JPS6137263B2 - - Google Patents
Info
- Publication number
- JPS6137263B2 JPS6137263B2 JP60160393A JP16039385A JPS6137263B2 JP S6137263 B2 JPS6137263 B2 JP S6137263B2 JP 60160393 A JP60160393 A JP 60160393A JP 16039385 A JP16039385 A JP 16039385A JP S6137263 B2 JPS6137263 B2 JP S6137263B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- general formula
- bromo
- minutes
- following general
- 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.)
- Expired
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- 150000001875 compounds Chemical class 0.000 claims description 27
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 8
- -1 methoxy, ethoxy Chemical group 0.000 claims description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- FKCMADOPPWWGNZ-YUMQZZPRSA-N [(2r)-1-[(2s)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O FKCMADOPPWWGNZ-YUMQZZPRSA-N 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 7
- 229930182821 L-proline Natural products 0.000 description 7
- 229960002429 proline Drugs 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- BUPXDXGYFXDDAA-UHFFFAOYSA-N 3-bromo-2-methylpropanoic acid Chemical compound BrCC(C)C(O)=O BUPXDXGYFXDDAA-UHFFFAOYSA-N 0.000 description 2
- ZVDKTPOXSAEUQU-UHFFFAOYSA-N 3-bromo-2-methylpropanoyl chloride Chemical compound BrCC(C)C(Cl)=O ZVDKTPOXSAEUQU-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JPVQCHVLFHXNKB-UHFFFAOYSA-N 1,2,3,4,5,6-hexamethyldisiline Chemical compound CC1=C(C)[Si](C)=[Si](C)C(C)=C1C JPVQCHVLFHXNKB-UHFFFAOYSA-N 0.000 description 1
- VFVHNRJEYQGRGE-UHFFFAOYSA-N 3-acetylsulfanyl-2-methylpropanoic acid Chemical compound OC(=O)C(C)CSC(C)=O VFVHNRJEYQGRGE-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- LWFWUJCJKPUZLV-UHFFFAOYSA-N n-trimethylsilylacetamide Chemical compound CC(=O)N[Si](C)(C)C LWFWUJCJKPUZLV-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- LUDPWTHDXSOXDX-SCSAIBSYSA-N s-[(2r)-3-chloro-2-methyl-3-oxopropyl] ethanethioate Chemical compound ClC(=O)[C@H](C)CSC(C)=O LUDPWTHDXSOXDX-SCSAIBSYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000005406 washing 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
-
- 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は高血圧の緩圧又は低下に有効なる下記
構造式（）のピロリジン誘導体の製造方法に関
するものである。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing a pyrrolidine derivative of the following structural formula () which is effective for moderating or lowering hypertension.
〔従来の技術〕
日本公開特許公報第52−116457号によれば、メ
タクリル酸とチオ酢酸にて３−アセチルチオ−２
−メチルプロパン酸を製造し、Ｌ−プロリンｔ−
ブチルエステルをＬ−プロリンより３段階を介し
て製造した後、３−アセチルチオ−２−メチルプ
ロパン酸でアシル化し、引きつづきジシクロヘキ
シルアミン塩とした後、アセチル基を除いて目的
物を製造するか、シヨートンバウマン反応を利用
した、即ち、Ｌ−プロリンとチオニルクロリドを
使用して製造した３−アセチルチオ−２−メチル
プロピオニルクロリドと反応させた後、アセチル
基を除いて目的とする化合物を製造する方法が記
載されている。 [Prior art] According to Japanese Patent Publication No. 52-116457, methacrylic acid and thioacetic acid produce 3-acetylthio-2
-Producing methylpropanoic acid, L-proline t-
After producing butyl ester from L-proline through three steps, acylating it with 3-acetylthio-2-methylpropanoic acid and subsequently converting it into a dicyclohexylamine salt, and then removing the acetyl group to produce the desired product, or A method of producing a desired compound by removing the acetyl group after reacting with 3-acetylthio-2-methylpropionyl chloride using Schioton-Baumann reaction, that is, produced using L-proline and thionyl chloride. is listed.
