CN103193747A - Method for preparing fesoterodine fumarate intermediate - Google Patents
Method for preparing fesoterodine fumarate intermediate Download PDFInfo
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- CN103193747A CN103193747A CN2013101350900A CN201310135090A CN103193747A CN 103193747 A CN103193747 A CN 103193747A CN 2013101350900 A CN2013101350900 A CN 2013101350900A CN 201310135090 A CN201310135090 A CN 201310135090A CN 103193747 A CN103193747 A CN 103193747A
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Abstract
The invention relates to a method for preparing fesoterodine fumarate intermediate 2-oxo--4-phenyl benzopyran-6-carboxylic acid methyl ester (I). The method is characterized in that the 2-oxo--4-phenyl benzopyran-6-carboxylic acid methyl ester (I) is obtained by 2-oxo--4-phenyl benzopyran-6-carboxylic acid methyl ester (II) and dimethyl sulfate under the action of alkali. Based on the method, the reaction steps are shortened, the yield is high, the reaction conditions are moderate, the quality is stable, the post treatment is simple, the cost is low, the operation is simple; and the method is applied to industrial production.
Description
Technical field
The present invention relates to the new preparation method of fumaric acid Fu Site Luoding intermediate.
Background technology
Fumaric acid Fu Site Luoding (Fesoterodine Fumarate), chemistry isopropylformic acid 2-[(R by name)-3-Diisopropylamine-1-hydrocinnamyl]-4-methylol phenyl ester fumarate, by a kind of selectivity muscarine M of Pfizer (Pfizer) company research and development
3Receptor antagonist, the clinical bladder excessive activities syndrome that is used for the treatment of, trade(brand)name: Toviaz obtains the drugs approved by FDA listing in October, 2008.This product belongs to prodrug, is the activity in vivo metabolite of 5-methylol tolterodine (5-HMT), and 5-HMT then is the metabolite of the highest bladder excessive activities syndrome medicine tolterodine of present sales volume.Structural formula is as follows:
2-oxo-4-phenyl chroman-6-carboxylate methyl ester (I) is the key intermediate of synthetic fumaric acid Fu Site Luoding, and structural formula is as follows:
(I) through selective reduction, the hemiacetal reduction amination, methyl esters reduction, chiral separation selectivity isopropyl acidylate again obtain the Fu Site Luoding.Shown in the formula specific as follows:
According to existing document WO 2007144097 and US6809214 report, be shown below, the synthetic route of 2-oxo-4-phenyl chroman-6-carboxylate methyl ester mainly is to generate acyl chlorides with 2-oxo-4-phenyl chroman-6-carboxylic acid and sulfur oxychloride reaction, obtains (I) with quantitative methyl alcohol generation esterification again.This procedure is operated in two steps, and step is long, uses high malicious irritating sulfur oxychloride, and reaction solvent need not have water treatment, and obtaining (I) is pale yellow powder, and color is difficult for removing, and influences the finished product quality, and yield only is 65%.
Summary of the invention
The present invention is exactly shortcomings such as synthetic method yield at 2-oxo-4-phenyl chroman-6-carboxylate methyl ester in the existing existing synthetic technology is low, step length, separation and purification difficulty, the new preparation method of a kind of fumaric acid Fu Site Luoding intermediate (I) is provided, reactions steps shortens, time shortens, mild condition, aftertreatment is easy, and combined coefficient height, cost are low, yield brings up to 95%, is conducive to suitability for industrialized production.
Therefore, the present invention relates to the preparation of a kind of 2-of being shown below oxo-4-phenyl chroman-6-carboxylate methyl ester, comprising the following step:
By (II) and methyl-sulfate under the alkali effect, (I).
(II) the reaction mol ratio with methyl-sulfate is 1: 0.5～3.0, preferred 1: 0.5～1.5.
(II) with the alkali of methyl-sulfate reaction such as yellow soda ash, Quilonum Retard, salt of wormwood, sodium bicarbonate, saleratus, cesium carbonate, Strontium carbonate powder, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium formiate, potassium formiate, sodium acetate, potassium acetate, lithium acetate, S-WAT, potassium sulfite, sodium methylate, sodium ethylate, sodium hydride, lithium hydride, hydrolith, calcium hydroxide, potassiumphosphate, sodium phosphate, Sodium phosphate dibasic, dipotassium hydrogen phosphate, sodium amide.Preferred yellow soda ash, sodium bicarbonate.
