WO2007063869A1 - Process for production of highly pure quinolone compound - Google Patents

Process for production of highly pure quinolone compound Download PDF

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Publication number
WO2007063869A1
WO2007063869A1 PCT/JP2006/323763 JP2006323763W WO2007063869A1 WO 2007063869 A1 WO2007063869 A1 WO 2007063869A1 JP 2006323763 W JP2006323763 W JP 2006323763W WO 2007063869 A1 WO2007063869 A1 WO 2007063869A1
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WIPO (PCT)
Prior art keywords
compound
solution
methylpropyl
hydroxymethyl
carboxylic acid
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PCT/JP2006/323763
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French (fr)
Japanese (ja)
Inventor
Koji Matsuda
Koji Ando
Shigeji Ohki
Takahiro Yamasaki
Jun-Ichi Hoshi
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Japan Tobacco Inc.
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Publication of WO2007063869A1 publication Critical patent/WO2007063869A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4

Definitions

  • the present invention relates to a known compound of 6- (3 chloro-2-fluorobenzyl) 1 [(S) — 1 hydroxymethyl 2 methylpropyl] 7-methoxy-1-oxo-1,4 dihydroquinoline-3-carboxylic acid.
  • the present invention relates to a new manufacturing method.
  • Patent Document 1 6- (3 chloro-2-fluorobenzyl) -7 fluoro-1— [(S) -1-hydroxymethyl-2-methylpropyl] 4-oxo- A method for producing compound [A] from 1,4-dihydroquinoline-3-strong rubonic acid (hereinafter referred to as compound [A-1]) is described.
  • TBDMS represents a tert-butyldimethylsilyl group.
  • the mixture was stirred and separated with 20% brine (200 L), and the organic layer was dissolved three times with 20% brine (200 L).
  • 0.5N hydrochloric acid (200 L) and The organic layer was concentrated under reduced pressure and azeotroped with ethyl acetate (200 L), and ethyl acetate (320 L) and water (200 L) were added to the residue.
  • the organic layer was concentrated under reduced pressure, azeotroped twice with isobutyl acetate (200 L), the residue was dissolved by heating, filtered while hot, and washed with isobutyl acetate (20 L).
  • Patent Document l WO2004Z046115 (Example 4-32, pages 108-111)
  • Patent Document 2 Specification of PCTZJP2005Z009604
  • the inventors of the present invention have intensively studied the conditions of the purification step in the method of producing the compound [A-1] which can solve the above-mentioned problems. As a result, the present inventors have found a condition that can solve the above problems and have completed the present invention.
  • the present invention is as follows.
  • step (ii) 6- (3-chlorobenzyl 2-fluoropropyl) produced in step (i) 1- [(S)-1 hydroxymethyl-1-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinoline (1)
  • step (c) Step of adding isopropanol to the concentrated residue obtained in step (b) and then concentrating;
  • step (d) Step of adding an aqueous solution of inorganic salt and a sole to the concentrated residue obtained in step (c) and separating the solution;
  • step (e) Step of washing the organic layer obtained in step (d) with an aqueous inorganic salt solution, neutralizing and concentrating;
  • step (f) Step of adding heptane to the concentrated residue obtained in step (e) and filtering.
  • the production method of the present invention can remove sodium fluoride as a by-product and has high purification efficiency with respect to compound [B] as a by-product. A] can be obtained in high yield.
  • high-purity compound [A] means the ratio of compound [A] in compound [A] containing impurities, preferably 98% by weight or more, more preferably 98.5% by weight. More preferably, 99% by weight or more of the compound [A] and Z or the compound [B] in the crystal of the compound [A] [B] remaining capacity is preferably 1% by weight or less, more preferably 0.5% by weight or less. More preferably, the compound [A] is 0.1% by weight or less.
  • the production method of the present invention can operate the crystalline polymorph of compound [A] under conditions that do not cause any crystals to be crystallized. ] Can be obtained.
  • the high-purity compound [A] can be efficiently obtained without the need for complicated operations such as solvent replacement until the filtration operation of the compound [A]. Obtainable.
  • Fig. 1 is a graph showing the solubility at room temperature of a type III crystal of Compound [A] in a toluene isopropanol mixed solvent system and an iso-luo isopropanol mixed solvent system.
  • Compound [A] has been confirmed to have a crystalline polymorph (eg, PCTZJP2 005Z009604 specification). Specifically, type I crystals, cage crystals and cage crystals identified by the following powder X-ray diffraction peaks have been found.
  • a crystalline polymorph eg, PCTZJP2 005Z009604 specification.
  • Form I crystal main diffraction peak (20); 6. 58, 14. 40, 14. 64, 15. 24, 16. 48, 19. 16, 20. 90, 21. 14, 22. 24, 24. 74, 25. 64, 26. 12, 27. 20 °, characteristic diffraction peak (20); 6. 58, 14. 40, 19. 16, 20. 90, 21. 14 °
  • V-shaped crystal Main diffraction peak (20); 6. 56, 9. 04, 13. 20, 14. 62, 15. 24, 16. 48, 19. 86, 20. 84, 21. 22, 22. 24, 25. 22, 25. 96, 26. 12, 27. 34 °, characteristic diffraction peak (2 ⁇ ); 6. 56, 13. 20, 19. 86, 20. 84, 21. 22, 25. 22 °
  • V-shaped crystal Main diffraction peak (20); 8.54, 14.02, 15.68, 15.90, 16.00, 17.06, 17.24, 17.84, 18.12, 19 50, 19.90, 22.26, 22.68, 23.02, 24.16, 24.76, 25.18, 25.74, 25.98, 27.50, 28.80, 30.38 , 30.72, 32.54 °, characteristic diffraction peak (2 ⁇ ); 8. 54, 14. 02, 15. 68, 17. 06, 17. 24, 24. 16, 25. 74 °
  • type II crystals and cocoon crystals are stable crystals, and that type III crystals have lower solubility than type I crystals and cocoon crystals (for example, (See PCT / JP2005 / 0 09604 specification).
  • Table 1 below shows data on solubility.
  • Test solution No. 1 solution for disintegration test method of JP General Test Method Sodium chloride 2. Dissolve 7. OmL of hydrochloric acid and water in Og and dissolve to make 1OOOmL. This solution is clear and colorless and has a pH of about 1.2.
  • Test solution second liquid for disintegration test method of JP General Test Method Add 0.2 mL of 0.2 mol ZL sodium hydroxide test solution and water to 250 mL of 0.2 mol ZL potassium dihydrogen phosphate test solution to make 100 OmL. This solution is clear and colorless and has a pH of about 6.8.
  • Matsuquilvein buffer It can be obtained by mixing disodium hydrogen phosphate and citrate at a predetermined ratio and adjusting to a predetermined pH.
  • the method for producing the compound [A] of the present invention is carried out under the above-mentioned production conditions without causing the misaligned crystal form to precipitate, and the steps (i) and ( ii), more specifically, including steps (a) to (f) described below.
  • step (i) and step (a) More specific operation procedures of step (i) and step (a) are shown below.
  • the air in the reaction vessel is replaced with an inert gas, and compound [A-1] and methanol are placed in the reaction vessel.
  • the inert gas include nitrogen, argon, and the like, preferably nitrogen.
  • the amount of methanol added is preferably 1.5 to 12 v Zw, more preferably 3 to 7 vZw, most preferably 5.5 to 6.5 vZw, relative to 1 equivalent of compound [A-l]. It is.
  • a sodium methoxide Z-methanol solution is added dropwise, preferably at an internal temperature of 0-30 ° C, more preferably 15-25 ° C.
  • the amount of sodium methoxide to be added is preferably 5 to 40 equivalents, more preferably 9 to 20 equivalents, and most preferably 9 to ⁇ ⁇ equivalents per 1 equivalent of compound [A-1]. is there.
  • the concentration of the sodium methoxide / methanol solution is not particularly limited, but it is preferable to use a 28% sodium methoxide / methanol solution because of its availability in the factory.
  • the reaction mixture is preferably stirred at an internal temperature of 25 to 75 ° C, more preferably 65 to 75 ° C, and most preferably 70 to 75 ° C.
  • the reaction is carried out by HPLC analysis until the peak area of the starting compound [A-1] is preferably 2% or less, more preferably 1% or less with respect to the peak area of the main product compound [A].
  • the HPLC analysis method is as follows.
  • Mobile phase Mobile phase A: 10 mM phosphate buffer pH 6.9>
  • Activated carbon is added to the reaction mixture, preferably at an internal temperature of 15 to 30 ° C, more preferably 20 to 25 ° C, and stirred.
  • the amount of the activated carbon added is preferably 0.05 to 0.25 wZw, more preferably 0.05 to 0.2 wZw, most preferably 0.09 to 0.1 equivalent to 1 equivalent of the compound [A-1]. 0. l lwZw.
  • the characteristics of the activated carbon to be used are not particularly limited, but steam activated charcoal generally used in the industry, for example, Shirasagi A (trade name; manufactured by NIPPON BYKOKA CHEMICALS, INC.) Should be used. Is preferred.
  • the filter is filled with powdered cellulose as a filter aid, and the reaction mixture is filtered. It is preferable that the reaction vessel and the filter are washed with methanol, this washing solution is also filtered, and the obtained filtrate is combined with the first filtrate.
  • a filter aid it is preferable to use powdered cellulose approved as a food additive, for example, KC Flock W-300G (trade name, manufactured by Nippon Paper Chemicals Co., Ltd.), etc. It is preferable to wash with.
  • the amount of powdered cellulose used is preferably 0.5 to 0.25 w / w, more preferably 0.1 to 0.21 w / w for 1 equivalent of compound [A-1]. Most preferred It is 0. 19-0.
  • the amount of methanol used for washing the reaction vessel and the filter is preferably 1 to 5 vZw, more preferably 1.8 to 3 vZw, most preferably, relative to 1 equivalent of the compound [A-l]. 1. 8 to 2.2 vZw.
  • step (b) A more specific operation procedure of step (b) is shown below.
  • step (a) Add water to the filtrate obtained in step (a) 5.
  • the amount of water added is preferably 9 to 30 equivalents, more preferably 10 to 20 equivalents, and most preferably 17 to 19 equivalents relative to 1 equivalent of compound [A1].
  • an inert gas after adding water.
  • step (c) A more specific operation procedure of step (c) is shown below.
  • step (b) Addition of isopropanol to the concentrated residue obtained in step (b) 2., preferably at an external temperature of 30-60 ° C, more preferably 30-50 ° C,
  • the compound [A 1] is concentrated under reduced pressure, preferably 8 vZw or less, more preferably 7.5 vZw or less, relative to 1 equivalent.
  • the addition amount of isopropanol is preferably 4 to 8 vZw, more preferably 5 to 7 vZw, most preferably 5.5 to 6.5 vz w with respect to 1 equivalent of the compound [A-1]. .
  • [0033] Add isopropanol to the concentrated residue, preferably at an external temperature of 30 to 60 ° C, more preferably 30 to 50 ° C, so that the amount of the concentrated residue obtained is reduced to 1 equivalent of compound [A-l].
  • the amount of isopropanol added is preferably 1 to 4 vZw, more preferably 2 to 3.3 vZw, and most preferably 2.7 to 3.3 vZw with respect to 1 equivalent of the compound [A-1]. It is.
  • the remaining amount of methanol in the resulting concentrated residue is preferably 30% by weight or less, more preferably 25% by weight or less, based on the remaining amount of isopropanol. If the remaining amount of methanol exceeds 30% by weight, it is desirable to repeat this step (c) until it reaches 30% by weight or less.
  • the remaining amount of methanol can be determined by, for example, the following GC analysis method.
  • FID hydrogen flame ion detector
  • Carrier gas flow rate Standard solution 1 ⁇ L obtained. Adjust so that the retention time of ⁇ ⁇ (isopropanol) is about 3.5 minutes.
  • step (d) A more specific operation procedure of step (d) is shown below.
  • the inorganic salt aqueous solution is not particularly limited as long as it forms a salt with the compound [A] and dissolves in the alcohol.
  • the inorganic salt aqueous solution is not particularly limited as long as it forms a salt with the compound [A] and dissolves in the alcohol.
  • sodium salt, salt salt An aqueous solution of sodium, sodium sulfate or the like can be mentioned, and an aqueous solution of sodium chloride and potassium salt is preferable, and an aqueous sodium chloride solution is most preferable.
  • the concentration of the sodium chloride aqueous solution is preferably 13 to 17%, more preferably 14 to 16%.
  • the amount of the inorganic salt aqueous solution added is, for example, preferably 5 to 8 vZw, more preferably 6 to 7.5 vZw with respect to 1 equivalent of the compound [A-1] when using a 15% sodium chloride aqueous solution.
  • the most preferable is 6.8 to 7.2 vZw.
  • the amount of additive of the solvent is preferably 3 to 7 vZw, more preferably 4 to 6 vZw, most preferably 4.8 to 5 with respect to 1 equivalent of the compound [A-l]. 2vZw.
  • Step (e) A step in which the organic layer obtained in step (d) is washed with an aqueous inorganic salt solution, neutralized, and concentrated.
  • step (e) A more specific operation procedure of step (e) is shown below.
  • the organic layer obtained by the liquid separation operation in step (d) is washed with an inorganic salt aqueous solution.
  • the inorganic salt aqueous solution include aqueous solutions of sodium chloride sodium, potassium salt sodium, sodium sulfate, etc., preferably sodium chloride sodium salt solution, sodium salt potassium aqueous solution, most preferably sodium chloride aqueous solution. is there. It is preferable to use the same inorganic salt aqueous solution as that used in step (d).
  • the concentration of the aqueous sodium chloride solution is preferably 15 to 25%, more preferably 18 to 22%.
  • the amount of the inorganic salt aqueous solution used is, for example, preferably 3 to 7 v Zw, more preferably 4 to 6 vZw with respect to 1 equivalent of the compound [A-1] when using a 20% sodium chloride aqueous solution. Most preferably, it is 4.8 to 5.2 vZw.
  • This washing operation is usually repeated a plurality of times, preferably three times, to remove sodium fluoride, which is a byproduct of the reaction in step (a), to 1 ppm or less.
  • Residual fluorine can be quantified by, for example, measuring the fluorine ion concentration in the washed water layer using a fluorine ion meter Ti-5101 (manufactured by Toko University). .
  • the organic layer is neutralized by washing sequentially with an acid and an aqueous inorganic salt solution.
  • the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like, preferably hydrochloric acid and sulfuric acid, and most preferably hydrochloric acid.
  • the concentration and amount of the acid may be any concentration and amount necessary for neutralization.
  • the concentration is preferably 0.1 to 1 mol ZL, more preferably.
