CN101260120B - Preparation of P(NMeOMe)3 agent and application thereof in synthesizing N-methyl-N-methoxylamide - Google Patents
Preparation of P(NMeOMe)3 agent and application thereof in synthesizing N-methyl-N-methoxylamide Download PDFInfo
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- CN101260120B CN101260120B CN2007100191066A CN200710019106A CN101260120B CN 101260120 B CN101260120 B CN 101260120B CN 2007100191066 A CN2007100191066 A CN 2007100191066A CN 200710019106 A CN200710019106 A CN 200710019106A CN 101260120 B CN101260120 B CN 101260120B
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Abstract
The invention discloses a method for synthesizing an intermediate of Weinreb amide compounds, namely the N, N', N''-trimethyl- N, N', N''-trimethoxy phosphinidene amide(P(NMeOMe)3) reagent. The reagent is generated by taking ether as a solvent and tri-hexylamine(NEt3) as a catalyst, and reacting phosphorus trichloride(PCl3) with N-methyl-N-methoxy amine(Me(MeO)NH). When the P(NMeOMe)3 reagent of the invention is used to synthesize the Weinreb amide compounds, benzene or methylbenzene is used as a solvent, and the P(NOMeMe)3 and chiral or non-chiral carboxylic acids are directly reacted, and various Weinreb amide compounds are obtained after processes of filtering, drying and separation. Because the P(NMeOMe)3 is used to synthesize the Weinreb amide in the invention, the method of the invention has the advantages of simple process, easy available materials, mild reaction condition, friendly environment, high synthesized efficiency(the reaction can finish in 30 minutes at a temperature of 60 DEG C), high yield( between 89 to 96 percent) and easy after-treatment, and is applied to all types of acids.
Description
Technical field
The invention belongs to the organic synthesis field, relate to a kind of organic synthesis intermediate, relate in particular to a kind of intermediate of synthetic Weinreb acid amides---N, N ', N "-trimethylammonium-N, N ', N "-trimethoxy phosphoramide P (NMeOMe)
3Preparation, also relate to the application of this reagent in synthetic Weinreb acid amides simultaneously.
Background technology
Weinreb acid amides (N-methyl-N-methoxyamide) is the crucial acylting agent of a class, has been widely used in the synthetic of natural product and biologically active substance at present.This class acid amides is different with other acid amides, does the time spent with organometallic reagent (as Grignard reagent), generates ketone rather than alcohol.It is aldehyde that the Weinreb acid amides also is easy to by metal hydride reduction.What be worth emphasizing is, has optically active Weinreb acid amides and organometallic reagent or metal hydride and does the time spent, and its configuration can not change.Since Nahm in 1981 and Weinreb report Weinreb acid amides synthetic, the research of relevant this compounds becomes the big focus in the organic chemical reactions research in recent years, has obtained using widely and paying close attention to, and has developed many novel synthesis.Directly from carboxylic acid, one-step synthesis Weinreb acid amides is a perfect method.But carboxyl activation earlier just can generate acid amides with N-methyl-N-methoxyl group amine reaction.DCC (N, N '-dicyclohexyl carbodiimide), DEPC (diethyl cyano group phosphoric acid ester), CDI (1,1 '-carbonyl dimidazoles), BOP etc. are the activators of normal use.Giampaolo Giacomelli etc. adopt comparatively cheap 2-chloro-4, and 6-dimethoxy-[1,3,5] triazine CDMT is a carboxyl activator, and it is effective that this method is compared, but CDMT has pungency.In recent years, many reports about synthetic Weinreb acid amides novel method: GundaGeorg etc. have appearred respectively at reporting a kind of easy single stage method (one kettle way) synthesis of chiral or the novel method of achirality Weinreb acid amides in 2000 and 2004, they are at N, the N-diisopropylethylamine exists down, carboxylic acid elder generation and deoxofluorination agent ([bis (2-methoxyethyl) amino] sulfur trifluoride)) effect generation acyl fluorides intermediate product, acyl fluorides reacts generation Weinreb acid amides with N-methyl-N-methoxyl group amine again.The shortcoming of this method is that employed deoxofluorination agent is comparatively expensive, and reacted residuum or by product are difficult to remove from mixture, cause wastage of material and productive rate low.
