Synthetic method of cyclobutyl-containing methyl propionate and propylene glycol derivative

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a synthetic method of cyclobutyl-containing methyl propionate and propylene glycol derivatives. Specifically, dimethyl methylmalonate represented by a formula A and a quaternary tension ring substrate represented by a formula B are taken as basic raw materials, under the action of a catalyst, a quaternary ring-containing methyl propionate represented by a formula C is prepared through a nucleophilic addition reaction, and further a propylene glycol derivative represented by a formula D or a formula E: # imgabs0 # is prepared through a decarboxylation reaction or a reduction reaction.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing methyl propionate and propylene glycol derivatives containing cyclobutyl. Background Art

[0002] Studies have shown that methyl propionate and propylene glycol derivatives containing cyclobutyl are important structural units and are widely used in liquid crystals, medicine, food and other fields. Among them, methyl propionate compounds containing cyclobutyl are important synthons of TGF-β inhibitors and orphan receptor γ modulators, and tetra-membered cyclopropylene glycol derivatives are used as synthons in liquid crystals, optics and other fields. Their synthesis methods have always been a research hotspot in organic chemistry, but most methods have obvious limitations such as many reaction steps and harsh reaction conditions. Based on this, we proposed a method for preparing methyl propionate and propylene glycol derivatives containing cyclobutyl. This method uses active methyl compounds and tetra-membered strained ring substrates as raw materials, and can cleanly and efficiently synthesize the target compounds in two steps.

[0003] The reaction of removing a single ester group from dimethyl malonate to obtain a methyl ester compound has been reported, such as patent (EP0671380A1). This method successfully achieves the degreasing of chain diester compounds to obtain a series of monoester compounds, but there are still obvious limitations, such as: the reaction requires the use of an autoclave and the reaction temperature is greater than 200°C. Therefore, it is urgent to find a greener and more efficient method.

[0004]

[0005] At present, most of the synthetic routes of tetracyclic alkyl esters have limitations and are not suitable for large-scale industrial production. For example, the synthetic method reported in the patent (WO2004024159A1) uses cyclobutylmethanol as the initial raw material and undergoes five steps of reaction to synthesize the target compound. In addition, dangerous chemicals such as pyridine, hydrogen peroxide, and oxalyl chloride are required in the synthetic process. The danger and cost of the synthetic process are very high, and the yield cannot be guaranteed, making it difficult to achieve large-scale industrial production.

[0006]

[0007] On this basis, the patent (WO2014086894A1) reported a methylation method for the compound. This method requires the use of dangerous compound iodomethane at -70°C, and the experimental operation is complicated and the reaction time is long, which further restricts the industrial prospects of this method.

[0008]

[0009] The synthesis method of tetracyclic propanediol derivatives has been reported, such as the tetracyclic propanediol diethyl ester proposed in Chinese patent (CN105481824A) as raw material, under the action of lithium chloride and potassium borate, tetrahydrofuran as solvent, reflux for two hours to obtain the reduction product, tetracyclic propanediol. Although the method is simple and easy to operate, the initial raw material 2-cyclobutyl propanediol diethyl ester is difficult to obtain, which greatly reduces the application prospect of the method.

[0010] Summary of the invention

[0011] Although methods for synthesizing cyclobutylpropionic acid methyl ester and propylene glycol derivatives have been reported, they all have obvious limitations.

[0012] In order to achieve the technical purpose of the present invention, the technical solution of the present invention is:

[0013] The present invention first provides a compound of formula E, the structural formula of which is:

[0014]

[0015] On the other hand, the present invention provides a method of using dimethyl methylmalonate Formula A and a four-membered strained ring substrate Formula B as basic raw materials, and obtaining a four-membered ring-containing methyl propionate Formula C through a nucleophilic addition reaction under the action of a catalyst, and further obtaining a propylene glycol derivative Formula D or Formula E through a decarboxylation reaction or a reduction reaction:

[0016]

[0017] The nucleophilic addition reaction is to prepare a four-membered ring-containing methyl propionate compound of formula C from dimethyl methylmalonate of formula A and a four-membered strained ring substrate of formula B under the action of a catalyst:

[0018]

[0019] The catalyst may be DMAP, 4-pyrrolidinopyridine, 4-pyridylpiperazine or TBD, and most preferably DMAP, ie, p-dimethylaminopyridine.

[0020] The above-mentioned nucleophilic addition reaction solvent can be tetrahydrofuran, toluene, xylene, chlorobenzene, trifluorotoluene, 1,4-dioxane or ethyl acetate, and is most preferably toluene.

[0021] The molar ratio of the DMAP catalyst to the compound of formula B is most preferably 0.05:1.

