CN104151262B - 4,5-bis-replaces-thiazolamine compound and preparation method thereof - Google Patents

Abstract

The invention discloses a 4,5-disubstituted-2-aminothiazole compound, the structural formula of which is: ; The R ¹ is 4-tolyl, 4-chlorophenyl, 4-methoxyphenyl, 4-nitrophenyl or propoxy, R ² is phenyl, 4-tolyl, 4-fluoro Phenyl, 4-methoxyphenyl, 2-furyl, isopropyl, 4-nitrophenyl or n-propyl. The present invention also simultaneously provides a preparation method for the above-mentioned 4,5-disubstituted-2-aminothiazole compound, comprising the following steps: preparing an alkene azide compound and potassium thiocyanate in the presence of a solvent and a metal catalyst at 75 to 85 ° C reaction, the obtained reaction solution was concentrated, extracted with water and ethyl acetate, the obtained organic layer was washed, dried, and concentrated by a rotary evaporator; the obtained concentrate was subjected to silica gel column chromatography to obtain 4,5-disubstituted- 2-aminothiazole compounds.

Description

4,5-disubstituted-2-aminothiazole compound and its preparation method

technical field

The invention belongs to a synthesis method of a compound, and mainly relates to a 4,5-disubstituted-2-aminothiazole compound and a preparation method thereof.

Background technique

Thiazole compounds are an important class of heterocyclic compounds, which have important applications in the fields of medicine, agriculture, materials, and life sciences. Aminothiazole compounds can undergo a series of reactions through the amino functional group, and the compounds thus synthesized have a wide range of applications in pesticides, dyes, etc., such as for the synthesis of herbicides, monoazo disperse dyes, etc. 2-aminothiazole compounds are widely used in the synthesis of drugs for the treatment of tumors, hypertension and other diseases.

Because of the important application value of 2-aminothiazole compound, its synthesis method has been widely concerned, and the most classic one is the thiazole synthesis method proposed by Hantzsch et al. (Hantzsch, A.; Weber, J.H.ChemischeBerichte.1887, 20, 3118) , it reacts with α-halogenated ketone or α-halogenated aldehyde and thiourea to obtain 2-aminothiazole compounds (Formula 1).

However, the Hantzsch thiazole synthesis method reacts under acidic conditions, adopts polar organic solvents, has a long reaction time, and the yield is not very satisfactory. Later generations have carried out a lot of improvement to synthetic method on the basis of Hantzsch, Biswanath etc. (Biswanath, D.; Reddy, VSJournalofMolecularCatalysisA:Chemical.2006,252,235.) react with heteropolyacid salt AMP as catalyst; Yadav etc. (Yadav, JS; Subba; Reddy, BV Tetraheron Letters. 2008, 49, 231) Cu(OTf) catalyzed reaction of α _- diazonone and thiourea.

In addition to the Hantzsch thiazole synthesis method and its improvement, Aoyama et al. (Aoyama, T.; Murata, S.; Arai, I. Tetrahedron, 2006,62,14) reported the use of α-halogenated ketones and KSCN/SiO ₂ -NH ₄ OAc/Al ₂ O ₃ supports a one-pot reaction to obtain 2-aminothiazole (Formula 2),; Pradip et al. (Pradip, KS; Chandrasekhar, A.; Sridhar, S.; Javed, I. 1) Intramolecular thia-Michael addition reaction between isothiocyanic acid and alkynyl amine with ester group to obtain aminothiazole compound (Formula 3).

Although there are many reports on the synthesis of 2-aminothiazole, the known synthesis methods still have problems such as difficult acquisition of raw materials, low product yield, poor applicability to different functional groups, and cumbersome operations. In addition, the above methods usually introduce an alkyl group, aryl group, hydrogen or alkoxy group at the 4-position of the thiazole ring, and there are few reports on the introduction of an acyl group or alkoxycarbonyl group at the 4-position of the thiazole ring.

The known method of introducing an acyl or alkoxycarbonyl group at the 4-position of the thiazole ring is usually to change the substrate α-halogenated ketone of the Hantzsch thiazole synthesis method into a 3-halogenated-1,2-propanedione compound, thereby in The 4th position of the thiazole ring introduces an acyl group (Raihan, MustafaJ. etal. Advanced Synthesis & Catalysis, 2012, 354, 2251), or the α-halogenated ketone is changed to a 3-halo-2-oxo-propionate compound in the thiazole ring 4 The introduction of alkoxycarbonyl (Roppe, JeffreyR; etal. WO2007117778), but the raw materials required for the synthesis are difficult to obtain, and the reaction needs to be carried out under high temperature reflux conditions.

