Method of obtaining secondary amides by carbonylation of respective tertiary amines

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining secondary amides. Method is realised by carbonylation of respective tertiary amines by means of carbon monoxide in presence of catalyst, containing less than 750 parts per million (ppm) of palladium, and halogen-containing promoter.

EFFECT: increased catalytic activity of catalyst with reduction of palladium concentration and increase of reaction selectivity.

39 cl, 7 tbl

 

The technical field to which the invention relates.

The present invention relates to a method for secondary amides by carbonylation of the corresponding tertiary amines with the use of carbon monoxide in the reaction mixture in the presence of a metal-containing catalyst and promoter containing halogen.

The level of technology

Amides represent a vast group of weakly basic nitrogen-containing organic compounds, which are used in large quantities, for example as solvents or monomers and small - as more complex substances, such as pharmaceutical drugs, peptides and so on. Traditionally, N-alkylamide obtained by classical reactions of organic chemistry: interaction of suitable primary or secondary amines with a suitable carboxylic acid or its derivative, for example ether, chloride or anhydride. However, these methods are sometimes limited by the availability of suitable raw materials and have a low atomic efficiency.

Also in recent years has developed ways of ORGANOMETALLIC catalysis for a wide range of amides. Among them, of particular interest is aminocarbonylmethyl as to obtain the amide group is used, the carbon monoxide is very cheap and available reagent. These m the methods allow to turn aryl halide or vinyl halide in amide, spending primary or secondary amine and carbon monoxide. In the first stage of the catalytic cycle in relationship to the carbon-halogen halide main part or aryl embedded metal (oxidative addition). Then one molecule of carbon monoxide is transferred from the coordination sphere of the metal alkyl or aryl radical (introduction of CO). Finally, the newly formed carbonyl group attacks the primary or secondary amine and the final amide product is released from the coordination sphere of the metal together with one equivalent of HX. The acid HX, released during the reaction, must be neutralized with a suitable base. For this you can use another equivalent of the above-mentioned primary or secondary amine. However, as this usually means the loss of valuable reagent, usually add another reason, which is inert in relation to the amidation reaction. You can use cheap inorganic bases, for example sodium carbonate, but for reasons of solubility often take organic bases, for example tertiary amine is triethylamine or tri-n-butylamine. The example described in the patent EP 0365382; in this work as a catalyst for the reaction of aminocarboxylate palladium was used, and as the base is triethylamine. This tertiary amine is not involved in the reaction of amine is carbonyl and during it he himself is not subject to carbonyliron.

As a result of reaction between the acid and the base in each molecule of the desired amide is always formed at least one molecule of salt. This method because of its low atomic efficiency and high cost halogenated starting materials for commercial purposes is used only in relation to complex compounds (for example, the active ingredients of pharmaceutical preparations). For small molecules, for example, to retrieve dimethylacetamide, this method is economically disadvantageous.

However, for the production of dimethylacetamide (DMAc) is known as the method of obtaining the secondary amide is not of the alkyl halide, and from the corresponding tertiary amine, namely, from trimethylamine (TMA). TMA - cheap and readily available reagent. He produced along with methylamine and dimethylamine and has limited application. Therefore, TMA has to be reused in the production cycle, which increases the size and power consumption of the equipment. Thus, the production of DMAc, based on TMA, can serve as an acceptable use of TMA and will provide substantial savings of energy and time/space for the production of the original amine.

Receiving DMAc from TMA described in several patents. In the publication DE948056 reported the synthesis of DMAc from TMA and CO/H2using (NMe4)2CoBr2I2in is the quality of the catalyst. Example 6 provides data on the output DMAc (90%) at full conversion of TMA after 7 hours at 200°C and a pressure of 680 bar. Despite the high pressures used in this method, the catalyst had only a low catalytic activity. The speed of the catalytic reaction (TOF), expressed by the number of moles converted to product per mole of the metal-catalyst per hour, in Example 6 this work was only about 5 moles of product per mole of catalyst per hour. In addition, a longer duration of response and very high pressure limit industrial application of this method. Also produces undesirable by-products. In Example 1 of DE 948056, where instead of TMA was used more reactive dimethylaniline or diethylaniline, the catalyst activity was slightly higher, but, as seen from Example 5, in which this method is carried out at a lower pressure (200 bar), requires a very high pressure - otherwise the catalytic activity is much lower.

There were several ways of turning TMA in DMAc using the well-known carbonylation catalyst Co2(CO)8. However, with this carbonyl complex, difficult to operate because of its instability in air and under moderate heating. Decomposition and catalytic cycle it to what talization form highly toxic volatile compounds of cobalt. But according to U.S. patent No. 3407231 the use of Co2(CO)8allows to conduct the reaction at a lower pressure CO: transformation TMA 95% is achieved at a temperature of 225°C and a pressure of 138 bar. The description of this patent, the reaction proceeds without the addition of the promoter. DMAc is recovered from the reaction mixture after removal of the volatile compounds, reaching a purity of 99%. However, the reaction lasts for a very long time - 16 hours, which is inconvenient. In this way the speed is very low, namely only 0.7 moles of TMA per mole of catalyst per hour. In the patent EP 0185823 reported use as a promoter of water together with Co2(CO)8that made it possible to achieve conversion of TMA 92% in just 5 hours. In this way the reaction is carried out at a temperature of 250°C and a relatively high pressure of 172 bar. However, the catalyst activity was relatively low, namely about 5 moles of TMA per mole of catalyst per hour. In addition, following the DMAc formed DMF (1%). It should be noted that in these methods, using a cobalt catalyst were taken in a rather large unit quantities that can explain the very low activity of cobalt catalysts.

