[1]The present invention relates to a process for the preparation of an intermediate material for producing a derivative of the efficacy as antagonists of the vanilloid receptor -1 (VR1, or TRPV1 (transient receptor potential vanilloid-1), such as formula (5).
[2]
BACKGROUND
[3]
Derivatives of vanilloid receptor corresponding to the formula (5) is a pungent component of red peppers capsaicin receptor (8-methyl-imidazol-6-nonene amide -N- bar). Molecular cloning of TRPV1 belongs to the TRP channel system (channel family) of the non-selective cation channel (non-selective cation channel) have been reported in 1997 (Caterina (Caterina) et al., 1997, Nature (Nature), 389, 816-824 side).
[4]
The TRPV1 is capsaicin, les shinny Blow toxin (resiniferatoxin), heat, acid, anandamide (anandamide), lipid is activated by stimuli such as metabolites or sensitization important as harmful integration Stimulator (molecular integrator) in mammals serve (Tommy out (Tominaga). in addition, severe pain accompanying increases the TRPV1 protein in the disease state. endogenous / exogenous (endogenous / exogenous) activation of TRPV1 by stimulation noxious stimulus delivery, as well as sub-instance blood from nerve, CGRP glass by the neuropeptide (neuropeptide), such as (calcitonin gene related peptide (calcitonin gene-related peptide)) resulting in neurogenic inflammation.
[5]
Also TRPV1 is highly expressed in inflammatory disorders such as gastrointestinal system (gastrointestinal tract) of the expressed on sensory neurons distributed over the entire region of irritable bowel syndrome (irritable bowel syndrome) and IBD (inflammatory bowel disease) (Chan (Chan ) et al., 2003, lancet (lancet), 361, p. 385-391; Glasgow amount (Yiangou), etc., 2001, lancet, 357, 1338-1339 side). The activation of TRPV1 stimulate the sensory nerves above-esophageal reflux disease (gastro-esophageal reflux disease, GERD) and stomach - which is known to play a decisive role in the onset of gastrointestinal disturbances (gastrointestinal disorder), such as duodenal ulcer (stomach duodenal ulcer) results in neuropeptide release (Holzer P., 2004, Pharma Blossom European Journal (Eur J. Pharmacol), p. 231-241;.. and so on to Petty (Geppetti), 2004, Pharma Blossom British Journal (Br.J. Pharmacol.), 141, 1313-1320 side). TRPV1- expressing afferent nerves and are abundantly distributed in the airway mucosa, bronchial hypersensitivity is very similar to the hyperalgesia and mechanisms. As the endogenous ligand (endogenous ligand) on TRPV1 known as proton and Lee Foxy past kinase (lipoxygenase) the product is well known as a major factor leading to the onset of asthma and chronic obstructive pulmonary disease (Huang et al., 2002, Pharma Blossom recent opinion ( ... Curr Opin Pharmacol) 235-242 pages;.. Spina (Spina), etc., 2002, Curr Opin Pharmacol 264-272 pages).
[6]
TRPV1 is the primary afferent sensory nerve, as well as distributed in human epidermal keratinocytes (human epidermal keratinocytes), and (denda (Denda), etc., 2001, Biochem Biophys Res Commun, 291, 1250-1250 side;.... Inoue ( Inoue), etc., 2002, Biochem Biophys Res Commun., 291, p. 124-129), and by delivering a variety of hazards irritation and pain, such as skin irritation and itching neurogenic / non-neurogenic factors (neurogenic / non-neurogenic factors caused by) closely related to the pathogenesis of skin diseases such as skin irritation and disturbances.
[7]
Recently, there is evidence for a role of TRPV1 and other collected over the years. TRPV1 may be involved in the blood flow / blood pressure control and control of plasma glucose concentration or type 1 diabetes pathogenesis through the sense functional vascular neuropeptide release (Inoue, etc., Cir Res, 2006, 99,119-31 side; La ratio (Razavi), etc., 2006, cell (cell), 127, p. 1123-35;.. etc grams (gram), 2007, Eur J. Neurosci, 25, 213-23 side). In addition, TRPV1 knockout mice have been reported than the wild-type pups times there is no difference in the movement looks less anxiety-related behaviors (anxiety-related behavior) (Marsh (Marsch), etc., 2007, J. Neurosci., 27 (4 ), p. 832-9).
[8]
And a variety of TRPV1 antagonists developed based on the above information in progress, several patents and patent applications related to TRPV1 being developed are public (Sala Municipality (Szallasi), etc., 2007, Nature Reviews dragged Discovery (Nat. Rev. Drug. Discov .), 6, p. 357-72; Appenzell Dino (Appendino), etc., 2006, progress in medicinal Chemistry (progress in medicinal Chemistry), 44, p. 145-180; and so on lamina (Rami), 2004, drag Discovery Today (Drug Discovery Today); treatment Strategy (therapeutic Strategies), 1, 97-104 pages;. Corel (Correll), etc., 2006, Expert Opin Ther Patents, 16, 783-795 pages; Kyle (Kyle), etc., 2006, Expert Opin . Ther. Patents, 16, 977-996 pages).
