A process for the ethynylation of certain α,β-unsaturated ketones

Abstract

The present invention relates to an improved process for the ethynylation of certain α,β-unsaturated ketones to produce tertiary acetylenic alcohols.

Description

Detailed Description of the Invention

[0001] The present invention relates to an improved process for the ethynylation of certain α,β-unsaturated ketones to produce tertiary acetylenic alcohols.

[0002] The process of ethynylation of α,β-unsaturated ketones to produce tertiary acetylenic alcohols is well known and has been disclosed and described in patent applications and publications, for example, U.S. Patent No. 4,320,236 or Chimia 40(9), 1986 p.323-330, which describes such ethynylation in detail.

[0003] The present invention relates to a compound represented by formula (I) [ka] (wherein R represents H, an aliphatic or aromatic hydrocarbon moiety, and the wavy bond means that the carbon-carbon double bond to which it is attached may be in either the (E) or (Z) configuration). The present invention relates to an improved process for producing the compound of formula (I).

[0004] Such compounds can be used as such or, additionally, they can be used as intermediates in the synthesis of other industrially relevant compounds, such as vitamin A derivatives and carotenoids.

[0005] Due to the importance of compounds of formula (I), there is a continuing need to provide improved syntheses.

[0006] As mentioned above, there are several methods for preparing the compounds of formula (I).

[0007] According to the literature (e.g. U.S. Pat. No. 4,320,236 or Chimia 40(9), 1986 p. 323-330), a specific ethynylation can be carried out according to the following scheme: [ka] where R is as defined above and in more detail below. This can be summarized as follows:

[0008] As proposed in the above-mentioned document, step (I) is divided into the following two steps (step (Ia) and step (Ib)): [ka] It consists of:

[0009] One of the main drawbacks and shortcomings of the processes described in the prior art is the control of the process.

[0010] Prior art processes use large excesses of starting materials to obtain good yields, resulting in large amounts of waste, especially when unsaturated ketones such as those of formula (II) are in excess, which can result in oligomers and polymers that are very difficult to remove and result in significant yield loss.

[0011] Furthermore, the exact timing of the addition of starting materials in the various steps (step (I), step (II) and step (III)) is also an issue: adding starting materials too early or too late can result in undesirable by-products that then have to be removed in a time-consuming large-scale process.

[0012] In chemical reactions, it is important to use the correct stoichiometry of the reagents, and the ideal situation is for just the right amount of reagent to completely consume the starting material. If an excess of one component (starting material or reagent) is used, this usually reduces the yield and increases the cost of the value of the unreacted excess. The excess reagent may produce a more hazardous reaction mixture and require more safety controls. Furthermore, the excess reagent must be removed from the product, which may require additional costly purification steps. Furthermore, the excess of one component may react to produce by-products that need to be removed from the product. In particular, compounds of formula (II) are known to be toxic and also prone to polymerization. The polymers make removal in purification steps rather difficult and cause additional costs. Therefore, the amount of reagent used in the reaction should be minimized, and the addition of that reagent to the reaction should be stopped as soon as the other reaction components are completely consumed.

[0013] It was therefore an object of the present invention to find a method and process for producing certain tertiary acetylenic alcohols which reduces the amount of undesirable by-products.

[0014] Surprisingly, it has been found that by using Raman spectroscopy to monitor the progress of a reaction, it is possible to find the ideal points for adding the various starting materials, as well as when to optimally stop the reaction.

[0015] Raman spectroscopy (named after the Indian physicist CV Raman) is a non-destructive vibrational spectroscopic technique that provides complete information about intermolecular interactions, polymorphism, crystallinity and overall chemical structure.

[0016] Raman spectroscopy is based on the so-called Raman effect, whereby the incident light of a high intensity laser source is scattered from a sample at a wavelength different from the laser source, which wavelength depends on the chemical structure of the sample.

[0017] Thus, a Raman spectrum is characterized by the intensity and wavenumber position of scattered light, which can be correlated to specific molecular bonds, allowing the identification of unknown samples or the monitoring of reaction pathways of substances.

[0018] Some functional groups are more Raman active than others, resulting in more intense bands. For example, the C=O bond characteristic of aldehydes is not Raman active. Instead, triple bonds such as C≡C are highly active.

