CN103172640A - Preparation method of (R)-N-bromine-methyl naltrexone and naltrexone derivatives - Google Patents
Preparation method of (R)-N-bromine-methyl naltrexone and naltrexone derivatives Download PDFInfo
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- CN103172640A CN103172640A CN2012105620726A CN201210562072A CN103172640A CN 103172640 A CN103172640 A CN 103172640A CN 2012105620726 A CN2012105620726 A CN 2012105620726A CN 201210562072 A CN201210562072 A CN 201210562072A CN 103172640 A CN103172640 A CN 103172640A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical class N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 title claims abstract description 16
- 229960002921 methylnaltrexone Drugs 0.000 title abstract description 7
- AXFDDKKRVFMVHY-OFAZKWMESA-N (4r,4as,7s,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxyspiro[2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7,5'-imidazolidine]-2',4'-dione Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC[C@]25C(NC(=O)N2)=O)O)CC1)O)CC1CC1 AXFDDKKRVFMVHY-OFAZKWMESA-N 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 229960003086 naltrexone Drugs 0.000 claims abstract description 20
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical group [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims abstract description 14
- 238000005349 anion exchange Methods 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 13
- -1 halogen anion Chemical class 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 150000007530 organic bases Chemical class 0.000 claims description 8
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 7
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 150000001450 anions Chemical class 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 239000003957 anion exchange resin Substances 0.000 claims description 4
- 150000002891 organic anions Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000011987 methylation Effects 0.000 abstract description 5
- 238000007069 methylation reaction Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 30
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 12
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- JVLBPIPGETUEET-WIXLDOGYSA-O (3r,4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one Chemical compound C([N@+]1(C)[C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)C1CC1 JVLBPIPGETUEET-WIXLDOGYSA-O 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 150000001793 charged compounds Chemical class 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229940005483 opioid analgesics Drugs 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940102396 methyl bromide Drugs 0.000 description 3
- 239000012022 methylating agents Substances 0.000 description 3
- 238000004611 spectroscopical analysis Methods 0.000 description 3
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010010774 Constipation Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 2
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 206010013954 Dysphoria Diseases 0.000 description 1
- 206010021518 Impaired gastric emptying Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010046555 Urinary retention Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000030135 gastric motility Effects 0.000 description 1
- 230000007160 gastrointestinal dysfunction Effects 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000008991 intestinal motility Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930013053 morphinan alkaloid Natural products 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
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- 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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of (R)-N-bromine-methyl naltrexone. The preparation method adopting naltrexone as the raw material comprises the following steps of: protecting 3-phenolic hydroxyl by adopting an organic silicon group to obtain a first naltrexone derivative; reacting the first naltrexone derivative with a methylation reagent CH3X to obtain a second naltrexone derivative; and removing the phenolic hydroxyl protective group from the second naltrexone derivative, and carrying out bromine anion exchange while necessary to obtain a target product. The invention further provides the two naltrexone derivatives related in the preparation method. The preparation method provided by the invention is high in directional rate and purity, less in steps, simple to operate, gentle in reaction conditions, low in device requirements and convenient to realize industrial production.
Description
Technical Field
The present invention relates to a process for the preparation of (R) -N-bromomethylnaltrexone and to naltrexone derivatives which are intermediates for the preparation.
Background
Methylnaltrexone (MNTX), a quaternary ammonium derivative of the pure opioid antagonist naltrexone, has greater polarity and less lipid solubility than naltrexone due to the addition of the methyl group. This feature makes MNTX more difficult to cross the blood brain barrier, it acts more on the periphery than the central nerve, with the advantage of not countering the analgesic effect of opioids on the central nervous system.
