TW520359B - Practical syntheses of chiral trans-3,4-disubstituted piperidines and the intermediates - Google Patents

Abstract

A new method for the preparation of chiral 4-substituted 2-piperidinones, trans-3,4-disubstituted 2-piperidinones, and trans-3,4-disubstituted piperidines is invented. Chiral paroxetine can be obtained from a chiral trans-3,4-disubstituted piperidine intermediate in high purity and good selectivity.

Description

520359

V. Description of the invention 6 Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economics The present invention relates to a method for the preparation of palm-trans-M-di-substituted hexahydroethanoate, especially the use of palm amines. As a palm adjuvant, Qi prepared for palm parsi; Ding. Take the heavy arts to teach that paroxetine is a type of trans_3,4_disubstituted hexaammonium bite derivative, which is an effective selective 5-hydroxytryptamine reuptake inhibitor and has been widely used Use 'as an anti-suppressive drug and anti-Parkinson's disease (Parkn-drug:

Trans_3,4-disubstituted p-trans-(-)-(3 S, 4R) paxetine palmitic hexahydrop ratio hydrazone hydrochloride trans seven)-(3S, 4R) paxetine is The pharmacologically active isomers are usually synthesized from the corresponding opposite precursors. The current process used to make these homophobic precursors involves the selective recrystallization of diastereomeric salts 1b, e, the biocatalytic kinetic analysis of racemic esters, lf, and, extractability Adjuvant assisted asymmetric Michael addition 2. In general, +., Force and & successfully resolve the requirements of a racemic compound because its diastereomeric salt must be in a good crystalline form. However, it has been reported that a π-trans-trans-3,4-hexahydropyridine derivative cannot be resolved due to an amorphous salt. Also -4- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -------------------- Order ----:- ---- Line C, please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 520359 V. Description of the invention Different damage, non-crystalline. In the past few years, although several palladium 3_ or 4_ substituted I hexahydrofluorene derivatives have been made by chemical or enzymatic methods, the purity of palladium isomers is 2-5, deduction p ° .. ^. Ren has found that purification of non-solid products will hinder its application in large-scale process towels and industry. The material series are shown at the end of this patent specification, and the full text is close to it. A few specific symmetric 3 ·, 4 · substitutions and 3 1 2 generation 1 hexahydroelidenes have been published. Synthesis of 2,3. However, the general synthesis method for the preparation of paraoxan 4,4, substituted 2-hexahydropyridone and hexahydropyridine derivatives is still extremely limited 2,3. Since palmitic 2Hydrogenene has been considered as a useful precursor for the synthesis of its corresponding palmitic hexahydropyridine, the present invention is interested in developing a suitable method for preparing such compounds. Here, 1 · fayue series provides diastereoselective synthesis of the enantioselective 4_ substitution and 3,4_ disubstituted hexahydroeodonium, which uses commercially available para-amino amines, Includes: Para palmitic primary amines or para palmitic amino acid derivatives, such as ⑻ Ψ fluorenyl ammonium amine 'as a paraliming adjuvant, and several para-trans-3,4-disubstituted six Hydropyridine derivatives, such as paroxetine, are prepared using this method. ^ 3 Abstract Therefore, one of the items of the present invention is to provide a 3_ substituted pentane-fe liver and p-lemonamine as an intermediate for synthesizing p-palladium di-substituted dihydrofluorenone to prepare Palm 4 replaces 2 / Six | ^ Bite new method. ___- 5- This paper size applies to China National Standard (CNS) A4 specifications (Norway Love)-

520359

V. Description of the Invention Another item of the invention printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs is to provide a palm-like auxiliary using a commercially available palm-like amine as a palm-like 4-substitution. And 3,4_bis. Diastereoselective synthesis of substituted 2-hexahydropyridones, which can be used in large-scale processes. Still another item of the present invention is to provide a method for producing trans-disubstituted 2-hexahydropyridone by carrying out the fermentation at the α-carbon of 4-substituted 2 • hexahydro p ratio lake. The reduction of the product is a method for preparing trans · 3,4-disubstituted hexahydrogen ρ specific bite. Another item of the present invention is to provide a self-palladium 4-aryl substituted 2-hexahydropyridone, through four steps, to prepare a palmitridin combination J1 method. Fermentation to produce palm-trans-trans-disubstituted 2-hexahydropyridone, reduction to form pure trans 3,4-di-substituted hexahydropyridine is the conversion of this amino alcohol to an aryl ether, and Hydrolysis of palm adjuvant to obtain palm paroxetine. These and other objects, advantages, and features of the present invention will be more fully understood and understood after reference to the written patent specification and accompanying drawings accompanying this article. Detailed description of the invention The present invention relates to a 3-substituted glutaric anhydride and a palmitic amine, such as (SH-phenylethylamine). Novel method. Diastereoselective amidation of 3-arylglutaric anhydride and p-palmylamine will give p-palm hemiamine. Functional conversion of p-amine and subsequent cyclization Provides palmaryl-substituted 12-hexahydropyridone. According to the present invention, a method for preparing palmar-substituted 2-hexahydropyridone includes: (Please read the precautions on the back before filling this page ) -------- Order ---- ^ ----- line] -6-520359 Α7 Β7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention <) Use the following formula 3 -Substituted glutaric acid R1 〇, /, 〇 ^^ 〇, where R is aryl, alkyl or any other group, react with palmitic amine of formula (I) as a palmitic adjuvant NH2

