Title of Invention	A METHOD FOR PURIFICATION OF AN ALKYL (3R, 5S)-7-[2-CYCLOPROPYL-4-(4-FLUOROPHENYL) QUINOLINE-3-YL]-3, 5-DIHYDROXY-6-HEPTENOATE.
Abstract	A method for producing an alkyl (3R,5S)-7-[2- cyclopropyl-4- \|4-fluoraphenyl)quinclin-3-yl]-3,5- dihydroxy-6-haptenoate of the formula (1) (wherein R is a 5 C1-4 alkyl group], which is an intermediate for a cholesterol-reducing agent (a HMG-COA reductase inhibitor) , etc- A solution containing a compound of the formula (1) is subjected to liquid chromatography treatment using silica gel as the packing material, 10 separated its epimers contained therein.

Title of Invention

A METHOD FOR PURIFICATION OF AN ALKYL (3R, 5S)-7-[2-CYCLOPROPYL-4-(4-FLUOROPHENYL) QUINOLINE-3-YL]-3, 5-DIHYDROXY-6-HEPTENOATE.

Abstract

A method for producing an alkyl (3R,5S)-7-[2- cyclopropyl-4- |4-fluoraphenyl)quinclin-3-yl]-3,5- dihydroxy-6-haptenoate of the formula (1) (wherein R is a 5 C1-4 alkyl group], which is an intermediate for a cholesterol-reducing agent (a HMG-COA reductase inhibitor) , etc- A solution containing a compound of the formula (1) is subjected to liquid chromatography treatment using silica gel as the packing material, 10 separated its epimers contained therein.