[0019] Raman spectroscopy can be performed using any commonly available instrument. There are several manufacturers and suppliers of Raman instruments, such as Kaiser Optical Systems, Bruker, and Mettler Toledo. These instruments can be equipped with a variety of probes and optics for the analysis of liquids, solids, and gases. A very suitable method for performing Raman spectroscopy during chemical reactions is by using a dip probe that is placed in the reaction mixture within the vessel.

[0020] The process according to the invention is carried out as follows.

[0021] In step (Ia), lithium metal is added to NH3, followed by the addition of ethyne (HCCH) to form lithium carbide. [ka]

[0022] Subsequent addition of ethyne (HCCH) (step (Ib)) converts the lithium carbide to lithium acetylide. [ka]

[0023] The key feature is to identify the exact point at which the lithium carbide is completely converted to lithium acetylide. At this point, the lithium carbide of formula (II) [ka] where R is as defined above and in more detail below. of ketone is added.

[0024] Addition of the ketone of formula (II) too early or too late results in significant amounts of undesirable by-products, which must be removed by applying extensive, time-consuming purification processes.

[0025] Additionally, step (II) can also be better controlled by following the reaction using Raman spectroscopy. [ka] wherein R is as defined above and in more detail below.

[0026] As mentioned above, the exact point at which the ketone of formula (II) is added can be determined by Raman spectroscopy. Additionally, Raman spectroscopy can be used to identify when all the lithium acetylide has been consumed, and thus the exact point at which the addition of the ketone of formula (II) should be stopped.

[0027] The final step (Step III) [ka] where R is as defined above and in more detail below. Then, hydrolysis is carried out to obtain the compound of formula (I) in good yield. The hydrolysis of the compound of general formula (III) can be carried out by methods known per se, such as, but not limited to, the use of a Bronsted acid, e.g., sulfuric acid, acetic acid, water, ammonium chloride.

[0028] As previously mentioned, the amount of undesirable by-products and waste is significantly reduced throughout the process.

[0029] Thus, the present invention relates to a compound of formula (I) [ka] (wherein R is H; a linear, branched or cyclic C1-C alkyl group which may contain a ring system and may be substituted with an oxygen atom; 30 or a linear, branched or cyclic C2-C alkyl group which may contain a ring system and may be substituted with an oxygen atom. 30 (the alkylene moiety) A process (P) for the preparation of the compound of In the first step, lithium is added to NH3, and then Ethyne (HCCH) is added to the reaction mixture, and In the second step (step (II)), a compound represented by formula (II) [ka] (wherein R and the wavy bond have the same meaning as defined for compounds of formula (I). is a compound of the formula: Then, in a third step (step (III)), the obtained product is hydrolyzed. In process (P), steps (I) and (II) and optionally step (III) are controlled by monitoring the progress of the reaction by using Raman spectroscopy.

[0030] In a preferred embodiment of the invention, R is H; a linear, branched or cyclic C1-C aryl group which may include a ring system and may be substituted with an oxygen atom. 15 or a linear, branched or cyclic C1-C alkyl group which may contain a ring system and may be substituted with an oxygen atom. 15 It is an alkenyl group.

[0031] In a more preferred embodiment of the present invention, R is H; a linear or branched C1-C 10Alkyl groups; linear, branched or cyclic C1-C groups containing one carbon-carbon double bond. 15 an alkenyl group; or [ka] (wherein "*" indicates C bonded to the compound of formula (I) and the compound of formula (II), and R' is H, or a C1-C4 alkyl group, or -(CO)C1-C4 alkyl, or -C(COCH3)(CH3)2. is a substituted cyclohexene ring selected from the group consisting of:

[0032] In an even more preferred embodiment of the present invention, R is H; 10 Alkyl groups; linear, branched or cyclic C1-C groups containing one carbon-carbon double bond. 15 an alkenyl group; or [ka] (wherein "*" indicates C bonded to formulae (I) and (II). is a substituted cyclohexene ring selected from the group consisting of:

[0033] In the most preferred embodiment of the present invention, [ka] The compound is used.

