JP2002504157A - Antibacterial side chain intermediate in crystalline form - Google Patents
Antibacterial side chain intermediate in crystalline formInfo
- Publication number
- JP2002504157A JP2002504157A JP50883899A JP50883899A JP2002504157A JP 2002504157 A JP2002504157 A JP 2002504157A JP 50883899 A JP50883899 A JP 50883899A JP 50883899 A JP50883899 A JP 50883899A JP 2002504157 A JP2002504157 A JP 2002504157A
- Authority
- JP
- Japan
- Prior art keywords
- ion
- crystalline
- pyrrolidinyl
- mercapto
- cis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000000844 anti-bacterial effect Effects 0.000 title 1
- -1 4-mercapto-2-pyrrolidinyl Chemical group 0.000 claims abstract description 32
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000012453 solvate Substances 0.000 claims abstract description 21
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 11
- 239000005711 Benzoic acid Substances 0.000 claims abstract description 10
- 235000010233 benzoic acid Nutrition 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 24
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 7
- 239000002253 acid Substances 0.000 claims 1
- 239000013078 crystal Substances 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 description 16
- 150000002500 ions Chemical class 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 5
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 229920002230 Pectic acid Polymers 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229940113720 aminosalicylate Drugs 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940006461 iodide ion Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UWTATZPHSA-M malate ion Chemical compound [O-]C(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-M 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
(57)【要約】 結晶性の２Ｓ−ｃｉｓ−３−［［（４−メルカプト−２−ピロリジニル）カルボニル］−アミノ］安息香酸ならびにその塩および溶媒和物を開示する。３種類の異なる結晶型を開示する。 (57) [Summary] Disclosed are crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl) carbonyl] -amino] benzoic acid and salts and solvates thereof. Three different crystal forms are disclosed.
Description
【発明の詳細な説明】 結晶形態の抗菌性側鎖中間体 発明の背景 カルバペネム系抗生物質を得るための中間体の結晶形態は、安定性および純度 の観点から望ましい。このような化合物によって、商業スケールでのカルバペネ ム系抗生物質の合成が容易になる。 本発明において、結晶形態の化合物２Ｓ−ｃｉｓ−３−［［（４−メルカプト −２−ピロリジニル）カルボニル］−アミノ］安息香酸が見出され、特徴づけが 行われた。結晶性の２Ｓ−ｃｉｓ−３−［［（４−メルカプト−２−ピロリジニ ル）カルボニル］−アミノ］安息香酸ならびに薬剤として受容可能なその塩およ び溶媒和物を開示する。これらの化合物は、一般的には、米国特許第５，４７８ ，８２０号（１９９５年１２月２６日特許付与）の開示を考慮して合成すること ができる。この特許は、結晶形態の側鎖を開示していない。 発明の要旨 結晶性の２Ｓ−ｃｉｓ−３−［［（４−メルカプト−２−ピ ロリジニル）カルボニル］−アミノ］安息香酸ならびにその薬剤として受容可能 な塩および溶媒和物を開示する。 