JPWO2010079605A1 - Method for producing high purity 1-benzyl-3-aminopyrrolidine - Google Patents
Method for producing high purity 1-benzyl-3-aminopyrrolidine Download PDFInfo
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- JPWO2010079605A1 JPWO2010079605A1 JP2010545664A JP2010545664A JPWO2010079605A1 JP WO2010079605 A1 JPWO2010079605 A1 JP WO2010079605A1 JP 2010545664 A JP2010545664 A JP 2010545664A JP 2010545664 A JP2010545664 A JP 2010545664A JP WO2010079605 A1 JPWO2010079605 A1 JP WO2010079605A1
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- Prior art keywords
- aminopyrrolidine
- benzyl
- water
- tartaric acid
- salt
- Prior art date
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- HBVNLKQGRZPGRP-UHFFFAOYSA-N 1-benzylpyrrolidin-3-amine Chemical compound C1C(N)CCN1CC1=CC=CC=C1 HBVNLKQGRZPGRP-UHFFFAOYSA-N 0.000 title claims abstract description 162
- 238000004519 manufacturing process Methods 0.000 title claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 73
- 150000003839 salts Chemical class 0.000 claims abstract description 60
- 239000000126 substance Substances 0.000 claims abstract description 41
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 28
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000012535 impurity Substances 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 239000012046 mixed solvent Substances 0.000 claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- 239000000203 mixture Substances 0.000 claims description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- 238000002425 crystallisation Methods 0.000 claims description 26
- 230000008025 crystallization Effects 0.000 claims description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- HBVNLKQGRZPGRP-LLVKDONJSA-N (3r)-1-benzylpyrrolidin-3-amine Chemical compound C1[C@H](N)CCN1CC1=CC=CC=C1 HBVNLKQGRZPGRP-LLVKDONJSA-N 0.000 claims description 9
- HBVNLKQGRZPGRP-NSHDSACASA-N (3s)-1-benzylpyrrolidin-3-amine Chemical compound C1[C@@H](N)CCN1CC1=CC=CC=C1 HBVNLKQGRZPGRP-NSHDSACASA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 229960001270 d- tartaric acid Drugs 0.000 claims description 8
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 150000007514 bases Chemical class 0.000 claims 1
- 239000011975 tartaric acid Substances 0.000 abstract description 19
- 235000002906 tartaric acid Nutrition 0.000 abstract description 19
- 238000000034 method Methods 0.000 abstract description 17
- 238000000746 purification Methods 0.000 abstract description 9
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical compound NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 182
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 38
- 238000004817 gas chromatography Methods 0.000 description 31
- 238000003756 stirring Methods 0.000 description 19
- 229960001367 tartaric acid Drugs 0.000 description 18
- YUBDLZGUSSWQSS-UHFFFAOYSA-N 1-benzylpiperidin-4-amine Chemical compound C1CC(N)CCN1CC1=CC=CC=C1 YUBDLZGUSSWQSS-UHFFFAOYSA-N 0.000 description 16
- 230000003287 optical effect Effects 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 239000002002 slurry Substances 0.000 description 12
- 239000002994 raw material Substances 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- 150000003892 tartrate salts Chemical class 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 150000004684 trihydrates Chemical class 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 229940048879 dl tartaric acid Drugs 0.000 description 4
- 125000003944 tolyl group Chemical group 0.000 description 4
- NGEHALHRMKANSX-WCYBWAGNSA-N (2S,3S)-2,3-dihydroxybutanedioic acid trihydrate Chemical compound O.O.O.O[C@@H]([C@H](O)C(O)=O)C(O)=O NGEHALHRMKANSX-WCYBWAGNSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NGEHALHRMKANSX-QXMMYYGRSA-N O.O.O.C(=O)(O)[C@H](O)[C@@H](O)C(=O)O Chemical compound O.O.O.C(=O)(O)[C@H](O)[C@@H](O)C(=O)O NGEHALHRMKANSX-QXMMYYGRSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- LFNQMUOLIMKYBH-VAWYXSNFSA-N (ne)-n-(1-benzylpyrrolidin-3-ylidene)hydroxylamine Chemical compound C1C(=N/O)/CCN1CC1=CC=CC=C1 LFNQMUOLIMKYBH-VAWYXSNFSA-N 0.000 description 2
- NBBRIIZFMWSCHJ-UHFFFAOYSA-N 1-benzylpyrrolidin-3-amine;dihydrochloride Chemical compound Cl.Cl.C1C(N)CCN1CC1=CC=CC=C1 NBBRIIZFMWSCHJ-UHFFFAOYSA-N 0.000 description 2
- DHGMDHQNUNRMIN-UHFFFAOYSA-N 1-benzylpyrrolidin-3-one Chemical compound C1C(=O)CCN1CC1=CC=CC=C1 DHGMDHQNUNRMIN-UHFFFAOYSA-N 0.000 description 2
- ASNHGEVAWNWCRQ-UHFFFAOYSA-N 4-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OCC1(O)COC(O)C1O ASNHGEVAWNWCRQ-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical compound NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- KQCMTOWTPBNWDB-UHFFFAOYSA-N 2,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C=C1Cl KQCMTOWTPBNWDB-UHFFFAOYSA-N 0.000 description 1
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- FWFGVMYFCODZRD-UHFFFAOYSA-N oxidanium;hydrogen sulfate Chemical compound O.OS(O)(=O)=O FWFGVMYFCODZRD-UHFFFAOYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
Abstract
高い化学純度の１−ベンジル−３−アミノピロリジンが高い収率で製造できる工業的に実用可能な精製方法を提供する。不純物が混入している化学純度の低い１−ベンジル−３−アミノピロリジンと酒石酸から塩を形成し、水と混和する有機溶媒と水の混合溶媒中で晶析して、高純度１−ベンジル−３−アミノピロリジンを製造する。Provided is an industrially practical purification method capable of producing high-purity 1-benzyl-3-aminopyrrolidine with high yield. A salt is formed from 1-benzyl-3-aminopyrrolidine and tartaric acid having a low chemical purity contaminated with impurities, and crystallized in a mixed solvent of water and an organic solvent miscible with water. 3-aminopyrrolidine is produced.
Description
本発明は、不純物が混入している化学純度の低い１−ベンジル−３−アミノピロリジンの精製方法に関する。 The present invention relates to a method for purifying 1-benzyl-3-aminopyrrolidine having low chemical purity and contaminating impurities.
従来、１−ベンジル−３−アミノピロリジンを精製する方法として、例えば低い光学純度の光学活性１−ベンジル−３−アミノピロリジンを非光学活性な酸の塩とし、溶媒中で晶析させて光学純度を向上させる方法（特許文献１）が知られている。また、ラセミ１−ベンジル−３−アミノピロリジンを光学分割して必要とする光学活性な１−ベンジル−３−アミノピロリジンの塩を取得する方法として、光学活性な酒石酸を用いる方法（特許文献２）や光学活性なアミノ酸誘導体を用いる方法（特許文献３）が知られている。しかし、不純物が混入した化学純度の低い１−ベンジル−３−アミノピロリジンから高い化学純度の１−ベンジル−３−アミノピロリジンを高い収率で製造するための精製方法は知られていない。 Conventionally, as a method for purifying 1-benzyl-3-aminopyrrolidine, for example, optically active 1-benzyl-3-aminopyrrolidine having a low optical purity is converted to a salt of a non-optically active acid and crystallized in a solvent to obtain an optical purity. There is known a method (Patent Document 1) for improving the above. Further, as a method for obtaining an optically active salt of 1-benzyl-3-aminopyrrolidine by optical resolution of racemic 1-benzyl-3-aminopyrrolidine, a method using optically active tartaric acid (Patent Document 2) And a method using an optically active amino acid derivative (Patent Document 3) is known. However, there is no known purification method for producing 1-benzyl-3-aminopyrrolidine having high chemical purity in high yield from 1-benzyl-3-aminopyrrolidine having low chemical purity contaminated with impurities.
１−ベンジル−３−アミノピロリジンは、医薬品の中間体として重要な光学活性１−ベンジル−３−アミノピロリジンを製造するための原料として有用である。また、１−ベンジル−３−アミノピロリジンを貴金属触媒下に接触還元して３−アミノピロリジンとし、次いで光学活性な酸を用いて光学分割して製造される医薬品の中間体として重要な光学活性３−アミノピロリジンを製造するための原料としても有用である。ここで、１−ベンジル−３−アミノピロリジンや３−アミノピロリジンを光学活性な酸を用いて光学分割して光学活性な１−ベンジル−３−アミノピロリジンや光学活性な３−アミノピロリジンを製造するに際して不純物が混入した原料を使用すると、目的とする光学活性体も化学純度が低いものしか得られず、また光学分割プロセスにおける収率低下の原因にもなる。また、１−ベンジル−３−アミノピロリジンを貴金属触媒の存在下に接触還元するに際して、不純物を多く含んだ純度の低い１−ベンジル−３−アミノピロリジンを使用すると、含まれる不純物が触媒を被毒して反応を阻害することもある。従って、医薬品の中間体として重要な光学活性１−ベンジル−３−アミノピロリジンや光学活性３−アミノピロリジン等をより安価に製造するために、高い収率で高い化学純度の１−ベンジル−３−アミノピロリジンを製造する方法の開発が望まれていた。
本発明の目的は、不純物が混入している化学純度の低いラセミ１−ベンジル−３−アミノピロリジンをはじめとする１−ベンジル−３−アミノピロリジンの（Ｒ）−体と（Ｓ）−体の混合物から、高い収率で高い化学純度の１−ベンジル−３−アミノピロリジンを製造することにある。 The object of the present invention is to provide (R)-and (S) -forms of 1-benzyl-3-aminopyrrolidine including low-purity racemic 1-benzyl-3-aminopyrrolidine contaminated with impurities. The objective is to produce 1-benzyl-3-aminopyrrolidine with high yield and high chemical purity from the mixture.