日本公開特許公報第56−100760号によれば、公
知の方法であるメタクリル酸と臭化水素を反応さ
せて３−ブロモ−２−メチルプロパン酸を製造し
た後、チオニルクロリドを使用して３−ブロモ−
２−メチルプロピオニルクロリドを製造し、シヨ
トンバウマン反応を利用した、即ち、Ｌ−プロリ
ンと３−ブロモ−２−メチルプロピオニルクロリ
ドとを反応させ１−〔３−ブロモ−（2S）−メチル
プロピオニル〕−ピロリジン−（2S）−カルボキシ
ル酸を製造したのち、チオ硫酸ナトリウムでブン
テ（Bunte）塩を製造した後、塩酸で加水分解し
目的化合物を製造する方法が記載されている。 According to Japanese Patent Publication No. 56-100760, 3-bromo-2-methylpropanoic acid is produced by reacting methacrylic acid and hydrogen bromide using a known method, and then 3-bromo-2-methylpropanoic acid is produced using thionyl chloride. Bromo
2-Methylpropionyl chloride was produced using Schioton-Baumann reaction, that is, L-proline and 3-bromo-2-methylpropionyl chloride were reacted to produce 1-[3-bromo-(2S)-methylpropionyl]. A method is described in which -pyrrolidine-(2S)-carboxylic acid is produced, Bunte salt is produced with sodium thiosulfate, and then the target compound is produced by hydrolysis with hydrochloric acid.
上記の如き公知方法は共にチオルニクロリドを
使用することにより、反応段階中公害防止施設を
必要とし、総収率が低く、経済性が望ましくな
い。 Both of the above-mentioned known methods use thiolnichloride, require pollution control facilities during the reaction stage, have low overall yields, and are not economical.
本発明者は反応段階中において公害防止施設が
不要であり、３−ハロ−２−メチルプロパン酸よ
り簡便なる反応工程で本発明の化合物を製造する
ことにより経済性及び収率が著しく高い望ましい
方法を発見したのである。
The present inventors have proposed a desirable method that does not require pollution control facilities during the reaction step and has significantly higher economic efficiency and yield by producing the compounds of the present invention in a reaction step that is simpler than that of 3-halo-2-methylpropanoic acid. I discovered this.
本発明による構造式（）の化合物を次の如き
段階を経て製造する。
The compound of structural formula () according to the present invention is prepared through the following steps.
(i) 次の一般式（）の化合物を塩化メチレン、
クロロホルム、四塩化炭素、ベンゼン、酢酸エ
チル、ニトロメタン、ジクロロエタン等で溶解
し、５℃乃至−30℃で有機塩基存在下において
一般式CICOR′の化合物と反応させ一般式
（）の化合物を得る。(i) Compound of the following general formula () in methylene chloride,
It is dissolved in chloroform, carbon tetrachloride, benzene, ethyl acetate, nitromethane, dichloroethane, etc., and reacted with a compound of general formula CICOR' at 5°C to -30°C in the presence of an organic base to obtain a compound of general formula ().
式中、Ｘは塩素又は臭素原子を表わし、
R′はメトキシ、エトキシ又はｔ−ブトキシ基
を表わす。 In the formula, X represents a chlorine or bromine atom,
R' represents a methoxy, ethoxy or t-butoxy group.
上記反応において使用される有機塩基は、例
えばピリジン、トリエチルアミン、ジエチルア
ミン、ジメチルアニリンである。 The organic base used in the above reaction is, for example, pyridine, triethylamine, diethylamine, dimethylaniline.
