CN115716799A - Method for preparing cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof by reduction of organic borohydride metal reagent - Google Patents
Method for preparing cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof by reduction of organic borohydride metal reagent Download PDFInfo
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- CN115716799A CN115716799A CN202211456218.9A CN202211456218A CN115716799A CN 115716799 A CN115716799 A CN 115716799A CN 202211456218 A CN202211456218 A CN 202211456218A CN 115716799 A CN115716799 A CN 115716799A
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- 230000009467 reduction Effects 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 10
- 239000011737 fluorine Substances 0.000 claims abstract description 8
- 229910052796 boron Inorganic materials 0.000 claims abstract description 4
- -1 aryl boron Chemical compound 0.000 claims description 23
- 238000006722 reduction reaction Methods 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 4
- CJXGPJZUDUOZDX-UHFFFAOYSA-N fluoromethanone Chemical group F[C]=O CJXGPJZUDUOZDX-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 238000006197 hydroboration reaction Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims 4
- 238000006243 chemical reaction Methods 0.000 abstract description 12
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 11
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 4
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052799 carbon Inorganic materials 0.000 abstract description 3
- 125000004429 atom Chemical group 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 230000007613 environmental effect Effects 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 15
- 229940079593 drug Drugs 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000011161 development Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000002547 new drug Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- BZSUXEBLJMWFSV-UHFFFAOYSA-N 3-fluoropiperidin-4-ol Chemical compound OC1CCNCC1F BZSUXEBLJMWFSV-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
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- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
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- 230000002503 metabolic effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000003053 piperidines Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
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- 230000019491 signal transduction Effects 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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 discloses a method for preparing cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof shown in (I) by reduction of an organic boron hydrogenation metal reagent, chiral fluorine carbonyl or a dihydroxy compound is used as a raw material to generate the cis-chiral-3-fluoro-4-hydroxypiperidine and the derivatives thereof by reduction, and the stereoselectivity of carbon where fluorine atoms are located is maintained in the reaction process. The method has good yield, simple operation and easy treatment. Has better cis-selectivity and single product (cis-form is more than 97 percent), thereby having easy purification, more atom economy of the whole reaction and more environmental protection.
Description
Technical Field
The invention relates to the field of preparation of fluorine-containing piperidine structures, in particular to a method for preparing cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof by reduction of an organic boron hydrogenation metal reagent.
Background
Because fluorine is the element with the strongest electronegativity, the required hydrogen bond action is provided in the action process of the drug molecules and biological targets, so that the combination degree of the drug molecules and the targets is improved, and the activity of the drug is improved; because the strong fluorocarbon bond causes the difficulty of breaking the fluorocarbon bond, the introduction of fluorine atoms into drug molecules can often improve the metabolic stability of the drug; the strong electron withdrawing effect of fluorine atoms changes the distribution of electron density in molecules, influences the acid-base property of compounds, further changes the activity and bioavailability of drug molecules, and the introduction of fluorine atoms can change the fat solubility of the drug molecules and further influence the absorption of the drug molecules in human bodies; in addition, the introduction of fluorine atoms can change the selective recognition of drug molecules to targets; the conformation of the molecule can also be altered, etc. Therefore, the introduction of fluorine atoms into drug molecules is a powerful means in the development of new drugs. (refer to "fluorine-containing drugs", xiaogechang, lushoufu, linjinghong, chemical Press, publication time: 2022, 04/01/s; CIP approval No. 2021257632: ISBN 978-7-122-40413-8).
The piperidine structure is a very important intermediate in the research and development of new drugs, and the structure is contained in a plurality of drugs. In consideration of the special role of fluorine atoms in drug molecules, introduction of fluorine atoms and fluorine-containing groups into piperidine molecules for development of new drugs is a new strategy.
The molecule shown as the formula (1) is a novel ErbB family receptor, especially an inhibitor of HER2 receptor, developed by the Dichen pharmaceutical industry. The chiral 3-fluoro-4-hydroxypiperidine segment in the structure is an important component. Studies have shown that aberrant signaling of ErbB family members plays an important role in the development of a variety of malignancies. Molecularly targeted drugs directed against these signaling pathways have shown strong clinical efficacy. The molecules may play a role in the treatment of various cancers including breast cancer, gastric cancer, esophageal cancer and the like.
Through literature search, the synthesized fluorine substituted piperidine structure, especially the chiral product obtained by a chemical method, also has very wide application in drug molecules.
However, the prior method for synthesizing cis-chiral-3-fluoro-4-hydroxypiperidine is mainly prepared by a chiral chromatographic resolution method, and the chromatographic separation method has the advantages of high separation speed, high separation efficiency and simple operation, and particularly has good selectivity. However, the chromatographic separation is expensive, and the large-scale production cannot be performed due to the restriction of the separation equipment, and the application in industrial production is relatively small.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a method for preparing cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof by reducing an organic boron hydrogenation metal reagent.
The method is suitable for chiral substrates, and the configuration of the chiral carbon atom where the fluorine atom is located is maintained in the reaction process.
