CN104529872A - Synthetic method for benidipine hydrochloride intermediate - Google Patents
Synthetic method for benidipine hydrochloride intermediate Download PDFInfo
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- CN104529872A CN104529872A CN201410747523.2A CN201410747523A CN104529872A CN 104529872 A CN104529872 A CN 104529872A CN 201410747523 A CN201410747523 A CN 201410747523A CN 104529872 A CN104529872 A CN 104529872A
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- benzyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a synthetic method for a benidipine hydrochloride intermediate. The synthetic method comprises performing a nucleophilic substitution reaction on 3-hydroxypyridine and a benzyl halide under a solvent refluxing condition, so as to generate 1-benzyl-3-hydroxypyridiniumhalide; taking an alcohol as a solvent and reducing 1-benzyl-3-hydroxypyridiniumhalide to generate 1-benzyl-3-piperidinol; then performing transesterification reaction on 1-benzyl-3-piperidinol and ethyl acetoacetate under a refluxing condition by taking toluene as a solvent in the presence/absence of a catalyst, and under the condition that less than 30% of the alcohol is left, performing normal-pressure distillation until the alcohol completely finishes reaction, so as to obtain the product. The synthetic method is simple and has the three-step total yield of 80% or more, and all employed materials are industrialized products and are cheap and easily obtained, and the quality is easily controlled.
Description
Technical field
The invention belongs to medical chemistry synthesis technical field, relate to a kind of synthetic method of KW-3049 intermediate.
Background technology
KW-3049, molecular formula is C
28h
32clN
3o
6, chemical name is (R, R)-(+/-)-2,6-dimethyl-4-(3-oil of mirbane)-Isosorbide-5-Nitrae-dihydro-3,5-pyridine dicarboxylic acids-methyl-(R)-1-benzyl-3-piperidyl ester hydrochloride, and structural formula is as follows:
KW-3049, is a kind of dihydropyridine calcium ion antagonist, is combined with dihydropyridines receptor binding site, has efficient, specific restraining effect to calcium channel.KW-3049 not only has restraining effect to muscularity (L-type) calcium channel, still has restraining effect to voltage independent type N-type and T-shaped calcium channel, is unique to above-mentioned three kinds of effective calcium ion antagonists of passage tool at present.In addition, KW-3049 also has the high affinity interaction of cell membrane, cardioselective effect and renal protection, is a kind of desirable, hypertension and disease such as treatment Renal hypertension, stenocardia etc. safely and effectively medicine.
For the synthesis of KW-3049, be done research for a long time.Nineteen eighty-three EP0106275A2 refer to the KW-3049 compound with treatment hypertension and stenocardia effect first, and proposes following five routes.JP61158962 and JP2005289894 successively reports the Optimization Technology of route Scheme 4 afterwards.
Scheme 5：
From top alignment analysis, 3-hydroxy piperidine has all been used in Scheme 1 and Scheme 2, and 3-hydroxy piperidine itself has two can participate in reaction and active similar alcoholic extract hydroxyl group and secondary amino group, so the by product needed outside product can be generated, by product is similar to product property, add very large purifying difficulty, also result in the waste of raw material simultaneously, and relative to the market value of present KW-3049, the raw material that 3-hydroxy piperidine is somewhat expensive at last, therefore these two lines are not preferred routes.And following three all each have their own advantages of route, but they have used compd A (chemical name: etheric acid (1-benzyl-3-piperidyl) ester) and have synthesized, and up to the present, the preparation method of compd A rarely has report.
Summary of the invention
Compd A is as preparing the important intermediate of KW-3049, and a kind of suitable preparation method is absolutely necessary.The invention provides that a raw material is cheaply easy to get, simple to operation and easy the to be industrialized route that yield is higher.
Technical scheme of the present invention is as follows:
A synthetic method for KW-3049 intermediate, is characterized in that being undertaken by following step:
(1) there is nucleophilic substitution reaction in 3-pyridone and halogenation benzyl under the condition of solvent refluxing, generates 1-benzyl-3-pyridone drone halogenide;
Halogenation benzyl in step 1 refers to Benzyl Chloride or cylite; The solvent of indication selects to but is not limited to following solvent: toluene, dimethylbenzene, acetonitrile, methyl alcohol, ethanol, Virahol, particular methanol, acetonitrile, toluene; Wherein the molar ratio of 3-pyridone and halogenation benzyl is 1:1.2-1.5.
(2) take alcohol as solvent, 1-benzyl-3-pyridone drone halogenide is become 1-benzyl-3-piperidine alcohols by sodium borohydride reduction;
In step 2, alcohol selects to but is not limited to following solvent: methyl alcohol, ethanol, Virahol, particular methanol; Wherein the molar ratio of 1-benzyl-3-pyridone drone halogenide and sodium borohydride is 1:3-5; The reaction of step 2 is accelerated along with the rising speed of response of temperature, and temperature of reaction preferably refluxes.
