CN107198690A - A kind of preparation method of Aprepitant compound - Google Patents

A kind of preparation method of Aprepitant compound Download PDF

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Publication number
CN107198690A
CN107198690A CN201710447851.4A CN201710447851A CN107198690A CN 107198690 A CN107198690 A CN 107198690A CN 201710447851 A CN201710447851 A CN 201710447851A CN 107198690 A CN107198690 A CN 107198690A
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Prior art keywords
degrees celsius
aprepitant
mixture
polysaccharide
copolyvidone
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Pending
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CN201710447851.4A
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Chinese (zh)
Inventor
彭凡
李娜
田军
叶杨欢
陈金利
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Wuhan Lihe Biological Pharmaceutical Co Ltd
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Wuhan Lihe Biological Pharmaceutical Co Ltd
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Priority to CN201710447851.4A priority Critical patent/CN107198690A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Inorganic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a kind of preparation method of Aprepitant compound, comprise the following steps：Aprepitant and copolyvidone are placed in blender, and 5 8min are mixed in the environment of 40 60 degrees Celsius, temperature to mixture A is down to 60 70 degrees Celsius, carry out filtration treatment, in the agitator that mixture A is again placed in 100 120 degrees Celsius, epiphysin is inserted thereto, and it is uniformly mixed, heat after 5 8min, add polysaccharide thereto again, and it is uniformly mixed, generate mixture B, then mixture B is moved again in extruder, extrusion process is carried out to it under conditions of 20 30 degrees Celsius, 120 140min are placed in the environment of 58 degrees Celsius, cooling and solidifying, obtain Aprepitant compound.The inventive method is easy, is suitable for industrialized production, and the high yield rate of this method, can effectively reduce unnecessary waste.

Description

A kind of preparation method of Aprepitant compound
Technical field
The present invention relates to chemicals preparing technical field, more particularly to a kind of preparation method of Aprepitant compound.
Background technology
Aprepitant is U.S. FDA in first neurokinin nk 1 receptor retarding agent of approval listing in 2003.It is former The exploitation producer for grinding product is United States Merck company, be mainly used in the prevention of postoperative vomiting, and using being vomitted after chemotherapeutic Prevention and control.Its chemical entitled 5- [[(2R, 3S) -2- [(R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3- (4- Fluorophenyl) morpholinyl] methyl] -1 hydrogen -1,2,4- triazoles -3 (2 hydrogen) -one, molecular formula is C23H21F7N4O3.Aprepitant It is mainly used for the adverse reaction such as acute and delayed property Nausea and vomiting caused by Prophylactic chemotherapy, reduces the pain of patient.
Aprepitant is almost insoluble in water, and the Log P (P is Determination of oil-water partition coefficient) under the conditions of pH7.0 are 4.8, because This, according to Biopharmaceutics Classification, it belongs to the 4th class medicine, i.e. low-solubility hypotonicity medicine.Such medicine is difficult often The product of clinical efficacy is formed with, its reason is that medicine is difficult to be absorbed by organisms, and internal release rate is too fast, bioavilability Difference.Therefore, we have proposed a kind of preparation method of Aprepitant compound.
The content of the invention
The present invention proposes a kind of preparation method of Aprepitant compound, with asking for solving to propose in above-mentioned background technology Topic.
The present invention proposes a kind of preparation method of Aprepitant compound, comprises the following steps：
S1：It is raw material to choose Aprepitant, epiphysin, polysaccharide, copolyvidone；
S2：Aprepitant and copolyvidone are placed in blender, and mix in the environment of 40-60 degrees Celsius 5- 8min, is then moved in extruder, and it is crushed, melted, extrusion, wherein melting heating-up temperature is 120 DEG C -130 DEG C, it is raw Resulting mixture A；
S3：Temperature to the mixture A in S2 is down to 60-70 degrees Celsius, carries out filtration treatment, and filter diameter is not more than 55 mesh, to remove the bulky grain thing in mixture A；
S4：Mixture A is again placed in 100-120 degrees Celsius of agitator, after 5-8min to be heated, inserted thereto Epiphysin, and it is uniformly mixed, after heating 5-8min, add polysaccharide thereto again, and to its uniform mixing Stirring, generation mixture B；
S5：After the completion of above-mentioned, then mixture B is moved again in extruder, to it under conditions of 20-30 degrees Celsius Extrusion process is carried out, 120-140min is placed in the environment of 5-8 degrees Celsius, cools and solidifies, obtains Aprepitant compound.
