CN114957098A - Method for preparing pentazocine intermediate - Google Patents
Method for preparing pentazocine intermediate Download PDFInfo
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- CN114957098A CN114957098A CN202210621250.1A CN202210621250A CN114957098A CN 114957098 A CN114957098 A CN 114957098A CN 202210621250 A CN202210621250 A CN 202210621250A CN 114957098 A CN114957098 A CN 114957098A
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- 238000000034 method Methods 0.000 title claims abstract description 44
- 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 16
- 229960005301 pentazocine Drugs 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 36
- 239000012043 crude product Substances 0.000 claims abstract description 27
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 13
- 125000006239 protecting group Chemical group 0.000 claims abstract description 9
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 19
- 239000012074 organic phase Substances 0.000 claims description 18
- 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
- 238000005406 washing Methods 0.000 claims description 15
- 239000012065 filter cake Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- 238000004537 pulping Methods 0.000 claims description 10
- 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
- 238000000967 suction filtration Methods 0.000 claims description 8
- 239000012071 phase Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 5
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 4
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical group CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- -1 dichloroacetyl Chemical group 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 125000003099 maleoyl group Chemical group C(\C=C/C(=O)*)(=O)* 0.000 claims description 4
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 4
- 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 claims description 4
- 238000010626 work up procedure Methods 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 230000009615 deamination Effects 0.000 claims description 3
- 238000006481 deamination reaction Methods 0.000 claims description 3
- 238000012805 post-processing Methods 0.000 claims 2
- 239000012535 impurity Substances 0.000 abstract description 18
- 238000000746 purification Methods 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 125000003277 amino group Chemical group 0.000 abstract description 2
- 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
- FVDSDSNMOWANSX-UHFFFAOYSA-N 3-methylpent-3-en-1-amine Chemical compound CC=C(C)CCN FVDSDSNMOWANSX-UHFFFAOYSA-N 0.000 description 6
- 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
- 239000007787 solid Substances 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000203 mixture Substances 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
- 239000002994 raw material 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
- 239000010410 layer Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- CUHUYVNPCQYRLG-UHFFFAOYSA-N 3-(4-methoxyphenyl)oxirane-2-carboxylic acid Chemical compound C1=CC(OC)=CC=C1C1C(C(O)=O)O1 CUHUYVNPCQYRLG-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
- 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
- 230000001270 agonistic effect Effects 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 150000001923 cyclic compounds Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 238000004519 manufacturing process Methods 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
- 238000000655 nuclear magnetic resonance spectrum Methods 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
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 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
- 238000010268 HPLC based assay Methods 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 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
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003402 opiate agonist Substances 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 230000002980 postoperative effect Effects 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
- 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
- 238000001228 spectrum Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 108020001588 κ-opioid receptors Proteins 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Images
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of chemical synthesis and provides a crude product method for purifying a compound shown in a formula 113-C and a method for preparing a pentazocine intermediate by using the purified 113-C compound. The crude process of the present invention for purifying a compound of formula 113-C 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 carrying out first post-treatment to obtain an N-protected compound; (12) and (3) under the alkaline condition, removing the amino protecting group of the N-protected compound generated in the step (11), and carrying out second post-treatment to obtain purified 113-C. The invention solves the problem of difficult 113-C purification by means of firstly protecting the amino group in the compound 113-C and then removing the amino protecting group, the yield of one-step purification reaches 85 percent, 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 effective control of single impurities in the bulk drugs is finally realized.
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 by the swesber group of stirling, uk in 1967. Pentazocine is a derivative of benzomorphan, has mixed agonistic and antagonistic effects on opioid receptors, mainly excites opioid kappa receptors, can excite sigma receptors at a larger dose, and has partial agonistic or weak antagonistic effect on mu receptors. Pentazocine is suitable for relieving pain of moderate to severe pain, and has wide clinical application. For example, intraoperative adjuvant analgesia, postoperative analgesia, chronic pain therapy, cancer pain therapy, and the like can be applied. Pentazocine tablets for oral administration are currently the only orally available opioid agonist and antagonist analgesics.
