Preparation method of 1-decyne-5-alcohol and derivatives thereof

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of 1-decyne-5-alcohol and a derivative thereof. The invention discloses a preparation method of 1-(trimethylsilyl)-decane-1-alkyne-5-alcohol, which comprises the following steps: in the presence of methyl tert-butyl ether and n-butyllithium, reacting 1-trimethylsilyl propyne with 1, 2-epoxyheptane to prepare the 1-(trimethylsilyl)-decane-1-alkyne-5-alcohol. According to the method, methyl tert-butyl ether is selected as a reaction solvent, so that on one hand, the purity of the product can be increased to 90% or above under the condition that the product only needs to be simply purified; on the other hand, the reaction can be carried out under milder conditions, and industrial application is facilitated. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and specifically relates to a preparation method of 1-decyn-5-ol and its derivatives. Background Art

[0002] 1-Alkyne-5-ol compounds are organic compounds containing unsaturated carbon-carbon triple bonds (alkynyl) and hydroxyl functional groups. Their unique structure enables them to participate in a variety of organic chemical reactions, making them important raw materials and intermediates in the fields of organic chemistry and medicinal chemistry. Among them, (S)-1-(trimethylsilyl)-dec-1-alkyne-5-ol and (S)-1-decyn-5-ol disclosed in CN104892555B are both important intermediates of Treprostinil, a drug for treating pulmonary hypertension.

[0003]

[0004] In the prior art, CN104892555B discloses a method for preparing (S)-1-decyn-5-ol:

[0005] Step 1: Using tetrahydrofuran as solvent, 1-trimethylsilylpropyne and (S)-1,2-epoxyheptane react at below -20°C in the presence of tert-butyllithium n-hexane solution to obtain a product, an oily substance with a purity of 74.9%, namely (S)-1-(trimethylsilyl)-dec-1-yn-5-ol.

[0006] Step 2: The oily substance obtained in the first step was treated with sodium hydroxide to obtain (S)-1-decyn-5-ol with a purity of 68.4%. Compared with the first step, the purity of the product was reduced by 6.5%.

[0007]

[0008] The (S)-1-(trimethylsilyl)-dec-1-yn-5-ol and (S)-1-decyn-5-ol obtained by the above method have low purities of 74.9% and 68.4%, respectively, which are lower than the purity of the product in the first step, which increases a lot of workload for subsequent purification work and is not conducive to the subsequent reaction. Summary of the invention

[0009] In order to overcome the technical problem of too low purity of 1-decyn-5-ol in the prior art, a preparation method of 1-(trimethylsilyl)-dec-1-yn-5-ol and 1-decyn-5-ol is proposed. The product obtained by the preparation method can reach a purity of more than 90% in two steps without purification or simple extraction, which is more conducive to industrial utilization.

[0010] The invention provides a method for preparing 1-(trimethylsilyl)-dec-1-yn-5-ol, the steps of which are as follows: in the presence of methyl tert-butyl ether and n-butyl lithium, 1-trimethylsilyl propyne and 1,2-epoxyheptane are reacted to prepare 1-(trimethylsilyl)-dec-1-yn-5-ol;

[0011]

[0012] In one embodiment, the reaction temperature of the reaction may be -15 to 0°C, preferably -10 to -5°C.

[0013] In one embodiment, the molar ratio of the 1-trimethylsilylpropyne to the 1,2-epoxyheptane may be (1-3):1, preferably (1.5-2.0):1.

[0014] In one embodiment, the n-butyl lithium is reacted in the form of a n-hexane solution of n-butyl lithium, wherein the concentration of the n-hexane solution of n-butyl lithium may be (1.5-2.5) mol / L.

[0015] In one embodiment, the molar ratio of the n-butyl lithium to the 1,2-epoxyheptane may be (1-3):1, preferably (1.5-2.0):1.

[0016] In one embodiment, the volume mass ratio of the methyl tert-butyl ether to the 1,2-epoxyheptane may be (5-50) L:1 g, preferably (10-30) L:1 g.

[0017] In one embodiment, the reaction needs to be carried out under a protective gas atmosphere. The protective gas may be nitrogen and / or a rare gas.

