Oxidation of santalene to santalol

Abstract

To provide a method for oxidizing santalene to santalol that reduces the risk of accumulation of explosive intermediates or toxic substances, and enables safe scale-up to an industrial scale while achieving good selectivity for the desired product.SOLUTION: The starting material may be a mixture comprising alpha-santalene, beta-santalene, and the like. The oxidation of santalene proceeds via an intermediate chloro-santalene compound, and substitution of the chloro group by acetate ions yields a mixture of the corresponding santalyl acetates, which are hydrolyzed to yield a corresponding mixture of santalols represented by Formula (I), where R is a, b, c, d, or e as shown below.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for oxidizing santalene to santalol. [Background technology]

[0002] Sandalwood oil is a highly valued natural fragrance that constitutes an important ingredient in air fresheners, cosmetics, toiletries, aromatherapy, and medicines. Sandalwood oil has a soft, sweet, woody, balsamic aroma imparted primarily by the sesquiterpene alcohols alpha-santalol and beta-santalol. The source of true sandalwood oil is the sandalwood (Santalum album), a slow-growing, shelter tree that is overharvested and unable to meet demand.

[0003] To alleviate the high expectations for natural sources of sandalwood oil, several biochemical production methods for obtaining sandalwood or its precursors have been developed, particularly by applying genetically modified microorganisms. For example, the precursor santalene is now readily available on an industrial scale through genetically engineered microorganisms with improved expression of the gene encoding santalene synthase ( WO 2018 / 160066 ). Furthermore, this santalene synthase produces a wide range of santalene sesquiterpenes (most notably beta-santalene, alpha-santalene, epi-beta-santalene, trans-alpha-bergamotene, and beta-bisabolene), which affect the composition of the corresponding santalol in sandalwood oil. Therefore, efficient and scalable oxidation of santalene to santalol appears to pave the way for producing an attractive substitute for true natural sandalwood oil on an industrial scale.

[0004] U.S. Patent No. 4,510,319 describes a method for oxidizing santalene (the "Willis method"), in which santalene is first reacted with calcium hypochlorite in the presence of dry ice (solid CO2) to form the intermediate compound chlorosantalene, an allylic halide. This intermediate is then reacted with potassium acetate to form the corresponding santalyl acetate ester. Final hydrolysis of this ester then affords the desired santalol. Summary of the Invention

[0005] However, a problem with this method is that it is difficult to scale up. For example, the method exhibits variability in the selectivity of the chlorination reaction. This variability becomes more pronounced as the scale of the reaction increases, resulting in unacceptable proportions of various sesquiterpenoids in the product. Similarly, the addition of solid CO to the reaction mixture initiates a highly exothermic reaction, which makes safe scale-up of this reaction unfeasible.

[0006] Another problem with the Willis process is the presence of solids in the reaction mixture during multiple stages of the oxidation process, such as calcium hypochlorite used in the first step and calcium chloride produced during ester formation. These solids hinder the stirring of the mixture and slow down the reaction. This seriously complicates the scale-up of this reaction. Furthermore, the disposal of stoichiometric amounts of solid salts, such as calcium chloride, is undesirable from an environmental point of view.

[0007] Nussbaumer and coworkers have disclosed the fragrance ingredient found in the synthesis Iso E Super®, which is a stereoselective synthesis starting from alpha-ionone, in which Me2CuLi is added to alpha-ionone diastereoselectively, followed by haloform reaction, esterification, and isomerization of a single C=C bond by treatment with NaOCl, and the resulting allyl chloride is ozonized to convert it into trimethyl(vinyl)octahydrocoumarin, which is then subjected to other modifications.However, this method is still problematic for industrial application due to the risk of accumulation of explosive Cl2O and / or toxic Cl2, which may be formed locally when adding acid to a mixture containing bleach, and for other target molecules, a lack of specificity occurs when more than one double bond is available for chlorination.

[0008] It is therefore an object of the present invention to provide a novel method for oxidizing santalene to santalol that reduces the risk of accumulation of explosive intermediates such as ClO or toxic substances such as Cl, achieves good selectivity for the desired product, yet allows for safe scale-up to industrial scale (e.g., process batches producing over 100 kg of santalol). It is also an object of the present invention to minimize chemical waste in such a process. A further object of the present invention is to provide a method for producing various santalol sesquiterpenoids in proportions closer to those of natural sandalwood oil than are possible using conventional synthetic methods, particularly traditional oxidation methods.

[0009] It has now been found that one or more of these objectives can be met by applying specific oxidizing agents in combination with specific reagents and additives.

