Method of manufacturing an organic compound

Abstract

A process for preparing homofarnesol (1) is provided, the process comprising the steps of: a) providing homofarnesyl cyanide (2); b) reacting homofarnesyl cyanide (2) to homofarnesic acid (3); and c) reacting homofarnesic acid (3) to homofarnesol (1), wherein the configuration of the double bonds in compounds 1, 2 and 3 is maintained.

Description

[0001] This invention relates to a novel method for preparing high-farnesol, particularly (3E,7E)-high-farnesol. The invention further relates to the use of said high-farnesol as an intermediate in the preparation of fragrance and flavor components.

[0002] background

[0003] Kafarniol is an important intermediate in the production of the popular fragrance ingredient (-)-ambroxan (3a,6,6,9a-tetramethyldodecano[2,1-b]furan). Various methods for its preparation have been described in the literature. For example, it can be prepared via a lengthy process of nerolidinyl (3,7,11-trimethyldodecano-1,6,10-trien-3-ol) via a kafarniol amide (AF Barrero et al., J. Org. Chem. 1996, 61, 2215). Alternatively, kafarniol can be prepared by carbonylating nerolidinyl in the presence of a polar solvent and a palladium halide catalyst (WO92 / 06063). P. Kociensiki et al. (J. Org. Chem. 1989, 54, 1215) describe another method for producing kafarniol, which begins with dihydrofuran and proceeds via kafarniol in five steps. The literature (WO2013 / 156398) also describes the synthesis of high farnesol from geranylacetone via vitiformation, followed by cyclopropane ring-opening and formicooxylation. Those methods are relatively lengthy and costly.

[0004] A compound worth considering as an intermediate for homofarenoic acid is homofarenoic acid. According to the literature, it can be obtained from the corresponding nitrile (G. Lucius, Chem. Ber. 1960, 93, 2663; L. Ahlquist et al., Chemica Scripta 1971, 1, 237; DE 3240054). However, all known routes via the nitrile to date involve hydrolysis under reflux with KOH, EtOH, and H₂O to the intermediate acid, resulting in an EZ equilibrium of the C₃ double bond. This route has been unusable so far in the preparation of homofarenoic acid with a defined double bond configuration.

[0005] Therefore, there is a need to provide new or improved methods for the preparation of high farnesol, while having control over the configuration of the double bonds.

[0006] Overview

[0007] According to a first aspect of the present invention, a method for preparing high farnesol (1) is provided.

[0008]

[0009] The method includes the following steps:

[0010] a) Provide high-farnitrile (2)

[0011]

[0012] b) React perfarnesine (2) to form perfarnesic acid (3).

[0013] and

[0014] c) React perfarnesic acid (3) to perfarnesol (1),

[0015] The configuration of the double bonds in compounds 1, 2 and 3 is preserved.

[0016] According to a second aspect of the invention, high farnesamide (4, also known as high farnesamide) is provided.

[0017]

[0018] According to a third aspect of the present invention, a method for preparing high farnesol (1) is provided.

[0019]

[0020] The method includes the following steps:

[0021] f) Provide high-farnitrile (2)

[0022]

[0023] g) In the presence of a metal catalyst and water, high-farnesyl nitrile (2) is reacted with hydrogenation to form high-farnesol (1).

[0024] The configuration of the double bonds in compounds 1 and 2 is preserved.

[0025] Certain embodiments of any aspect of the present invention may provide one or more of the following advantages:

[0026] ● Retention of double bond configuration;

[0027] ●High-efficiency conversion;

[0028] ● Mild reaction conditions;

[0029] ● Simple and cost-effective reagents;

[0030] ●Avoid waste that is difficult to handle;

[0031] ● Avoid difficult post-processing and purification; and

[0032] ● Avoid using toxic reagents that are difficult to handle.

[0033] Details, embodiments, and preferences relating to any particular aspect or one of the described aspects of the invention will be further described herein and are equally applicable to all aspects of the invention. Unless otherwise stated herein or obviously contradicted by the context, any combination of all possible variations of the embodiments, embodiments, and preferences described herein is included in the invention.

[0034] Detailed description

[0035] This invention is based on the surprising discovery that high-farnesol (1) can be obtained from the corresponding nitrile under conditions that allow the configuration of the double bond to be preserved. High-farnesol (1) is obtained in good yield without EZ isomerization.

[0036] Therefore, the present invention provides a method for preparing high farnesol (1),

[0037]

[0038] The method includes the following steps:

[0039] a) Provide high-farnitrile (2)

[0040]

[0041] b) React perfarnesine (2) to form perfarnesic acid (3).

[0042] and

[0043] c) React perfarnesic acid (3) to perfarnesol (1),

[0044] The configuration of the double bonds in compounds 1, 2 and 3 is preserved.

[0045] By this method, high farnesol (1) can be obtained in good yields without isomerization of the double bond, especially without isomerization of the double bond at C3 near the reaction site of the compound.

[0046] If the configuration of the double bond is not specified for a given compound, then the configuration is either unspecified or refers to a mixture of isomers. For a certain configuration of a compound, the prefixes E- and Z- are used, such as (E,E)-1 or (3E,7E)-1.

[0047] For example, if the perfarnesyl nitrile (2) has a certain double bond configuration, then that configuration will be retained in the resulting perfarnesol (1). If the nitrile is provided as a mixture of double bond isomers, the resulting perfarnesol (1) will be obtained as a mixture of double bond isomers in the appropriate ratio. The method is suitable for obtaining perfarnesol (1) with the desired double bond configuration because the configuration of the double bonds is maintained throughout the entire reaction sequence from the starting material to the final product. The method is suitable for providing perfarnesol (1) with any double bond configuration, particularly (3E,7E)-1. For the preparation of (3E,7E)-1, the starting material and the intermediate compound also have their respective two double bonds in the E,E configuration, namely (E,E)-perfarnesyl nitrile ((E,E)-2) and (E,E)perfarnesic acid ((E,E)-3).