Full Text	1 DESCRIPTION METHOD FOR PRODUCING A 3 , 5-DIHYDFOXY-6-HEPTENOATE TECHNICAL FIELD The present invention relates to a method for 5 producing an alkyl (3R, 5s) -7- [2-cyclopropyl-4- (4- fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoate of the formula (1) (wherein R is a C1-4 alkyl group, which is a compound useful as an intermediate for pharmaceuticals and which can be used for the production 10 of a cholesterol-reducing agent (a HMG-CoA reductase inhibitor), etc (JP-A-1-279866, EP304063A or U S Patent 5,011,930). 15 BACKGFOOND ART As methods for producing an alkyl (3P,5S)-7-[2- cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5- dihydroxy-6-heptenoate of the formula (1) (wherein P is a 20 C1-4 alkyl group), the following methods (a) to (c) by optical resolution of its racemic modification and the following methods (d) to ( f) by an asymmetric synthesis, 2 are known (a) A method for producing it by an optical resolution of its rscemic modification by means of a high performance liquide chromatography(HPLC) column (suchas 5 CHIRALCEL OF, manufactured by Daicel Chemical Industries, Ltd)for separation of optical isomers (e g International Patent Publication NO 95/23125, U S Patent 5,939,552] (b) A method for optical resolution of a racemic 10 modification by means of an enzyme (e g JP-A-2001- 3529961 (c) A method wherein the racemic modification is hydrolyzed, and the obtained carboxylic acid are subject to optical resolution by means of a resolving 15 agent such as an optically active a methylbenzylamine, followed by esterification (e g JP-A-5-148237, U S Patent 5,284,95) (d) A method tor producing it by means of a chiral synthon of the formula (4) (e.g. JP-A-8-127585) (e) A method of chemically selectively reducing an alkyl 7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]- 3 5-hydroxy-3-oxo-6-heptenoate of the formula (5) (wherein R is as defined above) obtainable by e g an asymmetric aldol reaction (e g JP-A-8-92217) The compound of the formula (5) can be obtained by an asymmetric synthesis 5 (e g International Patent Publication No 03/0421801 (f) A method of selectively reducing an optically active compound of the formula (5) or an alkyl 7-[2- 15 cyclopropyl -4- (4- fluorophenyl) quinoline—3, 5dioxo — 6- heptenoate of the formula (6) (wherein R is as defined above) by a biochemical technique (e g International Patent Publication Ho 02/063028! 25 By the above-mentioned method (a) or (b), by recrystallizing the racemic modification corresponding to 4 the compound of the formula (1), its epimers (all mixture of compounds of the formulae (2) and (3)) can easily be removed, whereby the compound of the formula (1) of high purity can be obtained without separating the 5 epimers after the optical reso lution However,such a technique by optical resolution of the racemic modification has an essential problem that its antipode (an alkyl (35,5R)-7-[2-cyclopropy)-4-(4- fluorophenyl)quinolm-3-yl]-3,5-dihydroxy-6-heptenoate) 10 will be wasted By the method (c) , the two types of epimers can be removed together with the antipode in the step for the resolution of diastereomers, whereby no purification of the racemic modification is required However, this method is also essentially a resolution 15 method of the racemic modification and thus has the same essential drawback as the methods (a)and (b) 25 The above methods (c) to (f) are production methods via an optically active compound of the formula (5) or (7), but neither the chemical reaction Method nor the 5 biochemical reduction method is a completely eelective reaction whereby inclusion of a small amount of epimers is unvoidable To secure the quality useful as an intermediate for pharmaceutica1s, it is necessary to 5 remove such epimers, but, as is different from the racemic modification, the optically active substance of the formula (1) is a compound which is extremely difficult to purify by recrystallization A purification method by leading it to a p-toluene sulfonate or the 10 like, has also been tried, but the purpose has not been accomplised in any case for such a reason that lactone modification tends to proceed during the purification operation However,by each of the asymmetric systhesis and the 15 chiral synthon method, the optically active compound of the formula (5) or (7) can be produced with a high optical purity, whereby the antipode will not be wasted Accordingly, if it can be establishaed as an industrial production method, the economical effects will be 20 substantial Therefore, it has been disered to establish an efficient purification method for the compound of the formula (1] 6 DISCLOSURE OF THE INVENTION The present inventors have studied separation of the optically active substance of the formula (1) and its epimers and as a result, have found it possible to 5 separate them by employing a chromatography treatment and using, as its packing material, silica gel which preferably has certain specific physical properties preferably by using a mixture of hexane/isopropyl alcohol as the eluent 10 Further, the present inventors have found that by the method of employing a simulated moving bed system for the chormatography treatment,and it is possible to substantially reduce the amount of the solvent to be used, which used to be a problem in the 15 conventional chromatography treatment, and it is possible to resuse the eluent recovered in the chromatography treatment, whereby the method can be carried out industrially advantageously The present invention is based on such discoveries 20 and provides the following 1 A method for producing a compound of the formula (1) 7 which comprises subjecting a solution containing an alkyl (3R,5S]-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3- yl]-3,5-dihydroxy-6-heptenoate of the formula (1) (wherein R is a C1-4 alkyl group) to liquid chromatography 5 treatment using silica gel as the packing material, to separate its epimers contained therein 2 The method according to Item 1, wherein in the chromatography treatment, a mixed solvent comprising hexane/isopropyl alcohol is used as an eluent 10 3 The method according to Item 2, wherein the ratio of hexane/isopropyl alcohol in the mixed solvent is from 99/1 to 50/SO in a volume ratio 4 The method according to any one of Items 1 to 3, wherein the the silica gel as the packing material has an 15 average particle diameter of from 01 μm to10mm and an average pore diameter of from 1 nm to 100 μm 5 The method according to any one of Items 1 to 4, wherein the chromatography treatment is atreatment employing a simulated moving bed apparatus 20 6 The method according to Item 5, wherein either component of the ccording to a distillate of the extract and raffiate recovered in the chromatography treatment, to adjust the compositional ratio of the distillate to the compositional ratio of the eluent 25 before use, and the distillate so adjusted, is reused 7 The method according to any one of Items 1 to 6, wherein R in the compound of the formula (1) is an ethyl 8 group BRIEF DESCRIPTION OF THE DRAWINGS Fig 1 is a view illustrating a true moving bed (TMB) The definitions of zones I to IV are as follows 5 Zone I between the eluent flow path, and the extract flow path zone II between the extract flow path and the feed flow path Zone III between the feed flow path and the 10 raffinate flow path Zone IV between the raffinate flow path and the eluent flow path Fig 2 is a view showing the concept of a simulated moving bed (SMB) 15 Fig 3 is a view illustrating a 4-zone simulated moving bed (SMB) of one embodiment of the apparatus to carry out the method of the object to be separated BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the object to be separated 20 and puirified is an alkyl (3R, 5S) -7- [3-cyclopropyl-4- (4- fluorophenyl) quinolin-3-yl]-3,5-dihydrozy-6-heptenoate of the formula (1) wherein P is a C1-4 alkyl group) containing one or both of an alkyl cyclopropyl-4-(4-fluorphenyl)quinolin-3-yl]-3,5- as defined above) and an alkyl (3P, 5R)-7- [2-c clopropyl- 4-(4-flurophenyl)quinolin-3-yl]-3,5-dishydrozy 9 heptenoate of the formula (3) (wherein R is as defined above). The alkyl group R may, for example, be a methyl group, an ethyl group, an isoprophyl 5 group, a butyl group a sec-butyl group, an isobutyl group or a tert-butyl group Among them, the alkyl group is preferably one having 1 or 2 carbon atoms, particularly preferably an ethyl 1 group. The proportions of the compounds of the formulae 10 (1),(2)and (3) to be contained, are not particulary limited However, the higher the proportion of the compound of the formula (1), the higher the separation efficiency, whereby one having a high purity can be obtained. 