CN1330636C - Synthesis process of Tilofiban hydrochloride intermediate - Google Patents
Synthesis process of Tilofiban hydrochloride intermediate Download PDFInfo
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- CN1330636C CN1330636C CNB2005101052019A CN200510105201A CN1330636C CN 1330636 C CN1330636 C CN 1330636C CN B2005101052019 A CNB2005101052019 A CN B2005101052019A CN 200510105201 A CN200510105201 A CN 200510105201A CN 1330636 C CN1330636 C CN 1330636C
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- pyridyl
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- butyryl chloride
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- chloride
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Abstract
The present invention discloses a method for synthesizing intermediate 4-(4-pyridyl) butyl chloride of tirofiban hydrochloride monohydrate which is a medicine for treating angina pectoris.
Description
Technical field
The present invention relates to prepare the key intermediate of Tirofiban hydrochloride---the new chemical process of 4-(4-pyridyl) Butyryl Chloride.
Background technology
Tirofiban hydrochloride (English name: Tirofiban hydrochloride, chemical name: (S)-N-(normal-butyl alkylsulfonyl)-O-[4-(4-piperidyl) butane]-L-tyrosine hydrochloride monohydrate) be the salt compounds of platelet suppressant drug.
European patent application EP 478363 discloses the method by 4-(4-pyridyl) Butyryl Chloride synthetic hydrochloric acid Tirofiban, and the method for being synthesized 4-(4-pyridyl) Butyryl Chloride by the 4-picoline.This method is that raw material and butyllithium prepare 4-(4-pyridyl) Butyryl Chloride with 3-bromo-n-propyl chloride linked reaction after the reaction down at-70 ℃ with the 4-picoline.Owing under extremely low temperature, react, and need anhydrous and oxygen-free tetrahydrofuran solvent, above-mentioned condition to make Tirofiban hydrochloride be difficult to realize suitability for industrialized production; Because used butyllithium is difficult to industrial preparation, storage, transportation, make that the Tirofiban hydrochloride cost is higher again.
Summary of the invention
In view of the defective that present 4-(4-pyridyl) Butyryl Chloride synthetic method exists, the invention provides a kind of easy and simple to handle, yield is higher, reaction conditions is gentle and be suitable for the method for suitability for industrialized production 4-(4-pyridyl) Butyryl Chloride.
The present invention is a raw material with the 4-picoline, and in the presence of suitable alkali, in appropriate solvent, the regular hour obtain 4-(4-pyridyl) Butyryl Chloride with the reaction of 3-bromo-n-propyl chloride, above-mentioned reaction scheme is:
The alkali that the present invention adopts is a kind of in amido metal, the MAGNESIUM METAL compound, a kind of in for example two (TMS) potassium amides, two (TMS) Lithamide, two (TMS) sodium amide, LDA (lithium diisopropylamine), the sec.-propyl bromination magnesium; The solvent that adopts is ethers, aromatic solvent or its mixture; For example: tetrahydrofuran (THF) (THF), ether, glycol dimethyl ether and toluene, or its mixture; Temperature of reaction is-10～110 ℃; Reaction times is 1～24 hour.
The invention has the advantages that initiative use amido metal, MAGNESIUM METAL compound replace butyllithium, avoided low-temp reaction, easy and simple to handle; And gained 4-(4-pyridyl) Butyryl Chloride yield and quality are better.
Embodiment
Further elaborate preparation method of the present invention below by embodiment.
The preparation of (1.4-4-pyridyl) Butyryl Chloride:
Logical drying nitrogen protection adds anhydrous diethyl ether 1.6L, 1250 milliliters of Diisopropylamines in 5 L three-necked bottles; metal lithium sheet 50 grams, heating in water bath to reflux state drips the solution of 460 milliliters of vinylbenzene and 300 milliliters of anhydrous diethyl ethers down, adds the back backflow and stirs 2 hours; the completely dissolve of lithium sheet gets grey solution.
Below the frozen water cooling reaction solution to 5 ℃, drip 4-picoline 465 grams (5 moles), rise to stirring at room and reacted 2 hours with 300 milliliters of anhydrous diethyl ethers dilutions.Below the frozen water cooling reaction solution to 5 ℃, drip 3-bromo-n-propyl chloride 820 grams (5.2 moles), rise to the stirring at room reaction, TLC monitors to reacting completely, and adds 400 milliliters of saturated ammonium chloride solutions, layering, ether layer is water, saturated common salt water washing successively, behind the anhydrous sodium sulfate drying, concentrate 4-(4-pyridyl) Butyryl Chloride crude product, about 800 grams, purity is 85% (HPLC).
The preparation of (2.4-4-pyridyl) Butyryl Chloride:
Logical drying nitrogen is protected in the 5L three-necked bottle, adds anhydrous diethyl ether 2L, magnesium powder 192 grams (8 moles), and catalytic amount iodine, and dropping 984 gram different N-PROPYLE BROMIDEs (8 moles) add back heating in water bath backflow and stirred 2 hours under the room temperature, and the completely dissolve of magnesium powder gets grey solution.
