Oxidation of santalen to santalol

Abstract

The present invention relates to a process of oxidizing santalene to santallol. The starting material is a mixture comprising, in particular, alpha-santalene, beta-santalene, epi-beta-santalene, trans-alpha-bergamoten, and beta-bisabolene. The oxidation of santalene occurs through an intermediate chloro-santalene compound. Substitution of a chloro-substituent with an acetate produces a mixture of corresponding santalyl acetate, which is hydrolyzed to produce a corresponding mixture of santallol.

Description

Technology Field

[0001] The present invention relates to the oxidation process of santalene to santallol. Background Technology

[0002] Sandalwood oil is a highly valuable, naturally occurring fragrance that constitutes an important ingredient in perfumes, cosmetics, toiletries, aromatherapy, and pharmaceuticals. It possesses a soft, sweet, woody balsamic scent derived primarily from the sesquiterpene alcohols alpha-santhalol and beta-santhalol. The source of genuine sandalwood oil is Santalum albuginea ( Santalum album As such, it is a slow-growing protected tree that is overharvested, and the demand for it cannot be met.

[0003] To alleviate pressure on natural sources of sandalwood oil, numerous biochemical production processes have been developed to obtain sandalwood or its precursors, particularly through the application of genetically modified microorganisms. For example, the precursor santalene is now readily available on an industrial scale due to genetically modified microorganisms with improved expression of the gene encoding santalene synthase (WO2018 / 160066). Furthermore, this santalene synthase produces various santalene sesquiterpenes (most notably including beta-santalene, alpha-santalene, epi-beta-santalene, trans-alpha-bergamoten, and beta-bisabolene), which reflect the composition of the corresponding santarol in sandalwood oil. Thus, the efficient and scalable oxidation of santalene to santarol will pave the way for the industrial production of an attractive substitute for genuine natural sandalwood oil.

[0004] In US 4,510,319, a method for oxidizing santalene is described ("Willis method"), in which santalene is first reacted with calcium hypochlorite in the presence of dry ice (solid CO2) to form the intermediate compound chloro-santalene, an allyl halide. Then, this intermediate is reacted with potassium acetate to form the corresponding santalyl acetate ester. Then, the desired santalene is obtained by the final hydrolysis of this ester.

[0005] However, a problem with this method is that it is difficult to scale up. For example, this method exhibits variability in the selectivity of the chlorination reaction. This variability becomes more pronounced as the scale of the reaction increases, making the proportion of different sesquiterpenoids in the product unacceptable. In addition, the addition of solid CO2 to the reaction mixture initiates a highly exothermic reaction, making it impossible to safely scale up the reaction.

[0006] Another problem associated with the Willis method is the presence of solids in the reaction mixture at various stages of the oxidation process, such as calcium hypochlorite used in the first stage and calcium chloride generated during ester formation. These solids hinder the stirring of the mixture and slow down the reaction rate. This makes scaling up the reaction very complicated. Furthermore, the disposal of stoichiometric amounts of solid salts, such as calcium chloride, is undesirable from an environmental perspective.

[0007] Nussbaumer and colleagues synthesized Iso E Super ®Stereoselective synthesis starting from alpha-ionone was initiated for perfume components found in [a substance]; diastereoselective conjugate addition of Me2CuLi to alpha-ionone was followed by haloform reaction, esterification, and isomerization of a single C=C bond by NaOCl treatment, and the resulting allyl chloride was ozone-treated and converted to trimethyl(vinyl)octahydrocoumarin, which was then applied to other modifications. However, this process is applicable to different materials and poses problems for industrial-scale applications and other target molecules due to the risk of accumulation of explosive Cl2O and / or toxic Cl2 that may be locally formed, for example, when acid is added to a bleach-containing mixture, and the lack of specificity in cases where more than one double bond is available in the chloride.

[0008] Therefore, the objective of the present invention is to provide a novel oxidation process of santalene to santalene that reduces the risk of accumulation of explosive intermediates such as Cl2O or toxic substances such as Cl2, and also provides good selectivity for the desired product while allowing safe scaling up to an industrial scale (e.g., a process batch producing more than 100 kg of santalene). Minimizing chemical waste generated in such a process is also an objective. An additional objective of the present invention is to provide a process that produces different santalene sesquiterpenoids at a ratio closer to natural sandalwood oil than when using conventional synthesis methods, particularly traditional oxidation methods.

[0009] It has now been revealed that one or more of these tasks can be satisfied by applying a specific oxidizing agent in combination with specific reagents and additives.

[0010] Accordingly, the present invention is a synthesis process for a compound of formula (I), wherein

[0011]

[0012] In the equation, R = a, b, c, d, or e;

[0013]

[0014] - of the starting compound of Formula (II)

[0015]

[0016] Chlorination to the intermediate of formula (III)

[0017]

[0018] - Conversion of the intermediate of Formula (III) into the compound of Formula (I)

[0019] Including;

[0020] Chlorination relates to a synthesis process involving combining the starting compound of formula (II) with an acidic and aqueous NaOCl solution.