[9]
On the other hand, has been known as a production method for the derivative corresponding to the formula (5), the Republic of Korea Patent Publication No. 10-2009-0033916 discloses a base material a derivative and a method that corresponds to the formula (5) as VR-1 antagonists, in particular after the manufacture the cinnamoyl acid, discloses a method for preparing derivatives corresponding to formula (V) by a chiral amine and amidation. Manufacturing efficiency of cinnamoyl acid key intermediate in the method affects the production efficiency of the general formula (V). In addition, the efficiency of the pyridine intermediate produced is important in the production of the intermediate, cinnamoyl acid because it contains a pyridine structure, a key intermediate, cinnamoyl acid corresponding to the formula (V) efficiently. In order to produce a common intermediate pyridine sseuyigi wider method shown in Scheme 1 or 2, but this has the disadvantage that use a long reaction step and the raw material high risk to apply to mass production. Accordingly, due to uneconomic production process manufacturing efficiencies falling hard to the mass production applications. Also reported is the prior literature, but it improved low purity, the cost is relatively high due to the long reaction time and low batch efficiency is not easy to apply mass production
[10]
The present inventors, in the pyridine intermediate produced and completed the present invention having a high production efficiency and economic efficiency to identify the problems of the prior art and to improve by improving the disadvantage of low purity, the long reaction times and low placement efficiency of the prior art, this .
[11]
[Reaction Scheme 1]
[12]
[13]
[Reaction Scheme 2]
[14]
Detailed Description of the Invention
SUMMARY
[15]
Herein is to provide a method for efficiently producing the pyridine intermediates required for the preparation of a derivative corresponding to the formula (5) as described above efficiently. In particular, the present disclosure was to find a highly effective and can be applied to mass production manufacturing method in the manufacture of such a pyridine intermediate. To provide a method of and to utilize the nitrogen source efficiency is not used in the existing order to find a high production method for the pyridine intermediates, such as the manufacture of high yield and of high purity enamine in a short period of time producing the pyridine intermediate efficiently do.
Problem solving means
[16]
Filed on June 5, 2015 Korea Patent Application No. 10-2015-0079802 call is incorporated by reference herein as a whole for all purposes. The present application claims the Korea Patent Application No. 10-2015-0079802 favors profit, incorporated by reference herein in its entirety.
[17]
Herein in order to achieve the above object, the enamine prepared using the ammonium carbamate with a nitrogen source in the intermediate compounds, and provides a method for preparing a substituted pyridine intermediates by reacting them in the absence of a solvent.
Effects of the Invention
[18]
According to the method in accordance with one aspect of the invention, it is possible to prepare a substituted pyridine in high yield and short reaction time by a method consisting of at least two steps: Also disposed efficiency shows a high effect as that according to this method was to improve the yield and the reaction proceeds under a solvent-free and catalyst-free condition.
Best Mode for Carrying Out the Invention
[19]
The invention can relate to a process for preparing a compound having the structure of formula (3) according, to through a process of Scheme 3 to one side.
[20]
[Reaction Scheme 3]
[21]
[22]
The invention according to one aspect, there is provided a method for preparing a compound having the structure of formula 4,
[23]
(A) preparing an enamine (enamine) intermediate compound having the structure of formula (II) by reacting a compound having the structure and ammonium carbamate of the formula (1);
[24]
It can relate to a process comprising the; (b) reacting a compound having the structure of formula (III) and intermediates having the structure of formula (II) to prepare a compound having the structure of formula (4).
[25]
Formula 1
[26]
[27]
[Formula 2]
[28]
[29]
[Formula 3]
[30]
[31]
[Formula 4]
[32]
[33]