  • the amount is preferably 3 to 7 vZw, more preferably 4 to 5 mol per 1 equivalent of the compound [A-1].
  • the acid for example, it is desirable to use an acid solution to which a base such as sodium chloride or potassium salt, preferably sodium chloride sodium is added.
  • a base such as sodium chloride or potassium salt
  • the inorganic salt aqueous solution include an aqueous solution of sodium chloride sodium, potassium salt potassium, etc., preferably an aqueous solution of sodium chloride sodium, and the same inorganic salt aqueous solution as used in the above operation 1. It is preferred to use an aqueous salt solution.
  • the concentration of the sodium chloride aqueous solution is preferably 15 to 25%, more preferably 18 to 22%.
  • the amount of the inorganic salt aqueous solution used is, for example, preferably 0.25-1.5 vZw, more preferably 1 to 1 with respect to 1 equivalent of the compound [A 1] when a 20% sodium chloride aqueous solution is used. 5v / w, most preferably 1.2 to 1.3vZw.
  • Steps 1 and 2 of Step (d) and Step (e) above the concentration of inorganic salt in the aqueous layer is such that the salt is precipitated and the compound [A] is eluted into the cleaning solution. Adjustments may be made as appropriate in consideration of effective prevention.
  • the isopropanol concentration in the organic layer should not lower the solubility of the compound [A] in the organic layer! It is desirable to have it.
  • the organic layer is preferably at an external temperature of 30 to 70 ° C, more preferably 50 to 70 ° C, and the amount of the concentrated residue is preferably 5 to 1 equivalent of the compound [A-l] l. Concentrate under reduced pressure until 5vZw or less, more preferably 5vZw or less.
  • Carsol is added to the concentrated residue, preferably at an external temperature of 30 to 70 ° C, more preferably 50 to 70 ° C, and the amount of the concentrated residue is reduced to the compound [A-l] l Concentrate in vacuo until the equivalent weight is preferably 5.5 v / w or less, more preferably 5 vZw or less.
  • the amount of alcohol added is preferably 3 to 7 vZw, more preferably 4 to 6 vZw, and most preferably 4.8 to 5.2 vZw with respect to 1 equivalent of the compound [A-1]. .
  • Carsol is added to the concentrated residue so that the amount of the concentrated residue is preferably 4 to 6 vZw, more preferably 4.5 to 5.5 vZw.
  • the remaining amount of isopropanol in the resulting concentrated residue is Preferably it is 0.1 wt% or less, more preferably below the detection limit.
  • the amount of isopropanol remaining is large, there is a problem that the amount of crystals obtained decreases. For example, if the remaining amount of isopropanol is 1% by weight, the amount of crystals obtained will be reduced by about 5%, and if the amount of remaining isopropanol is 2% by weight, the amount of crystals obtained will be reduced by about 10%. If the remaining amount of isopropanol exceeds 0.1% by weight, it is desirable to repeat steps 4 and 5 until the remaining amount is 0.1% by weight or less.
  • the remaining amount of isopropanol can be determined by a GC analysis method, for example, in the same manner as in step 2 of step (c) above.
  • the concentrated residue is preferably stirred at an internal temperature of 0 to 30 ° C, more preferably 15 to 30 ° C, preferably for 10 hours or more, more preferably for 12 to 15 hours. This stirring operation is preferably performed after inoculating type II crystals (seed crystals) of compound [A], and at this point, the concentrated residue is preferably crystallized.
  • the amount of seed crystal added is preferably 0.05 to 0.2 v Zw, more preferably 0.09 to 0.1 lvZw, relative to 1 equivalent of the compound [A-l].
  • the type II crystal of compound [A] can be obtained, for example, by the method described in the specification of PCTZJP2005Z009604.
  • Step (f) A step of adding heptane to the concentrated residue obtained in step (e) and filtering.
  • step (f) A more specific operation procedure of step (f) is shown below.
  • step (e) Add the heptane to the concentrated residue obtained in step 6 at an internal temperature of 20 to 35 ° C, more preferably 25 to 35 ° C, and preferably 2 hours. Above, more preferably, stirring for 3 hours or more to precipitate crystals.
  • the amount of heptane added is preferably 0.5-2 vZw, more preferably 0.9-1.5 vZw, most preferably 0.9-1 with respect to 1 equivalent of compound [A-l]. It is lv / w.
  • the remaining amount of the compound [B] in the precipitated crystals is preferably 1% by weight or less, more preferably 0.5% by weight or less.
  • the remaining amount of Compound [B] exceeds 1% by weight, it is desirable to repeat the following steps 2 and 3 until it is less than 1% by weight.
  • the remaining amount of the compound [B] can be determined by, for example, an HPLC analysis method in the same manner as in Step 3 of the above step (a). [0044] 2. Stir the concentrated residue at an internal temperature of 40-50 ° C for 3 hours or more.
  • the precipitated crystals are collected by filtration, and the obtained wet crystals are washed successively with a mixed solution of hesol / heptane and heptane.
  • the amount of azole in the mixed solution of azole / heptane is preferably 0.5 to 2 vZw, more preferably 0.5 to LvZw, relative to 1 equivalent of the compound [A-1]. Preferably it is 0.82-0.84vZw.
  • the amount of heptane in the sol / heptane mixed solution is preferably 0.1 to 0.3 vZw, more preferably 0.1 to 0.2 vZw, relative to 1 equivalent of the compound [A-1].
  • the asol: heptane mixing ratio in the asol / heptane mixed solution is preferably 5 to 20: 1 to 3, more preferably 5 to: L0: 1 to 2, and further preferably 5 to 5. 2: 1 to 1.1.
  • the amount of washing heptane (when washing with heptane alone) is preferably 0.5 to 2 vZw, more preferably 0.9 to 2 vZw, relative to 1 equivalent of compound [A-1]. Preferably 0.9 to 1. lvZw.
  • the washed wet crystals are taken out and dried under reduced pressure, preferably at an external temperature of 40 to 70 ° C, more preferably 50 to 60 ° C.
  • the drying loss is measured by sampling the crystals during drying, and the point at which the drying loss is preferably 1% or less, more preferably 0.1% or less is defined as the end point of drying.
  • the production method of the compound [A] of the present invention may further include the following step (g).
  • This recrystallization process makes it possible to remove residual solvents and residual inorganic salts, and shows a high recovery rate.
  • step (g) A more specific operation procedure of the step (g) is shown below.
  • step (f) Add the crystals of the compound [ ⁇ ] obtained in step 5 to a mixed solvent of ethanol and water.
  • the amount of ethanol used is preferably 5.0 to 8.
  • OvZw more preferably 5.5 to 7.5 vZw, and most preferably 6.0 to 0.01 to 1 equivalent of crystal of compound [ ⁇ ].
  • 7. OvZw.
  • the amount of water used is preferably 0.3-2. 2 vZw, more preferably 0.5-2. OvZw, and most preferably 0.75 per 1 equivalent of compound [A] crystals. ⁇ 1.5vZw.
  • the internal temperature is 75 to 85 ° C, more preferably 78 to 81 ° C, and the crystals are completely dissolved, followed by dust removal filtration.
  • [0050] Wash the used container and filter with ethanol, filter this washing solution in the same manner as in the above step 2. Combine the obtained filtrate with the filtrate in step 2.
  • the amount of ethanol to be used is preferably 0.3 to 2.2 vZw, more preferably 0.5 to 2 OvZw, and most preferably 0.5 to 1 equivalent of the crystal of compound [A].
  • [0051] 4. Add water to the filtrate.
  • the amount of water added is preferably 2.5 to 5.5 vZw, more preferably 3.0 to 5. OvZw, and most preferably with respect to 1 equivalent of crystal of compound [A].
  • the internal temperature is 75 to 85 ° C, more preferably 78 to 81 ° C to completely dissolve the partially precipitated crystals.
  • the compound is preferably used as a seed crystal at an internal temperature of 60 to 70 ° C, more preferably 62 to 67 ° C.
  • the addition amount of the seed crystal is preferably 0.1 to 0.20 w / w, more preferably 0.05 to 0.15 w / w, with respect to 1 equivalent of the crystal of the compound [A].
  • the type III crystal of compound [A] can be obtained, for example, by the method described in the specification of PCTZJP2005Z009604.
  • stirring is performed for 2 hours or more at an internal temperature of 40-50 ° C, more preferably 42-47 ° C.
  • [0056] 9. Stir for preferably 2 hours or more at an internal temperature of preferably 15-30 ° C, more preferably 20-25 ° C. A portion of the precipitated crystal is sampled, and the powder X-ray diffraction pattern is compared with the diffraction pattern of the II-II crystal of Compound [A]. Confirm that the two diffraction patterns match.
  • the measurement conditions for powder X-ray diffraction are, for example, as follows.
  • the precipitated crystals are collected by filtration, and the obtained wet crystals are washed with a cooled ethanol Z water mixed solution.
  • the amount of ethanol used is preferably 0.5 to 2. OvZw, more preferably 0.8 to 1.7 vZw, and most preferably 1.0 to 0.1 equivalent to 1 equivalent of the crystal of compound [A]. 1. 5vZw.
  • the amount of water used is preferably from 0.3 to 1.5 vZw, more preferably from 0.5 to 1.2 vZw, most preferably from 0.6 to 1 equivalent to 1 equivalent of the crystal of compound [A]. 1. OvZw.
  • the washed wet crystals are dried under reduced pressure, preferably at an external temperature of 70 ° C or lower, more preferably 60 ° C or lower. Sample the crystal during drying and measure the ethanol content in the crystal. Ethanol content power The time when the ethanol content is preferably less than 0.5% by weight, more preferably less than 0.1% by weight, is the end point of drying.
  • the ethanol content can be measured, for example, by a GC analysis method in the same manner as in step 2 of step (c) above.
  • step (d) and (e)) using a mixed solvent of asol-isopropanol will be described.
  • Fig. 1 shows the solubility of compound [A] at room temperature in compound isoform [A] in a toluene-isopropanol mixed solvent system and an arsol-isopropanol mixed solvent system.
  • the solubility of compound [A] at room temperature for type III crystals is 29.9 mgZml in a toluene isopropanol (50:50 vol%) mixed solvent system, compared to the absolute isopropanol (50:50 vol%). (50% by volume) In mixed solvent system, it is 65.9 mg / ml, and dissolves more compound [A] can do.
  • step (d) operation of separating a concentrated residue containing isopropanol
  • step (e) subsequent operation of step (e).
  • step (e) washing liquid
  • step (e) washing liquid
  • the organic layer was washed successively with 20% saline (250 mL) three times and with 0.5 mol / L hydrochloric acid aqueous solution (250 mL) and 20% brine (250 mL) in which sodium chloride (62.5 g) was dissolved.
  • the organic layer was concentrated under reduced pressure until the concentration residue was 250 mL.
  • Carsol (250 mL) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure until the concentrated residue became 250 mL.
  • the concentrated residue was cooled to room temperature, crystallized by adding II type crystals (50. Omg) of the compound [A] obtained according to the method described in PCTZJP2005 Z009604, and stirred for 15 hours.
  • Mobile phase Mobile phase A: 1 OmM phosphate buffer ⁇ pH 6.9>
  • the crude compound [A] (20. Og) obtained in the previous step was dissolved in ethanol (130 mL) and water (20 mL) with heating, and filtered while hot. The vessel and filter used for dissolution were washed with ethanol (20 mL), and this washing was filtered and combined with the previous filtrate. Water (80 mL) was added to this filtrate, and the mixture was heated and refluxed again to completely dissolve the crude compound [A]. 20. Omg) was added at an internal temperature of 65 ° C, and the mixture was stirred for 4 hours. Next, the mixture was stirred at an internal temperature of 45 ° C for 2 hours, and further stirred at room temperature for 16 hours and ice-cooled for 2 hours.
  • the precipitated crystals were collected by filtration and washed with a mixed solution of ethanol (24 mL) -water (16 mL). The washed crystals were dried under reduced pressure to obtain the purified compound [A] as white crystals (19.2 g, yield 96.0%).
  • Step 2 of Example 1 various compounds shown in Table 4 below were used as crystallization solvents to obtain crude compound [A] as white crystals, and compound [A] and compound [B] in the obtained crystals were obtained. The content of was determined by HPLC analysis. The results obtained are shown in Table 4.
  • the production method of the present invention can produce the compound [A] having anti-HIV activity more efficiently, and is particularly effective when mass-producing the compound [A].
  • This application is based on Japanese Patent Application No. 2005-346044 filed in Japan and US6 / 748,258 filed in the United States, the contents of which are incorporated in full herein.

Abstract

The object is to provide a process for production of a highly pure quinolone compound with good efficiency. Disclosed is a process for production of a highly pure 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2- methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinolin-3- carboxylic acid comprising the following steps (i) and (ii); (i) reacting 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1- [(S)-hydroxymethyl-2-methylpropyl]-4-oxo-1,4-dihydroquinolin-3-carboxylic acid with sodium methoxide in a methanol solvent; and (ii) purifying 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1- hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1,4- dihydroquinolin-3-carboxylic acid with anisole. In a preferred embodiment, The step (ii) comprises the following steps (b) to (f): (b) adding water to the reaction solution and then condensing the resultant mixed solution; (c) adding isopropanol to the condensation residue and further condensing the resultant mixed solution; (d) adding an aqueous inorganic salt solution and anisole to the condensation residue and subjecting the resultant mixed solution to phase separation; (e) washing an organic phase with an aqueous inorganic salt solution and neutralizing and condensing the resultant solution; and (f) adding heptane to the condensation residue and filtering the resultant mixed solution.

Description

高純度キノロン化合物の製造方法  Method for producing high purity quinolone compound
技術分野  Technical field
[0001] 本発明は、公知化合物である 6—（3 クロロー 2 フルォロベンジル） 1 [ (S) — 1 ヒドロキシメチル 2 メチルプロピル] 7—メトキシ一 4—ォキソ 1 , 4 ジヒ ドロキノリン— 3—カルボン酸の新規製造方法に関する。  [0001] The present invention relates to a known compound of 6- (3 chloro-2-fluorobenzyl) 1 [(S) — 1 hydroxymethyl 2 methylpropyl] 7-methoxy-1-oxo-1,4 dihydroquinoline-3-carboxylic acid. The present invention relates to a new manufacturing method.
背景技術  Background art
[0002] 6- (3—クロ口一 2 フルォロベンジル） 1 [ (S)—1—ヒドロキシメチル一 2—メ チルプロピル] 7—メトキシ一 4—ォキソ 1 , 4 ジヒドロキノリン一 3 カルボン酸（ 以下、化合物 [A]と示す）は、 HIVインテグラーゼ阻害作用を有する化合物として知 られ、また、その製造方法も公知である。  [0002] 6- (3-Chronoyl-2-fluorobenzyl) 1 [(S) -1-Hydroxymethyl-2-methylpropyl] 7-Methoxy-1-oxo-1,4 dihydroquinoline 1-3 carboxylic acid (hereinafter referred to as compound) [A] is known as a compound having HIV integrase inhibitory activity, and its production method is also known.