[0021] Preferably, the chlorination step comprises a subsequent step of providing all or at least part of the acid to a mixture of the starting compounds of Formula (II) in the presence of a solvent, for example, toluene, optionally, and subsequently contacting the mixture with all or part of an aqueous NaOCl solution. If only a portion of the required amount of the aqueous NaOCl solution is used to initially contact the mixture, the step of contacting the mixture with the aqueous NaOCl solution is repeated as needed until the conversion of the starting compounds of Formula (II) to the intermediate of Formula (III) to the desired degree is achieved. In one embodiment, the step of contacting the mixture with the aqueous NaOCl solution is performed stepwise or continuously at a slow rate. Mixing is preferably used during or after each contact between the mixture and the aqueous NaOCl solution. The step of contacting the mixture with the aqueous NaOCl solution may optionally include the simultaneous addition of a portion of the acid.

[0022] In one embodiment, the chloride comprises providing a starting compound of formula (II) in the presence of a solvent, for example, non-limitingly toluene, and then combining the starting compound of formula (II) with an acid and an aqueous NaOCl solution by the simultaneous addition of an aqueous NaOCl solution and an acid, preferably while mixing.

[0023] In one embodiment, the acid used in the method of the present invention may be a mixture of two or more acids, preferably a mixture of weak acids. In a further embodiment, the starting mixture of the starting compound of Formula (II) comprises one or more types of acids, and the same or different types of acids are added simultaneously while the mixture is in contact with an aqueous NaOCl solution.

[0024] In one embodiment, the pH value of the mixture containing the starting compound of formula (II) is stable or increases during the reaction, preferably increasing at the end of the conversion of the intermediate of formula (III) to the compound of formula (I) compared to the beginning of the chlorination step.

[0025] The starting material of the process of the present invention comprises one or more santalene sesquiterpenes of formula (II) selected from the group consisting of alpha-santalene (IIa), beta-santalene (IIb), epi-beta-santalene (IIc), trans-alpha-bergamoten (IId), and beta-bisabolene (IIe). Possibly, other santalene sesquiterpenes are also present in the starting material.

[0026]

[0027] In the equation, R = a, b, c, d, or e

[0028]

[0029] Subsequently, the product of the process comprises one or more of the corresponding santarol sesquiterpenoids of formula (I), namely alpha-santarol (Ia), beta-santarol (Ib), epi-beta-santarol (Ic), trans-alpha-bergamottol (Id) and lanseol (Ie), respectively.

[0030]

[0031] In the equation, R = a, b, c, d, or e

[0032]

[0033] In this specification, the term "santalene sesquiterpene" refers to a compound of formula (II), and the term "santalene sesquiterpenoid" refers to a compound of formula (I). Other isomers of santalene sesquiterpenoids, which are present in small amounts in natural sandalwood oil, can also be produced by the process of the present invention when the corresponding santalene sesquiterpene precursor is used as a starting material in the process. For example, cis-alpha-bergamottol and trans-beta-bergamottol may be formed in small amounts from cis-alpha-bergamotton and trans-beta-bergamotton, respectively.

[0034] The conversion of santalene sesquiterpene (II) to santalene sesquiterpenoid (I) occurs through an intermediate that is chlorinated santalene of formula (III).

[0035]

[0036] In the equation, R = a, b, c, d, or e

[0037]

[0038] Also, in this specification, the term “chloro-santalene” means a compound of formula (III), i.e., a santalene sesquiterpene chloro-substituted at the tail (i.e., terminal isoprene fragment).

[0039] The conversion of chloro-santalene (III) to the intended santarol sesquiterpenoid product (I) is SN It is an allyl rearrangement believed to occur via a 2' reaction mechanism. This is preferably a carboxylate R'-COO - This is carried out by reacting with to obtain the intermediate santallyl acetate of formula (IV), and then hydrolyzing it to obtain the intended santallol sesquiterpenoid product (I).

[0040]

[0041] In the equation, R = a, b, c, d, or e;

[0042]

[0043] In the formula, R' contains an alkyl group of 1 to 7 carbon atoms.

[0044] The process of the present invention may be carried out for only one of the santalene sesquiterpenes (II) or for any mixture thereof, as the reactivity required in the tail for different santalene sesquiterpenes is expected to be similar. For the purpose of producing a close mimic of sandalwood oil (which is a mixture comprising at least five santalene sesquiterpenoids (Ia-Ie) as mentioned above), the starting material typically comprises a mixture of five santalene sesquiterpenes (IIa-IIe) as mentioned above, possibly supplemented, for example, with trace components cis-alpha-bergamoten and trans-beta-bergamoten.