MNTX is a chiral molecule with a chiral center, quaternary ammonium nitrogen, having both R and S configurations. Us patents 4176186, 4719215, 4861781, 5102887, 5972954, 6274591, 6559158 and 6608075, chinese patents 200480009190.8, 2004800009191.2, 200680008123.3, 200680022957.X, etc. are described. R-type isomer (R) -N-bromomethylnaltrexone (code number is R-MNTX), and the structure of the R-type isomer is shown as the formula (I):
R-MNTX has the characteristic of reducing the side effects of opioids without reducing the analgesic effect of opioids, including nausea, vomiting, dysphoria, urinary retention, slow intestinal motility, constipation, slow gastric motility, and delayed gastric emptying, among others. In addition, R-MNTX can reduce not only side effects from opioid analgesic therapy, but also side effects mediated by endogenous opioids alone, including inhibition of gastrointestinal motility, post-operative gastrointestinal dysfunction, idiopathic constipation, and other conditions.
WO2004043964a2 discloses the reaction of naltrexone starting material with methyl bromide in various organic base solvents. Quaternization of naltrexone at the 17-position yields bromomethylnaltrexone, i.e., MNTX. But the problem of chiral orientation of the reaction is not mentioned.
In view of the literature (Funke, de Graaf, j. chem. soc., Perkins trans. ii, 1985.385), studies have shown that the stereoselective formation of the R configuration by 17-N methylation of morphinan alkaloids is associated with steric hindrance at the 3-position. WO2006127899A2 uses isobutyryl to protect the phenolic hydroxyl group at the 3-position and increase the steric hindrance at the 3-position, so as to directionally synthesize R-MNTX. The reaction process is as follows:
the method uses isobutyryl to increase the steric hindrance of the 3-position, thereby realizing the directional reaction of the N methylation of the 17-position. But the yield of the ester formed by isobutyryl chloride and 3-phenolic hydroxyl in the route is not high, only 76.8 percent, and the post-treatment needs column chromatography purification. When methyl iodide is methylated, the orientation rate of methyl iodide can be ensured only by pressurizing and heating, the requirement on equipment is high, and column chromatography purification is also needed for post-treatment. The orientation rate is not very high, and the de value of the final product is lower than 95 percent. As the multi-step of the route requires column chromatography purification, the methylation operation has high requirements on reaction equipment, and large-scale industrial production is difficult to realize.
Chinese patent CN200810069852.0 discloses another synthetic route:
the route begins with the protection of the carbonyl group at the 6-position with ethylene glycol, followed by the protection of the phenolic hydroxyl group at the 3-position, followed by methylation of the nitrogen at the 17-position. The reaction yield of the route is high, but the problem of chiral orientation rate is not mentioned.
Disclosure of Invention
Therefore, the invention aims to provide a preparation method of (R) -N-bromomethylnaltrexone and a naltrexone derivative.
The purpose of the invention is realized by the following technical scheme.
The invention provides a preparation method of (R) -N-bromomethylnaltrexone, which comprises the following steps:
(1) reacting naltrexone shown in a formula (IV) with a compound shown in a formula R-Hal in the presence of organic base to obtain a first naltrexone derivative shown in a formula (II);
in the formula (II), R is an organosilicon group, preferably tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl or 2- (trimethylsilyl) ethoxymethyl, more preferably 2- (trimethylsilyl) ethoxymethyl;
in the formula R-Hal, R is defined as the same as R in the formula (II), and Hal represents halogen;
(2) reacting said first naltrexone derivative with CH3X reacts to obtain a second naltrexone derivative shown in a formula (III);
in the formula (III), X-Is an anion, preferably a halogen anion or an organic anion, more preferably a halogen anion. Suitable halide anions are selected from Br-、I-、Cl-Or F-Preferably Br-Or I-。
The CH3X is a methylating agent, wherein X is as defined for X in formula (III).
Preferably, the CH3X is methyl iodide or methyl bromide.
(3) Removing the group R from the second naltrexone derivative under acidic conditions; wherein,
when X in step (2)-Is Br-Then, removing a group R on the second naltrexone derivative to obtain a target product (R) -N-bromomethyl naltrexone shown in the formula (I);
when X in step (2)-Is Br-When other anions are contained, the method further comprises the step (4): and (3) removing the group R on the second naltrexone derivative, and then carrying out bromine anion exchange to obtain a target product (R) -N-bromomethyl naltrexone shown in the formula (I).