Wherein R 1 is hydrogen; C 1 -C 6 alkyl; Hydroxy C 1 -C 6 alkyl; C 1 -C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 halo-alkenyl; C 1 -C 2 vinyl substituted with alkoxycarbonyl or phenyl; C 2 -C 6 alkynyl; C 2 -C 6 haloalkyl alkynyl; Trimethylsilyl, hydroxyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxycarbonyl or an ethynyl substituted with phenyl; C 3 -C 6 Allen one (allenyl); C 3 -C 6 cycloalkyl; Substituted by halogen, C 3 -C 6 cycloalkyl; C 1 -C 6 alkoxy; C 3 -C 6 alkenyl-yloxy; C 3 -C 6 alkynyl-yloxy; C 1 -C 6 haloalkoxy; C 3 -C 6 halo-alkenyl-yloxy; Cyano -C 1 -C 4 alkoxy; C 1 -C 4 alkoxy -C 1 -C 4 alkoxy; C 1 -C 4 alkylthio -C 1 -C 4 alkoxy; C 1 -C 4 alkylsulfinyl -C 1 -C 4 alkoxy; C 1 -C 4 alkylsulfonyl -C 1 -C 4 alkoxy; C 1 -C 4 alkoxy-carbonyl -C 1 -C 4 alkoxy; C 1 - 6 alkylthio; C 1 -C 6 alkylsulfinyl group; C 1 -C 6 alkylsulfonyl; C 1 -C 6 haloalkylthio; C 1 -C 6 haloalkylsulfinyl group; C 1 -C 6 haloalkyl sulfonyl; C 1 -C 4 alkoxycarbonyl - C 1 -C 4 alkylthio; C 1 -C 4 alkoxy-carbonyl -C 1 -C 4 alkylsulfinyl; C 1 -C 4 alkoxy-carbonyl -C 1 -C 4 alkylsulfonyl; Benzyl -S (O) n1 -; C 1 -C 6 alkylamino; C 2 -C 6 dialkylamino; C 1 -C 6 alkylamino-sulfonyl; Di - (C 1 -C 6 alkylamino) sulfonyl; Benzyloxy; benzyl; Phenyl; Phenoxy; Phenylthio; Phenyl sulfinyl; Phenylsulfonyl; And C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, halogen, cyano, nitro or a phenyl-containing group (pheynyl-containing groups) is substituted by; OS (O) n2 -R 21 ; N (R 23 ) -S (O) n3 -R 22 ; Cyano; Carbamoyl; C 1 -C 4 alkoxycarbonyl; Formyl; halogen; Thiocyanate NATO; Amino; C 1 -C 4 alkoxy -C 1 -C 4 alkyl; C 1 -C 4 alkyl -S (O) n4 -C 1 -C 4 alkyl; Cyano -C 1 -C 4 alkyl; C 1 -C 6 alkylcarbonyloxy -C 1 -C 4 alkyl; C 1 -C 4 alkoxy-carbonyl -C 1 -C 4 alkyl; C 1 -C 4 alkoxycarbonyloxy -C 1 -C 4 alkyl; C 1 -C 4 alkylthio cyanatophenyl -C 1 -C 4 alkyl; Benzoyloxy -C 1 -C 4 alkyl; C 2 -C 6 oxiranylmethyl (oxiranyl); C 1 -C 4 alkylamino, -C 1 -C 4 alkyl; Di - (C 1 -C 4 - alkyl) amino -C 1 -C 4 alkyl; C 1 -C 12 alkylthio-carbonyl -C 1 -C 4 alkyl; Formyl -C 1 -C 4Alkyl; A 5- to 10 atom monocyclic or fused bicyclic ring system, may be a saturated or partially aromatic, the heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur and may contain 1 to 4 and, C 1 -C 4 alkylene, -CH = CH-, -C≡C-, -CH 2 O-, -CH 2 N (C 1 -C 4 alkyl) - , -CH 2 SO-, or- CH 2 SO 2 - may be bonded to the pyridine ring via a group, and each ring system may contain an oxygen atom and a sulfur atom no more than two, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 halo-alkenyl, C 3 -C 6 alkynyl, C 3 -C 6 halo-alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 alkene yloxy, C 3 -C 6 alkynyl-yloxy, mercapto, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 3 -C 6 alkenyl, alkylthio, C 3 -C 6 halo-alkenyl, alkylthio, C 3 -C 6 alkynyl, thio, C 2 -C 5 alkoxy alkylthio, C 3 -C 5 -acetyl-alkylthio, C 3 -C 6 al Cock Brassica Viterbo carbonyl alkylthio, C 2 -C 4 cyano alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkyl sulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkyl alkylsulfonyl, aminosulfonyl, C 1 -C 2 alkylamino-sulfonyl, di - (C 1 -C 2 alkyl) aminosulfonyl, di - (C 1 -C 4 alkyl) amino, halogen, cyano, nitro, , a mono-substituted with phenyl and benzylthio, di-or tri is one selected from the group consisting of substituted-type ring system;
[34]
Wherein R 2 is C 1-6 halo-alkyl;
[35]
Wherein R 3 is hydrogen or C 1 -C 6 can be an alkyl.
[36]
[37]
In one aspect of the invention, the R 1 is hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 halo-alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 halo-alkynyl, C 3 -C 6 substituted by cycloalkyl, halogen-C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 alkenyl-yloxy, C 3 -C 6 alkynyl-yloxy, C 1 -C 6 haloalkoxy, C 3 -C 6 halo-alkenyl-yloxy, C 1 - 6 alkylthio, C 1 -C 6 alkylsulfinyl , C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylthio, C 1 -C 6 haloalkyl sulfinyl, C 1 -C 6 haloalkyl sulfonyl, C 1 -C 6 alkylamino, C 2 - C 6 dialkylamino, C 1 -C 6 alkylamino sulfonyl, benzyloxy, benzyl, phenyl, phenoxy, phenylthio, phenyl-sulfinyl, phenylsulfonyl, or a;
[38]
Wherein R 2 is trifluoromethyl, difluoro-chloro-methyl, pentafluoroethyl, heptafluoropropyl or difluoromethyl methyl; Wherein R 3 is hydrogen or C 1 -C 3 may be alkyl.
[39]
In one aspect of the invention, the R 1 is C 1 -C 6 alkyl; Wherein R 2 is trifluoromethyl, difluoro-chloro-methyl, pentafluoroethyl, heptafluoropropyl or difluoromethyl methyl; Wherein R 3 is C 1 -C 3 may be alkyl.
[40]
In one aspect of the invention, the R 1 is n- propyl; Wherein R 2 is trifluoromethyl; Wherein R 3 may be methyl or ethyl.