[0045] In particular, when the santalene sesquiterpene starting material is obtained by a microbiological method as described in WO2018 / 160066, the most relevant santalene sesquiterpenes present are alpha-santalene (IIa; ~40 wt%), beta-santalene (IIb; ~20 wt%), epi-beta-santalene (IIc; ~2 wt%), trans-alpha-bergamoten (IId; ~20 wt%), and beta-bisabolene (IIe; ~3 wt%). When this mixture is applied to the process of the present invention, the corresponding santalene sesquiterpenoids are obtained in similar proportions. Possible deviations are, for example, due to the perchlorination of certain santalene sesquiterpenes (II) in the mixture (see below), because the perchlorinated product generally cannot be converted into the corresponding santalene sesquiterpenoids. A perfumer who evaluated the product obtained by the process of the present invention for its similarity to natural sandalwood oil described the perceived smell as "very good."

[0046] The first attempt to avoid the use and generation of solids in the process (as in the case of the Willis procedure) was the substitution of Ca(ClO)2 with a solution of NaOCl in water (i.e., a bleach). While this initially yielded promising results regarding the yield and selectivity of the reaction, undesirable fluctuations in the selectivity of the reaction were observed when the reaction was performed multiple times, particularly when attempts were made to scale up the reaction. This was due to pH fluctuations caused by the addition of solid CO2.

[0047] Subsequently, attempts were made to carry out the reaction under buffered conditions in the absence of dry ice. Thus, different buffer solutions were tested in the pH range of 4–10, but all of them resulted in almost no conversion of the santalene sesquiterpene starting material. More acidic environments were initially avoided in terms of the risk of forming Cl2O, a highly reactive and explosive gas that is particularly undesirable when carrying out the reaction on a large scale. The accumulation of these species in the reaction mixture is hazardous in terms of explosion risk.

[0048] When the reaction was carried out under more acidic conditions, the yield was also very low (the conversion rate to the desired santarol sesquiterpenoid was only a few percent). Surprisingly, however, when a slight excess of acid (relative to NaOCl) was used in the reaction, chloro-santalene was obtained with a yield and selectivity at least as high as that reported for the Willis procedure. Furthermore, when different runs were performed on a large scale (e.g., 10 kg of santalene), no variation in the selectivity of the reaction was observed as in the case of dry ice. The excess acid is generally 5 acid equivalents or less relative to NaOCl. Typically, the excess is in the range of 1.05–3.0 acid equivalents relative to NaOCl. Preferably, it is in the range of 1.1–2.0 acid equivalents, and more preferably, 1.2–1.6 acid equivalents. It may also be in the 1.2-2.5 acid equivalent range, the 1.4-2.2 acid equivalent range, or the 1.6-1.9 acid equivalent range. It may also be in the 1.05-1.8 acid equivalent range, the 1.1-1.6 acid equivalent range, the 1.15-1.5 acid equivalent range, or the 1.2-1.4 acid equivalent range. In chlorides, NaOCl is typically present as an aqueous solution of 5-50 wt% NaOCl.

[0049] Generally, NaOCl is present in excess relative to santalene. For example, the molar excess of NaOCl relative to santalene is typically in the range of 1.0-2.0, particularly in the range of 1.1-1.9, more particularly in the range of 1.2-1.8, and even more particularly in the range of 1.3-1.7. It may also be in the range of 1.1-1.7, 1.2-1.5, or 1.25-1.45.

[0050] In particular, the acid exists in a range of 1.2-1.5 molar equivalents for NaOCl, while NaOCl exists in a range of 1.25-1.75 molar equivalents for santalene sesquiterpenes. More specifically, the acid exists in a range of 1.25-1.45 molar equivalents for NaOCl, while NaOCl exists in a range of 1.3-1.7 molar equivalents for santalene sesquiterpenes.

[0051] In the procedure, the acid is typically first mixed with the santalene sesquiterpene, optionally in the presence of a solvent such as toluene. Subsequently, chlorination is performed by very slowly adding NaOCl as an aqueous solution in water (e.g., a 10-20 wt% solution) to the santalene mixture. It is also possible to administer the acid simultaneously with the bleaching agent so that the reaction mixture remains acidic during the reaction, which is typically done at a relative rate corresponding to the relative amount added in total. Simultaneous administration has the advantage that the pH of the reaction mixture changes less during the reaction, and in particular, the initial pH is not as low as when all the acid is present in the reaction mixture before the addition of the bleaching agent.

[0052] Another advantage of this method is that the conversion rate and selectivity are almost independent of the dosing protocol, allowing for slow dosing of the NaOCl solution in the reactor. This minimizes the risk associated with having large batches of these oxidizing agents in the reaction mixture. Furthermore, when the conversion of santalene sesquiterpenes was followed during the addition of the NaOCl solution, the chlorideation of santalene sesquiterpenes upon the addition of NaOCl appeared to be almost instantaneous. Thus, the risk of accumulation of explosive Cl2O is low. This opens the way for safe scale-up of the conversion to the intermediate chloro-santalene (III).