In the current production route of domestic markets, cyanoacetic acid is mainly used as a raw material and is added with butanone to obtain 3-methyl-3-alkene-valeronitrile (compound XV), and then the 3-methyl-3-pentenylamine (compound XVII) is obtained through a high-pressure (5-6 MPa) hydrogenation reaction. The 3-methyl-3-pentene-1-amine is firstly condensed, and then subjected to cyclization reaction under the acid condition to obtain a key intermediate 5, 9-dimethyl-2-hydroxy-6, 7-benzomorphane (113-D), and finally reacted with 4-bromo-2-methyl-butene to obtain pentazocine.
In the existing process, because 113-C is difficult to obtain a pure product all the time, the product 113-D generated in the subsequent reaction step has more and complicated impurities, and finally the impurity index in the synthesized 113-API is unqualified (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 drugs due to the difficulty in purification of 113C at present.
The purpose of the invention is realized 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, maleoyl and triphenylmethyl;
(11) carrying out amino protection reaction on the crude product of the compound 113-C and an amino protection reagent, and carrying out first post-treatment to obtain an N-protected compound;
(12) and (3) under the alkaline condition, removing the amino protecting group of the N-protected compound generated in the step (11), and performing second post-treatment to obtain purified 113-C.
In the process of the present invention, the crude compound 113-C may be a crude product prepared by a conventional synthesis method.
According to one embodiment of the process for purifying the crude compound of formula 113-C of the present invention, in step (11), the amino protecting reagent in the amino protecting reaction is selected from pivaloyl chloride, trifluoroacetic anhydride, preferably trifluoroacetic anhydride. Surprisingly, the use of trifluoroacetic anhydride can greatly reduce the formation of impurities and significantly improve the purity of the 113-C compound.
Preferably, the amino protecting reagent is trifluoroacetic anhydride, and the molar ratio of the crude compound 113-C to the trifluoroacetic anhydride is 1:1.05-1.3, preferably 1:1.05-1:1.2, based on the compound 113-C. More preferably, in step (11), the amino protection reaction is carried out at a temperature below-10 ℃. 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 of the crude compound 113-C is high and the reaction produces less impurities. 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. Further, the amino group protecting reaction is preferably carried out at a temperature of-10 ℃ or lower to-20 ℃). Excessive temperatures result in the formation of more hydroxylated by-product, while excessive temperatures result in too slow a reaction rate.
According to one embodiment of the process of the present invention for purifying a crude compound of formula 113-C, in step (11), the first work-up comprises: pouring the reaction liquid obtained by the amino protection reaction into 10% sodium dihydrogen phosphate aqueous solution, stirring, washing the organic phase with 10% sodium dihydrogen phosphate aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution for one time, 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, performing suction filtration, washing a filter cake with isopropyl ether, and drying the filter cake to obtain the purified compound 113-Cp. By this post-treatment, the purity of the compound 113-Cp can be improved.
According to one embodiment of the process of the present invention for purifying a crude compound of formula 113-C, in step (12), the second work-up comprises: adding water and Dichloromethane (DCM) into a reaction system obtained after the deamination protection reaction is finished, stirring, separating liquid, extracting a water phase for 1 time by using dichloromethane, combining organic phases, sequentially washing the water phase for 1 time by using water and a saturated sodium chloride solution, separating the organic phase, drying the organic phase, filtering, and concentrating in vacuum to obtain a 113-C purified crude product; adding isopropyl ether into the 113-C purified crude product, pulping, performing suction filtration, washing the filter cake with isopropyl ether, and drying the filter cake to obtain a 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 pentazocine intermediate 113-D, comprising the following synthetic route:
wherein R is selected from pivaloyl, trifluoroacetyl, acetyl, dichloroacetyl, maleoyl 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 carrying out first post-treatment to obtain an N-protected compound;
(22) under alkaline conditions, removing the amino protecting group of the N-protected compound generated in the step (11), and performing second post-treatment to obtain purified 113-C;
(23) 48 wt% HBr solution was added to the purified 113C and reacted at 120-125 deg.C to obtain compound 113-D.
