Synthesis method of cis-7-dodecenol acetate

Abstract

The invention discloses a synthesis method of cis-7-dodecenol acetate, which is characterized in that 7-bromo-1-heptanol is used as an initial raw material, and accurate construction of cis-double bonds and efficient conversion of acetate are realized through hydroxyl protection, Sonogashira coupling, Lidlar hydrogenation, deprotection and acetylation reaction. The preparation method has the advantages that 1) TBDMS-Cl is adopted to protect hydroxyl, so that coupling side reaction is avoided; 2) high-selectivity cis-hydrogenation (greater than 94%) is realized through a Lidlar catalyst; 3) the synthetic route is simple, and the total yield can reach 60% or above; and 4) use of highly toxic reagents (such as mercury salts) is avoided, by-products are easy to treat, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and more specifically to a method for synthesizing cis-7-dodecenol acetate. Background Art

[0002] Cis-7-Dodecenyl acetate is an organic compound with the molecular formula: C 14 H 26 O 2 , the structural formula is: CH 3 (CH 2 ) 4 CH=CH(CH 2 ) 5 OCOCH 3 It is an important component of the sex pheromone of many lepidopteran insects such as cutworms, and can be used for green agricultural pest control.

[0003] At present, the synthesis method of cis-7-dodecenol acetate generally has the following problems:

[0004] (1) Insufficient control of double bond configuration: Traditional hydrogenation methods tend to generate trans byproducts;

[0005] (2) The steps are complicated: multiple protection / deprotection operations are required, and the overall yield is low;

[0006] (3) High cost: reliance on precious metal catalysts.

[0007] Therefore, how to develop an efficient synthesis method for cis-7-dodecenol acetate is a problem that those skilled in the art need to solve urgently. Summary of the invention

[0008] In view of this, the object of the present invention is to provide a method for synthesizing cis-7-dodecenol acetate to overcome the deficiencies in the prior art.

[0009] In order to achieve the above object, the present invention adopts the following technical solution:

[0010] A method for synthesizing cis-7-dodecenol acetate specifically comprises the following steps:

[0011] (1) Hydroxyl protection

[0012] Dissolve 7-bromo-1-heptanol in dichloromethane, add imidazole, dropwise add TBDMS-Cl, stir, wash with water, dry, and concentrate to obtain TBDMS-O-(CH 2 ) 6 -CH 2 Br;

[0013] (2) Sonogashira coupling

[0014] TBDMS-O-(CH 2 ) 6 -CH 2 Br, 1-pentyne, Pd(PPh 3 ) 2 Cl 2 and CuI were dissolved in THF, triethylamine was added, reacted, filtered, concentrated, and column chromatography was performed to obtain TBDMS-O-(CH 2 ) 6 -C≡C-(CH 2 ) 3 CH 3 ;

[0015] (3) Lindlar hydrogenation

[0016] TBDMS-O-(CH 2 ) 6 -C≡C-(CH 2 ) 3 CH 3 Dissolve in ethanol, add Lindlar catalyst, pass hydrogen, stir, filter, and concentrate to obtain TBDMS-O-(CH 2 ) 6 -CH=CH-(CH 2 ) 3 CH 3 ;

[0017] (4) Deprotection

[0018] TBDMS-O-(CH 2 ) 6 -CH=CH-(CH 2 ) 3 CH 3 Dissolve in THF, add TBAF, stir, concentrate, and column chromatograph to obtain cis-7-dodecenol;

[0019] (5) Acetylation

[0020] Dissolve cis-7-dodecenol, acetic anhydride and pyridine in dichloromethane, react, wash with water, dry and concentrate to obtain cis-7-dodecenol acetate.

[0021] The present invention significantly improves the synthesis efficiency and economy of cis-7-dodecenol acetate by optimizing the reaction sequence and stereochemical control strategy.

[0022] Furthermore, in the above step (1), the usage ratio of 7-bromo-1-heptanol, dichloromethane, imidazole and TBDMS-Cl is (10.0-20.0) g: (100-300) mL: (7.0-14.0) g: (9.28-18.56) g. Preferably, the usage of TBDMS-Cl is 1.2 times the molar amount of 7-bromo-1-heptanol.

[0023] A further beneficial effect of the above method is that the hydroxyl group of 7-bromo-1-heptanol is protected by TBDMS-Cl, thereby avoiding interference and elimination of the hydroxyl group in the subsequent coupling reaction.

[0024] Furthermore, in the above step (1), the TBDMS-Cl was added dropwise in an ice bath; the stirring temperature was 0-5°C and the stirring time was 3h.