図面の簡単な説明 本発明を、下記の図面とともに説明する。 第１図は、非溶媒和形態の化合物ＩのＸ線粉末回折パターンである。 第２図は、１−ブタノール溶媒和物としての化合物ＩのＸ線粉末回折パターン である。 第３図は、酢酸溶媒和物としての化合物ＩのＸ線粉末回折パターンである。 発明の詳細な説明 本発明の化合物は、下記の構造式を有する：ただし、Ｐは、Ｈまたは保護基を表す。 この化合物の塩形態は、下記に示すようにプロトン化され得る： ただし、Ｘ-は、負電荷を有する対イオンを表す。塩形態はまた、溶媒和物とし て存在し得る。 結晶形態の化合物は、そのＸ線粉末回折（ＸＲＰＤ）パターンにより下記のよ うな特徴を有する。ＸＲＰＤパターンは、フィリップス（Ｐｈｉｌｉｐｓ）ＡＰ Ｄ３７２０自動粉末回折計で収集した。Ｘ線発生源には銅ターゲットを用い、加 速電位を４５ｋＶとし、フィラメント電流を４０ｍＡとした。回折パターンを２ ℃から４０℃まで収集した。 塩酸塩の化合物（非溶媒和物）は、５．５Å、５．３Å、４．９Å、４．３Å 、４．１Å、３．９Å、３．８Å、３．７Å、３．６Å、３．３Å、３．２Å、 ２．９Å、２．６Åおよび２．３ÅにおけるＸＲＰＤパターンを有するとして特 徴づけられた。この化合物に関連する、より完全なＸＲＰＤデータを下記の表１ に示す。備考： 発生源設定条件： ４５ｋＶ、４０ｍＡ Ｃｕα１、α２波長 １．５４０６０Å、１．５４４３９Å ステップサイズ、サンプル時間 ０．０１５ｄｅｇ、０．２０秒、０．０７５ｄｅｇ／秒 使用モノクロメーター 発散スリット 自動（照射サンプル長 １２．５ｍｍ） ピーク角度範囲 ２．００７〜４０．００２ｄｅｇ 使用モノクロメーター 発散スリット 自動（照射サンプル長 １２．５ｍｍ） ピーク角度範囲 ２．００７〜４０．００２ｄｅｇ Ｄ間隔の範囲 ２．２５２０７〜４３．９７２３Å ピーク位置規準 平滑化データの頂部 結晶ピーク幅範囲 ０．００〜２．００ｄｅｇ 最小ピーク値 ０．７５ 格納ピーク数 ３３（α１：３３、アモルファス：０） 最大強度 ４３７カウント、２１８４．１ｃｐｓ 表１に対応するＸＲＰＤパターンを第１図として示す。 塩酸塩の１−ブタノール溶媒和物は、第２図として示すＥＲＰＤパターンなど のパターンを示すことが明らかとなった。特徴的なＤ間隔は、１４．６Å、７． ３Å、５．６Å、４．９Å、４．２Å、４．０Å、３．９Å、３．８Å、３．７ Å、３．６Å、３．５Å、３．３Å、３．０Åおよび２．９Åである。この溶媒 和物に対応する、より完全なＸＲＰＤデータを下記の表２に示す。備考： 発生源設定条件： ４５ｋＶ、４０ｍＡ Ｃｕα１、α２波長 １．５４０６０Å、１．５４４３９Å ステップサイズ、サンプル時間 ０．０１５ｄｅｇ、０．２０秒、０．０７５ｄｅｇ／秒 使用モノクロメーター 発散スリット 自動（照射サンプル長 １２．５ｍｍ） ピーク角度範囲 ２．００７〜４０．００２ｄｅｇ Ｄ間隔の範囲 ２．２５２０７〜４３．９７２３Å ピーク位置規準 平滑化データの頂部 結晶ピーク幅範囲 ０．００〜２．００ｄｅｇ 最小ピーク値 ０．７５ 格納ピーク数 ３３（α１：３３、アモルファス：０） 最大強度 ４３７カウント、２１８４．１ｃｐｓ 表２に対応するＸＲＰＤパターンを第２図として示す。 酢酸に曝された固体物質は、５．４Å、５．３Å、５．１Å、４．２Å、３． ８Å、３．６Å、３．４Å、３．１Å、２．７Åおよび２．６ÅにおいてＸＲＰ Ｄパターンを有するとして特徴づけられた。この溶媒和物に対応する、より完全 なＸＲＰＤデータを下記の表３に示す。備考： 発生源設定条件： ４５ｋＶ、４０ｍＡ Ｃｕα１、α２波長 １．５４０６０Å、１．５４４３９Å ステップサイズ、サンプル時間 ０．０１５ｄｅｇ、０．２０秒、０．０７５ｄｅｇ／秒 使用モノクロメーター 発散スリット 自動（照射サンプル長 １２．５ｍｍ） ピーク角度範囲 ２．００７〜４０．００２ｄｅｇ Ｄ間隔の範囲 ２．２５２０７〜４３．９７２３Å ピーク位置規準 平滑化データの頂部 結晶ピーク幅範囲 ０．００〜２．００ｄｅｇ 最小ピーク値 ０．７５ 格納ピーク数 ３３（α１：３３、アモルファス：０） 最大強度 ４３７カウント、２１８４．１ｃｐｓ 表３に対応するＸＲＰＤパターンを第３図として示す。 本発明の結晶性化合物は、様々な薬剤として受容可能な塩の形態において有用 であり、同様に、動物被験体およびヒト被験体の細菌感染の処置に有用なカルバ ペネム系化合物を合成するために有用である。用語「薬剤として受容可能な塩」 は、製薬 化学者には明らかなそのような塩の形態、すなわち、実質的に毒性がなく、所望 の薬物動態学的特性、良好な服用感、吸収、分布、代謝または排出が得られる塩 の形態をいう。選択する際の同様に重要な他の要因、本質的にはより実際的な要 因は、原材料コスト、容易な結晶化、収量、安定性、吸湿性および得られる大量 の薬物の流動性である。 中間体化合物は典型的にはプロトン化されており、一般的にはＸ-で示される 負電荷の対イオンと会合して見出される。電荷を中和する対イオンＸ-には様々 な可能性がある。そのような対イオンの代表的な例を下記に示す。酢酸イオン、 アジピン酸イオン、アミノサリチル酸イオン、アンヒドロメチレンクエン酸イオ ン、アスコルビン酸イオン、アスパラギン酸イオン、安息香酸イオン、ベンゼン スルホン酸イオン、重炭酸イオン、重硫酸イオン、臭化物イオン、クエン酸イオ ン、ショウノウ酸イオン、ショウノウスルホン酸イオン、炭酸イオン、塩化物イ オン、ジグルコン酸イオン、エデト酸（エチレンジアミン四酢酸）イオン、エジ シレート（１，２−エタンジスルホン酸）イオン、エストレート（ｅｓｔｏｌａ ｔｅ）イオン、エタンスルホン酸イオン、フマル酸イオン、グルコヘプタン酸イ オン、グルコン 酸イオン、グルタミン酸イオン、グリセロリン酸イオン、グリコール酸イオン、 ヒドロキシナフトエ酸イオン、２−ヒドロキシエタンスルホン酸イオン、ヨウ化 物イオン、乳酸イオン、ラクトビオン酸イオン、リンゴ酸イオン、マレイン酸イ オン、マンデル酸イオン、メチレンビス（サリチル酸）イオン、ムチン酸イオン 、メタンスルホン酸イオン、ナパジシレート（ｎａｐａｄｉｓｙｌａｔｅ）イオ ン、ナプシレート（２−ナフタレンスルホン酸）イオン、パモエート（４，４’ −メチレンビス（３−ヒドロキシ−２−ナフトエ酸））イオン、パントテン酸イ オン、ペクチン酸イオン、リン酸イオン／二リン酸イオン、ポリガラクツロン酸 イオン、プロピオン酸イオン、サリチル酸イオン、ステアリン酸イオン、コハク 酸イオン、硫酸イオン、酒石酸イオン、トリフレート（トリフルオロメチルスル ホン酸）イオン、トシレート（ｐ−トルエンスルホン酸）イオンおよびウンデカ ン酸イオン。