[41]
In one aspect of the invention, the R 1 is n- propyl, and wherein R 2 is a trifluoromethyl, said R 3 -methyl-2-propyl-6- (trifluoromethyl with the case where the structure of formula (4) methyl Romero may be a teal) nicotinate. Specifically, R 3 is methyl and R 1 is a profile compound having the structure of Formula 2 may be a methyl butyryl acetate. In addition, the R concretely second case is a trifluoromethyl compound having the structure of formula (3) may be turned on-3-butene-2-ethoxy-l, l-trifluoro-4-on.
[42]
[43]
In one aspect of the invention, the step (a) may be reacted under the organic solvent.
[44]
In one aspect of the invention, the organic solvent may be at least one selected from methanol, ethanol, propanol, isopropyl alcohol, butanol, ethyl acetate, dichloromethane, acetone, hexane, toluene, benzene, xylene, and the group consisting of acetonitrile can. Specifically, in one aspect of the invention, the organic solvent may be methanol.
[45]
In one aspect of the invention, the step (a) may be a step of reacting the mixture was stirred for 30 minutes to 90 minutes at a temperature of 15 ~ 30 ℃ the compound with ammonium carbamate having a structure of the formula (I). Specifically, the stirring temperature may be in the 10 to 30 ℃, may be more specifically 15 ~ 25 ℃, more specifically 25 ℃. In addition, the mixing time may be a concrete is 90 min to 30 min, may be 50 minutes to 70 minutes, and more specifically, more specifically 60 minutes.
[46]
In one aspect of the invention, the step (b) may be to (a) back to the product produced by step removal of the organic solvent in the reaction solvent and the non-catalytic conditions.
[47]
In one aspect of the invention, the (b) step may be step, characterized in that is reacted in the absence of a solvent and a catalyst to prepare a compound having the structure of formula (4).
[48]
Method in accordance with one aspect of the present invention is characterized by showing a yen significantly higher yield than the method of reaction by the addition of solvent or catalyst, by the reaction in which the amine is involved reacting in the absence of solvent and non-catalytic conditions as described above do. For example, in a method using the ammonium acetate can be used, but an excess of acetic acid as a catalyst President and solvent, it is for preparing the compound under these conditions, low yield as compared to the present invention. In the case of the method of synthesis it does not generate the enamine as an intermediate, but as toluene, a catalyst with a solvent to use trifluoroacetic acid, the yield is low in comparison to the present invention, even in this case. Thus, the method of the present invention is remarkably effective to give the arrangement efficiency of the compound as to progress the reaction in the absence of solvent and non-catalytic conditions or state represents a high effect.
[49]
In one aspect of the invention, the step (b) reacting the mixture was stirred for 2 hours to 4 hours the compound with the structure of the enamine of the formula 3 having the structure of formula 2 at a temperature of 70 ~ 120 ℃ days can.
[50]
In one aspect of the present invention, the reaction of step (b) may be to stir for 2 hours to 4 hours at a temperature of 70 ~ 120 ℃. Specifically, the stirring temperature may be 70 ~ 120 ℃, may be specifically 70 ~ 110 ℃, 70 ~ 100 ℃, 70 ~ 90 ℃, 75 ~ 85 ℃, or 78 ~ 82 ℃, more specifically 80 ℃ one can. In addition, the stirring time, specifically may be a 2-hour to 4 hours, may be more specifically 3 hours.
[51]
In one aspect of the invention, the method may be a method yields more than 70% to obtain a compound having the structure of formula (4). Specifically, the yield is 60% or more, 65% or higher, 70% or more, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 99% or more days, and 100% or less, 95% or less, and may be 90% or less, 85% or less, 80% or less, 75% or less, 70%, or up to 65%.
[52]
In one aspect of the present invention, (a) step can be reacted with the ammonium carbamate from 0.8 to 1.2 equivalents relative to 1 equivalent of the compound having the structure of formula (1). Specifically equivalent weight of ammonium carbamate for the compound 1 equivalent having the structure of formula (I) is more than 0.1 equivalent, at least 0.2 equivalents, more than 0.5 equivalent, at least 0.8 equivalents, 0.9 equiv., 1.0 eq., At least 1.05 equivalents, 1.1 eq. , at least 1.2 equivalents, more than 1.3 equivalents, or a range from 1.5 equivalents or 2.0 equivalents, 1.5 equivalents or less, 1.3 equivalents or less, less than 1.2 equivalents, 1.1 equivalents or less, less than 1.05 equivalents, 1.0 equivalent or less, less than 0.9 eq., 0.8 eq. , it may be up to more than 0.5 equivalent weight, more than 0.2 eq., or 0.1 eq.
[53]
The invention in one aspect, may be of having a structure of the formula (4) produced by the method according to an aspect of the invention compound.
[54]
The invention can relate to a process for the preparation of compound having the structure of Formula 4 comprising the steps as described below, in one aspect:
[55]
(1) mixing a compound with ammonium carbamate having a structure of formula (I) in an organic solvent.
[56]
In one aspect of the invention, after the method (1) was stirred for 2 mixed solution after the step at room temperature (15 ~ 25 ℃), further comprising the step of distillation under reduced pressure to remove the organic solvent can.
[57]
In one aspect of the invention, the above-mentioned (2) was stirred at step is 30 minutes to 90 minutes, more specifically 40 min to 80 min, more specifically 50 min to 70 min, more specifically 55 min to 65 min. Stirring for It may be to.
