CN115057896A - Synthetic method of fondaparinux sodium - Google Patents
Synthetic method of fondaparinux sodium Download PDFInfo
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- CN115057896A CN115057896A CN202210898288.3A CN202210898288A CN115057896A CN 115057896 A CN115057896 A CN 115057896A CN 202210898288 A CN202210898288 A CN 202210898288A CN 115057896 A CN115057896 A CN 115057896A
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- 229960003661 fondaparinux sodium Drugs 0.000 title claims abstract description 19
- 238000010189 synthetic method Methods 0.000 title claims abstract description 5
- 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 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 51
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 claims abstract description 24
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 20
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 19
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 10
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 6
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 5
- 238000010931 ester hydrolysis Methods 0.000 claims abstract description 5
- 125000006239 protecting group Chemical group 0.000 claims abstract description 5
- 230000009467 reduction Effects 0.000 claims abstract description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000013341 scale-up Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- XEKSTYNIJLDDAZ-JASSWCPGSA-D decasodium;(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5r,6r)-6-[(2r,3s,4s,5r,6r)-2-carboxylato-4-hydroxy-6-[(2r,3s,4r,5r,6s)-4-hydroxy-6-methoxy-5-(sulfonatoamino)-2-(sulfonatooxymethyl)oxan-3-yl]oxy-5-sulfonatooxyoxan-3-yl]oxy-5-(sulfonatoamino)-4-sulfonatooxy-2-(sul 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-D 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 229910052708 sodium Inorganic materials 0.000 description 9
- 238000001914 filtration Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000004537 pulping Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WQZGKKKJIJFFOK-UHFFFAOYSA-N alpha-D-glucopyranose Natural products OCC1OC(O)C(O)C(O)C1O WQZGKKKJIJFFOK-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- DETWPIPSLUQGPS-KVIJGQROSA-N (2S,3S,4S,5R,6R)-3,6-dihydroxy-4,5-bis(phenylmethoxy)oxane-2-carboxylic acid Chemical compound C(C1=CC=CC=C1)O[C@H]1[C@H](O)O[C@@H]([C@H]([C@@H]1OCC1=CC=CC=C1)O)C(=O)O DETWPIPSLUQGPS-KVIJGQROSA-N 0.000 description 1
- -1 2, 3-di-O-benzyl- β -D-glucopyranose sodium salt Chemical compound 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 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
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003055 low molecular weight heparin Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 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
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- 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
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 synthetic method of fondaparinux sodium, which comprises the following synthetic route: step 1: performing ester hydrolysis reaction on the compound I under the action of strong alkali to obtain a compound II; step 2: nitrine reduction of the compound II under the catalysis of trimethylphosphorus to obtain a compound III; and step 3: sulfonating a compound III and a sulfur trioxide pyridine complex, and salifying with sodium hydroxide to obtain a compound IV; and 4, step 4: and (3) hydrogenating and removing a protecting group of the compound IV under the catalysis of palladium to obtain a compound V. The synthesis method has the advantages of simple process, short reaction time, high efficiency, higher yield, mild reaction conditions and lower cost, and is suitable for industrial scale-up production.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a synthesis method of fondaparinux sodium.
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, french scientists completed the entire synthesis of this compound through up to 70 chemical reaction steps (carbohydr. res.,1986,147, 221-.
The synthetic literature of fondaparinux sodium is more reported, and the current common synthetic route is as follows: cabohydrar. Res.1987,167,67-75 or WO2013003001A1/US2013005954A1, the main synthetic route of which is shown in the following formula:
the above literature route uses an initial reaction procedure for the conversion of the fully protected pentasaccharide (i.e. starting from the compound FOND-010) to fondaparinux sodium, which is generally a four-step reaction:
1. hydrolyzing the hydroxyl and carboxyl by using acetate and formate in the structure through alkali hydrolysis of the fully-protected pentasaccharide;
2. sulfonating the hydrolyzed hydroxyl group;
3. reducing carbobenzoxy and benzyl groups by palladium catalytic hydrogenation to reduce azido groups to amino groups;
4. optionally conducting sulphonylation of the amino group
The polarity of the intermediate in each step of the four-step synthesis process is high, the separation and purification difficulty is high, and the impurity residue of the intermediate in each step has great influence on the quality and yield of subsequent products. And the normal phase silica gel is used for purification, so that the product is seriously trailing, the elution difficulty is higher, and the yield is low. The reaction time in the hydrogenation step is longer, the conversion rate is lower, and the product purity and yield are difficult to ensure due to raw material residues.
