Process for enzymatic synthesis of amides from amines and carboxylic acids or esters

Abstract

The present invention relates to a process for the enzymatic synthesis of an amide of formula III from an amine of formula I and a compound of formula II, [C36] JPEG2024519439000043.jpg14117Lipase is immobilized in a rotating bed reactor or a spin fixed bed reactor, and a Dean-Stark apparatus is used for dehydration. (Figure 1)

Description

[Technical Field]

[0001] The present invention relates to a process for enzymatically synthesizing amides from amines and carboxylic acids or esters using lipase. [Background technology]

[0002] Amide bonds are crucial in the development of many compounds, including pharmaceuticals and polymers. Several processes for direct catalytic amidation have been developed over the years.

[0003] In thermal amidation, a catalyst may not be required. This process is carried out at high temperatures (>140°C), and the yield depends on the temperature used, the substrate concentration, the solvent used, and other parameters.

[0004] Metal-based amidation is carried out using boron-based or palladium-based catalysts. Compared to thermal amidation, higher yields can be obtained, but the process is expensive and time-consuming. Catalyst and solvent recycling is a challenge.

[0005] Thermal or metal-based amidation is not an environmentally friendly process. Several attempts have been made to improve process efficiency and reduce costs and carbon footprint.

[0006] In the amidation process, water must be removed to improve the process yield. Therefore, most amidation processes are carried out under reduced pressure. This increases costs and thus makes large-scale amidation more difficult. Molecular sieves can also be used, but they are still expensive for large-scale use. Dean-Stark apparatus can also be used to remove water from the amidation process.

[0007] Enzymatic amidation has been developed over many years using different types of enzymes, such as lipases. These so-called biocatalysts are available at low temperatures and exhibit good selectivity. However, modern techniques exhibit a very limited substrate range and often require long reaction times (several days). Combining enzymatic amidation with a palladium catalyst can yield a yield of approximately 70%, as demonstrated by Palo-Nieto et al., ACS Catal., 2016, 6, 3932-3940.

[0008] Another drawback of biocatalysts is cost. To reduce costs and improve the efficiency of the amidation process, enzymes can be immobilized, for example, on the reaction bead during the reaction. This allows for enzyme recycling. The use of flow reactors has further improved the biocatalytic amidation process. However, lipase recycling is inefficient in terms of both time and cost.

[0009] To date, no environmentally friendly catalytic amidation process exists that is sufficiently efficient, cost-effective, and suitable for large-scale production. This is a top priority for the American Chemical Society Green Chemistry Pharmaceutical Roundtable (https: / / www.acsgcipr.org). Currently, most methods utilize stoichiometric amounts of toxic activating reagents (Dunetz et. Org. Process. Res. Dev. 2016, 20, 140). Therefore, there is still a need for a more environmentally friendly and cost-effective amidation process that can be used on a large scale.

[0010] Capsaicinoids are commonly used in environmentally friendly foods. Capsaicin is also widely used in the pharmaceutical industry. Capsaicin is used, for example, as an analgesic in topical ointments and skin patches to relieve mild muscle and joint pain and soreness associated with arthritis, back pain, bruises, and sprains, or to alleviate symptoms of peripheral neuropathy.

[0011] Capsaicinoids can be isolated from natural sources (e.g., the fruit of the Capsicum genus), but this mainly produces capsaicin and dihydrocapsaicin because many other capsaicinoids are present only in trace amounts. Therefore, chemical synthesis is useful for obtaining rarer capsaicinoids such as nonibamide and for producing non-natural capsaicinoids. Capsaicinoids can be prepared from vanillin by first reducing vanillin oxime under reflux using a mixture of excess metal (Zn) from methanol and ammonium formate to obtain vanillylamine. Alternatively, amide bond formation can be achieved by enzymatic catalytic conversion between vanillylamine and various fatty acid derivatives. WO2015 / 144902A1 discloses a multi-catalyst cascade relay sequence that includes an enzyme cascade system that, when integrated with other catalytic systems such as heterogeneous metal catalysts and organic catalysts, sequentially or in a one-pot manner converts alcohols to amines and amides.

[0012] US2017081277A1 discloses amidation using a dialkylamine as a substrate. Novozyme 435 is immobilized on the bead. (商標) A Dean-Stark apparatus can be used to remove ethanol from the reaction mixture. The reaction is carried out under reduced pressure. For large-scale production, the bead is undesirable because separating the bead from the reaction mixture is costly and time-consuming. Furthermore, for large-scale production, pressure reduction is preferable to avoid in order to reduce the overall cost and time of the process.

[0013] US6022718 discloses a process for preparing capsaicin analogs using hydrolysis and capsaicin as starting materials.

[0014] Pithani S., "Using spinchem rotation bed reactor technology for immobilized enzymatic reactions: a case study," Org. Process Res. Dev., 2019, vol.23, pages 1926-1931, discloses the advantages of using rotation bed immobilized lipase. The acylation reaction is performed using lipase (novozyme 435). (商標) ) is used to demonstrate that it can be used in a rotary bed reactor. Due to the high cost, the loading was limited to 10 wt%. Loading of 5 to 10 wt% was deemed sufficient to achieve a conversion of 45 to 50% within 6 hours. After upscaling, the overall yield was 39%. Pithani shows that rotary bed reactors are useful for acylation, but also that they are expensive and the conversion rate is 45 to 50%, with an overall yield of 39%. The results disclosed in Pithani are discouraging for large-scale production using rotary bed reactors.

[0015] There is an increasing need for the large-scale production of amide compounds such as capsaicinoids. Such processes are preferably highly efficient and effective, and offer improved yields compared to known processes. Such amidation processes are preferably environmentally friendly and, in particular, cost-effective. [Overview of the Initiative]

[0016] The object of the present invention is to overcome, at least partially, the aforementioned problems and to provide an improved process for synthesizing amides from amines and carboxylic acids or esters.

[0017] This objective is achieved by the process defined in the claim.

[0018] One embodiment relates to a process for enzymatically synthesizing an amide of formula III from an amine of formula I and a compound of formula II, [ka]

[0019] where R 1 is C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 1-12 alkoxy, C 1-12 alkyl-O-C 1-12 alkyl, C 1-12 alkyl-OC(O)-C 1-12 alkyl, C 1-12 alkyl-NH-C 1-12 alkyl, C 1-12 alkyl-NHC(O)-C 1-12 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 5-12 aryl, C 3-12 cycloalkyl-C 1-6 alkyl, C 3-12 cycloalkenyl-C 1-6 alkyl and C 5-12 aryl-C 1-6 alkyl, selected from the group consisting of or containing, R 1 is optionally hydrogen, hydroxy, oxy, halogen, carboxy, amine, amide, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 amineoxyalkyl, C 1-6 alkylamide, C 1-6 carboxyalkyl, C 1-6 sulfraalyl, C 1-6 alkylsulfide and C 1-6 alkoxy, and may be substituted with one or more substituents selected from the group consisting of or containing, where one or more carbons of cycloalkyl, cycloalkenyl, or aryl may be substituted with one or more heteroatoms selected from O, N, or S, where R 2 is hydrogen, C 1-30 alkyl, C 1-30 alkenyl, C 1-30Alkinyl, C 1-30 Alkoxy, C 1-30 Alkyl-OC 1-12 Alkyl, C 1-30 Alkyl-OC(O)-C 1-12 Alkyl, C 1-30 Alkyl-NH-C 1-12 Alkyl, C 1-30 Alkyl-NHC(O)-C 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group consisting of or containing alkyl groups, R 2 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amide, C 1-6 Hydroxyalkyl, C 1-6 Halloyalkyl, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. R in the formula 3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, C 1-6 Alkyl-NH-C 1-6 Alkyl, C 1-6 Alkyl-NHC(O)-C 1-6Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Aryl, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group consisting of or containing alkyl, R 3 Is optionally hydrogen, hydroxy, oxy, halogen, carboxy, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Aminooxyalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfraalalkyl, C 1-6 Alkyl sulfide and C 1-6 May be substituted with one or more substituents selected from the group consisting of or containing alkoxy, Where one or more carbons of cycloalkyl, cycloalkenyl, or aryl may be substituted with one or more heteroatoms selected from O, N, or S, Where R is a bond or C 1-6 Is alkyl, The lipase is immobilized in a rotating bed reactor or a spin fixed bed reactor, and a Dean-Stark apparatus is used for dehydration.

[0020] In some embodiments, the lipase is immobilized in a rotating bed reactor, and a Dean-Stark apparatus is used for dehydration.

[0021] In some embodiments, the lipase immobilized on beads is discarded.

[0022] In the process of the present invention, a combination of enzyme catalysis and azeotropic dehydration is used for direct catalytic amide synthesis, as defined elsewhere in this specification. The enzyme lipase is immobilized in a rotating bed reactor or a spin-fixed bed reactor. Compared to immobilizing the lipase on a bead or using a sieve, the lipase in the process of the present invention can be easily recycled. This makes it possible to carry out the process in a time- and cost-effective manner, especially on a large scale.

[0023] The unique combination of a rotary bed reactor or a spin-fixed bed reactor and the Dean-Stark apparatus improves yield (>90 or 99%) and conversion rate (>90 or 99%). The unique combination allows for the use of wet raw materials. The process can be run at atmospheric pressure and temperatures below 100°C (60 to 90°C). The process is environmentally friendly. The process is suitable for large-scale amide production.

[0024] The straightforward processing and purification process makes the process suitable for large-scale use. The enzymes and solvents used, if available, are easily recyclable, thereby enabling large-scale production. The unique combination of immobilized enzymes with a rotating bed reactor or spin-fixed bed reactor and Dean trap apparatus allows the process to be extended to the synthesis of other amides and esters.

[0025] In one embodiment, the process is carried out in a neat state. The process can be carried out without any solvent. This can potentially improve the efficiency, effectiveness, and environmental friendliness of the process. It also reduces the cost of running the process. A neat process further reduces the cost of large-scale processes.

[0026] Compared with known processes, the direct amidation process of the present invention has improved conversion rates and yields. The amidation requires fewer process steps, which reduces time and costs. The mass flow rate is improved in the process of the present invention. Since the enzyme is immobilized / fixed, the reaction product can be easily filtered and purified. The process of the present invention has an improved reaction ratio.

[0027] The process enables the effective and efficient large-scale production of amide compounds such as capsinoids. The process improves the yield compared to known processes. The amidation process is environmentally friendly and particularly cost-effective.

[0028] Using a rotating bed reactor and a Dean-Stark apparatus in combination enables control of the water content during the process. A low water content improves the conversion rate and yield. The results of cycle 2 in Table 1 of Example 14 show that raw materials with a water content of 23 wt% can even be used. This improves the flexibility of the process. This also improves the feasibility of large-scale use of the process.

[0029] In some embodiments, the option of R in (dialkyl)-amine 2 is waived.

[0030] According to some embodiments of the present invention, R 1 is C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 1-12 alkoxy, C 1-12 alkyl-O-C 1-12 alkyl, C 1-12 alkyl-OC(O)-C 1-12 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 5-12 aryl, C 3-12 cycloalkyl-C 1-6 alkyl, C 3-12 cycloalkenyl-C 1-6 alkyl and C5-12 Aryl-C 1-6 Selected from the group consisting of or containing alkyl groups, R 1 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, and C. 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. R in the formula 2 is hydrogen, C 1-30 Alkyl, C 1-30 Alkenil, C 1-30 Alkinyl, C 1-30 Alkoxy, C 1-30 Alkyl-OC 1-12 Alkyl, C 1-30 Alkyl-OC(O)-C 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group consisting of or containing alkyl groups, R 2 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, and C. 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. R in the formula 3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkenil, C 1-6Alkinyl, C 1-6 Alkoxy, C 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group consisting of or containing alkyl groups, R 3 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, and C. 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. In the formula, R is either a bond or C 1-6 It is alkyl.