Summary of the invention
The purpose of this invention is to provide a kind of can be directly and chirality or the effect of achirality carboxylic acid generate intermediate---the N of Weinreb acid amides, N ', N "-trimethylammonium-N, N ', N "-trimethoxy phosphoramide P (NMeOMe)
3Reagent.
Another object of the present invention provides a kind of P (NMeOMe)
3The preparation method of reagent and P (NMeOMe)
3Reagent is in the concrete application of synthetic Weinreb acid amides.
(1) P (NOMeMe)
3Reagent
P of the present invention (NOMeMe)
3The structural formula of reagent is as follows:
P (NOMeMe)
3Three N-methyl-N-methoxyl group amine is arranged in the structure of reagent, and (NCH3OCH3) group can fully directly act on the important organic intermediate Weinreb acid amides of generation with its derivative of carboxylic acid.
(2) P (NOMeMe)
3The preparation of reagent
P of the present invention (NOMeMe)
3The preparation method of reagent is to be solvent with the ether, with trihexylamine (NEt
3) be acid binding agent, make phosphorus trichloride PCl
3Generate P (NOMeMe) with N-methyl-N-methoxyl group amine Me (MeO) NH reaction
3Reagent.Its concrete building-up process is as follows:
Bathe under cooling and the nitrogen protection at cryosel, with Me (MeO) NH and and NEt
3Be dissolved in the anhydrous diethyl ether with 1: 1.1～1: 1.2 mol ratio, under agitation add Me (MeO) NH
6The phosphorus trichloride PCl of 1/3～1/4 molar weight
3, be warming up to room temperature naturally, after 10～12 hours, be heated to 36～40 ℃ of reactions then after 2～4 hours, reduce to room temperature, remove by filter ammonia salt, steam solvent and get light yellow liquid (still having amine salt to separate out continues to remove by filter) in the process of steaming, underpressure distillation gets colourless liquid, be target product N, N ', N "-trimethylammonium-N; N ', N "-trimethoxy phosphoramide P (NOMeMe)
3Its reaction formula is as follows:
Consider that amine must be excessive in the reaction process, and N-methyl-N-methoxyl group amine Me (MeO) NH costs an arm and a leg, we use trihexylamine (NEt
3) hydrogen halide HCl that neutralization reaction generates, only need Me (MeO) NH excessive a little, excessive greatly (three's the mol ratio: PCl of trihexylamine
3: HN (OMeMe): NEt
3=1: 3.1: 3.5), just can obtain P (NOMeMe) with higher yields 66.7%
3Experiment finds even amine is all used Me (MeO) NH, what (69.5%) productive rate does not improve yet.
(3) the weinreb acid amides is synthetic
The present invention synthesizes the method for Weinreb acid amides (N-methyl-N-methoxyamide), is to be solvent with benzene or toluene, with chirality or achirality carboxylic acid directly and P (NOMeMe)
3One step of effect generates the Weinreb acid amides.Its concrete synthesis technique is: with P (NOMeMe)
3Reagent is dissolved in benzene or the toluene, adds P (NOMeMe)
31.5 the carboxylic acid of～2.5 times of molar weights under nitrogen atmosphere,, detects through TLC after 30～60 minutes in 40～70 ℃ of reactions, after raw material reaction is intact, is cooled to room temperature, adds P (NOMeMe)
3The saturated NaHCO of 3～5 times of molar weights
3Extracted with diethyl ether is used in aqueous solution cancellation reaction 10～30 minutes again, and dry, column chromatography gets the weinreb amide compound.Its reaction formula is as follows:
Carboxylic acid can adopt any chiral carboxylic acids or achirality carboxylic acid, can also be all kinds of acid such as aliphatic acid, diprotic acid, unsaturated acid and amino acid.
The present invention adopts chirality or the achirality carboxylic acid is direct and P (NOMeMe)
3Effect one-step synthesis Weinreb acid amides, reaction process is simple, and raw material is easy to get, the reaction conditions gentleness, environmental friendliness, combined coefficient height (can finish in 30 minutes) 60 ℃ of reactions, yield height (89～96%), aftertreatment is easy.
