CN115057898A - Preparation method of fondaparinux sodium intermediate - Google Patents
Preparation method of fondaparinux sodium intermediate Download PDFInfo
- Publication number
- CN115057898A CN115057898A CN202210899788.9A CN202210899788A CN115057898A CN 115057898 A CN115057898 A CN 115057898A CN 202210899788 A CN202210899788 A CN 202210899788A CN 115057898 A CN115057898 A CN 115057898A
- Authority
- CN
- China
- Prior art keywords
- formula
- reaction
- compound
- reagent
- compound shown
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960003661 fondaparinux sodium Drugs 0.000 title claims abstract description 21
- XEKSTYNIJLDDAZ-JASSWCPGSA-F fondaparinux sodium Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O[C@@H]1[C@@H](NS([O-])(=O)=O)[C@@H](OC)O[C@H](COS([O-])(=O)=O)[C@H]1O[C@H]1[C@H](OS([O-])(=O)=O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](OS([O-])(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS([O-])(=O)=O)O4)NS([O-])(=O)=O)[C@H](O3)C(O)=O)O)[C@@H](COS([O-])(=O)=O)O2)NS([O-])(=O)=O)[C@H](C(O)=O)O1 XEKSTYNIJLDDAZ-JASSWCPGSA-F 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 11
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012346 acetyl chloride Substances 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 8
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000008103 glucose Substances 0.000 claims abstract description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 238000006640 acetylation reaction Methods 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 239000011230 binding agent Substances 0.000 claims abstract description 4
- 230000021736 acetylation Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000012445 acidic reagent Substances 0.000 claims description 8
- HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 claims description 6
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000007069 methylation reaction Methods 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 238000001308 synthesis method Methods 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 7
- 238000007031 hydroxymethylation reaction Methods 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 5
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 abstract description 3
- MSWZFWKMSRAUBD-QZABAPFNSA-N beta-D-glucosamine Chemical compound N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-QZABAPFNSA-N 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 3
- 150000001540 azides Chemical class 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 239000012535 impurity Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 18
- 238000001035 drying Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 230000002194 synthesizing effect Effects 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 208000005189 Embolism Diseases 0.000 description 1
- 206010014522 Embolism venous Diseases 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- -1 Methyl glycoside monosaccharide Chemical class 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000003055 low molecular weight heparin Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000004043 venous thromboembolism Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a preparation method of fondaparinux sodium intermediate, which comprises a synthetic method of methyl glycoside-2-benzyloxy carbonyl amido-3-O-benzyl-6-O-acetyl-2-deoxy-alpha-D-pyran type glucose shown in formula (1), and the synthetic method of methyl glycoside-2-benzyloxy carbonyl amido-3-O-benzyl-6-O-acetyl-2-deoxy-alpha-D-pyran type glucose comprises the following steps: performing hydroxyl acetylation on the compound shown in the formula (2) and acetyl chloride in a solvent in the presence of an acid binding agent to generate a compound shown in the formula (1); controlling the reaction temperature to be between-10 and 10 ℃; the preparation method adopts the protection of amino in D-glucosamine by the benzyloxycarbonyl chloride, avoids the use of dangerous goods such as azide and the like, simultaneously reduces the purification difficulty of the product, can obtain more ideal product yield, has less reaction impurities in each step, controllable quality and less three wastes, uses raw materials and reagents which are easy to obtain, is beneficial to industrial scale production, and can meet the industrial production of fondaparinux sodium.
Description
Technology neighborhood
The invention belongs to the field of chemical synthesis of sugar, and particularly relates to a preparation method of a fondaparinux sodium intermediate.
Background
Fondaparinux sodium is the only new chemically synthesized selected factor XA inhibitor at present, and is a new generation anticoagulant drug taking factor Xa as a main target. Compared with the common heparin and the low molecular heparin, the heparin has incomparable inherent advantages.
Fondaparinux sodium is used for preventing and treating venous thromboembolism. A great deal of exploration and clinical research are carried out in the international medical field, and especially in the prevention and treatment of thromboembolism and venous thrombotic diseases in orthopedic joint replacement surgery, the anticoagulant drug has been used as the first choice anticoagulant drug in clinical to wide application and is agreed to be accepted.
