GB2482525A - A process for the production of acyloxymethyldioxanylacetic derivatives - Google Patents
A process for the production of acyloxymethyldioxanylacetic derivatives Download PDFInfo
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- GB2482525A GB2482525A GB1013180.3A GB201013180A GB2482525A GB 2482525 A GB2482525 A GB 2482525A GB 201013180 A GB201013180 A GB 201013180A GB 2482525 A GB2482525 A GB 2482525A
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- methyl
- acetate
- ionic liquid
- butyl
- carboxylate
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- 238000000034 method Methods 0.000 title abstract description 37
- 238000004519 manufacturing process Methods 0.000 title description 3
- 150000007942 carboxylates Chemical class 0.000 abstract description 27
- 239000002608 ionic liquid Substances 0.000 abstract description 26
- 239000000203 mixture Substances 0.000 abstract description 17
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 abstract description 17
- 150000001875 compounds Chemical class 0.000 abstract description 13
- 238000002360 preparation method Methods 0.000 abstract description 10
- 235000011056 potassium acetate Nutrition 0.000 abstract description 7
- 150000001450 anions Chemical class 0.000 abstract description 6
- 125000003118 aryl group Chemical group 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 5
- 239000001257 hydrogen Substances 0.000 abstract description 5
- 239000012429 reaction media Substances 0.000 abstract description 5
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 4
- BMQZYMYBQZGEEY-UHFFFAOYSA-M 1-ethyl-3-methylimidazolium chloride Chemical compound [Cl-].CCN1C=C[N+](C)=C1 BMQZYMYBQZGEEY-UHFFFAOYSA-M 0.000 abstract description 3
- NGABCYSYENPREI-NEPJUHHUSA-N tert-butyl 2-[(4r,6s)-6-(acetyloxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate Chemical compound CC(=O)OC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1 NGABCYSYENPREI-NEPJUHHUSA-N 0.000 abstract description 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 abstract 2
- XIYUIMLQTKODPS-UHFFFAOYSA-M 1-ethyl-3-methylimidazol-3-ium;acetate Chemical compound CC([O-])=O.CC[N+]=1C=CN(C)C=1 XIYUIMLQTKODPS-UHFFFAOYSA-M 0.000 abstract 2
- 150000002431 hydrogen Chemical group 0.000 abstract 2
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical group 0.000 abstract 1
- TXLXWCARAPIXGH-ZJUUUORDSA-N tert-butyl 2-[(4r,6s)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate Chemical compound CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1 TXLXWCARAPIXGH-ZJUUUORDSA-N 0.000 abstract 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- ILFIRBGRMCGNOO-UHFFFAOYSA-N 1,1-bis($l^{1}-oxidanyl)ethene Chemical group [O]C([O])=C ILFIRBGRMCGNOO-UHFFFAOYSA-N 0.000 description 6
- 150000001768 cations Chemical class 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 150000001734 carboxylic acid salts Chemical class 0.000 description 4
- 239000003444 phase transfer catalyst Substances 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- 238000010626 work up procedure Methods 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- -1 sullonate Chemical compound 0.000 description 2
- RYNROCNODWBDCM-UHFFFAOYSA-N 1,3-diethyl-2h-imidazole Chemical compound CCN1CN(CC)C=C1 RYNROCNODWBDCM-UHFFFAOYSA-N 0.000 description 1
- KAIPKTYOBMEXRR-UHFFFAOYSA-N 1-butyl-3-methyl-2h-imidazole Chemical compound CCCCN1CN(C)C=C1 KAIPKTYOBMEXRR-UHFFFAOYSA-N 0.000 description 1
- QQAJQOSQIHCXPL-UHFFFAOYSA-N 1-butyl-3-methyl-2h-pyridine Chemical compound CCCCN1CC(C)=CC=C1 QQAJQOSQIHCXPL-UHFFFAOYSA-N 0.000 description 1
- IBZJNLWLRUHZIX-UHFFFAOYSA-N 1-ethyl-3-methyl-2h-imidazole Chemical compound CCN1CN(C)C=C1 IBZJNLWLRUHZIX-UHFFFAOYSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-O Imidazolium Chemical compound C1=C[NH+]=CN1 RAXXELZNTBOGNW-UHFFFAOYSA-O 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- 125000005497 tetraalkylphosphonium group Chemical group 0.000 description 1
