WO2011132070A1 - Process for the preparation of 2-amino-substituted 1,3-benzothiazine-4-ones - Google Patents
Process for the preparation of 2-amino-substituted 1,3-benzothiazine-4-ones Download PDFInfo
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- WO2011132070A1 WO2011132070A1 PCT/IB2011/000877 IB2011000877W WO2011132070A1 WO 2011132070 A1 WO2011132070 A1 WO 2011132070A1 IB 2011000877 W IB2011000877 W IB 2011000877W WO 2011132070 A1 WO2011132070 A1 WO 2011132070A1
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- halogen
- alkyl
- benzothiazin
- benzothiazine
- nitro
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- 0 *c(cc12)cc(*)c1SC(S*)=NC2=O Chemical compound *c(cc12)cc(*)c1SC(S*)=NC2=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
Definitions
- the present invention relates to a novel process for the preparation of 2-aminosubstituted 1, 3 -benzothiazine-4 -ones, and to intermediates for use in this process.
- 2-Aminosubstituted 1 , 3 -benzothiazine-4 -ones can be used as drugs for the treatment of mammals diseases, for example, infectious diseases of mammals (humans and animals) caused by- bacteria, especially diseases like tuberculosis (TB) and leprosy caused by mycobacteria.
- mammals diseases for example, infectious diseases of mammals (humans and animals) caused by- bacteria, especially diseases like tuberculosis (TB) and leprosy caused by mycobacteria.
- Y is halogen
- R is independently selected from Ci_g-alkyl which may be selected from Ci_g-alkyl which may be selected from Ci_g-alkyl which may be selected from Ci_g-alkyl which may be selected from Ci_g-alkyl which may be selected from Ci_g-alkyl which may be selected from Ci_g-alkyl which may be selected from Ci_g-alkyl which may be selected from Ci_g-alkyl which may be selected from Ci_g-alkyl which may
- R4 is hydrogen or Ci_g-alkyl
- R 3 is C 1 . 3 -alkyl which may be substituted by halogen
- X is halogen; and n is 0 or an integer of 1 to 4 , and if n is 2, 3 or 4 , multiple Rs may be the same or different.
- the present invention provides a process for preparing 2- aminosubstituted 1 , 3 -benzothiazine-4 -ones which comprises the following step:
- Y is halogen, preferably chlorine
- R is independently selected from Cx-g-alkyl which may optionally be substituted by halogen, -N0 2 , halogen, -CHO, -COOR4 (wherein R4 is hydrogen or C ⁇ .g-alkyl) and -CN;
- R3 is Ci_3-alkyl which may be substituted by halogen, preferably methyl;
- X is halogen, preferably iodine; and n is 0 or an integer of 1 to 4 , and if n is 2, 3 or 4 , multiple Rs may be the same or different.
- the process comprises the following step:
- Y is halogen, preferably chlorine
- Rl is H, -CF3, -N0 2 , or halogen
- R2 is -COOR4 (wherein R4 is hydrogen or C ⁇ .g-alkyl.) , -CN, halogen, or -CF3;
- R3 is C -3-alkyl which may be substituted by halogen, preferably methyl
- Y is halogen, preferably iodine.
- the reaction is preferably carried out in the presence of a base, more preferably in the presence of an alkali metal hydroxide, most preferably in the presence of LiOH, NaOH or KOH.
- the alkali metal hydroxide is advantageously employed in a molar ratio of 1-4, particularly 2-2.5, based on the 2- halogenobenzamide derivative of formula (1) .
- Carbon disulfide (CS2) is suitably employed in a molar ratio of 1-10, preferably 2-5, based on the 2 -halogenobenzamide derivative of formula (1) .
- the alkylating agent R3-X is preferably CH3I or CH 2 l2- This alkylating agent is preferably employed in a molar ratio of 1-10, preferably 2-5, based on the 2 -halogenobenzamide derivative of formula (1) .
- the reaction may be conducted in an appropriate solvent.
- the reaction is conducted in DMSO.
- a suitable amine such as ammonia, a primary or secondary amine.
- the reaction according to the present invention can be used to prepare various 2-amino-l, 3 -benzothiazine-4 -ones .
- reaction with the amine can be depicted by the following scheme :
- R, R3 and n are as defined above;
- R 5 and RQ are independently selected from H, a saturated or unsaturated, linear, branched or cyclic aliphatic radical having 1-8 carbon atoms,
- Z is saturated or unsaturated, linear or branched aliphatic radical having 1-5 carbon atoms; W is 0, NH or N-C ⁇ .g-alkyl;
- R 7 and Rs are independently selected from H, Ci_g- alkyl, -OH, -OC 1 .5 -alkyl , halogen, or -CN; and Rg may together represent
- Rg and R]_g are H » Ci_3-alkyl
- Rll is H, a saturated or unsaturated, linear, branched or cyclic aliphatic radical having 1-8 carbon atoms, -OH, -OC ] __g-alkyl , phenyl, benzyl, benzoyl, halogen; and multiple R ⁇ s may be the same or different;
- Rj_2 1S methyl, benzyl, benzoyl or phenyl (which may be. substituted by C]__g-alkyl, -OH, -OCi_g-alkyl, halogen or -CN) ;
- n is an integer of 1-3;
- reaction with the amine can be depicted by the following scheme :
- R ⁇ , R 2 , 3 , R5 and Rg are as defined above.
