CN100391955C - Synthetic method for strotium renelate intermediate - Google Patents
Synthetic method for strotium renelate intermediate Download PDFInfo
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- CN100391955C CN100391955C CNB2005100124861A CN200510012486A CN100391955C CN 100391955 C CN100391955 C CN 100391955C CN B2005100124861 A CNB2005100124861 A CN B2005100124861A CN 200510012486 A CN200510012486 A CN 200510012486A CN 100391955 C CN100391955 C CN 100391955C
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- strontium ranelate
- crown ether
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Abstract
The present invention discloses a synthetic and preparation method for strontium ranelate intermediates. The method comprises the procedures that 1, a compound of 5-amino-4-cyano-3-(2-ethoxy-2-oxoethyl)-2-ethyl thiohenate is used as a raw material; 2, in the presence of a catalyst and potassium carbonate, the raw material reacts with the reflux of an organic solvent; 3, a reaction mixture is filtered; 4, the organic solvent is processed via reduced pressure distillation, a crystallizing solvent is added for dissolving, and the mixture is cooled for recrystallizing. The present invention is characterized in that the used catalyst is crown ether or KF/Al2O3. The purity of the strontium ranelate intermediate compound II prepared by the method is 95 to 98%, yield is 85 to 90%, and reaction time is shortened to 6 to 8 hours.
Description
Technical field
The present invention relates to the synthetic method of compound, specifically a kind of synthetic method of medicinal compound intermediate.
Background technology
Strontium Ranelate (Strontium ranelate) chemistry 5-[two (carboxymethyl) amino by name]-3-carboxymethyl-4-cyano group-2-Thiophene Carboxylic Acid two strontium salt, its chemical structural formula is:
Compound I
Strontium Ranelate is a kind of osteoporosis due to the menopausal women that is mainly used in.It has the stimulating osteoblast bone forming and suppresses the function of osteoclast bone resorption, has the mechanical resistance that improves bone simultaneously, does not influence the mineralising of bone, does not change the characteristic of bone structure.
Strontium Ranelate is normally by chemistry 5-[two (2-oxyethyl group-2-oxoethyl) amino by name]-compound (hereinafter to be referred as Compound I I) and the strontium hydroxide of 4-cyano group-3-(2-oxyethyl group-2-oxoethyl)-2-thiophene ethyl formate interact and generate.
The chemical structural formula of Compound I I is:
Compound I I
Compound I I is the important intermediate compound of producing strontium ranelate.Because Strontium Ranelate is insoluble to most of solvents, thus its feedstock purification complex process, the cost height.For obtaining highly purified Strontium Ranelate, people normally solve this problem by purity and the yield that improves Compound I I.
Bull.Soc.Chim.France 1975, the 1786-1792 page or leaf discloses the method for a kind of synthetic compound II, this method is that the compound (hereinafter to be referred as compound III) with chemistry 5-amino by name-4-cyano group-3-(2-oxyethyl group-2-oxoethyl)-2-thiophene ethyl formate is a raw material, with the 0.1mol compound III is raw material, with the 0.25mol ethyl bromoacetate is alkylating reagent, 250ml acetone is solvent, 20～30g salt of wormwood is acid absorber, do recrystallisation solvent with 120ml ethanol then and separate, thereby obtain Compound I I.The weak point of this method is productive rate low (65%), and long reaction time (5 days) can produce a large amount of salt solution waste materials in the reaction process, be harmful to environment protection.
Summary of the invention
The purpose of the inventive method just provides the synthesis preparation method that a kind of productive rate height, purity height and technological process help the Strontium Ranelate intermediate (Compound I I) of environment protection.
The purpose of the inventive method is achieved in that
Synthetic preparation Strontium Ranelate midbody compound II may further comprise the steps:
A, be raw material with the compound III and the ethyl bromoacetate of the amino 4-cyano group-3-(2-oxyethyl group-2-oxoethyl) of chemistry 5-by name-2-thiophene ethyl formate, the chemical structural formula of this compound III is:
Compound III
B, in the presence of catalyzer and salt of wormwood, under the backflow of organic solvent, react;
C, reaction mixture is filtered;
D, underpressure distillation organic solvent add the recrystallisation solvent dissolving, the process of cooling recrystallization;
E, collection Compound I I;
The innovative point of invention is that selected catalyzer is crown ether or KF/Al
2O
3
By the Strontium Ranelate midbody compound II of method for preparing, purity can reach 95-98%, and productive rate is 85-90%, and the reaction times can foreshorten to 6-8 hour.
Because the chemical process of synthetic compound II is an alkylated reaction, and the reaction times is longer, old friends can expect utilizing quaternary ammonium salt compound as phase-transfer catalyst usually, to shorten the reaction times.(as hydrogen sulfate four basic ammoniums, N, N-two (2-hydroxyethyl)-N-methyl isophthalic acid-dodecane brometo de amonio).Though these quaternary ammonium salt catalysts can shorten the reaction times in varying degrees, need bigger consumption (every gram reactant needs quaternary ammonium salt 40mg).Thereby influenced degree of purity of production.