[0010] Thus, the present invention provides a compound of formula (I)

[0011] [ka] (Wherein, R=a, b, c, d or e

[0012] [ka] is) A method for synthesizing - a starting compound of formula (II)

[0013] [ka] is chlorinated to give an intermediate of formula (III)

[0014] [ka] To make - converting the intermediate of formula (III) into a compound of formula (I) Including, The synthetic method involves combining the starting compound of formula (II) with an acid and aqueous NaOCl.

[0015] Preferably, the chlorination step includes providing a mixture of the starting compound of formula (II) and all or at least a portion of the acid, optionally in the presence of a solvent such as, but not limited to, toluene, followed by a subsequent step of contacting the mixture with all or a portion of aqueous NaOCl. If only a portion of the required amount of aqueous NaOCl is initially used to contact the mixture, the step of contacting the mixture with aqueous NaOCl is repeated as necessary until the desired degree of conversion of the starting compound of formula (II) to the intermediate of formula (III) is achieved. In one embodiment, the step of contacting the mixture with aqueous NaOCl is carried out stepwise or continuously at a slow rate. Mixing is preferably used between or after each step of contacting the mixture with aqueous NaOCl. The step of contacting the mixture with aqueous NaOCl may optionally include the simultaneous addition of a partial amount of acid.

[0016] In one embodiment, the chlorination comprises providing a starting compound of formula (II), optionally in the presence of a solvent, such as, but not limited to, toluene, and then combining the starting compound of formula (II) with an acid and aqueous NaOCl, preferably by simultaneous addition of aqueous NaOCl and acid while mixing.

[0017] In one embodiment, the acid used in the process of the present invention can be a mixture of two or more acids, preferably a mixture of mild acids. In a further embodiment, the starting mixture of starting compounds of formula (II) contains one or more acids, and the same or different acids are added simultaneously during contacting the mixture with aqueous NaOCl.

[0018] In one embodiment, the pH value of the mixture comprising the starting compound of formula (II) remains 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 start of the chlorination step.

[0019] The starting material for 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-bergamotene (IId) and beta-bisabolene (IIe). Possibly, other santalene sesquiterpenes are also present in the starting material.

[0020] [ka] (Wherein, R=a, b, c, d or e

[0021] [ka] is)

[0022] The product of the process then comprises one or more of the corresponding santalol sesquiterpenoids of formula (I), namely, alpha-santalol (Ia), beta-santalol (Ib), epi-beta-santalol (Ic), trans-alpha-bergamotol (Id), and lantheol (Ie), respectively.

[0023] [ka] (Wherein, R=a, b, c, d or e

[0024] [ka] is)

[0025] In this description, the term "santalene sesquiterpene" refers to a compound of formula (II), and the term "santalol sesquiterpenoid" refers to a compound of formula (I). When the corresponding santalene sesquiterpene precursor is used as the starting material in the present method, it is believed that other isomers of santalol sesquiterpenoids present in trace amounts in natural sandalwood oil can also be produced by the method of the present invention. For example, cis-alpha-bergamotol and trans-beta-bergamotol can be formed in trace amounts from cis-alpha-bergamotene and trans-beta-bergamotene, respectively.

[0026] The conversion of santalene sesquiterpene (II) to santalol sesquiterpenoid (I) occurs via an intermediate, the chlorinated santalene of formula (III).

[0027] [ka] (Wherein, R=a, b, c, d or e

[0028] [ka] is)

[0029] Furthermore, in this description, the term "chlorosantalene" refers to a compound of formula (III), i.e., a santalene sesquiterpene that has been chloro-substituted in its tail (i.e., in the terminal isoprene fragment).

[0030] The conversion of chlorosantalene (III) to the desired santalol sesquiterpenoid product (I) is achieved by S N 2'Allylic rearrangement is thought to occur via the reaction mechanism. Allylic rearrangement occurs when the carboxylate ion R'-COO - to form the santalyl acetate intermediate of formula (IV), which is then hydrolyzed to form the desired santalol sesquiterpenoid product (I).

[0031] [ka] (Wherein, R=a, b, c, d or e

[0032] [ka] and R' comprises an alkyl group of 1 to 7 carbon atoms.

[0033] Since the required reactivity in the tail is expected to be similar for various santalene sesquiterpenes, the method of the present invention can be carried out on only one santalene sesquiterpene (II) or any mixture thereof. With the goal of producing a close simulant of sandalwood oil (which is a mixture containing at least the five santalol sesquiterpenoids (Ia-Ie) described above), the starting material will typically contain a mixture of the five santalene sesquiterpenes (IIa-IIe) described above, possibly supplemented with, for example, minor components cis-alpha-bergamotene and trans-beta-bergamotene.