[0003] [化 1]  [0003] [Chemical 1]
化合物 [ A ]Compound [A]
Figure imgf000003_0001
Figure imgf000003_0001
[0004] 例えば、特許文献 1には、以下に示す工程を経て、 6—（3 クロロー 2 フルォロ ベンジル）—7 フルオロー 1— [ (S)—1—ヒドロキシメチル— 2—メチルプロピル] 4ーォキソ—1, 4ージヒドロキノリンー3—力ルボン酸 (以下、化合物 [A—1]と示す） から化合物 [A]を製造する方法が記載されて!ヽる。  [0004] For example, in Patent Document 1, 6- (3 chloro-2-fluorobenzyl) -7 fluoro-1— [(S) -1-hydroxymethyl-2-methylpropyl] 4-oxo- A method for producing compound [A] from 1,4-dihydroquinoline-3-strong rubonic acid (hereinafter referred to as compound [A-1]) is described.
[0005] [化 2] [0005] [Chemical 2]
Figure imgf000004_0001
Figure imgf000004_0001
化合物 [ A]  Compound [A]
[0006] 更に、化合物 [A]の別の製造方法として、特許文献 2に記載のように、以下に示す 工程を経て、化合物 [A— 1 ]から化合物 [A]を製造する方法も利用可能である。  [0006] Further, as another method for producing compound [A], as described in Patent Document 2, a method for producing compound [A] from compound [A-1] through the following steps is also available. It is.
[0007] [化 3] [0007] [Chemical 3]
Figure imgf000005_0001
Figure imgf000005_0001
化合物 [ A - 1 ] 化合物 [ A ]  Compound [A-1] Compound [A]
(ここで、 TBDMSは、 tert—ブチルジメチルシリル基を示す。） (Here, TBDMS represents a tert-butyldimethylsilyl group.)
また最終工程において、メトキシ基の導入力 結晶化に至るまでの操作について、 「ィ匕合物 [A— 1] (39. 2kg, 89. 9mol)をメタノーノレ（240L)に溶解し、 28%ナトリウ ムメトキシドメタノール溶液（173kg, 899mol)を 10°Cで滴下し、 70°Cで 21時間加熱 攪拌した。反応液に活性炭（3. 9kg)を加え、室温で 1時間攪拌した後に粉末セル口 ースでろ過し、メタノール（80L)で洗い込んだ。ろ液に水（29kg, 1620mol)をカロえ て減圧濃縮し、残さをイソプロパノール（240L, 120L)で 2回共沸した。残さに 15% 食塩水（200L)とトルエン（200L)を加え、攪拌した後に分液した。有機層を 20%食 塩水（200L)で 3回、食塩（10kg)を溶解した 0. 5N塩酸（200L)及び 20%食塩水（ 200L)で順次洗浄した。有機層を減圧濃縮し、酢酸ェチル (200L)で共沸した。残 さに酢酸ェチル（320L)と水（200L)を加え、攪拌した後に分液した。有機層を減圧 濃縮し、酢酸イソブチル（200L)で 2回共沸した。残さを加熱溶解して熱時ろ過し、酢 酸イソブチル（20L)で洗い込んだ。 60°Cでろ液に種晶（ィ匕合物 Aの II形晶， 39g)を 加え、同温で 1. 5時間攪拌した。混合物を 80°Cで 2時間加熱攪拌し、室温まで放冷 し、さらに 6時間攪拌し、晶析した固体をろ取した。得られた固体を酢酸イソブチル (4 OL)で洗浄し、減圧乾燥することにより白色固体の化合物 Aの結晶（Π形晶）（29. Ok g,収率 72%)を得た。」旨記載されている。 In addition, in the final step, the methoxy group introduction force For the operation up to crystallization, “I compound [A-1] (39.2 kg, 89.9 mol) was dissolved in methanol (240 L) and 28% sodium Mumethoxide methanol solution (173 kg, 899 mol) was added dropwise at 10 ° C, and the mixture was heated and stirred for 21 hours at 70 ° C. Activated charcoal (3.9 kg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, and then the powder cell opening. The filtrate was concentrated in vacuo with water (29 kg, 1620 mol), and the residue was azeotroped twice with isopropanol (240 L, 120 L). The mixture was stirred and separated with 20% brine (200 L), and the organic layer was dissolved three times with 20% brine (200 L). 0.5N hydrochloric acid (200 L) and The organic layer was concentrated under reduced pressure and azeotroped with ethyl acetate (200 L), and ethyl acetate (320 L) and water (200 L) were added to the residue. The organic layer was concentrated under reduced pressure, azeotroped twice with isobutyl acetate (200 L), the residue was dissolved by heating, filtered while hot, and washed with isobutyl acetate (20 L). To the filtrate was added a seed crystal (form II crystal of Compound A, 39 g), and the mixture was stirred at the same temperature for 1.5 hours.The mixture was heated and stirred at 80 ° C. for 2 hours, allowed to cool to room temperature, The mixture was further stirred for 6 hours, and the crystallized solid was collected by filtration. OL) and dried under reduced pressure to give crystals of compound A as a white solid (basket crystals) (29. Ok g, yield 72%). "Is written.
し力しながら、上記特許文献 1および 2の製造方法では、最終工程である化合物 [A 1]とナトリウムメトキシドとの反応において、目的の主生成物である化合物 [A]の他 に、フッ化ナトリウムおよび以下の化合物 [B]が副生成物として生成する。  However, in the production methods of Patent Documents 1 and 2 above, in the reaction of compound [A 1], which is the final step, and sodium methoxide, in addition to compound [A], which is the main product of interest, Sodium chloride and the following compound [B] are formed as by-products.
[0009] [化 3]  [0009] [Chemical 3]
Figure imgf000006_0001
Figure imgf000006_0001
[0010] また、特に特許文献 2の方法では、その後の精製工程にぉ 、て、溶媒としてイソプ ロパノール、トルエン、酢酸ェチルおよび酢酸イソブチルが使用されており、トルエン 力 エーテルへの溶媒置換という生産上煩雑な操作が含まれる。しかし、これら文献 には、本発明に示される、精製工程においてイソプロパノールおよびァ-ソ一ルを溶 媒として用いた製造方法にっ 、ては開示されて 、な 、。  [0010] In particular, in the method of Patent Document 2, isopropanol, toluene, ethyl acetate, and isobutyl acetate are used as the solvent in the subsequent purification step. A complicated operation is included. However, these documents disclose the production method using isopropanol and ethanol as a solvent in the purification step shown in the present invention.
[0011] 特許文献 l :WO2004Z046115号公報（実施例 4— 32、頁 108— 111) Patent Document l: WO2004Z046115 (Example 4-32, pages 108-111)
特許文献 2： PCTZJP2005Z009604明細書  Patent Document 2: Specification of PCTZJP2005Z009604
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0012] 医薬品として、化合物 [A]又はそれらの製薬上許容される塩を使用するにあたり、 不純物 (例えば、製造工程で生成する副生成物）を除去し、その純度を高めることが 必要である。 [0012] When using Compound [A] or a pharmaceutically acceptable salt thereof as a pharmaceutical product, it is necessary to remove impurities (for example, by-products generated in the manufacturing process) and increase their purity. .
とりわけ、化合物 [A—1]とナトリウムメトキシドとから化合物 [A]を製造する場合、副 生成物として生成するフッ化ナトリウムは、フッ素源となり、その後の精製工程におい て望ましくない反応を引き起こす恐れがあるため、中和の前にその大部分を除去する ことが必要である。 In particular, when compound [A] is produced from compound [A-1] and sodium methoxide, sodium fluoride produced as a by-product becomes a fluorine source and is used in the subsequent purification process. Most of them need to be removed before neutralization.
また、化合物 [A]には結晶多形が確認されており（例えば、 PCT/JP2005/009 604明細書を参照）、これら結晶が製造中、特に抽出'洗浄時に析出することを防止 する製造方法が望まれる。このような結晶の析出は、化合物 [A]の収率を低下させる よって、本発明は、これら課題を解決し、かつ、効率的な化合物 [A]の製造方法を 見出すことを課題とする。  In addition, a crystalline polymorph has been confirmed for compound [A] (see, for example, PCT / JP2005 / 009604), and a production method for preventing these crystals from being precipitated during production, particularly during extraction and washing. Is desired. Precipitation of such crystals reduces the yield of compound [A]. Therefore, the present invention aims to solve these problems and to find an efficient method for producing compound [A].
課題を解決するための手段  Means for solving the problem
[0013] 本発明者らは、上記課題を解決すベぐ化合物 [A—1]力も化合物 [A]を製造する 方法において、精製工程の条件について鋭意検討を行った。その結果、上記課題を 解決し得る条件を見出し、本発明を完成するに至った。 [0013] The inventors of the present invention have intensively studied the conditions of the purification step in the method of producing the compound [A-1] which can solve the above-mentioned problems. As a result, the present inventors have found a condition that can solve the above problems and have completed the present invention.
[0014] すなわち、本発明は以下の通りである。 That is, the present invention is as follows.
[ 1 ]以下の工程 (i)および (ii)を含む、高純度な 6—（3 クロロー 2 フルォロベン ジル） 1—[ (S) 1 ヒドロキシメチル— 2—メチルプロピル]— 7—メトキシ— 4—ォ キソ 1, 4ージヒドロキノリン 3 カルボン酸を製造する方法：  [1] High-purity 6- (3 chloro-2-fluorobenzil) 1- [(S) 1 hydroxymethyl-2-methylpropyl] -7-methoxy-4-, which includes the following steps (i) and (ii) Process for the preparation of oxo 1,4-dihydroquinoline 3 carboxylic acid:
(i)メタノール溶媒中、 6—（3 クロロー 2 フルォロベンジル） - 7-フルォロ 1一 [ (S)—1—ヒドロキシメチル一 2—メチルプロピル]— 4—ォキソ 1, 4ージヒドロキノリ ン一 3—カルボン酸とナトリウムメトキシドとを反応させる工程;および  (i) 6- (3 Chloro-2-fluorobenzyl) -7-fluoro 1- 1 [(S) -1-hydroxymethyl 1- 2-methylpropyl]-4-oxo 1,4-dihydroquinoline 1 3-carboxylic acid in methanol solvent Reacting sodium methoxide with; and
(ii)工程（i)で生成した 6— (3 クロ口一 2 フルォロベンジル） 1— [ (S)— 1 ヒド 口キシメチル一 2—メチルプロピル]— 7—メトキシ一 4—ォキソ 1, 4ージヒドロキノリ ン一 3—カルボン酸を、ァ-ソールを用いて精製する工程。  (ii) 6- (3-chlorobenzyl 2-fluoropropyl) produced in step (i) 1- [(S)-1 hydroxymethyl-1-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinoline (1) A step of purifying 3-carboxylic acid using azole.
[2]以下の工程 (a)から (f)を含む、高純度な 6 - (3 クロ口 2 フルォロベンジ ル）一 1 [ (S) 1—ヒドロキシメチル一 2—メチルプロピル]— 7—メトキシ一 4—ォキ ソ 1 , 4 ジヒドロキノリン 3 カルボン酸を製造する方法：  [2] High-purity 6- (3 black 2 fluorobenzil) 1 1 [(S) 1-hydroxymethyl 1 2-methylpropyl] -7-methoxy 1 including the following steps (a) to (f) Method for producing 4-oxo 1,4 dihydroquinoline 3 carboxylic acid:
(a)メタノール溶媒中、 6— (3—クロ口一 2—フルォロベンジル） - 7-フルォロ 1— [ (S)—1—ヒドロキシメチル一 2—メチルプロピル]— 4—ォキソ 1, 4 ジヒドロキノ リン一 3—カルボン酸とナトリウムメトキシドとを反応させる工程； (b)工程 (a)で得られた反応混合物に水を添加後、濃縮する工程； (a) 6- (3-chlorobenzyl 2-fluorobenzyl) -7-fluoro 1— [(S) -1-hydroxymethyl-2-methylpropyl] — 4-oxo 1,4 dihydroquinoline in methanol solvent Reacting 3-carboxylic acid with sodium methoxide; (b) Step of adding water to the reaction mixture obtained in step (a) and then concentrating;
(c)工程 (b)で得られた濃縮残渣にイソプロパノールを添加後、濃縮する工程； (c) Step of adding isopropanol to the concentrated residue obtained in step (b) and then concentrating;
(d)工程 (c)で得られた濃縮残渣に無機塩水溶液およびァ-ソールを添加し、分液 する工程； (d) Step of adding an aqueous solution of inorganic salt and a sole to the concentrated residue obtained in step (c) and separating the solution;
(e)工程 (d)で得られた有機層を無機塩水溶液で洗浄後、中和し、濃縮する工程;お よび  (e) Step of washing the organic layer obtained in step (d) with an aqueous inorganic salt solution, neutralizing and concentrating; and
(f)工程 (e)で得られた濃縮残渣にヘプタンを添加し、ろ過する工程。  (f) Step of adding heptane to the concentrated residue obtained in step (e) and filtering.
発明の効果  The invention's effect
[0015] 本発明の製造方法は、副生成物であるフッ化ナトリウムの除去が可能であり、かつ、 副生成物である化合物 [B]に対して精製効率が高いため、高純度の化合物 [A]を 高収率で得ることができる。  [0015] The production method of the present invention can remove sodium fluoride as a by-product and has high purification efficiency with respect to compound [B] as a by-product. A] can be obtained in high yield.
なお、本明細書において、「高純度の化合物 [A]」とは、不純物を含む化合物 [A] 中の化合物 [A]の割合力 好ましくは 98重量％以上、より好ましくは 98. 5重量％以 上、更に好ましくは 99重量％以上の化合物 [A]、及び Z又は、化合物 [A]の結晶中 の化合物 [B]残量力 好ましくは 1重量％以下、より好ましくは 0. 5重量％以下、更に 好ましくは 0. 1重量％以下である化合物 [A]を示す。  In the present specification, “high-purity compound [A]” means the ratio of compound [A] in compound [A] containing impurities, preferably 98% by weight or more, more preferably 98.5% by weight. More preferably, 99% by weight or more of the compound [A] and Z or the compound [B] in the crystal of the compound [A] [B] remaining capacity is preferably 1% by weight or less, more preferably 0.5% by weight or less. More preferably, the compound [A] is 0.1% by weight or less.