15 The compounds of the formulae (2) and (3) are in the relation of enantiomers to each other, and their chromatographic behaviors are the same, and the ratio of the two compounds may be 11 or different. Further, there is no particular limitation to the 20 optical purity of the compound of the formula (1), but from the viewpoint of the prodution of an intermediate for Pharmaceuticals as the object of the present invention, an optical purity of at least 95%e is preferred. 25 In the chromatography treatment of the present invention, the object can be accomplished by using either one of a common batch system using a single column {see 10 Example 2) and a simulated moving bed method wherein continuous separation is possible (see Examples 3 to 6) However as the process for carrying out the method of the present invention, it is more preferred to employ a 5 simulated moving bed method The simulated moving bed method is industrially used, for example, in the separation of pute p-xylene from a mixture of xylenes (Jp-B-42-15681, etc ] , and its concept will be briefly explained 10 The concept of the simulated moving bed (SMB) may readily be understood by examining a true moving bed method (TMB)as shown in Fig 1 The true moving bed method (TMB) is designed for counter-current adsorption separation treatment and is constituted by 4—zones, directions There are two inlet paths, whereby the solution (the feed) to be separated and the eluent are continuously introduced From two outlet flow path(for the extract and the raffinate) , pure products are 20 continuously recovered The liquid coming out from zone IV is returned (recycled) to zone I, and the solid coming out from zone I is returned (recycled) to zone TV For example, in the case of a two component mixture (A + B) wherein component A has a shorter retention time, the 25 operation conditions (the flow rates in the respective zones are set so that component A moves upward, and component, B moves downward Component A and component B 11 can be recovered as pure products, respectively, from the raffinate outlet and the extract outlet However, in such a true moving bed method (TMB) , the operation, is practically very difficult,since it is necessary to 5 circulate the solid adsorbent Now, on the basis of the true moving bed (TMB), the simulated moving bed (SMB) is considered In the simulated moving bed (SMB) , several fixed columns are connected in series, and introducing points and 10 recovering points are properly moved (Fig 2)to let counter-current actually take place Accordingly, each flow path for the feed, the eluent, the extract or the raffinate is moved for every column (or every few columns) at constant time intervals in the flow direction 15 of the solution. A specific method will be described in Examples given hereinafter In the chromatography treatment of the present invention, as the packing material, silica gel may be advantageously used by virtue of its separation characteristics Silica 20 gel is inexpensive, and one having a constant quality can readily be available, such being particularly advantageous.In the present invention, if a packing material other then silica gel, such as alumina, is used the compound of the formula (1) is likely to undergo 25 lactonization, such being undersirable. Further, if a silicate, diatomaceous earth or the like is used, inclusion of impurities such as metals or organic 12 substances, is likely, such being undesirable, particularly when the compound of the present invention will be used as a material for Pharmaceuticals. As silica gel, pulverized one may be used, but spherical one 5 is preferred.The silica gel preferably has an average particle size of from 0.1μm,to10mm, particularly preferably from 1μm to μm, more preferably from 5 μm to 100 μm. The average pore diameter of the silica gel is preferably from 1 nm to 100μm,particularly 10 preferably from 5 nm to 5 μm Here, the average particle diameter, median diameter or mode diameter, is obtained by a light scattering/laser diffraction method, and the average micropore diameter is obtaied by a gas adsorption method or mercury porosimeter. 15 As the eluent for chromatography, a mixed solvent of hydrocarbon/alcohol may, for example, be used Particularly preferred is a mixture of hexane/isopropyl alcohol. However,the eluent is not particularly limited so long as it presents no adverse effect to the stability 20 of the packing material. In a case where a mixed solvent of hexane/isopropyl alcohol is to be employed, the ratio of hexane/isopropyl alcohol is usually within a range of from 99 1 to 50/50, preferably from 98/2 to 70/30, more preferably from 96/4 to 85/15, in a volume ratio. A 25 third solvent may be incorporated, but in the case of chromatography treatment, particularly in the case of the simulated moving bed method, the composition is 13 preferably as simple as possible for the recovery and reuse of the solvents. From the recovered eluent (the raffinate and the extract in the simulated moving bed method) , the solvents 5 can be distilled and reused. The composition of the solvents may be analyzed, for example, by gas chromatography, and either component of the eluent is added thereto to adjust the composition to the predetermined composition of the eluent, whereupon the 10 adjusted mixed solvent can readily be reused for column separation (see Example 6)For the above distillation of the solvents, an evaporator or condenser may be employed Usually, a thin membrane type condenser can suitably be used, 15 In the chromatography treatment of the present invention, the column temperature is preferably set to be a constant temperature (for example, at 40ºC as in Example 1) within a range of from 10 to 50ºC, preferably within a range of from 20 to 45ºC. Other conditions for 20 carrying out the chromatography treatment such as the supply rates of the eluent and the solution containing a mixture of isomers, the flow rates at the discharge outlets of the raffinate and the extract, the time for switching the column, the pressure,etc,are 25 properly set in accordance with the chromatography techniques know to those skilled in the art so that they are suitable for the conditons for e g the packing 14 material, the eluent, the production quantity, etc EXAMPLES Now, the present invention will be described in detail with reference to Examples, but it should be 5 understood that the present invention is by no means restricted to such specific Examples In the following Examples, a compound of the formula (1), wherein R -IS an ethyl group is used, and this compound will be referred to as (3R,5S)DOLE(1), the 10 compound of the formula (2) will be referred to as 3S,5S}DOLE(2) , and the compound of the formula (3) will be referred to as (3F,5R)DOLE(3) EXAMPLE 1 Using a commercially available silica gel column for 15 high performance liquid chromatography (HPLC) analysis, a 1.1 mixture of (3S,5S)DOLE(2) and (3R,5S)DOLE(1) was separated. The conditions are shown below Column YMC Pack Sil S-5 (manufactured by YMC Company, diameter 4 6 mm, length 350 mm, packing 20 material salica gel having an average particule dimeter of 5 μm and an average pore diameter of 12nm) Eluent hexane/isopropyl alcohol = 20/1 Temperature 40°C Flow rate 1 0 mL/min 25 Detection UV (254 nm) Retention time (3S, 5S)DOLE (2) 11 4 min (3R,5S]DOLE(1) 13 7 min 15 EXAMPLE 2 Using YMC-Pack SIL as a commercially available silica gel column, batch system separation by HPCL was carried out. The conditions were as follows: 5 Column YMC0 Pack Sil (manufactured by YMC Company, diameter 2 cm, length 25 cm, packing material silica gel having an averge particule diameter of 10 μm and an average pore diameter of 12 nm) Eluent hexane/isopropyl alcohol = 95/5 10 Temperature 40°C Flow rate 8 0 ml/min The sample used for separation was 1 01 g of (3R,5S)DOLE(1) containing 3% by mass of (3S,5S)DOLE(2) This sample was dissolved in a solvent having the same 15 composition as the eluent, and the concentration was adjusted to 3% w/v, and 2 mL of the adjusted sample was injected, whereupon a fraction (containing (3S,5S)DOLE(2)) corresponding to the retention time of from 9 42 min to 10 54 min and a fraction 20 (containing (3R,5S)DOLE (1)) corresponding to a retention time of from 11 03 min to 13 03 min,were collected This operation was repeated 17 times, whereupon the respective solvents were distilled off, thereby 892 mg (yield 89% of [3P,5S)DOLE(1) having no epimers detected 25 by the HPLC analysis and 29 0 mg (yield 2 8%) of (3S,5S)DOLE[2) having a HPLC relative area percentage of 96 5%, were obtained. The conditions for the HPLC analysis were the same as in Example 1 (3R,5S)D0LE (1) 1H NMR (CDC)a TMS) δ (ppm) 1. 01. 1. 05 (2H, m, C9 + Cl0 ) 1. 27. 1. 35 (3H, m, C9 + C10 + C4) 1 29 (3H, t, J=72 H2, Et), 1. 48. 1. 55 (1H m C4), 2 .36. 