(3) 1-benzyl-3-piperidine alcohols and methyl aceto acetate or methyl esters take toluene as solvent, under the existence having catalyzer or catalyst-free, there is transesterification reaction and generate etheric acid (1-benzyl-3-piperidyl) ester in backflow, and when alcohol is left to be less than 30%, air distillation, until react completely.
Catalyzer described in step 3 refers to boric acid, manganous sulfate, manganous carbonate, iodine or DMAP, and reaction is very fast in the presence of a catalyst, reacts relatively slow, preferably add catalyzer boric acid, manganous sulfate when catalyst-free; Wherein 1-benzyl-3-piperidine alcohols: methyl aceto acetate or methyl esters: the mol ratio of catalyzer is 1:1.2-2:0.1-0.2 or 0.
Synthetic route of the present invention is as follows:
The positively effect that the synthetic method of KW-3049 intermediate disclosed by the invention is compared with prior art had is:
(1) comprehensively current documents and materials, neither one specifically prepares the method for compd A, the invention provides one
The concrete route of synthetic compound A;
(2) material used by route provided by the invention is all industrialization product, cheap and easy to get, all has commercially available;
(3) route provided by the invention is not only simple to operate, and yield is higher, and three step total recoverys are more than 80%.
Embodiment:
Following embodiment is convenient to understand the present invention better, but does not limit the present invention.
Embodiment 1:
Drone the halid preparation of 1-benzyl-3-pyridone:
Successively methyl alcohol (10 L), 3-pyridone (1 kg) and cylite (2.15 kg) are added in 20 L reaction flasks of stirring, are heated to backflow, within 3 hours, react completely, direct concentrating under reduced pressure steams methyl alcohol, with sherwood oil making beating washing, filters, dry, obtain white solid 2.73 kg.
LCMS（ESI）：186[M-Br
-]
Successively by acetonitrile (150 mL), 3-pyridone (10 g) and Benzyl Chloride (19.9 g) are added in 250 mL reaction flasks, be heated to backflow, within 2 hours, react completely, directly concentrating under reduced pressure steams acetonitrile, with sherwood oil making beating washing, filters, dry, obtain white solid 22.6g.
Embodiment 2:
The preparation of 1-benzyl-3-piperidine alcohols:
Methyl alcohol (10 L) and 1-benzyl-3-pyridone drone bromide, (500 g) are added in reaction flask, add sodium borohydride (215 g) in batches, temperature is no more than 25 DEG C, after adding, be heated to backflow, react 4 hours, react completely, be cooled to 0 ~ 10 DEG C, drip hydrochloric acid, adjust pH value to 8, concentrating under reduced pressure goes out solvent, add ethyl acetate and saturated common salt water dissolution, separatory, to be extracted with ethyl acetate in aqueous phase product twice, combined ethyl acetate phase, with anhydrous sodium sulfate drying, filter, concentrated dryly obtain light yellow oil 342.6 g.
LCMS（ESI）：192[M+H
+]
Ethanol (1 L) and 1-benzyl-3-pyridone drone muriate, (50 g) are added in reaction flask, add sodium borohydride (43 g) in batches, temperature is no more than 25 DEG C, after adding, be heated to backflow, react 2 ~ 3 hours, react completely, be cooled to 0 ~ 10 DEG C, drip hydrochloric acid, adjust pH value to 8, concentrating under reduced pressure goes out solvent, add ethyl acetate and saturated common salt water dissolution, separatory, to be extracted with ethyl acetate in aqueous phase product twice, combined ethyl acetate phase, with anhydrous sodium sulfate drying, filter, concentrated dryly obtain light yellow oil 38.9 g.
Embodiment 3:
The preparation of etheric acid (1-benzyl-3-piperidyl) ester:
By 1-benzyl-3-piperidine alcohols, (600 g), toluene (6 L), (490.2 g) for methyl aceto acetate, (19.5 g) are added in the reaction flask of 10 L boric acid, heated overnight at reflux, HPLC detects, 1-benzyl-3-piperidine alcohols residue 26.2%, add atmospheric distillation plant, steam the ethanol that reaction generates, within 2 hours, react completely, be cooled to 0 ~ 10 DEG C, adjust pH value to being about 3, by water (1 L × 2) extracted products, merge aqueous phase, and the pH value of aqueous phase is transferred to is about 7, extract by ethyl acetate (1L × 2), merge organic phase, wash with saturated aqueous common salt (500 mL × 2), with anhydrous sodium sulfate drying, filter, concentrated dryly obtain yellow oil 786.1 g.