また、本発明の製造方法は、化合物 [A]の結晶多形について、何れの結晶をも析 出させない条件で操作を行うことができるため、結晶形によらず、高収率で化合物 [A ]を得ることができる。  In addition, the production method of the present invention can operate the crystalline polymorph of compound [A] under conditions that do not cause any crystals to be crystallized. ] Can be obtained.
さらに、本発明の製造方法では、フッ化ナトリウムの除去操作力 化合物 [A]の濾 取操作まで、溶媒置換の様な煩雑な操作を行う必要がなぐ効率よく高純度の化合 物 [A]を得ることができる。  Further, in the production method of the present invention, the high-purity compound [A] can be efficiently obtained without the need for complicated operations such as solvent replacement until the filtration operation of the compound [A]. Obtainable.
図面の簡単な説明  Brief Description of Drawings
[0016] [図 1]トルエン イソプロパノール混合溶媒系およびァ-ソ一ルーイソプロパノール混 合溶媒系における化合物 [A]の III型晶の室温での溶解度を示すグラフである。 発明を実施するための最良の形態  [0016] Fig. 1 is a graph showing the solubility at room temperature of a type III crystal of Compound [A] in a toluene isopropanol mixed solvent system and an iso-luo isopropanol mixed solvent system. BEST MODE FOR CARRYING OUT THE INVENTION
[0017] 以下に、本発明を詳細に説明する。 [0017] The present invention is described in detail below.
化合物 [A]には、結晶多形が存在することが確認されている（例えば、 PCTZJP2 005Z009604明細書を参照)。具体的には、下記の粉末 X線回折ピークで同定さ れる I型晶、 Π型晶および ΠΙ型晶が見出されている。 Compound [A] has been confirmed to have a crystalline polymorph (eg, PCTZJP2 005Z009604 specification). Specifically, type I crystals, cage crystals and cage crystals identified by the following powder X-ray diffraction peaks have been found.
I型晶：主要回折ピーク（2 0 ) ; 6. 58、 14. 40、 14. 64, 15. 24、 16. 48、 19. 16 、 20. 90、 21. 14、 22. 24、 24. 74、 25. 64、 26. 12、 27. 20° 、特徴的回折ピ ーク（2 0 ) ; 6. 58、 14. 40、 19. 16、 20. 90、 21. 14°  Form I crystal: main diffraction peak (20); 6. 58, 14. 40, 14. 64, 15. 24, 16. 48, 19. 16, 20. 90, 21. 14, 22. 24, 24. 74, 25. 64, 26. 12, 27. 20 °, characteristic diffraction peak (20); 6. 58, 14. 40, 19. 16, 20. 90, 21. 14 °
Π型晶：主要回折ピーク（2 0 ) ; 6. 56、 9. 04、 13. 20、 14. 62、 15. 24、 16. 48 、 19. 86、 20. 84、 21. 22、 22. 24、 25. 22、 25. 96、 26. 12、 27. 34° 、特徴 的回折ピーク（2 Θ ) ; 6. 56、 13. 20、 19. 86、 20. 84、 21. 22、 25. 22°  V-shaped crystal: Main diffraction peak (20); 6. 56, 9. 04, 13. 20, 14. 62, 15. 24, 16. 48, 19. 86, 20. 84, 21. 22, 22. 24, 25. 22, 25. 96, 26. 12, 27. 34 °, characteristic diffraction peak (2Θ); 6. 56, 13. 20, 19. 86, 20. 84, 21. 22, 25. 22 °
ΠΙ型晶：主要回折ピーク（2 0 ) ; 8. 54、 14. 02、 15. 68、 15. 90、 16. 00、 17. 0 6、 17. 24、 17. 84、 18. 12、 19. 50、 19. 90、 22. 26、 22. 68、 23. 02、 24. 16 、 24. 76、 25. 18、 25. 74、 25. 98、 27. 50、 28. 80、 30. 38、 30. 72、 32. 54 ° 、特徴的回折ピーク（2 Θ ) ; 8. 54, 14. 02、 15. 68, 17. 06、 17. 24, 24. 16、 25. 74°  V-shaped crystal: Main diffraction peak (20); 8.54, 14.02, 15.68, 15.90, 16.00, 17.06, 17.24, 17.84, 18.12, 19 50, 19.90, 22.26, 22.68, 23.02, 24.16, 24.76, 25.18, 25.74, 25.98, 27.50, 28.80, 30.38 , 30.72, 32.54 °, characteristic diffraction peak (2Θ); 8. 54, 14. 02, 15. 68, 17. 06, 17. 24, 24. 16, 25. 74 °
[0018] また、 II型晶および ΠΙ型晶は安定形結晶であること、および、 III型晶は I型晶およ び Π型晶に比べて溶解度が低いことが確認されている（例えば、 PCT/JP2005/0 09604明細書を参照)。下記表 1に、溶解度に関するデータを示す。  [0018] In addition, it has been confirmed that type II crystals and cocoon crystals are stable crystals, and that type III crystals have lower solubility than type I crystals and cocoon crystals (for example, (See PCT / JP2005 / 0 09604 specification). Table 1 below shows data on solubility.
[0019] [表 1]  [0019] [Table 1]
溶解性試験  Solubility test
Figure imgf000009_0001
Figure imgf000009_0001
1)日局一般試験法の崩壊試験法の試験液第 1液。塩ィ匕ナトリウム 2. Ogに塩酸 7. OmLおよび水をカ卩えて溶かし、 lOOOmLとする。この液は無色透明で、その pHは約 1. 2である。 2)日局一般試験法の崩壊試験法の試験液第 2液。 0. 2molZLリン酸二水素カリ ゥム試液 250mLに 0. 2molZL水酸化ナトリウム試液 118mLおよび水をカ卩えて 100 OmLとする。この液は無色透明で、その pHは約 6. 8である。 1) Test solution No. 1 solution for disintegration test method of JP General Test Method. Sodium chloride 2. Dissolve 7. OmL of hydrochloric acid and water in Og and dissolve to make 1OOOmL. This solution is clear and colorless and has a pH of about 1.2. 2) Test solution second liquid for disintegration test method of JP General Test Method. Add 0.2 mL of 0.2 mol ZL sodium hydroxide test solution and water to 250 mL of 0.2 mol ZL potassium dihydrogen phosphate test solution to make 100 OmL. This solution is clear and colorless and has a pH of about 6.8.
3)マツクイルバイン緩衝液。リン酸水素ニナトリウムおよびクェン酸を所定の割合で 配合して所定の pHに調整することにより得られる。  3) Matsuquilvein buffer. It can be obtained by mixing disodium hydrogen phosphate and citrate at a predetermined ratio and adjusting to a predetermined pH.
[0021] 本発明の化合物 [A]の製造方法は、上記の 、ずれの結晶形をも析出させな!/、製 造条件下で行うものであり、以下に説明する工程 (i)および (ii)を含み、より具体的に は、以下に説明する工程 (a)から (f)を含む。  [0021] The method for producing the compound [A] of the present invention is carried out under the above-mentioned production conditions without causing the misaligned crystal form to precipitate, and the steps (i) and ( ii), more specifically, including steps (a) to (f) described below.
[0022] 工程 (i)および工程 (a)：メタノール溶媒中、化合物 [A—1]とナトリウムメトキシドとを 反応させる工程。  [0022] Step (i) and step (a): a step of reacting compound [A-1] with sodium methoxide in a methanol solvent.
工程 (i)および工程 (a)のより具体的な操作手順を以下に示す。  More specific operation procedures of step (i) and step (a) are shown below.
1.反応容器内の空気を不活性ガスで置換し、化合物 [A—1]とメタノールとを反応 容器に入れる。不活性ガスとしては、窒素、アルゴン等が挙げられ、好ましくは窒素で ある。メタノールの添カ卩量は、化合物 [A—l] l当量に対して、好ましくは 1. 5〜12v Zwであり、より好ましくは 3〜7vZwであり、最も好ましくは 5. 5〜6. 5vZwである。  1. The air in the reaction vessel is replaced with an inert gas, and compound [A-1] and methanol are placed in the reaction vessel. Examples of the inert gas include nitrogen, argon, and the like, preferably nitrogen. The amount of methanol added is preferably 1.5 to 12 v Zw, more preferably 3 to 7 vZw, most preferably 5.5 to 6.5 vZw, relative to 1 equivalent of compound [A-l]. It is.
[0023] 2.好ましくは内温 0〜30°C、より好ましくは 15〜25°Cにて、ナトリウムメトキシド Zメ タノール溶液を滴下する。ナトリウムメトキシドの添加量は、化合物 [A— 1] 1当量に対 して、好ましくは 5〜40当量であり、より好ましくは 9〜20当量であり、最も好ましくは 9 〜： ί Γ当量である。ナトリウムメトキシド Ζメタノール溶液の濃度は特に限定されるもの ではないが、巿場での入手の容易さから、 28%ナトリウムメトキシド Ζメタノール溶液 を用いることが好ましい。  [0023] 2. A sodium methoxide Z-methanol solution is added dropwise, preferably at an internal temperature of 0-30 ° C, more preferably 15-25 ° C. The amount of sodium methoxide to be added is preferably 5 to 40 equivalents, more preferably 9 to 20 equivalents, and most preferably 9 to ί Γ equivalents per 1 equivalent of compound [A-1]. is there. The concentration of the sodium methoxide / methanol solution is not particularly limited, but it is preferable to use a 28% sodium methoxide / methanol solution because of its availability in the factory.
[0024] 3.反応混合物を、好ましくは内温 25〜75°C、より好ましくは 65〜75°C、最も好ま しくは 70°C〜75°Cにて撹拌する。反応は、 HPLC分析により、原料化合物 [A— 1] のピーク面積が主生成物である化合物 [A]のピーク面積に対して好ましくは 2%以下 、より好ましくは 1%以下になるまで行う。なお、 HPLC分析方法は以下の通りである  [0024] 3. The reaction mixture is preferably stirred at an internal temperature of 25 to 75 ° C, more preferably 65 to 75 ° C, and most preferably 70 to 75 ° C. The reaction is carried out by HPLC analysis until the peak area of the starting compound [A-1] is preferably 2% or less, more preferably 1% or less with respect to the peak area of the main product compound [A]. The HPLC analysis method is as follows.
HPLC分析方法： HPLC analysis method:
カラム ： L—カラム ODS 5 ！!1< 150111111 4. 61111111. 0. > (ィ匕学物質評価 研究機構製） Column: L—Column ODS 5! ! 1 <150111111 4. 61111111. 0. Made by Research Organization)
カラム温度 ：40°C付近の一定温度  Column temperature: Constant temperature around 40 ° C
移動相 ：移動相 A : 10mM リン酸緩衝液く pH6. 9 >  Mobile phase: Mobile phase A: 10 mM phosphate buffer pH 6.9>
移動相 B : MeCN く HPLCグレード〉  Mobile Phase B: MeCN + HPLC Grade>
グラジ ント条件  Gradient conditions
[0025] [表 2]  [0025] [Table 2]
Figure imgf000011_0001
Figure imgf000011_0001
[0026] 流速 ：1. 0mLZ分 [0026] Flow rate: 1.0 mLZ min
検出方法 ： UV220nm  Detection method: UV220nm
注入量 : 5 μ L·  Injection volume: 5 μL
分析時間 ：55分  Analysis time: 55 minutes
[0027] 4.反応混合物に、好ましくは内温 15〜30°C、より好ましくは 20〜25°Cにて活性炭 を添加し、撹拌する。活性炭の添加量は、化合物 [A— 1 ] 1当量に対して、好ましくは 0. 05〜0. 25wZwであり、より好ましくは 0. 05〜0. 2wZwであり、最も好ましくは 0. 09〜0. l lwZwである。使用する活性炭の特性は特に限定されるものではない が、産業上で一般的に使用される水蒸気賦活炭、例えば、白鷲 A (商品名；日本ェン バイ口ケミカルズ株式会社製)を用いることが好まし 、。  [0027] 4. Activated carbon is added to the reaction mixture, preferably at an internal temperature of 15 to 30 ° C, more preferably 20 to 25 ° C, and stirred. The amount of the activated carbon added is preferably 0.05 to 0.25 wZw, more preferably 0.05 to 0.2 wZw, most preferably 0.09 to 0.1 equivalent to 1 equivalent of the compound [A-1]. 0. l lwZw. The characteristics of the activated carbon to be used are not particularly limited, but steam activated charcoal generally used in the industry, for example, Shirasagi A (trade name; manufactured by NIPPON BYKOKA CHEMICALS, INC.) Should be used. Is preferred.
[0028] 5.濾過器に濾過助剤として粉末セルロースを充填し、反応混合物を濾過する。反 応容器ならびに濾過器はメタノールで洗浄し、この洗浄液も濾過し、得られた濾液も 最初の濾液と合わせることが好ましい。濾過補助剤としては、食品添加物として認可 されている粉末セルロースを用いることが好ましぐ例えば、 KCフロック W— 300G ( 商品名、 日本製紙ケミカル株式会社製)等が挙げられ、使用前にメタノールで洗浄す ることが好ましい。粉末セルロースの使用量は、化合物 [A— 1 ] 1当量に対して、好ま しく ίま 0. 05〜0. 25w/wであり、より好ましく ίま 0. 1〜0. 21w/wであり、最も好ま しくは 0. 19-0. 21wZwである。反応容器と濾過器の洗浄のためのメタノールの使 用量は、化合物 [A—l] l当量に対して、好ましくは l〜5vZwであり、より好ましくは 1. 8〜3vZwであり、最も好ましくは 1. 8〜2. 2vZwである。 [0028] 5. The filter is filled with powdered cellulose as a filter aid, and the reaction mixture is filtered. It is preferable that the reaction vessel and the filter are washed with methanol, this washing solution is also filtered, and the obtained filtrate is combined with the first filtrate. As a filter aid, it is preferable to use powdered cellulose approved as a food additive, for example, KC Flock W-300G (trade name, manufactured by Nippon Paper Chemicals Co., Ltd.), etc. It is preferable to wash with. The amount of powdered cellulose used is preferably 0.5 to 0.25 w / w, more preferably 0.1 to 0.21 w / w for 1 equivalent of compound [A-1]. Most preferred It is 0. 19-0. 21wZw. The amount of methanol used for washing the reaction vessel and the filter is preferably 1 to 5 vZw, more preferably 1.8 to 3 vZw, most preferably, relative to 1 equivalent of the compound [A-l]. 1. 8 to 2.2 vZw.