他のアニオン種は、当業者には明らかである。 結晶性化合物の好ましい形態は、塩酸塩の形態である。 本発明の化合物は、下記の非限定的な実施例に従って製造することができる。 実施例１ Ａ．合成 ＢＯＣ保護の側鎖１（ＰＣＴ公開ＷＯ９７／０６１５４（１９９７年２月２０ 日公開）の教示に従って調製）を、酢酸における乾燥塩化水素の１Ｎ溶液の１． ５Ｌに溶解した（３０分）。ガスの発生が認められ、反応生成物がゆっくりと結 晶化した。ろ過、洗浄（酢酸およびヘキサンを用いる）および乾燥を行った後に 、１３７ｇの生成物が得られた。得られた結晶は酢酸を含有するが、溶媒和物で はない。 Ｂ．再結晶手順 １−プロパノール溶媒和物 上記の生成物（２５ｇ）を１−プロパノール（５００ｍＬ）に１００℃で溶解 した。冷却すると、生成物が析出した。ろ過、洗浄（１−プロパノールおよびヘ キサンを用いる）および乾燥を行った後に、２０ｇの１−プロパノール溶媒和物 が得られた。 １−ブタノール溶媒和物 上記の生成物（２５ｇ）を１−ブタノール（２２５ｍＬ）および水（２５ｍＬ ）の混合物にＲＴで溶解した。得られた溶液を、全量が１２５ｍＬになるまで減 圧下で濃縮して、標準品の１−ブタノール溶媒和物を種結晶として加えた。結晶 のろ過、洗浄（１−ブタノールおよびヘキサンを用いる）およびＲＴでの乾燥を 行い、２５ｇの１−ブタノール溶媒和物を得た。 酢酸溶媒和物 上記の生成物を、一晩、酢酸および水の９５／５混合物においてＲＴでスラリ ーにし、次いで、減圧蒸留によって少し濃縮した。結晶のろ過、洗浄（酢酸およ びヘキサンを用いる）および乾燥を行い、酢酸溶媒和物を得た。DETAILED DESCRIPTION OF THE INVENTION Antimicrobial Side-Chain Intermediates in Crystalline Background The crystalline form of the intermediates for obtaining carbapenem antibiotics is desirable from the standpoint of stability and purity. Such compounds facilitate the synthesis of carbapenem antibiotics on a commercial scale. In the present invention, the crystalline form of the compound 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl) carbonyl] -amino] benzoic acid has been found and characterized. Disclosed are crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl) carbonyl] -amino] benzoic acid and pharmaceutically acceptable salts and solvates thereof. These compounds can generally be synthesized in view of the disclosure of US Pat. No. 5,478,820 (patented Dec. 26, 1995). This patent does not disclose side chains in crystalline form. SUMMARY OF THE INVENTION Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl) carbonyl] -amino] benzoic acid and pharmaceutically acceptable salts and solvates thereof are disclosed. BRIEF DESCRIPTION OF THE DRAWINGS The invention will be described with reference to the following drawings. FIG. 1 is an X-ray powder diffraction pattern of Compound I in unsolvated form. FIG. 2 is an X-ray powder diffraction pattern of Compound I as a 1-butanol solvate. FIG. 3 is an X-ray powder diffraction pattern of Compound I as an acetic acid solvate. DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention have the following structural formula: Here, P represents H or a