JPS6128666B2 - - Google Patents
Info
- Publication number
- JPS6128666B2 JPS6128666B2 JP1795776A JP1795776A JPS6128666B2 JP S6128666 B2 JPS6128666 B2 JP S6128666B2 JP 1795776 A JP1795776 A JP 1795776A JP 1795776 A JP1795776 A JP 1795776A JP S6128666 B2 JPS6128666 B2 JP S6128666B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- formula
- pyrrolidines
- present
- oxo
- 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
Links
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical class O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 4
- 150000003235 pyrrolidines Chemical class 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WAPNOHKVXSQRPX-UHFFFAOYSA-N 1-phenylethanol Chemical compound CC(O)C1=CC=CC=C1 WAPNOHKVXSQRPX-UHFFFAOYSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 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 description 1
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- XPNGNIFUDRPBFJ-UHFFFAOYSA-N alpha-methylbenzylalcohol Natural products CC1=CC=CC=C1CO XPNGNIFUDRPBFJ-UHFFFAOYSA-N 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical class C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- -1 α-methyl-α-phenyl-F-chlorobenzyl Chemical group 0.000 description 1
Landscapes
- Pyrrole Compounds (AREA)
Description
【発明の詳細な説明】 本発明は、ピロリジン類の製造法に関する。[Detailed description of the invention] The present invention relates to a method for producing pyrrolidines.
本発明者は、立体化学の研究上重要であり、か
つ直接医薬品としても用いられる新規且つ有用な
化合物であるピロリジン類を工業的に有利に製造
する方法を提供すべく研究をした結果、５−オキ
ソピロリジン類を還元することにより、高収率で
目的物を製造しうることを究明し、本発明に到達
したものである。 The present inventor conducted research to provide an industrially advantageous method for producing pyrrolidines, which are new and useful compounds that are important in stereochemistry research and can also be used directly as pharmaceuticals. The present invention was achieved by discovering that the desired product can be produced in high yield by reducing oxopyrrolidines.
すなわち、本発明は、
下記式〔〕
〔式中、Ｒは炭素数１〜４のアルキル基、
X1、X2はそれぞれ独立に水素、フツ素、塩素、
臭素を表わす。〕
で表わされる５−オキソ−ピロリジン類を還元す
ることを特徴とする下記式〔〕
〔式中、ＲおよびX1、X2の定義は上記に同
じ〕
で表わされるピロリジン類の製造法である。 That is, the present invention provides the following formula [] [In the formula, R is an alkyl group having 1 to 4 carbon atoms,
X 1 and X 2 are each independently hydrogen, fluorine, chlorine,
Represents bromine. ] The following formula [] is characterized by reducing 5-oxo-pyrrolidines represented by [In the formula, the definitions of R, X 1 and X 2 are the same as above] This is a method for producing pyrrolidines represented by the following formula.
本発明方法において用いられる上記式〔〕で
あらわされる５−オキソ−ピロリジン類は、新規
化合物であり、本発明方法ではピロリジン類の２
−位の炭素原子に対し光学活性体であつても、ラ
セミ体であつても、いずれでも使用することがで
きる。 The 5-oxo-pyrrolidines represented by the above formula [] used in the method of the present invention are new compounds.
Either an optically active form or a racemic form with respect to the carbon atom at the - position can be used.
かかる化合物は対応する５−オキソ−２−（β
−ハロエチル）−ピロリジン類と対応するベンズ
ヒドロール類とをアルカリの存在下に縮合せしめ
ることにより容易に製造することができる。 Such compounds have the corresponding 5-oxo-2-(β
-haloethyl)-pyrrolidines and the corresponding benzhydrols in the presence of an alkali.
上記式〔〕中、Ｒは炭素数１〜４のアルキル
基であり、X1、X2はそれぞれ独立に水素、フツ
素、塩素、臭素である。 In the above formula [], R is an alkyl group having 1 to 4 carbon atoms, and X 1 and X 2 are each independently hydrogen, fluorine, chlorine, or bromine.
本発明方法は、上記式〔〕で表わされる５−
オキソピロリジン類を還元することにより行なわ
れる。 The method of the present invention provides 5-
This is done by reducing oxopyrrolidines.
還元剤としては、LiAlH4、NaAlH2
（OCH2CH2OCH3）2等が好ましく用いられる。 As a reducing agent, LiAlH 4 , NaAlH 2
(OCH 2 CH 2 OCH 3 ) 2 and the like are preferably used.