(ii) (i)段階において得られた化合物（）を次の
一般式（）の化合物と10℃乃至−30℃でアシ
ル化した後、水を加えてシルリル化合物を除
き、水酸化ナトリウム、炭酸ナトリウム、水酸
化カリウム、炭酸カリウムでPHを4.0乃至6.0に
調整した後、水層を分離し、塩酸でPH2.0に調
整して一般式（）の化合物を得る。(ii) The compound () obtained in step (i) is acylated with a compound of the following general formula () at 10℃ to -30℃, water is added to remove the siluryl compound, sodium hydroxide, carbonate After adjusting the pH to 4.0 to 6.0 with sodium, potassium hydroxide, and potassium carbonate, the aqueous layer is separated and the pH is adjusted to 2.0 with hydrochloric acid to obtain a compound of general formula ().
式中、Ｘは塩素又は臭素原子を表わす。 In the formula, X represents a chlorine or bromine atom.
上記反応において使用された構造式（）の
化合物は、Ｌ−プロリンを塩化メチレン、クロ
ロホルム、四塩化炭素、ベンゼン、酢酸エチ
ル、ニトロメタン、ジクロロエタン等の有機溶
媒中においてトリメチルシルリルクロリド、ヘ
キサメチルジシラジン又はトリメチルシルリル
アセトアミドでシルリル化して製造する。 The compound of structural formula () used in the above reaction is prepared by adding L-proline to trimethylsilyl chloride, hexamethyldisilazine, etc. in an organic solvent such as methylene chloride, chloroform, carbon tetrachloride, benzene, ethyl acetate, nitromethane, or dichloroethane. Alternatively, it can be produced by silylation with trimethylsilylacetamide.
(iii) 上記の段階において得られた一般式（）の
化合物を、水、メタノール、エタノール、イソ
プロパノール又はこれらの水溶液中において60
℃乃至100℃で１乃至2.5モル倍のチオウレアと
反応させ、次の一般式（）の化合物を得た
後、該化合物（）を１乃至２モル倍の水酸化
ナトリウム、水酸化カリウム、炭酸ナトリウ
ム、炭酸カリウムの如きアルカリ金属の水酸化
物又は炭酸塩を加えて加水分解し、塩酸にてPH
0.5乃至2.5に調整し、上記構造式（）の化合
物を製造する。(iii) The compound of general formula () obtained in the above step is dissolved in water, methanol, ethanol, isopropanol or an aqueous solution thereof for 60 min.
After reacting with 1 to 2.5 moles of thiourea at a temperature of 1 to 100 °C to obtain a compound of the following general formula (), the compound () was reacted with 1 to 2 moles of sodium hydroxide, potassium hydroxide, or sodium carbonate. , hydrolyze by adding alkali metal hydroxide or carbonate such as potassium carbonate, and PH with hydrochloric acid.
0.5 to 2.5 to produce the compound of the above structural formula ().
上記一般式において、Ｘは塩素又は臭化原子
を表わす。 In the above general formula, X represents a chlorine or bromide atom.
下記実施例は本発明を説明したものであり、こ
れによつて発明の範囲を制限しようとするもので
はない。nmrはV.I.D.（Varian Instrument
Division）製のEM−360、60MHzNMR分光計を
使用して測定した。 The following examples are illustrative of the invention and are not intended to limit the scope thereof. nmr is VID (Varian Instrument
Measurements were made using an EM-360, 60 MHz NMR spectrometer manufactured by Div.
実験１
(イ) 20mlの塩化メチレンに1.03ｇのＬ−プロリン
と2.2mlのヘキサメチルジシラザンを加え還流
させた後、室温まで冷却させる。
Experiment 1 (a) 1.03 g of L-proline and 2.2 ml of hexamethyldisilazane were added to 20 ml of methylene chloride, refluxed, and then cooled to room temperature.