Disclosure of Invention
In view of the above problems, the present invention aims to provide a novel synthesis method for converting fully protected pentasaccharide into fondaparinux sodium. The quality of the intermediate in each step can be controlled.
A synthetic method of fondaparinux sodium comprises the following synthetic route:
step 1: carrying out ester hydrolysis reaction on the compound I under the action of strong alkali to obtain a compound II;
and 2, step: nitrine reduction of the compound II under the catalysis of trimethylphosphorus to obtain a compound III;
and step 3: sulfonating the compound III with sulfur trioxide pyridine complex, and salifying with sodium hydroxide to obtain a compound IV;
and 4, step 4: and (3) hydrogenating and removing a protecting group of the compound IV under the catalysis of palladium to obtain a compound V.
The reaction equation is as follows:
further, it has one or more of the following features,
in the step 1, the molar ratio of the compound I to the strong base is 1 (1.2-2.0);
in the step 2, the molar ratio of the compound II to the trimethylphosphorus is 1 (0.05-0.2);
in the step 2, the molar ratio of the compound II to the sodium hydroxide is 1 (1.5-3.0);
the molar ratio of the compound III to the sulfur trioxide pyridine complex in the step 3 is 1 (9.0-13.0);
the molar ratio of the compound III to the catalyst in the step 3 is 1 (0.1-0.3);
in the step 3, the molar ratio of the compound III to the acid-binding agent is 1 (2.0-4.0);
the mass ratio or the molar ratio of the compound IV to the catalyst in the step 4 is 1 (0.05-0.10);
in the step 4, the pressure of hydrogen required by the reaction of the compound IV is 0.4-0.8 Mpa.
Further, in the step 1, the strong alkali is selected from one or more of sodium hydroxide and potassium hydroxide.
Further, the catalyst in the step 3 is selected from one or more of pyridine and N, N-dimethylaminopyridine.
Further, the acid-binding agent is selected from one or more of triethylamine, diisopropylethylamine and pyridine.
Further, the catalyst in the step 4 is selected from one or more of palladium acetate, palladium hydroxide and palladium carbon.
The synthesis method has the advantages of simple process, short reaction time, high efficiency, higher yield, mild reaction conditions and lower cost, and is suitable for industrial scale-up production.
Detailed Description
In order to make the technical solution and advantages of the present invention more comprehensible, a detailed description is given below by way of specific examples.
In one aspect, the present application provides a method for converting a fully protected pentasaccharide to fondaparinux sodium, comprising the synthetic route:
step 1: carrying out ester hydrolysis reaction on the compound I under the action of strong alkali to obtain a compound II;
step 2: nitrine reduction of the compound II under the catalysis of trimethylphosphorus to obtain a compound III;
and step 3: sulfonating the compound III with sulfur trioxide pyridine complex, and salifying with sodium hydroxide to obtain a compound IV;
and 4, step 4: and (3) hydrogenating and removing a protecting group of the compound IV under the catalysis of palladium to obtain a compound V.
In some embodiments, the strong base in step 1 is selected from sodium hydroxide, potassium hydroxide.
In some embodiments, the catalyst in step 3 is selected from pyridine, N-dimethylaminopyridine.
In some embodiments, the acid scavenger in step 3 is selected from triethylamine, diisopropylethylamine, pyridine.
In some embodiments, the acid-binding agent in step 3 is selected from palladium acetate, palladium hydroxide, palladium on carbon.
