Synthesis of OXA-bicycloalkenes

Abstract

The present invention relates to a process for the preparation of an oxa-bicycloalkene from a hydroxyalkyl cycloalkanone in the presence of an acid and using a thin film evaporator and the use of a thin film evaporator to conduct such a process.

Description

[0001] DSM-Firmenich 16390 / WO

[0002] SYNTHESIS OF OXA-BICYCLOALKENES

[0003] Technical field

[0004] The present invention relates to a process for the preparation of an oxa-bicycloalkene from a hydroxyalkyl cycloalkanone in the presence of an acid and using a thin film evaporator and the use of a thin film evaporator to conduct such a process.

[0005] Background of the invention

[0006] The field of chemical synthesis has continually sought to enhance the efficiency and selectivity of various reactions to meet growing industrial demands. A notable area of focus is the transformation of hydroxyalkyl cycloalkanones into oxa-bicycloalkenes. These compounds are valuable intermediates used in the synthesis of pharmaceuticals, cosmetic ingredients, and other fine chemicals. Traditional approaches to synthesizing oxa- bicycloalkenes often involve multiple reaction steps, extended reaction times, and the use of harsh reagents, which can lead to low yields and significant by-product formation.

[0007] One common method employed in these processes is the continuously stirred tank reactor (CSTR). While CSTR setups are widely used, they present certain limitations, including poor volumetric productivity, low surface-to-volume ratio, poor mixing efficiency and poor product recovery.

[0008] The inventors found that the application of thin film evaporators to the preparation of oxa- bicycloalkenes from hydroxyalkyl cycloalkanones presents a promising advancement. By leveraging the advantages of thin film evaporator technology, this approach can overcome the limitations of traditional methods, offering a more efficient, sustainable, and cost-effective process for synthesizing oxa-bicycloalkenes.

[0009] Summary of the invention

[0010] In a first aspect, the invention relates to a process for the preparation of an oxa-bicycloalkene from a hydroxyalkyl cycloalkanone in the presence of an acid and using a thin film evaporator.

[0011] In a second aspect, the invention relates to the use of a thin film evaporator, preferably a short path evaporator, falling film evaporator, a wiped film evaporator, a rising film evaporator for producing an oxa-bicycloalkene from a hydroxyalkyl cycloalkanone in the presence of an acid. DSM-Firmenich 16390 / WO

[0012] Brief Description of the Figures

[0013] Figure 1 shows an exemplary setup for the claimed process.

[0014] Figure 2 shows a further exemplary setup for the claimed process.

[0015] Detailed description of the invention

[0016] A first object of the invention is a process for the preparation of an oxa-bicycloalkene from a hydroxyalkyl cycloalkanone in the presence of an acid and using a thin film evaporator.

[0017] According to an embodiment the reaction of the hydroxyalkyl cycloalkanone in the presence of an acid to form an oxa-bicycloalkene is carried out in a thin film evaporator.

[0018] The reaction product of the process is an oxa-bicycloalkene.

[0019] The term "oxa-bicycloalkene" refers to a bicyclic compound characterized by the presence of an oxygen atom within one of its rings and a double bond (alkene) within the bicyclic framework. The term encompasses compounds where the bicyclic structure can vary in the number of carbon atoms and the position of the oxygen atom and the double bond. Specifically, the term "oxa" indicates the inclusion of an oxygen heteroatom, while "bicyclo" denotes the presence of two fused rings, and "alkene" signifies at least one carbon-carbon double bond within the bicyclic system.

[0020] The starting material of the process is a hydroxyalkyl cycloalkanone.

[0021] The term "cycloalkanone" refers to a class of organic compounds characterized by a cyclic structure containing one or more carbon atoms arranged in a ring, with a single ketone functional group (carbonyl group, C=O) bonded to one of the carbon atoms in the ring. The general formula for cycloalkanones is C1H21-2O, where I represents the number of carbon atoms in the ring.

[0022] According to an embodiment, the cycloalkanone does not comprise a bicyclic moiety.

[0023] The term "hydroxyalkyl" refers to an organic functional group characterized by an alkyl chain that includes one or more hydroxyl groups (-OH) attached to one or more of its carbon atoms. The alkyl chain is a saturated hydrocarbon chain that can vary in length and structure, DSM-Firmenich 16390 / WO comprising linear, branched, or cyclic configurations. The hydroxyl group is a functional group consisting of an oxygen atom bonded to a hydrogen atom (-OH).

[0024] According to an embodiment the hydroxyalkyl group comprises a terminal hydroxyl group or wherein the hydroxyl group is bonded to a secondary carbon atom, which is a carbon atom bonded to two other carbon atoms.

[0025] According to an embodiment, the hydroxyalkyl group comprises only one hydroxyl group.

[0026] According to an embodiment, the formation of the oxa-bicycloalkene is the result of a cyclisation-condensation reaction between the keto-functionality of the cycloalkanone and the hydroxyl-functionality of the hydroxyalkyl moiety.

[0027] According to an embodiment, the hydroxyalkyl cycloalkanone comprises a cycloalkanone moiety comprising a 5-16 membered ring comprising carbon and, optionally, oxygen sulfur and / or nitrogen.

[0028] According to an embodiment, the hydroxyalkyl cycloalkanone comprises a C2-12 hydroxyalkyl group, preferably a C3-4 hydroxyalkyl group.

[0029] According to an embodiment, the oxa-bicycloalkene is a compound of formula (I)

[0030] (I), wherein m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8,

[0031] R1 to Rs each independently, represents H, OH, SH, CN, NO2, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, C3-8 heterocycloalkyl, C1-8 heterocycloalkyl, C1-10 acyloxy, aryl, aryloxy, arylthio, C1-10 arylalkyl, heteroaryl, heteroarlyoxy, heteroarylthio, C1-10 heteroarylalkyl, C1-10 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1-10 alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, C1-10 alkylmercapto, aryl mercapto or heteroaryl mercapto group and

[0032] R9 represents H or a C1-10 hydrocarbyl group. DSM-Firmenich 16390 / WO

[0033] The dashed double bond in formula (I) indicates that the presence of a double bond at that position is variable and not fixed. Each dashed double bond may represent a double bond (C=C) or a single bond (C-C). It is herewith understood that two double bonds next to each other, such as forming an allene, is not encompassed by formula (I).

[0034] The position of Rg is not fixed and can be located at any carbon atom within the dihydropyran ring, provided that Rg is attached to a saturated carbon atom.

[0035] The term “hydrocarbyl group” refers to a chemical group consisting primarily of carbon and hydrogen atoms. The term also encompasses groups wherein one or more carbon and / or hydrogen is / are replaced by heteroatoms such as oxygen, nitrogen, sulfur, or phosphorus.