Contents of the invention

The technical problem to be solved by the present invention is to provide a 4,5-disubstituted-2-aminothiazole compound and a preparation method thereof.

In order to solve the above technical problems, the present invention provides a 4,5-disubstituted-2-aminothiazole compound whose structural formula is:

The R is ⁴ -tolyl, 4-chlorophenyl, 4-methoxyphenyl, 4-nitrophenyl or propoxy,

R2 is phenyl, ⁴ -tolyl, 4-fluorophenyl, 4-methoxyphenyl, 2-furyl, isopropyl, 4-nitrophenyl or n-propyl.

As the improvement of the 4,5-disubstituted-2-aminothiazole compound of the present invention: it is any one of the following:

4-(4-Chlorobenzoyl)-5-phenyl-2-aminothiazole,

4-(4-Chlorobenzoyl)-5-(4-fluorophenyl)-2-aminothiazole,

4-(4-nitrobenzoyl)-5-(4-methoxyphenyl)-2-aminothiazole,

4-benzoyl-5-(2-furyl)-2-aminothiazole.

The present invention also provides a preparation method for the above-mentioned 4,5-disubstituted-2-aminothiazole compound, which includes the following steps in sequence:

1), react olefin azides and potassium thiocyanate at 75-85°C (preferably 80°C) in the presence of a solvent and a metal catalyst, and the reaction time is 11-13 hours (preferably 12 hours ); the molar ratio of olefin azides, potassium thiocyanate and metal catalyst is 2:4:1;

The structural formula of the olefin azides is:

Said R is phenyl, ⁴ -methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-nitrophenyl or propoxy,

R is phenyl, ⁴ -tolyl, 4-fluorophenyl, 4-methoxyphenyl, 2-furyl, isopropyl, 4-nitrophenyl or n-propyl;

Remarks: Generally speaking, 2.0-4.0ml of solvent is used for every 0.5mmol of olefin azide compound;

2), after the reaction solution obtained in step 1) is concentrated (that is, the solvent is removed), it is first cooled to room temperature (15-30° C.), then extracted with water and ethyl acetate, and the resulting organic layer (located on the upper layer) is washed (with Saturated brine), dried, and concentrated in a rotary evaporator (until there is basically no slip-out liquid);

3) Perform silica gel column chromatography on the concentrate obtained in step 2) to obtain 4,5-disubstituted-2-aminothiazole compound.

As an improvement to the preparation method of the 4,5-disubstituted-2-aminothiazole compound of the present invention: the metal catalyst is ferrous sulfate heptahydrate, ferric nitrate nonahydrate, and copper chloride.

As a further improvement of the preparation method of the 4,5-disubstituted-2-aminothiazole compound of the present invention:

Described solvent is polar solvent or non-polar solvent;

The polar solvent is n-propanol, 1,4-dioxane, N,N-dimethylformamide or nitromethane; the non-polar solvent is toluene.

As a further improvement of the preparation method of the 4,5-disubstituted-2-aminothiazole compound of the present invention: the silica gel column chromatography in step 3) is: the eluent is composed of petroleum ether:ethyl acetate=2:1 volume ratio mixed.

The inventor synthesized a 4,5-disubstituted-2-aminothiazole compound (as shown in formula 4) with a novel structure by using FeSO ₄ .7H ₂ O as a catalyst. The synthesis method has mild conditions, high yield and convenient post-treatment , the catalyst used is low in price and less polluted, and the raw materials used are easily available, which provides a simple and feasible method for efficiently synthesizing 4,5-disubstituted-2-aminothiazole compounds. In addition, this synthesis method introduces an acyl group or acyloxyacyl group at the 4-position of the thiazole ring, which provides the possibility for the construction of a compound library with novel structure and biological activity. At the same time, it is found that the synthesized compound has the activity of inhibiting tumor cells in vitro, which is helpful for the discovery of antitumor activity The lead compound of the present invention is of great significance, and the synthetic method of the present invention has not been reported in the literature.

Specifically, the present invention provides a new method for the synthesis of 4,5-disubstituted-2-aminothiazole compounds, that is, potassium thiocyanate, olefin azide compounds, metal catalysts (such as FeSO ₄ .7H ₂ O ) in a one-pot method at 75-85° C. (preferably 80° C.) for cyclization reaction to obtain the target compound 4,5-disubstituted-2-aminothiazole compound in high yield (the highest yield is 98%).