In the process for the preparation of pentazocine intermediate 113-D according to the invention, step (23) may be performed using established techniques.
In one embodiment of the process of the present invention for the preparation of pentazocine intermediate 113-D, in step (1), the amino protecting reagent is selected from pivaloyl chloride, trifluoroacetic anhydride. Preferably, the molar ratio of the crude compound 113-C to the trifluoroacetic anhydride is 1:1.05-1.3 based on the compound 113-C. Preferably, the amino protecting reagent is trifluoroacetic anhydride. Preferably, in step (11), the amino protection reaction is carried out at a temperature of-10 ℃ to-20 ℃.
The invention has the advantages of
The invention unexpectedly solves the problem that 113-C is difficult to purify by means of firstly protecting amino in the compound 113-C and then removing amino protecting groups, the yield of one-step purification operation reaches 85 percent, and the purity reaches more than 99.5 percent. 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 effective control of single impurities in the subsequently obtained bulk drugs is finally realized.
The method avoids high-pressure reaction in each step, has high safety coefficient and low production cost, and is more suitable for industrial production of the raw material medicines.
Drawings
FIG. 1 is a central HPLC profile for 113-Cp preparation at step one of the process of example 1 of the present invention;
FIG. 2 is an HPLC plot of 113-Cp obtained in step one of the process of example 1 of the present invention;
FIG. 3 is a controlled HPLC profile for preparation of 113-C at step two of the method of example 1 of the present invention;
FIG. 4 is an HPLC chromatogram of 113-C obtained in step two of the method of example 1 of the present invention;
FIG. 5 is a controlled HPLC chromatogram for preparation of 113-D from 113-C in example 15 of the present invention;
FIG. 6 is an HPLC chromatogram of purified 113-D from 113-C prepared 113-D in example 15 that was not purified by the method of the present invention;
FIG. 7 is an HPLC chromatogram of purified 113-D from preparation 113-D of 113-C purified by the method of the present invention in example 16;
FIG. 8 is 113-D prepared in example 16 1 An H NMR spectrum;
FIG. 9 is an HPLC chromatogram of 113-API prepared in example 17;
FIG. 10 is an HPLC plot of 113-API prepared in example 18.
Detailed Description
The present invention is further illustrated by the following specific examples.
Compound 113-C was prepared using a prior art method:
in the method of the embodiment of the present invention, the synthesis of intermediate 113-C of pentazocine can refer to chinese patent application CN 112679363 a, and can also adopt other methods disclosed in the prior art to synthesize. 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 were added to a 1000ml three-necked flask, and the mixture was stirred vigorously, heated to reflux, dehydrated and reacted overnight.
The reaction system became darker and TLC plates showed the starting material to react completely.
And (3) post-treatment: 5mL of water was added to the reaction system, and toluene and 2-butanone were distilled off at 110 ℃ under normal pressure. Washed three times with 10 wt% sodium carbonate solution and then three times with water. The organic layer was separated by extraction with methyl tert-butyl ether. Acetonitrile is added into the water layer, the mixture is separated again, water and ethyl acetate are added into the organic layer, and after the separation, the organic phase at the upper layer is dried in a rotary mode to obtain the reaction raw material containing the compounds XV and XVI. The starting materials for the reaction, which contained compounds XV and XVI, were directly charged to the next reaction without further purification. The reaction process is as follows:
compound XVII was prepared by the following procedure:
(1) adding 2.1kg of Raney nickel into a reaction kettle, adding a small amount of ethanol, keeping the Raney nickel not dry, and stirring;
(2) introducing ammonia gas into 21L of ethanol, controlling the temperature of the ethanol to be less than or equal to 10 ℃, and adopting an ammonia gas reduction 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 (3kg) 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 within the range of 6-7MPa, and stirring. The reaction system is slowly heated to 35 ℃, and the reaction lasts for about 6 hours to finish the reaction. Ammonia gas and the 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 route for synthesizing pentazocine intermediate 113C from product XVII is as follows.