[0036] The terms “alkyl”, “alkenyl” and “alkynyl” are understood as comprising branched and linear alkyl, alkenyl and alkynyl groups. The term “alkyl group” refers to a saturated hydrocarbon chain, which may be linear, branched, or cyclic, comprising carbon and hydrogen atoms. The term “alkenyl group” refers to an unsaturated hydrocarbon chain comprising 1, 2 or 3 olefinic bonds, preferably 1 or 2 olefinic bonds. The term "alkynyl" refers to a hydrocarbon chain that contains at least one triple bond between carbon atoms. It can be linear or branched. The term "heteroalkyl" refers to a hydrocarbon chain that includes one or more heteroatoms (such as oxygen, nitrogen, or sulfur) in place of one or more carbon atoms within the chain. The term "heterocycloalkyl" refers to a cyclic hydrocarbon structure that includes one or more heteroatoms within the ring. The heterocycloalkyl group is a cyclic structure composed of carbon and heteroatoms (such as oxygen, nitrogen, or sulfur). The term "acyloxy" refers to a functional group consisting of an ester linkage where the acyl part is derived from a carboxylic acid. The general formula is RCOO-, where R represents an alkyl or aryl group, and the group is characterized by a carbonyl (C=O) and an alkoxy (O-) group. The term “aryl” designates the normal meaning in the art, i.e., an aromatic hydrocarbon group such as phenyl, pyridine, biphenyl, anthryl or naphthyl group optionally substituted. Non-limiting examples of the optional substituent of the aryl group may include a C1-4 alkyl or alkoxy group, a hydroxy group or a halogen atom. The term "aryloxy" refers to an aryl group bonded to an oxygen atom, forming an aromatic ether. It is represented by the general formula Ar-O-, where Ar denotes the aryl group. The term "arylthio" refers to an aryl group bonded to a sulfur atom, forming an aromatic thioether. The general formula is Ar-S-, where Ar denotes the aryl group. The term "arylalkyl" refers to a hydrocarbon chain (alkyl) bonded to an aryl group. It consists of an alkyl chain connected to an aryl group. The term "heteroaryl" refers to DSM-Firmenich 16390 / WO an aromatic ring system that contains one or more heteroatoms (such as nitrogen, oxygen, or sulfur) within the ring. The term "heteroaryloxy" refers to a heteroaryl group bonded to an oxygen atom, forming an aromatic ether. The term "heteroarylthio" refers to a heteroaryl group bonded to a sulfur atom, forming an aromatic thiol or thioether. The term "heteroarylalkyl" refers to a hydrocarbon chain (alkyl) bonded to a heteroaryl group. It consists of an alkyl chain connected to a heteroaryl group. The term "alkylsulfonyl" refers to a sulfonyl group (SO2) bonded to an alkyl group. The general formula is R-SO2-, where R denotes the alkyl group. The term "arylsulfonyl" refers to a sulfonyl group (SO2) bonded to an aryl group. The general formula is Ar-SO2-, where Ar denotes the aryl group. The term "heteroarylsulfonyl group" refers to a sulfonyl group (SO2) bonded to a heteroaryl group. The general formula is HetAr-SO2-, where HetAr denotes the heteroaryl group. The term "alkylsulfonamide" refers to a sulfonamide group (SO2NH) where the sulfonyl part is bonded to an alkyl group. The general formula is R-SO2-NH-, where R denotes the alkyl group. The term "arylsulfonamide" refers to a sulfonamide group (SO2NH) where the sulfonyl part is bonded to an aryl group. The general formula is Ar-SO2-NH-, where Ar denotes the aryl group. The term "heteroarylsulfonamide" refers to a sulfonamide group (SO2NH) where the sulfonyl part is bonded to a heteroaryl group. The general formula is HetAr-SCh-NH-, where HetAr denotes the heteroaryl group. The term "alkylmercapto" refers to a mercapto group (- SH) bonded to an alkyl group. The general formula is R-SH, where R denotes the alkyl group. The term "arylmercapto" refers to a mercapto group (-SH) bonded to an aryl group. The general formula is Ar-SH, where Ar denotes the aryl group. The term “heteroaryl mercapto” refers to a mercapto group (-SH) bonded to an heteroaryl group. The general formula is HetAr-SH, where HetAr denotes the heteroaryl group.

[0037] According to an embodiment, the oxa-bicycloalkene is a compound of formula (I), wherein the dashed double bonds represent a total of 2 double bonds.

[0038] According to an embodiment R1 to R9, each independently represents a hydrogen, m is equal to 1 and n is 7 and the dashed double bonds represent a total of 2 double bonds.

[0039] According to a preferred embodiment, the oxa-bicycloalkene is a compound of formula (I), wherein all dashed double bonds represent saturated hydrocarbon groups.

[0040] According to a preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) wherein all dashed double bonds represent saturated hydrocarbon groups, m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and R1 to Rs, DSM-Firmenich 16390 / WO each independently, represents H or a C1-10 alkyl group and R9 represents H or a C1-10 hydrocarbyl group.

[0041] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) wherein all dashed double bonds represent saturated hydrocarbon groups, m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and R1 to Rs, each independently, represents H and R9 represents H or a C1-10 hydrocarbyl group.

[0042] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) wherein all dashed double bonds represent saturated hydrocarbon groups, m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and R1 to R9, each independently, represents H.

[0043] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) wherein all dashed double bonds represent saturated hydrocarbon groups, m is 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and R1 to R9, each independently represents H.

[0044] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) wherein all dashed double bonds represent saturated hydrocarbon groups, m is 1 , n is 7 and R1 to R9, each independently represents H.

[0045] According to an embodiment, the hydroxyalkyl cycloalkanone is a compound of formula (II)

[0046] (II), wherein n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8,

[0047] R1 to Rs each independently, represents H, OH, SH, CN, NO2, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, C3-8 heterocycloalkyl, C1-8 heterocycloalkyl, C1-10 acyloxy, aryl, aryloxy, arylthio, C1-10 arylalkyl, heteroaryl, heteroarlyoxy, heteroarylthio, C1-10 heteroarylalkyl, C1-10 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1-10 alkylsulfonamide, DSM-Firmenich 16390 / WO arylsulfonamide, heteroarylsulfonamide, Ci- alkylmercapto, aryl mercapto, or heteroaryl mercapto group and

[0048] Rw represents a C2-12 hydroxyalkyl group, optionally substituted with a C1-10 hydrocarbyl group, preferably wherein R10 represents a C3-4 hydroxyalkyl group.