Data on catalysts based on other metals is very small. In Japan patent No. 46 043 527 reported low output DMAc in the reaction of TMA with CO on the catalyst HgI2 at a temperature of 260°C. To catalyse the carbonylation of tertiary amines is only one noble metal. In Japan patent No. 3275656 A reported receiving DMAc exit 56% of TMA, which was subjected to transformation by 72%, using as a catalyst RhCl3and as promoter under the conditions at a temperature of 270°C. was formed by-products - DMF and N-methylacetamide - in the amount of 1% and 4% respectively. The catalytic activity of the rhodium catalyst is much higher than the above-described cobalt catalysts. The speed of the reaction, achievable with a cobalt catalyst was 19 moles of TMA per mole of catalyst per hour. But even with such high catalytic activity expected investments in production will be high, since rhodium is very expensive. Therefore, its use as a catalyst limits the economic benefits of this method. Recently in the patent Canada No. 101003491A reported using combinations of halides Rh together with halides Ir (which is taken in is equal to or smaller amounts) for the conversion of TMA in DMAc in similar conditions.

Disclosure of inventions

The present invention is to develop a method for the carbonylation of tertiary amines, which uses a catalyst comprising a good alternative Rodi is, being cheaper it and allowing you to achieve equal or higher speed response.

This task is achieved in this invention by using a catalyst containing palladium. Thus, the present invention relates to a method for secondary amides of the following formula:

where

R1represents an aromatic group, or an unbranched or branched aliphatic carbon chain containing at least one carbon atom which may be substituted or unsubstituted;

R2and R3are (independently from each other) aromatic group, or an unbranched or branched aliphatic hydrocarbon chain containing at least one carbon atom which may be substituted or unsubstituted, or R2and R3form a cyclic structure containing the amide nitrogen,

which includes phase carbonylation tertiary amine of the formula:

carbon monoxide in the reaction mixture in the presence containing palladium catalyst containing a halogen promoter, which is mostly not absorbed in the reaction mixture.

It was found that relatively cheap precious metal palladium able to catalyze the carbonylation is rimacillin education dimethylacetamide, providing such speed and selectivity of the reaction, which is no worse or even better than those using expensive noble metals Rh or Ir. With palladium achieved the same or even greater catalytic activity (TOF), and rhodium. In addition, when using as a catalyst of palladium can carbanilate more high molecular weight tertiary amines and aromatic tertiary amines, and the corresponding secondary amides are obtained in good yield and selectivity. In all the above mentioned reactions is used suitable halogen-containing promoter, which is required in amounts less equivalent. Thus, the present invention describes the synthesis of secondary amides from the corresponding tertiary amines characterized by almost 100%nuclear efficiency.

As mentioned above, in the patent EP 0365382 discloses the use of palladium as catalyst reactions aminocarbonylmethyl, in which as the neutralizing base can be used tertiary amines. However, in these reactions aminocarbonylmethyl there is no carbonylation of these tertiary amines, so that on the basis of the claim in the patent EP 0365382 not obvious that palladium is not only a catalyst for aminocarbonylmethyl, but tachiev suitable conditions, effectively catalyze the carbonylation tertiary amines.

In the method according to this invention, tertiary amines Carboniferous preferably with a speed of at least 9, preferably at least 19, more preferably at least 30 and most preferably at least 50 moles of tertiary amine per mole of palladium per hour.

In the preferred embodiment of the method according to this invention, the reaction mixture contains less than 5000 parts per million (ppm), preferably less than 3000 ppm, more preferably less than 1500 ppm, and most preferably less than 750 ppm of palladium. In an even more preferred embodiment of this invention, the reaction mixture contains less than 500 ppm and preferably less than 250 ppm of palladium.

It was found that, oddly enough, the catalytic activity of the palladium catalyst is significantly increased with the decrease of its concentration, and to such an extent that when you reduce the amount of catalyst in the reaction mixture the reaction rate practically does not change or decreases only slightly. This observation is very important, because the less you need of the catalyst, the cheaper the process and the less effort required for the Department and recyclization catalyst. In the method according to this invention palladium was active at concentrations of 10 ppm or less. This phenomenon for other noble metals (Rh, Ir) have not been previously reported. It JV which contributes to the efficiency of the method carbonylation using palladium. Palladium is added preferably in a concentration of at least 1 ppm, more preferably in a concentration of at least 10 ppm.

Palladium can be added in the form of inorganic salts, for example (the following examples are not limiting): PdCl2, PdBr2, PdI2Pd(OAc)2, PdSO4, (NH4)2[PdCl6], (NH4)2[PdCl4], PdC2O4Pd(acac)2; in the form of an oxide or in the form of complex Pd(0)carrying organic ligands, for example (the following example is not limiting) Pd(PPh3)4. As the catalyst precursor can also add preobrazovaniya metal complex compounds, PdCl2(CH3CN)2deflorationteen-palladium, dichloropyridine-palladium, Pd(TMA)2Cl2Pd(NH3)4Cl2Pd(NH3)2Cl2etc. it is Known that carbon monoxide and amines behave as ligands of intermediate complexes. The catalyst is preferably deposited on a substrate: palladium is put on carbon, aluminum, silicon, zeolite, ceramic, porous polymers, hybrid polymers and other substrates. Found that the catalytic activity is even higher - this may well be due to the fact that in this heterogeneous catalyst by fixing the palladium atoms on p is dloce not formed clusters.

The promoter containing halogen, preferably is present in the specified reaction mixture in a molar ratio higher than 0.1, preferably greater than 1, more preferably above 5 (relative to the catalytic metal). This ratio is preferably lower than 10000, more preferably below 2000.

