JP2021176830A - ベンズインデンプロスタグランジン中間体の結晶及びその製造方法 - Google Patents
ベンズインデンプロスタグランジン中間体の結晶及びその製造方法 Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 15
- -1 benzindene prostaglandins Chemical class 0.000 title abstract description 6
- 229940094443 oxytocics prostaglandins Drugs 0.000 title abstract description 5
- 238000002360 preparation method Methods 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 130
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 37
- 239000000203 mixture Substances 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims description 56
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 25
- 239000002244 precipitate Substances 0.000 claims description 22
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 20
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 14
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 12
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 12
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 12
- 239000012456 homogeneous solution Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000003860 storage Methods 0.000 abstract description 4
- 238000009472 formulation Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000005457 ice water Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229940093499 ethyl acetate Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229960005032 treprostinil Drugs 0.000 description 2
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- RDYMFSUJUZBWLH-UHFFFAOYSA-N endosulfan Chemical compound C12COS(=O)OCC2C2(Cl)C(Cl)=C(Cl)C1(Cl)C2(Cl)Cl RDYMFSUJUZBWLH-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- XOKCXRVJBBLBSX-HDMCCQRMSA-N hexadecyl 2-[[(1r,2r,3as,9as)-2-hydroxy-1-[(3s)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalen-5-yl]oxy]acetate Chemical compound C1[C@@H]2[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]2CC2=C1C=CC=C2OCC(=O)OCCCCCCCCCCCCCCCC XOKCXRVJBBLBSX-HDMCCQRMSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- FZZQNEVOYIYFPF-UHFFFAOYSA-N naphthalene-1,6-diol Chemical compound OC1=CC=CC2=CC(O)=CC=C21 FZZQNEVOYIYFPF-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960001726 treprostinil sodium Drugs 0.000 description 1
- IQKAWAUTOKVMLE-ZSESPEEFSA-M treprostinil sodium Chemical compound [Na+].C1=CC=C(OCC([O-])=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 IQKAWAUTOKVMLE-ZSESPEEFSA-M 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/37—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by etherified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/16—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same carbon atom of an acyclic carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
- C07C405/0058—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a not condensed ring different from a five-membered ring
- C07C405/0066—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a not condensed ring different from a five-membered ring to a six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/11—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton
- C07C255/13—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B63/00—Purification; Separation; Stabilisation; Use of additives
- C07B63/02—Purification; Separation; Stabilisation; Use of additives by treatment giving rise to a chemical modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
- C07C253/34—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
- C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
- C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/14—Benz[f]indenes; Hydrogenated benz[f]indenes
Abstract
Description
(b)温度を下げる及び/又はペンタン、ヘキサン、ヘプタン、オクタン、ノナン、デカン、シクロペンタン、シクロヘキサン、シクロヘプタン及びそれらの混合物からなる群から選択される第4の溶媒を前記均一溶液に加える工程;
(c)沈殿が形成されるまで撹拌する工程;
(d)必要に応じて、第2の溶媒又は第1の溶媒と第2の溶媒との混合物を添加して沈殿物をすすぐ工程;
(e)任意に沈殿物を濾別して化合物(I)の結晶形Iを単離する工程;
(f)任意に化合物(I)の結晶形Iを乾燥する工程
を含む。
(b)温度を下げる及び/又はペンタン、ヘキサン、ヘプタン、オクタン、ノナン、デカン、シクロペンタン、シクロヘキサン、シクロヘプタン及びそれらの混合物からなる群から選択される第4の溶媒を前記均一溶液に加える工程;
(c)沈殿が形成されるまで撹拌する工程;
(d)必要に応じて、沈殿物をすすぐための第4の溶媒又は第3の溶媒と第4の溶媒との混合物を添加する工程;
(e)任意に沈殿物を濾別して化合物(I)の結晶形IIを単離する工程;
(f)任意に化合物(I)の結晶形IIを乾燥する工程
を含む。
Claims (15)
- 前記XRPDパターンが、さらに以下の2θ反射角:9.7±0.2°、15.0±0.2°、16.6±0.2°、18.9±0.2°、19.7±0.2°、20.3±0.2°、22.2±0.2°、23.4±0.2°及び25.7±0.2°において特徴的なピークを含む、請求項2に記載の化合物(I)の結晶形I。
- 前記XRPDパターンが実質的に図1に示される、請求項2に記載の化合物(I)の結晶形I。
- さらにピーク開始温度が約55.3±1℃であり、最大ピークが約58.3±1℃である吸熱ピークを含む示差走査熱量測定(DSC)熱記録パターンを有する、請求項2に記載の化合物(I)の結晶形I。
- 前記DSC熱記録パターンが実質的に図2に示される、請求項5に記載の化合物(I)の結晶形I。
- エチルエーテル、イソプロピルエーテル、メチルtert−ブチルエーテル、及びそれらの混合物からなる群から選択される第1の溶媒中に化合物(I)を溶解して、均一溶液を形成する工程;
温度を下げる工程及び/又はペンタン、ヘキサン、ヘプタン、オクタン、ノナン、デカン、シクロペンタン、シクロヘキサン、シクロヘプタン及びそれらの混合物からなる群から選択される第4の溶媒を前記均一溶液に加える工程;並びに
沈殿物が形成されるまで撹拌する工程
を含む、請求項10に記載の結晶形IIを製造する方法(ただし、第1の溶媒としてメチルtert−ブチルエーテルを使用する場合、第1の溶媒の体積は、粗化合物(I)1g当たり約20mL未満である)。 - 第2の溶媒又は第1の溶媒と第2の溶媒との混合物を添加して沈殿をすすぐ工程;
沈殿物を濾別して化合物(I)の結晶形Iを単離する工程;及び
任意に化合物(I)の結晶形Iを乾燥する工程
をさらに含む、請求項7に記載の方法。 - 以下の2θ反射角:4.5±0.2°、8.3±0.2°、11.7±0.2°、16.6±0.2°、18.2±0.2°及び25.8±0.2°においてその6つの最も強い特徴的なピークを含むXRPDパターンを有することを特徴とする、化合物(I)の結晶形II。
- XRPDパターンが実質的に図4に示される、請求項9に記載の化合物(I)の結晶形II。
- 約55.6±1℃のピーク開始温度及び約61.8±1℃の最大ピークを有する吸熱ピークを含むDSC熱記録パターンをさらに有する、請求項9に記載の化合物(I)の結晶形II。
- DSC熱記録パターンが実質的に図5に示される、請求項12の化合物(I)の結晶形II。
- 第3の溶媒メチルtert−ブチルエーテルに化合物(I)を溶解して均一溶液を形成する工程であって、第3の溶媒の体積は化合物(I)1g当たり約20mL以上である工程;
温度を下げる工程及び/又はペンタン、ヘキサン、ヘプタン、オクタン、ノナン、デカン、シクロペンタン、シクロヘキサン、シクロヘプタン及びそれらの混合物からなる群から選択される第4の溶媒を前記均一溶液に加える工程;並びに
沈殿物が形成されるまで撹拌する工程
を含む、請求項9に記載の化合物(I)の結晶形IIを製造する方法。 - 第4の溶媒又は第3の溶媒と第4の溶媒との混合物を添加して沈殿物をすすぐ工程;
沈殿物を濾別し、それによって化合物(I)の結晶形IIを単離する工程;
任意に化合物(I)の結晶形IIを乾燥する工程
を更に含む、請求項14に記載の方法。
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