- the reaction with the amine may be conducted in an
- the amine is preferably used in a molar ratio of 1-2,
- the 2-amino-l , 3 -benzothiazine- -ones may be further processed into a suitable pharmaceutical composition, e.g. by
- NMR spectra were determined with a Varian Unity Plus 400 (USA) . Shifts for NMR are reported in ppm downfield from TMS ( ⁇ ) .
- Mass spectra were obtained using a Finnigan SSQ-700 (USA) instrument with direct injection.
- reaction was conducted in a manner similar to method A, but the final product was crystallized from isopropanol.
- Compound 6 was prepared in the same manner as Example 5 but using 2 , 2-dimethyl-l, 4-dioxa-8-azaspiro [4.5] decane as the amine, and a light yellow crystalline solid was obtained.
- Compound 8 was prepared in the same manner as Example 5 but using 1- ( 2 -methoxyphenyl) piperazine as the amine, and a yellow crystalline solid was obtained.
- Compound 8 was prepared in the same manner as Example 5 but using thiomorpholine as the amine, and a light yellow crystalline solid was obtained.
- Compound 10 was prepared in the same manner as Example 5 but using 4 -hydroxypiperidine as the amine, and a light yellow crystalline solid was obtained.
- Compound 12 was prepared in the same manner as Example 11 but using 1 , 4 -dioxa- 8 -azaspiro [4.5] decane as amine, and a white crystalline solid was obtained. Yield: 36%
- Compound 15 was prepared in the same manner as Example 14 but using N-methyl-l-phenylmethanamine as the amine, and a white crystalline solid. was obtained.
Abstract
A process for preparing 2-aminosubstituted 1, 3 -benzothiazine- 4 -ones is provided which comprises the following step: Formula (I) wherein Y is halogen; R is independently selected from C1-6-alkyl which may optionally be substituted by halogen, -NO2, halogen, -CHO -COOR4 (wherein R4 is hydrogen or C1-6-alkyl) and -CN; R3 is C1-6-alkyl which may be substituted by halogen; X is halogen; and n is 0 or an integer of 1 to 4; if n is 2, 3 or 4, multiple Rs may be the same or different.
Description
00877
PROCESS FOR THE PREPARATION OF 2 -AMINO - SUBSTITUTED 1,3- BENZOTHIA INE - 4 - ONES
Technical Field
The present invention relates to a novel process for the preparation of 2-aminosubstituted 1, 3 -benzothiazine-4 -ones, and to intermediates for use in this process.
Background
2-Aminosubstituted 1 , 3 -benzothiazine-4 -ones can be used as drugs for the treatment of mammals diseases, for example, infectious diseases of mammals (humans and animals) caused by- bacteria, especially diseases like tuberculosis (TB) and leprosy caused by mycobacteria.
Specific 2-aminosubstituted 1, 3 -benzothiazine-4 -ones are disclosed e.g. i WO' 2007/134625 and WO 2009/010163.
Several methods for synthesis of 2-aminosubstituted 1,3 - benzothiazine-4 -ones are described in the prior art. These methods include:
1) the reaction of thiocyanate salts with 2-,· .
chlorobenzylchloroanhydride, and subsequent treatment of the reaction mass with the corresponding amine (see, for example, Coll. Czech. Chem. Commun. , 1982, 47, 3268-3282; Coll. Czech. Chem. Commun., 1983, 48 , .3315-3328 ; Coll. Czech. Chem.
Commun., 1983, 48, 3427-3432);
2) the condensation reaction of 3 , 4 -disubstituted-6- mercaptobenzoic acids with a suitable cyanamide (see US
3 , 522, 247) ;
3) the conversion of a 2-halogen- H-1, 3-benzothiazin-4-one with an appropriate amine (see US 3,470,168).
None of these methods allows for preparing 2-aminosubstituted 1, 3-benzothiazine-4-ones in an acceptable yield. In addition, the key intermediate of method 3, i.e. the 2-halogen- 1, 3-4H- benzothiazone, is not readily accessible.
Recent methods for preparing 2-aminosubstituted 1,3- benzothiazine-4-ones are described in WO 2007/134625 and WO 2009/010163 which disclose the following processes:
Method A Method B
However, these processes result in the formation of free hydrogen sulfide which can react with the starting materials and the final product, thereby giving rise to several byproducts .
However, the yield of this method is unsatisfactory, in particular for secondary amines .