[0034] In particular, when the santalene sesquiterpene starting material is obtained by the microbiological method described in WO 2018 / 160066, the most relevant santalene sesquiterpenes present are alpha-santalene (IIa, approximately 40% by weight), beta-santalene (IIb, approximately 20% by weight), epi-beta-santalene (IIc, approximately 2% by weight), trans-alpha-bergamotene (IId, approximately 20% by weight), and beta-bisabolene (IIe, approximately 3% by weight). Subjecting this mixture to the method of the present invention produces the corresponding santalol sesquiterpenoids in similar proportions. Possible deviations are, for example, due to overchlorination of certain santalene sesquiterpenes (II) in the mixture, since overchlorinated products usually cannot be converted to the corresponding santalol sesquiterpenoids (see below). Perfumers evaluating the products obtained using the method of the present invention for their similarity to natural sandalwood oil indicated that the perceived odor was "very good."

[0035] An initial attempt to avoid the use and production of solids in this process (as in the Willis procedure) was to replace Ca(ClO) with a solution of NaOCl in water (i.e., bleach). While this gave initially promising results in terms of reaction yield and selectivity, undesirable variations in the selectivity of the reaction were observed when this reaction was performed multiple times, especially when attempts were made to scale up the reaction. This was attributed to pH fluctuations caused by the addition of solid CO.

[0036] Next, we attempted to carry out the reaction under buffered conditions in the absence of dry ice. Therefore, various buffers were tested in the pH range of 4 to 10, but all of these resulted in almost no conversion of the santalene sesquiterpene starting material. More acidic environments were initially avoided due to the risk of ClO formation, a highly reactive and especially undesirable explosive gas if the reaction were carried out on a large scale. The accumulation of such species in the reaction mixture is dangerous due to the risk of explosion.

[0037] When the reaction was carried out under more acidic conditions, the yields were also very low (only a few percent conversion to the desired santalol sesquiterpenoid). Surprisingly, however, when a small excess of acid (relative to NaOCl) was used in the reaction, chlorosantalene was obtained in yield and selectivity at least as high as that reported for the Willis procedure. Furthermore, no variability in the selectivity of the reaction was observed when run on various large scales (e.g., 10 kg of santalene), as well as when dry ice was used. The excess acid is typically no more than 5 equivalents of acid relative to NaOCl. Typically, the excess ranges from 1.05 to 3.0 equivalents of acid relative to NaOCl. Preferably, the excess ranges from 1.1 to 2.0 equivalents of acid, more preferably from 1.2 to 1.6 equivalents of acid. The excess can also range from 1.2 to 2.5 equivalents of acid, from 1.4 to 2.2 equivalents of acid, or from 1.6 to 1.9 equivalents of acid. The excess may also be in the range of 1.05 to 1.8 equivalents of acid, 1.1 to 1.6 equivalents of acid, 1.15 to 1.5 equivalents of acid, or 1.2 to 1.4 equivalents of acid. In the chlorination, NaOCl is typically present as a 5 to 50 wt % aqueous solution of NaOCl.

[0038] Typically, 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 to 2.0, particularly 1.1 to 1.9, more particularly 1.2 to 1.8, and even more particularly 1.3 to 1.7. The molar excess of NaOCl may also be in the range of 1.1 to 1.7, 1.2 to 1.5, or 1.25 to 1.45.

[0039] In particular, the acid is present in the range of 1.2 to 1.5 molar equivalents relative to NaOCl, while NaOCl is present in the range of 1.25 to 1.75 molar equivalents relative to the santalene sesquiterpene. More particularly, the acid is present in the range of 1.25 to 1.45 molar equivalents relative to NaOCl, while NaOCl is present in the range of 1.3 to 1.7 molar equivalents relative to the santalene sesquiterpene.

[0040] In this procedure, the acid is typically first mixed with the santalene sesquiterpene, optionally in the presence of a solvent such as toluene. Chlorination is then carried out by very slowly adding NaOCl as an aqueous solution in water (e.g., a 10-20% by weight solution) to the santalene mixture. It is also possible to add the acid simultaneously with the bleach, typically at a relative rate corresponding to the relative amounts added, so that the reaction mixture remains acidic throughout the reaction. Simultaneous addition has the advantage that the pH of the reaction mixture does not change significantly during the reaction, particularly since the initial pH is not as low as it would be if all the acid were present in the reaction mixture prior to the addition of the bleach.