It is preferred that, Aprepitant, epiphysin, polysaccharide, copolyvidone in S1 are deposited need to individually be sealed before Put.
It is preferred that, the molal weight ratio of Aprepitant and copolyvidone in S2 is 3:0.5.
Present invention also offers a kind of extracting method of polysaccharide, comprise the following steps that：
It is raw material that mushroom, which is chosen, with Momordica grosvenori, and mushroom is crushed respectively with Momordica grosvenori, then mixes, is mixed Compound, and water is added into mixture, add protease and 30-45min is digested under conditions of 40-60 degrees Celsius, then in 90- Under conditions of 100 degrees Celsius, 45-60min is extracted in medicine extractor, is finally filtered, and collect filtrate, be many Sugar.
It is preferred that, described mixture and the molal weight ratio of water are 1：1.
A kind of preparation method of Aprepitant compound proposed by the present invention, beneficial effect is：The present invention helps to carry The bioavilability of high Aprepitant, there is larger clinical value.The inventive method is easy, is suitable for industrialized production, and The high yield rate of this method, can effectively reduce unnecessary waste.
Embodiment
With reference to specific embodiment, the present invention will be further described.
Embodiment 1
The present invention proposes a kind of preparation method of Aprepitant compound, comprises the following steps：
S1：It is raw material to choose Aprepitant, epiphysin, polysaccharide, copolyvidone；
S2：Aprepitant and copolyvidone are placed in blender, and 5min is mixed in the environment of 40 degrees Celsius, then Move in extruder, it is crushed, melted, extrude, wherein melting heating-up temperature is 120 DEG C, generation mixture A；
S3：Temperature to the mixture A in S2 is down to 60 degrees Celsius, carries out filtration treatment, and filter diameter is not more than 55 Mesh, to remove the bulky grain thing in mixture A；
S4：In the agitator that mixture A is again placed in 100 degrees Celsius, after 5min to be heated, insert thereto take off it is black Element, and it is uniformly mixed, after heating 5min, add polysaccharide thereto again, and it is uniformly mixed, it is raw Resulting mixture B；
S5：After the completion of above-mentioned, then mixture B is moved again in extruder, it entered under conditions of 20 degrees Celsius Row extrusion process, places 120min in the environment of 5 degrees Celsius, cooling and solidifying, obtains Aprepitant compound.
Aprepitant, epiphysin, polysaccharide, copolyvidone in S1 are using preceding needing individually to seal storage.
The molal weight ratio of Aprepitant and copolyvidone in S2 is 3:0.5.
Present invention also offers a kind of extracting method of polysaccharide, comprise the following steps that：
It is raw material that mushroom, which is chosen, with Momordica grosvenori, and mushroom is crushed respectively with Momordica grosvenori, then mixes, is mixed Compound, and water is added into mixture, add protease and 30min is digested under conditions of 40 degrees Celsius, then at 90 degrees Celsius Under conditions of, 45min is extracted in medicine extractor, is finally filtered, and collects filtrate, as polysaccharide.
Described mixture and the molal weight ratio of water are 1：1.
