CN113135874A - Synthetic method of roxatidine acetate - Google Patents
Synthetic method of roxatidine acetate Download PDFInfo
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- CN113135874A CN113135874A CN202110404728.0A CN202110404728A CN113135874A CN 113135874 A CN113135874 A CN 113135874A CN 202110404728 A CN202110404728 A CN 202110404728A CN 113135874 A CN113135874 A CN 113135874A
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- acetate
- roxatidine
- compound
- roxatidine acetate
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- SMTZFNFIKUPEJC-UHFFFAOYSA-N Roxane Chemical compound CC(=O)OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 SMTZFNFIKUPEJC-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 229960003287 roxatidine acetate Drugs 0.000 title claims abstract description 24
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 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 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- COWNFYYYZFRNOY-UHFFFAOYSA-N oxazolidinedione Chemical compound O=C1COC(=O)N1 COWNFYYYZFRNOY-UHFFFAOYSA-N 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- YHRUOJUYPBUZOS-UHFFFAOYSA-N 1,3-dichloropropane Chemical compound ClCCCCl YHRUOJUYPBUZOS-UHFFFAOYSA-N 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 235000011056 potassium acetate Nutrition 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 239000000126 substance Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 abstract 2
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- RQZFADOMHWNDFU-UHFFFAOYSA-N 1-[[3-(3-chloropropoxy)phenyl]methyl]piperidine Chemical compound ClCCCOC1=CC=CC(CN2CCCCC2)=C1 RQZFADOMHWNDFU-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- ORGBERFQYFWYGX-UHFFFAOYSA-N 3-(piperidin-1-ylmethyl)phenol Chemical compound OC1=CC=CC(CN2CCCCC2)=C1 ORGBERFQYFWYGX-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229960003320 roxatidine Drugs 0.000 description 4
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 2
- 208000007882 Gastritis Diseases 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 229960000627 roxatidine acetate hydrochloride Drugs 0.000 description 2
- BZFKSWOGZQMOMO-UHFFFAOYSA-N 3-chloropropan-1-amine Chemical compound NCCCCl BZFKSWOGZQMOMO-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002243 Anastomotic ulcer Diseases 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 206010035669 Pneumonia aspiration Diseases 0.000 description 1
- FEWCTJHCXOHWNL-UHFFFAOYSA-N Roxatidine acetate hydrochloride Chemical compound Cl.CC(=O)OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 FEWCTJHCXOHWNL-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000007281 aminoalkylation reaction Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- -1 chloro roxatidine Chemical compound 0.000 description 1
- 208000023652 chronic gastritis Diseases 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides Roxatidine acetate (Roxatidine acetate), the chemical name of which is 2-acetoxyl-N- [3- [3- (1-piperidylmethyl) phenoxy group]Propyl radical]A process for the preparation of acetamide (formula VI). The method provided by the invention has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, high yield, simple and convenient post-treatment operation, green and environment-friendly solvent reagent and the like, reduces the cost, has certain technical advantages, is environment-friendly and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of roxatidine acetate and an intermediate thereof.
Background
Roxatidine acetate hydrochloride (Roxatidine acetate hydrochloride), chemical name 2-acetoxy-N- [3- [3- (1-piperidinylmethyl) phenoxy ] propyl ] acetamide hydrochloride, is a histamine H2-receptor blocker developed by the organ pharmaceutical Co., Ltd., Japan, and is first marketed in Japan in 1986. The product is deacetylated by hydrolysis in vivo and then rapidly converted into active metabolite Roxatidine (RXT), and is mainly used for preventing and treating digestive system diseases caused by high gastric acid secretion state, such as gastric ulcer, duodenal ulcer, anastomotic ulcer, reflux esophagitis, acute gastritis, and acute attack of chronic gastritis; it is also used for preventing inhalation pneumonia by pre-anesthesia administration.
In the existing synthesis method of roxatidine acetate, 3-hydroxybenzaldehyde is mainly used as a starting material, and a key intermediate 3-3[3- (1-piperidinylmethyl) phenoxy) ] propylamine is prepared through reductive amination and ether formation, and is shown as follows:
the main disadvantages of the preparation of key intermediates from Williamson's ether formation of 3- (1-piperidinylmethyl) phenol and 3-chloropropylamine are: impurities such as amino alkylation, quaternary ammonium salt and the like can be formed, and difficulty is brought to the research on the yield and quality of the product.