The inventor in numerous catalyzer, selects crown ether or KF/Al through experiment screening repeatedly
2O
3Be catalyzer, obtained the effect of highly significant.Wherein crown ether can also significantly shorten synthesising reacting time.
Crown ether used in the present invention can carry out complexing with potassium ion, and this positive ion is soluble in the organic solvent, and enters in the organic solvent with its corresponding negative ion also companion.Since crown ether not with the negative ion complexing, free negative ion reactive behavior is increased, accelerated speed of response.
KF/Al
2O
3For being adsorbed on the Potassium monofluoride on the carrier alundum, also there is document to be referred to as acid binding agent.Its preparation method is: add anhydrous potassium fluoride (10g) in the flask, water (100ml), stir, treat that Potassium monofluoride dissolving back adds chromatography neutral alumina (15g, 100～200 orders). with mechanical stirrer vigorous stirring half an hour. at 50～60 ℃ of following pressure reducing and steaming water to pasty state. add dehydrated alcohol (50ml * 2) again, be warming up to 80 ℃, decompression is fully steamed down and is removed ethanol, obtain a white loose shape solid, with the KF/Al that makes
2O
3Place moisture eliminator to preserve.
Preferable amount part ratio of crown ether is in the inventive method: 1 part of 5-amino-4-cyano group-3-(2-oxyethyl group-2-oxoethyl)-2-thiophene ethyl formate raw material, crown ether 0.005-0.015 part.KF/Al
2O
3Preferable amount part ratio be: 1 part of 5-amino-4-cyano group-3-(2-oxyethyl group-2-oxoethyl)-2-thiophene ethyl formate raw material, KF/Al
2O
30.1-0.38 part
Beneficial effect of the present invention has obtained confirmation by following experiment contrast.
Experimental technique:
The method for preparing Compound I I in the following experiment is except that the catalyzer difference of selecting for use, and all the other processing steps are all identical.
That is: selecting compound III for use is raw material, in the presence of phase-transfer catalyst and salt of wormwood, reacts under the backflow of organic solvent.Reaction mixture is filtered; Reaction mixture is also filtered; Dry cake gets crude product, and product is carried out recrystallization; Cold filtration so obtains Compound I I once more.
Concrete outcome is as shown in table 1:
Table 1:
| Catalyzer | Reaction times | Productive rate | Purity | Color |
| The hydrogen sulfate TBuA | 12 hours | 82％ | 89％ | Faint yellow |
| N, N-two (2-hydroxyethyl)-N-methyl isophthalic acid-dodecane brometo de amonio | 18 hours | 75％ | 81％ | Faint yellow |
| Crown ether | 6 hours | 89％ | 98％ | Off-white color |
| KF/Al 2O 3 | 8 hours | 85％ | 95％ | Off-white color |
The synthetic method of compound (III), the Heterocyclen aus CH-acidenNitrilen (VIII) as far back as 1966, existing report in the 94-95 page or leaf; It is by compound IV
Compound IV
Obtain with propane dinitrile, elemental sulfur cyclization; At periodical Bull.Soc.Chim.France 1975,1786-1792 page or leaf and J.Chem.Tech.Biotechnol.1990,47, description is also arranged in the 39-46 page or leaf.Its concrete synthetic method is as follows:
The 3-keto-glutaric acid diethyl ester that in reactor, adds 0.1mol, i.e. (compound IV), the propane dinitrile of 0.1mol and the ethanol of 28ml keeping reaction mixture to be lower than in 40 ℃, add the morpholine of 0.1mol then.The sublimed sulphur that adds 0.1mol then, stirring and refluxing at least 2 hours.Reaction finishes and adds water to the precipitation generation, filters and washing and dry, promptly gets compound III.
Wherein compound IV is the commercially available prod, and its manufacturer is Johnson Matthey Company; Lot number is I6165A.
Embodiment:
Embodiment 1:
Get 300 liters of compound III 280kg, Anhydrous potassium carbonate 350kg, 2000 liters in acetone, crown ether 3kg, ethyl bromoacetate.Bath temperature is 60 ℃.Stirring and refluxing 6 hours, reaction mixture is filtered then.Decompression steams acetone, puts to room temperature.Add dehydrated alcohol 200ml, place refrigerator overnight, wait to separate out crystal and filter, dry cake promptly gets crude product.With crude product ethanol, water recrystallization, filtration, drying get the off-white color crystallization.
The acquisition Compound I I of productive rate that promptly can 89%, 98% purity.
Embodiment 2:
Get compound III 28g, Anhydrous potassium carbonate 35g, acetone 200ml, crown ether 0.14g, ethyl bromoacetate 30ml.Adopt under the microwave radiation and reacted 3 minutes.Operation is later on pressed embodiment 1 and is got final product, and obtains Compound I I.