245 5 (3H, m, C8 + C2), 3 .17 (1H, d, J = 1 .7 Hz, OH), 3 .64 (1H, d, J'= 2 .7 HZ, OH), 4 .08. 4. 29 (1H, m C3), 4 .19 (2H,q, J=72 HZ,Et), 4 .38. 4 .43 (1H,m,C5) 5 .53 (1H, dd, J = 6 .2,' 16. 1 HZ, C6),6 .64 (1H dd,J ='l 3, 16 .1 HZ, C7),' 7. 12. 7. 23 (4H, m, Ar), 7 .29. 7. 36 (2H, m, Ar), 7 .58 (1H, ddd, J = 2 .1, 6. 3, 8. 5 HZ C17), 7. 96 (1H, d J = 83HZ Cl8) (3S,5S)D0LE (2) 1H NMR (CDCLS, TMS) δ (ppm) 1. 08 (2H dd, J = 2 .8, 8. 0 Hz C9 + C10) 1. 29 15 (3H, t, J= 7 .2 HZ,Et),1. 27. 1. 36 (2H, m C9 + C10) 1. 37 .1. 44 (1H, m C4) 1 .62. l.'7l (1H m, C4) 2 .33. 2.49 (3H, m C2+ C8) 2 .95 (1H, d, J = 5 .5 Hz, 3 OH) 3. 47 (1H brs, 5 OH), 9 .97. 4. 08 (lH m C3), 4 .20 (2H q J = 7. 2 Hz, Et) 4. 39. 4. 49(1H,m, C5) 5. 66 (lH, dd, J = 5.5, 16. 2 HZ C6), 6 .70 (1H dd J = 1 .4, 16 0 HZ, C7) 7. 13. 7. 35 (6H m, Ar), 7.58 (1H, ddd, J = 3. 0 5. 2, 8. 3 Hz, C17) 7. 95 (1H,d J = 8. 5 Hz C18) 25 EXAMPLE 3 (3R,5S)DOLE(1) containing 3% by mass of (3S,5S) DOLE (2) was dissolved in a mixed liquid of 17 hexane/isopropyl alcohol (in a volume ratio of 20/1) and a starting material liquid (feed) having a concentration of 30 g/L was prepared. Eight columns having an inner diameter of 3 cm and a 5 length of 10 cm and having a commercially available silica gel (YMC-SIL-120-S15/30 (average particle diameter 15/30 μm, average pore diameter 12 nm) ) packed to the simulated moving bed type fractionation apparatus LTCOSEP-LAB (manufactured by Novasep Company) as shown in 10 Fig 3, were connected in series, and fractionation was initiated by such an apparatus construction that the feed was introduced at position 7 the sluent was introduced at position 3, the extract was recovered at position5. and the raffinate is recovered at position 1. Using a 15 mixed liquid of hexane/isopropyl alcofrol (in a volume ratio of 20/1)as the eluent, the operation temperature was set to be 35ºC,and the feed was set to be 30 g/l. The operation was carried out at a recycling flow rate of 98.6 ml/min, at a feed flow rate of 4.14 mL/min, at a 20 raffinate flow rate of 13.56 mL/min at an extract flow rate of 12.84 mL/min, at an eluent flow rate of 22.26 mL/min and for a switching time of 2.68 min whereby from the extract,(3R,5S)DOLE (1)having a HPLC purity of 99.98% (refer to Example 1 for the analytical conditions) 25 was obtained. On the other hand, from the raffinate, a mixture of (3S,5S)DOLE(2) (HPLC purity of 96.83%) and (3R,5S)DOLE(1) (HPLC purity of 3.17%)was obtained. 18 Thus, (3R,5S)DOLE(1) was separated substantially quantitatively EXAMPLE 4 In example 3,the operation was carried out by 5 Charging the recycling flow rate to 132.12 mL/min,the feed flow rate to 5.55mL/min,the raffinate flow rate to 18 17 mL/min, the extract flow rate to 17.21 mL/min, the eluent flow rate to 29.83 mL/min and the switching time to 2.00 min, whereby from the extract, (3R,5S)DOLE(1) 10 having a purity of 99.96% was obtained. On the other hand, from the raffinate, a mixture of (3S, 5S)DOLE(2) (HPLC purity of 88.14%) and (3R,5S)DOLE(1) (HPLC purity of 11 86%] was obtained EXAMPLE 5 15 The same simulated, moving bed apparatus as in Example 3,was used.The ratio of the mixed liquid of hexane/isopropyl alcohol was changed to 20/3 in a volume ratio,and the concentration of the starting material liquid (feed) was also changed to 45 g/L 20 The operation was carried out at a recycling flow rate of 132.00 mL/min, at a feed flow rate of 5.66 mL/min,at a raffinate flow rate of 21.79 mL/min,at an extract flow rate of 18.58 mL/min,at an eluent flow rate of 34.71 mL/min for a switching time of 0.83 min, whereby 25 from the extract, (3P, 5S)DOLE (1) having a HPLC purity of 99.66% was obtained ((3S,5S)DOLE(2) 0.26%). On the other hand, from the raffinate, a mixture of 19 (3S,5S)DOLE(2) (HPLC purity of 38.36%) and (3R,5S)DOLE(1) (HPLC purity of 60.38%) was obtained EXAMPLE 6 The same simulated moving bed apparatus as in 5 Example 3 was used, the ratio of the mixed liquid of hexane/isopropyl alcohol was adjusted to be 20/3 in a volume ratio, and the concentration of the starting material liquid (feed) was adjusted to be 45 g/L. The operation was carried out at a recycling flow 10 rate of 132.00mL/min, at a feed flow rate of 5.66 mL/min,at raffinate flow rate of 20.79 mL/min,at an extract flow rate of 19.58 mL/mm, at an eluent flow rate of 34.71 mL/min for a switching time of 0.83 min, whereby from the extract,((3S,5S)DOLE(2) 0.35%).On the 15 99.31%, was obtained ((3S,5S)DOLE (2) 0.35%).On the other hand, from the raffinate, a mixture of (3S,5S)DOLE(2) (HPLC purity of 68.99%) and [3F,5S)DOLE(1) (HPLC purity of 30.79%) was obtained Then, the extract and the raffinate obtained by the 20 above operation corresponding to about 40 cycles were, respectively, concentrated by thin film condensers, and the respective concentrated were put togethar to recover about 9.87L.The compositional ratio of the distillate was analysed by gas chromatography, and 2154 mL of hexane 25 was added so that the compositional ratio of hexane/isopropyl alcohol would be 20.3. Further, 5L of a mixed liquid of hexane, isopropyl alcohol (20/3) freshly 20 prepared, was added, to obtain a total of about 17L of an eluent. Using this liquid, a starting material liquid of 45 g/L was prepared, and separation was again carried out by 5 the same simulated moving bed apparatus as in Example 3 The operation was carried out at a recycling flow rate of 132.00 mL/min, at a feed flow rate of 5.66 mL/min,at a raffinate flow rate of 20.79 mL/min,at an extract flow rate of 19.58 mL/min, at an eluent flow rate 10 of 34.71 mL/min for a switching time of 0.83 min, whereby from the extract,(3R,5S)(1) having a HPCL purity of 99.22% was obtained ( (3S, 5S) DOLE (2) 0.21%). On the other hand, from the raffinate, a mixture of (3S,5S)DOLE(2) (HPLC purity of 30.51%) and (3R,5S)DOLE(1) 15 (HPLC purity of 68.50%) was obtained A similar operation was further repeated twice In the second time, from the extract, (3R,5S) DOLE(1) having a HPLC purity of 99.12% was obtained ((3S,5S9DOLE(2) 0.41%). On the other hand, from the 34.07%) and (3R, 5S) DOLE (1) [HPLC purity of 65.83% was obtained. In the third time, from the extract, (3R,5s)DOLE (1) having a HPLC purity of 99.33% was obtained 25 ((3S,5S)DOLE(2) 0.45%). On the other hand, from the raffinate, a mixture of (3S,5S)DOLE (2) (HPCL purity of 28.12% and (3R,5S)DOLE (1)(HPCL purity of 71.78%) was 21 obtained. From the foregoing Examples,it was confirmed that the desired products can be separated even by the recovered solvents, and it is evident that the 5 chromatography method is an industrially superior method INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a novel method for efficiently separating an alkyl (3P,5S)-7-[2-cyclopropyl-4-(4-fluorphenyl)quinolin- 10 3-yl]-3,5-dishydroxy-6- heptenoate epimer useful as an intermediate for Pharmaceuticals and its epimer by specific chromatography treatment. According to the method of the present invention the desired product can be obtained in good yield without wasting the antipode 15 Conventional optical resolution, whereby an economical effect is substantial, and further the eluent and the chromatography treatment,can be recovered and reused, whereby an excellent industrial production method will be provided. 20 22 CLAIMS 1 A method for producing a compound of the formula (1) which comprises subjecting a solution containing an alkyl. 5 (3R, 5S)-7-[2-cyclopropyl-4-(-4-fluorophenyl)quinolin-3- yl]-3 , 5-dihydroxy-6-heptenoat of the formula (1) (wherein P is a C1-4 alkyl group) to liquid chromatography treatment using silica gel as the packing material, to separate using silica gel as the packing material, to 10 2 The method according to Claim 1, wherein in the chomatography treatment, a mixed solvent comprising hexane/isopropyl alcohol in the mixed solvent is from 3 The method according to Claim 2, wherein the ratio of hexane/isopropyl alcohol in the mixed solvent is from 15 99/1 to 50/50 in a volume ratio 4 The method according to any one of claims 1to3, wherein the silica gel as the packing material has an average particle diameter of from 0.1 μm to 10mm and an average pore diameter of from 1 nm to 100 μm 20 5. The method according to any one of claims 1to4, wherein the chromatography treatment is a treatment employing a simulated moving bed apparatus. 23 6 The method according to Claim 5, wherein either component of the eluent is added to a distillate of the extract and raffinate recovered in the chromatography treatment,to adjust the compositional ratio of the 5 distillate to the compositional ratio of the eluent before use, and the distillate so adjusted, is reused 7 The method according to any one of Claims 1 to 6, wherein R in the compound of the formula (1) is an ethyl group. 10