protecting group. The salt form of this compound can be protonated as shown below: Here, X − represents a counter ion having a negative charge. Salt forms may also exist as solvates. The crystalline form of the compound has the following characteristics according to its X-ray powder diffraction (XRPD) pattern. XRPD patterns were collected on a Philips AP D3720 automated powder diffractometer. A copper target was used as the X-ray source, the acceleration potential was 45 kV, and the filament current was 40 mA. Diffraction patterns were collected from 2 ° C to 40 ° C. The compound of the hydrochloride (non-solvate) is 5.5Å, 5.3Å, 4.9Å, 4.3Å, 4.1Å, 3.9Å, 3.8Å, 3.7Å, 3.6Å, 3 .．. It was characterized as having XRPD patterns at 3 °, 3.2 °, 2.9 °, 2.6 ° and 2.3 °. More complete XRPD data relating to this compound is shown in Table 1 below. Remarks: Source setting conditions: 45 kV, 40 mA Cuα1, α2 wavelength 1.54060Å, 1.54439Å Step size, sample time 0.015 deg, 0.20 sec, 0.075 deg / sec Monochromator divergence slit Automatic (irradiation sample length 12.5mm) Peak angle range 2.007-40.002deg Monochromator divergence slit used Automatic (irradiation sample length 12.5mm) Peak angle range 2.007-40.002deg D interval range 2.25207-43.9723４３ Peak Position criteria Top crystal peak width range of smoothed data 0.00 to 2.00 deg Minimum peak value 0.75 Number of stored peaks 33 (α1: 33, amorphous: 0) Maximum intensity 437 count, 2184.1 cps Corresponding to Table 1. XRPD pattern It is shown as FIG. It was revealed that the 1-butanol solvate of the hydrochloride exhibited a pattern such as the ERPD pattern shown in FIG. The characteristic D intervals are 14.6 °, 7. 3Å, 5.6Å, 4.9Å, 4.2Å, 4.0Å, 3.9Å, 3.8Å, 3.7Å, 3.6Å, 3.5Å, 3.3Å, 3.0Å and 2.9Å It is. The more complete XRPD data corresponding to this solvate is shown in Table 2 below. Remarks: Source setting conditions: 45 kV, 40 mA Cuα1, α2 wavelength 1.54060Å, 1.54439Å Step size, sample time 0.015 deg, 0.20 sec, 0.075 deg / sec Monochromator divergence slit Automatic (irradiation sample length 12.5 mm) Peak angle range 2.007-40.002 deg D interval range 2.25207-43.9723． Peak position standard Top crystal peak width range of smoothed data 0.00-2.00 deg Minimum peak value 0.75 Number of stored peaks 33 (α1: 33, amorphous: 0) Maximum intensity 437 counts, 2184.1 cps The XRPD pattern corresponding to Table 2 is shown in FIG. The solid material exposed to acetic acid was 5.4%, 5.3%, 5.1%, 4.2%, 3.