CN101928247B - Synthetic method of xylometazoline hydrochloride compound - Google Patents
Synthetic method of xylometazoline hydrochloride compound Download PDFInfo
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- 229960001095 xylometazoline hydrochloride Drugs 0.000 title claims abstract description 16
- -1 xylometazoline hydrochloride compound Chemical class 0.000 title claims abstract description 8
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 29
- YGWFCQYETHJKNX-UHFFFAOYSA-N 2-[(4-tert-butyl-2,6-dimethylphenyl)methyl]-4,5-dihydro-1h-imidazol-3-ium;chloride Chemical compound [Cl-].CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCC[NH2+]1 YGWFCQYETHJKNX-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000007265 chloromethylation reaction Methods 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000007333 cyanation reaction Methods 0.000 claims abstract description 6
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 40
- HUCJFAOMUPXHDK-UHFFFAOYSA-N Xylometazoline Chemical compound CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCCN1 HUCJFAOMUPXHDK-UHFFFAOYSA-N 0.000 claims description 32
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 19
- UGLCODVVPJQIDC-UHFFFAOYSA-N 1-butyl-2-(chloromethyl)benzene Chemical group CCCCC1=CC=CC=C1CCl UGLCODVVPJQIDC-UHFFFAOYSA-N 0.000 claims description 18
- 229960000833 xylometazoline Drugs 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 14
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 14
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 12
- HRQGCQVOJVTVLU-UHFFFAOYSA-N bis(chloromethyl) ether Chemical compound ClCOCCl HRQGCQVOJVTVLU-UHFFFAOYSA-N 0.000 claims description 11
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 claims description 10
- 229950004288 tosilate Drugs 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical group N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 235000007715 potassium iodide Nutrition 0.000 claims description 7
- 229960004839 potassium iodide Drugs 0.000 claims description 6
- 235000005074 zinc chloride Nutrition 0.000 claims description 6
- 239000011592 zinc chloride Substances 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- FZSPYHREEHYLCB-UHFFFAOYSA-N 1-tert-butyl-3,5-dimethylbenzene Chemical compound CC1=CC(C)=CC(C(C)(C)C)=C1 FZSPYHREEHYLCB-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 18
- 239000000047 product Substances 0.000 description 14
- 238000001914 filtration Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000003643 water by type Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 206010039083 rhinitis Diseases 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 201000009890 sinusitis Diseases 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- 206010020565 Hyperaemia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028748 Nasal obstruction Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 201000009151 chronic rhinitis Diseases 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229940061607 dibasic sodium phosphate Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical class [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 1
- UQFSVBXCNGCBBW-UHFFFAOYSA-M tetraethylammonium iodide Chemical compound [I-].CC[N+](CC)(CC)CC UQFSVBXCNGCBBW-UHFFFAOYSA-M 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a method for synthesizing a compound xylometazoline hydrochloride, which takes 1, 3-dimethyl-5-tert-butyl benzene as an initial raw material and obtains xylometazoline hydrochloride through chloromethylation, cyanation, cyclization and salification. The synthesis method is simple, the raw materials are easy to obtain, the operation is safe, the yield is high, and the method is suitable for industrial production.
Description
Technical field
The invention belongs to the synthetic field of medicine, be specifically related to a kind of compound method of xylometazoline hydrochloride compound.
Background technology
Xylometazoline hydrochloride (Xylometazoline Hydrochloride, 1), chemistry is by name: 2-(the 4-tertiary butyl-2,6-dimethyl benzyl)-2-imidazoline salt hydrochlorate, its chemical structure is following.Xylometazoline hydrochloride has direct exciting α 1 acceptor and causes vasoconstrictive effect, thus hyperemia due to reducing inflammation and oedema, clinically in order to alleviate the nasal obstruction symptom that diseases such as acute and chronic rhinitis, sinusitis paranasal sinusitis, allergic rhinitis, hypertrophic rhinitis cause.
