KR101942757B1 - Microwave-assisted process for preparing N-nonyldeoxynojirimycin - Google Patents

Abstract

The present invention relates to a method of manufacturing N-nonyl deoxynojirimycin having an excellent inhibitory activity against α-glucoside. To be specifically, the present invention relates to the method of manufacturing N-nonyl deoxynojirimycin using microwave which is manufactured by conducting a substitution reaction of deoxynojirimycin, which is a starting material, into 1-bromononane in the presence of K_2CO_3 base, diluting the same with a dimethyl formamide (DMF) solvent and conducting a heating reaction of the same by microwave.

Description

TECHNICAL FIELD The present invention relates to a microwave-assisted process for preparing N-nonyldeoxynojirimycin,

The present invention relates to a method for producing N -nonyloxyojirimycin which is excellent in the ability to inhibit? -Glucosidase. In more detail, the starting deoxynojirimycin is dissolved in K ₂ CO ₃ The presence of a base bromo monomethyl I (1-bromononane) as sikidoe metathesis, these dimethylformamide (DMF) is diluted in a solvent and then, N- using a microwave characterized in that the heat produced by the reaction in a microwave (microwave) And to a process for producing nonyldeoxynojirimycin.

Deoxynojirimycin (hereinafter abbreviated as 'DNJ') is a piperidine-based substance having a hexacyano monocycle structure (Tetrahedron, 2000, 11, 1645), a sugar molecule Is an alkaloid material having a structural feature in which oxygen is substituted with nitrogen. The DNJ has an excellent inhibitory effect on? -Glucosidase present in the small intestine of mammals and is effective as an agent for the treatment of non-insulin dependent diabetes mellitus which causes postprandial hyperglycemia by inhibiting glucose uptake into the blood from small intestine Nogeikagaku Kaishi, 1976, 50, 571). The compounds substituted with a nitrogen position of said nonyl DNJ N- furnace nilde oxy Nojiri azithromycin (N-nonyldeoxy nojirimycin;. Is used with the abbreviations is below, 'N N-DNJ') a.

The N N-DNJ also has a strong inhibitory effect on? -Glucosidase like DNJ (Nat. Med. 1988, 4, 610). The N N-DNJ is also a therapeutic agent for Gaucher's disease, a rare hereditary metabolic disease in which lipid such as bone marrow, spleen, and liver glycocerebroside are accumulated in a large amount due to a deficiency of an enzyme called glucocerebrosidase (Proc Nat'l Acad Sci, 2002, 99, 15428).

Among the various activities of N N-DNJ, the most known activity is an inhibitory effect against animal viruses, and is particularly effective in preventing diseases associated with viruses belonging to the field virus family (Bunyaviridae) or Togaviridae. As a typical virus corresponding to the above-mentioned viruses, there are Rift Valley Fever Virus (RVFV), and representative viruses corresponding to the above-mentioned Tovirus are Venezuelan horse encephalitis virus (VEEV) and Chikunguniya virus (CHIKV). The IC ₅₀ values of N N-DNJ for these viruses are known to exhibit relatively good activity with RVFV: 58 μM, VEEV: 12 μM, and CHIKV: 56 μM (WO2010 / 144759).

It has also been reported that N N-DNJ is also effective against Ebola zyla virus belonging to Filoviridae, Dengue virus and Orthomyxoviridae belonging to influenza A, B and C, respectively (WO2011 / 028779, WO2010 / 096764, WO2011 / 028775).

In addition, there have been reports of porcine and respiratory syndrome virus (PRRSV), porcine epidemic disease virus (PEDV), transmissible gastro-enteritis virus (PEDV) TGEV), classical swine fever virus (hog cholera), and influenza A virus, and as avian poultry virus, avian infectious bronchitis virus (IBV), avian infectious laryngeal bronchitis virus avian infectious laryngotrachetis virus, ILTV, mareck's disease virus, avian metapnuemo virus, avian paramyo virus, new castle disease virus, and avian leukemia virus avian leucosis sarcoma virus, and the like.

One common feature of these viruses is that they have an envelope outside the virus. In order to create an outer membrane of an animal virus, a glycoprotein must be synthesized from an ER in an animal cell. An α-glucosidase enzyme is involved in the synthesis of such a glycoprotein. In this process, N N-DNJ strongly inhibits the α-glucosidase enzyme, thereby inhibiting the growth of animal virus.

By using the method for the synthesis of N N-DNJ is a method of synthesizing diphenyl groups nonyl the nitrogen in 1-DNJ, if roughly divided them nonyl aldehyde (nonyl-andehyde) method using the nonyl halide (nonyl-halide) known in the art . First reaction using nonyl aldehydes are reduced using the method of the following [Scheme A] (WO2011 / 028781), a reaction using Pd / C as shown in the following [Scheme B] and _{NaBH 3 CN (BioChem. J. 2002} , 366, 225) are known.

[Reaction Scheme A]

[Scheme B]

Further, as a method using nonyl halide, a general SN ₂ (Org, Biomol, Chem, 2011, 9, 5373).