In the prior literature, there are mainly 3 methods for synthesizing roxatidine acetate from the key intermediates, and the synthetic route is as follows:
route 1: roxatidine is obtained by high-temperature condensation with glycolic acid, and roxatidine acetate is obtained by esterification; the condensation temperature is as high as: 140-160 ℃, is not beneficial to safety production, has large energy consumption, and needs to add a decoloring step because the product color is darkened due to high temperature.
Route 2: introducing two structures of amide and ester group through one-step reaction with acetoxyacetyl chloride; because the acetoxy acetyl chloride has relatively high price, active property and weak ultraviolet absorption, derivatization is needed for quality research, the detection is difficult, the quality of raw materials is not easy to control, and the acetoxy acetyl chloride has direct influence on the quality of products.
Route 3: reacting with chloroacetyl chloride to obtain chloro roxatidine, and reacting with potassium acetate to obtain roxatidine acetate. Similarly, the use of active acyl chloride in the route brings certain difficulties for the quality research work.
In view of the above, in view of the deficiencies of the prior art, there is an urgent need to find a method for preparing roxatidine acetate, which has the advantages of cheap and easily available raw materials, mild reaction conditions, high yield, and simple post-treatment and purification operations.
Disclosure of Invention
The invention provides a preparation method of Roxatidine acetate (Roxatidine acetate), the chemical name of which is 2-acetoxyl-N- [3- [3- (1-piperidylmethyl) phenoxy ] propyl ] acetamide (formula IV), and the method comprises the following steps:
step 1:
and reacting the compound of the formula I with 1, 3-dichloropropane in a solvent at the reaction temperature of 20-130 ℃ in the presence of alkali to prepare the compound of the formula II. Specifically, in some embodiments, the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, or lithium hydroxide. In some embodiments, the solvent is selected from one or more of water, ethanol, acetonitrile, N-dimethylformamide, dichloromethane, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, or methyltetrahydrofuran. In still other embodiments, wherein the reaction temperature is preferably: 50 to 100 ℃.
Step 2:
and reacting the compound of the formula II with 2, 4-oxazolidinedione in the presence of alkali in a solvent at a reaction temperature of 0-120 ℃ to prepare the compound of the formula III. Specifically, in some embodiments, the base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, or lithium hydroxide. In some embodiments, the solvent is selected from one or more of water, ethanol, acetonitrile, toluene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, or methyltetrahydrofuran. In other embodiments, wherein the reaction temperature is preferably: 60-90 ℃.
And step 3:
and (3) reacting the compound shown in the formula III with acetate or acetic acid \ acetic anhydride in a solvent at the reaction temperature of 20-150 ℃ to prepare the compound shown in the formula IV. Specifically, in some embodiments, the acetate salt is selected from one or a mixture of potassium acetate and sodium acetate. In some embodiments, the solvent is selected from one or more of water, methanol, ethanol, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, DMSO, tetrahydrofuran, or methyltetrahydrofuran. In other embodiments, wherein the reaction temperature is preferably: 80-120 ℃.
Detailed Description
The preparation process described in the present invention is further illustrated by the following examples, which include, but are not limited to.
The following examples are intended only to illustrate specific embodiments of the present invention, so as to enable those skilled in the art to more fully understand the present invention, but not to limit the present invention in any way. In the embodiments of the present invention, technical means or methods which are not specifically described are conventional in the art.
The chemicals used in the following examples are all commercially available chemicals.
In an exemplary embodiment of the invention, the synthetic route for formula IV is as follows:
in the above synthetic routes, those skilled in the art can also make changes to the above synthetic routes, such as changing specific reaction conditions or making adjustments to the synthetic route of one or more steps, etc., as needed, and such changes are within the scope of the present application without departing from the spirit of the present invention.
Example 1: synthesis of Compound II 1- [3- (3-chloropropyloxy) benzyl ] piperidine
3- (1-Piperidinylmethyl) phenol (90.0g,0.47mol) was added to 500mL of ethanol at room temperature, followed by potassium hydroxide (26.4g,0.47mol) and 1, 3-dichloropropane (106.2g,0.94 mol). Then, the mixture was refluxed while being heated to 90 ℃ and, after completion of the reaction, the solvent was concentrated, 800mL of methylene chloride was added, the mixture was washed twice with 500mL of 2 water, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 109.1g of a liquid with a yield of 86.7%.
