CN105198794A - Preparation method of alvimopan - Google Patents

Preparation method of alvimopan Download PDF

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Publication number
CN105198794A
CN105198794A CN201510665375.4A CN201510665375A CN105198794A CN 105198794 A CN105198794 A CN 105198794A CN 201510665375 A CN201510665375 A CN 201510665375A CN 105198794 A CN105198794 A CN 105198794A
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CN
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Prior art keywords
compound
aiweimopan
preparation
organic solvent
methyl
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陈芳军
李书耘
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Hunan Huateng Pharmaceutical Co Ltd
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Hunan Huateng Pharmaceutical Co Ltd
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Priority to CN201510665375.4A priority Critical patent/CN105198794A/en
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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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The invention discloses a preparation method of alvimopan and belongs to the field of medical and pharmaceutical technologies. According to the method, a compound V, namely, diethyl benzylmalonate or dimethyl benzylmalonate is taken as an initial raw material and reacts with glycine, a compound IV is obtained, selective reduction of ester groups of the compound IV is performed, a compound III is obtained and has a sulfonylation reaction, a compound II is obtained and has a substitution reaction with (3R,4R)-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, and a compound I is obtained.

Description

A kind of preparation method of Aiweimopan
Technical field
The present invention relates to a kind of preparation method of Aiweimopan, belong to medical pharmaceutical technology sectors.
Technical background
Aiweimopan, chemistry 2-([(2S)-2-([(3R by name, 4R)-4-(3-hydroxy phenyl)-3,4-lupetidine-1-base] methyl)-3-phenylpropionyl] amino) acetic acid, commodity are called Entereg, and this medicine is developed with the joint study of A Daoluo (Adolor) company by GlaxoSmithKline PLC company (GlaxoSmithKline).Aiweimopan obtains FDA approval listing on May 20th, 2008, clinically for the gastrointestinal dysfunction of performing the operation and use opioid drug to cause, and idiopathic constipation and irritable bowel syndrome etc.
Aiweimopan is a kind of peripheral mu type opiate receptor antagonist of highly selective.In operation, owing to using opioid analgesic medicine, make gi tract malfunction, show as apocleisis, feel sick, flatulence, abdominal distension, defecation reduce and intestinal obstruction etc.Use optionally opiate receptor antagonist effectively can alleviate above-mentioned symptom, the opiate receptor studying more at present has μ, κ and δ tri-kinds.Aiweimopan has good avidity to opiate receptor, especially μ receptor is had to the selectivity of height.
Postoperative intestinal obstruction (Post-operativeileus, POI) see among all abdominal operations, its genesis mechanism is comparatively complicated, still not exclusively removes at present, and main manifestations is: stomachache, Nausea and vomiting, can not take food, abdominal distension/flatulence, defecation delay etc.POI makes troubles to patient's operative results, and puts off long length of patient stay, causes very large economical load, and how overcoming POI and recovering patient's gastrointestinal tract function is as early as possible a postoperative difficult problem always.There is no special medicine clinically at present to treat, main method is some simple supportive treatments, and effect is very undesirable.Therefore the good medicine of a kind of clear curative effect, security is developed to the treatment of POI and to improve the prognosis of patients with abdominal surgery significant.Aiweimopan is at present unique in this field one and has medicine that is well clinical, market outlook, and the peripheral action mechanism of its uniqueness makes it have very high target feature.Aiweimopan enters GI μ type opiate receptor performance antagonistic action, owing to through hemato encephalic barrier, therefore can not affect the opium effect mediated by nervus centralis, not affecting the use of opioid analgesic medicine in operation.Aiweimopan has determined curative effect, the advantage that untoward reaction is little, and it has good prospect in the application of operation.The structural formula of Aiweimopan is:
The preparation method of the Aiweimopan of report mostly is by (3R both at home and abroad at present, 4R)-3, there is N-alkylated reaction in 4-dimethyl-4-(3-hydroxy phenyl) piperidines and methyl acrylate, carry out Benzylation reaction, hydrolysis reaction, amidate action more afterwards, obtain Aiweimopan finally by hydrolysis, reaction scheme is as follows:
This method with expensive (3R, 4R)-3,4-dimethyl-4-(3-hydroxy phenyl) piperidines for starting raw material, obtain Aiweimopan through polystep reaction, therefore use the method synthesis Aiweimopan cost higher.
Patent CN102757379A announces the preparation method of another kind of Aiweimopan, and reaction scheme is as follows:
R is (C1-C6) alkyl.
This method take diethyl benzyl malonate as starting raw material, use expensive enzyme catalyst, and uses heavy metal oxide Jones reagent, and the heavy-metal residual of product not easily removes, and reaction scheme is long, and cost is high, and ring is difficult to realize suitability for industrialized production.
Therefore, need a kind of efficient, easy, low cost of exploitation, be applicable to industrial method and synthesize Aiweimopan.
Summary of the invention
The invention discloses a kind of preparation method of Aiweimopan, belong to medical pharmaceutical technology sectors.The method with compound V and diethyl benzyl malonate or benzyl malonic acid dimethyl ester for initial feed; compound IV is obtained with glycine reactant; IV obtains compound III through selective reduction ester group; III obtains Compound II per through sulfonylation; II and (3R; 4R)-3,4-dimethyl-4-(3-hydroxy phenyl) piperidines generation substitution reaction obtains Compound I and Aiweimopan.The method obtains target product by four-step reaction, shortens reactions steps greatly, improves overall yield of reaction, reduces cost, is suitable for suitability for industrialized production.
The preparation method of Aiweimopan disclosed in this invention comprises the following steps:
(1) join in organic solvent by compound V and glycine, constantly steam the lower boiling small molecules of generation under hot conditions simultaneously, some plate monitoring reaction disappears to raw material mottle, concentrated, crosses silicagel column and obtains compound IV;
Wherein, R is methyl or ethyl;
Described organic solvent is one or several the mixture in Isosorbide-5-Nitrae-dioxane or benzene or toluene or dimethylbenzene or DMF;
Described hot conditions is 80 DEG C-160 DEG C;
Described lower boiling small molecules is methyl alcohol or ethanol;
Described compound V: the mol ratio of glycine is 1:1-1:3.
(2) join in organic solvent by compound IV, add hydride ion reductive agent under keeping cold condition toward reaction solution in batches, react and disappear to raw material spot, regulate reaction solution PH to acid, filter, concentrated, recrystallization obtains compound III;
Wherein, R is methyl or ethyl;
Described organic solvent is one or several the mixture in ethanol or methyl alcohol or tetrahydrofuran (THF) or ether or methyl tertiary butyl ether;
Described hydride ion reductive agent is one or several the mixture in lithium borohydride or sodium borohydride or POTASSIUM BOROHYDRIDE or sodium cyanoborohydride;
Described cold condition is-10 DEG C-10 DEG C;
Described compound IV: the mol ratio of hydride ion reductive agent is 1:1.5-1:4.