Ar ^^ R to obtain a mixture of hemiamines, where & represents an aromatic group and R represents an alkyl group; (2) reducing the acid group of the hemiamine to a primary alcohol; (3) making the primary alcohol _ From the compound; and hydration of the compound with a base to produce a 2-hexahydropyridone. The palmitic amine used in step (i) of the process of the present invention may be a palmitic diamine or a palmitic amino acid derivative. Preferably, the aromatic group of the para-amine is phenyl 'and the alkyl group of the para-amine is methyl. More preferably, the palmitic adjuvant used in the present invention is p-phenylethylamine, especially (SH-phenylethylamine. This palmitic amine can sufficiently react with 3-arylglutaric acid liver I is added in an amount, and is preferably added in a stoichiometric amount. Any conventional reaction conditions can be used in the present invention. The substituent R may be substituted with an aryl group, an alkyl group or any other group, such as an alkyloxy group, an amino group , Fluorinated fluorene, gas-based (α), molybdenum, iodo ------------------------------- ^ ( (Please read the notes on the back before filling out this page)

520359 A7 B7 V. Description of the invention f (D. The substituent R1 is preferably substituted at the 4 position, and is M 夂 & The self-chemical in step (3) of the process of the present invention, preferably ㈣, so The product formed in step (3) is a desert. ^ Nature 4 · Substituted 2_hexa ^ phase, which is used to synthesize the opposite palmity # disubstituted 2_hexahydroρ than ketone ketone and * ★, * Ah, its corresponding important intermediate of Emei. In this four steps, the production of p-palladium I-anhydride from 3-substituted pentamidine and p-amylamine is used to prepare p-palladium 4-substituted 2- 7T 氲 P. After the precipitation, the reaction at the carbon and carbon sites will produce the anti-trans-3,4-disubstituted 2-hexahydrop-pyridone. At this time, the hydrazone is reduced. After that, 2-pyridoxone can be smoothly converted into para palmar isomerically pure hexahydropyridine. ^? ^ Therefore, the present invention provides a method for preparing para palmar trans-derivatives. A method comprising: (1) making a 3-substituted glutaric acid R1 of the following formula & an auxiliary wherein R1 is an aryl group, an alkyl group or any other group, and acting as a counterpart, via the agent Formula (I) reaction to palm amine j

Ar ^ RS | A mixture of semi-fermented amines is obtained, in which the meaning represents an aromatic group, Fei group;% small spot combination, printed by the company -8 · This paper size applies to China National Standard (CNS) A4 specifications⑵〇x 297 Gongai 52〇359 A7 B7 V. Description of the invention ^ (2) Reduce the acid group of the hemiamine to a primary alcohol; (Please read the precautions on the back before filling this page) (3) Make the primary alcohol 卣(4) cyclize the hydrazone with a base to produce a 2-hydroxyhexahydropyridine; and (5) ubicarbonate the hexahydropyridone, Instead, the palmar trans 3 * ~ substituted 2-hexahydrop-pyridone. Furthermore, it should be noted that most of the compounds in the process of this application are solid and can be easily converted by simple recrystallization: In addition, 'all reagents are almost non-toxic and are Environmentally benign. In another aspect, the present invention provides a method for preparing a para-trans-3,4-disubstituted-hexahydropyridine of the formula R1. R2, N, R3 where R1 is an aryl group, an alkyl group, or any other group Group, R2 is an alkyl group or any radical substituted group, and R3 is a hydrogen, fluorenyl group or any radical substituted group, the method includes: printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (1) Formula 3-Substituted glutaric acid liver R1 〇 person 〇 person 〇 where R1 is an aryl group, an alkyl group or any other group, and reacts with a palmitic amine of formula (I) as a palmitic adjuvant. Paper size applies to China National Standard (CNS) A4 (210 X 297 public love) 520359

V. Invention Description I)

It is known that a mixture of semi-fermented amines, in which it is known that it represents an aromatic group, and r represents an alkyl group; (2) the acid group of the hemiphosphonium is reduced to a primary alcohol; (3) the primary alcohol is converted into a halogenation (4) cyclize the halide with a base to produce p-hexahydropyridone; (5) acylate the 2-carbon-pyridone to form an alpha carbohydrazone to give a palmate trans _3,4_ di-substituted 2-hexahydrometaphenone; and ⑹ reduce the para-trans 3, 'di-substituted hexahydropyridone ester and the amine group to form trans-3,4- Disubstituted hexahydropyridine. The present invention also provides a method for preparing palmitine paxetine, which comprises: (1) making 3-arylglutaric anhydride of the following formula (* Please read the precautions on the back before filling this page) -Order ---------- Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 〇 0〇 〇 Among them, R1 is an aryl group, and it is used as an assistant agent for palmity ① palmity Amine reaction

