Method for producing 4-substituted thiomorpholines

FIELD: chemistry.

SUBSTANCE: invention refers to a method for producing N-substituted thiomorpholines of formula (I) wherein divinylsulphide is reacted with an amine substrate (propylamine, aniline, o-, p-toluidine, monoethanolamine, acetamide) in the presence of the catalyst PdCl2-CF3COOH-PPh3 in the molar ratio of divinylsulphide : amine substrate : PdCl2 : CF3COOH : PPh3 = 10 : 10: (0.3-0.7) : (1.5-3.5) : (0.3-0.7), at a temperature of 55-65°C and an atmospheric pressure for 38-42 h in toluene. In general formula (I), R=CH3(CH2)2, C6H5, o-, p-CH3C6H4, C2H4OH, CH3CO.

EFFECT: one-stage high-yield production of the divinylsulhide compounds.

1 tbl, 1 ex

 

The present invention relates to the field of organic chemistry, in particular to a method for producing 4-substituted of thiomorpholine of the General formula (I):

where R=CH3(CH2)2, C6H5, o-, p-CH3With6N4, C4H4OH, CH3WITH.

N-substituted thiomorpholine may be of interest as pharmaceuticals with analgesic activity [Patent RF №2101284 C2, Azasuke the Terada, Yoshio Iizuka, Kazuyuki Vathi, Kenji Fujibayashi], with antagonistic activity against tachykinin receptors [RF Patent No. 237905 C2, Masami Takahashi, Yamanaka remember, Tsutomu Miyake] as a highly efficient sorbents of heavy metals in wastewater treatment, extractants for the separation of rare, noble and precious metals [B. A. Trofimov, S. I. Amosov. Diphenylsulfide and its derivatives. Novosibirsk: Nauka, 1983; V. A. Sviridov, E. N. Prilezhaeva, Uspekhi khimii, 1974, Vol. 43, No. 3, P. 519].

Known methods for producing 4-substituted of thiomorpholine based on the reactions thiomorpholine with various electrophiles.

Thus, the interaction of 2-(tert-butoxycarbonylamino-)propyl ester methanesulfonic acid 4-thiomorpholine in the presence of potassium carbonate in acetonitrile at 50°C leads to the formation of (S)-1-methyl-2-thiomorpholine-4-yl-ethylamine (2) [By Chen, Li et al. From U. S. Pat. Apl. Publ., 20100152203, 17 Jun 2010] under the scheme:

The known method [By Vennerstrom, Jonathan L. et al. From PCT Int. Appl., 2009058859, 07 May 2009] obtain 4-(3-chlorpropyl)-thiomorpholine hydrochloride (3) vzaimodeistvie thiomorpholine with 1-chloro-3-jumprope in dry THF in the presence of powdered Zn at room temperature with a yield of 19% according to the scheme:

The known method [By Estevam, Idalia H. S. and Bieber, Lothar W., Tetrahedron Letters, 44 (4), 667-670, 2003] obtain 4-(3-butenyl)-thiomorpholine (4) interaction of 4-thiomorpholine with formaldehyde and bromopropene in acetic acid in the presence of cuprous iodide at room temperature according to the scheme:

The known method [By Apodaka, Richard et al, From U.S. Pat. Appl. PubL, 20040002604, 01 Jan 2004] obtain 4-(3-butenyl)-thiomorpholine (5) interaction thiomorpholine with 3-Butin-1-yl-4-toluensulfonate in ethanol in the presence of potassium carbonate at 80°C for 2 h according to the scheme:

The known method [By Baxter, Ellen W. and Reitz, Alien From B. Organic Reactions (Hoboken, NJ, United States), 59, No pp. Given, 2002] obtain 4-(1-methylpropyl")-thiomorpholine-dioxide (6) the interaction of 2-amino-butane with sulfoxidation dialdehyde (7) in a solvent mixture of CH2Cl2:MeOH (4:1) at a temperature of -60°C followed by reduction with laborgerate sodium under the scheme. Yield of product (6) is 26%:

The known method cannot be obtained 4-substituted thiomorpholine of the General formula (1).

Thus, the literature contains no information on obtaining a 4-substituted of thiomorpholine of the General formula (1).

A new method for selective receipt of 4-substituted of thiomorpholine of the General formula (1).