Present in the reaction mixture promoter containing halogen, preferably includes a halide of the formula R1X, where X represents I, Br or Cl, preferably a halide of the formula R1X is R1I. Hydrocarbon group, particularly an alkyl or aryl group, halogen is preferably corresponds to the hydrocarbon group of the amine, in which it is desirable to implement CO. Suitable halides are the iodides, bromides or chlorides, for example methyliodide, ethyliodide, bensulide, periodid.

The best results are obtained with alkylidene, although you can use and the corresponding chlorides and bromides.

The promoter containing halogen can be added to the reaction mixture as such, but it is also possible to add compounds that form the promoter in situ in the reaction mixture. For example, it is known that alkylhalogenide and benzylchloride easily interact with tertiary amines with the formation of salts of tetraalkylammonium halides. Therefore, these salts can also be added to R. the promotional mix instead of the original alkylhalogenide. Suitable salts of this type can be choose from the following number (not limited to these examples): Tetramethylammonium iodide (TMAI), tetraethylammonium iodide, tetrapropylammonium iodide, tetrabutylammonium iodide, designed iodide, ... and the corresponding chlorides and bromides. The same purpose can also be used the corresponding halides tetraallylsilane. In addition, as a promoter, you can use other agents that can form alkylhalogenide or aryl halides in the reaction mixture under the conditions of flow of the discussed reactions. Examples of such agents are (not limited to named here) I2, Br2, Cl2, LiI, NaI, KI, HI. Also for the formation of a promoter in the reaction mixture, you can add the acid halides of the formula R1COX, which are possible intermediates of the catalytic cycle.

When the reaction mixture is introduced sufficient amount of tertiary amine, the regeneration promoter in the reaction mixture under normal catalytic activity. This means that the promoter can be added in amounts less than the equivalent in the reaction mixture is less than the moles of promoter, what becomes of moles of the tertiary amine. Thus, the promoter added to the reaction mixture, preferably in the molar quantities of the x, less than molar quantities of the selected tertiary amine, which carbanilide. However, when the reaction mixture is not sufficient tertiary amine, adverse reactions occur due to the absorption promoter.

To avoid absorption promoter, the reaction mixture preferably should not contain primary and secondary amines.

In the preferred embodiment of the method according to this invention, the tertiary amine and carbon monoxide is served in the reaction mixture is preferably continuously so that the content of the tertiary amine in the reaction mixture is maintained at from 0.1 to 20% (weight/weight), more preferably from 0.1 to 5% (weight/weight), most preferably from 0.1 to 2% (weight/weight).

It was found that the reaction rate strongly depends on the concentration of the tertiary amine. Very high reaction speed and excellent selectivity was observed at near-zero concentrations of tertiary amine. From this we can take advantage of if you perform the reaction in the reactor, in which the tertiary amine is maintained low by continuous (or intermittent) adding a tertiary amine in the reaction mixture.

The combination of the catalyst promoter can be used for carbonylation tertiary amines of General formula

where R12, R3are not H, and represent (independent from each other saturated or unsaturated, branched or unbranched carbon chain containing from 1 to 23 carbon atoms, or an aromatic ring. The carbon chain may also be substituted, such as phenyl group, CNS group, a carboxyl group, aminogroups..., and can thus be composed of, for example, benzyl group, 2-ethoxyethylene group, carboxymethyl group... . R2and R3can also form a cyclic structure. In addition, the circuit R1, R2, R3may contain heteroatoms, for example oxygen in the ether linkages. These circuits are also covered by the term "carbon chain", and the number of heteroatoms is not included in the number of carbon atoms.

The resulting amides include at least amides having the following formula:

where R1, R2, R3are defined the same as in the original Amina.

If R1, R2, R3unequal or if the promoter containing halogen, contains the group R2or R3other than R1we get the amides may also include one or more amides of the following formula:

and

where R1, R2, R3 are defined as, as in the original Amina.

All of these are secondary amides. In the present description, the term "secondary amide" means that when the amide nitrogen is not hydrogen.

In one specific embodiment of this invention R1, R2and R3are (independently from each other) unbranched or branched aliphatic carbon chain containing 1 to 23 carbon atoms, preferably 1-9 carbon atoms, and these carbon chain, preferably unsubstituted. Group R1, R2and R3preferably identical, more preferably they are all metal bands.

In another specific embodiment of this invention R1is unbranched or branched aliphatic carbon chain containing 1 to 23 carbon atoms, preferably 1-9 carbon atoms, a R2and R3together with the amide nitrogen atom form azacyclonol structure, and the carbon chain, preferably unsubstituted. An example of such compound is N-acetylpiperidine derived from N-methylpiperidine.

In yet another specific embodiment of this invention R1is unbranched or branched aliphatic carbon chain containing 1 to 23 carbon atoms, preferably 1-9 carbon atoms, a R2and R3together with the amide nitrogen atom form het is riikliku structure, containing at least one additional heteroatom, in particular nitrogen or oxygen, with the carbon chain, preferably unsubstituted. An example of such a tertiary amine is N-methylmorpholin giving after phase carbonylation of N-acetylmorpholine.

In another specific embodiment of the present invention, each of R1 and R2is unbranched or branched aliphatic carbon chain containing 1 to 23 carbon atoms, preferably 1-9 carbon atoms, a R3is an aromatic group, particularly phenyl or functionalized phenyl group, for example chloraniline, metoksifenilny, forfamilies... or unbranched or branched carbon chain containing 1 to 23 carbon atoms, preferably 1-9 carbon atoms and substituted aromatic group, particularly phenyl or functionalized phenyl group. An example of such a tertiary amine is N,N-dimethyl-N-benzylamine giving after phase carbonylation of N,N-dimethyl-2-phenylacetamide and N-methyl-N-benzyl-2-phenylacetamide. Another example is N,N-dimethylaniline.