The chemical structural formula of fondaparinux sodium is shown as follows:
in the last 80 s of the century, french scientists completed the entire synthesis of this compound through up to 70 chemical reaction steps (carbohydr. res.,1986,147, 221-. Because of its complex structure, long synthesis route and high cost, its popularization and promotion are always limited. The difficulty in the synthesis is that multistep glycoside stereoselective reactions of alpha and beta isomers are involved, the synthesis of a Methyl glycoside monosaccharide intermediate with the following structure (formula 1) is an important intermediate, and the intermediate is named Methyl-2-benzyloxycarbonylamino-3-O-benzyl-6-O-acetyl-2-deoxygroup-alpha-D-glucopyranose (the English name is Methyl-2-benzyloxy carbamate-3-O-benzyl-6-O-acetyl-2-deoxy-D-pyran Glucose):
the synthesis method of the multi-intermediate formula (1) in the prior art is single, and the synthesis strategies of monosaccharide amino in azide-protected fondaparinux sodium are used, and are shown as follows:
the preparation method uses azide protection, so that the industrial risk is too high, the compound of the formula (a) is a mixture of alpha and beta isomers, the alpha isomer accounts for only 66%, the purification and the refining need to adopt complex column chromatography, the purification and the refining of the later intermediate and the product are not facilitated, the product quality is reduced, and the yield is lower.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method of an intermediate of fondaparinux sodium, which comprises a preparation method of a monosaccharide intermediate of the fondaparinux sodium, namely, methyl glycoside-2-benzyloxy carbonyl amido-3-O-benzyl-6-O-acetyl-2-deoxy-alpha-D-pyran type glucose.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a synthetic method of methyl glycoside-2-benzyloxy carbonyl amido-3-O-benzyl-6-O-acetyl-2-deoxy-alpha-D-pyran glucose shown as a formula (1) comprises the following steps:
(v) carrying out amino protection reaction on the compound shown in the formula (5) and benzyloxycarbonyl chloride in a solvent in the presence of an alkaline reagent to generate a compound shown in the formula (4); controlling the reaction temperature to be 20-50 ℃;
(vi) carrying out hydroxymethyl reaction on the compound shown in the formula (4) and methanol in a solvent in the presence of an acidic reagent to generate a compound shown in the formula (3); controlling the reaction temperature to be 50-80 ℃;
(vii) the compound benzaldehyde dimethyl acetal shown in the formula (3) reacts in a solvent in the presence of a camphorsulfonic acid reagent, and then the product and benzyl bromide react in the presence of a sodium hydride reagent in the solvent for protecting hydroxyl groups to generate the compound shown in the formula (2); controlling the reaction temperature to be 30-70 ℃;
(viii) performing hydroxyl acetylation on the compound shown in the formula (2) and acetyl chloride in a solvent in the presence of an acid binding agent to generate a compound shown in the formula (1); controlling the reaction temperature to be between-10 and 10 ℃;
according to some preferred aspects of the invention, in step (i), the alkaline agent is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, calcium carbonate, potassium bicarbonate.
According to some preferred aspects of the present invention, in step (i), the compound of formula (5), the benzyloxycarbonyl chloride and the basic agent are fed in a molar ratio of 1: 1-1.5: 1.2 to 1.8.
According to some preferred aspects of the invention, the benzyloxycarbonyl chloride is added in step (i) at a temperature of-5 to 5 ℃.
According to some preferred aspects of the present invention, in the step (i), the amino protection reaction temperature is 20 to 50 ℃.
According to some preferred aspects of the present invention, in the step (i), the reaction reagent for the amino protection reaction is 12-24 hours.
According to some preferred aspects of the invention, in step (ii), the acidic reagent is one or more of acetyl chloride and concentrated sulfuric acid.
According to some preferred aspects of the present invention, in step (ii), the compound of formula (4) and the acidic agent are fed in a molar ratio of 1: 1 to 1.5.
According to some preferred aspects of the invention, in the step (ii), the acidic reagent is added at a temperature of-5 to 5 ℃.
According to some preferred aspects of the present invention, in the step (ii), the reaction temperature of the methylation reaction is 50 to 80 ℃.
According to some preferred aspects of the present invention, in the step (ii), the reaction time of the methylation reaction is 5 to 12 hours.
According to some preferred aspects of the present invention, in step (iii), the compound of formula (3), the benzaldehyde dimethyl acetal, the camphorsulfonic acid, the benzyl bromide and the sodium hydride are fed in a molar ratio of 1: 1.2-2.0: 0.05-0.15: 1.1-1.5: 0.8 to 1.2.
According to some preferred aspects of the invention, in step (iv), the acid scavenger is one or more of triethylamine, diisopropylethylamine, and pyridine.