Furthermore, the synthetic route of the 4,5-disubstituted-2-aminothiazole compound provided by the present invention is shown in formula 5.

Wherein R ¹ is phenyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-nitrophenyl, propoxy, R ² is phenyl, 4-methylbenzene 4-fluorophenyl, 4-methoxyphenyl, 2-furyl, isopropyl, 4-nitrophenyl, n-propyl.

Olefin azide compound (I), potassium thiocyanate (II) and ferrous sulfate heptahydrate (III) are reacted at 75-85°C (preferably 80°C) in the presence of a solvent to obtain the target compound (IV). A polar solvent or a non-polar solvent is selected as the solvent, and the obtained product is subjected to silica gel column chromatography to obtain a pure compound.

The synthesis method of 4,5-disubstituted-2-aminothiazole compound provided by the invention has the following characteristics:

(1) The used catalyst of this method is cheap and easy to get, less to environmental pollution;

(2) The reaction temperature is mild, no high-temperature reflux is required, and it is safe and convenient;

(3) The yield is high, most of the product yields are above 85%.

Olefin azides are an important class of synthons, which are widely used in the synthesis of heterocyclic compounds. They have the characteristics of high reactivity and fast reaction speed, and the reactions that olefin azides participate in are generally mild. Therefore, the present invention uses potassium thiocyanate, ferrous sulfate heptahydrate and olefin azide compounds as raw materials to synthesize 4,5-disubstituted-2-aminothiazole compounds under mild conditions. This synthetic method is carried out at 75-85°C (preferably 80°C). The synthetic method is novel and has no literature reports; the synthesized compound has a novel structure and has no literature reports; the synthesized compound has in vitro tumor cell inhibitory activity, which is ideal. antitumor lead compounds.

In summary, the use of the 4,5-disubstituted-2-aminothiazole compound obtained in the present invention is an anti-tumor lead compound.

detailed description

The present invention will be further described below through embodiment.

Embodiment 1, 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole (m1)

Add 141.9 mg (0.5 mmol) of 1-p-chlorophenyl-2-azido-3-phenyl-2-propen-1-one and 97.2 mg (1 mmol) of potassium thiocyanate to the reaction flask, and then add CH ₃ CH ₂ CH ₂ OH (n-propanol) 2.0ml, ferrous sulfate heptahydrate 69.5mg (0.25mmol), after the addition, stirred at 80°C for 12 hours, TLC detection reaction (petroleum ether: ethyl acetate = 1 :1 volume ratio).

Remarks: When TLC detection shows that 1-p-chlorophenyl-2-azido-3-phenyl-2-propen-1-one disappears, it means that the reaction has ended.

After the reaction was completed, concentrate to remove n-propanol, cool to room temperature, add 60ml of water, and extract the reaction solution three times with 3×20mL ethyl acetate, and wash the organic layer (at the upper layer) with 3×30mL saturated brine three times after merging, and then use Anhydrous sodium sulfate (2.0g) was dried for 30 minutes, and concentrated by a rotary evaporator (until there was basically no slip-out liquid) to obtain a concentrate;

Concentrate column chromatography (petroleum ether: the volume ratio of ethyl acetate=2:1), the concrete process parameter of described column chromatography is as follows:

Select a silica gel column (200-300 mesh silica gel equipped with 30g) as the chromatographic column;

Use petroleum ether: ethyl acetate = 2:1 as the eluent; the flow rate is 3mL/min; collect the eluate from the 30th to the 40th minute; then remove the solvent (ie, the eluent) by a rotary evaporator to obtain The product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was 153.9 mg, and the yield was 98%.

The structural formula of this 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole is:

Yellowsolid; mp: 218.6-219.5℃; ¹ HNMR (500MHz, DMSO) δ7.87(d, J＝8.48, 2H), 7.54(d, J＝8.47, 2H), 7.39(s, 2H), 7.30-7.24 (m,5H); ¹³ CNMR(125MHz,DMSO)δ189.11,166.13,143.04,137.93,135.90,131.55,130.98,130.11,128.58,128.54,128.46,127.75; _HRMS (ESI):m/ _{zcalcdforC 16} H OS[M+H] ⁺ :315.0359,found:315.0359.

The following are control experiments under different conditions:

Comparative example 1-1, the stirring reaction at 80°C for 12 hours was changed to the stirring reaction at 20°C for 24 hours, and the rest were the same as in Example 1. 0 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, and the yield was 0%.

Comparative example 1-2, the stirring reaction at 80°C for 12 hours was changed to the stirring reaction at 60°C for 18 hours, and the rest were the same as in Example 1. 147.6 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 94%.