[0048] For example, high-farnesyl nitrile (2) can be prepared according to the methods described in the literature (N. Yamazaki et al., Heterocycles 2008, 75, 285-290; DVPatel et al., Synthetic Communications 1995, 25, 413-421).

[0049] Step b) of the method for preparing perfarnesol (1), namely the reaction of perfarnesyl nitrile (2) to perfarnesic acid (3), can be carried out in one step or in a stepwise manner. The direct conversion can be accomplished, for example, by enzyme-mediated techniques, particularly by using nitrile hydrolases (nitrile aminohydrolases; EC 3.5.5.1) (enzymes suitable for catalyzing the hydrolysis of nitrile to carboxylic acids). The double bond configuration of the substrate is preserved.

[0050] In contrast to the method described above, it is known in the literature to use alkali metal hydroxides as bases in ethanol and water under reflux to provide acids in high yields; however, this causes significant isomerization of the C3 double bond, as demonstrated in Comparative Example 9.

[0051] Step c) of the method for preparing perfarnesol (1), namely the reaction of perfarnesic acid (3) to perfarnesol (1), can be completed in one step or in a stepwise manner. For example, perfarnesic acid (3) can be directly converted by reduction with NaAlH2(OCH2CH2OCH3)2 (CAS No. 22722-98-1, trade name Red-Al or Vitride), or by a combination of AlEt3 deprotonation and Vitride reduction.

[0052] In one embodiment of the invention, the EZ ratio of the double bond at C3 of the high farnesol (1) is greater than 80:20, more particularly greater than 85:15, and still more particularly greater than 90:10.

[0053] In one embodiment of the invention, 3E,7E-hofarnesol ((3E,7E)-1) is present in the isomer mixture at a percentage of 50% or higher, more particularly at 75%, more particularly at 85% or higher, and still more particularly at 90% or higher.

[0054] Therefore, in one embodiment of the present invention, a method for preparing (3E,7E)-high farnesol ((3E,7E)-1) is provided.

[0055] Pure or highly enriched (3E,7E)-hofarnesol ((3E,7E)-1) is of particular interest because, upon cyclization under conditions known in the art, depending on the cyclizing reagent and conditions, it provides a very valuable fragrance component known as ambroxol, which has high amounts of the desired olfactory activity of the 3aR,5aS,9aS,9bR enantiomers or racemic mixtures of 3aRS,5aSR,9aSR,9bRS.

[0056] As described above, step b) of the method for preparing perfarnesol (1), namely the reaction of perfarnesyl nitrile (2) to perfarnesic acid (3), can also be carried out stepwise. The reagents required for stepwise conversion are readily available and relatively inexpensive.

[0057] Therefore, in one embodiment of the present invention, a method for preparing highfarnesol (1) is provided, wherein step b) is carried out in two steps via highfarnesamide (4).

[0058]

[0059] High-farinate nitrile (2) is first converted into high-farinate amide (4), and then into high-farinate acid (3).

[0060] Several methods are available for converting high-farnesyl nitrile (2) into high-farnesyl amide (4). For example, the amide can be obtained by hydrolyzing the nitrile in DMSO with K2CO3 and then oxidizing it with H2O2. This method utilizes relatively simple and cost-effective reagents. Alternatively, metal catalysts for oxidation, particularly transition metal catalysts, can be used. For example, Pt, Rh, or Cu catalysts can be used, such as those represented by Pt(PPh2OH)3, RhCl(PPh3)3, or CuCl2.

[0061] High-farnitramide (4) can be obtained without isomerization of the double bond, especially without isomerization of the double bond at C3 near the reaction site of the compound.

[0062] Kafarniamide (4) is further converted into kafarni acid (3). For example, it can be hydrolyzed in ethanol solution under alkaline conditions.

[0063] Perfarnesic acid (3) can be obtained without isomerization of the double bond, especially without isomerization of the double bond at C3 near the reaction site of the compound.

[0064] In another embodiment of the invention, step b) of the method is carried out in a stepwise manner as a one-pot reaction, for example, metal-catalyzed hydrolysis and subsequent treatment of the generated amide with LiOH.

[0065] In another embodiment of the invention, step b) of the method is an enzymatic hydrolysis by a nitrile hydrolase (nitrile aminohydrolase; EC 3.5.5.1) (an enzyme suitable for catalyzing the hydrolysis of nitrile to carboxylic acid). The double bond configuration of the substrate is maintained.

[0066] As described above, step c) of the method for preparing high-farnesol (1), namely the reaction of high-farnesol (3) to high-farnesol (1), can also be carried out stepwise. By stepwise reaction, the total amount of red aluminum is reduced, thereby reducing costs and the amount of aluminum waste, making post-processing easier.

[0067] Therefore, in one embodiment of the present invention, a method for preparing highfarnesol (1) is provided, wherein step c) is carried out in two steps via highfarnesol ester (5).

[0068]

[0069] R is a C1-C20 alkyl group, preferably methyl or ethyl.

[0070] Kaofarnesic acid (3) is first converted into kaofarnesic acid ester (5), and then into kaofarnesic alcohol (1).

[0071] For example, perfarnesic acid ester (5) can be obtained by esterification of perfarnesic acid (3) under acidic conditions.

[0072] Perfarnesate (5) can be obtained without isomerization of the double bond, especially without isomerization of the double bond at C3 near the reaction site of the compound.

[0073] Perfarnesate (5) is further converted to perfarnesol (1). For example, it can be reduced with aluminum hydroxide. The conversion is carried out without isomerization of the double bond, especially without isomerization of the double bond at C3 near the reaction site of the compound.