(3) join in organic solvent by compound III and alkali, add p-dimethylamino-azo-benzene acyl chlorides under cold condition, complete, stirring at room temperature disappears to raw material spot, and cancellation is reacted, and extraction concentrates to obtain Compound II per;
Described organic solvent is acetonitrile or methylene dichloride or trichloromethane or tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane;
Described alkali is pyridine or triethylamine or diisopropyl ethyl amine or salt of wormwood or sodium carbonate or sodium bicarbonate or saleratus;
Described cold condition is-5 DEG C-5 DEG C;
Described compound III: the mol ratio of p-dimethylamino-azo-benzene acyl chlorides is 1:1-1:3.
(4) by Compound II per, alkali and (3R, 4R)-3,4-dimethyl-4-(3-hydroxy phenyl) piperidines join in organic solvent, be stirred to raw material spot under heating condition and disappear, filter, concentrated, recrystallization obtains Compound I.
Described organic solvent is trichloromethane or tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane;
Described alkali is triethylamine or di-isopropyl diethylamide or salt of wormwood or sodium carbonate;
Described heating condition is 50 DEG C-80 DEG C;
Described Compound II per: (3R, 4R)-3,4-the mol ratio of dimethyl-4-(3-hydroxy phenyl) piperidines be 1:1-1:4.
The invention will be further described by way of example more below, provides implementation detail of the present invention, but be not be intended to limit protection scope of the present invention.
Embodiment
Below provide specific embodiments of the invention, to show possible implementation process.
Embodiment 1:
(1) preparation of compound IV:
By compound V (500g, 2mol) with glycine (90g, 1.2mol) join in dimethylbenzene, be heated to 145 DEG C, constantly steam the ethanol of generation simultaneously, react 15 hours, TLC display reacts completely, concentrated, add water and ethyl acetate, extraction, separate organic phase, drying, concentrated, residuum silicagel column is separated, elutriant adopts ethanol: ammoniacal liquor: ethyl acetate: sherwood oil=1:0.1:10:3 system, it is white solid 152.4g that separation obtains compound IV, yield 45.5%, ee%:95%.
(2) preparation of compound III:
Compound IV (139.5g, 0.5mol) is joined in methyl alcohol (2000ml), be cooled to 0 DEG C, add sodium borohydride (38g, 1mol) in batches, complete, naturally room temperature is warming up to, continue reaction 4 hours, TLC display reacts completely, and drips 1N hydrochloric acid until reactant PH is 2, filter, concentrated, residuum recrystallization obtains compound III 101.9g, yield 86%.
(3) preparation of Compound II per:
Compound III (94.8g, 0.4mol) and triethylamine (60.7g, 0.6mol) are joined in methylene dichloride (800ml), be cooled to 0 DEG C, slowly drip Methanesulfonyl chloride (68.7g, 0.6mol), complete, continue stirring at room temperature and react 5 hours, TLC display reacts completely, add mixture of ice and water cancellation reaction, extraction, separates organic layer, concentrate to obtain Compound II per 119.7g, yield 95%, without the need to purifying, is directly used in next step reaction.
(4) preparation of Aiweimopan:
By Compound II per (110.25g, 0.35mol) with salt of wormwood (55.2g, 0.4mol) join in tetrahydrofuran (THF) (1200ml), add (3R again, 4R)-3, 4-dimethyl-4-(3-hydroxy phenyl) piperidines (101.6g, 0.35mol), be heated to 60 DEG C of reactions 12 hours, TLC display reacts completely, acid adding adjusts PH to 5, add water and ethyl acetate, extraction, separate organic layer, use saturated common salt water washing again three times, dry, concentrated, residuum ethyl acetate and sherwood oil mixed solvent carry out recrystallization and obtain product 109.8g, yield 74%.
Embodiment 2:
(1) preparation of compound IV:
