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Title:
PROCESS
Document Type and Number:
WIPO Patent Application WO/2012/017242
Kind Code:
A1
Abstract:
A process is provided for preparing a compound of the following general formula (I) 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) with a carboxylate source in the presence of an ionic liquid of the general formula (III)

Inventors:
PROCTOR, Lee David (Godre'r Foel, Ffordd GlyndwrNercwys, Flintshire CH7 4AU, GB)
GREIG, Stuart Alexander James (20 Lindale Close, Moreton, Wirral CH46 9SL, GB)
Application Number:
GB2011/051469
Publication Date:
February 09, 2012
Filing Date:
August 03, 2011
Export Citation:
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Assignee:
BAKHU PHARMA LIMITED (10 Gainsborough Road, Southport, Merseyside PE8 2EY, GB)
PROCTOR, Lee David (Godre'r Foel, Ffordd GlyndwrNercwys, Flintshire CH7 4AU, GB)
GREIG, Stuart Alexander James (20 Lindale Close, Moreton, Wirral CH46 9SL, GB)
International Classes:
C07D319/06
Domestic Patent References:
Foreign References:
US5278313A
EP1619191A2
EP1461331A1
US5278313A
EP1024139A1
EP1461331A1
EP1619191A2
DE10202838A1
EP1893651A2
Other References:
REDDY M S N ET AL: "An efficient industrial process for the preparation of fluvastatin sodium", ORIENTAL JOURNAL OF CHEMISTRY, IQBAL, BHOPAL, IN, vol. 24, no. 1, 1 January 2008 (2008-01-01), pages 167-174, XP009119035, ISSN: 0970-020X
BIN ZHAO ET AL: "Esterification of carboxylate-based ionic liquids with alkyl halides", CHEMICAL COMMUNICATIONS, vol. 47, no. 10, 1 January 2011 (2011-01-01), page 2973, XP55013080, ISSN: 1359-7345, DOI: 10.1039/c0cc04798h
GREEN CHEMISTRY vol. 11, 2009, pages 1507 - 1510
Attorney, Agent or Firm:
W.P. THOMPSON & CO. (55 Drury Lane, London WC2B 5SQ, GB)
Download PDF:
Claims:
CLAIMS

1. A process for preparing a compound of the following general formula (I)

wherein R 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)

(II)

with a carboxylate source in the presence of an ionic liquid of the general formula (III)

[A]+ [B]-

(III)

2. The process of Claim 1 , wherein the anion [B] comprises a carboxylate moiety.

3. The process of Claim 2, wherein the carboxylate moiety is comprised in a carboxylate of the general formula (IV)

(IV) wherein R is as defined above.

4. The process of Claims 2 or 3, wherein the ionic liquid is substantially the sole carboxylate source.

5. The process of Claim 1 , wherein the anion [B]~ comprises trifluoroactetate, borate, dicyanamide, halide, imide, phosphate, sulphate, sulfonate, cyanate, thiocyanate, tricyanomethide, nonaflate, perchlorate, nitrate or a carboxylate moiety.

6. The process of Claim 5, wherein the carboxylate moiety is comprised in a carboxylate of the general formula (IV)

(IV) wherein R3 is as defined above.

7. The process of Claim 5 or 6, wherein the carboxylate source comprises a carboxylate moiety.

8. The process of Claim 7, wherein the carboxylate moiety is comprised in carboxylic acid or a carboxylic acid salt.

9. The process of Claim 8, wherein the carboxylic acid salt has the general formula (V)

(V)

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.

10. The process of Claim 8 or 9, wherein the carboxylic acid salt is sodium acetate or potassium acetate.

11 . The process of any one of Claims 1 to 10, wherein the cation [A]+ comprises a 5 or 6 membered heterocyclic compound.

12. The process of Claim 11 , wherein the cation [A]+ comprises 1-ethyl-3- methyl imidazole, 1 -ethyl-3-ethyl imidazole, 1 -butyl-3-methyl imidazole, 1 -allyl-3- methyl imidazole, 3-methyl-N-butyl-pyridine, 1-methylimidazole or mixtures thereof.

13. The process of any one of Claims 1 to 10, wherein the cation [A]+ comprises a tetra-alkyl ammonium or tetra-alkyl phosphonium compound

14. The process of any one of Claims 1 to 13, wherein the ionic liquid has a melting point which is less than about 180°C.

15. The process of any one of Claims 1 to 14, wherein the ionic liquid has a melting point of about -20°C to about 120°C.

16. The process of any one of Claims 1 to 15, wherein the obtained compound of the general formula (I) is extracted from the reaction mixture using a substantially non-aqueous solvent.

17. The process of Claim 16, wherein the substantially non-aqueous solvent comprises a hydrocarbon solvent.

18. The process of any one of Claims 1 to 17, wherein the process has an E factor of less than 10.

19. A composition comprising a compound of the general formula (II)

and an ionic liquid of the general formula (III)

[Af [ΒΓ

(III)

wherein R1, R4, R5, X1, [Af , and [B] are as defined above.