In view of this background, it is highly desirable to provide a process for preparing 2-aminosubstituted 1, 3-benzothiazine- 4 -ones which results in a high yield and purity, and can easily be carried out.
Summary of the Invention
The above object is surprisingly solved by a process for preparing 2-aminosubstituted 1, 3-benzothiazine-4-ones which comprises the following step:
(1) (2) wherein
Y is halogen;
R is independently selected from Ci_g-alkyl which may
optionally be substituted by halogen, - O2, halogen, - -COOR4 (wherein R4 is hydrogen or Ci_g-alkyl) and -CN;
R3 is C1.3-alkyl which may be substituted by halogen;
X is halogen; and n is 0 or an integer of 1 to 4 , and if n is 2, 3 or 4 , multiple Rs may be the same or different.
Detailed Description of the Invention
The present invention provides a process for preparing 2- aminosubstituted 1 , 3 -benzothiazine-4 -ones which comprises the following step:
(1) (2) wherein
Y is halogen, preferably chlorine;
R is independently selected from Cx-g-alkyl which may optionally be substituted by halogen, -N02, halogen, -CHO, -COOR4 (wherein R4 is hydrogen or C^.g-alkyl) and -CN;
R3 is Ci_3-alkyl which may be substituted by halogen, preferably methyl;
X is halogen, preferably iodine; and n is 0 or an integer of 1 to 4 , and if n is 2, 3 or 4 , multiple Rs may be the same or different.
In a preferred embodiment of the present invention, the process comprises the following step:
(1a) (2a)
wherein
Y is halogen, preferably chlorine;
Rl is H, -CF3, -N02, or halogen;
R2 is -COOR4 (wherein R4 is hydrogen or C^.g-alkyl.) , -CN, halogen, or -CF3;
R3 is C -3-alkyl which may be substituted by halogen, preferably methyl; and
Y is halogen, preferably iodine.
The reaction is preferably carried out in the presence of a base, more preferably in the presence of an alkali metal hydroxide, most preferably in the presence of LiOH, NaOH or KOH. The alkali metal hydroxide is advantageously employed in a molar ratio of 1-4, particularly 2-2.5, based on the 2- halogenobenzamide derivative of formula (1) .
Carbon disulfide (CS2) is suitably employed in a molar ratio of 1-10, preferably 2-5, based on the 2 -halogenobenzamide derivative of formula (1) .
The alkylating agent R3-X is preferably CH3I or CH2l2- This alkylating agent is preferably employed in a molar ratio of 1-10, preferably 2-5, based on the 2 -halogenobenzamide derivative of formula (1) .
The reaction may be conducted in an appropriate solvent.
Preferably, the reaction is conducted in DMSO.
When preparing 2-aminosubstituted 1, 3 -benzothiazine-4 -ones, the 2-alkylthio-l, 3 -benzothiazine-4 -one of formula (2) is further reacted with a suitable amine, such as ammonia, a primary or secondary amine.
The reaction according to the present invention can be used to prepare various 2-amino-l, 3 -benzothiazine-4 -ones .
Preferred embodiments of these 2-amino-l, 3 -benzothiazine-4 - ones are disclosed in WO 2007/134625, WO 2009/010163 and applicant's copending application EP 09 003 876.1, the disclosure of these compounds is herewith incorporated by reference .
In an especially preferred embodiment of the invention, the reaction with the amine can be depicted by the following scheme :
wherein R, R3 and n are as defined above;
R5 and RQ are independently selected from H, a saturated or unsaturated, linear, branched or cyclic aliphatic radical having 1-8 carbon atoms,
Z is saturated or unsaturated, linear or branched aliphatic radical having 1-5 carbon atoms; W is 0, NH or N-C^.g-alkyl;
R7 and Rs are independently selected from H, Ci_g- alkyl, -OH, -OC1.5 -alkyl , halogen, or -CN;
and Rg may together represent
Rg and R]_g are H» Ci_3-alkyl;
Rll is H, a saturated or unsaturated, linear, branched or cyclic aliphatic radical having 1-8 carbon atoms, -OH, -OC]__g-alkyl , phenyl, benzyl, benzoyl, halogen; and multiple R^s may be the same or different;
Rj_2 1S methyl, benzyl, benzoyl or phenyl (which may be. substituted by C]__g-alkyl, -OH, -OCi_g-alkyl, halogen or -CN) ; and
m is an integer of 1-3;
In a further preferred embodiment of the invention, the reaction with the amine can be depicted by the following scheme :
The reaction with the amine may be conducted in an
appropriate solvent, such as an alcoholic solvent
(particularly methanol, ethanol and isopropanol) , chloroform, tetrachlorometane, etc.
The amine is preferably used in a molar ratio of 1-2,
preferably 1-1.2, based on the 2-alkylthio-l, 3 -benzothiazine- -one of formula (2) .
The 2-amino-l , 3 -benzothiazine- -ones may be further processed into a suitable pharmaceutical composition, e.g. by
compounding with appropriate excipients .