本発明者らは高い化学純度の１−ベンジル−３−アミノピロリジンの製造方法を鋭意検討した結果、ラセミ１−ベンジル−３−アミノピロリジンとラセミ酒石酸から塩を形成し、水と混和する有機溶媒と水の混合溶媒中で晶析することによって高い化学純度のラセミ１−ベンジル−３−アミノピロリジンが高い収率で製造でき、またこれを片方の光学異性体がもう一方の光学異性体よりも多くなった（Ｒ）−体と（Ｓ）-−体の混合物においても適用できることを見いだした。 As a result of intensive studies on a method for producing 1-benzyl-3-aminopyrrolidine having high chemical purity, the present inventors have formed an organic solvent that forms a salt from racemic 1-benzyl-3-aminopyrrolidine and racemic tartaric acid and is miscible with water. Highly pure racemic 1-benzyl-3-aminopyrrolidine can be produced in high yield by crystallization in a mixed solvent of water and water, and one optical isomer is more than the other optical isomer. It has been found that the present invention can be applied to a mixture of increased (R) -form and (S) -form.
すなわち、本発明は、不純物が混入している化学純度の低い式（１） That is, the present invention relates to the formula (1) having a low chemical purity in which impurities are mixed.
で表される（Ｒ）−１−ベンジル−３−アミノピロリジンと（Ｓ）−１−ベンジル−３−アミノピロリジンの混合物とＬ−酒石酸とＤ−酒石酸の混合物から塩を形成し、水と混和する有機溶媒と水の混合溶媒中で晶析することを特徴とする、高純度１−ベンジル−３−アミノピロリジンの製造方法である。 A salt is formed from a mixture of (R) -1-benzyl-3-aminopyrrolidine and (S) -1-benzyl-3-aminopyrrolidine, and a mixture of L-tartaric acid and D-tartaric acid, and is mixed with water. And crystallization in a mixed solvent of an organic solvent and water to produce high-purity 1-benzyl-3-aminopyrrolidine.
本発明によれば、工業的に実施可能な簡便な方法で、低い化学純度の１−ベンジル−３−アミノピロリジンから高い化学純度の１−ベンジル−３−アミノピロリジンが高い収率で取得できる。 According to the present invention, high chemical purity 1-benzyl-3-aminopyrrolidine can be obtained in high yield from low chemical purity 1-benzyl-3-aminopyrrolidine by a simple industrially feasible method.
本発明を具体的に述べる。 The present invention will be specifically described.
尚、本発明における「高い収率」とは収率が７０％以上のことであり、「高い化学純度」とは化学純度が９９．０％以上のことである。従って、「高い収率で高い化学純度の１−ベンジル−３−アミノピロリジンを製造する方法」とは化学純度が９９．０％以上の１−ベンジル−３−アミノピロリジンを原料に含まれる１−ベンジル−３−アミノピロリジンに対して７０％以上の収率で製造する方法のことである。 In the present invention, “high yield” means that the yield is 70% or more, and “high chemical purity” means that the chemical purity is 99.0% or more. Therefore, “a method for producing 1-benzyl-3-aminopyrrolidine having a high chemical purity with a high yield” means that 1-benzyl-3-aminopyrrolidine having a chemical purity of 99.0% or more is contained in the raw material. It is a method of producing with a yield of 70% or more based on benzyl-3-aminopyrrolidine.
本発明において使用できる原料の１−ベンジル−３−アミノピロリジンは、不斉点が存在しない物質を出発物質として立体選択的な反応条件を設定しないで合成されたラセミ１−ベンジル−３−アミノピロリジン、光学活性１−ベンジル−３−アミノピロリジンをラセミ化したラセミ１−ベンジル−３−アミノピロリジン、製造の過程において片方の光学異性体がもう一方の光学異性体よりも多くなった（Ｒ）−体と（Ｓ）−体の混合物等であり、その製造方法は特に限定されない。 The starting material 1-benzyl-3-aminopyrrolidine that can be used in the present invention is a racemic 1-benzyl-3-aminopyrrolidine synthesized without a stereoselective reaction condition using a substance having no asymmetric point as a starting material. Racemic 1-benzyl-3-aminopyrrolidine racemized from optically active 1-benzyl-3-aminopyrrolidine, one optical isomer in the production process was more than the other optical isomer (R)- It is a mixture of the body and the (S) -body, and its production method is not particularly limited.
本発明で用いる１−ベンジル−３−アミノピロリジンは、その製造方法により種々の不純物を含有している。例えば、ラセミ１−ベンジル−３−アミノピロリジンは、Ｊｏｕｒｎａｌ ｏｆ Ｃｈｅｍｉｃａｌ Ｅｎｇｉｎｅｅｒｉｎｇ ｏｆ Ｃｈｉｎｅｓｅ Ｕｎｉｖｅｒｓｉｔｉｅｓ Ｎｏ．４ Ｖｏｌ．１７ Ａｕｇ． ４３８−４４１（２００３）に記載の方法で製造することができる。 1-Benzyl-3-aminopyrrolidine used in the present invention contains various impurities depending on its production method. For example, racemic 1-benzyl-3-aminopyrrolidine is available from Journal of Chemical Engineering of China University Nos. 4 Vol. 17 Aug. 438-441 (2003).
上記において、Ｒ１、Ｒ２，Ｒ３はアルキル基を表し、好ましくは炭素数１〜４のアルキル基、さらに好ましくはメチル基、エチル基である。baseは塩基を表し、好ましくはナトリウムメトキシド、ナトリウムエトキシド、ナトリウムｔ−ブトキシド、カリウムメトキシド、カリウムエトキシド、カリウムｔ−ブトキシドであり、さらに好ましくはナトリウムメトキシド、ナトリウムエトキシドである。Acidは酸を表し、好ましくは鉱酸であり、さらに好ましくは塩酸である。
しかし、このような方法で製造したラセミ１−ベンジル−３−アミノピロリジンは、ベンジルアミンや式（２）In the above, R1, R2, and R3 represent an alkyl group, preferably an alkyl group having 1 to 4 carbon atoms, more preferably a methyl group or an ethyl group. base represents a base, preferably sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, and more preferably sodium methoxide or sodium ethoxide. Acid represents an acid, preferably a mineral acid, and more preferably hydrochloric acid.
However, racemic 1-benzyl-3-aminopyrrolidine produced by such a method is benzylamine or the formula (2)
で表される４−アミノ−１−ベンジルピペリジン等の不純物を多く含んでいるためその化学純度は低い。このような不純物はその性質がラセミ１−ベンジル−３−アミノピロリジンと類似しているために除去が難しく、低い化学純度のラセミ１−ベンジル−３−アミノピロリジンから高い化学純度のラセミ１−ベンジル−３−アミノピロリジンを得ようとすると、不純物を除去するための操作において高い精製収率は達成できない。従って、高い化学純度のラセミ１−ベンジル−３−アミノピロリジンを高い収率で取得する精製方法を開発する必要があった。 The chemical purity is low because it contains a large amount of impurities such as 4-amino-1-benzylpiperidine. Such impurities are difficult to remove because their properties are similar to racemic 1-benzyl-3-aminopyrrolidine, and low chemical purity of racemic 1-benzyl-3-aminopyrrolidine to high chemical purity of racemic 1-benzyl. When trying to obtain -3-aminopyrrolidine, a high purification yield cannot be achieved in the operation for removing impurities. Therefore, it was necessary to develop a purification method for obtaining high-purity racemic 1-benzyl-3-aminopyrrolidine in high yield.
本発明者らは、化学純度の低い１−ベンジル−３−アミノピロリジンの精製方法を鋭意検討した結果、１−ベンジル−３−アミノピロリジンと酒石酸から塩を形成し、水と混和する有機溶媒と水の混合溶媒中で晶析する方法を開発するに至った。本発明によれば、高い化学純度の１−ベンジル−３−アミノピロリジンと酒石酸の塩が３水和物として取得できるので、一般的な方法で処理することによって高い化学純度の１−ベンジル−３−アミノピロリジンを製造することができる。 As a result of intensive studies on a method for purifying 1-benzyl-3-aminopyrrolidine having a low chemical purity, the present inventors have formed an organic solvent that forms a salt from 1-benzyl-3-aminopyrrolidine and tartaric acid and is miscible with water. A method for crystallization in a mixed solvent of water has been developed. According to the present invention, since a salt of 1-benzyl-3-aminopyrrolidine and tartaric acid having a high chemical purity can be obtained as a trihydrate, 1-benzyl-3 having a high chemical purity can be obtained by treatment by a general method. -Aminopyrrolidine can be produced.
