WO2007063869A1 - Procede de fabrication d’un compose de quinolone de grande purete - Google Patents

Procede de fabrication d’un compose de quinolone de grande purete 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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English (en)
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/fr

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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

L’invention concerne un procédé de fabrication d’un composé de quinolone de grande pureté avec une bonne efficacité. Le procédé de fabrication d’un acide 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxyméthyl-2-méthylpropyl]-7-méthoxy-4-oxo-1,4-dihydroquinoléine-3-carboxylique de grande pureté selon l’invention comprend les étapes (i) et (ii) suivantes : (i) faire réagir de l’acide 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1-[(S)-hydroxyméthyl-2-méthylpropyl]-4-oxo-1,4-dihydroquinoléine-3-carboxylique avec du méthoxyde de sodium dans un solvant méthanol ; et (ii) purifier l’acide 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxyméthyl-2-méthylpropyl]-7-méthoxy-4-oxo-1,4- dihydroquinoléine-3-carboxylique avec de l’anisole. Selon un mode de réalisation préféré, l’étape (ii) comprend les étapes (b) à (f) suivantes : (b) ajouter de l’eau à la solution réactionnelle, puis condenser la solution mélangée résultante ; (c) ajouter de l’isopropanol au résidu de condensation, puis condenser à nouveau la solution mélangée résultante ; (d) ajouter une solution aqueuse de sel inorganique et de l’anisole au résidu de condensation et soumettre la solution mélangée résultante à une séparation de phase ; (e) laver une phase organique avec une solution aqueuse de sel inorganique et neutraliser et condenser la solution résultante ; et (f) ajouter de l’heptane au résidu de condensation et filtrer la solution mélangée résultante.
PCT/JP2006/323763 2005-11-30 2006-11-29 Procede de fabrication d’un compose de quinolone de grande purete WO2007063869A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2005-346044 2005-11-30
JP2005346044 2005-11-30
US74825805P 2005-12-07 2005-12-07
US60/748,258 2005-12-07

Publications (1)

Publication Number Publication Date
WO2007063869A1 true WO2007063869A1 (fr) 2007-06-07

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7825252B2 (en) 2006-09-12 2010-11-02 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
US8877931B2 (en) 2012-08-03 2014-11-04 Gilead Sciences, Inc. Process and intermediates for preparing integrase inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004046115A1 (fr) * 2002-11-20 2004-06-03 Japan Tobacco Inc. Composes 4-oxoquinoliniques et leur utilisation comme inhibiteur de la vih-integrase
WO2005113508A1 (fr) * 2004-05-20 2005-12-01 Japan Tobacco Inc. Cristal stable de compose 4-oxoquinoline

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004046115A1 (fr) * 2002-11-20 2004-06-03 Japan Tobacco Inc. Composes 4-oxoquinoliniques et leur utilisation comme inhibiteur de la vih-integrase
WO2005113508A1 (fr) * 2004-05-20 2005-12-01 Japan Tobacco Inc. Cristal stable de compose 4-oxoquinoline

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7825252B2 (en) 2006-09-12 2010-11-02 Gilead Sciences, Inc. Process and intermediates for preparing integrase inhibitors
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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