JPH0549672B2 - - Google Patents
Info
- Publication number
- JPH0549672B2 JPH0549672B2 JP83179070A JP17907083A JPH0549672B2 JP H0549672 B2 JPH0549672 B2 JP H0549672B2 JP 83179070 A JP83179070 A JP 83179070A JP 17907083 A JP17907083 A JP 17907083A JP H0549672 B2 JPH0549672 B2 JP H0549672B2
- Authority
- JP
- Japan
- Prior art keywords
- vincamine
- formula
- bromo
- protecting group
- add
- 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 - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 15
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical class C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 229960002726 vincamine Drugs 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 229950002641 brovincamine Drugs 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000031709 bromination Effects 0.000 description 4
- 238000005893 bromination reaction Methods 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- KRZJRNZICWNMOA-GXSJLCMTSA-N (3s,4r)-4,8-dihydroxy-3-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=CC=C2[C@@H](O)[C@@H](OC)CC(=O)C2=C1O KRZJRNZICWNMOA-GXSJLCMTSA-N 0.000 description 1
- ZXZLVQGNVOKCAS-UHFFFAOYSA-N 4-(cyclopentylamino)-2-[(2-methoxyphenyl)methylamino]-n-[3-(2-oxopyrrolidin-1-yl)propyl]pyrimidine-5-carboxamide Chemical compound COC1=CC=CC=C1CNC(N=C1NC2CCCC2)=NC=C1C(=O)NCCCN1C(=O)CCC1 ZXZLVQGNVOKCAS-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride 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
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 本発明は、式： （式中、Ｘは10位または11位の臭素を表わす。） 示されるビンカミン誘導体の製法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the formula: (In the formula, X represents bromine at the 10th or 11th position.) The present invention relates to a method for producing the vincamine derivative shown.
式の化合物は、3S、14S、16Sの配位を示す。
式の化合物は、スイス特許第593283号、スイス
特許第633797号およびアメリカ特許第4146643号
に開示された物質であり、それらの開示自体、本
明細書の一部としてここに引用する。式の化合
物は、脳不全処理の薬剤として有用であることが
認められている。上記の明細書には、ビンカミン
を直接ブロム化する製法が記載されているが、本
発明は保護基の導入を行つてからブロム化を行う
製法である。これによつて驚くべき利点が見出さ
れたのであつて、たとえば14位におけるエピマー
化が阻害されるため、副生物の生成が著しく抑制
され、式が高収量かつ高純度で得られるに至つ
た。 The compound of formula exhibits 3S, 14S, 16S coordination.
Compounds of formula are those disclosed in Swiss Patent No. 593283, Swiss Patent No. 633797 and US Pat. No. 4,146,643, the disclosures of which are incorporated herein by reference. Compounds of formula have been found to be useful as agents in the treatment of brain failure. Although the above specification describes a production method in which vincamine is directly brominated, the present invention is a production method in which bromination is carried out after introducing a protecting group. Surprising advantages have been found in this, for example, by inhibiting epimerization at position 14, the formation of by-products is significantly suppressed, and the formula can be obtained in high yield and purity. .
本発明によれば、式のビンカミン誘導体の遊
離塩基または酸付加塩は、式：
（式中、Ｘは前記と同意義であり、Ｒは保護基を
表わす。）
で示される化合物から保護基を離脱せしめ、生成
する式の化合物を遊離塩基または酸付加塩とし
て採取することによつて得られる。 According to the invention, the free base or acid addition salt of a vincamine derivative of the formula: (In the formula, X has the same meaning as above, and R represents a protecting group.) By removing the protecting group from the compound represented by the formula and collecting the resulting compound of the formula as a free base or an acid addition salt. You can get it.
ここにおいてＲは、ブロム化条件下でROH基
の分解がなるべく生じ難いようなものであること
を要する。そのようなものとして、たとえばトリ
メチルシリル基が挙げられる。トリメチルシリル
保護基の離脱は自体公知の方法で行われてよい。
たとえば、式の化合物をメタノールの如き不活
性溶媒中、硫酸の如き酸の存在下で処理すればよ
い。反応温度は通常０〜50℃である。 Here, R is required to be such that decomposition of the ROH group is as unlikely to occur under the bromination conditions. Such a group includes, for example, a trimethylsilyl group. Removal of the trimethylsilyl protecting group may be carried out by methods known per se.
For example, a compound of formula may be treated in an inert solvent such as methanol in the presence of an acid such as sulfuric acid. The reaction temperature is usually 0 to 50°C.