The method has the advantages of mild reaction conditions, convenient operation, good yield, high cis-form selectivity and suitability for industrial mass production.
In order to realize the purpose of the invention, the adopted technical scheme is as follows:
the method for preparing the cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof by reducing an organic hydroboration metal reagent comprises the following steps:
starting from a chiral fluorocarbonyl or dihydroxy compound shown as a structural formula (II);
cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof shown in a structural formula (I) are obtained by cis-reduction of carbonyl or dihydroxy;
wherein R is hydrogen, C 1 -C 9 Alkyl, aryl, benzyl, CF 3 CO、R 2 CO or R 3 Any one or more of OCO;
R 2 is C 1 -C 9 Any one or more of alkyl, aryl or benzyl,
R 3 is C 1 -C 9 Any one or more of alkyl, aryl or benzyl;
the R group is optionally unsubstituted or substituted with one or more substituents including those consisting of alkyl, hydroxyalkyl, alkoxy or hydroxy;
the cis-chiral-3-fluoro-4-hydroxypiperidine and the derivatives thereof are cis-chiral-3-fluoro-4-hydroxypiperidine and the derivatives thereof with chiral structures or achiral structures;
the cis-form reduction is specifically that under the action of a reducing agent, a fluorine carbonyl or dihydroxy compound shown in a structural formula (II) undergoes a reduction reaction at 0-150 ℃ in an organic solvent to obtain cis-form chiral-3-fluorine-4-hydroxypiperidine shown in a structural formula (I) and derivatives thereof;
the reducing agent is an organoboron hydrogenation metal reagent.
In a preferred embodiment of the present invention, the reducing agent is any one of lithium triethylborohydride, lithium tri-sec-butylborohydride, lithium tripentyl borohydride, sodium tri-sec-butylborohydride, sodium tri (1-pyrazolyl) borohydride, potassium triethylborohydride, potassium tri-sec-butylborohydride, potassium tripyrazolyl borohydride or potassium triphenyl borohydride. Most preferred is lithium triethylborohydride or lithium tri-sec-butylborohydride.
In a preferred embodiment of the present invention, the reducing agent is used in an equivalent amount of 1.0 to 3.0 equivalents relative to the starting fluorocarbonyl or bishydroxy compound of formula (II).
In a preferred embodiment of the present invention, the organic solvent is anhydrous tetrahydrofuran.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a novel method for preparing a cis-chiral-3-fluoro-4-hydroxypiperidine structure, which is simple to select and operate and easy to process. In addition, the method has better cis-selectivity, and the product is single (the cis-selectivity is more than 97%), so that the purification is easy, the overall reaction has atom economy, and the method is more green and environment-friendly.
Secondly, the method of the invention maintains the chirality of the carbon atom where the fluorine atom is located in the reaction process, and provides a new idea for preparing the chiral cis-chiral-3-fluoro-4-hydroxypiperidine derivative. It is easier to meet the large number of requirements than the chiral chromatographic resolution methods reported heretofore.
Detailed Description
The following examples are given to aid in the understanding of the invention, but are not intended to limit the scope of the invention. In particular, the synthesis of chiral compounds in the examples is understood to be the opposite configuration of intermediates and products, and is also within the scope of the present patent application.
Unless otherwise stated, substituents and groups are as defined in formula (I).
The present invention is further illustrated below by reference to specific examples, which are intended to be illustrative only and not to limit the scope of the invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Proportions and percentages are by weight unless otherwise indicated.
Example 1:
preparation of N-Boc- (3S, 4R) -3-fluoro-4-carbonylpiperidine (IV)
The compound represented by the formula (III) (100g, 460mmol, 1.0eq) was dissolved in anhydrous tetrahydrofuran (600 mL), the reaction solution was cooled to-60 ℃ under nitrogen protection, and a lithium triethylborohydride solution (506mL, 1mol/L,1.1 eq) was slowly added. The reaction solution slowly returns to room temperature and is continuously stirred until the reaction is completed. And adding saturated ammonium chloride into the reaction solution for quenching, extracting with ethyl acetate for three times, combining organic phases, drying, and concentrating to obtain a cis-main compound crude product shown in the formula (VIII) which is a light yellow solid. Slurry with n-hexane/ethyl acetate =20 until the product is a white solid (91.8 g, 97% pure).
The data for the product are as follows:
1 HNMR(400MHz,CDCl 3 ),δ(ppm)4.35(ddd,0.5H),4.18(ddd,0.5H), 4.15(br s,1H),3.89-3.74(m,2H),2.97(br s,1H),2.93(ddd,1H),2.47(s,1H), 2.05-1.92(m,1H),1.58-1.46(m,1H),1.44(s,9H).
example 2:
preparation of N-Cbz- (3R, 3S) -3-fluoro-4-carbonylpiperidine (VI)
Dissolving the raw material (100g, 398mmol and 1.0eq) shown in the formula (V) in anhydrous THF (600 mL), cooling the reaction liquid to-60 ℃, slowly adding a lithium tri-sec-butylborohydride (L-selectre) solution (458mL, 1.0mol/L and 1.15 eq) under the protection of nitrogen, slowly returning to room temperature after adding, and stirring until the detection reaction is complete.