R Obtained the corpse of hemiamidamine, where Ar represents an aromatic group, a radical; -10- This paper is scaled to Gu㈣me m ^ g) A4 (210 x 297 520359 A7 B7 Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs Printing 5. Description of the invention?) (2) The acid group of the hemiamine is reduced to a primary alcohol; (3) The primary alcohol is dentified to obtain a compound; (4) The compound is cyclized with a base (5) The "carbohydrazone" of 2-hexahydropyridone is obtained, and the palm trans-3,4_disubstituted 2-rat 17 ratio is obtained ^^ § ); 对 reduction of palmitic trans · 3,4-disubstituted 2-hexahydropyridone esters and sulfonylamino groups' & for trans-3,4_disubstituted hexahydropyridine; and ⑺Convert the hydroxyl group of trans-3,4-disubstituted hexahydropyridine to an aryl ether, and then remove the palmar adjuvant by hydrogenolysis to obtain palmaroxetine hydrochloride. Step 方法 of the method of the present invention for the preparation of palmaroxetine can be replaced by the following three steps: ⑺ crystallize trans, 3,4_-substituted anhydropyrazine, and convert the hydroxyl group of this compound into a continuous acid vinegar , And then sesame alcohol and burning oxidation To provide a free amine; ⑻ convert the free amine to a salt, and purify the hydrochloride by recrystallization; and (9) remove the palm-like adjuvant by hydrogenolysis to obtain a sex amine West hydrochloride. As mentioned above, the palmitic amine used in step 本 of the present invention may be a chiral primary amine or a palmitic amino acid derivative. The palmitic amine may be sufficiently The glutaric acid is the best solution for the amount of taiga, and is preferably a stoichiometry plus 0. According to the present invention, the preferred process is: Describing this Tingzhang Tim -------- ^ ---------- ^ (Please read the precautions on the back before filling this page) This paper rule ㈣Fortune Pass ^ 73ns) A4 -11 -520359 A7 V. Description of the invention {0) Stubborn palmitic 2-hexahydropyridone 10. The proton spectrum shows that hexahydropyridone is a pure diastereomer (> 99% de) without any Other diastereomers exist. Excess bases, such as lithium diisopropylamine (LDA), lithium hexamethyldisilanes (LiHMDS) and sodium hydride (NaH), and methyl chloroformate, such as tetrahydro Furan (THF) Solvent such as ether in the treatment, acting acylated 'carbon of the pyridone ι〇 2_ hexahydro to a satisfactory yield of the non-enantioselective obtain novel ester 11. Proton NMR spectroscopy showed that only one compound was obtained, which was designated as the trans stereoisomer. The single crystal X-ray of this novel compound 11 and spring knife analysis confirmed its absolute configuration of (4S, 3R), so the stereochemistry of acid 7a was confirmed. Reduction of the ester of 2-hexahydropyridone n with amidinoyl group with lithium aluminum hydride provides a novel amino alcohol 12, where R represents hydrogen. Compound ^ is a viscous oil and solidifies very slowly when left standing. However, compound 12 is easy to be chemically modified after column chromatography. The radical-free compound in compound 12 is converted into a novel methylsalcatelic acid ester, which is then treated with sesitol and potassium alkoxide to provide a novel free-state amine 14a. Purification of this novel free-state amine 14a can be achieved by converting 14a into novel hydrochloride 14b. Hydrogenolysis of the fluorenyl group in 14b formed parstine hydrochloride 15 'as a viscous mass, which was purified by recrystallization according to literature procedures. (Please read the notes on the back before filling out this page) ^ ---- I ---- ^. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -13- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 520359 A7 B7 V. Description of the invention Γ Scheme 1 4-F-C6H4

-CC ^ R 1 R = H 2 R = CH3

RO2C CO2R 3 R = CH3 4R = H 4-F-CeK4

HO2C CO2H 5 4-F-C6H4

(e)

CH3 ihL ·

Nj / \ ph H

〇CH3 Ph ^ ^ CH3 Ph '\ cH3 (Please read the notes on the back before filling this page) 7a R1 = 4-F-C6H4i R2 = H 8 X = OH 7b R1 = H, R2 = 4-F- C6H4 9 X = 巳 r 10 11 G), (k) 4-F-C6H4 4-F-C6H4 4-Fi 06Η4 〇

-〇 -install -------- order ---------- line one, 〇R (I) 〇, 〇 (m>

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 12R = H 13 R = 02SCH3 14a Free state amine 14b HC 丨 Salt 15aR = H, HC 丨 Salt 15b R = H, please refer to the middle of Figure 1 Compounds 7a, 7b, 8, 9, 10, 11, 12, 13, 14a and 14b are novel. Any appropriate reagents and reaction conditions can be used in the process of the present invention. The reagents and conditions used in each step shown in Figure 1 are -14- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 520359 V. Strict description of the invention

A preferred embodiment is, for example: (a) methanol H diol; reflux for 20 hours, 7 °% yield; (hydrazone hydroxide :, = hour, (C) trace hydrochloric acid, reflux for 20 hours, 7 〇% production of acetamidine chloride, refluxing for 20 hours, 9000 / amidine production step); (d) R, 90 / y yield, ㈨ (S) -methylbenzylamine, di-amine, toluene , _78 ° C, 10 hours, 蚨 尨, person,-Eichuan ", and then at 1: temperature for 10 hours, the rate; (f) triethylamine, chloroformic acid, butyric acid, chlorobenzene, J酉 said four wind furan, · 78-0 ° C, 20, j, h; then 'sodium borohydride, water' ㈣. c, 2 () hours, 8 g% phosphorus tribromide, concentrated hydrofluoric acid, O ^ C, 4 δ ^ acupoint 70 /. Yield; (h) Sodium hydride, tetrahydrofuran, and 85% yield at reflux; ㈣ diisopropylamine formic acid, tetrahydrofuran for 10 hours, 78% yield; Hidden bond, tetrahydrofuran Ran, reflux for 72 hours, 62% yield; ⑻methanesulfonium chloride, dichloromethane, room temperature for 20 hours; ①① sesame alcohol, osmium, propanol, reflux for 36 hours; ⑻ hydrochloric acid, 65% yield; ( m) H2, 5% pd_c, methanol, 96% yield. The following examples are presented by way of illustration. These examples are not intended to limit the scope of the invention in any way, and should not be interpreted as such. EXAMPLES Example 1: (3S) -3- (4-fluorophenyl) -5_keto-5- (lS) _ (l-phenylethylamino) valeric acid (7a) 5.0 g of anhydride 6 in 100 ml Toluene was added dropwise to a -78 ° C solution of 525 ml (S) -methylamidamine in 200 ml toluene. After the addition was complete, 3.5 ml of triethylamine was added dropwise. The mixture was stirred from this temperature to room temperature overnight. After the toluene had evaporated, the mixture was stirred with 50 ml of 1 N hydrochloric acid and then extracted with hot ethyl acetate. Combine the organic layers, wash with brine, and use 15 sulfur paper sizes. Applicable to China National Standards (CNS) A4 specifications (210 X 297 mm). Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs. Printed by the Consumer Consumption Cooperative of 520359 Α7 Β7 V. Description of invention p ) The acid solution is dried and evaporated to dryness. The crude product was recrystallized, and the title compound was supplied in the first (please read the precautions on the back before filling this page) portion of the collected product as a colorless solid (700 /. Yield, 90-95% de): Melting point i95. (M95.5 ° C; (a) 25D = -78 8 (cl〇CH3〇BQ; ijj NMR (200 MHz, CDC13) ci 7.30-7.00 (m, 7H)? 6.95 (t? J = 8.7 Hz, 2H), 5.60 (m? 1H), 4.94 (J = 6.9 Hz, 3H); 1 3 C NMR (125 MHz, CDC13 / CD3 OD) J 176 · 8, 173.6, 164.3, 145.8, 140.8 , 131.6, 131.0, 129.7, 128.6, 117.8, 51.1, 45.3, 43.0, 41.1, 23.9