生成した式の化合物は自体常套の方法、たと
えばクロマトグラフイーや再結晶により単離、精
製することが出来る。 The produced compound of the formula can be isolated and purified by conventional methods such as chromatography or recrystallization.
原料物質としての式の化合物は、式：
（式中、Ｒは保護基を表わす。）
で示される化合物をブロム化することによつて得
られる。ブロム化は自体常套の方法、たとえばス
イス特許第593283号やアメリカ特許第4146643号
に開示されているように−79〜−10℃の温度で臭
素と処理すればよい（後記実施例(b)参照）。 A compound of the formula as a raw material has the formula: (In the formula, R represents a protecting group.) It can be obtained by brominating the compound shown below. Bromination can be carried out in a conventional manner, for example by treatment with bromine at a temperature of -79 to -10°C, as disclosed in Swiss Patent No. 593,283 and US Pat. No. 4,146,643 (see Example (b) below). ).
式の化合物は、ビンカミンをたとえばトリメ
チルシリル保護基で保護すればよい（後記実施例
(a)参照）。 In the compound of the formula, vincamine may be protected with, for example, a trimethylsilyl protecting group (see Examples below).
(see (a)).
以下に実施例を挙げて本発明を更に具体的に説
明する。なお、温度はすべて摂氏である。 The present invention will be explained in more detail with reference to Examples below. Note that all temperatures are in degrees Celsius.
実施例
（3S、14S、16S）−11−ブロム−ビンカミンと
（3S、14S、16S）−10−ブロム−ビンカミン
後記(b)における生成物、すなわち（3S、14S、
16S）−11−ブロム−ビンカミン−トリメチルシ
リルエーテルと（3S、14S、16S）−10−ブロム−
ビンカミン−トリメチルシリルエーテルをメタノ
ール530mlに懸濁させ、冷却下、硫酸120ｇの水
550ml溶液を加える。この懸濁液を室温で数時間
反応させてから、10℃に保持した約25％アンモニ
ア水295mlと水420mlの混液に加える。これによつ
て反応成績体は直ちに沈殿する。この懸濁物を10
℃で約30分間攪拌し、ガラスフイルターで過す
る。取物を水洗し、湿つた結晶を減圧乾燥す
る。Example (3S, 14S, 16S)-11-bromo-vincamine and (3S, 14S, 16S)-10-bromo-vincamine The product in (b) below, i.e. (3S, 14S,
16S)-11-bromo-vincamine-trimethylsilyl ether and (3S, 14S, 16S)-10-bromo-
Vincamine-trimethylsilyl ether was suspended in 530 ml of methanol, and while cooling, 120 g of sulfuric acid and water were added.
Add 550ml solution. This suspension is allowed to react at room temperature for several hours and then added to a mixture of about 295 ml of 25% aqueous ammonia and 420 ml of water kept at 10°C. As a result, the reaction product is immediately precipitated. 10 of this suspension
Stir for about 30 minutes at °C and filter through a glass filter. Wash the sample with water and dry the wet crystals under reduced pressure.
得られた粗結晶をキーゼルゲル上のクロマトグ
ラフイーに付し、溶剤としてメチレンクロリド／
メタノール（98：２）を用いて溶出し、２−プロ
パノールから再結晶すれば純粋な（3S、14S、
16S）−11−ブロム−ビンカミンが得られる。 The obtained crude crystals were subjected to chromatography on Kieselgel, using methylene chloride/methylene chloride as a solvent.
Elution with methanol (98:2) and recrystallization from 2-propanol yields pure (3S, 14S,
16S)-11-bromo-vincamine is obtained.
融点214℃（分解）
［α］20 D＝＋8.7゜（１％、クロロホルム）
常套の方法により、（3S、14S、16S）−11−ブ
ロム−ビンカミンとフマール酸から、（3S、14S、
16S）−11−ブロム−ビンカミン・水素フマール
酸塩を得る。融点180℃。純度98〜99％以上。 Melting point 214℃ (decomposition) [α] 20 D = +8.7゜ (1%, chloroform) From (3S, 14S, 16S)-11-bromo-vincamine and fumaric acid, (3S, 14S,
16S)-11-bromo-vincamine hydrogen fumarate is obtained. Melting point: 180℃. Purity 98-99% or higher.
粗結晶をキーゼルゲル上のクロマトグラフイー
に付し、溶剤として３％メタノール含有クロロホ
ルムを用いて溶出し、純粋な（3S、14S、16S）−
10−ブロム−ビンカミンを得る。 The crude crystals were chromatographed on Kieselgel and eluted with chloroform containing 3% methanol as the solvent to obtain pure (3S, 14S, 16S)-
10-bromo-vincamine is obtained.