In the prior art, US6124338 discloses a kind of method for preparing xylometazoline, by 2; 6-dimethyl--4-the tertiary butyl-1-aniline (2) gets 2 with polyformaldehyde reaction after diazotization, the 6-dimethyl--4-tertiary butyl-1-phenyl aldehyde (3) gets 2 with sodium borohydride reduction then; 6-dimethyl--4-the tertiary butyl-1-phenylcarbinol (4), hydroxyl becomes chlorine in the presence of sulfur oxychloride, gets 2; 6-dimethyl--4-the tertiary butyl-1-chloromethylbenzene (5); After reacting in ethanol with sodium cyanide compound (7), last and quadrol cyclization obtains target compound (1), its reaction formula is following:
Diazotization reaction in this compound method, general yield is not high; And use sulfur oxychloride that environment is had very big pollution; The aftertreatment of cyanation need be carried out the high-vacuum fractionation distillation, is difficult to amplify produce.The product impurity of this patented process gained is many, and it is low particularly to prepare the product purity of (1) by compound (7).In a word, this synthetic method craft route is long, and aftertreatment is loaded down with trivial details, and product yield is low, production cost is high, and this makes this difficult technique to realize industrialized production.
And ES323985 is disclosed by 1, and 3-dimethyl--5-tert.-butylbenzene (8) is prepared into the method for compound (5), and its chloromethylation is with ZnCl
2Make catalyzer, but this reaction conversion ratio is low, is merely 59%.
CN1088574 discloses the method by compound (8) preparation (5), adopts Paraformaldehyde 96, is catalyzer with the vitriol oil and feeds hydrogen chloride gas, yield 80-90%.Its reaction formula is following:
The bullion impurity that this chloromethylation obtains is many, need carry out the high-vacuum fractionation distillation, and post-processing difficulty is big.In addition, this technology need feed a large amount of hydrogen chloride gas, causes the spent acid solution discharging to increase, and environment is had very big pollution.
Summary of the invention
The object of the invention is exactly to the prior art defective, provides that a kind of technology is simple, raw material is easy to get, operational safety, yield be high, is fit to the synthesis technique of the xylometazoline hydrochloride of suitability for industrialized production.
Technical scheme of the present invention is: with 1,3-dimethyl--5-tert.-butylbenzene (8) is a starting raw material, in the presence of catalyzer, gets 2 with the chloromethylation reagent react, the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene (5); Carry out cyanation with sodium cyanide and get 2, the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide (6); Get tosic acid xylometazoline (10) with quadrol tosilate (9) cyclization then; Xylometazoline is got xylometazoline hydrochloride (1) with the free back of alkali with the hydrogenchloride salify, and the total recovery of four-step reaction is 44%.
Synthetic route of the present invention is following:
The concrete synthesis technique step of the present invention is following:
(a) chloromethylation: with 1; 3-dimethyl--5-tert.-butylbenzene (8) is as starting raw material; With compound (8): chloromethylation reagent: catalyst molar ratio is 1: (1.0～1.2): (0.1～0.2) feeds intake; Reacted 1～3 hour down at 40～60 ℃, aftertreatment gets 2, the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene (5);
(b) cyanation: with compound (5): sodium cyanide: the mol ratio of catalyzer is 1: (1.0～1.4): (0.02～0.08) feeds intake, reflux 14～22 hours, and aftertreatment and recrystallization get 2, the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide (6);
(c) ring-closure reaction: with compound (6) and quadrol tosilate (9) with 1: (1.0～1.3) mol ratio feeds intake, and is heated to 210～240 ℃ of reactions 0.5～2 hour, tosic acid xylometazoline (10).
(d) salt-forming reaction: compound (10) with alkali free after, again in organic solvent with the hydrogenchloride salify, regulate pH=4～5, xylometazoline hydrochloride (1) bullion, refining finished product.
In the above-mentioned reactions step (a), said chloromethylation reagent is one or more mixing in chloromethyl ether, bischlormethyl ether, the chloromethyl ether, preferred chloromethyl ether.
In the above-mentioned reactions step (a), said catalyzer is zinc chloride or aluminum trichloride (anhydrous).
In the above-mentioned reactions step (a), when temperature of reaction is 48～52 ℃, compound (8) is 1: 0.15 o'clock with catalyst molar ratio, reacts 2 hours, and the yield of compound (5) is the highest.
In the above-mentioned reactions step (b), said solvent is one or more mixing in acetone, butanone, methylene dichloride, trichloromethane, toluene, chlorobenzene or the diethyl carbonate, preferred acetone.
In the above-mentioned reactions step (b), said catalyzer is one or more mixing in potassiumiodide, Soiodin, potassiumiodide, Soiodin, Tetrabutyl amonium bromide, tetrabutylammonium iodide, tetraethylammonium bromide, the tetraethyl ammonium iodide, preferred potassiumiodide.