Analytical calculation of CbH ^ oFnO3 値 · c, 6929; H, 6 u; N, 425 Measured 値: C, 69.07; H, 6.09; N, 3.83. The mother liquor was concentrated, and the solid was recrystallized from ethyl acetate and hexane, to obtain a second recovered product containing a mixture of% and several percent 'and hydrolyzed in a rolling acid to recover the diacid 5. Example 2: (3R) -3- (4-fluorophenyl) _ 5-isopropylvaleric acid (1S) + phenylethylphosphonium amine ⑻ Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 3 liters of diethylamine, At room temperature, was added to a solution of 5 g of compound 7a in 200 liters of tetrahydrofuran. This solution was stirred at room temperature for 60 minutes' and then transferred to a -78 C dry ice acetone bath. To this solution was added dropwise 2 $ mL of isobutyl chloroformate. Place this suspension from _78. (: Stir to room temperature overnight. Filter the mixture through a pad of diatomaceous earth and silica gel, and wash with a small amount of tetrahydrofuran. At this place in the ice bath, add 2.0 grams of sodium borohydride, then dropwise. 10 ml of water. Carbon dioxide gas is violently released. The reaction mixture is stirred for 2-4 hours and filtered through a pad of diatomaceous earth. After evaporation of the solvent, the aqueous layer is extracted several times with ethyl acetate. The organic layers are combined and brine Washing, dehydration drying with magnesium sulfate, and concentration. The solid was recrystallized from ethyl acetate and hexane to form a compound, which is a colorless solid (SO% yield, 95% and): melting point Ο ί -16- Paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 520359 A7 ___B7_ V. Description of invention ϋ4) 170.0-170.5 ° C; [^] 25D = .86.4 (cl.0? CH3OH); 1H NMR (200 MHz, (Please read the notes on the back before filling this page) CDC13) d 7.40-7.10 (m, 7H), 6.98 (t, J = 8.7 Hz, 2H), 5.51 (br d, J = 7.7 Hz , 1Π), 5.00 (quintet, J = 7.4 Hz, 1H), 3.60-3.50 (m5 2H), 3.33 (m, 1H), 2.55 (d4 J = 6.6, 14.2 Hz? 1H)? 2.38 (dd, J = 8.6, 14.2 Hz, 1H)? 1.95-1.75 (m? 2H)? 1.27 (d? J = 6.9 Hz, 3H); 1 3 C NMR (125 MHz, CDC13) d 170.6, 161.6, 142.9, 139.6, 128.9, 128 · 6, 127 · 4, 126 · 1, 115 · 4, 60.1, 48.6, 44.0, 38.9, 38.4, 21.3. Analytical calculations for C19H22FN-〇2: C, 72J6; H, 7.03; N, 4.44. Found: C, 72.35; H, 6.83; N, 4.33. Example 3: (3S) _5-bromo · 3_ (4_Fluorophenyl) valeric acid (is) -i · Phenethyl ethyl amine ⑼ Printed in a solution of 4.5 g of alcohol 8 in 250 ml of anhydrous ether in the Intellectual Property Bureau of the Ministry of Economic Affairs, located in In an ice bath, 1.7 ml of phosphorus tribromide was added dropwise. After stirring for 3 days in an ice bath, 0.5 ml of concentrated hydrobromic acid was added to the mixture. The resulting solution was continuously stirred overnight at room temperature, and 100 ml of ice was added to quench the reaction. The white solid was collected, dissolved in ethyl acetate, and washed with saturated sodium bicarbonate solution and saturated saline. The organic layer was filtered through a silicone pad. After evaporation of the solvent, the crude solid was recrystallized from ethyl acetate and hexane to form 3.8 g of the title compound as a white solid (72% yield, > 95% de). Melting point 156.5-157.5 ° C; [a] 25D = -38.2 (c 1.05 CH3 OH); 1H NMR (200 MHz, CDC13); 7.40-7.10 (m? 7H)? 6.99 (m, 2H), 5.52 (br d, J = 7.6 Hz, 1H), 4.98 (m, IK), 3.35-3 · 20 (m, 2H), 3.05 (m, lH), 2.51 (dd5J = 6.3, 14.0Hz, m), 2.37 (dd, J = 8.7, 14.0Hz, lH ), 2.25-2.05 (m? 2H)? 1.25 (d, J = 6.9 Hz, 3H); 13 C NMR (125 MHz, CDC13) ά 169.7, 161.8, 142.8, 137.7, 129.1, 128.6, 127.4 , 126.1, 115.7, 48.6, 44.0, 40.6, 38.7, 30.9, 21 · 3. Analysis and calculation of C19H21BrFNO 値: c, 60.33; H, 5.60; -17- This paper standard applies to China National Standard (CNS) A4 specifications ( 210 χ 297 public love) ^ 520359 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the invention {5 N, 3.70 · Measured 値: c5 60.57; H, 5.54; Ν, 3.82. Example 4 : (4R)-[4_ (4_fluorophenyl) _1 > < 1! § > < 1-phenylethyl)] hexahydropyridine: ketone ⑼) 0.7 g of hydrogen Sodium (8〇〇 / dispersion) w floating solution in 10 ml of dry tetrahydrofuran 'at the primary temperature, added to a solution of 3.5 g of compound 3 in 9 ml of anhydrous 4〇 of tetrahydrofuran. The mixture was heated at 65-75 ° C overnight. After cooling: to room temperature, the reaction mixture was slowly quenched with 10 ml of material in an ice bath. After all solvents were evaporated, the residue was diluted with ethyl acetate and then washed with brine. The organic layer was collected and filtered through a silicone pad. After removing the solvent, the crude solid was recrystallized from ethyl acetate and hexane to form 2 • hexahydropyridine 嗣 10 as colorless crystals (87% yield,> 99% de): melting point 163 5_ 164.0Ό a ^] 25D = -108.4 (c 1.0, CHC13); 1HNMR (200 MHz? CDC13) ^ 7.36-7.25 (m, 5H), 7.13 (m, 2H), 7.00 (m, 2H), 6.18 (q, J = 7.08Hz, lH), 3.16-2 · 87 (m, 2H), 2.87-2 · 69 (m, 2H), 2.55 (dd, J = 10.1, 17.4 Hz, 1H), 2.05-1.78 ( m? 2H)? 