Example 2: synthesis of Compound II 1- [3- (3-chloropropyloxy) benzyl ] piperidine
3- (1-Piperidinomethyl) phenol (90.0g,0.47mol) was added to 300mL of DMF at room temperature, followed by potassium carbonate (84.5g,0.61mol) and 1, 3-dichloropropane (132.8g,1.18 mol). After completion of the reaction at 60 ℃, 600mL of 13% saline was added, followed by extraction with 800mL of dichloromethane, and the organic phase was washed twice with 500mL of 2 saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain 120.5g of a liquid with a yield of 95.7%.
Example 3: synthesis of Compound II 1- [3- (3-chloropropyloxy) benzyl ] piperidine
3- (1-Piperidinomethyl) phenol (90.0g,0.47mol) was added to 100mL of water and 300mL of DMF, and sodium hydroxide (18.8g,0.47mol) was added to dissolve the solution, and the solution was added dropwise slowly with stirring to a solution of 1, 3-dichloropropane (53.2g,0.47mol) in DMF (150mL) at 100 ℃ over 4 h. After completion of the reaction, 1L of saturated saline was added, followed by extraction with 800mL of ethyl acetate. The organic phase was washed twice with 500mL x 2 saturated brine, dried over anhydrous sodium sulfate and concentrated to give 119.6g of a liquid with a yield of 95.0%.
Example 4: synthesis of Compound III 3- [3- [3- (3-piperidin-1-ylmethyl) phenoxy ] propyl ] oxazolidine-2, 4-dione
1- [3- (3-Chloropropoxy) benzyl ] piperidine (56.2g,0.21mol) was added to 300mL ethanol at room temperature, sodium carbonate (33.9g,0.32mol) and 2, 4-oxazolidinedione (21.2g,0.21mol) were added. Reacting for 2-4 h at 70-80 ℃, cooling, adding 500mL of water, filtering, and crystallizing the obtained solid with toluene to obtain 64.6g of off-white solid with the yield of 92.6%.
Example 5: synthesis of Compound III 3- [3- [3- (3-piperidin-1-ylmethyl) phenoxy ] propyl ] oxazolidine-2, 4-dione
1- [3- (3-Chloropropoxy) benzyl ] piperidine (56.2g,0.21mol) was added to 300mL acetonitrile at room temperature, and potassium carbonate (43.5g,0.32mol) and 2, 4-oxazolidinedione (21.2g,0.21mol) were added. Reacting for 2-4 h at 70-80 ℃, cooling, adding 500mL of water, filtering, and crystallizing the obtained solid with toluene to obtain 63.7g of off-white solid with the yield of 91.2%.
Example 6: synthesis of Compound III 3- [3- [3- (3-piperidin-1-ylmethyl) phenoxy ] propyl ] oxazolidine-2, 4-dione
1- [3- (3-Chloropropoxy) benzyl ] piperidine (56.2g,0.21mol) was added to 300mL DMF at room temperature, potassium carbonate (43.5g,0.32mol), 2, 4-oxazolidinedione (22.3g,0.22mol) and a catalytic amount of potassium iodide (0.35g,2.1mmol) were added. Reacting for 2-3 h at 60-70 ℃, cooling, adding 500mL of half-saturated saline solution, filtering, and crystallizing the obtained solid with toluene to obtain 60.9g of off-white solid with the yield of 87.2%.
Example 7: synthesis of compound IV roxatidine acetate
At room temperature, adding 3- [3- [3- (3-piperidine-1-ylmethyl) phenoxy ] propyl ] oxazolidine-2, 4-dione (96.4g,0.29mol) into 600mL of water, adding potassium acetate (65.8g,0.67mol), reacting at 90-100 ℃ for 4-6 h, cooling, extracting, concentrating to dryness, pulping with acetonitrile, filtering, and drying to obtain 94.5g of solid with a yield of 93.5%.
Example 8: synthesis of compound IV roxatidine acetate
At room temperature, adding 3- [3- [3- (3-piperidine-1-ylmethyl) phenoxy ] propyl ] oxazolidine-2, 4-dione (96.4g,0.29mol) into 300mL of DMF, adding sodium acetate (55.0g,0.67mol), reacting at 90-100 ℃ for 4-6 h, cooling, extracting, concentrating to dryness, pulping with acetonitrile, filtering, and drying to obtain 90.1g of solid with the yield of 89.2%.
