Synthesis method of bicyclol

Abstract

The invention provides a method for synthesizing bicyclol, and belongs to the field of medicine synthesis. The invention provides a method for synthesizing bicyclol, which comprises the following steps: by taking biphenyl alcohol acid as an initial raw material, adding methyl tert-butyl ether and a catalyst for reaction, and purifying, thereby obtaining the bicyclol. The catalyst is iron trifluoromethanesulfonate; the synthetic route of the compound is # imgabs0 #. According to the method for synthesizing the bicyclol, provided by the invention, a new methylation reagent methyl tert-butyl ether and a catalyst iron trifluoromethanesulfonate are adopted, and methylation reagents which are high in toxicity, easy to explode and the like and are extremely easy to generate dangers in the use process are avoided, so that the defects of harsh post-treatment, poor reaction selectivity, low yield and the like in the existing process are overcome; the method has the advantages of short reaction steps, simple process operation, mild conditions, high yield, safe and reliable product quality, stable process and good reproducibility; the materials in the whole process are cheap, easy to obtain and non-toxic, the used materials and the operation process are friendly to EHS, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a method for synthesizing bicyclic alcohol, and belongs to the field of drug synthesis. Background Art

[0004] Gu Shi-jie first reported the synthesis route of bicyclic alcohol in 1988 (US4868207A). This route uses biphenyl diester as the starting material, and after hydrolysis, anhydride dehydration, and sodium borohydride reduction, biphenyl lactone is obtained, and biphenyl lactone is further reacted with methanol in the presence of carboxylate to obtain bicyclic alcohol. In this route, the one-step yield of biphenyl lactone ring opening and methanol reaction is only 38.5%, which affects its industrial application.

[0005]

[0006] Subsequently, Chinese patent CN103242286A improved the last step and other steps, mainly changing the last step to dimethyl sulfate for methylation. However, this route still has problems with the selectivity of carboxyl and hydroxyl methylation, and dimethyl sulfate is very toxic. The introduction of the last step poses certain risks to the safety of the raw material.

[0007]

[0008] Chinese patent CN 111205263 A further improves the last step of methylation reaction, which is characterized by using methyl p-toluenesulfonate to carry out methylation reaction under sodium hydride. This route has the following problems: 1. Sodium hydride has safety risks of being flammable and explosive. 2. Methyl p-toluenesulfonate is a genotoxic impurity, and its introduction in the last step may affect the quality of the raw material drug. 3. The selectivity of hydroxyl and carboxyl methylation has not been effectively solved.

[0009]

[0010] Patent CN103724317A proposes a new route, which avoids the selectivity problem of hydroxyl and carboxyl methylation. However, the last step of this route uses borane reduction, and the actual conversion rate of borane-reduced esters is not high, which is not suitable for industrial production.

[0011]

[0012] Patent CN106243079B also proposes a new route to avoid the selectivity problem of hydroxyl and carboxyl methylation, but this route uses 2-mercaptothiazoline with a strong odor and is not suitable for industrial production.

[0013]

[0014] In the prior art, the synthesis process of bicyclic alcohol from biphenyl alcohol or other intermediates has problems such as selective methylation of carboxyl and hydroxyl groups or the use of highly toxic reagents, which makes the production cycle relatively long, causes great harm to operators and the environment, produces a large amount of waste liquid and has high production costs. Summary of the invention

[0015] In order to overcome the above defects, the present invention provides a method for synthesizing bicyclic alcohol.

[0016] The invention provides a method for synthesizing bicyclic alcohol, which is prepared by using biphenyl alcohol acid as a starting material, adding methyl tert-butyl ether and a catalyst for reaction, and then purifying the product; the catalyst is iron trifluoromethanesulfonate; Its synthetic route is: .

[0017] Wherein, the purification method is a crystallization method.

[0018] The synthetic method of bicyclic alcohol of the present invention comprises the steps: a. Take methyl tert-butyl ether, biphenyl alcohol acid and iron trifluoromethanesulfonate, stir and heat to 50°C to 90°C; wherein the mass volume ratio of biphenyl alcohol acid to methyl tert-butyl ether is 1:1 to 1:4; the molar ratio of biphenyl alcohol acid to iron trifluoromethanesulfonate is 1:0.005 to 1:0.12; b. Keep the reaction warm for 2 hours to 6 hours until the reaction is almost complete or the biphenyl alcohol acid is ≤ 0.5% w / w; c. After the reaction is completed, cool to room temperature; filter, add sodium hydroxide solution to the filtrate, separate the phases, add a poor solvent, continue to cool and crystallize for 1 to 4 hours, filter, and dry to obtain the product.