Full Text

1
DESCRIPTION
METHOD FOR PRODUCING A 3 , 5-DIHYDFOXY-6-HEPTENOATE
TECHNICAL FIELD
The present invention relates to a method for
5 producing an alkyl (3R, 5s) -7- [2-cyclopropyl-4- (4-
fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoate of
the formula (1) (wherein R is a C1-4 alkyl group, which
is a compound useful as an intermediate for
pharmaceuticals and which can be used for the production
10 of a cholesterol-reducing agent (a HMG-CoA reductase
inhibitor), etc (JP-A-1-279866, EP304063A or U S Patent
5,011,930).

15
BACKGFOOND ART
As methods for producing an alkyl (3P,5S)-7-[2-
cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-
dihydroxy-6-heptenoate of the formula (1) (wherein P is a
20 C1-4 alkyl group), the following methods (a) to (c) by
optical resolution of its racemic modification and the
following methods (d) to ( f) by an asymmetric synthesis,

2
are known
(a) A method for producing it by an optical
resolution of its rscemic modification by means of a high
performance liquide chromatography(HPLC) column (suchas
5 CHIRALCEL OF, manufactured by Daicel Chemical Industries,
Ltd)for separation of optical isomers (e g
International Patent Publication NO 95/23125, U S
Patent 5,939,552]
(b) A method for optical resolution of a racemic
10 modification by means of an enzyme (e g JP-A-2001-
3529961
(c) A method wherein the racemic modification is
hydrolyzed, and the obtained carboxylic acid are
subject to optical resolution by means of a resolving
15 agent such as an optically active a methylbenzylamine,
followed by esterification (e g JP-A-5-148237, U S
Patent 5,284,95)
(d) A method tor producing it by means of a chiral
synthon of the formula (4) (e.g. JP-A-8-127585)

(e) A method of chemically selectively reducing an
alkyl 7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-

3
5-hydroxy-3-oxo-6-heptenoate of the formula (5) (wherein
R is as defined above) obtainable by e g an asymmetric
aldol reaction (e g JP-A-8-92217) The compound of the
formula (5) can be obtained by an asymmetric synthesis
5 (e g International Patent Publication No 03/0421801
(f) A method of selectively reducing an optically
active compound of the formula (5) or an alkyl 7-[2-
15 cyclopropyl -4- (4- fluorophenyl) quinoline—3, 5dioxo — 6-
heptenoate of the formula (6) (wherein R is as defined
above) by a biochemical technique (e g International
Patent Publication Ho 02/063028!
25
By the above-mentioned method (a) or (b), by
recrystallizing the racemic modification corresponding to

4
the compound of the formula (1), its epimers (all
mixture of compounds of the formulae (2) and (3)) can
easily be removed, whereby the compound of the formula
(1) of high purity can be obtained without separating the
5 epimers after the optical reso lution However,such a
technique by optical resolution of the racemic
modification has an essential problem that its antipode
(an alkyl (35,5R)-7-[2-cyclopropy)-4-(4-
fluorophenyl)quinolm-3-yl]-3,5-dihydroxy-6-heptenoate)
10 will be wasted By the method (c) , the two types of
epimers can be removed together with the antipode in the
step for the resolution of diastereomers, whereby no
purification of the racemic modification is required
However, this method is also essentially a resolution
15 method of the racemic modification and thus has the same
essential drawback as the methods (a)and (b)

25 The above methods (c) to (f) are production methods
via an optically active compound of the formula (5) or
(7), but neither the chemical reaction Method nor the

5
biochemical reduction method is a completely eelective
reaction whereby inclusion of a small amount of epimers
is unvoidable To secure the quality useful as an
intermediate for pharmaceutica1s, it is necessary to
5 remove such epimers, but, as is different from the
racemic modification, the optically active substance of
the formula (1) is a compound which is extremely
difficult to purify by recrystallization A purification
method by leading it to a p-toluene sulfonate or the
10 like, has also been tried, but the purpose has not been
accomplised in any case for such a reason that lactone
modification tends to proceed during the purification
operation
However,by each of the asymmetric systhesis and the
15 chiral synthon method, the optically active compound of
the formula (5) or (7) can be produced with a high
optical purity, whereby the antipode will not be wasted
Accordingly, if it can be establishaed as an industrial
production method, the economical effects will be
20 substantial Therefore, it has been disered to establish
an efficient purification method for the compound of the
formula (1]

6
DISCLOSURE OF THE INVENTION
The present inventors have studied separation of the
optically active substance of the formula (1) and its
epimers and as a result, have found it possible to
5 separate them by employing a chromatography treatment and
using, as its packing material, silica gel which
preferably has certain specific physical properties
preferably by using a mixture of hexane/isopropyl alcohol
as the eluent
10 Further, the present inventors have found that by
the method of employing a simulated moving bed system for
the chormatography treatment,and it is
possible to substantially reduce the amount of the
solvent to be used, which used to be a problem in the
15 conventional chromatography treatment, and it is possible
to resuse the eluent recovered in the chromatography
treatment, whereby the method can be carried out
industrially advantageously
The present invention is based on such discoveries
20 and provides the following
1 A method for producing a compound of the formula (1)

7
which comprises subjecting a solution containing an alkyl
(3R,5S]-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-
yl]-3,5-dihydroxy-6-heptenoate of the formula (1)
(wherein R is a C1-4 alkyl group) to liquid chromatography
5 treatment using silica gel as the packing material, to
separate its epimers contained therein
2 The method according to Item 1, wherein in the
chromatography treatment, a mixed solvent comprising
hexane/isopropyl alcohol is used as an eluent
10 3 The method according to Item 2, wherein the ratio of
hexane/isopropyl alcohol in the mixed solvent is from
99/1 to 50/SO in a volume ratio
4 The method according to any one of Items 1 to 3,
wherein the the silica gel as the packing material has an
15 average particle diameter of from 01 μm to10mm and an
average pore diameter of from 1 nm to 100 μm
5 The method according to any one of Items 1 to 4,
wherein the chromatography treatment is atreatment
employing a simulated moving bed apparatus
20 6 The method according to Item 5, wherein either
component of the ccording to a distillate of the
extract and raffiate recovered in the chromatography
treatment, to adjust the compositional ratio of the
distillate to the compositional ratio of the eluent
25 before use, and the distillate so adjusted, is reused
7 The method according to any one of Items 1 to 6,
wherein R in the compound of the formula (1) is an ethyl

8
group
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 is a view illustrating a true moving bed
(TMB) The definitions of zones I to IV are as follows
5 Zone I between the eluent flow path, and the
extract flow path
zone II between the extract flow path and the feed
flow path
Zone III between the feed flow path and the
10 raffinate flow path
Zone IV between the raffinate flow path and the
eluent flow path
Fig 2 is a view showing the concept of a simulated
moving bed (SMB)
15 Fig 3 is a view illustrating a 4-zone simulated
moving bed (SMB) of one embodiment of the apparatus to
carry out the method of the object to be separated
BEST MODE FOR CARRYING OUT THE INVENTION
In the present invention, the object to be separated
20 and puirified is an alkyl (3R, 5S) -7- [3-cyclopropyl-4- (4-
fluorophenyl) quinolin-3-yl]-3,5-dihydrozy-6-heptenoate of
the formula (1) wherein P is a C1-4 alkyl group)
containing one or both of an alkyl cyclopropyl-4-(4-fluorphenyl)quinolin-3-yl]-3,5-
as defined above) and an alkyl (3P, 5R)-7- [2-c clopropyl-
4-(4-flurophenyl)quinolin-3-yl]-3,5-dishydrozy