The present invention will hereinafter be described in more detail by way of the following non-limiting examples.
Examples
Chemicals and solvents were purchased from Alfa-Aesar (GB) or from Aldrich Co. (Sigma-Aldrich Company, St-Louis, US) . They were used without additional purification.
Melting points were determined according to the BP procedure and are uncorrected (Electrothermal 9001, GB) .
If analyses are indicated only by the symbols of the
elements, analytical results are within ±0.3% of the
theoretical values (Carlo-Erba 5500, Italy) .
NMR spectra were determined with a Varian Unity Plus 400 (USA) . Shifts for NMR are reported in ppm downfield from TMS (δ) .
Mass spectra were obtained using a Finnigan SSQ-700 (USA) instrument with direct injection.
Reactions and purity of compounds were controlled by TLC using Silicagel 60 F254 aluminium sheets (Merck Co, Germany) .
Example 1
2 -methylthio- 8 -nitro- 6 -trifluoromethyl -4H- 1 , 3 -benzothiazin-4 - one (compound 1)
Method A
Sodium hydroxide (0.9 g; powder) was dissolved in 10 ml DMSO, and 2.1 mL of carbon disulfide was added at a temperature of 10-15°C. 3.0 g of 2-chloro-3-nitro-5-trifluoromethylbenzamide was added to the solution in small portions at a temperature of 10°C. After 15 minutes, 0.7 mL of Mel was added at a temperature of. 10-20°C. The reaction was allowed to proceed for 30 min, and subsequently 100 mL of water was added. The resulting yellow solid was separated by filtration.
Yield: 47%
mp: 200-203°C (ethyl acetate)
MS (m/z) : 322 (M+)
XH NMR (DMSO-d6) : δ 8.95 and 8.81 (two 1H, two s, 2CH) , 2.73 (3H, S, CH3) ppm
Anal. (C10H5F3N2O3S2) :
Calc: C, 37.28; H, 1.56; N, 8.69; S, 19.90
Found: C, 37.01; H, 1.53 ; N, 8.7 ; S , 20.11
Method B
The reaction was conducted in a manner similar to method A, but the final product was crystallized from isopropanol.
Method C
The reaction was conducted in a manner similar to method A, but the final product was crystallized from ethanol.
Method D
Sodium hydroxide (0.3 g; powder) was added to a solution of 1.0 g of 2-chloro-3-nitro-5-trifluoromethylbenzamide in 10 ml DMSO at a temperature 10°C. 0.70 mL of carbon disulfide was added to the solution at a temperature of 10°C, and the reaction mixture allowed to stand for 15 minutes. 0.23 mL of Mel was added to the reaction mixture at a temperature of 10- 20°C. The reaction mixture was allowed to stand for another 30 min, subsequently 100 mL of water was added. The resulting yellow solid was separated by filtration.
Yield: 39%
mp: 200-203°C (purified by crystallization according Methods A, B or C)
Example 2
2-methylthio-6, 8-bis (trifluoromethyl) -4H-1, 3-benzothiazin-4- one (compound 2)
0.88 g of 2-chloro-3 , 5-ditrifluoromethylbenzamide was dissolved in 5 ml DMSO, and 0.55 mL of carbon disulfide was added at a temperature of 10°C. 0.24 g of sodium hydroxide (powder) was added to the reaction mixture, and the mixture was allowed to stand for 15 minutes. Subsequently, 0.2 mL of Mel was added. The reaction mixture was allowed to stand for another 30 min, and 50 mL of water was added. The resulting white solid was separated by filtration.
Yield: 46%
mp: 108-110°C (EtOH)
MS (m/z) : 345 (M+)
¾ MR (DMS0-d6) : δ 8.69 and 8.41 (two 1H, two s, 2CH) , 2.73 (3H, s, CH3) ppm
Anal . for C H5F6NOS2 :
Calc: C, 38.26; H, 1.46; N, 4.06; S, 18.57
Found: C, 38.23; H, 1.50; N, 4.15; S, 18.42
Example 3
2 -methylthio- 6 -nitro-4ii-l, 3 -benzothiazin-4 -one (compound 3)
Sodium hydroxide (0.4 g; powder) was added to a solution of 1.0 g of 2-chloro-5-nitrobenzamide in 5 ml DMSO at a
temperature of 10°C. 0.90 mL of carbon disulfide was added to the solution at a temperature of 10°C, and the reaction mixture was allowed to stand for 15 minutes. Mel (0.31 mL) was added to the reaction mixture at a temperature of 10- 20°C. The reaction mixture was allowed to stand for another 30 min, and 50 mL of water was added. The resulting yellow solid was separated by filtration.