%. It was characterized as having an XRPD pattern at 8 °, 3.6 °, 3.4 °, 3.1 °, 2.7 ° and 2.6 °. The more complete XRPD data corresponding to this solvate is shown in Table 3 below. Remarks: Source setting conditions: 45 kV, 40 mA Cuα1, α2 wavelength 1.54060Å, 1.54439Å Step size, sample time 0.015 deg, 0.20 sec, 0.075 deg / sec Monochromator divergence slit Automatic (irradiation sample length 12.5 mm) Peak angle range 2.007-40.002 deg D interval range 2.25207-43.9723． Peak position standard Top crystal peak width range of smoothed data 0.00-2.00 deg Minimum peak value 0.75 Number of stored peaks 33 (α1: 33, amorphous: 0) Maximum intensity 437 counts, 2184.1 cps The XRPD pattern corresponding to Table 3 is shown in FIG. The crystalline compounds of the present invention are useful in the form of various pharmaceutically acceptable salts, as well as for synthesizing carbapenem-based compounds useful for treating bacterial infections in animal and human subjects. It is. The term "pharmaceutically acceptable salt" refers to such salt forms apparent to pharmaceutical chemists, i.e., having substantially no toxicity, the desired pharmacokinetic properties, good feel, absorption, and distribution. , Metabolism or excretion. Other equally important factors in selection, essentially more practical, are raw material cost, easy crystallization, yield, stability, hygroscopicity and the flowability of the bulk drug obtained. Intermediate compounds typically are protonated, generally X - are found in association with counter ions of the negative charge exhibited by. Counterion X to neutralize the charge - there are various possibilities for. Representative examples of such counterions are shown below. Acetate, adipate, aminosalicylate, anhydromethylene citrate, ascorbate, aspartate, benzoate, benzenesulfonate, bicarbonate, bisulfate, bromide, citrate, Camphorate ion, camphorsulfonate ion, carbonate ion, chloride ion, digluconate ion, edetate (ethylenediaminetetraacetic acid) ion, edisylate (1,2-ethanedisulfonic acid) ion, estrate ion, ethane Sulfonate ion, fumarate ion, glucoheptanoate ion, gluconate ion, glutamate ion, glycerophosphate ion, glycolate ion, hydroxynaphthoate ion, 2-hydroxyethanesulfonate ion , Iodide ion, lactate ion, lactobionate ion, malate ion, maleate ion, mandelic ion, methylenebis (salicylate) ion, mucinate ion, methanesulfonic acid ion, napadisylate ion, napsylate (2-naphthalene) Sulfonic acid) ion, pamoate (4,4'-methylenebis (3-hydroxy-2-naphthoic acid)) ion, pantothenate ion, pectate ion, phosphate / diphosphate ion, polygalacturonic acid ion, propionic acid Ion, salicylate ion, stearate ion, succinate ion, sulfate