The reaction is carried out in a closed vessel in an atmosphere containing CO, at pressures above 20 bar, more preferably above 50 bar. The total pressure is limited only by the capabilities of the equipment. At Opera in the reaction vessel can contain only CO or a mixture of CO/H 2. However, when using a mixture of CO/H2catalytic activity and selectivity is slightly lower. And result in more formamido, which is a byproduct of the reaction.

The carbonylation reaction is carried out at a temperature higher than that at which the catalyst becomes active. The magnitude of this temperature depends on the type of tertiary amine. For aromatic amines this minimum temperature, usually below, and alkylamines followed, as a rule, above. Amines containing heteroatoms, such as oxygen, occupy in this sense an intermediate position. The difference in temperature activation can be explained by the fact that aromatic amines, apparently, are very effective ligands and form active complexes at lower temperatures, whereas in the case of alkylamines followed to obtain the corresponding catalytic system often requires a higher temperature. Phase carbonylation is carried out at temperatures above 120°C, more preferably at temperatures above 180°C, especially when the tertiary amine is not aromatic.

Above the temperature required to activate the catalyst, the catalytic activity of the system increases with increasing temperature. It is preferable to maintain the temperature below 285°C, because at higher temperatures there is correspondingly a decrease in the selectivity.

The reaction mixture preferably contains a solvent. Preferably the solvent used, the reaction product - amide. But can be used in this role and other amides in addition to the expected product of the reaction. Very good results are obtained by using as a solvent of N-methylpyrrolidone (NMP).

When using the described catalytic system in optimal conditions, by-products are formed, surprisingly, in small quantities. The main side product is the corresponding primary amide (in particular, the corresponding N-alkylamine), which has lost one alkyl or aryl group. Other byproducts include carboxylic acids, NITRILES and formamide. The latter, as is well known, are formed from secondary amines and carbon monoxide.

The implementation of the invention

EXAMPLES

Example 1

50-ml chemical reactor (autoclave) was loaded 0.45 mmol of catalyst and 4.3 mmol of a suitable promoter containing halogen. Closing the vessel, missed 4 times the carbon monoxide (10 bar). Then introduced into the reactor through the septum with a syringe of 17.5 ml of 7.3% (weight/weight) solution of TMA in NMP. The reaction mixture thus contained 2736 ppm of the metal-catalyst. It was vigorously stirred for 10 minutes at room temperature and gave m noxid carbon (65 bar). The reaction mixture was heated to 240°C for 24 minutes. At the end of the reaction the mixture was cooled to 0°C, was carefully degirolami and analyzed by gas chromatography. This example demonstrates higher activity and selectivity of the catalytic system PdCl2/TMAI compared with other options source of iodide of the metal. Especially it should be noted that with cheaper palladium catalyst achieved the same or even higher catalytic activity, as with more expensive rhodium catalyst.

CatalystThe promoterTime (min)Output (%)The speed of reaction (h-1)
DMAcMIAsDMFAcNHOAc
PdCl2TMAI13096,00,00,00,05,224
PdCl2 Mel5083,93,50,00,014,787
PdCl2I29663,718,01,11,95,923
[(C6H5)3R]4PdTMAI21667,06,11,50,012,29
RhCl3TMAI11494,30,40,50,010,922
AuCl3TMAI15619,82,10,00,00, 3
H2IrCl3TMAI19139,81,45,20,00,06
DMAc - N,N-dimethylacetamide; MIAS - N-methylacetamide; DMF IS N,N-dimethylformamide; ACN is acetonitrile; HOAc is acetic acid.

Example 2

In these experiments served as a catalyst PdCl2, promoter - TMAI (TMAI:Pd=10), and the solvent was taken NMP. First in 50-ml chemical reactor (autoclave) was loaded 0.45 mmol PdCl2and 4.3 mmol TMAI. Closing the vessel, missed 4 times the carbon monoxide (10 bar). Then introduced into the reactor through the septum with a syringe of 17.5 ml of the studied agent in NMP. The reaction mixture was vigorously stirred for 10 minutes at room temperature and gave monoxide (65 bar). The reaction mixture was heated to 240°C for 24 minutes (unless otherwise indicated - see table). At the end of the reaction the mixture was cooled to 10°C, were carefully degirolami and analyzed by gas chromatography. This example shows that our catalytic system can be used for the carbonylation of a number of tertiary amines.

Reagent (% in NMP)The duration of reaction (min)The degree of conversion (%)The output of the main product (mol.%)
DMAn* (12,0)7510092% of N-methyl-N-phenylacetamide
DMEA (7,3)7710074% of N-methyl-N-ethylacetamide
21% N,N-diethylacetamide
TEA (12,1)14010043% of N,N-diethylacetamide
37% of N, N-diethylpropane
12% N-methyl-N-ethylacetamide
N,N-dimethylaniline (17,0)17010067% N-methyl-N-nonracemic
N-methylpiperidin (9,9)1808875% N-acetylpiperidine
N-methylmorpholin (10,0)9010060% N-atilmotin
N,N-dimethyl-N-benzylamine(13,5)2107718% N,N-dimethyl-2-phenylacetamide
8% N,N-methyl-2-benzyl-2-phenylacetamide
* the reaction was carried out at 190°C.
DMAn - N,N-dimethylaniline; DMEA - dimethylethylamine; TEA is triethylamine.