Yield: 45%
mp: 168-170°C (ethyl acetate)
MS (m/z) : 277 (M+)
Calc: C, 43.31; H, 2.18; N, 5.05; S, 23.13
Found: C, 43.46; H, 2.17; N, 5.14; S, 23.19
Example 4
8 -bromo-2 -methylthio- 6 -trifluoromethyl -4H- 1 , 3 -benzothiazin-4 - one (compound 4)
Sodium hydroxide (1.5 g; powder) was dissolved in 15 ml DMSO, and 3.36 mL of carbon disulfide was added at a temperature of 10-15°C. 5.6g of 3 -bromo- 2 -chloro- 5 - fluoromethylbenzamide was
added to the solution in small portions at a temperature of 10°C. After 15 minutes, 1.14 mL Mel was added at a
temperature of 10-20°C. The reaction mixture was allowed to stand for 30 min, and 130 mL of water was added. The
resulting white solid was separated by filtration.
Yield: 41%
mp: 143-145°C (ethanol or hexane)
MS (m/z) : 356 (M+)
XH MR (DMS0-d6) : δ 8.30 and 8.07 (two 1H, two s, 2CH) , 2.67 (3H, s, CH3) ppm
Anal, for CioH5BrF3NOS2 :
CalC : C,. 33.72;Ή, 1.41; , 4.06; S, 18.57
Found: C, 33.64; H, 1.55; N, 4.11; S, 18.72
Example 5
2- [2S-2 -methyl -1, 4-dioxa-8-azaspiro [4.5] dec-8-yl] -8-nitro-6- trifluoromethyl-4H-l, 3 -benzothiazin-4 -one (compound 5)
A suspension of 3.0 g of 2-methylthio-8-nitrp-6- trifluoromethyl-4H-l, 3 -benzothiazin-4 -one (compound 1) in
15 mL of ethanol was treated with 1.5 g of ( 2 S) -2 -methyl -1 , - dioxa-8-azaspiro [4.5] decane at room temperature. The reaction mixture was heated to 50-60°C for 20 minutes. After cooling,
100 mL of water was added. The resulting light yellow solid was separated by filtration.
Yield: .76% (based on 2-chloro-3-nitro-5- trifluoromethylbenzamide)
mp: 191-193°C (ethyl acetate) .
MS (m/z) : 431 (M+)
λΗ NMR (DMSO-d6) : δ 8.81 and 8.76 (two 1H, two s, 2CH) , 4.26 (1H, ra, CH) , 4.11 (1H, m, CH) , 3.94 (4H, broad s, 2CH2), 3,47 (1H, t, CH) , 1.80 (4H, broad s, 2CH2) , 1.23 (3H, d, CH3) ppm
Anal . for CnH16F3N305S :
CalC: C, 47.33; H, 3.74; N, 9.74; S, 7.43
Found: C, 47.36; H, 3.72; N, 9.84; S, 7-55
Example 6
2- (2 , 2-dimethyl-l, 4-dioxa- 8 -azaspiro [4.5] dec-8-yl) -8-nitro-6- (trifluoromethyl) -4H-1, 3-benzothiazin-4-one (compound 6)
Compound 6 was prepared in the same manner as Example 5 but using 2 , 2-dimethyl-l, 4-dioxa-8-azaspiro [4.5] decane as the amine, and a light yellow crystalline solid was obtained.
Yield: 70%
mp: 209-212°C (EtOH)
MS (m/z) : 445 (M+)
XH NMR (DMSO-d6) : δ 8.84 and 8.76 (two 1H, two s , 2CH) , 3.93 (4H, broad s, N(CH2)2), 3.73 (2H, s, CH2) , 1.79 (4H, broad s, C(CH2)2), 1.28 (6H, s, C(CH3)2) ppm
Anal, for C18H18F3N305S :
CalC: C, 48.54; H, 4.07; N, 9.43; S, 7.20
Found: C, 48.56; H, 4.21; N, 9.37; S, 7.30
Example 7
2- (4-methylpiperazin-l-yl) -8-nitro-6- (trifluoromethyl) -4H- 1, 3-benzothiazin-4-one (compound 7)
Compound 7 was prepared in the same manner as Example 5 but using N-methylpiperazine as the amine, and a light yellow crystalline solid was obtained.
Yield: 15%
mp: 180-183°C (EtOH/water)
MS (m/.z) : 374 (M+) aH NMR (DMSO-d6) : 6 8.85 and 8.76 (two 1H, two s, 2CH) ,
(4H, broad s, N(CH2)2), 2.46 (4H, s, N(CH2)2), 2.23 (3H, CH3) ppm
Anal, for C14H13F3 403S :
CalC: C, 44.92; H, 3.50; N, 14.97; S, 8.57
Found: C, 44.79; H, 3.61; N, 14.42; S, 8.61
Example 8
2- [4- (2-methoxyphenyl)piperazin-l-yl] -8-nitro-6-
(trifluoromethyl) -4H-1, 3-benzothiazin-4-one (compound 8)
Compound 8 was prepared in the same manner as Example 5 but using 1- ( 2 -methoxyphenyl) piperazine as the amine, and a yellow crystalline solid was obtained.