- 238000010490 three component reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process comprises reacting a compound of formula (II) with a carboxylate source in the presence of an ionic liquid (of general formula [A]+[B]-) to give (I). R1 is hydrogen, C1-12 alkyl, C6-12 aryl or C7-12 aralkyl; X1 is halogen; R3, R4 and R5 are hydrogen, C1-12 alkyl, C6-12 aryl or a C7-12 aralkyl group; R4 and R5 may be conjoined to each other to form a ring. Anion [B]- may comprise a carboxylate moiety. Alternatively, a composition comprises (II) and an ionic liquid [A]+[B]-. Alternatively, ionic liquid [A]+[B]- is used in the preparation of a reaction medium for use in the acyloxylation of compound (II). Thus tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-[(methylcarbonyloxy)methyl]-1,3-dioxan-4-yl]acetate may be obtained from tert-butyl 2-[(4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate and either 1-ethyl-3-methyl imidazolium acetate (EMIMOAc) or 1-ethyl-3-methyl imidazolium chloride (EMIMCl) with potassium acetate (KOAc).
Description
PROCESS
The invention relates to an improved process for the preparation of an acyloxymethyldioxanylacetic acid derivative in which an ionic liquid is employed.
Acyloxymethyldioxanylacetic acid derivatives of the general formula (I) 5<:5 R3OCO2R1 II (I) are useful in the preparation of active pharmaceutical ingredients, especially HMGCoA reductase inhibiting compounds. As a result of their utility, numerous processes for preparing such derivatives have been developed.
In several of these processes, a compound of the general formula (II) >< x1co2R1 (Il) is converted to a compound of formula (I) by an acyloxylation step, in which the X1 group is substituted with an acyloxy group. Examples of such processes are disciosed in US5278313, EP1 024139, EP1461331 and EP1619191.
In the processes recited in those documents, stoichiometric equivalents of a phase transfer catalyst are employed. Examples of such catalysts include tetraalkylammonium or tetraalkylphosphonium salts in polar aprotic solvents, such as N-methyl-2-pyrrolidone (NMP) or N,N-dimethylformamide (DMF). A source of carboxylate, in the form of carboxylic acid or a carboxylic acid salt (for example sodium or potassium acetate) is added in situ. Once the acyloxylation step is completed, the reaction product is isolated after aqueous work-up and solvent extraction.
Thus, each of the prior art processes discussed above require a three component system comprising (a) a solvent, (b) a phase transfer catalyst and (c) a source of carboxylate.
Further, those processes all require aqueous work-up to obtain a product having acceptably low levels of reaction solvent. The aqueous work-up step results in the formation of significant amounts of waste material and also limits the operator's ability to recover the costly aprotic reaction solvent for reuse.
To quantify the wastefulness of the prior art processes, an environmental (E) factor can be determined. The E factor of a chemical process is calculated dividing the total amount of waste materials produced (kg) by the amount of product obtained (kg).
Even if the prior art processes result in a 70% molar product yield and 80% of the hydrocarbon extraction solvent is re-used, the E factor may still be as high as 40.
Accordingly, there exists a need in the art for a process for preparing a acyloxymethyldioxanylacetic derivative of the general formula (I) which achieves one or more of the following aims: the process is not reliant on a three component reaction mixture and is ideally not reliant on a two component reaction mixture, the process does not require an aqueous work-up step to isolate the reaction product, the process produces low amounts of waste material, the process has a low E factor, the process produces high yields of product, the process produces high purity product.
