CN109535201B - Synthesis method of cyclophosphamide - Google Patents
Synthesis method of cyclophosphamide Download PDFInfo
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- CN109535201B CN109535201B CN201910070427.1A CN201910070427A CN109535201B CN 109535201 B CN109535201 B CN 109535201B CN 201910070427 A CN201910070427 A CN 201910070427A CN 109535201 B CN109535201 B CN 109535201B
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- cyclophosphamide
- dichloroethane
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- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 229960004397 cyclophosphamide Drugs 0.000 title claims abstract description 27
- 238000001308 synthesis method Methods 0.000 title abstract description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 26
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002808 molecular sieve Substances 0.000 claims abstract description 10
- 229920000137 polyphosphoric acid Polymers 0.000 claims abstract description 10
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 10
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 239000011259 mixed solution Substances 0.000 claims abstract description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000012074 organic phase Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- ZZVDXRCAGGQFAK-UHFFFAOYSA-N 2h-oxazaphosphinine Chemical compound N1OC=CC=P1 ZZVDXRCAGGQFAK-UHFFFAOYSA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000008213 purified water Substances 0.000 claims description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- -1 β -chloroethyl Chemical group 0.000 description 3
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 150000008300 phosphoramidites Chemical class 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- YMDZDFSUDFLGMX-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)ethanamine;hydron;chloride Chemical compound [Cl-].ClCC[NH2+]CCCl YMDZDFSUDFLGMX-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 208000005678 Rhabdomyoma Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 238000009096 combination chemotherapy Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- JQHANBBNVGNBHA-UHFFFAOYSA-N diaminophosphorylcarbamic acid Chemical compound NP(N)(=O)NC(O)=O JQHANBBNVGNBHA-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 208000025189 neoplasm of testis Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- IRTWXRWGKPXWAV-UHFFFAOYSA-N oxaphosphinane Chemical compound C1CCPOC1 IRTWXRWGKPXWAV-UHFFFAOYSA-N 0.000 description 1
- RJXQSIKBGKVNRT-UHFFFAOYSA-N phosphoramide mustard Chemical compound ClCCN(P(O)(=O)N)CCCl RJXQSIKBGKVNRT-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
- C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
The invention provides a synthesis method of cyclophosphamide, which comprises the steps of slowly adding phosphorus oxychloride into a mixed solution of dichloroethane, polyphosphoric acid and acetic anhydride, and dropwise adding 3-aminopropanol to prepare 2-chloro-2-oxo- [1.3.2] oxazaphosphorane; adding dichloroethane and a 5a molecular sieve, introducing ammonia gas, keeping the pressure at 4 atmospheric pressures, heating to 120 ℃, reacting for 2-2.5 hours, and processing to obtain cyclophosphamide. The invention has the advantages of relatively mild reaction conditions, high yield and high content.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of cyclophosphamide.
Background
Cyclophosphamide (Cyclophosphamide, CTX, C7H15C12N2O2P, chemical name is N, N-bis- (β -chloroethyl) -N' - (3-hydroxypropyl) phosphorodiamidate lactone)) is a nitrogen mustard derivative which enters human body and is hydrolyzed by excessive amount of phosphoramidase or phosphatase existing in liver or tumor to become activated phosphoramidite, and the activated phosphoramidite acts.
The product has no activity in vitro, and mainly plays a role by hydrolyzing liver P450 enzyme into aldehyde phosphoramide and then transporting the aldehyde phosphoramide to tissues to form phosphoramide mustard. Cyclophosphamide can be inactivated by the conversion of dehydrogenase to carboxyphosphoramide or excreted as acrolein, resulting in urinary tract toxicity. Belongs to a non-specific drug in the period, and has the same action mechanism as nitrogen mustard.