[0074] Therefore, in one embodiment of the present invention, a method for preparing high farnesol (1) is provided, the method comprising the following steps:

[0075] a) Provide high-farnitrile nitrile (2);

[0076] b) React kauraniline (2) to kauranilic acid (3); and

[0077] c) React perfarnesic acid (3) to perfarnesol (1),

[0078] The configuration of the double bonds in compounds 1, 2 and 3 is preserved.

[0079] In one embodiment of the present invention, a method for preparing high farnesol (1) is provided, the method comprising the following steps:

[0080] a) Provide high-farnitrile nitrile (2);

[0081] b) React high-farnitrile nitrile (2) to high-farnitramide (4) and further react to high-farnitr acid (3); and

[0082] c) React perfarnesic acid (3) to perfarnesol (1),

[0083] The configurations of the double bonds in compounds 1, 2, 3, and 4 were preserved.

[0084] In one embodiment of the present invention, a method for preparing high farnesol (1) is provided, the method comprising the following steps:

[0085] a) Provide high-farnitrile nitrile (2);

[0086] b) React kauraniline (2) to kauranilic acid (3); and

[0087] c) React perfarnesic acid (3) to perfarnesic ester (5) and further react to form perfarnesic alcohol (1).

[0088] The configurations of the double bonds in compounds 1, 2, 3 and 5 were preserved.

[0089] In one embodiment of the present invention, a method for preparing high farnesol (1) is provided, the method comprising the following steps:

[0090] a) Provide high-farnitrile nitrile (2);

[0091] b) React high-farnitrile nitrile (2) to high-farnitramide (4) and further react to high-farnitr acid (3); and

[0092] c) React perfarnesic acid (3) to perfarnesic ester (5) and further react to form perfarnesic alcohol (1).

[0093] The configurations of the double bonds in compounds 1, 2, 3, 4, and 5 were preserved.

[0094] In another embodiment of the invention, high farnesamide (4) is provided.

[0095]

[0096] High farnesamide (4) can be obtained from farnesyl nitrile (2). It is a useful intermediate in the preparation of high farnesol (1).

[0097] In another embodiment of the invention, the use of kafarniamide (4) as an intermediate in the preparation of kafarniol (1) is provided.

[0098] In another embodiment of the invention, the use of high-farfenamide (4) as an intermediate in the preparation of ambroxol is provided.

[0099] Furthermore, the present invention provides a method for preparing high farnesol (1),

[0100]

[0101] The method includes the following steps:

[0102] f) Provide high-farnitrile (2)

[0103]

[0104] g) In the presence of a metal catalyst and water, high-farnesyl nitrile (2) is reacted with hydrogenation to form high-farnesol (1).

[0105] The configuration of the double bonds in compounds 1 and 2 is preserved.

[0106] By this method, high-farnesyl nitrile (2) can be obtained directly from high-farnesol (1) without the isomerization of the double bond, especially without the isomerization of the double bond at C3 near the reaction site of the compound.

[0107] For example, if the perfarnesyl nitrile (2) has a certain double bond configuration, then that configuration will be retained in the resulting perfarnesol (1). If the nitrile is provided as a mixture of double bond isomers, then the resulting perfarnesol (1) will be obtained as a mixture of double bond isomers with a corresponding ratio. The method is suitable for obtaining perfarnesol (1) with the desired double bond configuration because the configuration of the double bonds is maintained throughout the entire reaction sequence from the starting material to the final product. The method is suitable for providing perfarnesol (1) with any double bond configuration, and in particular it is suitable for providing (3E,7E)-1. For the preparation of (3E,7E)-1, the starting material and the intermediate compound also have their respective two double bonds in the E,E- configuration.

[0108] In one embodiment of the invention, the EZ ratio of the double bond at C3 of the high farnesol (1) is greater than 80:20, more particularly greater than 85:15, and still more particularly greater than 90:10.

[0109] In one embodiment of the invention, 3E,7E-hofarnesol ((3E,7E)-1) is present in the isomer mixture at a percentage of 50% or higher, more particularly at 75%, more particularly at 85% or higher, and still more particularly at 90% or higher.

[0110] In one embodiment of the present invention, a method for preparing (E,E)-high farnesol ((E,E)-1) is provided.

[0111] In one embodiment of the invention, the metal catalyst for hydrogenation in its presence is a transition metal catalyst, such as Fe-, Ru-, Os-, Rh-, or Ir- catalysts, preferably Fe- or Ru- catalysts. For example, the catalyst may be... -Funk catalyst or Ru(II) catalyst.

[0112] In one embodiment of the invention, the hydrogenation reaction is carried out under elevated pressure. For example, the reaction is carried out at a pressure of at least 10 bar, or at least 20 bar, or at least 50 bar, or at least 80 bar or higher.

[0113] In one embodiment of the invention, the hydrogenation reaction is carried out at an elevated temperature. For example, the reaction temperature is between 100°C and 160°C, preferably at 140°C.

[0114] The C3 double bond EZ-ratio of high farnesol (1) prepared from (E,E)-high farnesyl nitrile ((E,E)-2) by the above method is as high as 95:5, which is higher than the EZ-ratio obtained by known methods in the literature, such as the rearrangement of cyclopropane-modified β-farnesene (EZ 80:20, WO 2015059293).

[0115] As described above, high farnesyl nitrile (2) can be prepared according to the methods described in the literature, for example from farnesyl chloride, which in turn can be obtained from farnesene.

[0116] Therefore, in another embodiment of the present invention, a method for preparing the above-mentioned high-farnesol (1) is provided, the method further comprising preparing high-farnesol nitrile (2) from β-farnesene (6) by the following additional steps:

[0117] i) Provide farnesene (6)

[0118]

[0119] ii) React farnesene (6) to farnesylamine (7).

[0120]

[0121] iii) React farnesylamine (7) to farnesyl chloride (8).

[0122]

[0123] iv) React farnesyl chloride (8) to form high farnesyl nitrile (2).