Below by various carboxylic acids and P (NOMeMe)
3Reagent react synthesizes the weinreb acid amides, reaction conditions optimized, and from material ratio, temperature, the time compares respectively, the results are shown in following table.Discovery is at 60 ℃, and during 30min, material ratio is with P (NOMeMe)
3: RCOOH=1: during 2 molar ratio ingredient, productive rate is the highest: 94.7%.
| Sequence number | ?PhCOOH(mol) | ?P(NOMeMe) 3(mol) | Time | Temperature | Productive rate (%) |
| 1 | 3 | 1 | 60min | 80℃ | 78.9 |
| 2 | 2.5 | 1 | 60min | 80℃ | 86.2 |
| 3 | 2 | 1 | 60min | 80℃ | 94.7 |
| 4 | 2 | 1 | 30min | 60℃ | 93.4 |
| 5 | 2 | 1 | 30min | 40℃ | 89.4 |
| 6 | 2 | 1 | 60min | 60℃ | 93.6 |
| 7 | 2 | 1 | 60min | 40℃ | 93 |
| 8 | 2 | 1 | 120min | 25℃ | 86.7 |
Embodiment
Synthesizing of embodiment 1, weinreb acid amides---N-methyl-N-methoxy benzamide
Step 1, P (NOMeMe)
3Synthetic: cryosel is bathed under cooling and the nitrogen protection, adds Me (MeO) NH 62mmol (3.78g) and NEt in the there-necked flask of 250ml
370mmol (20ml) in the 100ml anhydrous diethyl ether mixed solution, stirs and slowly drips PCl down
3The anhydrous diethyl ether mixed solution of 20mmol (2.74g) after dropwising, allows it be warming up to room temperature naturally.Stirring is spent the night, and heating in second day was reduced to room temperature and removed by filter ammonia salt after 4 hours, steams solvent and gets light yellow liquid.Underpressure distillation gets the 2.81g colourless liquid, is target product 3.Productive rate 66.7%.Its reaction formula is as follows:
Synthesizing of step 2, weinreb acid amides: in the 50mL three-necked bottle, Compound P (NOMeMe)
30.211g (1mmol) be dissolved in the 10ml toluene, add phenylformic acid 0.244g (2mmol), under nitrogen atmosphere, mixture heated 30 minutes down in 60 ℃, detected through TLC, after raw material reaction is intact, was cooled to room temperature, added saturated NaHCO
3Aqueous solution cancellation reaction.Use extracted with diethyl ether, MgSO
4Dry.Column chromatography gets compound N-methyl-N-methoxy benzamide.Productive rate is 94.6%.Its reaction formula is as follows:
The detection of step 3, weinreb amides: above-mentioned synthetic weinreb amides, warp
1HNMR, IR,
13CNMR detects, and its product is pure target compound.Its each performance index are as follows:
IR(cm
-1)：1600.49，1659.04，1449.49
1HNMR(400MHz，CDCl
3，ppm)：δ＝7.68-766(m，2H)，δ＝7.46-7.38(m，3H)，
δ＝3.54(S，3H)δ＝3.36(S，3H).
13CNMR(100MHz，CDCl
3)：169.9，134.1，130.5，128.1，127.9，60.98，33.8.
Synthesizing of embodiment 2, weinreb acid amides---N-methyl-N-methoxyl group and two thiophene-2-carboxamide derivatives
Step 1, P (NOMeMe)
3Synthetic: identical with embodiment 1.
Synthesizing of step 2, weinreb acid amides: in the 50mL three-necked bottle, Compound P (NOMeMe)
30.211g (1mmol) be dissolved in the 10ml toluene, add and two thiophene-2-carboxylic acid 0.368g (2mmol), under nitrogen atmosphere, mixture heated 30 minutes down in 60 ℃, detected through TLC, after raw material reaction is intact, was cooled to room temperature, added saturated NaHCO
3Aqueous solution cancellation reaction.Use extracted with diethyl ether, MgSO
4Dry.Column chromatography gets compound N-methyl-N-methoxyl group and two thiophene-2-carboxamide derivatives.Productive rate is 96.6%.Its reaction formula is as follows:
The detection of step 3, weinreb amides: above-mentioned synthetic weinreb amides, warp
1HNMR, IR,
13CNMR detects, and its product is pure target compound N-methyl-N-methoxyl group and two thiophene-2-carboxamide derivatives.Its each performance index are as follows:
IR(KBr，cm
-1)：1621.95，1498.30，1457.40，1408.81.