According to some preferred aspects of the invention, in step (iv), the compound of formula (2) and the acetyl chloride are fed in a molar ratio of 1: 0.9 to 1.3.
According to some preferred aspects of the present invention, in the step (iv), the reaction temperature of the acetylation reaction is-10 to 10 ℃.
According to some preferred aspects of the present invention, in the step (ii), the reaction time of the acetylation reaction is 0.5 to 2 hours.
Due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention provides a preparation method of an intermediate of fondaparinux sodium, which comprises a preparation method of a monosaccharide intermediate of the fondaparinux sodium, namely methyl glycoside-2-benzyloxy carbonyl carbonamide-3-O-benzyl-6-O-acetyl-2-deoxy-alpha-D-pyran glucose.
Detailed Description
The above-described scheme is further illustrated below with reference to specific examples; it is to be understood that these embodiments are provided to illustrate the general principles, essential features and advantages of the invention, and that the invention is not to be limited in scope by the following embodiments; the conditions used in the examples may be further adjusted according to specific requirements, and the conditions not specified are generally used in routine experiments.
In the following, all starting materials are either commercially available or prepared by conventional methods in the art, unless otherwise specified.
In the following examples, the synthesis route of methyl glycoside-2-benzyloxycarbonylamino-3-O-benzyl-6-O-acetyl-2-deoxy-alpha-D-glucopyranose represented by formula (1) is as follows:
example 1
A) Synthesis of an intermediate compound 2-deoxy-2-benzyloxycarbonylamino-a-D-glucopyranose (compound represented by formula (4)):
a500 ml reaction vessel was charged with 150ml of purified water, D-glucosamine (a compound represented by formula (5)) (10g, 55.8mmol) and sodium hydrogencarbonate (7.5g, 89.3mmol), and then cooled to 0 ℃ to add benzyloxycarbonyl chloride (11.4g, 67.0 mmol). After the reaction is finished at the temperature of 30-40 ℃, the reaction is carried out for 15h, the reaction is carried out for filtration, the filter cake is recrystallized by using ethyl acetate-n-heptane mixed solvent, and the 2-deoxy-2-benzyloxy carbonyl amido-a-D-glucopyranose is obtained after drying, and white solid (17.0g) with the yield of 97.1 percent is obtained.
B) Synthesizing an intermediate compound methyl glycoside-2-benzyloxy carbonyl amido-2-deoxy-a-D-glucopyranose (a compound shown in a formula (3)):
100ml of methanol and 2-deoxy-2-benzyloxycarbonylamino-a-D-glucopyranose (17.0g, 54.2mmol) are added to a 500ml reaction flask, the temperature is lowered, and acetyl chloride (5.1g, 65.0mmol) is added dropwise at 0 ℃. After the addition, the reaction is carried out for 7 hours at the temperature of 60-70 ℃, sodium bicarbonate is used for neutralizing (pH is 8-9), the reaction is carried out by spin-drying, 100ml of water is added, the mixture is pulped, filtered and dried to obtain the methyl glycoside-2-benzyloxy carbonyl amido-2-deoxy-a-D-glucopyranose, white solid (16.2g) with the yield of 91.2 percent.