[Scheme C]

International Patent WO2011 / 028781A1

Biochem. J, 2002, 366, 225 Org. Biomol. Chem, 2011, 9, 5373

As described above, various synthesis methods for N N-DNJ have been conventionally introduced. However, when Pd / C and H ₂ are used as a reducing agent in a reduction reaction using nonylaldehyde as in the above reaction scheme A, , There is a problem that mass synthesis is difficult. When NaBH ₃ CN is used as a reducing agent as in the above reaction scheme B, hydrogen cyanide (HCN) having high toxicity is generated and the reaction time is long. Also, as shown in the above-mentioned Scheme C, the substitution reaction using an alkyl halide has a low reaction yield and a long reaction time.

Accordingly, an object of the present invention is to provide a method for producing N N-DNJ which is excellent in the ability to inhibit α-glucosidase, in which the overall reaction process is safer, the reaction yield is higher and the reaction time can be shortened To provide a new manufacturing method.

The present invention relates to a method of producing N- furnace nilde oxy Nojiri azithromycin, deoxy Nojiri bromo mono eda I azithromycin (DNJ) 0.2 ~ 4.0 equivalent weight and K ₂ CO ₃ 0.1 to 4.0 equivalents are added to the mixture, and the mixture is diluted with dimethylformamide (DMF) to a concentration of 0.05 to 0.5 M and then heated and reacted at a temperature of 50 to 150 ° C for 1 to 5 hours using a microwave And a method for producing N -nonyloxyojirimycin using microwaves.

The present invention having a substitution reaction by an oxy Nojiri azithromycin (DNJ) as the alkyl halide was prepared N- furnace nilde oxy Nojiri azithromycin (N N-DNJ), by carrying out the heating reaction using a microwave (microwave), conventional The overall reaction process is safe, the reaction yield is high, and the reaction time can be shortened.

1 is a photograph showing changes in TLC of a starting material (DNJ) and a target material ( N N-DNJ) according to microwave reaction time in the manufacturing method of the present invention,
2 is a ¹ H NMR analysis of a target material ( N N-DNJ) prepared according to Example 1 of the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the technical composition and effects of the present invention will be described in detail. Although the present invention has been described in connection with preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, is intended to cover various modifications and similarities.

The present invention relates to a process for the production of N, N- dimethylaniline (DNJ) by displacement reaction of bromoanane in the presence of K ₂ CO ₃ base, diluting it in a solvent of dimethylformamide (DMF) a method of manufacturing a furnace nilde oxy Nojiri azithromycin (N N-DNJ), are shown in the following [Scheme 1].

[Reaction Scheme 1]

In the above Reaction Scheme 1, the amount of the bromonic acid is 0.2 to 4.0 equivalents, preferably 1.5 to 2.5 equivalents, relative to DNJ. When the amount of the bromonic acid is less than 0.2 equivalent, there is a problem in that the yield of N N-DNJ synthesis is low. On the contrary, when the amount exceeds 4.0 equivalent, unreacted bromonic acid remains, There is a problem.

In addition, K ₂ CO ₃ Is 0.1 to 4.0 equivalents, preferably 1.5 to 2.5 equivalents to DNJ. When the amount of K ₂ CO ₃ is less than 0.1 equivalent, there is a problem in that the yield of synthesis of N 2 N-DNJ is low. Conversely, if the amount of K ₂ CO ₃ is over 4.0, K ₂ CO ₃ And there is a problem that additional procedures and costs are required to purify it from the final target material.

The amount of dimethylformamide (DMF) used as a reaction solvent in the above Reaction Scheme 1 is 0.05 ~ 0.5M, preferably 0.1 ~ 0.3M. If the concentration of the DMF is less than 0.05 M as the solvent of the reaction, there is a problem that the yield of N N-DNJ synthesis is lowered. Conversely, if the concentration exceeds 0.5 M, the synthesis yield does not increase but the cost increases.

One of the characteristics of the present invention is to irradiate a microwave while proceeding the reaction of the above Reaction Scheme 1. At this time, the microwave reaction is performed at a temperature of 50 to 150 ° C, preferably 80 to 120 ° C for 1 to 5 hours, preferably 2.5 to 4.0 hours.

If the treatment conditions of the microwave are less than 50 ° C and less than 1 hour, there is a problem that the yield of N N-DNJ synthesis is lowered. Conversely, if the temperature is more than 150 ° C and more than 5 hours, There is a problem in extending.

For reference, microwave reaction is a heating reaction using microwaves with a wavelength range of 1 mm to 1 m. It started to be used in the field of inorganic chemistry in the late 1970s, but since the mid 1980s, have. The use of a microwave synthesizer enables the reaction of a reaction with a long reaction time or a reaction under a severe condition to proceed more quickly, and the reaction yield can be increased.

Hereinafter, the present invention will be described in more detail with reference to preferred embodiments and comparative examples. Therefore, the scope of protection of the present invention is not limited by these embodiments.