[0053] In principle, the acid may be any acid compatible with the reaction conditions. The acid may be an inorganic acid selected from the group consisting of, for example, sulfuric acid, hydrochloric acid, and boric acid. Preferably, the acid is an acid with a pKa greater than 0, more preferably a weak acid with a pKa of 3.0 or higher. In a preferred embodiment, the acid is a carboxylic acid. Generally, it is most effective for the applied acid to be soluble in water and / or have a pKa value of 5.0 or lower under the applied reaction conditions. If the acid is not soluble during the reaction, it is preferable for the acid to be liquid during the reaction.

[0054] When a carboxylic acid is used, it is preferably selected from the group consisting of formic acid, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, propionic acid, 2-chloropropionic acid, 3-chloropropionic acid, trifluoroacetic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, and benzoic acid. In one embodiment, a weak carboxylic acid having a pKa of 3 or higher is used in the method of the present invention.

[0055] More preferably, the acid is acetic acid or formic acid or a mixture thereof, more preferably acetic acid. It was found that the reaction carried out in the presence of acetic acid provides a very good conversion rate and good selectivity toward the desired monochlorinated product. Furthermore, the reaction showed excellent reproducibility.

[0056] The chlorination reaction is preferably carried out in a two-phase system having an aqueous phase containing NaOCl and an organic phase containing santalene sesquiterpene starting material (II) and chloro-santalene (III). The solvent of the organic phase preferably contains or consists of toluene. Other solvents that may be applied are hydrocarbons such as solvents selected from the group consisting of heptane, hexane, cyclohexane, methylcyclohexane, decane, and dodecane. Halogenated hydrocarbons, for example, dichloromethane, may also be used. However, the chlorination reaction appeared to be much cleaner in toluene than in dichloromethane, for example, in that there were fewer chlorinated byproducts. Additionally, it was confirmed that the yield was particularly good when methylcyclohexane was used as the solvent.

[0057] Another solvent that can be used is diethyl ether. In addition, it is also possible to carry out the reaction purely, that is, without a solvent.

[0058] A protocol using aqueous NaOCl under acidic conditions in combination with an organic phase is also particularly convenient for scale-up protocols because 1) all reagents are liquid; 2) no solids are produced during the process; and 3) mechanical stirring is very efficient in the two-phase system (aqueous and organic phases) formed upon the addition of the bleaching agent.

[0059] Although the direct conversion of chloro-santalene (III) to the intended santarol sesquiterpenoid product (I) appeared difficult, a two-step process via an ester intermediate proved successful. Therefore, the conversion is preferably

[0060] - Chloro-santhalene (III) carboxylate R'-COO - React with to form a corresponding carboxylate ester of formula (IV) (wherein R' contains an alkyl group of 1-7 carbon atoms);

[0061]

[0062] - This is carried out by hydrolyzing the ester of formula (IV) into the corresponding compound of formula (I).

[0063] In this process involving a substitution reaction, the carboxylate is typically an alkyl carboxylate, for example, its alkyl chain having 1 to 8 carbon atoms and may include branches. In the case of a branched chain, the total number of carbon atoms of the carboxylate is preferably in the range of 3 to 10. Preferably, the carboxylate is a C1-C5 carboxylate, such as formate, acetate, propionate, butyrate, and valerate. More preferably, the carboxylate is acetate and / or formate.

[0064] In the method of the present invention, when the formate is used as a carboxylate, the reaction time is further improved, and the isomer ratio of Z to E santarol is further increased.

[0065] In another embodiment, potassium and / or sodium salts of acid, preferably potassium acetate and / or potassium formate, are used.

[0066] The carboxylate may also be selected from the group consisting of formate, benzoate, and pivalate. The carboxylate is typically added before or during the reaction as a metal carboxylate, for example, sodium or potassium carboxylate (R'-COONa or R'-COOK).

[0067] In one embodiment, a mixture of carboxylates is used instead of a single carboxylate.

[0068] The hydrolysis of the carboxylate ester of formula (IV) to santarol (I) can be carried out according to standard ester hydrolysis procedures known in the art. For example, it can be carried out in methanol using potassium hydroxide as a base.

[0069] The present invention is therefore a synthesis process for a compound of formula (I),

[0070]

[0071] In the equation, R = a, b, c, d, or e;

[0072]

[0073] This relates to a synthesis process comprising the following steps:

[0074] - A step of providing a mixture of an acid or an acid mixture and a starting compound of formula (II) in the presence of an optional solvent, e.g., toluene, but not limited to.

[0075] ;

[0076] and

[0077] - A step of contacting the mixture with an aqueous NaOCl solution to produce an intermediate of formula (III).