20. The use of an ionic liquid of the general formula (III)

[Af [B] (Hi) in the preparation of a reaction medium for use in the acyloxylation of a compound of the general formula (II)

(ll)

wherein R1, R4, R5, X1, [Af , and [B] are as defined above.

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)

are useful in the preparation of active pharmaceutical ingredients, especially HMG-CoA 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)

is converted to a compound of formula (I) by an acyloxylation step, in which the X 1 group is substituted with an acyloxy group. Examples of such processes are disclosed in US5278313, EP1024139, 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 Ν,Ν-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)

wherein R 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, X 1 represents a halogen atom, R 3 , R 4 and R 5 each independently represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms or an aralkyi group of 7 to 12 carbon atoms, and R 4 and R 5 may conjoined to each other to form a ring,

which comprises reacting a compound of the following general formula (II)

with a carboxylate source in the presence of an ionic liquid of the general formula

(III)

[Af [ΒΓ

(III)

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 [B] " 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 [B] " 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 1507-1510. In preferred embodiments of the present invention, the anion [B] comprises one or more of trifluoroactetate, borate, dicyanamide, halide, imide, phosphate, sulphate, sulfonate, cyanate, thiocyanate, tricyanomethide, nonaflate, perchlorate nitrate or a carboxylate moiety. In particularly preferred embodiments, the carboxylate moiety is comprised in a carboxylate group of the general formula (IV)

(IV) wherein R 3 is 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.

As mentioned above, regardless of whether or not the ionic liquid 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 (V)

(V)

where R 3 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 [B] ~ 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 / 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 imidazole, 1-allyl-3-methyl imidazole, 3-methyl-N- butyl-pyridine, 1-methylimidazole or mixtures thereof.

Further examples of compounds that maybe employed as cations [A include tetra-alkyl ammonium and tetra-alkyl phosphonium cations.

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 150°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 / 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 (II)

and an ionic liquid of the general formula (III)

[A] + [ΒΓ

(III)

wherein R 1 , R 4 , R 5 , X 1 , [A] ' , and [B] ~ 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 composition may be prepared and supplied to customers, enabling them to conveniently perform such an acyloxylation process. In such embodiments, the anion [B] 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 (III)

[Af [ΒΓ

(III)

in the preparation of a reaction medium for use in the acyloxylation of a compound of the general formula (II)

is provided, wherein R 1 , R 4 , R 5 , X 1 , [A] + , and [B] ~ 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 1 - Preparation of tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-[(methyl- carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate from EMIM.OAc

In a 100ml_ round vessel was added crude tert-butyl 2-[(4R,6S)-6~(chloromethyl)- 2,2-dimethyl-1 ,3-dioxan-4-yl]acetate (10, Og) and 1-ethyl-3-methyl imidazolium acetate (30.0g). The mixture was heated at 100°C for 3 hours.

Heptane (30mL) 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,6S)-2,2-dimethyl-6- [(methyl-carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate crystallised. Yield = 2.8g

Example 2 - Preparation of tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-[(methyl- carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate from EMIM.OAc

The reaction was carried out as per Example 1 except the mixture was heated at 90°C for 5 hours. Yield = 2.4g white needles

Example 3 - Preparation of tert-butyl 2-[(4R,6S)-2,2-dimethy!-6-[(methyl- carbonyIoxy)methylJ-1,3-dioxan-4-yI]acetate from EMIM.OAc

The reaction was carried out as per Example 1 except the mixture was heated at 80°C for 23 hours. Yield = 2.3g white needles Example 4 Preparation of tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-[(methyl- carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate from EMIM.OAc

The reaction was carried out as per Example 1 except the mixture was heated at 70°C for 23 hours. Yield = 2.4g white needles

Example 5 - Preparation of tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-[(methyl- carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate from EMIM.CI and potassium acetate

In a 100mL round vessel was added crude tert-butyl 2-[(4R,6S)-6-(chloromethyl)- 2,2-dimethyl-1 ,3-dioxan-4-yl]acetate (5.0g) and 1 -ethyl-3-methyl imidazolium chloride (13.1 g) and potassium acetate (8.8g). The mixture was heated at 1 10°C for 2.5 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- dimethyl-6-[(methyl-carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate crystallised. Yield = 0.5g Example 6 - Preparation of tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-[(methyl- carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate from BMI .OAc with three recycles of the ionic liquid

Run 1

In a "lOOmL round vessel was added crude tert-butyl 2-[(4R,6S)-6-(chloromethyl)- 2,2-dimethyl-1 ,3-dioxan-4-yl]acetate (5.0g) and 1-butyl-3-methyl imidazolium 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- dimethyl-6-[(methyl-carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate crystallised. Yield = 1.32g.

Run 2

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-(chloromethyl)-2,2-dimethyl-1 ,3-dioxan-4-yi]acetate (5.0g). The mixture was heated at 100°C for 4 hours. 11 051469

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- dimethyl-6-[(methyl-carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate crystallised. Yield = 1.25g.

Run 3

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-(chloromethyl)-2,2-dimethyl-1 ,3-dioxan-4-yl]acetate (5.0g). 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- dimethyl-6-[(methyl-carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate crystallised. Yield = 1.23g.