1.51 (d, J = 7.1 Hz? 3H); 1 3 C NMR (125 MHz, CDC13) 168.7, 161.6, 140.0, 139.3, 128.5, 128.0, 127.6, 127.4, 115.5, 49.8, 40.3, 39.6, 37.5, 3 0 · 3, 15 · 1. Analysis and calculation of C19H20FNO 値: C, 76.74; Η, 6.78; Ν, 4.71 · Measured 値: C, 76 · 93; Η, 6.82 Ν, 4.30. Example 5: (3S, 4R)-[4- (4-fluorophenyl) -3-methoxycarbonyl small (1S)-(1-phenylethyl)] hexahydropyridine-2_嗣 (11a) Add 19.5 ml of 1.5 M solution of monopropylamine in J. hexane, dropwise to 2 g of lactam 10 in 50 ml of tetrahydrofuran, and stir the solution at -78 ° C. . After 1 hour, 0.8 ml of methyl chloroformate was added dropwise.所 所 -18-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------------ Installation -------- Order ---- ------ Line 'C Please read the notes on the back before filling in this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 520359 A7 B7 V. Description of the invention t6) The solution formed at -78 ° C Stir for 4 hours, then quench at this temperature with chlorinated aqueous solution. The mixture was concentrated to evaporate tetrahydromethane, 'and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to form a yellow viscous oil, which solidified very slowly upon standing. Recrystallized from ethyl acetate and hexane to obtain 1.85 g (78%) of the title compound as white needle crystals: melting point 73.5-74.5T; [α] 25D = -181.2 (cl.0? CHCl3); 1HNMR (500 MHz, CDC13) ά 7.45-7.30 (m, 5HX 7.20-7.16 (m5 2H), 7.06-7.00 (m, 2H), 6.17 (q5 J = 7.03 Hz, lH), 3.70 (s? 3H)? 3.64 (d, J = 10.2 Hz, 3H)? 3.39 (td, J = 3.5? 10.7 Hz? 1H)? 3.17 (dt? J = 4.9? 12 · 6 Hz, 1H), 2.88 (m, 1H), 2.05 (m, 1H), 1.96 (m, 1H), 1.57 (d, J = 7.0 Hz, 3H); 13 C NMR (125 MHz, CDC13) d 170.6, 165.4, 161.9, 139.4, 137.4, 128.6, 128.3, 127.5, 115.7, 56.6, 52.3, 50.4, 41.4, 40.5, 29.4, 15.0 · Analysis and calculation of C21H24FN03 値: C, 70 · 57; H, 6.77; N, 3.92. Measured 値: C, 70.97; H, 6.17; N, 4.01 · Example 6: (3S, 4RH4- (4 · fluorophenyl) -3-lemethyl small (is)-(ljylethyl)] hexahydropyridine (12) 5. 6 g of ester 11. Under a nitrogen atmosphere, add dropwise to a suspension of 6 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. The mixture is refluxed for three days. Then, in an ice bath, 10 ml of water and 6 ml of 15% hydroxide are added. Sodium solution Treated with 25 ml of water. After filtering the precipitate, the organic solution was washed with brine, dried over magnesium sulfate, filtered, and concentrated in the air to form 3.2 g (62%) of a crude product as a pale yellow solid. From ethyl acetate The ester was recrystallized from hexane to obtain the title compound as a white flake: melting point 130.0 (M31. (TC; [a] 25D = -17.4 (cl.0, CHCl3); 1HNMR (200 MHz, CDC13) d 7.40- 7.10 (m? -19- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------ Installation -------- Order- --------- Line Φ (Please read the notes on the back before filling this page) 520359 A7 B7 V. Description of the invention Γ) (Please read the notes on the back before filling this page) 7Η), 7.05 -6.90 (m, 2Η), 3.51 (q, J = 6.78 Ηζ, 1Η), 3.45-3.34 (m, 2H), 3.23 (m, 1H), 2.89 (m, 1H), 2.20 (m, 1H ), 2.05-1.80 (m, 4H), 1.80-1.65 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H); 1 3 C NMR (125 MHz, CDC13) d 161.4, 143.2, 1403, 128.8 , 128.2, 127,8, 127.0, 115.3, 65.1, 63.9, 54.7, 50.6, 44.4, 34.6, 19.6. Analysis and calculation of C20H24FNONO: C , 76.65; H, 7.72; N, 4.47. Measured radon: C, 76.86; H, 7.77; N, 4.58. Example 7: (3S, 4R)-[3- (benzenehydrazone [1,3] dioxy Vinoline_5-yloxymethyl) winter (4-fluorophenyl) small (1S)-(1-phenylethyl)]-hexahydroTT than bite hydrochloride (14b) in an ice bath 1.65 ml of triethylamine and 0.86 ml of gasified methanesulfonium were added dropwise to a solution of 2 g of alcohol 12 in 60 ml of digas methane. The mixture was stirred at this temperature for 3 hours and quenched with 30 ml of saturated sodium bicarbonate. The aqueous solution was extracted with dichloromethane. The combined organic layers were washed green with brine, dried over magnesium sulfate, and concentrated to provide phanane sulfonic acid g13 as a yellow viscous oil. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. A solution of 3 g of sesamol in 30 ml of propanol was added to a solution of 028 g of sodium in 20 ml of propanol. After 30 minutes of gentle reflux, a solution of methanesulfonic acid 13 in 50 ml of propanol was added. The mixture was refluxed for 15 days, cooled to room temperature, and then quenched with 30 ml of ice water. After the propanol was evaporated, the aqueous solution was extracted with ether. The combined organic layers were washed with 1 N sodium hydroxide solution, brine, dried over magnesium sulfate, filtered and concentrated to form the free amine 14a as a reddish brown viscous oil. This free state amine was diluted with 50 liters of methanol 'and treated with 0.5¾ liters of concentrated hydrochloric acid. The resulting solution was allowed to stand for several days, and a yellow solid appeared in Shen Dian. Collect solids, recrystallize from methanol and ethyl acetate, ____ -20- Specifications (210 X 297 mm) This paper size applies Chinese National Standard (CNS) a ^ 520359 A7. _____ B7 V. Strict description of the invention) (please first Read the notes on the reverse side and fill out this page again.) 1.92 g of hydrochloride is formed as white needles. Melting point> 25 ° C (decomposition); 〇] 2 5D = -87.4 (cl.O, CH3OH); 1HNMR (500 MHz, CDC13) d 7.65-7.60 (m? 2H), 7.55-7.45 (m, 3H) ), 7.30-7.20 (m, 2H), 6.97 (t, J = 8.7 Hz, 2H), 6.66 (d, J = 8.5 Hz, 1 Hz), 6.34 (4 J = 2.5 Hz, 1 Hz ), 6.14 (dd, J = 2.5, 8.5 Hz, 1H), 5.92 (s, 2H), 4.23 (quintet, J = 6.0 Hz, 1H), 3.86 (m, 1H), 3.64 (dd, J = 2.3, 9.6 Hz, 1H), 3.49 (d4 J = 3.9, 9.6 Hz, 1H), 3.32 (m, 1H), 2.9-2.8 (m, 3H), 2.57 (m, 1Π), 2.02 (d, J = 6.9 Hz, 3H), 1.9 (m, 1H); 13 C NMR (125 MHz, CDC13) d 161.8, 153.7, 148.2, 142.0, 136.9, 133.9, 123.0, 129.4, 129.2, 115.7, 107.9, 105.5, 101.2 , 97.9, 67.6, 67.5, 54.6, 49.5, 41.2, 39.3, 29.9, 17.5. Analysis and calculation of C27H29C1FN〇3: C, 09.00, · H, 6.22; N, 2.98 · Measured: C, 69.36; pyrene, 6.22; N, 3.07. Example 8: Parsetin hydrochloride or (3S, 4R)-[3- (benzo [1,3] dioxolene-5-yloxymethyl ) -4- (4-fluorophenyl)] hexahydropyridine hydrochloride (Industrial 5) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1. A suspension of 6 g of compound 14b and 20 mg of 10% Pd-C in 140 ml of anhydrous methanol was stirred at room temperature under 1 atmosphere of hydrogen for 48 hours. The resulting suspension was filtered through celite, washed with methanol, and concentrated in vacuo. Crude paracetin hydrochloride was obtained as a red sticky mass. Recrystallized from methanol-ether-hexane to achieve purification, forming 0.85 g (68%) of paxetine hydrochloride as pink crystals: melting point 123-124 ° C (Reference 1 c 129-13TC); [ α) 2 5 D = -88.6 (c 1.0, CH3 〇H); 1H NMR (500 MHz, CDC13) J 7.35-7.25 (m, 2H) 5 7.05 (t? J = 8.5 Hz, 2H)? 6.68 (d3 J = 8.4 Hz, 1H) 5 6.40 (d, J = 2.3 Hz? 1H)? 6.18 (dd, J = 2.3, 8.5 Hz, 1 Hz), 5.95 (s, 2H), 3.83 (d, J = 10.3 Hz , 1H), 3.75 (d, J = 12.4 Hz, 1H), 3.68 (d, J = 9.5 Hz, 1H), 3.24 (m, 1H), 3.12 (m, 1H), 2.97 (td, J = -21- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 520359 A7 B7 V. Description of the invention (19) 3.3, 12.9 Hz, 1H), 2.75 (m, 1H), 2.50 (m9 1H)? 2.01 (d, J = 13.1 Hz, 1H); 13 C NMR (125MHz, CDC13) d 161.9, 153.7, 148.2, 142.0, 137.1, 128.9, 115.8, 107.9, 105.6, 101.2, 97.9, 67.5, 46.8, 44.5, 41.7, 39.4, 30.1 · Although the present invention has been described with reference to certain preferred examples and specific embodiments, it is not intended to limit the scope of the invention Wherein, but is appended with the text of the patent is only limited by the scope. References and Notes 1 (a) Christensen, J. A *; Squires, K F. US Patent 3912743, 1975. (b) Christensen, J. A .; Squires, R F. US Patent 4007196, 1977. (c) Bames, RD; Wood-Kaczmar, MW; Richardson, JE; Lynch, I R .; Buxton, P.C .; Curzons, AD · European Patent 0234403, 1987 · (d) Borrett, G · T. US Patent 4861893, 1989. (e) Faruk ^ E. A; Martin, K. D. US Patent 4902801, 1990. (f) Zepp, C. ML; Gao, J .; Heefiier, DL US Patent 5285517, 1993. (g) Kozikowski, AP; Araldi, GL; Boja, X; Meil, WM; Johnson, KM; Flippen-Anderson, JL; George, C .; Saiah? EJ Med Chem. 1998, 41, 1962. 2 Amat M .; Hidalgo, X; Bosch, J. TetrahedronAsymmetry, 1996, 7? 1591. 3 (a) Herdeis, C .; Kaschinski, C .; Karla, R.? Lotter, H. Tetrahedron: Asymmetry, 1996, 73 867. (b) Weber , K .; Gmeiner, P. Synlett, 1998, 885. (c) Matsuo, J., Kobayashi, S .; Koga, K. Tetrahedron Lett. 1996, 7, 9723. 4 (a) Wirz, B .; Walther , Tetrahedron: Asymmetry, 1992, 3, 1049. (b) Alten bach, Blanda, G. Tetrahedron: Asymmetry 1998, 9, 1519. 5 (a) Meyers, AI; Natale, NR; Aettlaufer, DG; Rafii, S .; Clardy, I Tetrahedron Lett. 1981, 22, 5123. (b ) Meyers, A. I; Natale, NR -22 ------- Line one 520359 A7 B7 V. Description of the invention (2 °)