In the above-mentioned reactions step (c), preferred compound (6) is 1: 1.12 with the mol ratio of quadrol tosilate (9), and temperature of reaction is 220～230 ℃, and the reaction times is 1 hour.
In the above-mentioned reactions step (d), used alkali is one or more mixing in yellow soda ash, sodium hydrogencarbonate, sodium hydroxide, salt of wormwood, saleratus, Pottasium Hydroxide, sodium-acetate, ammoniacal liquor, SODIUM PHOSPHATE, MONOBASIC, the Sodium phosphate, dibasic.Preferred sodium hydroxide, Pottasium Hydroxide or ammoniacal liquor.
In the above-mentioned reactions step (d); Employed organic solvent is N; One or more mixing, ethyl acetate and ethanol mixed solvent in dinethylformamide, sherwood oil, ethanol, methyl alcohol, acetone, THF, ETHYLE ACETATE, methyl acetate, propyl acetate, isopropyl acetate, normal hexane, hexanaphthene, the methylene dichloride.
Synthesis technique of the present invention has been simplified operational process of craft, has improved xylometazoline hydrochloride midbody and final product quality, has reduced the discharging of spent acid solution, has improved production efficiency.
Synthesis technique particular embodiment of the present invention is in the following areas:
1) starting raw material 1, and 3-dimethyl--5-tert.-butylbenzene (8) is cheap and easy to get.
2) chloromethyl ether is active strong chloromethylation reagent, and transformation efficiency is high, and simultaneously, reaction product purity is high, and impurity is few, and reaction conditions is gentle.
3) compound (5) that obtains of chloromethylation need not purifying, can directly be used for next step reaction, has shortened the technological operation step, has improved yield.
4) cyanation mild condition, side reaction is few, and is simple to operate, is easy to aftertreatment, reduced labour intensity, improved Working environment.
5) solved the problem that is difficult to industrial amplification production in the patent route in the past.
6) product purity high (greater than 99.5%), yield high (total recovery 44%), quality reaches the newest standards of Chinese Pharmacopoeia, USP, British Pharmacopoeia, European Pharmacopoeia, Japanese Pharmacopoeia.
Embodiment
Following embodiment is used for further narrating the present invention, but does not do any restriction.
Embodiment 12, the preparation of the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene
With 1,3-dimethyl--5-tert.-butylbenzene 81 grams (0.5 mole) and aluminum trichloride (anhydrous) 13.4 grams (0.1 mole) mix, and slowly drip 41 gram chloromethyl ethers (0.5 mole), then 40-45 ℃ of reaction 3 hours.Drip 100 ml waters after reducing to room temperature, fully stir, behind the branch vibration layer; Organic layer is washed till pH=7 with saturated nacl aqueous solution, and anhydrous sodium sulfate drying gets oily matter 2 after the filtering and concentrating; 6-dimethyl--4-the tertiary butyl-1-chloromethylbenzene 88.4 grams (0.42 mole), yield 84%.
Embodiment 22, the preparation of the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene
With 1,3-dimethyl--5-tert.-butylbenzene 81 grams (0.5 mole) and zinc chloride 13.6 grams (0.1 mole) mix, and slowly drip 41 gram chloromethyl ethers (0.5 mole), then 45-50 ℃ of reaction 2.5 hours.Drip 120 ml waters after reducing to room temperature, post-treating method gets product 93.6 grams (0.44 mole), yield 89% with embodiment 1.
Embodiment 32, the preparation of the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene
With 1,3-dimethyl--5-tert.-butylbenzene 50 grams (0.31 mole) and zinc chloride 6.3 grams (0.046 mole) mix, and slowly drip chloromethyl ether 27 grams (0.34 mole), then 48-52 ℃ of reaction 2 hours.Drip 60 ml waters after reducing to room temperature, post-treating method gets product 59.6 grams (0.28 mole), yield 92% with embodiment 1.
Embodiment 42, the preparation of the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene
With 1,3-dimethyl--5-tert.-butylbenzene 81 grams (0.5 mole) and aluminum trichloride (anhydrous) 3.6 grams (0.05 mole) mix, and slowly drip 48 gram chloromethyl ethers (0.6 mole), then 50-55 ℃ of reaction 2 hours.Drip 900 ml waters after reducing to room temperature, post-treating method gets product 92.6 grams (0.44 mole), yield 88% with embodiment 1.