As antitumor agent, it can be used for treating malignant lymphoma, multiple myeloma, breast cancer, small cell lung cancer, ovarian cancer, neuroblastoma, retinoblastoma, Ewing's sarcoma, soft tissue sarcoma, acute leukemia, and chronic lymphocytic leukemia. It also has therapeutic effect on testis tumor, head and neck squamous carcinoma, nasopharyngeal carcinoma, rhabdomyoma, and osteosarcoma. Currently, combination chemotherapy is often combined with other anticancer drugs.
The main synthetic route of the existing cyclophosphamide synthetic method is as follows: phosphorus oxychloride reacts with 3-aminopropanol to produce 2-chloro-2-oxo- [1.3.2] oxazaphosphorane, which then reacts with bis (2-chloroethyl) amine hydrochloride to produce cyclophosphamide. The yield is low in the reaction process, and side reactions are more.
Chinese patent (CN1268950A) discloses a synthesis method of cyclophosphamide, which comprises the steps of adding pyridine, triethylamine and alkali metal or alkaline earth metal carbonate as auxiliary alkali of acid-binding agent into phosphoryl halide and two organic bases with different general formulas to react in the presence of inert solvent or diluent, wherein the initial reaction temperature is kept between-40 ℃ and 20 ℃, and the temperature is raised to 100 ℃ after half an hour of reaction; if additives (molecular sieves, various forms of alumina, etc.) are added to treat the reactant mixture before re-reaction, the formation of by-products can be reduced; the product is obtained through extraction, crystallization and drying. Although the process can react in a relatively wide temperature range, the reaction is carried out under normal pressure, the reaction efficiency is low, the product yield is low, and the purity is not high.
In Chinese patent (CN108676032A), acetic anhydride is adopted to acidylate (R) -1- (2-azido) -N, N-dimethylphenylethylamine into an acetylation product, then after ammoniation reaction, hydrogenation reduction is carried out under high pressure, phosphorus oxychloride is added into a toluene solution, and ammonia water is introduced to obtain the product. The (R) -1- (2-azido) -N, N-dimethylphenylethylamine prepared by the process is prepared from a raw material at a low temperature of-50 ℃, has high requirements on equipment, and has more subsequent synthesis steps and high impurity content.
Chinese patent (CN107936061A) discloses a synthesis method of cyclophosphamide, which comprises the steps of adding dichloroethane into a reaction bottle, slowly adding phosphorus oxychloride, cooling to-5 ℃, starting to dropwise add a mixed solvent of 3-aminopropanol and triethylamine, and reacting after dropwise addition is finished to obtain a 2-chloro-2-oxo- [1.3.2] oxazaphosphorane solution; then transferring the solution into a pressure reaction bottle, adding triethylamine, controlling the temperature, continuously introducing ammonia gas, and keeping a certain pressure for reaction. Separating out organic phase from the reaction solution, concentrating the organic phase under reduced pressure until the organic phase is dry, and adding a solvent for crystallization to obtain the cyclophosphamide. The invention has the problems that the reaction temperature in the first step is too high, a large amount of triethylamine is used in the two steps, the industrial production is not facilitated, and the reaction in the second step cannot be carried out after the experiment process is repeated.
Taiwan patent No. (TW1546312A) discloses a synthesis method for solvent-free preparation of cyclophosphamide, which comprises placing bis (2-chloroethyl) amic acid, a catalyst and N-methylmorpholine in a reaction bottle, cooling the reactants in the bottle to 4 ℃, slowly adding phosphorus oxychloride (POCl3) dropwise, stirring at room temperature for 5 hours, then continuously cooling to 4 ℃, adding 3-amino-1-propanol dropwise, stirring at room temperature for 15 hours, and then performing extraction crystallization to obtain a product.
Based on various problems in the prior art, a cyclophosphamide synthesis method which is simple and convenient to operate, high in product yield and low in cost is urgently needed.