[0124] For the preparation of (E,E)-high farnesyl nitrile ((E,E)-2), the starting material is (β-E)-farnesene ((β-E)-6).

[0125] E,E-farnesyl chloride (E,E-8) can be obtained from β-E-farnesene (β-E-6,(6E)-7,11-dimethyl-3-methylenedodec-1,6,10-triene, CAS No. 18794-84-8), as described in WO2019237005. The resulting E,E-high-farnesyl nitrile (E,E-2) can be further converted into (3E,7E)-high-farnesol ((3E,7E)-1).

[0126] (3E,7E)-hofarnesol ((3E,7E)-4,8,12-trimethyldecadec-3,7,11-trien-1-ol, (3E,7E)-1, disclosed, for example, in US2013 / 0273619A1 or by Kocienski et al., J. Org. Chem. 54(5), 1215-1217, 1989) is of particular interest because, upon cyclization under conditions known in the art, depending on the cyclizing agent and conditions, specific configurations provide highly valuable fragrance components known as ambroxol, having high concentrations of the desired olfactory activity of the 3aR,5aS,9aS,9bR-enantiomers or the corresponding racemic mixtures (3aRS,5aSR,9aSR,9bRS). For example, the cyclization can be carried out by a biocatalytic method using squalene-hopaene cyclase (SHC).

[0127]

[0128] Therefore, in one embodiment of the present invention, a method for preparing ambroxan is provided, the method comprising preparing (3E,7E)-hofarnesol ((3E,7E)-1) according to the above method, and then cyclizing (3E,7E)-hofarnesol ((3E,7E)-1), the cyclization preferably being carried out by using the bacterial enzyme squalene-hopaene cyclase (SHC).

[0129]

[0130] The invention will now be further illustrated by the following non-limiting embodiments. Example

[0131] General:

[0132] GCMS: 50℃ / 2min, 20℃ / min 240℃, 35℃ / min 270℃. Agilent 5975C MSD with HP7890A series GC system. Nonpolar column: BPX5 from SGE, 5% phenyl 95% dimethyl polysiloxane, 0.2mm x 0.25μm x 12m. Carrier gas: Helium. Injector temperature: 230℃. Split ratio 1:50. Flow rate: 1.0ml / min. Transfer line: 250℃. MS-quadrupole: 160℃. MS-source: 230℃. Injection volume 1μL. Ionization mode electron collision (EI) at 70eV.

[0133] GC: 100℃ / 2min, 15℃ / min, 240℃, 240℃ / 5min. Thermal focusing GC. Non-polar column: Agilent Technologies J&W Scientific DB-5 ((5% phenyl)-methylpolysiloxane) 0.32mm x 0.25μm x 30m. Carrier gas: Helium. FID detector, detector temperature 270℃. Injector temperature: 240℃. Split ratio 1:42.3. Pressure 70kPa.

[0134] Both GC methods allow for the determination of the purity and 3-EZ ratio of all compounds; however, due to signal overlap, the 3-EZ ratio of farnesonitrile 2 and perfarnesic acid 3 can be determined by NMR (see below).

[0135] 1 H- and 13 C-NMR: Bruker-DPX-400MHz spectrometer; in CDCl3, at 400MHz ( 1 H) and 100MHz 13 C) Recorded spectrum; δ, in ppm, relative to SiMe4; coupling constant J, in Hz.

[0136] pass 1 H-NMR determination of the 3-EZ ratio of nitronitrile 2:

[0137] a) at δ 3.0 ppm CH2 The integral of the CN signal (2H, E+Z).

[0138] b) Z- at δ 1.75 ppm CH3 The integral of the signal (3H, Z).

[0139] Where (ax 1.5)-b = E-isomer and ((ax 1.5-b) / b = 3-EZ ratio.

[0140] Similarly, through 1 H-NMR determination of the 3-EZ ratio of perfaronic acid 3:

[0141] a) at δ 3.1 ppm CH2 The integral of the CO2H signal (2H, E+Z).

[0142] b) Z- at δ 1.75 ppm CH3 The integral of the signal (3H, Z).

[0143] c) E- at δ 1.65 ppm CH3 The integral of the signal (3H, E).

[0144] Where (ax 1.5)-b=c=E-isomer and ((ax 1.5-b) / b=c / b=3-EZ ratio

[0145] abbreviation:

[0146] CAS (Chemical Abstracts Service) number

[0147] conc. thick

[0148] DMSO (dimethyl sulfoxide)

[0149] EDTA (ethylenediaminetetraacetic acid)

[0150] Et Ethyl

[0151] FC rapid chromatography

[0152] FID Flame Ionization Detector

[0153] GC gas chromatography

[0154] See GC and MS for GCMS.

[0155] Hz Hertz

[0156] M is the molecular weight of a metal.

[0157] Me methyl

[0158] MHz

[0159] MS mass spectrometry, molecular sieve

[0160] MTBE (methyl tert-butyl ether)

[0161] NMR (Nuclear Magnetic Resonance)

[0162] Ph phenyl

[0163] quantification

[0164] rpa Total peak area (GC)

[0165] Example 1. (3E,7E)-4,8,12-trimethyldecadec-3,7,11-trienamide (highfarniform (3E,7E)-4)

[0166] For the synthesis of (E,E)-high farnesonitrile ((E,E)-2), see N. Yamazaki, T. Suzuki, Y. Yoshimura, C. Kibayashi, S. Aoyagi Heterocycles 75, 285-290 (2008) or DVPatel, RJSchmidt Synthetic Communications 25, 413-421 (1995). For the determination of the 3-EZ ratio of 2, see General Information.