Embodiment 52, the preparation of the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene
With 1,3-dimethyl--5-tert.-butylbenzene 162 grams (1.0 moles) and zinc chloride 18 grams (0.13 mole) mix, and slowly drip 89 gram chloromethyl ethers (1.1 moles), then 50-55 ℃ of reaction 2 hours.Drip 220 ml waters after reducing to room temperature, post-treating method gets product 190.0 grams (0.90 mole), yield 90% with embodiment 1.
Embodiment 62, the preparation of the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene
With 1,3-dimethyl--5-tert.-butylbenzene 162 grams (1.0 moles) and zinc chloride 14 grams (0.1 mole) mix, and slowly drip 97 gram chloromethyl ethers (1.2 moles), then 55-60 ℃ of reaction 1 hour.Drip 250 ml waters after reducing to room temperature, post-treating method gets product 183.6 grams (0.87 mole), yield 87% with embodiment 1.
Embodiment 72, the preparation of the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide
Sodium cyanide 30.5 grams (0.62 mole), Soiodin 3.6 grams (0.024 mole) and 75 milliliters of acetone are added in the there-necked flask, stir down and drip 2, the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene 100 grams (0.48 mole), reflux is 18 hours then.Suction filtration is removed solid salt after reducing to room temperature, uses the small amount of acetone washing salt.Filtrating merges, and concentrating under reduced pressure, gained oily matter are cooled to 5 ℃ of crystallizations with 40 milliliters of dissolve with ethanol, gets 2 after the solid filtering drying, the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide 75.6 grams (0.38 mole), yield 79%.
Embodiment 82, the preparation of the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide
24 gram sodium cyanides (0.49 mole), 4 gram potassiumiodides (0.024 mole) and 400 milliliters of methylene dichloride are added in the there-necked flask, stir down and drip 2, the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene 100 grams (0.48 mole), reflux is 20 hours then.Post-treating method gets product 65.3 grams (0.32 mole), yield 68% with embodiment 7.
Embodiment 92, the preparation of the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide
Sodium cyanide 28 grams (0.57 mole), potassiumiodide 4 grams (0.024 mole) and 250 milliliters of acetone are added in the there-necked flask, stir down and drip 2, the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene 100 grams (0.48 mole), reflux is 20 hours then.Post-treating method gets product 76.4 grams (0.38 mole), yield 80% with embodiment 7.
Embodiment 10 2, the preparation of the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide
Sodium cyanide 23.5 grams (0.48 mole), potassiumiodide 1.6 grams (0.01 mole) and 250 milliliters of acetone are added in the there-necked flask, stir down and drip 2, the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene 100 grams (0.48 mole), reflux is 22 hours then.Post-treating method gets product 71.8 grams (0.36 mole), yield 75% with embodiment 7.
Embodiment 11 2, the preparation of the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide
Sodium cyanide 33 grams (0.67 mole), 5.7 gram Soiodins (0.038 mole) and 350 milliliters of acetone are added in the there-necked flask, stir down and drip 2, the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene 100 grams (0.48 mole), reflux is 14 hours then.Post-treating method gets product 71.6 grams (0.36 mole), yield 75% with embodiment 7.
The preparation of embodiment 12 tosic acid xylometazolines
With 2, the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide 50 grams (0.25 mole) and quadrol tosilate 75 grams (0.325 mole) mix, and are warming up to 210～220 ℃ of reactions 1.5 hours.Pour out while hot, the cooling after fixing gets tosic acid xylometazoline 99.6 grams (0.240 mole), yield 96%.
The preparation of embodiment 13 tosic acid xylometazolines
With 2, the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide 50 grams (0.25 mole) and quadrol tosilate 70 grams (0.30 mole) mix, and are warming up to 225～235 ℃ of reactions 1 hour.Post-treating method gets tosic acid xylometazoline 100.5 grams (0.242 mole), yield 97% with embodiment 12.
The preparation of embodiment 14 tosic acid xylometazolines
With 2, the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide 50 grams (0.25 mole) and quadrol tosilate 65 grams (0.28 mole) mix, and are warming up to 220～230 ℃ of reactions 1 hour.Post-treating method gets tosic acid xylometazoline 101.2 grams (0.243 mole), yield 98% with embodiment 12.
The preparation of embodiment 15 tosic acid xylometazolines
With 2, the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide (0.25 mole) and quadrol tosilate 58 grams (0.25 mole) mix, and are warming up to 230～240 ℃ of reactions 30 minutes.Post-treating method gets tosic acid xylometazoline 98.5 grams (0.237 mole), yield 95% with embodiment 12.
The preparation of embodiment 16 xylometazoline hydrochlorides
30 gram tosic acid xylometazolines (0.072 mole) are dissolved in 900 ml waters, are warming up to 90 ℃; Add 150 milliliter of 10% aqueous sodium hydroxide solution, stirred 30 minutes, reduce to the room temperature after-filtration; Filter cake is washed with water to washing lotion pH=7; The solid xylometazoline that after drying, must dissociate after the xylometazoline that will dissociate is dissolved in 150 milliliters of ETHYLE ACETATE, drips ethanol solution of hydrogen chloride to pH5.Use 50 milliliters of absolute ethyl alcohol heating for dissolving after the gained solid filtering drying again, the activated carbon decolorizing after-filtration, filtrating adds 135 milliliters of ETHYLE ACETATE; Be cooled to 5 ℃; Stir 1 hour after-filtration, filter cake washs with ETHYLE ACETATE, gets xylometazoline hydrochloride 12.4 grams (0.044 mole) after the drying; Yield 61%, purity 99.76% (performance liquid).
The preparation of embodiment 17 xylometazoline hydrochlorides
30 gram tosic acid xylometazolines (0.072 mole) are dissolved in 1000 ml waters, are warming up to 90 ℃; Add ammoniacal liquor, stirred 20 minutes, reduce to the room temperature after-filtration; Filter cake is washed with water to washing lotion pH=7; The solid xylometazoline that after drying, must dissociate after the xylometazoline that will dissociate is dissolved in 150 milliliters of ETHYLE ACETATE, drips ethanol solution of hydrogen chloride to pH4.Use 50 milliliters of absolute ethyl alcohol heating for dissolving after the gained solid filtering drying again, the activated carbon decolorizing after-filtration, filtrating adds 150 milliliters of ETHYLE ACETATE; Be cooled to 10 ℃; Stir 1 hour after-filtration, filter cake washs with ETHYLE ACETATE, gets xylometazoline hydrochloride 11.8 grams (0.042 mole) after the drying; Yield 58%, purity 99.80% (performance liquid).
Claims (1)
1. the compound method of an xylometazoline hydrochloride compound, this method comprises the steps:
(a) chloromethylation: with 1,3-dimethyl--5-tert.-butylbenzene is a starting raw material, in the presence of catalyzer, gets 2 with the chloromethylation reagent react, the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene;
The reagent of chloromethylation described in the reactions step a is chloromethyl ether,
Catalyzer described in the reactions step a is zinc chloride or aluminum trichloride (anhydrous),
Among the reactions step a 1,3-dimethyl--5-tert.-butylbenzene: chloromethylation reagent: catalyst molar ratio is 1: 1.0～1.2: 0.1～0.2,
Temperature of reaction is at 40～60 ℃ among the reactions step a;
(b) cyanation: 2, the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene and sodium cyanide in the presence of catalyzer, react 2, the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide;
The said catalyzer of reactions step b is: Soiodin or potassiumiodide;
Among the reactions step b 2, the 6-dimethyl--4-tertiary butyl-1-chloromethylbenzene: sodium cyanide: the mol ratio of catalyzer is 1: 1.0～1.4: 0.02～0.08;
(c) ring-closure reaction: with 2, the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide mixes with the quadrol tosilate, and cyclization is carried out in heating, gets the tosic acid xylometazoline;
Among the reactions step c 2, the 6-dimethyl--4-tertiary butyl-1-benzyl cyanide: quadrol tosilate mol ratio is 1: 1.0～1.3,
Temperature of reaction is at 210～240 ℃ among the reactions step c;
(d) salt-forming reaction: tosic acid xylometazoline alkalization is for behind the free alkali, again in solvent with the hydrochloric acid salify, xylometazoline hydrochloride;
The said solvent of reactions step d is an ETHYLE ACETATE.
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