Thus, according to a first aspect of the present invention, there is provided a process for preparing a compound of the following general formula (I) R3OCQ2R1 If (I) 0 wherein R1 represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms or an aralkyl group of 7 to 12 carbon atoms, X1 represents a halogen atom, R3, R4 and R5 each independently represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms or an aralkyl group of 7 to 12 carbon atoms, and R4 and R5 may be conjoined to each other to form a ring, which comprises reacting a compound of the following general formula (II) >< X1CQ2R1 (II) with a carboxylate source in the presence of an ionic liquid of the general formula (Ill) [A] [B] (Ill) It has unexpectedly been found that if acyloxylation is carried out in the presence of an ionic liquid, the ionic liquid not only functions as a solvent, but also as a phase transfer catalyst. Thus, acyloxylation can be carried in a two component system.
Additionally, if the anion [Bf of the ionic liquid comprises a carboxylate moiety, especially a carboxylate group, it has surprisingly been found that no additional carboxylate source is required to achieve acyloxylation. Thus, acyloxylation can be carried out in a single component system.
The calculated E factor for such a process, with a nominal yield of 70% and 80% re-use of the hydrocarbon extraction solvent, is 6, which equates to a six fold reduction in the amount of waste materials generated, compared to prior art processes.
For the avoidance of any doubt, the ionic liquid employed in the process of the present invention may be the sole carboxylate source, and / or an additional carboxylate source material may be included in the reaction mixture.
Additionally, in the event that an ionic liquid including an anion [Bf which comprises a carboxylate moiety is utilised in the process of the present invention, this does not preclude the use of additional carboxylate source material/s in the reaction mixture. In fact, it has advantageously been found that if an ionic liquid comprising a carboxylate moiety is used in the process of the present invention alongside an additional carboxylate source material, for example a carboxylic acid salt, the ionic liquid is continually regenerated in situ, facilitating its re-use and reducing the amount of fresh ionic liquid which is required and thus the overall E factor of the process.
Additionally or alternatively, in arrangements where the ionic liquid is the total or partial carboxylate source, the ionic liquid can be regenerated off line' using conventional ion exchange techniques known to those skilled in the art, such as the methods described in Green Chemistry, Volume 11, 2009, pages 15O7151O.
In preferred embodiments of the present kuventlon, the anion IBT comprises one or more of trilluoroactetate, borate, dicyanamide, halide, imlde, phosphate, sulphate, sullonate, cyanate, thiocyanate, trlcyanomethlde, nonaflate, perchiorate, nitrate or a carboxylate moiety. In particularly preferred embodiments, the carboxylate moiety Is comprised in a carboxylate group of the general formula (V) whereki R9s hydrogen, an alkyl group of I to 12 carbon atoms, an aryl group of 6to l2carbonatomsoranaralkylgroupof7to 12 carbon atoms.
As mentioned above, rega,tlless of whether or not the Ionic lkjuid is the total or partial source of carboxylate, an additional carboxylate source material may be employed. Any material whIch provides a carboxylate moiety to the reaction mixture may be employed. However; preferred carboxylate sources include carboxylic acids and carboxylic acid salts, such as sodium acetate and potassium acetate and any other salt having the general formula (IV) 3y8) (VI) where R3 is as defined above, M represents an alkali metal or an alkaline earth metal and n represents an integer of 1 or 2.
Any cationic species may be employed as cation [A] in the process of the present invention provided that the combination of cation [A} and anion [Bf results in an ionic liquid which is capable of functioning as a solvent and as a phase transfer catalyst in the process of the present invention.
Examples of compounds which may be employed as cations [A] in the ionic liquids used in the present invention are disclosed in DE10202838, the contents of which are incorporated by reference. Preferred cations comprise oxygen, phosphorus, sulphur and I or nitrogen atoms.
In especially preferred arrangements, the compounds used as cations in the ionic liquids employed in the present invention comprise at least one five or six membered heterocyclic ring, which optionally has one, two or three nitrogen atoms and possibly an oxygen or sulphur atom.