Comparative example 1-3, change the stirring reaction at 80°C for 12 hours to 100°C for 9 hours, and the rest are the same as in Example 1. 150.7 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 96%.

Comparative example 1-4, ferrous sulfate heptahydrate is changed into 0.1 equivalent by 0.5 equivalent, and all the other are the same as embodiment 1. 56.5 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 36%.

Comparative example 1-5, ferrous sulfate heptahydrate is changed into 0.3 equivalent by 0.5 equivalent, all the other are the same as embodiment 1. 131.9 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 84%.

Comparative example 1-6, ferrous sulfate heptahydrate is changed into 1 equivalent from 0.5 equivalent, all the other are the same as embodiment 1. 153.9 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 98%.

Comparative example 1-7, replace n-propanol with toluene, all the other are the same as embodiment 1. 138.2 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 88%.

Comparative Examples 1-8, using 1,4-dioxane instead of n-propanol, and the rest are the same as in Example 1. 149.2 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 95%.

Comparative example 1-9, replace n-propanol with water, all the other are the same as embodiment 1. 0 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, and the yield was 0%.

Comparative example 1-10, replace n-propanol with nitromethane, all the other are the same as embodiment 1. 146.0 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 93%.

Comparative example 1-11, DMF (N,N-dimethylformamide) was used instead of n-propanol, and the rest were the same as in Example 1. 138.2 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 88%.

Comparative Example 1-12, ferric nitrate nonahydrate was used to replace ferrous sulfate heptahydrate, the molar weight was constant, and the rest were the same as in Example 1. 44.0 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 28%.

Comparative example 1-13, replace ferrous sulfate heptahydrate with cuprous cyanide, the molar weight is constant, all the other are the same as embodiment 1. 0 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, and the yield was 0%.

Comparative example 1-14, replace ferrous sulfate heptahydrate with cupric chloride, the molar weight is constant, all the other are the same as embodiment 1. 65.9 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 42%.

Comparative example 1-15, cancel the use of catalyst, all the other are the same as embodiment 1. 0 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, and the yield was 0%.

Comparative example 1-16, change potassium thiocyanate from 2 equivalents to 1 equivalent, all the other are the same as embodiment 1. 130.3 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 83%.

Comparative example 1-17, change potassium thiocyanate from 2 equivalents to 3 equivalents, all the other are the same as embodiment 1. 153.9 mg of the product 4-(4-chlorobenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 98%.

Embodiment 2, 4-benzoyl-5-phenyl-2-aminothiazole (m2)

Replace 1-p-chlorophenyl-2-azido-3-phenyl-2-propen-1-one with 1-phenyl-2-azido-3-phenyl-2-propen-1-one, mol Quantity is constant, all the other are equal to embodiment 1. 128.8 mg of the product 4-benzoyl-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 92%.

Its structural formula is:

Yellowsolid; mp: 160.4-160.8℃; ¹ HNMR (500MHz, DMSO) δ7.84(d, J＝7.05, 2H), 7.59(t, J＝6.88, 1H), 7.47(d, J＝7.31, 2H) ,7.35-7.24(m,7H); ¹³ CNMR(125MHz,DMSO) _{δ190.76,166.14,143.60,137.12,133.12,131.11,129.66,128.99,128.56,128.39,128.35,127.69} ; HRMS(ESI) for m/ H ₁₂ N ₂ OS[M+H] ⁺ :281.0749,found:281.0748.

Example 3, 4-(4-methylbenzoyl)-5-phenyl-2-aminothiazole (m3)

Replace 1-p-chlorophenyl-2-azido-3-phenyl-2-propene-1-one with 1-p-methylphenyl-2-azido-3-phenyl-2-propene-1-one Ketone, molar weight is constant, all the other are equal to embodiment 1. 138.2 mg of the product 4-(4-methylbenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 94%.

Its structural formula is:

Yellowsolid; mp:189.4-189.9℃; ¹ HNMR (500MHz, DMSO) δ7.75(d, J=8.07, 2H), 7.33(s, 2H), 7.28-7.21(m, 7H), 2.35(s, 3H ); ¹³ CNMR (125MHz, DMSO) δ190.63, 166.21, 143.88, 143.74, 134.45, 131.18, 129.85, 128.98, 128.60, 128.19, 127.91, 127.47, 21.22; _HRMS (ESI): m/z2 H ₁₄ N ₁₇ M+H] ⁺ :295.0905, found: 295.0907.