The method consists in the interaction of diphenylsulfide with aminosubstituted R-NH2(Propylamine, aniline, o-, p-toluidine, monoethanolamine, acetamide) in the presence of a catalyst PdCl2-CF3COOH-Ph3P, taken in the molar ratio of diphenylsulfide:aminocoumarin (Propylamine, aniline, o-, p-toluidine, monoethanolamine, acetamide): PdCl2:CF3COOH:Ph3P=10:10:(0.3-0.7):(1.5-3.5):(0.3-0.7), preferably 10:10:0.5:2.5:0.5 in toluene as solvent, at a temperature of 55-65°C and atmospheric pressure within 38-42 hours, preferably 40 h. the 4-substituted of thiomorpholine of the General formula (1) is 50-78%. The reaction proceeds according to the scheme:

where R=CH3(CH2)2With6N5, o-, p-CH3With6N4With2N4HE, CH3WITH.

4-Substituted thiomorpholine of the General formula (1) are formed only with the participation of diphenylsulfide and aminosubstituted (Propylamine, aniline, o-, p-toluidine, monoethanolamine, acetamide), taken in the stoichiometric ratio 1:1. Pridraga the ratio of initial reagents decreases the yield of 4-substituted of thiomorpholine of the General formula (1). In the presence of other catalysts (NiCl2, CoCl2, FeCl3, ZrCl4) and in their absence the target products of the General formula (1) are not formed.

Reactions were carried out at a temperature of 55-65°C. At temperatures below 55°C. (e.g. 40°C) decreases the reaction rate and decreases the yield of product (1). At temperatures above 65°C (e.g., 100°C) decreases the selectivity of the reaction and increase energy costs. The experiments were carried out in toluene, as in the specified solvent readily soluble reactants and the desired products (1).

Significant differences of the proposed method

In the proposed method, as the initial reagents used diphenylsulfide and aminosubstituted (Propylamine, aniline, o-, p-toluidine, monoethanolamine, acetamide), and as a catalyst PdCl2-CF3COOH-PPh3. The method allows to selectively obtain 4-substituted thiomorpholine of the General formula (1). In the known methods as the initial reagents used thiomorpholine or sulfacetamide aldehyde, and a catalyst CuI, K2CO3or Zn.

The method is illustrated by examples

Example 1. In the vessel the Harness, mounted on a magnetic stirrer in an argon atmosphere at room temperature (~20°C) is placed 5 ml of toluene, 0.09 g (0.5 mmol) PdCl2, 0.3 ml (2.5 mmol) of CF3COOH and 0.13 g (0.5 mmol) PPh3stir in the�Linux for 30 minutes, add 0.9 ml (10 mmol) of diphenylsulfide and 0.6 ml (10 mmol) of Propylamine was stirred at 60°C for 40 h. From the reaction mass allocate 4-(propyl)-thiomorpholine (1A) with a yield of 64%. Other examples of the method are shown in table.1.

Table 1
Examples of preparation of 4-substituted of thiomorpholine
№p/pSource aminosubstituted R-NH2The ratio R-NH2: diphenylsulfide: PdCl2:CF3COOH:PPh3mmolTemperature, °CReaction time, hOutput (1), %
1The Propylamine10:10:0,5:2,5:0,5604064
210:10:0,7:3,5:0,7604078
310:10:0,3:1,5:0,36040 50
410:10:0,5:2,5:0,5654069
510:10:0,5:2,5:0,5554060
610:10:0,5:2,5:0,5604265
710:10:0,5:2,5:0,5603861
8Aniline10:10:0,5:2,5:0,5604052
9o-Toluidine10:10:0,5:2,5:0,5604065
10p-Toluidine10:10:0,5:2,5:0,560408
11Monoethanolamine10:10:0,5:2,5:0,5604073
12The acetamide10:10:0,5:2,5:0,5604075

All experiments were performed in toluene. TLC was performed on plates "Sorbfie" in the system C6N6-CHCl3-EtOAc-MeOH, 2:3:2:1.

Physico-chemical and spectral characteristics of the obtained compounds are:

4-(Propyl)-thiomorpholine (1a)

Butter yellow. Rf=0,65, nD=1.5650

The IR spectrum, ν, cm-1: 690, 720, 1098, 1120, 1380, 1469, 1475, 3428.

