CN115433194B - Synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative - Google Patents
Synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative Download PDFInfo
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives, which comprises the following steps: (1) 2, 3-dihydro-furan reacts with trichloroacetyl chloride and alkali after being mixed to prepare 2, 3-dihydro-4-trichloroacetyl furan; (2) 2, 3-dihydro-4-trichloroacetyl furan reacts with N- (methoxymethyl) -N- (trimethylsilyl) benzylamine and methanol to prepare the hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative. The invention is an ideal synthesis route with short reaction steps, easily available raw materials, high reaction activity and more general reaction conditions.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives.
Background
Pyrrole and furan are important compounds widely applied in the fields of medicine, pesticides, materials and the like, and are often introduced into pharmaceutical compounds as active molecular fragments in view of the structural characteristics of the pyrrole and furan, and at present, more than 50 medicines only containing pyrrolidine fragments exist. Hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives have pyrrole and furan fragments and multiple potential active sites, and have been reported to show high activity for preventing and treating diseases such as inflammation, metabolic syndrome and the like, and have great prospect in biological activity of themselves and downstream products thereof. Based on this, it is necessary to explore an ideal synthetic route.
The synthesis report of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative is less, and the key step is the construction of a furopyrrole framework; in the prior art, the construction of the furopyrrole framework is mainly realized by adopting the action of 2, 3-dihydro-4-furoic acid methyl ester and N- (methoxymethyl) -N- (trimethylsilyl) benzylamine, wherein the 2, 3-dihydro-4-furoic acid methyl ester is not yet commercialized, gamma-butyrolactone is used as a raw material, etherification and esterification are realized with methyl formate in the presence of methanol, and then the esterification is performed by strong acid dehydration, so that the furopyrrole is prepared.
The synthesis method has certain defects in the aspects of universality and amplified production; firstly, the gamma-butyrolactone which is a synthetic raw material of an intermediate 2, 3-dihydro-4-furoic acid methyl ester is an easily-made toxic tube product and is not easy to obtain; secondly, when the 2, 3-dihydro-4-furoic acid methyl ester and N- (methoxymethyl) -N- (trimethylsilyl) benzylamine are used for constructing the furopyrrole framework, under the conventional reaction condition, only the product yield of less than 10 percent is obtained, if the target product is required to be obtained in a high yield, no solvent reaction is needed at the high temperature of 140 ℃, certain potential safety hazard exists in the high temperature condition, the solvent-free state is only suitable for preparing a small amount of products, and the preparation of a large amount of products is unsuitable.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives. The invention is an ideal synthesis route with short reaction steps, easily available raw materials, high reaction activity and more general reaction conditions.
The technical scheme of the invention is as follows:
the first object of the invention is to provide a synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative, which is carried out according to the following route:
(1) 2, 3-dihydro-4-trichloroacetyl furan (compound 2) is prepared by mixing 2, 3-dihydro-furan (compound 1) with trichloroacetyl chloride and alkali for reaction;
(2) 2, 3-dihydro-4-trichloroacetyl furan (compound 2) reacts with N- (methoxymethyl) -N- (trimethylsilyl) benzylamine (compound 3) and methanol to prepare the hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative (compound 4).
In one embodiment of the present invention, in step (1), the base is one or more of diisopropylamine, triethylamine, pyridine.
In one embodiment of the invention, in the step (1), the molar ratio of the 2, 3-dihydrofuran to the trichloroacetyl chloride is 1 (1-2); the molar ratio of the 2, 3-dihydrofuran to the alkali is 1:1-3.
In one embodiment of the present invention, in step (1), an organic solvent is further included, and the organic solvent is one or more of dichloromethane, dichloroethane, N-dimethylformamide and acetonitrile.
In one embodiment of the invention, in the step (1), the reaction temperature is 20-30 ℃ and the reaction time is 2-6 h.
Preferably, in the step (1), the specific process of the reaction is as follows:
adding an organic solvent into a reaction device, firstly adding the organic solvent and 2, 3-dihydrofuran, then controlling the temperature to-5-15 ℃, then adding trichloroacetyl chloride, then controlling the temperature to-5 ℃, finally adding alkali, heating to 20-30 ℃ after adding, and reacting for 2-6 hours;
after the reaction is finished, diluting the reaction solution with an organic solvent, washing with dilute hydrochloric acid twice, washing with saturated sodium bicarbonate solution once, drying with anhydrous sodium sulfate, filtering, and desolventizing the filtrate to obtain a crude product compound 2, namely crude product 2, 3-dihydro-4-trichloroacetyl furan;
more preferably, the diluted hydrochloric acid concentration is 1 to 2M.