9
heptenoate of the formula (3) (wherein R is as defined
above).
The alkyl group R may, for example, be a methyl
group, an ethyl group, an isoprophyl
5 group, a butyl group a sec-butyl group, an isobutyl
group or a tert-butyl group Among them, the alkyl group
is preferably one having 1 or 2 carbon atoms,
particularly preferably an ethyl 1 group.
The proportions of the compounds of the formulae
10 (1),(2)and (3) to be contained, are not particulary
limited However, the higher the proportion of the
compound of the formula (1), the higher the separation
efficiency, whereby one having a high purity can be
obtained.
15 The compounds of the formulae (2) and (3) are in the
relation of enantiomers to each other, and their
chromatographic behaviors are the same, and the ratio of
the two compounds may be 11 or different.
Further, there is no particular limitation to the
20 optical purity of the compound of the formula (1), but
from the viewpoint of the prodution of an intermediate
for Pharmaceuticals as the object of the present
invention, an optical purity of at least 95%e is
preferred.
25 In the chromatography treatment of the present
invention, the object can be accomplished by using either
one of a common batch system using a single column {see

10
Example 2) and a simulated moving bed method wherein
continuous separation is possible (see Examples 3 to 6)
However as the process for carrying out the method of
the present invention, it is more preferred to employ a
5 simulated moving bed method The simulated moving bed
method is industrially used, for example, in the
separation of pute p-xylene from a mixture of xylenes
(Jp-B-42-15681, etc ] , and its concept will be briefly
explained
10 The concept of the simulated moving bed (SMB) may
readily be understood by examining a true moving bed
method (TMB)as shown in Fig 1 The true moving bed
method (TMB) is designed for counter-current adsorption
separation treatment and is constituted by 4—zones,
directions There are two inlet paths, whereby the
solution (the feed) to be separated and the eluent are
continuously introduced From two outlet flow path(for
the extract and the raffinate) , pure products are
20 continuously recovered The liquid coming out from zone
IV is returned (recycled) to zone I, and the solid coming
out from zone I is returned (recycled) to zone TV For
example, in the case of a two component mixture (A + B)
wherein component A has a shorter retention time, the
25 operation conditions (the flow rates in the respective
zones are set so that component A moves upward, and
component, B moves downward Component A and component B

11
can be recovered as pure products, respectively, from the
raffinate outlet and the extract outlet However, in
such a true moving bed method (TMB) , the operation, is
practically very difficult,since it is necessary to
5 circulate the solid adsorbent
Now, on the basis of the true moving bed (TMB), the
simulated moving bed (SMB) is considered In the
simulated moving bed (SMB) , several fixed columns are
connected in series, and introducing points and
10 recovering points are properly moved (Fig 2)to let
counter-current actually take place Accordingly, each
flow path for the feed, the eluent, the extract or the
raffinate is moved for every column (or every few
columns) at constant time intervals in the flow direction
15 of the solution. A specific method will be described in
Examples given hereinafter
In the chromatography treatment of the present invention,
as the packing material, silica gel may be advantageously
used by virtue of its separation characteristics Silica
20 gel is inexpensive, and one having a constant quality can
readily be available, such being particularly
advantageous.In the present invention, if a packing
material other then silica gel, such as alumina, is used
the compound of the formula (1) is likely to undergo
25 lactonization, such being undersirable. Further, if a
silicate, diatomaceous earth or the like is used,
inclusion of impurities such as metals or organic

12
substances, is likely, such being undesirable,
particularly when the compound of the present invention
will be used as a material for Pharmaceuticals. As
silica gel, pulverized one may be used, but spherical one
5 is preferred.The silica gel preferably has an average
particle size of from 0.1μm,to10mm, particularly
preferably from 1μm to μm, more preferably from 5 μm
to 100 μm. The average pore diameter of the silica gel
is preferably from 1 nm to 100μm,particularly
10 preferably from 5 nm to 5 μm Here, the average particle
diameter, median diameter or mode diameter, is obtained
by a light scattering/laser diffraction method, and the
average micropore diameter is obtaied by a gas
adsorption method or mercury porosimeter.
15 As the eluent for chromatography, a mixed solvent of
hydrocarbon/alcohol may, for example, be used
Particularly preferred is a mixture of hexane/isopropyl
alcohol. However,the eluent is not particularly limited
so long as it presents no adverse effect to the stability
20 of the packing material. In a case where a mixed solvent
of hexane/isopropyl alcohol is to be employed, the ratio
of hexane/isopropyl alcohol is usually within a range of
from 99 1 to 50/50, preferably from 98/2 to 70/30, more
preferably from 96/4 to 85/15, in a volume ratio. A
25 third solvent may be incorporated, but in the case of
chromatography treatment, particularly in the case of the
simulated moving bed method, the composition is

13
preferably as simple as possible for the recovery and
reuse of the solvents.
From the recovered eluent (the raffinate and the
extract in the simulated moving bed method) , the solvents
5 can be distilled and reused. The composition of the
solvents may be analyzed, for example, by gas
chromatography, and either component of the eluent is
added thereto to adjust the composition to the
predetermined composition of the eluent, whereupon the
10 adjusted mixed solvent can readily be reused for column
separation (see Example 6)For the above distillation
of the solvents, an evaporator or condenser may be
employed Usually, a thin membrane type condenser can
suitably be used,
15 In the chromatography treatment of the present
invention, the column temperature is preferably set to be
a constant temperature (for example, at 40ºC as in
Example 1) within a range of from 10 to 50ºC, preferably
within a range of from 20 to 45ºC. Other conditions for
20 carrying out the chromatography treatment such as the
supply rates of the eluent and the solution containing a
mixture of isomers, the flow rates at the discharge
outlets of the raffinate and the extract, the time for
switching the column, the pressure,etc,are
25 properly set in accordance with the chromatography
techniques know to those skilled in the art so that
they are suitable for the conditons for e g the packing

14
material, the eluent, the production quantity, etc
EXAMPLES
Now, the present invention will be described in
detail with reference to Examples, but it should be
5 understood that the present invention is by no means
restricted to such specific Examples
In the following Examples, a compound of the formula
(1), wherein R -IS an ethyl group is used, and this
compound will be referred to as (3R,5S)DOLE(1), the
10 compound of the formula (2) will be referred to as
3S,5S}DOLE(2) , and the compound of the formula (3) will
be referred to as (3F,5R)DOLE(3)
EXAMPLE 1
Using a commercially available silica gel column for
15 high performance liquid chromatography (HPLC) analysis, a
1.1 mixture of (3S,5S)DOLE(2) and (3R,5S)DOLE(1) was
separated. The conditions are shown below
Column YMC Pack Sil S-5 (manufactured by YMC
Company, diameter 4 6 mm, length 350 mm, packing
20 material salica gel having an average particule dimeter
of 5 μm and an average pore diameter of 12nm)
Eluent hexane/isopropyl alcohol = 20/1
Temperature 40°C
Flow rate 1 0 mL/min
25 Detection UV (254 nm)
Retention time (3S, 5S)DOLE (2) 11 4 min
(3R,5S]DOLE(1) 13 7 min