[0018] In one embodiment, the preparation method of 1-(trimethylsilyl)-dec-1-yn-5-ol further comprises the following steps:

[0019] (a) mixing a methyl tert-butyl ether solution of 1-trimethylsilylpropyne and a n-hexane solution of n-butyllithium;

[0020] (b) mixing the mixed solution of step (a) with a methyl tert-butyl ether solution of 1,2-epoxyheptane to react, to prepare 1-(trimethylsilyl)-dec-1-yn-5-ol.

[0021] In one embodiment, the reaction time of step (a) can be 2-10 h, preferably 2-4 h; the reaction time of step b) can be 1-10 h, preferably 1-3 h.

[0022] In one embodiment, the 1,2-epoxyheptane is (S)-1,2-epoxyheptane and / or (R)-1,2-epoxyheptane.

[0023] In one embodiment, the 1,2-epoxyheptane is The 1-(trimethylsilyl)-dec-1-yn-5-ol is

[0024] In one embodiment, the preparation process of 1-(trimethylsilyl)-dec-1-yn-5-ol is as follows:

[0025] Add 1-trimethylsilylpropyne to methyl tert-butyl ether, cool to -15 to 0°C, add n-butyl lithium n-hexane solution, react for 2-10 hours, then add 1,2-epoxyheptane methyl tert-butyl ether solution, react for 1-10 hours; after the reaction is completed, quench with ammonium chloride solution, take the organic phase and concentrate it.

[0026] The present invention also provides a method for preparing 1-decyn-5-ol, the steps of which are as follows:

[0027] (c) reacting 1-trimethylsilylpropyne with 1,2-epoxyheptane in the presence of methyl tert-butyl ether and n-butyl lithium to obtain 1-(trimethylsilyl)-dec-1-yn-5-ol;

[0028] (d) reacting the 1-(trimethylsilyl)-dec-1-yn-5-ol in the presence of a solvent and an inorganic base to obtain 1-decyn-5-ol;

[0029]

[0030] In one embodiment, the preparation method of the 1-(trimethylsilyl)-dec-1-yn-5-ol is as described above.

[0031] In step (d), the inorganic base may be one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; preferably sodium hydroxide and / or potassium hydroxide.

[0032] In step (d), the molar ratio of the inorganic base to the 1-(trimethylsilyl)-dec-1-yn-5-ol may be (1.0-2.0):1, preferably 1.0:1.

[0033] In step (d), the solvent may be a mixed solvent of an alkyl alcohol solvent and water, wherein the alkyl alcohol solvent is preferably methanol or ethanol, and the volume ratio of the alkyl alcohol solvent to water is (0.5-2.0):1, preferably 1.0:1.

[0034] In step (d), the molar volume ratio of the 1-(trimethylsilyl)-dec-1-yn-5-ol to the solvent may be (0.3-1.5) mol:1L, preferably 0.72 mol / L.

[0035] In step (d), the reaction temperature of the reaction may be 25-40°C, preferably 30-35°C.

[0036] In step (d), the reaction time is 12-20 h, preferably 16 h.

[0037] In step (d), after the reaction is completed, post-treatment is also included, and the post-treatment includes: acidifying the reaction solution to neutrality and extracting with methyl tert-butyl ether.

[0038] In one embodiment, the 1,2-epoxyheptane is (S)-1,2-epoxyheptane and / or (R)-1,2-epoxyheptane.

[0039] In one embodiment, the 1-(trimethylsilyl)-dec-1-yn-5-ol is (S)-1-(trimethylsilyl)-dec-1-yn-5-ol and / or (R)-1-(trimethylsilyl)-dec-1-yn-5-ol.

[0040] In one embodiment, the 1,2-epoxyheptane is The 1-(trimethylsilyl)-dec-1-yn-5-ol is The 1-decyn-5-ol is

[0041]

[0042] In one embodiment, the preparation process of 1-decyn-5-ol is as follows:

[0043] (e) 1-trimethylsilyl propyne is added to methyl tert-butyl ether, the temperature is lowered to -15 to 0°C, n-butyl lithium n-hexane solution is added, the reaction is carried out for 2 to 10 hours, and then 1,2-epoxyheptane methyl tert-butyl ether solution is added, and the reaction is carried out for 1 to 10 hours; after the reaction is completed, the ammonium chloride solution is quenched, the organic phase is taken, and concentrated to obtain 1-(trimethylsilyl)-dec-1-yn-5-ol;

[0044] (f) Add 1-(trimethylsilyl)-dec-1-yn-5-ol to an alkyl alcohol solvent, add an aqueous solution of an inorganic base, raise the temperature to 25-40° C., and react for 12-20 hours; add an acid to adjust the pH to neutral, add methyl tert-butyl ether to extract, and concentrate the organic phase to obtain 1-decyn-5-ol.