[0019] Preferably, the mass volume ratio of the biphenyl alcohol acid to methyl tert-butyl ether in step a is 1:2 to 1:3; the molar ratio of the biphenyl alcohol acid to iron trifluoromethanesulfonate is 1:0.01 to 1:0.1.

[0020] Wherein, the sodium hydroxide concentration in step c is 0.1% to 10% w / w; the poor solvent is ethyl acetate or ethanol; the crystallization temperature is -10°C to 20°C; preferably, the sodium hydroxide concentration in step c is 2% to 5%; the crystallization temperature is 5°C to 15°C.

[0021] The poor solvent in step c is ethyl acetate, and the usage ratio of ethyl acetate to methyl tert-butyl ether is 6:1 to 2:1; or the poor solvent is ethanol, and the usage ratio of ethyl acetate to methyl tert-butyl ether is 5:1 to 2:1.

[0022] Further preferably, the poor solvent is ethyl acetate, and the usage ratio of ethyl acetate to methyl tert-butyl ether is 4:1 to 5:1; or the poor solvent is ethanol, and the usage ratio of ethyl acetate to methyl tert-butyl ether is 4:1 to 3:1.

[0023] The beneficial effects of the present invention are: The synthesis method of the bicyclic alcohol provided by the present invention adopts a new methylation reagent methyl tert-butyl ether and a catalyst iron trifluoromethanesulfonate, thereby avoiding the use of a methylation reagent that is highly toxic and easily explosive and is extremely dangerous during use, thereby overcoming the shortcomings of the existing process such as harsh post-treatment, poor reaction selectivity, and low yield; when a carboxyl group and a hydroxyl group exist at the same time, the methylation reaction can be selectively carried out only with the carboxyl group; The reaction steps are short, the process operation is simple, the conditions are mild, the yield is high, the product quality is safe and reliable, the process is stable, and the reproducibility is good; the materials in the whole process are cheap, easy to obtain, non-toxic, and the materials used and the operation process are EHS-friendly and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 HPLC chromatogram of the bicyclic alcohol synthesized by the present invention; Figure 2 LC-MS spectrum of the bicyclic alcohol synthesized by the present invention; Figure 3 The hydrogen spectrum of the bicyclic alcohol synthesized by the present invention ( 1 H-NMR) spectrum; Figure 4 The carbon spectrum of the bicyclic alcohol synthesized by the present invention ( 13 C-NMR) spectrum; Figure 5 The XRD pattern of the bicyclic alcohol synthesized by the present invention; Figure 6 HPLC spectrum of the bicyclic alcohol synthesized by the present invention; Figure 7 is the HPLC spectrum of the synthesized bicyclic alcohol; Figure 8 It is the HPLC chromatogram of Comparative Example 1; Fig. 9 This is the HPLC chromatogram of Comparative Example 2. DETAILED DESCRIPTION

[0025] The present invention is further described below in conjunction with specific implementation methods. The following description is only for explaining the present invention. The protection scope of the present invention is not limited to these embodiments. Those skilled in the art should understand that equivalent substitutions or corresponding improvements made to the contents of the present invention still fall within the protection scope of the present invention.

[0026] Example 1 Synthesis method of bicyclic alcohol of the present invention Add 100g of biphenyl alcohol acid, 2.7g of iron trifluoromethanesulfonate and 250ml of methyl tert-butyl ether to the reaction flask. After the addition, heat to 80-90℃ and react for about 2h. Then monitor the reaction until the biphenyl alcohol acid is ≤0.5%, then stop the reaction. Cool to room temperature, add 50ml*2 of 4% sodium hydroxide aqueous solution, wash once with 50ml of saturated brine, and collect the organic phase.