Yield: 89%
mp: 245-247°C (EtOH/DMF or ethyl acetate)
MS m/z 466 (M+) λΗ NMR (DMSO-d6) : 6 8.88 and 8.81 (two 1H, two s, 2CH) , 6.87- 7.03 (4H, m, C6H4) , 4.04 (4H, broad s, N(CH2)2), 3.13 (4Ή, broad s , Ph (CH2 ) 2 ) ppm
Anal, for C20Hi F3N4O4S :
Calc: C, 51.50; H, 3.67; N, 12.01; S, 6.87
Found: C, 51.43; H, 3.69; N, 11.94; S, 6.98
Example 9
8-nitro-2-thiomorpholin-4-yl-6- (trifluoromethyl) -4H-1,3- benzothiazin-4 -one (compound 9)
Compound 8 was prepared in the same manner as Example 5 but using thiomorpholine as the amine, and a light yellow crystalline solid was obtained.
Yield: 85%
mp: 202-205°C (EtOH) ..
MS (m/z) : 377 (M+)
XH NMR (DMSO-d6/CDCl3) : δ 8.84 and 8.75 (two 1H, two s, 2CH) , 4.21 (4H, broad s, N (CH2) 2) , 2.82 (4H, broad s, S(CH2)2) ppm
Anal , for dsHxoFs sOaS;, :
Calc: C, 41.38; H, 2.67; N, 11.14; S, 16.99
Found: C, 41.53; H, 2.59; N, 10.98; S , 17.12
Example 10
2- (4-hydroxypiperidin-l-yl) -8-nitro-6- (trifluoromethyl) -4H- 1, 3-benzothiazin-4-one (compound 10)
Compound 10 was prepared in the same manner as Example 5 but using 4 -hydroxypiperidine as the amine, and a light yellow crystalline solid was obtained.
Yield: 93%
mp: 134-136°C (EtOH/water)
MS (m/z) : 375 (M+)
¾ NMR (DMSO-d6) : δ 8.85 and 8.75 (two 1H, two s, 2CH) , 4.93 (1H, broad s, CH) , 4.23 and 3.73 (each 2H, broad s, N(CH2)2), 1.86 and 1.53 (each 2H, broad s, C(CH2)2) ppm
Anal, for C^H^Fa^C^S :
CalC: C, 44.80; H, 3.22; N, 11.20; S, 8.54
Found: C, 44.73; H, 3.27 ; . N, 11.22 ; S, 8.69
Example 11
2- [(25) -2-methyl-l,4-dioxa-8-azaspiro[4.5]dec-8-yl] -6,8- bis (trifluoromethyl) -4H-1, 3-benzothiazin-4-one (compound 11)
A suspension of 0.2 g of 2-methylthio-6 , 8-ditrifluoromethyl-
4H-1, 3-benzothiazin-4-one (compound 2) in 5 mL of ethanol was treated with 0.08 g of ( 2 S) -2-methyl-l, 4-dioxa-8- azaspiro [ .5] decane at room temperature . The reaction mixture was heated to 50-60°C for 5 minutes. After cooling, 70 mL of water was added. The resulting white solid was separated by filtration.
Yield: 31%
mp: 189-191°C (EtOH)
MS (m/z) : 454 (M+)
¾ NMR (DMSO-d6) : δ 8.68 and 8.36 (two 1H, two s, 2CH) , 4.23 (1H, q, CH) , 4.09 (1H, t, CH) , 3.89 (4H, broad s, 2CH2) , 3,47 (1H, t, CH) , 1.80 (4H, broad s, 2CH2) , 1.23 (3H, d, CH3) ppm
Anal, for C18H16F3N203S :
CalC. : C, 47.58; H, 3.55; N, 6.17; S, 7.06
Found: C, 47.64; H, 3.57; N, 6.13; S, 7.22
Example 12
2- (l,4-dioxa-8-azaspiro [4.5] dec-8-yl) -6, 8- bis (trifluoromethyl) -4H-1, 3 -benzothiazin-4 -one (compound 12)
Compound 12 was prepared in the same manner as Example 11 but using 1 , 4 -dioxa- 8 -azaspiro [4.5] decane as amine, and a white crystalline solid was obtained.
Yield: 36%
mp: 195-197°C (EtOH)
MS (m/z) : 440 (M+)
XU NMR (DMSO-d6) : δ 8.68 and 8.47 (two 1H, two s, 2CH) , 3.98 (4H, s, N(CH2)2, 3.89 (4H, broad s, C(CH2)2), 1.79 (4H, broad s, C(CH2)2) ppm
Anal, for Ci7H14F6N203S :
CalC: C, 46.37; H, 3.20; N, 6.36; S, 7.28
Found-: C, 46.29; H, 3.25; N, 6.30; S, 7.39
Example 13
2- (2-methyl-l, 4 -dioxa- 8-azaspiro [4.5] dec-8-yl) -6-nitro-4i-'- 1, 3-benzothiazin-4-one (compound 13)
A suspension of 8.5 g of 2-methylthio-6-nitro-4H-l, 3- benzothiazin-4 -one , (compound 3) in 50 mL of ethanol was treated with 5.25 g of 2-methyl-l, 4 -dioxa- 8- azaspiro [4.5] decane at room temperature. The reaction mixture was heated to 50-60°C for 60 minutes. After cooling, 200 mL of water was added. The resulting white solid was separated by filtration.