本発明で使用する酒石酸としては一般に市販されているラセミ酒石酸や市販のＬ−酒石酸とＤ−酒石酸を混合したものを使用することができる。その使用量は、収率良く高純度１−ベンジル−３−アミノピロリジンを得るという観点から、原料中に含まれる１−ベンジル−３−アミノピロリジンに対して０．９５〜１．１５倍モルが好ましい。原料の１−ベンジル−３−アミノピロリジンに含まれる塩基性の不純物が多い場合には、それら不純物を中和する分の酒石酸を増量することで高い精製収率が達成できる。例えば、ラセミ１−ベンジル−３−アミノピロリジンを原料として使用する場合には、１−ベンジル−３−アミノピロリジンに対して０．９５〜１．１５倍モルのラセミ酒石酸が存在する系で晶析することによって高い精製収率が達成できる。また、その製造の過程において片方の光学異性体がもう一方の光学異性体よりも多くなった１−ベンジル−３−アミノピロリジンを原料として使用する場合には、そこに含まれる（Ｒ）−１−ベンジル−３−アミノピロリジンに対して０．９５〜１．１５倍モルのＤ−酒石酸と（Ｓ）−１−ベンジル−３−アミノピロリジンに対して０．９５〜１．１５倍モルのＬ−酒石酸が存在する系で晶析することによって高い精製収率が達成できる。 As tartaric acid used in the present invention, commercially available racemic tartaric acid or a mixture of commercially available L-tartaric acid and D-tartaric acid can be used. From the viewpoint of obtaining high-purity 1-benzyl-3-aminopyrrolidine with high yield, the amount used is 0.95 to 1.15 times mol with respect to 1-benzyl-3-aminopyrrolidine contained in the raw material. preferable. When there are many basic impurities contained in the raw material 1-benzyl-3-aminopyrrolidine, a high purification yield can be achieved by increasing the amount of tartaric acid to neutralize these impurities. For example, when racemic 1-benzyl-3-aminopyrrolidine is used as a raw material, crystallization is performed in a system in which 0.95 to 1.15 times moles of racemic tartaric acid are present relative to 1-benzyl-3-aminopyrrolidine. By doing so, a high purification yield can be achieved. Further, when 1-benzyl-3-aminopyrrolidine in which one optical isomer is larger than the other optical isomer in the production process is used as a raw material, (R) -1 is included therein. 0.95-1.15 moles of D-tartaric acid with respect to benzyl-3-aminopyrrolidine and 0.95-1.15 moles of L with respect to (S) -1-benzyl-3-aminopyrrolidine A high purification yield can be achieved by crystallization in a system in which tartaric acid is present.
本発明で使用する水と混和する有機溶媒は、特に限定されないが、メタノール、エタノール、ｎ−プロパノール、２−プロパノール、テトラヒドロフラン、アセトニトリル、アセトン、および／または、これらから選ばれる一種または二種以上の混合液が好ましく使用することができる。その使用量は、精製収率や生産性等を考えた場合に、原料のラセミ１−ベンジル−３−アミノピロリジンに対して０．８〜３．５重量倍が好ましい。 The organic solvent miscible with water used in the present invention is not particularly limited, but is methanol, ethanol, n-propanol, 2-propanol, tetrahydrofuran, acetonitrile, acetone, and / or one or more selected from these. A mixed solution can be preferably used. The amount used is preferably 0.8 to 3.5 times the weight of the raw material racemic 1-benzyl-3-aminopyrrolidine in view of purification yield, productivity and the like.
本発明では水の存在は不可欠である。本発明に従って晶析をおこなうと、水と混和する有機溶媒と水の混合溶媒への溶解度が小さい（Ｒ）−１−ベンジル−３−アミノピロリジンとＤ−酒石酸の塩の３水和物と（Ｓ）−１−ベンジル−３−アミノピロリジンとＬ−酒石酸の塩の３水和物が析出する。一方、（Ｒ）−１−ベンジル−３−アミノピロリジンとＬ−酒石酸の塩や（Ｓ）−１−ベンジル−３−アミノピロリジンとＤ−酒石酸の塩は水和物を形成せず、水と混和する有機溶媒と水の混合溶媒への溶解度が高いために析出し難い。本発明で使用する水の量は、上記３水和物が効率よく生成するという観点から原料に含まれる１−ベンジル−３−アミノピロリジンに対して好ましくは８倍モル以上であり、更に好ましくは９倍モル以上である。これより少ないと、１−ベンジル−３−アミノピロリジンと酒石酸の塩の３水和物が析出しにくくなり、大幅に収率が低下するので好ましくない。使用量の上限は特に限定されないが、精製収率や生産性等を考えた場合に、原料の１−ベンジル−３−アミノピロリジンに対して３重量倍程度である。 In the present invention, the presence of water is essential. When crystallization is carried out according to the present invention, a trihydrate of (R) -1-benzyl-3-aminopyrrolidine and D-tartaric acid salt, which has low solubility in a mixed solvent of water and an organic solvent miscible with water, S) -1-Benzyl-3-aminopyrrolidine and L-tartaric acid salt trihydrate are precipitated. On the other hand, the salt of (R) -1-benzyl-3-aminopyrrolidine and L-tartaric acid or the salt of (S) -1-benzyl-3-aminopyrrolidine and D-tartaric acid does not form a hydrate, Precipitation is difficult due to the high solubility of the organic solvent and water in the mixed solvent. The amount of water used in the present invention is preferably 8 times mol or more with respect to 1-benzyl-3-aminopyrrolidine contained in the raw material from the viewpoint of efficiently producing the trihydrate, and more preferably It is 9 times mole or more. If it is less than this, the trihydrate of 1-benzyl-3-aminopyrrolidine and a tartaric acid salt is difficult to precipitate, which is not preferable because the yield is greatly reduced. The upper limit of the amount used is not particularly limited, but is about 3 times the weight of the raw material 1-benzyl-3-aminopyrrolidine in view of purification yield, productivity and the like.
本発明においては、１−ベンジル−３−アミノピロリジンの（Ｒ）−体と（Ｓ）−体の混合物と酒石酸のＤ−体とＬ−体の混合物を用いて上記混合溶媒中で塩の水和物を形成させることにより、混合溶媒中で析出しやすい（Ｒ）−１−ベンジル−３−アミノピロリジンとＤ−酒石酸の塩の３水和物と（Ｓ）−１−ベンジル−３−アミノピロリジンとＬ−酒石酸の塩の３水和物が析出していくため、平衡状態にいたることなく高収率で高化学純度化することができるのである。 In the present invention, salt water is used in the above mixed solvent using a mixture of (R)-and (S) -forms of 1-benzyl-3-aminopyrrolidine and a mixture of D-form and L-form of tartaric acid. (R) -1-benzyl-3-aminopyrrolidine and D-tartaric acid salt trihydrate and (S) -1-benzyl-3-amino which are easily precipitated in a mixed solvent by forming a solvate Since the trihydrate of the salt of pyrrolidine and L-tartaric acid precipitates, it can be highly purified with high yield without reaching an equilibrium state.
１−ベンジル−３−アミノピロリジンと酒石酸の塩を形成する方法や形成された塩を水と混和する有機溶媒と水の混合溶媒中から析出させる方法としては特に限定されないが、例えば水、水と混合する有機溶媒、ラセミ酒石酸、１−ベンジル−３−アミノピロリジンの順に晶析装置に仕込み、混合物を加熱して均一溶液としたのち、適当な温度で種晶（（Ｒ）−１−ベンジル−３−アミノピロリジン・Ｄ−酒石酸塩の３水和物と（Ｓ）−１−ベンジル−３−アミノピロリジン・Ｌ−酒石酸塩の３水和物）を加えてから冷却する方法が採用できる。種晶を加える時機は、水と混和する有機溶媒と水の混合比率やその使用量によって異なるが、おおよそ２０〜４０℃の範囲である。析出した結晶を濾別する温度は特に限定されないが、高い収率で塩を得るためにはその温度は低い方が好ましく、通常は０〜２０℃である。 The method for forming a salt of 1-benzyl-3-aminopyrrolidine and tartaric acid and the method for precipitating the formed salt from a mixed solvent of water and an organic solvent miscible with water are not particularly limited. The organic solvent to be mixed, racemic tartaric acid, and 1-benzyl-3-aminopyrrolidine were charged in this order in the crystallizer, and the mixture was heated to obtain a homogeneous solution, and then seed crystals ((R) -1-benzyl- A method of cooling after adding 3-aminopyrrolidine · D-tartrate trihydrate and (S) -1-benzyl-3-aminopyrrolidine · L-tartrate trihydrate) can be employed. The timing for adding the seed crystal varies depending on the mixing ratio of the organic solvent and water mixed with water and the amount of the water used, but is in the range of about 20 to 40 ° C. The temperature at which the precipitated crystals are separated by filtration is not particularly limited, but in order to obtain a salt with a high yield, the temperature is preferably low and is usually 0 to 20 ° C.