[0025] Further, in the above step (2), TBDMS-O-(CH 2 ) 6 -CH 2 Br, 1-pentyne, Pd(PPh 3 ) 2 Cl 2 , CuI, THF and triethylamine are used in a ratio of (14.2-28.1) g: (3.76-7.44) g: (0.62-1.28) g: (0.17-0.36) g: (150-400) mL: (20-50) mL. Preferably, Pd(PPh 3 ) 2 Cl 2 The dosage is TBDMS-O-(CH 2 ) 6 -CH 2 2%-5% of Br molar amount.

[0026] A further beneficial effect of the above method is that a CC bond is constructed under the coordinated catalysis of palladium / copper to form a dodecynyl ether intermediate.

[0027] Furthermore, in the above step (2), the reaction atmosphere is argon, the temperature is 60° C., and the reaction time is 12-14 h.

[0028] Further, in the above step (3), TBDMS-O-(CH 2 ) 6 -C≡C-(CH 2 ) 3 CH 3 The usage ratio of ethanol and Lindlar catalyst is (11.8-23.7) g: (120-200) mL: (1.2-2.3) g.

[0029] A further beneficial effect of the above method is that alkynes are selectively hydrogenated to cis-olefins using the Lindlar catalyst poisoned with quinoline.

[0030] Furthermore, in the above step (3), the hydrogen pressure is 0.1-0.5 MPa; the stirring temperature is 25-30° C., and the stirring time is 6-7 h.

[0031] Further, in the above step (4), TBDMS-O-(CH 2 ) 6 -CH=CH-(CH 2 ) 3 CH 3 The dosage ratio of THF and TBAF is (11.1-22.1) g: (50-200) mL: (14.5-29.2) g. Preferably, the dosage of TBAF is TBDMS-O-(CH 2 ) 6 -CH=CH-(CH 2 ) 3 CH 3 1.5 times the molar amount.

[0032] A further beneficial effect of the above method is that TBAF can mildly remove the silyl ether protecting group to produce the target alcohol product.

[0033] Furthermore, in the above step (4), the stirring temperature is 25-30°C and the stirring time is 2-3h.

[0034] Furthermore, in the above step (5), the usage ratio of cis-7-dodecenol, acetic anhydride, pyridine and dichloromethane is (6.1-12.3) g: (4.1-8.2) g: (5-15) mL: (100-300) mL.

[0035] A further beneficial effect of the above method is that acetic anhydride esterifies the hydroxyl group to generate the target product.

[0036] Furthermore, in the above step (5), the reaction temperature is 25-30°C and the reaction time is 2-3h.

[0037] It can be seen from the above technical solution that compared with the prior art, the beneficial effects of the present invention are as follows:

[0038] 1. Use TBDMS-Cl to protect hydroxyl groups to avoid coupling side reactions;

[0039] 2. Highly selective cis hydrogenation (>94%) achieved by Lindlar catalyst;

[0040] 3. The synthetic route is simple and the total yield can reach more than 60%;

[0041] 4. Avoid using highly toxic reagents (such as mercury salts), the by-products are easy to handle, and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 Schematic diagram of the synthesis route of cis-7-dodecenol acetate in Example 1-2;

[0043] Figure 2 is the mass spectrum of cis-7-dodecenol acetate in Example 2;

[0044] Figure 3 The cis percentage of cis-7-dodecenyl acetate in Example 2 is reported. DETAILED DESCRIPTION

[0045] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0046] Example 1

[0047] A method for synthesizing cis-7-dodecenol acetate, such as Figure 1 As shown, the specific steps include:

[0048] (1) Hydroxyl protection

[0049] Dissolve 7-bromo-1-heptanol (10.0 g, 51.3 mmol) in dichloromethane (100 mL), add imidazole (7.0 g, 102.6 mmol), add TBDMS-Cl (9.28 g, 61.5 mmol) dropwise under ice bath, stir at 0°C for 3 h, wash with water, dry, and concentrate to obtain TBDMS-O-(CH 2 ) 6 -CH 2 Br;

[0050] (2) Sonogashira coupling

[0051] TBDMS-O-(CH 2 ) 6 -CH 2 Br (14.2 g, 46 mmol), 1-pentyne (3.76 g, 55.2 mmol), Pd (PPh 3 ) 2 Cl 2(0.62 g, 0.89 mmol) and CuI (0.17 g, 0.89 mmol) were dissolved in THF (150 mL), triethylamine (20 mL) was added, and the mixture was reacted at 60 °C for 12 h under argon protection, filtered, concentrated, and column chromatographed to obtain TBDMS-O-(CH 2 ) 6 -C≡C-(CH 2 ) 3 CH 3 ;

