阅读说明：本技术 一种直接合成n3f甲基羰基酰胺及其衍生物的方法 (Method for directly synthesizing N3F methylcarbonylamide and derivatives thereof ) 是由 付远 张友亮 谌昀 于 2020-05-07 设计创作，主要内容包括：本发明公开了一种获得酰胺的N3F甲基类似物和相关的羰基化合物直接的合成方法。该合成方案的可行是依赖于首先通过操作简单的制备稳定的氨基甲酰氟化物构建块,这些构建块可以很容易地多样化为相应的F3C-N酰胺、氨基甲酸酯、硫代氨基甲酸酯和尿素。这种方法可以容纳丰富的官能化,并且使得立体化学成为可能,本发明提供了许多高度官能化的化合物的直接合成方案,包括广泛使用的药物、抗生素、激素和聚合物单元的类似物。(The invention discloses a direct synthesis method for obtaining N3F methyl analogue of amide and related carbonyl compounds. The feasibility of this synthetic scheme relies on first preparing stable carbamoyl fluoride building blocks by simple manipulation, which can be easily diversified into the corresponding F3C-N amides, carbamates, thiocarbamates and ureas. This approach can accommodate abundant functionalization and enables stereochemistry, and the present invention provides a direct synthetic scheme for many highly functionalized compounds, including widely used drugs, antibiotics, hormones, and analogues of polymer units.)

1. A method for the direct synthesis of N3F methylcarbonylamide and its derivatives, characterized in that the method consists in first developing a simple method to obtain robust precursors, then modifying the precursors to produce various F3C-N carbonyl compounds, and finally deriving various stereochemical derivatives by continuing chemical modifications at F3C-N carbonyl.

2. The precursor according to claim 1 is N3F methylcarbamoyl fluoride, which belongs to a class of compounds that can be synthesized by a one-pot synthesis procedure starting from readily available isothiocyanate (R-NC) (1.0 eq) and adding an excess of silver fluoride (5.0 eq) and the solid reagent bis (trichloromethyl) carbonate (BTC) (0.4 eq), the reaction temperature being room temperature and the reaction solvent being acetonitrile, N3F methylcarbamoyl fluoride can be synthesized directly as building block (precursor), possibly as a basis for further derivatization, with a yield of precursor fluoride between 60% and 99% (precursor prepared by the present method, yield > 90% in > 75%).

3. Precursor modification according to claim 1, wherein the N3F methylamide can be easily obtained from these carbamoyl fluoride precursors by directly adding Grignard reagent, using the construct synthesized in claim 2 at room temperature, and toluene as solvent, by the following reaction processes: the amide was obtained by R-N (CF3) COF (1.0 equivalent, where R represents any functional group), RMgX (1.2 equivalent), standing in toluene at room temperature for 10 minutes.

4. The derivatization method for synthesizing N3F methylamide from trifluoromethyl aminocarboxamide is characterized in that the F3C-N carbonyl motif has stable properties, the stability enables the N3C-N carbonyl motif to play an important role in different disciplines, and various substances with different practicability can be derived by adopting corresponding chemical reaction processes, and the method ranges from various aspects such as disease resistance (drugs) and drug resistance (antibiotics and herbicides) to the creation of new materials (polymers and coatings) and the manipulation of biological processes.

5. The stability of the F3C-N carbonyl motif according to claim 4, wherein the motif stability F3CN > H3CN > HN is performed by placing the corresponding derivative precursor in NaOH pH =14 solution at room temperature.

Synthesis of F3C-N derivatives, characterized in that urea and carbamate are prepared from R-N (CF3) COF (1.0 equiv.), NUH and catalytic DMAP (0.1 equiv.) in dichloromethane at room temperature, C, N thio-and selenocarbamates are prepared from R-N (CF3) COF (1.0 equiv.), NaNu (1.2 equiv.).

Technical Field

The invention relates to a general and simple method for synthesizing N3F methylcarbonylamide and derivative compounds thereof.