[0029] 工程（ii)：工程（i)で生成した 6—（3 クロロー 2 フルォロベンジル） 1 [ (S)— 1 -ヒドロキシメチル 2 メチルプロピル] 7—メトキシ一 4—ォキソ 1, 4 ジヒド 口キノリン一 3—カルボン酸を、ァ-ソールを用いて精製する工程。より具体的には、 該工程 (ii)は、以下に示す工程 (b)力も (f)を含む。  [0029] Step (ii): 6- (3 chloro-2-fluorobenzyl) 1 [(S) — 1-hydroxymethyl 2 methylpropyl] 7-methoxy-1-oxo-1,4 dihydric quinoline produced in step (i) (1) A step of purifying 3-carboxylic acid using azole. More specifically, the step (ii) includes the following step (b) force (f).
[0030] 工程 (b)：工程 (a)で得られた反応混合物に水を添加後、濃縮する工程。  Step (b): A step of adding water to the reaction mixture obtained in step (a) and then concentrating.
工程 (b)のより具体的な操作手順を以下に示す。  A more specific operation procedure of step (b) is shown below.
1.工程 (a)の操作 5.で得られた濾液に水を添加する。水の添加量は、化合物 [A 1] 1当量に対して、好ましくは 9〜30当量であり、より好ましくは 10〜20当量であり 、最も好ましくは 17〜19当量である。なお、工程 (a)の操作 5.で得られた濾液の保 管に際しては、水の添加後、不活性ガスを添加することが好ましい。また、室温以下 で保存することが好ましい。  1. Add water to the filtrate obtained in step (a) 5. The amount of water added is preferably 9 to 30 equivalents, more preferably 10 to 20 equivalents, and most preferably 17 to 19 equivalents relative to 1 equivalent of compound [A1]. In addition, when storing the filtrate obtained in operation 5 of step (a), it is preferable to add an inert gas after adding water. Moreover, it is preferable to store at room temperature or lower.
[0031] 2.好ましくは外温 30〜60°C、より好ましくは 30〜50°Cにて、減圧濃縮する。減圧 濃縮は、得られる濃縮残渣の量が化合物 [A—l] l当量に対して、好ましくは 4. 5v Zw以下、より好ましくは 4vZw以下になるまで行う。  [0031] 2. Concentrate under reduced pressure, preferably at an external temperature of 30-60 ° C, more preferably 30-50 ° C. The concentration under reduced pressure is performed until the amount of the concentrated residue obtained is preferably 4.5 v Zw or less, more preferably 4 vZw or less, relative to 1 equivalent of the compound [A-l].
[0032] 工程 (c)：工程 (b)で得られた濃縮残渣にイソプロパノールを添加後、濃縮するェ 程。  [0032] Step (c): A step of adding isopropanol to the concentrated residue obtained in step (b) and then concentrating.
工程 (c)のより具体的な操作手順を以下に示す。  A more specific operation procedure of step (c) is shown below.
1.工程 (b)の操作 2.で得られた濃縮残渣にイソプロパノールを添加し、好ましくは 外温 30〜60°C、より好ましくは 30〜50°Cにて、得られる濃縮残渣の量が化合物 [A 1] 1当量に対して、好ましくは 8vZw以下、より好ましくは 7. 5vZw以下になるま で減圧濃縮する。イソプロパノールの添加量は、化合物 [A— 1] 1当量に対して、好 ましくは 4〜8vZwであり、より好ましくは 5〜7vZwであり、最も好ましくは 5. 5〜6. 5vz wであ 。  1. Addition of isopropanol to the concentrated residue obtained in step (b) 2., preferably at an external temperature of 30-60 ° C, more preferably 30-50 ° C, The compound [A 1] is concentrated under reduced pressure, preferably 8 vZw or less, more preferably 7.5 vZw or less, relative to 1 equivalent. The addition amount of isopropanol is preferably 4 to 8 vZw, more preferably 5 to 7 vZw, most preferably 5.5 to 6.5 vz w with respect to 1 equivalent of the compound [A-1]. .
[0033] 2.濃縮残渣にイソプロパノールを添加し、好ましくは外温 30〜60°C、より好ましく は 30〜50°Cにて、得られる濃縮残渣の量が化合物 [A—l] l当量に対して、好まし くは 7〜9vZw、より好ましくは 7. 5〜8. 5vZwになるまで減圧濃縮する。イソプロパ ノールの添カ卩量は、化合物 [A— 1] 1当量に対して、好ましくは l〜4vZwであり、より 好ましくは 2〜3. 3vZwであり、最も好ましくは 2. 7〜3. 3vZwである。 [0033] 2. Add isopropanol to the concentrated residue, preferably at an external temperature of 30 to 60 ° C, more preferably 30 to 50 ° C, so that the amount of the concentrated residue obtained is reduced to 1 equivalent of compound [A-l]. Against Or 7 to 9 vZw, more preferably 7.5 to 8.5 vZw. The amount of isopropanol added is preferably 1 to 4 vZw, more preferably 2 to 3.3 vZw, and most preferably 2.7 to 3.3 vZw with respect to 1 equivalent of the compound [A-1]. It is.
ここで、得られる濃縮残渣中のメタノール残量は、イソプロパノール残量に対して、 好ましくは 30重量％以下、より好ましくは 25重量％以下である。メタノール残量が 30 %重量を超える場合は、 30重量％以下になるまで本工程 (c)を繰り返し行うことが望 ましい。なお、メタノール残量は、例えば、以下に示す GC分析方法により決定するこ とがでさる。  Here, the remaining amount of methanol in the resulting concentrated residue is preferably 30% by weight or less, more preferably 25% by weight or less, based on the remaining amount of isopropanol. If the remaining amount of methanol exceeds 30% by weight, it is desirable to repeat this step (c) until it reaches 30% by weight or less. The remaining amount of methanol can be determined by, for example, the following GC analysis method.
メタノール残量の GC分析方法：  GC analysis method for residual methanol:
検出方法 ： FID (水素炎イオンィ匕検出器） Detection method: FID (hydrogen flame ion detector)
カラム ： Fused— silica Capillary Column DB— 624く 30mX O. 54mml. D. X膜厚 3 m> Ci&W社製） Column: Fused—silica Capillary Column DB—624 m 30 mX O. 54 mml. D. X film thickness 3 m> (Ci & W)
検出器温度:約 300°C Detector temperature: about 300 ° C
試料気化室:約 150°C Sample vaporization chamber: approx. 150 ° C
カラム温度： 60°Cにて 8分間保持した後、 20°CZ分の割合で 250°Cまで昇温させ、 同温にて 15分間保持する。 Column temperature: Hold at 60 ° C for 8 minutes, then heat up to 250 ° C at a rate of 20 ° CZ and hold at that temperature for 15 minutes.
キヤリヤーガス： He Carrier gas: He
キヤリヤーガス流量:標準溶液 1 μ L力も得た ΙΡΑ (イソプロパノール)の保持時間が 約 3. 5分になるように調整する。 Carrier gas flow rate: Standard solution 1 μL obtained. Adjust so that the retention time of イ ソ (isopropanol) is about 3.5 minutes.
スプリット比： 10 : 1 Split ratio: 10: 1
注入量 : l μ L· Injection volume: l μL
分析時間 ：15分間 Analysis time: 15 minutes
工程 (d)：工程 (c)で得られた濃縮残渣に無機塩水溶液およびァ-ソールを添加し 、分液する工程。  Step (d): a step of adding an aqueous solution of inorganic salt and a sole to the concentrated residue obtained in step (c) and separating the solution.
工程 (d)のより具体的な操作手順を以下に示す。  A more specific operation procedure of step (d) is shown below.
工程 (c)の操作 2.で得られた濃縮残渣に無機塩水溶液とァ-ノールとを添加して 撹拌後、分液する。無機塩水溶液としては、化合物 [A]と塩を形成してァ-ノールに 溶解するものであれば特に限定されるものではなぐ例えば、塩ィ匕ナトリウム、塩ィ匕カ リウム、硫酸ナトリウム等の水溶液が挙げられ、好ましくは塩ィ匕ナトリウム、塩ィ匕カリウム の水溶液であり、最も好ましくは塩ィ匕ナトリウム水溶液である。塩ィ匕ナトリウム水溶液の 濃度は、好ましくは 13〜17%であり、より好ましくは 14〜16%である。無機塩水溶液 の添加量は、例えば、 15%塩ィ匕ナトリウム水溶液を用いる場合、化合物 [A— 1] 1当 量に対して、好ましくは 5〜8vZwであり、より好ましくは 6〜7. 5vZwであり、最も好 ましくは 6. 8〜7. 2vZwである。ァ-ソ一ルの添カ卩量は、化合物 [A—l] l当量に対 して、好ましくは 3〜7vZwであり、より好ましくは 4〜6vZwであり、最も好ましくは 4. 8〜5. 2vZwである。 Add the aqueous inorganic salt solution and the alcohol to the concentrated residue obtained in step (c) 2. Stir and separate the layers. The inorganic salt aqueous solution is not particularly limited as long as it forms a salt with the compound [A] and dissolves in the alcohol. For example, sodium salt, salt salt An aqueous solution of sodium, sodium sulfate or the like can be mentioned, and an aqueous solution of sodium chloride and potassium salt is preferable, and an aqueous sodium chloride solution is most preferable. The concentration of the sodium chloride aqueous solution is preferably 13 to 17%, more preferably 14 to 16%. The amount of the inorganic salt aqueous solution added is, for example, preferably 5 to 8 vZw, more preferably 6 to 7.5 vZw with respect to 1 equivalent of the compound [A-1] when using a 15% sodium chloride aqueous solution. The most preferable is 6.8 to 7.2 vZw. The amount of additive of the solvent is preferably 3 to 7 vZw, more preferably 4 to 6 vZw, most preferably 4.8 to 5 with respect to 1 equivalent of the compound [A-l]. 2vZw.
[0035] 工程 (e)：工程 (d)で得られた有機層を無機塩水溶液で洗浄後、中和し、濃縮する 工程。  [0035] Step (e): A step in which the organic layer obtained in step (d) is washed with an aqueous inorganic salt solution, neutralized, and concentrated.
工程 (e)のより具体的な操作手順を以下に示す。  A more specific operation procedure of step (e) is shown below.
1.工程 (d)の分液操作によって得られた有機層を無機塩水溶液で洗浄する。無機 塩水溶液としては、例えば、塩ィ匕ナトリウム、塩ィ匕カリウム、硫酸ナトリウム等の水溶液 が挙げられ、好ましくは塩ィ匕ナトリウム、塩ィ匕カリウムの水溶液であり、最も好ましくは 塩化ナトリウム水溶液である。工程 (d)で用いた無機塩水溶液と同一の無機塩水溶 液を使用することが好ましい。塩ィ匕ナトリウム水溶液の濃度は、好ましくは 15〜25% であり、より好ましくは 18〜22%である。無機塩水溶液の使用量は、例えば、 20%塩 化ナトリウム水溶液を用いる場合、化合物 [A— 1] 1当量に対して、好ましくは 3〜7v Zwであり、より好ましくは 4〜6vZwであり、最も好ましくは 4. 8〜5. 2vZwである。 この洗浄操作を、通常複数回、好ましくは 3回繰り返し、工程 (a)の反応の副生成物 であるフッ化ナトリウムを lppm以下まで除去することが好ましい。  1. The organic layer obtained by the liquid separation operation in step (d) is washed with an inorganic salt aqueous solution. Examples of the inorganic salt aqueous solution include aqueous solutions of sodium chloride sodium, potassium salt sodium, sodium sulfate, etc., preferably sodium chloride sodium salt solution, sodium salt potassium aqueous solution, most preferably sodium chloride aqueous solution. is there. It is preferable to use the same inorganic salt aqueous solution as that used in step (d). The concentration of the aqueous sodium chloride solution is preferably 15 to 25%, more preferably 18 to 22%. The amount of the inorganic salt aqueous solution used is, for example, preferably 3 to 7 v Zw, more preferably 4 to 6 vZw with respect to 1 equivalent of the compound [A-1] when using a 20% sodium chloride aqueous solution. Most preferably, it is 4.8 to 5.2 vZw. This washing operation is usually repeated a plurality of times, preferably three times, to remove sodium fluoride, which is a byproduct of the reaction in step (a), to 1 ppm or less.
なお、残留フッ素の定量は、例えば、フッ素イオンメーター Ti— 5101 (東興ィ匕学研 究所製)を用いて、洗浄後の水層中のフッ素イオン濃度を測定することによって行うこ とがでさる。  Residual fluorine can be quantified by, for example, measuring the fluorine ion concentration in the washed water layer using a fluorine ion meter Ti-5101 (manufactured by Toko University). .
[0036] 2.有機層を、酸および無機塩水溶液で順次洗浄して中和する。酸としては、例え ば、塩酸、硫酸、トリフルォロ酢酸等が挙げられ、好ましくは塩酸、硫酸であり、最も好 ましくは塩酸である。酸の濃度および量は、中和に必要な濃度および量であればよく 、濃度は、例えば、塩酸を用いる場合、好ましくは 0. l〜lmolZLであり、より好まし くは 0. 45-0. 55molZLであり、量は、例えば、 0. 5molZL塩酸を用いる場合、 化合物 [A— 1] 1当量に対して、好ましくは 3〜7vZwであり、より好ましくは 4〜6vZ wであり、最も好ましくは 4. 8〜5. 2vZwである。酸の使用に際しては、例えば、塩 化ナトリウム、塩ィ匕カリウム等の塩基、好ましくは塩ィ匕ナトリウムを添加した酸溶液を用 いるのが望ましい。無機塩水溶液としては、例えば、塩ィ匕ナトリウム、塩ィ匕カリウム等 の水溶液が挙げられ、好ましくは塩ィ匕ナトリウムの水溶液であり、上記の操作 1.で用 いた無機塩水溶液と同一の無機塩水溶液を使用することが好ましい。塩化ナトリウム 水溶液の濃度は、好ましくは 15〜25%であり、より好ましくは 18〜22%である。無機 塩水溶液の使用量は、例えば、 20%塩ィ匕ナトリウム水溶液を用いる場合、化合物 [A 1] 1当量に対して、好ましくは 0. 25-1. 5vZwであり、より好ましくは 1〜1. 5v/ wであり、最も好ましくは 1. 2〜1. 3vZwである。 [0036] 2. The organic layer is neutralized by washing sequentially with an acid and an aqueous inorganic salt solution. Examples of the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like, preferably hydrochloric acid and sulfuric acid, and most preferably hydrochloric acid. The concentration and amount of the acid may be any concentration and amount necessary for neutralization. For example, when hydrochloric acid is used, the concentration is preferably 0.1 to 1 mol ZL, more preferably. For example, when 0.5 mol ZL hydrochloric acid is used, the amount is preferably 3 to 7 vZw, more preferably 4 to 5 mol per 1 equivalent of the compound [A-1]. 6vZw, most preferably from 4.8 to 5.2vZw. In using the acid, for example, it is desirable to use an acid solution to which a base such as sodium chloride or potassium salt, preferably sodium chloride sodium is added. Examples of the inorganic salt aqueous solution include an aqueous solution of sodium chloride sodium, potassium salt potassium, etc., preferably an aqueous solution of sodium chloride sodium, and the same inorganic salt aqueous solution as used in the above operation 1. It is preferred to use an aqueous salt solution. The concentration of the sodium chloride aqueous solution is preferably 15 to 25%, more preferably 18 to 22%. The amount of the inorganic salt aqueous solution used is, for example, preferably 0.25-1.5 vZw, more preferably 1 to 1 with respect to 1 equivalent of the compound [A 1] when a 20% sodium chloride aqueous solution is used. 5v / w, most preferably 1.2 to 1.3vZw.