反応溶媒としては、例えば、ジエチルエーテ
ル、テトラヒドロフラン、ジオキサン、モノグラ
イム、ジグライム等のエーテル類、またはＮ−メ
チルモルフオリン、Ｎ−エチルモルフオリン等の
Ｎ−アルキルモルフオリン類が好ましく用いられ
る。特に、NaAlH2（OCH2CH2OCH3）2
（Vitride）を用いる時は、ベンゼン、トルエン等
の芳香族炭化水素が好しく用いられる。反応温度
は、−20℃〜150℃、特に好ましくは０゜〜80℃で
ある。又、反応時間は還元剤の種類、溶媒および
反応温度によつて異なるが、通常15分ないし３時
間で十分である。しかして、本発明方法によれば
上記式〔〕で表わされるピロリジン誘導体を75
〜95％の高収率で取得することができる。反応生
成物よりの上記目的物の単離は蒸留、あるいはシ
リカゲルカラムクロマトグラフイーにより容易に
行うことができる。 As the reaction solvent, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, or N-alkylmorpholines such as N-methylmorpholine and N-ethylmorpholine are preferably used. In particular, NaAlH 2 (OCH 2 CH 2 OCH 3 ) 2
When (Vitride) is used, aromatic hydrocarbons such as benzene and toluene are preferably used. The reaction temperature is -20°C to 150°C, particularly preferably 0° to 80°C. Although the reaction time varies depending on the type of reducing agent, solvent and reaction temperature, 15 minutes to 3 hours is usually sufficient. According to the method of the present invention, the pyrrolidine derivative represented by the above formula [] can be
It can be obtained with high yields of ~95%. The target product can be easily isolated from the reaction product by distillation or silica gel column chromatography.
次に、実施例をあげて本発明を詳述するが本発
明はもとよりこれに限定されるものではない。 Next, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.
実施例 １
Ｄ−１−メチル−２−β−ブロモエチル−５−
オキソ−ピロリジンと１−（Ｐ−クロロフエニ
ル）−１−フエニルエタノールとを縮合させて得
られた２−〔２−〔（α−メチル−α−フエニル−
Ｐ−クロロベンジル）オキシ）−エチル〕−１−メ
チル−５−オキソピロリジン（3.5ｇ）のエーテ
ル溶液（100ml）に、氷冷下にリチウムアルミニ
ウムハイドライド（4.0ｇ）を添加した。冷却浴
を除き１時間加熱還流の後、再び冷却しながら５
mlの飽和食塩水を滴下し45分間撹拌した。生じた
白色固体を液を無水硫酸マグネシウムで乾燥し
た後濃縮すると、２−〔２−〔（α−メチル−α−
フエニル−Ｐ−クロロベンジル）オキシ〕エチ
ル〕−１−メチルピロリジンゐ粗生成物（3.4ｇ）
が得られた。この物を蒸留に付して２−〔２−
〔（α−メチル−α−フエニル−Ｆ−クロロベンジ
ル）オキシ〕エチル−１−メチルピロリジンの精
製物（2.9ｇ85％）を得た。この物は下記の物理
データを示し、よつて生成物と同定した。Example 1 D-1-methyl-2-β-bromoethyl-5-
2-[2-[(α-methyl-α-phenyl-
Lithium aluminum hydride (4.0 g) was added to an ether solution (100 ml) of P-chlorobenzyl)oxy)-ethyl]-1-methyl-5-oxopyrrolidine (3.5 g) under ice cooling. Remove the cooling bath and heat under reflux for 1 hour, then cool again for 5 minutes.
ml of saturated saline was added dropwise and stirred for 45 minutes. The resulting white solid was dried over anhydrous magnesium sulfate and then concentrated to give 2-[2-[(α-methyl-α-
Phenyl-P-chlorobenzyl)oxy]ethyl]-1-methylpyrrolidine crude product (3.4g)
was gotten. This material is subjected to distillation to give 2-[2-
A purified product (2.9 g, 85%) of [(α-methyl-α-phenyl-F-chlorobenzyl)oxy]ethyl-1-methylpyrrolidine was obtained. This material showed the following physical data and was therefore identified as the product.