The synthesis process of pentazocine intermediate 113-C is as follows:
the mixed product (500g) of the compound XVII and the compound XVIII and water (1.8L) are put into a reaction kettle, the pH is adjusted to 3 by hydrochloric acid, and then the ethyl ester of the lactone 2, 3-epoxy-3- (4-methoxyphenyl) -propionic acid (1120g) 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 original water is distilled out, and the reaction kettle is cooled and placed overnight. Filtering the solution the next day, neutralizing the filtrate with 40 wt% sodium hydroxide solution to pH10, standing at room temperature, filtering when crystallizing, standing at room temperature, and drying to obtain crude compound 113-C with purity of 93%. The yield is about 35 percent, and mp.134-140C. The crude 113-C thus obtained was used in the following examples of the present invention.
Example 1
Purification of Compound C
The first step,
103g of crude 113-C raw material with the purity of 93 percent is added into a 2L reaction bottle, the HPLC of the crude product is shown in figure 1, 721ml (7V) DCM and triethylamine (54.2g, 1.3eq) are added, the temperature is reduced to-15 ℃, donor trifluoroacetic anhydride (91.1g, 1.05eq) of an amino protecting group (group R) is added dropwise, the heat release is obvious during dropwise addition, the temperature is controlled to be lower than-10 ℃, the dropwise addition is finished at the temperature of-5 to-10 ℃, the reaction is carried out for 2.0h, the purity of the HPLC is controlled to be 96.89 percent, and the HPLC chart is shown in figure 1.
Pouring the reaction solution into 400mL of 10% sodium dihydrogen phosphate aqueous solution, stirring and washing for 10-15min, separating, respectively washing an organic phase with 400mL of 10% sodium dihydrogen phosphate aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution once, drying with anhydrous sodium sulfate, filtering, concentrating to obtain 133g of a crude product, adding 150mL of isopropyl ether into the crude product, pulping for 2.0h, performing suction filtration, leaching a filter cake with 50mL of isopropyl ether for 1 time, and performing forced air drying at 45 ℃ for 12h to obtain 113-Cp 121g of a white-like solid, wherein the purity is 99.56% (shown in figure 2), and the yield is 85%.
Step two,
A2L reaction flask was charged with 100g N-trifluoroacetyl group-protected compound (113-Cp), 500ml (5V) ethanol and 360ml of 2mol/L aqueous sodium hydroxide solution (2.5eq), and the mixture was heated to 60-65 ℃ for reaction for about 2 hours with a medium HPLC purity of 100% and the HPLC chart shown in FIG. 3.
And (3) post-treatment: cooling to room temperature, carrying out vacuum spin-drying on ethanol at 40 ℃, adding 300mL of water and 800mL of DCM into the system, stirring for 10-15min, separating liquid, extracting the water phase for 1 time by using 500mL of DCM, combining the organic phases, washing for 1 time by using a saturated sodium chloride solution, drying, filtering, and carrying out vacuum concentration to obtain 72g of a light yellow solid as a crude product, adding 300mL of isopropyl ether into the crude product, pulping for 2.0h, carrying out suction filtration, leaching the filter cake for 1 time by using 100mL of isopropyl ether, and carrying out forced air drying at 45 ℃ for 12h to obtain 66.5g of a white-like solid, namely the purified 113-C, wherein the yield is 92% and the purity is 99.5% (the purity HPLC chromatogram is shown in figure 4).
Example 2 to example 14
With reference to the procedure of example 1, the following examples 2 to 14 were examined about the protecting group donor and its charge equivalent, reaction solvent, solvent amount and base type, temperature. The results are shown in table 1 below.