[0049] According to an embodiment, the hydroxyalkyl cycloalkanone is a compound of formula (II), wherein the dashed double bonds represent a total of 2 double bonds.

[0050] According to an embodiment R1 to Rs, each independently represents a hydrogen, and the dashed double bonds represent a total of 2 double bonds, and Rw preferably represents a C3-4 hydroxyalkyl group.

[0051] According to a preferred embodiment, the hydroxyalkyl cycloalkanone is a compound of formula (II), wherein all dashed double bonds represent saturated hydrocarbon groups.

[0052] According to a preferred embodiment, the hydroxyalkyl cycloalkanone is a compound of formula (II), wherein all dashed double bonds represent saturated hydrocarbon groups, m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and R1 to Rs, each independently, represents H, or a Ci-w alkyl group and Rw represents a C2-12 hydroxyalkyl group optionally substituted with a Ci-w hydrocarbyl group, preferably a C2-12 hydroxyalkyl group a C3-4 hydroxyalkyl group.

[0053] According to a preferred embodiment, the hydroxyalkyl cycloalkanone is a compound of formula (II), wherein all dashed double bonds represent saturated hydrocarbon groups, , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and R1 to Rs, each independently, represents H and Rw represents a C2-12 hydroxyalkyl group, optionally substituted with a Ci-w hydrocarbyl group, preferably a C3-4 hydroxyalkyl group.

[0054] According to an even more preferred embodiment, the hydroxyalkyl cycloalkanone is a compound of formula (II), wherein all dashed double bonds represent saturated hydrocarbon groups, and R1 to Rs, each independently, represents H, and Rw represents a C3-4 hydroxyalkyl group, preferably a hydroxypropyl group.

[0055] According to an even more preferred embodiment, the hydroxyalkyl cycloalkanone is a compound of formula (II), wherein all dashed double bonds represent saturated hydrocarbon DSM-Firmenich 16390 / WO groups, n is 7 and Ri to Rs, each independently, represents H and Rw represents a hydroxypropyl group.

[0056] According to an embodiment, the oxa-bicycloalkene is a compound of formula (I) and the hydroxyalkyl cycloalkanone is a compound of formula (II), m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, more preferably 6 to 8, Ri to Rs, each independently, represents H, OH, SH, CN, NO2, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, C3-8 heterocycloalkyl, C1-8 heterocycloalkyl, C1-10 acyloxy, aryl, aryloxy, arylthio, C1-10 arylalkyl, heteroaryl, heteroarlyoxy, heteroarylthio, C1-10 heteroarylalkyl, C1-10 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1-10 alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, C1-10 alkylmercapto, aryl mercapto, or heteroaryl mercapto group, R9 represents H or a C1-10 hydrocarbyl group and R10, represents, a C2-12 hydroxyalkyl group optionally substituted with a Ci- hydrocarbyl group, preferably a C3-4 hydroxyalkyl group.

[0057] According to a preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) and the hydroxyalkyl cycloalkanone is a compound of formula (II), m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and Ri to Rs, each independently, represents H or a Ci- alkyl group and R9 represents H or a Ci- hydrocarbyl group and Rw represents, a C2-12 hydroxyalkyl group optionally substituted with a Ci-w hydrocarbyl group, preferably a C3-4 hydroxyalkyl group.

[0058] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) and the hydroxyalkyl cycloalkanone is a compound of formula (II), m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and Ri to Rs, each independently, represents H and R9 represents H or a Ci-w hydrocarbyl group and Rw, represents, a C2-12 hydroxyalkyl group optionally substituted with a Ci-w hydrocarbyl group, preferably a C3-4 hydroxyalkyl group.

[0059] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) and the hydroxyalkyl cycloalkanone is a compound of formula (II), m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and Ri to R9 each independently represents H and Rw represents, a C2-12 hydroxyalkyl group, preferably a C3-4 hydroxyalkyl group.

[0060] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) and the hydroxyalkyl cycloalkanone is a compound of formula (II), m is 1 , n is 0 to DSM-Firmenich 16390 / WO

[0061] 11 , preferably 4 to 9, even more preferably 6 to 8 and Ri to Rg each independently represents H and Rw represents a C3 hydroxyalkyl group, preferably a hydroxypropyl group.

[0062] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) and the hydroxyalkyl cycloalkanone is a compound of formula (II), m is 1 , n is 7 and R1 to R9 each independtly represents hydrogen and R10 represents a hydroxypropyl group.

[0063] According to an embodiment, the oxa-bicycloalkene is a compound of formula (I) and the hydroxyalkyl cycloalkanone is a compound of formula (II), wherein all dashed double bonds represent saturated hydrocarbon groups, m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, more preferably 6 to 8, R1 to Rs, each independently, represents H, OH, SH, CN, NO2, halogen, Ci-w alkyl, C2- alkenyl, C2- alkynyl, Ci-w heteroalkyl, C3-8 heterocycloalkyl, C1-8 heterocycloalkyl, Ci- acyloxy, aryl, aryloxy, arylthio, Ci- arylalkyl, heteroaryl, heteroarlyoxy, heteroarylthio, Ci- heteroarylalkyl, Ci- alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, Ci- alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, Ci- alkylmercapto, aryl mercapto, or heteroaryl mercapto group, R9 represents H or a Ci- hydrocarbyl group and Rw, represents, a C2-12 hydroxyalkyl group optionally substituted with a Ci-w hydrocarbyl group, preferably a C3-4 hydroxyalkyl group.

[0064] According to a preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) and the hydroxyalkyl cycloalkanone is a compound of formula (II), wherein all dashed double bonds represent saturated hydrocarbon groups, m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and R1 to Rs, each independently, represents H or a Ci-w alkyl group and R9 represents H or a Ci-w hydrocarbyl group and Rw, represents, a C2-12 hydroxyalkyl group optionally substituted with a Ci-w hydrocarbyl group, preferably a C3-4 hydroxyalkyl group.

[0065] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) and the hydroxyalkyl cycloalkanone is a compound of formula (II), wherein all dashed double bonds represent saturated hydrocarbon groups, m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and R1 to Rs, each independently, represents H and R9 represents H or a Ci-w hydrocarbyl group and Rw, represents, a C2-12 hydroxyalkyl group optionally substituted with a Ci-w hydrocarbyl group, preferably a C3-4 hydroxyalkyl group. DSM-Firmenich 16390 / WO

[0066] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) and the hydroxyalkyl cycloalkanone is a compound of formula (II), wherein all dashed double bonds represent saturated hydrocarbon groups, m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and Ri to Rg, each independently, represents H and Rw represents a C2-12 hydroxyalkyl group, preferably a C3-4 hydroxyalkyl group.