In some embodiments, the method for preparing fondaparinux sodium comprises the following synthetic route:
step 1: carrying out ester hydrolysis reaction on the compound I under the action of strong alkali to obtain a compound II;
step 2: nitrine reduction of the compound II under the catalysis of trimethylphosphorus to obtain a compound III;
and step 3: sulfonating the compound III with sulfur trioxide pyridine complex, and salifying with sodium hydroxide to obtain a compound IV;
and 4, step 4: and hydrogenating and removing the protecting group of the compound IV under the catalysis of palladium to obtain a compound V.
In some embodiments, the molar ratio of compound i to strong base in step 1 is 1 (1.2-2.0), e.g., 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, preferably 1: 1.6.
In some embodiments, the molar ratio of compound ii to trimethylphosphorus in step 2 is 1 (0.5-1.2), e.g. 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, preferably 1: 0.9.
In some embodiments, the molar ratio of compound ii to sodium hydroxide in step 2 is 1 (1.5-3.0), e.g., 1:1.5, 1:2.0, 1:2.5, 1: 3.0.
In some embodiments, the reaction temperature in step 2 is 0-50 ℃, preferably 30 ℃.
In some embodiments, the molar ratio of compound iii to sulfur trioxide pyridine complex in step 3 is 1 (9.0-13.0), e.g., 1:9.0, 1:10.0, 1:11.0, 1:12.0, 1:13.0, with a preferred molar ratio of 1: 11.0.
In some embodiments, the molar ratio of compound III to catalyst in step 3 is 1 (0.1-0.3), for example: 1:0.1, 1:0.2 and 1: 0.3.
In some embodiments, the molar ratio of compound iii to acid scavenger in step 3 is 1: (2.0-4.0), for example 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4.0, preferably in a molar ratio of 1: 3.0.
In some embodiments, the reaction temperature in step 3 is 15-45 ℃, preferably 25 ℃.
In some embodiments, the mass ratio of the compound IV to the catalyst in the step 4 is 1 (0.05-0.10), such as 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1: 0.10.
In some embodiments, the hydrogen pressure in step 4 is 0.4 to 0.8MPa, such as 0.4MPa, 0.5MPa, 0.6MPa, 0.7MPa, 0.8 MP.
In some embodiments, the reaction temperature in step 4 is 20 to 60 ℃, preferably 40 ℃.
Preparation method of intermediate compound ii, i.e., (2-azido-3, 4-di-O-benzyl-2-deoxy-a-D-glucopyranosuronic acid) - (1,4) -O- (2, 3-di-O-benzyl- β -D-glucopyranosuronic acid) - (1,4) -O- (2-azido-2-deoxy-a-D-glucopyranose) - (1,4) -O- (3-O-benzyl-a-L-glucopyranosiduronic acid) - (1,4) -2-azido-3-O-benzyl-2-deoxy-a-D-glucopyranosylglucoside:
example 1:
adding 50.0g (27.04mmol) of a fully protected pentasaccharide raw material (namely the compound I), 250ml of tetrahydrofuran and 100ml of water into a 1000ml reaction bottle, cooling to 0 ℃, slowly dropwise adding 50ml of a sodium hydroxide solution (containing 1.73g and 43.27mmol of sodium hydroxide), preserving heat at 30 ℃ for 12 hours after dropwise adding, removing tetrahydrofuran by using a rotary evaporator through reduced pressure concentration, adding 250ml of ethyl acetate for extraction for 2 times, combining organic phases, continuously concentrating under reduced pressure to remove ethyl acetate to form oily matter, adding 22550ml of n-heptane, preserving heat at 50 ℃ for crystallization for 1 hour, cooling to room temperature, filtering to obtain a wet compound II, and drying the wet product at 50 ℃ for 4 hours in vacuum to obtain a white-like solid of the compound II, wherein 39.9g of the compound II is obtained totally, and the yield is 98.3%.