[0031] According to some aspects of the present invention, R 1 C 1-12 Alkyl, C 1-12 Alkenil, C 1-12 Alkinyl, C 1-12 Alkoxy, C 1-12 Alkyl-OC 1-12 Alkyl, C 1-12 Alkyl-OC(O)-C 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C1-6 Selected from the group consisting of or containing alkyl groups, R 1 The elements are optionally hydrogen, hydroxyl, oxy, and C. 1-6 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. R in the formula 2 C 1-30 Alkyl, C 1-30 Selected from the group consisting of or including alkenils, R in the formula 3 is hydrogen, C 1-6 Selected from the group consisting of or containing alkyl groups, In the formula, R is either a bond or C 1-6 It is alkyl.

[0032] According to some aspects of the present invention, R 1 C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C6 aryl, C 3-6 Cycloalkyl-C 1-6 Alkyl, C 3-6 Cycloalkenyl-C 1-6 Alkyl and C6 aryl-C 1-3 Alkyl, Selected from the group including or consisting of, R 1 The elements are optionally hydrogen, hydroxyl, oxy, and C. 1-6 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. R in the formula 2 C 1-18 Alkyl, C 1-18 Selected from the group consisting of or including alkenils, R in the formula 3 is hydrogen, C 1-3Selected from the group consisting of or containing alkyl groups, In the formula, R is either a bond or C 1-3 It is alkyl.

[0033] According to some aspects of the present invention, R 1 C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkoxy, C 1-6 Alkyl-OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 6-7 Ariel, C 3-6 Cycloalkyl-C 1-3 Alkyl, C 3-6 Cycloalkenyl-C 1-3 Alkyl and C 5-7 Aryl-C 1-3 Selected from the group consisting of or containing alkyl groups, R 1 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, and C. 1-3 Hydroxyalkyl, C 1-3 Haloalkyl and C 1-3 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. R in the formula 2 is hydrogen, C 5-18 Alkyl, C 5-18 Alkenil, C 5-15 Alkoxy, C 5-15 Alkyl-OC 1-6 Alkyl and C 5-15 Alkyl-OC(O)-C 1-6 Selected from the group consisting of or containing alkyl groups, R 2 It may be optionally substituted with one or more substituents selected from the group consisting of hydrogen, hydroxyl, oxy, halogen, and carboxyl. R in the formula 3 is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkyl-OC 1-3Selected from the group consisting of or containing alkyl groups, In the formula, R is either a bond or C 1-3 It is alkyl.

[0034] According to some aspects of the present invention, R 1 is hydrogen, C 6-7 Aryl and C 5-7 Aryl-C 1-3 Selected from the group consisting of or containing alkyl groups, R 1 The elements are optionally hydrogen, hydroxyl, and C. 1-3 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. R in the formula 2 is hydrogen, C 5-15 Alkyl and C 5-15 Selected from the group consisting of or including alkenils, R in the formula 3 is hydrogen, C 1-3 Selected from the group consisting of or containing alkyl groups, In the formula, R is either a bond or C 1-3 It is alkyl.

[0035] According to some aspects of the present invention, R 1 is C 5-7 Aryl-C 1-3 It is alkyl, R 1 The elements are optionally hydrogen, hydroxyl, and C. 1-3 It may be substituted with one or more substituents selected from the group including alkoxys. R in the formula 2 is C 5-16 Alkyl and C 5-15 Selected from the group containing alkenils, R in the formula 3 is hydrogen, methyl, or ethyl. In the formula, R represents a bond.

[0036] Processes using these compounds improve yield and conversion rates, which is particularly important for large-scale production.

[0037] According to some aspects of the present invention, R 1 is C 5-7 Aryl-C 1-3 It is alkyl, R 1 Hydrogen, hydroxyl, and C are optional. 1-3 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. R in the formula 2 is hydrogen, C 5-16 Alkyl and C 5-15 Selected from the group consisting of or including alkenils, R in the formula 3 is hydrogen, methyl, or ethyl. In the formula, R is either a bond or C 1-2 It is alkyl.

[0038] According to some aspects of the present invention, R 1 is C6 aryl-C 1-2 It is alkyl, R 1 Hydrogen, hydroxyl, and C are optional. 1-2 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. R in the formula 2 is hydrogen, C 7-10 Alkyl and C 7-10 Selected from the group consisting of or including alkenils, R in the formula 3 is hydrogen, methyl, or ethyl. In the formula, R is either a bond or C 1-2 It is alkyl.

[0039] According to some aspects of the present invention, R 1 This is C6 aryl, or C6 aryl-C 1-2 It is an alkyl group and optionally substituted with one or more substituents selected from the group consisting of hydrogen, hydroxyl, oxy, and methoxy.

[0040] According to some aspects of the present invention, R 2These are hydrogen, methanyl, etanyl, heptanyl, octanyl, 8-methylnonanyl, octadecanyl, or 8-methylnonenyl.

[0041] Processes using these compounds improve yield and conversion rates, which is particularly important for large-scale production.

[0042] One embodiment relates to a process for enzymatically synthesizing an amide of formula III from an amine of formula I and a compound of formula IIa, [ka] R in the formula 1 C 1-12 Alkyl, C 1-12 Alkenil, C 1-12 Alkinyl, C 1-12 Alkoxy, C 1-12 Alkyl-OC 1-12 Alkyl, C 1-12 Alkyl-OC(O)-C 1-12 Alkyl, C 1-12 Alkyl-NH-C 1-12 Alkyl, C 1-12 Alkyl-NHC(O)-C 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group consisting of or containing alkyl groups, R 1 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Aminexylalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. R in the formula 2 is hydrogen, C 1-30 Alkyl, C 1-30 Alkenil, C 1-30 Alkinyl, C 1-30 Alkoxy, C 1-30 Alkyl-OC 1-12 Alkyl, C 1-30 Alkyl-OC(O)-C 1-12 Alkyl, C 1-30 Alkyl-NH-C 1-12 Alkyl, C 1-30 Alkyl-NHC(O)-C 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group consisting of or containing alkyl groups, R 2 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Aminexylalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. R in the formula 3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, C 1-6 Alkyl-NH-C 1-6 Alkyl, C 1-6 Alkyl-NHC(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group consisting of or containing alkyl groups, R 3 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Aminexylalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. The lipase is fixed in a rotating bed reactor or a spin-fixed bed reactor, and a Dean-Stark apparatus is used for dehydration.

[0043] According to some aspects of the present invention, R 1 C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkoxy, C 1-6 Alkyl-OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 6-7 Ariel, C 3-6 Cycloalkyl-C 1-3 Alkyl, C 3-6 Cycloalkenyl-C 1-3 Alkyl and C 5-7 Aryl-C 1-3 Selected from the group consisting of or containing alkyl groups, R 1 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, and C. 1-3 Hydroxyalkyl, C 1-3 Haloalkyl and C 1-3 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. R in the formula 2 is hydrogen, C 5-15 Alkyl, C 5-15 Alkenil, C 5-15 Alkoxy, C 5-15 Alkyl-OC 1-6 Alkyl and C 5-15 Alkyl-OC(O)-C 1-6 Selected from the group consisting of or containing alkyl groups, R 2 It may be optionally substituted with one or more substituents selected from the group consisting of hydrogen, hydroxyl, oxy, halogen, and carboxyl. R in the formula 3 is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkyl-OC 1-3 Selected from the group consisting of alkyl groups.

[0044] According to some aspects of the present invention, R 1 is C 5-7 Aryl-C 1-3 It is alkyl, R 1 Hydrogen, hydroxyl, and C are optional. 1-3 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. R in the formula 2 is hydrogen, C 5-15 Alkyl and C 5-15 Selected from the group consisting of or including alkenils, R in the formula 3 It is hydrogen, methyl, or ethyl.

[0045] According to some aspects of the present invention, R 1 is C6 aryl-C 1-2 It is alkyl, R 1 Hydrogen, hydroxyl, and C are optional. 1-2 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. R in the formula 2 C 7-10 Alkyl and C 7-10 Selected from the group consisting of or including alkenils, R in the formula 3 It is hydrogen, methyl, or ethyl.

[0046] The process enables the effective and efficient large-scale production of amide compounds such as capsaicinoids and their derivatives. The process improved yields compared to known processes. The amidation process is environmentally friendly and particularly cost-effective.

[0047] According to some aspects of the present invention, the compound of formula III is the compound of formula IV, [ka] IV In the formula, n is either 1 or 2. R in the formula 2 C3-30 Alkyl, C 3-30 Alkenil, C 3-30 Alkinyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Selected from the group containing or consisting of aryls, R 2 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 Alkoxy and C 5-12 It may be substituted with one or more substituents selected from the group consisting of or including aryl compounds. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. R in the formula 4 or R 5 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl and C 5-12 Independently selected from the group containing or consisting of aryls, R 4 or R 5 The following are optional: hydroxy, oxy, halogen, carboxy, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Amine oxyalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be independently substituted with one or more substituents selected from the group consisting of or including alkoxys. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. R in the formula 6 These are hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, and C. 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Selected from the group containing or consisting of aryls, R 6 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Amine oxyalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group consisting of or including alkoxys. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S.

[0048] Processes using these compounds improve yield and conversion rates, which is particularly important for large-scale production.

[0049] In some embodiments, the compound of formula III is the compound of formula IV, n is either 1 or 2. R 2 C 3-30 Alkyl, C 3-30 Selected from the group consisting of or including alkenils, R 4 or R 5 These are, independently, hydrogen and C 1-3Selected from the group consisting of or containing alkyl groups, R 6 It is hydrogen.

[0050] In some embodiments, the compound of formula III is the compound of formula IV, n is either 1 or 2. R 2 C 3-18 Alkyl and C 3-18 Selected from the group containing alkenils, R 4 or R 5 These are, independently, hydrogen and C 1-6 Selected from the group including alkyl groups, R 6 It is hydrogen.

[0051] In some embodiments, the compound of formula III is the compound of formula IV, n is either 1 or 2. R 2 C 5-16 Alkyl and C 5-15 Selected from the group containing alkenils, R 4 or R 5 These are, independently, hydrogen and C 1-3 Selected from the group including alkyl groups, R 6 It is hydrogen.

[0052] In some embodiments, the compound of formula III is the compound of formula IV, and R 2 These are metanyl, etanyl, heptanyl, octanyl, 8-methylnonanyl, octadecanyl, or 8-methylnonenyl.

[0053] Processes using these compounds improve yield and conversion rates, which is particularly important for large-scale production.

[0054] According to some aspects of the present invention, no solvent is used.

[0055] According to some aspects of the present invention, the solvent is methyl tert-butyl ether, diisopropyl ether, C 1-6 Alkyl-OC 1-6 Alkyl ethers, hexane and other C 5-10 Alkanes, cyclohexane and other C 5-10 Cycloalkanes, benzene, toluene, xylene, tert-butanol, tert-amyl alcohol, and other bulky secondary or tertiary C compounds. 5-10 The solvent is an organic solvent selected from the group comprising or consisting of alcohols and any ester thereof. In some embodiments, the organic solvent is selected from the group comprising or consisting of diisopropyl ether, cyclohexane, toluene, and tert-butanol, or mixtures thereof. In some embodiments, the solvent is cyclohexane, toluene, or diisopropyl ether (DIPE). In some embodiments, the solvent is diisopropyl ether (DIPE). In some embodiments, the solvent is cyclohexane. In some embodiments, the solvent is toluene. In some embodiments, the solvent is tert-butanol.