1HNMR(400MHz，CDCl
3，ppm)：δ＝8.16(S，1H)，δ＝7.56-7.55(d，J＝5.2Hz，1H)
δ＝7.28(S，1H)，δ＝3.82(S，1H)，δ＝3.41(S，1H).
13CNMR(100MHz，CDCl
3)：162.5，144.7，135.0，131.1，126.4，119.5，61.7，33.2.
Synthesizing of embodiment 3, weinreb acid amides---N-methyl-N-methoxyl group-2-(N-is to the Methyl benzenesulfonyl base) phenylacetamide
Step 1, P (NOMeMe)
3Synthetic: identical with embodiment 1;
Synthesizing of step 2, weinreb acid amides: in the 50mL three-necked bottle, Compound P (NOMeMe)
30.211g (1mmol) be dissolved in the 10ml toluene, add the phenylamino acid 0.67g (2mmol) of p-methyl benzenesulfonic acid protection, under nitrogen atmosphere, mixture heated 30 minutes down in 60 ℃, detected through TLC, after raw material reaction is intact, was cooled to room temperature, added saturated NaHCO
3Aqueous solution cancellation reaction.Use extracted with diethyl ether, MgSO
4Dry.Column chromatography gets target compound---N-methyl-N-methoxyl group-2-(N-is to the Methyl benzenesulfonyl base) phenylacetamide.Productive rate is 94.7%.Its reaction formula is as follows:
The detection of step 3, weinreb amides: above-mentioned synthetic weinreb amides, warp
1HNMR, IR,
13CNMR detects, and its product is pure target compound.Its each performance index are as follows:
IR(KBr，cm
-1)：1659.04，1600.49，1449.49，1383.58，1160.37
1HNMR(400MHz，CDCl
3，ppm：δ＝7.62-7.60(m2H)，δ＝7.26-7.12(m，7H)，δ＝6.03-6.02(d，J＝5.4Hz，1H)，δ＝5.44-5.42(d，J＝7.2Hz，1H)，δ＝3.28(S，3H)，δ＝2.99(S，3H)，δ＝2.37(S，3H).
3CNMR(100MHz，CDCl
3)：169.9，143.2，137.2，136.3，129.3，128.7，128.2，127.7，127.1，61.0，56.9，32.3，21.5.
Synthesizing of embodiment 4, weinreb acid amides---N-methyl-N-methoxyl group maleinamide
Step 1, P (NOMeMe)
3Synthetic: identical with embodiment 1
Synthesizing of step 2, weinreb acid amides: in the 50mL three-necked bottle, with Compound P (NOMeMe)
30.211g (1mmol) be dissolved in the 10ml toluene, add FUMARIC ACID TECH GRADE 0.232g (2mmol), under nitrogen atmosphere, mixture heated 30 minutes down in 60 ℃, detected through TLC, after raw material reaction is intact, was cooled to room temperature, added saturated NaHCO
3Aqueous solution cancellation reaction.Use extracted with diethyl ether, MgSO
4Dry.Column chromatography gets target compound N-methyl N-methoxyl group maleinamide.Productive rate is 90%.Its reaction formula is as follows:
The detection of step 3, weinreb amides: above-mentioned synthetic weinreb amides, warp
1HNMR, IR
13CNMR detects, and its product is pure target compound.Its each performance index are as follows:
IR(cm
-1)：2938.03，1654.98，1434.36，1389.17，1338.64
1HNMR(400MHz，CDCl
3，ppm)：δ＝6.58(S，1H)，δ＝3.71(S，3H)，δ＝3.52(S，3H)，?