According to the preparation method provided by the invention, the organic base in the step (1) is an organic amine reagent. The organic amine reagent is preferably one or more of pyridine, dimethylaminopyridine, pyrrole, triethylamine and diisopropylethylamine.
According to the preparation method provided by the invention, the reaction in the step (1) can be carried out in an organic solvent, and a suitable organic solvent comprises dichloromethane and/or benzene. Furthermore, it is also possible to carry out the reaction directly in an excess of organic base reagent.
According to the preparation method provided by the invention, the first naltrexone derivative prepared from naltrexone in the step (1) can react under a wide range of temperature conditions, and the suitable reaction temperature is preferably 0-150 ℃, and more preferably 20-60 ℃.
The production method provided according to the present invention, wherein the reaction in the step (2) may be carried out in a solvent, and suitable solvents are aprotic polar solvents such as acetone or N, N-dimethylformamide; it is also possible to carry out the reaction directly in an excess of methylating agent. For example, when the methylating agent is methyl iodide, an excess amount of methyl iodide is added to the first naltrexone derivative to effect reaction.
According to the preparation method provided by the invention, the reaction in the step (2) is carried out under the heating condition, and the reaction temperature is preferably 30-90 ℃, and more preferably 40-80 ℃.
According to the preparation method provided by the invention, the acidic condition in the step (3) is carried out in a mixed solution of diluted hydrobromic acid and methanol.
According to the preparation method provided by the invention, the reaction temperature in the step (3) is 50-80 ℃, and more preferably 60-70 ℃.
According to the preparation method provided by the invention, the step (4) comprises the following steps: bromine anion exchange is carried out in a strongly basic bromine-bearing anion exchange resin column.
As a preferred scheme, the invention provides a specific preparation method of (R) -N-bromomethylnaltrexone, comprising the following steps:
(1) reacting naltrexone shown in formula (IV) with RCl in the presence of organic base and dichloromethane to obtain a first naltrexone derivative shown in formula (II);
the organic base is dimethylaminopyridine, triethylamine or a mixture thereof;
r in the formulas (II) and RCl is 2- (trimethylsilyl) ethoxymethyl;
(2) reacting said first naltrexone derivative with an excess of CH3X reacts at 40-80 ℃ to prepare a second naltrexone derivative shown in a formula (III);
the CH3X is methyl iodide or methyl bromide;
x in the formula (III)-Is corresponding to I-Or Br-；
(3) Removing a group R on the disodium kojic ketone derivative under an acidic condition at 60-70 ℃; wherein,
when X in step (2)-Is Br-Then, directly obtaining a target product (R) -N-bromomethyl naltrexone shown in the formula (I) after removing a group R on the second naltrexone derivative;
when X in step (2)-Is I-When the method further comprises the step (4): and (3) removing the group R on the second naltrexone derivative, and then carrying out bromine anion exchange to obtain a target product (R) -N-bromomethyl naltrexone shown in the formula (I).
Preferably, the reaction temperature of the step (1) is 20-60 ℃, and more preferably room temperature.
Preferably, the reaction temperature in the step (2) is 40-80 ℃, and more preferably 40-45 ℃.
Preferably, the reaction temperature of the step (3) is 60-70 ℃.
The invention also provides two naltrexone derivatives as intermediate compounds involved in the preparation of (R) -N-bromomethylnaltrexone. In particular, the amount of the solvent to be used,
a naltrexone derivative having the structural formula shown in formula (II):
in the formula (II), R is an organosilicon group, preferably tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl or 2- (trimethylsilyl) ethoxymethyl, more preferably 2- (trimethylsilyl) ethoxymethyl.
Specifically, when R is 2- (trimethylsilyl) ethoxymethyl, the naltrexone derivative is 3- [ [2- (trimethylsilyl) ethoxymethyl ] oxy ] -4,5 α -epoxy-14-hydroxy-17-cyclopropylmethyl-6-one morphinan.
A methylnaltrexone derivative having the structural formula shown in formula (III):
in the formula (III), R is an organosilicon group, preferably tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl or 2- (trimethylsilyl) ethoxymethyl, and more preferably 2- (trimethylsilyl) ethoxymethyl.