Example 3

50-ml chemical reactor (autoclave) was loaded 0.45 mmol PdCl2as a catalyst and 4.3 mmol TMAI as a promoter. Closing the vessel, missed 4 times the carbon monoxide (10 bar). Then introduced into the reactor through the septum with a syringe of 17.5 ml of 7.3%or 8.3% (weight/weight) solution of TMA in NMP or DMAc. The reaction mixture was vigorously stirred for 10 minutes at room temperature and gave monoxide (65 bar). The reaction mixture was heated to 240°C and followed by reducing the pressure for absorption. When the degree of conversion reached approximately 50%, the reaction mixture was cooled to 0°C, was carefully degirolami and analyzed by gas chromatography. This example shows that in this reaction as a solvent in addition to the NMP can be used DMAc.

Time (min)Selectivity (%)
DMAcMIAsDMFSPLA
NMP8594,50,30,05,2
DMAc6594,51,02,12,4

Example 4

This example demonstrates the possibility of increasing the catalytic activity by reducing the concentration of the catalyst.

50-ml chemical reactor (autoclave) download the required amount (see table) catalyst, which served as PdCl2, and 4.3 mmol TMAI as a promoter. Closing the vessel, missed 4 times the carbon monoxide (10 bar). Then introduced into the reactor through the septum with a syringe of 17.5 ml of 7.0% (weight/weight) solution of TMA in NMP. The reaction mixture was vigorously stirred for 10 minutes at room temperature and gave monoxide (65 bar). The reaction mixture was heated to 240°C for 24 minutes. From this point, tracked time for to the / establishment, which were adsorbed amount of CO, the corresponding pressure drop in bar 9 (t9). Then gave the reaction to proceed to full conversion. At the end of the reaction the mixture was cooled to 0°C, was carefully degirolami and analyzed by gas chromatography. This example shows that the activity of the palladium catalyst is significantly increased by reducing its concentration - even to the extent that the same is essentially the amount of amide is obtained with a smaller amount of catalyst.

Number [Pd] (ppm)The speed of reaction (h-1)Time t9 (min)The output DMAc (%)
3771588694
17123810590
41110011897

Example 5

This example demonstrates the application of the discussed reactions heterogeneous palladium catalyst in a low concentration.

As the catalyst in this example was used zeolite type Y, loaded palladium. Zeolite NaY pogruzilis aqueous solution of PdCl 2(NH3)4and was stirred for 14 hours. The resulting zeolite contained 0.03 mmol Pd 1,

50-ml chemical reactor (autoclave) download the desired amount of catalyst and 4.3 mmol TMAI as a promoter. Closing the vessel, missed 4 times the carbon monoxide (10 bar). Then introduced into the reactor through the septum with a syringe of 17.5 ml of 7.1% (weight/weight) solution of TMA in NMP. The reaction mixture was vigorously stirred for 10 minutes at room temperature and gave monoxide (65 bar). The reaction mixture was heated to 240°C for 24 minutes. From this point, tracked time, which was absorbed quantity WITH corresponding pressure drop in bar 9 (t9). Then the reaction mixture was cooled to 0°C, was carefully degirolami and analyzed by gas chromatography.

The concentration of [Pd] (ppm)The speed of reaction (h-1)Time t9 (min)The degree of conversion (%)
5223405759

Example 6. Management catalyst

In a 1-liter Parr reactor equipped with a magnetic stirrer, a tube for which tbore samples and supply capacity, download NMP (252,2 g), TMAI (11.4 g; 57 mmol) and PdCl2(1.18 g; 6.7 mmol). Closing the reactor, missed three times the carbon monoxide. Then through the feeding capacity was added to 20.1 g (0,34 mol) of TMA and filed CO to a pressure of approximately 60 bar. The reaction mixture was heated to 240°C and was monitored by absorption WITH pressure drop. When the degree of conversion reached approximately 80%, the reaction mixture was cooled. In order to start the second cycle, adding more TMA, reduced pressure and the reaction mixture is again heated. After the third cycle analysis showed that the mixture was still quite present TMA in order to start the fourth cycle. The results presented in the table below, clearly demonstrate that PdCl2and TMAI act as a true catalyst system capable of recyclization without loss of selectivity. Both components can be used in amounts less equivalent.

1
The composition of the reaction mixture
CycleTMA addedTMADMAcMIAsDMFHOAc
20,1 g1,65%6,66%0,04%0,02%0,11%
220,2 g3,80%11,36%0,05%0,21%0,09%
319,4 g8,15%14,06%0,09%0,46%0,08%
40 g0,24%19,69%0,16%0,54%0,09%

Examples 7a and 7b

These examples demonstrate the effect of the concentration of TMA on the activity of the catalyst.

In a 1-liter reactor to work under pressure (autoclave) was filed TMA and CO in equimolar amounts to the full system pressure of the reactor was kept constant. While TMA and CO did in the reactor with the same speed with which they were absorbed. Any products from the reactor were not removed; thus, the reaction proceeded semi-continuous. In one experiment the concentration is s TMA was supported by about 6% (experiment 7a); in the second experiment, the concentration of TMA was supported by about 1% (experiment 7b). In both cases, the total pressure was 90 bar, the temperature was 260°C, the solvent was taken NMP. As a catalyst and promoter used respectively PdCl2and TMAI in similar amounts (see table). Upon completion of the reaction, the reaction mixture was cooled and analyzed by gas chromatography. In both cases, the output DMAc was almost quantitative. Two main by-product is presented in the table. To confirm that the reaction proceeded with the desired concentration of TMA, measured final concentration of TMA.