融点202〜205℃
［α］20 D＝＋35.2゜（ｃ＝１、クロロホルム）
原料物質として使用された（3S、14S、16S）−
11−ブロム−ビンカミン−トリメチルシリルエー
テルと（3S、14S、16S）−10−ブロム−ビンカミ
ン−トリメチルシリルエーテルは次のとおり製造
された。 Melting point 202-205℃ [α] 20 D = +35.2゜ (c = 1, chloroform) (3S, 14S, 16S) used as raw material -
11-bromo-vincamine-trimethylsilyl ether and (3S, 14S, 16S)-10-bromo-vincamine-trimethylsilyl ether were produced as follows.
(a) （3S、14S、16S）−ビンカミン−トリメチル
シリエーテル
窒素気流下、水素化ナトリウム31.18ｇにテ
トラヒドロフラン900mlを加える。この灰色懸
濁液に冷却下（3S、14S、16S）−ビンカミン
100ｇを添加する。テトラヒドロフラン100mlを
加えてから、２〜３時間反応を継続する。−２
℃まで冷却し、トリメチル塩化シリル38.3ｇを
−２〜０℃で滴加する。滴加ロートをテトラヒ
ドロフラン５mlで洗う。同様の温度で酢酸42.5
ｇを加える。反応混合物を室温まで温め、水
300mlを加える。アンモニア水が重量比で１：
２の混合物約18mlを加えて、PH９〜10に調整す
ると２層に分離する。下層の水層をテトラヒド
ロフラン100mlで抽出する。テトラヒドロフラ
ン層を合し、出来る限り、濃縮する。残留物に
メタノール270mlを加え、攪拌して懸濁物を得、
再度出来る限り濃縮する。残渣にメタノール
100mlと水200mlを加え、室温で１時間攪拌し、
過する。取物を水で洗い、乾燥すると粗結
晶を得る。これはそのままブロム化に使用する
ことが出来る。(a) (3S, 14S, 16S)-vincamine-trimethylsilyether Add 900 ml of tetrahydrofuran to 31.18 g of sodium hydride under a nitrogen stream. Vincamine under cooling (3S, 14S, 16S) in this gray suspension
Add 100g. After adding 100 ml of tetrahydrofuran, the reaction is continued for 2-3 hours. -2
Cool to 0.degree. C. and add 38.3 g of trimethylsilyl chloride dropwise at -2 to 0.degree. Wash the addition funnel with 5 ml of tetrahydrofuran. Acetic acid 42.5 at similar temperature
Add g. Warm the reaction mixture to room temperature and add water
Add 300ml. Ammonia water in a weight ratio of 1:
Add about 18 ml of the mixture in step 2 and adjust the pH to 9-10, and the mixture will separate into two layers. Extract the lower aqueous layer with 100 ml of tetrahydrofuran. Combine the tetrahydrofuran layers and concentrate as much as possible. Add 270ml of methanol to the residue and stir to obtain a suspension.
Concentrate again as much as possible. methanol to the residue
Add 100ml and 200ml of water, stir at room temperature for 1 hour,
pass Wash the sample with water and dry to obtain crude crystals. This can be used as is for bromination.
４〜５倍量のエチルメチルケトンから再結晶
すると純品が得られる。融点182.5〜184.5℃。 A pure product can be obtained by recrystallization from 4 to 5 times the amount of ethyl methyl ketone. Melting point 182.5-184.5℃.
(b) （3S、14S、16S）−11−ブロム−ビンカミン
シリルエーテルと（3S、14S、16S）−10−ブロ
ム−ビンカミンシリルエーテル
窒素雰囲気下、塩化亜鉛35.1ｇと酢酸エチル
820mlをよく攪きまぜて澄明溶液とし、−43℃ま
で冷却する。これにブロム43.1ｇの酢酸エチル
480ml溶液を−43〜−40℃で滴加する。同時に、
（3S、14S、16S）−ビンカミン−トリメチルシ
リルエーテル100ｇを12回にわけて添加する。
３時間にわたつて反応を行わせた後、反応混合
物をアンモニア200mlと水500mlの混合物に加え
る。これによつて２層に分離するから、下方の
水層をとり、酢酸エチル840mlで抽出する。有
機層を合し、出来る限り濃縮し、残渣にメタノ
ール150mlを加え、濃縮する。得られた残渣は
そのままシリルエーテルの脱離反応に使用する
ことが出来る。(b) (3S, 14S, 16S)-11-bromo-vincamine silyl ether and (3S, 14S, 16S)-10-bromo-vincamine silyl ether 35.1 g of zinc chloride and ethyl acetate under nitrogen atmosphere
Stir 820 ml well to make a clear solution and cool to -43°C. Add to this 43.1g of bromine and ethyl acetate.