The reaction is quenched by saturated ammonium chloride aqueous solution, and after the product is extracted by ethyl acetate, the organic phase is combined, washed by water, dried and concentrated. The crude product is purified by beating with a mixed solvent of n-hexane/ethyl acetate = 10. The product of formula (VI) was obtained as a pale yellow solid (88.7 g, 88% yield, 98% purity).
The data for the product of formula (VI) are as follows:
1 H MMR(400MHz,CDCl 3 ):δ(ppm)7.40-7.32(m,5H),5.20(s,2H), 4.72-4.52(m,1H),4.15-3.25(m,5H),2.17(s,1H),1.88-1.60(m,2H)。
example 3:
preparation of (3R, 4S) -N-benzyl-3-fluoro-4-hydroxypiperidine (VIII)
Prepared in the same manner as in example 2 to give the product of formula (VII) as a white solid (yield 75%, purity 97%).
The data for the product of formula (VII) are as follows:
1 HNMR(400MHz,DMSO-d6，δ(ppm)：7.36-7.28(m,5H),478-4.62(m, 1H),3.98-3.85(m,1H),3.61(s,2H),2.95-2.21(m,4H)1.98-1.85(m,2H)。
Claims (5)
1. the method for preparing the cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof by reducing an organic hydroboration metal reagent comprises the following steps:
starting from a chiral fluorocarbonyl or dihydroxy compound shown as a structural formula (II);
cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof shown in a structural formula (I) are obtained by cis-reduction of carbonyl or dihydroxy;
wherein R is hydrogen, C 1 -C 9 Alkyl, aryl, benzyl, CF 3 CO、R 2 CO or R 3 Any one or more of OCO;
R 2 is C 1 -C 9 Any one or more of alkyl, aryl or benzyl,
R 3 is C 1 -C 9 Any one or more of alkyl, aryl or benzyl;
the R group is optionally unsubstituted or substituted with one or more substituents including those consisting of alkyl, hydroxyalkyl, alkoxy or hydroxy;
the cis-form reduction is specifically that in an organic solvent, a chiral fluorine carbonyl or dihydroxy compound shown in a structural formula (II) is subjected to a reduction reaction at 0-150 ℃ under the action of a reducing agent to obtain cis-form chiral-3-fluorine-4-hydroxypiperidine shown in a structural formula (I) and derivatives thereof;
the reducing agent is an alkyl or aryl boron metal reagent.
2. The method for preparing cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof by reduction of an organoboron hydride metal reagent according to claim 1, wherein the reducing agent is any one of lithium triethylborohydride, lithium tri-sec-butylborohydride, lithium tripentyl borohydride, sodium tri-sec-butylborohydride, sodium tri (1-pyrazolyl) borohydride, potassium triethylborohydride, potassium tri-sec-butylborohydride, potassium tripyrazolyl borohydride or potassium triphenylborohydride.
3. The method for preparing cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof by organoboron hydride metal reagent reduction according to claim 1, wherein the reducing agent is lithium triethylborohydride or lithium tri-sec-butylborohydride.
4. The method for preparing cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof by organoboron hydride metal reagent reduction according to claim 1, wherein the reducing agent is used in an equivalent amount of 1.0 to 3.0 equivalents relative to the starting fluorocarbonyl group or dihydroxy compound represented by structural formula (II).
5. The method for preparing cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof by organoboron hydride metal reagent reduction according to claim 1, wherein the organic solvent is anhydrous tetrahydrofuran.
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| CN202211456218.9A CN115716799A (en) | 2022-11-21 | 2022-11-21 | Method for preparing cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof by reduction of organic borohydride metal reagent |
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| CN202211456218.9A CN115716799A (en) | 2022-11-21 | 2022-11-21 | Method for preparing cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof by reduction of organic borohydride metal reagent |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010128425A1 (en) * | 2009-05-08 | 2010-11-11 | Pfizer Inc. | Gpr 119 modulators |
| CN113661162A (en) * | 2019-02-06 | 2021-11-16 | 斯基霍克疗法公司 | Methods and compositions for modulating splicing |
-
2022
- 2022-11-21 CN CN202211456218.9A patent/CN115716799A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010128425A1 (en) * | 2009-05-08 | 2010-11-11 | Pfizer Inc. | Gpr 119 modulators |
| CN113661162A (en) * | 2019-02-06 | 2021-11-16 | 斯基霍克疗法公司 | Methods and compositions for modulating splicing |
Non-Patent Citations (1)
| Title |
|---|
| SIMON J. SHAW ET AL.: "Enantioselective Synthesis of cis-3-Fluoropiperidin-4-ol, a Building Block for Medicinal Chemistry", 《THE JOURNAL OF ORGANIC CHEMISTRY》, vol. 78, no. 17, 19 August 2013 (2013-08-19), pages 8892 - 8897 * |
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