Experience 7aExperience 7b
fPdl (ppm)122104
TMAI/Pd224228
The total time of reaction (h)62,5
The speed of reaction (h-1)4482277
Output DMF (%)1,10,3
The output of MIAS (%)0,60,1
The final concentration of TMA (%)5,3%0,64%

1. A method of obtaining a secondary amide of the following formula

where R1represents an aromatic group, or an unbranched or branched aliphatic carbon chain containing at least one carbon atom which may be substituted or unsubstituted;
R2and R3are (independently from each other) aromatic group, or an unbranched or branched aliphatic carbon chain containing at least one carbon atom which may be substituted or unsubstituted, or R2and R3form a cyclic structure containing amide nitrogen;
which includes phase carbonylation tertiary amine of the formula

with the help of carbon monoxide in the reaction mixture in the presence of a catalyst containing palladium, and in the presence of a promoter containing a halogen, which is not significantly absorbed in the reaction mixture, where the reaction mixture contains less than 750 parts per million (ppm) palladium.

2. The method according to claim 1, in which the promoter containing halogen, contains halog the NID of the formula R 1X, where X represents I, Br or Cl.

3. The method according to claim 1, in which the promoter containing halogen is injected into the reaction mixture by adding to the reaction mixture one or more compounds from the group consisting of halides of the formula R1X, halides of the formulaR41N+X-, halides of phosphonium formulaR41P+X-X2, metal halide and halogenized acids of the formula R1COX, and the halogen is chlorine, bromine or iodine.

4. The method according to claim 3, in which the promoter containing halogen is injected into the reaction mixture by adding the halide of formula R1X in the reaction mixture.

5. The method according to claim 1, in which R1, R2and R3are (independently from each other) unbranched or branched aliphatic carbon chain containing 1 to 23 carbon atoms.

6. The method according to claim 1, in which R1, R2and R3are (independently from each other) unbranched or branched aliphatic carbon chain containing 1-9 carbon atoms.

7. The method according to claim 5 or 6, in which the carbon chains are resumes nimi.

8. The method according to claim 5 or 6, in which R1, R2and R3are metal group.

9. The method according to claim 5 or 6, in which at least carbon chain group R1is a substituted aromatic group, particularly phenyl group, and R1is preferably benzyl group.

10. The method according to claim 5 or 6, in which at least carbon chain group R1is a substituted phenyl group.

11. The method according to claim 5 or 6, in which at least carbon chain group R1is a substituted benzyl group.

12. The method according to claim 1, in which R1represents an unbranched or branched aliphatic carbon chain containing 1 to 23 carbon atoms, and R2and R3together with the amide nitrogen atom form azacyclonol structure.

13. The method according to claim 1, in which R1represents an unbranched or branched aliphatic carbon chain containing 1-9 carbon atoms, and R2and R3together with the amide nitrogen atom form azacyclonol structure, and the carbon chain is unsubstituted.

14. The method according to claim 1, in which R1represents an unbranched or branched aliphatic carbon chain containing 1 to 23 carbon atoms, and R2and R3together with the amide nitrogen atom form a heterocyclic structures which, containing at least one additional heteroatom.

15. The method according to claim 1, in which R1represents an unbranched or branched aliphatic carbon chain containing 1-9 carbon atoms, and R2and R3together with the amide nitrogen atom form a heterocyclic structure containing at least one additional heteroatom selected from nitrogen and oxygen, and the carbon chain is unsubstituted.

16. The method according to claim 1, in which the catalyst contains Pd(II).

17. The method according to item 16, wherein said palladium is added to the reaction mixture as a salt selected from the group consisting of PdCl2, PdBr2, PdI2Pd(OAc)2, PdSO4, (NH4)2[PdCl6], (NH4)2[PdCl4], Pd(acac)2and PdC2O4.

18. The method according to claim 1, in which the catalyst contains Pd(0).

19. The method according to p, wherein said palladium is added to the reaction mixture in the form of Pd(PPh3)4.

20. The method according to claim 1, wherein said palladium is applied to the substrate.

21. The method according to claim 20, wherein said palladium is applied on a substrate which is selected from the group consisting of carbon, alumina, silica, zeolite, ceramics, porous polymers, and hybrid polymers.

22. The method according to claim 1, in which the promoter containing the halogen is present in the specified reaction mixture in molar the m with respect to the catalytic metal is higher than 0.1.

23. The method according to claim 1, in which the promoter containing the halogen is present in the specified reaction mixture in a molar ratio to the catalytic metal above 1.

24. The method according to claim 1, in which the promoter containing the halogen is present in the specified reaction mixture in a molar ratio to the catalytic metal above 5.

25. The method according to claim 1, in which the tertiary amine and carbon monoxide is served in the reaction mixture so that the content of the tertiary amine in the reaction mixture was maintained at the level of 0.1-20% (weight/weight).

26. The method according to claim 1, in which the tertiary amine and carbon monoxide is continuously served in the reaction mixture so that the content of the tertiary amine in the reaction mixture was maintained at the level of 0.1-20% (weight/weight).

27. The method according to claim 1, in which the tertiary amine and carbon monoxide is served in the reaction mixture so that the content of the tertiary amine in the reaction mixture was maintained at the level of 0.1-5% (weight/weight).

28. The method according to claim 1, in which the tertiary amine and carbon monoxide is served in the reaction mixture so that the content of the tertiary amine in the reaction mixture was maintained at the level of 0.1-2% (mass/mass).

29. The method according to claim 1, in which the phase carbonylation is carried out at a temperature below 285°C.

30. The method according to claim 1, in which the phase carbonylation implemented Aut at temperatures above 120°C.

31. The method according to claim 1, in which the phase carbonylation is carried out at a temperature above 180°C.

32. The method according to claim 1, in which the phase carbonylation is carried out at a pressure above 20 bar.

33. The method according to claim 1, in which the phase carbonylation is carried out at a pressure above 50 bar.

34. The method according to claim 1, wherein the reaction mixture contains almost no primary or secondary amines.

35. The method according to claim 1, in which the promoter added to the reaction mixture in molar quantities, less than molar quantities of tertiary amine being carbonyliron.