15
EXAMPLE 2
Using YMC-Pack SIL as a commercially available
silica gel column, batch system separation by HPCL was
carried out. The conditions were as follows:
5 Column YMC0 Pack Sil (manufactured by YMC Company,
diameter 2 cm, length 25 cm, packing material silica
gel having an averge particule diameter of 10 μm and an
average pore diameter of 12 nm)
Eluent hexane/isopropyl alcohol = 95/5
10 Temperature 40°C
Flow rate 8 0 ml/min
The sample used for separation was 1 01 g of
(3R,5S)DOLE(1) containing 3% by mass of (3S,5S)DOLE(2)
This sample was dissolved in a solvent having the same
15 composition as the eluent, and the concentration was
adjusted to 3% w/v, and 2 mL of the adjusted sample was
injected, whereupon a fraction (containing
(3S,5S)DOLE(2)) corresponding to the retention time of
from 9 42 min to 10 54 min and a fraction
20 (containing (3R,5S)DOLE (1)) corresponding to a retention
time of from 11 03 min to 13 03 min,were collected
This operation was repeated 17 times, whereupon the
respective solvents were distilled off, thereby 892 mg
(yield 89% of [3P,5S)DOLE(1) having no epimers detected
25 by the HPLC analysis and 29 0 mg (yield 2 8%) of
(3S,5S)DOLE[2) having a HPLC relative area percentage of
96 5%, were obtained. The conditions for the HPLC

analysis were the same as in Example 1
(3R,5S)D0LE (1)
1H NMR (CDC)a TMS) δ (ppm) 1. 01. 1. 05 (2H, m, C9 + Cl0 ) 1. 27. 1. 35 (3H, m,
C9 + C10 + C4) 1 29 (3H, t, J=72 H2, Et), 1. 48. 1. 55 (1H m C4), 2 .36. 245
5 (3H, m, C8 + C2), 3 .17 (1H, d, J = 1 .7 Hz, OH), 3 .64 (1H, d, J'= 2 .7 HZ, OH),
4 .08. 4. 29 (1H, m C3), 4 .19 (2H,q, J=72 HZ,Et), 4 .38. 4 .43 (1H,m,C5) 5 .53
(1H, dd, J = 6 .2,' 16. 1 HZ, C6),6 .64 (1H dd,J ='l 3, 16 .1 HZ, C7),' 7. 12. 7. 23
(4H, m, Ar), 7 .29. 7. 36 (2H, m, Ar), 7 .58 (1H, ddd, J = 2 .1, 6. 3, 8. 5 HZ C17),
7. 96 (1H, d J = 83HZ Cl8)

(3S,5S)D0LE (2)
1H NMR (CDCLS, TMS) δ (ppm) 1. 08 (2H dd, J = 2 .8, 8. 0 Hz C9 + C10) 1. 29
15 (3H, t, J= 7 .2 HZ,Et),1. 27. 1. 36 (2H, m C9 + C10) 1. 37 .1. 44 (1H, m C4)
1 .62. l.'7l (1H m, C4) 2 .33. 2.49 (3H, m C2+ C8) 2 .95 (1H, d, J = 5 .5 Hz,
3 OH) 3. 47 (1H brs, 5 OH), 9 .97. 4. 08 (lH m C3), 4 .20 (2H q J = 7. 2 Hz, Et)
4. 39. 4. 49(1H,m, C5) 5. 66 (lH, dd, J = 5.5, 16. 2 HZ C6), 6 .70 (1H dd J = 1 .4,
16 0 HZ, C7) 7. 13. 7. 35 (6H m, Ar), 7.58 (1H, ddd, J = 3. 0 5. 2, 8. 3 Hz, C17)
7. 95 (1H,d J = 8. 5 Hz C18)

25 EXAMPLE 3
(3R,5S)DOLE(1) containing 3% by mass of
(3S,5S) DOLE (2) was dissolved in a mixed liquid of

17
hexane/isopropyl alcohol (in a volume ratio of 20/1) and
a starting material liquid (feed) having a concentration
of 30 g/L was prepared.
Eight columns having an inner diameter of 3 cm and a
5 length of 10 cm and having a commercially available
silica gel (YMC-SIL-120-S15/30 (average particle
diameter 15/30 μm, average pore diameter 12 nm) ) packed
to the simulated moving bed type fractionation apparatus
LTCOSEP-LAB (manufactured by Novasep Company) as shown in
10 Fig 3, were connected in series, and fractionation was
initiated by such an apparatus construction that the feed
was introduced at position 7 the sluent was introduced
at position 3, the extract was recovered at position5.
and the raffinate is recovered at position 1. Using a
15 mixed liquid of hexane/isopropyl alcofrol (in a volume
ratio of 20/1)as the eluent, the operation temperature
was set to be 35ºC,and the feed was set to be 30 g/l.
The operation was carried out at a recycling flow rate of
98.6 ml/min, at a feed flow rate of 4.14 mL/min, at a
20 raffinate flow rate of 13.56 mL/min at an extract flow
rate of 12.84 mL/min, at an eluent flow rate of 22.26
mL/min and for a switching time of 2.68 min whereby from
the extract,(3R,5S)DOLE (1)having a HPLC purity of
99.98% (refer to Example 1 for the analytical conditions)
25 was obtained. On the other hand, from the raffinate, a
mixture of (3S,5S)DOLE(2) (HPLC purity of 96.83%) and
(3R,5S)DOLE(1) (HPLC purity of 3.17%)was obtained.

18
Thus, (3R,5S)DOLE(1) was separated substantially
quantitatively
EXAMPLE 4
In example 3,the operation was carried out by
5 Charging the recycling flow rate to 132.12 mL/min,the
feed flow rate to 5.55mL/min,the raffinate flow rate to
18 17 mL/min, the extract flow rate to 17.21 mL/min, the
eluent flow rate to 29.83 mL/min and the switching time
to 2.00 min, whereby from the extract, (3R,5S)DOLE(1)
10 having a purity of 99.96% was obtained. On the other
hand, from the raffinate, a mixture of (3S, 5S)DOLE(2)
(HPLC purity of 88.14%) and (3R,5S)DOLE(1) (HPLC purity
of 11 86%] was obtained
EXAMPLE 5
15 The same simulated, moving bed apparatus as in
Example 3,was used.The ratio of the mixed liquid of
hexane/isopropyl alcohol was changed to 20/3 in a volume
ratio,and the concentration of the starting material
liquid (feed) was also changed to 45 g/L
20 The operation was carried out at a recycling flow
rate of 132.00 mL/min, at a feed flow rate of 5.66
mL/min,at a raffinate flow rate of 21.79 mL/min,at an
extract flow rate of 18.58 mL/min,at an eluent flow rate
of 34.71 mL/min for a switching time of 0.83 min, whereby
25 from the extract, (3P, 5S)DOLE (1) having a HPLC purity of
99.66% was obtained ((3S,5S)DOLE(2) 0.26%). On the
other hand, from the raffinate, a mixture of