[0037] なお、上記工程 (d)および工程 (e)の操作 1.および 2.において、水層中の無機塩 濃度は、塩の析出、および、化合物 [A]の洗浄液への溶出をより効果的に防止する ことを考慮して、適宜調節を行えばよい。  [0037] In Steps 1 and 2 of Step (d) and Step (e) above, the concentration of inorganic salt in the aqueous layer is such that the salt is precipitated and the compound [A] is eluted into the cleaning solution. Adjustments may be made as appropriate in consideration of effective prevention.
また、上記操作 1.および 2.において、有機層中のイソプロパノール濃度は、化合 物 [A]の有機層中への溶解度を低下させな!/ヽと ヽぅ観点から、 20体積％以上に維 持しておくことが望ましい。  In addition, in the above operations 1 and 2, the isopropanol concentration in the organic layer should not lower the solubility of the compound [A] in the organic layer! It is desirable to have it.
[0038] 3.有機層を、好ましくは外温 30〜70°C、より好ましくは 50〜70°Cにて、濃縮残渣 の量が化合物 [A—l] l当量に対して、好ましくは 5. 5vZw以下、より好ましくは 5v Zw以下になるまで減圧濃縮する。  [0038] 3. The organic layer is preferably at an external temperature of 30 to 70 ° C, more preferably 50 to 70 ° C, and the amount of the concentrated residue is preferably 5 to 1 equivalent of the compound [A-l] l. Concentrate under reduced pressure until 5vZw or less, more preferably 5vZw or less.
[0039] 4.濃縮残渣にァ-ソールを添カ卩し、好ましくは外温 30〜70°C、より好ましくは 50 〜70°Cにて、濃縮残渣の量が化合物 [A—l] l当量に対して、好ましくは 5. 5v/w 以下、より好ましくは 5vZw以下になるまで減圧濃縮する。ァ-ノールの添加量は、 化合物 [A— 1] 1当量に対して、好ましくは 3〜7vZwであり、より好ましくは 4〜6vZ wであり、最も好ましくは 4. 8〜5. 2vZwである。  [0039] 4. Carsol is added to the concentrated residue, preferably at an external temperature of 30 to 70 ° C, more preferably 50 to 70 ° C, and the amount of the concentrated residue is reduced to the compound [A-l] l Concentrate in vacuo until the equivalent weight is preferably 5.5 v / w or less, more preferably 5 vZw or less. The amount of alcohol added is preferably 3 to 7 vZw, more preferably 4 to 6 vZw, and most preferably 4.8 to 5.2 vZw with respect to 1 equivalent of the compound [A-1]. .
[0040] 5.濃縮残渣の量が好ましくは 4〜6vZw、より好ましくは 4. 5〜5. 5vZwになるよ うに、濃縮残渣にァ-ソールを添加する。  [0040] 5. Carsol is added to the concentrated residue so that the amount of the concentrated residue is preferably 4 to 6 vZw, more preferably 4.5 to 5.5 vZw.
ここで、得られる濃縮残渣中のイソプロパノール残量は、ァ-ソール含量に対して、 好ましくは 0. 1重量％以下、より好ましくは検出限界以下である。イソプロパノール残 量が多いと、結晶の取得量が低下するという問題がある。例えば、イソプロパノール 残量が 1重量％の場合、結晶の取得量は約 5%低下し、イソプロパノール残量が 2重 量％の場合、結晶の取得量は約 10%低下する。イソプロパノール残量が 0. 1重量 %を超える場合は、 0. 1重量％以下になるまで上記 4.および 5.の操作を繰り返す ことが望ましい。なお、イソプロパノール残量は、例えば、上記工程 (c)の操作 2.と同 様にして GC分析方法により決定することができる。 Here, the remaining amount of isopropanol in the resulting concentrated residue is Preferably it is 0.1 wt% or less, more preferably below the detection limit. When the amount of isopropanol remaining is large, there is a problem that the amount of crystals obtained decreases. For example, if the remaining amount of isopropanol is 1% by weight, the amount of crystals obtained will be reduced by about 5%, and if the amount of remaining isopropanol is 2% by weight, the amount of crystals obtained will be reduced by about 10%. If the remaining amount of isopropanol exceeds 0.1% by weight, it is desirable to repeat steps 4 and 5 until the remaining amount is 0.1% by weight or less. The remaining amount of isopropanol can be determined by a GC analysis method, for example, in the same manner as in step 2 of step (c) above.
[0041] 6.濃縮残渣を、好ましくは内温 0〜30°C、より好ましくは 15〜30°Cにて、好ましく は 10時間以上、より好ましくは 12〜15時間撹拌する。この攪拌操作は、化合物 [A] の II型晶（種晶）を接種した後に行い、この時点で濃縮残渣を結晶化させることが好 ましい。種晶の添カ卩量は、化合物 [A—l] l当量に対して、好ましくは 0. 05〜0. 2v Zw、より好ましくは 0. 09〜0. l lvZwである。  [0041] 6. The concentrated residue is preferably stirred at an internal temperature of 0 to 30 ° C, more preferably 15 to 30 ° C, preferably for 10 hours or more, more preferably for 12 to 15 hours. This stirring operation is preferably performed after inoculating type II crystals (seed crystals) of compound [A], and at this point, the concentrated residue is preferably crystallized. The amount of seed crystal added is preferably 0.05 to 0.2 v Zw, more preferably 0.09 to 0.1 lvZw, relative to 1 equivalent of the compound [A-l].
なお、化合物 [A]の II型晶は、例えば、 PCTZJP2005Z009604明細書に記載 の方法によって得ることができる。  The type II crystal of compound [A] can be obtained, for example, by the method described in the specification of PCTZJP2005Z009604.
[0042] 工程 (f)：工程 (e)で得られた濃縮残渣にヘプタンを添加し、ろ過する工程。  [0042] Step (f): A step of adding heptane to the concentrated residue obtained in step (e) and filtering.
工程 (f)のより具体的な操作手順を以下に示す。  A more specific operation procedure of step (f) is shown below.
1.工程 (e)の操作 6.で得られた濃縮残渣に、好ましくは内温 20〜35°C、より好ま しくは 25〜35°Cにてヘプタンを添カ卩し、好ましくは 2時間以上、より好ましくは 3時間 以上撹拌し、結晶を析出させる。ヘプタンの添加量は、化合物 [A—l] l当量に対し て、好ましくは 0. 5〜2vZwであり、より好ましくは 0. 9〜1. 5vZwであり、最も好ま しくは 0. 9〜1. lv/wである。ヘプタンを添加することによって、工程（a)の反応の 副生成物である化合物 [B]をより完全に除去することが可能となり、更に高収率で化 合物 [A]を得ることができる。  1. Operation in step (e) 6. Add the heptane to the concentrated residue obtained in step 6 at an internal temperature of 20 to 35 ° C, more preferably 25 to 35 ° C, and preferably 2 hours. Above, more preferably, stirring for 3 hours or more to precipitate crystals. The amount of heptane added is preferably 0.5-2 vZw, more preferably 0.9-1.5 vZw, most preferably 0.9-1 with respect to 1 equivalent of compound [A-l]. It is lv / w. By adding heptane, compound [B], which is a by-product of the reaction in step (a), can be more completely removed, and compound [A] can be obtained in a higher yield. .
[0043] ここで、析出した結晶中の化合物 [B]残量は、好ましくは 1重量％以下、より好ましく は 0. 5重量％以下である。化合物 [B]残量が 1%重量を超える場合は、 1重量％以 下になるまで以下の 2.および 3.の操作を繰り返すことが望ましい。なお、化合物 [B ]残量は、例えば、上記工程 (a)の操作 3.と同様にして HPLC分析方法により決定 することができる。 [0044] 2.濃縮残渣を、内温 40〜50°Cにて、 3時間以上撹拌する。 Here, the remaining amount of the compound [B] in the precipitated crystals is preferably 1% by weight or less, more preferably 0.5% by weight or less. When the remaining amount of Compound [B] exceeds 1% by weight, it is desirable to repeat the following steps 2 and 3 until it is less than 1% by weight. The remaining amount of the compound [B] can be determined by, for example, an HPLC analysis method in the same manner as in Step 3 of the above step (a). [0044] 2. Stir the concentrated residue at an internal temperature of 40-50 ° C for 3 hours or more.
3.濃縮残渣を、内温 25〜35°Cにて、 3時間以上撹拌する。  3. Stir the concentrated residue at an internal temperature of 25-35 ° C for 3 hours or longer.
[0045] 4.析出した結晶を濾取し、得られた湿結晶をァ-ソール /ヘプタン混合溶液、ヘプ タンで順次洗浄する。ァ-ソール /ヘプタン混合溶液中のァ-ソール量は、化合物 [ A— 1] 1当量に対して、好ましくは 0. 5〜2vZwであり、より好ましくは 0. 5〜： LvZw であり、最も好ましくは 0. 82-0. 84vZwである。ァ-ソール /ヘプタン混合溶液中 のヘプタン量は、化合物 [A— 1] 1当量に対して、好ましくは 0. 1〜0. 3vZwであり 、より好ましくは 0. 1〜0. 2vZwであり、最も好ましくは 0. 16〜0. 18vZwである。 ァ-ソール /ヘプタン混合溶液中のァ-ソール:ヘプタン混合比率としては、好ましく は 5〜20: 1〜3であり、より好ましくは 5〜： L0: l〜2であり、更に好ましくは 5〜5. 2: 1 〜1. 1である。洗浄用ヘプタン (ヘプタン単独で洗浄する際）の使用量は、化合物 [ A— 1] 1当量に対して、好ましくは 0. 5〜2vZwであり、より好ましくは 0. 9〜2vZw であり、最も好ましくは 0. 9〜1. lvZwである。  [0045] 4. The precipitated crystals are collected by filtration, and the obtained wet crystals are washed successively with a mixed solution of hesol / heptane and heptane. The amount of azole in the mixed solution of azole / heptane is preferably 0.5 to 2 vZw, more preferably 0.5 to LvZw, relative to 1 equivalent of the compound [A-1]. Preferably it is 0.82-0.84vZw. The amount of heptane in the sol / heptane mixed solution is preferably 0.1 to 0.3 vZw, more preferably 0.1 to 0.2 vZw, relative to 1 equivalent of the compound [A-1]. Most preferably, it is 0.16 to 0.18 vZw. The asol: heptane mixing ratio in the asol / heptane mixed solution is preferably 5 to 20: 1 to 3, more preferably 5 to: L0: 1 to 2, and further preferably 5 to 5. 2: 1 to 1.1. The amount of washing heptane (when washing with heptane alone) is preferably 0.5 to 2 vZw, more preferably 0.9 to 2 vZw, relative to 1 equivalent of compound [A-1]. Preferably 0.9 to 1. lvZw.
[0046] 5.洗浄した湿結晶を取り出し、好ましくは外温 40〜70°C、より好ましくは 50〜60 °Cで減圧乾燥する。乾燥中の結晶をサンプリングして乾燥減量を測定し、乾燥減量 が好ましくは 1%以下、より好ましくは 0. 1%以下になった時点を乾燥終点とする。  [0046] 5. The washed wet crystals are taken out and dried under reduced pressure, preferably at an external temperature of 40 to 70 ° C, more preferably 50 to 60 ° C. The drying loss is measured by sampling the crystals during drying, and the point at which the drying loss is preferably 1% or less, more preferably 0.1% or less is defined as the end point of drying.
[0047] 本発明の化合物 [A]の製造方法は、以下に示す工程 (g)をさらに含んで 、てもよ い。  [0047] The production method of the compound [A] of the present invention may further include the following step (g).
工程 (g)：工程 (f)で得られた化合物 [A]の結晶を III型晶に変換する工程 (再結晶 工程)。  Step (g): a step of converting the crystal of the compound [A] obtained in the step (f) into a type III crystal (recrystallization step).
本再結晶工程は、残留溶媒 ·残留無機塩の除去を可能とし、かつ、高い回収率を 示す。  This recrystallization process makes it possible to remove residual solvents and residual inorganic salts, and shows a high recovery rate.
[0048] 工程 (g)のより具体的な操作手順を以下に示す。  [0048] A more specific operation procedure of the step (g) is shown below.
1.工程 (f)の操作 5.で得られたィ匕合物 [Α]の結晶を、エタノールと水との混合溶 媒に添加する。エタノールの使用量は、化合物 [Α]の結晶 1当量に対して、好ましく は 5. 0〜8. OvZwであり、より好ましくは 5. 5〜7. 5vZwであり、最も好ましくは 6. 0〜7. OvZwである。水の使用量は、化合物 [A]の結晶 1当量に対して、好ましくは 0. 3〜2. 2vZwであり、より好ましくは 0. 5〜2. OvZwであり、最も好ましくは 0. 75 〜1. 5vZwである。 1. Operation in step (f) Add the crystals of the compound [Α] obtained in step 5 to a mixed solvent of ethanol and water. The amount of ethanol used is preferably 5.0 to 8. OvZw, more preferably 5.5 to 7.5 vZw, and most preferably 6.0 to 0.01 to 1 equivalent of crystal of compound [化合物]. 7. OvZw. The amount of water used is preferably 0.3-2. 2 vZw, more preferably 0.5-2. OvZw, and most preferably 0.75 per 1 equivalent of compound [A] crystals. ~ 1.5vZw.
[0049] 2.好ましくは内温 75〜85°C、より好ましくは 78〜81°Cに加温して結晶を完全に溶 解させた後、除塵濾過を行なう。  [0049] 2. Preferably, the internal temperature is 75 to 85 ° C, more preferably 78 to 81 ° C, and the crystals are completely dissolved, followed by dust removal filtration.