NMR1N (δ, M. D. J, Hz): 0.91 (t, 3H, CH3, J=6.8); 1.36 (m, 2H, CH2(8)); 2.40 (t, 2H, CH2(7), J=5.4); 2.57 (d, 4H, CH2(2, 6). J=9.4); 3.24 (d, 4H, CH2(3, 5), J=7.6);

NMR13With (δ, M. D.): 13.92 (9); 20.57 (8); 27.76 (2,6); 29.70 (7); Is at 54.33 (3,5).

Mass spectrum, m/z 144 (10) [M-N]+, m/z 130 (87) [M-CH3]+, m/z 116 (55) [M-CH3CH2]+, m/z 102 (34) [M-CH2CH2CH3]+, m/z 85 (14) [M-CH2SCH2]+m/z 60 (74) [CH2SCH2]+m/z 43 (100) [C3H7]+. C7H15NS. Mtheory=Resulting gain of 145.7.

4-(-Phenyl)-thiomorpholine (1b)

Butter yellow. Rf=0.71, nD=1.6452

The IR spectrum, ν, cm-1: 690, 750, 1105, 1180, 1495, 1639.

NMR1N (δ, M. D. b (J, Hz): 2.58 (ush.s, 4H, CH2(2, 6)); 3.26 (d, 4H, CH2(3, 5), J=10); 6.36 (1H, CHAr,); 6.76 (2H, CHAr,); 7.22 (2H, CHAr,).

NMR13With (δ, M. D.): 27.84 (2,6); 54.44 (3,5); 115.02, 129.88, 130.52, 149.06 (CAr).

Mass spectrum, m/z 178 (32) [M-N]+, m/z 119 (100) [M-CH2NC6H5CH2]+, m/z 102 (55) [M-NCH2CH2SCH2CH2]+, m/z 11 (55) [M-C6H4]+m/z 60 (84) (CH2SCH2]+. C10H13NS. Mtheory=179,28.

4-(o-Toluidine)-thiomorpholine (1c)

Butter yellow. Rf=0,70, nD=1.6615

The IR spectrum, ν, cm-1: 690, 750, 1105, 1180, 1479, 1495, 1639.

NMR1N (δ, M. D., J, Hz) 2.17 (s, 3H, CH3(13)); 2.58 (s, 4H, CH2(2, 6)); 3.26 (ush.s, 4H, CH2(3, 5)); 6.60 (1H, CHAr,); 6.98 (1H, CHAr,); 7.27 (1H, CHAr,); 7.38 (1H, CHAr,).

The NMR spectrum13With (δ, M. D.): 16.45 (CH3); Is at 29.79 (2,6); 55.16 (C3,5); 120.39, 124.63, 128.81, 133.12, 135.06, 152.02 (CAr).

Mass spectrum, m/z 192 (6) [M-N]+178 (23) [M-CH3]+, m/z 105 (51) [M-CH2CH2SCH2CH2]+, m/z 91 (100) [M-CH2CH2SCH2CH2N]+, m/z 81 (55) [M-CH3C6H4N]+. C11H15NS. � theory=193,31.

4-(p-Toluidine)-thiomorpholine (1d)

Butter yellow. Rf=0,69, nD=1.6303

The IR spectrum, ν, cm-1: 690, 750, 1100, 1380, 1479, 1739.

NMR1N (δ, M. D., J, Hz) 2.16 (s, 3H, CH3(13)); 2.56 (t, 4H, CH2(2, 6)); 3.24 (t, 4H, CH2(3, 5)); 6.60 (d, 1H, CHAr,); 6.98 (d, 1H, CHAr,); 7.30 (t, 1H, CHAr,); 7.31 (d, 1H CHAr,).

The NMR spectrum13With (δ, M. D.): 16.45 (CH3); Is at 29.79 (2,6); 55.16 (C3,5); 119.89-151.92 (CAr).

Mass spectrum, m/z 192 (10) [M-N]+178 (23) [M-CH3]+, m/z 105 (51) [M-CH2CH2SCH2CH2]+, m/z 91 (100) [M-CH2CH2SCH2CH2N]+, m/z 81 (55) [M-CH3C6H4N]+. C11H15NS. Mtheory=193,31.

2-(Thiomorpholine-4-yl)ethanol (1e)

Butter yellow. Rf=0,70. nD=1.5601

IR spectrum, cm-1: 695, 744, 998, 1300, 1112, 1290, 1253, 1352, 3338.