Embodiment 2
The present invention proposes a kind of preparation method of Aprepitant compound, comprises the following steps：
S1：It is raw material to choose Aprepitant, epiphysin, polysaccharide, copolyvidone；
S2：Aprepitant and copolyvidone are placed in blender, and 6min is mixed in the environment of 45 degrees Celsius, then Move in extruder, it is crushed, melted, extrude, wherein melting heating-up temperature is 123 DEG C, generation mixture A；
S3：Temperature to the mixture A in S2 is down to 63 degrees Celsius, carries out filtration treatment, and filter diameter is not more than 55 Mesh, to remove the bulky grain thing in mixture A；
S4：In the agitator that mixture A is again placed in 105 degrees Celsius, after 6min to be heated, insert thereto take off it is black Element, and it is uniformly mixed, after heating 6min, add polysaccharide thereto again, and it is uniformly mixed, it is raw Resulting mixture B；
S5：After the completion of above-mentioned, then mixture B is moved again in extruder, it entered under conditions of 23 degrees Celsius Row extrusion process, places 125min in the environment of 6 degrees Celsius, cooling and solidifying, obtains Aprepitant compound.
Aprepitant, epiphysin, polysaccharide, copolyvidone in S1 are using preceding needing individually to seal storage.
The molal weight ratio of Aprepitant and copolyvidone in S2 is 3:0.5.
Present invention also offers a kind of extracting method of polysaccharide, comprise the following steps that：
It is raw material that mushroom, which is chosen, with Momordica grosvenori, and mushroom is crushed respectively with Momordica grosvenori, then mixes, is mixed Compound, and water is added into mixture, add protease and 35min is digested under conditions of 45 degrees Celsius, then at 93 degrees Celsius Under conditions of, 50min is extracted in medicine extractor, is finally filtered, and collects filtrate, as polysaccharide.
Described mixture and the molal weight ratio of water are 1：1.
Embodiment 3
The present invention proposes a kind of preparation method of Aprepitant compound, comprises the following steps：
S1：It is raw material to choose Aprepitant, epiphysin, polysaccharide, copolyvidone；
S2：Aprepitant and copolyvidone are placed in blender, and 7min is mixed in the environment of 50 degrees Celsius, then Move in extruder, it is crushed, melted, extrude, wherein melting heating-up temperature is 125 DEG C, generation mixture A；
S3：Temperature to the mixture A in S2 is down to 65 degrees Celsius, carries out filtration treatment, and filter diameter is not more than 55 Mesh, to remove the bulky grain thing in mixture A；
S4：In the agitator that mixture A is again placed in 110 degrees Celsius, after 7min to be heated, insert thereto take off it is black Element, and it is uniformly mixed, after heating 7min, add polysaccharide thereto again, and it is uniformly mixed, it is raw Resulting mixture B；
S5：After the completion of above-mentioned, then mixture B is moved again in extruder, to it under conditions of 20-30 degrees Celsius Extrusion process is carried out, 130min is placed in the environment of 7 degrees Celsius, cools and solidifies, obtains Aprepitant compound.
Aprepitant, epiphysin, polysaccharide, copolyvidone in S1 are using preceding needing individually to seal storage.
The molal weight ratio of Aprepitant and copolyvidone in S2 is 3:0.5.
Present invention also offers a kind of extracting method of polysaccharide, comprise the following steps that：
It is raw material that mushroom, which is chosen, with Momordica grosvenori, and mushroom is crushed respectively with Momordica grosvenori, then mixes, is mixed Compound, and water is added into mixture, add protease and 40min is digested under conditions of 50 degrees Celsius, then at 95 degrees Celsius Under conditions of, 55min is extracted in medicine extractor, is finally filtered, and collects filtrate, as polysaccharide.
Described mixture and the molal weight ratio of water are 1：1.