Disclosure of Invention
The invention aims to provide a method for synthesizing cyclophosphamide, which is simple and convenient to operate, high in product yield and low in cost.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
a method for synthesizing cyclophosphamide is characterized in that: the method comprises the following steps:
(1) slowly adding phosphorus oxychloride into a mixed solution of dichloroethane, polyphosphoric acid and acetic anhydride, dropwise adding 3-aminopropanol, reacting for 0.5-1 hour at 20 ℃, pouring into water, separating an organic phase, and concentrating to obtain 2-chloro-2-oxo- [1.3.2] oxazaphosphorine;
(2) transferring 2-chloro-2-oxo- [1.3.2] oxazaphosphorane into a pressure reaction bottle, adding dichloroethane and a 5a molecular sieve, introducing ammonia gas, keeping 4 atmospheric pressures, heating to 120 ℃, reacting for 2-2.5 hours, and finishing the reaction;
(3) filtering the reaction solution, adding an ice water mixture, stirring for 30 minutes, separating an organic phase, adding a 10% hydrochloric acid solution for washing, separating the organic phase, controlling the water bath temperature to be 50 ℃, concentrating the organic phase under reduced pressure until the organic phase is dry, adding a solvent, and crystallizing to obtain cyclophosphamide. .
Further, in the step 1, the molar ratio of the phosphorus oxychloride to the 3-aminopropanol is 1: 1.
Further, in the step 1, the mass ratio of the dichloroethane, the polyphosphoric acid and the acetic anhydride is 2: 1.
Further, in the step 1, the amount of the mixed solution of dichloroethane, polyphosphoric acid and acetic anhydride is 5 times of the mass of the phosphorus oxychloride.
Further, in the crystallization process in the step 3, adding a solvent, heating to 40 ℃ for dissolution, then cooling to below 5 ℃, crystallizing for 5 hours, performing suction filtration to obtain a white crystalline solid, and drying to obtain cyclophosphamide.
Further, the solvent used for crystallization in step 3 is purified water or acetone.
Further, dichloroethane in the step 2 is 5 times the mass of 2-chloro-2-oxo- [1.3.2] oxazaphosphorane.
Further, the molecular sieve of 5a in the step 2 is 1 time of the mass of the 2-chloro-2-oxo- [1.3.2] oxazaphosphorane.
The invention has the beneficial effects that: the synthesis method has the advantages of simple and convenient operation, high product yield, low cost and high purity. The low-temperature environment and the use of triethylamine are not needed, and the requirement that the technology disclosed by CN107936061A cannot reach the preset technical target is made up. The reaction temperature is increased by a composite system consisting of dichloroethane, polyphosphoric acid and acetic anhydride, the use of triethylamine is avoided, and the yield can be increased. In the second step, the molecular sieve is added, so that the reaction temperature and pressure are greatly increased, the reaction becomes feasible, and the reaction efficiency is improved. Presumably because the microchannels of the molecular sieve provide active sites and have the effect of adsorbing the exfoliated small molecules.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Any modifications that can be easily made by a person skilled in the art to the present invention without departing from the technical solutions of the present invention will fall within the scope of the claims of the present invention.
Example 1
A method for synthesizing cyclophosphamide, which comprises the following steps:
(1) adding 20g of phosphorus oxychloride slowly into 100g of a dichloroethane, polyphosphoric acid and acetic anhydride mixed solution with the mass ratio of 2: 1, dropwise adding 10g of 3-aminopropanol, reacting at 20 ℃ for 0.5 hour, pouring into water to separate an organic phase, washing with a saturated sodium carbonate aqueous solution for 2 times, and concentrating to obtain 2-chloro-2-oxo- [1.3.2] oxaphosphorinane;
(2) transferring 10g of 2-chloro-2-oxo- [1.3.2] oxazaphosphorane into a pressure reaction bottle, adding 50g of dichloroethane and 10g of 5a molecular sieve (used after activation treatment at 300 ℃), introducing ammonia gas, keeping 4 atmospheres, heating to 120 ℃, reacting for 2 hours, and finishing the reaction;
(3) filtering the reaction liquid, adding an ice water mixture, stirring for 30 minutes, separating an organic phase, adding 10% hydrochloric acid solution for washing, separating the organic phase, controlling the water bath temperature to be 50 ℃, decompressing and concentrating the organic phase to be dry, adding acetone, heating to 40 ℃ for dissolving, then cooling to below 5 ℃, crystallizing for 5 hours, carrying out suction filtration to obtain a white crystalline solid, and drying to obtain cyclophosphamide for crystallization.