In one embodiment of the present invention, in step (2), the specific reaction process is:
adding 2, 3-dihydro-4-trichloroacetyl furan into an organic solvent, controlling the temperature to be 20-30 ℃, adding N- (methoxymethyl) -N- (trimethylsilyl) benzylamine and lithium salt, and replacing argon for protection reaction after adding;
then heating to 60-100 ℃, reacting for 8-18h, cooling to room temperature after the reaction is finished, adding methanol, and reacting for 1-6 h at room temperature;
finally, pouring the reaction solution into ice water, regulating the reaction solution to be alkaline by using saturated sodium bicarbonate solution, and adding ethyl acetate for extraction for three times; the organic phases are combined, washed by saturated saline solution, dried by anhydrous sodium sulfate and purified by column chromatography to obtain the compound 4, namely the hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative.
In one embodiment of the present invention, in step (2), the molar ratio of 2, 3-dihydro-4-trichloroacetyl furan to N- (methoxymethyl) -N- (trimethylsilyl) benzylamine is 1 (1-3); the mol ratio of the 2, 3-dihydro-4-trichloroacetyl furan to the methanol is 1 (5-15).
In one embodiment of the invention, the lithium salt is one or more of lithium fluoride, lithium bromide, lithium chloride; the molar ratio of the 2, 3-dihydro-4-trichloroacetyl furan to the lithium salt is 1 (2-5).
In one embodiment of the invention, the organic solvent is one or more of dichloromethane, dichloroethane, N-dimethylformamide, acetonitrile.
The beneficial technical effects of the invention are as follows:
the invention is based on the synthesis of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative in the prior art, and has the problems of difficult obtainment of reaction raw materials, low reaction yield, poor universality of ring closing conditions, long reaction steps and the like.
The invention adopts 4-trichloroacetyl-2, 3-dihydrofuran as a ring-closing raw material, improves the reactivity, reduces the operation difficulty of the prior art, ensures that the reaction materials obtain the target compound under good fluidity and through proper reaction temperature, has short steps (only 2 steps), simple and convenient operation, ideal product yield and stronger controllability, is a candidate route for the amplified production of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives, provides reliable reference for the synthesis of furopyrrole similar compounds, and provides a more convenient approach for the research of the bioactivity of furopyrrole compounds.
The method adopts 4-trichloroacetyl-2, 3-dihydrofuran as a ring-closing raw material, is low in cost and easy to obtain, and improves the industrial production feasibility of the target compound to a great extent.
Drawings
FIG. 1 is a schematic diagram of the synthetic reaction of the present invention;
FIG. 2 is a schematic diagram of a prior art synthetic reaction;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the compound 4 prepared in example 1.
Detailed Description
The present invention will be described in detail below with reference to the drawings and examples.
Example 1
A synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative, comprising the following steps:
(1) Synthesis of Compound 2
200ml of methylene chloride, 20g of compound 1 (2, 3-dihydrofuran, 285.34mmol,1 eq) and 77.82g of trichloroacetyl chloride (428 mmol,1.5 eq) were added to the reaction flask, the temperature was controlled at 0℃and 45.14g of pyridine (570.69 mmol,2 eq) was added to the flask, and the reaction was carried out for 3 hours after the addition was completed;
after the reaction, the reaction mixture was poured into 500ml of dichloromethane, washed twice with 1M diluted hydrochloric acid (200 ml x 2), the separated organic phase was washed once with 200ml of saturated sodium bicarbonate solution, and finally the separated organic phase was washed once with 200ml of saturated brine, and the separated organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried to give 54g of compound 2 (2, 3-dihydro-4-trichloroacetyl furan) in a yield of 86.08% and a purity of 98%.
(2) Synthesis of Compound 4
54g of compound 2 (2, 3-dihydro-4-trichloroacetyl furan, 250.63mmol,1 eq) are added to 540ml of acetonitrile, the temperature is controlled at 25 ℃, 89.26g of compound 3 (N- (methoxymethyl) -N- (trimethylsilyl) benzylamine, 375.95mmol,1.5 eq) and 19.5g of lithium fluoride (751.90 mmol,3 eq) are added, after which the argon protection is replaced;
then heating to 82 ℃, stirring at a controlled temperature for reaction for 12 hours, cooling to room temperature after the reaction is finished, adding 80.31g of methanol (2510 mmol,10 eq), and reacting for 3 hours at room temperature;
finally, the reaction solution was poured into 1.5L of ice water with stirring, adjusted to ph=8 with saturated sodium bicarbonate solution, extracted three times with ethyl acetate (500 ml×3); all the organic phases were combined, washed with 500ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was desolventized and purified by column chromatography to give 41.84g of compound 4 (hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative) in a yield of 62.6% and a purity of 98%.