[0167] Method A: K₂CO₃ (16.1 g, 116 mmol) was added to a DMSO (240 mL) solution of (E,E)-high farnesonitrile (E,E)-2 (68% purity, 273 g, 0.8 mol, 3-EZ ratio >90:10) under stirring, followed by the addition of 30% H₂O₂ (107 g, 943 mmol) at 25–30 °C. After 1.5 h, 27.3 g, 240 mmol of 30% H₂O₂ was added, followed by two more additions (2 × 27.3 g, 480 mmol) after 2.5 h and 3.5 h. After a total of 5 h, almost quantitative conversion (98%) was detected by GC. Water (300 mL) and tert-butyl methyl ether were added. The phases were separated, and the aqueous layer was extracted with 2 × 300 mL of tert-butyl methyl ether. The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to obtain 286 g of crude amide (3E,7E)-4 with a purity of 74% (GC) and 92% (GCMS). 13 C-NMR analysis showed a 3-EZ ratio >90:10.

[0168] Analytical data for (3E,7E)-4,8,12-trimethyldecadec-3,7,11-trienamide ((3E,7E)-4):

[0169] 1H-NMR (400MHz, CDCl3): δ (ppm) = 6.5 (br, 1H, NH2), 6.0 (br, 1H, NH2), 5.3 (m, 1H ),5.05(2H),2.95(m,2H,CH2C=O),1.95-2.2(8H),1.65(2s,6H),1.55(2s,6H).

[0170] 13 C-NMR (100MHz, CDCl3): δ (ppm) = 174.7 (s), 140.8 (s), 135.5 (s), 131.2 (s), 124.2 (d), 123.7 (d), 116.9(d),39.65(t),39.5(t),35.4(t),26.6(t),26.3(t),25.6(q),17.6(q),16.1(q),16.0(q).

[0171] GCMS: m / z = 249 [M] + (1%), 206(3%), 180(8%), 136(11%), 122(12%), 121(53%), 112(35%), 107(11%), 93(18%), 81(20%), 69(100%), 53(12%), 41(57%).

[0172] Examples 2-4. Preparation of (3E,7E)-4,8,12-trimethyltridecane-3,7,11-trienamide ((3E,7E)-4) from (3E,7E)-4,8,12-trimethyltridecane-3,7,11-trienonitrile ((3E,7E)-2) by alternative method (BD)

[0173] The catalyst Pt(PPh2OH)3 was prepared as described in T. Ghaffar, AW Parkins Journal Molecular Catalysis A: Chemical 160, 249-261 (2000).

[0174] High farnesamide (3E,7E)-4 was prepared from (E,E)-farnesyl nitrile ((E,E)-2) by methods known in other literature, such as method B (using 5 eq acetaldehyde hydroxylamine, 1% RhCl(PPh3)3, toluene, 110 °C, 5 h, 82% conversion (GC), 57% (FC), under conditions described for similar substrates by H.-Y. Lee et al., Org. Lett. 11, 5598, 2009); method C (using 3 eq acetaldehyde hydroxylamine, 1% CuCl2 on MS A4, 40% ww, MeOH, 10 h, 65 °C, quantitative (GC), 65% (FC), under conditions described by A. Kiss, Z. Hell, Tet. Lett. 52,6021,2011 (under conditions described for similar substrates); and Method D (using 2% Pt(PPh2OH)3, EtOH, H2O, 80°C, 28h (quantitative), 66% (crude), under conditions described for similar substrates in X. Jiang, Groningen Research Database, 2004). The analytical data for amide (3E,7E)-4 purified by FC were identical to those obtained from the crude amide (3E,7E)-4 prepared in Example 1, and according to 13 C-NMR analysis yielded amide (3E,7E)-4 by all methods at a 3-EZ ratio >90:10.

[0175] Example 5. Preparation of (3E,7E)-4,8,12-trimethyltridecano-3,7,11-trienoic acid (perfarnesic acid ((3E,7E)-3)) from (3E,7E)-4,8,12-trimethyltridecano-3,7,11-trienoamide ((3E,7E)-4).

[0176] Lithium hydroxide (1.3 g, 54 mol) was added to amide (3E,7E)-4 (10 g, 36 mmol) in ethanol (90 mL) and water (30 mL). Quantitative conversion was detected by GC after reflux for 25 h. The reaction mixture was treated with water and tert-butyl methyl ether at ambient temperature. After phase separation, the organic phase was washed with water. The combined aqueous layers were acidified with 2 M HCl and extracted with tert-butyl methyl ether. The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure to give 0.915 g (94%) of perfarnaiseic acid (3E,7E)-3, 3-EZ ratio 93:7.

[0177] The analytical data are identical to those described in the literature for (3E,7E)-4,8,12-trimethyltridecano-3,7,11-trienoic acid ((3E,7E)-3), such as the NMR data in J. Org. Chem. 79, 8850 (2014) by H. Yamamoto et al. and the GCMS data in Tetrahedron Asymmetry 20, 1637 (2009) by SVBhat.

[0178] Example 6. Preparation of (E,E)-perfarnesic acid ((E,E)-3) from (E,E)-perfarnesic nitrile ((E,E)-2)

[0179] The preparation of the catalyst Pt(PMe2OH)3 is described by T. Ghaffar and A.W. Parkins in Journal Molecular Catalysis A: Chemical 160, 249-261 (2000).

[0180] (E,E)-perfarnesyl nitrile ((E,E)-2) (1 g, 4.3 mmol) and Pt(PMe2OH)3 (19 mg, 0.04 mmol) were stirred in ethanol (4 ml) and water (2 ml) at 80 °C. After 8 h at this temperature, LiOH (1.6 g, 6.5 mmol) was added at 60 °C, and the mixture was stirred again at 80 °C for 20 h. Complete conversion was detected by GC, and the mixture was treated with water and tert-butyl methyl ether, followed by phase separation. The organic phase was washed with water, the combined aqueous layer was acidified with 2 M HCl, and extracted with tert-butyl methyl ether. The combined organic phase was dried over MgSO4, filtered, and evaporated under reduced pressure to give 0.7 g (61%) of perfarnesic acid 3,3-EZ ratio 92:8. The analytical data were the same as those described in the reference given in Example 5.

