A method for selectively removing a hydroxyl protecting group

Abstract

The present invention belongs to the field of fine chemicals and related chemical technologies, and provides a method for selectively removing a hydroxyl protecting group. Using chloroacetate and its derivatives as raw materials, in the presence of a phosphine catalyst, in the presence of a base and an additive, under anhydrous organic solvent conditions, reacting at 80 °C for 1 to 16 hours, the corresponding deprotected compound can be obtained. The method of the present invention is free of transition metals, has mild reaction conditions, is easy to operate, has the possibility of industrialization, and obtains the deprotected compound in a relatively high yield; the deprotected compound obtained by using this method can be further functionalized to obtain various compounds, and this method is applied to the development and research of natural products, functional materials and fine chemicals.

Description

Technical Field

[0001] The present invention belongs to the technical field of fine chemicals and related chemical technologies, and provides a method for efficiently and selectively removing the chloroacetyl group as a hydroxyl protecting group. Background Art

[0002] Hydroxy compounds are a class of organic molecules containing a hydroxyl group (-OH), which are widely present in natural products and some important and complex compounds. As is well known, the hydroxyl group has active chemical reactivity. Therefore, in the synthesis of natural products and drugs containing hydroxyl groups, the protection and deprotection of hydroxyl groups are often involved. Therefore, it is crucial to select a suitable protecting group and develop a corresponding deprotection method. Compared with other protecting groups, the chloroacetyl group has the characteristics of simple introduction and relatively easy removal.

[0003] The following are several reported methods for removing the chloroacetyl protecting group: thiourea (M Bertolini, C.P.J. Glaudemans, Carbohyd. Rea. 1970, 15, 263 - 270), HDTC (C.A.A. van Boeckel and T. Beetz, Tetrahedron Lett. 1983, 24, 3775 - 3778), DABCO (I. Ohtsuka, T. Ako, R. Kato, S. Daikoku, S. Koroghi, T. Kanemitsu, O. Kanie, Carbohyd. Res. 2006, 341, 1476 - 1487), 1-Se-carbamoylpiperidine (S. Sogabe, H. Ando, M. Koketsub, H. Ishihara, Tetrahedron Lett. 2006, 47, 6603–6606) is also a good choice. In recent years, some people have also proposed to use NaBH 4 (E. Villedieu, C.L. Bon, S.B. Raboin, Tetrahedron Lett. 2010, 51, 2115–2118) to remove the chloroacetyl group.

[0004] However, these methods have their own drawbacks. For example, thiourea promotes the cleavage of the ClAc group, requires relatively harsh reaction conditions and a long reaction time, and occasionally causes acyl migration. HDTC has poor chemical stability and needs to be used immediately after fresh preparation. The application of DABCO is limited to the reaction medium, which is only limited to ethanol solvent. 1-Se-carbamoylpiperidine reported in recent years shows high chemoselectivity and wide tolerance to reaction solvents in the dechloroacetylation reaction, but it is also restricted by the cumbersome preparation of the selenourea intermediate and the high reaction temperature. The reducing ability of sodium borohydride leads to problems with functional group compatibility.

[0005] In recent years, metal-free catalytic reactions have been favored by more and more people because of their advantages of low pollution, low price, and industrial production. However, there are no reports on the method of removing chloroacetyl groups using phosphine compounds as catalysts. Summary of the invention

[0006] The invention provides a method for selectively removing chloroacetyl of a hydroxyl protecting group. The synthetic method has no transition metal, mild reaction conditions, simple operation, high efficiency and high yield.

[0007] The technical solution of the present invention:

[0008] A method for selectively removing a hydroxyl protecting group (AcCl), using a chloroacetyl ester compound and its derivatives as raw materials, reacting at 80°C for 1-16 hours in the presence of a phosphine catalyst, a base, and an additive, in an anhydrous organic solvent, to obtain the corresponding deprotected product alcohol. The synthesis route is as follows:

[0009]

[0010] R 1 is selected from aryl and alkyl;

[0011] The molar ratio of chloroacetate and its derivatives to the phosphine catalyst is 1:0.01 to 1:0.1;

[0012] The molar ratio of chloroacetate and its derivatives to base is 1:0.5 to 1:3;

[0013] The molar ratio of chloroacetate and its derivatives to the additive is 1:0.5 to 1:3;

[0014] The molar concentration of chloroacetate and its derivatives in the reaction system is 0.3 mmol / mL.

[0015] The anhydrous organic solvent is toluene, acetonitrile, 1,4-dioxane, and tetrahydrofuran, preferably toluene, acetonitrile, and 1,4-dioxane.