(ロ) 15mlの塩化メチレンに1.50ｇの３−ブロモ−
２−メチルプロパン酸と0.85ｇのメチルクロロ
フオメイトを加え−15℃まで冷却させた後、こ
の温度を保持し、５mlの塩化メチレンに稀釈し
た0.8mlのピリジンを15分間以上に亘つて徐々
に加えた後、−15℃乃至−20℃において90分間
撹拌する。該温度を保持し(イ)において完全に溶
解されて得た溶液を30分間以上にわたり徐々に
滴加し、−15℃乃至−20℃で60分間撹拌し、室
温で60分間放置した後、10mlの蒸溜水を加え、
20％の水酸化ナトリウム溶液でPH5.0にした
後、分離する。水層は濃い塩酸溶液でPH2.0に
合わせ、０℃乃至５℃で冷却した後、60分間撹
拌し、０℃乃至５℃で一夜放置した後ろ過し、
冷水で洗滌した後、五酸化リンで減圧乾燥し、
1.03ｇの白色結晶である１−〔３−ブロモ−
（2S）−メチルプロピオニル〕−ピロリジン−
（2S）−カルボキシル酸得ることができた。(b) 1.50 g of 3-bromo in 15 ml of methylene chloride
After adding 2-methylpropanoic acid and 0.85 g of methyl chlorophomate and cooling to -15°C, while maintaining this temperature, 0.8 ml of pyridine diluted in 5 ml of methylene chloride was slowly added over 15 minutes. After addition, stir at -15°C to -20°C for 90 minutes. While maintaining this temperature, the solution obtained by completely dissolving in (a) was gradually added dropwise over 30 minutes or more, stirred at -15℃ to -20℃ for 60 minutes, left at room temperature for 60 minutes, and then added to 10ml of the solution. Add distilled water,
After bringing the pH to 5.0 with 20% sodium hydroxide solution, separate. The aqueous layer was adjusted to pH 2.0 with concentrated hydrochloric acid solution, cooled at 0°C to 5°C, stirred for 60 minutes, left overnight at 0°C to 5°C, and filtered.
After washing with cold water, drying under reduced pressure with phosphorus pentoxide,
1.03g of white crystals of 1-[3-bromo-
(2S)-Methylpropionyl]-pyrrolidine-
(2S)-carboxylic acid could be obtained.
融点：113℃
T.L.C.：ベンゼン：ｎ−ブタノール：酢酸＝
25：３：３
Rf＝0.4
nmr（CdCl2）：第１図参照
実験２
(イ) 1.15ｇのＬ−プロリンを10mlの塩化メチレン
に加え、０℃乃至５℃に保持し、2.5mlのトリ
メチルシルシルクロリドを滴加した後、1.6ml
のピリジンを15分間に亘つて滴加し、２時間の
間５℃で撹拌する。Melting point: 113℃ TLC: Benzene: n-butanol: Acetic acid =
25:3:3 Rf=0.4 nmr (CdCl 2 ): See Figure 1 Experiment 2 (a) Add 1.15 g of L-proline to 10 ml of methylene chloride, keep at 0°C to 5°C, and add 2.5 ml of trimethyl After adding silyl chloride dropwise, 1.6ml
of pyridine is added dropwise over 15 minutes and stirred for 2 hours at 5°C.
(ロ) 10mlの塩化メチレンに1.67ｇの３−ブロモ−
２−メチルプロパン酸を加え−15℃で冷却した
後、1.1ｇのエチルクロロフオメイトを加え
る。0.9mlのピリジンを５mlの塩化メチレンに
稀釈して30分にわたり滴加し、−15℃乃至−20
℃を保持させながら90分間撹拌する。(b) 1.67 g of 3-bromo in 10 ml of methylene chloride
After adding 2-methylpropanoic acid and cooling to -15°C, 1.1 g of ethyl chlorophomate is added. 0.9 ml of pyridine was diluted in 5 ml of methylene chloride and added dropwise over 30 minutes at -15°C to -20°C.
Stir for 90 minutes while maintaining the temperature.