[0078]

[0079] and

[0080] - The intermediate of Formula (III) is one or more carboxylates R'-COO - A step of reacting with to form the corresponding carboxylate ester(s) of formula (IV) (wherein R' comprises an alkyl group having 1-7 carbon atoms);

[0081]

[0082] and

[0083] - A step of hydrolyzing the ester(s) of formula (IV) into the corresponding compound of formula (I).

[0084] In the case where the double bond of the allyl alcohol moiety of the compound of formula (I) is related to natural sandalwood oil Z - It is a three-dimensional structure ( E - No compounds having a stereostructure are observed). This is different when antarol compound(s) are obtained through the process of the present invention, which is that the process of the present invention is obtained in small amounts, for example, in the range of 25-45 mol% (depending on reaction conditions) E This is because it generates isomers. Fortunately, the effect of these isomers on sensory properties was found to be minimal.

[0085] The type of carboxylate and organic solvent of the formed santhalol Z / E It was found to have a significant effect on the ratio. The most desirable ratio was produced when the substitution reaction was performed using acetate or formate as the carboxylate in gamma-valerolactone. When acetate or formate was used, after converting the intermediate santalyl carboxylate (IV) to the final santalol (I), alpha-santalol (Ia) was produced as two stereoisomers in a 65:35 ratio ( Z and E It was confirmed that it was formed as ). In fact, other chloro-santalene (IIIb-IIIe) is presumed to provide the same Z / E ratio because only the terminal isoprene fragment (a common motif in all isomers) is involved in the substitution reaction.

[0086] One embodiment of the present invention relates to a method according to the present invention in which at least 55% of the compound of formula (I) is produced as a Z isomer, preferably at least 57%, 59%, 61%, 63%, or at least 65% of the santarol is produced as a Z isomer. In one embodiment, the method of the present invention produces an isomer of the compound of formula (I), such as santarol, in a ratio of 55:45, preferably 60:40, more preferably 65:35 or greater ( Z andE Creates with ).

[0087] As described above, the process of the present invention may be performed for only one of the santalene sesquiterpenes (II) or for any mixture thereof, because the reactivity required in the tail for different santalene sesquiterpenes is expected to be similar. Accordingly, when the starting material comprises two or more santalene sesquiterpenes of formula (II), the process of the present invention produces two or more corresponding santalene sesquiterpenoids of formula (I).

[0088] Therefore, the process of the present invention is

[0089] - Chlorination is performed on a mixture of compounds of formula (II) to obtain a mixture of corresponding intermediates of formula (III);

[0090] - It may be a process in which a mixture of intermediates of formula (III) is converted into a mixture of corresponding compounds of formula (I).

[0091] In one embodiment, the conversion rate of santalene to santarol is greater than 65%, preferably at least 70%, more preferably at least 80%, and even more preferably at least 90%.

[0092] In particular, a mixture of compounds of formula (II) includes compounds of formula (IIa), formula (IIb), formula (IIc), formula (IId) and formula (IIe).

[0093] Surprisingly, when more than 1 equivalent of NaOCl was used, perchlorination of the santalene starting material (II) occurred, and it was found that there was a strong preference for the perchlorination of trans-alpha-bergamoten (IId) compared to other santalenes (IIa), (IIb), (IIc), and (IIe). Perchlorination means the introduction of more than one chloro-substituent, specifically two or three chloro-substituents, into the santalene sesquiterpene starting material (II). Unexpectedly, perchlorination was selective toward trans-alpha-bergamoten (IId). This means that when chlorination is performed on a mixture of compounds of formulas (IIa), (IIb), (IIc), (IId), and (IIe), the amount of chloro-santalene of formula (IIId) is disproportionately small compared to other chloro-santalenes (IIIa), (IIIb), (IIIc), and (IIIe). This also affects the final santarol sesquiterpenoid product (I), as it will contain a significantly lower proportion of trans-alpha-bergamotto than when perchlorination is not applied. Since this is a particularly undesirable, and sometimes unwanted, isomer in santarol mixtures, the perchlorination method opens the way to producing sandalwood oil with a reduced proportion of trans-alpha-bergamotto.

[0094] To this end, perchlorinated trans-alpha-bergamoten (IId) must be removed or decomposed at some stage of the process toward santallol isoprenoid. It has been found that by distillation of the raw material mixture obtained after the hydrolysis of santallyl acetate of formula (IV), the final santallol sesquiterpenoid of formula (I) is produced without any measurable amount of perchlorinated product, any of its derivatives (e.g., diol or triol), or decomposition products.

[0095] In one embodiment, the method of the present invention is thus the method described herein in which at least 60%, preferably at least 70%, more preferably at least 80% of the trans-alpha-bergamoten is converted into derivatives and these unwanted bergamoten derivatives can be easily removed by distillation.