[0052] (3) Lindlar hydrogenation

[0053] TBDMS-O-(CH 2 ) 6 -C≡C-(CH 2 ) 3 CH 3 (11.8 g, 40 mmol) was dissolved in ethanol (120 mL), Lindlar catalyst (1.2 g) was added, 0.3 MPa hydrogen (0.3 MPa) was introduced, stirred at 25 ° C for 6 h, filtered and concentrated to obtain TBDMS-O-(CH 2 ) 6 -CH=CH-(CH 2 ) 3 CH 3 ;

[0054] (4) Deprotection

[0055] TBDMS-O-(CH 2 ) 6 -CH=CH-(CH 2 ) 3 CH 3 (11.1 g, 37.0 mmol) was dissolved in THF (50 mL), TBAF (14.5 g, 55.5 mmol) was added, stirred at 25 °C for 2 h, concentrated, and column chromatographed to obtain cis-7-dodecenol;

[0056] (5) Acetylation

[0057] Dissolve cis-7-dodecenol (6.1 g, 33.3 mmol), acetic anhydride (4.1 g, 40.0 mmol) and pyridine (5 mL) in dichloromethane (100 mL), react at 25 °C for 2 h, wash with water, dry and concentrate to obtain cis-7-dodecenol acetate.

[0058] Example 2

[0059] A method for synthesizing cis-7-dodecenol acetate, such as Figure 1 As shown, the specific steps include:

[0060] (1) Hydroxyl protection

[0061] Dissolve 7-bromo-1-heptanol (20.0 g, 102.6 mmol) in dichloromethane (300 mL), add imidazole (14.0 g, 205.2 mmol), add TBDMS-Cl (18.56 g, 123 mmol) dropwise under ice bath, stir at 0°C for 3 h, wash with water, dry, and concentrate to obtain TBDMS-O-(CH 2 ) 6 -CH 2 Br;

[0062] (2) Sonogashira coupling

[0063] TBDMS-O-(CH 2 ) 6 -CH 2 Br (28.1 g, 91 mmol), 1-pentyne (7.44 g, 109.2 mmol), Pd (PPh 3 ) 2 Cl 2 (1.28 g, 1.82 mmol) and CuI (0.36 g, 1.82 mmol) were dissolved in THF (400 mL), triethylamine was added, and the mixture was reacted at 60 °C for 14 h under argon protection, filtered, concentrated, and column chromatographed to obtain TBDMS-O-(CH 2 ) 6 -C≡C-(CH 2 ) 3 CH 3 ;

[0064] (3) Lindlar hydrogenation

[0065] TBDMS-O-(CH 2 ) 6 -C≡C-(CH 2 ) 3 CH 3 (23.7 g, 80 mmol) was dissolved in ethanol (200 mL), Lindlar catalyst (2.3 g) was added, 0.4 MPa hydrogen was introduced, stirred at 25 ° C for 7 h, filtered and concentrated to obtain TBDMS-O-(CH 2 ) 6 -CH=CH-(CH 2 ) 3 CH 3 ;

[0066] (4) Deprotection

[0067] TBDMS-O-(CH 2 )6 -CH=CH-(CH 2 ) 3 CH 3 (22.1 g, 74.4 mmol) was dissolved in THF (200 mL), TBAF (29.2 g, 111.6 mmol) was added, stirred at 30 °C for 2 h, concentrated, and column chromatographed to obtain cis-7-dodecenol;

[0068] (5) Acetylation

[0069] Dissolve cis-7-dodecenol (12.3 g, 66.7 mmol), acetic anhydride (8.2 g, 80 mmol) and pyridine (15 mL) in dichloromethane (300 mL), react at 30 ° C for 2 h, wash with water, dry and concentrate to obtain cis-7-dodecenol acetate.

[0070] Performance Testing

[0071] 1. Product characterization

[0072] The mass spectrum of cis-7-dodecenol acetate in Example 2 is as follows: Figure 2 As shown, the cis percentage is reported as Figure 3 shown.

[0073] Depend on Figure 2 It can be seen that the material fragments and molecular weight shown in the mass spectrum are consistent with the target product cis-7-dodecene acetate, confirming that the product synthesized in Example 2 is the target product cis-7-dodecene acetate.

[0074] Depend on Figure 3 It can be seen that the spectrum shows that the peak time at 15.988min is cis-7-dodecene acetate, the peak time at 15.735min is trans-7-dodecene acetate, and the proportion of cis-7-dodecene acetate is as high as 94.9%, confirming that Example 2 achieves highly selective cis reduction.

[0075] 2. Yield test

[0076] The mass of each product in steps (1) to (5) of the synthesis method of Example 1-2 was weighed respectively, and its yield and total yield were calculated respectively.

[0077] The results are shown in Table 1.

[0078] Table 1 Quality and yield of each product in steps (1) to (5) of the synthesis method of Example 1-2

[0079]

[0080] It can be seen from Table 1 that the total yield of the synthesis method of Example 1-2 can reach more than 60%.