[0034] Thus, the present invention provides a compound in which R is H; a linear, branched or cyclic C1-C cyclic ring system that may include and be substituted with oxygen atoms; 15 or a linear, branched or cyclic C1-C alkyl group which may contain a ring system and may be substituted with an oxygen atom. 15 Further relates to Process (P') wherein Process (P) is an alkenyl group.

[0035] Therefore, the present invention relates to a compound in which R is H; 10 Alkyl groups; linear, branched or cyclic C1-C groups containing one carbon-carbon double bond. 15 an alkenyl group; or [ka] (wherein "*" indicates C attached to formula (I) and (II), and R' is H or a C1-C4 alkyl group or -(CO)C1-C4 alkyl group or -C(COCH3)(CH3)2. The invention further relates to Process (P″), wherein Process (P) is a substituted cyclohexene ring selected from the group consisting of:

[0036] Therefore, the present invention relates to a compound in which R is H; 10 Alkyl groups; linear, branched or cyclic C1-C groups containing one carbon-carbon double bond. 15 an alkenyl group; or [ka] (wherein "*" indicates C bonded to formulae (I) and (II). The present invention further relates to Process (P'''), wherein Process (P) is a substituted cyclohexene ring selected from the group consisting of:

[0037] Thus, the present invention relates to a compound of formula (I') [ka] The present invention further relates to a process (P''''), which is a process (P) in which a compound of the formula:

[0038] Raman spectroscopy is used to determine when to add or stop adding various reaction compounds.

[0039] As described above, by introducing the wavy bond (of formula (I) and formula (II)), the compound of formula (I) can be converted into a compound of formula (Ia) or a compound of formula (Ib). [ka] (wherein R is as defined above). and mixtures of compounds of formula (Ia) and compounds of formula (Ib) in any ratio (R has the same meaning as defined above).

[0040] The same applies to the compounds of formula (II) and (III).

[0041] Any commonly known and commercially available Raman spectroscopy device can be used. Preferably, the dip probe is attached to a Raman analyzer or Raman spectrometer. Such Raman devices are commercially available from a variety of manufacturers and suppliers. The Raman dip probe can be easily integrated into process equipment.

[0042] All values ​​presented in this patent application are measured using a Kaiser Optical Systems Raman spectrometer (Kaiser Raman Rxn2 analyzer). This spectrometer is equipped with a CCD detector and is capable of recording a complete Raman spectrum in a few seconds. A 785 nm laser was used at 50 mW.

[0043] In the experiments described in this patent, -1 Spectra were recorded every minute with a resolution better than 100 s. Exposure times of 10 s were used throughout the reaction time. No fluorescence effects were observed.

[0044] As mentioned above, the exact points of addition of the various reagents during the process are determined by Raman spectroscopy.

[0045] The reaction conditions for ethynylation are similar to those disclosed in US Pat. No. 4,320,236.

[0046] Step (I) (both steps Ia and Ib) is typically carried out at a temperature range of −90° C. to −10° C. The lithium metal is typically added with stirring.

[0047] Thus, the present invention further relates to process (P1), which is process (P), (P'), (P'', (P''') or (P''''), wherein step (I) is carried out at a temperature range of -90°C to -10°C.

[0048] Step (Ia) [ka] uses Raman spectroscopy to determine when lithium is first added to ammonia and then monitors the formation of lithium carbide.

[0049] At the start of the process according to the invention (lithium has not yet been added to NH3), -1 ~3500cm -1 Three peaks are seen in (see FIG. 1) (NH stretching bands).

[0050] When lithium is added to NH3, the reaction rate is 3000cm -1 ~3500cm -1 The three peaks disappear in this region (see FIG. 2) and a shift is observed in the NH bending band.

[0051] After the lithium addition is complete, acetylene injection is started.

[0052] The incorporation of acetylene can be followed by Raman spectroscopy. Two bands appear at 1895–1865 cm -1 region, which can be attributed to acetylene solvated species (Figure 3).

[0053] As acetylene was continued to be added, the two Raman bands of the solvated species disappeared, and the bands at 1880–1835 cm-1 Two bands are detected in the region of (Figure 4). At this point, the addition of acetylene can be stopped and lithium carbide is formed.

[0054] Raman spectroscopy indicates when the formation of lithium carbide is complete and the addition of acetylene is stopped.