[0056] According to some aspects of the present invention, R 3 When the solvent is not hydrogen, the solvent is methyl tert-butyl ether, diisopropyl ether, C 1-6 Alkyl-OC 1-6 Alkyl ethers, hexane, and other C 5-10 Alkanes, cyclohexane and other C 5-10 Cycloalkanes, benzene, toluene, xylene, tert-butanol, tert-amyl alcohol, and other bulky secondary or tertiary C compounds. 5-10The solvent is selected from the group comprising or consisting of alcohols and their esters. In some embodiments, the organic solvent is selected from the group comprising or consisting of diisopropyl ether, cyclohexane, toluene, and tert-butanol, or mixtures thereof. In some embodiments, the solvent is cyclohexane, toluene, or diisopropyl ether (DIPE). In some embodiments, the solvent is diisopropyl ether (DIPE). In some embodiments, the solvent is cyclohexane. In some embodiments, the solvent is toluene. In some embodiments, the solvent is tert-butanol. In some embodiments, the solvent is recyclable. In some embodiments, the solvent is recycled. In some embodiments, the solvent is recycled by at least 70%, 80%, or 90%. Recycling the solvent reduces the overall cost of the process and also reduces the carbon footprint of the process.

[0057] According to several aspects of the present invention, the lipase is selected from the group comprising or consisting of Candida antarcticalipase A, Candida antarcticalipase B, cross-linked subtilisin A protease, porcine pancreatic lipase, Candida cylindracea lipase, Rhizopus arghiz, Penicillium cyclopium, Mucormiehei, Thermomyces lanuginosa lipase, Candida rugosa lipase, and Pseudomonas lipoprotein lipase. In one aspect, the lipase is selected from the group comprising or consisting of Candida antarcticalipase A and Candida antarcticalipase B. In one aspect, the lipase is Candida antarcticalipase. In one aspect, the lipase is Candida antarcticalipase B (Novozyme 435 (商標) ) is. Immobilized enzymes such as Candida antarcticalipase B or C, and antarcticalipase A are used in Novozyme 435. (商標) It is commercially available under product names such as [product name] and is easily obtainable. Its relatively low cost availability is important for cost-effective processes, especially large-scale processes.

[0058] According to some aspects of the present invention, the process temperature is between 15°C and 150°C, or between 15°C and 115°C, or between 50°C and 90°C, or between 70°C and 80°C. Relatively low temperatures are important for cost-effective processes, especially for large-scale processes.

[0059] According to some aspects of the present invention, the process is 0.090 The process is performed at pressures between 0.200 MPa and 0.200 MPa, or at atmospheric pressure (approximately 0.1 MPa). Running the process at atmospheric pressure is important for cost-effective processes, especially large-scale processes.

[0060] According to some aspects of the present invention, the rotary bed reactor is loaded with 10 to 75 wt% lipase. According to some aspects of the present invention, the rotary bed reactor is loaded with 11 to 60 wt% lipase. According to some aspects of the present invention, the rotary bed reactor is loaded with 15 to 50 wt% lipase. Unique combinations of immobilized enzymes in rotary bed reactors or spin-fixed bed reactors and Dean trap devices improve process conversion rates and yields. The process is time-efficient and cost-effective, so the potential additional cost for loading lipase beyond 10 wt% becomes reasonable.

[0061] According to some aspects of the present invention, the stirring speed is 150 to 600 rpm, 200 to 500 rpm, or 200 to 450 rpm.

[0062] The present invention also relates to a process for synthesizing the compound of formula II, wherein R 2 is C 6-18 Alkyl or C 6-18 It is an alkenyl. According to some embodiments, the compound of formula II is R in formula II. 2 C 6-18 Alkyl or C 6-18 It is an alkenyl, and can be linear or branched, in the following stages [ka] Prepared including, Step A-1: ​​The reaction is carried out using no solvent or an organic solvent. Step B-1, the solvent is an aprotic organic solvent. Step B-1, the base is sodium or potassium alkoxide. Optionally, the isomerization step C-1, the catalyst is selected from the group consisting of HNO2, HNO3, and combinations of NaNO2 / HNO3, NaNO2 / NaNO3 / H2SO4 that can produce HNO2 or HNO3, and Hydrogenation stage D-1: The catalyst is a heterogeneous hydrogenation catalyst, and the hydrogen source is hydrogen gas.

[0063] In some embodiments, R 2 is C 6-10 It is alkyl.

[0064] In some embodiments, the organic solvent in step A-1 is ethyl acetate. The aprotic organic solvent in step B-1 is selected from the group comprising or consisting of 2-methyltetrahydrofuran, tetrahydrofuran, and toluene. The sodium or potassium alkoxide base in step B-1 is selected from the group comprising or consisting of NaH, KH, t-BuOK, and t-BuONa. The heterogeneous hydrogenation catalyst in hydrogenation step D-1 is selected from the group consisting of or including Pd / C and Pd / Al2O3.

[0065] In some embodiments, the organic solvent in step A-1 is ethyl acetate, the aprotic organic solvent in step B-1 is 2-methyltetrahydrofuran, the sodium or potassium alkoxide base in step B-1 is t-BuOK, and the heterogeneous hydrogenation catalyst in hydrogenation step D-1 is Pd / C.

[0066] In the synthesis of 8-methyl-6-nonenic acid, using 2-MeTHF as a recyclable solvent for the crucial Wittig reaction between (6-carboxyhexyl)triphenylphosphonium bromide and isobutyraldehyde improves conversion rates and yields. The synthesis is time- and cost-effective, resulting in high yields and conversion rates. This is particularly important for large-scale processes.

[0067] Further solvents may be used in the process stages. Extraction and filtration may be performed between stages.

[0068] The process can be carried out at room temperature. The process can be carried out at atmospheric pressure (approximately 1 atm or 0.1 MPa).

[0069] The present invention also relates to a novel synthetic route for 8-methyl-6-nonanoic acid, which is used for the direct production of dihydrocapsaicin. The process starts from cyclohexanone and isobutyraldehyde as raw materials, with aldol condensation, Bayer-Villiger oxidation, and hydrogenation as key steps.

[0070] According to some aspects of the present invention, R 2 Compounds of formula II in which is 8-methylnonanyl are prepared by the following steps: [ka] Step A-2: The reaction is carried out using no solvent or any organic solvent, and the catalyst is selected from the group consisting of amines and inorganic bases. Step B-2: The reaction is carried out using no solvent or an organic solvent, and the catalyst is an acid. In stage C-2, the catalyst is a heterogeneous hydrogenation catalyst, and the hydrogen source is hydrogen gas. Step D-2, the oxidizing agent is a peroxide, the catalyst is lipase, and Step E-2, the reaction medium is an acidic solvent, and In stage F-2, the catalyst is a heterogeneous hydrogenation catalyst, and the hydrogen source is hydrogen gas.

[0071] According to some embodiments, the organic solvent in step A-2 is selected from the group comprising or consisting of toluene and aromatic solvents, THF and ethers, dichloromethane and halogenated solvents, and the catalyst is selected from the group comprising or consisting of pyrrolidine and corresponding salts, NaOH and KOH. The organic solvent in step B-2 is selected from the group consisting of or containing toluene, and the acid is selected from the group consisting of or containing p-TsOH, sulfuric acid, and Amberlist-15. The catalyst for step C-2 is selected from the group consisting of Pd / C and Pd / Al2O3. The oxidizing agent in step D-2 is selected from the group comprising or including aqueous H2O2 and peracids, and the lipase is selected from the group comprising or including Candida antarcticalipase A, Candida antarcticalipase B, cross-linked subtilisin A protease, porcine pancreatic lipase, Candida cylindracea lipase, Rhizopus arghiz, Penicillium cyclopium, Mucor miehei, Thermomyces lanuginosus lipase, Candida rugosa lipase, and Pseudomonas lipoprotein lipase. The reaction medium for step E-2 is selected from the group consisting of or containing an aqueous sulfuric acid solution. The catalyst for step F-2 is selected from the group comprising or consisting of Pd / C, Pd / Al2O3, Pd / molecular sieve, Pt / C, Pt / Al2O3, and Pt / molecular sieve.

[0072] The Dean Stark Trap can be used in stage B-2.

[0073] According to some embodiments, the organic solvent in step A-2 is toluene and the catalyst is pyrrolidine; the organic solvent in step B-2 is toluene and the acid is p-TsOH; the catalyst in step C-2 is Pd / C; the oxidizing agent in step D-2 is an aqueous H2O2 solution and the lipase is Candida antarcticalipase B; the reaction medium in step E-2 is an aqueous sulfuric acid solution and the catalyst in step F-2 is Pd / C.

[0074] Synthesis offers high yields and conversion rates, and is highly time- and cost-effective. This is particularly important for large-scale processes.

[0075] Further solvents may be used in the process stages. Extraction and filtration may be performed between stages.

[0076] The process can be carried out at room temperature. The process can be carried out at atmospheric pressure (approximately 1 atm or 0.1 MPa).

[0077] The processes defined in any of these specifications are useful for the large-scale production of compounds of formula III. In some embodiments, the processes are used for the large-scale production (>0.5 or >1 kg) of compounds of formula III. [Brief explanation of the drawing]

[0078] The present invention will be described in more detail hereby by the description of various embodiments of the present invention and by reference to the accompanying drawings.

[0079] [Figure 1] This document describes a system for carrying out the process of the present invention. [Modes for carrying out the invention]

[0080] definition Room temperature is between 15 and 25°C.

[0081] HCl is ethyl acetate.

[0082] DIPE is diisopropyl ether.

[0083] KOtBu is potassium tert-butoxide.

[0084] 2-MeTHF is 2-methyltetrahydrofuran.

[0085] ET2O is diethyl ether.

[0086] AcOH is acetic acid.

[0087] p-TsOH is p-toluenesulfonic acid or tosylic acid.

[0088] tBuOH is tert-butyl alcohol.

[0089] Equivalent (equiv.) is "equivalent." or "equivalent." As used herein, the terms "wt%", "w / w%", or "w%" mean weight percentage, which is a percentage of the total weight.

[0090] Where used herein, the terms “optional” or “optionally” mean that the events or circumstances described thereafter may occur but are not necessarily to occur, and the descriptions include both cases in which the events or circumstances occur and cases in which they do not.

[0091] As used herein, "C" can be used alone or as a suffix or prefix. n The term "contains hydrocarbon-containing groups" is intended to include a hydrocarbon-containing group; n is an integer from 1 to 30.

[0092] As used herein, the terms "halogen" or "halo," used alone or as a suffix or prefix, are intended to include bromine, chlorine, fluorine, and iodine.

[0093] As used herein, the term “hetero” is intended to include alkyl, cycloalkyl, and aryl groups in which one or more carbon atoms (and certain associated hydrogen atoms) are independently substituted with the same or different heteroatoms (S, O, or N) or heteroatomic groups. Examples of heteroatomic groups include, but are not limited to, -O-, -S-, -OO-, -SS-, -OS-, NR, =NN=, -N=N-, -N=N-NR-, -PR-, -P(O)2-, -POR-, -OP(O)2-, -SO-, -SO2-, -Sn(R)2-, etc.