(イ)の反応液を−15℃乃至−20℃に保持し、15分
間にわたつて滴加して60分間該温度で反応させた
後、60分間室温に放置する。８mlの蒸溜水を加
え、30％水酸化ナトリウム溶液にてPH4.8に合わ
せ、層を分離した後、水層をろ過する。水層を濃
い塩酸でPH2.0に合わせ、５℃で120分間撹拌した
後、５℃で一夜放置した後、ろ過して冷水で洗滌
した後、五酸化リンで減圧乾燥し、1.16ｇの白色
結晶である１−〔３−ブロモ−（2S）−メチルプロ
ピオニル〕−ピロリジン−（2S）−カルボキシル酸
を得た。 The reaction solution (a) is maintained at -15°C to -20°C, added dropwise over 15 minutes, reacted at this temperature for 60 minutes, and then left at room temperature for 60 minutes. Add 8 ml of distilled water, adjust the pH to 4.8 with 30% sodium hydroxide solution, separate the layers, and filter the aqueous layer. The aqueous layer was adjusted to pH 2.0 with concentrated hydrochloric acid, stirred at 5°C for 120 minutes, left overnight at 5°C, filtered, washed with cold water, dried under reduced pressure over phosphorus pentoxide, and yielded 1.16 g of white. Crystalline 1-[3-bromo-(2S)-methylpropionyl]-pyrrolidine-(2S)-carboxylic acid was obtained.
実験３
実施例１と同一なる方法で、但し、メチルクロ
ロフオメイトの代りにエチルクロロフオメイトを
使用して類似なる収率にて１−〔３−ブロモ−
（2S）−メチルプロピオニル〕＝ピロリジン−
（2S）−カルボキシル酸を得た。Experiment 3 1-[3-Bromo-
(2S)-methylpropionyl]=pyrrolidine-
(2S)-carboxylic acid was obtained.
実験４
実施例１と同一なる方法で、但し、エチルクロ
ロフオメイトの代りにビバロイルクロリドを使用
して類似なる収率で１−〔３−ブロモ−（2S）−メ
チルプロピオニル〕−ピロリジン−（2S）−カルボ
キシル酸を得た。Experiment 4 1-[3-Bromo-(2S)-methylpropionyl]-pyrrolidine-( 2S)-carboxylic acid was obtained.
実験５
15mlのエタノールに0.81ｇのチオウレアと1.41
ｇの１−〔３−ブロモ−（2S）−メチルプロピオニ
ル〕−ピロリジン−（2S）−カルボキシル酸を加
え、３時間還流後室温で冷却させ、0.39ｇを水酸
化ナトリウムを５mlの蒸留水に溶解して加え、１
時間還流させる。エタノールを減圧蒸溜して室温
で冷却してから塩酸でPH1.0を保持した後、20ml
のエチルアセテートを３度抽出した後、10ml飽和
塩水にて洗い落してから、硫酸ナトリウムで乾燥
してろ過する。Experiment 5 0.81g thiourea and 1.41 in 15ml ethanol
g of 1-[3-bromo-(2S)-methylpropionyl]-pyrrolidine-(2S)-carboxylic acid was added, refluxed for 3 hours, then cooled to room temperature, and 0.39 g of sodium hydroxide was dissolved in 5 ml of distilled water. and add 1
Reflux for an hour. Distill ethanol under reduced pressure, cool it at room temperature, maintain pH 1.0 with hydrochloric acid, and then add 20ml.
After extracting the ethyl acetate three times, it is washed with 10 ml of saturated brine, dried over sodium sulfate, and filtered.
減圧濃縮後、残りの残留物を５mlの酢酸エチル
に溶かした後ろ過し、ヘキサンを加えて沈澱を析
出させる。５℃で一夜放置した後ろ過し、40℃で
乾燥して0.85ｇの白色結晶である１−〔３−メル
カプト−（2S）−メチルプロピオニル〕−ピロリジ
ン−（2S）−カルボキシル酸を得た。 After concentration under reduced pressure, the remaining residue was dissolved in 5 ml of ethyl acetate, filtered, and hexane was added to precipitate. After standing overnight at 5°C, the mixture was filtered and dried at 40°C to obtain 0.85 g of white crystals of 1-[3-mercapto-(2S)-methylpropionyl]-pyrrolidine-(2S)-carboxylic acid.