The NMR spectrum1N (δ, M. D., J, Hz, 20°C): 2,0 (ush.s, 2H, CH2(6)); 2,079 (ush.s, 2H, CH2(2)); 2,58 (ush.s, 2H, CH2(5)); 2,64 (ush.s, 2H, CH2(3)); 3,45 (ush.s, 2H, CH2(7)); 3,79 (ush.s, 2H, CH2(8)).

The NMR spectrum13With (δ, M. D.): 27.31 (2,6); 54.53 (3,5); 56.06 (7); 60.15 (C8).

Mass spectrum, m/z 146 (15) [M-N]+, m/z 101 (38) [M-CH2CH2HE]+, m/z 31 (100) [M-CH2CH2SCH2CH2NCH2]+, m/z 45 (25) [M-CH2CH2/sub> SCH2CH2N]+, 115 (21) [M-CH2HE]. C6H13NSO. Mtheory=147,24

4-(Acyl)-thiomorpholine (1f)

Butter yellow. Rf=0,67, nD=1.5803

IR spectrum, cm-1: 695, 744, 1020, 1200, 1339, 1290,1700, 1745, 1405.

NMR1N (δ, M. D., J, Hz) 2.06 (s, 3H, CH3(9)); 2.83 (s, 4H, CH2(2, 6)); 3.72 (m, 4H, CH2(3,5), (J=8.4).

The NMR spectrum13With (δ, M. D.): 21.92 (CH3); 28.04 (2,6); 47.80 (3); 51.03 (5) 169.06 (7).

Mass spectrum, m/z 144 (17) [M-N]+, m/z 130 (42) [M-CH3]+, m/z 102 (100) [M-CH3CO]+, m/z 98 (25) [M-CH2CH2SCH2CH2]+m/z 47 (37) [M-CH2NCOCH3]+m/z 43 (17) [M-NCH2CH2SCH2CH2]+. C6H11NSO. Mtheory=145,22.

A method of producing 4-substituted of thiomorpholine of the General formula (I):

where R=CH3(CH2)2With6N5, o-, p-CH3With6N4With2N4HE, CH3WITH,
characterized in that diphenylsulfide is subjected to interaction with aminosubstituted R-NH2[R = above] in the presence of a catalyst dl2-CF3COOH-h3with a molar ratio of diphenylsulfide:aminosubstituted:dl2:CF3COOH:h3=10:10:(0.3-0.7):(1.5-3.5):(0.3-0.7), at 55-65°C and atmospheric pressure within 38-42 hours



 

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which are biologically active substances and can find application in pharmacology and adamant-1-ylamine is the basis of the drug midantana"

FIELD: chemistry.

SUBSTANCE: method includes reacting anilines of general formula R-C6H4NH2 (where R=H, o-, m-, n-CH3, o-C2H5, o-, m-, n-Cl, n-F) and α,ω-diols (1,4-butanediol, 1,5-pentanediol) in the presence of a catalyst FeCl3·6H2O in the medium of tetrachloromethane at 180°C for 4-8 hours with molar ratio [FeCl3·6H2O]:[RC6H4NH2]:[diol]:[CCl4]=0.2-0.5:100:100-400:20-100. At 180°C and reaction duration of 6 hours, output of N-arylpyrrolidines reaches 45-88%, and output of N-arylpiperidines reaches 33-85%. Synthesis is carried out in an argon atmosphere.

EFFECT: method reduces reaction time and enables to use more affordable catalyst.

1 tbl, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: device refers to new styrene derivatives with the structure formula A in the form of geometrical isomers or tautomers and their pharmaceutical acceptable salts. In structural formula (A) R1 represents hydrogen; R2 represents hydrogen or C1-C6alkyl; R3, R4, R5 and R6 are identical or different and independently represent hydrogen, halogen, C1-C6alkyl or -OR12; R7 represents hydrogen or C1-C6alkyl; R8 represents hydrogen; R9 represents hydrogen, C1-C6alkyl, or -C(=O)R13; R10 represents hydrogen or C1-C6alkyl; Z represents W-Y, wherein W represents -C(R14)(R15)-; Y represents -C(R16)(R17)-; each R12 independently represents hydrogen or C1-C6alkyl; each R13 independently represents C1-C6alkyl; R14 and R15 are identical or different, and independently specified in hydrogen, fluoro, methyl, ethyl, trifluoromethyl, -OH, -OCH3 or -NH2; or R14 and R15 together form oxo; R16 and R17 are identical or different and independently represent hydrogen, halogen, C1-C6alkyl or -OR12. The other radical values are specified in the patent claim.