Particularly preferred cations include those outlined in EP1893651, the contents of which are incorporated by reference, which include alkyl substituted heterocyclic compounds such as 1-ethyl-3-methyl imidazole, 1-ethyl-3-ethyl imidazole, 1 -butyl-3-methyl imid azole, I -allyl-3-methyl imidazole, 3-methyl-N -butyl-pyridine, 1-methylimidazole or mixtures thereof.
The ionic liquids utilised in the processes of the present invention preferably have a melting point of less than about 180°C, more preferably in the range of about - 50°C to about 150°C, still more preferably in the range from about -20°C to about 120°C and most preferably below about 100°C.
The processes of the present invention proceed in a reaction medium comprising ionic liquid, which may or may not be the sole carboxylate source. Regardless of whether the ionic liquid is the carboxylate source, or which may additionally include carboxylate source materials, such as carboxylic acids or carboxylic acid salts. These components, together with the compound which is to be acyloxylated may be added into a reaction vessel in any order to prepare the reaction mixture.
Once prepared, the reaction mixture may be heated to increase the rate of reaction. Reaction temperatures of about 50°C to 1 50°C are especially preferred.
The reaction is then allowed to continue until an acceptable yield of reaction product is obtained.
While the processes of the present invention are not limited to any particular product extraction technique, one advantage of those processes is that an aqueous extraction step is typically not required to isolate the reaction product from the reaction medium. Thus, in a preferred embodiment of the present invention, the reaction product is extracted from the reaction mixture using a substantially non-aqueous solvent. Preferred non-aqueous solvents include hydrocarbons, such as hexane and I or heptane.
Upon addition of a non-aqueous extraction solvent, a fraction is typically formed and the reaction product can conveniently be crystallised out from that fraction using techniques with which those skilled in the art will be familiar.
According to a second aspect of the present invention, there is provided a composition comprising a compound of the general formula (Il) C02R1 (Il) and an ionic liquid of the general formula (Ill) {AI [Bf (Ill) wherein R1, R4, R5, X1, [A], and [Bf are as defined above.
This composition may be prepared in situ, for example, shortly prior to commencement of a process for acyloxylating a compound of the general formula (II). Alternatively, the composiflon may be prepared and supplied to customers, enabling them to conveniently perform such an acyloxylation process.
In such embodiments, the anion [Bf present in the ionic liquid preferably does not include a carboxylate moiety and is not a carboxylate source.
According to a third aspect of the present invention, the use of an ionic liquid of the general formula (Ill) [A] [Bf (Ill) in the preparation of a reaction medium for use in the acyloxylation of a compound of the general formula (II) >< (II) is provided, wherein R1, R4, R5, X', [Ar, and [Bf are as defined above. ()
For the avoidance of any doubt, although numerous features and properties of components of the reaction mixture have been provided above, with reference to their use in the process of the above first aspect of the present invention, it will be appreciated that those features and properties are equally applicable to the compositions and reaction media of the second and third aspects of the present invention.
The various aspects of the invention will now be further illustrated in the following
examples.
Example I -Preparation of tert-butyl 2-[(4R,6S)-2,2-di methyl-6-[(methyl-carbonyl oxy)methylj-I, 3-d ioxan-4-yl]acetate °c3hrs In a lOOmL round vessel was added crude tert-butyl 2-[(4R,6S)-6-(ch!oromethyl)- 2,2-dirnethyl-1, 3-d ioxan-4-yl]acetate (10. Og) and I -ethyl-3-methyl imidazolium acetate (300g). The mixture was heated at 100°C for 3 hours.