[0096] The excess amount of NaOCl required for perchlorination must be sufficient to perchlorinate trans-alpha-bergamoten (IId), but a larger excess is undesirable as it results in unwanted perchlorination and / or decomposition of the desired chloro-santhalene (IIIa), (IIIb), (IIIc), and (IIIe). Therefore, when the objective is to reduce the content of trans-alpha-bergamoten (IId) in the product mixture, the molar excess of NaOCl is typically in the range of 2.1 to 3.5, preferably 2.2 to 3.2, relative to the amount of trans-alpha-bergamoten (IId).

[0097] However, since not all NaOCl can be consumed as an oxidizing agent, the above ratio may also vary depending on the reaction conditions applied. For example, a significant portion of NaOCl may be converted to Cl2. Any amount of this gas escaping from the reaction mixture must be compensated for by a larger amount of NaOCl used in the chlorination reaction. Those skilled in the art know how to achieve an appropriate excess of NaOCl under given specific reaction conditions without creative effort through conventional experimentation.

[0098] Therefore, in the process of the present invention, the chloride of the mixture is

[0099] - Convert the compounds of formulas (IIa), (IIb), (IIc) and (IIe) into intermediates of formulas (IIIa), (IIIb), (IIIc) and (IIIe);

[0100] - May include introducing two or three chloro-substituents onto the compound of formula (IId) to obtain a dichlorinated and / or trichlorinated analog of the compound of formula (IIId);

[0101] Here, dichlorinated and / or trichlorinated analogs are removed from intermediates of formulas (IIIa), (IIIb), (IIIc) and (IIIe) before or during the conversion of these intermediates to the corresponding compounds of formulas (IVa), (IVb), (IVc) and (IVe) and / or during the conversion of compounds of formulas (IVa), (IVb), (IVc) and (IVe) to the corresponding compounds of formulas (Ia), (Ib), (Ic) and (Ie).

[0102] The present invention also relates to a compound of formula (IIId) which is a chlorinated trans-alpha-bergamoten that can be separated from the reaction mixture after chlorination. As described above, this compound is an intermediate in the production of trans-alpha-bergamotol (Id).

[0103] The present invention also relates to a compound of formula (III).

[0104]

[0105] In the equation, R = a, b, c, d, or e;

[0106]

[0107] The present invention also comprises a composition obtainable by the method of the present invention comprising bergamotol, E-santarol and Z-santarol, wherein the amount of bergamotol, preferably trans-alpha-bergamotol, is 15% (w / w) or less of the composition, preferably 12% (w / w) or less, more preferably 10% (w / w) or less, and Z-santarol is present in excess of E-santarol. Preferably, Z-santarol is present in excess of at least 15% (w / w), 20% (w / w), 25% (w / w), 35% (w / w), 50% (w / w), 75% (w / w), 95% (w / w), 120% (w / w), 150% (w / w), 175% (w / w), 180% (w / w), or 185% (w / w), in order of increasing preference over E-santarol. In another embodiment, the ratio of Z to E santarol is at least 55:45, preferably 60:40 or more, and more preferably 65:35 or more. Preferably, the composition is a synthetic composition. Specific details for implementing the invention

[0108] Examples

[0109] 1. Chloride of santalene sesquiterpene (II)

[0110] Santalene mix (10.0 g, obtained via the procedure described in WO2018 / 160066), toluene (75 mL), and AcOH (6.0 mL) were added to a 250 mL three-necked round-bottom flask equipped with a magnetic stirrer, a thermometer, and a dropping funnel. NaOCl (14% Cl2 solution) (33.75 and 34.50 mL) was placed in the dropping funnel and added very slowly to the reaction mixture over a period of 2 hours. A fraction of the reaction was extracted and analyzed by GC. Subsequently, NaOCl (14% Cl2 solution) (1 mL portion) was added at 30-minute intervals until the starting Santalene mixture (II) was completely converted into the product. After the reaction was complete, NaHCO3 solution was added to the reaction mixture and the organic phase was extracted. The organic phase was washed twice with an NaCl solution, dried, and the solvent was evaporated under vacuum to obtain yellow oil (11.98 g). The residue was analyzed by GC. About 80% of the trans-alpha-bergamoten was converted into derivatives, and these unwanted bergamoten derivatives can be easily removed by distillation.

[0111] 2. Substitution of the chloro-group of chloro-santhalene (III)

[0112] KOAc (7.46 g) was charged into a 100 mL round-bottom flask equipped with a magnetic stirrer, and KI (800 mg) and the chloro-santhalene mix (5.0 g) obtained in Example 1 were added. DMA (30 mL) or toluene / TBAB (30 mL / 250 mg) was added as a solvent. The reaction mixture was placed in an oil bath and stirred at 110 °C for a 2-hour reaction (DMA) or an overnight reaction (toluene / TBAB). The progress of the reaction was monitored by GC. After the reaction was complete, the reaction mixture was cooled to room temperature, and an aqueous NaHCO3 solution and nPentane was added. The reaction mixture was transferred to a dropping funnel, the organic phase was extracted, and washed with brine (or several times with a LiCl solution in the case of DMA). The organic phase was dried over sodium sulfate, filtered, and the solvent was evacuated under vacuum to obtain a pale yellow oil. The residue was analyzed by GC and NMR.