36. The method according to claim 1, in which the tertiary amine carbonyliron speed of at least 9 moles of tertiary amine per mole of palladium per hour.

37. The method according to claim 1, in which the tertiary amine carbonyliron speed, at least 19 of moles of tertiary amine per mole of palladium per hour.

38. The method according to claim 1, in which the tertiary amine carbonyliron speed of at least 30 moles of tertiary amine per mole of palladium per hour.

39. The method according to claim 1, in which the tertiary amine carbonyliron speed of at least 50 moles of tertiary amine per mole of palladium per hour.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of short-chain fatty acids, in particular derivatives of butyric acid, having physicochemical characteristics suitable for an easy oral administration, being devoid of the unpleasant organoleptic properties that characterise butyrate.

EFFECT: novel compounds have an easily weighable form, are stable to acids and alkalis and are capable of releasing the acid in the small and large intestines continuously over a long time.

7 cl, 5 dwg, 15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 4-(azacycloalkyl)benzene-1,3-diol compounds of general formula (I) given below:

,

where: R1 is: - C1-C5-alkyl radical, - C3-C6-cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, and C1-C5 alkoxy group, a fluorine atom or a trifluoromethyl group, - aralkyl radical, - C1-C5-alkoxy radical, -amine radical, having the structure (a):

,

where R2 is: - hydrogen, - C1-C5-alkyl radical, - C3-C6- cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, and C1-C5 alkoxy group, a fluorine atom and a trifluoromethyl group, - pyridyl radical, - aralkyl radical of the structure (b):

,

where p is equal to 1 or 2, - a radical of the structure (c):

,

where R4 is: - carboxymethyl, -COOCH3, or carboxyethyl, -COOEt, radical, - C1-C3-alkyl radica, - hydrogen, and R5 is: - an unsubstituted aryl radical or an aryl radical substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy group, fluorine atom or a trifluoromethyl group, - C3-C6-cycloalkyl radical, - pyridyl, and R3 is: - hydrogen, - C1-C5-alkyl radical; or R1 can also be a radical of formula (d):

,

where R6 is: - hydrogen, - C1-C5-alkyl radical, - C3-C6-cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy group, a fluorine atom and a trifluoromethyl group, - pyridyl radical, - aralkyl radical, R7 is: - hydrogen, - C1-C5-alkyl radical, and R8 is: - hydrogen, - hydroxyl, - amine radical, - C1-C3-alkoxy radical; Y is hydrogen or fluorine, and m and n are equal to 0, 1 or 2, as well as isomeric and enantiomeric forms of compounds of formula (I). The invention also relates to use of said compounds as a drug for treating pigmentation disorders.

EFFECT: novel compounds, which can be used in pharmacology or cosmetology to treat or prevent pigmentation disorders, are obtained and described.

6 cl, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I) or to its stereoisomers, or to a pharmaceutically acceptable salt, wherein Ra represents H or (C1-C6)alkyl; Rb is specified in an optionally substituted group consisting of -(CH2)n-aryl, -CH(CH3)-aryl, -(CH2)n-arylaryl, -(CH2)n-arylheteroaryl, -(CH2)n-(C3-C8) cycloalkyl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl and -(C3-C8) cycloalkylaryl; or Ra and Rb taken together with a nitrogen atom form 2,3-dihydro-1H-isoindolyl, decahydroisoquinolinyl, optionally substituted piperidinyl or optionally substituted pyrrolidinyl; Y is specified in an an optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyl, -NH-(CH2)n-heterocyclyl, wherein NH is attached to carbonyl, and -heterocyclylaryl, wherein heterocyclyl is attached to carbonyl; and n is equal to 0, 1 or 2; wherein each heterocyclyl represents an independent non-aromatic ring system containing 3 to 12 ring atoms, and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; wherein each heteroaryl represents an independent non-aromatic ring system containing 3 to 12 ring atoms and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; and wherein the optional substitutes are independently specified in a group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen, CN, CF3, OCF3, NH2, NH(CH3), N(CH3)2, hydroxy, cyclohexyl, phenyl, pyrrolidinyl, -C(O)-piperidinyl, -N(H)-C(O)-C1-C6-alkyl and N(H)-S(O)2-C1-C6-alkyl. The invention also describes a pharmaceutical composition having chemokine receptor antagonist activity and a method of treating such diseases, such as rheumatoid arthritis, psoriasis, lupus, etc.

EFFECT: there are prepared and described new chemical compounds that can be used as chemokine receptor antagonists and, as such, may be used in treating certain pathological conditions and diseases, particularly inflammatory pathological conditions and diseases and proliferative disorders and conditions, eg rheumatoid arthritis, osteoarthritis, multiple sclerosis and asthma.

23 cl, 59 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new crystalline modifications of N-α-(2,4,6-triisopropylphenylsulphonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxycarbonyl piperazide and/or its salts. Such crystalline modifications have high stability particularly at low hygroscopicity compared to known amorphous forms of the compound.

EFFECT: invention relates to a method of obtaining such new crystalline modifications, to pharmaceutical compositions containing these new crystalline modifications and their use as an anti-tumour agent.

26 cl, 7 tbl, 13 ex, 20 dwg

FIELD: chemistry, pharmaceutical.