[0027] Add 400 ml of ethyl acetate at 5±5°C, control the temperature and crystallize for about 2 hours, filter, rinse the filter cake with 50 ml of ethyl acetate, and dry to obtain 91.27 g of bicyclic alcohol, with a yield of 88% and a purity of 99.989%. No genotoxic impurities (methyl trifluoromethanesulfonate, ethyl trifluoromethanesulfonate and isopropyl trifluoromethanesulfonate) were detected. LC-MS (C 19 H 18 O9:m / z=390.34): 413.1(M+Na), 429.0(M+K)). 1 H-NMR (400MHz, CDCl3) δ: 7.26 (s, 1H), 6.76 (s, 1H), 6.01 (d, 2H), 5.89-5.99(s, 2H), 4.36-4.39(m, 2H), 3.92-3.95(m, 6H), 3.69(s, 3H).2.41(s, 1H). 13 C-NMR (400MHz, CDCl3) δ :165.89,146.57,145.44,142.37,141.77,137.28,133.19,132.67,123.48,1 10.37,109.57,107.92,106.91,101.37,100.67,62.40,55.64,55.34,51.24.

[0028] Among them, the detection method for relevant substances is based on the [Inspection] item of Part II Bicyclic Alcohol in the 2020 edition of the Chinese Pharmacopoeia, and is determined according to high performance liquid chromatography (General Rule 0512).

[0029] Test solution: Take an appropriate amount of the product, dissolve it in acetonitrile and dilute it to make a solution containing about 1 mg per 1 ml. Chromatographic conditions: Use octadecylsilane bonded silica gel as filler (Agilent Zorbax SB C18 4.6mm×250mm, 5μm or chromatographic column with equivalent performance); acetonitrile-water-acetic acid (55:45: 0.01) as mobile phase; detection wavelength was 228nm; flow rate was 0.5ml per minute; column temperature was 40℃; Determination method: Accurately measure the test solution and blank solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0030] Among them, HPLC spectrum such as Figure 1 The characteristic peak information is shown in Table 1. The LC-MS spectrum is shown in Figure 2 As shown; hydrogen spectrum ( 1 H-NMR) spectrum Figure 3 As shown; carbon spectrum ( 13 C-NMR) spectrum Figure 4 shown.

[0031] Table 1 Characteristic peak information of HPLC chromatogram of bicyclic alcohol synthesized by the present invention Serial number Retention time (min) type Peak area Peak area% Peak height Resolution USP Tailing Factor Theoretical Plate Number USP 1 9.183 BB 27658.7411 99.989 1607.08 0.91 5588 2 14.739 BB 3.0851 0.011 0.12 8.92 0.93 6126 sum 27661.83 Example 2 Synthesis method of bicyclic alcohol of the present invention Add 100g of biphenyl alcohol acid, 16.0g of iron trifluoromethanesulfonate and 400ml of methyl tert-butyl ether to the reaction flask. After the addition, heat to 80-90℃ and react for about 2h. Then monitor the reaction until the biphenyl alcohol acid is ≤0.5%, then stop the reaction. Cool to room temperature, add 50ml*2 of 10% sodium hydroxide aqueous solution, wash once with 50ml of saturated brine, and collect the organic phase.

[0032] The temperature was controlled at 15℃~20℃, and 600ml of ethyl acetate was added. After the addition, the temperature was controlled and crystallization was carried out for about 2h. The filter cake was filtered, and 50ml of ethyl acetate was used to rinse the filter cake. After drying, 93.35g of bicyclic alcohol was obtained, with a yield of 80% and a purity of 99.927%. No genotoxic impurities (methyl trifluoromethanesulfonate, ethyl trifluoromethanesulfonate and isopropyl trifluoromethanesulfonate) were detected.

[0033] XRD spectrum Figure 5 As shown, the HPLC spectrum is as Figure 6 The characteristic peak information is shown in Table 2.

[0034] Table 2 HPLC chromatogram characteristic peak information of bicyclic alcohol synthesized by the present invention Serial number Retention time (min) type Peak area Peak area% High Resolution USP Tailing Factor Theoretical Plate Number USP 1 9.167 BB 27658.9011 99.927 1517.91 0.91 5588 2 14.728 BB 5.2350 0.019 0.12 8.72 1.81 5674 3 24.730 BB 15.0062 0.054 0.16 6.48 0.67 1841 sum 27679.14 Example 3 Catalyst and dosage, poor solvent screening test in the synthesis method of bicyclic alcohol Add 100g of biphenyl alcohol acid, 0.67g of iron trifluoromethanesulfonate and 100ml of methyl tert-butyl ether to the reaction flask. After the addition, heat to 80-90℃ and react for about 2h. Then monitor the reaction until the biphenyl alcohol acid is ≤0.5%, then stop the reaction. Cool to room temperature, add 50ml*2 of 0.1% sodium hydroxide aqueous solution, wash once with 50ml of saturated brine, and collect the organic phase.