Examples 2 to 7, comparative example 1
A synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative is characterized in that the conditions are the same as in example 1, and the type and amount of alkali are adjusted, and the specific type, amount and first step yield are shown in Table 1.
TABLE 1
| Sequence number | Alkali | Equivalent (eq) | Yield (%) |
| Example 1 | |
2 | 86.08 |
| Example 2 | |
2 | 62.4 |
| Example 3 | |
2 | 58.3 |
| Example 4 | |
1 | 70.8 |
| Example 5 | Pyridine compound | 1.5 | 76.4 |
| Example 6 | Pyridine compound | 2.5 | 82.3 |
| Example 7 | |
3 | 78.8 |
| Comparative example 1 | |
2 | 43.8 |
As can be seen from the table, in examples 2 to 4 and comparative example 1, the reaction was carried out using a different base in step (1) compared with example 1, and the reaction results showed that the acceleration of the reaction by pyridine was more excellent than that by triethylamine, diisopropylamine, and DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene). In examples 5 to 7, the amount of pyridine in step 1 was changed as compared with example 1, and the reaction results showed that increasing or decreasing the amount of pyridine based on example 1 would cause the yield of the reaction compound 2 to show a decreasing trend.
Examples 8 to 14, comparative example 2
A synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative is characterized in that the conditions are the same as in example 1, and the dosage of compound 2, compound 3 and lithium fluoride are adjusted, and are shown in Table 2 in detail.
TABLE 2
The compound 2 is replaced by 2, 3-dihydro-4-furoic acid methyl ester for ring closure.
As can be seen from the table, in examples 8 to 9, the amount of the compound 3 used in the step (2) was increased, the amount of by-products was increased, and the reaction yield was slightly decreased as compared with example 1; compared with example 1, example 10 has the advantages that the dosage of the compound 3 is reduced, the reaction rate is reduced, and the reaction yield is slightly reduced under the same reaction time; in examples 11 to 14, the amount of lithium fluoride was changed as compared with example 1, and the reaction yield was also lowered.
Notably, theIn comparative example 2, 3-dihydro-4-furoic acid methyl ester was used
As a ring-closing raw material, the reaction yield was only 4.9% under the same conditions as in example 1; therefore, the yield of the target product of the application of the invention is better than that of the comparative example.
Example 15
A synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative, comprising the following steps:
(1) Synthesis of Compound 2
Into a reaction flask, 100ml of methylene chloride and 10g of compound 1 (2, 3-dihydrofuran, 142.67mmol,1 eq) were added, the temperature was controlled at 0℃and 38.90g of trichloroacetyl chloride (214 mmol,1.5 eq) was further added, then 22.60g of pyridine (285.35 mmol,2 eq) was added at 0℃and the reaction was completed, and the temperature was raised to 20℃for 3 hours;
after the reaction, the reaction mixture was poured into 250ml of dichloromethane, washed twice with 1M diluted hydrochloric acid (100 ml x 2), the separated organic phase was washed once with 100ml of saturated sodium bicarbonate solution, and finally the separated organic phase was washed once with 100ml of saturated brine, and the separated organic phase was dried over anhydrous sodium sulfate, filtered and dried by spin-drying to give 25.79g of compound 2 (2, 3-dihydro-4-trichloroacetyl furan) in a yield of 82.30% and a purity of 98.1%.
(2) Synthesis of Compound 4
27g of Compound 2 (2, 3-dihydro-4-trichloroacetyl furan, 125.32mmol,1 eq) was added to 270ml of acetonitrile, the temperature was controlled at 25℃and 44.61g of Compound 3 (N- (methoxymethyl) -N- (trimethylsilyl) benzylamine, 187.98mmol,1.5 eq) and 9.73g of lithium fluoride (375.1 mmol,3 eq) were added, after which the argon protection was replaced;
then heating to 82 ℃, stirring at a controlled temperature for reaction for 8 hours, cooling to room temperature after the reaction is finished, adding 40.16g of methanol (1255 mmol,10 eq), and reacting at room temperature for 3 hours;
finally, pouring the reaction solution into 750mL of ice water under stirring, adjusting the pH to be 8 with saturated sodium bicarbonate solution, adding ethyl acetate for extraction three times (250 mL. Times.3); all the organic phases were combined, washed with 250ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and after desolventized, the filtrate was purified by column chromatography to give 18.90g of compound 4 (hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative) in 56.31% yield and 97.6% purity.