Background

Amide units are present in many drug complexes, such as atorvastatin (lipitor) and ledebovir (havoni), which is one of the best marketed drugs in the world to date (fig. 1). Families of compounds closely related to amides, such as urethanes and ureas, also have similar effects and are useful as pesticides, polymers (foams, elastomers, polyurethanes), preservatives, cosmetics, and pharmaceuticals (e.g., as chemotherapeutic and anti-aids drugs).

Despite the good enabling effects of both N-methylation and fluorination, the N3F methylamide motif has not been substantially explored to date. The most common strategy for forming amide bonds involves linking a primary or secondary amine to a suitable carbonyl electrophile. However, this approach is unlikely to provide a general route to F3C-N amide, not only because the secondary trifluoromethylamine, H-N (r) (CF3), is difficult to synthesize, but also because the non-aromatic example synthesis may have poor stability due to the elimination of fluorine (and the entire HF) with the aid of a nitrogen lone pair.

Disclosure of Invention

The invention provides a method for directly obtaining N3F methyl amide, carbamate, thiocarbamate and urea

The stereochemical building of such compounds, which is tolerant of abundant functionalization, and many examples of highly functionalized compounds-including widely used drugs, antibiotics, hormones, and analogs of polymer units-have been successfully synthesized by the present invention.

Drawings

Representative examples of amides and related compounds synthesized in figure 1. a. Selected pharmaceutical compounds containing amide or carbamate groups. Representative materials containing amide or urethane groups. c, we obtained a method of the F3C-N carbonyl family from stable precursors.

FIG. 2 is a schematic diagram showing the mechanism of synthesis and typical construction of N3F methylcarbamoyl building blocks.

FIG. 3 shows an example of a constructed block that has been successfully synthesized; superscript a denotes NMR¹H spectrum is used for quantitative analysis. Reaction conditions for superscript b were carried out at 50 ℃ OTF, trifluoromethaneA sulfonate salt.

FIG. 4 synthesis of N3F methylamide from trifluoromethylamino formamide and its derivatization principle; the amide was obtained by reaction of R-N (CF3) COF (1.0 equiv.), with RMgX (1.2 equiv.), and left in toluene at room temperature for 10 minutes.

FIG. 5 comparison of the stability of the F3C-N motif of the derivative.

FIG. 6 is a typical F3C-N motif derivative.

FIG. 7A typical F3C-N motif derivative two-step reaction process, derivatization reaction conditions: (i) pd (OAc)2(10mol%)/BINAP (15mol%), Cs2CO3, toluene, 110 ℃, 3 h; (ii) step 1: trifluoroacetic acid, dichloromethane, RT, 2 h; step 2: HBTU, DIPEA, amino acids, RT, 16h, BINAP, 2,2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (, 2,2 '-bis (diphenylphosphino) -1, 1' -binaphtyl); DIPEA, diisopropylethylamine, HBTU, 3- [ bis (dimethylamino) methyliumyl ] -3H-benzotriazol-1-oxidehyrophosphate; r., diastereomer ratio; ee. enantiomeric excess.

FIG. 8 Synthesis of additional F3C-N derivatives; urea was prepared from R-N (CF3) COF (1.0 equiv.), NUH and catalytic DMAP (0.1 equiv.). In dichloromethane at RT.

FIG. 9 preparation of carbamates is similar to urea.

FIG. 10 preparation of C, N thio and selenocarbamates using R-N (CF3) COF (1.0 equiv), NaNu (1.2 equiv). The reaction conditions were in Tetrahydrofuran (THF). Wherein the superscript a indicates that it was quantitatively analyzed by nmr hydrogen spectroscopy. Superscript b indicates that the reaction is based on tBuOK; the logP of penicillin G was also calculated (where P is the partition coefficient): 3.46(F3C-N), 2.49(N-Me), 1.40 (N-H).