Yield: 56%
mp: 216-219°C (EtOH)
MS (m/z) : 386 (M+)
XH NMR (DMSO-dg) : δ 8.82 (1H, s, CH) , 8.40 (1H, d, CH) , 7.91 (1H, d, CH) , 4.27 (1H, m, CH) , 4.10 (1H, m, CH) , 3.81 (4H, broad s, N(CH2)2), 3,47 (1H, t, CH) , 1.80 (4H, broad s,
C(CH2)2), 1.23 (3H, S, CH3) ppm
Anal, for C17H17F3 2O3S :
CalC.: C, 52.84; H, 4.43; N, 7.25; S, 8.30
Found: C, 52.88; H, 4.56; N, 7.37; S, 8.17
Example 14
8-bromo-2- (2-methyl-l, 4-dioxa-8-azaspiro [4.5] dec-8-yl) -6- nitro-4H-l, 3 -benzothiazin-4 -one (compound 14)
A suspension of 5.0 g of 8-bromo-2-methylthio-6- trifluoromethyl-4H-l , 3 -benzothiazin-4 -one (compound 4) in 50 mL of ethanol was treated with 2.2 g of 2-methyl-l, 4 -dioxa- 8- azaspiro [4.5] decane at room temperature. The reaction mixture was heated to 50-60°C for 30 minutes. After cooling, 150 mL of water was added. The resulting white solid was separated by filtration.
Yield: 57%
mp: 101-102°C (EtOH)
MS (m/z) : 465 (M+)
XH NMR (DMSO-dg) : δ 8.41 (2H, broad s, 2CH) , 4.21 (1H, q,
CH) , 4.09 (1H, t, CH) , 3.89 (4H, broad s, 2CH2), 3,46 (1H, t,
CH) , 1.80 (4H, broad s, 2CH2) , 1.23 (3H, d, CH3) ppm
Anal, for C17H16BrN03S :
Calc: C, 43.88; H, 3.47; N, 6.02; S, 6.89
Found: C, 43.89; H, 3.35; N, 6.12; S, 6.94
Example 15
2- [benzyl (methyl) amino] -8-bromo-6-nitro-4H-l, 3 -benzothiazin- 4 -one (compound 15)
Compound 15 was prepared in the same manner as Example 14 but using N-methyl-l-phenylmethanamine as the amine, and a white crystalline solid. was obtained.
Yield: 47%
mp: 179-181°C (EtOH)
MS - (m/z) : 429 (M+)
ΧΗ MR (DMSO-d6) δ 8.45 and 8.41 (two 1H, two s, 2CH) , 7.35- 7.45 (5H, m, C6H5) , 5.08 (2H, s, CH2), 3.33 (3H, s, CH3) ppm
Anal, for Ci7H12BrF3N2OS :
Calc: C, 47.57; H, 2.82; N, 6.53; S, 7.47
Found: C, 47.61; H, 2.81; N, 6.63; S, 7.42
Comparative Example 1 (Method C of WO 2009/010163)
2- (2S-2 -methyl- 1, 4-dioxa-8-azaspiro [4.5] dec-8-yl) -8-nitro-6- trifluoromethyl-4-H-l, 3-benzothiazin-4-one (compound 5)
4 g of 2-chloro-3-nitro-5-trifluoromethylbenzamide were treated with 3.3 g potassium xanthogenate in 80 mL ethanol at room temperature. The reaction mixture was allowed to stand for about 24 hours, and subsequently 250 mL water was added. The resulting light yellow precipitate was separated by filtration and crystallized from ethanol/water.
1 mmol of the reaction product obtained above was treated with 1.2 mmol of (2S) -2-methyl-l, 4-dioxa-8- azaspiro [ .5] decane in 30 mL acetic acid, and the mixture was refluxed for 24 hours. The reaction mixture was evaporated and the residue was treated by 50 ml water, the dark yellow precipitate was separated by filtration, washed with water and twice crystallized from ethanol/water.
Yield: 7% (based on 2-chloro-3-nitro-5- trifluoromethylbenzamide)
Claims
1.
(1) (2) wherein
Y is halogen;
R is independently selected from C^.g-alkyl which may optionally be substituted by halogen, - O2 , halogen, -CHO, -COOR4 (wherein R4 is hydrogen or Ci-g-alkyl) and -GN;
R3 is Ci_3-alkyl which may be substituted by halogen; X is halogen; and n is 0 or an integer of 1 to 4; if n is 2, 3 or 4 , multiple Rs may be the same or different.