[58]
In one aspect of the present invention, (2) pressure in the distillation step may be carried out at 50 ℃ to 70 ℃, more specifically 65 to 55 ℃ ℃, more specifically 58 to 62 ℃ ℃.
[59]
In one aspect of the present invention, (2) pressure in the distillation step may be carried out at a pressure 1torr to 20torr, specifically 5torr to 15torr, 8torr 12torr to be more specific.
[60]
In one aspect of the invention, the above-mentioned (2) was evaporated under reduced pressure in the step may be performed for 10 to 60 minutes, specifically 20 to 40 minutes, more specifically 25 min to 35 min.
[61]
In one aspect of the invention, the method (2) 3, distillation in a later stage the enamine having the structure rest of formula (2) may further comprise the steps of: In the compounds having the structure of formula (3) and the mixture was stirred have.
[62]
In one aspect of the invention, the stirring in (3) may be carried out at 60 ~ 100 ℃, more particularly 70 ~ 90 ℃, 75 ~ 85 ℃ in more detail.
[63]
In one aspect of the invention, the stirring in (3) can be carried out for 1 to 5 hours, more specifically 2 to 4 hours, more particularly 2.5 ~ 3.5 hours.
[64]
In one aspect of the invention, the method (3) If after the step (4) After stirring the reaction was completed and mixed further added after heptane and hydrochloric acid was cooled to room temperature, and further comprising the step of extracting the organic layer can.
[65]
In one aspect of the invention, the cooling of step (4) step may be one of 15 ~ 30 ℃, more particularly 20 ~ 30 ℃, more specifically, cooling to 23 ~ 27 ℃.
[66]
In one aspect of the invention, the hydrochloric acid in (4) steps is 0.1 ~ 3N, may be more specifically 0.5 ~ 1.5N, more specifically, a concentration of 0.8 ~ 1.2N.
[67]
In one aspect of the invention, the method (4) after step (5) After washing the extracted organic layer with water and brine, followed by stirring into a magnesium sulfate, comprising the step of obtaining a compound having the structure of formula (4) more can do.
[68]
In one aspect of the invention, the stirring in 4 steps can be carried out for 1 to 20 minutes, more specifically 2 to 10 minutes, more particularly from 3 to 7 minutes.
[69]
In one aspect of the invention, the above (4) step may further perform filtering after stirring. Specifically the above (4) step by filtration can be carried out on buchner funnel.
[70]
In one aspect of the invention, the above (4) step may be performed further was concentrated under reduced pressure after filtration.
[71]
In one aspect of the invention, the concentration under reduced pressure (4) step can be carried out at a pressure 1torr to 20torr, specifically 5torr to 15torr, 8torr 12torr to be more specific.
[72]
In one aspect of the invention, the concentration under reduced pressure (4) step can be carried out at a temperature of 20 ~ 60 ℃, 30 ~ 50 ℃, 35 ~ 45 ℃ more specifically in more detail.
[73]
In one aspect of the invention, the concentration under reduced pressure (4) step can be carried out for 20 to 60 minutes, 30 ~ 50 minutes, and more specifically, more particularly 35-45 minutes.
[74]
In one aspect of the invention, the above-mentioned (2) in step gapap distillation may be to remove the organic solvent.
[75]
The terms are intended to mean the term in a range that can be ordinary skill apparent recognized in the art, such as substituted alkyl are other atoms of one or more bonds other than hydrogen in the alkyl chain as used herein or may mean that a substitution in a different formula.
[76]
In one aspect of the invention, methyl butyryl acetate (methyl acetate butyryl) The compound is methyl 3-oxo-caproate, also called as (methyl 3-oxocaproate), and the Cas No. 30414-54-1, molecular weight of 144.17 Da the can mean.
[77]
In one aspect of the invention, l, l-ethoxy-4-trifluoro-3-butene-2-one (4-ethoxy-1,1,1-trifluoro-3-buten-2-one ) can be a Cas No. 17129-06-5, molecular weight means a compound of 168.11 Da.
[78]
In one aspect of the invention, the ammonium carbamate (ammonium carbamate) is a Cas No. 1111-78-0, and may be a compound having a molecular weight of 78.07 Da.
[79]
In one aspect of the invention, the methyl-2-propyl-6- (trifluoromethyl) nicotinate (methyl 2-propyl-6- (trifluoromethyl) nicotinate), methyl 2-propyl-6-trifluoromethyl-nicotinoyl can be referred to as a tinik acid methyl ester (2-propyl-6-trifluoromethyl-nicotinic acid methyl ester) also and which may be used less mutual and INT-4 herein exchange, molecular weight can mean 247.21 Da the compound have.
[80]
[81]
In the following, examples and test example, the configuration and effect of the present invention will be described in detail. However, these examples and test examples are not intended to be limited by the examples to the spirit and scope of the invention as only be provided for purposes of illustration to aid understanding of the present invention.