[0041] Another advantage of this method is that the conversion rate and selectivity are largely independent of the dosage protocol, allowing for slow dosing of the NaOCl solution in the reactor. This minimizes the risks associated with having large batches of such oxidizing substances in the reaction mixture. Furthermore, when the conversion of the santalene sesquiterpene continues during the addition of the NaOCl solution, the chlorination of the santalene sesquiterpene upon addition of NaOCl appears to be almost instantaneous. Therefore, there is little risk of explosive ClO accumulation. This paves the way for safe scale-up of the conversion to the chlorosantalene(III) intermediate.

[0042] The acid can in principle be any acid compatible with the reaction conditions. The acid can be an inorganic acid, for example, an acid selected from the group consisting of sulfuric acid, hydrochloric acid, and boric acid. Preferably, the acid has a pKa higher than 0, more preferably a mild acid with a pKa of 3.0 or higher. In a preferred embodiment, the acid is a carboxylic acid. Generally, the acid applied is most effective if it is soluble in water under the reaction conditions applied and / or has a pKa value of 5.0 or lower. If the acid does not dissolve during the reaction, it is preferred that the acid be liquid during the reaction.

[0043] If 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, mild carboxylic acids having a pKa of 3 or greater are used in the process of the present invention.

[0044] More preferably, the acid is acetic acid or formic acid, or a mixture thereof, more preferably acetic acid. It has been observed that carrying out the reaction in the presence of acetic acid resulted in very good conversion and good selectivity to the desired monochlorinated product. Furthermore, the reaction showed excellent reproducibility.

[0045] The chlorination reaction is preferably carried out in a two-phase system having an aqueous phase containing NaOCl and an organic phase containing the santalene sesquiterpene starting material (II) and chlorosantalene (III). The solvent for the organic phase preferably comprises or consists of toluene. Other solvents that can be applied are those selected from the group consisting of hydrocarbons, such as heptane, hexane, cyclohexane, methylcyclohexane, decane, and dodecane. Similarly, halogenated hydrocarbons, such as dichloromethane, may be used. However, the chlorination reaction appears to be significantly cleaner in toluene than in dichloromethane, for example, in terms of fewer chlorinated by-products. Furthermore, it has been found that particularly good yields are obtained when methylcyclohexane is used as the solvent.

[0046] Yet another solvent that may be used is diethyl ether. Additionally, the reaction can be carried out neat, i.e., without a solvent.

[0047] The 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 effective in the two-phase system (aqueous and organic phases) that forms upon addition of bleach.

[0048] Although the direct conversion of chlorosantalene (III) to the desired santalol sesquiterpenoid product (I) appeared to be difficult, a two-step process via an ester intermediate proved successful. - Chlorosantalene(III) to carboxylate ion R'-COO - to form the corresponding carboxylic acid ester of formula (IV)

[0049] [ka] (R' comprises an alkyl group of 1 to 7 carbon atoms), - hydrolyzing the ester of formula (IV) to the corresponding compound of formula (I) This is preferably carried out by

[0050] In this method, which entails a substitution reaction, the carboxylate ion is typically an alkylcarboxylate ion having an alkyl chain of, for example, 1 to 8 carbon atoms, which may include branches. In the case of a branched chain, the total number of carbon atoms in the carboxylate ion is preferably in the range of 3 to 10. Preferably, the carboxylate ion is a C1 to C5 carboxylate ion, such as formate, acetate, propionate, butyrate, and valerate. More preferably, the carboxylate ion is acetate and / or formate.

[0051] When formate ions are used as the carboxylate ions in the process of the present invention, the reaction time is further improved, and the isomer ratio between Z and E santalol is likewise further improved.

[0052] In another embodiment, potassium and / or sodium salts of acids are used, preferably potassium acetate and / or potassium formate.

[0053] The carboxylate ion may also be selected from the group of formate, benzoate and pivalate. The carboxylate ion is usually added before or during the reaction as a metal carboxylate salt (R'-COONa or R'-COOK), for example sodium or potassium.

[0054] In one embodiment, instead of one type of carboxylate ion, a mixture of carboxylate ions is used.

[0055] The hydrolysis of the carboxylic acid ester of formula (IV) to santalol (I) can be carried out according to standard ester hydrolysis procedures known in the art, for example, the hydrolysis can be carried out in methanol using potassium hydroxide as a base.