Heptane (3OmL) was then added to the reaction and the mixture stirred for 1 minute before decanting the heptane phase. The heptane extract was slowly cooled to -4°C whereupon white needles of tert-butyl 2-[(4R,OS)-2,2-dlmethyl-8- [(methyl-carbonyloxy)methyl]-1,3-dloxan-4-yl]acetate csystalllsed. Yield = 2.8g Example 2 -Preparation of tert-butyl 2-[(4R,6S)-2,2-dlmethyI-6-(methyl-carbonyloxy)methyl]-1,3-dloxan-4. y9acetate ThereactionwascardedoutasperExamplel exceptthembcturewasheatedat 90°C for 5 hours. Yield = 2.4g whIte needles Example 3 -PreparatIon of tert-butyl 2-[(4R,6S)-2,2-dlmethyl-6-ftmethyl-carbonyloxy)methyl]-1 3-dloxan-4-yljacetate The reaction was carried out as per Example I except the mIxture was heated at 80°C for 23 hours. Yield = 2.3g white needles Example 4 PreparatIon of tert-butyl 2-fl46S)-2,2-dlmethyl-6-flmethyl-carbonyloxy)methylj-1, 3-dloxan-4-ylacetate The reaction was carried out as per Example I except the mIxture was heated at 70°C for 23 hours. Yield = 2.4g white needles Example 5 -Preparation of tert-butyl 2-((4R6S)-2,2-dlmethyl-6-[(methyl-carbonyloxy)methyl]-1, 3-dloxan-4-yljacetate >K0 EMIMCI I KOAc Ot-Bu 11000 2.5hrs AcO Ot-Bu In a lOOmL round vessel was added crude tert-butyl 2-[(4R,6S)-6-(chloromethyl)- 2,2-dimethyl-1,3-d ioxan-4-yl]acetate (5.Og) and 1 -ethyl-3-methyl imidazolium chloride (l3Ag) and potassium acetate (88g). The mixture was heated at 11000 for 25 hours.
The mixture was extracted with heptane (3x25mL). The heptane extract was slowly cooled to -4°C whereupon white needles of tert-butyl 2-[(4R6S)-2,2-d imethyl-6-[(methyl-carbonyloxy)methyl]-1,3-d ioxan-4-yl]acetate crystallised.
Yield = O.5g Example 6 Preparation of tert-butyl 2-[(4R,6S)-2,2-di methyl-6-[(methyl-carbonyloxy)methyl]-1,3-dioxan-4-yl]acetate I II BMIMOAc/KOAc I I 100°C4hrs In a lOOmL round vessel was added crude tertbutyI 2-[(4ft6S)-6(chloromethyI) 2,2-dimethyl--1,3-d ioxan-4-yl]acetate (5Og) and I -butyl-3-rnethyl imidazolium L) acetate (17.8g) and potassium acetate (1.8g), The mixture was heated at 100°C for 4 hours.
The mixture was extracted with heptane (3x25mL). The heptane extract was slowly cooled to -4°C whereupon white needles of tert-butyl 2-[(4R,6S)-2,2-d imethyl-6-[(methyl-carbonyloxy)methyl]-1,3-d ioxan-4-yl}acetate crystallised.
Yield = 1.32g.
The ionic liquid phase was filtered. The filtrate was charged back into the reaction vessel and fresh potassium acetate (1.8g) added and crude tert-butyl 2- [(4R,6S)-6-(chloro methyl)-2,2-d imethyl-1 3-d ioxan-4-yl]acetate (5.Og). The mixture was heated at 100°C for 4 hours.
The mixture was extracted with heptane (3x25mL). The heptane extract was slowly cooled to -4°C whereupon white needles of tert-butyl 2-[(4R,6S)-2,2-d imethyl-6-[(methyl-carbonyloxy)methyl]-1,3-d ioxan-4-yl]acetate crystallised.
Yield = [25g.
The ionic liquid phase was filtered. The filtrate was charged back into the reaction vessel and fresh potassium acetate (1.8g) added and crude tert-butyl 2- [(4R6S)-6-(chloromethyl)-2,2-dimethyl-1 3-dioxan-4-yl]acetate (5.Og). The mixture was heated at 100°C for4 hours.
The mixture was extracted with heptane (3x25mL). The heptane extract was slowly cooled to -4°C whereupon whke needles of tert-butyl 2-I(4R,6S)-2,2-dimethyl-6-ftmethyl-carbonyloxy)methyl]-1, 3-dloxan-4-ylJacetate crystallised.