[0016] The phosphine catalyst is triphenylphosphine, DPPF, tri-n-butylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, tri(2-furyl)phosphine. Preferably, tri(2-furyl)phosphine, triphenylphosphine, DPPF;

[0017] The base is sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium fluoride, potassium carbonate, potassium acetate, potassium phosphate, potassium pyrophosphate, preferably potassium phosphate, sodium hydroxide, potassium hydroxide.

[0018] The additives described above are triisobutyl borate, triethyl borate, trimethyl borate, and boric acid. Preferably, they are trimethyl borate, triethyl borate, and triisobutyl borate.

[0019] The separation methods include recrystallization, column chromatography, etc.

[0020] The solvents used in the recrystallization method include petroleum ether, ethyl acetate, diethyl ether, acetone, chloroform, n-hexane, and dichloromethane.

[0021] When using column chromatography to separate the product, silica gel or neutral alumina can be used as the stationary phase, and the eluent is generally a mixed solvent of polar and non-polar solvents, such as ethyl acetate - petroleum ether, ethyl acetate - n-hexane, dichloromethane - petroleum ether, and methanol - petroleum ether.

[0022] The beneficial effects of the present invention are that the synthesis method has no transition metal reaction, mild reaction conditions, simple operation, and high yield; the hydroxyl compounds obtained by deprotection using this method can be further functionalized to obtain various compounds, which are applied to the development and research of natural products, functional materials, and fine chemicals. Description of the Drawings

[0023] Figure 1 is the 1 1H NMR spectrum of benzyl alcohol in Example 1.

[0024] Figure 2 is the 13 13C NMR spectrum of benzyl alcohol in Example 1.

[0025] Figure 3 is the 1 1H NMR spectrum of 2-allylphenol in Example 2.

[0026] Figure 4 is the 13 13C NMR spectrum of 2-allylphenol in Example 2.

[0027] Figure 5 is the 1 1H NMR spectrum of β-cholesterol in Example 3.

[0028] Figure 6 is the 13 13C NMR spectrum of β-cholesterol in Example 3.

[0029] Figure 7 is the 1 1H NMR spectrum of diacetone-D-galactose in Example 4.

[0030] Figure 8 is the 13 13C NMR spectrum of diacetone-D-galactose in Example 4.

[0031] Figure 9 is 1-adamantanol in Example 5 1 1H NMR spectrum.

[0032] Figure 10 is 1-adamantanol in Example 5 13 13C NMR spectrum.

[0033] Figure 11 is ethyl (S)-(-)-mandelate in Example 6 1 1H NMR spectrum.

[0034] Figure 12 is ethyl (S)-(-)-mandelate in Example 6 13 13C NMR spectrum.

[0035] Figure 13 is benzyl 3-(hydroxymethyl)benzoate in Example 7 1 1H NMR spectrum.

[0036] Figure 14 is benzyl 3-(hydroxymethyl)benzoate in Example 7 13 13C NMR spectrum.

[0037] Figure 15 is (-)-(1r,3r,4s,8r)-menthane-3,9-diol in Example 8 1 1H NMR spectrum.

[0038] Figure 16 is (-)-(1r,3r,4s,8r)-menthane-3,9-diol in Example 8 13 13C NMR spectrum. Detailed implementation manners

[0039] The synthetic method for removing the hydroxyl protecting group according to the present invention has the advantages of low raw material price, no participation of transition metals in the reaction, few reaction steps, mild reaction conditions, easy operation and high reaction yield.

[0040] The present invention will be further described below in conjunction with specific examples. These examples are only used to illustrate the present invention and not to limit the scope of the present invention. Any simple substitution or improvement made by those skilled in the art to the present invention falls within the scope of the technical solutions protected by the present invention.

[0041] Example 1: Synthesis of benzyl alcohol

[0042] In a 25 mL reactor, benzyl chloroacetate (0.055 g, 0.3 mmol), potassium phosphate (0.191 g, 0.9 mmol), triphenylphosphine (0.78 mg, 0.003 mmol), trimethyl borate (0.046 g, 0.45 mmol) were added, and 1.5 mL of anhydrous acetonitrile was added. The mixture was stirred at 80 °C under nitrogen for 1 h. Column chromatography separation (silica gel, 200 - 300 mesh; eluent, petroleum ether:dichloromethane = 1:2) gave 0.030 g of benzyl alcohol with a yield of 94%.

[0043]

[0044] Benzyl alcohol, a colorless oily liquid, 1 H NMR (400 MHz, CDCl 3 ) δ 7.33 (d, J = 6.1 Hz, 4H), 7.30–7.24 (m, 1H), 4.62 (s, 2H), 2.32 (s, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 140.9, 128.6, 127.6, 127.0, 65.2.