Example 7 - Preparation of tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-[(methyl- carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate from EMIM.OAc with 9 recycles of the ionic liquid

Run 1

In a 100mL round vessel was added crude tert-butyl 2-[(4R,6S)-6-(chloromethyl)- 2,2-dimethyl-1 ,3-dioxan-4-yl]acetate (10.0g) and 1-ethyl-3-methyl imidazolium acetate (30.0g). The mixture was heated at 90°C for 6.5 hours.

Heptane (40mL) was then added to the reaction. The mixture was then heated at reflux for 10 minutes then cooled to 60°C and the heptane phase decanted. The heptane extract was slowly cooled to -4°C whereupon white needles of tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-[(methyl-carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate crystallised. Yield = 3.0g with a purity of 97.7% determined by HPLC.

Run 2

The ionic liquid phase was added back to the reaction vessel. The vessel was charged with crude tert-butyl 2-[(4R,6S)-6-(chloromethyl)-2,2-dimethyl-1 ,3- dioxan-4-yl]acetate (12. Og) and fresh 1 -ethy!-3-methyl imidazolium acetate (6.0g). The mixture was heated at 90°C for 5 hours then potassium acetate (5.0g) was added. The mixture was heated at 90°C for 23.5 hours. The reaction mixture was extracted with refluxing heptane (2 x 40mL). The combined heptane extracts were cooled to -4°C whereupon tan needles of tert-butyl 2-[(4R,6S)-2,2-dimethyl- 6-[(methyl-carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate crystallised. Yield = 4.6g with a purity of 98.4% determined by HPLC.

Run 3

The ionic liquid phase was added back to the reaction vessel. The vessel was charged with crude tert-butyl 2-[(4R,6S)-6-(chloromethyl)-2,2-dimethyl-1 ,3- dioxan-4-yl]acetate (10. Og). The mixture was heated at 90°C for 23 hours then extracted with refluxing heptane (2 x 40mL). The combined heptane extracts were cooled to -4°C whereupon tan needles of tert-butyl 2-[(4R,6S)-2,2-dimethyl- 6-[(methyl-carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate crystallised. Yield = 2.6g with a purity of 98.5% determined by HPLC.

Run 4

As per Run 3. Yield 3.0g tan coloured needles with a purity of 97.8% determined by HPLC.

Run 5

As per Run 3 except potassium acetate (5.0g) was added. Yield 3.4g tan coloured needles with a purity of 97.2% determined by HPLC.

Run 6

The ionic liquid phase from Run 6 was purged of accumulated potassium chloride by dissolving the ionic liquid in methanol (50mL) and filtering the solution through a 54 micron filter. White crystals of potassium chloride (6.5g) were recovered. The ionic liquid filtrate was evaporated at 60°C to remove methanol and the ionic liquid charged back to the reaction vessel. The vessel was charged with crude tert-butyl 2-[(4R,6S)-6-(chloromethyl)-2,2-dimethyl-1 ,3-dioxan-4-yl]acetate (10. Og) and potassium acetate (2.0g). The mixture was heated at 90°C for 21 hours then extracted with refluxing heptane (2 x 40ml_). The combined heptane extracts were cooled to -4°C whereupon tan needles of tert-butyl 2-[(4R,6S)-2,2- dimethyl-6-[(methyl-carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate crystallised. Yield = 4.4g with a purity of 97.1 % determined by HPLC.

Run 7

As per Run 3 except potassium acetate (2.0g) was added. Yield 3.0g tan coloured needles with a purity of 96.1 % determined by HPLC

Run 8

As per Run 3 except potassium acetate (2.0g) was added. Yield 3.0g tan coloured needles with a purity of 97.0% determined by HPLC.

Run 9

As per Run 3 except potassium acetate (2.0g) was added. Yield 3.6g tan coloured needles with a purity of 96.1 % determined by HPLC. Second Crop Recovery

A second crop of product was isolated from the combined mother liquors from Runs 1 -5 (Yield 2.2g, 95.6% purity by HPLC) and Runs 6-9 (Yield 2.5g, 92.0% purity by HPLC)

Example 7 Summary

Example 8 - Preparation of tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-[(rnethyl- carbonyloxy)methyl]-1 ,3-dioxan-4-yl]acetate from tetra-n-butyl ammonium acetate

In a 100ml_ round vessel was added crude tert-butyl 2-[(4R,6S)-6-(chloromethyl)- 2,2-dimethyl-1 ,3-dioxan-4-yl]acetate (5.0g) and tetra-n-butyl ammonium acetate (4.3g). The mixture was heated to 115°C and became liquid at ~50°C. The mixture was heated for 7 hours.

Heptane (15mL) was added to the reaction and the mixture stirred for 5 minutes at 70°C before decanting the heptane phase. The mixture was further extracted with heptane (2 x 10ml_) at 70°C. The combined heptane extracts were washed with water (10mL) and then filtered through a bed of celite filter aid. The heptane filtrate was partially evaporated then cooled to -10°C. The pale yellow crystals were filtered and dried, yield = 1.1g with a purity of 99.1 % by HPLC.




 
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