[0056] Thus, the present invention provides a compound of formula (I)

[0057] [ka] (Wherein, R=a, b, c, d or e

[0058] [ka] is) A method for synthesizing - optionally in the presence of a solvent, such as but not limited to toluene,

[0059] [ka] and an acid or a mixture of acids; and - contacting the mixture with aqueous NaOCl to form an intermediate of formula (III)

[0060] [ka] generating and - reacting the intermediate of formula (III) with one or more carboxylate ions R'-COO - to form the corresponding carboxylic acid ester of formula (IV)

[0061] [ka] (R' comprises an alkyl group of 1 to 7 carbon atoms), and - hydrolyzing the ester of formula (IV) to the corresponding compound of formula (I) The present invention relates to a method of synthesis, including:

[0062] When the double bond in the allylic alcohol moiety of the compound of formula (I) is related to natural sandalwood oil, it is in the Z-configuration (compounds with E-configuration are not observed here). This is not the case when santalol compounds are obtained by the method of the present invention, since this method produces small amounts of the E-isomer, for example in the range of 25-45 mol % (depending on the reaction conditions). Fortunately, the impact of such isomers on organoleptic properties appears to be minimal.

[0063] The type of carboxylate and organic solvent appeared to significantly affect the Z / E ratio of the santalols formed. The most favorable ratios occurred when the substitution reaction was carried out in gamma-valerolactone using acetate or formate as the carboxylate. After conversion of the santalyl carboxylate (IV) intermediate to the final santalol (I), alpha-santalol (Ia) appeared to form as two stereoisomers (Z and E) in a 65:35 ratio when acetate or formate was used. Indeed, since only the terminal isoprene fragment (a common motif in all isomers) participates in the substitution reaction, it is expected that the other chlorosantalenes (IIIb-IIIe) would yield the same Z / E ratio.

[0064] One embodiment of the present invention relates to a process according to the invention in which the compound of formula (I) is produced in at least 55% as the Z isomer, preferably at least 57%, 59%, 61%, 63% or at least 65% of the santalol is produced as the Z isomer. In one embodiment, the process of the present invention produces a compound of formula (I), e.g., santalol, in a ratio of isomers (Z and E) of 55:45, preferably 60:40, more preferably 65:35 or higher.

[0065] As noted above, the reactivity required in the tail is expected to be similar for various santalene sesquiterpenes, so the method of the present invention can be performed on only one santalene sesquiterpene (II) or any mixture thereof. Thus, if the starting material contains two or more santalene sesquiterpenes of formula (II), the method of the present invention will produce two or more corresponding santalol sesquiterpenoids of formula (I).

[0066] Thus, the method of the present invention comprises: - chlorination is carried out on the mixture of compounds of formula (II) to produce a mixture of the corresponding intermediates of formula (III), and - a process in which a mixture of intermediates of formula (III) is converted into a mixture of the corresponding compounds of formula (I).

[0067] In one embodiment, the conversion of santalene to santalol is greater than 65%, preferably at least 70%, more preferably at least 80%, and even more preferably at least 90%.

[0068] In particular, the mixture of compounds of formula (II) comprises compounds of formula (IIa), formula (IIb), formula (IIc), formula (IId) and formula (IIe).

[0069] It has been surprisingly found that over-chlorination of the santalene starting material (II) occurs when more than one equivalent of NaOCl is used, with trans-alpha-bergamotene (IId) being preferred over the other santalenes (IIa), (IIb), (IIc), and (IIe). Over-chlorination refers to the introduction of more than one chloro substituent, particularly two or three chloro substituents, into the santalene sesquiterpene starting material (II). Unexpectedly, over-chlorination was selective for trans-alpha-bergamotene (IId). This means that when chlorination is performed on a mixture of compounds of formulas (IIa), (IIb), (IIc), (IId), and (IIe), the amount of chlorosantalene of formula (IIId) is disproportionately lower than the other chlorosantalenes (IIIa), (IIIb), (IIIc), and (IIIe). This also has implications for the final santalol sesquiterpenoid product (I), since it will contain a significantly lower proportion of trans-alpha-bergamotol than if no over-chlorination had been applied. Since this is a particularly undesired, and sometimes even unwanted, isomer in santalol mixtures, the over-chlorination process opens the way to producing sandalwood oil with a reduced proportion of trans-alpha-bergamotol.

[0070] For this purpose, the over-chlorinated trans-alpha-bergamotene (IId) must be removed or decomposed at some stage in the process to santalol isoprenoids. It has been found that distillation of the crude mixture obtained after hydrolysis of santalyl acetate of formula (IV) produces the final santalol sesquiterpenoid of formula (I) without any measurable amount of over-chlorinated products, neither derivatives (e.g., diols or triols) nor their decomposition products.

[0071] Thus, in one embodiment, the process of the present invention is a process as described herein, wherein at least 60%, preferably at least 70% and more preferably at least 80% of the trans-alpha-bergamotene is converted to derivatives, and these undesired bergamotene derivatives can be easily removed by distillation.