ion, tartrate ion, triflate (trifluoromethylsulfonic acid) ion, tosylate (p-toluenesulfonic acid) ion and undecanoate ion . Other anionic species will be apparent to those skilled in the art. The preferred form of the crystalline compound is the form of the hydrochloride. The compounds of the present invention can be made according to the following non-limiting examples. Example 1 A. Synthesis Side chain 1 of the BOC protection (prepared according to the teachings of PCT Publication WO 97/06154 (published February 20, 1997)) was prepared as follows: 1. Preparation of a 1N solution of dry hydrogen chloride in acetic acid. Dissolved in 5 L (30 minutes). Gas evolution was observed and the reaction product slowly crystallized. After filtration, washing (using acetic acid and hexane) and drying, 137 g of product was obtained. The resulting crystals contain acetic acid, but are not solvates. B. Recrystallization procedure 1-propanol solvate The above product (25 g) was dissolved in 1-propanol (500 mL) at 100 ° C. Upon cooling, the product precipitated. After filtration, washing (using 1-propanol and hexane) and drying, 20 g of 1-propanol solvate was obtained. 1-Butanol solvate The above product (25 g) was dissolved in a mixture of 1-butanol (225 mL) and water (25 mL) at RT. The obtained solution was concentrated under reduced pressure until the total volume became 125 mL, and a standard 1-butanol solvate was added as seed crystals. The crystals were filtered, washed (using 1-butanol and hexane) and dried at RT to give 25 g of 1-butanol solvate. Acetic acid solvate The above product was slurried at room temperature in a 95/5 mixture of acetic acid and water at RT and then slightly concentrated by vacuum distillation. The crystals were filtered, washed (using acetic acid and hexane), and dried to obtain an acetic acid solvate.
───────────────────────────────────────────────────── フロントページの続き (81)指定国 ＥＰ(ＡＴ，ＢＥ，ＣＨ，ＣＹ， ＤＥ，ＤＫ，ＥＳ，ＦＩ，ＦＲ，ＧＢ，ＧＲ，ＩＥ，Ｉ Ｔ，ＬＵ，ＭＣ，ＮＬ，ＰＴ，ＳＥ)，ＯＡ(ＢＦ，ＢＪ ，ＣＦ，ＣＧ，ＣＩ，ＣＭ，ＧＡ，ＧＮ，ＭＬ，ＭＲ， ＮＥ，ＳＮ，ＴＤ，ＴＧ)，ＡＰ(ＧＨ，ＧＭ，ＫＥ，Ｌ Ｓ，ＭＷ，ＳＤ，ＳＺ，ＵＧ，ＺＷ)，ＥＡ(ＡＭ，ＡＺ ，ＢＹ，ＫＧ，ＫＺ，ＭＤ，ＲＵ，ＴＪ，ＴＭ)，ＡＬ ，ＡＭ，ＡＵ，ＡＺ，ＢＡ，ＢＢ，ＢＧ，ＢＲ，ＢＹ， ＣＡ，ＣＮ，ＣＵ，ＣＺ，ＥＥ，ＧＥ，ＧＷ，ＨＲ，Ｈ Ｕ，ＩＤ，ＩＬ，ＩＳ，ＪＰ，ＫＧ，ＫＲ，ＫＺ，ＬＣ ，ＬＫ，ＬＲ，ＬＴ，ＬＶ，ＭＤ，ＭＧ，ＭＫ，ＭＮ， ＭＸ，ＮＯ，ＮＺ，ＰＬ，ＲＯ，ＲＵ，ＳＧ，ＳＩ，Ｓ Ｋ，ＳＬ，ＴＪ，ＴＭ，ＴＲ，ＴＴ，ＵＡ，ＵＳ，ＵＺ ，ＶＮ，ＹＵ (72)発明者 ジヨブソン，ロナルド・ビー アメリカ合衆国、ニユー・ジヤージー・ 07065、ローウエイ、イースト・リンカー ン・アベニユー・126────────────────────────────────────────────────── ─── Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, L S, MW, SD, SZ, UG, ZW), EA (AM, AZ , BY, KG, KZ, MD, RU, TJ, TM), AL , AM, AU, AZ, BA, BB, BG, BR, BY, CA, CN, CU, CZ, EE, GE, GW, HR, H U, ID, IL, IS, JP, KG, KR, KZ, LC , LK, LR, LT, LV, MD, MG, MK, MN, MX, NO, NZ, PL, RO, RU, SG, SI, S K, SL, TJ, TM, TR, TT, UA, US, UZ , VN, YU (72) Inventor Jyobson, Ronald Bee New Jersey, United States 07065, Lowway, East Linker N Avenue 126