[0067] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) and the hydroxyalkyl cycloalkanone is a compound of formula (II), wherein all dashed double bonds represent saturated hydrocarbon groups, m is 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and R1 to R9, each independently represents H, and R10 represents a C3 hydroxyalkyl group, preferably a hydroxypropyl group.

[0068] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (I) and the hydroxyalkyl cycloalkanone is a compound of formula (II), wherein all dashed double bonds represent saturated hydrocarbon groups, m is 1 , n is 7, R1 to R9, each independently, represents H, and Rw represents a hydroxypropyl group.

[0069] According to an embodiment, the oxa-bicycloalkene is a compound of formula (III)

[0070] (HI), wherein m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8, and

[0071] R1 to Rs each independently, represents H, OH, SH, CN, NO2, halogen, Ci-w alkyl, C2-W alkenyl, C2-W alkynyl, Ci-w heteroalkyl, C3-8 heterocycloalkyl, C1-8 heterocycloalkyl, Ci-w acyloxy, aryl, aryloxy, arylthio, Ci-w arylalkyl, heteroaryl, heteroarlyoxy, heteroarylthio, Ci-w heteroarylalkyl, Ci-w alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, Ci-w alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, Ci-w alkylmercapto, aryl mercapto or heteroaryl mercapto group.

[0072] According to a preferred embodiment, the oxa-bicycloalkene is a compound of formula (III) wherein m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and R1 to Rs, each independently, represents H or a Ci-w alkyl group. DSM-Firmenich 16390 / WO

[0073] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (III) wherein m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and Ri to Rs, each independently, represents H.

[0074] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (III) wherein m is 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and Ri to Rs, each independently represents H.

[0075] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (III) m is 1 , n is 7 and Ri to Rs, each independently represents H.

[0076] According to an embodiment, the hydroxyalkyl cycloalkanone is a compound of formula (IV)

[0077] (IV), wherein n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8,

[0078] Ri to Rs each independently, represents H, OH, SH, CN, NO2, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, C3-8 heterocycloalkyl, C1-8 heterocycloalkyl, C1-10 acyloxy, aryl, aryloxy, arylthio, C1-10 arylalkyl, heteroaryl, heteroarlyoxy, heteroarylthio, C1-10 heteroarylalkyl, C1-10 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1-10 alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, C1-10 alkylmercapto, aryl mercapto, or heteroaryl mercapto group and

[0079] R10 represents a C2-12 hydroxyalkyl group, optionally substituted with a C1-10 hydrocarbyl group, preferably wherein Rwrepresents a C3-4 hydroxyalkyl group.

[0080] According to a preferred embodiment, the hydroxyalkyl cycloalkanone is a compound of formula (IV), n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and Ri to Rs, each independently, represents H, or a C1-10 alkyl group and Rwrepresents a C2-12 hydroxyalkyl group optionally substituted with a C1-10 hydrocarbyl group, preferably a C2-12 hydroxyalkyl group a C3-4 hydroxyalkyl group. DSM-Firmenich 16390 / WO

[0081] According to a preferred embodiment, the hydroxyalkyl cycloalkanone is a compound of formula (IV), wherein n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and Ri to Rs, each independently, represents H and Rw represents a C2-12 hydroxyalkyl group, optionally substituted with a C1-10 hydrocarbyl group, preferably a C3-4 hydroxyalkyl group.

[0082] According to an even more preferred embodiment, the hydroxyalkyl cycloalkanone is a compound of formula (IV), wherein n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and R1 to Rs, each independently, represents H and R10 represents a C3-4 hydroxyalkyl group, preferably a hydroxypropyl group.

[0083] According to an even more preferred embodiment, the hydroxyalkyl cycloalkanone is a compound of formula (IV), n is 7 and R1 to Rs, each independently, represents H and Rw represents a hydroxypropyl group.

[0084] According to an embodiment, the oxa-bicycloalkene is a compound of formula (III) and the hydroxyalkyl cycloalkanone is a compound of formula (IV), wherein m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, more preferably 6 to 8, R1 to Rs, each independently, represents H, OH, SH, CN, NO2, halogen, Ci-w alkyl, C2-W alkenyl, C2-W alkynyl, Ci-w heteroalkyl, C3-8 heterocycloalkyl, C1-8 heterocycloalkyl, Ci-w acyloxy, aryl, aryloxy, arylthio, Ci-w arylalkyl, heteroaryl, heteroarlyoxy, heteroarylthio, Ci-w heteroarylalkyl, Ci-w alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, Ci-w alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, Ci-w alkylmercapto, aryl mercapto, or heteroaryl mercapto group, and Rw, represents, a C2-12 hydroxyalkyl group, preferably a C3-4 hydroxyalkyl group.

[0085] According to a preferred embodiment, the oxa-bicycloalkene is a compound of formula (III) and the hydroxyalkyl cycloalkanone is a compound of formula (IV), m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and R1 to Rs, each independently, represents H or a Ci-w alkyl group and Rw represents, a C2-12 hydroxyalkyl group, preferably a C3-4 hydroxyalkyl group.

[0086] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (III) and the hydroxyalkyl cycloalkanone is a compound of formula (IV), m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, even more preferably 6 to 8 and R1 to Rs, each independently, represents H and Rw, represents, a C2-12 hydroxyalkyl group, preferably a C3-4 hydroxyalkyl group. DSM-Firmenich 16390 / WO

[0087] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (III) and the hydroxyalkyl cycloalkanone is a compound of formula (IV), m is 1 , n is 0 to 11, preferably 4 to 9, even more preferably 6 to 8 and Ri to Rs each independently represents H and R represents a C3 hydroxyalkyl group, preferably a hydroxypropyl group.

[0088] According to an even more preferred embodiment, the oxa-bicycloalkene is a compound of formula (III) and the hydroxyalkyl cycloalkanone is a compound of formula (IV), m is 1 , n is 7 and R1 to Rs each independtly represents hydrogen and R10 represents a hydroxypropyl group.

[0089] According to an embodiment, the oxa-bicycloalkene is a compound of formula (V)

[0090] (V).

[0091] According to an embodiment, the hydroxyalkyl cycloalkanone is a compound of formula (VI)

[0092] According to a preferred embodiment, the oxa-bicycloalkene is a compound of formula (V) and the hydroxyalkyl cycloalkanone is a compound of formula (VI).

[0093] According to an embodiment, the hydroxyalkyl cycloalkanone is present in an amount of at least 1 wt%, preferably of at least 5 wt%, even more preferably in an amount of at least 8 wt% of the reaction mixture.