[0022] The molar ratio of the compound of formula A to the compound of formula B is most preferably 3:1.

[0023] The above nucleophilic addition reaction temperature is 90°C-110°C, most preferably 110°C.

[0024] The preparation method of the compound of formula D provided by the present invention comprises preparing the compound of formula C by decarboxylation reaction:

[0025]

[0026] The above-mentioned decarboxylation reaction reagent can be sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide or potassium phosphate, and is most preferably sodium methoxide. The above-mentioned decarboxylation reaction solvent can be methanol, ethanol or isopropanol, and is most preferably methanol.

[0027] In the above decarboxylation reaction, the molar ratio of sodium methoxide to the compound of formula C is most preferably 3:1.

[0028] The decarboxylation reaction temperature is 60°C to 90°C, and most preferably 80°C.

[0029] The preparation method of the compound of formula E provided by the present invention comprises preparing the compound of formula C by reduction reaction:

[0030]

[0031] The reduction reaction reagent may be lithium aluminum hydride or sodium borohydride, and lithium aluminum hydride is most preferred.

[0032] The reduction reaction solvent may be tetrahydrofuran or methanol, and tetrahydrofuran is most preferred.

[0033] In the above reduction reaction, the molar ratio of lithium aluminum hydride to the compound of formula C is most preferably 3:1.

[0034] The reduction reaction temperature is 0°C to 40°C, and most preferably 0°C to room temperature.

[0035] The present invention provides a method for synthesizing methyl propionate and propylene glycol derivatives containing four-membered rings in two steps in a green and efficient manner, using an active methine compound: dimethyl methylmalonate and a four-membered strained ring substrate as basic raw materials. The method has obvious advantages, mild reaction conditions, simple operation, and the reagents used are cheap, easily available, and not very dangerous. In the presence of sodium methoxide, a single ester group can be removed by heating at 80°C for 16 hours to obtain the corresponding four-membered ring alkyl ester compound, so it has good application prospects. DETAILED DESCRIPTION

[0036] In order to further understand the present invention, the synthesis method of a cyclobutyl-containing methyl propionate and propylene glycol derivative provided by the present invention is described in detail below in conjunction with the examples. It should be understood that these examples are only for further describing the features of the present invention in detail, and are not intended to limit the scope of the present invention or the scope of the claims of the present invention.

[0037] Embodiment 1:

[0038] Step 1

[0039] A (219.2 mg, 1.5 mmol, 3.0 eq.), B (97.0 mg, 0.5 mmol, 1.0 eq.), 5 mL of toluene and DMAP (3.05 mg, 0.025 mmol, 0.05 eq.) were added to a dry 50 mL sealed tube in sequence; the sealed tube was evacuated and replaced with nitrogen, and the cycle was repeated three times; the sealed tube was placed in a 110°C oil bath for 16 h; after 16 h, the temperature was cooled to room temperature, and the reaction was complete after TLC monitoring (n-Hexane:EA=4:1, Rf=0.3, 254 nm); the reaction solution was transferred to a 250 mL single-mouth bottle and silica gel was added, and the reaction was concentrated under reduced pressure and separated by column chromatography; n-Hexane:EA=10:1 was used as the eluent, and the desired eluent was collected and dried to obtain 161.7 mg of a colorless oily liquid (C, trans:cis=1:8, 161.7 mg, 95% yield, colourless oil); 1 H NMR (400MHz, CDCl3) δ7.77(d,J=6.8Hz,2H),7.57(t,J=6.8Hz,1H),7.48(d,J=7.2Hz,2H),3.65(s,6H),3.59–3.53(m,1H),2.82–2.72(m,1H),2.43–

[0040] 2.34(m,2H),2.18–2.11(m,2H),1.31(s,3H). 13 C NMR(101MHz, CDCl3)δ171.3,138.0,133.6,129.2,128.1,55.2,52.5,52.4,34.0,25.2,17.5.HRMS(ESI)m / z:[M+Na] + Calculated for C 16 H 20 NaO6S 363.0873; Found:363.0878.