Below the frozen water cooling reaction solution to 5 ℃, drip 4-picoline 560 grams (6 moles are diluted with 300 milliliters of anhydrous diethyl ethers), heating in water bath backflow stirring reaction 2 hours.Below the frozen water cooling reaction solution to 5 ℃, drip 3-bromo-n-propyl chloride 1025 grams (6.5 moles), rise to the stirring at room reaction, TLC monitors to reacting completely, and adds 500 milliliters of saturated ammonium chloride solutions, layering, ether layer is water, saturated common salt water washing successively, behind the anhydrous sodium sulfate drying, concentrate 4-(4-pyridyl) Butyryl Chloride crude product, about 1000 grams, purity is 80% (HPLC).
3.4-(4-pyridyl) Butyryl Chloride is refining:
4-(4-pyridyl) Butyryl Chloride crude product 800 is restrained (purity: 85%, HPLC) be dissolved in 1 liter of isopropyl acetate, cryosel is bathed and is cooled to-10 ℃, adds the isopropyl acetate solution of 2 liters of 5 moles of hydrogenchloride, stirs 1 hour.Solid collected by filtration with tetrahydrofuran (THF) washing, vacuum-drying, gets 600 gram white solids, is 4-(4-pyridyl) Butyryl Chloride hydrochloride, 119～120.5 ℃ of fusing points.
Owing to described the present invention according to its special embodiment, some modification and equivalent variations are conspicuous and comprise within the scope of the invention for the those of ordinary skill in this field.
Claims (5)
1. a method for preparing Tirofiban hydrochloride intermediate 4-(4-pyridyl) Butyryl Chloride is characterized in that this method is a raw material with the 4-picoline, in the presence of alkali, obtains 4-(4-pyridyl) Butyryl Chloride with the reaction of 3-bromo-n-propyl chloride in solvent,
2. the method for claim 1, the alkali that it is characterized in that reacting employing is two (TMS) potassium amides, two (TMS) Lithamide, two (TMS) sodium amide, lithium diisopropylamine, sec.-propyl bromination magnesium.
3. the method for claim 1 is characterized in that reacting that to adopt solvent be in tetrahydrofuran (THF), ether, glycol dimethyl ether or the toluene one or more.
4. as each described method of claim 1～3, it is characterized in that reaction is to carry out under-10 ℃～110 ℃.
5. as each described method of claim 1～3, it is characterized in that the reaction times is 1～24 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101052019A CN1330636C (en) | 2005-09-26 | 2005-09-26 | Synthesis process of Tilofiban hydrochloride intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101052019A CN1330636C (en) | 2005-09-26 | 2005-09-26 | Synthesis process of Tilofiban hydrochloride intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1740158A CN1740158A (en) | 2006-03-01 |
| CN1330636C true CN1330636C (en) | 2007-08-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB2005101052019A Active CN1330636C (en) | 2005-09-26 | 2005-09-26 | Synthesis process of Tilofiban hydrochloride intermediate |
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| CN (1) | CN1330636C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102452975A (en) * | 2010-11-01 | 2012-05-16 | 天津康鸿医药科技发展有限公司 | Synthesis method of tirofiban hydrochloride intermediate |
| CN108440393A (en) * | 2018-03-20 | 2018-08-24 | 成都倍特药业有限公司 | Method for detecting impurities in tirofiban material impurity, impurity preparation and material |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1069971A (en) * | 1990-09-27 | 1993-03-17 | 麦克公司 | The novel sulfonamide fibrinogen receptor antagonist |
| CN1050832C (en) * | 1992-02-28 | 2000-03-29 | 麦克公司 | Process for preparing fibrinogen receptor antagonists |
| CN1399639A (en) * | 1999-10-18 | 2003-02-26 | 阿斯特拉曾尼卡有限公司 | New oxabispidine compound useful in treatment of cardiac arrhythmias |
-
2005
- 2005-09-26 CN CNB2005101052019A patent/CN1330636C/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1069971A (en) * | 1990-09-27 | 1993-03-17 | 麦克公司 | The novel sulfonamide fibrinogen receptor antagonist |
| CN1050832C (en) * | 1992-02-28 | 2000-03-29 | 麦克公司 | Process for preparing fibrinogen receptor antagonists |
| CN1399639A (en) * | 1999-10-18 | 2003-02-26 | 阿斯特拉曾尼卡有限公司 | New oxabispidine compound useful in treatment of cardiac arrhythmias |
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| CN1740158A (en) | 2006-03-01 |
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Application publication date: 20060301 Assignee: Lunan Beite Pharmaceutical Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2013370000265 Denomination of invention: Synthesis process of Tilofiban hydrochloride intermediate Granted publication date: 20070808 License type: Exclusive License Record date: 20131210 |
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