YIeldl.23g.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1013180.3A GB2482525A (en) | 2010-08-05 | 2010-08-05 | A process for the production of acyloxymethyldioxanylacetic derivatives |
| PCT/GB2011/051469 WO2012017242A1 (en) | 2010-08-05 | 2011-08-03 | Process |
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| Application Number | Priority Date | Filing Date | Title |
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| GB1013180.3A GB2482525A (en) | 2010-08-05 | 2010-08-05 | A process for the production of acyloxymethyldioxanylacetic derivatives |
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| GB201013180D0 GB201013180D0 (en) | 2010-09-22 |
| GB2482525A true GB2482525A (en) | 2012-02-08 |
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| WO (1) | WO2012017242A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2532646A1 (en) * | 2011-06-07 | 2012-12-12 | Basf Se | Process for preparing esters and organic halides |
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| CN111675689B (en) * | 2020-06-16 | 2021-08-24 | 浙江工业大学 | A kind of chemical synthesis method of rosuvastatin intermediate |
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| US5278313A (en) * | 1992-03-27 | 1994-01-11 | E. R. Squibb & Sons, Inc. | Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors |
| EP1024139A1 (en) * | 1998-08-05 | 2000-08-02 | Kaneka Corporation | Process for the preparation of optically active 2- 6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivatives |
| CN1384091A (en) * | 2002-05-25 | 2002-12-11 | 中国科学院兰州化学物理研究所 | Clean method of esterifying halide |
| EP1323717A1 (en) * | 2001-12-27 | 2003-07-02 | Dsm N.V. | Process for the preparation of 2-(6-Substituted-1,3-Dioxane-4-yL) acetic acid derivatives |
| JP2006219477A (en) * | 2005-01-17 | 2006-08-24 | Sumitomo Chemical Co Ltd | Method for producing carboxylic acid ester |
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|---|---|---|---|---|
| NL1015744C2 (en) * | 2000-07-19 | 2002-01-22 | Dsm Nv | Process for the preparation of 2- (6-substituted-1,3-dioxan-4-yl) acetic acid derivatives. |
| DE10202838A1 (en) | 2002-01-24 | 2003-08-07 | Basf Ag | Separation of acids from reaction mixtures by means of an auxiliary base that forms a liquid salt with the acid to result in two non-miscible phases with the product or solution of the product in a suitable solvent |
| EP1375493A1 (en) * | 2002-06-17 | 2004-01-02 | Dsm N.V. | Process for the preparation of an dioxane acetic acid ester |
| DE102005017733A1 (en) | 2005-04-15 | 2006-10-19 | Basf Ag | Solubility of cellulose in ionic liquids with the addition of amine base |
-
2010
- 2010-08-05 GB GB1013180.3A patent/GB2482525A/en not_active Withdrawn
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2011
- 2011-08-03 WO PCT/GB2011/051469 patent/WO2012017242A1/en active Application Filing
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| US5278313A (en) * | 1992-03-27 | 1994-01-11 | E. R. Squibb & Sons, Inc. | Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors |
| EP1024139A1 (en) * | 1998-08-05 | 2000-08-02 | Kaneka Corporation | Process for the preparation of optically active 2- 6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivatives |
| EP1323717A1 (en) * | 2001-12-27 | 2003-07-02 | Dsm N.V. | Process for the preparation of 2-(6-Substituted-1,3-Dioxane-4-yL) acetic acid derivatives |
| CN1384091A (en) * | 2002-05-25 | 2002-12-11 | 中国科学院兰州化学物理研究所 | Clean method of esterifying halide |
| JP2006219477A (en) * | 2005-01-17 | 2006-08-24 | Sumitomo Chemical Co Ltd | Method for producing carboxylic acid ester |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2532646A1 (en) * | 2011-06-07 | 2012-12-12 | Basf Se | Process for preparing esters and organic halides |
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| Publication number | Publication date |
|---|---|
| GB201013180D0 (en) | 2010-09-22 |
| WO2012017242A1 (en) | 2012-02-09 |
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