[0050] 3.使用した容器および濾過器をエタノールで洗浄し、この洗浄液を上記操作 2.と 同様にして濾過し、得られた濾液を操作 2.の濾液と合わせる。エタノールの使用量 は、化合物 [A]の結晶 1当量に対して、好ましくは 0. 3〜2. 2vZwであり、より好まし くは 0. 5〜2. OvZwであり、最も好ましくは 0. 75〜： L 5vZwである。 [0050] 3. Wash the used container and filter with ethanol, filter this washing solution in the same manner as in the above step 2. Combine the obtained filtrate with the filtrate in step 2. The amount of ethanol to be used is preferably 0.3 to 2.2 vZw, more preferably 0.5 to 2 OvZw, and most preferably 0.5 to 1 equivalent of the crystal of compound [A]. 75-: L 5vZw.
[0051] 4.濾液に水を添加する。水の添加量は、化合物 [A]の結晶 1当量に対して、好ま しくは 2. 5〜5. 5vZwであり、より好ましくは 3. 0〜5. OvZwであり、最も好ましくは[0051] 4. Add water to the filtrate. The amount of water added is preferably 2.5 to 5.5 vZw, more preferably 3.0 to 5. OvZw, and most preferably with respect to 1 equivalent of crystal of compound [A].
3. 5〜4. 5vZwである。 3. 5 to 4.5 vZw.
[0052] 5.好ましくは内温 75〜85°C、より好ましくは 78〜81°Cに加温して、一部析出した 結晶を完全に溶解させる。 [0052] 5. Preferably the internal temperature is 75 to 85 ° C, more preferably 78 to 81 ° C to completely dissolve the partially precipitated crystals.
[0053] 6.好ましくは内温 60〜70°C、より好ましくは 62〜67°Cにて、種晶として化合物 [A[0053] 6. The compound is preferably used as a seed crystal at an internal temperature of 60 to 70 ° C, more preferably 62 to 67 ° C.
]の III型晶を添加する。種晶の添加量は、化合物 [A]の結晶 1当量に対して、好まし く ίま 0. 01〜0. 20w/w、より好ましく ίま 0. 05〜0. 15w/wである。 Add type III crystals. The addition amount of the seed crystal is preferably 0.1 to 0.20 w / w, more preferably 0.05 to 0.15 w / w, with respect to 1 equivalent of the crystal of the compound [A].
なお、化合物 [A]の III型晶は、例えば、 PCTZJP2005Z009604明細書に記載 の方法によって得ることができる。  The type III crystal of compound [A] can be obtained, for example, by the method described in the specification of PCTZJP2005Z009604.
[0054] 7.好ましくは内温 60〜70°C、より好ましくは 62〜67°Cにて、 4時間以上撹拌する [0054] 7. Stir for 4 hours or more, preferably at an internal temperature of 60-70 ° C, more preferably 62-67 ° C
[0055] 8.好ましくは内温 40〜50°C、より好ましくは 42〜47°Cにて、 2時間以上撹拌する [0055] 8. Preferably, stirring is performed for 2 hours or more at an internal temperature of 40-50 ° C, more preferably 42-47 ° C.
[0056] 9.好ましくは内温 15〜30°C、より好ましくは 20〜25°Cにて、 2時間以上撹拌する 。析出した結晶の一部をサンプリングし、その粉末 X線回折パターンをィ匕合物 [A]の I II型晶の回折パターンと比較する。 2つの回折パターンが一致することを確認する。 なお、粉末 X線回折の測定条件は、例えば、以下の通りである。 [0056] 9. Stir for preferably 2 hours or more at an internal temperature of preferably 15-30 ° C, more preferably 20-25 ° C. A portion of the precipitated crystal is sampled, and the powder X-ray diffraction pattern is compared with the diffraction pattern of the II-II crystal of Compound [A]. Confirm that the two diffraction patterns match. The measurement conditions for powder X-ray diffraction are, for example, as follows.
測定条件：  Measurement condition:
装置:粉末 X線回折装置  Apparatus: Powder X-ray diffractometer
X線： CuK a 1、 50kV、 300mA 走査モード:連続 X-ray: CuK a 1, 50kV, 300mA Scanning mode: Continuous
スキャンスピード：毎分 5。  Scan speed: 5 per minute.
スキャンステップ： 0. 02°  Scan step: 0.02 °
走査軸：  Scanning axis:
走査範囲： 3〜60°  Scanning range: 3-60 °
発散スリット： lZ2deg  Divergent slit: lZ2deg
散乱スリット： lZ2deg  Scattering slit: lZ2deg
受光スリット： 0. 15mm  Receiving slit: 0.15mm
試料の厚さ： 0. 5mm  Sample thickness: 0.5mm
[0057] 10.好ましくは内温 0〜10°C、より好ましくは 0〜5°Cにて、 2時間以上撹拌する。  [0057] 10. Stir for preferably 2 hours or more at an internal temperature of 0 to 10 ° C, more preferably 0 to 5 ° C.
[0058] 11.析出した結晶を濾取し、得られた湿結晶を冷却したエタノール Z水混合溶液 で洗浄する。エタノールの使用量は、化合物 [A]の結晶 1当量に対して、好ましくは 0 . 5〜2. OvZwであり、より好ましくは 0. 8〜1. 7vZwであり、最も好ましくは 1. 0〜 1. 5vZwである。水の使用量は、化合物 [A]の結晶 1当量に対して、好ましくは 0. 3 〜1. 5vZwであり、より好ましくは 0. 5〜1. 2vZwであり、最も好ましくは 0. 6〜1. OvZwである。 [0058] 11. The precipitated crystals are collected by filtration, and the obtained wet crystals are washed with a cooled ethanol Z water mixed solution. The amount of ethanol used is preferably 0.5 to 2. OvZw, more preferably 0.8 to 1.7 vZw, and most preferably 1.0 to 0.1 equivalent to 1 equivalent of the crystal of compound [A]. 1. 5vZw. The amount of water used is preferably from 0.3 to 1.5 vZw, more preferably from 0.5 to 1.2 vZw, most preferably from 0.6 to 1 equivalent to 1 equivalent of the crystal of compound [A]. 1. OvZw.
[0059] 12.洗浄した湿結晶を、好ましくは外温 70°C以下、より好ましくは 60°C以下にて、 減圧乾燥する。乾燥中の結晶をサンプリングし、結晶中のエタノール含量を測定する 。エタノール含量力 好ましくは 0. 5重量％未満、より好ましくは 0. 1重量％未満にな つた時点を乾燥終点とする。なお、エタノール含量の測定は、例えば、上記工程 (c) の操作 2.と同様にして GC分析方法により行うことができる。  [0059] 12. The washed wet crystals are dried under reduced pressure, preferably at an external temperature of 70 ° C or lower, more preferably 60 ° C or lower. Sample the crystal during drying and measure the ethanol content in the crystal. Ethanol content power The time when the ethanol content is preferably less than 0.5% by weight, more preferably less than 0.1% by weight, is the end point of drying. The ethanol content can be measured, for example, by a GC analysis method in the same manner as in step 2 of step (c) above.
[0060] 次に、本発明の製造方法において、ァ-ソール—イソプロパノール混合溶媒系を 用いて精製工程 (工程 (d)および (e) )を行うことに関して説明する。  [0060] Next, in the production method of the present invention, the purification step (steps (d) and (e)) using a mixed solvent of asol-isopropanol will be described.
図 1は、トルエン イソプロパノール混合溶媒系およびァ-ソール イソプロパノー ル混合溶媒系における化合物 [A]の III型晶の室温での溶解度を示す。例えば、化 合物 [A]の III型晶の室温での溶解度は、トルエン イソプロパノール（50 : 50体積 %)混合溶媒系では 29. 9mgZmlであるのに対し、ァ-ソ一ルーイソプロパノール（ 50 : 50体積％)混合溶媒系では 65. 9mg/mlであり、より多くの化合物 [A]を溶解 することができる。このことは、ある量の化合物 [A]の III型晶を溶解させる際、必要な ァ-ソ一ルーイソプロパノール（50 : 50体積％)混合溶媒の量は、必要なトルエン イソプロノ V—ル（50： 50体積0 /0)混合溶媒の量の 2分の 1以下でょ ヽことを示す。 また、ァ-ソ一ルーイソプロパノール（71. 4: 28. 6体積0 /0)混合溶媒系および同（ 50： 50体積％)混合溶媒系における 50°Cでの化合物 [A]の III型晶の溶解度は、そ れぞれ 163mgZmlおよび 181mgZmlであった。これは、化合物 [A]の III型晶を室 温にて少量のこれら混合溶媒に溶解した際に結晶の析出が見られる場合であっても 、加温することにより結晶を完全に溶解させることができることを示す。 Fig. 1 shows the solubility of compound [A] at room temperature in compound isoform [A] in a toluene-isopropanol mixed solvent system and an arsol-isopropanol mixed solvent system. For example, the solubility of compound [A] at room temperature for type III crystals is 29.9 mgZml in a toluene isopropanol (50:50 vol%) mixed solvent system, compared to the absolute isopropanol (50:50 vol%). (50% by volume) In mixed solvent system, it is 65.9 mg / ml, and dissolves more compound [A] can do. This means that when a certain amount of compound [A] type III crystals are dissolved, the amount of the solvent isopropanol (50: 50% by volume) mixed solvent required is the required amount of toluene isopronool (50 : indicates that Yoヽ50 volume 0/0) 1/2 of the amount of the mixed solvent below. Moreover, § - source one Lou isopropanol (71.4: 28.6 by volume 0/0) mixed solvent and the: III KataAkira of the compound in 50 ° C in (50 50% by volume) mixed solvent system [A] The solubility of was 163 mgZml and 181 mgZml, respectively. This is because even if crystal precipitation is observed when the type III crystal of compound [A] is dissolved in a small amount of these mixed solvents at room temperature, the crystal is completely dissolved by heating. Show that you can.
[0061] よって、工程 (d)の分液操作 (イソプロパノールを含む濃縮残渣を分液する操作)を 、少量のァ-ソールを用いて行うことができ、また、その後の工程 (e)の操作 1.およ び 2. (洗浄操作)を、化合物 [A]の析出を防止しつつ、少量の洗浄液を用いて行うこ とが可能となる。このためより小さな容器での製造が可能である。これらのことは、化 合物 [A]の大量製造の上で非常に有利である。  [0061] Therefore, the liquid separation operation of step (d) (operation of separating a concentrated residue containing isopropanol) can be performed using a small amount of a sole, and the subsequent operation of step (e). 1. and 2. (washing operation) can be performed using a small amount of washing liquid while preventing precipitation of the compound [A]. For this reason, manufacture in a smaller container is possible. These are very advantageous for mass production of the compound [A].
[0062] PCTZJP2005Z009604明細書に示される方法では、溶媒をイソプロパノールに 変換した後、トルエンを添加し、化合物 [A]の抽出 ·洗浄を行う。更に溶媒をトルエン 力も酢酸ェチルに変換し、濃縮を繰り返した後、更に、塩の除去のために抽出'洗浄 操作を行う。その後更に酢酸イソブチルへの溶媒置換を行い、濃縮を繰り返す。  [0062] In the method shown in the specification of PCTZJP2005Z009604, after the solvent is converted to isopropanol, toluene is added, and the compound [A] is extracted and washed. Further, after converting the solvent to toluene with ethyl acetate and repeating the concentration, an extraction and washing operation is further performed to remove the salt. Thereafter, the solvent is further replaced with isobutyl acetate, and the concentration is repeated.
[0063] 一方、本発明の製造方法では、溶媒をイソプロパノールに変換した後、ァ-ソール を添加し、化合物 [A]の抽出'洗浄を行った後、ァ-ソール溶媒を濃縮して操作を続 行することができ、更なる溶媒置換を必要としない。  [0063] On the other hand, in the production method of the present invention, after the solvent is converted to isopropanol, an azole is added, the compound [A] is extracted and washed, and then the azole solvent is concentrated to operate. Can be continued and does not require further solvent replacement.
よって製造工程の煩雑な操作を取り除くことができ、具体的には、溶媒置換の回数 を減らすこと、分液の回数を減らすこと、および濃縮の回数を減らすことができる。こ れによって、製造時間の短縮、高収率ィ匕が可能となる。  Therefore, complicated operations in the production process can be eliminated, and specifically, the number of solvent replacements can be reduced, the number of separations can be reduced, and the number of concentration can be reduced. This makes it possible to shorten manufacturing time and achieve high yield.
実施例  Example
[0064] 以下、本発明を実施例および参考例により具体的に説明するが、本発明はこれら の実施例および参考例に限定されるものではない。  [0064] The present invention will be specifically described below with reference to Examples and Reference Examples, but the present invention is not limited to these Examples and Reference Examples.
[0065] (実施例 1) [Example 1]
(工程 1) PCTZJP2005Z009604に記載の方法に従って、 6— (3 クロ口一 2 フノレオ口 ベンジル）—7 フルオロー 1— [ (S)—1—ヒドロキシメチル— 2—メチルプロピル] 4 -ォキソ 1 , 4 ジヒドロキノリン一 3 カルボン酸 (化合物 [ A— 1 ] )を合成した。 (Process 1) In accordance with the method described in PCTZJP2005Z009604, 6— (3 black 1 2 funoleo 2 benzyl) -7 fluoro 1— [(S) 1 -hydroxymethyl 2 -methylpropyl] 4 -oxo 1, 4 dihydroquinoline 1 3 carvone An acid (compound [A-1]) was synthesized.