19
(3S,5S)DOLE(2) (HPLC purity of 38.36%) and (3R,5S)DOLE(1)
(HPLC purity of 60.38%) was obtained
EXAMPLE 6
The same simulated moving bed apparatus as in
5 Example 3 was used, the ratio of the mixed liquid of
hexane/isopropyl alcohol was adjusted to be 20/3 in a
volume ratio, and the concentration of the starting
material liquid (feed) was adjusted to be 45 g/L.
The operation was carried out at a recycling flow
10 rate of 132.00mL/min, at a feed flow rate of 5.66
mL/min,at raffinate flow rate of 20.79 mL/min,at an
extract flow rate of 19.58 mL/mm, at an eluent flow rate
of 34.71 mL/min for a switching time of 0.83 min, whereby
from the extract,((3S,5S)DOLE(2) 0.35%).On the
15 99.31%, was obtained ((3S,5S)DOLE (2) 0.35%).On the
other hand, from the raffinate, a mixture of
(3S,5S)DOLE(2) (HPLC purity of 68.99%) and [3F,5S)DOLE(1)
(HPLC purity of 30.79%) was obtained
Then, the extract and the raffinate obtained by the
20 above operation corresponding to about 40 cycles were,
respectively, concentrated by thin film condensers, and
the respective concentrated were put togethar to recover
about 9.87L.The compositional ratio of the distillate
was analysed by gas chromatography, and 2154 mL of hexane
25 was added so that the compositional ratio of
hexane/isopropyl alcohol would be 20.3. Further, 5L of a
mixed liquid of hexane, isopropyl alcohol (20/3) freshly

20
prepared, was added, to obtain a total of about 17L of an
eluent.
Using this liquid, a starting material liquid of 45
g/L was prepared, and separation was again carried out by
5 the same simulated moving bed apparatus as in Example 3
The operation was carried out at a recycling flow
rate of 132.00 mL/min, at a feed flow rate of 5.66
mL/min,at a raffinate flow rate of 20.79 mL/min,at an
extract flow rate of 19.58 mL/min, at an eluent flow rate
10 of 34.71 mL/min for a switching time of 0.83 min, whereby
from the extract,(3R,5S)(1) having a HPCL purity of
99.22% was obtained ( (3S, 5S) DOLE (2) 0.21%). On the
other hand, from the raffinate, a mixture of
(3S,5S)DOLE(2) (HPLC purity of 30.51%) and (3R,5S)DOLE(1)
15 (HPLC purity of 68.50%) was obtained
A similar operation was further repeated twice
In the second time, from the extract, (3R,5S) DOLE(1)
having a HPLC purity of 99.12% was obtained
((3S,5S9DOLE(2) 0.41%). On the other hand, from the
34.07%) and (3R, 5S) DOLE (1) [HPLC purity of 65.83% was
obtained.
In the third time, from the extract, (3R,5s)DOLE (1)
having a HPLC purity of 99.33% was obtained
25 ((3S,5S)DOLE(2) 0.45%). On the other hand, from the
raffinate, a mixture of (3S,5S)DOLE (2) (HPCL purity of
28.12% and (3R,5S)DOLE (1)(HPCL purity of 71.78%) was

21
obtained.
From the foregoing Examples,it was confirmed that
the desired products can be separated even by the
recovered solvents, and it is evident that the
5 chromatography method is an industrially superior method
INDUSTRIAL APPLICABILITY
According to the present invention, it is possible
to provide a novel method for efficiently separating an
alkyl (3P,5S)-7-[2-cyclopropyl-4-(4-fluorphenyl)quinolin-
10 3-yl]-3,5-dishydroxy-6- heptenoate epimer useful as an
intermediate for Pharmaceuticals and its epimer by
specific chromatography treatment. According to the
method of the present invention the desired product can
be obtained in good yield without wasting the antipode
15 Conventional optical resolution, whereby an economical
effect is substantial, and further the eluent and
the chromatography treatment,can be recovered and
reused, whereby an excellent industrial production method
will be provided.
20

22
CLAIMS
1 A method for producing a compound of the formula (1)

which comprises subjecting a solution containing an alkyl.
5 (3R, 5S)-7-[2-cyclopropyl-4-(-4-fluorophenyl)quinolin-3-
yl]-3 , 5-dihydroxy-6-heptenoat of the formula (1)
(wherein P is a C1-4 alkyl group) to liquid chromatography
treatment using silica gel as the packing material, to
separate using silica gel as the packing material, to
10 2 The method according to Claim 1, wherein in the
chomatography treatment, a mixed solvent comprising
hexane/isopropyl alcohol in the mixed solvent is from
3 The method according to Claim 2, wherein the ratio of
hexane/isopropyl alcohol in the mixed solvent is from
15 99/1 to 50/50 in a volume ratio
4 The method according to any one of claims 1to3,
wherein the silica gel as the packing material has an
average particle diameter of from 0.1 μm to 10mm and an
average pore diameter of from 1 nm to 100 μm
20 5. The method according to any one of claims 1to4,
wherein the chromatography treatment is a treatment
employing a simulated moving bed apparatus.

23
6 The method according to Claim 5, wherein either
component of the eluent is added to a distillate of the
extract and raffinate recovered in the chromatography
treatment,to adjust the compositional ratio of the
5 distillate to the compositional ratio of the eluent
before use, and the distillate so adjusted, is reused
7 The method according to any one of Claims 1 to 6,
wherein R in the compound of the formula (1) is an ethyl
group.
10

Documents:

« Previous Patent

Next Patent »

Patent Number

214067

Indian Patent Application Number

00588/KOLNP/2005

PG Journal Number

05/2008

Publication Date

01-Feb-2008

Grant Date

30-Jan-2008

Date of Filing

06-Apr-2005

Name of Patentee

NISSAN CHEMICAL INDUSTRIES, LTD.

Applicant Address

7-1, KANDA-NISHIKI-CHO 3-CHOME, CHIYODA-KU, TOKYO 101-0054, JAPAN

Inventors:

#	Inventor's Name	Inventor's Address
1	YOSHIMURA, YUJI	C/O, NISSAN CHEMICAL INDUSTRIES, LTD. ONODA PLANT, 6903-1, OAZA-ONODA, ONODA-SHI, YAMAGUCHI 756-0093, JAPAN
2	YASUKAWA, MASAMI	C/O, NISSAN CHEMICAL INDUSTRIES, LTD. SODEGAURA PLANT, 11-1, KITA-SODE, SODEGAURA- SHI, CHIBA 299-0266, JAPAN
3	MORIKIYO, SYUJI	C/O, NISSAN CHEMICAL INDUSTRIES, LTD. ONODA PLANT, 6903-1, OAZA-ONODA, ONODA-SHI, YAMAGUCHI 756-0093, JAPAN
4	MATSUMOTO, HIROO	C/O, NISSAN CHEMICAL INDUSTRIES, LTD. CHEMICAL RESEARCH LABORATORIES 722-1, TSUBOI-CHO, FUNABASHI-SHI, CHIBA 274-8507, JAPAN
5	TAKADA, YASUTAKA	C/O, NISSAN CHEMICAL INDUSTRIES, LTD. CHEMICAL RESEARCH LABORATORIES 722-1, TSUBOI-CHO, FUNABASHI-SHI, CHIBA 274-8507, JAPAN
6	ADACHI, MICHIAKI	C/O, NISSAN CHEMICAL INDUSTRIES, LTD. CHEMICAL RESEARCH LABORATORIES 722-1, TSUBOI-CHO, FUNABASHI-SHI, CHIBA 274-8507, JAPAN

PCT International Classification Number

C07D 215/14

PCT International Application Number

PCT/JP2003/011643

PCT International Filing date

2003-09-11

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2002-275015	2002-09-20	Japan