[0055] Therefore, the present invention relates to a method for producing a 1880-1835 cm -1 The present invention further relates to process (P2), which is process (P), (P'), (P'', (P''', (P'''',) or (P1), wherein the injection of acetylene is stopped when a new peak (in the region of

[0056] At this point, at least one inert solvent is added to the reaction mixture. Suitable inert solvents for the process according to the invention are ethers and aromatic hydrocarbon compounds, such as diethyl ether, di-n-propyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, benzene and toluene.

[0057] Therefore, the present invention relates to a method for producing a 1880-1835 cm -1 The present invention further relates to process (P3), which is process (P), (P'), (P'', (P''', (P'''', (P1) or (P2), wherein at least one inert solvent is added to the reaction mixture when two peaks in the region of

[0058] Thus, the present invention further relates to process (P3'), which is process (P3), wherein the at least one inert solvent is selected from the group consisting of ethers and aromatic hydrocarbon compounds.

[0059] Thus, the present invention further relates to process (P3″), which is process (P3), wherein the at least one inert solvent is selected from the group consisting of diethyl ether, di-n-propyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, benzene and toluene.

[0060] In step (Ib), after the addition of at least one solvent, acetylene is further added to the reaction mixture. [ka]

[0061] After solvent exchange (from NH3 to at least one inert solvent) and further addition of acetylene, the lithium carbide bands decreased (1880–1835 cm -1 At this point complete conversion to lithium acetylide is achieved, which can be observed by Raman (approximately 1885 cm -1 (see FIG. 5).

[0062] Therefore, the present invention relates to a method for producing a 1880-1835 cm -1 The two peaks in the region of 1885 cm disappeared, and -1 The present invention further relates to process (P4), which is process (P), (P'), (P'', (P''', (P'''', (P1), (P2), (P3), (P3') or (P3''), wherein the injection of acetylene is stopped when a peak in the region of

[0063] At this point (Step II), the compound represented by formula (II) [ka] (wherein R has the same meaning as defined above). is added to the reaction mixture, [ka] (wherein R has the same meaning as defined above). is formed.

[0064] [Reaction scheme for step (II):] [ka] In the formula, R has the same meaning as defined above.

[0065] The compound of formula (III) has a molecular weight of about 1885 cm -1 is added to the reaction mixture until the Raman band of disappears, at which point the addition of the compound of formula (II) is stopped (see Figure 6).

[0066] Raman spectroscopy indicates the complete consumption of lithium acetylide and the formation of the compound of formula (III) (at about 2090 cm -1 The time point of the band in the

[0067] Therefore, the present invention relates to -1 The present invention further relates to process (P5), which is process (P), (P'), (P'', (P'"), (P''"), (P1), (P2), (P3), (P3'), (P3'') or (P4), wherein the charging of the compound of formula (II) is stopped when the band at

[0068] The temperature in step (II) is usually from -70°C to 0°C.

[0069] Thus, the present invention further relates to process (P6), which is process (P), (P'), (P'', (P'"), (P''"), (P1), (P2), (P3), (P3'), (P3"), (P4) or (P5), wherein step (II) is carried out at a temperature between -70°C and 0°C.

[0070] Final step (Step (III)) [ka] (wherein R has the same meaning as defined above). This step is optional if Raman spectroscopy is performed after this step, since it is of little importance in terms of the production of undesired by-products.

[0071] The hydrolysis step, step (III), is usually carried out at a temperature of -70°C to 0°C, preferably -40°C to -5°C.

[0072] Thus, the present invention further relates to process (P7), which is process (P), (P'), (P'', (P'"), (P''"), (P1), (P2), (P3), (P3'), (P3'', (P4), (P5) or (P6), wherein step (III) is carried out at a temperature between -70°C and 0°C.

[0073] Thus, the present invention further relates to process (P7'), which is process (P), (P'), (P'', (P''', (P'''',), (P1), (P2), (P3), (P3'), (P3'', (P4), (P5) or (P6), wherein step (III) is carried out at a temperature of -40°C to -5°C.

[0074] The hydrolysis in step (III) is carried out using at least one Bronsted acid, such as sulfuric acid, acetic acid, water, ammonium chloride.

[0075] Thus, the present invention further relates to process (P8), which is process (P), (P'), (P'', (P''', (P'''',) (P1), (P2), (P3), (P3'), (P3'', (P4), (P5), (P6), (P7) or (P7'), wherein in step (III), at least the compound is selected from the group consisting of sulfuric acid, acetic acid, water and ammonium chloride.

[0076] Thus, the present invention further relates to process (P9), which is process (P), (P'), (P'', (P''', (P'''',), (P1), (P2), (P3), (P3'), (P3'', (P4), (P5), (P6), (P7), (P7') or (P8), wherein step (III) is carried out at a temperature between -70°C and 0°C.

[0077] Thus, the present invention further relates to process (P9'), which is process (P), (P'), (P'', (P''', (P'''',), (P1), (P2), (P3), (P3'), (P3'', (P4), (P5), (P6), (P7), (P7') or (P8), wherein step (III) is carried out at a temperature of -40°C to -5°C.

[0078] At the end of step (III), a compound of formula (I) is obtained, which may be isolated and purified by using commonly known methods. [Brief description of the drawings]

[0079] [Figure 1] 1 is a Raman spectrum of ammonia. [Diagram 2] 1 is a Raman spectrum of ammonia after partial addition of lithium. [Diagram 3] 1 is a Raman spectrum of solvated acetylene in ammonia. [Figure 4] 1 is a Raman spectrum of lithium carbide. [Diagram 5] This is a Raman spectrum of lithium acetylide. [Figure 6] 1 is a Raman spectrum of the lithium alkoxide product III. [Figure 7] 1 is a Raman spectrum of the reactions of Example 1 and Comparative Example 1 (C1).

[0080] The following examples illustrate the invention without limiting it in any way: all percentages and parts given are by weight, temperatures are given in ° C. and pressures are absolute, unless otherwise stated.

[0081] [Example] [Example 1] Ammonia gas is condensed under argon in a cooled (-50 to -30 °C) 2 L jacketed vessel equipped with a Raman probe until the vessel contains approximately 500 ml of liquid ammonium. Lithium metal (10.5 g) is added slowly with stirring (Figure 1 → Figure 2). Acetylene gas is added to the reaction mixture at a rate of approximately 1 L / min (Figure 3). The addition of acetylene is stopped when the Raman spectrum indicates the formation of lithium carbide (Figure 4).

[0082] The reaction temperature is raised to -10 to -10 °C and diethyl ether (approximately 625 ml) is added. The reaction mixture is cooled to -15 to -5 °C and acetylene gas is added at a rate of approximately 1 L / min. Once complete formation of lithium acetylide is observed (Figure 5), a methyl vinyl ketone solution (120 g in 120 ml of diethyl ether) is prepared and added to the lithium acetylide solution at approximately 3.3 ml / min. The reaction is monitored by Raman spectroscopy and as soon as the consumption of lithium acetylide is complete (Figure 6), the addition is stopped and the unused methyl vinyl ketone solution is discarded (approximately 171 g of MVK solution is added). The reaction mixture is stirred and then added to a cooled sulfuric acid solution (30%, approximately 400 ml) over approximately 20 min.

[0083] The ether layer is separated, dried over sodium sulfate, and most of the ether is removed at normal pressure to give crude 3-methylpent-1-en-4-yn-3-ol (248.5 g, 53.3% content by weight, 97.9% yield based on MVK and 91.3% yield based on lithium) as a yellow oil.

[0084] Comparative Example 1 (C1) (Raman spectroscopy not used to monitor reaction progress) The procedure of Example 1 was repeated, but without Raman spectroscopy and using the same amounts of lithium metal and methyl vinyl ketone solution. Complete consumption of the lithium acetylide was predicted to be reached after the addition of about 193 g of MVK solution (about 1.59 moles).

[0085] After workup, 255.8 g of crude 3-methylpent-1-en-4-yn-3-ol (51.5 wt. % content, 86.6% yield based on MVK) was obtained as a yellow oil. In addition, polymer was formed (see FIG. 7), which made removal of the mixture from the reactor and purification rather difficult.