Preparation method of intermediate compound iii, i.e., (2-amino-3, 4-di-O-benzyl-2-deoxy-a-D-glucopyranose) - (1,4) -O- (2, 3-di-0-benzyl- β -D-glucopyranose-uronic acid) - (1,4) -O- (2-amino-2-deoxy-a-D-glucopyranose) - (1,4) -O- (3-O-benzyl-a-L-glucopyranose-iduronic acid) - (1,4) -2-amino-3-O-benzyl-2-deoxy-a-D-glucopyranose-methylglycoside:
example 2:
adding 39.0g (25.99mmol) of compound II, 100ml of tetrahydrofuran and 100ml of water into a 1000ml reaction bottle, cooling to 0 ℃, adding 2.29g of sodium hydroxide (57.18mmol), dropwise adding 50ml of trimethylphosphorus solution (1.78g, 23.39mmol of trimethylphosphorus dissolved in 50ml of tetrahydrofuran) at 0-10 ℃, after the addition, keeping the temperature at 30 ℃ for reaction for 15 hours. Concentrating under reduced pressure to remove tetrahydrofuran, adding 160ml ethyl acetate for extraction twice, combining organic phases, spin-drying again, pulping with 150ml n-heptane, and filtering to obtain a wet product of the compound III. The wet product was dried under vacuum at 50 ℃ for 8 hours to give compound iii as a white solid, 35.2g in total, yield: 95.2 percent.
Example 3:
adding 39.0g (25.99mmol) of compound II, 100ml of tetrahydrofuran and 100ml of water into a 1000ml reaction bottle, cooling to 0 ℃, adding 2.29g of sodium hydroxide (57.18mmol), dropwise adding 50ml of trimethylphosphorus solution (1.19g, 15.59mmol of trimethylphosphorus dissolved in 50ml of tetrahydrofuran) at 0-10 ℃, after the addition, keeping the temperature at 30 ℃ for reaction for 15 hours. Concentrating under reduced pressure to remove tetrahydrofuran, adding 160ml ethyl acetate, extracting twice, combining organic phases, spin-drying again, pulping with 150ml n-heptane, and filtering to obtain compound III wet product. The wet product was dried under vacuum at 50 ℃ for 8 hours to give compound iii as a white solid, 32.2g total, yield: 87.1 percent.
The intermediate compound iv, i.e., (2-sodium sulfamate-3, 4-di-O-benzyl-2-deoxy-6-0-sodium sulfonate- α -D-glucopyranosate) - (1,4) -O- (2, 3-di-O-benzyl- β -D-glucopyranose sodium salt) - (1,4) -O- (2-sodium sulfamate-2-deoxy-3, 6-O-disulfonate- α -D-glucopyranosate) - (1,4) -O- (3-O-benzyl-2-O-sodium sulfonate- α -L-glucopyranose sodium salt) - (1,4) the preparation method of the (E) -2-sodium sulfamate-3-O-benzyl-2-deoxy-6-O-disulfonate-alpha-D-glucopyranosyl methyl glycoside comprises the following steps:
example 4:
a1000 ml reaction vessel was charged with 30.0g (21.3mmol) of Compound III, 100ml of tetrahydrofuran, 0.3g (3.8mmol) of pyridine and 6.5g (64.2mmol) of triethylamine, cooled to 0 ℃ and charged with 37.3g (0.23mol) of sulfur trioxide pyridine complex, and the reaction was allowed to proceed for 16 hours at 25 ℃. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, 120ml of ethyl acetate and 90ml of water were added thereto, extraction was performed twice, and the organic phases were combined and spin-dried to obtain a yellow oil.
And adding 120ml of methanol into the oily matter, dissolving, dropwise adding 60ml of sodium hydroxide solution (11.1g, 0.28mol of sodium hydroxide solution and 60ml of water) at room temperature, reacting for 6 hours at room temperature, removing the solvent by rotary evaporation, adding methanol to remove the methanol, adding 90ml of methanol to dissolve, filtering to remove salt, drying the filtrate by rotary evaporation, pulping by using 150ml of ethyl acetate, and filtering to obtain a wet compound IV. The wet product was dried under vacuum at 50 ℃ for 8 hours to give a compound IV as a white solid, 42.6g in total, yield: 88.1 percent.
Preparation method of intermediate compound v, i.e. (sodium 2-sulfamate-2-deoxy-6-O-sodium sulfonate- α -D-glucopyranose) - (1,4) -O- (- β -D-glucopyranosuronate) - (1,4) -O- (sodium 2-sulfamate-2-deoxy-3, 6-O-disulfonate- α -D-glucopyranose) - (1,4) -O- (2-O-sodium sulfonate- α -L-glucopyranosuronate- α -D-glucopyranosylmethylglycoside):
example 5:
40.0g (21.3mmol) of compound IV (17.6mmol), 120ml of methanol and 0.4g of 10% palladium on carbon were charged into a 1000ml hydrogenation vessel, and the system was replaced with hydrogen gas 3 times, and the reaction was carried out under a hydrogen pressure of 0.5MPa at 40 ℃ for 8 hours. After the reaction is finished, filtering to remove palladium carbon, concentrating methanol to be thick, adding 160ml of ethyl acetate, pulping, filtering and drying to obtain a compound V, namely the fondaparinux sodium 28.0g, with the yield of 91.9 percent
It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations encompassed by the claims. Various modifications and changes may also be made on the basis of the above embodiments without departing from the scope of the present disclosure. Likewise, various features of the above embodiments may be arbitrarily combined to form additional embodiments of the present invention that may not be explicitly described. Therefore, the above examples only represent some embodiments of the present invention, and do not limit the scope of the present invention.
Claims (6)
1. A synthetic method of fondaparinux sodium is characterized by comprising the following synthetic route:
step 1: carrying out ester hydrolysis reaction on the compound I under the action of strong alkali to obtain a compound II;
step 2: nitrine reduction of the compound II under the catalysis of trimethylphosphorus to obtain a compound III;
and step 3: sulfonating the compound III with sulfur trioxide pyridine complex, and salifying with sodium hydroxide to obtain a compound IV;
and 4, step 4: and (3) hydrogenating and removing a protecting group of the compound IV under the catalysis of palladium to obtain a compound V.
The reaction equation is as follows:
2. the method of claim 1, wherein the method further comprises one or more of the following features,
in the step 1, the molar ratio of the compound I to the strong base is 1 (1.2-2.0);
in the step 2, the molar ratio of the compound II to the trimethylphosphorus is 1 (0.05-0.2);
in the step 2, the molar ratio of the compound II to the sodium hydroxide is 1 (1.5-3.0);
the molar ratio of the compound III to the sulfur trioxide pyridine complex in the step 3 is 1 (9.0-13.0);
the molar ratio of the compound III to the catalyst in the step 3 is 1 (0.1-0.3);
in the step 3, the molar ratio of the compound III to the acid-binding agent is 1 (2.0-4.0);
the mass ratio or the molar ratio of the compound IV to the catalyst in the step 4 is 1 (0.05-0.10);
the pressure of hydrogen required by the reaction of the compound IV in the step 4 is 0.4-0.8 Mpa.
3. The method for preparing fondaparinux sodium according to any one of claims 1-2, wherein the strong base in step 1 is one or more selected from sodium hydroxide and potassium hydroxide.
4. The method for preparing fondaparinux sodium according to claim 2, wherein the catalyst in step 3 is one or more selected from pyridine and N, N-dimethylaminopyridine.
5. The method for preparing fondaparinux sodium according to claim 2, wherein the acid-binding agent is one or more selected from triethylamine, diisopropylethylamine, and pyridine.
6. The method for preparing fondaparinux sodium according to claim 2, wherein the catalyst in step 4 is one or more selected from palladium acetate, palladium hydroxide and palladium on carbon.
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Non-Patent Citations (1)
| Title |
|---|
| FENG LIN 等: "Synthesis of Fondaparinux: modular synthesis investigation for heparin synthesis", CARBOHYDRATE RESEARCH, vol. 371, pages 32 - 39, XP028527227, DOI: 10.1016/j.carres.2013.01.003 * |
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