[0094] As used herein, "C" can be used alone or as a suffix or prefix. 1-30 The term "alkyl" is intended to include both branched and straight saturated aliphatic hydrocarbon groups having 1 to 30 carbon atoms. 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and tert-butyl.

[0095] The term "alkenyl" refers to a monovalent linear or branched hydrocarbon radical having at least one carbon-carbon double bond and containing at least 2 to about 30 carbon atoms. The double bond of an alkenyl is either unconjugated or conjugated to other unsaturated groups. A preferred alkenyl group is C 2-6 The alkenyl group includes, but is not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-butene)-pentenyl. The alkenyl may be unsubstituted or substituted with one or two suitable substituents.

[0096] The term "alkynyl" refers to a monovalent linear or branched hydrocarbon radical having at least one carbon-carbon triple bond and containing at least 2 to about 12 carbon atoms. The triple bond of the alkynyl is either not conjugated to other unsaturated groups or may be conjugated. Preferred alkynyl groups include acetylenyl, methylacetylenyl, butynyl, pentynyl, hexynyl, etc. 2-6 The material contains, but is not limited to, an alkynyl group. The alkynyl group may be unsubstituted or substituted with one or two suitable substituents.

[0097] As used herein, "C" can be used alone or as a suffix and prefix. 1-6 The term "-alkoxy" is C 1-6 - Refers to an alkyl radical, which is bonded to the rest of the molecule via an oxygen atom. C 1-4 Examples of alkoxys include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, and tert-butoxy.

[0098] As used herein, the terms “cycloalkyl” and “cycloalkenyl,” used alone or as suffixes or prefixes, are intended to include saturated or partially unsaturated cyclic alkyl radicals. Where a specific level of saturation is intended, the nomenclature cycloakanyl or cycloalkenyl is used. Examples of cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutene, cyclopentane, cyclohexane, and others.

[0099] As used herein, the term "aryl" refers to either a monocyclic aromatic ring having 5 or 12 ring members, or a polycyclic system having at least one carbocyclic aromatic ring fused to at least one carbocyclic aromatic ring, a cycloalkyl ring, or a heterocycloalkyl ring. For example, aryls include phenyl rings fused to a 5- to 7-membered heterocycloalkyl ring containing one or more heteroatoms independently selected from N, O, and S.

[0100] As used herein, the term "C 5-12 -Aryl-C 1-6 -alkyl is C 1-6 - Indicates a phenyl group bonded via an alkyl radical. C6-aryl-C 1-3 -Examples of alkyl groups include phenylmethyl (benzyl), 1-phenylethyl, and 2-phenylethyl.

[0101] Figure 1 shows the system for carrying out the process. In reactor 5, the lipase is fixed on a rotating stationary base 2. Motor 3 is used to rotate the stationary base 2. Reactor 5 is connected to a Dean-Stark apparatus 1, which is connected to a condenser 4.

[0102] In the present invention, the process is carried out using lipase immobilized in a rotating bed reactor, together with a Dean-Stark apparatus for dehydration.

[0103] This process can be used for the preparation of capsaicinoids and for the amidation of many other amines with carboxylic acids or esters.

[0104] The process can be used to synthesize an amide of formula III from an amine of formula I and a compound of formula II or IIa, as shown below. [ka] or [ka]

[0105] R 1 C 1-12 Alkyl, C 1-12 Alkenil, C 1-12 Alkinyl, C 1-12 Alkoxy, C 1-12 Alkyl-OC 1-12 Alkyl, C 1-12Alkyl-OC(O)-C 1-12 Alkyl, C 1-12 Alkyl-NH-C 1-12 Alkyl, C 1-12 Alkyl-NHC(O)-C 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group including alkyl groups, R 1 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Aminexylalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group including alkoxys.

[0106] R 1 C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkoxy, C 1-6 Alkyl-OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 6-7 Ariel, C 3-6 Cycloalkyl-C 1-3 Alkyl, C 3-6 Cycloalkenyl-C 1-3 Alkyl and C 5-7 Aryl-C 1-3 Selected from the group including alkyl groups, R 1The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, and C. 1-3 Hydroxyalkyl, C 1-3 Haloalkyl and C 1-3 It may be substituted with one or more substituents selected from the group including alkoxys.

[0107] Or, R 1 C is optionally substituted with hydrogen, hydroxyl, and / or methoxy. 5-7 Aryl-C 1-3 Alkyl, or C 6-7 Aryl-C 1-2 Alkyl, or C6 aryl-C 1-3 It can be alkyl.

[0108] R 2 is hydrogen, C 1-30 Alkyl, C 1-30 Alkenil, C 1-30 Alkinyl, C 1-30 Alkoxy, C 1-30 Alkyl-OC 1-12 Alkyl, C 1-30 Alkyl-OC(O)-C 1-12 Alkyl, C 1-30 Alkyl-NH-C 1-12 Alkyl, C 1-30 Alkyl-NHC(O)-C 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group including alkyl groups, R 2 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Aminexylalkyl, C 1-6 Alkylamide, C1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group including alkoxys.

[0109] R 2 is hydrogen, C 3-30 Alkyl, C 3-30 Alkenil, C 3-30 Alkinyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 The group may be selected from those containing aryls.

[0110] R 2 is hydrogen, C 5-18 Alkyl, C 5-18 Alkenil, C 5-18 Alkoxy, C 5-18 Alkyl-OC 1-6 Alkyl and C 5-18 Alkyl-OC(O)-C 1-6 Selected from the group including alkyl groups, R 2 This can be optionally substituted with one or more substituents selected from the group including hydrogen, hydroxyl, oxy, halogen, and carboxyl.

[0111] Or, R 2 is hydrogen, C 5-16 Alkyl and C 5-16 Alkenyl or C 7-17 Alkyl and C 7-16 Alkenyl, or C 7-10 Alkyl and C 7-10 The group may be selected from those containing alkenils.

[0112] R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Alkyl-OC 1-6 Alkyl, C1-6 Alkyl-OC(O)-C 1-6 Alkyl, C 1-6 Alkyl-NH-C 1-6 Alkyl, C 1-6 Alkyl-NHC(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group including alkyl groups, R 3 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Aminexylalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group including alkoxys. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. 3 is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, and C 1-3 Alkyl-OC 1-3 It may be selected from the group including alkyl groups.

[0113] Or, R 3 R can be hydrogen, methyl, or ethyl. 3 It can be hydrogen.

[0114] R can be a bond. R is C 1-3 It may be alkyl, methyl, or ethyl.

[0115] The compound of formula III may represent structure IV. [ka] IV In the formula, n is either 1 or 2. R in the formula 2 C 3-20 Alkyl, C 3-20 Alkenil, C 3-20 Alkinyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Selected from the group containing aryls, R 2 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Aminexylalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 Alkoxy and C 5-12 It may be substituted with one or more substituents selected from the group including aryls. R in the formula 4 or R 5 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl and C 5-12 Selected from the group containing aryls, R in the formula 6 These are hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl and C 5-6 Selected from the group containing aryls, R6 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Aminexylalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group including alkoxys.

[0116] The compound of formula III may represent structure IV. In the formula, n is either 1 or 2. R in the formula 2 C 5-18 Alkyl, C 5-18 Alkenil, C 5-15 Alkoxy, C 5-18 Alkyl-OC 1-6 Alkyl-, and C 5-18 Alkyl-OC(O)-C 1-6 Selected from the group consisting of or containing alkyl groups, R 2 This can be optionally substituted with one or more substituents selected from the group consisting of hydroxy, oxy, halogen, and carboxy. R in the formula 4 or R 5 is hydrogen and C 1-3 Selected from the group consisting of or containing alkyl groups, R 6 This can be selected from the group consisting of or including hydrogen, hydroxyl, and oxy.

[0117] The compound of formula III may represent structure IV. In the formula, n is either 1 or 2. R in the formula 2 is C 6-12 Alkyl and C 6-12 Alkenyl, or C 7-10 Alkyl and C 7-10 Selected from the group containing alkenils, R in the formula4 or R 5 This is selected from the group including hydrogen, methyl, or ethyl. R 6 It is hydrogen.

[0118] Conventional process for preparing capsaicinoids Esters as acyl donors: A fairly dry amine (<3 wt% water content) is required; otherwise, water will cover the amine at the bottom and slow the reaction. It is difficult to achieve complete ester conversion without adding excess amine. [ka] Expensive anhydrous solvent and toxic SOCl2 were required in this process. Compared to the enzymatic process, the yield was largely significantly lower, and the resulting product was quite crude. The product was brownish-yellow and viscous. See Example 25.

[0119] Enzyme process [ka] This process requires a large quantity of molecular sieves, which necessitates larger facilities if scaled up. Filtration and purification are required, which are time-consuming and costly. See Example 23.

[0120] Both conventional processes are time-consuming, expensive, and yield too low to be used for large-scale production in an economically viable manner.

[0121] The process of the present invention can be used for the preparation of capsaicinoids according to the following schematic diagram. [ka] In the process of the present invention, no solvent may be used.

[0122] When using a solvent, the solvents are methyl tert-butyl ether, diisopropyl ether, and C 1-6 Alkyl-OC 1-6 Alkyl ethers, hexane and other C 5-10 Alkanes, cyclohexane and other C 5-10 Cycloalkanes, benzene, toluene, xylene, tert-butanol, tert-amyl alcohol, and other bulky secondary or tertiary C compounds. 5-10 The solvent may be an organic solvent selected from the group comprising or consisting of alcohols and any ester thereof. The solvent may be toluene, diisopropyl ether, or cyclohexane.

[0123] R 3 When the solvent is not hydrogen, the solvent is methyl tert-butyl ether, diisopropyl ether, C 1-6 Alkyl-OC 1-6 Alkyl ethers, hexane, and other C 5-10 Alkanes, cyclohexane and other C 5-10 Cycloalkanes, benzene, toluene, xylene, tert-butanol, tert-amyl alcohol, and other bulky secondary or tertiary C compounds. 5-10 Alcohols and their esters may be included or selected from the group comprising these.

[0124] The solvent may be toluene, diisopropyl ether, or cyclohexane.

[0125] The lipase may be selected from the group comprising or consisting of Candida antarcticalipase A, Candida antarcticalipase B, cross-linked subtilisin A protease, porcine pancreatic lipase, Candida cylindracea lipase, Rhizopus arghiz, Penicillium cyclopium, Mucormiehei, Thermomyces lanuginosa lipase, Candida rugosa lipase, and Pseudomonas lipoprotein lipase.

[0126] The process can be carried out at temperatures between room temperature and 150°C, or between room temperature and 115°C.

[0127] The process is 0.090 It can be performed at a pressure of 0.200 MPa or approximately 0.1 MPa.

[0128] The compound of formula II may be prepared by comprising or consisting of the following steps: [ka] R in the formula 2 is C 6-18 Alkyl or C 6-18 It is an alkenyl, and can be linear or branched. Step A-1: ​​The reaction is carried out without a solvent or using any organic solvent such as alkyl solvent. Step B-1, the solvent is selected from the group comprising or consisting of 2-methyltetrahydrofuran, tetrahydrofuran, toluene, and any other aprotic organic solvent. Step B-1, the base is selected from the group comprising or consisting of NaH, KH, t-BuOK, t-BuONa, and another sodium or potassium alkoxide. In isomerization step C-1, the catalyst is selected from the group comprising or consisting of HNO2, HNO3, and any other combination capable of producing HNO2 or HNO3, and Hydrogenation step D-1: The catalyst is selected from the group consisting of Pd / C, Pd / Al2O3, and any other heterogeneous hydrogenation catalyst, and the hydrogen source is hydrogen gas.