Claims (1)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US5219797P | 1997-07-10 | 1997-07-10 | |
| US60/052,197 | 1997-07-10 | ||
| GB9800463.3 | 1998-01-09 | ||
| GB60/052,197 | 1998-01-09 | ||
| GBGB9800463.3A GB9800463D0 (en) | 1998-01-09 | 1998-01-09 | Crystalline forms of antibiotic side chain intermediates |
| PCT/US1998/014036 WO1999002492A1 (en) | 1997-07-10 | 1998-07-07 | Crystalline forms of antibiotic side chain intermediates |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2002504157A true JP2002504157A (en) | 2002-02-05 |
| JP3378021B2 JP3378021B2 (en) | 2003-02-17 |
Family
ID=26312922
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP50883899A Expired - Fee Related JP3378021B2 (en) | 1997-07-10 | 1998-07-07 | Antibacterial side chain intermediate in crystalline form |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0998457A4 (en) |
| JP (1) | JP3378021B2 (en) |
| AU (1) | AU736136B2 (en) |
| CA (1) | CA2294341C (en) |
| WO (1) | WO1999002492A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4068452B2 (en) | 2000-07-19 | 2008-03-26 | エフ．ホフマン−ラ ロシュ アーゲー | Pyrrolidine derivatives as endothelin converting enzyme inhibitors |
| WO2010073706A1 (en) * | 2008-12-25 | 2010-07-01 | 株式会社カネカ | Improved process for producing intermediate for side chain of carbapenem |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9202298D0 (en) * | 1992-02-04 | 1992-03-18 | Ici Plc | Antibiotic compounds |
| WO1999002531A1 (en) * | 1997-07-09 | 1999-01-21 | Merck & Co., Inc. | Process for synthesizing carbapenem side chain intermediates |
-
1998
- 1998-07-07 CA CA002294341A patent/CA2294341C/en not_active Expired - Fee Related
- 1998-07-07 AU AU82920/98A patent/AU736136B2/en not_active Ceased
- 1998-07-07 EP EP98933212A patent/EP0998457A4/en not_active Withdrawn
- 1998-07-07 JP JP50883899A patent/JP3378021B2/en not_active Expired - Fee Related
- 1998-07-07 WO PCT/US1998/014036 patent/WO1999002492A1/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| JP3378021B2 (en) | 2003-02-17 |
| CA2294341C (en) | 2007-09-25 |
| AU8292098A (en) | 1999-02-08 |
| AU736136B2 (en) | 2001-07-26 |
| CA2294341A1 (en) | 1999-01-21 |
| EP0998457A1 (en) | 2000-05-10 |
| EP0998457A4 (en) | 2010-03-10 |
| WO1999002492A1 (en) | 1999-01-21 |
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