(II) with methyl-sulfate reaction in the mol ratio of compound (II) and alkali be 1: 0.5～3.0, preferred 1: 0.5～1.5.
Selected organic solvent is N, dinethylformamide, N, one or more of N-N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, normal hexane, hexanaphthene, dioxane, acetone, butanone, ether, isopropyl ether, toluene, dimethylbenzene, more preferably select for use polar aprotic solvent to do reaction solvent, as acetone, tetrahydrofuran (THF), N, dinethylformamide.
(II) carry out with methyl-sulfate stirring at normal temperature in solvent, temperature prioritisedly select 0～25 ℃ for use.
(II) with the methyl-sulfate post-reaction treatment, under agitation condition, to pour in the ice dilute hydrochloric acid solution, the suction filtration solid adds and is washed to neutrality and obtains (I).
Embodiment
Following example further specifies the present invention, but the present invention is not limited.
Embodiment 1:
The preparation of 2-oxo-4-phenyl chroman-6-carboxylate methyl ester (I)
Step:
(30.70g 0.1146mol) adds to N to 2-oxo-4-phenyl chroman-6-carboxylic acid (II), in the dinethylformamide (90ml), stirring and dissolving under the room temperature, add in batches anhydrous sodium carbonate (15.80g, 0.1491mol) and methyl-sulfate (18.76g, 0.1490mol).TLC tracks to and reacts completely, and pours under stirring in the ice dilute hydrochloric acid solution, filters, and is washed to filtrate neutrality.The oven dry filter cake obtains white powder (I) 30.76g, yield 95.2%, mp95-97 ℃.
1H-NMR(DMSO-d
6)δ：7.92(dd，1H)，7.65(d，1H)，7.38(t，2H)，7.30(q，2H)，7.19(d，2H)，?4.64(t，1H)，3.78(s，3H)，3.18(dd，2H)。.
ESI-MS(m/z)：305.1[M+Na]
+。
Embodiment 2:
The preparation of 2-oxo-4-phenyl chroman-6-carboxylate methyl ester (I)
Step:
2-oxo-4-phenyl chroman-6-carboxylic acid (II) (13.40g 0.05mol) adds in the acetone (150ml), stirs under the room temperature, add sodium bicarbonate (6.30g, 0.075mol) and methyl-sulfate (6.93g, 0.055mol).TLC tracks to and reacts completely, and pours under stirring in the ice dilute hydrochloric acid solution, filters, and is washed to filtrate neutrality.The oven dry filter cake obtains white powder (I) 12.42g, yield 88.7%.
Embodiment 3:
The preparation of 2-oxo-4-phenyl chroman-6-carboxylate methyl ester (I)
Step:
(5.361g 0.0200mol) adds to N to 2-oxo-4-phenyl chroman-6-carboxylic acid (II), in the dinethylformamide (30ml), stirring and dissolving under the room temperature, add anhydrous sodium carbonate (3.000g, 0.0283mol) and methyl-sulfate (3.532g, 0.0280mol).TLC tracks to and reacts completely, and pours under stirring in the ice dilute hydrochloric acid solution, filters, and is washed to filtrate neutrality.The oven dry filter cake obtains white powder (I) 5.52g, yield 97.8%.
Embodiment 4:
The preparation of 2-oxo-4-phenyl chroman-6-carboxylate methyl ester (I)
Step:
2-oxo-4-phenyl chroman-6-carboxylic acid (II) (6.70g, 0.025mol) add to that to contain volume fraction be 5%N, in the tetrahydrofuran (THF) of dinethylformamide (100ml), stirring and dissolving under the room temperature, add anhydrous sodium carbonate (2.92g, 0.0275mol) and methyl-sulfate (3.47g, 0.0275mol).TLC tracks to and reacts completely, and decompression steams solvent, pours under stirring in the ice dilute hydrochloric acid solution, filters, and is washed to filtrate neutrality.The oven dry filter cake obtains white powder (I) 5.94g, yield 84.3%.