かくして得られた１−ベンジル−３−アミノピロリジンと酒石酸の塩の３水和物から１−ベンジル−３−アミノピロリジンの単離は、一般的な方法に従って実施できる。例えば、塩を水とトルエン中で撹拌しながら水酸化ナトリウムの水溶液を添加して塩基性とし、分液して得たトルエン層を濃縮することによって１−ベンジル−３−アミノピロリジが取得できる。 Isolation of 1-benzyl-3-aminopyrrolidine from the trihydrate of 1-benzyl-3-aminopyrrolidine and tartaric acid thus obtained can be carried out according to a general method. For example, 1-benzyl-3-aminopyrrolidi can be obtained by adding a sodium hydroxide aqueous solution while stirring the salt in water and toluene to make it basic, and concentrating the toluene layer obtained by liquid separation.
以下、実施例により本発明を更に詳細に説明するが、本発明はこれらに限定されるものではない。尚、以下の実施例や比較例における１−ベンジル−３−アミノピロリジンの含有率は高速液体クロマトグラフィーを用いて決定し、化学純度はガスクロマトグラフィーを用いて決定した。
＜１−ベンジル−３−アミノピロリジンの含有率（ＨＰＬＣ）＞
カラム：Ｍｉｇｈｔｙｓｉｌ ＲＰ−１８ＧＰ（関東化学）４．６ｍｍφ×１５０ｍｍ
移動相：２．５ｍＭ ドデシル硫酸ナトリウム水溶液（ｐＨ２．２、リン酸使用）６３０ｍｌとアセトニトリル３７０ｍｌの混合液
カラムオーブン温度：４０℃
検出器：ＵＶ ２０５ｎｍ
内部標準物質：２，４−ジクロロアニリン
＜１−ベンジル−３−アミノピロリジンの化学純度（ＧＣ）＞
カラム：ＮＥＵＴＲＡ ＢＯＮＤ−１（ジーエルサイエンス）０．２５ｍｍＩ．Ｄ．×６０ｍ、０．４μｍ
カラムオーブン温度：７０℃（１５分）−２０℃／分→２７０℃（２０分）
注入口：２００℃
検出器：２００℃
キャリヤーガス：ヘリウム 全流量５２ｍｌ／分
スプリット比：１９
参考例
撹拌機、温度計を装着した容量１Ｌのフラスコに、ベンジルアミン５３．６ｇ（０．５０モル）とメタノール２６．８ｇを仕込んだ。撹拌しながら、この混合液にアクリル酸メチル４３．１ｇ（０．５０モル）を２時間かけて添加した。このとき反応液の温度を約５０℃に保った。添加終了後、更に同温度で２時間撹拌を続けた。この反応液にトリエチルアミン６４．０ｇ（０．６３モル）を添加したのち、クロロ酢酸メチル６８．６ｇ（０．６３モル）を２時間かけて添加した。添加終了後、約７０℃加熱して４時間撹拌を続けた。この反応液を室温まで冷却し、トルエン２１６ｇと水１３０ｇを加えて撹拌した。靜置後、水層を抜き出し、残ったトルエン層を減圧下に濃縮して濃縮液１７８ｇを得た。この濃縮液にメタノール７３ｇを加えて希釈し、２０から２５℃で２８％ナトリウムメトキシドのメタノール溶液１２２．７ｇ（０．６４モル）を３時間かけて仕込み、更に同温度で３時間撹拌を続けた。EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these. In the following Examples and Comparative Examples, the content of 1-benzyl-3-aminopyrrolidine was determined using high performance liquid chromatography, and the chemical purity was determined using gas chromatography.
<Content of 1-benzyl-3-aminopyrrolidine (HPLC)>
Column: Mightysil RP-18GP (Kanto Chemical) 4.6 mmφ × 150 mm
Mobile phase: 2.5 mM sodium dodecyl sulfate aqueous solution (pH 2.2, using phosphoric acid) 630 ml and acetonitrile 370 ml mixed liquid Column oven temperature: 40 ° C.
Detector: UV 205nm
Internal standard substance: 2,4-dichloroaniline <chemical purity of 1-benzyl-3-aminopyrrolidine (GC)>
Column: NEUTRA BOND-1 (GL Science) 0.25 mmI. D. × 60m, 0.4μm
Column oven temperature: 70 ° C. (15 minutes) −20 ° C./minute→270° C. (20 minutes)
Inlet: 200 ° C
Detector: 200 ° C
Carrier gas: Helium Total flow rate 52 ml / min Split ratio: 19
Reference Example 53.6 g (0.50 mol) of benzylamine and 26.8 g of methanol were charged into a 1 L flask equipped with a stirrer and a thermometer. While stirring, 43.1 g (0.50 mol) of methyl acrylate was added to the mixed solution over 2 hours. At this time, the temperature of the reaction solution was kept at about 50 ° C. After completion of the addition, stirring was further continued at the same temperature for 2 hours. After adding 64.0 g (0.63 mol) of triethylamine to the reaction solution, 68.6 g (0.63 mol) of methyl chloroacetate was added over 2 hours. After completion of the addition, the mixture was heated at about 70 ° C. and stirred for 4 hours. The reaction solution was cooled to room temperature, and 216 g of toluene and 130 g of water were added and stirred. After laying, the aqueous layer was extracted, and the remaining toluene layer was concentrated under reduced pressure to obtain 178 g of a concentrated solution. This concentrated liquid was diluted with 73 g of methanol, charged with 122.7 g (0.64 mol) of 28% sodium methoxide in methanol at 20 to 25 ° C. over 3 hours, and further stirred at the same temperature for 3 hours. It was.
この反応液に水１６７ｇと３５％塩酸１６７ｇ（１．６モル）の混合液を約１時間かけて加え、約７５℃で７時間撹拌した。反応液を減圧下に濃縮して、４７９ｇの濃縮液を得た。２０から４０℃で、ｐＨが約１２になるまで４８％水酸化ナトリウム水溶液を加えた。トルエン１１８ｇを加えて撹拌したのち、水層を抜き出した。残ったトルエン層を減圧下に濃縮して濃縮液１１０ｇを得た。濃縮液中には１−ベンジル−３−ピロリジノンが５８．２％含まれていた。 A mixed solution of 167 g of water and 167 g (1.6 mol) of 35% hydrochloric acid was added to this reaction solution over about 1 hour, and the mixture was stirred at about 75 ° C. for 7 hours. The reaction solution was concentrated under reduced pressure to obtain 479 g of a concentrated solution. At 20-40 ° C., 48% aqueous sodium hydroxide was added until the pH was about 12. 118 g of toluene was added and stirred, and then the aqueous layer was extracted. The remaining toluene layer was concentrated under reduced pressure to obtain a concentrated solution 110 g. The concentrate contained 58.2% of 1-benzyl-3-pyrrolidinone.
撹拌機、温度計を装着した容量５００ｍｌのフラスコに、水２２０ｇ、硫酸ヒドロキシルアミン３１．４ｇを仕込んだ。この溶液を約２５℃に保ちながら、１−ベンジル−３−ピロリジノンを含む濃縮液を１時間かけて添加した。靜置したのちに分液してトルエン層を除いた。残った水層に、ｐＨが約１２になるまで４８％水酸化ナトリウム水溶液を約２時間かけて添加した。このとき内液の温度を約２５℃に保った。析出した結晶を濾別して、１０４．８ｇのウェットケークを得た。ウェットケークには１−ベンジル−３−ピロリジノンオキシムが５５．７％含まれていた。 A 500 ml flask equipped with a stirrer and a thermometer was charged with 220 g of water and 31.4 g of hydroxylamine sulfate. While maintaining this solution at about 25 ° C., a concentrated solution containing 1-benzyl-3-pyrrolidinone was added over 1 hour. After placing the solution, the solution was separated to remove the toluene layer. A 48% sodium hydroxide aqueous solution was added to the remaining aqueous layer over about 2 hours until the pH reached about 12. At this time, the temperature of the internal liquid was kept at about 25 ° C. The precipitated crystals were separated by filtration to obtain 104.8 g of wet cake. The wet cake contained 55.7% 1-benzyl-3-pyrrolidinone oxime.
容量１Ｌのオートクレーブに１−ベンジル−３−ピロリジノンオキシムを含むウェットケーク全量、メタノール２３５ｇ、２８％アンモニア水５４ｇ、およびラネーニッケル触媒１５ｇを仕込んだ。水素ガスで約０．５ＭＰａに加圧しながら、約５０℃で２時間撹拌した。反応終了後、触媒を濾別し、濾過液を減圧下に濃縮して濃縮液５７．０ｇを得た。濃縮液には１−ベンジル−３−アミノピロリジンが８４．４％含まれていた。１−ベンジル−３−アミノピロリジンの収率は出発原料であるベンジルアミンに対して５４．６モル％であった。濃縮液をガスクロマトグラフィーで分析したところ、その組成は、１−ベンジル−３−アミノピロリジン９４．７％、ベンジルアミン０．６％、その他４．７％であった。濃縮液を１規定塩酸で中和滴定したところ、その中に含まれる塩基性の成分は、１０．０ｍｅｑ．／ｇであった。 A 1 L autoclave was charged with a total amount of wet cake containing 1-benzyl-3-pyrrolidinone oxime, 235 g of methanol, 54 g of 28% aqueous ammonia, and 15 g of Raney nickel catalyst. The mixture was stirred at about 50 ° C. for 2 hours while being pressurized to about 0.5 MPa with hydrogen gas. After completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain 57.0 g of a concentrated solution. The concentrate contained 84.4% of 1-benzyl-3-aminopyrrolidine. The yield of 1-benzyl-3-aminopyrrolidine was 54.6 mol% based on the starting material benzylamine. When the concentrate was analyzed by gas chromatography, the composition was 94.7% 1-benzyl-3-aminopyrrolidine, 0.6% benzylamine, and 4.7% other. The concentrated solution was neutralized and titrated with 1N hydrochloric acid, and the basic component contained therein was 10.0 meq. / G.