[0094] The term “reaction mixture” refers to the combination of reactants (or starting materials), solvents, catalysts, and any other additives present in a chemical reaction. This mixture encompasses all the substances involved in the reaction process, both those that participate directly in the reaction and those that facilitate or influence the reaction conditions. DSM-Firmenich 16390 / WO

[0095] According to an embodiment the hydroxyalkyl cycloalkanone is present in an amount of less than or equal to 90 wt%, preferably of less than or equal to 50 wt%, even more preferably of less than or equal to 20 wt% of the reaction mixture.

[0096] According to an embodiment, the hydroxyalkyl cycloalkanone is present in an amount ranging from 1 to 90 wt%, preferably from 5 to 50 wt%, even more preferably from 8 to 20 wt% of the reaction mixture.

[0097] The process further comprises an acid.

[0098] The term "acid" refers to any chemical compound that, when dissolved in water or another solvent, releases hydrogen ions (H+), also known as protons. Acids can be organic or inorganic in nature and are characterized by their ability to donate protons to other substances, a property defined by the Bronsted-Lowry theory of acids and bases.

[0099] According to an embodiment, the acid is non-volatile.

[0100] The term "non-volatile" refers to a substance that has a low tendency to vaporize under standard temperature and pressure conditions. Non-volatile substances exhibit low vapor pressure and high boiling points, meaning they remain predominantly in the liquid or solid state and do not readily evaporate into the gas phase.

[0101] According to a preferred embodiment, the acid is bis(2-ethylhexyl) phosphoric acid.

[0102] According to an embodiment, the acid is added in an amount of at least 0.01%, preferably of at least 0.1%, even more preferably of at least 0.4% by molar mass of the hydroxyalkyl cycloalkanone.

[0103] According to an embodiment, the acid is added in an amount of less than or equal to 10%, preferably of less than or equal to 5%, even more preferably of less than or equal to 4% by molar mass of the hydroxyalkyl cycloalkanone.

[0104] According to an embodiment, the acid is added in an amount ranging from 0.01 to 10%, preferably from 0.1 to 5%, even more preferably from 0.4 to 4% by molar mass of the hydroxyalkyl cycloalkanone. DSM-Firmenich 16390 / WO

[0105] The process may be carried out in the absence of a solvent.

[0106] The process may be carried out in the presence of a solvent. A suitable solvent is particularly stable under reaction conditions.

[0107] According to an embodiment, the process is carried out in the presence of a solvent, wherein the solvent is selected from the group consisting of cycloalkanones, toluene, linear alkanes and mixtures thereof, preferably wherein the solvent is cyclododecanone.

[0108] According to an embodiment, the process is carried out in the presence of a solvent, wherein the solvent is selected from the group consisting of cyclohexanone, toluene, linear alkanes and mixtures thereof.

[0109] The process further comprises a thin film evaporator.

[0110] According to an embodiment the process is carried out in a thin film evaporator.

[0111] The term "thin film evaporator" refers to a specialized apparatus designed to facilitate the efficient evaporation of volatile components from a liquid mixture by creating a thin film of the liquid on a heated surface. The primary function of a thin film evaporator is to achieve rapid and uniform heat transfer, which results in the evaporation of the solvent and concentration of the non-volatile components under controlled temperature and pressure conditions.

[0112] According to an embodiment, the process is carried out using a short path evaporator, a falling film evaporator a wiped film evaporator or a rising film evaporator.

[0113] The term "short path evaporator" refers to a distillation apparatus designed for the efficient evaporation and condensation of volatile components over a very short distance, typically within a few centimeters. This design minimizes thermal degradation by keeping the distance between the heated surface and the condenser minimal. It operates under high vacuum conditions to reduce boiling points and enable evaporation at lower temperatures. The short path evaporator is ideal for purifying and concentrating heat-sensitive materials, facilitating rapid and efficient separation of volatile and non-volatile components.

[0114] The term "wiped film evaporator" refers to a device used for the continuous separation of mixtures by evaporation. It spreads the liquid feed into a thin film on a heated surface using rotating wipers or blades. This design maximizes heat transfer and enhances the evaporation DSM-Firmenich 16390 / WO process while operating under vacuum or atmospheric pressure. The wiped film evaporator is particularly useful for processing viscous, heat-sensitive, or fouling materials, ensuring efficient and uniform evaporation with minimal thermal degradation.

[0115] The term "falling film evaporator" refers to an evaporator where the liquid feed flows downward as a thin film along the inner walls of vertically arranged tubes or surfaces. This apparatus utilizes gravity to create the film, and the heat applied to the outside of the tubes or surfaces induces evaporation. The falling film evaporator is designed to handle large volumes of liquid with high thermal efficiency and is suitable for applications requiring gentle evaporation, such as in the food, pharmaceutical, and chemical industries. It operates effectively at low temperature differentials and maintains a high rate of heat transfer.

[0116] The term “rising film evaporator” refers to an evaporator where the liquid feed flows upwards as a thin film along the inner walls of vertically arranged tubes or surfaces. The liquid is introduced at the bottom of the tubes and heated to generate vapor. The heat source may be steam or another thermal fluid surrounding the exterior of the tubes to induce boiling at the liquid interface. As the liquid absorbs heat, vaporization occurs and the resultant vapor-liquid mixture rises through the tubes, forming a film along the inner surfaces of the tubes. The vapor formed during this process aids in lifting the remaining liquid upward, thereby facilitating continued evaporation and concentration of the solution. The rising film evaporator is characterized by its ability to promote efficient heat transfer, minimize residence time, and operate at relatively low temperatures, which is advantageous in the concentration of temperature-sensitive materials.

[0117] According to a preferred embodiment, the oxa-bicycloalkene is recovered in the distillate to avoid the condensation of the water and the byproducts in the solution of interest.

[0118] According to an embodiment, the process is carried out under subatmospheric pressure.

[0119] According to an embodiment, the process is carried out at a pressure of less than or equal to 100 mbar, preferably of less than or equal to 80 mbar, even more preferably of less than or equal to 50 mbar.

[0120] According to an embodiment, the process is carried out at a pressure ranging from 20 mbar to 100 mbar, preferably from 30 mbar to 80 mbar, even more preferably from 40 mbar to 50 mbar. DSM-Firmenich 16390 / WO

[0121] According to an embodiment, the process is carried out in a continuous process.

[0122] The term "continuous process" refers to a method of production where raw materials are continuously fed into the system, and products are continuously discharged, without interruption. This process is designed to operate non-stop over an extended period, ensuring a steady and consistent flow of materials through various stages of the operation.

[0123] According to an embodiment, the hydroxyalkyl cycloalkanone and the oxa-bicycloalkene are collected in different compartments connected to the thin film evaporator.

[0124] According to an embodiment, the process is carried out at a temperature of at least 150 °C, preferably of at least 180 °C, even more preferably of at least 190 °C.

