
2H).13C NMR(150MHz,CDCl3)δ172.94,169.34,158.75,145.70,144.97,138.12,137.64,
135.75,129.78,128.68,127.65 127.54,127.33,125.31,122.70,122.28,120.82,115.88,
114.81,110.48,69.00,61.25,55.26,53.37,52.86,45.29,45.04,41.83,29.27,27.95,
24.22,16.55。
The synthesis of compound 22a-c:
Under protection of argon gas, compound 19c (22.5mg, 0.07mmol) and 8a-c (0.07mmol) are dissolved in 2mL drying
Methylene chloride in, sequentially add DMAP (8.4mg, 0.07mmol), carbodiimides to reaction system under room temperature
(EDCI) (26.5mg, 0.134mmol), charging, which finishes to be placed on, to be stirred overnight at room temperature, TLC monitoring reaction to completion.It is added and steams
Distilled water (10mL) quenching reaction, is extracted with dichloromethane water phase three times, anhydrous Na2SO4It dries, filters, is concentrated under reduced pressure.Crude product is logical
Column chromatographic isolation and purification is crossed, compound 22a-c is obtained.
Compound 22a: light yellow solid, 68%.1H NMR(600MHz,CDCl3)δ8.09-8.03(m,2H),7.77-
7.72 (m, 1H), 7.62 (t, J=7.9Hz, 2H), 7.17-7.07 (m, 4H), 6.92-6.85 (m, 4H), 5.08 (t, J=
1.8Hz, 2H), 4.75 (t, J=1.8Hz, 2H), 3.94 (t, J=6.7Hz, 2H), 3.53 (d, J=5.4Hz, 2H), 3.38 (t,
J=5.1Hz, 2H), 2.68 (t, J=6.6Hz, 2H), 2.60 (t, J=6.6Hz, 2H), 2.47 (t, J=6.9Hz, 2H), 2.36
(dt, J=21.6,5.0Hz, 4H), 1.93 (p, J=6.8Hz, 2H)13C NMR(150MHz,CDCl3)δ172.38,169.25,
157.99,145.26,137.89,135.82,129.80,128.70,127.53,127.29,125.22,122.54,115.65,
110.63,84.14,78.58,58.72,55.25,53.31,52.80,52.06,45.28,44.94,41.83,29.11,
27.82,24.26。
Compound 22b: light yellow oil, 66%.1H NMR(600MHz,CDCl3)δ8.11-8.01(m,2H),7.75
(td, J=7.5,1.5Hz, 1H), 7.66-7.58 (m, 2H), 7.22-7.07 (m, 4H), 7.03 (d, J=1.6Hz, 1H),
6.96-6.88 (m, 2H), 5.08 (t, J=1.7Hz, 2H), 4.74 (t, J=1.7Hz, 2H), 3.98 (t, J=6.6Hz, 2H),
3.53 (s, 2H), 3.39 (t, J=5.0Hz, 2H), 2.69 (t, J=6.6Hz, 2H), 2.61 (t, J=6.6Hz, 2H), 2.49
(t, J=6.8Hz, 2H), 2.38 (dt, J=24.3,5.3Hz, 4H), 1.93 (p, J=6.7Hz, 2H)13C NMR(150MHz,
CDCl3) δ 172.38,169.28,158.01,145.74,144.37,137.94,135.82,130.14,129.65 (q, J=
33.2Hz), 129.81,128.72,127.76,127.67,127.58,124.25 (d, J=272.5Hz), 124.21,
123.26,119.15 (q, J=3.5Hz), 116.06,112.03 (q, J=3.5Hz), 110.65,84.16,78.60,58.74,