Embodiment 3:
Get compound III 28g, salt of wormwood 35g, acetone 200ml, KF/Al
2O
310g, ethyl bromoacetate 30ml obtain Compound I I according to the method with embodiment 1.
Embodiment 4:
Get compound III 28g, salt of wormwood 35g, acetone 200ml, KF/Al
2O
32.8g, ethyl bromoacetate 30ml, according to obtaining Compound I I with the method for embodiment 1.
Claims (3)
1. the synthetic method of Strontium Ranelate midbody compound II, step comprises following:
A, be raw material with the compound III and the ethyl bromoacetate of chemistry 5-amino by name-4-cyano group-3-(2-oxyethyl group-2-oxoethyl)-2-thiophene ethyl formate, the chemical structural formula of this compound III is:
Compound III
B, in the presence of catalyzer and salt of wormwood, under the backflow of organic solvent, react;
C, reaction mixture is filtered;
D, underpressure distillation organic solvent add the recrystallisation solvent dissolving, the process of cooling recrystallization;
E, collection Compound I I, the chemical structural formula of this Compound I I is:
Compound I I
It is characterized in that selected catalyzer is crown ether or KF/Al
2O
3
2. the synthetic method of Strontium Ranelate midbody compound II according to claim 1, the consumption part ratio that it is characterized in that said crown ether is: 1 part of 5-amino-4-cyano group-3-(2-oxyethyl group-2-oxoethyl)-2-thiophene ethyl formate raw material, crown ether 0.005-0.015 part.
3. the synthetic method of Strontium Ranelate midbody compound II according to claim 1 is characterized in that said KF/Al
2O
3Consumption part ratio be: 1 part of 5-amino-4-cyano group-3-(2-oxyethyl group-2-oxoethyl)-2-thiophene ethyl formate raw material, KF/Al
2O
30.1-0.38 part.
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| CNB2005100124861A CN100391955C (en) | 2005-04-30 | 2005-04-30 | Synthetic method for strotium renelate intermediate |
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| CNB2005100124861A CN100391955C (en) | 2005-04-30 | 2005-04-30 | Synthetic method for strotium renelate intermediate |
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| CN100391955C true CN100391955C (en) | 2008-06-04 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101665483B (en) * | 2008-09-01 | 2013-01-23 | 河北医科大学 | Synthesis method for strontium ranelate intermediate compound II |
| CN101775002B (en) * | 2009-12-23 | 2015-07-15 | 浙江华海药业股份有限公司 | Method for preparing strontium ranelate |
| CN102180864B (en) * | 2011-03-28 | 2012-12-12 | 中国药科大学 | Preparation method of strontium ranelate |
| CN104230883B (en) * | 2014-09-02 | 2017-08-22 | 中国科学院青岛生物能源与过程研究所 | A kind of preparation method of the thiophenic acid isopropyl ester of 3 amino 2 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0415850A1 (en) * | 1989-09-01 | 1991-03-06 | Adir Et Compagnie | Bivalent metal salts of 2-N,N-di(carboxymethyl)amino,3-cyano,4-carboxymethyl,5-carboxy-thiophene-acid, process for their preparation and pharmaceutical compositions containing them |
| CN1496986A (en) * | 2002-09-24 | 2004-05-19 | 瑟维尔实验室 | Industrial synthetising strontium salt and method of its hydrate |
| CN1500784A (en) * | 2002-09-24 | 2004-06-02 | ɪά��ʵ���� | New process for the industrial synthesis of the methyl diester of 5-amino-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid, and application to the synthesis of bivalent salts ofranelic acid and thei |
-
2005
- 2005-04-30 CN CNB2005100124861A patent/CN100391955C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0415850A1 (en) * | 1989-09-01 | 1991-03-06 | Adir Et Compagnie | Bivalent metal salts of 2-N,N-di(carboxymethyl)amino,3-cyano,4-carboxymethyl,5-carboxy-thiophene-acid, process for their preparation and pharmaceutical compositions containing them |
| CN1496986A (en) * | 2002-09-24 | 2004-05-19 | 瑟维尔实验室 | Industrial synthetising strontium salt and method of its hydrate |
| CN1500784A (en) * | 2002-09-24 | 2004-06-02 | ɪά��ʵ���� | New process for the industrial synthesis of the methyl diester of 5-amino-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid, and application to the synthesis of bivalent salts ofranelic acid and thei |
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Assignee: Shijiazhuang No.4 Pharmaceutical Co., Ltd. Assignor: Hebei Medical University Contract fulfillment period: 2009.9.12 to 2014.9.11 contract change Contract record no.: 2009130000230 Denomination of invention: Synthetic method for strotium renelate intermediate Granted publication date: 20080604 License type: Exclusive license Record date: 2009.11.3 |
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Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2009.9.12 TO 2014.9.11; CHANGE OF CONTRACT Name of requester: SHIJIAZHUANG SIYAO CO., LTD. Effective date: 20091103 |
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