By compound V (440g, 2mol) with glycine (90g, 1.2mol) join in dimethylbenzene (2500ml), be heated to 145 DEG C, constantly steam the methyl alcohol of generation simultaneously, react 13 hours, TLC display reacts completely, concentrated, add water and ethyl acetate, extraction, separate organic phase, drying, concentrated, residuum silicagel column is separated, elutriant adopts ethanol: ammoniacal liquor: ethyl acetate: sherwood oil=1:0.1:10:3 system, it is white solid 152.4g145.6 that separation obtains compound IV, yield 42.9%, ee%:94.8%.
(2) preparation of compound III:
Compound IV (132.55g, 0.5mol) is joined in methyl alcohol (2000ml), be cooled to-5 DEG C, add sodium borohydride (38g, 1mol) in batches, complete, naturally room temperature is warming up to, continue reaction 5 hours, TLC display reacts completely, and drips 1N hydrochloric acid until reactant PH is 2, filter, concentrated, residuum recrystallization obtains compound III 84.57g, yield 83%.
(3) preparation of Compound II per:
Compound III (82.9g, 0.35mol) and pyridine (47.4g, 0.6mol) are joined in methylene dichloride (750ml), be cooled to 0 DEG C, slowly drip Methanesulfonyl chloride (68.7g, 0.6mol), complete, continue stirring at room temperature and react 5 hours, TLC display reacts completely, add mixture of ice and water cancellation reaction, extraction, separates organic layer, concentrate to obtain Compound II per 101.4g, yield 92%, without the need to purifying, is directly used in next step reaction.
(4) preparation of Aiweimopan:
By Compound II per (94.5g, 0.3mol) with sodium carbonate (37.1g, 0.35mol) join in trichloromethane (1100ml), add (3R, 4R)-3,4-dimethyl-4-(3-hydroxy phenyl) piperidines (87.1g again, 0.3mol), be heated to 60 DEG C of reactions 12 hours, TLC display reacts completely, and acid adding adjusts PH to 5, add water and ethyl acetate, extraction, separates organic layer, then uses saturated common salt water washing three times, dry, concentrated, residuum ethyl acetate and sherwood oil mixed solvent carry out recrystallization and obtain product 105.3g, yield 71%.
Embodiment 3:
(1) preparation of compound IV:
By compound V (450g, 2mol) with glycine (75g, 1mol) join in toluene, be heated to 115 DEG C, constantly steam the ethanol of generation simultaneously, react 24 hours, TLC display reacts completely, concentrated, add water and ethyl acetate, extraction, separate organic phase, drying, concentrated, residuum silicagel column is separated, elutriant adopts ethanol: ammoniacal liquor: ethyl acetate: sherwood oil=1:0.1:10:3 system, it is white solid 103.2g that separation obtains compound IV, yield 37%, ee%:94%.
(2) preparation of compound III:
Compound IV (90.06g, 0.38mol) is joined in ethanol (1500ml), be cooled to 0 DEG C, add POTASSIUM BOROHYDRIDE (41g, 0.76mol) in batches, complete, naturally room temperature is warming up to, continue reaction 3.5 hours, TLC display reacts completely, and drips 1N hydrochloric acid until reactant PH is 2, filter, concentrated, residuum recrystallization obtains compound III 101.9g, yield 79%.
(3) preparation of Compound II per:
Compound III (94.8g, 0.4mol) and triethylamine (60.7g, 0.6mol) are joined in methylene dichloride (800ml), be cooled to 0 DEG C, slowly drip Methanesulfonyl chloride (68.7g, 0.6mol), complete, continue stirring at room temperature and react 5 hours, TLC display reacts completely, add mixture of ice and water cancellation reaction, extraction, separates organic layer, concentrate to obtain Compound II per 119.7g, yield 95%, without the need to purifying, is directly used in next step reaction.
(4) preparation of Aiweimopan:
By Compound II per (110.25g, 0.35mol) with salt of wormwood (55.2g, 0.4mol) join in trichloromethane (1100ml), add (3R again, 4R)-3, 4-dimethyl-4-(3-hydroxy phenyl) piperidines (101.6g, 0.35mol), be heated to 60 DEG C of reactions 12 hours, TLC display reacts completely, acid adding adjusts PH to 5, add water and ethyl acetate, extraction, separate organic layer, use saturated common salt water washing again three times, dry, concentrated, residuum ethyl acetate and sherwood oil mixed solvent carry out recrystallization and obtain product 109.8g, yield 74%.