[0181] Example 7. Preparation of (E,E)-perfarnesic acid ((E,E)-3) from (E,E)-perfarnesic nitrile ((E,E)-2) using nitrile hydrolase

[0182] The ability of nitrile hydrolase (nitrile hydrolase screening kit from Codexis Inc., USA) to catalyze the hydrolysis of E,E-nitrile 2 to perfarnesic acid E,E-3 was tested.

[0183] The reaction mixture (4.6 mL total volume) contained 2 mL of reaction buffer (50 mM potassium phosphate, pH 7.5, supplemented with 2 mM dithiothreitol and 1 mM EDTA) and 4 mg E,E-high farnesonitrile 2, supplemented with 4% DMSO stock solution. The reaction was initiated by adding 4 mg of nitrile hydrolase. The reaction was incubated at 30 °C with constant stirring (200 rpm, orbital oscillation). The reaction was carried out for 20 h, and samples were taken over time for conversion analysis (GC-FID). For this purpose, 0.2 mL of the reaction mixture was extracted into 0.7 mL of tert-butyl methyl ether (MTBE). 1 μl of solvent phase was injected into a 30 m x 0.32 mm x 0.25 μm Zebron ZB-5 column (split ratio 3) at a flow rate of 4 ml / min H2. The oven temperature gradient was 100 °C, 15 °C / min to 200 °C, 120 °C / min to 240 °C, and 240 °C for 4 min (inlet temperature: 200 °C, detector temperature: 300 °C).

[0184] E,E-pofarnesyl nitrile 2 was hydrolyzed to E,E-pofarnesic acid 3 using four enzymes (NIT-103, NIT-104, NIT-P1-122, and NIT-P1-121). As determined by GC-FID analysis (under unoptimized conditions), approximately 10-55% conversion was observed after a 20-hour reaction time. GC-MS analysis confirmed that pofarnesic acid 3 is the product of the hydrolysis of pofarnesyl nitrile by the tested nitrile hydrolases.

[0185] Example 8. Preparation of (E,E)-perfarnesic acid ((E,E)-3) from (E,E)-perfarnesic nitrile ((E,E)-2) by enzymatic hydrolysis

[0186] The preparative hydrolysis of high-farnesyl nitrile was performed in a 750 ml Infors HT reactor (400 ml volume): DMSO (20 ml) and E,E-high-farnesyl nitrile 2 (1.6 g, 6.9 mmol) were added to 0.1 M potassium phosphate buffer (380 ml) at pH 7.0. The reaction was initiated by adding NIT-P1-121 nitrile hydrolase (0.8 g) from Codexis and incubated at 30 °C with constant stirring (800 rpm).

[0187] The reaction was sampled over time to analyze the conversion (GC-FID). For this purpose, 0.2 mL of the reactant was extracted into 0.7 mL of tert-butyl methyl ether. 1 μL of the solvent phase was injected into a 30 m x 0.32 mm x 0.25 μm Zebron ZB-5 column (split ratio 3) at a flow rate of 4 mL / min H₂ and a temperature gradient of 100 °C, 15 °C / min to 200 °C, 120 °C / min to 240 °C, and 240 °C for 4 min (inlet temperature: 200 °C, detector temperature: 300 °C). The high farnesonitrile conversion calculated at the end of the reaction was 98.6% (GC-FID).

[0188] Post-treatment: The reaction mixture was adjusted to pH 9 by adding aqueous NaOH and extracted with tert-butyl methyl ether (3x). The organic layer from this extraction was discarded. The aqueous layer was acidified to pH 3 with 2M HCl. The resulting emulsion was extracted with tert-butyl methyl ether (3x). These organic layers were combined and washed with water. The organic layers were dried, filtered, and evaporated to give 1.95 g of crude product containing 73% E,E-perfarnesic acid 3 (yield 61%), according to quantitative... 1 ¹H-NMR analysis showed a 3-EZ ratio >10:1. The analytical data are identical to those described in the reference given in Example 5 for this compound.

[0189] Example 9 (Comparative). Preparation of (3-EZ,7-E)-perfarnesic acid (3) from (E,E)-perfarnesic nitrile 2.

[0190] As described in DE3240054 (Consortium 1984), a mixture of farnesonitrile (82% purity, 6.5 g, 22.9 mmol, 3-EZ ratio >90:10), KOH (3.8 g, 57.8 mmol), ethanol (27 ml), and water (2.6 ml) was heated to reflux. After 5 h, quantitative conversion was detected by GC. Ethanol was removed under reduced pressure, and the aqueous residue was diluted with water (150 ml). The aqueous solution was extracted with diethyl ether and acidified with 20% H2SO4. The diethyl ether extract was discarded. Free acid (3) was extracted from the aqueous phase with diethyl ether. The diethyl ether extracts of these acids 3 were washed with water, dried over Na2SO4, filtered, and evaporated to give 5.6 g of crude acid 3 with a 3-EZ ratio of 62:38. The analytical data for the 3-E-isomer were the same as those for the compound described in the reference of Example 5.

[0191] Table 1 describes the results for different inorganic bases under the same reaction conditions as KOH (above). Yamazaki et al. (Heterocycles 75, 285-290, 2008) noted the use of NaOH (entry 2) instead of KOH. The equilibrium of the 3,4-double bond occurred more or less in all tested M(I)OH bases.

[0192] Table 1:

[0193]

[0194] Example 10. Preparation of (E,E)-perfarnesol ((E,E)-1) from (E,E)-perfarnesic acid ((E,E)-3) by reduction with red aluminum.