[0045] Functions and Effects of the Invention

[0046] The invention provides a preparation method of 1-(trimethylsilyl)-dec-1-yn-5-ol. Methyl tert-butyl ether is selected as a reaction solvent. The preparation method can improve the purity of the product to more than 90% under the condition of simple purification. On the other hand, the reaction can be carried out under milder conditions, which is more conducive to industrial application.

[0047] The present invention provides a method for preparing 1-decyn-5-ol. Compared with the prior art, high-purity 1-decyn-5-ol can be obtained by adjusting the solvent used for extraction in post-treatment, which is conducive to industrial application. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 A spectrum showing the GC detection of (S)-1-(trimethylsilyl)-dec-1-yn-5-ol in Example 1;

[0049] Figure 2 A spectrum showing the GC detection of (S)-1-(trimethylsilyl)-dec-1-yn-5-ol in Example 2;

[0050] Figure 3 The spectrum showing the GC detection of the crude (S)-1-decyn-5-ol in Example 3;

[0051] Figure 4 The GC spectrum of (S)-1-decyn-5-ol after purification in Example 4 is shown. DETAILED DESCRIPTION

[0052] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0053] The reagents and raw materials used in the present invention are commercially available.

[0054] In the following examples, the yields were calculated as follows:

[0055] Theoretical mass of product = mass of raw material / molecular weight of raw material × molecular weight of product;

[0056] Yield = crude mass × purity / theoretical mass of product.

[0057] Example 1

[0058]

[0059] Under nitrogen protection, 39.3 g of 1-trimethylsilylpropyne (0.35 mol, 2.0 eq) and 360 mL of methyl tert-butyl ether were added into a 500 mL jacketed bottle; the temperature was lowered to -10 to -5 °C, 140 mL of 2.5 M n-butyl lithium hexane solution (0.35 mol, 2.0 eq) was added dropwise, and the mixture was kept warm for 3 h. Then, a mixed solution of 20.0 g of (S)-1,2-epoxyheptane (0.175 mol, 1.0 eq) and 50 mL of methyl tert-butyl ether was added dropwise, and the mixture was kept warm for 2 h.

[0060] The temperature was controlled below 20°C, 30 mL of saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and 60 mL of water was added. The organic phase was taken and evaporated under reduced pressure to obtain 43.3 g of (S)-1-(trimethylsilyl)-dec-1-yn-5-ol, with a yield of 100% and a purity of 91.49% by GC (RT = 12.421 min, Figure 1 ).

[0061] Example 2

[0062]

[0063] Under nitrogen protection, 4.4 kg 1-trimethylsilylpropyne (39.2 mol, 1.5 eq) and 30 L methyl tert-butyl ether were added to a 100 L reactor; the temperature was lowered to -10 to -5 °C, 15.24 L 2.5 M n-butyl lithium hexane solution (38.1 mol, 1.45 eq) was added dropwise, and the mixture was kept warm for 3 h. Then, a mixed solution of 3.0 kg (S)-1,2-epoxyheptane (26.25 mol, 1.0 eq) and 6 L methyl tert-butyl ether was added dropwise, and the mixture was kept warm for 2 h.

[0064] The temperature was controlled below 20°C, 4 L of saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and then 1.8 L of water was added. The organic phase was taken and vacuum rotary distilled to obtain 6.5 kg of (S)-1-(trimethylsilyl)-dec-1-yn-5-ol, with a yield of 99.1% and a purity of 90.68% detected by GC (RT = 12.547 min, Figure 2 ).

[0065] Example 3

[0066]

[0067] 5.4 kg (S) -1- (trimethylsilyl) - dec-1-yn-5-ol (prepared in Example 2, purity 90.68%, 21.6 mol, 1.0 eq) and 15 L ethanol were added to a 100 L reactor, 2.99 kg potassium carbonate (21.6 mol, 1.0 eq) was dissolved in 15 L water to obtain a potassium carbonate aqueous solution; the potassium carbonate aqueous solution was added dropwise to the reactor; the temperature was raised to 30-35 ° C, and stirred for 16 h; 9 L 3N hydrochloric acid was added dropwise to adjust the pH to neutral, 15 L methyl tert-butyl ether was added for extraction, and the mixture was stirred for 20 min. The liquid was separated and the organic phase was concentrated to obtain 3.31 kg of a crude product with a purity of 94.7% (RT = 11.578 min, Figure 3 ), crude product yield 94.1%.