[0086] Comparative Example 2 (C2) (Raman spectroscopy not used to monitor reaction progress) The procedure of Example 1 was repeated, but without Raman spectroscopy and using the same amounts of lithium metal and methyl vinyl ketone solution. Complete consumption of the lithium acetylide was predicted to be reached after the addition of about 146 g of MVK solution (about 1.20 moles).

[0087] After workup, 209.8 g of crude 3-methylpent-1-en-4-yn-3-ol (52.9% wt content, 96.3% yield based on MVK and 76.5% yield based on lithium) was obtained as a yellow oil.

Claims

1. A process for the production of a compound of formula (I), 【Chemical 1】 (In the formula, R is H; a linear, branched or cyclic C that may contain a ring system and may be substituted with an oxygen atom １ ~C ３０ alkyl group; or a linear, branched or cyclic C that may contain a ring system and may be substituted with an oxygen atom ２ ~C ３０ alkylene moiety). wherein ethyne (HCCH) is added to the reaction mixture, and In the first step, lithium is added to NH ３ and then in a second step (step (II)), a compound of formula (II) wherein R and the wavy bond have the same meaning as defined for said compound of formula (I), 【Chemical 2】 and then, in a third step (step (III)), the resulting product is hydrolyzed, in the process, said step (I) and step (II) and optionally step (III) are controlled by monitoring the progress of the reaction by using Raman spectroscopy. A process characterized by this.

2.

3. (wherein, “*” represents C bonded to said formula (I) and (II), and R is H; a linear, branched or cyclic C which may contain a ring system and may be substituted with an oxygen atom １ -C １５ alkyl group; or a linear, branched or cyclic C which may contain a ring system and may be substituted with an oxygen atom １ -C １５ The process according to claim 1, wherein the alkenyl group is A substituted cyclohexene ring selected from the group consisting of, the process according to claim 1. R is H; linear or branched C １ -C １０ alkyl group; linear, branched or cyclic C containing one carbon-carbon double bond １ -C １５ alkenyl group; or [Chemical Formula 3]

4. R' is H, or C １ ~C ４ alkyl group, or -(CO)C １ ~C ４ alkyl, or -C(COCH ３ )(CH ３ ) ２ is) (wherein, “*” represents C bonded to said formula (I) and (II)) A substituted cyclohexene ring selected from the group consisting of, the process according to claim 1. R is H; linear or branched C １ ~C １０ alkyl group; linear, branched or cyclic C containing one carbon-carbon double bond １ ~C １５ alkenyl group; or 【Chemical Formula 4】

5. R is H, the process according to claim 1.

6. Step (I) is carried out in a temperature range of -90°C to -10°C, the process according to any one of claims 1 to 5.

7.

8.

9. The introduction of the acetylene is stopped when a new peak appears in the region of 1880 to 1835 cm －１ The process according to any one of claims 1 to 5, wherein the process is stopped when a new peak appears in the region of 1880 to 1835 cm. Said at least one inert solvent is selected from the group consisting of ethers and aromatic hydrocarbon compounds, the process according to claim 8. At least one inert solvent is added to the reaction mixture when two peaks in the region of 1880 to 1835 cm －１ are observed, the process according to any one of claims 1 to 5.

10. Said at least one inert solvent is selected from the group consisting of diethyl ether, di-n-propyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, benzene and toluene, the process according to claim 8.

11.

12. Formula (II) The introduction of the acetylene is stopped when two peaks in the region of 1880 to 1835 cm －１ disappear and a peak appears at about 1885 cm －１ The process according to any one of claims 1 to 5.

13. Step (II) is carried out at a temperature of -70°C to 0°C, the process according to any one of claims 1 to 5. [Chemical Formula 5] (In the formula, R is H; a linear, branched or cyclic C that may contain a ring system and may be substituted with an oxygen atom １ to C ３０ alkyl group; or a linear, branched or cyclic C that may contain a ring system and may be substituted with an oxygen atom ２ to C ３０ alkylene moiety) The introduction of said compound is stopped when the band at about 1885 cm －１ disappears, the process according to any one of claims 1 to 5.

14. Step (III) is carried out at a temperature of -70°C to 0°C, the process according to any one of claims 1 to 5.

15. In step (III), at least the compound is selected from the group consisting of sulfuric acid, acetic acid, water and ammonium chloride, the process according to any one of claims 1 to 5. ​ ​

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