2. The process of claim 1 which comprises the following step:
(1a) (2a) wherein
Y is halogen;
Rl is H, -CF3, -N02, or halogen;
R2 is -COOR4 (wherein R4 is hydrogen or C]__g-alkyl) , -CN, halogen, or -CF3;
R3 is Ci_3-alkyl which may be substituted by halogen; and
Y is halogen.
The process of claim 1 or 2 , wherein the reaction is carried out in the presence of a base, preferably in the presence of an alkali metal hydroxide, more preferably in the presence of LiOH, NaOH or KOH.
The' process according to any one of claims 1-3, wherein R3-X is selected from CH3I or CH2I2-.
The process according to any one of claims 1-4 which further comprises the conversion of compound (2) with a primary or secondary amine.
6. The process according to any one of claims 1-4, which further comprises the following step:
R, R3 and n are as defined in claim 1;
R5 and Rg are independently selected from H, a saturated or unsaturated, linear, branched or cyclic aliphatic radical having 1-8 carbon atoms,
Z is saturated or unsaturated, linear or branched aliphatic radical having 1-5 carbon atoms; W is 0, NH or N-Cx-g-alkyl;
R and RQ are independently selected from H, C^.g- alkyl, -OH, -OC^g-alkyl, halogen, or -CN; epresent
R9 and R]_o are H' C]__3-alkyl;
R]_! is H, a saturated or unsaturated, linear, branched or cyclic aliphatic, radical having 1-8 carbon atoms, -OH, -OC;j__ g -alkyl , phenyl, benzyl, benzoyl, halogen; and multiple Rus may be the same or different ; " "
R12 is H, methyl, benzyl, benzoyl or phenyl (which may be substituted by C^.g-alkyl, -OH, -OC]__g- alkyl, halogen or -CN) ; and
m is an integer of 1-3.
7. The process according to any one of claims 1-4, which further comprises the following step:
wherein R^, R2 and R3 are as defined in claim 2; and R5 and Rg are as defined in claim 6.
Use of the process according to any one of claims 1-7 for preparing a 2-aminosubstituted 1 , 3 -benzothiazine-4 - one or a pharmaceutical preparation thereof.
Use according to claim 8 wherein the 2-aminosubstituted 1 , 3 -benzothiazine-4 -one is characterized by the
following formula:
R5 and Rg are as defined in claim 6
Use according to claim δ or S, wherein, the
aminosubstituted 1 , 3 -benzothiazine-4 -one i
characterized by the following formula:
wherein R^ and R2 are as defined in claim 2; and
R5 and RQ are as defined in claim 6. compound of formula
(2)
wherein R, n and R3 are as defined in claim 1.
A compound according to claim 11, which is characterized by the following formula:
(2)
wherein Ri, R2 and R3 are as defined in claim 2.
13. A compound according to claim 11 or 12 which is selected from
2-R3-8-nitro-6- (trifluoromethyl) -4H-1, 3-benzothiazin-4- one ;
2-methylthio-8-nitro-6-R2-4H-l, 3 -benzothiazin-4 -one ; and 2 -methylthio- 8 -bromo- 6-R2 -4H-1 , 3 -benzothiazin-4 -one .
14. A compound according to claim 10 or 11 which is selected from:
2-methylthio-8-nitro-6- (trifluoromethyl) -4H-1, 3- benzothiazin-4 -one;
2-methylthio-6, 8-bis (trifluoromethyl) )-4H-l,3- benzothiazin-4-one ;
2 -methylthio-6-nitro-4H-1 , 3 -benzothiazin-4 -one ;
8-bromo-2-methylthio-6-trifluoromethyl-4H-1, 3- benzothiazin-4-one; and
2- (ethylthio) -8-nitro-6- (trifluoromethyl) -4H-1, 3- benzothiazin-4 -one .
15. Use of the compound according to any one of claims 11-14 for preparing a 2 -aminosubstituted 1 , 3 -benzothiazine-4 - one or a pharmaceutical preparation thereof.
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DE102014012546A1 (en) * | 2014-09-26 | 2016-03-31 | Martin-Luther-Universität Halle-Wittenberg | Antimycobacterially active substances, process for their preparation and their use |
CN108456204B (en) * | 2017-02-17 | 2023-05-26 | 四川大学 | Benzothiazine derivative, and preparation method and application thereof |
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Cited By (3)
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WO2013185507A1 (en) * | 2012-06-14 | 2013-12-19 | 四川大学 | Benzothiazine-4-one derivatives, preparation method therefor and use thereof |
CN103508980A (en) * | 2012-06-14 | 2014-01-15 | 四川大学 | Benzothiazine-4-one derivative, and preparation method and applications thereof |
CN103508980B (en) * | 2012-06-14 | 2016-07-06 | 四川大学 | Benzothiazine-4-ketone derivatives and its production and use |
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