[0129] The compound of formula II may be prepared by comprising or consisting of the following steps: [ka] Step A-2, the reaction is carried out without a solvent or with an organic solvent such as toluene, and the catalyst is selected from the group consisting of pyrrolidine, other amines and their corresponding salts, NaOH, KOH, and other inorganic bases. Step B-2: The reaction is carried out without a solvent or with an organic solvent such as toluene, and the catalyst is selected from the group comprising or consisting of p-TsOH, sulfuric acid, Amberlist-15, and other acids. In stages C-2 and F-2, the hydrogen source is hydrogen gas, and the catalyst is selected from the group comprising or including Pd / C, Pd / Al2O3, and another heterogeneous hydrogenation catalyst. Step D-2, the oxidizing agent is selected from the group comprising or consisting of aqueous H2O2 solution, peracids, and other peroxides, and the catalyst is selected from the group comprising or consisting of Candida antarcticalipase A, Candida antarcticalipase B, cross-linked subtilisin A protease, porcine pancreatic lipase, Candida cylindracea lipase, Rhizopus arghiz, Penicillium cyclopium, Mucor miehei, Thermomyces lanuginosus lipase, Candida rugosa lipase, and Pseudomonas lipoprotein lipase, and Step E-2, the reaction medium is selected from the group consisting of an aqueous sulfuric acid solution or another strongly acidic solvent, and In step F-2, the catalyst is selected from the group comprising or consisting of Pd / C, Pd / Al2O3, Pd / molecular sieve, Pt / C, Pt / Al2O3, and Pt / molecular sieve, and the hydrogen source is hydrogen gas.

[0130] The process for preparing the compound of formula II may be carried out at a temperature between room temperature and 150°C, or between room temperature and 115°C. These processes are 0.090 It can be performed at a pressure of 0.200 MPa or approximately 0.1 MPa.

[0131] Experiment section Preparation of vanillylamine Vanillylamine was prepared from its hydrochloride salt. The HCl salt was purchased from a commercial supplier or prepared according to the literature (ChemBioChem 2009, 10, 823; J. Med. Chem. 2018, 61, 8225). [ka] Example 1: 50.00 g of vanillylamine HCl was dissolved in 500 mL of cold water (approximately 5°C), cooled in an ice bath, and 87.9 mL of 3 M NaOH (1 equivalent) was partially added over 10 minutes while vigorously stirring. The internal temperature was maintained at approximately 5°C. After all the groups had been added, the milky white solution was stirred for a further 5 minutes and then filtered. The white product in the funnel was washed twice with cold water (5°C, 100 mL x 2) and then dried under vacuum until the weight remained the same. 37.32 g of product (92.4% yield) was obtained. Example 2: 500.0 g of vanillylamine HCl was dissolved in 5 mL of water (10-15°C), and 3 M NaOH (1 equivalent) was partially added over 20 minutes while vigorously stirring. After all the groups had been added, the milky white solution was stirred for a further 10 minutes and then filtered. The white product in the funnel was washed twice with cold water (1 L x 2) and then dried in a vacuum chamber at 50°C for 24 hours. 478.0 g of off-white product was obtained with a water content of 19.5 wt% (determined by a Kern DBS 60-3 moisture analyzer).

[0132] Preparation of fatty acids: Preparation of fatty acids by the Wittig reaction as an important step. [ka] Example 3: Preparation of (6-carboxyhexyl)triphenylphosphonium bromide.

[0133] In a 1 L round-bottom flask, 97.53 g of 6-bromohexanoic acid and 131.15 g (1.0 equivalent) of triphenylphosphine (PPh3) were dissolved in 500 mL of ethyl acetate. The mixture was heated at 75–80°C and stirred for 7 days. After filtration, the collected product was washed with ethyl acetate (50 mL × 2) and then dried under vacuum to obtain 221.80 g of white powder (yield 97.0%). The combined filtrate was recycled as a solvent for further batches.

[0134] Example 4: Preparation of (Z)-8-methyl-6-nonenic acid.

[0135] In a 1 L two-necked round-bottom flask, 100.00 g (6-carboxyhexyl)triphenylphosphonium (Ph3PO) bromide and 49.07 g (2.0 equivalents) KOtBu were dissolved in 300 mL of 2-MeTHF under the protection of a nitrogen atmosphere, and the mixture was cooled using an ice bath. While the compounds were dissolving, the reaction mixture turned bright orange. When 18.92 g (1.2 equivalents) of isobutyraldehyde solution in 200 mL of 2-MeTHF was slowly added to the cooled reaction mixture, it quickly turned white. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 6 hours. The reaction was quenched by adding 500 mL of H2O. The MeTHF solvent was recovered by distillation. After cooling to room temperature, most of the Ph3PO settled and was collected as a white powder by filtration. The filtrate was oxidized to pH 2 using concentrated HCl, and the resulting organic layer was collected. The aqueous phase was extracted with Et2O (100 mL x 2). The organic phase was combined, dried over anhydrous Na2SO4, and concentrated to yield 56.6 g of crude product. This crude product was then distilled under reduced pressure to obtain (Z)-8-methyl-6-nonenic acid (32.76 g, yield 88%, Z / E 11:1 by NMR analysis) as a colorless oily product.

[0136] Example 5: Preparation of 8-methylnonanoic acid.

[0137] 32 g of (Z)-8-methyl-6-nonenoic acid was dissolved in 150 mL of diisopropyl ether. Then, 0.5 mol% of Pd / C powder was dispersed in this solution. The mixture was hydrogenated overnight at room temperature using an H2 balloon. The catalyst was recovered by filtration. The solvent was recovered by distillation. 8-methylnonanoic acid was obtained as a colorless oil in >99% yield.

[0138] Example 6: Preparation of (E)-8-methyl-6-nonenic acid.

[0139] In a 1 L two-necked round-bottom flask, 100.00 g (6-carboxyhexyl)triphenylphosphonium bromide and 49.07 g (2.0 equivalents) KOtBu were dissolved in 300 mL of 2-MeTHF under the protection of a nitrogen atmosphere and cooled using an ice bath. While the compounds were dissolving, the reaction mixture turned bright orange. When 18.92 g (1.2 equivalents) of isobutyraldehyde solution in 200 mL of 2-MeTHF was slowly added to the cooled reaction mixture, it quickly turned white. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 6 hours. The reaction was quenched by adding 500 mL of H2O. The MeTHF solvent was recovered by distillation. After cooling to room temperature, most of the Ph3PO precipitated and was collected as a white powder by filtration. The filtrate was oxidized to pH 2 by oxidizing concentrated HCl, and the formed organic layer was collected. The aqueous phase was extracted using DIPE (100 mL x 2). The organic phases were combined and concentrated. This crude intermediate was then treated with concentrated HNO3 (0.03 equivalents) at 85°C for 24 hours under the protection of a nitrogen atmosphere. After cooling, the mixture was washed with water (50 mL x 2). The aqueous phase was combined and extracted using DIPE (50 mL x 2). The organic phases were combined, dried over anhydrous Na2SO4, and concentrated to obtain 53.1 g of crude product. This crude product was then distilled under reduced pressure to obtain (E)-8-methyl-6-nonenic acid (30.2 g, yield 81%, E / Z86:14 by NMR analysis) as a colorless oily product.

[0140] Preparation of 8-methylnonanoic acid starting from cyclohexanone and isobutyraldehyde [ka] Example 7: Preparation of 2-(2-methylpropyridene)cyclohexane-1-one [ka] 50 g of isobutyraldehyde, 102 g of cyclohexanone (1.5 equivalents), 5 mol% of pyrrolidine, and 5 mol% of AcOH were heated and stirred at 40°C for 12 hours. After cooling to room temperature, the mixture was dispersed in 200 mL of water and 100 mL of toluene, and the organic phase was separated. The aqueous phase was extracted with toluene (50 mL x 2). The organic phase was bound and treated in a Dean-Stark trap with a 4 mol% p-TsOH·H2O catalyst under reflux conditions for 2 hours, and the resulting water was collected. After cooling again to room temperature, the acid was removed by washing with 30 mL of 1 M aqueous NaOH solution. Toluene and excess cyclohexanone were recovered by distillation. The enone product (87.6 g, yield 83%, bright yellow) was then distilled under reduced pressure.

[0141] Example 8: Preparation of 2-isobutylcyclohexanone 5 g of 2-(2-methylpropyridene)cyclohexane-1-one was dissolved in 10 mL of siRNA. 0.2 mol% Pd / C was added, and hydrogenation was carried out at room temperature for 4 hours using an H2 balloon. Complete conversion was achieved by NMR analysis. The catalyst was recovered by filtration, and the filtrate was used directly for the next oxidation.

[0142] Example 9: Preparation of 7-Isobutyloxepant-2-one Novozyme 435 in an siRNA solution of 2-Isobutylcyclohexanone (商標) (250 mg) and 3 equivalents of a 30% H2O2 aqueous solution were added. The mixture was stirred and heated at 50°C. After 24 hours, 91% conversion was achieved based on NMR analysis. After cooling to room temperature, the catalytic lipase was recovered by filtration. The filtrate was washed with a 5% Na2S2O3 aqueous solution and brine to remove excess peroxides. The organic phase was concentrated, and crude lactone was produced.

[0143] Example 10: Preparation of 8-methyl-6-nonanoic acid The crude lactone described above was dispersed in 5 M H2SO4 (40 mL) and heated in an oil bath at 110°C. After 20 hours, the mixture was cooled to room temperature and extracted with DIPE (20 mL x 3). The organic phase was washed with brine, dehydrated with anhydrous Na2SO4, and filtered. 0.5 mol% Pd / C powder was added to the filtrate, and hydrogenation was carried out at room temperature for 24 hours using an H2 balloon. After filtration to recover the Pd catalyst, the filtrate was concentrated and purified by flash chromatography on silica gel to obtain 8-methyl-6-nonanoic acid (2.1 g, 37% yield from 5 g of the enone product in Example 7).

[0144] Preparation of capsaicinoids [ka] Example 11: Preparation of capsaicin with excess amine in DIPE. At normal atmospheric pressure (approximately 1 atm), 8-methyl-6-nonenic acid (3.65 g), vanillylamine (1.1 equivalents), and Novozyme 435 of Bead were used. (商標) (498.8 mg, 14 w / w% E / S) was refluxed in diisopropyl ether (45 mL) at approximately 69°C using a Dean-Stark trap, and the resulting water was collected. After stirring overnight (19 hours) at approximately 300 rpm, the mixture was filtered to recover the catalytic lipase, and the filtrate was washed with 0.5 M aqueous HCl (10 mL). The aqueous phase was extracted with Et2O (10 mL x 2), combined with the organic phase, dehydrated with anhydrous Na2SO4, and concentrated to yield 6.53 g of product (yield 99.7%, very pale yellow).

[0145] Example 12: Preparation of nonibamide with excess fatty acids in toluene. At normal atmospheric pressure (approximately 1 atm), vanillylamine (4.89 g, 2.00 wt% water), nonanoic acid (1.01 equivalents), and Novozyme 435 of Bead were used. (商標)(1 g, 20 w / w% E / S) was refluxed in toluene (50 mL) using a Dean-Stark trap (approximately 110°C), and the resulting water was collected. After stirring overnight (16 hours) at approximately 300 rpm, the conversion of nonanoic acid was >99%. After filtration to recover the enzyme catalyst, the mixture was concentrated to yield 9.14 g of product (yield 99.6%, white).