[82]
[83]
[Example 1] (trifluoromethyl) methyl-2-propyl-6 by a method according to an aspect of the invention the production of nicotinate
[84]
[85]
A 500ml round bottom flask was charged methyl butyryl acetate (22.8g, 0.158mol) (Alfa Aesar) and ammonium carbamate (13.5g, 0.173mol) (Sigma Aldrich) was mixed in 200ml of methanol. The mixture was distilled in and then stirred for 60 minutes at 25 ℃ 60 ℃, 10torr reduced pressure for 30 minutes. In the l, l-ethoxy-4-trifluoromethyl in the remaining liquid (enamine) after distillation 3-butene-2-one (32g, 0.190mol) and stirred at 80 ℃ for 3 hours. After the reaction terminated, the reaction cooled to 25 ℃ and then a solution further added 300ml of heptane and 300ml of 1N hydrochloric acid and extracted the organic layer. After washing the extracted organic layer with saturated brine, 400ml and 400ml water, put the sodium sulfate 5g 5 min. Stirring a rear, view with a Buchner funnel and filtered 10torr, and concentrated under reduced pressure at 40 ℃ for 40 minutes a yellow liquid 31.2g (80% for ) was obtained.
[86]
So NMR result of the obtained yellow liquid was as follows.
[87]
1H NMR(400MHz, DMSO-d6): δ8.40 (d, 1H, J = 1.2Hz), δ7.87 (d, 1H, J = 1.2Hz), 3.91 (s, 3H), 3.08 ~ 3.04 (m, 2H), 1.69 ~ 1.65 (m, 2H), 0.94 ~ 0.90 (t, 3H, J = 1.2Hz).
[88]
[89]
Comparative Example 1
[90]
By putting the ammonium carbamate instead of ammonia gas in the process of Example 1 of yellow liquid 3.9g (10%) was obtained in the same process.
[91]
[92]
Comparative Example 2
[93]
By putting the ammonium carbamate instead of ammonium acetate in the process of Example 1 of yellow liquid 7.8g (20%) was obtained in the same process.
[94]
[95]
[Comparative Example 3]
[96]
Example 1 process, a yellow liquid 5.85g (15%) was obtained in the same process without performing the step of removing the methanol by distillation under reduced pressure in the.
[97]
[98]
Comparative Example 4
[99]
The first embodiment of the process, methyl butyryl acetate (1 eq) and ammonium acetate (2 equiv.) Without generating in Nu INC was stirred for 3 hours at 80 ℃ a mixture of acetic acid 200ml. Then when the reaction was completed, the reaction was cooled to 25 ℃ and the organic layer was extracted and mixed with further adding 300ml of heptane and 300ml of 1N hydrochloric acid. After washing the extracted organic layer with saturated brine, 400ml and 400ml water, put the sodium sulfate 5g stirring, then filtered and concentrated under reduced pressure to obtain a yellow liquid 21.06g (54%).
[100]
[101]
Comparative Example 5
[102]
The Example 1 process, INC seeds generated when methyl butyryl acetate (1 equivalent) in an ammonia gas (excess) was mixed in 200ml of toluene. Then, without performing the process of removing the toluene solvent, the mixed solution was stirred at 25 ℃ for 4 hours. In a Then-ethoxy-l, l-trifluoro-4-on-3-butene-2-one (1.2 eq.) Of trifluoroacetic acid, and with the further stirred at 80 ℃ for 3 hours. After the reaction terminated, the reaction cooled to 25 ℃ and then a solution further added 300ml of heptane and 300ml of 1N hydrochloric acid and extracted the organic layer. After washing the extracted organic layer with saturated brine, 400ml and 400ml water, put the sodium sulfate 5g stirring, then filtered and concentrated under reduced pressure to obtain a yellow liquid 16.77g (43%).
[103]
[104]
Shown in the Examples and Comparative Examples in the process yen to the yield of the reaction time in the preparation of amines, (trifluoromethyl) kinds of ammonium source and an equivalent weight using the 2-propyl-6-methyl nicotinate Table 1 It was.
[105]
TABLE 1
Ammonia sources The amount (eq) Enamine produced during the reaction time (hr) Yield (%) of the product
Example 1 Ammonium carbamate, 1.05 1 80
Comparative Example 1 Ammonia gas Excess 1 10
Comparative Example 2 Ammonium acetate 2 1 20
Comparative Example 3 Ammonium carbamate, 1.05 1 15
Comparative Example 4 Ammonium acetate 2 - 54
Comparative Example 5 Ammonia gas Excess 4 43

[106]
[107]
According to the results of Table 1, according as the yen prepared amine as a method according to an aspect of the invention ammonium cover When using a formate, yen FIG yield of the production and the reaction time of the amine the shortest, and the product as a 1 hour it was confirmed that the highest.
[108]
In the yield of the product, according to the method according to an aspect of the invention the INT-4 is obtained in a yield of 80% it was able to obtain a product with the highest yield. But it goes to the steps as was shown ammonia source to the 10 and 20% and the yield of the resulting product was conducted with ammonia gas, and ammonium acetate, which is a remarkable increase in the yield of the ammonia source to the ammonium carbamate according to the present invention by the effect was found to represent.
[109]
Comparing the results of the comparison by the experiment without removing the solvent in the process according to one aspect of the invention Example 3, compared without removing the methanol solvent in comparison with the case of the present invention the absence of solvent conditions, Example 3 of the product the yield was very low at 15%. Therefore, This was confirmed to be significantly increased the efficiency of the product to proceed with the reaction in a solvent-free condition as in the present invention.