融点：103℃
〔α〕２５ Ｄ：−131.7℃（Ｃ＝1.7、エタノール）
nmr（CdCl2）：第２図参照
実験６
20mlの蒸溜水に1.52ｇのチオウレアと2.82ｇの
１−〔３−ブロモ−（2S）−メチルプロピオニル〕
−ピロリジン−（2S）−カルボキシル酸を加え
て、５時間80℃乃至85℃で保持させた後、室温で
冷却してから0.8ｇの水酸化ナトリウムを６mlの
蒸溜水で溶かして加えて、１時間還流の室温で冷
却させる。Melting point: 103℃ [α] 25 D : -131.7℃ (C=1.7, ethanol) nmr (CdCl 2 ): See Figure 2 Experiment 6 1.52g of thiourea and 2.82g of 1-[3- Bromo-(2S)-methylpropionyl]
-Pyrrolidine-(2S)-carboxylic acid was added and kept at 80°C to 85°C for 5 hours, then cooled to room temperature, and 0.8g of sodium hydroxide dissolved in 6ml of distilled water was added. Cool to room temperature at reflux for an hour.
2N−塩酸溶液でPH1.0に合わせ25mlの酢酸エチ
ルにて３度抽出後、15mlの飽和塩水で洗滌した
後、硫酸マグネシウムで乾燥してろ過した後、減
圧濃縮する。 Adjust the pH to 1.0 with 2N hydrochloric acid solution, extract three times with 25 ml of ethyl acetate, wash with 15 ml of saturated brine, dry over magnesium sulfate, filter, and concentrate under reduced pressure.
残つた残留物を８mlの酢酸エチルで溶かした後
ろ過し、ヘキサンで沈澱を析出させる。 The remaining residue was dissolved in 8 ml of ethyl acetate, filtered, and precipitated with hexane.
５℃で一夜放置後ろ過して40℃で乾燥し、1.72
ｇの白色結晶である１−〔３−メルカプト−
（2S）−メチルプロピオニル〕−ピロリジン−
（2S）−カルボキシル酸を得た。 Leave overnight at 5℃, filter and dry at 40℃, 1.72
The white crystals of 1-[3-mercapto-
(2S)-Methylpropionyl]-pyrrolidine-
(2S)-carboxylic acid was obtained.
第１図は本発明による実験１の化合物のnmrス
ペクトラムを示す図面、第２図は本発明による実
験５の化合物nmrスペクトラムを示す図面であ
る。
FIG. 1 is a drawing showing the nmr spectrum of the compound of Experiment 1 according to the present invention, and FIG. 2 is a drawing showing the nmr spectrum of the compound of Experiment 5 according to the present invention.
Claims (1)
CICOR′の化合物と反応させて得られた次の一般
式（）の化合物を次の構造式（）の化合物と
アシル化し、次の一般式（）の化合物を得、該
化合物をチオウレアと反応させ、下記一般式
（）の化合物を得た後、加水分解させることを
特徴とし、下記構造式（）のピロリジン誘導体
を製造する方法。 上記一般式において、 Ｘは塩素又は臭素原子を示し、 R′はメトキシ、エトキシ又はｔ−ブトキシ基
を示す。 ２ 一般式（）の化合物は一般式（）の化合
物を有機塩基存在下においてメチルクロロフオメ
イト、エチルクロロフオメイト、又はピバロイル
クロリドと反応させる特許請求の範囲第１項記載
の製造方法。 ３ 一般式（）の化合物の加水分解をアルカリ
金属の水酸化物又は炭酸塩存在下において遂行
し、最終的にはPHを0.5乃至2.5で調整する特許請
求の範囲第１項記載の製造方法。[Scope of Claims] 1. A compound of the following general formula () is represented by the general formula
A compound of the following general formula () obtained by reacting with a compound of CICOR' is acylated with a compound of the following structural formula () to obtain a compound of the following general formula (), and this compound is reacted with thiourea. A method for producing a pyrrolidine derivative of the following structural formula (), which comprises obtaining a compound of the following general formula () and then hydrolyzing it. In the above general formula, X represents a chlorine or bromine atom, and R' represents a methoxy, ethoxy or t-butoxy group. 2. The manufacturing method according to claim 1, wherein the compound of general formula () is reacted with methyl chlorophomate, ethyl chlorophomate, or pivaloyl chloride in the presence of an organic base. 3. The manufacturing method according to claim 1, wherein the hydrolysis of the compound of general formula () is carried out in the presence of an alkali metal hydroxide or carbonate, and the pH is finally adjusted to 0.5 to 2.5.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019840004361A KR860001391B1 (en) | 1984-07-23 | 1984-07-23 | Method for preparing pyrrolidine derivative |