[0195] At 20–30 °C, an anhydrous toluene (15 mL) solution of E,E-perfarnesic acid ((E,E)-3, 5 g, 18.3 mmol) was added dropwise to a 70% toluene solution of red aluminum (16 g, 55 mmol). Another 5 g (17 mmol) of red aluminum was added to achieve complete conversion. The reaction mixture was poured onto 2 M HCl and extracted three times with tert-butyl methyl ether. The combined organic layers were washed with saturated NaCl, dried over MgSO4, filtered, and evaporated to give 4 g (91%) of crude (E,E)-perfarnesic alcohol 1,3-EZ > 93:7. Analytical data for (E,E)-perfarnesic alcohol ((E,E)-1) were consistent with those in the literature, see, for example, P. Kocienski, S. Wadman, J. Org. Chem. 54, 1215 (1989).

[0196] Example 11. Preparation of (E,E)-kaofarnesol ((E,E)-1) from (E,E)-kaofarnesic acid ((E,E)-3) by AlEt3 deprotonation and red aluminum reduction.

[0197] At 20-30°C, a solution of (E,E)-perfarnesic acid ((E,E)-3) (10 g, 40 mmol) in anhydrous toluene (100 mL) was added dropwise to a 1 M triethylaluminum solution in hexane (13 mL, 13 mmol). The reaction mixture was heated to 70°C for 1 h. At 25-30°C, a 60% toluene solution of red aluminum (13.5 g, 40 mmol) was added. After 2 h, complete conversion of acid 3 was detected by GC. The mixture was poured into 2 M HCl, and the phases were separated. The aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give 10 g (quantitative) of crude (E,E)-perfarnesol ((E,E)-1), with a 3-EZ ratio >93:7 according to GCMS. The analytical data for (E,E)-1 were consistent with those in Example 10.

[0198] Example 12. Preparation of (E,E)-methyl perfarnesate ((E,E)-5a) from (E,E)-perfarnesic acid ((E,E)-3).

[0199] A methanol solution of concentrated H₂SO₄ (0.82 g, 8 mmol) in 17 mL was added to a methanol solution of (E,E)-perfarnesic acid ((E,E)-3, 10 g, 40 mmol) in 50 mL with stirring at room temperature. The brown solution was heated to reflux, and complete conversion was detected by GC after 40 min. After cooling to room temperature, the mixture was poured onto ice-cooled 15% K₂CO₃. Water and tert-butyl methyl ether were added, and the phases were separated. The aqueous layer was extracted with tert-butyl methyl ether, and the combined organic layers were washed with brine and water, dried over MgSO₄, filtered, and the solvent was removed under reduced pressure to give 10.5 g of crude methyl perfarnesic acid 5a with a 3-EZ ratio of 96:4 and a purity of 83% (according to GCMS). The IR and mass spectra of 5a were consistent with those described by L. Ahlquist et al. (Chemica Scripta 1, 237-246, 1971).

[0200] 5a 1 H-NMR (400MHz, CDCl3): δ (ppm) = 5.3.5 (m, 1H), 5.1 (2H), 3.7 (s, 3H), 3.1 (d, 2H), 2.0-2.2 (4H), 1.68 (s,3H),1.6(2s,6H),1.3-1.7(4H),1.1-1.2(2H),0.9(d,2H),1.68(s,3H),1.64(s,3H),1.4(s,3H).

[0201] 5a 13 C-NMR (100MHz, CDCl3): δ (ppm) = 172.9 (s), 139.1 (s), 135.2 (s), 131.2 (s), 124.3 (d), 123.8 (d), 115. 6(d),51.7(q),39.7(t),39.5(t),33.6(t),26.7(t),26.2(t),25.7(q),17.7(q),16.3(q),15.8(q).

[0202] GCMS(t R 9.62,3-Z-isomer, 4%. t R 9.72,3-E-isomer, 96%): m / z = 264 [M] +(1%), 221(2%), 180(2%), 153(4%), 136(20%), 121(32%), 85(13%), 81(27%), 55(9%), 53(10%), 41(43%).

[0203] Example 13. Preparation of (E,E)-higherfarnesol ((E,E)-1) from (E,E)-higherfarnesol ((E,E-5a)) by reduction with red aluminum.

[0204] For the synthesis of (E,E)-methyl perfarnesate ((E,E)-5a), see E. Dunach et al., Electrochimica Acta 56, 4384 (2011).

[0205] Under nitrogen atmosphere and stirring, 81% purity (E,E)-perfarnesate ((E,E)-5a) (645 g, 1.9 mol, 3-EZ>90:1) was added dropwise to a 65% toluene solution (769 g, 2.5 mol) of red aluminum. One hour after complete addition, the reaction mixture was cooled to ambient temperature and slowly poured into 1 L of 20% NaOH with stirring. After 30 min, the phases were separated. The aqueous phase was washed with toluene. The combined organic phases were washed with water and brine, dried over MgSO4, and filtered. The solvent was removed under reduced pressure to obtain 634 g of crude product, which was rapidly distilled and then fractionated at 128 °C / 1 mbar to give 351 g (69%) of (E,E)-hofarnesol ((E,E)-1) with a purity of 87% (GC rpa, based on the E,E-isomer) and a 3-EZ ratio of 92:8. The analytical data are consistent with those in the reference of Example 10.

[0206] Example 14. Using -Funk catalyst for the preparation of (E,E)-higherfarnesol ((E,E)-1) from (E,E)-higherfarnesyl nitrile ((E,E)-2)

[0207] Preparation as described by TWFunk et al. in Adv. Synth. Catal. 354, 597-601 (2012) -Funk catalyst.