[0035] The temperature was controlled at about -10°C, and 200 ml of ethyl acetate was added. After the addition, the temperature was controlled and crystallization was carried out for about 2 hours. The filter cake was filtered, and 50 ml of ethyl acetate was used to rinse the filter cake. After drying, 89.20 g of bicyclic alcohol was obtained, with a yield of 86% and a purity of 99.933%. No genotoxic impurities (methyl trifluoromethanesulfonate, ethyl trifluoromethanesulfonate and isopropyl trifluoromethanesulfonate) were detected.

[0036] HPLC spectrum Figure 7 The characteristic peak information is shown in Table 3.

[0037] Table 3 Characteristic peak information of HPLC chromatogram of synthesized bicyclic alcohol Serial number Retention time (min) type Peak area Peak area% Peak height Resolution USP Tailing Factor Theoretical Plate Number USP 1 9.178 BB 27661.3950 99.933 1591.04 0.91 5588 2 14.741 BV 3.6839 0.013 0.13 8.64 0.89 5513 3 23.796 BV 8.0051 0.029 0.15 6.70 0.74 2479 4 24.742 VB 6.8521 0.025 0.16 0.55 1.14 4479 sum 27679.94 Referring to Example 3, run according to the following parameters: Table 4 Investigation of different catalysts

[0038] Note: The molar ratio of catalyst to biphenyl alcohol acid is 0.01:1.

[0039] It can be seen from the above table that the three catalysts screened are all capable of catalyzing the reaction, among which iron trifluoromethanesulfonate is the preferred catalyst.

[0040] Referring to Example 3, run according to the following parameters: Table 5 Investigation of catalyst dosage

[0041] Note: [1]. The amount of catalyst used is the molar ratio of iron trifluoromethanesulfonate to biphenyl alcohol acid.

[0042] From the above table, it can be seen that the amount of catalyst used has little effect on the reaction effect. However, when the amount is large, genotoxic impurities may be produced. Therefore, the optimal molar ratio of iron trifluoromethanesulfonate to biphenyl alcohol acid is 0.02:1, that is, for every 100g of biphenyl alcohol acid, the amount of iron trifluoromethanesulfonate used is 2.7g.

[0043] Referring to Example 3, run according to the following parameters: Table 6 Investigation of solvent screening

[0044] From the above table, we can see that both crystallization systems can well control product quality and the ability to remove genotoxic impurities. However, since the presence of ethanol in the ethanol and methyl tert-butyl ether system will increase the possibility of genotoxic impurities, ethyl acetate is the preferred poor solvent.

[0045] Comparative Example 1 Referring to the method of US4868207A, biphenyl diester is used as the starting material, and biphenyl lactone is obtained after hydrolysis, anhydride dehydration, sodium borohydride reduction ring opening and p-toluenesulfonate treatment. Biphenyl lactone is further reacted with methanol in the presence of carboxylate to obtain bicyclic alcohol. The yield of the route biphenyl lactone ring opening and methanol reaction is only 35.4%. The purity is 98.825%. The HPLC chromatogram is as follows Figure 8 The characteristic peak information is shown in Table 7.

[0046] Table 7 Characteristic peak information of HPLC chromatogram Serial number Retention time [min] type Peak area Peak area% Peak height Resolution USP Tailing Factor Theoretical Plate Number USP 1 5.792 BB 105.8331 0.386 8.82 0.98 4946 2 8.635 BV 12.9160 0.047 0.90 7.00 0.67 5099 3 9.207 VB 27127.6348 98.825 1557.64 1.17 0.91 5478 4 15.590 BB 199.3926 0.726 7.03 9.66 0.88 5744 5 24.852 BB 4.4904 0.016 0.13 10.59 0.81 11536 sum 27450.27 Comparative Example 2 Add 100g of biphenyl alcohol acid, 1.5g of iron trifluoromethanesulfonate and 200ml of methyl tert-butyl ether to the reaction flask. After the addition, heat to 80-90℃ and react for about 2h. Then monitor the reaction until the biphenyl alcohol acid is ≤0.5%, then stop the reaction. Cool to room temperature, add 2% sodium hydroxide aqueous solution 50ml*2, wash once with 50ml of saturated brine, and collect the organic phase.