X-Is an anion, preferably a halogen anion or an organic anion, more preferably a halogen anion. Suitable halide anions are selected from Br-、I-、Cl-Or F-Preferably Br-Or I-。
Specifically, when R is 2- (trimethylsilyl) ethoxymethyl, X-Is I-When the methylnaltrexone derivative is R-17, 17-cyclopropylmethyl, methyl-3- [ [2- (trimethylsilyl) ethoxymethyl]Oxy radical]-4,5 α -epoxy-14-hydroxy-6-keto morphinan iodide.
According to the preparation method of (R) -N-bromomethyl naltrexone provided by the invention, a group with larger steric hindrance is selected in the protection of 3-position phenolic hydroxyl, such as 2- (trimethylsilyl) ethoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl, and the orientation rate is high and can reach 99.5%; the increase of reaction specificity greatly improves the purity and yield of the product, and the total yield of the preparation method is improved to more than 60 percent from less than 40 percent of the method of WO2006127899A2 and the de value of the final product is higher than 99.8 percent based on the raw material naltrexone, so that the post-treatment purification process of the preparation method is greatly simplified, and the industrial production is convenient to realize. In addition, the preparation method provided by the invention avoids the protection of 6-carbonyl and the deprotection step, has the advantages of few steps, simple and convenient operation, high yield, mild reaction conditions and lower equipment requirements, and is more convenient for realizing industrial production.
Drawings
Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of R-MNTX prepared by the invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of R-MNTX prepared by the invention;
fig. 3 is a high performance liquid chromatogram of R-MNTX prepared in the present invention.
Detailed Description
The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.
High performance liquid chromatography conditions for the product R-MNTX of the invention reference is made to the method for detecting R-MNTX and S-MNTX disclosed in WO2006127899A2, and the high performance liquid chromatography conditions of the general gradient are used.
The de value (i.e., the diastereomer excess percentage) of the prepared sample according to the present invention is calculated by (R configuration peak area-S configuration peak area)/(R configuration peak area + S configuration peak area) in the liquid chromatogram. The HPLC instrument detector used was Warters2487 and the workstation was Labliance.
Example 1: preparation of the first naltrexone derivative
This example illustrates 3- [ [2- (trimethylsilyl) ethoxymethyl ] oxy ] -4,5 α -epoxy-14-hydroxy-17-cyclopropylmethyl-6-one morphinan and its preparation.
(1) Dissolving 11 g (32 mmol) of naltrexone (17- (cyclopropylmethyl) -4,5 alpha-epoxy-3, 14-dihydroxy-6-oxomorphinan) in 70 ml of dichloromethane, sequentially adding 5.6 g (34 mmol) of 2- (trimethylsilyl) ethoxymethyl chloride (SEMCl), 100 mg of Dimethylaminopyridine (DMAP) and 7 ml of triethylamine to the solution, and stirring at room temperature until the reaction is completed;
(2) pouring the reaction solution obtained in the step (1) into 100 ml of saturated sodium bicarbonate aqueous solution, stirring for 5 minutes, standing for layering, separating an upper water layer, and extracting the water layer by using 50 ml of dichloromethane;
(3) the dichloromethane layers in step (2) were combined, washed with 100 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and finally the solvent was evaporated under reduced pressure, and the residue was recrystallized by adding anhydrous ethanol to obtain 14.5 g of a white solid with a yield of 95.4%.
Nuclear magnetic resonance Hydrogen Spectroscopy (abbreviation) of the white solid obtained in this example1H-NMR) data were as follows: δ 0.02(s,9H), 0.30(m,4H), 0.45(m,1H), 0.79(m,2H), 1.75(m,2H), 1.91(m,2H), 2.20-2.35(m,6H), 2.80(m,1H), 3.04(m,2H), 3.40(t,2H), 4.79(s,1H), 6.02(s,2H), 6.33-6.46(q,2H), 9.04(s, 1H). Wherein, the above1H-NMR data were obtained using deuterated dimethyl sulfoxide (abbreviated as DMSO-d 6) as a solvent.