Example 4, 4-(4-methoxybenzoyl)-5-phenyl-2-aminothiazole (m4)

Replace 1-p-chlorophenyl-2-azido-3-phenyl-2-propene-1 with 1-p-methoxyphenyl-2-azido-3-phenyl-2-propene-1-one -ketone, the molar weight is constant, and all the other are equal to embodiment 1. 139.5 mg of the product 4-(4-methoxybenzoyl)-5-phenyl-2-aminothiazole was obtained as a yellow solid, with a yield of 90%.

Its structural formula is:

Yellowsolid; mp: 220.5-220.9℃; ¹ HNMR (500MHz, DMSO) δ7.84(d, J=8.89, 2H), 7.35(s, 2H), 7.29-7.20(m, 5H), 7.00(d, J ＝8.92,2H),3.82(s,3H); ¹³ CNMR(125MHz,DMSO)δ189.66,166.25,163.32,144.08,132.15,131.25,129.64,128.61,128.05,127.36,127.10,113.76,55.5I6 :m/zcalcdforC ₁₇ H ₁₄ N ₂ O ₂ S[M+H] ⁺ :311.0854,found:311.0855.

Example 5, 4-(4-nitrobenzoyl)-5-(4-methylphenyl)-2-aminothiazole (m5)

Replace 1-p-chlorophenyl-2-azido-3-phenyl-2-propene with 1-p-nitrophenyl-2-azido-3-p-methylphenyl-2-propen-1-one -1-ketone, molar weight is constant, all the other are equal to embodiment 1. 142.4 mg of the product 4-(4-nitrobenzoyl)-5-(4-methylphenyl)-2-aminothiazole was obtained as a yellow solid, with a yield of 84%.

Its structural formula is:

Yellowsolid; mp: 190.4-190.9℃; ¹ HNMR (500MHz, DMSO) δ8.28(d, J＝8.87, 2H), 8.04(d, J＝8.88, 2H), 7.38(s, 2H), 7.26(d ,J=8.11,2H),7.13(d,J=7.96,2H),2.27(s,3H); ¹³ CNMR(125MHz,DMSO)δ188.33,165.66,149.38,143.02,142.05,137.71,133.11,130.81,129.05 , 128.88, 127.89, 123.29, 20.73; HRMS (ESI): m/zcalcdforC ₁₇ H ₁₃ N ₃ O ₃ S[M+H] ⁺ : 340.0756, found: 340.0758.

Example 6, 4-(4-chlorobenzoyl)-5-(4-fluorophenyl)-2-aminothiazole (m6)

Replace 1-p-chlorophenyl-2-azido-3-phenyl-2-propene-1 with 1-p-chlorophenyl-2-azido-3-p-fluorophenyl-2-propene-1-one -ketone, the molar weight is constant, and all the other are equal to embodiment 1. 152.7 mg of the product 4-(4-chlorobenzoyl)-5-(4-fluorophenyl)-2-aminothiazole was obtained as a pale yellow solid, with a yield of 92%.

Its structural formula is:

Paleyellowsolid; mp: 197.4-197.7℃; ¹ HNMR (500MHz, DMSO) δ7.87(d, J＝8.31, 2H), 7.54(d, J＝8.27, 2H), 7.40-7.35(m, 4H), 7.15 (t, J=8.65, 2H); ¹³ CNMR (125MHz, DMSO) δ188.71, 165.99, 162.61, 160.65, 143.12, 137.87, 135.99, 131.62, 130.93, 130.87, 129.54, 128.40, 127.443, 127.5 HR (ESI): m/z calcd for C ₁₆ H ₁₀ ClFN ₂ OS[M+H] ⁺ : 333.0265, found: 333.0264.

Example 7, 4-(4-nitrobenzoyl)-5-(4-methoxyphenyl)-2-aminothiazole (m7)

Substitute 1-p-nitrophenyl-2-azido-3-p-methoxyphenyl-2-propen-1-one for 1-p-chlorophenyl-2-azido-3-phenyl-2- Propylene-1-one, the molar weight is constant, all the other are equal to embodiment 1. 152.7 mg of the product 4-(4-nitrobenzoyl)-5-(4-methoxyphenyl)-2-aminothiazole was obtained as an orange solid, with a yield of 86%.