[0047] The organic phase was concentrated at 30±5°C until a large amount of solid precipitated, then cooled to 5±5°C and crystallized for about 2 hours, filtered and dried to obtain 89.20 g of bicyclic alcohol with a yield of 86% and a purity of 99.239%. 0.007% methyl trifluoromethanesulfonate, 0.003% ethyl trifluoromethanesulfonate and no isopropyl trifluoromethanesulfonate were detected.

[0048] This comparative example proves that direct concentration and crystallization will lead to excessive genotoxic impurities; adding ethyl acetate or ethanol can effectively control genotoxic impurities. Fig. 9 The characteristic peak information is shown in Table 8.

[0049] Table 8 Characteristic peak information of HPLC chromatogram Serial number Retention time [min] type Peak area Peak area% Peak height Resolution USP Tailing Factor Theoretical Plate Number USP 1 5.781 BB 63.7927 0.231 5.33 0.98 4976 2 8.610 BV 7.4704 0.027 0.54 7.02 0.65 5165 3 9.179 VB 27371.9764 99.239 1581.73 1.16 0.91 5518 4 15.530 BB 134.8693 0.489 4.81 9.76 0.87 5924 5 24.730 BB 3.8154 0.014 0.12 10.94 0.82 12777 sum 27581.92

Claims

1. A method for synthesizing a bicyclic alcohol, characterized in that: The method is prepared by using biphenyl alcohol acid as the starting material, adding methyl tert-butyl ether and a catalyst for reaction, and then purifying the catalyst; the catalyst is iron trifluoromethanesulfonate; Its synthetic route is: .

2. The synthetic method of bicyclic alcohol according to claim 1, characterized in that: The purification method is a crystallization method.

3. The synthetic method of bicyclic alcohol according to claim 1 or 2, characterized in that: It includes the following steps: a. Take methyl tert-butyl ether, biphenyl alcohol acid and iron trifluoromethanesulfonate, stir and heat to 50°C to 90°C; wherein the mass volume ratio of biphenyl alcohol acid to methyl tert-butyl ether is 1:1 to 1:4; the molar ratio of biphenyl alcohol acid to iron trifluoromethanesulfonate is 1:0.005 to 1:0.12; b. Keep the reaction warm for 2 hours to 6 hours until the reaction is almost complete or the biphenyl alcohol acid is ≤ 0.5% w / w; c. After the reaction is completed, cool to room temperature; filter, add sodium hydroxide solution to the filtrate, separate the phases, add a poor solvent, continue to cool and crystallize for 1 to 4 hours, filter, and dry to obtain the product.

4. The synthetic method of bicyclic alcohol according to claim 3, characterized in that: The mass volume ratio of the biphenyl alcohol acid to methyl tert-butyl ether in step a is 1:2 to 1:3; the molar ratio of the biphenyl alcohol acid to iron trifluoromethanesulfonate is 1:0.01 to 1:0.

1.

5. The synthetic method of bicyclic alcohol according to claim 3, characterized in that: The sodium hydroxide concentration in step c is 0.1% to 10% w / w; the poor solvent is ethyl acetate or ethanol; and the crystallization temperature is -10°C to 20°C.

6. The synthetic method of bicyclic alcohol according to claim 5, characterized in that: In step c, the sodium hydroxide concentration is 2% to 5%; and the crystallization temperature is 5°C to 15°C.

7. The synthetic method of bicyclic alcohol according to claim 5, characterized in that: The poor solvent in step c is ethyl acetate, and the usage ratio of ethyl acetate to methyl tert-butyl ether is 6:1 to 2:1; or the poor solvent is ethanol, and the usage ratio of ethyl acetate to methyl tert-butyl ether is 5:1 to 2:

1.

8. The synthesis method according to claim 7, characterized in that: The poor solvent in step c is ethyl acetate, and the usage ratio of ethyl acetate to methyl tert-butyl ether is 4:1 to 5:1; or the poor solvent is ethanol, and the usage ratio of ethyl acetate to methyl tert-butyl ether is 4:1 to 3:1.

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