In the mass spectrum data of the white solid, the mass-to-charge ratio (M + H)/Z of the molecular ion peak was 472.24.
Nuclear magnetic resonance carbon spectrum of the white solid (i.e. nuclear magnetic resonance carbon spectrum of the white solid13C-NMR) data were as follows: 0.3,2.1,7.5, 16.9, 21.0, 27.5, 28.1, 29.0, 46.2, 48.5, 61.2, 61.4, 66.4, 80.3, 89.2, 98.5, 111.4, 120.5, 129.0, 133.6, 140.9, 144.5, 208.2.
From the above data, the white solid was 3- [ [2- (trimethylsilyl) ethoxymethyl ] oxy ] -4,5 α -epoxy-14-hydroxy-17-cyclopropylmethyl-6-one morphinan.
Example 2: preparation of the second naltrexone derivative
This example illustrates R-17, 17-cyclopropylmethyl, methyl-3- [ [2- (trimethylsilyl) ethoxymethyl ] oxy ] -4,5 α -epoxy-14-hydroxy-6-one morphinan iodide and the process for its preparation.
To 10 g (i.e., 21.2 mmol) of 3- [ [2- (trimethylsilyl) ethoxymethyl ] oxy ] -4,5 α -epoxy-14-hydroxy-17-cyclopropylmethyl-6-one morphinan was added 20 ml of methyl iodide, stirred well, and heated to 42 ℃ for reaction for 16 hours. Finally, the excess methyl iodide was distilled off under reduced pressure (wherein the methyl iodide was recovered for reuse) to give 13 g of a yellow powdery solid with a yield of 99.9%.
Nuclear magnetic resonance Hydrogen Spectroscopy (abbreviated as "NMR") of the yellow powdery solid obtained in this example1H-NMR) data were as follows: δ 0.02(s,9H), 0.30(m,4H), 0.79(m,2H), 0.84(m,1H), 1.91(m,2H), 1.98(m,2H), 2.22(m,2H), 3.20(m,2H), 3.24(t,2H), 3.30(m,3H), 3.40(t,2H), 3.75(m,1H), 4.79(s,1H), 6.02(s,2H), 6.33-6.46(q,2H), 9.04(s, 1H). Wherein, the above1H-NMR data were obtained using deuterated dimethyl sulfoxide (abbreviated as DMSO-d 6) as a solvent.
The mass spectrum data of the yellow powdery solid shows the mass-to-charge ratio M of molecular ion peaks+Is 486.3.
Nuclear magnetic resonance carbon spectrum of the yellow powdery solid (i.e.13C-NMR) data were as follows: 0.3,1.2,2.9, 16.9, 21.0, 21.8, 28.3, 29.0, 43.7, 53.0, 59.3, 61.2, 71.0, 80.3, 85.5, 89.6, 98.5, 111.4, 120.5, 129.0, 133.6, 140.9, 144.5, 208.2.
From the above data, the yellow powdered solid was R-17, 17-cyclopropylmethyl, methyl-3- [ [2- (trimethylsilyl) ethoxymethyl ] oxy ] -4,5 α -epoxy-14-hydroxy-6-one morphinan iodide.
Example 3
This example illustrates R-17, 17-cyclopropylmethyl, methyl-3-hydroxy-4, 5 α -epoxy-14-hydroxy-6-one morphinan iodide/bromide and its preparation.
To 10 g (i.e., 16.3 mmol) of R-17, 17-cyclopropylmethyl, methyl-3- [ [2- (trimethylsilyl) ethoxymethyl ] oxy ] -4,5 α -epoxy-14-hydroxy-6-one morphinan iodide was added 70 ml of methanol, dissolved with stirring and purged with nitrogen. And (3) dropwise adding 50 ml of 6% hydrobromic acid aqueous solution at room temperature, heating to 60-70 ℃ after adding, and stirring for reacting for 5 hours. The reaction was concentrated under reduced pressure to give 6.8 g of a pale yellow solid.