LCMS（ESI）：276[M+H
+]
1HNMR（DMSO，400 M）：δ=1.26-1.83（m,4H), 2.09-2.13（m,2H), 2.17(s,3H), 2.50-2.53(m,1H)，2.66-2.80(m,1H), 3.56(s, 2H), 3.48(s, 2H), 4.72-4.76(m, 1H), 7.22-7.33(m, 5H).
By 1-benzyl-3-piperidine alcohols, (20 g), toluene (200 mL), (24.3 g) are added in the reaction flask of 500 mL methyl acetoacetate, reflux 24 hours, HPLC detects, 1-benzyl-3-piperidine alcohols residue 27.0%, add atmospheric distillation plant, steam the ethanol that reaction generates, within 2 hours, react completely, be cooled to 0 ~ 10 DEG C, adjust pH value to being about 3, by water (50 mL × 2) extracted products, merge aqueous phase, and the pH value of aqueous phase is transferred to is about 7, extract by ethyl acetate (50 mL × 2), merge organic phase, wash with saturated aqueous common salt (30 mL × 2), with anhydrous sodium sulfate drying, filter, concentrated dryly obtain yellow oil 25.1 g.
By 1-benzyl-3-piperidine alcohols, (20 g), toluene (200 mL), (24.3 g) for methyl acetoacetate, (3.54 g) are added in the reaction flask of 500 mL manganous sulfate, reflux 6 hours, HPLC detects, 1-benzyl-3-piperidine alcohols residue 25.6%, add atmospheric distillation plant, steam the ethanol that reaction generates, within 2 hours, react completely, be cooled to 0 ~ 10 DEG C, adjust pH value to being about 3, by water (50 mL × 2) extracted products, merge aqueous phase, and the pH value of aqueous phase is transferred to is about 7, extract by ethyl acetate (50 mL × 2), merge organic phase, wash with saturated aqueous common salt (30 mL × 2), with anhydrous sodium sulfate drying, filter, concentrated dryly obtain yellow oil 26.5 g.
Conclusion: the synthetic method of preparation KW-3049 midbody compound A proposed by the invention, raw material is all industrialization product, cheap and easy to get, and technological operation is simple, and three step total recoverys are greater than 80%.This route is a very easily industrialized route.
Embodiment 4:
Compd A of the present invention (chemical name: etheric acid (1-benzyl-3-piperidyl) ester) is adopted to prepare KW-3049:
Successively 2-(3-nitro-benzylidene) (9.96 g), (12.1 g) and ammoniacal liquor (29% for ethanol (50 mL), etheric acid (1-benzyl-3-piperidyl) ester for-3-Oxo-butyric acid methyl, 3.52 g) are added in the there-necked flask of 100 mL, be heated to backflow, react 12 hours.Concentrating under reduced pressure falls solvent, cross post and be separated (methylene dichloride: methyl alcohol (volume ratio)=15:1), obtain the crude product containing free benidipine, dissolve with methylene dichloride (200), add 4N hydrochloric acid (40 mL) and stir 30 minutes, separatory, organic phase uses saturated aqueous common salt (70 mL × 2) to wash again, with anhydrous sodium sulfate drying, concentrated dry, add ethanol (12 mL) and acetone (108 mL) recrystallization obtains 6.2 g KW-3049
LCMS（ESI）：506[M-Cl
-]
1HNMR（DMSO，400 M）：δ=1.31-2.25（m,4H）, 2.33(s,6H), 2.70-3.42(m,4H), 3.57(s, 3H), 4.40(s, 2H), 4.98 (m, 1H), 5.20(s, 1H), 7.31-8.24(m, 9H), 9.47(s,1H)。
Claims (8)
1. a synthetic method for KW-3049 intermediate, is characterized in that being undertaken by following step::
(1) there is nucleophilic substitution reaction in 3-pyridone and halogenation benzyl under the condition of solvent refluxing, generates 1-benzyl-3-pyridone drone halogenide;
(2) take alcohol as solvent, 1-benzyl-3-pyridone drone halogenide is become 1-benzyl-3-piperidine alcohols by sodium borohydride reduction;
(3) 1-benzyl-3-piperidine alcohols and methyl aceto acetate or methyl esters take toluene as solvent, under the existence having catalyzer or catalyst-free, there is transesterification reaction and generate etheric acid (1-benzyl-3-piperidyl) ester in backflow, and when alcohol is left to be less than 30%, air distillation, until alcohol reacts completely.
2. preparation method according to claim 1, the halogenation benzyl wherein described in step 1 refers to Benzyl Chloride, cylite.