EFFECT: compounds may be used for treating an ophthalmic disease or disorder in an individual which can represent age-related macular degeneration or Stargardt macular degeneration.

17 cl, 14 tbl, 143 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing cyclohexane and derivatives thereof of general formula R=H, . The method involves producing saturated hydrocarbons and derivatives thereof, which can be used as semi-products in organic synthesis. The method involves hydrogenation of cyclohexene or a derivative thereof, which is selected from 1-(N-piperidino)cyclohexene-1,1-(N-morpholino)cyclohexene-1 or 1,4-dicyclohex-1-enylpiperazine with hydrogen gas at atmospheric pressure of hydrogen in the presence of a nanocatalyst in tetrahydrofuran medium at temperature of 50-70°C for 5-6 hours, followed by extraction of the end product. The nanocatalyst used is nickel nanoparticles which are obtained by reducing nickel (II) chloride with lithium aluminium hydride in situ. The method can also be used to obtain a wider range of cyclohexane derivatives which contain heterocyclic groups.

EFFECT: method enables to conduct the process at atmospheric pressure using a catalyst obtained using a simpler technique, which simplifies the method overall.

4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a heterocyclic compound, involving: reaction of a mixture of 1-methylpiperazine and 5-halogen-2-nitroaniline in a first solvent and at a first temperature ranging from approximately 90°C to approximately 110°C to obtain a compound of formula where the first solvent contains alcohol; cooling the mixture containing the compound of formula VIH to a second temperature ranging from approximately 85°C to approximately 95°C; adding a volume of a second solvent which is different from the first solvent to the mixture, where the second solvent contains water; and forming a suspension of the compound of formula VIH; where the second solvent is heated to the second temperature. The invention also relates to methods of producing a compound of formula VIH using other solvents such as heptane and HO-(CH2)q-OH or HO-CH2CH2OCH2CH2-OH, where q is selected from 2, 3 or 4.

EFFECT: novel method of producing a compound of formula VIH, which enables to obtain a highly pure product which does not require additional purification and is more suitable for use on a large scale owing to the solvents used.

74 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing cycloalkylamines of general formula Alk-R, where

, , , , , , , , , . The method is realised by reacting a cyclic ketone with an amine derivative and formic acid in the presence of a catalyst. The cyclic ketones used include cyclopentanone, cyclohexanone and 2-adamantanone, and the amine derivative used is formamide, cyclohexylamine, piperidine, morpholine, piperazine, 2-aminoethanol, 1,2-ethylenediamine, and the catalyst used is copper nanoparticles. The process is carried out in molar ratio ketone: amine derivative: HCOOH equal to 1:3-4:5-10, at temperature 100°C for 3-9 hours. The copper nanoparticles can be obtained in situ, as well as beforehand.

EFFECT: high output of cycloalkylamines under milder conditions for carrying out the process.

3 cl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new chemical compound - N-1-[(4-fluorophenyl)-2-(1-ethyl-4-piperidyl)-ethyl]-4-nitrobenzamide hydrochloride of formula Also, the invention refers to drugs.

EFFECT: preparation of a new biologically active compound which exhibits antiarhythmic and antifibrillatory activity.

2 cl, 1 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to application in an effective amount and to new nicotine receptor agonists described by general formula (i) or (ii) for treating inflammatory diseases chosen from a group including asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary tissue fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis (HP), chronic hypersensitivity pneumonitis and bronchiolitis obliterans organising pneumonia (BOOP). The compounds (i) and compounds (ii) relate to formulae (i) (ii) where in formula (i) R1 and R2 independently mean alkyl with 1-10 carbon atoms; Xa means CH or N; Ya means one or more substitutes chosen from hydrogen, halogen, cyano, hydroxyl, alkyl with 1-10 carbon atoms optionally substituted with one or more halogen atoms, and alkoxy with 1-10 carbon atoms; n means an integer 0 or 2; J means a counterion representing a compound for maintaining electric neutrality, e.g., halogen, sulphate, sulphonate; in formula (ii) R3 is chosen from or Xb means N or N+-R10; R4 means one or more substitutes chosen from hydrogen, halogen; each R10, R11 and R12 independently means alkyl with 1-10 carbon atoms; provided the presence of the counterion when Xb means N+-R10.

EFFECT: use of nicotine receptor agonists in the effective amount for treating inflammatory diseases.

26 cl, 40 dwg, 3 tbl, 38 ex

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