Example 4
This example illustrates R-17, 17-cyclopropylmethyl, methyl-3-hydroxy-4, 5 α -epoxy-14-hydroxy-6-one morphinan bromide and its preparation.
To 6.8 g of the pale yellow solid of R-17, 17-cyclopropylmethyl, methyl-3-hydroxy-4, 5 α -epoxy-14-hydroxy-6-one morphinan iodide/bromide obtained in example 3 was added 40 ml of distilled water for dissolution. The resulting solution was passed through a strongly basic bromide-loaded anion exchange resin column, eluted with distilled water, and about 200 ml of the eluate was collected.
The eluate was concentrated under reduced pressure, and then 20 ml of methanol was added to the residue, cooled to crystallize, and filtered to obtain white crystals. To the white crystals was added 35 ml of 95% ethanol for recrystallization, 5.2 g of white powdery solid, and the yield of example 3 and example 4 was 73.1%.
The obtained white powdery solid was analyzed by nuclear magnetic resonance, and the results are shown in fig. 1 and 2. As can be seen from fig. 1 and 2, the white powdery solid is R-MNTX product. The purity of the R-MNTX product was analyzed by high performance liquid chromatography. The HPLC profile is shown in FIG. 3, and the data are detailed in Table 1.
From the results, it can be seen that the HPLC purity was 99.91%, the S-isomer of (R) -N-bromomethylnaltrexone was hardly detected in the product, and the minimum detection limit under the HPLC conditions was 0.02%, the content of the S-isomer was less than the minimum detection limit of 0.02%, and the de value of the sample was higher than (99.91% -0.02%)/(99.91% + 0.02%) =99.96%, i.e., higher than 99.96%, according to the calculation method of the de value.
TABLE 1 HPLC DATA OF R-MNTX
| Serial number | Retention time | Concentration of | Peak area | Degree of peak separation | Number of |
| 1 | 6.913 | 0.04695 | 2414 | 26.23 | 8197 |
| 2 | 16.518 | 99.91 | 5137631 | 11.57 | 25256 |
| 3 | 21.339 | 0.04986 | 2564 | 6.69 | 44540 |
| Total of | - | 100 | 5142609 | - | - |
Example 5: preparation of the first naltrexone derivative
This example illustrates 3- [ [ tert-butyldiphenylsilyl ] oxy ] -4,5 α -epoxy-14-hydroxy-17-cyclopropylmethyl-6-one morphinan and its preparation.
(1) Dissolving 20 g (58.6 mmol) of naltrexone (i.e. 17- (cyclopropylmethyl) -4,5 alpha-epoxy-3, 14-dihydroxy-6-oxomorphinan) in 100 ml of dichloromethane, sequentially adding 16.5 g (60.0 mmol) of tert-butyldiphenylsilyl chloride (TBDPSCl), 190 mg of Dimethylaminopyridine (DMAP) and 13 ml of triethylamine to the solution, and stirring at room temperature to react completely;
(2) pouring the reaction solution obtained in the step (1) into 200 ml of saturated sodium bicarbonate aqueous solution, stirring for 5 minutes, standing for layering, separating an upper water layer, and extracting the water layer by using 100 ml of dichloromethane;
(3) the dichloromethane layers in step (2) were combined, washed with 200 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and finally the solvent was evaporated under reduced pressure, and the residue was recrystallized by adding anhydrous ethanol to obtain 30.8 g of a white solid with a yield of 90.7%.
Nuclear magnetic resonance Hydrogen Spectroscopy (abbreviation) of the white solid obtained in this example1H-NMR) data were as follows: δ 0.08 to 0.30(m,4H), 0.45(m,1H), 0.98(s,9H), 1.75(m,2H), 1.91(m,2H), 2.20 to 2.35(m,6H), 2.80(m,1H), 3.04(q,2H), 3.40(t,2H), 4.79(s,1H), 6.29 to 6.31(m,2H), 7.36(m,6H), 7.54(m,4H), 9.22(s, 1H). Wherein, the above1H-NMR data were obtained using deuterated dimethyl sulfoxide (abbreviated as DMSO-d 6) as a solvent.