[0125] According to an embodiment, the process is carried out at a temperature of less than or equal to 310 °C, preferably of less than or equal to 250 °C, even more preferably of less than 200 °C.

[0126] According to an embodiment, the process is carried out at a temperature ranging from 150 °C to 310 °C, preferably from 180 °C to 250 °C, even more preferably from 190 °C to 200 °C.

[0127] A second object of the invention is the use of a thin film evaporator, preferably a short path evaporator, falling film evaporator, a wiped film evaporator, or a rising film evaporator for producing oxa-bicycloalkene from a hydroxyalkyl cycloalkanone in the presence of an acid.

[0128] All definitions and embodiments related to the first object of the invention apply mutatis mutandis for the second object of the invention.

[0129] According to an embodiment, the process is carried out in a setup according to Figure 1.

[0130] The acid in stream (a) is added to a stream (b) comprising the hydroxyalkyl cycloalkanone that is optionally dissolved in a solvent. The mixture is fed into a thin film evaporator (i), preferably a short path evaporator, falling film evaporator, a wiped film evaporator, or a rising film evaporator. The temperature of the thin film evaporator is controlled by a heat exchanger (ii) comprising a heating fluid. Component (iii) is a condensate trap comprising a cooling fluid. Component (iv) is a vacuum pump wherein a reduced pressure can be applied, (c) is an DSM-Firmenich 16390 / WO outlet stream wherein the distillate comprising the oxa-bicycloalkene is collected, (d) is a second outlet stream wherein the solvent and other byproducts can be collected, (e) allows the reaction mixture to be fed back into the thin film evaporator.

[0131] All definitions and embodiments related to the first object of the invention apply mutatis mutandis for the components of the reaction setup according to Figure 1.

[0132] According to an embodiment, component (ii) is a heat exchanger comprising a heating fluid, wherein the heating fluid has a temperature of at least 150 °C, preferably of at least 180 °C, even more preferably of at least 190 °C.

[0133] According to an embodiment, component (ii) is a heat exchanger comprising a heating fluid, wherein the heating fluid has a temperature of less than or equal to 310 °C, preferably of less than or equal to 250 °C, even more preferably of less than 200 °C.

[0134] According to an embodiment, component (ii) is a heat exchanger comprising a heating fluid, wherein the heating fluid has a temperature ranging from 150 °C to 310 °C, preferably from 180 °C to 250 °C, even more preferably from 190 °C to 200 °C.

[0135] According to an embodiment, component (iii) is a condensate trap comprising a cooling fluid wherein the cooling fluid has a temperature that is lower than the boiling point of the oxa- bicycloalkene.

[0136] According to an embodiment, the cooling fluid in (iii) has a temperature of less than 95 °C preferably of less than or equal to 80 °C, even more preferably of less than or equal to 70 °C

[0137] According to an embodiment, component (iii) is a condensate trap comprising a cooling fluid wherein the cooling fluid has a temperature of at least 30 °C, preferably of at least 40 °C, even more preferably of at least 50 °C.

[0138] According to an embodiment, component (iii) is a condensate trap comprising a cooling fluid wherein the cooling fluid has a temperature ranging from 30 to 95 °C, preferably ranging from 40 to 80 °C, even more preferably ranging from 50 to 70 °C. DSM-Firmenich 16390 / WO

[0139] According to an embodiment, component (iv) is a vacuum pump wherein a reduced pressure can be applied, wherein the applied pressure is at least 20 mbar, preferably at least 30 mbar, even more preferably at least 40 mbar.

[0140] According to an embodiment, component (iv) is a vacuum pump wherein a reduced pressure can be applied, wherein the applied pressure is less than or equal to 1013.25 mbar, preferably less than or equal to 100 mbar, even more preferably less than or equal to 80 mbar, even more preferably less than or equal to 50 mbar.

[0141] According to an embodiment, component (iv) is a vacuum pump wherein a pressure is applied, wherein the applied pressure ranges from 20 mbar to 100 mbar, preferably from 30 mbar to 80 mbar, even more preferably from 40 mbar to 50 mbar.

[0142] According to a preferred embodiment the hydroxyalkyl cycloalkanone is a compound of formula (V) and is dissolved in cyclododecanone and added via stream (b) to the process and the heating fluid of component (ii) has a temperature ranging from 190 °C to 200 °C and the cooling fluid of component (iii) has a temperature ranging from 50 to 70 °C and the pressure applied from component (iv) ranges from 40 to 50 mbar.

[0143] According to a preferred embodiment, the process is carried out in a setup according to Figure 2.

[0144] The acid in stream (a’) is added to a stream (b’) comprising the hydroxyalkyl cycloalkanone that is optionally dissolved in a solvent. Component (i’) is a thin film evaporator, preferably a short path evaporator, falling film evaporator, a wiped film evaporator, a rising film evaporator. Component (ii’) is a heat exchanger comprising a heating fluid. Component (iii’) is a condensate trap comprising a cooling fluid. Component (iv’) is a vacuum pump wherein a reduced pressure can be applied. Component (v’) is a second heat exchanger comprising a second heating fluid, (o’) is an outlet stream wherein the distillate comprising byproducts is collected, (d’) is a second outlet stream wherein the oxa-bicycloalkene can be collected, (f’) allows the reaction mixture to be fed back into the thin film evaporator, (e’) is a third outlet stream wherein the residue and other byproducts can be collected.

[0145] All definitions and embodiments related to the first object of the invention apply mutatis mutandis for the components of the reaction setup according to Figure 2. DSM-Firmenich 16390 / WO

[0146] According to an embodiment, component (ii’) is a heat exchanger comprising a heating fluid, wherein the heating fluid has a temperature of at least 150 °C, preferably of at least 180 °C, even more preferably of at least 190 °C.

[0147] According to an embodiment, component (ii’) is a heat exchanger comprising a heating fluid, wherein the heating fluid has a temperature of less than or equal to 310 °C, preferably of less than or equal to 250 °C, even more preferably of less than 200 °C.

[0148] According to an embodiment, component (ii’) is a heat exchanger comprising a heating fluid, wherein the heating fluid has a temperature ranging from 150 °C to 310 °C, preferably from 180 °C to 250 °C, even more preferably from 190 °C to 200 °C.

[0149] According to an embodiment, component (v’) is a second heat exchanger comprising a second heating fluid, wherein the second heating fluid has a temperature of at least 30 °C, preferably of at least 40 °C, even more preferably of at least 50 °C.

[0150] According to an embodiment, component (v’) is a second heat exchanger comprising a second heating fluid, wherein the second heating fluid has a temperature of less than or equal to 110 °C, preferably of less than or equal to 90 °C, even more preferably of less than or equal to 70 °C.