Its structural formula is:

Orangesolid; mp: 217.8-218.3℃; ¹ HNMR (500MHz, DMSO) δ8.27 (d, J=8.59, 2H), 8.03 (d, J=8.60, 2H), 7.33-7.32 (m, 4H), 6.89 (d, J=8.60, 2H), 3.74 (s, 3H); ¹³ CNMR (125MHz, DMSO) δ188.15, 165.27, 159.24, 149.29, 143.26, 141.69, 133.57, 130.79, 130.49, 123.23, 122.97, 113.90, 5; HRMS (ESI): m/z calcd for C ₁₇ H ₁₃ N ₃ O ₄ S [M+H] ⁺ : 356.0705, found: 356.0708.

Example 8, 4-(4-nitrobenzoyl)-5-phenyl-2-aminothiazole (m8)

Replace 1-p-chlorophenyl-2-azido-3-phenyl-2-propene-1-one with 1-p-nitrophenyl-2-azido-3-phenyl-2-propene-1-one Ketone, molar weight is constant, all the other are equal to embodiment 1. 130.0 mg of the product 4-(4-nitrobenzoyl)-5-phenyl-2-aminothiazole was obtained as a red solid, with a yield of 80%.

Its structural formula is:

Redsolid; mp: 215.3-215.8℃; ¹ HNMR (500MHz, DMSO) δ8.28(d, J=8.63, 2H), 8.04(d, J=8.60, 2H), 7.42(s, 2H), 7.37(d ,J＝6.89,2H),7.33-7.27(m,3H); ¹³ CNMR (125MHz,DMSO)δ188.41,166.00,149.44,142.90,142.40,132.73,130.87,130.82,129.01,128.53,128.13,123.3 ESI): m/z calcd for C ₁₆ H ₁₁ N ₃ O ₃ S[M+H] ⁺ : 326.0599, found: 326.0598.

Example 9, 4-benzoyl-5-(2-furyl)-2-aminothiazole (m9)

Replace 1-p-chlorophenyl-2-azido-3-phenyl-2-propene-1 with 1-phenyl-2-azido-3-(2-furyl)-2-propene-1-one -ketone, the molar weight is constant, and all the other are equal to embodiment 1. 120.2 mg of the product 4-benzoyl-5-(2-furyl)-2-aminothiazole was obtained as a brown solid, with a yield of 89%.

Its structural formula is:

Brownsolid; mp:115.4-115.8℃; ¹ HNMR (500MHz, DMSO) δ7.88(d, J=7.22,2H),7.67(d,J=0.99,1H),7.60(t,J=7.35,1H) ,7.50-7.47(m,4H),6.94(d,J=3.18,1H),6.53(d,J=1.51,1H); ¹³ CNMR(125MHz,DMSO)δ189.16,165.50,145.66,143.21,142.91,137.67 , 132.72, 129.67, 128.17, 120.91, 112.15, 109.53; HRMS (ESI): m/z calcd for C ₁₄ H ₁₀ N ₂ O ₂ S[M+H] ⁺ : 271.0541, found: 271.0542.

Example 10, 4-benzoyl-5-isopropyl-2-aminothiazole (m10)

Substituting 1-phenyl-2-azido-3-isopropyl-2-propen-1-one for 1-p-chlorophenyl-2-azido-3-phenyl-2-propen-1-one, Molar weight is constant, all the other are equal to embodiment 1. 114.4 mg of the product 4-benzoyl-5-isopropyl-2-aminothiazole was obtained as a pale yellow solid, with a yield of 93%.

Its structural formula is:

Paleyellowsolid; mp: 115.3-115.7℃; ¹ HNMR (500MHz, DMSO) δ7.90(d, J＝7.48, 2H), 7.57(t, J＝7.33, 1H), 7.47(t, J＝7.58, 2H) ,7.01(s,2H),3.71-3.63(m,1H),1.22(d,J=6.75,6H); ¹³ CNMR(125MHz,DMSO)δ189.22,163.74,145.40,142.51,138.67,132.12,129.68,127.91 , 27.09, 24.95; HRMS (ESI): m/zcalcdforC ₁₃ H ₁₄ N ₂ OS [M+H] ⁺ : 247.0905, found: 247.0905.

Example 11, 4-propoxycarbonyl-5-(4-methylphenyl)-2-aminothiazole (m11)

Replace 1-p-chlorophenyl-2-azido-3-phenyl-2-propen-1-one with 2-azido-3-p-methylphenyl-ethyl acrylate, the molar weight remains the same, and the rest are the same Example 1. 131.1 mg of the product 4-propoxycarbonyl-5-(4-methylphenyl)-2-aminothiazole was obtained as a white solid, with a yield of 95%.