[110]
In the case of Comparative Example 4 corresponds to the use of ammonium acetate as an ammonia source, and a method using an acid catalyst in a solvent president, without separately yen-amine proceed with a reaction. These non-catalytic conditions in the absence of solvent and ammonium carbamate, a yield of the product as compared to the present invention, the reaction proceeds as in the case it was confirmed that remarkably low.
[111]
Comparative Example 5 In the case of yen using ammonia gas generated during the amine in toluene solvent, and an amine-en-3-acetic acid under the catalyst trifluoro-ethoxy -1, 1, 1-trifluoro-2-butene back to the 4 It corresponds to a method in which the whole reaction. These non-catalytic conditions in the absence of solvent and ammonium carbamate, a yield of the product as compared to the present invention, the reaction proceeds as in the case it was confirmed that remarkably low. Moreover, Yen at the time methods are significantly reduced in accordance with the invention in the generation time of an amine yen was more economical to produce an amine.
[112]
Therefore, in the case of the process according to the invention in spite of Sikkim proceeding the reaction without a catalyst and a solvent, and a high to a yield of INT-4 significantly over other comparative examples, and thus cost-effective and high purity in an efficient manner INT-4 It can be produced. In addition, the use of ammonium carbamate as an ammonia source as intermediate in preparing a pyridine such as methyl 2-propyl-6- (trifluoromethyl) nicotinate as compared to other ammonia sources, notably the time and yield It shows the effect of rising, which results will be able to synthesize the compound in a more economical.

Claims

[Claim 1]A method for preparing a compound having the structure of formula 4, (a) preparing an enamine (enamine) intermediate compound having the structure of formula 2 by reacting structure having compound and ammonium carbamate of the formula (1); ( b) reacting the intermediate with a compound having the structure of formula 3 having the structure of formula (II) to prepare a compound having the structure of formula 4; comprising the [formula 1] [Chemical formula 2] [Chemical formula 3] [Chemical formula 4] wherein R 1 is hydrogen; C 1 -C 6 alkyl; Hydroxy C 1 -C 6 alkyl; C 1 -C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 halo-alkenyl; C 1 -C 2 vinyl substituted with alkoxycarbonyl or phenyl; C 2 -C 6 alkynyl; C 2 -C 6 haloalkyl alkynyl; Trimethylsilyl, hydroxyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxycarbonyl or an ethynyl substituted with phenyl; C 3 -C 6 Allen one (allenyl); C 3 -C 6 cycloalkyl; Substituted by halogen, C 3 -C 6 cycloalkyl; C 1 -C 6 alkoxy; C 3 -C 6 alkenyl-yloxy; C 3 -C 6 alkynyl-yloxy; C 1 -C 6 haloalkoxy; C 3 -C 6 halo-alkenyl-yloxy; Cyano -C 1 -C 4 alkoxy; C 1 -C 4 alkoxy -C 1 -C 4 alkoxy; C 1 -C 4 alkylthio -C 1 -C 4 alkoxy; C 1 -C 4 alkylsulfinyl -C 1 -C 4 alkoxy; C 1 -C 4 alkylsulfonyl -C 1 -C 4 alkoxy; C 1 -C 4 alkoxy-carbonyl -C 1 -C 4 alkoxy; C 1 - 6 alkylthio; C 1 -C 6 alkylsulfinyl group; C 1 -C 6 alkylsulfonyl; C 1 -C 6 haloalkylthio; C 1 -C 6 haloalkylsulfinyl group; C 1 -C 6 haloalkyl sulfonyl; C 1 -C 4 alkoxycarbonyl - C 1 -C 4 alkylthio; C 1 -C 4 alkoxy-carbonyl -C 1 -C 4 alkylsulfinyl; C 1 -C 4 alkoxy-carbonyl -C 1 -C 4 alkylsulfonyl; Benzyl -S (O) n1 -; C 1 -C 6 alkylamino; C 2 -C 6 dialkylamino; C 1 -C 6 alkylamino-sulfonyl; Di - (C 1 -C 6 alkylamino) sulfonyl; Benzyloxy; benzyl; Phenyl; Phenoxy; Phenylthio; Phenyl sulfinyl; Phenylsulfonyl; And C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, halogen, cyano, nitro or a phenyl-containing group (pheynyl-containing groups) is substituted by; OS (O) n2 -R 21 ; N (R 23 ) -S (O) n3 -R 22 ; Cyano; Carbamoyl; C 1 -C 4 alkoxycarbonyl; Formyl; halogen; Thiocyanate NATO; Amino; C 1 -C 4 alkoxy -C 1 -C 4 alkyl; C 1 -C 4 alkyl -S (O) n4 -C 1 -C 4 alkyl; Cyano -C 1 -C 4 alkyl; C 1 -C 6 alkylcarbonyloxy -C 1 -C 4 alkyl; C 1 -C 4 alkoxy-carbonyl -C 1 -C 4 alkyl; C 1 -C 4 alkoxycarbonyloxy -C 1 -C 4 alkyl; C 1 -C 4 alkylthio cyanatophenyl -C 1 -C 4 alkyl; Benzoyloxy -C 1 -C 4 alkyl; C 2 -C 6 oxiranylmethyl (oxiranyl); C 1 -C 4 alkylamino, -C 1 -C 4 alkyl; Di - (C 1 -C 4 - alkyl) amino -C 1 -C 4 alkyl; C 1 -C 12 alkylthio-carbonyl -C 1 -C 4 alkyl; Formyl -C 1 -C 4 alkyl; A 5- to 10 atom monocyclic or fused bicyclic ring system, may be a saturated or partially aromatic, the heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur and may contain 1 to 4 and, C 1 -C 4 alkylene, -CH = CH-, -C≡C-, -CH 2 O-, -CH 2 N (C 1 -C 4 alkyl) - , -CH 2 SO-, or- CH 2 SO 2 - may be bonded to the pyridine ring via a group, and each ring system may contain an oxygen atom and a sulfur atom no more than two, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 halo-alkenyl, C 3 -C 6 alkynyl, C 3 -C 6 halo-alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 alkene yloxy, C 3 -C 6 alkynyl-yloxy, mercapto, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 3 -C 6 alkenyl, alkylthio, C 3 -C 6 halo-alkenyl, alkylthio, C 3 -C 6 alkynyl, thio, C 2 -C 5 alkoxy alkylthio, C 3 -C 5 -acetyl-alkylthio, C 3 -C 6 al Cock Brassica Viterbo carbonyl alkylthio, C 2 -C 4 cyano alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkyl sulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkyl alkylsulfonyl, aminosulfonyl, C 1 -C 2 alkylamino-sulfonyl, di - (C 1 -C 2 alkyl) aminosulfonyl, di - (C 1 -C 4 alkyl) amino, halogen, cyano, nitro, , a mono-substituted with phenyl and benzylthio, di-or tri selected from the group consisting of a substituted cyclic system and; wherein R 2 is C 1-6 halo-alkyl; wherein R 3 is hydrogen or C 1 -C 6 alkyl.
[Claim 2]
2. The method of claim 1, wherein R 1 is hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkyl alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 halo-alkynyl, C 3 -C 6 cycloalkyl, by halogen-substituted C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 - C 6 alkene yloxy, C 3 -C 6 alkynyl-yloxy, C 1 -C 6 haloalkoxy, C 3 -C 6 halo-alkenyl-yloxy, C 1 - 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylthio, C 1 -C 6 haloalkyl sulfinyl, C 1 -C 6 haloalkyl sulfonyl, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, C 1 -C 6 alkylamino sulfonyl, benzyloxy, benzyl, phenyl, phenoxy, phenylthio, phenyl-sulfinyl, phenylsulfonyl, or a; wherein R 2 is a methyl, difluoro-trifluoromethyl-chloro methyl, pentafluoroethyl, heptafluoro-in profile, or difluoromethyl methyl; wherein R 3 is hydrogen or C 1 -C 3 method alkyl.
[Claim 3]
3. The method of claim 2, wherein R 1 is C 1 -C 6 alkyl; wherein R 2 is trifluoromethyl, difluoro-chloro-methyl, pentafluoroethyl, heptafluoro-in profile, or difluoromethyl methyl; wherein R 3 is C 1 -C 3 alkyl manner.
[Claim 4]
4. The method of claim 3, wherein R 1 is n- propyl; wherein R 2 is trifluoromethyl; wherein R 3 is methyl or ethyl method.
[Claim 5]
The method of claim 1, wherein said (a) step is to reaction in an organic solvent.
[Claim 6]
The method of claim 5, wherein the organic solvent is one or more method selected from the group consisting of methanol, ethanol, propanol, isopropyl alcohol, butanol, ethyl acetate, dichloromethane, acetone, hexane, toluene, benzene, xylene, and acetonitrile.
[Claim 7]
7. The method of claim 6 wherein the organic solvent is methanol manner.
[Claim 8]
6. The method of claim 5, the method of the step (b) (a) back to the product produced by step removal of the organic solvent in the reaction solvent and the non-catalytic conditions.
[Claim 9]
The method of claim 1 wherein the (b) step is a step, characterized in that is reacted in the absence of a solvent and a catalyst to prepare a compound having the structure of formula (4).
[Claim 10]
The method of claim 1 wherein the method yields more than 70% to obtain a compound having the structure of formula (4).
[Claim 11]
The method of claim 1 wherein, (a) step is the one of reacting the ammonium carbamate from 0.8 to 1.2 equivalents relative to 1 equivalent of the compound having the structure of formula (1).
[Claim 12]
In, (a) step is a step of reacting the mixture was stirred for 50 minutes to 70 minutes at a temperature of 15 ~ 30 ℃ the compound with ammonium carbamate having a structure of formula (I) in claim 1.
[Claim 13]
In, (b) step is a step of reacting the mixture was stirred for 2 hours to 4 hours at a temperature of the compound having the structure of the enamine of the formula 3 having the structure of formula 2 70 ~ 120 ℃ to claim 1.
[Claim 14]
Any one of claims 1 to 13 compounds having the structure of formula (IV) prepared by the method according to any one of items.