Claims (7)
1. the preparation method of fumaric acid Fu Site Luoding intermediate 2-oxo-4-phenyl chroman-6-carboxylate methyl ester (I), it is characterized in that 2-oxo-4-phenyl chroman-6-carboxylic acid (II) and methyl-sulfate react under the effect of alkali obtains 2-oxo-4-phenyl chroman-6-carboxylate methyl ester (I), and its reaction formula is as follows:
2. the preparation method of fumaric acid Fu Site Luoding intermediate according to claim 1 (I) is characterized in that: wherein compound (II) is 1: 0.5～3.0 with methyl-sulfate consumption mol ratio.
3. the preparation method of fumaric acid Fu Site Luoding intermediate according to claim 1 (I), it is characterized in that: used alkali is selected from one or more in yellow soda ash, Quilonum Retard, salt of wormwood, sodium bicarbonate, saleratus, cesium carbonate, Strontium carbonate powder, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium formiate, potassium formiate, sodium acetate, potassium acetate, lithium acetate, S-WAT, potassium sulfite, sodium methylate, sodium ethylate, sodium hydride, lithium hydride, hydrolith, calcium hydroxide, potassiumphosphate, sodium phosphate, Sodium phosphate dibasic, dipotassium hydrogen phosphate, the sodium amide.
4. the preparation method of fumaric acid Fu Site Luoding intermediate according to claim 1 (I), it is characterized in that: compound (II) is selected from N with methyl-sulfate reaction organic solvent, one or more of dinethylformamide, N,N-dimethylacetamide, tetrahydrofuran (THF), methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, normal hexane, hexanaphthene, dioxane, acetone, butanone, ether, isopropyl ether, toluene, dimethylbenzene.
5. the preparation method of fumaric acid Fu Site Luoding intermediate according to claim 1 (I) is characterized in that: compound (II) is 1: 0.5～3.0 with consumption and compound (II) molar weight ratio that methyl-sulfate reacts used alkali.
6. the preparation method of fumaric acid Fu Site Luoding intermediate according to claim 1 (I) is characterized in that: compound (II) is-20～60 ℃ with the methyl-sulfate temperature of reaction.
7. the preparation method of fumaric acid Fu Site Luoding intermediate according to claim 1 (I) is characterized in that: compound (II) is 1: 1～20 with the weightmeasurement ratio of solvent in compound (II) and the methyl-sulfate reaction.
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| CN2013101350900A CN103193747A (en) | 2013-04-18 | 2013-04-18 | Method for preparing fesoterodine fumarate intermediate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001096279A1 (en) * | 2000-06-14 | 2001-12-20 | Schwarz Pharma Ag | Shortened synthesis of 3,3-diarylpropylamine derivatives |
| CN101466695A (en) * | 2006-06-12 | 2009-06-24 | 施瓦茨制药有限公司 | New chiral intermediate, process for rpoducing the same and its use in the manufacture of tolerodine, fesoterodine, or the active metabolitte thereof |
| CN101508689A (en) * | 2009-03-26 | 2009-08-19 | 中国药科大学 | Synthesis of oroxylin |
-
2013
- 2013-04-18 CN CN2013101350900A patent/CN103193747A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001096279A1 (en) * | 2000-06-14 | 2001-12-20 | Schwarz Pharma Ag | Shortened synthesis of 3,3-diarylpropylamine derivatives |
| CN101466695A (en) * | 2006-06-12 | 2009-06-24 | 施瓦茨制药有限公司 | New chiral intermediate, process for rpoducing the same and its use in the manufacture of tolerodine, fesoterodine, or the active metabolitte thereof |
| CN101508689A (en) * | 2009-03-26 | 2009-08-19 | 中国药科大学 | Synthesis of oroxylin |
Non-Patent Citations (2)
| Title |
|---|
| 张业等: "12-溴-13,14-脱氢松香酸甲酯氧化呋咱的合成与表征", 《化学试剂》 * |
| 朱素娟等: "硫酸二甲酯作为色谱法测定某些羧酸的甲酯化试剂", 《江苏农学院学报》 * |
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Application publication date: 20130710 |