実施例１
撹拌機、温度計を装着した容量３００ｍｌのフラスコに、参考例で取得したラセミ１−ベンジル−３−アミノピロリジンを含む濃縮液３９．９ｇ、エタノール４２ｇ、水４２ｇ、およびＤＬ−酒石酸３０．０ｇを仕込んだ。撹拌しながら、約５５℃に加熱して固形物を溶解したのち、約３３℃まで冷却した。そこに（Ｒ）−１−ベンジル−３−アミノピロリジンとＤ−酒石酸の塩の３水和物と（Ｓ）−１−ベンジル−３−アミノピロリジンとＬ−酒石酸の塩の３水和物の混合物（以下、種晶と略称する）を約０．１ｇ添加し、３０〜３５℃に保って１時間撹拌した。次いで、２時間かけて約３℃まで冷却し、更に０〜５℃で２時間撹拌を続けた。スラリーを、遠心濾過器を使用して濾過し、ケークに５０％エタノール水溶液２５ｇを噴霧して洗浄した。ケークを取り出し、真空乾燥して１−ベンジル−３−アミノピロリジンと酒石酸の塩６８．７ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は４６．６％であり、晶析収率は９５％であった。また、塩の中の水分は１４．３％であった。この塩の全量に水７４ｇとトルエン７４ｇを加え、撹拌しながらｐＨが約１２になるまで４８％水酸化ナトリウム水溶液を加えた。分液して得たトルエン層を約８０℃に加熱し、圧力が約１．３ｋＰａでトルエンが留出しなくなるまで濃縮した。濃縮液量は３１．４ｇであった。ガスクロマトグラフィーで分析したところ、その組成は、１−ベンジル−３−アミノピロリジン９９．１％、トルエン０．９％、その他０．１％であった。Example 1
In a 300 ml flask equipped with a stirrer and a thermometer, 39.9 g of the concentrated solution containing racemic 1-benzyl-3-aminopyrrolidine obtained in Reference Example, 42 g of ethanol, 42 g of water, and 30.0 g of DL-tartaric acid were added. Prepared. While stirring, the mixture was heated to about 55 ° C. to dissolve the solid, and then cooled to about 33 ° C. (R) -1-benzyl-3-aminopyrrolidine and D-tartaric acid salt trihydrate and (S) -1-benzyl-3-aminopyrrolidine and L-tartaric acid salt trihydrate About 0.1 g of a mixture (hereinafter abbreviated as seed crystal) was added, and the mixture was stirred for 1 hour while maintaining the temperature at 30 to 35 ° C. Subsequently, the mixture was cooled to about 3 ° C. over 2 hours, and further stirred at 0 to 5 ° C. for 2 hours. The slurry was filtered using a centrifugal filter, and the cake was washed by spraying 25 g of 50% aqueous ethanol. The cake was taken out and vacuum-dried to obtain 68.7 g of 1-benzyl-3-aminopyrrolidine and tartaric acid salt. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 46.6%, and the crystallization yield was 95%. The water content in the salt was 14.3%. 74 g of water and 74 g of toluene were added to the total amount of this salt, and a 48% aqueous sodium hydroxide solution was added until the pH reached about 12 while stirring. The toluene layer obtained by the liquid separation was heated to about 80 ° C., and concentrated until the toluene was not distilled at a pressure of about 1.3 kPa. The amount of the concentrated liquid was 31.4 g. As a result of analysis by gas chromatography, the composition was 99.1% 1-benzyl-3-aminopyrrolidine, 0.9% toluene, and 0.1% other.
実施例２
市販の、１−ベンジル−３−アミノピロリジンの含有率が８７．６％であり、ガスクロマトグラフィーで分析した組成が、１−ベンジル−３−アミノピロリジン９１．８％、ベンジルアミン２．３％、４−アミノ−１−ベンジルピペリジン３．８％、その他成分２．１％である純度の低いラセミ１−ベンジル−３−アミノピロリジン３．９ｇ、メタノール１３．４ｇ、水２．８ｇ、およびＤＬ−酒石酸３．１ｇを仕込んだ。撹拌しながら、約５５℃に加熱して固形物を溶解したのち、約３０℃まで冷却した。そこに種晶を約２０ｍｇ添加し、２０〜３０℃に保って１時間撹拌した。次いで、３０分かけて約３℃まで冷却し、更に０〜５℃で２時間撹拌を続けた。スラリーを濾過し、ケークに５０％メタノール水溶液５ｍｌを振りかけて洗浄した。ケークを取り出し、真空乾燥して１−ベンジル−３−アミノピロリジンと酒石酸の塩５．８ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は４６．８％であり、晶析収率は７９％であった。また、水分は１３．３％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析したところ、トルエンを除いて計算した１−ベンジル−３−アミノピロリジンの化学純度は９９．８％であった。Example 2
The commercially available 1-benzyl-3-aminopyrrolidine content was 87.6%, and the composition analyzed by gas chromatography was 91.8% 1-benzyl-3-aminopyrrolidine, 2.3% benzylamine. 4-amino-1-benzylpiperidine 3.8%, other components 2.1% low purity racemic 1-benzyl-3-aminopyrrolidine 3.9 g, methanol 13.4 g, water 2.8 g, and DL -3.1 g of tartaric acid was charged. While stirring, the mixture was heated to about 55 ° C. to dissolve the solid, and then cooled to about 30 ° C. About 20 mg of seed crystals were added thereto, and the mixture was stirred for 1 hour while maintaining the temperature at 20 to 30 ° C. Subsequently, it cooled to about 3 degreeC over 30 minutes, and also continued stirring at 0-5 degreeC for 2 hours. The slurry was filtered, and the cake was washed with 5 ml of 50% aqueous methanol solution. The cake was taken out and vacuum-dried to obtain 5.8 g of 1-benzyl-3-aminopyrrolidine and tartaric acid salt. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 46.8%, and the crystallization yield was 79%. Moreover, the water | moisture content was 13.3%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. When the toluene layer was analyzed by gas chromatography, the chemical purity of 1-benzyl-3-aminopyrrolidine calculated by removing toluene was 99.8%.
実施例３
水の使用量を３．２ｇに変えた以外は実施例２と同じ操作をおこなって、１−ベンジル−３−アミノピロリジンと酒石酸の塩６．０ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は４６．６％であり、晶析収率は８２％であった。また、水分は１３．７％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析したところ、トルエンを除いて計算した１−ベンジル−３−アミノピロリジンの化学純度は９９．７％であった。Example 3
The same operation as in Example 2 was carried out except that the amount of water used was changed to 3.2 g to obtain 6.0 g of a salt of 1-benzyl-3-aminopyrrolidine and tartaric acid. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 46.6%, and the crystallization yield was 82%. The water content was 13.7%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. When the toluene layer was analyzed by gas chromatography, the chemical purity of 1-benzyl-3-aminopyrrolidine calculated by removing toluene was 99.7%.
実施例４
メタノールの使用量を１１．４ｇ、水の使用量を４．１ｇに変えた以外は実施例２と同じ操作をおこなって、１−ベンジル−３−アミノピロリジンと酒石酸の塩６．４ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は４６．３％であり、晶析収率は８７％であった。また、水分は１４．２％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析したところ、トルエンを除いて計算した１−ベンジル−３−アミノピロリジンの化学純度は９９．８％であった。Example 4
The same operation as in Example 2 was performed except that the amount of methanol used was changed to 11.4 g and the amount of water used was changed to 4.1 g to obtain 6.4 g of a salt of 1-benzyl-3-aminopyrrolidine and tartaric acid. . The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 46.3%, and the crystallization yield was 87%. Moreover, the water | moisture content was 14.2%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. When the toluene layer was analyzed by gas chromatography, the chemical purity of 1-benzyl-3-aminopyrrolidine calculated by removing toluene was 99.8%.