Example 15
Preparation of Cyclic Compound 113-D
1.0Kg of 113-C crude product (prepared by the existing method, which is not purified by the invented method and has a purity of 71%) and 10Kg of HBr (48%) are added into a 50L reaction kettle, the temperature is raised to an internal temperature of 120 ℃ and 125 ℃ for reaction for 20-24h, and a central control HPLC chromatogram is shown in FIG. 5.
And (3) post-treatment: adding 10L of water, adjusting the pH value to 12 by ammonia water, stirring, separating, extracting the water phase for 2 times, performing vacuum spin-drying to obtain 1.36kg of crude product, adding 0.5L of methanol, pulping, filtering and drying to obtain 436g of light yellow solid, namely the compound 113-D, wherein the purity is 93.89%, the yield is 50.0%, and an HPLC (high performance liquid chromatography) spectrum is shown in figure 6.
Example 16
Preparation of Cyclic Compound 113-D
1.0Kg of 113-C (purified by the method of the present invention) and 10Kg of HBr (48%) are added into a 50L reaction kettle, and the temperature is raised to an internal temperature of 120-125 ℃ for reaction for 20-24 h.
And (3) post-treatment: adding 10L water, adjusting pH to 12 with ammonia water, stirring, separating, extracting water phase for 2 times, vacuum drying to obtain 1.36kg crude product, adding 0.5L methanol, pulping, vacuum filtering, and drying to obtain 436g light yellow solidCompound 113-D, yield 50.0%, HPLC profile is shown in FIG. 7, 1 the H NMR spectrum is shown in FIG. 8.
Example 17
Preparation of 113-API
The compound 113-D prepared in example 15 was added to a 100ml three-necked flask, NMP (30g) was stirred at room temperature, bromoisoamylene was added, and NaHCO was added after most of the solid was dissolved 3 (2.7g), and the temperature was raised to 95 to 100 ℃ to react for 3 hours. And (4) finishing the reaction, and cooling the temperature of the reaction system to room temperature.
And (3) post-treatment: with about 4ml NH 3 ·H 2 O the pH of the reaction system was adjusted to 9 to 10, and then methyl t-butyl ether (50ml) and water (75ml) were added thereto, stirred for 10 to 15 minutes, and allowed to stand for liquid separation. The organic phase was washed with water (15ml x 2) and the layers were separated further. The organic phase was dried over anhydrous sodium sulfate, filtered and the solvent removed by rotary evaporation to give 6.3g of a viscous oil. 30ml of n-heptane was added to the viscous oil, and the mixture was slurried and filtered to obtain 4.05g of a cake. 3.58g of the cake was crystallized from 4 volumes of an 80% by weight ethanol solution to obtain 3.06g of crystals (yield 85.5%). And continuously crystallizing the crystals by using 10 volumes of acetone, performing secondary acetone recrystallization on the obtained acetone recrystallization product by using 10 volumes of acetone again, filtering out the solid obtained by secondary acetone recrystallization, and obtaining a compound 113-API, and sending the compound to an HPLC (high performance liquid chromatography) for detection, wherein an HPLC map 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 one impurity content exceeds the single impurity limit value of 0.1% and reaches 3.36%.
Example 18
This example operates the same as example 17, except that: compound 113-D the compound 113-D prepared in example 16 was used to obtain compound 113-API, which was subjected to HPLC assay, and the HPLC profile is shown in fig. 10, with a purity of 99.80% and a single impurity content of less than 0.1%, meeting the content requirement for a single impurity of API.
Claims (6)
1. A process for purifying a crude compound of formula 113-C, the process comprising:
wherein R is selected from pivaloyl, trifluoroacetyl, acetyl, dichloroacetyl, maleoyl and triphenylmethyl;
(11) carrying out amino protection reaction on the crude product of the compound 113-C and an amino protection reagent, and carrying out first post-treatment to obtain an N-protected compound;
(12) and (3) under the alkaline condition, removing the amino protecting group of the N-protected compound generated in the step (11), and carrying out second post-treatment to obtain purified 113-C.
