CN1931854A - Intermediate for synthesizing fasidotril and its synthesis use - Google Patents
Intermediate for synthesizing fasidotril and its synthesis use Download PDFInfo
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- CN1931854A CN1931854A CN 200510029734 CN200510029734A CN1931854A CN 1931854 A CN1931854 A CN 1931854A CN 200510029734 CN200510029734 CN 200510029734 CN 200510029734 A CN200510029734 A CN 200510029734A CN 1931854 A CN1931854 A CN 1931854A
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Abstract
The present invention provides the intermediate compound for synthesizing N-[(2S)-2-acetylthiomethyl-1-oxo-3-(3, 4- methylene dioxy)phenyl propyl]-L-alanine benzoate and its synthetic use. By using (R)-2-(3, 4- methylene dioxy phenyl)-3- hydroxyl propionic acid as initial material and through halogenation, amidation and substitution, the present invention synthesizes fasidotril. The synthesis path is simple, low in cost and suitable for industrial production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to the intermediate and the synthetic method thereof of synthetic drugs Fasidotril (fasidotril), be used for the treatment of hypertension and congestive heart failure.
Background technology
The chemistry of Fasidotril is called N-[(2S)-2-acetyl thiomethyl-1-oxo-3-(3, the 4-methylene-dioxy) phenyl propyl]-the L-alanine benzene methyl, structural formula is as shown in the formula shown in (3), it is the oral prodrugs of alatrioprilat, develop by Bioprojet company, calendar year 2001 is permitted the company to Lilly, is used for the treatment of hypertension and congestive heart failure.Fasidotril is vasopeptidase inhibitors (Vasopeptidase inhibitor, VPI), it can suppress angiotensin-converting enzyme (ACE) and neutral endopeptidase (neutralendopeptidase simultaneously, NEP) activity, studies show that the ACE/NEP double inhibitor is used nep inhibitor to the effect of cardiac hemodynamic and kidney than simultaneously and ACE inhibitor is stronger, at the antihypertensive drug that is better than present clinical application aspect the step-down; The treatment in heart failure aspect, be better than captopril (captopril), enalapril (enalapril).
The synthetic route of the Fasidotril of document US 5670531 reports is from 3,4-methylene-dioxy Benzyl Chloride sets out, prepare compound 4 through alkylation, hydrolysis, Manich reaction, Michael addition, split by ephedrine again and obtain optical isomer 5, so in alkaline condition down and the alanine benzyl ester condensation make formula (3) compound.
The Fasidotril synthetic route of bibliographical information
Splitting 4 used resolving agents in this method only be ephedrine, and the salt that need obtain by 9 recrystallizations just can obtain optically purely 5 through free, and fractionation efficient (salify yield * optical purity * 100%) is 33.6%.There is following shortcoming and defect in this method: used resolving agent ephedrine is difficult to obtain; The recrystallization number of times has increased workload too much undoubtedly; Fractionation efficient is low.
Summary of the invention
The midbody compound that uses in the Fasidotril synthetic route that one object of the present invention is to provide new.
Another object of the present invention is to provide the method for using the synthetic Fasidotril of above-mentioned midbody compound.
According to the present invention, set out from (R)-2-(3, the 4-methylenedioxyphenyl)-3-hydroxy-propionic acid (6), synthesize Fasidotril through two halogenations, one-tenth acid amides, replacement:
The whole piece synthetic route only needs the reaction of 3 steps, and step is shorter, and easy and simple to handle, and cost is low, is fit to suitability for industrialized production.
According to the present invention, each step reaction division is as follows:
(a) individual isomer 6 is through reacting with halide reagent, and functional group's activation synchronously obtains compound 2:
X=Cl, Br etc. in the formula;
Chlorinating agent comprises sulfur oxychloride, oxalyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride etc.;
Brominated reagent comprises thionyl bromide, phosphorus tribromide, boron tribromide etc.;
Solvent comprises one or more mixtures in methylene dichloride, ethylene dichloride, toluene, the acetone;
Temperature-20～120 ℃.