[0068] The crude product was subjected to vacuum distillation, and the fraction at 60-65°C was collected to obtain 2.5 kg of product with a GC purity of 98.4% (RT = 11.069 min, Figure 4 ), yield 73.9%.

[0069] Functions and Effects of the Embodiments

[0070] The above embodiment provides a method for preparing 1-(trimethylsilyl)-dec-1-yn-5-ol, and methyl tert-butyl ether is selected as the reaction solvent. On the one hand, the preparation method can increase the purity of the product to more than 90% with only simple purification; on the other hand, the reaction can be carried out at -10 to -5°C, which is milder than the existing technology and more conducive to industrial application.

[0071] The above embodiment provides a method for preparing 1-decyn-5-ol. Since the reaction solvent used in the detrimethylsilylation step is a mixed solvent of ethanol and water, and methyl tert-butyl ether is used in the extraction process, low-boiling point materials such as the solvent can be taken out as much as possible during the concentration process and will not be wrapped by the oily product. Even without further purification, 1-decyn-5-ol with a purity of 94.7% can be obtained, which is conducive to industrial application.

[0072] The above-mentioned embodiments are preferred examples of the present invention and are not intended to limit the protection scope of the present invention.

Claims

1. A method for preparing 1-(trimethylsilyl)-dec-1-yn-5-ol, characterized in that: The steps are as follows: in the presence of methyl tert-butyl ether and n-butyl lithium, 1-trimethylsilyl propyne and 1,2-epoxyheptane react to prepare 1-(trimethylsilyl)-dec-1-yn-5-ol; 2. The preparation method according to claim 1, characterized in that The reaction temperature of the reaction is -15 to 0°C.

3. The preparation method according to claim 1, characterized in that: The molar ratio of the 1-trimethylsilylpropyne to the 1,2-epoxyheptane is (1-3):

1.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the n-butyl lithium to the 1,2-epoxyheptane is (1-3):

1.

5. The preparation method according to claim 1, characterized in that: The volume mass ratio of the methyl tert-butyl ether to the 1,2-epoxyheptane is (5-50) L:1 g.

6. The preparation method according to claim 1, characterized in that: The preparation method of the 1-(trimethylsilyl)-dec-1-yn-5-ol comprises the following steps: (a) mixing a methyl tert-butyl ether solution of 1-trimethylsilylpropyne and a n-hexane solution of n-butyllithium; (b) mixing the mixed solution of step (a) with a methyl tert-butyl ether solution of 1,2-epoxyheptane to react, to prepare 1-(trimethylsilyl)-dec-1-yn-5-ol.

7. A method for preparing 1-decyn-5-ol, characterized in that: The steps are as follows: (c) reacting 1-trimethylsilylpropyne with 1,2-epoxyheptane in the presence of methyl tert-butyl ether and n-butyl lithium to obtain 1-(trimethylsilyl)-dec-1-yn-5-ol; (d) reacting the 1-(trimethylsilyl)-dec-1-yn-5-ol in the presence of a solvent and an inorganic base to obtain 1-decyn-5-ol; 8. The preparation method according to claim 7, characterized in that: The preparation method of the 1-(trimethylsilyl)-dec-1-yn-5-ol is as described in any one of claims 1 to 6.

9. The preparation method according to claim 7, characterized in that: The preparation method of 1-decyn-5-ol satisfies any one or more of the following conditions: (1) The inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; (2) the molar ratio of the inorganic base to the 1-(trimethylsilyl)-dec-1-yn-5-ol is (1.0-2.0):1; (3) The solvent is a mixed solvent of an alkyl alcohol solvent and water; (4) the molar volume ratio of the 1-(trimethylsilyl)-dec-1-yn-5-ol to the solvent is (0.3-1.5) mol:1L; (5) In step (d), the reaction temperature is 25-40°C; (6) In step (d), the reaction time is 12-20 h.

10. The preparation method according to claim 7, characterized in that: In step (d), after the reaction is completed, post-treatment is also included, and the post-treatment includes: acidifying the reaction solution to neutrality and extracting with methyl tert-butyl ether.

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