[0151] According to an embodiment, component (v’) is a second heat exchanger comprising a second heating fluid, wherein the second heating fluid has a temperature ranging from 30 °C to 110 °C, preferably from 40 °C to 90 °C, even more preferably from 50 °C to 70 °C.

[0152] According to an embodiment, component (iii’) is a condensate trap comprising a cooling fluid wherein the cooling fluid has a temperature that is lower than the boiling point of the oxabicycloalkene preferably wherein the cooling fluid has a temperature of less than or equal to 20 °C.

[0153] According to an embodiment, component (iii’) is a condensate trap comprising a cooling fluid wherein the cooling fluid has a temperature of at least 0 °C.

[0154] According to an embodiment, component (iii’) is a condensate trap comprising a cooling fluid wherein the cooling fluid has a temperature ranging from 0 to 20 °C. DSM-Firmenich 16390 / WO

[0155] According to an embodiment, component (iv’) is a vacuum pump wherein a pressure can be applied, wherein the applied pressure is at least 20 mbar, preferably at least 30 mbar, even more preferably at least 40 mbar.

[0156] According to an embodiment, component (iv’) is a vacuum pump wherein a pressure can be applied, wherein the applied pressure is less than or equal to 1013.25 mbar, preferably less than or equal to 100 mbar, even more preferably less than or equal to 80 mbar, even more preferably less than or equal to 50 mbar.

[0157] According to an embodiment, component (iv’) is a vacuum pump wherein a pressure is applied, wherein the applied pressure ranges from 20 mbar to 100 mbar, preferably from 30 mbar to 80 mbar, even more preferably from 40 mbar to 50 mbar.

[0158] According to a preferred embodiment the hydroxyalkyl cycloalkanone is a compound of formula (V) and is dissolved in cyclododecanone and added via stream (b’) to the process and the heating fluid of component (ii’) has a temperature ranging from 190 °C to 200 °C and the heating fluid of component (v’) has a temperature ranging from 50 to 70 °C and and the cooling fluid of component (iii’) gas a temperature ranging from 0 to 20 °C and the pressure applied from component (iv’) ranges from 40 to 50 mbar.

[0159] DSM-Firmenich 16390 / WO

[0160] Examples

[0161] Example 1 (short-path evaporator setup)

[0162] A solution of 2-(3-Hydroxypropyl)cyclododecanone crude (16.7 wt.% 2-(3- Hydroxypropyl)cyclododecanone) is pumped at 2.8 g / min and pre-mixed in-line with bis(2- ethylhexyl) phosphoric acid (0.023 g / min, fed with a syringe pump) at 70 °C inside a shortpath evaporator (-0.03 m2, 300 rpm, T = 180 °C, 40 mbar). The solution was pumped for 210 min and 538 g of distillate was recovered (15.9 wt% 3,4,5,6,7,8,9,10,11 ,12,13,14- dodecahydro-2H-cyclododeca[b]pyran, 93 % molar yield, 93% conversion). 18.2 g of byproduct were recovered in the secondary condenser. 47.7 g of residues was collected at the bottom of the apparatus. All solutions were analyzed by gas chromatography using an external standard.

[0163] Example 2 (short-path evaporator setup using recycled residues)

[0164] A solution of 2-(3-Hydroxypropyl)cyclododecanone crude (7.7 wt.% 2-(3- Hydroxypropyl)cyclododecanone) is pumped at 2.4 g / min and pre-mixed in-line with residues from Example 1 (0.63 g / min, fed with a syringe pump) at 70 °C inside a short-path evaporator (-0.03 m2, 300 rpm, T = 180 °C, 40 mbar). The solution was pumped for 5 min and 13.34 g of distillate was recovered (8.0 wt% 3,4,5,6,7,8,9,10,11,12, 13, 14-dodecahydro-2H- cyclododeca[b]pyran, >99 % molar yield, 100 % conversion). 0.05 g of byproduct were recovered in the secondary condenser. 3.94 g of residues was collected at the bottom of the apparatus. All solutions were analyzed by gas chromatography using an external standard.

[0165] Example 3 (wiped-film evaporator setup)

[0166] A solution of 2-(3-Hydroxypropyl)cyclododecanone (9.8 wt.% 2-(3- Hydroxypropyl)cyclododecanone in cyclododecanone) is pumped at 18.3 g / min and premixed in-line with bis(2-ethylhexyl) phosphoric acid (0.146 g / min, fed with a syringe pump) at 70 °C inside a wiped-film evaporator (T = 200 °C, 40 mbar). The solution was pumped for 30 min and 523 g of distillate was recovered (10.3 wt% 3,4,5,6,7,8,9,10,11,12,13,14- dodecahydro-2H-cyclododeca[b]pyran, 96 % molar yield, 100% conversion). 5.6 g of byproducts were recovered in the secondary condenser. 7.9 g of residues was collected at DSM-Firmenich 16390 / WO the bottom of the apparatus. All solutions were analyzed by gas chromatography using an external standard.

[0167] Example 4 (wiped-film evaporator setup)

[0168] A solution of 2-(3-Hydroxypropyl)cyclododecanone (8.0 wt.% 2-(3- Hydroxypropyl)cyclododecanone in cyclododecanone) is pumped at 18.3 g / min and premixed in-line with bis(2-ethylhexyl) phosphoric acid (0.037 g / min, fed with a syringe pump) at 70 °C inside a wiped-film evaporator (T = 205 °C, 40 mbar). The solution was pumped for 22 min and 370.6 g of distillate was recovered (7.3 wt% 3,4,5,6,7,8,9,10,11,12,13,14- dodecahydro-2H-cyclododeca[b]pyran, 91 % molar yield, 95 % conversion). 3.0 g of byproducts were recovered in the secondary condenser. 13.5 g of residues was collected at the bottom of the apparatus. All solutions were analyzed by gas chromatography using an external standard.

[0169] Example 5 (short-path evaporator setup)

[0170] A solution of 2-(3-Hydroxypropyl)cyclododecanone crude (16.7 wt.% 2-(3- Hydroxypropyl)cyclododecanone) is pumped at 4.7 g / min and pre-mixed in-line with bis(2- ethylhexyl) phosphoric acid (0.0141 g / min, fed with a syringe pump) at 70 °C inside a shortpath evaporator (-0.03 m2, 300 rpm, T = 200 °C, 40 mbar). The solution was pumped for 15 min and 63.5 g of distillate was recovered (13.9 wt% 3,4,5,6,7,8,9,10,11,12,13,14- dodecahydro-2H-cyclododeca[b]pyran, 81 % molar yield, 88 % conversion). 5.0 of residues was collected at the bottom of the apparatus. All solutions were analyzed by gas chromatography using an external standard.