13CNMR(100MHz，CDCl
3)：166.65，129.04，61.49，3192
Synthesizing of embodiment 5, weinreb acid amides---N-methyl-N-methoxyl group 3-chlorine propionic acid amide
Step 1, P (NOMeMe)
3Synthetic: identical with embodiment 1
Synthesizing of step 2, weinreb acid amides: in the 50mL three-necked bottle, with Compound P (NOMeMe)
30.211g (1mmol) be dissolved in the 10ml toluene, add anti-3-chloropropionic acid 0.217g (2mmol), under nitrogen atmosphere, mixture heated 30 minutes down in 60 ℃, detected through TLC, after raw material reaction is intact, was cooled to room temperature, added saturated NaHCO
3Aqueous solution cancellation reaction.Use extracted with diethyl ether, MgSO
4Dry.Column chromatography gets target compound N-methyl-N-methoxyl group 3-chlorine propionic acid amide.Productive rate is 95%.Its reaction formula is as follows:
The detection of step 3, weinreb amides: above-mentioned synthetic weinreb amides, warp
1HNMR, IR
13CNMR detects, and its product is pure target compound---N-methyl-N-methoxyl group 3-chlorine propionic acid amide.Its each performance index are as follows:
IR(cm
-1)：2970.79，2940.36，1664.82，1426.661389.03
1HNMR(400MHz，CDCl
3，ppm)：δ＝3.83-3.79(t，2H)，δ＝3.72(S，3H)，
δ＝3.21(S，3H)，δ＝2.94-2.91(t，2H)
13CNMR(100MHz，CDCl
3)：170.8，61.3，39.2，34.9，32.0
Claims (6)
1. N, N ', N "-trimethylammonium-N, N ', N "-trimethoxy phosphoramide P (NOMeMe)
3Reagent, structural formula is as follows:
2. N according to claim 1, N ', N "-trimethylammonium-N, N ', N "-trimethoxy phosphoramide P (NOMeMe)
3The preparation method of reagent is to bathe under cooling and the nitrogen protection at cryosel, with Me (MeO) NH and and NEt
3Be dissolved in the anhydrous diethyl ether with 1: 1.1～1: 1.2 mol ratio, under agitation add the PCl of Me (MeO) NH1/3～1/4 molar weight
3, be warming up to room temperature naturally, after 10～12 hours, be heated to 36～40 ℃, react after 2～4 hours, be cooled to room temperature, filtering ammonia salt, solvent is fallen in steaming, underpressure distillation gets colourless liquid, is target product P (NOMeMe)
3
3. N according to claim 1, N ', N "-trimethylammonium-N, N ', N "-trimethoxy phosphoramide P (NOMeMe)
3The preparation method of reagent is characterized in that: described HN (OMeMe), NEt
3, PCl
3Mol ratio proportioning with 3.1: 3.5: 1.
4. N according to claim 1, N ', N "-trimethylammonium-N, N ', N "-trimethoxy phosphoramide P (NOMeMe)
3The application of reagent in synthetic N-methyl-N-methoxyamide: with P (NOMeMe)
3Reagent is dissolved in benzene or the toluene, adds P (NOMeMe)
31.5 the carboxylic acid of～2.5 times of molar weights under nitrogen atmosphere, after 30～60 minutes, is cooled to room temperature in 40～70 ℃ of reactions, adds P (NOMeMe)
3The saturated NaHCO of 3～5 times of molar weights
3Extracted with diethyl ether is used in aqueous solution cancellation reaction 10～30 minutes again, and dry, column chromatography gets N-methyl-N-methoxyamide compound.
5. as N as described in the claim 4, N ', N "-trimethylammonium-N, N ', N "-trimethoxy phosphoramide P (NOMeMe)
3The application of reagent in synthetic N-methyl-N-methoxyamide is characterized in that: P (NOMeMe)
3With 1: 2 mol ratio proportioning of carboxylic acid; Temperature of reaction is 60 ℃, and the reaction times is 30min.
6. as N as described in the claim 4, N ', N "-trimethylammonium-N, N ', N "-trimethoxy phosphoramide P (NOMeMe)
3The application of reagent in synthetic N-methyl-N-methoxyamide, it is characterized in that: described drying is MgSO
4, Na
2SO
4Or CaCl
2For siccative carries out drying.
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| CN102491941B (en) * | 2011-11-25 | 2014-01-22 | 西北师范大学 | Preparation method of N-methoxy-N-methyl-1-p-toluenesulfonyl piperidine-4-amide |
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Non-Patent Citations (3)
| Title |
|---|
| Nahm, S. |
| Nahm, S.;Weinreb, S. M..Preparation of Amides Using Organozinc Iodides.Tetrahedron Lett. 22.1981,(22),3815. * |
| Weinreb, S. M..Preparation of Amides Using Organozinc Iodides.Tetrahedron Lett. 22.1981,(22),3815. |
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