[0146] Example 13: Preparation of nonibamide with excess fatty acids in cyclohexane. At normal atmospheric pressure (approximately 1 atm), vanillylamine (4.89 g, 2.00 wt% water), nonanoic acid (1.01 equivalents), and Novozyme 435 of Bead were used. (商標) (1 g, 20 w / w% E / S) was refluxed in cyclohexane (50 mL) using a Dean-Stark trap (approximately 81°C), and the resulting water was collected. After stirring overnight (16 hours) at approximately 300 rpm, the conversion of nonanoic acid was >99%. After filtration to recover the enzyme catalyst, the mixture was concentrated to yield 9.10 g of product (yield 99.1%, pale yellow).

[0147] Using lipase in a bead is not feasible for large-scale production due to the cost of post-processing such as lipase filtration. Therefore, the following experiment was conducted using lipase fixed in a rotating bed reactor.

[0148] Example 14: Preparation of dihydrocapsaicin in a fixed-bed reactor. At normal atmospheric pressure (approximately 1 atm), 12 units of novozyme 435 (商標) In a 1 L reactor equipped with a fixed-bed reactor packed with (45 to 60 w / w% E / S), vanillylamine, a slightly excess of 8-methylnonanoic acid (1.01 equivalents), and diisopropyl ether (600 mL) were refluxed through a Dean-Stark trap (approximately 69°C), and the resulting water was collected (Figure 1). The rpm was fixed at approximately 300 rpm during the reaction.

[0149] After the reaction, the hot solution was released and cooled to room temperature. The dihydrocapsaicin product was crystallized and collected by filtration. The filtrate was recycled directly as a solvent for further batches. The results are shown in Table 1. The average yield of dihydrocapsaicin was 99.7%.

[0150] Table 1. Preparation of dihydrocapsaicin in a fixed-bed reactor. [ka] [Table 1] The results show a good conversion rate and yield after 6 cycles.

[0151] Example 15: Preparation of capsaicin in a fixed-bed reactor (45 w / w% E / S). The reactor system from Example 14 was washed by reflux with DIPE solvent to remove residual dihydrocapsaicin. In this reactor, vanillylamine, a slightly excess of 8-methyl-6-nonenic acid (1.01 equivalents), and diisopropyl ether (600 mL) were refluxed (approximately 69°C) using a Dean-Stark trap at normal atmospheric pressure (approximately 1 atm), and the resulting water was collected. The rpm was fixed at approximately 300 rpm during the reaction. After the reaction, the hot solution was released and cooled to room temperature. The capsaicin product was crystallized and collected by filtration. The filtrate was recycled directly as a solvent for further batches. The results are shown in Table 2. The average yield of capsaicin was 99.4%.

[0152] Table 2. Preparation of capsaicin in a fixed-bed reactor. [ka] [Table 2] The results show a good conversion rate and yield after 5 cycles.

[0153] Example 16a: Preparation of nonibamide in a fixed-bed reactor (15 to 21 w / w% E / S). The reactor system from Example 15 was washed by reflux with DIPE solvent to remove residual dihydrocapsaicin. In this reactor, vanillylamine, a slightly excess of nonanoic acid (1.01 equivalents), and diisopropyl ether (600 mL) were refluxed (approximately 69°C) using a Dean-Stark trap at normal atmospheric pressure (approximately 1 atm), and the resulting water was collected. The rpm was fixed at approximately 300 rpm during the reaction. After the reaction, the hot solution was released and cooled to room temperature. The nonibamide product was crystallized and collected by filtration. The filtrate was recycled directly as a solvent for further batches. The results are shown in Table 3a. The yield of nonibamide was an average of 99.8%.

[0154] Table 3a. Preparation of nonibamide in a fixed-bed reactor. [ka] [Table 3] The results show a good conversion rate and yield after 11 cycles.

[0155] Example 16b: Preparation of nonibamide in a 100L fixed-bed reactor. 1 kg of novozyme 435 at normal atmospheric pressure (approximately 1 atm). (商標) In a 100 L reactor equipped with a fixed-bed reactor packed with (50 to 100 w / w% E / S), vanillylamine, excess 8-methylnonanoic acid (1.03 equivalents), and diisopropyl ether (90 L) were refluxed (approximately 69°C) through a Dean-Stark trap, and the resulting water was collected. During the reaction, the rpm was fixed at approximately 250 rpm. After the reaction, the hot solution was released and cooled to 15°C. The nonibamide product was crystallized and collected by filtration. The filtrate was recycled directly as a solvent for further batches. The results are shown in Table 3b. The results indicate that the process of the present invention can be used for large-scale production of amides.

[0156] Table 3b. Preparation of nonibamide in a 100L fixed-bed reactor. [Table 4] The results show good conversion rates and yields after 3 cycles when the process is used on a large scale.

[0157] Comparative example:

[0158] Preparation of capsaicin from fatty acids using a desiccant [ka] Example 17: In a 200 mL reactor, toluene (150 mL), 4 Å molecular sieve (10 g), and immobilized enzyme (novozyme 435) were added. (商標) 0.59 g of , 2.02 g of 8-methyl-6-nonenic acid, and 2 equivalents of vanillylamine were added. The reaction was carried out at 80°C and monitored by NMR. After 6 hours, the acid conversion was >99%. After filtration, the organic filtrate was cooled and washed sequentially with 1 M HCl (20 mL x 2), water (20 mL x 2), and brine (20 mL). After drying with anhydrous Na2SO4, the solvent was removed under vacuum. 3.07 g of capsaicin (yield 84.7%) was obtained.

[0159] Example 18: In a 25 mL flask, combine t-BuOH (8 mL), 4 Å molecular sieve (600 mg), and immobilized enzyme (Novozyme 435 (商標) (75 mg), 8-methyl-6-nonenic acid (341 g), and vanillylamine (1.06 equivalents) were added. The reaction was carried out at 80°C and monitored by NMR. After 10 hours, the acid conversion was approximately 95%.

[0160] Preparation of capsaicin using esters as acyl donors: [ka] Example 19: Preparation of methyl ester. 4.73 g of 8-methyl-6-nonenic acid was dissolved in 30 mL of MeOH. Five drops of concentrated H2SO4 were added to this solution as a catalyst. The resulting solution was refluxed overnight. After cooling to room temperature, most of the MeOH was removed using a rotary evaporator, and the residue was dissolved in Et2O (30 mL) and washed with 5% Na2CO3 solution (10 mL x 2). The organic phase was dried over anhydrous Na2SO4 and concentrated to yield an ester product in >99% yield.

[0161] Example 20: Preparation of capsaicin by ester in a fixed-bed reactor. 6 g of Novozyme 435 (商標) Ethyl ester of 8-methyl-6-nonenate, excess vanillylamine (1.1 equivalents), and diisopropyl ether (600 mL) were refluxed into a 1 L reactor equipped with a rotating stationary stand packed with (10 to 20 w / w% E / S). After the reaction, the hot solution was released and cooled to room temperature. The solution was continuously washed with 0.5 M HCl (60 mL), water (60 mL), and brine (20 mL). After drying with anhydrous Na2SO4, the solvent was recovered by rotary evaporation. The capsaicin product was obtained as a bright yellow. The results are shown in Table 4.

[0162] Table 4. Preparation of capsaicin by esters in a fixed-bed reactor. [Table 5] Example 21: Preparation of capsaicin from esters by distillation apparatus. 923 mg of methyl ester of 8-methyl-6-nonenic acid and 200 mg of Novozyme 435 bead were added to a flask equipped with a short-path distillation apparatus. (商標) The esters and 1.1 equivalents of vanillylamine were heated at 80°C in 20 mL of t-BuOH. After 20 hours, NMR analysis showed that the ester conversion was >99%.

[0163] The results show that while esters can be used, the yields are lower compared to previous examples 14, 15, and 16. Since methyl esters are prepared from the corresponding acids, an additional process step is required. Furthermore, the upscaling process is cumbersome. Additionally, solvent recycling is difficult, which is important for reducing process costs and environmental impact in large-scale production.

[0164] Example 22: Preparation of capsaicinoids in a neat state (without solvent). The experimental results are shown in Table 5.

[0165] Table 5. Preparation of capsaicinoids in a neat state. [Table 6] * Under vacuum.

[0166] The results show that using pressure reduction reduces process yield (Entry 1).

[0167] Example 23: Preparation of capsaicin without dehydration using catalytic lipase.

[0168] Vanillylamine (1 mmol), 8-methyl-6-nonenic acid (1 mmol), and Novozyme 435 (商標) (45 mg) was stirred in toluene (4 mL) and heated at 80°C for 48 hours. 72% conversion was achieved based on NMR analysis.

[0169] Example 24: Preparation of capsaicin using Dean-Stark distillation without catalytic lipase.

[0170] Using a Dean-Stark trap, the generated water was collected, and vanillylamine (1 mmol) and 8-methyl-6-nonenic acid (1 mmol) were refluxed in toluene (4 mL) in a bath of oil at 115°C for 20 hours. A 19% conversion was achieved based on NMR analysis.

[0171] Example 25: Preparation of capsaicin using acid chlorides as acyl donors [ka] In a 1 L flask, 47.17 g of 8-methyl-6-nonenic acid was dissolved in 400 mL of anhydrous Et2O. 30.1 mL of SOCl2 (equivalent to 1.5) was dissolved in 100 mL of anhydrous Et2O and slowly added to the acid solution. The resulting solution was refluxed for 3 hours, after which excess SOCl2 and solvent were removed under reduced pressure. The resulting acid chloride was then dissolved in 200 mL of anhydrous Et2O. The acid chloride solution was slowly added over 2 hours to 84.7 g of vanillylamine slurry (2 equivalents) in 400 mL of anhydrous Et2O. After the addition, reflux was continued for 2 hours. The mixture was cooled in an ice bath, and the precipitate was filtered. The organic filtrate was continuously washed with 1 M HCl (50 mL x 2), water (50 mL x 2), and brine (50 mL). After drying with anhydrous Na2SO4, the solvent was removed under vacuum. 54.3 g of capsaicin (yield 64.2%) was obtained.

[0172] Preparation of other amides by a combination of enzyme catalysis and Dean-Stark distillation.

[0173] Preparation of R)-2-methoxy-N-(1-phenylethyl)acetamide [ka] Example 26. In a Dean-Stark trap, the generated water was collected and 1-phenylethane-1-amine (1 mmol), ethyl 2-methoxyethyl acetate (2 mmol), and Novozyme 435 of the bead were added. (商標) (45 mg) was refluxed in diisopropyl ether (30 mL) in an oil bath at 90°C for 10 hours. After treatment, (R)-2-methoxy-N-(1-phenylethyl)acetamide was obtained in 85% yield and 8% ee.

[0174] Example 27. In a Dean-Stark trap, the generated water was collected and 1-phenylethane-1-amine (1 mmol), ethyl 2-methoxyethyl acetate (2 mmol), and novozyme of the bead. (商標) 435 (45 mg) was refluxed in diisopropyl ether (30 mL) in an oil bath at 90°C for 3 hours. After treatment, (R)-2-methoxy-N-(1-phenylethyl)acetamide was obtained in 75% yield and 55% ee.

[0175] Example 28. In a Dean-Stark trap, the generated water was collected and 1-phenylethane-1-amine (1 mmol), ethyl 2-methoxyethyl acetate (2 mmol), and Novozyme 435 of the bead were added. (商標) (45 mg) was refluxed in diisopropyl ether (30 mL) in an oil bath at 90°C for 1 hour. After treatment, (R)-2-methoxy-N-(1-phenylethyl)acetamide was obtained in 48% yield and 97% ee.