Claims (8)

1. a preparation method for Aiweimopan, is characterized in that having following reactions steps:
(1) join in organic solvent by compound V and glycine, constantly steam the lower boiling small molecules of generation under hot conditions simultaneously, some plate monitoring reaction disappears to raw material mottle, concentrated, crosses silicagel column and obtains compound IV;
Wherein, R is methyl or ethyl;
(2) join in organic solvent by compound IV, add hydride ion reductive agent under keeping cold condition toward reaction solution in batches, react and disappear to raw material spot, regulate reaction solution PH to acid, filter, concentrated, recrystallization obtains compound III;
Wherein, R is methyl or ethyl;
(3) join in organic solvent by compound III and alkali, add p-dimethylamino-azo-benzene acyl chlorides under cold condition, complete, stirring at room temperature disappears to raw material spot, extracts reaction of going out, and extraction concentrates and to obtain Compound II per;
(4) by Compound II per, alkali and (3R, 4R)-3,4-dimethyl-4-(3-hydroxy phenyl) piperidines join in organic solvent, be stirred to raw material spot under heating condition and disappear, filter, concentrated, recrystallization obtains Compound I.
2. the preparation method of a kind of Aiweimopan as claimed in claim 1, is characterized in that in described step (1),
Described organic solvent is one or several the mixture in Isosorbide-5-Nitrae-dioxane or benzene or toluene or dimethylbenzene or DMF;
Described hot conditions is 80 DEG C-160 DEG C;
Described lower boiling small molecules is methyl alcohol or ethanol;
Described compound V: the mol ratio of glycine is 1:1-1:3.
3. the preparation method of a kind of Aiweimopan as claimed in claim 1, is characterized in that in described step (2),
Described organic solvent is one or several the mixture in ethanol or methyl alcohol or tetrahydrofuran (THF) or ether or methyl tertiary butyl ether;
Described hydride ion reductive agent is one or several the mixture in lithium borohydride or sodium borohydride or POTASSIUM BOROHYDRIDE or sodium cyanoborohydride;
Described cold condition is-10 DEG C-10 DEG C;
Described compound IV: the mol ratio of hydride ion reductive agent is 1:1.5-1:4.
4. the preparation method of a kind of Aiweimopan as claimed in claim 1, is characterized in that in described step (3),
Described organic solvent is acetonitrile or methylene dichloride or trichloromethane or tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane;
Described alkali is pyridine or triethylamine or diisopropyl ethyl amine or salt of wormwood or sodium carbonate or sodium bicarbonate or saleratus;
Described cold condition is-5 DEG C-5 DEG C;
Described compound III: the mol ratio of p-dimethylamino-azo-benzene acyl chlorides is 1:1-1:3.
5. the preparation method of a kind of Aiweimopan as claimed in claim 1, is characterized in that in described step (4),
Described organic solvent is trichloromethane or tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane;
Described alkali triethylamine or di-isopropyl diethylamide or salt of wormwood or sodium carbonate;
Described heating condition is 50 DEG C-80 DEG C;
Described Compound II per: (3R, 4R)-3,4-the mol ratio of dimethyl-4-(3-hydroxy phenyl) piperidines be 1:1-1:4.
6. a kind of intermediate used in the preparation method of a kind of Aiweimopan as claimed in claim 1, is characterized in that such as formula the compound shown in IV,
Wherein, R is methyl or ethyl.
7. a kind of intermediate used in the preparation method of a kind of Aiweimopan as claimed in claim 1, is characterized in that the compound as shown in formula III,
8. a kind of intermediate used in the preparation method of a kind of Aiweimopan as claimed in claim 1, is characterized in that such as formula the compound shown in II,
CN201510665375.4A 2015-10-14 2015-10-14 Preparation method of alvimopan Pending CN105198794A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110128324A (en) * 2019-06-19 2019-08-16 中南林业科技大学 A kind of Chiral Synthesis and its intermediate of Aiweimopan intermediate

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102757379A (en) * 2012-07-17 2012-10-31 上海皓元生物医药科技有限公司 Preparation method of alvimopan

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102757379A (en) * 2012-07-17 2012-10-31 上海皓元生物医药科技有限公司 Preparation method of alvimopan

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DISCLOSED ANONYMOUSLY: "COMPOUNDS SUITABLE AS REFERENCE MARKERS IN THE ANALYSIS OF 2-([(2S)-2-([(3R,4R)-4-(3-HYDROXYPHENYL)-3,4-DIMETHYLPIPERIDIN-1-YL]METHYL)-3-PHENYLPROPANOYL]AMINO)ACETIC ACID", 《IP COM》 *
JOHN A. WERNER，ET AL.: "Synthesis oftrans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine Opioid Antagonists: Application of theCis-Thermal Elimination of Carbonates to Alkaloid Synthesis", 《J. ORG. CHEM.》 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110128324A (en) * 2019-06-19 2019-08-16 中南林业科技大学 A kind of Chiral Synthesis and its intermediate of Aiweimopan intermediate

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Application publication date: 20151230