Heterocycles 1982, 18. Commercon, M .; Alexakis, AJ Org. Chem. 1994, 59, 1877. 6 Cason, J. Organic Syntheses Collective Vol. 4? 1963, 630. 7 Theisen, PD; Heathcock, CHJ Org. Chem. 1993, 58, 142.8 Fieser, LF; Martin, EL Organic Syntheses Collective Vol. 2, 1943? 560. 9 Karanewsky, D .; Malley, M .; Gougoutas, JZJ Org. Chem. 1991, 56, 3744. 10 Rodriguez, M. ; Llinares, M .; Doulut, S .; Heitz, A .; Martinez, I Tetrahedron Lett. 1991, 32, 923. (Please read the notes on the back before filling out this page) -23-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Claims (1)

520359% Way to bite, including A8 B8 Patent Application No. 89114422 First, I am requesting a revised range of patents (91 gross and monthly) g88, and a range of patent applications for the preparation of 4-palladium 2-hexahydropyrazine: (1) Make the following formula 3-substituted glutaric acid Anhydride R1 Among them is phenyl or fluorenyl ', which is optionally substituted by a prime, and reacts with palladium amine of formula NH2 NH 2) Ar ^^ R and R represents Ci-which is obtained from hemiamine A mixture in which Ar represents a phenyl group and a pit group; (2) reducing the acid group of the semi-fermented amine to a primary alcohol; (3) toothing the primary alcohol to obtain a halide; and (4) using a base to make the The hydrazone is cyclized to produce palmitate hexahydropyridone. 2. The method according to item 1 of the scope of patent application, wherein the palmitic amine is a palmitic primary amine or a palmitic amino acid derivative. 3. The method according to item 1 of the application, wherein the alkyl group of the p-amine is methyl. 4. The coating according to item 丨 of the patent application scope, wherein the palm amine is methylbenzylamine. 5. The method according to item} in the scope of patent application, where palm amine is ⑶_ This paper size applies Chinese National Standard (CNS) A4 specification (210X297 public love) 20359 Scope of patent application Methyl benzylamine. 6. The method according to item 1 of the scope of patent application, wherein Ri is 4-F-C6H4. 7. · A method for preparing para-trans--3,4-disubstituted fluorene hexahydropyridone, comprising: (1) making 3-substituted glutaric anhydride R1 of the following formula wherein Ri is epitope or Ci-C6 Tingyi ', which is optionally substituted by halogen, reacts with palmitic amine of formula (I) as a palmitic adjuvant (I) A mixture of hemiamines is obtained, where Ar represents a phenyl group and R represents a Cl-C6 alkyl group; (2) the acid group of the hemiamine is reduced to a primary alcohol; (3) the primary alcohol is toothed (4) cyclize the halide to produce p-palladium 2. hexahydropyridone; and (5) acylate the 2-carboxhydropyridone α carbohydrazone to obtain Palm trans_ 3,4-disubstituted 2-hexahydropyridone. 8. The method according to item 7 of the patent application park, wherein the palmitic amine is a palmitic primary amine or a palmitic amino acid derivative. -2- This paper size applies to China National Standard (CNS) A4 specification (21〇X 297 male sauce) 520359 A8 B8 C8 ____________ D8 VI. Application scope of patent 9. According to the method of the scope of patent application No. 7, among which the applicability The alkyl group of the amine is methyl. 10. The method according to item 7 of the scope of patent application, wherein the palm amine is methylbenzylamine. 11. The method according to item 7 of the scope of patent application, wherein the palmitic amine is ammonium methylamine. 12. The method according to item 7 of the scope of patent application, wherein Ri is 4-F_c6 仏. 13 · —A method for preparing trans · 3,4-disubstituted hexahydropyridine of the formula, R1 R3 * Where R is a radical or Ci_C6 alkyl, R2 is alkyl, coor, (R, is Η or Ci-Cg pit) or CH ^ OR " (R "is Η, Q2SCH3 or, and R3 is argon, q-C6 alkyl or (CH2) n〇R ", (r "" is Η, ^ q alkyl or aromatic ring, n = 1-6), the method includes: ⑴ making the following formula 3-substituted pentane Anhydride R1 Λ, where R1 is phenyl SCi-C: 6 alkyl, and reacts with palmitic amine of formula (I) as a palmitic adjuvant. -3- This paper applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 520 359 Six A8 B8 C8 _ D8 (I) obtaining a mixture of semi-fermented amines, wherein Ar represents a cyclyl group, and R represents a