Example 9: synthesis of compound IV roxatidine acetate
Adding 3- [3- [3- (3-piperidine-1-ylmethyl) phenoxy ] propyl ] oxazolidine-2, 4-dione (96.4g,0.29mol) into acetic anhydride \ acetic acid (50mL \150mL) at room temperature, reacting for 4-6 h at 110-120 ℃, cooling, concentrating under reduced pressure, adding water, adjusting pH to 10 with sodium carbonate, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating to dryness, pulping with acetonitrile, filtering, and drying to obtain 90.1g of solid with the yield of 89.2%.
The above-mentioned embodiments are merely exemplary embodiments for fully illustrating the present invention, and the scope of the present invention is not limited to the above-mentioned embodiments, but defined by the contents of the claims. All matters disclosed in the specification including the abstract and all methods and steps disclosed herein may be combined in any combination, except combinations where the features and/or steps are mutually exclusive. Each feature disclosed in this specification, including the abstract, can be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. Those skilled in the art should also realize that such equivalent substitutions and alterations can be made without departing from the spirit and scope of the present invention. Such modifications are also intended to be within the scope of the present invention. Each reference cited in this application is incorporated herein in its entirety.
Claims (10)
1. A method for preparing roxatidine acetate is characterized in that: the method comprises the following steps:
in the process of the step 1, reacting a compound of a formula I with 1, 3-dichloropropane in the presence of alkali in a solvent at a reaction temperature of 20-130 ℃ to prepare a compound of a formula II;
in the process of the step 2, reacting the compound of the formula II with 2, 4-oxazolidinedione in the presence of alkali in a solvent at a reaction temperature of 0-120 ℃ to prepare a compound of the formula III;
in the process of the step 3, the compound of the formula III reacts with acetate or acetic acid \ acetic anhydride in a solvent at the reaction temperature of 20-150 ℃ to prepare the compound of the formula IV.
2. The process for the preparation of roxatidine acetate as set forth in claim 1, wherein the base in step 1 is one or more selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide and lithium hydroxide.
3. The process for preparing roxatidine acetate as set forth in claim 1, wherein the solvent in step 1 is one or more selected from the group consisting of water, ethanol, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran and methyltetrahydrofuran.
4. The method for preparing roxatidine acetate as set forth in claim 1, wherein the reaction temperature in step 1 is 50-100 ℃.
5. The process for the preparation of roxatidine acetate as set forth in claim 1, wherein the base in step 2 is one or more selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide and lithium hydroxide.
6. The method of claim 1, wherein the solvent of step 2 is one or more selected from the group consisting of water, methanol, ethanol, acetonitrile, toluene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, and methyltetrahydrofuran.
7. The method for preparing roxatidine acetate as set forth in claim 1, wherein the reaction temperature in the step 2 is 60-90 ℃.
8. The process for preparing roxatidine acetate as set forth in claim 1, wherein the acetate in step 3 is selected from one or a mixture of potassium acetate and sodium acetate.
9. The process for preparing roxatidine acetate as set forth in claim 1, wherein the solvent in step 3 is one or more selected from the group consisting of water, methanol, ethanol, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran and methyltetrahydrofuran.
10. The method for preparing roxatidine acetate as set forth in claim 1, wherein the reaction temperature in step 3 is 80-120 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1986535A (en) * | 2005-12-20 | 2007-06-27 | 中国科学院兰州化学物理研究所 | Synthesis process of roxatidine acetate hydrochloride |
| CN102993121A (en) * | 2012-12-11 | 2013-03-27 | 哈药集团三精制药股份有限公司 | Synthetic method for preparing roxatidine acetate hydrochloride with high purity |
| CN107857743A (en) * | 2017-10-20 | 2018-03-30 | 四环医药控股集团有限公司 | A kind of method for preparing hydrochloric acid roxatidine acetate and intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1986535A (en) * | 2005-12-20 | 2007-06-27 | 中国科学院兰州化学物理研究所 | Synthesis process of roxatidine acetate hydrochloride |
| CN102993121A (en) * | 2012-12-11 | 2013-03-27 | 哈药集团三精制药股份有限公司 | Synthetic method for preparing roxatidine acetate hydrochloride with high purity |
| CN107857743A (en) * | 2017-10-20 | 2018-03-30 | 四环医药控股集团有限公司 | A kind of method for preparing hydrochloric acid roxatidine acetate and intermediate |
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