[0171] Example 6 (Continuously Stirred Tank Reactor, Comparative Example)

[0172] A solution of 2-(3-Hydroxypropyl)cyclododecanone crude (16.7 wt.% 2-(3- Hydroxypropyl)cyclododecanone) is pumped at 4.7 g / min and pre-mixed in-line with bis(2- ethylhexyl) phosphoric acid (0.0141 g / min, fed with a syringe pump) at 70 °C inside a continuously stirred tank reactor (100 ml, T = 200 °C, 40 mbar). The solution was pumped for 120 min and 122.07 g of distillate was recovered (14.5 wt% 3,4,5,6,7,8,9,10,11,12,13,14- dodecahydro-2H-cyclododeca[b]pyran, 49% molar yield, 93% conversion). 152.17 g of residues was collected at the bottom of the apparatus. All solutions were analyzed by gas chromatography using an external standard. DSM-Firmenich 16390 / WO

[0173] It can be concluded from Examples 1 to 5 that using the thin-film evaporator set-up the cyclization reaction can be performed at complete conversion and high yield in a continuous manner, and only a very low level of residue production was observed. In the thin film evaporator set-up the recovery of the solvent and product can be performed simultaneously with the reaction, promoting a very high productivity compared to a batch process. Furthermore, as seen from Example 2, the acid catalyst present in the residues can be recycled in subsequent operations yielding high conversion (100 %) and yield (> 99%).

[0174] In contrast the Continuously Stirred Tank Reactor set-up (comparative Example 6) led to significantly lower molar yield and the production of significantly higher levels of residues. It was noted that as the content of the Continuously Stirred Tank Reactor shifted from the initial mixture composition towards the residues, a significant increase in viscosity and density was observed, preventing the efficient mixing of fresh material, and resulting in significantly higher boiling point of the resulting mixture, contributing to the observed less efficient recovery of product.

Claims

DSM-Firmenich 16390 / WOCLAIMS1. A process for the preparation of an oxa-bicycloalkene from a hydroxyalkyl cycloalkanone in the presence of an acid and using a thin film evaporator.

2. The process according to claim 1 , wherein the hydroxyalkyl cycloalkanone comprises a cycloalkanone moiety comprising a 5-16 membered ring comprising carbon and, optionally, oxygen, sulfur and / or nitrogen.

3. The process according to any of the previous claims, wherein the hydroxyalkyl cycloalkanone comprises a C2-12 hydroxyalkyl group, even more preferably a C3-4 hydroxyalkyl group.

4. The process according to any of the previous claims, wherein the oxa-bicycloalkene is a compound of formula (I)(I), and the hydroyxalkyl cycloalkanone is a compound of formula (II)(II), wherein m is 0 to 10, preferably 0 to 1, n is 0 to 11 , preferably 4 to 9, more preferably 6 to 8,R1 to Rs, each independently, represents H, OH, SH, CN, NO2, halogen, C1-10 alkyl, C2-10 alkenyl, C2- alkynyl, C1-10 heteroalkyl, C3-8 heterocycloalkyl, C1-8 heterocycloalkyl, C1-10 acyloxy, aryl, aryloxy, arylthio, C1-10 arylalkyl, heteroaryl, heteroarlyoxy, heteroarylthio, C1-10 heteroarylalkyl, C1-10 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1-10 alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, C1-10 alkylmercapto, aryl mercapto, or heteroaryl mercapto group,R9 represents H or a C1-10 hydrocarbyl group andDSM-Firmenich 16390 / WOR10 represents, a C2-12 hydroxyalkyl group optionally substituted with a C1-10 hydrocarbyl group, preferably wherein R represents C3-4 hydroxyalkyl group.

5. The process according to any of the previous claims, wherein the oxa-bicycloalkene is a compound of formula (III)(HI), and the hydroxyalkyl cycloalkanone is a compound of formula (IV),(IV), wherein m is 0 to 10, preferably 0 to 1 , n is 0 to 11 , preferably 4 to 9, more preferably 6 to 8, R1 to Rs, each independently, represents H, OH, SH, CN, NO2, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, C3-8 heterocycloalkyl, C1-8 heterocycloalkyl, C1-10 acyloxy, aryl, aryloxy, arylthio, C1-10 arylalkyl, heteroaryl, heteroarlyoxy, heteroarylthio, C1-10 heteroarylalkyl, C1-10 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1-10 alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, Ci- 10 alkylmercapto, aryl mercapto, or heteroaryl mercapto group, and R10, represents, a C2-12 hydroxyalkyl group, preferably a C3-4 hydroxyalkyl group.

6. The process according to any of the previous claims, wherein the oxa-bicycloalkene is a compound of formula (V)and wherein the hydroxyalkyl cycloalkanone is a compound of formula (VI)DSM-Firmenich 16390 / WO7. The process according to any of the previous claims, wherein the acid is added in an amount ranging from 0.01 to 10%, preferably from 0.1 to 5%, even more preferably from 0.4 to 4% by molar mass of the hydroxyalkyl cycloalkanone.

8. The process according to any of the previous claims, wherein the process is carried out in the presence of a solvent, preferably in the presence of cyclododecanone.

9. The process according to any of the previous claims, wherein the process is carried out under subatmospheric pressure.

10. The process according to any of the previous claims, wherein the process is carried out using a short path evaporator, a falling film evaporator a wiped film evaporator, or a rising film evaporator.

11. The process according to any of the previous claims, wherein the process is carried out using a continuous process.

12. The process according to any of the previous claims, wherein hydroxyalkyl cycloalkanone and the oxa-bicycloalkene are collected in different compartments connected to the thin film evaporator.

13. The use of a thin film evaporator, preferably a short path evaporator, falling film evaporator, a wiped film evaporator, a rising film evaporator for producing oxa- bicycloalkene from a hydroxyalkyl cycloalkanone in the presence of an acid.

14. The use of a thin film evaporator, preferably a short path evaporator, falling film evaporator or a wiped film evaporator according to claim 12, wherein the oxa- bicycloalkene is of formula (I) and the hydroxyalkyl cycloalkanone is of formula (II) according to claim 4 in the presence of an acid.DSM-Firmenich 16390 / WO15. The use of a thin film evaporator, preferably a short path evaporator, falling film evaporator, a wiped film evaporator or a rising film evaporator according to any of claims 12 and 13, wherein the oxa-bicycloalkene is of formula (V) and the hydroxyalkyl cycloalkanone is of formula (VI), according to claim 6, in the presence of an acid.28

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