(b), or react in the lump with iodination reagent more with this understanding and obtain compound (1) with amino acid ester (7) amidation:
X=Cl, Br, I etc.;
React used alkali and comprise in triethylamine, pyridine, salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, sodium hydroxide, the potassium hydroxide one or more;
Iodination reagent comprises potassiumiodide, sodium iodide;
Solvent is one or more a mixed solvent in methylene dichloride, acetone, acetonitrile and DMF, DMSO and the water;
Temperature-10～140 ℃.
(c) obtain target molecule (3) with replacing reagent (8) reaction,
CH
3COSY (8)
Y＝H，K+，Na+；
Solvent comprises acetone, acetonitrile, DMF, DMSO etc.;
Catalyzer is Aliquat336, benzyltriethylammoinium chloride, CuCl, KI etc.;
0～180 ℃ of temperature.
The invention has the advantages that and existent method is compared that synthetic route of the present invention is raw materials used and reagent is all inexpensive is easy to get, the three wastes are less, and simple to operate, and reactions steps is few, and yield is higher, is applicable to industrial production.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment do not constitute any restriction to the present invention.
Fusing point is measured with capillary tube technique, and thermometer is not proofreaied and correct; Varian Inova type nuclear magnetic resonance analyser (interior mark TMS, solvent C DCl
3); Finnign-MAT212 type mass spectrograph; Polarimeter341 type polarimeter.
Embodiment 1
Preparation (R)-2-chloromethyl-3-(3, the 4-methylene-dioxy) phenylpropyl alcohol acyl chlorides
Add in three mouthfuls of reaction flasks of I 25ml 2.0g (4.5mmol) (R)-2-(3, the 4-methylene-dioxy) phenmethyl-3-hydroxy-propionic acid, add 10ml methylene dichloride and 1% pyridine, stirring and dissolving.Room temperature drips 2.0ml (13.7mmol) sulfur oxychloride, finishes, and reacts 50 minutes, and the solution decompression evaporate to dryness gets colorless oil 1.8g.MS(EI)：260(M
+)
Add in three mouthfuls of reaction flasks of II 25ml 2.0g (4.5mmol) (R)-2-(3, the 4-methylene-dioxy) phenmethyl-3-hydroxy-propionic acid, add the 10ml ethylene dichloride, stirring and dissolving.Ice bath adds 2.8gPCl after being cooled to-10 ℃
5, kept this thermotonus 30 minutes, be warming up to 60 ℃ of reactions 20 minutes, the TLC judgement reacts completely, and the solution decompression evaporate to dryness gets colorless oil 2.2g.
Add in three mouthfuls of reaction flasks of III 25ml 2.0g (4.5mmol) (R)-2-(3, the 4-methylene-dioxy) phenmethyl-3-hydroxy-propionic acid, add 10ml toluene, ice bath is cooled to-5 ℃, drip 2.0ml (13.7mmol) oxalyl chloride, kept this thermotonus 30 minutes, it is complete to be warming up to 120 ℃ of 2 hours afterreactions that reflux, the solution decompression evaporate to dryness gets colorless oil 2.2g.
Embodiment 2
Preparation (R)-2-brooethyl-3-(3, the 4-methylene-dioxy) phenylpropyl alcohol acylbromide
Add in three mouthfuls of reaction flasks of I 25ml 2.0g (4.5mmol) (R)-2-(3, the 4-methylene-dioxy) phenmethyl-3-hydroxy-propionic acid, add 10ml methylene dichloride and 1% pyridine, stirring and dissolving.Ice bath is cooled to-5 ℃, drips 2.84g (13.7mmol) thionyl bromide, keeps this thermotonus 50 minutes, and the solution decompression evaporate to dryness gets colorless oil 1.8g.MS(EI)：349(M
+)
Add in three mouthfuls of reaction flasks of II 25ml 2.0g (4.5mmol) (R)-2-(3, the 4-methylene-dioxy) phenmethyl-3-hydroxy-propionic acid, add the 10ml ethylene dichloride, stirring and dissolving.Add the 4.5g boron tribromide after ice bath is cooled to-10 ℃, kept this thermotonus 30 minutes, be warming up to 60 ℃ of reactions 20 minutes, the TLC judgement reacts completely, and the solution decompression evaporate to dryness gets colorless oil 2.2g.