b.p.：154℃（0.02mmＨｇ），
〔α〕２３ Ｄ＝＋41.1゜（CH9OH，Ｃ＝１），
IR（Neat or NaCl plate）：
3050，2900，2780，1480，1440cm-1，
NMR（100MHz，CDCl3，TMSよりの値）：
1.4〜2.6（8H，複雑なるｍ），
1.84 （3H，Ｓ），
2.33 （3H，Ｓ），
3.20 （3H，ｍ），
7.28 （9H，ｍ），
MS（70eV）：
342（Ｍ+），344（Ｍ+＋２），128，84
（100％），
実施例 ２
Ｌ−１−メチル−５−オキソ−２−β−ブロモ
エチルピロリジンと１−（Ｐ−クロロフエニル）−
１−フエニルエタノールとを縮合させて得られた
２−〔２−〔（α−メチル−α−フエニル−Ｐ−ク
ロロベンジル）オキシ〕エチル〕−１−メチル−
５−オキソピロリジン（5.0ｇ）のベンゼン溶液
（50ml）を、ナトリウムビスメトキシエトキシア
ルミニウムハイドライド（4.0ｇ）のベンゼン溶
液（50ml）に５℃にて滴下し、次で30分間加熱還
流した。再び５℃に冷却して飽和食塩水（５ml）
を添加し、室温下30分間撹拌した。生じた白色固
体を液し、液を芒硝で乾燥した後濃縮して得
られた液体を蒸留すると、２−〔２−〔（α−メチ
ル−α−フエニル−Ｐ−クロロベンジル）オキ
シ〕エチル〕−１−メチル−ピロリジン（3.7ｇ収
率77％）が得られた。この物は〔α〕２３ Ｄ＝−41.1
゜（CH3OH，Ｃ＝１）を示し、その他の物性デ
ータは実施例１の方法で得た生成物と全く同一で
あつた。 bp: 154℃ (0.02mmHg), [α] 23D = +41.1゜ (CH 9 OH, C = 1), IR (Neat or NaCl plate): 3050, 2900, 2780, 1480, 1440cm -1 , NMR (Values from 100MHz, CDCl 3 , TMS): 1.4 to 2.6 (8H, complicated m), 1.84 (3H, S), 2.33 (3H, S), 3.20 (3H, m), 7.28 (9H, m) , MS (70eV): 342 (M + ), 344 (M + +2), 128, 84
(100%), Example 2 L-1-methyl-5-oxo-2-β-bromoethylpyrrolidine and 1-(P-chlorophenyl)-
2-[2-[(α-methyl-α-phenyl-P-chlorobenzyl)oxy]ethyl]-1-methyl- obtained by condensation with 1-phenylethanol
A solution of 5-oxopyrrolidine (5.0 g) in benzene (50 ml) was added dropwise to a solution of sodium bismethoxyethoxyaluminum hydride (4.0 g) in benzene (50 ml) at 5°C, and then heated under reflux for 30 minutes. Cool to 5℃ again and add saturated saline (5ml)
was added and stirred at room temperature for 30 minutes. The resulting white solid was liquefied, the liquid was dried with Glauber's salt, and the resulting liquid was distilled to yield 2-[2-[(α-methyl-α-phenyl-P-chlorobenzyl)oxy]ethyl]. -1-Methyl-pyrrolidine (3.7 g, yield 77%) was obtained. This object is [α] 23 D = -41.1
(CH 3 OH, C=1), and other physical property data were exactly the same as the product obtained by the method of Example 1.
Claims (1)
X1，X2はそれぞれ独立に水素，フツ素，塩素，
臭素を表わす。〕 で表わされる５−オキソ−ピロリジン類を還元す
ることを特徴とする下記式〔〕 〔式中、ＲおよびX1，X2の定義は上記に同
じ〕 で表わされるピロリジン類の製造法。[Claims] 1. The following formula [] [In the formula, R is an alkyl group having 1 to 4 carbon atoms,
X 1 and X 2 are each independently hydrogen, fluorine, chlorine,
Represents bromine. ] The following formula [] is characterized by reducing 5-oxo-pyrrolidines represented by [In the formula, the definitions of R, X 1 and X 2 are the same as above] A method for producing pyrrolidines represented by the following.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1795776A JPS52102272A (en) | 1976-02-23 | 1976-02-23 | Synthesis of novel benzophenone derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1795776A JPS52102272A (en) | 1976-02-23 | 1976-02-23 | Synthesis of novel benzophenone derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS52102272A JPS52102272A (en) | 1977-08-27 |
| JPS6128666B2 true JPS6128666B2 (en) | 1986-07-01 |
Family
ID=11958218
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1795776A Granted JPS52102272A (en) | 1976-02-23 | 1976-02-23 | Synthesis of novel benzophenone derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS52102272A (en) |
-
1976
- 1976-02-23 JP JP1795776A patent/JPS52102272A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS52102272A (en) | 1977-08-27 |
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