2. The process of claim 1 for purifying the crude compound of formula 113-C, wherein in step (11), the amino protecting reagent is selected from pivaloyl chloride, trifluoroacetic anhydride.
3. The process of claim 1 for purifying a crude compound of formula 113-C, wherein in step (11), the amino protecting reagent in the amino protecting reaction is trifluoroacetic anhydride, and the molar ratio of crude compound 113-C to trifluoroacetic anhydride is 1:1.05-1.3 based on compound 113-C;
preferably, in step (11), the amino protection reaction is carried out at a temperature of-10 ℃ to-20 ℃.
4. The process of claim 1 for purifying the crude compound of formula 113-C, wherein in step (11), the first work-up comprises: pouring the reaction liquid obtained by the amino protection reaction into 10% sodium dihydrogen phosphate aqueous solution, stirring, washing the organic phase with 10% sodium dihydrogen phosphate aqueous solution, saturated sodium bicarbonate aqueous solution and saturated NaCl aqueous solution for one time, 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, performing suction filtration, washing a filter cake with isopropyl ether, and drying the filter cake to obtain the purified compound 113-Cp.
5. The process of claim 1 for purifying the crude compound of formula 113-C, wherein in step (12), the second work-up comprises: adding water and dichloromethane into a reaction system obtained after the deamination protection reaction is finished, stirring, separating liquid, extracting a water phase for 1 time by using dichloromethane, combining organic phases, sequentially washing for 1 time by using water and saturated sodium chloride, separating the organic phase, drying, filtering and concentrating in vacuum to obtain a 113-C purified crude product; adding isopropyl ether into the 113-C purified crude product, pulping, performing suction filtration, washing the filter cake with isopropyl ether, and drying the filter cake to obtain a 113-C pure product.
6. A process for the preparation of pentazocine intermediate 113-D, comprising the following synthetic route:
wherein R is selected from pivaloyl, trifluoroacetyl, acetyl, dichloroacetyl, maleoyl 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 carrying out first post-treatment to obtain an N-protected compound;
(22) under alkaline conditions, removing the amino protecting group of the N-protected compound generated in the step (11), and performing second post-treatment to obtain purified 113-C;
(23) adding 48% HBr solution into the purified 113C, and reacting at 120-125 ℃ to obtain a compound 113-D;
preferably, in step (21), the amino protecting reagent is selected from pivaloyl chloride, trifluoroacetic anhydride;
preferably, in step (11), the amino protecting reagent is trifluoroacetic anhydride, and the molar ratio of the crude compound 113-C to the trifluoroacetic anhydride is 1:1.05-1.3 based on the compound 113-C;
preferably, in step (11), the amino protection reaction is carried out at a temperature of-10 ℃ to-20 ℃;
preferably, in step (21), the first post-processing includes: pouring the reaction liquid obtained by the amino protection reaction into 10% sodium dihydrogen phosphate aqueous solution, stirring, washing the organic phase with 10% sodium dihydrogen phosphate aqueous solution, saturated sodium bicarbonate aqueous solution and saturated NaCl aqueous solution in turn, drying the organic phase, filtering, and concentrating the filtrate to obtain a crude product of 113-Cp; adding isopropyl ether into the 113-Cp crude product, pulping, performing suction filtration, washing a filter cake with isopropyl ether, and drying the filter cake to obtain a purified compound 113-Cp;
preferably, in step (12), the second post-processing includes: adding water and dichloromethane into a reaction system obtained after the deamination protection reaction is finished, stirring, separating liquid, extracting a water phase for 1 time by using dichloromethane, combining organic phases, sequentially washing for 1 time by using water and saturated sodium chloride, separating the organic phase, drying, filtering and concentrating in vacuum to obtain a 113-C purified crude product; adding isopropyl ether into the 113-C purified crude product, pulping, performing suction filtration, washing the filter cake with isopropyl ether, and drying the filter cake to obtain a 113-C pure product.
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