Detailed Description

N-methylation is an efficient method to convert secondary amines (R2N-H) to the corresponding tertiary trifluoromethylamines (R2F 3C-N). However, this method is only applicable to nucleophilic secondary amines and does not touch the electron-deficient N-H position in the amide, and therefore, an efficient method has been recently developed to convert secondary amines (R2N-H) to the corresponding tertiary trifluoromethylamines (R2F 3C-N). Any direct chemical modification may require relatively harsh reaction conditions in view of the stability of the amide, and therefore has limited applicability. In fact, N-methylation of amides has currently presented synthetic challenges such as racemization of key stereocenters. Thus, the indirect synthesis of the F3C-N carbonyl motif employed in the present invention is a more promising approach.

Only a few low functionality F3C-N amides were previously prepared; the yields are moderate, the reaction requires toxic or highly electrophilic reagents, or involves intermediates that are difficult to prepare. These methods are not compatible with additional reactive functional groups or stereocenters, nor do they provide a route to the broader F3C-N carbonyl family. We assume that the method of building blocks (precursors) is the most possible. The present invention therefore focuses on developing a simple method to obtain robust precursors, which are then possibly modified to produce various F3C-N carbonyl compounds.

The present invention begins with the discovery that silver fluoride treatment of isothiocyanates results in their formal desulfurization. We propose that difluoromethylimine is not formed in this process (figure 2) and the use of additional silver fluoride may lead to the formation of a nucleophilic derivative which may then be captured by a suitable carbonyl electrophile, resulting in a trifluoromethylated carbonyl motif in a simple step. In view of safety and practicality, we used the solid reagent bis (trichloromethyl) carbonate (BTC) as the carbonyl source, which was found to be easily converted to carbonyl difluoride with silver fluoride. Thus, we used a one-pot procedure-starting from readily available isothiocyanate (R-NC), adding excess silver fluoride and solid test BTC to synthesize N3F methylcarbamoyl fluoride directly, possibly as a basis for further derivatization.

When biphenyl isothiocyanate was reacted with solid reagents BTC and silver fluoride in acetonitrile for 16h at room temperature, the corresponding N3F methylcarbamoyl fluoride 1 was obtained in 98% yield (fig. 2). It is to be noted that (1) has been proved to be stable to moisture and oxygen and can be stored stably in nature. Previous synthetic routes only allowed the formation of low functionality analogues, with moderate yields and the use of toxic reagents such as mercury salts and fluorophosphone. With the encouragement of transformation efficiency, we tested whether N3F methylcarbamoyl fluoride, which is more complex in molecular and functional, is also available. As a result this transformation proved to be very general (fig. 2) and a large number of functional groups could be tolerated, such as tertiary amines (32), amides (31), nitriles (6), esters (15), sulfones (20), sulfides (19), halogens (2, 11, 13 and 18), nitro groups (7) and diazo groups (25). Free alcohols, acids or primary amines require protecting groups. Optically pure protected amino acids can also be converted while preserving stereochemistry (26-30). The substrate is efficiently converted at room temperature (or slightly elevated temperature) and after precipitation of the salt by-product with diethyl ether, the product is easily purified by filtration through Celite.

With these building blocks (precursors) in hand, we next set out to develop a process for their conversion to the broader carbonyl series of compounds. We can easily obtain N3F methylamide from these carbamoyl fluoride precursors by direct addition of grignard reagents at room temperature (fig. 3). Of the solvents we tested (dichloromethane, diethyl ether, toluene and tetrahydrofuran), toluene proved to be the most effective. Even in the presence of sterically demanding ortho-substituents (e.g., 45), alkyl, aromatic and heterocyclic substituents can be effectively introduced within 10 minutes. The reactivity of the carbamoyl fluoride is high enough to outperform the metal-halogen exchange, enabling the synthesis of the haloamides (39), (43) and (45), which can serve as a valuable platform for further derivatization. We have also synthesized the N3F methyl analogue of the hormone melatonin (37), the analgesic paracetamol (36), and the major macromolecular building blocks including the bis (N3F methyl) amide (47) and (49) building blocks of nylon (6, 6) and kevlar F3C-N analogues, respectively, and (48), which is an analogue of a microporous organic polymer precursor. In addition, amino acid-derived carbamoyl fluorides can also be converted to the corresponding amides, provided they are protected with a t-butyl ester group. Notably, stereochemistry was retained, resulting in amides (50-59) and (62) in high yield and excellent enantioselectivity (96-99% enantiomeric excess).