[0045] Example 2: Synthesis of 2 - allylphenol

[0046] In a 25 mL reactor, 2 - allylphenyl 2 - chloroacetate (0.063 g, 0.3 mmol), potassium phosphate (0.191 g, 0.9 mmol), tris(2 - furyl)phosphine (0.1 mg, 0.003 mmol), triethyl borate (0.065 g, 0.45 mmol) were added, and 1.5 mL of anhydrous acetonitrile was added. The mixture was stirred at 80 °C under nitrogen for 4 h. Column chromatography separation (silica gel, 200 - 300 mesh; eluent, petroleum ether:dichloromethane = 1:2) gave 0.039 g of 2 - allylphenol with a yield of 97%.

[0047]

[0048] 2 - Allylphenol, a colorless liquid, 1 H NMR (400 MHz, CDCl3) δ 7.18–7.07 (m, 2H), 6.91–6.87 (m, J = 7.5, 1.2 Hz, 1H), 6.82–8.80 (dd, J = 7.9, 1.1 Hz, 1H), 6.07 - 5.97 (m, J = 17.9, 9.6, 6.3 Hz, 1H), 5.20–5.11 (m, 2H), 5.00 (s, 1H), 3.41 (dt, J = 6.4, 1.7 Hz, 2H); 1313C NMR (101 MHz, CDCl3) δ 154.1, 136.4, 130.5, 127.9, 125.3, 121.0, 116.5, 115.8, 35.1.

[0049] Example 3: Synthesis of β-cholesterol

[0050] The operation was the same as in Example 1. β-Cholesterol was obtained from cholesterol chloroacetate, 0.060 g, with a yield of 52%.

[0051]

[0052] β-Cholesterol, light yellow solid, 1 1H NMR (400 MHz, CDCl 3 ) δ 5.35 (s, 1H), 3.52 (tt, J = 10.6, 4.7 Hz, 1H), 2.35–2.16 (m, 2H), 1.99 (tt, J = 16.3, 3.1 Hz, 2H), 1.84 (dq, J = 14.4, 5.1, 4.3 Hz, 3H), 1.73 (s, 1H), 1.62–0.94 (m, 24H), 0.91 (d, J = 6.5 Hz, 3H), 0.86 (dd, J = 6.6, 1.8 Hz, 6H), 0.68 (s, 3H); 13 13C NMR (101 MHz, CDCl 3 ) δ 140.8, 121.7, 71.8, 56.8, 56.2, 50.1, 42.33, 42.30, 39.8, 39.5, 37.3, 36.5, 36.2, 35.8, 31.93, 31.91, 31.7, 28.3, 28.0, 24.3, 23.9, 22.9, 22.6, 21.1, 19.4, 18.7, 11.9.

[0053] Example 4: Synthesis of diacetone-D-galactose

[0054] The operation was the same as in Example 2. Diacetone-D-galactose was obtained from diacetone-D-galactose chloroacetate, 0.048 g, with a yield of 64%.

[0055]

[0056] Diacetone-D-galactose, colorless oily liquid, 1 1H NMR (400 MHz, CDCl 3) δ 5.94 (d, J = 3.6 Hz, 1H), 4.53 (d, J = 3.6 Hz, 1H), 4.39–4.26 (m, 2H), 4.17 (dd, J = 8.7, 6.4 Hz, 1H), 4.06 (dd, J = 7.9, 2.6 Hz, 1H), 4.00 (dd, J = 8.7, 5.3 Hz, 1H), 2.82 (d, J = 3.9 Hz, 1H), 1.47 (d, J = 21.5 Hz, 6H), 1.34 (d, J = 19.1 Hz, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 111.8, 109.6, 105.3, 85.1, 81.1, 75.0, 73.3, 67.6, 26.84, 26.78, 26.2, 25.2.

[0057] Example 5: Synthesis of 1 - Adamantanol

[0058] In a 25 mL reactor, add adamantyl chloroacetate (0.067 g, 0.3 mmol), sodium hydroxide (0.036 g, 0.9 mmol), DPPF (0.002 g, 0.003 mmol), triisobutyl borate (0.103 g, 0.45 mmol), add 1.5 mL of anhydrous toluene, and stir at 80 °C under nitrogen for 16 h. Column chromatography separation (silica gel, 200 - 300 mesh; eluent, petroleum ether : dichloromethane = 1:2) gave 0.033 g of 1 - adamantanol, with a yield of 73%.

[0059]

[0060] 1 - Adamantanol, white solid, 1 H NMR (400 MHz, CDCl 3 ) δ 4.94 (s, 1H), 3.97 (s, 1H), 2.13 (t, J = 3.0 Hz, 4H), 1.71 (d, J = 3.0 Hz, 4H), 1.66 (d, J = 3.4 Hz, 2H), 1.64–1.59 (m, 4H); 13 C NMR (101 MHz, CDCl 3 ) δ 68.2, 45.3, 36.1, 30.7.