Add in three mouthfuls of reaction flasks of III 25ml 2.0g (4.5mmol) (R)-2-(3, the 4-methylene-dioxy) phenmethyl-3-hydroxy-propionic acid, add 10ml toluene, ice bath is cooled to-5 ℃, drips 1.28ml (13.7mmol) PBr
3, kept this thermotonus 30 minutes, it is complete to be warming up to 120 ℃ of 2 hours afterreactions that reflux, the solution decompression evaporate to dryness, colorless oil 2.2g.
Embodiment 3
Preparation N-[(2S)-2-chloromethyl-1-oxo-3-(3, the 4-methylene-dioxy) hydrocinnamyl]-the L-alanine benzene methyl
Add 33.6g (192.2mmol) L-alanine benzene methyl and 100ml acetone, 100ml water in the 100ml there-necked flask, after being cooled to 0 ℃, ice bath adds 40.0g (290mmol) salt of wormwood, stirred 10 minutes, Dropwise 5 0ml be dissolved with 25g (96.1mmol) (R)-acetone soln of 2-chloromethyl-3-(3, the 4-methylene-dioxy) phenylpropyl alcohol acyl chlorides.It is complete to react 2 hours afterreactions, washes 2 times, and anhydrous sodium sulfate drying filters, be concentrated into dried, with the crystallization of 200ml petroleum ether and stirring, solid 34.0g (yield 90.2%), 106 ℃ of mp.
1HNMR：2.74-2.9(2H，m)，2.63-2.69(1H，m)，3.51-3.75(2H，m)，6.58-6.69(3H，m)，5.89(1H，s)，6.01(1H，br)，4.5(1H，m)，1.4(3H，d)，5.15(2H，m)，7.31-7.38(5H，m)
MS(EI)：403(M
+)
[α]
D 23(c1, methyl alcohol)=+ 43.8 °
Embodiment 4
Preparation N-[(2S)-2-brooethyl-1-oxo-3-(3, the 4-methylene-dioxy) hydrocinnamyl]-the L-alanine benzene methyl
Add 33.6g (192.2mmol) L-alanine benzene methyl and 100ml acetone, 100ml water in the 100ml there-necked flask, after being cooled to 0 ℃, ice bath adds 40.0g (290mmol) salt of wormwood, stirred 10 minutes, Dropwise 5 0ml be dissolved with 33.5g (96.1mmol) (R)-acetone soln of 2-brooethyl-3-(3, the 4-methylene-dioxy) phenylpropyl alcohol acylbromide.It is complete to react 2 hours afterreactions, washes 2 times, and anhydrous sodium sulfate drying filters, be concentrated into dried, with the crystallization of 200ml petroleum ether and stirring, solid 40.0g (yield 94.2%), 128 ℃ of mp.
MS(EI)：447.5(M
+)
Embodiment 5
Preparation N-[(2S)-2-iodomethyl-1-oxo-3-(3, the 4-methylene-dioxy) hydrocinnamyl]-the L-alanine benzene methyl
Add 33.6g (192.2mmol) L-alanine benzene methyl and 100ml acetone, 100ml water in the 100ml there-necked flask, after being cooled to 0 ℃, ice bath adds 40.0g (290mmol) salt of wormwood and 48.1g (290mmol) potassiumiodide, stirred 10 minutes, Dropwise 5 0ml be dissolved with 25g (96.1mmol) (R)-acetone soln of 2-chloromethyl-3-(3, the 4-methylene-dioxy) phenylpropyl alcohol acyl chlorides.It is complete to react 2 hours afterreactions, washes 2 times, and anhydrous sodium sulfate drying filters, be concentrated into dried, with the crystallization of 200ml petroleum ether and stirring, solid 45.0g (yield 88.1%), 136 ℃ of mp.