C) Synthesizing an intermediate compound methyl glycoside-2-benzyloxy carbonyl amido-3-O-benzyl-2-deoxy-a-D-glucopyranose (a compound shown as a formula (2)):
a500 ml reaction bottle is filled with acetonitrile 110ml, methyl glycoside-2-benzyloxy carbonyl amido-2-deoxy-a-D-glucopyranose (16.0g, 48.9mmol), camphor sulfonic acid (1.1g, 4.89mmol) and benzaldehyde dimethyl acetal (11.2, 73.3mmol), the temperature is raised to 50-60 ℃ for reaction for 8h, and the white solid is obtained after filtration. And after drying the solid, continuously adding the solid into a 500ml reaction bottle, then adding 120ml tetrahydrofuran, cooling, and adding sodium hydride (1.2g, 48.9mmol) in 3-5 batches at 0 ℃. After the addition, benzyl bromide (10.8g, 63.1mmol) is added, and the reaction is carried out for 9 hours at the temperature of 45-55 ℃. After the reaction is finished, slowly adding 150ml of water, stirring, filtering and drying, adding 60ml of dichloromethane and 110ml of 80% acetic acid aqueous solution into the solid, stirring for 6 hours at the temperature of 50-60 ℃, adding 100ml of water and 150ml of dichloromethane, adjusting the pH value to 8-9 with sodium carbonate, stirring until a large amount of solid is separated out, filtering and drying to obtain the methyl glycoside-2-benzyloxy carbonyl amido-3-O-benzyl-2-deoxy-a-D-glucopyranose, wherein the yield is 85.3% of a white solid (17.4g)
D) Synthesizing an intermediate compound methyl glycoside-2-benzyloxy carbonyl amido-3-O-benzyl-6-O-acetyl-2-deoxy-a-D-glucopyranose (a compound shown as a formula (1)):
a500 ml reaction bottle is added with dichloromethane 170ml, methyl glycoside-2-benzyloxy carbonyl amido-3-O-benzyl-2-deoxy-a-D-glucopyranose (17.0g, 40.7mmol) and triethylamine (5.4, 53.5mmol), acetyl chloride (3.5g, 44.8mmol) is dropped at the temperature of 0 ℃, the mixture reacts for 1 hour at the temperature of 5 ℃ to 5 ℃, 100ml of 20 percent hydrochloric acid aqueous solution is used for extraction, and the water layer is extracted for 2 times by using 60ml of dichloromethane. The combined organic phases were dried by rotary evaporation and crystallized from ethyl acetate-n-heptane (2: 1) to give the methyl glycoside-2-benzyloxycarbonylamino-3-O-benzyl-6-O-acetyl-2-deoxy-a-D-glucopyranose as a white solid (13.6g) in 72.6% yield.
Example 2
A) Synthesis of intermediate Compound 2-deoxy-2-benzyloxycarbonylamino-a-D-glucopyranose (Compound represented by the formula (4)):
a500 ml reaction vessel was charged with 150ml of purified water, D-glucosamine (a compound represented by the formula (5)) (10g, 55.8mmol) and sodium carbonate (7.1g, 67.0mmol), and then cooled, followed by dropwise addition of benzyloxycarbonyl chloride (11.4g, 67.0mmol) at 0 ℃. After the reaction is finished at the temperature of 30-40 ℃, the reaction is carried out for 15h, the reaction is carried out for filtration, the filter cake is recrystallized by using ethyl acetate-n-heptane mixed solvent, and the 2-deoxy-2-benzyloxy carbonyl amido-a-D-glucopyranose is obtained after drying, and white solid (16.1g) with the yield of 92.1 percent is obtained.
B) Synthesizing an intermediate compound methyl glycoside-2-benzyloxy carbonyl amido-2-deoxy-a-D-glucopyranose (a compound shown in a formula (3)):
a500 ml reaction flask was charged with 90ml of methanol, 2-deoxy-2-benzyloxycarbonylamino-a-D-glucopyranose (16.0g, 51.1mmol), cooled and concentrated sulfuric acid (6.0g, 61.0mmol) was added dropwise at 0 ℃. After the addition, the reaction is carried out for 7 hours at the temperature of 60-70 ℃, sodium bicarbonate is used for neutralization (pH is 8-9), the reaction is carried out for spin-drying, 90ml of water is added, and the methyl glycoside-2-benzyloxy carbonyl amido-2-deoxy-a-D-glucopyranose is obtained after pulping, filtering and drying, and the white solid (14.1g) with the yield of 84.3 percent is obtained.