55.08,53.33,52.86,52.07,45.22,45.09,41.77,29.12,27.82,23.98。
Compound 22c: light yellow solid, 81%.1H NMR(600MHz,CDCl3)δ8.08-8.01(m,2H),7.73
(td, J=7.4,1.3Hz, 1H), 7.63-7.58 (m, 2H), 7.15-7.06 (m, 2H), 7.01 (d, J=7.8Hz, 1H),
6.91-6.85 (m, 2H), 6.79 (d, J=7.7Hz, 2H), 5.07 (t, J=1.8Hz, 2H), 4.74 (t, J=1.8Hz, 2H),
3.92 (t, J=6.6Hz, 2H), 3.54 (d, J=5.4Hz, 2H), 3.39 (t, J=5.0Hz, 2H), 2.67 (t, J=6.6Hz,
2H), 2.60 (t, J=6.6Hz, 2H), 2.44 (s, 5H), 2.36 (dt, J=22.6,5.1Hz, 4H), 1.91 (p, J=6.8Hz,
2H).13C NMR(150MHz,CDCl3)δ172.30,169.20,157.95,145.62,144.88,137.86,137.60,
135.77,129.75,128.63,127.59,127.47,127.29,125.23,122.65,122.17,120.74,115.84,
114.72,110.59,84.11,78.56,58.69,55.18,53.27,52.77,52.00,45.19,44.96,41.75,
29.07,27.76,24.11,16.46。
The synthesis of compound 23a-c:
Under protection of argon gas, compound 19d (22.5mg, 0.07mmol) and 8a-c (0.07mmol) are dissolved in 2mL drying
Methylene chloride in, sequentially add DMAP (8.4mg, 0.07mmol), carbodiimides to reaction system under room temperature
(EDCI) (26.5mg, 0.134mmol), charging, which finishes to be placed on, to be stirred overnight at room temperature, TLC monitoring reaction to completion.It is added and steams
Distilled water (10mL) quenching reaction, is extracted with dichloromethane water phase three times, anhydrous Na2SO4It dries, filters, is concentrated under reduced pressure.Crude product is logical
Column chromatographic isolation and purification is crossed, compound 23a-c is obtained.
Compound 23a: light yellow oil, 77%.1H NMR(600MHz,CDCl3)δ8.08-8.02(m,2H),
7.76-7.71(m,1H),7.63-7.57(m,2H),7.15-7.10(m,4H),6.91-6.86(m,4H),4.57-4.52(m,
2H), 4.30-4.25 (m, 2H), 3.94 (t, J=6.7Hz, 2H), 3.91-3.88 (m, 2H), 3.80-3.75 (m, 2H), 3.56-
3.48 (m, 2H), 3.38 (t, J=5.0Hz, 2H), 2.67 (t, J=6.8Hz, 2H), 2.59 (t, J=6.4Hz, 2H), 2.47
(t, J=7.0Hz, 2H), 2.35 (dt, J=19.9,5.0Hz, 4H), 1.92 (p, J=6.8Hz, 2H)13C NMR(100MHz,
CDCl3)δ173.19,169.51,158.99,145.27,138.17,135.72,129.76,128.64,127.53,127.30,
125.25,122.55,115.66,110.54,70.63,69.50,68.42,63.61,55.27,53.32,52.82,45.26,
44.97,41.77,29.26,27.90,24.26。
Compound 23b: light yellow oil, 63%.1H NMR(600MHz,CDCl3)δ8.08-8.00(m,2H),7.73
(t, J=7.4Hz, 1H), 7.60 (t, J=7.7Hz, 2H), 7.18-7.08 (m, 4H), 7.02 (d, J=1.6Hz, 1H), 6.95-
6.88 (m, 2H), 4.59-4.51 (m, 2H), 4.31-4.24 (m, 2H), 3.97 (t, J=6.6Hz, 2H), 3.89 (dd, J=
5.5,3.6Hz, 2H), 3.80-3.74 (m, 2H), 3.50 (t, J=5.1Hz, 2H), 3.37 (t, J=5.0Hz, 2H), 2.66 (t,
J=6.6Hz, 2H), 2.59 (t, J=6.6Hz, 2H), 2.46 (t, J=6.8Hz, 2H), 2.34 (dt, J=22.2,5.0Hz,
4H), 1.90 (p, J=6.7Hz, 2H)13C NMR(150MHz,CDCl3)δ173.15,169.45,158.95,145.69,
(144.31,138.10,135.69,130.07,129.73,129.57 q, J=32.4Hz), 128.59,127.72,127.60,
127.52,124.21 (d, J=270.3Hz), 124.11,123.20,119.08 (q, J=3.8Hz), 116.00,111.97 (q,
), J=3.8Hz 110.49,70.59,69.45,68.37,63.58,55.03,53.28,52.83,45.18,4 5.04,41.69,
29.21,27.84,23.94。
Compound 23c: light yellow oil, 79%.1H NMR(600MHz,CDCl3)δ8.07-8.01(m,2H),
7.76-7.69 (m, 1H), 7.63-7.56 (m, 2H), 7.14-7.08 (m, 2H), 7.01 (dd, J=7.7,1.7Hz, 1H),
6.91-6.85 (m, 2H), 6.78 (dd, J=7.5,1.6Hz, 2H), 4.53 (td, J=4.3,1.9Hz, 2H), 4.30-4.24
(m, 2H), 3.94-3.86 (m, 4H), 3.77 (dt, J=5.5,2.6Hz, 2H), 3.56-3.47 (m, 2H), 3.41-3.34 (m,
2H), 2.66 (t, J=6.6Hz, 2H), 2.59 (t, J=6.6Hz, 2H), 2.47-2.42 (m, 5H), 2.34 (dt, J=20.3,
5.0Hz, 4H), 1.90 (p, J=6.8Hz, 2H)13C NMR(150MHz,CDCl3)δ173.13,169.44,158.93,
145.63,144.89,138.09,137.60,135.68,129.72,128.58,127.59,127.47,127.29,125.23,
122.65,122.16,120.73,115.83,114.71,110.48,70.58,69.43,68.36,63.56,55.20,
53.29,52.80,45.19,44.97,41.71,29.21,27.84,24.13,16.46。
Route five:
The synthesis of compound 25:
Under ice-water bath, compound 24 (5.0g, 82mmol) and sodium hydroxide (17.0g, 400mmol) are dissolved in 550mL
In the mixed solution of Isosorbide-5-Nitrae-dioxane and water (Isosorbide-5-Nitrae-dioxane: water=10:1), di-tert-butyl dicarbonate (19.6g,
It 90mmol) is slowly dropped in reaction system, is reacted at 0 DEG C about 2 hours, TLC monitoring reaction to completion.Then it is added
5% aqueous potassium hydrogen sulfate quenching reaction of 500mL, ethyl acetate aqueous phase extracted three times, merge organic phase and with water and be saturated chlorine
Change sodium solution successively to wash, anhydrous Na2SO4It dries, filters, is concentrated under reduced pressure.Crude product is obtained faint yellow by column chromatographic isolation and purification
Oily compound 25 (12.1mg, 91%)1H NMR (600MHz, DMSO-d6) δ 6.95 (t, J=6.3Hz, 1H), 3.95 (t, J
=5.7Hz, 2H), 3.14 (q, J=5.7Hz, 2H), 1.41 (s, 9H).
The synthesis of compound 26:
10mL single necked round bottom flask is taken, compound 15 (100mg, 0.27mmol) is dissolved in about 3mL tetrahydrofuran, room temperature
Under the conditions of sequentially added into reaction system compound 25 (181mg, 1.09mmol), 50%NaOH (22mg, 0.55mmol) adds
The reaction was continued after material about 2 hours, TLC monitoring reaction to completion.It directly removes THF under reduced pressure after completion of the reaction, is added appropriate
Distilled water and methylene chloride, liquid separation continue to be extracted with dichloromethane water phase twice, merge organic phase, anhydrous Na2SO4It is dry, mistake
Filter is concentrated under reduced pressure.Crude product is isolated and purified by column chromatography (PE:EA=7:1), obtains compound as white solid 26 (70mg, 66%).1H
NMR(600MHz,CDCl3)δ8.12-8.03(m,2H),7.79-7.74(m,1H),7.67-7.59(m,2H),4.97(s,1H),
4.47 (t, J=5.1Hz, 2H), 3.61 (q, J=5.5Hz, 2H), 1.46 (s, 9H)13C NMR(150MHz,CDCl3)δ
158.89,155.84,138.00,135.80,129.90,128.68,110.54,80.06,70.92,39.47,28.47。
The synthesis of compound 27:
Under ice-water bath, compound 26 (60mg, 0.16mmol) is dissolved in 1.5mL methylene chloride, three second are sequentially added
Base silane (75mg, 0.64mmol), 0.5mL trifluoroacetic acid, 1.5 hours after the reaction was continued after charging, TLC monitoring reaction is extremely
It completes.Saturated sodium bicarbonate solution quenching reaction is added at 0 DEG C after completion of the reaction, adjusts pH value to 8 or so, then uses dichloromethane
Alkane extracts three times, merges organic phase, anhydrous Na2SO4It dries, filters, decompression is spin-dried for, and obtains crude white solid chemical compound 27, directly
Into in next step.
The synthesis of compound 28:
10mL single necked round bottom flask is taken, compound 27 (184mg, 0.65mmol) is dissolved in 3mL dry methylene chloride, room
It sequentially adds DMAP (39mg, 0.32mmol), succinic anhydride (77mg, 0.77mmol), feeds into reaction system under the conditions of temperature
It finishes and is placed on oil bath lower 40 DEG C of heating 5 hours, TLC monitoring reaction to completion.Reaction solution is poured into water (50mL/mmol),
Water phase is extracted with dichloromethane three times, anhydrous Na2SO4It dries, filters, is concentrated under reduced pressure.Compound as white solid 28, directly into
Enter in next step.
The synthesis of compound 29a:
Under protection of argon gas, compound 28 (47mg, 0.12mmol) and 8a (40mg, 0.12mmol) are dissolved in 2mL drying
Methylene chloride in, sequentially added DMAP (15mg, 0.12mmol) to reaction system under room temperature, EDCI (47mg,
0.25mmol), charging, which finishes to be placed on, is stirred overnight at room temperature, TLC monitoring reaction to completion.Distilled water (15mL) is added to be quenched instead
It answers, water phase is extracted with dichloromethane three times, anhydrous Na2SO4It dries, filters, is concentrated under reduced pressure.Crude product passes through column chromatographic isolation and purification,
It obtains yellow oil 29a (53mg, 62%).1H NMR (600MHz, CDCl3) δ 8.06 (d, J=7.9Hz, 2H), 7.73 (t, J
=7.5Hz, 1H), 7.61 (t, J=7.7Hz, 2H), 7.12 (td, J=8.0,7.6,2.2Hz, 4H), 6.91-6.81 (m, 5H),
4.47 (t, J=5.2Hz, 2H), 3.94 (t, J=6.6Hz, 2H), 3.69 (q, J=5.4Hz, 2H), 3.49 (s, 2H), 3.38
(t, J=5.1Hz, 2H), 2.64 (t, J=6.5Hz, 2H), 2.54 (t, J=6.5Hz, 2H), 2.48 (d, J=7.0Hz, 2H),
2.42-2.29 (m, 4H), 1.93 (p, J=6.9Hz, 2H)13C NMR(150MHz,CDCl3)δ173.14,170.24,
158.96,145.26,138.01,135.74,129.78,128.73,127.54,127.32,125.26,122.57,115.68,
110.59,70.32,55.23,53.22,52.75,45.24,44.94,41.72,38.21,31.45,28.69,24.19。
The synthesis of compound 29b-c:
Under protection of argon gas, compound 28 (68.0mg, 0.1765mmol) is dissolved in 2.5mL methylene chloride, successively plus
Enter diisopropylethylamine (DIPEA) (68.4mg, 0,5294mmol), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethyl
Base urea hexafluorophosphate (HATU) (80.5mg, 0.2118mmol) reacts at room temperature about 0.5 hour, and compound 8b-c is then added
(69.4mg, 0.1765mmol) the reaction was continued about 3 hours, TLC monitoring reaction to completion.Distilled water quenching reaction is added, with two
Chloromethanes extracts three times, merges organic phase, organic phase is washed with water and saturated sodium chloride solution later, anhydrous Na2SO4It is dry, mistake
Filter, decompression are spin-dried for.Crude product is isolated and purified by column chromatography (DCM:MeOH=50:1), obtains grease 29b-c.
Compound 29b: yellow oil, 50%.1H NMR (600MHz, CDCl3) δ 8.07 (d, J=7.6Hz, 2H),
7.77-7.70 (m, 1H), 7.61 (t, J=7.7Hz, 2H), 7.21-7.07 (m, 4H), 7.02 (d, J=1.7Hz, 1H), 6.96-
6.88 (m, 2H), 6.80 (d, J=6.3Hz, 1H), 4.47 (t, J=5.2Hz, 2H), 3.97 (t, J=6.6Hz, 2H), 3.70
(q, J=5.4Hz, 2H), 3.48 (s, 2H), 3.38 (s, 2H), 2.65 (t, J=6.5Hz, 2H), 2.55 (t, J=6.5Hz,
2H),2.51-2.23(m,6H),1.99-1.83(m,2H).13C NMR(100MHz,CDCl3)δ173.15,170.23,
(158.99,145.76,144.39,138.05,135.75,130.18,129.80,129.68 q, J=32.2Hz), 128.76,
(127.78,127.69,127.60,124.27 d, J=270.7Hz), 124.25,123.29,119.18 (q, J=3.7Hz),
(116.08,112.05 q, J=3.7Hz), 110.61,70.36,55.08,53.27,52.83,45.25,45.11,41.75,
38.23,31.49,28.71,23.98。
Compound 29c: yellow oil, 55%.1H NMR(600MHz,CDCl3)δ8.11-8.02(m,2H),7.74
(ddt, J=8.8,7.1,1.3Hz, 1H), 7.65-7.57 (m, 2H), 7.15-7.09 (m, 2H), 7.02 (d, J=7.8Hz,
1H), 6.92-6.85 (m, 2H), 6.84-6.77 (m, 3H), 4.47 (t, J=5.2Hz, 2H), 3.93 (t, J=6.7Hz, 2H),
3.70 (q, J=5.4Hz, 2H), 3.49 (s, 2H), 3.39 (t, J=5.0Hz, 2H), 2.65 (t, J=6.5Hz, 2H), 2.54
(t, J=6.5Hz, 2H), 2.44 (s, 5H), 2.35 (dt, J=26.8,5.6Hz, 4H), 1.91 (p, J=6.7Hz, 2H)13C
NMR(150MHz,CDCl3)δ173.13,170.21,158.95,145.68,144.94,137.99,137.65,135.75,
129.78,128.73,127.67,127.55,127.26,125.35,122.73,122.28,120.82,115.89,114.79,
110.58,70.32,55.23,53.24,52.79,45.22,45.00,41.71,38.20,31.45,28.69,24.12,
16.53。
Active testing
For the purchase of MTT powder in Sigma company, being configured to concentration with phosphate buffer (PBS) is 5 mg/mls
Solution is chosen 0.22 μm of filter membrane and is filtered, is then kept in dark place at 4 DEG C.MDA-MB-231 cell is purchased from triumphant base biology section
Skill Co., Ltd.Cell culture medium used in experiment is modified form RPMI-1640 (Kai Ji) basal medium, addition 10%
Fetal calf serum (lonsera).
MTT colorimetric method for determining cell activity include following several steps (by taking the test method of MDA-MB-231 cell as an example,
The test method of SUM159, MCF-7, SKBR-3, A375, B16BL6 cell is consistent with the method for MDA-MB-231 cell):
(1) the MDA-MB-231 cell for being in logarithmic growth phase is chosen, by every hole 3 × 103It is inoculated in 96 orifice plates, 5%CO2,
37 DEG C of incubation overnight incubations.
(2) dosing is provided with 6-9 concentration gradient in this experiment, as needed using different concentration gradients, Mei Genong
5 multiple holes are spent, while control group (not dosing only inoculating cell) and blank well (non-inoculating cell only adds culture medium) are set, 5%
CO2, 37 DEG C of incubators are incubated for 48 hours.
(3) every hole adds 20 μ L MTT solution (5mg/ml, i.e. 0.5%MTT), continues culture 4 hours.If drug with
MTT can react, and can first be centrifuged and discard culture solution afterwards, carefully rinse 2-3 after with PBS, add the culture solution containing MTT.
Culture is terminated after (4) 4 hours, carefully sucks the liquid in hole.And the dimethyl that 150 μ L are added to every hole is sub-
Sulfone.It is subsequently placed in low-speed oscillation 15min or so on shaking table, dissolves crystal sufficiently.Using enzyme-linked immunosorbent assay instrument
MULTISKAN FC (Thermo scientific) is measured at 490nm and the absorbance value in each hole 570nm, with blank when measurement
Hole is as zeroing hole.
(5) data are handled.Using drug concentration as abscissa, cell number is ordinate, with data processing software Graphpad
Software carries out probit weighted regression method (Bliss method) and carries out data processing, and mapping obtains IC50 value, is shown in Table 1.
1 compound of table is to MDA-MB-231, SUM159, MCF-7, SKBR-3, A375, the IC of B16BL6 cell50Value
By the data of the IC50 of table 1 it is found that the compound synthesized is to breast cancer cell MDA-MB-231, SUM159, MCF-
7, SKBR-3 and melanoma cells A375, B16BL6 have inhibitory activity, and inhibitory activity is higher than triperazine and sulphur benefit
Up to piperazine, treatment breast cancer and melanoma can be applied to.
It will be understood by those skilled in the art that above embodiments are only exemplary embodiments, without departing substantially from spirit herein
In the case where range, a variety of variations can be carried out, replaced and changed.
Claims (6)
1. a kind of phenothiazine compound, the general formula of the phenothiazine compound are as follows:
Wherein, R1ForR2For
Wherein, n=1,2,3 or 4；X is O or N.
2. application of the phenothiazine compound according to claim 1 in the drug of preparation breast cancer and melanoma.
3. the drug of a kind of anti-breast cancer and melanoma, including described in claim 1 phenothiazine compound and its
Pharmaceutically acceptable salt and auxiliary material.
4. the drug of anti-breast cancer according to claim 3 and melanoma, wherein the pharmaceutically acceptable salt is
Organic salt or inorganic salts, organic salt are mesylate, formates, benzene sulfonate, toluenesulfonate, naphthalene sulfonate, lactic acid
Salt, acetate or benzoate, inorganic salts are hydrochloride, hydrobromate, sulfate or phosphate.
5. the drug of anti-breast cancer according to claim 3 and melanoma, wherein the anti-breast cancer and melanoma
Drug dosage form be selected from tablet, capsule, pill, suppository, aerosol, oral liquid, granule, powder, injection,
Syrup or their combination.
6. the drug of anti-breast cancer according to claim 3 and melanoma, wherein the medicine of anti-breast cancer and melanoma
The administration mode of object include take orally, inject, being implanted into, external application, spraying, sucking or their combination.
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