3. preparation method according to claim 1, the solvent wherein described in step 1 selects to but is not limited to following solvent: toluene, dimethylbenzene, acetonitrile, methyl alcohol, ethanol, Virahol.
4. preparation method according to claim 1, wherein in step 1, the molar ratio of 3-pyridone and halogenation benzyl is 1:1.2-1.5.
5. preparation method according to claim 1, the alcohol wherein in step 2 selects to but is not limited to following solvent: methyl alcohol, ethanol, Virahol.
6. preparation method according to claim 1, wherein in step 2, the molar ratio of 1-benzyl-3-pyridone drone halogenide and sodium borohydride is 1:3-5.
7. preparation method according to claim 1, the catalyzer wherein described in step 3 refers to boric acid, manganous sulfate, manganous carbonate, iodine or DMAP.
8. preparation method according to claim 1, wherein 1-benzyl-3-piperidine alcohols in step 3: methyl aceto acetate or methyl esters: the mol ratio of catalyzer is 1:1.2-2:0.1-0.2 or 0.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107698493A (en) * | 2017-11-15 | 2018-02-16 | 上海皓伯化工科技有限公司 | A kind of preparation method of the piperidones of N Boc 3 |
| CN111778297A (en) * | 2020-06-02 | 2020-10-16 | 山东华素制药有限公司 | Improved synthesis method of 1-benzyl-3-piperidinol intermediate |
| CN112724070A (en) * | 2021-01-08 | 2021-04-30 | 南京方生和医药科技有限公司 | Preparation method of alpha, alpha-diphenyl-4-piperidinemethanol |
| CN114907256A (en) * | 2022-04-18 | 2022-08-16 | 苏州东瑞制药有限公司 | Preparation method of benidipine hydrochloride |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0063365A1 (en) * | 1981-04-17 | 1982-10-27 | Kyowa Hakko Kogyo Co., Ltd. | 1,4-Dihydropyridine derivative and pharmaceutical composition containing same |
| EP0106275A2 (en) * | 1982-10-15 | 1984-04-25 | Kyowa Hakko Kogyo Co., Ltd. | 1,4-Dihydropyridine derivatives |
| CN102351783A (en) * | 2011-08-23 | 2012-02-15 | 兰州博氏精细化工有限公司 | Synthesizing method of 1-benzyl-piperidone hydrochloride |
| CN103204801A (en) * | 2013-04-12 | 2013-07-17 | 兰州远辉生物科技有限公司 | Synthesis method for N-Boc-3-piperidone |
-
2014
- 2014-12-10 CN CN201410747523.2A patent/CN104529872B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0063365A1 (en) * | 1981-04-17 | 1982-10-27 | Kyowa Hakko Kogyo Co., Ltd. | 1,4-Dihydropyridine derivative and pharmaceutical composition containing same |
| EP0106275A2 (en) * | 1982-10-15 | 1984-04-25 | Kyowa Hakko Kogyo Co., Ltd. | 1,4-Dihydropyridine derivatives |
| CN102351783A (en) * | 2011-08-23 | 2012-02-15 | 兰州博氏精细化工有限公司 | Synthesizing method of 1-benzyl-piperidone hydrochloride |
| CN103204801A (en) * | 2013-04-12 | 2013-07-17 | 兰州远辉生物科技有限公司 | Synthesis method for N-Boc-3-piperidone |
Non-Patent Citations (1)
| Title |
|---|
| G. C. M. KONDAIAH等: "Boric acid: an efficient and environmentally benign catalyst for transesterification of ethyl acetoacetate", 《TETRAHEDRON LETTERS》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107698493A (en) * | 2017-11-15 | 2018-02-16 | 上海皓伯化工科技有限公司 | A kind of preparation method of the piperidones of N Boc 3 |
| CN111778297A (en) * | 2020-06-02 | 2020-10-16 | 山东华素制药有限公司 | Improved synthesis method of 1-benzyl-3-piperidinol intermediate |
| CN111778297B (en) * | 2020-06-02 | 2022-07-29 | 山东华素制药有限公司 | Improved synthesis method of 1-benzyl-3-piperidinol intermediate |
| CN112724070A (en) * | 2021-01-08 | 2021-04-30 | 南京方生和医药科技有限公司 | Preparation method of alpha, alpha-diphenyl-4-piperidinemethanol |
| CN114907256A (en) * | 2022-04-18 | 2022-08-16 | 苏州东瑞制药有限公司 | Preparation method of benidipine hydrochloride |
| CN114907256B (en) * | 2022-04-18 | 2024-01-12 | 苏州东瑞制药有限公司 | Preparation method of benidipine hydrochloride |
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