[0113] 3. Hydrolysis of xantallyl acetate ester (IV)

[0114] The xantallyl acetate mixture obtained in Example 2 (5.0 g), KOH (5.0 g), H2O (6.8 mL), and MeOH (34 mL) were filled into a 100 mL round-bottom flask equipped with a magnetic stirrer. The reaction mixture was heated to 60 °C for 10 minutes and stirred at room temperature for an additional 30 minutes. After the reaction was complete, water (approx. 60 mL) and n -Pentane / AcOEt (4 / 1; 60 / 15 mL) was added to the reaction mixture. The organic phase was extracted and washed with brine. The organic phase was then dried on sodium sulfate and filtered. The solvent was removed under vacuum to obtain a pale yellow oil (4.0 g), which was analyzed by GC. After distillation of this oil, the santarol sesquiterpenoid of formula (I) was isolated as a mixture.

[0115] The conversion rate of antalene to antarol was over 90%, and antarol is a 65:35 stereoisomer ( Z and E It was formed as ). It was also found that trans-alpha-bergamoten resulted in trans-alpha-bergamotol existing at much lower levels compared to the initial levels of trans-alpha-bergamoten and the levels when perchlorination was not applied.

[0116] In Experiment 2, when potassium formate replaced potassium acetate, much better results were achieved.

[0117] Cited Literature:

[0118] Nussbaumer, C., Fraeter, G. and Kraft, P. (1999), (±)-1-[(1R*,2R*,8aS*)-1,2,3,5,6,7,8,8a-Octahydro-1,2,8,8-tetramethylnaphthalen-2-yl]ethan-1-one: Isolation and Stereoselective Synthesis of a Powerful Minor Constituent of the Perfumery Synthetic Iso E Super®. HCA, 82: 1016-1024. doi:10.1002 / (SICI)1522-2675(19990707)82:7<1016::AID-HLCA1016>3.0.CO;2-Y