The widespread use of these compounds depends both on the nature of the CF3 substituent induction and on the overall stability of the class of compounds. In the compounds we prepared, we observed neither decomposition of the carbamoyl fluoride nor decomposition of the final target compound. To evaluate the stability of F3C-N amide, we placed the amide (35) in hydrochloric acid solution (pH1) or NaOH solution (pH14) at room temperature for 6h (in acetonitrile/water). We observed that there was essentially no decomposition in acid, only a small amount in base, while the corresponding N-Me amide showed more decomposition in base, while the N-H analogue showed a large amount of decomposition in base. (46) And nylon derivative (47) showed no decomposition by acid-base analogous test. This indicates that the N3F methylamides are quite robust and that they appear to be more stable than their N-H amide counterparts.

Consistent with the observed stability, we have found that subsequent synthetic transformations are also possible, palladium catalyzed (59) aminated amino acids proceed smoothly and withstand prolonged heating at 110 deg.C cleavage with trifluoroacetic acid in dichloromethane with amides (62) to 20% followed by peptide coupling under typical conditions, we obtained the corresponding peptides (63) and (64) in extremely high yields, thus, although peptides consisting only of the naturally occurring F3C-N analog of the α -amino acid are not available, peptides containing the F3C-N moiety can be readily prepared in this way.

We investigated the conformational properties of compound (35) relative to the N-Me analogue using 1H Nuclear Magnetic Resonance (NMR) spectroscopy. Although evidence of rotamers can be seen in the spectrum of the N-Me derivative at ≦ 5 ℃, the spectrum of the corresponding N-CF-3 amide (35) shows the presence of rotamers at temperatures below-45 ℃; this indicates less rotational restriction in the F3C-N amide series. These observations are consistent with the observed infrared carbonyl stretching frequencies of these compounds and our calculation of bond lengths, which indicates that the C-N bond is the longest in the F3C-N amide. Our computational studies of the F3C-N analogue of the antibiotic penicillin G (in FIG. 4) showed that a similar conformation to the corresponding N-Me or N-H motif was favored and predicted to have higher partition coefficients and pKa values for the F3C-N analogue.

Next, we investigated the feasibility of synthesizing the N-CF 3 carbonyl heteroatom motif. Carbamoyl fluoride does not react to weaker nucleophiles unless a catalytic amount of 4-Dimethylaminopyridine (DMAP) and a base are added; this enables them to be converted into the corresponding carbamates or ureas (fig. 4). Stronger nucleophilic agents, such as alkoxides, thiocyanates or selenates, are used, and can be efficiently converted at room temperature without additives. Thus, a diverse library consisting of more than 30 examples of N3F methylcarbamates, -ureas, -thiocarbamates and-selenocarbamates with abundant functions can be generated in a fast and operationally simple manner (FIG. 4). Notable examples are N-CF 3 analogs of oxybutynin (70) (anesthetic), aspartame (65), and penicillin derivatives (67), as well as widely used analogs of the protecting groups tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and fluorenylmethoxycarbonyl (Fmoc) (80, 84, 86, and 87), the pharmaceutical compound mexiletine (82) (for the treatment of heart disease), the carbohydrate (81), analogs of estrogen (85), diazo derivatives (89), and analogs of the nonlinear optical material dispersed orange 3.

Consistent with our findings on N-CF 3 amides, the reaction of chiral carboxamide fluorides was carried out with retention of stereochemistry: despite the use of DMAP and 15 hours of reaction time, the synthesis of carbamate (87) still did not result in detectable racemization, and optically pure ureas (66) and (77) were synthesized with a degree of racemization of less than 5%.

In summary, we describe a simple, safe, robust and versatile method to obtain the N3F methylcarbonyl family. The nature and stability of the F3C-N carbonyl motif lay the foundation for its ability to function in different disciplines, ranging from disease resistance (drugs) and drug resistance (antibiotics, herbicides) to the creation of new materials (polymers, coatings) and the manipulation of biological processes.