[0081] 3. Field moth trapping test

[0082] In May 2023, in Dongwu Town, Yinzhou District, Ningbo City, Zhejiang Province, the cis-7-dodecenol acetate synthesized in Example 2 was configured into a small cutworm bait core to conduct a moth-attracting effect test in the field, and a commercially available small cutworm bait core was used as a comparison.

[0083] The results are shown in Table 2.

[0084] Table 2 Example 2 Moth-attracting effect of cis-7-dodecenol acetate

[0085]

[0086] It can be seen from Table 2 that, compared with commercially available products, the cis-7-dodecene acetate synthesized in Example 2 has a very good trapping effect.

[0087] The above description of the disclosed embodiments enables one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for synthesizing cis-7-dodecenol acetate, characterized in that: The specific steps include: (1) Hydroxyl protection Dissolve 7-bromo-1-heptanol in dichloromethane, add imidazole, dropwise add TBDMS-Cl, stir, wash with water, dry, and concentrate to obtain TBDMS-O-(CH2)6-CH2Br; (2) Sonogashira coupling Dissolve TBDMS-O-(CH2)6-CH2Br, 1-pentyne, Pd(PPh3)2Cl2 and CuI in THF, add triethylamine, react, filter, concentrate, and perform column chromatography to obtain TBDMS-O-(CH2)6-C≡C-(CH2)3CH3; (3) Lindlar hydrogenation Dissolve TBDMS-O-(CH2)6-C≡C-(CH2)3CH3 in ethanol, add Lindlar catalyst, pass hydrogen, stir, filter, and concentrate to obtain TBDMS-O-(CH2)6-CH=CH-(CH2)3CH3; (4) Deprotection Dissolve TBDMS-O-(CH2)6-CH=CH-(CH2)3CH3 in THF, add TBAF, stir, concentrate, and column chromatograph to obtain cis-7-dodecenol; (5) Acetylation Dissolve cis-7-dodecenol, acetic anhydride and pyridine in dichloromethane, react, wash with water, dry and concentrate to obtain the cis-7-dodecenol acetate.

2. The method for synthesizing cis-7-dodecenol acetate according to claim 1, characterized in that: In step (1), the usage ratio of 7-bromo-1-heptanol, dichloromethane, imidazole and TBDMS-Cl is (10.0-20.0) g: (100-300) mL: (7.0-14.0) g: (9.28-18.56) g.

3. The method for synthesizing cis-7-dodecenol acetate according to claim 1, characterized in that: In step (1), the TBDMS-Cl is added dropwise in an ice bath; the stirring temperature is 0-5°C and the stirring time is 3h.

4. The method for synthesizing cis-7-dodecenol acetate according to claim 1, characterized in that: In step (2), the usage ratio of TBDMS-O-(CH2)6-CH2Br, 1-pentyne, Pd(PPh3)2Cl2, CuI, THF and triethylamine is (14.2-28.1) g: (3.76-7.44) g: (0.62-1.28) g: (0.17-0.36) g: (150-400) mL: (20-50) mL.

5. The method for synthesizing cis-7-dodecenol acetate according to claim 1, characterized in that: In step (2), the reaction atmosphere is argon, the temperature is 60° C., and the reaction time is 12-14 h.

6. The method for synthesizing cis-7-dodecenol acetate according to claim 1, characterized in that: In step (3), the usage ratio of TBDMS-O-(CH2)6-C≡C-(CH2)3CH3, ethanol and Lindlar catalyst is (11.8-23.7) g: (120-200) mL: (1.2-2.3) g.

7. The method for synthesizing cis-7-dodecenol acetate according to claim 1, characterized in that: In step (3), the pressure of the hydrogen is 0.1-0.5 MPa; the stirring temperature is 25-30° C., and the stirring time is 6-7 h.

8. The method for synthesizing cis-7-dodecenol acetate according to claim 1, characterized in that: In step (4), the usage ratio of TBDMS-O-(CH2)6-CH=CH-(CH2)3CH3, THF and TBAF is (11.1-22.1) g: (50-200) mL: (14.5-29.2) g.

9. The method for synthesizing cis-7-dodecenol acetate according to claim 1, characterized in that: In step (4), the stirring temperature is 25-30°C and the stirring time is 2-3h.

10. The method for synthesizing cis-7-dodecenol acetate according to claim 1, characterized in that: In step (5), the amount ratio of cis-7-dodecenol, acetic anhydride, pyridine and dichloromethane is (6.1-12.3) g: (4.1-8.2) g: (5-15) mL: (100-300) mL; the reaction temperature is 25-30° C. and the reaction time is 2-3 h.

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