Example 16
A synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative, comprising the following steps:
(1) Synthesis of Compound 2
Into a reaction flask, 100ml of methylene chloride and 10g of compound 1 (2, 3-dihydrofuran, 142.67mmol,1 eq) were added, the temperature was controlled at 0℃and 38.90g of trichloroacetyl chloride (214 mmol,1.5 eq) was further added, then 22.60g of pyridine (285.35 mmol,2 eq) was added at 0℃and the reaction was completed, and the temperature was raised to 30℃for 3 hours;
after the reaction was completed, the reaction solution was poured into 250ml of dichloromethane, washed twice with 1M diluted hydrochloric acid (100 ml x 2), the separated organic phase was washed once with 100ml of saturated sodium bicarbonate solution, finally the separated organic phase was washed once with 100ml of saturated brine, and the separated organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried to obtain 25.20g of compound 2 (2, 3-dihydro-4-trichloroacetyl furan) in a yield of 80.00% and a purity of 97.6%.
(2) Synthesis of Compound 4
27g of Compound 2 (2, 3-dihydro-4-trichloroacetyl furan, 125.32mmol,1 eq) was added to 270ml of acetonitrile, the temperature was controlled at 25℃and 44.58g of Compound 3 (N- (methoxymethyl) -N- (trimethylsilyl) benzylamine, 187.98mmol,1.5 eq) and 9.72g of lithium fluoride (374.7 mmol,3 eq) were added, after which the argon protection was replaced;
then heating to 60 ℃, stirring at a controlled temperature for reaction for 18h, cooling to room temperature after the reaction is finished, adding 40.20g of methanol (1255 mmol,10 eq), and reacting at room temperature for 3h;
finally, pouring the reaction solution into 750mL of ice water under stirring, adjusting the pH to be 8 with saturated sodium bicarbonate solution, adding ethyl acetate for extraction three times (250 mL. Times.3); all the organic phases were combined, washed with 250ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was desolventized and purified by column chromatography to give 17.27g of compound 4 (hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative) in a yield of 51.3% and a purity of 97.3%.
Claims (9)
1. The synthesis method of the hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative is characterized by comprising the following steps of:
(1) 2, 3-dihydro-furan reacts with trichloroacetyl chloride and alkali after being mixed to prepare 2, 3-dihydro-4-trichloroacetyl furan;
(2) 2, 3-dihydro-4-trichloroacetyl furan reacts with N- (methoxymethyl) -N- (trimethylsilyl) benzylamine and methanol to prepare the hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative.
2. The method according to claim 1, wherein in the step (1), the base is one or more of diisopropylamine, triethylamine, and pyridine.
3. The synthesis method according to claim 1, wherein in the step (1), the molar ratio of 2, 3-dihydrofuran to trichloroacetyl chloride is 1 (1-2); the molar ratio of the 2, 3-dihydrofuran to the alkali is 1:1-3.
4. The method of claim 1, further comprising an organic solvent in step (1), wherein the organic solvent is one or more of dichloromethane, dichloroethane, N-dimethylformamide, and acetonitrile.
5. The method according to claim 1, wherein in the step (1), the reaction temperature is 20 to 30℃and the reaction time is 2 to 6 hours.
6. The synthetic method according to claim 1, wherein in step (2), the specific reaction process is:
adding 2, 3-dihydro-4-trichloroacetyl furan into an organic solvent, controlling the temperature to be 20-30 ℃, adding N- (methoxymethyl) -N- (trimethylsilyl) benzylamine and lithium salt, and replacing argon for protection reaction after adding;
then heating to 60-100 ℃, reacting for 8-18h, cooling to room temperature after the reaction is finished, adding methanol, and reacting for 1-6 h at room temperature.
7. The synthetic method according to claim 1 or 6, wherein in the step (2), the molar ratio of 2, 3-dihydro-4-trichloroacetyl furan to N- (methoxymethyl) -N- (trimethylsilyl) benzylamine is 1 (1-3); the mol ratio of the 2, 3-dihydro-4-trichloroacetyl furan to the methanol is 1 (5-15).
8. The method according to claim 6, wherein the lithium salt is one or more of lithium fluoride, lithium bromide, and lithium chloride; the molar ratio of the 2, 3-dihydro-4-trichloroacetyl furan to the lithium salt is 1 (2-5).
9. The method according to claim 6, wherein the organic solvent is one or more of dichloromethane, dichloroethane, N-dimethylformamide, and acetonitrile.
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