[Example 1]

A microwave synthesizer (Anton Paar, Monowave 100) was charged with 0.2 mmol of DNJ, 0.4 mmol of bromoanane, K ₂ CO ₃ 0.42 mmol, and 1 mL of dimethylformamide (DMF) was added thereto, followed by heating at 100 ° C for 3 hours using a microwave.

After the reaction was completed, the reaction was filtered through celite and extracted three times with 5 mL of methanol (MeOH). The obtained filtrate was reduced in pressure and subjected to column chromatography (MeOH: MC = 10: 90) to obtain 52 mg (yield 90%) of N N-DNJ in the form of white solid.

In the first embodiment, the power of the microwave synthesizer (Monowave 10) was rapidly increased to 100 W, and after reaching the target temperature of 100 캜 in about 40 seconds after the start of the reaction, the power was slowly lowered to about 4 W The reaction temperature was maintained at 100 캜 while power was applied.

During the microwave reaction at a temperature of 100 ° C, the reaction state was confirmed by thin layer chromatography (TLC) analysis every one hour. As a result, as shown in the attached FIG. 1, the starting material, DNJ, remained at 1 hour and 2 hours but almost no DNJ was detected after 3 hours.

¹ HNMR analysis was performed on N N-DNJ prepared according to Example 1 and the results are shown in FIG. The instrument used for the NMR analysis was a Bruker ADVANCE III 400 NMR spectrometer and MeOD (methanol-d4) was used as the NMR solvent. The analysis results are as follows.

_{^{1 HNMR (400MHz, CD 3 OD}} ) δ0.90 (t, J = 6.72Hz, 3H), 1.30 (brs, 12H), 1.47-1.51 (m, 2H), 2.10-2.14 (m, 1H), 2.18 ( J = 10.9 Hz, 1H), 2.54-2.62 (m, 1H), 2.76-2.83 (m, 1H), 2.99 (dd, J = 4.88,11.16 Hz, 1H), 3.32-3.37 (m, 1H), 3.44-3.48 (m, 1H), 3.84-3.85 (m, 2H).

[Example 2]

Bromide to give the mono-I N N-DNJ 47mg (yield 81%) except that there was used a 0.3 mmol was carried out as Example 1.

[Example 3]

I to give the mono bromo, would be other than the above Example 1 was carried out as and N N-DNJ 48mg (83% yield) extending the heating time using a reaction using 0.3 mmol, and microwave to 5 hours.

[Comparative Example 1]

0.2 mmol of DNJ and 0.2 mmol of nonylaldehyde were mixed and 0.2 mmol of NaBH ₃ CN was added thereto and then reacted at 60 ° C for 8 hours or longer to obtain 41 mg of N N-DNJ (yield 71%) (Ref. BioChem. J. 2002, 366, 225).

[Comparative Example 2]

0.2 mmol of DNJ, 0.3 mmol of bromonoan and K ₂ CO ₃ (Ref. Org, Biomol, Chem, 2011, p. 29) was prepared by mixing N, N'-dicyclohexylcarbodiimide hydrochloride (0.42 mmol), and dissolving them in 1 ml of MeCN followed by reaction at reflux temperature for 8 hours or more. 9, 5373).

[Comparative Example 3]

0.2 mmol of DNJ, 0.3 mmol of bromonoan and K ₂ CO ₃ Mixture of 0.42 mmol, and these dissolved in DMF 1ml, and then to prepare a N N-DNJ 38 mg (yield 66%) by the reaction for 8 hours or more (overnight) at a temperature of 90 ℃ (Ref; Org, Biomol , Chem, 2011, 9, 5373).

, N- furnace nilde oxy Nojiri method of producing clarithromycin (N N-DNJ) is a target substance compared with the conventional N N-DNJ manufacturing method using a microwave according to the invention as identified in the Examples and Comparative Examples The yield is improved and the reaction time is shortened.

Claims (4)

Deoxynojirimycin 0.2-4.0 equivalents of 1-bromononane and K ₂ CO ₃ 0.1 to 4.0 equivalents are added thereto and diluted to a concentration of 0.05-0.5 M in dimethylformamide (DMF), followed by heating reaction at a temperature of 50-150 ° C. for 1 to 5 hours using microwave N- furnace nilde method of oxy Nojiri rapamycin characterized in that the.
According to claim 1, N- furnace nilde oxy Nojiri method of rapamycin characterized in that the heating reaction using the microwave (microwave) is performed at temperature of 80 ~ 120 ℃ for 2.5 ~ 4.0 hours.
3. The method according to claim 1 or 2, wherein the amount of the bromonic acid and the K ₂ CO ₃ is 1.5 to 2.5 equivalents.
Deoxynojirimycin 2 equivalents of 1-bromononane and 2 equivalents of K ₂ CO ₃ 2.1 equivalents of N , N -dimethylformamide (DMF), diluting them in dimethylformamide (DMF) to a concentration of 0.2M, and heating in microwave at a temperature of 100 DEG C for 3 hours. A method for producing nojirimycin.

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