| KR84-4361 | 1984-07-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6193157A JPS6193157A (en) | 1986-05-12 |
| JPS6137263B2 true JPS6137263B2 (en) | 1986-08-22 |
Family
ID=19234716
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60160393A Granted JPS6193157A (en) | 1984-07-23 | 1985-07-22 | Manufacture of pyrrolidine derivative |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS6193157A (en) |
| KR (1) | KR860001391B1 (en) |
| DE (1) | DE3526023A1 (en) |
| ES (1) | ES545451A0 (en) |
| FR (1) | FR2567881B1 (en) |
| GB (1) | GB2162181B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU208954B (en) * | 1990-09-21 | 1994-02-28 | Egyt Gyogyszervegyeszeti Gyar | Process for producing 1-(3-mercapto-(2s)-methyl-1-oxo-propyl)-l-prolyn |
| AT395012B (en) * | 1986-06-27 | 1992-08-25 | Richter Gedeon Vegyeszet | METHOD FOR PRODUCING N- (1 (S) | THOXYCARBONYL-3-PHENYL-PROPYL) - (S) -ALANYL- (S) PROLIN AND ITS ACID ADDITION SALTS |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU509899B2 (en) * | 1976-02-13 | 1980-05-29 | E.R. Squibb & Sons, Inc. | Proline derivatives and related compounds |
| US4192945A (en) * | 1978-12-07 | 1980-03-11 | E. R. Squibb & Sons, Inc. | Process for preparing proline and homoproline derivatives |
| GB2065643B (en) * | 1979-12-13 | 1983-08-24 | Kanegafuchi Chemical Ind | Optically active n-mercaptoalkanoylamino acids |
| HU184082B (en) * | 1979-12-29 | 1984-06-28 | Egyt Gyogyszervegyeszeti Gyar | Process for preparing 1-3-/3mercapto-/2s/-methyl-propinyl/-pyrrolidine-/2s/-carboxylic acid |
| JPS58124764A (en) * | 1982-01-20 | 1983-07-25 | Kanegafuchi Chem Ind Co Ltd | Production of optically active thiol |
-
1984
- 1984-07-23 KR KR1019840004361A patent/KR860001391B1/en not_active Expired
-
1985
- 1985-07-20 DE DE19853526023 patent/DE3526023A1/en active Granted
- 1985-07-22 FR FR8511194A patent/FR2567881B1/en not_active Expired
- 1985-07-22 JP JP60160393A patent/JPS6193157A/en active Granted
- 1985-07-22 ES ES545451A patent/ES545451A0/en active Granted
- 1985-07-23 GB GB08518550A patent/GB2162181B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2567881B1 (en) | 1987-12-24 |
| KR860001066A (en) | 1986-02-22 |
| ES8603819A1 (en) | 1986-01-01 |
| GB8518550D0 (en) | 1985-08-29 |
| GB2162181A (en) | 1986-01-29 |
| FR2567881A1 (en) | 1986-01-24 |
| ES545451A0 (en) | 1986-01-01 |
| GB2162181B (en) | 1988-04-20 |
| KR860001391B1 (en) | 1986-09-22 |
| JPS6193157A (en) | 1986-05-12 |
| DE3526023C2 (en) | 1988-10-20 |
| DE3526023A1 (en) | 1986-01-23 |
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