[0208] The container will contain (E,E)-high farnesonitrile ((E,E)-2, 1 g, 4.3 mmol), A high-pressure autoclave containing -Funk catalyst (38 mg, 0.09 mmol, 2 mol%) and water (20 mL) was evacuated and filled three times with hydrogen at 20 bar. Finally, a hydrogen pressure of 80 bar was applied, and the autoclave was heated to 140 °C with vigorous stirring. After 20 h at this temperature, complete conversion was detected by GC. Tert-butyl methyl ether was added to the green reaction mixture, and the phases were separated. The aqueous phase was extracted twice with tert-butyl methyl ether. The combined organic layers were washed with water, dried over MgSO4, filtered, and evaporated to give 1 g of a clear yellow oil, which was purified with silica gel FC using hexane / tert-butyl methyl ether 5:1 as the eluent. After evaporation, (E,E)-hofarnesol ((E,E)-1, 0.53 g, 57%) with a purity of 90% and a 3-EZ ratio of 93:7 was given as a clear pale yellow oil. The analytical data of 1 are consistent with those in the reference of Example 10.

[0209] Example 15. Using -Funk catalyst for the preparation of (E,E)-higherfarnesol ((E,E)-1) from (E,E)-higherfarnesyl nitrile ((E,E)-2)

[0210] The container will contain (E,E)-farnesyl nitrile ((E,E)-2, 1 g, 4.3 mmol), A high-pressure autoclave containing -Funk catalyst (65 mg, 0.13 mmol, 3 mol%) and water (20 ml) was evacuated and filled with hydrogen three times. Finally, a hydrogen pressure of 10 bar was applied, and the autoclave was heated to 140 °C with vigorous stirring. After 20 h at this temperature, complete conversion was detected by GC. At ambient temperature, tert-butyl methyl ether was added, and the phases were separated. The organic phase was washed with water, dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel FC with hexane / tert-butyl methyl ether 5:1 as eluent to give 0.44 g (55%) of (E,E)-hofarnesol 1,3-EZ ratio 92:8 as a clear yellow oil. The analytical data of 1 are consistent with those in the reference of Example 10.

[0211] Example 16. Preparation of (E,E)-higherfarnesol ((E,E)-1) from (E,E)-higherfarnesol ((E,E)-2) using Ru(II)-catalyst

[0212] An autoclave containing (E,E)-farnesyl nitrile ((E,E)-2, 0.96 g, 4.2 mmol), RuH(CO)Cl(PPh3)3 (29 mg, 0.03 mmol, 1 mol%), water (9 mL), and dioxane (9 mL) was evacuated and filled with hydrogen three times. Finally, a hydrogen pressure of 10 bar was applied, and the autoclave was heated to 140 °C with vigorous stirring. After 18 h, complete conversion was detected by GC. Dioxane was removed under reduced pressure, tert-butyl methyl ether was added, and the phases were separated. The organic phase was washed with water, dried over MgSO4, filtered, and evaporated to give 0.83 g of a brown liquid, which was purified by bulb-to-bulb distillation to give 0.67 g of a clear liquid, which, according to GC-MS, contained 69% rpa(E,E)-high farnesol 1 ((E,E)-1, 65% corrected yield) and 13% of over-hydrogenated product 9 (M 238). The analytical data for 1 are consistent with those in the reference of Example 10. Analytical data for by-product 9:

[0213]

[0214] 9 1 H-NMR (400MHz, CDCl3): δ (ppm) = 5.2 (2H), 3.6 (m, 2H), 1.9-2.1 (6H), 1.68 (s, 3H), 1.6 (2s, 6H), 1.3-1.7 (4H), 1.1-1.2 (2H), 0.9 (d, 2H).

[0215] 9 13 C-NMR (100MHz, CDCl3): δ (ppm) = 134.7 (s), 131.2 (s), 124.7 (d), 124.3 (d), 63.4 (t), 39.7 (t), 37.0(t),32.8(t),32.2(d),30.3(t),26.7(t),25.7(q),25.4(t),19.5(q),17.6(q),15.9(q).

[0216] GCMS of 9: m / z = 238 [M] + (1%), 223 [M-15] + (1%), 195(21%), 177(3%), 151(2%), 135(3%), 123(70%), 109(27%), 95(57%), 82(10%), 81(29%), 69(100%), 68(10%), 67(22%), 55(23%), 41(43%).

Claims

1. A method for preparing high farnesol (1), (1), The method includes the following steps: a) Provide high-farinate nitrile (2) (2); b) React perfarnesine (2) to perfarnesic acid (3). (3); and c) React perfarnesic acid (3) to perfarnesol (1), The configurations of the double bonds in compounds 1, 2, and 3 are preserved. Its characteristic is that step b) is selected from i) Enzymatic hydrolysis by nitrile hydrolases, or ii) The process is carried out in two steps via high-farnesylamide (4). (4)。 2. The method according to claim 1, wherein the double bond at C3 of the perfarnesol (1) is EZ The ratio is greater than 80:

20.

3. The method according to claim 2, wherein the double bond at C3 of the perfarnesol (1) is EZ The ratio is greater than 85:

15.

4. The method according to claim 3, wherein the double bond at C3 of the perfarnesol (1) is EZ The ratio is greater than 90:

10.

5. The method according to any one of claims 1 to 4, wherein the high-farnitro nitrile (2) is obtained by hydrolyzing the high-farnitro nitrile (2) in DMSO with K2CO3 and oxidizing it with H2O2.

6. The method according to any one of claims 1 to 4, wherein the high farnesylamide (4) is obtained by oxidation using a metal catalyst.

7. The method according to any one of claims 1 to 4, wherein step b) is carried out in a one-pot reaction.

8. The method according to any one of claims 1 to 4, wherein step c) is carried out in two steps via perfarnesic acid ester (5). (5), Where R is a C1-C20 alkyl group.

9. The method of claim 8, wherein R is methyl or ethyl.

10. High-farfenac (4) (4)。 11. Use of perfarniamide (4) as an intermediate in the preparation of perfarniol (1). (4) (1)。

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