Its structural formula is:

Whitesolid; mp: 123.9-124.3℃; ¹ HNMR (500MHz, DMSO) δ7.27(d, J＝7.89, 2H), 7.23(s, 2H), 7.17(d, J＝7.81, 2H), 3.99(t ,J=6.56,2H),2.31(s,3H),1.52-1.45(m,2H),0.74(t,J=7.37,3H); ¹³ CNMR(125MHz,DMSO)δ165.51,162.19,137.46,135.68, 132.46 ^{, 129.28, 128.65, 128.27, 65.61, 21.35, 20.77, 10.19; HRMS(ESI): m/zcalcdforC14H16N2O2S[M+H]+} _{: 277.1011 , found} :277.1015.

Example 12, 4-propoxycarbonyl-5-(4-nitrophenyl)-2-aminothiazole (m12)

Replace 1-p-chlorophenyl-2-azido-3-phenyl-2-propen-1-one with 2-azido-3-p-nitrophenyl-ethyl acrylate, the molar weight remains unchanged, and the rest are the same In Example 1. 145.9 mg of the product 4-propoxycarbonyl-5-(4-nitrophenyl)-2-aminothiazole was obtained as a yellow solid, with a yield of 83%.

Its structural formula is:

Yellowsolid; mp: 153.8-154.2℃; ¹ HNMR (500MHz, DMSO) δ8.21(d, J＝8.24, 2H), 7.67(d, J＝8.20, 2H), 7.55(s, 2H), 4.04(t ,J=5.97,2H),1.53-1.49(m,2H),0.74(t,J=7.02,3H); ¹³ CNMR(125MHz,DMSO)δ167.01,161.97,146.47,138.25,137.87,130.46,128.72,123.29 , 66.06, 21.26, 10.15; HRMS (ESI): m/zcalcdforC ₁₃ H ₁₃ N ₃ O ₄ S[M+H] ⁺ : 308.0705, found: 308.0707.

Example 13, 4-propoxycarbonyl-5-(4-methoxyphenyl)-2-aminothiazole (m13)

Replace 1-p-chlorophenyl-2-azido-3-phenyl-2-propen-1-one with 2-azido-3-p-methoxyphenyl-ethyl acrylate, the molar weight remains unchanged, and the rest Identical to Example 1. 138.7 mg of the product 4-propoxycarbonyl-5-(4-methoxyphenyl)-2-aminothiazole was obtained as a white solid, with a yield of 95%.

Its structural formula is:

Whitesolid; mp: 169.5-169.9℃; ¹ HNMR (500MHz, DMSO) δ7.32(d, J＝8.55, 2H), 7.21(s, 2H), 6.92(d, J＝8.61, 2H), 3.99(t ,J=6.58,2H),3.77(s,3H),1.53-1.46(m,2H),0.75(t,J=7.37,3H); ¹³ CNMR(125MHz,DMSO)δ165.19,162.14,159.12,135.33, 132.72, 130.78, 123.33, 113.54, 65.56, 55.20, 21.37, 10.23; HRMS (ESI): m/ _{zcalcdforC14H16N2O3S} [ _{M +} H] ⁺ : _293.0960 ,found:293.0963.

Example 14, 4-propoxycarbonyl-5-(2-furyl)-2-aminothiazole (m14)

Replace 1-p-chlorophenyl-2-azido-3-phenyl-2-propen-1-one with 2-azido-3-(2-furyl)-ethyl acrylate, the molar weight remains unchanged, and the rest Identical to Example 1. 113.4 mg of the product 4-propoxycarbonyl-5-(2-furyl)-2-aminothiazole was obtained as a brown solid, with a yield of 90%.

Its structural formula is:

Brownsolid; mp: 100.7-101.1℃; ¹ HNMR (500MHz, DMSO) δ7.70(s, 1H), 7.43(s, 2H), 7.12(d, J=3.30, 1H), 6.58(s, 1H), 4.13(t, J=6.71,2H),1.67-1.60(m,2H),0.89(t,J=7.37,3H); ¹³ CNMR(125MHz,DMSO)δ165.32,162.07,145.36,143.04,134.93,122.82, 112.28, 110.83, 65.92, 21.54, 10.30; HRMS (ESI): m/z calcd for C ₁₁ H ₁₂ N ₂ O ₃ S[M+H] ⁺ : 253.0647, found: 253.0647.

Example 15, 4-propoxycarbonyl-5-n-propyl-2-aminothiazole (m15)

Replace 1-p-chlorophenyl-2-azido-3-phenyl-2-propen-1-one with 2-azido-3-n-propyl-acrylic acid ethyl ester, the molar weight is unchanged, and the rest are equal to the implementation example 1. 102.6 mg of the product 4-propoxycarbonyl-5-n-propyl-2-aminothiazole was obtained as a white solid, with a yield of 90%.