In the mass spectrum data of the white solid, the mass-to-charge ratio (M + H)/Z of the molecular ion peak was 580.3.
Nuclear magnetic resonance carbon spectrum of the white solid (i.e. nuclear magnetic resonance carbon spectrum of the white solid13C-NMR) data were as follows: 2.1,7.5, 14.1, 20.5, 21.0, 27.5, 28.1, 29.0, 46.2, 48.5, 61.2, 61.4, 66.4, 80.3, 89.6, 113.0, 120.9, 128.1, 129.3, 129.8, 133.0, 134.0, 135.8, 139.8, 142.5, 208.2.
From the above data, the white solid was 3- [ [ tert-butyldiphenylsilyl ] oxy ] -4,5 α -epoxy-14-hydroxy-17-cyclopropylmethyl-6-one morphinan.
Example 6: preparation of the second naltrexone derivative
This example illustrates R-17, 17-cyclopropylmethyl, methyl-3- [ [ tert-butyldiphenylsilyl ] oxy ] -4,5 α -epoxy-14-hydroxy-6-one morphinan iodide and its preparation.
To 25 g (i.e., 43.1 mmol) of 3- [ [ tert-butyldiphenylsilyl ] oxy ] -4,5 α -epoxy-14-hydroxy-17-cyclopropylmethyl-6-one morphinan was added 40 ml of methyl iodide, stirred well, and heated to 45 ℃ for reaction for 18 hours. Finally, excess methyl iodide was distilled off under reduced pressure (methyl iodide was recovered for reuse) to obtain 29.7 g of pale yellow powdery solid with a yield of 95.4%.
Core of the yellow powdery solid obtained in this exampleMagnetic resonance hydrogen spectrum (abbreviation)1H-NMR) data were as follows: δ 0.08 to 0.30(m,4H), 0.84(m,1H), 0.98(s,9H), 1.91 to 2.10(m,4H), 2.22(m,2H), 3.20(m,2H), 3.25(m,2H), 3.30(m,3H), 3.75(t,1H), 4.79(s,1H), 6.29 to 6.31(m,2H), 7.36(m,6H), 7.54(m,4H), 9.08(s, 1H). Wherein, the above1H-NMR data were obtained using deuterated dimethyl sulfoxide (abbreviated as DMSO-d 6) as a solvent.
The mass spectrum data of the yellow powdery solid shows the mass-to-charge ratio M of molecular ion peaks+Is 594.3.
Nuclear magnetic resonance carbon spectrum of the yellow powdery solid (i.e.13C-NMR) data were as follows: 1.2,2.9, 14.1, 20.5, 21.0, 21.8, 28.3, 29.0, 43.7, 53.0, 59.3, 71.0, 80.3, 85.5, 89.6, 113.0, 120.9, 128.1, 129.3, 129.8, 133.0, 134.0, 135.8, 139.8, 142.5, 208.2.
From the above data, the yellow powdery solid is R-17, 17-cyclopropylmethyl, methyl-3- [ [ tert-butyldiphenylsilyl ] oxy ] -4,5 α -epoxy-14-hydroxy-6-one morphinanium iodide.
Example 7
This example illustrates R-17, 17-cyclopropylmethyl, methyl-3-hydroxy-4, 5 α -epoxy-14-hydroxy-6-one morphinan iodide/bromide and its preparation.
To 25 g (i.e., 34.6 mmol) of R-17, 17-cyclopropylmethyl, methyl-3- [ [ tert-butyldiphenylsilyl ] oxy ] -4,5 α -epoxy-14-hydroxy-6-one morphinan iodide was added 150 ml of methanol, dissolved with stirring, and then purged with nitrogen. And (3) dropwise adding 100 ml of 8% hydrobromic acid aqueous solution at room temperature, heating to 60-70 ℃ after adding, and stirring for reacting for 5 hours. The reaction was concentrated under reduced pressure to give 17.8 g of a pale yellow solid.