cK C6 alkyl group; (2) reduction of the acid group of the hemiamidine to a primary alcohol; (3) the primary alcohol, (4) cyclize the halide with a base to produce para-hexahydropyridine_; (5) acetylate the 2-carbohydroxanthone to obtain palmity Trans_ 3,4 · disubstituted 2-hexahydrohydroxanthone; and) (6) reducing the g of the palato 3,4-disubstituted 2-hexahydroρ-pyridone with the amino group to form The ratio of trans-3,4-disubstituted hexahydrogen is far. 14. A method for preparing paclitaxel, which comprises: (1) making 3-arylglutaric anhydride R1 of the following formula Where R1 is a phenyl group and reacts with a palmitic amine of formula (I) as a palmitic adjuvant (I) Obtaining a mixture of hemiamines, where Ar represents phenyl and R represents Cr -4- The paper size applies to China National Standard (CNS) A4 (210X297 mm) ^ > 20359 A8 B8 C8 D8 'Fanyuan base for patent application; (2) reducing the acid group of hemiamine to a primary alcohol; (3) hydrating the primary alcohol to obtain a halide; (4) verifying the halide Cyclization to produce palmitic 2-hexahydro P ratio _; (5) The α-carbohydrazone of 2-hexahydropyridone is obtained to obtain palmitic trans-3, "disubstituted 2-hexahydro Pyridone; ⑹ reducing para palmar trans · 3,4-disubstituted 2-hexahydropyridone ester and fluorenylamine group to provide trans-3,4-disubstituted hexaargyridine; and 反 trans · The hydroxyl group of 3,4-disubstituted hexahydropyridine is converted into an aryl mystery, and the palmarity adjuvant is removed by hydrogenolysis to obtain palmarthic hydrochloride. According to the scope of application patent No. 1 4 The method of item, comprising: (1) making 3-arylglutaric anhydride of formula Where R1 is phenyl, and para-amine as formula (1) Obtain a mixture of hemiamine, where M represents phenyl, and Han represents ^ C6 alkyl; not 1 paper size applies Chinese National Standard (CNS) A4 specifications (210X 297 public love) 520359 A8 B8 C8 ___ D8, patent application Range (2) The acid group of the hemiamine is reduced to a primary alcohol; (3) The primary alcohol is converted to obtain a halide; ⑷ The base is used to cyclize the halide to produce a palmar 2_hexahydro Late Lake_; (5) The α-carbohydrazone of 2.hexahydrohydroxidone was obtained to give the palmate trans_ 3,4-disubstituted 2-hexahydropyridone; -3,4-disubstituted 2-hexahydro p ratio bite _ g and amine amino group ▲ proton 'to provide trans-3,4-disubstituted hexaamine p ratio; ⑺ make trans _3,4_ Disubstituted hexachloropyridine crystal, and converted the hydroxyl group of this compound into sulfonate, and then treated with sesanol and alkoxide to provide the free amine;-(8) convert the free amine to the hydrochloride And purifying the hydrochloride by recrystallization; and (9) removing the palmarity adjuvant by hydrogenolysis to obtain palmaroxetine hydrochloride. 16. · (3S) -3- (4-fluorophenyl) of the formula 7a below: 5-keto-5- (lS)-(l-phenylethylamino) valeric acid, Where R1 represents 4-F-C6H4, and R2 represents Η. 17 · — (3S) -3- (4 · fluorophenyl) -5-_yl-5- (lS)-(l-phenylethylamino) valeric acid of formula 7b, -6- this paper Standards are applicable to China National Standard (CNS) A4 specifications (210X297 mm) 520359 8 8 8 8 AB c D Patent application scope R2, Η〇2〇 , N / \ ph Η 7b where R1 represents Η and R2 represents 4-F-C6H4 18. — (3R) -3- (4 · fluorophenyl) _5 · hydroxyvaleric acid (1S) _1_phenylethyl Methylamine. 19. A type of (3S) -5-bromo-3- (4-fluorophenyl) pentanoic acid (1S) _1-phenylethylamidamine. 20.-(4R)-[4- (4-fluorophenyl) -l- (lS)-(l-phenylethyl)] hexahydropyridin-2-one. 21 · —Species (3S, 4R) _ [4- (4-fluorophenyl) · 3-methoxycarbonyl-1- (1SM1-phenylethyl)] hexahydroexogen 1: Yodo-2-one. 22 · —Species (3S, 4R)-[4- (4 · fluorophenyl) -3_hydroxymethyl-l-ClSMl-phenylethyl)] hexahydro leaf dagger. 23. —Methanesulfonate of formula 13, • 4-F-CgH4 OR N〆.I Ph ^^ CHa 13 where R represents 02SCH3. 24. —A free form amine of formula 14a 4-F-c6H4 14a Ph '' Chb This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 520359 8 8 8 8 ABCD, scope of patent application 25. —Species (3S, 4R)-[3- (benzo [1,3] dioxo-5-yloxymethyl) · 4- (4-fluorophenyl) -l- (lS )-(l-phenylethyl)]-hexahydropyridine hydrochloride. -8- This paper size applies to China National Standard (CNS) A4 (210X297 mm)