Its structural formula is:

Whitesolid; mp:92.3-92.7℃; ¹ HNMR(500MHz,DMSO)δ7.00(s,2H),4.09(t,J=6.61,2H),2.93(t,J=7.51,2H),1.68-1.61 (m,2H),1.58-1.50(m,2H),0.93-0.88(m,6H); ¹³ CNMR(125MHz,DMSO)δ163.96,162.13,137.68,135.97,65.40,28.31,24.47,21.60,13.51,10.41 ; HRMS (ESI): m/z calcd for C ₁₀ H ₁₆ N ₂ O ₂ S [M+H] ⁺ : 229.1011, found: 229.1009.

Antitumor Activity Experiment

In the experiment, A431 (human epidermal carcinoma cell) was used as the test cell line, and the antitumor activity of the above compounds was evaluated by the MTT method. After the test compound was formulated into a certain concentration and co-incubated with the human cancer cell line, its inhibitory rate on the cancer cell line was measured, and the results are shown in Table 1.

The detection method is as follows:

1. Collect the A431 cells grown in the logarithmic phase, and adjust the concentration of the cell suspension to 1*10 ⁴ /well;

2. Add the compound so that the final concentration of the compound reaches 20umol/L;

3. Incubate at 37°C, 5% CO ₂ for 44 hours;

4. Add 20ul of MTT solution (5mg/ml, prepared in PBS, pH=7.4) to each well, and continue to incubate for 4 hours;

5. Centrifuge for 6 minutes, remove the supernatant, add 150ul of DMSO per well, shake the shaker at low speed for 10min, and measure the absorbance of each well at OD570nm (calibrated at 630nm) of an enzyme-linked immunosorbent assay instrument;

The formula for calculating the inhibition rate is: cell inhibition rate=1-(OD value of drug-dosed group-OD value of zero-adjusted well)/(OD value of control group-OD value of zero-adjusted well).

The inhibitory rate of table 1 compound to A431 tumor cell

compound Inhibition rate(%) compound Inhibition rate(%) m1 70 m9 67 m2 53 m10 32 m3 50 m11 20 m4 55 m12 twenty two m5 48 m13 27 m6 72 m14 30 m7 62 m15 10 m8 54 Gefitinib (comparison) 58

It can be seen from Table 1 that some compounds synthesized (m1, m6, m7, m9) have greater antitumor cell activity in vitro than the control substance gefitinib, which shows that the synthesized compounds are novel anti-tumor lead compounds. Modifications are expected to discover novel anti-tumor drug candidates.

Finally, it should be noted that the above examples are only some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and many variations are possible. All deformations that can be directly derived or associated by those skilled in the art from the content disclosed in the present invention should be considered as the protection scope of the present invention.

Claims (3)

1.4, the preparation method of 5-disubstituted-2-aminothiazole compound is characterized in that comprising the following steps in sequence: 1), react olefin azides and potassium thiocyanate at 75-85°C in the presence of a solvent and a metal catalyst, and the reaction time is 11-13 hours; olefin azides, potassium thiocyanate, metal The molar ratio of the catalyst is 2:4:1; The metal catalyst is ferrous sulfate heptahydrate, ferric nitrate nonahydrate or cupric chloride; The structural formula of the olefin azides is: Said R is phenyl, ⁴ -methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-nitrophenyl or propoxy, R is phenyl, ⁴ -tolyl, 4-fluorophenyl, 4-methoxyphenyl, 2-furyl, isopropyl, 4-nitrophenyl or n-propyl; 2), after the reaction solution obtained in step 1) was concentrated, extracted with water and ethyl acetate, the obtained organic layer was washed, dried, and concentrated by a rotary evaporator; 3), the concentrate obtained in step 2) is subjected to silica gel column chromatography to obtain a 4,5-disubstituted-2-aminothiazole compound; its structural formula is: 2. according to claim 1, the preparation method of 4,5-disubstituted-2-aminothiazole compound is characterized in that: Described solvent is polar solvent or non-polar solvent; The polar solvent is n-propanol, 1,4-dioxane, N,N-dimethylformamide or nitromethane; the non-polar solvent is toluene. 3. the preparation method of 4,5-disubstituted-2-aminothiazole compound according to claim 2, is characterized in that: the silica gel column chromatography of described step 3) is: The eluent was obtained by mixing petroleum ether:ethyl acetate=2:1 volume ratio.