[0072] The excess amount of NaOCl required for over-chlorination should be sufficient to over-chlorinate trans-alpha-bergamotene (IId), but a greater excess is not preferred because it results in undesirable over-chlorination and / or decomposition of the desired chlorosantalenes (IIIa), (IIIb), (IIIc), and (IIIe). Thus, when the aim is to reduce the content of trans-alpha-bergamotene (IId) in the product mixture, the molar excess of NaOCl relative to the amount of trans-alpha-bergamotene (IId) is typically in the range of 2.1 to 3.5, preferably 2.2 to 3.2.

[0073] However, this ratio may also depend on the reaction conditions applied, since not all of the NaOCl may be consumed as oxidizing agent. For example, a significant portion of the NaOCl may be converted to Cl. Any amount of this gas escaping from the reaction mixture should be offset by a greater amount of NaOCl being used in the chlorination reaction. Those skilled in the art will know, by routine experimentation and without inventive effort, how to arrive at an appropriate excess amount of NaOCl for a given particular reaction condition.

[0074] Thus, in the process of the present invention, the chlorination of the mixture is - converting the compounds of formula (IIa), (IIb), (IIc) and (IIe) into intermediates of formula (IIIa), (IIIb), (IIIc) and (IIIe), and - introducing two or three chloro substituents in a compound of formula (IId) to produce dichlorinated and / or trichlorinated analogues of a compound of formula (IIId); and The dichlorinated and / or trichlorinated analogs are removed from intermediates of formula (IIIa), (IIIb), (IIIc) and (IIIe) before or during the conversion of these intermediates to the corresponding compounds of formula (IVa), (IVb), (IVc) and (IVe) and / or during the conversion of compounds of formula (IVa), (IVb), (IVc) and (IVe) to the corresponding compounds of formula (Ia), (Ib), (Ic) and (Ie).

[0075] The present invention further relates to a compound of formula (IIId), which is chlorinated trans-alpha-bergamotene, which can be separated from the reaction mixture after chlorination. As detailed above, this compound is an intermediate in the production of trans-alpha-bergamotol (Id).

[0076] The present invention relates to a compound of formula (III)

[0077] [ka] (Wherein, R=a, b, c, d or e

[0078] [ka] is) Further related to.

[0079] The present invention further includes a composition obtainable by the method of the present invention, comprising bergamotol, E-santalol, and Z-santalol, wherein the amount of bergamotol, preferably trans-alpha-bergamotol, is 15% (w / w) or less, preferably 12% (w / w) or less, and more preferably 10% (w / w) or less of the composition, and Z-santalol is present in excess of E-santalol. Preferably, Z-santalol is present in excess of E-santalol by 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) to improve the preference ratio. In another embodiment, the ratio of Z santalol to E santalol is at least 55:45, preferably 60:40 or more, more preferably 65:35 or more. Preferably, the composition is a synthetic composition.

[0080] [Example] 1. Chlorination of Santalene Sesquiterpene (II) In a 250 mL three-necked round-bottom flask equipped with a magnetic stirrer, thermometer, and dropping funnel, santalene mix (10.0 g, obtained by the procedure described in WO2018 / 160066), toluene (75 mL), and AcOH (6.0 mL) were added. NaOCl (14% Cl2 solution) (33.75 mL and 34.50 mL) was placed in the dropping funnel and added very slowly to the reaction mixture over a period of 2 hours. Aliquots of the reaction were extracted and analyzed by GC. Subsequently, 1 mL portions of NaOCl (14% Cl2 solution) were added at 30-minute intervals until the starting santalene mix (II) was completely converted to the product. After completion of the reaction, NaHCO3 solution was added to the reaction mixture, and the organic phase was extracted. The organic phase was washed twice with NaCl solution, dried, and the solvent was evaporated in vacuo to give a yellow oil (11.98 g). The residue was analyzed by GC. Approximately 80% of the trans-alpha-bergamotene is converted to derivatives, and these undesired bergamotene derivatives can be easily removed by distillation.

[0081] 2. Substitution of the chloro group in chlorosantalene(III) A 100 mL round-bottom flask equipped with a magnetic stirrer was charged with KOAc (7.46 g), KI (800 mg), and the chlorosantalene mix (5.0 g) obtained in Example 1. 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 2 hours (DMA) or overnight (toluene / TBAB). The reaction progress was monitored by GC. After completion of the reaction, the reaction mixture was cooled to room temperature, and an aqueous NaHCO3 solution and n-pentane were added. The reaction mixture was transferred to a dropping funnel, and the organic phase was extracted and washed with brine (or several times with LiCl solution in the case of DMA). The organic phase was dried over sodium sulfate, filtered, and the solvent was removed in vacuo to yield a light yellow oil. The residue was analyzed by GC and NMR.