[0176] Example 29. Preparation of R)-2-methoxy-N-(1-(4-methoxyphenyl)ethyl)acetamide. [ka] In the Dean Stark trap, the generated water was collected and 1-(4-methoxyphenyl)ethane-1-amine (1 mmol), 2-methoxyethyl acetate (2 mmol), and Novozyme 435 of the bead were added. (商標) (45 mg) was refluxed in diisopropyl ether (30 mL) in an oil bath at 90°C for 0.83 hours. After treatment, R)-2-methoxy-N-(1-(4-methoxyphenyl)ethyl)acetamide was obtained in 44% yield and 97% ee.

[0177] Example 30. Preparation of N-phenethylnonanamide. [ka] In the Dean Stark trap, the generated water was collected and 2-phenylethane-1-amine (1 mmol), nonanoic acid (1.05 mmol), and Novozyme 435 of the bead were added. (商標) (45 mg) was refluxed in diisopropyl ether (30 mL) in a bath of oil at 90°C for 10 hours. After treatment, N-phenethylnonanamide was obtained in 98% yield.

[0178] Example 31. Preparation of N-phenethyl stearamide. [ka] In the Dean Stark trap, the generated water was collected and 2-phenylethane-1-amine (1 mmol), stearic acid (1.05 mmol), and Novozyme 435 of the bead were added. (商標) (45 mg) was refluxed in diisopropyl ether (30 mL) in a bath of oil at 90°C for 10 hours. After treatment, N-phenethyl stearamide was obtained in 98% yield.

[0179] The present invention may be modified and altered within the scope of the hereafter disclosed embodiments, without being limited to those embodiments. The following items will also be disclosed. [Item 1] A process for enzymatically synthesizing an amide of formula III from an amine of formula I and a compound of formula II, [C29] JPEG0007855817000035.jpg16117 R in the formula 1 C 1-12 Alkyl, C 1-12 Alkenil, C 1-12 Alkinyl, C 1-12 Alkoxy, C 1-12 Alkyl-OC 1-12 Alkyl, C 1-12 Alkyl-OC(O)-C 1-12 Alkyl, C 1-12 Alkyl-NH-C 1-12 Alkyl, C 1-12 Alkyl-NHC(O)-C 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group including alkyl groups, R 1 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Amine oxyalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group including alkoxys. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. R in the formula 2 is hydrogen, C 1-30 Alkyl, C 1-30 Alkenil, C 1-30 Alkinyl, C 1-30 Alkoxy, C 1-30 Alkyl-OC 1-12 Alkyl, C 1-30 Alkyl-OC(O)-C 1-12 Alkyl, C 1-30 Alkyl-NH-C 1-12 Alkyl, C 1-30 Alkyl-NHC(O)-C 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group including alkyl groups, R 2 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group including alkoxys. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. R in the formula 3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, C 1-6 Alkyl-NH-C 1-6 Alkyl, C 1-6 Alkyl-NHC(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group including alkyl groups, R 3 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Amine oxyalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group including alkoxys. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. In the formula, R is either a bond or C 1-6 It is alkyl, The process involves fixing the lipase in a rotating bed reactor or a spin-fixed bed reactor, and using a Dean-Stark apparatus for dehydration. [Item 2] R in the formula 1 is C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkoxy, C 1-6 Alkyl-OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 6-7 Ariel, C 3-6 Cycloalkyl-C 1-3 Alkyl, C 3-6 Cycloalkenyl-C 1-3 Alkyl and C 5-7 Aryl-C 1-3 Selected from the group including alkyl groups, R 1 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, and C. 1-3 Hydroxyalkyl, C 1-3 Haloalkyl and C 1-3 It may be substituted with one or more substituents selected from the group including alkoxys. R in the formula 2 is hydrogen, C5-15 Alkyl, C 5-15 Alkenil, C 5-15 Alkoxy, C 5-15 Alkyl-OC 1-6 Alkyl and C 5-15 Alkyl-OC(O)-C 1-6 Selected from the group including alkyl groups, R 2 It may be optionally substituted with one or more substituents selected from the group including hydrogen, hydroxyl, oxy, halogen, and carboxyl. R in the formula 3 is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkyl-OC 1-3 Selected from the group including alkyl groups, In the formula, R is either a bond or C 1-3 The alkyl process described in item 1. [Item 3] R in the formula 1 is C 5-7 Aryl-C 1-3 Alkyl, R 1 Hydrogen, hydroxyl, and C are optional. 1-3 It may be substituted with one or more substituents selected from the group including alkoxys. R in the formula 2 C 5-16 Alkyl and C 5-15 Selected from the group containing alkenils, R in the formula 3 is hydrogen, methyl, or ethyl. In the formula, R is a combination, as described in item 1. [Item 4] The compound of formula III is the compound of formula IV,

[30] JPEG0007855817000036.jpg1221 IV In the formula, n is either 1 or 2. R in the formula 2 is hydrogen, C 3-30 Alkyl, C 3-30 Alkenil, C 3-30 Alkinyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Selected from the group containing aryls, R 2 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 Alkoxy and C 5-12 It may be substituted with one or more substituents selected from the group including aryls. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. R in the formula 4 or R 5 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl and C 5-12 Selected from the group containing aryls, R 4 or R 5 The following are optional: hydroxy, oxy, halogen, carboxy, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Amine oxyalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group including alkoxys. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. R in the formula 6 These are hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, and C. 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Selected from the group containing aryls, R 6 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Amine oxyalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group including alkoxys. The process according to item 1, wherein one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms in the formula may be substituted with one or more heteroatoms selected from O, N, or S. [Item 5] The compound of formula III is the compound of formula IV,

[31] JPEG0007855817000037.jpg1221 IV In the formula, n is either 1 or 2. R in the formula 2 C 3-18 Alkyl and C 3-18 Selected from the group containing alkenils, R in the formula 4 or R 5 is hydrogen, C 1-6 Selected from the group including alkyl groups, R 6 The process described in item 4, where hydrogen is used. [Item 6] The compound of formula III is the compound of formula IV,

[32] JPEG0007855817000038.jpg1221 IV In the formula, n is either 1 or 2. R in the formula 2 C 5-16 Alkyl and C 5-15 Selected from the group containing alkenils, R in the formula 4 or R 5 is hydrogen, C 1-3 Selected from the group including alkyl groups, R 6 The process described in item 4, where hydrogen is used. [Item 7] To enzymatically synthesize the amide of formula III from the amine of formula I and the compound of formula IIa,

[33] JPEG0007855817000039.jpg14117 R in the formula 1 C 1-12 Alkyl, C 1-12 Alkenil, C 1-12 Alkinyl, C 1-12 Alkoxy, C 1-12 Alkyl-OC 1-12 Alkyl, C 1-12 Alkyl-OC(O)-C 1-12 Alkyl, C 1-12 Alkyl-NH-C 1-12 Alkyl, C 1-12 Alkyl-NHC(O)-C 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group including alkyl groups, R 1 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Aminexylalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group including alkoxys. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. R in the formula 2 is hydrogen, C 1-30 Alkyl, C 1-30 Alkenil, C 1-30 Alkinyl, C 1-30 Alkoxy, C 1-30 Alkyl-OC 1-12 Alkyl, C 1-30 Alkyl-OC(O)-C 1-12 Alkyl, C 1-30 Alkyl-NH-C 1-12 Alkyl, C 1-30 Alkyl-NHC(O)-C 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group including alkyl groups, R 2 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Aminexylalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group including alkoxys. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. R in the formula 3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, C 1-6 Alkyl-NH-C 1-6 Alkyl, C 1-6 Alkyl-NHC(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and C 5-12 Ariel, C 3-12 Cycloalkyl-C 1-6 Alkyl, C 3-12 Cycloalkenyl-C 1-6 Alkyl and C 5-12 Aryl-C 1-6 Selected from the group including alkyl groups, R 3 The following are optional: hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Aminexylalkyl, C 1-6 Alkylamide, C 1-6 Carboxyalkyl, C 1-6 Sulfuralkyl, C 1-6 Alkyl sulfides and C 1-6 It may be substituted with one or more substituents selected from the group including alkoxys. In the formula, one or more carbon atoms among cycloalkyl, cycloalkenyl, or aryl atoms may be substituted with one or more heteroatoms selected from O, N, or S. The process described in item 1, wherein the lipase is fixed in a rotating bed reactor or a spin-fixed bed reactor, and a Dean-Stark apparatus is used for dehydration. [Item 8] R in the formula 1 is C 5-7 Aryl-C 1-3 Alkyl, R 1 Hydrogen, hydroxyl, and C are optional. 1-3 It may be substituted with one or more substituents selected from the group including alkoxys. R in the formula 2 is C 5-15 Alkyl and C 5-15 Selected from the group containing alkenils, R in the formula 3 is hydrogen, methyl, or ethyl. The process described in item 7. [Item 9] Either no solvent is used, or the solvent is methyl tert-butyl ether, diisopropyl ether, C 1-6 Alkyl-OC 1-6 Alkyl ethers, hexane and other C 5-10 Alkanes, cyclohexane and other C 5-10 Cycloalkanes, benzene, toluene, xylene, tert-butanol, tert-amyl alcohol, and other bulky secondary or tertiary C compounds. 5-10 The process according to any one of items 1 to 8, wherein the organic solvent is selected from the group comprising alcohols and any esters thereof or mixtures thereof. [Item 10] The process according to item 1, wherein no solvent is used, or the solvent is an organic solvent selected from the group including diisopropyl ether, cyclohexane, toluene, or tert-butanol, or mixtures thereof. [Item 11] The process according to item 1, wherein the lipase is selected from the group comprising Candida antarcticalipase A, Candida antarcticalipase B, cross-linked subtilisin A protease, porcine pancreatic lipase, Candida cylindracea lipase, Rhizopus arghiz, Penicillium cyclopium, Mucor miehei, Thermomyces lanuginosa lipase, Candida rugosa lipase, and Pseudomonas lipoprotein lipase. [Item 12] The process described in item 1, wherein the lipase is Candida antarcticalipase. [Item 13] The process described in item 1, wherein the process temperature is between room temperature and 150°C, and the pressure is between 0.900 and 0.200 MPa, or approximately 0.1 MPa. [Item 14] The process according to item 1, wherein the rotating bed reactor is loaded with 10 to 75 wt% of the lipase. [Item 15] In the compound of formula II, R in the formula 2 is C 6-18 Alkyl or C 6-18 Alkenyls, which can be linear or branched, are prepared by the following steps:

[34] JPEG0007855817000040.jpg88164 Step A-1: ​​The reaction is carried out using no solvent or an organic solvent. Step B-1, the solvent is an aprotic organic solvent. Step B-1, the base is sodium or potassium alkoxide. Optionally, isomerization step C-1 occurs, where the catalyst is HNO 2 HNO 3 , and HNO 2 or HNO 3 NaNO can be produced 2 / HNO 3 , NaNO 2 / NaNO 3 / H 2 SO 4 Selected from a group that includes combinations of and Hydrogenation step D-1, where the catalyst is a heterogeneous hydrogenation catalyst and the hydrogen source is hydrogen gas, is the process described in item 1. [Item 16] The organic solvent in step A-1 is ethyl acetate. The aprotic organic solvent in step B-1 is selected from the group including 2-methyltetrahydrofuran, tetrahydrofuran, and toluene. The sodium or potassium alkoxide base in step B-1 is selected from the group including NaH, KH, t-BuOK, and t-BuONa. The heterogeneous hydrogenation catalyst in hydrogenation step D-1 consists of Pd / C and Pd / Al. 2 O 3 A process described in item 15, selected from the group including the following. [Item 17] In the compound of formula II, R in the formula 2 It is 8-methylnonanyl, which is prepared by the following steps:

[35] JPEG0007855817000041.jpg78170 Step A-2: The reaction is carried out without a solvent or using any organic solvent, and the catalyst is selected from the group including amines and inorganic bases. Step B-2: The reaction is carried out using no solvent or an organic solvent, and the catalyst is an acid. In stage C-2, the catalyst is a heterogeneous hydrogenation catalyst, and the hydrogen source is hydrogen gas. In step D-2, the oxidizing agent is a peroxide, the catalyst is lipase, and Step E-2, the reaction medium is an acidic solvent, and Stage F-2, the catalyst is a heterogeneous hydrogenation catalyst and the hydrogen source is hydrogen gas, as described in item 1. [Item 18] The organic solvent in step A-2 is selected from the group including toluene, and the catalyst is selected from the group including pyrrolidine and its corresponding salt, NaOH and KOH. The organic solvent in step B-2 is selected from the group including toluene, and the acid is selected from the group including p-TsOH, sulfuric acid, and Amberlist-15. The catalyst in step C-2 is Pd / C, Pd / Al 2 O 3 Selected from the group including, The oxidizing agent in step D-2 is H 2 O 2 Selected from the group including aqueous solutions and peracids, the lipase is selected from the group including Candida antarcticalipase A, Candida antarcticalipase B, cross-linked subtilisin A protease, porcine pancreatic lipase, Candida cylindracea lipase, Rhizopus arghiz, Penicillium cyclopium, Mucor miehei, Thermomyces lanuginosus lipase, Candida rugosa lipase, and Pseudomonas lipoprotein lipase. The reaction medium in step E-2 is selected from the group including aqueous sulfuric acid solution. The catalyst in step F-2 is Pd / C, Pd / Al 2 O 3 Pd / Molecular Sieve, Pt / C, Pt / Al 2 O 3 The process described in item 17, selected from the group including Pt / molecular sieves. [Item 19] The process described in item 1 for large-scale production (>1 kg) of the compound of formula III.

Claims

1. A process for enzymatically synthesizing an amide of formula III from an amine of formula I and a compound of formula II, 【Chemistry 29】 In the formula R １ C ５－１２ Aryl and C ５－１２ Aryl-C １－６ Selected from the group including alkyl groups, R １ The following are optional: hydrogen, hydroxyl, and C １－６ It may be substituted with one or more substituents selected from the group including alkoxys. where R ２ is selected from the group consisting of hydrogen, C １－３０ alkyl, C １－３０ alkenyl, C １－３０ alkoxy, In the formula R ３ is hydrogen and C １－６ Selected from the group including alkyl groups, In the formula, R is either a bond or C １－６ It is alkyl, The process involves fixing the lipase in a rotating bed reactor or a spin-fixed bed reactor, and using a Dean-Stark apparatus for dehydration.

2. In the formula R １ is C ６－７ Aryl and C ５－７ Aryl-C １－３ Selected from the group including alkyl groups, R １ The elements are optionally hydrogen, hydroxyl, and C. １－３ It may be substituted with one or more substituents selected from the group including alkoxys. In the formula R ２ is hydrogen, C ５－１５ Alkyl, C ５－１５ Alkenil, C ５－１５ Alkoxy and C ５－１５ Alkyl-O-C １－６ Selected from the group including alkyl groups, In the formula R ３ is hydrogen and C １－３ Selected from the group including alkyl groups, In the formula, R is either a bond or C １－３ The process according to claim 1, wherein the alkyl group is involved.

3. In the formula R １ is C ５－７ Aryl-C １－３ Alkyl, R １ Hydrogen, hydroxyl, and C are optional. １－３ It may be substituted with one or more substituents selected from the group including alkoxys. In the formula R ２ C ５－１６ Alkyl and C ５－１５ Selected from the group containing alkenils, In the formula R ３ is hydrogen, methyl, or ethyl. The process according to claim 1, wherein R is a bond.

4. The compound of formula III is the compound of formula IV, 【Transformation 30】 IV In the formula, n is either 1 or 2. In the formula R ２ is hydrogen, C ３－３０ Alkyl and C ３－３０ Selected from the group containing alkenils, In the formula R ４ or R ５ is hydrogen and C １－６ Selected from the group including alkyl groups, In the formula R ６ These are hydrogen, hydroxyl, oxy, halogen, carboxyl, amine, amide, and C. １－１０ Alkyl, C ２－１０ Alkenil, C ２－１０ Alkinyl, C ３－１２ Cycloalkyl, C ３－１２ Cycloalkenyl and C ５－１２ Selected from the group containing aryls, R ６ The elements are optionally hydrogen, hydroxyl, and C. １－６ The process according to claim 1, which can be substituted with one or more substituents selected from the group including alkoxys.

5. The compound of formula III is the compound of formula IV, 【Chemistry 31】 IV In the formula, n is either 1 or 2. In the formula R ２ C ３－１８ Alkyl and C ３－１８ Selected from the group containing alkenils, In the formula R ４ or R ５ is hydrogen, C １－６ Selected from the group including alkyl groups, R ６ The process according to claim 4, wherein is hydrogen.

6. The compound of formula III is the compound of formula IV, 【Chemistry 32】 IV In the formula, n is either 1 or 2. In the formula R ２ C ５－１６ Alkyl and C ５－１５ Selected from the group containing alkenils, In the formula R ４ or R ５ is hydrogen, C １－３ Selected from the group including alkyl groups, R ６ The process according to claim 4, wherein is hydrogen.

7. To enzymatically synthesize the amide of formula III from the amine of formula I and the compound of formula IIa, 【Transformation 33】 In the formula R １ C ５－１２ Aryl and C ５－１２ Aryl-C １－６ Selected from the group including alkyl groups, R １ The following are optional: hydrogen, hydroxyl, and C １－６ It may be substituted with one or more substituents selected from the group including alkoxys. In the formula R ２ is hydrogen, C １－３０ Alkyl, C １－３０ Alkenil, C １－３０ Selected from the group containing alkoxy, In the formula R ３ is hydrogen and C １－６ Selected from the group including alkyl groups, The process according to claim 1, wherein the lipase is fixed in a rotating bed reactor or a spin-fixed bed reactor, and a Dean-Stark apparatus is used for dehydration.

8. In the formula R １ is C ５－７ Aryl-C １－３ Alkyl, R １ Hydrogen, hydroxyl, and C are optional. １－３ It may be substituted with one or more substituents selected from the group including alkoxys. In the formula R ２ is C ５－１５ Alkyl and C ５－１５ It is alkenyl, In the formula R ３ is hydrogen, methyl, or ethyl. The process according to claim 7.

9. Either no solvent is used or the solvent is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, C １－６ alkyl-O-C １－６ alkyl ether, hexane and other C ５－１０ alkanes, cyclohexane and other C ５－１０ cycloalkanes, benzene, toluene, xylene, tert-butanol, tert amyl alcohol, other sterically hindered secondary or tertiary C ５－１０ alcohols and any esters thereof or mixtures thereof, the process according to claim 1.

10. The process according to claim 1, wherein no solvent is used, or the solvent is an organic solvent selected from the group comprising diisopropyl ether, cyclohexane, toluene, or tert-butanol, or mixtures thereof.

11. The process according to claim 1, wherein the lipase is selected from the group comprising Candida antarcticalipase A, Candida antarcticalipase B, cross-linked subtilisin A protease, porcine pancreatic lipase, Candida cylindracea lipase, Rhizopus arghiz, Penicillium cyclopium, Mucormiehei, Thermomyces lanuginosa lipase, Candida rugosa lipase, and Pseudomonas lipoprotein lipase.

12. The process according to claim 1, wherein the lipase is Candida antarcticalipase.

13. The process according to claim 1, wherein the process temperature is between room temperature and 150°C, and the pressure is between 0.09 and 0.200 MPa, or about 0.1 MPa.

14. The process according to claim 1, wherein the process is carried out at atmospheric pressure and at a temperature below 100°C.

15. The process according to claim 1, wherein the rotating bed reactor is loaded with 10 to 75 wt% of the lipase.

16. In the compound of formula II, R in the formula ２ is C ６－１８ Alkyl or C ６－１８ Alkenyls, which can be linear or branched, are prepared by the following steps: 【Transformation 34】 Step A-1: ​​Here the reaction is carried out using no solvent or an organic solvent. Step B-1, here the solvent is an aprotic organic solvent. Step B-1, here the base is sodium or potassium alkoxide. Optionally, the isomerization step C-1, where the catalyst is HNO ２ , HNO ３ , and HNO ２ or HNO ３ and can generate NaNO ２ / HNO ３ , NaNO ２ / NaNO ３ / H ２ SO ４ selected from the group consisting of combinations of, and The process according to claim 1, wherein the hydrogenation step D-1 is a heterogeneous hydrogenation catalyst and the hydrogen source is hydrogen gas.

17. The organic solvent in step A-1 is ethyl acetate. The aprotic organic solvent in step B-1 is selected from the group including 2-methyltetrahydrofuran, tetrahydrofuran, and toluene. Here, the sodium or potassium alkoxide base in step B-1 is selected from the group including NaH, KH, t-BuOK, and t-BuONa. The heterogeneous hydrogenation catalyst in hydrogenation step D-1 is Pd / C and Pd / Al ２ O ３ The process according to claim 16, selected from the group including the following.

18. In the compound of formula II, R in the formula ２ It is 8-methylnonanyl, which is prepared by the following steps: 【Chemistry 35】 Step A-2: The reaction is carried out without a solvent or using any organic solvent, and the catalyst is selected from the group including amines and inorganic bases. Step B-2: The reaction is carried out using no solvent or an organic solvent, and the catalyst is an acid. In stage C-2, the catalyst is a heterogeneous hydrogenation catalyst, and the hydrogen source is hydrogen gas. Step D-2, the oxidizing agent is a peroxide, the catalyst is lipase, and Step E-2, the reaction medium is an acidic solvent, and The process according to claim 1, in step F-2, the catalyst is a heterogeneous hydrogenation catalyst and the hydrogen source is hydrogen gas.

19. The organic solvent in step A-2 is selected from the group including toluene, and the catalyst is selected from the group including pyrrolidine and its corresponding salt, NaOH and KOH. The organic solvent in step B-2 is selected from the group including toluene, and the acid is selected from the group including p-TsOH, sulfuric acid, and amberlist-15. The catalyst in step C-2 is Pd / C, Pd / Al ２ O ３ Selected from the group including, The oxidizing agent in step D-2 is H ２ O ２ The group is selected from aqueous solutions and peracids, and the lipase is selected from the group including Candida antarcticalipase A, Candida antarcticalipase B, cross-linked subtilisin A protease, porcine pancreatic lipase, Candida cylindracea lipase, Rhizopus arghiz, Penicillium cyclopium, Mucormiehei, Thermomyces lanuginosa lipase, Candida rugosa lipase, and Pseudomonas lipoprotein lipase. The reaction medium in step E-2 is selected from the group including aqueous sulfuric acid solution. The catalyst in step F-2 is Pd / C, Pd / Al ２ O ３ Pd / molecular sieve, Pt / C, Pt / Al ２ O ３ The process according to claim 18, selected from the group including, and Pt / molecular sieves.

20. The process according to claim 1 for large-scale production (>1 kg) of the compound of formula III.

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