[0041] Embodiment 2:

[0042] Step 2

[0043] Sodium methoxide (81.03 mg, 1.5 mmol, 3.0 eq.) was added to a dry 50 mL sealed tube in sequence; the sealed tube was evacuated and replaced with nitrogen, and the cycle was repeated three times; while nitrogen was introduced, methanol (5 mL) containing C (170.2 mg, 0.5 mmol, 1.0 eq.) was added to the tube; the sealed tube was placed in an 80 °C oil bath for 16 h; after 16 h, it was cooled to room temperature and monitored by TLC (n-Hexane:EA=4:1, R f =0.5, 254nm), the reaction was complete; the reaction solution was transferred to a 250mL single-mouth bottle and silica gel was added, and the mixture was concentrated under reduced pressure and then separated by column chromatography; n-Hexane:EA=10:1 was used as the eluent, and the desired eluate was collected and dried to obtain 73.4mg of a light yellow oily liquid (D, 73.4mg, 52% yield, yellow oil); 1 H NMR (400MHz, CDCl3) δ7.84(d,J=8.0Hz,2H),7.60(t,J=7.6Hz,1H),7.53(t,J=7.6Hz, 2H),3.67–3.59(m,4H),2.52–2.44(m,1H),2.38–2.19(m,5H),1.05(d,J=7.2Hz,3H). 13 C NMR(101MHz, CDCl3)δ175.3,138.3,133.7,129.4,128.3,53.1,51.7,44.8,32.8,28.2,27.1,14.0.HRMS(ESI)m / z:[M+Na] + Calculated for C 14 H 18 NaO4 305.0818; Found 305.0789.

[0044] Embodiment 3:

[0045] Step 3

[0046] A dry 50 mL three-necked flask was evacuated and replaced with nitrogen, and the cycle was repeated three times; C (340.39 mg, 1 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL) and added to the three-necked flask; the three-necked flask was placed in an ice bath and cooled to 0°C; a tetrahydrofuran solution of lithium aluminum hydride (113.85 mg, 3 mmol, 3.0 eq.) was added dropwise to the flask; the mixture was returned to room temperature after 0.5 h, and the reaction mixture was monitored by TLC (EA, R f=0.3, 254nm), the reaction was complete; saturated NH4Cl solution (1mL) was added to quench, anhydrous MgSO4 was added to remove water, and then filtered; the filtered filtrate was transferred to a 250mL single-mouth bottle, silica gel was added, and the mixture was concentrated under reduced pressure and then separated by column chromatography; EA was used as the eluent, and the desired eluate was collected and dried to obtain 205mg of a white solid (E, 205mg, 72% yield, white solid); 1 H NMR (400MHz, CDCl3) δ7.86(d,J=7.6Hz,2H),7.64(t,J=7.6Hz,1H),7.55(t,J=7.6Hz,2H),3.68–

[0047] 3.60(m,1H),3.51(s,3H),2.57–2.43(m,3H),2.22(br,2H),2.13–2.07(m,2H),0.76(s,3H). 13 CNMR(101MHz, CDCl3)δ138.2,133.8,129.4,128.3,68.4,53.2,40.2,33.0,24.2,15.3.HRMS(ESI)m / z:[M+Na] + Calculated for C 14 H 20 NaO4S 307.0975; Found307.0983.

Claims

1. A compound of formula E, characterized in that The structural formula is:

2. A method for preparing a compound of formula E, characterized in that: Prepared by reduction reaction of a compound of formula C, 3. A method for preparing a compound of formula E or a compound of formula D, characterized in that: Dimethyl methylmalonate Formula A and four-membered strained ring substrate Formula B are used as basic raw materials. Under the action of a catalyst, a four-membered ring-containing methyl propionate Formula C is obtained through a nucleophilic addition reaction, and further a decarboxylation reaction or a reduction reaction is performed to prepare a propylene glycol derivative Formula D or Formula E:

4. The preparation method according to claim 3, characterized in that: The catalyst is dimethylaminopyridine, 4-pyrrolidinopyridine, 4-pyridylpiperazine or TBD.

5. The preparation method according to claim 3, characterized in that: The decarboxylation reaction reagent is sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide or potassium phosphate.

6. The preparation method according to claim 2 or 3, characterized in that: The reduction reaction reagent is lithium aluminum hydride or sodium borohydride.

7. The preparation method according to claim 3 or 4, characterized in that: The molar ratio of dimethylaminopyridine to the compound of formula B is 0.05:

1.

8. The preparation method according to claim 3 or 5, characterized in that: The molar ratio of sodium methoxide to the compound of formula C is 3:

1.

9. The preparation method according to claim 3 or 6, characterized in that: The molar ratio of lithium aluminum hydride to the compound of formula C is 3:

1.

10. The preparation method according to claim 2, 3, 4, 5 or 6, characterized in that: The reaction is carried out in the presence of a solvent, and the reaction solvent is toluene, tetrahydrofuran, xylene, chlorobenzene, trifluorotoluene, 1,4-dioxane, ethyl acetate, methanol, ethanol or isopropanol.

11. The preparation method according to claim 2, 3 or 6, characterized in that: The reduction reaction temperature is 0°C to 40°C.

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