[0082] 3. Hydrolysis of santalyl acetate (IV) A 100 mL round-bottom flask equipped with a magnetic stirrer was charged with the santalyl acetate mixture obtained in Example 2 (5.0 g), KOH (5.0 g), HO (6.8 mL), and MeOH (34 mL). The reaction mixture was heated to 60° C. for 10 minutes and stirred at room temperature for an additional 30 minutes. After completion of the reaction, water (approximately 60 mL) and n-pentane / AcOEt (4 / 1, 60 / 15 mL) were added to the reaction mixture. The organic phase was extracted and washed with brine. The organic phase was then dried over sodium sulfate and filtered. The solvent was removed in vacuo to give a light yellow oil (4.0 g), which was analyzed by GC. After distillation of this oil, the santalol sesquiterpenoids of formula (I) were isolated as a mixture.

[0083] The conversion of santalene to santalol was over 90%, and santalol was formed as two stereoisomers (Z and E) in a ratio of 65:35. It was also found that trans-alpha-bergamotol was present at levels significantly lower than the initial trans-alpha-bergamotene levels, compared to the levels when no over-chlorination was applied.

[0084] In experiment 2, even better results were obtained when potassium formate was replaced with potassium acetate.

[0085] References: Nussbaumer, C., Frater, 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 Aspects of the present disclosure include the following. [1] Compounds of formula (I) [ka] (Wherein, R=a, b, c, d or e [ka] is) A method for synthesizing - a starting compound of formula (II) [ka] is chlorinated to give an intermediate of formula (III) [ka] To make - converting the intermediate of formula (III) into a compound of formula (I) Including, The synthetic method wherein the chlorination comprises combining the starting compound of formula (II) with an acid and aqueous NaOCl. [2] The method of embodiment 1, wherein the acid is a carboxylic acid. [3] 3. The method of claim 2, wherein the carboxylic acid is selected from the group 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. [4] The method of any one of aspects 1 to 3, wherein the acid is present in an amount ranging from 1.05 to 3.0 equivalents of acid relative to NaOCl, particularly ranging from 1.1 to 2.0 equivalents of acid, and more particularly ranging from 1.2 to 1.5 equivalents of acid. 5. The method according to any one of aspects 1 to 4, wherein NaOCl is present in an amount in the range of 1.1 to 1.9 molar equivalents, in particular in the range of 1.3 to 1.7 molar equivalents, relative to the starting compound of formula (II). [6] 4. The method of any one of aspects 1 to 3, wherein the acid is present in an amount ranging from 1.2 to 1.5 equivalents of acid relative to NaOCl, while NaOCl is present in an amount ranging from 1.25 to 1.75 molar equivalents relative to the starting compound of Formula (II). [7] Aspect 7. The method according to any one of aspects 1 to 6, wherein the chlorination is carried out in the presence of an organic solvent, in particular a solvent selected from the group of toluene, dichloromethane and methylcyclohexane. [8] Conversion of the intermediate of formula (III) to a compound of formula (I) - The intermediate of formula (III) is reacted with the carboxylate ion R'-COO - to form the corresponding carboxylic acid ester of formula (IV)

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[10] - chlorination is carried out on the mixture of compounds of formula (II) to produce a mixture of the corresponding intermediates of formula (III), The method according to any one of aspects 1 to 9, wherein a mixture of intermediates of formula (III) is converted into a mixture of corresponding compounds of formula (I).

[11] The method of embodiment 10, wherein the mixture of compounds of Formula (II) comprises compounds of Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), and Formula (IIe).

[12] Chlorination of the mixture - converting starting compounds of formula (IIa), (IIb), (IIc) and (IIe) into intermediates of formula (IIIa), (IIIb), (IIIc) and (IIIe); and - introducing di- or tri-chloro substituents in the starting compound of formula (IId) to produce di- and / or tri-chlorinated analogs of the intermediate of formula (IIId); 12. The method of embodiment 11, comprising: Prior to or during the conversion of the intermediates of formula (IIIa), formula (IIIb), formula (IIIc), and formula (IIIe) to the corresponding santalol sesquiterpenoids of formula (Ia), formula (Ib), formula (Ic), and formula (Ie), the dichlorinated and / or trichlorinated analogs are removed from the mixture. method.

[13] The method of embodiment 12, wherein NaOCl is present in the chlorination reaction in an amount in the range of 2.1 to 3.5 molar equivalents, preferably in the range of 2.2 to 3.2 molar equivalents, relative to the starting compound of formula (IId).