[0066] (工程 2) [0066] (Process 2)
窒素雰囲気下、化合物 [A 1] (50. Og)をメタノール（300mL)に懸濁した。この 懸濁液に 28%ナトリウムメトキシド Zメタノール溶液（221g)を 13分かけて滴下し、滴 下終了後、 21時間加熱還流した。反応液を室温まで冷却し、活性炭 5. Ogを加えて 0. 5時間撹拌した後、粉末セルロース (KCフロック W— 300G ;日本製紙ケミカル 株式会社製)を通して濾過した。得られた濾液に水（37. 2g)を加え、濃縮残渣が 22 5mLになるまで減圧濃縮した。濃縮残渣にイソプロパノール（300mL)を添加し、濃 縮残渣が 375mLになるまで再度減圧濃縮した。濃縮残渣にイソプロパノール（150 mL)を添加し、濃縮残渣カ 00mLになるまで減圧濃縮した。濃縮残渣に 15%食塩 水（350mL)とァ-ソール（250mL)とを添カ卩して撹拌した後、分液し、水層を除いた 。ここで、フッ素イオンメーター Ti— 5101 (東興ィ匕学研究所製)を用い、洗浄後の水 層中の残留フッ素イオン濃度が lppm以下であることを確認した。有機層を 20%食 塩水（250mL)で 3回、塩ィ匕ナトリウム（62. 5g)を溶解した 0. 5mol/L塩酸水溶液（ 250mL)、 20%食塩水（250mL)で順次洗浄した。有機層を濃縮残渣が 250mLに なるまで減圧濃縮した。濃縮残渣にァ-ソール（250mL)を添加し、濃縮残渣が 250 mLになるまで再度減圧濃縮した。濃縮残渣を室温まで冷却した後、 PCTZJP2005 Z009604に記載の方法に従って得られたィ匕合物 [A]の II型晶（50. Omg)を添カロ して結晶化させ、 15時間撹拌した。さらにこの懸濁液に n—ヘプタン（50mL)を添カロ し、室温で 3時間撹拌後、結晶を濾取し、ァ-ソール (41. 5mL)—n—ヘプタン（8. 5mL)混合液で洗浄した。洗浄した結晶を減圧乾燥して、粗化合物 [A]を白色結晶 (36. 8g、収率 71. 7%)として得た。  Under a nitrogen atmosphere, Compound [A 1] (50. Og) was suspended in methanol (300 mL). To this suspension, 28% sodium methoxide Z methanol solution (221 g) was added dropwise over 13 minutes, and after completion of the dropwise addition, the mixture was heated to reflux for 21 hours. The reaction mixture was cooled to room temperature, and 5. Og of activated carbon was added and stirred for 0.5 hour, followed by filtration through powdered cellulose (KC Flock W-300G; manufactured by Nippon Paper Chemicals Co., Ltd.). Water (37.2 g) was added to the obtained filtrate, and the mixture was concentrated under reduced pressure until the concentrated residue was 225 mL. Isopropanol (300 mL) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure until the concentrated residue became 375 mL. Isopropanol (150 mL) was added to the concentrated residue, and the mixture was concentrated under reduced pressure to 00 mL. To the concentrated residue, 15% brine (350 mL) and carbole (250 mL) were added and stirred, followed by liquid separation to remove the aqueous layer. Here, using a fluorine ion meter Ti-5101 (manufactured by Toko University), it was confirmed that the residual fluorine ion concentration in the washed water layer was 1 ppm or less. The organic layer was washed successively with 20% saline (250 mL) three times and with 0.5 mol / L hydrochloric acid aqueous solution (250 mL) and 20% brine (250 mL) in which sodium chloride (62.5 g) was dissolved. The organic layer was concentrated under reduced pressure until the concentration residue was 250 mL. Carsol (250 mL) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure until the concentrated residue became 250 mL. The concentrated residue was cooled to room temperature, crystallized by adding II type crystals (50. Omg) of the compound [A] obtained according to the method described in PCTZJP2005 Z009604, and stirred for 15 hours. Further, n-heptane (50 mL) was added to the suspension, and the mixture was stirred at room temperature for 3 hours. The crystals were collected by filtration, and mixed with arsol (41.5 mL) -n-heptane (8.5 mL). Washed. The washed crystals were dried under reduced pressure to obtain crude compound [A] as white crystals (36.8 g, yield 71.7%).
[0067] 得られた粗ィ匕合物 [A] (白色結晶）中の化合物 [A]の含量は、 HPLC分析によって 測定したところ、 98. 45重量％ (ィ匕合物 [B]の含量は 0. 18重量％)であり、高純度 の化合物 [A]が得られたことが分かる。なお、 HPLC分析の測定条件は、次の通りで ある。 分析条件 [0067] The content of the compound [A] in the obtained crude compound [A] (white crystals) was measured by HPLC analysis and found to be 98.45% by weight (content of the compound [B]. Is 0.18% by weight), indicating that a highly pure compound [A] was obtained. The measurement conditions for HPLC analysis are as follows. Analysis conditions
カラム ： L—カラム ODS 5 111< 150111111 4. 61111111. 0. > (ィ匕学物質評価 研究機構製）  Column: L—Column ODS 5 111 <150111111 4. 61111111. 0.> (manufactured by Research Institute for Chemical Evaluation)
カラム温度 ：40°C付近の一定温度  Column temperature: Constant temperature around 40 ° C
移動相 ：移動相 A： 1 OmM リン酸緩衝液 <pH6. 9 >  Mobile phase: Mobile phase A: 1 OmM phosphate buffer <pH 6.9>
移動相 B : MeCN く HPLCグレード〉  Mobile Phase B: MeCN + HPLC Grade>
グラジェント条件  Gradient conditions
[0068] [表 3]  [0068] [Table 3]
Figure imgf000022_0001
Figure imgf000022_0001
[0069] 流速 ：1. 0mLZ分 [0069] Flow rate: 1.0 mLZ min
検出方法 ： UV220nm  Detection method: UV220nm
注入直 ^. 5 μ L·  Direct injection ^. 5 μL ·
分析時間 ：55分  Analysis time: 55 minutes
[0070] (工程 3) [0070] (Step 3)
前工程で得られた粗ィ匕合物 [A] (20. Og)をエタノール（130mL)と水（20mL)と に加熱溶解し、熱時濾過した。溶解に使用した容器および濾過器をエタノール (20 mL)で洗浄し、この洗浄液を濾過し、先の濾液と合わせた。この濾液に水（80mL)を 添加し、再度加熱還流して粗ィ匕合物 [A]を完全に溶解した後、 PCTZJP2005Z0 09604に記載の方法に従って得られた化合物 [A]の III型晶（20. Omg)を内温 65 °Cで添加し、 4時間撹拌した。次いで内温 45°Cで 2時間撹拌後、さらに室温で 16時 間、氷冷下で 2時間撹拌した。析出した結晶を濾取し、エタノール（24mL)—水（16 mL)混合液で洗浄した。洗浄した結晶を減圧乾燥して、精製ィ匕合物 [A]を白色結晶 (19. 2g、収率 96. 0%)として得た。  The crude compound [A] (20. Og) obtained in the previous step was dissolved in ethanol (130 mL) and water (20 mL) with heating, and filtered while hot. The vessel and filter used for dissolution were washed with ethanol (20 mL), and this washing was filtered and combined with the previous filtrate. Water (80 mL) was added to this filtrate, and the mixture was heated and refluxed again to completely dissolve the crude compound [A]. 20. Omg) was added at an internal temperature of 65 ° C, and the mixture was stirred for 4 hours. Next, the mixture was stirred at an internal temperature of 45 ° C for 2 hours, and further stirred at room temperature for 16 hours and ice-cooled for 2 hours. The precipitated crystals were collected by filtration and washed with a mixed solution of ethanol (24 mL) -water (16 mL). The washed crystals were dried under reduced pressure to obtain the purified compound [A] as white crystals (19.2 g, yield 96.0%).
[0071] 得られた精製化合物 [A] (白色結晶）中の化合物 [A]の含量は、 HPLC分析によ つて測定したところ、 98. 71重量％ (ィ匕合物 [B]の含量は 0. 22重量0 /0)であり、 ΠΙ型 晶への変換によってより高純度の化合物 [A]が得られたことが分かる。なお、 HPLC 分析の測定条件は、上記の通りである。 [0071] The content of the compound [A] in the obtained purified compound [A] (white crystals) was measured by HPLC analysis, and was found to be 98.71% by weight (the content of the compound [B] was 0.22 weight 0/0), and, Paiiota type It can be seen that the higher purity compound [A] was obtained by the conversion to crystals. The measurement conditions for HPLC analysis are as described above.
[0072] (参考例 1) [0072] (Reference Example 1)
化合物 [A]の純度を高めるためには、結晶化の際に不純物をなるベく除去すること が必要である。そこで、特に、工程 (i)および工程 (a)の反応の主な副生成物である 二量体化合物 [B]の混入量に対する結晶化溶媒の影響を検討した。  In order to increase the purity of the compound [A], it is necessary to remove impurities at the time of crystallization. Therefore, in particular, the influence of the crystallization solvent on the amount of the dimer compound [B], which is the main by-product of the reaction in step (i) and step (a), was examined.
実施例 1の工程 2において、結晶化溶媒として以下の表 4に示す各種溶媒を用 、て 粗化合物 [A]を白色結晶として得、得られた結晶中の化合物 [A]および化合物 [B] の含量を HPLC分析によって測定した。得られた結果を表 4に示す。  In Step 2 of Example 1, various compounds shown in Table 4 below were used as crystallization solvents to obtain crude compound [A] as white crystals, and compound [A] and compound [B] in the obtained crystals were obtained. The content of was determined by HPLC analysis. The results obtained are shown in Table 4.
[0073] [表 4] [0073] [Table 4]
Figure imgf000023_0001
Figure imgf000023_0001
1)化合物 [A— 1] 1当量に対して 1) Compound [A-1] per 1 equivalent
[0074] 表 4から、ァ-ソールを用いて結晶化を行った場合、他の溶媒に比べて化合物 [B] の混入量を著しく低減させることが可能であることが分かる。よって、ァ-ソールは、 化合物 [B]に対して精製効率が高ぐ高純度の化合物 [A]を得るために有利である 産業上の利用可能性 [0074] From Table 4, it can be seen that the amount of compound [B] mixed can be remarkably reduced when crystallization is performed using carbole as compared to other solvents. Therefore, arsol is advantageous for obtaining high-purity compound [A] having high purification efficiency with respect to compound [B]. Industrial Applicability
[0075] 本発明の製造方法は、抗 HIV作用を有する化合物 [A]の製造をより効率的に行う ことができ、特に、化合物 [A]の大量生産を行う際に有効である。 本出願は、日本で出願された特願 2005— 346044および米国で出願された US6/748, 258を基礎としており、それらの内容は本明細書に全て包含される。 [0075] The production method of the present invention can produce the compound [A] having anti-HIV activity more efficiently, and is particularly effective when mass-producing the compound [A]. This application is based on Japanese Patent Application No. 2005-346044 filed in Japan and US6 / 748,258 filed in the United States, the contents of which are incorporated in full herein.

Claims

請求の範囲 The scope of the claims
[1] 以下の工程 (i)および (ii)を含む、高純度な 6—（3 クロロー 2 フルォ口べンジル )— 1 [ (S) 1 ヒドロキシメチル一 2—メチルプロピル]— 7—メトキシ一 4—ォキソ 1 , 4ージヒドロキノリン 3 カルボン酸を製造する方法：  [1] High-purity 6- (3 Chloro-2 fluorobenzoyl)-1 [(S) 1 Hydroxymethyl-1-2-methylpropyl] -7-methoxy-one, including the following steps (i) and (ii) Method for producing 4-oxo1,4-dihydroquinoline 3 carboxylic acid:
(i)メタノール溶媒中、 6—（3 クロロー 2 フルォロベンジル） - 7-フルォロ 1一 [ (S)—1—ヒドロキシメチル一 2—メチルプロピル]— 4—ォキソ 1, 4ージヒドロキノリ ン一 3—カルボン酸とナトリウムメトキシドとを反応させる工程;および  (i) 6- (3 Chloro-2-fluorobenzyl) -7-fluoro 1- 1 [(S) -1-hydroxymethyl 1- 2-methylpropyl]-4-oxo 1,4-dihydroquinoline 1 3-carboxylic acid in methanol solvent Reacting sodium methoxide with; and
(ii)工程（i)で生成した 6— (3 クロ口一 2 フルォロベンジル） 1— [ (S)— 1 ヒド 口キシメチル一 2—メチルプロピル]— 7—メトキシ一 4—ォキソ 1, 4ージヒドロキノリ ン一 3—カルボン酸を、ァ-ソールを用いて精製する工程。  (ii) 6- (3-chlorobenzyl 2-fluoropropyl) produced in step (i) 1- [(S)-1 hydroxymethyl-1-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinoline (1) A step of purifying 3-carboxylic acid using azole.
[2] 以下の工程 (a)から (f)を含む、高純度な 6— (3—クロ口 2 フルォロベンジル） — 1 [ (S) 1 ヒドロキシメチル一 2—メチルプロピル]— 7—メトキシ一 4—ォキソ 1 , 4ージヒドロキノリン 3 カルボン酸を製造する方法：  [2] High-purity 6- (3-Cro2 Fluorobenzyl) containing the following steps (a) to (f) — 1 [(S) 1 Hydroxymethyl mono 2-methylpropyl] — 7-methoxy mono 4 —Method for producing oxo 1,4-dihydroquinoline 3 carboxylic acid:
(a)メタノール溶媒中、 6— (3—クロ口一 2—フルォロベンジル） - 7-フルォロ 1— [ (S)—1—ヒドロキシメチル一 2—メチルプロピル]— 4—ォキソ 1, 4 ジヒドロキノ リン一 3—カルボン酸とナトリウムメトキシドとを反応させる工程；  (a) 6- (3-chlorobenzyl 2-fluorobenzyl) -7-fluoro 1- [(S) -1-hydroxymethyl 2-methylpropyl]-4-oxo 1,4 dihydroquinoline in methanol solvent Reacting 3-carboxylic acid with sodium methoxide;
(b)工程 (a)で得られた反応混合物に水を添加後、濃縮する工程；  (b) Step of adding water to the reaction mixture obtained in step (a) and then concentrating;
(c)工程 (b)で得られた濃縮残渣にイソプロパノールを添加後、濃縮する工程； (c) Step of adding isopropanol to the concentrated residue obtained in step (b) and then concentrating;
(d)工程 (c)で得られた濃縮残渣に無機塩水溶液およびァ-ソールを添加し、分液 する工程； (d) Step of adding an aqueous solution of inorganic salt and a sole to the concentrated residue obtained in step (c) and separating the solution;
(e)工程 (d)で得られた有機層を無機塩水溶液で洗浄後、中和し、濃縮する工程;お よび  (e) Step of washing the organic layer obtained in step (d) with an aqueous inorganic salt solution, neutralizing and concentrating; and
(f)工程 (e)で得られた濃縮残渣にヘプタンを添加し、ろ過する工程。  (f) Step of adding heptane to the concentrated residue obtained in step (e) and filtering.
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US8324244B2 (en) 2006-09-12 2012-12-04 Gilead Sciences, Inc. Process and intermediates for preparing integrase inhibitors
US8796459B2 (en) 2006-09-12 2014-08-05 Gilead Sciences, Inc. Process and intermediates for preparing integrase inhibitors
US8153801B2 (en) 2007-09-11 2012-04-10 Gilead Sciences, Inc. Process and intermediates for preparing integrase inhibitors
US8440831B2 (en) 2007-09-11 2013-05-14 Gilead Sciences, Inc. Process and intermediates for preparing integrase inhibitors
US8759525B2 (en) 2007-09-11 2014-06-24 Gilhead Sciences, Inc. Process and intermediates for preparing integrase inhibitors
US8877931B2 (en) 2012-08-03 2014-11-04 Gilead Sciences, Inc. Process and intermediates for preparing integrase inhibitors

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