Add 480 ml solution dropwise at -43 to -40°C. at the same time,
Add 100 g of (3S, 14S, 16S)-vincamine-trimethylsilyl ether in 12 portions.
After running the reaction for 3 hours, the reaction mixture is added to a mixture of 200 ml ammonia and 500 ml water. This separates into two layers, and the lower aqueous layer is taken and extracted with 840 ml of ethyl acetate. Combine the organic layers and concentrate as much as possible, add 150 ml of methanol to the residue, and concentrate. The obtained residue can be used as it is in the elimination reaction of silyl ether.
９倍量の２−プロパノールから再結晶すると
純粋の（3S、14S、16S）−11−ブロム−ビンカ
ミンシリルエーテルが得られる。融点約160℃
（分解）。 Recrystallization from 9 times the amount of 2-propanol yields pure (3S, 14S, 16S)-11-bromo-vincamine silyl ether. Melting point approximately 160℃
(Disassembly).
キーゼルゲル上のクロマトグラフイーに付
し、ヘキサン100溶、クロロホルム10溶、ジメ
チルホルムアミド８溶および酢酸１溶から成る
溶媒系で溶出すると純粋の（3S、14S、16S）−
10−ブロム−ビンカミンシリルエーテルが得ら
れる。 Chromatography on Kieselgel and elution with a solvent system consisting of 100 parts of hexane, 10 parts of chloroform, 8 parts of dimethylformamide and 1 part of acetic acid resulted in pure (3S, 14S, 16S)-
10-bromo-vincamine silyl ether is obtained.
なお、（3S、14S、16S）−ビンカミンからの
（3S、14S、16S）−ビンカミン−トリメチルシ
リルエーテルの収率は94％以上である。また、
（3S、14S、16S）−ビンカミン−トリメチルシ
リルエーテルからの（3S、14S、16S）−11−ブ
ロム−ビンカミンの収率は72％以上であり、他
のブロム−ビンカミン類の収率は13％以下であ
る。 Note that the yield of (3S, 14S, 16S)-vincamine-trimethylsilyl ether from (3S, 14S, 16S)-vincamine is 94% or more. Also,
The yield of (3S, 14S, 16S)-11-bromo-vincamine from (3S, 14S, 16S)-vincamine-trimethylsilyl ether is more than 72%, and the yield of other bromo-vincamines is less than 13%. It is.
Claims (1)
で取得することを特徴とするビンカミン誘導体の
製法（式中、Ｘは10位または11位の臭素、Ｒは保
護基を表わす。）。 ２ 式： で示される化合物をブロム化して、 式： で示される化合物を得ることを特徴とするビンカ
ミン誘導体の製法（式中、Ｘは10位または11位の
臭素、Ｒは保護基を表わす。）。 ３ ビンカミンのヒドロキシ基に保護基Ｒを導入
して、 式： で示される化合物を得ることを特徴とするビンカ
ミン誘導体の製法（式中、Ｒは保護基を表わ
す。）。[Claims] 1 Formula: The protecting group R is removed from the compound represented by the formula: A method for producing a vincamine derivative, which comprises obtaining the compound represented by the above in the form of a free base or an acid addition salt (wherein, X is bromine at the 10th or 11th position, and R represents a protecting group). 2 formula: By brominating the compound represented by the formula: A method for producing a vincamine derivative, which is characterized by obtaining a compound represented by the formula (wherein, X is bromine at the 10th or 11th position, and R represents a protecting group). 3 Introducing a protecting group R to the hydroxy group of vincamine, formula: A method for producing a vincamine derivative, characterized by obtaining a compound represented by (wherein R represents a protecting group).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH5682/82 | 1982-09-27 | ||
| CH5682/82A CH651039A5 (en) | 1982-09-27 | 1982-09-27 | Process for preparing a vincamine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5980681A JPS5980681A (en) | 1984-05-10 |
| JPH0549672B2 true JPH0549672B2 (en) | 1993-07-26 |
Family
ID=4297625
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58179070A Granted JPS5980681A (en) | 1982-09-27 | 1983-09-26 | Manufacture of vincamine derivative |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS5980681A (en) |
| CH (1) | CH651039A5 (en) |
-
1982
- 1982-09-27 CH CH5682/82A patent/CH651039A5/en not_active IP Right Cessation
-
1983
- 1983-09-26 JP JP58179070A patent/JPS5980681A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| CH651039A5 (en) | 1985-08-30 |
| JPS5980681A (en) | 1984-05-10 |
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