Embodiment 4
The present invention proposes a kind of preparation method of Aprepitant compound, comprises the following steps：
S1：It is raw material to choose Aprepitant, epiphysin, polysaccharide, copolyvidone；
S2：Aprepitant and copolyvidone are placed in blender, and 7.5min is mixed in the environment of 55 degrees Celsius, so After move in extruder, it is crushed, melted, is extruded, wherein melting heating-up temperature is 128 DEG C, generation mixture A；
S3：Temperature to the mixture A in S2 is down to 68 degrees Celsius, carries out filtration treatment, and filter diameter is not more than 55 Mesh, to remove the bulky grain thing in mixture A；
S4：In the agitator that mixture A is again placed in 115 degrees Celsius, after 7.5min to be heated, insert thereto take off it is black Element, and it is uniformly mixed, after heating 7.5min, add polysaccharide thereto again, and it is uniformly mixed, Generate mixture B；
S5：After the completion of above-mentioned, then mixture B is moved again in extruder, it entered under conditions of 28 degrees Celsius Row extrusion process, places 135min in the environment of 7.5 degrees Celsius, cooling and solidifying, obtains Aprepitant compound.
Aprepitant, epiphysin, polysaccharide, copolyvidone in S1 are using preceding needing individually to seal storage.
The molal weight ratio of Aprepitant and copolyvidone in S2 is 3:0.5.
Present invention also offers a kind of extracting method of polysaccharide, comprise the following steps that：
It is raw material that mushroom, which is chosen, with Momordica grosvenori, and mushroom is crushed respectively with Momordica grosvenori, then mixes, is mixed Compound, and water is added into mixture, add protease and 42min is digested under conditions of 55 degrees Celsius, then at 98 degrees Celsius Under conditions of, 58min is extracted in medicine extractor, is finally filtered, and collects filtrate, as polysaccharide.
Described mixture and the molal weight ratio of water are 1：1.
Embodiment 5
The present invention proposes a kind of preparation method of Aprepitant compound, comprises the following steps：
S1：It is raw material to choose Aprepitant, epiphysin, polysaccharide, copolyvidone；
S2：Aprepitant and copolyvidone are placed in blender, and 8min is mixed in the environment of 60 degrees Celsius, then Move in extruder, it is crushed, melted, extrude, wherein melting heating-up temperature is 130 DEG C, generation mixture A；
S3：Temperature to the mixture A in S2 is down to 70 degrees Celsius, carries out filtration treatment, and filter diameter is not more than 55 Mesh, to remove the bulky grain thing in mixture A；
S4：In the agitator that mixture A is again placed in 120 degrees Celsius, after 8min to be heated, insert thereto take off it is black Element, and it is uniformly mixed, after heating 8min, add polysaccharide thereto again, and it is uniformly mixed, it is raw Resulting mixture B；
S5：After the completion of above-mentioned, then mixture B is moved again in extruder, it entered under conditions of 30 degrees Celsius Row extrusion process, places 140min in the environment of 8 degrees Celsius, cooling and solidifying, obtains Aprepitant compound.
Aprepitant, epiphysin, polysaccharide, copolyvidone in S1 are using preceding needing individually to seal storage.
The molal weight ratio of Aprepitant and copolyvidone in S2 is 3:0.5.
Present invention also offers a kind of extracting method of polysaccharide, comprise the following steps that：
It is raw material that mushroom, which is chosen, with Momordica grosvenori, and mushroom is crushed respectively with Momordica grosvenori, then mixes, is mixed Compound, and water is added into mixture, add protease and 45min is digested under conditions of 60 degrees Celsius, then taken the photograph in 90-100 Under conditions of family name's degree, 60min is extracted in medicine extractor, is finally filtered, and collect filtrate, as polysaccharide.
Described mixture and the molal weight ratio of water are 1：1.
The foregoing is only a preferred embodiment of the present invention, but protection scope of the present invention be not limited thereto, Any one skilled in the art the invention discloses technical scope in, technique according to the invention scheme and its Inventive concept is subject to equivalent substitution or change, should all be included within the scope of the present invention.