SUBSTANCE: invention pertains to compounds with formula I , where: n is an integer equal 1 or 2; p is an integer from 1 to 7; A is chosen from one or more radicals X and/or Y; X represents methylene group, substituted when necessary by one or two C1-6-alkyl groups; Y represents C2-alkenyl, C2-alkenyl; G represents a single bonds, oxygen or C=O. The compound can be used as ferment FAAH inhibitor for pain killing, inflammation or nerve-degenerative diseases. Description is given of the method of obtaining compounds, pharmaceutical compositions based on them and their use.

EFFECT: design of a method of obtaining alkylhomopiperazinecarboxylates and their use for pain killing, treating inflammation or nervous degenerative diseases.

11 cl, 2 tbl, 7 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

The invention relates to piperazinone derivatives, to processes for their production, to their use and to the containing pharmaceutical compositions

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of (R)-2-arylpropionamides of general formula I, in which Ar is phenyl group, substituted in 3(meta) position by group R1, selected from: linear or branched C1-C8-alkanoyl, C3-C6- cycloalkanoyl, heteroarylcarbonyl, C1-C6-alkylaminocarbonyl, arylaminocarbonyl, C1-C6-alkylamino, C1-C6-acylamino, arylamino, benzoylamino, aryloxy, heteroaryl, C1-C6-alkoxycarbonyl, C6-aryloxycarbonyl, C1-C8-alkansulfonyl, arylsulfonyl, or 3,4-dihydro-1H-quinolyl-2-on; R is selected from: -H, OH; - heteroaryl group is selected from: pyridine, pyrimidine, pyrrole, thiophene, furan, indole, thiazole, oxazole; - α or β carboxyl residue can consist of straight or branched C1-C6-alkyl, C3-C6-cycloalkyl, optionally substituted with other carboxyl (COOH) group; - residue with formula SO2Rd, in which Rd is C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl or pyridyl, on condition that compounds of formula I are not the following compounds: (R)-2-(3-phenoxyphenyl)-propanoyl-phenylglycine; (R)-2-( phenoxyphenyl)-propanoyl-glycine; (R)-2-[(3'-acetyl)phenyl]-R-4''-pyrimidyl)propionamide. Invention also relates to method of obtaining formulaI compound and application of formula I compound for preparation of medications for treatment of diseases including C5a induced hemotaxis of human PMNs.

EFFECT: obtained are novel derivatives of (R)-2-arylpropionamide, possessing useful biological properties.

9 cl, 3 dwg, 2 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: method of detecting a compound which is a noncompetitive inhibitor of human immunodeficiency virus (HIV) protease (SEQ ID No:1) involves detection using alanine scanning methods and molecular docking of the compound at least with one atom of an amino acid residue selected from a group consisting of Asn98, Phe99, Asp29, Asp30, Arg8, Gly49, Gly51 and Gly52 SEQ ID NO:1, at a distance of not more than 5 Å.

EFFECT: increased effectiveness of the compounds.

4 cl, 2 dwg, 4 tbl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to (R)-enantiomers of 2-arylpropionamides of the formula (Ia): and their pharmaceutically acceptable salts wherein Aryl represents phenyl group substituted with a group chosen from isopropyl, acetyl, (2'',6''-dichlorophenyl)amino-group, α-hydroxyisopropyl, (R,S)-α-hydroxybenzyl and its individual R-isomers, (R,S)-(α-methylbenzyl) and its individual R-isomer and (R,S)-α-hydroxy-α-methylbenzyl and its individual R-isomer; R represents hydrogen atom (H) or (C1-C4)-alkyl; R' represents the following groups: -amino acid residue consisting of linear or branched (C1-C6)-alkyl substituted with carboxy-group -CO2H; -residue of the formula: -CH2-CH2X-(CH2-CH2O)nR wherein R has abovementioned values; n means a whole number from 0 to 1 while X represents oxygen atom; -heteroaryl chosen from the group consisting of 2-pyrimidinyl or 4-pyrimidinyl. Also, invention proposes a pharmaceutical composition inhibiting of interleukin-8-induced chemotaxis of neutrophiles and comprising as an active components (R)-enantiomers of 2-arylpropionamides of the formula (I) and their pharmaceutically acceptable salts in mixture with a suitable carrier. Also, invention proposes a method for preparing compounds of the formula (Ia). Also, invention proposes (R)-enantiomers of 2-arylpropionic acids of the formula (Va) given in the invention description and their pharmaceutically acceptable salts. Proposed (R)-2-arylpropionamides are useful in prophylaxis and treatment of tissue damage caused by enhanced accumulation of polymorphonuclear neutrophiles in the inflammation sites.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

13 cl, 6 tbl, 24 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

The invention relates to new derivatives of 2- (iminomethyl) aminobenzoyl General formula (I) where a represents either a radical represented by the formula of the invention in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms, R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4, R4means a linear or branched alkyl with 1-6 carbon atoms, or radicals represented by the formula of the invention, R5means a hydrogen atom, a group HE or linear or branched alkyl or alkoxy with 1-6 carbon atoms, means thienyl, X means Z1-, -Z1-CO-, -Z1-NR3-CO, -CH=CH-CO - or a simple bond, Y represents a radical chosen from the radicals Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2Q-in which Q means a simple bond, -O-Z3and-N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is an integer, R

The invention relates to analogs of 2-aminoindane General formula I, where R1and R2independently represent hydrogen, C1-C8alkyl; X is CH2R3or NHSO2R4; Y represents hydrogen, NHSO2R4, SO2(Ph); R3is NHSO2R4,

SO2R4, CONR1R2; R4represents C1-C8alkyl, phenyl or phenyl, substituted by-CN or-CF3; and their pharmaceutically acceptable salts, active receptor Dopamine D3
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