[0061] Example 6: Synthesis of (S)-(-)-Ethyl mandelate

[0062] The operation was the same as in Example 5. Ethyl mandelate, 0.045 g, with a yield of 86%, was obtained from (S)-2-(2 - chloroacetoxy)-2 - phenylacetic acid ethyl ester.

[0063]

[0064] Ethyl mandelate, colorless liquid, 1 H NMR(400MHz,CDCl 3 )δ7.47–7.39(m,2H),7.39–7.27(m,3H),5.15(d,J=5.8Hz,1H),4.30–4.10(m,2H),3.56(d,J=5.8Hz,1H),1.22(t,J=7.1Hz,3H); 13 C NMR(101MHz,CDCl 3 )δ173.7,138.5,128.6,128.4,126.6,72.9,62.2,14.0.

[0065] Example 7: Synthesis of benzyl 3-(hydroxymethyl)benzoate

[0066] The operation was the same as in Example 5. 0.057 g of 2-allylphenol was obtained from benzyl 3-((2-chloroacetoxy)methyl)benzoate, with a yield of 79%.

[0067]

[0068] Benzyl 3-(hydroxymethyl)benzoate, light yellow liquid, 1 H NMR(400MHz,CDCl 3 )δ8.12–8.04(m,2H),7.60–7.46(m,J=7.4Hz,1H),7.49–7.41(m,3H),7.43–7.31(m,3H),5.37(s,2H),4.72(s,2H),2.25(s,1H); 13 C NMR(101MHz,CDCl 3 )δ166.5,141.4,136.4,133.1,130.1,129.7,128.9,128.4,127.4,126.9,126.7,66.6,65.0;IR(neat)3337,1718,1451,1273,1112,1026,887,788,744,711cm -1 ;HMRS(ESI)calcd for C 15 H 14 NaO 3 265.0841[M+Na] + ,found265.0831.

[0069] Example 8: Synthesis of (-)-(1r,3r,4s,8r)-menthane-3,9-diol

[0070] In a 25 mL reactor, (1R,2S,5R)-2-(((R)-1-hydroxypropyl-2-yl)-5-methylcyclohexyl 2-chloroacetate (0.074 g, 0.3 mmol), potassium hydroxide (0.050 g, 0.9 mmol), DPPF (0.002 g, 0.003 mmol), and triisobutyl borate (0.103 g, 0.45 mmol) were added. 1.5 mL of anhydrous 1,4-dioxane was added, and the mixture was stirred at 80 °C under nitrogen for 1 h. Column chromatography separation (silica gel, 200 - 300 mesh; eluent, petroleum ether:dichloromethane = 1:2) gave (-)-(1r,3r,4s,8r)-menthane-3,9-diol, 0.048 g, with a yield of 93%.

[0071]

[0072] (-)-(1r,3r,4s,8r)-Menthane-3,9-diol, a colorless liquid, 1 H NMR (400 MHz, CDCl 3 ) δ 4.09 (s, 1H), 3.64 (dd, J = 10.7, 5.3 Hz, 1H), 3.56 (dd, J = 10.7, 3.4 Hz, 1H), 3.43 (td, J = 10.4, 4.3 Hz, 1H), 1.98 (d, J = 4.4 Hz, 1H), 1.82 (s, 1H), 1.69–1.50 (m, 2H), 1.47–1.29 (m, 2H), 1.23 (qd, J = 12.7, 3.4 Hz, 1H), 0.99 (d, J = 11.6 Hz, 1H), 0.95 (d, J = 7.2 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 0.88–0.81 (m, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 69.9, 66.9, 48.6, 44.4, 38.6, 34.6, 31.4, 29.6, 22.1, 12.0。

Claims

1. A method for selectively removing hydroxyl protecting groups, It is characterized in that Using chloroacetate compound as raw material, in the presence of phosphine catalyst, in the presence of base and additive, in anhydrous organic solvent, react at 80°C for 1-16 hours to obtain the corresponding deprotected product alcohol. The synthesis route is as follows: The molar ratio of chloroacetate to phosphine catalyst is 1:0.01 to 1:0.1; The molar ratio of chloroacetate to base is 1:0.5 to 1:3; The molar ratio of chloroacetate to additive is 1:0.5 to 1:3; The molar concentration of chloroacetate in the reaction system is 0.3 mmol / mL; The anhydrous organic solvent is one or a mixture of two or more of toluene, acetonitrile, 1,4-dioxane, and tetrahydrofuran; The phosphine catalyst is one or a mixture of two or more of triphenylphosphine, DPPF, tri-n-butylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, and tri(2-furyl)phosphine; The base is one or a mixture of two or more of sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium fluoride, potassium carbonate, potassium acetate, potassium phosphate, and potassium pyrophosphate; The additive is one or a mixture of two or more of triisobutyl borate, triethyl borate, trimethyl borate and boric acid; The product alcohol is

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