Claims (5)

1. a kind of preparation method of Aprepitant compound, it is characterised in that comprise the following steps：
S1：It is raw material to choose Aprepitant, epiphysin, polysaccharide, copolyvidone；
S2：Aprepitant and copolyvidone are placed in blender, and 5-8min is mixed in the environment of 40-60 degrees Celsius, so After move in extruder, it is crushed, melted, extrude, wherein melting heating-up temperature be 120 DEG C -130 DEG C, generation mixing Thing A；
S3：Temperature to the mixture A in S2 is down to 60-70 degrees Celsius, carries out filtration treatment, and filter diameter is not more than 55 Mesh, to remove the bulky grain thing in mixture A；
S4：Mixture A is again placed in 100-120 degrees Celsius of agitator, after 5-8min to be heated, insert thereto take off it is black Element, and it is uniformly mixed, after heating 5-8min, add polysaccharide thereto again, and it is uniformly mixed, Generate mixture B；
S5：After the completion of above-mentioned, then mixture B is moved again in extruder, it carried out under conditions of 20-30 degrees Celsius Extrusion process, places 120-140min in the environment of 5-8 degrees Celsius, cooling and solidifying, obtains Aprepitant compound.
2. a kind of preparation method of Aprepitant compound according to claim 1, it is characterised in that：A Rui in S1 Smooth, epiphysin, polysaccharide, copolyvidone are using preceding needing individually to seal storage.
3. a kind of preparation method of Aprepitant compound according to claim 1, it is characterised in that：A Rui in S2 The smooth molal weight ratio with copolyvidone is 3:0.5.
4. a kind of extracting method of polysaccharide according to claim 1, it is characterised in that：Comprise the following steps that：
It is raw material that mushroom, which is chosen, with Momordica grosvenori, and mushroom is crushed respectively with Momordica grosvenori, then mixes, is mixed Thing, and water is added into mixture, add protease and 30-45min is digested under conditions of 40-60 degrees Celsius, then in 90- Under conditions of 100 degrees Celsius, 45-60min is extracted in medicine extractor, is finally filtered, and collect filtrate, be many Sugar.
5. a kind of extracting method of polysaccharide according to claim 4, it is characterised in that：Described mixture and mole of water Mass ratio is 1：1.
CN201710447851.4A 2017-06-14 2017-06-14 A kind of preparation method of Aprepitant compound Pending CN107198690A (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1452972A (en) * 2003-05-23 2003-11-05 李森青 Plant extractive composition containing ginkgetin and its use
CN102525880A (en) * 2010-12-31 2012-07-04 江苏正大天晴药业股份有限公司 Aprepitant solid dispersion composition
CN102525879A (en) * 2010-12-31 2012-07-04 江苏正大天晴药业股份有限公司 Method for preparing aprepitant solid dispersing composition
CN103356618A (en) * 2013-06-27 2013-10-23 海南卫康制药(潜山)有限公司 Tropisetron composition for injection
CN103694366A (en) * 2013-12-12 2014-04-02 上海市农业科学院 Preparation method of high-content lentinan
CN104367551A (en) * 2013-08-15 2015-02-25 上海星泰医药科技有限公司 Aprepitant compound and its preparation method

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1452972A (en) * 2003-05-23 2003-11-05 李森青 Plant extractive composition containing ginkgetin and its use
CN102525880A (en) * 2010-12-31 2012-07-04 江苏正大天晴药业股份有限公司 Aprepitant solid dispersion composition
CN102525879A (en) * 2010-12-31 2012-07-04 江苏正大天晴药业股份有限公司 Method for preparing aprepitant solid dispersing composition
CN103356618A (en) * 2013-06-27 2013-10-23 海南卫康制药(潜山)有限公司 Tropisetron composition for injection
CN104367551A (en) * 2013-08-15 2015-02-25 上海星泰医药科技有限公司 Aprepitant compound and its preparation method
CN103694366A (en) * 2013-12-12 2014-04-02 上海市农业科学院 Preparation method of high-content lentinan

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Application publication date: 20170926