C) Synthesizing an intermediate compound methyl glycoside-2-benzyloxy carbonyl amido-3-O-benzyl-2-deoxy-a-D-glucopyranose (a compound shown as a formula (2)):
adding 100ml of acetonitrile, 14.0g of methyl glycoside-2-benzyloxycarbonylamino-2-deoxy-a-D-glucopyranose (42.8 mmol), 1.0g of camphorsulfonic acid (4.3 mmol) and 9.8 mmol of benzaldehyde dimethyl acetal (64.2 mmol) into a 500ml reaction bottle, heating to 50-60 ℃, reacting for 8 hours, and filtering to obtain a white solid. And after the solid is dried, continuously adding the solid into a 500ml reaction bottle, then adding 100ml tetrahydrofuran, cooling, and adding sodium hydride (1.0g, 42.8mmol) in 3-5 batches at 0 ℃. After the addition, adding benzyl bromide (9.5g, 55.6mmol), and reacting at 45-55 ℃ for 9 h. After the reaction is finished, slowly adding 120ml of water, stirring, filtering and drying, adding 50ml of dichloromethane and 100ml of 80% acetic acid aqueous solution into the solid, stirring for 8 hours at the temperature of 50-60 ℃, adding 100ml of water and 120ml of dichloromethane, adjusting the pH value to 8-9 with sodium carbonate, stirring until a large amount of solid is separated out, filtering and drying to obtain the methyl glycoside-2-benzyloxy carbonyl amido-3-O-benzyl-2-deoxy-a-D-glucopyranose, wherein the yield is 84.6% of a white solid (15.1g)
D) Synthesizing an intermediate compound methyl glycoside-2-benzyloxy carbonyl amido-3-O-benzyl-6-O-acetyl-2-deoxy-a-D-glucopyranose (a compound shown as a formula (1)):
150ml of dichloromethane, 15.0g of methyl glycoside-2-benzyloxy carbonyl amido-3-O-benzyl-2-deoxy-a-D-glucopyranose (35.9 mmol) and pyridine (4.3g, 54.4mmol) are added into a 500ml reaction bottle, acetyl chloride (2.8g, 35.9mmol) is added dropwise when the temperature is reduced to 0 ℃, the mixture reacts for 1 hour at the temperature of 5-5 ℃, 100ml of 20 percent hydrochloric acid aqueous solution is used for extraction, and the water layer is extracted for 2 times by 60ml of dichloromethane. The combined organic phases were dried by rotary evaporation and crystallized from ethyl acetate-n-heptane (2: 1) to give the methyl glycoside-2-benzyloxycarbonylamino-3-O-benzyl-6-O-acetyl-2-deoxy-a-D-glucopyranose as a white solid (11.5g) in 69.9% yield.
Claims (8)
1. A preparation method of fondaparinux sodium intermediate comprises a synthesis method of methyl glycoside-2-benzyloxy carbonyl amido-3-O-benzyl-6-O-acetyl-2-deoxy-alpha-D-pyran type glucose shown in formula (1), and is characterized in that the synthesis method of methyl glycoside-2-benzyloxy carbonyl amido-3-O-benzyl-6-O-acetyl-2-deoxy-alpha-D-pyran type glucose comprises the following steps:
(i) carrying out amino protection reaction on the compound shown in the formula (5) and benzyloxycarbonyl chloride in a solvent in the presence of an alkaline reagent to generate a compound shown in the formula (4); controlling the reaction temperature to be 20-50 ℃;
(ii) carrying out a hydroxymethylation reaction on the compound shown in the formula (4) and methanol in a solvent in the presence of an acidic reagent to generate a compound shown in the formula (3); controlling the reaction temperature to be 50-80 ℃;
(iii) the compound benzaldehyde dimethyl acetal shown in the formula (3) reacts in a solvent in the presence of a camphorsulfonic acid reagent, and then the product and benzyl bromide react in the presence of a sodium hydride reagent in the solvent for protecting hydroxyl groups to generate the compound shown in the formula (2); controlling the reaction temperature to be 30-70 ℃;
(iv) performing hydroxyl acetylation on the compound shown in the formula (2) and acetyl chloride in a solvent in the presence of an acid binding agent to generate a compound shown in the formula (1); controlling the reaction temperature to be between-10 and 10 ℃;
2. the method for preparing fondaparinux sodium intermediate according to claim 1, wherein, in step (i),
the alkaline reagent is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, calcium carbonate and potassium bicarbonate.
3. The method for preparing fondaparinux sodium intermediate according to claim 1, wherein in step (i), the compound of formula (5), the benzyloxycarbonyl chloride and the alkaline reagent are fed in a molar ratio of 1: 1-1.5: 1.2-1.8, and controlling the reaction reagent of the amino protection reaction to be 12-24 h.
4. The method for preparing fondaparinux sodium intermediate according to claim 1, wherein in step (ii), the acidic reagent is one or more of acetyl chloride and concentrated sulfuric acid.
5. The method for preparing fondaparinux sodium intermediate according to claim 1, wherein in step (ii), the compound of formula (4) and the acidic reagent are fed in a molar ratio of 1: 1-1.5, and controlling the reaction reagent of the methylation reaction for 5-12 h.
6. The method for preparing fondaparinux sodium intermediate as claimed in claim 1, wherein in step (iii), the compound of formula (3), the benzaldehyde dimethyl acetal, the camphorsulfonic acid, the benzyl bromide and the sodium hydride are fed in a molar ratio of 1: 1.2-2.0: 0.05-0.15: 1.1-1.5: 0.8 to 1.2.