実施例５
市販の、１−ベンジル−３−アミノピロリジンの含有率が８７．６％であり、ガスクロマトグラフィーで分析した組成が、１−ベンジル−３−アミノピロリジン９１．８％、ベンジルアミン２．３％、４−アミノ−１−ベンジルピペリジン３．８％、その他成分２．１％である純度の低いラセミ１−ベンジル−３−アミノピロリジン３．９ｇ、メタノール７．２ｇ、水８．４ｇ、およびＤＬ−酒石酸３．１ｇを仕込んだ。撹拌しながら、約５５℃に加熱して固形物を溶解したのち、約３０℃まで冷却した。そこに種晶を約２０ｍｇ添加し、２０〜３０℃に保って１時間撹拌した。次いで、３０分かけて約３℃まで冷却し、更に０〜５℃で２時間撹拌を続けた。スラリーを濾過し、ケークに５０％メタノール水溶液５ｍｌを振りかけて洗浄した。ケークを取り出し、真空乾燥して１−ベンジル−３−アミノピロリジンと酒石酸の塩６．３ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は４６．７％であり、晶析収率は８６％であった。また、水分は１３．６％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析したところ、トルエンを除いて計算した１−ベンジル−３−アミノピロリジンの化学純度は９９．６％であった。Example 5
The commercially available 1-benzyl-3-aminopyrrolidine content was 87.6%, and the composition analyzed by gas chromatography was 91.8% 1-benzyl-3-aminopyrrolidine, 2.3% benzylamine. 4-amino-1-benzylpiperidine 3.8%, other components 2.1% low purity racemic 1-benzyl-3-aminopyrrolidine 3.9 g, methanol 7.2 g, water 8.4 g, and DL -3.1 g of tartaric acid was charged. While stirring, the mixture was heated to about 55 ° C. to dissolve the solid, and then cooled to about 30 ° C. About 20 mg of seed crystals were added thereto, and the mixture was stirred for 1 hour while maintaining the temperature at 20 to 30 ° C. Subsequently, it cooled to about 3 degreeC over 30 minutes, and also continued stirring at 0-5 degreeC for 2 hours. The slurry was filtered, and the cake was washed with 5 ml of 50% aqueous methanol solution. The cake was taken out and vacuum-dried to obtain 6.3 g of 1-benzyl-3-aminopyrrolidine and tartaric acid salt. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 46.7%, and the crystallization yield was 86%. The water content was 13.6%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. When the toluene layer was analyzed by gas chromatography, the chemical purity of 1-benzyl-3-aminopyrrolidine calculated by removing toluene was 99.6%.
実施例６
メタノールの使用量を４．４ｇ、水使用量を１１．１ｇに変えた以外は実施例２と同じ操作をおこなって、１−ベンジル−３−アミノピロリジンと酒石酸の塩６．２ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は４６．７％であり、晶析収率は８５％であった。また、水分は１３．５％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析したところ、トルエンを除いて計算した１−ベンジル−３−アミノピロリジンの化学純度は９９．９％であった。Example 6
The same operation as in Example 2 was carried out except that the amount of methanol used was changed to 4.4 g and the amount of water used was changed to 11.1 g to obtain 6.2 g of 1-benzyl-3-aminopyrrolidine and tartaric acid salt. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 46.7%, and the crystallization yield was 85%. The water content was 13.5%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. When the toluene layer was analyzed by gas chromatography, the chemical purity of 1-benzyl-3-aminopyrrolidine calculated by removing toluene was 99.9%.
実施例７
ＤＬ−酒石酸の使用量を２．８ｇに変えた以外は実施例５と同じ操作をおこなって、１−ベンジル−３−アミノピロリジンと酒石酸の塩５．２ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は４７．２％であり、晶析収率は７１％であった。また、水分は１２．５％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析したところ、トルエンを除いて計算した１−ベンジル−３−アミノピロリジンの化学純度は９９．６％であった。Example 7
Except having changed the usage-amount of DL-tartaric acid into 2.8g, the same operation as Example 5 was performed and the salt of 1-benzyl-3-aminopyrrolidine and tartaric acid was obtained. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 47.2%, and the crystallization yield was 71%. The water content was 12.5%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. When the toluene layer was analyzed by gas chromatography, the chemical purity of 1-benzyl-3-aminopyrrolidine calculated by removing toluene was 99.6%.
実施例８
ＤＬ−酒石酸の使用量を３．４ｇに変えた以外は実施例５と同じ操作をおこなって、１−ベンジル−３−アミノピロリジンと酒石酸の塩６．３ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は４７．１％であり、晶析収率は８７％であった。また、水分は１２．７％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析したところ、トルエンを除いて計算した１−ベンジル−３−アミノピロリジンの化学純度は９９．９％であった。Example 8
The same operation as in Example 5 was carried out except that the amount of DL-tartaric acid was changed to 3.4 g to obtain 6.3 g of a salt of 1-benzyl-3-aminopyrrolidine and tartaric acid. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 47.1%, and the crystallization yield was 87%. The water content was 12.7%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. When the toluene layer was analyzed by gas chromatography, the chemical purity of 1-benzyl-3-aminopyrrolidine calculated by removing toluene was 99.9%.
実施例９
メタノールをアセトンに変えた以外は実施例５と同じ操作をおこなって、１−ベンジル−３−アミノピロリジンと酒石酸の塩６．６ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は４６．５％であり、晶析収率は８９％であった。また、水分は１３．７％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析したところ、トルエンを除いて計算した１−ベンジル−３−アミノピロリジンの化学純度は９９．８％であった。Example 9
The same operation as in Example 5 was carried out except that methanol was changed to acetone to obtain 6.6 g of a salt of 1-benzyl-3-aminopyrrolidine and tartaric acid. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 46.5%, and the crystallization yield was 89%. The water content was 13.7%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. When the toluene layer was analyzed by gas chromatography, the chemical purity of 1-benzyl-3-aminopyrrolidine calculated by removing toluene was 99.8%.
実施例１０
メタノールをアセトニトリルに変えた以外は実施例５と同じ操作をおこなって、１−ベンジル−３−アミノピロリジンと酒石酸の塩６．１ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は４６．７％であり、晶析収率は８３％であった。また、水分は１３．７％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析したところ、トルエンを除いて計算した１−ベンジル−３−アミノピロリジンの化学純度は９９．９％であった。Example 10
Except for changing methanol to acetonitrile, the same operation as in Example 5 was performed to obtain 6.1 g of 1-benzyl-3-aminopyrrolidine and a tartaric acid salt. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 46.7%, and the crystallization yield was 83%. The water content was 13.7%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. When the toluene layer was analyzed by gas chromatography, the chemical purity of 1-benzyl-3-aminopyrrolidine calculated by removing toluene was 99.9%.
実施例１１
メタノールをテトラヒドロフランに変えた以外は実施例５と同じ操作をおこなって、１−ベンジル−３−アミノピロリジンと酒石酸の塩６．４ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は４６．８％であり、晶析収率は８８％であった。また、水分は１３．８％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析したところ、トルエンを除いて計算した１−ベンジル−３−アミノピロリジンの化学純度は９９．９％であった。
実施例１２
市販の、光学純度が９９．０％ｅ．ｅ．以上、化学純度が９９．０％以上、１−ベンジル−３−アミノピロリジンの含有率が９９．４％の光学活性（Ｒ）−１−ベンジル−３−アミノピロリジン１．０ｇ、市販の１−ベンジル−３−アミノピロリジンの含有率が８７．６％であり、ガスクロマトグラフィーで分析した組成が、１−ベンジル−３−アミノピロリジン９１．８％、ベンジルアミン２．３％、４−アミノ−１−ベンジルピペリジン３．８％、その他成分２．１％である純度の低いラセミ１−ベンジル−３−アミノピロリジン２．８ｇ、メタノール１１．４ｇ、水４．１ｇ、ＤＬ−酒石酸２．２ｇ、およびＤ−酒石酸０．８ｇを仕込んだ。撹拌しながら、約５５℃に加熱して固形物を溶解したのち、約３０℃まで冷却した。そこに種晶を約２０ｍｇ添加し、２０〜３０℃に保って１時間撹拌した。次いで、３０分かけて約３℃まで冷却し、更に０〜５℃で２時間撹拌を続けた。スラリーを濾過し、ケークに５０％メタノール水溶液５ｍｌを振りかけて洗浄した。ケークを取り出し、真空乾燥して１−ベンジル−３−アミノピロリジンと酒石酸の塩６．６ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は４７．９％であり、晶析収率は９２％であった。また、水分は１１．３％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析したところ、トルエンを除いて計算した１−ベンジル−３−アミノピロリジンの化学純度は９９．８％であった。Example 11
The same operation as in Example 5 was carried out except that methanol was changed to tetrahydrofuran to obtain 6.4 g of a salt of 1-benzyl-3-aminopyrrolidine and tartaric acid. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 46.8%, and the crystallization yield was 88%. The water content was 13.8%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. When the toluene layer was analyzed by gas chromatography, the chemical purity of 1-benzyl-3-aminopyrrolidine calculated by removing toluene was 99.9%.
Example 12
A commercially available optical purity of 99.0% e.e. e. As described above, 1.0 g of optically active (R) -1-benzyl-3-aminopyrrolidine having a chemical purity of 99.0% or more and a content of 1-benzyl-3-aminopyrrolidine of 99.4%, commercially available 1-benzyl The content of benzyl-3-aminopyrrolidine was 87.6%, and the composition analyzed by gas chromatography was 91.8% 1-benzyl-3-aminopyrrolidine, 2.3% benzylamine, 4-amino- 1-benzylpiperidine 3.8%, other components 2.1% low-purity racemic 1-benzyl-3-aminopyrrolidine 2.8 g, methanol 11.4 g, water 4.1 g, DL-tartaric acid 2.2 g, And 0.8 g of D-tartaric acid were charged. While stirring, the mixture was heated to about 55 ° C. to dissolve the solid, and then cooled to about 30 ° C. About 20 mg of seed crystals were added thereto, and the mixture was stirred for 1 hour while maintaining the temperature at 20 to 30 ° C. Subsequently, it cooled to about 3 degreeC over 30 minutes, and also continued stirring at 0-5 degreeC for 2 hours. The slurry was filtered, and the cake was washed with 5 ml of 50% aqueous methanol solution. The cake was taken out and dried under vacuum to obtain 6.6 g of 1-benzyl-3-aminopyrrolidine and tartaric acid salt. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 47.9%, and the crystallization yield was 92%. Moreover, the water | moisture content was 11.3%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. When the toluene layer was analyzed by gas chromatography, the chemical purity of 1-benzyl-3-aminopyrrolidine calculated by removing toluene was 99.8%.
比較例１
市販の、１−ベンジル−３−アミノピロリジンの含有率が８７．６％であり、ガスクロマトグラフィーで分析した組成が、１−ベンジル−３−アミノピロリジン９１．８％、ベンジルアミン２．３％、４−アミノ−１−ベンジルピペリジン３．８％、その他成分２．１％である純度の低いラセミ１−ベンジル−３−アミノピロリジン２０．１ｇ、メタノール１３０ｇ、水１４．２ｇ、および９８％硫酸１０．２ｇを仕込んだ。撹拌しながら、約６０℃に加熱し、そこにラセミ１−ベンジル−３−アミノピロリジンと硫酸の塩（１水和物）を約５０ｍｇ添加した。スラリーを５０〜６０℃に保って０．５時間撹拌したのち、１時間かけて約３℃まで冷却し、更に０〜５℃で２時間撹拌を続けた。スラリーを濾過し、ケークにメタノール１０ｍｌを振りかけて洗浄した。ケークを取り出し、真空乾燥してラセミ１−ベンジル−３−アミノピロリジンと硫酸の塩２６．３ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は５９．９％であり、晶析収率は８９％であった。また、水分は６．１％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析した組成は、１−ベンジル−３−アミノピロリジン９８．２％、ベンジルアミン０．４％、４−アミノ−１−ベンジルピペリジン１．４％であった（但し、トルエンは除いて計算した）。Comparative Example 1
The commercially available 1-benzyl-3-aminopyrrolidine content was 87.6%, and the composition analyzed by gas chromatography was 91.8% 1-benzyl-3-aminopyrrolidine, 2.3% benzylamine. 4-amino-1-benzylpiperidine 3.8%, other components 2.1% low purity racemic 1-benzyl-3-aminopyrrolidine 20.1 g, methanol 130 g, water 14.2 g, and 98% sulfuric acid 10.2 g was charged. While stirring, the mixture was heated to about 60 ° C., and about 50 mg of racemic 1-benzyl-3-aminopyrrolidine and sulfuric acid salt (monohydrate) was added thereto. The slurry was kept at 50-60 ° C. and stirred for 0.5 hour, then cooled to about 3 ° C. over 1 hour, and further stirred at 0-5 ° C. for 2 hours. The slurry was filtered and washed with 10 ml of methanol in the cake. The cake was taken out and vacuum-dried to obtain 26.3 g of a racemic 1-benzyl-3-aminopyrrolidine and sulfuric acid salt. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 59.9%, and the crystallization yield was 89%. Moreover, the water | moisture content was 6.1%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. The composition of the toluene layer analyzed by gas chromatography was 98.2% 1-benzyl-3-aminopyrrolidine, 0.4% benzylamine, and 1.4% 4-amino-1-benzylpiperidine (provided that Calculated excluding toluene).
比較例２
市販の、１−ベンジル−３−アミノピロリジンの含有率が８７．６％であり、ガスクロマトグラフィーで分析した組成が、１−ベンジル−３−アミノピロリジン９１．８％、ベンジルアミン２．３％、４−アミノ−１−ベンジルピペリジン３．８％、その他成分２．１％である純度の低いラセミ１−ベンジル−３−アミノピロリジン２０．０ｇ、エタノール１２０ｇ、および３５％塩酸２１．７ｇを仕込んだ。撹拌しながら、約６０℃に加熱して溶解した。溶液を冷却して約２３℃とし、そこにラセミ１−ベンジル−３−アミノピロリジンの２塩酸塩を約５０ｍｇ添加した。スラリーを２０〜２５℃に保って５時間撹拌した。スラリーを濾過し、ケークにエタノール７ｍｌを振りかけて洗浄した。ケークを取り出し、真空乾燥してラセミ１−ベンジル−３−アミノピロリジンと塩酸の塩１１．８ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は６９．９％であり、晶析収率は４７％であった。また。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析した組成は、１−ベンジル−３−アミノピロリジン９９．０％、ベンジルアミン０．１％、４−アミノ−１−ベンジルピペリジン０．９％であった（但し、トルエンは除いて計算した）。Comparative Example 2
The commercially available 1-benzyl-3-aminopyrrolidine content was 87.6%, and the composition analyzed by gas chromatography was 91.8% 1-benzyl-3-aminopyrrolidine, 2.3% benzylamine. 4-amino-1-benzylpiperidine 3.8%, other components 2.1% low-purity racemic 1-benzyl-3-aminopyrrolidine 20.0 g, ethanol 120 g, and 35% hydrochloric acid 21.7 g It is. While stirring, it was heated to about 60 ° C. to dissolve. The solution was cooled to about 23 ° C., and about 50 mg of racemic 1-benzyl-3-aminopyrrolidine dihydrochloride was added thereto. The slurry was kept at 20-25 ° C. and stirred for 5 hours. The slurry was filtered and washed by sprinkling 7 ml of ethanol on the cake. The cake was taken out and dried under vacuum to obtain 11.8 g of racemic 1-benzyl-3-aminopyrrolidine and hydrochloric acid salt. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 69.9%, and the crystallization yield was 47%. Also. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. The composition of the toluene layer analyzed by gas chromatography was 19.0-benzyl-3-aminopyrrolidine, 9% benzylamine, 0.9% 4-amino-1-benzylpiperidine (provided that Calculated excluding toluene).
比較例３
市販の、１−ベンジル−３−アミノピロリジンの含有率が８７．６％であり、ガスクロマトグラフィーで分析した組成が、１−ベンジル−３−アミノピロリジン９１．８％、ベンジルアミン２．３％、４−アミノ−１−ベンジルピペリジン３．８％、その他成分２．１％である純度の低いラセミ１−ベンジル−３−アミノピロリジン２０．２ｇ、水２１．１ｇ、および３５％塩酸２１．９ｇを混合したのち約８０℃に加熱し、圧力約４．７ｋＰａで水が留出しなくなるまで濃縮した。濃縮液にエタノール１００ｇを加えたのち約８０℃に加熱し、再度圧力約４．７ｋＰａで留出しなくなるまで濃縮した。濃縮液にエタノール９６ｇを加え、約２０℃まで冷却したのちラセミ１−ベンジル−３−アミノピロリジンの２塩酸塩５０ｍｇを添加した。スラリーを１時間かけて約３℃まで冷却し、更に０〜５℃で１時間撹拌を続けた。スラリーを濾過し、ケークにエタノール１０ｍｌを振りかけて洗浄した。ケークを取り出し、真空乾燥してラセミ１−ベンジル−３−アミノピロリジンと塩酸の塩２１．７ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は６８．９％であり、晶析収率は８５％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析した組成は、１−ベンジル−３−アミノピロリジン９８．１％、ベンジルアミン０．３％、４−アミノ−１−ベンジルピペリジン１．５％であった（但し、トルエンは除いて計算した）。Comparative Example 3
The commercially available 1-benzyl-3-aminopyrrolidine content was 87.6%, and the composition analyzed by gas chromatography was 91.8% 1-benzyl-3-aminopyrrolidine, 2.3% benzylamine. 4-amino-1-benzylpiperidine 3.8%, other components 2.1% low purity racemic 1-benzyl-3-aminopyrrolidine 20.2 g, water 21.1 g, and 35% hydrochloric acid 21.9 g After mixing, the mixture was heated to about 80 ° C. and concentrated at a pressure of about 4.7 kPa until no water distilled off. After adding 100 g of ethanol to the concentrate, the mixture was heated to about 80 ° C. and concentrated again at a pressure of about 4.7 kPa until no distillation occurred. Ethanol 96g was added to the concentrate, and after cooling to about 20 ° C, 50 mg of racemic 1-benzyl-3-aminopyrrolidine dihydrochloride was added. The slurry was cooled to about 3 ° C. over 1 hour and further stirred at 0-5 ° C. for 1 hour. The slurry was filtered, and the cake was washed with 10 ml of ethanol. The cake was taken out and dried under vacuum to obtain 21.7 g of racemic 1-benzyl-3-aminopyrrolidine and hydrochloric acid salt. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 68.9%, and the crystallization yield was 85%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. The composition of the toluene layer analyzed by gas chromatography was 98.1% 1-benzyl-3-aminopyrrolidine, 0.3% benzylamine, and 1.5% 4-amino-1-benzylpiperidine (provided that Calculated excluding toluene).