Claims

Claim 1 A synthesis process for a mixture of compounds of formula (I) comprising compounds of formula (Ia), formula (Ib), formula (Ic), formula (Id) and formula (Ie), In the equation, R = a, b, c, d or e; Formulas (Ia), (Ib), (Ic), (Id) and (Ie) each correspond to Formula (I) where R = a, b, c, d, e; the above process is a chlorination step of a mixture of compounds of Formula (II) comprising compounds of Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId) and Formula (IIe), In the equation, R = a, b, c, d or e; Formulas (IIa), (IIb), (IIc), (IId) and (IIe) each correspond to Formula (II) where R = a, b, c, d, e; the chlorination step of the mixture comprises—conversion of starting compounds of Formula (IIa), Formula (IIb), Formula (IIc) and (IIe) into intermediates of Formula (IIIa), Formula (IIIb), Formula (IIIc) and (IIIe); and—obtaining dichlorinated and / or trichlorinated analogs of the intermediate of Formula (IIId) by introducing two or three chloro-substituents onto the starting compound of Formula (IId), thereby obtaining a mixture of intermediates of Formula (III) comprising the corresponding intermediates of Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId) and Formula (IIIe). In the equation, R = a, b, c, d or e; Formulas (IIIa), (IIIb), (IIIc), (IIId), and (IIIe) each correspond to Formula (III) where R = a, b, c, d, e; the mixture comprises dichlorinated and / or trichlorinated analogs of the intermediate of Formula (IIId); and- comprising a step of converting a mixture of intermediates of formula (III) into a mixture of corresponding compounds of formula (Ia), formula (Ib), formula (Ic), formula (Id) and formula (Ie); wherein dichlorinated and / or trichlorinated analogs are removed from the mixture before or during the conversion of intermediates of formula (IIIa), formula (IIIb), formula (IIIc) and formula (IIIe) into corresponding santarol sesquiterpenoids of formula (Ia), formula (Ib), formula (Ic) and formula (Ie); and the chlorination step comprises combining a starting mixture of compounds of formula (II) with an acidic and aqueous NaOCl solution; wherein NaOCl is present in an amount ranging from 1.1 to 1.9 molar equivalents relative to the starting mixture of compounds of formula (II), a synthesis process. Claim 2 A synthesis process in which the acid is a carboxylic acid, according to claim 1. Claim 3 A synthesis process according to claim 2, wherein the carboxylic acid is selected from the group consisting of formic acid, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, propionic acid, 2-chloropropionic acid, 3-chloropropionic acid, trifluoroacetic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, and benzoic acid. Claim 4 A synthesis process according to claim 1, wherein the acid is present in an amount ranging from 1.05 to 3.0 molar equivalents relative to NaOCl. Claim 5 A synthesis process according to claim 2, wherein the acid is present in an amount ranging from 1.05 to 3.0 molar equivalents relative to NaOCl. Claim 6 A synthesis process according to claim 3, wherein the acid is present in an amount ranging from 1.05 to 3.0 molar equivalents relative to NaOCl. Claim 7 A synthesis process according to claim 1, wherein the acid is present in an amount ranging from 1.1 to 2.0 molar equivalents relative to NaOCl. Claim 8 A synthesis process according to claim 2, wherein the acid is present in an amount ranging from 1.1 to 2.0 molar equivalents relative to NaOCl. Claim 9 A synthesis process according to claim 3, wherein the acid is present in an amount ranging from 1.1 to 2.0 molar equivalents relative to NaOCl. Claim 10 A synthesis process according to claim 1, wherein the acid is present in an amount ranging from 1.2 to 1.5 molar equivalents relative to NaOCl. Claim 11 A synthesis process according to claim 2, wherein the acid is present in an amount in the range of 1.2-1.5 molar equivalents relative to NaOCl. Claim 12 A synthesis process according to claim 3, wherein the acid is present in an amount ranging from 1.2 to 1.5 molar equivalents relative to NaOCl. Claim 13 A synthesis process according to any one of claims 1 to 12, wherein NaOCl is present in an amount ranging from 1.3 to 1.7 molar equivalents with respect to a starting mixture of compounds of formula (II). Claim 14 A synthesis process according to any one of claims 1 to 3, wherein the acid is present in an amount in the range of 1.2 to 1.5 molar equivalents relative to NaOCl, and NaOCl is present in an amount in the range of 1.25 to 1.75 molar equivalents relative to a starting mixture of compounds of formula (II). Claim 15 A synthesis process according to any one of claims 1 to 12, wherein the chlorination step is performed in the presence of an organic solvent. Claim 16 A synthesis process according to claim 13, wherein the chlorination step is performed in the presence of an organic solvent. Claim 17 A synthesis process according to claim 14, wherein the chlorination step is performed in the presence of an organic solvent. Claim 18 A synthesis process according to claim 16, wherein the solvent is selected from toluene, dichloromethane, and methylcyclohexane. Claim 19 In any one of claims 1 to 12, the step of converting the intermediates of formula (III) into the compounds of formula (I) is—the intermediates of formula (III) into carboxylate R'-COO - React with to form the corresponding carboxylate ester of formula (IV) (where R'-COO in the formula) - is selected from the group consisting of formate, acetate, propionate, butyrate, valerate, benzoate, pivalate, and mixtures thereof), In the equation, R = a, b, c, d or e; Formulas (IVa), (IVb), (IVc), (IVd) and (IVe) each correspond to Formula (IV) where R = a, b, c, d, e; then—a synthesis process performed by hydrolyzing the ester of Formula (IV) into the corresponding compound of Formula (I). Claim 20 In claim 18, the conversion step of the intermediates of formula (III) to the compounds of formula (I) is—the intermediates of formula (III) to the carboxylate R'-COO - React with to form the corresponding carboxylate ester of formula (IV) (where R'-COO in the formula) - is selected from the group consisting of formate, acetate, propionate, butyrate, valerate, benzoate, pivalate, and mixtures thereof), In the equation, R = a, b, c, d or e; Formulas (IVa), (IVb), (IVc), (IVd) and (IVe) each correspond to Formula (IV) where R = a, b, c, d, e; then—a synthesis process performed by hydrolyzing the ester of Formula (IV) into the corresponding compound of Formula (I). Claim 21 A synthesis process according to claim 19, wherein the carboxylate is acetate, formate, or propionate. Claim 22 A synthesis process according to claim 20, wherein the carboxylate is acetate, formate, or propionate. Claim 23 A synthesis process according to claim 1, wherein NaOCl is present in an amount ranging from 2.1 to 3.5 molar equivalents relative to the starting compound of formula (IId) in the chlorination reaction. Claim 24 A synthesis process according to claim 23 in which NaOCl is present in an amount ranging from 2.2 to 3.2 molar equivalents with respect to the starting compound of formula (IId) in the chlorination reaction. Claim 25 A synthesis process according to claim 1, wherein compounds of formula (I) are produced in a ratio of isomer Z and isomer E of 55:45 or greater. Claim 26 A synthesis process according to claim 25, wherein compounds of formula (I) are produced in a ratio of isomer Z and isomer E of 60:40 or more. Claim 27 A synthesis process according to claim 25, wherein compounds of formula (I) are produced in a ratio of isomer Z and isomer E of 65:35 or greater.

Images