Example 8
This example illustrates R-17, 17-cyclopropylmethyl, methyl-3-hydroxy-4, 5 α -epoxy-14-hydroxy-6-one morphinan bromide and its preparation.
To 17.8 g of the pale yellow solid of R-17, 17-cyclopropylmethyl, methyl-3-hydroxy-4, 5 α -epoxy-14-hydroxy-6-one morphinan iodide/bromide obtained in example 7 was added 100 ml of distilled water for dissolution. The resulting solution was applied to a strongly basic bromide-loaded anion exchange resin column, eluted with distilled water, and about 500 ml of the eluate was collected.
The eluate was concentrated under reduced pressure, and then 40 ml of methanol was added to the residue, cooled to crystallize, and filtered to obtain white crystals. 70 ml of 95% ethanol was added to the white crystals for recrystallization to give 10.4 g of a white powdery solid, and the combined yield of the two steps of example 7 and example 8 was 68.8%.
Claims (9)
1. A method for preparing (R) -N-bromomethylnaltrexone, comprising the steps of:
(1) reacting naltrexone shown in a formula (IV) with a compound shown in a formula R-Hal in the presence of organic base to obtain a first naltrexone derivative shown in a formula (II);
in the formula (II), R is an organosilicon group, preferably tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl or 2- (trimethylsilyl) ethoxymethyl, more preferably 2- (trimethylsilyl) ethoxymethyl;
in the formula R-Hal, R is defined as the same as R in the formula (II), and Hal represents halogen;
(2) reacting said first naltrexone derivative with CH3X reacts to obtain a second naltrexone derivative shown in a formula (III);
in the formula (III), X-Is an anion, preferably a halogen anion or an organic anion, more preferably a halogen anion, and further preferably Br-Or I-；
The CH3X in X is as defined for X in formula (III);
(3) removing the group R from the second naltrexone derivative under acidic conditions; wherein,
when X in step (2)-Is Br-Then, removing a group R on the second naltrexone derivative to obtain a target product (R) -N-bromomethyl naltrexone shown in the formula (I);
when X in step (2)-Is Br-When other anions are contained, the method further comprises the step (4): and (3) removing the group R on the second naltrexone derivative, and then carrying out bromine anion exchange to obtain a target product (R) -N-bromomethyl naltrexone shown in the formula (I).
2. The preparation method according to claim 1, wherein the organic base in step (1) is an organic amine reagent, preferably one or more of pyridine, dimethylaminopyridine, pyrrole, triethylamine and diisopropylethylamine.
3. The production method according to claim 1 or 2, wherein the reaction in the step (1) is carried out in an organic solvent; preferably, the organic solvent comprises dichloromethane and/or benzene.
4. The production method according to any one of claims 1 to 3, wherein the reaction temperature of the step (1) is 0 to 150 ℃, preferably 20 to 60 ℃.
5. The production method according to any one of claims 1 to 4, wherein the reaction temperature in the step (2) is 30 to 90 ℃, preferably 40 to 80 ℃.
6. The production method according to any one of claims 1 to 5, wherein the acidic condition in the step (3) is carried out in a mixed solution of dilute hydrobromic acid and methanol;
preferably, the reaction temperature is 50-80 ℃, and preferably 60-70 ℃.
7. The production method according to any one of claims 1 to 6, wherein the step (4) includes: bromine anion exchange is carried out in a strongly basic bromine-bearing anion exchange resin column.
8. A naltrexone derivative having the structural formula shown in formula (II):
in the formula (II), R is an organosilicon group, preferably tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl or 2- (trimethylsilyl) ethoxymethyl, more preferably 2- (trimethylsilyl) ethoxymethyl.
9. A naltrexone derivative having the structural formula shown in formula (III):
in the formula (III), R is an organosilicon group, preferably tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl or 2- (trimethylsilyl) ethoxymethyl, and more preferably 2- (trimethylsilyl) ethoxymethyl;
X-is an anion, preferably a halogen anion or an organic anion, more preferably a halogen anion, and further preferably Br-Or I-。
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