[14] A method according to embodiment 12, wherein the compound of formula (I) is produced in a ratio of isomers (Z and E) of 55:45, preferably 60:40, more preferably 65:35 or higher.

[15] Compound of formula (III)

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[16] A composition comprising bergamotol, preferably trans-alpha-bergamotol, Z santalol and E santalol, wherein the bergamotol, preferably trans-alpha-bergamotol, is present in an amount of 10% (w / w) or less, and Z santalol is present in excess of E santalol.

Claims

1. Compounds of formula (I) 【Chemical 1】 (Wherein, R=a, b, c, d or e 【Chemistry 2】 is) A method for synthesizing - a starting compound of formula (II) 【Chemistry 3】 is chlorinated to give an intermediate of formula (III) 【Chemistry 4】 To make - converting the intermediate of formula (III) into a compound of formula (I) Including, The synthetic method wherein the chlorination comprises combining the starting compound of formula (II) with an acid and aqueous NaOCl.

2. 10. The method of claim 1, wherein the acid is a carboxylic acid.

3. 3. The method of 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.

4. 4. The process according to any one of claims 1 to 3, wherein the acid is present in an amount in the range of 1.05 to 3.0 equivalents of acid relative to NaOCl, particularly in the range of 1.1 to 2.0 equivalents of acid, more particularly in the range of 1.2 to 1.5 equivalents of acid.

5. 5. The process according to claim 1, wherein NaOCl is present in an amount ranging from 1.1 to 1.9 molar equivalents, in particular in the range from 1.3 to 1.7 molar equivalents, relative to the starting compound of formula (II).

6. 4. The process according to any one of claims 1 to 3, wherein the acid is present in an amount ranging from 1.2 to 1.5 equivalents of acid relative to NaOCl, while NaOCl is present in an amount ranging from 1.25 to 1.75 molar equivalents relative to the starting compound of formula (II).

7. 7. The process according to any one of claims 1 to 6, wherein the chlorination is carried out in the presence of an organic solvent, in particular a solvent selected from the group of toluene, dichloromethane and methylcyclohexane.

8. Conversion of the intermediate of formula (III) to a compound of formula (I) - The intermediate of formula (III) is reacted with the carboxylate ion R'-COO - to form the corresponding carboxylic acid ester of formula (IV) 【Chemistry 5】 (R' comprises an alkyl group of 1 to 7 carbon atoms), followed by - hydrolyzing the ester of formula (IV) to the corresponding compound of formula (I) The method according to any one of claims 1 to 7, wherein the method is carried out by

9. 9. The method according to claim 8, wherein the carboxylate ion is an acetate ion, a formate ion, or a propionate ion.

10. - chlorination is carried out on the mixture of compounds of formula (II) to produce a mixture of the corresponding intermediates of formula (III), 10. The process according to any one of claims 1 to 9, wherein a mixture of intermediates of formula (III) is converted into a mixture of the corresponding compounds of formula (I).

11. 11. The method of claim 10, wherein the mixture of compounds of formula (II) comprises compounds of formula (IIa), formula (IIb), formula (IIc), formula (IId), and formula (IIe).

12. Chlorination of the mixture - converting starting compounds of formula (IIa), (IIb), (IIc) and (IIe) into intermediates of formula (IIIa), (IIIb), (IIIc) and (IIIe); and - introducing di- or tri-chloro substituents in the starting compound of formula (IId) to produce di- and / or tri-chlorinated analogs of the intermediate of formula (IIId); 12. The method of claim 11, comprising: Prior to or during the conversion of the intermediates of formula (IIIa), formula (IIIb), formula (IIIc), and formula (IIIe) to the corresponding santalol sesquiterpenoids of formula (Ia), formula (Ib), formula (Ic), and formula (Ie), the dichlorinated and / or trichlorinated analogs are removed from the mixture. method.

13. 13. The process according to claim 12, wherein NaOCl is present in the chlorination reaction in an amount ranging from 2.1 to 3.5 molar equivalents, preferably in the range from 2.2 to 3.2 molar equivalents, relative to the starting compound of formula (IId).

14. 13. The method of claim 12, wherein the compound of formula (I) is produced in a ratio of isomers (Z and E) of 55:45, preferably 60:40, more preferably 65:35 or higher.

15. Compound of formula (III) 【Chemistry 6】 (Wherein, R=d or e 【Chemistry 7】 (It is).

16. A composition comprising bergamotol, preferably trans-alpha-bergamotol, Z santalol and E santalol, wherein the bergamotol, preferably trans-alpha-bergamotol, is present in an amount of 10% (w / w) or less, and Z santalol is present in excess of E santalol.

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