比較例４
市販の、１−ベンジル−３−アミノピロリジンの含有率が８７．６％であり、ガスクロマトグラフィーで分析した組成が、１−ベンジル−３−アミノピロリジン９１．８％、ベンジルアミン２．３％、４−アミノ−１−ベンジルピペリジン３．８％、その他成分２．１％である純度の低いラセミ１−ベンジル−３−アミノピロリジン３．９ｇ、エタノール１８．０ｇ、およびコハク酸２．４ｇを仕込んだ。撹拌しながら、２０〜２５℃に保って５時間撹拌した。スラリーを濾過し、ケークにエタノール５ｍｌを振りかけて洗浄した。ケークを取り出し、真空乾燥してラセミ１−ベンジル−３−アミノピロリジンとコハク酸の塩４．８ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は６０．３％であり、晶析収率は８６％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析した組成は、１−ベンジル−３−アミノピロリジン９６．９％、ベンジルアミン０．３％、４−アミノ−１−ベンジルピペリジン２．８％であった（但し、トルエンは除いて計算した）。Comparative Example 4
The commercially available 1-benzyl-3-aminopyrrolidine content was 87.6%, and the composition analyzed by gas chromatography was 91.8% 1-benzyl-3-aminopyrrolidine, 2.3% benzylamine. 4-amino-1-benzylpiperidine 3.8%, other components 2.1% low-purity racemic 1-benzyl-3-aminopyrrolidine 3.9 g, ethanol 18.0 g, and succinic acid 2.4 g. Prepared. While stirring, the mixture was kept at 20 to 25 ° C. and stirred for 5 hours. The slurry was filtered and washed by sprinkling 5 ml of ethanol on the cake. The cake was taken out and dried under vacuum to obtain 4.8 g of a racemic 1-benzyl-3-aminopyrrolidine and succinic acid salt. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 60.3%, and the crystallization yield was 86%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. The composition of the toluene layer analyzed by gas chromatography was 96.9% 1-benzyl-3-aminopyrrolidine, 0.3% benzylamine, and 2.8% 4-amino-1-benzylpiperidine (however, Calculated excluding toluene).
比較例５
市販の、１−ベンジル−３−アミノピロリジンの含有率が８７．６％であり、ガスクロマトグラフィーで分析した組成が、１−ベンジル−３−アミノピロリジン９１．８％、ベンジルアミン２．３％、４−アミノ−１−ベンジルピペリジン３．８％、その他成分２．１％である純度の低いラセミ１−ベンジル−３−アミノピロリジン３．９ｇ、エタノール１８．０ｇ、およびＤＬ−リンゴ酸２．７ｇを仕込んだ。撹拌しながら、０〜５℃に保って１２時間撹拌した。析出した結晶は性状の悪い凝集物であり、濾過することができなかった。Comparative Example 5
The commercially available 1-benzyl-3-aminopyrrolidine content was 87.6%, and the composition analyzed by gas chromatography was 91.8% 1-benzyl-3-aminopyrrolidine, 2.3% benzylamine. 4-amino-1-benzylpiperidine 3.8%, other components 2.1% low purity racemic 1-benzyl-3-aminopyrrolidine 3.9 g, ethanol 18.0 g, and DL-malic acid 2. 7g was charged. While stirring, the mixture was kept at 0 to 5 ° C. and stirred for 12 hours. The precipitated crystals were aggregates with poor properties and could not be filtered.
比較例６
市販の、１−ベンジル−３−アミノピロリジンの含有率が８７．６％であり、ガスクロマトグラフィーで分析した組成が、１−ベンジル−３−アミノピロリジン９１．８％、ベンジルアミン２．３％、４−アミノ−１−ベンジルピペリジン３．８％、その他成分２．１％である純度の低いラセミ１−ベンジル−３−アミノピロリジン３．９ｇ、エタノール８．９ｇ、およびマレイン酸２．４ｇを仕込んだ。撹拌しながら、０〜５℃に保って１２時間撹拌したが結晶は析出しなかった。Comparative Example 6
The commercially available 1-benzyl-3-aminopyrrolidine content was 87.6%, and the composition analyzed by gas chromatography was 91.8% 1-benzyl-3-aminopyrrolidine, 2.3% benzylamine. 4-amino-1-benzylpiperidine 3.8%, other components 2.1% low-purity racemic 1-benzyl-3-aminopyrrolidine 3.9 g, ethanol 8.9 g, and maleic acid 2.4 g. Prepared. While stirring, the mixture was stirred at 0 to 5 ° C. for 12 hours, but no crystals were precipitated.
比較例７
市販の、１−ベンジル−３−アミノピロリジンの含有率が８７．６％であり、ガスクロマトグラフィーで分析した組成が、１−ベンジル−３−アミノピロリジン９１．８％、ベンジルアミン２．３％、４−アミノ−１−ベンジルピペリジン３．８％、その他成分２．１％である純度の低いラセミ１−ベンジル−３−アミノピロリジン３．９ｇ、エタノール９．１ｇ、および酢酸２．４ｇを仕込んだ。撹拌しながら、０〜５℃に保って１２時間撹拌したが結晶は析出しなかった。Comparative Example 7
The commercially available 1-benzyl-3-aminopyrrolidine content was 87.6%, and the composition analyzed by gas chromatography was 91.8% 1-benzyl-3-aminopyrrolidine, 2.3% benzylamine. 4-amino-1-benzylpiperidine 3.8%, other components 2.1% low purity racemic 1-benzyl-3-aminopyrrolidine 3.9 g, ethanol 9.1 g and acetic acid 2.4 g It is. While stirring, the mixture was stirred at 0 to 5 ° C. for 12 hours, but no crystals were precipitated.
比較例８
メタノールを使用せず、水の使用量を１５．５ｇに変えた以外は実施例２と同じ操作をおこなって、１−ベンジル−３−アミノピロリジンと酒石酸の塩４．６ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は４６．９％であり、晶析収率は６２％であった。また、水分は１３．３％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析したところ、１−ベンジル−３−アミノピロリジンの化学純度は１００．０％であった（但し、トルエンは除いて計算した）。Comparative Example 8
The same operation as in Example 2 was carried out except that methanol was not used and the amount of water used was changed to 15.5 g to obtain 4.6 g of 1-benzyl-3-aminopyrrolidine and tartaric acid salt. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 46.9%, and the crystallization yield was 62%. Moreover, the water | moisture content was 13.3%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. When the toluene layer was analyzed by gas chromatography, the chemical purity of 1-benzyl-3-aminopyrrolidine was 100.0% (however, it was calculated excluding toluene).
比較例９
市販の、１−ベンジル−３−アミノピロリジンの含有率が８７．６％であり、ガスクロマトグラフィーで分析した組成が、１−ベンジル−３−アミノピロリジン９１．８％、ベンジルアミン２．３％、４−アミノ−１−ベンジルピペリジン３．８％、その他成分２．１％である純度の低いラセミ１−ベンジル−３−アミノピロリジン３．９ｇ、メタノール７．２、水８．４ｇ、およびＤ−酒石酸３．１ｇを仕込んだ。撹拌しながら、約５５℃に加熱して固形物を溶解したのち、約３０℃まで冷却した。そこに種晶を約２０ｍｇ添加し、２０〜３０℃に保って１時間撹拌した。次いで、３０分かけて約３℃まで冷却し、更に０〜５℃で２時間撹拌を続けた。スラリーを濾過し、ケークに５０％メタノール水溶液５ｍｌを振りかけて洗浄した。ケークを取り出し、真空乾燥して１−ベンジル−３−アミノピロリジンと酒石酸の塩３．２ｇを取得した。取得した塩の中の１−ベンジル−３−アミノピロリジンの含有率は４７．０％であり、晶析収率は４４％であった。また、水分は１３．８％であった。容量２０ｍｌの蓋付きサンプル瓶に、取得した塩１ｇ、水１ｇ、トルエン１ｇ、および４８％水酸化ナトリウム水溶液０．６ｇを採取して良く振り混ぜた。トルエン層をガスクロマトグラフィーで分析したところ、トルエンを除いて計算した１−ベンジル−３−アミノピロリジンの化学純度は９９．９％であった。取得した塩の中の１−ベンジル−３−アミノピロリジンは（Ｒ）−体であり、その光学純度は９７．０％ｅ．ｅ．であった。Comparative Example 9
The commercially available 1-benzyl-3-aminopyrrolidine content was 87.6%, and the composition analyzed by gas chromatography was 91.8% 1-benzyl-3-aminopyrrolidine, 2.3% benzylamine. 4-amino-1-benzylpiperidine 3.8%, other components 2.1% low purity racemic 1-benzyl-3-aminopyrrolidine 3.9 g, methanol 7.2, water 8.4 g, and D -3.1 g of tartaric acid was charged. While stirring, the mixture was heated to about 55 ° C. to dissolve the solid, and then cooled to about 30 ° C. About 20 mg of seed crystals were added thereto, and the mixture was stirred for 1 hour while maintaining the temperature at 20 to 30 ° C. Subsequently, it cooled to about 3 degreeC over 30 minutes, and also continued stirring at 0-5 degreeC for 2 hours. The slurry was filtered, and the cake was washed with 5 ml of 50% aqueous methanol solution. The cake was taken out and dried under vacuum to obtain 3.2 g of 1-benzyl-3-aminopyrrolidine and tartaric acid salt. The content of 1-benzyl-3-aminopyrrolidine in the obtained salt was 47.0%, and the crystallization yield was 44%. The water content was 13.8%. In a sample bottle with a capacity of 20 ml, 1 g of the obtained salt, 1 g of water, 1 g of toluene, and 0.6 g of 48% aqueous sodium hydroxide solution were collected and shaken well. When the toluene layer was analyzed by gas chromatography, the chemical purity of 1-benzyl-3-aminopyrrolidine calculated by removing toluene was 99.9%. 1-Benzyl-3-aminopyrrolidine in the obtained salt is (R) -form, and its optical purity is 97.0% e.e. e. Met.
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