Embodiment 6
Preparation N-[(2S)-2-acetyl thiomethyl-1-oxo-3-(3, the 4-methylene-dioxy) hydrocinnamyl]-the L-alanine benzene methyl
Add N-[(2S in the 50ml single port bottle)-2-chloromethyl-1-oxo-3-(3, the 4-methylene-dioxy) hydrocinnamyl]-L-alanine benzene methyl 500mg (1.2mmol), the 30ml ethyl acetate, 1%Aliquat336, add 170mg (1.5mmol) thioacetic acid potassium again, room temperature reaction 10 hours, the TLC judgement reacts completely, and solvent evaporated adds the 30ml ethyl acetate in the residuum, wash 3 times, anhydrous sodium sulfate drying filters, and concentrates, with the mixed solvent crystallization of 30ml ethyl acetate and sherwood oil, get white solid 474mg (yield 86.5%).mp104℃
1HNMR：2.31(3H，s)，3.06(2H，m)，2.52-2.56(1H，m)，2.73-2.9(2H，m)，6.58-6.68(3H，s)，7.25-7.38(5H，m)，4.5(1H，m)，5.88(2H，s)，5.9(1H，d)，4.5(1H，m)，1.3(3H，d)，5.13(2H，m)
MS(EI)：443(M
+)
[α]
D 23(c1, methyl alcohol)=-51.8 °
Embodiment 7
Preparation N-[(2S)-2-chloromethyl-1-oxo-3-(3, the 4-methylene-dioxy) hydrocinnamyl]-the L-alanine benzene methyl
The tosilate and the 60ml methylene dichloride that add 3.0g (8.5mmol) L-alanine benzene methyl in the 100ml there-necked flask, after being cooled to 0 ℃, ice bath adds the 7ml triethylamine, stirred 10 minutes, drip 30ml be dissolved with 1.2g (4.6mmol) (R)-dichloromethane solution of 2-chloromethyl-3-(3, the 4-methylenedioxy group) phenylpropyl alcohol acyl chlorides.React after 2 hours, TLC judges and to react completely, and wash 2 times, and anhydrous sodium sulfate drying filters, be concentrated into dried, with the crystallization of 30ml petroleum ether and stirring, must solid 1.6g (yield 88.4%).
Embodiment 8
Preparation N-[(2S)-2-acetyl thiomethyl-1-oxo-3-(3, the 4-methylene-dioxy) hydrocinnamyl]-the L-alanine benzene methyl
Add N-[(2S in the 50ml single port bottle)-2-chloromethyl-1-oxo-3-(3, the 4-methylene-dioxy) hydrocinnamyl]-L-alanine benzene methyl 500mg (1.2mmol), 30ml acetone and 309mg (1.9mmol) potassiumiodide, reflux after 3 hours, add 420mg (3.7mmol) thioacetic acid potassium, continue to reflux 24 hours, the TLC judgement reacts completely, and solvent evaporated adds the 30ml ethyl acetate in the residuum, wash 3 times, anhydrous sodium sulfate drying filters, and concentrates, with the mixed solvent crystallization of 30ml ethyl acetate and sherwood oil, get white solid 450mg (yield 82.0%).
More than show and described ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in the foregoing description and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (7)
1. midbody compound that is used for chemosynthesis, its structural formula is as shown in the formula shown in (1):
Wherein, X is Cl, Br or I.
2. the intermediate that is used for compound shown in the synthesis type (1), its structural formula is as shown in the formula shown in (2):
Wherein, X is Cl, Br.