7. The method for preparing fondaparinux sodium intermediate according to claim 1, wherein in step (iv), the acid-binding agent is one or more of triethylamine, diisopropylethylamine, and pyridine.
8. The method for preparing fondaparinux sodium intermediate as claimed in claim 1, wherein in step (iv), the compound of formula (2) and the acetyl chloride are fed in a molar ratio of 1: 0.9 to 1.3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210899788.9A CN115057898A (en) | 2022-07-28 | 2022-07-28 | Preparation method of fondaparinux sodium intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210899788.9A CN115057898A (en) | 2022-07-28 | 2022-07-28 | Preparation method of fondaparinux sodium intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115057898A true CN115057898A (en) | 2022-09-16 |
Family
ID=83205313
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210899788.9A Pending CN115057898A (en) | 2022-07-28 | 2022-07-28 | Preparation method of fondaparinux sodium intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115057898A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4818816A (en) * | 1981-04-28 | 1989-04-04 | Choay, S.A. | Process for the organic synthesis of oligosaccharides and derivatives thereof |
| CN102775419A (en) * | 2011-05-13 | 2012-11-14 | 上海医药工业研究院 | Preparation method of 4,6-O-benzylene-3-O-acetyl-D-glucal |
| US20130005954A1 (en) * | 2011-06-28 | 2013-01-03 | Apicore, Llc | Process for preparing heparinoids and intermediates useful in the synthesis thereof |
-
2022
- 2022-07-28 CN CN202210899788.9A patent/CN115057898A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4818816A (en) * | 1981-04-28 | 1989-04-04 | Choay, S.A. | Process for the organic synthesis of oligosaccharides and derivatives thereof |
| CN102775419A (en) * | 2011-05-13 | 2012-11-14 | 上海医药工业研究院 | Preparation method of 4,6-O-benzylene-3-O-acetyl-D-glucal |
| US20130005954A1 (en) * | 2011-06-28 | 2013-01-03 | Apicore, Llc | Process for preparing heparinoids and intermediates useful in the synthesis thereof |
Non-Patent Citations (1)
| Title |
|---|
| COLEMAN, RS 等: "A CONVENIENT PREPARATION OF TERMINALLY DIFFERENTIATED, SELECTIVELY PROTECTED 6-CARBON SYNTHONS FROM D-GLUCOSAMINE", JOURNAL OF ORGANIC CHEMISTRY, vol. 57, no. 13, pages 3732 - 3735 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106810426B (en) | Method for synthesizing cannabidiol | |
| CN113214320A (en) | Preparation method of Reidesciclovir compound | |
| CN108610316B (en) | Preparation method of dapagliflozin | |
| CN109553610B (en) | Preparation method of emtricitabine isomer | |
| CN115057898A (en) | Preparation method of fondaparinux sodium intermediate | |
| CN108358979B (en) | Purification method of tulathromycin | |
| KR100908363B1 (en) | Stereoselective preparation method of tri-O-acetyl-5-deoxy-β-D-ribofuranose and separation method thereof | |
| CN112358514B (en) | Synthesis process of arbutin | |
| CN113667006B (en) | Preparation method of cable Ma Lutai dipeptide side chain | |
| CN112094290B (en) | Preparation method of eldecalcitol A ring intermediate | |
| CN104592254B (en) | The synthetic method of everolimus | |
| CN107325070B (en) | Preparation method of 2,3, 4-tri-O-benzyl-6-deoxy-D-glucopyranose-1, 5-lactone | |
| CN111747857A (en) | Amino sugar compounds, preparation method and application thereof | |
| CN112538067B (en) | Preparation method of tetraacetylglucal | |
| CN110746471B (en) | Preparation method of fondaparinux sodium disaccharide intermediate | |
| CN116768910B (en) | Refining method of rifabutin | |
| CN112209976B (en) | Decitabine intermediate compound V | |
| CN111333553B (en) | Synthetic method of florfenicol dimer impurity | |
| CN111662260B (en) | Synthetic method of natural product saffloneoside | |
| CN108997454B (en) | Chemical synthesis method of beta-arbutin | |
| CN115490737A (en) | Industrial gastrodin raw material medicine purification method | |
| CN113004352B (en) | Preparation method of fondaparinux sodium and fondaparinux sodium monosaccharide intermediate | |
| CN114634543A (en) | Preparation method of alpha-mouse cholic acid | |
| CN117866025A (en) | Preparation method of capecitabine | |
| CN117624100A (en) | Efficient production process of dapagliflozin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |