CN114957098B - Method for preparing pentazocine intermediate - Google Patents
Method for preparing pentazocine intermediate Download PDFInfo
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- CN114957098B CN114957098B CN202210621250.1A CN202210621250A CN114957098B CN 114957098 B CN114957098 B CN 114957098B CN 202210621250 A CN202210621250 A CN 202210621250A CN 114957098 B CN114957098 B CN 114957098B
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- 238000000034 method Methods 0.000 title claims abstract description 41
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 title claims abstract description 19
- 229960005301 pentazocine Drugs 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 33
- 239000012043 crude product Substances 0.000 claims abstract description 27
- 125000006239 protecting group Chemical group 0.000 claims abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical group FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000012074 organic phase Substances 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 19
- 238000001914 filtration Methods 0.000 claims description 17
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 239000012065 filter cake Substances 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- 239000000047 product Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- 238000004537 pulping Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 8
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 8
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 8
- 238000002386 leaching Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 4
- 230000009615 deamination Effects 0.000 claims description 3
- 238000006481 deamination reaction Methods 0.000 claims description 3
- 239000012535 impurity Substances 0.000 abstract description 18
- 238000000746 purification Methods 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000008186 active pharmaceutical agent Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 4
- 239000003223 protective agent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000003042 antagnostic effect Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- -1 dichloroacetyl Chemical group 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000000349 (Z)-3-carboxyprop-2-enoyl group Chemical group O=C([*])/C([H])=C([H])\C(O[H])=O 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- FVDSDSNMOWANSX-UHFFFAOYSA-N 3-methylpent-3-en-1-amine Chemical compound CC=C(C)CCN FVDSDSNMOWANSX-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 239000007805 chemical reaction reactant Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- AGJSNMGHAVDLRQ-HUUJSLGLSA-N methyl (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-HUUJSLGLSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- OZAGLZYGLSIUTG-UHFFFAOYSA-N 1-bromo-3-methylbut-1-ene Chemical compound CC(C)C=CBr OZAGLZYGLSIUTG-UHFFFAOYSA-N 0.000 description 1
- IZMWJUPSQXIVDN-UHFFFAOYSA-N 4-bromo-2-methylbut-1-ene Chemical compound CC(=C)CCBr IZMWJUPSQXIVDN-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 108010085082 sigma receptors Proteins 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 108020001588 κ-opioid receptors Proteins 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/26—Benzomorphans
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to the technical field of chemical synthesis and provides a method for purifying a crude product of a compound of formula 113-C and a method for preparing a pentazocine intermediate by using the purified compound of formula 113-C. The crude process for purifying a compound of formula 113-C of the present invention comprises the steps of: (11) Carrying out amino protection reaction on the crude product of the compound 113-C and an amino protection reagent, and obtaining an N-protected compound through first post-treatment; (12) Removing the amino protecting group of the N-protected compound from the N-protected compound obtained in the step (11) under alkaline conditions, and obtaining the purified 113-C through second post-treatment. The invention solves the problem of difficult purification of 113-C by protecting the amino in the compound 113-C and removing the amino protecting group, the yield of one-step purification reaches 85%, and the purity reaches the requirement. The intermediate 113-D is prepared by adopting the purified 113-C, so that the purity of the intermediate 113-D can be further improved, the impurity content is reduced, and the single impurity in the bulk drug is effectively controlled finally.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a pentazocine intermediate.
Background
Pentazocine was developed and successfully marketed in 1967 by the schdulon dulobate group of stelin, england. Pentazocine is a derivative of benzomorphinan, has both agonizing and antagonizing effects on mixtures of opioid receptors, mainly agonizes the opioid kappa receptor, agonizes the sigma receptor at higher doses, and has partial agonizing or weaker antagonizing effects on the mu receptor. Pentazocine is suitable for relieving pain of moderate to severe pain and has wide clinical application. For example, intraoperative auxiliary analgesia, postoperative analgesia, chronic pain treatment, cancer pain treatment, and the like are applicable. Pentazocine Xin Pianji for oral administration is currently the only orally available opioid receptor agonistic and antagonistic analgesic.
At present, the production line in the domestic market mainly takes cyanoacetic acid as a raw material, and carries out addition reaction with butanone to obtain 3-methyl-3-alkene-valeronitrile (compound XV), and then carries out hydrogenation reaction under high pressure (5-6 MPa) to obtain 3-methyl-3-pentenamine (compound XVII). 3-methyl-3-pentene-1-amine is condensed firstly, then cyclization reaction is carried out under the condition of acid, thus obtaining a key intermediate 5, 9-dimethyl-2-hydroxy-6, 7-benzomorphinan (113-D), and finally the key intermediate reacts with 4-bromo-2-methyl-butene to obtain the pentazocine.
In the existing process, since 113-C is difficult to obtain a pure product, the 113-D product generated in the subsequent reaction step is high in impurity content and is mixed, and finally, the impurity index in the synthesized 113-API is disqualified (the single impurity needs to be controlled below 0.1%).
Disclosure of Invention
The invention aims to solve the problems that 113-API single impurity is difficult to control and does not meet the quality standard of bulk drug because 113C is difficult to purify at present.
The aim of the invention is achieved by the following technical scheme.
The present invention provides a process for purifying a crude compound of formula 113-C, the process comprising:
wherein R is selected from pivaloyl, trifluoroacetyl, acetyl, dichloroacetyl, maleyl and triphenylmethyl;
(11) Carrying out amino protection reaction on the crude product of the compound 113-C and an amino protection reagent, and obtaining an N-protected compound through first post-treatment;
(12) Removing the amino protecting group of the N-protected compound from the N-protected compound obtained in the step (11) under alkaline conditions, and obtaining the purified 113-C through second post-treatment.
In the process of the present invention, the crude product of compound 113-C may be a crude product prepared by an existing synthesis method.
According to one embodiment of the process for purifying crude compounds of formula 113-C according to the invention, in step (11), the amino protecting agent in the amino protecting reaction is selected from pivaloyl chloride, trifluoroacetic anhydride, preferably trifluoroacetic anhydride. Unexpectedly, the use of trifluoroacetic anhydride can greatly reduce the formation of impurities and significantly increase the purity of 113-C compounds.
Preferably, the amino protecting agent is trifluoroacetic anhydride and the molar ratio of crude compound 113-C to trifluoroacetic anhydride is 1:1.05-1.3, preferably 1:1.05-1:1.2, based on compound 113-C. More preferably, in step (11), the amino-protecting reaction is carried out at a temperature of-10 ℃ or less. In the present invention, the inventors found that when the molar ratio of the crude compound 113-C to trifluoroacetic anhydride is 1:1.05-1.3, the conversion rate of the crude compound 113-C is higher, and fewer impurities are produced by the reaction. Once the molar ratio of the crude compound 113-C to trifluoroacetic anhydride exceeds 1:1.3, the impurities are significantly increased and the impurity species become more complex. Furthermore, the amino-protecting reaction is preferably carried out at a temperature below-10℃between-10℃and-20 ℃). Too high a temperature results in the formation of more hydroxylation by-products, while too high a temperature results in too slow a reaction rate.
According to one embodiment of the process for purifying crude compounds of formula 113-C of the present invention, in step (11), the first work-up comprises: pouring the reaction solution obtained by the amino protection reaction into 10% sodium dihydrogen phosphate aqueous solution, stirring, washing an organic phase once by using 10% sodium dihydrogen phosphate aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in sequence, drying the organic phase, filtering, and concentrating the filtrate to obtain a 113-Cp crude product; adding isopropyl ether into the 113-Cp crude product, pulping, filtering, leaching a filter cake by using the isopropyl ether, and drying the filter cake to obtain the purified compound 113-Cp. By this post-treatment, the purity of compound 113-Cp can be improved.
According to one embodiment of the method of purifying a crude compound of formula 113-C of the present invention, in step (12), the second post-treatment comprises: adding water and Dichloromethane (DCM) into a reaction system obtained after the deamination protection reaction is finished, stirring, separating liquid, extracting an aqueous phase with dichloromethane for 1 time, combining organic phases, sequentially washing with water and saturated sodium chloride solution for 1 time, separating out the organic phases, drying the organic phases, filtering, and concentrating in vacuum to obtain a 113-C purified crude product; adding isopropyl ether into the 113-C purified crude product, pulping, filtering, leaching the filter cake with isopropyl ether, and drying the filter cake to obtain the 113-C pure product. By this post-treatment, the purity of compound 113-C can be further improved.
The invention also provides a method for preparing the pentazocine intermediate 113-D, which comprises the following synthetic routes:
wherein R is selected from pivaloyl, trifluoroacetyl, acetyl, dichloroacetyl, maleyl and triphenylmethyl;
the method comprises the following steps:
(21) Carrying out amino protection reaction on the crude product of the compound 113-C and an amino protection reagent, and obtaining an N-protected compound through first post-treatment;
(22) Removing the amino protecting group of the N-protected compound from the N-protected compound obtained in the step (21) under alkaline conditions, and obtaining purified 113-C through second post-treatment;
(23) To the purified 113C was added 48wt% HBr solution and reacted at 120-125℃to give compound 113-D.
In the method of preparing pentazocine intermediate 113-D of the present invention, step (23) may be performed using existing well-established procedures.
In one embodiment of the process for preparing pentazocine intermediate 113-D according to the invention, in step (1), the amino protecting agent is selected from pivaloyl chloride, trifluoroacetic anhydride. Preferably, the molar ratio of the crude compound 113-C to trifluoroacetic anhydride is 1:1.05-1.3 based on compound 113-C. Preferably, the amino protecting agent is trifluoroacetic anhydride. Preferably, in step (21), the amino protection reaction is carried out at a temperature of from-10 ℃ to-20 ℃.
The beneficial effects of the invention are that
The invention solves the problem that 113-C is difficult to purify unexpectedly by means of protecting the amino in the compound 113-C and removing the amino protecting group, the yield of one-step purification operation reaches 85%, and the purity reaches more than 99.5%. The intermediate 113-D is prepared by adopting the purified 113-C, so that the purity of the intermediate 113-D can be further improved, the impurity content is reduced, and finally, the single impurity in the subsequently obtained bulk drug can be effectively controlled.
The method has the advantages of avoiding high-pressure reaction in each step, along with high safety coefficient and low production cost, and is more suitable for industrial production of bulk drugs.
Drawings
FIG. 1 is a pilot HPLC plot of the process of example 1 of the present invention in the preparation of 113-Cp;
FIG. 2 is an HPLC plot of 113-Cp obtained in step one of the method of example 1 of the present invention;
FIG. 3 is a pilot HPLC plot of the process of example 1 of the present invention at step two of preparation 113-C;
FIG. 4 is a HPLC chart of 113-C obtained in step two of the method of example 1 of the present invention;
FIG. 5 is a plot of a pilot HPLC during the preparation of 113-D from 113-C in example 15 of the present invention;
FIG. 6 is an HPLC plot of 113-D obtained after purification from 113-C prepared in example 15 without purification by the method of the present invention;
FIG. 7 is an HPLC plot of 113-D prepared from 113-C purified by the method of the present invention in example 16, resulting in purified 113-D;
FIG. 8 is 113-D prepared in example 16 1 H NMR spectrum;
FIG. 9 is an HPLC chart of 113-API prepared in example 17;
FIG. 10 is an HPLC chart of 113-API prepared in example 18.
Detailed Description
The invention is further illustrated by the following specific examples.
Compound 113-C was prepared using prior art methods:
in the method of the embodiment of the invention, the synthesis of the intermediate 113-C of pentazocine can be referred to Chinese patent application CN 112679363A, and can also be synthesized by other methods disclosed in the prior art.
Specifically, intermediate compound 11C can be synthesized by the following route and procedure.
10g of toluene, 12g of 2-butanone, 20g of cyanoacetic acid, 2g of ammonium acetate and 3.4g of acetic acid are added into a 1000ml three-necked flask, stirred vigorously, heated to reflux, and separated into water for reaction overnight.
The reaction system became dark in color and TLC plates showed complete reaction of the starting materials.
Post-treatment: 5mL of water was added to the reaction system, and toluene and 2-butanone were distilled off at 110℃under normal pressure. The washing was performed three times with 10wt% sodium carbonate solution followed by three times with water. The organic layer was separated by extraction with methyl tert-butyl ether. Acetonitrile was added to the aqueous layer and the layers were separated again, water and ethyl acetate were added to the organic layer, after which the upper organic phase was spin-dried to give the reaction starting material containing the compounds XV and XVI. The reaction starting material containing the compounds XV and XVI was directly fed to the next reaction without further purification. The reaction process is as follows:
compound XVII is prepared by the following steps:
(1) Adding 2.1kg of Raney nickel into a reaction kettle, adding a small amount of ethanol, keeping Raney nickel not dried, and stirring;
(2) Introducing ammonia gas into 21L ethanol, controlling the temperature of the ethanol within the range of less than or equal to 10 ℃, and adopting an ammonia gas decrement method to ensure that the mass content of the ammonia gas relative to the ethanol is within the range of 10-30%;
(3) Putting the ethanol solution of ammonia gas obtained in the step (2) into a reaction kettle containing Raney nickel, then putting a mixture (3 kg) of a compound XV and a compound XVI into the kettle, and replacing air in the reaction kettle with nitrogen;
(4) Introducing hydrogen into the reaction kettle, controlling the pressure of the hydrogen to be within the range of 6-7MPa, and stirring. The reaction system was slowly heated to 35℃and the reaction was ended for about 6 hours. Ammonia gas and solvent were distilled off under reduced pressure to obtain 2.8kg of a mixed product of compound XVII and compound XVIII. The obtained mixed product is directly put into the next reaction without purification. The synthesis of pentazocine intermediate 113C from product XVII is routed as follows.
The synthesis process of pentazocine intermediate 113-C is as follows:
a mixed product (500 g) of the compound XVII and the compound XVIII and water (1.8L) are put into a reaction kettle, the pH value is regulated to 3 by hydrochloric acid, then, the ethyl ester (1120 g) of the lactoyl 2, 3-epoxy-3- (4-methoxyphenyl) -propionate is put into the reaction kettle, the temperature is raised to reflux, the reaction is carried out for 48 hours, the reduced pressure distillation is carried out, half of the accumulated water of the original body is distilled off, and the reaction kettle is cooled and left overnight. The next day of filtration, the filtrate was neutralized to pH10 with 40wt% sodium hydroxide solution, left at room temperature, and dried at room temperature to give crude compound 113-C in 93% purity. The yield is about 35%, mp.134-140 ℃. The crude 113-C product thus obtained was used in the following examples of the present invention.
Example 1
Purification of Compound C
Step one,
103g of crude 113-C with 93% purity, HPLC of the crude product shown in figure 1), 721ml (7V) of DCM and triethylamine (54.2 g,1.3 eq) are added into a 2L reaction flask, the temperature is reduced to-15 ℃, the donor trifluoroacetic anhydride (91.1 g,1.05 eq) of amino protecting group (group R) is added dropwise, the heat release is obvious during the dropwise addition, the temperature is controlled to be lower than-10 ℃, the dropwise addition is completed, the reaction is carried out at-5 to-10 ℃ for 2.0h, the purity in HPLC is controlled to 96.89%, and the HPLC diagram is shown in figure 1.
The reaction solution was poured into 400mL of 10% sodium dihydrogen phosphate aqueous solution and stirred for 10-15min, the solution was separated, the organic phase was washed once again with 400mL of 10% sodium dihydrogen phosphate aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, respectively, dried over anhydrous sodium sulfate and filtered, the crude product 133g of pale yellow solid was concentrated, 150mL of isopropyl ether was added to the crude product, slurried for 2.0h, suction-filtered, the filter cake was rinsed 1 time with 50mL of isopropyl ether, and air-blown for 12h at 45℃to give 113-Cp 121g of off-white solid with a purity of 99.56% (see FIG. 2) and a yield of 85%.
Step two,
Into a 2L reaction flask, 100g N-trifluoroacetyl protected compound (113-Cp), 500ml (5V) ethanol and 360ml 2mol/L aqueous sodium hydroxide solution (2.5 eq) were added, and the temperature was raised to 60-65 ℃ to react for about 2 hours, the purity of the medium control HPLC was 100%, and the HPLC diagram is shown in FIG. 3.
Post-treatment: cooling to room temperature, vacuum spin-drying ethanol at 40 ℃, adding 300mL of water, 800mL of DCM, stirring for 10-15min, separating liquid, extracting the water phase with 500mL of DCM for 1 time, combining the organic phases, washing with water for 1 time, washing with saturated sodium chloride solution for 1 time, drying, filtering, concentrating in vacuum to obtain 72g of crude pale yellow solid, adding 300mL of isopropyl ether into the crude product, pulping for 2.0h, suction filtering, leaching the filter cake with 100mL of isopropyl ether for 1 time, drying with air at 45 ℃ for 12h, and obtaining 66.5g of off-white solid, namely purified 113-C with the yield of 92% and the purity of 99.5% (the purity HPLC chart is shown in figure 4).
Example 2-example 14
With reference to the procedure of example 1, examples 2 to 14 below examine the protecting group donor and its charge equivalent, the reaction solvent, the solvent amount, and the base type, temperature. The results are shown in Table 1 below.
Example 15
Preparation of the Ring Compound 113-D
In a 50L reaction kettle, adding 1.0Kg of 113-C crude product (prepared by the existing method, without purification by the method, and with purity of 71%), 10Kg of HBr (48%), heating to an internal temperature of 120-125 ℃ for reaction for 20-24h, and performing a central control HPLC (high performance liquid chromatography) diagram shown in figure 5.
Post-treatment: adding 10L of water, regulating pH to 12 with ammonia water, stirring, separating liquid, extracting with water phase for 2 times, vacuum spin-drying to obtain 1.36kg crude product, adding 0.5L of methanol, pulping, filtering, and drying to obtain 436g pale yellow solid, namely compound 113-D, purity 93.89%, yield 50.0%, and HPLC chart shown in figure 6.
Example 16
Preparation of the Ring Compound 113-D
In a 50L reactor, 113-C (purified by the method of the invention) 1.0Kg and HBr (48%) 10Kg were added, and the mixture was heated to an internal temperature of 120-125℃to react for 20-24 hours.
Post-treatment: adding water 10L, adjusting pH to 12 with ammonia water, stirring, separating, extracting with water phase for 2 times, vacuum spin drying to obtain 1.36kg crude product, adding 0.5L methanol, pulping, vacuum filtering, drying to obtain 436g pale yellow solid, namely compound 113-D, yield 50.0%, HPLC chart shown in figure 7, 1 the H NMR spectrum is shown in FIG. 8.
Example 17
Preparation of 113-API
Into a 100ml three-necked flask, the compound 113-D obtained in example 15 was introduced, NMP (30 g) was stirred at room temperature, bromoisopentene was added, and NaHCO was added after most of the solid was dissolved 3 (2.7 g), and the reaction was carried out at 95-100℃for 3 hours. Ending the reaction, andthe temperature of the reaction system is reduced to room temperature.
Post-treatment: with about 4ml NH 3 ·H 2 The pH of the reaction system was adjusted to 9-10 by O, then methyl t-butyl ether (50 ml) and water (75 ml) were added thereto, and the mixture was stirred for 10-15 minutes, and left to stand for separation. The organic phase was washed with water (15 ml x 2) and the separation was continued. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to give 6.3g of a viscous oil. 30ml of n-heptane was added to the viscous oil, slurried and filtered to give 4.05g of a cake. 3.58g of the cake was crystallized from 4 volumes of 80% by weight ethanol solution to give 3.06g of crystals (yield 85.5%). The crystallization is continued by using 10 volumes of acetone, the obtained acetone recrystallization product is subjected to secondary acetone recrystallization again by using 10 volumes of acetone, the solid of the secondary acetone recrystallization is filtered out to obtain a compound 113-API, the compound is detected by HPLC, the HPLC chart is shown in figure 9, the purity is 95.94%, the content of a plurality of impurities exceeds the single impurity content standard (0.1%) of the API, and the content of one impurity is far more than the single impurity limit value of 0.1%, and the content reaches 3.36%.
Example 18
This example operates identically to example 17, except that: the compound 113-D is prepared by adopting the compound 113-D prepared in the example 16, and finally the compound 113-API is obtained, and is subjected to HPLC detection, wherein the HPLC chart is shown in figure 10, the purity is 99.80%, the content of single impurities is less than 0.1%, and the content requirement of single impurities of the API is met.
Claims (8)
1. A process for purifying a crude compound of formula 113-C, the process comprising:
wherein R is selected from trifluoroacetyl;
(11) Carrying out amino protection reaction on the crude product of the compound 113-C and an amino protection reagent, and obtaining an N-protected compound through first post-treatment; the amino protecting reagent is trifluoroacetic anhydride; and the amino protection reaction is carried out at a temperature of between-10 ℃ and-20 ℃;
(12) Removing the amino protecting group of the N-protected compound from the N-protected compound obtained in the step (11) under alkaline conditions, and obtaining the purified 113-C through second post-treatment.
2. The process for purifying a crude compound of formula 113-C according to claim 1, wherein in step (11), the molar ratio of the crude compound 113-C to trifluoroacetic anhydride is 1:1.05-1.3, based on the compound 113-C.
3. The method of purifying a crude compound of formula 113-C according to claim 1, wherein in step (11), the first post-treatment comprises: pouring the reaction solution obtained by the amino protection reaction into 10% sodium dihydrogen phosphate aqueous solution, stirring, washing an organic phase once by using 10% sodium dihydrogen phosphate aqueous solution, saturated sodium bicarbonate aqueous solution and saturated NaCl aqueous solution in sequence, drying the organic phase, filtering, and concentrating the filtrate to obtain a 113-Cp crude product; adding isopropyl ether into the 113-Cp crude product, pulping, filtering, leaching a filter cake by using the isopropyl ether, and drying the filter cake to obtain the purified compound 113-Cp.
4. The method of purifying a crude compound of formula 113-C according to claim 1, wherein in step (12), the second post-treatment comprises: adding water and methylene dichloride into a reaction system obtained after the deamination protection reaction is finished, stirring, separating liquid, extracting a water phase with methylene dichloride for 1 time, combining organic phases, washing with water and saturated sodium chloride for 1 time in sequence, separating out the organic phases, drying the organic phases, filtering, and concentrating in vacuum to obtain a 113-C purified crude product; adding isopropyl ether into the 113-C purified crude product, pulping, filtering, leaching the filter cake with isopropyl ether, and drying the filter cake to obtain the 113-C pure product.
5. A process for preparing pentazocine intermediate 113-D, comprising the following synthetic route:
wherein R is selected from trifluoroacetyl;
the method comprises the following steps:
(21) Carrying out amino protection reaction on the crude product of the compound 113-C and an amino protection reagent, and obtaining an N-protected compound through first post-treatment; the amino protecting reagent is trifluoroacetic anhydride; and the amino protection reaction is carried out at a temperature of between-10 ℃ and-20 ℃;
(22) Removing the amino protecting group of the N-protected compound from the N-protected compound obtained in the step (21) under alkaline conditions, and obtaining purified 113-C through second post-treatment;
(23) 48% HBr solution is added to the purified 113C, and the mixture is reacted at 120-125 ℃ to obtain a compound 113-D.
6. The process for preparing pentazocine intermediate 113-D according to claim 5, wherein in step (21), the molar ratio of the crude compound 113-C to trifluoroacetic anhydride is 1:1.05-1.3, based on compound 113-C.
7. A process for the preparation of pentazocine intermediate 113-D according to claim 5, wherein in step (21), the first post-treatment comprises: pouring the reaction solution obtained by the amino protection reaction into 10% sodium dihydrogen phosphate aqueous solution, stirring, washing an organic phase once by using 10% sodium dihydrogen phosphate aqueous solution, saturated sodium bicarbonate aqueous solution and saturated NaCl aqueous solution in sequence, drying the organic phase, filtering, and concentrating the filtrate to obtain a 113-Cp crude product; adding isopropyl ether into the 113-Cp crude product, pulping, filtering, leaching a filter cake by using the isopropyl ether, and drying the filter cake to obtain the purified compound 113-Cp.
8. A process for preparing pentazocine intermediate 113-D according to claim 5, wherein in step (22), the second post-treatment comprises: adding water and methylene dichloride into a reaction system obtained after the deamination protection reaction is finished, stirring, separating liquid, extracting a water phase with methylene dichloride for 1 time, combining organic phases, washing with water and saturated sodium chloride for 1 time in sequence, separating out the organic phases, drying the organic phases, filtering, and concentrating in vacuum to obtain a 113-C purified crude product; adding isopropyl ether into the 113-C purified crude product, pulping, filtering, leaching the filter cake with isopropyl ether, and drying the filter cake to obtain the 113-C pure product.
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