3. by the synthetic Fasidotril (N-[(2S) of claim 1 and 2 described intermediates-2-acetyl thiomethyl-1-oxo-3-(3, the 4-methylene-dioxy) phenyl propyl]-the L-alanine benzene methyl) method, it is characterized in that comprising the following steps:
A, set out, make as the formula (2) midbody compound through the two halogenations of halide reagent from (R)-2-(3, the 4-methylenedioxyphenyl)-3-hydroxy-propionic acid;
Compound shown in b, the formula (2) in the presence of alkali with alanine benzyl ester salt amidate action, or react compound shown in the formula of obtaining (1) in the lump with iodination reagent more with this understanding;
Compound and Compound C H shown in c, the formula (1)
3COSY carries out substitution reaction and obtains Fasidotril;
Y=H wherein, K
+, Na
+
4. method as claimed in claim 3, wherein the halide reagent that adopted of step a comprises sulfur oxychloride, oxalyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, thionyl bromide, phosphorus tribromide, boron tribromide.
5. method as claimed in claim 3, wherein the alanine benzyl ester salt that is adopted among the step b comprises hydrochloride, tosilate, mesylate.
6. method as claimed in claim 3, wherein the iodination reagent that is adopted among the step b comprises potassiumiodide, sodium iodide.
7. method as claimed in claim 3, wherein the used alkali of amidate action amidate action of step b comprises one or more in triethylamine, pyridine, salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, sodium hydroxide, the potassium hydroxide.
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|---|---|---|---|
| CNB2005100297343A CN100448865C (en) | 2005-09-16 | 2005-09-16 | Intermediate for synthesizing fasidotril and its synthesis use |
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|---|---|---|---|
| CNB2005100297343A CN100448865C (en) | 2005-09-16 | 2005-09-16 | Intermediate for synthesizing fasidotril and its synthesis use |
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| CN1931854A true CN1931854A (en) | 2007-03-21 |
| CN100448865C CN100448865C (en) | 2009-01-07 |
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Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2652087B1 (en) * | 1989-09-15 | 1993-10-15 | Bioprojet Ste Civile | AMINO ACID DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATIONS. |
| FR2731219B1 (en) * | 1995-03-03 | 1997-04-25 | Bioprojet Soc Civ | PROCESS FOR THE SYNTHESIS OF ALPHA-SUBSTITUTED ACRYLIC ACIDS AND THEIR APPLICATION |
| WO2004060885A1 (en) * | 2002-12-27 | 2004-07-22 | Kaneka Corporation | Processes for producing optically active 2-thiomethyl-3-phenylpropionic acid derivative and for producing intermediate therefor |
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Assignee: Shanghai Modern Hasen (Shangqiu) Pharmaceutical Co., Ltd. Assignor: Shanghai Institute of pharmaceutical industry|Shanghai Modern Pharmaceutical Co., Ltd. Contract fulfillment period: 2009.3.28 to 2015.3.28 contract change Contract record no.: 2009410000149 Denomination of invention: Intermediate for synthesizing fasidotril and its synthesis use Granted publication date: 20090107 License type: Exclusive license Record date: 2009.5.20 |
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Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2009.3.28 TO 2015.3.28; CHANGE OF CONTRACT Name of requester: SHANGHAI MODERN (SHANGQIU) PHARMACEUTICAL CO.,LTD. Effective date: 20090520 |
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Effective date of registration: 20170215 Address after: 200137 Shanghai, Pudong New Area, No. 378 building land road, room 21, 220 Patentee after: Shanghai Modern Pharmaceutical Marketing Co., Ltd. Patentee after: Shanghai Institute of pharmaceutical industry Address before: 200040 Beijing West Road, Shanghai, No. 1320 Patentee before: Shanghai Institute of pharmaceutical industry Patentee before: Shanghai Modern Pharmaceutical Co., Ltd. |
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Effective date of registration: 20170609 Address after: 200137 Shanghai Road, Pudong New Area, No. 378 Co-patentee after: Shanghai Institute of pharmaceutical industry Patentee after: Shanghai Modern Pharmaceutical Co., Ltd. Address before: 200137 Shanghai, Pudong New Area, No. 378 building land road, room 21, 220 Co-patentee before: Shanghai Institute of pharmaceutical industry Patentee before: Shanghai Modern Pharmaceutical Marketing Co., Ltd. |