Comparative example 1
The synthesis was performed according to the route disclosed in CN107936061A, and the overall yield and purity were calculated.
Comparative example 2
The same procedure as in example 1 was repeated, except that in the first step, polyphosphoric acid and acetic anhydride were not added, and 40g of triethylamine was added.
Comparative example 3
Same as example 1 except that in the second step, no 5a molecular sieve was added.
Compared with the prior art, the method has the advantages of simple reaction, high yield, strong operability and mild reaction conditions.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (4)
1. A method for synthesizing cyclophosphamide is characterized in that: the method comprises the following steps:
(1) slowly adding phosphorus oxychloride into a mixed solution of dichloroethane, polyphosphoric acid and acetic anhydride, dropwise adding 3-aminopropanol, reacting for 0.5-1 hour at 20 ℃, pouring into water, separating an organic phase, and concentrating to obtain 2-chloro-2-oxo- [ l.3.2 ] oxazaphosphorine;
(2) transferring 2-chloro-2-oxo- [ l.3.2 ] oxazaphosphorane into a pressure reaction bottle, adding dichloroethane and a 5a molecular sieve, introducing ammonia gas, keeping 4 atmospheric pressures, heating to 120 ℃, reacting for 2-2.5 hours, and finishing the reaction;
(3) filtering the reaction solution, adding an ice water mixture, stirring for 30 minutes, separating an organic phase, adding a 10% hydrochloric acid solution for washing, separating the organic phase, controlling the water bath temperature to be 50 ℃, concentrating the organic phase under reduced pressure until the organic phase is dry, adding a solvent for crystallization to obtain cyclophosphamide;
in the step 1, the mass ratio of dichloroethane, polyphosphoric acid and acetic anhydride is 2: 2: 1;
the molecular sieve of 5a in the step 2 is 1 time of the mass of 2-chloro-2-oxo- [1.3.2] oxazaphosphorane;
in the step 1, the molar ratio of the phosphorus oxychloride to the 3-aminopropanol is 1: 1;
and 3, in the crystallization process in the step 3, adding a solvent, heating to 40 ℃ for dissolution, then cooling to below 5 ℃, crystallizing for 5 hours, performing suction filtration to obtain a white crystalline solid, and drying to obtain the cyclophosphamide.
2. The process for the synthesis of cyclophosphamide as claimed in claim 1, characterized in that: in the step 1, the amount of the mixed solution of dichloroethane, polyphosphoric acid and acetic anhydride is 5 times of the mass of phosphorus oxychloride.
3. The process for the synthesis of cyclophosphamide as claimed in claim 1, characterized in that: and the solvent used for crystallization in the step 3 is purified water or acetone.
4. The process for the synthesis of cyclophosphamide as claimed in claim 1, characterized in that: in the step 2, dichloroethane is 5 times of the mass of 2-chloro-2-oxo- [ l.3.2 ] oxazaphosphorane.
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| CN201910070427.1A CN109535201B (en) | 2019-01-25 | 2019-01-25 | Synthesis method of cyclophosphamide |
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| CN201910070427.1A CN109535201B (en) | 2019-01-25 | 2019-01-25 | Synthesis method of cyclophosphamide |
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| CN109535201B true CN109535201B (en) | 2020-04-03 |
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| DE19739159C1 (en) * | 1997-09-06 | 1999-01-28 | Asta Medica Ag | Preparation of oxazaphosphorine-2-amine(s) used as, and to prepare, cytostatics and immunosuppressants |
| CN107936061B (en) * | 2017-12-28 | 2019-08-06 | 山东铂源药业有限公司 | A kind of synthetic method of cyclophosphamide |
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